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  • A conversation with Marc Feldmann, Jacques Miller, and Max Cooper
    J. Clin. Invest. (IF 12.282) Pub Date : 2020-01-02
    Marc Feldmann; Ushma S. Neill

    Excerpt: This month, we shift our format to listen in on the conversation of three legends of immunology. Sir Marc Feldmann, Lasker awardee in 2003 for his role in discovering anti-TNF therapy, acts as interviewer, speaking with the two winners of the 2019 Albert Lasker Basic Medical Research Award: Max D....

    更新日期:2020-01-04
  • The 2019 Nobel Prize honors fundamental discoveries in hypoxia response
    J. Clin. Invest. (IF 12.282) Pub Date : 2019-11-25
    Javid Moslehi; W. Kimryn Rathmell

    The 2019 Nobel Prize for Physiology or Medicine was awarded to Professors Sir Peter J. Ratcliffe (University of Oxford), Gregg L. Semenza (Johns Hopkins University), and William G. Kaelin Jr. (Dana-Farber Cancer Institute) for their discoveries of a fundamental aspect of cellular physiology, the cellular sensing of oxygen levels and regulation of physiologic hypoxia. Each of these physician-scientists was intrigued by a different clinically relevant observation and utilized very basic biochemical tools to address their questions. These separate lines of investigation converged, delineating a central cellular pathway with far-ranging implications for human physiology, disease states, and medicine. The story of how they uncovered hypoxia response begins with a deep interest in basic human biology. Uncovering a hypoxia-inducible pathway Semenza, a pediatric geneticist, was studying the triggers for the production of erythropoietin, a hematopoietic growth factor produced by the liver and kidney that promotes the generation of red blood cells. His group identified a sequence-specific binding site (termed hypoxia-response element [HRE]) for a transcription factor in the 3′ flanking region of the human erythropoietin gene (EPO). He biochemically purified the factor, which he called hypoxia-inducible factor 1 (HIF-1) (1). HIF-1 is a heterodimer composed of HIF-1α, a protein expressed in an oxygen-regulated manner, and a constitutively expressed factor, HIF-1β. This dimer formed a potent transcription factor complex, and Semenza showed that in addition to erythropoietin, HIF-1 induces a number of other genes that are critical for cellular and systemic response to hypoxia, and maintenance of cellular homeostasis. Among these was vascular endothelial growth factor (VEGF), which plays important roles in angiogenesis (2). A cancer connection Simultaneously, Kaelin was studying von Hippel–Lindau (VHL) disease, a rare genetic syndrome in which mutations in the affected gene (VHL) lead to specific cancer types, such as renal cell carcinoma (RCC) and cerebellar hemangioblastomas. Trained as an internist (he was chief resident of the Johns Hopkins Osler service) and oncologist, he was intrigued by VHL syndrome because the associated tumors were always highly vascular in nature, with affected patients occasionally having secondary polycythemia. Pivotal biochemical studies showed that the protein product of VHL (pVHL) forms a complex that plays an important role in the ubiquitination and subsequent degradation of specific proteins. Importantly, the proper assembly of the VHL complex was critical for regulation of hypoxia-inducible genes (3). X-ray crystallography of the VHL complex suggested that pVHL serves as an E3 ubiquitin ligase, conferring specificity to the ubiquitination and subsequent degradation of one or more proteins (4). The quest to find the protein was on. Putting the pieces together A crucial observation connecting these lines of research came from the Ratcliffe group. Ratcliffe, a nephrologist, was intrigued by how kidneys serve as oxygen-sensing organs and thus regulate the production of erythropoietin systemically. In early experiments, his group showed that multiple cell types are capable of sensing hypoxia and driving EPO transcription via the HRE that Semenza had identified (5). This suggested that HIF possibly serves as a universal response mechanism to hypoxia. Importantly, in 1999, the Ratcliffe team showed that pVHL regulates HIF-1α and most likely acts as its E3 ubiquitin ligase (6). Regulating the VHL-HIF interaction The mechanisms underpinning HIF-1α stabilization and activation of a massive transcriptional program of hypoxia response were elegantly delineated by the Kaelin, Semenza, and Ratcliffe groups, revealing a beautifully simple model. During normoxia, when oxygen is ample, specific proline residues on HIF-1α undergo hydroxylation. This covalently modified form of HIF-1α is recognized in a contact-dependent manner by pVHL, marking HIF-1α for ubiquitination and proteasome-mediated destruction. During hypoxia, HIF-1α is not hydroxylated and escapes tagging for degradation (7, 8). This suggested that regulation of HIF is posttranscriptional: HIF-1α is transcribed, translated, and quickly degraded, unless oxygen becomes limiting. Notably, a second homologous protein, HIF-2α, was identified, featuring identical hydroxylation-dependent regulation via VHL. HIF-1/2α, when stabilized, rapidly heterodimerizes with HIF-1β, transcribing hundreds of genes that are critical for the cellular response to hypoxia. The genes involved in this tightly controlled response pathway include notable heavyweights such as VEGF, erythropoietin, mediators of glycolysis and other metabolic pathways, and genes involved in cell survival and homeostasis — and new target genes continue to be uncovered. Knowing the importance of hydroxylation in the recognition of HIF-1α by pVHL, the hunt to identify the responsible enzymes began. Prolyl hydroxylation had been well defined in the setting of stabilization of procollagen chains. There were striking similarities; both reactions required oxygen, iron, and ascorbate, and were inhibited by cobalt and by 2-oxoglutarate analogs, suggesting that the HIF prolyl hydroxylase was a member of the 2-oxoglutrate–dependent dioxygenase enzyme family. A group of enzymes were identified as the key oxygen sensors based on the discovery of the egl9 protein in Caenorhabditis elegans: the EglN (Egl nine homolog), or PHD (prolyl hydroxylase domain), proteins. These three orthologs catalyze hydroxylation of human HIF-1/2α (9–11). EglN1 (also called prolyl hydroxylase domain–containing protein–2 [PHD2]) was shown to be the critical hydroxylase for HIF-α in vivo (12). The requirement for 2-oxoglutate for the reaction provided an additional link between hypoxia and metabolism. EglNs’ unusual low oxygen affinity suggested that these molecules were indeed oxygen sensors, an observation that was confirmed genetically. In murine models in which EglN1 is temporally genetically deleted, mice display hypervascular features and polycythemia (12). The phenotype of these mice mimicked responses to high altitude. Further, inactivating mutations in EglN1 or activating mutations in HIF-2α have been shown to cause familial erythrocytosis (13, 14). Even more intriguing, single nucleotide polymorphisms (SNPs) or missense mutations in EglN1 allow for high-altitude adaptation in populations living in high altitudes (e.g., Tibet) (15). Hypoxia in the patient setting Let’s put the discoveries of hypoxia response in context with a clinical case: A middle-aged woman was admitted to the hospital with pathologic fracture of the femur as a result of metastatic clear cell RCC. Past medical history was significant for coronary artery disease, and she had mild cardiomyopathy. A smoker, she had chronic kidney disease and anemia. Hypoxia signaling played a central role in nearly every feature of her disease process, providing for an outstanding teaching opportunity with the house staff team. This patient’s cancer is likely driven by inactivation of the VHL gene. She had been treated for 11 months with a VEGFR inhibitor, with good disease control. The model proposed by which VHL loss resulted in stabilization of HIF factors and transcriptional activation of hypoxia-associated genes immediately explained why VHL syndrome–associated cancers were hypervascular. Somatic mutations in VHL are tightly linked to sporadic clear cell RCC. Not surprisingly, clear cell RCC is one of the select groups of cancers for which VEGF pathway–directed therapy (Figure 1) has been proven to induce substantial responses in tumor volume and an increase in overall survival (16). This discovery can be directly linked to the emergence of a class of drugs targeting VEGF signaling that have become a staple of the cancer targeted therapy armamentarium. Figure 1 The discovery of the VHL/EglN/HIF pathway as a central mediator of hypoxia signaling has paved the way for introduction of drugs that modulate the pathway for the treatment of human disease. Because the pathway is so central to so many pathological conditions, pharmacologics are being used for the treatment of cancer, as well as being tested for other conditions, such as anemia and cardiovascular and pulmonary diseases. Therapeutics targeting this pathway include VEGF pathway inhibitors (bevacizumab, sorafenib, sunitinib, pazopanib, axitinib, cabozantinib, and lenvatinib), mTOR inhibitors (temsirolimus and everolimus), EglN inhibitors in phase III trials (daprodustat, molidustat, roxadustat, and vadadustat), and investigational HIF-2α inhibitors (PT2385, PT2977, and RNAi [phase I]). Critical for our patient, the physiologic and chronic response to hypoxia resulting from coronary artery disease, damaged lung epithelium, and recurrently injured kidneys plays important roles in tissue remodeling and disease states. VEGFR inhibition may have potentially contributed directly to microvascular dysfunction, myocardial hypoxia, and (ironically) stabilization of HIF in myocytes and subsequent myocardial dysfunction (17). Hypoxia signaling alters the metabolic properties of these tissues, shifts the balance of reactive oxygen species, and accumulates free radical–induced damage. Hypoxia-mediated effects can impact any tissue in which delivery of oxygen and nutrients is critical, wherein hypoxia signaling underlies serious nonmalignant and malignant conditions. The bone marrow and kidneys are worthy of special consideration in this case. Hypoxic signaling acts as a rheostat that maintains the necessary growth signals for stem cells. The bone marrow niche is where blood stem cells reside, and perturbations — such as infiltration with cancer cells, fractures and disrupted blood flow, and radiation exposure — have the potential to damage this critical space. Similarly, cells with exquisite sensory capacity, predominately localized in the kidney, utilize HIF signaling to maintain erythropoietin production that stimulates erythroid precursor differentiation in that marrow niche. End organ damage at either site can significantly impact a patient’s ability to keep up with demand for red cell production. Conclusions The discoveries by Semenza, Kaelin, and Ratcliff began with a keen focus on fundamental aspects of human physiology: signaling that alters red blood cell production and ultimately oxygen carrying capacity, and the vasculature that delivers that essential cargo. In the realm of cancer, while VHL-associated tumors and RCC display a remarkable pseudohypoxic state and vascular dependence due to constitutive stabilization of HIF-2α, in many other tumor types one or both HIF factors are stabilized or upregulated, which can frequently be a potent biomarker of aggressive tumors. Importantly, small molecules that target HIF proteins are emerging as cancer therapeutics (18). As a result of these seminal discoveries, therapies that dampen hypoxic response have also been applied or tested in other settings, including retinal diseases, pulmonary hypertension, cardiovascular disease, renovascular disease, and immune regulation. Conversely, therapies are being developed that apply a precision approach to selectively stabilize HIF, inhibiting the EglN/HIF axis as a treatment for patients with chronic anemia and chronic kidney disease (19), bringing the original observations full circle. The three physician-scientists honored with the 2019 Nobel Prize in Physiology or Medicine highlight the tight coupling between clinical observations and fundamental aspects of human biology, inspire future physicians to apply that level of attention to clinical medicine, and pave the way for innovative therapeutic advances through their unwavering pursuit of basic research into the mechanisms by which cells sense and respond to oxygen. Acknowledgments JM is supported by NIH R56 HL141466 and R01 HL141466. WKR is supported by R01 CA198482 and R01 CA203012. Footnotes Conflict of interest: JM has served on an advisory boards for Pfizer, Novartis, Bristol-Myers Squibb, Audentes Therapeutics, Nektar, and AstraZeneca. WKR serves on the Board of Scientific Advisors for the National Cancer Institute, and on the scientific advisory board for Aravive. WKR serves as the lead investigator for clinical trials at VUMC supported by Pfizer, Novartis, Bristol-Myers Squibb, Peloton, Calithera, and Roche. Copyright: © 2020, American Society for Clinical Investigation. Reference information: J Clin Invest. 2020;130(1):4–6. https://doi.org/10.1172/JCI134813. References Wang GL, Semenza GL. Purification and characterization of hypoxia-inducible factor 1. J Biol Chem. 1995;270(3):1230–1237.View this article via: PubMedCrossRefGoogle Scholar Forsythe JA, et al. Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol. 1996;16(9):4604–4613.View this article via: PubMedCrossRefGoogle Scholar Lonergan KM, et al. Regulation of hypoxia-inducible mRNAs by the von Hippel-Lindau tumor suppressor protein requires binding to complexes containing elongins B/C and Cul2. Mol Cell Biol. 1998;18(2):732–741.View this article via: PubMedCrossRefGoogle Scholar Stebbins CE, Kaelin WG, Pavletich NP. Structure of the VHL-ElonginC-ElonginB complex: implications for VHL tumor suppressor function. Science. 1999;284(5413):455–461.View this article via: PubMedCrossRefGoogle Scholar Maxwell PH, Pugh CW, Ratcliffe PJ. Inducible operation of the erythropoietin 3′ enhancer in multiple cell lines: evidence for a widespread oxygen-sensing mechanism. Proc Natl Acad Sci U S A. 1993;90(6):2423–2427.View this article via: PubMedCrossRefGoogle Scholar Maxwell PH, et al. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature. 1999;399(6733):271–275.View this article via: PubMedCrossRefGoogle Scholar Jaakkola P, et al. Targeting of HIF-α to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science. 2001;292(5516):468–472.View this article via: PubMedCrossRefGoogle Scholar Ivan M, et al. HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science. 2001;292(5516):464–468.View this article via: PubMedCrossRefGoogle Scholar Epstein AC, et al. C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell. 2001;107(1):43–54.View this article via: PubMedCrossRefGoogle Scholar Bruick RK, McKnight SL. A conserved family of prolyl-4-hydroxylases that modify HIF. Science. 2001;294(5545):1337–1340.View this article via: PubMedCrossRefGoogle Scholar Ivan M, et al. Biochemical purification and pharmacological inhibition of a mammalian prolyl hydroxylase acting on hypoxia-inducible factor. Proc Natl Acad Sci U S A. 2002;99(21):13459–13464.View this article via: PubMedCrossRefGoogle Scholar Minamishima YA, Moslehi J, Bardeesy N, Cullen D, Bronson RT, Kaelin WG. Somatic inactivation of the PHD2 prolyl hydroxylase causes polycythemia and congestive heart failure. Blood. 2008;111(6):3236–3244.View this article via: PubMedCrossRefGoogle Scholar Percy MJ, et al. A family with erythrocytosis establishes a role for prolyl hydroxylase domain protein 2 in oxygen homeostasis. Proc Natl Acad Sci U S A. 2006;103(3):654–659.View this article via: PubMedCrossRefGoogle Scholar Percy MJ, et al. A gain-of-function mutation in the HIF2A gene in familial erythrocytosis. N Engl J Med. 2008;358(2):162–168.View this article via: PubMedCrossRefGoogle Scholar Simonson TS, et al. Genetic evidence for high-altitude adaptation in Tibet. Science. 2010;329(5987):72–75.View this article via: PubMedCrossRefGoogle Scholar Rini BI. Targeted therapy for patients with renal-cell carcinoma. Lancet Oncol. 2011;12(12):1085–1087.View this article via: PubMedCrossRefGoogle Scholar Moslehi JJ. Cardiovascular toxic effects of targeted cancer therapies. N Engl J Med. 2016;375(15):1457–1467.View this article via: PubMedCrossRefGoogle Scholar Courtney KD, et al. Phase I dose-escalation trial of PT2385, a first-in-class hypoxia-inducible factor-2α antagonist in patients with previously treated advanced clear cell renal cell carcinoma. J Clin Oncol. 2018;36(9):867–874.View this article via: PubMedCrossRefGoogle Scholar Chen N, et al. Roxadustat for anemia in patients with kidney disease not receiving dialysis. N Engl J Med. 2019;381(11):1001–1010.View this article via: PubMedCrossRefGoogle Scholar

    更新日期:2020-01-04
  • Are genetic approaches still needed to cure sickle cell disease?
    J. Clin. Invest. (IF 12.282) Pub Date : 2019-11-18
    Robert A. Brodsky; Michael R. DeBaun

    Sickle cell disease (SCD) is a heritable disorder of hemoglobin that affects 1 of every 400 black newborns and approximately 100,000 persons in the United States (1). This disease burden has a considerable impact on individuals affected and on health care systems. In the United States alone, the medical cost of caring for patients with SCD exceeds $1 billion annually. SCD is caused by a point mutation in codon 6 of the β-globin chain that results in an amino acid substitution of valine for glutamic acid, and promotes the formation of long hemoglobin polymers under hypoxic conditions. This abnormal polymerization deforms erythrocytes and causes significant alterations in red cell integrity, rheologic properties, and lifespan. SCD leads to chronic hemolysis and a vasculopathy that involves virtually every organ. Most adults and many children develop a chronic, debilitating condition, leading to high rates of disability and unemployment. A current cohort of adults that were followed and treated with disease-modifying therapy at two large academic medical centers had a median survival of 48 years (2), which is not much different when compared with a NIH-sponsored multicenter, prospective study of a cohort of adults with SCD that was published 25 years ago (3). Allogeneic blood or marrow transplantation (alloBMT) is the only cure for patients with sickle cell disease (SCD) (4). Worldwide, nearly 2000 children and adults with SCD have received alloBMT (5). Depending on the type of transplant and donor source, the cure rate is 90%–95%, and the risk of graft-versus-host disease (GVHD) is 4%–15% in the United States and Europe. Most of these data are from pediatric studies involving myeloablative conditioning regimens and stem cell grafts from matched sibling donors. Adult patients with SCD are often excluded from myeloablative BMT trials because of projected excess morbidity and mortality resulting from accumulated end-organ damage from decades of living with SCD. Additionally, many parents of children or affected individuals with SCD are reluctant to allow or receive myeloablative conditioning because of the nearly universal gonadal failure. Finding suitable donors has also been challenging. HLA-matched sibling donors are available in less than 15% of potential alloBMT recipients with SCD. Less than a quarter of African Americans have HLA matches in unrelated registries (6). Accordingly, broad application of alloBMT in SCD is dependent on novel strategies that address donor availability and limit toxicity from myeloablative conditioning regimens and GVHD. These limitations of donor availability and GVHD are driving research for novel approaches to BMT that use autologous cells with gene therapy or gene editing (Figure 1). Figure 1 Curative approaches to SCD. (A) Gene therapy requires the harvesting of HSPCs from the patient, transduction of these cells with a nonsickling viral vector, and myeloablative chemotherapy followed by autologous BMT. (B) Gene editing also requires the harvesting of HSPCs from the patient. Gene editing of HSPCs is accomplished with electroporation of gene-editing reagents, followed by myeloablative conditioning and autologous BMT using the gene-corrected cells. (C) alloBMT can be from an HLA-matched sibling donor, a matched unrelated donor, or an HLA-haploidentical family donor. Bone marrow is harvested from a healthy donor. Traditionally, patients received myeloablative chemotherapy, but in recent years nonmyeloablative therapy, especially for HLA-haploidentical BMT with post-transplantation cyclophosphamide, has become more common. Healthy donor HSPCs are infused, followed by post-transplantation administration of cyclophosphamide to prevent GVHD and graft rejection. Children with strokes and adults with severe heart, lung, or kidney disease or strokes are typically excluded from gene therapy trials but are eligible to participate in the NIH-supported HLA-haploidentical BMT with post-transplantation cyclophosphamide phase II trial (NCT03263559). Myeloablative gene therapy for SCD Gene therapy involves the harvesting of hematopoietic stem/progenitor cells (HSPCs), ex vivo transduction using a retroviral vector carrying a γ-globin or β-globin transgene, and reinfusion of transduced HSPCs following myeloablative chemotherapy. Since HSPCs are patient derived, there is no risk of GVHD; however, myeloablative chemotherapy (usually with busulfan) is required to reduce or eliminate host hematopoiesis. Myeloablative chemotherapy leads to infertility, alopecia, mucositis, and infections and may exclude patients with moderate-to-severe end-organ damage due to dose-limiting toxicities from busulfan. Stroke, a major source of morbidity, is an exclusion criterion for most gene therapy trials. There is also the potential for secondary malignancies from insertional mutagenesis and from busulfan. Self-inactivating lentiviral vectors mitigate, but do not eliminate, the risk for insertional mutagenesis. Furthermore, busulfan is seldom 100% myeloablative, and surviving HSPCs may also lead to late myeloid malignancies. Mobilizing enough HSPCs from patients with SCD and collecting enough self-renewing HSPCs to allow life-long expression of the transgene is also a challenge. Stem cell mobilization with granulocyte CSF (G-CSF) is contraindicated in SCD; therefore, current trials are using bone marrow harvesting, which is especially painful for patients with SCD and may still result in insufficient HSPC yields for successful BMT. Plerixifor mobilization is under investigation, and early results appear promising (7). Ensuring sufficient transduction of HSPCs to allow long-term engraftment is more problematic. Lentiviral vectors can transduce self-renewing G0 stem cells required for long-term transgene expression; however, the majority of transduced cells following peripheral blood mobilization are progenitor cells with limited to no self-renewal capacity. Progenitor cells survive three to four months and generate red cells that survive for 120 days. Moreover, autologous recovery following BMT leads to increased fetal hemoglobin that can decrease acute vaso-occlusive episodes for a year or more after BMT (8); thus, follow-up beyond two years is necessary to ensure that the transduced HSPCs are stable and sufficient to lead to long-term control of the disease. Despite these limitations, preliminary results of gene therapy for SCD and severe β-thalassemia are encouraging, with the largest experience in severe β-thalassemia (9). In two phase I–II studies of gene therapy using a lentiviral vector and myeloablative busulfan conditioning, 12 of 13 patients with a non-β0/β0 genotype achieved transfusion independence, with a median follow-up of over two years. In nine patients with the β0/β0 genotype, transfusion requirements decreased, but just three of nine were able to discontinue transfusions. The first successful case report of a patient with SCD treated with gene therapy was in 2017 (10). At the time of the report, the child was 15 months from having received his transplant and no longer experiencing vaso-occlusive crises. Of note, one of two additional patients treated in the same clinical trial benefitted from the therapy. Another exciting approach to gene therapy in clinical trials is to increase production of fetal hemoglobin by knockdown of BCL11A, a gene whose product, BCL11A, regulates hemoglobin F expression. Reducing BCL11A thus increases the amount of nonsickling γ-globin. A number of other clinical trials involving gene therapy to treat SCD are underway. Initial data should be available within the next two to three years, but long-term data of at least five- and ten-year intervals are necessary to address late graft failure and other late effects. Myeloablative gene editing for SCD The approach to gene editing is similar to that for gene therapy and involves the harvesting of HSPCs, ex vivo electroporation of target cells to correct the β-globin gene or to knock down BCL11A using CRISPR/Cas9 or zinc finger nucleases, and reinfusion of genetically modified HSPCs following myeloablative chemotherapy. The toxicities and limitations from mobilization and myeloablative chemotherapy are identical to those for gene therapy protocols. No retroviral transduction is needed, but recent data on CRISPR/Cas9 editing show that the frequency of large deletions and insertions that arise near the on-target site is higher than originally thought (11). Moreover, since DNA breaks induce apoptosis in healthy cells, it appears that there is enrichment of edited HSPCs with deficient p53, raising additional safety concerns regarding cancer risk (12). Nonmyeloablative haploidentical BMT for SCD The approach to nonmyeloablative haploidentical BMT was developed to increase donor availability and to provide curative options for adults with SCD who have preexisting heart, lung, and kidney dysfunction that would preclude myeloablative therapy. For children and adults with SCD, multiple previous unsuccessful single-center nonmyeloablative, haploidentical BMT protocols were initiated and abandoned because of transplant-related mortality. However, the more recent generation of nonmyeloablative, HLA-haploidentical BMT with post-transplantation cyclophosphamide, roughly one-third the cost of myeloablative gene therapy and gene editing, has dramatically improved the clinical outcome of children and adults with SCD. Virtually every patient eligible for a gene therapy or gene editing trial is also eligible for an HLA-haploidentical BMT with post-transplantation cyclophosphamide. Transplantation trials are more inclusive in that most gene therapy trials exclude patients who have had a stroke. The first clinical trial of nonmyeloablative, HLA-haploidentical BMT with post-transplantation cyclophosphamide for SCD in 2012 reported a graft failure rate of approximately 40% (13); however, subsequent modifications to the preparative regimens involving the addition of thiotepa or an increase in the dose of total body irradiation from 200 cGy to 400 cGy increased engraftment to 90% without adding to toxicity (14–16). The collective results from these three recent studies (n = 39 patients with SCD) showed no mortality, an engraftment rate of 90%, and a rate of GVHD above grade 2 of 8%. A clinical trial sponsored by the National Heart, Lung, and Blood Institute (NHLBI) involving HLA-haploidentical BMT with post-transplantation cyclophosphamide for SCD at more than 30 clinical centers throughout the United States and Europe is currently underway (NCT03263559). Confirmation of these encouraging early results will confirm that myeloablative conditioning and full-matched HLA donors are no longer necessary to cure SCD. Are genetic approaches still necessary to cure SCD? The era of curative therapy for patients with SCD is upon us. NIH-sponsored nonmyeloablative, HLA-haploidentical BMT with post-transplantation cyclophosphamide offers the opportunity to cure up to 95% of the children and 90% of the adults with severe SCD. Clinical trials involving myeloablative gene therapy and genome editing are also underway with 100% donor availability but are limited predominantly to children who can tolerate the myeloablative regimen. Although randomized, controlled trials comparing the two strategies are not likely to be undertaken, understandably, curative therapies that include nonmyeloablative methods will commonly be selected over those that are myeloablative. Informed families with SCD have multiple options to enroll in clinical trials designed to cure and advance care for the next generation. The pressing challenges are to include full disclosure of the various curative options for children and adults with SCD, to minimize late effects from preparative regimens, and to advance innovative science leading to nonmyeloablative, haploidentical BMT, gene therapy, or gene-editing trials. The future for curing children and adults with SCD looks bright. Footnotes Conflict of interest: The authors have declared that no conflict of interest exists. Copyright: © 2020, American Society for Clinical Investigation. Reference information: J Clin Invest. 2020;130(1):7–9. https://doi.org/10.1172/JCI133856. References Kato GJ, et al. Sickle cell disease. Nat Rev Dis Primers. 2018;4:18010. View this article via: PubMedGoogle Scholar DeBaun MR, et al. Decreased median survival of adults with sickle cell disease after adjusting for left truncation bias: a pooled analysis. Blood. 2019;133(6):615–617.View this article via: PubMedCrossRefGoogle Scholar Platt OS, et al. Mortality in sickle cell disease. Life expectancy and risk factors for early death. N Engl J Med. 1994;330(23):1639–1644.View this article via: PubMedCrossRefGoogle Scholar Bolaños-Meade J, Brodsky RA. Blood and marrow transplantation for sickle cell disease: is less more? Blood Rev. 2014;28(6):243–248.View this article via: PubMedCrossRefGoogle Scholar Gluckman E, et al. Sickle cell disease: an international survey of results of HLA-identical sibling hematopoietic stem cell transplantation. 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N Engl J Med. 2018;378(16):1479–1493.View this article via: PubMedCrossRefGoogle Scholar Ribeil JA, et al. Gene therapy in a patient with sickle cell disease. N Engl J Med. 2017;376(9):848–855.View this article via: PubMedCrossRefGoogle Scholar Kosicki M, Tomberg K, Bradley A. Repair of double-strand breaks induced by CRISPR-Cas9 leads to large deletions and complex rearrangements. Nat Biotechnol. 2018;36(8):765–771.View this article via: PubMedCrossRefGoogle Scholar Haapaniemi E, Botla S, Persson J, Schmierer B, Taipale J. CRISPR-Cas9 genome editing induces a p53-mediated DNA damage response. Nat Med. 2018;24(7):927–930.View this article via: PubMedCrossRefGoogle Scholar Bolaños-Meade J, et al. HLA-haploidentical bone marrow transplantation with posttransplant cyclophosphamide expands the donor pool for patients with sickle cell disease. Blood. 2012;120(22):4285–4291.View this article via: PubMedCrossRefGoogle Scholar Fitzhugh CD, et al. 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    更新日期:2020-01-04
  • Medications for opioid use disorders: clinical and pharmacological considerations
    J. Clin. Invest. (IF 12.282) Pub Date : 2019-11-25
    Nora D. Volkow; Carlos Blanco

    The opioid epidemic, now in its second decade, is one of the most challenging public health crises in the US. Providing an effective response is complicated by multiple underlying causes and consequences as well as a misunderstanding of addiction and the medications used to treat it (1). Indeed, medications for opioid use disorder (MOUDs) are the most effective interventions for treating opioid addiction, but are not prescribed to many who would benefit. Here, we describe the distinction between physical dependence and addiction along with its implication for treatment, and discuss the mechanisms of action of MOUDs. Opioid withdrawal versus opioid dependence Opioid use disorder (OUD) is defined as a pattern of maladaptive opioid use that leads to significant impairment or distress. Severity is classified on the basis of the number of symptoms (Table 1) present: mild (one or two), moderate (three or four), and severe (six or more) (2). In this description, opioid addiction corresponds to moderate and severe OUD. Table 1 DSM-5 criteria for diagnostic criteria OUD In diagnosing OUD, many confuse opioid physical dependence with OUD, yet this distinction is crucial for selecting treatment. Physical dependence develops rapidly and occurs in most people who are given repeated doses of opioid medications and manifests as the emergence of acute withdrawal symptoms following discontinuation of opioid drugs. When physical dependence is associated with tolerance, it can lead to a diagnosis of mild OUD (two of the criteria in Table 1). Note that physical dependence and tolerance will be present in many pain patients who are properly treated with opioid medications; hence, the distinction from mild OUD requires the clinician to assess whether significant impairment or distress is present. Physical dependence and the associated acute withdrawal symptoms are adaptations that recover rapidly (within days) and can be managed by slowly tapering the opioid drug without the need of maintenance on opioid medications (3). In contrast, opioid addiction develops in less than 10% of those exposed repeatedly to opioids and is the result of neuroplastic adaptations in brain circuits underlying reward and motivation, self-regulation and decision-making, and mood and stress reactivity that are long lasting, persisting years after drug discontinuation (4, 5). Opioid addiction significantly benefits from the use of medications for OUD. Abrupt cessation of opioids after repeated use can produce an intense but rarely life-threatening withdrawal syndrome, which can be understood as an adaptation to maintaining homeostasis or allostatic process (3). Common symptoms of early withdrawal include mydriasis, piloerection, muscle twitching, lacrimation, rhinorrhea, diaphoresis, yawning, tremor, insomnia, restlessness, myalgia, arthralgia, diarrhea, and nausea or vomiting. As withdrawal progresses, tachycardia, tachypnea, hypertension or hypotension, and dehydration can appear. Note that this is distinct from the protracted withdrawal syndrome characterized by dysphoria, craving, and insomnia that reflects brain circuitry neuroadaptations associated with addiction. Symptoms of acute withdrawal (as well as protracted withdrawal) can be a powerful trigger for relapse for individuals with OUD (1), but can also lead to opioid seeking in pain patients in whom acute opioid withdrawal is not properly managed. Multiple neuroadaptations underlie physical dependence (6), including desensitization and internalization of the μ-opioid receptor (MOR), impaired MOR signaling with intracellular effectors, intracellular upregulation of cAMP/PKA in opioid-sensitive neurons, adaptations in neuropeptide systems that interact with μ-opioid–sensitive neurons, and activation of glial signaling (7). Hyperactivity of the locus coeruleus (LC) underlies many of the symptoms of acute withdrawal, and α1 adrenergic agonists, such as lofexidine and clonidine, which reduce noradrenergic release, are useful for the management of acute opioid withdrawal. In contrast to withdrawal, which is a physiological response to the abrupt decline in MOR occupancy and signaling, addiction is predominantly a disorder of brain circuits that impairs motivation, self regulation, and hedonic tone. The brain mechanisms underlying addiction include the following (3): (a) reward circuitry, originating in the dopamine neurons in the ventral tegmental area and projecting to the nucleus accumbens, ventral prefrontal cortex, and amygdala; (b) emotional circuitry, including the hippocampus, extended amygdala, lateral habenula, dorsal raphe, and insula; and (c) executive control circuitry, which involves widely distributed and complex prefrontal cortex–subcortical circuitry (3). In addition, circuitry involved in interoception modulates awareness of drug-conditioned cues, stress, and negative emotional states (3). Disruption of these circuits underlies the compulsive pattern of drug taking despite its adverse consequences (8). MOUDs MOUDs are the standard of care for OUD (9). They are associated with reduced risk of relapse, overdose deaths, infections, and criminal behavior and are more cost-effective than no OUD treatment or treatment with no medication. There are three medications approved by the FDA for the treatment of OUD: methadone (full MOR agonist), buprenorphine (partial MOR agonist, κ-opioid receptor [KOR] antagonist, and nociceptor receptor agonist), and naltrexone (MOR and KOR antagonist). The MOR is both the therapeutic target for MOUDs and the target for heroin and other opioids when misused for their rewarding effects. For this reason, many have dismissed agonist medications (methadone and buprenorphine) as only substituting one drug for another; however, this view ignores fundamental differences between drugs of abuse and MOUDs. These distinctions include differences in pharmacokinetics, pharmacological effects at the MOR, and doses and routes of administration. Pharmacokinetics and route of administration. The rate at which opioid drugs enter the brain and bind to the MOR modulates their rewarding effects such that drugs with fast uptake into the brain and that interact rapidly with the MOR, such as heroin and fentanyl, are the most rewarding. The route of administration also affects pharmacokinetics; intravenous or smoking administration results in faster brain delivery than taking orally. When used therapeutically, MOUDs are either given orally or in slow-release formulations, which slows the rate of brain entry and clearance. The relatively slow brain clearance of buprenorphine and, to a lesser extent, methadone leads to milder severity of withdrawal upon their discontinuation than when discontinuing heroin or fentanyl. In this respect, buprenorphine leads to a milder withdrawal than methadone. Additionally, the slower pharmacokinetics of MOUDs result in more stable levels of MOR occupancy than misuse of opioid drugs for their rewarding effects. Stable occupancy of MOR by MOUDs controls opioid craving and prevents the emergence of acute withdrawal symptoms. Doses and frequency of administration also differ when opioid drugs are misused for their rewarding effects than when used therapeutically. Methadone is typically injected when it is misused. In the case of buprenorphine, its injection is limited by the combination with the antagonist opioid drug naloxone (Suboxone formulation), which has very poor bioavailability when given sublingually, but if injected, will trigger an acute withdrawal. Nonetheless, there are multiple reports of diversion and misuse of buprenorphine, though it appears that misuse of buprenorphine is mostly to alleviate opiate withdrawal or achieve abstinence from other opioids, particularly when access to this medication is restricted (10). Though MOR is the target for the rewarding and analgesic effects of opioids, the KOR is implicated in the aversive negative emotional states associated with addictions. Preclinical data indicate an upregulation of KOR signaling in animal models of addiction that, when blocked, prevents relapse into drug taking (11). Hence, a priority in addiction treatment has been the development of κ antagonist medications. In this respect the KOR antagonist effects of buprenorphine and naltrexone are likely to contribute to their therapeutic effects. Additionally, buprenorphine also binds to the nociceptin receptor where its agonist effects could also contribute to its efficacy in OUD (12). Which MOUD to use Although there are no empirically based predictors for selecting a specific MOUD, expert consensus and qualitative studies suggest that the selection should be based on the patient’s response to prior treatment with MOUDs, their level of physical dependence, the presence of coexisting conditions, and the patient’s preference (9). Often, the selection is determined by what is available in a given treatment program. Increasingly, however, there is recognition that patients might respond better to a particular MOUD depending on their characteristics and that optimal medication may be different during treatment initiation than stabilization. Methadone has been available for more than 50 years and has the largest evidence of efficacy (13). Methadone would be indicated in patients with severe tolerance in whom buprenorphine treatment might trigger withdrawal symptoms. In general, there is overall better retention with methadone than buprenorphine and higher methadone doses up to 100 mg/day are associated with better outcomes than lower doses (14). As a full agonist, methadone has no ceiling effect, which increases risk for overdoses when used at doses above the patient’s tolerance or when combined with other central nervous depressants such as alcohol, benzodiazepines, heroin, or other synthetic opioids. Methadone is administered daily in an oral formulation. In the US methadone must be administered in licensed outpatient treatment programs (OTPs), which constitutes an important barrier to treatment to many patients, though it might improve outcomes in individuals who benefit from daily behavioral intervention given in OTPs (1). There is interest in exploring expanded access to methadone, such as office-based or via pharmacies (15), and developing extended release formulations of methadone to improve adherence, minimize diversion, and facilitate use in healthcare or justice settings. Buprenorphine has been available to treat OUD for almost two decades (13). Buprenorphine is prescribed in medical offices by clinicians who require a waiver to do so. There are currently 102,570 waivered clinicians in the US, though many are not treating OUD patients (16). Buprenorphine requires daily or every other day dosing, and typical doses range between 8 to 24 mg, with a recommended target dose of 16 mg. Optimal responses to buprenorphine have been obtained in OUD patients with depressive symptoms, which might reflect in part the mood-enhancing effect of KOR antagonists. As a partial MOR agonist, buprenorphine can precipitate acute withdrawal in individuals with OUD who use high doses of heroin or fentanyl or have been maintained on high doses of methadone. In those instances, it might be best to initiate treatment with methadone and, after slowly tapering the dose, continue with buprenorphine. Buprenorphine is less likely to induce respiratory depression than methadone, but it can still be lethal when combined with other central nervous depressant substances (17). Extended-release (XR) formulations of buprenorphine were recently developed that include an FDA-approved six-month implant, a one-week formulation that is being reviewed by the FDA, and one-month formulations of buprenorphine, one of which was already approved by FDA (1). Limited data are available regarding the acceptability and efficacy of these new formulations in OUD. Naltrexone is a MOR antagonist, but the utility of the immediate release formulation for OUD treatment has been limited by poor adherence. The development of a monthly XR–extended release naltrexone (XR-NTX) formulation significantly improved treatment retention and outcomes (18). Naltrexone is an antagonist drug that triggers acute withdrawal if OUD patients are not detoxified prior to induction. Current recommendations are for patients to be abstinent for one week prior to XR-NTX induction, which constitutes a barrier to induct some patients into treatment. Some protocols have been developed for faster supervised medical withdrawal (formerly known as detoxification), but further research is needed before adoption in routine clinical practice. The KOR antagonist effects could contribute to the mood improvements reported in OUD patients treated with naltrexone. Presence of cooccurring disorders may be another consideration in MOUD selection. For example, naltrexone is also effective for alcohol dependence so comorbid OUD with alcoholism might benefit uniquely from this medication, whereas the KOR antagonist properties of buprenorphine may offer unique benefits for OUD patients with comorbid depression. For pregnant women, methadone or buprenorphine is recommended, due to insufficient data on safety of naltrexone. Conclusion MOUDs are among the most effective interventions for preventing overdose mortality and improving outcomes in patients with OUD. However, stigmatization and lack of understanding of addiction and the medications used to treat OUD have interfered with their implementation. The increased recognition that MOUDs are crucial for controlling the current opioid crisis highlights the importance of engaging healthcare in the screening and treatment of OUD. The views and opinions expressed in this report are those of the authors and should not be construed to represent the views of any of the sponsoring organizations or agencies or the US government. Footnotes Conflict of interest: The authors have declared that no conflict of interest exists. Copyright: © 2020, American Society for Clinical Investigation. Reference information: J Clin Invest. 2020;130(1):10–13. https://doi.org/10.1172/JCI134708. References Blanco C, Volkow ND. Management of opioid use disorder in the USA: present status and future directions. Lancet. 2019;393(10182):1760–1772.View this article via: PubMedCrossRefGoogle Scholar American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Washington, DC, USA: American Psychiatric Publishing; 2013. Koob GF, Volkow ND. Neurobiology of addiction: a neurocircuitry analysis. Lancet Psychiatry. 2016;3(8):760–773.View this article via: PubMedCrossRefGoogle Scholar Kalivas PW, Volkow ND. The neural basis of addiction: a pathology of motivation and choice. Am J Psychiatry. 2005;162(8):1403–1413.View this article via: PubMedCrossRefGoogle Scholar Pérez de los Cobos J, Batlle F, Casas M. [Proposal for improving the integration of drug dependencies in psychiatric nosology]. Actas Luso Esp Neurol Psiquiatr Cienc Afines. 1996;24(2):63–65.View this article via: PubMedGoogle Scholar Christie MJ. Cellular neuroadaptations to chronic opioids: tolerance, withdrawal and addiction. Br J Pharmacol. 2008;154(2):384–396.View this article via: PubMedGoogle Scholar Rich MM, Wenner P. Sensing and expressing homeostatic synaptic plasticity. Trends Neurosci. 2007;30(3):119–125.View this article via: PubMedCrossRefGoogle Scholar Volkow ND, Wang GJ, Fowler JS, Tomasi D, Telang F. Addiction: beyond dopamine reward circuitry. Proc Natl Acad Sci U S A. 2011;108(37):15037–15042.View this article via: PubMedCrossRefGoogle Scholar Substance Abuse Mental Health Services Administration. 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J Addict Med. 2014;8(5):315–326.View this article via: PubMedCrossRefGoogle Scholar Krupitsky E, Nunes EV, Ling W, Illeperuma A, Gastfriend DR, Silverman BL. Injectable extended-release naltrexone for opioid dependence: a double-blind, placebo-controlled, multicentre randomised trial. Lancet. 2011;377(9776):1506–1513.View this article via: PubMedCrossRefGoogle Scholar

    更新日期:2020-01-04
  • Prediction algorithms: pitfalls in interpreting genetic variants of autosomal dominant monogenic diabetes
    J. Clin. Invest. (IF 12.282) Pub Date : 2019-12-09
    Sian Ellard; Kevin Colclough; Kashyap A. Patel; Andrew T. Hattersley

    The increasing availability of DNA sequence data and access to sophisticated bioinformatic algorithms mean that an unbiased bioinformatics-based assessment of the predicted impact of a genomic variant is rapidly available. The key point of this Viewpoint article is that such bioinformatic assessments are not equivalent to an expert diagnostic interpretation and may be misleading in both research and clinical care. Predication algorithms in genomic medicine Recently published examples involving monogenic diabetes demonstrate how pathogenicity prediction algorithms can be very inaccurate for predicting which genetic variants are likely causal of dominant monogenic disease (1–4). Here, we highlight the potential pitfalls of variant classification and how they can be avoided. A recent study used a bioinformatic algorithm to identify 88 “likely pathogenic” monogenic diabetes variants in 80 individuals (8.6%) from a cohort of 1019 individuals with type 1 diabetes for 50 or more years (4). Application of the widely used American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) standards and guidelines (5) classifies only nine of these 88 variants as likely pathogenic or pathogenic variants that would be reported by our clinical diagnostic laboratory as likely causative of the patients’ diabetes. This is not an isolated occurrence; other published research studies with an overreliance on in silico prediction tools have reported high levels (~90%) of false positive “likely pathogenic” monogenic diabetes variants (1–3). We have seen clinical diagnostic reports from laboratories in eight countries across Europe, Asia, the Middle East, and the United States that have similarly reported such variants as incorrectly likely causative of a patient’s diabetes. Such great discrepancies occur not because the bioinformatic algorithm is wrong, or even based on incorrect scientific principles, but because variant interpretation in the clinical setting requires other information in addition to the predicted effect upon protein function. This additional information includes knowledge regarding the gene-disease validity, mode of inheritance, appropriate allele frequency cutoff thresholds, most clinically relevant transcript, and specificity of disease-causing variant type for each gene. Each of these is discussed in turn below and illustrated in Figure 1. Figure 1 Flowchart to illustrate key steps in the interpretation of genetic variants to identify autosomal dominant (likely) pathogenic variants for clinical diagnostic or research reporting. gnomAD, Genome Aggregation Database. How should expert disease-related knowledge guide the interpretation and reporting of genetic variants that might cause autosomal dominant monogenic disease? Do not analyze genes without robust evidence to support the gene-disease association (6), for example the BLK, KLF11, and PAX4 genes, where current evidence is limited (7). Reputable clinical diagnostic laboratories do not include these genes in their monogenic diabetes testing. Do not report a heterozygous variant in autosomal recessive disorders caused by biallelic variants (homozygous or compound heterozygous). For example, biallelic pathogenic WFS1 variants cause Wolfram syndrome (8), a very rare disorder with an estimated prevalence of 1 in 500,000 (heterozygous carrier frequency ~0.3%). WFS1 is an extremely polymorphic gene with rare (allele frequency < 0.1%) missense variants present in more than 2% of the population. Although there are reports of autosomal dominant diabetes caused by heterozygous WFS1 variants, these are extremely rare: one family with dominantly inherited nonsyndromic diabetes (9) and five patients with neonatal- or infancy-onset diabetes, deafness, and cataracts (10). The finding of a rare heterozygous variant is therefore highly unlikely to be causative of monogenic diabetes and should not be reported. Use appropriate gene-specific allele frequency cutoffs in control population data to exclude variants that are too common to be highly penetrant disease-causing variants. For example, Ming-Qiang et al. found that PAX4 variants were the second most common cause of monogenic diabetes in their Chinese cohort (3), but the missense variants they reported are present in more than 1% of the East Asian population cohort (approximately 15,000 individuals) in the publicly available gnomAD database (https://gnomad.broadinstitute.org) (11). A tool is available (http://cardiodb.org/alleleFrequencyApp) that allows the user to input inheritance mode, disease prevalence, penetrance, genetic heterogeneity (how many cases can be attributed to the gene), and allelic heterogeneity (how many cases can be attributed to a single variant) and calculate a maximum credible allele frequency (12). Using HNF1A monogenic diabetes as an example with monoallelic inheritance, disease prevalence of 1 in 10,000, allelic heterogeneity 0.16, genetic heterogeneity 0.35, and penetrance 0.95, the maximum tolerated pathogenic allele count is 2 in the gnomAD database (n = 141,456). In a study of diabetic subjects from South India, Mohan et al. reported HNF1A variants as the most common subtype of monogenic diabetes in their study (1). However, six of the 11 patients had variants that are too common in the European ancestry population in gnomAD (allele counts of 4 or more in approximately 60,000 Europeans) to be highly penetrant variants causative of monogenic diabetes. It is essential to check the variant frequency in large variant data sets to avoid this type of misclassification. Check that the most clinically relevant transcript is used. For example, there are multiple isoforms of the transcription factor HNF4A. For interpretation of monogenic diabetes variants, the messenger RNA transcript that encodes the pancreatic isoform, rather than the liver isoform, should be used because there is a pancreatic specific promoter and exon 1 (NM_175914.4). Using this transcript, the HNF4A variant p.A417T Yu et al. reported (4) is noncoding (c.1063+120) and likely benign. Identify the specific subtypes of heterozygous mutations that result in the specific change of function required to cause monogenic disease. Heterozygous pathogenic variants in the GCK, HNF1A, HNF1B, and HNF4A genes cause diabetes by reducing the level of functional protein, described as haploinsufficiency (7). For other monogenic diabetes subtypes there is a different disease mechanism, and heterozygous predicted loss-of-function (frameshift, nonsense, or essential splice site) variants are not causative. The KCNJ11 and ABCC8 genes encode the subunits of the β cell potassium channel. Activating variants prevent the channel from closing in response to raised blood glucose, and this prevents insulin release in patients with diabetes (13). Recessive loss-of-function KCNJ11 and ABCC8 variants cause the opposite phenotype of hyperinsulinism (14). This means that a heterozygous loss of function variant in one of these genes confers carrier status for congenital hyperinsulinism but does not cause monogenic diabetes. Other examples include the CEL gene, where only variants within the first or fourth repeats of the VNTR region are pathogenic (15); RFX6, where there is only evidence to implicate protein truncating variants (16); and the sole heterozygous PDX1 pathogenic variant, p.P63fs, known to cause monogenic diabetes through a dominant negative effect (17). Exclude variants of uncertain significance. These are variants lacking evidence for classification as pathogenic or likely pathogenic (5). Examples include novel missense variants in constrained genes where the amino acid substitution is predicted to have a deleterious effect upon protein function. Any individual has about 100 variants of this type and should be treated as “uncertain until proven guilty” (18). Why are errors in the interpretation of genetic variants common in both academic and diagnostic reports? Misinterpretation of genetic variants is common, both in the published literature (19) and in reports from diagnostic laboratories. Next-generation sequencing technology has facilitated both the ease and scale of genetic testing, but obtaining genotype data is far more straightforward than interpreting it correctly. Academic studies often use bespoke criteria for defining pathogenicity rather than applying guidelines developed to improve the quality and consistency of variant interpretation (5). Studies may base their variant classifications solely on in silico prediction of pathogenicity using tools such as REVEL or SIFT, PolyPhen, and MutationTaster that provide only supporting evidence within the ACMG/AMP guidelines framework recommended for diagnostic reporting (5). The availability of large variant data sets such as the gnomAD (11) has shown that many previously reported pathogenic variants are too common to be highly penetrant disease-causing variants (20). In some cases the evidence supporting gene-disease associations is no longer valid, but publications refuting these genes are rare and may consider only a single putative mutation (21, 22). The utility of population variant databases will increase as more exome and genome sequence data are aggregated from a wider range of populations (11). An overemphasis on bioinformatic tools for predicting pathogenicity has resulted in false positive assertions. Although curated databases of pathogenic/likely pathogenic variants are widely used, the level of curating varies, and there are often insufficient data available for users to assess the provenance of individual variant pathogenicity assertions. The prior probability of a monogenic etiology is an important consideration for variant classification. For monogenic diabetes the prior probability will be low because only a small proportion of patients with diabetes have a monogenic subtype (3.6% of patients diagnosed at age ≤ 30 years; ref. 23). Sensitivity/specificity estimates for pathogenicity prediction tools like REVEL and PolyPhen are calculated from a set of pathogenic and benign variants in genes with a higher likelihood of a monogenic etiology (24). How can the accuracy of variant interpretation and reporting be improved? A number of initiatives are addressing various aspects of variant interpretation. For example the NIH-funded ClinGen resource (https://clinicalgenome.org/) includes curating of gene-disease validity evidence, the ClinVar variant repository, and expert groups developing gene- or disease-specific criteria for variant classification. Sharing genetic variant data on a global scale is an essential requirement (25). The ACMG/AMP variant classification guidelines have been adopted in many countries, and we recommend that all academic studies use these guidelines for variant classification (5). Genetic testing for clinical diagnosis should be performed in an accredited laboratory that participates in external quality assessment schemes that include variant classification. Conclusion We have entered a new era in which the generation of massive quantities of accurate genetic data from an individual is no longer difficult, but the new challenge is how to correctly interpret this data. This Viewpoint emphasizes how disease-specific expertise is required when interpreting genetic data and how failure to use this information will result in errors. Misdiagnosis not only affects the individual patients for whom testing is being performed but also can be amplified through predictive testing of relatives and use of incorrect variant classifications in databases and publications for interpretation of the same variant in other patients. Accurate genetic diagnosis is needed to predict disease prognosis and guide clinical management. Acknowledgments SE and ATH are Wellcome Senior Investigators (098395/Z/12/Z). ATH is a Senior Investigator at the National Institute for Health Research and is supported by the National Institute for Health Research Exeter Clinical Research Facility. KAP has a postdoctoral fellowship funded by the Wellcome Trust (110082/Z/15/Z). Footnotes Conflict of interest: The authors have declared that no conflict of interest exists. Copyright: © 2020, American Society for Clinical Investigation. Reference information: J Clin Invest. 2020;130(1):14–16. https://doi.org/10.1172/JCI133516. References Mohan V, et al. Comprehensive genomic analysis identifies pathogenic variants in maturity-onset diabetes of the young (MODY) patients in South India. BMC Med Genet. 2018;19(1):22. View this article via: PubMedCrossRefGoogle Scholar Pezzilli S, et al. Insights from molecular characterization of adult patients of families with multigenerational diabetes. Diabetes. 2018;67(1):137–145.View this article via: PubMedCrossRefGoogle Scholar Ming-Qiang Z, et al. Maturity onset diabetes of the young (MODY) in Chinese children: genes and clinical phenotypes. J Pediatr Endocrinol Metab. 2019;32(7):759–765.View this article via: PubMedCrossRefGoogle Scholar Yu MG, et al. Residual β cell function and monogenic variants in long-duration type 1 diabetes patients. J Clin Invest. 2019;129(8):3252–3263.View this article via: JCIPubMedCrossRefGoogle Scholar Richards S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405–424.View this article via: PubMedCrossRefGoogle Scholar Strande NT, et al. Evaluating the clinical validity of gene-disease associations: an evidence-based framework developed by the clinical genome resource. Am J Hum Genet. 2017;100(6):895–906.View this article via: PubMedCrossRefGoogle Scholar McDonald TJ, Ellard S. Maturity onset diabetes of the young: identification and diagnosis. Ann Clin Biochem. 2013;50(Pt 5):403–415.View this article via: PubMedGoogle Scholar National Library of Medicine. Wolfram syndrome. Genetics Home Reference website. https://ghr.nlm.nih.gov/condition/wolfram-syndrome Accessed November 12, 2019. Bonnycastle LL, et al. Autosomal dominant diabetes arising from a Wolfram syndrome 1 mutation. 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    更新日期:2020-01-04
  • Using admission statistics to encourage diverse applicants to MD-PhD programs
    J. Clin. Invest. (IF 12.282) Pub Date : 2019-12-09
    Briana Christophers; Ruth Gotian

    There has been consistent interest in bolstering the physician-scientist workforce to fuel discovery and translational research (1, 2). In 2014, the Physician-Scientist Workforce Working Group assembled by the NIH identified increasing diversity of the physician-scientist workforce as a priority for the future advancement of the profession; at the time, almost three-quarters of NIH research project grant recipients with an MD-PhD were White, and greater than two-thirds were male (3, 4). Even so, women and underrepresented minorities (URMs), which include Black/African Americans, Hispanics/Latinos, and Native Americans/American Indians, remain underrepresented. The enrollment data for 2018–2019 show that women made up 39.9% of matriculated MD-PhD students, up from 37.7% in 2014–2015 (5). In the past five years, the rate for women enrolled has increased at about 0.55% per year. Even if growth continued at the 2018–2019 rate (1.1%), it would take another ten years for parity to be reached between men and women enrolled in MD-PhD programs. Similar trends emerge for URM MD-PhD students: the graduating class of 2018 had 13.8% URM graduates, whereas 2018–2019 matriculants included 12.1% URMs (6, 7). For that academic year, 16% of applicants were URMs (8). These data highlight that there has been almost no growth in the number of URM MD-PhD students matriculating compared with those who matriculated 8–10 years prior (i.e., graduating class of 2018). Additionally, it is necessary to examine reasons why potential women and URM applicants decide not to apply to MD-PhD programs from the outset. The story admissions statistics tell Potential applicants spend considerable time on the internet looking for information about individual MD-PhD programs. A study focused on minority students who applied to medical school revealed that “[t]he few [participants] who searched school websites for information about the admissions process reported that the quality of the websites mattered, being critical resources for students with no other access to information” (9). Although the study population focused on medical students, this suggests that providing accurate and clear data on websites could be a way of raising awareness about programs for women and URM applicants with no other source of reliable information about applying, such as a mentor, family member, or pre-health advisor. URM premedical students cite lack of mentorship and advising as a barrier to applying to medical school, with some receiving information when they felt it was too late, leaving them at a disadvantage (10). Data on premedical women college students show that they are more likely than male undergraduates to view premedical course grades as a barrier to medical school admission (11). Thus, potential applicants look online for details to inform whether or not they should apply in order to maximize their chances relative to the upfront costs of applying. Applicants have access to the Medical School Admissions Requirements database if they purchase it through the Association of American Medical Colleges (AAMC), which compiles statistics such as grade point average (GPA) and Medical College Admission Test (MCAT) scores that are useful for those creating a list of schools to which to apply. However, these data are not as useful for those applying to MD-PhD programs, who have a slightly different application process. For MD-PhD applicants, quantity and quality of research experience often play into the admissions decision, but this is difficult to compare across applicants, since many (29.7%) who end up matriculating in programs have at least one year of prior research (12). Therefore, potential applicants may try to use metrics that can be compared among applicants, such as MCAT score or GPA, to guide their application process. Some potential applicants might even turn to anonymous online forums such as Student Doctor Network and Reddit, where they can scroll through posts to gauge their chances of being considered for, and accepted into, an MD-PhD program. The self-selection bias of those who post on these sites may paint an unbalanced picture of who is applying, and the advice provided is given by anyone on the internet, whether or not they are familiar with the admissions procedures at different programs. Furthermore, postings represent the perception of just one person using a pseudonym, so their reliability cannot be confirmed. Some potential applicants may come across statistics published by the AAMC that show the mean, minimum, and maximum GPA and MCAT scores for MD-PhD matriculants. For 2018 matriculants the mean GPA was 3.79 ± 0.19 with a range of 2.68–4.00, and the mean MCAT score was 515.6 ± 5.6 with a range of 497–528 (13). These data can be both intimidating and comforting. The data are intimidating if one considers the means and standard deviations, which suggest a distribution with a very negative skew, with 50 percent of matriculants earning an MCAT score above the 92nd percentile or having a GPA greater than 3.8. However, the data might be comforting to some because the minimum GPA and MCAT composite score of matriculants are 2.75 and 495.0, respectively. It should also be noted that a study of MD-PhD enrollees who took the MCAT in the early 2000s showed that 92.1% of applicants had an MCAT score in the upper two quintiles, which may be daunting to those with lower scores (14). The fact that this information can be both intimidating and comforting simply adds to the uncertainty of potential applicants trying to determine whether they are competitive. The MCAT and GPA data on interviewees, accepted applicants, and matriculants provided by MD-PhD programs vary drastically. Searching the internet in late June 2019, we identified that 116 of 121 MD-PhD programs had a website with specific admissions-related details. More than 50 percent of programs included no information regarding MCAT score or GPA for individuals who applied to, interviewed at, were accepted to, or matriculated into their program (Figure 1). One-fifth of program websites listed a mean MCAT score and GPA; the majority did not include a standard deviation, making the mean difficult to interpret. Less than ten percent of programs included a range for these statistics on their website, although NIH-funded Medical Scientist Training Programs were more likely than other MD-PhD programs to include a range (13% vs. 1%, respectively). Figure 1 Categories of admissions statistics reported by MD-PhD programs on their websites. (A) MCAT exam scores. (B) Grade point averages. Pie charts represent the data for all MD-PhD programs (left), Medical Scientist Training Programs (MSTPs; middle), and other MD-PhD programs (right). The colors represent the categories of admissions statistics (minimum, median, mean, range, and no statistics reported) presented on the websites. These data points are used by potential applicants as critical information when deciding whether and where to apply. Therefore, these data can serve to encourage more potential applicants to submit applications because they may feel more qualified, or they can be a deterrent, depending on how they are presented. Similarly, information (e.g., means without standard deviations) suggesting that only those with high scores are accepted into a program may contribute to self-selection by women and URM applicants out of the application process due to fear of not being sufficiently qualified. The lack of accurate information may be feeding into imposter syndrome for women and URM applicants and thus acting as a deterrent. Interestingly, women are more likely to apply to lower-ranking MD-PhD programs, again suggesting that some applicants may be applying depending on the programs for which they believe they are qualified (15). Imposter syndrome Students battling impostor syndrome feel they are not smart or talented enough to pursue this profession (16). Furthermore, they live in constant fear that they will be exposed as a fraud and asked to leave their program. This perception is internalized and over time eats away at their self-confidence. The fear, when exacerbated, can result in anxiety, stress, or depression (17). Imposter syndrome is manifested by comparing oneself to others, not feeling academically prepared and on par with peers, and questioning the validity of one’s acceptance into a program (18, 19). The literature about the experience of premedical students, especially women and minorities, is currently limited. However, there is evidence for increased attrition of these groups in premedical required courses and STEM majors due to seeing grades and GPA as a marker of competency or fit for the career path (11, 20, 21). The fear associated with imposter syndrome may cause individuals not to apply if they do not feel they are the perfect applicant with average or above-average MCAT scores and GPA. Lack of knowledge as to the full ranges of these scores does little to alleviate their concerns. Redefining the ideal MD-PhD candidate Having clear and accessible information on successful applicants to individual programs would be a simple step toward improving equity in the MD-PhD application process. Publishing the range of MCAT scores and GPAs of those that a program has accepted, perhaps over a range of time such as ten years, would allow those considering applying to make informed decisions about their candidacy. In this way, women and URM applicants who may have been deterred by lack of information or misleading high-mean statistics for many programs would instead have sufficient information that might make them more likely to apply. Pooling the data for accepted students over a certain period of time would ensure that this range would not identify individuals who matriculate at smaller programs or specific individuals in a matriculating class. Above all, this strategy would be a simple step toward redefining the manufactured image of academic perfection (i.e., high GPA and MCAT score with many publications) that many believe represents those who will be successful applicants and future physician-scientists. Acknowledgments BC was supported by a Medical Scientist Training Program grant from the National Institute of General Medical Sciences of the NIH under award number T32GM007739 to the Weill Cornell/Rockefeller/Memorial Sloan Kettering Tri-Institutional MD-PhD Program. Footnotes Conflict of interest: The authors have declared that no conflict of interest exists. Copyright: © 2020, American Society for Clinical Investigation. Reference information: J Clin Invest. 2020;130(1):17–19. https://doi.org/10.1172/JCI134941. References Daye D, Patel CB, Ahn J, Nguyen FT. Challenges and opportunities for reinvigorating the physician-scientist pipeline. J Clin Invest. 2015;125(3):883–887.View this article via: JCIPubMedCrossRefGoogle Scholar Martin DM, Rathmell WK, Tavazoie SF. Balancing dual demands on the physician-scientist workforce. J Clin Invest. 2018;128(8):3204–3205.View this article via: JCIPubMedCrossRefGoogle Scholar NIH. Physician Scientist Working Group Report 2014. https://report.nih.gov/workforce/psw/index.aspx Updated June 30, 2018. Accessed November 11, 2019. Milewicz DM, Lorenz RG, Dermody TS, Brass LF, , National Association of MD-PhD Programs Executive Committee. Rescuing the physician-scientist workforce: the time for action is now. J Clin Invest. 2015;125(10):3742–3747.View this article via: JCIPubMedCrossRefGoogle Scholar Association of American Medical Colleges. Table B-11.2: Total MD-PhD Enrollment by U.S. Medical School and Sex, 2014-2015 through 2018-2019. http://www.aamc.org/download/321554/data/factstableb11-2.pdf Updated November 19, 2018. Accessed November 11, 2019. Association of American Medical Colleges. Table B-13: Race/Ethnicity Responses (Alone and In Combination) of MD-PhD Graduates of U.S. Medical Schools, 2013-2014 through 2017-2018. http://www.aamc.org/download/450638/data/factstableb13.pdf Updated November 27, 2018. Accessed November 11, 2019. Association of American Medical Colleges. Table B-9: MD-PhD Matriculants to U.S. Medical Schools by Race/Ethnicity and State of Legal Residence, 2018-2019. http://www.aamc.org/download/321546/data/factstableb9.pdf Updated November 13, 2018. Accessed November 11, 2019. Association of American Medical Colleges. Table B-7: MD-PhD Applicants to U.S. Medical Schools by Race/Ethnicity and State of Legal Residence, 2018-2019. http://www.aamc.org/download/321542/data/factstableb7.pdf Updated November 13, 2018. Accessed November 11, 2019. Hadinger MA. Underrepresented minorities in medical school admissions: a qualitative study. Teach Learn Med. 2017;29(1):31–41.View this article via: PubMedCrossRefGoogle Scholar Freeman BK, Landry A, Trevino R, Grande D, Shea JA. Understanding the leaky pipeline: perceived barriers to pursuing a career in medicine or dentistry among underrepresented-in-medicine undergraduate students. Acad Med. 2016;91(7):987–993.View this article via: PubMedCrossRefGoogle Scholar Grace MK. Parting ways: sex-based differences in premedical attrition. Soc Sci Med. 2019;230:222–233.View this article via: PubMedCrossRefGoogle Scholar Ahn J, Watt CD, Man LX, Greeley SA, Shea JA. Educating future leaders of medical research: analysis of student opinions and goals from the MD-PhD SAGE (Students’ Attitudes, Goals, and Education) survey. Acad Med. 2007;82(7):633–645.View this article via: PubMedCrossRefGoogle Scholar Association of American Medical Colleges. Table B-10: MCAT Scores and GPAs for MD-PhD Applicants and Matriculants to U.S. Medical Schools, 2016-2017 through 2018-2019. http://www.aamc.org/download/321548/data/factstableb10.pdf Updated November 27, 2019. Accessed November 11, 2019. Jeffe DB, Andriole DA, Wathington HD, Tai RH. The emerging physician-scientist workforce: demographic, experiential, and attitudinal predictors of MD-PhD program enrollment. Acad Med. 2014;89(10):1398–1407.View this article via: PubMedCrossRefGoogle Scholar Bowen CJ, Kersbergen CJ, Tang O, Cox A, Beach MC. Medical school research ranking is associated with gender inequality in MSTP application rates. BMC Med Educ. 2018;18(1):187. View this article via: PubMedCrossRefGoogle Scholar Brookfield SD. The Skillful Teacher. 3rd ed. San Francisco, California, USA: Jossey-Bass; 2015. Clance PR, Imes SA. The impostor phenomenon in high achieving women: dynamics and therapeutic intervention. Psychotherapy: Theory, Research and Practice. 1978;15(3):241–247.View this article via: CrossRefGoogle Scholar Sakulku J. The impostor phenomenon. The Journal of Behavioral Science. 2011;6(1):75–97. Hoang Q. The impostor phenomenon: overcoming internalized barriers and recognizing achievements. The Vermont Connection. 2013;34:42–51. Beasley MA. Why they leave: the impact of stereotype threat on the attrition of women and minorities from science, math and engineering majors. Social Psychology of Education. 2012;15(4):427–448.View this article via: CrossRefGoogle Scholar Witherspoon EB, Vincent-Ruz P, Schunn CD. When making the grade isn’t enough: the gendered nature of premed science course attrition. Educational Researcher. 2019;48(4):193–204.View this article via: CrossRefGoogle Scholar

    更新日期:2020-01-04
  • Integrative omics approaches provide biological and clinical insights: examples from mitochondrial diseases
    J. Clin. Invest. (IF 12.282) Pub Date : 2020-01-02
    Sofia Khan; Gulayse Ince-Dunn; Anu Suomalainen; Laura L. Elo

    High-throughput technologies for genomics, transcriptomics, proteomics, and metabolomics, and integrative analysis of these data, enable new, systems-level insights into disease pathogenesis. Mitochondrial diseases are an excellent target for hypothesis-generating omics approaches, as the disease group is mechanistically exceptionally complex. Although the genetic background in mitochondrial diseases is in either the nuclear or the mitochondrial genome, the typical downstream effect is dysfunction of the mitochondrial respiratory chain. However, the clinical manifestations show unprecedented variability, including either systemic or tissue-specific effects across multiple organ systems, with mild to severe symptoms, and occurring at any age. So far, the omics approaches have provided mechanistic understanding of tissue-specificity and potential treatment options for mitochondrial diseases, such as metabolome remodeling. However, no curative treatments exist, suggesting that novel approaches are needed. In this Review, we discuss omics approaches and discoveries with the potential to elucidate mechanisms of and therapies for mitochondrial diseases.

    更新日期:2020-01-04
  • The application of big data to cardiovascular disease: paths to precision medicine
    J. Clin. Invest. (IF 12.282) Pub Date : 2020-01-02
    Jane A. Leopold; Bradley A. Maron; Joseph Loscalzo

    Advanced phenotyping of cardiovascular diseases has evolved with the application of high-resolution omics screening to populations enrolled in large-scale observational and clinical trials. This strategy has revealed that considerable heterogeneity exists at the genotype, endophenotype, and clinical phenotype levels in cardiovascular diseases, a feature of the most common diseases that has not been elucidated by conventional reductionism. In this discussion, we address genomic context and (endo)phenotypic heterogeneity, and examine commonly encountered cardiovascular diseases to illustrate the genotypic underpinnings of (endo)phenotypic diversity. We highlight the existing challenges in cardiovascular disease genotyping and phenotyping that can be addressed by the integration of big data and interpreted using novel analytical methodologies (network analysis). Precision cardiovascular medicine will only be broadly applied to cardiovascular patients once this comprehensive data set is subjected to unique, integrative analytical strategies that accommodate molecular and clinical heterogeneity rather than ignore or reduce it.

    更新日期:2020-01-04
  • It’s about time: clocks in the developing lung
    J. Clin. Invest. (IF 12.282) Pub Date : 2020-01-02
    Colleen M. Bartman; Aleksey Matveyenko; Y.S. Prakash

    The discovery of peripheral intracellular clocks revealed circadian oscillations of clock genes and their targets in all cell types, including those in the lung, sparking exploration of clocks in lung disease pathophysiology. While the focus has been on the role of these clocks in adult airway diseases, clock biology is also likely to be important in perinatal lung development, where it has received far less attention. Historically, fetal circadian rhythms have been considered irrelevant owing to lack of external light exposure, but more recent insights into peripheral clock biology raise questions of clock emergence, its concordance with tissue-specific structure/function, the interdependence of clock synchrony and functionality in perinatal lung development, and the possibility of lung clocks in priming the fetus for postnatal life. Understanding the perinatal molecular clock may unravel mechanistic targets for chronic airway disease across the lifespan. With current research providing more questions than answers, it is about time to investigate clocks in the developing lung.

    更新日期:2020-01-04
  • Time to dissect the autoimmune etiology of cancer antibody immunotherapy
    J. Clin. Invest. (IF 12.282) Pub Date : 2020-01-02
    Michael Dougan; Massimo Pietropaolo

    Immunotherapy has transformed the treatment landscape for a wide range of human cancers. Immune checkpoint inhibitors (ICIs), monoclonal antibodies that block the immune-regulatory “checkpoint” receptors CTLA-4, PD-1, or its ligand PD-L1, can produce durable responses in some patients. However, coupled with their success, these treatments commonly evoke a wide range of immune-related adverse events (irAEs) that can affect any organ system and can be treatment-limiting and life-threatening, such as diabetic ketoacidosis, which appears to be more frequent than initially described. The majority of irAEs from checkpoint blockade involve either barrier tissues (e.g., gastrointestinal mucosa or skin) or endocrine organs, although any organ system can be affected. Often, irAEs resemble spontaneous autoimmune diseases, such as inflammatory bowel disease, autoimmune thyroid disease, type 1 diabetes mellitus (T1D), and autoimmune pancreatitis. Yet whether similar molecular or pathologic mechanisms underlie these apparent autoimmune adverse events and classical autoimmune diseases is presently unknown. Interestingly, evidence links HLA alleles associated with high risk for autoimmune disease with ICI-induced T1D and colitis. Understanding the genetic risks and immunologic mechanisms driving ICI-mediated inflammatory toxicities may not only identify therapeutic targets useful for managing irAEs, but may also provide new insights into the pathoetiology and treatment of autoimmune diseases.

    更新日期:2020-01-04
  • SSBP1 faux pas in mitonuclear tango causes optic neuropathy
    J. Clin. Invest. (IF 12.282) Pub Date : 2019-11-18
    Lina Zelinger; Anand Swaroop

    Mitochondrial dysfunction or loss is evident in neurodegenerative diseases. Furthermore, mitochondrial DNA (mtDNA) mutations associated with NADH dehydrogenase subunits and nuclear gene mutations that affect mitochondrial function result in optic neuropathies. In this issue of the JCI, Del Dotto et al. and Piro-Mégy et al. identify heterozygous mutations in nuclear-encoded mitochondrial single-strand binding protein 1 (SSBP1) in patients with apparently dominant optic neuropathy with or without extraocular phenotypes. Both research groups reported similar mitochondrial findings in response to SSBP1 mutations. However, the specific SSBP1 mitochondria–associated function in retinal ganglion cells (RGCs) and the resulting optic nerve remains unclear. We suggest that high expression of SSBP1 during RGC differentiation is critical for mtDNA maintenance to produce appropriate optic nerve connectivity and that SSBP1 mutations in dominant optic atrophy patients do not permit stable binding to N6-methyldeoxyadenosine on the heavy strand involved with replication, leading to disruptions of mtDNA and, eventually, optic nerve dysfunction.

    更新日期:2020-01-04
  • Cellular heterogeneity in brown adipose tissue
    J. Clin. Invest. (IF 12.282) Pub Date : 2019-11-25
    Yasuo Oguri; Shingo Kajimura

    Brown adipose tissue (BAT) contains mitochondria-enriched thermogenic fat cells (brown adipocytes) that play a crucial role in the regulation of energy metabolism and systemic glucose homeostasis. It was presumed that brown adipocytes are composed of a homogeneous cell population. In this issue of the JCI, however, Song and colleagues report a previously uncharacterized subpopulation of brown adipocytes that display distinct characteristics from the conventional brown adipocytes in their molecular signature, regulation, and fuel utilization. The present study provides novel insight into our understanding of cellular heterogeneity in adipose tissues.

    更新日期:2020-01-04
  • Clonal enrichments of Vδ2– γδ T cells in Mycobacterium tuberculosis–infected human lungs
    J. Clin. Invest. (IF 12.282) Pub Date : 2019-11-25
    Corinna A. Kulicke; Deborah A. Lewinsohn; David M. Lewinsohn

    Unconventional T cell subsets, including donor-unrestricted T cells (DURTs) and γδ T cells, are promising new players in the treatment and prevention of infectious diseases. In this issue of the JCI, Ogongo et al. used T cell receptor (TCR) sequencing to characterize unconventional T cell subsets in surgical lung resections and blood from Mycobacterium tuberculosis–infected (Mtb-infected) individuals with and without HIV coinfection. The study revealed highly localized expansions of γδ T cell clonotypes not previously associated with the immune response to Mtb and demonstrates the power of high-throughput analysis of the TCR repertoire directly from infected tissue. The findings contribute to our understanding of tuberculosis control and have implications for the development of both therapeutic and vaccination strategies.

    更新日期:2020-01-04
  • Disrupting a converging metabolic target turns up the immunologic-heat in pancreatic tumors
    J. Clin. Invest. (IF 12.282) Pub Date : 2019-12-03
    Won Jin Ho; Elizabeth M. Jaffee

    Pancreatic ductal adenocarcinomas (PDACs) are classically immunologically cold tumors that have failed to demonstrate a significant response to immunotherapeutic strategies. This feature is attributed to both the immunosuppressive tumor microenvironment (TME) and limited immune cell access due to the surrounding stromal barrier, a histological hallmark of PDACs. In this issue of the JCI, Sharma et al. employ a broad glutamine antagonist, 6-diazo-5-oxo-l-norleucine (DON), to target a metabolic program that underlies both PDAC growth and hyaluronan production. Their findings describe an approach to converting the PDAC TME into a hot TME, thereby empowering immunotherapeutic strategies such as anti-PD1 therapy.

    更新日期:2020-01-04
  • Not all proteinuria is created equal
    J. Clin. Invest. (IF 12.282) Pub Date : 2019-12-03
    Andrew Beenken; Jonathan M. Barasch; Ali G. Gharavi

    Albuminuria acts as a marker of progressive chronic kidney disease and as an indicator for initiation of hypertension treatment via modulation of the renin-angiotensin-aldosterone system with angiotensin receptor blockers or angiotensin-converting enzyme inhibitors. However, the true significance of albuminuria has yet to be fully defined. Is it merely a marker of underlying pathophysiology, or does it play a causal role in the progression of kidney disease? The answer remains under debate. In this issue of the JCI, Bedin et al. used next-generation sequencing data to identify patients with chronic proteinuria who had biallelic variants in the cubilin gene (CUBN). Through investigation of these pathogenic mutations in CUBN, the authors have further illuminated the clinical implications of albuminuria.

    更新日期:2020-01-04
  • Chronic diarrhea, bile acids, and Clostridia
    J. Clin. Invest. (IF 12.282) Pub Date : 2019-12-09
    Julian R.F. Walters; Julian R. Marchesi

    Excessive fecal bile acid (BA) loss causes symptoms in a large proportion of people diagnosed with irritable bowel syndrome with diarrhea, a common functional bowel disorder. This BA diarrhea (BAD) results from increased hepatic synthesis of BAs, with impaired negative feedback regulation by the ileal hormone fibroblast growth factor 19 (FGF19). In this issue of the JCI, Zhao et al. investigated BA metabolism, including fecal BAs, serum BAs, and FGF19, in patients and controls. They identified associations between fecal bacterial BA metabolism and specific microbiota, especially Clostridium scindens. These findings have been tested in a mouse model using microbiota transplants and antibiotic treatment. This group of organisms has potential as a biomarker for BAD and to be a target for therapy.

    更新日期:2020-01-04
  • XMEN: welcome to the glycosphere
    J. Clin. Invest. (IF 12.282) Pub Date : 2019-12-09
    Hudson H. Freeze

    XMEN (X-linked immunodeficiency with magnesium defect, EBV infection, and neoplasia) is a complex primary immunological deficiency caused by mutations in MAGT1, a putative magnesium transporter. In this issue of the JCI, Ravell et al. greatly expand the clinical picture. The authors investigated patients’ mutations and symptoms and reported distinguishing immunophenotypes. They also showed that MAGT1 is required for N-glycosylation of key T cell and NK cell receptors that can account for some of the clinical features. Notably, transfection of the affected lymphocytes with MAGT1 mRNA restored both N-glycosylation and receptor function. Now we can add XMEN to the ever-growing family of congenital disorders of glycosylation (CDG).

    更新日期:2020-01-04
  • Chemogenetic activation of adrenocortical Gq signaling causes hyperaldosteronism and disrupts functional zonation
    J. Clin. Invest. (IF 12.282) Pub Date : 2019-11-18
    Matthew J. Taylor; Matthew R. Ullenbruch; Emily C. Frucci; Juilee Rege; Mark S. Ansorge; Celso E. Gomez-Sanchez; Salma Begum; Edward Laufer; David T. Breault; William E. Rainey

    The mineralocorticoid aldosterone is produced in the adrenal zona glomerulosa (ZG) under the control of the renin–angiotensin II (AngII) system. Primary aldosteronism (PA) results from renin-independent production of aldosterone and is a common cause of hypertension. PA is caused by dysregulated localization of the enzyme aldosterone synthase (Cyp11b2), which is normally restricted to the ZG. Cyp11b2 transcription and aldosterone production are predominantly regulated by AngII activation of the Gq signaling pathway. Here, we report the generation of transgenic mice with Gq-coupled designer receptors exclusively activated by designer drugs (DREADDs) specifically in the adrenal cortex. We show that adrenal-wide ligand activation of Gq DREADD receptors triggered disorganization of adrenal functional zonation, with induction of Cyp11b2 in glucocorticoid-producing zona fasciculata cells. This result was consistent with increased renin-independent aldosterone production and hypertension. All parameters were reversible following termination of DREADD-mediated Gq signaling. These findings demonstrate that Gq signaling is sufficient for adrenocortical aldosterone production and implicate this pathway in the determination of zone-specific steroid production within the adrenal cortex. This transgenic mouse also provides an inducible and reversible model of hyperaldosteronism to investigate PA therapeutics and the mechanisms leading to the damaging effects of aldosterone on the cardiovascular system.

    更新日期:2020-01-04
  • Apelin directs endothelial cell differentiation and vascular repair following immune-mediated injury
    J. Clin. Invest. (IF 12.282) Pub Date : 2019-11-18
    Andrew G. Masoud; Jiaxin Lin; Abul K. Azad; Maikel A. Farhan; Conrad Fischer; Lin F. Zhu; Hao Zhang; Banu Sis; Zamaneh Kassiri; Ronald B. Moore; Daniel Kim; Colin C. Anderson; John C. Vederas; Benjamin A. Adam; Gavin Y. Oudit; Allan G. Murray

    Sustained, indolent immune injury of the vasculature of a heart transplant limits long-term graft and recipient survival. This injury is mitigated by a poorly characterized, maladaptive repair response. Vascular endothelial cells respond to proangiogenic cues in the embryo by differentiation to specialized phenotypes, associated with expression of apelin. In the adult, the role of developmental proangiogenic cues in repair of the established vasculature is largely unknown. We found that human and minor histocompatibility–mismatched donor mouse heart allografts with alloimmune-mediated vasculopathy upregulated expression of apelin in arteries and myocardial microvessels. In vivo, loss of donor heart expression of apelin facilitated graft immune cell infiltration, blunted vascular repair, and worsened occlusive vasculopathy in mice. In vitro, an apelin receptor agonist analog elicited endothelial nitric oxide synthase activation to promote endothelial monolayer wound repair and reduce immune cell adhesion. Thus, apelin acted as an autocrine growth cue to sustain vascular repair and mitigate the effects of immune injury. Treatment with an apelin receptor agonist after vasculopathy was established markedly reduced progression of arterial occlusion in mice. Together, these initial data identify proangiogenic apelin as a key mediator of coronary vascular repair and a pharmacotherapeutic target for immune-mediated injury of the coronary vasculature.

    更新日期:2020-01-04
  • SSBP1 mutations cause mtDNA depletion underlying a complex optic atrophy disorder
    J. Clin. Invest. (IF 12.282) Pub Date : 2019-09-24
    Valentina Del Dotto; Farid Ullah; Ivano Di Meo; Pamela Magini; Mirjana Gusic; Alessandra Maresca; Leonardo Caporali; Flavia Palombo; Francesca Tagliavini; Evan Harris Baugh; Bertil Macao; Zsolt Szilagyi; Camille Peron; Margaret A. Gustafson; Kamal Khan; Chiara La Morgia; Piero Barboni; Michele Carbonelli; Maria Lucia Valentino; Rocco Liguori; Vandana Shashi; Jennifer Sullivan; Shashi Nagaraj; Mays El-Dairi; Alessandro Iannaccone; Ioana Cutcutache; Enrico Bertini; Rosalba Carrozzo; Francesco Emma; Francesca Diomedi-Camassei; Claudia Zanna; Martin Armstrong; Matthew Page; Nicholas Stong; Sylvia Boesch; Robert Kopajtich; Saskia Wortmann; Wolfgang Sperl; Erica E. Davis; William C. Copeland; Marco Seri; Maria Falkenberg; Holger Prokisch; Nicholas Katsanis; Valeria Tiranti; Tommaso Pippucci; Valerio Carelli

    Inherited optic neuropathies include complex phenotypes, mostly driven by mitochondrial dysfunction. We report an optic atrophy spectrum disorder, including retinal macular dystrophy and kidney insufficiency leading to transplantation, associated with mitochondrial DNA (mtDNA) depletion without accumulation of multiple deletions. By whole-exome sequencing, we identified mutations affecting the mitochondrial single-strand binding protein (SSBP1) in 4 families with dominant and 1 with recessive inheritance. We show that SSBP1 mutations in patient-derived fibroblasts variably affect the amount of SSBP1 protein and alter multimer formation, but not the binding to ssDNA. SSBP1 mutations impaired mtDNA, nucleoids, and 7S-DNA amounts as well as mtDNA replication, affecting replisome machinery. The variable mtDNA depletion in cells was reflected in severity of mitochondrial dysfunction, including respiratory efficiency, OXPHOS subunits, and complex amount and assembly. mtDNA depletion and cytochrome c oxidase–negative cells were found ex vivo in biopsies of affected tissues, such as kidney and skeletal muscle. Reduced efficiency of mtDNA replication was also reproduced in vitro, confirming the pathogenic mechanism. Furthermore, ssbp1 suppression in zebrafish induced signs of nephropathy and reduced optic nerve size, the latter phenotype complemented by WT mRNA but not by SSBP1 mutant transcripts. This previously unrecognized disease of mtDNA maintenance implicates SSBP1 mutations as a cause of human pathology.

    更新日期:2020-01-04
  • Extrahypothalamic GABAergic nociceptin–expressing neurons regulate AgRP neuron activity to control feeding behavior
    J. Clin. Invest. (IF 12.282) Pub Date : 2019-09-26
    Mark A. Smith; Agharul I. Choudhury; Justyna A. Glegola; Paulius Viskaitis; Elaine E. Irvine; Pedro Caldas Custodio de Campos Silva; Sanjay Khadayate; Hanns Ulrich Zeilhofer; Dominic J. Withers

    Arcuate nucleus agouti–related peptide (AgRP) neurons play a central role in feeding and are under complex regulation by both homeostatic hormonal and nutrient signals and hypothalamic neuronal pathways. Feeding may also be influenced by environmental cues, sensory inputs, and other behaviors, implying the involvement of higher brain regions. However, whether such pathways modulate feeding through direct synaptic control of AgRP neuron activity is unknown. Here, we show that nociceptin-expressing neurons in the anterior bed nuclei of the stria terminalis (aBNST) make direct GABAergic inputs onto AgRP neurons. We found that activation of these neurons inhibited AgRP neurons and feeding. The activity of these neurons increased upon food availability, and their ablation resulted in obesity. Furthermore, these neurons received afferent inputs from a range of upstream brain regions as well as hypothalamic nuclei. Therefore, aBNST GABAergic nociceptin neurons may act as a gateway to feeding behavior by connecting AgRP neurons to both homeostatic and nonhomeostatic neuronal inputs.

    更新日期:2020-01-04
  • Dominant mutations in mtDNA maintenance gene SSBP1 cause optic atrophy and foveopathy
    J. Clin. Invest. (IF 12.282) Pub Date : 2019-09-24
    Camille Piro-Mégy; Emmanuelle Sarzi; Aleix Tarrés-Solé; Marie Péquignot; Fenna Hensen; Mélanie Quilès; Gaël Manes; Arka Chakraborty; Audrey Sénéchal; Béatrice Bocquet; Chantal Cazevieille; Agathe Roubertie; Agnès Müller; Majida Charif; David Goudenège; Guy Lenaers; Helmut Wilhelm; Ulrich Kellner; Nicole Weisschuh; Bernd Wissinger; Xavier Zanlonghi; Christian Hamel; Johannes N. Spelbrink; Maria Sola; Cécile Delettre

    Mutations in genes encoding components of the mitochondrial DNA (mtDNA) replication machinery cause mtDNA depletion syndromes (MDSs), which associate ocular features with severe neurological syndromes. Here, we identified heterozygous missense mutations in single-strand binding protein 1 (SSBP1) in 5 unrelated families, leading to the R38Q and R107Q amino acid changes in the mitochondrial single-stranded DNA-binding protein, a crucial protein involved in mtDNA replication. All affected individuals presented optic atrophy, associated with foveopathy in half of the cases. To uncover the structural features underlying SSBP1 mutations, we determined a revised SSBP1 crystal structure. Structural analysis suggested that both mutations affect dimer interactions and presumably distort the DNA-binding region. Using patient fibroblasts, we validated that the R38Q variant destabilizes SSBP1 dimer/tetramer formation, affects mtDNA replication, and induces mtDNA depletion. Our study showing that mutations in SSBP1 cause a form of dominant optic atrophy frequently accompanied with foveopathy brings insights into mtDNA maintenance disorders.

    更新日期:2020-01-04
  • Epithelial membrane protein 2 governs transepithelial migration of neutrophils into the airspace
    J. Clin. Invest. (IF 12.282) Pub Date : 2019-09-24
    Wan-Chi Lin; Kymberly M. Gowdy; Jennifer H. Madenspacher; Rachel L. Zemans; Kazuko Yamamoto; Miranda Lyons-Cohen; Hideki Nakano; Kyathanahalli Janardhan; Carmen J. Williams; Donald N. Cook; Joseph P. Mizgerd; Michael B. Fessler

    Whether respiratory epithelial cells regulate the final transit of extravasated neutrophils into the inflamed airspace or are a passive barrier is poorly understood. Alveolar epithelial type 1 (AT1) cells, best known for solute transport and gas exchange, have few established immune roles. Epithelial membrane protein 2 (EMP2), a tetraspan protein that promotes recruitment of integrins to lipid rafts, is highly expressed in AT1 cells but has no known function in lung biology. Here, we show that Emp2–/– mice exhibit reduced neutrophil influx into the airspace after a wide range of inhaled exposures. During bacterial pneumonia, Emp2–/– mice had attenuated neutrophilic lung injury and improved survival. Bone marrow chimeras, intravital neutrophil labeling, and in vitro assays suggested that defective transepithelial migration of neutrophils into the alveolar lumen occurs in Emp2–/– lungs. Emp2–/– AT1 cells had dysregulated surface display of multiple adhesion molecules, associated with reduced raft abundance. Epithelial raft abundance was dependent upon putative cholesterol-binding motifs in EMP2, whereas EMP2 supported adhesion molecule display and neutrophil transmigration through suppression of caveolins. Taken together, we propose that EMP2-dependent membrane organization ensures proper display on AT1 cells of a suite of proteins required to instruct paracellular neutrophil traffic into the alveolus.

    更新日期:2020-01-04
  • BubR1 allelic effects drive phenotypic heterogeneity in mosaic-variegated aneuploidy progeria syndrome
    J. Clin. Invest. (IF 12.282) Pub Date : 2019-11-18
    Cynthia J. Sieben; Karthik B. Jeganathan; Grace G. Nelson; Ines Sturmlechner; Cheng Zhang; Willemijn H. van Deursen; Bjorn Bakker; Floris Foijer; Hu Li; Darren J. Baker; Jan M. van Deursen

    Mosaic-variegated aneuploidy (MVA) syndrome is a rare childhood disorder characterized by biallelic BUBR1, CEP57, or TRIP13 aberrations; increased chromosome missegregation; and a broad spectrum of clinical features, including various cancers, congenital defects, and progeroid pathologies. To investigate the mechanisms underlying this disorder and its phenotypic heterogeneity, we mimicked the BUBR1L1012P mutation in mice (BubR1L1002P) and combined it with 2 other MVA variants, BUBR1X753 and BUBR1H, generating a truncated protein and low amounts of wild-type protein, respectively. Whereas BubR1X753/L1002P and BubR1H/X753 mice died prematurely, BubR1H/L1002P mice were viable and exhibited many MVA features, including cancer predisposition and various progeroid phenotypes, such as short lifespan, dwarfism, lipodystrophy, sarcopenia, and low cardiac stress tolerance. Strikingly, although these mice had a reduction in total BUBR1 and spectrum of MVA phenotypes similar to that of BubR1H/H mice, several progeroid pathologies were attenuated in severity, which in skeletal muscle coincided with reduced senescence-associated secretory phenotype complexity. Additionally, mice carrying monoallelic BubR1 mutations were prone to select MVA-related pathologies later in life, with predisposition to sarcopenia correlating with mTORC1 hyperactivity. Together, these data demonstrate that BUBR1 allelic effects beyond protein level and aneuploidy contribute to disease heterogeneity in both MVA patients and heterozygous carriers of MVA mutations.

    更新日期:2020-01-04
  • Trypsin activity governs increased susceptibility to pancreatitis in mice expressing human PRSS1R122H
    J. Clin. Invest. (IF 12.282) Pub Date : 2019-09-24
    Fu Gui; Yuebo Zhang; Jianhua Wan; Xianbao Zhan; Yao Yao; Yinghua Li; Ashley N. Haddock; Ji Shi; Jia Guo; Jiaxiang Chen; Xiaohui Zhu; Brandy H. Edenfield; Lu Zhuang; Cheng Hu; Ying Wang; Debabrata Mukhopadhyay; Evette S. Radisky; Lizhi Zhang; Aurelia Lugea; Stephen J. Pandol; Yan Bi; Baoan Ji

    Currently, an effective targeted therapy for pancreatitis is lacking. Hereditary pancreatitis (HP) is a heritable, autosomal-dominant disorder with recurrent acute pancreatitis (AP) progressing to chronic pancreatitis (CP) and a markedly increased risk of pancreatic cancer. In 1996, mutations in PRSS1 were linked to the development of HP. Here, we developed a mouse model by inserting a full-length human PRSS1R122H gene, the most commonly mutated gene in human HP, into mice. Expression of PRSS1R122H protein in the pancreas markedly increased stress signaling pathways and exacerbated AP. After the attack of AP, all PRSS1R122H mice had disease progression to CP, with similar histologic features as those observed in human HP. By comparing PRSS1R122H mice with PRSS1WT mice, as well as enzymatically inactivated Dead-PRSS1R122H mice, we unraveled that increased trypsin activity is the mechanism for R122H mutation to sensitize mice to the development of pancreatitis. We further discovered that trypsin inhibition, in combination with anticoagulation therapy, synergistically prevented progression to CP in PRSS1R122H mice. These animal models help us better understand the complex nature of this disease and provide powerful tools for developing and testing novel therapeutics for human pancreatitis.

    更新日期:2020-01-04
  • Myelin-specific CD8+ T cells exacerbate brain inflammation in CNS autoimmunity
    J. Clin. Invest. (IF 12.282) Pub Date : 2019-10-01
    Catriona A. Wagner; Pamela J. Roqué; Trevor R. Mileur; Denny Liggitt; Joan M. Goverman

    Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the CNS. Although CD4+ T cells are implicated in MS pathogenesis and have been the main focus of MS research using the animal model experimental autoimmune encephalomyelitis (EAE), substantial evidence from patients with MS points to a role for CD8+ T cells in disease pathogenesis. We previously showed that an MHC class I–restricted epitope of myelin basic protein (MBP) is presented in the CNS during CD4+ T cell–initiated EAE. Here, we investigated whether naive MBP-specific CD8+ T cells recruited to the CNS during CD4+ T cell–initiated EAE engaged in determinant spreading and influenced disease. We found that the MBP-specific CD8+ T cells exacerbated brain but not spinal cord inflammation. We show that a higher frequency of monocytes and monocyte-derived cells presented the MHC class I–restricted MBP ligand in the brain compared with the spinal cord. Infiltration of MBP-specific CD8+ T cells enhanced ROS production in the brain only in these cell types and only when the MBP-specific CD8+ T cells expressed Fas ligand (FasL). These results suggest that myelin-specific CD8+ T cells may contribute to disease pathogenesis via a FasL-dependent mechanism that preferentially promotes lesion formation in the brain.

    更新日期:2020-01-04
  • Differential skewing of donor-unrestricted and γδ T cell repertoires in tuberculosis-infected human lungs
    J. Clin. Invest. (IF 12.282) Pub Date : 2019-11-25
    Paul Ogongo; Adrie J.C. Steyn; Farina Karim; Kaylesh J. Dullabh; Ismael Awala; Rajhmun Madansein; Alasdair Leslie; Samuel M. Behar

    Unconventional T cells that recognize mycobacterial antigens are of great interest as potential vaccine targets against tuberculosis (TB). This includes donor-unrestricted T cells (DURTs), such as mucosa-associated invariant T cells (MAITs), CD1-restricted T cells, and γδ T cells. We exploited the distinctive nature of DURTs and γδ T cell receptors (TCRs) to investigate the involvement of these T cells during TB in the human lung by global TCR sequencing. Making use of surgical lung resections, we investigated the distribution, frequency, and characteristics of TCRs in lung tissue and matched blood from individuals infected with TB. Despite depletion of MAITs and certain CD1-restricted T cells from the blood, we found that the DURT repertoire was well preserved in the lungs, irrespective of disease status or HIV coinfection. The TCRδ repertoire, in contrast, was highly skewed in the lungs, where it was dominated by Vδ1 and distinguished by highly localized clonal expansions, consistent with the nonrecirculating lung-resident γδ T cell population. These data show that repertoire sequencing is a powerful tool for tracking T cell subsets during disease.

    更新日期:2020-01-04
  • Deregulating MYC in a model of HER2+ breast cancer mimics human intertumoral heterogeneity
    J. Clin. Invest. (IF 12.282) Pub Date : 2019-11-25
    Tyler Risom; Xiaoyan Wang; Juan Liang; Xiaoli Zhang; Carl Pelz; Lydia G. Campbell; Jenny Eng; Koei Chin; Caroline Farrington; Goutham Narla; Ellen M. Langer; Xiao-Xin Sun; Yulong Su; Colin J. Daniel; Mu-Shui Dai; Christiane V. Löhr; Rosalie C. Sears

    The c-MYC (MYC) oncoprotein is often overexpressed in human breast cancer; however, its role in driving disease phenotypes is poorly understood. Here, we investigate the role of MYC in HER2+ disease, examining the relationship between HER2 expression and MYC phosphorylation in HER2+ patient tumors and characterizing the functional effects of deregulating MYC expression in the murine NeuNT model of amplified-HER2 breast cancer. Deregulated MYC alone was not tumorigenic, but coexpression with NeuNT resulted in increased MYC Ser62 phosphorylation and accelerated tumorigenesis. The resulting tumors were metastatic and associated with decreased survival compared with NeuNT alone. MYC;NeuNT tumors had increased intertumoral heterogeneity including a subtype of tumors not observed in NeuNT tumors, which showed distinct metaplastic histology and worse survival. The distinct subtypes of MYC;NeuNT tumors match existing subtypes of amplified-HER2, estrogen receptor–negative human tumors by molecular expression, identifying the preclinical utility of this murine model to interrogate subtype-specific differences in amplified-HER2 breast cancer. We show that these subtypes have differential sensitivity to clinical HER2/EGFR–targeted therapeutics, but small-molecule activators of PP2A, the phosphatase that regulates MYC Ser62 phosphorylation, circumvents these subtype-specific differences and ubiquitously suppresses tumor growth, demonstrating the therapeutic utility of this approach in targeting deregulated MYC breast cancers.

    更新日期:2020-01-04
  • Low- and high-thermogenic brown adipocyte subpopulations coexist in murine adipose tissue
    J. Clin. Invest. (IF 12.282) Pub Date : 2019-10-01
    Anying Song; Wenting Dai; Min Jee Jang; Leonard Medrano; Zhuo Li; Hu Zhao; Mengle Shao; Jiayi Tan; Aimin Li; Tinglu Ning; Marcia M. Miller; Brian Armstrong; Janice M. Huss; Yi Zhu; Yong Liu; Viviana Gradinaru; Xiwei Wu; Lei Jiang; Philipp E. Scherer; Qiong A. Wang

    Brown adipose tissue (BAT), as the main site of adaptive thermogenesis, exerts beneficial metabolic effects on obesity and insulin resistance. BAT has been previously assumed to contain a homogeneous population of brown adipocytes. Utilizing multiple mouse models capable of genetically labeling different cellular populations, as well as single-cell RNA sequencing and 3D tissue profiling, we discovered a brown adipocyte subpopulation with low thermogenic activity coexisting with the classical high-thermogenic brown adipocytes within the BAT. Compared with the high-thermogenic brown adipocytes, these low-thermogenic brown adipocytes had substantially lower Ucp1 and Adipoq expression, larger lipid droplets, and lower mitochondrial content. Functional analyses showed that, unlike the high-thermogenic brown adipocytes, the low-thermogenic brown adipocytes have markedly lower basal mitochondrial respiration, and they are specialized in fatty acid uptake. Upon changes in environmental temperature, the 2 brown adipocyte subpopulations underwent dynamic interconversions. Cold exposure converted low-thermogenic brown adipocytes into high-thermogenic cells. A thermoneutral environment had the opposite effect. The recruitment of high-thermogenic brown adipocytes by cold stimulation is not affected by high-fat diet feeding, but it does substantially decline with age. Our results revealed a high degree of functional heterogeneity of brown adipocytes.

    更新日期:2020-01-04
  • Selective DNA-PKcs inhibition extends the therapeutic index of localized radiotherapy and chemotherapy
    J. Clin. Invest. (IF 12.282) Pub Date : 2019-10-03
    Catherine E. Willoughby; Yanyan Jiang; Huw D. Thomas; Elaine Willmore; Suzanne Kyle; Anita Wittner; Nicole Phillips; Yan Zhao; Susan J. Tudhope; Lisa Prendergast; Gesa Junge; Luiza Madia Lourenco; M. Raymond V. Finlay; Paul Turner; Joanne M. Munck; Roger J. Griffin; Tommy Rennison; James Pickles; Celine Cano; David R. Newell; Helen L. Reeves; Anderson J. Ryan; Stephen R. Wedge

    Potentiating radiotherapy and chemotherapy by inhibiting DNA damage repair is proposed as a therapeutic strategy to improve outcomes for patients with solid tumors. However, this approach risks enhancing normal tissue toxicity as much as tumor toxicity, thereby limiting its translational impact. Using NU5455, a newly identified highly selective oral inhibitor of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) activity, we found that it was indeed possible to preferentially augment the effect of targeted radiotherapy on human orthotopic lung tumors without influencing acute DNA damage or a late radiation-induced toxicity (fibrosis) to normal mouse lung. Furthermore, while NU5455 administration increased both the efficacy and the toxicity of a parenterally administered topoisomerase inhibitor, it enhanced the activity of doxorubicin released locally in liver tumor xenografts without inducing any adverse effect. This strategy is particularly relevant to hepatocellular cancer, which is treated clinically with localized drug-eluting beads and for which DNA-PKcs activity is reported to confer resistance to treatment. We conclude that transient pharmacological inhibition of DNA-PKcs activity is effective and tolerable when combined with localized DNA-damaging therapies and thus has promising clinical potential.

    更新日期:2020-01-04
  • Increased expression of anion transporter SLC26A9 delays diabetes onset in cystic fibrosis
    J. Clin. Invest. (IF 12.282) Pub Date : 2019-10-03
    Anh-Thu N. Lam; Melis A. Aksit; Briana Vecchio-Pagan; Celeste A. Shelton; Derek L. Osorio; Arianna F. Anzmann; Loyal A. Goff; David C. Whitcomb; Scott M. Blackman; Garry R. Cutting

    Diabetes is a common complication of cystic fibrosis (CF) that affects approximately 20% of adolescents and 40%–50% of adults with CF. The age at onset of CF-related diabetes (CFRD) (marked by clinical diagnosis and treatment initiation) is an important measure of the disease process. DNA variants associated with age at onset of CFRD reside in and near SLC26A9. Deep sequencing of the SLC26A9 gene in 762 individuals with CF revealed that 2 common DNA haplotypes formed by the risk variants account for the association with diabetes. Single-cell RNA sequencing (scRNA-Seq) indicated that SLC26A9 is predominantly expressed in pancreatic ductal cells and frequently coexpressed with CF transmembrane conductance regulator (CFTR) along with transcription factors that have binding sites 5′ of SLC26A9. These findings were replicated upon reanalysis of scRNA-Seq data from 4 independent studies. DNA fragments derived from the 5′ region of SLC26A9-bearing variants from the low-risk haplotype generated 12%–20% higher levels of expression in PANC-1 and CFPAC-1 cells compared with the high- risk haplotype. Taken together, our findings indicate that an increase in SLC26A9 expression in ductal cells of the pancreas delays the age at onset of diabetes, suggesting a CFTR-agnostic treatment for a major complication of CF.

    更新日期:2020-01-04
  • Cross-dressed dendritic cells sustain effector T cell responses in islet and kidney allografts
    J. Clin. Invest. (IF 12.282) Pub Date : 2019-11-25
    Andrew D. Hughes; Daqiang Zhao; Hehua Dai; Khodor I. Abou-Daya; Roger Tieu; Rayan Rammal; Amanda L. Williams; Douglas P. Landsittel; Warren D. Shlomchik; Adrian E. Morelli; Martin H. Oberbarnscheidt; Fadi G. Lakkis

    Activation of host T cells that mediate allograft rejection is a 2-step process. The first occurs in secondary lymphoid organs where T cells encounter alloantigens presented by host DCs and differentiate to effectors. Antigen presentation at these sites occurs principally via transfer of intact, donor MHC-peptide complexes from graft cells to host DCs (cross-dressing) or by uptake and processing of donor antigens into allopeptides bound to self-MHC molecules (indirect presentation). The second step takes place in the graft, where effector T cells reengage with host DCs before causing rejection. How host DCs present alloantigens to T cells in the graft is not known. Using mouse islet and kidney transplantation models, imaging cytometry, and 2-photon intravital microscopy, we demonstrate extensive cross-dressing of intragraft host DCs with donor MHC-peptide complexes that occurred early after transplantation, whereas host DCs presenting donor antigen via the indirect pathway were rare. Cross-dressed DCs stably engaged TCR-transgenic effector CD8+ T cells that recognized donor antigen and were sufficient for sustaining acute rejection. In the chronic kidney rejection model, cross-dressing declined over time but was still conspicuous 8 weeks after transplantation. We conclude that cross-dressing of host DCs with donor MHC molecules is a major antigen presentation pathway driving effector T cell responses within allografts.

    更新日期:2020-01-04
  • Smooth muscle cell–specific fibronectin-EDA mediates phenotypic switching and neointimal hyperplasia
    J. Clin. Invest. (IF 12.282) Pub Date : 2019-11-25
    Manish Jain; Nirav Dhanesha; Prakash Doddapattar; Mehul R. Chorawala; Manasa K. Nayak; Anne Cornelissen; Liang Guo; Aloke V. Finn; Steven R. Lentz; Anil K. Chauhan

    Fibronectin–splice variant containing extra domain A (Fn-EDA) is associated with smooth muscle cells (SMCs) following vascular injury. The role of SMC-derived Fn-EDA in SMC phenotypic switching or its implication in neointimal hyperplasia remains unclear. Herein, using human coronary artery sections with a bare metal stent, we demonstrate the expression of Fn-EDA in the vicinity of SMC-rich neointima and peri-strut areas. In mice, Fn-EDA colocalizes with SMCs in the neointima of injured carotid arteries and promotes neointima formation in the comorbid condition of hyperlipidemia by potentiating SMC proliferation and migration. No sex-based differences were observed. Mechanistic studies suggested that Fn-EDA mediates integrin- and TLR4-dependent proliferation and migration through activation of FAK/Src and Akt1/mTOR signaling, respectively. Specific deletion of Fn-EDA in SMCs, but not in endothelial cells, reduced intimal hyperplasia and suppressed the SMC synthetic phenotype concomitant with decreased Akt1/mTOR signaling. Targeting Fn-EDA in human aortic SMCs suppressed the synthetic phenotype and downregulated Akt1/mTOR signaling. These results reveal that SMC-derived Fn-EDA potentiates phenotypic switching in human and mouse aortic SMCs and neointimal hyperplasia in the mouse. We suggest that targeting Fn-EDA could be explored as a potential therapeutic strategy to reduce neointimal hyperplasia.

    更新日期:2020-01-04
  • Chronic myeloid leukemia stem cells require cell-autonomous pleiotrophin signaling
    J. Clin. Invest. (IF 12.282) Pub Date : 2019-10-15
    Heather A. Himburg; Martina Roos; Tiancheng Fang; Yurun Zhang; Christina M. Termini; Lauren Schlussel; Mindy Kim; Amara Pang; Jenny Kan; Liman Zhao; Hyung Suh; Joshua P. Sasine; Gopal Sapparapu; Peter M. Bowers; Gary Schiller; John P. Chute

    Tyrosine kinase inhibitors (TKIs) induce molecular remission in the majority of patients with chronic myelogenous leukemia (CML), but the persistence of CML stem cells hinders cure and necessitates indefinite TKI therapy. We report that CML stem cells upregulate the expression of pleiotrophin (PTN) and require cell-autonomous PTN signaling for CML pathogenesis in BCR/ABL+ mice. Constitutive PTN deletion substantially reduced the numbers of CML stem cells capable of initiating CML in vivo. Hematopoietic cell–specific deletion of PTN suppressed CML development in BCR/ABL+ mice, suggesting that cell-autonomous PTN signaling was necessary for CML disease evolution. Mechanistically, PTN promoted CML stem cell survival and TKI resistance via induction of Jun and the unfolded protein response. Human CML cells were also dependent on cell-autonomous PTN signaling, and anti-PTN antibody suppressed human CML colony formation and CML repopulation in vivo. Our results suggest that targeted inhibition of PTN has therapeutic potential to eradicate CML stem cells.

    更新日期:2020-01-04
  • Epidermal hepcidin is required for neutrophil response to bacterial infection
    J. Clin. Invest. (IF 12.282) Pub Date : 2019-10-10
    Mariangela Malerba; Sabine Louis; Sylvain Cuvellier; Srikanth Mairpady Shambat; Camille Hua; Camille Gomart; Agnès Fouet; Nicolas Ortonne; Jean-Winoc Decousser; Annelies S. Zinkernagel; Jacques R.R. Mathieu; Carole Peyssonnaux

    Novel approaches for adjunctive therapy are urgently needed for complicated infections and patients with compromised immunity. Necrotizing fasciitis (NF) is a destructive skin and soft tissue infection. Despite treatment with systemic antibiotics and radical debridement of necrotic tissue, lethality remains high. The key iron regulatory hormone hepcidin was originally identified as a cationic antimicrobial peptide (AMP), but its putative expression and role in the skin, a major site of AMP production, have never been investigated. We report here that hepcidin production is induced in the skin of patients with group A Streptococcus (GAS) NF. In a GAS-induced NF model, mice lacking hepcidin in keratinocytes failed to restrict systemic spread of infection from an initial tissue focus. Unexpectedly, this effect was due to its ability to promote production of the CXCL1 chemokine by keratinocytes, resulting in neutrophil recruitment. Unlike CXCL1, hepcidin is resistant to degradation by major GAS proteases and could therefore serve as a reservoir to maintain steady-state levels of CXCL1 in infected tissue. Finally, injection of synthetic hepcidin at the site of infection can limit or completely prevent systemic spread of GAS infection, suggesting that hepcidin agonists could have a therapeutic role in NF.

    更新日期:2020-01-04
  • Human C-terminal CUBN variants associate with chronic proteinuria and normal renal function
    J. Clin. Invest. (IF 12.282) Pub Date : 2019-10-15
    Mathilda Bedin; Olivia Boyer; Aude Servais; Yong Li; Laure Villoing-Gaudé; Marie-Josephe Tête; Alexandra Cambier; Julien Hogan; Veronique Baudouin; Saoussen Krid; Albert Bensman; Florie Lammens; Ferielle Louillet; Bruno Ranchin; Cecile Vigneau; Iseline Bouteau; Corinne Isnard-Bagnis; Christoph J. Mache; Tobias Schäfer; Lars Pape; Markus Gödel; Tobias B. Huber; Marcus Benz; Günter Klaus; Matthias Hansen; Kay Latta; Olivier Gribouval; Vincent Morinière; Carole Tournant; Maik Grohmann; Elisa Kuhn; Timo Wagner; Christine Bole-Feysot; Fabienne Jabot-Hanin; Patrick Nitschké; Tarunveer S. Ahluwalia; Anna Köttgen; Christian Brix Folsted Andersen; Carsten Bergmann; Corinne Antignac; Matias Simons

    BACKGROUND. Proteinuria is considered an unfavorable clinical condition that accelerates renal and cardiovascular disease. However, it is not clear whether all forms of proteinuria are damaging. Mutations in CUBN cause Imerslund-Gräsbeck syndrome (IGS), which is characterized by intestinal malabsorption of vitamin B12 and in some cases proteinuria. CUBN encodes for cubilin, an intestinal and proximal tubular uptake receptor containing 27 CUB domains for ligand binding.

    更新日期:2020-01-04
  • Gabapentinoid treatment promotes corticospinal plasticity and regeneration following murine spinal cord injury
    J. Clin. Invest. (IF 12.282) Pub Date : 2019-12-03
    Wenjing Sun; Molly J.E. Larson; Conrad M. Kiyoshi; Alexander J. Annett; William A. Stalker; Juan Peng; Andrea Tedeschi

    Axon regeneration failure causes neurological deficits and long-term disability after spinal cord injury (SCI). Here, we found that the α2δ2 subunit of voltage-gated calcium channels negatively regulates axon growth and regeneration of corticospinal neurons, the cells that originate the corticospinal tract. Increased α2δ2 expression in corticospinal neurons contributed to loss of corticospinal regrowth ability during postnatal development and after SCI. In contrast, α2δ2 pharmacological blockade through gabapentin administration promoted corticospinal structural plasticity and regeneration in adulthood. Using an optogenetic strategy combined with in vivo electrophysiological recording, we demonstrated that regenerating corticospinal axons functionally integrate into spinal circuits. Mice administered gabapentin recovered upper extremity function after cervical SCI. Importantly, such recovery relies on reorganization of the corticospinal pathway, as chemogenetic silencing of injured corticospinal neurons transiently abrogated recovery. Thus, targeting α2δ2 with a clinically relevant treatment strategy aids repair of motor circuits after SCI.

    更新日期:2020-01-04
  • GPR101 mediates the pro-resolving actions of RvD5n-3 DPA in arthritis and infections
    J. Clin. Invest. (IF 12.282) Pub Date : 2019-12-03
    Magdalena B. Flak; Duco S. Koenis; Agua Sobrino; James Smith; Kimberly Pistorius; Francesco Palmas; Jesmond Dalli

    N-3 docosapentaenoic acid–derived resolvin D5 (RvD5n-3 DPA) is diurnally regulated in peripheral blood and exerts tissue-protective actions during inflammatory arthritis. Here, using an orphan GPCR screening approach coupled with functional readouts, we investigated the receptor(s) involved in mediating the leukocyte-directed actions of RvD5n-3 DPA and identified GPR101 as the top candidate. RvD5n-3 DPA bound to GPR101 with high selectivity and stereospecificity, as demonstrated by a calculated KD of approximately 6.9 nM. In macrophages, GPR101 knockdown limited the ability of RvD5n-3 DPA to upregulate cyclic adenosine monophosphate, phagocytosis of bacteria, and efferocytosis. Inhibition of this receptor in mouse and human leukocytes abrogated the pro-resolving actions of RvD5n-3 DPA, including the regulation of bacterial phagocytosis in neutrophils. Knockdown of the receptor in vivo reversed the protective actions of RvD5n-3 DPA in limiting joint and gut inflammation during inflammatory arthritis. Administration of RvD5n-3 DPA during E. coli–initiated inflammation regulated neutrophil trafficking to the site of inflammation, increased bacterial phagocytosis by neutrophils and macrophages, and accelerated the resolution of infectious inflammation. These in vivo protective actions of RvD5n-3 DPA were limited when Gpr101 was knocked down. Together, our findings demonstrate a fundamental role for GPR101 in mediating the leukocyte-directed actions of RvD5n-3 DPA.

    更新日期:2020-01-04
  • U3-1402 sensitizes HER3-expressing tumors to PD-1 blockade by immune activation
    J. Clin. Invest. (IF 12.282) Pub Date : 2019-10-29
    Koji Haratani; Kimio Yonesaka; Shiki Takamura; Osamu Maenishi; Ryoji Kato; Naoki Takegawa; Hisato Kawakami; Kaoru Tanaka; Hidetoshi Hayashi; Masayuki Takeda; Naoyuki Maeda; Takashi Kagari; Kenji Hirotani; Junji Tsurutani; Kazuto Nishio; Katsumi Doi; Masaaki Miyazawa; Kazuhiko Nakagawa

    Immunotherapy targeting programmed cell death-1 (PD-1) induces durable antitumor efficacy in many types of cancer. However, such clinical benefit is limited because of the insufficient reinvigoration of antitumor immunity with the drug alone; therefore, rational therapeutic combinations are required to improve its efficacy. In our preclinical study, we evaluated the antitumor effect of U3-1402, a human epidermal growth factor receptor 3–targeting (HER3–targeting) antibody-drug conjugate, and its potential synergism with PD-1 inhibition. Using a syngeneic mouse tumor model that is refractory to anti–PD-1 therapy, we found that treatment with U3-1402 exhibited an obvious antitumor effect via direct lysis of tumor cells. Disruption of tumor cells by U3-1402 enhanced the infiltration of innate and adaptive immune cells. Chemotherapy with exatecan derivative (Dxd, the drug payload of U3-1402) revealed that the enhanced antitumor immunity produced by U3-1402 was associated with the induction of alarmins, including high-mobility group box-1 (HMGB-1), via tumor-specific cytotoxicity. Notably, U3-1402 significantly sensitized the tumor to PD-1 blockade, as a combination of U3-1402 and the PD-1 inhibitor significantly enhanced antitumor immunity. Further, clinical analyses indicated that tumor-specific HER3 expression was frequently observed in patients with PD-1 inhibitor–resistant solid tumors. Overall, U3-1402 is a promising candidate as a partner of immunotherapy for such patients.

    更新日期:2020-01-04
  • Relief of tumor hypoxia unleashes the tumoricidal potential of neutrophils
    J. Clin. Invest. (IF 12.282) Pub Date : 2019-10-10
    Karim Mahiddine; Adam Blaisdell; Stephany Ma; Amandine Créquer-Grandhomme; Clifford A. Lowell; Adrian Erlebacher

    Polymorphonuclear neutrophils (PMNs) are increasingly recognized to influence solid tumor development, but why their effects are so context dependent and even frequently divergent remains poorly understood. Using an autochthonous mouse model of uterine cancer and the administration of respiratory hyperoxia as a means to improve tumor oxygenation, we provide in vivo evidence that hypoxia is a potent determinant of tumor-associated PMN phenotypes and direct PMN–tumor cell interactions. Upon relief of tumor hypoxia, PMNs were recruited less intensely to the tumor-bearing uterus, but the recruited cells much more effectively killed tumor cells, an activity our data moreover suggested was mediated via their production of NADPH oxidase–derived reactive oxygen species and MMP-9. Simultaneously, their ability to promote tumor cell proliferation, which appeared to be mediated via their production of neutrophil elastase, was rendered less effective. Relieving tumor hypoxia thus greatly improved net PMN-dependent tumor control, leading to a massive reduction in tumor burden. Remarkably, this outcome was T cell independent. Together, these findings identify key hypoxia-regulated molecular mechanisms through which PMNs directly induce tumor cell death and proliferation in vivo and suggest that the contrasting properties of PMNs in different tumor settings may in part reflect the effects of hypoxia on direct PMN–tumor cell interactions.

    更新日期:2020-01-04
  • Exosomal long noncoding RNA LNMAT2 promotes lymphatic metastasis in bladder cancer
    J. Clin. Invest. (IF 12.282) Pub Date : 2019-10-08
    Changhao Chen; Yuming Luo; Wang He; Yue Zhao; Yao Kong; Hongwei Liu; Guangzheng Zhong; Yuting Li; Jun Li; Jian Huang; Rufu Chen; Tianxin Lin

    Patients with bladder cancer (BCa) with clinical lymph node (LN) metastasis have an extremely poor prognosis. VEGF-C has been demonstrated to play vital roles in LN metastasis in BCa. However, approximately 20% of BCa with LN metastasis exhibits low VEGF-C expression, suggesting a VEGF-C–independent mechanism for LN metastasis of BCa. Herein, we demonstrate that BCa cell–secreted exosome-mediated lymphangiogenesis promoted LN metastasis in BCa in a VEGF-C–independent manner. We identified an exosomal long noncoding RNA (lncRNA), termed lymph node metastasis-associated transcript 2 (LNMAT2), that stimulated human lymphatic endothelial cell (HLEC) tube formation and migration in vitro and enhanced tumor lymphangiogenesis and LN metastasis in vivo. Mechanistically, LNMAT2 was loaded to BCa cell–secreted exosomes by directly interacting with heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1). Subsequently, exosomal LNMAT2 was internalized by HLECs and epigenetically upregulated prospero homeobox 1 (PROX1) expression by recruitment of hnRNPA2B1 and increasing the H3K4 trimethylation level in the PROX1 promoter, ultimately resulting in lymphangiogenesis and lymphatic metastasis. Therefore, our findings highlight a VEGF-C–independent mechanism of exosomal lncRNA-mediated LN metastasis and identify LNMAT2 as a therapeutic target for LN metastasis in BCa.

    更新日期:2020-01-04
  • Norepinephrine metabolite DOPEGAL activates AEP and pathological Tau aggregation in locus coeruleus
    J. Clin. Invest. (IF 12.282) Pub Date : 2019-12-03
    Seong Su Kang; Xia Liu; Eun Hee Ahn; Jie Xiang; Fredric P. Manfredsson; Xifei Yang; Hongbo R. Luo; L. Cameron Liles; David Weinshenker; Keqiang Ye

    Aberrant Tau inclusions in the locus coeruleus (LC) are the earliest detectable Alzheimer’s disease–like (AD-like) neuropathology in the human brain. However, why LC neurons are selectively vulnerable to developing early Tau pathology and degenerating later in disease and whether the LC might seed the stereotypical spread of Tau pathology to the rest of the brain remain unclear. Here, we show that 3,4-dihydroxyphenylglycolaldehyde, which is produced exclusively in noradrenergic neurons by monoamine oxidase A metabolism of norepinephrine, activated asparagine endopeptidase that cleaved Tau at residue N368 into aggregation- and propagation-prone forms, thus leading to LC degeneration and the spread of Tau pathology. Activation of asparagine endopeptidase–cleaved Tau aggregation in vitro and in intact cells was triggered by 3,4-dihydroxyphenylglycolaldehyde, resulting in LC neurotoxicity and propagation of pathology to the forebrain. Thus, our findings reveal that norepinephrine metabolism and Tau cleavage represent the specific molecular mechanism underlying the selective vulnerability of LC neurons in AD.

    更新日期:2020-01-04
  • A Clostridia-rich microbiota enhances bile acid excretion in diarrhea-predominant irritable bowel syndrome
    J. Clin. Invest. (IF 12.282) Pub Date : 2019-12-09
    Ling Zhao; Wei Yang; Yang Chen; Fengjie Huang; Lin Lu; Chengyuan Lin; Tao Huang; Ziwan Ning; Lixiang Zhai; Linda L.D. Zhong; Waiching Lam; Zhen Yang; Xuan Zhang; Chungwah Cheng; Lijuan Han; Qinwei Qiu; Xiaoxiao Shang; Runyue Huang; Haitao Xiao; Zhenxing Ren; Dongfeng Chen; Silong Sun; Hani El-Nezami; Zongwei Cai; Aiping Lu; Xiaodong Fang; Wei Jia; Zhaoxiang Bian

    An excess of fecal bile acids (BAs) is thought to be one of the mechanisms for diarrhea-predominant irritable bowel syndrome (IBS-D). However, the factors causing excessive BA excretion remain incompletely studied. Given the importance of gut microbiota in BA metabolism, we hypothesized that gut dysbiosis might contribute to excessive BA excretion in IBS-D. By performing BA-related metabolic and metagenomic analyses in 290 IBS-D patients and 89 healthy volunteers, we found that 24.5% of IBS-D patients exhibited excessive excretion of total BAs and alteration of BA-transforming bacteria in feces. Notably, the increase in Clostridia bacteria (e.g., C. scindens) was positively associated with the levels of fecal BAs and serum 7α-hydroxy-4-cholesten-3-one (C4), but negatively correlated with serum fibroblast growth factor 19 (FGF19) concentration. Furthermore, colonization with Clostridia-rich IBS-D fecal microbiota or C. scindens individually enhanced serum C4 and hepatic conjugated BAs but reduced ileal FGF19 expression in mice. Inhibition of Clostridium species with vancomycin yielded opposite results. Clostridia-derived BAs suppressed the intestinal FGF19 expression in vitro and in vivo. In conclusion, this study demonstrates that the Clostridia-rich microbiota contributes to excessive BA excretion in IBS-D patients, which provides a mechanistic hypothesis with testable clinical implications.

    更新日期:2020-01-04
  • Targeting tumor-intrinsic hexosamine biosynthesis sensitizes pancreatic cancer to anti-PD1 therapy
    J. Clin. Invest. (IF 12.282) Pub Date : 2019-10-15
    Nikita S. Sharma; Vineet K. Gupta; Vanessa T. Garrido; Roey Hadad; Brittany C. Durden; Kousik Kesh; Bhuwan Giri; Anthony Ferrantella; Vikas Dudeja; Ashok Saluja; Sulagna Banerjee

    Pancreatic ductal adenocarcinoma (PDAC) is considered to be a highly immunosuppressive and heterogenous neoplasm. Despite improved knowledge regarding the genetic background of the tumor and better understanding of the tumor microenvironment, immune checkpoint inhibitor therapy (targeting CTLA4, PD1, PDL1) has not been very successful against PDAC. The robust desmoplastic stroma, along with an extensive extracellular matrix (ECM) that is rich in hyaluronan, plays an integral role in this immune evasion. Hexosamine biosynthesis pathway (HBP), a shunt pathway of glycolysis, is a metabolic node in cancer cells that can promote survival pathways on the one hand and influence the hyaluronan synthesis in the ECM on the other. The rate-limiting enzyme of the pathway, glutamine-fructose amidotransferase 1 (GFAT1), uses glutamine and fructose 6-phosphate to eventually synthesize uridine diphosphate N-acetylglucosamine (UDP-GlcNAc). In the current manuscript, we targeted this glutamine-utilizing enzyme by a small molecule glutamine analog (6-diazo-5-oxo-l-norleucine [DON]). Our results showed that DON decreased the self-renewal potential and metastatic ability of tumor cells. Further, treatment with DON decreased hyaluronan and collagen in the tumor microenvironment, leading to an extensive remodeling of the ECM and an increased infiltration of CD8+ T cells. Additionally, treatment with DON sensitized pancreatic tumors to anti-PD1 therapy, resulting in tumor regression and prolonged survival.

    更新日期:2020-01-04
  • Gut microbiota modulate dendritic cell antigen presentation and radiotherapy-induced antitumor immune response
    J. Clin. Invest. (IF 12.282) Pub Date : 2019-12-09
    Mireia Uribe-Herranz; Stavros Rafail; Silvia Beghi; Luis Gil-de-Gómez; Ioannis Verginadis; Kyle Bittinger; Sergey Pustylnikov; Stefano Pierini; Renzo Perales-Linares; Ian A. Blair; Clementina A. Mesaros; Nathaniel W. Snyder; Frederic Bushman; Constantinos Koumenis; Andrea Facciabene

    Alterations in gut microbiota impact the pathophysiology of several diseases, including cancer. Radiotherapy (RT), an established curative and palliative cancer treatment, exerts potent immune modulatory effects, inducing tumor-associated antigen (TAA) cross-priming with antitumor CD8+ T cell elicitation and abscopal effects. We tested whether the gut microbiota modulates antitumor immune response following RT distal to the gut. Vancomycin, an antibiotic that acts mainly on gram-positive bacteria and is restricted to the gut, potentiated the RT-induced antitumor immune response and tumor growth inhibition. This synergy was dependent on TAA cross presentation to cytolytic CD8+ T cells and on IFN-γ. Notably, butyrate, a metabolite produced by the vancomycin-depleted gut bacteria, abrogated the vancomycin effect. In conclusion, depletion of vancomycin-sensitive bacteria enhances the antitumor activity of RT, which has important clinical ramifications.

    更新日期:2020-01-04
  • Autoreactive CD8+ T cell exhaustion distinguishes subjects with slow type 1 diabetes progression
    J. Clin. Invest. (IF 12.282) Pub Date : 2019-12-09
    Alice E. Wiedeman; Virginia S. Muir; Mario G. Rosasco; Hannah A. DeBerg; Scott Presnell; Bertrand Haas; Matthew J. Dufort; Cate Speake; Carla J. Greenbaum; Elisavet Serti; Gerald T. Nepom; Gabriele Blahnik; Anna M. Kus; Eddie A. James; Peter S. Linsley; S. Alice Long

    Although most patients with type 1 diabetes (T1D) retain some functional insulin-producing islet β cells at the time of diagnosis, the rate of further β cell loss varies across individuals. It is not clear what drives this differential progression rate. CD8+ T cells have been implicated in the autoimmune destruction of β cells. Here, we addressed whether the phenotype and function of autoreactive CD8+ T cells influence disease progression. We identified islet-specific CD8+ T cells using high-content, single-cell mass cytometry in combination with peptide-loaded MHC tetramer staining. We applied a new analytical method, DISCOV-R, to characterize these rare subsets. Autoreactive T cells were phenotypically heterogeneous, and their phenotype differed by rate of disease progression. Activated islet-specific CD8+ memory T cells were prevalent in subjects with T1D who experienced rapid loss of C-peptide; in contrast, slow disease progression was associated with an exhaustion-like profile, with expression of multiple inhibitory receptors, limited cytokine production, and reduced proliferative capacity. This relationship between properties of autoreactive CD8+ T cells and the rate of T1D disease progression after onset make these phenotypes attractive putative biomarkers of disease trajectory and treatment response and reveal potential targets for therapeutic intervention.

    更新日期:2020-01-04
  • Oral ferroportin inhibitor ameliorates ineffective erythropoiesis in a model of β-thalassemia
    J. Clin. Invest. (IF 12.282) Pub Date : 2019-10-22
    Vania Manolova; Naja Nyffenegger; Anna Flace; Patrick Altermatt; Ahmet Varol; Cédric Doucerain; Hanna Sundstrom; Franz Dürrenberger

    β-Thalassemia is a genetic anemia caused by partial or complete loss of β-globin synthesis, leading to ineffective erythropoiesis and RBCs with a short life span. Currently, there is no efficacious oral medication modifying anemia for patients with β-thalassemia. The inappropriately low levels of the iron regulatory hormone hepcidin enable excessive iron absorption by ferroportin, the unique cellular iron exporter in mammals, leading to organ iron overload and associated morbidities. Correction of unbalanced iron absorption and recycling by induction of hepcidin synthesis or treatment with hepcidin mimetics ameliorates β-thalassemia. However, hepcidin modulation or replacement strategies currently in clinical development all require parenteral drug administration. We identified oral ferroportin inhibitors by screening a library of small molecular weight compounds for modulators of ferroportin internalization. Restricting iron availability by VIT-2763, the first clinical stage oral ferroportin inhibitor, ameliorated anemia and the dysregulated iron homeostasis in the Hbbth3/+ mouse model of β-thalassemia intermedia. VIT-2763 not only improved erythropoiesis but also corrected the proportions of myeloid precursors in spleens of Hbbth3/+ mice. VIT-2763 is currently being developed as an oral drug targeting ferroportin for the treatment of β-thalassemia.

    更新日期:2020-01-04
  • Defective glycosylation and multisystem abnormalities characterize the primary immunodeficiency XMEN disease
    J. Clin. Invest. (IF 12.282) Pub Date : 2019-11-05
    Juan C. Ravell; Mami Matsuda-Lennikov; Samuel D. Chauvin; Juan Zou; Matthew Biancalana; Sally J. Deeb; Susan Price; Helen C. Su; Giulia Notarangelo; Ping Jiang; Aaron Morawski; Chrysi Kanellopoulou; Kyle Binder; Ratnadeep Mukherjee; James T. Anibal; Brian Sellers; Lixin Zheng; Tingyan He; Alex B. George; Stefania Pittaluga; Astin Powers; David E. Kleiner; Devika Kapuria; Marc Ghany; Sally Hunsberger; Jeffrey I. Cohen; Gulbu Uzel; Jenna Bergerson; Lynne Wolfe; Camilo Toro; William Gahl; Les R. Folio; Helen Matthews; Pam Angelus; Ivan K. Chinn; Jordan S. Orange; Claudia M. Trujillo-Vargas; Jose Luis Franco; Julio Orrego-Arango; Sebastian Gutiérrez-Hincapié; Niraj Chandrakant Patel; Kimiyo Raymond; Turkan Patiroglu; Ekrem Unal; Musa Karakukcu; Alexandre G.R. Day; Pankaj Mehta; Evan Masutani; Suk S. De Ravin; Harry L. Malech; Grégoire Altan-Bonnet; V. Koneti Rao; Matthias Mann; Michael J. Lenardo

    X-linked immunodeficiency with magnesium defect, EBV infection, and neoplasia (XMEN) disease are caused by deficiency of the magnesium transporter 1 (MAGT1) gene. We studied 23 patients with XMEN, 8 of whom were EBV naive. We observed lymphadenopathy (LAD), cytopenias, liver disease, cavum septum pellucidum (CSP), and increased CD4–CD8–B220–TCRαβ+ T cells (αβDNTs), in addition to the previously described features of an inverted CD4/CD8 ratio, CD4+ T lymphocytopenia, increased B cells, dysgammaglobulinemia, and decreased expression of the natural killer group 2, member D (NKG2D) receptor. EBV-associated B cell malignancies occurred frequently in EBV-infected patients. We studied patients with XMEN and patients with autoimmune lymphoproliferative syndrome (ALPS) by deep immunophenotyping (32 immune markers) using time-of-flight mass cytometry (CyTOF). Our analysis revealed that the abundance of 2 populations of naive B cells (CD20+CD27–CD22+IgM+HLA-DR+CXCR5+CXCR4++CD10+CD38+ and CD20+CD27–CD22+IgM+HLA-DR+CXCR5+CXCR4+CD10–CD38–) could differentially classify XMEN, ALPS, and healthy individuals. We also performed glycoproteomics analysis on T lymphocytes and show that XMEN disease is a congenital disorder of glycosylation that affects a restricted subset of glycoproteins. Transfection of MAGT1 mRNA enabled us to rescue proteins with defective glycosylation. Together, these data provide new clinical and pathophysiological foundations with important ramifications for the diagnosis and treatment of XMEN disease.

    更新日期:2020-01-04
  • Epitope-specific airway-resident CD4+ T cell dynamics during experimental human RSV infection
    J. Clin. Invest. (IF 12.282) Pub Date : 2019-12-09
    Aleks Guvenel; Agnieszka Jozwik; Stephanie Ascough; Seng Kuong Ung; Suzanna Paterson; Mohini Kalyan; Zoe Gardener; Emma Bergstrom; Satwik Kar; Maximillian S. Habibi; Allan Paras; Jie Zhu; Mirae Park; Jaideep Dhariwal; Mark Almond; Ernie H.C. Wong; Annemarie Sykes; Jerico Del Rosario; Maria-Belen Trujillo-Torralbo; Patrick Mallia; John Sidney; Bjoern Peters; Onn Min Kon; Alessandro Sette; Sebastian L. Johnston; Peter J. Openshaw; Christopher Chiu

    BACKGROUND. Respiratory syncytial virus (RSV) is an important cause of acute pulmonary disease and one of the last remaining major infections of childhood for which there is no vaccine. CD4+ T cells play a key role in antiviral immunity, but they have been little studied in the human lung.

    更新日期:2020-01-04
  • Quadrivalent VesiculoVax vaccine protects nonhuman primates from viral-induced hemorrhagic fever and death
    J. Clin. Invest. (IF 12.282) Pub Date : 2019-10-22
    Robert W. Cross; Rong Xu; Demetrius Matassov; Stefan Hamm; Theresa E. Latham; Cheryl S. Gerardi; Rebecca M. Nowak; Joan B. Geisbert; Ayuko Ota-Setlik; Krystle N. Agans; Amara Luckay; Susan E. Witko; Lena Soukieh; Daniel J. Deer; Chad E. Mire; Heinz Feldmann; Christian Happi; Karla A. Fenton; John H. Eldridge; Thomas W. Geisbert

    Recent occurrences of filoviruses and the arenavirus Lassa virus (LASV) in overlapping endemic areas of Africa highlight the need for a prophylactic vaccine that would confer protection against all of these viruses that cause lethal hemorrhagic fever (HF). We developed a quadrivalent formulation of VesiculoVax that contains recombinant vesicular stomatitis virus (rVSV) vectors expressing filovirus glycoproteins and that also contains a rVSV vector expressing the glycoprotein of a lineage IV strain of LASV. Cynomolgus macaques were vaccinated twice with the quadrivalent formulation, followed by challenge 28 days after the boost vaccination with each of the 3 corresponding filoviruses (Ebola, Sudan, Marburg) or a heterologous contemporary lineage II strain of LASV. Serum IgG and neutralizing antibody responses specific for all 4 glycoproteins were detected in all vaccinated animals. A modest and balanced cell-mediated immune response specific for the glycoproteins was also detected in most of the vaccinated macaques. Regardless of the level of total glycoprotein-specific immune response detected after vaccination, all immunized animals were protected from disease and death following lethal challenges. These findings indicate that vaccination with attenuated rVSV vectors each expressing a single HF virus glycoprotein may provide protection against those filoviruses and LASV most commonly responsible for outbreaks of severe HF in Africa.

    更新日期:2020-01-04
  • X-linked macrocytic dyserythropoietic anemia in females with an ALAS2 mutation
    J. Clin. Invest. (IF 12.282) Pub Date : 2020-01-02
    Vijay G. Sankaran; Jacob C. Ulirsch; Vassili Tchaikovskii; Leif S. Ludwig; Aoi Wakabayashi; Senkottuvelan Kadirvel; R. Coleman Lindsley; Rafael Bejar; Jiahai Shi; Scott B. Lovitch; David F. Bishop; David P. Steensma

    X-linked macrocytic dyserythropoietic anemia in females with an ALAS2 mutation Vijay G. Sankaran, … , David F. Bishop, David P. Steensma Vijay G. Sankaran, … , David F. Bishop, David P. Steensma Categories: Brief Report Hematology

    更新日期:2020-01-04
  • Human α1 type IV collagen NC1 domain exhibits distinct antiangiogenic activity mediated by α1β1 integrin
    J. Clin. Invest. (IF 12.282) Pub Date : 2020-01-02
    Akulapalli Sudhakar; Pia Nyberg; Venkateshwar G. Keshamouni; Arjuna P. Mannam; Jian Li; Hikaru Sugimoto; Dominic Cosgrove; Raghu Kalluri

    Human α1 type IV collagen NC1 domain exhibits distinct antiangiogenic activity mediated by α1β1 integrin Akulapalli Sudhakar, … , Dominic Cosgrove, Raghu Kalluri Akulapalli Sudhakar, … , Dominic Cosgrove, Raghu Kalluri Categories: Research Article Angiogenesis

    更新日期:2020-01-04
  • Diversification in the medical sciences fuels growth of physician-scientists
    J. Clin. Invest. (IF 12.282) Pub Date : 2019-11-20
    John M. Carethers

    Introduction It has been a privilege and pleasure to serve as the 2018–2019 president of the Association of American Physicians (AAP). This venerable organization was founded October 10, 1885, by William Osler (president, 1895), William Pepper (president, 1891), William Draper (president, 1888), Francis Delafield (president, 1886), James Tyson (president, 1908), Robert Edes, and George Peabody, who was joined by William Welch (president, 1901) at the first meeting of this organization in Washington, D.C., in 1886 for the “advancement of scientific and practical medicine” (1). Under Linda Fried (president, 2016), the goals of the AAP were further articulated as to “inspire the full breadth of physician-led research across all fields of science related to medicine and health, and to build a community of physician scientists in support of the principle that objective science and evidence are essential foundations for improving patient care and the health of Americans” (1). Additional key goals of the AAP include elections honoring physicians who have made outstanding and enduring contributions to medical science across all spectrums of specialties and to holding an annual meeting in which to meet, interact, and exchange information. The AAP now has more than 2300 elected members, of which 1700 are active and 600 are emeritus (triggered by 75 or more years of age beginning in 2019), with 60 new members elected annually (moving to up to 70 new members in 2020). The AAP spawned the American Society for Clinical Investigation (ASCI) in 1907 and helped spawn the American Federation for Clinical Research (AFCR) in 1940. Beginning in 1940, trisociety meetings were held. In more recent years, the Joint Meeting programming is contributed by the AAP, the ASCI and the American Physician Scientists Association (APSA). All three societies have an entrenched vested interest in furthering the physician-scientist and the knowledge generated to continue to improve patient care (2). AAP and diversification The AAP has grown more diverse over time. As of 2019, there are now over 200 women members of the organization. At the leadership level, there have been 6 women AAP presidents: Helen Ranney (1985), Judith Swain (2007), Christine Seidman (2015), Linda Fried (2016), Serpil Erzurum (2017) and Mary Klotman (2019). There has now been one president from a historically underrepresented group (John Carethers, 2018). Further, the AAP has over 90 foreign members from 19 countries. Elected member specialties have also diversified. In the early days, members were largely internists with an interest in pathology who operated large practices. Early in the twentieth century, elected membership shifted towards full-time university physicians. By the 1930s, elected membership was being drawn from physicians conducting basic and clinical research. Over the past several decades, elected membership has moved to a wide variety of specialties that includes internal medicine, pathology, pediatrics, general surgery and its subspecialties, neurosurgery, orthopedic surgery, dermatology, otolaryngology, urology, emergency medicine, obstetrics/gynecology, ophthalmology, radiation oncology, neurology, psychiatry, anesthesiology, and others. AAP diversification has accelerated in recent times due to conscious evaluation of qualified individuals by an energetic AAP council. It has been my outstanding pleasure to work with such a talented group of individuals before, leading up to, and during my presidential year. Lori Ennis, AAP’s executive director, is the most facile person (ever) to keep AAP running strong. The 2018–2019 AAP Council consisted of Mary Klotman (infectious diseases), Mitch Lazar (endocrinology), Peter Igarashi (nephrology), Robert Brown (neurology), Paul Noble (pulmonology), Maurizio Fava (psychiatry), David Ginsburg (genetics), Todd Golub (pediatric oncology), Nancy Davidson (medical oncology), John Ioannidis (metascience), Dan Kelly (metabolic cardiology), Warren Leonard (molecular immunology), Elizabeth McNally (cardiology and genetics), David Thomas (infectious diseases), and Anna Huttenlocher (pediatric rheumatology). With me and Robert Brown coming off of the council for 2019, this esteemed council group will be joined by Juanita Merchant (gastroenterology) and Jeff Rothstein (neurology). Diversity of the biomedical workforce Data from the US Census Bureau show diversification of the scientific workforce. Changes from 1990 to 2014 show that there is a marked increase in the private sector biomedical workforce, with slight increases in the public sector and with relative shrinkage of the biomedical workforce in academia (3). The private sector, which includes biotechnology firms, hospitals, and pharmaceutical companies, pays higher average salaries than academic positions (and is a likely driver for that growth). The majority of the biomedical workforce is under 45 years of age, ranging from 64% in 2002 to 55% in 2013 (3). This young biomedical workforce often has children at home, with 82% of married researchers age 40 to 49 years having children in their household (3). Women in the workforce often have an employed spouse as compared to men, and men from ages 30 to 39 years are seven times more likely to have a nonworking spouse (3). From 1990 to 2014, biomedical scientists have grown from 27,500 in number to over 69,000. Increasing proportions of biomedical scientists are from diverse backgrounds, with growth of Asians from 12% to 34%, Blacks from 1% to 2%, and other backgrounds from 2% to 6% (3). Comparing 1990 to 2014, the percentage of naturalized citizens in the biomedical workforce has grown from 8% to 18%, and the percentage of noncitizens conducting biomedical research has grown from 14% to 34% (3). Although there have been gains over time for minority men and women in the biomedical workforce, the distribution gets smaller among minority persons with advancing higher education degrees. Minority men and women make up 20% of the 726,000 first-time freshmen in science and engineering, but only 17% of the 452,000 with bachelor’s degrees in science and engineering and only 10% of the 145,000 advanced degrees in science and engineering (4). The NIH-funded biomedical workforce portfolio shows a similar picture between minorities and NIH funding. White females with advanced degrees are underrepresented, whereas White female postdocs and White males with research project grants (RPG) or R01s are overrepresented relative to the labor market (5). Black males and females with bachelor’s and advanced degrees are underrepresented, and those with RPGs or R01s are woefully underrepresented relative to the labor market (5). Asian males and females are overrepresented with bachelor’s and advanced degrees, but underrepresented relative to the labor market for holders of RPGs and R01s (5). Hispanic males are about on par regarding K awards, RPGs and R01s, but Hispanic women are underrepresented for RPGs and R01s (5). The pipeline for developing physician-scientists is good, with challenges for racial and ethnic diversity. Medical scientist training programs (MSTPs) have graduated nearly 10,000 MD-PhD students since 1975, with a total of 356 (3.7%) Black and 386 (4%) Hispanic students (6). The percentage of women in MSTPs has grown from 15.7% (1975–1984) to 36.7% (2005–2014) (6) but has not yet reached the level of 50% women observed for regular MD programs. The percentage of Hispanics in MSTPs has grown from 0.8% (1975–1984) to 6.2% (2005–2014), and there are no data released for Blacks in MSTPs, since the numbers are low (6). This is highly relevant for minority men and women because overall, MSTP students in the long run do well in terms of competing for grants and MSTP could be a pipeline for future diverse faculty. Between 1980 and 1989, MSTPs who applied for R01s or equivalent grants had an 80% success rate and between 1990 and 1999 a 63% success rate, much higher than those of non–MD-PhDs (6). While the underrepresented minority population in the US continues to rise as a percentage of the population, the population of underrepresented minority matriculants to medical schools is flat (7). These medical school diversity pipeline issues extend into specialty training. For instance, while Blacks and Hispanics make up 13% and 18% of the US population, respectively, they make up only 6% and 8% of all residents and fellows, 4% and 5% of practicing physicians, 4% and 5% of oncology fellows, and 2% and 3% of practicing oncologists (8). Within the subspecialty of gastroenterology from 2010 to 2017, the percentage of underrepresented in medicine applicants to fellowship fell from 14.3% to 12.1%, and there has been no change in the percentage of matriculated Hispanic, Black, or Native American gastroenterology fellows (9). There has also been no change in the percentage of underrepresented in medicine gastroenterology faculty; collectively, as a group, they are less than 10% of faculty from 2010 to 2017, with no increase over time (9). This observation extends to multiple other specialties. In evaluation of 16 medical specialties (internal medicine, pediatrics, surgery, psychiatry, radiology, obstetrics/gynecology, anesthesia, neurology, family medicine, pathology, emergency medicine, orthopedics, ophthalmology, otolaryngology, physical medicine and rehabilitation, dermatology) from 1990 (52,939 faculty) compared to 2016 (129,545 faculty), assistant professor Hispanic males and females are underrepresented in all 16 specialties at that faculty level relative to the US Census, with trends over time towards greater representation (10). Assistant professor Black males and females are underrepresented in 15 specialties relative to the US Census (the exception being obstetrics/gynecology), with representation trends worsening for internal medicine, pediatrics, surgery, psychiatry, radiology, anesthesia, neurology, emergency medicine, orthopedics, and ophthalmology (10). Assistant professor White females are underrepresented in internal medicine, surgery, radiology, emergency medicine, and orthopedics relative to the US Census, and assistant professor White males and Asians are overrepresented in several specialties (10). More troubling is that, at the associate and full professor levels, Blacks and Hispanics are more underrepresented as faculty in 2016 than 1990 relative to the US Census (10). While there are challenges with the pipeline of diverse faculty, there are observed disparities with promotion and retention of diverse faculty. Based on the Association of American Medical Colleges (AAMC) Faculty Roster from 2003 to 2006 for four specialties (surgery, internal medicine, pediatrics, and obstetrics/gynecology), the 10-year promotion rates for Black assistant professors to associate professor were statistically markedly lower compared to Whites, Asians, and Hispanics for all four specialties (11). Promotion from associate to full professor was equivalent across all racial/ethnic groups in the four specialties (11), suggesting that once a faculty member was more senior and invested in, their promotion to full professor is on equal footing. Retention rates over 10 years, the ability to keep a faculty member at one’s institution, was also disparate across racial/ethnic groups. White assistant professors in surgery and internal medicine and White associate professors in internal medicine had statistically higher retention rates over other racial/ethnic groups, and Black assistant professors in pediatrics had the lowest statistical retention rates compared to other racial/ethnic groups (11). Research funding and challenges to overcome for the diverse medical workforce Once a faculty member gets through the pipeline, promotion, and retention challenges, what is the success of NIH funding, a key milestone for physician-scientists as faculty members? Data from the NIH indicate growth from 2016 to 2018 in the number and total amount of awards, with success rates for RPGs at 20.2% for 2018 (12). In particular, those who held K awards have a 24% increased likelihood of obtaining an RPG over those who were not ever awarded a K award (12). In analysis of dermatology faculty, trends from 2009 to 2014 show a slight uptick in R01s awarded to PhD faculty, a slight downtick for MD-PhD faculty, and a more marked downtick for MD-only faculty (13). The number of R01 awards to male and female dermatology faculty was steady from 2009 to 2014; however, men held 73% of all grants compared to 27% for women (13). In evaluation of trends from 2009 to 2016 for NIH funding, the number of funded scientists increased 2% to 5% per year, with a higher proportion of awards going to experienced investigators (increasing from 52% in 2009 to 60% in 2016) and a smaller proportion to early stage investigators (ESIs, those within the time frame from training, dropping from 18.8% to 16.2%) and new investigators (NIs, those receiving first RPG but not ESIs, dropping from 28.4% to 23.1%) (14). The overall success rate for 24,545 grant applicants in 2016 was 5,577 awards or 23% of applicants (14). The funding rate for ESIs did mirror the funding rate for experienced investigators from 2009 to 2016, with NI training tracking about 7% below both (14). The average age of the investigator to receive the first R01 is increased from 39 years in 1990 to 44.2 years in 2016 and to receive a second R01 is increased from 43 years to 46.9 years (14). The age trend was not different between men and women; however, underrepresented minorities tended to be slightly older than majority awardees (14). Overall, there was no major difference in the RPG funding rate between men and women from 2002 to 2016; however, women only make up 29% of the applicants and only one-quarter of the awardees (14). In contrast, there is a persistent 7.5% lower funding gap rate for underrepresented minorities as compared to majority RPG applicants from 2002 to 2016, and underrepresented minorities make up only 2.8%, 2.1%, and 1.0% of the ESI, NI, and experienced investigators, respectively (14). The probability for R01 funding was lowest for Black NIH applicants who ranged 5% to 10% lower than any other racial/ethnic group between 2000 and 2006 (15–17). Compared to White NIH applicants, the percentage change in R01 award probability was 27% lower for Black applicants for those who were previously on F32 or T32 training awards (17). The overall R01 award probability for Black NIH applicants was 16.6%, compared to 26.6%, 25.3%, and 28.7% for Asians, Hispanics, and Whites, respectively, from 2000 to 2006 (18). The R01 award probability remained lower for Black men and women irrespective of whether the applicant’s degree was PhD or MD (18). Comparing 1054 matched pairs of applicants for R01 grants between 2010 and 2015, White applicants had 46.7% proposals not discussed, 37.5% proposals discussed but not funded, and 15.8% proposals discussed and funded, compared to 55.1% not discussed, 33.2% discussed but not funded, and 11.7% discussed and funded for Black applicants (15). The data highlighted a disparity, demonstrating a deficit of 133 awards that should be awarded to Black applicants to reach parity with White applicants (15). My own pathway to becoming a physician-scientist I was fortunate to have nurturing parents who, despite not having the financial means, pushed higher education on all 12 of their children (19). During my undergraduate education, where I had a strong desire to apply for medical school, I had no real lab experiences. After my first year in medical school, I was fortunate to have research laboratory exposure that piqued my interest in academia and research (and my first research publications), followed by fourth-year electives in a research laboratory (19). During residency, there was minimal time to conduct research, but specific role models steered and solidified my thinking towards an investigative career. After applying to fellowship programs that held T32 grants, and after evaluating one potential mentor who introduced me to my ultimate research mentor, I began a research focus in colorectal cancer and was mentored in grant and manuscript writing and approaches to answer patient-oriented scientific questions. I spent five years in my research mentor’s laboratory to gain a footing in research (19). Along the way, I also learned and was exposed to work-life balance approaches emulating from my mentor (and role model). Dually applying for a VA Career Development Award as well as a K08 award saw both eventually awarded, with me choosing the K08 as the pathway. With my “extended postdoc,” I was able to convert from a K08 to an R01 at age 37, with eventually subsequent awards over time via R01, T32, R24, U54, U01, and VA Merit mechanisms. With research funding and productivity, I was an assistant professor for 6 years and associate professor for 4 years before moving to full professor. In my experience, my mentors and role models looked at me as a potentially successful academic person and not specifically as an underrepresented minority, and afforded me opportunities and lessons with hard work to succeed academically. Based on data presented earlier in this article, in many ways, I defied the odds to eventually succeed in academia. This is despite not having very many others in faculty roles with similar racial/ethnic backgrounds. Diversification leads to better science Are there data that even suggest that diversification leads to better science? In the business and education worlds, there is strong evidence that diversity improves innovation and outcomes. The author and academic Scott E. Page wrote from his research that “diverse groups of problem solvers outperformed the groups of the best individuals at solving complex problems. The reason: the diverse groups got stuck less often than the smart individuals, who tended to think similarly” (20). “Diversity in” does not automatically lead to “creativity out”; maximizing diversity’s benefits requires careful management, including having a positive climate, engaging managers, having nonhierarchical structures, and critical mass to effectualize diversifying knowledge outcomes, collective intelligence, diversifying research methods, and utilizing team expertise (21). In the biosciences, there is strong evidence that ethnic diversity enhances scientific impact (22). Data from over 6 million scientists and over 10 million published papers (examining their citations within five years) in eight main and 24 subfields of science show that ethnic diversity had the strongest correlation with scientific impact (22). Ethnic diversity consistently outperformed the nondiverse regardless of the year of paper publication, the number of authors per paper, and the number of collaborators per scientist (22). Group ethnic diversity (e.g., diverse teams) trumped individual ethnic diversity, and ethnic diversity resulted in a 11% impact gain for papers and a 48% impact gain for scientists when comparing the upper ninetieth percentile group versus the lower tenth percentile group (22). There remain challenges to building diverse research groups. As mentioned above, the diversity physician-scientist pipeline is constrained and there are academic barriers to propel one to the level of a funded senior faculty. In many instances, life barriers are also in place due to issues of student debt, timing of starting a family, obligations towards caring for family members, exposure to science, and role models and mentorship (4). However, there are opportunities to AAP members as senior physician-scientists to provide opportunity to build diverse groups to produce high-impact science and publications. AAP members should be mentors and/or advisors to underrepresented minorities at any stage of their careers, be it high school, undergraduate, medical school, residency, fellowship, or faculty (23). AAP members should be great role models to show the importance of being a physician-scientist and the potential role that faculty could potentially become over time. AAP members should invite underrepresented students to experience their research program and expose them to clinical medicine. AAP members should participate with students in programs that are geared towards research exposure to underrepresented students, such as NIH CURE and NIH R25-funded programs, and foster NIH research supplements that promote diversity (4, 23). AAP members can specifically pay attention to junior underrepresented faculty at their institutions and help guide them through milestones to become senior faculty (23). I am grateful that my research mentor, an AAP member, provided much-needed guidance, particularly at the beginning of my academic career, and I also provide that same guidance to a new generation of diverse students and junior faculty. I look forward to the next 100 years of outstanding science and the AAP, as both will fuel the growth of diverse physician-scientists that will lead the way for discovery to improve care of our patients. Acknowledgments This work is supported by the United States Public Health Service (NIH grant CA206010) and the A. Alfred Taubman Medical Research Institute of the University of Michigan (to JMC). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. JMC was President of AAP from April 2018 to April 2019. Footnotes Copyright: © 2019, American Society for Clinical Investigation. Reference information: J Clin Invest. 2019;129(12):5051–5054. https://doi.org/10.1172/JCI131589. This article is adapted from a presentation at the 2019 AAP/ASCI/APSA Joint Meeting, April 6, 2019, in Chicago, Illinois, USA. References Association of American Physicians Web Site. https://aap-online.org Accessed July 24, 2019. Carethers JM, et al. The imperative to invest in science has never been greater [AAP Position Statement]. J Clin Invest. 2014;124(9):3680–3681.View this article via: JCIPubMedCrossRefGoogle Scholar Heggeness ML, Gunsalus KT, Pacas J, McDowell G. The new face of US science. Nature. 2017;3;541(7635):21–23.View this article via: PubMedGoogle Scholar Duncan GA, et al. National Heart, Lung, and Blood Institute Workshop Summary: enhancing opportunities for training and retention of a diverse biomedical workforce. Ann Am Thorac Soc. 2016;13(4):562–567.View this article via: PubMedGoogle Scholar Heggeness ML, Evans L, Pohlhaus JR, Mills SL. Measuring diversity of the National Institutes of Health-funded workforce. Acad Med. 2016;91(8):1164–1172.View this article via: PubMedCrossRefGoogle Scholar Harding CV, Akabas MH, Andersen OS. History and outcomes of 50 years of physician-scientist training in medical scientist training programs. Acad Med. 2017;92(10):1390–1398.View this article via: PubMedCrossRefGoogle Scholar Cohen JJ, Gabriel BA, Terrell C. The case for diversity in the health care workforce. Health Affairs. 2002;21(5):90–102.View this article via: PubMedCrossRefGoogle Scholar Winkfield KM, et al. American Society of Clinical Oncology strategic plan for increasing racial and ethnic diversity in the oncology workforce. J Clin Oncol. 2017;35(22):2576–2579.View this article via: PubMedCrossRefGoogle Scholar Carethers JM, Quezada SM, Carr RM, Day LW. Diversity within US gastroenterology physician practices: the pipeline, cultural competencies, and US gastroenterology societies approaches. Gastroenterology. 2019;156(4):829–833.View this article via: PubMedCrossRefGoogle Scholar Lett LA, Orji WU, Sebro R. Declining racial and ethnic representation in clinical academic medicine: a longitudinal study of 16 US medical specialties. PLoS ONE. 2018;13(11):e0207274. View this article via: PubMedCrossRefGoogle Scholar Abelson JS, Wong NZ, Symer M, Eckenrode G, Watkins A, Yeo HL. Racial and ethnic disparities in promotion and retention of academic surgeons. Am J Surgery. 2018;216(4):678–682.View this article via: PubMedCrossRefGoogle Scholar Lauer M. Association between receiving an individual mentored career development (K) award and subsequent research support. NIH Office of Extramural Research Web site. https://nexus.od.nih.gov/all/2019/04/02/association-between-receiving-an-individual-mentored-career-development-k-award-and-subsequent-research-support/ Created April 2, 2019. Accessed July 24, 2019. Cheng MY, Sukhov A, Sultani H, Kim K, Maverakis E. Trends in National Institutes of Health funding of principle investigators in dermatology research by academic degree and sex. JAMA Dermatol. 2016;152(8):883–888.View this article via: PubMedCrossRefGoogle Scholar Nikaj S, Roychowdhury D, Lund PK, Matthews M, Pearson K. Examining trends in the diversity of the U.S. National Institutes of Health participating and funded workforce. FASEB J. 2018;:fj201800639. View this article via: PubMedGoogle Scholar Mervis J. Mentoring’s moment. Science. 2016;353(6303):980–982.View this article via: PubMedCrossRefGoogle Scholar Ginther DK, et al. Race, ethnicity, and NIH research awards. Science. 2011;333(6045):1015–1019.View this article via: PubMedCrossRefGoogle Scholar Ginther DK, Haak LL, Schaffer WT, Kington R. Are race, ethnicity, and medical school affiliation associated with NIH R01 type 1 award probability for physician investigators? Acad Med. 2012;87(11):1516–1524.View this article via: PubMedCrossRefGoogle Scholar Ginther DK, Kahn S, Schaffer WT. Gender, race/ethnicity, and National Institutes of Health R01 Research Awards: is there evidence of a double bind for women of color? Acad Med. 2016;91(8):1098–1107.View this article via: PubMedCrossRefGoogle Scholar Carethers JM. GRG profiles: John M. Carethers. Dig Dis Sci. 2016;61(6):1429–1435.View this article via: PubMedCrossRefGoogle Scholar Page SE. The Diversity Bonus: How Great Teams Pay off in the Knowledge Economy. Princeton, New Jersey, USA: Princeton University Press. 2017:328. Neilsen MW, et al. Opinion: gender diversity leads to better science. 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    更新日期:2019-12-03
  • The ownership paradox: nurturing continuity and change for the future ASCI
    J. Clin. Invest. (IF 12.282) Pub Date : 2019-11-20
    Kieren A. Marr

    Introduction Dear friends, colleagues, and mentors, it has been a tremendous honor for me to serve the society for the past several years. This time has been one of reflection, growth, and change for me, both professionally and personally, and I stand before you humbled and inspired by your work, the depth of our society’s tradition, and the importance of our mission. I sincerely thank you, the membership, for entrusting me to serve and to lead. I thank the Council for your friendship, your support, and your dedication, and I thank the executive leadership team for your guidance and your expertise. Later I will draw attention to some of the individuals who have been instrumental to the ASCI over the last year; for now, please accept my introduction of gratitude. I have prepared for this moment in a similar manner to those who came before me, with a study of Presidential Addresses delivered since 1939. This is an arduous, but rewarding task, as these addresses illustrate overarching thematic concerns to our society for over a century. As we reflect on where we have been and who we are today, an important reminder is that the ASCI was developed by the need for change, and to reinforce change. We are structured as a society to recognize excellent young physician-scientists. As part of the ASCI’s inception, the youth label represented more than age, but also signified a rebel, nonauthoritarian outlook underlying physician-scientists who worked with then new scientific methods (1). Now, more than 100 years later, it’s hard to imagine that establishing a scientific foundation to medicine was such a foreign concept that it would have required an entire change movement to establish momentum — but it did. This reflection was the impetus of a question that guided my last year as president of the Council — what do we need to do today to enable this society to remain continuous, whilst promoting change that is inherent to and born out of our growth as physician scientists? Indeed, the tension between continuity and change has caused angst to many prior ASCI presidents. Core themes that emerged include the identity of the “new” physician-scientist, definitions of clinical science itself, and stresses within funding and training. I would recommend that anyone who wants to understand our society, or the history of physician-scientists, invest time in reading the ASCI Presidential Addresses published in JCI. You will appreciate how historical events, time-dependent cultural shifts, and individual personalities flavored the content, perspective, and approach to our written history. The ownership paradox The ASCI is an honorary society that was initiated during a period of change. We exist to recognize, support, and promote the work of young physician-scientists, towards the overall goal of “improving the health of all people.” A paradox arises when considering how to assure continuity of our organization whilst enabling the nimbleness to stay in integrity with our founders’ mission of promoting change. This is what I’m calling an “ownership paradox.” Ownership refers to the personal motivations that are instrumental in informing organizational culture. Building a culture of ownership is similar to that of accountability but differs in that the latter is typically more externally imposed. In contrast, people who care about a mission and share an organizational vision can not only account for, but “own” their roles in an organization. A simple behavioral analogy illustrates this distinction: no one changes the oil of or washes rented cars — but when we own a car, we care for it to assure longevity. The concept of a shared ownership culture has been evoked to support policy movements, such as those pertinent to public and environment health (2). On an organizational level, shared ownership is instrumental for employee satisfaction and growth, and it’s been cited as an essential element to promote safety in health care (3, 4). However, one problem that arises in health care is a tension generated from a hierarchical structure, which more naturally motivates externally, through rewards and punishment (5). Perhaps the best analogy for an ownership paradox is that which we experience as parents. At very early years, parents must own our roles. Feeding, cleaning, and transporting these beings through time and growth requires not just 100% accountability, but the internal diligence of true caring — an ownership culture. However, as our children grow and have become their own semiautonomous human beings, our sense of ownership has to be tolerant of change. As the mother of teenage daughters, I’m now frequently reminded of my role as a “renter.” Similarly, the written history of ASCI Presidential Addresses illustrates the challenges the society has faced in assuring societal continuity whilst functioning in a world of vast change. Ultimately, the membership is transient, and the leaders are volunteers. As the mission of supporting physician-scientists is greatly impacted by extrinsic forces, such as the economic environment that dictates research funding, every ASCI Council member has reflected on how much he or she is accountable for the fate of the organization. While we are elected for our individual scientific achievements, those skills are not necessarily what we need to lead a nonprofit organization. I believe that supporting the mission of the society — assuring the continuity of physician-scientists — mandates that we create a more transparent culture of ownership. This requires teamwork, an appetite for change, and assurance of organizational diversity. Like parents, we need to be accountable enough to “own” the outcomes of our behaviors and our decisions, and know when action is needed to assure health of the ASCI; at the same time, we need to understand the transience of our roles, as we are ultimately passing on the baton of ownership to future generations who will work in a world of massive, sometimes unpredictable scientific and economic change. Like our children, the body of evidence that we have created as physician-scientists continues to mature; a paradox emerges from the need to simultaneously assure continuity and nurture change. Science, evidence, and technology changes Change is inherent to discovery and technologic advancement, yet it is one of the strongest forces of human discomfort. Our inability to imagine the future and accept the unknown has certainly been illustrated by many famous physician-scientists. In a famous quote presented in 1919, Osler warned, “The extraordinary development of modern science may be her undoing. Specialism, now a necessity, has fragmented the specialties themselves in a way that makes the outlook hazardous. The workers lose all sense of proportion in a maze of minutiae” (6). While there is wisdom in this statement, even Osler failed to envision that technologic developments would emerge to not only enable scientists to manage the maze of minutiae, but to harness the power in big data sets. Warnings of growth and the implications of complexity have also been a recurrent theme in the historical records of the ASCI Presidential Addresses. Change has led to some very grim depictions of the future by some of our past presidents. Indeed, the 1939 address given by Dr. Tinsley Randolph Harrison presented a unique launching point: “If we assume that a presidential address has any useful function at all, it follows that this function is to try to benefit the organization to which the address is delivered. Such a purpose can best be served, not by praising accomplishments of the past, but by considering the dangers of the future.” He went on to outline a “disease” that he termed institutional arteriosclerosis, in which societies, like individuals, grow to reach maturity, then accomplish little, and ultimately decay (7). After reading many such warnings of “decay” and the impending demise of physician-scientists, I decided that this year I would focus on the more positive outcomes of change. Other ASCI presidents have discussed various aspects of technologic change, and most recently, innovation, with different understandings and analogies. In 1952, Dr. Barry Wood delivered his address entitled, “The ‘Logarithmic Phase’ of Medical Progress.” He described the productivity and growth of medical knowledge in the mid-20th century as similar to that of a conventional bacterial growth curve, with a lag phase, a logarithmic phase, and a stationary phase (8). As a microbiologist, I find the analogy somewhat appealing, but it does not adequately depict growth dynamics that reflect the iterative nature of scientific discovery. With the benefit of having the whole century of medical science to examine, one can contextualize our scientific history, and better understand some of the warnings that have been delivered, using economic theories. An important theory of technologic growth was borne out of the observation that disruptive innovations create cycles that ultimately come and go, in a wavelike fashion (9, 10). These waves, called Kondratiev waves (or K-waves for short), are initiated by the development of technologies that create new ways of living and working. Figure 1 demonstrates these waves by depicting the pace of large innovations on the y axis and years on the x axis (11). The wavelike appearance is created by disruptive technologies that grow over time, reflecting technologic dissemination and adoption, which ultimately gives rise to new industries and the spread of discovery. However, technologic growth subsequently slows and enters a downswing, as one technology leads to development of another, sometimes resulting in replacement, through major changes in the way that we do things. Figure 1 Kondratieff cycles (from ref. 11). The rolling 10-year yield on the S&P 500 is shown on the y axis, in percentage. Reprinted by permission from Springer Nature: Springer, Cham, “Creative Destruction, Long Waves and the Age of the Smart City” by Michael Batty © 2016. These waves were initially described in the beginning of the 20th century by a Russian economist (Kondratiev). In the middle of the 20th century, another influential economist named Joseph Schumpeter suggested that technology grows on itself in this way, creating an acceleration of the waves, such that growth becomes faster, and the years between major innovations become shorter (9). In a general sense, these development cycles impact the way we live, creating broad eras of advancement. In early eras, technologies to harness power through water, develop textiles, and use iron impacted human life by enabling the machine manufacture of clothing and transportation. There was a century of growth in transportation. More recently, information technology has created a communication era. Why is this relevant? Consider that the ASCI, and our current approach to medical sciences, were born during the upswing of the third technologic wave, which was created by advancements in chemistry, electricity, and the internal combustion engine. Studying our ASCI written history with these technology cycles in mind, it becomes evident that many of the most pessimistic predictions emerged during periods of economic decline that followed the upswings brought about by growth and change. Consider that our role as physician-scientists is both to discover — or cause change — and to most effectively utilize the tools that come of technology development. If we understand these dynamics of change, it becomes easier to adapt to the ups and downs inherent in anticipated economic cycles and the future unknown. Right now we’re in the sixth wave, characterized by growth emergent from application of information technology and data science. The contrasting outlook of growth cycles can be appreciated in the current debate on the impact of precision medicine. In a recent issue of JCI, Rosen and Zeger presented their perspective while taking a positive outlook, “riding up” the technologic wave: “American medicine is on the precipice of dramatic change, forced by disruptive technologies in measurement, computation, and communication” (12). In the same issue, Joyner and Paneth offer a Viewpoint in which they appear to be acknowledging stalled growth, or even “riding down” the wave, especially in the application of genomics towards precision medicine: “Nearly two decades after the first predictions of dramatic success, we find no impact of the human genome project on the population’s life expectancy or any other public health measure, notwithstanding the vast resources that have been directed at genomics” (13). Is it possible that both these accounts are correct, and what we have observed is the wavelike motion of scientific discovery and then stalled dissemination and advancement? Either way, the dynamics of technologic change do not predict doom for the physician-scientist community, but instead, emphasize that we are central to — and impacted by — iterative cycles of growth. You may sense some of this change in this year’s meeting, with themes in immunotherapy and big data. A more personal lesson here is to embrace change as the result of, and inherent to the process of our own growth. Studying how this happens has expanded my viewpoint on the subject. I reflect back on one auspicious moment as a Duke intern some years ago. Working late at night, I observed a fellow intern sitting at a recently installed computer station, using a platform that he patiently described to me as “email.” My response to him was that this email thing is a passing fancy and that he should instead do something important with his time. This was clearly an auspicious predictor. I still think that email absorbs too much time and I stumble through all things electronic. And you probably wouldn’t be surprised that the intern who introduced me to email later became the chief medical officer for WebMD. We should all pay attention to these auspicious “email” moments as they may be predictors of the future. The discussion on technological change also presents another consideration for the ASCI as we look towards the future — the definition of science and the composition of our membership. If we consider that the society was developed to promote physician-scientists in the emerging industry of evidence-based medicine, and that science is influenced by technologies that grow iteratively over time, how can we be anything other than a society that honors the contributions of physician-scientists who use different technologies towards hypothesis-driven science? In evaluating the cycles of innovation in technology over the history of the ASCI, I see a compelling argument for the nurturing of a diverse membership of physician-scientists defined by excellence across basic, lab-driven mechanism research and those who utilize newer tools to perform discovery science. The composition, and culture, of the ASCI continues to evolve. Culture changes Over the last several years I had the privilege of studying business and management at MIT. This was compelled by a desire to learn a scientific foundation for innovation and leadership. I grew tremendously and would definitely recommend cross-disciplinary education as a very productive midlife crisis! One big takeaway lesson that I feel is relevant to our field right now is the impact of culture on making change. I learned to see organizations through three lenses, which include structure (or strategic design), culture, and politics. If you want to make change, a view from any of these three lenses demonstrates the different levers that can compel change. Here, I’d like to examine the ASCI through the cultural lens. Promotion of a diverse culture is one of the most important elements to enable advancement in science and health of organizations; in this annual meeting, we made deliberate decisions to highlight this topic, and tomorrow I would encourage you to attend the morning special session focused on the National Academy report on sexual harassment of women in academic sciences, engineering, and medicine. In a robust, scientific report, the National Academies, including some of our colleagues sitting here, reviewed data and provided 15 recommendations to improve workplace culture; most prominently, this includes moving beyond legal compliance by improving transparency and accountability, striving for strong and diverse leadership, and making the entire academic community responsible for reducing and preventing sexual harassment. One specific recommendation is to encourage involvement of professional societies and other organizations (14). In an effort to own our role in shaping the culture of the physician-scientist community, I sought to review the composition, and the culture, of the ASCI. First, let me thank John Hawley for helping me with manual data extraction to understand demographics that were poorly tracked over history. For the same reason, there may be errors in measurements, so if you can update our data, please do so. Figure 2 summarizes our membership composition to date, summarizing that approximately 90% of our membership are men, and 10% women. Only 1.5% of the membership are identified as within an underrepresented minority group. The smallest demographic are minority women, of which we have elected only 18. Figure 2 ASCI membership composition, 1908–2019. Absolute numbers for each group and relative percentages are shown. URM, underrepresented minorities. The first woman elected is Dr. Marian Wilkins Ropes (Figure 3), who became a member of ASCI in 1940. She was also the first female medical resident and assistant professor at the Mass General Hospital, where she studied autoimmunity. She set the stage for many more women to be elected, and eventually to serve on Council. Figure 4 shows the women who served in Council during the 20th century, with Dr. Judith Swain as the first female president in the 1990s. Since 2000, the Council has varied in gender distribution, ranging from 18% to 55% women. Before me, four more women have served as president (Figure 5). Figure 3 The first female ASCI inductee, Marian Wilkins Ropes, elected to ASCI in 1940. Figure 4 Female ASCI Council members, pre-2000. Figure 5 Four female ASCI presidents, 2001–2018. Although data have been poorly tracked, we believe that the first underrepresented minority elected into ASCI was Dr. Manuel Martinez Maldonado, a nephrologist originally from Puerto Rico, elected in 1973 (Figure 6). Four African American men were elected prior to 2000 (Figure 7), and in 2003, Dr. Funmi Olopade became our first ASCI African woman, originally from Nigeria (Figure 8). Finally, three underrepresented minority men have served on the Council in different roles, after 2009. Levi Garraway was the first underrepresented minority officer (2013–2016) and president (2015–2016) (Figure 9). Figure 6 The first underrepresented minority ASCI inductee, Manuel Martinez Maldonado, elected to ASCI in 1973. Figure 7 The first African American men elected to ASCI, pre-2000. Figure 8 The first African female ASCI inductee, Olufunmilayo Olopade, elected to ASCI in 2003. Figure 9 Three African American men of the ASCI Council since 2009. Why is this important? Because culture is shaped by — and directly impacts — diversity. We not only want to promote a membership and leadership that adequately reflects societal changes, but one that is prepared to lead healthy change in the future. As the National Academies report illustrates, academic institutions have historically done this poorly. This year, attention has been drawn to several institutions that have made deliberate changes to the symbols that they display in their surroundings in order to promote a more diverse working environment. If you saw your face in any of the figures presented, I want to thank you. Being the first in anything is a personally brave and important act of leadership, as you ultimately create opportunity for newer generations. In this century, we have elected many different faces and Figure 10 serves as a healthy symbol of a more diverse ASCI. Our promotion of cultural change will bode well for our role in supporting the diverse community of physician-scientists in the future. Figure 10 Many diverse faces of ASCI members elected after 2000. Priorities change I can’t talk about ownership, continuity, and change without ending on priorities. Our ASCI Council this year understood that our role was more than to elect new members, but to own our leadership to enable continuity, and change. Following the organization’s mission statement, created in 2012, we worked to establish a small number of strategic priorities that will better enable us to use our societal resources to support physician-scientists. We developed structures to create more transparency in the organization, and initiated a new program to improve our Institutional Representatives program. Much of this has been summarized in a recent Viewpoint in JCI (15), and we will detail progress in the business meeting this evening. As honorary societies, individuals are celebrated for transformative discovery. It’s easy to overly idolize and create symbols that serve as barriers to teamwork — so I really want to emphasize the strength of our society as a team. Our executive leadership, John Hawley and Karen Guth, serve their positions with skill, enthusiasm, approachability, and provide the experience of decades. I need to say a very large thank-you to Dr. Kim Rathmell, who is your next president. With several years of service on Council, insight, and unparalleled energy, Kim has been instrumental with everything that we have done this year. She embodies the notion of leading through ownership. This group has been phenomenal to work with. Finally, to the new members, congratulations. Your work has been recognized as excellent and transformative and you’re now part of a team of colleagues that form this historical — but not old — honorary society. To assure a healthy future, I encourage you to “own” your roles by active participation in the primary mission of supporting physician-scientists. Ultimately, the culture that supports growth, honors diversity, and rewards this level of engagement will ensure continuity and future change for physician-scientists. Footnotes Copyright: © 2019, American Society for Clinical Investigation. Reference information: J Clin Invest. 2019;129(12):5055–5061. https://doi.org/10.1172/JCI134851. This article is adapted from a presentation at the 2019 AAP/ASCI/APSA Joint Meeting, April 5, 2019, in Chicago, Illinois, USA. References Howell JD. A history of the American Society for Clinical Investigation. 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    更新日期:2019-12-03
  • Waiting to “make it” versus “making it happen”: empowering physician-scientists in training
    J. Clin. Invest. (IF 12.282) Pub Date : 2019-11-20
    Audra N. Iness

    As trainees, we aspire to be physician-scientists someday. As we progress through our long and intense training pathway, it often seems that “someday” is still too far away. It can become challenging to draw strength from the motivations that initially inspired us to pursue this noble profession. We tend to focus on the external obstacles of the journey. Indeed, belonging to both the medical community and scientific community brings several unique challenges and is further complicated by our highly individualized training experiences. Although understanding these challenges is an important step toward being able to address them, today I task you with shifting the focus toward taking ownership of your training pathway. Instead of being submissive to these challenges, challenge them in return! The most significant favor you can do for yourself is to be confident in your ability to overcome challenges. Once you do, you will be invincible. Even as a trainee with limited knowledge and experience, you have enabled yourself to learn and you are acquiring the tools needed to get the job done. You are resourceful. You have a voice. You have agency to shape your training experience and career. Take possession of your physician-scientist training experience, embrace self-efficacy, and appreciate the liberties that come with this powerful training. Allow me to share with you how involvement in the American Physician Scientists Association (APSA) is emboldening trainees like me and transforming the physician-scientist training experience. APSA’s mission is to serve physician-scientist trainees. As we enter our fifteenth year as an organization, we celebrate our growth as a physician-scientist trainee community and continued progress toward improving physician-scientist training as a whole (1). Importantly, APSA was formed as a means of bringing trainees together as a united front; as such, our organization and initiatives are trainee driven. We advocate for ourselves and recognize that no one understands our needs better than our peers. APSA values the bonds between peers and camaraderie shared among us. This year, we expanded and strengthened the camaraderie of the physician-scientist training community on an international scale by establishing the International Consortium of Clinician Scientist Training Organizations (ICCSTO). The ICCSTO brings together APSA, the Asian Medical Student Association (AMSA), French Association Médecine/Pharmacie Sciences (AMPS), Swiss MD-PhD Association (SMPA), Clinician Investigator Trainee Association of Canada (CITAC), and European MD-PhD Association (EMPA), with the common goals of creating mutual understanding and support between our organizations; developing international scientific collaborations among clinician-scientist trainees; and enabling equal access to career development resources among trainees worldwide. Through exposure to various systems and mechanisms of physician-scientist training across the globe, ICCSTO ultimately aims to study the outcomes and perceptions of these training models to further inform the physician-scientist community. Within the United States, APSA is conducting a similar study aimed at determining the prevalence of specific interventions that provide clinical continuity during PhD training for dual-degree (MD-DO/PhD) trainees and recognizing which of these interventions trainees feel best prepares them for their transition back into clinical training. While physician-scientist trainees begin preclinical curriculum at the same time as their MD-DO track colleagues, dual-degree trainees typically take a leave of absence from medical school to complete the formal requirements of their PhD program. Unfortunately, after several years away from clinical training, many dual-degree students lose confidence and feel unprepared for clinical clerkships at the end of the graduate phase (2). It is recognized that different dual-degree programs use various means of addressing this “major chasm,” yet the specific structure of these curricula is largely understudied. Though we anticipate that the clinical continuity survey of dual-degree trainees and program directors will help to fill in this gap, the more exciting part of this study is how it came about. It was a topic of discussion among APSA institutional representatives on one of their quarterly phone calls. This survey is one of many examples of how APSA serves as the structure by which trainee-driven initiatives are enacted. Another key example is APSA’s diversity initiative. The long-standing lack of diversity among the physician-scientist community is well known, yet there are still insufficient means of addressing this problem (3). Despite equivalent representation of women and men among medical school trainees, men still outnumber women by about 13% in the population of MD/PhD applicants (4). Similarly, the small number of gender and racial minority groups may be partly explained by lower medical school matriculation rates, lack of representation in early pipeline programs, limited accessibility of mentors, deficient representation in academic leadership roles, and unconscious bias (5). APSA, along with our numerous trainee partner organizations, established the Diversity Working Group in our efforts to promote diversity in the physician-scientist trainee community. Our session at the 2018 APSA Annual Meeting experienced an amazing turnout, significant interest, and candid discussion of issues facing trainees from underrepresented groups. The meeting, scheduled for one and a quarter hours, ran almost forty-five minutes overtime, as trainees shared their personal encounters with barriers in their pursuit of a physician-scientist career. The passionate discussion at this meeting spawned the idea of having a formal conference to bring together the key stakeholders in physician-scientist trainee diversity. With the generous support of the Burroughs Wellcome Fund (BWF), we are hosting the inaugural BWF-APSA Physician Scientist Trainee Diversity Summit on June 21–22, 2019. This event marks a significant milestone in our progress toward a diversified physician-scientist training pipeline by strategically bringing together 50 to 60 individuals with the expertise and resources to effect change across the training pipeline. These individuals are experienced in addressing barriers to successful physician-scientist careers and include representatives of the NIH, Association of American Physicians (AAP), American Society for Clinical Investigation (ASCI), Student National Medical Association (SNMA), Latino Medical Student Association (LMSA), American Medical Student Association (AMSA), American Medical Women’s Association (AMWA), and Clinical Investigator Association of Canada (CITAC). The major goals of this summit are to utilize human-centered design thinking sessions as a mechanism for developing a strategic plan, coordinating a research study to address questions related to physician-scientist diversity, and to codify outcomes from our discussion for publication. This summit will not only give APSA an opportunity to convene its stakeholders and discuss the important topic of diversity in the physician-scientist community, but will also enable individuals from diverse backgrounds to support one another across various stages of training. The theme of diversity is also reflected in this year’s AAP/ASCI/APSA Joint Meeting. In addition to including prominent physician-scientist speakers on the themes of Inflammation and Big Data, the Joint Meeting ventures, for the first time, into discussions of the social climate surrounding us in science and academic medicine. In light of the National Academies report on sexual harassment and gender diversification (6) and the #MeToo movement (7), we look forward to the timely discussion of how sexual harassment and unconscious bias affect us and how we, as physician-scientists, can best tackle these issues. These plenary sessions are a landmark achievement in our fifteen-year evolution as a Joint Meeting, reflecting the needs and concerns of the members we represent. Indeed, the diverse topics and speakers on our agenda this year serve as an indicator of our continued efforts to comprehensively support the physician-scientist community. Another means by which APSA promotes peer support of trainees is through the mentorship program. The mentorship program has seen a tremendous growth in participants in recent years, many of whom are from underrepresented groups. During the 2017–2018 term, over 700 individuals participated in the program, with diverse representation of mentees: 74% women, 33% underrepresented minority, and 33% first-generation college students (8). With the generous support of the BWF, we were able to encourage further interactions across peer groups, with local informal “meet-ups” aimed at promoting networking opportunities between undergraduates, trainees at the medical school level, and established physician-scientists. The first of these sessions was piloted in the Boston area in 2017 and was a tremendous success. We now have five meet-ups in the works, spanning from coast to coast — the first of which, the Massachusetts Physician Scientist Student Symposium, brought together over one hundred participants. Similarly, the Bay Area Underrepresented Minority Outreach Event (a collaboration between the University of California, San Francisco, and Stanford University) was met with much enthusiasm from its 70 participants (Figure 1). The high degree of participation in these events reflects the underlying need for advocacy and networking among trainees. Figure 1 APSA outreach to underrepresented minority trainees. Undergraduate attendees at the Bay Area Underrepresented Minority Outreach Event fill the room and listen in on a Q & A session about MD/PhD training programs by a panel of current physician-scientist trainees and established physician-scientists. This represents one of five events sponsored by the Burroughs Wellcome Fund as part of APSA’s mentorship program expansion. Panelists (from left to right): Krister Barkovich, PhD (UCSF Medical Scientist Training Program [MSTP] student), Catherine Blish, MD, PhD (Stanford MSTP Associate Director), David Darevsky (UCSF MSTP student), Mitchel Cole (UCSF MSTP student), Mercedes Paredes, MD, PhD (UCSF faculty), Alice Tang (UCSF MSTP student), Mark Anderson, MD/PhD (UCSF MSTP Program Director); not pictured: Misty Montoya (UCSF MSTP student). We also aim to continue this program’s expansion to cover all stages of the training spectrum — from undergraduate through junior faculty — recognizing that the transitions into residency, fellowship, and junior faculty are particularly vulnerable times for aspiring physician-scientists (4). To address these “leaky” areas in the pipeline, APSA has forged a strong partnership with a group of active Physician Scientist Training Program (PSTP)/Research in Residency (RiR) directors. These directors represent the leaders of formalized postgraduate medical training programs that offer protected research time for residents and/or fellows. Years ago, we recognized the need for a centralized resource of information regarding these research-intensive programs and established a Research Residency and Fellowship Program Database in an effort to compile all of the pertinent information regarding PSTP/RiR programs for prospective applicants. Since 2015, APSA has also been present at the table to advocate for trainees at the Alliance for Academic Internal Medicine (AAIM) Research Pathways Directors Workshops (9) and the Association of American Medical Colleges (AAMC) Graduate Research, Education, and Training Meetings (10). Our presence at these workshops prompted the establishment of an annual meeting of PSTP/RiR directors at the Joint Meeting. The first of these meetings took place in 2018, when APSA compiled a list of questions from our members specifically addressed to PSTP/RiR directors. The content of the questions revealed a substantial disconnect between the desired messages sent by the directors and the trainees’ understanding of what PSTP/RiR programs are all about. The rich discussion yielded a collaborative perspectives piece, published in JCI Insight (11) (Figure 2). This year, we are encouraging further trainee-director crosstalk during a Q & A panel session at the Joint Meeting. We will have another meeting with the program directors as well. Here, we will take the initiative of establishing a centralized resource for prospective applicants one step further by discussing potential improvements to the Electronic Residency Application Service (ERAS) system, with our recommendations ultimately collated and sent to the AAMC for further review. Our ultimate goals are to clearly define research-intensive residency programs and modify the application process so that all programs are readily identifiable. These changes will revolutionize the accessibility and visibility of PSTP/RiR programs, streamline the residency application process, and hopefully promote an increase in applications from non-dual-degree trainees — a particularly critical population for sustaining the physician-scientist workforce. Figure 2 APSA’s initiative to increase crosstalk between trainees and Physician Scientist Training Program/Research in Residency directors. APSA trainee leaders speak on behalf of physician-scientist trainees to PSTP/RiR program directors and promote further discussion among representatives from internal medicine, pediatrics, and umbrella PSTP/RiR programs. Collectively, the described examples demonstrate how our initiatives are indeed trainee driven. APSA takes its role as a trainee organization seriously and is continuously improving the means by which we encourage trainee action. In addition to our quarterly town hall conference calls and policy resolutions processes, we have also sought a framework within our leadership governance to directly incorporate member-driven initiatives. Ad hoc committees are formed and dissolved on an as-needed basis to reflect the representativeness of trainee needs. For example, if a member has a particular passion for further studying issues concerning mental health in dual-degree trainees, we welcome the formation of a committee solely dedicated to that purpose. This way, APSA members have the ability to drive initiatives with the support of the national organization. Whatever your passion may be, APSA has a place for you. Even with highlighting only select initiatives, APSA has evidently made great strides in improving physician-scientist training over our fifteen-year history, and we must continue these efforts to sustain our community. However, we are only as strong as our participation, which is why the passion and commitment of our trainee volunteers drive this organization. We welcome your voice. To echo the message of my predecessors, realize your potential and become a trainee leader (12, 13). For those of you trainees in attendance at the Joint Meeting, I urge you to take a few moments to appreciate all of the grassroots efforts that your peers poured into making our presence known. For fifteen years, APSA has sat trainees side-by-side with Nobel laureates and their peers alike (1). We represent all trainees to the NIH and AAMC, program directors, and leaders from the most important stakeholders in your training. We are here for you. We are invested in your success and fulfillment. I encourage you to now go one step further. After taking those few moments to appreciate what APSA has become, think about who you will become. On a personal note, being a leader of APSA transformed me. I used to be that quiet, shy, uncertain graduate student sitting in the last row at conferences. I now not only sit in the front row, but I also hand out business cards and am not afraid to express my thoughts. I am definitely stronger than I used to be, and I attribute that strength to knowing that I represent something much bigger than myself: I represent all of you. It is my job to act in our best interest. It is my job to serve as a voice for each trainee and advocate for policy change. It is my job to be strong for all of us. I encourage you to do the same — use leadership to help you discover your potential and step out of your comfort zone. We often talk about how long and confusing the path is, but what we forget to remind ourselves of is the liberty to carve our own path and future — what a magnificent opportunity! There is a whole world waiting for us to take the lead and develop. We are not being held back, we are being trained for a future of liberated exploration as critical thinkers. We can leverage our training in the scientific method to expand medicine — from the level of cells to patients, populations, and entire healthcare systems. We are becoming physician-scientists because we are driven by the idea of making critical strides and improving the health outcomes of the world around us; I invite you to do this in all areas of your life. Become the physician-scientist leader you inspire to be “someday.” Someday is now. We do not have to wait forever to “make it” — it is up to you to make it happen and know that APSA is here to support you along the way. Acknowledgments ANI is supported in part by a National Cancer Institute fellowship (F30CA221004). She is grateful to Abhik Banerjee, Jeanette Iness, and Marty Iness for their thoughtful review of this address and encouragement throughout her training, as well as to Geri T. Ehle for her great work on the Bay Area Underrepresented Minority Outreach Event. APSA is thankful for the generous support of the Burroughs Wellcome Fund. Footnotes Copyright: © 2019, American Society for Clinical Investigation. Reference information: J Clin Invest. 2019;129(12):5062–5065. https://doi.org/10.1172/JCI131669. This article is adapted from a presentation at the 2019 AAP/ASCI/APSA Joint Meeting, April 5, 2019, in Chicago, Illinois, USA. References Nguyen FT. The birth of the American Physician Scientists Association — the next generation of Young Turks. 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Am J Med. 2018;131(5):578–584.View this article via: PubMedCrossRefGoogle Scholar The GREAT Group, 1994–2014. Advancing Biomedical Research Training. Washington, DC, USA: Association of American Medical Colleges. https://www.aamc.org/download/414322/data/greatgroup20thanniversaryreport.pdf Published 2014. Accessed August 1, 2019. Williams CS, et al. Training the physician-scientist: views from program directors and aspiring young investigators. JCI Insight. 2018;3(23):125651. View this article via: JCI InsightPubMedGoogle Scholar Adami AJ. Lessons in leadership and the impact of trainee leaders [2017 American Physician Scientists Association Presidential Address]. J Clin Invest. 2017;127(10):3571–3574.View this article via: JCIPubMedCrossRefGoogle Scholar DelloStritto DJ. Why societies? [2016 American Physician Scientists Association Presidential Address]. J Clin Invest. 2016;126(12):4723–4726.View this article via: JCIPubMedCrossRefGoogle Scholar

    更新日期:2019-12-03
  • C. Ronald Kahn: The Louisville Slugger of metabolic science
    J. Clin. Invest. (IF 12.282) Pub Date : 2019-11-20
    Jeffrey S. Flier

    Good afternoon. It’s an extraordinary honor and pleasure for me to be asked by the AAP to present the 2019 Kober Medal to Professor C. Ronald Kahn, my close friend and colleague for the past 45 years. I can think of no person more deserving of this prestigious award. The early days As some of you know, Ron grew up in Louisville, Kentucky, so my celebratory comments will have a Kentucky theme. Just as the Kentucky Derby begins with a call to the Derby, we might begin this event with a “Call to the Kober, 2019” (Supplemental Video 1; supplemental material available online with this article; https://doi.org/10.1172/JCI133156DS1). At his core, those who know him well see Ron as basically “the boy from Louisville.” This is a city known for the Louisville Slugger baseball bat and the Kentucky Derby, but in the realm of medical science, it is also known as the birthplace of C. Ronald Kahn. Ron’s “Old Kentucky Home” was a house on Meadow Road. If it hasn’t yet, this house should someday be decorated with a prominent brass plaque to record this history. The core Kahn family included his mom and dad, Reva and Dave, and his older brother Arnie (Figure 1). They were a source of great love and support during his childhood. Speaking of love, here is a wedding picture of Ron and Suzi from 1966 (Figure 2A). Fifty-three years later they are still happily together (Figure 2B). Figure 1 The core Kahn family in front of their Louisville home. Left to right: Ron, Reva, Dave, and Arnie Kahn. Figure 2 (A) The wedding of Ron and Suzi in 1966. (B) Ron and Suzi in 2019. After graduating with highest honors from the University of Louisville, Ron set his sights on a medical career, and entered the University of Louisville Medical School. Ron performed at a high level in med school, and then matched at Barnes Hospital and Washington University in St. Louis for his medical residency. Suzi took this picture as Ron walked into the Hospital on the first day of his internship (Figure 3). Figure 3 Ron entering Barnes Hospital on the first day of his internship. The NIH days Two years later, Ron set out for Bethesda to begin a glorious 11-year career at the NIH, working in the Clinical Center, Building 10. Ron set up home in the Diabetes Branch of the NIDDK as a fellow of Jesse Roth, the Branch Chief, who became my mentor three years later. When Ron arrived in 1970, Jesse had been working for several years to begin to define, characterize, and understand the biology and disease relevance of membrane receptors for peptide hormones. While these started with studies of ACTH, insulin receptors soon became the most critical model employed in the lab. Jesse and the people working with him during that period were really responsible for establishing this critical field, the precursor to what is now referred to as the field of signal transduction. Before this work, it was still debated whether insulin action began at the cell surface or began inside the cell, and if it began at the surface, what was the “second messenger” that mediated its action. Although they made fundamental discoveries, and established that the first step of insulin action was binding to a cell surface receptor, in retrospect what they actually understood then about the insulin receptor and insulin action was very limited. This is captured in an immortal cartoon drawn in 1979 by the scientist and cartoonist Pierre DeMeyts (Figure 4) showing that insulin binds to its receptor, then something happens, but what happened was really a black box! A long way since the black box concept! Figure 4 Cartoon by Pierre DeMeyts from 1979, illustrating knowledge at the time on insulin action. Phil Gorden, one of Ron’s early mentors, and a close collaborator of Jesse Roth, was a product of an even deeper place in the South — Mississippi (Supplemental Video 2)! The clinical associate who immediately preceded Ron in the lab was Bob Lefkowitz. Bob, or Lefko as he was called, was not from Kentucky or Mississippi, but from the Bronx. Bob attended the Bronx High School of Science, as I did a few years later. Bronx Science was and remains an amazing school that graduated many Nobel Laureates, of which Lefkowitz is one (Supplemental Video 3). Jesse Roth was not from Kentucky, or the Bronx, but from Brooklyn. I asked him to say a few words (Supplemental Video 4). To prepare for this talk, I actually did substantial research, aiming to uncover details on when and how Ron gained his interest in diabetes research. I went into the archives of the Banting and Best Institute in Toronto, where Banting and Best (and their experimental dog Margie) accomplished the impossible in 1921 — they discovered insulin. What I found, at the bottom of a box of old pictures, will astound you, as it did me (Figure 5). Somehow, Ron was actually there! Whether he was subsequently deleted from the picture and the story because he was not Canadian, or because he wore plaid pants like those seen here, will require more years of historical analysis. Figure 5 Banting, Kahn, and Best in 1921, celebrating the earliest phase of insulin discovery. Scientific contributions To briefly review Ron’s scientific contributions, I will run through some of Ron’s greatest hits. Part one involves his contributions during the NIH years. In 1973, Ron and colleagues established that insulin receptor expression was altered in the severely insulin-resistant ob/ob mice (1). Although discovery that the cause of this obesity syndrome was a mutation in the gene for the fat cell hormone leptin would not be discovered until 1994 (2), this work established that receptor binding activity could be altered in an important disease model, increasing interest in receptor biology. In 1974, Ron published a paper characterizing in great detail the kinetics and specificity of liver membrane insulin receptors (3). In 1975 (4) and 1976 (5), Ron and colleagues identified two human syndromes of severe insulin resistance, and showed that these were in fact disorders of insulin receptors, one caused by antibodies against the receptor (work with me) (4, 5) and the other most likely due to genetic defects in the receptor. In 1978, the anti-receptor antibodies were shown to be capable of being agonists of insulin action in adipocytes, through receptor crosslinking (6). In 1982, Ron and colleagues showed for the first time that activating the insulin receptor would stimulate its own phosphorylation, a major breakthrough (7). In 1983 this was shown to be tyrosine phosphorylation (8). Part 2 of Ron’s greatest hits continued in Boston. In 1991, he and associates identified and defined the first insulin receptor substrate, IRS-1 (9), and in 1994 this allowed them to expand and clarify understanding of downstream signaling pathways (10). Beginning in 1999, the Kahn lab used gene targeting to knock out insulin receptors in numerous tissues, including β cells (11), neurons (12), and adipocytes (13), producing many new insights into the complex biology of insulin. Not resting on his laurels, Ron has extended his research into new areas. Most recently, his work on the microbiome (14) and discovery of virally encoded insulin-like peptides (15) pushes our understanding of insulin action and the Kahn discovery envelope even further. Now, sometimes Ron’s productivity creates problems for other scientists in the field. Mike Czech and his fellows explain this in this video (Supplemental Video 5). Another way to capture Ron’s productivity is to graph his number of publications as a function of time. This plot reveals a nearly perfectly linear productivity from 1975 onwards (Figure 6A). We might then ask what effect this research has had on the prevalence of diabetes. Unfortunately, after an initial lag, there is a clear positive correlation between Ron’s scientific productivity and the prevalence of diabetes, which his research, as stated in numerous grant proposals, was aiming to reduce (Figure 6B). Fortunately, correlation doesn’t imply causation! In fact, my research reveals for the first time that diabetes prevalence would have been far greater if not for Ron’s scientific output, a point that Ron stresses in all grant proposals (Figure 6C). Figure 6 Top: The number of papers by Ron Kahn over time. Bottom: Correlation between Ron Kahn’s publications and the prevalence of diabetes in the US. Boston, Joslin, and Harvard After 11 amazing years in Bethesda, including 4 when we closely interacted, Ron left the NIH, and was presented with his scientific symbol, a Louisville Slugger bat (Figure 7). The Harvard/Joslin Era began in 1981. I asked Dr. Eugene Braunwald, who recruited Ron to Boston, to offer a few comments. I asked him to inject some humor, but he replied — I don’t do humor (Supplemental Video 6). Figure 7 Jesse Roth marks Ron’s departure from the NIH for Boston by presenting a Louisville Slugger bat. Ron has assembled amazing lab groups over the years, a remarkable number of whom became leaders in the field of diabetes research, in the US and around the world. One of his legacies was outstanding mentorship of women scientists, one of whom was my wife, Terry Maratos-Flier (Supplemental Video 7). Ron has won every award in the field of diabetes, and many outside the field. When he won the Banting award in 1993, he stood between Jesse Roth, who won it before he did, and me, who would go on to win this award (Figure 8). Figure 8 Celebrating the presentation of the Banting Award from the American Diabetes Association to Ron Kahn in 1993. Left to right: Susan Roth, Suzi Kahn, Jesse Roth, Ron Kahn, Jeff Flier, Terry Maratos-Flier. Turning back to his personal life, you can remove Ron from Louisville, but you can’t remove Louisville from Ron. Here’s the extended Kahn family in 2009, at Ron’s father Dave’s 100th birthday celebration (Figure 9). His daughter Stacy and son Jeff, doctor and lawyer, are the apple of their dad’s eye (Figure 10). And Ron with his four wonderful grandkids (Figure 11)! Figure 9 The extended Kahn family celebrates Dave’s 100th birthday in 2009. Figure 10 Ron Kahn with son Jeffrey and daughter Stacy. Figure 11 Ron Kahn with his four grandkids. With all of his success, Ron is still taking risks in both his research and his recreation (Figure 12). So much has been learned about insulin action since Pierre DeMeyts drew his famous cartoon in 1979 (Figure 4). Today, insulin signaling is no longer a black box. Instead, everything about insulin action is perfectly explained. To illustrate, I commissioned a new cartoon on the current state of insulin action by Pierre DeMeyts (Figure 13). Those of us there from the beginning confess that on some level, we do miss the simplicity of the black box. While a lot has been learned, not everything about insulin action is yet explained. Figure 12 Ron Kahn skydiving. Figure 13 Cartoon by Pierre DeMeyts, illustrating how far we have come since the “black box” in explaining insulin action pathways. So, in the end, Ron Kahn is a man for the ages, and a true scientific Louisville slugger. His impact on the Joslin Diabetes Center, Harvard Medical School, and the international scientific community will last far into the future. In the end, I can say this: Through research conducted over the past 48 years at the NIH, Joslin, and Harvard, no one has contributed more than Ron Kahn to our understanding of insulin, insulin signal transduction, insulin’s complex multiorgan physiologic actions, and insulin’s role in human disease. He is most deserving of the 2019 Kober Medal, and it’s a great pleasure for me to present him to you today. Supplemental material View Supplemental Video 1 View Supplemental Video 2 View Supplemental Video 3 View Supplemental Video 4 View Supplemental Video 5 View Supplemental Video 6 View Supplemental Video 7 Footnotes Copyright: © 2019, American Society for Clinical Investigation. Reference information: J Clin Invest. 2019;129(12):5066–5070. https://doi.org/10.1172/JCI133156. This article is adapted from a presentation at the AAP/ASCI/APSA Joint Meeting, April 6, 2019, in Chicago, Illinois, USA. References Kahn CR, Neville DM, Roth J. Insulin-receptor interaction in the obese-hyperglycemic mouse. A model of insulin resistance. J Biol Chem. 1973;248(1):244–250.View this article via: PubMedGoogle Scholar Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature. 1994;372(6505):425–432.View this article via: PubMedCrossRefGoogle Scholar Kahn CR, Freychet P, Roth J, Neville DM. Quantitative aspects of the insulin-receptor interaction in liver plasma membranes. J Biol Chem. 1974;249(7):2249–2257.View this article via: PubMedGoogle Scholar Flier JS, Kahn CR, Roth J, Bar RS. Antibodies that impair insulin receptor binding in an unusual diabetic syndrome with severe insulin resistance. Science. 1975;190(4209):63–65.View this article via: PubMedCrossRefGoogle Scholar Kahn CR, et al. The syndromes of insulin resistance and acanthosis nigricans. Insulin-receptor disorders in man. N Engl J Med. 1976;294(14):739–745.View this article via: PubMedCrossRefGoogle Scholar Kahn CR, Baird KL, Jarrett DB, Flier JS. Direct demonstration that receptor crosslinking or aggregation is important in insulin action. Proc Natl Acad Sci U S A. 1978;75(9):4209–4213.View this article via: PubMedCrossRefGoogle Scholar Kasuga M, Karlsson FA, Kahn CR. Insulin stimulates the phosphorylation of the 95,000-dalton subunit of its own receptor. Science. 1982;215(4529):185–187.View this article via: PubMedCrossRefGoogle Scholar Kasuga M, Zick Y, Blithe DL, Crettaz M, Kahn CR. Insulin stimulates tyrosine phosphorylation of the insulin receptor in a cell-free system. Nature. 1982;298(5875):667–669.View this article via: PubMedCrossRefGoogle Scholar Sun XJ, et al. Structure of the insulin receptor substrate IRS-1 defines a unique signal transduction protein. Nature. 1991;352(6330):73–77.View this article via: PubMedCrossRefGoogle Scholar Araki E, et al. Alternative pathway of insulin signalling in mice with targeted disruption of the IRS-1 gene. Nature. 1994;372(6502):186–190.View this article via: PubMedCrossRefGoogle Scholar Kulkarni RN, Brüning JC, Winnay JN, Postic C, Magnuson MA, Kahn CR. Tissue-specific knockout of the insulin receptor in pancreatic beta cells creates an insulin secretory defect similar to that in type 2 diabetes. Cell. 1999;96(3):329–339.View this article via: PubMedCrossRefGoogle Scholar Brüning JC, et al. Role of brain insulin receptor in control of body weight and reproduction. Science. 2000;289(5487):2122–2125.View this article via: PubMedCrossRefGoogle Scholar Blüher M, Kahn BB, Kahn CR. Extended longevity in mice lacking the insulin receptor in adipose tissue. Science. 2003;299(5606):572–574.View this article via: PubMedCrossRefGoogle Scholar Ussar S, et al. Interactions between gut microbiota, host genetics and diet modulate the predisposition to obesity and metabolic syndrome. Cell Metab. 2015;22(3):516–530.View this article via: PubMedCrossRefGoogle Scholar Altindis E, et al. Viral insulin-like peptides activate human insulin and IGF-1 receptor signaling: A paradigm shift for host-microbe interactions. Proc Natl Acad Sci U S A. 2018;115(10):2461–2466.View this article via: PubMedCrossRefGoogle Scholar

    更新日期:2019-12-03
  • Challenges in optimizing preexposure prophylaxis development, engagement, and access for HIV prevention
    J. Clin. Invest. (IF 12.282) Pub Date : 2019-11-11
    Eileen P. Scully; Ethel D. Weld; Joel N. Blankson

    One of the greatest successes of modern science is the development of effective antiretroviral therapy (ART) for control of HIV-1 infection. Arguably one of the more innovative responses to the ongoing HIV epidemic is the repurposing of ART for preventive efforts as preexposure prophylaxis (PrEP). This strategy has been critical in the face of approximately 1.7 million new infections in 2018 and in the absence of an effective HIV vaccine. Notwithstanding this advance, significant scientific challenges remain for the optimal implementation of PrEP, and novel approaches are still needed (1). In the United States, currently approved PrEP consists of a single pill containing two antiretroviral drugs taken daily. While this regimen substantially reduces the risk of HIV-1 acquisition, PrEP has still not reached the majority of at-risk individuals, even in resource-rich settings (2). Comprehensive preventive services are a cornerstone of the Department of Health and Human Services’ strategic plan to end the HIV epidemic (3), and PrEP is the biomedical intervention currently available. Preventive interventions are at the intersection of medical and behavioral science, and their rollout can highlight disparities in health care access. PrEP is no different, requiring rigorous efforts to achieve its potential equitably across diverse groups. We propose that PrEP offers a window into the efforts to end the HIV epidemic while also illuminating the tension between innovation in biomedical science and its application in public health efforts. How effective is PrEP and for whom? PrEP efficacy was initially demonstrated among men who have sex with men (MSM) with high-risk sexual behavior, reducing risk of HIV acquisition versus placebo (relative risk reduction [RRR] of 44%), with even greater protection (89% RRR) in a subgroup with confirmed presence of the study drug in blood (4). Similar results were seen in serodiscordant couples in which the partner with HIV was not on ART and the uninfected partner was randomized to receive PrEP: an overall RRR of 75% with PrEP, and 90% RRR with detectable drug levels (5). Of note, initial studies done exclusively in women at risk of sexual acquisition were not as successful (6, 7); the apparent failures were driven predominantly by very low adherence (8). More recent studies have helped to clarify that PrEP is indeed effective in women, although because of differences in tissue site drug levels and other factors, daily adherence may be required to achieve full protection (8). Direct interactions between the vaginal microbiome and tenofovir may impact efficacy at least for topical therapy approaches (9), which suggests the need for caution when extrapolating data between populations. These concerns are highlighted by the recent FDA approval of a second drug for PrEP, emtricitabine/tenofovir alafenamide; this approval excludes women with vaginal receptive sex as their risk, as the formulation has not been studied in women. In sub-Saharan Africa, four in five new infections among adolescents aged 15–19 years are in girls, therefore appropriate testing and validation in women, and optimization of delivery and uptake are paramount (10). Testing PrEP in the context of conception, pregnancy, and the postpartum period is also important for meaningful risk mitigation, particularly given the high risk of transmission to the infant in the context of acute infection during pregnancy (11). Implementation and demonstration projects have highlighted that PrEP must be acceptable and accessible to people who need it; scientific demonstration of efficacy is inadequate to achieve full impact (12). PrEP is also highly effective in preventing transmission via injection drug use (13), although implementation of PrEP in this population is minimal. This deficit in the use of PrEP is particularly relevant in regions where adjunctive harm reduction strategies (e.g., needle exchanges) are inadequate and drug use is highly criminalized. A cluster of HIV transmission through injection in the United States highlights the potential for an intersection between the opioid and HIV epidemics and the need to offer preventive options (3). What are the risks of PrEP? As with any medication, there is a small risk of idiosyncratic drug reaction and a risk of adverse effects, including modest declines in bone mineral density or renal impairment. However, with real-world implementation of PrEP, these risks have proven to be minimal (14). There are also scattered case reports of PrEP failure and a lingering concern for inadvertent initiation of PrEP in individuals already infected with HIV, but this has been a rare phenomenon overall. Perhaps a greater detriment to the adoption of PrEP has been a perceived risk that PrEP could lead to a rise in sexually transmitted infections (STIs) due to risky sexual practices. Increased STI incidence has been seen in a subset (~25%) of PrEP users, but this observation needs to be viewed in the context of increased frequency of testing for STIs (15, 16). The clinical decision-making impact of a perceived risk compensation must be directly addressed, as it is likely to bias providers away from PrEP prescription (17, 18). What is limiting the effectiveness of PrEP? A 2019 study by the CDC examined the impact of targeted outreach to MSM about PrEP, with PrEP awareness increasing from 60% to 90% from 2014 to 2017 (2). However, despite this rise in awareness, active use of PrEP remained limited, increasing from 6% to 35% of eligible individuals over the same period. There is a notable racial disparity in PrEP uptake, with Black MSM using PrEP at approximately half the rate of White MSM (Figure 1). Moreover, PrEP use is also linked to higher educational attainment, income, and insurance status (2). Figure 1 HIV infection risk and PrEP prescriptions in the United States. (A) Estimated proportions of people living in the United States at risk for HIV infection (2015 data) and distribution of PrEP prescriptions in 2016 among the subset for whom race/ethnicity data is available. (B) Risk versus prescription frequency among men and women (2015 data). Figure based on data in refs. 19, 21. Of note, PrEP education efforts have primarily engaged MSM. Transgender women, who have a disproportionate risk of HIV infection, often have limited engagement with health care services. In the United States, women at risk for HIV infection are unlikely to self-identify or to be assessed to be at risk of HIV by health care providers. PrEP use among women has remained very low and static, at less than 5% of prescriptions and 2% of the women at risk during a period of expanding use among MSM (19). The best ways of reaching women at risk remains a topic of active investigation. In addition to the challenges of identifying and engaging people at risk for HIV, continued adherence to the PrEP regimen is required. Recent studies have demonstrated that high levels of initial adherence are often not sustained over time (12). Future strategies that address this challenge may include event-driven prophylaxis, proven effective among MSM (20); longer-acting formulations of PrEP; behaviorally congruent delivery methods; and other novel drugs and formulations (reviewed in ref. 21). A single PrEP modality, as is currently available, is unlikely sufficient for broad population-based impact, and consistent with the experience of contraception, offering a choice among an array of acceptable methods is likely to be a major driver of improved uptake (1). Can PrEP interrupt the HIV epidemic? Outside the rarefied setting of a clinical trial, PrEP has shown high preventive efficacy, and, in some cases, implementation and demonstration projects have shown decreases in local HIV incidence. Together with early treatment to prevent transmission (treatment as prevention) and in an era when patients on ART with undetectable viral loads have been shown not to transmit the virus (undetectable = transmissible), PrEP can bring us closer to the goal of ending the HIV epidemic, which has already claimed 35 million lives (3). However, even with more diverse implementation options, PrEP is not likely to be the only solution to the problem. As seen in the hepatitis C epidemic, even highly successful curative therapy will not be sufficient alone to end the epidemic, and an adjunctive vaccine would be highly impactful. Similarly, a vaccine is still urgently needed for HIV prevention. This need does not diminish the role of PrEP as an immediately available and effective intervention — one that further scientific innovation can certainly extend and improve. Conclusions The story of the development of PrEP is one of the astounding successes in medicine. The efficacy of this intervention has exceeded our best efforts to date at HIV vaccine design. But PrEP is also a story of barriers for both people at risk of HIV infection and providers, and an important illustration of how interventions are only successful when they can be effectively implemented. We would also argue that PrEP highlights the critical need for innovation from basic scientists and clinicians even after an initial “solution” has been achieved (1, 21). Although currently available PrEP is efficacious, the challenges of adherence and access emphasize the need for novel approaches to deliver therapies in ways that are acceptable, feasible, and available to the individuals at risk of HIV infection. Some of these strategies were highlighted at the recent 10th International AIDS Society Conference on HIV Science in Mexico City, and the recent call for new investigation in this arena from the NIH is an opportunity to expand and develop the science of prevention. Now more than ever, physicians and scientists have a critical role in developing new approaches, advocating for effective interventions, and translating the best possible science to at-risk populations as well as to providers and policy makers in order to realize the optimal benefits of PrEP. Acknowledgments We thank Craig Hendrix and Guido Massacessi for thoughtful comments on a draft of this article. Footnotes Conflict of interest: The authors have declared that no conflict of interest exists. Copyright: © 2019, American Society for Clinical Investigation. Reference information: J Clin Invest. 2019;129(12):5071–5073. https://doi.org/10.1172/JCI134389. References Hendrix CW. HIV Antiretroviral pre-exposure prophylaxis: development challenges and pipeline promise. Clin Pharmacol Ther. 2018;104(6):1082–1097.View this article via: PubMedCrossRefGoogle Scholar Finlayson T, et al. Changes in HIV preexposure prophylaxis awareness and use among men who have sex with men — 20 urban areas, 2014 and 2017. MMWR Morb Mortal Wkly Rep. 2019;68(27):597–603.View this article via: PubMedCrossRefGoogle Scholar Fauci AS, Redfield RR, Sigounas G, Weahkee MD, Giroir BP. Ending the HIV epidemic: a plan for the United States. JAMA. 2019;321(9):844–845.View this article via: PubMedCrossRefGoogle Scholar Grant RM, et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med. 2010;363(27):2587–2599.View this article via: PubMedCrossRefGoogle Scholar Baeten JM, et al. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N Engl J Med. 2012;367(5):399–410.View this article via: PubMedCrossRefGoogle Scholar Marrazzo JM, et al. Tenofovir-based preexposure prophylaxis for HIV infection among African women. N Engl J Med. 2015;372(6):509–518.View this article via: PubMedCrossRefGoogle Scholar Van Damme L, et al. Preexposure prophylaxis for HIV infection among African women. N Engl J Med. 2012;367(5):411–422.View this article via: PubMedCrossRefGoogle Scholar Sheth AN, Rolle CP, Gandhi M. HIV pre-exposure prophylaxis for women. J Virus Erad. 2016;2(3):149–155.View this article via: PubMedGoogle Scholar Klatt NR, et al. Vaginal bacteria modify HIV tenofovir microbicide efficacy in African women. Science. 2017;356(6341):938–945.View this article via: PubMedCrossRefGoogle Scholar [No authors listed]. Global HIV & AIDS statistics — 2019 fact sheet. UNAIDS. https://www.unaids.org/en/resources/fact-sheet Accessed November 4, 2019. Matthews LT, et al. Protocol for a longitudinal study to evaluate the use of tenofovir-based PrEP for safer conception and pregnancy among women in South Africa. BMJ Open. 2019;9(7):e027227. Celum CL, et al. HIV pre-exposure prophylaxis for adolescent girls and young women in Africa: from efficacy trials to delivery. J Int AIDS Soc. 2019;22(suppl 4):e25298. View this article via: PubMedGoogle Scholar Choopanya K, et al. Antiretroviral prophylaxis for HIV infection in injecting drug users in Bangkok, Thailand (the Bangkok Tenofovir Study): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2013;381(9883):2083–2090.View this article via: PubMedCrossRefGoogle Scholar Marcus JL, et al. Preexposure prophylaxis for HIV prevention in a large integrated health care system: adherence, renal safety, and discontinuation. J Acquir Immune Defic Syndr. 2016;73(5):540–546.View this article via: PubMedCrossRefGoogle Scholar Beymer MR, et al. Does HIV pre-exposure prophylaxis use lead to a higher incidence of sexually transmitted infections? A case-crossover study of men who have sex with men in Los Angeles, California. Sex Transm Infect. 2018;94(6):457–462.View this article via: PubMedCrossRefGoogle Scholar Traeger MW, et al. Association of HIV preexposure prophylaxis with incidence of sexually transmitted infections among individuals at high risk of HIV infection. JAMA. 2019;321(14):1380–1390.View this article via: PubMedCrossRefGoogle Scholar Gandhi M, Spinelli MA, Mayer KH. Addressing the sexually transmitted infection and HIV syndemic. JAMA. 2019;321(14):1356–1358.View this article via: PubMedCrossRefGoogle Scholar Marcus JL, Katz KA, Krakower DS, Calabrese SK. Risk compensation and clinical decision making — the case of HIV preexposure prophylaxis. N Engl J Med. 2019;380(6):510–512.View this article via: PubMedCrossRefGoogle Scholar Huang YA, Zhu W, Smith DK, Harris N, Hoover KW. HIV preexposure prophylaxis, by race and ethnicity — United States, 2014-2016. MMWR Morb Mortal Wkly Rep. 2018;67(41):1147–1150.View this article via: PubMedCrossRefGoogle Scholar Molina JM, et al. Efficacy, safety, and effect on sexual behaviour of on-demand pre-exposure prophylaxis for HIV in men who have sex with men: an observational cohort study. Lancet HIV. 2017;4(9):e402–e410.View this article via: PubMedCrossRefGoogle Scholar Beymer MR, Holloway IW, Pulsipher C, Landovitz RJ. Current and future PrEP medications and modalities: on-demand, injectables, and topicals. Curr HIV/AIDS Rep. 2019;16(4):349–358.View this article via: PubMedCrossRefGoogle Scholar

    更新日期:2019-12-03
  • Paroxysmal nocturnal hemoglobinuria without GPI-anchor deficiency
    J. Clin. Invest. (IF 12.282) Pub Date : 2019-10-22
    Robert A. Brodsky

    Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired disorder characterized by hemolysis, thrombosis, and bone marrow failure caused by defective expression of glycosylphosphatidylinositol-anchored (GPI-anchored) complement inhibitors. Most commonly, PNH is caused by loss of function of PIGA, which is required for GPI biosynthesis. In this issue of the JCI, Höchsmann et al. report on 4 PNH patients who also had marked autoinflammatory manifestations, including aseptic meningitis. All 4 patients had a germline mutation of the related gene PIGT and a somatically acquired myeloid common deleted region (CDR) on chromosome 20q that deleted the second PIGT allele. The biochemistry and clinical manifestations indicate that these patients have subtle but important differences from those with PNH resulting from PIGA mutations, suggesting PIGT-PNH may be a distinct clinical entity.

    更新日期:2019-12-03
  • Adding chimeric antigen receptor–induced killer cells to the medical oncology shelf
    J. Clin. Invest. (IF 12.282) Pub Date : 2019-10-22
    Brigett D. Brandjes; Marco L. Davila

    With the approval of CD19-targeted chimeric antigen receptor (CAR) T cells for the treatment of B cell malignancies, clinicians have gained valuable insights into the power and challenges of cellular therapies. In this issue of the JCI, Maluski et al. showed that a CAR containing a CD28 costimulatory domain drives progeny differentiation to resemble that of NK cells, which have the potential for an off-the-shelf cell therapy. These CAR-induced killer (CARiK) cells displayed potent antitumor function and killed across the MHC barrier in vivo. After performing in vitro and in vivo mouse studies, the authors also successfully differentiated human umbilical cord blood–derived progenitor cells into CARiK cells. These unique cells may address some of the current challenges associated with first-generation CARs, such as prolonged production that requires patients to wait weeks for infusion. We believe this innovative progenitor gene-engineered lymphoid system has the potential for clinical translation.

    更新日期:2019-12-03
  • Beclin-1 as a neutrophil-specific immune checkpoint
    J. Clin. Invest. (IF 12.282) Pub Date : 2019-10-28
    Yu-Lin Su; Marcin Kortylewski

    Neutrophils are early wound healing and inflammation regulators that, due to functional plasticity, can adopt either pro- or antitumor functions. Until recently, beclin-1 was a protein known mainly for its role as a critical regulator of autophagy. In this issue of the JCI, Tan et al. describe the effects of the beclin-1 conditional myeloid cell–specific deletion in mice, in which immunostimulation resulted in hypersensitive neutrophils. The chronic proinflammatory effect of these neutrophils triggered spontaneous B cell malignancies to develop. Such tumorigenic effects were mediated primarily by IL-21 and CD40 signaling, leading to the upregulation of tolerogenic molecules, such as IL-10 and PD-L1. The authors went on to examine samples derived from patient lymphoid malignancies and showed that beclin-1 expression in neutrophils positively correlated with pre–B cell leukemia/lymphoma. Overall, the study provides an elegant model for neutrophil-driven carcinogenesis and identifies potential targets for immunotherapy of B cell malignancies.

    更新日期:2019-12-03
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