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  • Filamin A inhibition reduces seizure activity in a mouse model of focal cortical malformations
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-02-19
    Longbo Zhang, Tianxiang Huang, Shannon Teaw, Lena H. Nguyen, Lawrence S. Hsieh, Xuan Gong, Lindsay H. Burns, Angélique Bordey

    Epilepsy treatments for patients with mechanistic target of rapamycin (mTOR) disorders, such as tuberous sclerosis complex (TSC) or focal cortical dysplasia type II (FCDII), are urgently needed. In these patients, the presence of focal cortical malformations is associated with the occurrence of lifelong epilepsy, leading to severe neurological comorbidities. Here, we show that the expression of the actin cross-linking protein filamin A (FLNA) is increased in resected cortical tissue that is responsible for seizures in patients with FCDII and in mice modeling TSC and FCDII with mutations in phosphoinositide 3-kinase (PI3K)–ras homolog enriched in brain (Rheb) pathway genes. Normalizing FLNA expression in these mice through genetic knockdown limited cell misplacement and neuronal dysmorphogenesis, two hallmarks of focal cortical malformations. In addition, Flna knockdown reduced seizure frequency independently of mTOR signaling. Treating mice with a small molecule targeting FLNA, PTI-125, before the onset of seizures alleviated neuronal abnormalities and reduced seizure frequency compared to vehicle-treated mice. In addition, the treatment was also effective when injected after seizure onset in juvenile and adult mice. These data suggest that targeting FLNA with either short hairpin RNAs or the small molecule PTI-125 might be effective in reducing seizures in patients with TSC and FCDII bearing mutations in PI3K-Rheb pathway genes.

    更新日期:2020-02-19
  • Long noncoding RNA SNHG12 integrates a DNA-PK–mediated DNA damage response and vascular senescence
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-02-19
    Stefan Haemmig, Dafeng Yang, Xinghui Sun, Debapria Das, Siavash Ghaffari, Roberto Molinaro, Lei Chen, Yihuan Deng, Dan Freeman, Norman Moullan, Yevgenia Tesmenitsky, A.K.M. Khyrul Wara, Viorel Simion, Eugenia Shvartz, James F. Lee, Tianlun Yang, Galina Sukova, Jarrod A. Marto, Peter H. Stone, Warren L. Lee, Johan Auwerx, Peter Libby, Mark W. Feinberg

    Long noncoding RNAs (lncRNAs) are emerging regulators of biological processes in the vessel wall; however, their role in atherosclerosis remains poorly defined. We used RNA sequencing to profile lncRNAs derived specifically from the aortic intima of Ldlr−/− mice on a high-cholesterol diet during lesion progression and regression phases. We found that the evolutionarily conserved lncRNA small nucleolar host gene-12 (SNHG12) is highly expressed in the vascular endothelium and decreases during lesion progression. SNHG12 knockdown accelerated atherosclerotic lesion formation by 2.4-fold in Ldlr−/− mice by increased DNA damage and senescence in the vascular endothelium, independent of effects on lipid profile or vessel wall inflammation. Conversely, intravenous delivery of SNHG12 protected the tunica intima from DNA damage and atherosclerosis. LncRNA pulldown in combination with liquid chromatography–tandem mass spectrometry (LC-MS/MS) analysis showed that SNHG12 interacted with DNA-dependent protein kinase (DNA-PK), an important regulator of the DNA damage response. The absence of SNHG12 reduced the DNA-PK interaction with its binding partners Ku70 and Ku80, abrogating DNA damage repair. Moreover, the anti-DNA damage agent nicotinamide riboside (NR), a clinical-grade small-molecule activator of NAD+, fully rescued the increases in lesional DNA damage, senescence, and atherosclerosis mediated by SNHG12 knockdown. SNHG12 expression was also reduced in pig and human atherosclerotic specimens and correlated inversely with DNA damage and senescent markers. These findings reveal a role for this lncRNA in regulating DNA damage repair in the vessel wall and may have implications for chronic vascular disease states and aging.

    更新日期:2020-02-19
  • BRCAness, SLFN11, and RB1 loss predict response to topoisomerase I inhibitors in triple-negative breast cancers
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-02-19
    Florence Coussy, Rania El-Botty, Sophie Château-Joubert, Ahmed Dahmani, Elodie Montaudon, Sophie Leboucher, Ludivine Morisset, Pierre Painsec, Laura Sourd, Léa Huguet, Fariba Nemati, Jean-Luc Servely, Thibaut Larcher, Sophie Vacher, Adrien Briaux, Cécile Reyes, Philippe La Rosa, Georges Lucotte, Tatiana Popova, Pierre Foidart, Nor Eddine Sounni, Agnès Noel, Didier Decaudin, Laetitia Fuhrmann, Anne Salomon, Fabien Reyal, Christopher Mueller, Petra Ter Brugge, Jos Jonkers, Marie-France Poupon, Marc-Henri Stern, Ivan Bièche, Yves Pommier, Elisabetta Marangoni

    Topoisomerase I (TOP1) inhibitors trap TOP1 cleavage complexes resulting in DNA double-strand breaks (DSBs) during replication, which are repaired by homologous recombination (HR). Triple-negative breast cancer (TNBC) could be eligible for TOP1 inhibitors given the considerable proportion of tumors with a defect in HR-mediated repair (BRCAness). The TOP1 inhibitor irinotecan was tested in 40 patient-derived xenografts (PDXs) of TNBC. BRCAness was determined with a single-nucleotide polymorphism (SNP) assay, and expression of Schlafen family member 11 (SLFN11) and retinoblastoma transcriptional corepressor 1 (RB1) was evaluated by real-time polymerase chain reaction (RT-PCR) and immunohistochemistry analyses. In addition, the combination of irinotecan and the ataxia telangiectasia and Rad3-related protein (ATR) inhibitor VE-822 was tested in SLFN11-negative PDXs, and two clinical non-camptothecin TOP1 inhibitors (LMP400 and LMP776) were tested. Thirty-eight percent of the TNBC models responded to irinotecan. BRCAness combined with high SLFN11 expression and RB1 loss identified highly sensitive tumors, consistent with the notion that deficiencies in cell cycle checkpoints and DNA repair result in high sensitivity to TOP1 inhibitors. Treatment by the ATR inhibitor VE-822 increased sensitivity to irinotecan in SLFN11-negative PDXs and abolished irinotecan-induced phosphorylation of checkpoint kinase 1 (CHK1). LMP400 (indotecan) and LMP776 (indimitecan) showed high antitumor activity in BRCA1-mutated or BRCAness-positive PDXs. Last, low SLFN11 expression was associated with poor survival in 250 patients with TNBC treated with anthracycline-based chemotherapy. In conclusion, a substantial proportion of TNBC respond to irinotecan. BRCAness, high SLFN11 expression, and RB1 loss are highly predictive of response to irinotecan and the clinical indenoisoquinoline TOP1 inhibitors.

    更新日期:2020-02-19
  • A geometrically adaptable heart valve replacement
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-02-19
    Sophie C. Hofferberth, Mossab Y. Saeed, Lara Tomholt, Matheus C. Fernandes, Christopher J. Payne, Karl Price, Gerald R. Marx, Jesse J. Esch, David W. Brown, Jonathan Brown, Peter E. Hammer, Richard W. Bianco, James C. Weaver, Elazer R. Edelman, Pedro J. del Nido

    Congenital heart valve disease has life-threatening consequences that warrant early valve replacement; however, the development of a growth-accommodating prosthetic valve has remained elusive. Thousands of children continue to face multiple high-risk open-heart operations to replace valves that they have outgrown. Here, we demonstrate a biomimetic prosthetic valve that is geometrically adaptable to accommodate somatic growth and structural asymmetries within the heart. Inspired by the human venous valve, whose geometry is optimized to preserve functionality across a wide range of constantly varying volume loads and diameters, our balloon-expandable synthetic bileaflet valve analog exhibits similar adaptability to dimensional and shape changes. Benchtop and acute in vivo experiments validated design functionality, and in vivo survival studies in growing sheep demonstrated that mechanical valve expansion accommodated growth. As illustrated in this work, dynamic size adaptability with preservation of unidirectional flow in prosthetic valves thus offers a paradigm shift in the treatment of heart valve disease.

    更新日期:2020-02-19
  • Anti–PD-1 treatment impairs opioid antinociception in rodents and nonhuman primates
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-02-19
    Zilong Wang, Changyu Jiang, Qianru He, Megumi Matsuda, Qingjian Han, Kaiyuan Wang, Sangsu Bang, Huiping Ding, Mei-Chuan Ko, Ru-Rong Ji

    Emerging immunotherapies with monoclonal antibodies against programmed cell death protein–1 (PD-1) have shown success in treating cancers. However, PD-1 signaling in neurons is largely unknown. We recently reported that dorsal root ganglion (DRG) primary sensory neurons express PD-1 and activation of PD-1 inhibits neuronal excitability and pain. Opioids are mainstay treatments for cancer pain, and morphine produces antinociception via mu opioid receptor (MOR). Here, we report that morphine antinociception and MOR signaling require neuronal PD-1. Morphine-induced antinociception after systemic or intrathecal injection was compromised in Pd1−/− mice. Morphine antinociception was also diminished in wild-type mice after intravenous or intrathecal administration of nivolumab, a clinically used anti–PD-1 monoclonal antibody. In mouse models of inflammatory, neuropathic, and cancer pain, spinal morphine antinociception was compromised in Pd1−/− mice. MOR and PD-1 are coexpressed in sensory neurons and their axons in mouse and human DRG tissues. Morphine produced antinociception by (i) suppressing calcium currents in DRG neurons, (ii) suppressing excitatory synaptic transmission, and (iii) inducing outward currents in spinal cord neurons; all of these actions were impaired by PD-1 blockade in mice. Loss of PD-1 also enhanced opioid-induced hyperalgesia and tolerance and potentiates opioid-induced microgliosis and long-term potentiation in the spinal cord in mice. Last, intrathecal infusion of nivolumab inhibited intrathecal morphine-induced antinociception in nonhuman primates. Our findings demonstrate that PD-1 regulates opioid receptor signaling in nociceptive neurons, leading to altered opioid-induced antinociception in rodents and nonhuman primates.

    更新日期:2020-02-19
  • Inhibition of the ALDH18A1-MYCN positive feedback loop attenuates MYCN-amplified neuroblastoma growth
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-02-19
    Yu-Feng Guo, Jiang-Jie Duan, Jun Wang, Lin Li, Di Wang, Xun-Zhou Liu, Jing Yang, Hua-Rong Zhang, Jing Lv, Yong-Jun Yang, Ze-Yu Yang, Jiao Cai, Xue-Mei Liao, Tao Tang, Ting-Ting Huang, Feng Wu, Xian-Yan Yang, Qian Wen, Xiu-Wu Bian, Shi-Cang Yu

    MYCN-amplified neuroblastoma (NB) is characterized by poor prognosis, and directly targeting MYCN has proven challenging. Here, we showed that aldehyde dehydrogenase family 18 member A1 (ALDH18A1) exerts profound impacts on the proliferation, self-renewal, and tumorigenicity of NB cells and is a potential risk factor in patients with NB, especially those with MYCN amplification. Mechanistic studies revealed that ALDH18A1 could both transcriptionally and posttranscriptionally regulate MYCN expression, with MYCN reciprocally transactivating ALDH18A1 and thus forming a positive feedback loop. Using molecular docking and screening, we identified an ALDH18A1-specific inhibitor, YG1702, and demonstrated that pharmacological inhibition of ALDH18A1 was sufficient to induce a less proliferative phenotype and confer tumor regression and prolonged survival in NB xenograft models, providing therapeutic insights into the disruption of this reciprocal regulatory loop in MYCN-amplified NB.

    更新日期:2020-02-19
  • How to reverse acetyl-aging
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-02-19
    Emily J. Gallagher

    SIRT2 deacetylation of NLRP3 reduces inflammation and reverses age-related glucose dysregulation.

    更新日期:2020-02-19
  • Microbiome goes to the ICU
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-02-19
    Shaon Sengupta

    Lung microbiota predicts outcomes in critically ill mechanically ventilated patients.

    更新日期:2020-02-19
  • Microfluidic modeling of bone marrow pathophysiology
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-02-19
    Ioannis Zervantonakis

    Human bone-marrow-on-a-chip improves drug studies of hematopoietic cell function and identifies a neutrophil maturation defect in a genetic disorder.

    更新日期:2020-02-19
  • Engineered probiotics for local tumor delivery of checkpoint blockade nanobodies
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-02-12
    Candice R. Gurbatri, Ioana Lia, Rosa Vincent, Courtney Coker, Samuel Castro, Piper M. Treuting, Taylor E. Hinchliffe, Nicholas Arpaia, Tal Danino

    Checkpoint inhibitors have revolutionized cancer therapy but only work in a subset of patients and can lead to a multitude of toxicities, suggesting the need for more targeted delivery systems. Because of their preferential colonization of tumors, microbes are a natural platform for the local delivery of cancer therapeutics. Here, we engineer a probiotic bacteria system for the controlled production and intratumoral release of nanobodies targeting programmed cell death–ligand 1 (PD-L1) and cytotoxic T lymphocyte–associated protein-4 (CTLA-4) using a stabilized lysing release mechanism. We used computational modeling coupled with experimental validation of lysis circuit dynamics to determine the optimal genetic circuit parameters for maximal therapeutic efficacy. A single injection of this engineered system demonstrated an enhanced therapeutic response compared to analogous clinically relevant antibodies, resulting in tumor regression in syngeneic mouse models. Supporting the potentiation of a systemic immune response, we observed a relative increase in activated T cells, an abscopal effect, and corresponding increases in systemic T cell memory populations in mice treated with probiotically delivered checkpoint inhibitors. Last, we leveraged the modularity of our platform to achieve enhanced therapeutic efficacy in a poorly immunogenic syngeneic mouse model through effective combinations with a probiotically produced cytokine, granulocyte-macrophage colony-stimulating factor (GM-CSF). Together, these results demonstrate that our engineered probiotic system bridges synthetic biology and immunology to improve upon checkpoint blockade delivery.

    更新日期:2020-02-12
  • The tick tock of toxicity
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-02-12
    Jennifer M. Hurley

    A cell-intrinsic circadian program diminishes neutrophil toxicity to protect organs from excessive inflammation.

    更新日期:2020-02-12
  • Bilirubin enhances the activity of ASIC channels to exacerbate neurotoxicity in neonatal hyperbilirubinemia in mice
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-02-12
    Ke Lai, Xing-Lei Song, Hao-Song Shi, Xin Qi, Chun-Yan Li, Jia Fang, Fan Wang, Oleksandr Maximyuk, Oleg Krishtal, Tian-Le Xu, Xiao-Yan Li, Kun Ni, Wan-Peng Li, Hai-Bo Shi, Lu-Yang Wang, Shan-Kai Yin

    Neonatal hyperbilirubinemia is a common clinical condition that can lead to brain encephalopathy, particularly when concurrent with acidosis due to infection, ischemia, and hypoxia. The prevailing view is that acidosis increases the permeability of the blood-brain barrier to bilirubin and exacerbates its neurotoxicity. In this study, we found that the concentration of the cell death marker, lactate dehydrogenase (LDH) in cerebrospinal fluid (CSF), is elevated in infants with both hyperbilirubinemia and acidosis and showed stronger correlation with the severity of acidosis rather than increased bilirubin concentration. In mouse neonatal neurons, bilirubin exhibits limited toxicity but robustly potentiates the activity of acid-sensing ion channels (ASICs), resulting in increases in intracellular Ca2+ concentration, spike firings, and cell death. Furthermore, neonatal conditioning with concurrent hyperbilirubinemia and hypoxia-induced acidosis promoted long-term impairments in learning and memory and complex sensorimotor functions in vivo, which are largely attenuated in ASIC1a null mice. These findings suggest that targeting acidosis and ASICs may attenuate neonatal hyperbilirubinemia complications.

    更新日期:2020-02-12
  • JAK inhibition increases bone mass in steady-state conditions and ameliorates pathological bone loss by stimulating osteoblast function
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-02-12
    Susanne Adam, Nils Simon, Ulrike Steffen, Fabian T. Andes, Carina Scholtysek, Dorothea I. H. Müller, Daniela Weidner, Darja Andreev, Arnd Kleyer, Stephan Culemann, Madelaine Hahn, Georg Schett, Gerhard Krönke, Silke Frey, Axel J. Hueber

    Janus kinase (JAK)–mediated cytokine signaling has emerged as an important therapeutic target for the treatment of inflammatory diseases such as rheumatoid arthritis (RA). Accordingly, JAK inhibitors compose a new class of drugs, among which tofacitinib and baricitinib have been approved for the treatment of RA. Periarticular bone erosions contribute considerably to the pathogenesis of RA. However, although the immunomodulatory aspect of JAK inhibition (JAKi) is well defined, the current knowledge of how JAKi influences bone homeostasis is limited. Here, we assessed the effects of the JAK inhibitors tofacitinib and baricitinib on bone phenotype (i) in mice during steady-state conditions or in mice with bone loss induced by (ii) estrogen-deficiency (ovariectomy) or (iii) inflammation (arthritis) to evaluate whether effects of JAKi on bone metabolism require noninflammatory/inflammatory challenge. In all three models, JAKi increased bone mass, consistent with reducing the ratio of receptor activator of NF-κB ligand/osteoprotegerin in serum. In vitro, effects of tofacitinib and baricitinib on osteoclast and osteoblast differentiation were analyzed. JAKi significantly increased osteoblast function (P < 0.05) but showed no direct effects on osteoclasts. Additionally, mRNA sequencing and ingenuity pathway analyses were performed in osteoblasts exposed to JAKi and revealed robust up-regulation of markers for osteoblast function, such as osteocalcin and Wnt signaling. The anabolic effect of JAKi was illustrated by the stabilization of β-catenin. In humans with RA, JAKi induced bone-anabolic effects as evidenced by repair of arthritic bone erosions. Results support that JAKi is a potent therapeutic tool for increasing osteoblast function and bone formation.

    更新日期:2020-02-12
  • Mannose receptor (CD206) activation in tumor-associated macrophages enhances adaptive and innate antitumor immune responses
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-02-12
    Jesse M. Jaynes, Rushikesh Sable, Michael Ronzetti, Wendy Bautista, Zachary Knotts, Abisola Abisoye-Ogunniyan, Dandan Li, Raul Calvo, Myagmarjav Dashnyam, Anju Singh, Theresa Guerin, Jason White, Sarangan Ravichandran, Parimal Kumar, Keyur Talsania, Vicky Chen, Anghesom Ghebremedhin, Balasubramanyam Karanam, Ahmad Bin Salam, Ruksana Amin, Taivan Odzorig, Taylor Aiken, Victoria Nguyen, Yansong Bian, Jelani C. Zarif, Amber E. de Groot, Monika Mehta, Lixin Fan, Xin Hu, Anton Simeonov, Nathan Pate, Mones Abu-Asab, Marc Ferrer, Noel Southall, Chan-Young Ock, Yongmei Zhao, Henry Lopez, Serguei Kozlov, Natalia de Val, Clayton C. Yates, Bolormaa Baljinnyam, Juan Marugan, Udo Rudloff

    Solid tumors elicit a detectable immune response including the infiltration of tumor-associated macrophages (TAMs). Unfortunately, this immune response is co-opted into contributing toward tumor growth instead of preventing its progression. We seek to reestablish an antitumor immune response by selectively targeting surface receptors and endogenous signaling processes of the macrophage subtypes driving cancer progression. RP-182 is a synthetic 10-mer amphipathic analog of host defense peptides that selectively induces a conformational switch of the mannose receptor CD206 expressed on TAMs displaying an M2-like phenotype. RP-182–mediated activation of this receptor in human and murine M2-like macrophages elicits a program of endocytosis, phagosome-lysosome formation, and autophagy and reprograms M2-like TAMs to an antitumor M1-like phenotype. In syngeneic and autochthonous murine cancer models, RP-182 suppressed tumor growth, extended survival, and was an effective combination partner with chemo- or immune checkpoint therapy. Antitumor activity of RP-182 was also observed in CD206high patient-derived xenotransplantation models. Mechanistically, via selective reduction of immunosuppressive M2-like TAMs, RP-182 improved adaptive and innate antitumor immune responses, including increased cancer cell phagocytosis by reprogrammed TAMs.

    更新日期:2020-02-12
  • Two drugs converged in a pancreatic β cell
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-02-12
    Marissa A. Scavuzzo, Malgorzata Borowiak

    Combining a DYRK1A inhibitor and GLP-1 receptor agonist boosts human pancreatic β cell proliferation and glucose homeostasis in vivo (Ackeifi et al., this issue).

    更新日期:2020-02-12
  • Elevated plasma β-hydroxybutyrate predicts adverse outcomes and disease progression in patients with arrhythmogenic cardiomyopathy
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-02-12
    Jiang-Ping Song, Liang Chen, Xiao Chen, Jie Ren, Ning-Ning Zhang, Tiara Tirasawasdichai, Zhen-Liang Hu, Wei Hua, Yi-Ran Hu, Hui-Ru Tang, Huei-Sheng Vincent Chen, Sheng-Shou Hu

    Sudden death could be the first symptom of patients with arrhythmogenic cardiomyopathy (AC), a disease for which clinical indicators predicting adverse progression remain lacking. Recent findings suggest that metabolic dysregulation is present in AC. We performed this study to identify metabolic indicators that predicted major adverse cardiac events (MACEs) in patients with AC and their relatives. Comparing explanted hearts from patients with AC and healthy donors, we identified deregulated metabolic pathways using quantitative proteomics. Right ventricles (RVs) from patients with AC displayed elevated ketone metabolic enzymes, OXCT1 and HMGCS2, suggesting higher ketone metabolism in AC RVs. Analysis of matched coronary artery and sinus plasma suggested potential ketone body synthesis at early-stage AC, which was validated using patient-derived induced pluripotent stem cell–derived cardiomyocytes (iPSC-CMs) in vitro. Targeted metabolomics analysis in RVs from end-stage AC revealed a “burned-out” state, with predominant medium-chain fatty acid rather than ketone body utilization. In an independent validation cohort, 65 probands with mostly non–heart failure manifestations of AC had higher plasma β-hydroxybutyrate (β-OHB) than 62 healthy volunteers (P < 0.001). Probands with AC with MACE had higher β-OHB than those without MACE (P < 0.001). Among 94 relatives of probands, higher plasma β-OHB distinguished 25 relatives having suspected AC from nonaffected relatives. This study demonstrates that elevated plasma β-OHB predicts MACE in probands and disease progression in patients with AC and their clinically asymptomatic relatives.

    更新日期:2020-02-12
  • Maybe not an overreaction
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-02-12
    Li-Hsin Han

    A mathematical simulation of coronavirus COVID-19 estimated the number of infections to be far worse than reported.

    更新日期:2020-02-12
  • A spring-like renewal in the lungs
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-02-12
    Kamila Naxerova

    Epithelial cells with a low mutation burden expand after smoking cessation.

    更新日期:2020-02-12
  • GLP-1 receptor agonists synergize with DYRK1A inhibitors to potentiate functional human β cell regeneration
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-02-12
    Courtney Ackeifi, Peng Wang, Esra Karakose, Jocelyn E. Manning Fox, Bryan J. González, Hongtao Liu, Jessica Wilson, Ethan Swartz, Cecilia Berrouet, Yansui Li, Kunal Kumar, Patrick E. MacDonald, Roberto Sanchez, Bernard Thorens, Robert DeVita, Dirk Homann, Dieter Egli, Donald K. Scott, Adolfo Garcia-Ocaña, Andrew F. Stewart

    Glucagon-like peptide-1 receptor (GLP1R) agonists and dipeptidyl peptidase 4 inhibitors are widely prescribed diabetes drugs due to their ability to stimulate insulin secretion from remaining β cells and to reduce caloric intake. Unfortunately, they fail to increase human β cell proliferation. Small-molecule inhibitors of dual-specificity tyrosine-regulated kinase 1A (DYRK1A) are able to induce adult human β cell proliferation, but rates are modest (~2%), and their specificity to β cells is limited. Here, we provide evidence that combining any member of the GLP1R agonist class with any member of the DYRK1A inhibitor class induces a synergistic increase in human β cell replication (5 to 6%) accompanied by an actual increase in numbers of human β cells. GLP1R agonist–DYRK1A inhibitor synergy required combined inhibition of DYRK1A and an increase in cAMP and did not lead to β cell dedifferentiation. These beneficial effects on proliferation were seen in both normal human β cells and β cells derived from individuals with type 2 diabetes. The ability of the GLP1R agonist–DYRK1A inhibitor combination to enhance human β cell proliferation, human insulin secretion, and blood glucose control extended in vivo to studies of human islets transplanted into euglycemic and streptozotocin-diabetic immunodeficient mice. No adverse events were observed in the mouse studies during a 1-week period. Because of the relative β cell specificity of GLP1R agonists, the combination provides an improved, although not complete, degree of human β cell specificity.

    更新日期:2020-02-12
  • Distinct immune phenotypes in infants developing asthma during childhood
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-02-05
    Anna Hammerich Thysen, Johannes Waage, Jeppe Madura Larsen, Morten Arendt Rasmussen, Jakob Stokholm, Bo Chawes, Nadia Rahman Fink, Tine Marie Pedersen, Helene Wolsk, Sunna Thorsteinsdottir, Thomas Litman, Harald Renz, Klaus Bønnelykke, Hans Bisgaard, Susanne Brix

    Early exposure to environmental triggers may elicit trajectories to chronic inflammatory disease through deregulated immune responses. To address relations between early immune competence and development of childhood asthma, we performed functional immune profiling of 186 parameters in blood of 541 18-month-old infants and examined links between their response phenotype and development of transient or persistent disease at 6 years of age. An abnormal neutrophil-linked antiviral response was associated with increased risk of transient asthma. Children who exhibited persistent asthma at year 6 showed enhanced interleukin-5 (IL-5) and IL-13 production in stimulated T cells at 18 months of age, which was associated with early life bacterial colonization of the airways. These findings highlight the early appearance of distinct immune characteristics in infants developing different asthma endotypes during childhood.

    更新日期:2020-02-06
  • APOE4 exacerbates α-synuclein pathology and related toxicity independent of amyloid
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-02-05
    Na Zhao, Olivia N. Attrebi, Yingxue Ren, Wenhui Qiao, Berkiye Sonustun, Yuka A. Martens, Axel D. Meneses, Fuyao Li, Francis Shue, Jiaying Zheng, Alexandra J. Van Ingelgom, Mary D. Davis, Aishe Kurti, Joshua A. Knight, Cynthia Linares, Yixing Chen, Marion Delenclos, Chia-Chen Liu, John D. Fryer, Yan W. Asmann, Pamela J. McLean, Dennis W. Dickson, Owen A. Ross, Guojun Bu

    The apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for late-onset Alzheimer’s disease mainly by driving amyloid-β pathology. Recently, APOE4 has also been found to be a genetic risk factor for Lewy body dementia (LBD), which includes dementia with Lewy bodies and Parkinson’s disease dementia. How APOE4 drives risk of LBD and whether it has a direct effect on α-synuclein pathology are not clear. Here, we generated a mouse model of synucleinopathy using an adeno-associated virus gene delivery of α-synuclein in human APOE-targeted replacement mice expressing APOE2, APOE3, or APOE4. We found that APOE4, but not APOE2 or APOE3, increased α-synuclein pathology, impaired behavioral performances, worsened neuronal and synaptic loss, and increased astrogliosis at 9 months of age. Transcriptomic profiling in APOE4-expressing α-synuclein mice highlighted altered lipid and energy metabolism and synapse-related pathways. We also observed an effect of APOE4 on α-synuclein pathology in human postmortem brains with LBD and minimal amyloid pathology. Our data demonstrate a pathogenic role of APOE4 in exacerbating α-synuclein pathology independent of amyloid, providing mechanistic insights into how APOE4 increases the risk of LBD.

    更新日期:2020-02-06
  • APOE genotype regulates pathology and disease progression in synucleinopathy
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-02-05
    Albert A. Davis, Casey E. Inman, Zachary M. Wargel, Umber Dube, Brittany M. Freeberg, Alexander Galluppi, Jessica N. Haines, Dhruva D. Dhavale, Rebecca Miller, Fahim A. Choudhury, Patrick M. Sullivan, Carlos Cruchaga, Joel S. Perlmutter, Jason D. Ulrich, Bruno A. Benitez, Paul T. Kotzbauer, David M. Holtzman

    Apolipoprotein E (APOE) ε4 genotype is associated with increased risk of dementia in Parkinson’s disease (PD), but the mechanism is not clear, because patients often have a mixture of α-synuclein (αSyn), amyloid-β (Aβ), and tau pathologies. APOE ε4 exacerbates brain Aβ pathology, as well as tau pathology, but it is not clear whether APOE genotype independently regulates αSyn pathology. In this study, we generated A53T αSyn transgenic mice (A53T) on Apoe knockout (A53T/EKO) or human APOE knockin backgrounds (A53T/E2, E3, and E4). At 12 months of age, A53T/E4 mice accumulated higher amounts of brainstem detergent-insoluble phosphorylated αSyn compared to A53T/EKO and A53T/E3; detergent-insoluble αSyn in A53T/E2 mice was undetectable. By immunohistochemistry, A53T/E4 mice displayed a higher burden of phosphorylated αSyn and reactive gliosis compared to A53T/E2 mice. A53T/E2 mice exhibited increased survival and improved motor performance compared to other APOE genotypes. In a complementary model of αSyn spreading, striatal injection of αSyn preformed fibrils induced greater accumulation of αSyn pathology in the substantia nigra of A53T/E4 mice compared to A53T/E2 and A53T/EKO mice. In two separate cohorts of human patients with PD, APOE ε4/ε4 individuals showed the fastest rate of cognitive decline over time. Our results demonstrate that APOE genotype directly regulates αSyn pathology independent of its established effects on Aβ and tau, corroborate the finding that APOE ε4 exacerbates pathology, and suggest that APOE ε2 may protect against αSyn aggregation and neurodegeneration in synucleinopathies.

    更新日期:2020-02-06
  • Osteoclast-mediated bone resorption is controlled by a compensatory network of secreted and membrane-tethered metalloproteinases
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-02-05
    Lingxin Zhu, Yi Tang, Xiao-Yan Li, Evan T. Keller, Jingwen Yang, Jung-Sun Cho, Tamar Y. Feinberg, Stephen J. Weiss

    Osteoclasts actively remodel both the mineral and proteinaceous components of bone during normal growth and development as well as pathologic states ranging from osteoporosis to bone metastasis. The cysteine proteinase cathepsin K confers osteoclasts with potent type I collagenolytic activity; however, cathepsin K–null mice, as well as cathepsin K–mutant humans, continue to remodel bone and degrade collagen by as-yet-undefined effectors. Here, we identify a cathepsin K–independent collagenolytic system in osteoclasts that is composed of a functionally redundant network of the secreted matrix metalloproteinase MMP9 and the membrane-anchored matrix metalloproteinase MMP14. Unexpectedly, whereas deleting either of the proteinases individually leaves bone resorption intact, dual targeting of Mmp9 and Mmp14 inhibited the resorptive activity of mouse osteoclasts in vitro and in vivo and human osteoclasts in vitro. In vivo, Mmp9/Mmp14 conditional double-knockout mice exhibited marked increases in bone density and displayed a highly protected status against either parathyroid hormone– or ovariectomy-induced pathologic bone loss. Together, these studies characterize a collagenolytic system operative in mouse and human osteoclasts and identify the MMP9/MMP14 axis as a potential target for therapeutic interventions for bone-wasting disease states.

    更新日期:2020-02-06
  • The prolactin receptor long isoform regulates nociceptor sensitization and opioid-induced hyperalgesia selectively in females
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-02-05
    Yanxia Chen, Aubin Moutal, Edita Navratilova, Caroline Kopruszinski, Xu Yue, Megumi Ikegami, Michele Chow, Iori Kanazawa, Shreya Sai Bellampalli, Jennifer Xie, Amol Patwardhan, Kenner Rice, Howard Fields, Armen Akopian, Volker Neugebauer, David Dodick, Rajesh Khanna, Frank Porreca

    Pain is more prevalent in women for reasons that remain unclear. We have identified a mechanism of injury-free nociceptor sensitization and opioid-induced hyperalgesia (OIH) promoted by prolactin (PRL) in females. PRL signals through mutually inhibitory long (PRLR-L) and short (PRLR-S) receptor isoforms, and PRLR-S activation induces neuronal excitability. PRL and PRLR expression were higher in females. CRISPR-mediated editing of PRLR-L promoted nociceptor sensitization and allodynia in naïve, uninjured female mice that depended on circulating PRL. Opioids, but not trauma-induced nerve injury, decreased PRLR-L promoting OIH through activation of PRLR-S in female mice. Deletion of both PRLR-L and PRLR-S (total PRLR) prevented, whereas PRLR-L overexpression rescued established OIH selectively in females. Inhibition of circulating PRL with cabergoline, a dopamine D2 agonist, up-regulated PRLR-L and prevented OIH only in females. The PRLR-L isoform therefore confers protection against PRL-promoted pain in females. Limiting PRL/PRLR-S signaling pharmacologically or with gene therapies targeting the PRLR may be effective for reducing pain in a female-selective manner.

    更新日期:2020-02-06
  • Livening up pertussis vaccine development
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-02-05
    Michelle Boyle

    Vaccination with a Bordetella pertussis live attenuated vaccine induces a beneficial TH1 cell bias and broadly targeting functional antibodies in humans.

    更新日期:2020-02-06
  • Undressing drug reactions, one cell at a time
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-02-05
    Rajan P. Kulkarni

    Single-cell transcriptomic analysis allowed successful treatment of a patient with refractory severe drug-induced hypersensitivity syndrome.

    更新日期:2020-02-06
  • Let’s switch on AAV!
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-02-05
    Giuseppe Ronzitti

    RNA switches expand the reach of AAV vectors.

    更新日期:2020-02-06
  • Immune system development varies according to age, location, and anemia in African children
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-02-05
    Danika L. Hill, Edward J. Carr, Tobias Rutishauser, Gemma Moncunill, Joseph J. Campo, Silvia Innocentin, Maxmillian Mpina, Augusto Nhabomba, Anneth Tumbo, Chenjerai Jairoce, Henriëtte A. Moll, Menno C. van Zelm, Carlota Dobaño, Claudia Daubenberger, Michelle A. Linterman

    Children from low- and middle-income countries, where there is a high incidence of infectious disease, have the greatest need for the protection afforded by vaccination, but vaccines often show reduced efficacy in these populations. An improved understanding of how age, infection, nutrition, and genetics influence immune ontogeny and function is key to informing vaccine design for this at-risk population. We sought to identify factors that shape immune development in children under 5 years of age from Tanzania and Mozambique by detailed immunophenotyping of longitudinal blood samples collected during the RTS,S malaria vaccine phase 3 trial. In these cohorts, the composition of the immune system is dynamically transformed during the first years of life, and this was further influenced by geographical location, with some immune cell types showing an altered rate of development in Tanzanian children compared to Dutch children enrolled in the Generation R population–based cohort study. High-titer antibody responses to the RTS,S/AS01E vaccine were associated with an activated immune profile at the time of vaccination, including an increased frequency of antibody-secreting plasmablasts and follicular helper T cells. Anemic children had lower frequencies of recent thymic emigrant T cells, isotype-switched memory B cells, and plasmablasts; modulating iron bioavailability in vitro could recapitulate the B cell defects observed in anemic children. Our findings demonstrate that the composition of the immune system in children varies according to age, geographical location, and anemia status.

    更新日期:2020-02-06
  • Immune correlates of tuberculosis disease and risk translate across species
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-01-29
    Mushtaq Ahmed, Shyamala Thirunavukkarasu, Bruce A. Rosa, Kimberly A. Thomas, Shibali Das, Javier Rangel-Moreno, Lan Lu, Smriti Mehra, Stanley Kimbung Mbandi, Larissa B. Thackray, Michael S. Diamond, Kenneth M. Murphy, Terry Means, John Martin, Deepak Kaushal, Thomas J. Scriba, Makedonka Mitreva, Shabaana A. Khader

    One quarter of the world’s population is infected with Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB). Although most infected individuals successfully control or clear the infection, some individuals will progress to TB disease. Immune correlates identified using animal models are not always effectively translated to human TB, thus resulting in a slow pace of translational discoveries from animal models to human TB for many platforms including vaccines, therapeutics, biomarkers, and diagnostic discovery. Therefore, it is critical to improve our poor understanding of immune correlates of disease and protection that are shared across animal TB models and human TB. In this study, we have provided an in-depth identification of the conserved and diversified gene/immune pathways in TB models of nonhuman primate and diversity outbred mouse and human TB. Our results show that prominent differentially expressed genes/pathways induced during TB disease progression are conserved in genetically diverse mice, macaques, and humans. In addition, using gene-deficient inbred mouse models, we have addressed the functional role of individual genes comprising the gene signature of disease progression seen in humans with Mtb infection. We show that genes representing specific immune pathways can be protective, detrimental, or redundant in controlling Mtb infection and translate into identifying immune pathways that mediate TB immunopathology in humans. Together, our cross-species findings provide insights into modeling TB disease and the immunological basis of TB disease progression.

    更新日期:2020-01-29
  • Airway macrophages reveal their origins
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-01-29
    Stephanie G. Dakin

    Airway macrophages are derived from recipient circulating monocytes after transplant.

    更新日期:2020-01-29
  • Unfolding the mystery of UPR in astrocytes
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-01-29
    Gilbert Gallardo

    Activation of the unfolded protein response in astrocytes leads to a distinct reactive state detrimental to neuronal health in prion disease.

    更新日期:2020-01-29
  • Immunomodulation in the front, bone-binding in the back
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-01-29
    Bethany A. Kerr

    Zoledronic acid–tethered nanoparticles bind remodeling bone, polarize macrophages, and reduce osteoclasts to prevent breast cancer–induced osteolysis.

    更新日期:2020-01-29
  • Mapping global variation in dengue transmission intensity
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-01-29
    Lorenzo Cattarino, Isabel Rodriguez-Barraquer, Natsuko Imai, Derek A. T. Cummings, Neil M. Ferguson

    Intervention planning for dengue requires reliable estimates of dengue transmission intensity. However, current maps of dengue risk provide estimates of disease burden or the boundaries of endemicity rather than transmission intensity. We therefore developed a global high-resolution map of dengue transmission intensity by fitting environmentally driven geospatial models to geolocated force of infection estimates derived from cross-sectional serological surveys and routine case surveillance data. We assessed the impact of interventions on dengue transmission and disease using Wolbachia-infected mosquitoes and the Sanofi-Pasteur vaccine as specific examples. We predicted high transmission intensity in all continents straddling the tropics, with hot spots in South America (Colombia, Venezuela, and Brazil), Africa (western and central African countries), and Southeast Asia (Thailand, Indonesia, and the Philippines). We estimated that 105 [95% confidence interval (CI), 95 to 114] million dengue infections occur each year with 51 (95% CI, 32 to 66) million febrile disease cases. Our analysis suggests that transmission-blocking interventions such as Wolbachia, even at intermediate efficacy (50% transmission reduction), might reduce global annual disease incidence by up to 90%. The Sanofi-Pasteur vaccine, targeting only seropositive recipients, might reduce global annual disease incidence by 20 to 30%, with the greatest impact in high-transmission settings. The transmission intensity map presented here, and made available for download, may help further assessment of the impact of dengue control interventions and prioritization of global public health efforts.

    更新日期:2020-01-29
  • Preclinical efficacy of the GPER-selective agonist G-1 in mouse models of obesity and diabetes
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-01-29
    Geetanjali Sharma, Chelin Hu, Daniela I. Staquicini, Jonathan L. Brigman, Meilian Liu, Franck Mauvais-Jarvis, Renata Pasqualini, Wadih Arap, Jeffrey B. Arterburn, Helen J. Hathaway, Eric R. Prossnitz

    Human obesity has become a global health epidemic, with few safe and effective pharmacological therapies currently available. The systemic loss of ovarian estradiol (E2) in women after menopause greatly increases the risk of obesity and metabolic dysfunction, revealing the critical role of E2 in this setting. The salutary effects of E2 are traditionally attributed to the classical estrogen receptors ERα and ERβ, with the contribution of the G protein–coupled estrogen receptor (GPER) still largely unknown. Here, we used ovariectomy- and diet-induced obesity (DIO) mouse models to evaluate the preclinical activity of GPER-selective small-molecule agonist G-1 (also called Tespria) against obesity and metabolic dysfunction. G-1 treatment of ovariectomized female mice (a model of postmenopausal obesity) reduced body weight and improved glucose homeostasis without changes in food intake, fuel source usage, or locomotor activity. G-1–treated female mice also exhibited increased energy expenditure, lower body fat content, and reduced fasting cholesterol, glucose, insulin, and inflammatory markers but did not display feminizing effects on the uterus (imbibition) or beneficial effects on bone health. G-1 treatment of DIO male mice did not elicit weight loss but prevented further weight gain and improved glucose tolerance, indicating that G-1 improved glucose homeostasis independently of its antiobesity effects. However, in ovariectomized DIO female mice, G-1 continued to elicit weight loss, reflecting possible sex differences in the mechanisms of G-1 action. In conclusion, this work demonstrates that GPER-selective agonism is a viable therapeutic approach against obesity, diabetes, and associated metabolic abnormalities in multiple preclinical male and female models.

    更新日期:2020-01-29
  • Different human resting memory CD4+ T cell subsets show similar low inducibility of latent HIV-1 proviruses
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-01-29
    Kyungyoon J. Kwon, Andrew E. Timmons, Srona Sengupta, Francesco R. Simonetti, Hao Zhang, Rebecca Hoh, Steven G. Deeks, Janet D. Siliciano, Robert F. Siliciano

    The latent reservoir of HIV-1 in resting CD4+ T cells is a major barrier to cure. It is unclear whether the latent reservoir resides principally in particular subsets of CD4+ T cells, a finding that would have implications for understanding its stability and developing curative therapies. Recent work has shown that proliferation of HIV-1–infected CD4+ T cells is a major factor in the generation and persistence of the latent reservoir and that latently infected T cells that have clonally expanded in vivo can proliferate in vitro without producing virions. In certain CD4+ memory T cell subsets, the provirus may be in a deeper state of latency, allowing the cell to proliferate without producing viral proteins, thus permitting escape from immune clearance. To evaluate this possibility, we used a multiple stimulation viral outgrowth assay to culture resting naïve, central memory (TCM), transitional memory (TTM), and effector memory (TEM) CD4+ T cells from 10 HIV-1–infected individuals on antiretroviral therapy. On average, only 1.7% of intact proviruses across all T cell subsets were induced to transcribe viral genes and release replication-competent virus after stimulation of the cells. We found no consistent enrichment of intact or inducible proviruses in any T cell subset. Furthermore, we observed notable plasticity among the canonical memory T cell subsets after activation in vitro and saw substantial person-to-person variability in the inducibility of infectious virus release. This finding complicates the vision for a targeted approach for HIV-1 cure based on T cell memory subsets.

    更新日期:2020-01-29
  • A dual apolipoprotein C-II mimetic–apolipoprotein C-III antagonist peptide lowers plasma triglycerides
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-01-29
    Anna Wolska, Larry Lo, Denis O. Sviridov, Mohsen Pourmousa, Milton Pryor, Soumitra S. Ghosh, Rahul Kakkar, Michael Davidson, Sierra Wilson, Richard W. Pastor, Ira J. Goldberg, Debapriya Basu, Steven K. Drake, Antony Cougnoux, Ming Jing Wu, Saskia B. Neher, Lita A. Freeman, Jingrong Tang, Marcelo Amar, Matt Devalaraja, Alan T. Remaley

    Recent genetic studies have established that hypertriglyceridemia (HTG) is causally related to cardiovascular disease, making it an active area for drug development. We describe a strategy for lowering triglycerides (TGs) with an apolipoprotein C-II (apoC-II) mimetic peptide called D6PV that activates lipoprotein lipase (LPL), the main plasma TG-hydrolyzing enzyme, and antagonizes the TG-raising effect of apoC-III. The design of D6PV was motivated by a combination of all-atom molecular dynamics simulation of apoC-II on the Anton 2 supercomputer, structural prediction programs, and biophysical techniques. Efficacy of D6PV was assessed ex vivo in human HTG plasma and was found to be more potent than full-length apoC-II in activating LPL. D6PV markedly lowered TG by more than 80% within a few hours in both apoC-II–deficient mice and hAPOC3-transgenic (Tg) mice. In hAPOC3-Tg mice, D6PV treatment reduced plasma apoC-III by 80% and apoB by 65%. Furthermore, low-density lipoprotein (LDL) cholesterol did not accumulate but rather was decreased by 10% when hAPOC3-Tg mice lacking the LDL-receptor (hAPOC3-Tg × Ldlr−/−) were treated with the peptide. D6PV lowered TG by 50% in whole-body inducible Lpl knockout (iLpl−/−) mice, confirming that it can also act independently of LPL. D6PV displayed good subcutaneous bioavailability of about 80% in nonhuman primates. Because it binds to high-density lipoproteins, which serve as a long-term reservoir, it also has an extended terminal half-life (42 to 50 hours) in nonhuman primates. In summary, D6PV decreases plasma TG by acting as a dual apoC-II mimetic and apoC-III antagonist, thereby demonstrating its potential as a treatment for HTG.

    更新日期:2020-01-29
  • Mixed chimerism and acceptance of kidney transplants after immunosuppressive drug withdrawal
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-01-29
    Stephan Busque, John D. Scandling, Robert Lowsky, Judith Shizuru, Kent Jensen, Jeffrey Waters, Hsin-Hsu Wu, Kevin Sheehan, Asha Shori, Okmi Choi, Thomas Pham, Marcelo A. Fernandez Vina, Richard Hoppe, John Tamaresis, Philip Lavori, Edgar G. Engleman, Everett Meyer, Samuel Strober

    Preclinical studies have shown that persistent mixed chimerism is linked to acceptance of organ allografts without immunosuppressive (IS) drugs. Mixed chimerism refers to continued mixing of donor and recipient hematopoietic cells in recipient tissues after transplantation of donor cells. To determine whether persistent mixed chimerism and tolerance can be established in patients undergoing living donor kidney transplantation, we infused allograft recipients with donor T cells and hematopoietic progenitors after posttransplant lymphoid irradiation. In 24 of 29 fully human leukocyte antigen (HLA)–matched patients who had persistent mixed chimerism for at least 6 months, complete IS drug withdrawal was achieved without subsequent evidence of rejection for at least 2 years. In 10 of 22 HLA haplotype–matched patients with persistent mixed chimerism for at least 12 months, reduction of IS drugs to tacrolimus monotherapy was achieved. Withdrawal of tacrolimus during the second year resulted in loss of detectable chimerism and subsequent rejection episodes, unless tacrolimus therapy was reinstituted. Posttransplant immune reconstitution of naïve B cells and B cell precursors was more rapid than the reconstitution of naïve T cells and thymic T cell precursors. Robust chimerism was observed only among naïve T and B cells but not among memory T cells. No evidence of rejection was observed in all surveillance graft biopsies obtained from mixed chimeric patients withdrawn from IS drugs, and none developed graft-versus-host disease. In conclusion, persistent mixed chimerism established in fully HLA- or haplotype-matched patients allowed for complete or partial IS drug withdrawal without rejection.

    更新日期:2020-01-29
  • Gene therapy delivering a paraoxonase 1 variant offers long-term prophylactic protection against nerve agents in mice
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-01-22
    Venkaiah Betapudi, Reena Goswami, Liliya Silayeva, Deborah M. Doctor, Nageswararao Chilukuri

    Chemical warfare nerve agents are organophosphorus chemical compounds that induce cholinergic crisis, leaving little or no time for medical intervention to prevent death. The current chemical treatment regimen may prevent death but does not prevent postexposure complications such as brain damage and permanent behavioral abnormalities. In the present study, we have demonstrated an adeno-associated virus 8 (AAV8)–mediated paraoxonase 1 variant IF-11 (PON1-IF11) gene therapy that offers asymptomatic prophylactic protection to mice against multiple lethal doses of G-type chemical warfare nerve agents, namely, tabun, sarin, cyclosarin, and soman, for up to 5 months in mice. A single injection of liver-specific adeno-associated viral particles loaded with PON1-IF11 gene resulted in expression and secretion of recombinant PON1-IF11 in milligram quantities, which has the catalytic power to break down G-type chemical warfare nerve agents into biologically inactive products in vitro and in vivo in rodents. Mice containing milligram concentrations of recombinant PON1-IF11 in their blood displayed no clinical signs of toxicity, as judged by their hematological parameters and serum chemistry profiles. Our study unfolds avenues to develop a one-time application of gene therapy to express a near-natural and circulating therapeutic PON1-IF11 protein that can potentially protect humans against G-type chemical warfare nerve agents for several weeks to months.

    更新日期:2020-01-23
  • Deep phenotyping during pregnancy for predictive and preventive medicine
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-01-22
    Alison G. Paquette, Leroy Hood, Nathan D. Price, Yoel Sadovsky

    Deep phenotyping during pregnancy offers an opportunity to define the antecedents of lifelong health and wellness, and to improve pregnancy outcomes.

    更新日期:2020-01-23
  • The IDH-TAU-EGFR triad defines the neovascular landscape of diffuse gliomas
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-01-22
    Ricardo Gargini, Berta Segura-Collar, Beatriz Herránz, Vega García-Escudero, Andrés Romero-Bravo, Felipe J. Núñez, Daniel García-Pérez, Jacqueline Gutiérrez-Guamán, Angel Ayuso-Sacido, Joan Seoane, Angel Pérez-Núñez, Juan M. Sepúlveda-Sánchez, Aurelio Hernández-Laín, María G. Castro, Ramón García-Escudero, Jesús Ávila, Pilar Sánchez-Gómez

    Gliomas that express the mutated isoforms of isocitrate dehydrogenase 1/2 (IDH1/2) have better prognosis than wild-type (wt) IDH1/2 gliomas. However, how these mutant (mut) proteins affect the tumor microenvironment is still a pending question. Here, we describe that the transcription of microtubule-associated protein TAU (MAPT), a gene that has been classically associated with neurodegenerative diseases, is epigenetically controlled by the balance between wt and mut IDH1/2 in mouse and human gliomas. In IDH1/2 mut tumors, we found high expression of TAU that decreased with tumor progression. Furthermore, MAPT was almost absent from tumors with epidermal growth factor receptor (EGFR) mutations, whereas its trancription negatively correlated with overall survival in gliomas carrying wt or amplified (amp) EGFR. We demonstrated that the overexpression of TAU, through the stabilization of microtubules, impaired the mesenchymal/pericyte-like transformation of glioma cells by blocking EGFR, nuclear factor kappa-light-chain-enhancer of activated B (NF-κB) and the transcriptional coactivator with PDZ-binding motif (TAZ). Our data also showed that mut EGFR induced a constitutive activation of this pathway, which was no longer sensitive to TAU. By inhibiting the transdifferentiation capacity of EGFRamp/wt tumor cells, TAU protein inhibited angiogenesis and favored vascular normalization, decreasing glioma aggressiveness and increasing their sensitivity to chemotherapy.

    更新日期:2020-01-23
  • Pan-viral protection against arboviruses by activating skin macrophages at the inoculation site
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-01-22
    Steven R. Bryden, Marieke Pingen, Daniella A. Lefteri, Janne Miltenburg, Leen Delang, Sofie Jacobs, Rana Abdelnabi, Johan Neyts, Emilie Pondeville, Jack Major, Marietta Müller, Henna Khalid, Andrew Tuplin, Margus Varjak, Andres Merits, Julia Edgar, Gerard J. Graham, Kave Shams, Clive S. McKimmie

    Arthropod-borne viruses (arboviruses) are important human pathogens for which there are no specific antiviral medicines. The abundance of genetically distinct arbovirus species, coupled with the unpredictable nature of their outbreaks, has made the development of virus-specific treatments challenging. Instead, we have defined and targeted a key aspect of the host innate immune response to virus at the arthropod bite that is common to all arbovirus infections, potentially circumventing the need for virus-specific therapies. Using mouse models and human skin explants, we identify innate immune responses by dermal macrophages in the skin as a key determinant of disease severity. Post-exposure treatment of the inoculation site by a topical TLR7 agonist suppressed both the local and subsequent systemic course of infection with a variety of arboviruses from the Alphavirus, Flavivirus, and Orthobunyavirus genera. Clinical outcome was improved in mice after infection with a model alphavirus. In the absence of treatment, antiviral interferon expression to virus in the skin was restricted to dermal dendritic cells. In contrast, stimulating the more populous skin-resident macrophages with a TLR7 agonist elicited protective responses in key cellular targets of virus that otherwise proficiently replicated virus. By defining and targeting a key aspect of the innate immune response to virus at the mosquito bite site, we have identified a putative new strategy for limiting disease after infection with a variety of genetically distinct arboviruses.

    更新日期:2020-01-23
  • Hitting a double to treat cancer
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-01-22
    Asmaa El-Kenawi

    Simultaneous targeting of polyamine and methionine pathways may be a promising strategy to treat prostate cancer.

    更新日期:2020-01-23
  • Neurodevelopment and risk for ADHD and depression
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-01-22
    Dylan G. Gee

    Childhood brain connectivity predicts psychiatric difficulties four years later.

    更新日期:2020-01-23
  • Angling for a bug-inspired method of coating therapeutics onto microneedles
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-01-22
    Eoin O’Cearbhaill

    Mimicking the microstructures on the surface of European true bugs may help optimize loading of therapeutics onto transdermal microneedle patches.

    更新日期:2020-01-23
  • PI4KIIIβ is a therapeutic target in chromosome 1q–amplified lung adenocarcinoma
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-01-22
    Xiaochao Tan, Priyam Banerjee, Edward A. Pham, Florentine U. N. Rutaganira, Kaustabh Basu, Neus Bota-Rabassedas, Hou-Fu Guo, Caitlin L. Grzeskowiak, Xin Liu, Jiang Yu, Lei Shi, David H. Peng, B. Leticia Rodriguez, Jiaqi Zhang, Veronica Zheng, Dzifa Y. Duose, Luisa M. Solis, Barbara Mino, Maria Gabriela Raso, Carmen Behrens, Ignacio I. Wistuba, Kenneth L. Scott, Mark Smith, Khanh Nguyen, Grace Lam, Ingrid Choong, Abhijit Mazumdar, Jamal L. Hill, Don L. Gibbons, Powel H. Brown, William K. Russell, Kevan Shokat, Chad J. Creighton, Jeffrey S. Glenn, Jonathan M. Kurie

    Heightened secretion of protumorigenic effector proteins is a feature of malignant cells. Yet, the molecular underpinnings and therapeutic implications of this feature remain unclear. Here, we identify a chromosome 1q region that is frequently amplified in diverse cancer types and encodes multiple regulators of secretory vesicle biogenesis and trafficking, including the Golgi-dedicated enzyme phosphatidylinositol (PI)-4-kinase IIIβ (PI4KIIIβ). Molecular, biochemical, and cell biological studies show that PI4KIIIβ-derived PI-4-phosphate (PI4P) synthesis enhances secretion and accelerates lung adenocarcinoma progression by activating Golgi phosphoprotein 3 (GOLPH3)–dependent vesicular release from the Golgi. PI4KIIIβ-dependent secreted factors maintain 1q-amplified cancer cell survival and influence prometastatic processes in the tumor microenvironment. Disruption of this functional circuitry in 1q-amplified cancer cells with selective PI4KIIIβ antagonists induces apoptosis and suppresses tumor growth and metastasis. These results support a model in which chromosome 1q amplifications create a dependency on PI4KIIIβ-dependent secretion for cancer cell survival and tumor progression.

    更新日期:2020-01-23
  • Long-gap peripheral nerve repair through sustained release of a neurotrophic factor in nonhuman primates
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-01-22
    Neil B. Fadia, Jacqueline M. Bliley, Gabriella A. DiBernardo, Donald J. Crammond, Benjamin K. Schilling, Wesley N. Sivak, Alexander M. Spiess, Kia M. Washington, Matthias Waldner, Han-Tsung Liao, Isaac B. James, Danielle M. Minteer, Casey Tompkins-Rhoades, Adam R. Cottrill, Deok-Yeol Kim, Riccardo Schweizer, Debra A. Bourne, George E. Panagis, M. Asher Schusterman, Francesco M. Egro, Insiyah K. Campwala, Tyler Simpson, Douglas J. Weber, Trent Gause, Jack E. Brooker, Tvisha Josyula, Astrid A. Guevara, Alexander J. Repko, Christopher M. Mahoney, Kacey G. Marra

    Severe injuries to peripheral nerves are challenging to repair. Standard-of-care treatment for nerve gaps >2 to 3 centimeters is autografting; however, autografting can result in neuroma formation, loss of sensory function at the donor site, and increased operative time. To address the need for a synthetic nerve conduit to treat large nerve gaps, we investigated a biodegradable poly(caprolactone) (PCL) conduit with embedded double-walled polymeric microspheres encapsulating glial cell line–derived neurotrophic factor (GDNF) capable of providing a sustained release of GDNF for >50 days in a 5-centimeter nerve defect in a rhesus macaque model. The GDNF-eluting conduit (PCL/GDNF) was compared to a median nerve autograft and a PCL conduit containing empty microspheres (PCL/Empty). Functional testing demonstrated similar functional recovery between the PCL/GDNF-treated group (75.64 ± 10.28%) and the autograft-treated group (77.49 ± 19.28%); both groups were statistically improved compared to PCL/Empty-treated group (44.95 ± 26.94%). Nerve conduction velocity 1 year after surgery was increased in the PCL/GDNF-treated macaques (31.41 ± 15.34 meters/second) compared to autograft (25.45 ± 3.96 meters/second) and PCL/Empty (12.60 ± 3.89 meters/second) treatment. Histological analyses included assessment of Schwann cell presence, myelination of axons, nerve fiber density, and g-ratio. PCL/GDNF group exhibited a statistically greater average area occupied by individual Schwann cells at the distal nerve (11.60 ± 33.01 μm2) compared to autograft (4.62 ± 3.99 μm2) and PCL/Empty (4.52 ± 5.16 μm2) treatment groups. This study demonstrates the efficacious bridging of a long peripheral nerve gap in a nonhuman primate model using an acellular, biodegradable nerve conduit.

    更新日期:2020-01-23
  • Cerebellar oscillations driven by synaptic pruning deficits of cerebellar climbing fibers contribute to tremor pathophysiology
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-01-15
    Ming-Kai Pan, Yong-Shi Li, Shi-Bing Wong, Chun-Lun Ni, Yi-Mei Wang, Wen-Chuan Liu, Liang-Yin Lu, Jye-Chang Lee, Etty P. Cortes, Jean-Paul G. Vonsattel, Qian Sun, Elan D. Louis, Phyllis L. Faust, Sheng-Han Kuo

    Essential tremor (ET) is one of the most common movement disorders and the prototypical disorder for abnormal rhythmic movements. However, the pathophysiology of tremor generation in ET remains unclear. Here, we used autoptic cerebral tissue from patients with ET, clinical data, and mouse models to report that synaptic pruning deficits of climbing fiber (CF)–to–Purkinje cell (PC) synapses, which are related to glutamate receptor delta 2 (GluRδ2) protein insufficiency, cause excessive cerebellar oscillations and might be responsible for tremor. The CF-PC synaptic pruning deficits were correlated with the reduction in GluRδ2 expression in the postmortem ET cerebellum. Mice with GluRδ2 insufficiency and CF-PC synaptic pruning deficits develop ET-like tremor that can be suppressed with viral rescue of GluRδ2 protein. Step-by-step optogenetic or pharmacological inhibition of neuronal firing, axonal activity, or synaptic vesicle release confirmed that the activity of the excessive CF-to-PC synapses is required for tremor generation. In vivo electrophysiology in mice showed that excessive cerebellar oscillatory activity is CF dependent and necessary for tremor and optogenetic-driven PC synchronization was sufficient to generate tremor in wild-type animals. Human validation by cerebellar electroencephalography confirmed that excessive cerebellar oscillations also exist in patients with ET. Our findings identify a pathophysiologic contribution to tremor at molecular (GluRδ2), structural (CF-to-PC synapses), physiological (cerebellar oscillations), and behavioral levels (kinetic tremor) that might have clinical applications for treating ET.

    更新日期:2020-01-16
  • Weighing in on asthma
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-01-15
    Patrick M. Brunner

    Immune activation and microbiota alterations are accentuated in obese asthmatics.

    更新日期:2020-01-16
  • The “cancer flu shot”?
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-01-15
    Anand D. Jeyasekharan

    Direct injection of an influenza vaccine into tumors in mice increases immune infiltration and prolongs survival.

    更新日期:2020-01-16
  • Organoid optimization: Engineering a better cell therapy to treat type 1 diabetes
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-01-15
    Jessica D. Weaver

    Islet organoids reaggregated in endothelialized collagen constructs improve engraftment and function in the subcutaneous space in diabetic mice.

    更新日期:2020-01-16
  • Human umbilical cord perivascular cells improve human pancreatic islet transplant function by increasing vascularization
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-01-15
    Shareen Forbes, Andrew R. Bond, Kayleigh L. Thirlwell, Paul Burgoyne, Kay Samuel, June Noble, Gary Borthwick, David Colligan, Neil W. A. McGowan, Philip Starkey Lewis, Alasdair R. Fraser, Joanne C. Mountford, Roderick N. Carter, Nicholas M. Morton, Marc L. Turner, Gerard J. Graham, John D. M. Campbell

    Islet transplantation is an efficacious therapy for type 1 diabetes; however, islets from multiple donor pancreata are required, and a gradual attrition in transplant function is seen. Here, we manufactured human umbilical cord perivascular mesenchymal stromal cells (HUCPVCs) to Good Manufacturing Practice (GMP) standards. HUCPVCs showed a stable phenotype while undergoing rapid ex vivo expansion at passage 2 (p2) to passage 4 (p4) and produced proregenerative factors, strongly suppressing T cell responses in the resting state and in response to inflammation. Transplanting an islet equivalent (IEQ):HUCPVC ratio of 1:30 under the kidney capsule in diabetic NSG mice demonstrated the fastest return to normoglycemia by 3 days after transplant: Superior glycemic control was seen at both early (2.7 weeks) and later stages (7, 12, and 16 weeks) versus ratios of 1:0, 1:10, and 1:50, respectively. Syngeneic islet transplantation in immunocompetent mice using the clinically relevant hepatic portal route with a marginal islet mass showed that mice transplanted with an IEQ:HUCPVC ratio of 1:150 had superior glycemic control versus ratios of 1:0, 1:90, and 1:210 up to 6 weeks after transplant. Immunodeficient mice transplanted with human islets (IEQ:HUCPVC ratio of 1:150) exhibited better glycemic control for 7 weeks after transplant versus islet transplant alone, and islets transplanted via the hepatic portal vein in an allogeneic mouse model using a curative islet mass demonstrated delayed rejection of islets when cotransplanted with HUCPVCs (IEQ:HUCPVC ratio of 1:150). The immunosuppressive and proregenerative properties of HUCPVCs demonstrated long-term positive effects on graft function in vivo, indicating that they may improve long-term human islet allotransplantation outcomes.

    更新日期:2020-01-16
  • Engraftment of rare, pathogenic donor hematopoietic mutations in unrelated hematopoietic stem cell transplantation
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-01-15
    Wing Hing Wong, Sima Bhatt, Kathryn Trinkaus, Iskra Pusic, Kevin Elliott, Nitin Mahajan, Fei Wan, Galen E. Switzer, Dennis L. Confer, John DiPersio, Michael A. Pulsipher, Nirali N. Shah, Jennifer Sees, Amelia Bystry, Jamie R. Blundell, Bronwen E. Shaw, Todd E. Druley

    Clonal hematopoiesis is associated with various age-related morbidities. Error-corrected sequencing (ECS) of human blood samples, with a limit of detection of ≥0.0001, has demonstrated that nearly every healthy individual >50 years old harbors rare hematopoietic clones below the detection limit of standard high-throughput sequencing. If these rare mutations confer survival or proliferation advantages, then the clone(s) could expand after a selective pressure such as chemotherapy, radiotherapy, or chronic immunosuppression. Given these observations and the lack of quantitative data regarding clonal hematopoiesis in adolescents and young adults, who are more likely to serve as unrelated hematopoietic stem cell donors, we completed this pilot study to determine whether younger adults harbored hematopoietic clones with pathogenic mutations, how often those clones were transferred to recipients, and what happened to these clones over time after transplantation. We performed ECS on 125 blood and marrow samples from 25 matched unrelated donors and recipients. Clonal mutations, with a median variant allele frequency of 0.00247, were found in 11 donors (44%; median, 36 years old). Of the mutated clones, 84.2% of mutations were predicted to be molecularly pathogenic and 100% engrafted in recipients. Recipients also demonstrated de novo clonal expansion within the first 100 days after hematopoietic stem cell transplant (HSCT). Given this pilot demonstration that rare, pathogenic clonal mutations are far more prevalent in younger adults than previously appreciated, and they engraft in recipients and persist over time, larger studies with longer follow-up are necessary to correlate clonal engraftment with post-HSCT morbidity.

    更新日期:2020-01-16
  • β-amyloid redirects norepinephrine signaling to activate the pathogenic GSK3β/tau cascade
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-01-15
    Fang Zhang, Mary Gannon, Yunjia Chen, Shun Yan, Sixue Zhang, Wendy Feng, Jiahui Tao, Bingdong Sha, Zhenghui Liu, Takashi Saito, Takaomi Saido, C. Dirk Keene, Kai Jiao, Erik D. Roberson, Huaxi Xu, Qin Wang

    The brain noradrenergic system is critical for normal cognition and is affected at early stages in Alzheimer’s disease (AD). Here, we reveal a previously unappreciated direct role of norepinephrine signaling in connecting β-amyloid (Aβ) and tau, two key pathological components of AD pathogenesis. Our results show that Aβ oligomers bind to an allosteric site on α2A adrenergic receptor (α2AAR) to redirect norepinephrine-elicited signaling to glycogen synthase kinase 3β (GSK3β) activation and tau hyperphosphorylation. This norepinephrine-dependent mechanism sensitizes pathological GSK3β/tau activation in response to nanomolar accumulations of extracellular Aβ, which is 50- to 100-fold lower than the amount required to activate GSK3β by Aβ alone. The significance of our findings is supported by in vivo evidence in two mouse models, human tissue sample analysis, and longitudinal clinical data. Our study provides translational insights into mechanisms underlying Aβ proteotoxicity, which might have strong implications for the interpretation of Aβ clearance trial results and future drug design and for understanding the selective vulnerability of noradrenergic neurons in AD.

    更新日期:2020-01-16
  • Intratumoral expression of IL-7 and IL-12 using an oncolytic virus increases systemic sensitivity to immune checkpoint blockade
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-01-15
    Shinsuke Nakao, Yukinori Arai, Mamoru Tasaki, Midori Yamashita, Ryuji Murakami, Tatsuya Kawase, Nobuaki Amino, Motomu Nakatake, Hajime Kurosaki, Masamichi Mori, Masahiro Takeuchi, Takafumi Nakamura

    The immune status of the tumor microenvironment is a key indicator in determining the antitumor effectiveness of immunotherapies. Data support the role of activation and expansion of tumor-infiltrating lymphocytes (TILs) in increasing the benefit of immunotherapies in patients with solid tumors. We found that intratumoral injection of a tumor-selective oncolytic vaccinia virus encoding interleukin-7 (IL-7) and IL-12 into tumor-bearing immunocompetent mice activated the inflammatory immune status of previously poorly immunogenic tumors and resulted in complete tumor regression, even in distant tumor deposits. Mice achieving complete tumor regression resisted rechallenge with the same tumor cells, suggesting establishment of long-term tumor-specific immune memory. Combining this virotherapy with anti–programmed cell death-1 (PD-1) or anti–cytotoxic T lymphocyte antigen 4 (CTLA4) antibody further increased the antitumor activity as compared to virotherapy alone, in tumor models unresponsive to either of the checkpoint inhibitor monotherapies. These findings suggest that administration of an oncolytic vaccinia virus carrying genes encoding for IL-7 and IL-12 has antitumor activity in both directly injected and distant noninjected tumors through immune status changes rendering tumors sensitive to immune checkpoint blockade. The benefit of intratumoral IL-7 and IL-12 expression was also observed in humanized mice bearing human cancer cells. These data support further investigation in patients with non-inflamed solid tumors.

    更新日期:2020-01-16
  • Stromal cell protein kinase C-β inhibition enhances chemosensitivity in B cell malignancies and overcomes drug resistance
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-01-15
    Eugene Park, Jingyu Chen, Andrew Moore, Maurizio Mangolini, Antonella Santoro, Joseph R. Boyd, Hilde Schjerven, Veronika Ecker, Maike Buchner, James C. Williamson, Paul J. Lehner, Luca Gasparoli, Owen Williams, Johannes Bloehdorn, Stephan Stilgenbauer, Michael Leitges, Alexander Egle, Marc Schmidt-Supprian, Seth Frietze, Ingo Ringshausen

    Overcoming drug resistance remains a key challenge to cure patients with acute and chronic B cell malignancies. Here, we describe a stromal cell–autonomous signaling pathway, which contributes to drug resistance of malignant B cells. We show that protein kinase C (PKC)–β–dependent signals from bone marrow–derived stromal cells markedly decrease the efficacy of cytotoxic therapies. Conversely, small-molecule PKC-β inhibitors antagonize prosurvival signals from stromal cells and sensitize tumor cells to targeted and nontargeted chemotherapy, resulting in enhanced cytotoxicity and prolonged survival in vivo. Mechanistically, stromal PKC-β controls the expression of adhesion and matrix proteins, required for activation of phosphoinositide 3-kinases (PI3Ks) and the extracellular signal–regulated kinase (ERK)–mediated stabilization of B cell lymphoma–extra large (BCL-XL) in tumor cells. Central to the stroma-mediated drug resistance is the PKC-β–dependent activation of transcription factor EB, regulating lysosome biogenesis and plasma membrane integrity. Stroma-directed therapies, enabled by direct inhibition of PKC-β, enhance the effectiveness of many antileukemic therapies.

    更新日期:2020-01-16
  • Bystanders get in the game
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-01-08
    Heather D. Hickman

    Tissue-resident memory T cells respond in a nonspecific manner to reduce bacteria in the lungs of mice.

    更新日期:2020-01-09
  • Microglial sex affects Alzheimer’s disease
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-01-08
    Josh Neman

    Sex-specific microglial microRNAs impact tau pathogenesis.

    更新日期:2020-01-09
  • A potential gut punch to gastric cancer
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-01-08
    Vikramaditya G. Yadav

    Combination chemotherapies that also inhibit the proline isomerase Pin1 may overcome the notorious drug resistance of gastric cancer.

    更新日期:2020-01-09
  • GDNF rescues the fate of neural progenitor grafts by attenuating Notch signals in the injured spinal cord in rodents
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-01-08
    Mohamad Khazaei, Christopher S. Ahuja, Hiroaki Nakashima, Narihito Nagoshi, Lijun Li, Jian Wang, Jonathon Chio, Anna Badner, David Seligman, Ayaka Ichise, Shinsuke Shibata, Michael G. Fehlings

    Neural progenitor cell (NPC) transplantation is a promising strategy for the treatment of spinal cord injury (SCI). In this study, we show that injury-induced Notch activation in the spinal cord microenvironment biases the fate of transplanted NPCs toward astrocytes in rodents. In a screen for potential clinically relevant factors to modulate Notch signaling, we identified glial cell–derived neurotrophic factor (GDNF). GDNF attenuates Notch signaling by mediating delta-like 1 homolog (DLK1) expression, which is independent of GDNF’s effect on cell survival. When transplanted into a rodent model of cervical SCI, GDNF-expressing human-induced pluripotent stem cell–derived NPCs (hiPSC-NPCs) demonstrated higher differentiation toward a neuronal fate compared to control cells. In addition, expression of GDNF promoted endogenous tissue sparing and enhanced electrical integration of transplanted cells, which collectively resulted in improved neurobehavioral recovery. CRISPR-induced knockouts of the DLK1 gene in GDNF-expressing hiPSC-NPCs attenuated the effect on functional recovery, demonstrating that this effect is partially mediated through DLK1 expression. These results represent a mechanistically driven optimization of hiPSC-NPC therapy to redirect transplanted cells toward a neuronal fate and enhance their integration.

    更新日期:2020-01-09
  • Thrombin contributes to cancer immune evasion via proteolysis of platelet-bound GARP to activate LTGF-β
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-01-08
    Alessandra Metelli, Bill X. Wu, Brian Riesenberg, Silvia Guglietta, John D. Huck, Catherine Mills, Anqi Li, Saleh Rachidi, Carsten Krieg, Mark P. Rubinstein, Daniel T. Gewirth, Shaoli Sun, Michael B. Lilly, Amy H. Wahlquist, David P. Carbone, Yiping Yang, Bei Liu, Zihai Li

    Cancer-associated thrombocytosis and high concentrations of circulating transforming growth factor–β1 (TGF-β1) are frequently observed in patients with progressive cancers. Using genetic and pharmacological approaches, we show a direct link between thrombin catalytic activity and release of mature TGF-β1 from platelets. We found that thrombin cleaves glycoprotein A repetitions predominant (GARP), a cell surface docking receptor for latent TGF-β1 (LTGF-β1) on platelets, resulting in liberation of active TGF-β1 from the GARP–LTGF-β1 complex. Furthermore, systemic inhibition of thrombin obliterates TGF-β1 maturation in platelet releasate and rewires the tumor microenvironment toward favorable antitumor immunity, which translates into efficient cancer control either alone or in combination with programmed cell death 1–based immune checkpoint blockade therapy. Last, we demonstrate that soluble GARP and GARP–LTGF-β1 complex are present in the circulation of patients with cancer. Together, our data reveal a mechanism of cancer immune evasion that involves thrombin-mediated GARP cleavage and the subsequent TGF-β1 release from platelets. We propose that blockade of GARP cleavage is a valuable therapeutic strategy to overcome cancer’s resistance to immunotherapy.

    更新日期:2020-01-09
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