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  • Cancer metabolism gets physical
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-05-23
    Peter DelNero, Benjamin D. Hopkins, Lewis C. Cantley, Claudia Fischbach

    Patient-derived culture models enable assessment of drug sensitivity and can connect personalized genomics with therapeutic options. However, their clinical translation is constrained by limited fidelity. We outline how the physical microenvironment regulates cell metabolism and describe how engineered culture systems could enhance the predictive power for precision medicine.

    更新日期:2018-05-24
  • Adult rat myelin enhances axonal outgrowth from neural stem cells
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-05-23
    Gunnar H. D. Poplawski, Richard Lie, Matt Hunt, Hiromi Kumamaru, Riki Kawaguchi, Paul Lu, Michael K. E. Schäfer, Grace Woodruff, Jacob Robinson, Philip Canete, Jennifer N. Dulin, Cedric G. Geoffroy, Lutz Menzel, Binhai Zheng, Giovanni Coppola, Mark H. Tuszynski

    Axon regeneration after spinal cord injury (SCI) is attenuated by growth inhibitory molecules associated with myelin. We report that rat myelin stimulated the growth of axons emerging from rat neural progenitor cells (NPCs) transplanted into sites of SCI in adult rat recipients. When plated on a myelin substrate, neurite outgrowth from rat NPCs and from human induced pluripotent stem cell (iPSC)–derived neural stem cells (NSCs) was enhanced threefold. In vivo, rat NPCs and human iPSC–derived NSCs extended greater numbers of axons through adult central nervous system white matter than through gray matter and preferentially associated with rat host myelin. Mechanistic investigations excluded Nogo receptor signaling as a mediator of stem cell–derived axon growth in response to myelin. Transcriptomic screens of rodent NPCs identified the cell adhesion molecule neuronal growth regulator 1 (Negr1) as one mediator of permissive axon-myelin interactions. The stimulatory effect of myelin-associated proteins on rodent NPCs was developmentally regulated and involved direct activation of the extracellular signal–regulated kinase (ERK). The stimulatory effects of myelin on NPC/NSC axon outgrowth should be investigated further and could potentially be exploited for neural repair after SCI.

    更新日期:2018-05-24
  • Striatal dopamine regulates systemic glucose metabolism in humans and mice
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-05-23
    Kasper W. ter Horst, Nicolette M. Lammers, Richard Trinko, Darren M. Opland, Martijn Figee, Mariette T. Ackermans, Jan Booij, Pepijn van den Munckhof, P. Richard Schuurman, Eric Fliers, Damiaan Denys, Ralph J. DiLeone, Susanne E. la Fleur, Mireille J. Serlie

    The brain is emerging as an important regulator of systemic glucose metabolism. Accumulating data from animal and observational human studies suggest that striatal dopamine signaling plays a role in glucose regulation, but direct evidence in humans is currently lacking. We present a series of experiments supporting the regulation of peripheral glucose metabolism by striatal dopamine signaling. First, we present the case of a diabetes patient who displayed strongly reduced insulin requirements after treatment with bilateral deep brain stimulation (DBS) targeting the anterior limb of the internal capsule. Next, we show that DBS in this striatal area, which induced dopamine release, increased hepatic and peripheral insulin sensitivity in 14 nondiabetic patients with obsessive-compulsive disorder. Conversely, systemic dopamine depletion reduced peripheral insulin sensitivity in healthy subjects. Supporting these human data, we demonstrate that optogenetic activation of dopamine D1 receptor–expressing neurons in the nucleus accumbens increased glucose tolerance and insulin sensitivity in mice. Together, these findings support the hypothesis that striatal neuronal activity regulates systemic glucose metabolism.

    更新日期:2018-05-24
  • A rationally designed NRP1-independent superagonist SEMA3A mutant is an effective anticancer agent
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-05-23
    Noemi Gioelli, Federica Maione, Chiara Camillo, Michela Ghitti, Donatella Valdembri, Noemi Morello, Marie Darche, Lorena Zentilin, Gabriella Cagnoni, Yaqi Qiu, Mauro Giacca, Maurizio Giustetto, Michel Paques, Ilaria Cascone, Giovanna Musco, Luca Tamagnone, Enrico Giraudo, Guido Serini

    Vascular normalizing strategies, aimed at ameliorating blood vessel perfusion and lessening tissue hypoxia, are treatments that may improve the outcome of cancer patients. Secreted class 3 semaphorins (SEMA3), which are thought to directly bind neuropilin (NRP) co-receptors that, in turn, associate with and elicit plexin (PLXN) receptor signaling, are effective normalizing agents of the cancer vasculature. Yet, SEMA3A was also reported to trigger adverse side effects via NRP1. We rationally designed and generated a safe, parenterally deliverable, and NRP1-independent SEMA3A point mutant isoform that, unlike its wild-type counterpart, binds PLXNA4 with nanomolar affinity and has much greater biochemical and biological activities in cultured endothelial cells. In vivo, when parenterally administered in mouse models of pancreatic cancer, the NRP1-independent SEMA3A point mutant successfully normalized the vasculature, inhibited tumor growth, curbed metastatic dissemination, and effectively improved the supply and anticancer activity of chemotherapy. Mutant SEMA3A also inhibited retinal neovascularization in a mouse model of age-related macular degeneration. In summary, mutant SEMA3A is a vascular normalizing agent that can be exploited to treat cancer and, potentially, other diseases characterized by pathological angiogenesis.

    更新日期:2018-05-24
  • Derepression of co-silenced tumor suppressor genes by nanoparticle-loaded circular ssDNA reduces tumor malignancy
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-05-23
    Jing Meng, Shuang Chen, Jing-xia Han, Qiang Tan, Xiao-rui Wang, Hong-zhi Wang, Wei-long Zhong, Yuan Qin, Kai-liang Qiao, Chao Zhang, Wan-feng Gao, Yue-yang Lei, Hui-juan Liu, Yan-rong Liu, Hong-gang Zhou, Tao Sun, Cheng Yang

    The co-silencing of multiple tumor suppressor genes can lead to escalated malignancy in cancer cells. Given the limited efficacy of anticancer therapies targeting single tumor suppressor genes, we developed small circular single-stranded DNA (CSSD) that can up-regulate the expression of co-silenced tumor suppressor genes by sequestering microRNAs (miRNAs) that negatively regulate these genes. We found that cancer patients with low tumor expression of the tumor suppressor genes KLF17, CDH1, and LASS2 had shortened survival times. The up-regulation of these genes upon transfection of artificial CSSD-9 inhibited tumor proliferation and metastasis and promoted apoptosis in vitro as well as in ex vivo and patient-derived xenograft models. In addition, CSSD is more stable and effective than current miRNA inhibitors, and transfecting CSSDs via nanoparticles substantially improved delivery efficiency. The use of a single CSSD can promote the inhibition of multiple tumor suppressor genes. This study provides evidence for the possibility of using CSSDs as therapeutic miRNA inhibitors to target the co-silencing of multiple tumor suppressor genes.

    更新日期:2018-05-24
  • Opening the eyes on autism
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-05-23
    Rebecca M. Jones

    Nine- to 10-month-old infants who develop autism show early enhanced pupillary light reflex compared with infants who did not develop autism.

    更新日期:2018-05-24
  • Blocking IL-6 signaling deflates pulmonary arterial hypertension
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-05-23
    Kory Lavine

    IL-6 signaling contributes to the pathogenesis of pulmonary arterial hypertension by orchestrating pulmonary arterial smooth muscle cell expansion.

    更新日期:2018-05-24
  • A fatty link between heart disease and autoimmunity
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-05-23
    Hu Zeng

    Atherogenic hyperlipidemia drives IL-27 production by dendritic cells to support follicular T cell differentiation and systemic autoimmune disorders in mice.

    更新日期:2018-05-24
  • The broad socioeconomic benefits of vaccination
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-05-16
    David E. Bloom, Victoria Y. Fan, J. P. Sevilla

    Evaluating vaccination programs according to their broad socioeconomic benefits, beyond their health benefits, will help to address the twin problems of vaccine underutilization and weak incentives for vaccine innovation.

    更新日期:2018-05-17
  • Targeted inhibition of histone H3K27 demethylation is effective in high-risk neuroblastoma
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-05-16
    Timothy L. Lochmann, Krista M. Powell, Jungoh Ham, Konstantinos V. Floros, Daniel A. R. Heisey, Richard I. J. Kurupi, Marissa L. Calbert, Maninderjit S. Ghotra, Patricia Greninger, Mikhail Dozmorov, Madhu Gowda, Andrew J. Souers, C. Patrick Reynolds, Cyril H. Benes, Anthony C. Faber

    High-risk neuroblastoma is often distinguished by amplification of MYCN and loss of differentiation potential. We performed high-throughput drug screening of epigenetic-targeted therapies across a large and diverse tumor cell line panel and uncovered the hypersensitivity of neuroblastoma cells to GSK-J4, a small-molecule dual inhibitor of lysine 27 of histone 3 (H3K27) demethylases ubiquitously transcribed tetratricopeptide repeat, X chromosome (UTX), and histone demethylase Jumonji D3 (JMJD3). Mechanistically, GSK-J4 induced neuroblastoma differentiation and endoplasmic reticulum (ER) stress, with accompanying up-regulation of p53 up-regulated modulator of apoptosis (PUMA) and induction of cell death. Retinoic acid (RA)–resistant neuroblastoma cells were sensitive to GSK-J4. In addition, GSK-J4 was effective at blocking the growth of chemorefractory and patient-derived xenograft models of high-risk neuroblastoma in vivo. Furthermore, GSK-J4 and RA combination increased differentiation and ER stress over GSK-J4 effects and limited the growth of neuroblastomas resistant to either drug alone. In MYCN-amplified neuroblastoma, PUMA induction by GSK-J4 sensitized tumors to the B cell lymphoma 2 (BCL-2) inhibitor venetoclax, demonstrating that epigenetic-targeted therapies and BCL-2 homology domain 3 mimetics can be rationally combined to treat this high-risk subset of neuroblastoma. Therefore, H3K27 demethylation inhibition is a promising therapeutic target to treat high-risk neuroblastoma, and H3K27 demethylation can be part of rational combination therapies to induce robust antineuroblastoma activity.

    更新日期:2018-05-17
  • The protective role of macrophage migration inhibitory factor in acute kidney injury after cardiac surgery
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-05-16
    Christian Stoppe, Luisa Averdunk, Andreas Goetzenich, Josefin Soppert, Arnaud Marlier, Sandra Kraemer, Jil Vieten, Mark Coburn, Ana Kowark, Bong-Song Kim, Gernot Marx, Steffen Rex, Akinobu Ochi, Lin Leng, Gilbert Moeckel, Andreas Linkermann, Omar El Bounkari, Alexander Zarbock, Jürgen Bernhagen, Sonja Djudjaj, Richard Bucala, Peter Boor

    Acute kidney injury (AKI) represents the most frequent complication after cardiac surgery. Macrophage migration inhibitory factor (MIF) is a stress-regulating cytokine that was shown to protect the heart from myocardial ischemia-reperfusion injury, but its role in the pathogenesis of AKI remains unknown. In an observational study, serum and urinary MIF was quantified in 60 patients scheduled for elective conventional cardiac surgery with the use of cardiopulmonary bypass. Cardiac surgery triggered an increase in MIF serum concentrations, and patients with high circulating MIF (>median) 12 hours after surgery had a significantly reduced risk of developing AKI (relative risk reduction, 72.7%; 95% confidence interval, 12 to 91.5%; P = 0.03). Experimental AKI was induced in wild-type and Mif−/− mice by 30 min of ischemia followed by 6 or 24 hours of reperfusion, or by rhabdomyolysis. Mif-deficient mice exhibited increased tubular cell injury, increased regulated cell death (necroptosis and ferroptosis), and enhanced oxidative stress. Therapeutic administration of recombinant MIF after ischemia-reperfusion in mice ameliorated AKI. In vitro treatment of tubular epithelial cells with recombinant MIF reduced cell death and oxidative stress as measured by glutathione and thiobarbituric acid reactive substances in the setting of hypoxia. Our data provide evidence of a renoprotective role of MIF in experimental ischemia-reperfusion injury by protecting renal tubular epithelial cells, consistent with our observation that high MIF in cardiac surgery patients is associated with a reduced incidence of AKI.

    更新日期:2018-05-17
  • Targeted complement inhibition salvages stressed neurons and inhibits neuroinflammation after stroke in mice
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-05-16
    Ali Alawieh, E. Farris Langley, Stephen Tomlinson

    Ischemic stroke results from the interruption of blood flow to the brain resulting in long-term motor and cognitive neurological deficits, and it is a leading cause of death and disability. Current interventions focus on the restoration of blood flow to limit neuronal death, but these treatments have a therapeutic window of only a few hours and do not address post-stroke cerebral inflammation. The complement system, a component of the innate immune system, is activated by natural immunoglobulin M (IgM) antibodies that recognize neoepitopes expressed in the brain after ischemic stroke. We took advantage of this recognition system to inhibit complement activation locally in the ischemic area in mice. A single chain antibody recognizing a post-ischemic neoepitope linked to a complement inhibitor (termed B4Crry) was administered systemically as a single dose after stroke and shown to specifically target the ischemic hemisphere and improve long-term motor and cognitive recovery. We show that complement opsonins guide microglial phagocytosis of stressed but salvageable neurons, and that by locally and transiently inhibiting complement deposition, B4Crry prevented phagocytosis of penumbral neurons and inhibited pathologic complement and microglial activation that otherwise persisted for several weeks after stroke. B4Crry was protective in adult, aged, male and female mice and had a therapeutic window of at least 24 hours after stroke. Furthermore, the epitope recognized by B4Crry in mice is overexpressed in the ischemic penumbra of acute stroke patients, but not in the contralateral tissue, highlighting the translational potential of this approach.

    更新日期:2018-05-17
  • Metarrestin, a perinucleolar compartment inhibitor, effectively suppresses metastasis
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-05-16
    Kevin J. Frankowski, Chen Wang, Samarjit Patnaik, Frank J. Schoenen, Noel Southall, Dandan Li, Yaroslav Teper, Wei Sun, Irawati Kandela, Deqing Hu, Christopher Dextras, Zachary Knotts, Yansong Bian, John Norton, Steve Titus, Marzena A. Lewandowska, Yiping Wen, Katherine I. Farley, Lesley Mathews Griner, Jamey Sultan, Zhaojing Meng, Ming Zhou, Tomas Vilimas, Astin S. Powers, Serguei Kozlov, Kunio Nagashima, Humair S. Quadri, Min Fang, Charles Long, Ojus Khanolkar, Warren Chen, Jinsol Kang, Helen Huang, Eric Chow, Esthermanya Goldberg, Coral Feldman, Romi Xi, Hye Rim Kim, Gary Sahagian, Susan J. Baserga, Andrew Mazar, Marc Ferrer, Wei Zheng, Ali Shilatifard, Jeffrey Aubé, Udo Rudloff, Juan Jose Marugan, Sui Huang

    Metastasis remains a leading cause of cancer mortality due to the lack of specific inhibitors against this complex process. To identify compounds selectively targeting the metastatic state, we used the perinuclear compartment (PNC), a complex nuclear structure associated with metastatic behaviors of cancer cells, as a phenotypic marker for a high-content screen of over 140,000 structurally diverse compounds. Metarrestin, obtained through optimization of a screening hit, disassembles PNCs in multiple cancer cell lines, inhibits invasion in vitro, suppresses metastatic development in three mouse models of human cancer, and extends survival of mice in a metastatic pancreatic cancer xenograft model with no organ toxicity or discernable adverse effects. Metarrestin disrupts the nucleolar structure and inhibits RNA polymerase (Pol) I transcription, at least in part by interacting with the translation elongation factor eEF1A2. Thus, metarrestin represents a potential therapeutic approach for the treatment of metastatic cancer.

    更新日期:2018-05-17
  • Fasting the microbiome to treat diabetes
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-05-16
    Louis J. Cohen

    Intermittent fasting helps to reduce diabetes-associated retinopathy through changes in microbiome bile acid metabolism.

    更新日期:2018-05-17
  • Slow and steady wins the race
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-05-16
    Steven M. Jay

    A biomaterial-based approach to sustained delivery of therapeutic extracellular vesicles leads to cardiac recovery after myocardial infarction in rats.

    更新日期:2018-05-17
  • A change of heart: Altered cardiac reactivity in frontotemporal dementia
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-05-16
    Hannah M. Tully

    Cardiac response to emotional stimuli differs by frontotemporal dementia subtype.

    更新日期:2018-05-17
  • PGD2/DP2 receptor activation promotes severe viral bronchiolitis by suppressing IFN-λ production
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-05-09
    Rhiannon B. Werder, Jason P. Lynch, Jennifer C. Simpson, Vivian Zhang, Nick H. Hodge, Matthew Poh, Elizabeth Forbes-Blom, Christina Kulis, Mark L. Smythe, John W. Upham, Kirsten Spann, Mark L. Everard, Simon Phipps

    Prostaglandin D2 (PGD2) signals through PGD2 receptor 2 (DP2, also known as CRTH2) on type 2 effector cells to promote asthma pathogenesis; however, little is known about its role during respiratory syncytial virus (RSV) bronchiolitis, a major risk factor for asthma development. We show that RSV infection up-regulated hematopoietic prostaglandin D synthase expression and increased PGD2 release by cultured human primary airway epithelial cells (AECs). Moreover, PGD2 production was elevated in nasopharyngeal samples from young infants hospitalized with RSV bronchiolitis compared to healthy controls. In a neonatal mouse model of severe viral bronchiolitis, DP2 antagonism decreased viral load, immunopathology, and morbidity and ablated the predisposition for subsequent asthma onset in later life. This protective response was abolished upon dual DP1/DP2 antagonism and replicated with a specific DP1 agonist. Rather than mediating an effect via type 2 inflammation, the beneficial effects of DP2 blockade or DP1 agonism were associated with increased interferon-λ (IFN-λ) [interleukin-28A/B (IL-28A/B)] expression and were lost upon IL-28A neutralization. In RSV-infected AEC cultures, DP1 activation up-regulated IFN-λ production, which, in turn, increased IFN-stimulated gene expression, accelerating viral clearance. Our findings suggest that DP2 antagonists or DP1 agonists may be useful antivirals for the treatment of viral bronchiolitis and possibly as primary preventatives for asthma.

    更新日期:2018-05-10
  • Computational modeling guides tissue-engineered heart valve design for long-term in vivo performance in a translational sheep model
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-05-09
    Maximilian Y. Emmert, Boris A. Schmitt, Sandra Loerakker, Bart Sanders, Hendrik Spriestersbach, Emanuela S. Fioretta, Leon Bruder, Kerstin Brakmann, Sarah E. Motta, Valentina Lintas, Petra E. Dijkman, Laura Frese, Felix Berger, Frank P. T. Baaijens, Simon P. Hoerstrup

    Valvular heart disease is a major cause of morbidity and mortality worldwide. Current heart valve prostheses have considerable clinical limitations due to their artificial, nonliving nature without regenerative capacity. To overcome these limitations, heart valve tissue engineering (TE) aiming to develop living, native-like heart valves with self-repair, remodeling, and regeneration capacity has been suggested as next-generation technology. A major roadblock to clinically relevant, safe, and robust TE solutions has been the high complexity and variability inherent to bioengineering approaches that rely on cell-driven tissue remodeling. For heart valve TE, this has limited long-term performance in vivo because of uncontrolled tissue remodeling phenomena, such as valve leaflet shortening, which often translates into valve failure regardless of the bioengineering methodology used to develop the implant. We tested the hypothesis that integration of a computationally inspired heart valve design into our TE methodologies could guide tissue remodeling toward long-term functionality in tissue-engineered heart valves (TEHVs). In a clinically and regulatory relevant sheep model, TEHVs implanted as pulmonary valve replacements using minimally invasive techniques were monitored for 1 year via multimodal in vivo imaging and comprehensive tissue remodeling assessments. TEHVs exhibited good preserved long-term in vivo performance and remodeling comparable to native heart valves, as predicted by and consistent with computational modeling. TEHV failure could be predicted for nonphysiological pressure loading. Beyond previous studies, this work suggests the relevance of an integrated in silico, in vitro, and in vivo bioengineering approach as a basis for the safe and efficient clinical translation of TEHVs.

    更新日期:2018-05-10
  • Humidity-regulated CLCA2 protects the epidermis from hyperosmotic stress
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-05-09
    Kristin Seltmann, Michael Meyer, Jitka Sulcova, Tobias Kockmann, Ulrike Wehkamp, Stephan Weidinger, Ulrich auf dem Keller, Sabine Werner

    Low environmental humidity aggravates symptoms of the inflammatory skin disease atopic dermatitis (AD). Using mice that develop AD-like signs, we show that an increase in environmental humidity rescues their cutaneous inflammation and associated epidermal abnormalities. Quantitative proteomics analysis of epidermal lysates of mice kept at low or high humidity identified humidity-regulated proteins, including chloride channel accessory 3A2 (CLCA3A2), a protein with previously unknown function in the skin. The epidermis of patients with AD, organotypic skin cultures under dry conditions, and cultured keratinocytes exposed to hyperosmotic stress showed up-regulation of the nonorthologous human homolog CLCA2. Hyperosmolarity-induced CLCA2 expression occurred via p38/c-Jun N-terminal kinase–activating transcription factor 2 signaling. CLCA2 knockdown promoted keratinocyte apoptosis induced by hyperosmotic stress through impairment of cell-cell adhesion. These findings provide a mechanistic explanation for the beneficial effect of high environmental humidity for AD patients and identify CLCA3A2/CLCA2 up-regulation as a mechanism to protect keratinocytes from damage induced by low humidity.

    更新日期:2018-05-10
  • The root problem of heart valve engineering
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-05-09
    Jonathan T. Butcher

    Acellular heart valve grafts optimized through computational modeling recellularize and function in sheep for up to 1 year (Emmert et al., this issue).

    更新日期:2018-05-10
  • High-throughput sequencing of the T cell receptor β gene identifies aggressive early-stage mycosis fungoides
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-05-09
    Adele de Masson, John T. O’Malley, Christopher P. Elco, Sarah S. Garcia, Sherrie J. Divito, Elizabeth L. Lowry, Marianne Tawa, David C. Fisher, Phillip M. Devlin, Jessica E. Teague, Nicole R. Leboeuf, Ilan R. Kirsch, Harlan Robins, Rachael A. Clark, Thomas S. Kupper

    Mycosis fungoides (MF), the most common cutaneous T cell lymphoma (CTCL) is a malignancy of skin-tropic memory T cells. Most MF cases present as early stage (stage I A/B, limited to the skin), and these patients typically have a chronic, indolent clinical course. However, a small subset of early-stage cases develop progressive and fatal disease. Because outcomes can be so different, early identification of this high-risk population is an urgent unmet clinical need. We evaluated the use of next-generation high-throughput DNA sequencing of the T cell receptor β gene (TCRB) in lesional skin biopsies to predict progression and survival in a discovery cohort of 208 patients with CTCL (177 with MF) from a 15-year longitudinal observational clinical study. We compared these data to the results in an independent validation cohort of 101 CTCL patients (87 with MF). The tumor clone frequency (TCF) in lesional skin, measured by high-throughput sequencing of the TCRB gene, was an independent prognostic factor of both progression-free and overall survival in patients with CTCL and MF in particular. In early-stage patients, a TCF of >25% in the skin was a stronger predictor of progression than any other established prognostic factor (stage IB versus IA, presence of plaques, high blood lactate dehydrogenase concentration, large-cell transformation, or age). The TCF therefore may accurately predict disease progression in early-stage MF. Early identification of patients at high risk for progression could help identify candidates who may benefit from allogeneic hematopoietic stem cell transplantation before their disease becomes treatment-refractory.

    更新日期:2018-05-10
  • Survival of syngeneic and allogeneic iPSC–derived neural precursors after spinal grafting in minipigs
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-05-09
    Jan Strnadel, Cassiano Carromeu, Cedric Bardy, Michael Navarro, Oleksandr Platoshyn, Andreas N. Glud, Silvia Marsala, Jozef Kafka, Atsushi Miyanohara, Tomohisa Kato, Takahiro Tadokoro, Michael P. Hefferan, Kota Kamizato, Tetsuya Yoshizumi, Stefan Juhas, Jana Juhasova, Chak-Sum Ho, Taba Kheradmand, PeiXi Chen, Dasa Bohaciakova, Marian Hruska-Plochan, Andrew J. Todd, Shawn P. Driscoll, Thomas D. Glenn, Samuel L. Pfaff, Jiri Klima, Joseph Ciacci, Eric Curtis, Fred H. Gage, Jack Bui, Kazuhiko Yamada, Alysson R. Muotri, Martin Marsala

    The use of autologous (or syngeneic) cells derived from induced pluripotent stem cells (iPSCs) holds great promise for future clinical use in a wide range of diseases and injuries. It is expected that cell replacement therapies using autologous cells would forego the need for immunosuppression, otherwise required in allogeneic transplantations. However, recent studies have shown the unexpected immune rejection of undifferentiated autologous mouse iPSCs after transplantation. Whether similar immunogenic properties are maintained in iPSC-derived lineage-committed cells (such as neural precursors) is relatively unknown. We demonstrate that syngeneic porcine iPSC-derived neural precursor cell (NPC) transplantation to the spinal cord in the absence of immunosuppression is associated with long-term survival and neuronal and glial differentiation. No tumor formation was noted. Similar cell engraftment and differentiation were shown in spinally injured transiently immunosuppressed swine leukocyte antigen (SLA)–mismatched allogeneic pigs. These data demonstrate that iPSC-NPCs can be grafted into syngeneic recipients in the absence of immunosuppression and that temporary immunosuppression is sufficient to induce long-term immune tolerance after NPC engraftment into spinally injured allogeneic recipients. Collectively, our results show that iPSC-NPCs represent an alternative source of transplantable NPCs for the treatment of a variety of disorders affecting the spinal cord, including trauma, ischemia, or amyotrophic lateral sclerosis.

    更新日期:2018-05-10
  • Memorable cerebral inflammation
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-05-09
    Frank J. Attenello

    Exposure to peripheral inflammation induces microglia to alter subsequent course of stroke and Alzheimer’s pathologies.

    更新日期:2018-05-10
  • Sweet skin remedy
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-05-09
    Riekelt Houtkooper

    Up-regulation of glucose transport drives keratinocyte proliferation, whereas its inhibition offers therapeutic potential against psoriasis.

    更新日期:2018-05-10
  • Inflammatory signatures of smoking
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-05-09
    Leopoldo N. Segal

    Smoking is associated with distinct pro- and anti-inflammatory signatures in squamous cell carcinomas of the lung and the head and neck.

    更新日期:2018-05-10
  • Microbial ecology perturbation in human IgA deficiency
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-05-02
    Jehane Fadlallah, Hela El Kafsi, Delphine Sterlin, Catherine Juste, Christophe Parizot, Karim Dorgham, Gaëlle Autaa, Doriane Gouas, Mathieu Almeida, Patricia Lepage, Nicolas Pons, Emmanuelle Le Chatelier, Florence Levenez, Sean Kennedy, Nathalie Galleron, Jean-Paul Pais de Barros, Marion Malphettes, Lionel Galicier, David Boutboul, Alexis Mathian, Makoto Miyara, Eric Oksenhendler, Zahir Amoura, Joel Doré, Claire Fieschi, S. Dusko Ehrlich, Martin Larsen, Guy Gorochov

    Paradoxically, loss of immunoglobulin A (IgA), one of the most abundant antibodies, does not irrevocably lead to severe infections in humans but rather is associated with relatively mild respiratory infections, atopy, and autoimmunity. IgA might therefore also play covert roles, not uniquely associated with control of pathogens. We show that human IgA deficiency is not associated with massive quantitative perturbations of gut microbial ecology. Metagenomic analysis highlights an expected pathobiont expansion but a less expected depletion in some typically beneficial symbionts. Gut colonization by species usually present in the oropharynx is also reminiscent of spatial microbiota disorganization. IgM only partially rescues IgA deficiency because not all typical IgA targets are efficiently bound by IgM in the intestinal lumen. Together, IgA appears to play a nonredundant role at the forefront of the immune/microbial interface, away from the intestinal barrier, ranging from pathobiont control and regulation of systemic inflammation to preservation of commensal diversity and community networks.

    更新日期:2018-05-03
  • Development of a stress response therapy targeting aggressive prostate cancer
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-05-02
    Hao G. Nguyen, Crystal S. Conn, Yae Kye, Lingru Xue, Craig M. Forester, Janet E. Cowan, Andrew C. Hsieh, John T. Cunningham, Charles Truillet, Feven Tameire, Michael J. Evans, Christopher P. Evans, Joy C. Yang, Byron Hann, Constantinos Koumenis, Peter Walter, Peter R. Carroll, Davide Ruggero

    Oncogenic lesions up-regulate bioenergetically demanding cellular processes, such as protein synthesis, to drive cancer cell growth and continued proliferation. However, the hijacking of these key processes by oncogenic pathways imposes onerous cell stress that must be mitigated by adaptive responses for cell survival. The mechanism by which these adaptive responses are established, their functional consequences for tumor development, and their implications for therapeutic interventions remain largely unknown. Using murine and humanized models of prostate cancer (PCa), we show that one of the three branches of the unfolded protein response is selectively activated in advanced PCa. This adaptive response activates the phosphorylation of the eukaryotic initiation factor 2–α (P-eIF2α) to reset global protein synthesis to a level that fosters aggressive tumor development and is a marker of poor patient survival upon the acquisition of multiple oncogenic lesions. Using patient-derived xenograft models and an inhibitor of P-eIF2α activity, ISRIB, our data show that targeting this adaptive brake for protein synthesis selectively triggers cytotoxicity against aggressive metastatic PCa, a disease for which presently there is no cure.

    更新日期:2018-05-03
  • ER stress in prostate cancer: A therapeutically exploitable vulnerability?
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-05-02
    Christopher Logothetis, Ana Aparicio, Timothy C. Thompson

    Cooperative oncogenic effects resulting from the loss of PTEN and overexpression of MYC overcome the deleterious effects of endoplasmic reticulum stress not only to promote the growth of aggressive prostate cancer but also to expose a new therapy target for this disease (Nguyen et al., this issue).

    更新日期:2018-05-03
  • TLR7 agonists induce transient viremia and reduce the viral reservoir in SIV-infected rhesus macaques on antiretroviral therapy
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-05-02
    So-Yon Lim, Christa E. Osuna, Peter T. Hraber, Joe Hesselgesser, Jeffrey M. Gerold, Tiffany L. Barnes, Srisowmya Sanisetty, Michael S. Seaman, Mark G. Lewis, Romas Geleziunas, Michael D. Miller, Tomas Cihlar, William A. Lee, Alison L. Hill, James B. Whitney

    Antiretroviral therapy (ART) can halt HIV-1 replication but fails to target the long-lived latent viral reservoir. Several pharmacological compounds have been evaluated for their ability to reverse HIV-1 latency, but none has demonstrably reduced the latent HIV-1 reservoir or affected viral rebound after the interruption of ART. We evaluated orally administered selective Toll-like receptor 7 (TLR7) agonists GS-986 and GS-9620 for their ability to induce transient viremia in rhesus macaques infected with simian immunodeficiency virus (SIV) and treated with suppressive ART. In an initial dose-escalation study, and a subsequent dose-optimization study, we found that TLR7 agonists activated multiple innate and adaptive immune cell populations in addition to inducing expression of SIV RNA. We also observed TLR7 agonist–induced reductions in SIV DNA and measured inducible virus from treated animals in ex vivo cell cultures. In a second study, after stopping ART, two of nine treated animals remained aviremic for more than 2 years, even after in vivo CD8+ T cell depletion. Moreover, adoptive transfer of cells from aviremic animals could not induce de novo infection in naïve recipient macaques. These findings suggest that TLR7 agonists may facilitate reduction of the viral reservoir in a subset of SIV-infected rhesus macaques.

    更新日期:2018-05-03
  • Gene transfer delivers (β-globin)
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-05-02
    Christian S. Hinrichs

    Transplantation of genetically engineered hematopoietic stem cells eliminates or reduces transfusion dependence in β-thalassemia.

    更新日期:2018-05-03
  • Alerting stem cells to regenerate
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-05-02
    Julianne L. Holloway

    Alarmin delivery accelerates tissue regeneration by transitioning quiescent stem cells to the metabolically active GAlert state.

    更新日期:2018-05-03
  • Mother’s inflammation shapes baby’s brain
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-05-02
    Kathleen A. Page

    Exposure to maternal inflammation during pregnancy affects newborn brain organization and cognitive abilities during early childhood.

    更新日期:2018-05-03
  • Arginine vasopressin in cerebrospinal fluid is a marker of sociality in nonhuman primates
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-05-02
    Karen J. Parker, Joseph P. Garner, Ozge Oztan, Erna R. Tarara, Jiang Li, Valentina Sclafani, Laura A. Del Rosso, Katie Chun, Sean W. Berquist, Michael G. Chez, Sonia Partap, Antonio Y. Hardan, Elliott H. Sherr, John P. Capitanio

    Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by core social impairments. ASD remains poorly understood because of the difficulty in studying disease biology directly in patients and the reliance on mouse models that lack clinically relevant, complex social cognition abilities. We use ethological observations in rhesus macaques to identify male monkeys with naturally occurring low sociality. These monkeys showed differences in specific neuropeptide and kinase signaling pathways compared to socially competent male monkeys. Using a discovery and replication design, we identified arginine vasopressin (AVP) in cerebrospinal fluid (CSF) as a key marker of group differences in monkey sociality; we replicated these findings in an independent monkey cohort. We also confirmed in an additional monkey cohort that AVP concentration in CSF is a stable trait-like measure. Next, we showed in a small pediatric cohort that CSF AVP concentrations were lower in male children with ASD compared to age-matched male children without ASD (but with other medical conditions). We demonstrated that CSF AVP concentration was sufficient to accurately distinguish ASD cases from medical controls. These data suggest that AVP and its signaling pathway warrant consideration in future research studies investigating new targets for diagnostics and drug development in ASD.

    更新日期:2018-05-03
  • PPARγ agonist pioglitazone reverses pulmonary hypertension and prevents right heart failure via fatty acid oxidation
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-04-25
    Ekaterina Legchenko, Philippe Chouvarine, Paul Borchert, Angeles Fernandez-Gonzalez, Erin Snay, Martin Meier, Lavinia Maegel, S. Alex Mitsialis, Eva A. Rog-Zielinska, Stella Kourembanas, Danny Jonigk, Georg Hansmann

    Right ventricular (RV) heart failure is the leading cause of death in pulmonary arterial hypertension (PAH). Peroxisome proliferator–activated receptor γ (PPARγ) acts as a vasoprotective metabolic regulator in smooth muscle and endothelial cells; however, its role in the heart is unclear. We report that deletion of PPARγ in cardiomyocytes leads to biventricular systolic dysfunction and intramyocellular lipid accumulation in mice. In the SU5416/hypoxia (SuHx) rat model, oral treatment with the PPARγ agonist pioglitazone completely reverses severe PAH and vascular remodeling and prevents RV failure. Failing RV cardiomyocytes exhibited mitochondrial disarray and increased intramyocellular lipids (lipotoxicity) in the SuHx heart, which was prevented by pioglitazone. Unbiased ventricular microRNA (miRNA) arrays, mRNA sequencing, and lipid metabolism studies revealed dysregulation of cardiac hypertrophy, fibrosis, myocardial contractility, fatty acid transport/oxidation (FAO), and transforming growth factor–β signaling in the failing RV. These epigenetic, transcriptional, and metabolic alterations were modulated by pioglitazone through miRNA/mRNA networks previously not associated with PAH/RV dysfunction. Consistently, pre-miR-197 and pre-miR-146b repressed genes that drive FAO (Cpt1b and Fabp4) in primary cardiomyocytes. We recapitulated our major pathogenic findings in human end-stage PAH: (i) in the pressure-overloaded failing RV (miR-197 and miR-146b up-regulated), (ii) in peripheral pulmonary arteries (miR-146b up-regulated, miR-133b down-regulated), and (iii) in plexiform vasculopathy (miR-133b up-regulated, miR-146b down-regulated). Together, PPARγ activation can normalize epigenetic and transcriptional regulation primarily related to disturbed lipid metabolism and mitochondrial morphology/function in the failing RV and the hypertensive pulmonary vasculature, representing a therapeutic approach for PAH and other cardiovascular/pulmonary diseases.

    更新日期:2018-04-26
  • Fundamental science behind today’s important medicines
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-04-25
    Jonathan M. Spector, Rosemary S. Harrison, Mark C. Fishman

    Today’s most transformative medicines exist because of fundamental discoveries that were made without regard to practical outcome and with their relevance to therapeutics only appearing decades later.

    更新日期:2018-04-26
  • Targeting protein biotinylation enhances tuberculosis chemotherapy
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-04-25
    Divya Tiwari, Sae Woong Park, Maram M. Essawy, Surendra Dawadi, Alan Mason, Madhumitha Nandakumar, Matthew Zimmerman, Marizel Mina, Hsin Pin Ho, Curtis A. Engelhart, Thomas Ioerger, James C. Sacchettini, Kyu Rhee, Sabine Ehrt, Courtney C. Aldrich, Véronique Dartois, Dirk Schnappinger

    Successful drug treatment for tuberculosis (TB) depends on the unique contributions of its component drugs. Drug resistance poses a threat to the efficacy of individual drugs and the regimens to which they contribute. Biologically and chemically validated targets capable of replacing individual components of current TB chemotherapy are a major unmet need in TB drug development. We demonstrate that chemical inhibition of the bacterial biotin protein ligase (BPL) with the inhibitor Bio-AMS (5′-[N-(d-biotinoyl)sulfamoyl]amino-5′-deoxyadenosine) killed Mycobacterium tuberculosis (Mtb), the bacterial pathogen causing TB. We also show that genetic silencing of BPL eliminated the pathogen efficiently from mice during acute and chronic infection with Mtb. Partial chemical inactivation of BPL increased the potency of two first-line drugs, rifampicin and ethambutol, and genetic interference with protein biotinylation accelerated clearance of Mtb from mouse lungs and spleens by rifampicin. These studies validate BPL as a potential drug target that could serve as an alternate frontline target in the development of new drugs against Mtb.

    更新日期:2018-04-26
  • Alloreactive fetal T cells promote uterine contractility in preterm labor via IFN-γ and TNF-α
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-04-25
    Michela Frascoli, Lacy Coniglio, Russell Witt, Cerine Jeanty, Shannon Fleck-Derderian, Dana E. Myers, Tzong-Hae Lee, Sheila Keating, Michael P. Busch, Philip J. Norris, Qizhi Tang, Giovanna Cruz, Lisa F. Barcellos, Nardhy Gomez-Lopez, Roberto Romero, Tippi C. MacKenzie

    Healthy pregnancy is the most successful form of graft tolerance, whereas preterm labor (PTL) may represent a breakdown in maternal-fetal tolerance. Although maternal immune responses have been implicated in pregnancy complications, fetal immune responses against maternal antigens are often not considered. To examine the fetal immune system in the relevant clinical setting, we analyzed maternal and cord blood in patients with PTL and healthy term controls. We report here that the cord blood of preterm infants has higher amounts of inflammatory cytokines and a greater activation of dendritic cells. Moreover, preterm cord blood is characterized by the presence of a population of central memory cells with a type 1 T helper phenotype, which is absent in term infants, and an increase in maternal microchimerism. T cells from preterm infants mount a robust proliferative, proinflammatory response to maternal antigens compared to term infants yet fail to respond to third-party antigens. Furthermore, we show that T cells from preterm infants stimulate uterine myometrial contractility through interferon-γ and tumor necrosis factor–α. In parallel, we found that adoptive transfer of activated T cells directly into mouse fetuses resulted in pregnancy loss. Our findings indicate that fetal inflammation and rejection of maternal antigens can contribute to the signaling cascade that promotes uterine contractility and that aberrant fetal immune responses should be considered in the pathogenesis of PTL.

    更新日期:2018-04-26
  • Human fetal immune cells fight back
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-04-25
    Claire A. Chougnet

    Immune dysregulation begins in utero, influenced by inflammation, maternal microchimerism, and the activation of fetal immune responses (Frascoli et al., this issue).

    更新日期:2018-04-26
  • A firsthand view of how secondhand smoke disrupts airway immunity
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-04-25
    Chaz Langelier

    Chronic tobacco smoke exposure exacerbates Haemophilus influenzae infection by disrupting innate and adaptive immune responses in mice.

    更新日期:2018-04-26
  • Nano livers: A sobering discovery
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-04-25
    Elizabeth A. Nance

    Hepatocyte-mimicking nanocapsules carrying key liver enzymes reduce blood alcohol concentration in intoxicated mice.

    更新日期:2018-04-26
  • Needles no more
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-04-25
    Keyue Shen

    A needle-free graphene-based biosensor monitors blood glucose levels in real time.

    更新日期:2018-04-26
  • A digital microfluidic system for serological immunoassays in remote settings
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-04-25
    Alphonsus H. C. Ng, Ryan Fobel, Christian Fobel, Julian Lamanna, Darius G. Rackus, Aimee Summers, Christopher Dixon, Michael D. M. Dryden, Charis Lam, Man Ho, Nooman S. Mufti, Victor Lee, Mohd Afiq Mohd Asri, Edward A. Sykes, M. Dean Chamberlain, Rachael Joseph, Maurice Ope, Heather M. Scobie, Alaine Knipes, Paul A. Rota, Nina Marano, Paul M. Chege, Mary Njuguna, Rosemary Nzunza, Ngina Kisangau, John Kiogora, Michael Karuingi, John Wagacha Burton, Peter Borus, Eugene Lam, Aaron R. Wheeler

    Serosurveys are useful for assessing population susceptibility to vaccine-preventable disease outbreaks. Although at-risk populations in remote areas could benefit from this type of information, they face several logistical barriers to implementation, such as lack of access to centralized laboratories, cold storage, and transport of samples. We describe a potential solution: a compact and portable, field-deployable, point-of-care system relying on digital microfluidics that can rapidly test a small volume of capillary blood for disease-specific antibodies. This system uses inexpensive, inkjet-printed digital microfluidic cartridges together with an integrated instrument to perform enzyme-linked immunosorbent assays (ELISAs). We performed a field validation of the system’s analytical performance at Kakuma refugee camp, a remote setting in northwestern Kenya, where we tested children aged 9 to 59 months and caregivers for measles and rubella immunoglobulin G (IgG). The IgG assays were determined to have sensitivities of 86% [95% confidence interval (CI), 79 to 91% (measles)] and 81% [95% CI, 73 to 88% (rubella)] and specificities of 80% [95% CI, 49 to 94% (measles)] and 91% [95% CI, 76 to 97% (rubella)] (measles, n = 140; rubella, n = 135) compared with reference tests (measles IgG and rubella IgG ELISAs from Siemens Enzygnost) conducted in a centralized laboratory. These results demonstrate a potential role for this point-of-care system in global serological surveillance, particularly in remote areas with limited access to centralized laboratories.

    更新日期:2018-04-26
  • Systemic administration of the antisense oligonucleotide NS-065/NCNP-01 for skipping of exon 53 in patients with Duchenne muscular dystrophy
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-04-18
    Hirofumi Komaki, Tetsuya Nagata, Takashi Saito, Satoru Masuda, Eri Takeshita, Masayuki Sasaki, Hisateru Tachimori, Harumasa Nakamura, Yoshitsugu Aoki, Shin’ichi Takeda

    Duchenne muscular dystrophy (DMD) is a lethal hereditary muscle disease caused by mutations in the gene encoding the muscle protein dystrophin. These mutations result in a shift in the open reading frame leading to loss of the dystrophin protein. Antisense oligonucleotides (ASOs) that induce exon skipping correct this frame shift during pre-mRNA splicing and partially restore dystrophin expression in mouse and dog models. We conducted a phase 1, open-label, dose-escalation clinical trial to determine the safety, pharmacokinetics, and activity of NS-065/NCNP-01, a morpholino ASO that enables skipping of exon 53. Ten patients with DMD (6 to 16 years old), carrying mutations in the dystrophin gene whose reading frame would be restored by exon 53 skipping, were administered NS-065/NCNP-01 at doses of 1.25, 5, or 20 mg/kg weekly for 12 weeks. The primary endpoint was safety; the secondary endpoints were pharmacokinetics and successful exon skipping. No severe adverse drug reactions were observed, and no treatment discontinuation occurred. Muscle biopsy samples were taken before and after treatment and compared by reverse transcription polymerase chain reaction (RT-PCR), immunofluorescence, and Western blotting to assess the amount of exon 53 skipping and dystrophin expression. NS-065/NCNP-01 induced exon 53 skipping in dystrophin-encoding mRNA in a dose-dependent manner and increased the dystrophin/spectrin ratio in 7 of 10 patients. Furthermore, the amount of exon skipping correlated with the maximum drug concentration in plasma (Cmax) and the area under the concentration-time curve in plasma (AUC0-t). These results indicate that NS-065/NCNP-01 has a favorable safety profile and promising pharmacokinetics warranting further study in a phase 2 clinical trial.

    更新日期:2018-04-19
  • Cholesterol, cancer, and rebooting a treatment for athlete’s foot
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-04-18
    Ngee Kiat Chua, Hudson W. Coates, Andrew J. Brown

    A key enzyme in cholesterol synthesis is placed firmly on the oncogenic map and demonstrated to be a potential therapeutic target in liver cancer by repurposing a common antifungal agent (Liu et al., this issue).

    更新日期:2018-04-19
  • Shaking up cellular therapy
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-04-18
    Claire Conway

    Stem cell preparation technique determines the outcome of transplant therapy for myocardial infarction.

    更新日期:2018-04-19
  • An epigenetic target for autism
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-04-18
    Conor Liston

    A transient 3-day course of treatment with a histone deacetylase inhibitor persistently rescues atypical social behavior in a Shank3-deficiency mouse model of autism.

    更新日期:2018-04-19
  • A (synthetic) lethal weapon for cancer
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-04-18
    Amaia Lujambio

    ROS1 inhibition in E-cadherin–deficient tumors leads to synthetic lethality, which could be exploited for the selective treatment of breast cancer patients.

    更新日期:2018-04-19
  • CD32 is expressed on cells with transcriptionally active HIV but does not enrich for HIV DNA in resting T cells
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-04-18
    Mohamed Abdel-Mohsen, Leticia Kuri-Cervantes, Judith Grau-Exposito, Adam M. Spivak, Racheal A. Nell, Costin Tomescu, Surya Kumari Vadrevu, Leila B. Giron, Carla Serra-Peinado, Meritxell Genescà, Josep Castellví, Guoxin Wu, Perla M. Del Rio Estrada, Mauricio González-Navarro, Kenneth Lynn, Colin T. King, Sai Vemula, Kara Cox, Yanmin Wan, Qingsheng Li, Karam Mounzer, Jay Kostman, Ian Frank, Mirko Paiardini, Daria Hazuda, Gustavo Reyes-Terán, Douglas Richman, Bonnie Howell, Pablo Tebas, Javier Martinez-Picado, Vicente Planelles, Maria J. Buzon, Michael R. Betts, Luis J. Montaner

    The persistence of HIV reservoirs, including latently infected, resting CD4+ T cells, is the major obstacle to cure HIV infection. CD32a expression was recently reported to mark CD4+ T cells harboring a replication-competent HIV reservoir during antiretroviral therapy (ART) suppression. We aimed to determine whether CD32 expression marks HIV latently or transcriptionally active infected CD4+ T cells. Using peripheral blood and lymphoid tissue of ART-treated HIV+ or SIV+ subjects, we found that most of the circulating memory CD32+ CD4+ T cells expressed markers of activation, including CD69, HLA-DR, CD25, CD38, and Ki67, and bore a TH2 phenotype as defined by CXCR3, CCR4, and CCR6. CD32 expression did not selectively enrich for HIV- or SIV-infected CD4+ T cells in peripheral blood or lymphoid tissue; isolated CD32+ resting CD4+ T cells accounted for less than 3% of the total HIV DNA in CD4+ T cells. Cell-associated HIV DNA and RNA loads in CD4+ T cells positively correlated with the frequency of CD32+ CD69+ CD4+ T cells but not with CD32 expression on resting CD4+ T cells. Using RNA fluorescence in situ hybridization, CD32 coexpression with HIV RNA or p24 was detected after in vitro HIV infection (peripheral blood mononuclear cell and tissue) and in vivo within lymph node tissue from HIV-infected individuals. Together, these results indicate that CD32 is not a marker of resting CD4+ T cells or of enriched HIV DNA–positive cells after ART; rather, CD32 is predominately expressed on a subset of activated CD4+ T cells enriched for transcriptionally active HIV after long-term ART.

    更新日期:2018-04-19
  • Synthetic biology-based cellular biomedical tattoo for detection of hypercalcemia associated with cancer
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-04-18
    Aizhan Tastanova, Marc Folcher, Marius Müller, Gieri Camenisch, Aaron Ponti, Thomas Horn, Maria S. Tikhomirova, Martin Fussenegger

    Diagnosis marks the beginning of any successful therapy. Because many medical conditions progress asymptomatically over extended periods of time, their timely diagnosis remains difficult, and this adversely affects patient prognosis. Focusing on hypercalcemia associated with cancer, we aimed to develop a synthetic biology-inspired biomedical tattoo using engineered cells that would (i) monitor long-term blood calcium concentration, (ii) detect onset of mild hypercalcemia, and (iii) respond via subcutaneous accumulation of the black pigment melanin to form a visible tattoo. For this purpose, we designed cells containing an ectopically expressed calcium-sensing receptor rewired to a synthetic signaling cascade that activates expression of transgenic tyrosinase, which produces melanin in response to persistently increased blood Ca2+. We confirmed that the melanin-generated color change produced by this biomedical tattoo could be detected with the naked eye and optically quantified. The system was validated in wild-type mice bearing subcutaneously implanted encapsulated engineered cells. All animals inoculated with hypercalcemic breast and colon adenocarcinoma cells developed tattoos, whereas no tattoos were seen in animals inoculated with normocalcemic tumor cells. All tumor-bearing animals remained asymptomatic throughout the 38-day experimental period. Although hypercalcemia is also associated with other pathologies, our findings demonstrate that it is possible to detect hypercalcemia associated with cancer in murine models using this cell-based diagnostic strategy.

    更新日期:2018-04-19
  • Squalene epoxidase drives NAFLD-induced hepatocellular carcinoma and is a pharmaceutical target
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-04-18
    Dabin Liu, Chi Chun Wong, Li Fu, Huarong Chen, Liuyang Zhao, Chuangen Li, Yunfei Zhou, Yanquan Zhang, Weiqi Xu, Yidong Yang, Bin Wu, Gong Cheng, Paul Bo-San Lai, Nathalie Wong, Joseph J. Y. Sung, Jun Yu

    Nonalcoholic fatty liver disease (NAFLD)–induced hepatocellular carcinoma (HCC) is an emerging malignancy in the developed world; however, mechanisms that contribute to its formation are largely unknown, and targeted therapy is currently not available. Our RNA sequencing analysis of NAFLD-HCC samples revealed squalene epoxidase (SQLE) as the top outlier metabolic gene overexpressed in NAFLD-HCC patients. Hepatocyte-specific Sqle transgenic expression in mice accelerated the development of high-fat, high-cholesterol diet–induced HCC. SQLE exerts its oncogenic effect via its metabolites, cholesteryl ester and nicotinamide adenine dinucleotide phosphate (NADP+). Increased SQLE expression promotes the biosynthesis of cholesteryl ester, which induces NAFLD-HCC cell growth. SQLE increased the NADP+/NADPH (reduced form of NADP+) ratio, which triggered a cascade of events involving oxidative stress–induced DNA methyltransferase 3A (DNMT3A) expression, DNMT3A-mediated epigenetic silencing of PTEN, and activation of AKT-mTOR (mammalian target of rapamycin). In human NAFLD-HCC and HCC, SQLE is overexpressed and its expression is associated with poor patient outcomes. Terbinafine, a U.S. Food and Drug Administration–approved antifungal drug targeting SQLE, markedly inhibited SQLE-induced NAFLD-HCC cell growth in NAFLD-HCC and HCC cells and attenuated tumor development in xenograft models and in Sqle transgenic mice. Suppression of tumor growth by terbinafine is associated with decreased cholesteryl ester concentrations, restoration of PTEN expression, and inhibition of AKT-mTOR, consistent with blockade of SQLE function. Collectively, we established SQLE as an oncogene in NAFLD-HCC and propose that repurposing SQLE inhibitors may be a promising approach for the prevention and treatment of NAFLD-HCC.

    更新日期:2018-04-19
  • Dual inhibition of MDMX and MDM2 as a therapeutic strategy in leukemia
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-04-11
    Luis A. Carvajal, Daniela Ben Neriah, Adrien Senecal, Lumie Benard, Victor Thiruthuvanathan, Tatyana Yatsenko, Swathi-Rao Narayanagari, Justin C. Wheat, Tihomira I. Todorova, Kelly Mitchell, Charles Kenworthy, Vincent Guerlavais, D. Allen Annis, Boris Bartholdy, Britta Will, Jesus D. Anampa, Ioannis Mantzaris, Manuel Aivado, Robert H. Singer, Robert A. Coleman, Amit Verma, Ulrich Steidl

    The tumor suppressor p53 is often inactivated via its interaction with endogenous inhibitors mouse double minute 4 homolog (MDM4 or MDMX) or mouse double minute 2 homolog (MDM2), which are frequently overexpressed in patients with acute myeloid leukemia (AML) and other cancers. Pharmacological disruption of both of these interactions has long been sought after as an attractive strategy to fully restore p53-dependent tumor suppressor activity in cancers with wild-type p53. Selective targeting of this pathway has thus far been limited to MDM2-only small-molecule inhibitors, which lack affinity for MDMX. We demonstrate that dual MDMX/MDM2 inhibition with a stapled α-helical peptide (ALRN-6924), which has recently entered phase I clinical testing, produces marked antileukemic effects. ALRN-6924 robustly activates p53-dependent transcription at the single-cell and single-molecule levels and exhibits biochemical and molecular biological on-target activity in leukemia cells in vitro and in vivo. Dual MDMX/MDM2 inhibition by ALRN-6924 inhibits cellular proliferation by inducing cell cycle arrest and apoptosis in cell lines and primary AML patient cells, including leukemic stem cell–enriched populations, and disrupts functional clonogenic and serial replating capacity. Furthermore, ALRN-6924 markedly improves survival in AML xenograft models. Our study provides mechanistic insight to support further testing of ALRN-6924 as a therapeutic approach in AML and other cancers with wild-type p53.

    更新日期:2018-04-12
  • T cell–induced CSF1 promotes melanoma resistance to PD1 blockade
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-04-11
    Natalie J. Neubert, Martina Schmittnaegel, Natacha Bordry, Sina Nassiri, Noémie Wald, Christophe Martignier, Laure Tillé, Krisztian Homicsko, William Damsky, Hélène Maby-El Hajjami, Irina Klaman, Esther Danenberg, Kalliopi Ioannidou, Lana Kandalaft, George Coukos, Sabine Hoves, Carola H. Ries, Silvia A. Fuertes Marraco, Periklis G. Foukas, Michele De Palma, Daniel E. Speiser

    Colony-stimulating factor 1 (CSF1) is a key regulator of monocyte/macrophage differentiation that sustains the protumorigenic functions of tumor-associated macrophages (TAMs). We show that CSF1 is expressed in human melanoma, and patients with metastatic melanoma have increased CSF1 in blood compared to healthy subjects. In tumors, CSF1 expression correlated with the abundance of CD8+ T cells and CD163+ TAMs. Human melanoma cell lines consistently produced CSF1 after exposure to melanoma-specific CD8+ T cells or T cell–derived cytokines in vitro, reflecting a broadly conserved mechanism of CSF1 induction by activated CD8+ T cells. Mining of publicly available transcriptomic data sets suggested co-enrichment of CD8+ T cells with CSF1 or various TAM-specific markers in human melanoma, which was associated with nonresponsiveness to programmed cell death protein 1 (PD1) checkpoint blockade in a smaller patient cohort. Combination of anti-PD1 and anti–CSF1 receptor (CSF1R) antibodies induced the regression of BRAFV600E-driven, transplant mouse melanomas, a result that was dependent on the effective elimination of TAMs. Collectively, these data implicate CSF1 induction as a CD8+ T cell–dependent adaptive resistance mechanism and show that simultaneous CSF1R targeting may be beneficial in melanomas refractory to immune checkpoint blockade and, possibly, other T cell–based therapies.

    更新日期:2018-04-12
  • The systemic response to surgery triggers the outgrowth of distant immune-controlled tumors in mouse models of dormancy
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-04-11
    Jordan A. Krall, Ferenc Reinhardt, Oblaise A. Mercury, Diwakar R. Pattabiraman, Mary W. Brooks, Michael Dougan, Arthur W. Lambert, Brian Bierie, Hidde L. Ploegh, Stephanie K. Dougan, Robert A. Weinberg

    Patients undergoing surgical resection of primary breast tumors confront a risk for metastatic recurrence that peaks sharply 12 to 18 months after surgery. The cause of early metastatic relapse in breast cancer has long been debated, with many ascribing these relapses to the natural progression of the disease. Others have proposed that some aspect of surgical tumor resection triggers the outgrowth of otherwise-dormant metastases, leading to the synchronous pattern of relapse. Clinical data cannot distinguish between these hypotheses, and previous experimental approaches have not provided clear answers. Such uncertainty hinders the development and application of therapeutic approaches that could potentially reduce early metastatic relapse. We describe an experimental model system that definitively links surgery and the subsequent wound-healing response to the outgrowth of tumor cells at distant anatomical sites. Specifically, we find that the systemic inflammatory response induced after surgery promotes the emergence of tumors whose growth was otherwise restricted by a tumor-specific T cell response. Furthermore, we demonstrate that perioperative anti-inflammatory treatment markedly reduces tumor outgrowth in this model, suggesting that similar approaches might substantially reduce early metastatic recurrence in breast cancer patients.

    更新日期:2018-04-12
  • Spooked neutrophils unmask sepsis
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-04-11
    Sam H. Au

    Microfluidic mazes detect sepsis in patients by monitoring neutrophil motility patterns.

    更新日期:2018-04-12
  • RNase moonlights as a cancer instigator
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-04-11
    Qing Zhang

    RNase 5 is a bona fide EGFR ligand that promotes oncogenic transformation in pancreatic cancer.

    更新日期:2018-04-12
  • Adult neurogenesis in humans: Dogma overturned, again and again?
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-04-11
    Laura C. Andreae

    The controversy continues as to whether new neurons are born in adult human hippocampus.

    更新日期:2018-04-12
  • Personalized cancer vaccine effectively mobilizes antitumor T cell immunity in ovarian cancer
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-04-11
    Janos L. Tanyi, Sara Bobisse, Eran Ophir, Sandra Tuyaerts, Annalisa Roberti, Raphael Genolet, Petra Baumgartner, Brian J. Stevenson, Christian Iseli, Denarda Dangaj, Brian Czerniecki, Aikaterini Semilietof, Julien Racle, Alexandra Michel, Ioannis Xenarios, Cheryl Chiang, Dimitri S. Monos, Drew A. Torigian, Harvey L. Nisenbaum, Olivier Michielin, Carl H. June, Bruce L. Levine, Daniel J. Powel, David Gfeller, Rosemarie Mick, Urania Dafni, Vincent Zoete, Alexandre Harari, George Coukos, Lana E. Kandalaft

    We conducted a pilot clinical trial testing a personalized vaccine generated by autologous dendritic cells (DCs) pulsed with oxidized autologous whole-tumor cell lysate (OCDC), which was injected intranodally in platinum-treated, immunotherapy-naïve, recurrent ovarian cancer patients. OCDC was administered alone (cohort 1, n = 5), in combination with bevacizumab (cohort 2, n = 10), or bevacizumab plus low-dose intravenous cyclophosphamide (cohort 3, n = 10) until disease progression or vaccine exhaustion. A total of 392 vaccine doses were administered without serious adverse events. Vaccination induced T cell responses to autologous tumor antigen, which were associated with significantly prolonged survival. Vaccination also amplified T cell responses against mutated neoepitopes derived from nonsynonymous somatic tumor mutations, and this included priming of T cells against previously unrecognized neoepitopes, as well as novel T cell clones of markedly higher avidity against previously recognized neoepitopes. We conclude that the use of oxidized whole-tumor lysate DC vaccine is safe and effective in eliciting a broad antitumor immunity, including private neoantigens, and warrants further clinical testing.

    更新日期:2018-04-12
  • Increased neutrophil extracellular trap formation promotes thrombosis in myeloproliferative neoplasms
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-04-11
    Ofir Wolach, Rob S. Sellar, Kimberly Martinod, Deya Cherpokova, Marie McConkey, Ryan J. Chappell, Alexander J. Silver, Dylan Adams, Cecilia A. Castellano, Rebekka K. Schneider, Robert F. Padera, Daniel J. DeAngelo, Martha Wadleigh, David P. Steensma, Ilene Galinsky, Richard M. Stone, Giulio Genovese, Steven A. McCarroll, Bozenna Iliadou, Christina Hultman, Donna Neuberg, Ann Mullally, Denisa D. Wagner, Benjamin L. Ebert

    Thrombosis is a major cause of morbidity and mortality in Philadelphia chromosome–negative myeloproliferative neoplasms (MPNs), clonal disorders of hematopoiesis characterized by activated Janus kinase (JAK)–signal transducer and activator of transcription (STAT) signaling. Neutrophil extracellular trap (NET) formation, a component of innate immunity, has been linked to thrombosis. We demonstrate that neutrophils from patients with MPNs are primed for NET formation, an effect blunted by pharmacological inhibition of JAK signaling. Mice with conditional knock-in of Jak2V617F, the most common molecular driver of MPN, have an increased propensity for NET formation and thrombosis. Inhibition of JAK-STAT signaling with the clinically available JAK2 inhibitor ruxolitinib abrogated NET formation and reduced thrombosis in a deep vein stenosis murine model. We further show that expression of PAD4, a protein required for NET formation, is increased in JAK2V617F-expressing neutrophils and that PAD4 is required for Jak2V617F-driven NET formation and thrombosis in vivo. Finally, in a population study of more than 10,000 individuals without a known myeloid disorder, JAK2V617F-positive clonal hematopoiesis was associated with an increased incidence of thrombosis. In aggregate, our results link JAK2V617F expression to NET formation and thrombosis and suggest that JAK2 inhibition may reduce thrombosis in MPNs through cell-intrinsic effects on neutrophil function.

    更新日期:2018-04-12
  • Hematopoietic stem cell transplantation in its 60s: A platform for cellular therapies
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-04-11
    Christian Chabannon, Jurgen Kuball, Attilio Bondanza, Francesco Dazzi, Paolo Pedrazzoli, Antoine Toubert, Annalisa Ruggeri, Katharina Fleischhauer, Chiara Bonini

    Over the last 60 years, more than a million patients received hematopoietic cell transplantation. Having incorporated multiple changes in clinical practices, it remains a complex procedure facing a dual challenge: cure of the underlying disease and prevention of relapse while controlling potentially severe complications. Improved understanding of underlying biological processes resulted in the design of innovative therapies engineered from defined cell populations and testing of these therapies as addition or substitution at virtually every step of the procedure. This review provides an overview of these developments, many of them now applied outside the historical field of hematopoietic cell transplantation.

    更新日期:2018-04-12
  • Fighting leukemia with “duel”-targeted therapy
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-04-04
    Tríona Ní Chonghaile

    Combining BCL-2 inhibitor venetoclax with monoclonal CD20 antibody rituximab greatly enhances progression-free survival compared with bendamustine-rituximab in a phase 3 trial of relapsed or refractory chronic lymphocytic leukemia patients.

    更新日期:2018-04-05
Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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