Mitochondrial dysfunction in pathophysiology of heart failure
Mitochondrial dysfunction has been implicated in the development of heart failure. Oxidative metabolism in mitochondria is the main energy source of the heart, and the inability to generate and transfer energy has long been considered the primary mechanism linking mitochondrial dysfunction and contractile failure. However, the role of mitochondria in heart failure is now increasingly recognized to be beyond that of a failed power plant. In this Review, we summarize recent evidence demonstrating vicious cycles of pathophysiological mechanisms during the pathological remodeling of the heart that drive mitochondrial contribut...
Source: Journal of Clinical Investigation - August 21, 2018 Category: Biomedical Science Authors: Bo Zhou, Rong Tian Source Type: research

Lose appetite, lose control: integrins and noncanonical autophagy regulate germinal center reactions
T cell–dependent germinal center (GC) reactions are the pinnacle of adaptive immune responses, with profound effects on human health and disease. It has long been known that ligands of an innate immune pattern recognition receptor subgroup, TLRs, amplify antibody responses; however, the mechanisms regulating this phenomenon are poorly understood. In this issue of the JCI, Raso et al. demonstrate that αvβ3 integrins regulate the magnitude and speed of TLR-augmented GC reactions, limiting both short- and long-term humoral immunity. This phenomenon is dependent on a noncanonical form of the autophagy pathway ...
Source: Journal of Clinical Investigation - August 21, 2018 Category: Biomedical Science Authors: Jeremy S. Leventhal Source Type: research

Hgf/Met activation mediates resistance to BRAF inhibition in murine anaplastic thyroid cancers
Anaplastic thyroid carcinomas (ATCs) have a high prevalence of BRAF and TP53 mutations. A trial of vemurafenib in nonmelanoma BRAFV600E-mutant cancers showed significant, although short-lived, responses in ATCs, indicating that these virulent tumors remain addicted to BRAF despite their high mutation burden. To explore the mechanisms mediating acquired resistance to BRAF blockade, we generated mice with thyroid-specific deletion of p53 and dox-dependent expression of BRAFV600E, 50% of which developed ATCs after dox treatment. Upon dox withdrawal there was complete regression in all mice, although recurrences were later det...
Source: Journal of Clinical Investigation - August 21, 2018 Category: Biomedical Science Authors: Jeffrey A. Knauf, Kathleen A. Luckett, Kuen-Yuan Chen, Francesca Voza, Nicholas D. Socci, Ronald Ghossein, James A. Fagin Source Type: research

Constitutive activation of WASp in X-linked neutropenia renders neutrophils hyperactive
Congenital neutropenia is characterized by low absolute neutrophil numbers in blood, leading to recurrent bacterial infections, and patients often require life-long granulocyte CSF (G-CSF) support. X-linked neutropenia (XLN) is caused by gain-of-function mutations in the actin regulator Wiskott-Aldrich syndrome protein (WASp). To understand the pathophysiology in XLN and the role of WASp in neutrophils, we here examined XLN patients and 2 XLN mouse models. XLN patients had reduced myelopoiesis and extremely low blood neutrophil number. However, their neutrophils had a hyperactive phenotype and were present in normal number...
Source: Journal of Clinical Investigation - August 21, 2018 Category: Biomedical Science Authors: Marton Keszei, Julien Record, Joanna S. Kritikou, Hannah Wurzer, Chiara Geyer, Meike Thiemann, Paul Drescher, Hanna Brauner, Laura Köcher, Jaime James, Minghui He, Marisa A.P. Baptista, Carin I.M. Dahlberg, Amlan Biswas, Sonia Lain, David P. Lane, Wenxia Source Type: research

Polymerase-mediated ultramutagenesis in mice produces diverse cancers with high mutational load
We describe what we believe to be a novel approach to mutagenesis and cancer studies based on the DNA polymerase ε (POLE) ultramutator phenotype recently described in human cancers, in which a single amino acid substitution (most commonly P286R) in the proofreading domain results in error-prone DNA replication. We engineered a conditional PoleP286R allele in mice. PoleP286R/+ embryonic fibroblasts exhibited a striking mutator phenotype and immortalized more efficiently. PoleP286R/+ mice were born at Mendelian ratios but rapidly developed lethal cancers of diverse lineages, yielding the most cancer-prone monoallelic...
Source: Journal of Clinical Investigation - August 21, 2018 Category: Biomedical Science Authors: Hao-Dong Li, Ileana Cuevas, Musi Zhang, Changzheng Lu, Md Maksudul Alam, Yang-Xin Fu, M. James You, Esra A. Akbay, He Zhang, Diego H. Castrillon Source Type: research

Mitochondrial reprogramming via ATP5H loss promotes multimodal cancer therapy resistance
The host immune system plays a pivotal role in the emergence of tumor cells that are refractory to multiple clinical interventions including immunotherapy, chemotherapy, and radiotherapy. Here, we examined the molecular mechanisms by which the immune system triggers cross-resistance to these interventions. By examining the biological changes in murine and tumor cells subjected to sequential rounds of in vitro or in vivo immune selection via cognate cytotoxic T lymphocytes, we found that multimodality resistance arises through a core metabolic reprogramming pathway instigated by epigenetic loss of the ATP synthase subunit A...
Source: Journal of Clinical Investigation - August 21, 2018 Category: Biomedical Science Authors: Kwon-Ho Song, Jae-Hoon Kim, Young-Ho Lee, Hyun Cheol Bae, Hyo-Jung Lee, Seon Rang Woo, Se Jin Oh, Kyung-Mi Lee, Cassian Yee, Bo Wook Kim, Hanbyoul Cho, Eun Joo Chung, Joon-Yong Chung, Stephen M. Hewitt, Tae-Wook Chung, Ki-Tae Ha, Young-Ki Bae, Chih-Ping M Source Type: research

The endothelial cell receptor stabilin-2 regulates VWF-FVIII complex half-life and immunogenicity
Quantitative abnormalities of the von Willebrand factor–factor VIII (VWF-FVIII) complex associate with inherited bleeding or thrombotic disorders. Receptor-mediated interactions between plasma VWF-FVIII and phagocytic or immune cells can influence their hemostatic and immunogenic activities. Genetic association studies have demonstrated that variants in the STAB2 gene, which encodes the scavenger receptor stabilin-2, associate with plasma levels of VWF-FVIII. However, the mechanistic basis and pathophysiological consequences of this association are unknown. We have demonstrated that stabilin-2–expressing cells ...
Source: Journal of Clinical Investigation - August 21, 2018 Category: Biomedical Science Authors: Laura L. Swystun, Jesse D. Lai, Colleen Notley, Ilinca Georgescu, A. Simonne Paine, Jeff Mewburn, Kate Nesbitt, Kai Schledzewski, Cyrill Géraud, Julia Kzhyshkowska, Sergij Goerdt, Wilma Hopman, Robert R. Montgomery, Paula D. James, David Lillicrap Source Type: research

αv Integrins regulate germinal center B cell responses through noncanonical autophagy
Germinal centers (GCs) are major sites of clonal B cell expansion and generation of long-lived, high-affinity antibody responses to pathogens. Signaling through TLRs on B cells promotes many aspects of GC B cell responses, including affinity maturation, class switching, and differentiation into long-lived memory and plasma cells. A major challenge for effective vaccination is identifying strategies to specifically promote GC B cell responses. Here, we have identified a mechanism of regulation of GC B cell TLR signaling, mediated by αv integrins and noncanonical autophagy. Using B cell–specific αv-KO mice,...
Source: Journal of Clinical Investigation - August 21, 2018 Category: Biomedical Science Authors: Fiona Raso, Sara Sagadiev, Samuel Du, Emily Gage, Tanvi Arkatkar, Genita Metzler, Lynda M. Stuart, Mark T. Orr, David J. Rawlings, Shaun W. Jackson, Adam Lacy-Hulbert, Mridu Acharya Source Type: research

Cyclin D1 overexpression induces global transcriptional downregulation in lymphoid neoplasms
Cyclin D1 is an oncogene frequently overexpressed in human cancers that has a dual function as cell cycle and transcriptional regulator, although the latter is widely unexplored. Here, we investigated the transcriptional role of cyclin D1 in lymphoid tumor cells with cyclin D1 oncogenic overexpression. Cyclin D1 showed widespread binding to the promoters of most actively transcribed genes, and the promoter occupancy positively correlated with the transcriptional output of targeted genes. Despite this association, the overexpression of cyclin D1 in lymphoid cells led to a global transcriptional downmodulation that was propo...
Source: Journal of Clinical Investigation - August 21, 2018 Category: Biomedical Science Authors: Robert Albero, Anna Enjuanes, Santiago Demajo, Giancarlo Castellano, Magda Pinyol, Noelia García, Cristina Capdevila, Guillem Clot, Helena Suárez-Cisneros, Mariko Shimada, Kennosuke Karube, Mónica López-Guerra, Dolors Colomer, Sílvia Beà, José Igna Source Type: research

A simple but profound mutation in mouse DNA polymerase ε drives tumorigenesis
Over 40 years ago, Loeb and colleagues proposed that errors in DNA replication produce a mutator phenotype that is involved in generating the multiple mutations required for tumor development. In this issue of the JCI, Li, Castrillon, and colleagues describe a mouse model containing a single base change in the gene encoding replicative DNA polymerase ε (POLE) that mimics the “ultramutator” phenotype recently reported in many human tumors. Their seminal accomplishment validates Loeb’s hypothesis and the use of mutational signatures to understand the origins and potentially the treatment of human tu...
Source: Journal of Clinical Investigation - August 21, 2018 Category: Biomedical Science Authors: Thomas A. Kunkel Source Type: research

HIV-1 proviral landscapes distinguish posttreatment controllers from noncontrollers
HIV posttreatment controllers (PTCs) represent a natural model of sustained HIV remission, but they are rare and little is known about their viral reservoir. We obtained 1,450 proviral sequences after near-full-length amplification for 10 PTCs and 16 posttreatment noncontrollers (NCs). Before treatment interruption, the median intact and total reservoir size in PTCs was 7-fold lower than in NCs, but the proportion of intact, defective, and total clonally expanded proviral genomes was not significantly different between the 2 groups. Quantification of total but not intact proviral genome copies predicted sustained HIV remis...
Source: Journal of Clinical Investigation - August 21, 2018 Category: Biomedical Science Authors: Radwa Sharaf, Guinevere Q. Lee, Xiaoming Sun, Behzad Etemad, Layla M. Aboukhater, Zixin Hu, Zabrina L. Brumme, Evgenia Aga, Ronald J. Bosch, Ying Wen, Golnaz Namazi, Ce Gao, Edward P. Acosta, Rajesh T. Gandhi, Jeffrey M. Jacobson, Daniel Skiest, David M. Source Type: research

Platelet-RBC interaction mediated by FasL/FasR induces procoagulant activity important for thrombosis
Red blood cells (RBCs) influence rheology, and release ADP, ATP, and nitric oxide, suggesting a role for RBCs in hemostasis and thrombosis. Here, we provide evidence for a significant contribution of RBCs to thrombus formation. Anemic mice showed enhanced occlusion times upon injury of the carotid artery. A small population of RBCs was located to platelet thrombi and enhanced platelet activation by a direct cell contact via the FasL/FasR (CD95) pathway known to induce apoptosis. Activation of platelets in the presence of RBCs led to platelet FasL exposure that activated FasR on RBCs responsible for externalization of phosp...
Source: Journal of Clinical Investigation - August 14, 2018 Category: Biomedical Science Authors: Christoph Klatt, Irena Krüger, Saskia Zey, Kim-Jürgen Krott, Martina Spelleken, Nina Sarah Gowert, Alexander Oberhuber, Lena Pfaff, Wiebke Lückstädt, Kerstin Jurk, Martin Schaller, Hadi Al-Hasani, Jürgen Schrader, Steffen Massberg, Konstantin Stark, Source Type: research

SNAP23 regulates BAX-dependent adipocyte programmed cell death independently of canonical macroautophagy
The t-SNARE protein SNAP23 conventionally functions as a component of the cellular machinery required for intracellular transport vesicle fusion with target membranes and has been implicated in the regulation of fasting glucose levels, BMI, and type 2 diabetes. Surprisingly, we observed that adipocyte-specific KO of SNAP23 in mice resulted in a temporal development of severe generalized lipodystrophy associated with adipose tissue inflammation, insulin resistance, hyperglycemia, liver steatosis, and early death. This resulted from adipocyte cell death associated with an inhibition of macroautophagy and lysosomal degradatio...
Source: Journal of Clinical Investigation - August 14, 2018 Category: Biomedical Science Authors: Daorong Feng, Dulguun Amgalan, Rajat Singh, Jianwen Wei, Jennifer Wen, Tszki Peter Wei, Timothy E. McGraw, Richard N. Kitsis, Jeffrey E. Pessin Source Type: research

The red blood cell death receptor and thrombosis
RBCs are the most abundant circulating cells in humans and typically comprise 35% to 45% of the blood volume (hematocrit). Anemia is associated with an increase in bleeding, and epidemiological studies have shown an association between an elevated hematocrit and thrombosis. RBCs may contribute to hemostasis and thrombosis via mechanisms that include platelet margination leading to an increase in the near-wall platelet concentration, blood viscosity, thrombin generation, and platelet activation. In this issue of the JCI, Klatt et al. report that binding of the Fas ligand FasL on the surface of platelets to its cognate recep...
Source: Journal of Clinical Investigation - August 14, 2018 Category: Biomedical Science Authors: Nigel Mackman Source Type: research

Epsin deficiency promotes lymphangiogenesis through regulation of VEGFR3 degradation in diabetes
Impaired lymphangiogenesis is a complication of chronic complex diseases, including diabetes. VEGF-C/VEGFR3 signaling promotes lymphangiogenesis, but how this pathway is affected in diabetes remains poorly understood. We previously demonstrated that loss of epsins 1 and 2 in lymphatic endothelial cells (LECs) prevented VEGF-C–induced VEGFR3 from endocytosis and degradation. Here, we report that diabetes attenuated VEGF-C–induced lymphangiogenesis in corneal micropocket and Matrigel plug assays in WT mice but not in mice with inducible lymphatic-specific deficiency of epsins 1 and 2 (LEC-iDKO). Consistently, LEC...
Source: Journal of Clinical Investigation - August 14, 2018 Category: Biomedical Science Authors: Hao Wu, H.N. Ashiqur Rahman, Yunzhou Dong, Xiaolei Liu, Yang Lee, Aiyun Wen, Kim H.T. To, Li Xiao, Amy E. Birsner, Lauren Bazinet, Scott Wong, Kai Song, Megan L. Brophy, M. Riaj Mahamud, Baojun Chang, Xiaofeng Cai, Satish Pasula, Sukyoung Kwak, Wenxia Yan Source Type: research

CD28 blockade controls T cell activation to prevent graft-versus-host disease in primates
Controlling graft-versus-host disease (GVHD) remains a major unmet need in stem cell transplantation, and new, targeted therapies are being actively developed. CD28-CD80/86 costimulation blockade represents a promising strategy, but targeting CD80/CD86 with CTLA4-Ig may be associated with undesired blockade of coinhibitory pathways. In contrast, targeted blockade of CD28 exclusively inhibits T cell costimulation and may more potently prevent GVHD. Here, we investigated FR104, an antagonistic CD28-specific pegylated-Fab′, in the nonhuman primate (NHP) GVHD model and completed a multiparameter interrogation comparing i...
Source: Journal of Clinical Investigation - August 14, 2018 Category: Biomedical Science Authors: Benjamin K. Watkins, Victor Tkachev, Scott N. Furlan, Daniel J. Hunt, Kayla Betz, Alison Yu, Melanie Brown, Nicolas Poirier, Hengqi Betty Zheng, Agne Taraseviciute, Lucrezia Colonna, Caroline Mary, Gilles Blancho, Jean-Paul Soulillou, Angela Panoskaltsis- Source Type: research

Intestinal P-glycoprotein exports endocannabinoids to prevent inflammation and maintain homeostasis
Neutrophil influx into the intestinal lumen is a critical response to infectious agents, but is also associated with severe intestinal damage observed in idiopathic inflammatory bowel disease. The chemoattractant hepoxilin A3, an eicosanoid secreted from intestinal epithelial cells by the apically restricted efflux pump multidrug resistance protein 2 (MRP2), mediates this neutrophil influx. Information about a possible counterbalance pathway that could signal the lack of or resolution of an apical inflammatory signal, however, has yet to be described. We now report a system with such hallmarks. Specifically, we identify en...
Source: Journal of Clinical Investigation - August 14, 2018 Category: Biomedical Science Authors: Rose L. Szabady, Christopher Louissaint, Anneke Lubben, Bailu Xie, Shaun Reeksting, Christine Tuohy, Zachary Demma, Sage E. Foley, Christina S. Faherty, Alejandro Llanos-Chea, Andrew J. Olive, Randall J. Mrsny, Beth A. McCormick Source Type: research

Neuropilin-1 upregulation elicits adaptive resistance to oncogene-targeted therapies
Cancer cell dependence on activated oncogenes is therapeutically targeted, but acquired resistance is virtually unavoidable. Here we show that the treatment of addicted melanoma cells with BRAF inhibitors, and of breast cancer cells with HER2-targeted drugs, led to an adaptive rise in neuropilin-1 (NRP1) expression, which is crucial for the onset of acquired resistance to therapy. Moreover, NRP1 levels dictated the efficacy of MET oncogene inhibitors in addicted stomach and lung carcinoma cells. Mechanistically, NRP1 induced a JNK-dependent signaling cascade leading to the upregulation of alternative effector kinases EGFR ...
Source: Journal of Clinical Investigation - August 14, 2018 Category: Biomedical Science Authors: Sabrina Rizzolio, Gabriella Cagnoni, Chiara Battistini, Stefano Bonelli, Claudio Isella, Jo A. Van Ginderachter, René Bernards, Federica Di Nicolantonio, Silvia Giordano, Luca Tamagnone Source Type: research

Expression of mutant Sftpc in murine alveolar epithelia drives spontaneous lung fibrosis
Epithelial cell dysfunction is postulated as an important component in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Mutations in the surfactant protein C (SP-C) gene (SFTPC), an alveolar type II (AT2) cell–restricted protein, have been found in sporadic and familial IPF. To causally link these events, we developed a knockin mouse model capable of regulated expression of an IPF-associated isoleucine-to-threonine substitution at codon 73 (I73T) in Sftpc (SP-CI73T). Tamoxifen-treated SP-CI73T cohorts developed rapid increases in SftpcI73T mRNA and misprocessed proSP-CI73T protein accompanied by increased ear...
Source: Journal of Clinical Investigation - August 14, 2018 Category: Biomedical Science Authors: Shin-Ichi Nureki, Yaniv Tomer, Alessandro Venosa, Jeremy Katzen, Scott J. Russo, Sarita Jamil, Matthew Barrett, Vivian Nguyen, Meghan Kopp, Surafel Mulugeta, Michael F. Beers Source Type: research

Acute inflammation: endogenous cannabinoids mellow the harsh proinflammatory environment
Under normal conditions, there is a paucity of neutrophils within the intestinal mucosa; however, these innate immune cells rapidly infiltrate the mucosa in response to infection and are critical for pathogen control. Unfortunately, these cells can cause extensive damage to the intestine if the initial inflammatory influx is not resolved. Factors that promote resolution of inflammation are of great interest, as they have therapeutic potential for limiting uncontrolled inflammatory damage. In this issue of the JCI, Szabady et al. demonstrate that the multidrug resistance transporter P-glycoprotein (P-gp) secretes endocannab...
Source: Journal of Clinical Investigation - August 14, 2018 Category: Biomedical Science Authors: Andrew S. Neish Source Type: research

Lung injury and fibrosis induced by a mutant form of surfactant protein C
Although mutant forms of the gene encoding surfactant protein C (SFTPC) have been linked to interstitial lung disease, the mechanisms by which the most common of these mutations, SFTPCI73T, results in lung fibrosis are uncertain. In this issue of the JCI, Nureki et al. developed a knockin mouse model and showed that SFTPCI73T is expressed by alveolar type II (AT2) epithelial cells in the lungs. These mice developed an age-related fibrotic phenotype when the mutant allele was expressed at low levels and acute lung inflammation/injury followed by lung fibrosis when mutant SFTPCI73T expression was enhanced. This work provides...
Source: Journal of Clinical Investigation - August 14, 2018 Category: Biomedical Science Authors: Timothy S. Blackwell Source Type: research

ATR kinase inhibitor AZD6738 potentiates CD8+ T cell–dependent antitumor activity following radiation
DNA-damaging chemotherapy and radiation therapy are integrated into the treatment paradigm of the majority of cancer patients. Recently, immunotherapy that targets the immunosuppressive interaction between programmed death 1 (PD-1) and its ligand PD-L1 has been approved for malignancies including non–small cell lung cancer, melanoma, and head and neck squamous cell carcinoma. ATR is a DNA damage–signaling kinase activated at damaged replication forks, and ATR kinase inhibitors potentiate the cytotoxicity of DNA-damaging chemotherapies. We show here that the ATR kinase inhibitor AZD6738 combines with conformal r...
Source: Journal of Clinical Investigation - August 14, 2018 Category: Biomedical Science Authors: Frank P. Vendetti, Pooja Karukonda, David A. Clump, Troy Teo, Ronald Lalonde, Katriana Nugent, Matthew Ballew, Brian F. Kiesel, Jan H. Beumer, Saumendra N. Sarkar, Thomas P. Conrads, Mark J. O’Connor, Robert L. Ferris, Phuoc T. Tran, Greg M. Delgoffe, C Source Type: research

Th1/Th17 polarization persists following whole-cell pertussis vaccination despite repeated acellular boosters
In conclusion, our data suggest that there are long-lasting effects and differences in polarization and proliferation of T cell responses in adults originally vaccinated with aP compared with those that initially received wP, despite repeated acellular boosters. (Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - August 6, 2018 Category: Biomedical Science Authors: Ricardo da Silva Antunes, Mariana Babor, Chelsea Carpenter, Natalie Khalil, Mario Cortese, Alexander J. Mentzer, Grégory Seumois, Christopher D. Petro, Lisa A. Purcell, Pandurangan Vijayanand, Shane Crotty, Bali Pulendran, Bjoern Peters, Alessandro Sette Source Type: research

The good and the bad of vitamin D inactivation
While disorders of impaired vitamin D activation and action have long been appreciated, the consequences of abnormalities in pathways leading to the inactivation of vitamin D metabolites have only recently been identified. Two recent articles have shed new light on this area of vitamin D biology. The report by Martineau et al., published in the JCI, describes a pathway in which binding of the vitamin D metabolite 24R,25(OH)2D3 to its effector molecule FAM57B2 plays an important role in endochondral ossification during bone repair. This work follows, and adds to, another recent JCI publication by Roizen et al., showing that...
Source: Journal of Clinical Investigation - August 6, 2018 Category: Biomedical Science Authors: Marie B. Demay Source Type: research

Autophagy orchestrates the regulatory program of tumor-associated myeloid-derived suppressor cells
Myeloid-derived suppressor cells (MDSCs) densely accumulate into tumors and potently suppress antitumor immune responses, promoting tumor development. Targeting MDSCs in tumor immunotherapy has been hampered by lack of understanding of the molecular pathways that govern MDSC differentiation and function. Herein, we identify autophagy as a crucial pathway for MDSC-mediated suppression of antitumor immunity. Specifically, MDSCs in patients with melanoma and mouse melanoma exhibited increased levels of functional autophagy. Ablation of autophagy in myeloid cells markedly delayed tumor growth and endowed antitumor immune respo...
Source: Journal of Clinical Investigation - August 6, 2018 Category: Biomedical Science Authors: Themis Alissafi, Aikaterini Hatzioannou, Konstantinos Mintzas, Roza Maria Barouni, Aggelos Banos, Sundary Sormendi, Alexandros Polyzos, Maria Xilouri, Ben Wielockx, Helen Gogas, Panayotis Verginis Source Type: research

TET2 controls chemoresistant slow-cycling cancer cell survival and tumor recurrence
Dormant or slow-cycling tumor cells can form a residual chemoresistant reservoir responsible for relapse in patients, years after curative surgery and adjuvant therapy. We have adapted the pulse-chase expression of H2BeGFP for labeling and isolating slow-cycling cancer cells (SCCCs). SCCCs showed cancer initiation potential and enhanced chemoresistance. Cells at this slow-cycling status presented a distinctive nongenetic and cell-autonomous gene expression profile shared across different tumor types. We identified TET2 epigenetic enzyme as a key factor controlling SCCC numbers, survival, and tumor recurrence. 5-Hydroxymeth...
Source: Journal of Clinical Investigation - August 6, 2018 Category: Biomedical Science Authors: Isabel Puig, Stephan P. Tenbaum, Irene Chicote, Oriol Arqués, Jordi Martínez-Quintanilla, Estefania Cuesta-Borrás, Lorena Ramírez, Pilar Gonzalo, Atenea Soto, Susana Aguilar, Cristina Eguizabal, Ginevra Caratù, Aleix Prat, Guillem Argilés, Stefania Source Type: research

Recurrent hypoglycemia inhibits the counterregulatory response by suppressing adrenal activity
Hypoglycemia activates the counterregulatory response (CRR), a neural-endocrine reflex that restores euglycemia. Although effective if occasionally activated, repeated induction of the CRR leads to a decline in responsiveness and prolonged exposure to hypoglycemia. The mechanism underlying this impairment is not known. We found that the reduction in epinephrine release that characterizes a suppressed CRR involves a long-lasting form of sympatho-adrenal synaptic plasticity. Using optogenetically evoked catecholamine release, we show that recurrent hypoglycemia reduced the secretory capacity of mouse adrenal chromaffin cells...
Source: Journal of Clinical Investigation - August 6, 2018 Category: Biomedical Science Authors: Yunbing Ma, Qian Wang, Debria Joe, Manqi Wang, Matthew D. Whim Source Type: research

Mitochondrial metabolism in pulmonary hypertension: beyond mountains there are mountains
Pulmonary hypertension (PH) is a heterogeneous and fatal disease of the lung vasculature, where metabolic and mitochondrial dysfunction may drive pathogenesis. Similar to the Warburg effect in cancer, a shift from mitochondrial oxidation to glycolysis occurs in diseased pulmonary vessels and the right ventricle. However, appreciation of metabolic events in PH beyond the Warburg effect is only just emerging. This Review discusses molecular, translational, and clinical concepts centered on the mitochondria and highlights promising, controversial, and challenging areas of investigation. If we can move beyond the “mounta...
Source: Journal of Clinical Investigation - August 6, 2018 Category: Biomedical Science Authors: Miranda K. Culley, Stephen Y. Chan Source Type: research

High-accuracy determination of internal circadian time from a single blood sample
CONCLUSION. The BodyTime assay provides a new diagnostic tool for personalization of health care according to the patient’s circadian clock. FUNDING. This study was supported by the Bundesministerium für Bildung und Forschung, Germany (FKZ: 13N13160 and 13N13162) and Intellux GmbH, Germany. (Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - August 6, 2018 Category: Biomedical Science Authors: Nicole Wittenbrink, Bharath Ananthasubramaniam, Mirjam Münch, Barbara Koller, Bert Maier, Charlotte Weschke, Frederik Bes, Jan de Zeeuw, Claudia Nowozin, Amely Wahnschaffe, Sophia Wisniewski, Mandy Zaleska, Osnat Bartok, Reut Ashwal-Fluss, Hedwig Lammert Source Type: research

Beyond the brain: do peripheral mechanisms develop impaired awareness of hypoglycemia?
The mechanisms responsible for the development of the impaired awareness of hypoglycemia often seen in insulin-treated patients with diabetes remain uncertain, but cerebral adaptations to recurrent hypoglycemia are frequently hypothesized. In this issue of the JCI, Ma et al. demonstrate that neuropeptide Y (NPY) secretion from adrenal chromaffin cells persists during exposure to recurrent hypoglycemia and activation of the sympathetic nerves at the same time that epinephrine secretion is reduced. This results in the inhibition of tyrosine hydroxylase, the rate-limiting enzyme for catecholamine synthesis. These observations...
Source: Journal of Clinical Investigation - August 6, 2018 Category: Biomedical Science Authors: Elizabeth R. Seaquist Source Type: research

A tribute to Lloyd Hollingsworth “Holly” Smith Jr. (1924–2018)
(Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - August 6, 2018 Category: Biomedical Science Authors: Robert M. Wachter, Talmadge E. King Jr. Source Type: research

Inherited p40phox deficiency differs from classic chronic granulomatous disease
We report on 24 p40phox-deficient patients from 12 additional families in 8 countries. These patients display 8 different in-frame or out-of-frame mutations of NCF4 that are homozygous in 11 of the families and compound heterozygous in another. When overexpressed in NB4 neutrophil-like cells and EBV-transformed B cells in vitro, the mutant alleles were found to be LOF, with the exception of the p.R58C and c.120_134del alleles, which were hypomorphic. Particle-induced NADPH oxidase activity was severely impaired in the patients’ neutrophils, whereas PMA-induced dihydrorhodamine-1,2,3 (DHR) oxidation, which is widely u...
Source: Journal of Clinical Investigation - August 6, 2018 Category: Biomedical Science Authors: Annemarie van de Geer, Alejandro Nieto-Patlán, Douglas B. Kuhns, Anton T.J. Tool, Andrés A. Arias, Matthieu Bouaziz, Martin de Boer, José Luis Franco, Roel P. Gazendam, John L. van Hamme, Michel van Houdt, Karin van Leeuwen, Paul J.H. Verkuijlen, Timo Source Type: research

Composition of pertussis vaccine given to infants determines long-term T cell polarization
The introduction of a whole-cell vaccine against Bordetella pertussis, the causative agent of whooping cough, dramatically reduced disease incidence. Unfortunately, the whole-cell formulation also induces severe reactions in some infants. Because of this, acellular vaccines have been developed, but they are used exclusively in high-income countries. However, the acellular vaccines do not provide long-term protection, and despite the use of routine boosters, the disease is on the rise. In this issue of the JCI, da Silva Antunes and colleagues demonstrate that the whole-cell vaccines promote long-term polarization toward Th1...
Source: Journal of Clinical Investigation - August 6, 2018 Category: Biomedical Science Authors: Stanley A. Plotkin Source Type: research

Ezh2 loss propagates hypermethylation at T cell differentiation–regulating genes to promote leukemic transformation
Early T cell precursor acute lymphoblastic leukemia (ETP-ALL) is a new pathological entity with poor outcomes in T cell ALL (T-ALL) that is characterized by a high incidence of loss-of-function mutations in polycomb repressive complex 2 (PRC2) genes. We generated a mouse model of ETP-ALL by deleting Ezh2, one of the PRC2 genes, in p53-null hematopoietic cells. The loss of Ezh2 in p53-null hematopoietic cells impeded the differentiation of ETPs and eventually induced ETP-ALL–like disease in mice, indicating that PRC2 functions as a bona fide tumor suppressor in ETPs. A large portion of PRC2 target genes acquired DNA h...
Source: Journal of Clinical Investigation - August 6, 2018 Category: Biomedical Science Authors: Changshan Wang, Motohiko Oshima, Daisuke Sato, Hirotaka Matsui, Sho Kubota, Kazumasa Aoyama, Yaeko Nakajima-Takagi, Shuhei Koide, Jun Matsubayashi, Makiko Mochizuki-Kashio, Takako Nakano-Yokomizo, Jie Bai, Toshitaka Nagao, Akinori Kanai, Atsushi Iwama, Go Source Type: research

Oncogenic TRK fusions are amenable to inhibition in hematologic malignancies
Rearrangements involving the neurotrophic receptor kinase genes (NTRK1, NTRK2, and NTRK3; hereafter referred to as TRK) produce oncogenic fusions in a wide variety of cancers in adults and children. Although TRK fusions occur in fewer than 1% of all solid tumors, inhibition of TRK results in profound therapeutic responses, resulting in Breakthrough Therapy FDA approval of the TRK inhibitor larotrectinib for adult and pediatric patients with solid tumors, regardless of histology. In contrast to solid tumors, the frequency of TRK fusions and the clinical effects of targeting TRK in hematologic malignancies are unknown. Here,...
Source: Journal of Clinical Investigation - August 6, 2018 Category: Biomedical Science Authors: Justin Taylor, Dean Pavlick, Akihide Yoshimi, Christina Marcelus, Stephen S. Chung, Jaclyn F. Hechtman, Ryma Benayed, Emiliano Cocco, Benjamin H. Durham, Lillian Bitner, Daichi Inoue, Young Rock Chung, Kerry Mullaney, Justin M. Watts, Eli L. Diamond, Lee Source Type: research

Emerging strategies for combination checkpoint modulators in cancer immunotherapy
Current immune checkpoint-modulating agents have demonstrated clinical efficacy in certain tumor types, particularly those with a high burden of tumor-specific neoantigens, high tumor-mutational burden, and abundant tumor-infiltrating T cells. However, these tumors often stop responding, with signs of T cells exhaustion, decreased T cell effector function, and upregulated inhibitory checkpoints. To enhance antitumor immunity and rescue exhausted T cells, newer inhibitory and stimulatory checkpoint modulators are being tested as monotherapy or in combination with approved checkpoint inhibitors. In contrast, tumors with low ...
Source: Journal of Clinical Investigation - August 2, 2018 Category: Biomedical Science Authors: Aleksandra Popovic, Elizabeth M. Jaffee, Neeha Zaidi Source Type: research

SUMO-defective c-Maf preferentially transactivates Il21 to exacerbate autoimmune diabetes
SUMOylation is involved in the development of several inflammatory diseases, but the physiological significance of SUMO-modulated c-Maf in autoimmune diabetes is not completely understood. Here, we report that an age-dependent attenuation of c-Maf SUMOylation in CD4+ T cells is positively correlated with the IL-21–mediated diabetogenesis in NOD mice. Using 2 strains of T cell–specific transgenic NOD mice overexpressing wild-type c-Maf (Tg-WTc) or SUMOylation site–mutated c-Maf (Tg-KRc), we demonstrated that Tg-KRc mice developed diabetes more rapidly than Tg-WTc mice in a CD4+ T cell–autonomous mann...
Source: Journal of Clinical Investigation - July 31, 2018 Category: Biomedical Science Authors: Chao-Yuan Hsu, Li-Tzu Yeh, Shin-Huei Fu, Ming-Wei Chien, Yu-Wen Liu, Shi-Chuen Miaw, Deh-Ming Chang, Huey-Kang Sytwu Source Type: research

Ca2+-binding protein NECAB2 facilitates inflammatory pain hypersensitivity
Pain signals are transmitted by multisynaptic glutamatergic pathways. Their first synapse between primary nociceptors and excitatory spinal interneurons gates the sensory load. In this pathway, glutamate release is orchestrated by Ca2+-sensor proteins, with N-terminal EF-hand Ca2+-binding protein 2 (NECAB2) being particular abundant. However, neither the importance of NECAB2+ neuronal contingents in dorsal root ganglia (DRGs) and spinal cord nor the function determination by NECAB2 has been defined. A combination of histochemical analyses and single-cell RNA-sequencing showed NECAB2 in small- and medium-sized C- and A&delt...
Source: Journal of Clinical Investigation - July 31, 2018 Category: Biomedical Science Authors: Ming-Dong Zhang, Jie Su, Csaba Adori, Valentina Cinquina, Katarzyna Malenczyk, Fatima Girach, Changgeng Peng, Patrik Ernfors, Peter Löw, Lotta Borgius, Ole Kiehn, Masahiko Watanabe, Mathias Uhlén, Nicholas Mitsios, Jan Mulder, Tibor Harkany, Tomas Hökf Source Type: research

Wnt signaling suppresses MAPK-driven proliferation of intestinal stem cells
Intestinal homeostasis depends on a slowly proliferating stem cell compartment in crypt cells, followed by rapid proliferation of committed progenitor cells in the transit amplifying (TA) compartment. The balance between proliferation and differentiation in intestinal stem cells (ISCs) is regulated by Wnt/β-catenin signaling, although the mechanism remains unclear. We previously targeted PORCN, an enzyme essential for all Wnt secretion, and demonstrated that stromal production of Wnts was required for intestinal homeostasis. Here, a PORCN inhibitor was used to acutely suppress Wnt signaling. Unexpectedly, the treatmen...
Source: Journal of Clinical Investigation - July 31, 2018 Category: Biomedical Science Authors: Zahra Kabiri, Gediminas Greicius, Hamed Zaribafzadeh, Amanda Hemmerich, Christopher M. Counter, David M. Virshup Source Type: research

The role of mitochondria in aging
The biological basis of human aging remains one of the greatest unanswered scientific questions. Increasing evidence, however, points to a role for alterations in mitochondrial function as a potential central regulator of the aging process. Here, we focus primarily on three aspects of mitochondrial biology that link this ancient organelle to how and why we age. In particular, we discuss the role of mitochondria in regulating the innate immune system, the mechanisms linking mitochondrial quality control to age-dependent pathology, and the possibility that mitochondrial-to-nuclear signaling might regulate the rate of aging. ...
Source: Journal of Clinical Investigation - July 31, 2018 Category: Biomedical Science Authors: Jiyong Yang, Arnon Blum, Jie Liu, Toren Finkel Source Type: research

Galactose protects against cell damage in mouse models of acute pancreatitis
Acute pancreatitis (AP), a human disease in which the pancreas digests itself, has substantial mortality with no specific therapy. The major causes of AP are alcohol abuse and gallstone complications, but it also occurs as an important side effect of the standard asparaginase-based therapy for childhood acute lymphoblastic leukemia. Previous investigations into the mechanisms underlying pancreatic acinar cell death induced by alcohol metabolites, bile acids, or asparaginase indicated that loss of intracellular ATP generation is an important factor. We now report that, in isolated mouse pancreatic acinar cells or cell clust...
Source: Journal of Clinical Investigation - July 31, 2018 Category: Biomedical Science Authors: Shuang Peng, Julia V. Gerasimenko, Tetyana M. Tsugorka, Oleksiy Gryshchenko, Sujith Samarasinghe, Ole H. Petersen, Oleg V. Gerasimenko Source Type: research

Mitochondrial fidelity and metabolic agility control immune cell fate and function
Remodeling of mitochondrial metabolism plays an important role in regulating immune cell fate, proliferation, and activity. Furthermore, given their bacterial ancestry, disruption in mitochondrial fidelity leading to extravasation of their content initiates and amplifies innate immune surveillance with a myriad of physiologic and pathologic consequences. Investigations into the role of mitochondria in the immune system have come to the fore, and appreciation of mitochondrial function and quality control in immune regulation has enhanced our understanding of disease pathogenesis and identified new targets for immune modulat...
Source: Journal of Clinical Investigation - July 31, 2018 Category: Biomedical Science Authors: Michael N. Sack Source Type: research

Modulation of EZH2 expression in T cells improves efficacy of anti–CTLA-4 therapy
Enhancer of zeste homolog 2–mediated (EZH2-mediated) epigenetic regulation of T cell differentiation and Treg function has been described previously; however, the role of EZH2 in T cell–mediated antitumor immunity, especially in the context of immune checkpoint therapy, is not understood. Here, we showed that genetic depletion of EZH2 in Tregs (FoxP3creEZH2fl/fl mice) leads to robust antitumor immunity. In addition, pharmacological inhibition of EZH2 in human T cells using CPI-1205 elicited phenotypic and functional alterations of the Tregs and enhanced cytotoxic activity of Teffs. We observed that ipilimumab (...
Source: Journal of Clinical Investigation - July 31, 2018 Category: Biomedical Science Authors: Sangeeta Goswami, Irina Apostolou, Jan Zhang, Jill Skepner, Swetha Anandhan, Xuejun Zhang, Liangwen Xiong, Patrick Trojer, Ana Aparicio, Sumit K. Subudhi, James P. Allison, Hao Zhao, Padmanee Sharma Source Type: research

Itaconic acid mediates crosstalk between macrophage metabolism and peritoneal tumors
Control of cellular metabolism is critical for efficient cell function, although little is known about the interplay between cell subset–specific metabolites in situ, especially in the tumor setting. Here, we determined how a macrophage-specific (Mϕ-specific) metabolite, itaconic acid, can regulate tumor progression in the peritoneum. We show that peritoneal tumors (B16 melanoma or ID8 ovarian carcinoma) elicited a fatty acid oxidation–mediated increase in oxidative phosphorylation (OXPHOS) and glycolysis in peritoneal tissue–resident macrophages (pResMϕ). Unbiased metabolomics identified itaconic acid,...
Source: Journal of Clinical Investigation - July 31, 2018 Category: Biomedical Science Authors: Jonathan M. Weiss, Luke C. Davies, Megan Karwan, Lilia Ileva, Michelle K. Ozaki, Robert Y.S. Cheng, Lisa A. Ridnour, Christina M. Annunziata, David A. Wink, Daniel W. McVicar Source Type: research

HECTD3 mediates TRAF3 polyubiquitination and type I interferon induction during bacterial infection
Lysine-63–linked (K63-linked) polyubiquitination of TRAF3 coordinates the engagement of pattern-recognition receptors with recruited adaptor proteins and downstream activator TBK1 in pathways that induce type I IFN. Whether autoubiquitination or other E3 ligases mediate K63-linked TRAF3 polyubiquitination remains unclear. We demonstrated that mice deficient in the E3 ligase gene Hectd3 remarkably increased host defense against infection by intracellular bacteria Francisella novicida, Mycobacterium, and Listeria by limiting bacterial dissemination. In the absence of HECTD3, type I IFN response was impaired during bact...
Source: Journal of Clinical Investigation - July 31, 2018 Category: Biomedical Science Authors: Fubing Li, Yang Li, Huichun Liang, Tao Xu, Yanjie Kong, Maobo Huang, Ji Xiao, Xi Chen, Houjun Xia, Yingying Wu, Zhongmei Zhou, Xiaomin Guo, Chunmiao Hu, Chuanyu Yang, Xu Cheng, Ceshi Chen, Xiaopeng Qi Source Type: research

Mosaic-variegated aneuploidy syndrome mutation or haploinsufficiency in Cep57 impairs tumor suppression
This study identifies Cep57 as a haploinsufficient tumor suppressor with biologically diverse roles in centrosome maturation and Fgf2-mediated bone formation. (Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - July 23, 2018 Category: Biomedical Science Authors: Khaled Aziz, Cynthia J. Sieben, Karthik B. Jeganathan, Masakazu Hamada, Brian A. Davies, Raul O. Fierro Velasco, Nazneen Rahman, David J. Katzmann, Jan M. van Deursen Source Type: research

Eupatilin rescues ciliary transition zone defects to ameliorate ciliopathy-related phenotypes
Ciliopathies are clinically overlapping genetic disorders involving structural and functional abnormalities of cilia. Currently, there are no small-molecule drugs available to treat ciliary defects in ciliopathies. Our phenotype-based screen identified the flavonoid eupatilin and its analogs as lead compounds for developing ciliopathy medication. CEP290, a gene mutated in several ciliopathies, encodes a protein that forms a complex with NPHP5 to support the function of the ciliary transition zone. Eupatilin relieved ciliogenesis and ciliary receptor delivery defects resulting from deletion of CEP290. In rd16 mice harboring...
Source: Journal of Clinical Investigation - July 23, 2018 Category: Biomedical Science Authors: Yong Joon Kim, Sungsoo Kim, Yooju Jung, Eunji Jung, Ho Jeong Kwon, Joon Kim Source Type: research

Hijacking a key chromatin modulator creates epigenetic vulnerability for MYC-driven cancer
While the genomic binding of MYC protein correlates with active epigenetic marks on chromatin, it remains largely unclear how major epigenetic mechanisms functionally impact the tumorigenic potential of MYC. Here, we show that, compared with the catalytic subunits, the core subunits, including DPY30, of the major H3K4 methyltransferase complexes were frequently amplified in human cancers and selectively upregulated in Burkitt lymphoma. We show that DPY30 promoted the expression of endogenous MYC and was also functionally important for efficient binding of MYC to its genomic targets by regulating chromatin accessibility. Dp...
Source: Journal of Clinical Investigation - July 23, 2018 Category: Biomedical Science Authors: Zhenhua Yang, Kushani Shah, Theodore Busby, Keith Giles, Alireza Khodadadi-Jamayran, Wei Li, Hao Jiang Source Type: research

PRDM16 isoforms differentially regulate normal and leukemic hematopoiesis and inflammatory gene signature
PRDM16 is a transcriptional coregulator involved in translocations in acute myeloblastic leukemia (AML), myelodysplastic syndromes, and T acute lymphoblastic leukemia that is highly expressed in and required for the maintenance of hematopoietic stem cells (HSCs), and can be aberrantly expressed in AML. Prdm16 is expressed as full-length (fPrdm16) and short (sPrdm16) isoforms, the latter lacking the N-terminal PR domain. The role of both isoforms in normal and malignant hematopoiesis is unclear. We show here that fPrdm16 was critical for HSC maintenance, induced multiple genes involved in GTPase signaling, and repressed inf...
Source: Journal of Clinical Investigation - July 23, 2018 Category: Biomedical Science Authors: David J. Corrigan, Larry L. Luchsinger, Mariana Justino de Almeida, Linda J. Williams, Alexandros Strikoudis, Hans-Willem Snoeck Source Type: research

Trefoil factor 1 inhibits epithelial-mesenchymal transition of pancreatic intraepithelial neoplasm
This study indicates that the acquisition of TFF1 expression is an early event in pancreatic carcinogenesis and that TFF1 might act as a tumor suppressor to prevent EMT and the invasive transformation of PanIN. (Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - July 23, 2018 Category: Biomedical Science Authors: Junpei Yamaguchi, Yukihiro Yokoyama, Toshio Kokuryo, Tomoki Ebata, Atsushi Enomoto, Masato Nagino Source Type: research