MedWorm.com provides a medical RSS filtering service. Over 6000 RSS medical sources are combined and output via different filters. This feed contains the latest items from the 'Journal of Clinical Investigation' source. Thu, 09 Feb 2012 14:07:54 +0100 http://www.medworm.com/index.php?rid=5664032&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F62595 Thermogenesis in brown adipose tissue (BAT) is well characterized as being under the control of the sympathetic nervous system. The energy-burning capacity of BAT makes it an attractive target for anti-obesity therapies. However, previous attempts to manipulate BAT’s sympathetic activation have lacked specificity. In this issue of the JCI, Bordicchia et al. provide new data indicating that cardiac natriuretic peptides (NPs) are also able to activate thermogenic machinery in adipose tissue. Their findings suggest a novel strategy to increase energy dissipation in adipose tissue, independent of adrenergic receptors. (Source: Journal of Clinical Investigation) Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5664032 Mon, 06 Feb 2012 18:32:05 +0100 5664032 http://www.medworm.com/index.php?rid=5664031&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F61466 Epidemiological studies have revealed an inverse association between Helicobacter pylori infection and the incidence of allergic asthma. This association is consistent with the hygiene hypothesis, which posits that exposure to microbes early in life prevents the later development of allergic diseases, and has been reproduced in mouse models of asthma. In this issue of the JCI, Oertli and colleagues report that H. pylori infection in neonates elicits tolerogenic DCs that produce IL-18, which drive the generation of Tregs that subsequently protect the mice from allergic asthma. This finding strengthens the intriguing link between pathogen exposure and allergic disease. (Source: Journal of Clinical Investigation) Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5664031 Mon, 06 Feb 2012 18:32:05 +0100 5664031 http://www.medworm.com/index.php?rid=5664030&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F61029 Persistent colonization with the gastric bacterial pathogen Helicobacter pylori causes gastritis and predisposes infected individuals to gastric cancer. Conversely, it is also linked to protection from allergic, chronic inflammatory, and autoimmune diseases. We demonstrate here that H. pylori inhibits LPS-induced maturation of DCs and reprograms DCs toward a tolerance-promoting phenotype. Our results showed that DCs exposed to H. pylori in vitro or in vivo failed to induce T cell effector functions. Instead, they efficiently induced expression of the forkhead transcription factor FoxP3, the master regulator of Tregs, in naive T cells. Depletion of DCs in mice infected with H. pylori during the neonatal period was sufficient to break H. pylori–specific tolerance. DC depletion result... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5664030 Mon, 06 Feb 2012 18:32:05 +0100 5664030 http://www.medworm.com/index.php?rid=5664029&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F60818 Dysregulation of the G1/S transition in the cell cycle contributes to tumor development. The oncogenic transcription factors c-Jun and c-Myc are indispensable regulators at this transition, and their aberrant expression is associated with many malignancies. Degradation of c-Jun/c-Myc is a critical process for the G1/S transition, which is initiated upon phosphorylation by glycogen synthase kinase 3 β (GSK3β). However, a specific kinase or kinases responsible for priming phosphorylation events that precede this GSK3β modification has not been definitively identified. Here, we found that the dual-specificity tyrosine phosphorylation–regulated kinase DYRK2 functions as a priming kinase of c-Jun and c-Myc. Knockdown of DYRK2 in human cancer cells shortened the G... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5664029 Mon, 06 Feb 2012 18:32:05 +0100 5664029 http://www.medworm.com/index.php?rid=5664028&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F60256 Chromosomal instability (CIN) in tumors is characterized by chromosomal abnormalities and an altered gene expression signature; however, the mechanism of CIN is poorly understood. CCND1 (which encodes cyclin D1) is overexpressed in human malignancies and has been shown to play a direct role in transcriptional regulation. Here, we used genome-wide ChIP sequencing and found that the DNA-bound form of cyclin D1 occupied the regulatory region of genes governing chromosomal integrity and mitochondrial biogenesis. Adding cyclin D1 back to Ccnd1–/– mouse embryonic fibroblasts resulted in CIN gene regulatory region occupancy by the DNA-bound form of cyclin D1 and induction of CIN gene expression. Furthermore, increased chromosomal aberrations, aneuploidy, and centrosome abnormaliti... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5664028 Mon, 06 Feb 2012 18:32:05 +0100 5664028 http://www.medworm.com/index.php?rid=5664027&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F59701 The ability of mammals to resist body fat accumulation is linked to their ability to expand the number and activity of “brown adipocytes” within white fat depots. Activation of β-adrenergic receptors (β-ARs) can induce a functional “brown-like” adipocyte phenotype. As cardiac natriuretic peptides (NPs) and β-AR agonists are similarly potent at stimulating lipolysis in human adipocytes, we investigated whether NPs could induce human and mouse adipocytes to acquire brown adipocyte features, including a capacity for thermogenic energy expenditure mediated by uncoupling protein 1 (UCP1). In human adipocytes, atrial NP (ANP) and ventricular NP (BNP) activated PPARγ coactivator-1α (PGC-1α) and UCP1 expression, induce... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5664027 Mon, 06 Feb 2012 18:32:05 +0100 5664027 http://www.medworm.com/index.php?rid=5664026&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F59110 In the Guillain-Barré syndrome subform acute motor axonal neuropathy (AMAN), Campylobacter jejuni enteritis triggers the production of anti-ganglioside Abs (AGAbs), leading to immune-mediated injury of distal motor nerves. An important question has been whether injury to the presynaptic neuron at the neuromuscular junction is a major factor in AMAN. Although disease modeling in mice exposed to AGAbs indicates that complement-mediated necrosis occurs extensively in the presynaptic axons, evidence in humans is more limited, in comparison to the extensive injury seen at nodes of Ranvier. We considered that rapid AGAb uptake at the motor nerve terminal membrane might attenuate complement-mediated injury. We found that PC12 rat neuronal cells rapidly internalized AGAb, which were traffi... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5664026 Mon, 06 Feb 2012 18:32:05 +0100 5664026 http://www.medworm.com/index.php?rid=5664025&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F59087 Gastric gland mucin secreted from the lower portion of the gastric mucosa contains unique O-linked oligosaccharides (O-glycans) having terminal α1,4-linked N-acetylglucosamine residues (αGlcNAc). Previously, we identified human α1,4-N-acetylglucosaminyltransferase (α4GnT), which is responsible for the O-glycan biosynthesis and characterized αGlcNAc function in suppressing Helicobacter pylori in vitro. In the present study, we engineered A4gnt–/– mice to better understand its role in vivo. A4gnt–/– mice showed complete lack of αGlcNAc expression in gastric gland mucin. Surprisingly, all the mutant mice developed gastric adenocarcinoma through a hyperplasia-dysplasia-carcinoma sequence in the absence of H. pylori... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5664025 Mon, 06 Feb 2012 18:32:05 +0100 5664025 http://www.medworm.com/index.php?rid=5656195&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F60376 p27Kip1 (p27) acts as a tumor suppressor by inhibiting cyclin–cyclin-dependent kinase (cyclin-CDK) activity. However, mice expressing a form of p27 that is unable to bind or inhibit cyclin-CDK complexes (p27CK–) have increased incidence of tumor development as compared with wild-type and p27–/– mice, revealing an oncogenic role for p27. Here, we identified a phenotype of multinucleation and polyploidy in p27CK– mice not present in p27–/– animals, suggesting a role for p27 in G2/M that is independent of cyclin-CDK regulation. Further analysis revealed that p27CK– expression caused a cytokinesis and abscission defect in mouse embryonic fibroblasts. We identified the Rho effector citron kinase (citron-K) as a p27-interacting prot... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5656195 Fri, 03 Feb 2012 18:50:49 +0100 5656195 http://www.medworm.com/index.php?rid=5656194&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F60015 Myxoid round cell liposarcoma (MRCLS) is a common liposarcoma subtype characterized by a translocation that results in the fusion protein TLS:CHOP as well as by mixed adipocytic histopathology. Both the etiology of MRCLS and the mechanism of action of TLS:CHOP remain poorly understood. It was previously shown that ET-743, an antitumor compound with an unclear mechanism of action, is highly effective in patients with MRCLS. To identify the cellular origin of MRCLS, we engineered a mouse model in which TLS:CHOP was expressed under the control of a mesodermally restricted promoter (Prx1) in a p53-depleted background. This model resembled MRCLS histologically as well as functionally in terms of its specific adipocytic differentiation–based response to ET-743. Specifically, endogenous m... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5656194 Fri, 03 Feb 2012 18:50:49 +0100 5656194 http://www.medworm.com/index.php?rid=5656193&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F58530 Infections by viruses are associated with approximately 12% of human cancer. Kaposi’s sarcoma-associated herpesvirus (KSHV) is causally linked to several malignancies commonly found in AIDS patients. The mechanism of KSHV-induced oncogenesis remains elusive, due in part to the lack of an adequate experimental system for cellular transformation of primary cells. Here, we report efficient infection and cellular transformation of primary rat embryonic metanephric mesenchymal precursor cells (MM cells) by KSHV. Cellular transformation occurred at as early as day 4 after infection and in nearly all infected cells. Transformed cells expressed hallmark vascular endothelial, lymphatic endothelial, and mesenchymal markers and efficiently induced tumors in nude mice. KSHV established latent ... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5656193 Fri, 03 Feb 2012 18:50:49 +0100 5656193 http://www.medworm.com/index.php?rid=5656192&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F58215 In this study, we demonstrated that the extracellular sulfatase, SULF2, an enzyme that regulates multiple HSPG-dependent RTK signaling pathways, was expressed in primary human GBM tumors and cell lines. Knockdown of SULF2 in human GBM cell lines and generation of gliomas from Sulf2–/– tumorigenic neurospheres resulted in decreased growth in vivo in mice. We found a striking SULF2 dependence in activity of PDGFRα, a major signaling pathway in GBM. Ablation of SULF2 resulted in decreased PDGFRα phosphorylation and decreased downstream MAPK signaling activity. Interestingly, in a survey of SULF2 levels in different subtypes of GBM, the proneural subtype, characterized by aberrations in PDGFRα, demonstrated the strongest SULF2 expression. Therefore, in a... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5656192 Fri, 03 Feb 2012 18:50:49 +0100 5656192 http://www.medworm.com/index.php?rid=5656191&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F45817 Appropriate localization and migration of T cells is a prerequisite for antitumor immune surveillance. Studies using fixed tumor samples from human patients have shown that T cells accumulate more efficiently in the stroma than in tumor islets, but the mechanisms by which this occurs are unknown. By combining immunostaining and real-time imaging in viable slices of human lung tumors, we revealed that the density and the orientation of the stromal extracellular matrix likely play key roles in controlling the migration of T cells. Active T cell motility, dependent on chemokines but not on β1 or β2 integrins, was observed in loose fibronectin and collagen regions, whereas T cells migrated poorly in dense matrix areas. Aligned fibers in perivascular regions and around tumor epi... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5656191 Fri, 03 Feb 2012 18:50:49 +0100 5656191 http://www.medworm.com/index.php?rid=5624493&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F62204 This study highlights the relevance of miR-29b in aortic disease but also raises questions about its specific role. (Source: Journal of Clinical Investigation) Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5624493 Tue, 24 Jan 2012 19:12:02 +0100 5624493 http://www.medworm.com/index.php?rid=5624492&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F62002 The evolutionary struggles from which mutants arise have been documented in almost every living system. In this issue of the JCI, Varela and colleagues extend this list of systems to include neural derivatives of human embryonic stem cells, which they show exhibit a repeated gain of material from chromosome 1q. Although this raises safety issues for therapeutic use of such cells, the frequent observation of a particular change may direct screening strategies for detection and removal of these unwanted cellular variants. (Source: Journal of Clinical Investigation) Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5624492 Tue, 24 Jan 2012 19:12:02 +0100 5624492 http://www.medworm.com/index.php?rid=5624491&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F61598 MicroRNAs (miRs) regulate gene expression at the posttranscriptional level and play crucial roles in vascular integrity. As such, they may have a role in modifying abdominal aortic aneurysm (AAA) expansion, the pathophysiological mechanisms of which remain incompletely explored. Here, we investigate the role of miRs in 2 murine models of experimental AAA: the porcine pancreatic elastase (PPE) infusion model in C57BL/6 mice and the AngII infusion model in Apoe–/– mice. AAA development was accompanied by decreased aortic expression of miR-29b, along with increased expression of known miR-29b targets, Col1a1, Col3a1, Col5a1, and Eln, in both models. In vivo administration of locked nucleic acid anti–miR-29b greatly increased collagen expression, leading to an early fib... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5624491 Tue, 24 Jan 2012 19:12:02 +0100 5624491 http://www.medworm.com/index.php?rid=5624490&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F60957 Several adenosine receptor subtypes on endothelial, epithelial, mesangial, and inflammatory cells have been implicated in ischemic acute kidney injury, a life-threatening condition that frequently complicates the care of hospitalized patients. In this issue of the JCI, Grenz and coworkers provide novel insight into how preservation of postischemic renal perfusion by endothelial cell adenosine A2B receptors is antagonized by adenosine reuptake into proximal tubule cells by equilibrative nucleotide transporter 1, which can be inhibited by dipyridamole. The work suggests that adenosine A2B receptor agonists and inhibition of equilibrative nucleoside transporters by dipyridamole may have therapeutic potential in ischemic acute kidney injury, a condition for which there are currently no specifi... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5624490 Tue, 24 Jan 2012 19:12:02 +0100 5624490 http://www.medworm.com/index.php?rid=5624489&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F60941 That adult humans possess brown fat is now accepted — but is the brown fat metabolically active? Does human brown fat actually combust fat to release heat? In this issue of the JCI, Ouellet et al. demonstrate that metabolism in brown fat really is increased when adult humans are exposed to cold. This boosts the possibility that calorie combustion in brown fat may be of significance for our metabolism and, correspondingly, that the absence of brown fat may increase our proneness to obesity — provided that brown fat becomes activated not only by cold but also through food-related stimuli. (Source: Journal of Clinical Investigation) Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5624489 Tue, 24 Jan 2012 19:12:02 +0100 5624489 http://www.medworm.com/index.php?rid=5624488&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F60433 Brown adipose tissue (BAT) is vital for proper thermogenesis during cold exposure in rodents, but until recently its presence in adult humans and its contribution to human metabolism were thought to be minimal or insignificant. Recent studies using PET with 18F-fluorodeoxyglucose (18FDG) have shown the presence of BAT in adult humans. However, whether BAT contributes to cold-induced nonshivering thermogenesis in humans has not been proven. Using PET with 11C-acetate, 18FDG, and 18F-fluoro-thiaheptadecanoic acid (18FTHA), a fatty acid tracer, we have quantified BAT oxidative metabolism and glucose and nonesterified fatty acid (NEFA) turnover in 6 healthy men under controlled cold exposure conditions. All subjects displayed substantial NEFA and glucose uptake upon cold exposure. Furthermore,... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5624488 Tue, 24 Jan 2012 19:12:02 +0100 5624488 http://www.medworm.com/index.php?rid=5624487&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F60214 A complex biologic network regulates kidney perfusion under physiologic conditions. This system is profoundly perturbed following renal ischemia, a leading cause of acute kidney injury (AKI) — a life-threatening condition that frequently complicates the care of hospitalized patients. Therapeutic approaches to prevent and treat AKI are extremely limited. Better understanding of the molecular pathways promoting postischemic reflow could provide new candidate targets for AKI therapeutics. Due to its role in adapting tissues to hypoxia, we hypothesized that extracellular adenosine has a regulatory function in the postischemic control of renal perfusion. Consistent with the notion that equilibrative nucleoside transporters (ENTs) terminate adenosine signaling, we observed that pharmacol... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5624487 Tue, 24 Jan 2012 19:12:02 +0100 5624487 http://www.medworm.com/index.php?rid=5624486&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F46268 Human pluripotent stem cells offer a limitless source of cells for regenerative medicine. Neural derivatives of human embryonic stem cells (hESCs) are currently being used for cell therapy in 3 clinical trials. However, hESCs are prone to genomic instability, which could limit their clinical utility. Here, we report that neural differentiation of hESCs systematically produced a neural stem cell population that could be propagated for more than 50 passages without entering senescence; this was true for all 6 hESC lines tested. The apparent spontaneous loss of evolution toward normal senescence of somatic cells was associated with a jumping translocation of chromosome 1q. This chromosomal defect has previously been associated with hematologic malignancies and pediatric brain tumors with poor... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5624486 Tue, 24 Jan 2012 19:12:02 +0100 5624486 http://www.medworm.com/index.php?rid=5603690&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F61345 Imiquimod is a TLR agonist that is used as an antitumor agent, mainly against skin tumors. Its clinical benefits are well described in several studies; however, the mechanisms behind its antitumor effects are not completely understood. In this issue of the JCI, Drobits and colleagues demonstrate that topical application of imiquimod suppresses cutaneous melanoma by TLR7-dependent recruitment and transformation of plasmacytoid dendritic cells into killer cells; this occurs independently of conventional adaptive immune mechanisms. (Source: Journal of Clinical Investigation) Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5603690 Wed, 18 Jan 2012 19:38:56 +0100 5603690 http://www.medworm.com/index.php?rid=5603689&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F61034 Imiquimod is a synthetic compound with antitumor properties; a 5% cream formulation is successfully used to treat skin tumors. The antitumor effect of imiquimod is multifactorial, although its ability to modulate immune responses by triggering TLR7/8 is thought to be key. Among the immune cells suggested to be involved are plasmacytoid DCs (pDCs). However, a direct contribution of pDCs to tumor killing in vivo and the mechanism of their recruitment to imiquimod-treated sites have never been demonstrated. Using a mouse model of melanoma, we have now demonstrated that pDCs can directly clear tumors without the need for the adaptive immune system. Topical imiquimod treatment led to TLR7-dependent and IFN-α/β receptor 1–dependent (IFNAR1-dependent) upregulation of expre... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5603689 Wed, 18 Jan 2012 19:38:56 +0100 5603689 http://www.medworm.com/index.php?rid=5603688&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F60070 The morphology of healthy podocyte foot processes is necessary for maintaining the characteristics of the kidney filtration barrier. In most forms of glomerular disease, abnormal filter barrier function results when podocytes undergo foot process spreading and retraction by remodeling their cytoskeletal architecture and intercellular junctions during a process known as effacement. The cell adhesion protein nephrin is necessary for establishing the morphology of the kidney podocyte in development by transducing from the specialized podocyte intercellular junction phosphorylation-mediated signals that regulate cytoskeletal dynamics. The present studies extend our understanding of nephrin function by showing that nephrin activation in cultured podocytes induced actin dynamics necessary for la... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5603688 Wed, 18 Jan 2012 19:38:56 +0100 5603688 http://www.medworm.com/index.php?rid=5603687&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F58847 HBV infection remains a leading cause of death worldwide. IFN-α inhibits viral replication in vitro and in vivo, and pegylated IFN-α is a commonly administered treatment for individuals infected with HBV. The HBV genome contains a typical IFN-stimulated response element (ISRE), but the molecular mechanisms by which IFN-α suppresses HBV replication have not been established in relevant experimental systems. Here, we show that IFN-α inhibits HBV replication by decreasing the transcription of pregenomic RNA (pgRNA) and subgenomic RNA from the HBV covalently closed circular DNA (cccDNA) minichromosome, both in cultured cells in which HBV is replicating and in mice whose livers have been repopulated with human hepatocytes and infected with HBV. Administration of ... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5603687 Wed, 18 Jan 2012 19:38:56 +0100 5603687 http://www.medworm.com/index.php?rid=5603686&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F43937 Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Its pathogenesis is frequently linked to liver inflammation. Gain-of-function mutations in the gene encoding β-catenin are frequent genetic modifications found in human HCCs. Thus, we investigated whether inflammation was a component of β-catenin–induced tumorigenesis using genetically modified mouse models that recapitulated the stages of initiation and progression of this tumoral process. Oncogenic β-catenin signaling was found to induce an inflammatory program in hepatocytes that involved direct transcriptional control by β-catenin and activation of the NF-κB pathway. This led to a specific inflammatory response, the intensity of which determined t... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5603686 Wed, 18 Jan 2012 19:38:56 +0100 5603686 http://www.medworm.com/index.php?rid=5576527&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F60560 Hereditary spastic paraplegias (HSPs) are a group of genetically heterogeneous neurodegenerative conditions. They are characterized by progressive spastic paralysis of the legs as a result of selective, length-dependent degeneration of the axons of the corticospinal tract. Mutations in 3 genes encoding proteins that work together to shape the ER into sheets and tubules — receptor accessory protein 1 (REEP1), atlastin-1 (ATL1), and spastin (SPAST) — have been found to underlie many cases of HSP in Northern Europe and North America. Applying Sanger and exome sequencing, we have now identified 3 mutations in reticulon 2 (RTN2), which encodes a member of the reticulon family of prototypic ER-shaping proteins, in families with spastic paraplegia 12 (SPG12). These autosomal domin... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5576527 Mon, 09 Jan 2012 22:32:58 +0100 5576527 http://www.medworm.com/index.php?rid=5576526&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F59526 Bilirubin, a breakdown product of heme, is normally glucuronidated and excreted by the liver into bile. Failure of this system can lead to a buildup of conjugated bilirubin in the blood, resulting in jaundice. The mechanistic basis of bilirubin excretion and hyperbilirubinemia syndromes is largely understood, but that of Rotor syndrome, an autosomal recessive disorder characterized by conjugated hyperbilirubinemia, coproporphyrinuria, and near-absent hepatic uptake of anionic diagnostics, has remained enigmatic. Here, we analyzed 8 Rotor-syndrome families and found that Rotor syndrome was linked to mutations predicted to cause complete and simultaneous deficiencies of the organic anion transporting polypeptides OATP1B1 and OATP1B3. These important detoxification-limiting proteins mediate u... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5576526 Mon, 09 Jan 2012 22:32:58 +0100 5576526 http://www.medworm.com/index.php?rid=5576525&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F59227 Pancreatic cancer is almost invariably associated with mutations in the KRAS gene, most commonly KRASG12D, that result in a dominant-active form of the KRAS GTPase. However, how KRAS mutations promote pancreatic carcinogenesis is not fully understood, and whether oncogenic KRAS is required for the maintenance of pancreatic cancer has not been established. To address these questions, we generated two mouse models of pancreatic tumorigenesis: mice transgenic for inducible KrasG12D, which allows for inducible, pancreas-specific, and reversible expression of the oncogenic KrasG12D, with or without inactivation of one allele of the tumor suppressor gene p53. Here, we report that, early in tumorigenesis, induction of oncogenic KrasG12D reversibly altered normal epithelial differentiation followi... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5576525 Mon, 09 Jan 2012 22:32:58 +0100 5576525 http://www.medworm.com/index.php?rid=5576524&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F58815 Allergic asthma is the most common form of asthma, affecting more than 10 million Americans. Although it is clear that mast cells have a key role in the pathogenesis of allergic asthma, the mechanisms by which they regulate airway narrowing in vivo remain to be elucidated. Here we report that mice lacking αvβ6 integrin are protected from exaggerated airway narrowing in a model of allergic asthma. Expression microarrays of the airway epithelium revealed mast cell proteases among the most prominent differentially expressed genes, with expression of mouse mast cell protease 1 (mMCP-1) induced by allergen challenge in WT mice and expression of mMCP-4, -5, and -6 increased at baseline in β6-deficient mice. These findings were most likely explained by loss of TGF-&#x003b2... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5576524 Mon, 09 Jan 2012 22:32:58 +0100 5576524 http://www.medworm.com/index.php?rid=5576523&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F57313 Hemolytic uremic syndrome (HUS) is a potentially life-threatening condition. It often occurs after gastrointestinal infection with E. coli O157:H7, which produces Shiga toxins (Stx) that cause hemolytic anemia, thrombocytopenia, and renal injury. Stx-mediated changes in endothelial phenotype have been linked to the pathogenesis of HUS. Here we report our studies investigating Stx-induced changes in gene expression and their contribution to the pathogenesis of HUS. Stx function by inactivating host ribosomes but can also alter gene expression at concentrations that minimally affect global protein synthesis. Gene expression profiling of human microvascular endothelium treated with Stx implicated a role for activation of CXCR4 and CXCR7 by their shared cognate chemokine ligand (stromal cell&#... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5576523 Mon, 09 Jan 2012 22:32:58 +0100 5576523 http://www.medworm.com/index.php?rid=5576522&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F46116 RASA1 (also known as p120 RasGAP) is a Ras GTPase–activating protein that functions as a regulator of blood vessel growth in adult mice and humans. In humans, RASA1 mutations cause capillary malformation–arteriovenous malformation (CM-AVM); whether it also functions as a regulator of the lymphatic vasculature is unknown. We investigated this issue using mice in which Rasa1 could be inducibly deleted by administration of tamoxifen. Systemic loss of RASA1 resulted in a lymphatic vessel disorder characterized by extensive lymphatic vessel hyperplasia and leakage and early lethality caused by chylothorax (lymphatic fluid accumulation in the pleural cavity). Lymphatic vessel hyperplasia was a consequence of increased proliferation of lymphatic endothelial cells (LECs) and was al... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5576522 Mon, 09 Jan 2012 22:32:58 +0100 5576522 http://www.medworm.com/index.php?rid=5576521&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F45977 Chronic myelogenous leukemia (CML) results from a chromosomal translocation in hematopoietic stem or early progenitor cells that gives rise to the oncogenic BCR/ABL fusion protein. Clinically, CML has a chronic phase that eventually evolves into an accelerated stage and blast crisis. A CML-specific immune response is thought to contribute to the control of disease. Whether the immune system can also promote disease progression is not known. In the present study, we investigated the possibility that the TNF receptor family member CD27 is present on leukemia stem cells (LSCs) and mediates effects of the immune system on CML. In a mouse model of CML, BCR/ABL+ LSCs and leukemia progenitor cells were found to express CD27. Binding of CD27 by its ligand, CD70, increased expression of Wnt target ... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5576521 Mon, 09 Jan 2012 22:32:58 +0100 5576521 http://www.medworm.com/index.php?rid=5568568&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F61857 Thrombotic complications represent a highly significant component of morbidity and mortality associated with hypercholesterolemia and atherosclerosis. In this issue of the JCI, Owens et al. report possible mechanisms underlying the prothrombotic, proinflammatory state accompanying hypercholesterolemia. Using rodent, monkey, and human subjects, they show that circulating oxidized LDL and circulating monocyte-derived tissue factor are important instigating factors driving the thrombotic, inflammatory phenotype and, surprisingly, that statin therapy ameliorated the phenotype even in the absence of lowering cholesterol levels. The studies raise the intriguing possibility that therapies directed at pathways generating oxidant stress or pathways involved in transmitting oxidized LDL–medi... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5568568 Sat, 07 Jan 2012 01:06:50 +0100 5568568 http://www.medworm.com/index.php?rid=5568567&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F60556 Herpes simplex virus type 1 (HSV-1) not only causes painful recurrent oral-labial infections, it can also cause permanent brain damage and blindness. There is currently no HSV-1 vaccine. An effective vaccine must stimulate coordinated T cell responses, but the large size of the genome and the low frequency of HSV-1–specific T cells have hampered the search for the most effective T cell antigens for inclusion in a candidate vaccine. We have now developed what we believe to be novel methods to efficiently generate a genome-wide map of the responsiveness of HSV-1–specific T cells, and demonstrate the applicability of these methods to a second complex microbe, vaccinia virus. We used cross-presentation and CD137 activation–based FACS to enrich for polyclonal CD8+ T effe... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5568567 Sat, 07 Jan 2012 01:06:50 +0100 5568567 http://www.medworm.com/index.php?rid=5568566&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F59309 Mutations in the gene encoding the p110α subunit of PI3K (PIK3CA) that result in enhanced PI3K activity are frequently observed in human cancers. To better understand the role of mutant PIK3CA in the initiation or progression of tumorigenesis, we generated mice in which a PIK3CA mutation commonly detected in human cancers (the H1047R mutation) could be conditionally knocked into the endogenous Pik3ca locus. Activation of this mutation in the mouse ovary revealed that alone, Pik3caH1047R induced premalignant hyperplasia of the ovarian surface epithelium but no tumors. Concomitantly, we analyzed several human ovarian cancers and found PIK3CA mutations coexistent with KRAS and/or PTEN mutations, raising the possibility that a secondary defect in a co-regulator of PI3K activity may be ... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5568566 Sat, 07 Jan 2012 01:06:50 +0100 5568566 http://www.medworm.com/index.php?rid=5568565&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F58969 Hypercholesterolemia is a major risk factor for atherosclerosis. It also is associated with platelet hyperactivity, which increases morbidity and mortality from cardiovascular disease. However, the mechanisms by which hypercholesterolemia produces a procoagulant state remain undefined. Atherosclerosis is associated with accumulation of oxidized lipoproteins within atherosclerotic lesions. Small quantities of oxidized lipoproteins are also present in the circulation of patients with coronary artery disease. We therefore hypothesized that hypercholesterolemia leads to elevated levels of oxidized LDL (oxLDL) in plasma and that this induces expression of the procoagulant protein tissue factor (TF) in monocytes. In support of this hypothesis, we report here that oxLDL induced TF expression in h... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5568565 Sat, 07 Jan 2012 01:06:50 +0100 5568565 http://www.medworm.com/index.php?rid=5568564&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F58780 Increased expression of the regulatory subunit of HIFs (HIF-1α or HIF-2α) is associated with metabolic adaptation, angiogenesis, and tumor progression. Understanding how HIFs are regulated is of intense interest. Intriguingly, the molecular mechanisms that link mitochondrial function with the HIF-regulated response to hypoxia remain to be unraveled. Here we describe what we believe to be novel functions of the human gene CHCHD4 in this context. We found that CHCHD4 encodes 2 alternatively spliced, differentially expressed isoforms (CHCHD4.1 and CHCHD4.2). CHCHD4.1 is identical to MIA40, the homolog of yeast Mia40, a key component of the mitochondrial disulfide relay system that regulates electron transfer to cytochrome c. Further analysis revealed that CHCHD4 proteins conta... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5568564 Sat, 07 Jan 2012 01:06:50 +0100 5568564 http://www.medworm.com/index.php?rid=5568563&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F58620 The CBX7 gene encodes a polycomb group protein that is known to be downregulated in many types of human cancers, although the role of this protein in carcinogenesis remains unclear. To shed light on this issue, we generated mice null for Cbx7. Mouse embryonic fibroblasts derived from these mice had a higher growth rate and reduced susceptibility to senescence compared with their WT counterparts. This was associated with upregulated expression of multiple cell cycle components, including cyclin E, which is known to play a key role in lung carcinogenesis in humans. Adult Cbx7-KO mice developed liver and lung adenomas and carcinomas. In in vivo and in vitro experiments, we demonstrated that CBX7 bound to the CCNE1 promoter in a complex that included HDAC2 and negatively regulated CCNE1 expres... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5568563 Sat, 07 Jan 2012 01:06:50 +0100 5568563 http://www.medworm.com/index.php?rid=5568562&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F58618 Zinc deficiency can be an inherited disorder, in which case it is known as acrodermatitis enteropathica (AE), or an acquired disorder caused by low dietary intake of zinc. Even though zinc deficiency diminishes cellular and humoral immunity, patients develop immunostimulating skin inflammation. Here, we have demonstrated that despite diminished allergic contact dermatitis in mice fed a zinc-deficient (ZD) diet, irritant contact dermatitis (ICD) in these mice was more severe and prolonged than that in controls. Further, histological examination of ICD lesions in ZD mice revealed subcorneal vacuolization and epidermal pallor, histological features of AE. Consistent with the fact that ATP release from chemically injured keratinocytes serves as a causative mediator of ICD, we found that the se... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5568562 Sat, 07 Jan 2012 01:06:50 +0100 5568562 http://www.medworm.com/index.php?rid=5568561&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F58470 Paroxysmal nonkinesigenic dyskinesia (PNKD) is an autosomal dominant episodic movement disorder. Patients have episodes that last 1 to 4 hours and are precipitated by alcohol, coffee, and stress. Previous research has shown that mutations in an uncharacterized gene on chromosome 2q33–q35 (which is termed PNKD) are responsible for PNKD. Here, we report the generation of antibodies specific for the PNKD protein and show that it is widely expressed in the mouse brain, exclusively in neurons. One PNKD isoform is a membrane-associated protein. Transgenic mice carrying mutations in the mouse Pnkd locus equivalent to those found in patients with PNKD recapitulated the human PNKD phenotype. Staining for c-fos demonstrated that administration of alcohol or caffeine induced neuronal activity... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5568561 Sat, 07 Jan 2012 01:06:50 +0100 5568561 http://www.medworm.com/index.php?rid=5568560&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F43027 BM-derived endothelial progenitor cells (EPCs) are critical and essential for neovascularization in tissue repair and tumorigenesis. EPCs migrate from BM to tissues via the bloodstream, but specific chemotactic cues have not been identified. Here we show in mice that the absence of CCR5 reduced vascular EPC accumulation and neovascularization, but not macrophage recruitment, and eventually delayed healing in wounded skin. When transferred into Ccr5–/– mice, Ccr5+/+ BM cells, but not Ccr5–/– cells, accumulated in the wound site, were incorporated into the vasculature, and restored normal neovascularization. Consistent with these observations, CCL5 induced in vitro EPC migration in a CCR5-dependent manner. Moreover, expression of VEGF and TGF-β was sub... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5568560 Sat, 07 Jan 2012 01:06:50 +0100 5568560 http://www.medworm.com/index.php?rid=5549516&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F61858 Glomerulosclerosis is a general term for scarring of the kidney glomerulus. It cannot be reversed. As glomerulosclerosis accumulates, the diseased kidney progresses to end-stage renal disease. Treatment with inhibitors of the renin-angiotensin system often decreases the rate of progression of glomerulosclerosis in chronic kidney diseases. Although the mechanisms by which these inhibitors mediate their beneficial effects are incompletely understood, it has been suggested that they act, at least in part, by reducing intraglomerular blood pressure and thereby shear stress–induced loss of podocytes, a key component of the glomerular filtration barrier. In this issue of the JCI, Sachs and colleagues provide experimental confirmation of the critical role of tight adhesion of podocytes to... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5549516 Thu, 29 Dec 2011 11:17:32 +0100 5549516 http://www.medworm.com/index.php?rid=5549515&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F61677 Chronic inflammation has long been appreciated to play a critical role in tumor development and maintenance. Among the mechanisms involved in coordinating the initiation and resolution of inflammation are those responsible for modifying mRNA stability and/or translation. Several studies have linked the RNA-binding protein HuR, which increases mRNA stability, with malignant transformation. However, in this issue of the JCI, Yiakouvaki et al. compellingly demonstrate in mice that increased HuR activity in myeloid cells has a protective role in the onset of pathologic intestinal inflammation (i.e., colitis) and colitis-associated cancer (CAC). These observations highlight the need to understand the roles of HuR in distinct cell populations in vivo and suggest that enhancing HuR activity may b... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5549515 Thu, 29 Dec 2011 11:17:32 +0100 5549515 http://www.medworm.com/index.php?rid=5549514&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F61562 The number of people who suffer from obesity and one or more of its adverse complications is rapidly increasing. It is becoming clear that diet, exercise, and other lifestyle modifications are insufficient strategies to combat this growing problem. Greater understanding of the mechanisms controlling our desire to feed and our ability to balance energy intake with energy expenditure are key to the development of pharmacological approaches for treating obesity. Although great strides have been made in our understanding of how the hypothalamus regulates feeding and energy balance, much less is known about how obesity affects the structure of the hypothalamus. The authors of two papers in this issue of the JCI have addressed this issue by examining the effects of obesity on neurons and glia in... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5549514 Thu, 29 Dec 2011 11:17:32 +0100 5549514 http://www.medworm.com/index.php?rid=5549513&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F61467 Cardiac ischemia-reperfusion (I-R) injury occurs upon prompt restoration of blood flow to the ischemic myocardium after an acute myocardial infarction. Interestingly, many of the features of I-R injury are related to impaired mitochondrial signaling and mitochondrial dysfunction. Restoring cardiac energy bioavailability and reduction-oxidation (redox) signaling are therefore important in recovery after I-R injury. In this issue of the JCI, Yoshioka and colleagues describe an important and unexpected role for thioredoxin-interacting protein (TXNIP) in the control of mitochondrial respiration and cell energy metabolism. Their findings could open the door for development of TXNIP-targeted therapeutic approaches for the treatment of cardiac I-R injury. (Source: Journal of Clinical Investigatio... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5549513 Thu, 29 Dec 2011 11:17:32 +0100 5549513 http://www.medworm.com/index.php?rid=5549512&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F61163 Inflammation is a critical component of atherosclerosis. IL-1 is a classic proinflammatory cytokine that has been linked to atherosclerosis. A clinical trial has been launched in which an antibody specific for IL-1β is being studied for its effects on cardiovascular events in patients with atherosclerosis. In this issue of the JCI, Alexander et al. report that mice lacking the receptor for IL-1 unexpectedly have features of advanced atherosclerosis that suggest the atherosclerotic plaques may be less stable. These findings illustrate the complexity of inflammatory pathways in atherosclerosis and suggest the need for careful calibration of antiinflammatory approaches to atherosclerosis. (Source: Journal of Clinical Investigation) Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5549512 Thu, 29 Dec 2011 11:17:32 +0100 5549512 http://www.medworm.com/index.php?rid=5549511&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F60988 Human adenoviral vectors are being developed for use in candidate vaccines for HIV-1 and other pathogens. However, this approach suffered a setback when an HIV-1 vaccine using an adenovirus type 5 (Ad5) vector failed to reduce, and might even have increased, the rate of HIV infection in men who were uncircumcised and who had preexisting antibodies specific for Ad5. This increased interest in the evaluation of serologically distinct adenoviral vectors. In this issue of the JCI, Frahm and coworkers report evidence that preexisting cellular immune responses directed toward Ad5 reduce the immunogenicity of antigens expressed in Ad5-vectored vaccines and have cross-reacting potential with non-Ad5 adenoviral vectors. The implications of this observation need to be carefully evaluated in future c... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5549511 Thu, 29 Dec 2011 11:17:32 +0100 5549511 http://www.medworm.com/index.php?rid=5549510&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F60202 Recombinant viruses hold promise as vectors for vaccines to prevent infectious diseases with significant global health impacts. One of their major limitations is that preexisting anti-vector neutralizing antibodies can reduce T cell responses to the insert antigens; however, the impact of vector-specific cellular immunity on subsequent insert-specific T cell responses has not been assessed in humans. Here, we have identified and compared adenovirus-specific and HIV-specific T cell responses in subjects participating in two HIV-1 vaccine trials using a vaccine vectored by adenovirus serotype 5 (Ad5). Higher frequencies of pre-immunization adenovirus-specific CD4+ T cells were associated with substantially decreased magnitude of HIV-specific CD4+ T cell responses and decreased breadth of HIV... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5549510 Thu, 29 Dec 2011 11:17:32 +0100 5549510 http://www.medworm.com/index.php?rid=5549509&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F59660 Rodent models of obesity induced by consuming high-fat diet (HFD) are characterized by inflammation both in peripheral tissues and in hypothalamic areas critical for energy homeostasis. Here we report that unlike inflammation in peripheral tissues, which develops as a consequence of obesity, hypothalamic inflammatory signaling was evident in both rats and mice within 1 to 3 days of HFD onset, prior to substantial weight gain. Furthermore, both reactive gliosis and markers suggestive of neuron injury were evident in the hypothalamic arcuate nucleus of rats and mice within the first week of HFD feeding. Although these responses temporarily subsided, suggesting that neuroprotective mechanisms may initially limit the damage, with continued HFD feeding, inflammation and gliosis returned permane... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5549509 Thu, 29 Dec 2011 11:17:32 +0100 5549509 http://www.medworm.com/index.php?rid=5549508&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F58878 Podocytes of the kidney adhere tightly to the underlying glomerular basement membrane (GBM) in order to maintain a functional filtration barrier. The clinical importance of podocyte binding to the GBM via an integrin-laminin-actin axis has been illustrated in models with altered function of α3β1 integrin, integrin-linked kinase, laminin-521, and α-actinin 4. Here we expanded on the podocyte-GBM binding model by showing that the main podocyte adhesion receptor, integrin α3β1, interacts with the tetraspanin CD151 in situ in humans. Deletion of Cd151 in mouse glomerular epithelial cells led to reduced adhesive strength to laminin by redistributing α3β1 at the cell-matrix interface. Moreover, in vivo podocyte-specific deletion of Cd151 le... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5549508 Thu, 29 Dec 2011 11:17:32 +0100 5549508 http://www.medworm.com/index.php?rid=5549507&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F57426 ATP is required for normal cardiac contractile function, and it has long been hypothesized that reduced energy delivery contributes to the contractile dysfunction of heart failure (HF). Despite experimental and clinical HF data showing reduced metabolism through cardiac creatine kinase (CK), the major myocardial energy reserve and temporal ATP buffer, a causal relationship between reduced ATP-CK metabolism and contractile dysfunction in HF has never been demonstrated. Here, we generated mice conditionally overexpressing the myofibrillar isoform of CK (CK-M) to test the hypothesis that augmenting impaired CK-related energy metabolism improves contractile function in HF. CK-M overexpression significantly increased ATP flux through CK ex vivo and in vivo but did not alter contractile function... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5549507 Thu, 29 Dec 2011 11:17:32 +0100 5549507 http://www.medworm.com/index.php?rid=5549506&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F45021 The innate immune response involves a variety of inflammatory reactions that can result in inflammatory disease and cancer if they are not resolved and instead are allowed to persist. The effective activation and resolution of innate immune responses relies on the production and posttranscriptional regulation of mRNAs encoding inflammatory effector proteins. The RNA-binding protein HuR binds to and regulates such mRNAs, but its exact role in inflammation remains unclear. Here we show that HuR maintains inflammatory homeostasis by controlling macrophage plasticity and migration. Mice lacking HuR in myeloid-lineage cells, which include many of the cells of the innate immune system, displayed enhanced sensitivity to endotoxemia, rapid progression of chemical-induced colitis, and severe suscep... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5549506 Thu, 29 Dec 2011 11:17:32 +0100 5549506 http://www.medworm.com/index.php?rid=5549505&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F44927 We examined hearts from Txnip-KO mice by polony multiplex analysis of gene expression and an independent proteomic approach; both methods indicated suppression of genes and proteins participating in mitochondrial metabolism. Consistently, Txnip-KO mitochondria were functionally and structurally altered, showing reduced oxygen consumption and ultrastructural derangements. Given the central role that mitochondria play during hypoxia, we hypothesized that Txnip deletion would enhance ischemia-reperfusion damage. Surprisingly, Txnip-KO hearts had greater recovery of cardiac function after an ischemia-reperfusion insult. Similarly, cardiomyocyte-specific Txnip deletion reduced infarct size after reversible coronary ligation. Coordinated with reduced mitochondrial function, deletion of Txnip enh... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5549505 Thu, 29 Dec 2011 11:17:32 +0100 5549505 http://www.medworm.com/index.php?rid=5549504&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F43713 Clinical complications of atherosclerosis arise primarily as a result of luminal obstruction due to atherosclerotic plaque growth, with inadequate outward vessel remodeling and plaque destabilization leading to rupture. IL-1 is a proinflammatory cytokine that promotes atherogenesis in animal models, but its role in plaque destabilization and outward vessel remodeling is unclear. The studies presented herein show that advanced atherosclerotic plaques in mice lacking both IL-1 receptor type I and apolipoprotein E (Il1r1–/–Apoe–/– mice) unexpectedly exhibited multiple features of plaque instability as compared with those of Il1r1+/+Apoe–/– mice. These features included reduced plaque SMC content and coverage, reduced plaque collagen content, and... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5549504 Thu, 29 Dec 2011 11:17:32 +0100 5549504 http://www.medworm.com/index.php?rid=5549503&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F43134 In the CNS, the hypothalamic arcuate nucleus (ARN) energy-balance circuit plays a key role in regulating body weight. Recent studies have shown that neurogenesis occurs in the adult hypothalamus, revealing that the ARN energy-balance circuit is more plastic than originally believed. Changes in diet result in altered gene expression and neuronal activity in the ARN, some of which may reflect hypothalamic plasticity. To explore this possibility, we examined the turnover of hypothalamic neurons in mice with obesity secondary to either high-fat diet (HFD) consumption or leptin deficiency. We found substantial turnover of neurons in the ARN that resulted in ongoing cellular remodeling. Feeding mice HFD suppressed neurogenesis, as demonstrated by the observation that these mice both generated fe... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5549503 Thu, 29 Dec 2011 11:17:32 +0100 5549503 http://www.medworm.com/index.php?rid=5520194&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F61453 Epoxyeicosatrienoic acids (EETs) generated from arachidonic acid by cytochrome P450 (CYP) epoxygenases have beneficial effects in certain cardiovascular and kidney diseases. Hence, great efforts have been made to develop drugs targeting the EET pathway. Some of these agents are currently under evaluation in clinical trials for treatment of hypertension and diabetes. In this issue of the JCI, Panigrahy et al. evaluate in a systematic way the role of CYP epoxygenases and the metabolites they generate in cancer progression. Their findings, along with previous studies, raise concerns about using these drugs in humans. (Source: Journal of Clinical Investigation) Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5520194 Tue, 20 Dec 2011 06:52:29 +0100 5520194 http://www.medworm.com/index.php?rid=5520193&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F59877 Rhabdomyosarcoma (RMS) is a malignancy of muscle myoblasts, which fail to exit the cell cycle, resist terminal differentiation, and are blocked from fusing into syncytial skeletal muscle. In some patients, RMS is caused by a translocation that generates the fusion oncoprotein PAX-FOXO1, but the underlying RMS pathogenetic mechanisms that impede differentiation and promote neoplastic transformation remain unclear. Using a Drosophila model of PAX-FOXO1–mediated transformation, we show here that mutation in the myoblast fusion gene rolling pebbles (rols) dominantly suppresses PAX-FOXO1 lethality. Further analysis indicated that PAX-FOXO1 expression caused upregulation of rols, which suggests that Rols acts downstream of PAX-FOXO1. In mammalian myoblasts, gene silencing of Tanc1, an or... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5520193 Tue, 20 Dec 2011 06:52:29 +0100 5520193 http://www.medworm.com/index.php?rid=5520192&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F58128 Epoxyeicosatrienoic acids (EETs) are small molecules produced by cytochrome P450 epoxygenases. They are lipid mediators that act as autocrine or paracrine factors to regulate inflammation and vascular tone. As a result, drugs that raise EET levels are in clinical trials for the treatment of hypertension and many other diseases. However, despite their pleiotropic effects on cells, little is known about the role of these epoxyeicosanoids in cancer. Here, using genetic and pharmacological manipulation of endogenous EET levels, we demonstrate that EETs are critical for primary tumor growth and metastasis in a variety of mouse models of cancer. Remarkably, we found that EETs stimulated extensive multiorgan metastasis and escape from tumor dormancy in several tumor models. This systemic metastas... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5520192 Tue, 20 Dec 2011 06:52:29 +0100 5520192 http://www.medworm.com/index.php?rid=5520191&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F46425 Defining the genetic contribution of rare variants to common diseases is a major basic and clinical science challenge that could offer new insights into disease etiology and provide potential for directed gene- and pathway-based prevention and treatment. Common and rare nonsynonymous variants in the GCKR gene are associated with alterations in metabolic traits, most notably serum triglyceride levels. GCKR encodes glucokinase regulatory protein (GKRP), a predominantly nuclear protein that inhibits hepatic glucokinase (GCK) and plays a critical role in glucose homeostasis. The mode of action of rare GCKR variants remains unexplored. We identified 19 nonsynonymous GCKR variants among 800 individuals from the ClinSeq medical sequencing project. Excluding the previously described common missens... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5520191 Tue, 20 Dec 2011 06:52:29 +0100 5520191 http://www.medworm.com/index.php?rid=5520190&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F46215 Chronic obstructive pulmonary disease (COPD) is a prevalent smoking-related disease for which no disease-altering therapies currently exist. As dysregulated TGF-β signaling associates with lung pathology in patients with COPD and in animal models of lung injury induced by chronic exposure to cigarette smoke (CS), we postulated that inhibiting TGF-β signaling would protect against CS-induced lung injury. We first confirmed that TGF-β signaling was induced in the lungs of mice chronically exposed to CS as well as in COPD patient samples. Importantly, key pathological features of smoking-associated lung disease in patients, e.g., alveolar injury with overt emphysema and airway epithelial hyperplasia with fibrosis, accompanied CS-induced alveolar cell apoptosis caused b... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5520190 Tue, 20 Dec 2011 06:52:29 +0100 5520190 http://www.medworm.com/index.php?rid=5520189&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F46177 The autoimmune type 1 diabetes (T1D) that arises spontaneously in NOD mice is considered to be a model of T1D in humans. It is characterized by the invasion of pancreatic islets by mononuclear cells (MNCs), which ultimately leads to destruction of insulin-producing β cells. Although T cell dependent, the molecular mechanisms triggering β cell death have not been fully elucidated. Here, we report that a glycosaminoglycan, heparan sulfate (HS), is expressed at extraordinarily high levels within mouse islets and is essential for β cell survival. In vitro, β cells rapidly lost their HS and died. β Cell death was prevented by HS replacement, a treatment that also rendered the β cells resistant to damage from ROS. In vivo, autoimmune destruction of... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5520189 Tue, 20 Dec 2011 06:52:29 +0100 5520189 http://www.medworm.com/index.php?rid=5520188&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F42497 Glucagon-like peptide-1 (GLP-1) circulates at low levels and acts as an incretin hormone, potentiating glucose-dependent insulin secretion from islet β cells. GLP-1 also modulates gastric emptying and engages neural circuits in the portal region and CNS that contribute to GLP-1 receptor–dependent (GLP-1R–dependent) regulation of glucose homeostasis. To elucidate the importance of pancreatic GLP-1R signaling for glucose homeostasis, we generated transgenic mice that expressed the human GLP-1R in islets and pancreatic ductal cells (Pdx1-hGLP1R:Glp1r–/– mice). Transgene expression restored GLP-1R–dependent stimulation of cAMP and Akt phosphorylation in isolated islets, conferred GLP-1R–dependent stimulation of β cell proliferatio... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5520188 Tue, 20 Dec 2011 06:52:29 +0100 5520188 http://www.medworm.com/index.php?rid=5520187&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F42204 Insulin like growth factor–1 (IGF-1) stimulates increased proliferation and survival of mammary epithelial cells and also promotes mammary tumorigenesis. To study the effects of IGF-1 on the mammary gland in vivo, we used BK5.IGF-1 transgenic (Tg) mice. In these mice, IGF-1 overexpression is controlled by the bovine keratin 5 promoter and recapitulates the paracrine exposure of breast epithelium to stromal IGF-1 that is seen in women. Studies have shown that BK5.IGF-1 Tg mice are more susceptible to mammary tumorigenesis than wild-type littermates. Investigation of the mechanisms underlying increased mammary cancer risk, reported here, revealed that IGF-1 preferentially activated the PI3K/Akt pathway in glands from prepubertal Tg mice, resulting in increased cyclin D1 expression an... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5520187 Tue, 20 Dec 2011 06:52:29 +0100 5520187 http://www.medworm.com/index.php?rid=5500941&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F59411 In this study, we analyzed sequential blood and liver tissue samples collected from liver transplant recipients enrolled in a prospective multicenter immunosuppressive drug withdrawal clinical trial. Before initiation of drug withdrawal, operationally tolerant and non-tolerant recipients differed in the intra-graft expression of genes involved in the regulation of iron homeostasis. Furthermore, as compared with non-tolerant recipients, operationally tolerant patients exhibited higher serum levels of hepcidin and ferritin and increased hepatocyte iron deposition. Finally, liver tissue gene expression measurements accurately predicted the outcome of immunosuppressive withdrawal in an independent set of patients. These results point to a critical role for iron metabolism in the regulation of ... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5500941 Wed, 14 Dec 2011 08:26:02 +0100 5500941 http://www.medworm.com/index.php?rid=5500940&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F59334 Glioblastoma multiforme (GBM) is the most common and lethal of all gliomas. The current standard of care includes surgery followed by concomitant radiation and chemotherapy with the DNA alkylating agent temozolomide (TMZ). O6-methylguanine–DNA methyltransferase (MGMT) repairs the most cytotoxic of lesions generated by TMZ, O6-methylguanine. Methylation of the MGMT promoter in GBM correlates with increased therapeutic sensitivity to alkylating agent therapy. However, several aspects of TMZ sensitivity are not explained by MGMT promoter methylation. Here, we investigated our hypothesis that the base excision repair enzyme alkylpurine–DNA–N-glycosylase (APNG), which repairs the cytotoxic lesions N3-methyladenine and N7-methylguanine, may contribute to TMZ resistance. S... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5500940 Wed, 14 Dec 2011 08:26:02 +0100 5500940 http://www.medworm.com/index.php?rid=5500939&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F59130 Amyotrophic lateral sclerosis (ALS) is characterized by progressive motor neuron degeneration, which ultimately leads to paralysis and death. Mutation of TAR DNA binding protein 43 (TDP-43) has been linked to the development of an inherited form of ALS. Existing TDP-43 transgenic animals develop a limited loss of motor neurons and therefore do not faithfully reproduce the core phenotype of ALS. Here, we report the creation of multiple lines of transgenic rats in which expression of ALS-associated mutant human TDP-43 is restricted to either motor neurons or other types of neurons and skeletal muscle and can be switched on and off. All of these rats developed progressive paralysis reminiscent of ALS when the transgene was switched on. Rats expressing mutant TDP-43 in motor neurons alone lost... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5500939 Wed, 14 Dec 2011 08:26:02 +0100 5500939 http://www.medworm.com/index.php?rid=5500938&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F59011 Depletion of CD4+ T cells from the gut occurs rapidly during acute HIV-1 infection. This has been linked to systemic inflammation and disease progression as a result of translocation of microbial products from the gut lumen into the bloodstream. Combined antiretroviral therapy (cART) substantially restores CD4+ T cell numbers in peripheral blood, but the gut compartment remains largely depleted of such cells for poorly understood reasons. Here, we show that a lack of recruitment of CD4+ T cells to the gut could be involved in the incomplete mucosal immune reconstitution of cART-treated HIV-infected individuals. We investigated the trafficking of CD4+ T cells expressing the gut-homing receptors CCR9 and integrin α4β7 and found that many of these T cells remained in the circu... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5500938 Wed, 14 Dec 2011 08:26:02 +0100 5500938 http://www.medworm.com/index.php?rid=5500937&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F58849 Constitutive activation of NF-κB is a frequent event in human cancers, playing important roles in cancer development and progression. In nontransformed cells, NF-κB activation is tightly controlled by IκBs. IκBs bind NF-κB in the cytoplasm, preventing it from translocating to the nucleus to modulate gene expression. Stimuli that activate NF-κB signaling trigger IκB degradation, enabling nuclear translocation of NF-κB. Among the genes regulated by NF-κB are those encoding the IκBs, providing a negative feedback loop that limits NF-κB activity. How transformed cells override this NF-κB/IκB negative feedback loop remains unclear. Here, we report in human glioma cell lines that microRNA-30e*... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5500937 Wed, 14 Dec 2011 08:26:02 +0100 5500937 http://www.medworm.com/index.php?rid=5500936&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F58753 In hematologic diseases, such as sickle cell disease (SCD) and hemolytic uremic syndrome (HUS), pathological biophysical interactions among blood cells, endothelial cells, and soluble factors lead to microvascular occlusion and thrombosis. Here, we report an in vitro “endothelialized” microfluidic microvasculature model that recapitulates and integrates this ensemble of pathophysiological processes. Under controlled flow conditions, the model enabled quantitative investigation of how biophysical alterations in hematologic disease collectively lead to microvascular occlusion and thrombosis. Using blood samples from patients with SCD, we investigated how the drug hydroxyurea quantitatively affects microvascular obstruction in SCD, an unresolved issue pivotal to understanding ... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5500936 Wed, 14 Dec 2011 08:26:02 +0100 5500936 http://www.medworm.com/index.php?rid=5500935&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F58393 The most abundant immune cell type is the neutrophil, a key first responder after pathogen invasion. Neutrophil numbers in the periphery are tightly regulated to prevent opportunistic infections and aberrant inflammation. In healthy individuals, more than 1 × 109 neutrophils per kilogram body weight are released from the bone marrow every 24 hours. To maintain homeostatic levels, an equivalent number of senescent cells must be cleared from circulation. Recent studies indicate that clearance of senescent neutrophils by resident tissue macrophages and DCs helps to set homeostatic levels of neutrophils via effects on the IL-23/IL-17/G-CSF cytokine axis, which stimulates neutrophil production in the bone marrow. However, the molecular events in phagocytes underlying this feedback loop ... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5500935 Wed, 14 Dec 2011 08:26:02 +0100 5500935 http://www.medworm.com/index.php?rid=5500934&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F58344 Immune tolerance to transplanted organs is impaired when the innate immune system is activated in response to the tissue necrosis that occurs during harvesting and implantation procedures. A key molecule in this immune pathway is the intracellular TLR signal adaptor known as myeloid differentiation primary response gene 88 (MyD88). After transplantation, MyD88 induces DC maturation as well as the production of inflammatory mediators, such as IL-6 and TNF-α. However, upstream activators of MyD88 function in response to transplantation have not been identified. Here, we show that haptoglobin, an acute phase protein, is an initiator of this MyD88-dependent inflammatory process in a mouse model of skin transplantation. Necrotic lysates from transplanted skin elicited higher inflammator... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5500934 Wed, 14 Dec 2011 08:26:02 +0100 5500934 http://www.medworm.com/index.php?rid=5500933&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F57990 Suppression of immune responses is necessary to limit damage to host tissue during inflammation, but it can be detrimental in specific immune responses, such as sepsis and antitumor immunity. Recently, immature myeloid cells have been implicated in the suppression of immune responses in mouse models of cancer, infectious disease, bone marrow transplantation, and autoimmune disease. Here, we report the identification of a subset of mature human neutrophils (CD11cbright/CD62Ldim/CD11bbright/CD16bright) as what we believe to be a unique circulating population of myeloid cells, capable of suppressing human T cell proliferation. These cells were observed in humans in vivo during acute systemic inflammation induced by endotoxin challenge or by severe injury. Local release of hydrogen peroxide fr... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5500933 Wed, 14 Dec 2011 08:26:02 +0100 5500933 http://www.medworm.com/index.php?rid=5500932&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F42534 Ectodermal dysplasia with immune deficiency (EDI) is an immunological and developmental disorder caused by alterations in the gene encoding NF-κB essential modulator (NEMO; also known as IκB kinase γ subunit [IKKγ]). Missense mutations in the gene encoding NEMO are associated with reduced signal-induced nuclear translocation of NF-κB proteins, resulting in defective expression of NF-κB target genes. Here, we report 2 unrelated male patients with EDI, both of whom have normal NEMO coding sequences, but exhibit a marked reduction in expression of full-length NEMO protein. TLR4 stimulation of APCs from these patients induced normal cytoplasmic activation and nuclear translocation of NF-κB. However, cells deficient in full-length NEMO wer... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5500932 Wed, 14 Dec 2011 08:26:02 +0100 5500932 http://www.medworm.com/index.php?rid=5465019&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F61899 (Source: Journal of Clinical Investigation) Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5465019 Fri, 02 Dec 2011 08:01:27 +0100 5465019 http://www.medworm.com/index.php?rid=5465018&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F59466 Mutations in the coactivator CREB-binding protein (CBP) are a major cause of the human skeletal dysplasia Rubinstein-Taybi syndrome (RTS); however, the mechanism by which these mutations affect skeletal mineralization and patterning is unknown. Here, we report the identification of 3-phosphoinositide-dependent kinase 1 (PDK1) as a key regulator of CBP activity and demonstrate that its functions map to both osteoprogenitor cells and mature osteoblasts. In osteoblasts, PDK1 activated the CREB/CBP complex, which in turn controlled runt-related transcription factor 2 (RUNX2) activation and expression of bone morphogenetic protein 2 (BMP2). These pathways also operated in vivo, as evidenced by recapitulation of RTS spectrum phenotypes with osteoblast-specific Pdk1 deletion in mice (Pdk1osx mice... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5465018 Fri, 02 Dec 2011 08:01:27 +0100 5465018 http://www.medworm.com/index.php?rid=5465017&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F59285 Type 1 diabetes (T1D) is caused by autoimmune destruction of the insulin-producing β cells in the pancreatic islets, which are essentially mini-organs embedded in exocrine tissue. CTLs are considered to have a predominant role in the autoimmune destruction underlying T1D. Visualization of CTL-mediated killing of β cells would provide new insight into the pathogenesis of T1D, but has been technically challenging to achieve. Here, we report our use of intravital 2-photon imaging in mice to visualize the dynamic behavior of a virally expanded, diabetogenic CTL population in the pancreas at cellular resolution. Following vascular arrest and extravasation, CTLs adopted a random motility pattern throughout the compact exocrine tissue and displayed unimpeded yet nonlinear migratio... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5465017 Fri, 02 Dec 2011 08:01:27 +0100 5465017 http://www.medworm.com/index.php?rid=5465016&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F59251 Spinal cord injury (SCI) often leads to persistent functional deficits due to loss of neurons and glia and to limited axonal regeneration after injury. Here we report that transplantation of human dental pulp stem cells into the completely transected adult rat spinal cord resulted in marked recovery of hind limb locomotor functions. Transplantation of human bone marrow stromal cells or skin-derived fibroblasts led to substantially less recovery of locomotor function. The human dental pulp stem cells exhibited three major neuroregenerative activities. First, they inhibited the SCI-induced apoptosis of neurons, astrocytes, and oligodendrocytes, which improved the preservation of neuronal filaments and myelin sheaths. Second, they promoted the regeneration of transected axons by directly inhi... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5465016 Fri, 02 Dec 2011 08:01:27 +0100 5465016 http://www.medworm.com/index.php?rid=5465015&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F59072 IgE-mediated activation of mast cells and basophils underlies allergic diseases such as asthma. Histamine-releasing factor (HRF; also known as translationally controlled tumor protein [TCTP] and fortilin) has been implicated in late-phase allergic reactions (LPRs) and chronic allergic inflammation, but its functions during asthma are not well understood. Here, we identified a subset of IgE and IgG antibodies as HRF-interacting molecules in vitro. HRF was able to dimerize and bind to Igs via interactions of its N-terminal and internal regions with the Fab region of Igs. Therefore, HRF together with HRF-reactive IgE was able to activate mast cells in vitro. In mouse models of asthma and allergy, Ig-interacting HRF peptides that were shown to block HRF/Ig interactions in vitro inhibited IgE/H... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5465015 Fri, 02 Dec 2011 08:01:27 +0100 5465015 http://www.medworm.com/index.php?rid=5465014&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F58928 Oncogenic Ras and p53 loss-of-function mutations are common in many advanced sporadic malignancies and together predict a limited responsiveness to conventional chemotherapy. Notably, studies in cultured cells have indicated that each of these genetic alterations creates a selective sensitivity to ataxia telangiectasia and Rad3-related (ATR) pathway inhibition. Here, we describe a genetic system to conditionally reduce ATR expression to 10% of normal levels in adult mice to compare the impact of this suppression on normal tissues and cancers in vivo. Hypomorphic suppression of ATR minimally affected normal bone marrow and intestinal homeostasis, indicating that this level of ATR expression was sufficient for highly proliferative adult tissues. In contrast, hypomorphic ATR reduction potentl... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5465014 Fri, 02 Dec 2011 08:01:27 +0100 5465014 http://www.medworm.com/index.php?rid=5465013&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F58227 Antagonists of L-type Ca2+ channels (LTCCs) have been used to treat human cardiovascular diseases for decades. However, these inhibitors can have untoward effects in patients with heart failure, and their overall therapeutic profile remains nebulous given differential effects in the vasculature when compared with those in cardiomyocytes. To investigate this issue, we examined mice heterozygous for the gene encoding the pore-forming subunit of LTCC (calcium channel, voltage-dependent, L type, α1C subunit [Cacna1c mice; referred to herein as α1C–/+ mice]) and mice in which this gene was loxP targeted to achieve graded heart-specific gene deletion (termed herein α1C-loxP mice). Adult cardiomyocytes from the hearts of α1C–/+ mice at 10 weeks of a... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5465013 Fri, 02 Dec 2011 08:01:27 +0100 5465013 http://www.medworm.com/index.php?rid=5465012&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F57292 DNA methyltransferase 3B (Dnmt3b) belongs to a family of enzymes responsible for methylation of cytosine residues in mammals. DNA methylation contributes to the epigenetic control of gene transcription and is deregulated in virtually all human tumors. To better understand the generation of cancer-specific methylation patterns, we genetically inactivated Dnmt3b in a mouse model of MYC-induced lymphomagenesis. Ablation of Dnmt3b function using a conditional knockout in T cells accelerated lymphomagenesis by increasing cellular proliferation, which suggests that Dnmt3b functions as a tumor suppressor. Global methylation profiling revealed numerous gene promoters as potential targets of Dnmt3b activity, the majority of which were demethylated in Dnmt3b–/– lymphomas, but not in ... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5465012 Fri, 02 Dec 2011 08:01:27 +0100 5465012 http://www.medworm.com/index.php?rid=5465011&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F46252 It is estimated that one-third of the world’s population is infected with Mycobacterium tuberculosis. Infection typically remains latent, but it can reactivate to cause clinical disease. The only vaccine, Mycobacterium bovis bacillus Calmette-Guérin (BCG), is largely ineffective, and ways to enhance its efficacy are being developed. Of note, the candidate booster vaccines currently under clinical development have been designed to improve BCG efficacy but not prevent reactivation of latent infection. Here, we demonstrate that administering a multistage vaccine that we term H56 in the adjuvant IC31 as a boost to vaccination with BCG delays and reduces clinical disease in cynomolgus macaques challenged with M. tuberculosis and prevents reactivation of latent infection. H56 con... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5465011 Fri, 02 Dec 2011 08:01:27 +0100 5465011 http://www.medworm.com/index.php?rid=5437122&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F61367 Decline in immune function with age has been attributed to defects or alterations in both the innate and the adaptive immune system. In this issue of the JCI, Zhao and coworkers provide evidence for a novel mechanism of immune dysfunction in aging mice. They show that migration of respiratory DCs from the site of virus replication to the draining lymph nodes in response to infection with several different respiratory viruses is markedly diminished with increasing age. The impaired DC migration was a result of increased levels of the lipid mediator prostaglandin D2 (PGD2) in the respiratory tract with age and could be partially reversed by blockade of PGD2 synthesis or action. (Source: Journal of Clinical Investigation) Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5437122 Wed, 23 Nov 2011 07:09:35 +0100 5437122 http://www.medworm.com/index.php?rid=5437121&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F61167 Central to our ability to hear and sense gravity is a cellular process known as mechanotransduction, which is initiated by the opening of mechanosensitive cation channels located near the tips of the stereocilia of auditory and vestibular inner ear hair cells. The molecular identity of the mechanotransduction channels has eluded researchers despite intensive investigations over the years. In this issue of the JCI, Kawashima et al. report their results obtained using mice with targeted deletion of both transmembrane channel–like 1 (Tmc1) and Tmc2. The use of inner ear hair cells isolated from these mice provided a nearly perfect system for testing the mechanotransduction channels without disrupting functions of other accessory proteins needed in the complicated molecular apparatus, ... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5437121 Wed, 23 Nov 2011 07:09:35 +0100 5437121 http://www.medworm.com/index.php?rid=5437120&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F61127 Members of the ErbB family of cell surface tyrosine kinase receptors are important targets for cancer treatment because they frequently contribute to the pathogenesis of malignancy. In this issue of the JCI, Fukuoka et al. generate data that suggest that using a tyrosine kinase inhibitor (TKI) against epidermal growth factor receptor (EGFR; also known as ErbB1) may be a novel approach for treating patients with hypercortisolemia due to pituitary corticotroph adenomas (Cushing disease). While surgical resection remains the cornerstone of treatment for individuals with such tumors, this study suggests that TKIs could perhaps be used to reduce tumor size prior to surgery or to treat recurrent disease after surgery. (Source: Journal of Clinical Investigation) Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5437120 Wed, 23 Nov 2011 07:09:35 +0100 5437120 http://www.medworm.com/index.php?rid=5437119&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F61126 Inclusion body myopathy with Paget disease of the bone and frontotemporal dementia (IBMPFD) is a multisystem degenerative disorder caused by mutations in the valosin-containing protein (VCP) gene. How missense mutations in this abundant, ubiquitously expressed, multifunctional protein lead to the degeneration of disparate tissues is unclear. VCP participates in diverse cellular functions by associating with an expanding collection of substrates and cofactors that dictate its functionality. In this issue of the JCI, Wang and colleagues have further expanded the VCP interactome by identifying neurofibromin-1 (NF1) as a novel VCP interactor in the CNS. IBMPFD-associated mutations disrupt binding of VCP to NF1, resulting in reduced synaptogenesis. Thus, aberrant interactions between VCP and NF... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5437119 Wed, 23 Nov 2011 07:09:35 +0100 5437119 http://www.medworm.com/index.php?rid=5437118&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F60417 Cushing disease is a condition in which the pituitary gland releases excessive adrenocorticotropic hormone (ACTH) as a result of an adenoma arising from the ACTH-secreting cells in the anterior pituitary. ACTH-secreting pituitary adenomas lead to hypercortisolemia and cause significant morbidity and mortality. Pituitary-directed medications are mostly ineffective, and new treatment options are needed. As these tumors express EGFR, we tested whether EGFR might provide a therapeutic target for Cushing disease. Here, we show that in surgically resected human and canine corticotroph cultured tumors, blocking EGFR suppressed expression of proopiomelanocortin (POMC), the ACTH precursor. In mouse corticotroph EGFR transfectants, ACTH secretion was enhanced, and EGF increased Pomc promoter activit... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5437118 Wed, 23 Nov 2011 07:09:35 +0100 5437118 http://www.medworm.com/index.php?rid=5437117&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F60405 Inner ear hair cells convert the mechanical stimuli of sound, gravity, and head movement into electrical signals. This mechanotransduction process is initiated by opening of cation channels near the tips of hair cell stereocilia. Since the identity of these ion channels is unknown, and mutations in the gene encoding transmembrane channel–like 1 (TMC1) cause hearing loss without vestibular dysfunction in both mice and humans, we investigated the contribution of Tmc1 and the closely related Tmc2 to mechanotransduction in mice. We found that Tmc1 and Tmc2 were expressed in mouse vestibular and cochlear hair cells and that GFP-tagged TMC proteins localized near stereocilia tips. Tmc2 expression was transient in early postnatal mouse cochlear hair cells but persisted in vestibular hair ... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5437117 Wed, 23 Nov 2011 07:09:35 +0100 5437117 http://www.medworm.com/index.php?rid=5437116&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F59777 The morbidity and mortality associated with respiratory virus infection is felt most keenly among the elderly. T cells are necessary for viral clearance, and many age-dependent intrinsic T cell defects have been documented. However, the development of robust T cell responses in the lung also requires respiratory DCs (rDCs), which must process antigen and migrate to draining LNs (DLNs), and little is known about age-related defects in these T cell–extrinsic functions. Here, we show that increases in prostaglandin D2 (PGD2) expression in mouse lungs upon aging correlate with a progressive impairment in rDC migration to DLNs. Decreased rDC migration resulted in diminished T cell responses and more severe clinical disease in older mice infected with respiratory viruses. Diminished rDC ... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5437116 Wed, 23 Nov 2011 07:09:35 +0100 5437116 http://www.medworm.com/index.php?rid=5437115&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F59652 While it has been well established that the fetal liver originates from foregut endoderm, the identity of the mechanisms that maintain liver mass under both basal and injury conditions remains controversial. Dramatically different models have been proposed based on the experimental design employed. In this issue of the JCI, Malato and colleagues report their elegant new model for genetic lineage tracing of mature mouse hepatocytes using an adenoassociated virus–driven Cre recombinase. They show convincingly that maintenance of liver mass during normal turnover or in response to mild injury is achieved by mature hepatocytes, rather than cholangiocytes or specialized progenitor cells, as has been suggested by others. (Source: Journal of Clinical Investigation) Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5437115 Wed, 23 Nov 2011 07:09:35 +0100 5437115 http://www.medworm.com/index.php?rid=5437114&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F59261 Recent evidence has contradicted the prevailing view that homeostasis and regeneration of the adult liver are mediated by self duplication of lineage-restricted hepatocytes and biliary epithelial cells. These new data suggest that liver progenitor cells do not function solely as a backup system in chronic liver injury; rather, they also produce hepatocytes after acute injury and are in fact the main source of new hepatocytes during normal hepatocyte turnover. In addition, other evidence suggests that hepatocytes are capable of lineage conversion, acting as precursors of biliary epithelial cells during biliary injury. To test these concepts, we generated a hepatocyte fate-tracing model based on timed and specific Cre recombinase expression and marker gene activation in all hepatocytes of ad... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5437114 Wed, 23 Nov 2011 07:09:35 +0100 5437114 http://www.medworm.com/index.php?rid=5437113&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F59259 We report here unrelated HSE children with AR or AD TRIF deficiency. The AR form of the disease was found to be due to a homozygous nonsense mutation that resulted in a complete absence of the TRIF protein. Both the TLR3- and the TRIF-dependent TLR4 signaling pathways were abolished. The AD form of disease was found to be due to a heterozygous missense mutation, resulting in a dysfunctional protein. In this form of the disease, the TLR3 signaling pathway was impaired, whereas the TRIF-dependent TLR4 pathway was unaffected. Both patients, however, showed reduced capacity to respond to stimulation of the DExD/H-box helicases pathway. To date, the TRIF-deficient patients with HSE described herein have suffered from no other infections. Moreover, as observed in patients with other genetic etio... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5437113 Wed, 23 Nov 2011 07:09:35 +0100 5437113 http://www.medworm.com/index.php?rid=5437112&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F57755 In this study, we engineered a transgenic zebrafish with temperature-inducible expression of an EGFP-labeled single-chain human monoclonal antibody, IK17, which binds to MDA-LDL, and used optically transparent zebrafish larvae for imaging studies. Feeding a high-cholesterol diet (HCD) supplemented with a red fluorescent lipid marker to the transgenic zebrafish resulted in vascular lipid accumulation, quantified in live animals using confocal microscopy. After heat shock–induced expression of IK17-EGFP, we measured the time course of vascular accumulation of IK17-specific MDA epitopes. Treatment with either an antioxidant or a regression diet resulted in reduced IK17 binding to vascular lesions. Interestingly, homogenates of IK17-EGFP–expressing larvae bound to MDA-LDL and i... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5437112 Wed, 23 Nov 2011 07:09:35 +0100 5437112 http://www.medworm.com/index.php?rid=5437111&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F46382 Advanced human thyroid cancers, particularly those that are refractory to treatment with radioiodine (RAI), have a high prevalence of BRAF (v-raf murine sarcoma viral oncogene homolog B1) mutations. However, the degree to which these cancers are dependent on BRAF expression is still unclear. To address this question, we generated mice expressing one of the most commonly detected BRAF mutations in human papillary thyroid carcinomas (BRAFV600E) in thyroid follicular cells in a doxycycline-inducible (dox-inducible) manner. Upon dox induction of BRAFV600E, the mice developed highly penetrant and poorly differentiated thyroid tumors. Discontinuation of dox extinguished BRAFV600E expression and reestablished thyroid follicular architecture and normal thyroid histology. Switching on BRAFV600E rap... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5437111 Wed, 23 Nov 2011 07:09:35 +0100 5437111 http://www.medworm.com/index.php?rid=5437110&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F45677 Inclusion body myopathy with Paget disease of bone and frontotemporal dementia (IBMPFD) is an autosomal dominant disorder characterized by progressive myopathy that is often accompanied by bone weakening and/or frontotemporal dementia. Although it is known to be caused by mutations in the gene encoding valosin-containing protein (VCP), the underlying disease mechanism remains elusive. Like IBMPFD, neurofibromatosis type 1 (NF1) is an autosomal dominant disorder. Neurofibromin, the protein encoded by the NF1 gene, has been shown to regulate synaptogenesis. Here, we show that neurofibromin and VCP interact and work together to control the density of dendritic spines. Certain mutations identified in IBMPFD and NF1 patients reduced the interaction between VCP and neurofibromin and impaired spi... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5437110 Wed, 23 Nov 2011 07:09:35 +0100 5437110 http://www.medworm.com/index.php?rid=5417212&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F60001 Genome-wide association studies (GWAS) have identified a large number of SNPs that are linked to human autoimmune diseases. However, the functional consequences of most of these genetic variations remain undefined. T cell protein tyrosine phosphatase (TCPTP, which is encoded by PTPN2) is a JAK/STAT and growth factor receptor phosphatase that has been linked to the pathogenesis of type 1 diabetes, rheumatoid arthritis, and Crohn’s disease by GWAS. In this issue of the JCI, Wiede and colleagues have generated a T cell–specific deletion of TCPTP and identified a novel role for this phosphatase as a negative regulator of TCR signaling. These data provide new insight as to how noncoding PTPN2 SNPs identified in GWAS could drive human autoimmune diseases. (Source: Journal of Clin... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5417212 Thu, 17 Nov 2011 21:51:18 +0100 5417212 http://www.medworm.com/index.php?rid=5417211&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F59492 In this study, we have identified TCPTP as a key negative regulator of TCR signaling, which might explain the association of PTPN2 SNPs with autoimmune disease. We found that TCPTP dephosphorylates and inactivates Src family kinases to regulate T cell responses. Using T cell–specific TCPTP-deficient mice, we established that TCPTP attenuates T cell activation and proliferation in vitro and blunts antigen-induced responses in vivo. TCPTP deficiency lowered the in vivo threshold for TCR-dependent CD8+ T cell proliferation. Consistent with this, T cell–specific TCPTP-deficient mice developed widespread inflammation and autoimmunity that was transferable to wild-type recipient mice by CD8+ T cells alone. This autoimmunity was associated with increased serum levels of proinflamm... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5417211 Thu, 17 Nov 2011 21:51:18 +0100 5417211 http://www.medworm.com/index.php?rid=5417210&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F59472 Human mutations in or variants of TBX20 are associated with congenital heart disease, cardiomyopathy, and arrhythmias. To investigate whether cardiac disease in patients with these conditions results from an embryonic or ongoing requirement for Tbx20 in myocardium, we ablated Tbx20 specifically in adult cardiomyocytes in mice. This ablation resulted in the onset of severe cardiomyopathy accompanied by arrhythmias, with death ensuing within 1 to 2 weeks of Tbx20 ablation. Accounting for this dramatic phenotype, we identified molecular signatures that posit Tbx20 as a central integrator of a genetic program that maintains cardiomyocyte function in the adult heart. Expression of a number of genes encoding critical transcription factors, ion channels, and cytoskeletal/myofibrillar proteins was... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5417210 Thu, 17 Nov 2011 21:51:18 +0100 5417210 http://www.medworm.com/index.php?rid=5417209&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F58577 Individuals who are obese are frequently insulin resistant, putting them at increased risk of developing type 2 diabetes and its associated adverse health conditions. The accumulation in adipose tissue of macrophages in an inflammatory state is a hallmark of obesity-induced insulin resistance. Here, we reveal a role for AMPK β1 in protecting macrophages from inflammation under high lipid exposure. Genetic deletion of the AMPK β1 subunit in mice (referred to herein as β1–/– mice) reduced macrophage AMPK activity, acetyl-CoA carboxylase phosphorylation, and mitochondrial content, resulting in reduced rates of fatty acid oxidation. β1–/– macrophages displayed increased levels of diacylglycerol and markers of inflammation, effects... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5417209 Thu, 17 Nov 2011 21:51:18 +0100 5417209 http://www.medworm.com/index.php?rid=5417208&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F58559 Two hallmarks of glioblastoma multiforme, the most common malignant brain cancer in humans, are aggressive growth and the ability of single glioma cells to disperse throughout the brain. These characteristics render tumors resistant to current therapies and account for the poor prognosis of patients. Although it is known that oncogenic signaling caused by overexpression of genes such as PDGFRA is responsible for robust glioma growth and cell infiltration, the mechanisms underlying glioblastoma malignancy remain largely elusive. Here, we report that PDGFRα signaling in glioblastomas leads to Src-dependent phosphorylation of the guanine nucleotide exchange factor Dock180 at tyrosine 1811 (Dock180Y1811) that results in activation of the GTPase Rac1 and subsequent cell growth and invas... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5417208 Thu, 17 Nov 2011 21:51:18 +0100 5417208 http://www.medworm.com/index.php?rid=5417207&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F57332 Erythropoiesis, the production of red blood cells, must be tightly controlled to ensure adequate oxygen delivery to tissues without causing thrombosis or stroke. Control of physiologic and pathologic erythropoiesis is dependent predominantly on erythropoietin (EPO), the expression of which is regulated by hypoxia-inducible factor (HIF) activity in response to low oxygen tension. Accumulating evidence indicates that oxygen-independent mediators, including inflammatory stimuli, cytokines, and growth factors, also upregulate HIF activity, but it is unclear whether these signals also result in EPO production and erythropoiesis in vivo. Here, we found that signaling through herpesvirus entry mediator (HVEM), a molecule of the TNF receptor superfamily, promoted HIF-1α activity in the kid... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5417207 Thu, 17 Nov 2011 21:51:18 +0100 5417207 http://www.medworm.com/index.php?rid=5417206&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F41769 Cutaneous T cell lymphomas (CTCLs) represent a heterogeneous group of non-Hodgkin lymphomas that affect the skin. The pathogenesis of these conditions is poorly understood. For example, the signaling mechanisms contributing to the dysregulated growth of the neoplastic T cells are not well defined. Here, we demonstrate that loss of nuclear localization of pro–IL-16 facilitates CTCL cell proliferation by causing a decrease in expression of the cyclin dependent–kinase inhibitor p27Kip1. The decrease in p27Kip1 expression was directly attributable to an increase in expression of S-phase kinase-associated protein 2 (Skp2). Regulation of Skp2 is in part attributed to the nuclear presence of the scaffold protein pro–IL-16. T cells isolated from 11 patients with advanced CT... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5417206 Thu, 17 Nov 2011 21:51:18 +0100 5417206 http://www.medworm.com/index.php?rid=5396497&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F61608 (Source: Journal of Clinical Investigation) Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5396497 Fri, 11 Nov 2011 07:52:36 +0100 5396497 http://www.medworm.com/index.php?rid=5396496&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F59145 We examined SVZ function in mice in which we targeted an MS-like pathology to the forebrain. In these mice, which we refer to herein as targeted EAE (tEAE) mice, there was a reduction in the number of neuroblasts compared with control mice. Altered expression of the transcription factors Olig2 and Dlx2 in the tEAE SVZ niche was associated with amplification of pro-oligodendrogenic transit-amplifying cells and decreased neuroblast generation, which resulted in persistent reduction in olfactory bulb neurogenesis. Altered SVZ neurogenesis led to impaired long-term olfactory memory, mimicking the olfactory dysfunction observed in MS patients. Importantly, we also found that neurogenesis was reduced in the SVZ of MS patients compared with controls. Thus, our findings suggest that neuroinflammat... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5396496 Fri, 11 Nov 2011 07:52:36 +0100 5396496 http://www.medworm.com/index.php?rid=5396495&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F58814 Solid tumors are complex masses with a local microenvironment, or stroma, that supports tumor growth and progression. Among the diverse tumor-supporting stromal cells is a heterogeneous population of myeloid-derived cells. These cells are alternatively activated and contribute to the immunosuppressive environment of the tumor; overcoming their immunosuppressive effects may improve the efficacy of cancer immunotherapies. We recently found that engineering tumor-specific CD8+ T cells to secrete the inflammatory cytokine IL-12 improved their therapeutic efficacy in the B16 mouse model of established melanoma. Here, we report the mechanism underlying this finding. Surprisingly, direct binding of IL-12 to receptors on lymphocytes or NK cells was not required. Instead, IL-12 sensitized bone marr... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5396495 Fri, 11 Nov 2011 07:52:36 +0100 5396495 http://www.medworm.com/index.php?rid=5396494&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F58035 Increased endogenous glucose production (EGP) is a hallmark of type 2 diabetes mellitus. While there is evidence for central regulation of EGP by activation of hypothalamic ATP-sensitive potassium (KATP) channels in rodents, whether these central pathways contribute to regulation of EGP in humans remains to be determined. Here we present evidence for central nervous system regulation of EGP in humans that is consistent with complementary rodent studies. Oral administration of the KATP channel activator diazoxide under fixed hormonal conditions substantially decreased EGP in nondiabetic humans and Sprague Dawley rats. In rats, comparable doses of oral diazoxide attained appreciable concentrations in the cerebrospinal fluid, and the effects of oral diazoxide were abolished by i.c.v. administ... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5396494 Fri, 11 Nov 2011 07:52:36 +0100 5396494 http://www.medworm.com/index.php?rid=5396493&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F46134 Parathyroid hormone–related protein (PTHrP) is a secreted factor expressed in almost all normal fetal and adult tissues. It is involved in a wide range of developmental and physiological processes, including serum calcium regulation. PTHrP is also associated with the progression of skeletal metastases, and its dysregulated expression in advanced cancers causes malignancy-associated hypercalcemia. Although PTHrP is frequently expressed by breast tumors and other solid cancers, its effects on tumor progression are unclear. Here, we demonstrate in mice pleiotropic involvement of PTHrP in key steps of breast cancer — it influences the initiation and progression of primary tumors and metastases. Pthrp ablation in the mammary epithelium of the PyMT-MMTV breast cancer mouse model ... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5396493 Fri, 11 Nov 2011 07:52:36 +0100 5396493 http://www.medworm.com/index.php?rid=5396492&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F45797 The majority of human pancreatic cancers have activating mutations in the KRAS proto-oncogene. These mutations result in increased activity of the NF-κB pathway and the subsequent constitutive production of proinflammatory cytokines. Here, we show that inhibitor of κB kinase 2 (Ikk2), a component of the canonical NF-κB signaling pathway, synergizes with basal Notch signaling to upregulate transcription of primary Notch target genes, resulting in suppression of antiinflammatory protein expression and promotion of pancreatic carcinogenesis in mice. We found that in the KrasG12DPdx1-cre mouse model of pancreatic cancer, genetic deletion of Ikk2 in initiated pre-malignant epithelial cells substantially delayed pancreatic oncogenesis and resulted in downregulation of the... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5396492 Fri, 11 Nov 2011 07:52:36 +0100 5396492 http://www.medworm.com/index.php?rid=5396491&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F40509 Type 1 diabetes develops when most insulin-producing β cells of the pancreas are killed by an autoimmune attack. The in vivo conditions modulating the sensitivity and resistance of β cells to this attack remain largely obscure. Here, we show that connexin 36 (Cx36), a trans-membrane protein that forms gap junctions between β cells in the pancreatic islets, protects mouse β cells against both cytotoxic drugs and cytokines that prevail in the islet environment at the onset of type 1 diabetes. We documented that this protection was at least partially dependent on intercellular communication, which Cx36 and other types of connexin channels establish within pancreatic islets. We further found that proinflammatory cytokines decreased expression of Cx36 and that ex... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5396491 Fri, 11 Nov 2011 07:52:36 +0100 5396491 http://www.medworm.com/index.php?rid=5374797&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F60511 Hereditary neuropathies are common neurological conditions characterized by progressive loss of motor and/or sensory function. There are no effective treatments. Among the many causes of hereditary neuropathies are dominant mutations in serine palmitoyltransferase, long chain base subunit 1 (SPTLC1), which cause hereditary sensory and autonomic neuropathy type 1 (HSAN1). By incorporating l-alanine in place of l-serine, the mutant HSAN1–associated serine palmitoyltransferase generates deoxysphingolipids, which are thought to be neurotoxic. In this issue of the JCI, Garofalo and colleagues report that oral l-serine reverses the accumulation of deoxysphingolipids in humans with HSAN1 and in a transgenic mouse model. As oral l-serine reduces the severity of neuropathy in the mouse mode... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5374797 Fri, 04 Nov 2011 17:40:50 +0100 5374797 http://www.medworm.com/index.php?rid=5374796&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F59150 The two most common forms of inflammatory bowel disease (IBD), Crohn’s disease and ulcerative colitis, affect approximately 1 million people in the United States. Uncontrolled APC reactivity toward commensal bacteria is implicated in the pathogenesis of the disease. A number of functionally distinct APC populations exist in the mucosal lamina propria (LP) below the intestinal epithelium, but their relative contributions to inflammation remain unclear. Here, we demonstrate in mice important roles for the chemokine receptor CX3CR1 in maintaining LP macrophage populations, preventing translocation of commensal bacteria to mesenteric lymph nodes (mLNs), and limiting colitogenic Th17 responses. CX3CR1 was found to be expressed in resident LP macrophages (defined as CD11b+F4/80+) but not... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5374796 Fri, 04 Nov 2011 17:40:50 +0100 5374796 http://www.medworm.com/index.php?rid=5374795&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F57693 Iron overload is the hallmark of hereditary hemochromatosis and a complication of iron-loading anemias such as β-thalassemia. Treatment can be burdensome and have significant side effects, and new therapeutic options are needed. Iron overload in hereditary hemochromatosis and β-thalassemia intermedia is caused by hepcidin deficiency. Although transgenic hepcidin replacement in mouse models of these diseases prevents iron overload or decreases its potential toxicity, natural hepcidin is prohibitively expensive for human application and has unfavorable pharmacologic properties. Here, we report the rational design of hepcidin agonists based on the mutagenesis of hepcidin and the hepcidin-binding region of ferroportin and computer modeling of their docking. We identified specif... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5374795 Fri, 04 Nov 2011 17:40:50 +0100 5374795 http://www.medworm.com/index.php?rid=5374794&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F57549 Hereditary sensory and autonomic neuropathy type 1 (HSAN1) causes sensory loss that predominantly affects the lower limbs, often preceded by hyperpathia and spontaneous shooting or lancinating pain. It is caused by several missense mutations in the genes encoding 2 of the 3 subunits of the enzyme serine palmitoyltransferase (SPT). The mutant forms of the enzyme show a shift from their canonical substrate l-serine to the alternative substrate l-alanine. This shift leads to increased formation of neurotoxic deoxysphingolipids (dSLs). Our initial analysis showed that in HEK cells transfected with SPTLC1 mutants, dSL generation was modulated in vitro in the presence of various amino acids. We therefore examined whether in vivo specific amino acid substrate supplementation influenced dSL levels... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5374794 Fri, 04 Nov 2011 17:40:50 +0100 5374794 http://www.medworm.com/index.php?rid=5374793&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F44943 NF-κB–inducing kinase (NIK) is an essential upstream kinase in noncanonical NF-κB signaling. NIK-dependent NF-κB activation downstream of several TNF receptor family members mediates lymphoid organ development and B cell homeostasis. Peripheral T cell populations are normal in the absence of NIK, but the role of NIK during in vivo T cell responses to antigen has been obscured by other developmental defects in NIK-deficient mice. Here, we have identified a T cell–intrinsic requirement for NIK in graft-versus-host disease (GVHD), wherein NIK-deficient mouse T cells transferred into MHC class II mismatched recipients failed to cause GVHD. Although NIK was not necessary for antigen receptor signaling, it was absolutely required for costimulation through ... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5374793 Fri, 04 Nov 2011 17:40:50 +0100 5374793 http://www.medworm.com/index.php?rid=5355112&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F60749 Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a condition characterized by thrombocytopenia in the newborn. If severe, the thrombocytopenia can lead to intracranial hemorrhage. FNAIT arises when maternal antibodies specific for platelet antigens, most commonly β3 integrin, cross the placenta and destroy fetal platelets. Surprisingly, few cases of FNAIT are associated with antibodies specific for the platelet antigen GPIbα, which is a common target in patients with immune thrombocytopenia. In this issue of the JCI, Li et al. have identified a potential reason for this — they find that in the majority of pregnant mice, anti-GPIbα antibodies enhance platelet activation and accelerate thrombus formation in the placenta and that this leads to miscarri... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5355112 Thu, 27 Oct 2011 23:52:43 +0100 5355112 http://www.medworm.com/index.php?rid=5355111&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F59266 Current therapies for non-Hodgkin lymphoma commonly include CD20 mAb to deplete tumor cells. However, the response is not durable in a substantial proportion of patients. Herein, we report our studies in mice testing the hypothesis that heterogeneity in endogenous tissue CD20+ B cell depletion influences in vivo lymphoma therapy. Using highly effective CD20 mAbs that efficiently deplete endogenous mature B cells and homologous CD20+ primary lymphoma cells through monocyte- and antibody-dependent mechanisms, we found that lymphoma depletion and survival were reduced when endogenous host B cells were not depleted, particularly a rare IL-10–producing B cell subset (B10 cells) known to regulate inflammation and autoimmunity. Even small numbers of adoptively transferred B10 cells dramat... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5355111 Thu, 27 Oct 2011 23:52:43 +0100 5355111 http://www.medworm.com/index.php?rid=5355110&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F57850 Fetal and neonatal immune thrombocytopenia (FNIT) is a severe bleeding disorder caused by maternal antibody–mediated destruction of fetal/neonatal platelets. It is the most common cause of severe thrombocytopenia in neonates, but the frequency of FNIT-related miscarriage is unknown, and the mechanism(s) underlying fetal mortality have not been explored. Furthermore, although platelet αIIbβ3 integrin and GPIbα are the major antibody targets in immune thrombocytopenia, the reported incidence of anti-GPIbα–mediated FNIT is rare. Here, we developed mouse models of FNIT mediated by antibodies specific for GPIbα and β3 integrin and compared their pathogenesis. We found, unexpectedly, that miscarriage occurred in the majority of preg... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5355110 Thu, 27 Oct 2011 23:52:43 +0100 5355110 http://www.medworm.com/index.php?rid=5355109&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F46475 Wounds that fail to heal in a timely manner, for example, diabetic foot ulcers, pose a health, economic, and social problem worldwide. For decades, conventional wisdom has pointed to growth factors as the main driving force of wound healing; thus, growth factors have become the center of therapeutic developments. To date, becaplermin (recombinant human PDGF-BB) is the only US FDA-approved growth factor therapy, and it shows modest efficacy, is costly, and has the potential to cause cancer in patients. Other molecules that drive wound healing have therefore been sought. In this context, it has been noticed that wounds do not heal without the participation of secreted Hsp90α. Here, we report that a 115-aa fragment of secreted Hsp90α (F-5) acts as an unconventional wound heali... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5355109 Thu, 27 Oct 2011 23:52:43 +0100 5355109 http://www.medworm.com/index.php?rid=5355108&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F46187 Type 1 diabetes (T1D) is an autoimmune disease that shows familial aggregation in humans and likely has genetic determinants. Disease linkage studies have revealed many susceptibility loci for T1D in mice and humans. The mouse T1D susceptibility locus insulin-dependent diabetes susceptibility 3 (Idd3), which has a homologous genetic interval in humans, encodes cytokine genes Il2 and Il21 and regulates diabetes and other autoimmune diseases; however, the cellular and molecular mechanisms of this regulation are still being elucidated. Here we show that T cells from NOD mice produce more Il21 and less Il2 and exhibit enhanced Th17 cell generation compared with T cells from NOD.Idd3 congenic mice, which carry the protective Idd3 allele from a diabetes-resistant mouse strain. Further, APCs from... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5355108 Thu, 27 Oct 2011 23:52:43 +0100 5355108 http://www.medworm.com/index.php?rid=5330251&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F60122 Dengue virus (DV) reacts with myeloid DAP12-associating lectin–1 (MDL-1) on immature polymorphonuclear leukocytes. Interaction of DV with MDL-1+ cells triggers systemic inflammatory response syndrome (SIRS) and dengue shock syndrome (DSS), with subsequent multi-organ failure. In this issue of the JCI, Cheung et al. find that sterile acute liver injury in mice is associated with the accumulation of MDL-1+ cells and that triggering of these cells by DV or an MDL-1–specific agonist antibody leads to SIRS, shock, and death. These findings may have broad mechanistic and therapeutic implications for the development of SIRS, sepsis, and shock in humans exposed to a wide array of infectious and non-infectious conditions. (Source: Journal of Clinical Investigation) Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5330251 Wed, 19 Oct 2011 17:53:30 +0100 5330251 http://www.medworm.com/index.php?rid=5330250&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F59291 Diabetes mellitus is associated with platelet hyperactivity, which leads to increased morbidity and mortality from cardiovascular disease. This is coupled with enhanced levels of thromboxane (TX), an eicosanoid that facilitates platelet aggregation. Although intensely studied, the mechanism underlying the relationship among hyperglycemia, TX generation, and platelet hyperactivity remains unclear. We sought to identify key signaling components that connect high levels of glucose to TX generation and to examine their clinical relevance. In human platelets, aldose reductase synergistically modulated platelet response to both hyperglycemia and collagen exposure through a pathway involving ROS/PLCγ2/PKC/p38α MAPK. In clinical patients with platelet activation (deep vein thrombos... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5330250 Wed, 19 Oct 2011 17:53:30 +0100 5330250 http://www.medworm.com/index.php?rid=5330249&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F57734 Pulmonary hypertension is a severe and progressive disease, a key feature of which is pulmonary vascular remodeling. Several growth factors, including EGF, PDGF, and TGF-β1, are involved in pulmonary vascular remodeling during pulmonary hypertension. However, increased knowledge of the downstream signaling cascades is needed if effective clinical interventions are to be developed. In this context, calpain provides an interesting candidate therapeutic target, since it is activated by EGF and PDGF and has been reported to activate TGF-β1. Thus, in this study, we examined the role of calpain in pulmonary vascular remodeling in two rodent models of pulmonary hypertension. These data showed that attenuated calpain activity in calpain-knockout mice or rats treated with a calpain ... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5330249 Wed, 19 Oct 2011 17:53:30 +0100 5330249 http://www.medworm.com/index.php?rid=5330248&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F57728 Biliary atresia (BA) is a destructive cholangiopathy of childhood in which Th1 immunity has been mechanistically linked to the bile duct inflammation and obstruction that culminate in liver injury. Based on reports of decreased Th1 cytokines in some patients and the development of BA in mice lacking CD4+ T cells, we hypothesized that Th1-independent mechanisms can also activate effector cells and induce BA. Here, we tested this hypothesis using Stat1–/– mice, which lack the ability to mount Th1 immune responses. Infection of Stat1–/– mice with rhesus rotavirus type A (RRV) on postnatal day 1 induced a prominent Th2 response, duct epithelial injury and obstruction within 7 days, and atresia shortly thereafter. A high degree of phosphorylation of the Th2 trans... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5330248 Wed, 19 Oct 2011 17:53:30 +0100 5330248 http://www.medworm.com/index.php?rid=5330247&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F57682 Systemic inflammatory response syndrome (SIRS) is a potentially lethal condition, as it can progress to shock, multi-organ failure, and death. It can be triggered by infection, tissue damage, or hemorrhage. The role of tissue injury in the progression from SIRS to shock is incompletely understood. Here, we show that treatment of mice with concanavalin A (ConA) to induce liver injury triggered a G-CSF–dependent hepatic infiltration of CD11b+Gr-1+Ly6G+Ly6C+ immature myeloid cells that expressed the orphan receptor myeloid DAP12–associated lectin–1 (MDL-1; also known as CLEC5A). Activation of MDL-1 using dengue virus or an agonist MDL-1–specific antibody in the ConA-treated mice resulted in shock. The MDL-1+ cells were pathogenic, and in vivo depletion of MDL-1... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5330247 Wed, 19 Oct 2011 17:53:30 +0100 5330247 http://www.medworm.com/index.php?rid=5330246&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F46023 CD4+ T cells play a central role in the immunopathogenesis of HIV/AIDS, and their depletion during chronic HIV infection is a hallmark of disease progression. However, the relative contribution of CD4+ T cells as mediators of antiviral immune responses and targets for virus replication is still unclear. Here, we have generated data in SIV-infected rhesus macaques (RMs) that suggest that CD4+ T cells are essential in establishing control of virus replication during acute infection. To directly assess the role of CD4+ T cells during primary SIV infection, we in vivo depleted these cells from RMs prior to infecting the primates with a pathogenic strain of SIV. Compared with undepleted animals, CD4+ lymphocyte–depleted RMs showed a similar peak of viremia, but did not manifest any post... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5330246 Wed, 19 Oct 2011 17:53:30 +0100 5330246 http://www.medworm.com/index.php?rid=5330245&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F45144 Chronic obstructive pulmonary disease (COPD), which is caused primarily by cigarette smoking, is a major health problem worldwide. The progressive decline in lung function that occurs in COPD is a result of persistent inflammation of the airways and destruction of the lung parenchyma. Despite the key role of inflammation in the pathogenesis of COPD, treatment with corticosteroids — normally highly effective antiinflammatory drugs — has little therapeutic benefit. This corticosteroid resistance is largely caused by inactivation of histone deacetylase 2 (HDAC2), which is critical for the transrepressive activity of the glucocorticoid receptor (GR) that mediates the antiinflammatory effect of corticosteroids. Here, we show that in alveolar macrophages from patients with COPD, ... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5330245 Wed, 19 Oct 2011 17:53:30 +0100 5330245 http://www.medworm.com/index.php?rid=5330244&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F44999 TLRs are a family of receptors that mediate immune system pathogen recognition. In the respiratory system, TLR activation has both beneficial and deleterious effects in asthma. For example, clinical data indicate that TLR6 activation exerts protective effects in asthma. Here, we explored the mechanism or mechanisms through which TLR6 mediates this effect using mouse models of Aspergillus fumigatus–induced and house dust mite antigen–induced (HDM antigen–induced) chronic asthma. Tlr6–/– mice with fungal- or HDM antigen–induced asthma exhibited substantially increased airway hyperresponsiveness, inflammation, and remodeling compared with WT asthmatic groups. Surprisingly, whole-lung levels of IL-23 and IL-17 were markedly lower in Tlr6–... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5330244 Wed, 19 Oct 2011 17:53:30 +0100 5330244 http://www.medworm.com/index.php?rid=5310551&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F60243 Huntington disease (HD) is a dominantly inherited neurodegenerative disorder that is caused by a mutant huntingtin (HTT) gene encoding a version of the Htt protein with an expanded polyglutamine stretch. Although the HTT gene was discovered more than 18 years ago, the functions of normal Htt and the mechanisms by which mutant Htt causes disease are not well defined. In this issue of the JCI, Keryer et al. uncovered a novel function for normal Htt in ciliogenesis and report that mutant Htt causes hypermorphic ciliogenesis and ciliary dysfunction. These observations suggest that it is now critical to understand the extent to which ciliary dysfunction contributes to the different symptoms of HD and to determine whether therapeutic strategies designed to normalize ciliary function can ameliora... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5310551 Thu, 13 Oct 2011 08:41:05 +0100 5310551 http://www.medworm.com/index.php?rid=5310550&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F58554 Skeletal muscle insulin resistance is a key component of the etiology of type 2 diabetes. Caloric restriction (CR) enhances the sensitivity of skeletal muscle to insulin. However, the molecular signals within skeletal muscle linking CR to improved insulin action remain largely unknown. Recently, the mammalian ortholog of Sir2, sirtuin 1 (Sirt1), has been identified as a potential transducer of perturbations in cellular energy flux into subsequent metabolic adaptations, including modulation of skeletal muscle insulin action. Here, we have demonstrated that CR increases Sirt1 deacetylase activity in skeletal muscle in mice, in parallel with enhanced insulin-stimulated phosphoinositide 3-kinase (PI3K) signaling and glucose uptake. These adaptations in skeletal muscle insulin action were compl... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5310550 Thu, 13 Oct 2011 08:41:05 +0100 5310550 http://www.medworm.com/index.php?rid=5310549&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F58097 During lung development, parabronchial SMC (PSMC) progenitors in the distal mesenchyme secrete fibroblast growth factor 10 (Fgf10), which acts on distal epithelial progenitors to promote their proliferation. β-catenin signaling within PSMC progenitors is essential for their maintenance, proliferation, and expression of Fgf10. Here, we report that this Wnt/Fgf10 embryonic signaling cascade is reactivated in mature PSMCs after naphthalene-induced injury to airway epithelium. Furthermore, we found that this paracrine Fgf10 action was essential for activating surviving variant Clara cells (the cells in the airway epithelium from which replacement epithelial cells originate) located at the bronchoalveolar duct junctions and adjacent to neuroendocrine bodies. After naphthalene injury, PS... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5310549 Thu, 13 Oct 2011 08:41:05 +0100 5310549 http://www.medworm.com/index.php?rid=5310548&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F57909 Therapies inhibiting receptor tyrosine kinases (RTKs) are effective against some human cancers when they lead to simultaneous downregulation of PI3K/AKT and MEK/ERK signaling. However, mutant KRAS has the capacity to directly activate ERK and PI3K signaling, and this is thought to underlie the resistance of KRAS mutant cancers to RTK inhibitors. Here, we have elucidated the molecular regulation of both the PI3K/AKT and MEK/ERK signaling pathways in KRAS mutant colorectal cancer cells and identified combination therapies that lead to robust cancer cell apoptosis. KRAS knockdown using shRNA suppressed ERK signaling in all of the human KRAS mutant colorectal cancer cell lines examined. However, no decrease, and actually a modest increase, in AKT phosphorylation was often seen. By performing P... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5310548 Thu, 13 Oct 2011 08:41:05 +0100 5310548 http://www.medworm.com/index.php?rid=5310547&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F57552 Huntington disease (HD) is a devastating autosomal-dominant neurodegenerative disorder. It is caused by expansion of a CAG repeat in the first exon of the huntingtin (HTT) gene that encodes a mutant HTT protein with a polyglutamine (polyQ) expansion at the amino terminus. Here, we demonstrate that WT HTT regulates ciliogenesis by interacting through huntingtin-associated protein 1 (HAP1) with pericentriolar material 1 protein (PCM1). Loss of Htt in mouse cells impaired the retrograde trafficking of PCM1 and thereby reduced primary cilia formation. In mice, deletion of Htt in ependymal cells led to PCM1 mislocalization, alteration of the cilia layer, and hydrocephalus. Pathogenic polyQ expansion led to centrosomal accumulation of PCM1 and abnormally long primary cilia in mouse striatal cell... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5310547 Thu, 13 Oct 2011 08:41:05 +0100 5310547 http://www.medworm.com/index.php?rid=5310546&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F46122 Chronic kidney disease (CKD) is a public health epidemic that increases risk of death due to cardiovascular disease. Left ventricular hypertrophy (LVH) is an important mechanism of cardiovascular disease in individuals with CKD. Elevated levels of FGF23 have been linked to greater risks of LVH and mortality in patients with CKD, but whether these risks represent causal effects of FGF23 is unknown. Here, we report that elevated FGF23 levels are independently associated with LVH in a large, racially diverse CKD cohort. FGF23 caused pathological hypertrophy of isolated rat cardiomyocytes via FGF receptor–dependent activation of the calcineurin-NFAT signaling pathway, but this effect was independent of klotho, the coreceptor for FGF23 in the kidney and parathyroid glands. Intramyocardi... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5310546 Thu, 13 Oct 2011 08:41:05 +0100 5310546 http://www.medworm.com/index.php?rid=5310545&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F45008 Colorectal cancer is the second leading cause of death from cancer in the United States. Metastases in the liver, the most common metastatic site for colorectal cancer, are found in one-third of the patients who die of colorectal cancer. Currently, the genes and molecular mechanisms that are functionally critical in modulating colorectal cancer hepatic metastasis remain unclear. Here, we report our studies using functional selection in an orthotopic mouse model of colorectal cancer to identify a set of genes that play an important role in mediating colorectal cancer liver metastasis. These genes included APOBEC3G, CD133, LIPC, and S100P. Clinically, we found these genes to be highly expressed in a cohort of human hepatic metastasis and their primary colorectal tumors, suggesting that it mi... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5310545 Thu, 13 Oct 2011 08:41:05 +0100 5310545 http://www.medworm.com/index.php?rid=5281240&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F59353 Mutations in human SLC26A4 are a common cause of hearing loss associated with enlarged vestibular aqueducts (EVA). SLC26A4 encodes pendrin, an anion-base exchanger expressed in inner ear epithelial cells that secretes HCO3– into endolymph. Studies of Slc26a4-null mice indicate that pendrin is essential for inner ear development, but have not revealed whether pendrin is specifically necessary for homeostasis. Slc26a4-null mice are profoundly deaf, with severe inner ear malformations and degenerative changes that do not model the less severe human phenotype. Here, we describe studies in which we generated a binary transgenic mouse line in which Slc26a4 expression could be induced with doxycycline. The transgenes were crossed onto the Slc26a4-null background so that all functional pen... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5281240 Tue, 04 Oct 2011 06:40:31 +0100 5281240 http://www.medworm.com/index.php?rid=5281239&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F59320 Peripheral nerves are easily damaged, resulting in loss of motor and sensory function. Recovery of motor and sensory function after peripheral nerve injury is suboptimal, even after appropriate surgical repair. This is due to the slow rate of axonal elongation during regeneration and atrophic changes that occur in denervated Schwann cells and target muscle with proximal lesions. One way to solve this problem is to accelerate the rate at which the axons regenerate. In this issue of the JCI, Ma and colleagues show that this can be achieved in mice by overexpression of heat shock protein 27, providing hope for enhanced functional recovery in patients after peripheral nerve damage. (Source: Journal of Clinical Investigation) Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5281239 Tue, 04 Oct 2011 06:40:31 +0100 5281239 http://www.medworm.com/index.php?rid=5281238&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F59041 Mutations in human FYVE, RhoGEF, and PH domain–containing 1 (FGD1) cause faciogenital dysplasia (FGDY; also known as Aarskog syndrome), an X-linked disorder that affects multiple skeletal structures. FGD1 encodes a guanine nucleotide exchange factor (GEF) that specifically activates the Rho GTPase CDC42. However, the mechanisms by which mutations in FGD1 affect skeletal development are unknown. Here, we describe what we believe to be a novel signaling pathway in osteoblasts initiated by FGD1 that involves the MAP3K mixed-lineage kinase 3 (MLK3). We observed that MLK3 functions downstream of FGD1 to regulate ERK and p38 MAPK, which in turn phosphorylate and activate the master regulator of osteoblast differentiation, Runx2. Mutations in FGD1 found in individuals with FGDY ablated it... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5281238 Tue, 04 Oct 2011 06:40:31 +0100 5281238 http://www.medworm.com/index.php?rid=5281237&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F58675 Although peripheral nerves can regenerate after injury, proximal nerve injury in humans results in minimal restoration of motor function. One possible explanation for this is that injury-induced axonal growth is too slow. Heat shock protein 27 (Hsp27) is a regeneration-associated protein that accelerates axonal growth in vitro. Here, we have shown that it can also do this in mice after peripheral nerve injury. While rapid motor and sensory recovery occurred in mice after a sciatic nerve crush injury, there was little return of motor function after sciatic nerve transection, because of the delay in motor axons reaching their target. This was not due to a failure of axonal growth, because injured motor axons eventually fully re-extended into muscles and sensory function returned; rather, it ... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5281237 Tue, 04 Oct 2011 06:40:31 +0100 5281237 http://www.medworm.com/index.php?rid=5281236&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F58653 CD8+ T cells are a key component of the adaptive immune response to viral infection. An inadequate CD8+ T cell response is thought to be partly responsible for the persistent chronic infection that arises following infection with HIV. It is therefore critical to identify ways to define what constitutes an adequate or inadequate response. IFN-γ production has been used as a measure of T cell function, but the relationship between cytokine production and the ability of a cell to lyse virus-infected cells is not clear. Moreover, the ability to assess multiple CD8+ T cell functions with single-cell resolution using freshly isolated blood samples, and subsequently to recover these cells for further functional analyses, has not been achieved. As described here, to address this need, we h... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5281236 Tue, 04 Oct 2011 06:40:31 +0100 5281236 http://www.medworm.com/index.php?rid=5281235&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F58509 Loss of cellular polarity is a hallmark of epithelial cancers, raising the possibility that regulators of polarity have a role in suppressing tumorigenesis. The Scribble complex is one of at least three interacting protein complexes that have a critical role in establishing and maintaining epithelial polarity. In human colorectal, breast, and endometrial cancers, expression of the Scribble complex member SCRIB is often mislocalized and deregulated. Here, we report that Scrib is indispensable for prostate homeostasis in mice. Scrib heterozygosity initiated prostate hyperplasia, while targeted biallelic Scrib loss predisposed mice to prostate intraepithelial neoplasia. Mechanistically, Scrib was shown to negatively regulate the MAPK cascade to suppress tumorigenesis. Further analysis reveale... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5281235 Tue, 04 Oct 2011 06:40:31 +0100 5281235 http://www.medworm.com/index.php?rid=5281234&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F57456 Tregs not only keep immune responses to autoantigens in check, but also restrain those directed toward pathogens and the commensal microbiota. Control of peripheral immune homeostasis by Tregs relies on their capacity to accumulate at inflamed sites and appropriately adapt to their local environment. To date, the factors involved in the control of these aspects of Treg physiology remain poorly understood. Here, we show that the canonical Th2 transcription factor GATA3 is selectively expressed in Tregs residing in barrier sites including the gastrointestinal tract and the skin. GATA3 expression in both murine and human Tregs was induced upon TCR and IL-2 stimulation. Although GATA3 was not required to sustain Treg homeostasis and function at steady state, GATA3 played a cardinal role in Tre... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5281234 Tue, 04 Oct 2011 06:40:31 +0100 5281234 http://www.medworm.com/index.php?rid=5281233&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F46279 Stroke is the third leading cause of death in the United States. Fewer than 5% of patients benefit from the only intervention approved to treat stroke. Thus, there is an enormous need to identify new therapeutic targets. The role of inducible cyclooxygenase (COX-2) activity in stroke and other neurologic diseases is complex, as both activation and sustained inhibition can engender cerebral injury. Whether COX-2 induces cerebroprotective or injurious effects is probably dependent on which downstream prostaglandin receptors are activated. Here, we investigated the function of the PGE2 receptor EP4 in a mouse model of cerebral ischemia. Systemic administration of a selective EP4 agonist after ischemia reduced infarct volume and ameliorated long-term behavioral deficits. Expression of EP4 was ... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5281233 Tue, 04 Oct 2011 06:40:31 +0100 5281233 http://www.medworm.com/index.php?rid=5281232&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F46243 Insulin resistance is a major risk factor for type 2 diabetes mellitus. The protein encoded by the sirtuin 1 (Sirt1) gene, which is a mouse homolog of yeast Sir2, is implicated in the regulation of glucose metabolism and insulin sensitivity; however, the underlying mechanism remains elusive. Here, using mice with a liver-specific null mutation of Sirt1, we have identified a signaling pathway involving Sirt1, Rictor (a component of mTOR complex 2 [mTorc2]), Akt, and Foxo1 that regulates gluconeogenesis. We found that Sirt1 positively regulates transcription of the gene encoding Rictor, triggering a cascade of phosphorylation of Akt at S473 and Foxo1 at S253 and resulting in decreased transcription of the gluconeogenic genes glucose-6-phosphatase (G6pase) and phosphoenolpyruvate carboxykinas... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5281232 Tue, 04 Oct 2011 06:40:31 +0100 5281232 http://www.medworm.com/index.php?rid=5281231&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F38760 The growth arrest and DNA damage–inducible 45 (Gadd45) proteins act in many cellular processes. In the liver, Gadd45b (encoding Gadd45β) is the gene most strongly induced early during both compensatory regeneration and drug-induced hyperplasia. The latter response is associated with the dramatic and rapid hepatocyte growth that follows administration of the xenobiotic TCPOBOP (1,4-bis[2-(3,5)-dichoropyridyloxy] benzene), a ligand of the nuclear receptor constitutive androstane receptor (CAR). Here, we have shown that Gadd45b–/– mice have intact proliferative responses following administration of a single dose of TCPOBOP, but marked growth delays. Moreover, early transcriptional stimulation of CAR target genes was weaker in Gadd45b–/– mice tha... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5281231 Tue, 04 Oct 2011 06:40:31 +0100 5281231 http://www.medworm.com/index.php?rid=5257134&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F60457 Atherosclerosis is a chronic inflammatory disease of the arterial walls that often leads to myocardial infarction and/or stroke. Hypercholesterolemia and an imbalance of peripheral leukocyte counts, leading to arterial leukocyte infiltration, are considered independent risk factors for atherosclerosis. However, in this issue of the JCI, Murphy and colleagues identify a mechanistic link between hypercholesterolemia, leukocytosis, and the subsequent development of atherosclerotic lesions in mice. These findings could pave the way for the development of novel treatment strategies to control leukocyte homeostasis and atherosclerosis. (Source: Journal of Clinical Investigation) Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5257134 Tue, 27 Sep 2011 00:06:15 +0100 5257134 http://www.medworm.com/index.php?rid=5257133&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F60005 Medulloblastoma is the most common malignant brain tumor in children. Overall survival rates have improved in recent years as a result of risk-stratified treatment regimens. However, medulloblastoma remains associated with substantial mortality, and survivors often experience debilitating neurological, endocrinological, and social sequelae as a result of treatment. Targeted and less toxic therapeutic strategies are therefore needed. In this issue of the JCI, Baryawno et al. report their findings that a large percentage of primary medulloblastomas and medulloblastoma cell lines are infected with human cytomegalovirus (HCMV) and suggest that targeting this virus could provide a new way to treat individuals with medulloblastoma. (Source: Journal of Clinical Investigation) Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5257133 Tue, 27 Sep 2011 00:06:15 +0100 5257133 http://www.medworm.com/index.php?rid=5257132&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F60003 In the 18th century, Thomas Bayes developed his eponymous theorem that teaches us that pretest probabilities can be altered by new information, such as when game show host Monty Hall revealed the goat behind one of the remaining doors in “Let’s Make A Deal.” Bayesian analysis is a key feature of many medical decisions. In this issue of the JCI, Lee and colleagues apply this concept to inflammatory bowel disease to identify gene expression–based biomarkers of disease severity. Importantly, these biomarkers allowed patients to be stratified into two groups: those at high risk for disease recurrence or the need for immunosuppressive treatment escalation and those with a more benign disease course. (Source: Journal of Clinical Investigation) Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5257132 Tue, 27 Sep 2011 00:06:15 +0100 5257132 http://www.medworm.com/index.php?rid=5257131&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F60002 Deciphering the complexities of human β cell physiology is critical to our understanding of the pathophysiology behind both type 1 and type 2 diabetes. One way to do this is to study individuals with congenital hyperinsulinism (CHI), a rare genetic disease characterized by dysregulation of insulin secretion resulting in hypoglycemia. In this issue of the JCI, Henquin et al. report in vitro studies of pancreatic tissue obtained from CHI patients during therapeutic pancreatectomy that have yielded exciting new insights into human β cell physiology. The data validate and extend observations made in model organisms. (Source: Journal of Clinical Investigation) Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5257131 Tue, 27 Sep 2011 00:06:15 +0100 5257131 http://www.medworm.com/index.php?rid=5257130&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F59763 Oculocutaneous albinism (OCA) is a group of genetic disorders characterized by hypopigmentation of the skin, hair, and eyes. Affected individuals experience reduced visual acuity and substantially increased skin cancer risk. There are four major types of OCA (OCA1–OCA4) that result from disruption in production of melanin from tyrosine. Current treatment options for individuals with OCA are limited to attempts to correct visual problems and counseling to promote use of sun protective measures. However, Onojafe et al., reporting in this issue of the JCI, provide hope for a new treatment approach for OCA, as they demonstrate that treating mice that model OCA-1b with nitisinone, which is FDA approved for treating hereditary tyrosinemia type 1, elevates plasma tyrosine levels, and incr... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=5257130 Tue, 27 Sep 2011 00:06:15 +0100 5257130