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. Sat, 20 Mar 2010 16:02:51 +0100 http://www.medworm.com/index.php?rid=3321630&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F39901C1 (Source: Journal of Clinical Investigation) Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3321630 Tue, 02 Mar 2010 17:25:43 +0100 3321630 http://www.medworm.com/index.php?rid=3321629&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F37672E1 (Source: Journal of Clinical Investigation) Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3321629 Tue, 02 Mar 2010 17:25:43 +0100 3321629 http://www.medworm.com/index.php?rid=3321628&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F37284C1 (Source: Journal of Clinical Investigation) Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3321628 Tue, 02 Mar 2010 17:25:43 +0100 3321628 http://www.medworm.com/index.php?rid=3321627&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F40094 A paucity of versatile small animal models of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection has been an impediment to both furthering understanding of virus biology and testing antiviral therapies. We recently described a regulatable system for repopulating the liver of immunodeficient mice (specifically mice lacking fumaryl acetoacetate hydrolase [Fah], recombination activating gene 2 [Rag2], and the γ-chain of the receptor for IL-2 [Il-2rγ]) with human hepatocytes. Here we have shown that a high transplantation dose (3 × 106 to 5 × 106 human hepatocytes/mouse) generates a higher rate of liver chimerism than was previously obtained in these mice, up to 95% human hepatocyte chimerism. Mice with a high level of human liver chimerism propagated... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3321627 Tue, 02 Mar 2010 17:25:43 +0100 3321627 http://www.medworm.com/index.php?rid=3321626&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F40645 The chemokines are a large family of mainly secreted molecules involved in the regulation of numerous physiological and pathophysiological processes. Despite many years of investigation, the precise cellular sources of most chemokines have remained incompletely defined as a consequence of the limited availability of suitable reagents to visualize the expression of chemokine proteins at the single-cell level. Here, we developed a simple flow cytometry–based assay using commercially available chemokine-specific antibodies for efficient cell-associated detection of 37 of 39 murine chemokines. To demonstrate the utility of this methodology, we used it to reevaluate the nature of homeostatic chemokines in the hematopoietic compartment, to delineate the complete chemokine profiles of NK ... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3321626 Tue, 02 Mar 2010 17:25:43 +0100 3321626 http://www.medworm.com/index.php?rid=3321625&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F40104 Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that induces in humans a disease characterized by fever, rash, and pain in muscles and joints. The recent emergence or reemergence of CHIKV in the Indian Ocean Islands and India has stressed the need to better understand the pathogenesis of this disease. Previous CHIKV disease models have used young or immunodeficient mice, but these do not recapitulate human disease patterns and are unsuitable for testing immune-based therapies. Herein, we describe what we believe to be a new model for CHIKV infection in adult, immunocompetent cynomolgus macaques. CHIKV infection in these animals recapitulated the viral, clinical, and pathological features observed in human disease. In the macaques, long-term CHIKV infection was observed in joints, ... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3321625 Tue, 02 Mar 2010 17:25:43 +0100 3321625 http://www.medworm.com/index.php?rid=3321624&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F40926 Tregs play an important role in protecting the skin from autoimmune attack. However, the extent of Treg trafficking between the skin and draining lymph nodes (DLNs) is unknown. We set out to investigate this using mice engineered to express the photoconvertible fluorescence protein Kaede, which changes from green to red when exposed to violet light. By exposing the skin of Kaede-transgenic mice to violet light, we were able to label T cells in the periphery under physiological conditions with Kaede-red and demonstrated that both memory phenotype CD4+Foxp3– non-Tregs and CD4+Foxp3+ Tregs migrated from the skin to DLNs in the steady state. During cutaneous immune responses, Tregs constituted the major emigrants and inhibited immune responses more robustly than did LN-resident Tregs. ... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3321624 Tue, 02 Mar 2010 17:25:43 +0100 3321624 http://www.medworm.com/index.php?rid=3321623&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F41440 The human epidermis serves 2 crucial barrier functions: it protects against water loss and prevents penetration of infectious agents and allergens. The physiology of the epidermis is maintained by a balance of protease and antiprotease activities, as illustrated by the rare genetic skin disease Netherton syndrome (NS), in which impaired inhibition of serine proteases causes severe skin erythema and scaling. Here, utilizing mass spectrometry, we have identified elastase 2 (ELA2), which we believe to be a new epidermal protease that is specifically expressed in the most differentiated layer of living human and mouse epidermis. ELA2 localized to keratohyalin granules, where it was found to directly participate in (pro-)filaggrin processing. Consistent with the observation that ELA2 was hypera... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3321623 Tue, 02 Mar 2010 17:25:43 +0100 3321623 http://www.medworm.com/index.php?rid=3321622&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F41443 Neurofibromatosis type 1 (NF1) results from mutations in the NF1 tumor suppressor gene, which encodes the protein neurofibromin. NF1 patients display diverse clinical manifestations, including vascular disease, which results from neointima formation and vessel occlusion. However, the pathogenesis of NF1 vascular disease remains unclear. Vessel wall homeostasis is maintained by complex interactions between vascular and bone marrow–derived cells (BMDCs), and neurofibromin regulates the function of each cell type. Therefore, utilizing cre/lox techniques and hematopoietic stem cell transplantation to delete 1 allele of Nf1 in endothelial cells, vascular smooth muscle cells, and BMDCs alone, we determined which cell lineage is critical for neointima formation in vivo in mice. Here we de... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3321622 Tue, 02 Mar 2010 17:25:43 +0100 3321622 http://www.medworm.com/index.php?rid=3321621&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F41013 Tropomyosin-related kinase receptor C (TrkC) is a neurotrophin receptor with tyrosine kinase activity that was expected to be oncogenic. However, it has several characteristics of a tumor suppressor: its expression in tumors has often been associated with good prognosis; and it was recently demonstrated to be a dependence receptor, transducing different positive signals in the presence of ligand but inducing apoptosis in the absence of ligand. Here we show that the TrkC ligand neurotrophin-3 (NT-3) is upregulated in a large fraction of aggressive human neuroblastomas (NBs) and that it blocks TrkC-induced apoptosis of human NB cell lines, consistent with the idea that TrkC is a dependence receptor. Functionally, both siRNA knockdown of NT-3 expression and incubation with a TrkC-specific blo... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3321621 Tue, 02 Mar 2010 17:25:43 +0100 3321621 http://www.medworm.com/index.php?rid=3321620&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F40728 Transformation of epithelial cells is associated with loss of cell polarity, which includes alterations in cell morphology as well as changes in the complement of plasma membrane proteins. Rab proteins regulate polarized trafficking to the cell membrane and therefore represent potential regulators of this neoplastic transition. Here we have demonstrated a tumor suppressor function for Rab25 in intestinal neoplasia in both mice and humans. Human colorectal adenocarcinomas exhibited reductions in Rab25 expression independent of stage, with lower Rab25 expression levels correlating with substantially shorter patient survival. In wild-type mice, Rab25 was strongly expressed in cells luminal to the proliferating cells of intestinal crypts. While Rab25-deficient mice did not exhibit gross pathol... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3321620 Tue, 02 Mar 2010 17:25:43 +0100 3321620 http://www.medworm.com/index.php?rid=3321619&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F36362 Mutation of the von Hippel–Lindau (VHL) tumor suppressor protein at codon 200 (R200W) is associated with a disease known as Chuvash polycythemia. In addition to polycythemia, Chuvash patients have pulmonary hypertension and increased respiratory rates, although the pathophysiological basis of these symptoms is unclear. Here we sought to address this issue by studying mice homozygous for the R200W Vhl mutation (VhlR/R mice) as a model for Chuvash disease. These mice developed pulmonary hypertension independently of polycythemia and enhanced normoxic respiration similar to Chuvash patients, further validating VhlR/R mice as a model for Chuvash disease. Lungs from VhlR/R mice exhibited pulmonary vascular remodeling, hemorrhage, edema, and macrophage infiltration, and lungs from older ... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3321619 Tue, 02 Mar 2010 17:25:43 +0100 3321619 http://www.medworm.com/index.php?rid=3321618&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F40736 Signaling via the neuronal NOS (nNOS) splice variant nNOSμ is essential for skeletal muscle health and is commonly reduced in neuromuscular disease. nNOSμ is thought to be the predominant source of NO in skeletal muscle. Here we demonstrate the existence of what we believe to be a novel signaling pathway, mediated by the nNOS splice variant nNOSβ, localized at the Golgi complex in mouse skeletal muscle cells. In contrast to muscles lacking nNOSμ alone, muscles missing both nNOSμ and nNOSβ were severely myopathic, exhibiting structural defects in the microtubule cytoskeleton, Golgi complex, and mitochondria. Skeletal muscles lacking both nNOSμ and nNOSβ were smaller in mass, intrinsically weak, highly susceptible to fatigue, an... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3321618 Tue, 02 Mar 2010 17:25:43 +0100 3321618 http://www.medworm.com/index.php?rid=3321617&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F40051 Many signaling pathways that contribute to tumorigenesis are also functional in pregnancy, although they are dysregulated in the former and tightly regulated in the latter. Transformation-related protein 53 (Trp53), which encodes p53, is a tumor suppressor gene whose mutation is strongly associated with cancer. However, its role in normal physiological processes, including female reproduction, is poorly understood. Mice that have a constitutive deletion of Trp53 exhibit widespread development of carcinogenesis at early reproductive ages, compromised spermatogenesis, and fetal exencephaly, rendering them less amenable to studying the role of p53 in reproduction. To overcome this obstacle, we generated mice that harbor a conditional deletion of uterine Trp53 and examined pregnancy outcome in... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3321617 Tue, 02 Mar 2010 17:25:43 +0100 3321617 http://www.medworm.com/index.php?rid=3321616&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F40076 The autosomal recessive kidney disease nephronophthisis (NPHP) constitutes the most frequent genetic cause of terminal renal failure in the first 3 decades of life. Ten causative genes (NPHP1–NPHP9 and NPHP11), whose products localize to the primary cilia-centrosome complex, support the unifying concept that cystic kidney diseases are “ciliopathies”. Using genome-wide homozygosity mapping, we report here what we believe to be a new locus (NPHP-like 1 [NPHPL1]) for an NPHP-like nephropathy. In 2 families with an NPHP-like phenotype, we detected homozygous frameshift and splice-site mutations, respectively, in the X-prolyl aminopeptidase 3 (XPNPEP3) gene. In contrast to all known NPHP proteins, XPNPEP3 localizes to mitochondria of renal cells. However, in vivo analyse... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3321616 Tue, 02 Mar 2010 17:25:43 +0100 3321616 http://www.medworm.com/index.php?rid=3321615&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F41619 The receptor tyrosine kinase ret protooncogene (RET) is implicated in the pathogenesis of several diseases and in several developmental defects, particularly those in neural crest–derived structures and the genitourinary system. In order to further elucidate RET-mediated mechanisms that contribute to these diseases and decipher the basis for specificity in the pleiotropic effects of RET, we characterized development of the enteric and autonomic nervous systems in mice expressing RET9 or RET51 isoforms harboring mutations in tyrosine residues that act as docking sites for the adaptors Plcγ, Src, Shc, and Grb2. Using this approach, we found that development of the genitourinary system and the enteric and autonomic nervous systems is dependent on distinct RET-stimulated signal... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3321615 Tue, 02 Mar 2010 17:25:43 +0100 3321615 http://www.medworm.com/index.php?rid=3321614&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F39569 The glomerular basement membrane (GBM) is a key component of the filtering unit in the kidney. Mutations involving any of the collagen IV genes (COL4A3, COL4A4, and COL4A5) affect GBM assembly and cause Alport syndrome, a progressive hereditary kidney disease with no definitive therapy. Previously, we have demonstrated that the bone morphogenetic protein (BMP) antagonist uterine sensitization–associated gene-1 (USAG-1) negatively regulates the renoprotective action of BMP-7 in a mouse model of tubular injury during acute renal failure. Here, we investigated the role of USAG-1 in renal function in Col4a3–/– mice, which model Alport syndrome. Ablation of Usag1 in Col4a3–/– mice led to substantial attenuation of disease progression, normalization of GBM... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3321614 Tue, 02 Mar 2010 17:25:43 +0100 3321614 http://www.medworm.com/index.php?rid=3321613&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F36066 Diet-induced obesity (DIO) leads to inflammatory activation of macrophages in white adipose tissue (WAT) and subsequently to insulin resistance. PPARγ agonists are antidiabetic agents known to suppress inflammatory macrophage activation and to induce expression of the triacylglycerol (TG) synthesis enzyme acyl CoA:diacylglycerol acyltransferase 1 (DGAT1) in WAT and in adipocytes. Here, we investigated in mice the relationship between macrophage lipid storage capacity and DIO-associated inflammatory macrophage activation. Mice overexpressing DGAT1 in both macrophages and adipocytes (referred to herein as aP2-Dgat1 mice) were more prone to DIO but were protected against inflammatory macrophage activation, macrophage accumulation in WAT, systemic inflammation, and insulin resistance. ... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3321613 Tue, 02 Mar 2010 17:25:43 +0100 3321613 http://www.medworm.com/index.php?rid=3321612&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F39678 Wolfram syndrome is an autosomal-recessive disorder characterized by insulin-dependent diabetes mellitus, caused by nonautoimmune loss of β cells, and neurological dysfunctions. We have previously shown that mutations in the Wolfram syndrome 1 (WFS1) gene cause Wolfram syndrome and that WFS1 has a protective function against ER stress. However, it remained to be determined how WFS1 mitigates ER stress. Here we have shown in rodent and human cell lines that WFS1 negatively regulates a key transcription factor involved in ER stress signaling, activating transcription factor 6α (ATF6α), through the ubiquitin-proteasome pathway. WFS1 suppressed expression of ATF6α target genes and repressed ATF6α-mediated activation of the ER stress response element (ERS... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3321612 Tue, 02 Mar 2010 17:25:43 +0100 3321612 http://www.medworm.com/index.php?rid=3321611&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F41360 Islet transplantation for the treatment of type 1 diabetes mellitus is limited in its clinical application mainly due to early loss of the transplanted islets, resulting in low transplantation efficiency. NKT cell–dependent IFN-γ production by Gr-1+CD11b+ cells is essential for this loss, but the upstream events in the process remain undetermined. Here, we have demonstrated that high-mobility group box 1 (HMGB1) plays a crucial role in the initial events of early loss of transplanted islets in a mouse model of diabetes. Pancreatic islets contained abundant HMGB1, which was released into the circulation soon after islet transplantation into the liver. Treatment with an HMGB1-specific antibody prevented the early islet graft loss and inhibited IFN-γ production by NKT ... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3321611 Tue, 02 Mar 2010 17:25:43 +0100 3321611 http://www.medworm.com/index.php?rid=3321610&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F39620 Protein tyrosine phosphatase 1B (PTP1B) and SH2 domain–containing protein tyrosine phosphatase–2 (SHP2) have been shown in mice to regulate metabolism via the central nervous system, but the specific neurons mediating these effects are unknown. Here, we have shown that proopiomelanocortin (POMC) neuron–specific deficiency in PTP1B or SHP2 in mice results in reciprocal effects on weight gain, adiposity, and energy balance induced by high-fat diet. Mice with POMC neuron–specific deletion of the gene encoding PTP1B (referred to herein as POMC-Ptp1b–/– mice) had reduced adiposity, improved leptin sensitivity, and increased energy expenditure compared with wild-type mice, whereas mice with POMC neuron–specific deletion of the gene encoding... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3321610 Tue, 02 Mar 2010 17:25:43 +0100 3321610 http://www.medworm.com/index.php?rid=3321609&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F41366 Narcolepsy is a sleep disorder characterized by excessive daytime sleepiness and attacks of muscle atonia triggered by strong emotions (cataplexy). Narcolepsy is caused by hypocretin (orexin) deficiency, paralleled by a dramatic loss in hypothalamic hypocretin-producing neurons. It is believed that narcolepsy is an autoimmune disorder, although definitive proof of this, such as the presence of autoantibodies, is still lacking. We engineered a transgenic mouse model to identify peptides enriched within hypocretin-producing neurons that could serve as potential autoimmune targets. Initial analysis indicated that the transcript encoding Tribbles homolog 2 (Trib2), previously identified as an autoantigen in autoimmune uveitis, was enriched in hypocretin neurons in these mice. ELISA analysis sh... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3321609 Tue, 02 Mar 2010 17:25:43 +0100 3321609 http://www.medworm.com/index.php?rid=3321608&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F31474 Urolithiasis, a condition in which stones are present in the urinary system, including the kidneys and bladder, is a poorly understood yet common disorder worldwide that leads to significant health care costs, morbidity, and work loss. Acetaminophen-induced liver damage is a major cause of death in patients with acute liver failure. Kidney and urinary stones and liver toxicity are disturbances linked to alterations in oxalate and sulfate homeostasis, respectively. The sulfate anion transporter–1 (Sat1; also known as Slc26a1) mediates epithelial transport of oxalate and sulfate, and its localization in the kidney, liver, and intestine suggests that it may play a role in oxalate and sulfate homeostasis. To determine the physiological roles of Sat1, we created Sat1–/– ... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3321608 Tue, 02 Mar 2010 17:25:43 +0100 3321608 http://www.medworm.com/index.php?rid=3321607&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F40283 Despite the high doses of radiation delivered in the treatment of patients with glioblastoma multiforme (GBM), the tumors invariably recur within the irradiation field, resulting in a low cure rate. Understanding the mechanism of such recurrence is therefore important. Here we have shown in an intracranial GBM xenograft model that irradiation induces recruitment of bone marrow–derived cells (BMDCs) into the tumors, restoring the radiation-damaged vasculature by vasculogenesis and thereby allowing the growth of surviving tumor cells. BMDC influx was initiated by induction of HIF-1 in the irradiated tumors, and blocking this influx prevented tumor recurrence. Previous studies have indicated that BMDCs are recruited to tumors in part through the interaction between the HIF-1–d... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3321607 Tue, 02 Mar 2010 17:25:43 +0100 3321607 http://www.medworm.com/index.php?rid=3321606&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F40535 Irreversible cell growth arrest, a process termed cellular senescence, is emerging as an intrinsic tumor suppressive mechanism. Oncogene-induced senescence is thought to be invariably preceded by hyperproliferation, aberrant replication, and activation of a DNA damage checkpoint response (DDR), rendering therapeutic enhancement of this process unsuitable for cancer treatment. We previously demonstrated in a mouse model of prostate cancer that inactivation of the tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (Pten) elicits a senescence response that opposes tumorigenesis. Here, we show that Pten-loss–induced cellular senescence (PICS) represents a senescence response that is distinct from oncogene-induced senescence and can be targeted for cancer therapy. ... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3321606 Tue, 02 Mar 2010 17:25:43 +0100 3321606 http://www.medworm.com/index.php?rid=3321605&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F36667 Ewing sarcoma (EWS) is an aggressive bone tumor of uncertain cellular origin. CD99 is a membrane protein that is expressed in most cases of EWS, although its function in the disease is unknown. Here we have shown that endogenous CD99 expression modulates EWS tumor differentiation and malignancy. We determined that knocking down CD99 expression in human EWS cell lines reduced their ability to form tumors and bone metastases when xenografted into immunodeficient mice and diminished their tumorigenic characteristics in vitro. Further, reduction of CD99 expression resulted in neurite outgrowth and increased expression of β-III tubulin and markers of neural differentiation. Analysis of a panel of human EWS cells revealed an inverse correlation between CD99 and H-neurofilament expression... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3321605 Tue, 02 Mar 2010 17:25:43 +0100 3321605 http://www.medworm.com/index.php?rid=3321604&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F42345 The cellular and molecular events that initiate and promote malignant glioma development are not completely understood. The treatment modalities designed to promote its demise are all ultimately ineffective, leading to disease progression. In this issue of the JCI, Kioi et al. demonstrate that vasculogenesis and angiogenesis potentially play distinct roles in the etiology of primary and recurrent malignant gliomas, suggesting that patient therapy should perhaps be tailored specifically against the predominant vasculature pathway at a given specific stage of gliomagenesis. (Source: Journal of Clinical Investigation) Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3321604 Tue, 02 Mar 2010 17:25:43 +0100 3321604 http://www.medworm.com/index.php?rid=3321603&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F42378 While erudite cell biologists have for many decades described singular immotile appendages known as primary cilia to be present on most cells in our bodies, cilial function(s) long remained an enigma. Driven largely by an ever increasing number of discoveries of genetic defects in primary cilia during the past decade, cilia were catapulted from a long lasting existence in obscurity into the bright spotlight in cell biology and medicine. The study by O’Toole et al. in this issue of the JCI adds a novel “enzymatic” facet to the rapidly growing information about these little cellular tails, by demonstrating that defects in the XPNPEP3 gene, which encodes mitochondrial and cytosolic splice variants of X-prolyl aminopeptidase 3, can cause nephronophthisis-like ciliopathy... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3321603 Tue, 02 Mar 2010 17:25:43 +0100 3321603 http://www.medworm.com/index.php?rid=3321602&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F42392 Chikungunya disease is a severely debilitating, mosquito-borne, viral illness that has reached epidemic proportions in Africa, Asia, and the islands of the Indian Ocean. A mutation enhancing the ability of the chikungunya virus (CHIKV) to infect and be transmitted by Aedes albopictus has increased the geographical range at risk for infection due to the continuing global spread of this mosquito. Research into disease pathogenesis, vaccine development, and therapeutic design has been hindered by the lack of appropriate animal models of this disease. The meticulous study reported in this issue of the JCI by Labadie et al. is one of the first reports describing CHIKV infection of adult immunocompetent nonhuman primates. Using traditional and modern molecular and immunological approaches, the a... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3321602 Tue, 02 Mar 2010 17:25:43 +0100 3321602 http://www.medworm.com/index.php?rid=3321601&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F42280 Although several homing receptors are known to be differentially expressed by Tregs in lymphoid tissues compared with those found in peripheral tissues, it remains unclear whether these cells traffic between the two locations. In this issue of the JCI, Tomura et al. report steady-state Treg migration from the skin to draining LNs in mice. Furthermore, they report that not only does skin inflammation exacerbate LN-directed Treg homing, it also triggers reverse circulation of Tregs from LNs to skin, whereby these cells contribute to regulation of the immune response. These results now form a new framework for our understanding of Treg homing. (Source: Journal of Clinical Investigation) Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3321601 Tue, 02 Mar 2010 17:25:43 +0100 3321601 http://www.medworm.com/index.php?rid=3321600&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F42338 The liver serves as a target organ for several important pathogens, including hepatitis B and C viruses (HBV and HCV, respectively) and the human malaria parasites, all of which represent serious global health problems. Because these pathogens are restricted to human hepatocytes, research in small animals has been compromised by the frailty of the current mouse xenotransplantation models. In this issue of the JCI, Bissig et al. demonstrate robust HBV and HCV infection in a novel xenotransplantation model in which large numbers of immunodeficient mice with liver injury were engrafted with significant quantities of human hepatocytes. This technical advance paves the way for more widespread use of human liver chimeric mice and forms the basis for creating increasingly complex humanized mouse ... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3321600 Tue, 02 Mar 2010 17:25:43 +0100 3321600 http://www.medworm.com/index.php?rid=3321599&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F42104 (Source: Journal of Clinical Investigation) Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3321599 Tue, 02 Mar 2010 17:25:43 +0100 3321599 http://www.medworm.com/index.php?rid=3321598&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F42025 (Source: Journal of Clinical Investigation) Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3321598 Tue, 02 Mar 2010 17:25:43 +0100 3321598 http://www.medworm.com/index.php?rid=3321597&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F42436 (Source: Journal of Clinical Investigation) Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3321597 Tue, 02 Mar 2010 17:25:43 +0100 3321597 http://www.medworm.com/index.php?rid=3230790&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F39845C1 (Source: Journal of Clinical Investigation) Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3230790 Tue, 02 Feb 2010 16:14:14 +0100 3230790 http://www.medworm.com/index.php?rid=3230789&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F38543C1 (Source: Journal of Clinical Investigation) Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3230789 Tue, 02 Feb 2010 16:14:14 +0100 3230789 http://www.medworm.com/index.php?rid=3230788&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F40724 Intratumor genetic heterogeneity is a key mechanism underlying tumor progression and therapeutic resistance. The prevailing model for explaining intratumor diversity, the clonal evolution model, has recently been challenged by proponents of the cancer stem cell hypothesis. To investigate this issue, we performed combined analyses of markers associated with cellular differentiation states and genotypic alterations in human breast carcinomas and evaluated diversity with ecological and evolutionary methods. Our analyses showed a high degree of genetic heterogeneity both within and between distinct tumor cell populations that were defined based on markers of cellular phenotypes including stem cell–like characteristics. In several tumors, stem cell–like and more-differentiated c... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3230788 Tue, 02 Feb 2010 16:14:14 +0100 3230788 http://www.medworm.com/index.php?rid=3230787&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F39843 In this study, we tested this hypothesis in an experimental SCD mouse model and found that statin therapy prolonged survival following pneumococcal challenge. The protective effect resulted in part from decreased platelet-activating factor receptor expression on endothelia and epithelia, which led to reduced bacterial invasion. An additional protective effect resulted from inhibition of host cell lysis by pneumococcal cholesterol-dependent cytotoxins (CDCs), including pneumolysin. We conclude therefore that statins may be of prophylactic benefit against invasive pneumococcal disease in patients with SCD and, more broadly, in settings of bacterial pathogenesis driven by receptor-mediated endocytosis and the CDC class of toxins produced by Gram-positive invasive bacteria. (Source: Journal of... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3230787 Tue, 02 Feb 2010 16:14:14 +0100 3230787 http://www.medworm.com/index.php?rid=3230786&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F40545 In conclusion, conditional expression of I-1c or I-1S67A enhanced steady-state phosphorylation of 2 key Ca2+-regulating sarcoplasmic reticulum enzymes. This was associated with increased contractile function in young animals but also with arrhythmias and cardiomyopathy after adrenergic stress and with aging. These data should be considered in the development of novel therapies for heart failure. (Source: Journal of Clinical Investigation) Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3230786 Tue, 02 Feb 2010 16:14:14 +0100 3230786 http://www.medworm.com/index.php?rid=3230785&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F39293 TLR ligands are promising candidates for the development of novel vaccine adjuvants that can elicit protective immunity against emerging infectious diseases. Adjuvants have been used most frequently to increase the quantity of an immune response. However, the quality of a T cell response can be more important than its quantity. Stimulating certain pairs of TLRs induces a synergistic response in terms of activating dendritic cells and eliciting/enhancing T cell responses through clonal expansion, which increases the number of responding T cells. Here, we have found that utilizing ligands for 3 TLRs (TLR2/6, TLR3, and TLR9) greatly increased the protective efficacy of vaccination with an HIV envelope peptide in mice when compared with using ligands for only any 2 of these TLRs; surprisingly,... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3230785 Tue, 02 Feb 2010 16:14:14 +0100 3230785 http://www.medworm.com/index.php?rid=3230784&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F38030 Mixed-lineage leukemia (MLL) is a proto-oncogene frequently involved in chromosomal translocations associated with acute leukemia. These chromosomal translocations commonly result in MLL fusion proteins that dysregulate transcription. Recent data suggest that the MYB proto-oncogene, which is an important regulator of hematopoietic cell development, has a role in leukemogenesis driven by the MLL-ENL fusion protein, but exactly how is unclear. Here we have demonstrated that c-Myb is recruited to the MLL histone methyl transferase complex by menin, a protein important for MLL-associated leukemic transformation, and that it contributes substantially to MLL-mediated methylation of histone H3 at lysine 4 (H3K4). Silencing MYB in human leukemic cell lines and primary patient material evoked a glo... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3230784 Tue, 02 Feb 2010 16:14:14 +0100 3230784 http://www.medworm.com/index.php?rid=3230783&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F40568 Effective osteoporosis therapy requires agents that increase the amount and/or quality of bone. Any modification of osteoclast-mediated bone resorption by disease or drug treatment, however, elicits a parallel change in osteoblast-mediated bone formation because the processes are tightly coupled. Anabolic approaches now focus on uncoupling osteoblast action from osteoclast formation, for example, by inhibiting sclerostin, an inhibitor of bone formation that does not influence osteoclast differentiation. Here, we report that oncostatin M (OSM) is produced by osteoblasts and osteocytes in mouse bone and that it has distinct effects when acting through 2 different receptors, OSM receptor (OSMR) and leukemia inhibitory factor receptor (LIFR). Specifically, mouse OSM (mOSM) inhibited sclerostin... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3230783 Tue, 02 Feb 2010 16:14:14 +0100 3230783 http://www.medworm.com/index.php?rid=3230782&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F40055 TLRs sense various microbial products. Their function has been best characterized in DCs and macrophages, where they act as important mediators of innate immunity. TLR4 is also expressed on CD4+ T cells, but its physiological function on these cells remains unknown. Here, we have shown that TLR4 triggering on CD4+ T cells affects their phenotype and their ability to provoke intestinal inflammation. In a model of spontaneous colitis, Il10–/–Tlr4–/– mice displayed accelerated development of disease, with signs of overt colitis as early as 8 weeks of age, when compared with Il10–/– and Il10–/–Tlr9–/– mice, which did not develop colitis by 8 months. Similar results were obtained in a second model of colitis in whic... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3230782 Tue, 02 Feb 2010 16:14:14 +0100 3230782 http://www.medworm.com/index.php?rid=3230781&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F40008 TLRs are recognized as promoters of tissue damage, even in the absence of pathogens. TLR binding to damage-associated molecular patterns (DAMPs) released by injured host cells unleashes an inflammatory cascade that amplifies tissue destruction. However, whether TLRs possess the reciprocal ability to curtail the extent of sterile inflammation is uncertain. Here, we investigated this possibility in mice by studying the role of conventional DCs (cDCs) in liver ischemia/reperfusion (I/R) injury, a model of sterile inflammation. Targeted depletion of mouse cDCs increased liver injury after I/R, as assessed by serum alanine aminotransferase and histologic analysis. In vitro, we identified hepatocyte DNA as an endogenous ligand to TLR9 that promoted cDCs to secrete IL-10. In vivo, cDC production ... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3230781 Tue, 02 Feb 2010 16:14:14 +0100 3230781 http://www.medworm.com/index.php?rid=3230780&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F39319 The enzyme sirtuin 1 (SIRT1) is a critical regulator of many cellular functions, including energy metabolism. However, the precise mechanisms that modulate SIRT1 activity remain unknown. As SIRT1 activity in vitro was recently found to be negatively regulated by interaction with the deleted in breast cancer–1 (DBC1) protein, we set out to investigate whether DBC1 regulates SIRT1 activity in vivo. We found that DBC1 and SIRT1 colocalized and interacted, and that DBC1 modulated SIRT1 activity, in multiple cell lines and tissues. In mouse liver, increased SIRT1 activity, concomitant with decreased DBC1-SIRT1 interaction, was detected after 24 hours of starvation, whereas decreased SIRT1 activity and increased interaction with DBC1 was observed with high-fat diet (HFD) feeding. Consist... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3230780 Tue, 02 Feb 2010 16:14:14 +0100 3230780 http://www.medworm.com/index.php?rid=3230779&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F38379 Metastatic disease is responsible for the majority of human cancer deaths. Understanding the molecular mechanisms of metastasis is a major step in designing effective cancer therapeutics. Here we show that the T-box transcription factor Brachyury induces in tumor cells epithelial-mesenchymal transition (EMT), an important step in the progression of primary tumors toward metastasis. Overexpression of Brachyury in human carcinoma cells induced changes characteristic of EMT, including upregulation of mesenchymal markers, downregulation of epithelial markers, and an increase in cell migration and invasion. Brachyury overexpression also repressed E-cadherin transcription, an effect partially mediated by Slug. Conversely, inhibition of Brachyury resulted in downregulation of mesenchymal markers ... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3230779 Tue, 02 Feb 2010 16:14:14 +0100 3230779 http://www.medworm.com/index.php?rid=3230778&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F40706 DNA methyltransferase 1 (DNMT1) catalyzes DNA methylation and is overexpressed in many human diseases, including cancer. The tobacco-specific carcinogen NNK also induces DNA methylation. However, the role of DNMT1-mediated methylation in tobacco carcinogenesis remains unclear. Here we used human and mouse lung cancer samples and cell lines to determine a mechanism whereby NNK induced DNMT1 expression and activity. We determined that in a human lung cell line, glycogen synthase kinase 3β (GSK3β) phosphorylated DNMT1 to recruit β-transducin repeat–containing protein (βTrCP), resulting in DNMT1 degradation, and that NNK activated AKT, inhibiting GSK3β function and thereby attenuating DNMT1 degradation. NNK also induced βTrCP translocatio... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3230778 Tue, 02 Feb 2010 16:14:14 +0100 3230778 http://www.medworm.com/index.php?rid=3230777&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F40045 Cellular plasticity in adult organs is involved in both regeneration and carcinogenesis. WT mouse acinar cells rapidly regenerate following injury that mimics acute pancreatitis, a process characterized by transient reactivation of pathways involved in embryonic pancreatic development. In contrast, such injury promotes the development of pancreatic ductal adenocarcinoma (PDA) precursor lesions in mice expressing a constitutively active form of the GTPase, Kras, in the exocrine pancreas. The molecular environment that mediates acinar regeneration versus the development of PDA precursor lesions is poorly understood. Here, we used genetically engineered mice to demonstrate that mutant Kras promotes acinar-to-ductal metaplasia (ADM) and pancreatic cancer precursor lesion formation by blocking ... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3230777 Tue, 02 Feb 2010 16:14:14 +0100 3230777 http://www.medworm.com/index.php?rid=3230776&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F39447 Disruption of mitotic events contributes greatly to genomic instability and results in mutator phenotypes. Indeed, abnormalities of mitotic components are closely associated with malignant transformation and tumorigenesis. Here we show that ninein-like protein (Nlp), a recently identified BRCA1-associated centrosomal protein involved in microtubule nucleation and spindle formation, is an oncogenic protein. Nlp was found to be overexpressed in approximately 80% of human breast and lung carcinomas analyzed. In human lung cancers, this deregulated expression was associated with NLP gene amplification. Further analysis revealed that Nlp exhibited strong oncogenic properties; for example, it conferred to NIH3T3 rodent fibroblasts the capacity for anchorage-independent growth in vitro and tumor ... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3230776 Tue, 02 Feb 2010 16:14:14 +0100 3230776 http://www.medworm.com/index.php?rid=3230775&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F39397 We report here the development of a strategy to target these breast cancer stem cells (CSCs) through blockade of the IL-8 receptor CXCR1. CXCR1 blockade using either a CXCR1-specific blocking antibody or repertaxin, a small-molecule CXCR1 inhibitor, selectively depleted the CSC population in 2 human breast cancer cell lines in vitro. Furthermore, this was followed by the induction of massive apoptosis in the bulk tumor population via FASL/FAS signaling. The effects of CXCR1 blockade on CSC viability and on FASL production were mediated by the FAK/AKT/FOXO3A pathway. In addition, repertaxin was able to specifically target the CSC population in human breast cancer xenografts, retarding tumor growth and reducing metastasis. Our data therefore suggest that CXCR1 blockade may provide a novel me... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3230775 Tue, 02 Feb 2010 16:14:14 +0100 3230775 http://www.medworm.com/index.php?rid=3230774&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F39434 PDGFR is an important target for novel anticancer therapeutics because it is overexpressed in a wide variety of malignancies. Recently, however, several anticancer drugs that inhibit PDGFR signaling have been associated with clinical heart failure. Understanding this effect of PDGFR inhibitors has been difficult because the role of PDGFR signaling in the heart remains largely unexplored. As described herein, we have found that PDGFR-β expression and activation increase dramatically in the hearts of mice exposed to load-induced cardiac stress. In mice in which Pdgfrb was knocked out in the heart in development or in adulthood, exposure to load-induced stress resulted in cardiac dysfunction and heart failure. Mechanistically, we showed that cardiomyocyte PDGFR-β signaling pla... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3230774 Tue, 02 Feb 2010 16:14:14 +0100 3230774 http://www.medworm.com/index.php?rid=3230773&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F40483 Myeloid-derived suppressor cells (MDSCs) have been identified in humans and mice as a population of immature myeloid cells with the ability to suppress T cell activation. They accumulate in tumor-bearing mice and humans and have been shown to contribute to cancer development. Here, we have isolated tumor-derived exosomes (TDEs) from mouse cell lines and shown that an interaction between TDE-associated Hsp72 and MDSCs determines the suppressive activity of the MDSCs via activation of Stat3. In addition, tumor-derived soluble factors triggered MDSC expansion via activation of Erk. TDE-associated Hsp72 triggered Stat3 activation in MDSCs in a TLR2/MyD88-dependent manner through autocrine production of IL-6. Importantly, decreasing exosome production using dimethyl amiloride enhanced the in vi... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3230773 Tue, 02 Feb 2010 16:14:14 +0100 3230773 http://www.medworm.com/index.php?rid=3230772&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F36478 The Rho family GTPases Cdc42 and Rac1 are critical regulators of the actin cytoskeleton and are essential for skin and hair function. Wiskott-Aldrich syndrome family proteins act downstream of these GTPases, controlling actin assembly and cytoskeletal reorganization, but their role in epithelial cells has not been characterized in vivo. Here, we used a conditional knockout approach to assess the role of neural Wiskott-Aldrich syndrome protein (N-WASP), the ubiquitously expressed Wiskott-Aldrich syndrome–like (WASL) protein, in mouse skin. We found that N-WASP deficiency in mouse skin led to severe alopecia, epidermal hyperproliferation, and ulceration, without obvious effects on epidermal differentiation and wound healing. Further analysis revealed that the observed alopecia was li... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3230772 Tue, 02 Feb 2010 16:14:14 +0100 3230772 http://www.medworm.com/index.php?rid=3230771&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F39733 Cerebral ischemic small vessel disease (SVD) is the leading cause of vascular dementia and a major contributor to stroke in humans. Dominant mutations in NOTCH3 cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a genetic archetype of cerebral ischemic SVD. Progress toward understanding the pathogenesis of this disease and developing effective therapies has been hampered by the lack of a good animal model. Here, we report the development of a mouse model for CADASIL via the introduction of a CADASIL-causing Notch3 point mutation into a large P1-derived artificial chromosome (PAC). In vivo expression of the mutated PAC transgene in the mouse reproduced the endogenous Notch3 expression pattern and main pathological features of CADASIL,... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3230771 Tue, 02 Feb 2010 16:14:14 +0100 3230771 http://www.medworm.com/index.php?rid=3230770&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F38136 Complicated abdominal aortic aneurysm (AAA) is a major cause of mortality in elderly men. Ang II–dependent TGF-β activity promotes aortic aneurysm progression in experimental Marfan syndrome. However, the role of TGF-β in experimental models of AAA has not been comprehensively assessed. Here, we show that systemic neutralization of TGF-β activity breaks the resistance of normocholesterolemic C57BL/6 mice to Ang II–induced AAA formation and markedly increases their susceptibility to the disease. These aneurysms displayed a large spectrum of complications on echography, including fissuration, double channel formation, and rupture, leading to death from aneurysm complications. The disease was refractory to inhibition of IFN-γ, IL-4, IL-6, or TNF... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3230770 Tue, 02 Feb 2010 16:14:14 +0100 3230770 http://www.medworm.com/index.php?rid=3230769&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F39778 Although several cytokines and neurotrophic factors induce sympathetic neurons to transdifferentiate into cholinergic neurons in vitro, the physiological and pathophysiological roles of this remain unknown. During congestive heart failure (CHF), sympathetic neural tone is upregulated, but there is a paradoxical reduction in norepinephrine synthesis and reuptake in the cardiac sympathetic nervous system (SNS). Here we examined whether cholinergic transdifferentiation can occur in the cardiac SNS in rodent models of CHF and investigated the underlying molecular mechanism(s) using genetically modified mice. We used Dahl salt-sensitive rats to model CHF and found that, upon CHF induction, the cardiac SNS clearly acquired cholinergic characteristics. Of the various cholinergic differentiation f... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3230769 Tue, 02 Feb 2010 16:14:14 +0100 3230769 http://www.medworm.com/index.php?rid=3230768&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F42014 TGF-β regulates many aspects of cellular performance relevant to tissue morphogenesis and homeostasis. Postnatal perturbation of TGF-β signaling contributes to the pathogenesis of many disease states, as recently exemplified through the study of Marfan syndrome (MFS), including aortic aneurysm and skeletal muscle myopathy. Heterogeneity in the regulation and consequences of TGF-β signaling, amplified in the context of disease, has engendered confusion and controversy regarding its utility as a therapeutic target. Three studies recently published in the JCI, including one in this issue, underscore the complexity of this subject. Heydemann and colleagues implicate dimorphic variation in latent TGF-β–binding protein 4 (LTBP4), a regulator of TGF-&#x003b... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3230768 Tue, 02 Feb 2010 16:14:14 +0100 3230768 http://www.medworm.com/index.php?rid=3230767&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F42088 The role of genetic heterogeneity within neoplasms is increasingly recognized as important for understanding the dynamics of cancer progression, cancer stem cells, and therapeutic resistance, and there is interest in intratumoral heterogeneity measurements as potential biomarkers for risk stratification. In this issue of the JCI, Park et al. characterize this genetic diversity in carcinoma in situ and in invasive regions from 3 types of human breast cancers and lay the groundwork for translation of these measures to the clinic. (Source: Journal of Clinical Investigation) Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3230767 Tue, 02 Feb 2010 16:14:14 +0100 3230767 http://www.medworm.com/index.php?rid=3230766&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F42033 (Source: Journal of Clinical Investigation) Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3230766 Tue, 02 Feb 2010 16:14:14 +0100 3230766 http://www.medworm.com/index.php?rid=3230765&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F42070 (Source: Journal of Clinical Investigation) Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3230765 Tue, 02 Feb 2010 16:14:14 +0100 3230765 http://www.medworm.com/index.php?rid=3230764&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F42243 (Source: Journal of Clinical Investigation) Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3230764 Tue, 02 Feb 2010 16:14:14 +0100 3230764 http://www.medworm.com/index.php?rid=3175185&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F39832C1 (Source: Journal of Clinical Investigation) Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3175185 Fri, 15 Jan 2010 15:58:26 +0100 3175185 http://www.medworm.com/index.php?rid=3175184&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F36714C1 (Source: Journal of Clinical Investigation) Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3175184 Fri, 15 Jan 2010 15:58:26 +0100 3175184 http://www.medworm.com/index.php?rid=3175183&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F25437C1 (Source: Journal of Clinical Investigation) Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3175183 Fri, 15 Jan 2010 15:58:26 +0100 3175183 http://www.medworm.com/index.php?rid=3141871&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F40221 We report here that inactivation of Tsc1 and overexpression of the Ras homolog Rheb each resulted in duplication of the bristle and socket cells, progeny of the pIIa cell, and loss of the neuronal cell, a product of pIIb cell division. Live imaging of ESO development revealed this cell-fate switch occurred at the pIIa-pIIb 2-cell stage. In human angiomyolipomas, benign renal neoplasms often found in tuberous sclerosis patients, we found evidence of Notch receptor cleavage and Notch target gene activation. Further, an angiomyolipoma-derived cell line carrying biallelic TSC2 mutations exhibited TSC2- and Rheb-dependent Notch activation. Finally, inhibition of Notch signaling using a γ-secretase inhibitor suppressed proliferation of Tsc2-null rat cells in a xenograft model. Together, ... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3141871 Tue, 05 Jan 2010 15:53:09 +0100 3141871 http://www.medworm.com/index.php?rid=3141870&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F41738 Arterial injury results in the formation of neointimal lesions. Lack of resolution of the pathologic neointima leads to stenosis, tissue ischemia, and organ dysfunction. In this issue of the JCI, Kovacic et al. show that, in response to arterial injury in mice, the cytokine TNF-α triggers a novel signaling pathway involving the combinatorial action of two transcription factors, STAT3 and NF-κB (p65 subunit), in VSMCs (see the related article beginning on page 303). Upon activation, these factors turn on transcription of a potent T cell chemokine, RANTES, which selectively recruits T cells into the vessel wall as part of the vascular wound–healing response. (Source: Journal of Clinical Investigation) Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3141870 Tue, 05 Jan 2010 15:53:09 +0100 3141870 http://www.medworm.com/index.php?rid=3141869&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F41780 Connexin 43 (Cx43) is the major protein component of gap junctions that electrically couple cardiomyocytes at the intercalated disc. Oxidant stress, reduced Cx43 expression, and altered subcellular localization are present in many forms of structural heart disease. These changes in Cx43 lead to alterations in electrical conduction in the ventricle and predispose to lethal cardiac arrhythmias. In their study in this issue of the JCI, Smyth et al. tested the hypothesis that oxidant stress perturbs connexon forward trafficking along microtubules to gap junctions (see the related article beginning on page 266). Failing human ventricular myocardium exhibited a reduction in Cx43 and the microtubule-capping protein EB1 at intercalated discs. Oxidant stress in the adult mouse heart reduced N-cadhe... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3141869 Tue, 05 Jan 2010 15:53:09 +0100 3141869 http://www.medworm.com/index.php?rid=3141868&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F41897 Tuberous sclerosis complex (TSC) is a dominantly inherited disease that is characterized by the growth of multiple benign tumors that are often difficult to treat. TSC is caused by mutations that inactivate the TSC1 or TSC2 genes, which normally function to inhibit activation of mammalian target of rapamycin signaling. In this issue of the JCI, two studies reported by Karbowniczek et al. and Ma et al. link TSC inactivation with activated Notch signaling (see the related articles beginning on pages 93 and 103, respectively). Using a variety of approaches, both studies show that inactivation of TSC leads to Notch1 activation. Furthermore, studies in tumor cells suggest that inhibiting Notch slows growth of the tumor cells. Although much remains to be learned about the precise mechanisms by w... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3141868 Tue, 05 Jan 2010 15:53:09 +0100 3141868 http://www.medworm.com/index.php?rid=3141867&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F41340 Voltage-dependent sodium channels are the central players in the excitability of neurons, cardiac muscle, and skeletal muscle. Hundreds of mutations in sodium channels have been associated with human disease, particularly genetic forms of epilepsy, arrhythmias, myotonia, and periodic paralysis. In this issue of the JCI, Jarecki and colleagues present evidence suggesting that many such mutations alter the gating of sodium channels to produce resurgent sodium current, an unusual form of gating in which sodium channels reopen following an action potential, thus promoting the firing of another action potential (see the related article beginning on page 369). The results of this study suggest a widespread pathophysiological role for this mechanism, previously described to occur normally in only... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3141867 Tue, 05 Jan 2010 15:53:09 +0100 3141867 http://www.medworm.com/index.php?rid=3141866&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F41801 Over the last decade, a remarkable number of papers have been published in which the biology of stem cells is introduced with words and phrases such as “promise,” “rapid progress,” and “future therapies.” To separate myth and hype from reality, the articles in this Stem Cells Review series comprise a rich resource on the state of this fast-paced field and provide a balanced perspective on some of the major advances. They recount what the field has achieved over the past decade and where the field is headed. They also highlight the challenges to be faced in translating what is indeed highly promising science into proven therapies that will regenerate and repair diseased tissues. (Source: Journal of Clinical Investigation) Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3141866 Tue, 05 Jan 2010 15:53:09 +0100 3141866 http://www.medworm.com/index.php?rid=3141865&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F41811 Attenuating coinhibitory molecules for the treatment of cancer is gaining a great deal of attention as a strategy for immunotherapy. The B and T lymphocyte attenuator (BTLA, CD272) is a novel coinhibitory molecule structurally and functionally related to CTLA-4 and PD-1. A study in this issue of the JCI by Derré et al. reveals that BTLA is expressed on virus-specific human CD8+ T cells but is progressively downregulated after their differentiation from a naive to effector phenotype (see the related article beginning on page 157). Surprisingly, tumor-specific human CD8+ T cells continue to express BTLA even after their differentiation to an effector phenotype. Remarkably, vaccination of melanoma patients with CpG led to BTLA downregulation on tumor-specific human CD8+ T cells, conco... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3141865 Tue, 05 Jan 2010 15:53:09 +0100 3141865 http://www.medworm.com/index.php?rid=3141864&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F40435 Discussion of the bioethics of human stem cell research has transitioned from controversies over the source of human embryonic stem cells to concerns about the ethical use of stem cells in basic and clinical research. Key areas in this evolving ethical discourse include the derivation and use of other human embryonic stem cell–like stem cells that have the capacity to differentiate into all types of human tissue and the use of all types of stem cells in clinical research. Each of these issues is discussed as I summarize the past, present, and future bioethical issues in stem cell research. (Source: Journal of Clinical Investigation) Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3141864 Tue, 05 Jan 2010 15:53:09 +0100 3141864 http://www.medworm.com/index.php?rid=3141863&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F41158 Enabling stem cell–targeted therapies requires an understanding of how to create local microenvironments (niches) that stimulate endogenous stem cells or serve as a platform to receive and guide the integration of transplanted stem cells and their derivatives. In vivo, the stem cell niche is a complex and dynamic unit. Although components of the in vivo niche continue to be described for many stem cell systems, how these components interact to modulate stem cell fate is only beginning to be understood. Using the HSC niche as a model, we discuss here microscale engineering strategies capable of systematically examining and reconstructing individual niche components. Synthetic stem cell–niche engineering may form a new foundation for regenerative therapies. (Source: Journal o... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3141863 Tue, 05 Jan 2010 15:53:09 +0100 3141863 http://www.medworm.com/index.php?rid=3141862&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F40553 Induced pluripotent stem (iPS) cells are generated by epigenetic reprogramming of somatic cells through the exogenous expression of transcription factors. These cells, just like embryonic stem cells, are likely to have a major impact on regenerative medicine, because they self-renew and retain the potential to be differentiated into all cell types of the human body. In this Review, we describe the current state of iPS cell technology, including approaches by which they are generated and what is known about their biology, and discuss the potential applications of these cells for disease modeling, drug discovery, and, eventually, cell replacement therapy. (Source: Journal of Clinical Investigation) Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3141862 Tue, 05 Jan 2010 15:53:09 +0100 3141862 http://www.medworm.com/index.php?rid=3141861&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F41708 (Source: Journal of Clinical Investigation) Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3141861 Tue, 05 Jan 2010 15:53:09 +0100 3141861 http://www.medworm.com/index.php?rid=3141860&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F41004 Cancer stem cells (CSCs) are a subpopulation of tumor cells that selectively possess tumor initiation and self-renewal capacity and the ability to give rise to bulk populations of nontumorigenic cancer cell progeny through differentiation. As we discuss here, they have been prospectively identified in several human malignancies, and their relative abundance in clinical cancer specimens has been correlated with malignant disease progression in human patients. Furthermore, recent findings suggest that clinical cancer progression driven by CSCs may contribute to the failure of existing therapies to consistently eradicate malignant tumors. Therefore, CSC-directed therapeutic approaches might represent translationally relevant strategies to improve clinical cancer therapy, in particular for tho... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3141860 Tue, 05 Jan 2010 15:53:09 +0100 3141860 http://www.medworm.com/index.php?rid=3141859&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F41900 (Source: Journal of Clinical Investigation) Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3141859 Tue, 05 Jan 2010 15:53:09 +0100 3141859 http://www.medworm.com/index.php?rid=3141858&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F39832C1 (Source: Journal of Clinical Investigation) Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3141858 Tue, 05 Jan 2010 15:53:09 +0100 3141858 http://www.medworm.com/index.php?rid=3141857&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F36714C1 (Source: Journal of Clinical Investigation) Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3141857 Tue, 05 Jan 2010 15:53:09 +0100 3141857 http://www.medworm.com/index.php?rid=3141856&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F25437C1 (Source: Journal of Clinical Investigation) Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3141856 Tue, 05 Jan 2010 15:53:09 +0100 3141856 http://www.medworm.com/index.php?rid=3141855&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F41934 (Source: Journal of Clinical Investigation) Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3141855 Tue, 05 Jan 2010 15:53:09 +0100 3141855 http://www.medworm.com/index.php?rid=3141854&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F36666 Directed gene transfer into specific cell lineages in vivo is an attractive approach for both modulating gene expression and correcting inherited mutations such as emphysema caused by human α1 antitrypsin (hAAT) deficiency. However, somatic tissues are mainly comprised of heterogeneous, differentiated cell lineages that can be short lived and difficult to specifically transfect. Here, we describe an intratracheally instilled lentiviral system able to deliver genes selectively to as many as 70% of alveolar macrophages (AMs) in the mouse lung. Following a single in vivo lentiviral transduction, genetically tagged AMs persisted in lung alveoli and expressed transferred genes for the lifetime of the adult mouse. A prolonged macrophage lifespan, rather than precursor cell proliferation,... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3141854 Tue, 05 Jan 2010 15:53:09 +0100 3141854 http://www.medworm.com/index.php?rid=3141853&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F40801 Inherited mutations in voltage-gated sodium channels (VGSCs; or Nav) cause many disorders of excitability, including epilepsy, chronic pain, myotonia, and cardiac arrhythmias. Understanding the functional consequences of the disease-causing mutations is likely to provide invaluable insight into the roles that VGSCs play in normal and abnormal excitability. Here, we sought to test the hypothesis that disease-causing mutations lead to increased resurgent currents, unusual sodium currents that have not previously been implicated in disorders of excitability. We demonstrated that a paroxysmal extreme pain disorder (PEPD) mutation in the human peripheral neuronal sodium channel Nav1.7, a paramyotonia congenita (PMC) mutation in the human skeletal muscle sodium channel Nav1.4, and a long-QT3/SID... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3141853 Tue, 05 Jan 2010 15:53:09 +0100 3141853 http://www.medworm.com/index.php?rid=3141852&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F39901 Osteoblasts have recently been found to play a role in regulating glucose metabolism through secretion of osteocalcin. It is unknown, however, how this osteoblast function is regulated transcriptionally. As FoxO1 is a forkhead family transcription factor known to regulate several key aspects of glucose homeostasis, we investigated whether its expression in osteoblasts may contribute to its metabolic functions. Here we show that mice lacking Foxo1 only in osteoblasts had increased pancreatic β cell proliferation, insulin secretion, and insulin sensitivity. The ability of osteoblast-specific FoxO1 deficiency to affect metabolic homeostasis was due to increased osteocalcin expression and decreased expression of Esp, a gene that encodes a protein responsible for decreasing the bioactiv... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3141852 Tue, 05 Jan 2010 15:53:09 +0100 3141852 http://www.medworm.com/index.php?rid=3141851&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F39395 Thymic graft-versus-host disease (tGVHD) can contribute to profound T cell deficiency and repertoire restriction after allogeneic BM transplantation (allo-BMT). However, the cellular mechanisms of tGVHD and interactions between donor alloreactive T cells and thymic tissues remain poorly defined. Using clinically relevant murine allo-BMT models, we show here that even minimal numbers of donor alloreactive T cells, which caused mild nonlethal systemic graft-versus-host disease, were sufficient to damage the thymus, delay T lineage reconstitution, and compromise donor peripheral T cell function. Furthermore, to mediate tGVHD, donor alloreactive T cells required trafficking molecules, including CCR9, L selectin, P selectin glycoprotein ligand-1, the integrin subunits αE and β7,... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3141851 Tue, 05 Jan 2010 15:53:09 +0100 3141851 http://www.medworm.com/index.php?rid=3141850&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F38702 The IL-23/IL-17 and IL-12/IFN-γ cytokine pathways have a role in chronic autoimmunity, which is considered mainly a dysfunction of adaptive immunity. The extent to which they contribute to innate immunity is, however, unknown. We used a mouse model of acute kidney ischemia-reperfusion injury (IRI) to test the hypothesis that early production of IL-23 and IL-12 following IRI activates downstream IL-17 and IFN-γ signaling pathways and promotes kidney inflammation. Deficiency in IL-23, IL-17A, or IL-17 receptor (IL-17R) and mAb neutralization of CXCR2, the p19 subunit of IL-23, or IL-17A attenuated neutrophil infiltration in acute kidney IRI in mice. We further demonstrate that IL-17A produced by GR-1+ neutrophils was critical for kidney IRI in mice. Activation of the IL-12/IF... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3141850 Tue, 05 Jan 2010 15:53:09 +0100 3141850 http://www.medworm.com/index.php?rid=3141849&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F38356 The regulation of arterial contractility is essential for blood pressure control. The GTPase RhoA promotes vasoconstriction by modulating the cytoskeleton of vascular smooth muscle cells. Whether other Rho/Rac pathways contribute to blood pressure regulation remains unknown. By studying a hypertensive knockout mouse lacking the Rho/Rac activator Vav2, we have discovered a new signaling pathway involving Vav2, the GTPase Rac1, and the serine/threonine kinase Pak that contributes to nitric oxide–triggered blood vessel relaxation and normotensia. This pathway mediated the Pak-dependent inhibition of phosphodiesterase type 5, a process that favored RhoA inactivation and the subsequent depolymerization of the F-actin cytoskeleton in vascular smooth muscle cells. The inhibition of phosph... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3141849 Tue, 05 Jan 2010 15:53:09 +0100 3141849 http://www.medworm.com/index.php?rid=3141848&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F40364 Inflammation is a key component of arterial injury, with VSMC proliferation and neointimal formation serving as the final outcomes of this process. However, the acute events transpiring immediately after arterial injury that establish the blueprint for this inflammatory program are largely unknown. We therefore studied these events in mice and found that immediately following arterial injury, medial VSMCs upregulated Rantes in an acute manner dependent on Stat3 and NF-κB (p65 subunit). This led to early T cell and macrophage recruitment, processes also under the regulation of the cyclin-dependent kinase inhibitor p21Cip1. Unique to VSMCs, Rantes production was initiated by Tnf-α, but not by Il-6/gp130. This Rantes production was dependent on the binding of a p65/Stat3 compl... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3141848 Tue, 05 Jan 2010 15:53:09 +0100 3141848 http://www.medworm.com/index.php?rid=3141847&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F41988 (Source: Journal of Clinical Investigation) Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3141847 Tue, 05 Jan 2010 15:53:09 +0100 3141847 http://www.medworm.com/index.php?rid=3141846&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F39194 In this study, we report that TGF-β1–activated SMA- and MAD3 (Smad3/4) transcription factors specifically bound to the second promoter region of HDM2, leading to increased HDM2 protein expression and destabilization of p53 in human cancer cell lines. Additionally, TGF-β1 expression led to Smad3 activation and murine double minute 2 (Mdm2) expression in murine mammary epithelial cells during epithelial-to-mesenchymal transition (EMT). Furthermore, histological analyses of human breast cancer samples demonstrated that approximately 65% of late-stage carcinomas were positive for activated Smad3 and HDM2, indicating a strong correlation between TGF-β1–mediated induction of HDM2 and late-stage tumor progression. Identification of Hdm2 as a downstream targ... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3141846 Tue, 05 Jan 2010 15:53:09 +0100 3141846 http://www.medworm.com/index.php?rid=3141845&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F40543 Stem cell–based approaches have received much hype as potential treatments for neurodegenerative disorders. Indeed, transplantation of stem cells or their derivatives in animal models of neurodegenerative diseases can improve function by replacing the lost neurons and glial cells and by mediating remyelination, trophic actions, and modulation of inflammation. Endogenous neural stem cells are also potential therapeutic targets because they produce neurons and glial cells in response to injury and could be affected by the degenerative process. As we discuss here, however, significant hurdles remain before these findings can be responsibly translated to novel therapies. In particular, we need to better understand the mechanisms of action of stem cells after transplantation and learn h... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3141845 Tue, 05 Jan 2010 15:53:09 +0100 3141845 http://www.medworm.com/index.php?rid=3141844&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F39085 Sporadic heart failure is thought to have a genetic component, but the contributing genetic events are poorly defined. Here, we used ultra-high-throughput resequencing of pooled DNAs to identify SNPs in 4 biologically relevant cardiac signaling genes, and then examined the association between allelic variants and incidence of sporadic heart failure in 2 large Caucasian populations. Resequencing of DNA pools, each containing DNA from approximately 100 individuals, was rapid, accurate, and highly sensitive for identifying common and rare SNPs; it also had striking advantages in time and cost efficiencies over individual resequencing using conventional Sanger methods. In 2,606 individuals examined, we identified a total of 129 separate SNPs in the 4 cardiac signaling genes, including 23 nonsy... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3141844 Tue, 05 Jan 2010 15:53:09 +0100 3141844 http://www.medworm.com/index.php?rid=3141843&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F39740 Gap junctions form electrical conduits between adjacent myocardial cells, permitting rapid spatial passage of the excitation current essential to each heartbeat. Arrhythmogenic decreases in gap junction coupling are a characteristic of stressed, failing, and aging myocardium, but the mechanisms of decreased coupling are poorly understood. We previously found that microtubules bearing gap junction hemichannels (connexons) can deliver their cargo directly to adherens junctions. The specificity of this delivery requires the microtubule plus-end tracking protein EB1. We performed this study to investigate the hypothesis that the oxidative stress that accompanies acute and chronic ischemic disease perturbs connexon forward trafficking. We found that EB1 was displaced in ischemic human hearts, s... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3141843 Tue, 05 Jan 2010 15:53:09 +0100 3141843 http://www.medworm.com/index.php?rid=3141842&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F40295 Fibroblasts, which are the most numerous cell type in the heart, interact with cardiomyocytes in vitro and affect their function; however, they are considered to play a secondary role in cardiac hypertrophy and failure. Here we have shown that cardiac fibroblasts are essential for the protective and hypertrophic myocardial responses to pressure overload in vivo in mice. Haploinsufficiency of the transcription factor–encoding gene Krüppel-like factor 5 (Klf5) suppressed cardiac fibrosis and hypertrophy elicited by moderate-intensity pressure overload, whereas cardiomyocyte-specific Klf5 deletion did not alter the hypertrophic responses. By contrast, cardiac fibroblast–specific Klf5 deletion ameliorated cardiac hypertrophy and fibrosis, indicating that KLF5 in fibrobl... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3141842 Tue, 05 Jan 2010 15:53:09 +0100 3141842 http://www.medworm.com/index.php?rid=3141841&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F39942 Atrial fibrillation (AF) is a common arrhythmia that increases the risk of stroke and heart failure. Here, we have shown that mast cells, key mediators of allergic and immune responses, are critically involved in AF pathogenesis in stressed mouse hearts. Pressure overload induced mast cell infiltration and fibrosis in the atrium and enhanced AF susceptibility following atrial burst stimulation. Both atrial fibrosis and AF inducibility were attenuated by stabilization of mast cells with cromolyn and by BM reconstitution from mast cell–deficient WBB6F1-KitW/W-v mice. When cocultured with cardiac myocytes or fibroblasts, BM-derived mouse mast cells increased platelet-derived growth factor A (PDGF-A) synthesis and promoted cell proliferation and collagen expression in cardiac fibroblas... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3141841 Tue, 05 Jan 2010 15:53:09 +0100 3141841 http://www.medworm.com/index.php?rid=3141840&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F38012 The epigenetic silencing of tumor suppressor genes is a crucial event during carcinogenesis and metastasis. Here, in a human genome-wide survey, we identified scavenger receptor class A, member 5 (SCARA5) as a candidate tumor suppressor gene located on chromosome 8p. We found that SCARA5 expression was frequently downregulated as a result of promoter hypermethylation and allelic imbalance and was associated with vascular invasion in human hepatocellular carcinoma (HCC). Furthermore, SCARA5 knockdown via RNAi markedly enhanced HCC cell growth in vitro, colony formation in soft agar, and invasiveness, tumorigenicity, and lung metastasis in vivo. By contrast, SCARA5 overexpression suppressed these malignant behaviors. Interestingly, SCARA5 was found to physically associate with focal adhesion... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3141840 Tue, 05 Jan 2010 15:53:09 +0100 3141840 http://www.medworm.com/index.php?rid=3141839&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F40231 We describe here a juvenile patient with CD20 deficiency due to a homozygous mutation in a splice junction of the CD20 gene (also known as MS4A1) that results in “cryptic” splicing and nonfunctional mRNA species. Analysis of this patient has led us to conclude that CD20 has a central role in the generation of T cell–independent (TI) antibody responses. Key evidence to support this conclusion was provided by the observation that although antigen-independent B cells developed normally in the absence of CD20 expression, antibody formation, particularly after vaccination with TI antigens, was strongly impaired in the patient. Consistent with this, TI antipolysaccharide B cell responses were severely impeded in CD20-deficient mice. Our study therefore identifies what we ... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3141839 Tue, 05 Jan 2010 15:53:09 +0100 3141839 http://www.medworm.com/index.php?rid=3141838&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F37672 Although supraphysiological concentrations of urea are known to increase oxidative stress in cultured cells, it is generally thought that the elevated levels of urea in chronic renal failure patients have negligible toxicity. We previously demonstrated that ROS increase intracellular protein modification by O-linked β-N-acetylglucosamine (O-GlcNAc), and others showed that increased modification of insulin signaling molecules by O-GlcNAc reduces insulin signal transduction. Because both oxidative stress and insulin resistance have been observed in patients with end-stage renal disease, we sought to determine the role of urea in these phenotypes. Treatment of 3T3-L1 adipocytes with urea at disease-relevant concentrations induced ROS production, caused insulin resistance, increased ex... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3141838 Tue, 05 Jan 2010 15:53:09 +0100 3141838 http://www.medworm.com/index.php?rid=3141837&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F40820 The ability to create new functional cardiomyocytes is the holy grail of cardiac regenerative medicine. From studies using model organisms, new insights into the fundamental pathways that drive heart muscle regeneration have begun to arise as well as a growing knowledge of the distinct families of multipotent cardiovascular progenitors that generate diverse lineages during heart development. In this Review, we highlight this intersection of the “pregenerative” biology of heart progenitor cells and heart regeneration and discuss the longer term challenges and opportunities in moving toward a therapeutic goal of regenerative cardiovascular medicine. (Source: Journal of Clinical Investigation) Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3141837 Tue, 05 Jan 2010 15:53:09 +0100 3141837 http://www.medworm.com/index.php?rid=3141836&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F41795 The regular articles and technical advances published in this issue are an average of 9,050 words, with 8.4 display items (figures and tables). Do we always need so many words to convey a message? We think not. With this editorial, we issue a call for brief reports. (Source: Journal of Clinical Investigation) Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3141836 Tue, 05 Jan 2010 15:53:09 +0100 3141836 http://www.medworm.com/index.php?rid=3141835&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F38388 Adipose tissue inflammation is linked to the pathogenesis of insulin resistance. In addition to exerting death-promoting effects, the death receptor Fas (also known as CD95) can activate inflammatory pathways in several cell lines and tissues, although little is known about the metabolic consequence of Fas activation in adipose tissue. We therefore sought to investigate the contribution of Fas in adipocytes to obesity-associated metabolic dysregulation. Fas expression was markedly increased in the adipocytes of common genetic and diet-induced mouse models of obesity and insulin resistance, as well as in the adipose tissue of obese and type 2 diabetic patients. Mice with Fas deficiency either in all cells or specifically in adipocytes (the latter are referred to herein as AFasKO mice) were ... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3141835 Tue, 05 Jan 2010 15:53:09 +0100 3141835 http://www.medworm.com/index.php?rid=3141834&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F39503 The nature of the in vivo cellular events underlying thrombus formation mediated by platelet activation remains unclear because of the absence of a modality for analysis. Lymphocyte adaptor protein (Lnk; also known as Sh2b3) is an adaptor protein that inhibits thrombopoietin-mediated signaling, and as a result, megakaryocyte and platelet counts are elevated in Lnk–/– mice. Here we describe an unanticipated role for Lnk in stabilizing thrombus formation and clarify the activities of Lnk in platelets transduced through integrin αIIbβ3–mediated outside-in signaling. We equalized platelet counts in wild-type and Lnk–/– mice by using genetic depletion of Lnk and BM transplantation. Using FeCl3- or laser-induced injury and in vivo imaging t... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3141834 Tue, 05 Jan 2010 15:53:09 +0100 3141834 http://www.medworm.com/index.php?rid=3141833&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F40178 Immunity to infections relies on clonal expansion of CD8+ T cells, their maintenance as effector CTLs, and their selection into a memory population. These processes rely on delivery of survival signals to activated CD8+ T cells. We here reveal the mechanism by which costimulatory CD27-CD70 interactions sustain survival of CD8+ effector T cells in infected tissue. By unbiased genome-wide gene expression analysis, we identified the Il2 gene as the most prominent CD27 target gene in murine CD8+ T cells. In vitro, CD27 directed IL-2 expression and promoted clonal expansion of primed CD8+ T cells exclusively by IL-2–dependent survival signaling. In mice intranasally infected with influenza virus, Cd27–/– CD8+ effector T cells displayed reduced IL-2 production, accompanie... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3141833 Tue, 05 Jan 2010 15:53:09 +0100 3141833 http://www.medworm.com/index.php?rid=3141832&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F40070 The function of antigen-specific CD8+ T cells, which may protect against both infectious and malignant diseases, can be impaired by ligation of their inhibitory receptors, which include CTL-associated protein 4 (CTLA-4) and programmed cell death 1 (PD-1). Recently, B and T lymphocyte attenuator (BTLA) was identified as a novel inhibitory receptor with structural and functional similarities to CTLA-4 and PD-1. BTLA triggering leads to decreased antimicrobial and autoimmune T cell responses in mice, but its functions in humans are largely unknown. Here we have demonstrated that as human viral antigen–specific CD8+ T cells differentiated from naive to effector cells, their surface expression of BTLA was gradually downregulated. In marked contrast, human melanoma tumor antigen–... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3141832 Tue, 05 Jan 2010 15:53:09 +0100 3141832 http://www.medworm.com/index.php?rid=3141831&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F38942 The traditional view is that cancer cells predominately produce ATP by glycolysis, rather than by oxidation of energy-providing substrates. Mitochondrial uncoupling — the continuing reduction of oxygen without ATP synthesis — has recently been shown in leukemia cells to circumvent the ability of oxygen to inhibit glycolysis, and may promote the metabolic preference for glycolysis by shifting from pyruvate oxidation to fatty acid oxidation (FAO). Here we have demonstrated that pharmacologic inhibition of FAO with etomoxir or ranolazine inhibited proliferation and sensitized human leukemia cells — cultured alone or on bone marrow stromal cells — to apoptosis induction by ABT-737, a molecule that releases proapoptotic Bcl-2 proteins such as Bak from antiapoptot... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3141831 Tue, 05 Jan 2010 15:53:09 +0100 3141831 http://www.medworm.com/index.php?rid=3141830&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F40027 Tumor hypoxia is a common microenvironmental factor that adversely influences tumor phenotype and treatment response. Cellular adaptation to hypoxia occurs through multiple mechanisms, including activation of the unfolded protein response (UPR). Recent reports have indicated that hypoxia activates a lysosomal degradation pathway known as autophagy, and here we show that the UPR enhances the capacity of hypoxic tumor cells to carry out autophagy, and that this promotes their survival. In several human cancer cell lines, hypoxia increased transcription of the essential autophagy genes microtubule-associated protein 1 light chain 3β (MAP1LC3B) and autophagy-related gene 5 (ATG5) through the transcription factors ATF4 and CHOP, respectively, which are regulated by PKR-like ER kinase (P... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3141830 Tue, 05 Jan 2010 15:53:09 +0100 3141830 http://www.medworm.com/index.php?rid=3141829&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F39721 Pancreatic β cell failure is thought to underlie the progression from glucose intolerance to overt diabetes, and ER stress is implicated in such β cell dysfunction. We have now shown that the transcription factor CCAAT/enhancer-binding protein β (C/EBPβ) accumulated in the islets of diabetic animal models as a result of ER stress before the onset of hyperglycemia. Transgenic overexpression of C/EBPβ specifically in β cells of mice reduced β cell mass and lowered plasma insulin levels, resulting in the development of diabetes. Conversely, genetic ablation of C/EBPβ in the β cells of mouse models of diabetes, including Akita mice, which harbor a heterozygous mutation in Ins2 (Ins2WT/C96Y), and leptin receptor–def... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3141829 Tue, 05 Jan 2010 15:53:09 +0100 3141829 http://www.medworm.com/index.php?rid=3141828&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F40373 Skeletal muscle damaged by injury or by degenerative diseases such as muscular dystrophy is able to regenerate new muscle fibers. Regeneration mainly depends upon satellite cells, myogenic progenitors localized between the basal lamina and the muscle fiber membrane. However, other cell types outside the basal lamina, such as pericytes, also have myogenic potency. Here, we discuss the main properties of satellite cells and other myogenic progenitors as well as recent efforts to obtain myogenic cells from pluripotent stem cells for patient-tailored cell therapy. Clinical trials utilizing these cells to treat muscular dystrophies, heart failure, and stress urinary incontinence are also briefly outlined. (Source: Journal of Clinical Investigation) Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3141828 Tue, 05 Jan 2010 15:53:09 +0100 3141828 http://www.medworm.com/index.php?rid=3141827&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F37964 The receptor tyrosine kinase/PI3K/AKT/mammalian target of rapamycin (RTK/PI3K/AKT/mTOR) pathway is frequently altered in cancer, but the underlying mechanism leading to tumorigenesis by activated mTOR remains less clear. Here we show that mTOR is a positive regulator of Notch signaling in mouse and human cells, acting through induction of the STAT3/p63/Jagged signaling cascade. Furthermore, in response to differential cues from mTOR, we found that Notch served as a molecular switch to shift the balance between cell proliferation and differentiation. We determined that hyperactive mTOR signaling impaired cell differentiation of murine embryonic fibroblasts via potentiation of Notch signaling. Elevated mTOR signaling strongly correlated with enhanced Notch signaling in poorly differentiated ... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3141827 Tue, 05 Jan 2010 15:53:09 +0100 3141827 http://www.medworm.com/index.php?rid=3141826&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F41820 (Source: Journal of Clinical Investigation) Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3141826 Tue, 05 Jan 2010 15:53:09 +0100 3141826 http://www.medworm.com/index.php?rid=3047609&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F34997 Growth hormone (GH) is a major metabolic regulator that functions by stimulating lipolysis, preventing protein catabolism, and decreasing insulin-dependent glucose disposal. Modulation of hepatic sensitivity to GH and the downstream effects on the GH/IGF1 axis are important events in the regulation of metabolism in response to variations in food availability. For example, during periods of reduced nutrient availability, the liver becomes resistant to GH actions. However, the mechanisms controlling hepatic GH resistance are currently unknown. Here, we investigated the role of 2 tetraspanning membrane proteins, leptin receptor overlapping transcript (LEPROT; also known as OB-RGRP) and LEPROT-like 1 (LEPROTL1), in controlling GH sensitivity. Transgenic mice expressing either human LEPROT or h... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3047609 Wed, 02 Dec 2009 15:58:54 +0100 3047609 http://www.medworm.com/index.php?rid=3047608&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F39054 Oxidative myofibers, also known as slow-twitch myofibers, help maintain the metabolic health of mammals, and it has been proposed that decreased numbers correlate with increased risk of obesity. The transcriptional coactivator PPARγ coactivator 1α (PGC-1α) plays a central role in maintaining levels of oxidative myofibers in skeletal muscle. Indeed, loss of PGC-1α expression has been linked to a reduction in the proportion of oxidative myofibers in the skeletal muscle of obese mice. MAPK phosphatase-1 (MKP-1) is encoded by mkp-1, a stress-responsive immediate-early gene that dephosphorylates MAPKs in the nucleus. Previously we showed that mice deficient in MKP-1 have enhanced energy expenditure and are resistant to diet-induced obesity. Here we show in mice t... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3047608 Wed, 02 Dec 2009 15:58:54 +0100 3047608 http://www.medworm.com/index.php?rid=3047607&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F39738 We examined the role of MIF in regulating JNK activation and cardiac injury during experimental ischemia/reperfusion in mouse hearts. Isolated perfused Mif–/– hearts had greater contractile dysfunction, necrosis, and JNK activation than WT hearts, with increased upstream MAPK kinase 4 phosphorylation, following ischemia/reperfusion. These effects were reversed if recombinant MIF was present during reperfusion, indicating that MIF deficiency during reperfusion exacerbated injury. Activated JNK acts in a proapoptotic manner by regulating BCL2-associated agonist of cell death (BAD) phosphorylation, and this effect was accentuated in Mif–/– hearts after ischemia/reperfusion. Similar detrimental effects of MIF deficiency were observed in vivo following coronary o... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3047607 Wed, 02 Dec 2009 15:58:54 +0100 3047607 http://www.medworm.com/index.php?rid=3047606&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F37976 Cardiac complications are a common cause of death in individuals with the inherited multisystemic disease myotonic dystrophy type 1 (DM1). A characteristic molecular feature of DM1 is misregulated alternative splicing due to disrupted functioning of the splicing regulators muscleblind-like 1 (MBNL1) and CUG-binding protein 1 (CUGBP1). CUGBP1 is upregulated in DM1 due to PKC pathway activation and subsequent CUGBP1 protein hyperphosphorylation and stabilization. Here, we blocked PKC activity in a heart-specific DM1 mouse model to determine its pathogenic role in DM1. Animals given PKC inhibitors exhibited substantially increased survival that correlated with reduced phosphorylation and decreased steady-state levels of CUGBP1. Functional studies demonstrated that PKC inhibition ameliorated t... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3047606 Wed, 02 Dec 2009 15:58:54 +0100 3047606 http://www.medworm.com/index.php?rid=3047605&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F39724 In noncontractile cells, increases in intracellular Ca2+ concentration serve as a second messenger to signal proliferation, differentiation, metabolism, motility, and cell death. Many of these Ca2+-dependent regulatory processes operate in cardiomyocytes, although it remains unclear how Ca2+ serves as a second messenger given the high Ca2+ concentrations that control contraction. T-type Ca2+ channels are reexpressed in adult ventricular myocytes during pathologic hypertrophy, although their physiologic function remains unknown. Here we generated cardiac-specific transgenic mice with inducible expression of α1G, which generates Cav3.1 current, to investigate whether this type of Ca2+ influx mechanism regulates the cardiac hypertrophic response. Unexpectedly, α1G transgenic m... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3047605 Wed, 02 Dec 2009 15:58:54 +0100 3047605 http://www.medworm.com/index.php?rid=3047604&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F39692 When used as therapy for hematopoietic malignancies, allogeneic BM transplantation (BMT) relies on the graft-versus-leukemia (GVL) effect to eradicate residual tumor cells through immunologic mechanisms. However, graft-versus-host disease (GVHD), which is initiated by alloreactive donor T cells that recognize mismatched major and/or minor histocompatibility antigens and cause severe damage to hematopoietic and epithelial tissues, is a potentially lethal complication of allogeneic BMT. To enhance the therapeutic potential of BMT, we sought to find therapeutic targets that could inhibit GVHD while preserving GVL and immune responses to infectious agents. We show here that T cell responses triggered in mice by either Listeria monocytogenes or administration of antigen and adjuvant were relati... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3047604 Wed, 02 Dec 2009 15:58:54 +0100 3047604 http://www.medworm.com/index.php?rid=3047603&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F40732 Familial hemophagocytic lymphohistiocytosis (FHL) is a genetically heterogeneous autosomal recessive immune disorder characterized by the occurrence of uncontrolled activation of lymphocytes and macrophages infiltrating multiple organs. Disease-causing mutations in the perforin (PRF1; also known as FHL2), Munc13-4 (UNC13D; also known as FHL3), and syntaxin-11 (STX11; also known as FHL4) genes have been identified in individuals with FHL. These genes all encode proteins involved in the cytotoxic activity of lymphocytes. Here, we show that the gene encoding syntaxin-binding protein 2 (Munc18-2; official gene symbol STXBP2) is mutated in another subset of patients with FHL (designated by us as “FHL5”). Lymphoblasts isolated from these patients had strongly decreased STXBP2 pro... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3047603 Wed, 02 Dec 2009 15:58:54 +0100 3047603 http://www.medworm.com/index.php?rid=3047602&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F38521 Studies in rodents have shown that male sexual function can be disrupted by fetal or neonatal administration of compounds that alter endocrine homeostasis, such as the synthetic nonsteroidal estrogen diethylstilbestrol (DES). Although the molecular basis for this effect remains unknown, estrogen receptors likely play a critical role in mediating DES-induced infertility. Recently, we showed that the orphan nuclear receptor small heterodimer partner (Nr0b2), which is both a target gene and a transcriptional repressor of estrogen receptors, controls testicular function by regulating germ cell entry into meiosis and testosterone synthesis. We therefore hypothesized that some of the harmful effects of DES on testes could be mediated through Nr0b2. Here, we present data demonstrating that Nr0b2 ... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3047602 Wed, 02 Dec 2009 15:58:54 +0100 3047602 http://www.medworm.com/index.php?rid=3047601&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F39335 Cutaneous wounds heal more slowly in elderly males than in elderly females, suggesting a role for sex hormones in the healing process. Indeed, androgen/androgen receptor (AR) signaling has been shown to inhibit cutaneous wound healing. AR is expressed in several cell types in healing skin, including keratinocytes, dermal fibroblasts, and infiltrating macrophages, but the exact role of androgen/AR signaling in these different cell types remains unclear. To address this question, we generated and studied cutaneous wound healing in cell-specific AR knockout (ARKO) mice. General and myeloid-specific ARKO mice exhibited accelerated wound healing compared with WT mice, whereas keratinocyte- and fibroblast-specific ARKO mice did not. Importantly, the rate of wound healing in the general ARKO mice... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3047601 Wed, 02 Dec 2009 15:58:54 +0100 3047601 http://www.medworm.com/index.php?rid=3047600&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F39717 This study has revealed a crucial role for IMs in maintaining immune homeostasis in the respiratory tract and provides an explanation for the paradox that although airborne LPS has the ability to promote the induction of Th2 responses by lung DCs, it does not provoke airway allergy under normal conditions. (Source: Journal of Clinical Investigation) Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3047600 Wed, 02 Dec 2009 15:58:54 +0100 3047600 http://www.medworm.com/index.php?rid=3047599&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F40053 We report here that Mfge8 does decrease the severity of tissue fibrosis in a mouse model of pulmonary fibrosis; however, it does so not through effects on inflammation and apoptotic cell clearance, but by binding and targeting collagen for cellular uptake through its discoidin domains. Initial analysis revealed that Mfge8–/– mice exhibited enhanced pulmonary fibrosis after bleomycin-induced lung injury. However, they did not have increased inflammation or impaired apoptotic cell clearance after lung injury compared with Mfge8+/+ mice; rather, they had a defect in collagen turnover. Further experiments indicated that Mfge8 directly bound collagen and that Mfge8–/– macrophages exhibited defective collagen uptake that could be rescued by recombinant Mfge8 conta... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3047599 Wed, 02 Dec 2009 15:58:54 +0100 3047599 http://www.medworm.com/index.php?rid=3047598&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F39845 Most single-gene diseases, including muscular dystrophy, display a nonuniform phenotype. Phenotypic variability arises, in part, due to the presence of genetic modifiers that enhance or suppress the disease process. We employed an unbiased mapping approach to search for genes that modify muscular dystrophy in mice. In a genome-wide scan, we identified a single strong locus on chromosome 7 that influenced two pathological features of muscular dystrophy, muscle membrane permeability and muscle fibrosis. Within this genomic interval, an insertion/deletion polymorphism of 36 bp in the coding region of the latent TGF-β–binding protein 4 gene (Ltbp4) was found. Ltbp4 encodes a latent TGF-β–binding protein that sequesters TGF-β and regulates its availabilit... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3047598 Wed, 02 Dec 2009 15:58:54 +0100 3047598 http://www.medworm.com/index.php?rid=3047597&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F39716 Ectopic cell cycle events (CCEs) mark vulnerable neuronal populations in human Alzheimer disease (AD) and are observed early in disease progression. In transgenic mouse models of AD, CCEs are found before the onset of β-amyloid peptide (Aβ) deposition to form senile plaques, a hallmark of AD. Here, we have demonstrated that alterations in brain microglia occur coincidently with the appearance of CCEs in the R1.40 transgenic mouse model of AD. Furthermore, promotion of inflammation with LPS at young ages in R1.40 mice induced the early appearance of neuronal CCEs, whereas treatment with 2 different nonsteroidal antiinflammatory drugs (NSAIDs) blocked neuronal CCEs and alterations in brain microglia without altering amyloid precursor protein (APP) processing and steady-state ... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3047597 Wed, 02 Dec 2009 15:58:54 +0100 3047597 http://www.medworm.com/index.php?rid=3047596&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F37914 Adult neural stem cells (aNSCs) derived from the subventricular zone of the brain show therapeutic effects in EAE, an animal model of the chronic inflammatory neurodegenerative disease MS; however, the beneficial effects are modest. One critical weakness of aNSC therapy may be an insufficient antiinflammatory effect. Here, we demonstrate that i.v. or i.c.v. injection of aNSCs engineered to secrete IL-10 (IL-10–aNSCs), a potent immunoregulatory cytokine, induced more profound functional and pathological recovery from ongoing EAE than that with control aNSCs. IL-10–aNSCs exhibited enhanced antiinflammatory effects in the periphery and inflammatory foci in the CNS compared with control aNSCs, more effectively reducing myelin damage, a hallmark of MS. When compared with mice tr... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3047596 Wed, 02 Dec 2009 15:58:54 +0100 3047596 http://www.medworm.com/index.php?rid=3047595&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F39832 MicroRNAs (miRNAs) interfere with translation of specific target mRNAs and are thought to thereby regulate many cellular processes. Recent studies have suggested that miRNAs might play a role in osteoblast differentiation and bone formation. Here, we identify a new miRNA (miR-2861) in primary mouse osteoblasts that promotes osteoblast differentiation by repressing histone deacetylase 5 (HDAC5) expression at the post-transcriptional level. miR-2861 was found to be transcribed in ST2 stromal cells during bone morphogenetic protein 2–induced (BMP2-induced) osteogenesis, and overexpression of miR-2861 enhanced BMP2-induced osteoblastogenesis, whereas inhibition of miR-2861 expression attenuated it. HDAC5, an enhancer of runt-related transcription factor 2 (Runx2) degradation, was confi... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3047595 Wed, 02 Dec 2009 15:58:54 +0100 3047595 http://www.medworm.com/index.php?rid=3047594&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F39401 Lyme disease is caused by transmission of the spirochete Borrelia burgdorferi from ticks to humans. Although much is known about B. burgdorferi replication, the routes and mechanisms by which it disseminates within the tick remain unclear. To better understand this process, we imaged live, infectious B. burgdorferi expressing a stably integrated, constitutively expressed GFP reporter. Using isolated tick midguts and salivary glands, we observed B. burgdorferi progress through the feeding tick via what we believe to be a novel, biphasic mode of dissemination. In the first phase, replicating spirochetes, positioned at varying depths throughout the midgut at the onset of feeding, formed networks of nonmotile organisms that advanced toward the basolateral surface of the epithelium while adheri... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3047594 Wed, 02 Dec 2009 15:58:54 +0100 3047594 http://www.medworm.com/index.php?rid=3047593&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F38308 Vascular inflammation contributes to cardiovascular diseases such as aortic aneurysm and dissection. However, the precise inflammatory pathways involved have not been clearly defined. We have shown here that subcutaneous infusion of Ang II, a vasopressor known to promote vascular inflammation, into older C57BL/6J mice induced aortic production of the proinflammatory cytokine IL-6 and the monocyte chemoattractant MCP-1. Production of these factors occurred predominantly in the tunica adventitia, along with macrophage recruitment, adventitial expansion, and development of thoracic and suprarenal aortic dissections. In contrast, a reduced incidence of dissections was observed after Ang II infusion into mice lacking either IL-6 or the MCP-1 receptor CCR2. Further analysis revealed that Ang II ... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3047593 Wed, 02 Dec 2009 15:58:54 +0100 3047593 http://www.medworm.com/index.php?rid=3047592&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F39374 The polycomb group protein B lymphoma Mo-MLV insertion region 1 homolog (Bmi-1) is dysregulated in various cancers, and its upregulation strongly correlates with an invasive phenotype and poor prognosis in patients with nasopharyngeal carcinomas. However, the underlying mechanism of Bmi-1–mediated invasiveness remains unknown. In the current study, we found that upregulation of Bmi-1 induced epithelial-mesenchymal transition (EMT) and enhanced the motility and invasiveness of human nasopharyngeal epithelial cells, whereas silencing endogenous Bmi-1 expression reversed EMT and reduced motility. Furthermore, upregulation of Bmi-1 led to the stabilization of Snail, a transcriptional repressor associated with EMT, via modulation of PI3K/Akt/GSK-3β signaling. Chromatin immunopre... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3047592 Wed, 02 Dec 2009 15:58:54 +0100 3047592 http://www.medworm.com/index.php?rid=3047591&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F38988 In this study, we demonstrate that genetic deletion and pharmacologic inhibition of FAP inhibited tumor growth in both an endogenous mouse model of lung cancer driven by the K-rasG12D mutant and a mouse model of colon cancer, in which CT26 mouse colon cancer cells were transplanted into immune competent syngeneic mice. Interestingly, growth of only the K-rasG12D–driven lung tumors was also attenuated by inhibition of the closely related protease dipeptidyl peptidase IV (DPPIV). Our results indicate that FAP depletion inhibits tumor cell proliferation indirectly, increases accumulation of collagen, decreases myofibroblast content, and decreases blood vessel density in tumors. These data provide proof of principle that targeting stromal cell–mediated modifications of the tumo... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3047591 Wed, 02 Dec 2009 15:58:54 +0100 3047591 http://www.medworm.com/index.php?rid=3047590&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F38433 Hypertension and its complications represent leading causes of morbidity and mortality. Although the cause of hypertension is unknown in most patients, genetic factors are recognized as contributing significantly to an individual’s lifetime risk of developing the condition. Here, we investigated the role of the G protein regulator phosducin (Pdc) in hypertension. Mice with a targeted deletion of the gene encoding Pdc (Pdc–/– mice) had increased blood pressure despite normal cardiac function and vascular reactivity, and displayed elevated catecholamine turnover in the peripheral sympathetic system. Isolated postganglionic sympathetic neurons from Pdc–/– mice showed prolonged action potential firing after stimulation with acetylcholine and increased fi... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3047590 Wed, 02 Dec 2009 15:58:54 +0100 3047590 http://www.medworm.com/index.php?rid=3047589&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F39929 Intestinal ganglioneuromatosis is a benign proliferation of nerve ganglion cells, nerve fibers, and supporting cells of the enteric nervous system (ENS) that can result in abnormally large enteric neuronal cells (ENCs) in the myenteric plexus and chronic intestinal pseudoobstruction (CIPO). As phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a phosphatase that is critical for controlling cell growth, proliferation, and death, we investigated the role of PTEN in the ENS by generating mice with an embryonic, ENC-selective deletion within the Pten locus. Mutant mice died 2 to 3 weeks after birth, with clinical signs of CIPO and hyperplasia and hypertrophy of ENCs resulting from increased activity of the PI3K/PTEN-AKT-S6K signaling pathway. Further analysis revealed that PTEN ... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3047589 Wed, 02 Dec 2009 15:58:54 +0100 3047589 http://www.medworm.com/index.php?rid=3047588&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F40202 In conclusion, the human Th22 subset may represent a separate T cell subset with a distinct identity with respect to gene expression and function, present within the epidermal layer in inflammatory skin diseases. Future strategies directed against the Th22 subset may be of value in chronic inflammatory skin disorders. (Source: Journal of Clinical Investigation) Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3047588 Wed, 02 Dec 2009 15:58:54 +0100 3047588 http://www.medworm.com/index.php?rid=3047587&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F40115 Natural SIV infection of sooty mangabeys (SMs) is nonprogressive despite chronic virus replication. Strikingly, it is characterized by low levels of immune activation, while pathogenic SIV infection of rhesus macaques (RMs) is associated with chronic immune activation. To elucidate the mechanisms underlying this intriguing phenotype, we used high-density oligonucleotide microarrays to longitudinally assess host gene expression in SIV-infected SMs and RMs. We found that acute SIV infection of SMs was consistently associated with a robust innate immune response, including widespread upregulation of IFN-stimulated genes (ISGs) in blood and lymph nodes. While SMs exhibited a rapid resolution of ISG expression and immune activation, both responses were observed chronically in RMs. Systems biolo... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3047587 Wed, 02 Dec 2009 15:58:54 +0100 3047587 http://www.medworm.com/index.php?rid=3047586&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F40093 In conclusion, SIV infection triggered a rapid and strong IFN-α response in vivo in both AGMs and RMs, with this response being efficiently controlled only in AGMs, possibly as a result of active regulatory mechanisms. (Source: Journal of Clinical Investigation) Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3047586 Wed, 02 Dec 2009 15:58:54 +0100 3047586 http://www.medworm.com/index.php?rid=3047585&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F38263 The RNA-binding protein HuR (also known as ELAV1) binds to the 3′-untranslated region of mRNAs and regulates transcript stability and translation. However, the in vivo functions of HuR are not well understood. Here, we report that murine HuR is essential for life; postnatal global deletion of Elavl1 induced atrophy of hematopoietic organs, extensive loss of intestinal villi, obstructive enterocolitis, and lethality within 10 days. Upon Elavl1 deletion, progenitor cells in the BM, thymus, and intestine underwent apoptosis, whereas quiescent stem cells and differentiated cells were unaffected. The survival defect of hematopoietic progenitor cells was cell intrinsic, as transplant of Elavl1–/– BM led to compromised hematopoietic reconstitution but did not cause lethali... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3047585 Wed, 02 Dec 2009 15:58:54 +0100 3047585 http://www.medworm.com/index.php?rid=3047584&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F40572 Hematopoietic stem cell (HSC) homeostasis depends on the balance between self renewal and lineage commitment, but what regulates this decision is not well understood. Using loss-of-function approaches in mice, we found that glycogen synthase kinase–3 (Gsk3) plays a pivotal role in controlling the decision between self renewal and differentiation of HSCs. Disruption of Gsk3 in BM transiently expanded phenotypic HSCs in a β-catenin–dependent manner, consistent with a role for Wnt signaling in HSC homeostasis. However, in assays of long-term HSC function, disruption of Gsk3 progressively depleted HSCs through activation of mammalian target of rapamycin (mTOR). This long-term HSC depletion was prevented by mTOR inhibition and exacerbated by β-catenin knockout. T... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3047584 Wed, 02 Dec 2009 15:58:54 +0100 3047584 http://www.medworm.com/index.php?rid=3047583&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F41508 Repeated exposure to stress may favor, both in experimental animals and in humans, an increase in blood pressure, leading in some instances to a true hypertensive state. It is thought that stress-induced hypertension is mediated by sympathetic nervous system activation that in turn, by exerting vasoconstrictor effects and increasing heart rate (and thus cardiac output), may promote the development and progression of the hypertensive state. A new study by Beetz and colleagues in this issue of the JCI, which reports the results of experimental studies carried out in both mice and humans, reveals the potential role of the phosducin gene in modulating the adrenergic and blood pressure responses to stress (see the related article beginning on page 3597). (Source: Journal of Clinical Investigati... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3047583 Wed, 02 Dec 2009 15:58:54 +0100 3047583 http://www.medworm.com/index.php?rid=3047582&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F41509 Natural nonhuman primate hosts of SIV do not succumb to AIDS despite significant viral replication, a phenomenon attributed to reduced levels of chronic and deleterious “immune activation.” Two studies in this issue of the JCI, by Bosinger et al. and Jacquelin et al., now show that SIV induces vigorous immune activation and upregulation of IFN-stimulated genes in both natural and susceptible hosts, but strikingly, the responses resolve only in the former (see the related articles, beginning on pages 3556 and 3544, respectively). Thus, natural hosts for SIV actively engage mechanisms to abort sustained immune activation and its associated harmful effects. (Source: Journal of Clinical Investigation) Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3047582 Wed, 02 Dec 2009 15:58:54 +0100 3047582 http://www.medworm.com/index.php?rid=3047581&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F40599 Inflammation is the coordinated immune response to harmful stimuli that appear during infections or after tissue damage. Cells of the innate immune system are the central players in mediating inflammatory tissue responses. These cells are equipped with an array of signaling receptors that detect foreign molecular substances or altered endogenous molecules that appear under situations of stress. This review provides an overview of recent progress in elucidating the molecular mechanisms that lead to inflammatory reactions. We discuss the current knowledge of the mechanisms leading to the activation of cytoplasmic, multimolecular protein complexes, termed “inflammasomes,” which regulate the activity of caspase-1 and the maturation and release of IL-1β. (Source: Journal... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3047581 Wed, 02 Dec 2009 15:58:54 +0100 3047581 http://www.medworm.com/index.php?rid=3047580&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F41461 (Source: Journal of Clinical Investigation) Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3047580 Wed, 02 Dec 2009 15:58:54 +0100 3047580 http://www.medworm.com/index.php?rid=3047579&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F41648 (Source: Journal of Clinical Investigation) Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3047579 Wed, 02 Dec 2009 15:58:54 +0100 3047579 http://www.medworm.com/index.php?rid=3047578&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F41623 (Source: Journal of Clinical Investigation) Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=3047578 Wed, 02 Dec 2009 15:58:54 +0100 3047578 http://www.medworm.com/index.php?rid=2953933&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F38662C1 (Source: Journal of Clinical Investigation) Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=2953933 Tue, 03 Nov 2009 15:54:21 +0100 2953933 http://www.medworm.com/index.php?rid=2953932&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F39482 Arteriovenous malformations (AVMs) are vascular anomalies where arteries and veins are directly connected through a complex, tangled web of abnormal arteries and veins instead of a normal capillary network. AVMs in the brain, lung, and visceral organs, including the liver and gastrointestinal tract, result in considerable morbidity and mortality. AVMs are the underlying cause of three major clinical symptoms of a genetic vascular dysplasia termed hereditary hemorrhagic telangiectasia (HHT), which is characterized by recurrent nosebleeds, mucocutaneous telangiectases, and visceral AVMs and caused by mutations in one of several genes, including activin receptor–like kinase 1 (ALK1). It remains unknown why and how selective blood vessels form AVMs, and there have been technical limita... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=2953932 Tue, 03 Nov 2009 15:54:21 +0100 2953932 http://www.medworm.com/index.php?rid=2953931&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F39199 We describe here the development of what we believe to be a novel in vitro model of HIV-1 latency that we used to search for compounds that can reverse latency. Human primary CD4+ T cells were transduced with the prosurvival molecule Bcl-2, and the resulting cells were shown to recapitulate the quiescent state of resting CD4+ T cells in vivo. Using this model system, we screened small-molecule libraries and identified a compound that reactivated latent HIV-1 without inducing global T cell activation, 5-hydroxynaphthalene-1,4-dione (5HN). Unlike previously described latency-reversing agents, 5HN activated latent HIV-1 through ROS and NF-κB without affecting nuclear factor of activated T cells (NFAT) and PKC, demonstrating that TCR pathways can be dissected and utilized to purge late... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=2953931 Tue, 03 Nov 2009 15:54:21 +0100 2953931 http://www.medworm.com/index.php?rid=2953930&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F37412 Patients with classic fibrodysplasia ossificans progressiva, a disorder characterized by extensive extraskeletal endochondral bone formation, share a recurrent mutation (R206H) within the glycine/serine-rich domain of ACVR1/ALK2, a bone morphogenetic protein type I receptor. Through a series of in vitro assays using several mammalian cell lines and chick limb bud micromass cultures, we determined that mutant R206H ACVR1 activated BMP signaling in the absence of BMP ligand and mediated BMP-independent chondrogenesis that was enhanced by BMP. We further investigated the interaction of mutant R206H ACVR1 with FKBP1A, a glycine/serine domain–binding protein that prevents leaky BMP type I receptor activation in the absence of ligand. The mutant protein exhibited reduced binding to FKBP1... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=2953930 Tue, 03 Nov 2009 15:54:21 +0100 2953930 http://www.medworm.com/index.php?rid=2953929&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F38432 In this study, when mice housed in a rodent, specific pathogen–free barrier room were challenged with MHC I mAb, there was significant protection from TRALI compared with nonbarrier mice. Priming mice with LPS restored lung injury with mAb challenge. Using TLR4-deficient bone marrow chimeras, the priming phenotype was restricted to animals with WT hematopoietic cells, and depletion of either neutrophils or platelets was protective. Both neutrophils and platelets were sequestered in the lungs of mice with TRALI, and retention of platelets was neutrophil dependent. Interestingly, treatment with aspirin prevented lung injury and mortality, but blocking the P selectin or CD11b/CD18 pathways did not. These data suggest a 2-step mechanism of TRALI: priming of hematopoietic cells, followe... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=2953929 Tue, 03 Nov 2009 15:54:21 +0100 2953929 http://www.medworm.com/index.php?rid=2953928&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F39109 Atrial fibrillation is the most common clinical cardiac arrhythmia. It is often initiated by ectopic beats arising from the pulmonary veins and atrium, but the source and mechanism of these beats remains unclear. The melanin synthesis enzyme dopachrome tautomerase (DCT) is involved in intracellular calcium and reactive species regulation in melanocytes. Given that dysregulation of intracellular calcium and reactive species has been described in patients with atrial fibrillation, we investigated the role of DCT in this process. Here, we characterize a unique DCT-expressing cell population within murine and human hearts that populated the pulmonary veins, atria, and atrioventricular canal. Expression profiling demonstrated that this population expressed adrenergic and muscarinic receptors an... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=2953928 Tue, 03 Nov 2009 15:54:21 +0100 2953928 http://www.medworm.com/index.php?rid=2953927&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F39703 Rhabdomyosarcoma (RMS) is a childhood cancer originating from skeletal muscle, and patient survival is poor in the presence of metastatic disease. Few determinants that regulate metastasis development have been identified. The receptor tyrosine kinase FGFR4 is highly expressed in RMS tissue, suggesting a role in tumorigenesis, although its functional importance has not been defined. Here, we report the identification of mutations in FGFR4 in human RMS tumors that lead to its activation and present evidence that it functions as an oncogene in RMS. Higher FGFR4 expression in RMS tumors was associated with advanced-stage cancer and poor survival, while FGFR4 knockdown in a human RMS cell line reduced tumor growth and experimental lung metastases when the cells were transplanted into mice. Mor... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=2953927 Tue, 03 Nov 2009 15:54:21 +0100 2953927 http://www.medworm.com/index.php?rid=2953926&cid=s_29928_61_f&fid=29928&url=http%3A%2F%2Fwww.jci.org%2Farticles%2Fview%2F39378 A key adaptation to environmental hypoxia is an increase in erythropoiesis, driven by the hormone erythropoietin (EPO) through what is traditionally thought to be primarily a renal response. However, both neurons and astrocytes (the largest subpopulation of glial cells in the CNS) also express EPO following ischemic injury, and this response is known to ameliorate damage to the brain. To investigate the role of glial cells as a component of the systemic response to hypoxia, we created astrocyte-specific deletions of the murine genes encoding the hypoxia-inducible transcription factors HIF-1α and HIF-2α and their negative regulator von Hippel–Lindau (VHL) as well as astrocyte-specific deletion of the HIF target gene Vegf. We found that loss of the hypoxic response in... Journal of Clinical Investigation journals http://www.medworm.com/rss/comments.php?id=2953926 Tue, 03 Nov 2009 15:54:21 +0100 2953926