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Normal mouse intestinal mucus release requires cystic fibrosis transmembrane regulator-dependent bicarbonate secretionEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
(Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - November 3, 2009 Category: Biomedical Science Authors: Mary Abigail S. Garcia, Ning Yang, Paul M. Quinton Source Type: journals

Real-time imaging of de novo arteriovenous malformation in a mouse model of hereditary hemorrhagic telangiectasiaEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
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 seve...
Source: Journal of Clinical Investigation - November 3, 2009 Category: Biomedical Science Authors: Sung Ok Park, Mamta Wankhede, Young Jae Lee, Eun-Jung Choi, Naime Fliess, Se-Woon Choe, Seh-Hoon Oh, Glenn Walter, Mohan K. Raizada, Brian S. Sorg, S. Paul Oh Source Type: journals

Small-molecule screening using a human primary cell model of HIV latency identifies compounds that reverse latency without cellular activationEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
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 throu...
Source: Journal of Clinical Investigation - November 3, 2009 Category: Biomedical Science Authors: Hung-Chih Yang, Sifei Xing, Liang Shan, Karen O’Connell, Jason Dinoso, Anding Shen, Yan Zhou, Cynthia K. Shrum, Yefei Han, Jun O. Liu, Hao Zhang, Joseph B. Margolick, Robert F. Siliciano Source Type: journals

The fibrodysplasia ossificans progressiva R206H ACVR1 mutation activates BMP-independent chondrogenesis and zebrafish embryo ventralizationEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
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 glycin...
Source: Journal of Clinical Investigation - November 3, 2009 Category: Biomedical Science Authors: Qi Shen, Shawn C. Little, Meiqi Xu, Julia Haupt, Cindy Ast, Takenobu Katagiri, Stefan Mundlos, Petra Seemann, Frederick S. Kaplan, Mary C. Mullins, Eileen M. Shore Source Type: journals

Platelet depletion and aspirin treatment protect mice in a two-event model of transfusion-related acute lung injuryEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
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...
Source: Journal of Clinical Investigation - November 3, 2009 Category: Biomedical Science Authors: Mark R. Looney, John X. Nguyen, Yongmei Hu, Jessica A. Van Ziffle, Clifford A. Lowell, Michael A. Matthay Source Type: journals

Melanocyte-like cells in the heart and pulmonary veins contribute to atrial arrhythmia triggersEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
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...
Source: Journal of Clinical Investigation - November 3, 2009 Category: Biomedical Science Authors: Mark D. Levin, Min Min Lu, Nataliya B. Petrenko, Brian J. Hawkins, Tara H. Gupta, Deborah Lang, Peter T. Buckley, Jeanine Jochems, Fang Liu, Christopher F. Spurney, Li J. Yuan, Jason T. Jacobson, Christopher B. Brown, Li Huang, Friedrich Beermann, Kenneth Source Type: journals

Identification of FGFR4-activating mutations in human rhabdomyosarcomas that promote metastasis in xenotransplanted modelsEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
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 canc...
Source: Journal of Clinical Investigation - November 3, 2009 Category: Biomedical Science Authors: James G. Taylor VI, Adam T. Cheuk, Patricia S. Tsang, Joon-Yong Chung, Young K. Song, Krupa Desai, Yanlin Yu, Qing-Rong Chen, Kushal Shah, Victoria Youngblood, Jun Fang, Su Young Kim, Choh Yeung, Lee J. Helman, Arnulfo Mendoza, Vu Ngo, Louis M. Staudt, Ju Source Type: journals

The glial cell response is an essential component of hypoxia-induced erythropoiesis in miceEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
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 ...
Source: Journal of Clinical Investigation - November 3, 2009 Category: Biomedical Science Authors: Alexander Weidemann, Yann M. Kerdiles, Karl X. Knaup, Christopher A. Rafie, Adam T. Boutin, Christian Stockmann, Norihiko Takeda, Miriam Scadeng, Andy Y. Shih, Volker H. Haase, M. Celeste Simon, David Kleinfeld, Randall S. Johnson Source Type: journals

Semaphorin 3A is an endogenous angiogenesis inhibitor that blocks tumor growth and normalizes tumor vasculature in transgenic mouse modelsEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Tumor growth and progression rely upon angiogenesis, which is regulated by pro- and antiangiogenic factors, including members of the semaphorin family. By analyzing 3 different mouse models of multistep carcinogenesis, we show here that during angiogenesis, semaphorin 3A (Sema3A) is expressed in ECs, where it serves as an endogenous inhibitor of angiogenesis that is present in premalignant lesions and lost during tumor progression. Pharmacologic inhibition of endogenous Sema3A during the angiogenic switch, the point when pretumoral lesions initiate an angiogenic phase that persists throughout tumor growth, enhanced angioge...
Source: Journal of Clinical Investigation - November 3, 2009 Category: Biomedical Science Authors: Federica Maione, Fabiola Molla, Claudia Meda, Roberto Latini, Lorena Zentilin, Mauro Giacca, Giorgio Seano, Guido Serini, Federico Bussolino, Enrico Giraudo Source Type: journals

Impaired autophagic flux mediates acinar cell vacuole formation and trypsinogen activation in rodent models of acute pancreatitisEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The pathogenic mechanisms underlying acute pancreatitis are not clear. Two key pathologic acinar cell responses of this disease are vacuole accumulation and trypsinogen activation. We show here that both result from defective autophagy, by comparing the autophagic responses in rodent models of acute pancreatitis to physiologic autophagy triggered by fasting. Pancreatitis-induced vacuoles in acinar cells were greater in number and much larger than those induced with fasting. Degradation of long-lived proteins, a measure of autophagic efficiency, was markedly inhibited in in vitro pancreatitis, while it was stimulated by aci...
Source: Journal of Clinical Investigation - November 3, 2009 Category: Biomedical Science Authors: Olga A. Mareninova, Kip Hermann, Samuel W. French, Mark S. O’Konski, Stephen J. Pandol, Paul Webster, Ann H. Erickson, Nobuhiko Katunuma, Fred S. Gorelick, Ilya Gukovsky, Anna S. Gukovskaya Source Type: journals

Autophagy regulates adipose mass and differentiation in miceEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The relative balance between the quantity of white and brown adipose tissue can profoundly affect lipid storage and whole-body energy homeostasis. However, the mechanisms regulating the formation, expansion, and interconversion of these 2 distinct types of fat remain unknown. Recently, the lysosomal degradative pathway of macroautophagy has been identified as a regulator of cellular differentiation, suggesting that autophagy may modulate this process in adipocytes. The function of autophagy in adipose differentiation was therefore examined in the current study by genetic inhibition of the critical macroautophagy gene autop...
Source: Journal of Clinical Investigation - November 3, 2009 Category: Biomedical Science Authors: Rajat Singh, Youqing Xiang, Yongjun Wang, Kiran Baikati, Ana Maria Cuervo, Yen K. Luu, Yan Tang, Jeffrey E. Pessin, Gary J. Schwartz, Mark J. Czaja Source Type: journals

Selective modulation of TLR4-activated inflammatory responses by altered iron homeostasis in miceEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
In this study, we show that the abnormal cytokine production is related to impaired TLR4 signaling. Despite their abnormal response to LPS, Hfe KO macrophages produced amounts of TNF-α similar to those in WT cells after TLR2 stimulation. Consistent with this finding, LPS-induced activation of Mal/MyD88-dependent events was normal in the mutant macrophages. However, LPS-induced IFN-β expression, a TRAM/TRIF-dependent response activated by TLR4, was reduced by Hfe deficiency. This reduction could be replicated in WT macrophages with the use of iron chelators. In contrast, TLR3-activated expression of IFN-�...
Source: Journal of Clinical Investigation - November 3, 2009 Category: Biomedical Science Authors: Lijian Wang, Lynne Harrington, Estela Trebicka, Hai Ning Shi, Jonathan C. Kagan, Charles C. Hong, Herbert Y. Lin, Jodie L. Babitt, Bobby J. Cherayil Source Type: journals

Antigen-specific Tregs control T cell responses against a limited repertoire of tumor antigens in patients with colorectal carcinomaEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Spontaneous antitumor T cell responses in cancer patients are strongly controlled by Tregs, and increased numbers of tumor-infiltrating Tregs correlate with reduced survival. However, the tumor antigens recognized by Tregs in cancer patients and the impact of these cells on tumor-specific T cell responses have not been systematically characterized. Here we used a broad panel of long synthetic peptides of defined tumor antigens and normal tissue antigens to exploit a newly developed method to identify and compare ex vivo the antigen specificities of Tregs with those of effector/memory T cells in peripheral blood of colorect...
Source: Journal of Clinical Investigation - November 3, 2009 Category: Biomedical Science Authors: Andreas Bonertz, Jürgen Weitz, Dong-Ho Kim Pietsch, Nuh N. Rahbari, Christoph Schlude, Yingzi Ge, Simone Juenger, Israel Vlodavsky, Khashayarsha Khazaie, Dirk Jaeger, Christoph Reissfelder, Dalibor Antolovic, Maximilian Aigner, Moritz Koch, Philip Source Type: journals

Great vessel development requires biallelic expression of Chd7 and Tbx1 in pharyngeal ectoderm in miceEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Aortic arch artery patterning defects account for approximately 20% of congenital cardiovascular malformations and are observed frequently in velocardiofacial syndrome (VCFS). In the current study, we screened for chromosome rearrangements in patients suspected of VCFS, but who lacked a 22q11 deletion or TBX1 mutation. One individual displayed hemizygous CHD7, which encodes a chromodomain protein. CHD7 haploinsufficiency is the major cause of coloboma, heart defect, atresia choanae, retarded growth and development, genital hypoplasia, and ear anomalies/deafness (CHARGE) syndrome, but this patient lacked the major diagnosti...
Source: Journal of Clinical Investigation - November 3, 2009 Category: Biomedical Science Authors: Victoria Randall, Karen McCue, Catherine Roberts, Vanessa Kyriakopoulou, Sarah Beddow, Angela N. Barrett, Francesca Vitelli, Katrina Prescott, Charles Shaw-Smith, Koen Devriendt, Erika Bosman, Georg Steffes, Karen P. Steel, Subreena Simrick, M. Albert Bas Source Type: journals

Inactivation of Notch signaling in the renal collecting duct causes nephrogenic diabetes insipidus in miceEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The heterogeneous cellular composition of the mammalian renal collecting duct enables regulation of fluid, electrolytes, and acid-base homeostasis, but the molecular mechanism of its development has yet to be elucidated. The Notch signaling pathway is involved in cell fate determination and has been implicated in proximal-distal patterning in the mammalian kidney. To investigate the role of Notch signaling in renal collecting duct development, we generated mice in which Mind bomb-1 (Mib1), an E3 ubiquitin ligase required for the initiation of Notch signaling, was specifically inactivated in the ureteric bud of the developi...
Source: Journal of Clinical Investigation - November 3, 2009 Category: Biomedical Science Authors: Hyun-Woo Jeong, Un Sil Jeon, Bon-Kyoung Koo, Wan-Young Kim, Sun-Kyoung Im, Juhee Shin, Yunje Cho, Jin Kim, Young-Yun Kong Source Type: journals

Tregs control the development of symptomatic West Nile virus infection in humans and miceEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
West Nile virus (WNV) causes asymptomatic infection in most humans, but for undefined reasons, approximately 20% of immunocompetent individuals develop West Nile fever, a potentially debilitating febrile illness, and approximately 1% develop neuroinvasive disease syndromes. Notably, since its emergence in 1999, WNV has become the leading cause of epidemic viral encephalitis in North America. We hypothesized that CD4+ Tregs might be differentially regulated in subjects with symptomatic compared with those with asymptomatic WNV infection. Here, we show that in 32 blood donors with acute WNV infection, Tregs expanded signific...
Source: Journal of Clinical Investigation - November 3, 2009 Category: Biomedical Science Authors: Marion C. Lanteri, Katie M. O’Brien, Whitney E. Purtha, Mark J. Cameron, Jennifer M. Lund, Rachel E. Owen, John W. Heitman, Brian Custer, Dale F. Hirschkorn, Leslie H. Tobler, Nancy Kiely, Harry E. Prince, Lishomwa C. Ndhlovu, Douglas F. Nixon, Ha Source Type: journals

Tyrosine and serine phosphorylation of {alpha}-synuclein have opposing effects on neurotoxicity and soluble oligomer formationEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Mutations in the neuronal protein α-synuclein cause familial Parkinson disease. Phosphorylation of α-synuclein at serine 129 is prominent in Parkinson disease and influences α-synuclein neurotoxicity. Here we report that α-synuclein is also phosphorylated at tyrosine 125 in transgenic Drosophila expressing wild-type human α-synuclein and that this tyrosine phosphorylation protects from α-synuclein neurotoxicity in a Drosophila model of Parkinson disease. Western blot analysis of fly brain homogenates showed that levels of soluble oligomeric species of α-synuclein were...
Source: Journal of Clinical Investigation - November 3, 2009 Category: Biomedical Science Authors: Li Chen, Magali Periquet, Xu Wang, Alessandro Negro, Pamela J. McLean, Bradley T. Hyman, Mel B. Feany Source Type: journals

Suppression of KATP channel activity protects murine pancreatic {beta} cells against oxidative stressEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The enhanced oxidative stress associated with type 2 diabetes mellitus contributes to disease pathogenesis. We previously identified plasma membrane–associated ATP-sensitive K+ (KATP) channels of pancreatic β cells as targets for oxidants. Here, we examined the effects of genetic and pharmacologic ablation of KATP channels on loss of mouse β cell function and viability following oxidative stress. Using mice lacking the sulfonylurea receptor type 1 (Sur1) subunit of KATP channels, we found that, compared with insulin secretion by WT islets, insulin secretion by Sur1–/– islets was less...
Source: Journal of Clinical Investigation - November 3, 2009 Category: Biomedical Science Authors: Belinda Gier, Peter Krippeit-Drews, Tatiana Sheiko, Lydia Aguilar-Bryan, Joseph Bryan, Martina Düfer, Gisela Drews Source Type: journals

Syndecan-1 is the primary heparan sulfate proteoglycan mediating hepatic clearance of triglyceride-rich lipoproteins in miceEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
In this study, we found by RT-PCR analysis that mouse hepatocytes expressed the membrane proteoglycans syndecan-1, -2, and -4 and glypican-1 and -4. Analysis of available proteoglycan-deficient mice showed that only syndecan-1 mutants (Sdc1–/– mice) accumulated plasma triglycerides. Sdc1–/– mice also exhibited prolonged circulation of injected human VLDL and intestinally derived chylomicrons. We found that mice lacking both syndecan-1 and hepatocyte heparan sulfate did not display accentuated triglyceride accumulation compared with single mutants, suggesting that syndecan-1 is the primary HS...
Source: Journal of Clinical Investigation - November 3, 2009 Category: Biomedical Science Authors: Kristin I. Stanford, Joseph R. Bishop, Erin M. Foley, Jon C. Gonzales, Ingrid R. Niesman, Joseph L. Witztum, Jeffrey D. Esko Source Type: journals

Adoptive immunotherapy with liver allograft-derived lymphocytes induces anti-HCV activity after liver transplantation in humans and humanized miceEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
After liver transplantation in HCV-infected patients, the virus load inevitably exceeds pre-transplantation levels. This phenomenon reflects suppression of the host-effector immune responses that control HCV replication by the immunosuppressive drugs used to prevent rejection of the transplanted liver. Here, we describe an adoptive immunotherapy approach, using lymphocytes extracted from liver allograft perfusate (termed herein liver allograft–derived lymphocytes), which includes an abundance of NK/NKT cells that mounted an anti-HCV response in HCV-infected liver transplantation recipients, despite the immunosuppre...
Source: Journal of Clinical Investigation - November 3, 2009 Category: Biomedical Science Authors: Masahiro Ohira, Kohei Ishiyama, Yuka Tanaka, Marlen Doskali, Yuka Igarashi, Hirotaka Tashiro, Nobuhiko Hiraga, Michio Imamura, Naoya Sakamoto, Toshimasa Asahara, Kazuaki Chayama, Hideki Ohdan Source Type: journals

In liver fibrosis, dendritic cells govern hepatic inflammation in mice via TNF-{alpha}Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Hepatic fibrosis occurs during most chronic liver diseases and is driven by inflammatory responses to injured tissue. Because DCs are central to modulating liver immunity, we postulated that altered DC function contributes to immunologic changes in hepatic fibrosis and affects the pathologic inflammatory milieu within the fibrotic liver. Using mouse models, we determined the contribution of DCs to altered hepatic immunity in fibrosis and investigated the role of DCs in modulating the inflammatory environment within the fibrotic liver. We found that DC depletion completely abrogated the elevated levels of many inflammatory ...
Source: Journal of Clinical Investigation - November 3, 2009 Category: Biomedical Science Authors: Michael K. Connolly, Andrea S. Bedrosian, Jon Mallen-St. Clair, Aaron P. Mitchell, Junaid Ibrahim, Andrea Stroud, H. Leon Pachter, Dafna Bar-Sagi, Alan B. Frey, George Miller Source Type: journals

Acromegaly pathogenesis and treatmentEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Dysregulated growth hormone (GH) hypersecretion is usually caused by a GH-secreting pituitary adenoma and leads to acromegaly — a disorder of disproportionate skeletal, tissue, and organ growth. High GH and IGF1 levels lead to comorbidities including arthritis, facial changes, prognathism, and glucose intolerance. If the condition is untreated, enhanced mortality due to cardiovascular, cerebrovascular, and pulmonary dysfunction is associated with a 30% decrease in life span. This Review discusses acromegaly pathogenesis and management options. The latter include surgery, radiation, and use of novel medications. Som...
Source: Journal of Clinical Investigation - November 3, 2009 Category: Biomedical Science Authors: Shlomo Melmed Source Type: journals

Fixing my gaze A scientist’s journey into seeing in three dimensionsEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
(Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - November 3, 2009 Category: Biomedical Science Authors: Elizabeth A. Debski Source Type: journals

Life at the Duke of SingaporeEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
(Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - November 3, 2009 Category: Biomedical Science Authors: Karen Honey Source Type: journals

In This IssueEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
(Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - November 3, 2009 Category: Biomedical Science Source Type: journals

Smad4: gatekeeper gene in head and neck squamous cell carcinomaEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Unchecked cell growth is a hallmark of cancer. During oncogenesis, cancerous cells become resistant to the TGF-β signaling pathway that usually keeps cell growth in check. The role of a critical mediator of this pathway, Smad4, in head and neck squamous cell carcinoma (HNSCC) remains unclear. In this issue of the JCI, Bornstein and colleagues report that Smad4 expression is decreased in malignant HNSCC and, surprisingly, also in normal-appearing buccal mucosa adjacent to HNSCC (see the related article, doi:10.1172/JCI38854). They also show that targeted conditional deletion of Smad4 in the head and neck epithelium ...
Source: Journal of Clinical Investigation - October 23, 2009 Category: Biomedical Science Authors: Murray Korc Source Type: journals

Homocysteine-mediated thrombosis and angiostasis in vascular pathobiologyEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The mechanisms by which homocysteine contributes to atherothrombosis are complex and their in vivo relevance uncertain. In this issue of the JCI, Jacovina and colleagues report a unique in vivo mechanism by which homocysteine may contribute to vascular disease (see the related article, doi:10.1172/JCI39591). This group had previously reported that homocysteine impairs endothelial cell surface plasminogen activation by posttranslationally modifying annexin A2, the coreceptor for plasminogen and tissue plasminogen activator. They now show that an annexin A2–deficient mouse rendered hyperhomocysteinemic by dietary mea...
Source: Journal of Clinical Investigation - October 23, 2009 Category: Biomedical Science Authors: Joseph Loscalzo Source Type: journals

The APCs of neuroprotectionEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Mutations in the enzyme superoxide dismutase 1 (SOD1) have been linked to the neurodegenerative disease amyotrophic lateral sclerosis (ALS). In this issue of the JCI, Zhong et al. report that the endogenous anticoagulant activated protein C (APC) is able to cross the blood–spinal cord barrier in mice and signal to both neuronal and non-neuronal cells (see the related article, doi:10.1172/JCI38476). This signaling resulted in the suppression of mutant SOD1 synthesis and retarded disease progression in a murine model of ALS. Here we discuss the potential importance of these data and possible relevance to human neurod...
Source: Journal of Clinical Investigation - October 23, 2009 Category: Biomedical Science Authors: Charles T. Esmon, Jonathan D. Glass Source Type: journals

Homocysteine inhibits neoangiogenesis in mice through blockade of annexin A2-dependent fibrinolysisEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
When plasma levels of homocysteine (HC), a thiol amino acid formed upon methionine demethylation, exceed 12 μM, individuals are at increased risk of developing large vessel atherothrombosis and small vessel dysfunction. The annexin A2 complex (termed “A2”) is the cell surface coreceptor for plasminogen and TPA and accelerates the catalytic activation of plasmin, the major fibrinolytic agent in mammals. We previously showed that HC prevents A2-mediated, TPA-dependent activation of plasminogen in vitro by disulfide derivatization of the “tail” domain of A2. We also demonstrated that fi...
Source: Journal of Clinical Investigation - October 23, 2009 Category: Biomedical Science Authors: Andrew T. Jacovina, Arunkumar B. Deora, Qi Ling, M. Johan Broekman, Dena Almeida, Caroline B. Greenberg, Aaron J. Marcus, Jonathan D. Smith, Katherine A. Hajjar Source Type: journals

Smad4 loss in mice causes spontaneous head and neck cancer with increased genomic instability and inflammationEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
In this study, we found that Smad4 was frequently downregulated not only in human head and neck squamous cell carcinoma (HNSCC) malignant lesions, but also in grossly normal adjacent buccal mucosa. To gain insight into the importance of this observation, we generated mice in which Smad4 was deleted in head and neck epithelia (referred to herein as HN-Smad4–/– mice) and found that they developed spontaneous HNSCC. Interestingly, both normal head and neck tissue and HNSCC from HN-Smad4–/– mice exhibited increased genomic instability, which correlated with downregulated expression and function ...
Source: Journal of Clinical Investigation - October 23, 2009 Category: Biomedical Science Authors: Sophia Bornstein, Ruth White, Stephen Malkoski, Masako Oka, Gangwen Han, Timothy Cleaver, Douglas Reh, Peter Andersen, Neil Gross, Susan Olson, Chuxia Deng, Shi-Long Lu, Xiao-Jing Wang Source Type: journals

Activated protein C therapy slows ALS-like disease in mice by transcriptionally inhibiting SOD1 in motor neurons and microglia cellsEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Activated protein C (APC) is a signaling protease with anticoagulant activity. Here, we have used mice expressing a mutation in superoxide dismutase-1 (SOD1) that is linked to amyotrophic lateral sclerosis (ALS) to show that administration of APC or APC analogs with reduced anticoagulant activity after disease onset slows disease progression and extends survival. A proteolytically inactive form of APC with reduced anticoagulant activity provided no benefit. APC crossed the blood–spinal cord barrier in mice via endothelial protein C receptor. When administered after disease onset, APC eliminated leakage of hemoglobi...
Source: Journal of Clinical Investigation - October 23, 2009 Category: Biomedical Science Authors: Zhihui Zhong, Hristelina Ilieva, Lee Hallagan, Robert Bell, Itender Singh, Nicole Paquette, Meenakshisundaram Thiyagarajan, Rashid Deane, Jose A. Fernandez, Steven Lane, Anna B. Zlokovic, Todd Liu, John H. Griffin, Nienwen Chow, Francis J. Castellino, Kon Source Type: journals

The ARH adaptor protein regulates endocytosis of the ROMK potassium secretory channel in mouse kidneyEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Renal outer medullary potassium (ROMK) channels are exquisitely regulated to adjust renal potassium excretion and maintain potassium balance. Clathrin-dependent endocytosis plays a critical role, limiting urinary potassium loss in potassium deficiency. In renal disease, aberrant ROMK endocytosis may contribute to potassium retention and hyperkalemia. Previous work has indicated that ROMK endocytosis is stimulated by with-no-lysine (WNK) kinases, but the endocytotic signal and the internalization machinery have not been defined. Here, we found that ROMK bound directly to the clathrin adaptor molecule autosomal recessive hyp...
Source: Journal of Clinical Investigation - October 23, 2009 Category: Biomedical Science Authors: Liang Fang, Rita Garuti, Bo-Young Kim, James B. Wade, Paul A. Welling Source Type: journals

HIF2{alpha} cooperates with RAS to promote lung tumorigenesis in miceEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
(Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - October 2, 2009 Category: Biomedical Science Authors: William Y. Kim, Samanthi Perera, Bing Zhou, Julian Carretero, Jen Jen Yeh, Samuel A. Heathcote, Autumn L. Jackson, Petros Nikolinakos, Beatriz Ospina, George N. Naumov, Kathleyn A. Brandstetter, Victor J. Weigman, Sara Zaghlul, D. Neil Hayes, Robert F. Pa Source Type: journals

A view from a European medical academic who spends time in the USEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
(Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - October 2, 2009 Category: Biomedical Science Authors: Marc Feldmann Source Type: journals

Health care reform — need for less emotion and more scienceEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
(Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - October 2, 2009 Category: Biomedical Science Authors: C. Ronald Kahn Source Type: journals

A case for a science-informed perspective on health care reformEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
(Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - October 2, 2009 Category: Biomedical Science Authors: Paul Mischel Source Type: journals

Health care reform: without a correct diagnosis, there is no cureEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
(Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - October 2, 2009 Category: Biomedical Science Authors: Jeffrey S. Flier Source Type: journals

The debate over health care reform: Houston, we have a problemEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
(Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - October 2, 2009 Category: Biomedical Science Authors: Eric G. Neilson Source Type: journals

The physician’s voice in the health care debateEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Physicians in the United States have a unique appreciation of the tremendous successes and even greater potential of our health care system, yet we also endure firsthand its woeful deficiencies. In the ongoing debate about how to improve the current health care structure in the United States, our individual voices have been all too quiet. No single health care organization, nor its spokesmen, speaks for the broad range of physicians’ opinions. Rather, doctors must make every effort, and indeed have an obligation, to speak forcefully as informed participants in...
Source: Journal of Clinical Investigation - October 2, 2009 Category: Biomedical Science Authors: Jonathan A. Epstein, Laurence A. Turka, Morris Birnbaum, Gary Koretzky Source Type: journals

HIF2{alpha} cooperates with RAS to promote lung tumorigenesis in miceEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
(Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - September 23, 2009 Category: Biomedical Science Authors: William Y. Kim, Samanthi Perera, Bing Zhou, Julian Carretero, Jen Jen Yeh, Samuel A. Heathcote, Autumn L. Jackson, Petros Nikolinakos, Beatriz Ospina, George N. Naumov, Kathleyn A. Brandstetter, Victor J. Weigman, Sara Zaghlul, D. Neil Hayes, Robert F. Pa Source Type: journals

A simple biological imaging system for detecting viable human circulating tumor cellsEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The presence of circulating tumor cells (CTCs) in the peripheral blood is associated with short survival, making the detection of CTCs clinically useful as a prognostic factor of disease outcome and/or a surrogate marker of treatment response. Recent technical advances in immunocytometric analysis and quantitative real-time PCR have made it possible to detect a few CTCs in the blood; however, there is no sensitive assay to specifically detect viable CTCs. Here, we report what we believe to be a new approach to visually detect live human CTCs among millions of peripheral blood leukocytes, using a telomerase-specific replica...
Source: Journal of Clinical Investigation - September 23, 2009 Category: Biomedical Science Authors: Toru Kojima, Yuuri Hashimoto, Yuichi Watanabe, Shunsuke Kagawa, Futoshi Uno, Shinji Kuroda, Hiroshi Tazawa, Satoru Kyo, Hiroyuki Mizuguchi, Yasuo Urata, Noriaki Tanaka, Toshiyoshi Fujiwara Source Type: journals

Expression of human BRCA1 variants in mouse ES cells allows functional analysis of BRCA1 mutationsEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
In this study we developed a functional assay using mouse ES cells to study variants of BRCA1. We introduced BAC clones with human wild-type BRCA1 or variants into Brca1-null ES cells and confirmed that only wild-type and a known neutral variant rescued cell lethality. The same neutral variant was also able to rescue embryogenesis in Brca1-null mice. A test of several BRCT domain mutants revealed all to be deleterious, including a VUS. Furthermore, we used this assay to determine the effects of BRCA1 variants on cell cycle regulation, differentiation, and genomic stability. Importantly, we discovered that ES cells rescued ...
Source: Journal of Clinical Investigation - September 23, 2009 Category: Biomedical Science Authors: Suhwan Chang, Kajal Biswas, Betty K. Martin, Stacey Stauffer, Shyam K. Sharan Source Type: journals

The antiapoptotic protein Bcl-xL negatively regulates the bone-resorbing activity of osteoclasts in miceEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The B cell lymphoma 2 (Bcl-2) family member Bcl-xL has a well-characterized antiapoptotic function in lymphoid cells. However, its functions in other cells — including osteoclasts, which are of hematopoietic origin — and other cellular processes remain unknown. Here we report an unexpected function of Bcl-xL in attenuating the bone-resorbing activity of osteoclasts in mice. To investigate the role of Bcl-xL in osteoclasts, we generated mice with osteoclast-specific conditional deletion of Bcl-x (referred to herein as Bcl-x cKO mice) by mating Bcl-xfl/fl mice with mice in which the gene encoding the Cre reco...
Source: Journal of Clinical Investigation - September 23, 2009 Category: Biomedical Science Authors: Mitsuyasu Iwasawa, Tsuyoshi Miyazaki, Yuichi Nagase, Toru Akiyama, Yuho Kadono, Masaki Nakamura, Yasushi Oshima, Tetsuro Yasui, Takumi Matsumoto, Takashi Nakamura, Shigeaki Kato, Lothar Hennighausen, Kozo Nakamura, Sakae Tanaka Source Type: journals

Sumoylated PPAR{alpha} mediates sex-specific gene repression and protects the liver from estrogen-induced toxicity in miceEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
As most metabolic studies are conducted in male animals, understanding the sex specificity of the underlying molecular pathways has been broadly neglected; for example, whether PPARs elicit sex-dependent responses has not been determined. Here we show that in mice, PPARα has broad female-dependent repressive actions on hepatic genes involved in steroid metabolism and immunity. In male mice, this effect was reproduced by the administration of a synthetic PPARα ligand. Using the steroid oxysterol 7α-hydroxylase cytochrome P450 7b1 (Cyp7b1) gene as a model, we elucidated the molecular mechanism of this...
Source: Journal of Clinical Investigation - September 23, 2009 Category: Biomedical Science Authors: Nicolas Leuenberger, Sylvain Pradervand, Walter Wahli Source Type: journals

A positive FGFR3/FOXN1 feedback loop underlies benign skin keratosis versus squamous cell carcinoma formation in humansEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Seborrheic keratoses (SKs) are common, benign epithelial tumors of the skin that do not, or very rarely, progress into malignancy, for reasons that are not understood. We investigated this by gene expression profiling of human SKs and cutaneous squamous cell carcinomas (SCCs) and found that several genes previously connected with keratinocyte tumor development were similarly modulated in SKs and SCCs, whereas the expression of others differed by only a few fold. In contrast, the tyrosine kinase receptor FGF receptor–3 (FGFR3) and the transcription factor forkhead box N1 (FOXN1) were highly expressed in SKs, and clo...
Source: Journal of Clinical Investigation - September 23, 2009 Category: Biomedical Science Authors: Anna Mandinova, Vihren Kolev, Victor Neel, Bing Hu, Wesley Stonely, Jocelyn Lieb, Xunwei Wu, Claudia Colli, Rong Han, Mike Pazin, Paola Ostano, Reinhard Dummer, Janice L. Brissette, G. Paolo Dotto Source Type: journals

A selective EP4 PGE2 receptor agonist alleviates disease in a new mouse model of X-linked nephrogenic diabetes insipidusEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
X-linked nephrogenic diabetes insipidus (XNDI) is a severe kidney disease caused by inactivating mutations in the V2 vasopressin receptor (V2R) gene that result in the loss of renal urine-concentrating ability. At present, no specific pharmacological therapy has been developed for XNDI, primarily due to the lack of suitable animal models. To develop what we believe to be the first viable animal model of XNDI, we generated mice in which the V2R gene could be conditionally deleted during adulthood by administration of 4-OH-tamoxifen. Radioligand-binding studies confirmed the lack of V2R-binding sites in kidneys following 4-O...
Source: Journal of Clinical Investigation - September 23, 2009 Category: Biomedical Science Authors: Jian Hua Li, Chung-Lin Chou, Bo Li, Oksana Gavrilova, Christoph Eisner, Jürgen Schnermann, Stasia A. Anderson, Chu-Xia Deng, Mark A. Knepper, Jürgen Wess Source Type: journals

The peptidyl-prolyl isomerase Pin1 determines parathyroid hormone mRNA levels and stability in rat models of secondary hyperparathyroidismEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Secondary hyperparathyroidism is a major complication of chronic kidney disease (CKD). In experimental models of secondary hyperparathyroidism induced by hypocalcemia or CKD, parathyroid hormone (PTH) mRNA levels increase due to increased PTH mRNA stability. K-homology splicing regulator protein (KSRP) decreases the stability of PTH mRNA upon binding a cis-acting element in the PTH mRNA 3′ UTR region. As the peptidyl-prolyl isomerase (PPIase) Pin1 has recently been shown to regulate the turnover of multiple cytokine mRNAs, we investigated the role of Pin1 in regulating PTH mRNA stability in rat parathyroids and tra...
Source: Journal of Clinical Investigation - September 23, 2009 Category: Biomedical Science Authors: Morris Nechama, Takafumi Uchida, Irit Mor Yosef-Levi, Justin Silver, Tally Naveh-Many Source Type: journals

Cyclin I activates Cdk5 and regulates expression of Bcl-2 and Bcl-XL in postmitotic mouse cellsEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Cyclin I is an atypical cyclin because it is most abundant in postmitotic cells. We previously showed that cyclin I does not regulate proliferation, but rather controls survival of podocytes, terminally differentiated epithelial cells that are essential for the structural and functional integrity of kidney glomeruli. Here, we investigated the mechanism by which cyclin I safeguards against apoptosis and found that cyclin I bound and activated cyclin-dependent kinase 5 (Cdk5) in isolated mouse podocytes and neurons. Cdk5 activity was reduced in glomeruli and brain lysates from cyclin I–deficient mice, and inhibition ...
Source: Journal of Clinical Investigation - September 23, 2009 Category: Biomedical Science Authors: Paul T. Brinkkoetter, Paul Olivier, Jimmy S. Wu, Scott Henderson, Ronald D. Krofft, Jeffrey W. Pippin, David Hockenbery, James M. Roberts, Stuart J. Shankland Source Type: journals

Cdc42 is an antihypertrophic molecular switch in the mouse heartEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
To improve contractile function, the myocardium undergoes hypertrophic growth without myocyte proliferation in response to both pathologic and physiologic stimulation. Various membrane-bound receptors and intermediate signal transduction pathways regulate the induction of cardiac hypertrophy, but the cardioprotective regulatory pathways or effectors that antagonize cardiac hypertrophy remain poorly understood. Here we identify the small GTPase Cdc42 as a signaling intermediate that restrained the cardiac growth response to physiologic and pathologic stimuli. Cdc42 was specifically activated in the heart after pressure over...
Source: Journal of Clinical Investigation - September 23, 2009 Category: Biomedical Science Authors: Marjorie Maillet, Jeffrey M. Lynch, Bastiano Sanna, Allen J. York, Yi Zheng, Jeffery D. Molkentin Source Type: journals

Evidence of premature immune aging in patients thymectomized during early childhoodEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
While the thymus is known to be essential for the initial production of T cells during early life, its contribution to immune development remains a matter of debate. In fact, during cardiac surgery in newborns, the thymus is completely resected to enable better access to the heart to correct congenital heart defects, suggesting that it may be dispensable during childhood and adulthood. Here, we show that young adults thymectomized during early childhood exhibit an altered T cell compartment. Specifically, absolute CD4+ and CD8+ T cell counts were decreased, and these T cell populations showed substantial loss of naive cell...
Source: Journal of Clinical Investigation - September 23, 2009 Category: Biomedical Science Authors: Delphine Sauce, Martin Larsen, Solène Fastenackels, Anne Duperrier, Michael Keller, Beatrix Grubeck-Loebenstein, Christophe Ferrand, Patrice Debré, Daniel Sidi, Victor Appay Source Type: journals