tbuckley/cabot-search huggingface dataset:
Activation of liver X receptors inhibits experimental fibrosis by interfering with interleukin-6 release from macrophages
Authors: Christian Beyer, Jingang Huang, Jürgen Beer, Yun Zhang, Katrin Palumbo-Zerr, Pawel Zerr, Alfiya Distler, Clara Dees, Christiane Maier, Louis Munoz, Gerhard Krönke, Stefan Uderhardt, Oliver Distler, Simon Jones, Stefan Rose-John, Tamas Oravecz, Georg Schett, Jörg HW Distler
Journal: Annals of the Rheumatic Diseases (2014)

Objectives To investigate the role of liver X receptors (LXRs) in experimental skin fibrosis and evaluate their potential as novel antifibrotic targets. Methods We studied the role of LXRs in bleomycin-induced skin fibrosis, in the model of sclerodermatous graft-versus-host disease (sclGvHD) and in tight skin-1 (Tsk-1) mice, reflecting different subtypes of fibrotic disease. We examined both LXR isoforms using LXRα-, LXRβ- and LXR-α/β-double-knockout mice. Finally, we investigated the effects of LXRs on fibroblasts and macrophages to establish the antifibrotic mode of action of LXRs. Results LXR activation by the agonist T0901317 had antifibrotic effects in bleomycin-induced skin fibrosis, in the sclGvHD model and in Tsk-1 mice. The antifibrotic activity of LXRs was particularly prominent in the inflammation-driven bleomycin and sclGvHD models. LXRα-, LXRβ- and LXRα/β-double-knockout mice showed a similar response to bleomycin as wildtype animals. Low levels of the LXR target gene ABCA-1 in the skin of bleomycin-challenged and control mice suggested a low baseline activation of the antifibrotic LXR signalling, which, however, could be specifically activated by T0901317. Fibroblasts were not the direct target cells of LXRs agonists, but LXR activation inhibited fibrosis by interfering with infiltration of macrophages and their release of the pro-fibrotic interleukin-6. Conclusions We identified LXRs as novel targets for antifibrotic therapies, a yet unknown aspect of these nuclear receptors. Our data suggest that LXR activation might be particularly effective in patients with inflammatory disease subtypes. Activation of LXRs interfered with the release of interleukin-6 from macrophages and, thus, inhibited fibroblast activation and collagen release.
Phase II Study of Cisplatin Plus Etoposide and Bevacizumab for Previously Untreated, Extensive-Stage Small-Cell Lung Cancer: Eastern Cooperative Oncology Group Study E3501
Authors: Leora Horn, Suzanne E. Dahlberg, Alan B. Sandler, Afshin Dowlati, Dennis F. Moore, John R. Murren, Joan H. Schiller
Journal: Journal of Clinical Oncology (2009)

Purpose To investigate the efficacy and safety of bevacizumab plus cisplatin and etoposide in patients with extensive-stage disease, small-cell lung cancer (ED-SCLC). Patients and Methods In this phase II trial, 63 patients were treated with bevacizumab 15 mg/kg plus cisplatin 60 mg/m 2 and etoposide 120 mg/m 2 , which was followed by bevacizumab alone until death or disease progression occurred. The primary end point was the proportion of patients alive at 6 months without disease progression (ie, progression-free survival [PFS]). Secondary end points included overall survival (OS), objective response rate, and toxicity. Correlative studies were performed to explore the relationship between baseline and changes in plasma vascular endothelial growth factor (VEGF), soluble cell adhesion molecules (ie, vascular cell adhesion molecule [VCAM], intercellular cell adhesion molecule [ICAM], and E-selectin) and basic fibroblast growth factor and outcome. Results The 6-month PFS was 30.2%, the median PFS was 4.7 months, and OS was 10.9 months. The response rate was 63.5%. The most common adverse event was neutropenia (57.8%). Only one patient had grade 3 pulmonary hemorrhage. Patients who had high baseline VCAM had a higher risk of progression or death compared with those who had low baseline VCAM levels. No relationships between outcome and any other biomarkers were seen. Conclusion The addition of bevacizumab to cisplatin and etoposide in patients with ED-SCLC results in improved PFS and OS relative to historical controls who received this chemotherapy regimen without bevacizumab. This regimen appears to be well tolerated and has minimal increase in toxicities compared with chemotherapy alone. Baseline VCAM levels predicted survival, but no other relationships among treatment, biomarkers, and outcome were identified.
Domestic Terrorism With Chemical or Biological Agents: Psychiatric Aspects
Authors: Cleto DiGiovanni
Journal: American Journal of Psychiatry (1999)

OBJECTIVE: This article highlights the mental health consequences of a domestic terrorist incident involving chemical or biological weapons. METHOD: The author reviews the literature on the neuropsychiatric effects of selected chemical and biological weapon agents, on the psychological sequelae of mass disasters, and on approaches to crisis intervention. RESULTS: Disturbances of behavior, affect, and cognition can result directly from the pharmacological actions of some chemical and biological weapon agents. In addition, an incident involving these agents can have considerable psychological effects on individuals and the community. In either case, some disorders are acute and others are prolonged or delayed in onset. Effective therapeutic intervention involves a broad range of clinical, social, and administrative actions. CONCLUSIONS: Psychiatrists have an important role in the management of a chemical or biological terrorist incident and, along with their other medical colleagues, should train and prepare for it.
How to Keep Up with the Medical Literature: V. Access by Personal Computer to the Medical Literature
Authors: R. BRIAN HAYNES
Journal: Annals of Internal Medicine (1986)

Access to the medical literature through personal computers is now readily available and can greatly reduce logistical barriers to using recently published journal articles to support clinical decisions. In this article, we describe many of the options available to clinicians who wish to do their own computer searching of MEDLINE, the largest of the electronic services for the biomedical literature. The "bare bones" computer equipment needed includes a terminal or personal computer, a modem and telephone line, and a printer. Access to MEDLINE is then gained through subscribing to any of a burgeoning number of database vendors. A comparison of 17 permutations and combinations of software and vendors shows that the software and vendors vary substantially in efficiency, cost, and ease of use. Direct subscription to MEDLINE is least expensive, PaperChase is the simplest service to use, and Colleague and Medis provide both MEDLINE access plus full-text journals online. Basic search techniques are illustrated for three clinical problems.
Structure of Human Histocompatibility Leukocyte Antigen (Hla)-Cw4, a Ligand for the Kir2d Natural Killer Cell Inhibitory Receptor
Authors: Qing R. Fan, Don C. Wiley
Journal: The Journal of Experimental Medicine (1999)

The crystal structure of the human class I major histocompatibility complex molecule, human histocompatibility leukocyte antigen (HLA)-Cw4, the ligand for a natural killer (NK) cell inhibitory receptor, has been determined, complexed with a nonameric consensus peptide (QYDDAVYKL). Relative to HLA-A2, the peptide binding groove is widened around the COOH terminus of the alpha 1 helix, which contains residues that determine the specificity of HLA-Cw4 for the inhibitory NK receptor, KIR2D. The structure reveals an unusual pattern of internal hydrogen bonding among peptide residues. The peptide is anchored in four specificity pockets in the cleft and secured by extensive hydrogen bonds between the peptide main chain and the cleft. The surface of HLA-Cw4 has electrostatic complementarity to the surface of the NK cell inhibitory receptor KIR2D.
Hospital closures: the great taboo
Authors: Nick Timmins
Journal: BMJ (2007)

Poor communication between primary care trusts and GPs is seriously compromising the safety of patients in England, a group of MPs said this week.In its latest report the House of Commons Committee of Public Accounts also warns that 96% of GPs are failing to report dangerous incidents to the National Patient Safety Agency.For its report, which examines the Department of Health's progress in implementing clinical governance in primary care, the committee had taken evidence from the chief executive of the NHS, the deputy chief medical officer, and the NHS's director general of commissioning.Committee chairman Edward Leigh said, "Too many primary care organisations are paying lip service to the principles of the Department of Health's clinical governance agenda.The lines of communication between the primary care trusts, on the one hand, and their GPs and other healthcare contractors, on the other, are defective."He added: "How can we be confident in the NHS's ability to share learning locally and nationally about what can go wrong in health care when only a tiny proportion of GPs-4%-routinely report patient safety events and incidents to the National Patient Safety Agency?"In response to a series of high profile problems in the 1990s, including the Shipman murders and events at the Bristol Royal Infirmary, the health department introduced its 10 year programme to boost patient safety.The centrepiece was the clinical governance system.The new report suggests, however, that clinical governance is not as well established in primary care as in secondary care.The committee says that this is due largely to the complexity of the role of primary care trusts in commissioning and providing care and to the independence of contractors delivering health care, particularly GPs.The Committee of Public Accounts' 47th report of the current session can be found at www. parliament.uk/pac.Primary� care pay�s only� "lip service" to clinical governance, MPs say� UK NEWS Regulator gives green light to research using human-animal embryos, p 531 WoRld NEWS US me�ical authorities are accuse� o�� ��ailing to act over �octors in �uantanamo, p 53� US me�ical authorities are accuse� o�� ��ailing to act over �octors in �uantanamo, p 53� , p 53� bmj.comNumber o�� bipolar �isor�er �iagnoses leaps among US young people Number o�� bipolar �isor�er �iagnoses leaps among US young people
Biologic and Biochemical Properties of Detergent-Solubilized Tumor-Specific Transplantation Antigen From a Simian Virus 40-Induced Neoplasm: Brief Communication
Authors: T. Natori, L. W. Law, E. Appella
Journal: JNCI Journal of the National Cancer Institute (1977)

Journal Article Biologic and Biochemical Properties of Detergent-Solubilized Tumor-Specific Transplantation Antigen From a Simian Virus 40-Induced Neoplasm: Brief Communication Get access T. Natori, T. Natori 2Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Public Health Service, U.S. Department of Health, Education, and Welfare, Bethesda, Md. 20014. Search for other works by this author on: Oxford Academic PubMed Google Scholar L. W. Law, L. W. Law 3 2Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Public Health Service, U.S. Department of Health, Education, and Welfare, Bethesda, Md. 20014. 3Address reprint requests to Dr. Law. Search for other works by this author on: Oxford Academic PubMed Google Scholar E. Appella E. Appella 2Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Public Health Service, U.S. Department of Health, Education, and Welfare, Bethesda, Md. 20014. 4We thank Mr. Donald Foor for technical assistance and Ms. Linda Brunson for typing the manuscript. Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 59, Issue 4, October 1977, Pages 1331–1333, https://doi.org/10.1093/jnci/59.4.1331 Published: 01 October 1977 Article history Received: 03 March 1977 Accepted: 05 May 1977 Published: 01 October 1977
Imatinib inhibits VEGF-independent angiogenesis by targeting neuropilin 1–dependent ABL1 activation in endothelial cells
Authors: Claudio Raimondi, Alessandro Fantin, Anastasia Lampropoulou, Laura Denti, Anissa Chikh, Christiana Ruhrberg
Journal: The Journal of Experimental Medicine (2014)

To enable new blood vessel growth, endothelial cells (ECs) express neuropilin 1 (NRP1), and NRP1 associates with the receptor tyrosine kinase VEGFR2 after binding the vascular endothelial growth factor A (VEGF) to enhance arteriogenesis. We report that NRP1 contributes to angiogenesis through a novel mechanism. In human and mouse ECs, the integrin ligand fibronectin (FN) stimulated actin remodeling and phosphorylation of the focal adhesion component paxillin (PXN) in a VEGF/VEGFR2-independent but NRP1-dependent manner. NRP1 formed a complex with ABL1 that was responsible for FN-dependent PXN activation and actin remodeling. This complex promoted EC motility in vitro and during angiogenesis on FN substrates in vivo. Accordingly, both physiological and pathological angiogenesis in the retina were inhibited by treatment with Imatinib, a small molecule inhibitor of ABL1 which is widely used to prevent the proliferation of tumor cells that express BCR-ABL fusion proteins. The finding that NRP1 regulates angiogenesis in a VEGF- and VEGFR2-independent fashion via ABL1 suggests that ABL1 inhibition provides a novel opportunity for anti-angiogenic therapy to complement VEGF or VEGFR2 blockade in eye disease or solid tumor growth.
H3K4me3 inversely correlates with DNA methylation at a large class of non-CpG-island-containing start sites
Authors: Dheepa Balasubramanian, Batool Akhtar-Zaidi, Lingyun Song, Cynthia F. Bartels, Marty L Veigl, Lydia Beard, Lois Myeroff, Kishore Guda, James Lutterbaugh, Joseph E. Willis, Gregory E. Crawford, Sanford D Markowitz, Peter Christopher Scacheri
Journal: Genome Medicine (2012)

Abstract Background In addition to mutations, epigenetic silencing of genes has been recognized as a fundamental mechanism that promotes human carcinogenesis. To date, characterization of epigenetic gene silencing has largely focused on genes in which silencing is mediated by hypermethylation of promoter-associated CpG islands, associated with loss of the H3K4me3 chromatin mark. Far less is known about promoters lacking CpG-islands or genes that are repressed by alternative mechanisms. Methods We performed integrative ChIP-chip, DNase-seq, and global gene expression analyses in colon cancer cells and normal colon mucosa to characterize chromatin features of both CpG-rich and CpG-poor promoters of genes that undergo silencing in colon cancer. Results Epigenetically repressed genes in colon cancer separate into two classes based on retention or loss of H3K4me3 at transcription start sites. Quantitatively, of transcriptionally repressed genes that lose H3K4me3 in colon cancer (K4-dependent genes), a large fraction actually lacks CpG islands. Nonetheless, similar to CpG-island containing genes, cytosines located near the start sites of K4-dependent genes become DNA hypermethylated, and repressed K4-dependent genes can be reactivated with 5-azacytidine. Moreover, we also show that when the H3K4me3 mark is retained, silencing of CpG island-associated genes can proceed through an alternative mechanism in which repressive chromatin marks are recruited. Conclusions H3K4me3 equally protects from DNA methylation at both CpG-island and non-CpG island start sites in colon cancer. Moreover, the results suggest that CpG-rich genes repressed by loss of H3K4me3 and DNA methylation represent special instances of a more general epigenetic mechanism of gene silencing, one in which gene silencing is mediated by loss of H3K4me3 and methylation of non-CpG island promoter-associated cytosines.
Eicosanoid Transcellular Biosynthesis: From Cell-Cell Interactions to in Vivo Tissue Responses
Authors: Giancarlo Folco, Robert C. Murphy
Journal: Pharmacological Reviews (2006)

The biosynthesis of the biologically active metabolites of arachidonic acid involves a number of enzymes that are differentially expressed in cells. Prostaglandins and thromboxanes are derived from the chemically unstable prostaglandin (PG) H<sub>2</sub> intermediate synthesized by PGH synthases (cyclooxygenase-1/2) and leukotrienes from chemically unstable leukotriene A<sub>4</sub> by 5-lipoxygenase. Additional enzymes transform these reactive intermediates to a variety of chemical structures known collectively as the lipid mediators. Although some cells have the complete cassette of enzymes required for the production of biolog-ically active prostaglandins and leukotrienes, the actual biosynthetic events often are a result of cell-cell interaction and a transfer of these chemically reactive intermediates, PGH<sub>2</sub> and leukotriene A<sub>4</sub>, between cells. This process has come to be known as transcellular biosynthesis of eicosanoids and requires a donor cell to synthesize and release one component of the biosynthetic cascade and a second, accessory cell to take up that intermediate and process each into the final biologically active product. This review focuses on the evidence for transcellular biosynthetic events for prostaglandins, leukotrienes, and lipoxins occurring during cell-cell interactions. Evidence for arachidonic acid serving as a transcellular biosynthetic intermediate is presented. Experiments for transcellular events taking place in vivo that reveal the true complexity of eicosanoid biosynthesis within tissues are also reviewed.
Quantitative Plasma Hypermethylated DNA Markers of Undifferentiated Nasopharyngeal Carcinoma
Authors: Thian-Sze Wong, Dora Lai-Wan Kwong, Jonathan Shun-Tong Sham, William Ignace Wei, Yok-Lam Kwong, Anthony Po-Wing Yuen
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Gene-specific methylation is common in primary undifferentiated nasopharyngeal carcinoma (NPC). DNA released from apoptotic or necrotic cell death including those aberrantly methylated promoter DNA of cancer cells is absorbed into the circulation as cell-free plasma DNA of the patient. This study aims at evaluation of the potential use of methylated gene promoter DNA as a serological tumor marker of primary and potentially salvageable local or nodal recurrent NPC. Experimental Design: The quantity of plasma hypermethylated gene promoters of CDH1, DAPK1, p15, p16, RASSF1A, and MLH1 of 41 NPC patients before treatment and 43 normal individuals were studied using real-time quantitative PCR. The post-treatment plasma hypermethylated CDH1, DAPK1,and p16were also measured in 13 NPC patients with locoregional recurrence and 17 patients in remission. Results: Concentrations of cell-free circulating DNA were significantly higher in NPC patients than normal controls (28.79 ng/ml versus 16.57 ng/ml, respectively). There was no significant difference in plasma DNA concentration of EBV-positive and -negative normal individuals. Methylated DNA was detectable in plasma of NPC patients before treatment including 46% for CDH1,42% for p16,20% for DAPK1,20% for p15,and 5% for RASSF1A.Hypermethylated MLH1was not detected in plasma of all of the NPC patients and normal individuals. Aberrantly hypermethylated promoter DNA of at least one of the five genes was detectable in 29 of 41 (71%) plasma of NPC patients before treatment. Hypermethylated promoter DNA of at least one of the three genes (CDH1, DAPK1, and p16) was detectable in post-treatment plasma of 5 of 13 (38%) recurrent NPC patients and none of the patients in remission. Conclusions: Our results suggested that cell-free circulating methylated gene promoter DNA is a possibly useful serological marker in assisting in screening of primary and potentially salvageable local or regional recurrent NPC.
Prorenin Receptor Blockade Inhibits Development of Glomerulosclerosis in Diabetic Angiotensin II Type 1a Receptor–Deficient Mice
Authors: Atsuhiro Ichihara, Fumiaki Suzuki, Tsutomu Nakagawa, Yuki Kaneshiro, Tomoko Takemitsu, Mariyo Sakoda, A.H.M. Nurun Nabi, Akira Nishiyama, Takeshi Sugaya, Matsuhiko Hayashi, Tadashi Inagami
Journal: Journal of the American Society of Nephrology (2006)

Blockade of the renin-angiotensin system slows the progression of diabetic nephropathy but fails to abolish the development of end-stage nephropathy of diabetes. The prorenin-to-active renin ratio significantly increases in diabetes, and prorenin binding to its receptor in diabetic animal kidney induces the nephropathy without its conventional proteolytic activation, suggesting that angiotensin II (AngII) may not be the decisive factor causing the nephropathy. For identification of an AngII-independent mechanism, diabetes was induced in wild-type mice and AngII type 1a receptor gene-deficient mice by streptozotocin treatment, and their development and progression of diabetic nephropathy were assessed. In addition, prolonged inhibition of angiotensin-converting enzyme and prolonged prorenin receptor blockade were compared for their efficacy in preventing the nephropathy that occurred in diabetic AngII type 1a receptor gene-deficient mice. Only the prorenin receptor blockade with a short peptide of prorenin practically abolished the increased mitogen-activated protein kinase (MAPK) activation and nephropathy despite unaltered increase in AngII in diabetic kidney. These results indicate that the MAPK activation signal leads to the diabetic nephropathy but not other renin-angiotensin system-activated mechanisms in the glomeruli. It is not only AngII but also intraglomerular activation of MAPK by the receptor-associated prorenin that plays a pivotal role in diabetic nephropathy.
Thrombomodulin inhibits intrahepatic spread in human hepatocellular carcinoma
Authors: Taketoshi Suehiro, Mitsuo Shimada, Takashi Matsumata, Akinobu Taketomi, Kazuharu Yamamoto, Keizo Sugimachi
Journal: Hepatology (1995)

Thrombomodulin (TM) converts thrombin from procoagulant into anticoagulant protein to activate protein C. Thrombin also plays an important role in the metastatic process of cancer cells. We performed an immunohistochemical and clinicopathological study of TM in 141 cases with resected hepatocellular carcinoma (HCC) measuring less than 6 cm in diameter. Twenty-five specimens (17.73%) stained positive for TM. TM was found in the cytoplasm and surface of cancer cells. The clinicopathological findings according to the positive of TM are examined in HCC. The preoperative plasma TM level of the patients with tissue that stained positive for TM was significantly higher than that of the patients with negative results; for the postoperative TM level, there were no differences between them. In addition, the frequencies of intrahepatic metastasis, tumor thrombus in the portal vein, and capsular infiltration were significantly lower in patients whose tissue stained positive for TM than in patients whose tissue stained negative for TM. The recurrence freedom rate was significantly higher in patients whose tissue stained positive for TM than patients whose tissue stained negative for TM. Thus, TM-producing HCC shows a slow intrahepatic spread. Therefore, these findings suggest that TM may inhibit the adhesion of tumor cells to the portal vein because of anticoagulant activity and thus prevent the spread of intrahepatic metastasis.