tbuckley/cabot-search huggingface dataset:
Absence of TRAM Restricts Toll-Like Receptor 4 Signaling in Vascular Endothelial Cells to the MyD88 Pathway
Authors: Olivier A. Harari, Pilar Alcaide, Daniela Ahl, F. William Luscinskas, James K. Liao
Journal: Circulation Research (2006)

Mammalian cells respond to bacterial lipopolysaccharide (LPS) through a cognate receptor: Toll-like receptor 4 (TLR4). The signaling pathways, which link TLR4 to the proinflammatory transcription factor nuclear factor κB (NF-κB), occur through the intracellular docking proteins MyD88 and Trif. We hypothesize that unlike antigen-presenting cells, vascular endothelial cells (ECs) lack the Trif protein TRAM and are therefore incapable of eliciting Trif-dependent immune responses to LPS. Stimulation of wild-type mice with LPS leads to the activation of NF-κB in ECs and macrophages in vitro and in vivo. In contrast to macrophages, LPS did not activate endothelial NF-κB or NF-κB–dependent genes in MyD88 −/− mice, suggesting the absence of a functional Trif pathway in vascular ECs. Indeed, the Trif-dependent gene cxcl10 was not expressed in ECs after LPS stimulation. This correlated with diminished expression of the Trif accessory TIR protein TRAM in ECs. Overexpression of TRAM cDNA in ECs reconstituted LPS-induced Trif-dependent NF-κB activation and cxcl10 promoter activity. The functional absence of TRAM in vascular ECs restricts TLR4 signaling to MyD88-dependent pathway. This is in contrast to macrophages, which respond to LPS via both Trif- and MyD88-dependent pathways. These findings indicate that vascular ECs do not express the Trif-dependent gene subset. This implies that these genes may be dispensable for the endothelial response to bacterial infection and play no role in the endothelial contribution to the development of atherosclerosis.
Associations Between Liver Histology and Severity of the Metabolic Syndrome in Subjects With Nonalcoholic Fatty Liver Disease
Authors: Marno C. Ryan, Andrew M. Wilson, John Slavin, James D. Best, Alicia J. Jenkins, Paul V. Desmond
Journal: Diabetes Care (2005)

Nonalcoholic fatty liver disease (NAFLD) is associated with a histopathological picture resembling alcohol-induced liver injury occurring in subjects who consume insignificant amounts of alcohol. In NAFLD, steatosis alone is associated with good prognosis, whereas nonalcoholic steatohepatitis (NASH) can progress to fibrosis and cirrhosis in up to 30% of cases, potentially leading to liver failure and hepatocellular carcinoma. The prevalence of NAFLD and NASH in the U.S. is estimated at 10–20 and 2–3%, respectively (1,2,3).

The metabolic syndrome, as defined by Adult Treatment Panel (ATP) III criteria, incorporates features known to predict cardiovascular disease and type 2 diabetes (4). NAFLD has been demonstrated to be associated with features of the metabolic syndrome, including hyperglycemia (5,6), dyslipidemia (5,6), hypertension (7), and central obesity (7,8). In addition, insulin resistance, even without these other features, is almost universal in subjects with NAFLD (6). However, the factors specifically associated with hepatic inflammation, fibrosis, and thus liver disease progression are still being elucidated.

In this study of human subjects with NAFLD, we explored specific relationships between hepatic histology and markers of the metabolic syndrome.

Forty-six subjects with NAFLD were recruited from clinics. The diagnosis was based on the histological presence of macrovesicular steatosis, with or without lobular inflammation, hepatocellular degeneration, or fibrosis (8,9). All subjects …
NKX3.1 stabilizes p53, inhibits AKT activation, and blocks prostate cancer initiation caused by PTEN loss
Authors: Qunying Lei, Jing Jiao, Li Xin, Chun-Ju Chang, Shunyou Wang, Jing Gao, Martin E. Gleave, Owen N. Witte, Xin Liu, Hong Wu
Journal: Cancer Cell (2006)
Disease Biomarkers in Cerebrospinal Fluid of Patients with First-Onset Psychosis
Authors: Jeffrey T.-J Huang, F. Markus Leweke, David Oxley, Lan Wang, Nathan Harris, Dagmar Koethe, Christoph W Gerth, Brit M Nolden, Sonja Gross, Daniela Schreiber, Benjamin Reed, Sabine Bahn
Journal: PLoS Medicine (2006)

Background Psychosis is a severe mental condition that is characterized by a loss of contact with reality and is typically associated with hallucinations and delusional beliefs. There are numerous psychiatric conditions that present with psychotic symptoms, most importantly schizophrenia, bipolar affective disorder, and some forms of severe depression referred to as psychotic depression. The pathological mechanisms resulting in psychotic symptoms are not understood, nor is it understood whether the various psychotic illnesses are the result of similar biochemical disturbances. The identification of biological markers (so-called biomarkers) of psychosis is a fundamental step towards a better understanding of the pathogenesis of psychosis and holds the potential for more objective testing methods. Methods and Findings Surface-enhanced laser desorption ionization mass spectrometry was employed to profile proteins and peptides in a total of 179 cerebrospinal fluid samples (58 schizophrenia patients, 16 patients with depression, five patients with obsessive-compulsive disorder, ten patients with Alzheimer disease, and 90 controls). Our results show a highly significant differential distribution of samples from healthy volunteers away from drug-naïve patients with first-onset paranoid schizophrenia. The key alterations were the up-regulation of a 40-amino acid VGF-derived peptide, the down-regulation of transthyretin at ~4 kDa, and a peptide cluster at ~6,800–7,300 Da (which is likely to be influenced by the doubly charged ions of the transthyretin protein cluster). These schizophrenia-specific protein/peptide changes were replicated in an independent sample set. Both experiments achieved a specificity of 95% and a sensitivity of 80% or 88% in the initial study and in a subsequent validation study, respectively. Conclusions Our results suggest that the application of modern proteomics techniques, particularly mass spectrometric approaches, holds the potential to advance the understanding of the biochemical basis of psychiatric disorders and may in turn allow for the development of diagnostics and improved therapeutics. Further studies are required to validate the clinical effectiveness and disease specificity of the identified biomarkers.
The nuclear receptor LRH-1 critically regulates extra-adrenal glucocorticoid synthesis in the intestine
Authors: Matthias Mueller, Igor Cima, Mario Noti, Andrea Fuhrer, Sabine Jakob, Laurent Dubuquoy, Kristina Schoonjans, Thomas Brunner
Journal: The Journal of Experimental Medicine (2006)

The nuclear receptor liver receptor homologue-1 (LRH-1, NR5A2) is a crucial transcriptional regulator of many metabolic pathways. In addition, LRH-1 is expressed in intestinal crypt cells where it regulates the epithelial cell renewal and contributes to tumorigenesis through the induction of cell cycle proteins. We have recently identified the intestinal epithelium as an important extra-adrenal source of immunoregulatory glucocorticoids. We show here that LRH-1 promotes the expression of the steroidogenic enzymes and the synthesis of corticosterone in murine intestinal epithelial cells in vitro. Interestingly, LRH-1 is also essential for intestinal glucocorticoid synthesis in vivo, as LRH-1 haplo-insufficiency strongly reduces the intestinal expression of steroidogenic enzymes and glucocorticoid synthesis upon immunological stress. These results demonstrate for the first time a novel role for LRH-1 in the regulation of intestinal glucocorticoid synthesis and propose LRH-1 as an important regulator of intestinal tissue integrity and immune homeostasis.
Time trends in glioblastoma multiforme survival: the role of temozolomide
Authors: R. Dubrow, A. S. Darefsky, D. I. Jacobs, L. S. Park, M. G. Rose, M. S. H. Laurans, J. T. King
Journal: Neuro-Oncology (2013)

In 2005, maximum safe surgical resection, followed by radiotherapy with concomitant temozolomide (TMZ), followed by adjuvant TMZ became the standard of care for glioblastoma (GBM). Furthermore, a modest, but meaningful, population-based survival improvement for GBM patients occurred in the US between 1999 (when TMZ was first introduced) and 2008. We hypothesized that TMZ usage explained this GBM survival improvement. We used national Veterans Health Adminis-tration (VHA) databases to construct a cohort of GBM patients, with detailed treatment information, diagnosed 1997–2008 (n = 1645). We compared survival across 3 periods of diagnosis (1997–2000, 2001–2004, and 2005–2008) using Kaplan–Meier curves. We used proportional hazards models to calculate period hazard rate ratios (HRs) and 95% confidence intervals (CIs), adjusted for demographic, clinical, and treatment covariates. Survival increased over calendar time (stratified log-rank P < .0001). After adjusting for age and Charlson comorbidity score, for cases diagnosed in 2005–2008 versus 1997–2000, the HR was 0.72 (95% CI, 0.64–0.82; p-trend < .0001). Sequentially adding non-TMZ treatment variables (ie, surgery, radiotherapy, non-TMZ chemotherapy) to the model did not change this result. However, adding TMZ to the model containing age, Charlson comorbidity score, and all non-TMZ treatments eliminated the period effect entirely (HR = 1.01; 95% CI, 0.86–1.19; p-trend = 0.84). The observed survival improvement among GBM patients diagnosed in the VHA system between 1997 and 2008 was completely explained by TMZ. Similar studies in other populations are warranted to test the generalizability of our finding to other patient cohorts and health care settings.
Oncofetal Antigen: A Tumor-Associated Fetal Antigen Immunogenic in Man&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: R F Irie, A E Giuliano, D L Morton
Journal: JNCI Journal of the National Cancer Institute (1979)

Oncofetal antigen (OFA) has been defined with the use of human natural antibodies as a membrane antigen of human cancer cells that cross-reacts with human fetal brain tissues. The immunogen that elicits the antibody is unknown. The present study was undertaken to examine the immunogenicity of the OFA found on tumor cells. Postoperative melanoma patients were immunized with OFA-positive melanoma cells. Anti-OFA reactivities in the immunized sera were titrated by the immune adherence assay with the use of a known OFA-positive cultured melanoma cell line, M14, as target cell. Alloantibodies were excluded by absorption with lymphoblastoid cells autologous to M14. Anti-OFA antibody then was identified by absorption with fetal brain. In 6 months of immunization, 19 of 23 patients produced increased anti-OFA antibodies. The peak titers ranged from 1:16 to 1:2,048. Sera from 18 patients who were not immunized also were tested for 6 months postoperatively, and none had significant increases in antibody titers. The increase of anti-OFA antibody titer in response to the immunization with OFA-positive tumor cells suggests the immunogenic capability of tumor-related OFA in man.
STEM CELL IN GASTROINTESTINAL STRUCTURE AND NEOPLASTIC DEVELOPMENT
Authors: M Brittan
Journal: Gut (2004)

tem cells are primitive cells located in a specialised mesenchymal ''niche'' that lack expression of any definitive markers of lineage commitment and are therefore difficult to define and identify.Stem cells maintain their capacity for limitless self replication throughout the lifetime of their host, and can also divide to produce daughter cells, committed to the formation of every adult cell lineage within their tissue of origin.The stem cells of the gastrointestinal tract remain unidentified which has led to many conflicting hypotheses as to their precise nature and function.For example, the numbers and location of stem cells in the intestinal crypts and gastric glands have never been conclusively proven and, consequently, the clonal origins of these structures under normal circumstances and in neoplasia are clouded issues.The morphological events of gastrointestinal carcinoma formation are hotly debated, with two main conflicting hypotheses of the mechanisms of expansion of a mutated stem cell clone.However, with the emergence of the molecular pathways governing gastrointestinal stem cell function, and the identification of putative intestinal molecular stem cell markers, such as Musashi-1, comes a clearer insight into the properties of the gastrointestinal stem cell.Adult stem cells from several tissues can leave their niche and engraft into extraneous tissues, including the gastrointestinal mucosa and underlying mesenchyme, and transform to produce adult cell lineages common to these foreign environments.This process is optimal when the requirement for regeneration is enhanced (that is, in diseased or damaged tissue) and indeed, the contribution of transplanted bone marrow stem cells to intestinal myofibroblasts is significantly upregulated in colitis.However, adult stem cell plasticity has recently been disparaged by reports suggesting that stem cells spontaneously fuse with indigenous adult cells to form a diploid cell with an aberrant karyotype, and it is important to investigate if bone marrow cells contribute to a gastrointestinal stem cell population, and indeed the mechanisms by which they do so.Identification of the origins, location, and molecular regulators of the gastrointestinal stem cell will provide a clearer understanding of normal gastrointestinal function and the genetic pathways involved in neoplastic change.
On the Role of Melanoma-Specific CD8+ T-Cell Immunity in Disease Progression of Advanced-Stage Melanoma Patients
Authors: Monique van Oijen, Adriaan Bins, Sjoerd Elias, Johan Sein, Pauline Weder, Gijsbert de Gast, Henk Mallo, Maarten Gallee, Harm van Tinteren, Ton Schumacher, John Haanen
Journal: Clinical Cancer Research (2004)

Cytotoxic T-cell immunity directed against melanosomal differentiation antigens is arguably the best-studied and most prevalent form of tumor-specific T-cell immunity in humans. Despite this, the role of T-cell responses directed against melanosomal antigens in disease progression has not been elucidated. To address this issue, we have related the presence of circulating melanoma-specific T cells with disease progression and survival in a large cohort of patients with advanced-stage melanoma who had not received prior treatment. In 42 (68%) of 62 patients, melanoma-specific T cells were detected, sometimes in surprisingly large numbers. Disease progression during treatment was more frequent in patients with circulating melanoma-specific T cells, and mean survival of patients with circulating melanoma-specific T cells was equal to the survival of patients without melanoma-specific T cells. These data suggest that the induction of melanosomal differentiation antigen-specific T-cell reactivity in advanced stage melanoma is a late event most likely due to antigen load and spreading and is not accompanied by a clinically significant antitumor effect. These melanoma-specific T cells may be functionally distinct from T cells raised during spontaneous regression or up vaccination.
Adiponectin, an Adipocyte-Derived Plasma Protein, Inhibits Endothelial NF-κB Signaling Through a cAMP-Dependent Pathway
Authors: Noriyuki Ouchi, Shinji Kihara, Yukio Arita, Yoshihisa Okamoto, Kazuhisa Maeda, Hiroshi Kuriyama, Kikuko Hotta, Makoto Nishida, Masahiko Takahashi, Masahiro Muraguchi, Yasukazu Ohmoto, Tadashi Nakamura, Shizuya Yamashita, Tohru Funahashi, Yuji Matsuzawa
Journal: Circulation (2000)

Background —Among the many adipocyte-derived endocrine factors, we found an adipocyte-derived plasma protein, adiponectin, that was decreased in obesity. We recently demonstrated that adiponectin inhibited tumor necrosis factor-α (TNF-α)–induced expression of endothelial adhesion molecules and that plasma adiponectin level was reduced in patients with coronary artery disease ( Circulation . 1999;100:2473–2476). However, the intracellular signal by which adiponectin suppressed adhesion molecule expression was not elucidated. The present study investigated the mechanism of modulation for endothelial function by adiponectin. Methods and Results —The interaction between adiponectin and human aortic endothelial cells (HAECs) was estimated by cell ELISA using biotinylated adiponectin. HAECs were preincubated for 18 hours with 50 μg/mL of adiponectin, then exposed to TNF-α (10 U/mL) or vehicle for the times indicated. NF-κB–DNA binding activity was determined by electrophoretic mobility shift assays. TNF-α–inducible phosphorylation signals were detected by immunoblotting. Adiponectin specifically bound to HAECs in a saturable manner and inhibited TNF-α–induced mRNA expression of monocyte adhesion molecules without affecting the interaction between TNF-α and its receptors. Adiponectin suppressed TNF-α–induced IκB-α phosphorylation and subsequent NF-κB activation without affecting other TNF-α–mediated phosphorylation signals, including Jun N-terminal kinase, p38 kinase, and Akt kinase. This inhibitory effect of adiponectin is accompanied by cAMP accumulation and is blocked by either adenylate cyclase inhibitor or protein kinase A (PKA) inhibitor. Conclusions —These observations raise the possibility that adiponectin, which is naturally present in the blood stream, modulates the inflammatory response of endothelial cells through cross talk between cAMP-PKA and NF-κB signaling pathways.
Helicobacter pylori , hyperammonemia and subclinical portosystemic encephalopathy: effects of eradication
Authors: Celia Vásconez, J.Ignasi Elizalde, Josep Llach, Angels Ginès, Carmen de la Rosa, Rosa M. Fernández, Antoni Mas, Joan Santamaría, Josep M. Bordas, Josep M. Piqué, Josep Terés
Journal: Journal of Hepatology (1999)
Specific Leukocyte Receptors for Small Endogenous Hormones. DETECTION BY CELL BINDING TO INSOLUBILIZED HORMONE PREPARATIONS
Authors: Yacob Weinstein, Kenneth L. Melmon, Henry R. Bourne, Michael Sela
Journal: Journal of Clinical Investigation (1973)

Receptors for small endogenous hormones on human leukocytes were studied by insolubilizing the hormones and incubating them with the cells. Histamine, norepinephrine, and prostaglandin E(2) (PGE(2)) were conjugated to either of two types of carrier: (bovine or rabbit) serum albumin or a random copolymer of DL-alanine and L-tyrosine. The conjugates were linked to agarose beads (Sepharose) and the resultant drug-conjugate-beads were incubated with leukocytes. Norepinephrine (when linked to its carrier via glutaraldehyde) and histamine preparations bound the majority of leukocytes. The binding appeared to be specific for the hormones tested. For example, the binding by histamine-rabbit serum albumin-Sepharose was prevented or reversed by high concentrations of histamine and histamine antagonists, but not by catecholamines or their pharmacologic antagonists. Similarly, binding of cells to the norepinephrine conjugate was inhibited by some catecholamines and propranolol, but not by histamine or histamine antagonists. Conjugates of norepinephrine linked via carbodiimide did not bind cells. The protein or copolymer carriers did not contribute to binding per se. The hormone-protein-conjugates bound more cells than the hormone-polymer conjugates. The former (unlike the free amines) failed to stimulate accumulation of cyclic AMP in leukocytes. The norepinephrine linked to polymer via glutaraldehyde, however, did stimulate leukocyte cyclic AMP accumulation, possibly because of the flexibility of the polymer. Columns of the various Sepharoses were used to determine the distribution of receptors to each hormone in mixed leukocyte populations. The majority of cells appeared to have receptors for both histamine and norepinephrine (bound through glutaraldehyde). Receptors to prostaglandins may have been detected by the column procedure, but their distribution could not be quantitated. The approach described provides a means to separate leukocytes on the basis of what are likely to be preformed receptors to small endogenous hormones, and to study the physiologic importance and function of the receptors.
Unexplained gastrointestinal dysmotility: the clue may lie in the brain
Authors: A. Parry-Jones, P. Paine, R. Ramdass, N. Townsend, R. Hammonds, A. Teubner, J. Shaffer, P. Cooper, S. Lal
Journal: Gut (2010)

<h3>Abstract</h3> <h3>Background</h3> Concerns have been expressed about a number of drugs that potentially worsen outcomes in patients with COVID-19. We sought to identify all potentially deleterious drug groups in COVID-19 and critically assess the underpinning strength of evidence pertaining to the harmful effects of these drugs. <h3>Methods and findings</h3> We performed a rapid systematic review, searching Medline, Embase and two COVID-19 portfolios (WHO COVID-19 database and NIH iSearch COVID-19 portfolio) for papers and preprints related to primary studies investigating drugs identified as potentially deleterious. Primary outcomes were direct measures of susceptibility to infection, disease severity and mortality. Study quality was assessed using the National Heart, Lung, and Blood Institute quality assessment tools. Random-effects meta-analyses were used for data synthesis with further subgroup analyses where possible for specific outcome, study design, statistical adjustment and drug groups when two were combined. Sensitivity analyses were performed by removing any studies at high risk of bias and by publication status. 49 observational studies (15 peer-reviewed papers and 34 preprints) reported primary outcomes for eight drug groups hypothesised to be deleterious. Meta-analysis showed that acute inpatient corticosteroid use was associated with increased mortality (OR 2.22, 95% CI 1.26-3.90), however this result appeared to have been biased by confounding via indication. One subgroup analysis indicated an association between immunosuppressant use and susceptibility to COVID-19 among case control and cross-sectional studies (OR 1.29, 95% CI 1.19-1.40) but this was not found with cohort studies (OR 1.11, 95% CI 0.86-1.43). Studies which adjusted for multiple confounders showed that people taking angiotensin-converting-enzyme inhibitors (ACEIs) or angiotensin-II-receptor blockers (ARBs) required a lower level of care (OR 0.85, 95% CI 0.74-0.98). Furthermore, studies which combined these two drug groups in their analysis demonstrated an association with a lower mortality (OR 0.68, 95% CI 0.55-0.85). <h3>Conclusions</h3> We found minimal high quality or consistent evidence that any drug groups increase susceptibility, severity or mortality in COVID-19. Converse to initial hypotheses, we found some evidence that regular use of ACEIs and ARBs prior to infection may be effective in reducing the level of care required, such as requiring intensive care, in patients with COVID-19.