tbuckley/cabot-search huggingface dataset:
Co-occurrence of Risk Alleles in or Near Genes Modulating Insulin Secretion Predisposes Obese Youth to Prediabetes
Authors: Cosimo Giannini, Chiara Dalla Man, Leif Groop, Claudio Cobelli, Hongyu Zhao, Melissa M. Shaw, Elvira Duran, Bridget Pierpont, Allen E. Bale, Sonia Caprio, Nicola Santoro
Journal: Diabetes Care (2013)

Paralleling the rise of pediatric obesity, the prevalence of impaired glucose tolerance (IGT) and type 2 diabetes (T2D) is increasing among youth. In this study, we asked whether the co-occurrence of risk alleles in or near five genes modulating insulin secretion (TCF7L2 rs7903146, IGF2BP2 rs4402960, CDKAL1 rs7754840, HHEX rs1111875, and HNF1A rs1169288) is associated with a higher risk of IGT/T2D in obese children and adolescents.We studied 714 obese subjects (290 boys and 424 girls; mean age 13.6 ± 3.1 years; mean z score BMI 2.2 ± 0.4) and evaluated the insulin secretion by using the oral minimal model and, in a subgroup of 37 subjects, the hyperglycemic clamp. Also, 203 subjects were followed up for a mean of 2.1 years.We observed that the increase of risk alleles was associated with a progressive worsening of insulin secretion (P < 0.001) mainly due to an impairment of the dynamic phase of insulin secretion (P = 0.004); the higher the number of the risk alleles, the higher the chance of progression from normal glucose tolerance (NGT) to IGT/T2D (P = 0.022). Also, for those who were IGT at baseline, a higher risk score was associated with a lower odds to revert to NGT (P = 0.026).Obese children and adolescents developing IGT/T2D have a higher genetic predisposition than those who do not show these diseases, and this predisposition is mainly related to gene variants modulating the early phase of insulin secretion. Although these data are very interesting, they need to be replicated in other cohorts.
Modelling dysplasia detection in ulcerative colitis: clinical implications of surveillance intensity
Authors: D Awais, C A Siegel, P D R Higgins
Journal: Gut (2009)

<h3>Background:</h3> Endoscopic surveillance of chronic colitis uses random biopsies to find dysplastic fields. Enhanced endoscopic methods are more sensitive for dysplasia detection, but their specificity for colorectal cancer risk is unknown. <h3>Aims:</h3> To develop a mathematical model of the sensitivity of random biopsy surveillance, and determine the implications of negative, a single positive, or multiple positive biopsies for dysplasia, and compare the detection threshold to that detectable by enhanced endoscopy. <h3>Methods:</h3> Using mathematical modelling, we calculated the confidence level with which dysplasia can be excluded, the dysplastic field size detection threshold, the predicted area of a dysplastic field, and the number of biopsies needed for a given dysplasia detection threshold and confidence level. <h3>Results:</h3> 32 random biopsies provide only 80% confidence that dysplasia involving ⩾5% of the colon can be detected. When a single biopsy of 18 is dysplastic, this predicts a dysplastic area (89 cm<sup>2</sup>) several orders of magnitude greater than dysplastic fields that are readily detectable by enhanced endoscopy (1 cm diameter), and the predicted field size increases rapidly with multiple positive biopsies. <h3>Conclusions:</h3> Random biopsy surveillance is sufficiently sensitive to detect large dysplastic fields with significant colorectal cancer risk. Enhanced endoscopy can detect much smaller dysplastic fields, but these have unknown (perhaps much lower) colorectal cancer risk. Small dysplastic fields should not be assumed to indicate a high colorectal cancer risk that warrants colectomy. Prospective studies are needed to define the colorectal cancer risk and optimal management of small dysplastic lesions.
Race, Pharmacogenomics, and Marketing: Putting BiDil in Context
Authors: Jonathan Kahn
Journal: The American Journal of Bioethics (2006)

This article endeavors to place into context recent developments surrounding the United States Food and Drug Administration recent approval of BiDil (isosorbide dinitrate/hydralazine hydrochloride) (NitroMed, Inc., Lexington, MA) as the first ever race-specific drug--in this case to treat heart failure in African Americans. It focuses in particular on both commercial incentives and statistical manipulation of medical data as framing the drive to bring BiDil to market as a race-specific drug. In current discourse about pharmacogenomics, targeting a racial audience is perceived as necessary because at this point the technology and resources do not exist to scan efficiently every individual's genetic profile. The article argues that medical researchers may say they are using race as a surrogate to target biology in drug development, but corporations are using biology as a surrogate to target race in drug marketing. Pharmacogenomics may hold great promise, but on our way to that Promised Land, it is imperative to review such short cuts with a critical eye.
Development of human lymphohematopoietic stem and progenitor cells defined by expression of CD34 and CD81
Authors: Feng Ma, Mika Wada, Hiroshi Yoshino, Yasuhiro Ebihara, Takefumi Ishii, Atsushi Manabe, Ryuhei Tanaka, Taira Maekawa, Mamoru Ito, Hideo Mugishima, Shigetaka Asano, Tatsutoshi Nakahata, Kohichiro Tsuji
Journal: Blood (2001)

In this study, cord blood CD34+ cells expressed CD81, a member of the transmembrane 4 superfamily, and were classified into 3 subpopulations on the basis of their expression levels: CD34+CD81+, CD34lowCD81+, and CD34+CD81high. The lymphohematopoietic activity of each subpopulation was then examined by using suspension and clonogenic cultures for hematopoietic potential, coculture with MS-5 cells for B-cell potential, organ cultures of thymus lobes from nonobese diabetic/severe combined immunodeficiency disease (NOD/SCID) fetal mice, coculture with stromal cells derived from NOD/SCID fetal-mouse liver tissue for natural killer (NK) cell and mast cell potentials, and xenotransplantation into NOD/SCID mice for long-term repopulating (LTR) ability. CD34+CD81+ cells represented a heterogeneous population that had all the lymphohematopoietic activities, including NOD/SCID mouse-repopulating ability. CD34lowCD81+ cells were enriched in erythroid, megakaryocytic, and NK lineage potentials but had lost T-cell and B-cell potentials and LTR ability. The CD34+CD81high fraction was depleted of most lymphohematopoietic potentials except NK cell and mast cell potentials. Thus, along the differentiation cascade from CD34+CD81+ lymphohematopoietic stem cells, an up-regulation of CD81 or a down-regulation of CD34 results in a change in lymphohematopoietic properties. CD81 may serve as a marker for defining developmental stages of lymphohematopoietic stem cells.
Olfactory Function in Mild Cognitive Impairment and Alzheimer’s Disease: An Investigation Using Psychophysical and Electrophysiological Techniques
Authors: Jürgen M. Peters, Thomas Hummel, Tilman Kratzsch, Jörn Lötsch, Carsten Skarke, Lutz Frölich
Journal: American Journal of Psychiatry (2003)

OBJECTIVE: To clarify the olfactory deficit hypothesis regarding Alzheimer’s disease, the authors compared olfactory function in patients with Alzheimer’s disease, subjects with mild cognitive impairment, and healthy comparison subjects. METHOD: Olfactory function of 14 patients with mild Alzheimer’s disease, eight subjects with mild cognitive impairment, and eight healthy age-matched comparison subjects was assessed with both psychophysical tests and olfactory event-related potentials. RESULTS: Group comparison of the psychophysical test results showed a significant main effect of diagnosis for odor detection threshold, odor discrimination, and odor identification. These results correlated only partially with those obtained from olfactory event-related potentials. Seven Alzheimer’s disease patients and four with mild cognitive impairment showed no olfactory event-related potentials, suggesting hyposmia, while all comparison subjects had clearly discernible responses. Patients with Alzheimer’s disease were significantly more likely to be nonresponders. In the four Alzheimer’s disease patients and four subjects with mild cognitive impairment who had clear electrophysiological responses, amplitudes and latencies of the various event-related potential components were normal, i.e., similar to those of the comparison subjects, although 12 of the 14 Alzheimer’s disease patients and seven of the eight mildly impaired subjects were classified as functionally anosmic with psychophysical methods. CONCLUSIONS: The electrophysiological results confirm prior findings of olfactory dysfunction in patients with Alzheimer’s disease and preclinical Alzheimer’s disease. Investigations of larger study groups with detailed cognitive examination and postmortem diagnosis may resolve the intriguing possibility of early diagnosis and discrimination of Alzheimer’s disease subtypes through chemosensory event-related potentials in addition to existing biomarkers.
Toll-Like Receptor 2 Agonists Exacerbate Accelerated Nephrotoxic Nephritis
Authors: Heather J. Brown, Steven H. Sacks, Michael G. Robson
Journal: Journal of the American Society of Nephrology (2006)

Glomerulonephritis can be exacerbated by infection. This study investigated the effect of N-palmitoyl-S-(2,3-bis(palmitoyloxy)-(2R,S)-propyl)-(R)-cysteinyl-seryl-(lysyl)3-lysine (Pam3CysSK4), a synthetic Toll-like receptor 2 (TLR2) ligand, that was given at immunization on disease severity in accelerated nephrotoxic nephritis. Stimulation of TLR by microbial constituents is known to influence the development of the adaptive immunity. It was hypothesized that the TLR2 ligand Pam3CysSK4 can modulate the development of disease in accelerated nephrotoxic nephritis by influencing the development of adaptive immunity. It is shown that Pam3CysSK4, when given at immunization, can increase profoundly the severity of disease, and with the use of TLR2-deficient mice, it is shown that this disease exacerbation depends on the presence of TLR2. Wild-type mice that were given Pam3CysSK4 at immunization and had more severe disease also had a greater amount of antigen-specific IgG1, IgG2b, and IgG3 in the serum and more IgG2b and IgG3 deposited within the glomerulus. They also had increased numbers of glomerular CD4-positive T cells. Therefore, the more severe disease that was seen in the group that was immunized with lipopeptide can be attributed to an influence on the adaptive immune response.
Peritoneal Fluid and Solute Transport
Authors: Andreas Fußho[Combining Diaeresis]ller, Sandra zur Nieden, Bernd Grabensee, Jo[Combining Diaeresis]rg Plum
Journal: Journal of the American Society of Nephrology (2002)

ABSTRACT. The integrity of the peritoneal membrane in peritoneal dialysis (PD) is of major importance for adequate dialysis and fluid balance. However, alterations in peritoneal fluid transport, such as ultrafiltration failure, often develop during long-term PD. To investigate peritoneal solute and fluid transport and to analyze the influence of treatment time, peritonitis incidence, and PD modality (continuous ambulatory PD [CAPD] or automated PD [APD]), a cross-sectional study with an extended peritoneal transport test that used dextran 70 in 2 L of glucose was performed in 23 nonselected chronic PD patients. Compared were long-term (>40 mo) with short-term PD patients (<40 mo), CAPD with APD patients, and those with a peritonitis incidence of >0.25/yr to those with an incidence of <0.25/yr. Dialysate/plasma (D/P) ratio and mass transfer area coefficient of creatinine, lymphatic absorption rate (LAR), transcapillary ultrafiltration, and effective ultrafiltration were measured. Long-term PD patients had higher D/P ratio of creatinine (73.5 ± 2.3% versus 65.9 ± 2.2%; P < 0.01) and higher LAR (243 ± 69 ml/4 h versus 96 ± 31 ml/4 h; P < 0.03), both resulting in lower effective ultrafiltration (242 ± 35 ml/4 h versus 324 ± 30 ml/4 h; P < 0.05). D/P ratio (r = 0.66) and LAR (r = 0.67) were positively correlated to PD duration. Patients on APD compared with those on CAPD and patients with a history of peritonitis compared with those without did not differ in terms of D/P ratio, mass transfer area coefficient, LAR, transcapillary ultrafiltration, and effective ultrafiltration. Lower ultrafiltration after long-term PD is both the result of increased small solute transport and increased lymphatic absorption. APD or CAPD modality and peritonitis incidence do not have a significant influence on small solute transport or fluid kinetics.
Disorders of the Lower Esophageal Sphincter
Authors: R S Fisher, S Cohen
Journal: Annual Review of Medicine (1975)

The junction of the esophagus and stomach in man is marked by a zone of elevated pressure which has been called the lower esophageal sphincter (LES) (1, 2). The purpose of this sphincter mechanism is to prevent regurgitation of gastric contents from a positive pressure cavity into the esophagus which maintains a pressure negative to the atmosphere (3, 4). This sphincter must not only prevent gastroeso­ phageal reflux, but also it must open or relax when called upon to allow passage of food into the stomach (5). A number of diseases in which the LES fails as an antireflux mechanism or fails to relax properly during swallowing have been recognized. Clarification of the pathophysiology of these diseases and an approach to newer forms of therapy depend upon understanding the basic physiology of LES function. The purpose of this review is threefold: I. to discuss recent concepts involving the regulation of LES strength and LES relaxation; 2. to define the basic abnormalities recognized in disorders of LES function; and 3. to explore the physiological basis of new ap­ proaches to pharmacological and surgical therapy.
Three Immunomarker Support Vector Machines–Based Prognostic Classifiers for Stage IB Non–Small-Cell Lung Cancer
Authors: Zhi-Hua Zhu, Bing-Yu Sun, Yun Ma, Jian-Yong Shao, Hao Long, Xu Zhang, Jian-Hua Fu, Lan-Jun Zhang, Xiao-Dong Su, Qiu-Liang Wu, Peng Ling, Ming Chen, Ze-Ming Xie, Yi Hu, Tie-Hua Rong
Journal: Journal of Clinical Oncology (2009)

Approximately 30% of patients with stage IB non-small-cell lung cancer (NSCLC) die within 5 years after surgery. Current staging methods are inadequate for predicting the prognosis of this particular subgroup. This study identifies prognostic markers for NSCLC.We used computer-generated random numbers to study 148 paraffin-embedded specimens for immunohistochemical analysis. We studied gene expression in paraffin-embedded specimens of lung cancer tissue from 73 randomly selected patients with stage IB NSCLC who had undergone radical surgical resection and evaluated the association between the level of expression and survival. We used support vector machines (SVM)-based methods to develop three immunomarker-SVM-based prognostic classifiers for stage IB NSCLC. For validation, we used randomly assigned specimens from 75 other patients.We devised three immunomarker-SVM-based prognostic classifiers, including SVM1, SVM2, and SVM3, to refine prognosis of stage IB NSCLC successfully. The SVM1 model integrates age, cancer cell type, and five markers, including CD34MVD, EMA, p21ras, p21WAF1, and tissue inhibitors of metalloproteinases (TIMP) -2. The SVM2 model integrates age, cancer cell type, and 19 markers, including BCL2, caspase-9, CD34MVD, low-molecular-weight cytokeratin, high-molecular-weight cytokeratin, cyclo-oxygenase-2, EMA, HER2, matrix metalloproteinases (MMP) -2, MMP-9, p16, p21ras, p21WAF1, p27kip1, p53, TIMP-1, TIMP-2, vascular endothelial growth factor (VEGF), and beta-catenin. The SVM3 model consists of SVM1 and SVM2. The three models were independent predictors of overall survival. We validated the classifiers with data from an independent cohort of 75 patients with stage IB NSCLC.The three immunomarker-SVM-based prognostic characteristics are closely associated with overall survival among patients with stage IB NSCLC.
Gastric mucosal superoxide dismutases in Helicobacter pylori infection.
Authors: J M Gotz, C I van Kan, H W Verspaget, I Biemond, C B Lamers, R A Veenendaal
Journal: Gut (1996)

BACKGROUND--The mucosal pathology of Helicobacter pylori infection may in part be due to excessive production of reactive oxygen metabolites (ROMs) by phagocytes. The influence of H pylori infection on mucosal superoxide dismutases, some major scavenger enzymes of ROM was investigated. In humans superoxidase dismutase is present in at least two forms-that is, mitochondrial manganese (Mn)-superoxide dismutase and cytoplasmic copper-zinc (CuZn)-superoxide dismutase. METHODS--The amount and activity of both superoxide dismutases were measured, respectively by enzyme linked immunosorbent assay (ELISA) and spectrophotometrical enzyme activity assay, in gastric biopsy homogenates of patients with normal mucosa (n = 39) and in patients with H pylori related gastritis (n = 71). Infection and gastritis were confirmed by a combination of culture, serology, and histology. RESULTS--The amount (p &lt; 0.001) and activity (p &lt; or = 0.05) of Mn-superoxide dismutase were increased by about twofold to three-fold, whereas the amount and activity of CuZn-superoxide dismutase showed a slight decrease in gastric mucosa of patients with H pylori gastritis, in both antrum and corpus, compared with normal mucosa of patients without H pylori infection. Mn-superoxide dismutase concentrations in biopsy specimens of histologically normal corpus from patients with an inflamed antrum were significantly higher (p &lt; 0.01) than that of patients with a histologically normal antrum. CONCLUSION-- H pylori infection has a differential effect on mitochondrial and cytoplasmic superoxide dismutase in the gastric mucosa, reflected by a pronounced increase in the cytokine inducible Mn-superoxide dismutase and a marginal decrease in the constitutive CuZn-superoxide dismutase.
Press: Meningitis: the making of a "scandal"
Authors: T. Jackson
Journal: BMJ (2000)

In retrospect, it is easy to see that the latest cluster of cases displayed the tell tale signs. Yes, there was rapid onset, yes, there was a certain feverishness, yes, this was one rash of newspaper stories that looked as though it was not going to go away. But anyone reading London's Evening Standard on Tuesday November 14 would have been hard pushed to diagnose just how serious this “meningitis scandal” was going to be.

The paper gave up its front page to the story of 22 month old Jacob Fogg, who died of meningoccal septicaemia after being sent home from London's Whittington Hospital. According to the report, headlined “Hospital too busy to save dying boy,” doctors had said he had had only flu.

Readers were referred to a double page spread inside the paper where the boy's parents gave a minute by minute account of their terrifying wait for treatment. They described “a vision …
Plectin-1 as a Novel Biomarker for Pancreatic Cancer
Authors: Dirk Bausch, Stephanie Thomas, Mari Mino-Kenudson, Castillo Carlos Fernández-del, Todd W. Bauer, Mark Williams, Andrew L. Warshaw, Sarah P. Thayer, Kimberly A. Kelly
Journal: Clinical Cancer Research (2010)

Abstract Purpose: We are in great need of specific biomarkers to detect pancreatic ductal adenocarcinoma (PDAC) at an early stage, ideally before invasion. Plectin-1 (Plec1) was recently identified as one such biomarker. However, its suitability as a specific biomarker for human pancreatic cancer, and its usability as an imaging target, remain to be assessed. Experimental Design: Specimens of human PDAC, chronic pancreatitis, and normal pancreata were evaluated by immunohistochemistry and Western blot analysis. To validate Plec1 as an imaging target, Plec1-targeting peptides (tPTP) were used as a contrast agent for single photon emission computed tomography in an orthotopic and liver metastasis murine model of PDAC. Results: Plec1 expression was noted to be positive in all PDACs but negative in benign tissues. Plec1 expression increases during pancreatic carcinogenesis. It was found to be misexpressed in only 0% to 3.85% of early PDAC precursor lesions (PanIN I/II) but in 60% of PanIN III lesions. Plec1 expression was further noted to be retained in all metastatic foci assayed and clearly highlighted these metastatic deposits in lymph nodes, liver, and peritoneum. In vivo imaging using tPTP specifically highlighted the primary and metastatic tumors. Biodistribution studies performed after imaging show that the primary pancreatic tumors and liver metastases retained 1.9- to 2.9-fold of tPTP over normal pancreas and 1.7-fold over normal liver. Conclusions: Plec1 is the first biomarker to identify primary and metastatic PDAC by imaging and may also detect preinvasive PanIN III lesions. Strategies designed to image Plec1 could therefore improve detection and staging. Clin Cancer Res; 17(2); 302–9. ©2010 AACR.
Ephrin-A1 expression contributes to the malignant characteristics of -fetoprotein producing hepatocellular carcinoma
Authors: H. Iida, M. Honda, H. F. Kawai, T. Yamashita, Y. Shirota, Bingcheng Wang, H. Miao, S. Kaneko
Journal: Gut (2005)

<b>Background and aims:</b> α-Fetoprotein (AFP), a tumour marker for hepatocellular carcinoma (HCC), is associated with poor prognosis. Using cDNA microarray analysis, we previously found that ephrin-A1, an angiogenic factor, is the most differentially overexpressed gene in AFP producing hepatoma cell lines. In the present study, we investigated the significance of ephrin-A1 expression in HCC. <b>Methods:</b> We examined ephrin-A1 expression and its effect on cell proliferation and gene expression in five AFP producing hepatoma cell lines, three AFP negative hepatoma cell lines, and 20 human HCC specimens. <b>Results:</b> Ephrin-A1 expression levels were lowest in normal liver tissue, elevated in cirrhotic tissue, and further elevated in HCC specimens. Ephrin-A1 expression was strongly correlated with AFP expression (<i>r</i> = 0.866). We showed that ephrin-A1 induced expression of AFP. This finding implicates ephrin-A1 in the mechanism of AFP induction in HCC. Ephrin-A1 promoted the proliferation of ephrin-A1 underexpressing HLE cells, and an ephrin-A1 antisense oligonucleotide inhibited the proliferation of ephrin-A1 overexpressing Huh7 cells. Thus ephrin-A1 affects hepatoma cell growth. cDNA microarray analysis showed that ephrin-A1 induced expression of genes related to the cell cycle (p21), angiogenesis (angiopoietin 1 and thrombospondin 1), and cell-cell interactions (Rho, integrin, and matrix metalloproteinases) in cultured hepatoma cells. These ephrin-A1 induced genes are also activated in HCC tissues that overexpress AFP. <b>Conclusion:</b> These findings suggest that the poor prognosis of patients with AFP producing HCC is partially caused by ephrin-A1 expression, which induces expression of genes related to tumour cell growth, angiogenesis, invasion, and metastasis.