tbuckley/cabot-search huggingface dataset:
Rab25 Is a Tumor Suppressor Gene with Antiangiogenic and Anti-Invasive Activities in Esophageal Squamous Cell Carcinoma
Authors: Man Tong, Kwok Wah Chan, Jessie Y.J. Bao, Kai Yau Wong, Jin-Na Chen, Pak Shing Kwan, Kwan Ho Tang, Li Fu, Yan-Ru Qin, Si Lok, Xin-Yuan Guan, Stephanie Ma
Journal: Cancer Research (2012)

Esophageal squamous cell carcinoma (ESCC), the major histologic subtype of esophageal cancer, is a devastating disease characterized by distinctly high incidences and mortality rates. However, there remains limited understanding of molecular events leading to development and progression of the disease, which are of paramount importance to defining biomarkers for diagnosis, prognosis, and personalized treatment. By high-throughout transcriptome sequence profiling of nontumor and ESCC clinical samples, we identified a subset of significantly differentially expressed genes involved in integrin signaling. The Rab25 gene implicated in endocytic recycling of integrins was the only gene in this group significantly downregulated, and its downregulation was confirmed as a frequent event in a second larger cohort of ESCC tumor specimens by quantitative real-time PCR and immunohistochemical analyses. Reduced expression of Rab25 correlated with decreased overall survival and was also documented in ESCC cell lines compared with pooled normal tissues. Demethylation treatment and bisulfite genomic sequencing analyses revealed that downregulation of Rab25 expression in both ESCC cell lines and clinical samples was associated with promoter hypermethylation. Functional studies using lentiviral-based overexpression and suppression systems lent direct support of Rab25 to function as an important tumor suppressor with both anti-invasive and -angiogenic abilities, through a deregulated FAK-Raf-MEK1/2-ERK signaling pathway. Further characterization of Rab25 may provide a prognostic biomarker for ESCC outcome prediction and a novel therapeutic target in ESCC treatment.
Impact of Body Mass and Body Composition on Circulating Levels of Natriuretic Peptides
Authors: Sandeep R. Das, Mark H. Drazner, Daniel L. Dries, Gloria L. Vega, Harold G. Stanek, Shuaib M. Abdullah, Russell M. Canham, Anne K. Chung, David Leonard, Frank H. Wians, James A. de Lemos
Journal: Circulation (2005)

Background— The association between higher body mass index (BMI) and lower B-type natriuretic peptide (BNP) level is thought to be mediated by expression of the natriuretic peptide clearance receptor (NPR-C) in adipose tissue. To explore this association, we tested 2 hypotheses: (1) that N-terminal (NT)-proBNP, which is not believed to bind NPR-C, would not be associated with BMI and (2) that lower BNP would be more closely associated with fat mass than with lean mass. Methods and Results— Measurements of BNP, NT-proBNP, and body composition by direct dual energy x-ray absorptiometry (DEXA) were performed in 2707 subjects from the Dallas Heart Study. The associations between obesity and low BNP (&lt;4 ng/L) or low NT-proBNP (lowest sex-specific quartile) were evaluated with multivariable logistic regression models stratified by sex and adjusted for age, race/ethnicity, hypertension, left ventricular mass, and end-diastolic volume. Higher BMI was independently associated with lower BNP and NT-proBNP (all P &lt;0.001). When BMI was replaced with both DEXA-derived lean and fat mass, greater lean mass, but not fat mass, was associated with low BNP and NT-proBNP levels. Conclusions— In a large, population-based cohort, we confirm the previously described association between higher BMI and lower BNP and demonstrate a similar inverse association between BMI and NT-proBNP. Interestingly, both BNP and NT-proBNP are more closely associated with lean mass than with fat mass. These findings do not support the hypothesis that the lower BNP levels seen in obesity are driven by enhanced BNP clearance mediated via NPR-C.
ELECTROENCEPHALOGRAPHIC PATTERNS FROM THE BASE OF THE BRAIN
Authors: MILTON GREENBLATT, DANIEL FUNKENSTEIN, DANIEL MILLER, MAX RINKEL
Journal: American Journal of Psychiatry (1947)

Electroencephalographic recordings from the base of the brain give valuable supplementary information to data obtained from conventional scalp recordings. Various locations of the deep lead are possible—subsphenoid, spheno-ethmoidal or subfrontal. Several varieties of basal patterns are described and illustrated. The effect of visual stimulation, overbreathing, drugs, spontaneous and induced electrical discharges in epileptics, and of gross intracranial pathology is described. In general the basal rhythm response to various stimuli is similar to that of the cortical (superficial) rhythm. Visual stimulation flattens the basal rhythm and blocks the alpha activity. Hyperventilation induces a build-up in size of potentials and a slowing of rhythm, which may be greater or less than that of the cortex. Autonomic drugs (epinephrine and mecholyl) appear to affect base more than cortex. Sodium amytal in amounts sufficient to produce intoxication but not sleep, results in high voltage fast waves in base as well as cortex. Electrical paroxysms typical of epilepsy usually are more pronounced at the cortex than at the base. The basal lead is a valuable adjunct in localization of gross intracranial pathology.
Loss of signal transducer and activator of transcription 5 leads to hepatosteatosis and impaired liver regeneration
Authors: Yongzhi Cui, Atsushi Hosui, Rui Sun, Kezhen Shen, Oksana Gavrilova, Weiping Chen, Margaret C. Cam, Bin Gao, Gertraud W. Robinson, Lothar Hennighausen
Journal: Hepatology (2007)

Growth hormone controls many facets of a cell's biology through the transcription factors Stat5a and Stat5b (Stat5). However, whole body deletion of these genes from the mouse does not provide portentous information on cell-specific cytokine signaling. To explore liver-specific functions of Stat5, the entire Stat5 locus was deleted in hepatocytes using Cre-mediated recombination. Notably, Stat5-mutant mice developed fatty livers and displayed impaired proliferation of hepatocytes upon partial hepatectomy (PHx). Loss of Stat5 led to molecular consequences beyond the reduced expression of Stat5 target genes, such as those encoding suppressor of cytokine signaling 2 (SOCS2), Cish, and insulin-like growth factor 1 (IGF-1). In particular, circulating growth hormone levels were increased and correlated with insulin resistance and increased insulin levels. Aberrant growth hormone (GH)-induced activation of the transcription factors Stat1 and Stat3 was observed in mutant livers. To test whether some of the defects observed in liver-specific Stat5 deficient mice were due to aberrant Stat1 expression and activation, we generated Stat1−/− mice with a hepatocyte-specific deletion of Stat5. Concomitant loss of both Stat5 and Stat1 restored cell proliferation upon PHx but did not reverse fatty liver development. Thus the molecular underpinnings of some defects observed in the absence of Stat5 are the consequence of a deregulated activation of other signal transducers and activators of transcription (STAT) family members. Conclusion: Aberrant cytokine-Stat5 signaling in hepatocytes alters their physiology through increased activity of Stat1 and Stat3. Such cross-talk between different pathways could add to the complexity of syndromes observed in disease. (HEPATOLOGY 2007.)
Use of nitric oxide inhalation in chronic obstructive pulmonary disease
Authors: K. Ashutosh
Journal: Thorax (2000)

<h3>BACKGROUND</h3> Inhalation of nitric oxide with oxygen could be a promising treatment in patients with chronic obstructive pulmonary disease (COPD) and pulmonary hypertension. However, the current methods of delivery of NO are cumbersome and unsuitable for long term use. The present study was undertaken to investigate the safety and efficacy of a mixture of nitric oxide (NO) and oxygen administered via a nasal cannula for 24 hours in patients with oxygen dependent COPD. <h3>METHODS</h3> Twenty five parts per million (ppm) of NO was administered by inhalation combined with supplemental oxygen at a flow rate of 2 l/min via a nasal cannula for 24 hours to 11 ambulatory men with stable, oxygen dependent COPD. Room air with supplemental oxygen at 2 l/min was administered in an identical manner for another 24 hours as control therapy in a randomised, double blind, crossover fashion to all patients. Pulmonary function tests, exercise tolerance, dyspnoea grade, and lung volumes were measured at baseline, 24, and 48 hours. Pulmonary artery pressure (PAP), cardiac output (CO), pulmonary vascular resistance (PVR), arterial blood gas tensions, and minute ventilation were measured at baseline, after 30 minutes and 24 hours of breathing NO and oxygen. Venous admixture ratio (Qs/Qt) and dead space ratio (Vd/Vt) were also calculated. Concentrations of nitrogen dioxide (NO<sub>2</sub>) and NO in the inhaled and ambient air were monitored continuously. Differences in pulmonary function, arterial blood gas tensions, pulmonary haemodynamics, exercise tolerance, and dyspnoea between oxygen and NO breathing periods were analysed for significance using paired<i>t</i> tests. <h3>RESULTS</h3> A significant (p&lt;0.05) fall was observed in PVR (183.1 (116.05) and 137.2 (108.4) dynes.s.cm<sup>–3</sup> before and after breathing NO for 24 hours, respectively) with NO administration without significant changes in symptoms, pulmonary function, arterial oxygen tension, or exercise tolerance. <h3>CONCLUSIONS</h3> NO at a concentration of 25 ppm blended with oxygen can be safely administered by nasal cannula for 24 hours without significant adverse effects and lowers PVR in stable patients with COPD receiving long term oxygen therapy.
Increased airways responsiveness in mice depends on local challenge with antigen.
Authors: J Saloga, H Renz, G L Larsen, E W Gelfand
Journal: American Journal of Respiratory and Critical Care Medicine (1994)

In Balb/C mice, painting the skin with ovalbumin (OVA) over a period of 14 days resulted in sensitization of the animals. This was documented by the appearance of OVA-specific IgE and IgG1 antibodies and increased total serum IgE levels. In addition, in regional (inguinal) lymph nodes of sensitized animals, OVA-specific T cell proliferative responses and increased IgE and IgG production could be detected in vitro. Sensitized animals also developed immediate cutaneous responses to intradermal injection of OVA. In contrast to previous results following OVA sensitization via the airways, increased airways responsiveness to electrical field stimulation (AREFS) of tracheal smooth muscle preparations was not observed in skin-sensitized mice. Only 24 h after a single local challenge of the airways with aerosolized OVA on Day 14 could a significant increase in AREFS be observed in skin-sensitized but not nonsensitized control mice. These data indicate that sensitization of Balb/C mice to OVA via the skin provides an effective means for inducing a systemic IgE and IgG1 antibody response and immediate cutaneous hypersensitivity. Despite these IgE and IgG1-mediated responses, however, the development of altered function as reflected in an increase in AREFS was dependent on challenge with the allergen via the airways.
Epidemiological aspects of Crohn's disease in Clydesdale 1961-1970.
Authors: I S Smith, S Young, G Gillespie, J O'Connor, J R Bell
Journal: Gut (1975)

A retrospective study of Crohn9s disease has been carried out in Clydesdale covering the decade 1961-1970. Three hundred and fifty-seven patients had acceptable evidence of either acute ileitis or of chronic granulomatous bowel disease. Of those fulfilling the criteria for inclusion in the study of chronic disease, 95% had accurate pathological and/or operative documentation of the lesions. Overall, females outnumbered males by 1-6:1 but colonic disease alone tended to affect females, particularly those over the age of 50. The annual incidence of all forms of the chronic disease in both sexes has increased during the decade, but diagnosis of colonic disease alone increased two-fold in the latter half of the study.
Pazopanib in Locally Advanced or Metastatic Renal Cell Carcinoma: Results of a Randomized Phase III Trial
Authors: Cora N. Sternberg, Ian D. Davis, Jozef Mardiak, Cezary Szczylik, Eunsik Lee, John Wagstaff, Carlos H. Barrios, Pamela Salman, Oleg A. Gladkov, Alexander Kavina, Juan J. Zarbá, Mei Chen, Lauren McCann, Lini Pandite, Debasish F. Roychowdhury, Robert E. Hawkins
Journal: Journal of Clinical Oncology (2010)

PURPOSE Pazopanib is an oral angiogenesis inhibitor targeting vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and c-Kit. This randomized, double-blind, placebo-controlled phase III study evaluated efficacy and safety of pazopanib monotherapy in treatment-naive and cytokine-pretreated patients with advanced renal cell carcinoma (RCC). PATIENTS AND METHODS Adult patients with measurable, locally advanced, and/or metastatic RCC were randomly assigned 2:1 to receive oral pazopanib or placebo. The primary end point was progression-free survival (PFS). Secondary end points included overall survival, tumor response rate (Response Evaluation Criteria in Solid Tumors), and safety. Radiographic assessments of tumors were independently reviewed. Results Of 435 patients enrolled, 233 were treatment naive (54%) and 202 were cytokine pretreated (46%). PFS was significantly prolonged with pazopanib compared with placebo in the overall study population (median, PFS 9.2 v 4.2 months; hazard ratio [HR], 0.46; 95% CI, 0.34 to 0.62; P < .0001), the treatment-naive subpopulation (median PFS 11.1 v 2.8 months; HR, 0.40; 95% CI, 0.27 to 0.60; P < .0001), and the cytokine-pretreated subpopulation (median PFS, 7.4 v 4.2 months; HR, 0.54; 95% CI, 0.35 to 0.84; P < .001). The objective response rate was 30% with pazopanib compared with 3% with placebo (P < .001). The median duration of response was longer than 1 year. The most common adverse events were diarrhea, hypertension, hair color changes, nausea, anorexia, and vomiting. There was no evidence of clinically important differences in quality of life for pazopanib versus placebo. CONCLUSION Pazopanib demonstrated significant improvement in PFS and tumor response compared with placebo in treatment-naive and cytokine-pretreated patients with advanced and/or metastatic RCC.
Transgenic mice overexpressing insulin-like growth factor-II in β cells develop type 2 diabetes
Authors: Jean-Christophe Devedjian, Monica George, Alba Casellas, Anna Pujol, Joana Visa, Mireia Pelegrín, Laurent Gros, Fatima Bosch
Journal: Journal of Clinical Investigation (2000)

During embryonic development, insulin-like growth factor-II (IGF-II) participates in the regulation of islet growth and differentiation. We generated transgenic mice (C57BL6/SJL) expressing IGF-II in beta cells under control of the rat Insulin I promoter in order to study the role of islet hyperplasia and hyperinsulinemia in the development of type 2 diabetes. In contrast to islets from control mice, islets from transgenic mice displayed high levels of IGF-II mRNA and protein. Pancreases from transgenic mice showed an increase in beta-cell mass (about 3-fold) and in insulin mRNA levels. However, the organization of cells within transgenic islets was disrupted, with glucagon-producing cells randomly distributed throughout the core. We also observed enhanced glucose-stimulated insulin secretion and glucose utilization in islets from transgenic mice. These mice displayed hyperinsulinemia, mild hyperglycemia, and altered glucose and insulin tolerance tests, and about 30% of these animals developed overt diabetes when fed a high-fat diet. Furthermore, transgenic mice obtained from the N1 backcross to C57KsJ mice showed high islet hyperplasia and insulin resistance, but they also developed fatty liver and obesity. These results indicate that local overexpression of IGF-II in islets might lead to type 2 diabetes and that islet hyperplasia and hypersecretion of insulin might occur early in the pathogenesis of this disease.
Angiotensin I-converting enzyme gene polymorphisms
Authors: W Grzeszczak, M J Zychma, B Lacka, E Zukowska-Szczechowska
Journal: Journal of the American Society of Nephrology (1998)

Nephropathy is a frequent complication of long-term diabetes. Strong evidence exists that genetic predisposition plays a major role in the development of diabetic nephropathy. The role of the angiotensin I-converting enzyme gene (ACE) in the susceptibility to nephropathy in diabetes, especially in non-insulin dependent diabetes mellitus (NIDDM), remains unclear. This study examines the association of two ACE polymorphisms: a 287-bp insertion/deletion (I/D) in intron 16 and PstI (A/G substitution in intron 7; alleles P/M) with renal complications in 941 NIDDM patients. From this group, for further analysis 127 patients were selected with overt proteinuria or chronic renal failure, 335 patients with microalbuminuria, and a control group of 254 normoalbuminuric patients with a diabetes duration of at least 10 yr. No significant differences in the distribution of ACE I/D and PstI genotypes or allele frequencies were observed between the examined groups. The results of this study strongly suggest that there is no association between the ACE gene I/D and PstI polymorphisms and nephropathy in NIDDM.
Low “T” as in “Template”
Authors: Lisa M. Schwartz, Steven Woloshin
Journal: JAMA Internal Medicine (2013)

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A critical role for Apc in hematopoietic stem and progenitor cell survival
Authors: Zhijian Qian, Lina Chen, Anthony A. Fernald, Bart O. Williams, Michelle M. Le Beau
Journal: The Journal of Experimental Medicine (2008)

The adenomatous polyposis coli (Apc) tumor suppressor is involved in the initiation and progression of colorectal cancer via regulation of the Wnt signaling cascade. In addition, Apc plays an important role in multiple cellular functions, including cell migration and adhesion, spindle assembly, and chromosome segregation. However, its role during adult hematopoiesis is unknown. We show that conditional inactivation of Apc in vivo dramatically increases apoptosis and enhances cell cycle entry of hematopoietic stem cells (HSCs)/ hematopoietic progenitor cells (HPCs), leading to their rapid disappearance and bone marrow failure. The defect in HSCs/HPCs caused by Apc ablation is cell autonomous. In addition, we found that loss of Apc leads to exhaustion of the myeloid progenitor pool (common myeloid progenitor, granulocyte-monocyte progenitor, and megakaryocyte-erythroid progenitor), as well as the lymphoid-primed multipotent progenitor pool. Down-regulation of the genes encoding Cdkn1a, Cdkn1b, and Mcl1 occurs after acute Apc excision in candidate HSC populations. Together, our data demonstrate that Apc is essential for HSC and HPC maintenance and survival.
A SNP in a <i>let-7</i> microRNA Complementary Site in the <i>KRAS</i> 3′ Untranslated Region Increases Non–Small Cell Lung Cancer Risk
Authors: Lena J. Chin, Elena Ratner, Shuguang Leng, Rihong Zhai, Sunitha Nallur, Imran Babar, Roman-Ulrich Muller, Eva Straka, Li Su, Elizabeth A. Burki, Richard E. Crowell, Rajeshvari Patel, Trupti Kulkarni, Robert Homer, Daniel Zelterman, Kenneth K. Kidd, Yong Zhu, David C. Christiani, Steven A. Belinsky, Frank J. Slack, Joanne B. Weidhaas
Journal: Cancer Research (2008)

Abstract Lung cancer is the leading cause of cancer deaths worldwide, yet few genetic markers of lung cancer risk useful for screening exist. The let-7 family-of-microRNAs (miRNA) are global genetic regulators important in controlling lung cancer oncogene expression by binding to the 3′ untranslated regions of their target mRNAs. The purpose of this study was to identify single nucleotide polymorphisms (SNP) that could modify let-7 binding and to assess the effect of such SNPs on target gene regulation and risk for non–small cell lung cancer (NSCLC). let-7 complementary sites (LCS) were sequenced in the KRAS 3′ untranslated region from 74 NSCLC cases to identify mutations and SNPs that correlated with NSCLC. The allele frequency of a previously unidentified SNP at LCS6 was characterized in 2,433 people (representing 46 human populations). The frequency of the variant allele is 18.1% to 20.3% in NSCLC patients and 5.8% in world populations. The association between the SNP and the risk for NSCLC was defined in two independent case-control studies. A case-control study of lung cancer from New Mexico showed a 2.3-fold increased risk (confidence interval, 1.1–4.6; P = 0.02) for NSCLC cancer in patients who smoked &amp;lt;40 pack-years. This association was validated in a second independent case-control study. Functionally, the variant allele results in KRAS overexpression in vitro. The LCS6 variant allele in a KRAS miRANA complementary site is significantly associated with increased risk for NSCLC among moderate smokers and represents a new paradigm for let-7 miRNAs in lung cancer susceptibility. [Cancer Res 2008;68(20):8535–40]
Standard cardiopulmonary resuscitation versus active compression-decompression cardiopulmonary resuscitation with augmentation of negative intrathoracic pressure for out-of-hospital cardiac arrest: a randomised trial
Authors: Tom P Aufderheide, Ralph J Frascone, Marvin A Wayne, Brian D Mahoney, Robert A Swor, Robert M Domeier, Michael L Olinger, Richard G Holcomb, David E Tupper, Demetris Yannopoulos, Keith G Lurie
Journal: The Lancet (2011)
PHYSIOLOGIC SIGNIFICANCE ASSESSMENT OF INTERMEDIATE SEVERITY CORONARY LESIONS BY TRANSTHORACIC ENHANCED DOPPLER ECHOCARDIOGRAPHY IN CONVERGENT COLOR DOPPLER MODE: VALIDATION VERSUS FRACTIONAL FLOW RESERVE
Authors: Carlo Caiati, Mario Erminio Lepera, Daniela Santoro, Dario Grande, Antonio Tito, Paola Marolla, Monica Stufano, Giovanni Meliota, Fortunato Iacovelli, Filippo Masi, Stefano Favale
Journal: Journal of the American College of Cardiology (2014)
Genetic Predisposition to Increased Blood Cholesterol and Triglyceride Lipid Levels and Risk of Alzheimer Disease: A Mendelian Randomization Analysis
Authors: Petroula Proitsi, Michelle K. Lupton, Latha Velayudhan, Stephen Newhouse, Isabella Fogh, Magda Tsolaki, Makrina Daniilidou, Megan Pritchard, Iwona Kloszewska, Hilkka Soininen, Patrizia Mecocci, Bruno Vellas, Julie Williams, Robert Stewart, Pak Sham, Simon Lovestone, John F. Powell
Journal: PLoS Medicine (2014)

In this study, Proitsi and colleagues use a Mendelian randomization approach to dissect the causal nature of the association between circulating lipid levels and late onset Alzheimer's Disease (LOAD) and find that genetic predisposition to increased plasma cholesterol and triglyceride lipid levels is not associated with elevated LOAD risk. Please see later in the article for the Editors' Summary