tbuckley/cabot-search huggingface dataset:
CLINICAL EVALUATION OF MERATRAN AND FRENQUEL ON A CHRONIC PSYCHOTIC POPULATION
Authors: BURTON S. ROSNER, LOUIS B. FIERMAN, JOHN F. KRAMER
Journal: American Journal of Psychiatry (1957)

Meratran and Frenquel were administered by a double-blind procedure to 63 chronic psychotics whose behavior was rated by psychiatric residents, nurses, and aides. Frenquel produced no significant changes in the rated behavior. Meratran seemed to exacerbate social withdrawal and irresponsibility. Meratran failed to increase the over-all activity level and failed to decrease depressive symptoms. Finally, Meratran had a significant tendency to aggravate perceptual distortion in some patients but also counteracted hallucinatory phenomena and disorientation in a few other patients.
Breast Cancer Prevention in the Era of Precision Medicine
Authors: S. A. Narod
Journal: JNCI Journal of the National Cancer Institute (2015)

After the cloning of the second breast cancer gene in 1995 (BRCA2), gene researchers took divergent paths.Some searched for new and rare genes while others sought to explain unusual cancer clusters, but at Cambridge University, a group of genetic epidemiologists devoted their energies to the development of a polygenic model for breast cancer (1).They sought to account for the missing heritability through a model that postulated that there were many genes, each of which contributed in a small way to a woman's vulnerability.The effort was facilitated through the completion of a genomic map of nucleotide variants (HapMap) and the engineering of a DNA chip that secured many thousands of single nucleotide polymorphisms (SNPs) from across the genome.The first genome-wide association study (GWAS) for breast cancer was published by the Cambridge group in 2007 (2), and there have been many others since.Doug Easton and his Cambridge colleagues engendered an extraordinary collaborative spirit, which culminates in a landmark paper boasting 218 authors (3) published in this issue of the Journal.The fruits of the enterprise are presented as a genetic risk assessment model that incorporates 77 SNPs.The authors use the model to generate personal risk scores and thereby stratify women according to their lifetime risk.The paper by Mavvadat et al. is important, because it enables us to evaluate the clinical utility of the polygene paradigm-it is unlikely that the model will be improved substantially if we add more SNPs (or different SNPs).For the 77 SNPs, the frequency of the rarer of the two alleles ranged from 0.001% to 48.2% and the corresponding odds ratios range from 0.86 to 1.36.The baseline risk of breast cancer to age 74 years in the UK is 8.2% (4).Based on her personal risk score, a woman in the top one percentile had a three-fold increase in risk relative to the mean (hazard ratio [HR] = 3.36, 95% confidence interval [CI] = 2.95 to 3.83), or roughly 25% lifetime.If the GWAS studies were the first step towards precision medicine and the development of the model is the second step, then the third step is to show that the personal risk score is useful.Who should be tested and who will pay?There is no reason to assume that scores in the mother and daughter will be correlated, and the effects of family history and the risks score appear to be
Effects of exercise on gas exchange in patients recovering from acute severe asthma.
Authors: G E Packe, W Freeman, R M Cayton
Journal: Thorax (1990)

The effect of exercise on gas exchange was studied in 17 patients (seven male and 10 female) recovering in hospital from acute severe asthma. On admission the patients (mean age 26 (SD 8) years) had a mean peak expiratory flow (PEF) of 26.8% (5.7%) predicted, a mean arterial oxygen tension (PaO2) of 8.63 (1.26) kPa, and a mean alveolar-arterial oxygen difference (A-aDO2) of 5.98 (1.34) kPa. Once resting symptoms had resolved (after 3.7 (1.6) days) patients performed a constant load exercise test (100 watts for men, 75 watts for women) on a bicycle ergometer for five minutes. PEF was measured before exercise and at five minute intervals for 30 minutes after exercise. Blood gas tensions were measured on capillary blood before, during, and 10 minutes after exercise. Treatment was not interrupted for this study. Mean PEF at rest was 87.6% (21.1%) predicted and showed no significant change after exercise. Mean PaO2 was 13.13 (1.37) kPa before exercise; it showed no significant change during exercise (13.93 (1.34) kPa) or 10 minutes after exercise (13.50 (2.15) kPa). Mean A-aDO2 also showed no change, being 1.82 (1.31) kPa before exercise, 1.79 (1.27) kPa during exercise, and 2.53 (0.93) kPa after exercise. It is concluded that moderate exercise carried out shortly after treatment for acute severe asthma is unlikely to result in worsening gas exchange during or after exercise if resting PEF, PaO2 and A-aDO2 have attained normal or near normal values.
Neutrophil serine proteinases and defensins in chronic obstructive pulmonary disease: effects on pulmonary epithelium
Authors: PS Hiemstra, S van Wetering, J Stolk
Journal: European Respiratory Journal (1998)

Neutrophils have the capacity to accumulate in high numbers in the lung during infection and inflammation. Because they play an important role in host defence against infection, but may also cause tissue injury, these cells are thought to be involved in the pathogenesis of various inflammatory lung disorders, including chronic bronchitis and chronic obstructive pulmonary disease. Neutrophil products that may mediate tissue injury at sites of neutrophil-dominated inflammation include the neutrophil serine proteinases elastase, cathepsin G and proteinase 3, and the nonenzymatic defensins. One of the targets of the neutrophil is the lung epithelium, and in vitro studies have revealed that both the serine proteinases and neutrophil defensins markedly affect the integrity of the epithelial layer, decrease the frequency of ciliary beat, increase the secretion of mucus, and induce the synthesis of epithelium-derived mediators that may influence the amplification and resolution of neutrophil-dominated inflammation. Both neutrophil elastase and defensins induce the release of the neutrophil chemoattractant chemokine interleukin-8 from respiratory epithelial cells. The alpha1-proteinase inhibitor (alpha1-PI) is a well-characterized inhibitor of neutrophil elastase, that also blocks the cytotoxic and stimulatory activity of defensins towards epithelial cells. The elastase inhibitory activity of alpha1-PI is also abrogated by the binding of defensins to this inhibitor. Incubation of epithelial cells with neutrophil defensins in combination with either elastase or cathepsin G resulted in decreased effects on the epithelial cells compared with those observed when the cells were incubated with defensins, elastase or cathepsin G separately. These results suggest that neutrophil defensins and serine proteinases cause injury and stimulate epithelial cells to produce chemokines that attract more neutrophils to the site of inflammation. The effects of neutrophil defensins and serine proteinases on epithelial cells appear to be restricted by proteinase inhibitors and by inhibitory interactions between these sets of neutrophil granule proteins.
miR-143 and miR-145 synergistically regulate ERBB3 to suppress cell proliferation and invasion in breast cancer
Authors: Xin Yan, Xi Chen, Hongwei Liang, Ting Deng, Weixu Chen, Suyang Zhang, Minghui Liu, Xiujuan Gao, Yanqing Liu, Chihao Zhao, Xueliang Wang, Nan Wang, Jialu Li, Rui Liu, Ke Zen, Chen Yu Zhang, Baorui Liu, Yi Ba
Journal: Molecular Cancer (2014)

ERBB3, one of the four members of the ErbB family of receptor tyrosine kinases, plays an important role in breast cancer etiology and progression. In the present study, we aimed to identify novel miRNAs that can potentially target ERBB3 and their biological functions. The expression levels of miR-143/145 and target mRNA were examined by relative quantification RT-PCR, and the expression levels of target protein were detected by Western blot. We used bioinformatic analyses to search for miRNAs that can potentially target ERBB3. Luciferase reporter plasmids were constructed to confirm direct targeting. Furthermore, the biological consequences of the targeting of ERBB3 by miR-143/145 were examined by cell proliferation and invasion assays in vitro and by the mouse xenograft tumor model in vivo. We identified an inverse correlation between miR-143/145 levels and ERBB3 protein levels, but not between miR-143/145 levels and ERBB3 mRNA levels, in breast cancer tissue samples. We identified specific targeting sites for miR-143 and miR-145 (miR-143/145) in the 3'-untranslated region (3'-UTR) of the ERBB3 gene and regulate ERBB3 expression. We demonstrated that the repression of ERBB3 by miR-143/145 suppressed the proliferation and invasion of breast cancer cells, and that miR-143/145 showed an anti-tumor effect by negatively regulating ERBB3 in the xenograft mouse model. Interestingly, miR-143 and miR-145 showed a cooperative repression of ERBB3 expression and cell proliferation and invasion in breast cancer cells, such that the effects of the two miRNAs were greater than with either miR-143 or miR-145 alone. Taken together, our findings provide the first clues regarding the role of the miR-143/145 cluster as a tumor suppressor in breast cancer through the inhibition of ERBB3 translation. These results also support the idea that different miRNAs in a cluster can synergistically repress a given target mRNA.
Hypoxaemia in young Kenyan children with acute lower respiratory infection.
Authors: F E Onyango, M C Steinhoff, E M Wafula, S Wariua, J Musia, J Kitonyi
Journal: BMJ (1993)

OBJECTIVES--To determine the prevalence, clinical correlates, and outcome of hypoxaemia in acutely ill children with respiratory symptoms. DESIGN--Prospective observational study. SETTING--Paediatric casualty ward of a referral hospital at 1670 m altitude in Nairobi, Kenya. SUBJECTS--256 Infants and children under 3 years of age with symptoms of respiratory infection. MAIN OUTCOME MEASURES--Prevalence of hypoxaemia, defined as arterial oxygen saturation &lt; 90% determined by pulse oximetry, and condition of patient on the fifth day after admission. RESULTS--Over half (151) of the children were hypoxaemic, and short term mortality was 4.3 times greater in these children. In contrast, the relative risk of a fatal outcome in children with radiographic pneumonia was only 1.03 times that of children without radiographic pneumonia. A logistic regression model showed that in 3-11 month old infants a respiratory rate &gt; or = 70/min, grunting, and retractions were the best independent clinical signs for the prediction of hypoxaemia. In the older children a respiratory rate of &gt; or = 60/min was the single best clinical predictor of hypoxaemia. The presence of hypoxaemia predicted radiographic pneumonia with a sensitivity of 71% and specificity of 55%. CONCLUSIONS--Over half the children presenting to this referral hospital with respiratory symptoms were hypoxaemic. A group of specific clinical signs seem useful in predicting hypoxaemia. The clear association of hypoxaemia with mortality suggests that the detection and effective treatment of hypoxaemia are important aspects of the clinical management of acute infections of the lower respiratory tract in children in hospital in developing regions.
Platelet alpha-granule fibrinogen, albumin, and immunoglobulin G are not synthesized by rat and mouse megakaryocytes.
Authors: P Handagama, D A Rappolee, Z Werb, J Levin, D F Bainton
Journal: Journal of Clinical Investigation (1990)

It has been assumed that endogenous synthesis by the platelet precursor cell, the bone marrow megakaryocyte, is the major source of platelet alpha-granule protein. To test this hypothesis, we used mRNA phenotyping to detect in megakaryocytes the presence of mRNA transcripts specific for various proteins. Our results indicate that megakaryocytes synthesize platelet factor 4, a protein relatively specific for platelets, but do not express mRNA transcripts for the fibrinogen, albumin, or IgG found in alpha-granules. We have previously shown that megakaryocytes endocytose circulating proteins, including fibrinogen, albumin, and IgG, and incorporate them into alpha-granules. Thus, platelets appear to contain a unique type of secretory granule whose contents originate by both endogenous synthesis and endocytosis from plasma. Under basal conditions, the source of alpha-granule fibrinogen is plasma.
The Oct4 and Nanog transcription network regulates pluripotency in mouse embryonic stem cells
Authors: Yuin-Han Loh, Qiang Wu, Joon-Lin Chew, Vinsensius B Vega, Weiwei Zhang, Xi Chen, Guillaume Bourque, Joshy George, Bernard Leong, Jun Liu, Kee-Yew Wong, Ken W Sung, Charlie W H Lee, Xiao-Dong Zhao, Kuo-Ping Chiu, Leonard Lipovich, Vladimir A Kuznetsov, Paul Robson, Lawrence W Stanton, Chia-Lin Wei, Yijun Ruan, Bing Lim, Huck-Hui Ng
Journal: Nature Genetics (2006)
Lactate: A Metabolic Key Player in Cancer
Authors: Franziska Hirschhaeuser, Ulrike G.A. Sattler, Wolfgang Mueller-Klieser
Journal: Cancer Research (2011)

Increased glucose uptake and accumulation of lactate, even under normoxic conditions (i.e., aerobic glycolysis or the Warburg Effect), is a common feature of cancer cells. This phenomenon clearly indicates that lactate is not a surrogate of tumor hypoxia. Tumor lactate can predict for metastases and overall survival of patients, as shown by several studies of different entities. Metastasis of tumors is promoted by lactate-induced secretion of hyaluronan by tumor-associated fibroblasts that create a milieu favorable for migration. Lactate itself has been found to induce the migration of cells and cell clusters. Furthermore, radioresistance has been positively correlated with lactate concentrations, suggesting an antioxidative capacity of lactate. Findings on interactions of tumor metabolites with immune cells indicate a contribution of lactate to the immune escape. Furthermore, lactate bridges the gap between high lactate levels in wound healing, chronic inflammation, and cancer development. Tumor cells ensure sufficient oxygen and nutrient supply for proliferation through lactate-induced secretion of VEGF, resulting in the formation of new vessels. In summary, accumulation of lactate in solid tumors is a pivotal and early event in the development of malignancies. The determination of lactate should enter further clinical trials to confirm its relevance in cancer biology.
RhBG and RhCG, the Putative Ammonia Transporters, Are Expressed in the Same Cells in the Distal Nephron
Authors: Fabienne Quentin, Dominique Eladari, Lydie Cheval, Claude Lopez, Dominique Goossens, Yves Colin, Jean-Pierre Cartron, Michel Paillard, Re[Combining Acute Accent]gine Chambrey
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. Two nonerythroid homologs of the blood group Rh proteins, RhCG and RhBG, which share homologies with specific ammonia transporters in primitive organisms and plants, could represent members of a new family of proteins involved in ammonia transport in the mammalian kidney. Consistent with this hypothesis, the expression of RhCG was recently reported at the apical pole of all connecting tubule (CNT) cells as well as in intercalated cells of collecting duct (CD). To assess the localization along the nephron of RhBG, polyclonal antibodies against the Rh type B glycoprotein were generated. In immunoblot experiments, a specific polypeptide of Mr approximately 50 kD was detected in rat kidney cortex and in outer and inner medulla membrane fractions. Immunocytochemical studies revealed RhBG expression in distal nephron segments within the cortical labyrinth, medullary rays, and outer and inner medulla. RhBG expression was restricted to the basolateral membrane of epithelial cells. The same localization was observed in rat and mouse kidney. RT-PCR analysis on microdissected rat nephron segments confirmed that RhBG mRNAs were chiefly expressed in CNT and cortical and outer medullary CD. Double immunostaining with RhCG demonstrated that RhBG and RhCG were coexpressed in the same cells, but with a basolateral and apical localization, respectively. In conclusion, RhBG and RhCG are present in a major site of ammonia secretion in the kidney, i.e., the CNT and CD, in agreement with their putative role in ammonium transport. E-mail: [email protected]
Moderate vitamin D deficiency is associated with changes in knee and hip pain in older adults: a 5-year longitudinal study
Authors: Laura L Laslett, Stephen Quinn, John R Burgess, Venkateswaran Parameswaran, Tania M Winzenberg, Graeme Jones, Changhai Ding
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Vitamin D is important for bone, cartilage and muscle function but there are few studies on its association with joint pain. <h3>Objective</h3> To investigate whether serum vitamin D predicts change in knee and hip pain in older adults. <h3>Methods</h3> Longitudinal population-based cohort study of randomly selected older adults (n=769) aged 50–80 years (mean 62 years); 50% were male. Serum 25-hydroxyvitamin D (25-OHD) was assessed at baseline by radioimmunoassay, and pain at baseline, 2.6 and/or 5 years using the Western Ontario and McMaster University Osteoarthritis Index (WOMAC) questionnaire. We used linear regression with adjustment for age, sex, body mass index and season, then further adjusted for potential structural mechanisms (radiographic osteoarthritis, bone marrow lesions, chondral defects and muscle strength). <h3>Results</h3> Mean total knee WOMAC score was 3.2 (range 0–39). 4.2% of participants had moderate vitamin D deficiency at baseline (25-OHD 12.5–25 nmol/l). 25-OHD &lt;25 nmol/l predicted change in knee pain (using total WOMAC score) over 5 years (β=2.41, p=0.002) with a similar effect size for hip pain over 2.4 years (β=2.20, p=0.083). Results were consistent within pain subscales, and the association was independent of demographic, anthropometric and structural covariates. No association was present when 25-OHD was analysed as a continuous measure. <h3>Conclusions</h3> Moderate vitamin D deficiency independently predicts incident, or worsening of, knee pain over 5 years and, possibly, hip pain over 2.4 years. Therefore correcting moderate vitamin deficiency may attenuate worsening of knee or hip pain in elderly people but giving supplements to those with a higher 25-OHD level is unlikely to be effective.
Thromboembolic disease in patients with high-grade glioma
Authors: J. R. Perry
Journal: Neuro-Oncology (2012)

Venous thromboembolism (VTE) is common throughout the course of disease in high-grade glioma (HGG). The interactions between the coagulation cascade, endothelium, and regulation of angiogenesis are complex and drive glioblastoma growth and invasion. We reviewed the incidence of VTE in HGG, the biology of the coagulome as related to glioblastoma progression, prevention and treatment of thrombosis, and the putative role of anticoagulants as anti-cancer therapy. VTE can be significantly reduced during the postoperative period with adherence to the use of mechanical and medical thromboprophylaxis. Activation of the coagulation cascade occurs throughout the course of disease because of a variety of complex interactions, including tumor hypoxia, upregulation of VEGR expression, and increases in both tumor cell-specific tissue factor (TF) expression and inducible TF expression in numerous intrinsic regulatory pathways. Long-term anticoagulation to prevent VTE is an attractive therapy; however, the therapeutic window is narrow and current data do not support its routine use. Most patients with proven symptomatic VTE can be safely anticoagulated, including those receiving anti-VEGF therapy, such as bevacizumab. Initial therapy should include low molecular weight heparin (LMWH), and protracted anticoagulant treatment, perhaps indefinitely, is indicated for patients with HGG because of the ongoing risk of thrombosis. A variety of coagulation- and tumor-related proteins, such as TF and circulating microparticles, may serve as potential disease-specific biomarkers in relation to disease recurrence, monitoring of therapy, and as potential therapeutic targets.
Role of Fibroblast Growth Factor Receptor Signaling in Prostate Cancer Cell Survival
Authors: M. Ozen, D. Giri, F. Ropiquet, A. Mansukhani, M. Ittmann
Journal: JNCI Journal of the National Cancer Institute (2001)

Expression of fibroblast growth factors (FGFs) is increased in a substantial fraction of human prostate cancers in vivo and in prostate cancer cell lines. Altered FGF signaling can potentially have a variety of effects, including stimulating cell proliferation and inhibiting cell death. To determine the biologic significance of altered FGF signaling in human prostate cancer, we disrupted signaling by expression of a dominant-negative (DN) FGF receptor in prostate cancer cell lines.PC-3, LNCaP, and DU145 prostate cancer cells were stably transfected with DN FGFR constructs, and LNCaP and DU145 cells were infected with a recombinant adenovirus expressing DN FGFR-1. The effect of DN FGFR-1 expression was assessed by colony-formation assays, cell proliferation assays, flow cytometry, and cytogenetic analysis. Key regulators involved in the G(2)-to-M cell cycle transition were assessed by western blotting to examine cyclin B1 expression and by in vitro kinase assay to assess cdc2 kinase activity.Stable transfection of the DN FGFR-1 construct inhibited colony formation by more than 99% in all three cell lines. Infection of LNCaP and DU145 prostate cancer cells with adenovirus expressing DN FGFR-1 led to extensive cell death within 48 hours. Flow cytometry and cytogenetic analysis revealed that the DN FGFR-1 receptor led to arrest in the G(2) phase of the cell cycle before cell death. Cyclin B1 accumulated in DN FGFR-1-infected LNCaP cells, but cdc2 kinase activity was decreased.These findings reveal an unexpected dependence of prostate cancer cells on FGF receptor signal transduction to traverse the G(2)/M checkpoint. The mechanism for the G(2) arrest is not clear. Our results raise the possibility that FGF-signaling antagonists might enhance the cell death induced by other prostate cancer therapies.