tbuckley/cabot-search huggingface dataset:
Small RNA sequencing reveals miR-642a-3p as a novel adipocyte-specific microRNA and miR-30 as a key regulator of human adipogenesis
Authors: Laure-Emmanuelle Zaragosi, Brigitte Wdziekonski, Kevin Le Brigand, Phi Villageois, Bernard Mari, Rainer Waldmann, Christian Dani, Pascal Barbry
Journal: Genome biology (2011)

Abstract Background In severe obesity, as well as in normal development, the growth of adipose tissue is the result of an increase in adipocyte size and numbers, which is underlain by the stimulation of adipogenic differentiation of precursor cells. A better knowledge of the pathways that regulate adipogenesis is therefore essential for an improved understanding of adipose tissue expansion. As microRNAs (miRNAs) have a critical role in many differentiation processes, our study aimed to identify the role of miRNA-mediated gene silencing in the regulation of adipogenic differentiation. Results We used deep sequencing to identify small RNAs that are differentially expressed during adipogenesis of adipose tissue-derived stem cells. This approach revealed the un-annotated miR-642a-3p as a highly adipocyte-specific miRNA. We then focused our study on the miR-30 family, which was also up-regulated during adipogenic differentiation and for which the role in adipogenesis had not yet been elucidated. Inhibition of the miR-30 family blocked adipogenesis, whilst over-expression of miR-30a and miR-30d stimulated this process. We additionally showed that both miR-30a and miR-30d target the transcription factor RUNX2, and stimulate adipogenesis via the modulation of this major regulator of osteogenesis. Conclusions Overall, our data suggest that the miR-30 family plays a central role in adipocyte development. Moreover, as adipose tissue-derived stem cells can differentiate into either adipocytes or osteoblasts, the down-regulation of the osteogenesis regulator RUNX2 represents a plausible mechanism by which miR-30 miRNAs may contribute to adipogenic differentiation of adipose tissue-derived stem cells.
Function of the autonomic nervous system in patients with hepatic encephalopathy
Authors: Kurt Lenz, Heide Hörtnagl, Dieter Magometschnigg, Gunter Kleinberger, Wilfred Druml, Anton Laggner
Journal: Hepatology (1985)

To obtain further pathophysiological details concerning the development of cardiovascular disturbances in severe liver disease, the state of the autonomic nervous system, the function of the baroreceptor reflex pathway and the responsiveness of the cardiovascular system to noradrenaline, angiotensin II and isoprenaline were investigated in 11 patients with hepatic encephalopathy and in 10 healthy control subjects. Increased plasma levels of noradrenaline and adrenaline and an attenuated increase in heart rate in response to atropine were found in patients with hepatic encephalopathy. These changes and the hemodynamic disturbances tended to be more pronounced in patients with hepatic encephalopathy Grades III-IV as compared to hepatic encephalopathy Grades I-II. The increase in systolic blood pressure induced by infusion of noradrenaline (400 ng per kg per min) and angiotensin II (20 ng per kg per min) was higher in the patients than in healthy control subjects (hepatic encephalopathy Grades I-II: p less than 0.001; hepatic encephalopathy Grades III-IV: p less than 0.02). The changes in mean and diastolic blood pressure in response to angiotensin II were more pronounced in hepatic encephalopathy grades I-II than in hepatic encephalopathy Grades III-IV (p less than 0.02). The decrease of heart rate in response to blood pressure increase in patients with hepatic encephalopathy was not different from control subjects except a smaller decrease during angiotensin II infusion in hepatic encephalopathy grades III-IV (p less than 0.05). The responsiveness to isoprenaline was diminished (p less than 0.001). The present results indicate that the increased activity of the sympathetic nervous system in hepatic encephalopathy is associated with decreased parasympathetic tone.(ABSTRACT TRUNCATED AT 250 WORDS)
Reduced Hospitalizations and Death Associated With Influenza Vaccination Among Patients With and Without Diabetes
Authors: Anthony D. Heymann, Yonaton Shapiro, Gabriel Chodick, Varda Shalev, Ehud Kokia, Eyal Kramer, Joshua Shemer
Journal: Diabetes Care (2004)

To assess whether the influenza vaccination of community-dwelling, diabetic, elderly individuals is associated with reduced rates of hospitalization and death.In this outcome-research study, we compared mortality and hospitalization rates of 15,556 patients aged >or=65 years followed using a diabetes registry in a large health maintenance organization to that of 69,097 members not suffering from chronic disease who were considered as a reference group. The study outcomes included all-cause death and hospitalization in internal medicine or geriatric wards for any reason over winter and summer (control) periods.Vaccination rates were 48.8 and 42.0% among patients with diabetes and the reference population, respectively. Influenza vaccination was associated with a 12.3% reduction in hospitalization rates for patients with diabetes compared with 23.0% in the reference group (P = 0.08). The reduction in hospitalization rates was similar in both sexes among patients with diabetes. In addition, there was a significant reduction in mortality for the vaccinated group of patients with diabetes when compared with the nonvaccinated group except for female patients aged >or=85 years.The study results support the use of influenza vaccine among an elderly population. However, there does not appear to be an additional benefit for patients with diabetes.
The Value of Routine Microbial Investigation in Ventilator-Associated Pneumonia
Authors: JORDI RELLO, MIGUEL GALLEGO, DOLORS MARISCAL, ROSARIO SOÑORA, JORDI VALLES
Journal: American Journal of Respiratory and Critical Care Medicine (1997)

The use of microbiologic investigations in routine clinical practice, their value in guiding antibiotic prescription, and their influence on outcome were prospectively studied in 113 consecutive adults who developed ventilator-associated pneumonia (VAP). Blood cultures were performed in 78.7% of cases, protected specimen brushing in 95.5%, and bronchoalveolar lavage in only 45.1%. No causative agent was identified in 13 episodes (11.5%), and results of microbial tests directed a change in therapy in 43 (38.0%). Bronchoscopic results revealed inadequate initial selection of antibiotic therapy in 27 cases (23.9%) and led to a change in antibiotic treatment. Inadequate initial selection was still associated with a significantly greater increase in related mortality than adequate initial therapy (37.0% versus 15.4%, p < 0.05), although the change in therapy permitted clinical resolution in 17 (62.9%) of these 27 episodes, and 10 patients were discharged alive. Bronchoscopic results also permitted the reduction of the antibiotic spectrum in seven episodes (6.1%). This study suggests that in patients with VAP, bronchoscopic results are frequently associated with changes in antibiotic therapy. Nevertheless, our findings also emphasize the critical importance of an appropriate early antibiotic therapy.
The linear ubiquitin assembly complex (LUBAC) is essential for NLRP3 inflammasome activation
Authors: Mary A. Rodgers, James W. Bowman, Hiroaki Fujita, Nicole Orazio, Mude Shi, Qiming Liang, Rina Amatya, Thomas J. Kelly, Kazuhiro Iwai, Jenny Ting, Jae U. Jung
Journal: The Journal of Experimental Medicine (2014)

Linear ubiquitination is a newly discovered posttranslational modification that is currently restricted to a small number of known protein substrates. The linear ubiquitination assembly complex (LUBAC), consisting of HOIL-1L, HOIP, and Sharpin, has been reported to activate NF-κB–mediated transcription in response to receptor signaling by ligating linear ubiquitin chains to Nemo and Rip1. Despite recent advances, the detailed roles of LUBAC in immune cells remain elusive. We demonstrate a novel HOIL-1L function as an essential regulator of the activation of the NLRP3/ASC inflammasome in primary bone marrow–derived macrophages (BMDMs) independently of NF-κB activation. Mechanistically, HOIL-1L is required for assembly of the NLRP3/ASC inflammasome and the linear ubiquitination of ASC, which we identify as a novel LUBAC substrate. Consequently, we find that HOIL-1L−/− mice have reduced IL-1β secretion in response to in vivo NLRP3 stimulation and survive lethal challenge with LPS. Together, these data demonstrate that linear ubiquitination is required for NLRP3 inflammasome activation, defining the molecular events of NLRP3 inflammasome activation and expanding the role of LUBAC as an innate immune regulator. Furthermore, our observation is clinically relevant because patients lacking HOIL-1L expression suffer from pyogenic bacterial immunodeficiency, providing a potential new therapeutic target for enhancing inflammation in immunodeficient patients.
Signal Transducer and Activator of Transcription-5 Activation and Breast Cancer Prognosis
Authors: Marja T. Nevalainen, Jianwu Xie, Joachim Torhorst, Lukas Bubendorf, Philippe Haas, Juha Kononen, Guido Sauter, Hallgeir Rui
Journal: Journal of Clinical Oncology (2004)

Purpose Transcription factor signal transducer and activator of transcription-5 (Stat5) promotes breast epithelial cell differentiation. We retrospectively analyzed whether levels of active Stat5 in breast cancer were linked to clinical outcome. Materials and Methods Immunohistochemistry was used to detect active, tyrosine-phosphorylated Stat5 in paraffin-embedded breast cancer specimens from three archival tissue microarray materials A, B, and C. Material A included 19 healthy human breast tissues and a progression series of primary lymph node-negative, primary lymph node-positive, and metastatic breast cancer (n = 400). Materials B (n = 785) and C (n = 570) represented two independent arrays of unselected primary breast cancer specimens with clinical follow-up data. Results Material A demonstrated that Stat5 activation, but not Stat5 protein expression, was gradually lost during cancer progression, with detectable activation in 100% of healthy breast specimens compared with less than 20% of node-positive breast cancers and metastases. Stat5 activation in tumors of material B was associated with favorable prognosis. This observation was confirmed and extended in material C to include both breast cancer-specific survival and disease-free survival. Stat5 activation remained an independent prognostic marker after adjusting for patient age, tumor size, histological grade, estrogen receptor, progesterone receptor, and Her2/neu status by Cox multivariate analysis (hazard ratio, 2.0; P = .029). Stat5 activation was a particularly favorable marker in the lymph node-negative breast cancer subpopulation (hazard ratio, 7.5; P = .003). Conclusion In our study, active Stat5 distinguishes breast cancer patients with favorable prognosis, and may be a useful marker for selection of more individualized treatment, especially in localized disease. These findings require confirmation in a large prospective study.
Mutation of NIMA-related kinase 1 (NEK1) leads to chromosome instability
Authors: Yumay Chen, Chi-Fen Chen, Huai-Chin Chiang, Michelle Pena, Rosaria Polci, Randy L Wei, Robert A Edwards, Donna E Hansel, Phang-Lang Chen, Daniel J Riley
Journal: Molecular Cancer (2011)

NEK1, the first mammalian ortholog of the fungal protein kinase never-in-mitosis A (NIMA), is involved early in the DNA damage sensing/repair pathway. A defect in DNA repair in NEK1-deficient cells is suggested by persistence of DNA double strand breaks after low dose ionizing radiation (IR). NEK1-deficient cells also fail to activate the checkpoint kinases CHK1 and CHK2, and fail to arrest properly at G1/S or G2/M-phase checkpoints after DNA damage. We show here that NEK1-deficient cells suffer major errors in mitotic chromosome segregation and cytokinesis, and become aneuploid. These NEK1-deficient cells transform, acquire the ability to grow in anchorage-independent conditions, and form tumors when injected into syngeneic mice. Genomic instability is also manifest in NEK1 +/- mice, which late in life develop lymphomas with a much higher incidence than wild type littermates. NEK1 is required for the maintenance of genome stability by acting at multiple junctures, including control of chromosome stability.
Gender Differences in Fecal Immunochemical Test Performance for Early Detection of Colorectal Neoplasia
Authors: Atija Kapidzic, Miriam P van der Meulen, Lieke Hol, Aafke H C van Roon, Caspar W N Looman, Iris Lansdorp-Vogelaar, Marjolein van Ballegooijen, Anneke J van Vuuren, Jacqueline C I Y Reijerink, Monique E van Leerdam, Ernst J Kuipers
Journal: Clinical Gastroenterology and Hepatology (2015)
Adrenergic Regulation of Cardiac Contractility Does Not Involve Phosphorylation of the Cardiac Ryanodine Receptor at Serine 2808
Authors: Scott M. MacDonnell, Gerardo García-Rivas, Joseph A. Scherman, Hajime Kubo, Xiongwen Chen, Héctor Valdivia, Steven R. Houser
Journal: Circulation Research (2008)

The sympathetic nervous system is a critical regulator of cardiac function (heart rate and contractility) in health and disease. Sympathetic nervous system agonists bind to adrenergic receptors that are known to activate protein kinase A, which phosphorylates target proteins and enhances cardiac performance. Recently, it has been proposed that protein kinase A-mediated phosphorylation of the cardiac ryanodine receptor (the Ca(2+) release channel of the sarcoplasmic reticulum at a single residue, Ser2808) is a critical component of sympathetic nervous system regulation of cardiac function. This is a highly controversial hypothesis that has not been confirmed by several independent laboratories. The present study used a genetically modified mouse in which Ser2808 was replaced by alanine (S2808A) to prevent phosphorylation at this site. The effects of isoproterenol (a sympathetic agonist) on ventricular performance were compared in wild-type and S2808A hearts, both in vivo and in isolated hearts. Isoproterenol effects on L-type Ca(2+) current (I(CaL)), sarcoplasmic reticulum Ca(2+) release, and excitation-contraction coupling gain were also measured. Our results showed that isoproterenol caused significant increases in cardiac function, both in vivo and in isolated hearts, and there were no differences in these contractile effects in wild-type and S2808A hearts. Isoproterenol increased I(CaL), the amplitude of the Ca(2+) transient and excitation-contraction coupling gain, but, again, there were no significant differences between wild-type and S2808A myocytes. These results show that protein kinase A phosphorylation of ryanodine receptor Ser2808 does not have a major role in sympathetic nervous system regulation of normal cardiac function.
Normal Findings in Oral and Cholecystokinin Cholecystography
Authors: M. Herbert Nathan
Journal: JAMA (1978)

Normal findings in oral cholecystography and normal response of the gallbladder to cholecystokinin are established in 200 normal controls. These include absence of right upper quadrant pain in 98.5%, absence of spasm of the body of the gallbladder and of severe spasm in the fundus, a common bile duct diameter of 6 mm or less in those 182 that were visualized, and gallbladder size of less than 11 cm in length in about 97% and less than 4 cm in width in about 97%. If normal contraction occurs after cholecystokinin (or sincalide), an unusually large gallbladder is of no importance. Little or no gallbladder contraction in the presence of normal concentration is probably of no importance.
Respiratory intensive care in Europe: lessons for the UK
Authors: M W ELLIOTT, S V BAUDOUIN
Journal: Thorax (1998)

In this issue of Thorax Nava et al review the provision of respiratory intensive and high dependency care in Europe.1 Medically orientated high dependency units (HDUs) are rare in the UK and in a recent survey only 26% of 190 general hospitals with an intensive care unit (ICU) had an HDU2; the proportion of beds allocated for medical patients was not stated. With increasing pressure on intensive care beds and the development of non-invasive ventilation, it is timely to consider the provision of a clinical area intermediate between intensive care and a general medical ward. Common sense suggests that, if the choice is between an ICU—with one nurse to each patient and a high level of monitoring—and a general ward—with a much lower nurse:patient ratio and little or no monitoring equipment—patients will either need to remain in the ICU longer than is necessary or be discharged to the ward earlier than is ideal.

However, we live in an era of evidence based medicine and business cases. A recent Medical Research Council/Department of Health Working Party paper3 highlighted the fact that little hard evidence exists, in the form of clinical controlled trials, to prove that HDU (or ICU) care is effective or even cost effective. This makes it difficult to argue for increasing provision of these facilities or to decide on the best way to organise this type of care. There are some persuasive financial and organisational arguments in favour of the establishment of HDUs. Significant financial savings could be made by caring for some proportion of the current ICU population in an HDU. A number of studies indicate that a significant proportion (23–33%) of ICU beds are occupied by patients who …
β-Cell Function Improvements in Grade I/II Obese Subjects With Type 2 Diabetes 1 Month After Biliopancreatic Diversion
Authors: Ana Carolina Junqueira Vasques, José Carlos Pareja, Maria da Saude de Oliveira, Fernanda Satake Novaes, Marcelo Miranda de Oliveira Lima, Élinton A. Chaim, Francesca Piccinini, Chiara Dalla Man, Claudio Cobelli, Bruno Geloneze
Journal: Diabetes Care (2013)

To investigate the effect of biliopancreatic diversion (BPD) surgery on β-cell function in grade I and II obese patients with type 2 diabetes using oral and intravenous glucose loads.Sixty-eight women were divided into the following three groups: 19 lean-control (23.0 ± 2.2 kg/m(2)) and 18 obese-control (35.0 ± 4.8 kg/m(2)) subjects with normal glucose tolerance, and 31 obese patients with type 2 diabetes (36.3 ± 3.7 kg/m(2)). Of the 31 diabetic women, 64% underwent BPD (n = 20, BMI: 36.5 ± 3.7 kg/m(2)) and were reassessed 1 month after surgery. Oral glucose tolerance tests and hyperglycemic clamps were performed. Mathematical modeling was used to analyze basal and stimulated β-cell function, insulin sensitivity (IS), hepatic extraction (HE) of insulin, and delay time of β-cell response to a specific plasma glucose concentration.After BPD, restoration of the basal disposition index (P < 0.001) and improvement of the stimulated disposition indices in oral and intravenous glucose stimulation of the β-cell were observed (P < 0.05). In both dynamic tests, there were no changes in the delay time of β-cell response. IS for oral glucose stimulation (IS(oral)) and intravenous clamp glucose stimulation (IS(clamp)) was completely normalized (P < 0.001). IS(oral) and IS(clamp) increased approximately 5.0-fold and 3.5-fold, respectively (P < 0.01). The HE of insulin increased in the basal (P < 0.05) and stimulated states (P < 0.01).β-Cell function, IS, and HE of insulin improved after BPD, which improved glycemic control.
Quadriceps atrophy: to what extent does it exist in patellofemoral pain syndrome?
Authors: M J Callaghan, J A Oldham
Journal: British Journal of Sports Medicine (2004)

Background: Quadriceps atrophy is a commonly cited accompaniment to patellofemoral pain syndrome (PFPS), yet there is little valid, objective evidence for its existence. Objective: To investigate atrophy and weakness of the quadriceps femoris muscle group in patients with PFPS using measures of cross-sectional area and peak extension torque. Methods: A total of 57 patients with insidious onset of PFPS and 10 healthy control subjects had ultrasound scanning of the quadriceps femoris. The scans were analysed using computerised planimetry to estimate the cross-sectional area of the quadriceps femoris. Lower limb peak torque was also measured using a Biodex dynamometer. Results: The mean of % differences revealed a 3.38% (95% confidence interval (CI) 1.3 to 5.45) difference in cross-sectional area (CSA) between the affected and unaffected limb in PFPS patients and a 1.31% (95% CI 0.06 to 2.55) difference in the dominant and non-dominant limb of the control group; the between-groups difference was not significant (p = 0.409). There was a 18.4% (95% CI 13 to 23.8) difference between the affected and unaffected limb in peak torque in PFPS patients and a 7.6% (95% CI 3.2 to 12) difference between the dominant and non-dominant limb in the control group; the between-groups difference was significant (p = 0.002). Conclusions: The mean of % differences of 3.38% quadriceps atrophy between limbs was considerably less than the only other study using ultrasound scanning on the quadriceps in PFPS and was not significant between the groups. There were greater and more significant between-group differences in lower limb peak torque indicating that muscle strength may not be related to muscle size. These results help to re-appraise of the amount of quadriceps atrophy in PFPS.
A new locus on chromosome 18 that influences normal variation in activated protein C resistance phenotype and factor VIII activity and its relation to thrombosis susceptibility
Authors: José Manuel Soria, Laura Almasy, Joan Carles Souto, Alfonso Buil, Elisabeth Martı́nez-Sánchez, José Mateo, Montserrat Borrell, William H. Stone, Mark Lathrop, Jordi Fontcuberta, John Blangero
Journal: Blood (2002)
PIM Kinase Inhibitor AZD1208 for Treatment of MYC-Driven Prostate Cancer
Authors: Austin N. Kirschner, Jie Wang, Riet van der Meer, Philip D. Anderson, Omar E. Franco-Coronel, Max H. Kushner, Joel H. Everett, Omar Hameed, Erika K. Keeton, Miika Ahdesmaki, Shaun E. Grosskurth, Dennis Huszar, Sarki A. Abdulkadir
Journal: JNCI Journal of the National Cancer Institute (2014)

Background:PIM1 kinase is coexpressed with c-MYC in human prostate cancers (PCs) and dramatically enhances c-MYC-induced tumorigenicity. Here we examine the effects of a novel oral PIM inhibitor, AZD1208, on prostate tumorigenesis and recurrence.
Wnt Signaling and Dupuytren's Disease
Authors: Guido H. Dolmans, Paul M. Werker, Hans C. Hennies, Dominic Furniss, Eleonora A. Festen, Lude Franke, Kerstin Becker, Pieter van der Vlies, Bruce H. Wolffenbuttel, Sigrid Tinschert, Mohammad R. Toliat, Michael Nothnagel, Andre Franke, Norman Klopp, H.-Erich Wichmann, Peter Nürnberg, Henk Giele, Roel A. Ophoff, Cisca Wijmenga
Journal: New England Journal of Medicine (2011)

Dupuytren's disease is a benign fibromatosis of the hands and fingers that leads to flexion contractures. We hypothesized that multiple genetic and environmental factors influence susceptibility to this disease and sought to identify susceptibility genes to better understand its pathogenesis.
Gastrointestinal Stromal Tumors (Gist) and Second Malignancies: a Novel ‘Sentinel Tumor"?
Authors: M.G. Rodriquenz, R. Ricci, M. Iezzi, M. Martini, M. Basso, V. Dadduzio, L.M. Larocca, C. Barone, A. Cassano
Journal: Annals of Oncology (2014)
Cardiac catheterisation guided by MRI in children and adults with congenital heart disease
Authors: Reza Razavi, Derek LG Hill, Stephen F Keevil, Marc E Miquel, Vivek Muthurangu, Sanjeet Hegde, Kawal Rhode, Michael Barnett, Joop van Vaals, David J Hawkes, Edward Baker
Journal: The Lancet (2003)