tbuckley/cabot-search huggingface dataset:
Meta-Analysis: Glycosylated Hemoglobin and Cardiovascular Disease in Diabetes Mellitus
Authors: Elizabeth Selvin, Spyridon Marinopoulos, Gail Berkenblit, Tejal Rami, Frederick L. Brancati, Neil R. Powe, Sherita Hill Golden
Journal: Annals of Internal Medicine (2004)

Background: In persons with diabetes, chronic hyperglycemia (assessed by glycosylated hemoglobin level) is related to the development of microvascular disease; however, the relation of glycosylated hemoglobin to macrovascular disease is less clear. Purpose: To conduct a meta-analysis of observational studies of the association between glycosylated hemoglobin and cardiovascular disease in diabetic persons. Data Sources: Search of the MEDLINE database by using Medical Subject Heading search terms and key words related to glycosylated hemoglobin, diabetes, and cardiovascular disease. Study Selection: Prospective cohort studies with data on glycosylated hemoglobin levels and incident cardiovascular disease. Data Extraction: Relative risk estimates were derived or abstracted from each cohort study that met the inclusion criteria. Data Synthesis: Adjusted relative risk estimates for glycosylated hemoglobin (total glycosylated hemoglobin, hemoglobin A1, or hemoglobin A1c levels) and cardiovascular disease events (coronary heart disease and stroke) were pooled by using random-effects models. Three studies involved persons with type 1 diabetes (n = 1688), and 10 studies involved persons with type 2 diabetes (n = 7435). The pooled relative risk for cardiovascular disease was 1.18; this represented a 1–percentage point increase in glycosylated hemoglobin level (95% CI, 1.10 to 1.26) in persons with type 2 diabetes. Results in persons with type 1 diabetes were similar but had a wider CI (pooled relative risk, 1.15 [CI, 0.92 to 1.43]). Limitations: This review largely reflects the limitations of the literature. Important concerns were residual confounding, the possibility of publication bias, the small number of studies, and the heterogeneity of study results. Conclusions: Pending confirmation from large, ongoing clinical trials, this analysis shows that observational studies are consistent with limited clinical trial data and suggests that chronic hyperglycemia is associated with an increased risk for cardiovascular disease in persons with diabetes.
Human Papillomavirus and Survival of Patients with Oropharyngeal Cancer
Authors: K. Kian Ang, Jonathan Harris, Richard Wheeler, Randal Weber, David I. Rosenthal, Phuc Felix Nguyen-Tân, William H. Westra, Christine H. Chung, Richard C. Jordan, Charles Lu, Harold Kim, Rita Axelrod, C. Craig Silverman, Kevin P. Redmond, Maura L. Gillison
Journal: New England Journal of Medicine (2010)

Oropharyngeal squamous-cell carcinomas caused by human papillomavirus (HPV) are associated with favorable survival, but the independent prognostic significance of tumor HPV status remains unknown.We performed a retrospective analysis of the association between tumor HPV status and survival among patients with stage III or IV oropharyngeal squamous-cell carcinoma who were enrolled in a randomized trial comparing accelerated-fractionation radiotherapy (with acceleration by means of concomitant boost radiotherapy) with standard-fractionation radiotherapy, each combined with cisplatin therapy, in patients with squamous-cell carcinoma of the head and neck. Proportional-hazards models were used to compare the risk of death among patients with HPV-positive cancer and those with HPV-negative cancer.The median follow-up period was 4.8 years. The 3-year rate of overall survival was similar in the group receiving accelerated-fractionation radiotherapy and the group receiving standard-fractionation radiotherapy (70.3% vs. 64.3%; P=0.18; hazard ratio for death with accelerated-fractionation radiotherapy, 0.90; 95% confidence interval [CI], 0.72 to 1.13), as were the rates of high-grade acute and late toxic events. A total of 63.8% of patients with oropharyngeal cancer (206 of 323) had HPV-positive tumors; these patients had better 3-year rates of overall survival (82.4%, vs. 57.1% among patients with HPV-negative tumors; P<0.001 by the log-rank test) and, after adjustment for age, race, tumor and nodal stage, tobacco exposure, and treatment assignment, had a 58% reduction in the risk of death (hazard ratio, 0.42; 95% CI, 0.27 to 0.66). The risk of death significantly increased with each additional pack-year of tobacco smoking. Using recursive-partitioning analysis, we classified our patients as having a low, intermediate, or high risk of death on the basis of four factors: HPV status, pack-years of tobacco smoking, tumor stage, and nodal stage.Tumor HPV status is a strong and independent prognostic factor for survival among patients with oropharyngeal cancer. (ClinicalTrials.gov number, NCT00047008.)
MicroRNA-128 coordinately targets Polycomb Repressor Complexes in glioma stem cells
Authors: Pierpaolo Peruzzi, Agnieszka Bronisz, Michal O. Nowicki, Yan Wang, Daisuke Ogawa, Richard Price, Ichiro Nakano, Chang-Hyuk Kwon, Josie Hayes, Sean E. Lawler, Michael C. Ostrowski, E. Antonio Chiocca, Jakub Godlewski
Journal: Neuro-Oncology (2013)

The Polycomb Repressor Complex (PRC) is an epigenetic regulator of transcription whose action is mediated by 2 protein complexes, PRC1 and PRC2. PRC is oncogenic in glioblastoma, where it is involved in cancer stem cell maintenance and radioresistance. We used a set of glioblastoma patient samples, glioma stem cells, and neural stem cells from a mouse model of glioblastoma. We characterized gene/protein expression and cellular phenotypes by quantitative PCR/Western blotting and clonogenic, cell-cycle, and DNA damage assays. We performed overexpression/knockdown studies by lentiviral infection and microRNA/small interfering RNA oligonucleotide transfection. We show that microRNA-128 (miR-128) directly targets mRNA of SUZ12, a key component of PRC2, in addition to BMI1, a component of PRC1 that we previously showed as a target as well. This blocks the partially redundant functions of PRC1/PRC2, thereby significantly reducing PRC activity and its associated histone modifications. MiR-128 and SUZ12/BMI1 show opposite expression in human glioblastomas versus normal brain and in glioma stemlike versus neural stem cells. Furthermore, miR-128 renders glioma stemlike cells less radioresistant by preventing the radiation-induced expression of both PRC components. Finally, miR-128 expression is significantly reduced in neural stem cells from the brain of young, presymptomatic mice in our mouse model of glioblastoma. This suggests that loss of miR-128 expression in brain is an early event in gliomagenesis. Moreover, knockdown of miR-128 expression in nonmalignant mouse and human neural stem cells led to elevated expression of PRC components and increased clonogenicity. MiR-128 is an important suppressor of PRC activity, and its absence is an early event in gliomagenesis.
NADPH oxidase activation by hyperglycaemia in cardiomyocytes is independent of glucose metabolism but requires SGLT1
Authors: Magali Balteau, Nicolas Tajeddine, Carole de Meester, Audrey Ginion, Christine Des Rosiers, Nathan R. Brady, Caroline Sommereyns, Sandrine Horman, Jean-Louis Vanoverschelde, Philippe Gailly, Louis Hue, Luc Bertrand, Christophe Beauloye
Journal: Cardiovascular Research (2011)

Exposure to high glucose (HG) stimulates reactive oxygen species (ROS) production by NADPH oxidase in cardiomyocytes, but the underlying mechanism remains elusive. In this study, we have dissected the link between glucose transport and metabolism and NADPH oxidase activation under hyperglycaemic conditions. Primary cultures of adult rat cardiomyocytes were exposed to HG concentration (HG, 21 mM) and compared with the normal glucose level (LG, 5 mM). HG exposure activated Rac1GTP and induced p47phox translocation to the plasma membrane, resulting in NADPH oxidase (NOX2) activation, increased ROS production, insulin resistance, and eventually cell death. Comparison of the level of O-linked N-acetylglucosamine (O-GlcNAc) residues in LG- and HG-treated cells did not reveal any significant difference. Inhibition of the pentose phosphate pathway (PPP) by 6-aminonicotinamide counteracted ROS production in response to HG but did not prevent Rac-1 upregulation and p47phox translocation leading to NOX2 activation. Modulation of glucose uptake barely affected oxidative stress and toxicity induced by HG. More interestingly, non-metabolizable glucose analogues (i.e. 3-O-methyl-d-glucopyranoside and α-methyl-d-glucopyranoside) reproduced the toxic effect of HG. Inhibition of the sodium/glucose cotransporter SGLT1 by phlorizin counteracted HG-induced NOX2 activation and ROS production. Increased glucose metabolism by itself does not trigger NADPH oxidase activation, although PPP is required to provide NOX2 with NADPH and to produce ROS. NOX2 activation results from glucose transport through SGLT1, suggesting that an extracellular metabolic signal transduces into an intracellular ionic signal.
Hepatic release of erythropoietin induced by transarterial chemoembolization in patients with hepatocellular carcinoma
Authors: Mario Pirisi, Carlo Fabris, Giorgio Soardo, Edmondo Falleti, Daniele Gasparini, Daniela Vitulli, Pierluigi Toniutto, Fabio Gonano, Ettore Bartoli
Journal: Hepatology (1995)

It has been shown previously that erythropoietin expression in vitro by hepatoma cells increases in response to hypoxia. To verify whether hypoxia of the tumor might result in hepatic release of erythropoietin in vivo, serum erythropoietin concentrations were measured immunoenzymatically in 12 patients (5 women, 7 men) who underwent transarterial chemoembolization for hepatocellular carcinoma. Peripheral blood samples were collected at baseline, and after 6 hours and 1, 2, 3, and 7 days after the procedure. In a second set of experiments, performed in three male patients also undergoing chemoembolization for hepatocellular carcinoma, paired blood samples were collected after catheterization of the hepatic veins and of the right antecubital vein. None of the patients had erythrocytosis. In comparison with a baseline mean value +/- SEM of 100.6 +/- 12.6 micrograms/L, serum erythropoietin concentrations were the following; +6 hours, 55.4 +/- 18.0 (P < .001); +1 day, 102.4 +/- 24.7 (P = NS), +2 days, 183.0 +/- 31.1 (P < .05); +3 days, 155.0 +/- 26.0 (P < .05); +7 days, 153.3 +/- 27.4 (P < .05) (matched Student's t-test). The ratio of hepatic vein/antecubital vein serum erythropoietin concentrations increased from 0.85 at baseline to 1.30 at +2 days, paralleling the increase of aspartate transaminase (r = .914, P < .005). After chemoembolization, no correlation was found between serum erythropoietin and alpha-1-fetoprotein concentrations. The concentration of the latter, stable initially, decreased 7 days after the procedure.(ABSTRACT TRUNCATED AT 250 WORDS)
Nonalcoholic Fatty Liver Disease Is a Risk Factor for Type 2 Diabetes in Middle-Aged Japanese Men
Authors: Michihiko Shibata, Yasuyuki Kihara, Masashi Taguchi, Mitsuo Tashiro, Makoto Otsuki
Journal: Diabetes Care (2007)

To determine the association between nonalcoholic fatty liver disease and the risk for development of diabetes.We conducted an observational cohort study in male workers > or = 40 years old in a Japanese company from 1997 to 2005. We excluded workers with alcohol intake > or = 20 g/day and those with impaired glucose tolerance by a 75-g oral glucose tolerance test. The remaining 3,189 workers were classified into fatty liver (FL) and non-FL group based on the findings of abdominal ultrasonography. Both groups were followed for the development of diabetes. Hazard ratio (HR) was determined in Cox proportional hazard analysis. A nested case-control study was conducted to determine the odds ratio (OR).The average age of participants was 48.0 years at the entry, and the average follow-up period was 4.0 years. The incidence of diabetes in the FL group was 2,073 per 100,000 person-years (65 cases), whereas 452 per 100,000 person-years (44 cases) in the non-FL group. The age- and BMI-adjusted HR of diabetes associated with FL was 5.5 (95% CI 3.6-8.5, P < 0.001). In the nested case-control analysis, the OR adjusted for age and BMI was 4.6 (3.0-6.9, P < 0.001).Nonalcoholic fatty liver disease significantly increases the risk of diabetes in middle-aged Japanese men.
Reduced Expression of the <b> <i>let-7</i> </b> MicroRNAs in Human Lung Cancers in Association with Shortened Postoperative Survival
Authors: Junichi Takamizawa, Hiroyuki Konishi, Kiyoshi Yanagisawa, Shuta Tomida, Hirotaka Osada, Hideki Endoh, Tomoko Harano, Yasushi Yatabe, Masato Nagino, Yuji Nimura, Tetsuya Mitsudomi, Takashi Takahashi
Journal: Cancer Research (2004)

Abstract In this study, we report for the first time reduced expression of the let-7 microRNA in human lung cancers. Interestingly, 143 lung cancer cases that had undergone potentially curative resection could be classified into two major groups according to let-7 expression in unsupervised hierarchical analysis, showing significantly shorter survival after potentially curative resection in cases with reduced let-7 expression (P = 0.0003). Multivariate COX regression analysis showed this prognostic impact to be independent of disease stage (hazard ratio = 2.17; P = 0.009). In addition, overexpression of let-7 in A549 lung adenocarcinoma cell line inhibited lung cancer cell growth in vitro. This study represents the first report of reduced expression of let-7 and the potential clinical and biological effects of such a microRNA alteration.
Antifolate Resistance in a HeLa Cell Line Associated With Impaired Transport Independent of the Reduced Folate Carrier
Authors: Rongbao Zhao, Shrikanta Chattopadhyay, Marie Hanscom, I. David Goldman
Journal: Clinical Cancer Research (2004)

Abstract Prior studies from this laboratory documented the prevalence of methotrexate (MTX) transport activity with a low pH optimum in human solid tumor cell lines. In HeLa cells, this low pH activity has high affinity for pemetrexed [PMX (Alimta)] and is reduced folate carrier (RFC)-independent because it is not diminished in a RFC-null subline (R5). R5 cells also have residual transport activity, with high specificity for PMX, at neutral pH. In the current study, a R5 subline, R1, was selected under MTX selective pressure at a modest reduction in pH. There was markedly decreased MTX and PMX transport at both pH 5.5 and pH 7.4. When MTX was removed, there was a slow return of transport activity, and when MTX was added back, there was loss of transport at both pH values within 8 weeks. In R1 cells, there was a marked decrease in accumulation of PMX, MTX, and folic acid along with a decrease in growth inhibition by these and other antifolates that require a facilitative process to gain entry into cells. These data demonstrate that (i) RFC-independent transport in HeLa cells at low and neutral pH contributes to antifolate activity (in particular, to PMX activity) and can be diminished by antifolate selective pressure and (ii) the loss of these activities results in marked resistance to PMX, an agent for which there is little or no loss of activity when transport mediated by RFC is abolished. These observations suggest that transport activity in RFC-null HeLa R5 cells at neutral and low pH may reflect the same carrier-mediated process.
Endochondral bone formation in gelatin methacrylamide hydrogel with embedded cartilage-derived matrix particles
Authors: Jetze Visser, Debby Gawlitta, Kim E.M. Benders, Selynda M.H. Toma, Behdad Pouran, P. René van Weeren, Wouter J.A. Dhert, Jos Malda
Journal: Biomaterials (2014)
Hydrogen peroxide enhanced ultrasound- fistulography in the assessment of enterocutaneous fistulas complicating Crohn's disease
Authors: G Maconi, F Parente, G B. Porro
Journal: Gut (1999)

<h3>BACKGROUND/AIMS</h3> Proper management of enterocutaneous fistulas complicating Crohn9s disease largely depends on the anatomical characteristics of the sinus tracks as well as the coexistence of complications such as abscesses and distal bowel stenosis. The aim of this prospective study was to evaluate the accuracy of a new technique (hydrogen peroxide enhanced ultrasound (US)-fistulography) compared with conventional <i>x</i>ray fistulogram and/or surgical findings in the detection of Crohn9s disease associated enterocutaneous fistulas. <h3>METHODS</h3> Patients with known Crohn9s disease and a suspicion of enterocutaneous fistulas were prospectively studied with this novel technique, conventional<i>x </i>ray fistulogram, and barium radiography as well as with computed tomography whenever an abdominal abscess was suspected at US. In those undergoing surgery, intraoperative findings were also compared. <h3>RESULTS</h3> Seventeen of 502 (3.4%) consecutive patients with Crohn9s disease seen over a ten month period had associated enterocutaneous fistulas and were enrolled. Hydrogen peroxide enhanced US-fistulography visualised the extent and configuration of fistula in all cases: 13 patients had a fistula arising from the ileum and two from the sigmoid colon, whereas in two there was no evidence of communication with intestinal loops; in contrast, conventional <i>x</i> ray fistulography missed a correct definition of the fistulous branches or communication with intestinal loops in 50% (4/8) and 36% (4/11) of patients respectively; barium radiography showed fistulas in two cases only. The presence of abscesses along or close to the sinus track, as well as the coexistence of intestinal stenosis, was correctly detected at US in all patients. <h3>CONCLUSIONS</h3> Hydrogen peroxide enhanced US-fistulography could be considered the diagnostic procedure of choice in Crohn9s disease associated enterocutaneous fistulas, as it is at least as accurate, simple, and safe as conventional<i>x</i> ray fistulogram, does not miss coexisting abdominal complications, and also provides information on the diseased bowel segments. In addition, it can be easily repeated over time in order to monitor the course of fistulas undergoing conservative treatment.
Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction
Authors: Volker Schächinger, Birgit Assmus, Martina B. Britten, Jörg Honold, Ralf Lehmann, Claudius Teupe, Nasreddin D. Abolmaali, Thomas J. Vogl, Wolf-Karsten Hofmann, Hans Martin, Stefanie Dimmeler, Andreas M. Zeiher
Journal: Journal of the American College of Cardiology (2004)
A role for ITPA variants in the clinical course of pulmonary Langerhans' cell histiocytosis?
Authors: J.A. Bakker, J. Bierau, M. Drent
Journal: European Respiratory Journal (2010)

To the Editors:

Interstitial lung diseases (ILD) comprise a number of clinical conditions, including sarcoidosis, pulmonary fibrosis and pulmonary Langerhans' cell histiocytosis (PLCH; histiocytosis X). The diagnostic workup for the classification of ILD is often complicated and tedious. PLCH is characterised by the proliferation of Langerhans' cells and their infiltration into pulmonary tissues. In disseminated LCH, additional tissues are affected. PLCH is strongly associated with smoking and the clinical outcome depends upon cessation of smoking 1.

Treatment of ILD often requires corticosteroids and immunosuppressant drugs, including thiopurines and biologicals. It is mandatory to exclude genetic polymorphisms in genes involved in metabolism of thiopurine metabolism, because of the pharmacogenetic consequences of the use of thiopurines. The prospective measuring of erythrocyte enzyme activity of thiopurine S -methyltransferase (TPMT) and inosine triphosphatase (ITPase) or molecular analyses of the genes encoding these enzymes is recommended in clinical practice 2.

Aberrant enzyme activity of either TPMT or ITPase gives rise to a broad spectrum of adverse drug reactions (ADR) associated with thiopurines, ranging from therapeutic failure to life-threatening leukopenia 3, 4.

In order to avoid these ADR, we have incorporated pre-treatment screening of TPMT and ITPase of patients with ILD who are candidates for treatment with thiopurines in our hospital.

An unexpectedly high number of decreased ITPase activities in patients with PLCH was found, all of which had an unfavourable outcome. We hypothesised about the role of the ITPA gene in relation to immunity, which might …
Charles Nathaniel ("Natty") Armstrong Charles Richard Berkin George Duncan Campbell John William Carter David Alfred Davies Humphrey William Elcock Christopher Rupert Bailey Hole Edward Brian Lewis William Weir Marshall John Ross Milne Colin George Mitchell Joseph Dunbar Paterson
Authors: H A Dewar, K E Berkin, G Hoyle, Y K Seedat, S. Marshall, J G Wingfield, J. Topham, J. Bryson, J. Warwick, L. Davison, J. Appleyard, W G. Semple, G. Dale, D. Grieve, T M Paterson
Journal: BMJ (1999)
Sequencing the Entire Genomes of Free-Living Organisms: The Foundation of Pharmacology in the New Millennium
Authors: Samuel Broder, J. Craig Venter
Journal: The Annual Review of Pharmacology and Toxicology (2000)

The power and effectiveness of clinical pharmacology are about to be transformed with a speed that earlier in this decade could not have been foreseen even by the most astute visionaries. In the very near future, we will have at our disposal the reference DNA sequence for the entire human genome, estimated to contain approximately 3.5 billion bp. At the same time, the science of whole genome sequencing is fostering the computational science of bioinformatics needed to develop practical applications for pharmacology and toxicology. Indeed, it is likely that pharmacology, toxicology, bioinformatics, and genomics will merge into a new branch of medical science for studying and developing pharmaceuticals from molecule to bedside.
<i>S</i> -Nitrosoglutathione Reduces Asymptomatic Embolization After Carotid Angioplasty
Authors: Zoltan Kaposzta, Andrew Clifton, Jane Molloy, John F. Martin, Hugh S. Markus
Journal: Circulation (2002)

Background— The major complication of carotid angioplasty is embolic stroke, which may occur after balloon inflation and deflation or in the early postintervention period. Platelet adhesion and aggregation to the angioplasty site with subsequent embolization seems to plays a major role in early postangioplasty embolization and stroke. During this period, asymptomatic embolic signals can be detected in patients by transcranial Doppler ultrasound despite aspirin and heparin treatment. S -Nitrosoglutathione (GSNO) is a nitric oxide donor that appears to have relative platelet specificity. We evaluated its effectiveness in reducing embolization after carotid angioplasty. Methods and Results— Sixteen patients undergoing carotid angioplasty and stenting for symptomatic ≥70% internal carotid artery stenosis were randomized in a double-blind manner to GSNO or placebo given after surgery for 90 minutes. All patients were pretreated with aspirin and given heparin for 24 hours after the procedure. Transcranial Doppler recordings were made from the ipsilateral middle cerebral artery for 1 hour before treatment and at 0 to 3, 6, and 24 hours after treatment. GSNO resulted in a rapid reduction in the frequency of embolic signals of 95% at 0 to 3 hours and 100% at 6 hours ( P =0.007 and P =0.01 versus placebo, respectively). In the placebo group, 2 patients experienced ipsilateral stroke after the angioplasty. No cerebrovascular events occurred in the GSNO group. Conclusions— S -Nitrosoglutathione was highly effective in rapidly reducing the frequency of embolic signals after endovascular treatment for symptomatic high-grade carotid stenosis.