tbuckley/cabot-search huggingface dataset:
Failure to Develop Hepatic Injury From Rosiglitazone in a Patient With a History of Troglitazone-Induced Hepatitis
Authors: M. James Lenhard, William B. Funk
Journal: Diabetes Care (2001)

The thiazolidinediones (TZDs) are an important class of antidiabetic drugs that improve glycemic control by improving sensitivity to insulin (1). The first agent in this class was troglitazone, which has been associated with idiosyncratic hepatotoxicity that included cases of liver failure, liver transplantation, and death (2,3). Troglitazone was voluntarily withdrawn from the market in the U.S. in March 2000. Two additional second-generation agents in this class remain on the market: rosiglitazone maleate (Avandia; SmithKline Beecham Pharmaceuticals) and pioglitazone (Actos; Takeda Pharmaceuticals America/Eli Lilly and Co.). Post-marketing surveillance by the manufacturers of the second-generation TZDs have shown no confirmed hepatotoxicity with either agent. Two isolated cases of drug-induced liver disease with rosiglitazone have been reported (4,5), although some debate over the strength of this association has been raised (6). We present a case of a patient with extreme insulin resistance who developed classic troglitazone-induced liver disease but showed no signs of this while on rosiglitazone.

A 36-year-old woman presented with crampy abdominal pain and evidence of jaundice. She had a 4-year history of uncomplicated type 2 diabetes, initially treated with glyburide and acarbose. Insulin was required, and she was eventually treated with 35 U of U-500 insulin twice a day. Troglitazone 400 …
Innovation, or reverse causation?
Authors: D. Rosen, T. Frischer
Journal: European Respiratory Journal (2009)

Longitudinal, multi-year cohort studies with large numbers of participants offer the only scientific possibility of clearly identifying the causes of childhood asthma (setting aside, for the moment, the difficulties in defining it). While the goal of these studies is clear, the exposure variables tested in them are often not well defined, and their main result is the generation of hypotheses which can then be tested in further studies. Limitations in funding, the enormous amount of time invested in the collection and subsequent analysis of data sets comprised of thousands of participants and several hundred variables, and the loss of patients to follow-up, all present formidable difficulties to investigators. Owing to their sheer size, these studies require the labour of numerous epidemiologists, post-doctoral fellows and bio-statisticians. Across their lifespan, some of the core understandings about the disease, the research questions and even statistical methods may undergo significant evolution and change. For example, the method of generalised estimating equations now used to analyse longitudinal data by regression analyses was only published in 1986 1. Because of all these reasons, one must recognise that the data structure of a study initiated in 1989 may not be appropriate for answering research questions posed 20 or 30 yrs later. One also needs to be aware that the processing of large data sets through sophisticated statistical models enables researchers to find statistically significant …
Contralateral Breast Cancer in <i>BRCA1</i> and <i>BRCA2</i> Mutation Carriers
Authors: Kelly Metcalfe, Henry T. Lynch, Parviz Ghadirian, Nadine Tung, Ivo Olivotto, Ellen Warner, Olufunmilayo I. Olopade, Andrea Eisen, Barbara Weber, Jane McLennan, Ping Sun, William D. Foulkes, Steven A. Narod
Journal: Journal of Clinical Oncology (2004)

To estimate the risk of contralateral breast cancer in BRCA1 and BRCA2 carriers after diagnosis and to determine which factors are predictive of the risk of a second primary breast cancer.Patients included 491 women with stage I or stage II breast cancer, for whom a BRCA1 or BRCA2 mutation had been identified in the family. Patients were followed from the initial diagnosis of cancer until contralateral mastectomy, contralateral breast cancer, death, or last follow-up.The actuarial risk of contralateral breast cancer was 29.5% at 10 years. Factors that were predictive of a reduced risk were the presence of a BRCA2 mutation (v BRCA1 mutation; hazard ratio [HR], 0.73; 95% CI, 0.47 to 1.15); age 50 years or older at first diagnosis (v <or= 49 years; HR, 0.63; 95% CI, 0.36 to 1.10); use of tamoxifen (HR, 0.59; 95% CI, 0.35 to 1.01); and history of oophorectomy (HR, 0.44; 95% CI, 0.21 to 0.91). The effect of oophorectomy was particularly strong in women first diagnosed prior to age 49 years (HR, 0.24; 95% CI, 0.07 to 0.77). For women who did not have an oophorectomy or take tamoxifen, the 10-year risk of contralateral cancer was 43.4% for BRCA1 carriers and 34.6% for BRCA2 carriers.The risk of contralateral breast cancer in women with a BRCA mutation is approximately 40% at 10 years, and is reduced in women who take tamoxifen or who undergo an oophorectomy.
Efficient elimination of chronic lymphocytic leukaemia B cells by autologous T cells with a bispecific anti-CD19/anti-CD3 single-chain antibody construct
Authors: A Löffler, M Gruen, C Wuchter, F Schriever, P Kufer, T Dreier, F Hanakam, P A Baeuerle, K Bommert, L Karawajew, B Dörken, R C Bargou
Journal: Leukemia (2003)
Candidate Pathways for Promoting Differentiation or Quiescence of Oligodendrocyte Progenitor-like Cells in Glioma
Authors: Joseph D. Dougherty, Elena I. Fomchenko, Afua A. Akuffo, Eric Schmidt, Karim Y. Helmy, Elena Bazzoli, Cameron W. Brennan, Eric C. Holland, Ana Milosevic
Journal: Cancer Research (2012)

Platelet-derived growth factor receptor alpha-positive oligodendrocyte progenitor cells (OPC) located within the mature central nervous system may remain quiescent, proliferate, or differentiate into oligodendrocytes. Human glioblastoma multiforme tumors often contain rapidly proliferating oligodendrocyte lineage transcription factor 2 (Olig2)-positive cells that resemble OPCs. In this study, we sought to identify candidate pathways that promote OPC differentiation or quiescence rather than proliferation. Gene expression profiling conducted in both normal murine OPCs and highly proliferative Olig2-positive glioma cells identified all the transcripts associated with the highly proliferative state of these cells and showed that among the various cell types found within the brain, Olig2-positive tumor cells are most similar to OPCs. We then subtracted OPC transcripts found in tumor samples from those found in normal brain samples and identified 28 OPC transcripts as candidates for promoting differentiation or quiescence. Systematic analysis of human glioma data revealed that these genes have similar expression profiles in human tumors and were significantly enriched in genomic deletions, suggesting an antiproliferative role. Treatment of primary murine glioblastoma cells with agonists of one candidate gene, Gpr17, resulted in a decreased number of neurospheres. Together, our findings show that comparison of the molecular phenotype of progenitor cells in tumors to the equivalent cells in the normal brain represents a novel approach for the identification of targeted therapies.
Oxysterol-Induced Soluble Endoglin Release and Its Involvement in Hypertension
Authors: Ana C. Valbuena-Diez, Francisco J. Blanco, Barbara Oujo, Carmen Langa, María Gonzalez-Nuñez, Elena Llano, Alberto M. Pendas, Mercedes Díaz, Antonio Castrillo, José M. Lopez-Novoa, Carmelo Bernabeu
Journal: Circulation (2012)

Ischemia in the placenta is considered the base of the pathogenesis of preeclampsia, a pregnancy-specific syndrome in which soluble endoglin (sEng) is a prognostic marker and plays a pathogenic role. Here, we investigated the effects of hypoxia and the downstream pathways in the release of sEng.Under hypoxic conditions, the trophoblast-like cell line JAR showed an increase in sEng parallel to an elevated formation of reactive oxygen species. Because reactive oxygen species are related to the formation of oxysterols, we assessed the effect of 22-(R)-hydroxycholesterol, a natural ligand of the liver X receptor (LXR), and the LXR synthetic agonist T0901317. Treatment of JAR cells or human placental explants with 22-(R)-hydroxycholesterol or T0901317 resulted in a clear increase in sEng that was dependent on LXR. These LXR agonists induced an increased matrix metalloproteinase-14 expression and activity and a significant reduction of its endogenous inhibitor, tissue inhibitor of metalloproteinase-3. In addition, mice treated with LXR agonists underwent an increase in the plasma sEng levels, concomitant with an increase in arterial pressure. Moreover, transgenic mice overexpressing sEng displayed high blood pressure. Finally, administration of an endoglin peptide containing the consensus matrix metalloproteinase-14 cleavage site G-L prevented the oxysterol-dependent increase in arterial pressure and sEng levels in mice.These studies provide a clue to the involvement of the LXR pathway in sEng release and its pathogenic role in vascular disorders such as preeclampsia.
Fluorouracil, Leucovorin, and Irinotecan Plus Either Sunitinib or Placebo in Metastatic Colorectal Cancer: A Randomized, Phase III Trial
Authors: Alfredo Carrato, Anna Swieboda-Sadlej, Marzanna Staszewska-Skurczynska, Robert Lim, Laslo Roman, Yaroslav Shparyk, Igor Bondarenko, Derek J. Jonker, Yan Sun, Jhony A. De la Cruz, J. Andrew Williams, Beata Korytowsky, James G. Christensen, Xun Lin, Jennifer M. Tursi, Maria J. Lechuga, Eric Van Cutsem
Journal: Journal of Clinical Oncology (2013)

Purpose This double-blind, phase III study aimed to demonstrate that sunitinib plus FOLFIRI (fluorouracil, leucovorin, and irinotecan) was superior to placebo plus FOLFIRI in previously untreated metastatic colorectal cancer (mCRC). Patients and Methods Patients were randomly assigned to receive FOLFIRI and either sunitinib (37.5 mg per day) or placebo (4 weeks on treatment, followed by 2 weeks off [schedule 4/2]) until disease progression. The primary end point was progression-free survival (PFS). Secondary end points included overall survival, safety, and patient-reported outcomes. The correlation between genotype and clinical outcomes was also analyzed. Results In all, 768 patients were randomly assigned to sunitinib plus FOLFIRI (n = 386) or placebo plus FOLFIRI (n = 382). Following a second prespecified interim analysis, the study was stopped because of potential futility of sunitinib plus FOLFIRI. Final results are reported. The PFS hazard ratio was 1.095 (95% CI, 0.892 to 1.344; one-sided stratified log-rank P = .807), indicating a lack of superiority for sunitinib plus FOLFIRI. Median PFS for the sunitinib arm was 7.8 months (95% CI, 7.1 to 8.4 months) versus 8.4 months (95% CI, 7.6 to 9.2 months) for the placebo arm. Sunitinib plus FOLFIRI was associated with more grade ≥ 3 adverse events and laboratory abnormalities than placebo (especially diarrhea, stomatitis/oral syndromes, fatigue, hand-foot syndrome, neutropenia, thrombocytopenia, anemia, and febrile neutropenia). More deaths as a result of toxicity (12 v four) and significantly more dose delays, dose reductions, and treatment discontinuations occurred in the sunitinib arm. Conclusion Sunitinib 37.5 mg per day (schedule 4/2) plus FOLFIRI is not superior to FOLFIRI alone and has a poorer safety profile. This combination regimen is not recommended for previously untreated mCRC.
Management of miscarriage: expectant, medical, or surgical? Results of randomised controlled trial (miscarriage treatment (MIST) trial)
Authors: J Trinder, P Brocklehurst, R Porter, M Read, S Vyas, L Smith
Journal: BMJ (2006)

<h3>Abstract</h3> <b>Objective</b> To ascertain whether a clinically important difference exists in the incidence of gynaecological infection between surgical management and expectant or medical management of miscarriage. <b>Design</b> Randomised controlled trial comparing medical and expectant management with surgical management of first trimester miscarriage. <b>Setting</b> Early pregnancy assessment units of seven hospitals in the United Kingdom. <b>Participants</b> Women of less than 13 weeks9 gestation, with a diagnosis of early fetal demise or incomplete miscarriage. <b>Interventions</b> Expectant management (no specific intervention); medical management (vaginal dose of misoprostol preceded, for women with early fetal demise, by oral mifepristone 24-48 hours earlier); surgical management (surgical evacuation). <b>Main outcome measures</b> Confirmed gynaecological infection at 14 days and eight weeks; need for unplanned admission or surgical intervention. <b>Results</b> 1200 women were recruited: 399 to expectant management, 398 to medical management, and 403 to surgical management. No differences were found in the incidence of confirmed infection within 14 days between the expectant group (3%) and the surgical group (3%) (risk difference 0.2%, 95% confidence interval − 2.2% to 2.7%) or between the medical group (2%) and the surgical group (0.7%, − 1.6% to 3.1%). Compared with the surgical group, the number of unplanned hospital admissions was significantly higher in both the expectant group (risk difference − 41%, − 47% to − 36%) and the medical group (− 10%, − 15% to − 6%). Similarly, when compared with the surgical group, the number of women who had an unplanned surgical curettage was significantly higher in the expectant group (risk difference − 39%, − 44% to − 34%) and the medical group (− 30%, − 35% to − 25%). <b>Conclusions</b> The incidence of gynaecological infection after surgical, expectant, and medical management of first trimester miscarriage is low (2-3%), and no evidence exists of a difference by the method of management. However, significantly more unplanned admissions and unplanned surgical curettage occurred after expectant management and medical management than after surgical management. <b>Trial registration</b> National Research Register: N0467011677/N0467073587.
Exercise over-stress and maximal muscle oxidative metabolism: a<sup>31</sup>P magnetic resonance spectroscopy case report
Authors: B R Newcomer, B Sirikul, G R Hunter, E Larson-Meyer, M Bamman
Journal: British Journal of Sports Medicine (2005)

Objective: 31 P magnetic resonance spectroscopy (MRS) was used to document long lasting losses in muscle oxidative capacity after bouts of intense endurance exercise. Methods: The subject was a 34 year old highly fit female cyclist (V o 2 max = 53.3 ml/kg/min). Over a five month period, she participated in three separate intense bouts of acute unaccustomed exercise. 31 P MRS measurements were performed seven weeks after the first bout and every two weeks for 14 more weeks. In all cases, 31 P MRS measurements followed three days after each bout. Results: The subject showed a decreased ability to generate ATP from oxidative phosphorylation and an increased reliance on anaerobic ATP production during the 70% and 100% maximal voluntary contractions after the exercise bouts. Increased rates of fatigue and increased indicators of exercise difficulty also accompanied these reductions in muscle oxidative capacity. Increased oxidative and anaerobic ATP production were needed to maintain the work level during a submaximal 45% maximal voluntary contraction exercise. Conclusions: Acute increases in intensity accompanied by a change in exercise mode can influence the ability of muscle to generate ATP. The muscles were less economical and required more ATP to generate force during the submaximal exercises. During the maximal exercises, the muscle’s mitochondria showed a reduced oxidative capacity. However, these reductions in oxidative capacity at the muscle level were not associated with changes in whole body maximal oxygen uptake. Finally, these reductions in muscular oxidative capacity were accompanied by increased rates of anaerobic ATP production, fatigue, and indicators of exercise difficulty.
Quality-of-Life Effects of Prostate-Specific Antigen Screening
Authors: Eveline A.M. Heijnsdijk, Elisabeth M. Wever, Anssi Auvinen, Jonas Hugosson, Stefano Ciatto, Vera Nelen, Maciej Kwiatkowski, Arnauld Villers, Alvaro Páez, Sue M. Moss, Marco Zappa, Teuvo L.J. Tammela, Tuukka Mäkinen, Sigrid Carlsson, Ida J. Korfage, Marie-Louise Essink-Bot, Suzie J. Otto, Gerrit Draisma, Chris H. Bangma, Monique J. Roobol, Fritz H. Schröder, Harry J. de Koning
Journal: New England Journal of Medicine (2012)

After 11 years of follow-up, the European Randomized Study of Screening for Prostate Cancer (ERSPC) reported a 29% reduction in prostate-cancer mortality among men who underwent screening for prostate-specific antigen (PSA) levels. However, the extent to which harms to quality of life resulting from overdiagnosis and treatment counterbalance this benefit is uncertain.
Are synchronised swimmers at risk of amenorrhoea?
Authors: R Ramsay, R Wolman
Journal: British Journal of Sports Medicine (2001)

Synchronised swimming is a sport that shares certain characteristics with other aesthetically pleasing sports such as gymnastics and dance. The purpose of this investigation was to ascertain whether the highest ranked synchronised swimmers in the United Kingdom experience menstrual abnormalities, a common medical problem seen in these related activities.Twenty three members of the Great Britain synchronised swimming squad completed a questionnaire on menstrual history. Body composition and VO(2)MAX were measured in the laboratory during regular physiological screening.Three of the 23 subjects were oligomenorrhoeic and none were amenorrhoeic. All were postmenarchal. Mean estimated body fat percentage was 23%, and mean VO(2)MAX was 47.2 ml/kg/min.It appears that synchronised swimmers in the United Kingdom are relatively protected from menstrual disturbances for reasons that cannot be explained in isolation.
Frequent detection of high human papillomavirus DNA loads in oral potentially malignant disorders
Authors: A. Pierangeli, F. Cannella, C. Scagnolari, M. Gentile, I. Sciandra, G. Antonelli, C. Ciolfi, C. Russo, G. Palaia, U. Romeo, A. Polimeni
Journal: Clinical Microbiology and Infection (2015)
Effect of Helicobacter pylori eradication on gastric metaplasia of the duodenum.
Authors: S Khulusi, M A Mendall, S Badve, P Patel, C Finlayson, T C Northfield
Journal: Gut (1995)

Helicobacter pylori associated duodenal ulcers occur in patches of gastric metaplasia. The pathogenesis of gastric metaplasia is unclear, but it has been produced in experimental animals by acute injury and has been shown to be present to a greater extent of H pylori positive subjects. This study aimed to discover if gastric metaplasia regressed with eradication of H pylori or healing of duodenal ulcers, or both. Thirty two duodenal ulcer patients with H pylori infection confirmed by biopsy urease test and by antral histological examination were studied. Patients were treated with triple therapy (deNol 240 mg twice daily, amoxycillin 500 mg three times daily, and metronidazole 400 mg three times daily) for two weeks after the first endoscopy and were subsequently re-endoscoped. Three duodenal bulb biopsy specimens were obtained per patient at each endoscopy. Biopsy sections were stained with haematoxylin and eosin to determine the severity of duodenitis, and with diastase periodic acid-Schiff/alcian blue to assess the extent of gastric metaplasia. Slides were assessed by two histopathologists unaware of treatment status. H pylori was eradicated in 63% of subjects and all ulcers were healed at follow up. The median extent of gastric metaplasia at the start of treatment and 6-18 months (median 10) after treatment was compared in the two groups. Gastric metaplasia declined in eradicators from 16% to 8% (p < 0.05) while in non-eradicators there was no significant change (25% initially and at follow up). A positive relation between extent of gastric metaplasia and duodenal inflammation score was present before treatment (r(s) = 0.74, p < 0.001) and was unchanged after treatment in the non-eradicator group (r(s) = 0.89, p < 0.001). In the eradicator group, however, the inflammation score had significantly declined (p < 0.02) and the close relation with gastric metaplasia was no longer present. These results suggest that H pylori itself is at least in part responsible for producing gastric metaplasia of the duodenum.
IL-6-driven STAT signalling in circulating CD4+ lymphocytes is a marker for early anticitrullinated peptide antibody-negative rheumatoid arthritis
Authors: Amy E Anderson, Arthur G Pratt, Mamdouh A K Sedhom, John Paul Doran, Christine Routledge, Ben Hargreaves, Philip M Brown, Kim-Anh Lê Cao, John D Isaacs, Ranjeny Thomas
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Objectives</h3> A previously identified signal transduction and activator of transcription-3 (STAT3) target-enriched gene signature in circulating CD4+ T cells of patients with early rheumatoid arthritis (RA) was prominent in autoantibody-negative individuals. Here, interleukin (IL)-6-mediated STAT signalling was investigated in circulating lymphocytes of an independent early arthritis patient cohort, seeking further insight into RA pathogenesis and biomarkers of potential clinical utility. <h3>Methods</h3> Constitutive and IL-6-induced expression of phosphorylated STAT1 (pSTAT1) and pSTAT3 was determined in T and B cells using Phosflow cytometric analysis in patients with RA and controls. Contemporaneous levels of serum cytokines were measured by immunoassay. Induced gene expression was measured in cultured CD4+T cells by quantitative real-time PCR. <h3>Results</h3> Among circulating lymphocytes of 187 patients with early arthritis, constitutive pSTAT3 correlated with serum IL-6 levels maximally in CD4+ T cells. Increased constitutive pSTAT3, but not pSTAT1, was observed in circulating CD4+ T cells of patients with early anticitrullinated peptide autoantibody (ACPA)-negative RA compared with disease controls, and these levels decreased alongside markers of disease activity with IL-6R-targeted treatment. Among patients presenting with seronegative undifferentiated arthritis (UA) the ratio of constitutive pSTAT3:pSTAT1 in CD4+ T cells contributed substantially to an algorithm for predicting progression to classifiable RA during a median of 20 months follow-up (area under receiver operator characteristic curve=0.84; p&lt;0.001). <h3>Conclusions</h3> Our findings support a particular role for IL-6-driven CD4+ T cell activation via STAT3 during the induction of RA, particularly as a feature of ACPA-negative disease. CD4+ T cell pSTAT measurements show promise as biomarkers of UA–RA progression and now require independent validation.
Smart Interface Materials Integrated with Microfluidics for On‐Demand Local Capture and Release of Cells
Authors: Umut Atakan Gurkan, Savas Tasoglu, Derya Akkaynak, Oguzhan Avci, Sebnem Unluisler, Serli Canikyan, Noah MacCallum, Utkan Demirci
Journal: Advanced Healthcare Materials (2012)

Stimuli responsive, smart interface materials are integrated with microfluidic technologies creating new functions for a broad range of biological and clinical applications by controlling the material and cell interactions. Local capture and on-demand local release of cells are demonstrated with spatial and temporal control in a microfluidic system.