tbuckley/cabot-search huggingface dataset:
Association Between Maternal Diabetes in Utero and Age at Offspring's Diagnosis of Type 2 Diabetes
Authors: David J. Pettitt, Jean M. Lawrence, Jennifer Beyer, Teresa A. Hillier, Angela D. Liese, Beth Mayer-Davis, Beth Loots, Giuseppina Imperatore, Lenna Liu, Lawrence M. Dolan, Barbara Linder, Dana Dabelea
Journal: Diabetes Care (2008)

The purpose of this study was to examine age of diabetes diagnosis in youth who have a parent with diabetes by diabetes type and whether the parent's diabetes was diagnosed before or after the youth's birth.The cohort comprised SEARCH for Diabetes in Youth Study participants (diabetes diagnosis 2001-2005) with a diabetic parent. SEARCH is a multicenter survey of youth with diabetes diagnosed before age 20 years.Youth with type 2 diabetes were more likely to have a parent with either type 1 or type 2 diabetes (mother 39.3%; father 21.2%) than youth with type 1 diabetes (5.3 and 6.7%, respectively, P < 0.001 for each). Type 2 diabetes was diagnosed 1.68 years earlier among those exposed to diabetes in utero (n = 174) than among those whose mothers' diabetes was diagnosed later (P = 0.018, controlled for maternal diagnosis age, paternal diabetes, sex, and race/ethnicity). Age at diagnosis of type 1 diabetes for 269 youth with and without in utero exposure did not differ significantly (difference 0.96 year, P = 0.403 after adjustment). Controlled for the father's age of diagnosis, father's diabetes before the child's birth was not associated with age at diagnosis (P = 0.078 for type 1 diabetes; P = 0.140 for type 2 diabetes).Type 2 diabetes was diagnosed at younger ages among those exposed to hyperglycemia in utero. Among youth with type 1 diabetes, the effect of the intrauterine exposure was not significant when controlled for mother's age of diagnosis. This study helps explain why other studies have found higher age-specific rates of type 2 diabetes among offspring of women with diabetes.
Cediranib With mFOLFOX6 Versus Bevacizumab With mFOLFOX6 As First-Line Treatment for Patients With Advanced Colorectal Cancer: A Double-Blind, Randomized Phase III Study (HORIZON III)
Authors: Hans-Joachim Schmoll, David Cunningham, Alberto Sobrero, Christos S. Karapetis, Philippe Rougier, Sheryl L. Koski, Ilona Kocakova, Igor Bondarenko, György Bodoky, Paul Mainwaring, Ramon Salazar, Peter Barker, Bijoyesh Mookerjee, Jane Robertson, Eric Van Cutsem
Journal: Journal of Clinical Oncology (2012)

To compare the efficacy of cediranib (a vascular endothelial growth factor receptor tyrosine kinase inhibitor [VEGFR TKI]) with that of bevacizumab (anti-VEGF-A monoclonal antibody) in combination with chemotherapy as first-line treatment for advanced metastatic colorectal cancer (mCRC).HORIZON III [Cediranib Plus FOLFOX6 Versus Bevacizumab Plus FOLFOX6 in Patients With Untreated Metastatic Colorectal Cancer] had an adaptive phase II/III design. Patients randomly assigned 1:1:1 received mFOLFOX6 [oxaliplatin 85 mg/m(2) and leucovorin 400 mg/m(2) intravenously followed by fluorouracil 400 mg/m(2) intravenously on day 1 and then continuous infusion of 2,400 mg/m(2) over the next 46 hours every 2 weeks] with cediranib (20 or 30 mg per day) or bevacizumab (5 mg/kg every 14 days). An independent end-of-phase II analysis concluded that mFOLFOX6/cediranib 20 mg met predefined criteria for continuation; subsequent patients received mFOLFOX6/cediranib 20 mg or mFOLFOX6/bevacizumab (randomly assigned 1:1). The primary objective was to compare progression-free survival (PFS).In all, 1,422 patients received mFOLFOX6/cediranib 20 mg (n = 709) or mFOLFOX6/bevacizumab (n = 713). Primary analysis revealed no significant difference between arms for PFS (hazard ratio [HR], 1.10; 95% CI, 0.97 to 1.25; P = .119), overall survival (OS; HR, 0.95; 95% CI, 0.82 to 1.10; P = .541), or overall response rate (46.3% v 47.3%). Median PFS and OS were 9.9 and 22.8 months for mFOLFOX6/cediranib and 10.3 and 21.3 months for mFOLFOX6/bevacizumab. The PFS upper 95% CI was outside the predefined noninferiority limit (HR < 1.2). Common adverse events with more than 5% incidence in the cediranib arm included diarrhea, neutropenia, and hypertension. Cediranib-treated patients completed fewer chemotherapy cycles than bevacizumab-treated patients (median 10 v 12 cycles). Patient-reported outcomes (PROs) were significantly less favorable in cediranib-treated versus bevacizumab-treated patients (P < .001).Cediranib activity, in terms of PFS and OS, was comparable to that of bevacizumab when added to mFOLFOX6; however, the predefined boundary for PFS noninferiority was not met. The cediranib safety profile was consistent with previous studies but led to less favorable PROs compared with bevacizumab. Investigation of oral TKIs in CRC continues.
Multiple Acquisition of Methanogenic Archaeal Symbionts by Anaerobic Ciliates
Authors: A H van Hoek, T A van Alen, V S Sprakel, J A Leunissen, T Brigge, G D Vogels, J H Hackstein
Journal: Molecular Biology and Evolution (2000)

Anaerobic heterotrichous ciliates (Armophoridae and Clevelandellidae) possess hydrogenosomes that generate molecular hydrogen and ATP. This intracellular source of hydrogen provides the basis for a stable endosymbiotic association with methanogenic archaea. We analyzed the SSU rRNA genes of 18 heterotrichous anaerobic ciliates and their methanogenic endosymbionts in order to unravel the evolution of this mutualistic association. Here, we show that the anaerobic heterotrichous ciliates constitute at least three evolutionary lines. One group consists predominantly of gut-dwelling ciliates, and two to three, potentially four, additional clades comprise ciliates that thrive in freshwater sediments. Their methanogenic endosymbionts belong to only two different taxa that are closely related to free-living methanogenic archaea from the particular ecological niches. The close phylogenetic relationships between the endosymbionts and free-living methanogenic archaea argue for multiple acquisitions from environmental sources, notwithstanding the strictly vertical transmission of the endosymbionts. Since phylogenetic analysis of the small-subunit (SSU) rRNA genes of the hydrogenosomes of these ciliates indicates a descent from the mitochondria of aerobic ciliates, it is likely that anaerobic heterotrichous ciliates hosted endosymbiotic methanogens prior to their radiation. Therefore, our data strongly suggest multiple acquisitions and replacements of endosymbiotic methanogenic archaea during their host's adaptation to the various ecological niches.
Isoprenaline stimulates gene transcription of the inhibitory G protein alpha-subunit Gi alpha-2 in rat heart.
Authors: F U Müller, K R Boheler, T Eschenhagen, W Schmitz, H Scholz
Journal: Circulation Research (1993)

In vitro transcription reactions were performed with isolated ventricular nuclei of adult rats to investigate whether increased mRNA levels of the inhibitory G protein alpha-subunit Gi alpha-2 after prolonged in vivo stimulation with the beta-adrenoceptor agonist isoprenaline are caused by increased transcription. Rats were treated by a 4-day subcutaneous infusion of isoprenaline (2.4 mg/kg per day) or 0.9% NaCl as control. To avoid the influence of developmental expression patterns, adult rats were chosen for all experiments. Signals for Gi alpha-2 and the stimulatory G protein alpha-subunit Gs alpha were specific and due to hybridization of nascent mRNA transcripts. In the isoprenaline group the transcriptional activity of Gi alpha-2 gene increased to 140% of the control value, whereas gene specific hybridization for Gs alpha remained unchanged. These results show that increased Gi alpha-2 mRNA levels after stimulation with isoprenaline are at least partially caused by enhanced transcription of Gi alpha-2 mRNA.
Expression analysis and in silico characterization of intronic long noncoding RNAs in renal cell carcinoma: emerging functional associations
Authors: Angela A Fachel, Ana C Tahira, Santiago A Vilella-Arias, Vinicius Maracaja-Coutinho, Etel RP Gimba, Giselle M Vignal, Franz S Campos, Eduardo M Reis, Sergio Verjovski-Almeida
Journal: Molecular Cancer (2013)

Intronic and intergenic long noncoding RNAs (lncRNAs) are emerging gene expression regulators. The molecular pathogenesis of renal cell carcinoma (RCC) is still poorly understood, and in particular, limited studies are available for intronic lncRNAs expressed in RCC.Microarray experiments were performed with custom-designed arrays enriched with probes for lncRNAs mapping to intronic genomic regions. Samples from 18 primary RCC tumors and 11 nontumor adjacent matched tissues were analyzed. Meta-analyses were performed with microarray expression data from three additional human tissues (normal liver, prostate tumor and kidney nontumor samples), and with large-scale public data for epigenetic regulatory marks and for evolutionarily conserved sequences.A signature of 29 intronic lncRNAs differentially expressed between RCC and nontumor samples was obtained (false discovery rate (FDR) < 5%). A signature of 26 intronic lncRNAs significantly correlated with the RCC five-year patient survival outcome was identified (FDR < 5%, p-value ≤ 0.01). We identified 4303 intronic antisense lncRNAs expressed in RCC, of which 22% were significantly (p < 0.05) cis correlated with the expression of the mRNA in the same locus across RCC and three other human tissues. Gene Ontology (GO) analysis of those loci pointed to 'regulation of biological processes' as the main enriched category. A module map analysis of the protein-coding genes significantly (p < 0.05) trans correlated with the 20% most abundant lncRNAs, identified 51 enriched GO terms (p < 0.05). We determined that 60% of the expressed lncRNAs are evolutionarily conserved. At the genomic loci containing the intronic RCC-expressed lncRNAs, a strong association (p < 0.001) was found between their transcription start sites and genomic marks such as CpG islands, RNA Pol II binding and histones methylation and acetylation.Intronic antisense lncRNAs are widely expressed in RCC tumors. Some of them are significantly altered in RCC in comparison with nontumor samples. The majority of these lncRNAs is evolutionarily conserved and possibly modulated by epigenetic modifications. Our data suggest that these RCC lncRNAs may contribute to the complex network of regulatory RNAs playing a role in renal cell malignant transformation.
A telemedicine intervention to improve adherence to continuous positive airway pressure: a randomised controlled trial
Authors: D. Sparrow, M. Aloia, D. A. DeMolles, D. J. Gottlieb
Journal: Thorax (2010)

<h3>Background</h3> Continuous positive airway pressure (CPAP) is the most widely prescribed treatment for obstructive sleep apnoea syndrome (OSAS). Although it has been shown to improve the symptoms of OSAS, many patients have difficulty adhering to this treatment. The purpose of this study was to investigate the effectiveness of an automated telemedicine intervention to improve adherence to CPAP. <h3>Methods</h3> A randomised clinical trial was undertaken in 250 patients being started on CPAP therapy for OSAS. Patients were randomly assigned to use a theory-driven interactive voice response system designed to improve CPAP adherence (telephone-linked communications for CPAP (TLC-CPAP), n=124) or to an attention placebo control (n=126) for 12 months. TLC-CPAP monitors patients9 self-reported behaviour and CPAP-related symptoms and provides feedback and counselling through a structured dialogue to enhance motivation to use CPAP. A Sleep Symptoms Checklist, the Functional Outcomes of Sleep Questionnaire, the Center for Epidemiological Studies Depression Scale and the Psychomotor Vigilance Task were administered at study entry and at 6-month and 12-month follow-up. Hours of CPAP usage at effective mask pressure were measured by the CPAP device stored in its memory and retrieved at each visit. <h3>Results</h3> Median observed CPAP use in patients randomised to TLC-CPAP was approximately 1 h/night higher than in the control subjects at 6 months and 2 h/night higher at 12 months. Using generalised estimating equation modelling, the intervention had a significant effect on CPAP adherence. For secondary analysis, the effect of CPAP adherence on the secondary outcomes was analysed. CPAP adherence was significantly associated with a greater reduction in sleep apnoea symptoms and depressive symptoms and a greater improvement in functional status. No significant association was observed between CPAP adherence and reaction time. <h3>Conclusions</h3> The TLC-CPAP intervention resulted in improved CPAP adherence, which was associated with improved functional status and fewer depressive symptoms. <h3>Clinical trial.gov</h3> NCT00232544.
Posterior Cortical Atrophy as an Extreme Phenotype of<i>GRN</i>Mutations
Authors: Paola Caroppo, Catherine Belin, David Grabli, Didier Maillet, Anne De Septenville, Raffaella Migliaccio, Fabienne Clot, Foudil Lamari, Agnès Camuzat, Alexis Brice, Bruno Dubois, Isabelle Le Ber
Journal: JAMA Neurology (2014)

Posterior cortical atrophy (PCA) is characterized by progressive visuoperceptual and visuospatial deficits and commonly considered to be an atypical variant of Alzheimer disease. Mutations of the GRN gene are responsible for a large phenotypic spectrum, but, to our knowledge, the association of PCA with GRN mutations has never been described.We studied a patient presenting with insidious impairment of basic visuoperceptual skills and apperceptive visual agnosia with predominant posterior atrophy corresponding to a visual/ventral variant of PCA. A heterozygous p.Arg110* (c.328C>T) GRN mutation was identified in this patient.This study extends the clinical spectrum of GRN mutations that may be responsible for a PCA phenotype. The GRN phenotypes overlap other degenerative dementias and highlight the limits of actual nosologic boundaries in dementias. The GRN gene should be analyzed in patients with PCA, particularly when the damage progresses to anterior cerebral regions and a family history of dementia is present.
Secondary leukemia after epirubicin-based adjuvant chemotherapy in operable breast cancer patients: 16 years experience of the French Adjuvant Study Group
Authors: M. Campone, H. Roché, P. Kerbrat, J. Bonneterre, P. Romestaing, P. Fargeot, M. Namer, A. Monnier, P. Montcuquet, M.-J. Goudier, P. Fumoleau
Journal: Annals of Oncology (2005)
Evidence of NLRP3-inflammasome activation in rheumatoid arthritis (RA); genetic variants within the NLRP3-inflammasome complex in relation to susceptibility to RA and response to anti-TNF treatment
Authors: Rebeccah J Mathews, James I Robinson, Michele Battellino, Chi Wong, John C Taylor, Steve Eyre, Sarah M Churchman, Anthony G Wilson, John D Isaacs, Kimme Hyrich, Anne Barton, Darren Plant, Sinisa Savic, Graham P Cook, Piercarlo Sarzi-Puttini, Paul Emery, Jennifer H Barrett, Ann W Morgan, Michael F McDermott
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> The NLRP3-inflammasome, implicated in the pathogenesis of several inflammatory disorders, has been analysed in rheumatoid arthritis (RA). <h3>Methods</h3> Relative gene expression of NLRP3-inflammasome components was characterised in PBMCs of 29 patients receiving infliximab. A total of 1278 Caucasian patients with RA from the Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate (BRAGGSS) cohort receiving tumour necrosis factor (TNF) antagonists (infliximab, adalimumab and etanercept) were genotyped for 34 single nucleotide polymorphisms (SNPs), spanning the genes <i>NLRP3, MEFV</i> and <i>CARD8</i>. Regression analyses were performed to test for association between genotype and susceptibility and treatment response (disease activity score across 28 joints (DAS28) and EULAR improvement criteria) at 6 months, with secondary expression quantitative trait loci (eQTL) analyses. <h3>Results</h3> At baseline, gene expression of <i>ASC, MEFV, NLRP3</i>-FL<i>, NLRP3</i>-SL and <i>CASP1</i> were significantly higher compared with controls whereas <i>CARD8</i> was lower in the patients. Caspase-1 and interleukin-18 levels were significantly raised in patients with RA. SNPs in <i>NLRP3</i> showed association with RA susceptibility and EULAR response to anti-TNF in the BRAGGSS cohort, and in monocytes but not B cells, in eQTL analysis of 283 healthy controls. <i>CARD8</i> SNPs were associated with RA susceptibility and DAS28 improvement in response to anti-TNF and eQTL effects in monocytes and B cells. <h3>Conclusions</h3> This study found evidence of modulation of the NLRP3-inflammasome in patients with RA prior to receiving infliximab and some evidence of association for SNPs at <i>NLRP3</i> and <i>CARD8</i> loci with RA susceptibility and response to anti-TNF. The SNPs associated with susceptibility/response are not the main eQTL variants for either locus, and the associations with treatment response require replication in an independent cohort.
Increased circulating levels of tissue kallikrein in systemic sclerosis correlate with microvascular involvement
Authors: A Del Rosso
Journal: Annals of the Rheumatic Diseases (2004)

In systemic sclerosis (SSc) the lack of an angiogenic response to hypoxia may be due to inappropriate synthesis of angiogenic and angiostatic factors. Tissue kallikrein (t-kallikrein), regulating the kallikrein-kinin system and acting on the microcirculation, is a potent angiogenic agent, and kallistatin is its natural inhibitor.To evaluate, in patients with SSc, t-kallikrein and kallistatin levels and their correlation with clinical features and measures of microvascular involvement.Serum levels of t-kallikrein and kallistatin (ELISA) and t-kallikrein skin expression (immunohistochemistry) were studied in patients with SSc, and evaluated for subset (dSSc or lSSc), clinical and immunological features, and microvascular involvement (ulcers, telangiectasias, nailfold videocapillaroscopy).Circulating levels of t-kallikrein were higher in SSc than in controls (p<0.001). T-kallikrein did not differ between lSSc and dSSc, although it was higher in lSSc than in controls (p<0.001).T-kallikrein levels were higher in patients with early and active capillaroscopic pattern than in those with late pattern (p = 0.019 and 0.023). Patients with giant capillaries and capillary microhaemorrhages had higher t-kallikrein concentrations than patients with architectural derangement (p = 0.04). No differences in kallistatin levels were detected between patients with SSc and controls, or between lSSc and dSSc. In early SSc skin, the presence of t-kallikrein was found in endothelial and in perivascular inflammatory cells, while no staining in skin of advanced SSc was detected.T-kallikrein levels are increased in patients with SSc, particularly in lSSc, and are associated with early and active capillaroscopic patterns. T-kallikrein may play a part in SSc microvascular changes.
Objective Benefit of a 1-day Training Course in Endoscopic Hemostasis Using the “compactEASIE” Endoscopy Simulator
Authors: J. Maiss, J. Wiesnet, A. Proeschel, K. Matthes, F. Prat, J. Cohen, S. Chaussade, D. Sautereau, A. Naegel, N. Krauss, A. Peters, E. G. Hahn, J. Hochberger
Journal: Endoscopy (2005)

The Erlangen Active Simulator for Interventional Endoscopy (EASIE) was introduced in 1997 as a training model for interventional endoscopy. Objective evidence of the benefits of training with this model has not previously been published. As part of two long-term projects, the benefits of a 1-day training course with the "compactEASIE" simulator were evaluated.Fourteen American and 18 French gastroenterology fellows were enrolled. These fellows were participants in the intensive groups performing training in endoscopic hemostasis, with a total number of 28 fellows in New York and 36 in France. Gastrointestinal endoscopy faculty members in New York and France evaluated and timed the fellows in four disciplines to establish baseline skills (manual skills; injection and coagulation; Hemoclip application; and variceal ligation) with the compactEASIE simulator. The trainees were reevaluated after an intensive 1-day course (with two or three fellows and one instructor per station), also including preparation and assistance for each procedure. The assessment (overall and parts) was done by expert tutors using an ordinal scale ranging from 1 to 10 (1 = poorest, 10 = best), recording also mistakes and performance time. The compactEASIE simulator, equipped with an upper gastrointestinal organ package and an artificial blood perfusion system, was used as the training tool.A highly significant improvement ( P < or = 0.001) was observed in the performance of all endoscopic techniques. A significant reduction in performance time was also observed with three of the four endoscopic techniques. Successful hemostasis was significantly improved in two out of three techniques.A 1-day training course on endoscopic hemostasis using the compactEASIE simulator is capable of improving the performance of hemostasis procedures. Long-term effects of repeated training sessions are currently subject of collaborative studies in New York and France.
MicroRNA/gene profiling unveils early molecular changes and nuclear factor erythroid related factor 2 (NRF2) activation in a rat model recapitulating human hepatocellular carcinoma (HCC)
Authors: Annalisa Petrelli, Andrea Perra, Davide Cora, Pia Sulas, Silvia Menegon, Claudia Manca, Cristina Migliore, Marta Anna Kowalik, Giovanna Maria Ledda-Columbano, Silvia Giordano, Amedeo Columbano
Journal: Hepatology (2013)

Studies on gene and/or microRNA (miRNA) dysregulation in the early stages of hepatocarcinogenesis are hampered by the difficulty of diagnosing early lesions in humans. Experimental models recapitulating human hepatocellular carcinoma (HCC) are then used to perform this analysis. We performed miRNA and gene expression profiling to characterize the molecular events involved in the multistep process of hepatocarcinogenesis in the resistant-hepatocyte rat model. A high percentage of dysregulated miRNAs/genes in HCC were similarly altered in early preneoplastic lesions positive for the stem/progenitor cell marker cytokeratin-19, indicating that several HCC-associated alterations occur from the very beginning of the carcinogenic process. Our analysis also identified miRNA/gene-target networks aberrantly activated at the initial stage of hepatocarcinogenesis. Activation of the nuclear factor erythroid related factor 2 (NRF2) pathway and up-regulation of the miR-200 family were among the most prominent changes. The relevance of these alterations in the development of HCC was confirmed by the observation that NRF2 silencing impaired while miR-200a overexpression promoted HCC cell proliferation in vitro. Moreover, T3-induced in vivo inhibition of the NRF2 pathway accompanied the regression of cytokeratin-19-positive nodules, suggesting that activation of this transcription factor contributes to the onset and progression of preneoplastic lesions towards malignancy. The finding that 78% of genes and 57% of dysregulated miRNAs in rat HCC have been previously associated with human HCC as well underlines the translational value of our results.This study indicates that most of the molecular changes found in HCC occur in the very early stages of hepatocarcinogenesis. Among these, the NRF2 pathway plays a relevant role and may represent a new therapeutic target.