tbuckley/cabot-search huggingface dataset:
Effect of maximal coronary vasodilation on transmural myocardial perfusion during tachycardia in the awake dog.
Authors: R J Bache, F R Cobb
Journal: Circulation Research (1977)

We studied the influence of active coronary vasomotion on transmural myocardial perfusion during tachycardia.Regional myocardial blood flow was estimated in chronically prepared awake dogs by injecting radioactive microspheres (7-10 /xm in diameter) into the left atrium.Studies were performed during ventricular pacing at 100, 150, 200, and 250 beats/min under control conditions with intact coronary vasomotor tone, and during maximal coronary vasodilation induced by intravenous infusion of adenosine.During control conditions, mean myocardial blood flow was 1.27 ± 0.12 ml/min per g of myocardium at a heart rate of 100 beats/min, and increased regularly with increasing heart rates.Transmural myocardial perfusion remained essentially uniform as heart rates were increased from 100 to 250 beats/min.During administration of adenosine, mean myocardial blood flow increased to 5.49 ± 0.39 ml/min per g at a heart rate of 100 beats/min, and transmural myocardial perfusion was uniform.As heart rates were increased, flow to the subendocardium decreased as a linear function of heart rate while subepicardial flow was maintained so that the ratio of subendocardial-subepicardial flow fell from 1.00 at a heart rate of 100 beats/min to 0.40 at a heart rate of 250 beats/min.The reduction of subendocardial perfusion with increasing heart rate was most marked in the deepest myocardial layers.This rate-dependent decrease in subendocardial blood flow resulted in a decrease in mean myocardial blood flow with increasing heart rates (mean change at 250 beats/min = -18%; P < 0.05).These data indicate that active coronary vasomotion is necessary for maintenance of uniform transmural myocardial perfusion during tachycardia.
Prolonged Postovulatory Proinflammatory Signaling in the Fallopian Tube Epithelium May Be Mediated through a BRCA1/DAB2 Axis
Authors: Alicia A. Tone, Carl Virtanen, Patricia Shaw, Theodore J. Brown
Journal: Clinical Cancer Research (2012)

Abstract Purpose: To assess inflammation-related gene expression in nonmalignant fallopian tube epithelium (FTE) from BRCA1/2 mutation carriers and control patients obtained during the luteal and follicular phase, and to determine the impact of BRCA1 and disabled homolog 2 (DAB2) on NF-κB–mediated proinflammatory signaling. Experimental Design: A list of inflammation-related and NF-κB–responsive genes was compiled through gene set enrichment and PubMed database search, corresponding probes identified, and unpaired t tests conducted to identify differentially expressed genes in previously profiled FTE samples. ES2 and A549 cells were cotransfected with DAB2- or BRCA1-targeting siRNA and an NF-κB–responsive luciferase reporter, treated with TNF-α and luciferase activity determined. To determine whether DAB2 or BRCA1 alters mRNA expression of NF-κB target genes, cells were transfected with siRNA, treated with TNF-α, and harvested for total RNA extraction and quantitative real-time PCR. Results: A subset of BRCA1-mutated luteal phase samples previously found to group with adnexal high–grade serous carcinomas (HGSCs) differentially expressed 124 inflammation–associated probesets relative to remaining FTE samples. These samples also differentially expressed 264 probes relative to other luteal phase samples exposed to the same postovulatory environment. Both BRCA1- and DAB2–targeting siRNA increased TNF-α-induced NF-κB activity and mRNA expression of NF-κB–dependent target gene SOD2 relative to nontargeting siRNA, suggesting that both proteins repress proinflammatory signaling. Conclusions: These data provide evidence of elevated proinflammatory signaling in a subset of BRCA1-mutated luteal phase FTE, consistent with an altered response to ovulation-associated cytokines. Furthermore, both BRCA1 and DAB2 affect NF-κB activity, indicating a novel link between BRCA mutation status, ovulation, and predisposition to HGSC. Clin Cancer Res; 18(16); 4334–44. ©2012 AACR.
The influence of hepatitis B virus genotype on the development of lamivudine resistance during long-term treatment
Authors: Norio Akuta, Fumitaka Suzuki, Mariko Kobayashi, Akihito Tsubota, Yoshiyuki Suzuki, Tetsuya Hosaka, Takashi Someya, Masahiro Kobayashi, Satoshi Saitoh, Yasuji Arase, Kenji Ikeda, Hiromitsu Kumada
Journal: Journal of Hepatology (2003)
S168 Evaluation of the MRC dyspnoea scale and a novel extended version in prediction of in-hospital death and early readmission in acute exacerbations of COPD
Authors: J. Steer, E. Norman, G. Afolabi, G. J. Gibson, S. C. Bourke
Journal: Thorax (2010)

<h3>Introduction and objectives</h3> Acute exacerbations of COPD (AECOPD) requiring hospitalisation are associated with substantial in-hospital mortality and frequent readmissions. The MRC Dyspnoea Scale (MRCD) is a strong predictor of mortality in stable disease and may predict in-hospital mortality in AECOPD.1 We investigated the relative value, for predicting mortality and early readmission, of both the MRCD and an extended MRCD scale (eMRCD),2 which dichotomises MRCD 5 according to whether the individual can wash and dress independently (5a) or not (5b). <h3>Methods</h3> We prospectively assessed MRCD and eMRCD (based on the patient9s clinically stable state over the preceding 3 months) in patients hospitalised with AECOPD. The ability of the two scales to predict (a) in-hospital mortality and (b) readmission within 28 days of discharge was evaluated. <h3>Results</h3> 639 patients were identified; mean (SD) age 73 (10) years, 55.6% female and mean (SD) FEV<sub>1</sub> (n=412) 43.5 (18) % predicted. The distribution of scores for the MRCD and eMRCD are shown in Abstract S168 Table 1. Due to a small number of individuals with MRCD scores 1 (n=4) and 2 (n=26), groups 1–3 were combined. Abstract S168 Table 1 Compared to the reference category (MRCD 1–3), MRCD 5, eMRCD 5a and eMRCD 5b predicted both in-hospital mortality and early readmission (Abstract S168 Table 1). Of importance, eMRCD 5b was a stronger predictor of in-hospital death then eMRCD 5a (OR 2.30, 95% CI 1.25 to 4.26, p=0.008) however, the predictive strength of 5a and 5b, with regards to early readmission, was similar (OR 1.32, 95% CI 0.67 to 2.58, p=0.42). Paired comparisons between groups showed that MRCD 5 (OR 5.29, 95% CI 2.87 to 9.80, p&lt;0.001), eMRCD 5a (OR 3.56, 95% CI 1.77 to 7.14, p&lt;0.001) and eMRCD 5b (OR 8.20, 95% CI 4.15 to 16.20, p&lt;0.001) were all stronger predictors of in-hospital mortality than MRCD 4, whereas only MRCD 5b was a stronger predictor of readmission (OR 2.24, 95% CI 1.20 to 4.18, p=0.011). <h3>Conclusion</h3> The MRCD during the stable state prior to hospitalisation predicts both in-hospital death and readmission within 28 days. Extending the scale to include an assessment of the patient9s capacity to manage personal care (the eMRCD) improves the ability to predict in-hospital mortality and readmission, compared to the traditional instrument.
Universal parenting programme to prevent early childhood behavioural problems: cluster randomised trial
Authors: Harriet Hiscock, Jordana K Bayer, Anna Price, Obioha C Ukoumunne, Susan Rogers, Melissa Wake
Journal: BMJ (2008)

<b>Objective</b> To determine whether a parenting programme, offered universally in primary care, can prevent behavioural problems in children and improve parenting and maternal mental health. <b>Design</b> Cluster randomised trial. <b>Setting</b> 40 primary care nursing centres (clusters) in Victoria, Australia. <b>Participants</b> 733 English speaking mothers of 8 month old children sequentially recruited from well child appointments; 656 retained at 24 months. <b>Intervention</b> Structured three session programme at age 8-15 months, co-led by well child providers and a parenting expert. The programme covered normal development and behaviour, strategies to increase desired behaviour, and strategies to reduce unwanted behaviour. <b>Main outcome measures</b> Maternal report of child externalising behaviour (child behavior checklist 1½-5 year old), parenting (parent behavior checklist), and maternal mental health (depression anxiety stress scales) at 18 and 24 months. <b>Results</b> At 18 months, child behaviour and parenting scores were similar in the two groups. At 24 months, externalising scores in the intervention and control groups were similar (mean 11.9 (SD 7.2) <i>v</i> 12.9 (7.4)); however, on the parent behavior checklist subscale scores, intervention group parents were less likely to report harsh/abusive parenting (mean 38.9 (SD 7.7) <i>v</i> 40.5 (8.8); adjusted mean difference −1.83, 95% confidence interval −3.12 to −0.55) and unreasonable expectations of child development (40.9 (9.9) <i>v</i> 42.7 (9.6); −2.18, −3.74 to −0.62). Mean scores for nurturing parenting and maternal mental health were similar in the two groups at both times. <b>Conclusions</b> A universal parenting programme resulted in modest improvement in parenting factors that predict behavioural problems in children but did not reduce externalising behavioural problems or affect maternal mental health at 2 years. <b>Trial registration</b> ISRCTN 77531789.
Are we meeting the standards set for ERCP?
Authors: J. Baillie, P.-A. Testoni
Journal: Gut (2007)

ERCP practice today: implications for training

The study by Williams et al , 1 published in this issue of Gut (see page 796) , reports the findings of a UK National Confidential Enquiry into Patient Outcomes and Deaths relating to endoscopic retrograde cholangiopancreatography (ERCP). Approximately 48 000 ERCPs are performed annually in the UK. For this study, five metropolitan areas of England were surveyed. The authors estimate that about 20% of all the ERCP procedures performed in adults (>18 years of age) over a 6-month period were captured. The results offer a cornucopia of food for thought. In all, 94% (76/81) of endoscopy units polled responded. Personal questionnaires were returned by 89% of staff endoscopists and by 81% of their trainees. Aspects of ERCP that were examined ranged from the experience and success of the physicians performing the procedures, to indications, informed consent, adequacy of monitoring and resuscitation, and outcomes, including complications and mortality. More than a few of the findings are sobering, concerning and demand remedial action. But we acknowledge that it is easy to be an armchair critic of another country’s ERCP practice. An in-depth look at ERCP practice in the US and Italy, for example, would probably reveal some, if not many, of the same problems arising from marginal training, inexperience, inadequate volume of cases to maintain skills and so on.

The current study looked at the success rates of trainees as a function of their experience. Those with experience of >200 ERCPs had an unsupervised cannulation rate (to enter the duct of choice) of 66%; this fell to 40% for those with experience of <200 ERCPs. The overall trainee cannulation success rate with procedures whose trainee involvement was not documented, was reportedly 54%. The American Society for Gastrointestinal Endoscopy (ASGE) considers a selective cannulation success …
Screening for Gestational Diabetes Mellitus: U.S. Preventive Services Task Force Recommendation Statement
Authors: Virginia A. Moyer
Journal: Annals of Internal Medicine (2008)

Update of 2003 U.S. Preventive Services Task Force (USPSTF) recommendation about screening for gestational diabetes.The USPSTF weighed the evidence on maternal and neonatal benefits (reduction in preeclampsia, mortality, brachial plexus injury, clavicular fractures, admission to the neonatal intensive care unit for serious illnesses) and harms (physical and psychological harms) of screening for gestational diabetes identified for their 2003 recommendation and the accompanying systematic review of articles published since the 2003 review for screening after 24 weeks' gestation. Additional searches were performed for evidence published from 1966 to 1999 on screening before 24 weeks.Current evidence is insufficient to assess the balance of benefits and harms of screening for gestational diabetes mellitus, either before or after 24 weeks' gestation. (I statement.).
Effect and Reporting Bias of RhoA/ROCK-Blockade Intervention on Locomotor Recovery After Spinal Cord Injury
Authors: Ralf Watzlawick, Emily S. Sena, Ulrich Dirnagl, Benedikt Brommer, Marcel A. Kopp, Malcolm R. Macleod, David W. Howells, Jan M. Schwab
Journal: JAMA Neurology (2013)

Blockade of small GTPase-RhoA signaling pathway is considered a candidate translational strategy to improve functional outcome after spinal cord injury (SCI) in humans. Pooling preclinical evidence by orthodox meta-analysis is confounded by missing data (publication bias).To conduct a systematic review and meta-analysis of RhoA/Rho-associated coiled-coil containing protein kinase (ROCK) blocking approaches to (1) analyze the impact of bias that may lead to inflated effect sizes and (2) determine the normalized effect size of functional locomotor recovery after experimental thoracic SCI.We conducted a systematic search of PubMed, EMBASE, and Web of Science and hand searched related references. Studies were selected if they reported the effect of RhoA/ROCK inhibitors (C3-exoenzmye, fasudil, Y-27632, ibuprofen, siRhoA, and p21) in experimental spinal cord hemisection, contusion, or transection on locomotor recovery measured by the Basso, Beattie, and Bresnahan score or the Basso Mouse Scale for Locomotion. Two investigators independently assessed the identified studies. Details of individual study characteristics from each publication were extracted and effect sizes pooled using a random effects model. We assessed risk for bias using a 9-point-item quality checklist and calculated publication bias with Egger regression and the trim and fill method. A stratified meta-analysis was used to assess the impact of study characteristics on locomotor recovery.Thirty studies (725 animals) were identified. RhoA/ROCK inhibition was found to improve locomotor outcome by 21% (95% CI, 16.0-26.6). Assessment of publication bias by the trim and fill method suggested that 30% of experiments remain unpublished. Inclusion of these theoretical missing studies suggested a 27% overestimation of efficacy, reducing the overall efficacy to a 15% improvement in locomotor recovery. Low study quality was associated with larger estimates of neurobehavioral outcome.Taking into account publication bias, RhoA/ROCK inhibition improves functional outcome in experimental SCI by 15%. This is a plausible strategy for the pharmacological augmentation of neurorehabilitation after human SCI. These findings support the necessity of a systematic analysis to identify preclinical bias before embarking on a clinical trial.
<i>ASS1</i>as a Novel Tumor Suppressor Gene in Myxofibrosarcomas: Aberrant Loss via Epigenetic DNA Methylation Confers Aggressive Phenotypes, Negative Prognostic Impact, and Therapeutic Relevance
Authors: Hsuan-Ying Huang, Wen-Ren Wu, Yu-Hui Wang, Jun-Wen Wang, Fu-Min Fang, Jen-Wei Tsai, Shau-Hsuan Li, Hsiao-Chin Hung, Shih-Chen Yu, Jui Lan, Yow-Ling Shiue, Chung-His Hsing, Li-Tzong Chen, Chien-Feng Li
Journal: Clinical Cancer Research (2013)

The principal goals were to identify and validate targetable metabolic drivers relevant to myxofibrosarcoma pathogenesis using a published transcriptome.As the most significantly downregulated gene regulating amino acid metabolism, argininosuccinate synthetase (ASS1) was selected for further analysis by methylation-specific PCR, pyrosequencing, and immunohistochemistry of myxofibrosarcoma samples. The roles of ASS1 in tumorigenesis and the therapeutic relevance of the arginine-depriving agent pegylated arginine deiminase (ADI-PEG20) were elucidated in ASS1-deficient myxofibrosarcoma cell lines and xenografts with and without stable ASS1 reexpression.ASS1 promoter hypermethylation was detected in myxofibrosarcoma samples and cell lines and was strongly linked to ASS1 protein deficiency. The latter correlated with increased tumor grade and stage and independently predicted a worse survival. ASS1-deficient cell lines were auxotrophic for arginine and susceptible to ADI-PEG20 treatment, with dose-dependent reductions in cell viability and tumor growth attributable to cell-cycle arrest in the S-phase. ASS1 expression was restored in 2 of 3 ASS1-deficient myxofibrosarcoma cell lines by 5-aza-2'-deoxycytidine, abrogating the inhibitory effect of ADI-PEG20. Conditioned media following ASS1 reexpression attenuated HUVEC tube-forming capability, which was associated with suppression of MMP-9 and an antiangiogenic effect in corresponding myxofibrosarcoma xenografts. In addition to delayed wound closure and fewer invading cells in a Matrigel assay, ASS1 reexpression reduced tumor cell proliferation, induced G1-phase arrest, and downregulated cyclin E with corresponding growth inhibition in soft agar and xenograft assays.Our findings highlight ASS1 as a novel tumor suppressor in myxofibrosarcomas, with loss of expression linked to promoter methylation, clinical aggressiveness, and sensitivity to ADI-PEG20.
Metabolic Inhibition Alters Subcellular Calcium Release Patterns in Rat Ventricular Myocytes
Authors: Gary H. Fukumoto, Scott T. Lamp, Christi Motter, John H.B. Bridge, Alan Garfinkel, Joshua I. Goldhaber
Journal: Circulation Research (2005)

Metabolic inhibition (MI) contributes to contractile failure during cardiac ischemia and systolic heart failure, in part due to decreased excitation-contraction (E-C) coupling gain. To investigate the underlying mechanism, we studied subcellular Ca2+ release patterns in whole cell patch clamped rat ventricular myocytes using two-dimensional high-speed laser scanning confocal microscopy. In cells loaded with the Ca2+ buffer EGTA (5 mmol/L) and the fluorescent Ca2+-indicator fluo-3 (1 mmol/L), depolarization from -40 to 0 mV elicited a striped pattern of Ca2+ release. This pattern represents the simultaneous activation of multiple Ca2+ release sites along transverse-tubules. During inhibition of both oxidative and glycolytic metabolism using carbonyl cyanide-p-trifluoromethoxyphenylhydrazone (FCCP, 50 nmol/L) and 2-deoxyglucose (2-DG, 10 mmol/L), there was a decrease in inward Ca2+ current (ICa), the spatially averaged Ca2+ transient, and E-C coupling gain, but no reduction in sarcoplasmic reticulum Ca2+ content. The striped pattern of subcellular Ca2+ release became fractured, or disappeared altogether, corresponding to a marked decrease in the area of the cell exhibiting organized Ca2+ release. There was no significant change in the intensity or kinetics of local Ca2+ release. The mechanism is not fully explained by dephosphorylation of L-type Ca2+ channels, because a similar degree of ICa"rundown" in control cells did NOT result in fracturing of the Ca2+ release pattern. We conclude that metabolic inhibition interferes with E-C coupling by (1) reducing trigger Ca2+, and (2) directly inhibiting sarcoplasmic reticulum Ca2+ release site open probability.
The pre-T cell receptor (TCR) complex is functionally coupled to the TCR-zeta subunit.
Authors: N S van Oers, H von Boehmer, A Weiss
Journal: The Journal of Experimental Medicine (1995)

The pre-T cell receptor (TCR) complex regulates early T cell development and consists of a heterodimer of the TCR-beta subunit in association with the pre-TCR-alpha chain. Notably, in contrast to alpha/beta-expressing T cells, several studies suggested that the TCR-zeta chain is not stably associated with this pre-TCR complex. To examine the proximal signaling processes mediated by the pre-TCR complex and the role of the TCR-zeta chain in these processes, we stimulated pre-TCR-expressing cells and analyzed the interactions of the TCR/CD3 invariant chains with the Syk/ZAP-70 family of protein tyrosine kinases. Stimulation of the pre-TCR complex led to the tyrosine phosphorylation of the CD3 epsilon and TCR-zeta chains, as well as the phosphorylation and association of ZAP-70 and Syk with phosphorylated CD3 epsilon and TCR-zeta. These results demonstrate that the pre-TCR complex is functionally coupled to the TCR-zeta subunit and to the ZAP-70 and Syk protein tyrosine kinases.
Linking genes to diseases: it's all in the data
Authors: Nicki Tiffin, Miguel A Andrade-Navarro, Carolina Perez-Iratxeta
Journal: Genome Medicine (2009)

Genome-wide association analyses on large patient cohorts are generating large sets of candidate disease genes. This is coupled with the availability of ever-increasing genomic databases and a rapidly expanding repository of biomedical literature. Computational approaches to disease-gene association attempt to harness these data sources to identify the most likely disease gene candidates for further empirical analysis by translational researchers, resulting in efficient identification of genes of diagnostic, prognostic and therapeutic value. Existing computational methods analyze gene structure and sequence, functional annotation of candidate genes, characteristics of known disease genes, gene regulatory networks, protein-protein interactions, data from animal models and disease phenotype. To date, a few studies have successfully applied computational analysis of clinical phenotype data for specific diseases and shown genetic associations. In the near future, computational strategies will be facilitated by improved integration of clinical and computational research, and by increased availability of clinical phenotype data in a format accessible to computational approaches.
Cabozantinib Inhibits Prostate Cancer Growth and Prevents Tumor-Induced Bone Lesions
Authors: Jinlu Dai, Honglai Zhang, Andreas Karatsinides, Jill M. Keller, Kenneth M. Kozloff, Dana T. Aftab, Frauke Schimmoller, Evan T. Keller
Journal: Clinical Cancer Research (2013)

Cabozantinib, an orally available multityrosine kinase inhibitor with activity against mesenchymal epithelial transition factor (MET) and VEGF receptor 2 (VEGFR2), induces resolution of bone scan lesions in men with castration-resistant prostate cancer bone metastases. The purpose of this study was to determine whether cabozantinib elicited a direct antitumor effect, an indirect effect through modulating bone, or both.Using human prostate cancer xenograft studies in mice, we determined the impact of cabozantinib on tumor growth in soft tissue and bone. In vitro studies with cabozantinib were performed using (i) prostate cancer cell lines to evaluate its impact on cell growth, invasive ability, and MET and (ii) osteoblast cell lines to evaluate its impact on viability and differentiation and VEGFR2.Cabozantinib inhibited progression of multiple prostate cancer cell lines (Ace-1, C4-2B, and LuCaP 35) in bone metastatic and soft tissue murine models of prostate cancer, except for PC-3 prostate cancer cells in which it inhibited only subcutaneous growth. Cabozantinib directly inhibited prostate cancer cell viability and induced apoptosis in vitro and in vivo and inhibited cell invasion in vitro. Cabozantinib had a dose-dependent biphasic effect on osteoblast activity and inhibitory effect on osteoclast production in vitro that was reflected in vivo. It blocked MET and VEGFR2 phosphorylation in prostate cancer cells and osteoblast-like cells, respectively.These data indicate that cabozantinib has direct antitumor activity, and that its ability to modulate osteoblast activity may contribute to its antitumor efficacy.