tbuckley/cabot-search huggingface dataset:
A Predictive Model for Progression of Chronic Kidney Disease to Kidney Failure
Authors: Navdeep Tangri, Lesley A Stevens, John Griffith, Hocine Tighiouart, Ognjenka Djurdjev, David Naimark, Adeera Levin, Andrew S Levey
Journal: JAMA (2011)

<h3>Context</h3>Chronic kidney disease (CKD) is common. Kidney disease severity can be classified by estimated glomerular filtration rate (GFR) and albuminuria, but more accurate information regarding risk for progression to kidney failure is required for clinical decisions about testing, treatment, and referral.<h3>Objective</h3>To develop and validate predictive models for progression of CKD.<h3>Design, Setting, and Participants</h3>Development and validation of prediction models using demographic, clinical, and laboratory data from 2 independent Canadian cohorts of patients with CKD stages 3 to 5 (estimated GFR, 10-59 mL/min/1.73 m<sup>2</sup>) who were referred to nephrologists between April 1, 2001, and December 31, 2008. Models were developed using Cox proportional hazards regression methods and evaluated using C statistics and integrated discrimination improvement for discrimination, calibration plots and Akaike Information Criterion for goodness of fit, and net reclassification improvement (NRI) at 1, 3, and 5 years.<h3>Main Outcome Measure</h3>Kidney failure, defined as need for dialysis or preemptive kidney transplantation.<h3>Results</h3>The development and validation cohorts included 3449 patients (386 with kidney failure [11%]) and 4942 patients (1177 with kidney failure [24%]), respectively. The most accurate model included age, sex, estimated GFR, albuminuria, serum calcium, serum phosphate, serum bicarbonate, and serum albumin (C statistic, 0.917; 95% confidence interval [CI], 0.901-0.933 in the development cohort and 0.841; 95% CI, 0.825-0.857 in the validation cohort). In the validation cohort, this model was more accurate than a simpler model that included age, sex, estimated GFR, and albuminuria (integrated discrimination improvement, 3.2%; 95% CI, 2.4%-4.2%; calibration [Nam and D’Agostino χ<sup>2</sup> statistic, 19 vs 32]; and reclassification for CKD stage 3 [NRI, 8.0%; 95% CI, 2.1%-13.9%] and for CKD stage 4 [NRI, 4.1%; 95% CI, −0.5% to 8.8%]).<h3>Conclusion</h3>A model using routinely obtained laboratory tests can accurately predict progression to kidney failure in patients with CKD stages 3 to 5.
Iatrogenic left ventricular--right atrial fistula following mitral valve replacement
Authors: R. Seabra-Gomes, D. N. Ross, L. Gonzalez-Lavin
Journal: Thorax (1973)

A case of an acquired left ventricular-right atrial fistula complicating Starr-Edwards replacement of a non-calcific mitral valve is reported. Emphasis is placed on the diagnostic methods and the anatomical relationship of the mitral valve to the atrioventricular septum. Surgical repair is advocated as soon as this complication of mitral valve replacement is discovered.
Stimulation of bile duct epithelial secretion by glybenclamide in normal and cholestatic rat liver.
Authors: M H Nathanson, A D Burgstahler, A Mennone, J A Dranoff, L Rios-Velez
Journal: Journal of Clinical Investigation (1998)

Cholestasis is a cardinal complication of liver disease, but most treatments are merely supportive. Here we report that the sulfonylurea glybenclamide potently stimulates bile flow and bicarbonate excretion in the isolated perfused rat liver. Video-microscopic studies of isolated hepatocyte couplets and isolated bile duct segments show that this stimulatory effect occurs at the level of the bile duct epithelium, rather than through hepatocytes. Measurements of cAMP, cytosolic pH, and Ca2+ in isolated bile duct cells suggest that glybenclamide directly activates Na+-K+-2Cl- cotransport, rather than other transporters or conventional second-messenger systems that link to secretory pathways in these cells. Finally, studies in livers from rats with endotoxin- or estrogen-induced cholestasis show that glybenclamide retains its stimulatory effects on bile flow and bicarbonate excretion even under these conditions. These findings suggest that bile duct epithelia may represent an important new therapeutic target for treatment of cholestatic disorders.
Menopausal Hormone Therapy After Breast Cancer: The Stockholm Randomized Trial
Authors: E. von Schoultz, L. E. Rutqvist
Journal: JNCI Journal of the National Cancer Institute (2005)

In 1997 two independent randomized clinical trials, Hormonal Replacement Therapy After Breast Cancer—Is It Safe? (HABITS; 434 patients) and the Stockholm trial (378 patients), were initiated in Sweden to compare menopausal hormone therapy with no menopausal hormone therapy after diagnosis of early-stage breast cancer. Much of the design of both studies was similar; however, a goal of the Stockholm protocol, not shared with the HABITS trial, was to minimize the use of progestogen combined with estrogen. The HABITS trial was prematurely stopped in December 2003, because, at a median follow-up of 2.1 years, the risk for recurrence of breast cancer among patients receiving menopausal hormone therapy was statistically significantly higher (relative hazard [RH] = 3.3, 95% confidence interval [CI] = 1.5 to 7.4) than among those receiving no treatment. In the Stockholm trial, however, at a median follow-up of 4.1 years, the risk of breast cancer recurrence was not associated with menopausal hormone therapy (RH = 0.82, 95% CI = 0.35 to 1.9). Statistically significant heterogeneity in the rate of recurrence was observed ( P = .02; two-sided likelihood-ratio test) between the two studies, indicating that chance may not be the only explanation. Doses of estrogen and progestogen and treatment regimens for menopausal hormone therapy may be associated with the recurrence of breast cancer.
Caspase-Mediated p65 Cleavage Promotes TRAIL-Induced Apoptosis
Authors: Hun Sik Kim, Inik Chang, Ja Young Kim, Kyung-Hee Choi, Myung-Shik Lee
Journal: Cancer Research (2005)

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is cytotoxic to a wide variety of transformed cells, but not to most normal cells, implying potential therapeutic value against advanced cancer. However, signal transduction in TRAIL-mediated apoptosis is not clearly understood compared with other TNF family members. Specifically, it is not yet understood how TRAIL controls nuclear factor kappaB (NF-kappaB) activation and overcomes its anti-apoptotic effect. We explored the regulation of NF-kappaB activity by TRAIL and its role in apoptosis. TRAIL combined with IkappaBalpha-"superrepressor" induced potent apoptosis of SK-Hep1 hepatoma cells at low concentrations of TRAIL that do not independently induce apoptosis. Apoptosis by high concentrations of TRAIL was not affected by IkappaBalpha-superrepressor. Although TRAIL alone did not induce NF-kappaB activity, TRAIL combined with z-VAD significantly increased NF-kappaB activation. Analysis of the NF-kappaB activation pathway indicated that TRAIL unexpectedly induced cleavage of p65 at Asp97, which was blocked by z-VAD, accounting for all of these findings. p65 expression abrogated apoptosis and increased NF-kappaB activity in TRAIL-treated cells. Cleavage-resistant p65D97A further increased NF-kappaB activity in TRAIL-treated cells, whereas the COOH-terminal p65 fragment acted as a dominant-negative inhibitor. XIAP levels were increased by TRAIL in combination with z-VAD, whereas XIAP levels were decreased by TRAIL alone. Cleavage of p65 was also detected after FRO thyroid cancer cells were treated with TRAIL. These results suggest that TRAIL induces NF-kappaB activation, but simultaneously abrogates NF-kappaB activation by cleaving p65, and thereby inhibits the induction of anti-apoptotic proteins such as XIAP, which contributes to the strong apoptotic activity of TRAIL compared with other TNF family members.
Quantifying Antivascular Effects of Monoclonal Antibodies to Vascular Endothelial Growth Factor: Insights from Imaging
Authors: James P.B. O'Connor, Richard A.D. Carano, Andrew R. Clamp, Jed Ross, Calvin C.K. Ho, Alan Jackson, Geoff J.M. Parker, Chris J. Rose, Franklin V. Peale, Michel Friesenhahn, Claire L. Mitchell, Yvonne Watson, Caleb Roberts, Lynn Hope, Sue Cheung, Hani Bou Reslan, Mary Ann T. Go, Glenn J. Pacheco, Xiumin Wu, Tim C. Cao, Sarajane Ross, Giovanni A. Buonaccorsi, Karen Davies, Jurjees Hasan, Paula Thornton, Olivia del Puerto, Napoleone Ferrara, Nicholas van Bruggen, Gordon C. Jayson
Journal: Clinical Cancer Research (2009)

Abstract Purpose: Little is known concerning the onset, duration, and magnitude of direct therapeutic effects of anti–vascular endothelial growth factor (VEGF) therapies. Such knowledge would help guide the rational development of targeted therapeutics from bench to bedside and optimize use of imaging technologies that quantify tumor function in early-phase clinical trials. Experimental Design: Preclinical studies were done using ex vivo microcomputed tomography and in vivo ultrasound imaging to characterize tumor vasculature in a human HM-7 colorectal xenograft model treated with the anti-VEGF antibody G6-31. Clinical evaluation was by quantitative magnetic resonance imaging in 10 patients with metastatic colorectal cancer treated with bevacizumab. Results: Microcomputed tomography experiments showed reduction in perfused vessels within 24 to 48 h of G6-31 drug administration (P ≤ 0.005). Ultrasound imaging confirmed reduced tumor blood volume within the same time frame (P = 0.048). Consistent with the preclinical results, reductions in enhancing fraction and fractional plasma volume were detected in patient colorectal cancer metastases within 48 h after a single dose of bevacizumab that persisted throughout one cycle of therapy. These effects were followed by resolution of edema (P = 0.0023) and tumor shrinkage in 9 of 26 tumors at day 12. Conclusion: These data suggest that VEGF-specific inhibition induces rapid structural and functional effects with downstream significant antitumor activity within one cycle of therapy. This finding has important implications for the design of early-phase clinical trials that incorporate physiologic imaging. The study shows how animal data help interpret clinical imaging data, an important step toward the validation of image biomarkers of tumor structure and function. (Clin Cancer Res 2009;15(21):6674–82)
Differences in clinical features and biomarkers of subsequent acute cystic fibrosis pulmonary exacerbations - Analysing exacerbations as separate entities
Authors: Iara Sequeiros, Nabil Jarad
Journal: European Respiratory Journal (2013)

Background: Adult cystic fibrosis (CF) patients often suffer repeated acute pulmonary exacerbations (PExs). As CF is a relatively uncommon disease, previously published studies in the literature have included more than one exacerbation per patient in their data set and considered individual exacerbations of the same patient as separate entities. The validity of this approach has not yet been examined.  Materials & Methods: This was a prospective study. Adult CF patients were included if they experienced 3 PExs treated with intravenous antibiotics in one year. Features of PExs included in the analysis were: CF symptom score, spirometry, oxygen saturation, heart rate, body mass index, C-reactive protein, and the time until the next exacerbation. For each parameter, comparisons were made by plotting differences against average using Bland and Altman method. The number of points where differences fell within and outside the 2 standard error of the mean (SEM) from equality were identified.  Results: A total of 93 PExs in 31 patients (15 females) were analysed. Percentage of data that fell outside SEM ranged between 20% for BMI to 80% for the time until the next exacerbation. Minimal clinically important differences were also found in at least 40% of pairs of PExs for symptom score, CRP and spirometry measurements.  Conclusions: Features of successive PExs differed in the same individual. The findings of this study lends support to considering acute CF pulmonary exacerbations to be separate entities in selected research projects.
Risk of Non-Hodgkin Lymphoma in Celiac Disease
Authors: Carlo Catassi
Journal: JAMA (2002)

HE ASSOCIATION BETWEEN CEliac disease (CD) and lymphoma has long been established.In 1937, Fairly and Mackie 1 reported the association of malignant lymphoma of the small intestine with steatorrhea.In 1962, Gough et al 2 described 5 cases of small intestinal lymphoma in patients with longstanding CD.4][5] The most frequent malignancy associated with CD is a high-grade, T-cell non-Hodgkin lymphoma (NHL) of the upper small intestine, currently defined as enteropathy-associ-ated T-cell lymphoma (EATL), that peaks in the sixth or seventh decade of life. 6Also CD may be associated with other
Violent crime, suicide, and premature mortality in patients with schizophrenia and related disorders: a 38-year total population study in Sweden
Authors: Seena Fazel, Achim Wolf, Camilla Palm, Paul Lichtenstein
Journal: The Lancet Psychiatry (2014)

People with schizophrenia and related disorders are at an increased risk of adverse outcomes, including conviction of a violent offence, suicide, and premature mortality. However, the rates of, and risk factors for, these outcomes need clarification as a basis for population-based and targeted interventions. We aimed to determine rates and risk factors for these outcomes, and investigate to what extent they are shared across outcomes and are specific to schizophrenia and related disorders.
The cognitive cost of being a twin: evidence from comparisons within families in the Aberdeen children of the 1950s cohort study
Authors: Georgina A Ronalds, Bianca L De Stavola, David A Leon
Journal: BMJ (2005)

To determine whether twins have lower IQ scores in childhood than singletons in the same family and, if so, whether differences in fetal growth explain this deficit.Cohort study.Scotland.9832 singletons and 236 twins born in Aberdeen between 1950 and 1956.At age 7, the mean IQ score of twins was 5.3 points lower (95% confidence interval 1.5 to 9.1) and at age 9, 6.0 points lower (1.7 to 10.2) than that of singletons in the same family. Adjustment for sex, mother's age, and number of older siblings had little effect on these differences. Further adjustment for birth weight and gestational age attenuated the IQ difference between twins and singletons: the difference in mean IQ was 2.6 points (-1.5 to 6.7) at age 7 and 4.1 points (-0.5 to 8.8) at age 9.Twins have substantially lower IQ in childhood than singletons in the same family. This effect cannot be explained by confounding due to socioeconomic, maternal, or other family characteristics, or by recruitment bias. The reduced prenatal growth and shorter gestations of twins may explain an important part of their lower IQ in childhood.
Starving the Addiction: New Opportunities for Durable Suppression of AR Signaling in Prostate Cancer
Authors: Karen E. Knudsen, Howard I. Scher
Journal: Clinical Cancer Research (2009)

Abstract Clinical data and models of human disease indicate that androgen receptor (AR) activity is essential for prostate cancer development, growth, and progression. The dependence of prostatic adenocarcinoma on AR signaling at all stages of disease has thereby been exploited in the treatment of disseminated tumors, for which ablation of AR function is the goal of first-line therapy. Although these strategies are initially effective, recurrent tumors arise with restored AR activity, and no durable treatment has yet been identified to combat this stage of disease. New insights into AR regulation and the mechanisms underlying resurgent AR activity have provided fertile ground for the development of novel strategies to more effectively inhibit receptor activity and prolong the transition to therapeutic failure.
Differential Gene Expression in Gram-negative and Gram-positive Sepsis
Authors: Sung-Liang Yu, Huei-Wen Chen, Pan-Chyr Yang, Konan Peck, Min-Hui Tsai, Jeremy J. W. Chen, Fang-Yue Lin
Journal: American Journal of Respiratory and Critical Care Medicine (2004)

Sepsis is the most common cause of death in patients in the intensive care unit. Genome-wide gene expression analysis can provide insights into the molecular alterations of sepsis. Total mRNA was extracted from the livers of 6 uninfected control mice and 60 septic mice after infusion of either live Escherichia coli or Staphylococcus aureus. Using a murine complementary DNA microarray system, changes in gene expression were monitored at six time points (uninfected, 2, 8, 24, 48, and 72 hours). Overall, 4.8% of 6,144 assessed genes were differentially regulated with a greater than twofold change across all time points. Most of the genes with altered expression were commonly present in gram-negative and gram-positive sepsis, but the expression levels of 17 genes were different between both types of sepsis at particular time points after infection. The microarray results support the hypothesis that both gram-positive and gram-negative sepsis share a final common pathway involved in the pathogenesis of sepsis, but certain genes are differentially expressed under distinct regulation. These results may provide insights into the pathogenesis of sepsis and may also help identify some altered genes that can serve as new targets for diagnostic tools and therapeutic strategies.
Transcriptional Regulation of Bim by FOXO3a and Akt Mediates Scleroderma Serum–Induced Apoptosis in Endothelial Progenitor Cells
Authors: Shoukang Zhu, Sarah Evans, Bin Yan, Thomas J. Povsic, Victor Tapson, Pascal J. Goldschmidt-Clermont, Chunming Dong
Journal: Circulation (2008)

Endothelial progenitor cells (EPCs) contribute to vascular regeneration/repair and thus may protect against scleroderma vasculopathy. We aimed to determine whether circulating EPCs were reduced in scleroderma, whether scleroderma sera could induce EPC apoptosis, and, if so, what the underlying apoptotic signaling pathway was.Circulating EPC levels were quantified in 54 patients with scleroderma and 18 healthy control subjects by colony-forming unit assay and flow cytometry, which revealed markedly decreased EPC levels in scleroderma patients relative to healthy subjects. Substantial apoptosis was detected in EPCs after culturing in the presence of scleroderma sera compared with normal sera. Intriguingly, depletion of the IgG fraction from scleroderma sera completely abolished the apoptotic effects. Furthermore, scleroderma sera inhibited the activation/phosphorylation of Akt, which in turn suppressed the phosphorylation and degradation of forkhead transcription factor FKHRL1 (FOXO3a), resulting in the upregulation of apoptotic protein Bim. siRNA-mediated FOXO3a and Bim knockdown substantially reduced scleroderma serum-induced EPC apoptosis. Importantly, Bim expression and baseline apoptosis were increased in EPCs freshly isolated from scleroderma patients relative to that obtained from healthy subjects.Scleroderma serum-induced EPC apoptosis is mediated chiefly by the Akt-FOXO3a-Bim pathway, which may account, at least in part, for the decreased circulating EPC levels in scleroderma patients.
Microbial community function and biomarker discovery in the human microbiome
Authors: Nicola Segata, Sahar Abubucker, Johannes Goll, Alyxandria M Schubert, Jacques Izard, Brandi L Cantarel, Beltran Rodriguez-Mueller, Levi Waldron, Jeremy Zucker, Mathangi Thiagarajan, Bernard Henrissat, Owen White, Scott T Kelley, Barbara Methé, Patrick D Schloss, Wendy S Garrett, Dirk Gevers, Makedonka Mitreva, Curtis Huttenhower
Journal: Genome biology (2011)

Deep exome resequencing is a powerful approach for delineating patterns of protein-coding variation among genes, pathways, individuals and populations.We analyzed exome data from 2,440 individuals of European and African ancestry as part of the National Heart, Lung, and Blood Institute's Exome Project, the aim of which is to discover novel genes and mechanisms that contribute to heart, lung and blood disorders.Each exome was sequenced to a mean coverage of 116×, allowing detailed inferences about the population genomic patterns of both common variation and rare coding variation.We identifi ed more than 500,000 single nucleotide variations, the majority of which were novel and rare (76% of variants had a minor allele frequency of less than 0.1%), refl ecting the recent dramatic increase in the size of the human population.The unprecedented magnitude of this dataset allowed us to rigorously characterize the large variation in nucleotide diversity among genes (ranging from 0 to 1.32%), as well as the role of positive and purifying selection in shaping patterns of proteincoding variation and the diff erential signatures of population structure from rare and common variation.This dataset provides a framework for personal genomics and is an important resource that will allow inferences of broad importance to human evolution and health.
Randomized Phase III Study of Trastuzumab, Paclitaxel, and Carboplatin Compared With Trastuzumab and Paclitaxel in Women With HER-2–Overexpressing Metastatic Breast Cancer
Authors: Nicholas Robert, Brian Leyland-Jones, Lina Asmar, Robert Belt, Des Ilegbodu, David Loesch, Robert Raju, Elizabeth Valentine, Robert Sayre, Melody Cobleigh, Kathy Albain, Cecelia McCullough, Lea Fuchs, Dennis Slamon
Journal: Journal of Clinical Oncology (2006)

Purpose This randomized, multicenter, phase III trial evaluated the efficacy and safety of trastuzumab and paclitaxel with or without carboplatin as first-line therapy for women with HER-2–overexpressing metastatic breast cancer (MBC). Patients and Methods HER-2 overexpression was defined as immunohistochemical staining scores of 2+ or 3+. Between November 1998 and May 2002, 196 women with HER-2–overexpressing MBC were randomly assigned to six cycles of either trastuzumab 4 mg/kg loading dose plus 2 mg/kg weekly thereafter with paclitaxel 175 mg/m 2 every 3 weeks (TP), or trastuzumab 4 mg/kg loading dose plus 2 mg/kg weekly thereafter with paclitaxel 175 mg/m 2 and carboplatin area under the time-concentration curve = 6 every 3 weeks (TPC) followed by weekly trastuzumab alone. Results Baseline characteristics of the 196 patients were well balanced between study arms. Objective response rate (ORR) was 52% (95% CI, 42% to 62%) for TPC versus 36% (95% CI, 26% to 46%) for TP (P = .04). Median progression-free survival (PFS) was 10.7 months for TPC and 7.1 months for TP (hazard ratio [HR], 0.66; 95% CI, 0.59 to 0.73; P = .03). Improved clinical outcomes with TPC were most evident in HER-2 3+ patients, with an ORR of 57% (95% CI, 45% to 70%) v 36% (95% CI, 25% to 48%; P = .03) and median PFS of 13.8 v 7.6 months (P = .005) for TPC and TP, respectively (HR, 0.55; 95% CI, 0.46 to 0.64). Both regimens were well tolerated, and febrile neutropenia and neurotoxicity occurred infrequently; grade 4 neutropenia occurred more frequently with TPC (P &lt; .01). Conclusion The addition of carboplatin to paclitaxel and trastuzumab improved ORR and PFS in women with HER-2–overexpressing MBC. This well-tolerated regimen represents a new therapeutic option.