tbuckley/cabot-search huggingface dataset:
Androgens, Bilateral Oophorectomy, and Cardiovascular Disease Mortality in Postmenopausal Women With and Without Diabetes: The Study of Osteoporotic Fractures
Authors: Duke Appiah, Stephen J. Winters, Susan B. Muldoon, Carlton A. Hornung, Jane A. Cauley
Journal: Diabetes Care (2015)

Diabetes elevates cardiovascular disease (CVD) risk more markedly in women than in men. Because the high risk of CVD among women with type 2 diabetes (DM2) may be partly due to increased ovarian androgen production, we investigated whether a history of bilateral salpingo oophorectomy (BSO) is inversely associated with CVD mortality among women with DM2.Data were obtained from 7,977 women (a random subset of 564 had measurements of sex-steroid hormones) enrolled in the Study of Osteoporotic Fractures (SOF), a community-based, multicenter study that monitored women aged ≥65 years for a mean of 15.1 years. Adjusted hazard ratios (HRs) and 95% CIs were calculated using Cox proportional hazards regression.The average age at baseline was 71.5 years, with 6.3% and 18% of participants reporting a history of diabetes or BSO, respectively. In the subset of the SOF cohort with sex-steroid hormone measurements, those with DM2 had 43.6% significantly higher levels of free testosterone that were partly explained by age and adiposity, whereas total and free testosterone levels were lower in women with BSO than in those with intact ovaries. CVD mortality was elevated in women with DM2 without BSO (HR 1.95, 95% CI 1.62-2.35) as well as in women with DM2 and BSO (HR 2.56, 95% CI 1.79-3.65; P = 0.190 for interaction). Overall, BSO was not associated with CVD mortality (HR 1.05, 95% CI 0.89-1.23).The association of diabetes with CVD was not reduced by BSO, suggesting that ovarian hyperandrogenemia may not be a primary mechanism to explain the high risk for CVD among women with DM2.
Growth Factors in Milk as Mediators of Infant Development
Authors: S. M. Donovan, J. Odle
Journal: Annual Review of Nutrition (1994)

INTRODUCTION   147 EPIDERMAL GROWTH FACTOR (EGF)   148 Background and General Physiological Function   148 Milk Concentration and Sources   149 Effects on the Neonate   151 INSULIN, RELAX]N, AND INSULIN-LIKE GROWTH FACTOR-I AND -ll ....... 154 Background ~ General Physiological Function   154 l~.sulin   154 R¢laxin   156 IGF.I., IGF.II., AND IGF-BINDING PROTEINS   157 OTHER PEFrIDE GROWTH FACTORS IN MILK   159 CONCLUDING REMARKS   160
Increased local delivery of antagomir therapeutics to the rodent myocardium using ultrasound and microbubbles
Authors: Rick F.J. Kwekkeboom, Joost P.G. Sluijter, Ben J. van Middelaar, Corina H. Metz, Maike A. Brans, Otto Kamp, Walter J. Paulus, René J.P. Musters
Journal: Journal of Controlled Release (2015)
Abstract 1476: Effect of target therapies in liver cancer PDX tumor models: Response, resistance and predictive biomarkers
Authors: Tengfei Yu, Ying Yan, Wei Du, Liang Hua, Xuqin Yang, Tingting Tan, Jiali Gu, Jingjing Jiang, Xin K. Ye, Zhenyu Gu
Journal: Cancer Research (2015)

Abstract Liver cancer is one of the leading causes of cancer mortality worldwide. Hepatocelluar carcinoma (HCC) is the most common form of liver cancer, followed by intrahepatic cholangiocarcinoma (IHCC). HCC has dismal clinical outcome, whereas the prognosis is even worse for IHCC as it is more difficult to diagnose and to treat comparing to HCC. Surgical resection and local ablation remain the top choices of therapy for early liver cancer while chemoembolization-TACE is commonly used to treat intermediate HCC. Sorafenib is the only FDA approved target therapy for advanced HCC and its clinical utility in IHCC is still being examined in clinical trials. On-going clinical trials are also testing therapeutic modalities against oncogenic pathways including RTK signaling pathways, PI3K/Ras pathways and the angiogenesis pathway. PDX tumor models recapitulate the clinical complexity of the original human cancers. At GenenDesign, we have established over 800 PDX tumor models and conducted extensive drug response tests in a mouse trial format. GenenDesign liver cancer PDX tumor panel comprises of 36 HCC and over 10 IHCC models. Our in-house mouse trials in liver PDX tumor models include treatment with sorafenib as well as XL184, a multi-kinase inhibitor currently being evaluated in clinical trials. In addition, crizotinib (a cMET inhibitor) and AZD4547 (an FGFR inhibitor) as mono-therapies as well as in combination with sorafenib are also tested in search of therapeutic signals. From these studies, we have identified both drug sensitive and de novo drug resistant models. Through long-term treatment, acquired resistance models and reversible resistance models are also established. Currently, GD liver cancer PDX tumors are being analyzed by genetic and genomic profiling (hot-spot mutational analysis, exome-seq, RNA-seq, SNP array and gene expression array). Bioinformatics analysis is on-going to identify genomic signatures with the potential as predictive biomarkers for sorafenib and other targeted therapies in liver cancer. Together with genomic profiling, signal search in PDX mouse trials promise to be effective in generating preclinical datasets to facilitate clinical trial designs. Citation Format: Tengfei Yu, Ying Yan, Wei Du, Liang Hua, Xuqin Yang, Tingting Tan, Jiali Gu, Jingjing Jiang, Xin K. Ye, Zhenyu Gu. Effect of target therapies in liver cancer PDX tumor models: Response, resistance and predictive biomarkers. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1476. doi:10.1158/1538-7445.AM2015-1476
Epithelial–Mesenchymal Transition Predicts Polo-Like Kinase 1 Inhibitor–Mediated Apoptosis in Non–Small Cell Lung Cancer
Authors: Renata Ferrarotto, Ruchitha Goonatilake, Suk Young Yoo, Pan Tong, Uma Giri, Shaohua Peng, John Minna, Luc Girard, Yuehong Wang, Liguang Wang, Lerong Li, Lixia Diao, David H. Peng, Don L. Gibbons, Bonnie S. Glisson, John V. Heymach, Jing Wang, Lauren A. Byers, Faye M. Johnson
Journal: Clinical Cancer Research (2015)

To identify new therapeutic targets for non-small cell lung cancer (NSCLC), we systematically searched two cancer cell line databases for sensitivity data on a broad range of drugs. We identified polo-like kinase 1 (PLK1) as the most promising target for further investigation based on a subset of sensitive NSCLC cell lines and inhibitors that were in advanced clinical development.To identify potential biomarkers of response of NSCLC to PLK1 inhibition and mechanisms of PLK1 inhibitor-induced apoptosis, integrated analysis of gene and protein expression, gene mutations, and drug sensitivity was performed using three PLK1 inhibitors (volasertib, BI2536, and GSK461364) with a large panel of NSCLC cell lines.The NSCLC cell lines had different sensitivities to PLK1 inhibition, with a minority demonstrating sensitivity to all three inhibitors. PLK1 inhibition led to G2-M arrest, but only treatment-sensitive cell lines underwent substantial apoptosis following PLK1 inhibition. NSCLC lines with high epithelial-mesenchymal transition (EMT) gene signature scores (mesenchymal cell lines) were more sensitive to PLK1 inhibition than epithelial lines (P< 0.02). Likewise, proteomic profiling demonstrated that E-cadherin expression was higher in the resistant cell lines than in the sensitive ones (P< 0.01). Induction of an epithelial phenotype by expression of the miRNA miR-200 increased cellular resistance to PLK1 inhibition. Also, KRAS mutation and alterations in the tight-junction, ErbB, and Rho signaling pathways correlated with drug response of NSCLC.In this first reported large-scale integrated analysis of PLK1 inhibitor sensitivity, we demonstrated that EMT leads to PLK1 inhibition sensitivity of NSCLC cells. Our findings have important clinical implications for mesenchymal NSCLC, a significant subtype of the disease that is associated with resistance to currently approved targeted therapies.
A novel in vitro method to model the fate of subcutaneously administered biopharmaceuticals and associated formulation components
Authors: Hanne M. Kinnunen, Vikas Sharma, Luis Rodrigo Contreras-Rojas, Yafei Yu, Chlöe Alleman, Alavattam Sreedhara, Stefan Fischer, Leslie Khawli, Stefan T. Yohe, Daniela Bumbaca, Thomas W. Patapoff, Ann L. Daugherty, Randall J. Mrsny
Journal: Journal of Controlled Release (2015)
Antiphospholipid Anti-Bodies—Autoantibodies with a Difference
Authors: E N Harris, R A Asherson, G R Hughes
Journal: Annual Review of Medicine (1988)

Antiphospholipid antibodies may be detected by solid phase anticardiolipin antibody tests, the lupus anticoagulant test, or standard tests for syphilis (STS). The occurrence of these antibodies has been associated with venous or arterial thrombosis, fetal loss, and possibly thrombocytopenia. Other suggested features that may be associated with these antibodies include livedo reticularis, migraine, chorea, and heart valve lesions. Uncontrolled studies of small numbers of affected women with recurrent fetal loss suggest that prednisone and aspirin therapy during pregnancy may improve pregnancy outcome. Anticoagulant therapy is recommended for patients with thrombosis for as long as antiphospholipid antibodies persist.
CD103+ Dendritic Cells Elicit CD8+ T Cell Responses to Accelerate Kidney Injury in Adriamycin Nephropathy
Authors: Qi Cao, Junyu Lu, Qing Li, Changqi Wang, Xin Maggie Wang, Vincent W.S. Lee, Chengshi Wang, Hanh Nguyen, Guoping Zheng, Ye Zhao, Stephen I. Alexander, Yiping Wang, David C.H. Harris
Journal: Journal of the American Society of Nephrology (2015)

CD103 + dendritic cells (DCs) in nonlymphoid organs exhibit two main functions: maintaining tolerance by induction of regulatory T cells and protecting against tissue infection through cross-presentation of foreign antigens to CD8 + T cells. However, the role of CD103 + DCs in kidney disease is unknown. In this study, we show that CD103 + DCs are one of four subpopulations of renal mononuclear phagocytes in normal kidneys. CD103 + DCs expressed DC-specific surface markers, transcription factors, and growth factor receptors and were found in the kidney cortex but not in the medulla. The number of kidney CD103 + DCs was significantly higher in mice with adriamycin nephropathy (AN) than in normal mice, and depletion of CD103 + DCs attenuated kidney injury in AN mice. In vitro , kidney CD103 + DCs preferentially primed CD8 + T cells and did not directly induce tubular epithelial cell apoptosis. Adoptive transfer of CD8 + T cells significantly exacerbated kidney injury in AN SCID mice, whereas depletion of CD103 + DCs in these mice impaired activation and proliferation of transfused CD8 + T cells and prevented the exacerbation of kidney injury associated with this transfusion. In conclusion, kidney CD103 + DCs display a pathogenic role in murine CKD via activation of CD8 + T cells.
Nutrient Effects on DNA and Chromatin Structure
Authors: C. Elizabeth Castro
Journal: Annual Review of Nutrition (1987)

INTRODUCTION  407 ORGANIZATION OF DNA IN THE NUCLEUS  408 CHROMATIN STRUCTURE AND GENE EXPRESSION...... .........   410 NUTRIENT EFFECTS ON CHROMATIN STRUCTURE ......     410 Higher·Order Structure . . . . . .   .       . . . . . . . 410 Chromatin Subunit Organization  ....   414 Nutrient Effects on Nuclear Proteins.....     414 NUTRIENT EFFECTS ON DNA METHyLATION  415 CONCLUSIONS  417
Diseases of the Cardiovascular System (Excluding Hypertension and Atherosclerosis)
Authors: F D Johnston
Journal: Annual Review of Medicine (1959)

Electrocardiography has continued to be an active field, with studies relating to intraventricular conduction and leads or lead systems suitable for vectorcardiography contributing heavily. The important and contro­ versial problem is still undecided regarding the nature of excitation of the free wall of the left ventricle, namely, whether the subendocardial muscle is activated in a rapid and chaotic fashion with only the epicardial layers con­ tributing substantially to the QRS complex as recorded in external (direct or semidirect) leads, or whether radial spread 9f excitation occurs through the entire wall of this chamber. The group bf workers ( 1) whose studies have favored the latter view have provided no further evidence to support it, but in investigations using the same techniques, have shown that in the dog with left branch block the septum is excited from right to left, with the left ventricle activated earliest on the anterior, epicardial aspect. The latter causes excitation to pass inward toward the cavity of the left ventricle for a short time. In experimental studies and limited observations on the human heart directed toward an analysis of the form of the QRS complex in epicar­ dial leads, Pipberger and his associates (2) have confirmed their earlier im­ pression that only the outer layers of the left ventricle contribute signifi­ cantly to the R wave seen in: epicardial leads. The implications of these observations, particularly in myocardial infarction, were pointed out and in this connection, the frequent occurrence of a QRS complex with a small initial r wave and large S wave (rS) in the epicardial lead over an infarct was mentioned. Sodi-Pallares and his colleagues (3), in ingenious experimental studies, attempted to relate pathways of ventricular activation to findings in vector­ cardiograms. This was done by determining the locations of maximal posi­ tivity and negativity on the epicardial surface of the ventricles at a number of instants of time during excitation. These they designated as the apparent maximal potential gradients and, when represented by vectors, made it possible to construct vectorcardiograms in the three usual planes. These vectorcardiograms were compared with vector figures recorded by the use of the cube system of electrode placement, and agreement was sufficiently close to justify the conclusion that vectorcardiograms give valuable in-
Quality of life (QOL) evaluation within a randomized phase III study of gemcitabine plus S-1 (GS) versus S-1 versus gemcitabine (GEM) in unresectable, advanced pancreatic cancer (PC) in Japan and Taiwan: GEST study.
Authors: Y. Ohashi, M. Tanaka, N. Boku, H. Ueno, T. Okusaka
Journal: Journal of Clinical Oncology (2011)

9070 Background: The GEST study, a randomized 3-arm phase III study, was designed to assess the non-inferiority of S-1 alone and the superiority of GS to GEM. Primary endpoint was overall survival (OS). The non-inferiority of S-1 was confirmed, GS was superior to GEM but the difference was not statistically significant. QOL was a secondary endpoint. Here we report QOL results from this study. Methods: Chemotherapy-naïve patients with unresectable advanced PC, ECOG PS of 0-1, with adequate organ functions were enrolled. Patients were equally randomized to one of three arms: GEM (1000 mg/m2, iv, d1, 8 and 15, q4w) , S-1 (80/100/120 mg/day based on BSA, po, d1-28, q6w) , or GS (GEM 1000 mg/m2, iv, d1 and 8 plus S-1 60/80/100 mg/day based on BSA po, d1-14, q3w). The patients were assessed with EQ-5D questionnaire at baseline, and at 6,12,24,48 and 72 weeks from first administration. Changes over time of EQ-5D utility score and Quality-adjusted life years (QALY) were calculated. In addition, we explored the relationship between QOL and clinical characteristics. Results: Among 832 patients, full analysis set of this study, 736(88%) had completed both baseline questionnaire and at least one questionnaire after randomization. In the EQ-5D utility score analysis by including deaths as score 0, there was a statistically significant difference in score over time between GS and GEM (p=0.0031, repeated measures ANOVA), and no statistically significant difference between S-1 and GEM. In the analysis of QALY, there was a statistically significant difference between GS and GEM (p=0.0008, generalized Wilcoxon test), but no statistically significant difference between S-1 and GEM. In the population of PS 1, GS is remarkably better than GEM in favor of EQ-5D utility score and QALY. Conclusions: Patients treated with S-1 resulted in clinically equivalent efficacy outcomes without any impact on patient QOL compared with GEM. Patients treated with GS had a statistically significant difference in QOL compared with GEM, in both overall and PS1 populations. Further research is needed to confirm the efficacy of GS in unresectable advanced PC.
Stroke and recurrent haemorrhage associated with antithrombotic treatment after gastrointestinal bleeding in patients with atrial fibrillation: nationwide cohort study
Authors: Laila Staerk, Gregory Y H Lip, Jonas B Olesen, Emil L Fosbøl, Jannik L Pallisgaard, Anders N Bonde, Anna Gundlund, Tommi B Lindhardt, Morten L Hansen, Christian Torp-Pedersen, Gunnar H Gislason
Journal: BMJ (2015)

What are the risks of all cause mortality, thromboembolism, major bleeding, and recurrent gastrointestinal bleeding associated with restarting antithrombotic treatment after gastrointestinal bleeding in patients with atrial fibrillation?This Danish cohort study (1996-2012) included all patients with atrial fibrillation discharged from hospital after gastrointestinal bleeding while receiving antithrombotic treatment. Restarted treatment regimens were single or combined antithrombotic drugs with oral anticoagulation and antiplatelets. Follow-up started 90 days after discharge to avoid confounding from use of previously prescribed drugs on discharge. Risks of all cause mortality, thromboembolism, major bleeding, and recurrent gastrointestinal bleeding were estimated with competing risks models and time dependent multiple Cox regression models.4602 patients (mean age 78 years) were included. Within two years, 39.9% (95% confidence interval 38.4% to 41.3%, n=1745) of the patients had died, 12.0% (11.0% to 13.0%, n=526) had experienced thromboembolism, 17.7% (16.5% to 18.8%, n=788) major bleeding, and 12.1% (11.1% to 13.1%, n=546) recurrent gastrointestinal bleeding. 27.1% (n=924) of patients did not resume antithrombotic treatment. Compared with non-resumption of treatment, a reduced risk of all cause mortality was found in association with restart of oral anticoagulation (hazard ratio 0.39, 95% confidence interval 0.34 to 0.46), an antiplatelet agent (0.76, 0.68 to 0.86), and oral anticoagulation plus an antiplatelet agent (0.41, 0.32 to 0.52), and a reduced risk of thromboembolism was found in association with restart of oral anticoagulation (0.41, 0.31 to 0.54), an antiplatelet agent (0.76, 0.61 to 0.95), and oral anticoagulation plus an antiplatelet agent (0.54, 0.36 to 0.82). Restarting oral anticoagulation alone was the only regimen with an increased risk of major bleeding (1.37, 1.06 to 1.77) compared with non-resumption of treatment; however, the difference in risk of recurrent gastrointestinal bleeding was not significant between patients who restarted an antithrombotic treatment regimen and those who did not resume treatment.Among patients with atrial fibrillation who experience gastrointestinal bleeding while receiving antithrombotic treatment; subsequent restart of oral anticoagulation alone was associated with better outcomes for all cause mortality and thromboembolism compared with patients who did not resume treatment. This was despite an increased longitudinal associated risk of bleeding.This study was supported by a grant from Boehringer-Ingelheim. Competing interests are available in the full paper on bmj.com. The authors have no additional data to share.
Failure to refer for testing for cystic fibrosis
Authors: M. Super
Journal: BMJ (2001)

The genetics of cystic fibrosis are well understood. It is an autosomal recessive disorder, and relatives of a person with cystic fibrosis have a greatly increased chance of being carriers (two of three healthy siblings of an affected person will be carriers as will one in two aunts or uncles). People without a family history of the disease have a 1 in 25 chance of being carriers. Thus, a couple in which one member carries the disease and one has no family history is 12 to 16 times more likely to have an affected child (that is, in 1 in 150 to 1 in 200 births the child will be affected) than a couple in which neither partner carries the gene (in which 1 in 2500 newborns will be affected). Accurate, quality controlled tests for the common cystic fibrosis mutations have been available through regional genetics services in the United Kingdom for a decade. Yet the number of instances in which a general practitioner has not referred a concerned patient or has behaved in a dismissive …
Time for authors of paper to write to health secretary over misuse of weekend mortality data?
Authors: K. J. H. Newman
Journal: BMJ (2015)

Surely the answer to this difference in interpretation of Freemantle and colleagues’ paper is to ask Freemantle and colleagues to respond to Jeremy Hunt in a letter to The BMJ .1 2

It is easy for lay people, such as the health secretary, to misinterpret data in scientific papers, but part of the blame lies with the authors for not making their findings clearer …
The Roles of Compensatory Evolution and Constraint in Aminoacyl tRNA Synthetase Evolution
Authors: Jeffrey R. Adrion, P. Signe White, Kristi L. Montooth
Journal: Molecular Biology and Evolution (2015)

Mitochondrial protein translation requires interactions between transfer RNAs encoded by the mitochondrial genome (mt-tRNAs) and mitochondrial aminoacyl tRNA synthetase proteins (mt-aaRS) encoded by the nuclear genome. It has been argued that animal mt-tRNAs have higher deleterious substitution rates relative to their nuclear-encoded counterparts, the cytoplasmic tRNAs (cyt-tRNAs). This dynamic predicts elevated rates of compensatory evolution of mt-aaRS that interact with mt-tRNAs, relative to aaRS that interact with cyt-tRNAs (cyt-aaRS). We find that mt-aaRS do evolve at significantly higher rates (exemplified by higher dN and dN/dS) relative to cyt-aaRS, across mammals, birds, and Drosophila. While this pattern supports a model of compensatory evolution, the level at which a gene is expressed is a more general predictor of protein evolutionary rate. We find that gene expression level explains 10–56% of the variance in aaRS dN/dS, and that cyt-aaRS are more highly expressed in addition to having lower dN/dS values relative to mt-aaRS, consistent with more highly expressed genes being more evolutionarily constrained. Furthermore, we find no evidence of positive selection acting on either class of aaRS protein, as would be expected under a model of compensatory evolution. Nevertheless, the signature of faster mt-aaRS evolution persists in mammalian, but not bird or Drosophila, lineages after controlling for gene expression, suggesting some additional effect of compensatory evolution for mammalian mt-aaRS. We conclude that gene expression is the strongest factor governing differential amino acid substitution rates in proteins interacting with mitochondrial versus cytoplasmic factors, with important differences in mt-aaRS molecular evolution among taxonomic groups.