tbuckley/cabot-search huggingface dataset:
Polygenes, Risk Prediction, and Targeted Prevention of Breast Cancer
Authors: Paul D.P. Pharoah, Antonis C. Antoniou, Douglas F. Easton, Bruce A.J. Ponder
Journal: New England Journal of Medicine (2008)

New developments in the search for susceptibility alleles in complex disorders provide support for the possibility of a polygenic approach to the prevention and treatment of common diseases.We examined the implications, both for individualized disease prevention and for public health policy, of findings concerning the risk of breast cancer that are based on common genetic variation.Our analysis suggests that the risk profile generated by the known, common, moderate-risk alleles does not provide sufficient discrimination to warrant individualized prevention. However, useful risk stratification may be possible in the context of programs for disease prevention in the general population.The clinical use of single, common, low-penetrance genes is limited, but a few susceptibility alleles may distinguish women who are at high risk for breast cancer from those who are at low risk, particularly in the context of population screening.
Increased Cardiac Output as a Contributory Factor in Experimental Renal Hypertension in Dogs
Authors: CARLOS M. FERRARIO, IRVINE H. PAGE, JAMES W. McCUBBIN
Journal: Circulation Research (1970)

It has been suggested, but not established, that renal hypertension is initiated by increase incardiac output. Recent refinements in electromagnetic flowmeter technology allowed a critical reevaluation of this possibility. Flowmeters were implanted around dogs' ascending aortas and arterial catheters inserted; measurements were made daily before and after production of hypertension by the cellophane perinephritis method. Eight to 15 days after wrapping one kidney in cellophane, with the opposite kidney untouched, group averages for both stroke volume and cardiac output rose significantly (P &lt; 0.005) though there was no change in arterial pressure. Both heart rate and peripheral resistance decreased slightly. Following these measurements, the contralateral normal kidney was removed and measurements were recommenced 24 hours later. After 4 to 7 days, mean arterial pressure rose progressively in all dogs, reaching a plateau 77 ± 8 (SE) mm Hg above control after 14 to 25 days. Hypertension was associated initially with further rise in both stroke volume and cardiac output, and peripheral resistance now became elevated. Four weeks after nephrectomy, peripheral resistance progressively became the predominant cause of elevated pressure while cardiac output returned toward control values. Absence of change in plasma volume and increase in mean circulatory pressure measured in a separate series of 7 dogs suggest that the initial increase in cardiac output preceding rise in pressure was due to enhanced venous return consequent to constriction of capacitance vessels. We conclude that increased cardiac output probably has a contributory role in the development of renal hypertension.
Influence of long-term treatment with dipyridamole on the aorta-stenosed rabbit heart: morphometric and functional investigations
Authors: K.-E. BLASS, G. TRIEBE, F. TRAUB, W. FORSTER
Journal: Cardiovascular Research (1976)

The well-known effects of dipyridamole on the increase of the coronary vessel system and on cardiac metabolism suggest that dipyridamole may have a favourable influence on the chronic pressure loaded heart. In the model of the aorta-stenosed growing rabbit the cardiomegaly was diminished after a 3-month treatment using high doses of dipyridamole. Histometrically a marked decrease of the enlargement of the cross-sectional area of muscle fibres was found. It is assumed that dipyridamole retards myocardial hypertrophy and stimulates hyperplasia. Simultaneously the impairment of distinct parameters of cardiac contractility in the aorta-stenosed heart was prevented in growing rabbits by long-term dipyridamole treatment.
Oxidized LDL downregulates ATP-binding cassette transporter-1 in human vascular endothelial cells via inhibiting liver X receptor (LXR)
Authors: Y ZHU, H LIAO, X XIE, Y YUAN, T LEE, N WANG, X WANG, J SHYY, M STEMERMAN
Journal: Cardiovascular Research (2005)

Objective: ATP-binding cassette transporter-1 (ABCA1) mediates the active efflux of cholesterol and phospholipids, playing an important role in cholesterol homeostasis and atherogenesis. Oxidized low density lipoprotein (oxLDL) is an atherogenic molecule associated with the vascular endothelial dysfunction and development of atherosclerotic plaque. This report describes the effect of copper-catalyzed oxLDL on the regulation of ABCA1 in human endothelial cells (ECs).
REGULATION OF ANTIBODY RESPONSE BY CELLS EXPRESSING HISTAMINE RECEPTORS
Authors: G. M. Shearer, Kenneth L. Melmon, Yacob Weinstein, Michael Sela
Journal: The Journal of Experimental Medicine (1972)

Spleen cells from immunized and unimmunized mice were either passed over histamine-rabbit serum albumin-Sepharose columns or rabbit serum albumin-Sepharose control columns. The immune response potential of 5 x 10(6) cells excluded from the two columns were compared with each other, and with an equal number of unfiltered cells by injection of the cell suspensions mixed with sheep erythrocytes into irradiated, syngeneic recipients. The direct and indirect anti-sheep erythrocyte plaque-forming cell responses generated by the cells passed over the histamine-bead column were significantly greater than the responses resulting from the inocula of unfiltered cells or cells passed over control columns. These results indicate the existence of a cell population expressing surface receptors for histamine, which functions to regulate antibody responses.
Deletion of GSK-3β in mice leads to hypertrophic cardiomyopathy secondary to cardiomyoblast hyperproliferation
Authors: Risto Kerkela, Lisa Kockeritz, Katrina MacAulay, Jibin Zhou, Bradley W. Doble, Cara Beahm, Sarah Greytak, Kathleen Woulfe, Chinmay M. Trivedi, James R. Woodgett, Jonathan A. Epstein, Thomas Force, Gordon S. Huggins
Journal: Journal of Clinical Investigation (2008)

Based on extensive preclinical data, glycogen synthase kinase–3 (GSK-3) has been proposed to be a viable drug target for a wide variety of disease states, ranging from diabetes to bipolar disorder. Since these new drugs, which will be more powerful GSK-3 inhibitors than lithium, may potentially be given to women of childbearing potential, and since it has controversially been suggested that lithium therapy might be linked to congenital cardiac defects, we asked whether GSK-3 family members are required for normal heart development in mice. We report that terminal cardiomyocyte differentiation was substantially blunted in Gsk3b–/– embryoid bodies. While GSK-3α–deficient mice were born without a cardiac phenotype, no live-born Gsk3b–/– pups were recovered. The Gsk3b–/– embryos had a double outlet RV, ventricular septal defects, and hypertrophic myopathy, with near obliteration of the ventricular cavities. The hypertrophic myopathy was caused by cardiomyocyte hyperproliferation without hypertrophy and was associated with increased expression and nuclear localization of three regulators of proliferation — GATA4, cyclin D1, and c-Myc. These studies, which we believe are the first in mammals to examine the role of GSK-3α and GSK-3β in the heart using loss-of-function approaches, implicate GSK-3β as a central regulator of embryonic cardiomyocyte proliferation and differentiation, as well as of outflow tract development. Although controversy over the teratogenic effects of lithium remains, our studies suggest that caution should be exercised in the use of newer, more potent drugs targeting GSK-3 in women of childbearing age.
Biomarker and Pharmacologic Evaluation of the γ-Secretase Inhibitor PF-03084014 in Breast Cancer Models
Authors: Cathy C. Zhang, Adam Pavlicek, Qin Zhang, Maruja E. Lira, Cory L. Painter, Zhengming Yan, Xianxian Zheng, Nathan V. Lee, Mark Ozeck, Ming Qiu, Qing Zong, Patrick B. Lappin, Anthony Wong, Paul A. Rejto, Tod Smeal, James G. Christensen
Journal: Clinical Cancer Research (2012)

We aimed to assess the biologic activity of PF-03084014 in breast xenograft models. The biomarkers for mechanism and patient stratification were also explored.The in vitro and in vivo properties of PF-03084014 were investigated. The mRNA expressions of 40 key Notch pathway genes at baseline or after treatment were analyzed to link with the antitumor efficacy of PF-03084014 in a panel of breast cancer xenograft models.In vitro, PF-03084014 exhibited activity against tumor cell migration, endothelial cell tube formation, and mammosphere formation. In vivo, we observed apoptosis, antiproliferation, reduced tumor cell self-renewal ability, impaired tumor vasculature, and decreased metastasis activity after the treatment of PF-03084014. PF-03084014 treatment displayed significant antitumor activity in 10 of the 18 breast xenograft models. However, the antitumor efficacy in most models did not correlate with the in vitro antiproliferation results in the corresponding cell lines, suggesting the critical involvement of tumor microenvironment during Notch activation. In the tested breast xenograft models, the baseline expressions of the Notch receptors, ligands, and the cleaved Notch1 failed to predict the antitumor response to PF-03084014, whereas several Notch pathway target genes, including HEY2, HES4, and HES3, strongly corresponded with the response with a P value less than 0.01. Many of the best molecular predictors of response were also significantly modulated following PF-03084014 treatment.PF-03084014 showed antitumor and antimetastatic properties via pleiotropic mechanisms. The Notch pathway downstream genes may be used to predict the antitumor activity of PF-03084014 and enrich for responders among breast cancer patients.
Decision Making by Parents of Children With Incurable Cancer Who Opt for Enrollment on a Phase I Trial Compared With Choosing a Do Not Resuscitate/Terminal Care Option
Authors: Scott H. Maurer, Pamela S. Hinds, Sheri L. Spunt, Wayne L. Furman, Javier R. Kane, Justin N. Baker
Journal: Journal of Clinical Oncology (2010)

Parents of children with incurable cancer make complex and difficult decisions about remaining treatment options. We compared the self-reported rationale, good parent definition, and desired clinical staff behaviors of parents who recently decided for phase I (P1) chemotherapy with parents who chose a do not resuscitate (DNR) or terminal care (TC) option.Sixty-two parents of 58 children were asked for the basis of their decision, their definition of a good parent, and what staff behaviors supported their good parent role. After semantic content analysis, results were compared in the P1 versus DNR/TC groups. These categories were mutually exclusive but did not necessarily represent an either/or decision.Thirty-one decisions were for P1 chemotherapy and 27 for DNR/TC. Median survival time after study enrollment was greater in the P1 group (0.4 v 0.1 years). Most P1 group parents reported having felt compelled to continue cancer-directed therapy (71% v 7%), whereas those who opted for DNR/TC cited quality of life (QOL; 74% v 3%) and patient wishes (67% v 13%). Decision factors common to both groups were medical facts, doing right, and others' opinions. Both groups believed that a good parent did right, provided support and presence, and sacrificed for the child. The groups desired similar support from clinicians and expressed gratitude.Despite similar definitions of a good parent and desired staff behaviors, parents in the P1 group reported having felt compelled to continue cancer-directed therapy, whereas QOL and patient wishes were emphasized in decisions for DNR/TC.
Further Studies on the Effects of Changes in the Distribution of Extracellular Fluid on Sodium Excretion
Authors: JOHN A. LUSK, WILLIAM N. VIAR, TINSLEY R. HARRISON
Journal: Circulation (1952)

Bandaging of the legs of sitting subjects resulted in an increase in the renal excretion of sodium which declined after the bandages were removed. Consistent results were not obtained in recumbent subjects. The findings appear to constitute further evidence that the distribution, rather than the total volume of extracellular fluids, has a regulatory action on sodium excretion.
Choice of transcripts and software has a large effect on variant annotation
Authors: Davis J McCarthy, Peter Humburg, Alexander Kanapin, Manuel A Rivas, Kyle Gaulton, Jean-Baptiste Cazier, Peter Donnelly
Journal: Genome Medicine (2014)

Variant annotation is a crucial step in the analysis of genome sequencing data. Functional annotation results can have a strong influence on the ultimate conclusions of disease studies. Incorrect or incomplete annotations can cause researchers both to overlook potentially disease-relevant DNA variants and to dilute interesting variants in a pool of false positives. Researchers are aware of these issues in general, but the extent of the dependency of final results on the choice of transcripts and software used for annotation has not been quantified in detail.This paper quantifies the extent of differences in annotation of 80 million variants from a whole-genome sequencing study. We compare results using the RefSeq and Ensembl transcript sets as the basis for variant annotation with the software Annovar, and also compare the results from two annotation software packages, Annovar and VEP (Ensembl's Variant Effect Predictor), when using Ensembl transcripts.We found only 44% agreement in annotations for putative loss-of-function variants when using the RefSeq and Ensembl transcript sets as the basis for annotation with Annovar. The rate of matching annotations for loss-of-function and nonsynonymous variants combined was 79% and for all exonic variants it was 83%. When comparing results from Annovar and VEP using Ensembl transcripts, matching annotations were seen for only 65% of loss-of-function variants and 87% of all exonic variants, with splicing variants revealed as the category with the greatest discrepancy. Using these comparisons, we characterised the types of apparent errors made by Annovar and VEP and discuss their impact on the analysis of DNA variants in genome sequencing studies.Variant annotation is not yet a solved problem. Choice of transcript set can have a large effect on the ultimate variant annotations obtained in a whole-genome sequencing study. Choice of annotation software can also have a substantial effect. The annotation step in the analysis of a genome sequencing study must therefore be considered carefully, and a conscious choice made as to which transcript set and software are used for annotation.
Distribution patterns of extracellular matrix components and adhesion receptors are intricately modulated during first trimester cytotrophoblast differentiation along the invasive pathway, in vivo.
Authors: C H Damsky, M L Fitzgerald, S J Fisher
Journal: Journal of Clinical Investigation (1992)

Development of the human embryo depends on the ability of first trimester cytotrophoblastic stem cells to differentiate and invade the uterus. In this process, transient expression of an invasive phenotype is part of normal cytotrophoblast differentiation. Morphologically, this process begins when polarized chorionic villus cytotrophoblasts form multilayered columns of nonpolarized cells, and invade the uterus. Using immunocytochemistry, we compared the presence of adhesion receptors and extracellular matrix ligands on cytotrophoblasts in villi, cell columns, and the uterine wall. Villus cytotrophoblasts, anchored to basement membrane, stained for alpha 6 and beta 4 integrin subunits and both merosin and A-chain-containing laminin. Nonpolarized cytotrophoblasts in columns expressed primarily alpha 5 and beta 1 integrin subunits and a fibronectin-rich matrix. Cytotrophoblast clusters in the uterine wall stained for alpha 1, alpha 5, and beta 1 integrins, but not for most extracellular matrix antigens, suggesting that they interact primarily with maternal cells and matrices. Tenascin staining was restricted to stroma at sites of transition in cytotrophoblast morphology, suggesting that tenascin influences cytotrophoblast differentiation. Our results suggest that regulation of adhesion molecule expression contributes to acquisition of an invasive phenotype by cytotrophoblasts and provide a foundation for studying pathological conditions in which insufficient or excessive trophoblast invasion occurs, such as preeclampsia or choriocarcinoma.
Lymphocyte function-associated antigen 1 dominates very late antigen 4 in binding of activated T cells to endothelium.
Authors: Y van Kooyk, E van de Wiel-van Kemenade, P Weder, R J Huijbens, C G Figdor
Journal: The Journal of Experimental Medicine (1993)

Lymphocyte function-associated antigen 1/intercellular adhesion molecule 1 (LFA-1/ICAM-1)-and very late antigen 4/vascular cell adhesion molecule 1 (VLA-4/VCAM-1)-mediated adhesion of T lymphocytes to endothelial cells (EC) can be regulated by increased expression of ICAM-1 and VCAM-1 upon cytokine treatment of EC, or by activation of the integrin molecules LFA-1 and VLA-4 on T cells. Here, we provide evidence that preferential usage of LFA-1 over VLA-4 is yet another mechanism to control T cell adhesion. We observed that binding of activated T lymphocytes, as opposed to resting T cells, to EC is essentially mediated through LFA-1 and not through VLA-4. VLA-4-mediated adhesion of T cells to EC is only found when LFA-1 is not expressed or not functional, as observed for several T cell leukemia cell lines. These results suggest that LFA-1-mediated adhesion dominates and may downregulate VLA-4-mediated adhesion through an unidentified mechanism.
Postural changes in left ventricular and mitral valvular dynamics in the systolic click - late systolic murmur syndrome.
Authors: M E Fontana, C F Wooley, R F Leighton, R P Lewis
Journal: Circulation (1975)

Marked changes in the auscultatory pattern with posture have been noted in patients with mid-systolic clicks and/or late systolic murmurs (MSC-LSM). MSC tend to move earlier in systole and LSM become longer and often louder when patients assume upright posture. Systolic prolapse of the mitral leaflets with mild regurgitation account for MSC-LSM; earlier and greater prolapse with more and prolonged regurgitation associated with a reduced left ventricular volume (LVV) in the upright position would explain the auscultatory changes. Twenty-two patients with MSC-LSM were studied supine and at 45 degrees head-up tilt, recording intracardiac pressures, cardiac outputs, systolic time intervals, and performing LV cineangiography. Systolic prolapse of one or both mitral leaflets was demonstrated in all patients. Left ventricular end-diastolic and end-systolic volumes both decreased significantly at 45 degrees in all sixteen technically satisfactory studies. Greater mitral prolapse was noted upright in 12 of 14 studies with enough sinus beats to judge. The amount of mitral regurgitation was mild in all, and changes in amount from supine to upright posture could not be discerned angiographically. THE FINDINGS, SUGGEST THAT THE AUSCULTATORY CHANGES OCCURRING WITH UPRIGHT POSTURE IN PATIENTS WITH MSC-LSM are related to greater prolapse of the mitral leaflets which is associated with a small LVV in the upright position.
Dietary fructose, carbohydrates, glycemic indices and pancreatic cancer risk: a systematic review and meta-analysis of cohort studies
Authors: D. Aune, D.S.M. Chan, A.R. Vieira, D.A. Navarro Rosenblatt, R. Vieira, D.C. Greenwood, J.E. Cade, V.J. Burley, T. Norat
Journal: Annals of Oncology (2012)
Abstract 15166: The Effect of Ivabradine on Silent Ambulatory Myocardial Ischemia
Authors: Waleed Kadro, Maya Turkmani, Husam Rahim, Amr Al Karmi, Fares Al Ahdab
Journal: Circulation (2014)

Introduction:  Heart rate (HR) reduction is a powerful method used to reduce myocardial oxygen demand thus reducing the frequency and duration of angina in chronic ischemic heart disease (CIHD). Ivabradine selectively inhibits the Na+/K+ current (I/f current) in pacemaker cells of the sinoatrial node, this will reduce the slope of diastolic depolarization resulting in slower HR without causing other side effect on myocardial contractility or AV conduction. Treating silent myocardial ischemia has a prognostic effect and may improve long term mortality of (CIHD). The effect of Ivabradine on angina frequency was already studied but its effect on silent ambulatory myocardial ischemia (SAMI) has not been reported yet. In this study we report the effect of ivabradine on (SAMI)   Methods:  We enrolled 50 patients with proven stable coronary artery disease (CAD) and at least one episode of ST-segment depression on ambulatory ECG monitoring. All of them were receiving optimal therapy for CIHD. 25 patients were randomized to receive Ivabradine 7.5mg bid and the other 25 patients received placebo. Ambulatory monitoring was repeated after 4 to 6 months of therapy. The two groups were comparable with respect to baseline characteristics, number of episodes of ST-segment depression, and baseline serum cholesterol levels. Holters were read by a blinded cardiologist.   Results:  The Ivabradine group had lower mean HR at study end and experienced a significant reduction in the number of episodes of ST-segment depression compared with the placebo group. ST-segment depression was completely resolved in 9 of 25 patients (36%) in the Ivabradine group versus 3 of 25 (12%) in the placebo group. The Ivabradine group exhibited a highly significant reduction in (SAMI) (P   Conclusions:  Further lowering of HR with Ivabradine can result in reduction or resolution of (SAMI) recorded as episodes of ST-segment depression in ambulatory monitoring of the ECG. A larger study is required to confirm this theory and to see the effect of SAMI reduction on long term mortality of CIHD.
Finding the Right Level of Posthospital Care
Authors: Robert L. Kane
Journal: JAMA (2011)

Many families considering posthospital care options are ill-prepared and in need of guidance. They may not know the range of available options, the relative benefits of each, or have considered their therapeutic goals. Physicians should be informants, advocates, and facilitators of this big leap for their patients. Making a good long-term care decision requires information and structure, but such decisions are often made under great time pressure as part of a hospital discharge. Professional intervention and guidance by an informed but disinterested facilitator may be needed, but hospital discharge planners may not be well suited for this role because their mandate is a rapid discharge. Physicians have 2 crucial roles in these transitions: to ensure the seamless delivery of primary care and to advocate for and facilitate, however possible, better decision making. Physicians need at least a rudimentary knowledge of the array of options and the implications of each. Even if the physician cannot serve as the planning facilitator, the physician should ensure that this task is done well. This review describes the range of options and the implications of each option for long-term care in the United States. It suggests the need for evaluating each patient's care goals, family circumstances and resources, and clinical status to determine if more aggressive medical care might improve an individual's clinical trajectory.