tbuckley/cabot-search huggingface dataset:
Clarifying the PROGINS Allele Association in Ovarian and Breast Cancer Risk: A Haplotype-Based Analysis
Authors: C. L. Pearce, J. N. Hirschhorn, A. H. Wu, N. P. Burtt, D. O. Stram, S. Young, L. N. Kolonel, B. E. Henderson, D. Altshuler, M. C. Pike
Journal: JNCI Journal of the National Cancer Institute (2005)

Background: The PROGINS allele of the progesterone receptor (PGR) gene has been associated with an increased risk of ovarian cancer and a decreased risk of breast cancer. We set out to refine the association between common variation at the PGR gene locus and these two diseases. Methods: We characterized the haplotype structure of the PGR gene by genotyping 54 single-nucleotide polymorphisms (SNPs) in 349 women. We then selected a subset of 17 haplotype-tagging SNPs that captured variation across the locus and typed them in 267 ovarian cancer case patients and 397 control subjects from two case–control studies and in 1715 breast cancer case patients and 2505 control subjects from a cohort study. Results: The PGR locus was characterized by four blocks of strong linkage disequilibrium. Two SNPs in block 4 were associated with an increased risk of ovarian cancer among homozygous carriers as compared with noncarriers: rs1042838 (PROGINS allele; odds ratio [OR] = 3.23, 95% confidence interval [CI] = 1.19 to 8.75, P = .022) and rs608995 (minor allele; OR = 3.10, 95% CI = 1.63 to 5.89, P<.001). The PROGINS allele was observed on a subset of chromosomes carrying the minor allele at rs608995, and its association with ovarian cancer was fully explained by its association with rs608995. In addition, rs608995 fell on two common haplotypes (4-D and 4-E), whose association with ovarian cancer was the same as that of rs608995. These same two haplotypes were associated with a non–statistically significantly reduced risk of breast cancer. Conclusions: Variation in PGR was associated with ovarian cancer risk, although the strongest result was not with the PROGINS allele. Instead, any causal allele(s) are likely in or downstream of block 4 and carried on haplotypes 4-D and 4-E. There was some evidence that the same variation was associated with a reduced risk of breast cancer, but the association was not statistically significant.
Recombinant Gene Transfer of Endothelial Nitric Oxide Synthase Augments Coronary Artery Relaxations During Hypoxia
Authors: D. G. Cable, None Vincent J. Pompili, None Timothy O Brien, None Hartzell V. Schaff
Journal: Circulation (1999)

Coronary arteries respond to hypoxia with transient relaxations, which increases coronary blood flow, in part, by release of nitric oxide. We hypothesized that increased expression of nitric oxide synthase might further augment blood vessel relaxation during hypoxia. The present study examined the effect of adenovirus-mediated transfer of bovine endothelial nitric oxide synthase (eNOS) on hypoxia-induced transient relaxations in canine coronary arteries.Paired segments of coronary arteries were exposed to vehicle (phosphate-buffered saline with albumin) or an adenovirus encoding either E coli beta-galactosidase (Ad.CMVLacZ, viral control; 10(10) pfu/mL) or eNOS (Ad.CMVeNOS; 10(10) pfu/mL) for 2 hours at 37 degrees C. Immunohistochemistry with a monoclonal antibody specific for eNOS documented both endothelial and adventitial expression in Ad.CMVeNOS arteries, whereas vehicle and viral controls demonstrated only constitutive expression. Levels of cGMP were increased 5-fold in Ad.CMVeNOS arteries compared with controls. In arteries exposed to Ad.CMVeNOS, maximum contraction to prostaglandin F(2alpha) was reduced compared with viral controls, and this effect was eliminated by pretreatment with a competitive inhibitor of eNOS (N(G)-monomethyl-L-arginine, 10(-3) mol/L). Hypoxia-induced transient relaxation (95% N(2)-5% CO(2)) in Ad.CMVeNOS arteries (45.2+/-8.8%, n=6) was augmented compared with vehicle (26.3+/-6.0%) or viral (27.2+/-7.1%) controls.Adenovirus-mediated gene transfer of nitric oxide synthase reduces receptor-dependent contractions and augments hypoxia-induced relaxations in canine coronary arteries; this method of augmentation of NO production might be advantageous for reduction of coronary artery vasospasm.
STUDIES ON THE SHWARTZMAN PHENOMENON
Authors: Herbert M. Klein
Journal: The Journal of Experimental Medicine (1932)

Formalin induces a considerable change in meningococcus culture filtrates. This consists of a marked decrease in toxidty as concerns both the Shwartzman phenomenon and the lethal effect, with relative preservation of the antibody-combining capacity and antigenicity. A similar modification occurs spontaneously in meningococcus culture filtrates on standing. Inasmuch as these changes parallel those occurring in the conversion of diphtheria toxin into toxoid, it is justifiable to consider such altered meningococcus toxin as meningococcus toxoid.
Kinesio taping in musculoskeletal pain and disability that lasts for more than 4 weeks: is it time to peel off the tape and throw it out with the sweat? A systematic review with meta-analysis focused on pain and also methods of tape application
Authors: Edwin Choon Wyn Lim, Mathew Guo Xiang Tay
Journal: British Journal of Sports Medicine (2015)

Introduction In recent years, Kinesio tape has been used to support injured muscle and joints, and relieve pain. We compared the pain and disability in individuals with chronic musculoskeletal pain who were treated with Kinesio taping with those using minimal or other treatment approaches. Methods Searches of eight major electronic databases were conducted. Data for pain and disability scores were extracted. Meta-analyses (wherever possible) with either a fixed or random effect(s) model, standardised mean differences (SMDs) and tests of heterogeneity were performed. Results Seventeen clinical-controlled trials were identified and included in the meta-analyses. When compared to minimal intervention, Kinesio taping provided superior pain relief (pooled SMD=−0.36, 95% CI −0.64 to −0.09, p=0.009) but the pooled disability scores were not significantly different (pooled SMD=−0.41, 95% CI −0.83 to 0.01, p=0.05). No significant differences were found when comparing Kinesio taping to other treatment approaches for pain (pooled SMD=−0.44, 95% CI −1.69 to 0.82, p=0.49) and disability (pooled SMD=0.08, 95% CI −0.27 to 0.43, p=0.65). Discussion Kinesio taping is superior to minimal intervention for pain relief. Existing evidence does not establish the superiority of Kinesio taping to other treatment approaches to reduce pain and disability for individuals with chronic musculoskeletal pain.
IgE synthesis by chronic lymphocytic leukemia cells.
Authors: M Sarfati, H Luo, G Delespesse
Journal: The Journal of Experimental Medicine (1989)

The present results indicate that B cells isolated from chronic lymphocytic leukemia (B-CLL) from 11 of 14 patients are capable of specifically producing IgE upon costimulation with IL-4 and hydrocortisone (HC). IgE is detected by intracytoplasmic fluorescence staining and by RIA. Clinical, hematological, and immunological parameters (including Rai stage, WBC, Lc, sIg kappa/lambda, CD5, and CD23 expression) cannot distinguish the IgE responder from the nonresponder patients. IL-4 alone is a potent inducer of human IgE synthesis by normal PBMC and we show here that its effect is strikingly enhanced by HC. The IgE produced by B-CLLs are monoclonal since they display the same L chain type as the freshly isolated CD5+ B-CLLs. We, therefore, conclude that the combination of IL-4 and HC can abrogate the maturation arrest of CD5+ B-CLLs by inducing their differentiation into IgE-producing cells. The present data provide a unique model to study the isotype switching to IgE and the regulation of human IgE synthesis by monoclonal human B cells.
Protein Kinase Cα, but Not PKCβ or PKCγ, Regulates Contractility and Heart Failure Susceptibility
Authors: Qinghang Liu, Xiongwen Chen, Scott M. MacDonnell, Evangelia G. Kranias, John N. Lorenz, Michael Leitges, Steven R. Houser, Jeffery D. Molkentin
Journal: Circulation Research (2009)

Protein kinase (PK)Calpha, PKCbeta, and PKCgamma comprise the conventional PKC isoform subfamily, which is thought to regulate cardiac disease responsiveness. Indeed, mice lacking the gene for PKCalpha show enhanced cardiac contractility and reduced susceptibility to heart failure. Recent data also suggest that inhibition of conventional PKC isoforms with Ro-32-0432 or Ro-31-8220 enhances heart function and antagonizes failure, although the isoform responsible for these effects is unknown. Here, we investigated mice lacking PKCalpha, PKCbeta, and PKCgamma for effects on cardiac contractility and heart failure susceptibility. PKCalpha(-/-) mice, but not PKCbetagamma(-/-) mice, showed increased cardiac contractility, myocyte cellular contractility, Ca(2+) transients, and sarcoplasmic reticulum Ca(2+) load. PKCalpha(-/-) mice were less susceptible to heart failure following long-term pressure-overload stimulation or 4 weeks after myocardial infarction injury, whereas PKCbetagamma(-/-) mice showed more severe failure. Infusion of ruboxistaurin (LY333531), an orally available PKCalpha/beta/gamma inhibitor, increased cardiac contractility in wild-type and PKCbetagamma(-/-) mice, but not in PKCalpha(-/-) mice. More importantly, ruboxistaurin prevented death in wild-type mice throughout 10 weeks of pressure-overload stimulation, reduced ventricular dilation, enhanced ventricular performance, reduced fibrosis, and reduced pulmonary edema comparable to or better than metoprolol treatment. Ruboxistaurin was also administered to PKCbetagamma(-/-) mice subjected to pressure overload, resulting in less death and heart failure, implicating PKCalpha as the primary target of this drug in mitigating heart disease. As an aside, PKCalphabetagamma triple-null mice showed no defect in cardiac hypertrophy following pressure-overload stimulation. In conclusion, PKCalpha functions distinctly from PKCbeta and PKCgamma in regulating cardiac contractility and heart failure, and broad-acting PKC inhibitors such as ruboxistaurin could represent a novel therapeutic approach in treating human heart failure.
Adherence to advance directives in critical care decision making: vignette study
Authors: T. Thompson
Journal: BMJ (2003)

To explore health professionals' decision making in a critical care scenario when there is an advance directive.Qualitative study.Scotland.Interviewees (n = 12) comprising general practitioners, hospital specialists, and nurses, and six focus groups (n = 34 participants) comprising general practitioners, geriatricians (consultants and specialist registrars), hospital nurses, and hospice nurses.When presented with an advance directive that applied to the same hypothetical scenario, health professionals came to divergent conclusions as to the "right thing to do." Arguments opposing treatment centred on the supremacy of autonomy as an ethical principle. Other arguments were that the decision to treat was consistent with the terms of the advance directive, or that, notwithstanding the advance directive, the patient's quality of life was sufficient to warrant treatment.Advance directives are open to widely varying interpretation. Some of this variability is related to the ambiguity of the directive's terminology whereas some is related to the willingness of health professionals to make subjective value judgments concerning quality of life.
Mutations in Transforming Growth Factor-β Receptor Type II Cause Familial Thoracic Aortic Aneurysms and Dissections
Authors: Hariyadarshi Pannu, Van Tran Fadulu, Jessica Chang, Andrea Lafont, Sumera N. Hasham, Elizabeth Sparks, Philip F. Giampietro, Christina Zaleski, Anthony L. Estrera, Hazim J. Safi, Sanjay Shete, Marcia C. Willing, C.S. Raman, Dianna M. Milewicz
Journal: Circulation (2005)

Background— A genetic predisposition for progressive enlargement of thoracic aortic aneurysms leading to type A dissection (TAAD) is inherited in an autosomal-dominant manner in up to 19% of patients, and a number of chromosomal loci have been identified for the condition. Having mapped a TAAD locus to 3p24–25, we sequenced the gene for transforming growth factor-β receptor type II ( TGFBR2 ) to determine whether mutations in this gene resulted in familial TAAD. Methods and Results— We sequenced all 8 coding exons of TGFBR2 by using genomic DNA from 80 unrelated familial TAAD cases. We found TGFBR2 mutations in 4 unrelated families with familial TAAD who did not have Marfan syndrome. Affected family members also had descending aortic disease and aneurysms of other arteries. Strikingly, all 4 mutations affected an arginine residue at position 460 in the intracellular domain, suggesting a mutation “hot spot” for familial TAAD. Despite identical mutations in the families, assessment of linked polymorphisms suggested that these families were not distantly related. Structural analysis of the TGFBR2 serine/threonine kinase domain revealed that R460 is strategically located within a highly conserved region of this domain and that the amino acid substitutions resulting from these mutations will interfere with the receptor’s ability to transduce signals. Conclusion— Germline TGFBR2 mutations are responsible for the inherited predisposition to familial TAAD in 5% of these cases. Our results have broad implications for understanding the role of TGF-β signaling in the pathophysiology of TAAD.
SKLB1002, a Novel Potent Inhibitor of VEGF Receptor 2 Signaling, Inhibits Angiogenesis and Tumor Growth <i>In Vivo</i>
Authors: Shuang Zhang, Zhixing Cao, Hongwei Tian, Guobo Shen, Yongping Ma, Huanzhang Xie, Yalin Liu, Chengjian Zhao, Senyi Deng, Yang Yang, Renlin Zheng, Weiwei Li, Na Zhang, Shengyong Liu, Wei Wang, Lixia Dai, Shuai Shi, Lin Cheng, Youli Pan, Shan Feng, Xia Zhao, Hongxin Deng, Shengyong Yang, Yuquan Wei
Journal: Clinical Cancer Research (2011)

VEGF receptor 2 (VEGFR2) inhibitors, as efficient antiangiogenesis agents, have been applied in the cancer treatment. However, currently most of these anticancer drugs suffer some adverse effects. Discovery of novel VEGFR2 inhibitors as anticancer drug candidates is still needed.In this investigation, we adopted a restricted de novo design method to design VEGFR2 inhibitors. We selected the most potent compound SKLB1002 and analyzed its inhibitory effects on human umbilical vein endothelial cells (HUVEC) in vitro. Tumor xenografts in zebrafish and athymic mice were used to examine the in vivo activity of SKLB1002.The use of the restricted de novo design method indeed led to a new potent VEGFR2 inhibitor, SKLB1002, which could significantly inhibit HUVEC proliferation, migration, invasion, and tube formation. Western blot analysis was conducted, which indicated that SKLB1002 inhibited VEGF-induced phosphorylation of VEGFR2 kinase and the downstream protein kinases including extracellular signal-regulated kinase, focal adhesion kinase, and Src. In vivo zebrafish model experiments showed that SKLB1002 remarkably blocked the formation of intersegmental vessels in zebrafish embryos. It was further found to inhibit a new microvasculature in zebrafish embryos induced by inoculated tumor cells. Finally, compared with the solvent control, administration of 100 mg/kg/d SKLB1002 reached more than 60% inhibition against human tumor xenografts in athymic mice. The antiangiogenic effect was indicated by CD31 immunohistochemical staining and alginate-encapsulated tumor cell assay.Our findings suggest that SKLB1002 inhibits angiogenesis and may be a potential drug candidate in anticancer therapy.
Obesity, non-alcoholic fatty liver disease, and atherothrombosis: a role for the intestinal microbiota?
Authors: M. Knaapen, R.S. Kootte, E.G. Zoetendal, W.M. de Vos, G.M. Dallinga-Thie, M. Levi, E.S. Stroes, M. Nieuwdorp
Journal: Clinical Microbiology and Infection (2013)
Cancer Epigenetics: Modifications, Screening, and Therapy
Authors: Gal-Yam Einav Nili, Yoshimasa Saito, Gerda Egger, Peter A. Jones
Journal: Annual Review of Medicine (2007)

Deregulation of gene expression is a hallmark of cancer. Although genetic lesions have been the focus of cancer research for many years, it has become increasingly recognized that aberrant epigenetic modifications also play major roles in the tumorigenic process. These modifications are imposed on chromatin, do not change the nucleotide sequence of DNA, and are manifested by specific patterns of gene expression that are heritable through many cell divisions. We review these modifications in normal and cancer cells and the evolving approaches used to study them. Additionally, we outline advances in their potential use for cancer diagnostics and targeted epigenetic therapy.
Use of "spydergrams" to present and interpret SF-36 health-related quality of life data across rheumatic diseases
Authors: V Strand, B Crawford, J Singh, E Choy, J S Smolen, D Khanna
Journal: Annals of the Rheumatic Diseases (2009)

The Medical Outcomes Study Short Form-36 (SF-36) is a generic measure of health-related quality of life (HRQOL), validated and cross-culturally translated, which has been extensively utilised in rheumatology. In randomised controlled trials and observational studies, SF-36 provides rich data regarding HRQOL; but as typically portrayed, patterns of disease and treatment-associated effects can be difficult to discern. "Spydergrams" offer a simplified means to visualise complex results across all domains of SF-36 in a single figure: depicting disease and population-specific patterns of decrements in HRQOL compared with age and gender-matched normative data, as well as providing a tool for interpreting complex treatment-associated or longitudinal changes. Utilising spydergrams as a standard format to illustrate and report changes in SF-36 across different rheumatic diseases can greatly facilitate analyses and interpretations of clinical trial results, as well as providing patients an accessible means to compare baseline scores and treatment-associated improvements with normative data from individuals without arthritis. Furthermore, SF-6D utility scores based on mean changes across all eight domains of SF-36 are suggested as a quantitative means of summarising changes illustrated by spydergrams, offering a universal metric for cost-effectiveness analyses of therapeutic interventions.
Early-life wheeze: "the Child is father of the Man"
Authors: V. Hovland, A. Riiser, P. Mowinckel, K.-H. Carlsen, K. C. Lodrup Carlsen
Journal: European Respiratory Journal (2014)

We wish to thank R.J. Kurukulaaratchy and co-workers for their positive response to our article [1].We were happy to see that our paper encouraged the Isle of Wight Birth Cohort (IOWBC) to assess the prognosis of early recurrent wheeze into the beginning adulthood.As the corresponding findings in the IOWBC, with its high 18-year follow-up rate of 90% [2], are in line with those from our Environment and Childhood Asthma Study, it strengthens the message that the longer term prognosis of early recurrent wheeze might not be as favourable as previously conceived [3,4].Furthermore, the findings underline the importance of long-running birth cohorts enabling studies where recall bias is limited.As recent retrospective reports suggest that adult chronic obstructive pulmonary disease may have an early-life origin [5,6], the need for long-term prospective cohorts to address this specific question is obvious.With the additional data now presented by R.J. Kurukulaaratchy and co-workers on the natural course of early life wheeze, we suggest a reconsideration of the possibility of diagnosing asthma in preschool children as well as caution when addressing the potential favourable long-term prognosis of early recurrent wheezy illness.
Evans' syndrome associated with dermatomyositis.
Authors: E M Hay, M Makris, J Winfield, D A Winfield
Journal: Annals of the Rheumatic Diseases (1990)

Autoimmune haematological complications in dermatomyositis are very uncommon. This case report describes autoimmune haemolytic anaemia and thrombocytopenia in a patient with dermatomyositis and pulmonary fibrosis.
HDL of Patients with Type 2 Diabetes Mellitus Elevates the Capability of Promoting Breast Cancer Metastasis
Authors: Bing Pan, Hui Ren, Yubin He, Xiaofeng Lv, Yijing Ma, Jing Li, Li Huang, Baoqi Yu, Jian Kong, Chenguang Niu, Youyi Zhang, Wen-bing Sun, Lemin Zheng
Journal: Clinical Cancer Research (2012)

Abstract Purpose: Epidemiologic studies suggested complicated associations between type 2 diabetes mellitus and breast cancer. High-density lipoprotein (HDL) is inversely associated with the risk and mortality of breast cancer. Our study is to determine the different effects of normal and diabetic HDL on breast cancer cell metastasis. Experimental Design: MDA-MB-231 and MCF7 cells were treated with N-HDL, D-HDL, G-HDL, and Ox-HDL. Cell metastasis potency was examined using a tail-vein injection model, and cell adhesion abilities to human umbilical vein endothelial cells (HUVEC) and extracellular matrix (ECM) were determined in vitro. Integrin expression and protein kinase C (PKC) activity were evaluated, and PKC inhibitor was applied. Results: D-HDL dramatically promoted cell pulmonary metastasis (103.6% increase at P &amp;lt; 0.001 for MDA-MB-231 with 1 × 105 cell injection; 157.1% increase at P &amp;lt; 0.05 for MCF7 with 4 × 105 cell injection) and hepatic metastasis (18.1-fold increase at P &amp;lt; 0.001 for MCF7 with 4 × 105 cell injection), and stimulated higher TC-HUVECs adhesion (21.9% increase at P &amp;lt; 0.001 for MDA-MB-231; 23.6% increase at P &amp;lt; 0.05 for MCF7) and TC-ECM attachment (59.9% and 47.9% increase, respectively, for MDA-MB-231 and MCF7, both at P &amp;lt; 0.01) compared with N-HDL. D-HDL stimulated higher integrin (β1, β2, β3, and αν) expression on cell surface and induced higher PKC activity. Increased TC-HUVECs and TC-ECM adhesion induced by D-HDL, G-HDL, and Ox-HDL could be inhibited by staurosporine. Conclusions: Our study showed that glycation and oxidation of HDL in diabetic patients could lead to abnormal actions on breast cancer cell adhesion to HUVECs and ECM, thereby promoting metastasis progression of breast cancer. This will largely draw the attention of HDL-based treatments in the diabetes patients with breast cancer. Clin Cancer Res; 18(5); 1246–56. ©2012 AACR.