tbuckley/cabot-search huggingface dataset:
Genetic Susceptibility to Triple-Negative Breast Cancer
Authors: Kristen N. Stevens, Celine M. Vachon, Fergus J. Couch
Journal: Cancer Research (2013)

Triple-negative breast cancers (TNBC), defined by the absence of estrogen receptor, progesterone receptor, and HER-2 expression, account for 12% to 24% of all breast cancers. TNBC is associated with early recurrence of disease and poor outcome. Germline mutations in the BRCA1 and BRCA2 breast cancer susceptibility genes have been associated with up to 15% of TNBC, and TNBC accounts for 70% of breast tumors arising in BRCA1 mutation carriers and 16% to 23% of breast tumors in BRCA2 carriers. Whether germline mutations in other breast cancer susceptibility genes also predispose to TNBC remains to be determined. Common variation in a subset of the 72 known breast cancer susceptibility loci identified through genome-wide association studies and other large-scale genotyping efforts have also been associated with risk of TNBC (TOX3, ESR1, RAD51L1, TERT, 19p13.1, 20q11, MDM4, 2p24.1, and FTO). Furthermore, variation in the 19p13.1 locus and the MDM4 locus has been associated with TNBC, but not other forms of breast cancer, suggesting that these are TNBC-specific loci. Thus, TNBC can be distinguished from other breast cancer subtypes by a unique pattern of common and rare germline predisposition alleles. Additional efforts to combine genetic and epidemiologic data are needed to better understand the etiology of this aggressive form of breast cancer, to identify prevention and therapeutic targets, and to impact clinical practice through the development of risk prediction models.
Statins decrease perioperative cardiac complications in patients undergoing noncardiac vascular surgery
Authors: George Katsimaglis, Peter G. Danias, Peter G. Danias, Kristin O'Neil-Callahan, Jason Ryan, Carla Mosby, Peter G. Danias, George Katsimaglis, John P.A. Ioannidis, John P.A. Ioannidis, Micah R. Tepper
Journal: Journal of the American College of Cardiology (2005)
Effect of birch pollen–specific immunotherapy on birch pollen–related hazelnut allergy
Authors: Els van Hoffen, Kim A.B.M. Peeters, R.J. Joost van Neerven, Corrien W.H. van der Tas, Laurian Zuidmeer, Adrie G. van Ieperen-van Dijk, Carla A.F.M. Bruijnzeel-Koomen, Edward F. Knol, Ronald van Ree, André C. Knulst
Journal: Journal of Allergy and Clinical Immunology (2010)
Glucocorticoid-resistant asthma: pathogenesis and clinical implications for management
Authors: SJ Szefler, DY Leung
Journal: European Respiratory Journal (1997)

At the present time, emphasis is placed on viewing asthma as a manifestation of chronic airway inflammation, possibly secondary to allergen hypersensitivity. Consequently, one aspect of management is to institute measures of environmental control to minimize the inflammatory response related to allergen stimulation, and to administer anti-inflammatory therapy to resolve inflammation and prevent progression of disease. Most patients respond very favourably to conventional therapy, as recommended in recent guidelines for asthma management. Some cases, however, remain very difficult to control despite high-dose inhaled glucocorticoids, even combined with oral glucocorticoid therapy. Management of these patients raises questions about the conditions that alter response to glucocorticoid therapy. The patient with difficult to control asthma not only presents a challenge to clinical management but raises new questions concerning our ability to control the progression of disease. Is difficult to control asthma secondary to overwhelming or ongoing allergen exposure? Do anti-inflammatory medications, specifically inhaled glucocorticoids, really control the progression of the disease? Are these patients destined to become severe asthmatics at birth due to the inherent characteristics of their airways, or is this indeed a consequence of progressive inflammation? This review will summarize present concepts of glucocorticoid-resistant asthma, current knowledge of the mechanisms of persistent inflammation, and the implications for management. The gaps in information will also be addressed in order to stimulate interest in further research that could lead to better understanding of the disease and potential windows for therapeutic intervention.
Randomised trial of losartan versus captopril in patients over 65 with heart failure (Evaluation of Losartan in the Elderly Study, ELITE)
Authors: Bertram Pitt, Robert Segal, Felipe A Martinez, Georg Meurers, Alan J Cowley, Ignatius Thomas, Prakash C Deedwania, Dawn E Ney, Duane B Snavely, Paul I Chang
Journal: The Lancet (1997)
Palliation of proximal malignant biliary obstruction by endoscopic endoprosthesis insertion.
Authors: A A Polydorou, S R Cairns, J F Dowsett, A R Hatfield, P R Salmon, P B Cotton, R C Russell
Journal: Gut (1991)

For four years up to December 1987, 190 patients (median age 73 years) with proximal malignant biliary obstruction were treated by endoscopic endoprosthesis insertion. Altogether 101 had cholangiocarcinoma, 21 gall bladder carcinoma, 20 local spread of pancreatic carcinoma, and 48 metastatic malignancy. Fifty eight patients had type I, 54 type II, and 78 type III proximal biliary strictures (Bismuth classification). All patients were either unfit or unsuitable for an attempt at curative surgical resection. A single endoprosthesis was placed initially, with a further stent being placed only if relief of cholestasis was insufficient or sepsis developed in undrained segments. The combined percutaneous-endoscopic technique was used to place the endoprosthesis when appropriate, after failed endoscopic endoprosthesis insertion or for second endoprosthesis placement. Full follow up was available in 97%.Thirteen patients were still alive at the time of review and all but one had been treated within the past six months. Initial endoprosthesis insertion succeeded technically at the first attempt in 127 patients, at the second in 30, and at a combined procedure in a further 13 (cumulative total success rate 89% - type I: 93%; type II: 94%; and type III: 84%). There was adequate biliary drainage after single endoprosthesis insertion in 152 of the 170 successful placements, giving an overall successful drainage rate of 80%. Three patients had a second stent placed by combined procedure because of insufficient drainage, giving an overall successful drainage rate of 82% (155 of 190). The final overall drainage success rates were type I: 91%; type II: 83%; and type III: 73%. The early complication rates were type I: 7%; type II: 14%; and type III: 31%. The principle early complication was clinical cholangitis, which occurred in 13 patients (7%) and required second stent placement in five. The 30 day mortality was 22% overall (type I: 14%; type II: 15%; and type III: 32%) but the direct procedure related mortality was only 3%. Median survival overall for types I, II, and III strictures were 21, 12, and 10 weeks respectively but survival was significantly shorter for metastatic than primary malignancy (p&lt;0.05). Endoscopic insertion of a single endoprosthesis will provide good palliation of proximal malignant biliary obstruction caused by unresectable malignancy in 80% of patients. Second stents should be placed only if required. Extensive structuring because of metastatic disease carries a poor prognosis and careful patient selection for treatment is requires.
A polymorphism in TIM1 is associated with susceptibility to severe hepatitis A virus infection in humans
Authors: Hye Young Kim, María Belén Eyheramonho, Muriel Pichavant, Carlos Gonzalez Cambaceres, Ponpan Matangkasombut, Guillermo Cervio, Silvina Kuperman, Rita Moreiro, Krishnamurthy Konduru, Mohanraj Manangeeswaran, Gordon J. Freeman, Gerardo G. Kaplan, Rosemarie H. DeKruyff, Dale T. Umetsu, Sergio D. Rosenzweig
Journal: Journal of Clinical Investigation (2011)

During infection with the hepatitis A virus (HAV), most patients develop mild or asymptomatic disease. However, a small number of patients develop serious, life-threatening hepatitis. We investigated this variability in disease severity by examining 30 Argentinean patients with HAV-induced acute liver failure in a case-control, cross-sectional, observational study. We found that HAV-induced severe liver disease was associated with a 6-amino-acid insertion in TIM1/HAVCR1 (157insMTTTVP), the gene encoding the HAV receptor. This polymorphism was previously shown to be associated with protection against asthma and allergic diseases and with HIV progression. In binding assays, the TIM-1 protein containing the 157insMTTTVP insertion polymorphism bound HAV more efficiently. When expressed by human natural killer T (NKT) cells, this long form resulted in greater NKT cell cytolytic activity against HAV-infected liver cells, compared with the shorter TIM-1 protein without the polymorphism. To our knowledge, the 157insMTTTVP polymorphism in TIM1 is the first genetic susceptibility factor shown to predispose to HAV-induced acute liver failure. Furthermore, these results suggest that HAV infection has driven the natural selection of shorter forms of the TIM-1 protein, which binds HAV less efficiently, thereby protecting against severe HAV-induced disease, but which may predispose toward inflammation associated with asthma and allergy.
Spontaneous termination of reentry after one cycle or short nonsustained runs. Role of oscillations and excess dispersion of refractoriness.
Authors: L H Frame, E K Rhee
Journal: Circulation Research (1991)

This study describes factors that contribute to spontaneous termination of reentry lasting one to 10 cycles after induction by a single premature stimulus. Reentry was studied in vitro in rings of canine atrial tissue from around the tricuspid valve orifice. Activation was recorded from a circular array of 10 extracellular bipolar electrodes equally spaced around the ring. In some experiments, transmembrane or monophasic action potential recordings were made near critical sites. Termination of reentry within one cycle after induction was recorded 110 times in 11 of 35 experiments. Important factors contributing to termination were 1) an obligatory reversal of the activation sequence that resulted in a long coupling interval in the critical region beyond the site of unidirectional block after the premature stimulus and 2) much longer refractory periods limited to this critical region, which facilitated unidirectional block but contributed to termination when this region was first activated with a short coupling interval at the end of the first reentrant cycle. Termination of nonsustained reentry lasting longer than one cycle resulted from oscillations of conduction and refractoriness initiated by the abrupt shortening of cycle length after initiation of reentry. Oscillations of conduction resulted from interval-dependent conduction of reentrant impulses that encountered partially refractory tissue. For reentry to become sustained, the oscillations after induction of reentry must dampen. Thus, damped cycle length oscillations after induction may identify clinical tachycardias caused by reentry with a partially excitable gap.
Net Benefits: A Multicountry Analysis of Observational Data Examining Associations between Insecticide-Treated Mosquito Nets and Health Outcomes
Authors: Stephen S. Lim, Nancy Fullman, Andrew Stokes, Nirmala Ravishankar, Felix Masiye, Christopher J. L. Murray, Emmanuela Gakidou
Journal: PLoS Medicine (2011)

Stephen Lim and colleagues report findings from a multi-country analysis of household survey data on the association between possession of insecticide-treated mosquito nets and child mortality and parasitemia. Scale-up of net coverage was associated with a substantial reduction in childhood mortality and in parasitemia prevalence.
In vivo regulation of murine CYP7A1 by HNF-6: A novel mechanism for diminished CYP7A1 expression in biliary obstruction
Authors: Minhua Wang, Yongjun Tan, Robert H. Costa, Ai-Xuan L. Holterman
Journal: Hepatology (2004)

Disruption of the enterohepatic bile acid circulation during biliary tract obstruction leads to profound perturbation of the cholesterol and bile acid metabolic pathways. Several families of nuclear receptor proteins have been shown to modulate this critical process by regulating hepatic cholesterol catabolism and bile acid synthesis through the transcriptional control of cholesterol 7-α hydroxylase (CYP7A1). Hepatocyte nuclear factor (HNF) 6 (also known as OC-1) is a member of the ONECUT family of transcription factors that activate numerous hepatic target genes essential to liver function. We have previously shown that hepatic expression of mouse HNF-6 messenger RNA (mRNA) and protein significantly decrease following bile duct ligation. Because CYP7A1 contains potential HNF-6 binding sites in its promoter region, we tested the hypothesis that HNF-6 transcriptionally regulates CYP7A1. Following bile duct ligation, we demonstrated that diminished HNF-6 mRNA levels correlate with a reduction in CYP7A1 mRNA expression. Increasing hepatic levels of HNF-6 either by infection with recombinant adenovirus vector expressing HNF-6 cDNA by growth hormone treatment leads to an induction of CYP7A1 mRNA. To directly evaluate if HNF-6 is a transcriptional activator for CYP7A1, we used deletional and mutational analyses of CYP7A1 promoter sequences and defined sequences −206/−194 to be critical for CYP7A1 transcriptional stimulation by HNF-6 in cotransfection assays. In conclusion , the HNF-6 protein is a component of the complex network of hepatic transcription factors that regulates the expression of hepatic genes essential for bile acid homeostasis and cholesterol/lipid metabolism in normal and pathological conditions. (Hepatology 2004;40:600-608.)
Secukinumab failure in Crohn's disease: the yeast connection?
Authors: Jean Frédéric Colombel, Boualem Sendid, Thierry Jouault, Daniel Poulain
Journal: Gut (2012)

We read with great interest the article by Hueber et al 1 reporting on the dramatic failure of secukinumab, an anti-IL17A monoclonal antibody, in Crohn's disease (CD). This multicentre phase IIa study compared secukinumab with placebo in 59 patients with established moderate to severe CD. The study was prematurely stopped because the prespecified criterion for futility was met; for the first time to our knowledge in the history of recent CD trials, a statistical significant difference of mean Crohn's Disease Activity Index (CDAI) (between weeks 4 and 10) was observed in favour of placebo. Of the seven serious adverse events suspected to be drug related, five were worsening of CD, four on secukinumab. The study, thus, clearly showed that pharmacological blockade of IL-17A does not improve CD, but that it could …
Nitric Oxide/Cyclic Guanosine Monophosphate Signalling Mediates an Inhibitory Action on Sensory Pathways of the Micturition Reflex in the Rat
Authors: Romain Caremel, Stephanie Oger-Roussel, Delphine Behr-Roussel, Philippe Grise, François A. Giuliano
Journal: European Urology (2010)
Transplacental Carcinogenic Effect of 3-Methylcholanthrene in Mice and Its Quantitation in Fetal Tissues&lt;xref ref-type="fn" rid="FN1"&gt;2&lt;/xref&gt;
Authors: L. Tomatis, V. Turusov, D. Guibbert, B. Duperray, C. Malavellle, H. Pacheco
Journal: JNCI Journal of the National Cancer Institute (1971)

The administration of 8.4 mg 3-methylcholanthrene (MCA) to pregnant CF-1 mice, 1–7 days before delivery, resulted in a high incidence of tumors in the progeny, whether they were nursed by their own mothers or foster-nursed by untreated females. Thus the exposure to MCA in utero was sufficient per se to induce a high incidence of tumors. The average level of MCA per litter after administration to pregnant mice of either 10 or 3.3 mg MCA was evaluated. Only about 0.9% of the total radioactivity recovered in fetuses after administration of 14C-MCA to pregnant mice was due to unchanged MCA.
Regulation of antigen presentation by acidic pH.
Authors: P E Jensen
Journal: The Journal of Experimental Medicine (1990)

The effect of pH on functional association of peptide antigens with APC membranes was investigated by using aldehyde-fixed B cells and class II-restricted T cell hybridomas to assess antigen/MHC complex formation. The results indicated that the rate and extent of functional peptide binding was markedly increased at pH 5.0 as compared with pH 7.3. The pH dependence of binding was preserved after pretreatment of fixed APC with pH 5.0 buffer, suggesting that pH had a direct effect on the interaction of peptide with the APC membrane. Similar results were obtained by using several peptides and I-Ad- and I-Ed-restricted T cells, indicating that pH may be of general importance in regulating the formation of functional antigen/class II MHC complexes.
Deep Sequencing of Viral Genomes Provides Insight into the Evolution and Pathogenesis of Varicella Zoster Virus and Its Vaccine in Humans
Authors: Daniel P. Depledge, Samit Kundu, Nancy J. Jensen, Eleanor R. Gray, Meleri Jones, Sharon Steinberg, Anne Gershon, Paul R. Kinchington, D. Scott Schmid, Francois Balloux, Richard A. Nichols, Judith Breuer
Journal: Molecular Biology and Evolution (2013)

Immunization with the vOka vaccine prevents varicella (chickenpox) in children and susceptible adults.The vOka vaccine strain comprises a mixture of genotypes and, despite attenuation, causes rashes in small numbers of recipients.Like wildtype virus, the vaccine establishes latency in neuronal tissue and can later reactivate to cause Herpes zoster (shingles).Using hybridization-based methodologies, we have purified and sequenced vOka directly from skin lesions.We show that alleles present in the vaccine can be recovered from the lesions and demonstrate the presence of a severe bottleneck between inoculation and lesion formation.Genotypes in any one lesion appear to be descended from one to three vaccine-genotypes with a low frequency of novel mutations.No single vOka haplotype and no novel mutations are consistently present in rashes, indicating that neither new mutations nor recombination with wild type are critical to the evolution of vOka rashes.Instead, alleles arising from attenuation (i.e., not derived from free-living virus) are present at lower frequencies in rash genotypes.We identify 11 loci at which the ancestral allele is selected for in vOka rash formation and show genotypes in rashes that have reactivated from latency cannot be distinguished from rashes occurring immediately after inoculation.We conclude that the vOka vaccine, although heterogeneous, has not evolved to form rashes through positive selection in the mode of a quasispecies, but rather alleles that were essentially neutral during the vaccine production have been selected against in the human subjects, allowing us to identify key loci for rash formation.
Psoas and quadratus lumborum muscle asymmetry among elite Australian Football League players
Authors: J Hides, T Fan, W Stanton, P Stanton, K McMahon, S Wilson
Journal: British Journal of Sports Medicine (2008)

Objective In this study, asymmetry relative to the preferred kicking leg was determined if it exists for the psoas and quadratus lumborum muscles among elite Australian Football League (AFL) players. Design AFL players were assessed at three time points from 2005 to 2007 (start of preseason, end of season and end of preseason training). MRI was used to determine the cross-sectional areas (CSAs) of the psoas and quadratus lumborum muscles at the L4–L5 vertebral level (psoas) and the L3–L4 vertebral level (quadratus lumborum). Setting MRI was performed in a hospital setting. Participants 54 professional AFL players were eligible to participate in this study. The number of subjects at each of the three time points was 36 for time 1 (T1 Nov 2005), 31 for time 2 (T2 Aug 2006) and 43 for time 3 (T3 Feb Mar 2007). Risk factors The repeated measures factor in the analyses was “asymmetry”, defined as “ipsilateral” or “contralateral” to preferred kicking leg. Number of injuries (coded as 0, 1, 2 or more) was also included as a risk factor. Main outcome measurements The dependent variables were the CSAs of the psoas and quadratus lumborum muscles. Results At all three time points, the CSA of the psoas muscle was significantly greater ipsilateral to the kicking leg, while the CSA of the quadratus lumborum muscle was significantly greater on the side contralateral to the kicking leg. Asymmetry in muscle size was not related to number of injuries. Conclusions Asymmetry of the psoas and the quadratus lumborum muscles exists in elite AFL players.
Nonthrombogenic Approaches to Cardiovascular Bioengineering
Authors: Song Li, Jeffrey J.D. Henry
Journal: Annual Review of Biomedical Engineering (2011)

Cardiovascular devices such as vascular grafts, stents, and heart valves have been widely used to treat cardiovascular diseases. The failure of these devices is usually initiated by the formation of thrombus and neointima on the device surfaces. Antithrombogenic surface modifications have been employed to improve the performance of these devices. In addition to biochemical modifications, tissue engineering approaches hold the promise to fabricate nonthrombogenic biological substitutes for cardiovascular tissues and devices. Endothelial cells (ECs) and stem cells have been used to cover blood-contacting surfaces. Furthermore, for tissue-engineered vascularized tissues and organs, a nonthrombogenic vascular network is essential for mass transfer and the integration of functional tissues and organs into the host upon transplantation. This review discusses the advances in antithrombogenic approaches for surface modifications and cardiovascular tissue engineering.
Rapid Whole-Genome Sequencing for Genetic Disease Diagnosis in Neonatal Intensive Care Units
Authors: Carol Jean Saunders, Neil Andrew Miller, Sarah Elizabeth Soden, Darrell Lee Dinwiddie, Aaron Noll, Noor Abu Alnadi, Nevene Andraws, Melanie LeAnn Patterson, Lisa Ann Krivohlavek, Joel Fellis, Sean Humphray, Peter Saffrey, Zoya Kingsbury, Jacqueline Claire Weir, Jason Betley, Russell James Grocock, Elliott Harrison Margulies, Emily Gwendolyn Farrow, Michael Artman, Nicole Pauline Safina, Joshua Erin Petrikin, Kevin Peter Hall, Stephen Francis Kingsmore
Journal: Science Translational Medicine (2012)

Monogenic diseases are frequent causes of neonatal morbidity and mortality, and disease presentations are often undifferentiated at birth. More than 3500 monogenic diseases have been characterized, but clinical testing is available for only some of them and many feature clinical and genetic heterogeneity. Hence, an immense unmet need exists for improved molecular diagnosis in infants. Because disease progression is extremely rapid, albeit heterogeneous, in newborns, molecular diagnoses must occur quickly to be relevant for clinical decision-making. We describe 50-hour differential diagnosis of genetic disorders by whole-genome sequencing (WGS) that features automated bioinformatic analysis and is intended to be a prototype for use in neonatal intensive care units. Retrospective 50-hour WGS identified known molecular diagnoses in two children. Prospective WGS disclosed potential molecular diagnosis of a severe GJB2-related skin disease in one neonate; BRAT1-related lethal neonatal rigidity and multifocal seizure syndrome in another infant; identified BCL9L as a novel, recessive visceral heterotaxy gene (HTX6) in a pedigree; and ruled out known candidate genes in one infant. Sequencing of parents or affected siblings expedited the identification of disease genes in prospective cases. Thus, rapid WGS can potentially broaden and foreshorten differential diagnosis, resulting in fewer empirical treatments and faster progression to genetic and prognostic counseling.