tbuckley/cabot-search huggingface dataset:
Estrous influence on surgical cure of a mouse breast cancer.
Authors: H V Ratajczak, R B Sothern, W J Hrushesky
Journal: The Journal of Experimental Medicine (1988)

We have studied the effect of estrous stage, as reflected by vaginal cellularity, at the time of surgical resection of an estrogen receptor-bearing mammary adenocarcinoma upon the metastatic potential of that tumor in the C3HeB/FeJ mouse. Presence of the tumor prolonged the length of the estrous cycle by approximately 25% and removal of the tumor returned the cycle to its usual duration. Neither estrous stage at tumor implant nor size of tumor at resection (within a small range) had significant independent effects upon differences observed in the incidence of subsequent pulmonary metastases. However, estrous stage at time of surgical removal of the tumor, as reflected by cell types in vaginal smear, markedly affected whether or not metastases ultimately appeared. Because the estrous cycle in mice, comparable to the human menstrual cycle, reflects high-amplitude, rhythmic changes in hormone concentrations, it may be that the hormonal status of a women at the time of tumor resection is an important determinant of whether or not that breast cancer ultimately metastasizes.
Short-Term and Long-Term Health Risks of Nuclear-Power-Plant Accidents
Authors: John P. Christodouleas, Robert D. Forrest, Christopher G. Ainsley, Zelig Tochner, Stephen M. Hahn, Eli Glatstein
Journal: New England Journal of Medicine (2011)

Recent natural disasters in Japan led to a partial meltdown at the Fukushima nuclear power plant. This article reviews the history of such accidents, along with the short-term and long-term health risks associated with environmental exposure to nuclear fission products.
Pharmacogenomics and Individualized Drug Therapy
Authors: Michel Eichelbaum, Magnus Ingelman-Sundberg, William E. Evans
Journal: Annual Review of Medicine (2005)

Pharmacogenetics deals with inherited differences in the response to drugs. The best-recognized examples are genetic polymorphisms of drug-metabolizing enzymes, which affect about 30% of all drugs. Loss of function of thiopurine S-methyltransferase (TPMT) results in severe and life-threatening hematopoietic toxicity if patients receive standard doses of mercaptopurine and azathioprine. Gene duplication of cytochrome P4502D6 (CYP2D6), which metabolizes many antidepressants, has been identified as a mechanism of poor response in the treatment of depression. There is also a growing list of genetic polymorphisms in drug targets that have been shown to influence drug response. A major limitation that has heretofore moderated the use of pharmacogenetic testing in the clinical setting is the lack of prospective clinical trials demonstrating that such testing can improve the benefit/risk ratio of drug therapy.
Determining the Direction of the Cardiac Vectors in the Frontal Plane
Authors: Bobby J. Stinebaugh
Journal: JAMA (1967)

VECTOR interpretation of the clinical electrocardiogram is becoming increasingly popular.<sup>1-3</sup>This method relates the scalar ECG to the basic underlying electrophysiology and eliminates, in many instances, the need for memorizing multiple abnormal "patterns." The initial step in this approach is to determine the direction of the QRS and T wave vectors. The relationship of these two vectors to each other is called the QRS-T angle, and is a sensitive index of T wave abnormalities. Although vector analysis of the scalar ECG has been in use for many years, no detailed description is available of a simplified method for localization of the vectors from routine clinical tracings. The purpose of this report is to present such a method. <h3>Method</h3> This approach is a variation of the method of Grant<sup>1</sup>and is similar to that described more briefly by Nadas.<sup>3</sup>The basic principle of Grants's method is that a vector
Smoking is a major preventable risk factor for rheumatoid arthritis: estimations of risks after various exposures to cigarette smoke
Authors: Henrik Källberg, Bo Ding, Leonid Padyukov, Camilla Bengtsson, Johan Rönnelid, Lars Klareskog, Lars Alfredsson
Journal: Annals of the Rheumatic Diseases (2010)

Background Earlier studies have demonstrated that smoking and genetic risk factors interact in providing an increased risk of rheumatoid arthritis (RA). Less is known on how smoking contributes to RA in the context of genetic variability, and what proportion of RA may be caused by smoking. Objectives To determine the association between the amount of smoking and risk of RA in the context of different HLA-DRB1 shared epitope (SE) alleles, and to estimate proportions of RA cases attributed to smoking. Design, Setting and Participants Data from the Swedish Epidemiological Investigation of Rheumatoid Arthritis (EIRA) case–control study encompassing 1204 cases and 871 controls were analysed. Main Outcome Measure Estimated OR to develop RA and excess fraction of cases attributable to smoking according to the amount of smoking and genotype. Results Smoking was estimated to be responsible for 35% of anticitrullinated protein/peptide antibody (ACPA)-positive cases. For each HLA-DRB1 SE genotype, smoking was dose-dependently associated with an increased risk of ACPA-positive RA (p trend &lt;0.001). In individuals carrying two copies of the HLA-DRB1 SE, 55% of ACPA-positive RA was attributable to smoking. Conclusions Smoking is a preventable risk factor for RA. The increased risk due to smoking is dependent on the amount of smoking and genotype.
Surgical excision versus Mohs' micrographic surgery for primary and recurrent basal-cell carcinoma of the face: a prospective randomised controlled trial with 5-years' follow-up
Authors: Klara Mosterd, Gertruud AM Krekels, Fred HM Nieman, Judith U Ostertag, Brigitte AB Essers, Carmen D Dirksen, Peter M Steijlen, Anton Vermeulen, HAM Neumann, Nicole WJ Kelleners-Smeets
Journal: The Lancet Oncology (2008)
MicroRNA Cluster 221-222 and Estrogen Receptor α Interactions in Breast Cancer
Authors: Gianpiero Di Leva, Pierluigi Gasparini, Claudia Piovan, Apollinaire Ngankeu, Michela Garofalo, Cristian Taccioli, Marilena V. Iorio, Meng Li, Stefano Volinia, Hansjuerg Alder, Tatsuya Nakamura, Gerard Nuovo, Yunlong Liu, Kenneth P. Nephew, Carlo M. Croce
Journal: JNCI Journal of the National Cancer Institute (2010)

Several lines of evidence have suggested that estrogen receptor alpha (ERalpha)-negative breast tumors, which are highly aggressive and nonresponsive to hormonal therapy, arise from ERalpha-positive precursors through different molecular pathways. Because microRNAs (miRNAs) modulate gene expression, we hypothesized that they may have a role in ER-negative tumor formation.Gene expression profiles were used to highlight the global changes induced by miRNA modulation of ERalpha protein. miRNA transfection and luciferase assays enabled us to identify new targets of miRNA 206 (miR-206) and miRNA cluster 221-222 (miR-221-222). Northern blot, luciferase assays, estradiol treatment, and chromatin immunoprecipitation were performed to identify the miR-221-222 transcription unit and the mechanism implicated in its regulation.Different global changes in gene expression were induced by overexpression of miR-221-222 and miR-206 in ER-positive cells. miR-221 and -222 increased proliferation of ERalpha-positive cells, whereas miR-206 had an inhibitory effect (mean absorbance units [AU]: miR-206: 500 AU, 95% confidence interval [CI]) = 480 to 520; miR-221: 850 AU, 95% CI = 810 to 873; miR-222: 879 AU, 95% CI = 850 to 893; P < .05). We identified hepatocyte growth factor receptor and forkhead box O3 as new targets of miR-206 and miR-221-222, respectively. We demonstrated that ERalpha negatively modulates miR-221 and -222 through the recruitment of transcriptional corepressor partners: nuclear receptor corepressor and silencing mediator of retinoic acid and thyroid hormone receptor.These findings suggest that the negative regulatory loop involving miR-221-222 and ERalpha may confer proliferative advantage and migratory activity to breast cancer cells and promote the transition from ER-positive to ER-negative tumors.
Duodenal fat intensifies the perception of heartburn
Authors: J H Meyer, A Lembo, J D Elashoff, R Fass, E A Mayer
Journal: Gut (2001)

<h3>BACKGROUND</h3> Patients with gastro-oesophageal reflux disease (GORD) frequently report that meals high in fat worsen heartburn. Nevertheless, studies to determine whether high fat meals promote gastro-oesophageal reflux have produced conflicting and equivocal conclusions. <h3>PATIENTS AND METHODS</h3> To determine, alternatively, whether fat in the small intestinal lumen intensifies the perception of heartburn, we studied 11 patients with typical heartburn from GORD. After being placed on omeprazole to suppress endogenous acid, these fasting subjects underwent oesophageal perfusions with graded doses of HCl at pH values of 1.0, 1.5, 2.0, and 2.5. Oesophageal perfusions were conducted while the duodenum was perfused with saline (control) and again with fat at 8 g/h. <h3>RESULTS</h3> Time to onset, intensity, and severity of heartburn varied with dose of oesophageal acid (p&lt;0.01). Time to onset was significantly (p&lt;0.01) shorter, and intensity and severity of heartburn significantly (p&lt;0.05) greater, during duodenal perfusion with fat. <h3>CONCLUSION</h3> We conclude that duodenal fat intensifies the perception of heartburn.
Gluten specific, HLA-DQ restricted T cells from coeliac mucosa produce cytokines with Th1 or Th0 profile dominated by interferon gamma.
Authors: E M Nilsen, K E Lundin, P Krajci, H Scott, L M Sollid, P Brandtzaeg
Journal: Gut (1995)

Coeliac disease is precipitated in susceptible subjects by ingestion of wheat gluten or gluten related prolamins from some other cereals. The disease is strongly associated with certain HLA-DQ heterodimers, for example, DQ2 (DQ alpha 1*0501, beta 1*0201) in most patients and apparently DQ8 (DQ alpha 1*0301, beta 1*0302) in a small subset. Gluten specific T cell clones (TCC) from coeliac intestinal lesions were recently established and found to be mainly restricted by HLA-DQ2 or HLA-DQ8. Antigen induced production of cytokines was studied in 15 TCC from three patients, 10 being DQ2 and five DQ8 restricted. Cell culture supernatants were prepared by stimulation with gluten peptides in the presence of DQ2+ or DQ8+ Epstein-Barr virus transformed B cells as antigen presenting cells (APC). Supernatants were analysed for cytokines by bioassays, ELISA, and CELISA. Cellular cytokine mRNA was analysed semi-quantitatively by slot blotting and polymerase chain reaction (PCR). All TCC were found to secrete interferon (IFN) gamma, often at high concentrations (&gt; 2000 U/ml); some secreted in addition interleukin (IL) 4, IL 5, IL 6, IL 10, tumour necrosis factor (TNF), and transforming growth factor (TGF) beta. The last TCC thus displayed a Th0-like cytokine pattern. However, other TCC produced IFN gamma and TNF but no IL 4, or IL 5, compatible with a Th1-like pattern. In conclusion, most DQ8 restricted TCC seemed to fit with a Th0 profile whereas the DQ2 restricted TCC secreted cytokines more compatible with a Th1 pattern. The TCC supernatants induced upregulation of HLA-DR and secretory component (poly-Ig receptor) in the colonic adenocarcinoma cell line HT-29.E10, most probably reflecting mainly the high IFN gamma concentrations. This cytokine, particularly in combination with TNF alpha, might be involved in several pathological features of the coeliac lesion. The characterised cytokine profiles thus support the notion that mucosal T cells activated in situ by gluten in a DQ restricted fashion play a central part in the pathogenesis of coeliac disease.
Protein Kinase A Phosphorylation of the Ryanodine Receptor Does Not Affect Calcium Sparks in Mouse Ventricular Myocytes
Authors: Yanxia Li, Evangelia G. Kranias, Gregory A. Mignery, Donald M. Bers
Journal: Circulation Research (2002)

Ryanodine receptor (RyR) phosphorylation by protein kinase A (PKA) may be important in modulating resting sarcoplasmic reticulum (SR) Ca 2+ release, especially in heart failure. However, clear cellular data on PKA-dependent modulation of cardiac RyRs is limited because of difficulty in distinguishing between PKA effects on RyR, phospholamban (PLB), and Ca 2+ current. To clarify this, we measured resting Ca 2+ sparks in streptolysin-O permeabilized ventricular myocytes from wild-type (WT) and PLB knockout (PLB-KO) mice and transgenic mice expressing only double-mutant PLB (PLB-DM) that lacks the regulatory phosphorylation sites (S16A/T17A). In WT myocytes, cAMP dramatically increased Ca 2+ spark frequency (CaSpF) by 2- and 3-fold when [Ca 2+ ] was clamped at 50 and 10 nmol/L (and the SR Ca 2+ content also rose by 40% and 50%). However, in PLB-KO and PLB-DM, neither CaSpF nor SR Ca 2+ load was changed by the addition of 10 μmol/L cAMP (even with phosphatase inhibition). PKA activation also increased Ca 2+ spark amplitude, duration, and width in WT, but not in PLB-KO or PLB-DM. RyR phosphorylation was confirmed by measurements of 32 P incorporation on immunoprecipitated RyR. In intact resting myocytes, PKA activation increased CaSpF 2.8-fold in WT, but not in PLB-KO, confirming results in permeabilized myocytes. We conclude that the PKA-dependent increase in myocyte CaSpF and size is entirely attributable to PLB phosphorylation and consequent enhanced SR Ca 2+ load. PKA does not seem to have any appreciable effect on resting RyR function in these ventricular myocytes. Moreover, the data provide compelling evidence that elevated intra-SR [Ca 2+ ] increases RyR gating independent of cytosolic [Ca 2+ ] (which was clamped).
Performance of New Thresholds of the Glasgow Blatchford Score in Managing Patients With Upper Gastrointestinal Bleeding
Authors: Stig B Laursen, Harry R Dalton, Iain A Murray, Nick Michell, Matt R Johnston, Michael Schultz, Jane M Hansen, Ove B Schaffalitzky de Muckadell, Oliver Blatchford, Adrian J Stanley
Journal: Clinical Gastroenterology and Hepatology (2014)
Cytochrome P450 expression in oesophageal cancer.
Authors: G I Murray, D Shaw, R J Weaver, J A McKay, S W Ewen, W T Melvin, M D Burke
Journal: Gut (1994)

<h3>ABSTRACT</h3> COVID-19 is primarily known as a respiratory disease caused by the virus SARS-CoV-2. However, neurological symptoms such as memory loss, sensory confusion, cognitive and psychiatric issues, severe headaches, and even stroke are reported in as many as 30% of cases and can persist even after the infection is over (so-called ‘long COVID’). These neurological symptoms are thought to be caused by brain inflammation, triggered by the virus infecting the central nervous system of COVID-19 patients, however we still don’t fully understand the mechanisms for these symptoms. The neurological effects of COVID-19 share many similarities to neurodegenerative diseases such as Alzheimer’s and Parkinson’s in which the presence of cytotoxic protein-based amyloid aggregates is a common etiological feature. Following the hypothesis that some neurological symptoms of COVID-19 may also follow an amyloid etiology we performed a bioinformatic scan of the SARS-CoV-2 proteome, detecting peptide fragments that were predicted to be highly amyloidogenic. We selected two of these peptides and discovered that they do rapidly self-assemble into amyloid. Furthermore, these amyloid assemblies were shown to be highly toxic to a neuronal cell line. We introduce and support the idea that cytotoxic amyloid aggregates of SARS-CoV-2 proteins are causing some of the neurological symptoms commonly found in COVID-19 and contributing to long COVID, especially those symptoms which are novel to long COVID in contrast to other post-viral syndromes.
Long-term cognitive and cardiac outcomes after prenatal exposure to chemotherapy in children aged 18 months or older: an observational study
Authors: Frédéric Amant, Kristel Van Calsteren, Michael J Halaska, Mina Mhallem Gziri, Wei Hui, Lieven Lagae, Michèl A Willemsen, Livia Kapusta, Ben Van Calster, Heidi Wouters, Liesbeth Heyns, Sileny N Han, Viktor Tomek, Luc Mertens, Petronella B Ottevanger
Journal: The Lancet Oncology (2012)
A conformational heparan sulfate binding site essential to infectivity overlaps with the conserved hepatitis B virus A-determinant
Authors: Camille Sureau, Jessica Salisse
Journal: Hepatology (2012)

Two determinants of infectivity have been identified in the hepatitis B virus (HBV) envelope proteins: a pre-S1 receptor-binding site and an uncharacterized determinant in the antigenic loop (AGL), which is structurally related to the antigenic a-determinant. Infection would proceed through virus attachment to cell surface heparan sulfate (HS) proteoglycans (HSPGs) before pre-S1 engages a specific receptor for uptake. Using heparin binding and in vitro infection assays with hepatitis D virus as a surrogate for HBV, we established that HS binding is mediated by the AGL. Electrostatic interaction was shown to depend upon AGL residues R122 and K141, because their substitution with alanine modified the virus net-charge and prevented binding to heparin, attachment to hepatocytes, and infection. In addition to R122 and K141, the HS binding determinant was mapped to cysteines and prolines, which also define the conformational a-determinant. The importance of AGL conformation was further demonstrated by the concomitant loss of a-determinant and heparin binding upon treatment of viral particles with membrane-impermeable reducing agent. Furthermore, envelope proteins extracted from the viral membrane with a nonionic detergent were shown to conserve the a-determinant but to lose heparin affinity/avidity. Conclusion : Our findings support a model in which attachment of HBV to HSPGs is mediated by the AGL HS binding site, including only two positively charged residues (R122 and K141) positioned precisely in a three-dimensional AGL structure that is stabilized by disulfide bonds. HBV envelope proteins would individually bind to HS with low affinity, but upon their clustering in the viral membrane, they would reach sufficient avidity for a stable interaction between virus and cell surface HSPGs. Our data provide new insight into the HBV entry pathway, including the opportunity to design antivirals directed to the AGL-HS interaction. (Hepatology 2013)
Minding the store of Ca2+ during ischaemia/reperfusion
Authors: D. M. Bers, K. S. Ginsburg
Journal: Cardiovascular Research (2010)

Cardiac ischaemia puts a tremendous stress on cardiac myocytes, and abrupt reperfusion causes dramatic changes during the first seconds to minutes that profoundly affect cell survival vs. cell death.1–3 Myocyte ionic changes can contribute to these critical effects. During ischaemia, the concentration of intracellular Na+ ([Na+] i ) rises because of a combination of increased Na+ entry via Na+/H+ exchange and tetrodotoxin-sensitive Na+ channels and reduced extrusion via Na+/K+-ATPase (as ATP and phosphocreatine are gradually depleted and ΔGATP declines). The rise in [Na+] i  contributes to cellular Ca2+ gain via shifts in Na+/Ca2+ exchange, and thus elevation of diastolic [Ca2+] i . Contractile force and pressure development are abolished in the first minute or so of ischaemia because of rapidly developing acidosis. More gradually, phosphate rises and eventually rigor crossbridges form as [ATP] is dissipated. Reperfusion causes an abrupt normalization of extracellular pH, which drives a rapid rise in [Na+] i  via Na+/H+ exchange. This is thought to drive a rapid further rise in [Ca2+] i  (via Na+/Ca2+ exchange), which along with pH normalization causes a rise in diastolic force. Spontaneous Ca2+ transients, oscillations, and arrhythmias are also observed upon reperfusion, and agents that inhibit Na+ and Ca2+ loading can improve the long-term recovery after reperfusion.4

Despite intensive study of ischaemia/reperfusion, remarkably little is known about the dynamic changes in sarcoplasmic reticulum (SR) Ca … 

*Corresponding author. Tel: +1 530 752 6517; Fax: +1 530 752 7710, Email: dmbers{at}ucdavis.edu
Canagliflozin Lowers Postprandial Glucose and Insulin by Delaying Intestinal Glucose Absorption in Addition to Increasing Urinary Glucose Excretion
Authors: David Polidori, Sue Sha, Sunder Mudaliar, Theodore P. Ciaraldi, Atalanta Ghosh, Nicole Vaccaro, Kristin Farrell, Paul Rothenberg, Robert R. Henry
Journal: Diabetes Care (2013)

Canagliflozin, a sodium glucose cotransporter (SGLT) 2 inhibitor, is also a low-potency SGLT1 inhibitor. This study tested the hypothesis that intestinal canagliflozin levels postdose are sufficiently high to transiently inhibit intestinal SGLT1, thereby delaying intestinal glucose absorption.
Role of sperm chromatin abnormalities and DNA damage in male infertility
Authors: A. Agarwal, Tamer M. Said
Journal: Human Reproduction Update (2003)

Sperm DNA integrity is essential for the accurate transmission of genetic information.It has a highly compact and complex structure and is capable of decondensationÐfeatures that must be present in order for a spermatozoon to be considered fertile.Any form of sperm chromatin abnormalities or DNA damage may result in male infertility.In support of this conclusion, it was reported that in-vivo fecundity decreases progressively when >30% of the spermatozoa are identi®ed as having DNA damage.Several methods are used to assess sperm chromatin/DNA, which is considered an independent measure of sperm quality that may yield better diagnostic and prognostic approaches than standard sperm parameters (concentration, motility and morphology).The clinical signi®cance of this assessment lies in its association not only with natural conception rates, but also with assisted reproduction success rates.Also, it has a serious impact on the offspring and is highly prognostic in the assessment of fertility in cancer patients.Therefore, screening for sperm DNA damage may provide useful information in cases of male idiopathic infertility and in those men pursuing assisted reproduction.Treatment should include methods for prevention of sperm DNA damage.
Temozolomide in combination with BCNU before and after radiotherapy in patients with inoperable newly diagnosed glioblastoma multiforme
Authors: M. Barrié, C. Couprie, H. Dufour, D. Figarella-Branger, X. Muracciole, K. Hoang-Xuan, D. Braguer, P.M. Martin, J.C. Peragut, F. Grisoli, O. Chinot
Journal: Annals of Oncology (2005)
Mapping of a Novel Susceptibility Locus Suggests a Role for MC3R and CTSZ in Human Tuberculosis
Authors: Graham S. Cooke, Sarah J. Campbell, Steve Bennett, Christian Lienhardt, Keith P. W. J. McAdam, Giorgio Sirugo, Oumou Sow, Per Gustafson, Frank Mwangulu, Paul van Helden, Paul Fine, Eileen G. Hoal, Adrian V. S. Hill
Journal: American Journal of Respiratory and Critical Care Medicine (2008)

Tuberculosis remains a major cause of morbidity and mortality in the developing world. A better understanding of the mechanisms of disease protection could allow novel strategies to disease management and control.To identify human genomic loci with evidence of linkage to tuberculosis susceptibility and, within these loci, to identify individual genes influencing tuberculosis susceptibility.Affected sibling pair analysis in South African and Malawian populations. Independent case-control study in West Africa.Two novel putative loci for tuberculosis susceptibility are identified: chromosome 6p21-q23 and chromosome 20q13.31-33--the latter with the strongest evidence for any locus reported to date in human tuberculosis (single point LOD score of 3.1, P = 10(-4), with a maximum likelihood score [MLS] of 2.8). An independent, multistage genetic association study in West African populations mapped this latter region in detail, finding evidence that variation in the melanocortin 3 receptor (MC3R) and cathepsin Z (CTSZ) genes play a role in the pathogenesis of tuberculosis.These results demonstrate how a genomewide approach to the complex phenotype of human tuberculosis can identify novel targets for further research.