tbuckley/cabot-search huggingface dataset:
c-Src Modulates Estrogen-Induced Stress and Apoptosis in Estrogen-Deprived Breast Cancer Cells
Authors: Ping Fan, Obi L. Griffith, Fadeke A. Agboke, Pavana Anur, Xiaojun Zou, Russell E. McDaniel, Karen Creswell, Sung Hoon Kim, John A. Katzenellenbogen, Joe W. Gray, V. Craig Jordan
Journal: Cancer Research (2013)

The emergence of anti-estrogen resistance in breast cancer is an important clinical phenomenon affecting long-term survival in this disease. Identifying factors that convey cell survival in this setting may guide improvements in treatment. Estrogen (E2) can induce apoptosis in breast cancer cells that have been selected for survival after E2 deprivation for long periods (MCF-7:5C cells), but the mechanisms underlying E2-induced stress in this setting have not been elucidated. Here, we report that the c-Src kinase functions as a key adapter protein for the estrogen receptor (ER, ESR1) in its activation of stress responses induced by E2 in MCF-7:5C cells. E2 elevated phosphorylation of c-Src, which was blocked by 4-hydroxytamoxifen (4-OHT), suggesting that E2 activated c-Src through the ER. We found that E2 activated the sensors of the unfolded protein response (UPR), IRE1α (ERN1) and PERK kinase (EIF2AK3), the latter of which phosphorylates eukaryotic translation initiation factor-2α (eIF2α). E2 also dramatically increased reactive oxygen species production and upregulated expression of heme oxygenase HO-1 (HMOX1), an indicator of oxidative stress, along with the central energy sensor kinase AMPK (PRKAA2). Pharmacologic or RNA interference-mediated inhibition of c-Src abolished the phosphorylation of eIF2α and AMPK, blocked E2-induced ROS production, and inhibited E2-induced apoptosis. Together, our results establish that c-Src kinase mediates stresses generated by E2 in long-term E2-deprived cells that trigger apoptosis. This work offers a mechanistic rationale for a new approach in the treatment of endocrine-resistant breast cancer.
Nitrite activates protein kinase A in normoxia to mediate mitochondrial fusion and tolerance to ischaemia/reperfusion
Authors: Christelle Kamga Pride, Li Mo, Kelly Quesnelle, Ruben K. Dagda, Daniel Murillo, Lisa Geary, Catherine Corey, Rafael Portella, Sergey Zharikov, Claudette St Croix, Salony Maniar, Charleen T. Chu, Nicholas K. H. Khoo, Sruti Shiva
Journal: Cardiovascular Research (2013)

Nitrite (NO2–), a dietary constituent and nitric oxide (NO) oxidation product, mediates cardioprotection after ischaemia/reperfusion (I/R) in a number of animal models when administered during ischaemia or as a pre-conditioning agent hours to days prior to the ischaemic episode. When present during ischaemia, the reduction of nitrite to bioactive NO by deoxygenated haem proteins accounts for its protective effects. However, the mechanism of nitrite-induced pre-conditioning, a normoxic response which does not appear to require reduction of nitrite to NO, remains unexplored. Using a model of hypoxia/reoxygenation (H/R) in cultured rat H9c2 cardiomyocytes, we demonstrate that a transient (30 min) normoxic nitrite treatment significantly attenuates cell death after a hypoxic episode initiated 1 h later. Mechanistically, this protection depends on the activation of protein kinase A, which phosphorylates and inhibits dynamin-related protein 1, the predominant regulator of mitochondrial fission. This results morphologically, in the promotion of mitochondrial fusion and functionally in the augmentation of mitochondrial membrane potential and superoxide production. We identify AMP kinase (AMPK) as a downstream target of the mitochondrial reactive oxygen species (ROS) generated and show that its oxidation and subsequent phosphorylation are essential for cytoprotection, as scavenging of ROS prevents AMPK activation and inhibits nitrite-mediated protection after H/R. The protein kinase A-dependent protection mediated by nitrite is reproduced in an intact isolated rat heart model of I/R. These data are the first to demonstrate nitrite-dependent normoxic modulation of both mitochondrial morphology and function and reveal a novel signalling pathway responsible for nitrite-mediated cardioprotection.
Primary ciliary dyskinesia: diagnosis and standards of care
Authors: A Bush, P Cole, M Hariri, I Mackay, G Phillips, C O'Callaghan, R Wilson, JO Warner
Journal: European Respiratory Journal (1998)

Primary ciliary dyskinesia (PCD) is characterized by disease of the upper and lower respiratory tract, in association with visceral mirror image arrangement in 50% of cases, due to abnormal structure and/or function of cilia. The purpose of this paper is to review the clinical features, diagnosis and management of PCD. Presentations include neonatal respiratory distress, recurrent lower respiratory tract infection, chronic rhinosinusitis and male infertility. PCD enters the differential diagnosis of bronchiectasis, atypical asthma, and unusually severe upper airway disease. Diagnosis is by a cascade of investigations, starting with the saccharin test in patients older than 10 yrs; ciliary beat frequency and pattern on light microscopy; and electron microscopy to assess ciliary morphology and orientation. It is important not to confuse primary and secondary ciliary abnormalities. Nasal nitric oxide is low in PCD, and this measurement shows promise as a screening test for PCD. Diagnosis is important, in order to prevent the development of bronchiectasis and to avoid any unnecessary otorhinolaryngological procedures. Regular follow-up is essential, and management should be multidisciplinary, with input from centres with a special interest in PCD, having access to paediatric and adult chest physicians, otolaryngologists and audiological physicians, physiotherapists, counselling services and fertility clinics. The prognosis is good, but morbidity can be considerable if PCD is incorrectly managed.
Recipient body size and cadaveric renal allograft survival.
Authors: H I Feldman, I Fazio, D Roth, J A Berlin, K Brayman, J E Burns, R A Grossman
Journal: Journal of the American Society of Nephrology (1996)

Transplantation of renal allografts inadequate to meet recipient metabolic demands has been hypothesized to be one cause of chronic allograft failure. This cohort study examined the relationship of each of three measures of recipient body size and one measure of recipient metabolic rate to the rate of allograft failure among 239 recipients of cadaveric renal allografts between 1985 and 1990. All subjects were followed until allograft failure, death, or December 31, 1992, whichever occurred first. Using multivariate Cox proportional hazards analysis, all measures of recipient size and metabolic rate were found to be strong and statistically significant predictors of allograft survival adjusted for other predictors of allograft survival including allograft rejection, delayed allograft function, recipient race, prior renal transplantation, and donor age. The adjusted relative risk (RR) of allograft failure for a 15-kg increase in recipient body weight was 1.47, P < 0.0001 (95% confidence interval (CI), 1.21-1.78); adjusted RR for a 10-U increase in recipient body mass index was 2.34, P < 0.0001 (95% CI, 1.53-3.58); adjusted RR for a 0.5 m2 increase in recipient body surface area was 2.34, P < 0.001 (95% CI, 1.40-3.91); and adjusted RR for a 250 Kcal increase in metabolic rate was 1.49, P < 0.01 (95% CI, 1.17-1.89). These results are consistent with prior research indicating that a renal tissue supply-demand mismatch may accelerate failure of renal allografts. Alternative explanations of this relationship between recipient body size and allograft survival include inadequate immunosuppressive medication administration among recipients with a larger body size. Additional research is warranted to examine more fully the relationship between recipient body size and allograft survival.
The tight junction protein CAR regulates cardiac conduction and cell–cell communication
Authors: Ulrike Lisewski, Yu Shi, Uta Wrackmeyer, Robert Fischer, Chen Chen, Alexander Schirdewan, Rene Jüttner, Fritz Rathjen, Wolfgang Poller, Michael H. Radke, Michael Gotthardt
Journal: The Journal of Experimental Medicine (2008)

The Coxsackievirus-adenovirus receptor (CAR) is known for its role in virus uptake and as a protein of the tight junction. It is predominantly expressed in the developing brain and heart and reinduced upon cardiac remodeling in heart disease. So far, the physiological functions of CAR in the adult heart are largely unknown. We have generated a heart-specific inducible CAR knockout (KO) and found impaired electrical conduction between atrium and ventricle that increased with progressive loss of CAR. The underlying mechanism relates to the cross talk of tight and gap junctions with altered expression and localization of connexins that affect communication between CAR KO cardiomyocytes. Our results indicate that CAR is not only relevant for virus uptake and cardiac remodeling but also has a previously unknown function in the propagation of excitation from the atrium to the ventricle that could explain the association of arrhythmia and Coxsackievirus infection of the heart.
Classical Cyclophosphamide, Methotrexate, and Fluorouracil Chemotherapy Is More Effective in Triple-Negative, Node-Negative Breast Cancer: Results From Two Randomized Trials of Adjuvant Chemoendocrine Therapy for Node-Negative Breast Cancer
Authors: Marco Colleoni, Bernard F. Cole, Giuseppe Viale, Meredith M. Regan, Karen N. Price, Eugenio Maiorano, Mauro G. Mastropasqua, Diana Crivellari, Richard D. Gelber, Aron Goldhirsch, Alan S. Coates, Barry A. Gusterson
Journal: Journal of Clinical Oncology (2010)

Retrospective studies suggest that primary breast cancers lacking estrogen receptor (ER) and progesterone receptor (PR) and not overexpressing human epidermal growth factor receptor 2 (HER2; triple-negative tumors) are particularly sensitive to DNA-damaging chemotherapy with alkylating agents.Patients enrolled in International Breast Cancer Study Group Trials VIII and IX with node-negative, operable breast cancer and centrally assessed ER, PR, and HER2 were included (n = 2,257). The trials compared three or six courses of adjuvant classical cyclophosphamide, methotrexate, and fluorouracil (CMF) with or without endocrine therapy versus endocrine therapy alone. We explored patterns of recurrence by treatment according to three immunohistochemically defined tumor subtypes: triple negative, HER2 positive and endocrine receptor absent, and endocrine receptor present.Patients with triple-negative tumors (303 patients; 13%) were significantly more likely to have tumors > 2 cm and grade 3 compared with those in the HER2-positive, endocrine receptor-absent, and endocrine receptor-present subtypes. No clear chemotherapy benefit was observed in endocrine receptor-present disease (hazard ratio [HR], 0.90; 95% CI, 0.74 to 1.11). A statistically significantly greater benefit for chemotherapy versus no chemotherapy was observed in triple-negative breast cancer (HR, 0.46; 95% CI, 0.29 to 0.73; interaction P = .009 v endocrine receptor-present disease). The magnitude of the chemotherapy effect was lower in HER2-positive endocrine receptor-absent disease (HR, 0.58; 95% CI, 0.29 to 1.17; interaction P = .24 v endocrine receptor-present disease).The magnitude of benefit of CMF chemotherapy is largest in patients with triple-negative, node-negative breast cancer.
OC-013 Hospital attendances after outpatient colonoscopy: the hidden healthcare burden?: Abstract OC-013 Table 1
Authors: S Stevens, L Sergot, J Mawdsley, C E Collins, I Beveridge, K Sundaram, K J Monahan
Journal: Gut (2012)

<h3>Introduction</h3> With the introduction of national bowel cancer screening and increased surveillance, colonoscopy is being increasingly used as both a diagnostic and therapeutic tool. It is deemed a relatively safe procedure with the overall complication rate being reported at approximately 0.1%. However, it was recently reported in a study from the USA that procedure related hospital attendances within 14 days of colonoscopy were as high as 0.84%.<sup>1</sup> <h3>Methods</h3> The aim of this study was to identify the true morbidity and related healthcare costs after outpatient colonoscopy in a UK population. We performed an observational study of hospital visits occurring within 14 days of colonoscopy at West Middlesex University Hospital, London. We collected data from 2011, using the hospitals9 electronic records system, enterpriseCAMIS®. Cases meeting the predetermined criteria were analysed to assess whether presentations could be attributed to the colonoscopy, and overall healthcare costs were determined. <h3>Results</h3> Over the 12-month period, 1115 outpatient colonoscopies were performed; the Abstract OC-013 table 1 below summarises the number of hospital visits occurring within 14 days and associated healthcare costs. Of the 1115 colonoscopies performed, there were 22 visits to the A&amp;E department within 14 days; 14 of these visits were procedure-related, with five requiring admission. Abdominal pain was the commonest reason for emergency attendance, with bleeding, perforation, post-polypectomy syndrome, sedation and other gastro-intestinal causes accounting for the remaining. The average cost for patients attending A&amp;E was £145; £3338 for those requiring admission; working out as a total cost of £18 720 over the 12-month period. <h3>Conclusion</h3> Outpatient colonoscopy is an essential diagnostic and therapeutic tool. However, data on the overall morbidity burden is limited. With a 1.25% incidence of emergency attendances within 14 days of colonoscopy and significant associated healthcare costs, this study supports recently published data from the USA and highlights the importance of recognising these complications within a UK population. <h3>Competing interests</h3> None declared. <h3>Reference</h3> 1. <b>Leffler</b>, <i>et al.</i> The incidence and cost of unexpected hospital use after scheduled outpatient endoscopy. <i>Arch Intern Med</i> 2010;<b>170</b>:1752–7.
ANTIGENIC RELATIONSHIP OF BRITISH SWINE INFLUENZA STRAINS TO STANDARD HUMAN AND SWINE INFLUENZA VIRUSES
Authors: N. Paul Hudson, M. Michael Sigel, F. S. Markham
Journal: The Journal of Experimental Medicine (1943)

The antigenic relationships of Type A (PR 8, WS) and Type B (Lee) human strains and the Shope and British (Cambridge, North Ireland) swine strains were studied by specific antiserum inhibition of chicken red cell agglutination by the influenza virus. The Cambridge and North Ireland strains were found to be closely related to the Type A strains and differentiated from the Shope virus. The distinctive antigenicity of the Lee strain of Type B was confirmed. Specific antibodies were developed in chickens following single intraperitoneal injections of influenza virus. Inhibition tests yielded results, in the antigenic analysis of the influenza viruses examined, comparable to those obtained with ferret antisera. Specific inhibition of hemagglutination by influenza virus proved an effective method for the study of strain relationships.
Loss of integrin 2 1 reduces tumour necrosis factor-dependent inflammatory cartilage destruction and matrix metalloproteinase expression through modulating extracellular signal-regulated kinase
Authors: M A Peters, S Strietholt, D Wendholt, S Frank, A Korb, G Kollias, B Eckes, T Pap
Journal: Annals of the Rheumatic Diseases (2010)

Integrins are the main receptors for cell-matrix interactions and integrin signalling is critical for a variety of cellular functions such as adhesion, cell spreading and inflammatory responses. α2β1 integrin functions as a major receptor for type I collagen on a number of different cells, including fibroblasts and inflammatory cells. Although α2-deficient mice appear normal apart from mild platelet dysfunction, it was shown that α2β1 integrin contributes to the induction of matrix metalloproteinases (MMPs) in tissue remodelling. Based on the hypothesis …
S100A1 Genetically Targeted Therapy Reverses Dysfunction of Human Failing Cardiomyocytes
Authors: Henriette Brinks, David Rohde, Mirko Voelkers, Gang Qiu, Sven T. Pleger, Nicole Herzog, Joseph Rabinowitz, Arjang Ruhparwar, Scott Silvestry, Carolin Lerchenmüller, Paul J. Mather, Andrea D. Eckhart, Hugo A. Katus, Thierry Carrel, Walter J. Koch, Patrick Most
Journal: Journal of the American College of Cardiology (2011)
A pilot study of fluticasone propionate in untreated coeliac disease.
Authors: H C Mitchison, H al Mardini, S Gillespie, M Laker, A Zaitoun, C O Record
Journal: Gut (1991)

Although gluten withdrawal is likely to remain the mainstay of treatment for adult coeliac disease, many patients find the diet inconvenient and unpalatable and compliance among asymptomatic patients is often poor. Oral corticosteroids have been used for patients who seem to be resistant to gluten withdrawal but preparations with low systemic bioavailability might be preferable. We have given a new glucocorticoid (fluticasone propionate) to 12 adults with untreated coeliac disease for six weeks while they were on a normal diet. One patient defaulted and one suffered a relapse in a pre-existing neoplasm. Excluding these, there was an improvement of symptoms, a mean weight gain of 2 kg, and a rise in albumin of 5.4 g/l. There was a significant improvement in the lactulose/mannitol excretion ratio (p less than 0.05) and in all histological variables examined in paired biopsy specimens (surface and crypt intraepithelial lymphocyte/enterocyte and goblet cell/enterocyte ratios and enterocyte height, p less than 0.01 or better). In six paired specimens sucrase and alkaline phosphatase activity increased in all (p less than 0.05) and lactase in five of six. No appreciable side effects were observed, but two patients had suppressed cortisol values and synacthen responses at six weeks. A further three, with normal pretrial results, had a blunted tetracosactrin response at six weeks. Fluticasone propionate seems worthy of further assessment in the treatment of coeliac disease as an adjunct to gluten withdrawal.
Chromosome 9p21 Variant Predicts Mortality After Coronary Artery Bypass Graft Surgery
Authors: Jochen D. Muehlschlegel, Kuang-Yu Liu, Tjörvi E. Perry, Amanda A. Fox, Charles D. Collard, Stanton K. Shernan, Simon C. Body
Journal: Circulation (2010)

Recent genome-wide association studies have identified several chromosome 9p21 single nucleotide polymorphisms associated with coronary artery disease and myocardial infarction in nonsurgical populations. We have recently demonstrated an independent association between these 9p21 variants and perioperative myocardial injury after isolated primary coronary artery bypass graft (CABG) surgery. This study investigated the association of a 9p21 variant with mortality in patients after CABG surgery and its prognostic value to improve the EuroSCORE.In a 2-center, prospective, observational study of 846 white primary CABG surgery patients, we genotyped rs10116277, the 9p21 variant with the strongest association to perioperative myocardial injury in our cohort. To estimate the utility of rs10116277 for predicting all-cause mortality within 5 years after surgery, a Cox proportional hazard model was constructed to estimate the hazard ratios (HR) and 95% confidence intervals (CI) while adjusting for demographics and clinical covariates. The homozygote minor allele of rs10116277 was associated with significantly increased risk of all-cause mortality even after adjusting for other clinical predictors of mortality in a Cox proportional hazards model (HR, 1.7; 95% CI, 1.1-2.7; P=0.026). Addition of rs10116277 to the logistic EuroSCORE also significantly improved model prediction for mortality (HR, 1.82; 95% CI, 1.15-2.88; P=0.01).The 9p21 variant rs10116277 is independently associated with all-cause mortality after primary CABG surgery in whites and significantly improves the predictive value of the logistic EuroSCORE. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00281164.
The effect of exemestane, anastrozole, and tamoxifen on lipid profiles in Japanese postmenopausal early breast cancer patients: final results of National Surgical Adjuvant Study BC 04, the TEAM Japan sub-study
Authors: Y. Hozumi, K. Suemasu, H. Takei, T. Aihara, M. Takehara, T. Saito, S. Ohsumi, N. Masuda, Y. Ohashi
Journal: Annals of Oncology (2011)
THE PROPERTIES OF T ANTIGENS EXTRACTED FROM GROUP A HEMOLYTIC STREPTOCOCCI
Authors: Rebecca C. Lancefield, Vincent P. Dole
Journal: The Journal of Experimental Medicine (1946)

1. T antigens of group A hemolytic streptococci have been obtained in soluble form by digestion of the bacterial cells with pepsin or trypsin. Large quantities of this antigen were readily extracted from type 1 strains, whereas only small amounts could be obtained from strains of other types. 2. The T antigen, prepared in this way from a type 1 strain, was partially purified by chemical precipitation and further enzymatic digestion. An active fraction, apparently protein in nature, was separated electrophoretically at pH 7.00. The separated material, pooled and analyzed at the same pH, gave only a single peak. The isoelectric point of this substance was about pH 4.50. An elementary analysis was obtained. Although the T antigen was resistant to digestion with proteolytic enzymes and ribonuclease, it was readily inactivated by heat, especially in acid media and in strong salt solutions. The serological activity of this purified T substance was lost after exposure to ultraviolet radiation. 3. Analysis by means of the ultracentrifuge showed that the material was polydisperse and therefore probably impure. 4. The soluble form of the T substance was active in the precipitin reaction, in the fixation of complement, in inhibition of T agglutination, and as an antigen when injected into rabbits. The antibodies produced did not protect mice against infection with virulent strains of hemolytic streptococci containing the same T antigen. 5. The immunological specificity of T antigen in soluble form is the same as that of the T antigen in the intact streptococcus from which it was derived.
Stimulus onset quenches neural variability: a widespread cortical phenomenon
Authors: Mark M. Churchland, Byron M. Yu, John P. Cunningham, Leo P. Sugrue, Marlene R. Cohen, Greg S. Corrado, William T. Newsome, Andrew M. Clark, Paymon Hosseini, Benjamin B. Scott, David C. Bradley, Matthew A. Smith, Adam Kohn, J. Anthony Movshon, Katherine M. Armstrong, Tirin Moore, Steve W. Chang, Lawrence H. Snyder, Stephen G. Lisberger, Nicholas J. Priebe, Ian M. Finn, David L Ferster, Stephen I. Ryu, Gopal Santhanam, Maneesh Sahani, Krishna V. Shenoy
Journal: Nature Neuroscience (2010)
Cardiac arrhythmias following pneumonectomy
Authors: J. Stougard
Journal: Thorax (1969)

A series of 260 patients who underwent pneumonectomy for cancer of the lung was analysed for post-operative arrhythmias. Of these patients 28% developed such arrhythmias, usually in the form of atrial fibrillation, on the first to third post-operative day, rapidly yielding to fast-acting digitalis preparations. Possible aetiological factors were investigated, but no single cause was demonstrable. The indication for pre-operative digitalization, if any, is discussed.