tbuckley/cabot-search huggingface dataset:
Regulation of Lymphocyte Apoptosis by Interferon Regulatory Factor 4 (IRF-4)
Authors: Jessica C. Fanzo, Chuan-Min Hu, So Young Jang, Alessandra B. Pernis
Journal: The Journal of Experimental Medicine (2003)

To ensure that homeostasis of the immune system is maintained, the sensitivity of lymphocytes to Fas-mediated apoptosis is differentially regulated during their activation. The molecular mechanisms that link the activation program of lymphocytes to changes in sensitivity to Fas-mediated apoptosis have, however, not been fully characterized. In these studies, we have investigated whether Fas-mediated apoptosis can be regulated by interferon regulatory factor 4 (IRF-4), a lymphoid-restricted member of the IRF family of transcription factors. IRF-4 expression is upregulated during lymphocyte activation and IRF-4–deficient mice have defects in both lymphocyte activation and homeostasis. Here, we show that stable expression of IRF-4 in a human lymphoid cell line that normally lacks IRF-4 leads to a significantly enhanced apoptotic response on Fas receptor engagement. A systematic examination of the downstream effectors of Fas signaling in IRF-4–transfected cells demonstrates an increased activation of caspase-8, as well as an increase in Fas receptor polarization. We demonstrate that IRF-4–deficient mice display defects in activation-induced cell death, as well as superantigen-induced deletion, and that these defects are accompanied by impairments in Fas receptor polarization. These data suggest that IRF-4, by modulating the efficiency of the Fas-mediated death signal, is a novel participant in the regulation of lymphoid cell apoptosis.
Maintenance Therapy for Advanced Non-small Cell Lung Cancer: Current Status, Controversies, and Emerging Consensus
Authors: Taofeek K. Owonikoko, Suresh S. Ramalingam, Chandra P. Belani
Journal: Clinical Cancer Research (2010)

Maintenance therapy refers to the use of an active therapeutic agent for extended duration following frontline induction therapy for patients with advanced stage non-small cell lung cancer (NSCLC). Multiple clinical trials reported within the last few months have shown a beneficial role for maintenance therapy especially in select patient groups characterized by histology and/or molecular profile. With the recent approval by the U.S. Food and Drug Administration and European Medicines Agency of pemetrexed for maintenance therapy, a new treatment paradigm has been introduced to the treatment of NSCLC. This article reviews recent data with maintenance therapy in advanced NSCLC and discusses the implications for routine patient care and future drug development.
Impact of Atrial Fibrillation on the Diagnostic Performance of B-Type Natriuretic Peptide Concentration in Dyspneic Patients
Authors: Cathrine Wold Knudsen, Torbjørn Omland, Paul Clopton, Arne Westheim, Alan H.B. Wu, Philippe Duc, James McCord, Richard M. Nowak, Judd E. Hollander, Alan B. Storrow, William T. Abraham, Peter A. McCullough, Alan Maisel
Journal: Journal of the American College of Cardiology (2005)
Pathogenic Mechanisms of HIV Disease
Authors: Susan Moir, Tae-Wook Chun, Anthony S. Fauci
Journal: Annual Review of Pathology Mechanisms of Disease (2011)

Human immunodeficiency virus (HIV) infection is generally characterized by inefficient viral transmission; an acute phase of intense viral replication and dissemination to lymphoid tissues; a chronic, often asymptomatic phase of sustained immune activation and viral replication; and an advanced phase of marked depletion of CD4(+) T cells that leads to acquired immune deficiency syndrome. Major insight into HIV transmission and each phase of infection has been gained from studies on blood and tissue specimens obtained from HIV-infected individuals, as well as from animal and ex vivo models. Not only has the introduction of effective antiretroviral therapy greatly diminished the morbidity and mortality associated with HIV disease progression, it has also provided new avenues of research toward delineating the mechanisms of HIV-induced pathogenesis. Further advances in therapeutics and informative technologies, combined with a better understanding of the immunologic and virologic components of HIV disease, hold promise for new preventative and even curative strategies.
Incidence of the coexistence of left ventricular false tendons and premature ventricular contractions in apparently healthy subjects.
Authors: M Suwa, Y Hirota, H Nagao, M Kino, K Kawamura
Journal: Circulation (1984)

The incidence of the coexistence of left ventricular false tendons and premature ventricular contractions (PVCs) was evaluated prospectively. Over 14 months, left ventricular false tendons were found in 71 (6.4%) of 1117 consecutive patients examined echocardiographically. Two types of false tendons were observed: longitudinal, from the ventricular septum to the posteroapical wall (n = 62), and transverse, between the septum and the lateral wall (n = 9). Among 62 patients with PVCs and no underlying heart disease, false tendons were detected in 35 (56%); 28 had unifocal and seven had bifocal PVCs. Episodes of ventricular tachycardia were documented in one of the 28 patients with unifocal PVCs and in one of the seven patients with bifocal PVCs. These PVCs were poorly controlled by antiarrhythmic drugs but easily suppressed by exercise. Left ventricular false tendons were detected in 36 patients on routine echocardiographic examinations performed in the other 1055 subjects, and 10 of these patients were judged to have no underlying heart disease. PVCs were detected in two (20%) of these 10 patients. Although a definite conclusion that left ventricular false tendons are arrhythmogenic cannot be derived from these results, the unexpectedly high incidence of the coexistence suggests that left ventricular false tendons may be an etiologic factor in the development of PVCs, especially the rate-dependent and medically uncontrollable PVCs seen in apparently healthy individuals.
Elevated circulating cardiac troponin I in patients with cirrhosis
Authors: Dominique Pateron, Pascale Beyne, Thierry Laperche, Damien Logeard, Pascale Lefilliatre, Philippe Sogni, Richard Moreau, Philippe Langlet, Annie Elman, Jacques Bernuau, Dominique Valla, Serge Erlinger, Didier Lebrec
Journal: Hepatology (1999)

It has been shown that certain patients with cirrhosis have asymptomatic cardiac abnormalities that have not yet been explained. Thus, cardiac troponin I, a specific marker of myocardial injury, has been measured in patients with cirrhosis without previous cardiac disease. Thirty–two consecutive patients (age 49 ± 11) with cirrhosis and normal ECG were selected, 22 of which were alcoholic. Hemodynamic investigations were performed. Left ventricular function and mass were evaluated by echocardiography. Serum creatine kinase MB mass, myoglobin, and cardiac troponin I concentrations were measured. Cardiac troponin I concentrations were elevated in 10 patients (32%) (range 0.06–0.25 μg/L) whereas creatine kinase MB mass and myoglobin were normal in all patients. Abnormal troponin I values were not related to the severity of cirrhosis, to the degree of portal hypertension, or to other hemodynamic values. In contrast, elevated serum cardiac troponin I concentrations were related to a decreased stroke–volume index ( P &lt; .05) and a decreased left ventricular mass ( P &lt; .05). These results show a high prevalence of slightly elevated serum cardiac troponin I in patients with cirrhosis, especially in those with alcoholic cirrhosis. Elevated troponin I is associated with subclinical left ventricular myocardial damage. These findings may be linked to a lack of left ventricular adaptation in certain patients with cirrhosis and alcoholic cardiomyopathy.
Complete cystic fibrosis transmembrane conductance regulator gene sequencing in patients with idiopathic chronic pancreatitis and controls
Authors: F U Weiss
Journal: Gut (2005)

Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene-many of which cause cystic fibrosis-have also been reported in patients with chronic pancreatitis. The authors examine whether mild or severe CFTR mutations, homozygous or compound heterozygous CFTR mutations, or even simple cystic fibrosis carrier status alone increases the risk of developing pancreatitis.After exclusion of patients with trypsinogen (PRSS1) mutations, cystic fibrosis, or pulmonary disease, and with known risk factors for pancreatitis 67 patients with idiopathic chronic pancreatitis (ICP) from northwest Germany and 60 geographically and ethnically matched controls were recruited. The entire coding region of the CFTR gene was sequenced in all patients and controls. ICP patients were also analysed for serine protease inhibitor Kazal type 1 (SPINK1) gene mutations.Abnormal CFTR alleles were found to be twice as frequent in ICP patients as in controls (25/134 v 11/120; p<0.05). Three of four severe CFTR mutations detected in patients were compound heterozygous with another abnormal CFTR allele, whereas among controls three severe CFTR mutations were found in heterozygous cystic fibrosis carriers. In ICP patients 19 uncommon/mild mutations, including combinations of the 5T allele with 12TG repeats, were identified compared with only five in controls (p = 0.012). Heterozygous SPINK1 mutations were detected in eight ICP patients (15% v 1% in controls) but only one also carried an additional mild CFTR mutation.These data show that not only compound heterozygosity, but also cystic fibrosis carrier status for different types of CFTR mutations, including uncommon/mild mutations, significantly increase the risk of developing pancreatitis. Although 45% of the study's ICP patients carried predisposing genetic risk factors (for example, mutations in CFTR or SPINK1), the authors found no evidence that the risk conveyed by CFTR mutations depends on co-inherited SPINK1 mutations.
Virulence genes of clinical Vibrio cholerae O1 isolates in Thailand and their ribotypes
Authors: Pramuan Tapchaisri, Mathukorn Na-Ubol, Jirayut Jaipaew, Potjanee Srimanote, Manas Chongsa-nguan, Shinji Yamasaki, Hideo Hayashi, G. Balakrish Nair, Hisao Kurazono, Wanpen Chaicumpa
Journal: Journal of Infection (2007)
Support the opposition to force feeding of hunger strikers in Israel
Authors: M. Porter, D. McCoy, C. Katona, I. Chalmers, F. Arnold
Journal: BMJ (2014)

The Israeli parliament, the Knesset, is set to vote on an amendment to its Prisons Act mandating doctors to force feed mentally competent prisoners on hunger strikes.1 The proposed amendment is a response to a mass hunger strike staged by Palestinian detainees against their internment without trial (“administrative detention”).

Force feeding of hunger strikers is …
Hypocomplementaemic urticarial vasculitis associated with Jaccoud's syndrome
Authors: O. ISHIKAWA, Y. MIYACHI, H. WATANABE
Journal: British Journal of Dermatology (1997)

We report a 33-year-old Japanese man diagnosed as having hypocomplementaemic urticarial vasculitis at the age of 21, who subsequently developed Jaccoud's syndrome. Although Jaccoud's syndrome has been most frequently seen in patients with systemic lupus erythematosus, an association with other diseases has occasionally been described. Jaccoud's syndrome clinically shows joint deformities similar to rheumatoid arthritis, and needs to be differentiated from it. Patients with hypocomplementaemic urticarial vasculitis may develop Jaccoud's syndrome.
IBS with intestinal microbial dysbiosis: a new and clinically relevant subgroup?
Authors: Magnus Simrén
Journal: Gut (2014)

Symptoms compatible with IBS, that is, abdominal pain and discomfort, bloating, abdominal distention and an erratic bowel function, are very common reasons for GI consultations in primary care1 and patients with IBS are one of the most frequent patient categories in gastroenterology outpatient clinics.2 Despite being very common and in spite of considerable research effort during the last decades, the pathophysiology of IBS is still considered to be complex and incompletely understood3 ,4 and even though our understanding of this disabling condition arguably has increased tremendously, we still cannot use knowledge from pathophysiology studies to subgroup IBS patients in a clinically meaningful way. In everyday clinical work, we still rely on subgrouping patients based on the predominant bowel habit when we decide how to manage and treat the patients.5 Even though we have new pharmacological treatment options targeting specific molecules in the GI tract,6–9 only a subset of patients will respond favourably when we choose patients based on the current imperfect system to subgroup patients, that is, into patients with predominant diarrhoea, constipation or mixed bowel habit.5 Ideally, clinical subgrouping based on the underlying pathophysiology should have the potential to lead to targeted …
A Pathogenic Role for c-Jun Amino-Terminal Kinase Signaling in Renal Fibrosis and Tubular Cell Apoptosis
Authors: Frank Y. Ma, Robert S. Flanc, Greg H. Tesch, Yingjie Han, Robert C. Atkins, Brydon L. Bennett, Glenn C. Friedman, Jui-Hsiang Fan, David J. Nikolic-Paterson
Journal: Journal of the American Society of Nephrology (2007)

Renal fibrosis and tubular apoptosis are common mechanisms of progressive kidney disease. In vitro studies have implicated the c-Jun amino-terminal kinase (JNK) pathway in these processes. Both of the major JNK isoforms, JNK1 and JNK2, are expressed in the kidney, but their relative contribution to JNK signaling is unknown. This study investigated the role of JNK signaling in renal fibrosis and tubular apoptosis in the unilateral ureteral obstruction model using two different approaches: (1) Mice that were deficient in either JNK1 or JNK2 and (2) a specific inhibitor of all JNK isoforms, CC-401. Western blotting and immunostaining identified a marked increase in JNK signaling in the obstructed kidney, with substantial redundancy between JNK1 and JNK2 isoforms. Administration of CC-401 blocked JNK signaling in the rat obstructed kidney and significantly inhibited renal fibrosis in terms of interstitial myofibroblast accumulation and collagen IV deposition. This effect was attributed to suppression of gene transcription for the profibrotic molecules TGF-beta1 and connective tissue growth factor. CC-401 treatment also significantly reduced tubular apoptosis in the obstructed kidney. Genetic deletion of JNK1 or JNK2 did not protect mice from renal fibrosis in the unilateral ureteral obstruction model, but JNK1 deletion did result in a significant reduction in tubular cell apoptosis. In conclusion, this is the first study to demonstrate that JNK signaling plays a pathogenic role in renal fibrosis and tubular apoptosis. Furthermore, JNK1 plays a nonredundant role in tubular cell apoptosis. These studies identify the JNK pathway as a potential therapeutic target in progressive kidney disease.
Diaphragm strength in acute systemic lupus erythematosus in a patient with paradoxical abdominal motion and reduced lung volumes
Authors: P Hawkins
Journal: Thorax (2001)

Diaphragmatic weakness is reported as a common feature of the shrinking lung syndrome of systemic lupus erythematosus (SLE). However, in chronic stable SLE it has been shown that, despite poor performance of voluntary tests of diaphragm strength, twitch pressures obtained by stimulating the phrenic nerves are normal. We present a patient with acute SLE and pulmonary involvement who, despite having paradoxical abdominal motion and low maximal inspiratory pressures during voluntary manoeuvres, had normal diaphragm strength when assessed with magnetic stimulation of the phrenic nerves. Following immunosuppressive therapy symptoms and lung function improved, yet diaphragm contractility remained normal and unchanged. We suggest that this case supports the view that reduced diaphragm muscle contractility per se does not explain the small volume lungs and respiratory symptoms in patients with acute SLE.
Risk of endometrial, ovarian and breast cancer in women with polycystic ovary syndrome: a systematic review and meta-analysis
Authors: John A. Barry, Mallika M. Azizia, Paul J. Hardiman
Journal: Human Reproduction Update (2014)

Polycystic ovary syndrome (PCOS) is a common condition affecting ∼8% of women. The objective of the present study was to quantify separately the risk of endometrial cancer, ovarian cancer and breast cancer in women with PCOS compared with non-PCOS controls, and quantify separately the risk to women of all ages as well as the risk to premenopausal women.We conducted a systematic review and meta-analysis of observational studies. Studies were eligible for inclusion if they compared women with PCOS to non-PCOS groups for fatal or non-fatal gynaecological cancers. Studies listed in MEDLINE and EMBASE published up to 7 October 2013 in any language were identified, and relevant papers were also searched by hand. Relevant data (for example, study design, source of control data, diagnostic criteria) were extracted and tabulated.From 698 references, 11 studies (5 of endometrial cancer and 3 each of ovarian and breast cancer) met the inclusion criteria for the meta-analysis (919 women with PCOS and 72054 non-PCOS controls). Using the Mantel-Haenszel method, with fixed or random effects model as appropriate, women with PCOS were at a significantly increased risk of endometrial cancer (odds ratio (OR), 2.79; 95% confidence interval (CI), 1.31-5.95, P < 0.008), but the risk of ovarian and breast cancers was not significantly increased (OR, 1.41; 95% CI, 0.93-2.15, P < 0.11 and OR, 0.95; 95% CI, 0.64-1.39, P < 0.78, respectively). However when studies which included women aged over 54 years were excluded from the analysis, the risk for women with PCOS increased further for endometrial cancer (OR, 4.05; 95% CI, 2.42-6.76, P < 0.00001), became significantly increased for ovarian cancer (OR, 2.52; 95% CI, 1.08-5.89, P < 0.03), but remained non-significant for breast cancer (OR, 0.78; 95% CI, 0.46-1.32, P < 0.35).This is the first meta-analysis to examine gynaecological cancers in women with PCOS younger than 54 years of age compared with controls of similar age. Current data suggest that women of all ages with PCOS are at an increased risk of endometrial cancer but the risk of ovarian and breast cancer was not significantly increased overall. These results highlight the potential risk of gynaecological cancer morbidities associated with PCOS. However, the available evidence is far from robust and variation in diagnostic criteria for PCOS, associated risk factors (particularly obesity), and selection bias in the studies may have resulted in an exaggeration of the increased risk. Furthermore, women who have PCOS should also be made aware that any increased risk for endometrial cancer must be judged in the context of its relatively low incidence in the general population. A large well-controlled prospective study is required in order to gain a more accurate estimate of the risk of gynaecological cancers in women with PCOS.CRD42012003500.
EPIDEMIOLOGICAL STUDIES OF HEALTH EFFECTS OF WATER FROM DIFFERENT SOURCES
Authors: R. Masironi, A. G. Shaper
Journal: Annual Review of Nutrition (1981)

WATER HARDNESS AND CARDIOVASCULAR DISEASES   . Cardiovascular Mortality and Hardness of Drinking Water   . Water Components and Their Significance to Human Health   . Calcium   . Magnesium   . Sodium   . Chromium   . Lithium   . Iodine   . Fluorine   . Silicon   . Cadmium .• ••••  Other Variables   . Climate   . Latitude and temperature   . Epidemiological Plausibility of the Water Story   .. Conclusions   . BRITISH REGIONAL HEART STUDY: GEOGRAPHIC VARIATIONS IN CARDIOVASCULAR MORTALITY, AND THE ROLE OF WATER QUALITY     ......... ... .. . .. .   .. . . . .. ....... . Introduction   . Phase 1 Data   .
The Effect of Age on the Efficacy of Maintenance Bacillus Calmette-Guérin Relative to Maintenance Epirubicin in Patients with Stage Ta T1 Urothelial Bladder Cancer: Results from EORTC Genito-Urinary Group Study 30911
Authors: Jorg R. Oddens, Richard J. Sylvester, Maurizio A. Brausi, Wim J. Kirkels, Cees van de Beek, George van Andel, Theo M. de Reijke, Stephen Prescott, J. Alfred Witjes, Willem Oosterlinck
Journal: European Urology (2014)
Tumor-Specific Inhibition of Membrane-Bound Complement Regulatory Protein Crry with Bispecific Monoclonal Antibodies Prevents Tumor Outgrowth in a Rat Colorectal Cancer Lung Metastases Model
Authors: Kyra A. Gelderman, Peter J. K. Kuppen, Noriko Okada, Gert Jan Fleuren, Arko Gorter
Journal: Cancer Research (2004)

Abstract Membrane-bound complement regulatory proteins (mCRP) inhibit complement-mediated tumor cell eradication in vitro and in vivo. Immunotherapy of cancer with monoclonal antibodies (mAbs) that activate complement might be hampered by expression of mCRP on tumor cells. An important strategy to improve mAb immunotherapy can be blocking or overwhelming mCRP at the tumor cells surface in a tumor-specific manner. In our study, we investigated the feasibility of this approach in vivo using bispecific mAbs (bi-mAbs). This study, performed in a syngeneic lung metastases model of rat (WAG/Rij) colorectal cancer, showed that modulation of mCRP on tumor cells resulted in significantly decreased tumor outgrowth. Opsonization of tumor cells with a bi-mAb directed against a tumor-associated antigen and rat mCRP Crry (MG42a*5I2) almost completely prevented the outgrowth of lung tumors (0–7 tumors/rat; n = 17). Opsonization with mAb-cobra venom factor conjugates significantly reduced the number of lung tumors (23–59 tumors; n = 12) compared with the unconjugated MG42a (175–246 tumors; n = 17; P = 0.008 and 0.014, respectively). The effect of MG42a*5I2 was shown to be caused by increased complement activation due to inhibition of Crry. Moreover, prophylactic treatment with MG42a*5I2 or MG42a showed comparable results (3–24 and 215–472 tumors, P = 0.02; n = 6) as observed with pre-opsonized tumor cells without noticeable side effects, despite binding of MG42a*5I2 to endothelium and leukocytes. These results demonstrate that Crry inhibits complement-mediated tumor cell eradication by immunotherapeutic mAbs and show that tumor-specific inhibition of complement regulatory proteins using bi-mAbs can significantly improve mAb-mediated immunotherapy.