tbuckley/cabot-search huggingface dataset:
Gata-3 Induces T Helper Cell Type 2 (Th2) Cytokine Expression and Chromatin Remodeling in Committed Th1 Cells
Authors: Hyun Jun Lee, Naofumi Takemoto, Hirokazu Kurata, Yumiko Kamogawa, Shoichiro Miyatake, Anne O'Garra, Naoko Arai
Journal: The Journal of Experimental Medicine (2000)

Committed T helper type 1 (Th1) and Th2 effector cells, resulting from chronic antigenic stimulation in interleukin (IL)-12 and IL-4, are implicated in the pathology of autoimmune and allergic diseases. Committed Th1 cells cannot be induced to change their cytokine profiles in response to antigenic stimulation and Th2 cytokine–inducing conditions. Here, we report that ectopic expression of GATA-3 induced Th2-specific cytokine expression not only in developing Th1 cells but also in otherwise irreversibly committed Th1 cells and a Th1 clone, HDK1. Moreover, cAMP, an inhibitor of cytokine production by Th1 cells, markedly augmented Th2 cytokine production in GATA-3–expressing Th1 cells. Ectopic expression of GATA-3 in developing Th1 cells, but not in Th1 clone HDK1, induced endogenous GATA-3, suggesting an autoregulatory mechanism for maintenance of GATA-3 expression in Th2 cells. Structure–function analyses of GATA-3 revealed that the NH2-terminal transactivation domain and the COOH-terminal zinc finger domain of GATA-3 were critical, whereas the NH2-terminal zinc finger domain was dispensable for the induction of IL-4. Both zinc fingers, however, were required for IL-5 induction. A Th2-specific DNaseI-hypersensitive site of the IL-4 locus was detected in GATA-3–expressing Th1 cells. Thus, GATA-3 can change the phenotype of committed Th1 cells, previously considered to be irreversible.
Health watchdog criticises NHS helpline
Authors: S. Mayor
Journal: BMJ (2000)

England's health service helpline NHS Direct has been criticised in consumer research for providing callers with inconsistent advice. NHS Direct is a 24 hour telephone advice line first launched in 1998 and now covering over two thirds of the population of England. It was set up to provide fast advice and information on health issues or on the NHS. If patients call NHS Direct about specific symptoms they should be transferred by a call handler to a nurse who uses a computer package with guidelines on a range of conditions to prompt questions and assess what advice to give.

More than three million calls have been made to NHS Direct since it was launched. Researchers from the magazine Health Which? …
Purinergic Receptor Type 6 Contributes to Airway Inflammation and Remodeling in Experimental Allergic Airway Inflammation
Authors: Rodolfo Paula Vieira, Tobias Müller, Melanie Grimm, Volker von Gernler, Britta Vetter, Thorsten Dürk, Sanja Cicko, C. Korcan Ayata, Stephan Sorichter, Bernard Robaye, Robert Zeiser, Davide Ferrari, Andreas Kirschbaum, Gernot Zissel, J. Christian Virchow, Jean-Marie Boeynaems, Marco Idzko
Journal: American Journal of Respiratory and Critical Care Medicine (2011)

Extracellular nucleotides have recently been identified as proinflammatory mediators involved in asthma pathogenesis by signaling via purinergic receptors, but the role of the purinergic receptor type 6 (P2Y6R) has not been previously investigated.To investigate the role of P2Y6R in asthma pathogenesis.Acute and chronic OVA model and also HDM model of allergic inflammation in C57Bl/6 mice treated with specific P2Y6R antagonist and P2Y6R(-/-) mice were evaluated for classical features of asthmatic inflammation. In addition, primary epithelial cell culture from human and epithelial cell lines from mouse and human were stimulated with P2Y6R agonist and treated with P2Y6R antagonist and assessed for IL-6, IL-8/CXCL8 and KC levels. Experiments with P2Y6R(-/-) and P2Y6R(+/+) chimera were performed to discriminate the role of P2Y6R activation in structural lung cells and in cells from hematopoietic system.We observed that the intratracheal application of a P2Y6R antagonist (MRS2578) and P2Y6R deficiency inhibited cardinal features of asthma, such as bronchoalveolar lavage eosinophilia, airway remodeling, Th2 cytokine production, and bronchial hyperresponsiveness in the ovalbumin-alum model. MRS2578 was also effective in reducing airway inflammation in a model using house dust mite extracts to induce allergic lung inflammation. Experiments with bone marrow chimeras revealed the importance of the P2Y6R expression on lung structural cells in airway inflammation. In accordance with this finding, we found a strong up-regulation of P2Y6 expression on airway epithelial cells of animals with experimental asthma. Concerning the underlying mechanism, we observed that MRS2578 inhibited the release of IL-6 and IL-8/KC by lung epithelial cells in vivo, whereas intrapulmonary application of the P2Y6R agonist uridine-5'-diphosphate increased the bronchoalveolar levels of IL-6 and KC. In addition, selective activation of P2Y6 receptors induced the release of IL-6 and KC/IL-8 by murine and human lung epithelial cells in vitro.P2Y6R expression on airway epithelial cells is up-regulated during acute and chronic allergic airway inflammation, and selective blocking of P2Y6R or P2Y6R deficiency on the structural cells reduces cardinal features of experimental asthma. Thus, blocking pulmonary P2Y6R might be a target for the treatment of allergic airway inflammation.
Discovery and Characterization of Alamandine
Authors: Roberto Queiroga Lautner, Daniel C. Villela, Rodrigo A. Fraga-Silva, Neiva Silva, Thiago Verano-Braga, Fabiana Costa-Fraga, Joachim Jankowski, Vera Jankowski, Frederico Sousa, Andreia Alzamora, Everton Soares, Claudiane Barbosa, Frank Kjeldsen, Aline Oliveira, Janaina Braga, Silvia Savergnini, Gisele Maia, Antonio Bastos Peluso, Danielle Passos-Silva, Anderson Ferreira, Fabiana Alves, Almir Martins, Mohan Raizada, Renata Paula, Daisy Motta-Santos, Friederike Kemplin, Adriano Pimenta, Natalia Alenina, Ruben Sinisterra, Michael Bader, Maria Jose Campagnole-Santos, Robson A.S. Santos
Journal: Circulation Research (2013)

The renin-angiotensin system (RAS) is a key regulator of the cardiovascular system, electrolyte, and water balance. Here, we report identification and characterization of alamandine, a new heptapeptide generated by catalytic action of angiotensin-converting enzyme-2 angiotensin A or directly from angiotensin-(1-7).To characterize a novel component of the RAS, alamandine.Using mass spectrometry we observed that alamandine circulates in human blood and can be formed from angiotensin-(1-7) in the heart. Alamandine produces several physiological actions that resemble those produced by angiotensin-(1-7), including vasodilation, antifibrosis, antihypertensive, and central effects. Interestingly, our data reveal that its actions are independent of the known vasodilator receptors of the RAS, Mas, and angiotensin II type 2 receptor. Rather, we demonstrate that alamandine acts through the Mas-related G-protein-coupled receptor, member D. Binding of alamandine to Mas-related G-protein-coupled receptor, member D is blocked by D-Pro(7)-angiotensin-(1-7), the Mas-related G-protein-coupled receptor, member D ligand β-alanine and PD123319, but not by the Mas antagonist A-779. In addition, oral administration of an inclusion compound of alamandine/β-hydroxypropyl cyclodextrin produced a long-term antihypertensive effect in spontaneously hypertensive rats and antifibrotic effects in isoproterenol-treated rats. Alamandine had no noticeable proliferative or antiproliferative effect in human tumoral cell lines.The identification of these 2 novel components of the RAS, alamandine and its receptor, provides new insights for the understanding of the physiological and pathophysiological role of the RAS and may help to develop new therapeutic strategies for treating human cardiovascular diseases and other related disorders.
No H1N1 Detected in Children Admitted to Hospital with Asthma during the H1N1 Pandemic
Authors: Bircan Erbas, Molly O’Sullivan, Shyamali C. Dharmage, Julian Druce, Katrina J. Allen, Mimi L. K. Tang, Philip G. Bardin, Michael J. Abramson
Journal: American Journal of Respiratory and Critical Care Medicine (2012)
Sex Differences in 2-Year Mortality after Hospital Discharge for Myocardial Infarction
Authors: Viola Vaccarino, Harlan M. Krumholz, Jorge Yarzebski, Joel M. Gore, Robert J. Goldberg
Journal: Annals of Internal Medicine (2001)

An interaction between sex and age is thought to affect hospital mortality after myocardial infarction; younger, but not older, women have been shown to have higher mortality rates than men. It is currently unknown whether findings are similar after hospital discharge.To determine whether an interaction between sex and age affects 2-year mortality after myocardial infarction.Community-based prospective cohort study.16 community hospitals serving the Worcester, Massachusetts, metropolitan area.6826 patients who survived hospitalization for acute myocardial infarction during ten 1-year periods between 1975 and 1995.Mortality 2 years after hospital discharge.The overall 2-year mortality rate was higher in women (28.9%) than in men (19.6%). When patients were examined by age group, however, only women younger than 60 years of age had a higher mortality rate than men of similar age. The sex difference decreased with increasing age; among the oldest patients, women had a lower mortality rate than men (P = 0.009 for the interaction between sex and age). This relationship was not affected by adjustment for demographic characteristics and medical history, clinical characteristics, and hospital and discharge treatments; the hazard of 2-year death for women compared with men increased 15.4% (95% CI, 4.3% to 27.6%) for every 10-year decrease in age. In absolute terms, after adjustment for demographic characteristics and medical history, among patients younger than 60 years of age women were at greater risk than men (risk difference, 1.8 percentage points). At older ages, however, women were at lower risk than men.Younger, but not older, women who survive hospitalization for myocardial infarction have a higher long-term mortality rate than men. This provides additional evidence that younger women with myocardial infarction are at greater risk for death than men.
MicroRNA-7, a Homeobox D10 Target, Inhibits p21-Activated Kinase 1 and Regulates Its Functions
Authors: Sirigiri Divijendra Natha Reddy, Kazufumi Ohshiro, Suresh K. Rayala, Rakesh Kumar
Journal: Cancer Research (2008)

Abstract MicroRNAs are noncoding RNAs that inhibit the expression of their targets in a sequence-specific manner and play crucial roles during oncogenesis. Here we show that microRNA-7 (miR-7) inhibits p21-activated kinase 1 (Pak1) expression, a widely up-regulated signaling kinase in multiple human cancers, by targeting the 3′-untranslated region (UTR) of Pak1 mRNA. We noticed an inverse correlation between the levels of endogenous miR-7 and Pak1 expression in human cancer cells. We discovered that endogenous miR-7 expression is positively regulated by a homeodomain transcription factor, HoxD10, the loss of which leads to an increased invasiveness. HoxD10 directly interacts with the miR-7 chromatin. Accordingly, the levels of Pak1 protein are progressively up-regulated whereas those of miR-7 and its upstream activator HoxD10 are progressively down-regulated in a cellular model of breast cancer progression from low to highly invasive phenotypes. Furthermore, HoxD10 expression in highly invasive breast cancer cells resulted in an increased miR-7 expression but reduced Pak1 3′-UTR-luciferase activity and reduced Pak1 protein. Finally, we show that miR-7 introduction inhibits the motility, invasiveness, anchorage-independent growth, and tumorigenic potential of highly invasive breast cancer cells. Collectively, these findings establish for the first time that Pak1 is a target of miR-7 and that HoxD10 plays a regulatory role in modifying the expression of miR-7 and, consequently, the functions of the miR-7-Pak1 pathway in human cancer cells. [Cancer Res 2008;68(20):8195–200]
Chemotaxis Inhibitory Protein of <i>Staphylococcus aureus</i>, a Bacterial Antiinflammatory Agent
Authors: Carla J.C. de Haas, Karin Ellen Veldkamp, Andreas Peschel, Floor Weerkamp, Willem J.B. Van Wamel, Erik C.J.M. Heezius, Miriam J.J.G. Poppelier, Kok P.M. Van Kessel, Jos A.G. van Strijp
Journal: The Journal of Experimental Medicine (2004)

Leukocyte migration is a key event both in host defense against invading pathogens as well as in inflammation. Bacteria generate chemoattractants primarily by excretion (formylated peptides), complement activation (C5a), and subsequently through activation of leukocytes (e.g., leukotriene B4, platelet-activating factor, and interleukin 8). Here we describe a new protein secreted by Staphylococcus aureus that specifically impairs the response of neutrophils and monocytes to formylated peptides and C5a. This chemotaxis inhibitory protein of S. aureus (CHIPS) is a 14.1-kD protein encoded on a bacteriophage and is found in >60% of clinical isolates. CHIPS reduces the neutrophil recruitment toward C5a in a mouse peritonitis model, even though its activity is much more potent on human than on mouse cells. These findings suggest a new immune escape mechanism of S. aureus and put forward CHIPS as a potential new antiinflammatory therapeutic compound.
Detection of immunoglobulin gene rearrangement in lymphoid malignancies of B‐cell lineage by seminested polymerase chain reaction gene amplification
Authors: Raymond Liang, Vivian Chan, T. K. Chan, Thomas Wong, Edmond Chiu, Albert Lie, David Todd
Journal: American Journal of Hematology (1993)

Abstract Seminested polymerase chain reaction (PCR) was used to amplify the DNA fragments of the complementarity‐determining region 3 of the immunoglobulin (Ig) gene heavy chain from the malignant cell specimens of patients with leukemias and lymphomas of B‐cell lineage. Two different pairs of primers were used sequentially. Twenty of the 27 (74%) acute lymphoblastic leukemia (ALL) patients, 14 of 19 (74%) chronic lymphocytic leukemia (CLL) patients and eight of 20 (40%) non‐Hodgkin's lymphoma (NHL) patients, who had rearrangement of the Ig gene heavy chain by Southern analysis, were positive by the seminested PCR. False‐negative results appeared to occur more commonly in cases of lymphoma. The PCR analysis was also less likely to be positive if one‐stage PCR studies with either pair of primers were both negative. The seminested PCR technique was found to have a high sensitivity of detecting malignant cells at the level of 0.02%. The clinical application of this assay needs to be investigated further.
Serum Enterolactone and Prognosis of Postmenopausal Breast Cancer
Authors: Katharina Buck, Alina Vrieling, Aida Karina Zaineddin, Susen Becker, Anika Hüsing, Rudolf Kaaks, Jakob Linseisen, Dieter Flesch-Janys, Jenny Chang-Claude
Journal: Journal of Clinical Oncology (2011)

Lignans--plant-derived compounds with estrogen-dependent and -independent anticarcinogenic properties--have been associated with postmenopausal breast cancer risk, but data are limited regarding their effect on survival. Dietary lignans are metabolized to enterolignans, which are subsequently absorbed and become bioavailable.We assessed the prognosis of 1,140 postmenopausal patients with breast cancer age 50 to 74 years who were diagnosed between 2002 and 2005. Vital status through the end of 2009 was ascertained via local population registries, and deaths were verified by death certificates. Information on recurrences and secondary tumors was verified by clinical records and attending physicians. Associations of postdiagnostic serum enterolactone (a biomarker for dietary lignans) with overall survival and distant disease-free survival were assessed by using Cox proportional hazards models stratified by age at diagnosis and adjusted for prognostic factors.Median enterolactone levels for deceased patients and those still alive were 17.0 and 21.4 nmol/L, respectively. During a median of 6.1 years of follow-up after diagnosis, 162 deaths were confirmed. Higher serum enterolactone levels were associated with significantly reduced hazard ratios (HRs) for death (HR per 10 nmol/L increment, 0.94; P = .04; HR for the highest quartile, 0.58; 95% CI, 0.34 to 0.99). For distant disease, HR was 0.94 per 10 nmol/L increment (P = .08) and 0.62 (95% CI, 0.35 to 1.09) for the highest quartile. The highest quartile of serum enterolactone was associated with a significantly reduced risk of death only for estrogen receptor-negative tumors (HR, 0.27; 95% CI, 0.08 to 0.87) but not for estrogen receptor-positive tumors (HR, 0.91; 95% CI, 0.45 to 1.84: P for heterogeneity = .09).Postmenopausal patients with breast cancer who have high serum enterolactone levels may have better survival.
Obstructive sleep apnea and the kidney.
Authors: E C Fletcher
Journal: Journal of the American Society of Nephrology (1993)

Recent studies of obstructive sleep apnea and its comorbidity with other systemic diseases have stimulated interest in the relationship of apnea to renal disease and hypertension. Polysomnographic sleep studies in patients on dialysis who complain of day-time fatigue or sleepiness reveal significant apnea in up to 73% of those studied. Abnormalities in respiratory controller mechanisms from chronic hypocarbia, metabolic acidosis, and uremic toxins have been blamed for the occurrence of apnea in this setting. Proteinuria and sometimes nephrotic syndrome have been recognized in morbidly obese patients with sleep apnea syndrome. Renal biopsies of such patients have shown glomerulomegaly and focal segmental sclerosis. It is postulated that these lesions may result from increased glomerular filtration and blood flow. Elevated urine output, sodium and chloride excretion, and atrial natriuretic peptide have been well demonstrated in obstructive apnea patients and correct to control levels with treatment of the apnea. Both acute (with each apnea) and chronic daytime blood pressure elevation are frequently observed in sleep apnea patients, and occult sleep apnea is postulated as one possible cause of "primary" hypertension in middle-aged men. In younger patients, such hypertension seems to be more reversible with the elimination of apnea. In older patients, however, the cure of systemic hypertension cannot be guaranteed with the elimination of the apnea, and asymptomatic apnea patients tend not to tolerate the bother and discomfort of apnea treatment with nasal continuous positive airway pressure. Therefore, aside from a careful history regarding sleep symptomatology, polysomnographic studies of clinic populations with primary hypertension to search for apnea as a cause cannot be recommended.
YC-1 enhances the anti-tumor activity of sorafenib through inhibition of signal transducer and activator of transcription 3 (STAT3) in hepatocellular carcinoma
Authors: Jian Kong, Fandong Kong, Jun Gao, Qiangbo Zhang, Shuying Dong, Fang Gu, Shan Ke, Bing Pan, Qiang Shen, Huichuan Sun, Lemin Zheng, Wenbing Sun
Journal: Molecular Cancer (2014)

Abstract Background Traditional systemic chemotherapy does not provide survival benefits in patients with hepatocellular carcinoma (HCC). Molecular targeted therapy shows promise for HCC treatment, however, the duration of effectiveness for targeted therapies is finite and combination therapies offer the potential for improved effectiveness. Methods Sorafenib, a multikinase inhibitor, and YC-1, a soluble guanylyl cyclase (sGC) activator, were tested in HCC by proliferation assay, cell cycle analysis and western blot in vitro and orthotopic and ectopic HCC models in vivo . Results In vitro , combination of sorafenib and YC-1 synergistically inhibited proliferation and colony formation of HepG2, BEL-7402 and HCCLM3 cells. The combination also induced S cell cycle arrest and apoptosis, as observed by activated PARP and caspase 8. Sorafenib and YC-1 respectively suppressed the expression of phosphorylated STAT3 (p-STAT3) (Y705) in a dose- and time-dependent manner. Combination of sorafenib and YC-1 significantly inhibited the expression of p-STAT3 (Y705) (S727), p-ERK1/2, cyclin D1 and survivin and SHP-1 activity compared with sorafenib or YC-1 used alone in all tested HCC cell lines. In vivo , sorafenib-YC-1 combination significantly suppressed the growth of HepG2 tumor xenografts with decreased cell proliferation and increased apoptosis observed by PCNA and PARP. Similar results were also confirmed in a HCCLM3 orthotopic model. There was a reduction in CD31-positive blood vessels and reduced VEGF expression, which suggested a combinational effect of sorafenib and YC-1 on angiogenesis. The reduced expression of p-STAT3, cyclin D1 and survivin was also observed with the combination of sorafenib and YC-1. Conclusions Our data show that sorafenib-YC-1 combination is a novel potent therapeutic agent that can target the STAT3 signaling pathway to inhibit HCC tumor growth.
Specific food intolerance: its place as a cause of gastrointestinal symptoms.
Authors: D A Farah, I Calder, L Benson, J F MacKenzie
Journal: Gut (1985)

Thirteen out of 49 patients suspected of having specific food intolerance after withdrawal and reintroduction of specific foods, were further subjected to double blind placebo controlled food challenges. Only three of these subjects were thus shown to have proven specific food intolerance. Of the remaining 10, nine were strong 9placebo reactors9. The study suggests that a small number of patients with gastrointestinal symptoms have verifiable specific food intolerance but that a greater number have symptoms attributable to psychogenic causes.
VHL Tumor Suppressor Gene Alterations Associated With Good Prognosis in Sporadic Clear-Cell Renal Carcinoma
Authors: M. Yao
Journal: JNCI Journal of the National Cancer Institute (2002)

Somatic alteration of the von Hippel-Lindau disease tumor suppressor gene (VHL) is one of the most common genetic changes observed in the sporadic, clear-cell subtype of renal cell carcinoma (RCC). However, the prognostic utility of VHL mutations has not been examined. The purpose of this study was to explore the association between VHL mutations and the risk of death from sporadic clear-cell RCC.A total of 187 Japanese patients with clear-cell RCC who underwent nephrectomy from October 1986 through December 1995 were examined for somatic VHL gene alteration. Clinicopathologic and survival data were also collected. Kaplan-Meier analyses and Cox proportional hazards models were used to explore associations. All statistical tests were two-sided.A VHL alteration (mutation or hypermethylation) was detected in 108 RCC tumor samples: intragenic mutations in 98 (52%) and hypermethylation in 10 (5.3%). VHL alterations were strongly associated with better cancer-free survival and cancer-specific survival for the 134 patients with stage I-III clear-cell RCC treated by radical nephrectomy (log-rank P =.024 and.023, respectively). These associations were more statistically significant among patients with relatively advanced disease (stage III [P =.014 and.010, respectively] or stage II + III [P =.002 and.009]) or higher grade tumors (G3 or higher [P =.013 and.032] or G2 or higher [P =.013 and.018]) and among patients who presented with symptoms (P =.005 and.012). VHL alterations remained an independent prognostic factor for patients with stage I-III tumors after adjustment for sex, age, stage, grading, and symptomatic presentation. VHL alterations were not associated with cancer-specific survival for the 53 patients with stage IV tumors treated with palliative or adjunctive nephrectomy (log-rank P =.760).The VHL alteration status may provide useful prognostic information, as a biomolecular marker, for patients with stage I-III clear-cell RCC who have undergone nephrectomy.