tbuckley/cabot-search huggingface dataset:
Targeting of MAPK-associated molecules identifies SON as a prime target to attenuate the proliferation and tumorigenicity of pancreatic cancer cells
Authors: Toru Furukawa, Etsuko Tanji, Yuko Kuboki, Takashi Hatori, Masakazu Yamamoto, Kyoko Shimizu, Noriyuki Shibata, Keiko Shiratori
Journal: Molecular Cancer (2012)

Pancreatic cancer is characterized by constitutive activation of mitogen-activated protein kinase (MAPK). Activation of MAPK is associated with the upregulation of genes implicated in the proliferation and survival of pancreatic cancer cells. We hypothesized that knockdown of these MAPK-associated molecules could produce notable anticancer phenotypes. A RNA interference-mediated knockdown screening of 78 MAPK-associated molecules previously identified was performed to find molecules specifically associated with proliferation of pancreatic cancer cells in vitro. Expression of an identified molecule in pancreatic cancer tissues was examined by immunohistochemistry. In vivo tumorigenicity of cancer cells with stable knockdown of the molecule was assayed by using xenograft models. Flow cytometry and live cell imaging were employed to assess an association of the molecule with cell cycle. The knockdown screening revealed that knockdown of SON, the gene encoding SON, which is a large serine/arginine-rich protein involved in RNA processing, substantially suppressed pancreatic cancer cell proliferation and survival in vitro and tumorigenicity in vivo. SON expression was higher in ductal adenocarcinomas than in cells of normal ducts and precursor lesions in pancreatic cancer tissues. Knockdown of SON induced G2/M arrest and apoptosis in cultured cancer cells. The suppressive effect of SON knockdown on proliferation was less pronounced in cultured normal duct epithelial cells. SON formed nuclear speckles in the interphase of the cell cycle and dispersed in the cytoplasm during mitosis. Live cell imaging showed that SON diffusely dispersed in the early mitotic phase, accumulated in some foci in the cytoplasm in the late mitotic phase, and gradually reassembled into speckles after mitosis. These results indicate that SON plays a critical role in the proliferation, survival, and tumorigenicity of pancreatic cancer cells, suggesting that SON is a novel therapeutic molecular target for pancreatic cancer.
Signaling Molecules in Overcirculation-Induced Pulmonary Hypertension in Piglets
Authors: Benoit Rondelet, François Kerbaul, Ronald Van Beneden, Sophie Motte, Pierre Fesler, Ives Hubloue, Myriam Remmelink, Serge Brimioulle, Isabelle Salmon, Jean-Marie Ketelslegers, Robert Naeije
Journal: Circulation (2004)

Background— The phosphodiesterase type-5 (PDE-5) inhibitor sildenafil has been reported to improve pulmonary arterial hypertension (PAH), but the mechanisms that account for this effect are incompletely understood. Severe pulmonary hypertension has been characterized by defects in a signaling pathway involving angiopoietin-1 and the bone morphogenetic receptor-2 (BMPR-2). We investigated the effects of sildenafil on hemodynamics and signaling molecules in a piglet overcirculation-induced model of early PAH. Methods and Results— Thirty 3-week-old piglets were randomized to placebo or sildenafil therapy 0.75 mg/kg TID after anastomosis of the left subclavian artery to the pulmonary arterial trunk or after a sham operation. Three months later, the animals underwent a hemodynamic evaluation followed by pulmonary tissue sampling for morphometry, immunohistochemistry or radioimmunoassay, and real-time quantitative-polymerase chain reaction. Chronic systemic-to-pulmonary shunting increased pulmonary mRNA for angiopoietin-1, endothelin-1 (ET-1), angiotensin II, inducible nitric oxide synthase, vascular endothelial growth factor, and PDE-5. Pulmonary messenger RNA for BMPR-1A and BMPR-2 decreased. Pulmonary angiotensin II, ET-1, and vascular endothelial growth factor proteins increased. Pulmonary artery pressure increased from 20±2 to 33±1 mm Hg, and arteriolar medial thickness increased by 91%. The expressions of angiopoietin-1, ET-1, and angiotensin II were tightly correlated to pulmonary hypertension. Sildenafil prevented the increase in pulmonary artery pressure, limited the increase in medial thickness to 41%, and corrected associated biological perturbations except for the angiopoietin-1/BMPR-2 pathway, PDE-5, and angiotensin II. Conclusions— Sildenafil partially prevents overcirculation-induced PAH and associated changes in signaling molecules. Angiotensin II, PDE-5, and angiopoietin-1/BMPR-2 signaling may play a dominant role in the early stages of the disease.
AN EXPERIMENTAL STUDY OF PROTECTIVE INOCULATION WITH HEAT KILLED TUBERCLE BACILLI
Authors: Eugene L. Opie, Jules Freund
Journal: The Journal of Experimental Medicine (1937)

Heat killed tubercle bacilli repeatedly injected into or below the skin of rabbits increase conspicuously their resistance against infection with virulent tubercle bacilli. Protection against tuberculous infection following the administration of heat killed tubercle bacilli to rabbits is only slightly less than that given by BCG. Addition of certain antigens, notably heated horse serum, increases the protection given by heat killed tubercle bacilli so that it is approximately the same as that afforded by BCG. These experiments and tentative observations of persons exposed to tuberculous infection indicate that heat killed tubercle bacilli may be substituted for the living attenuated microorganism in the attempt to increase resistance against tuberculous infection and to influence favorably the delicate balance between asymptomatic or latent infection and progressive manifest disease that is characteristic of human tuberculosis.
The failed HIV Merck vaccine study: a step back or a launching point for future vaccine development?
Authors: Rafick-Pierre Sekaly
Journal: The Journal of Experimental Medicine (2008)

The world of human immunodeficiency virus (HIV) vaccines has suffered a baffling setback. The first trial of a vaccine designed to elicit strong cellular immunity has shown no protection against infection. More alarmingly, the vaccine appeared to increase the rate of HIV infection in individuals with prior immunity against the adenovirus vector used in the vaccine. A new study in this issue suggests that a different vaccine approach—using a DNA prime/poxvirus boost strategy—induces polyfunctional immune responses to an HIV immunogen. The disappointing results of the recent vaccine trial suggest that a more thorough assessment of vaccine-induced immune responses is urgently needed, and that more emphasis should be placed on primate models before efficacy trials are undertaken.
Prostacyclin deficiency in a young woman with recurrent thrombosis.
Authors: J G Lanham, M Levin, Z Brown, A E Gharavi, P A Thomas, G C Hanson
Journal: BMJ (1986)

A young woman with recurrent deep venous thromboses and spontaneous abortions was studied. She suffered an ovarian infarction followed by aortic thrombosis and renal failure. Evidence for deficient prostacyclin production was found and she responded to treatment with a prostacyclin infusion. This syndrome is identical with that seen in women with the lupus anticoagulant, but the lupus anticoagulant was not detected and no other cause was identified.
Adjuvant Vinorelbine and Cisplatin in Elderly Patients: National Cancer Institute of Canada and Intergroup Study JBR.10
Authors: Carmela Pepe, Baktiar Hasan, Timothy L. Winton, Lesley Seymour, Barbara Graham, Robert B. Livingston, David H. Johnson, James R. Rigas, Keyue Ding, Frances A. Shepherd
Journal: Journal of Clinical Oncology (2007)

Recent trials have shown significant survival benefit from adjuvant chemotherapy for non-small-cell lung cancer (NSCLC). Whether elderly patients tolerate platinum-based adjuvant chemotherapy and derive the same survival advantage is unknown. This retrospective study evaluated the influence of age on survival, adjuvant chemotherapy delivery, and toxicity in National Cancer Institute of Canada (NCIC) Clinical Trials Group study JBR.10.Pretreatment characteristics and survival were compared for 327 young (< or = 65 years) and 155 elderly (> 65 years) patients. Chemotherapy delivery and toxicity were compared for 213 treated patients (63 elderly, 150 young).Baseline demographics by age were similar with the exception of histology (adenocarcinoma: 58% young, 43% elderly; squamous: 32% young, 49% elderly; P = .001) and performance status (PS; PS 0: 53% young, 41% elderly; P = .01). Chemotherapy significantly prolonged overall survival for elderly patients (hazard ratio, 0.61; 95% CI, 0.38 to 0.98; P = .04). This benefit is similar to the effect for all patients in JBR.10. Mean dose-intensities of vinorelbine and cisplatin were 13.2 and 18.0 mg/m2/wk in young, respectively, and 9.9 and 14.1 mg/m2/wk in elderly patients (vinorelbine, P = .0004; cisplatin, P = .001), respectively. The elderly received significantly fewer doses of vinorelbine (P = .014) and cisplatin (P = .006). Fewer elderly patients completed treatment and more refused treatment (P = .03). There were no significant differences in toxicities, hospitalization, or treatment-related death by age group. Fifteen (11.9%) of 126 deaths in the young resulted from nonmalignant causes, and 15 (21.1%) of 71 in the elderly (P = .13).Despite elderly patients' receiving less chemotherapy, adjuvant vinorelbine and cisplatin improves survival in patients older than 65 years with acceptable toxicity. Adjuvant chemotherapy should not be withheld from elderly patients.
CFTR-knockout neonatal ferrets model may be useful in the understanding of CF pathogenesis and developing therapies
Authors: A. Y. Lim
Journal: Thorax (2010)

There is no adequate animal model of cystic fibrosis (CF) airways disease. This study investigated using CFTR-knockout neonatal ferrets as they show similarities to newborn humans with CF. These similarities include meconium ileus (MI), pancreatic disease, liver disease, …
Estimated Prevalence of Compulsive Buying Behavior in the United States
Authors: Lorrin M Koran, Ronald J Faber, Elias Aboujaoude, Michael D Large, Richard T Serpe
Journal: American Journal of Psychiatry (2006)

Objective: Compulsive buying (uncontrolled urges to buy, with resulting significant adverse consequences) has been estimated to affect from 1.8% to 16% of the adult U.S. population. To the authors’ knowledge, no study has used a large general population sample to estimate its prevalence. Method: The authors conducted a random sample, national household telephone survey in the spring and summer of 2004 and interviewed 2,513 adults. The interviews addressed buying attitudes and behaviors, their consequences, and the respondents’ financial and demographic data. The authors used a clinically validated screening instrument, the Compulsive Buying Scale, to classify respondents as either compulsive buyers or not. Results: The rate of response was 56.3%, which compares favorably with rates in federal national health surveys. The cooperation rate was 97.6%. Respondents included a higher percentage of women and people ages 55 and older than the U.S. adult population. The estimated point prevalence of compulsive buying among respondents was 5.8% (by gender: 6.0% for women, 5.5% for men). The gender-adjusted prevalence rate was 5.8%. Compared with other respondents, compulsive buyers were younger, and a greater proportion reported incomes under $50,000. They exhibited more maladaptive responses on most consumer behavior measures and were more than four times less likely to pay off credit card balances in full. Conclusions: A study using clinically valid interviews is needed to evaluate these results. The emotional and functional toll of compulsive buying and the frequency of comorbid psychiatric disorders suggests that studies of treatments and social interventions are warranted.
Role of Coronary Collaterals in Off-Pump and On-Pump Coronary Bypass Surgery
Authors: Hendrik M. Nathoe, Erik Buskens, Erik W.L. Jansen, Willem J.L. Suyker, Pieter R. Stella, Jaap R. Lahpor, Wim-Jan van Boven, Diederik van Dijk, Jan C. Diephuis, Cornelius Borst, Karel G.M. Moons, Diederick E. Grobbee, Peter P.T. de Jaegere
Journal: Circulation (2004)

Collaterals limit infarct size, preserve viability, and reduce mortality in patients with acute myocardial infarction. In patients with stable coronary disease, collaterals are associated with less angina and ischemia during angioplasty and fewer ischemic events during follow-up. The role of collaterals has not been studied in patients undergoing off-pump or on-pump bypass surgery.The population consisted of the 281 patients randomized to off-pump or on-pump CABG in the Octopus Study. Collaterals were defined on the baseline angiogram with the Rentrop score and were present in 49% and 51% of the patients in the off-pump and on-pump group, respectively. Perioperative myocardial infarction was defined by a creatine kinase-MB to CK ratio >10% and occurred in 18.2% in the off-pump group and 32.5% in the on-pump group. The unadjusted OR of perioperative myocardial infarction in the presence of collaterals was 0.31 (95% CI 0.17 to 0.84) in the off-pump group and 1.06 (95% CI 0.29 to 3.85) in the on-pump group After adjustment for age, gender, hypertension, hypercholesterolemia, diabetes, multivessel disease, ventricular dysfunction, incomplete revascularization, and ischemic time, the OR was 0.34 (95% CI 0.14 to 0.84) in the off-pump group and 1.28 (95% CI 0.30 to 5.40) in the on-pump group, respectively. Kaplan-Meier estimates of event-free survival at 1 year were 87% in patients with and 69% in those without collaterals after off-pump CABG. These estimates were 66% and 63%, respectively, after on-pump CABG.Collaterals protect against perioperative myocardial infarction during off-pump surgery but not during on-pump surgery and are associated with a better 1-year event-free survival.
Analysis of Hypoxia-Related Gene Expression in Sarcomas and Effect of Hypoxia on RNA Interference of Vascular Endothelial Cell Growth Factor A
Authors: Kara Y. Detwiller, Namali T. Fernando, Neil H. Segal, Sandra W. Ryeom, Patricia A. D'Amore, Sam S. Yoon
Journal: Cancer Research (2005)

Abstract Vascular endothelial cell growth factor A (VEGF-A) and hypoxia play important roles in tumor angiogenesis. VEGF-A gene expression is up-regulated in tumors under hypoxic conditions, yet it is unclear how such up-regulation will affect the efficacy of RNA interference strategies targeting VEGF-A. Four potential short interfering RNA (siRNA) sequences for the VEGF-A gene were cloned into expression plasmids and transfected into HT1080 human fibrosarcoma cells. Stable transfection of these plasmids decreased VEGF-A mRNA levels and protein secretion by up to 99%. Our analysis of &amp;gt;100 hypoxia-related genes using oligonucleotide microarrays of 38 human sarcoma samples and 14 normal tissues identified distinctly different patterns of expression between sarcomas and normal tissues as assessed by hierarchical clustering analysis. Numerous hypoxia-related genes were significantly up-regulated in sarcomas including hypoxia-inducible factor 1α (HIF-1α). Exposure of wild-type HT1080 cells to 1% hypoxia resulted in HIF-1α up-regulation and a 74% increase in VEGF-A secretion as compared with secretion under normoxic conditions. Surprisingly, stable cell lines expressing VEGF-A siRNAs silenced VEGF-A expression equally well in hypoxia and normoxia. S.c. injection of cells with VEGF-A siRNAs into athymic nude mice led to slower-growing tumors, decreased blood vessel density, and greater apoptosis when compared with controls. Immunofluorescence analysis of tumor sections revealed areas of HIF-1α nuclear expression, suggesting areas of hypoxia, in both control tumors and VEGF-suppressed tumors. We conclude that hypoxia plays an important role in human sarcomas but hypoxic up-regulation of VEGF-A expression does not attenuate the efficacy of VEGF-A RNA interference.
Acetaminophen-induced acute liver failure: Results of a United States multicenter, prospective study
Authors: Anne M. Larson, Julie Polson, Robert J. Fontana, Timothy J. Davern, Ezmina Lalani, Linda S. Hynan, Joan S. Reisch, Frank V. Schiødt, George Ostapowicz, A. Obaid Shakil, William M. Lee
Journal: Hepatology (2005)

Severe acetaminophen hepatotoxicity frequently leads to acute liver failure (ALF). We determined the incidence, risk factors, and outcomes of acetaminophen-induced ALF at 22 tertiary care centers in the United States. Detailed prospective data were gathered on 662 consecutive patients over a 6-year period fulfilling standard criteria for ALF (coagulopathy and encephalopathy), from which 275 (42%) were determined to result from acetaminophen liver injury. The annual percentage of acetaminophen-related ALF rose during the study from 28% in 1998 to 51% in 2003. Median dose ingested was 24 g (equivalent to 48 extra-strength tablets). Unintentional overdoses accounted for 131 (48%) cases, intentional (suicide attempts) 122 (44%), and 22 (8%) were of unknown intent. In the unintentional group, 38% took two or more acetaminophen preparations simultaneously, and 63% used narcotic-containing compounds. Eighty-one percent of unintentional patients reported taking acetaminophen and/or other analgesics for acute or chronic pain syndromes. Overall, 178 subjects (65%) survived, 74 (27%) died without transplantation, and 23 subjects (8%) underwent liver transplantation; 71% were alive at 3 weeks. Transplant-free survival rate and rate of liver transplantation were similar between intentional and unintentional groups. In conclusion, acetaminophen hepatotoxicity far exceeds other causes of acute liver failure in the United States. Susceptible patients have concomitant depression, chronic pain, alcohol or narcotic use, and/or take several preparations simultaneously. Education of patients, physicians, and pharmacies to limit high-risk use settings is recommended. (HEPATOLOGY 2005;42:1364–1372.)
Keeping health on the political agenda
Authors: Vitor Teixeira
Journal: European Respiratory Journal (2015)

Having already survived an attempted ousting, Jean-Claude Juncker, the new European Commission President only took office on November 1, 2014, together with his college of Commissioners representing each member state [1]. Having previously won the direct backing of Members of the European Parliament to lead the Commission, he was forced to face down this first challenge before even having the opportunity to reveal his first work plan for 2015 [2]. ERS and its ECDA partners met the new EU Health Commissioner to discuss a future EU framework on chronic diseases <http://ow.ly/GnVBM>
REMARKS ON A CASE OF HEREDITARY LOCALIZED OEDEMA PROVING FATAL BY LARYNGEAL OBSTRUCTION
Authors: T. W. Griffith
Journal: BMJ (1902)

probably by diffusion-raise the osmotic pressure of the lymp.i,and attract water from the blood.In this way.the increased lymph flow is accounted for.It is, of course, pos- sible that bile salt (and haemoglobin) stimulate the hepatic capillaries to secrete lymph, after the manner suggested by Heidenhain.But the experiments, though not actually op- posed to such a view, do not support it.
Confidentiality, disclosure and doping in sports medicine
Authors: M McNamee, N Phillips
Journal: British Journal of Sports Medicine (2009)

The manner in which healthcare and medical professionals serve their athlete patients is governed by a variety of relevant codes of conduct. A range of codified rules is presented that refer both the welfare of the patient and the maintaining of confidentiality, which is at the heart of trustworthy relations. The 2009 version of the World Anti-Doping Code (WADC), however, appears to oblige all healthcare professionals not to assist athletes if they are known to be engaged in doping behaviours under fear of removal from working with athletes from the respective sports. In contrast, serving the best interests of their athlete patients may oblige healthcare professionals to give advice and guidance, not least in terms of harm minimisation. In so far as the professional conduct of a healthcare professional is guided both by professional code and World Anti-Doping Code, they are obliged to fall foul of one or the other. We call for urgent and pressing inter-professional dialogue with the World Anti-Doping Agency to clarify this situation.
Rho-Kinase Mediates Hypoxia-Induced Downregulation of Endothelial Nitric Oxide Synthase
Authors: Masao Takemoto, Jianxin Sun, Junko Hiroki, Hiroaki Shimokawa, James K. Liao
Journal: Circulation (2002)

Background — Hypoxia-induced pulmonary hypertension is a major cause of morbidity and mortality. Hypoxia induces pulmonary vasoconstriction, in part, by decreasing endothelial nitric oxide synthase (eNOS) expression. The mechanism by which hypoxia decreases eNOS expression is not known but may involve Rho-kinase–induced actin cytoskeletal changes in vascular endothelial cells. Methods and Results — To determine whether hypoxia regulates eNOS expression through Rho-kinase, we exposed human saphenous and pulmonary artery endothelial cells to hypoxia (3% O 2 ) with and without a Rho-kinase inhibitor, hydroxyfasudil (0.1 to 100 μmol/L), for various durations (0 to 48 hours). Hypoxia increased Rho-kinase expression and activity by 50% and 74%, decreased eNOS mRNA and protein expression by 66±3% and 57±5%, and inhibited eNOS activity by 48±9%. All of these effects of hypoxia on eNOS were reversed by cotreatment with hydroxyfasudil. Furthermore, inhibition of Rho by Clostridium botulinum C3 transferase or Rho-kinase by overexpression of dominant-negative Rho-kinase reversed hypoxia-induced decrease in eNOS expression. Indeed, disruption of the actin cytoskeleton, the downstream target of Rho-kinase, by cytochalasin D also upregulated eNOS expression. Hypoxia reduced eNOS mRNA half-life from 22±2 to 13±2 hours, which was reversed by cotreatment with hydroxyfasudil. However, neither hypoxia nor hydroxyfasudil had any effects on eNOS gene transcription. Conclusions — These results indicate that hypoxia-induced decrease in eNOS expression is mediated by Rho-kinase and suggest that Rho-kinase inhibitors may have therapeutic benefits in patients with hypoxia-induced pulmonary hypertension.
Fc<sub>ε</sub>RII/CD23: The Low Affinity Receptor for IgE
Authors: D H Conrad
Journal: Annual Review of Immunology (1990)

Exhausted CD8 T (Tex) cells are a distinct cell lineage that arise during chronic infections and cancers in animal models and humans. Tex cells are characterized by progressive loss of effector functions, high and sustained inhibitory receptor expression, ...Read More
MicroRNA Control of High-Density Lipoprotein Metabolism and Function
Authors: Katey J. Rayner, Kathryn J. Moore
Journal: Circulation Research (2014)

Recent discoveries of microRNAs (miRNAs) that control high-density lipoprotein abundance and function have expanded our knowledge of the mechanisms regulating this important lipoprotein subclass. miRNAs have been shown to regulate gene networks that control high-density lipoprotein biogenesis and uptake, as well as discrete steps in the reverse cholesterol transport pathway. Furthermore, high-density lipoprotein itself has been shown to transport miRNAs selectively in health and disease, offering new possibilities of how this lipoprotein may alter gene expression in distal target cells and tissues. Collectively, these discoveries offer new insights into the mechanisms governing high-density lipoprotein metabolism and function and open new avenues for the development of therapeutics for the treatment of cardiovascular disease.