tbuckley/cabot-search huggingface dataset:
Exercise induced inspiratory symptoms
Authors: Carolina Campos, Ola Røksund, Maria Vollsæter, John-Helge Heimdal, Thomas Halvorsen, Hege Clemm
Journal: European Respiratory Journal (2014)

Introduction Exercise induced inspiratory symptoms or stridor (EIIS) is a compound set of symptoms, frequently occurring in physically active and otherwise healthy young people. Symptom descriptions and level of complaints vary between patients.

Aim Study symptoms in patients with EIIS

Method All patients referred to our clinic due to EIIS are offered an examination with continuous laryngoscopy during maximal treadmill exercise (CLE-test), and complete a standardized questionnaire. We report symptom scores obtained in 2012-13.

Results A total of 213 referrals were registered, 66% females, age range 7-62 years, 65% between 13-18 years. In 60% of subjects, EIIS first presented between 9-15 years of age. Symptoms were characterized as similar each time they occurred by 86% of subjects, occurring already at low intensity exercise in 35% and at high intensity in 83%. Panic reactions or fear during most episodes with breathing problems were reported by 25%, and 91% felt that EIIS prevented them from reaching their goals in sports. Half of the patients had reduced their level of physical activity due to EIIS, and 56% would have exercised more without EIIS. Laryngoscopy during exercise revealed moderate or severe supraglottic obstruction in 59% of patients, of whom 70% described this as an inspiratory problem, and 59% described stridor. There were minor differences regarding descriptions of breathing related problems between those with no or mild vs. moderate or severe supraglottic obstruction at the CLE-test.

Conclusion EIIS disturbs exercise performance in a notable number of young and otherwise healthy individuals; however, symptom descriptions and laryngoscopic findings were partly discordant, underlining the value of objective test methods.
Hexokinase II and Reperfusion Injury
Authors: Philippe Pasdois, Joanne E. Parker, Elinor J. Griffiths, Andrew P. Halestrap
Journal: Circulation Research (2013)

Mitochondrial-bound hexokinase II (HK2) was recently proposed to play a crucial role in the normal functioning of the beating heart and to be necessary to maintain mitochondrial membrane potential. However, our own studies confirmed that mitochondria from ischemic rat hearts were HK2-depleted, yet showed no indication of depolarization and responded normally to ADP.To establish whether the human TAT-HK2 peptide used to dissociate mitochondrial-bound HKII in the Langendorff-perfused heart may exert its effects indirectly by impairing coronary function.Ischemic preconditioning was blocked in rat hearts perfused with 2.5 µmol/L TAT-HK2 before ischemia or at the onset of reperfusion. However, TAT-HK2 also decreased the phosphocreatine:ATP ratio that correlated with reduced rate pressure product and increased diastolic pressure. These effects were preceded by increased aortic pressure (Langendorff constant flow) or decreased coronary flow (Langendorff constant pressure), which was also observed, albeit less pronounced, at 200 nmol/L TAT-HK2 and was prevented by coperfusion with the NO-donor diethylamine NONOate. Mitochondria from TAT-HK2-perfused hearts showed no loss of bound HK2, unlike mitochondria from ischemic hearts where the expected loss was prevented by ischemic preconditioning.In the perfused rat heart, TAT-HK2 should be used with caution and careful attention to dosage because some of its effects may be mediated by vasoconstriction of the coronary vasculature rather than dissociation of HK2 from myocyte mitochondria.
Seven-Transmembrane Receptors and Ubiquitination
Authors: Sudha K. Shenoy
Journal: Circulation Research (2007)

Regulation of protein function by posttranslational modification plays an important role in many biological pathways. The most well known among such modifications is protein phosphorylation performed by highly specific protein kinases. In the past decade, however, covalent linkage of the low-molecular-weight protein ubiquitin to substrate proteins (protein ubiquitination) has proven to be yet another widely used mechanism of protein regulation playing a crucial role in virtually all aspects of cellular functions. This review highlights some of the recently discovered and provocative roles for ubiquitination in the regulation of the life cycle and signal transduction properties of 7-transmembrane receptors that serve to integrate many biological functions and play fundamental roles in cardiovascular homeostasis.
Role of adenosine in coronary vasodilation during exercise.
Authors: R J Bache, X Z Dai, J S Schwartz, D C Homans
Journal: Circulation Research (1988)

This study examined the hypothesis that increases in myocardial blood flow during exercise are mediated by adenosine-induced coronary vasodilation. Active hyperemia associated with graded treadmill exercise and coronary reactive hyperemia were examined in chronically instrumented awake dogs during control conditions, after intracoronary infusion of adenosine deaminase (5 units/kg/min for 10 minutes), and after adenosine receptor blockade with 8-phenyltheophylline. Both adenosine deaminase and 8-phenyltheophylline caused a rightward shift of the dose-response curve to intracoronary adenosine; 8-phenyltheophylline was significantly more potent than adenosine deaminase. Adenosine deaminase caused a 33 +/- 7 to 39 +/- 3% decrease in reactive hyperemia blood flow following coronary occlusions of 5-20 seconds duration, respectively, while 8-phenyltheophylline produced a 40 +/- 6 to 62 +/- 8% decrease in reactive hyperemia. Increasing myocardial oxygen consumption during treadmill exercise was associated with progressive increase of coronary blood flow. Neither adenosine deaminase nor 8-phenyltheophylline attenuated the increase in coronary blood flow or the decrease of coronary vascular resistance during exercise. Neither agent altered the relation between myocardial oxygen consumption and coronary blood flow. Thus, although both adenosine deaminase and 8-phenyltheophylline antagonized coronary vasodilation in response to exogenous adenosine and blunted coronary reactive hyperemia, neither agent impaired coronary vasodilation associated with increased myocardial oxygen requirements produced by exercise. These findings fail to support a substantial role for adenosine in mediating coronary vasodilation during exercise.
Genome-wide DNA Methylation Analysis of Lung Carcinoma Reveals One Neuroendocrine and Four Adenocarcinoma Epitypes Associated with Patient Outcome
Authors: Anna Karlsson, Mats Jönsson, Martin Lauss, Hans Brunnström, Per Jönsson, Åke Borg, Göran Jönsson, Markus Ringnér, Maria Planck, Johan Staaf
Journal: Clinical Cancer Research (2014)

Abstract Purpose: Lung cancer is the worldwide leading cause of death from cancer. DNA methylation in gene promoter regions is a major mechanism of gene expression regulation that may promote tumorigenesis. However, whether clinically relevant subgroups based on DNA methylation patterns exist in lung cancer remains unclear. Experimental Design: Whole-genome DNA methylation analysis using 450K Illumina BeadArrays was performed on 12 normal lung tissues and 124 tumors, including 83 adenocarcinomas, 23 squamous cell carcinomas (SqCC), 1 adenosquamous cancer, 5 large cell carcinomas, 9 large cell neuroendocrine carcinomas (LCNEC), and 3 small-cell carcinomas (SCLC). Unsupervised bootstrap clustering was performed to identify DNA methylation subgroups, which were validated in 695 adenocarcinomas and 122 SqCCs. Subgroups were characterized by clinicopathologic factors, whole-exome sequencing data, and gene expression profiles. Results: Unsupervised analysis identified five DNA methylation subgroups (epitypes). One epitype was distinctly associated with neuroendocrine tumors (LCNEC and SCLC). For adenocarcinoma, remaining four epitypes were associated with unsupervised and supervised gene expression phenotypes, and differences in molecular features, including global hypomethylation, promoter hypermethylation, genomic instability, expression of proliferation-associated genes, and mutations in KRAS, TP53, KEAP1, SMARCA4, and STK11. Furthermore, these epitypes were associated with clinicopathologic features such as smoking history and patient outcome. Conclusions: Our findings highlight one neuroendocrine and four adenocarcinoma epitypes associated with molecular and clinicopathologic characteristics, including patient outcome. This study demonstrates the possibility to further subgroup lung cancer, and more specifically adenocarcinomas, based on epigenetic/molecular classification that could lead to more accurate tumor classification, prognostication, and tailored patient therapy. Clin Cancer Res; 20(23); 6127–40. ©2014 AACR.
Prostate-Cancer Mortality at 11 Years of Follow-up
Authors: Fritz H. Schröder, Jonas Hugosson, Monique J. Roobol, Teuvo L.J. Tammela, Stefano Ciatto, Vera Nelen, Maciej Kwiatkowski, Marcos Lujan, Hans Lilja, Marco Zappa, Louis J. Denis, Franz Recker, Alvaro Páez, Liisa Määttänen, Chris H. Bangma, Gunnar Aus, Sigrid Carlsson, Arnauld Villers, Xavier Rebillard, Theodorus van der Kwast, Paula M. Kujala, Bert G. Blijenberg, Ulf-Hakan Stenman, Andreas Huber, Kimmo Taari, Matti Hakama, Sue M. Moss, Harry J. de Koning, Anssi Auvinen
Journal: New England Journal of Medicine (2012)

Several trials evaluating the effect of prostate-specific antigen (PSA) testing on prostate-cancer mortality have shown conflicting results. We updated prostate-cancer mortality in the European Randomized Study of Screening for Prostate Cancer with 2 additional years of follow-up.
Does the biomedical revolution spell the end of sport?
Authors: A L Caplan
Journal: British Journal of Sports Medicine (2008)

Many professional and amateur sports including track and field, weight-lifting, boxing, canoeing, professional baseball and professional cycling have suffered scandals involving steroids and human growth hormone (HGH) and have done so for many years.1–4 It seems self-evident that the use of steroids and HGH is a problem. The amount of media and political attention paid to steroids and other pharmacological forms of enhancement in sports, such as the use of blood doping and stimulants, suggest that biochemical enhancement is one of the greatest moral problems the world faces.

Well, OK, upon deeper reflection, the challenge of getting the steroids out of bicycle racing is not on the same moral plane as eliminating poverty or AIDS. Still, many people all over the world seem to think that the latest generation of performance-enhancing substances threatens the very integrity of sport. There has been a burst of writing in recent years making precisely this case and the budget and clout of the World Anti-Doping Agency (WADA) and similar policing agencies are growing, reflecting the view that chemical enhancement and fair competition cannot coexist.

In one sense, the argument that the current techniques for enhancing sports performance threaten sport is irrefutable. Synthetic steroids are dangerous. HGH in large amounts can be too. There is a real need to protect children who admire athletes, so as to prevent them from taking serious risks with their health in imitating what their idols do or, in a few instances, from being forced by their own parents to engage in risky behaviour in order to succeed in athletics.

But, what if biomedical science could put the safety issue aside? Someday, probably soon, there will be drugs that do what steroids do without any real risk of harm to the user. Forms of gene therapy are …
Early Detection of Chemoradioresponse in Esophageal Carcinoma by 3′-Deoxy-3′-3H-Fluorothymidine Using Preclinical Tumor Models
Authors: Smith Apisarnthanarax, Mian M. Alauddin, Firas Mourtada, Hisanori Ariga, Uma Raju, Osama Mawlawi, Dongmei Han, William G. Bornmann, Jaffer A. Ajani, Luka Milas, Juri G. Gelovani, K.S. Clifford Chao
Journal: Clinical Cancer Research (2006)

Early identification of esophageal cancer patients who are responding or resistant to combined chemoradiotherapy may lead to individualized therapeutic approaches and improved clinical outcomes. We assessed the ability of 3'-deoxy-3'-(18)F-fluorothymidine positron emission tomography (FLT-PET) to detect early changes in tumor proliferation after chemoradiotherapy in experimental models of esophageal carcinoma.The in vitro and ex vivo tumor uptake of [(3)H]FLT in SEG-1 human esophageal adenocarcinoma cells were studied at various early time points after docetaxel plus irradiation and validated with conventional assessments of cellular proliferation [thymidine (Thd) and Ki-67] and [(18)F]FLT micro-PET imaging. Imaging-histologic correlation was determined by comparing spatial Ki-67 and [(18)F]FLT distribution in autoradiographs. Comparison with fluorodeoxyglucose (FDG) was done in all experiments.In vitro [(3)H]FLT and [(3)H]Thd uptake rapidly decreased in SEG-1 cells 24 hours after docetaxel with a maximal reduction of over 5-fold (P = 0.005). The [(3)H]FLT tumor-to-muscle uptake ratio in xenografts declined by 75% compared with baseline (P < 0.005) by 2 days after chemoradiotherapy, despite the lack of change in tumor size. In contrast, the decline of [(3)H]FDG uptake was gradual and less pronounced. Tumor uptake of [(3)H]FLT was more closely correlated with Ki-67 expression (r = 0.89, P < 0.001) than was [(3)H]FDG (r = 0.39, P = 0.08). Micro-PET images depicted similar trends in reduction of [(18)F]FLT and [(18)F]FDG tumor uptake. Autoradiographs displayed spatial correlations between [(18)F]FLT uptake and histologic Ki-67 distribution in preliminary studies.FLT-PET is suitable and more specific than FDG-PET for depicting early reductions in tumor proliferation that precede tumor size changes after chemoradiotherapy.
CONTRAINDICATIONS FOR P2Y12 INHIBITORS IN REAL-LIFE PATIENTS WITH ACUTE CORONARY SYNDROME: INSIGHTS FROM THE GREEK ANTIPLATELET (GRAPE) REGISTRY
Authors: Dimitrios Alexopoulos, Ioanna Xanthopoulou, Argyro Siapika, Spyridon Deftereos, George Sitafidis, Ioannis Goudevenos, Filippos Triposkiadis, Vlassis Pyrgakis, Ioannis Kanakakis, Periklis Davlouros
Journal: Journal of the American College of Cardiology (2013)
VIRUS-INDUCED DIABETES MELLITUS
Authors: D. Wark Boucher, Abner Louis Notkins
Journal: The Journal of Experimental Medicine (1973)

Infection of DBA/2N male mice with encephalomyocarditis virus resulted in a diabeteslike syndrome characterized by hyperglycemia, glycosuria, hypoinsulinemia, polydipsia, and polyphagia. Blood glucose levels were elevated within 4 days after infection and reached a maximum mean level of 320 mg/100 ml within 12 days. Approximately 60-80% of the animals developed a transient hyperglycemia while 10-15% of the animals remained hyperglycemic for well over 6 mo. The remaining animals failed to become hyperglycemic but many had abnormal glucose tolerance curves. Hyperglycemia was most pronounced when animals were allowed free access to food, and the incidence of byperglycemia was related both to the strain and sex of the animals, with few females developing hyperglycemia. The amount of immunoreactive insulin in the plasma of infected hyperglycemic mice was significantly lower than in appropriate controls, and injection of exogenous insulin resulted in a rapid drop in the blood glucose levels. Despite the fact that certain animals were hyperglycemic for many months, virus could not be recovered from the pancreas after the first 10 days of the infection.
Targeting phosphatidylinositol-3-kinase pathway for the treatment of Philadelphia-negative myeloproliferative neoplasms
Authors: Ruchi Pandey, Reuben Kapur
Journal: Molecular Cancer (2015)

Myeloproliferative neoplasms (MPN) are a diverse group of chronic hematological disorders that involve unregulated clonal proliferation of white blood cells. Sevearl of them are associated with mutations in receptor tyrosine kinases or cytokine receptor associated tyrosine kinases rendering them independent of cytokine-mediated regulation. Classically they have been broadly divided into BCR-ABL1 fusion + ve (Ph + ve) or –ve (Ph-ve) MPNs. Identification of BCR-ABL1 tyrosine kinase as a driver of chronic myeloid leukemia (CML) and successful application of small molecule inhibitors of the tyrosine kinases in the clinic have triggered the search for kinase dependent pathways in other Ph-ve MPNs. In the past few years, identification of mutations in JAK2 associated with a majority of MPNs raised the hopes for similar success with specific targeting of JAK2. However, targeting JAK2 kinase activity has met with limited success. Subsequently, mutations in genes other than JAK2 have been identified. These mutations specifically associate with certain MPNs and can drive cytokine independent growth. Therefore, targeting alternate molecules and pathways may be more successful in management of MPNs. Among other pathways, phosphatidylinositol −3 kinase (PI3K) has emerged as a promising target as different cell surface receptor induced signaling pathways converge on the PI3K signaling axis to regulate cell metabolism, growth, proliferation, and survival. Herein, we will review the clinically relevant inhibitors of the PI3K pathway that have been evaluated or hold promise for the treatment of Ph-ve MPNs.
The Four types of Tregs in malignant lymphomas
Authors: Jing Wang, Xiao-Yan Ke
Journal: Journal of Hematology & Oncology (2011)

Regulatory T cells (Tregs) are a specialized subpopulation of CD4+ T cells, which act to suppress the activation of other immune cells. Tregs represent important modulators for the interaction between lymphomas and host microenvironment. Lymphomas are a group of serious and frequently fatal malignant diseases of lymphocytes. Recent studies revealed that some lymphoma T cells might adopt a Treg profile. Assessment of Treg phenotypes and genotypes in patients may offer prediction of outcome in many types of lymphomas including diffuse large B-cell lymphoma, follicular lymphoma, cutaneous T cell lymphoma, and Hodgkin's lymphoma. Based on characterized roles of Tregs in lymphomas, we can categorize the various roles into four groups: (a) suppressor Tregs; (b) malignant Tregs; (c) direct tumor-killing Tregs; and (d) incompetent Tregs. The classification into four groups is significant in predicting prognosis and designing Tregs-based immunotherapies for treating lymphomas. In patients with lymphomas where Tregs serve either as suppressor Tregs or malignant Tregs, anti-tumor cytotoxicity is suppressed thus decreased numbers of Tregs are associated with a good prognosis. In contrast, in patients with lymphomas where Tregs serve as tumor-killing Tregs and incompetent Tregs, anti-tumor cytotoxicity is enhanced or anti-autoimmune Tregs activities are weakened thus increased numbers of Tregs are associated with a good prognosis and reduced numbers of Tregs are associated with a poor prognosis. However, the mechanisms underlying the various roles of Tregs in patients with lymphomas remain unknown. Therefore, further research is needed in this regard as well as the utility of Tregs as prognostic factors and therapy strategies in different lymphomas.
Reduced NAA Levels in the Dorsolateral Prefrontal Cortex of Young Bipolar Patients
Authors: Roberto B. Sassi, Jeffrey A. Stanley, David Axelson, Paolo Brambilla, Mark A. Nicoletti, Matcheri S. Keshavan, Renato T. Ramos, Neal Ryan, Boris Birmaher, Jair C. Soares
Journal: American Journal of Psychiatry (2005)

OBJECTIVE: Converging evidence implicates prefrontal circuits in the pathophysiology of bipolar disorder. Proton spectroscopy studies performed in adult bipolar patients assessing prefrontal regions have suggested decreased levels of N-acetylaspartate (NAA), a putative marker of neuronal integrity. In order to examine whether such abnormalities would also be found in younger patients, a 1H spectroscopy study was conducted that focused on the dorsolateral prefrontal cortex of children and adolescents with bipolar disorder. METHOD: The authors examined the levels of NAA, creatine plus phosphocreatine, and choline-containing molecules in the left dorsolateral prefrontal cortex of 14 bipolar disorder patients (mean age=15.5 years, SD=3, eight female) and 18 healthy comparison subjects (mean age=17.3, SD=3.7, seven female) using short echo time, single-voxel in vivo 1H spectroscopy. Absolute metabolite levels were determined using the water signal as an internal reference. RESULTS: Bipolar patients presented significantly lower NAA levels and a significant inverse correlation between choline-containing molecules and number of previous affective episodes. No differences were found for other metabolites. CONCLUSIONS: These findings suggest that young bipolar patients have decreased NAA levels in the dorsolateral prefrontal cortex, similar to what was previously reported in adult patients. Such changes may reflect an underdevelopment of dendritic arborizations and synaptic connections. These neuronal abnormalities in the dorsolateral prefrontal cortex of bipolar disorder youth are unlikely to represent long-term degenerative processes, at least in the subgroup of patients where the illness had relatively early onset.
Controlled trial of oral prednisone in outpatients with acute COPD exacerbation.
Authors: W H Thompson, C P Nielson, P Carvalho, N B Charan, J J Crowley
Journal: American Journal of Respiratory and Critical Care Medicine (1996)

Corticosteroids are often used in the outpatient treatment of acute exacerbation of chronic obstructive pulmonary disease (COPD). To date, there are few data documenting the benefit of this practice. The objective of this randomized, double-blind, placebo-controlled trial was to assess the efficacy of corticosteroids in the outpatient treatment of COPD exacerbations. Twenty-seven patients presenting with acute COPD exacerbation were studied. In addition to continuing their previous medications and increasing their use of beta-agonists, patients were randomized to receive a 9-d tapering dose of either oral prednisone or placebo. Treatment with prednisone rather than placebo resulted in a more rapid improvement in arterial PO2 (PaO2) (1.12 mm Hg/d versus -0.03 mm Hg/day; p = 0.002), alveolar-arterial oxygen gradient (A-aDO2) (-1.16 mm Hg/d versus -0.03 mm Hg/day; p = 0.04), FEV1 (0.05 L/d versus 0.00 L/d; p = 0.006), and peak expiratory flow (PEF) (0.15 L/s/d versus 0.04 L/s/d; p = 0.009). Prednisone also resulted in fewer treatment failures (p = 0.002) and in a trend toward more rapid improvement in dyspnea scale scores. Outpatient treatment of acute COPD exacerbation with prednisone accelerates recovery of PaO2, A-aDO2, FEV1, and PEF, reduces the treatment failure rate, and improves subjective dyspnea.