tbuckley/cabot-search huggingface dataset:
Antioxidized LDL Antibodies Are Associated With Different Metabolic Pathways in Patients With Atherosclerotic Plaque and Type 2 Diabetes
Authors: M. Rosa Bernal-Lopez, Lourdes Garrido-Sanchez, Victor Gomez-Carrillo, Jose Luis Gallego-Perales, Vicenta Llorente-Cortes, Fernando Calleja, Ricardo Gomez-Huelgas, Lina Badimon, Francisco J. Tinahones
Journal: Diabetes Care (2012)

Oxidized lipoproteins and antioxidized LDL antibodies (antioxLDL abs) have been detected in human plasma and atherosclerotic lesions. The principle aim of this study was to analyze the possible relationship between IgG and IgM antioxLDL abs and factors involved in different metabolic pathways (inflammation, lipid metabolism, apoptosis, and cell cycle arrest profile) in the occluded popliteal artery (OPA) compared with the femoral vein (FV).Fifteen patients with advanced atherosclerosis and type 2 diabetes undergoing lower limb amputation participated in this study. Each patient had OPA and FV biopsy specimens and peripheral arterial occlusive disease. By real-time PCR, gene expression was analyzed from the OPA and FV specimens, and antioxLDL ab levels were measured by specific enzyme-linked immunosorbent assay.The OPA and FV showed a positive correlation between only IgM antioxLDL ab levels and the expression of genes involved in different metabolic pathways, including inflammation (TFPI), apoptosis (BAX, caspase 3, AKT1), plaque disruption (MMP2 and MMP10), lipid metabolism (SCARB1, PPARg), and cell turnover (CDKN1A), and genes for transcription and growth factors (NFkB and VEGFA, respectively).The results show that gene expression in the metabolic pathways (apoptosis, lipid metabolism, and inflammation) in the OPA and FV are directly related to the levels of IgM antioxLDL abs.
Long-Term Follow-Up of Cisplatin Combination Chemotherapy in Patients With Disseminated Nonseminomatous Germ Cell Tumors: Is a Postchemotherapy Retroperitoneal Lymph Node Dissection Needed After Complete Remission?
Authors: Yaron Ehrlich, Mary J. Brames, Stephen D.W. Beck, Richard S. Foster, Lawrence H. Einhorn
Journal: Journal of Clinical Oncology (2009)

Controversy arises regarding the optimal management of patients with nonseminomatous germ cell tumor (NSGCT) who achieve a serologic and radiographic complete remission (CR) to systemic chemotherapy. Some authors recommend postchemotherapy retroperitoneal lymph node dissection (PC-RPLND), whereas others omit surgery and observe these patients. In an attempt to address this question, we report the long-term follow-up of patients treated at Indiana University who were observed without PC-RPLND.This is a retrospective analysis of patients with NSGCT who achieved a CR to first-line chemotherapy and were monitored without further therapy. CR was defined as normalization of serum tumor markers and resolution of radiographic disease (residual mass < 1 cm).One hundred forty-one patients were identified. Five patients (4%) had less than 2 years of follow-up. After a median follow-up of 15.5 years, 12 patients (9%) experienced relapse. Of these 12 patients, eight patients currently have no evidence of disease (NED), and four patients died of disease. The estimated 15-year recurrence-free survival (RFS) and cancer-specific survival rates were 90% and 97%, respectively. The estimated 15-year RFS for good-risk patients (n = 109) versus intermediate- or poor-risk patients (n = 32) was 95% and 73% (P = .001), respectively. Six patients (4%) experienced recurrence in the retroperitoneum, of whom two patients died of disease. Five patients had late relapse (range, 3 to 13 years), including two patients in the retroperitoneum. All five patients currently have NED.Patients obtaining a CR after first-line chemotherapy can be safely observed without PC-RPLND. Relapses are rare and potentially curable with further treatment.
Endurance training and testing with the ball in young elite soccer players
Authors: K Chamari, Y Hachana, F Kaouech, R Jeddi, I Moussa-Chamari, U Wisløff
Journal: British Journal of Sports Medicine (2004)

The aerobic capacity of soccer players substantially influences their technical performance and tactical choices. Thus, the assessment of soccer players' aerobic performance should be of interest for soccer coaches in order to evaluate and improve their endurance training sessions. In this study, we present a new test to assess aerobic performance in soccer by means of a specific dribbling track: the Hoff test. We further determined whether improvement in maximal oxygen uptake was reflected in increased distance covered in the Hoff test.We tested 18 male soccer players (14 years old) both in the laboratory and using the Hoff test before and after 8 weeks of soccer training.The distance covered in the Hoff test correlated significantly with maximum oxygen uptake, and improved by 9.6% during the 8 week training period, while maximum oxygen uptake and running economy improved by 12 and 10%, respectively. Backward multiple regression showed maximum oxygen uptake to be the main explanatory variable for the distance covered in the Hoff test.The present study demonstrated a significant correlation between laboratory testing of VO(2max) and performance in the Hoff test. Furthermore, training induced improvements in VO(2max) were reflected in improved performance in the Hoff test. We suggest that it should be a goal for active U-15 soccer players to cover more than 2100 metres in the Hoff test, as this requires a VO(2max) of above 200 ml/kg(0.75)/min, which should serve as a minimum in modern soccer.
Phase I Trial of the Prostate-Specific Membrane Antigen–Directed Immunoconjugate MLN2704 in Patients With Progressive Metastatic Castration-Resistant Prostate Cancer
Authors: Matthew D. Galsky, Mario Eisenberger, Sandra Moore-Cooper, W. Kevin Kelly, Susan F. Slovin, Anthony DeLaCruz, Yih Lee, Iain J. Webb, Howard I. Scher
Journal: Journal of Clinical Oncology (2008)

MLN2704 is an immunoconjugate designed to deliver the maytansinoid antimicrotubule agent drug maytansinoid-1 directly to prostate-specific membrane antigen (PSMA)-expressing cells via the PSMA-targeted monoclonal antibody MLN591. This novel immunoconjugate has shown cytotoxic anti-prostate cancer activity. This study investigated the safety profile, pharmacokinetics, immunogenicity, and preliminary antitumor activity of MLN2704.Patients with progressive, metastatic, castration-resistant prostate cancer received MLN2704 intravenously over 2.5 hours. Dose-limiting toxicity (DLT), maximum-tolerated dose (MTD), pharmacokinetics, immunogenicity, and antitumor activity were assessed.Twenty-three patients received MLN2704 at doses of 18 to 343 mg/m(2). Eighteen of these patients received >or= three doses at 4-week intervals. Pharmacokinetics of conjugate levels were dose proportional. There was no correlation between clearance and body-surface area. MLN2704 was nonimmunogenic. Study drug-related grade 3 toxicities occurred in three (13%) of 23 patients, including uncomplicated febrile neutropenia (the only DLT) in one patient, reversible elevations in hepatic transaminases, leukopenia, and lymphopenia. No grade 4 toxicities were observed. The most frequent grade 1 or 2 toxicities included fatigue, nausea, and diarrhea. Neuropathy occurred in eight (35%) of 23 patients, including five of six patients treated at 343 mg/m(2). Two (22%) of the nine patients treated at 264 or 343 mg/m(2) had sustained a more than 50% decrease in prostate-specific antigen versus baseline, accompanied by measurable tumor regression in the patient treated at 264 mg/m(2).Therapeutic doses of MLN2704 can be administered safely on a repetitive basis. An MTD was not defined. MLN2704 is being administered at more frequent intervals in ongoing trials to determine an optimal dosing schedule.
Can Game Theory Explain Invasive Tumor Metabolism?
Authors: Mike Martin
Journal: JNCI Journal of the National Cancer Institute (2009)

“In the evolutionary sense, only traits that allow successful adaptations survive,” said Phillip Manno, M.D., chief of clinical oncology and hematology at the Nevada Cancer Institute in Las Vegas. “This idea can certainly be applied to cancer, in which cells acquire a needed phenotype to survive.” With the right mathematical approach, researchers can frame intercellular interactions that lead to phenotype acquisitions as survival games. Coming from a long tradition in sociology, economics, and more recently, biology, “game theory has been used successfully to study the evolutionary dynamics of populations made of different phenotypes in traditional ecosystems,” said Basanta. “We believe it can be used to study the evolutionary trajectories of cancer.” Some researchers consider carcinogenesis itself an evolutionary trajectory. In almost stepwise progression, cancer cells evolve by acquiring different phenotypes, including the ability to trigger blood vessel growth, invade surrounding tissue, me tastasize, and grow autono mously. As these phenotypes evolve, survival
A dichotomy in bronchiolitis obliterans syndrome after lung transplantation revealed by azithromycin therapy
Authors: B. M. Vanaudenaerde, I. Meyts, R. Vos, N. Geudens, W. De Wever, E. K. Verbeken, D. E. Van Raemdonck, L. J. Dupont, G. M. Verleden
Journal: European Respiratory Journal (2008)

Bronchiolitis obliterans syndrome (BOS) is the most important cause of late mortality following lung transplantation, resulting in major morbidity and a huge burden on healthcare resources. Treatment options are limited, resulting in a mere stabilisation of the lung function decline. Recent introduction of the macrolide antibiotic azithromycin raised new hope after demonstrating lung function improvement in subsets of patients. The present study aimed to provide an overview of the clinical effects on azithromycin in the setting of BOS after lung transplantation, with special emphasis on the anti-inflammatory actions. Moreover, the authors proposed a new frame of thinking centred on a dichotomy in the pathogenesis and clinical phenotype of BOS. Subsets of BOS patients were identified who do or do not respond to azithromycin (regarding forced expiratory volume in one second (FEV 1 ), bronchoalveolar lavage (BAL) neutrophilia/interleukin-8). These observations have shed new light on the current belief that BOS represents a homogenous clinical entity in which the neutrophil is the main culprit. Recent clinical observations, supported by research findings, have revealed a dichotomy in the clinical spectrum of BOS with neutrophilic (partially) reversible allograft dysfunction (responding to azithromycin) and fibroproliferative BOS (not responding to azithromycin). This concept is reinforced by unique data obtained in BOS patients, consisting of histology specimens, physical and radiological examination, FEV 1 and BAL examination. The acceptance of this dichotomy can improve understanding of the heterogeneous pathological condition that constitutes bronchiolitis obliterans syndrome, thus encouraging a more accurate diagnosis and, ultimately, better tailored treatment for each bronchiolitis obliterans syndrome patient.
Temporal Constraints on the Incorporation of Regulatory Mutants in Evolutionary Pathways
Authors: K. M. Brown, M. A. DePristo, D. M. Weinreich, D. L. Hartl
Journal: Molecular Biology and Evolution (2009)

Understanding the molecular details of the sequence of events in multistep evolutionary pathways can reveal the extent to which natural selection exploits regulatory mutations affecting expression, amino acid replacements affecting the active site, amino acid replacements affecting protein folding or stability, or variations affecting gene copy number. In experimentally exploring the adaptive landscape of the evolution of resistance to beta-lactam antibiotics in enteric bacteria, we noted that a regulatory mutation that increases beta-lactamase expression by about 2-fold has a very strong tendency to be fixed at or near the end of the evolutionary pathway. This pattern contrasts with previous experiments selecting for the utilization of novel substrates, in which regulatory mutations that increase expression are often fixed early in the process. To understand the basis of the difference, we carried out experiments in which the expression of beta-lactamase was under the control of a tunable arabinose promoter. We find that the fitness effect of an increase in gene expression is highly dependent on the catalytic activity of the coding sequence. An increase in expression of an inefficient enzyme has a negligible effect on drug resistance; however, the effect of an increase in expression of an efficient enzyme is very large. The contrast in the temporal incorporation of regulatory mutants between antibiotic resistance and the utilization of novel substrates is related to the nature of the function that relates enzyme activity to fitness. A mathematical model of beta-lactam resistance is examined in detail and shown to be consistent with the observed results.
Complex systems model of fatigue: integrative homoeostatic control of peripheral physiological systems during exercise in humans
Authors: E V Lambert, A St Clair Gibson, T D Noakes
Journal: British Journal of Sports Medicine (2004)

Fatigue is hypothesised as being the result of the complex interaction of multiple peripheral physiological systems and the brain. In this new model, all changes in peripheral physiological systems such as substrate depletion or metabolite accumulation act as afferent signallers which modulate control processes in the brain in a dynamic, non-linear, integrative manner.
How social marketing works in health care
Authors: W Douglas Evans
Journal: BMJ (2006)

Social marketing applies commercial marketing strategies to promote public health. Social marketing is effective on a population level, and healthcare providers can contribute to its effectiveness.

In the preface to Marketing Social Change , Andreasen defines social marketing as “the application of proven concepts and techniques drawn from the commercial sector to promote changes in diverse socially important behaviors such as drug use, smoking, sexual behavior… This marketing approach has an immense potential to affect major social problems if we can only learn how to harness its power.”1 By “proven techniques” Andreasen meant methods drawn from behavioural theory, persuasion psychology, and marketing science with regard to health behaviour, human reactions to messages and message delivery, and the “marketing mix” or “four Ps” of marketing (place, price, product, and promotion).2 These methods include using behavioural theory to influence behaviour that affects health; assessing factors that underlie the receptivity of audiences to messages, such as the credibility and likeability of the argument; and strategic marketing of messages that aim to change the behaviour of target audiences using the four Ps.3

Social marketing is widely used to influence health behaviour. Social marketers use a wide range of health communication strategies based on mass media; they also use mediated (for example, through a healthcare provider), interpersonal, and other modes of communication; and marketing methods such as message placement (for example, in clinics), promotion, dissemination, and community level outreach. Social marketing encompasses all of these strategies.



Fig 1 
Social marketing wheel



Communication channels for health information have changed greatly in recent years. One-way dissemination of information has given way to a multimodal transactional model of communication. Social marketers face challenges such as increased numbers and types of health issues competing for the public's attention; limitations on people's time; and increased numbers and types of …
A phase I–II study of everolimus (RAD001) in combination with imatinib in patients with imatinib-resistant gastrointestinal stromal tumors
Authors: P. Schöffski, P. Reichardt, J.-Y. Blay, H. Dumez, J.A. Morgan, I. Ray-Coquard, N. Hollaender, A. Jappe, G.D. Demetri
Journal: Annals of Oncology (2010)
β-Adrenergic Signaling Inhibits G <sub>q</sub> -Dependent Protein Kinase D Activation by Preventing Protein Kinase D Translocation
Authors: C. Blake Nichols, Chia-Wei Chang, Maura Ferrero, Brent M. Wood, Matthew L. Stein, Amanda J. Ferguson, Derrick Ha, Robert R. Rigor, Sven Bossuyt, Julie Bossuyt
Journal: Circulation Research (2014)

Rationale: Both β-adrenergic receptor (β-AR) and G q -coupled receptor (G q R) agonist–driven signaling play key roles in the events, leading up to and during cardiac dysfunction. How these stimuli interact at the level of protein kinase D (PKD), a nodal point in cardiac hypertrophic signaling, remains unclear. Objective: To assess the spatiotemporal dynamics of PKD activation in response to β-AR signaling alone and on coactivation with G q R-agonists. This will test our hypothesis that compartmentalized PKD signaling reconciles disparate findings of PKA facilitation and inhibition of PKD activation. Methods and Results: We report on the spatial and temporal profiles of PKD activation using green fluorescent protein-tagged PKD (wildtype or mutant S427E) and targeted fluorescence resonance energy transfer–based biosensors (D-kinase activity reporters) in adult cardiomyocytes. We find that β-AR/PKA signaling drives local nuclear activation of PKD, without preceding sarcolemmal translocation. We also discover pronounced interference of β-AR/cAMP/PKA signaling on G q R-induced translocation and activation of PKD throughout the cardiomyocyte. We attribute these effects to direct, PKA-dependent phosphorylation of PKD-S427. We also show that phosphomimetic substitution of S427 likewise impedes G q R-induced PKD translocation and activation. In neonatal myocytes, S427E inhibits G q R-evoked cell growth and expression of hypertrophic markers. Finally, we show altered S427 phosphorylation in transverse aortic constriction–induced hypertrophy. Conclusions: β-AR signaling triggers local nuclear signaling and inhibits G q R-mediated PKD activation by preventing its intracellular translocation. PKA-dependent phosphorylation of PKD-S427 fine-tunes the PKD responsiveness to G q R-agonists, serving as a key integration point for β-adrenergic and G q -coupled stimuli.
Distinct roles of Smad pathways and p38 pathways in cartilage-specific gene expression in synovial fibroblasts
Authors: Hiroaki Seto, Satoshi Kamekura, Toshiki Miura, Aiichiro Yamamoto, Hirotaka Chikuda, Toru Ogata, Hisatada Hiraoka, Hiromi Oda, Kozo Nakamura, Hisashi Kurosawa, Ung-il Chug, Hiroshi Kawaguchi, Sakae Tanaka
Journal: Journal of Clinical Investigation (2004)

The role of TGF-beta/bone morphogenetic protein signaling in the chondrogenic differentiation of human synovial fibroblasts (SFs) was examined with the adenovirus vector-mediated gene transduction system. Expression of constitutively active activin receptor-like kinase 3 (ALK3CA) induced chondrocyte-specific gene expression in SFs cultured in pellets or in SF pellets transplanted into nude mice, in which both the Smad and p38 pathways are essential. To analyze downstream cascades of ALK3 signaling, we utilized adenovirus vectors carrying either Smad1 to stimulate Smad pathways or constitutively active MKK6 (MKK6CA) to activate p38 pathways. Smad1 expression had a synergistic effect on ALK3CA, while activation of p38 MAP kinase pathways alone by transduction of MKK6CA accelerated terminal chondrocytic differentiation, leading to type X collagen expression and enhanced mineralization. Overexpression of Smad1 prevented MKK6CA-induced type X collagen expression and maintained type II collagen expression. In a mouse model of osteoarthritis, activated p38 expression as well as type X collagen staining was detected in osteochondrophytes and marginal synovial cells. These results suggest that SFs can be differentiated into chondrocytes via ALK3 activation and that stimulating Smad pathways and controlling p38 activation at the proper level can be a good therapeutic strategy for maintaining the healthy joint homeostasis and treating degenerative joint disorders.
Rheumatoid Arthritis–Interstitial Lung Disease–associated Mortality
Authors: Amy L. Olson, Jeffrey J. Swigris, David B. Sprunger, Aryeh Fischer, Evans R. Fernandez-Perez, Josh Solomon, James Murphy, Marc Cohen, Ganesh Raghu, Kevin K. Brown
Journal: American Journal of Respiratory and Critical Care Medicine (2010)

Mortality rates from rheumatoid arthritis-associated interstitial lung disease (RA-ILD) are largely unknown.We sought to determine mortality rates from rheumatoid arthritis-associated interstitial lung disease in the United States from 1988 through 2004.Using data from the National Center for Health Statistics, we calculated age-adjusted mortality rates from the deaths of persons with rheumatoid arthritis-associated interstitial lung disease, determined the prevalence of interstitial lung disease in all decedents with rheumatoid arthritis, and compared the age and underlying cause of death in these two cohorts of decedents.From 1988 to 2004, there were 39,138,394 deaths in U.S. residents and 162,032 rheumatoid arthritis-associated deaths. Of these deaths, 10,725 (6.6%) met criteria for rheumatoid arthritis-associated interstitial lung. Mortality rates from rheumatoid arthritis fell over the course of this study in both women and men. However, mortality rates from rheumatoid arthritis-associated interstitial lung disease increased 28.3% in women (to 3.1 per million persons in 2004) and declined 12.5% in men (to 1.5 per million persons in 2004). Because the rate of decline in rheumatoid arthritis outpaced rheumatoid arthritis-associated interstitial lung disease in men, the prevalence of rheumatoid arthritis-associated interstitial lung disease increased in both sexes over time.Clinically significant RA-ILD occurs in nearly 10% of the RA population, and is associated with shortened survival and more severe underlying disease. Whereas overall mortality rates for RA have fallen, those associated with RA-ILD have increased significantly in older age groups.
The humoral immune response after BCG vaccination in humans: consequences for the serodiagnosis of tuberculosis
Authors: M Turneer, JP Van Vooren, J Nyabenda, F Legros, A Lecomte, J Thiriaux, E Serruys, JC Yernault
Journal: European Respiratory Journal (1988)

The IgM and IgG response to BCG vaccination was investigated in 75 adults, tuberculin negative before vaccination, using an enzyme-linked immunosorbent assay with purified protein derivative (PPD) as antigen. The mean optical density (OD) increased significantly (p less than 0.001) in both immunoglobulin classes. Increase in at least one class was significant in 89% of the subjects. The observed increase in anti-PPD IgG was rather small but comparable to that seen in 17 newly diagnosed tuberculosis patients with negative direct smear [mean OD (SD): 0.59 (0.38) in vaccinated and 0.70 (0.48) in patients] but significantly lower (p less than 0.001) than that seen in 31 newly diagnosed patients with positive direct smear [mean OD (SD): 1.07 (0.67)]. With 55% of sera above the upper normal limit, smear positive patients differentiated (p less than 0.001) from vaccinated subjects (20% of positive sera) whilst smear negative patients (29% of positive sera) did not. We conclude that BCG vaccination induces a definite but small increase in anti-PPD serum IgM and IgG, which is likely to interfere when interpreting serological tests for the diagnosis of tuberculosis, especially in those patients who would most benefit from an early and fast diagnosis.