tbuckley/cabot-search huggingface dataset:
Orienteering performance and ingestion of glucose and glucose polymers.
Authors: U M Kujala, O J Heinonen, M Kvist, O P Kärkkäinen, J Marniemi, K Niittymäki, E Havas
Journal: British Journal of Sports Medicine (1989)

The benefit of glucose polymer ingestion in addition to 2.5 per cent glucose before and during a prolonged orienteering competition was studied. The final time in the competition in the group ingesting 2.5 per cent glucose (group G, n = 10) was 113 min 37 s +/- 8 min 11 s, and in the group which had additionally ingested glucose polymer (group G + GP, n = 8) 107 min 18s +/- 4 min 41 s (NS). One fifth (21 per cent) of the time difference between the two groups was due to difference in orienteering errors. Group G + GP orienteered the last third of the competition faster than group G (p less than 0.05). The time ratio between the last third of the competition and the first third of the competition was lower in group G + GP than in group G (p less than 0.05). After the competition, there was statistically insignificant tendency to higher serum glucose and lower serum free fatty acid concentrations in group G + GP, and serum insulin concentration was higher in group G + GP than in group G (p less than 0.05). Three subjects reported that they exhausted during the competition. These same three subjects had the lowest serum glucose concentrations after the competition (2.9 mmol.1(-1), 2.9 mmol.1(-1), 3.5 mmol.1(-1] and all of them were from group G. It is concluded that glucose polymer syrup ingestion is beneficial for prolonged psychophysical performance.
Alcohol's evaporating health benefits
Authors: M. Daube
Journal: BMJ (2015)

Industry lobbying and promotion are rife and unchecked by governments

Given the harms attributed to alcohol use, it is not surprising that reports1 2 showing possible mortality benefits for low level users attracted enthusiasm among consumers, the media, and the alcohol industry, along with those who welcomed this as a positive response to accusations that calls for action were based on moral fervour. These apparent benefits are now evaporating, helped along by an important contribution in this week’s issue (doi:10.1136/bmj.h384).3 Through analyses based on the Health Survey for England, particularly designed to identify whether any reductions in mortality risk were greatest in older populations, Knott and colleagues show that if there is any beneficial dose-response relation, it is limited to women aged 65 or more—and even that association is at best modest and likely to be explained by selection bias.3

From the early days, headlines such as “a few drinks may help curb heart attacks”4 promoted messages around alcohol’s cardioprotective properties; many doctors felt comfortable advising patients that alcohol consumption could be beneficial and politicians used evidence on possible benefits to justify their failure to act on reducing harms.5

Alcohol companies …
Dendritic Cell-Based Vaccination in Solid Cancer
Authors: A. Stift, J. Friedl, P. Dubsky, T. Bachleitner-Hofmann, G. Schueller, T. Zontsich, T. Benkoe, K. Radelbauer, C. Brostjan, R. Jakesz, M. Gnant
Journal: Journal of Clinical Oncology (2002)

Purpose: Dendritic cell (DC)-based immunotherapy is rapidly emerging as a viable tool in cancer treatment. This approach has been used mostly in patients in the presence of defined tumor antigens such as melanoma. In this study, cancer patients with advanced disease that lacks defined tumor antigens were vaccinated with tumor lysate-pulsed DCs. Patients and Methods: Twenty patients (pancreatic, hepatocellular, cholangiocellular, and medullary thyroid carcinoma) with stage IV disease were enrolled in the study. In 3-week intervals, freshly isolated autologous CD14 magnetic bead-selected monocytes were cultured in granulocyte-macrophage colony-stimulating factor and interleukin-4 to obtain immature DCs. These cells were pulsed with autologous tumor lysate and matured with tumor necrosis factor alpha. Mature DCs were applied into a groin lymph node, under ultrasound guidance. Adjuvant interleukin-2 (20,000 U/kg) was given subcutaneously daily, for 12 days, after each vaccination. Toxicity, tumor marker profile, immune response, and clinical response were determined. Results: Vaccination was well tolerated. No physical signs of autoimmunity were detected. DC vaccination induced delayed-type hypersensitivity reactivity in 18 patients. Tumor marker responses were observed in eight patients. In addition, in three patients the generation of interferon gamma-positive T cells was induced during the vaccination. Objective changes in measurable lesions or tumor markers were evident in seven of 20 assessed patients. None of the patients was found to meet the criteria for partial or complete responses. Conclusion: These data indicate that vaccination with autologous tumor-pulsed DCs generated from peripheral blood is safe and can induce tumor-specific cellular cytotoxicity. Clinical responses are achievable, even in patients with advanced disease.
Medication Adherence and Racial Differences in A1C Control
Authors: Alyce S. Adams, Connie Mah Trinacty, Fang Zhang, Ken Kleinman, Richard W. Grant, James B. Meigs, Stephen B. Soumerai, Dennis Ross-Degnan
Journal: Diabetes Care (2008)

The purpose of this study was to examine medication adherence and other self-management practices as potential determinants of higher glycemic risk among black relative to white patients.We used a retrospective, longitudinal repeated-measures design to model the contribution of medication adherence to black-white differences in A1C among type 2 diabetic patients at a large multispecialty group practice. We identified 1,806 adult (aged >/=18 at diagnosis) patients (467 black and 1,339 white) with newly initiated oral hypoglycemic therapy between 1 December 1994 and 31 December 2000. Race was identified using an electronic medical record and patient self-report. Baseline was defined as the 13 months preceding and included the month of therapy initiation. All patients were required to have at least 12 months of follow-up.At initiation of therapy, black patients had higher average A1C values compared with whites (9.8 vs. 8.9, a difference of 0.88; P < 0.0001). Blacks had lower average medication adherence during the first year of therapy (72 vs. 78%; P < 0.0001). Although more frequent medication refills were associated with lower average A1C values, adjustment for adherence did not eliminate the black-white gap.We found persistent racial differences in A1C that were not explained by differences in medication adherence. Our findings suggest that targeting medication adherence alone is unlikely to reduce disparities in glycemic control in this setting. Further research is needed to explore possible genetic and environmental determinants of higher A1C among blacks at diagnosis, which may represent a critical period for more intensive intervention.
Plasma Selenium, Manganese Superoxide Dismutase, and Intermediate- or High-Risk Prostate Cancer
Authors: June M. Chan, William K. Oh, Wanling Xie, Meredith M. Regan, Meir J. Stampfer, Irena B. King, Miyako Abe, Philip W. Kantoff
Journal: Journal of Clinical Oncology (2009)

Purpose In vitro, in vivo, and epidemiologic studies support a role for selenium in reducing the risk of prostate cancer. Our group previously demonstrated a strong interaction between plasma selenium and the manganese superoxide dismutase (SOD2) gene and incident prostate cancer risk. We now hypothesized that SOD2 modifies the association between selenium level and risk of aggressive prostate cancer at diagnosis. Patients and Methods We assessed SOD2 variants and plasma selenium in 489 patients with localized/locally advanced prostate cancer from an ongoing retrospective cohort. Cross-sectional associations with aggressive prostate cancer (ie, stage T2b-3, prostate-specific antigen &gt; 10 ng/mL, or biopsy Gleason score ≥ 7) were evaluated using the χ 2 test, Cochran-Armitage test for trend, and estimations of relative risk (RR) and 95% CIs. Results SOD2 genotype alone was not associated with disease aggressiveness, whereas higher versus lower selenium levels were associated with a slightly increased likelihood of presenting with aggressive disease (RR = 1.35; 95% CI, 0.99 to 1.84). There was evidence of an interaction between SOD2 and selenium levels such that among men with the AA genotype, higher selenium levels were associated with a reduced risk of presenting with aggressive disease (RR = 0.60; 95% CI, 0.32 to 1.12), whereas among men with a V allele, higher selenium levels were associated with an increased risk of aggressive disease (for VV or VA men, RR = 1.82; 95% CI, 1.27 to 2.61; P for interaction = .007). Conclusion These data suggest that the relationship between circulating selenium levels at diagnosis and prognostic risk of prostate cancer is modified by SOD2 genotype and indicate caution against broad use of selenium supplementation for men with prostate cancer.
Membrane-associated Hsp72 from tumor-derived exosomes mediates STAT3-dependent immunosuppressive function of mouse and human myeloid-derived suppressor cells
Authors: Fanny Chalmin, Sylvain Ladoire, Grégoire Mignot, Julie Vincent, Mélanie Bruchard, Jean-Paul Remy-Martin, Wilfrid Boireau, Alain Rouleau, Benoit Simon, David Lanneau, Aurélie De Thonel, Gabriele Multhoff, Arlette Hamman, François Martin, Bruno Chauffert, Eric Solary, Laurence Zitvogel, Carmen Garrido, Bernhard Ryffel, Christophe Borg, Lionel Apetoh, Cédric Rébé, François Ghiringhelli
Journal: Journal of Clinical Investigation (2010)

Myeloid-derived suppressor cells (MDSCs) have been identified in humans and mice as a population of immature myeloid cells with the ability to suppress T cell activation. They accumulate in tumor-bearing mice and humans and have been shown to contribute to cancer development. Here, we have isolated tumor-derived exosomes (TDEs) from mouse cell lines and shown that an interaction between TDE-associated Hsp72 and MDSCs determines the suppressive activity of the MDSCs via activation of Stat3. In addition, tumor-derived soluble factors triggered MDSC expansion via activation of Erk. TDE-associated Hsp72 triggered Stat3 activation in MDSCs in a TLR2/MyD88-dependent manner through autocrine production of IL-6. Importantly, decreasing exosome production using dimethyl amiloride enhanced the in vivo antitumor efficacy of the chemotherapeutic drug cyclophosphamide in 3 different mouse tumor models. We also demonstrated that this mechanism is relevant in cancer patients, as TDEs from a human tumor cell line activated human MDSCs and triggered their suppressive function in an Hsp72/TLR2-dependent manner. Further, MDSCs from cancer patients treated with amiloride, a drug used to treat high blood pressure that also inhibits exosome formation, exhibited reduced suppressor functions. Collectively, our findings show in both mice and humans that Hsp72 expressed at the surface of TDEs restrains tumor immune surveillance by promoting MDSC suppressive functions.
Nebivolol improves insulin sensitivity in the TGR(Ren2)27 rat
Authors: Camila Manrique, Guido Lastra, Javad Habibi, Lakshmi Pulakat, Rebecca Schneider, William Durante, Roger Tilmon, Jenna Rehmer, Melvin R. Hayden, Carlos M. Ferrario, Adam Whaley-Connell, James R. Sowers
Journal: Metabolism (2011)
Interleukin-4- and Interleukin-13-Mediated Alternatively Activated Macrophages: Roles in Homeostasis and Disease
Authors: Steven J. Van Dyken, Richard M. Locksley
Journal: Annual Review of Immunology (2013)

The macrophage, a versatile cell type prominently involved in host defense and immunity, assumes a distinct state of alternative activation in the context of polarized type 2 immune responses such as allergic inflammation and helminth infection. This alternatively activated phenotype is induced by the canonical type 2 cytokines interleukin (IL)-4 and IL-13, which mediate expression of several characteristic markers along with a dramatic shift in macrophage metabolic pathways that influence surrounding cells and tissues. We discuss recent advances in the understanding of IL-4- and IL-13-mediated alternatively activated macrophages and type 2 immune responses; such advances have led to an expanded appreciation for functions of these cells beyond immunity, including maintenance of physiologic homeostasis and tissue repair.
Associations Between Cigarette Smoking Status and Colon Cancer Prognosis Among Participants in North Central Cancer Treatment Group Phase III Trial N0147
Authors: Amanda I. Phipps, Qian Shi, Polly A. Newcomb, Garth D. Nelson, Daniel J. Sargent, Steven R. Alberts, Paul J. Limburg
Journal: Journal of Clinical Oncology (2013)

Purpose By using data from North Central Cancer Treatment Group Phase III Trial N0147, a randomized adjuvant trial of patients with stage III colon cancer, we assessed the relationship between smoking and cancer outcomes, disease-free survival (DFS), and time to recurrence (TTR), accounting for heterogeneity by patient and tumor characteristics. Patients and Methods Before random assignment to infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX) or FOLFOX plus cetuximab, 1,968 participants completed a questionnaire on smoking history and other risk factors. Cox models assessed the association between smoking history and the primary trial outcome of DFS (ie, time to recurrence or death), as well as TTR, adjusting for other clinical and patient factors. The median follow-up was 3.5 years among patients who did not experience events. Results Compared with never-smokers, ever smokers experienced significantly shorter DFS (3-year DFS proportion: 70% v 74%; hazard ratio [HR], 1.21; 95% CI, 1.02 to 1.42). This association persisted after multivariate adjustment (HR, 1.23; 95% CI, 1.02 to 1.49). There was significant interaction in this association by BRAF mutation status (P = .03): smoking was associated with shorter DFS in patients with BRAF wild-type (HR, 1.36; 95% CI, 1.11 to 1.66) but not BRAF mutated (HR, 0.80; 95% CI, 0.50 to 1.29) colon cancer. Smoking was more strongly associated with poorer DFS in those with KRAS mutated versus KRAS wild-type colon cancer (HR, 1.50 [95% CI, 1.12 to 2.00] v HR, 1.09 [95% CI, 0.85 to 1.39]), although interaction by KRAS mutation status was not statistically significant (P = .07). Associations were comparable in analyses of TTR. Conclusion Overall, smoking was significantly associated with shorter DFS and TTR in patients with colon cancer. These adverse relationships were most evident in patients with BRAF wild-type or KRAS mutated colon cancer.
Torn apart: membrane rupture in muscular dystrophies and associated cardiomyopathies
Authors: Jan Lammerding, Richard T. Lee
Journal: Journal of Clinical Investigation (2007)

Muscular dystrophies are often caused by mutations in cytoskeletal proteins that render cells more susceptible to strain-induced injury in mechanically active tissues such as skeletal or cardiac muscle. In this issue of the JCI, Han et al. report that dysferlin participates in membrane resealing in cardiomyocytes and that exercise results in increased membrane damage and disturbed cardiac function in dysferlin-deficient mice (see the related article beginning on page 1805). Thus, in addition to repetitive membrane damage, inadequate membrane repair may participate in the pathogenesis of muscular dystrophies and cardiomyopathies.
Immunogenicity of anti-TNF antibodies. Has the veil been lifted?
Authors: G. Van Assche
Journal: Gut (2010)

If you adhere to Homer's account of what happened in Troy, the greatest of all warriors, Achilles, would have been invincible if it hadn't been for the soft spot on his heel. So be it for all therapeutic antibodies, undoubtedly a successful innovation of modern-day pharmacotherapy and biotechnology. All engineered proteins, even recombinant human proteins such as γ-interferon or erythropoietin, are foreign to the human immune system and can induce antidrug antibodies, a phenomenon commonly known as immunogenicity.1–3 Antidrug antibodies are particularly important when they neutralise the drug or induce side effects such as infusion reactions. The antitumour necrosis factor (TNF) agents used to treat inflammatory bowel disease (IBD) are all engineered monocolonal antibodies or antibody fragments, and they are typically used in scheduled maintenance treatment. Therefore, a durable response over time is paramount and, as physicians caring for patients with Crohn's disease and ulcerative colitis, we have learnt to deal with immunogenicity and with the loss of response to anti-TNF treatment. However, burning questions on the nature and the relevance of antidrug antibodies remain unanswered >10 years after the introduction of these agents into the care of patients with IBD. Many open questions pertaining to the immunogenicity of monoclonal antibodies are generated by corporate proprietary interests of the pharmaceutical companies who have engineered these compounds. During the subsequent phases of clinical development antidrug antibodies are measured with in-house, not publically available, assays. Also for commercially available compounds, standardisation of trough level or antidrug antibody assays has not yet been achieved. Cohort studies released within years after the introduction of infliximab (IFX) into clinical practice have shown that anti-IFX antibodies (ATIs) are found in the majority of patients with IBD when this drug is used episodically.4 5 Scheduled maintenance use 6 7 concomitant immunosuppressives4 6 7 and premedication …
Detergent resistant membrane-associated IDE in brain tissue and cultured cells: Relevance to Aβ and insulin degradation
Authors: Ayelén Bulloj, María C Leal, Ezequiel I Surace, Xue Zhang, Huaxi Xu, Maria D Ledesma, Eduardo M Castaño, Laura Morelli
Journal: Molecular Neurodegeneration (2008)

Abstract Background Insulin degrading enzyme (IDE) is implicated in the regulation of amyloid β (Aβ) steady-state levels in the brain, and its deficient expression and/or activity may be a risk factor in sporadic Alzheimer's disease (AD). Although IDE sub-cellular localization has been well studied, the compartments relevant to Aβ degradation remain to be determined. Results Our results of live immunofluorescence, immuno gold electron-microscopy and gradient fractionation concurred to the demonstration that endogenous IDE from brain tissues and cell cultures is, in addition to its other localizations, a detergent-resistant membrane (DRM)-associated metallopeptidase. Our pulse chase experiments were in accordance with the existence of two pools of IDE: the cytosolic one with a longer half-life and the membrane-IDE with a faster turn-over. DRMs-associated IDE co-localized with Aβ and its distribution (DRMs vs. non-DRMs) and activity was sensitive to manipulation of lipid composition in vitro and in vivo. When IDE was mis-located from DRMs by treating cells with methyl-β-cyclodextrin (MβCD), endogenous Aβ accumulated in the extracellular space and exogenous Aβ proteolysis was impaired. We detected a reduced amount of IDE in DRMs of membranes isolated from mice brain with endogenous reduced levels of cholesterol (Chol) due to targeted deletion of one seladin-1 allele. We confirmed that a moderate shift of IDE from DRMs induced a substantial decrement on IDE-mediated insulin and Aβ degradation in vitro. Conclusion Our results support the notion that optimal substrate degradation by IDE may require its association with organized-DRMs. Alternatively, DRMs but not other plasma membrane regions, may act as platforms where Aβ accumulates, due to its hydrophobic properties, reaching local concentration close to its Km for IDE facilitating its clearance. Structural integrity of DRMs may also be required to tightly retain insulin receptor and IDE for insulin proteolysis. The concept that mis-location of Aβ degrading proteases away from DRMs may impair the physiological turn-over of Aβ in vivo deserves further investigation in light of therapeutic strategies based on enhancing Aβ proteolysis in which DRM protease-targeting may need to be taken into account.
Risk of Cardiovascular Disease and Total Mortality in Adults with Type 1 Diabetes: Scottish Registry Linkage Study
Authors: Shona J. Livingstone, Helen C. Looker, Eleanor J. Hothersall, Sarah H. Wild, Robert S. Lindsay, John Chalmers, Stephen Cleland, Graham P. Leese, John McKnight, Andrew D. Morris, Donald W. M. Pearson, Norman R. Peden, John R. Petrie, Sam Philip, Naveed Sattar, Frank Sullivan, Helen M. Colhoun
Journal: PLoS Medicine (2012)

Randomized controlled trials have shown the importance of tight glucose control in type 1 diabetes (T1DM), but few recent studies have evaluated the risk of cardiovascular disease (CVD) and all-cause mortality among adults with T1DM. We evaluated these risks in adults with T1DM compared with the non-diabetic population in a nationwide study from Scotland and examined control of CVD risk factors in those with T1DM.The Scottish Care Information-Diabetes Collaboration database was used to identify all people registered with T1DM and aged ≥20 years in 2005-2007 and to provide risk factor data. Major CVD events and deaths were obtained from the national hospital admissions database and death register. The age-adjusted incidence rate ratio (IRR) for CVD and mortality in T1DM (n = 21,789) versus the non-diabetic population (3.96 million) was estimated using Poisson regression. The age-adjusted IRR for first CVD event associated with T1DM versus the non-diabetic population was higher in women (3.0: 95% CI 2.4-3.8, p<0.001) than men (2.3: 2.0-2.7, p<0.001) while the IRR for all-cause mortality associated with T1DM was comparable at 2.6 (2.2-3.0, p<0.001) in men and 2.7 (2.2-3.4, p<0.001) in women. Between 2005-2007, among individuals with T1DM, 34 of 123 deaths among 10,173 who were <40 years and 37 of 907 deaths among 12,739 who were ≥40 years had an underlying cause of death of coma or diabetic ketoacidosis. Among individuals 60-69 years, approximately three extra deaths per 100 per year occurred among men with T1DM (28.51/1,000 person years at risk), and two per 100 per year for women (17.99/1,000 person years at risk). 28% of those with T1DM were current smokers, 13% achieved target HbA(1c) of <7% and 37% had very poor (≥9%) glycaemic control. Among those aged ≥40, 37% had blood pressures above even conservative targets (≥140/90 mmHg) and 39% of those ≥40 years were not on a statin. Although many of these risk factors were comparable to those previously reported in other developed countries, CVD and mortality rates may not be generalizable to other countries. Limitations included lack of information on the specific insulin therapy used.Although the relative risks for CVD and total mortality associated with T1DM in this population have declined relative to earlier studies, T1DM continues to be associated with higher CVD and death rates than the non-diabetic population. Risk factor management should be improved to further reduce risk but better treatment approaches for achieving good glycaemic control are badly needed. Please see later in the article for the Editors' Summary.
Identifying Gut Microbe–Host Phenotype Relationships Using Combinatorial Communities in Gnotobiotic Mice
Authors: Jeremiah J. Faith, Philip P. Ahern, Vanessa K. Ridaura, Jiye Cheng, Jeffrey I. Gordon
Journal: Science Translational Medicine (2014)

Identifying human gut bacterial strains that affect three diverse biological responses should facilitate discovery of next-generation probiotics and realization of the microbiota’s diagnostic potential.