tbuckley/cabot-search huggingface dataset:
Treatment with Soluble Interleukin-15Rα Exacerbates Intracellular Parasitic Infection by Blocking the Development of Memory CD8+ T Cell Response
Authors: Imtiaz A. Khan, Magali Moretto, Xiao-qing Wei, Martha Williams, Joseph D. Schwartzman, Foo Y. Liew
Journal: The Journal of Experimental Medicine (2002)

Interferon (IFN)-γ–producing CD8+ T cells are important for the successful resolution of the obligate intracellular parasite Toxoplasma gondii by preventing the reactivation or controlling a repeat infection. Previous reports from our laboratory have shown that exogenous interleukin (IL)-15 treatment augments the CD8+ T cell response against the parasite. However, the role of endogenous IL-15 in the proliferation of activated/memory CD8+ T cells during toxoplasma or any other infection is unknown. In this study, we treated T. gondii immune mice with soluble IL-15 receptor α (sIL-15Rα) to block the host endogenous IL-15. The treatment markedly reduced the ability of the immune animals to control a lethal infection. CD8+ T cell activities in the sIL-15Rα–administered mice were severely reduced as determined by IFN-γ release and target cell lysis assays. The loss of CD8+ T cell immunity due to sIL-15Rα treatment was further demonstrated by adoptive transfer experiments. Naive recipients transferred with CD44hi activated/memory CD8+ T cells and treated with sIL-15Rα failed to resist a lethal T. gondii infection. Moreover, sIL-15Rα treatment of the recipients blocked the ability of donor CD44hi activated/memory CD8+ T cells to replicate in response to T. gondii challenge. To our knowledge, this is the first demonstration of the important role of host IL-15 in the development of antigen-specific memory CD8+ T cells against an intracellular infection.
Concentrations of Urinary Phthalate Metabolites Are Associated with Increased Waist Circumference and Insulin Resistance in Adult U.S. Males
Authors: Richard W. Stahlhut, Edwin van Wijngaarden, Timothy D. Dye, Stephen Cook, Shanna H. Swan
Journal: Environmental Health Perspectives (2007)

Phthalates impair rodent testicular function and have been associated with anti-androgenic effects in humans, including decreased testosterone levels. Low testosterone in adult human males has been associated with increased prevalence of obesity, insulin resistance, and diabetes.Our objective in this study was to investigate phthalate exposure and its associations with abdominal obesity and insulin resistance.Subjects were adult U.S. male participants in the National Health and Nutrition Examination Survey (NHANES) 1999-2002. We modeled six phthalate metabolites with prevalent exposure and known or suspected antiandrogenic activity as predictors of waist circumference and log-transformed homeostatic model assessment (HOMA; a measure of insulin resistance) using multiple linear regression, adjusted for age, race/ethnicity, fat and total calorie consumption, physical activity level, serum cotinine, and urine creatinine (model 1); and adjusted for model 1 covariates plus measures of renal and hepatic function (model 2). Metabolites were mono-butyl phthalates (MBP), mono-ethyl phthalate (MEP), mono-(2-ethyl)-hexyl phthalate (MEHP), mono-benzyl phthalate (MBzP), mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), and mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP).In model 1, four metabolites were associated with increased waist circumference (MBzP, MEHHP, MEOHP, and MEP; p-values </= 0.013) and three with increased HOMA (MBP, MBzP, and MEP; p-values </= 0.011). When we also adjusted for renal and hepatic function, parameter estimates declined but all significant results remained so except HOMA-MBP.In this national cross-section of U.S. men, concentrations of several prevalent phthalate metabolites showed statistically significant correlations with abdominal obesity and insulin resistance. If confirmed by longitudinal studies, our findings would suggest that exposure to these phthalates may contribute to the population burden of obesity, insulin resistance, and related clinical disorders.
Angiopoietin-1 Overexpression Modulates Vascular Endothelium to Facilitate Tumor Cell Dissemination and Metastasis Establishment
Authors: Tanja Holopainen, Huilian Huang, Caiping Chen, Kyung Eun Kim, Luqing Zhang, Fei Zhou, Wencan Han, Chaojun Li, Jun Yu, Jun Wu, Gou Young Koh, Kari Alitalo, Yulong He
Journal: Cancer Research (2009)

Abstract The angiopoietin-1 (Ang1)/Tie2 signaling pathway is known to play an important role in the regulation of vascular maturation and maintenance of vessel integrity. In this study, we have investigated the effect of systemic Tie2 activation or inhibition on tumor growth and metastasis. We found that treatment with Ang1 delivered via an adenoviral vector promoted s.c. implanted tumor metastasis to the lungs. Ang1 treatment did not significantly increase vascular density in the tumors but induced enlargement of blood vessels in both the tumor and normal tissues, which increased tumor cell dissemination into the blood circulation. Ang1 also enhanced the formation of metastatic foci in the lungs when tumor cells were injected into the circulation via the tail vein. The effect of Ang1 on metastasis was validated by a simultaneous treatment with a soluble form of Tie2 (sTie2), which led to the suppression of Ang1-induced increase of tumor metastasis. Furthermore, using a highly metastatic tumor model, we confirmed that systemic treatment with sTie2 suppressed tumor metastasis to the lungs and lymph nodes, whereas tumor-associated angiogenesis and lymphangiogenesis were not significantly affected. This suggests that the Ang1/Tie2 signals contribute to tumor progression by increasing vascular entry and exit of tumor cells to facilitate tumor dissemination and establishment of metastases. [Cancer Res 2009;69(11):4656–64]
Positron Emission Tomography Using [18F]Galacto-RGD Identifies the Level of Integrin αvβ3 Expression in Man
Authors: Ambros J. Beer, Roland Haubner, Mario Sarbia, Michael Goebel, Stephan Luderschmidt, Anca Ligia Grosu, Oliver Schnell, Markus Niemeyer, Horst Kessler, Hans-Jürgen Wester, Wolfgang A. Weber, Markus Schwaiger
Journal: Clinical Cancer Research (2006)

Abstract Purpose: The integrin αvβ3 plays a key role in angiogenesis and tumor cell metastasis and is therefore an important target for new therapeutic and diagnostic strategies. We have developed [18F]Galacto-RGD, a highly αvβ3-selective tracer for positron emission tomography (PET). Here, we show, in man, that the intensity of [18F]Galacto-RGD uptake correlates with αvβ3 expression. Experimental Design: Nineteen patients with solid tumors (musculoskeletal system, n = 10; melanoma, n = 4; head and neck cancer, n = 2; gliobastoma, n = 2; and breast cancer, n = 1) were examined with PET using [18F]Galacto-RGD before surgical removal of the tumor lesions. Snap-frozen specimens (n = 26) were collected from representative areas with low and intense standardized uptake values (SUV) of [18F]Galacto-RGD. Immunohistochemistry was done using the αvβ3-specific antibody LM609. Intensity of staining (graded on a four-point scale) and the microvessel density of αvβ3-positive vessels were determined and correlated with SUV and tumor/blood ratios (T/B). Results: Two tumors showed no tracer uptake (mean SUV, 0.5 ± 0.1). All other tumors showed tracer accumulation with SUVs ranging from 1.2 to 10.0 (mean, 3.8 ± 2.3; T/B, 3.4 ± 2.2; tumor/muscle ratio, 7.7 ± 5.4). The correlation of SUV and T/B with the intensity of immunohistochemical staining (Spearman's r = 0.92; P &amp;lt; 0.0001) as well as with the microvessel density (Spearman's r = 0.84; P &amp;lt; 0.0001) were significant. Immunohistochemistry confirmed lack of αvβ3 expression in normal tissue (benign lymph nodes, muscle) and in the two tumors without tracer uptake. Conclusions: Molecular imaging of αvβ3 expression with [18F]Galacto-RGD in humans correlates with αvβ3 expression as determined by immunohistochemistry. PET with [18F]Galacto-RGD might therefore be used as a new marker of angiogenesis and for individualized planning of therapeutic strategies with αvβ3-targeted drugs.
A Phase I/II Trial of Pazopanib in Combination with Lapatinib in Adult Patients with Relapsed Malignant Glioma
Authors: David A. Reardon, Morris D. Groves, Patrick Y. Wen, Louis Nabors, Tom Mikkelsen, Steve Rosenfeld, Jeffrey Raizer, Jorge Barriuso, Roger E. McLendon, A. Benjamin Suttle, Bo Ma, C. Martin Curtis, Mohammed M. Dar, Johann de Bono
Journal: Clinical Cancer Research (2013)

Increased mitogenic signaling and angiogenesis, frequently facilitated by somatic activation of EGF receptor (EGFR; ErbB1) and/or loss of PTEN, and VEGF overexpression, respectively, drive malignant glioma growth. We hypothesized that patients with recurrent glioblastoma would exhibit differential antitumor benefit based on tumor PTEN/EGFRvIII status when treated with the antiangiogenic agent pazopanib and the ErbB inhibitor lapatinib.A phase II study evaluated the antitumor activity of pazopanib 400 mg/d plus lapatinib 1,000 mg/d in patients with grade 4 malignant glioma and known PTEN/EGFRvIII status not receiving enzyme-inducing anticonvulsants (EIAC). The phase II study used a two-stage Green-Dahlberg design for futility. An independent, parallel phase I component determined the maximum-tolerated regimen (MTR) of pazopanib and lapatinib in patients with grade 3/4 glioma receiving EIACs.The six-month progression-free survival (PFS) rates in phase II (n = 41) were 0% and 15% in the PTEN/EGFRvIII-positive and PTEN/EGFRvIII-negative cohorts, respectively, leading to early termination. Two patients (5%) had a partial response and 14 patients (34%) had stable disease lasting 8 or more weeks. In phase I (n = 34), the MTR was not reached. On the basis of pharmacokinetic and safety review, a regimen of pazopanib 600 mg plus lapatinib 1,000 mg, each twice daily, was considered safe. Concomitant EIACs reduced exposure to pazopanib and lapatinib.The antitumor activity of this combination at the phase II dose tested was limited. Pharmacokinetic data indicated that exposure to lapatinib was subtherapeutic in the phase II evaluation. Evaluation of intratumoral drug delivery and activity may be essential for hypothesis-testing trials with targeted agents in malignant glioma.
A GRADE Working Group approach for rating the quality of treatment effect estimates from network meta-analysis
Authors: M. A. Puhan, H. J. Schunemann, M. H. Murad, T. Li, R. Brignardello-Petersen, J. A. Singh, A. G. Kessels, G. H. Guyatt
Journal: BMJ (2014)

Network meta-analysis (NMA), combining direct and indirect comparisons, is increasingly being used to examine the comparative effectiveness of medical interventions. Minimal guidance exists on how to rate the quality of evidence supporting treatment effect estimates obtained from NMA. We present a four-step approach to rate the quality of evidence in each of the direct, indirect, and NMA estimates based on methods developed by the GRADE working group. Using an example of a published NMA, we show that the quality of evidence supporting NMA estimates varies from high to very low across comparisons, and that quality ratings given to a whole network are uninformative and likely to mislead.
INHERITANCE OF ANTIBODY SPECIFICITY
Authors: Thereza Imanishi, O. Mäkelä
Journal: The Journal of Experimental Medicine (1974)

Our data suggest that fine specificity of antihapten antibodies is a useful Mendelian marker of variable (V) genes. We found that some mouse strains (e.g., C57/BL6) consistently produced heteroclitic anti-(4-hydroxy-3-nitrophenyl)acetyl (NP) antibodies (relative affinity for related (4-hydroxy-5-iodo-3-nitrophenyl)acetyl and (4-hydroxy-3.5-dinitrophenyl)acetyl was always >2) while other strains (e.g., CBA) produced "conventional" anti-NP antibodies (relative affinities were consistently <1). 48 (CBA x C57BL/6)F(1) mice were studied and most of them had heteroclitic anti-NP antibodies. They were backcrossed to the recessive CBA parent, and 87 backcross animals were similarly tested. Those heterozygous for the C57BL/6 heavy (H)-chain allotype were similar to the C57BL/6 and the F(1) mice while mice homozygous for the CBA allotype were indistinguishable from the CBA. Such monogenic inheritance was observed only in the primary response. Predominance of allotype-linked genes in the control of the fine specificity characteristics was confirmed by immunizing selected homozygous mouse strains. These mice contained various mixtures of genes from C57BL, BALB/c, and other strains. Specificity of their anti-NP was exclusively determined by genes linked to the H-chain allotype, no influence could be attributed to other genes including the H-2-linked genes.
Angiotensin-Converting Enzyme <i>I/D</i> Polymorphism and Arterial Wall Thickness in a General Population
Authors: Maurizio Castellano, Maria Lorenza Muiesan, Damiano Rizzoni, Marina Beschi, Gianfranco Pasini, Angelo Cinelli, Massimo Salvetti, Enzo Porteri, Giorgio Bettoni, Reinhold Kreutz, Klaus Lindpaintner, Enrico Agabiti Rosei
Journal: Circulation (1995)

Background It has been reported that the D allele of an insertion/deletion ( I/D ) polymorphism of the angiotensin I–converting enzyme (ACE) gene is associated with conditions of increased cardiovascular risk, including left ventricular hypertrophy. Methods and Results Considering that a genetically determined overactivity of the renin-angiotensin system may influence cardiac as well as vascular growth, we investigated possible relations between ACE I/D genotype and carotid artery wall thickness (B-mode ultrasound) in 199 subjects, 50 to 64 years old, sampled from the general population of Vobarno, a small town in northern Italy. ACE DD genotype was associated with significantly higher common carotid artery intima-media thickness ( P =.003). The occurrence of carotid atherosclerotic plaques was similar in the different genotypes. There was no association of the ACE I/D genotype with blood pressure values (either casual or 24-hour ambulatory monitored). Conclusions ACE DD genotype may be considered a risk factor for the development of common carotid intima-media thickening in our study population.
A pilot study of therapeutic vaccination with envelope protein E1 in 35 patients with chronic hepatitis C
Authors: Frederik Nevens, Tania Roskams, Hans Van Vlierberghe, Yves Horsmans, Dirk Sprengers, Ann Elewaut, Valeer Desmet, Geert Leroux-Roels, Emmanuel Quinaux, Erik Depla, Stephanie Dincq, Christine Vander Stichele, Geert Maertens, Frank Hulstaert
Journal: Hepatology (2003)

New treatments are needed for chronic hepatitis C patients in whom viral clearance cannot be achieved. Thirty–five chronic hepatitis C patients (genotype 1) were randomized to receive 20 μg of recombinant HCV E1 (E1) (n = 26) or placebo (n = 9) intramuscularly at weeks 0, 4, 8, 12, and 24. Thirty–four then received open–label E1 vaccine at weeks 50, 53, 56, 59, 62, and 65. Twenty–four patients (12 men, 12 women; mean age, 52 y; 18 interferon–based treatment failures; mean baseline alanine aminotransferase [ALT] level, 118 IU/L) underwent a biopsy before and after 2 courses of E1, 17 months later. Liver histology was scored by 2 blinded pathologists according to the Ishak and Metavir systems. Postinjection reactions were similar to placebo (alum only). Nine of 24 patients (38%) had improvement of 2 points or more, 10 (41%) remained stable, and 5 (21%) showed worsening in total Ishak score. Nine patients (38%) improved both on Ishak and Metavir fibrosis scores. Plasma HCV–RNA levels remained unchanged, whereas ALT levels showed a trend toward a decrease during treatment. All but 3 patients developed a significant de novo E1–specific T–cell response. The increase in anti–E1 antibody levels correlated with the decrease in total Ishak score and with the relative decreases in both Ishak fibrosis score and ALT level (all P ≤ .01). In conclusion, E1 therapeutic vaccination is well tolerated and the observed effects warrant further study.
Has Epidemiology Become Infatuated With Methods? A Historical Perspective on the Place of Methods During the Classical (1945–1965) Phase of Epidemiology
Authors: Alfredo Morabia
Journal: Annual Review of Public Health (2015)

Before World War II, epidemiology was a small discipline, practiced by a handful of people working mostly in the United Kingdom and in the United States. Today it is practiced by tens of thousands of people on all continents. Between 1945 and 1965, during what is known as its "classical" phase, epidemiology became recognized as a major academic discipline in medicine and public health. On the basis of a review of the historical evidence, this article examines to which extent classical epidemiology has been a golden age of an action-driven, problem-solving science, in which epidemiologists were less concerned with the sophistication of their methods than with the societal consequences of their work. It also discusses whether the paucity of methods stymied or boosted classical epidemiology's ability to convince political and financial agencies about the need to intervene in order to improve the health of the people.
Multistate Point-Prevalence Survey of Health Care–Associated Infections
Authors: Shelley S. Magill, Jonathan R. Edwards, Wendy Bamberg, Zintars G. Beldavs, Ghinwa Dumyati, Marion A. Kainer, Ruth Lynfield, Meghan Maloney, Laura McAllister-Hollod, Joelle Nadle, Susan M. Ray, Deborah L. Thompson, Lucy E. Wilson, Scott K. Fridkin
Journal: New England Journal of Medicine (2014)

Currently, no single U.S. surveillance system can provide estimates of the burden of all types of health care-associated infections across acute care patient populations. We conducted a prevalence survey in 10 geographically diverse states to determine the prevalence of health care-associated infections in acute care hospitals and generate updated estimates of the national burden of such infections.
IDH1 Mutations Alter Citric Acid Cycle Metabolism and Increase Dependence on Oxidative Mitochondrial Metabolism
Authors: Alexandra R. Grassian, Seth J. Parker, Shawn M. Davidson, Ajit S. Divakaruni, Courtney R. Green, Xiamei Zhang, Kelly L. Slocum, Minying Pu, Fallon Lin, Chad Vickers, Carol Joud-Caldwell, Franklin Chung, Hong Yin, Erika D. Handly, Christopher Straub, Joseph D. Growney, Matthew G. Vander Heiden, Anne N. Murphy, Raymond Pagliarini, Christian M. Metallo
Journal: Cancer Research (2014)

Abstract Oncogenic mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) occur in several types of cancer, but the metabolic consequences of these genetic changes are not fully understood. In this study, we performed 13C metabolic flux analysis on a panel of isogenic cell lines containing heterozygous IDH1/2 mutations. We observed that under hypoxic conditions, IDH1-mutant cells exhibited increased oxidative tricarboxylic acid metabolism along with decreased reductive glutamine metabolism, but not IDH2-mutant cells. However, selective inhibition of mutant IDH1 enzyme function could not reverse the defect in reductive carboxylation activity. Furthermore, this metabolic reprogramming increased the sensitivity of IDH1-mutant cells to hypoxia or electron transport chain inhibition in vitro. Lastly, IDH1-mutant cells also grew poorly as subcutaneous xenografts within a hypoxic in vivo microenvironment. Together, our results suggest therapeutic opportunities to exploit the metabolic vulnerabilities specific to IDH1 mutation. Cancer Res; 74(12); 3317–31. ©2014 AACR.
Declare all or be damned OR Bias in the eye of the beholder
Authors: Ian Jessiman
Journal: Journal of the Royal Society of Medicine (2009)

Have I been wrong all these years in thinking that ‘declarations of competing interest’ were intended to prevent any deliberate (or even inadvertent) misrepresentation of findings or conclusions in research studies? Your final sentence1 requires the declaration of all competing interests, be they financial, political, religious or even related to being a public servant or academic. This is getting dangerous!

None of us can be sure our opinions, however carefully formed, can be entirely free of bias, but we should not be prevented or inhibited from expressing them by some supposed higher ‘authority’ (current notions of ‘PC’, or the editor, perhaps?), or by fear of provoking bias in the reader. Smith et al.2 point out that ‘we are all conflicted’ but their paper shows that the bias in interpreting the presented facts is as much in the reader as in the author(s). If we follow the path you propose will not all further scientific progress be inhibited?
Role of exercise counselling in health promotion
Authors: Abby C King
Journal: British Journal of Sports Medicine (2000)

Despite the clear health benefits that can be attained through adopting a more active lifestyle, most adults in the United Kingdom as well as other industrial nations remain underactive. Faced with this epidemic, there is a growing need for physical activity interventions that can be widely disseminated to all segments of the population across the lifespan.

One promising avenue for physical activity counselling and support lies with the primary care doctor and other health care professionals. The strengths of incorporating physical activity advice and support as part of routine health care include the ability to reach a substantial portion of the population repeatedly over time, the consistency and continuity of message content and delivery, and the willingness among patients to act on their doctor's advice.1,2 Despite these strengths, however, a number of barriers to physical activity counselling in primary care have been documented, including lack of time, reimbursement, and training in physical activity or behaviour change counselling.3 Although such barriers present continuing challenges to the health promotion and health care fields, the potential public health impact that primary care settings can have on health behaviour change, including physical …
Survival After Coronary Revascularization Among Patients With Kidney Disease
Authors: Brenda R. Hemmelgarn, Danielle Southern, Bruce F. Culleton, L. Brent Mitchell, Merril L. Knudtson, William A. Ghali
Journal: Circulation (2004)

The optimal approach to revascularization in patients with kidney disease has not been determined. We studied survival by treatment group (CABG, percutaneous coronary intervention [PCI], or no revascularization) for patients with 3 categories of kidney function: dialysis-dependent kidney disease, non-dialysis-dependent kidney disease, and a reference group (serum creatinine <2.3 mg/dL).Data were derived from the Alberta Provincial Project for Outcomes Assessment in Coronary Heart Disease (APPROACH), which captures information on all patients undergoing cardiac catheterization in Alberta, Canada. Characteristics and patient survival in 662 dialysis patients (1.6%) and 750 non-dialysis-dependent kidney disease patients (1.8%) were compared with the remainder of the 40,374 patients (96.6%). For the reference group, the adjusted 8-year survival rates for CABG, PCI, and no revascularization (NR) were 85.5%, 80.4%, and 72.3%, respectively (P<0.001 for CABG versus NR; P<0.001 for PCI versus NR). Adjusted survival rates were 45.9% for CABG, 32.7% for PCI, and 29.7% for NR in the nondialysis kidney disease group (P<0.001 for CABG versus NR; P=0.48 for PCI versus NR) and 44.8% for CABG, 41.2% for PCI, and 30.4% for NR in the dialysis group (P=0.003 for CABG versus NR; P=0.03 for PCI versus NR).Compared with no revascularization, CABG was associated with better survival in all categories of kidney function. PCI was also associated with a lower risk of death than no revascularization in reference patients and dialysis-dependent kidney disease patients but not in patients with non-dialysis-dependent kidney disease. The presence of kidney disease or dependence on dialysis should not be a deterrent to revascularization, particularly with CABG.