tbuckley/cabot-search huggingface dataset:
Towards gene therapy for the treatment of rheumatoid arthritis: production and bioactivity of interferon in fibroblast-like synoviocytes transduced with adeno-associated virus type 5 expressing human interferon 
Authors: C. J. Aalbers, S. A. Loiler, F. Mingozzi, P. P. Tak, M. J. Vervoordeldonk
Journal: Annals of the Rheumatic Diseases (2011)

<h3>Background and objectives</h3> The authors are developing local intra-articular gene therapy for the treatment of rheumatoid arthritis (RA) using human interferon β (hIFNβ) as therapeutic gene expressed under control of an inflammation-inducible promoter and recombinant adeno-associated virus type 5 as vector (ART-I02). To evaluate hIFNβ expression by ART-I02 and bioactivity, fibroblast-like synoviocytes (FLS) from RA patients and different animal species were transduced with ART-I02 and the culture medium was analysed. Since most RA patients in their future phase I trial will be on methotrexate (MTX) treatment, the authors investigated the influence of MTX on transduction efficacy. <h3>Methods</h3> Primary human, monkey, mouse and rat and non-primary rabbit FLS were transduced with ART-I02 (MOI 200.000). To activate the nuclear factor-κB promoter, cells were stimulated with tumour necrosis factor (TNF) (1 ng/ml) with or without interleukin 1β (IL-1β) (10 ng/ml) 4 or 24 h post-transduction. In addition, human FLS were incubated in medium with MTX (10 nM, 1 μM, 100 μM) added pretransduction and post-transduction. Supernatants were harvested 48 h after stimulation. Production of hIFNβ was measured by ELISA. Bioactivity was established by analysing the effect on pro-inflammatory cytokine (IL-6, IL-8) and matrix metalloproteinases (MMP) production by ELISA and with a quantitative gene reporter bioassay. <h3>Results</h3> Human IFNβ production was detectable in supernatants of FLS of all species, with comparable levels in human and monkey FLS. In human FLS transduced with ART-I02, the inhibition of IL-8 (80%) and MMP3 (60%) secretion was most pronounced after stimulation with TNF 24 h after transduction (p&lt;0.05). IL-6 production was significantly (p&lt;0.05) reduced by hIFNβ in cells stimulated with both TNF and IL-1β. Monkey FLS expressing hIFNβ showed a 40% decrease in IL-8 secretion (p&lt;0.01) after stimulation with TNF. No effect of hIFNβ on cytokine and MMP secretion was observed in rabbit and rodent FLS. Human IFNβ produced by both human and monkey FLS showed robust levels of bioactivity in the gene reporter bioassay. MTX treatment did not influence hIFNβ production by ART-I02 or bioactivity. <h3>Conclusion</h3> Transduction of FLS with ART-I02 resulted in significant hIFNβ expression in FLS of all species. Moreover, hIFNβ produced by ART-I02-transduced cells is bioactive in human and monkey FLS. This study supports the use of non-human primates in a non-clinical pharmacology-toxicity programme and represents a next step towards a phase I clinical trial in RA patients.
Prediction of Mortality Using Measures of Cardiac Autonomic Dysfunction in the Diabetic and Nondiabetic Population
Authors: Dan Ziegler, Christian P. Zentai, Siegfried Perz, Wolfgang Rathmann, Burkhard Haastert, Angela Döring, Christa Meisinger
Journal: Diabetes Care (2008)

To evaluate whether reduced heart rate variability (HRV), prolonged corrected QT (QTc) interval, or increased QT dispersion (QTD) are predictors of mortality in the general diabetic and nondiabetic population.Nondiabetic (n = 1,560) and diabetic (n = 160) subjects aged 55-74 years were assessed to determine whether reduced HRV, prolonged QTc interval, and increased QTD may predict all-cause mortality. Lowest quartiles for the maximum-minimum R-R interval difference (max-min, as measured at baseline from a 20-s standard 12-lead resting electrocardiogram without controlling for depth and rate of respiration), QTc >440 ms and QTD >60 ms, were used as cutpoints.During a 9-year follow-up, 10.5% of the nondiabetic and 30.6% of the diabetic population deceased. In the nondiabetic individuals, multivariate Cox proportional hazard models adjusted for cardiovascular risk factors and demographic variables showed that prolonged QTc interval (hazard ratio 2.02 [95% CI 1.29-3.17]; P = 0.002) but not low max-min (0.93 [0.65-1.34]; P = 0.700), and increased QTD (0.98 [0.60-1.60]; P = 0.939) were associated with increased mortality. In the diabetic subjects, prolonged QTc was also a predictor of mortality (3.00 [1.34-6.71]; P = 0.007), while a trend for an increased risk was noted in those with low max-min (1.74 [0.95-3.18]; P = 0.075), whereas increased QTD did not predict mortality (0.42 [0.06-3.16]; P = 0.402).Prolonged QTc interval, but not increased QTD, is an independent predictor of a twofold and threefold increased risk of mortality in the nondiabetic and diabetic elderly general population, respectively. Low HRV during spontaneous breathing tends to be associated with excess mortality in the diabetic but not nondiabetic population.
EAACI Position Paper on Rhinosinusitis and Nasal Polyps Executive Summary
Authors: W. Fokkens, V. Lund, C. Bachert, P. Clement, P. Helllings, M. Holmstrom, N. Jones, L. Kalogjera, D. Kennedy, M. Kowalski, H. Malmberg, J. Mullol, D. Passali, H. Stammberger, P. Stierna
Journal: Allergy (2005)
Phylo-MCOA: A Fast and Efficient Method to Detect Outlier Genes and Species in Phylogenomics Using Multiple Co-inertia Analysis
Authors: D. M. de Vienne, S. Ollier, G. Aguileta
Journal: Molecular Biology and Evolution (2012)

Full genome data sets are currently being explored on a regular basis to infer phylogenetic trees, but there are often discordances among the trees produced by different genes. An important goal in phylogenomics is to identify which individual gene and species produce the same phylogenetic tree and are thus likely to share the same evolutionary history. On the other hand, it is also essential to identify which genes and species produce discordant topologies and therefore evolve in a different way or represent noise in the data. The latter are outlier genes or species and they can provide a wealth of information on potentially interesting biological processes, such as incomplete lineage sorting, hybridization, and horizontal gene transfers. Here, we propose a new method to explore the genomic tree space and detect outlier genes and species based on multiple co-inertia analysis (MCOA), which efficiently captures and compares the similarities in the phylogenetic topologies produced by individual genes. Our method allows the rapid identification of outlier genes and species by extracting the similarities and discrepancies, in terms of the pairwise distances, between all the species in all the trees, simultaneously. This is achieved by using MCOA, which finds successive decomposition axes from individual ordinations (i.e., derived from distance matrices) that maximize a covariance function. The method is freely available as a set of R functions. The source code and tutorial can be found online at http://phylomcoa.cgenomics.org.
Potent Antimyeloma Activity of a Novel ERK5/CDK Inhibitor
Authors: Stela Álvarez-Fernández, María Jesús Ortiz-Ruiz, Tracy Parrott, Sara Zaknoen, Enrique M. Ocio, Jesús San Miguel, Francis J. Burrows, Azucena Esparís-Ogando, Atanasio Pandiella
Journal: Clinical Cancer Research (2013)

To analyze the antimyeloma potential of TG02, an ERK5/CDK inhibitory drug.Utilizing different multiple myeloma cell lines we determined the effect of TG02 over viability by MTT assays. The apoptotic effect over multiple myeloma patient samples was studied ex vivo by cytometry. The mechanism of action of TG02 was analyzed in the cell line MM1S, studying its effect on the cell cycle, the induction of apoptosis, and the loss of mitochondrial membrane potential by cytometry and Western blot. Two models of multiple myeloma xenograft were utilized to study the in vivo action of TG02.TG02 potently inhibited proliferation and survival of multiple myeloma cell lines, even under protective bone marrow niche conditions, and selectively induced apoptosis of primary patient-derived malignant plasma cells. TG02 displayed significant single-agent activity in two multiple myeloma xenograft models, and enhanced the in vivo activity of bortezomib and lenalidomide. Signaling analyses revealed that the drug simultaneously blocked the activity of CDKs 1, 2, and 9 as well as the MAP kinase ERK5 in MM1S cells, leading to cell-cycle arrest and rapid commitment to apoptosis. TG02 induced robust activation of both the intrinsic and extrinsic pathways of apoptosis, and depletion of XIAP and the key multiple myeloma survival protein Mcl-1.TG02 is a promising new antimyeloma agent that is currently in phase I clinical trials in leukemia and multiple myeloma patients.
Cardiac Monitoring During Adjuvant Trastuzumab-Based Chemotherapy Among Older Patients With Breast Cancer
Authors: Mariana Chavez-MacGregor, Jiangong Niu, Ning Zhang, Linda S. Elting, Benjamin D. Smith, Jose Banchs, Gabriel N. Hortobagyi, Sharon H. Giordano
Journal: Journal of Clinical Oncology (2015)

Purpose Patients treated with adjuvant trastuzumab require adequate cardiac monitoring. We describe the patterns of cardiac monitoring and evaluate factors associated with adequate monitoring in a large population-based study of older patients with breast cancer. Patients and Methods Patients age 66 years or older with full Medicare coverage, diagnosed with stage I to III breast cancer between 2005 and 2009, and treated with adjuvant trastuzumab-based chemotherapy were identified in the SEER-Medicare and the Texas Cancer Registry-Medicare databases. The adequacy of cardiac monitoring was determined. Chemotherapy, trastuzumab use, cardiac monitoring, and comorbidities were identified by using International Classification of Diseases, 9th revision and Healthcare Common Procedure Coding System codes. Prescribing physician characteristics were also evaluated. Analyses included descriptive statistics and multilevel logistic regression models. Results In all, 2,203 patients were identified; median age was 72 years. Adequate monitoring was identified in only 36.0% of the patients (n = 793). In the multivariable model, factors associated with optimal cardiac monitoring included a more recent year of diagnosis (hazard ratio [HR], 1.83; 95% CI, 1.32 to 2.54), anthracycline use (HR, 1.39; 95% CI, 1.14 to 1.71), female prescribing physician (HR, 1.37; 95% CI, 1.10 to 1.70), and physician graduating after 1990 (HR, 1.66; 95% CI, 1.29 to 2.12). The presence of cardiac comorbidities was not a determinant for cardiac monitoring. Of the variance in the adequacy of cardiac monitoring, 15.3% was attributable to physician factors and 5.2% to measured patient factors. Conclusion A large proportion of patients had suboptimal cardiac monitoring. Physician characteristics had more influence than measured patient-level factors in the adequacy of cardiac monitoring. Because trastuzumab-related cardiotoxicity is reversible, efforts to improve the adequacy of cardiac monitoring are needed, particularly in vulnerable populations.
Effect of pretreatment HIV-1 drug resistance on immunological, virological, and drug-resistance outcomes of first-line antiretroviral treatment in sub-Saharan Africa: a multicentre cohort study
Authors: Raph L Hamers, Rob Schuurman, Kim CE Sigaloff, Carole L Wallis, Cissy Kityo, Margaret Siwale, Kishor Mandaliya, Prudence Ive, Mariette E Botes, Maureen Wellington, Akin Osibogun, Ferdinand W Wit, Michèle van Vugt, Wendy S Stevens, Tobias F Rinke de Wit
Journal: The Lancet Infectious Diseases (2011)
B12 Deficiency in AIDS
Authors: Victor Herbert
Journal: JAMA (1988)

To the Editor.—  A letter in the June 3 issue of JAMA focuses attention on the frequency of vitamin B 12 deficiency in patients with acquired immunodeficiency syndrome (AIDS). 1 Beach et al 2 found low serum vitamin B 12 (cobalamin) levels in about 25% of 31 patients. Burkes et al 3 found that 20% of 40 patients had low serum vitamin B 12 levels and we that found 13 (16%) of 80 sequential adult men with AIDS, mainly drug abusers, had low levels ( 4 Harriman et al 5 found that 15% of 121 patients with AIDS had low serum vitamin B 12 levels. More strikingly, they did Schilling test evaluations on 11 patients with AIDS and found that eight (three with and five without low serum vitamin B 12 levels) had
Alternate transcription of the Toll-like receptor signaling cascade.
Authors: Christine A Wells, Alistair M Chalk, Alistair Forrest, Darrin Taylor, Nic Waddell, Kate Schroder, S Roy Himes, Geoffrey Faulkner, Sandra Lo, Takeya Kasukawa, Hideya Kawaji, Chikatoshi Kai, Jun Kawai, Shintaro Katayama, Piero Carninci, Yoshihide Hayashizaki, David A Hume, Sean M Grimmond
Journal: Genome biology (2006)

Abstract Background Alternate splicing of key signaling molecules in the Toll-like receptor (Tlr) cascade has been shown to dramatically alter the signaling capacity of inflammatory cells, but it is not known how common this mechanism is. We provide transcriptional evidence of widespread alternate splicing in the Toll-like receptor signaling pathway, derived from a systematic analysis of the FANTOM3 mouse data set. Functional annotation of variant proteins was assessed in light of inflammatory signaling in mouse primary macrophages, and the expression of each variant transcript was assessed by splicing arrays. Results A total of 256 variant transcripts were identified, including novel variants of Tlr4, Ticam1, Tollip, Rac1, Irak1, 2 and 4, Mapk14/p38, Atf2 and Stat1. The expression of variant transcripts was assessed using custom-designed splicing arrays. We functionally tested the expression of Tlr4 transcripts under a range of cytokine conditions via northern and quantitative real-time polymerase chain reaction. The effects of variant Mapk14/p38 protein expression on macrophage survival were demonstrated. Conclusion Members of the Toll-like receptor signaling pathway are highly alternatively spliced, producing a large number of novel proteins with the potential to functionally alter inflammatory outcomes. These variants are expressed in primary mouse macrophages in response to inflammatory mediators such as interferon-γ and lipopolysaccharide. Our data suggest a surprisingly common role for variant proteins in diversification/repression of inflammatory signaling.
<i>PIK3CA</i> Mutation Is Associated With Poor Prognosis Among Patients With Curatively Resected Colon Cancer
Authors: Shuji Ogino, Katsuhiko Nosho, Gregory J. Kirkner, Kaori Shima, Natsumi Irahara, Shoko Kure, Andrew T. Chan, Jeffrey A. Engelman, Peter Kraft, Lewis C. Cantley, Edward L. Giovannucci, Charles S. Fuchs
Journal: Journal of Clinical Oncology (2009)

PIK3CA mutation and subsequent activation of the AKT pathway play an important role in colorectal carcinogenesis. However, little is known about the prognostic role of PIK3CA mutation in colon cancer.Using 450 resectable colon cancers (stage I to III) in two independent prospective cohorts, we detected PIK3CA mutation in 82 tumors (18%) by pyrosequencing. Cox proportional hazards models were used to calculate hazard ratios (HRs) of colon cancer-specific and overall mortalities, adjusted for patient characteristics and tumoral molecular features, including the CpG island methylation phenotype, microsatellite instability (MSI), LINE-1 hypomethylation, and p53, CIMP, KRAS and BRAF mutation.Compared with patients with PIK3CA wild-type tumors, those with PIK3CA-mutated tumors experienced an increase in colon cancer-specific mortality according to univariate analysis (HR = 1.64; 95% CI, 0.95 to 2.86), which persisted after adjusting for other known or potential risk factors for cancer recurrence (including MSI; multivariate HR = 2.23; 95% CI, 1.21 to 4.11). The effect of PIK3CA mutation on cancer survival seemed to differ according to KRAS mutational status. Among patients with KRAS wild-type tumors, the presence of PIK3CA mutation was associated with a significant increase in colon cancer-specific mortality (HR = 3.80; 95% CI, 1.56 to 9.27). In contrast, PIK3CA mutation conferred no significant effect on mortality among patients with KRAS-mutated tumors (HR = 1.25; 95% CI, 0.52 to 2.96).Among patients who undergo a curative resection of colon cancer, PIK3CA mutation is associated with shorter cancer-specific survival. The adverse effect of PIK3CA mutation may be potentially limited to patients with KRAS wild-type tumors.
Effect of Leupeptin, a Protease Inhibitor, on Induction of Bladder Tumors in Rats by N-Butyl-N- (4-hydroxybutyl ) nitrosamine23
Authors: Tadao Kakizoe, Hisao Takayasu, Takashi Kawachi, Takashi Sugimura, Tomio Takeuchi, Hamao Umezawa
Journal: JNCI Journal of the National Cancer Institute (1976)

Leupeptin, isolated from Actinomycetes, is a potent and specific inhibitor of proteases. We found that the administration of leupeptin enhanced that size of urinary bladder tumors induced in rats by the oral administration of N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN). BBN was given as a 0.05% solution in the drinking water for 6 weeks, and then animals were fed a diet with or without 0.1% leupeptin for 30 weeks. The average weight of the bladders with tumors in rats fed a leupeptin diet was about eight times that of rats on a diet without leupeptin, though the incidences and average numbers of tumors in the bladders were similar in the two groups.
Associations of Cancer Mortality With Halomethanes in Drinking Water
Authors: K P Cantor, R Hoover, T J Mason, L J McCabe
Journal: JNCI Journal of the National Cancer Institute (1978)

Associations between site- and sex-specific county cancer mortality rates and levels of trihalomethanes (THM's) in drinking water were examined after adjustment of rates for the influence of multiple socioeconomic, industrial, and demographic factors. U.S. counties with sampled supplies were grouped by percent of the county population receiving water from the supply, as well as by region of the country. For two sites (bladder and lung), county rates were also adjusted for the activity level in specific high-risk industries. Positive correlations with THM levels were observed for several cancers, including bladder and brain cancers in both sexes, and non-Hodgkin's lymphoma and kidney cancer in males. Stomach cancer in females showed a negative association. Bladder cancer mortality rates showed the strongest and most consistent association with a THM exposure index, after control for differences in social class, ethnic group, urban versus rural residence, region of the United States, and industrialization of the county. These ecologic associations suggested that further evaluation in analytic investigations is warranted.
Utilization Management: Issues, Effects, and Future Prospects
Authors: Thomas M. Wickizer, Daniel Lessler
Journal: Annual Review of Public Health (2002)

▪ Abstract Utilization management encompasses a diverse set of activities designed to influence the use of health care services and thereby constrain health care resource consumption. Utilization management, which has become one of the most widely used cost-containment approaches, has engendered debate and controversy. Physicians have been outspoken critics of utilization management because it has limited their clinical autonomy and has contributed to an intolerable administrative burden. Insurance carriers, managed care plans, and third-party payers have defended the use of utilization management as an imperfect—but necessary—practice that is needed to reduce consumption of unnecessary or inappropriate health care services. This review examines the operation and effects of three widely used utilization management procedures: prospective utilization review, case management, and physician gatekeeping programs. In addition, it explores the future role of utilization management in the health care system and outlines a set of principles that we believe should be used to guide the development of utilization management strategies in the future.
Calorie Restriction Increases Muscle Mitochondrial Biogenesis in Healthy Humans
Authors: Anthony E Civitarese, Stacy Carling, Leonie K Heilbronn, Mathew H Hulver, Barbara Ukropcova, Walter A Deutsch, Steven R Smith, Eric Ravussin
Journal: PLoS Medicine (2007)

Background Caloric restriction without malnutrition extends life span in a range of organisms including insects and mammals and lowers free radical production by the mitochondria. However, the mechanism responsible for this adaptation are poorly understood. Methods and Findings The current study was undertaken to examine muscle mitochondrial bioenergetics in response to caloric restriction alone or in combination with exercise in 36 young (36.8 ± 1.0 y), overweight (body mass index, 27.8 ± 0.7 kg/m2) individuals randomized into one of three groups for a 6-mo intervention: Control, 100% of energy requirements; CR, 25% caloric restriction; and CREX, caloric restriction with exercise (CREX), 12.5% CR + 12.5% increased energy expenditure (EE). In the controls, 24-h EE was unchanged, but in CR and CREX it was significantly reduced from baseline even after adjustment for the loss of metabolic mass (CR, −135 ± 42 kcal/d, p = 0.002 and CREX, −117 ± 52 kcal/d, p = 0.008). Participants in the CR and CREX groups had increased expression of genes encoding proteins involved in mitochondrial function such as PPARGC1A, TFAM, eNOS, SIRT1, and PARL (all, p < 0.05). In parallel, mitochondrial DNA content increased by 35% ± 5% in the CR group (p = 0.005) and 21% ± 4% in the CREX group (p < 0.004), with no change in the control group (2% ± 2%). However, the activity of key mitochondrial enzymes of the TCA (tricarboxylic acid) cycle (citrate synthase), beta-oxidation (beta-hydroxyacyl-CoA dehydrogenase), and electron transport chain (cytochrome C oxidase II) was unchanged. DNA damage was reduced from baseline in the CR (−0.56 ± 0.11 arbitrary units, p = 0.003) and CREX (−0.45 ± 0.12 arbitrary units, p = 0.011), but not in the controls. In primary cultures of human myotubes, a nitric oxide donor (mimicking eNOS signaling) induced mitochondrial biogenesis but failed to induce SIRT1 protein expression, suggesting that additional factors may regulate SIRT1 content during CR. Conclusions The observed increase in muscle mitochondrial DNA in association with a decrease in whole body oxygen consumption and DNA damage suggests that caloric restriction improves mitochondrial function in young non-obese adults.