tbuckley/cabot-search huggingface dataset:
Selective Induction of Expression of a Ligand for the NKG2D Receptor by Proteasome Inhibitors
Authors: Mar Valés-Gómez, Susan E. Chisholm, Robin L. Cassady-Cain, Pedro Roda-Navarro, Hugh T. Reyburn
Journal: Cancer Research (2008)

Abstract The interaction of the activating receptor NKG2D with its ligands plays an important role in immunosurveillance of tumors and infectious pathogens, but dysregulation of this system may lead to autoimmunity. The expression of NKG2D ligands is induced by cellular “stress.” However, the regulation of expression of these molecules is not well understood. Here, we show that cells treated with proteasome inhibitors can become more susceptible to cytotoxicity mediated by natural killer cells because of the induction of expression of ligands for NKG2D, specifically ULBP2, but not down-regulation of MHC class I. Treatment with proteasome inhibitors led to up-regulation of ULBP2 expression in multiple, but not all, cell lines tested. This increase in expression of ULBP2 at the cell surface correlated with induction of transcription of the ULBP2 gene and synthesis of ULBP2 protein. In contrast, treatment with inhibitors of histone deacetylases led to increased levels of mRNA and protein, for both ULBP2 and MHC class I–related chain A/B molecules. Thus, different types of stress can trigger up-regulated expression of different sets of NKG2D ligands. Proteasome inhibitors are proving to be of significant value in the treatment of hematologic malignancies and these observations may help to better understand the biology of therapy with these compounds. [Cancer Res 2008;68(5):1546–54]
Induction and maintenance therapy with intermittent interleukin-2 in HIV-1 infection
Authors: Claire E. Farel, Doreen G. Chaitt, Barbara K. Hahn, Jorge A. Tavel, Joseph A. Kovacs, Michael A. Polis, Henry Masur, Dean A. Follmann, H. Clifford Lane, Richard T. Davey
Journal: Blood (2004)
Forkhead Transcription Factors Coordinate Expression of Myocardial KATP Channel Subunits and Energy Metabolism
Authors: Pierre Philip-Couderc, Nadia Isidoro Tavares, Angela Roatti, René Lerch, Christophe Montessuit, Alex J. Baertschi
Journal: Circulation Research (2008)

Coordinate adaptation of myocyte metabolism and function is fundamental to survival of the stressed heart, but the mechanisms for this coordination remain unclear. Bioinformatics led us to discover that Foxs are key transcription factors involved. We performed experiments on the mouse atrial cell line HL-1, neonate rat heart myocytes, and an adult rat model of myocardial infarction. In electrophoretic mobility-shift assays, FoxO1 binds to the FoxO concensus site of the KATP channel subunit KIR6.1 promoter. In primary atrial culture, targeting FoxO1 and FoxO3 with siRNA specifically reduces mRNA expression of FoxO1 and -O3 and KIR6.1. Western blots, confocal immunofluorescence, and quantitative RT-PCR was applied for measuring expression of 10 Fox, 6 KATP channel subunits, and 12 metabolic genes. FoxF2, -O1, and -O3 strongly associate with expression of KATP channel subunits (in particular, KIR6.1, SUR1A and SUR2B) in different heart tissues and in the periinfarct zone of the left ventricle. Patch-clamp recordings demonstrate that molecular plasticity of these channels is matched by pharmacological plasticity and increased sensitivity to a metabolic challenge mimicked by the protonophore CCCP. A balance of FoxF2 and FoxO also regulates expression of at least 9 metabolic genes involved in setting the balance of glycolysis and beta-oxidation. Bioinformatics shows that the transcriptional mechanisms are highly conserved among chicken, mouse, rat, and human, and Fox are intimately linked to other metabolic sensors. Thus, FoxF2 and -O are key transcription factors coordinating expression of KATP channels and energy metabolism.
Socioeconomic Factors, Health Behaviors, and Mortality
Authors: Paula M. Lantz, James S. House, James M. Lepkowski, David R. Williams, Richard P. Mero, Jieming Chen
Journal: JAMA (1998)

Context.—A prominent hypothesis regarding social inequalities in mortality is that the elevated risk among the socioeconomically disadvantaged is largely due to the higher prevalence of health risk behaviors among those with lower levels of education and income.Objective.—To investigate the degree to which 4 behavioral risk factors (cigarette smoking, alcohol drinking, sedentary lifestyle, and relative body weight) explain the observed association between socioeconomic characteristics and all-cause mortality.Design.—Longitudinal survey study investigating the impact of education, income, and health behaviors on the risk of dying within the next 7.5 years.Participants.—A nationally representative sample of 3617 adult women and men participating in the Americans' Changing Lives survey.Main Outcome Measure.—All-cause mortality verified through the National Death Index and death certificate reviews.Results.—Educational differences in mortality were explained in full by the strong association between education and income. Controlling for age, sex, race, urbanicity, and education, the hazard rate ratio of mortality was 3.22 (95% confidence interval [CI], 2.01-5.16) for those in the lowest-income group and 2.34 (95% CI, 1.49-3.67) for those in the middle-income group. When health risk behaviors were considered, the risk of dying was still significantly elevated for the lowest-income group (hazard rate ratio, 2.77; 95% CI, 1.74-4.42) and the middle-income group (hazard rate ratio, 2.14; 95% CI, 1.38-3.25).Conclusion.—Although reducing the prevalence of health risk behaviors in low-income populations is an important public health goal, socioeconomic differences in mortality are due to a wider array of factors and, therefore, would persist even with improved health behaviors among the disadvantaged.
Longitudinal analysis of citrullinated protein/peptide antibodies (anti-CP) during 5 year follow up in early rheumatoid arthritis: anti-CP status predicts worse disease activity and greater radiological progression
Authors: J Rönnelid, M C Wick, J Lampa, S Lindblad, B Nordmark, L Klareskog, R F van Vollenhoven
Journal: Annals of the Rheumatic Diseases (2005)

<b>Objective:</b> To study serum levels of citrullinated protein/peptide antibodies (anti-CP) during up to 5 years' follow up of patients with early rheumatoid arthritis (RA), and to relate serum levels to disease course and to treatments in clinical practice. <b>Methods:</b> 279 patients with early RA were followed up with clinical investigations, radiographs, and measurement of anti-CP at baseline and after 3 months, 1, 2, 3, and 5 years. <b>Results:</b> 160/279 (57.3%) patients were anti-CP positive at the first visit (mean 5 months after first symptoms). During follow up only 11/279 (3.9%) of the patients changed their anti-CP status. Anti-CP levels fell significantly during the first year, and this drop correlated with the extent of sulfasalazine treatment but not with other drugs or clinical indices. Anti-CP positive and negative patients had similar disease activities at baseline, but during follow up the anti-CP positive patients had worse clinical disease and greater radiological progression, despite at least equally intensive antirheumatic treatment. <b>Conclusions:</b> Anti-CP are stable during the first 5 years of RA, suggesting that events before rather than after onset of clinical manifestations of disease determine this phenotype. The presence of anti-CP at diagnosis predicts a less favourable disease course and greater radiological progression despite antirheumatic treatment, but subsequent changes in antibody levels do not reflect changes in disease activity. Taken together, these observations suggest that anti-CP positive RA is a distinct clinical and pathophysiological entity.
Health-Related Quality of Life in Non–Small-Cell Lung Cancer: An Update of a Systematic Review on Methodologic Issues in Randomized Controlled Trials
Authors: Lily Claassens, Jan van Meerbeeck, Corneel Coens, Chantal Quinten, Irina Ghislain, Elizabeth K. Sloan, Xin Shelly Wang, Galina Velikova, Andrew Bottomley
Journal: Journal of Clinical Oncology (2011)

This study is an update of a systematic review of health-related quality-of-life (HRQOL) methodology reporting in non-small-cell lung cancer (NSCLC) randomized controlled trials (RCTs). The objective was to evaluate HRQOL methodology reporting over the last decade and its benefit for clinical decision making.
Narrow band imaging with magnification for dysplasia detection and pit pattern assessment in ulcerative colitis surveillance: a case with multiple dysplasia associated lesions or masses
Authors: J E East, N Suzuki, A von Herbay, B P Saunders
Journal: Gut (2006)

A 62 year old man with longstanding ulcerative colitis and previous endoscopic excision of two dysplasia associated lesions or masses (DALMs) was admitted to our endoscopy unit for evaluation and resection of other possible DALMs. He had previously been offered and refused colectomy because of comorbidity from Parkinson's disease. He had multiple polypoid and sessile lesions which were assessed using a third generation prototype narrow band imaging (NBI) colonoscope with magnification. Selected lesions were either biopsied or resected with a combination of endoscopic submucosal dissection and endoscopic mucosal resection techniques. We correlated the pit pattern and vascular pattern intensity seen with magnification NBI with histology of both inflammatory and dysplastic lesions. Dysplastic areas showed Kudo pit patterns II, IIIL, and IV and high vascular pattern intensity. Non-dysplastic and dysplastic areas of recurrence immediately adjacent to the scar from a previous endoscopic mucosal resection site were also assessed. This is the first case report where NBI has been shown to help in DALM detection and to distinguish dysplastic from non-dysplastic mucosa in ulcerative colitis.
Rhinovirus Disrupts the Barrier Function of Polarized Airway Epithelial Cells
Authors: Umadevi Sajjan, Qiong Wang, Ying Zhao, Dieter C. Gruenert, Marc B. Hershenson
Journal: American Journal of Respiratory and Critical Care Medicine (2008)

Secondary bacterial infection following rhinovirus (RV) infection has been recognized in chronic obstructive pulmonary disease.We sought to understand mechanisms by which RV infection facilitates secondary bacterial infection.Primary human airway epithelial cells grown at air-liquid interface and human bronchial epithelial (16HBE14o-) cells grown as polarized monolayers were infected apically with RV. Transmigration of bacteria (nontypeable Haemophilus influenzae and others) was assessed by colony counting and transmission electron microscopy. Transepithelial resistance (R(T)) was measured by using a voltmeter. The distribution of zona occludins (ZO)-1 was determined by immunohistochemistry and immunoblotting.Epithelial cells infected with RV showed 2-log more bound bacteria than sham-infected cultures, and bacteria were recovered from the basolateral media of RV- but not sham-infected cells. Infection of polarized airway epithelial cell cultures with RV for 24 hours caused a significant decrease in R(T) without causing cell death or apoptosis. Ultraviolet-treated RV did not decrease R(T), suggesting a requirement for viral replication. Reduced R(T) was associated with increased paracellular permeability, as determined by flux of fluorescein isothiocyanate (FITC)-inulin. Neutralizing antibodies to tumor necrosis factor (TNF)-alpha, IFN-gamma and IL-1beta reversed corresponding cytokine-induced reductions in R(T) but not that induced by RV, indicating that the RV effect is independent of these proinflammatory cytokines. Confocal microscopy and immunoblotting revealed the loss of ZO-1 from tight junction complexes in RV-infected cells. Intranasal inoculation of mice with RV1B also caused the loss of ZO-1 from the bronchial epithelium tight junctions in vivo.RV facilitates binding, translocation, and persistence of bacteria by disrupting airway epithelial barrier function.
Regulation of macrophage function by interferon-gamma. Somatic cell genetic approaches in murine macrophage cell lines to mechanisms of growth inhibition, the oxidative burst, and expression of the chronic granulomatous disease gene.
Authors: M Goldberg, L S Belkowski, B R Bloom
Journal: Journal of Clinical Investigation (1990)

The importance of oxidative cytocidal mechanisms of phagocytic cells in immune protection against microbial pathogens is uniquely revealed by chronic granulomatous disease (CGD), a genetic deficiency disease of man. This cytocidal response in mononuclear phagocytes is principally regulated by IFN-gamma. A somatic cell genetic approach was taken to select oxidative variants from a cloned murine macrophage cell line, J774.16, which formally permitted us to dissociate three regulatory effects of IFN-gamma on these cells: the antiproliferative effect, the antiviral effect, and production of superoxide anion. Half of the variants defective in O-2 production after phorbol myristate acetate stimulation were also resistant to the antiproliferative effects of IFN-gamma. This result suggests that IFN-gamma-induced growth inhibition and production of cytocidal oxygen intermediates are mediated via a common pathway. The somatic cell genetic approach has allowed us to develop in vitro macrophage models for several forms of CGD. One variant characterized in detail, D9, was unable to produce superoxide after stimulation by phorbol esters. At the molecular level, Northern blot analysis revealed that the mRNA encoding the large subunit of the putative CGD gene product, cytochrome b558, was absent in this variant. Another class of variants constitutively unable to produce O-2 or the cytochrome b558 mRNA could be induced to do so by IFN-gamma. These somatic mutants may be useful models in clarifying the role of the CGD gene product and its regulation in the production of cytocidal oxygen intermediates.
Primary care providers' perceptions of physical activity counselling in a clinical setting: a systematic review
Authors: Emily T Hébert, Margaret O Caughy, Kerem Shuval
Journal: British Journal of Sports Medicine (2012)

Objective The evidence regarding the effectiveness of promoting physical activity (PA) in primary care is varied. The present study systematically reviews the literature pertaining to primary care providers' perceptions about PA counselling to identify the barriers and enablers to PA counselling in clinical practice. Design A systematic literature review (through 2011) of quantitative and qualitative studies was conducted. Articles were included in the review if the study population consisted of primary care providers and the study evaluated providers' attitudes and perceptions pertaining to PA counselling. Results Nineteen articles met the inclusion criteria. Most primary care providers believe PA counselling is important and that they have a role in promoting PA among their patients. However, providers are uncertain about the effectiveness of counselling, feel uncomfortable providing detailed advice about PA, and cite lack of time, training and reimbursement as barriers. Providers are more likely to counsel their patients about PA if they are active themselves, or if they feel their patients' medical condition would benefit from a lifestyle change. Conclusion Primary care providers are receptive to the notion of PA promotion in the clinical setting, yet numerous individual and organisational barriers need to be addressed to integrate PA counselling into primary care effectively.
Promising SINEs for Embargoing Nuclear–Cytoplasmic Export as an Anticancer Strategy
Authors: David S.P. Tan, Philippe L. Bedard, John Kuruvilla, Lillian L. Siu, Albiruni R. Abdul Razak
Journal: Cancer Discovery (2014)

In cancer cells, the nuclear-cytoplasmic transport machinery is frequently disrupted, resulting in mislocalization and loss of function for many key regulatory proteins. In this review, the mechanisms by which tumor cells co-opt the nuclear transport machinery to facilitate carcinogenesis, cell survival, drug resistance, and tumor progression will be elucidated, with a particular focus on the role of the nuclear-cytoplasmic export protein. The recent development of a new generation of selective inhibitors of nuclear export (XPO1 antagonists) and how these novel anticancer drugs may bring us closer to the implementation of this therapeutic strategy in the clinic will be discussed.
CHK1 inhibition as a strategy for targeting fanconi anemia (FA) DNA repair pathway deficient tumors
Authors: Clark C Chen, Richard D Kennedy, Samuel Sidi, A Thomas Look, Alan D'Andrea
Journal: Molecular Cancer (2009)

Abstract Background DNA repair deficient tumor cells have been shown to accumulate high levels of DNA damage. Consequently, these cells become hyper-dependent on DNA damage response pathways, including the CHK1-kinase-mediated response. These observations suggest that DNA repair deficient tumors should exhibit increased sensitivity to CHK1 inhibition. Here we offer experimental evidence in support of this hypothesis. Results Using isogenic pairs of cell lines differing only in the Fanconi Anemia (FA) DNA repair pathway, we showed that FA deficient cell lines were hypersensitive to CHK1 silencing by independent siRNAs as well as CHK1 pharmacologic inhibition by Gö6976 and UCN-01. In parallel, an siRNA screen designed to identify gene silencings synthetically lethal with CHK1 inhibition identified genes required for FA pathway function. To confirm these findings in vivo , we demonstrated that whole zebrafish embryos, depleted for FANCD2 by a morpholino approach, were hypersensitive to Gö6976. Silencing of FA genes led to hyper-activation of CHK1 and vice versa. Furthermore, inactivation of CHK1 in FA deficient cell lines caused increased accumulation of DNA strand and chromosomal breakages. These results suggest that the functions subserved by CHK1 and the FA pathway mutually compensate in maintaining genome integrity. As CHK1 inhibition has been under clinical trial in combination with cisplatin, we showed that the FA specific tumoricidal effect of CHK1 inhibition and cisplatin was synergistic. Conclusion Taken together, these results suggest CHK1 inhibition as a strategy for targeting FA deficient tumors.
Genomic context analysis in Archaea suggests previously unrecognized links between DNA replication and translation
Authors: Jonathan Berthon, Diego Cortez, Patrick Forterre
Journal: Genome biology (2008)

Abstract Background Comparative analysis of genomes is valuable to explore evolution of genomes, deduce gene functions, or predict functional linking between proteins. Here, we have systematically analyzed the genomic environment of all known DNA replication genes in 27 archaeal genomes to infer new connections for DNA replication proteins from conserved genomic associations. Results Two distinct sets of DNA replication genes frequently co-localize in archaeal genomes: the first includes the genes for PCNA, the small subunit of the DNA primase (PriS), and Gins15; the second comprises the genes for MCM and Gins23. Other genomic associations of genes encoding proteins involved in informational processes that may be functionally relevant at the cellular level have also been noted; in particular, the association between the genes for PCNA, transcription factor S, and NudF. Surprisingly, a conserved cluster of genes coding for proteins involved in translation or ribosome biogenesis (S27E, L44E, aIF-2 alpha, Nop10) is almost systematically contiguous to the group of genes coding for PCNA, PriS, and Gins15. The functional relevance of this cluster encoding proteins conserved in Archaea and Eukarya is strongly supported by statistical analysis. Interestingly, the gene encoding the S27E protein, also known as metallopanstimulin 1 (MPS-1) in human, is overexpressed in multiple cancer cell lines. Conclusion Our genome context analysis suggests specific functional interactions for proteins involved in DNA replication between each other or with proteins involved in DNA repair or transcription. Furthermore, it suggests a previously unrecognized regulatory network coupling DNA replication and translation in Archaea that may also exist in Eukarya.
Elevated Serum Levels of CC Thymus and Activation-Related Chemokine (TARC) in Primary Hodgkin's Disease: Potential for a Prognostic Factor
Authors: Martin R. Weihrauch, Oliver Manzke, Marc Beyer, Heinz Haverkamp, Volker Diehl, Heribert Bohlen, Juergen Wolf, Joachim L. Schultze
Journal: Cancer Research (2005)

Abstract The CC thymus and activation-related chemokine (TARC) is a protein, which is highly expressed by Reed-Sternberg cells in Hodgkin's disease and is found in the majority of Hodgkin's disease patients. Within several trials conducted by the German Hodgkin study group, 62 Hodgkin's disease patients were elected based on availability of serum samples post and prior therapy to assess TARC levels by ELISA. TARC levels from 33 patients with continuous complete response (CCR), 20 patients with relapse, and nine patients with progressive disease (PD) were correlated with freedom from treatment failure and survival. As defined in healthy donors (mean value ± 2× SD), a TARC level of &amp;gt;500 pg/mL was considered as elevated. The median TARC levels of all patients at baseline and after completed primary treatment were 5,803 pg/mL (range, 116-73,074 pg/mL) and 663 pg/mL (50-24,709 pg/mL), respectively. TARC levels of patients with PD were higher than those of patients with CCR at baseline and after therapy. Baseline TARC correlated significantly with stage (P = 0.019), erythrocyte sedimentation rate (P = 0.004), leukocyte count (P &amp;lt; 0.001), and lymphocyte count (P = 0.026). A TARC level of &amp;gt;2,000 pg/mL after completed treatment was a significant risk factor for poorer survival (P = 0.02) but not for relapse. In conclusion, monitoring serum TARC levels in Hodgkin's disease patients may add valuable information about therapy success in Hodgkin's disease patients, especially those with PD and should therefore be prospectively evaluated in future trials.