tbuckley/cabot-search huggingface dataset:
Effect of gastric inhibitory polypeptide on plasma levels of chylomicron triglycerides in dogs.
Authors: T Wasada, K McCorkle, V Harris, K Kawai, B Howard, R H Unger
Journal: Journal of Clinical Investigation (1981)

To determine whether gastric inhibitory polypeptide (GIP) promotes the clearance of chylomicron triglycerides (TG) from the circulation in dogs, chyle collected from donor dogs via a thoracic duct fistula was infused at a rate of 2 ml/min i.v. into normal recipient dogs during an infusion of either porcine GIP (1 microgram/kg per h) or saline as a control. In the GIP-infused dogs the rise in plasma TG was significantly below that of the control animals [mean peak of 36 +/- 4 mg/dl vs. 82 +/- 18 mg/dl (P less than 0.05)]. It is concluded that GIP exerts an effect upon the removal of chylomicron TG from the blood. The results suggest that GIP may play a physiologic role in the disposition of ingested fat.
C10ORF10/DEPP, a transcriptional target of FOXO3, regulates ROS-sensitivity in human neuroblastoma
Authors: Stefan Salcher, Judith Hagenbuchner, Kathrin Geiger, Maximilian A Seiter, Johannes Rainer, Reinhard Kofler, Martin Hermann, Ursula Kiechl-Kohlendorfer, Michael J Ausserlechner, Petra Obexer
Journal: Molecular Cancer (2014)

FOXO transcription factors control cellular levels of reactive oxygen species (ROS) which critically contribute to cell survival and cell death in neuroblastoma. In the present study we investigated the regulation of C10orf10/DEPP by the transcription factor FOXO3. As a physiological function of C10orf10/DEPP has not been described so far we analyzed its effects on cellular ROS detoxification and death sensitization in human neuroblastoma cells. The effect of DEPP on cellular ROS was measured by catalase activity assay and live cell fluorescence microscopy using the ROS-sensitive dye reduced MitoTracker Red CM-H2XROS. The cellular localization of DEPP was determined by confocal microscopy of EYFP-tagged DEPP, fluorescent peroxisomal- and mitochondrial probes and co-immunoprecipitation of the PEX7 receptor. We report for the first time that DEPP regulates ROS detoxification and localizes to peroxisomes and mitochondria in neuroblastoma cells. FOXO3-mediated apoptosis involves a biphasic ROS accumulation. Knockdown of DEPP prevented the primary and secondary ROS wave during FOXO3 activation and attenuated FOXO3- and H2O2-induced apoptosis. Conditional overexpression of DEPP elevates cellular ROS levels and sensitizes to H2O2 and etoposide-induced cell death. In neuronal cells, cellular ROS are mainly detoxified in peroxisomes by the enzyme CAT/catalase. As DEPP contains a peroxisomal-targeting-signal-type-2 (PTS2) sequence at its N-terminus that allows binding to the PEX7 receptor and import into peroxisomes, we analyzed the effect of DEPP on cellular detoxification by measuring enzyme activity of catalase. Catalase activity was reduced in DEPP-overexpressing cells and significantly increased in DEPP-knockdown cells. DEPP directly interacts with the PEX7 receptor and localizes to the peroxisomal compartment. In parallel, the expression of the transcription factor peroxisome proliferator-activated receptor gamma (PPARG), a critical regulator of catalase enzyme activity, was strongly upregulated in DEPP-knockdown cells. The combined data indicate that in neuroblastoma DEPP localizes to peroxisomes and mitochondria and impairs cellular ROS detoxification, which sensitizes tumor cells to ROS-induced cell death.
Clinical Outcome and Predictors of Survival in Late Relapse of Germ Cell Tumor
Authors: David S. Sharp, Brett S. Carver, Scott E. Eggener, G. Varuni Kondagunta, Robert J. Motzer, George J. Bosl, Joel Sheinfeld
Journal: Journal of Clinical Oncology (2008)

Purpose Late relapse (LR) of germ cell tumor (GCT) is a well recognized entity associated with poor survival. We report on our experience with LR and determine predictors of survival. Patients and Methods From 1990 to 2004, 75 patients were managed for LR of GCT at our institution. Clinical and pathologic parameters were reviewed. Estimates of cancer-specific survival were generated using the Kaplan-Meier method, and a Cox proportional hazards model was used to assess potential predictors of outcome. Results The median time to LR was 6.9 years (range, 2.1 to 37.7 years). Overall, 56 patients (75%) had LR in the retroperitoneum, including 25 (93%) of 27 patients initially managed without retroperitoneal lymph node dissection. The 5-year cancer-specific survival (CSS) was 60% (95% CI, 46% to 71%). Patients who underwent complete surgical resection at time of LR (n = 45) had a 5-year CSS of 79% versus 36% for patients without complete resection (n = 30; P &lt; .0001). The 5-year CSS for chemotherapy-naive patients was significantly greater than patients with a prior history of chemotherapy as part of their initial management (5-year CSS, 93% v 49%, respectively). In multivariable analysis of pretreatment parameters available at the time of LR, the presence of symptoms (hazard ratio [HR] = 4.9) and multifocal disease (HR = 3.0) were associated with an inferior CSS. Conclusion The data suggest that meticulous control of the retroperitoneum is critical to prevent LR in the retroperitoneum. In multivariable analysis, patients with a symptomatic presentation and those with multifocal disease have a significantly decreased survival. Survival is greatly improved if complete surgical excision of disease is attained.
Development of a Real-time RT-PCR Assay for Detecting EGFRvIII in Glioblastoma Samples
Authors: Koji Yoshimoto, Julie Dang, Shaojun Zhu, David Nathanson, Tiffany Huang, Rebecca Dumont, David B. Seligson, William H. Yong, Zhenggang Xiong, Nagesh Rao, Henrik Winther, Arnab Chakravarti, Darell D. Bigner, Ingo K. Mellinghoff, Steve Horvath, Webster K. Cavenee, Timothy F. Cloughesy, Paul S. Mischel
Journal: Clinical Cancer Research (2008)

Epidermal growth factor receptor variant III (EGFRvIII) is an oncogenic, constitutively active mutant form of the EGFR that is commonly expressed in glioblastoma and is also detected in a number of epithelial cancers. EGFRvIII presents a unique antigenic target for anti-EGFRvIII vaccines and it has been shown to modulate response to EGFR kinase inhibitor therapy. Thus, detection in clinical samples may be warranted. Existing patents preclude the use of anti-EGFRvIII antibodies for clinical detection. Further, frozen tissue is not routinely available, particularly for patients treated in the community. Thus, detection of EGFRvIII in formalin-fixed paraffin-embedded (FFPE) clinical samples is a major challenge.We developed a real-time reverse transcription-PCR (RT-PCR) assay for detecting EGFRvIII in FFPE samples and analyzed 59 FFPE glioblastoma clinical samples with paired frozen tissue from the same surgical resection. We assessed EGFRvIII protein expression by immunohistochemistry using two distinct specific anti-EGFRvIII antibodies and examined EGFR gene amplification by fluorescence in situ hybridization.The FFPE RT-PCR assay detected EGFRvIII in 16 of 59 (27%) samples, exclusively in cases with EGFR amplification, consistent with the expected frequency of this alteration. The FFPE RT-PCR assay was more sensitive and specific for detecting EGFRvIII than either of the two antibodies alone, or in combination, with a sensitivity of 93% (95% confidence interval, 0.78-1.00) and a specificity of 98% (95% confidence interval, 0.93-1.00).This assay will facilitate accurate assessment of EGFRvIII in clinical samples and may aid in the development of strategies for stratifying patients for EGFRvIII-directed therapies.
Bioactive Peptide Signaling Within the Myocardial Interstitium and the Matrix Metalloproteinases
Authors: Francis G. Spinale
Journal: Circulation Research (2002)

n response to a prolonged cardiovascular pathophysiological stimulus, a cascade of compensatory structural events occurs within the myocardium.This process occurs as a continuum and has been defined as myocardial remodeling.This remodeling process has been demonstrated within the myocardial compartment after myocardial infarction (MI), with hypertrophy, or in cardiomyopathic disease.Pharmacological interventions targeted at altering the adverse LV myocardial remodeling processes that invariably occur in these cardiac disease states hold therapeutic promise.Although myocardial remodeling is accompanied by changes in the cellular constituents of the LV myocardium, significant alterations in the structure and composition of the extracellular matrix (ECM) also occur.Moreover, it has become increasingly evident that the fibrillar collagen matrix of the myocardial ECM is not a static structure, but rather a dynamic entity that may play a fundamental role in myocardial adaptation to a pathological stress and thereby facilitate the remodeling process.Therefore, identification and understanding of the biological systems responsible for ECM synthesis and degradation within the myocardium holds particular relevance.In this issue, Tsuruda and colleagues 1 from the Mayo Clinic report on the interactive effects of brain natriuretic peptide (BNP) and tumor necrosis factor-␣ (TNF-␣) on determinants of fibrillar collagen biosynthesis in cardiac fibroblasts.The results from this study emphasize the fact that the biologically active molecules that are contained within the myocardial interstitium do not act independently, but instead, a summation of signaling events ultimately determines the structure and function of the ECM.
Translationally controlled tumor protein induces mitotic defects and chromosome missegregation in hepatocellular carcinoma development
Authors: Tim Hon Man Chan, Leilei Chen, Ming Liu, Liang Hu, Bo-jian Zheng, Vincent Kwok-Man Poon, Pinzhu Huang, Yun-Fei Yuan, Jian-dong Huang, Jie Yang, George Sai-wah Tsao, Xin-Yuan Guan
Journal: Hepatology (2011)

Emerging evidence implicates the chromodomain helicase/ATPase DNA binding protein 1-like gene (CHD1L) as a specific oncogene in human hepatocellular carcinoma (HCC). To better understand the molecular mechanisms underlying HCC cases carrying CHD1L amplification (>50% HCCs), we identified a CHD1L target, translationally controlled tumor protein (TCTP), and investigated its role in HCC progression. Here, we report that CHD1L protein directly binds to the promoter region (nt -733 to -1,027) of TCTP and activates TCTP transcription. Overexpression of TCTP was detected in 40.7% of human HCC samples analyzed and positively correlated with CHD1L overexpression. Clinically, overexpression of TCTP was significantly associated with the advanced tumor stage (P = 0.037) and overall survival time of HCC patients (P = 0.034). In multivariate analyses, TCTP was determined to be an independent marker associated with poor prognostic outcomes. In vitro and in vivo functional studies in mice showed that TCTP has tumorigenic abilities, and overexpression of TCTP induced by CHD1L contributed to the mitotic defects of tumor cells. Further mechanistic studies demonstrated that TCTP promoted the ubiquitin-proteasome degradation of Cdc25C during mitotic progression, which caused the failure in the dephosphorylation of Cdk1 on Tyr15 and decreased Cdk1 activity. As a consequence, the sudden drop of Cdk1 activity in mitosis induced a faster mitotic exit and chromosome missegregation, which led to chromosomal instability. The depletion experiment proved that the tumorigenicity of TCTP was linked to its role in mitotic defects.Collectively, we reveal a novel molecular pathway (CHD1L/TCTP/Cdc25C/Cdk1), which causes the malignant transformation of hepatocytes with the phenotypes of accelerated mitotic progression and the production of aneuploidy.
Air pollution effects on childhood asthma
Authors: Burton Zweiman, Marc E. Rothenberg
Journal: Journal of Allergy and Clinical Immunology (2004)

Three recent reports revisited the question of whether exposure to outdoor air pollutants is a significant pathogenic factor in chronic childhood asthma. In one study,1 the relationship of bronchitic symptoms to ambient particulate matter and to particulate elemental and organic carbon, nitrogen dioxide, and other gaseous pollutants was examined in a cohort of asthmatic children in 12 communities in southern California. The investigators found that bronchitis symptoms, assessed yearly by questionnaires from 1996 through 1999, were associated with the yearly variability in the levels of a number of outdoor air pollutants, particularly within individual communities. However, the odds ratios for such associations of symptoms to the levels of individual pollutants were relatively modest. Nevertheless, the authors concluded that levels of organic carbon particles and NO2 deserve greater attention as potential causes of the chronic symptoms of bronchitis in asthmatic children. They postulated that previous cross-sectional studies might have underestimated the risks associated with air pollution.
DNA Adduct Formation by 7, 12-Dimethylbenz[&lt;italic&gt;a&lt;/italic&gt;]anthracene and Its Noncarcinogenic 2-Fluoro Analogue in Female Sprague-Dawley Rats&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: F B Daniel, N J Joyce
Journal: JNCI Journal of the National Cancer Institute (1983)

The potent polycyclic aromatic hydrocarbon 7,12 dimethylbenz[a]anthracene (DMBA) bound to the DNA of numerous organs of the female outbred Sprague-Dawley rat after iv administration under a regimen known to produce a high yield of mammary adenocarcinomas. The maximum DNA binding levels observed following iv administration of 5 mg (20 mumol) DMBA range from approximately 12 mumol hydrocarbon/mol deoxyribonucleic for the liver to approximately 5 mumol hydrocarbon/mol deoxyribonucleotide for the mammary gland, the target tissue. Administered under identical conditions, the noncarcinogenic analogue 2-fluoro-7,12-dimethylbenz[a]anthracene (2F-DMBA) bound to the DNA at levels of about 5-10% that of DMBA (i.e., 0.3-1.6 mumol/mol deoxyribonucleotide). Chromatographic analysis of the hydrocarbon-deoxyribonucleoside adducts produced showed that for DMBA at least two major types of identifiable adducts were observed in all tissues examined, the major one being that resulting from the reaction of a DMBA bay-region diol-epoxide. The other adduct type resulted from the binding of an analogous diol-epoxide of a DMBA metabolite, 7-hydroxymethyl-12-methylbenz[a]anthracene. Adducts from 2F-DMBA were observed on high-pressure liquid chromatography but were in quantities insufficient for characterization. The finding of higher levels of chromatographically identical DMBA-DNA adducts in the nontarget (liver) tissue than in the target tissue indicated that adduct formation per se was not a sufficient stimulus for the cancer induction. However, the failure of the structurally similar 2F-DMBA, which produced only very low levels of DNA adducts, to induce mammary cancer implies that certain levels of carcinogen-DNA adducts may be necessary for carcinogenesis.
The induction of antibody production by IL-6 is indirectly mediated by IL-21 produced by CD4+ T cells
Authors: Oliver Dienz, Sheri M. Eaton, Jeffrey P. Bond, Wendy Neveu, David Moquin, Rajkumar Noubade, Eva M. Briso, Colette Charland, Warren J. Leonard, Gennaro Ciliberto, Cory Teuscher, Laura Haynes, Mercedes Rincon
Journal: The Journal of Experimental Medicine (2009)

Interleukin (IL) 6 is a proinflammtory cytokine produced by antigen-presenting cells and nonhematopoietic cells in response to external stimuli. It was initially identified as a B cell growth factor and inducer of plasma cell differentiation in vitro and plays an important role in antibody production and class switching in vivo. However, it is not clear whether IL-6 directly affects B cells or acts through other mechanisms. We show that IL-6 is sufficient and necessary to induce IL-21 production by naive and memory CD4+ T cells upon T cell receptor stimulation. IL-21 production by CD4+ T cells is required for IL-6 to promote B cell antibody production in vitro. Moreover, administration of IL-6 with inactive influenza virus enhances virus-specific antibody production, and importantly, this effect is dependent on IL-21. Thus, IL-6 promotes antibody production by promoting the B cell helper capabilities of CD4+ T cells through increased IL-21 production. IL-6 could therefore be a potential coadjuvant to enhance humoral immunity.
Net Intestinal Transport of Oxalate Reflects Passive Absorption and SLC26A6-mediated Secretion
Authors: Felix Knauf, Narae Ko, Zhirong Jiang, William G. Robertson, Christina M. Van Itallie, James M. Anderson, Peter S. Aronson
Journal: Journal of the American Society of Nephrology (2011)

Mice lacking the oxalate transporter SLC26A6 develop hyperoxalemia, hyperoxaluria, and calcium-oxalate stones as a result of a defect in intestinal oxalate secretion, but what accounts for the absorptive oxalate flux remains unknown. We measured transepithelial absorption of [(14)C]oxalate simultaneously with the flux of [(3)H]mannitol, a marker of the paracellular pathway, across intestine from wild-type and Slc26a6-null mice. We used the anion transport inhibitor DIDS to investigate other members of the SLC26 family that may mediate transcellular oxalate absorption. Absorptive flux of oxalate in duodenum was similar to mannitol, insensitive to DIDS, and nonsaturable, indicating that it is predominantly passive and paracellular. In contrast, in wild-type mice, secretory flux of oxalate in duodenum exceeded that of mannitol, was sensitive to DIDS, and saturable, indicating transcellular secretion of oxalate. In Slc26a6-null mice, secretory flux of oxalate was similar to mannitol, and no net flux of oxalate occurred. Absorptive fluxes of both oxalate and mannitol varied in parallel in different segments of small and large intestine. In epithelial cell lines, modulation of the charge selectivity of the claudin-based pore pathway did not affect oxalate permeability, but knockdown of the tight-junction protein ZO-1 enhanced permeability to oxalate and mannitol in parallel. Moreover, formation of soluble complexes with cations did not affect oxalate absorption. In conclusion, absorptive oxalate flux occurs through the paracellular "leak" pathway, and net absorption of dietary oxalate depends on the relative balance between absorption and SLC26A6-dependent transcellular secretion.
The Association Between Statins and Cancer Incidence in a Veterans Population
Authors: W. R. Farwell, R. E. Scranton, E. V. Lawler, R. A. Lew, M. T. Brophy, L. D. Fiore, J. M. Gaziano
Journal: JNCI Journal of the National Cancer Institute (2008)

Meta-analyses of trials of 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors or statins for cardiovascular disease prevention have failed to show any statistically significant benefit of statins for cancer prevention. However, these trials included relatively young participants, who develop few cancers, and their follow-up periods may have been too short to detect an association between statin use and cancer incidence. We investigated this association in a population of veterans.We identified patients using antihypertensive medications but no cholesterol-lowering medications (n = 25,594) and patients using statins (n = 37,248) who were enrolled in the Veterans Affairs New England Healthcare System between January 1, 1997, and December 31, 2005. Age- and multivariable-adjusted Cox proportional hazards models were used to calculate the hazard ratio (HR) and its 95% confidence interval (CI) for cancer incidence, excluding nonmelanoma skin cancer, among patients taking statins compared with patients taking antihypertensive medications and among patients grouped by statin dose (as equivalent simvastatin dose). All statistical tests were two-sided.The absolute incidence of total cancers was 9.4% among statin users and 13.2% among nonusers (difference = 3.8%, 95% CI = 3.3% to 4.3%, P(difference) < .001). Statin users had a statistically significant lower risk for total cancer than nonusers after adjustment for age (HR = 0.76, 95% CI = 0.73 to 0.80) and multiple potential confounders (HR = 0.74, 95% CI = 0.70 to 0.78). After multivariable adjustment, a statistically significantly decreased risk of all cancers was also associated with increasing statin use (P(trend) < .001).Patients using statins may be at lower risk for developing cancer. Additional observational studies and randomized trials of statins for cancer prevention are warranted.
Role of Adipose Tissue as an Inflammatory Organ in Human Diseases
Authors: A. Schäffler, U. Müller-Ladner, J. Schölmerich, C. Büchler
Journal: Endocrine Reviews (2006)

Reviews on the inflammatory role of adipose tissue outside the field of metabolism are rare. There is increasing evidence provided by numerous basic research studies from nearly all internal medicine subspecializations that adipocytes and adipocytokines are involved in primary inflammatory processes and diseases. Therefore, it is the aim of the present review to discuss and to summarize the current knowledge on the inflammatory role of adipocytokines and special types of regional adipocytes such as retroorbital, synovial, visceral, subdermal, peritoneal, and bone marrow adipocytes in internal medicine diseases. Future clinical and therapeutic implications are discussed.
The fibrinogen cleavage product A -Val360, a specific marker of neutrophil elastase activity in vivo
Authors: R. I. Carter, R. A. Mumford, K. M. Treonze, P. E. Finke, P. Davies, Q. Si, J. L. Humes, A. Dirksen, E. Piitulainen, A. Ahmad, R. A. Stockley
Journal: Thorax (2011)

Alpha-1-antitrypsin (A1AT) deficiency is the only recognised genetic risk factor for chronic obstructive pulmonary disease (COPD), a leading cause of morbidity and mortality worldwide. Since A1AT is the major inhibitor of neutrophil elastase (NE), this enzyme has become widely implicated in the pathogenesis of COPD in general; however, there is currently no specific biomarker for its pre-inhibition activity. Such a biomarker should be a measure of elastase-specific COPD disease activity with the potential to assess early targeted therapeutic intervention, in contrast to traditional and non-specific disease severity markers such as forced expiratory volume in 1 s.In pilot studies, plasma Aα-Val(360) and markers of neutrophil activation were measured in 95 subjects with a range of A1AT concentrations. Aα-Val(360) and sputum elastase activity were also measured in a further seven PiZ A1AT-deficient subjects over the course of an acute exacerbation. Finally, Aα-Val(360) was measured in plasma from subjects randomised to receive A1AT replacement or placebo in the EXACTLE trial.The plasma concentrations of Aα-Val(360) and A1AT related exponentially, consistent with previous theoretical and in vitro experimental data. L-233 (an intracellular NE inhibitor) blocked generation of Aα-Val(360) and subsequent A1AT/NE complex formation. Aα-Val(360) was related to the spirometric severity of lung disease in A1AT deficiency, to sputum elastase activity in acute exacerbations and was decreased in subjects receiving A1AT replacement therapy (while remaining constant in those receiving placebo).Aα-Val(360) represents the first specific footprint of pre-inhibition NE activity and is a potential biomarker of disease activity and progression in subjects with elastase-dependent COPD.The EXACTLE study was registered in ClinicalTrials.gov as 'Antitrypsin (AAT) to Treat Emphysema in AAT-Deficient Patients'; ClinicalTrials.gov Identifier: NCT00263887.