tbuckley/cabot-search huggingface dataset:
Peroxisomal Lipid Metabolism
Authors: J K Reddy, G P Mannaerts
Journal: Annual Review of Nutrition (1994)

Peroxisomes are present in virtually all eukaryotic cells. At present, they are known to contain more than 50 enzymes, more than half of which play a role in lipid metabolism. During the past two decades, considerable knowledge has been gained about the role of peroxisomes in lipid metabolism, the implications of induction of hepatic peroxisome proliferation and the peroxisomal fatty acid beta-oxidation enzyme system in the development of hepatocellular carcinomas in rats and mice by structurally diverse groups of chemicals designated as peroxisome proliferators, and the biochemical basis for inheritable diseases in humans caused by disturbances and/or deficiencies in peroxisomal lipid metabolism. Nevertheless, many unanswered questions remain. The ontogeny and homeostatic interrelationships between the enzymes of the peroxisomal and mitochondrial lipid metabolism have yet to be fully elucidated. The mechanism(s) by which PPARs are activated also remains unclear. Information about the interplay between PPAR, RXR alpha, HSP72, and other possible regulatory molecules is necessary to elucidate the transcriptional activation of inducible peroxisomal genes. The assumption that multiple signaling pathways may be responsible for the pleiotropic responses induced by structurally different peroxisome proliferators requires further examination. Finally, studies to identify and characterize different PPARs and PPREs from inducible peroxisomal genes from a variety of species are also required for a clear understanding of the role of peroxisomal beta-oxidation enzyme system in the pathogenesis of hepatocellular carcinogenesis induced by peroxisome proliferators.
The New Zealand rugby injury and performance project. IV. Anthropometric and physical performance comparisons between positional categories of senior A rugby players.
Authors: K L Quarrie, P Handcock, M J Toomey, A E Waller
Journal: British Journal of Sports Medicine (1996)

OBJECTIVE--To describe the anthropometric and physical performance characteristics of a sample of senior A club rugby players and to highlight differences between the positional categories of the players within the forwards and backs. METHODS--94 senior A male rugby players were assessed on a number of anthropometric and physical performance assessments. The forwards were categorised into props, hookers, locks, and loose forwards. Backs were categorised into inside, midfield, and outside backs. Categories within the forwards were compared with each other, as were the categories within the backs. RESULTS--The anthropometric characteristics of forwards differed significantly between positional categories. Front row forwards (props and hookers) possessed highly endo-mesomorphic somatotypes, and typically rated very low for ectomorphy. Props possessed greater body mass than hookers. Locks and loose forwards were taller than the front row forwards. In terms of physical performance fewer differences were observed. Hookers performed better than props on an aerobic assessment. Locks and loose forwards were faster than the front row forwards on a 30 m sprint from a running start. The inside backs were shorter and lighter than the midfield and outside backs. CONCLUSIONS--The combination of anthropometric characteristics and physical performance attributes observed allows players to best meet the demands imposed on them by their position.
The role of thromboxane A2 in the pathogenesis of airway hyperresponsiveness
Authors: P M O'Byrne, R W Fuller
Journal: European Respiratory Journal (1989)

Thromboxane A 2  (TxA 2 ), may be an important mediator in the pathogenesis of airway hyperresponsiveness in animal models, and allergic responses as well as transient and persistent airway hyperresponsiveness in humans. This article will review the evidence that TxA 2  is involved in these responses
Development and translational imaging of a TP53 porcine tumorigenesis model
Authors: Jessica C. Sieren, David K. Meyerholz, Xiao-Jun Wang, Bryan T. Davis, John D. Newell, Emily Hammond, Judy A. Rohret, Frank A. Rohret, Jason T. Struzynski, J. Adam Goeken, Paul W. Naumann, Mariah R. Leidinger, Agshin Taghiyev, Richard Van Rheeden, Jussara Hagen, Benjamin W. Darbro, Dawn E. Quelle, Christopher S. Rogers
Journal: Journal of Clinical Investigation (2014)

Cancer is the second deadliest disease in the United States, necessitating improvements in tumor diagnosis and treatment. Current model systems of cancer are informative, but translating promising imaging approaches and therapies to clinical practice has been challenging. In particular, the lack of a large-animal model that accurately mimics human cancer has been a major barrier to the development of effective diagnostic tools along with surgical and therapeutic interventions. Here, we developed a genetically modified porcine model of cancer in which animals express a mutation in TP53 (which encodes p53) that is orthologous to one commonly found in humans (R175H in people, R167H in pigs). TP53(R167H/R167H) mutant pigs primarily developed lymphomas and osteogenic tumors, recapitulating the tumor types observed in mice and humans expressing orthologous TP53 mutant alleles. CT and MRI imaging data effectively detected developing tumors, which were validated by histopathological evaluation after necropsy. Molecular genetic analyses confirmed that these animals expressed the R167H mutant p53, and evaluation of tumors revealed characteristic chromosomal instability. Together, these results demonstrated that TP53(R167H/R167H) pigs represent a large-animal tumor model that replicates the human condition. Our data further suggest that this model will be uniquely suited for developing clinically relevant, noninvasive imaging approaches to facilitate earlier detection, diagnosis, and treatment of human cancers.
Early Response Assessment Using 3′-Deoxy-3′-[18F]Fluorothymidine-Positron Emission Tomography in High-Grade Non-Hodgkin's Lymphoma
Authors: Ken Herrmann, Hinrich A. Wieder, Andreas K. Buck, Marion Schöffel, Bernd-Joachim Krause, Falko Fend, Tibor Schuster, Christian Meyer zum Büschenfelde, Hans-Jürgen Wester, Justus Duyster, Christian Peschel, Markus Schwaiger, Tobias Dechow
Journal: Clinical Cancer Research (2007)

Abstract Purpose: To evaluate 3′-deoxy-3′-[18F]fluorothymidine-positron emission tomography (FLT-PET) for early monitoring response of high-grade non-Hodgkin's lymphoma to treatment with cyclophosphamide-adriamycin-vincristine-prednisone chemotherapy with or without rituximab immunotherapy (R-CHOP/CHOP). Experimental Design: Twenty-two patients with histologically proven high-grade non-Hodgkin's lymphoma scheduled to undergo first line treatment with R-CHOP/CHOP were included. All patients received baseline imaging before therapy with FLT-PET. For noninvasive assessment of treatment response, FLT-PET was repeated at following time points: group 1 (n = 6), 1 and 6 weeks after R-CHOP/CHOP; group 2 (n = 16), 2 days after rituximab and 2 days after CHOP application. Emission images were acquired 45 min after injection of 300 to 370 MBq of FLT. FLT uptake was quantified by region-of-interest technique on a lesion basis. Maximum standardized uptake values (SUV) for FLT were calculated using circular region of interest (diameter, 1.5 cm). Results: In all patients, morphologically proven lesions showed initially high FLT uptake (mean SUV, 8.1 ± 3.9). In group 1, mean FLT SUV decreased 7 days after R-CHOP/CHOP by 77% (P &amp;lt; 0.001), the reduction in FLT SUV from baseline was 85% after 40 days (P = 0.003). In group 2, FLT uptake in patients without dexamethasone pretreatment revealed no significant reduction after rituximab (P = 0.3) but significantly decreased 2 days after CHOP to 32% compared with the baseline value (P = 0.004). Conclusions: Administration of R-CHOP/CHOP is associated with an early decrease in lymphoma FLT uptake. Interestingly, there was no reduction of FLT uptake after rituximab alone, indicating no early antiproliferative effect of immunotherapy. FLT-PET seems to be promising for early evaluation of drug effects in lymphoma.
Chromosomal Instability Correlates with Genome-wide DNA Demethylation in Human Primary Colorectal Cancers
Authors: Jairo Rodriguez, Jordi Frigola, Elisenda Vendrell, Rosa-Ana Risques, Mario F. Fraga, Cristina Morales, Victor Moreno, Manel Esteller, Gabriel Capellà, Maria Ribas, Miguel A. Peinado
Journal: Cancer Research (2006)

Abstract DNA hypomethylation is a common trait of colorectal cancer. Studies in tumor cell lines and animal models indicate that genome-wide demethylation may cause genetic instability and hence facilitate or accelerate tumor progression. Recent studies have shown that DNA hypomethylation precedes genomic damage in human gastrointestinal cancer, but the nature of this damage has not been clearly established. Here, we show a thorough analysis of DNA methylation and genetic alterations in two series of colorectal carcinomas. The extent of DNA demethylation but not of hypermethylation (both analyzed by amplification of intermethylated sites in near 200 independent sequences arbitrarily selected) correlated with the cumulated genomic damage assessed by two different techniques (arbitrarily primed PCR and comparative genomic hybridization). DNA hypomethylation–related instability was mainly of chromosomal nature and could be explained by a genome-wide effect rather than by the concurrence of the most prevalent genetic and epigenetic alterations. Moreover, the association of p53 mutations with genomic instability was secondary to DNA hypomethylation and the correlation between DNA hypomethylation and genomic instability was observed in tumors with and without mutation in the p53 gene. Our data support a direct link between genome-wide demethylation and chromosomal instability in human colorectal carcinogenesis and are consistent with the studies in model systems demonstrating a role of DNA demethylation in inducing chromosomal instability. (Cancer Res 2006; 66(17): 8462-8)
Rocky Mountain Spotted Fever from an Unexpected Tick Vector in Arizona
Authors: Linda J. Demma, Marc S. Traeger, William L. Nicholson, Christopher D. Paddock, Dianna M. Blau, Marina E. Eremeeva, Gregory A. Dasch, Michael L. Levin, Joseph Singleton, Sherif R. Zaki, James E. Cheek, David L. Swerdlow, Jennifer H. McQuiston
Journal: New England Journal of Medicine (2005)

Rocky Mountain spotted fever is a life-threatening, tick-borne disease caused by Rickettsia rickettsii. This disease is rarely reported in Arizona, and the principal vectors, Dermacentor species ticks, are uncommon in the state. From 2002 through 2004, a focus of Rocky Mountain spotted fever was investigated in rural eastern Arizona.We obtained blood and tissue specimens from patients with suspected Rocky Mountain spotted fever and ticks from patients' homesites. Serologic, molecular, immunohistochemical, and culture assays were performed to identify the causative agent. On the basis of specific laboratory criteria, patients were classified as having confirmed or probable Rocky Mountain spotted fever infection.A total of 16 patients with Rocky Mountain spotted fever infection (11 with confirmed and 5 with probable infection) were identified. Of these patients, 13 (81 percent) were children 12 years of age or younger, 15 (94 percent) were hospitalized, and 2 (12 percent) died. Dense populations of Rhipicephalus sanguineus ticks were found on dogs and in the yards of patients' homesites. All patients with confirmed Rocky Mountain spotted fever had contact with tick-infested dogs, and four had a reported history of tick bite preceding the illness. R. rickettsii DNA was detected in nonengorged R. sanguineus ticks collected at one home, and R. rickettsii isolates were cultured from these ticks.This investigation documents the presence of Rocky Mountain spotted fever in eastern Arizona, with common brown dog ticks (R. sanguineus) implicated as a vector of R. rickettsii. The broad distribution of this common tick raises concern about its potential to transmit R. rickettsii in other settings.
Altered Patterns of MDM2 and TP53 Expression in Human Bladder Cancer
Authors: P. Lianes, I. Orlow, Z.-F. Zhang, M. R. Oliva, A. S. Sarkis, V. E. Reuter, C. Cordon-Cardo
Journal: JNCI Journal of the National Cancer Institute (1994)

The TP53 gene maps to the short arm of chromosome 17 (17p13.1) and encodes for a nuclear phosphoprotein of 53 kd (p53) involved in cell cycle control. The MDM2 gene is located on the long arm of chromosome 12 (12q13–14), and it encodes for a nuclear protein (Mdm2) of 90 kd of molecular mass. Genetic alterations in the TP53 gene have been reported as frequent events in bladder cancer and are associated with disease progression. The MDM2 gene has been shown to be amplified and overexpressed in sarcomas; however, these changes have not yet been analyzed in neoplastic lesions of the urinary bladder. We undertook the present study in order to determine the frequency of MDM2 and TP53 abnormalities in bladder tumors, as well as to examine the clinical relevance of identifying their altered patterns of expression in patients affected with bladder cancer. We analyzed a cohort of 87 patients affected by bladder tumors. Altered patterns of expression of Mdm2 proteins were determined using an immunohistochemical assay with monoclonal antibody 2 A10, and MDM2 gene amplifications were studied by Southern blotting. Mutant p53 proteins were identified using monoclonal antibody PAb1801. The presence of intragenic mutations in the TP53 gene were assessed utilizing single-strand conformation polymorphism and further characterized by sequencing. Associations were assessed statistically by the two-tailed Fisher's exact test. Twenty-six of 87 cases had abnormally high levels of Mdm2 proteins; however, only one case showed an MDM2 amplification. Thirty-six of 87 cases displayed p53 nuclear overexpression. Sixteen cases had abnormally high levels of both Mdm2 and p53 proteins. There was a strong statistical association between Mdm2 and p53 overexpression (Fisher's exact test: P =.018). Moreover, there was a striking association between Mdm2 overexpression and low-stage, low-grade bladder tumors (Fisher's exact test: P =.0005). The results suggest that aberrant Mdm2 and p53 phenotypes are frequent events in bladder cancer and may be involved in tumorigenesis or tumor progression in urothelial neoplasias. This study is the first to report altered patterns of MDM2 expression in human bladder tumors and demonstrates that aberrant Mdm2 and p53 phenotypes may be important diagnostic and prognostic markers in patients affected by bladder cancer. [J Natl Cancer Inst 86: 1325–1330, 1994]
HYAL1-v1, An Alternatively Spliced Variant of HYAL1 Hyaluronidase: A Negative Regulator of Bladder Cancer
Authors: Vinata B. Lokeshwar, Veronica Estrella, Luis Lopez, Mario Kramer, Pablo Gomez, Mark S. Soloway, Bal L. Lokeshwar
Journal: Cancer Research (2006)

Abstract Tumor cells express HYAL1 hyaluronidase, which degrades hyaluronic acid. HYAL1 expression in bladder cancer cells promotes tumor growth, invasion, and angiogenesis. We previously described five alternatively spliced variants of HYAL1 that encode enzymatically inactive proteins. The HYAL1-v1 variant lacks a 30-amino acid sequence that is present in HYAL1. In this study, we examined whether HYAL1-v1 expression affects bladder cancer growth and invasion by stably transfecting HT1376 bladder cancer cells with a HYAL1-v1 cDNA construct. Although HYAL1-v1 transfectants expressed equivalent levels of enzymatically active HYAL1 protein when compared with vector transfectants, their conditioned medium had 4-fold less hyaluronidase activity due to a noncovalent complex formed between HYAL1 and HYAL1-v1 proteins. HYAL1-v1 transfectants grew 3- to 4-fold slower due to cell cycle arrest in the G2-M phase and increased apoptosis. In HYAL1-v1 transfectants, cyclin B1, cdc2/p34, and cdc25c levels were ≥2-fold lower than those in vector transfectants. The increased apoptosis in HYAL1-v1 transfectants was due to the extrinsic pathway involving Fas and Fas-associated death domain up-regulation, caspase-8 activation, and BID cleavage, leading to caspase-9 and caspase-3 activation and poly(ADP-ribose) polymerase cleavage. When implanted in athymic mice, HYAL1-v1-expressing tumors grew 3- to 4-fold slower and tumor weights at day 35 were 3- to 6-fold less than the vector tumors (P &amp;lt; 0.001). Whereas vector tumors were infiltrating and had high mitoses and microvessel density, HYAL1-v1 tumors were necrotic, infiltrated with neutrophils, and showed low mitoses and microvessel density. Therefore, HYAL-v1 expression may negatively regulate bladder tumor growth, infiltration, and angiogenesis. (Cancer Res 2006; 66(23): 11219-27)
The Ly49Q Receptor Plays a Crucial Role in Neutrophil Polarization and Migration by Regulating Raft Trafficking
Authors: Shigemi Sasawatari, Mariko Yoshizaki, Choji Taya, Aya Tazawa, Kaori Furuyama-Tanaka, Hiromichi Yonekawa, Taeko Dohi, Andrew P. Makrigiannis, Takehiko Sasazuki, Kayo Inaba, Noriko Toyama-Sorimachi
Journal: Immunity (2010)
Commercial Serological Tests for the Diagnosis of Active Pulmonary and Extrapulmonary Tuberculosis: An Updated Systematic Review and Meta-Analysis
Authors: Karen R. Steingart, Laura L. Flores, Nandini Dendukuri, Ian Schiller, Suman Laal, Andrew Ramsay, Philip C. Hopewell, Madhukar Pai
Journal: PLoS Medicine (2011)

Background Serological (antibody detection) tests for tuberculosis (TB) are widely used in developing countries. As part of a World Health Organization policy process, we performed an updated systematic review to assess the diagnostic accuracy of commercial serological tests for pulmonary and extrapulmonary TB with a focus on the relevance of these tests in low- and middle-income countries. Methods and Findings We used methods recommended by the Cochrane Collaboration and GRADE approach for rating quality of evidence. In a previous review, we searched multiple databases for papers published from 1 January 1990 to 30 May 2006, and in this update, we add additional papers published from that period until 29 June 2010. We prespecified subgroups to address heterogeneity and summarized test performance using bivariate random effects meta-analysis. For pulmonary TB, we included 67 studies (48% from low- and middle-income countries) with 5,147 participants. For all tests, estimates were variable for sensitivity (0% to 100%) and specificity (31% to 100%). For anda-TB IgG, the only test with enough studies for meta-analysis, pooled sensitivity was 76% (95% CI 63%–87%) in smear-positive (seven studies) and 59% (95% CI 10%–96%) in smear-negative (four studies) patients; pooled specificities were 92% (95% CI 74%–98%) and 91% (95% CI 79%–96%), respectively. Compared with ELISA (pooled sensitivity 60% [95% CI 6%–65%]; pooled specificity 98% [95% CI 96%–99%]), immunochromatographic tests yielded lower pooled sensitivity (53%, 95% CI 42%–64%) and comparable pooled specificity (98%, 95% CI 94%–99%). For extrapulmonary TB, we included 25 studies (40% from low- and middle-income countries) with 1,809 participants. For all tests, estimates were variable for sensitivity (0% to 100%) and specificity (59% to 100%). Overall, quality of evidence was graded very low for studies of pulmonary and extrapulmonary TB. Conclusions Despite expansion of the literature since 2006, commercial serological tests continue to produce inconsistent and imprecise estimates of sensitivity and specificity. Quality of evidence remains very low. These data informed a recently published World Health Organization policy statement against serological tests. Please see later in the article for the Editors' Summary
Primary Tumor Location as a Prognostic Factor in Metastatic Colorectal Cancer
Authors: Fotios Loupakis, Dongyun Yang, Linda Yau, Shibao Feng, Chiara Cremolini, Wu Zhang, Martin K H Maus, Carlotta Antoniotti, Christiane Langer, Stefan J Scherer, Thomas Müller, Herbert I Hurwitz, Leonard Saltz, Alfredo Falcone, Heinz-Josef Lenz
Journal: JNCI Journal of the National Cancer Institute (2015)

We sought to clarify the prognostic impact of primary tumor location in metastatic colorectal cancer (mCRC). We evaluated the association between tumor location and survival parameters in patients with previously untreated mCRC receiving first-line chemotherapy ± bevacizumab in three independent cohorts: a prospective pharmacogenetic study (PROVETTA) and two randomized phase III trials, AVF2107g and NO16966. Cancers proximal or distal of the splenic flexure were classified as right-sided or left-sided, respectively. The primary end point was overall survival (OS). Data were analyzed with Cox proportional hazards and logistic regression models. All statistical tests were two-sided. Among evaluable patients in the PROVETTA (n = 200), AVF2107g (n = 559), and NO16966 (n = 1268) studies, 72.0%, 63.1%, and 73.7% had left-sided tumors, respectively. In PROVETTA, patients with left-sided tumors had superior OS (left-sided vs right-sided: hazard ratio [HR] = .44, 95% confidence interval [CI] = .28 to .70, P < .001) and progression-free survival (HR = .52, 95% CI = .36 to .75, P < .001) outcomes. Multivariable analyses confirmed right-sided location as a negative prognostic variable, independent of mucinous histology and BRAF mutational status. Data from the AVF2107g (HR for OS = .55, 95% CI = .43 to .70) and NO16966 trials (HR for OS = .71, 95% CI = .62 to .82 both P < .001) also showed favorable outcomes in patients with left-sided tumors. In both randomized studies, the efficacy of bevacizumab was independent of tumor location. These data demonstrate that primary tumor location is an important prognostic factor in previously untreated mCRC. Given the consistency across an exploratory set and two confirmatory phase III studies, side of tumor origin should be considered for stratification in randomized trials.
Redox Modulation of Chemotherapy-Induced Tumor Cell Killing and Normal Tissue Toxicity
Authors: James H. Doroshow
Journal: JNCI Journal of the National Cancer Institute (2006)

The traditional view of intracellular oxidation – reduction, or redox, balance in epithelial cells, which is more than three decades old ( 1 ) , emphasizes a dynamic equilibrium between the production of reactive oxygen species (ROS; these include superoxide anion, O 2 − ; hydrogen peroxide, H 2 O 2 ; and chemical species with the characteristics of the hydroxyl radical, • OH) by a variety of fl avin dehydrogenases that occupy essentially every cellular compartment, and the detoxifi cation of these species by a broad range of antioxidant enzymes and related small molecules ( 2 ) . ROS are produced by the mitochondrial electron transport chain during the course of cellular respiration, by cytochrome P450 – related components of microsomes ( 3 ) , and, in many human tumors, by the recently described family of membrane-bound NADPH oxidases that possess a high degree of homology with components of the NADPH oxidase system of polymorpho nuclear leukocytes and macrophages ( 4 ) . ROS are detoxifi ed by a complex and interactive series of proteins and small molecules — including members of the superoxide dismutase, glutathione peroxidase, and peroxiredoxin gene families, as well as catalase — that ultimately reduce O 2 − and H 2 O 2 (or lipid peroxides) to non