tbuckley/cabot-search huggingface dataset:
Myocardin related transcription factor A programs epigenetic activation of hepatic stellate cells
Authors: Wenfang Tian, Chenzhi Hao, Zhiwen Fan, Xinyu Weng, Hao Qin, Xiaoyan Wu, Mingming Fang, Qi Chen, Aiguo Shen, Yong Xu
Journal: Journal of Hepatology (2014)
Unconjugated Bilirubin and an Increased Proportion of Bilirubin Monoconjugates in the Bile of Patients with Gilbert's Syndrome and Crigler-Najjar Disease
Authors: Johan Fevery, Norbert Blanckaert, Karel P. M. Heirwegh, Anne-Marie Préaux, Pierre Berthelot
Journal: Journal of Clinical Investigation (1977)

Bilirubin pigments were studied in the bile of 20 normal adults, 25 patients with Gilbert's syndrome, 9 children with Crigler-Najjar disease, and 6 patients with hemolysis, to determine how a deficiency of hepatic bilirubin UDP-glucuronosyltransferase would affect the end products of bilirubin biotransformation.
Lymphocyte depletion with fludarabine in patients with psoriatic arthritis: clinical and immunological effects
Authors: K Takada
Journal: Annals of the Rheumatic Diseases (2003)

To obtain preliminary information on the safety and efficacy of fludarabine in PsA and analyse its immunomodulatory effects in peripheral blood and synovial tissue.15 patients with active PsA who did not respond to DMARDs were randomly allocated to receive fludarabine every four weeks or placebo. Primary outcomes were the proportion of patients who met the ACR20 and the psoriatic arthritis response criteria (PsARC) at 16 weeks. Secondary outcomes were changes in tender or swollen joint counts and scores of the psoriasis area and severity index (PASI). Phenotypic analysis of peripheral blood mononuclear cells (PBMC), synovial immunohistochemistry, and functional analysis of PBMC were used to determine the immunomodulatory effects of fludarabine.At 16 weeks the ACR20 criteria were met by 3/7 (43%) fludarabine treated v 0/8 placebo treated patients (p=0.08); the PsARC was achieved by 4/7 (57%) fludarabine treated v 2/8 (25%) placebo treated patients; and 3/7 (43%) fludarabine treated v 0/7 placebo treated patients had > or =20% improvement in the PASI. Marked peripheral lymphopenia involving naive (CD4(+) CD45RA(+)) and memory (CD4(+) CD45RO(+)) T cells, CD8(+) T cells, and B cells was seen in fludarabine treated patients.In PsA fludarabine induces significant peripheral, but modest, synovial lymphopenia, and a trend towards improved clinical response.
Flavonoids and laryngeal cancer risk in Italy
Authors: W. Garavello, M. Rossi, J.K. McLaughlin, C. Bosetti, E. Negri, P. Lagiou, R. Talamini, S. Franceschi, M. Parpinel, L. Dal Maso, C. La Vecchia
Journal: Annals of Oncology (2007)
Mitochondrial–Nuclear Interactions and Accelerated Compensatory Evolution: Evidence from the Primate Cytochrome c Oxidase Complex
Authors: Naoki Osada, Hiroshi Akashi
Journal: Molecular Biology and Evolution (2011)

Accelerated rates of mitochondrial protein evolution have been proposed to reflect Darwinian coadaptation for efficient energy production for mammalian flight and brain activity. However, several features of mammalian mtDNA (absence of recombination, small effective population size, and high mutation rate) promote genome degradation through the accumulation of weakly deleterious mutations. Here, we present evidence for "compensatory" adaptive substitutions in nuclear DNA- (nDNA) encoded mitochondrial proteins to prevent fitness decline in primate mitochondrial protein complexes. We show that high mutation rate and small effective population size, key features of primate mitochondrial genomes, can accelerate compensatory adaptive evolution in nDNA-encoded genes. We combine phylogenetic information and the 3D structure of the cytochrome c oxidase (COX) complex to test for accelerated compensatory changes among interacting sites. Physical interactions among mtDNA- and nDNA-encoded components are critical in COX evolution; amino acids in close physical proximity in the 3D structure show a strong tendency for correlated evolution among lineages. Only nuclear-encoded components of COX show evidence for positive selection and adaptive nDNA-encoded changes tend to follow mtDNA-encoded amino acid changes at nearby sites in the 3D structure. This bias in the temporal order of substitutions supports compensatory weak selection as a major factor in accelerated primate COX evolution.
Kinetics of Inhibitor Cycling Underlie Therapeutic Disparities between EGFR-Driven Lung and Brain Cancers
Authors: Krister J. Barkovich, Sujatmi Hariono, Adam L. Garske, Jie Zhang, Jimmy A. Blair, Qi-Wen Fan, Kevan M. Shokat, Theodore Nicolaides, William A. Weiss
Journal: Cancer Discovery (2012)

Although mutational activation of the epidermal growth factor receptor (EGFR) features prominently in glioma and non-small cell lung cancer (NSCLC), inhibitors of EGFR improve survival only in patients with NCSLC. To understand how mutations in EGFR influence response to therapy, we generated glioma cells expressing either glioma- or NSCLC-derived alleles and quantified kinase-site occupancy by clinical inhibitors with the use of a novel affinity probe and kinetic methodology. At equivalent doses, erlotinib achieved lower kinase-site occupancy in glioma-derived EGFRvIII compared with NSCLC-derived EGFR mutants. Kinase-site occupancy correlated directly with cell-cycle arrest. EGFRvIII released erlotinib rapidly compared with wild-type EGFR, whereas NSCLC-derived mutants released erlotinib slowly.These data suggest that kinase-site occupancy is a biomarker for efficacy of EGFR inhibitors, that rapid binding and release of erlotinib in glioma-derived EGFRvIII opposes the blockade of downstream signaling, and that slower cycling of erlotinib within the active site of NSCLC-derived mutants underlies their improved clinical response.
A Blocking Antibody to Nerve Growth Factor Attenuates Skeletal Pain Induced by Prostate Tumor Cells Growing in Bone
Authors: Kyle G. Halvorson, Kazufumi Kubota, Molly A. Sevcik, Theodore H. Lindsay, Julio E. Sotillo, Joseph R. Ghilardi, Thomas J. Rosol, Leila Boustany, David L. Shelton, Patrick W. Mantyh
Journal: Cancer Research (2005)

Abstract Prostate cancer is unique in that bone is often the only clinically detectable site of metastasis. Prostate tumors that have metastasized to bone frequently induce bone pain which can be difficult to fully control as it seems to be driven simultaneously by inflammatory, neuropathic, and tumorigenic mechanisms. As nerve growth factor (NGF) has been shown to modulate inflammatory and some neuropathic pain states in animal models, an NGF-sequestering antibody was administered in a prostate model of bone cancer where significant bone formation and bone destruction occur simultaneously in the mouse femur. Administration of a blocking antibody to NGF produced a significant reduction in both early and late stage bone cancer pain–related behaviors that was greater than or equivalent to that achieved with acute administration of 10 or 30 mg/kg of morphine sulfate. In contrast, this therapy did not influence tumor-induced bone remodeling, osteoblast proliferation, osteoclastogenesis, tumor growth, or markers of sensory or sympathetic innervation in the skin or bone. One rather unique aspect of the sensory innervation of bone, that may partially explain the analgesic efficacy of anti-NGF therapy in relieving prostate cancer–induced bone pain, is that nearly all nerve fibers that innervate the bone express trkA and p75, and these are the receptors through which NGF sensitizes and/or activates nociceptors. The present results suggest that anti-NGF therapy may be effective in reducing pain and enhancing the quality of life in patients with prostate tumor–induced bone cancer pain.
Epigenetic Modulation Enhances the Therapeutic Effect of Anti–IL-13Rα2 Antibody in Human Mesothelioma Xenografts
Authors: Makoto Takenouchi, Sachie Hirai, Naoya Sakuragi, Hideo Yagita, Hirofumi Hamada, Kazunori Kato
Journal: Clinical Cancer Research (2011)

Abstract Purpose: The interleukin-13 receptor α2 (IL-13Rα2) is expressed by a variety of human malignant cells. Here, we have examined the constitutive surface expression and the epigenetic regulation of IL-13Rα2 by human mesothelioma. We have also investigated the therapeutic effect of the DNA methylation inhibitor 5-aza-2′-deoxycytidine (5-aza-dC) and anti–IL-13Rα2 monoclonal antibody on mesothelioma xenografts. Experimental Design: Cell surface expression of IL-13Rα2 by various lung carcinomas was analyzed using flow cytometry. Therapeutic effects of anti–IL-13Rα2 and 5-aza-dC were investigated using antibody-dependent cellular cytotoxicity and proliferation assays and by monitoring the survival of mesothelioma-bearing mice. Results: We found that human malignant mesotheliomas expressed surface IL-13Rα2 on their surface and that it was upregulated by treatment with 5-aza-dC. This augmented expression of IL-13Rα2 resulted in growth inhibition of the mesothelioma cells when cocultured with anti-IL-13Rα2 and effector cells, such as splenocytes and peritoneal exudate cells. The growth inhibition of mesothelioma cells was mediated by IFN-γ that was only detected in the supernatant when effector cells were exposed to 5-aza-dC–treated tumors in the presence of anti–IL-13Rα2. Compared with the control or either regimen alone, in vivo administration of anti-IL-13Rα2 in combination with 5-aza-dC significantly prolonged the survival of mice with mesothelioma xenografts. Conclusions: These observations indicate a promising role for IL-13Rα2 as a target for antibody treatment in malignant mesothelioma, and, in combination with epigenetic regulation by a DNA methylation inhibitor, suggest the potential for a novel strategy to enhance therapeutic potency. Clin Cancer Res; 17(9); 2819–29. ©2011 AACR.
Which is the most useful patient-reported outcome in femoroacetabular impingement? Test–retest reliability of six questionnaires
Authors: Rana S Hinman, Fiona Dobson, Amir Takla, John O'Donnell, Kim L Bennell
Journal: British Journal of Sports Medicine (2013)

The most reliable patient-reported outcomes (PROs) for people with femoroacetabular impingement (FAI) is unknown because there have been no direct comparisons of questionnaires. Thus, the aim was to evaluate the test-retest reliability of six existing PROs in a single cohort of young active people with hip/groin pain consistent with a clinical diagnosis of FAI.Young adults with clinical FAI completed six PRO questionnaires on two occasions, 1-2 weeks apart. The PROs were modified Harris Hip Score, Hip dysfunction and Osteoarthritis Score, Hip Outcome Score, Non-Arthritic Hip Score, International Hip Outcome Tool, Copenhagen Hip and Groin Outcome Score.30 young adults (mean age 24 years, SD 4 years, range 18-30 years; 15 men) with stable symptoms participated. Intraclass correlation coefficient(3,1) values ranged from 0.73 to 0.93 (95% CI 0.38 to 0.98) indicating that most questionnaires reached minimal reliability benchmarks. Measurement error at the individual level was quite large for most questionnaires (minimal detectable change (MDC95) 12.4-35.6, 95% CI 8.7 to 54.0). In contrast, measurement error at the group level was quite small for most questionnaires (MDC95 2.2-7.3, 95% CI 1.6 to 11).The majority of the questionnaires were reliable and precise enough for use at the group level. Samples of only 23-30 individuals were required to achieve acceptable measurement variation at the group level. Further direct comparisons of these questionnaires are required to assess other measurement properties such as validity, responsiveness and meaningful change in young people with FAI.
Gene expression variation in African and European populations of Drosophila melanogaster
Authors: Stephan Hutter, Sarah S Saminadin-Peter, Wolfgang Stephan, John Parsch
Journal: Genome biology (2008)

Abstract Background Differences in levels of gene expression among individuals are an important source of phenotypic variation within populations. Recent microarray studies have revealed that expression variation is abundant in many species, including Drosophila melanogaster . However, previous expression surveys in this species generally focused on a small number of laboratory strains established from derived populations. Thus, these studies were not ideal for population genetic analyses. Results We surveyed gene expression variation in adult males of 16 D . melanogaster strains from two natural populations, including an ancestral African population and a derived European population. Levels of expression polymorphism were nearly equal in the two populations, but a higher number of differences was detected when comparing strains between populations. Expression variation was greatest for genes associated with few molecular functions or biological processes, as well as those expressed predominantly in males. Our analysis also identified genes that differed in expression level between the European and African populations, which may be candidates for adaptive regulatory evolution. Genes involved in flight musculature and fatty acid metabolism were over-represented in the list of candidates. Conclusion Overall, stabilizing selection appears to be the major force governing gene expression variation within populations. However, positive selection may be responsible for much of the between-population expression divergence. The nature of the genes identified to differ in expression between populations may reveal which traits were important for local adaptation to the European and African environments.
Dose-finding study of docetaxel and doxorubicin in first-line treatment of patients with metastatic breast cancer
Authors: J.L. Misset, V. Dieras, G. Gruia, H. Bourgeois, E. Cvitkovic, S. Kalla, L. Bozec, P. Beuzeboc, C. Jasmin, J.P. Aussel, A. Riva, N. Azli, P. Pouillart
Journal: Annals of Oncology (1999)
Alcohol dehydrogenase III exacerbates liver fibrosis by enhancing stellate cell activation and suppressing natural killer cells in mice
Authors: Hyon-Seung Yi, Young-Sun Lee, Jin-Seok Byun, Wonhyo Seo, Jong-Min Jeong, Ogyi Park, Gregg Duester, Takeshi Haseba, Sun Chang Kim, Keun-Gyu Park, Bin Gao, Won-Il Jeong
Journal: Hepatology (2014)

The important roles of retinols and their metabolites have recently been emphasized in the interactions between hepatic stellate cells (HSCs) and natural killer (NK) cells. Nevertheless, the expression and role of retinol metabolizing enzyme in both cell types have yet to be clarified. Thus, we investigated the expression of retinol metabolizing enzyme and its role in liver fibrosis. Among several retinol metabolizing enzymes, only alcohol dehydrogenase (ADH) 3 expression was detected in isolated HSCs and NK cells, whereas hepatocytes express all of them. In vitro treatment with 4-methylpyrazole (4-MP), a broad ADH inhibitor, or depletion of the ADH3 gene down-regulated collagen and transforming growth factor-β1 (TGF-β1) gene expression, but did not affect α-smooth muscle actin gene expression in cultured HSCs. Additionally, in vitro, treatments with retinol suppressed NK cell activities, whereas inhibition of ADH3 enhanced interferon-γ (IFN-γ) production and cytotoxicity of NK cells against HSCs. In vivo , genetic depletion of the ADH3 gene ameliorated bile duct ligation- and carbon tetrachloride-induced liver fibrosis, in which a higher number of apoptotic HSCs and an enhanced activation of NK cells were detected. Freshly isolated HSCs from ADH3-deficient mice showed reduced expression of collagen and TGF-β1, but enhanced expression of IFN-γ was detected in NK cells from these mice compared with those of control mice. Using reciprocal bone marrow transplantation of wild-type and ADH3-deficient mice, we demonstrated that ADH3 deficiency in both HSCs and NK cells contributed to the suppressed liver fibrosis. Conclusion : ADH3 plays important roles in promoting liver fibrosis by enhancing HSC activation and inhibiting NK cell activity, and could be used as a potential therapeutic target for the treatment of liver fibrosis. (Hepatology 2014;60:1044–1053)
Abstract IA9: The MEK network as a target for combination therapies
Authors: W. Michael Korn
Journal: Clinical Cancer Research (2012)

Abstract Small molecule inhibitors of signal transduction pathways can elicit complex and sometimes non-intuitive molecular responses in cancer cells. Increasing evidence supports the notion that these responses are important mediators of de novo drug resistance. We systematically assessed molecular and cellular responses to MEK inhibitors, aiming at identifying meaningful targets for combination therapies. Proteomic analyses revealed an EGFR-dependent feedback loop resulting in activation of the PI3 kinase pathway following MEK inhibition. In agreement with this, combinations of MEK inhibitors and inhibitors of EGFR inhibitors or PI3 kinase show synergistic effects on cell proliferation and apoptosis rates in molecularly defined disease subtypes. To further explore molecular networks affected by MEK inhibition, Bayesian network inference algorithms were applied and reverse-engineered networks were generated that are amenable to in silico forward-simulation. Using this technology, new, MEK-dependent, novel regulators of cell cycle and apoptosis were identified and experimentally validated. These findings highlight the potential of mathematical modeling approaches to efficiently reveal new and therapeutically relevant features of signal transduction networks.
Long-Term Outcome Associated with Early Repolarization on Electrocardiography
Authors: Jani T. Tikkanen, Olli Anttonen, M. Juhani Junttila, Aapo L. Aro, Tuomas Kerola, Harri A. Rissanen, Antti Reunanen, Heikki V. Huikuri
Journal: New England Journal of Medicine (2009)

Early repolarization, which is characterized by an elevation of the QRS–ST junction (J point) in leads other than V1 through V3 on 12-lead electrocardiography, has been associated with vulnerability to ventricular fibrillation, but little is known about the prognostic significance of this pattern in the general population.
BI-05 * MOLECULAR PROFILING OF LOW GRADE GLIOMAS (LGG) IN COLOMBIA (ONCOLGROUP)
Authors: A. Cardona, E. Jimenez, F. Hakim, N. Useche, S. Bermudez, O. Arrieta, J. Behaine, J. Rodriguez, H. Carranza, J. Otero, C. Vargas, L. Rojas, L. D. Ortiz
Journal: Neuro-Oncology (2014)

BACKGROUND: LGG are classified as being astrocytoma (DA), oligodendroglioma (OD) or mixed glioma (OA). TP53-m and 1p19q codeletion have been the main molecular abnormalities recorded to date. IDH1/2 mutations have been described in up to 85% of LGG. It has recently been found that ATRX plays a significant role in glioma oncogenesis. METHODS: We searched for P53 and Olig2 protein expression, MGMT methylation status (pMGMT), 1p19q codeletion and IDH/ATRX status in 63 Colombian LGG patients (pts). Overall survival (OS) rate was estimated and compared between groups and according to genotype. RESULTS: Mean age was 40.1-yo (±12.3), 50% of the pts were male, mean lesion diameter was 41.7 mm (±17.2 mm) and histological distribution was 61.9%, 25.4% and 12.7% for AD, OD and OA, respectively. Surgical resection was total in 47.6%, subtotal in 31.7% and biopsy was performed in 20.6% of the cases. Alterations in IDH1/2 were found in 57.1%, pMGMT+ in 65.1%, overexpression of p53 and Olig2 in 30.2% and 44.4%, and 1p19q codeletion in 34.9%. The presence of alterations in ATRX was analysed in 25 patients, being positive in 16% (all IDH1 + /1p19q-). Median follow-up was 15.8 months (95%CI 7.6-42.0), OS was 39.2 months (95%CI 1.3-114) and the variables positively modifying OS were pMGMT+ (p = 0.004), 1p19q codeletion (p = 0.015), the extension of surgical intervention (p = 0.011) and the number of lobes involved (p = 0.021). Multivariate analysis showed that pMGMT and 1p19q codeletion modified the OS in our population (p = 0.039 and 0.047, respectively). CONCLUSIONS: This is the first study which has evaluated the molecular profile in LGG pts from Latin-America. Our findings confirmed the prognostic relevance of pMGMT and 1p19q codeletion, without finding a positive relation for IDH1/2 mutations. This finding could have been explained by sample size and selection bias. Alterations in ATRX are limited to the population of pts having AD/OA and IDH1 + /1p19q-.
Renin, Angiotensin II, and Adrenal Corticosteroid Relationships during Sodium Deprivation and Angiotensin Infusion in Normotensive and Hypertensive Man
Authors: F. A. O. MENDELSOHN, C. I. JOHNSTON, A. E. DOYLE, B. A. SCOGGINS, D. A. DENTON, J. P. COGHLAN
Journal: Circulation Research (1972)

The responses of plasma renin activity, plasma angiotensin II, plasma aldosterone, cortisol, and corticosterone to sodium deprivation and to angiotensin II infusion (100 ng/min) were measured in 8 normotensive patients and in 17 patients with essential hypertension. Following sodium deprivations, plasma renin activity rose from 0.513 ± 0.100 to 1.029 ± 0.124 ng/ml hour -1 in normotensive patients and from 0.406 ± 0.077 to 0.629 ± 0.059 ng/ml hour -1 in hypertensive patients. Plasma angiotensin II did not parallel changes in plasma renin activity: in normotensive patients plasma angiotensin II was unchanged by sodium deprivation (31.8 ± 6.0 compared with 30.1 ± 4.6 pg/ml), but in hypertensive patients it rose from 22.2 ± 3.4 to 36.4 ± 5.1 pg/ml. Plasma aldosterone rose equally in both groups following sodium deprivation (5.8 ± 1.3 to 15.3 ± 2.4 ng/100 ml for normotensive patients and 5.9 ± 1.4 to 14.4 ± 1.6 ng/100 ml for hypertensive patients) and angiotensin infusion (5.8 ± 1.3 to 10.4 ± 2.1 ng/100 ml in sodium-loaded normotensive patients, 15.3 ± 2.4 to 19.6 ± 3.6 ng/100 ml in sodium-deprived normotensive patients, 5.9 ± 1.4 to 11.4 ± 2.7 ng/100 ml in sodium-loaded hypertensive patients, and 14.4 ± 1.6 to 22.2 ± 2.6 ng/100 ml in sodium-deprived hypertensive patients). However, changes in endogenous plasma angiotensin II did not correlate with the rise in plasma aldosterone caused by sodium deprivation, and, despite much larger increases in plasma angiotensin II during angiotensin II infusion, plasma aldosterone showed smaller rises than those accompanying sodium deprivation. Plasma renin activity fell during angiotensin II infusion, in both groups of patients during both sodium loading and sodium deprivation, and, hence, the infusion constitutes a potent feedback inhibition of renin release in normotensive and hypertensive man. Plasma cortisol and corticosterone were unaltered by sodium deprivation but fell significantly with the angiotensin II infusion.
Harnessing Immune Responses in the Tumor Microenvironment: All Signals Needed
Authors: Dung T. Le, Elizabeth M. Jaffee
Journal: Clinical Cancer Research (2013)

Abstract An agonist CD40 monoclonal antibody (CP-870,893), in combination with gemcitabine, is well tolerated in patients with advanced pancreatic adenocarcinoma. The combination results in induction of cytokines, B cell activation, and clinical responses. These findings support testing of immunotherapies in combination with other established and targeted therapies. Clin Cancer Res; 19(22); 6061–3. ©2013 AACR.
Swabbing Students: Should Universities Be Allowed to Facilitate Educational DNA Testing?
Authors: Shawneequa L. Callier
Journal: The American Journal of Bioethics (2012)

Recognizing the profound need for greater patient and provider familiarity with personalized genomic medicine, many university instructors are including personalized genotyping as part of their curricula. During seminars and lectures students run polymerase chain reactions on their own DNA or evaluate their experiences using direct-to-consumer genetic testing services subsidized by the university. By testing for genes that may influence behavioral or health-related traits, however, such as alcohol tolerance and cancer susceptibility, certain universities have stirred debate on the ethical concerns raised by educational genotyping. Considering the potential for psychosocial harm and medically relevant outcomes, how far should university-facilitated DNA testing be permitted to go? The analysis here distinguishes among these learning initiatives and critiques their approaches to the ethical concerns raised by educational genotyping.