tbuckley/cabot-search huggingface dataset:
Abstract 399: Establishment of hypomethylating agent-resistant cell lines using a cell line from a patient with acute myeloid leukemia evolved from myelodysplastic syndrome (MOLM-13)
Authors: Dae R. Choi, Eun-Hye Hur, Ju Hyun Moon, Bon-Kwan Goo, Yunsuk Choi, Do Young Lee, Seonggu Ro, Joong Myung Cho, Je-Hwan Lee
Journal: Cancer Research (2014)

Abstract Myelodysplastic syndrome (MDS) is a clonal disorder of the hematopoietic cells occurring in elderly patients in a majority of instances. They are defined by ineffective hematopoiesis with peripheral blood cytopenias and by the risk of evolution to acute myeloid leukemia (AML). Hypomethylating agents (HMA), 5-azacytidine (AZA) and 2-deoxy-5-azacytidine (DAC), have demonstrated clinical activities with cytologic and cytogenetic responses in patients with MDS, but potential problems of both agents include the development of intrinsic and acquired resistance. HMA-resistant patients have very poor prognosis, and this cohort of patients constitutes an important area of research. To understand mechanisms of HMA-resistance and overcome the resistance, we tried to establish HMA-resistant cells using MOLM-13, which is a cell line from a patient with AML evolved from MDS. Original MOLM-13 cell line was sensitive to both AZA and DAC in vitro. MOLM-13 cells were exposed continuously to increasing concetrations of AZA or DAC and we could establish an AZA-resistant cell line (MOLM/AZA-1) and a DAC-resistant cell line (MOLM/DAC-5). The IC50 of AZA in MOLM/AZA-1 was 96.26 µM compared to 0.11 µM of the parent cell line; 800-fold increase in resistance to AZA. The IC50 of DAC in MOLM/DAC-5 was 207.7 µM compared to 0.07 µM of the parent cell line; 2000-fold increase in resistance to DAC. We treated th AZA- and DAC-resistant cells with vorinostat (SAHA) and a novel agent, CG200745 to test whether the histone deacetylase (HDAC) inhibitors could overcome the HMA-resistance. Cell viability assays showed that HMA-resistant cells were sensitive to both HDAC inhibitors, which dramatically decreased anti-apoptotic proteins (XIAP, MCL-1 and BCL-2) and increased PARP cleavages in the HMA-resistant cell lines. In conclusion, we successfully established established AZA- and DAC-resistant cell lines from an AML/MDS cell line, MOLM-13, and found that HDAC inhibitors might be promising in overcoming HMA-resistance. Further studies with the HMA-resistant cell lines are ongoing for elucidation of resistance mechanisms and possible role of other novel agents to overcome the HMA-resistance. Citation Format: Dae Ro Choi, Eun-Hye Hur, Ju Hyun Moon, Bon-Kwan Goo, Yunsuk Choi, Do Young Lee, Seonggu Ro, Joong Myung Cho, Je-Hwan Lee. Establishment of hypomethylating agent-resistant cell lines using a cell line from a patient with acute myeloid leukemia evolved from myelodysplastic syndrome (MOLM-13). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 399. doi:10.1158/1538-7445.AM2014-399
Quality of randomised controlled trials in head injury
Authors: G. D Murray
Journal: BMJ (2000)

Editor—The review by Dickinson and colleagues1 shows a remarkably narrow view of research in head injury and virtually ignores the need to match the design to the research question. Historically, many clinical trials have been underpowered, but the authors' premise that the main aim of head injury trials should be to detect changes of “a few per cent” in the rate of death or disability does not apply, for example, to phase I/II trials in the acute stage nor the later interventions used in many of their reviewed trials. The authors might find it useful to reread the article “Why do we need some large, simple randomized trials?” by Yusuf et al (note the word “some” in the title).2

Several factors influence the relevant effect size and hence the size of the trial. Some potentially powerful interventions in severe head injury are not widely practicable and are likely to be expensive, and therefore evidence of a substantial effect is required if budget holders are to be persuaded to support them. The focus on a 10% benefit has reflected a perception that funding could be obtained for a treatment that benefits 1 person in 10. However, even this may be optimistic. Despite the 13% benefit obtained from nimodipine treatment in subarachnoid haemorrhage,3 corresponding to a number needed to treat of eight, clinicians have had difficulties in gaining funding for the routine use of this drug. The effectiveness in individual patients is also relevant.

Dickinson and colleagues say that unfamiliarity among ethics committees and investigators with the idea of randomisation without consent obstructs recruitment. This is erroneous and displays a dangerously superficial attitude towards a complex area. What urgently needs to be clarified is the legal framework in which research in incompetent adults takes place. Recent legislation in the Scottish parliament contained no provision for an exception to the requirement to obtain informed consent. Equally it is not clear that any legal framework exists to allow research without consent in the rest of the United Kingdom.

The authors highlighted inadequate funding as one obstacle that has prevented large randomised controlled trials of widely practicable treatments for head injuries. The corresponding author is an applicant to the Medical Research Council for substantial funding for developing the CRASH study4 into a full scale trial, a study that is in part supported by the manufacturer of the agent under trial. In view of this, and his apparently strong position on this issue,5 it may be found surprising that no competing interests were declared.
Gene set enrichment analysis of prostate cancer cells to study histone deacetylase inhibitor resistance
Authors: Madeleine Kortenhorst, Luigi Marchionni, Marianna Zahurak, Shabana Shabbeer, Sushant Kachhap, Giovanni Parmigiani, Henk Verheul, Michael Carducci
Journal: Cancer Research (2007)

4416   Histone Deacetylase inhibitors (HDACIs) are studied for their antitumor activity. By using microarray technology, we studied which pathways are affected by treatment with the HDACIs, valproic acid (VPA) and vorinostat, in androgen independent prostate cancer (PCA) cells. We performed gene set enrichment analysis (GSEA) to analyze our data. GSEA is a computational method that can recognize significant differences in an a priori defined set of genes that are related without pre-analysis thresholds. METHODS: In vitro sensitivity of PC3 and DU145 PCA cells to HDACI treatment was determined by MTT assay and flow cytometry. To study gene transcription, a multiple loop double cube microarray experiment was designed. PC3 and DU145 cells were treated for 48 or 96 hours (h) with 1 mM VPA or 1 uM vorinostat. In total 8 control and 8 treated samples were hybridized to 22 dual-color arrays. Statistical analysis included Loess normalization, an adjusted ANOVA model and empirical Bayes to correct for multiple hypothesis testing. High-throughput data mining was performed using an amended form of GSEA Statistical significance was calculated using the Wilcoxon rank sum test. Previously reported databases were used for these enrichment analyses. RESULTS: In the in vitro assays, PC3 cells were relatively resistant to HDACI treatment compared to DU145 cells. Microarray analysis showed differential gene expression levels between DU145 and PC3 cells. These differences were also dependent on drug (VPA>vorinostat) and duration of treatment (96h>48h). Gene expression levels in DU145 cells were altered to a higher extent compared to PC3 cells by HDACI treatment, 5.7-10.1% vs. 2.9-4.3% of all genes tested, respectively (p
Abstract P157: Leading Causes of Death Among Asian Americans
Authors: Katherine G Hastings
Journal: Circulation (2014)

Background: Asian Americans are one of the fastest growing racial/ethnic groups in the United States (U.S). Our current understanding of Asian American mortality patterns have been distorted by the aggregation of distinct subgroups, which masks the heterogeneity of the leading causes of death among diverse Asian American subgroups. There is currently a knowledge gap on the health of these rapidly expanding populations with little evidence to recommend research agendas, create public health policy, and offer clinical guidelines. In this analysis, we examined the leading causes of death among Asian American subgroups to determine racial/ethnic differences in mortality within the U.S. Methods: We examined national mortality rates for the six largest Asian American subgroups (Asian Indian, Chinese, Filipino, Japanese, Korean, and Vietnamese) from 2003-2010. U.S. death records from 34 U.S. states and the District of Columbia were used to identify race/ethnicity and cause of death by ICD-10 coding. Standardized mortality ratios (SMR), were calculated for each sex and racial/ethnic group relative to Non-Hispanic Whites (NHW), adjusting for age. Mortality counts were used to rank the top ten causes of death among Asian Americans and the leading causes of death, death counts, and overall death percentage for each Asian American subgroup by sex were determined. Results: We examined 15,943,806 U.S. death records. SMRs were lower for all Asian subgroups compared to NHWs (0.52 female, 0.5 male vs. 1.0 male and female) for all causes of mortality. There was heterogeneity in mortality rates across Asian subgroups. Filipino (0.59) and Japanese men (0.63) and women (0.58) had the highest SMRs compared to other Asian subgroups. Cancer is the leading cause of death for all Asian women (27.6% of all Asian deaths), except Asian Indian women with cardiovascular disease (CVD) as the leading cause of death (28% of all deaths). The leading cause of death varies among Asian subgroups for men. Aggregate data for Asian men indicates cancer as the leading cause of death (27.4% of all Asian deaths), however this is only true for Chinese (31.9%), Korean (33.9%) and Vietnamese men (32.4%). CVD is the leading cause of death for Filipino (28.5%), Japanese (26.5%), and Asian Indian (31.8%) men. Proportions of death among Asian Indian males due to CVD (31.8%) are nearly double that of cancer (17.7%). CVD is the leading cause of death for NHWs (25.9% females, 26.9% males) followed by cancer (21.9% females, 24.9% males). Conclusions: There is significant heterogeneity in mortality patterns among Asian American subgroups. While Asian Americans in general have lower rates of mortality, CVD is an important cause of death for some subgroups. This heterogeneity calls to attention the need for more research in the distinct subgroups to help direct treatment and prevention efforts to reduce health disparities for this rapidly growing population.
Training pharmacists in the stage-of-change model of smoking cessation: A randomised controlled trial in Sicily
Authors: Riccardo Polosa, Pasquale Caponnetto, Massimo Caruso
Journal: European Respiratory Journal (2011)

Introduction: Most pharmacists are eager to undertake an important role in health promotion but in italy pharmacists are not trained for smoking cessation counselling.

Aim and objectives This study set in pharmacies in Sicily has evaluate the effect of training pharmacists in the stage-of-change model of smoking cessation and motivational interviewing.

Methods: A training package based on the stage of change model of smoking cessation and motivational interviewing was been carried out by University. The training was been piloted on a cross-section of pharmacy personnel. A total of 46 pharmacies have participated in the trial and attended a 3 hour training on 2008 guideline Treating Tobacco Use and Dependence . Successively pharmacies were randomly allocated by sequential allocation to the intervention or control group. The intervention group attended a 6 hour training by scheduling a initiation workshops. During the 3 month customer recruitment period, all smokers who sought advice on stopping smoking or those who bought an OTC anti-smoking product in preparation for a new attempt to stop smoking was been eligible for inclusion.

Results: A total one 587 smokers participated. At 12 week 64.4% were lost at follow-up in active group and 69.7% in reference group. At 24 week subjects who were lost at follow-up accounted for 72.5% in active group and 90% in reference group. At 12 week the quit rate were 25,7%, for intervention group and 14,4% for control group. At 24 week the quit rate were 11,2%, for intervention group and 6,3% for control group.

Conclusion: The study demonstrated the utility of the stage-of-change model and motivational interviewing in a pharmacy setting.
Abstract 11510: Atorvastatin Affects Expression of Sirt1 via Microrna-34a in Circulating Their Progenitor Cells Get Pirated From be with Coronary Artery Disease
Authors: Tsuyoshi Tabuchi, Mamoru Satoh, Yoshitaka Minami, Yuji Takahashi, Tomonori Itoh, Motoyuki Nakamura
Journal: Circulation (2011)

Background: Endothelial senescence is thought to play a role in coronary artery disease (CAD). MicroRNA-34a (miR-34a) has recently been found to target class III deacetylase, silent information reg...
Development of bacteraemia or fungaemia after removal of colonized central venous catheters in patients with negative concomitant blood cultures
Authors: K-H. Park, S-H. Kim, E.H. Song, E-Y. Jang, E.J. Lee, Y.P. Chong, S-H. Choi, S-O. Lee, J.H. Woo, Y.S. Kim
Journal: Clinical Microbiology and Infection (2009)
Evolutionary conservation and selection of human disease gene orthologs in the rat and mouse genomes
Authors: Hui Huang, Eitan E Winter, Huajun Wang, Keith G Weinstock, Heming Xing, Leo Goodstadt, Peter D Stenson, David N Cooper, Douglas Smith, M Mar Albà, Chris P Ponting, Kim Fechtel
Journal: Genome biology (2004)

Model organisms have contributed substantially to our understanding of the etiology of human disease as well as having assisted with the development of new treatment modalities. The availability of the human, mouse and, most recently, the rat genome sequences now permit the comprehensive investigation of the rodent orthologs of genes associated with human disease. Here, we investigate whether human disease genes differ significantly from their rodent orthologs with respect to their overall levels of conservation and their rates of evolutionary change.Human disease genes are unevenly distributed among human chromosomes and are highly represented (99.5%) among human-rodent ortholog sets. Differences are revealed in evolutionary conservation and selection between different categories of human disease genes. Although selection appears not to have greatly discriminated between disease and non-disease genes, synonymous substitution rates are significantly higher for disease genes. In neurological and malformation syndrome disease systems, associated genes have evolved slowly whereas genes of the immune, hematological and pulmonary disease systems have changed more rapidly. Amino-acid substitutions associated with human inherited disease occur at sites that are more highly conserved than the average; nevertheless, 15 substituting amino acids associated with human disease were identified as wild-type amino acids in the rat. Rodent orthologs of human trinucleotide repeat-expansion disease genes were found to contain substantially fewer of such repeats. Six human genes that share the same characteristics as triplet repeat-expansion disease-associated genes were identified; although four of these genes are expressed in the brain, none is currently known to be associated with disease.Most human disease genes have been retained in rodent genomes. Synonymous nucleotide substitutions occur at a higher rate in disease genes, a finding that may reflect increased mutation rates in the chromosomal regions in which disease genes are found. Rodent orthologs associated with neurological function exhibit the greatest evolutionary conservation; this suggests that rodent models of human neurological disease are likely to most faithfully represent human disease processes. However, with regard to neurological triplet repeat expansion-associated human disease genes, the contraction, relative to human, of rodent trinucleotide repeats suggests that rodent loci may not achieve a 'critical repeat threshold' necessary to undergo spontaneous pathological repeat expansions. The identification of six genes in this study that have multiple characteristics associated with repeat expansion-disease genes raises the possibility that not all human loci capable of facilitating neurological disease by repeat expansion have as yet been identified.
Abstract #5510: Molecular mechanism of tamoxifen therapy for cholangiocarcinoma
Authors: Pritish Pawar, Liping Ma, Chang Hyun Byon, Nirag Jhala, Juan Arnoletti, Jay McDonald, Yabing Chen
Journal: Cancer Research (2009)

AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

Cholangiocarcinoma is a highly lethal tumor with limited therapeutic options. We have reported that tamoxifen (TMX), as a calmodulin (CaM) antagonist, induces apoptosis in cholangiocarcinoma cells. Here, we have determined the effects of TMX on tumorigenesis and the molecular mechanisms of TMX-induced apoptosis. A nude mouse xenograft model was used to characterize cholangiocarcinoma tumorigenesis with SK-ChA-1 cells. Intra-peritoneal or intra-tumoral injection of TMX did not affect mouse survival, but decreased cholangiocarcinoma tumorigenesis by 39% and 82% compared to PBS-injected control groups (n=10 mice in each group). Phosphorylated AKT (pAKT) was demonstrated in all non-treated tumors, but was absent in all TMX-treated tumors. In cholangiocarcinoma xenograft cells, TMX consistently inhibited pAKT and the expression of FLICE-like inhibitory protein (FLIP). TMX activated caspase-8 and -10, and their respective inhibitors partially blocked TMX-induced apoptosis in cholangiocarcinoma cells. Lentiviruse-mediated overexpression of FLIP in cholangiocarcinoma cells inhibited TMX-induced apoptosis and enhanced tumorigenesis of cholangiocarcinoma cells in nude mice. The role of FLIP on cell survival and TMX-induced apoptosis was confirmed with two additional cholangiocarcinoma cell lines, MZ-ChA-1 and HuCCT-1. Deletion of the CaM binding domain on FLIP restored the sensitivity of cholangiocarcinoma cells to TMX and inhibited tumorigenesis, suggesting CaM/FLIP binding is critical for FLIP-mediated cell survival. In summary, TMX inhibits cholangiocarcinoma tumorigenesis in nude mice. TMX-induced apoptosis is partially dependent on caspases, and associated with inhibition of pAKT and expression of FLIP. CaM-FLIP binding appears to be important in FLIP mediated resistance to TMX. These studies support that TMX may be used as therapy for cholangiocarcinoma and possibly other malignancies, in which the CaM targets, AKT and FLIP play important roles in tumor pathogenesis.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5510.
Abstract 5539: Therapeutic efficacy of novel selenium-containing HDACi in acute leukemia
Authors: Mansi Sachdev, Dhimant Desai, Sunil Muthusami, Chandrika Gowda, Chunhua Song, Shantu G. Amin, Sinisa Dovat
Journal: Cancer Research (2014)

Abstract Despite tremendous advances in treatment of leukemia that have resulted in increased survival of patients with this disease, therapy for high-risk and relapsed leukemia remains a clinical challenge. This necessitates the development of novel, more potent therapeutic modalities. Epigenetic therapy with various types of inhibitors of histone deacetylases (HDACi), have demonstrated therapeutic efficacy in a range of malignancies, often with minimal side effects. Dr. Shantu Amin's group recently reported the development of a potent, novel, selenium-containing HDAC inhibitor (SelSA-1), which showed efficacy against Hodgkin's lymphoma and chronic myelogenous leukemia cells, as well as against lung cancer and melanoma cell lines. Here we expand efficacy studies of selenium-containing HDAC inhibitors to include a broad range of hematopoietic malignancies and begin to address the drug effects on cellular functions. We tested the therapeutic efficacy of two novel HDAC inhibitors - SelSa-1 and SelSa-2 on acute lymphoblastic leukemia, acute myelogenous leukemia and non-Hodgkin's B cell lymphoma. Cell proliferation assays demonstrated sharp dose-dependent cytotoxic effects in all the above cell lines at 96-hours post-treatment. Quantitative analysis showed that SelSa-1 and SelSa-2 have distinct effects in different types of hematopoietic malignancies. In T-cell acute lymphoblastic leukemia (T-ALL) and in non-Hodgkin's lymphoma, both SelSa-1 and Selsa-2 have similar therapeutic activity with IC50 = 1uM and 1-2uM, respectively. In B-cell acute lymphoblastic leukemia, SelSa-1 has superior therapeutic activity compared to SelSa-2 with IC50 = 0.2 uM vs. 1.25, respectively. In acute promyelocytic leukemia (APML) without the t:15:17 translocation, SelSa-1 was superior to SelSa-2 (IC50= 0.25uM and 1uM respectively), while APML with the t:15:17 translocation showed similar sensitivity to both compounds with an IC50 of 1-2uM. Cell cycle analysis performed by flow cytometry revealed that these agents induce G1-cell cycle arrest in leukemia cells. Preliminary data suggest that both SelSa-1 and SelSa-2 have a synergistic effect with standard chemotherapeutic agents that induce DNA-damage. In summary, these results demonstrate the effectiveness of two selenium-containing analogs of SAHA, SelSA-1 and 2, on leukemia cells from multiple hematopoietic lineages. Additional studies to identify detailed mechanisms of the effects of these drugs on cellular function are underway. Citation Format: Mansi Sachdev, Dhimant Desai, Sunil Muthusami, Chandrika Gowda, Chunhua Song, Shantu G. Amin, Sinisa Dovat. Therapeutic efficacy of novel selenium-containing HDACi in acute leukemia. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5539. doi:10.1158/1538-7445.AM2014-5539
Epigenetic therapy restores normal hematopoiesis in a zebrafish model of NUP98–HOXA9-induced myeloid disease
Authors: A P Deveau, A M Forrester, A J Coombs, G S Wagner, C Grabher, I C Chute, D Léger, M Mingay, G Alexe, V Rajan, R Liwski, M Hirst, K Stegmaier, S M Lewis, A T Look, J N Berman
Journal: Leukemia (2015)