tbuckley/cabot-search huggingface dataset:
Abstract 2728: In silico identification of a MAD2-interacting motif in MAD2 spliced isoforms suggest a functional interaction with the spindle assemble checkpoint in cancer
Authors: Miguel Ramirez-Otero, Alejandro Lopez-Saavedra, Marco Andonegui, Jose Diaz-Chavez, Luis Alonso Herrera
Journal: Cancer Research (2016)

Abstract Abnormal chromosome segregation plays a key role in cancer development. MAD2 is a component of the spindle assembly checkpoint (SAC), a cell cycle control mechanism that ensures an accurate segregation of chromosomes during mitosis. Changes in MAD2 expression have been associated with chemo-resistance both to spindle inhibitors and to DNA damaging agents. Also, a previous study has shown that the exogenous expression of MAD2β, a splicing variant of MAD2, was associated with resistance to Adriamycin and Vincristine in gastric cell lines. Additionally, we have previously identified that exogenous overexpression of MAD2γ upon paclitaxel-induced SAC activation in the colorectal cancer cell HCT116, reduces drug-induced mitotic arrest. These findings suggested a possible structural interaction of MAD2 isoforms with SAC components. To determine possible structural interactions between MAD2 isoforms and key SAC components (i.e. MAD1 and CDC20), we performed an in silico analysis of MAD2 isoforms, Interestingly, we found that alternative splicing of MAD2 generates a premature stop codon and a frameshift in exon 4 in MAD2γ and MAD2β. This change generates a new C-terminal region in MAD2γ and MAD2β isoforms that comprise 16 amino acids, which are not present in the major isoform (MAD2α). We aligned this region with the amino acid sequence of CDC20 from various species and identified a MAD2-interacting motif (MIM). This finding suggests that MAD2 isoforms may interact with the active conformation of MAD2 (C-MAD2). Since MAD2 isoforms and CDC20 may compete for the same region in MAD2, we propose a new model whereby MAD2 isoforms inhibits SAC by interfering with C-MAD2/CDC20 formation. This model helps to explain previous results where MAD2 isoforms over expression seem to have an opposite role in SAC signaling. Citation Format: Miguel Ramirez-Otero, Alejandro Lopez-Saavedra, Marco Andonegui, Jose Diaz-Chavez, Luis Alonso Herrera. In silico identification of a MAD2-interacting motif in MAD2 spliced isoforms suggest a functional interaction with the spindle assemble checkpoint in cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2728.
PWE-061 Progastrin stimulates colonic myofibroblast proliferation in vitro and its transgenic overexpression results in increased numbers of myofibroblasts in the colonic mucosa in vivo
Authors: D Clyde, T C Wang, A Varro, D M Pritchard
Journal: Gut (2010)

<h3>Introduction</h3> Transgenic hGAS mice, which have high circulating progastrin concentrations show increased colonic epithelial proliferation and increased susceptibility to colorectal carcinogenesis. As signalling between colonic epithelial cells and their underlying myofibroblasts is known to regulate homeostasis and the colonic stem cell niche, we hypothesise that progastrin may regulate colonic carcinogenesis by exerting effects upon both myofibroblasts and epithelial cells. We have therefore assessed the numbers of pericryptal myofibroblasts in the colonic mucosa of hGAS mice and have investigated the effects of treating a human colonic myofibroblast cell line with exogenous recombinant progastrin. <h3>Methods</h3> hGAS mice were backcrossed onto a C57BL/6 genetic background and epithelial mitotic index and crypt length were assessed in the distal colon on a cell positional basis using H&amp;E sections. The numbers of total and proliferating myofibroblasts were assessed by dual immunohistochemistry with anti-α-smooth muscle actin or vimentin antibodies (to stain myofibroblasts); and anti-Ki67 antibody (to stain proliferating cells). CCD18co human colonic myofibroblasts were treated with 0-10 nM progastrin, gastrin-17 (G-17) or glycine-extended gastrin (G-Gly) for 18 h and proliferation was assessed using a luminescence-based assay. Signalling pathways were investigated by pre-treating cells with inhibitors for the CCK-2 receptor (YM022), Protein kinase C (RO-32-0432), MAP kinase (PD98059) or PI3 kinase (LY294002). <h3>Results</h3> Consistent with previous observations in hGAS mice on the FVB/N genetic background the percentage of colonic epithelial mitotic cells was increased by 90% in hGAS mice (p&lt;0.001), which also showed a 22% increase in colonic crypt length (p&lt;0.01). The percentage of colonic mucosal cells which were myofibroblasts was increased in hGAS mice by α-smooth muscle actin and vimentin staining (26% and 25%, respectively, p&lt;0.001); but no Ki67 staining was observed in myofibroblasts. 0.1 nM PG maximally increased proliferation of CCD18co cells by 86% (p&lt;0.001) and this was inhibited by RO-032-0432 (p&lt;0.001). G-17 and G-Gly did not affect CCD18co cell proliferation. <h3>Conclusion</h3> Progastrin overexpressing hGAS mice show increased numbers of colonic pericryptal myofibroblasts as well as increased colonic epithelial proliferation. Progastrin also stimulates the proliferation of colonic myofibroblasts in vitro via Protein kinase C pathway signalling. Progastrin therefore appears to increase colonic susceptibility to carcinogenesis by affecting both stromal and epithelial compartments.
Pegylated-asparaginase during induction therapy for adult acute lymphoblastic leukaemia: toxicity data from the UKALL14 trial
Authors: B Patel, A A Kirkwood, A Dey, D I Marks, A K McMillan, T F Menne, L Micklewright, P Patrick, S Purnell, C J Rowntree, P Smith, A K Fielding
Journal: Leukemia (2016)
Antibiotic perturbation of the preterm infant gut microbiome and resistome
Authors: Andrew J. Gasparrini, Terence S. Crofts, Molly K. Gibson, Phillip I. Tarr, Barbara B. Warner, Gautam Dantas
Journal: Gut Microbes (2016)

The gut microbiota plays important roles in nutrient absorption, immune system development, and pathogen colonization resistance. Perturbations early in life may be detrimental to host health in the short and the long-term. Antibiotics are among the many factors that influence the development of the microbiota. Because antibiotics are heavily administered during the first critical years of gut microbiota development, it is important to understand the effects of these interventions. Infants, particularly those born prematurely, represent an interesting population because they receive early and often extensive antibiotic therapy in the first months after birth. Gibson et al. recently demonstrated that antibiotic therapy in preterm infants can dramatically affect the gut microbiome. While meropenem, ticarcillin-clavulanate, and cefotaxime treatments were associated with decreased species richness, gentamicin and vancomycin had variable effects on species richness. Interestingly, the direction of species richness response could be predicted based on the abundance of 2 species and 2 genes in the microbiome prior to gentamicin or vancomycin treatment. Nonetheless, all antibiotic treatments enriched the presence of resistance genes and multidrug resistant organisms. Treatment with different antibiotics further resulted in unique population shifts of abundant organisms and selection for different sets of resistance genes. In this addendum, we provide an extended discussion of these recent findings, and outline important future directions for elucidating the interplay between antibiotics and preterm infant gut microbiota development.
Abstract CT029: The effect of tazemetostat on CYP3A-mediated metabolism of midazolam in patients with solid tumors
Authors: Sherri Smith, Benjamin Suttle, Nigel L. Waters, Vincent Ribrag, Antoine Italiano, Jean-Marie Michot, Sophie Postel-Vinay, Maud Toulmonde, Sophie Cousin, Maria Roche, Patricia Pimentel, Peter Ho
Journal: Cancer Research (2016)

Abstract Background: Tazemetostat is a selective oral small molecule inhibitor of enhancer of zeste homolog 2 (EZH2). Results from in vitro studies using human liver microsomes, recombinant CYP isoforms, and hepatocytes demonstrated that tazemetostat is an inhibitor, inducer, and substrate of CYP3A4. Previous results indicated that systemic exposure to tazemetostat decreased after multiple dose administration in patients with cancer, consistent with net induction of CYP3A-mediated metabolism. Therefore, a drug-drug interaction sub-study was performed as part of the ongoing study E7438-G000-101 (NCT01897571). Purpose: To investigate the effect of tazemetostat on CYP3A-mediated metabolism in patients with solid tumors using midazolam as a sensitive CYP3A probe substrate. Methods: This was a single-sequence, open-label, crossover study. Patients with solid tumors (n = 13) received a single oral dose of 2 mg midazolam on Day -1 and on Day 15. Tazemetostat 800 mg twice daily (BID) was administered continuously starting on Day 1. Serial blood samples for the analysis of plasma midazolam and metabolites were collected over 24 h on Day -1 (midazolam alone) and Day 15 (midazolam plus tazemetostat). Results: A summary of midazolam pharmacokinetic parameters after administration alone and with tazemetostat 800 mg BID in 12 evaluable patients is presented below: ParameterDay -1aDay 15aGLSMRb (90% CI)AUC(0-∞) ng*h/mL51.9 (87.2)31.1 (48.1)0.60 (0.46, 0.78)Cmax ng/mL16.5 (94.3)13.0 (48.3)0.78 (0.57, 1.08)t1/2 h5.67 (34.3)4.25 (32.4)NCaData presented as geometric mean (%CV)bGLSMR = geometric least squares mean ratioNC = not calculated Plasma midazolam AUC(0-?) and Cmax decreased approximately 40% and 22%, respectively, after administration with tazemetostat 800 mg BID relative to administration of midazolam alone. Geometric mean t1/2 for midazolam decreased approximately 25%, after administration of midazolam with tazemetostat 800 mg BID relative to administration of midazolam alone. Conclusions: Administration of tazemetostat 800 mg BID resulted in net induction of CYP3A-mediated metabolism in patients with cancer. Tazemetostat 800 mg BID resulted in a less than 50% decrease in midazolam AUC and therefore is a weak inducer of CYP3A-mediated metabolism. Citation Format: Sherri Smith, Benjamin Suttle, Nigel L. Waters, Vincent Ribrag, Antoine Italiano, Jean-Marie Michot, Sophie Postel-Vinay, Maud Toulmonde, Sophie Cousin, Maria Roche, Patricia Pimentel, Peter Ho. The effect of tazemetostat on CYP3A-mediated metabolism of midazolam in patients with solid tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT029.
Donabedian’s Lasting Framework for Health Care Quality
Authors: John Z. Ayanian, Howard Markel
Journal: New England Journal of Medicine (2016)

In a landmark article published 50 years ago, Avedis Donabedian proposed using the triad of structure, process, and outcome to evaluate the quality of health care. That triad, along with his eventual seven pillars of quality, continues to inform efforts to improve care.
Interest of Diffusion Weighted Magnetic Resonance Imaging for the Evaluation of Bone Marrow Infiltration in Multiple Myeloma, Smoldering Myeloma and Monoclonal Gammopathy of Undetermined Significance.
Authors: Olivier Decaux, Thierry Josseaume, Eric Brillet, Thierry Lamy, Marc Bernard, Martine Escoffre, Martine Sebillot, Bernard Grosbois, Regis Duvauferrier
Journal: Blood (2009)
Prevention of Firearm Suicide in the United States: What Works and What Is Possible
Authors: J. John Mann, Christina A. Michel
Journal: American Journal of Psychiatry (2016)

Objective: About 21,000 suicides in the United States in 2014 involved a firearm. The authors reviewed evidence from around the world regarding the relationship between firearm ownership rates and firearm suicide rates and the potential effectiveness of policy-based strategies for preventing firearm suicides in the United States. Method: Relevant publications were identified by searches of PubMed, PsycINFO, MEDLINE, and Google Scholar from 1980 to September 2015, using the search terms suicide AND firearms OR guns. Excluding duplicates, 1,687 results were found, 60 of which were selected for inclusion; these sources yielded an additional 10 studies, for a total of 70 studies. Results: Case-control and ecological studies investigating geographic and temporal variations in firearm ownership and firearm suicide rates indicate that greater firearm availability is associated with higher firearm suicide rates. Time-series analyses, mostly from other countries, show that legislation reducing firearm ownership lowers firearm suicide rates. Because the Second Amendment curtails legislation broadly restricting firearm access in the United States, the emphasis is shifted to restricting access for those at risk of harming themselves or others. Most suicides involve guns purchased years earlier. Targeted initiatives like gun violence restraining orders, smart gun technology, and gun safety education campaigns potentially reduce access to already purchased firearms by suicidal individuals. Such measures are too new to have evidence of effectiveness. Conclusions: Broadly reducing availability and access to firearms has lowered firearm suicide rates in other countries but does not appear feasible in the United States. Approaches restricting access of at-risk individuals to already purchased firearms by engaging the public and major stakeholders require urgent implementation and outcome evaluation for firearm suicide prevention.
Efficacy and Safety of Palonosetron in Preventing Chemotherapy-Induced Nausea and Vomiting in Patients with Non-Hodgkin's Lymphomas Undergoing Repeated Cycles of Moderately Emetogenic Chemotherapy
Authors: Brian Choi, Gabriela Borsaru, Daniel Voisin, Gianluca Ballinari, Nicola Di Renzo
Journal: Blood (2011)
Abstract 5103: Crosstalk between osteoprotegerin (OPG), fatty acid synthase (FASN), and cyclooxygenase-2 (COX-2) in breast cancer: implications in carcinogenesis
Authors: Sudeshna Goswami, Neelam Sharma-Walia
Journal: Cancer Research (2016)

Abstract The cross-talk between malignant and nonmalignant cells in the tumor microenvironment, as maneuvered by cytokines/chemokines, drives breast cancer progression. We demonstrated that OPG is expressed and secreted at very high levels from the highly invasive breast cancer cell lines SUM149PT and SUM1315MO2 as compared to human normal mammary epithelial HMEC cells (1). OPG was involved in modulating aneuploidy, cell proliferation, and angiogenesis in breast cancer (1). Mass spectrometry analysis performed in this study revealed OPG interacts with fatty acid synthase (FASN), which is a key enzyme of the fatty acid biosynthetic pathway in breast cancer cells. Further, electron microscopy, immunofluorescence, and fluorescence quantitation assay highlighted the presence of a large number of lipid bodies (lipid droplets) in SUM149PT and SUM1315MO2 cells in comparison to HMEC. We recently showed upregulation of COX-2 inflammatory pathway and its metabolite PGE2 secretion in SUM149PT and SUM1315MO2 breast cancer cells (2). Interestingly, human breast cancer tissue samples displayed high expression of OPG, PGE2 and FASN. Immunofluorescence staining exposed the co-existence of COX-2 and FASN in the lipid bodies of breast cancer cells. We reasoned that there might be cross-talk between OPG, FASN, and COX-2 that sustains the inflammatory pathways in breast cancer. Here, we identified cis-acting elements involved in the transcriptional regulation of COX-2 and FASN by recombinant human OPG (rhOPG). Treatment with FASN inhibitor C75 decreased the number of lipid body/cell, downregulated phosphorylation of ERK, GSK3β, and induced apoptosis by caspase-3 and caspapse-9 activation. Collectively, the novel biological cross-talk between OPG, FASN, and COX-2 advocates for combinatorial drug treatment to block these players of carcinogenesis as a promising therapeutic to target highly invasive breast cancer. References: 1. Goswami, S., &amp; Sharma-Walia, N. (2015). Osteoprotegerin secreted by inflammatory and invasive breast cancer cells induces aneuploidy, cell proliferation and angiogenesis. BMC. http://www.biomedcentral.com/1471-2407/15/935 2. Chandran, K., Goswami, S., &amp; Sharma-Walia, N. (2015). Implications of a peroxisome proliferator-activated receptor alpha (PPARα) ligand clofibrate in breast cancer. Oncotarget, 5. http://www.impactjournals.com/oncotarget/index.php?journal = oncotarget&amp;page = article&amp;op = view&amp;path%5B%5D = 6402 Citation Format: Sudeshna Goswami, Neelam Sharma-Walia. Crosstalk between osteoprotegerin (OPG), fatty acid synthase (FASN), and cyclooxygenase-2 (COX-2) in breast cancer: implications in carcinogenesis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5103.
Hierarchy for targeting prosurvival BCL2 family proteins in multiple myeloma: pivotal role of MCL1
Authors: Jia-Nan Gong, Tiffany Khong, David Segal, Yuan Yao, Chris D. Riffkin, Jean-Marc Garnier, Seong Lin Khaw, Guillaume Lessene, Andrew Spencer, Marco J. Herold, Andrew W. Roberts, David C. S. Huang
Journal: Blood (2016)
Abstract 4456: Preliminary investigation of the promoter methylation status of BRCA1, BRCA2, TP53 genes of some breast cancer patients
Authors: Titilola A. Samuel, babatunde ayo james, Muhammad HABEEB, temitope oshodi, olubunmi magbagbeola.
Journal: Cancer Research (2016)

Abstract Epigenetic alterations in BRCA1, BRCA2 and TP53, such as DNA methylation, may be an effective approach in diagnosis, prognosis and therapy in breast cancer. This study examines the DNA methylation signature of BRCA1, BRCA2 and TP53 in some breast cancer patients attending a Clinic in Lagos, Nigeria. In this study, 14 blood specimens with Invasive Ductal Carcinoma (IDC) were investigated. The samples were modified by Bisulfite modification, and then assessed by Methylation-Specific PCR (MSP). The methylation analysis indicates that 7(50%) of the 14 patients had a segment of the promoter region of BRCA1 gene methylated, 8 (57.14%) of BRCA2 methylated and 11(78.57%) of TP53 promoter region. This study provides preliminary evidence for the gene expression inactivation of BRCA 1, BRCA 2, and TP53 Genes in over 50% of the 14 patients with Stage 2 invasive ductal carcinoma who participated in this study. Citation Format: Titilola A. Samuel, babatunde ayo james, Muhammad HABEEB, temitope oshodi, olubunmi magbagbeola. Preliminary investigation of the promoter methylation status of BRCA1, BRCA2, TP53 genes of some breast cancer patients. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4456.
Abstract 830: Pin1 is a novel target of withaferin A, a mammary cancer chemopreventative steroidal lactone from <i>Withania somnifera</i>
Authors: Suman K. Samanta, Shivendra V. Singh
Journal: Cancer Research (2016)

Abstract We have shown previously that naturally occurring steroidal lactone withaferin A (WA) inhibits breast cancer development in a transgenic mouse model. Mammary cancer chemoprevention by WA in vivo was associated with suppression of peptidyl-prolyl isomerase Pin1 protein. Pin1 is known to regulate diverse cellular processes including cell proliferation, cell cycle progression, apoptosis, and migration. Moreover, Pin1 is overexpressed in breast tumor and its expression is positively correlated with tumor grade. Thus, we studied functional significance of Pin1 downregulation by WA. Consistent with in vivo observations, Pin1 protein and mRNA expression was decreased upon WA treatment in human breast cancer cells irrespective of ER, HER-2 or p53 status. Overexpression of Pin1 partly reversed the growth inhibitory effect of WA in both MCF-7 (wild-type p53) and SUM159 (mutant p53) cells. However, WA-induced mitotic arrest and apoptosis were partly abrogated only in MCF-7 cells upon ectopic expression of Pin1 perhaps due to p53 stabilization. Molecular docking suggested covalent binding of WA with Cys113 of Pin1, which was confirmed by mass spectrometry. Overexpression of mutant (C113A) Pin1 augmented WA-mediated inhibition of cell survival as well as mitotic arrest and apoptosis in MCF-7 cells indicating that decreased catalytic activity of Pin1 is essential for growth inhibition by WA in breast cancer cells. Taken together, the present study suggests a critical role for Pin1 in WA-mediated growth inhibition of breast cancer. This study was supported by the grant CA142604 awarded by the National Cancer Institute. Citation Format: Suman K. Samanta, Shivendra V. Singh. Pin1 is a novel target of withaferin A, a mammary cancer chemopreventative steroidal lactone from Withania somnifera. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 830.
Abstract 4221: Imaging formation of the tumor microenvironment in orthotopic liver tumors in red fluorescent protein (RFP) transgenic nude mice
Authors: Atsushi Suetsugu, Yukihiko Hiroshima, Takuro Matsumoto, Kosuke Hasegawa, Miki Nakamura, Masahito Shimizu, Shigetoyo Saji, Hisataka Moriwaki, Michael Bouvet, Robert M. Hoffman
Journal: Cancer Research (2016)

Abstract We report here dual-color imaging of the formation of the TME in orthotopic liver cancer in transgenic red fluorescent protein (RFP) nude mice, which express RFP in all organs. Non-colored HUH-7 human hepatoma cells were injected in the spleen of RFP nude mice to establish an orthotopic liver cancer model. TME formation in the liver tumor was observed using the Olympus OV100 small animal fluorescence imaging system. Non-colored liver cancer cells formed colonies in the liver 28 days after cell transplantation to the spleen. In the liver, RFP host-mouse cells accumulated around and in the liver tumor as visualized by fluorescence imaging. A desmin and sirus-red positive area increased around and within the liver tumor over time. These results indicate cancer-associated fibroblasts (CAFs) were recruited by the liver metastasis suggesting that CAFs, along with the angiogenic tumor blood vessels, could serve as visible therapeutic targets. Citation Format: Atsushi Suetsugu, Yukihiko Hiroshima, Takuro Matsumoto, Kosuke Hasegawa, Miki Nakamura, Masahito Shimizu, Shigetoyo Saji, Hisataka Moriwaki, Michael Bouvet, Robert M. Hoffman. Imaging formation of the tumor microenvironment in orthotopic liver tumors in red fluorescent protein (RFP) transgenic nude mice. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4221.
포스터 발표 : 만성 B형 간염 환자의 자발성 급성악화에서 라미부딘 치료의 유용성: 전향적 대조연구
Authors: 송혜경, 이한주, 장명국, 김인숙, 임영석, 정영화, 이영상, 서동진
Journal: Clinical and Molecular Hepatology (2003)