tbuckley/cabot-search huggingface dataset:
Abstract 4639: Metformin decreases cellular ceramides in MCF-7 and MDA-MB 231 breast cancer cell lines by inhibition of ceramide synthetic enzymes
Authors: Daniel Wann, Victoria Palau, Janet Lightner, Marianne Brannon, William Stone, Koyamangalath Krishnan
Journal: Cancer Research (2015)

Abstract Metformin, an anti-diabetic biguanide, has been shown to have cytotoxic and chemopreventive properties in in vitro and epidemiological studies, respectively. Metformin's predominant cytotoxic functions may be through activation of 5′ adenosine monophosphate-activated protein kinase (AMPK) with subsequent cell apoptosis. Ceramides, a group of waxy lipids found in the cellular membrane, are key players in many elements of cell signaling, including the regulation of cell differentiation, proliferation, and apoptosis. While traditionally thought of as being pro-apoptotic, this notion has been questioned with the discovery of pro-survival ceramides, as well as the demonstration that certain species of ceramides are increased in breast cancer cells. Metformin reduces ceramides in insulin-resistant mouse myoblasts and may reduce the vascular complications of diabetes mellitus. MCF-7 and MDA-MB-231 breast cancer cell lines were treated with increasing concentrations of metformin and cytotoxicity was determined by MTT cell culture experiments after 72 hours of drug exposure. Metformin induces cytotoxicity in these breast cancer cells at a lowest concentration of 1.25 mM, and percentage cytotoxicity increases in a dose-dependent manner. We then determined the effect of metformin on cell ceramide synthesis by analyzing key ceramide synthetic enzymes. Using western immunoblot and polymerase chain reaction (PCR) analysis, we determined that metformin induces a reduction in serine palmitoyl transferase, ceramide synthase, dihydroceramide desaturase, and neutral sphingomyelinase in MCF-7 and MDA-MB-231 breast cancer cells. We also analyzed the distribution of ceramides in treated breast cancer cells using polyclonal antibodies against ceramides. By confocal microscopy, ceramides are globally decreased in MCF-7 and MDA-MB-231 cells treated with metformin. This data suggests that the pro-apoptotic effect of metformin may be partly mediated through its disruption of the balance of ceramides and/or through the reduction of pro-survival ceramides within breast cancer cells. It is also possible that the predominant ceramides in MCF-7 and MDA-MB-231 breast cancer cells are pro-survival and metformin suppresses these ceramides. Further work is necessary to characterize the ceramide content of MCF-7 and MDA-MB-231 cancer cells before and after metformin treatment. Citation Format: Daniel Wann, Victoria Palau, Janet Lightner, Marianne Brannon, William Stone, Koyamangalath Krishnan. Metformin decreases cellular ceramides in MCF-7 and MDA-MB 231 breast cancer cell lines by inhibition of ceramide synthetic enzymes. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4639. doi:10.1158/1538-7445.AM2015-4639
Intrahepatic innate immune response pathways are downregulated in untreated chronic hepatitis B
Authors: Fanny Lebossé, Barbara Testoni, Judith Fresquet, Floriana Facchetti, Enrico Galmozzi, Maëlenn Fournier, Valérie Hervieu, Pascale Berthillon, Françoise Berby, Isabelle Bordes, David Durantel, Massimo Levrero, Pietro Lampertico, Fabien Zoulim
Journal: Journal of Hepatology (2016)
355. Effect of Fibrotic Tissue on Liver-Targeted Hydrodynamic Gene Delivery
Authors: Yuji Kobayashi, Kenya Kamimura, Hiroyuki Abe, Masato Ohtsuka, Hiromi Miura, Takeshi Yokoo, Tsutomu Kanefuji, Takeshi Suda, Guisheng Zhang, Masanori Tsuchida, Yutaka Aoyagi, Dexi Liu, Shuji Terai
Journal: Molecular Therapy (2015)

Hydrodynamic gene delivery has emerged as an effective method for gene transfer in vivo especially to the liver, and the liver-targeted hydrodynamic procedure has been evaluated in various animal models including rats, pigs, and dogs. In an effort to use hydrodynamic gene delivery for treatment of liver diseases that are commonly fibrotic, we have systematically examined the effect of liver fibrosis on efficiency of hydrodynamic gene delivery. Rat liver fibrosis model was developed by the bile duct ligation (BDL) procedure and hyaluronic acid (HA), a serum marker for liver fibrosis, was used to determine the degree of liver fibrosis. Gene delivery efficiency was assessed using luciferase reporter gene plasmid (pCMV-Luc) in normal rats (n=20) and BDL performed rats (liver fibrosis group, n=20) 10 weeks after the BDL, when liver fibrosis group showed significantly higher serum HA concentration of 231±167 ng/ml than that of 28±17 ng/ml in normal rats (p<0.05). The level of luciferase expression showed 2.5×106 RLU/mg of protein in liver fibrosis group which was 100-1,000 folds lower than normal rats. This decrease of gene delivery efficiency suggests that liver fibrosis significantly decreases gene delivery efficiency of hydrodynamic gene delivery. The evidence is supported by the recovery of gene delivery efficiency in liver fibrosis group treated by the liver-targeted hydrodynamic delivery of matrix metalloproteinase-13 gene, which achieved 2.2×108 RLU/mg of protein (p<0.05 to liver fibrosis group, N.S. to normal rats). The histological analysis using silver staining also showed significantly higher volume of fibrotic tissue in liver fibrosis group than in normal rats and treated group (p<0.05). These results suggest that the fibrotic tissue significantly decrease the gene delivery efficiency of the liver-targeted HGD procedure and the reduction of fibrotic tissue can recover it.
5. Newly Developed Measles Virus Vector Can Simultaneously Transfer Multiple Genes Into Human Hematopoietic Cells and Induce Ground State Like Pluripotent Stem Cells
Authors: Takafumi Hiramoto, Maino Tahara, Chika Sakamoto, Yuichiro Nakatsu, Toru Kubota, Hiroaki Ono, Hiroshi Kohara, Makoto Takeda, Kenzaburo Tani
Journal: Molecular Therapy (2015)

We reports newly developed virus vector, measles virus vector can transfer multiple genes into human hematopoietic cells effectively and induce ground state pluripotent stem cells from somatic cells without affecting the host genome. Measles virus (MV) which belongs to negative single strand RNA viruses has been known to have high affinity for human peripheral immune cells including monocytes, B cells and T cells. We recently have developed novel MV gene transfer vector which is non-transmissible, can transfer multiple genes simultaneously. The MV vector which carries 5 genes (GFP, human OCT3/4, SOX2, KLF4, and L-MYC) (MV-dF-OSKL-EGFP) could express these genes in various human cells with differential expression levels depending on the arrangement of the gene in the vector. Especially, MV-dF-OSKL-EGFP was able to transduce genes into more than 80% of hematopoietic cells besides natural killer cells. Naive and stem cell memory T cells were also transduced by MV-dF-OSKL-EGFP. These results indicated that the newly developed MV vector had the significant character as the new gene transfer vector compared with conventional viral gene transfer vectors including Sendai virus vector, which belongs to the same RNA virus vector. We could successfully generated induced pluripotent stem cells (iPS cells) from human fibroblasts or peripheral blood T cells using MV-dF-OSKL-EGFP. These iPS cells expressed the pluripotent markers of NANOG and Tra-1-60 and were demethylated. These iPS cells also differentiated into three germ line tissues in vitro and in vivo. Importantly, we also could establish the ground state like pluripotent cell (GSL-iPS cells) from hematopoietic cells by using MV-dF-OSKL-EGFP. In the presence of human leukemia inhibitory factor (LIF), GSK-3 inhibitor (CHIR99021), and MEK inhibitor (PD0325901), GSL-iPS cells were able to be cultured from a dissociated single cell with rapid cell growth. GSL-iPS cells also expressed pluripotent markers of NANOG and Tra-1-60, and were able to differentiate into three germ line cells. In conclusion, our newly developed MV vector may induce revolutional advance in the field of gene and cell therapy using iPS cells.
309. Optimization of Dual AAV Vectors for Gene Therapy of Inherited Retinal Diseases
Authors: Ivana Trapani, Sonia de Simone, Carolina Iodice, Pasqualina Colella, Settimio Rossi, Alberto Auricchio
Journal: Molecular Therapy (2015)

Retinal gene therapy with adeno-associated viral (AAV) vectors is safe and effective in humans. However, AAV limited cargo capacity prevents its application to therapies of inherited retinal diseases (IRD) due to mutations in genes over 5 kb. Dual AAV vectors, each containing one of the two halves of a large gene expression cassette, are emerging as promising tools to overcome this limitation. Dual AAV trans-splicing and hybrid vectors transduce efficiently the mouse and pig retina and are effective in animal models of IRD. However, some of dual AAV limitations include lower levels of transgene expression compared to a single AAV vector and the production of proteins shorter than expected from either the 5'- or 3'-half AAV. Thus, further development of dual AAV vectors is required before their clinical translation. To increase dual AAV recombination we have exploited various regions of homology while to mediate the degradation of the proteins shorter than expected we have tested the ability of various degradation signals. We found that the levels of transgene expression achieved with the alternative regions of homology are similar to those achieved with dual AAV vectors carrying the AK region of homology we have previously shown to be effective. Notably, we have identified a degradation signal which mediates the degradation of proteins shorter than expected from dual AAV vectors. In conclusion, our study outlines optimized features of dual AAV vectors that improve their safety and efficacy. This represents a step towards the clinical translation of dual AAV for retinal gene therapy.
Serum Dependency of t(8;21) AML Cell Line Is Associated with VEGF/VEGFR Pathway and Early Phosphorylation of Akt.
Authors: Norikazu Imai, Masato Shikami, Hiroshi Miwa, Akiko Hattori, Akihito Hiramatsu, Masaya Watarai, Atsushi Satoh, Masato Itoh, Akira Imamura, Hidetsugu Mihara, Masakazu Nitta
Journal: Blood (2005)
Association of matrix metalloproteinase-1 (MMP-1) and matrix metalloproteinase-2 (MMP-2) expression with KRAS/BRAF mutational status and survival outcomes in metastatic colorectal cancer (CRC) patients.
Authors: J. Ho, R. Woods, I. Tai, H. F. Kennecke, H. J. Lim
Journal: Journal of Clinical Oncology (2011)

e14088 Background: MMP-1 and MMP-2 proteins are felt to be involved in tumor growth, invasion and metastasis and may be regulated by the KRAS pathway. Methods: A tissue microarray was constructed from archival formalin-fixed paraffin-embedded primary tumor tissue samples of 96 patients who had undergone treatment for metastatic CRC. MMP-1 and MMP-2 expression was measured semiquantitatively by immunohistochemistry and graded 0 to 2. Mutation analysis was done for KRAS in codons 12 and 13, and patients without KRAS mutations were tested for BRAF V600E mutation. Chi-squared test, Fisher’s exact test and Cox-proportionate hazard ratios were used for statistical analysis. Results: 96 patients had samples available for analysis (median age at diagnosis 60, 57% male, 46% stage IV at diagnosis, 33/93 (35%) KRAS mutated, and 7/51 (14%) BRAF mutated. At the time of the analysis, all but 2 patients received first line therapy for metastatic disease. First line therapy was 5-Fluorouracil monotherapy among 7 pts (8%), irinotecan based in 50 pts (52%), and oxaliplatin based therapy in 35 pts (37%). 21 pts (22%) received anti-EGFR therapy. No significant association was identified between MMP-1 and KRAS (p=0.88) or BRAF (p=0.54), or between MMP-2 and KRAS (p=0.08) or BRAF (p=0.41). Neither overall survival nor survival from diagnosis of metastatic disease were affected by MMP-1 or MMP-2 expression. Conclusions: MMP-1 and MMP-2 expression is not associated with KRAS or BRAF mutational status and is not a prognostic factor in this cohort of CRC patients.
Abstract 183: Oncogenic miRNA miR-130a-induced inhibition of the growth regulator protein ZAR2 in TNBC cells
Authors: Smita Misra, Ashutosh Snghal, Gautam Chaudhuri
Journal: Cancer Research (2015)

Abstract ZAR2 is C4-type zinc-finger protein that we found to suppress the growth of breast tumor cells. In the dividing breast cancer cells ZAR2 is primarily located in the cytosol. It probably inhibits the growth of the tumor cells through sequence-specific capture and degradation of certain mRNAs which are critical for the growth of the cells. We found that the level of ZAR2 protein is significantly lower in the highly aggressive breast cancer cells of the triple negative subtype (TNBC). Forced expression of ZAR2 in the TNBC cells prevented the proliferation and invasiveness of these cells. Major objective of the research presented here is to understand the mechanism of suppression of ZAR2 level in the TNBC cells. As ZAR2 mRNA levels are very similar in the TNBC and non-TNBC cells, we postulated that ZAR2 protein levels are down-regulated in the TNBC cells due to the induction of a ZAR2-targeting miRNA in these cells. We used computational prediction to identify potential microRNAs down-regulating ZAR2 in the TNBC cells. One of the major miRNAs that is predicted by DIANA-Tools (http://diana.imis.athena-innovation.gr/DianaTools/index.php?r = MicroT_CDS/index) to target ZAR2 mRNA is hsa-miR-130a-5p. We found that the level of miR-130a-5p in the TNBC cells is inversely related to the level of ZAR2 protein in the TNBC cells. We validated the binding of miR130a-5p miRISC to several specific locations at the 3′-UTR of ZAR2 mRNA and the inhibition of translation of ZAR2 mRNA by this miRNA. We propose that targeted knockdown of miR130a-5p in the TNBC cells will elevate the level of ZAR2 protein resulting in the inhibition of the growth of these cells. This research is supported in part by NIH/NCIgrant1R21CA181920-01 to GC and NIH grant 1U54RR026140 to SM. Citation Format: Smita Misra, Ashutosh Snghal, Gautam Chaudhuri. Oncogenic miRNA miR-130a-induced inhibition of the growth regulator protein ZAR2 in TNBC cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 183. doi:10.1158/1538-7445.AM2015-183
Personally Tailored Risk Prediction of AML Based on Comprehensive Genomic and Clinical Data
Authors: Moritz Gerstung, Elli Papaemmanuil, Inigo Martincorena, Lars Bullinger, Verena I. Gaidzik, Peter Paschka, Michael Heuser, Felicitas Thol, Niccolo Bolli, Peter Ganly, Arnold Ganser, Ultan McDermott, Michael R Stratton, Konstanze Döhner, Hartmut Döhner, Richard F. Schlenk, Peter J Campbell
Journal: Blood (2015)
Acute Tumor Lysis Syndrome. Modulation of Cyclooxygenase-2, Alpha V Beta Integrin and Microsomal Prostaglandin E Synthase-1 In Human Immunodeficiency Virus-1 (HIV-1) Squamous Cell Carcinoma (SCC) of the Penis with Selenomethionine/Nsaids
Authors: Eugene McPherson
Journal: Blood (2010)
Mutations of STAT6 DNA Binding Domain Are Characteristic of PMBL and Belong to the Genetic Signature of This Entity.
Authors: Marlene Ochmann, Francois Lemonnier, Diane Damotte, Richard Delarue, Susana Ben-Neriah, Noel Milpied, Thierry Lamy, Herve Tilly, Randy D. Gascoyne, Christian Steidl, Philippe Gaulard, Karen Leroy
Journal: Blood (2012)
PTH-030 Management of sporadic duodenal polyps and risk of colorectal carcinoma
Authors: E L Culver, L Green, S Cullen, D Gorard, A S McIntyre
Journal: Gut (2010)

<h3>Introduction</h3> Duodenal polyps occur infrequently. Their natural history and association with colonic lesions is unclear, presenting diagnostic and therapeutic dilemmas. <h3>Methods</h3> This single-centre retrospective observational study identified patients with sporadic duodenal polyps (SDP) from endoscopy, histology and case records over a 10-year period (1998–2008). Patients with polyposis syndromes, peri-ampullary or ampullary polyps were excluded. <h3>Results</h3> SDP9s were recorded in 69 patients (97 polyps) out of 21 516 endoscopies, prevalence 0.32%, median age 69 years (range 23–90), equal sex distribution (M/F 32:37). Most frequent indications for endoscopy in this group were dyspepsia (28.9%) and anaemia (20.3%). Polyps were usually solitary (76.7%), between 5 and 10 mm in size (53.4%) and found in the first part of the duodenum (56.5%). Biopsies were taken in 82.6% of cases, most frequently finding gastric metaplasia (26%). Adenomas were identified in five cases (7.2%) prevalence 0.02%, were solitary (71.4%), of variable size (3–15 mm) and found in all parts of the duodenum. There were no duodenal carcinomas. Treatment was with endoscopic removal by snare polypectomy or hot biopsy for adenomas and large polyps over 15 mm (10.1%). Frailty and co-morbidity contraindicated therapeutic procedures in some (7.2%). Repeat endoscopy revealed residual disease in two-thirds and recurrence in a third of cases, over a mean follow-up of 13.6 months (range 2–34), all successfully treated with argon plasma coagulation. One patient required blood transfusion for post-polypectomy bleeding. There were no other complications. Five patients died of unrelated causes during a median follow-up of 49 months (range 1–120). Twenty patients (28.9%) underwent colonic imaging. Colorectal polyps were found in 40% (8/20) and carcinomas in 20% (4/20). Colonic investigation was performed in five patients (5 of 7) with duodenal adenomas in whom colorectal polyps were found in 40% (2/5) and carcinoma in 20% (1/5), suggesting no increased risk compared with other SDPs. <h3>Conclusion</h3> SDPs are largely benign and should not be removed unless symptomatic or adenomatous. Endoscopic removal is safe but there is a high rate of residual and recurrence at second-look endoscopy. Biopsy should be performed to identify large adenomas or carcinomas. The prevalence of colorectal neoplasia did not differ between the group with duodenal adenomas and those with other duodenal lesions. The high rate of colorectal neoplasia may be explained by the age of the population and indication for original procedure. As SDP are reported infrequently a larger study may have the power to test such an association and define the role for colonoscopy in such patients; the BSG website may provide a method for investigating this.
Genomic landscape of colorectal cancer in Japan: clinical implications of comprehensive genomic sequencing for precision medicine
Authors: Masayuki Nagahashi, Toshifumi Wakai, Yoshifumi Shimada, Hiroshi Ichikawa, Hitoshi Kameyama, Takashi Kobayashi, Jun Sakata, Ryoma Yagi, Nobuaki Sato, Yuko Kitagawa, Hiroyuki Uetake, Kazuhiro Yoshida, Eiji Oki, Shin-ei Kudo, Hiroshi Izutsu, Keisuke Kodama, Mitsutaka Nakada, Julie Tse, Meaghan Russell, Joerg Heyer, Winslow Powers, Ruobai Sun, Jennifer E. Ring, Kazuaki Takabe, Alexei Protopopov, Yiwei Ling, Shujiro Okuda, Stephen Lyle
Journal: Genome Medicine (2016)

Comprehensive genomic sequencing (CGS) has the potential to revolutionize precision medicine for cancer patients across the globe. However, to date large-scale genomic sequencing of cancer patients has been limited to Western populations. In order to understand possible ethnic and geographic differences and to explore the broader application of CGS to other populations, we sequenced a panel of 415 important cancer genes to characterize clinically actionable genomic driver events in 201 Japanese patients with colorectal cancer (CRC).Using next-generation sequencing methods, we examined all exons of 415 known cancer genes in Japanese CRC patients (n = 201) and evaluated for concordance among independent data obtained from US patients with CRC (n = 108) and from The Cancer Genome Atlas-CRC whole exome sequencing (WES) database (n = 224). Mutation data from non-hypermutated Japanese CRC patients were extracted and clustered by gene mutation patterns. Two different sets of genes from the 415-gene panel were used for clustering: 61 genes with frequent alteration in CRC and 26 genes that are clinically actionable in CRC.The 415-gene panel is able to identify all of the critical mutations in tumor samples as well as WES, including identifying hypermutated tumors. Although the overall mutation spectrum of the Japanese patients is similar to that of the Western population, we found significant differences in the frequencies of mutations in ERBB2 and BRAF. We show that the 415-gene panel identifies a number of clinically actionable mutations in KRAS, NRAS, and BRAF that are not detected by hot-spot testing. We also discovered that 26% of cases have mutations in genes involved in DNA double-strand break repair pathway. Unsupervised clustering revealed that a panel of 26 genes can be used to classify the patients into eight different categories, each of which can optimally be treated with a particular combination therapy.Use of a panel of 415 genes can reliably identify all of the critical mutations in CRC patients and this information of CGS can be used to determine the most optimal treatment for patients of all ethnicities.
A randomized, double-blind, phase III trial comparing ipilimumab versus placebo following radiotherapy (RT) in patients (pts) with castration-resistant prostate cancer (CRPC) who have received prior treatment with docetaxel (D).
Authors: C. G. Drake, H. I. Scher, W. R. Gerritsen, R. Ezzeddine, T. F. Fitzmaurice, J. Cuillerot, K. M. Chin, P. Gagnier
Journal: Journal of Clinical Oncology (2011)

TPS181 Background: Ipilimumab (Ipi), an anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) antibody, potentiates natural antitumor responses by blocking CTLA-4-mediated inhibition of T cells that have already mounted responses to tumor antigens. The drug showed antitumor effects in prostate cancer model systems and in phase I/II investigations in CRPC, with a side effect profile reflective of its mechanism of action. Recent studies in model systems suggested that the RT given prior to Ipi administration may increase tumor immunogenicity and enhance Ipi-mediated antitumor activity. Methods: For this study, pts with CRPC that has progressed during or after D are randomized 1:1 to receive bone-directed RT followed by Ipi or RT followed by placebo as induction therapy. Pts randomized to induction therapy with Ipi receive their initial dose (10mg/kg) within 2 days of RT administration (up to 5 fields at 8 Gy on a single day); Ipi is then given every 3 wks for 4 doses. After induction, pts not meeting Treatment Stopping Criteria (TSC, which have been prospectively defined to enable decision making) may continue to receive blinded study drug every 12 weeks until pts meet TSC, withdraw consent, or are lost to follow-up; or study closure. The primary endpoint is overall survival. Secondary endpoints include time to treatment failure, objective response, PSA response/kinetics, pain palliation, and safety. 800 pts are planned to be randomized. Enrollment has been ongoing since 2009 (ClinicalTrials.gov identifier: NCT00861614). Key inclusion criteria Metastatic CRPC At least 1 bone metastasis appropriate for RT Testosterone <50 ng/dl ECOG performance status 0-1 Progression on or within 6 months of a prior D-containing regimen Key exclusion criteria Brain metastasis Autoimmune disease Known HIV, Hep B, or Hep C infection >2 prior cytotoxic chemo regimens for CRPC Prior treatment on BMS CA180227