tbuckley/cabot-search huggingface dataset:
Abstract 4790: Let-7 mediates sulindac inhibition of tumor cell transformation
Authors: Zhipin Liang, Bin Yi, Hongyou Zhao, Ruixia Ma, Yaguang Xi
Journal: Cancer Research (2017)

Abstract Cell transformation is the process in which normal cells acquire the properties of cancer. Sulindac Sulfide (SS) is one of non-steroidal anti-inflammatory drugs (NSAIDs), and its anticancer activity in prevention of tumor occurrence and progression has been documented in various human cancers. In this study, we observed the anti-transformative activity of SS in NIH/3T3 cells by using a two-stage transformation assay induced by the carcinogens, 3-methylcholanthrene (MCA) and 2-O-tetradecanoylphorbol-13-acetate (TPA) in which foci formation is used to characterize the transformed cells. We found that SS could inhibit foci formation by attenuation of TPA’s promotive effect. K-Ras was upregulated in the transformed cells, while SS treatment could selectively inhibit the growth of transformed cell in which K-Ras was suppressed significantly. Loss-of-function study demonstrated that knockdown of K-Ras in NIH/3T3 cells could significantly reduce foci formation, which support that K-Ras might be one of the key targets involved in SS inhibiting tumor cell transformation. When studying the mechanism by which SS regulates K-Ras, we triggered tumor suppressor miRNA, let-7b, which was previously reported to target K-Ras and repress its expression through the post-transcriptional or translational modulation. We found that let-7b could be upregulated in the transformed cells by SS treatment. However, the inhibitory effect of SS on foci formation was significantly attenuated when let-7b was knocked down by CRISPR/Cas9. In parallel, K-Ras maintained static expression in the transformed cells, regardless of SS treatment. Meanwhile, the overexpression of endogenous let-7b can significantly inhibit tumor transformation. In addition, we demonstrated that SS could suppress the expression of Lin28 that interacts with let-7 through a documented feedback loop. Given our previous studies reporting that SS was able to inhibit the transcriptional activity of NF-κB that is involved in regulation of Lin28 expression, our study demonstrates that the NF-κB/Lin28/Let-7/K-Ras axis addresses a new mechanism responsible for anti-transformative activity of SS. These results will provide novel insights into understanding the mechanisms involved in tumorigenesis and benefiting identification of new targets for drug development in prevention of tumor progression. Citation Format: Zhipin Liang, Bin Yi, Hongyou Zhao, Ruixia Ma, Yaguang Xi. Let-7 mediates sulindac inhibition of tumor cell transformation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4790. doi:10.1158/1538-7445.AM2017-4790
A cluster of invasive meningococcal disease (IMD) caused by Neisseria meningitidis serogroup W among university students, France, February to May 2017
Authors: Clément Bassi, Muhamed-Kheir Taha, Christian Merle, Eva Hong, Daniel Lévy-Bruhl, Anne-Sophie Barret, Ibrahim Mounchetrou Njoya
Journal: Eurosurveillance (2017)

Between February and May 2017, two cases of invasive meningococcal disease caused by a new, rapidly expanding serogroup W meningococci variant were reported among students of an international university in Paris. Bacteriological investigations showed that isolates shared identical genotypic formula (W:P1.5,2:F1–1:cc11) and belonged to the South American/UK lineage. A vaccination campaign was organised that aimed at preventing new cases linked to potential persistence of the circulation of the bacteria in the students.
Abstract 1329: Inhibition of papillary thyroid cancer cells progression by targeting skp2 via <i>ros</i>-<i>erk</i>-<i>chop</i>-<i>dr5</i> pathways
Authors: Pratheeshkumar Poyil, Rong Bu, Abdul K. Siraj, Sandeep Kumar P, Khawla S. Al-Kuraya
Journal: Cancer Research (2017)

Abstract S-phase kinase protein 2 (SKP2), is an F-box protein with proteasomal properties and has been found to be overexpressed in a variety of cancers. However its role in papillary thyroid cancer (PTC) has not been elucidated. Therefore, inactivation of SKP2 could be a viable strategy for the treatment of PTC. In the present study, we investigated the role of SKP2 and its ubiquitin-proteasome pathway in PTC using a tissue microarray cohort of 1022 PTC samples, PTC cell lines and Nude mouse model. Our immunohistochemistry data showed that SKP2 was over-expressed in 75.1% of PTC cases and was clinically, significantly associated with extra thyroidal extension (p=0.0331), Tall cell variant (p=0.0070), and presence in surgical margins (p=0.0347). Bortezomib as well as SKP2 specific siRNA caused downregulation of SKP2 leading to dose-dependent growth inhibition and induction of apoptosis via mitochondrial apoptotic pathway in PTC cell lines. Furthermore, we found that treatment of PTC cells with Bortezomib caused up-regulation of DR5 via generation of reactive oxygen species (ROS). Finally, Bortezomib treatment augmented TRAIL mediated anti-cancer effect on PTC xenograft tumor growth in nude mice. These data suggest that Bortezomib is a viable therapeutic option for the treatment of PTC either alone or in combination with other apoptotic agents such as TRAIL. Note: This abstract was not presented at the meeting. Citation Format: Pratheeshkumar Poyil, Rong Bu, Abdul K. Siraj, Sandeep Kumar P, Khawla S. Al-Kuraya. Inhibition of papillary thyroid cancer cells progression by targeting skp2 via ros-erk-chop-dr5 pathways [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1329. doi:10.1158/1538-7445.AM2017-1329
Abstract 5448: An exosomal biomarker for prostate cancer
Authors: Divya Bhagirath, Thao Yang, Kirandeep Sekhon, Nathan Bucay, Shahana Majid, Yutaka Hashimoto, Priyanka Kulkarni, Pritha Dasgupta, Marisa Shiina, Varahram Shahryari, Mitsuho Imai-Sumida, Soichiro Yamamura, Z Laura Tabatabai, Yuichiro Tanaka, Rajvir Dahiya, Guoren Deng, Sharanjot Saini
Journal: Cancer Research (2017)

Abstract Prostate tumors are highly heterogeneous and molecular characterization based on biopsy sampling is often challenging. Hence, it is desirable to have an easily accessible, minimally invasive way to determine the molecular imprints of a patient’s tumor. Exosomes in blood are an important source of non-invasive, circulating biomarkers and provide an enriched source of microRNAs. With an objective of identifying microRNA based markers, we developed a comprehensive procedure for exosomal microRNA profiling analyses from sera of prostate cancer patients employing Nanostring nCounter technology. In a pilot study, we profiled exosomal miRNAs from a training cohort of normal individuals, patients with benign prostate hyperplasia (BPH), indolent form of PCa and aggressive metastatic prostate cancer. Exosomes were extracted from serum and the integrity of exosomal preparations was confirmed by nanoparticle tracking analysis and Western blot analyses for exosomal markers CD63, CD9 and TSG101. Levels of two miRNAs were significantly upregulated and several candidate miRNAs were markedly downregulated in metastatic PCa serum samples compared with controls. The candidate microRNAs were further validated in a larger cohort by real time PCR based microRNA assays. Of significance, we validated miR-1246 as an exosomal marker for prostate cancer. miR-1246 levels were specifically altered in prostate cancer patients and not significantly altered in BPH. Our analyses suggest that miR-1246 is a promising diagnostic biomarker for prostate cancer. Citation Format: Divya Bhagirath, Thao Yang, Kirandeep Sekhon, Nathan Bucay, Shahana Majid, Yutaka Hashimoto, Priyanka Kulkarni, Pritha Dasgupta, Marisa Shiina, Varahram Shahryari, Mitsuho Imai-Sumida, Soichiro Yamamura, Z Laura Tabatabai, Yuichiro Tanaka, Rajvir Dahiya, Guoren Deng, Sharanjot Saini. An exosomal biomarker for prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5448. doi:10.1158/1538-7445.AM2017-5448
Comparative activity of the potent selective CDK2 inhibitor NU6102 in CDK2 wild-type and knock-out mouse embryo fibroblasts
Authors: Yuzhu Cheng, Lan-Zhan Wang, Nicola J. Curtin, David R. Newell
Journal: Cancer Research (2005)

4409   Cyclin-dependent kinases (CDK) regulate cell cycle progression, and CDK deregulation due to cyclin over-expression, mutation or tumor suppressor gene malfunction is a common feature of human cancer. CDKs are being actively investigated as targets for cancer therapy, and CDK inhibitors have entered clinical trials, e.g. flavopiridol, R-roscovitine and BMS387032. CDK2, in association with cyclins E and A, is involved in G1/S and S phase progression, and molecular pathology studies have implicated CDK2 as a target for drug therapy. However, recent molecular genetic studies in tumor cell lines and in knock-out mouse models have questioned the validity of CDK2 as a target (Tetsu and McCormick Cancer Cell 2003 3:233; Ortega et al., Nature Genetics 2003 35:25). Specifically, mice with homozygous deletion of CDK2 grow normally and give rise to embryonic fibroblasts (MEFs) with equivalent replicative capacity to their WT counterparts. We have recently described the design and synthesis of NU6102 (6-cyclohexylmethoxy-2-(4’-sulfamoylanilino) purine), a potent and selective CDK2 inhibitor (Davies at al., Nature Structural Biology 2002, 9:745). The current study describes the growth inhibitory activity of NU6102 in CDK2 WT and KO MEFs in comparison to the standard compound R-roscovitine. The CDK inhibitory activities of NU6102 and R-roscovitine were defined using a panel of purified human CDKs, ATP concentrations of 12.5 microM (CDK1,2 and 4) or 100 microM (CDK5 and 7), and appropriate substrates. Concentrations (microM) required to inhibit CDKs (CDK1/B; CDK2/A3; CDK4/D; CDK5/p25; CDK7/H) by 50% were: 0.25+/−0.05; 0.005+/−0.001; 1.5+/−0.7; 0.48+/−0.07; 4.4+/−0.8 to NU6102; However, R-roscovitine against these CDKs were 6; 0.41+/−0.05; 5.5+/−1.1; 0.87+/−0.14; 0.84+/−0.04, respectively. Thus NU6102 shows 50-fold selectivity for CDK2, whereas R-roscovitine is less selective. In a 5-day sulphorhodamine B growth inhibition assay, NU6102 had a GI50 value of 9+/−2 microM for CDK2 WT MEFs, whereas there was no growth inhibition up to and including 25 microM in the CDK KO MEFs. At concentrations where NU6102 showed differential activity against the CDK2 WT MEFs (
Complete endoscopic sphincterotomy with vs. without large-balloon dilation for the removal of large bile duct stones: randomized multicenter study
Authors: David Karsenti, Emmanuel Coron, Geoffroy Vanbiervliet, Jocelyn Privat, Eric Kull, Philippe Bichard, Bastien Perrot, Vincent Quentin, Arnaud Duriez, Franck Cholet, Clément Subtil, Jean Duchmann, Christine Lefort, Hervé Hudziak, Stéphane Koch, Philippe Granval, Stéphane Lecleire, Antoine Charachon, Karl Barange, Elodie Cesbron, Axel De Widerspach, Yann Le Baleur, Marc Barthet, Laurent Poincloux
Journal: Endoscopy (2017)

Abstract Background and study aims Endoscopic sphincterotomy plus large-balloon dilation (ES-LBD) has been reported as an alternative to endoscopic sphincterotomy for the removal of bile duct stones. This multicenter study compared complete endoscopic sphincterotomy with vs. without large-balloon dilation for the removal of large bile duct stones. This is the first randomized multicenter study to evaluate these procedures in patients with exclusively large common bile duct (CBD) stones. Methods Between 2010 and 2015, 150 patients with one or more common bile duct stones ≥ 13 mm were randomized to two groups: 73 without balloon dilation (conventional group), 77 with balloon dilation (ES-LBD group). Mechanical lithotripsy was subsequently performed only if the stones were too large for removal through the papilla. Endoscopic sphincterotomy was complete in both groups. Patients could switch to ES-LBD if the conventional procedure failed. Results There was no between-group difference in number and size of stones. CBD stone clearance was achieved in 74.0 % of patients in the conventional group and 96.1 % of patients in the ES-LBD group (P &lt; 0.001). Mechanical lithotripsy was needed significantly more often in the conventional group (35.6 % vs. 3.9 %; P &lt; 0.001). There was no difference in terms of morbidity (9.3 % in the conventional group vs. 8.1 % in the ES-LBD group; P = 0.82). The cost and procedure time were not significantly different between the groups overall, but became significantly higher for patients in the conventional group who underwent mechanical lithotripsy. The conventional procedure failed in 19 patients, 15 of whom underwent a rescue ES-LBD procedure that successfully cleared all stones. Conclusions Complete endoscopic sphincterotomy with large-balloon dilation for the removal of large CBD stones has similar safety but superior efficiency to conventional treatment, and should be considered as the first-line step in the treatment of large bile duct stones and in rescue treatment. Trial registered at ClinicalTrials.gov (NCT02592811).
Abstract 607: PDL1 expression associated with triple negative breast ductal carcinomas in African American women
Authors: Farhan Khan, Yasmine Kanaan, Luisel J. Ricks-Santi, Rabia Zafar, Hagos Aymut, Tammey Naab
Journal: Cancer Research (2017)

Abstract Background: Tumor cells avoid host immune response through expression of inhibitory T cell regulator, Programmed cell death ligand (PDL1).Our objective was to evaluate PDL1 expression by immunohistochemistry in the four major subtypes of breast carcinoma (Luminal A, Luminal B, HER2, and Triple Negative) in a population of 202 African-American (AA) women with other clinicopathological factors. Design: Tissue microarrays (TMAs) were constructed from FFPE tumor blocks from primary ductal breast carcinomas in 202 African-American females. Two separate 1 mm cores represented each case. Five micrometer sections were stained with rabbit monoclonal antibody against PDL1. The sections were evaluated for the percentage and intensity of membrane staining in both tumor and immune cells. Cut off was &amp;gt; 1%. Bivariate analysis was done via χ2 analysis and survivability data was calculated via the generation of Kaplan-Meier curves (SPSS v19). Statistical significance was assumed if p &amp;lt; 0.05. Results: PDL1 expression in only tumor cells, only immune cells and in combination was associated with ER negative (p&amp;lt;0.0001), PR negative (p&amp;lt;0.0001), Triple negative subtype (p&amp;lt;0.0001) and high grade (p&amp;lt;0.0001) breast ductal cancers. Conclusion: Our study finding of selective expression of PDL1 in triple negative breast ductal cancers (TNBC) in AA women suggests that inhibition of adaptive immune response is involved in the progression of these cancers. PDL1/PD1 is the inhibitory check point of immune response resulting in decreased T cell activation and cytokine production. Some studies have shown that PDL1 expression is associated with loss of PTEN and phosphatide inositol 3 kinase pathway (PI3K) activation. Our previous study showed loss of PTEN in TNBC. Combining PDL1 inhibitors with PI3K inhibitors may be useful therapy for aggressive TNBC. Citation Format: Farhan Khan, Yasmine Kanaan, Luisel J. Ricks-Santi, Rabia Zafar, Hagos Aymut, Tammey Naab. PDL1 expression associated with triple negative breast ductal carcinomas in African American women [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 607. doi:10.1158/1538-7445.AM2017-607
Abstract 1536: CRISPR/Cas9 biased mutagenesis in the mouse genome: Is it useful or harmful for cancer therapeutics
Authors: Ha Youn Shin
Journal: Cancer Research (2017)

Abstract Advances in CRISPR/Cas9 genome editing have provided unprecedented opportunities to interrogate the functional significance of any given genomic site. While this technology is rapidly spreading and extended to with almost 4,000 PubMed entries as of today, there is a paucity of data on the extent of unexpected and undesired molecular consequences established upon targeting the mouse genome. We have introduced deletions at more than 20 genomic sites including CTCF and STAT5 transcription factor binding sites, screened over 500 founder mice and established and analyzed more than 50 lines. These data sets revealed hitherto unknown deletion patterns, unexpected large deletions using single sgRNAs and the consistent deletion of sequences bridging distant loci that were targeted simultaneously. Our findings provide guidelines for the application of CRISPR/Cas9 in the mouse germline and provide the insight into designing CRISPR-based cancer therapeutics. Note: This abstract was not presented at the meeting. Citation Format: Ha Youn Shin. CRISPR/Cas9 biased mutagenesis in the mouse genome: Is it useful or harmful for cancer therapeutics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1536. doi:10.1158/1538-7445.AM2017-1536
AG-348 enhances pyruvate kinase activity in red blood cells from patients with pyruvate kinase deficiency
Authors: Charles Kung, Jeff Hixon, Penelope A. Kosinski, Giovanni Cianchetta, Gavin Histen, Yue Chen, Collin Hill, Stefan Gross, Yaguang Si, Kendall Johnson, Byron DeLaBarre, Zhiyong Luo, Zhiwei Gu, Gui Yao, Huachun Tang, Cheng Fang, Yingxia Xu, Xiaobing Lv, Scott Biller, Shin-San Michael Su, Hua Yang, Janeta Popovici-Muller, Francesco Salituro, Lee Silverman, Lenny Dang
Journal: Blood (2017)
Abstract 4480: SerRS is a key inhibitor of VEGFA through both transcriptional and translational controls
Authors: Ze Liu, Yi Shi, Qian Zhang, Xianglei Yang
Journal: Cancer Research (2017)

Abstract Vascular endothelial growth factor A (VEGFA) is the most important mediator of angiogenesis and a major target for cancer therapy. Recent studies from our lab revealed that seryl-tRNA synthetase (SerRS), by counteracting transcription factor c-Myc in the nucleus, is the crucial transcriptional repressor of VEGFA and a potent inhibitor of angiogenesis (1,2). Here we report that SerRS controls the expression of VEGFA not only in the nucleus but also in the cytoplasm through mediating its translational readthrough. Translational read-through of the VEGFA mRNA generates a novel isoform called VEGF-Ax that, compared with the non-readthrough isoform VEGF165, has a 22-amino acid C-terminal extension and much weakened angiogenic activity (3,4). Interestingly, serine was identified as the amino acid inserted in the place of the UGA stop codon during the read-through (3). In unpublished work, wWe findound that SerRS can bind to the 3’UTR region of the VEGFA mRNA. The binding anchors SerRS to charge serine onto tRNASec (the tRNA for the 21st amino acid selenocysteine that decodes the UGA stop codon), while preventing the charged serine from being modified into selenocysteine. SerRS binding also blocks the release factors (eRFs) from terminating translation at the stop codon. Therefore, SerRS is the key mediator of the translational readthrough that generates VEGF-Ax. Collectively, we have established that a member of the aminoacyl-tRNA synthetase family plays a critical role in regulating VEGF and angiogenesis through both transcriptional and translational controls. References 1. Xu X, Shi Y, Zhang HM, Swindell EC, Marshall AG, Guo M, Kishi S, Yang XL*. Unique domain appended to vertebrate tRNA synthetase is essential for vascular development. Nat Commun. 2012 Feb 21;3:681. 2. Shi Y, Xu X, Zhang Q, Fu G, Mo Z, Wang GS, Kishi S, Yang XL*. tRNA synthetase counteracts c-Myc to develop functional vasculature. Elife. 2014 Jun 17;3:e02349. 3. Eswarappa SM, Potdar AA, Koch WJ, Fan Y, Vasu K, Lindner D, Willard B, Graham LM, DiCorleto PE, Fox PL. Programmed translational readthrough generates antiangiogenic VEGF-Ax. Cell. 2014 Jun 19;157(7):1605-18. 4. Xin H, Zhong C, Nudleman E, Ferrara N. Evidence for Pro-angiogenic Functions of VEGF-Ax. Cell. 2016 Sep 22;167(1):275-284. Citation Format: Ze Liu, Yi Shi, Qian Zhang, Xianglei Yang. SerRS is a key inhibitor of VEGFA through both transcriptional and translational controls [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4480. doi:10.1158/1538-7445.AM2017-4480
Abstract 2119: Acetylated secretory APE1/Ref-1 induces apoptotic cell death in orthotopic xenografts of triple-negative breast cancer
Authors: Yu Ran Lee, Hee Kyoung Joo, Eun Ok Lee, Myoung Soo Park, Byeong Hwa Jeon, Sunga Choi
Journal: Cancer Research (2017)

Abstract The anticancer properties of acetylated secretory apurinic/apyrimidinic endonuclease-1 (Ape1/Ref-1) was suggested in triple-negative breast cancer (TNBC) cells; Posttranslational modification, hyperacetylation in MDA-MB-231 cells caused extracellular secretion of acetylated-APE1/Ref-1 (Ac-APE1/Ref-1) and initiated apoptotic cell death by auto-, paracrine binding to the receptor for advanced glycation end products (RAGE). In the present study, we observed potential therapeutic efficacy of Ac-APE1/Ref-1 in preclinical orthotopic models of TNBC in response to hyperacetylation. The extracellular Ac-APE1/Ref-1 was confirmed by proximity ligation assay in hyperacetylated tumor tissue, showing direct binding of Ac-APE1/Ref-1 and RAGE. Treatment of orthotopic TNBC xenografts with acetylating agents induced a strong growth inhibition in the tumor development as observed in computed tomography: it caused an increase of RAGE expression and activation of caspase-3 and PARP. The tumors also exhibited markedly higher count of apoptotic bodies and reduced proliferation index and neovascularization compared with control tumors. However, the Ac-APE1/Ref-1-stimulated apoptotic cell death was remarkably retarded in RAGE-knockout tumor even in hyperacetylation compared with RAGE-overexpressed one. The functional role of secreted Ac-APE1/Ref-1 in hyperacetylated TNBC was confirmed in vivo, demonstrating its relevance to the anticancer agent. Our findings suggest that Ac-APE1/Ref-1 protein possesses potent chemotherapeutic efficacy against TNBC, resistant to standard chemotherapeutic agents, warranting further evaluation as an anticancer agent Citation Format: Yu Ran Lee, Hee Kyoung Joo, Eun Ok Lee, Myoung Soo Park, Byeong Hwa Jeon, Sunga Choi. Acetylated secretory APE1/Ref-1 induces apoptotic cell death in orthotopic xenografts of triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2119. doi:10.1158/1538-7445.AM2017-2119
Lazarus syndrome in nonsmall cell lung cancer patients with poor performance status and major leukocytosis following nivolumab treatment
Authors: Johan Pluvy, Solenn Brosseau, Charles Naltet, Marie-Agnès Opsomer, Aurélie Cazes, Claire Danel, Antoine Khalil, Gérard Zalcman, Valerie Gounant
Journal: European Respiratory Journal (2017)

Nivolumab appears efficacious in highly PD-L1-expressing NSCLC with poor PS, resulting in Lazarus syndrome http://ow.ly/X92e30coTsB