tbuckley/cabot-search huggingface dataset:
Abstract 1419: Role of a novel Senataxin-associated nuclease in DNA repair
Authors: Heather McCartney, Ian Macara
Journal: Cancer Research (2017)

Abstract Yeast two-hybrid analysis has identified a novel, uncharacterized Senataxin-interacting protein with 5’ exonuclease activity, and homology to the FEN1 nuclease domain. Senataxin is an RNA/DNA helicase that functions in resolving R loop structures which occur as a result of normal replication and transcription but can also persist resulting in genomic instability. We found that SAN1 (Senataxin-Associated Nuclease 1) is unable to cut dsDNA or bubbles, but is active against 5’ overhangs and against ssDNAs of greater than 15 nucleotides. SAN1 cleaves 3 or 8 nt fragments from the 5’ end of ssDNA and utilizes magnesium as a cofactor. As the definitive 5’ nuclease responsible for unhooking ICLs has yet to be identified we speculate that SAN1 might function in excising crosslinked nucleotides that result from interstrand crosslink (ICL) damage. We generated a SAN1 -/- HeLa cell line through CRISPR/Cas gene editing and found that SAN1 -/- cells are sensitized to ICL agents mitomycin-c and cisplatin. Interestingly, colony survival assays have shown that SAN1 does not appear to be epistatic of FANCD2, a key component of the classical pathway for resolving ICLs, the Fanconi Anemia pathway. Additionally, although the nuclease domain of SAN1 is homologous to the FEN1 family of structure-specific nucleases, SAN1 also possesses a unique and conserved C terminus of unknown function. Our goal is to understand the relationship between the structure and nuclease activity of SAN1 in DNA repair and how SAN1 relates to other known ICL-repair pathways. Understanding the components that regulate genome stability is crucial in understanding how cancer occurs and what protein targets will be the most advantageous to pursue in developing potential therapeutics. This study may also provide a better understanding of a novel factor in resistance to ICL-inducing chemotherapeutics such as cisplatin and MMC which are still widely used in the treatment of breast and ovarian cancers. Citation Format: Heather McCartney, Ian Macara. Role of a novel Senataxin-associated nuclease in DNA repair [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 1419. doi:10.1158/1538-7445.AM2017-1419
Abstract 2108: Imatinib-induced downregulation of Skp2 inhibits cell growth in human squamous cell carcinoma
Authors: Hyo Jin Jeong
Journal: Cancer Research (2017)

Abstract It is apparent that Skp2(S-phase kinase associated protein) plays a crucial role in tumorigenesis of various human cancers. Imatinib, inhibitor of BCR-ABL tyrosine kinase, KIT and PDGF receptor, has been approved for the treatment and investigation of chronic myeloid leukemia, gastrointestinal stromal tumors and additional various solid tumors. But An area of skin cancer has not been yet investigated. The aim of this study was to explore the role of the Skp2 in Imatinib antitumor effect on human skin cancer. To explore Imatinib effect on growth of A431 cells (squamous cell carcinoma / skin cancer) we conducted CCK8 assay and Flow cytometry. Western blot assay was performed for determining the functions and molecular mechanism of Imatinib in A431 cells. we found that Imatinib significantly inhibited cell growth and induced cell cycle arrest at G0/G1 phase. Furthermore, we observed that depletion of Skp2 triggered cell cycle arrest and colony formation inhibition by Imatinib. Mechanistically we identified that Imatinib markedly downregulated Skp2 protein expression and subsequently upregulated p21 expression via increased protein stability. In conclusion, Imatinib exerts its antitumor activity via inhibition of Skp2 - p21 axis and these findings suggest that targeting Skp2 by Imatinib could be promising therapeutic approach for Squamous cell carcinoma therapy. Note: This abstract was not presented at the meeting. Citation Format: Hyo Jin Jeong. Imatinib-induced downregulation of Skp2 inhibits cell growth in human squamous cell carcinoma [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 2108. doi:10.1158/1538-7445.AM2017-2108
Integrating Models to Quantify Environment-Mediated Drug Resistance
Authors: Noemi Picco, Erik Sahai, Philip K. Maini, Alexander R.A. Anderson
Journal: Cancer Research (2017)

Drug resistance is the single most important driver of cancer treatment failure for modern targeted therapies, and the dialog between tumor and stroma has been shown to modulate the response to molecularly targeted therapies through proliferative and survival signaling. In this work, we investigate interactions between a growing tumor and its surrounding stroma and their role in facilitating the emergence of drug resistance. We used mathematical modeling as a theoretical framework to bridge between experimental models and scales, with the aim of separating intrinsic and extrinsic components of resistance in BRAF-mutated melanoma; the model describes tumor-stroma dynamics both with and without treatment. Integration of experimental data into our model revealed significant variation in either the intensity of stromal promotion or intrinsic tissue carrying capacity across animal replicates. Cancer Res; 77(19); 5409-18. ©2017 AACR.
Abstract 109: Effects of trifluoperazine analogue on A549 human lung cancer cells
Authors: Joo Yeon Jeong, Jinhyun Ryu, Nal Ae Yoon, Seokmin Kang, Hyemin Seong, Ahmad Fudhaili, Juyeong Park, Jimin Sim, Jiyeon Lee, Soohyun Hwang, Sang Soo Kang
Journal: Cancer Research (2017)

Abstract Although there have been great advancement in technology, molecular diagnosis, therapeutics, lung cancer is still the leading cause of cancer related mortality all over the world. Recently, some antipsychotic drugs have been shown to possess the anticancer activity. Thus the present study was designed to evaluate the anticancer effects of trifluoperazine (TFP), a commonly used antipsychotic drug, and its synthetic analogs on human lung cancer cell lines. To this end, effects of TFP and its selected analog on A549 cells were investigated in vitro as well as in vivo experiments. Synthetic TFP analogs were evaluated by the viability of A549 cells following drug treatment and compared to TFP. KCFC51, a selected TFP analog, significantly inhibited the proliferation of A549 cells. Further experiment showed that TFP and KCFC51 had activities to inhibit the migration, and anchorage dependent/independent colony formation of A549 cells. Western blot analysis revealed that TFP and KCFC51 affect the protein expression levels related to cell apoptosis and cell cycle. KCFC51 showed stronger anticancer effects in all the experiment than TFP. Flow cytometric analysis showed that KCFC51 induced sub-G1 population and reduced cell population in S and G2/M phase. In addition, the two in vivo experimental models, KCFC51 also showed powerful anticancer effect in skin xenograft tumor growth and orthotropic lung cancer development than TFP. Thus present study demonstrates that a synthetic TFP analog has anti-lung cancer activity and provides a potential therapeutic candidate for lung cancer. Citation Format: Joo Yeon Jeong, Jinhyun Ryu, Nal Ae Yoon, Seokmin Kang, Hyemin Seong, Ahmad Fudhaili, Juyeong Park, Jimin Sim, Jiyeon Lee, Soohyun Hwang, Sang Soo Kang. Effects of trifluoperazine analogue on A549 human lung cancer cells [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 109. doi:10.1158/1538-7445.AM2017-109
Annals Graphic Medicine - American Doctors
Authors: Kartik A. Valluri
Journal: Annals of Internal Medicine (2017)

Web Exclusives1 August 2017Annals Graphic Medicine - American DoctorsFREEKartik A. Valluri, MDKartik A. Valluri, MDSearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/G17-0003 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Download figure Download PowerPoint Comments0 CommentsSign In to Submit A Comment Author, Article, and Disclosure InformationAffiliations: Disclosures: The author has disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=G17-0003.Author Information: Kartik A. Valluri, MD, is a Critical Care Fellow at Baylor College of Medicine and was previously Chief Medical Resident at the University of Miami at Holy Cross Hospital. He is passionate about innovating graduate medical education and strongly believes that art highlights today's social and medical challenges. He can be reached at srikartik.[email protected]edu.Author Contributions: Conception and design: K. A. Valluri. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 1 August 2017Volume 167, Issue 3Page: W35KeywordsConflicts of interestCritical careDisclosureGraduate medical educationHealth careHospital medicine ePublished: 1 August 2017 Issue Published: 1 August 2017 Copyright & PermissionsCopyright © 2017 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
The gRNA-miRNA-gRNA Ternary Cassette Combining CRISPR/Cas9 with RNAi Approach Strongly Inhibits Hepatitis B Virus Replication
Authors: Jie Wang, Ran Chen, Ruiyang Zhang, Shanlong Ding, Tianying Zhang, Quan Yuan, Guiwen Guan, Xiangmei Chen, Ting Zhang, Hui Zhuang, Frederick Nunes, Timothy Block, Shuang Liu, Zhongping Duan, Ningshao Xia, Zhongwei Xu, Fengmin Lu
Journal: Theranostics (2017)

The CRISPR/Cas9 system is a novel genome editing technology which has been successfully used to inhibit HBV replication. Here, we described a novel gRNA-microRNA (miRNA)-gRNA ternary cassette driven by a single U6 promoter. With an anti-HBV pri-miR31 mimic integrated between two HBV-specific gRNAs, both gRNAs could be separated from the long transcript of gRNA-miR-HBV-gRNA ternary cassette through Drosha/DGCR8 processing. The results showed that the gRNA-miR-HBV-gRNA ternary cassette could efficiently express two gRNAs and miR-HBV. The optimal length of pri-miRNA flanking sequence in our ternary cassette was determined to be 38 base pairs (bp). Besides, HBV-specific gRNAs and miR-HBV in gRNA-miR-HBV-gRNA ternary cassette could exert a synergistic effect in inhibiting HBV replication and destroying HBV genome
Dipeptidyl peptidase 4 inhibitor attenuates obesity-induced myocardial fibrosis by inhibiting transforming growth factor-βl and Smad2/3 pathways in high-fat diet-induced obesity rat model
Authors: Seul-Ki Hong, Eun-Ho Choo, Sang-Hyun Ihm, Kiyuk Chang, Ki-Bae Seung
Journal: Metabolism (2017)
Abstract 5454: Serum circulating microRNAs as potential biomarkers for prostate cancer
Authors: Khanmi Kasomva, Ignacimuthu Savarimuthu, Gabriel Michael Paulraj, Arnab Sen, Stephen Sailo, Ngachan SV
Journal: Cancer Research (2017)

Abstract MicroRNAs (miRNAs) are small non-coding RNA, whose differential expression has been involved in the development and progression of cancers, including prostate cancer (PCa). In recent studies circulating miRNAs have been demonstrated to have the potential as non-invasive biomarkers in various types of cancer. The aim of this study was to investigate the serum circulating miRNA-103 could be used in diagnosis of prostate cancer in North-Eastern India patient population. To evaluate this study blood samples were collected from prostate cancer patients and healthy controls following ethical approval and informed consent. The samples were reverse transcribed using stem loop primers and expression levels of miRNA-103 were determined using real time PCR. Differential expressions of miRNA-103 for each case were used to compare PCa serum with healthy serum samples. Serum circulating miR-103 levels was significantly down-regulated in the PCa patients comparison with healthy control. The serum circulating miRNA-103 could be potential for the diagnosis of PCa in North-Eastern India Population. Citation Format: Khanmi Kasomva, Ignacimuthu Savarimuthu, Gabriel Michael Paulraj, Arnab Sen, Stephen Sailo, Ngachan SV. Serum circulating microRNAs as potential biomarkers 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 5454. doi:10.1158/1538-7445.AM2017-5454
Abstract 5796: Heparan sulfate proteoglycans mediate tumor cell invasion and metastasis
Authors: Henry Qazi, Zhong-Dong Shi, Jonathan W. Song, Limary M. Cancel, Lance L. Munn, John M. Tarbell
Journal: Cancer Research (2017)

Abstract The surface proteoglycan/glycoprotein layer (glycocalyx) on tumor cells has been associated with cellular functions that can potentially enable invasion and metastasis. In addition, aggressive tumor cells with high metastatic potential have enhanced invasion rates in response to interstitial flow stimuli in vitro. Our previous studies suggest that heparan sulfate (HS) in the glycocalyx plays an important role in this flow mediated mechanostransduction and upregulation of invasive and metastatic potential. In this study, highly metastatic renal cell carcinoma cells were genetically modified to suppress HS production by knocking down its synthetic enzyme NDST1. Using modified Boyden chamber and microfluidic assays, we show that flow-enhanced invasion is suppressed in HS deficient cells. To assess the ability of these cells to metastasize in vivo, parental or knockdown cells expressing fluorescence reporters were injected into kidney capsules in SCID mice. Histological analysis confirmed that there was a large reduction (95%) in metastasis to distant organs by tumors formed from the NDST1 knockdown cells compared to control cells with intact HS. The ability of these cells to invade surrounding tissue was also impaired. The substantial inhibition of metastasis and invasion upon reduction of HS suggests an active role for the tumor cell glycocalyx in tumor progression. Citation Format: Henry Qazi, Zhong-Dong Shi, Jonathan W. Song, Limary M. Cancel, Lance L. Munn, John M. Tarbell. Heparan sulfate proteoglycans mediate tumor cell invasion and metastasis [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 5796. doi:10.1158/1538-7445.AM2017-5796
Association analysis in over 329,000 individuals identifies 116 independent variants influencing neuroticism
Authors: Michelle Luciano, Saskia P. Hagenaars, Gail Davies, W. David Hill, Toni-Kim Clarke, Masoud Shirali, Sarah E. Harris, Riccardo E. Marioni, David C. Liewald, Chloe Fawns-Ritchie, Mark J. Adams, David M. Howard, Cathryn M. Lewis, Catharine R. Gale, Andrew M. McIntosh, Ian J. Deary
Journal: Nature Genetics (2017)
Abstract 16370: Short Term Effects of Photochemical Oxidant on Heart Failure: A Case-Crossover Study
Authors: Bing Zhao, Farhad Salimi, Fay Johnston, Kiyohiro Oshima, Masahiko Kurabayashi, Kazuaki Negishi
Journal: Circulation (2016)

Introduction:  The cardiovascular health consequences of ambient air pollution generally equal or exceed those due to pulmonary diseases and cancers. However, few studies have determined culprit air pollutant for heart failure incidence. Over the past decade, fine particles  X ), nitric oxide(NO) and nitrogen dioxide(NO 2 )) have become a major focus of research. The most infamous component of photochemical oxidant is known as ozone. This study aimed to identify the associations between incidence of heart failure and air pollutants including PM2.5, NO, NO 2  and Ox.   Methods:  The association between air quality and heart failure was evaluated using a case-crossover design in Gunma Prefecture (population ~2million; area 6,363km 2 ), Japan. Incident cases with heart failure were identified through the Gunma Prefectural Ambulance Activity Database in 2015. Air quality data from the nearest station (among eight 24-hr monitoring) was for day of the event (lag 0) and for lag 1, lag 2, and lag 3. Conditional logistic regression was used for unadjusted analysis and adjusted for temperature and humidity.   Results:  There were 1002 heart failures among the total of 53006 emergency cases from January to December in 2015. Daily lag1 O X  level had significant association with incidence of heart failure in both unadjusted (OR: 1.003; 95%CI: 1.000, 1.005; p value: 0.017) and adjusted (OR: 1.003; 95%CI: 1.000, 1.005; p value: 0.026) model. No effects were found for PM2.5, NO and NO 2 .   Conclusions:  The increased risk of heart failure is associated with photochemical oxidant level of 1 day before the event but not with PM2.5, NO and NO 2 .
Abstract SY09-02: A novel genetic mechanism of evading antitumor immunity in multiple human cancers
Authors: Seishi Ogawa
Journal: Cancer Research (2017)

Abstract Immune checkpoint blockade therapy using antibodies against programmed cell death 1 (PD-1) and PD-1 ligand 1 (PD-L1) is revolutionizing cancer treatment. Surprising therapeutic responses to these agents are obtained in many advanced cancer patients with different tumor types, such as melanoma, non-small-cell lung cancer, kidney cancer, and Hodgkin lymphoma, suggesting that cancer cells depend critically on evading immune surveillance for their malignant growth. Accumulating evidence suggests that these antibodies convey their therapeutic effects through targeting the PD-1/PD-L1 immune checkpoint to unleash antitumor immune responses. However, the genetic basis for the PD-1/PD-L1-mediated immune escape has not been fully elucidated, with the exception of enhanced PD-L1 expression by gene amplification and utilization of an ectopic promoter by translocation, which were reported in Hodgkin and other B-cell lymphomas as well as stomach adenocarcinoma. Only a few genetic markers are currently available to reliably predict response to anti-PD-1/PD-L1 therapy as well. I will show a unique genetic mechanism of immune escape caused by structural variations (SVs) commonly disrupting the 3′ region of the PD-L1 gene. Widely affecting multiple common human cancer types, including adult T-cell leukemia/lymphoma (27%), diffuse large B-cell lymphoma (8%), and stomach adenocarcinoma (2%), these SVs invariably lead to a marked elevation of aberrant PD-L1 transcripts that are stabilized by truncation of the 3′-untranslated region (UTR). Disruption of Pd-l1 3′-UTR in mice enables immune evasion of EG7-OVA tumor cells with elevated PD-L1 expression in vivo, which is effectively inhibited by PD-1/PD-L1 blockade, supporting the role of relevant SVs in clonal selection through immune evasion. Our findings not only unmask a novel regulatory mechanism of PD-L1 expression, but also suggest that PD-L1 3′-UTR disruption could serve as a genetic marker to identify cancers that actively evade antitumor immunity through PD-L1 overexpression. Citation Format: Seishi Ogawa. A novel genetic mechanism of evading antitumor immunity in multiple human cancers [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 SY09-02. doi:10.1158/1538-7445.AM2017-SY09-02
Evaluating 17 years of latent tuberculosis infection screening in north-west England: a retrospective cohort study of reactivation
Authors: Dominik Zenner, Miranda G. Loutet, Ross Harris, Stephen Wilson, L. Peter Ormerod
Journal: European Respiratory Journal (2017)

Approximately 72% of tuberculosis (TB) cases in England occur among non-UK born individuals, mostly as a result of reactivation of latent TB infection (LTBI). Programmatic LTBI screening is a key intervention of the TB strategy for England. This article reviews the results of a long-standing LTBI screening initiative in England. A retrospective cohort was created through probabilistic linkage between LTBI screening data and national TB case notifications. Screened persons were followed until they died, became a case, emigrated or until cohort-end. TB incidence rates and rate ratios (IRR) were calculated. 97 out of 1820 individuals screened for LTBI were reported to have active TB. Crude incidence rates among LTBI-positive, treatment-naïve individuals were 4.1 and 2.3 per 100 person-years in the QuantiFERON and tuberculin skin test cohorts, respectively. Among the QuantiFERON cohort, Poisson regression showed that LTBI positivity (IRR 22.6, 95% CI 6.8–74.6) and no chemoprophylaxis increased the probability of becoming a TB case (IRR 0.17, 95% CI 0.05–0.6). We found high TB rates in LTBI-positive, treatment-naïve individuals and a strong association between no treatment and becoming a TB case, demonstrating feasibility and effectiveness of LTBI screening and providing important policy lessons for LTBI screening in England and beyond.
Abstract 1589: Zinc inhibits androgen receptor expression to inhibit prostate cancer cell growth
Authors: Phuong Kim To, Young-Suk Cho, Se-Young Kwon, Taek Won Kang, Kyung Keun Kim, Chaeyong Jung
Journal: Cancer Research (2017)

Abstract Background: Prostate gland contains high level of intracellular zinc which is dramatically diminished during cancer development. Due to the obscure role of zinc in this process, therapeutic application using zinc and its supplement is very limited. This study aims to clarify the role(s) of zinc and its intervening mechanism. Material and methods: Treated by zinc chloride (15-150 µM), several prostate cancer cell lines were applied to confocal microscopy for intracellular trafficking of exogenous zinc, in vitro proliferation assays for their growth, prostate specific antigen (PSA)-based reporter-mediated transactivation, and Western blot for detection of androgen receptor (AR), PSA and ubiquitination. Further in vivo studies were performed to demonstrate the effect of zinc (10-20 mg/kg) on xenograft cancer growth using syngeneic animals followed by tumor analyses. Results: Zinc chloride suppressed androgen-dependent proliferation of human prostate cancer cells and accordingly zinc chloride dramatically inhibited androgen-mediated transactivation and several androgen target protein expressions, including PSA and p21. Further investigation showed that addition of zinc chloride strikingly downregulated AR protein levels after 4 hours up to 24 hours in both human LNCaP and murine TRAMP C2 prostate cancer cell lines. AR downregulation resulted from facilitated protein degradation instead of transcriptional control. Further in vivo study was carried out using syngeneic mice bearing C2 subcutaneous tumors. Peritoneal injection of zinc chloride significantly reduced tumor size. Analysis of these tumors revealed that there were reduced expression of AR and increased cell death. Conclusions: Zinc has been shown to inhibit incumbent oncogenic NF-κB pathway. These results also suggest that intracellular zinc inhibits cell growth via downregulation of AR to inhibit growth of prostate cancer. Considering that AR functions as a major effector in prostate cancer development and progression into castration resistant prostate cancer, loss of zinc may be a critical step for this devastating disease and further studies can be performed to develop zinc-based cancer therapeutics. Citation Format: Phuong Kim To, Young-Suk Cho, Se-Young Kwon, Taek Won Kang, Kyung Keun Kim, Chaeyong Jung. Zinc inhibits androgen receptor expression to inhibit prostate cancer cell growth [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 1589. doi:10.1158/1538-7445.AM2017-1589