tbuckley/cabot-search huggingface dataset:
Abstract 354: Role of KAT5 in lung tumorigenesis
Authors: Gilbert Pan, Eunyoung Heo, Mariko Ando, Masanori Fujii, Ikei Kobayashi, Daniel G. Tenen, Hideo Watanabe, Susumu S. Kobayashi
Journal: Cancer Research (2018)

Abstract Epigenetic modifications in oncogenesis have long been an area of interest in cancer research. Histone modifications are crucial in activities such as transcriptional activation, gene silencing, and epigenetic cellular memory. In particular, lysine acetylation via lysine (K) acetyltransferases (KATs) have been implicated in cancer development. Interestingly, KAT5, also known as Tip60, has been reported to possess both tumor promoting and tumor suppressing properties depending on the context of malignancy. Herein we report that KAT5 contributes to tumorigenesis in EGFR-mutated lung cancer, and Kat5-knockout mice models demonstrate significantly reduced lung tumor burden. To probe the aberrant modification of KAT5, we demonstrated that KAT5 binds to and is phosphorylated by oncogenic EGFR in co-immunoprecipitation experiments. Next, to investigate whether KAT5 is involved in cell proliferation and survival, H1975 cells harboring L858R-T790M double-activating mutations were transfected with doxycycline inducible shRNA targeting KAT5 (shKAT5). Following treatment, shKAT5 cells were observed to have suppressed proliferation rates. Pharmacological inhibition using TH1834, a known KAT5 inhibitor, also suppressed proliferation rates in shKAT5 cells; in contrast BEAS-2B cells, an immortalized normal bronchial cell line, surprisingly exhibited increased viability compared to the transformed H1975 cells, supporting KAT5's context-dependent role in normal and abnormal cell homeostasis. To further investigate KAT5 in lung tumorigenesis in vivo, we generated EGFR-mutant conditional Kat5 knockout mice using a tetracycline-induced Cre/loxP system. Following doxycycline treatment for 10 weeks, isolated mice lungs for EGFRTL/CCSP-rtTA/Cre/Kat5F/F possessed significantly lower tumor volume compared to EGFRTL/CCSP-rtTA/Cre/Kat5W/F and EGFRTL/CCSP-rtTA/Cre/Kat5W/W mice lungs. Hemotoxylin and eosin staining showed no evident hyperproliferation in lungs isolated from EGFRTL/CCSP-rtTA/Cre/Kat5F/F mice whereas lungs isolated from EGFRTL/CCSP-rtTA/Cre/Kat5W/W and EGFRTL/CCSP-rtTA/Cre/Kat5W/F did, signifying that KAT5 has a potential regulatory role in cellular proliferation. RNA-Seq and ChIP-Seq analysis of shKAT5 H1975 cells identified downstream targets involved in tumorigenic pathways. Further studies are in progress to validate the mRNA and protein expression levels of reported targets. Taken together, these data offer insight into a KAT5 mediated oncogenic pathway that can provide novel therapeutic approaches in treating lung cancer. Citation Format: Gilbert Pan, Eunyoung Heo, Mariko Ando, Masanori Fujii, Ikei Kobayashi, Daniel G. Tenen, Hideo Watanabe, Susumu S. Kobayashi. Role of KAT5 in lung tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 354.
Cardiovascular Therapies Targeting Left Atrial Appendage
Authors: Mohit K. Turagam, Poonam Velagapudi, Saibal Kar, David Holmes, Vivek Y. Reddy, Marwan M. Refaat, Luigi Di Biase, Amin Al-Ahmed, Mina K. Chung, Thorsten Lewalter, James Edgerton, James Cox, John Fisher, Andrea Natale, Dhanunjaya R. Lakkireddy
Journal: Journal of the American College of Cardiology (2018)
Interactions between life expectancy and the incidence and mortality rates of cancer in China: a population‐based cluster analysis
Authors: Xiuying Gu, Rongshou Zheng, Changfa Xia, Hongmei Zeng, Siwei Zhang, Xiaonong Zou, Zhixun Yang, He Li, Wanqing Chen
Journal: Cancer Communications (2018)

Abstract Background The relationship between cancer and life expectancy is well established in both developed and developing countries. China is a vast country with significant geographical differences in population structure and healthcare, and thus provides a unique opportunity to analyze the complex relationship between life expectancy and cancer incidence and mortality rates. Methods Cancer data were extracted for a total of 255 units (cities or counties) from the 2013 National Central Cancer Registry. Life expectancy data at the unit level were obtained from the National Centers for Disease Control and Prevention. Linear regression analysis was used to analyze the relationship between life expectancy and crude incidence and mortality rates of cancer. In a separate analysis, life expectancy was rated as low (&lt; 76.0 years), middle (76–80 years), or high (&gt; 80 years). Results Overall, the cancer incidence and mortality rates positively correlated with life expectancy in both sexes (R at 0.37 and 0.50, P &lt; 0.001). The correlation was significant for the following cancers: lung, colorectal, prostate, bladder and pancreas, as well as for lymphoma in men (R 0.36–0.58, P &lt; 0.001), lung, breast, colorectal, thyroid, uterus, and ovary in women (R 0.18–0.51, P &lt; 0.001). We failed to observe an association between upper gastrointestinal cancer and life expectancy. The number of cities/counties with low, middle and high life expectancy levels were 110, 101 and 44, respectively. The highest age‐standardized cancer incidence rate was observed in areas with a high life expectancy level (192.83/100,000). The highest age‐standardized mortality rate was in areas with the lowest life expectancy (118.44/100,000). Cancers of the stomach, liver and esophagus are major cancer types in areas with low and middle life expectancy. In contrast, areas with high life expectancy had high incidence and mortality rates of colorectal cancer, breast cancer in women and prostate cancer in men. Conclusions Longer life expectancy is associated with higher overall cancer incidence and mortality in China. The cancer pattern also varies substantially across areas with different life expectancy levels. Life expectancy levels must be considered when developing strategies to prevent and treat cancers.
Abstract 3685: The BET inhibitor INCB057643 suppresses ALDH activity by targeting the ALDH1A1 super-enhancer in high-grade serous ovarian cancer
Authors: Sergey Karakashev
Journal: Cancer Research (2018)

Abstract The emergence of tumor cells with certain stem-like characteristics such as high aldehyde dehydrogenase (ALDH) activity due to ALDH1A1 expression contributes to chemotherapy resistance and tumor relapse. However, clinically applicable inhibitors of ALDH activity have not been reported. There is evidence to suggest that epigenetic regulation of stem-related genes contributes to the efficacy of chemotherapy. Here we show that the bromodomain and extra-terminal (BET) inhibitor INCB57643 suppresses ALDH activity by abrogating BRD4-mediated ALDH1A1 expression through a super-enhancer element and its associated enhancer RNA. INCB57643 suppressed the outgrowth of platinum-treated ovarian cancer cells in a concentration-dependent manner. Consistently, INCB57643 synergizes with carboplatin in suppressing the growth of ovarian cancer cells with BRD4 expression, which was accompanied by induction of apoptosis. These phenotypes correlate with inhibition of ALDH1A1 expression through a super-enhancer element and additional stem-related genes, including LIF, HES1 and WNT5a in promoter regions bound by BRD4. Thus, targeting the BET protein BRD4 using small molecule BET inhibitor INCB057643 is a promising strategy for targeting ALDH activity in epithelial ovarian cancer. Citation Format: Sergey Karakashev. The BET inhibitor INCB057643 suppresses ALDH activity by targeting the ALDH1A1 super-enhancer in high-grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3685.
Abstract 5294: CIMerge: A machine learning approach for merging and genotyping complex indel calls from NGS data
Authors: Tian Zheng, Yang Li, Yu Geng, Zhongmeng Zhao, Xuanping Zhang, Jiayin Wang
Journal: Cancer Research (2018)

Abstract Complex insertion and deletion (complex indel) is a rare category of genomic structural variations, which is formed by inserting one or multiple DNA fragments into the genomic location where a deletion occurs. A recent study conducts a systematic analysis from over 8,000 pan-cancer cases, which reports hundreds of complex indels in cancer-associated genes, some of which are considered potentially druggable. Several approaches are proposed to detect complex indels from the new-generation sequencing data (both 2nd and 3rd generation). However, as different data-mining algorithms vary the preferences on capturing data patterns, different approaches may report the conflicted complex indel calls. Here, we propose a machine learning approach to correct the conflicted calls from different approaches and further estimate the genotype of each call. The proposed approach, implemented as CIMerge, adopts a relevance vector machine framework. For each candidate call, CIMerge first extracts a set of features on the candidate region, which includes the read depth, variant allelic frequency, number of the splitting/unmapped reads, number of the discordant paired-end reads, aligned contig, etc. CIMerge also considers another set of features on data-mining algorithm(s) that reported the candidate call, which includes the parameter settings, etc. Both sets of features are trained by the relevance vector machine framework, which outputs the probability of each candidate of the conflicted call. As a byproduct, it outputs the genotype of the candidate call with highest likelihood. We tested CIMerge on multiple datasets generated by different simulation configurations and compared it to several state-of-the-art approaches. The experiment results demonstrate that CIMerge outperforms the existing approaches. The average success rate of recognition is approaching 90%, while Pindel and Gindel are reported as 62.53% and 65.202%, respectively. The software package CIMerge is freely available for academic uses at https://github.com/xjtu712-lab/CIMerge. Citation Format: Tian Zheng, Yang Li, Yu Geng, Zhongmeng Zhao, Xuanping Zhang, Jiayin Wang. CIMerge: A machine learning approach for merging and genotyping complex indel calls from NGS data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5294.
EFFICACY OF HEMOSPRAY AND ENDOCLOT IN THE TREATMENT OF GASTROINTESTINAL BLEEDING: RESULTS FROM A TERTIARY REFERRAL CENTER
Authors: F Vitali, A Nägel, J Siebler, MF Neurath, T Rath
Journal: Endoscopy (2018)

Gastrointestinal (GI) bleeding frequently leads to hospital admission and is associated with relevant morbidity and mortality. Due to the increasing administration of direct oral anticoagulants and the emerging role of antiplatelet agents treatment of GI bleeding may be challenging. Hemostatic powders (HP) represent novel “touch-free” and easy to use items for the management of GI bleeding. Our aim was to analyze the short and long term success for achieving hemostasis with HP and to directly compare the two agents Hemospray (HS) and Endoclot (EC) in their hemostatic efficacy
Near-infrared light-triggered drug delivery system based on black phosphorus for in vivo bone regeneration
Authors: Xuzhu Wang, Jundong Shao, Mustafa Abd El Raouf, Hanhan Xie, Hao Huang, Huaiyu Wang, Paul K. Chu, Xue-Feng Yu, Yang Yang, AbdelBasit M. AbdEl-Aal, Nefissa H.M. Mekkawy, Richard J. Miron, Yufeng Zhang
Journal: Biomaterials (2018)
Hemoglobin E protects against acute Plasmodium vivax infections in a Kachin population at the China–Myanmar border
Authors: Zeshuai Deng, Qing Li, Haoan Yi, Yanjie Zhang, Fang Yang, Hong Li, Lan Luo, Limei Ma, Zhaoqing Yang, Yongshu He, Liwang Cui
Journal: Journal of Infection (2018)
Abstract 307: Targeting BCL-2 and BCL-xL with a novel dual inhibitor APG-1252 triggers cell death and inhibits tumor growth in small cell lung cancer models
Authors: GuangFeng Wang, Ping Min, MiaoYi Wu, Shuo Dang, ChuanYan Tang, Fei Zhang, Ming Guo, Shaomeng Wang, Jing Deng, Douglas D. Fang, DaJun Yang, YiFan Zhai
Journal: Cancer Research (2018)

Abstract Small cell lung cancer (SCLC) is one of the most deadly diseases with a dismal five year survival rate less than 7%. Even though most SCLC patients respond to the initial platinum-based cytotoxic or radiation therapies, they inevitably relapse and succumb to the disease. Anti-apoptotic proteins BCL-2 and BCL-xL, which are highly expressed in 40-60% of SCLCs and play a critical role in tumorigenesis and drug resistance, have been emerging as a promising target for therapeutic intervention. We have recently developed a novel dual BCL-2/BCL-xL inhibitor APG-1252 for cancer therapy. In this study, the effect of APG-1252 was evaluated in a panel of SCLC cell lines for discovery of indications and predictive biomarkers. The results show that the sensitivity of SCLC cell lines with sub-µM or nM IC50 values are correlated with the higher expression levels of BCL-2/BCL-xL, BIM and/or PUMA but lower levels of MCL-1. Conversely, the resistant cell lines either lack of BCL-2/BCL-xL protein, or exhibit higher level of MCL-1 protein. In xenograft tumor models, consistent with in vitro results, APG-1252 exhibits antitumor activities in the models derived from the sensitive cells but not in those from the resistant cells. Interestingly, while ABT-263 failed to inhibit H146 xenograft tumor growth, despite of its similar in vitro killing ability as APG-1252, APG-1252 showed potent antitumor activity in the xenograft model. To overcome the drug resistance conferred by MCL-1 in the resistant cells, we explore the combination therapy with other targeted agents. We found that our novel MDM2 inhibitor APG-115 was able to overcome the intrinsic resistance and sensitize those cells to APG-1252 in vitro, suggesting that reducing the apoptotic threshold by inhibiting other anti-death proteins like MCL-1 or increasing apoptotic function through p53 can enhance SCLC sensitivity to APG-1252. Collectively, APG-1252 represents a novel opportunity that can neutralize the protection from BCL-2/BCL-xL and trigger cell death and inhibit tumor growth in SCLC models. With the significance of these preclinical data, APG-1252 has been granted for phase 1 clinical trials in USA (NCT03080311) and China. Citation Format: GuangFeng Wang, Ping Min, MiaoYi Wu, Shuo Dang, ChuanYan Tang, Fei Zhang, Ming Guo, Shaomeng Wang, Jing Deng, Douglas D. Fang, DaJun Yang, YiFan Zhai. Targeting BCL-2 and BCL-xL with a novel dual inhibitor APG-1252 triggers cell death and inhibits tumor growth in small cell lung cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 307.
Metabolic Effects of a Chronic Dietary Exposure to a Low-Dose Pesticide Cocktail in Mice: Sexual Dimorphism and Role of the Constitutive Androstane Receptor
Authors: Céline Lukowicz, Sandrine Ellero-Simatos, Marion Régnier, Arnaud Polizzi, Frédéric Lasserre, Alexandra Montagner, Yannick Lippi, Emilien L. Jamin, Jean-François Martin, Claire Naylies, Cécile Canlet, Laurent Debrauwer, Justine Bertrand-Michel, Talal Al Saati, Vassilia Théodorou, Nicolas Loiseau, Laïla Mselli-Lakhal, Hervé Guillou, Laurence Gamet-Payrastre
Journal: Environmental Health Perspectives (2018)

Background: Epidemiological evidence suggests a link between pesticide exposure and the development of metabolic diseases. However, most experimental studies have evaluated the metabolic effects of pesticides using individual molecules, often at nonrelevant doses or in combination with other risk factors such as high-fat diets. Objectives: We aimed to evaluate, in mice, the metabolic consequences of chronic dietary exposure to a pesticide mixture at nontoxic doses, relevant to consumers' risk assessment. Methods: A mixture of six pesticides commonly used in France, i.e., boscalid, captan, chlorpyrifos, thiofanate, thiacloprid, and ziram, was incorporated in a standard chow at doses exposing mice to the tolerable daily intake (TDI) of each pesticide. Wild-type (WT) and constitutive androstane receptor–deficient (CAR−/−) male and female mice were exposed for 52 wk. We assessed metabolic parameters [body weight (BW), food and water consumption, glucose tolerance, urinary metabolome] throughout the experiment. At the end of the experiment, we evaluated liver metabolism (histology, transcriptomics, metabolomics, lipidomics) and pesticide detoxification using liquid chromatography–mass spectrometry (LC-MS). Results: Compared to those fed control chow, WT male mice fed pesticide chow had greater BW gain and more adiposity. Moreover, these WT males fed pesticide chow exhibited characteristics of hepatic steatosis and glucose intolerance, which were not observed in those fed control chow. WT exposed female mice exhibited fasting hyperglycemia, higher reduced glutathione (GSH):oxidized glutathione (GSSG) liver ratio and perturbations of gut microbiota–related urinary metabolites compared to WT mice fed control chow. When we performed these experiments on CAR−/− mice, pesticide-exposed CAR−/− males did not exhibit BW gain or changes in glucose metabolism compared to the CAR−/− males fed control chow. Moreover, CAR−/− females fed pesticide chow exhibited pesticide toxicity with higher BWs and mortality rate compared to the CAR−/− females fed control chow. Conclusions: To our knowledge, we are the first to demonstrate a sexually dimorphic obesogenic and diabetogenic effect of chronic dietary exposure to a common mixture of pesticides at TDI levels, and to provide evidence for a partial role for CAR in an in vivo mouse model. This raises questions about the relevance of TDI for individual pesticides when present in a mixture. https://doi.org/10.1289/EHP2877
Pathological assessment of resection specimens after neoadjuvant therapy for metastatic melanoma
Authors: M.T. Tetzlaff, J.L. Messina, J.E. Stein, X. Xu, R.N. Amaria, C.U. Blank, B.A. van de Wiel, P.M. Ferguson, R.V. Rawson, M.I. Ross, A.J. Spillane, J.E. Gershenwald, R.P.M. Saw, A.C.J. van Akkooi, W.J. van Houdt, T.C. Mitchell, A.M. Menzies, G.V. Long, J.A. Wargo, M.A. Davies, V.G. Prieto, J.M. Taube, R.A. Scolyer
Journal: Annals of Oncology (2018)

Clinical trials have recently evaluated safety and efficacy of neoadjuvant therapy among patients with surgically resectable regional melanoma metastases. To capture informative prognostic data connected to pathological response in such trials, it is critical to standardize pathologic assessment and reporting of tumor response after this treatment.The International Neoadjuvant Melanoma Consortium meetings in 2016 and 2017 assembled pathologists from academic centers to develop consensus guidelines for pathologic examination and reporting of surgical specimens from AJCC (8th edition) stage IIIB/C/D or oligometastatic stage IV melanoma patients treated with neoadjuvant-targeted or immune therapy. Patterns of pathologic response are provided context to inform these guidelines.Based on our collective experience and guided by efforts in well-established neoadjuvant settings like breast cancer, procedures directing handling of pre- and post-neoadjuvant therapy-treated melanoma specimens are provided to facilitate comparison of findings across different trials and centers. Definitions of pathologic response are provided together with guidelines for reporting and quantifying the extent of pathologic response. Finally, the spectrum of histopathologic responses observed following neoadjuvant-targeted and immune-checkpoint therapy is described and illustrated.Standardizing pathologic evaluation of resected melanoma metastases following neoadjuvant-targeted or immune-checkpoint therapy allows more robust stratification of patient outcomes. This includes recognizing the spectrum of histopathologic response patterns to neoadjuvant therapy and a standard approach to grading pathologic responses. Such an approach will facilitate comparison of results across clinical trials and inform ongoing correlative studies into the mechanisms of response and resistance to agents applied in the neoadjuvant setting.
Abstract 4163: Space radiation-induced persistent DNA damage and alterations in cytoskeletal remodeling pathways affect intestinal epithelial cell migration in mice
Authors: Santosh Kumar, Shubhankar Suman, Albert Fornace, Kamal Datta
Journal: Cancer Research (2018)

Abstract Lombardi Comprehensive Cancer Center, and Department of Biochemistry and Molecular &amp; Cellular Biology Georgetown University, Washington, DC 20057, USA. Heavy ion space radiation is considered as a risk factor of gastrointestinal (GI) cancer and perturbed intestinal epithelial cell (IEC) migration has been implicated in GI carcinogenesis. The purpose of the current study was to assess rate of IEC migration as well as dissect key IEC migration signaling events after exposure to heavy ion 56Fe irradiation and compare the results to sham- and γ-irradiation. Male C57BL/6J mice were exposed to 0.5 Gy of either γ or 56Fe radiation and control mice were sham irradiated. IEC migration distance was measured 7 and 60 d after exposure using BrdU pulse labeling. We also analyzed cell polarity, microtubule dynamics, and adhesion dynamics using immunoblots and immunofluorescence. Measure of IEC migration rate showed a greater decrease after 56Fe relative to γ radiation at both the time points. At the molecular level, compared to sham and γ radiation, 56Fe radiation exhibited significantly greater impairment of cell adhesion dynamics evidenced by altered integrins and Rock1 as well as cytoskeletal dynamics evidenced by altered MLCK expression. Similarly, perturbed cell polarity, tight junction, and microtubule dynamics was revealed by the deregulation of Par3, Claudin1, Scribble, Occludin, ZO-1, phospho-Tau and MAP1B. Also, the Wnt/β-catenin and EphB/EphrinB pathways critical for IEC migration consistently showed greater deregulation at both the time points tested after 56Fe radiation relative to γ -rays. Taken together, our molecular findings correlate with the BrdU pulse labeling data, and demonstrate greater effects of heavy ion 56Fe on IEC migration relative to γ -rays. In summary, our results have demonstrated for the first time that radiation can disrupt cell migration dynamics through alteration of signaling molecules involved in crucial cellular processes and these results have implications for heavy ion space radiation-induced gastrointestinal homeostatic deregulation and carcinogenesis. Citation Format: Santosh Kumar, Shubhankar Suman, Albert Fornace, Kamal Datta. Space radiation-induced persistent DNA damage and alterations in cytoskeletal remodeling pathways affect intestinal epithelial cell migration in mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4163.