tbuckley/cabot-search huggingface dataset:
Abstract LB-398: DNA-PKcs protects irradiated cells from persistent DNA damage signaling and accelerated senescence
Authors: Yue Liu, Elena V. Efimova, Aishwarya Ramamurthy, Stephen J. Kron
Journal: Cancer Research (2018)

Abstract The DNA-dependent protein kinase catalytic subunit DNA-PKcs has long been considered as a promising target in cancer, based on its roles in DNA damage response and the potential for inhibitors to enhance sensitivity to genotoxic therapy. Multiple investigational DNA-PK inhibitors remain under evaluation, though several have failed in development and none have reached the clinic. DNA-PKcs has been assigned diverse roles in DNA damage response that overlap with ATM including direct phosphorylation of H2AX to form γH2AX and promoting double-strand break (DSB) repair by conventional non-homologous end-joining (NHEJ). Nonetheless, a recent report implicated DNA-PKcs as a negative regulator of ATM. This may resolve the paradox that while ATM inhibitors block H2AX phosphorylation, prevent ionizing radiation induced foci (IRIF) formation and suppress terminal arrest and onset of cellular senescence, DNA-PK inhibitors induce persistent γH2AX, delay IRIF resolution and promote senescence. Toward better defining DNA-PKcs roles in radiation response, we examined MCF7 mammary carcinoma cells for effects of DNA-PKcs shRNA knockdown or treatment with specific inhibitors on DNA damage response and senescence after irradiation. We confirmed a requirement for DNA-PK in resolution of γH2AX and IRIF by 24 h after irradiation. Rather than return to proliferation, surviving cells with DNA-PK defects developed characteristic features of senescence within five days in culture. To examine if this effect of DNA-PKcs inhibition was mediated by blocking DSB repair, we irradiated MCF7 cell lines expressing shRNAs targeting NHEJ factors Ku70, Ku80, XLF, XRCC4, PAXX, and LIG4 as well as scrambled control in the presence or absence of DNA-PKcs inhibitor NU7441. Strikingly, IRIF resolution at 24 h was similar to control in cell lines lacking NHEJ factors while NU7441 increased IRIF persistence and enhanced senescence in all cell lines. These results suggest that a critical role for DNA-PKcs in radiation response is to attenuate DNA damage signaling and prevent cellular senescence. Treating irradiated DNA-PKcs knockdown cells with the ATM inhibitor KU55933 at 24 h resolved persistent γH2AX and IRIF and blocked senescence. Taken together, our data demonstrate that DNA-PKcs regulates IRIF resolution and cell senescence by targeting ATM functions rather than directly affecting DSB repair. Citation Format: Yue Liu, Elena V. Efimova, Aishwarya Ramamurthy, Stephen J. Kron. DNA-PKcs protects irradiated cells from persistent DNA damage signaling and accelerated senescence [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 LB-398.
Abstract 33: Calsequestrin 2 regulates proliferation, migration, and invasion in triple-negative breast cancer cells
Authors: Ju Hee Kim, Bok sil Hong, Woohang Heo, Jong Min Han, Wonsik Han, Dong-Young Noh, Hyeong-Gon Moon
Journal: Cancer Research (2018)

Abstract Triple-negative breast cancer (TNBC) is the most heterogeneous and aggressive breast tumor subtype defined by absence of receptor for estrogen, progesterone, or HER2. However, the biologic mechanism for TNBC phenotype is still unclear. Here, we show that expression of Calsequestrin 2 (CASQ2), a Ca2+-binding protein, correlates with increase of proliferation, migration, and invasion, suggesting that intracellular Ca2+ may contribute to tumor growth and metastatic phenotype. CASQ2 is the main Ca2+-binding protein inside the sarcoplasmic reticulum of cardiomyocytes. CASQ2 forms a complex with ryodine receptor 2 (RyR2) luminal calcium release channel in cardiac muscle. Ca2+ is a sequestor and regulator of diverse cellular processes, and specific Ca2+ channels play important roles in cell proliferation and invasiveness of cancers. To know the role of CASQ2 TNBC cells, we established CASQ2-overexpressing stable cells in Hs578T (Hs578T-CASQ2) using retrovirus. Stimulation with caffeine triggered the remarkable increase of intracellular calcium in Hs578T-CASQ2 cells; in addition, the basal level of calcium in cells had much higher amount of Hs578T-CASQ2 than Hs578T. By contrast, calcium chelator BAPTM/AM blocked CASQ2-induced calcium release. Hs578T-CASQ2 cells showed higher level of proliferation, migration and invasion rate compared to Hs578T, which indicated that overexpression of CASQ2 related with cellular functions. We also found that CASQ2 overexpression elevates extracellular signal-related kinase (ERK) expression. In epidermal growth factor (EGF)-treated cells, Hs578T-CASQ2 cells had higher phosphorylated ERK compared to Hs578T, leading to the expression of epithelial-mesenchymal transition (EMT) marker, vimentin. These results indicate that CASQ2 overexpression increases the level of calcium and induces cell proliferation, migration and invasion through ERK signaling. Our findings from this study show a possible cause of migration and invasiveness in breast cancer cells. Taken together, these findings demonstrate that CASQ2 could be a new therapeutic target for breast cancer. Citation Format: Ju Hee Kim, Bok sil Hong, Woohang Heo, Jong Min Han, Wonsik Han, Dong-Young Noh, Hyeong-Gon Moon. Calsequestrin 2 regulates proliferation, migration, and invasion in triple-negative breast cancer cells [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 33.
TRPV4 Channel Signaling in Macrophages Promotes Gastrointestinal Motility via Direct Effects on Smooth Muscle Cells
Authors: Jialie Luo, Aihua Qian, Landon K. Oetjen, Weihua Yu, Pu Yang, Jing Feng, Zili Xie, Shenbin Liu, Shijin Yin, Dari Dryn, Jizhong Cheng, Terrence E. Riehl, Alexander V. Zholos, William F. Stenson, Brian S. Kim, Hongzhen Hu
Journal: Immunity (2018)
Abstract 20292: The Interaction Between Isolated Low High-Density Lipoprotein Cholesterol With Fitness and Mortality: The Henry Ford Exercise Testing Project (FIT Project)
Authors: Seamus Whelton, Zeina Dardari, Clinton Brawner, Jon Ehrman, Steve Keteyian, Mouaz Al Mallah, Michael Blaha
Journal: Circulation (2016)

Introduction: Isolated low high-density lipoprotein cholesterol (HDL-C) is associated with lower fitness and an increased risk of cardiovascular disease (CVD). Whether the association between isola...
Abstract 557A: The clinicopathoogical significance of FBXW7 expression in GIST
Authors: Yuki Koga, Masaaki Iwatsuki, Kouhei Yamashita, Yuki Kiyozumi, Hiroshi Sawayama, Yukiharu Hiyoshi, Yoshihfumi Baba, Yuji Miyamoto, Naoya Yoshida, Hideo Baba
Journal: Cancer Research (2018)

Abstract Objective: Gastrointestinal stromal tumor (GIST) is a rare mesenchymal tumor originated from the interstitial cells of Cajal in the gastrointestinal tract. A significant breakthrough was achieved with the identification of the expression of the c-kit (CD117) antigen in GISTs. However, alternate oncogenic pathways have not sufficiently been understood. FBXW7 is a ubiquitin ligase that mediates ubiquitylation of oncoproteins, which is known as tumor-suppressor gene in various malignancies. Previous reports showed that FBXW7 is associated with tumor progression by regulating some oncoprotein such as c-myc and c-jun. The aim of this study is to elucidate the clinicopathological significance of FBXW7 in GIST. Methodology: (i) We examined the FBXW7 expression in GIST cells by immunostaining and correlation clinicopathological characteristics. (ii) We examined cell proliferation by Cytotoxicity assays in GIST-T1 cells suppressed by FBXW7-specific siRNA. Results: (i) In 90 cases of GIST samples with surgical resection, high FBXW7 and observed are 47 cases and low expression are 43 cases. There are significantly more large size, located small intestine, high mitotic index in low FBXW7 cases (P=0.05, P=0.01, P=0.04). There are significantly more high risk cases in modified-Fletcher classification in low FBXW7 expression cases (P=0.0008). There are significantly higher value of SUV max in high risk cases of modified-Fletcher classification and low FBXW7 expression cases (P=0.007, P=0.02). In GIST cases with distant metastasis, there are significantly more low FBXW7 expression cases than GIST cases without distant metastasis (P=0.009). FBXW7 expression is significantly inversely correlated with C-MYC expression (P=0.0004). (ii) The GIST cells suppressed FBXW7 expression by siRNA have higher proliferation rate compared to control GIST cells (P=0.02). Conclusion: We demonstrated that FBXW7 expression is correlated with modified-Fletcher classification, SUV max value, c-myc expression and cell proliferation in GIST. These results are suggesting that FBXW7 may be associated with tumor progression. These findings suggest that it is possible that FBXW7 can be a promising biomarker for disease progression of GIST. Citation Format: Yuki Koga, Masaaki Iwatsuki, Kouhei Yamashita, Yuki Kiyozumi, Hiroshi Sawayama, Yukiharu Hiyoshi, Yoshihfumi Baba, Yuji Miyamoto, Naoya Yoshida, Hideo Baba. The clinicopathoogical significance of FBXW7 expression in GIST [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 557A.
Docetaxel, cisplatin, and fluorouracil chemotherapy for metastatic or unresectable locally recurrent anal squamous cell carcinoma (Epitopes-HPV02): a multicentre, single-arm, phase 2 study
Authors: Stefano Kim, Eric François, Thierry André, Emmanuelle Samalin, Marine Jary, Farid El Hajbi, Nabil Baba-Hamed, Simon Pernot, Marie-Christine Kaminsky, Olivier Bouché, Jérôme Desrame, Mustapha Zoubir, François Ghiringhelli, Aurélie Parzy, Christelle De La Fouchardiere, Denis Smith, Mélanie Deberne, Laurie Spehner, Nicolas Badet, Olivier Adotevi, Amélie Anota, Aurélia Meurisse, Dewi Vernerey, Julien Taieb, Véronique Vendrely, Bruno Buecher, Christophe Borg
Journal: The Lancet Oncology (2018)
Abstract 14503: Loss of Wnt5a Disrupts Endothelial-Pericyte Interaction During Pulmonary Angiogenesis
Authors: Ke Yuan, Mark Orcholski, Elya Shamskhou, Marielle Discipulo, Vinicio de Jesus Perez
Journal: Circulation (2016)

Introduction: Pulmonary arterial hypertension (PAH) is a life-threatening disorder characterized by impaired angiogenesis, progressive small vessel loss and occlusive vasculopathy. Pericyte recruit...
In vitro 3D blood/lymph-vascularized human stromal tissues for preclinical assays of cancer metastasis
Authors: Akihiro Nishiguchi, Michiya Matsusaki, Mitsunobu R. Kano, Hiroshi Nishihara, Daisuke Okano, Yoshiya Asano, Hiroshi Shimoda, Satoko Kishimoto, Soichi Iwai, Mitsuru Akashi
Journal: Biomaterials (2018)
Epidemic Thunderstorm Asthma Protection with Five-Grass Pollen Tablet Sublingual Immunotherapy: A Clinical Trial
Authors: Robyn E. O’Hehir, Nirupama P. Varese, Kirsten Deckert, Celia M. Zubrinich, Menno C. van Zelm, Jennifer M. Rolland, Mark Hew
Journal: American Journal of Respiratory and Critical Care Medicine (2018)
Abstract 19865: Exploring miRNA-mRNA Regulatory Network in Cardiac Pathology of Na+/H+ Exchanger Isoform 1 Transgenic Mouse Hearts
Authors: Jin Xue, Dan Zhou, Iain Hartley, Orit Poulsen, Gabriel G Haddad
Journal: Circulation (2016)

Numerous studies have demonstrated that elevated activity of Na + /H +  exchanger isoform 1 (NHE1) in myocardial diseases is detrimental. To better understand the involvement of NHE1, cardiac-specific NHE1 transgenic mice with overexpression of a constitutively active NHE1 allele were studied. We have previously shown that NHE1 transgenic mice develop cardiac hypertrophy, interstitial fibrosis as well as depressed cardiac function (Xue 2010). The purpose of the current study was to identify microRNAs (miRNAs) and their mRNA targets involved in NHE1-mediated cardiac injury. An un-biased high throughput sequencing study was performed on both miRNAs and mRNAs. RNA sequencing showed that differentially-expressed genes were enriched in hypertrophic/dilated cardiomyopathy (HCM/DCM) pathways by Kyoto Encyclopedia of Genes and Genomes (KEGG) annotation in NHE1 transgenic hearts. These genes were classified as contraction defects (e.g. Myl2, Myh6, Mybpc3 and Actb), impaired intracellular Ca 2+  homeostasis (e.g. SERCA2a, Ryr2, Rcan1 and CaMKII delta) and signaling molecules that cause HCM and DCM (e.g. Itga/b, IGF-1, Tgfb2/3 and Prkaa1/2). miRNA sequencing revealed that fifteen miRNAs were differentially-expressed (2 fold, P
Abstract 5645: Critical variables to reduce Western blot variability
Authors: Russ Yukhananov, Alex Margulis
Journal: Cancer Research (2018)

Abstract Reliable immunodetection of proteins is a critical step in the discovery of new biomarkers and diagnostic. The immunodetection protocol consists of multiple steps including blocking of nonspecific binding sites, incubation using primary and secondary antibodies and extensive washing between steps that easily introduce bias and errors. The quality and reproducibility of results depends on multiple subjective and objective factors such as the qualification and technical skills of the personnel performing the assay and the accuracy of temporal and temperature control, especially during the immunodetection step. BlotCycler™, automated western blot processor, use fluidic control system that allows to eliminate the variability associated with immunodetection and to achieve higher sensitivity by optimized washing procedure. We used BlotCycler to analyze critical source of errors during immunodetection. Relatively small changes in duration and temperature of incubation significantly affect not only the intensity of signal but also the specificity of antibody interaction with antigen. Automated immunodetection at 4ºC significantly improve the specificity of detection and sensitivity that allows reproducible detection of low expressing proteins. Automated processing using BlotCycler allows optimization and control of critical variables leading to improved reproducibility and specificity of immunodetection and should be routinely used for new biomarker discovery and diagnostics, reliable protein quantification, primary antibody specificity testing, and optimization of primary and secondary antibodies concentrations. Citation Format: Russ Yukhananov, Alex Margulis. Critical variables to reduce Western blot variability [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 5645.
Abstract 2108: Detection and molecular profiling of leptomeningeal disease in melanoma
Authors: Inna Smalley, Brittany Evernden, Vincent Law, Rajappa Kenchappa, John Puskas, Elena Ryzhova, Nam Tran, Arnold Etame, Solmaz Sahebjam, Anthony Magliocco, Peter Forsyth, Keiran S. Smalley
Journal: Cancer Research (2018)

Abstract Approximately 5% of melanoma patients develop leptomeningeal disease (LMDz), a highly symptomatic complication with a dismal survival of 8-10 weeks. The aim of this study was to determine whether diagnosis and personalized treatment for melanoma-LMDz could be improved by assessing patient-derived cerebrospinal fluid (CSF) specimens. Circulating tumor cells in CSF (CSF-CTCs) were detected by Veridex CellSearch® System and the circulating melanoma cell kit, based on anti-CD146 and anti-high molecular weight melanoma associated antigen (HMW-MAA-PE (MEL-PE)). Of the 12 patients with definitive LMDz diagnosis, all but 1 patient (92%) had CSF-CTCs (range 23-3055 CTCs/ml). In contrast, only 3/8 (37%) melanoma patients without LMDz diagnosis had CSF-CTCs detected, with significantly lower CTC counts per ml CSF (range 0.13-0.6 CTCs/ml). Ex vivo studies of CSF uncovered that although patient-derived CSF does not appear to act as a chemo-attractant or a stimulant of invasion to initiate melanoma migration to the leptomeninges, it significantly reduced the ability of BRAF inhibitors to induce apoptosis in established melanoma cell lines (p&amp;lt;0.005). Patient-derived CSF composition is complex but includes many growth factors and mediators of adhesion and TGFβ signaling. In melanoma cells, the CSF stimulated signaling through mTOR/AKT and STAT. BRAF inhibition amplified these signals further. We show that ex vivo expansion of isolated CSF-CTCs is possible for ~25% of samples, in the presence of FBS, FGF and EGF. At this time, there is a very limited understanding of the mechanisms underlying melanoma metastasis to the leptomeninges, a truly devastating and rapidly terminal complication of melanoma. This is the first report of patient-derived CSF eliciting a protective effect in melanoma cells, suggesting melanoma cells find a protective niche in the central nervous system. Furthermore, we demonstrate that patient-derived CSF biopsies serve as a critical tool for improving diagnosis and personalized treatment for melanoma-LMDz patients. Citation Format: Inna Smalley, Brittany Evernden, Vincent Law, Rajappa Kenchappa, John Puskas, Elena Ryzhova, Nam Tran, Arnold Etame, Solmaz Sahebjam, Anthony Magliocco, Peter Forsyth, Keiran S. Smalley. Detection and molecular profiling of leptomeningeal disease in melanoma [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 2108.
Abstract 1514: Role of polycomb proteins in neuroendocrine prostate cancer
Authors: Zachary Connelly, Shu Yang, Anthony Blankenship, Xiuping Yu
Journal: Cancer Research (2018)

Abstract Prostate cancer (PCa) is the most common non-skin cancer and the 3rd leading cause of cancer-related death in American men. Androgen ablation therapy has been the gold standard for treating advanced stage PCa since the 1960s. Initially, the PCa patients respond to hormone ablation very positively. However, over time these tumors almost always become resistant to androgen ablation therapy, and tumors begin to grow again. Recent studies found after failure of the new drugs that block androgen action, PCa has increased neuroendocrine phenotype. Understanding the mechanisms through which PCa cells gain neuroendocrine phenotype is critical for the development of novel therapeutics. Polycomb repressive complex are involved in early embryo development and carcinogenesis in several types of cancer including PCa. In this study, we evaluated the involvement of Polycomb proteins in neuroendocrine PCa. Using immunohistochemistry staining, we examined the expression of Polycomb protein EZH2 in advanced stage PCa. We found that EZH2 is highly expressed in both human and mouse neuroendocrine PCa. Also, we found when PCa cells are induced to undergo neuroendocrine differentiation, multiple Polycomb genes are induced. These data suggest that Polycomb genes play a role in the development of neuroendocrine PCa. Citation Format: Zachary Connelly, Shu Yang, Anthony Blankenship, Xiuping Yu. Role of polycomb proteins in neuroendocrine prostate 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 1514.
Bedaquiline and Repurposed Drugs for Fluoroquinolone-Resistant Multidrug-Resistant Tuberculosis: How Much Better Are They?
Authors: Mathieu Bastard, Lorenzo Guglielmetti, Helena Huerga, Armen Hayrapetyan, Naira Khachatryan, Lusine Yegiazaryan, Jamil Faqirzai, Lana Hovhannisyan, Francis Varaine, Catherine Hewison
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.
Parkinson's disease-associated protein Parkin: an unusual player in cancer
Authors: Juan Liu, Cen Zhang, Wenwei Hu, Zhaohui Feng
Journal: Cancer Communications (2018)

The mutation of the Parkin gene is a cause of familial Parkinson's disease. A growing body of evidence suggests that Parkin also functions as a tumor suppressor. Parkin is an ubiquitin E3 ligase, and plays important roles in a variety of cellular processes implicated in tumorigenesis, including cell cycle, cell proliferation, apoptosis, metastasis, mitophagy and metabolic reprogramming. Here we review the role and mechanism of Parkin in cancer.
Preventive healthcare strategies are a matter of social justice
Authors: Peter Chisholm, Vikas Wadhwa
Journal: BMJ (2018)

Targeted, early, and preventive interventions are paramount in tackling the marked disparities in healthcare outcomes and should be prioritised by society and government.1 Socioeconomic determinants of health should be considered in everyday acute care encounters as they have major effects on healthcare use, cost, and clinical outcomes. Social gradients exist in …
Abstract 3762: Novel RORγt agonist induces antitumor immune effect through enhancement of tumor antigen-specific CD8+ T-cell infiltration into the TME
Authors: Pankaj Gaur, Vivek Verma, Rahul Nandre, Pooja Vir, Hua Wang, Baolin Kang, Laura Carter, Xiao Hu, Xikui Liu, Seema Gupta, Samir Khleif
Journal: Cancer Research (2018)

Abstract RORγt is a master transcription factor, which regulates the proliferation and functionality of Type 17 T-cells (TH17 and Tc17). Recent nonclinical studies have shown that in addition to promoting effector differentiation, stemness and plasticity, RORγt also inhibits Treg differentiation, an important component of suppressive tumor microenvironment (TME). Therefore, stimulation of RORγt by synthetic, small-molecule agonists holds promise as an immunotherapy. We tested the effects of a RORγ agonist (LYC-54143; 100 mg/kg BID given continuously till the end of study) on the tumor growth and survival in mice in combination with a tumor antigen-specific vaccine (3 doses, one week apart), which is required for proper priming in this model. We found that the RORγ agonist resulted in a highly significant enhancement of the antitumor effect delaying the tumor growth (p≤0.001 at day 21 compared to vaccine alone treatment) and prolonging survival. At day 36 after tumor implantation, 80% of mice survived in the RORγ agonist + vaccine treatment group compared to 0% survival following RORγ agonist or vaccine alone treatments. Immunologically, we found that RORγ agonist treatment led to a significant decrease in the numbers of Tregs and a significant increase in IL-17+ IFNγ+ T cells in the TME. Moreover, RORγ agonist treatment led to a significant increase in the numbers of T cells including increased antigen-specific CD8+ T-cells in the TME. Interestingly, scheduling RORγ agonist before or with the vaccine demonstrated comparable antitumor activity, suggesting that the scheduling of RORγ agonist treatment does not affect the therapeutic outcomes. These results show that an RORγ agonist can enhance the antitumor immune response by enhancing effector functions and by decreasing immune suppression in the TME by increasing cytokine production and switching the differentiation of immune-suppressive Tregs to effector Th17 cells and support that RORγ agonists are promising immune-modulatory agents in cancer. Citation Format: Pankaj Gaur, Vivek Verma, Rahul Nandre, Pooja Vir, Hua Wang, Baolin Kang, Laura Carter, Xiao Hu, Xikui Liu, Seema Gupta, Samir Khleif. Novel RORγt agonist induces antitumor immune effect through enhancement of tumor antigen-specific CD8+ T-cell infiltration into the TME [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 3762.