tbuckley/cabot-search huggingface dataset:
Abstract 415: <i>In vivo</i> shRNA library screening to identify novel targets for head and neck squamous cell carcinoma
Authors: Curtis R. Pickering, Tongxin Xie, Manish Kumar, Ramya L. Parimi, Liang P. Yang, Jiping Wang, Sahil Seth, Christopher A. Bristow, Alessandro Carugo, Frederick S. Robinson, Giulio F. Draetta, Heath Skinner, Mitchell J. Frederick, Jeffrey N. Myers
Journal: Cancer Research (2017)

Abstract Head and neck squamous cell carcinoma (HNSCC) is a diverse group of tumors from the upper aerodigestive tract that are treated primarily with surgery, chemotherapy, and/or radiation. Recent genomic studies have characterized the genomic alterations in HNSCC but they failed to identify novel oncogenic drivers for therapeutic targeting. In order to identify novel targets we have utilized an in vivo shRNA library screening platform in a panel of genomically characterized HNSCC cell lines. The screens were performed alone or in combination with platinum-based chemotherapy or radiation, and the screening libraries included known druggable targets, DNA repair genes, and HNSCC candidate driver genes. Initial results indicate that this in vivo screening is able to identify targets that may not be found through traditional in vitro screening approaches and related to tumor-stromal interactions and metabolism. These genes emphasize the importance of including the tumor microenvironment in studies to understand driver genes and identify novel therapeutic interventions. Citation Format: Curtis R. Pickering, Tongxin Xie, Manish Kumar, Ramya L. Parimi, Liang P. Yang, Jiping Wang, Sahil Seth, Christopher A. Bristow, Alessandro Carugo, Frederick S. Robinson, Giulio F. Draetta, Heath Skinner, Mitchell J. Frederick, Jeffrey N. Myers. In vivo shRNA library screening to identify novel targets for head and neck 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 415. doi:10.1158/1538-7445.AM2017-415
Abstract 188: Atrial Tachyarrhythmia in Rgs5-Null Mice
Authors: Mu Qin, Teng Wang, He Hu, Yu Liu, He Huang, Hong L Li, Cong X Huang
Journal: Circulation Research (2012)

Abstract Aims The aim of this study was to elucidate the effects of regulator of G-protein signaling 5 (Rgs5), a negative regulator of G protein-mediated signaling, on atrial repolarization and tachyarrhythmia (ATA) in mice. Methods and Results In present study, the incidence of ATA were increased in isolated mouse Rgs5 -/- hearts during program electrical stimulation (PES) (46.7%, 7 of 15) and burst pacing (26.7%, 4 of 15) compared with wild-type (WT) mice (PES: 7.1%,1 of 14; burst:7.1%,1 of 14) (P&lt;0.05). And the duration of ATA also shown longer in Rgs5 [[Unable to Display Character: + ]]/- heart than that in WT, 2 out of 15 hearts exhibited sustained ATA (&gt;30s) but none of them observed in WT mice. Atrial prolonged repolarization was observed in Rgs5 -/- hearts including widened P wave in surface ECG recording, increased action potential duration (APD) and atrial effective refractory periods (AERP), all of them showed significant difference with WT mice (P&lt;0.05). At the cellular level, whole-cell patch clamp recorded markedly increased densities of repolarizing K + currents including I Kur (at + 60mV: 14.0 ± 2.2 pF/pA) and I to (at + 60mV: 16.7±1.3 pA/pF) in Rgs5 -/- atrial cardiomyocytes, compared to those of WT mice (at + 60mV I to : 20.4 ± 2.0 pA/pF; I kur : 17.9 ± 2.0 pF/pA) (P&lt;0.05). Conclusion These results suggest that Rgs5 is an important regulator of arrhythmogenesis in the mouse atrium and that the enhanced susceptibility to atrial tachyarrhythmias in Rgs5 -/- mice may contribute to abnormalities of atrial repolarization.
Meningitis Outbreak Caused by Vaccine-Preventable Bacterial Pathogens — Northern Ghana, 2016
Authors: Fortress Y. Aku, Fernanda C. Lessa, Franklin Asiedu-Bekoe, Phoebe Balagumyetime, Winfred Ofosu, Jennifer Farrar, Mahamoudou Ouattara, Jeni T. Vuong, Kofi Issah, Joseph Opare, Sally-Ann Ohene, Charles Okot, Ernest Kenu, Donne K. Ameme, David Opare, Abass Abdul-Karim
Journal: MMWR Morbidity and Mortality Weekly Report (2017)

Bacterial meningitis is a severe, acute infection of the fluid surrounding the brain and spinal cord that can rapidly lead to death. Even with recommended antibiotic treatment, up to 25% of infected persons in Africa might experience neurologic sequelae (1). Three regions in northern Ghana (Upper East, Northern, and Upper West), located in the sub-Saharan "meningitis belt" that extends from Senegal to Ethiopia, experienced periodic outbreaks of meningitis before introduction of serogroup A meningococcal conjugate vaccine (MenAfriVac) in 2012 (2,3). During December 9, 2015-February 16, 2016, a total of 432 suspected meningitis cases were reported to health authorities in these three regions. The Ghana Ministry of Health, with assistance from CDC and other partners, tested cerebrospinal fluid (CSF) specimens from 286 patients. In the first 4 weeks of the outbreak, a high percentage of cases were caused by Streptococcus pneumoniae; followed by an increase in cases caused by Neisseria meningitidis, predominantly serogroup W. These data facilitated Ghana's request to the International Coordinating Group* for meningococcal polysaccharide ACW vaccine, which was delivered to persons in the most affected districts. Rapid identification of the etiologic agent causing meningitis outbreaks is critical to inform targeted public health and clinical interventions, including vaccination, clinical management, and contact precautions.
Abstract 3433: Epigenetic silencing of miR-214-3p is associated with resistance to p53-induced apoptosis through up-regulation of gankyrin expression in hepatocellular carcinoma
Authors: Kohichiroh Yasui, Naoto Iwai, Kei Terasaki, Yasuyuki Gen, Yoshito Itoh
Journal: Cancer Research (2017)

Abstract Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide. MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression and can act as tumor suppressors or oncogenes. To identify miRNA involved in the development of HCC, a genome-wide miRNA gene expression analysis was performed using the human miRNA microarray (Agilent) in paired HCC tumors and non-tumorous liver tissues from patients with primary HCC. The array-based miRNA expression profiles were validated by quantitative PCR. We also screened for genes with promoter DNA hypermethylation using a genome-wide DNA methylation microarray analysis (the Illumina HumanMethylation27 BeadChip) in the same samples. We found that miR-214-3p were significantly down-regulated by aberrant promoter hypermethylation in HCC tumors compared to the non-tumorous liver tissues. We identified PSMD10, which encodes gankyrin, as a direct target of miR-214-3p using luciferase assay and immunoblotting. Gankyrin, an oncoprotein commonly overexpressed in HCC, binds to MDM2, a major E3 ubiquitin ligase for p53, and increases ubiquitylation and degradation of p53. Our experiments showed that reduced miR-214-3p expression was associated with resistance to p53-induced apoptosis through up-regulation of gankyrin expression in HCC cells. In conclusion, our results suggest that epigenetic silencing of tumor suppressor miR-214-3p is involved in hepatocarcinogenesis through up-regulation of gankyrin expression. Citation Format: Kohichiroh Yasui, Naoto Iwai, Kei Terasaki, Yasuyuki Gen, Yoshito Itoh. Epigenetic silencing of miR-214-3p is associated with resistance to p53-induced apoptosis through up-regulation of gankyrin expression in hepatocellular 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 3433. doi:10.1158/1538-7445.AM2017-3433
The unexpected intelligence: what is the naked mole–rat’s secret to surviving oxygen deprivation?
Authors: Senka Ljubojevic-Holzer
Journal: Cardiovascular Research (2017)

Commentary on 'Fructose-driven glycolysis supports anoxia resistance in the naked mole-rat' by Park et al., Science, 2017. 1 At low levels of oxygen (hypoxia), the stressed heart makes a variety of adjustments to maintain the supply of oxygen and nutrients to metabolically active tissues.These adjustments involve rapid and slower responses, such as coronary vasodilatation and altered patterns of gene expression, respectively. 2In an oxygen-deprived atmosphere (anoxia), however, survival depends on immediate rewiring of cellular metabolism to win time until the oxygen supply is stored. 3Under anoxia, the energycarrying molecule adenosine triphosphate (ATP) can only be produced by anaerobic metabolism, a process that yields <10% of oxidative ATP production.Due to the high energy demand of the heart, its stock of ATP is depleted within minutes under anoxic conditions, causing the loss of ionic gradients, cell membrane excitability and contractility of cardiomyocytes.Consequently, humans, like most mammals, can survive for no more than few minutes when deprived of oxygen due to myocardial and brain ischaemia, two major causes of death worldwide.Park et al. recently identified a rare example of anoxia tolerance among mammals-the naked mole-rat (Heterocephalus glaber). 1 Residing in their subterranean burrow systems, naked mole-rats developed the ability to cope with an atmosphere of extremely low oxygen and high carbon dioxide.The authors showed that naked mole-rats can tolerate an atmosphere of 5% oxygen for 5 h without apparent detrimental effects, whereas mice (Mus musculus) died in <15 min.During anoxia, both mice and naked mole-rats rapidly lost consciousness.However, while mice could not be resuscitated even when re-exposed
Abstract 4069: Trimethylation and acetylation of Histone H3K27 modulates 5-fluorouracil response by regulating DPYD expression
Authors: Rentian Wu, Qian Nie, Erin E. Tapper, Calvin R. Jerde, Steven M. Offer, Robert B. Diasio
Journal: Cancer Research (2017)

Abstract The antimetabolite 5-fluorouracil (5-FU) is one of the most widely used chemotherapy drugs. Dihydropyrimidine dehydrogenase (DPD) initiates the catabolic degradation of 5-FU to inactive metabolites and is widely accepted as a major determinant of 5-FU response and toxicity. While genetic variants in DPYD have been shown to variants may affect 5-FU metabolism, they are rare events and do not completely explain the reported variability in DPD function or the resultant differences in treatment response. Here, we report that DPYD expression is epigenetically regulated by histone modification at relevant promoter and enhancer regions. Using both chemical inhibitors and genetic approaches, we show that that H3K27 tri-methylation (H3K27me3) at the DPYD promoter is regulated by the epigenetic modifiers Ezh2 and UTX. Promoter H3K27me3 suppresses DPYD expression by inhibiting the binding of the transcription factor PU.1 bindingto the promoter and ,increases sensitivity leading to increased resistance to 5-FU. In a cohort of healthy volunteers, H3K27me3 levels were inversely correlated with An enhancer that regulates DPYD expression was also identified. Modifying the H3K27 status of the DPYD promoter or enhancer modulates DPYD gene expression. Deletions and mutations on the DPYD promoter or enhancer abolish their transcription regulation function. Enrichment of H3K27me3 at the DPYD promoter was negatively correlated with both DPYD expression and DPD enzyme activity in peripheral blood mononuclear cellsspecimens from healthy volunteers. Lastly, tumor expression data suggests that DPYD repression by Ezh2 is a strong predictor ofs poor survival in 5-FU treated cancers. By using a combination of in silico prediction and in vitro reporter assays we also identified a functional enhancer region for DPYD that is also likely to be clinically relevant to 5-FU treatment outcome. Collectively, the presentthese findings suggest that a previously uncharacterized mechanisms regulates DPD expression and may likely contribute to tumor resistance to 5-FU. Citation Format: Rentian Wu, Qian Nie, Erin E. Tapper, Calvin R. Jerde, Steven M. Offer, Robert B. Diasio. Trimethylation and acetylation of Histone H3K27 modulates 5-fluorouracil response by regulating DPYD expression [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 4069. doi:10.1158/1538-7445.AM2017-4069
Abstract 5416: Downregulation of PRMT6 promotes the Warburg effect in hepatocellular carcinoma via PKM2
Authors: Tin Lok Wong, Lok Hei Chan, Stephanie Ma
Journal: Cancer Research (2017)

Abstract Hepatocellular carcinoma (HCC) is one of the top ranked causes of cancer death in the world, accounting for more than 740,000 deaths in 2012. Treatment of HCC is hindered by recurrence and resistance to chemotherapy. Altered metabolism in cancer has been linked to increased tumorigenicity and resistance to chemotherapeutics. One of the main features of altered metabolism is the Warburg effect, which is widely observed in solid tumor including HCC. Recently, our group have identified protein arginine methyltransferase 6 (PRMT6) as a tumor suppressor protein in HCC. Protein arginine methylation is a post-translational modification implicated in a variety of cellular functions including signaling and regulation of gene expression.Downregulation of PRMT6 expression was observed in HCC patients and knockdown of PRMT6 in HCC cell lines increased the tumorigenicity and sensitivity to both chemo- and molecular-targeted therapies. Other members of the Type 1 PRMT protein has previously been reported to be involved in glucose metabolism. Microarray profiling of HCC cells stably knockdown and overexpressed of PRMT6 showed enrichment of genes in glycolysis. We therefore hypothesize that reduced expression of PRMT6 in HCC drives the Warburg effect to support cancer progression. Metabolome profiling of HCC cells stably knockdown and overexpressed of PRMT6 showed enrichment of metabolites in glycolysis. Using Seahorse Extracellular Flux Analyzer, we show that stable knockdown of PRMT6 in HCC cell line drives glycolysis. This enhanced glycolysis rate is coupled with increased uptake of glucose, lactate production and pyruvate kinase activity. mRNA expression level of several glycolysis-related genes was screened by real-time quantitative PCR and we identified PKM2, a well-known regulator of the Warburg effect, as a potential link between PRMT6 and enhanced glycolysis. Knockdown of PRMT6 leads to an increase in mRNA and protein expression level of PKM2, but not PKM1 and PKLR, suggesting that PKM2 is the sole contributor for enhanced pyruvate kinase activity. In addition, by immunofluorescence staining, PKM2 is shown to accumulate in the nucleus following PRMT6 knockdown, where it has been shown to drive the expression of other glycolysis-related genes. In conclusion, PRMT6 regulates the expression level PKM2 and glycolysis of HCC cell. Ongoing studies are in progress to delineate the underlying mechanisms by which PRMT6 regulates PKM2 to drive Warburg effect. Citation Format: Tin Lok Wong, Lok Hei Chan, Stephanie Ma. Downregulation of PRMT6 promotes the Warburg effect in hepatocellular carcinoma via PKM2 [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 5416. doi:10.1158/1538-7445.AM2017-5416
Abstract 3159: Lysosomal membrane permeabilization as potential mediator of resistance in pancreatic neuroendocrine tumors
Authors: Tabea Wiedmer, Rasmus M. Frank, Mario P. Tschan, Aurel Perren, Ilaria Marinoni
Journal: Cancer Research (2017)

Abstract Sunitinib, an anti-angiogenic tyrosine kinase inhibitor, is approved for treatment of pancreatic neuroendocrine tumors (pNETs). However, its efficacy is greatly limited due to resistance. Sunitinib is a lysosomotropic drug, thus accumulates in lysosomes, leading to their destabilization and to lysosomal membrane permeabilization (LMP), which in turn can lead to cell death. Autophagy might be activated for clearance of damaged lysosomes, thus promote survival and act as a mechanism of resistance. We found that the autophagy inhibitor chloroquine increases sunitinib efficacy in pNET cell lines and in a transgenic mouse model of pNETs. Interestingly, chloroquine is a lysosomotropic drug as well and the response towards sunitinib and chloroquine in pNET cell lines correlated with lysosome-associated membrane protein 2 (LAMP2) levels, which influence lysosome stability. We hypothesized that sunitinib and the combination with chloroquine induce LMP in pNETs and that LMP leads to activation of the transcription factor EB (TFEB), master regulator of genes involved in lysosomal biogenesis and autophagy, leading to therapy resistance. We found that LMP increased upon combined treatment of sunitinib and chloroquine compared to single treatment in pNET cell lines. Treatment of pNET cell lines with sunitinib or chloroquine led to activation of TFEB as assessed by nuclear/cytoplasmic fractionation and western blotting. Additionally, sunitinib significantly increased the expression of TFEB target genes, which were further upregulated upon combination with chloroquine. Interestingly, activation of TFEB and upregulation of TFEB target genes was more pronounced in the more resistant pNET cell line with respect to reduced viability and increased apoptosis. Our data indicate that sunitinib and chloroquine activate TFEB in pNET cell lines, leading to autophagy as a survival mechanism. Upon massive LMP or if autophagy is dysfunctional, cell death is induced. Based on our data, we suggest the combination of sunitinib and chloroquine as a treatment option for pNET patients and that TFEB could be an interesting therapeutic target in combination with lysosomotropic drugs. Citation Format: Tabea Wiedmer, Rasmus M. Frank, Mario P. Tschan, Aurel Perren, Ilaria Marinoni. Lysosomal membrane permeabilization as potential mediator of resistance in pancreatic neuroendocrine tumors [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 3159. doi:10.1158/1538-7445.AM2017-3159
Abstract 409: Genome engineering to generate models of chromosome arm-level aneuploidies in lung carcinoma
Authors: Alison M. Taylor, Gavin Ha, Juliann Shih, Xiaoyang Zhang, Joshua M. Francis, Matthew Meyerson
Journal: Cancer Research (2017)

Abstract Almost 90% of tumors are aneuploid and have arm- or whole- chromosome level copy number changes. Arm-level copy number alterations cluster by tumor type, suggesting that specific arm-level changes are influenced by cell type. Systematic methods of generating copy number changes on a particular chromosome have not been tested, leaving the effects of specific aneuploidies in cancer unclear. The most frequent genomic alteration in lung squamous cell carcinomas (SCCs) is loss of chromosome 3p. This alteration occurs in 90% of lung SCCs, and covers the entire length of the chromosome arm. Over two-thirds of 3p genes show significantly decreased expression. However, the phenotypic effects of 3p loss in tumorigenesis are not known. We used the CRISPR-Cas9 system to generate double-strand breaks (DSBs) and produce partial aneuploidies of arm-level loss. We have targeted guide RNAs adjacent to centromeric satellite-repeat sequences on chromosome arm 3p. At this location, we induced homologous recombination with a selection cassette and artificial telomere. We have successfully isolated almost 90 clones of immortalized lung epithelial cells with deletion of the 3p arm, with 8 validated by whole genome sequencing. Consistent with patient data, expression of 3p genes is also decreased upon deletion. Phenotypic characterization revealed that cells with chromosome 3p deletion proliferate more slowly than their siblings. 3p deleted cells show increased G1 arrest, but do not undergo increased apoptosis or cell death. We are currently testing 3p loss in combination with other frequent SCC alterations, such as SOX2 and TP63 gain. We have also identified expression changes in trans, outside of chromosome 3p. These studies provide a robust model that will address a gap in our understanding of aneuploidy in cancer by using targeted endonuclease technology to create models of partial aneuploidies. Future work will include investigation of how different chromosomal changes contribute to cancer formation, which will have implications on our understanding of tumorigenesis. Citation Format: Alison M. Taylor, Gavin Ha, Juliann Shih, Xiaoyang Zhang, Joshua M. Francis, Matthew Meyerson. Genome engineering to generate models of chromosome arm-level aneuploidies in lung 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 409. doi:10.1158/1538-7445.AM2017-409
Abstract 5482: Constitutive overexpression of nrf2 in esophageal adenocarcinoma protects cancer cells from bile salts-induced DNA damage and favors cancer cell survival
Authors: Dunfa Peng, Tianling Hu, Shoumin Zhu, Wael El-Rifai
Journal: Cancer Research (2017)

Abstract Background: Esophageal adenocarcinoma (EAC) is the major type of malignant cancer of esophagus in the USA. The incidence rate has increased 4-10% per year among men since 1976 in the USA, more rapidly than for any other type of cancer. EAC is known to originate from premalignant Barrett’s esophagus (BE) through BE-dysplasia-EAC process. Normal cells have intact anti-oxidative mechanisms, among which NFE2-related factor 2 (Nrf2) plays a pivotal role in regulating cellular response to various stimuli. Cancer cells have high levels of reactive oxygen species and oxidative stress due to activation of oncogenes, inflammatory microenvironment, and dysfunction of anti-oxidative mechanisms. However, the role of NRF2 in Barrett’s related esophageal carcinogenesis is barely known. Methods and Results: We have found that Nrf2 protein expression is significantly upregulated in EAC cell lines as compared to BE cell lines (CPA, BAR10T) and normal esophageal squamous cell lines. We detected a similar overexpression of NRF2 in primary EAC tissue samples. Using luciferase reporter assay, we demonstrated significant induction of NRF2 transcription activity in EAC cells in response to exposure to acidic bile acids, as compared to controls (P&amp;lt;.01). We detected significant increase in the expression of Heme Oxygenase 1 (HO-1) and Glutathione Reductase (GR) in these cells (P&amp;lt;.01). Knockdown of NRF2 by siRNA or crisp/cas9, significantly increased cellular ROS level, oxidative DNA damage (8-oxoguanine), and double strand DNA breaks (p-H2AX). Knockdown of NRF2 sensitized cells to apoptosis following exposure to bile acids and CDDP. Concordant with these results, the use of NRF2 inhibitor, Brusatol, sensitized EAC cells to CDDP treatment with a significant increase in cell death, as compared to single agent treatment (P&amp;lt;.01). Conclusion: These results indicate that constitutive overexpression of NRF2 in EAC cells protects cancer cells from high level of ROS and promotes cancer cell survival. Inhibition of NRF2 through its specific inhibitor may have therapeutic value in EAC. Citation Format: Dunfa Peng, Tianling Hu, Shoumin Zhu, Wael El-Rifai. Constitutive overexpression of nrf2 in esophageal adenocarcinoma protects cancer cells from bile salts-induced DNA damage and favors cancer cell survival [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 5482. doi:10.1158/1538-7445.AM2017-5482