tbuckley/cabot-search huggingface dataset:
Abstract 1443: Identification of enhancer elements at kidney cancer susceptibility loci using MPRA
Authors: Leandro Machado Colli, Lea Jessop, Mitchell Machiela, Jiyeon Choi, Timothy Myers, Stephen Chanock
Journal: Cancer Research (2017)

Abstract GWAS is an important tool for discovering regions in the genome associated with cancer susceptibility. For renal cell carcinoma (RCC), only two loci have had their functional basis explained (11q13 and 12p12). Here, we used a massively parallel reporter assay (MPRA) to investigate enhancer activity in 20 GWAS regions that had an RCC association p-value of at least 10-7. We selected 784 SNPs with an r2&amp;gt;0.4 or D’&amp;gt;0.5 and MAF&amp;lt;0.05 that had evidence for enhancer activity based on available ENCODE transcription factor or histone ChIP-seq, FAIRE, and DNase I hypersensitive data. The MPRA library was composed of 47461 oligonucleotides 201 bp in length, compelled of 145 bps contained the SNP in the forward or reverse orientation followed by 10 bp of barcode sequence to allow for identification. Each of the 784 SNPs tested were tagged 10 separate times for both orientations. Controls were constructed by randomizing the 10 nucleotides centered on the SNP. The MPRA library was the cloned into a luciferase reporter vector that was transfected into HEK293T and ACHN cell lines. NGS was performed on 5 replicates using the the Illumina HiSeq 2500. After correcting for multiple comparisons, 50 SNPs from 16 regions showed significant p-values. From these 50 SNPs, 29 showed enhancer activity that was independent of the forward/reverse orientation and had the same effect in both cell lines. This analysis has identified possible functional variants at RCC risk loci and opens opportunities to discover new molecular mechanisms of genetic susceptibility of RCC. Citation Format: Leandro Machado Colli, Lea Jessop, Mitchell Machiela, Jiyeon Choi, Timothy Myers, Stephen Chanock. Identification of enhancer elements at kidney cancer susceptibility loci using MPRA [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 1443. doi:10.1158/1538-7445.AM2017-1443
Abstract 358: Transient Receptor Potential Vanilloid 2 (TRPV2) contributes to myocardial contractility and hypertrophy via sarcoplasmic reticulum calcium handling
Authors: Jack Rubinstein, Vivek P Singh, Valerie M Lasko, Sheryl E Koch, Evangelia Kranias, W. Keith Jones, John N Lorenz
Journal: Circulation Research (2013)

Background: TRPV2 is a Ca2+ channel that we have recently discovered in cardiomyocytes. The absence of this channel negatively impacts baseline contractility while stimulation results in a positive inotropic response. What remains to be established is the mechanism of this receptor and its role, if any, in the development of hypertrophy. Methods and Results: We obtained isolated cardiomyocytes from wild type (WT) and TRPV2-/- (KO) mice and found that the sarcoplasmic reticulum Ca2+ content and Ca2+ transients were reduced along with fractional shortening in the KO cardiomyocytes (figure, panels A, B, C). In vivo echocardiography confirmed a decrease in ejection fraction in KO mice in comparison to the WT counterparts (panel D). The relevance of these findings was examined in 6 WT and 5 KO mice subjected to transverse aortic constriction (TAC). These mice were followed by echocardiography weekly for a total of 8 weeks post TAC. At the conclusion, the hearts were obtained for histological and molecular analyses. We demonstrated that the KO mice developed less LV hypertrophy in comparison to WT (via echocardiography and by heart weight/body weight ratios) (figure, panels E and F). Importantly, there was a 5 fold increase in TRPV2 expression assessed by PCR in TAC WT hearts, compared to WT not subjected to TAC (0.72±0.10 vs. 0.13±0.04; p&lt;0.01). This suggests a role for TRPV2 not only in contractility, but also in the development of hypertrophy. Conclusions: We have discovered a novel cardiac channel that alters Ca2+ cycling and is capable of modulating cardiomyocyte contractility and hypertrophy, which could lead to novel therapeutic options in heart failure and hypertrophy.
Abstract #3208: Ornithine decarboxylase and antizyme 2 are prognostic markers for aggressive neuroblastoma independent of MYCN amplification status
Authors: Andre Bachmann, Jan Koster, David Albert, Dana-Lynn Koomoa, David Feith, Anthony Pegg, Richard Volckmann, Huib Caron, Rogier Versteeg, Dirk Geerts
Journal: Cancer Research (2009)

High polyamine (PA) levels and ornithine decarboxylase (ODC) over-expression are well-known phenomena in many aggressive cancer types. We analyzed the expression of ODC and ODC-activity regulating genes antizymes 1-3 (AZ1-3) and AZ inhibitors 1-2 (AZ-IN1-2) in human neuroblastoma (NB) tumors to determine their potential correlations with genetic and clinical features of NB. Since ODC is a known target gene of MYCN, the correlation between ODC and MYCN was of special interest. Data were obtained from Affymetrix micro-array analysis of a set of NB tumors (88 samples). ODC mRNA was highly expressed in all 88 NB tumors, and ODC mRNA expression levels were significantly predictive of decreased overall survival probability along with unfavorable patient age at diagnosis,  MYCN  gene amplification, 1p loss-of-heterozygosity (LOH), and unfavorable INSS tumor stage and tumor histology (all  P   MYCN  amplification, suggesting an additional role for ODC independent of MYCN. Conversely, AZ2 mRNA expression levels correlated with increased overall survival probability along with favorable INSS tumor stage,  MYCN  amplification, and 1p LOH (all  P     Citation Information:  In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 3208.
Abstract 4035: A novel combi-molecule engineered to target the putative synthetic lethal interactions between the epidermal growth factor receptor (EGFR) and poly(ADP-ribose)polymerase (PARP)
Authors: Zhor Senhaji Mouhri, Martin Rupp, Bertrand J. Jean-Claude
Journal: Cancer Research (2017)

Abstract Over the past decade, PARP inhibition has been actively pursued as a novel approach for the selective therapy of tumors with BRCA1/2 mutations. The therapeutic benefits of PARP inhibitors have now been proven in the clinic against BRCA1/2 mutant ovarian cancers. This is hitherto limited to BRCA1/2 mutations, which only accounts for 5-10% of all cancers with hereditary mutations in the homologous recombination pathway. Therefore, new strategies are not only required to enhance the potency of PARP inhibitors but also to expand their use beyond BRCA mutation. While several combination modalities have been reported for PARP inhibitors, the concept of targeted PARP inhibitor has not yet been explored. Here using our novel combi-targeting approach, we report on the design of PARP inhibitors targeted to EGFR, a tyrosine kinase receptor overexpressed in several solid tumors. Recently, reports on the relationship between EGFR, PARP and BRCA have begun to emerge, one of which described a contextual synthetic lethality between EGFR and PARP (PloS one 7.10 (2012)). Here we report on the design and synthesis of novel PARP-EGFR combi-molecule based on structural modification of olaparib as a PARP inhibitor warhead and the quinazoline moiety for targeting EGFR. The results showed that: (a) it is capable of inducing a dose-dependent inhibition of PARP in isolated enzyme assay, (b) it induced a dose-dependent inhibition of EGFR in an isolated kinase assay, (c) it showed a dose-dependent inhibition of EGFR phosphorylation and downstream signaling in whole-cell assay, (d) it was selectively potent towards BRCA2 mutant and also EGFR-overexpressing cell lines, (d) it was extremely potent with activities superior to that of olaparib or gefitinib alone and their corresponding equimolar combination in three established triple negative breast cancer cell lines, (e) subcellular distribution analysis showed that it was abundantly localized in the perinuclear region. These results in toto suggest that this new combi-molecule could be developed as a single drug modality emulating the combination of PARP and EGFR inhibitors with the added benefit of being targeted to EGFR-expressing tumor cells. Citation Format: Zhor Senhaji Mouhri, Martin Rupp, Bertrand J. Jean-Claude. A novel combi-molecule engineered to target the putative synthetic lethal interactions between the epidermal growth factor receptor (EGFR) and poly(ADP-ribose)polymerase (PARP) [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 4035. doi:10.1158/1538-7445.AM2017-4035
Influence of international stakeholder and health-care agendas in the Palestinian Family Survey, 2010: a qualitative assessment of a national health survey
Authors: Rula Ghandour, Katie Bates, Sawsan Imseeh, Suzan Mitwalli, Shiraz Nasr, Doaa Hammoudeh, Ernestina Coast, Tiziana Leone, Rita Giacaman
Journal: The Lancet (2017)
Colorectal cancer treatment in elderly patients: A pilot study.
Authors: Marcello Ferretti Fanelli, Milena De Gaspari Gonzales, Emne Ali Abdallah, Ludmilla T.D. Chinen, Ana Claudia Urvanegia, Marcilei Eliza Cavicchioli Buim, Marcelo Corassa, Aldo A. Dettino
Journal: Journal of Clinical Oncology (2016)

e21520 Background: Colorectal cancer is the third most frequent cancer in men and women, corresponding about 9% of tumors in both sexes. Regarding mortality rate, it also ranks as the third one. Especially in the elderly patients, this cancer is lethal, as it brings the challenge of low tolerance of these individuals to the drugs´ toxicity, which often makes treatment deleterious, leading to its suspension. Methods: our intention was to compare the overall survival (OS) of elderly patients with colorectal cancer that did not receive any treatment (NT) or that were treated with standard chemotherapy (SC) or with chemotherapy plus cetuximabe/bevacizumabe (CC/CB) and to verify if was any difference in PFS when patients had their treatment interrupted by toxicity. Retrospective study made at ACCamargo Cancer Center, São Paulo, Brazil, by analysis of medical records of patients treated between 2009 and 2014. Results: The median age of patients was 75.5 years (60-87 years) and the majority of them were women (n = 34, 56.7%). The median OS was 12.6 months (0.66-92 m). There were included 60 patients in this analysis, 20 (33,3%) in each group of treatment. The median OS for NT patients was 3.45 m (0.66-34.8m), for those treated with SC was 12.93 m (0.98-92m) and those treated with CC/CB the median OS was 15.79 m (2.7-51m; p < 0.001). By comparison of groups that received treatment, we observed that patients treated with SC had less toxicity, as they had had less suspension of treatment, less dose reduction of chemotherapy and the same OS, as there were no statistical significance difference between them (12.93 x 15.79 m; p = 0.3) and those that received CC/CB. Conclusions: considering that elderly patients are treated an empiric way, as there are no clinical trials to define treatments for them, it is urgent to analyse what have been done. Here, in a pilot study, with a small number of patients, we could observe that biological treatment is not the best option for them. Patients treated with standard chemotherapy had less toxicity and the same OS as those who received the biological one.
Smartphones for Smarter Care? Self-Management in Schizophrenia
Authors: Luis R. Sandoval, John Torous, Matcheri S. Keshavan
Journal: American Journal of Psychiatry (2017)

A's case was presented as part of grand rounds at the Massachusetts Mental Health Center, and the resulting discussion is summarized below.The patient consented to publication of this report, but the case presentation above is nevertheless anonymized.The rapid rise of smartphone technology and increased rates of smartphone ownership among patients with serious mental illness (1) is narrowing the digital divide between thoseThe patient with schizophrenia described in this article sought out smartphone applications for which of the following reasons?A. Social networking with other patients.B. Antipsychotic medication information.C. Supplemental counseling for schizophrenia.D. Support in weight-loss management."Mr.A" is a 30-year-old orthodox Christian single man, originally from Eritrea, who has been diagnosed with schizophrenia.He lived in a refugee camp for 9 months before arriving in the United States.Five months after his arrival, Mr. A started to feel "irritable, aggressive, disoriented, and confused."Shortly thereafter, he experienced his first psychotic break.As a consequence, he could not retain his job, lost interest in school, and was asked to leave his relative's house: in the Eritrean community, mental health problems are poorly understood and not well received.He was soon hospitalized for psychosis, the first of many experiences with the U.S. mental health care system.After his discharge, he discontinued his medication and psychotherapy sessions because he denied having a mental illness.Beginning in his mid-20s, Mr. A had irritable mood, lack of sleep, constant interpersonal difficulties (not being able to understand the content and context of his social interactions), and psychotic symptoms (e.g., he was convinced that strangers on the street were talking disparagingly about him; voices persuaded him to travel from Boston to New York City, thinking that his symptoms would disappear if he moved to a different city).In his first year in the United States, Mr. A was hospitalized three times, precipitated by paranoia, fear of being attacked, and elevated mood.Mr. A attributed his relapse to his continued
Abstract 290: A novel function of HGF in the activation of Chk1 phosphorylation in colon cancer cells
Authors: Na Song, Xiaofang Che, Xiujuan Qu, Lu Xu, Kezuo Hou, Yunpeng Liu
Journal: Cancer Research (2017)

Abstract ATR/Chk1 pathway plays an essential role in modulation of DNA damage response (DDR) and homologous recombination (HR). Particularly, Chk1 phosphorylation is involved in cancer prognosis and therapeutic resistance. Although some receptor tyrosine kinases (RTKs) participate in the regulation of Chk1 phosphorylation, the effect of hepatocyte growth factor (HGF) on Chk1 phosphorylation is unknown. In the present study, Western blotting and subcellular fractionation were performed to identify the expression and the location of Chk1 phosphorylation in the presence of HGF. With small interfering RNA transfections, co-immunoprecipitations were performed to detect the interaction between TopBP1 and ATR complex. Our results demonstrated that HGF moderately activated Chk1 phosphorylation in colon cancer cells via upregulation of TopBP1, RAD51, and complex formation of TopBP1 and ATR. Furthermore, AKT activation promoted by HGF served as an important intermediator linking HGF/MET signaling and Chk1 phosphorylation. Depletion of AKT activity attenuated expression of basal line p-Chk1 and induced Chk1 activation due to HGF stimulation. Meantime, activation of AKT directly regulated expression of TopBP1 and RAD51. Suppression of AKT restored HGF-induced upregulation of TopBP1, RAD51, and enhancement of TopBP1/ATR complex as well. Our studies showed that HGF was implicated in regulating Chk1 phosphorylation and further demonstrated that AKT activity was responsible for HGF-induced Chk1 phosphorylation, which might potentially result in management of prognosis and therapeutic sensitivity in cancer therapy. Note: This abstract was not presented at the meeting. Citation Format: Na Song, Xiaofang Che, Xiujuan Qu, Lu Xu, Kezuo Hou, Yunpeng Liu. A novel function of HGF in the activation of Chk1 phosphorylation in colon 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 290. doi:10.1158/1538-7445.AM2017-290
Abstract 4092: Targeting compensatory mechanisms of resistance to phosphatidylinositol 3-kinase inhibitors in head and neck squamous cell carcinoma
Authors: Nicole L. Michmerhuizen, Elizabeth Leonard, Susan K. Foltin, Aditi Kulkarni, Thomas E. Carey, Carol R. Bradford, Hui Jiang, Chad Brenner
Journal: Cancer Research (2017)

Abstract Recent sequencing studies of head and neck squamous cell carcinomas (HNSCCs) have identified the phosphatidylinositol 3-kinase (PI3K) pathway as the most frequently mutated, oncogenic pathway in this cancer type. Despite the frequency of activating mutations or amplification in PIK3CA (the gene encoding the catalytic subunit of PI3K), targeted inhibitors of PI3K have not shown clinical efficacy as monotherapies. We tested a panel of more than 20 patient-derived oral cavity squamous cell carcinoma (OCSCC) cell lines, which were profiled by Nimblegen V3 exome sequencing, and observed resistance to PI3K inhibitors despite PIK3CA copy number amplification and/or mutation. Of six inhibitors tested, only alpha-isoform selective and pan-PI3K agents were somewhat effective; these inhibitors, despite on-target and downstream activity, did not cause an appreciable reduction in cell viability when administered at submicromolar concentrations. We hypothesized that other oncogenic pathways might still be functional in the presence of PI3K inhibitors and might serve as mediators of this resistance. For example, our group and others have evaluated co-dependence on the Ras-MEK-ERK pathway in OCSCC, showing that this serves as a compensatory mechanism in some models. In order to more fully characterize other novel mechanisms of resistance, we have also developed a high-throughput screening approach that utilizes a resazurin cell viability assay. This screen serves as an unbiased means of testing ~1400 inhibitors as monotherapies and in combination with alpha-isoform selective PI3K inhibitor HS-173 and pan-PI3K inhibitor BKM120 in several OCSCC models. Further validation of “hits” from this screen, which are drugs that are effective in combination but not as monotherapies, may identify additional resistance mechanisms and lead to combination therapies to improve HNSCC patient prognosis. Citation Format: Nicole L. Michmerhuizen, Elizabeth Leonard, Susan K. Foltin, Aditi Kulkarni, Thomas E. Carey, Carol R. Bradford, Hui Jiang, Chad Brenner. Targeting compensatory mechanisms of resistance to phosphatidylinositol 3-kinase inhibitors in 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 4092. doi:10.1158/1538-7445.AM2017-4092
Abstract 3616: Potential therapeutic use of Estrogen Receptor β agonist in the prevention and progression of breast cancer using HER-2/neu mouse model
Authors: Kumaraguruparan Ramasamy, Cathy Samayoa, Naveen K. Krishnegowda, Ratna K. Vadlamudi, Rajeshwar R. Tekmal
Journal: Cancer Research (2017)

Abstract Breast cancer is the most common cancer among women worldwide. Hormone-mediated therapy to treat estrogen receptor alpha (ERα) positive breast cancers include the use of ER antagonist, Tamoxifen, aromatase inhibitors and other compounds that degrade ERα. Unlike ERα, ERβ has been shown to have tumor-suppressive function in various cancers, including breast cancer. Recent studies have identified, synthesized, and tested the clinical safety of ERβ-selective agonists. Given the tumor-suppressive properties of ERβ, it may be possible to use these compounds to induce or activate the ERβ and test their role in the chemoprevention and blocking the progression of breast cancer. We have investigated the therapeutic utility of ERβ agonists in the prevention and progression of breast cancer using MMTV-HER2/neu mice transgenic mouse model. MMTV-HER2/neu mice develop premalignant lesions at 4-5 months, and tumors starting at month 7 due to overexpression of the HER2/neu proto-oncogene. MMTV-HER2/neu mice were treated with an ERβ agonist, LY500307 examined the prevention and progression of mammary cancers in these mice. When compared to controls, ERβ agonist-treated mice exhibited a significant decrease in the development of preneoplastic changes. Differential gene expression analysis revealed a significant change in the expression of a number of genes in response to LY500307 treatment. Pathway analysis identified an enrichment for chemokines signaling pathways, particularly TNF, in blocking the development of preneoplastic changes resulting from treatment with ERβ agonists. Our studies also show a decrease in the formation of mammary tumors in HER-2/neu mice with preexisting preneoplastic changes when treated with LY500307. This study suggests that ERβ agonist treatment may be a valuable therapeutic option for the prevention in women at increased risk of breast cancer and in blocking the progression of hormone receptor positive breast tumors. Citation Format: Kumaraguruparan Ramasamy, Cathy Samayoa, Naveen K. Krishnegowda, Ratna K. Vadlamudi, Rajeshwar R. Tekmal. Potential therapeutic use of Estrogen Receptor β agonist in the prevention and progression of breast cancer using HER-2/neu mouse model [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 3616. doi:10.1158/1538-7445.AM2017-3616