tbuckley/cabot-search huggingface dataset:
Abstract 5423: ZAP70 alters metabolism in chronic lymphocytic leukemic cells
Authors: Subhadip Das, RF Dielschneider, Elizabeth S. Henson, Spencer B. Gibson
Journal: Cancer Research (2017)

Abstract Chronic lymphocytic leukemia (CLL) has the highest incidence among adults in western countries. Prognosis of CLL is highly variable but one of the biomarker zeta-chain-associated protein 70 (ZAP70) over expression is associated with aggressive disease with time to treatment being 2.6 years for ZAP70 expressing (ZAP70+) patients and 8 years for ZAP70 deficient (ZAP70-) patients. Thus ZAP70 may play a role in CLL progression. Metabolic reprograming plays a central role in cancer progression and is altered in CLL cells. However, the role of ZAP70 in metabolism in CLL cells is remains unclear. We found that ZAP70 binds to pyruvate kinase M2 (PKM2). PKM2 is key isoform of pyruvate kinase which is rate limiting enzyme of the glycolytic pathway and provides a metabolic advantage to tumour cells allowing for increased growth. Our results also indicated the PKM2 is expressed in CLL cells and binding to ZAP70 is not affected by glucose starvation or treatment with kinase inhibitors. Furthermore immunofluorescence microscopy revealed that ZAP-70 and PKM2 colocalize in CLL cells in the cytoplasm. In addition, we found ZAP70+ cells have increased rate of oxygen consumption from basal level determined by addition of inhibitor (Oligomycin A) and mitochondrial uncoupler (FCCP). Simultaneously ZAP70+ cells also have higher extracellular acidification rates. This indicates ZAP70+ CLL cells have increased mitochondrial respiratory capacity with high glycolytic rate. In addition, fluorometric analysis indicates ZAP70+ CLL cells have high glucose consumption rate towards production of lactate compared to ZAP70- CLL cells. Collectively, our data reveals a new function for ZAP70, which is to regulate the Warburg effect and may play a role in CLL progression and may identify new therapeutic targets. Note: This abstract was not presented at the meeting. Citation Format: Subhadip Das, RF Dielschneider, Elizabeth S. Henson, Spencer B. Gibson. ZAP70 alters metabolism in chronic lymphocytic leukemic 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 5423. doi:10.1158/1538-7445.AM2017-5423
Abstract 4257: Dietary nutrient intake, ethnicity, and epigenetic silencing of lung cancer genes detected in sputum in New Mexican smokers
Authors: Shuguang Leng, Maria Picchi, Piotr Filipczak, Frank Gilliland, Steven A. Belinsky
Journal: Cancer Research (2017)

Abstract Promoter hypermethylation of lung cancer (LC) genes detected in sputum assesses field cancerization and predicts LC risk. Hispanic smokers have greater risk for methylation than non-Hispanic Whites (NHW). We aimed to identify novel dietary nutrients affecting methylation of LC genes in sputum and determine the degree of ethnic disparity explained by diet. A cross-sectional population-based study was conducted with dietary intake assessed using a validated Harvard food frequency questionnaire in 327 Hispanics and 1502 NHWs from the Lovelace Smokers cohort (LSC). Twelve LC genes with diverse cellular functions whose concomitant methylation strongly predicted LC risk were studied. A global association was identified between dietary intake and gene methylation (Ppermutation=0.003). Seventeen nutrient measurements were associated with methylation with magnitude greater than seen for folate and these nutrients together accounted for 36% of the variance in methylation. Six protective nutrients were identified and their insufficient intake in Hispanics explained approximately 42% of ethnic disparity in methylation. Functional validation of protective nutrients that also explained ethnic disparity was provided by showing an enhanced DNA repair capacity towards double-strand DNA breaks, a mechanistic biomarker strongly linked to acquisition of LC gene methylation in smokers. Dietary intake is a major modifiable factor for preventing promoter methylation of LC genes in smokers’ lungs. Altering the diet in Hispanics may alleviate ethnic disparity for methylation. Complex dietary supplements could be developed based on these protective nutrients for LC chemoprevention in smokers. This study was funded by NIH R01 CA097356, NIH/NCI P30 CA118100, and the State of New Mexico as a direct appropriation from the Tobacco Settlement Fund. Citation Format: Shuguang Leng, Maria Picchi, Piotr Filipczak, Frank Gilliland, Steven A. Belinsky. Dietary nutrient intake, ethnicity, and epigenetic silencing of lung cancer genes detected in sputum in New Mexican smokers [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 4257. doi:10.1158/1538-7445.AM2017-4257
Outbreak of Septic Arthritis Associated with Intra-Articular Injections at an Outpatient Practice — New Jersey, 2017
Authors: Kathleen Ross, Jason Mehr, Barbara Carothers, Rebecca Greeley, Isaac Benowitz, Lisa McHugh, David Henry, Lisa DiFedele, Eric Adler, Shereen Naqvi, Edward Lifshitz, Christina Tan, Barbara Montana
Journal: MMWR Morbidity and Mortality Weekly Report (2017)

One patient received an injection on March 1 but did not develop symptoms and seek medical care until the first week of May.This patient
Abstract 2812: Development and characterization of the ultra immunodeficient B6;129-<i>Rag2</i> <i>tm1Fwa</i> <i>IL2rg</i> <i>tm1Rsky</i>/DwlHsd (R2G2) mouse model
Authors: Sheryl J. Wildt, Jamie McClellan, Mandy Horn
Journal: Cancer Research (2017)

Abstract The “R2G2” (B6;129-Rag2tm1FwaIL2rgtm1Rsky/DwlHsd) knockout mouse is the latest advancement to provide an alternative option in the highly immunodeficient mouse model category for the oncology, immunology and other biomedical research communities. This model was generated by backcrossing an IL2rg (common gamma) knockout model to a RAG2 (recombinase activating gene) knockout model. The resulting mouse lacks various cytokines including IL-2, IL-4, IL-7, IL-9 and IL-15. In addition, this model lacks B cells, T cells, NK cells and has a deficit in lymphocyte development. The R2G2 model is not only ultra immunodeficient, but provides a model that is less leaky and more tolerant to gamma radiation than traditional SCID models. This model is particularly useful for both tumor transplantation and humanization studies. Herein we describe the development and characterization of the R2G2 model, which includes breeding history, growth curve, CBC/Chemistry, flow cytometry and both huHSC and huPMBC humanization studies. Citation Format: Sheryl J. Wildt, Jamie McClellan, Mandy Horn. Development and characterization of the ultra immunodeficient B6;129-Rag2tm1FwaIL2rgtm1Rsky/DwlHsd (R2G2) 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 2812. doi:10.1158/1538-7445.AM2017-2812
Abstract 2835: Potential opposing roles of AKT isoforms in indolent versus aggressive prostate cancer
Authors: Karina A. Miller, Hyun-Kyung Ko, Irwin H. Gelman
Journal: Cancer Research (2017)

Abstract Prostate cancer (CaP) is the most commonly diagnosed non-cutaneous cancer and the second highest contributor to cancer-related deaths in U.S. men. Localized CaP has a 5-year survival rate of approximately 100%, but disseminated, metastatic disease (mCaP) dramatically reduces 5-year survival to &amp;lt;30%. A known driving force in the progression of CaP is activation of the PI3K/Akt signaling pathway through loss of PTEN, with widespread effects on cell proliferation and migration. Additional genomic changes, such as the loss of TP53 or RB1, or the upregulation of MYC, correlate with increased incidence and aggressiveness of mCaP. However, only a fraction of men with high levels of circulating and disseminated CaP cells progress to overt, macro-metastatic disease - the lethal phenotype in CaP. Importantly, little is known regarding the drivers of indolent vs. aggressive mCaP. We used two transgenic (Tg) mouse models of mCaP with clinically relevant genetic alterations which exhibit Akt activation and Rb1 loss, yet one produces indolent mCaP and the other, systemic aggressive mCaP. Specifically, mice lacking Rb1 and the metastasis-suppressor, SSeCKS/Akap12, develop high-grade prostatic intraepithelial neoplasia (HG-PIN) and disseminated disease in the lymph nodes whereas those lacking Pten and Rb1 develop CaP and aggressive mCaP. The metastasis-suppressing functions of Akap12 relates to its ability to scaffold Src and PKC, thereby attenuating their oncogenic signaling pathways. We will show data suggesting that the pathological differences between these two Tg models is based on the differential use of PI3K-p110 and Akt isoforms, with aggressiveness correlating with the downregulation of Smad4, a known metastasis-suppressor in Tg CaP models. Additionally, differences in Akt isoform usage likely controls the expression of neurogenesis genes that are especially upregulated in castration-recurrent CaP that fails second-line androgen receptor antagonist inhibitors such as enzalutamide. By comparing the differential transcriptomes and signaling networks in primary-site tumors, lymph node metastases, and CaP cell lines derived from these two Tg models, several new potential therapeutic targets have been identified that could be exploited to prevent or treat aggressive mCaP. Citation Format: Karina A. Miller, Hyun-Kyung Ko, Irwin H. Gelman. Potential opposing roles of AKT isoforms in indolent versus aggressive prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2835. doi:10.1158/1538-7445.AM2017-2835
The GENIE Is Out of the Bottle: Landmark Cancer Genomics Dataset Released
Authors: Kevin Litchfield, Samra Turajlic, Charles Swanton
Journal: Cancer Discovery (2017)

Abstract Summary: In this issue of Cancer Discovery, an overview of the AACR Project GENIE, a landmark study in cancer genomics, is presented by The AACR Project GENIE Consortium. A summary of the goals and objectives of this ambitious program is provided, together with an analysis of the phase I cohort of 19,000 samples. Cancer Discov; 7(8); 796–8. ©2017 AACR. See related article by The AACR Project GENIE Consortium, p. 818.
Breast sarcomas: Is now the time to change our mind?
Authors: I. Galaychuk
Journal: Journal of Clinical Oncology (2009)

e21524 Background: Primary breast sarcoma usually was considered a rare malignant disease [Adem et al., 2004]. The aim of this study is to show the incidence of breast sarcoma in the region with female population of about 600,000. Methods: Retrospective comparative analysis of breast sarcoma and breast cancer incidence in female of Ternopil region for 2000 - 2008. Descriptive statistical method was used. Results: The total of 101 cases of breast sarcoma was diagnosed in female of 39 - 76 years of age. Every year about 11 (6–18) primary breast sarcomas and 256 (233–279) patients with primary breast cancer were detected. The incidence rate of breast sarcoma was 1.14 per 100,000 women in 2000, 2.94 (in 2001), 1.48 (2002), 0.99 (2003), 2.16 (2004), 1.67 (2005), 2.53 (2006), 2.03 (2007) and 1.87/100,000 in 2008. The incidence of breast cancer was ranged from 37.3 to 46.4 per 100,000 of female population. Breast sarcoma consisted of 2.5% of the breast malignancies in 2000, 6.5% (in 2001), 3.3% (2002), 2.6% (2003), 5.4% (2004), 4.1% (2005), 5.9% (2006), 4.4% (2007) and 4.7% in 2008. Pathohistologic examination revealed angiosarcoma in 92.1% of cases. Thus, our findings are significantly different than data of other authors: f.e., the incidence of primary breast sarcoma is at 45 new cases per 10 million women [Confavreux et al., 2003], or 17 new cases per million women [Moore and Kinne, 1996], and breast sarcoma accounting for 0.0006% of breast malignancies which were diagnosed in 1910–2000 [Adem, 2004]. Taking into account all historical and recent data we can suggest beginning of biological changing in correlation between breast malignant tumors–carcinoma and sarcoma. Conclusions: Our statistical finding shows that incidence of breast sarcoma is 1.87 (0.99–2.94) per of 100,000 female population, and now sarcomas consist of 4.4% (2.5–6.5%) of all malignant breast tumors. Angiosarcoma is a most common (92.1%) morphological type of breast sarcomas. No significant financial relationships to disclose.
Abstract 3078: The role of extracellular vesicles in chemotherapy resistance in gastric cancer
Authors: Edson Cassinela, Michele C. Landemberger, Gabriela P. de Oliveira, Vilma Regina Martins
Journal: Cancer Research (2017)

Abstract Gastric adenocarcinoma (GAd) is the fourth most common cancer and the second cause of cancer death in the world. Chemotherapy has been largely used to treat this disease however acquired drug resistance is a common event and is associated to the development of new more aggressive clones of tumor cells. Herein, a gastric adenocarcinoma cell line (AGS) resistant to the 5-fluorouracil (rAGS-FU) was generated in order to establish mechanisms associated to acquire drug resistance. In the presence of 5-FU (10μM) resistant cells show a 2-3 times higher proliferation ratio than parental cells, a plating efficiency of 38% compared to 1% of parental cells and a higher invasive phenotype. Remarkable, when compared to parental cells, rAGS-FU resistant cells secreted 2-3 times more extracellular vesicles, EVs (85-175nm). When parental cells were treated with EVs from rAGS-5-FU resistant cells they acquired the same phenotype of the latter cells regarding higher proliferation, plating efficiency and invasion. The proteomic analysis of parental and rAGS-FU cells showed 306 differentially expressed proteins, while 66 differentially expressed proteins were found when EVs secreted from these cells were compared. Our data suggest that cells resistant to chemotherapy have a more aggressive phenotype and are able to transfer these characteristics to non-resistant cells. These findings point to mechanisms of chemoresistance mediated by components that are carried from cell to cell by EVs, what may indicate novel approaches that can be addressed to impair drug resistance and improve treatment response. Supported by FAPESP Citation Format: Edson Cassinela, Michele C. Landemberger, Gabriela P. de Oliveira, Vilma Regina Martins. The role of extracellular vesicles in chemotherapy resistance in gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3078. doi:10.1158/1538-7445.AM2017-3078
Abstract 1714: Translating CTCs for clinical use: melanoma patient-derived CTCs evolution in xenografts
Authors: Monika Vishnoi, Haowen N. Liu, Debasish Boral, Wei Yin, Marc L. Sprouse, Jean P. Thiery, Isabella C. Glitza, Dario Marchetti
Journal: Cancer Research (2017)

Abstract Circulating tumor cells (CTCs) are known to disseminate from primary/metastatic tumors, survive in the circulation, and develop competency to colonize distant organs. Dissecting CTC heterogeneity is therefore crucial to provide improve prognostic and diagnostic tools (concept of “liquid biopsy”). However, the clinical significance of CTC heterogeneity is still unknown. We hypothesized that melanoma patient blood-derived, lineage-negative cells (CD45-/CD34-/CD73-/CD90-/CD105-) contain melanoma cell subpopulations (Melan A+, S100+, CD146+ and NG2+ CTCs) that evolve in vivo and achieve metastatic potency when reaching an organ-specific niche. We enriched Lin-negative cells from peripheral blood of melanoma patients clinically diagnosed with or without brain metastasis (MBM) by multi-parametric flow cytometry; and analyzed CTC heterogeneity in xenografts by longitudinal capturing and interrogation at the single-cell level (DEPArrayTM platform). First, we evaluated the presence of melanoma CTC subpopulations in Lin-negative cells and developed Lin-negative murine xenograft models. Human-cell derived melanoma metastasis in xenografts confirmed that CTCs require metastasis-potentiating factors present in the Lin-negative population. Second, we performed multi-parametric flow cytometry to isolate human-derived HLA+/Melan A+/- CTCs/DTCs population from murine blood and bone marrow at T0, Tmid and Tend phases of metastasis. We interrogated the differential levels of CTCs/DTCs in HLA+/Melan A+ cell population and established their neoplastic identity by genetic profiling and the expression of melanoma markers at single-cell level. Third, we dissected longitudinal transcriptional signatures of CTCs vs DTCs in association with MBM onset. We assessed the comprehensive EMT scores of CTCs and DTCs transcriptomics and identified the pathways associated with CTC/DTCs dynamic functional states depending upon melanoma progression. Collectively, this study provide important insights to identify novel EMT-related biomarkers of MBM progression. Further elucidation of these CTC biomarkers and properties may provide novel therapeutic strategies that can be clinically useful in melanoma patients which are yet to develop MBM. Citation Format: Monika Vishnoi, Haowen N. Liu, Debasish Boral, Wei Yin, Marc L. Sprouse, Jean P. Thiery, Isabella C. Glitza, Dario Marchetti. Translating CTCs for clinical use: melanoma patient-derived CTCs evolution in xenografts [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 1714. doi:10.1158/1538-7445.AM2017-1714
Abstract 3588: Computational method to identify non-coding cancer drivers
Authors: Eric Minwei Liu, Priyanka Dhingra, Alexander M. Fundichely, Ekta Khurana
Journal: Cancer Research (2017)

Abstract Cancer is caused by mutations in driver genes - yet ~25% patients do not show any mutations in known drivers. ~99% somatic mutations obtained from whole-genome sequencing localize to regions that do not code for proteins and many of these non-coding mutations regulate gene expression. Although variants in protein-coding regions have received the majority of attention, numerous studies have now noted the importance of non-coding variants in cancer - for example, mutations in the promoter of the TERT gene. Identification of functional non-coding variants that drive tumor growth remains a challenge and a bottleneck for the use of whole-genome sequencing in the clinic. Cancer drivers are generally identified by the high frequency at which their mutations occur across patients. However, mutation rate is highly heterogeneous across the genome and many non-driver elements show higher mutation frequency than others, such as regions bound by transcription factors (TFs) in melanoma or regions replicating late during cell division in colon cancer. We have developed a novel computational approach to predict non-coding cancer drivers that differentiates between regions highly mutated due to positive selection (true drivers) vs those due to mutation rate heterogeneity (false positives). This method integrates the signals of high functional impact of variants with the recurrence of variants across multiple tumor samples to identify the elements that show more and higher functional impact mutations than expected randomly. Our method controls for multiple covariates of mutation rates, such as replication timing, histone modification marks and open chromatin regions to identify the non-coding cancer drivers. The functional impact is predicted using the FunSeq scheme that uses the properties of ENCODE elements (including conservation, TF motif disruption and network properties) within a weighted scoring scheme to predict deleteriousness of non-coding variants. I will present the details of this method and discuss the ongoing efforts to analyze ~2,900 tumor whole-genomes in the ‘Pan-Cancer Analysis of Whole Genomes, PCAWG’ consortium. Citation Format: Eric Minwei Liu, Priyanka Dhingra, Alexander M. Fundichely, Ekta Khurana. Computational method to identify non-coding cancer drivers [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 3588. doi:10.1158/1538-7445.AM2017-3588
Abstract 1181: Discovery and development of novel highly potent and selective inhibitors of USP19 using UbiPlex™
Authors: Gerald Gavory, Colin O'Dowd, Ewelina Rozycka, Anthony Dossang, Ashling Henderson, Caroline Hughes, Hugues Miel, Oliver Barker, Joana Costa, Peter Hewitt, Mary McFarland, Lauren Proctor, Tim Harrison
Journal: Cancer Research (2017)

Abstract Over the past decade, protein ubiquitination has emerged as an important post-translational modification with regulatory functions in all important cellular processes. Deubiquitinating enzymes (DUBs) including ubiquitin specific proteases (USPs) are cysteine proteases that catalyse the de-ubiquitination of protein substrates including tumor suppressors and oncogenes, hence regulating their levels and/or function. As a result of their increasing implications in the etiology of numerous pathological conditions including cancer, DUBs are emerging as an attractive and promising target class for the development of 1st in class medicines with high therapeutic impact. However, despite 15 years of intense research DUBs have proved largely refractory to drug discovery efforts. Herein, we further describe the application of Ubi-Plex™, our drug discovery platform for the identification and optimisation of DUB inhibitors. In particular, we will highlight the versatility and robustness of Ubi-Plex™ by describing the outcome of our focussed library screening, hit identification, hit validation and elaboration activities on USP19. A series of novel, highly potent (e.g. IC50 &amp;lt; 10 nM) and reversible USP19 inhibitors have been identified. Further profiling has also demonstrated excellent selectivity against a large panel of DUBs and other non-related enzymes (e.g. kinases, proteases). These inhibitors are cell-permeable and exhibit potent target engagement in cells with EC50 values &amp;lt; 30 nM. Finally, we will describe our progress towards the development of lead molecules with drug-like properties with the aim to rapidly establish in vivo proof-of-concept studies. In summary, this work further exemplifies the tractability of the DUB target family and reports the discovery and detailed profiling of the first highly potent and selective inhibitors of USP19. These molecules may provide opportunities for the development of new anticancer therapeutics as well as for the treatment of muscle wasting disorders including cachexia. Citation Format: Gerald Gavory, Colin O'Dowd, Ewelina Rozycka, Anthony Dossang, Ashling Henderson, Caroline Hughes, Hugues Miel, Oliver Barker, Joana Costa, Peter Hewitt, Mary McFarland, Lauren Proctor, Tim Harrison. Discovery and development of novel highly potent and selective inhibitors of USP19 using UbiPlex™ [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 1181. doi:10.1158/1538-7445.AM2017-1181