bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 754: A comprehensive immunogenomics profiling platform enables the exploration of the intricate relationship between TMB, MSI, Neoantigen and HLA status among multiple cancers
Authors: Wang Jie , Li Ao , Wang Jiawei , Cheng Zhaoze 
Published: August 2019

Abstract
With the rapid advancement of immune therapy on cancer treatment, there is an increasing demand for accurate and comprehensive profile of tumor immunogenomics landscape in order to broaden our knowledge on predicting patient response as well as to facilitate drug development process. We established a cloud based analytical platform to comprehensively characterize genomic features that are potentially related to patients’ responses to immunotherapy. We implemented a neoantigen prediction pipeline based on whole exome sequencing (WES) and transcriptome sequencing data that integrates accurate HLA typing based on WES, somatic variant detection/phasing, RNA expression, class I MHC binding prediction as well as peptide epitope ranking. Among that, the HLA typing pipeline was validated using 73 Chinese and Japanese subjects covering &gt;60 known class I HLA alleles with an accuracy above 95%. In addition, we also developed and validated methods to compute microsatellite instability (MSI) and tumor mutation burden (TMB) based on either a 600 gene panel or WES. Thirdly, this platform also enables the detection of HLA somatic variants and loss of heterozygosity events based on WES data. Next, we applied this analysis platform to process 127 samples across four cancer types (colon, rectal, endometrial and gastric) from TCGA as well as two Chinese cohorts of 100 non-small cell lung cancers and 30 esophageal squamous cell carcinomas sequenced at WuXi NextCODE. Within the TCGA cohort, the data reveals that patients with MSI High status produces significantly more neoantigens than patients with MS Stable status (7.06±4.60 vs 0.71±0.64, p = 7.65e-16, neo-peptides per Mb). Number of neopeptides predicted from each frameshift event is significantly higher than that from each missense mutation (1.30±1.56 vs 0.58±0.54, p = 2.86e-11, neo-peptides per Mb). We also observed strong correlation between TMB and neoantigen burden across multiple cancer types. In conclusion, we have developed a immunogenomics solution that captures tumors’ TMB, MSI, neoantigen as well as deleterious events associated with their HLAs. This platform will allow more comprehensive molecular features assessed to potentially improve the prediction of patients’ response to immune therapy.
Citation Format: Jie Wang, Ao Li, Jiawei Wang, Zhaoze Cheng. A comprehensive immunogenomics profiling platform enables the exploration of the intricate relationship between TMB, MSI, Neoantigen and HLA status among multiple cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 754.
Abstract 770: MiR628-5p targets Jagged 1 and inhibits growth, stemness and invasiveness of advanced prostate cancer cells
Authors: Rios-Colon Leslimar , Chijioke Juliet , Srivastava Anvesha , Ramalinga Malathi , Kedir Habib , Arthur Elena , Cagle Patrice , Deep Gagan , Kumar Deepak 
Published: August 2019

Abstract
Prostate cancer (PCa) is the most common non-cutaneous cancer in men, and according to the American Cancer Society reports, 164,690 new cases and 29,430 deaths from PCa are estimated in the United States in 2018. To reduce PCa mortality, we need a better understanding of molecular regulators of prostate carcinogenesis. MicroRNAs (MiRs) are small, non-coding RNA molecules that have been implicated in various cancers, and offer a novel opportunity to diagnose and treat cancer. We have previously identified MiR628-5p as a potential biomarker in PCa patients. This miRNA was found to be downregulated in the serum of both African American and Caucasian men with PCa compared to healthy individuals. In the present study, we further characterized the anti-cancer role of MiR628-5p in various PCa cell culture models. Results showed that MiR628-5p mimic treatment (100 nM) for 5 days significantly decreased the cell proliferation (~43% inhibition, p&lt;0.001) in human prostate carcinoma PC3 cells compared to random mimic control. Similarly, MiR628-5p mimic treatment decreased the number of clones (clone size ≥50 cells) formed by PC3 cells by 40% (p&lt;0.001) compared to random mimic control. Interestingly, miRNA 628-5p mimic treatment also reduced the stemness of PC3 cells as reflected in significant decrease in prostasphere size and CD44 expression. In mechanistic studies, we identified Jagged-1 as a molecular target regulated by MiR628-5p. MiR628-5p mimic treatment strongly decreased the Jagged-1 expression in several PCa cell lines (PC3, DU145, LNCaP and C4-2) as well as reduced the Jagged-1 luciferase activity. Jagged 1 inhibition by MiR628-5p was associated with reduced Notch signaling as well as decreased expression of transcription factors (snail and slug) regulating EMT. Moreover, MiR628-5p mimic treatment increased the expression of epithelial biomarkers (E-cadherin and ZO1), reduced the expression of mesenchymal marker (vimentin) and strongly inhibited the invasiveness of PC3 cells. In conclusion, we present evidence that MiR628-5p is a key regulator of prostate carcinogenesis, and offers a novel therapeutic opportunity to inhibit the growth of advanced PCa.
Citation Format: Leslimar Rios-Colon, Juliet Chijioke, Anvesha Srivastava, Malathi Ramalinga, Habib Kedir, Elena Arthur, Patrice Cagle, Gagan Deep, Deepak Kumar. MiR628-5p targets Jagged 1 and inhibits growth, stemness and invasiveness of advanced prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 770.
Abstract 774: Regulation of autophagy and epigenetic modulator micro RNA by transient receptor potential melastatin 7 (TRPM7) channel in glioma
Authors: Liu Mingli 
Published: August 2019

Abstract
High grade malignant gliomas are devastating, uniformly fatal cancers for which no effective therapies currently exist. Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor. We have reported that TRPM7 channels, a subfamily member of the transient receptor potential (TRP), regulate glioma stem cell (GSC) growth/proliferation through STAT3 and Notch signaling pathways. Autophagy is a catabolic process that occurs during both physiological and pathological process which has been reported to have dual roles, functioning either as a tumor-suppressor or tumor-promoter in cancer, including glioma. In addition, because of the limited success of the traditional treatment in prolonging the overall survival in GBM patients, epigenetics and epigenetic modulators have been attracting an increasing amount of attention for their influence in many aspects of cancer. microRNAs (miRNA), which can be considered as epigenetic effectors, reversibly regulate transcription through binding to complementary sequences of mRNA and silencing its translation into proteins. Therefore, we first determined the role of autophagy process in regulating glioma by TRPM7 using real time RT2 Profile PCR arrays (SABioscience, PAHS-084Z). We found that ATG16L1, ATG9A, CDKN1B, CLN3, CXCR4, and RGS19 were upregulated in response to TRPM7 silencing with the fold change greater than 1.6 using the A172 cell line of human glioma. The gene changes were further validated in other three glioma cell lines U87MG, U373MG and SNB19, which demonstrated different glioma tumorigenicity. miroRNA microarray analysis were then were performed upon TRPM7 silencing in A172 cells (www.LCsciences.com). In-depth data analysis from miRNA microarray data showed a list of 16 downregulated and 10 upregulated miRNA whose transcripts are statistically significant with fold change greater than 2 by TRPM7 knock-down. Among these, the micro RNA of hsa-miR-26b-5p, has-miR4530, and has-miR-28-5p have shown to exert crucial influence on tumor growth and migration by modulating AKT, ERK and IGF-1 signaling pathways. Stem-loop RT-qPCR were then used to detect and quantify miRNAs identified in miRNA microarray data from U87MG, U373MG and SNB19 cell lines. Our data indicate that autophagy effects serve as tumor suppressors in gliomagenesis and are reversely regulated by TRPM7; while hsa-miR-26b-5p, has-miR4530, and has-miR-28-5p are regulated by TRPM7 and participate in glioma progression.
Citation Format: Mingli Liu. Regulation of autophagy and epigenetic modulator micro RNA by transient receptor potential melastatin 7 (TRPM7) channel in glioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 774.
Abstract 786: Metastasis is driven by mitochondrial protein A via mitochondrial reprogramming in colorectal cancer
Authors: Kim Dayeon , Kwon Sang-Mo 
Published: August 2019

Abstract
Colorectal cancer (CRC) is the third most common cancer worldwide, and CRC metastasis is the main cause of cancer-associated mortality. The hypoxia signaling pathway controls mediators to facilitate cancer progression and metastasis. Recently, mitochondrial reprogramming has emerged as a one of the mechanisms of hypoxia-induced metastasis; however, the link between hypoxia-induced metastasis and mitochondrial reprogramming remains to be elucidated. Here, we have focused on the novel mitochondrial protein A, to determine its role in the molecular mechanism of hypoxia-induced metastasis. Our results indicate that mitochondrial protein A is a downstream target of hypoxia-inducible factor 1 (HIF-1α) and plays an essential role in HIF-1-induced migration and invasion. In addition, we found a clinical correlation between hypoxia and mitochondrial protein A. To identify the role of mitochondrial protein A, we generated mitochondrial protein A deficient or silenced cells, which showed impaired migration, invasion, and colony-forming ability even under hypoxic condition. In contrast, ectopic expression of mitochondrial protein A elevated metastatic potential, both in vitro and in vivo. Mechanistically, mitochondrial protein A directly interacted with dynamin-related protein (DRP1) to retain it in mitochondria, thereby promoting mitochondrial fission. To confirm the effect of mitochondrial fission on mitochondrial protein A-induced metastasis, we blocked DRP1 in mitochondrial protein A overexpressing cells by pharmacological inhibition, which led to impairment of mitochondrial protein A-induced metastatic potential. Furthermore, mitochondrial protein A-silenced cells showed decreased metabolism and lactate production, suggesting that mitochondrial protein A regulates the mitochondrial reprogramming. In summary, we demonstrate that mitochondrial protein A is a novel DRP1 adaptor protein, facilitating mitochondrial fission and mitochondrial reprogramming, and plays a critical role in hypoxia-induced metastasis. We suggest that targeting of mitochondrial protein A maybe a strategy for cancer therapy.
Citation Format: Dayeon Kim, Sang-Mo Kwon. Metastasis is driven by mitochondrial protein A via mitochondrial reprogramming in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 786.
Abstract 794: Inhibition of mitochondrial metabolism by a novel agent targeting RUNX2-DNA binding in breast cancer
Authors: Kim Myoung Sook , Gernapudi Ramkishore , Cedeno Yessenia C. , Polster Brian M. , Girnun Geoffrey D. , Passaniti Antonino 
Published: August 2019

Abstract
The RUNX2 transcription factor promotes breast cancer growth and metastasis through interactions with a variety of cofactors that activate or repress target genes. RUNX2 knockdown decreases expression levels of glycolytic genes such as LDHA, HK2 and GLUT-1, but upregulates PDHA1 mRNA level and enzymatic activity, which is consistent with lower glycolytic potential. Using a direct computer-assisted drug discovery (CADD) approach, we identified CADD522 as a small molecule that inhibits the RUNX2-DNA binding, transcriptional activity of RUNX2, and expression of RUNX2 target genes. We also observed that CADD522 inhibits breast cancer growth and metastasis using in vitro and in vivo tumor models. RUNX2-activated glucose utilization and GLUT-1 levels were also reduced by CADD522. New data also define CADD522 as a potential antitumor agent that downregulates the levels of metabolites in the TCA cycle and inhibits mitochondrial oxygen consumption rates. Our results support the observations that CADD522 could regulate cellular metabolism through modulation of both glycolytic metabolism and mitochondrial oxidative phosphorylation. To address the mechanisms by which CADD522 exerts its inhibitory effects on mitochondrial metabolism, we performed RNA-Sequencing analysis in breast cancer cells and identified several specific molecular signatures that determine cellular response to RUNX2 and CADD522. Further pathway changes in mitochondrial function as well as validation of differentially expressed genes that play critical roles in mitochondrial metabolism are under investigation.
Citation Format: Myoung Sook Kim, Ramkishore Gernapudi, Yessenia C. Cedeno, Brian M. Polster, Geoffrey D. Girnun, Antonino Passaniti. Inhibition of mitochondrial metabolism by a novel agent targeting RUNX2-DNA binding in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 794.
Abstract 797: Obesity-associated, but not obesity-independent, tumors respond to insulin by increasing mitochondrial glucose oxidation
Authors: Rabin-Court Aviva , Shulman Gerald I. , Perry Rachel J. 
Published: August 2019

Abstract
Obesity is associated with increased incidence and worse prognosis of more than one dozen tumor types; however, the molecular mechanisms for this association are unknown. We hypothesized that insulin, which is elevated in obesity-driven insulin resistance, would increase tumor glucose oxidation in obesity-associated tumors. To test this hypothesis, we developed a stable isotope method in which tumor cells are incubated in physiological concentrations (5 mM) of [13C6] glucose and the ratio of pyruvate dehydrogenase flux to citrate synthase flux (VPDH/VCS, i.e. the percent of total mitochondrial oxidation fueled by glucose oxidation) is given as [4,5-13C2]glutamate/[13C3]alanine, measured by gas chromatography/mass spectrometry and liquid chromatography-tandem mass spectrometry respectively. Using this method, we found that both breast cancer (4T1) and colon cancer (MC38) cells, tumors that are associated with obesity, exhibit greater relative rates of glucose oxidation to total mitochondrial oxidation (VPDH/VCS 61±3% and 60±2%, respectively) than melanoma (YUMM) and Renca (renal cell carcinoma) cells (41±4% and 37±2%, respectively; P&lt;0.05 for all comparisons between obesity-associated and non-obesity-associated tumors). In addition, both 4T1 and MC38 cells increased VPDH/VCS upon incubation in 100 nM insulin (75±3% and 81±2%, respectively, P&lt;0.01 vs. the same tumor type without insulin), whereas there was no change in glucose oxidation with insulin in YUMM or Renca cells (35±3% and 36±2%, respectively). These data reveal that a shift in substrate preference may comprise a metabolic signature of obesity-associated tumors that differs from that of those not associated with obesity. In addition, contrary to the conventionally held view that glucose oxidation in tumor cells is constitutively high, these data reveal that obesity-driven tumors respond acutely to insulin by increasing mitochondrial glucose oxidation, whereas obesity-independent tumor cells do not. CONCLUSION: These data demonstrate that obesity associated tumors (breast and colon), in contrast to tumors that are not associated with obesity (melanoma, renal cell), are insulin-responsive and have higher rates of basal and insulin-stimulated mitochondrial glucose oxidation. Therefore assessment of in vitro tumor mitochondrial substrate preference may predict whether interventions to reverse hyperinsulinemia or reduce insulin-responsive glucose oxidation in tumors may be attractive therapeutic modalities in cancer types associated with obesity.
Citation Format: Aviva Rabin-Court, Gerald I. Shulman, Rachel J. Perry. Obesity-associated, but not obesity-independent, tumors respond to insulin by increasing mitochondrial glucose oxidation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 797.
Abstract 80: Electronic cigarette aerosols increase clonogenic survival in oral cancer cells after cisplatin treatment
Authors: Manyanga Jimmy , Mehta Toral R. , Queimado Lurdes 
Published: August 2019

Abstract
Background and Aim: Are electronic cigarettes (ECs) safer than combustible tobacco? No one knows the answer yet. ECs are devices that deliver an aerosol from a heated mixture of propylene glycol, vegetable glycerin, and flavors, with or without nicotine. Short-term EC studies are mostly limited and inconclusive. Despite unknown long-term health effects, the use of ECs has increased alarmingly over the past decade. EC aerosols contain unique chemicals as well as other chemicals similar to those found in tobacco smoke. Tobacco smoking during cancer treatment has been associated with increased drug resistance and reduced overall survival rate. The awareness of the dangers of cigarette smoking and the paucity of studies evaluating the safety of ECs pose a dilemma for cancer patients who might be considering switching to ECs during chemotherapy. Here, we sought to examine the effects of EC aerosol extracts exposure on cell survival in oral cancer cells during cisplatin treatment.
Methods: EC aerosol extracts were collected from two brands of ECs as previously described. Mainstream tobacco smoke (MS) extract was used as a positive control. To evaluate clonogenic survival after cisplatin treatment, oral cancer cells were exposed for 48 h to EC aerosol extracts at nicotine doses comparable to those observed in EC users. Next, cells were treated with both EC aerosol extracts and cisplatin (or vehicle-control) for another 48 h. After treatment, cells were counted and seeded in 6-well plates and colony formation was assessed two weeks later. Colonies were fixed with methanol followed by staining with 0.5% crystal violet in 25% methanol and counted manually. Only colonies with at least 50 cells were counted. Data were analyzed by Student's t-tests and one-way analysis of variance (ANOVA).
Results: After cisplatin treatment, cells exposed to EC aerosol extracts showed a significant increase in clonogenic survival fraction compared to vehicle-control treated cells. Furthermore, cells exposed to EC aerosol extracts formed visibly larger colonies. An increase in clonogenic survival was also observed in MS extract-treated cells.
Conclusions: Collectively, our data suggest that short-term exposure to EC aerosol can induce cisplatin resistance in oral cancer cells, thus allowing the cells to survive and form colonies. These findings are particularly important in paving the way to understanding whether ECs are a safer alternative for oral cancer patients undergoing chemotherapy.
Citation Format: Jimmy Manyanga, Toral R. Mehta, Lurdes Queimado. Electronic cigarette aerosols increase clonogenic survival in oral cancer cells after cisplatin treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 80.
Abstract 802: Effective breast cancer combination therapy targeting BACH1 and mitochondrial metabolism
Authors: Lee Jiyoung 
Published: August 2019

Abstract
Mitochondrial metabolism is an attractive target for cancer therapy. Reprogramming metabolic pathways could improve the ability of metabolic inhibitors to suppress cancers with limited treatment options like triple negative breast cancer (TNBC). Here we show that BACH1 (BTB and CNC homology1), a heme-binding transcription factor whose expression is enriched in TNBC patients, targets mitochondrial metabolism. BACH1 decreases glucose utilization in the TCA cycle and negatively regulates transcription of electron transport chain (ETC) genes. BACH1 depletion by shRNA or degradation by hemin sensitizes cells to ETC inhibitors such as metformin, suppressing growth of both cell line and patient-derived tumor xenografts. Expression of a heme-resistant BACH1 mutant in shBACH1 cells rescues the BACH1 phenotype and restores metformin resistance in hemin-treated cells and tumors. Finally, BACH1 gene expression inversely correlates with ETC gene expression in breast cancer patients as well as other tumor types, highlighting the clinical relevance. This study demonstrates that mitochondrial metabolism can be exploited through targeting BACH1 to sensitize breast cancer and potentially other tumor tissues to mitochondrial inhibitors.
Citation Format: Jiyoung Lee. Effective breast cancer combination therapy targeting BACH1 and mitochondrial metabolism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 802.