bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2993: Impaired PARP1 DNA repair defines chemo-sensitivity in IDH1 mutant cell
Authors: Yang Chunzhang , Lu Yanxin , Liu Yang , Gilbert Mark , Wu Jing 
Published: August 2019

Abstract
INTRODUCTION: Mutations in isocitrate dehydrogenase (IDH1/2) are the most prevalent genetic deficiency in lower grade gliomas. IDH-mutated in glioma exhibits better clinical outcomes with longer patient survival, as well as greater sensitivity to chemotherapy. In the present study, we explored the molecular mechanisms that determine the chemo-sensitivity in IDH1-mutated cells, and seek for potential therapeutic strategy by targeting PARP/BER DNA repair pathway.
METHODS: We investigated transcriptomic profile from WHO grade II/III glioma based on their IDH1/2 mutation status. We established IDH1-mutated cells and investigated the alterations in nicotinamide adenine dinucleotide (NAD+), Poly (ADP-ribose) polymerase (PARP)-associated DNA repair and DNA damage in these cells in respond to temozolomide (TMZ). Moreover, we evaluated a PARP inhibitor olaparib and its synergistic effect on TMZ-associated cytotoxicity.
RESULTS: Our results showed that the IDH1-mutated cells are more vulnerable to genotoxic agent, which recapitulate the disease phenotype in IDH1-mutated glioma. TMZ treatment resulted in over 20-fold increase of cell death in IDH1-mutated cells compared with wild type counterpart. IDH1-mutated cells exhibited over 1.3-fold DNA damage and over 1.42-fold cellular apoptosis under TMZ treatment. Mechanistically, IDH1-mutated cells exhibited compromised NAD+ metabolism, as well as concomitant PARP/BER DNA repair pathway. IDH1-mutated cells produced 83.8% less poly (ADP-ribose) polymer (pADPR), an important substrate for PARP-associated DNA repair, during TMZ treatment, suggesting their incompetence to maintain genomic integrity due to decreased availability of NAD+. Targeting the PARP-associated DNA repair pathway using olaparib, an FDA-approved PARP inhibitor, remarkably potentiated TMZ-induced cytotoxic effects by 2.16-fold in IDH1-mutated cells.
CONCLUSION: Our findings demonstrate that metabolic defects in IDH1-mutated cells affect PARP-associated DNA repair pathway via NAD+ depletion, and therefore prompt the sensitivity to chemotherapies. Targeting PARP-associated DNA repair pathway suggests a novel therapeutic avenue for IDH1-mutated gliomas.
Citation Format: Chunzhang Yang, Yanxin Lu, Yang Liu, Mark Gilbert, Jing Wu. Impaired PARP1 DNA repair defines chemo-sensitivity in IDH1 mutant cell [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 2993.
Abstract 2995: Thymoquinone attenuates breast cancer cell resistance to paclitaxel via targeting tumor associated stem cell population
Authors: Bashmail Hanan A. , Alamoudi Aliaa A. , Hegazy Gehan A. , Agabnoor Ghada M.A. , Noorwali Abdulwahab , Al-Abd Ahmed M. 
Published: August 2019

Abstract
Breast cancer remains the most common type of cancer in females, and remains to be one of the most leading causes of death worldwide. This led to increasing the interest to use adjuvant anti-cancer therapy to improve the efficacy of in-clinical use chemotherapeutic agents. Thymoquinone (TQ) is a naturally occurring bioactive compound which showed cumulative evidences of anticancer properties. Herein, we assessed the potential chemomodulatory effect of TQ as an adjuvant therapy in combination with paclitaxel (PTX) against breast cancer cells. Cytotoxic profiles of TQ alone or in combination with PTX were evaluated in MCF7 and T47D breast cancer cell lines. TQ showed cytotoxic effect against MCF7 and T47D cells with IC50’s of 64.93±14 µM and 165±2 µM, respectively. In MCF7, TQ did not change PTX’s IC50, and the combination index was indicative of antagonism (CI-value = 1.3). Similarly in T47D, combination of TQ with PTX increased PTX’s IC50 from 90±8 nM to 140±20 nM with CI-value of 1.5 indicating antagonism. However, it was found that TQ completely depleted PTX resistant fractions in both cancer cell lines under investigation. Moreover, apoptotic and autophagic cell death due to combination of PTX with TQ were significantly increased in T47D compared to PTX treatment alone by 5.6 and 1.7 folds, respectively. In MCF7, combination of TQ with PTX significantly increased autophagic cell death compared to PTX treatment alone. Furthermore, tumor associated stem cell clone (CD44(+)/CD24(-)/(low) was assessed by flow cytometry in MCF7 and T47D cells. TQ alone significantly decreased CD44+/CD24- tumor associated stem cell clone by 12.4±0.8%. In addition, combination of PTX with TQ further depleted CD44+/CD24- cell clone by 32.3±0.08%. Finally, TQ alone significantly downregulated TWIST-1, and upregulated SNAIL2 gene expression as an evidence to decreased cell resistance to PTX. In conclusion, TQ enhances PTX anticancer profile against breast cancer cells via depleting tumor associated stem cells clone rather than potentiating its direct cell killing effect.
Citation Format: Hanan A. Bashmail, Aliaa A. Alamoudi, Gehan A. Hegazy, Ghada M.A. Agabnoor, Abdulwahab Noorwali, Ahmed M. Al-Abd. Thymoquinone attenuates breast cancer cell resistance to paclitaxel via targeting tumor associated stem cell population [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 2995.
Abstract 2996: Systemic depletion of L-methionine with an engineered human enzyme for the treatment of melanoma
Authors: Wilder Carly S. , Saha Achinto , Georgiou George , Stone Everett , DiGiovanni John 
Published: August 2019

Abstract
Metastatic melanoma is an aggressive form of cancer responsible for the majority of skin cancer related deaths. While treatment for metastatic melanoma has improved in recent years with the introduction of targeted therapies and immunotherapies, the five-year survival rate for stage IV melanoma remains only 15-20%. To address the need for alternative options for melanoma treatment, we have begun exploring use of an engineered human enzyme called methionine-gamma-lyase (hMGL). Many cancers, including melanoma, have a high requirement for methionine in comparison with non-cancerous cells. The hMGL enzyme works to exploit this difference by degrading extracellular L-methionine resulting in cancer cell starvation. The hypothesis tested in this research is that the systemic depletion of L-methionine using hMGL will provide significant benefits for melanoma treatment alone or in combination with other therapeutic agents. Treatment of several melanoma cell lines (A375, Hs294T, Skmel28, and B16F10) with various concentrations of hMGL demonstrated that L-methionine depletion reduced survival and led to a G2 cell cycle arrest. To investigate the mechanism of action, analyses of melanoma cells treated with hMGL have shown that signal transducer and activator of transcription 3 (STAT3) tyrosine phosphorylation is significantly reduced. Additionally, hMGL treatment leads to activation of the uncharged tRNA amino acid sensing pathway as shown by an increase in p-eIF2α and Sestrin 2 and an increase in autophagy shown by a decrease in p-ULKSer757 and an increase in cleaved LC3B. Because L-methionine depletion affects levels of glutathione through reduction of cysteine synthesis, preliminary experiments were conducted to evaluate hMGL treatment combined with a thioredoxin reductase inhibitor. This combination, targeting two different intracellular antioxidant pathways, resulted in synergistic inhibition of survival in multiple melanoma cell lines. The current data support the hypothesis that L-methionine depletion using hMGL may have therapeutic efficacy either alone or in combinations for melanoma treatment. Research funded by CPRIT grant RP180590.
Citation Format: Carly S. Wilder, Achinto Saha, George Georgiou, Everett Stone, John DiGiovanni. Systemic depletion of L-methionine with an engineered human enzyme for the treatment of melanoma [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 2996.
Abstract 3004: Anticancer effects and associated molecular changes of Carica papaya against prostate cancer
Authors: Singh Surya Pratap , Mathan Sivapar V. , Dheeraj Arpit , Tailor Dhanir , Singh Rana P. , Acharya Arbind 
Published: August 2019

Abstract
Carica papaya (papaya), from the family of Caricaceae, is a perennial plant originating from the Southern part of Mexico. Carica papaya leaf extract (CPE) has been traditionally used to treat various diseases, including infectious diseases and cancer. However, the anticancer effects and molecular mechanism of CPE are elusive. The aim of our study is to examine the anticancer effects of aqueous leaf extract of Carica papaya against prostate cancer (PCa). We investigated the effect of CPE on LNCaP, DU145 and PC-3 PCa cells. CPE treatment (5, 10, 25µl/ml) significantly reduced the cell proliferation and induced cell death in PCa cells. Furthermore, we found that CPE induced G1, S and G1 as well as G2/M phase cell cycle arrest in LNCaP, DU145, and PC-3 cells, respectively. At molecular level, the cell cycle arrest was associated with decreased expression of CDK 4, cyclin D1, cyclin B1, and PCNA. CPE induced cell death was associatedwith depolarization of mitochondrial membrane potential, increase in ratio of Bax/Bcl2, cleavage of caspase-3 and cleaved -Poly(ADP-ribose) polymerase (PARP). CPE treatment also reduced mitochondrial fission and induced mitochondrial fusion by reducing the level of Drp1 protein. Further, we observed that CPE increased the expression of E-cadherin and decreased the expression of N-cadherin and vimentin. We checked the CPE toxicity in C57BL/6 male mice. We found that oral administration of CPE(0.25%, 0.5% and 1% v/v) in drinking water did not show any significant changes in body weight, water consumption and food intake as compared to control group. Collectively, CPE inhibited cell proliferation, induced cell death via apoptosis, mitochondrial fusion, epithelial marker and reduced mesenchymal markers.In vivo toxicity study with CPE treatment via drinking water was found to be non-toxic. These findings suggest that CPE has potential as anticancer therapeutic option for prevention and treatment of prostate cancer.
Citation Format: Surya Pratap Singh, Sivapar V. Mathan, Arpit Dheeraj, Dhanir Tailor, Rana P. Singh, Arbind Acharya. Anticancer effects and associated molecular changes of Carica papaya against prostate 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 3004.
Abstract 3005: High density lipoprotein mimics inhibit prostate cancer exosome-mediated communication with myeloid cells
Authors: Henrich Stephen E. , McMahon Kaylin M. , Plebanek Michael P. , Thaxton C. Shad 
Published: August 2019

Abstract
Introduction: Exosomes are 30-150 nm membrane-bound vesicles that mediate intercellular communication and are secreted in abundance by neoplastic cells. Tumor-derived exosomes are capable of transmitting pro-malignant signals to target cells at local or distant sites to enhance tumor invasiveness and promote metastasis. A sub-set of this pro-malignant intercellular communication is dependent upon target cell cholesterol homeostasis. Here, we show that prostate cancer exosome communication with myeloid cells can be inhibited by treatment with high density lipoprotein mimetic nanoparticles (HDL NPs), which reduce cholesterol in myeloid cells in a targeted fashion.
Methods: Exosomes were isolated by ultracentrifugation of conditioned media from enzalutamide resistant CWR-R1 cells and used for all experiments. In vitro assays were conducted using murine bone marrow macrophages obtained from culture of total murine bone marrow in M-CSF for 7 days. Confocal microscopy and flow cytometry were used for in vitro and in vivo uptake assays. Osteoclastogenesis assays were performed using a commercially available TRAP staining kit (Sigma-Aldrich). NF-kB signaling experiments were performed using a reporter human monocyte cell line (THP1-Dual). HDL NPs were synthesized using 5 nm gold nanoparticle templates, apolipoprotein A-1, and phospholipids.
Results: HDL NPs were found to inhibit the cellular uptake of prostate cancer exosomes in mouse bone marrow macrophages in vitro. Furthermore, HDL NPs inhibited exosome-induced osteoclastogenesis and exosome-induced monocyte NF-kB signaling. Finally, HDL NP-mediated inhibition of exosome communication was found to be dependent upon scavenger receptor type B-1 (SR-B1). SR-B1 was shown to be expressed ubiquitously in mouse bone marrow macrophages; and HDL NPs were unable to inhibit exosome communication in bone marrow macrophages derived from SR-B1-/- mouse bone marrow.
Conclusion: These data demonstrate that HDL NPs inhibit prostate cancer exosome communication with murine myeloid cells, as evidenced by cellular uptake, osteoclastogenesis, and NF-kB signaling. Moreover, SR-B1 is required for HDL NP inhibition of PCa exosome communication. In sum, these results indicate that target cell cholesterol homeostasis may be important for exosome-mediated signaling in prostate cancer, particularly in immune cells and in the bone microenvironment, and that HDL NPs are potent inhibitors of PCa exosome-mediated signaling.
Citation Format: Stephen E. Henrich, Kaylin M. McMahon, Michael P. Plebanek, C. Shad Thaxton. High density lipoprotein mimics inhibit prostate cancer exosome-mediated communication with myeloid 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 3005.
Abstract 3007: Validation of an NGS panel assay for detection of hotspot cancer somatic mutations
Authors: Li Wenzhi , She Henry , Tian Xiaohua , Neja Margaret , Harris Adrian , Li Yuhua 
Published: August 2019

Abstract
Background
The gene tests to predict whether cancers respond to specific targeted therapies or prediction of prognosis has quickly increased over the last decade. Next-generation sequencing (NGS) has become a powerful tool for high-throughput and sensitive gene mutation testing, which is required for development of targeted therapies, clinical trials, and further research. The aim of this study was to validate the AmpliSeq for Illumina Cancer Hotspot Panel v2 on the Illumina MiSeq platform and simultaneously analyze 2800 somatic mutations across the hotspot regions of 50 genes, including SNP and small INDEL, with known associations to cancer, as identified in the Catalogue of Somatic Mutations in Cancer (COSMIC) database. This panel enables the study of the genes associated with different cancer types, including the cancers of the lung, colon, breast, thyroid, oral, bladder, prostate, liver, kidney, ovarian and cervix, etc.
Methods and findings
We validated this assay using the genomic DNA extracted from human paraffin-embedded (FFPE) samples and peripheral blood with negative control DNA (NA12878), positive control DNA (HD701), blank control as well as the global proficiency testing samples. Following two lab scientists parallel NGS library preparation, sequenced on Miseq platform (2x150 PE) and analyzed using a pipeline centered on Illumina Basespace, the somatic mutations were called at an average number of reads coverage &gt;2500X, variant frequency cutoff 1%. An integrated test report can be generated within five working days. Panel sequencing analysis showed that the mutations are 100% concordance with known mutations and consistent in four runs, between lab personal performances, different input DNA concentrations (1ng-100ng), etc. Briefly, 25 mutations were detected in the FFPE samples and 20 mutations detected in proficiency testing samples. The variant types, HGVS ID and frequency are 100% match with its standard results which are a prove of precision and sensitivity.
Conclusions
A sensitive, high-throughput, pan-cancer mutation panel for NGS analysis of cancer hot-spot mutations in 50 genes was highly repeatable and reproducible and validated for routine application in a gene testing lab.
Note: This abstract was not presented at the meeting.
Citation Format: Wenzhi Li, Henry She, Xiaohua Tian, Margaret Neja, Adrian Harris, Yuhua Li. Validation of an NGS panel assay for detection of hotspot cancer somatic mutations [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 3007.
Abstract 301: Concurrent targeting of BMI1 and CDK4/6 inhibited breast cancer tumorigenicity in vitro and in vivo
Authors: Alajez Nehad M. 
Published: August 2019

Abstract
Despite recent advances in cancer management and therapy, resistance to cytotoxic medications remains a major clinical challenge. Intratumoral heterogeneity appears to play crucial role in drug resistance; therefore, combination-based approaches are currently gaining momentum. In the current study, we investigated the ramifications of concurrent targeting of tumor-initiating cells (using BMI1 specific inhibitor, PTC-209) and cell cycle progressiontargeting CDK4/CDK6 using palbociclib on breast, colorectal and prostate cancer cell growth in vitro and in vivo. PTC-209 reduced BMI1 protein expression, while palbociclib (PB) inhibitedCDK4, Rb, and PRb Ser795 phosphorylation. PTC-209 and palbociclib exhibited dose-dependent cytotoxic effects against MDA-MB-231, HCT-116, and PC-3 cell models, which was more profound in the combination group. Global gene expression profiling in MDA-MB-231 treated with PTC-209 revealed multiple affected cellular pathways including insulin signaling, focal adhesion, DNA damage response, and Wnt/pluripotency. On the other hand, PB treatment ofMDA-MB-231 led to substantial changes in gene expression affecting mainly cell cycle progression. PTC-209 and palbociclib reduced colony formation potential, sphere formation, cell migration, and cell viability, which was further enhanced in the combination group. Consistent with our results in vitro, combination treatment of PTC-209 and palbociclib reduced tumor growth more profoundly than either of these drugs alone in in vivo model of MDA-MD-231 cells. Therefore, our data suggest concurrent targeting of BMI1 and CDK4/CDK6 might provide novel therapeutic opportunity for breast, colorectal, and prostate cancer.
Citation Format: Nehad M. Alajez. Concurrent targeting of BMI1 and CDK4/6 inhibited breast cancer tumorigenicity in vitro and in vivo [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 301.
Abstract 3016: Dicer overexpression contributes to chemoresistance in colorectal cancer via up-regulating a set of miRNAs
Authors: Lin Li Jyuan , Hung Liang-Yi 
Published: August 2019

Abstract
Chemotherapy has a good success rate in the treatment of colorectal cancer; however, recurrence of colorectal cancer is still frequent due to acquired resistance. Aurora-A, a cell cycle-regulated kinase, plays an important role in colorectal cancer development and drug resistance. Dicer, one of the key enzymes of the microRNA (miRNA) biogenesis pathway, may be involved in chemoresistance through regulating the expression of miRNAs. According to the TCGA database, the expression levels of Dicer and Aurora-A were increased in colorectal cancer, which may contribute to chemoresistance. Our results showed that the protein levels of Dicer and Aurora-A are increased in oxaliplatin resistant cell lines. Knocked-down expression of Dicer or Aurora-A can enhance drug sensitivity in oxaliplatin-resistant cells; in contrast, overexpression of Dicer or Aurora-A increased drug resistance in parental drug sensitive cells. By next-generation sequencing, we found that the expression of a set of miRNAs is increased in oxaliplatin resistant cells. Dicer overexpression enhances the expression of those miRNAs in drug sensitive parental cells. Clinical evaluation further confirmed the increased expression of those miRNA in the plasma of CRC patients with a poor response to oxaliplatin. Our results suggest that those miRNAs may act as biomarkers to predict oxaliplatin response in colorectal cancer by detecting their plasma miRNAs. The molecular mechanism of those miRNAs in regulating the drug response is currently under our investigation.
Citation Format: Li Jyuan Lin, Liang-Yi Hung. Dicer overexpression contributes to chemoresistance in colorectal cancer via up-regulating a set of miRNAs [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 3016.
Abstract 3040: The expressional effects of RBBP6 in breast cancer cells are p53-dependent
Authors: Moela Pontsho , Motadi Lesetja , Lekganyane Marcia 
Published: August 2019

Abstract
The incidence rate of breast cancer has increased beyond that of lung cancer, making it the most common malignancy among women. Breast tumor progression is partly because of p53 inactivation by overexpressed that possess p53 binding domain. RBBP6 forms a member of ubiquitous regulatory proteins because its RING finger-like domain has an E3 ligase activity. The overexpression of RBBP6 in several malignancies makes it a potential target in cancer management. However, there is no evidence on whether the effect of RBBP6 on cell growth and apoptosis is cell line dependent, more especially in breast cancer cell lines that have distinct p53 expression profiles. Therefore, the aim of this study was to evaluate the RBBP6 effects on cell growth and apoptosis in breast cancer cell lines with different p53 expression profiles. RBBP6 expression was successfully manipulated using gene silencing and protein overexpression techniques in MCF-7 and MDA-MB-231 cell lines. Transfected cells were co-treated with anti-cancer agents followed by apoptosis detection using confocal microscopy and flow cytometry, which was further confirmed by caspase 3/7 activity and quantification of apoptotic genes. RBBP6 was overexpressed in breast cancer tissues that were classified as stage 3 and 4 while in stage 1 it was expressed but at much lower levels. The wt. p53-expressing MCF-7 cell line was more susceptible to apoptosis induction as opposed to the mt. p53-expressing MDA-MB-231. RBBP6 silencing led to a significant accumulation of p53 expression in MCF-7 as compared to MDA-MB-231. Co-treatment with GABA and camptothecin seemed to sensitize the cells to apoptosis induction. These data suggest that RBBP6 silencing triggers significant levels of intrinsic apoptosis and over-expression appears to promote cell proliferation in wild-type p53-expressing MCF-7 rather than in MDA-MB-231 cells. In conclusion, the effect of RBBP6 on cell proliferation and apoptosis induction in breast cancer seem to be cell line dependent based on p53 status.
Note: This abstract was not presented at the meeting.
Citation Format: Pontsho Moela, Lesetja Motadi, Marcia Lekganyane. The expressional effects of RBBP6 in breast cancer cells are p53-dependent [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 3040.