bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5483: SIRT1 stabilization provides a therapeutic opportunity for reversing cachexia in pancreatic cancer
Authors: Dasgupta Aneesha , Vernucci Enza , Shukla Surendra K. , Mulder Scott E. , King Ryan J. , Abrego Jaime , Chaika Nina V. , Buettner Kyla , Singh Pankaj K. , Singh Pankaj K. 
Published: August 2018

Abstract
Cancer-associated cachexia is a complex metabolic syndrome which leads to excessive loss of skeletal muscle and adipose deposits. Up to 80% of pancreatic cancer patients suffer from cachexia and nearly one third die due to complexities related to the syndrome. Treatment of cachexia will not only improve the standard of living of pancreatic cancer patients but would also improve the patient survival. In the clinic, majority of the cancer patients are diagnosed at the refractory phase of cachexia, which cannot be reversed by dietary interventions. Till late therapies have not shown promising results in clinical trials. Hence, there is an urgent need to identify new targets to combat cancer cachexia. Sirtuins are protein deacetylases which affect the activity of various transcription factors and signaling components. The expression of all the sirtuins were analyzed after culturing mouse myotubes with tumor cell-conditioned media. The expression of SIRT1 decreased consistently upon treatment of myotubes with conditioned media from multiple human pancreatic cancer cell lines. Resveratrol, which is an activator of SIRT1 rescued the wasting phenotype in the myotubes. However, treatment of pancreatic cancer cells with resveratrol also decreased cell proliferation. Hence, we designed in vivo experiments to examine the effect of resveratrol on muscle wasting irrespective of its effects on tumor burden. We generated SIRT1 knockdown pancreatic cancer cell lines and orthotopically implanted them into the pancreas in athymic nude mice. The tumor-bearing mice were subjected to an oral delivery of resveratrol. These studies demonstrated that while resveratrol had limited effect on cancer cells due to SIRT1 knockdown, resveratrol treatment still protected the mice from muscle wasting by stabilizing SIRT1 in muscles. Hence, our results indicate that resveratrol-mediated stabilization of SIRT1 in muscles can revert wasting irrespective of its effects on tumor cells. Overall, our studies demonstrate the therapeutic potential of SIRT1 stabilization by resveratrol or related class of drugs in managing cancer-associated cachexia.
Citation Format: Aneesha Dasgupta, Enza Vernucci, Surendra K. Shukla, Scott E. Mulder, Ryan J. King, Jaime Abrego, Nina V. Chaika, Kyla Buettner, Pankaj K. Singh, Pankaj K. Singh. SIRT1 stabilization provides a therapeutic opportunity for reversing cachexia in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5483.
Abstract 5498: Natural product-derived carbon nanodots overcome drug resistance through regulation of Hippo pathway effectors
Authors: Nurkesh Ayan A. , Balanay Mannix P. , Yeleusizov Tleubek , Tursynkhan Darkhan , Yang Qing , Wan Xiaoling , Manarbek Limara , Maipas Aisulu , Matkarimov Bakhyt , Zhang Yan , Fan Haiyan , Miao Li-Xia , Li Si-Pian , Chen Zhenbang , Xie Yingqiu 
Published: August 2018

Abstract
The yes-associated protein 1 (YAP) is a nuclear downstream effector of Hippo pathway that plays a critical role in various cancers. Literature shows that, in addition to nucleus, YAP also localizes in cytosol and membrane of cells. We and our collaborators previously reported that elevation of YAP associates with Arf in the genetically-engineered mouse (GEM) model of Pten/Trp53, implicating the possible correlation between Hippo/YAP and ARF in human cancers. We recently found ARF is indeed involved in dysregulation of Hippo pathway in prostate cancer. In details, ARF inhibited nuclear YAP translocation in cancer cells, and ARF knockdown suppressed the stability of YAP protein with upregulated active AKT and dysregulated phosphorylation of YAP through ARF/AKT/mTOR/YAP pathway. Here we further report that carbon nanodots (c-dots) can induce DNA damage through an increase of ROS by upregulation of γH2AX and DNA tails in PC3 and DU145 prostate cancer cells. We found that c-dots derived from natural products such as tea or beet can enter into cancer cell nucleus to interact with ARF for the regulation of the ARF-mediated signaling such as the nuclear translocation of YAP. Mechanistically, c-dots bind ARF to induce cell cycle arrest, apoptosis, and PARP cleavage in prostate cancer cells. Most importantly, addition of c-dots into cultured PC3 cells leads to the reversal of drug resistance to mTOR inhibitor Rapamycin and MET inhibitor Crizotinib by enhancing DNA damage. Moreover, c-dots suppress the tumor size and growth of PC3 cells in xenograft mouse model in vivo. Our data suggest that the nano-scale of c-dots derived from natural food may be efficient in overcoming drug resistance via augmentation of DNA damage linked cell death. Thus we reported a new approach of abolishing drug resistance of aggressive malignancy using nanoparticles, implicating an innovative avenue for precision cancer treatment.
Citation Format: Ayan A. Nurkesh, Mannix P. Balanay, Tleubek Yeleusizov, Darkhan Tursynkhan, Qing Yang, Xiaoling Wan, Limara Manarbek, Aisulu Maipas, Bakhyt Matkarimov, Yan Zhang, Haiyan Fan, Li-Xia Miao, Si-Pian Li, Zhenbang Chen, Yingqiu Xie. Natural product-derived carbon nanodots overcome drug resistance through regulation of Hippo pathway effectors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5498.
Abstract 5499: A potent BH3 mimetic targeting BCL-XL induces apoptosis regulated by PTEN loss and integrin alpha 5 in prostate cancer cells
Authors: Ren Wenying , Joshi Raghav , Mathew Paul 
Published: August 2018

Abstract
Background: PTEN-loss is a highly prevalent genomic event associated with higher risk of metastatic progression and resistance to hormonal therapy in prostate cancer. Akt inhibitor therapy in combination with abiraterone demonstrates early promise in the clinical control of PTEN-deficient prostate cancers. We have previously implicated BCL-XL in the survival of PTEN-null PC-3 prostate cancer cells in vitro, regulated by integrin alpha 5 (ITGA5) (Ren, MCR 2016). Toward advancing therapeutic strategies in PTEN-deficient prostate cancer we further assessed the link between PTEN and BCL-XL mediated prostate cancer cell survival.
Methods: Isogenic PTEN knockdown stable cell lines (VCAP and DU145) were generated by lentiviral transduction of pLKO-control-shRNA and two pLKO-PTEN-shRNAs, respectively. PTEN was exogenously expressed in PTEN-null prostate cancer cell lines (PC-3, LNCaP and C4-2B) by 1) transfecting cells with pCMV-Flag-vector or pCMV-Flag-PTEN 2) transfecting cells with pcDNA3-GFP-PTEN and then sorting GFP-PTEN-negative and GFP-PTEN-positive cells by flow cytometry. Cells were then treated with a single agent BCL-XL inhibitor (A1331852 or navitoclax (ABT263); AbbVie), PI3K (buparlisib; Selleck Chem) or Akt (ipatasertib, Selleck Chem) inhibitors or combined PI3K and BCL-2 family inhibitors. Cell survival was assessed by cell viability assay. Expression of pAkt, ITGA5 and apoptotic markers was assayed by Western blot analysis and/or flow cytometry.
Results: Notwithstanding the reduction of phospho-bad expression with PI3K inhibition, the potent BCL-XL-targeting BH3 mimetic, A1331852, compared to single agent PI3K or Akt inhibitors in titrated doses was alone sufficient to induce apoptosis and loss of cell viability in all PTEN-null prostate cancer lines tested. PTEN expression reversed the apoptotic response to BCL-XL targeting and blocked the anti-proliferative effect of PI3K or Akt inhibition in PTEN-mutant cells. PTEN knockdown induced membrane expression of ITGA5 whereas PTEN overexpression diminished ITGA5 expression.
Conclusions: PTEN regulates the apoptotic threshold in prostate cancer cells via BCL-XL independent of the PI3K/Akt pathway. The induction of ITGA5 membrane localization by PTEN loss defines a potential upstream signaling mechanism for the BCL-XL regulated apoptotic threshold in these cells. Highly potent BCL-XL inhibition requires further investigation as a therapeutic strategy in PTEN-deficient prostate cancer.
Citation Format: Wenying Ren, Raghav Joshi, Paul Mathew. A potent BH3 mimetic targeting BCL-XL induces apoptosis regulated by PTEN loss and integrin alpha 5 in prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5499.
Abstract 5500: Nitric oxide donor DETA/NO inhibits the growth of endometrial cancer cells by upregulating expression of RASSF1 and CDKN1
Authors: Taitz Hannah , Paucarmayta Ana , Cheng Robert , Maxwell George L. , Hamilton Chad A. , Wink David A. , Syed Viqar 
Published: August 2018

Abstract
Nitric oxide (NO), a small signaling molecule, is implicated in several biological processes including cancer progression. At low concentrations, it promotes cell survival and tumor progression, and at high concentrations it causes apoptosis and cell death. To date, the effects of NO donor on human endometrial cancer are largely unknown. Four endometrial cancer cell lines (Ishikawa, AN3CA, KLE and HEC-1B) with varying degrees of genetic complexity were treated with different concentrations (50-500 μM) of DETA/NO for 24 to 120 h. The effects of treatment on cell viability and invasion was determined using MTS, and Boyden chamber assays respectively. Treatment of endometrial cancer cells with DETA/NO induced a dose and time-dependent decrease in cell viability. Ishikawa and AN3CA cells were more responsive to DETA/NO induced growth inhibition compared to HEC-1B and KLE cells. Furthermore, DETA/NO effectively inhibited invasive potential of endometrial cancer cells. To understand the mechanisms by which DETA/NO elicits anti-cancer effects, RNA sequencing (RNA-seq) was used to ascertain alterations in the transcriptomes of human endometrial cancer cells. AN3CA, KLE, Ishikawa, and HEC-1B were treated with DETA/NO for 24 h and RNA was extracted. RNA-seq analysis revealed that of the twenty-one top differentially expressed genes, fourteen were upregulated and seven were downregulated in endometrial cancer cells with DETA/NO. The genes that were upregulated in all four cell lines with DETA/NO were tumor suppressors, RASSF1 and CDKN1A. The expression patterns of these genes were confirmed by Western blotting. Taken together, the results provide the first evidence in support of the anti-cancer effects of DETA/NO in endometrial cancer.
Citation Format: Hannah Taitz, Ana Paucarmayta, Robert Cheng, George L. Maxwell, Chad A. Hamilton, David A. Wink, Viqar Syed. Nitric oxide donor DETA/NO inhibits the growth of endometrial cancer cells by upregulating expression of RASSF1 and CDKN1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5500.
Abstract 5507: RAG1 high expression associated with IKZF1 dysfunction in adult B-cell acute lymphoblastic leukemia
Authors: Ge zheng , Han Qi , Ma Jinlong , Gu Yan , Song Huihui , Kapadia Malika , Dovat Sinisa , Song Chunhua 
Published: August 2018

Abstract
The recombination activating gene (RAG)-mediated recombination is the dominant mutational process and the predominant driver of oncogenic genomic rearrangement in acute lymphoblastic leukemia (ALL). This then leads to further leukemic clonal evolution. IKZF1 encodes a kruppel-like zinc finger protein, IKAROS that is essential for normal hematopoiesis and acts as a tumor suppressor in ALL. The genetic defects of a single IKZF1 allele are linked to the development of human ALL, characterized by an increased risk of relapses and poorer prognosis. We observed that RAG1 is significantly increased in subsets of B-ALL patients. High RAG1 expression correlates with high proliferation markers. IKAROS directly binds to the RAG1 promoter in B-ALL cells by quantitative chromatin-immunoprecipitation assay. IKAROS suppresses RAG1 promoter activity by luciferase reporter assay. Lentiviral IKAROS expression significantly suppresses RAG1 expression, but IKAROS shRNA promotes RAG1 expression in B-ALL cells. CK2 inhibitor by restoring IKAROS activity, significantly suppresses RAG1 expression in an IKAROS-dependent manner in B-ALL cells. RAG1 expression is significantly higher in patients with IKZF1 deletion, as compared to patients without IKZF1 deletion. Treatment with CK2 inhibitor also results in an increase in IKZF1 binding to the RAG1 promoter and suppression of RAG1 expression in primary B-ALL cells. Taken together, our results demonstrate that high expression of RAG1 correlates with high proliferation markers in B-ALL, and are the first to demonstrate that IKAROS directly suppresses RAG1 expression. Our data suggest RAG1 high expression works together with IKAROS dysfunction to drive oncogenesis of B-ALL, which have significance in an integrated prognostic model for adult ALL.
Citation Format: zheng Ge, Qi Han, Jinlong Ma, Yan Gu, Huihui Song, Malika Kapadia, Sinisa Dovat, Chunhua Song. RAG1 high expression associated with IKZF1 dysfunction in adult B-cell acute lymphoblastic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5507.
Abstract 5518: Bi-allelic loss of CDKN2A initiates melanoma invasion and metastasis via E2F1-BRN2 axis
Authors: Zeng Hanlin , Jorapur Aparna , Shain A. Hunter , Lang Ursula E. , Torres Rodrigo , Zhang Yuntian , Botton Thomas , Lin Jue , Mcneal Andrew S. , Donne Matthew , Bastian Ingmar N. , North Jeffrey , Pincus Laura , Yu Richard , Ruben Beth S. , Joseph Nancy , Ye Iwei , Bastian Boris C. , Judson Robert L. 
Published: August 2018

Abstract
CDKN2A acts as a critical tumor suppressor in melanoma, as evidenced by frequent loss of function mutations and deletion. Loss of CDKN2A is believed to permit escape from senescent pre-neoplastic cell populations through relieve of a cell cycle block mediated by its two gene products. We performed a comprehensive analysis of CDKN2A gene status, mRNA and protein expression levels of p16 and p14 in a cohort of melanomas and their adjacent pre-neoplastic lesions and observed that bi-allelic CDKN2A loss coincides with the progression stage when primary melanomas become invasive. In melanoma lines, p16INK4A, one of the protein products of the CDKN2A locus, is a potent barrier to metastasis, independent of its known role inhibiting cell proliferation. We genetically engineered primary human melanocytes to harbor CDKN2A deletions and/or BRAF V600E mutation at their endogenous BRAF locus. Using this physiologic model for the early phases of neoplastic transformation, we found no evidence for BRAF-induced senescence, rather observing that p16INK4A loss activates a master regulator of melanoma invasion, BRN2, through Rb-E2F1 pathway. These results demonstrate that one of the most frequently altered genes across human cancers, CDKN2A, has an unexpected novel role in inhibiting cellular invasion through lineage specific transcription factors and acts as an essential gatekeeper of early metastatic dissemination.
Citation Format: Hanlin Zeng, Aparna Jorapur, A. Hunter Shain, Ursula E. Lang, Rodrigo Torres, Yuntian Zhang, Thomas Botton, Jue Lin, Andrew S. Mcneal, Matthew Donne, Ingmar N. Bastian, Jeffrey North, Laura Pincus, Richard Yu, Beth S. Ruben, Nancy Joseph, Iwei Ye, Boris C. Bastian, Robert L. Judson. Bi-allelic loss of CDKN2A initiates melanoma invasion and metastasis via E2F1-BRN2 axis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5518.
Abstract 5524: Tumor suppressor Numb represses monocarboxylate transporters to reduce the glycolysis in oral carcinoma
Authors: Chou Chung-Hsien , Chaing Chun-Yu Fan , Lin Shu-Chun , Chang Kuo-Wei , Tu Hsi-Feng 
Published: August 2018

Abstract
Oral squamous cell carcinoma (OSCC) is one of the most common malignancies worldwide. Our previous studies have shown that Numb pluripotent gene drives suppressor activity against OSCC, and it is co-targeted by multiple oncogenic miRNAs. In this study, we further identified that Numb mRNA expression was down-regulated in a large fraction of OSCC tumors. We established the Numb-knockout (KO) OSCC cell subclones using CRISPR-Cas9 system. We also generated lentiviruses for exogenous expression of Numb 1 and Numb 4 isoforms. The anchorage independent growth potential was found increased in Numb-KO cell subclones. However, such eligibility was repressed after the rescue of the Numb expression by lentiviral infection. In addition, the level of lactate production and the ratio of ECAR/OCR in the Numb-KO cell subclones were higher than parental cells. The knockout of Numb was able to up-regulate the expression of monocarboxylate transporter (MCT) family members MCT1 and MCT4, but not other metabolism genes, to increase the lactate production. Knockdown of both MCT1 and MCT4 significantly decreased the anchorage independent growth and the lactate production of OSCC cells. This study provides new evidences denoting that Numb represses MCTs to attenuate the transformative capability and the glycolysis in oral carcinoma.
Citation Format: Chung-Hsien Chou, Chun-Yu Fan Chaing, Shu-Chun Lin, Kuo-Wei Chang, Hsi-Feng Tu. Tumor suppressor Numb represses monocarboxylate transporters to reduce the glycolysis in oral carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5524.
Abstract 5538: Arv7 validation in castrate resistant prostate tumors utilizing Rnascope in situ hybridization assay
Authors: Cash-Mason Tanesha , Wong Jackson , Martinez Martinez , Sharp Michael , Karkera Jayaprakash , Alvarez John D. , Chu Gerald C. , Thomas Shibu , Li Weiman , Tian S. Ken 
Published: August 2018

Abstract
Background
Androgen receptor splice variant 7 (ARV7) is a ligand-independent transcription factor associated with resistance to androgen deprivation therapy. There are efforts in development to monitor ARV7 expression during the treatment of patients with prostate cancer.
Methods
We evaluated ARV7 expression in primary and metastatic prostate adenocarcinomas tissues utilizing automated RNAScope (Advanced Cell Diagnostics) ISH assay, Immunohistochemistry (IHC) and quantitative PCR (qPCR). The novel RNAscope ISH assay was used for direct chromogenic visualization of RNA transcripts and to confirm positivity as an orthogonal approach to validate IHC and quantitative qPCR assay findings. We screened a total of 44 CRPC FFPE tumor samples by IHC and a subset of 28 (excluding controls) with the ISH and qPCR assays. Samples for qPCR were enriched for tumor by macrodissection. RNAScope Scoring Criteria was used to score ISH expression and raw Ct values were normalized to the RPL19 housekeeping gene for qPCR. Thresholds for each assay was established by comparing the findings with the other 2 assays. The data was calculated as ARV7 (+) or ARV7 (-) based on thresholds and compared to the other 2 assays to establish assay performance statistics.
Results
The ISH screening of 28 CRPC tumors resulted in 16 tumors with some level of positivity and approximately 10 tumors with significant positivity. Of the 44 CRPC tumors stained by IHC, 16 tumors showed various levels of ARV7 nuclear positivity and 8 tumors with strong positivity.
Conclusions
The detection of ARV7 was achieved in three independent assays. The correlation of three orthogonal data sets were used to identify positive and negative tissues. ISH has the potential for greater sensitivity compared to traditional IHC. The development of automated RNAscope ISH assay allows for more samples to run in a standardized manner with minimal inter-operator variably and requires less hands on-time gives consistently reproducible results.
Citation Format: Tanesha Cash-Mason, Jackson Wong, Martinez Martinez, Michael Sharp, Jayaprakash Karkera, John D. Alvarez, Gerald C. Chu, Shibu Thomas, Weiman Li, S. Ken Tian. Arv7 validation in castrate resistant prostate tumors utilizing Rnascope in situ hybridization assay [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5538.
Abstract 5541: Clinical impact of hypothyroidism and PD-L1 SNPs in patients having non-small cell lung cancer treated with nivolumab
Authors: Funazo Tomoko , Ozasa Hiroaki , Nomizo Takashi , Tsuji Takahiro , Yasuda Yuto , Yoshida Hironori , Sakamori Yuichi , Nagai Hiroki , Hirai Toyohiro , Kim Young Hak 
Published: August 2018

Abstract
Although Nivolumab is one of the immune-checkpoint inhibitors that improves the prognosis of lung cancer, it is known to cause immune-related adverse events (irAEs). It has recently been reported that patients with irAEs have a longer progression-free survival (PFS) than those without irAEs. However, there are few detailed reports on irAEs in patients with NSCLC. We previously reported the association between single nucleotide polymorphisms (SNPs) of programmed death ligand 1 (PD-L1) and PFS for nivolumab treatment. Therefore, we hypothesized that the SNPs of programed death 1 (PD-1) and PD-L1 were associated with irAEs and PFS.
Between January 2016 and March 2017, 95 consecutive patients with advanced NSCLC were treated with nivolumab and 80 of these patients participated in this study. Patients who did not provide informed consent, patients without follow-up blood tests, patients with double cancer history, and patients diagnosed with disease progression within 15 days were excluded. The prevalence of genotypes between patients with adverse events and those without adverse events was evaluated. PFS was calculated in 59 out of 80 patients excluding liver metastasis at baseline imaging.
The response rate was 15% and the median PFS was 85 days in this cohort. For all adverse events, hypothyroidism, which is defined as a low free T4 level, was associated with SNPs of PD-L1: rs1411262 and rs822339. Moreover, patients with hypothyroidism had a significantly longer PFS than those without hypothyroidism (67 days vs N.R.; P= 0.0055). The T/T genotype of rs1411262 and the A/A genotype of rs822339 were significantly associated with longer PFS than the C/T and C/C genotypes of rs1411262, and the A/G and G/G genotypes of rs822339, respectively (82 versus 175 days; P = 0.0468).
In conclusion, the T allele of rs1411262 and the A allele of rs822339 were significantly associated with hypothyroidism and longer PFS. SNPs of PD-L1 may be associated with functions of the PD-1 and PD-L1 pathway.
Hypothyroidism and SNPs of PD-L1hypothyroidism (-)hypothyroidism (+)P value(n=7)(n=73)rs14112620190.0386CC336CT418TTrs822339AA0190.0386AG336GG418
Citation Format: Tomoko Funazo, Hiroaki Ozasa, Takashi Nomizo, Takahiro Tsuji, Yuto Yasuda, Hironori Yoshida, Yuichi Sakamori, Hiroki Nagai, Toyohiro Hirai, Young Hak Kim. Clinical impact of hypothyroidism and PD-L1 SNPs in patients having non-small cell lung cancer treated with nivolumab [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5541.