bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2345: Statin use associated with reduced risk of hepatocellular carcinoma recurrence following liver resection: A systematic review and meta-analysis
Authors: Yeung Chun Philip , Cheung Siu Tim , Ng Kwok Chai Kelvin , Lai Bo San Paul , Chong Ching Ning Charing 
Published: September 2020

Abstract
The effect of statins in preventing hepatocellular carcinoma (HCC) recurrence after curative liver resection has been controversial. Some retrospective studies identified perioperative use of statins was associated with significantly lower risk of HCC recurrence and improve recurrence-free survival (RFS) after liver resection, among patients with or without chronic hepatitis viral infection in multivariate survival analysis. However, a recent single-center study enrolled 430 cases in Taiwan revealed that the protective effect of statins was only significant in univariate analysis but not significant in multivariate analyses. To evaluate the effect of statins on the risk of HCC recurrence after curative liver resections, we performed a systematic review and meta-analysis on this topic. A systematic search of Medline, Embase, and Web of Science was conducted through December 2019. Studies were included if they evaluated perioperative exposure to statins, reported the recurrence of HCC after curative resection, and reported hazard ratios (HR) of multivariable analysis by Cox proportional hazards model. Summary HR estimates with 95% confidence intervals (CI) were calculated using the random-effects model. The analysis included 5 studies reporting the recurrence of HCC among 8,586 patients after liver resection, in which 411 of them received perioperative statins treatments. A meta-analysis of the studies showed a significant (39%) reduction in the risk of HCC recurrence among patients who took statins (adjusted HR, 0.61; 95% CI, 0.49-0.76), with no or little heterogeneity among studies (χ2=5.58, df=4, I2=28%). In conclusion, perioperative statins use may improve recurrence-free survival and decrease the risk of HCC recurrence after curative liver resection. Further prospective studies and larger randomized controlled trials (RCTs) are warranted to validate the conclusion.
Statin usersNon-statin usersAdjusted Hazard RatioStudyTotalTotalWeightIV, Random, 95%CIYear of publicationWu 2012175439437.6%0.68 (0.53-0.87)2012Lee 2016132207831.2%0.66 (0.49-0.90)2016Kawaguchi 2017317037.0%0.34 (0.12-0.75)2017Nishio 20184360014.5%0.42 (0.25-0.71)2018Young 2019304009.8%0.79 (0.41-1.52)2019Total (95% CI)4118175100.0%0.61 (0.49-0.76)Heterogeneity: Tau2=0.02; Chi2=5.58, df=4 (p=0.23); I2=28%Test for overall effect: Z=4.43 (p&lt;0.00001)
Citation Format: Chun Philip Yeung, Siu Tim Cheung, Kwok Chai Kelvin Ng, Bo San Paul Lai, Ching Ning Charing Chong. Statin use associated with reduced risk of hepatocellular carcinoma recurrence following liver resection: A systematic review and meta-analysis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2345.
Abstract 2347: Incidence and mortality rate of liver and intrahepatic bile duct cancer in the United States, 2000-2016
Authors: Koko Michael Rutalira , Mutamba Glodi 
Published: September 2020

Abstract
Introduction: Liver and intrahepatic bile duct cancer is highly deadly. Incidence and mortality rates of Liver and intrahepatic bile duct cancer have increased significantly from 2000-2016 in the United States. The purpose of this study is to investigate the incidence and mortality rates of this cancer according to sex and race.
Methods: We used the Surveillance, Epidemiology, and End Results (SEER) 18 data to calculate age-adjusted incidence and mortality rates from 2000-2016. Annual Percent Change (APC) was obtained for incidence and mortality rates by sex and race.
Results: Between 2000 and 2016, the incidence rate increased significantly for both male and female from 8.9 to 13.0 and 3.3 to 4.7 per 100,000 persons, respectively. Additionally, the highest incidence rates have been reported among Hispanic, non-Hispanic American Indian/Alaska Native and non-Hispanic Asian or pacific Islander with 13.5, 14.6 and 11.6 per 100,000 persons, respectively. Overall mortality rate has increased specifically among male from 5.1 to 10.9 per 100,000 persons during the same period. Hispanic, non-Hispanic American Indian/Alaska Native and non-Hispanic Asian or Pacific Islander still have the highest mortality rate compared to other race/ethnicity with 11.3, 12.9 and 9.4 per 100,000 persons), respectively. From 2015 to 2016, incidence and mortality rates have decreased among all races and gender.
Conclusions: Hispanic, non-Hispanic American-Indian/Alaska native and non-Hispanic Asian or pacific Islander are at greater risk of developing and dying from this cancer. Additionally, males are more likely to acquire and die from this cancer. Prevention programs should focus on these populations in order to reduce the burden of this cancer. Further studies are necessary to examine the alarming increase in overall incidence and mortality rates of this cancer.
Citation Format: Michael Rutalira Koko, Glodi Mutamba. Incidence and mortality rate of liver and intrahepatic bile duct cancer in the United States, 2000-2016 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2347.
Abstract 240: Inhibition of glycogen degradation sensitizes glioblastoma cells to ionizing radiation
Authors: Hendriks Anne M. , Zois Christos E. , Haider Syed B. , Pires Elisabete , Kalamida Dimitra , Lagerholm Christoffer , Morris John , McCullagh James S. , Fehrmann Rudolf S. , den Dunnen Wilfred F. , Harris Adrian L. , Jalving Mathilde 
Published: September 2020

Abstract
Glycogen storage has been demonstrated in multiple cancer cell lines and is upregulated in response to hypoxia both in vitro and in vivo. Evidence supports a potential role of the “glycogen shunt”, that describes the cycling of glucose through glycogen to subsequently fuel glycolysis, in brain tumors. Glioblastoma (GBM) is the most common and most deadly central nervous system tumor, and is characterized by hypoxia and metabolic reprogramming. We found that inhibition of glycogen degradation by downregulation of glycogen phosphorylase liver isoform (PYGL) in GBM cells led to a decrease in clonogenic growth and sensitization to ionizing radiation (IR) doses of 10-12 Gy. Control cells also showed growth impairment but resumed growth 10 days after IR exposure, while PYGL knockdown cells did not. To understand these different responses to high dose IR, we studied the intra-cellular effects of IR in control and PYGL knockdown GBM cells. Five days after IR exposure of PYGL knockdown cells, mitotic catastrophe and a senescence-like morphology were seen. Dysregulation of autophagy, accumulation of elongated and fragmented mitochondria, decrease in oxygen consumption rate and extracellular acidification rate, and increased pAMPK and pACC expression were shown in irradiated PYGL knockdown cells compared to control cells, suggesting metabolic stress. In human GBMs, PYGL mRNA expression was higher than in normal brain tissue and low PYGL mRNA expression was correlated with improved survival rates (hazard ratio 1.32, 95% confidence interval 1.08 - 1.61, P = 0.006). Immunohistochemical PYGL expression was also increased in human GBM versus normal brain tissue. In conclusion, inhibition of glycogen degradation sensitizes GBM cells to high dose IR, the cornerstone of GBM treatment, and may provide a way forward to improve treatment of primary GBMs.
Citation Format: Anne M. Hendriks, Christos E. Zois, Syed B. Haider, Elisabete Pires, Dimitra Kalamida, Christoffer Lagerholm, John Morris, James S. McCullagh, Rudolf S. Fehrmann, Wilfred F. den Dunnen, Adrian L. Harris, Mathilde Jalving. Inhibition of glycogen degradation sensitizes glioblastoma cells to ionizing radiation [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 240.
Abstract 2402: Apoptosis induced by non-thermal atmospheric pressure bio-compatible soft jet plasma on brain tumor through p38/MAPK signaling pathways
Authors: Han Ihn 
Published: September 2020

Abstract
Brain tumor is one of the most lethal forms of cancer to human beings, among which Glioblastoma astrocytoma is the most familiar and quickly progressing type of astrocytic brain tumor in adults with poor prognosis are still a therapeutic challenge. Current therapy options at diagnosis are multimodal and include surgical resection, radiation, and chemotherapy but difficulty to failure of drug delivery through the blood-brain barrier, tumor response to chemotherapy and intrinsic resistance of tumor cells. Therefore new therapy is needed that can afford selective targeting of proliferating cells to promote current therapies. Non-thermal plasma can be considered as a potential cancer therapy for the alteration of biological and clinical applications by generating reactive oxygen species (ROS) and reactive nitrogen species (RNS). In our study, we designate the effects of a NBP-J device to U87MG cell line. Previous research work established that jet plasma could induce apoptosis of various cancer cells, in particular indicative the selective cytotoxicity of cancer cells over normal cells. In this study, we assessed the effects of NBP-J on the U87MG brain cancer cell line including different effects and the physicochemical and biological correlation between the RONS cascade and p38/MAPK signaling pathway on the dose (time) dependent manner. The results of this study shows that the soft jet plasma significantly inhibits cell proliferation, inhibit survival pathway and induce apoptosis by p38/MAPK pathway in U87MG cells. The current results reveal that soft jet plasma has a powerful cytotoxic effect against brain cancer cells. Taken together, our results showed that NBP-J can become potential applications for effective and safe clinical trials for cancer therapy.
Keywords: Non-thermal atmospheric-pressure plasma, soft jet plasma, Human glioblastoma, Cancer therapy.
Acknowledgement
This work was supported by the Leading Foreign Research Institute Recruitment Program through the National Research Foundation of Korea (NRF- 2016K1A4A3914113) funded by the Ministry of Science, ICT, and Future Planning (MSIP) of the Korean Government for EH. Choi, I. Han. Also this work was supported by the Basic Science Research Program through the Ministry of Science ICT of Korea (2019R1H1A2101686) for I. Han.
Citation Format: Ihn Han. Apoptosis induced by non-thermal atmospheric pressure bio-compatible soft jet plasma on brain tumor through p38/MAPK signaling pathways [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2402.
Abstract 2410: Supraphysiological androgens induce ferroptotic cell death in prostate cancer cells
Authors: Kumar Rajendra , Boyapati Kavya , Thomas Naiju , Topiwala Deven , Kanacharoen Suthicha , Owoyemi Olutosin , Coffey Max , Carducci Michael , Markowski Mark C. , Antonarakis Emmanuel S. , Pardoll Drew , Denmeade Samuel , Kachhap Sushant K. 
Published: September 2020

Abstract
Castration resistant prostate cancer (CRPC) first manifests as a sustained rise in the androgen-responsive gene, PSA, consistent with reactivation of a functioning androgen receptor (AR) axis. This observation led to the development of “second-line” therapies aimed at further blocking androgen/AR signaling. Unfortunately, resistance to these agents can also develop quickly. Paradoxically, several studies have suggested that the growth of AR-positive human CRPC cell lines may be inhibited by supraphysiologic levels of testosterone (SupT). These studies suggested that the adaptive reliance on AR signaling by CRPC cells becomes a therapeutic liability that can be exploited through the administration of SupT, which we termed as bipolar androgen therapy (BAT). Understanding how BAT works at the molecular and cellular levels might help in rationally combining BAT with other agents to achieve increased efficacy and tumor responses. Our data indicates that SupT induces autophagy mediated degradation of ferritin in prostate cancer (PCa) cells. Degradation of ferritin results in increase in labile iron pool increasing lipid peroxidation. Our data further indicates that SupT distinctly induces ferroptosis, a nonapoptotic regulated form of cell death induced by the accumulation of labile iron. Ferroptosis is thought to have tumor suppressing capabilities by clearing tumor cells via immune system activation. BAT has been discussed as a potential therapy for prostate cancer, but further research is needed to understand its full potential. Future combination of BAT with existing immunotherapeutics including immune checkpoint blockade may prove beneficial for treatment of CRPC.
Citation Format: Rajendra Kumar, Kavya Boyapati, Naiju Thomas, Deven Topiwala, Suthicha Kanacharoen, Olutosin Owoyemi, Max Coffey, Michael Carducci, Mark C. Markowski, Emmanuel S. Antonarakis, Drew Pardoll, Samuel Denmeade, Sushant K. Kachhap. Supraphysiological androgens induce ferroptotic cell death in prostate cancer cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2410.
Abstract 2461: Targeting eIF4A3 as a multifunctional translation initiation factor for breast cancer therapy
Authors: Ling Jun , Huang Allen , Ohno Ai , Chen Joe , Cavataio Maria 
Published: September 2020

Abstract
eIF4A3 is a unique eukaryotic translation initiation factor (eIF) with broad functions in the whole process of RNA metabolism, including mRNA splicing via exon junction complex (EJC), mRNA nuclear export, translation, and RNA surveillance through nonsense-mediated RNA decay (NMD). These post-transcriptional processes are highly involved in cancer development. However, the roles of eIF4A3 in cancers have not addressed. In this study, by analyzing a breast cancer patient database, we identified that the up-regulation of eIF4A3 is correlated with poor survival of triple negative breast cancer (TNBC) patients. Overexpression of eIF4A3, along with other EJC components (Magoh, Y14 and CASC3), were observed in multiple TNBC cell lines as compared to human normal cells and mouse normal tissues. Knockdown of eIF4A3 by RNAi was found to strongly inhibit TNBC cell proliferation in vitro; down-regulation of endogenous eIF4A3 also suppressed tumor growth in a mouse model. Dominant negative eIF4A3 and an ATP-binding defective mutants inhibited TNBC cell growth in the clonogenic assay. Furthermore, TNBC cells were found to be more sensitive to eIF4A3-specific inhibitors than luminal A and B subtypes of breast cancer cells. Thus, our study elucidates a strong cancer-promoting activity of eIF4A3 in breast cancer growth at cellular and animal model levels, warranting a new strategy to target eIF4A3 for breast cancer therapy, especially for TNBC as the most difficult subtype to treat.
Citation Format: Jun Ling, Allen Huang, Ai Ohno, Joe Chen, Maria Cavataio. Targeting eIF4A3 as a multifunctional translation initiation factor for breast cancer therapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2461.
Abstract 2467: Interaction of CYP3A5 with AR-HSP90 complex regulating AR activation in prostate cancer cells
Authors: Gorjala Priyatham , Goodman Oscar , Mitra Ranjana 
Published: September 2020

Abstract
Background: Previously we have demonstrated that CYP3A5 stimulates prostate cancer cell growth by promoting AR activation and downstream signaling. We further investigated the mechanism of CYP3A5's interaction with the AR-HSP90 complex known to regulate AR activation process. AR activation is tightly regulated and it involves several chaperons (HSP90, HSP70, HSP40, and HSP27), multiple cofactors and protein kinases. We hypothesize that stoichiometric CYP3A5 binding to the HSP90-AR complex can induce conformational changes in the chaperone complex, promoting AR nuclear migration and activation.
Method: We used co-immunoprecipitation to identify the interaction of CYP3A5 with the components of the AR-HSP90 complex. Immunofluorescence studies were performed to identify the components of the AR-HSP90 complex that co-localize with CYP3A5. FRET analysis was used to confirm the interactions of CYP3A5 with the AR-HSP90 complex.
Results: We performed co-immunoprecipitation (co-IP) experiments with extracts from flag-tagged CYP3A5 transfected LNCaP cells. Our data demonstrates that CYP3A5 co-immunoprecipitates with HSP90, AR, HSP70 and HSP40, all known components of the HSP90-AR complex. We further confirmed using reverse immunoprecipitation with AR/ HSP90 antibodies and agarose A/G beads that CYP3A5 is a part of the HSP90-AR mature complex. Empty vector transfected cell extract and IgG were used as controls for pull down and reverse IP respectively. Immunofluorescence studies demonstrated that HSP70 and HSP40 co-localized with CYP3A5 in the cytoplasm. Interestingly, the MDAPCa2b and LNCaP cells show co-localization of CYP3A5 and AR in the nucleus, in contrast to non-transformed RWPE1 cells where CYP3A5 remains in the cytoplasm. The nuclear presence of CYP3A5 is more pronounced in MDAPCa2b cells carrying the wild type CYP3A5. The FRET analysis further confirmed direct interaction between CYP3A5 and HSP40 a chaperon in the AR-HSP90 complex.
Conclusions: Our data confirms that CYP3A5 directly interacts with the AR-HSP90 complex regulating AR activation process. Further understanding of this interaction can help establish CYP3A5-AR axis as a novel therapeutic target.
Citation Format: Priyatham Gorjala, Oscar Goodman Jr., Ranjana Mitra. Interaction of CYP3A5 with AR-HSP90 complex regulating AR activation in prostate cancer cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2467.
Abstract 2474: Potent small molecule TEAD inhibitors targeting the Hippo pathway exhibit antiproliferation in vitro and anti-tumor effect in vivo
Authors: Amidon Ben , Syed Sakeena , Cavanaugh Jill , Frosch Hyejin , Natarajan Prabitha , Ecsedy Jeffrey , McGovern Karen , Castro Alfredo C. 
Published: September 2020

Abstract
The Hippo signaling cascade is an important pathway for cancer biogenesis and tumor maintenance. The Hippo pathway is heavily mutated across many cancer indications through loss of function mutations in genes such as NF2. These pro-tumor mutations lead to the constitutive activation of the downstream transcriptional coactivators YAP and TAZ that drive the expression of many pro-survival and proliferation genes through the essential interaction with a TEAD protein family member. In addition, this unrestrained transcriptional program drives enhanced immune suppression in the tumor microenvironment. To target this oncogenic pathway we identified novel small molecule inhibitors that selectively bind to TEAD and disrupt their interaction with YAP and TAZ thereby downregulating YAP- and TAZ-dependent transcription. These inhibitors prevent TEAD palmitoylation which is essential for the interaction between YAP and TEAD. Furthermore, they inhibit in vitro proliferation of YAP-dependent (i.e. Hippo pathway-deficient cancer cell lines), but not Hippo pathway wild type cancer cell lines. An attraction of targeting this pathway is that many differentiated cells and tissues do not rely on the Hippo pathway, but notable exceptions have been demonstrated with tissue specific mouse knockouts in the bile duct and kidney podocytes. Importantly, our compounds did not affect survival of a differentiated mouse podocyte cell line or compromise mouse kidney histology. Subsequent experiments in vivo demonstrate these inhibitors downregulate YAP-dependent genes in human tumor xenografts after oral dosing. In addition, these inhibitors exhibit single agent tumor growth inhibition of human tumor xenografts in mice at well tolerated oral doses. These data demonstrate the potential for targeting this critical pathway in cancers with small molecules. Additional studies to identify tumor types that are Hippo pathway-driven and dependent on TEAD function are in progress.
Citation Format: Ben Amidon, Sakeena Syed, Jill Cavanaugh, Hyejin Frosch, Prabitha Natarajan, Jeffrey Ecsedy, Karen McGovern, Alfredo C. Castro. Potent small molecule TEAD inhibitors targeting the Hippo pathway exhibit antiproliferation in vitro and anti-tumor effect in vivo [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2474.
Abstract 2497: Topological data analysis revealed complexity behind ER positive breast cancer subtypes in TCGA transcriptome data
Authors: Koyama Takahiko , Saenz Aldo G. , Parida Laxmi 
Published: September 2020

Abstract
Introduction:
Breast cancer subtyping is still not fully agreed among oncologists. Today, many guidelines separate patients into four subtypes, luminal A, luminal B, Her2 positive, and triple negative breast cancers. However, distinction between luminal A and luminal B cases is not clear cut although many use Ki67 index. As more treatment options including immune checkpoint blockade are available, it is imperative to define strata and to find optimum treatments for each stratum.
Method:
TCGA BRCA transcriptome data (BRCA-UQ) is used, which has a sample size of 1089. We employed topological data analysis (TDA) which can handle high dimensional nature of transcriptome data in elegant manner. For characterization of the clusters, we used clinical data such as metastasis status, tumor sizes, age of diagnosis, survival, and pathological data and molecular data including PIK3CA, TP53, GATA3 mutations, MYC amplification, 8p23.2 deletion, 16q24.3 deletion, and tumor mutation burden (TMB). In addition, state of tumor microenvironment is assessed using CD45 expression for tumor infiltrating leukocytes (TIL) and HOXD12 expression for cancer associated fibroblast (CAF).
Results:
TDA cleanly clustered breast cancer transcriptome data separating ER+, Her2+ and triple negative cases. However, among ER+ cases, boundary between Luminal A and Luminal B is vague except for ER+/Her2+ cases. In ER+ cases, there are four clusters with poor prognosis. One has PIK3CA mutation, high MYC, and low TIL. Another cluster is characterized by GATA3 mutations. The other has low TIL and PIK3CA mutations. Also, high CAF cluster coincides with poor prognosis ones.
Conclusions:
The study revealed complexity behind ER+ breast cancer stratification from molecular and clinical perspectives. A TDA based method will likely to classify a patient into a right stratum better than conventional methods. Identified clusters with high TIL and high TMB which are good candidates for immune checkpoint blockade. Further study on identification of optimal treatments for each stratum will be warranted.
Citation Format: Takahiko Koyama, Aldo G. Saenz, Laxmi Parida. Topological data analysis revealed complexity behind ER positive breast cancer subtypes in TCGA transcriptome data [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2497.