bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-101: Combined p53 dynamics and post-translational modifications determine subsequent protein expression and cell fate
Authors: Lu Dan , Holton Kristina , Hafner Antonina , DeHart Caroline , Sikora Jacek , Zhou Houjiang , Jambhekar Ashwini , Kelleher Neil , Gunawardena Jeremy , Lahav Galit 
Published: August 2019

Abstract
The tumor suppressor protein p53 is activated by a diverse repertoire of cellular stresses (e.g. oncogenic signalling, DNA damage) and as a transcription factor induces the expression of response pathways genes (including cell cycle arrest, senescence, apoptosis). While p53 is frequently lost during tumorigenesis, approximately 50% of human tumors retain intact p53, potentially rendering them sensitive to p53-induced cell death during radiotherapy. Recent single cell analysis from our lab has shown that irradiation of cells does not cause a simple sustained accumulation of p53, but rather, induces pulsatile p53 dynamic that oscillates at 5-hour periods resulting from a p53-Mdm2 negative feedback loop, leading to reversible cell cycle arrest. Disrupting this feedback loop by small molecules results in sustained p53 dynamics, leading to irreversible apoptosis or senescence. Moreover, extensive work by others has shown that post-translational modifications (PTM) on p53 also govern the cell fate decision process.
Here we show that aside from differences in p53 dynamics following irradiation, multiple PTMs on p53 also differ, with the latter causing quantitative changes of p53 binding to interactions proteins and subsequent alterations in promoter binding. In contrast, p53 dynamics govern broad transcription dynamics of target genes. For example, pulsatile p53 dynamics result in several distinct patterns of mRNA transcription including a cluster of oscillating p53 target genes. However, these oscillatory mRNA dynamics are lost at the protein level. The only p53 target protein that oscillates is the Mdm2 negative regulator of p53, while all other targets gradually accumulate over time. Furthermore, sustained p53 dynamics over 24h results in far greater accumulation of nearly all target proteins compared to pulsatile p53 dynamics, which likely explains the differences in the reversibility of cell fate decisions. The results described here uncover a link between p53 dynamics and p53 PTMs providing an overall mechanistic cell fate selection process by p53, which have important implications both for understanding of cell signalling processing as well as improving p53-mediated therapies.
Citation Format: Dan Lu, Kristina Holton, Antonina Hafner, Caroline DeHart, Jacek Sikora, Houjiang Zhou, Ashwini Jambhekar, Neil Kelleher, Jeremy Gunawardena, Galit Lahav. Combined p53 dynamics and post-translational modifications determine subsequent protein expression and cell fate [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 LB-101.
Abstract LB-111: Epidermal growth factor receptor oncogenes expressed in glioblastoma are activated as covalent dimers and exhibit unique pharmacology
Authors: O'Connor Matthew , Nicolaides Theodore , Zhang Jie , Flohr Alexander , Iacone Roberto , Mayweg Alexander V. , Epstein David M. , Buck Elizabeth 
Published: August 2019

Abstract
Mutation of either the intracellular catalytic domain or the extracellular domain of the receptor for epidermal growth factor (EGFR) drives oncogenicity. Extracellular domain EGFR mutations are highly expressed in patients with glioblastoma. Despite clinical success with targeting EGFR catalytic site mutants, no drugs have proven effective in glioblastoma patients expressing extracellular EGFR mutations. Herein, we define the molecular mechanism for oncogenic activation of families of extracellular EGFR mutations and reveal how this mechanism renders current generation small molecule ATP-site inhibitors ineffective. We demonstrate that a group of the most commonly expressed extracellular domain EGFR mutants expressed in glioblastomas is activated by disulfide-bond mediated covalent homodimerization, collectively referred to as locked dimerization (LoDi-EGFR oncogenes). Strikingly, current generation small molecules binding to the active kinase conformation potently inhibit catalytic site mutants, but induce covalent dimerization and activate LoDi-EGFR receptors, manifesting in paradoxical acceleration of proliferation. These data demonstrate how the locked-dimer mechanism of EGFR oncogenesis has profound impact on the activity of small molecules acting at the distal catalytic site, providing further evidence for “inside-out” allosteric signaling in EGFR. This provides a mechanistic understanding for the failure of current generation EGFR inhibitors to effectively treat LoDi-EGFR mutants in GBM and sets guidelines for discovery of selective LoDi-EGFR inhibitors.
Citation Format: Matthew O'Connor, Theodore Nicolaides, Jie Zhang, Alexander Flohr, Roberto Iacone, Alexander V. Mayweg, David M. Epstein, Elizabeth Buck. Epidermal growth factor receptor oncogenes expressed in glioblastoma are activated as covalent dimers and exhibit unique pharmacology [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 LB-111.
Abstract LB-125: KDM5D as a novel gender-specific gene target for metastatic colorectal cancer
Authors: Li Jiexi , Lan Zhengdao , Wang Alan Y. , DePinho Ron 
Published: August 2019

Abstract
Male colorectal cancer (CRC) patients have higher rates of incidence, mortality and poorer responsiveness to therapy compared to female patients, making it critical to identify the significant factors contributing to the gender differences and to explore gender-specific therapeutic interventions. Here, combining unbiased expression profiling and xenograft mouse model discovered the Y chromosome gene KDM5D as a male-specific pro-metastasis gene and its upregulation contributes to poorer survival in both human and mouse. Knockout of Kdm5d in male metastatic CRC cell lines aborted the liver metastasis occurrence while overexpressing Kdm5d in female primary CRC cell lines enabled their metastasis potential. Mechanistically, ChIP-seq analysis showed KDM5D primarily works as a demethylase for histone modification H3K4me2/3, downregulating metastasis-suppressing genes. KDM5D also regulates the chromosome accessibility, indicated by H3K27Ac level change and validated with ATAC-seq. Kras G12D mutation regulates Kdm5d expression and is correlated with poorer survival in male mice, which is validated in silico in human CRC data in TCGA. KDM5 family inhibitor "compound 48" showed significant power to inhibit the migration capability of human metastatic CRC cell line LoVo. This study provided a new understanding of the effect of gender on CRC and a novel gender specific therapeutic target for metastatic CRC.
Citation Format: Jiexi Li, Zhengdao Lan, Alan Y. Wang, Ron DePinho. KDM5D as a novel gender-specific gene target for metastatic 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 LB-125.
Abstract LB-127: Loss of function of GAS7 promotes neuroblastoma metastasis in the context of MYCN overexpression
Authors: Dong Zhiwei , Garcia Gonzalo Lepez , Zhang Cheng , Dankert Erin N. , Harenza Jo Lynne , Hou Xiaonan , Li Hu , Maris John M. , Zhu Shizhen (Jane) 
Published: August 2019

Abstract
Neuroblastoma is an embryonal tumor arising in the peripheral sympathetic nervous system (PSNS), and often presents with widespread metastasis at diagnosis. We recently demonstrated that overexpression of LMO1 can synergize with MYCN to promote tumor metastasis in our zebrafish model system. Here, we identify a “metastasis suppressor” gene – growth arrest specific 7 (GAS7) – whose loss of function or reduced expression can promote dissemination and migration of neuroblastoma cells with MYCN overexpression, both in vitro and in vivo. GAS7 resides on chromosome 17p13.1, a region that is deleted in high-risk neuroblastomas with higher frequency in MYCN-amplified cases. Expression levels of GAS7 are also significantly downregulated in MYCN-amplified or otherwise MYCN-overexpressing human neuroblastoma cells, as well as MYCN-overexpressing zebrafish PSNS cells, suggesting an inverse relationship between the oncogenic activities of MYCN and GAS7downregulation. To determine whether loss of function or reduced expression of GAS7 could contribute to neuroblastoma pathogenesis in the context of MYCN overexpression, we developed a gas7 knockout zebrafish line using a transcription activator-like effector nucleases (TALEN) method. Loss of function of gas7 promoted hematogenous metastasis of MYCN-overexpressing tumor cells to tissues and organs that paralleled the common sites of metastasis in neuroblastoma patients. Further RNA-sequencing and qRT-PCR analyses showed that representative signature genes encoding proteins involved in tumor cell-cell or cell-extracellular matrix interactions were significantly downregulated in fish tumors with loss of function of gas7, consistent with our electron microscopic finding in the fish model showing a loss of contact among tumor cells in fish lacking functional gas7, suggesting that GAS7 may physically act as a metastasis suppressor. Thus, in high-risk neuroblastoma with MYCNamplification or overexpression, we propose that deletion or reduced expression of GAS7 cooperates with MYCN to promote neuroblastoma cell dissemination. Although the precise mechanism of this interaction remains unclear, we suggest that it relies, in part, on the downregulation of pivotal genes involved in tumor cell-cell or cell-extracellular matrix contacts.
Citation Format: Zhiwei Dong, Gonzalo Lepez Garcia, Cheng Zhang, Erin N. Dankert, Jo Lynne Harenza, Xiaonan Hou, Hu Li, John M. Maris, Shizhen (Jane) Zhu. Loss of function of GAS7 promotes neuroblastoma metastasis in the context of MYCN overexpression [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 LB-127.
Abstract LB-135: Targeting the myeloid-cell specific SRC-kinase HCK improves anti-tumor immunity
Authors: Ernst Matthias R. , Chand Ashwini , Huntington Nicholas , O'Donoghue Robert , Poh Ashleigh 
Published: August 2019

Abstract
Elevated expression of the myeloid cell-specific Src-family kinase HCK occurs in a majority of solid malignancies and correlates with poor patient survival [Poh et al., Frontiers Oncol 2018]. We have recently shown that genetic ablation, or therapeutic inhibition, of HCK suppresses the growth of primary tumors arising in the colon, stomach, lung and other mutagenized epithelia of mice. Mechanistically, we have attributed this to the capacity of HCK activity to support and retain the polarization of a wound-healing, Tie2+ (i.e. alternative activated) endotype of tumor-associated macrophages and concomitant tumor vascularization [Poh et al., Cancer Cell2017].
Here we extend these observations to MC38 colon cancer, B6/F10 melanoma and EO771 breast cancer allograft model, where the growth of the primary lesion and its metastatic spread is suppressed in HCK knockout hosts. More importantly, HCK gene deletion or therapeutic HCK inhibition with a small kinase inhibitor in mouse models further enhances the anti-tumor effects conferred by either chemotherapy or single agent immunotherapies based on anti-PD-L1, anti-CTLA4 or agonistic-CD40 antibodies. These observations are underpinned by increased tumour cell apoptosis that coincides with enhanced expression of ifng, gzmb, prf1 and other effector proteins in NK and infiltrating CD8+ cells. Likewise, HCK inhibition confers increased expression of il12 and ifng in tumor-associated macrophages, which adopt a more conventional activated endotype. Because HCK-deficiency of the host also associated with increased abundance of tumor infiltrating effectors cells, we propose that therapeutic targeting of HCK not only “makes tumors hotter”, but also improves host anti-tumor immunity. We are therefore developing novel HCK-specific small molecule inhibitors.
Citation Format: Matthias R. Ernst, Ashwini Chand, Nicholas Huntington, Robert O'Donoghue, Ashleigh Poh. Targeting the myeloid-cell specific SRC-kinase HCK improves anti-tumor immunity [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 LB-135.
Abstract LB-139: The effects and mechanisms of TNF-α/TNFR2 in regulatory T cells on microenvironment and progression in gastric cancer
Authors: Qu Yang , Zhao Gang , Li Hui 
Published: August 2019

Abstract
Background: Regulatory T cells (Tregs) are potent immunosuppressive cells of the immune system. They facilitate the survival and progression of tumor through their ability to suppress the antitumor immunity. The expression of tumor necrosis factor receptor type II (TNFR2) on Tregs is reported to identify the maximally suppressive Treg population in both mice and human. According to our previous research, expression of TNFR2 appeared to correlate better than CD25+ and CD127− with FoxP3 expression.
Aim: The effects and mechanisms of TNF-α/TNFR2 in regulatory T cells on microenvironment and progression in gastric cancer are needed to be studied.
Methods: The expression and phenotype of TNFR2 + Tregs in peripheral blood and tumor tissues of 33 cases of gastric cancer patients and in peripheral blood of 15 normal controls were detected by flow cytometry. The ratio of Foxp3+Tregs and TNFR2+Tregs of 145 cases of gastric cancer patients was analyzed by multicolor immunofluorescence assay. We analyzed their relationship with gastric cancer stage, metastasis and other clinical indicators by clinical and pathological data.
Results: Flow cytometry showed that the expression of TNFR2 in human peripheral blood Tregs was significantly higher than that in conventional T cells (Tconvs) in peripheral blood CD4 + T cell subsets of gastric cancer patients and healthy individuals (P&lt;0.05). The proportion of TNFR2 + cells in peripheral blood Tregs cells was significantly higher in patients with gastric cancer than in normal subjects (P &lt;0.05). Tregs and Tconvs cells expressed very low level of CTLA-4 and TIM-3 in both normal controls and gastric cancer patients. Multicolour immunofluorescence showed that the ratio of Foxp3 + Tregs and TNFR2 + Tregs was increased in the tumor tissue, and TNFR2 + Tregs cells showed a tendency to increase with tumor progression and lymphatic metastasis. Higher levels of infiltration of TNFR2+ Tregs cells are significantly associated with patients’ OS (P&lt;0.05) and DFS (P&lt;0.05).
Conclusion: Our findings revealed that TNFR2 could be a promising molecular marker associated with poor prognosis. The mechanism by which TNFR2+Tregs promote tumor survival and progression in gastric cancer is still needed further research.
Citation Format: Yang Qu, Gang Zhao, Hui Li. The effects and mechanisms of TNF-α/TNFR2 in regulatory T cells on microenvironment and progression in gastric 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 LB-139.
Abstract LB-171: Global variation in prostate cancer incidence and mortality rates, 1980-2013
Authors: Freeman MaryBeth , Jemal Ahmedin 
Published: August 2019

Abstract
Context: Previous studies documented significant international variation in prostate cancer rates due to differences in detection practices, availability of treatment, and genetic factors.
Objective: To provide updated contemporary prostate cancer incidence and mortality patterns across five continents using the most recent cancer incidence data from the International Agency for Research on Cancer and mortality data from the World Health Organization (WHO).
Evidence acquisition: We present estimated age-standardized prostate cancer incidence and mortality rates by country and WHO regions for 2012 based on GLOBOCAN. We examined long-term (1980 onwards) trends in prostate cancer incidence and mortality rates for 38 countries with high quality population-based incidence and mortality data. Trends were expressed as annual percent change using Joinpoint model. We also examined short-term (most recent 5 years) trends in prostate cancer among 44 countries with available incidence data and 71 countries with available mortality data.
Evidence synthesis: The highest incidence rates during the most recent 5 years are found in Brazil, Lithuania, and Australia, whereas the lowest incidence rates are found in Asia (India, Thailand, and Bahrain). The highest mortality rates are found in the Caribbean (Barbados, Trinidad and Tobago, and Cuba), sub-Saharan Africa (South Africa), parts of former Soviet Union (Lithuania, Estonia, and Latvia), whereas the lowest rates are found in Asia (Thailand and Turkmenistan). Of the 44 countries with high quality incidence data, prostate cancer incidence rates during the most recent five data years increased in 4 countries (with Bulgaria showing the largest increase), decreased in 7 countries (with the biggest decrease in the United States), and stabilized in the remaining 31 countries. During the same time period, in contrast, among the 71 countries considered for the mortality trend, rates decreased in 14 countries, increased in 3 countries, and remained stable in 54 countries.
Conclusions: In 2012, prostate cancer was the most commonly diagnosed cancer among men in 96 countries and the leading cause of death in 51 countries. In the most recent 5 years of data examined, prostate cancer incidence and mortality rates are decreasing or stabilizing in most parts of the world. Future studies should monitor trends in mortality rates and late-stage disease to assess the impact of reduction in PSA testing in several countries.
Citation Format: MaryBeth Freeman, Ahmedin Jemal. Global variation in prostate cancer incidence and mortality rates, 1980-2013 [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 LB-171.
Abstract LB-172: Understanding the mechanism underlying vitamin D and prostate cancer: Exploring telomere length
Authors: Major Jacqueline M. , Graubard Barry I. , Weinstein Stephanie J. , Kim Jeeyun , Vivo Immaculata De , Virtamo Jarmo , Savage Sharon A. , Albanes Demetrius 
Published: August 2019

Abstract
Background: In an effort to understand the molecular mechanism behind the association between circulating vitamin D and prostate cancer, we measured relative telomere length and 25(OH)D levels in a cohort of older Finnish men.
Methods: Using a nested study design, we examined quantitative PCR measured telomere length, season-adjusted serum 25-hydroxyvitamin D [25(OH)D], and subsequent prostate cancer risk in 1000 men (n=500 cases, 500 matched controls) participating in the extension study of the Alpha-Tocopherol Beta-Carotene Cancer Prevention (ATBC) Trial. Conditional regression models were used to explore mediation and effect modification of telomere length on the relation between serum 25(OH)D and prostate cancer risk.
Results: An increased risk of prostate cancer was observed among men with longer (&gt;median) relative telomere length (OR = 1.41, 95% CI: 1.06 to 1.90; continuous: OR = 2.36, 95%CI: 0.96 to 5.83) as well as men with higher 25(OH)D concentrations (OR = 1.67, 95% CI: 1.08 to 2.57 for highest vs. lowest quintile, P-trend = 0.03). No significant association between 25(OH)D levels and telomere length was observed. A suggested joint effect of 25(OH)D and telomere length on prostate cancer risk was observed.
Conclusion: Serum 25(OH)D and relative telomere length are independent predictors of prostate cancer risk in this sample of older male Finnish smokers. No evidence of mediation between circulating vitamin D concentrations and telomere length was observed. Future studies are needed to further clarify the underlying biologic mechanisms of the 25(OH)D-prostate cancer association.
Citation Format: Jacqueline M. Major, Barry I. Graubard, Stephanie J. Weinstein, Jeeyun Kim, Immaculata De Vivo, Jarmo Virtamo, Sharon A. Savage, Demetrius Albanes. Understanding the mechanism underlying vitamin D and prostate cancer: Exploring telomere length [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 LB-172.
Abstract LB-174: Genome-wide association meta-analysis identifies novel GP2 gene risk variants for pancreatic cancer in the Japanese population
Authors: Lin Yingsong , Nakatochi Masahiro , Ito Hidemi , Kamatani Yoichiro , Sakamoto Hiromi , Ishii Hiroshi , Sasahira Naoki , Ueno Makoto , Egawa Naoto , Mori Mitsuru , Nakao Haruhisa , Adachi Yasushi , Wakai Kenji , Tsugane Shoichiro , Yamamoto Masayuki , Shimizu Atsushi , Kadowaki Takashi , Yoshida Teruhiko , Matsuda Fumihiko , Kubo Michiaki , Kikuchi Shogo , Matsuo Keitaro 
Published: August 2019

Abstract
Pancreatic cancer is one of the most challenging malignancies because of its dismal prognosis, largely unknown etiology, and absence of early detection method. Here we report the results of a meta-analysis of three genome-wide association studies (GWAS) involving 2039 pancreatic cancer cases and 32592 control subjects, which represent the largest sample size in the Japanese population. To complement the SNP-based GWAS, we performed a gene-based GWAS using MAGMA. Given the pleiotropic effects observed for the top variants, we performed a Mendelian randomization (MR) analysis to address the possible causal relationship between type-2 diabetes (T2D) and pancreatic cancer risk, using 82 T2D-related SNPs and 25 hemoglobin A1c (HbA1c)-related SNPs as instrumental variables. We identified 3 (13q12.2, 13q22.1, and 16p12.3) genome-wide significant loci (P&lt;5.0×10-8), as well as 4 loci with suggestive evidence of association (P&lt;1.0×10-6) for pancreatic cancer. Of the identified risk loci, 16p12.3 is novel; the lead SNP maps to rs78193826 (OR=1.46, 95%CI=1.29-1.66, P=4.28×10-9), an Asian-specific, non-synonymous variant of glycoprotein 2 (GP2) predicted to be highly deleterious. Additionally, gene-based GWAS identified a novel gene, KRT8, which is linked to exocrine pancreatic and liver diseases. The identified variants in the GP2 gene exhibited pleiotropic effects on multiple traits, including type 2 diabetes, Hemoglobin A1c (HbA1c) levels, and pancreatic cancer. MR analysis suggested that genetically increased HbA1c levels may be causally associated with increased pancreatic cancer risk. Further fine mapping and functional characterization are required to elucidate the effects of common GP2 gene variants on pancreatic cancer susceptibility. Moreover, our findings highlight genetic susceptibility factors shared between T2D and pancreatic cancer.
Citation Format: Yingsong Lin, Masahiro Nakatochi, Hidemi Ito, Yoichiro Kamatani, Hiromi Sakamoto, Hiroshi Ishii, Naoki Sasahira, Makoto Ueno, Naoto Egawa, Mitsuru Mori, Haruhisa Nakao, Yasushi Adachi, Kenji Wakai, Shoichiro Tsugane, Masayuki Yamamoto, Atsushi Shimizu, Takashi Kadowaki, Teruhiko Yoshida, Fumihiko Matsuda, Michiaki Kubo, Shogo Kikuchi, Keitaro Matsuo. Genome-wide association meta-analysis identifies novel GP2 gene risk variants for pancreatic cancer in the Japanese 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 LB-174.