bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3663: Allostatic load, tumor genomics, and outcomes in NSCLC
Authors: Nguyen Ryan H. , Weinfeld Michael , Pasquinelli Mary , Weinberg Frank , Reizine Natalie , Feldman Lawrence , Gadi Vijayakrishna K. 
Published: June 2022

Abstract
Introduction: Allostatic load (AL) is a multi-system measure of chronic stress shown to be an emerging framework for understanding disparities in cancer outcomes, but there have been no AL studies in lung cancer.
Methods: We conducted a retrospective review of patients diagnosed with stage IV lung adenocarcinoma from 2016 - 2020 at the University of Illinois Hospital and Health System. An AL index included 9 biomarkers (systolic blood pressure, diastolic blood pressure, resting heart rate, BMI, albumin, eGFR, creatinine, glucose, and use of medications for hypertension, diabetes, or hypocholesteremia) with 1 point assigned for each biomarker meeting a pre-determined cutoff. AL was dichotomized between AL-high (5-9) and AL-low (0-4) with median progression-free survival of first-line therapy (mPFS1) and median overall survival (mOS) estimated for both groups with Kaplan-Meier curves. Rates of clinically actionable driver mutations (driver-POS), including EGFR, ALK, ROS1, BRAF V600e, RET, MET, NTRK, and KRAS G12C, were compared for both groups using chi-squared test. Mean AL was compared between those who were driver-POS and those who did not have a clinically actionable driver mutation (driver-NEG) using independent samples t-test.
Results: A total of 61 patients were identified with 56% female and 74% former or current tobacco users. The cohort was 49% Black, 21% White, and 13% Hispanic or Latino. Mean AL at diagnosis was 3.3 (+/- 1.4). AL-high patients comprised 20% (12) of the cohort compared with 80% (49) AL-low. Between AL-high and AL-low cohorts, there was no statistically significant difference in mPFS1 (15 vs. 13 months, P = 0.98) and mOS (34 vs. 18 months, P = 0.33). Rates of driver-POS were lower in AL-high compared with AL-low (25% vs 69%, P &lt;0.01). Mean AL was higher in the driver-NEG population compared with driver-POS population (3.79 vs 3.03, P = 0.04).
Conclusions: Patients whose tumors did not have a clinically actionable driver mutation were associated with a higher AL, suggestive of higher chronic stress playing a role in more aggressive tumor biology. No statistically significant survival difference was observed in AL-high versus AL-low populations for mPFS1 and mOS. Larger, prospective trials are planned to correlate AL at diagnosis with clinical and biomarker data. AL, which serves as a measure of physiological dysfunction due to chronic stress associated with social disadvantage, may have implications for tumor biology and clinical outcomes in lung cancer.
Citation Format: Ryan H. Nguyen, Michael Weinfeld, Mary Pasquinelli, Frank Weinberg, Natalie Reizine, Lawrence Feldman, Vijayakrishna K. Gadi. Allostatic load, tumor genomics, and outcomes in NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3663.
Abstract 3694: The role of the p40 family in pancreatic cancer
Authors: Sheinin Monica 
Published: June 2022

Abstract
Pancreatic cancer is the fourth leading cause of cancer in the US, and mortality is rising rapidly with little improvement in survival rates. Treatment remains a major challenge of this disease and these poor outcomes have researchers targeting the tumor microenvironment for therapy. The diagnosis and therapeutic options remain an obstacle due to the immune system response and associated non- specific symptoms. Immunotherapy is an important treatment for pancreatic cancer, and its applications are currently being studied. Targeting T cells to recognize and kill tumor cells could be a potential strategy. Due to the behavior of pancreatic cancer and the tumor microenvironment, immunosuppressive cells such as myeloid - derived suppressor cells and regulatory T cells limit the efficacy of T cell infiltration. The cytokine interleukin-12 (IL-12) plays an essential role to regulate both innate (natural killer cells) and adaptive (cytokine T-lymphocytes) immunities in cancer therapies. IL-12 is composed of two subunits, p40 and p35. We found that various human pancreatic cancer cells produce greater levels of p40 monomer and p40 homodimer (p402), than IL-12, and IL-23. We further demonstrate that selective neutralization of p40 by p40 mAb (a3-3a), by p402 mAb (d7-12c) stimulated death in pancreatic cancer cells. Our studies aim to identify the roles of p40 and p402 in pancreatic cancer cells and underlie the importance of p40 monomer and p40 homodimer in helping cancer cells escape cell death.
Citation Format: Monica Sheinin. The role of the p40 family in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3694.
Abstract 3720: TACH101, a first-in-class inhibitor of KDM4 histone lysine demethylase for the treatment of diffuse large B-cell lymphoma
Authors: Perabo Frank , Chandhasin Chandtip , Yoo Sanghee , Rosario Joselyn Del , Chen Young K. , Filvaroff Ellen , Stafford Jeffrey A. , Quake Stephen , Clarke Michael F. 
Published: June 2022

Abstract
Background: Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma (NHL) in the US accounting for about 22% of newly diagnosed cases of B-cell NHL. It is considered to be more aggressive and to have worse prognosis due to low response to existing treatments. KDM4 is a family of histone demethylases that can drive tumor growth by regulating transcription, cell cycle, and DNA replication/repair. Overexpression of KDM4 alters post-translational histone modification and is associated with many types of cancer, including DLBCL. TACH101 is a novel, potent small molecule inhibitor of KDM4 that is being developed for treatment of advanced cancers, including DLBCL.
Methods: TACH101 was evaluated in vitro and in vivo using cancer cell lines and patient-derived organoid (PDO) and xenograft (PDX) models of DLBCL.
Results: TACH101 is a reversible, α-ketoglutarate competitive, selective and potent inhibitor of KDM4 isoforms A-D with IC50 values &lt; 0.100 μM for all four isoforms. An initial screen using a 301-cell line panel showed that DLBCL cell lines are sensitive to TACH101 (IC50 &lt; 10 nM). In an additional panel of DLBCL cell lines, TACH101 inhibited proliferation in a dose-dependent manner in all DLBCL cell lines, independent of molecular subtype, with mean IC50’s of 0.03 ± 0.01 μM in ABC DLBCL cell lines (n=6); 0.02 ± 0.01 μM in GCB DLBCL cell lines (n=7) and 0.02 ± 0.01 μM in PMBL DLBCL cell lines (n=2). In OCI-LY19 DLBCL xenografts in vivo, TACH101 was well tolerated and inhibited tumor growth by 55% to 100%, depending on dosing regimen (either QD or BID following a 3 days on/4 days off schedule). In PK studies, TACH101 exhibited low clearance, moderate volume of distribution, and good oral bioavailability in mouse, rat, and dog. Moreover, treatment with TACH101 resulted in little or no inhibitory effects on CYP enzymes. Toxicity studies in rats and dogs identified potential target tissues and provided safety guidance for the use of TACH101 in human studies.
Conclusions: The KDM4 inhibitor, TACH101, had compelling activity in preclinical DLBCL models, suggesting that TACH101 could be an effective therapy for DLBCL. Preparations to advance the drug into clinical trials are underway.
Citation Format: Frank Perabo, Chandtip Chandhasin, Sanghee Yoo, Joselyn Del Rosario, Young K. Chen, Ellen Filvaroff, Jeffrey A. Stafford, Stephen Quake, Michael F. Clarke. TACH101, a first-in-class inhibitor of KDM4 histone lysine demethylase for the treatment of diffuse large B-cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3720.
Abstract 3723: Role of KAT5 in non-small cell lung cancer
Authors: Shibahara Daisuke Jefferson , Akanuma Naoki , Heo Eunyoung , Ando Mariko , Kobayashi Ikei S. , Fujii Masanori , Paul Prin , Pan Gilbert , Tenen Danniel G. , Watanabe Hideo , Kobayashi Susumu S. 
Published: June 2022

Abstract
Histone modifications play crucial roles in transcriptional activation, and aberrant epigenetic changes are associated with oncogenesis. Lysine (K) acetyltransferases 5 (KAT5) is reportedly implicated in cancer development and maintenance, although the role of KAT5 in lung cancer largely remain unclear. Here we demonstrate that KAT5 expression was lower in lung adenocarcinoma than normal lung cells. Overexpression of KAT5 had no effect on tumor proliferation and migration, whereas knockdown of KAT5 paradoxically decreased those activities. To assess KAT5 function in lung tumorigenesis in adults, we generated a lung cancer mouse model in which Kat5 is conditionally deleted in lung. We achieved this by crossing lung-specific EGFR-L858R-T790M transgenic mice with conditional Kat5 knockout mice, and found that complete deletion of Kat5 resulted in suppression of tumor formation. To investigate downstream genes of KAT5, we performed RNA sequencing and chromatin immunoprecipitation sequencing analysis using H1975 KAT5 inducible knockdown cells and control cells. We identified a transglutaminase enzyme, TGM5, as one of downstream of KAT5. We furthermore identified artemisinin, an anti-malarial drug, as a potent KAT5 inhibitor by using the connectivity map database, and treatment with artemisinin suppressed tumor growth and induced apoptosis in vitro an in vivo. Taken together, suppression of KAT5 activity shows a tumor-specific efficacy against lung cancer in which KAT5 expression is lower, with no definite influence on normal tissues. Thereby, targeting KAT5 is a potent candidate for the treatment of lung cancer.
Citation Format: Daisuke Jefferson Shibahara, Naoki Akanuma, Eunyoung Heo, Mariko Ando, Ikei S. Kobayashi, Masanori Fujii, Prin Paul, Gilbert Pan, Danniel G. Tenen, Hideo Watanabe, Susumu S. Kobayashi. Role of KAT5 in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3723.
Abstract 3736: SETD2 aberrancy enhanced the synergetic anti-tumor effects of DNA hypomethylating agents and PARP inhibitors in aggressive clear cell renal cell carcinoma
Authors: Zhou Xinyi , Fu Guanghou , Li Hong-Tao , Gujar Hemant , Weisenberger Daniel J. , Quinn David I. , Han Bo , Liang Gangning 
Published: June 2022

Abstract
Purpose: SETD2 aberrancy, as the main reason of depleted levels of H3K36me3, plays an important role in diverse forms of cancer and is most notably in clear cell renal cell carcinoma (ccRCC). Altered chromatin modelers related to impaired H3K36me3 occupancy are linked to renal cancer aggressiveness and metastasis, where the latter dramatically drops the relative 5-year survival rate of ccRCC from 91% to 11%. Developing novel treatment targeting H3K36me3-compromised cancer cell is urgently needed for diagnostic and treatment purposes.
Methods: Phenotypic and animal experiments were conducted to test the sensitivity of kidney cancer cells with impaired H3K36me3 to hypomethylating agent (HMA), PARP inhibitor (PARPi), and HMA + PARPi combination treatments. Comet assay, flow cytometry, western blot and bioinformatic analysis were performed to explore the mechanism beneath.
Results: Combination treatment of 5-Aza-CdR (DAC) and Talazoparib (PARPi) generate more cytotoxicity in SETD2-altered ccRCC cell lines than in SETD2-intact cell lines, including inhibited cell growth, incomplete colony formation, more apoptosis, increased DNA damage and impaired DNA damage repair. The up-regulation of STING and transposable element (TE), as well as the loss of chromatin stability, were more remarkable in SETD2-altered ccRCC cell lines when treated with DAC + PARPi.
Conclusion: Combination treatment of DAC and Talazoparib showed greater synergistic anti-tumor effect in SETD2 aberrant than in SETD2 wild-type ccRCC cells, making it a potential treatment strategy for H3K36me3-compromised cancers. Further pre-clinical studies should be conducted to make a precise medicine-based approach.
Citation Format: Xinyi Zhou, Guanghou Fu, Hong-Tao Li, Hemant Gujar, Daniel J. Weisenberger, David I. Quinn, Bo Han, Gangning Liang. SETD2 aberrancy enhanced the synergetic anti-tumor effects of DNA hypomethylating agents and PARP inhibitors in aggressive clear cell renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3736.
Abstract 3754: 5-Hydroxymethylcytosine (5hmC) at or near Pathogenic Variant Hot Spots as Potential Targets for Early Cancer Detection
Authors: Lu Yabin , Lu Michael 
Published: June 2022

Abstract
Since 5-hydroxymethylcytosine (5hmC) emerged as an intermediate metabolite in active DNA demethylation, there have been increasing efforts to elucidate its function as a stable modification of the genome. In the current study, we demonstrate that discrete 5hmc sites within 80bp hotspot regions exist in a greater proportion of cancer versus normal cells. 5hmc was detected in 16 of 17 known hotspots having C to T or G to A mutations. The results show the presence of two characteristically distinct 5hmc groups: Tier 1 Group with 3 to 8-fold more 5hmcs detected in tumor-cells than in normal-cell derived DNA (as observed in 6 of 11 CpG sites). Tier 2 group with equal allele frequency of 5hmc among normal and tumor-cell derived DNA at 5 CpG hotspot sites as well as 5 non-CpG hotspots. Thus, detection and quantification of the Tier 1 group of 5hmc sites or its prevalence at or near cancer mutation hot spots in cells may enable early detection, screening and potentially prediction of the likelihood of cancer occurrence or the severity of the cancer.
Citation Format: Yabin Lu, Michael Lu. 5-Hydroxymethylcytosine (5hmC) at or near Pathogenic Variant Hot Spots as Potential Targets for Early Cancer Detection [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3754.
Abstract 3762: Applications of innovative whole-genome bisulfite sequencing (WGBS) for cancer biomarker discovery in plasma liquid biopsy
Authors: Ruiz Caila , Kim Hanjun , Zhang Zhenguo , Bhasin Jeffrey , Jin Mingda , Xu Yi , Yang Xiaojing 
Published: June 2022

Abstract
Circulating cell-free DNA (cfDNA) has been reported to contain valuable genetic and epigenetic information for the diagnosis and prognosis of cancer. Studies have shown that the blood from cancer patients contained more tumor-derived cfDNA compared to the healthy controls. DNA methylation, the most well-studied epigenetic marker, has been validated as one of the key drivers in the development of many diseases including cancer. cfDNA methylation thus holds great potential to become a biomarker that will enable early detection of cancer. However, cfDNA is also a challenging input for library preparation as cfDNA is mostly highly fragmented, and the amount of cfDNA from blood plasma is comparatively low. Therefore, multiple library preparation protocols were evaluated for profiling DNA methylation patterns at single nucleotide resolution from ultra-low amount of blood plasma cfDNA. These methods included two bisulfite conversion-based protocols and an enzymatic based protocol. The bisulfite conversion reaction was optimized allowing a milder treatment for less nucleic acid damage. One of the bisulfite conversion based protocols also contained a further optimized adapter ligation step, allowing a simpler procedure. Circulating cfDNA were extracted from blood plasma of a healthy control, a non-small cell lung cancer patient, and an adenocarcinoma lung cancer patient. 5-ng cfDNA was used as input and the libraries were successfully prepared using all three methods. Each library was sequenced to 300 - 600 million read pairs at a read length of 150 bp, enabling a mean coverage of about 10X per detected CpG, and over 90% of the CpG sites in human genome were detected. Unique alignment rate among all libraries were about or above 80%. The comprehensive coverage of the CpG sites across the entire human genome illustrated that the optimized bisulfite conversion reaction was compatible with fragmented cfDNA, proving the satisfactory efficacy in this simple and classic method for DNA methylation profiling of such a challenging sample type. This opens the door to apply the streamlined and simple Whole-Genome Bisulfite Sequencing (WGBS) protocol for cfDNA methylation profiling, which in turn shall facilitate further understanding in cfDNA epigenetic variations and advance the development of a cancer biomarker from the non-invasive, liquid biopsies.
Citation Format: Caila Ruiz, Hanjun Kim, Zhenguo Zhang, Jeffrey Bhasin, Mingda Jin, Yi Xu, Xiaojing Yang. Applications of innovative whole-genome bisulfite sequencing (WGBS) for cancer biomarker discovery in plasma liquid biopsy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3762.
Abstract 3768: Epigenetic dysregulation from chromosomal transit in micronuclei
Authors: Agustinus Albert S. , Raviram Ramya , Dameracharla Bhargavi , Luebeck Jens , Stransky Stephanie , Scipioni Lorenzo , Myers Robert M. , Bona Melody Di , Duran Mercedes , Weigelt Britta , Yomtoubian Shira , Toufektchan Eleonore , Mischel Paul S. , Mittal Vivek , Shah Sohrab , Maciejowski John , Gratton Enrico , Ly Peter , Bakhoum Mathieu F. , Landau Dan , Bafna Vineet , Sidoli Simone , David Yael , Bakhoum Samuel F. 
Published: June 2022

Abstract
Chromosomal instability (CIN) and epigenetic alterations are characteristics of advanced and metastatic cancers, yet whether they are mechanistically linked is unknown. Here we show that missegregation of mitotic chromosomes, their sequestration in micronuclei, and subsequent micronuclear envelope rupture profoundly disrupt normal histone post-translational modifications (PTMs), a phenomenon conserved across humans and mice as well as cancer and nontransformed cells. Some of the changes to histone PTMs occur due to micronuclear envelope rupture whereas others are inherited from mitotic abnormalities prior to micronucleus formation. Using orthogonal techniques, we show that micronuclei exhibit extensive differences in chromatin accessibility with a strong positional bias between promoters and distal or intergenic regions. Finally, we show that inducing CIN engenders widespread epigenetic dysregulation and that chromosomes which transit in micronuclei experience durable abnormalities in their accessibility long after they have been reincorporated into the primary nucleus. Thus, in addition to genomic copy number alterations, CIN can serve as a vehicle for epigenetic reprogramming and heterogeneity in cancer.
Citation Format: Albert S. Agustinus, Ramya Raviram, Bhargavi Dameracharla, Jens Luebeck, Stephanie Stransky, Lorenzo Scipioni, Robert M. Myers, Melody Di Bona, Mercedes Duran, Britta Weigelt, Shira Yomtoubian, Eleonore Toufektchan, Paul S. Mischel, Vivek Mittal, Sohrab Shah, John Maciejowski, Enrico Gratton, Peter Ly, Mathieu F. Bakhoum, Dan Landau, Vineet Bafna, Simone Sidoli, Yael David, Samuel F. Bakhoum. Epigenetic dysregulation from chromosomal transit in micronuclei [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3768.
Abstract 3771: Mitochondrial metabolism and racial disparity of bladder cancer
Authors: Reddy Karthik Reddy Kami , Park Jun Hyoung , Bollag Roni J. , Bellman Allison , Terris Martha , Lerner Seth P. , Ballester Leomar Y. , Lotan Yair , Kaipparettu Benny Abraham , Putluri Nagireddy 
Published: June 2022

Abstract
Potential differences and mechanism in metabolism among bladder cancer (BLCA) patients of diverse race or ethnicities remain largely unexplored. Even though the incidence rate of BLCA in African Americans (AA) is nearly half as that of European Americans (EA), but AA have the worst survival. We performed the transcriptomics and metabolomics profiling in ancestry verified patients from AA and EA BLCA and observed mitochondrial complex activities were uniquely enriched in AA tumors compared to EA tumors. In addition, in vitro assay demonstrated differences in mitochondrial complex protein and activity between AA and EA BLCA. We further confirmed the reprogramming of mitochondrial metabolism using in vitro 13C labeled tracers in both AA and EA BLCA. Integration of metabolomics and transcriptomics data reveals the enrichment of mTOR pathway in AA BLCA. Our findings indicate that an elevated mitochondrial oxphos activity through mTOR activation could be a factor for AA BLCA progression and provide the rationale to examine mitochondrial specific inhibitors along with mTOR inhibitors to target BLCA on subset of patients from the AA community.
Citation Format: Karthik Reddy Kami Reddy, Jun Hyoung Park, Roni J. Bollag, Allison Bellman, Martha Terris, Seth P. Lerner, Leomar Y. Ballester, Yair Lotan, Benny Abraham Kaipparettu, Nagireddy Putluri. Mitochondrial metabolism and racial disparity of bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3771.