bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2992: Conserved gene fusion ETV6/RUNX1 displays higher immunogenicity than patient-specific missense mutations within the context of HLA-A*02:01
Authors: Cygan Erin E. , Shah Ravi K. , Kozlik Tanya , Thomas Paul G. , Zamora Anthony E. 
Published: April 2023

Abstract
Tumor-specific antigens can be targeted by T cells and cancer immunotherapies directed against these neoantigens have resulted in regression across several cancer types. Both missense mutations and gene fusions can serve as targets for cytotoxic T cells, but it is unknown whether one of these classes of mutations has unique parameters that make it more immunogenic. This study compares the immunogenicity of patient-specific missense mutations and a conserved gene fusion, ETV6/RUNX1, present in approximately 25% of pediatric B cell acute lymphoblastic leukemia cases to determine which is more effective at inducing CD8+ T cell responses. Utilizing patient HLA haplotype, mutation data obtained from whole-genome and mRNA sequencing, and the online prediction algorithm NetMHCcons, we identified several putative neoepitopes. To experimentally validate these predicted neoantigens, we performed peptide exchange assays with antigen presenting beads to evaluate the efficiency of peptide-HLA interactions and complex formation. To further investigate the immunogenicity of single nucleotide variants (SNVs) compared to the conserved gene fusion ETV6/RUNX1, we assessed peptide-HLA stability by measuring the dissociation of SNV or ETV6/RUNX1 peptides from the HLA binding groove and calculating the corresponding half-life. Higher affinity peptides would have a greater exchange rate than lower affinity peptides and would have a higher stability/half-life; these assays validated that ETV6/RUNX1 has a greater affinity/stability for HLA-A*02:01 compared to any of the patient-specific SNVs evaluated. To determine whether the higher affinity and stability of the fusion peptide was able to induce greater CD8+ T cell responses, we performed co-culture assays using peptide-pulsed artificial antigen presenting cells expressing HLA-A*02:01 and measured CD8+ T cell cytokine secretion and cytotoxicity. Interestingly, while both mutation types were able to activate CD8+ T cells, those targeting the fusion peptides displayed greater polyfunctionality. Additionally, we found a greater frequency of clonally expanded CD8+ T cells targeting fusion peptides using tetramer-binding assays. Overall, our findings suggest fusion neoantigens have greater immunogenicity than missense mutations and may provide better targets for TCR-T cell-based immunotherapies.
Citation Format: Erin E. Cygan, Ravi K. Shah, Tanya Kozlik, Paul G. Thomas, Anthony E. Zamora. Conserved gene fusion ETV6/RUNX1 displays higher immunogenicity than patient-specific missense mutations within the context of HLA-A*02:01 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2992.
Abstract 2999: Hippo signaling pathway regulates cancer-cell-intrinsic MHC-II expression in melanoma
Authors: Gu Shengqing 
Published: April 2023

Abstract
MHC-II is known to be mainly expressed on the surface of antigen-presenting cells (APCs). Nevertheless, increasing evidence suggests that MHC-II is also expressed by solid tumor cancer cells and may be associated with better immunotherapy responses. However, the regulation of MHC-II in cancer cells remain unclear. In this study, we leveraged data mining and experimental validation to elucidate the regulation of MHC-II in cancer cells and its role in modulating the response to immunotherapy. We collated an extensive collection of omics data to examine the cancer-cell-intrinsic MHC-II expression and its association with immunotherapy outcomes. We then tested the functional relevance of cancer-cell-intrinsic MHC-II expression using a syngeneic transplantation model. Finally, we performed data mining to identify pathways potentially involved in the regulation of MHC-II expression, and experimentally validated candidate regulators. Comprehensive meta-analysis of multiomics data from an exhaustive collection of data revealed that MHC-II is heterogeneously expressed in various solid tumors, and its expression is particularly high in melanoma. Using a syngeneic transplantation model, we further established that melanoma cells with high MHC-II responded better to anti-PD-1 treatment. Data mining followed by experimental validation revealed the Hippo signaling pathway as a potential regulator of melanoma MHC-II expression.
Citation Format: Shengqing Gu. Hippo signaling pathway regulates cancer-cell-intrinsic MHC-II expression in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2999.
Abstract 3016: Cancers attributable to infectious agents in Italy
Authors: Collatuzzo Giulia , Boffetta Paolo 
Published: April 2023

Abstract
Objectives: The burden of cancer attributable to known risk factors has never been estimated in Italy. This study aimed to provide an evidence-based, consistent assessment of the burden of infection-related cancer in Italy.
Methods: We calculated the proportion of cancers attributable to infectious agents to estimate the burden of infection-related cancer incidence (2020) and mortality (2017). Data on prevalence of infection were mainly derived from cross-sectional surveys among representative sample of Italian population. Data on relative risk were mainly derived from meta-analysis and large-scale studies. Attributable fraction was calculated based on the counterfactual scenario of no exposure to infection. National registries were used to obtain on the number of cancer cases and deaths.
Results: We estimated 7.6% of total cancer deaths occurred in Italy in 2017 were attributable to infections, with higher proportion in men (8.1%) than in women (6.9%). Corresponding figures for incidence in 2020 were 6.9%, 6.1% and 6.5%. Helicobacter pylori (Hp) was the first cause of infection-related cancer deaths, with 3.3% of all cancer deaths and 2.4% of cancer cases followed by Hepatitis C virus (HCV, 1.8% and 1,3%) and Hepatitis B virus (0,9% and 0,6%), Human Papillomavirus 0.6% and 1,0%), Epstein-Barr virus ( 0,3% of both deaths and cases), Human Immunodeficiency Virus (0,9% for both) and Human Herpes Virus- 8 (0,4% and 0,2%).
Conclusions: The burden of cancer attributable to infections was higher in Italy than in other high-income countries in which similar studies were conducted, including the US, due to excess Hp and ACV. Most of the cancer burden related to infections in Italy is due to agents for which common therapies (Hp, HCV) or vaccination (HPV, HBV) are available. Screening prevention policies are needed to control these cancers, which are largely avoidable.
Population attributable fraction (%) of cancer deaths in selected studies, by sex. Sex Italy United States United Kingdom France Men 8.1 3.4 3.1 3.1 Women 6.9 3.3 4.3 4.4
Citation Format: Giulia Collatuzzo, Paolo Boffetta. Cancers attributable to infectious agents in Italy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3016.
Abstract 3018: Demographic and social patterns of average values of inflammatorymarkers in US adults: A 2009-2016 NHANES analysis
Authors: Camacho-Rivera Marlene , Ye Zachary , Haq Raisa , Calixte Rose 
Published: April 2023

Abstract
Several studies report the negative impact of elevated Neutrophil-to-Lymphocyte ratio (NLR) and elevated Platelet-to-Lymphocyte ratio (PLR) on outcomes in many surgical and medical conditions, including cancer. In order to use these inflammatory biomarkers as prognostic factors in disease, a normal value in disease-free individuals must be identified first. This study aims to (1) establish average values of various inflammatory markers using a healthy and nationally representative U.S. adult population and (2) explore heterogeneity in average values by sociodemographic and behavioral risk factors to better specify cut-off points accordingly. The National Health and Nutrition Examination Survey (NHANES) of aggregated cross-sectional data collected from 2009 to 2016 was analyzed; data extracted included markers of systemic inflammation and demographic variables. We excluded participants who were under 20 or had a history of inflammatory diseases such as arthritis and gout. Adjusted linear regression models were used to examine the association between demographic and behavioral characteristics and neutrophil counts, platelet counts, lymphocyte counts, NLR, and PLR. The average NLR is 2.16 and the average PLR is 121.31. Non-Hispanic Black participants have significantly lower mean NLR values (1.78, 95% CI 1.74–1.83 and 2.10, 95% CI 2.04–2.16 respectively) when compared to non-Hispanic Whites (2.27, 95% CI 2.22–2.30–p&lt;0.0001). Participants who reported any no smoking history had significantly lower NLR than subjects who reported any smoking history and higher PLR than current smokers. The average PLR for non-Hispanic blacks is significantly lower compared to non-Hispanic whites. Participants ages 20-29 have significantly lower mean PLR vs. participants in the age groups 30-59, 60-79, and 80 and older. Additionally, current smokers have significantly higher mean PLR compared to those who never smoke. Participants in the obese category also had higher mean PLR compared to normal weight participants. This study provides nationally representative estimates for demographic and behavioral effects on NLR, and PLR, which have been associated with several chronic disease outcomes, suggesting that different cut-off points for inflammatory markers should be set according to social factors.
Citation Format: Marlene Camacho-Rivera, Zachary Ye, Raisa Haq, Rose Calixte. Demographic and social patterns of average values of inflammatorymarkers in US adults: A 2009-2016 NHANES analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3018.
Abstract 3046: Association of XRCC1 Arg194Trp polymorphism and XPD Lys751Gln polymorphism with biochemical parameters, severity and risk of prostate cancer in Bangladesh Population
Authors: Ahmed Nafisa , Islam MD. Ariful , Hossain M. Mahboob , Kabir Yearul 
Published: April 2023

Abstract
a)To evaluate the association between x-ray cross-complementing gene 1 (XRCC1) polymorphism Arg194Gln and xeroderma pigmentosum group D (XPD) polymorphism Lys751Gln with severity and risk of prostate cancer as well as with biochemical parameters of prostate cancer patients in Bangladesh population.
b) Blood samples and data were collected from 132 prostate cancer patients and 135 healthy controls among Bangladesh population. Genotype analysis was done by the PCR-RFLP method. Statistical analysis was performed using GraphPad Prism 9.4.1 software.
c) Only the recessive model, that is, carrying two copies of the XRCC1 194 codon Trp allele was positively associated with prostate cancer, with an OR of 7.50 (95% CI, 1.227-85.12; p=0.035). No association was found between the XPD variants with prostate cancer risk. Keeping the wild type and heterozygous genotype as a reference, the combined effects of the XRCC1 codon 194 Arg/Arg and the XPD codon 751 Gln/Gln genotype were found to be significantly associated with prostate cancer risk with an OR of 3.25 (95% CI, 1.39-8.20; p=0.006).
XRCC1 194 Trp/Trp genotype was significantly associated with obstructive features, such as hematuria and creatinine levels of the prostate cancer patients (P&lt;0.05). Moreover, the homozygous mutant Gln/Gln genotype of XPD gene was also significantly associated with creatinine levels in prostate cancer patients. No association was found between any of the variants of XRCC1 and XPD with invasiveness, tumor grade, prostate ultrasound scan results, digital rectal examination, Urine R/E or Prostate Specific Antigen (PSA) results (P&gt;0.05).
d) Only the XRCC1 codon 194 Trp allele showed a modest association with prostate cancer risk with an 8.19-fold increased risk when two copies of the allele were present. When both alleles- XRCC1 codon 194 and XPD codon 751 Gln -were present in their homozygous states, the risk for prostate cancer increased by 3.2-folds. Our results showed a significant association between XRCC1 194 Trp/Trp with obstructive features and and levels of creatinine in prostate cancer patients of Bangladeshi men.
Citation Format: Nafisa Ahmed, MD. Ariful Islam, M. Mahboob Hossain, Yearul Kabir. Association of XRCC1 Arg194Trp polymorphism and XPD Lys751Gln polymorphism with biochemical parameters, severity and risk of prostate cancer in Bangladesh Population [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3046.
Abstract 3062: ROMO1 mediates mitochondrial function links to neuroendocrine differentiation of prostate cancer enhancement by the nuclear PKLR/MYCN/MAX complex
Authors: Liu Yen-Nien , Chen Wei-Yu , Dung Phan Vu Thuy , Yeh Hsiu-Lien , Chen Zi-Qing , Wang Wan-Hsin , Wen Yu-Ching 
Published: April 2023

Abstract
Conventional treatment of prostate cancer (PCa) uses androgen deprivation therapy (ADT) to inhibit androgen receptor (AR) signaling-driven tumor progression. ADT-induced PCa recurrence may progress to AR-negative phenotype with neuroendocrine (NE) features on histology, which is associated with metabolic disturbances and poor prognosis. However, the association between the metabolic pathways that regulate mitochondrial function and promote NE differentiation (NED) in PCa remains unclear. Here, we show a regulatory mechanism in PCa pathogenesis whereby overexpression of pyruvate kinase L/R (PKLR) mediates mitochondrial disorder and oxidative stress through upregulation of reactive oxygen species modulator 1 (ROMO1), thereby promoting NED-related aggressiveness. ADT mediates the nuclear translocation of PKLR, which binds to the MYCN/MAX complex to upregulate ROMO1 and NE-related genes, leading to mitochondrial dysfunction and NED in PCa. Targeting nuclear PKLR/MYCN using bromodomain and extra-terminal motif (BET) inhibitors has the potential to reduce PKLR/MYCN-driven NED. Abundant ROMO1 in serum samples may provide prognostic information in patients with ADT-induced NED. Our findings link ADT resistance-driven metabolic reprogramming to NED of PCa through upregulation of PKLR/MYCN/ROMO1 signaling, and further explored the clinical significance of targeting the nuclear PKLR/MYCN complex and evaluated serum ROMO1 as a potential biomarker for aggressive NE-like PCa.
Citation Format: Yen-Nien Liu, Wei-Yu Chen, Phan Vu Thuy Dung, Hsiu-Lien Yeh, Zi-Qing Chen, Wan-Hsin Wang, Yu-Ching Wen. ROMO1 mediates mitochondrial function links to neuroendocrine differentiation of prostate cancer enhancement by the nuclear PKLR/MYCN/MAX complex [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3062.
Abstract 3230: Tumor microenvironment modulation by immunotherapy sensitizes solid tumors to radiation
Authors: Kang Minjeong , Lee DaeYong , Wang Yifan , Kim Betty , Jiang Wen 
Published: April 2023

Abstract
Radiation therapy (RT) has been prevalently implemented to treat cancer in clinical settings by inducing DNA damage in tumor cells. However, tumor microenvironmental factors such as severe hypoxic conditions and vascular anomalies attenuate the therapeutic efficacy of RT, thus resulting in unsatisfactory outcomes in solid tumors. Recently, Immune checkpoint blockade (ICB) has improved immune recognition to tumor cells and normalized tumor vasculature to diminish hypoxia in solid tumors. Herein, we suggest that RT combined with ICB synergistically alters tumor microenvironments, thus facilitating the recruitment of cytotoxic immune cells into tumors as well as sensitizing radiation effectiveness. RT in combination with ICB not only normalized tumor vasculature to reduce hypoxia, but also increased anti-tumor effects from immune-mediated toxicity and DNA damage-mediated apoptosis in several solid tumor-bearing mouse models to a greater extent than did either monotreatment of RT or ICB. This study will provide mechanistic insight into synergistic effects conferred by RT and ICB as well as a strong preclinical rationale for combining the two therapeutic modalities in human cancers.
Citation Format: Minjeong Kang, DaeYong Lee, Yifan Wang, Betty Kim, Wen Jiang. Tumor microenvironment modulation by immunotherapy sensitizes solid tumors to radiation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3230.
Abstract 3249: Circulating cytokine associations with clinical outcomes in melanoma patients treated with checkpoint inhibitors
Authors: Chen Jiajia , Tarantino Giuseppe , Severgnini Mariano , Baginska Joanna , Giobbie-Hurder Anita , Manos Michael , Russell Janice D. , Weirather Jason L. , Pfaff Kathleen , Huang Amy Y. , Rodig Scott J. , Ranashinge Srinika , Liu David , Hodi F.Stephen 
Published: April 2023

Abstract
Background: aCTLA-4/aPD-1 combination therapy has significantly improved clinical outcomes in patients with metastatic melanoma, with 50%-60% of patients responding to treatment, but predictors of response are poorly characterized. In this study, we set out to evaluate the hypothesis that circulating cytokines and peripheral white blood cell composition may predict response to therapy.
Methods: We quantified cytokines and complete blood counts from 89 patients with advanced melanoma treated with combination therapy from three points in time: pre-treatment, one month and approximately three months after starting therapy. We evaluated the association between peripheral blood circulating features, cytokines and clinical labs values, and clinical outcome using predictive modeling, and investigated the prognostic values of these features using survival analysis.
Results: Pre-treatment, patients with durable clinical benefit (DCB) had higher IL23, lower CXCL6, and lower IL10 levels. The ratio of neutrophils to lymphocytes (NLR) pre-treatment was not associated with response, but higher NLR one month after starting therapy predicted poorer progression free survival (PFS) and overall survival (OS), primarily driven by an increase in absolute lymphocytes. A multivariate model demonstrated that baseline CXCL6, IL10, IL23 were independent predictors of therapy response, and the combined model has reached an area under the curve (AUC) of 0.8 in prediction of response to combination therapy. Low IL10 and CXCL6 identified an excellent prognosis group, while high CXCL6 and low IL23 characterized a very poor prognosis group of patients.
Conclusions: Baseline measurement of cytokines IL23, CXCL6, and IL10 can predict metastatic melanoma patients’ response to ipi/nivo combination treatment. Higher neutrophils-to-lymphocytes ratio approximately one month after therapy started associates with worse survival outcome. Our study presented circulating features from a relatively accessible and less costly avenue, peripheral blood, to be predictive of response to combination immune checkpoint blockade.
Citation Format: Jiajia Chen, Giuseppe Tarantino, Mariano Severgnini, Joanna Baginska, Anita Giobbie-Hurder, Michael Manos, Janice D. Russell, Jason L. Weirather, Kathleen Pfaff, Amy Y. Huang, Scott J. Rodig, Srinika Ranashinge, David Liu, F.Stephen Hodi. Circulating cytokine associations with clinical outcomes in melanoma patients treated with checkpoint inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3249.
Abstract 326: Identification of novel substrates of the UBR5 E3 ubiquitin ligase in ovarian cancer
Authors: Eblen Scott T. , Bethard Jennifer R. , Rogers D Ralph , Daoud Abdelkader , Madan Lalima K. , Ball Lauren E. 
Published: April 2023

Abstract
The ubiquitin proteasome system regulates the degradation of proteins in order to maintain cellular homeostasis, which is often disrupted in cancer cells. The UBR5 (Ubiquitin Protein Ligase E3 Component N-Recognin 5) protein is an E3 ubiquitin ligase that catalyzes the direct ubiquitination of protein substrates, most often resulting in substrate protein degradation. UBR5 is the human homolog of the Drosophilia hyperplastic discs (hyd) tumor suppressor gene. However, ubr5 is amplified and over-expressed in human ovarian and breast cancers, among others, and thought to play more of a tumor-promoting role in cancer. We previously demonstrated that targeting UBR5 expression in human ovarian cancer xenografts in mice with liposomal delivery of UBR5 siRNA inhibited tumor growth and sensitized tumors to the DNA-damaging agent cisplatin. To identify novel substrates of UBR5-stimulated degradation, we transduced OVCAR5 cells with doxycycline-inducible shRNA targeting UBR5 or a control shRNA and metabolically labelled proteins with heavy or light lysine and arginine using Stable Isotope Labeling with Amino acids in Cell culture (SILAC). Doxycycline was added for the last 48 hr and cisplatin for the last 12 hrs before cell harvest. Equal amounts of protein from both cultures were mixed, digested with trypsin and analyzed by LC-MS/MS (Orbitrap Elite MS) in three independent experiments including a label swap control. Peptides and proteins were identified and quantified using MaxQuant (FDR&lt;0.01). To identify proteins differentially expressed after UBR5 knockdown, relative protein abundance was compared by two-sided t-test with permutation-based correction of the p-value. We identified multiple proteins with increased expression following UBR5 knockdown, suggesting these proteins are regulated by ubiquitin-mediated degradation by UBR5. We validated UBR5-mediated regulation of several proteins by Western blotting, including an oncogene involved in breast and ovarian cancer progression, which we further characterized. In summary, we were able to identify several novel UBR5 candidate substrates whose expression is increased following UBR5 knockdown. Further characterization of these substrates will allow us to identify novel mechanisms of UBR5 regulation of tumor progression.
Citation Format: Scott T. Eblen, Jennifer R. Bethard, D Ralph Rogers, Abdelkader Daoud, Lalima K. Madan, Lauren E. Ball. Identification of novel substrates of the UBR5 E3 ubiquitin ligase in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 326.