bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1831: A long-acting and CD122-enhanced IL-2 analog, HM16390, synergizes with immune checkpoint inhibitor by remodeling an immune cell profile in tumor microenvironment
Authors: Choi Jaehyuk , Kim Jinyoung , Kim Yu Yon , Jeong Seongju , Bae Sungmin , Kim Daejin , Choi In Young 
Published: April 2023

Abstract
Immune checkpoint inhibitors (CPI) are widely used for cancer immunotherapy. However, the response to CPIs is dependent on phenotype of tumor microenvironment (TME). A cold tumor known as immune-excluded or -desert has shown poor response to CPIs due to an absence of effector T cells in TME. IL-2 analog, which is immune stimulator and able to recruit cancer-fighting cells into TME, may be promising therapeutic partner for overcoming a limitation of CPIs. Previously, HM16390, a long-acting CD-122-enhanced IL-2 analog, exerted dose-dependent anti-tumor activity in low immunogenic B16F10 melanoma mice. Here, we further investigated the immune cells composition in TME following HM16390 treatment and synergistic anti-tumor effect after combination with CPI. B16F10 mice were sacrificed at days 1, 3, and 8 following single subcutaneous administration of HM16390 or 5 consecutive daily administrations of aldesleukin. According to the result, HM16390 transiently increased peripheral cytokines (IFNγ and TNFα) more than aldesleukin. In line with this, we observed that the tumor-infiltrating NK/Treg ratio was significantly increased approximately 19 by treatment of HM16390 while showing 4.2 in aldesleukin treated group at Day 3. Furthermore, tumor-infiltrating CD8+/Treg ratio was also upregulated approximately 74 by treatment of HM16390 while only showing 6.1 in aldesleukin treated group at Day 8. Significantly increased pro-inflammatory molecules such as GrzB and IFNγ were also observed in HM16390 treated group compared to aldesleukin (p&lt;0.01 and p&lt;0.001, respectively). Next, we investigated synergistic anti-tumor effects in combination with CPI. B16F10 mice were repeatedly given HM16390 once a week or aldesleukin 5 consecutive days per week with or without mouse anti-PD1. After four weeks treatment, 25% of B16F10 mice showed complete response by treatment of HM16390, and significantly increased up to 88% by combination with anti-PD1. However, none of the mice showed complete response by treatment of aldesleukin/anti-PD1 combo. In conclusion, HM16390 effectively induced tumor growth inhibition through the activation and tumor infiltration of cytotoxic lymphocytes. This favorable immune alteration in tumor elicited a TME remodeling in which CPI could sufficiently respond.
Citation Format: Jaehyuk Choi, Jinyoung Kim, Yu Yon Kim, Seongju Jeong, Sungmin Bae, Daejin Kim, In Young Choi. A long-acting and CD122-enhanced IL-2 analog, HM16390, synergizes with immune checkpoint inhibitor by remodeling an immune cell profile in tumor microenvironment [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 1831.
Abstract 1906: MSH3: An underestimated DNA MMR gene in colorectal carcinogenesis and its potential role in disparity
Authors: Rashid Mudasir , Rashid Rumaisa , Koi Minoru , Carethers John M. , Brim Hassan , Ashktorab Hassan 
Published: April 2023

Abstract
Background: Unique mutations in cancer genes have been found in different races including African Americans (AA) population. Maintenance of proficient mismatch repair genes is important in colorectal cancer. Among them, MSH3 is found to be more important in colorectal cancer in AA particularly as its alterations associate with EMAST phenotype that has poor prognosis. However, there are regional variations in the classification and criteria used to determine the pathogenicity of these mutations particularly in AA due to their high genomic diversity. Aim: To analyze unique and novel MSH3 mutations using specific in-silico prediction tools and to validate their biological significances in AA-CRC. Results: In this study, we validated our targeted exome sequencing data of MSH3 mutations in AA and Caucasians (CA) CRC samples. A cost effective in-silico approach was employed to narrow down most significant MSH3 mutations. Interestingly, we and found six non-synonymous novel, pathogenic mutations in MSH3 gene (c.G1237A, c.C2759T, c.G1397A, c.G2926A, c.C3028T, c.G3241A) correspond to MSH3 protein (E413K; S466N; S920F; E976K; H1010Y; E1081K), in AA than CA samples. Also, we observed loss or gain of different chemical bonding patterns (hydrogen, ionic, hydrophobic, and di-sulfide bonding) between wild type and mutant MSH3 protein. Interestingly, some of these mutations were within the ATPase site while others are in MSH3-MSH2 interacting domains. Furthermore, Molecular Dynamics Simulation (MDS) of these six mutants of MSH3 proteins showed an overall effect on MSH3 protein stability especially in MSH3-MSH2 interaction compared to wild type MSH3 protein.Conclusion: Our data showed that, six MSH3 non-synonymous mutations are deleterious as they affect important sites within MSH3-MSH2 interactive and ATPase domain. Assessing the real frequency of these mutations in large cohort and their specific effect on function may shed light on EMAST phenotype, high prevalence, and overall poor prognosis in the AA population. In vitro functional assays using CRISPR-Cas9 knock-in and in vivo studies are underway to mimic these mutations.
Citation Format: Mudasir Rashid, Rumaisa Rashid, Minoru Koi, John M. Carethers, Hassan Brim, Hassan Ashktorab. MSH3: An underestimated DNA MMR gene in colorectal carcinogenesis and its potential role in disparity [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 1906.
Abstract 1953: Association between genetic ancestry and all-cause mortality among Black and White ever-smokers in the PLCO cohort
Authors: Dill Courtney D. , Crump Dontray , Landy Rebecca , Cheung Li C. , Huang Wen-Yi , Berndt Sonja , Freedman Neal , Katki Hormuzd 
Published: April 2023

Abstract
Introduction: It is unknown how much of the increased all-cause mortality risk in Black individuals who ever-smoked is due to race as a social construct versus biological factors such as genetic ancestry. We examined the association of genetic ancestry with all-cause mortality, controlling for risk factors and self-reported race/ethnicity, in the PLCO cohort.
Methods: We used PLCO data from 52,708 White individuals who ever-smoked (18281 deaths) and 2,585 Black individuals who ever-smoked (1108 deaths). Genetic ancestry was determined by GRAF (https://github.com/ncbi/graf) on a set of 10,000 pre-selected fingerprinting variants. Percent ancestry for each of Europe, Africa, and East-Asia was determined for each person. We fit Cox models for time to death, controlling for smoking history and other risk factors.
Results: Self-reported Black individuals who ever-smoked had increased all-cause mortality versus self-reported White individuals who ever-smoked (HR=1.14, 95%CI: 1.07-1.22, p=0.00007). For White individuals, increases in European ancestry were associated with increased death risk, (HR=1.009 per 1% increase in European ancestry, 95%CI:1.003-1.015, p=0.002). HRs for European ancestry, by quartile, were 1.040, 1.061 and 1.063, with the last two HRs demonstrating statistical significance (95%CI:1.0018-1.106, p = 0.005, and 95%CI:1.020-1.108, p=0.004), respectively. For Black individuals, increases in African ancestry were associated with increased death risk, (HR=1.003 per 1% increase in African ancestry, 95%CI: 0.998-1.008, p=0.214), although not statistically significant. HRs for African ancestry, by quartile, were 1, 1.16, 1.14, and 1.21, with the last HR demonstrating statistical significance (95%CI:1.010-1.450, p = 0.03).
Conclusions: For self-reported White individuals who ever-smoked, increasing European ancestry was associated with an increased all-cause mortality risk. For self-reported Black individuals who ever-smoked, there was suggestive evidence that increasing African ancestry may increase all-cause mortality risk. However, associations with ancestry were small and may be vulnerable to residual confounding.
Impact/Significance: A mechanistic explanation for this finding is unclear, but it could be related to population genetic “fitness” with reduced genetic admixture leading to decreased fitness for survival.
Citation Format: Courtney D. Dill, Dontray Crump, Rebecca Landy, Li C. Cheung, Wen-Yi Huang, Sonja Berndt, Neal Freedman, Hormuzd Katki. Association between genetic ancestry and all-cause mortality among Black and White ever-smokers in the PLCO cohort [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 1953.
Abstract 1965: Racially divergent mitochondrial ND5 gene mutation promotes prostate cancer progression and confers therapeutic resistance
Authors: Vikramdeo Kunwar Somesh , Keel Christopher E. , Heslin Martin J. , Singh Seema , Singh Ajay Pratap , Dasgupta Santanu 
Published: April 2023

Abstract
Compared to European American (EA), African American (AA) men often develop lethal forms of prostate cancer (PCa) and experience high mortality despite having a primary diagnosis of low-risk indolent disease. Understanding the molecular basis of this disparity is thus a dire need for better prevention, accurate monitoring, and guided therapeutics. Aggressive cancer growth is intimately associated with the reprogramming of metabolism and apoptosis, where mitochondrial DNA (mtDNA) alterations play a critical role. In the mitochondrial energy generation cascade, respiratory complex I (RCI) serves as the entry gate to initiate electron transfer through the oxidative phosphorylation system (OXPHOS). Alteration in RCI function could alter metabolism and attenuate apoptosis, hallmarks of malignant progression. Through next-generation sequencing of the entire mitochondrial genome, we identified a prevalence of RCI gene mutations in the AAPCa compared to the EAPCa patients. Among the RCI mutations, a homoplasmic 13709C&gt;G mutation in NADH dehydrogenase 5 (ND5) was identified as the most frequently occurring mtDNA mutation among AA men. Forced expression of the 13709C&gt;G mutation in the mitochondria of the AA-PCa patient-derived MDA PCa 2b and EA-PCa patient-derived LNCaP cells, remarkably enhanced their growth and malignant potential. The increased tumorigenicity was associated with a significant increase in the production of mitochondrial reactive oxygen species (ROS), O2 consumption, overall respiration, and ATP production. The ND5-mutant PCa cells exhibited remarkable resistance to androgen deprivation and docetaxel treatment. Induction of CXCR4, HIF-1α, and NF-kB was also noted in these ND5-mutant PCa cells. In clinical tissue samples, an abundance of CXCR4 protein expression was evident in AA-PCa patients harboring ND5 gene mutation but not in the AA or EA-PCa patients with wild-type ND5. Blockade of CXCR4 expression in the ND5-mutant PCa cells diminished NF-kB activity, thereby suggesting a potential role of the CXCR4/HIF-1α/NF-kB signaling axis in ND5 mutation-driven PCa tumorigenesis. The RCI-ND5 could be an attractive target for therapeutic and biomarker development for the better management of PCa in racially disparate populations.
Citation Format: Kunwar Somesh Vikramdeo, Christopher E. Keel, Martin J. Heslin, Seema Singh, Ajay Pratap Singh, Santanu Dasgupta. Racially divergent mitochondrial ND5 gene mutation promotes prostate cancer progression and confers therapeutic resistance [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 1965.
Abstract 1977: Body mass index genetic risk score and obesity related cancer risk in Black and White adults
Authors: Katzmarzyk Peter T. , Yang Shengping , Brown Justin C. , Mire Emily F. , Zabaleta Jovanny 
Published: April 2023

Abstract
A total of 13 cancers are known to be strongly associated with obesity. The purpose of this study was to examine the association between a composite genotype risk score (GRS) for high body mass index (BMI) and the odds of obesity-related cancer. A nested case-control study was created within the Pennington Center Longitudinal Study, an ongoing prospective cohort study of the effects of obesity and lifestyle factors on the development of chronic diseases and premature mortality in Black and White Americans. A total of 459 participants developed an obesity-related cancer, and after stratification by sex and race, incidence density sampling was applied to select matched control participants (2:1) of the same age as cases (± 2 y). After deletion of participants with missing data, the analytic sample included 1242 participants (435 cases;136 Black, 299 White). A BMI GRS was derived using 21 single nucleotide polymorphisms (SNPs) with consistent evidence of association from the literature and which showed concordant associations in effect size and direction in our cohort. The GRS score was computed by summing the number of BMI risk alleles. In a model including age, race, sex, exam year and smoking as covariates, the BMI GRS was significantly associated with obesity-related cancer [odds ratio (OR): 1.18; 95% confidence interval: 1.04, 1.34; p=0.01]. Further adjustment for BMI did not change the association [1.20; 1,06-1.36; p=0.004]. In conclusion, the BMI GRS appears to provide added value in identifying obesity-related cancer risk, even after adjustment for BMI. Future studies are required to validate these results and better delineate the phenotypic and genetic contributions of BMI to obesity-related cancer risk.
Citation Format: Peter T. Katzmarzyk, Shengping Yang, Justin C. Brown, Emily F. Mire, Jovanny Zabaleta. Body mass index genetic risk score and obesity related cancer risk in Black and White adults [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 1977.
Abstract 1987: Delivery of potent cytotoxic camptothecin derivatives to tumors by OncoFAP-based small molecule-drug conjugates
Authors: Bocci Matilde , Cazzamalli Samuele , Neri Dario , Galbiati Andrea 
Published: April 2023

Abstract
Small Molecule-Drug Conjugates (SMDCs) are anti-cancer pro-drugs composed by a tumor-targeting small organic ligand, a linker structure and a potent cytotoxic payload. OncoFAP is an ultra-high affinity ligand of Fibroblast Activation Protein (FAP), a stromal protein overexpressed in multiple types of solid human malignancies. Nuclear medicine studies validated the applicability of the OncoFAP technology for tumor-targeting applications in a wide variety of tumor types. We have recently reported the development of SMDC products in which OncoFAP is used to deliver Monomethyl Auristatin E (MMAE) to tumors, exploiting linkers that are selectively cleaved by FAP. Here we describe the generation and in vivo characterization of novel OncoFAP-based SMDC products bearing potent camptothecin derivatives acting as topoisomerase I inhibitors. Those drug payloads have been already included in approved ADC products (EnhertuTM and TrodelvyTM). The FAP-cleavable linker technology was directly compared against linker strategies used for approved ADCs. Therapy results in preclinical xenograft models of solid tumors revealed that SMDC products activated by FAP show superior anti-cancer activity and deserve industrial development for the treatment of various human solid tumors.
Citation Format: Matilde Bocci, Samuele Cazzamalli, Dario Neri, Andrea Galbiati. Delivery of potent cytotoxic camptothecin derivatives to tumors by OncoFAP-based small molecule-drug conjugates [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 1987.
Abstract 1989: DNA-encoded affinity maturation libraries enable the discovery of low picomolar fibroblast activation protein inhibitors suitable for radioligand therapy of solid tumors
Authors: Puglioli Sara , Prati Luca , Oehler Sebastian , Galbiati Andrea , Neri Dario , Cazzamalli Samuele , Bassi Gabriele , Favalli Nicholas 
Published: April 2023

Abstract
The discovery of potent ligands highly specific to accessible cancer-associated antigens is essential for the development of small molecule therapeutics with broad therapeutic index. DNA-encoded chemical libraries (DELs) can be used to discover novel binders and to improve binding affinity of existing small organic ligands by affinity maturation procedures. OncoFAP is a 680 pM inhibitor of the stromal pan-tumoral antigen Fibroblast Activation Protein (FAP). OncoFAP displays best-in-class tumor targeting performance in patients, although its relatively short half-life limits the applicability as radioligand therapeutic against solid malignancies. We designed three focused affinity maturation DELs, containing 50,730 compounds bearing two sets of building blocks coupled to a propargylglycine central scaffold. Library selections against FAP from multiple species enabled the discovery of novel FAP inhibitors with potencies in the low picomolar range. 177Lu-DOTAGA conjugates of the most potent novel ligands (named “OncoFAP-11” and “BiOncoFAP-11”) localized to tumors implanted in mice, with excellent tumor-to-blood and tumor-to-kidney ratios at late time-points after systemic administration. The high affinity FAP ligands described here enable the efficient delivery of therapeutic radionuclides to tumors with long residence time and with low uptake in normal tissues. The results presented here show that DEL-based affinity maturation procedures can lead to the improvement of the targeting performance of FAP binders, without compromising their tumor selectivity.
Citation Format: Sara Puglioli, Luca Prati, Sebastian Oehler, Andrea Galbiati, Dario Neri, Samuele Cazzamalli, Gabriele Bassi, Nicholas Favalli. DNA-encoded affinity maturation libraries enable the discovery of low picomolar fibroblast activation protein inhibitors suitable for radioligand therapy of solid tumors [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 1989.
Abstract 2033: Assessment of human reference genomes on cancer somatic mutation detection in tumor-normal paired reference samples using whole genome short-read sequencing data
Authors: Xiao Chunlin , Schneider Valerie 
Published: April 2023

Abstract
A typical cancer somatic mutation identification workflow involves using a standard human reference genome for aligning the sequencing reads and annotating the uncovered somatic variants. The completeness and the correctness of the reference genome, and the haplotype representations may all impact the sequencing read alignments and subsequent somatic variant identifications. However, the exact impacts of the underlying references being used on somatic mutation analysis has not been investigated. In this study, we selected 3 human reference genomes, including GRCh38, T2TCHM13, and a personalized genome (PG) that was derived from a normal cell line, and 12 tumor normal paired replicates of Illumina short read sequencing data for the HCC1395 breast cancer cell line and a matched normal cell line, and aim to illustrate and quantify the effects of the reference genomes on the accuracy of somatic SNV/SV mutation detection using various somatic variant callers. Our analysis shows that the use of a personalized haplotype-specific genome assembly, rather than an unrelated genome such as GRCh38 or T2TCHM13 as a reference, not only improves read alignments for short-read sequencing data but also ameliorates the detection accuracy of somatic SNVs and SVs. While most somatic mutation calls are identical or equivalent, we identify GRCh38 and T2TCHM13 specific somatic mutations that may need to be avoided for further pursuit of incorrect treatment options. We uncover novel somatic mutations only when personalized genome assembly is used as a reference, some of which overlap with genes involving with pathways related to cancer invasion and metastasis (e.g., CDH23, ST14 etc.). The predicted somatic SVs are found more precise. Such results may provide additional interventional target choices for patients, researchers or clinicians, and physicians to look into further for personalized patient care.
Citation Format: Chunlin Xiao, Valerie Schneider. Assessment of human reference genomes on cancer somatic mutation detection in tumor-normal paired reference samples using whole genome short-read sequencing data [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 2033.
Abstract 2052: High-plex spatial multiomics of pediatric and adult diffuse midline glioma, H3 K27-altered
Authors: Damodharan Sudarshawn , Rosenbloom Alyssa , Dey Mahua 
Published: April 2023

Abstract
Background: Diffuse midline glioma (DMG), H3 K27-altered are highly aggressive malignancies of the central nervous system that affect both pediatric and adult populations. The immune layout and genetic changes within the tumor microenvironment associated with these high-grade malignancies are thought to play an integral role in the phenotypic differences in tumor presentation and clinical course between both populations. Comparative landscapes between pediatric and adult DMGs is not known.
Methods: The NanoString GeoMxTM Digital Spatial Profiler platform was used to determine the immune marker and genetic layout in a cohort of both pediatric and adult DMG, H3 K27-altered tissue samples. Three fluorescently labeled antibodies targeting immune cells (CD45), epithelial cells (PanCK), tumor cells (H3 K27M) and a nucleic acid stain (SYTO-13) were used to identify and separate out the various components within the tumor tissues from selected regions of interest. The resultant information was then pooled into libraries that were run through the Illumina sequencing platform to assess transcriptomic and proteomic data for both cohorts of samples.
Results: Our data revealed the immune and genetic expression seen within both populations across multiple regions of interest within the samples. Differences were seen specific to each population that may have clinical significance and warrant further exploration including a significant increase in genes associated with RTK pathways in the pediatric samples.
Conclusion: The digital spatial analysis of pediatric and adult DMG, H3 K27-altered shows differences within the molecular landscape which may contribute to the clinical differences between both populations. These observed differences may play a role in future treatments and further research is needed to explore this.
Citation Format: Sudarshawn Damodharan, Alyssa Rosenbloom, Mahua Dey. High-plex spatial multiomics of pediatric and adult diffuse midline glioma, H3 K27-altered [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 2052.