bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 7577: A new cancer therapy strategy: Synthetic lethality induced by inhibition of mTOR and cMYC and JNK activation
Authors: Chen Hui , Rivera Jason , Paradise Marc , Xu Zihan , Mognol Giuliana , Varner Judith 
Published: March 2024

Abstract
Cancer cells are characterized by aberrant signal transduction and cell cycle control pathways that lead to unchecked cell proliferation. Uncontrolled cancer cell proliferation, as well as immune suppressive macrophage proliferation, contribute to tumor growth and spread. Effort to suppress tumor cell growth using Inhibitors of PI3K or MEK signaling pathways can initially inhibit tumor growth, but resistance develops due to upregulation of the alternative pathway. We identified a novel series of allosteric tyrosine kinase receptor inhibitors that induce synthetic lethality in AML, lung carcinoma, pancreatic carcinoma, and other tumor cells and in proliferating macrophages in vitro and in vivo by simultaneously inhibiting cMyc and Tor and activating the stress activated kinase JNK, leading to p53 mediated cell cycle arrest. Select kinase inhibitors with a unique positioning of a single side chain inhibited CDK8/19 and thereby Myc while stimulating phosphorylation and activation of JNK and p38. JNK activation promoted sustained ATF-2 and cJun-mediated p53 and Chk1/Chk2 activation, thereby promoting cell cycle arrest in G2/M and ultimately, apoptosis. These inhibitors potently suppressed tumor growth in vivo by halting both tumor cell and macrophage proliferation in G2/M. They synergized with anti-PD-1 and anti-CTLA-4 and led to tumor eradication and immunological memory formation. These studies identify novel allosteric inhibitors with potent synthetically lethal anti-tumor activity.
Citation Format: Hui Chen, Jason Rivera, Marc Paradise, Zihan Xu, Giuliana Mognol, Judith Varner. A new cancer therapy strategy: Synthetic lethality induced by inhibition of mTOR and cMYC and JNK activation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7577.
Abstract 760: Alteration to transcriptional rhythmicity in mammary glands from pubertal MMTV-PyMT mice fed a high-fat diet
Authors: Yan Lin , Palmer Daniel G. , Zeng Huawei 
Published: March 2024

Abstract
Biological clocks, existing in all human organ systems, cycle every 24 hours in a diurnal pattern and control the daily rhythms of human life (e.g., eating vs. fasting, sleep vs. wakefulness), which is essential for health and wellbeing. Disruption of the biological clocks, either by genetic or environmental alteration, disturbs circadian rhythms, which may lead to chronic diseases. Childhood obesity is a risk factor for breast cancer in adult women. Lifestyle changes in the modern world (e.g., energy-dense diets) serve as environmental factors that contribute to alterations in biological clocks and obesity. The present study examined transcriptional rhythmic changes in mammary glands from pubertal MMTV-PyMT mice fed a high-fat diet (HFD). Three-week-old female mice (FVB background) were randomly assigned into three groups - wild-type (WT) mice fed the AIN93G diet and MMTV-PyMT mice fed the AIN93G diet or an HFD for three weeks. At the end of the study, mammary glands were collected every 4 hours over a period of 24 hours (Zeitgeber time 0-24 hours) for RNA-sequencing analysis. The mammary weight was 0.45±0.02, 0.59±0.02, and 0.67±0.02 g for WT mice fed the AIN93G diet and MMTV-PyMT mice fed the AIN93G and HFD, respectively (means ± SEM, all p&lt;0.05 when three groups were compared each other). The rhythmicity analysis using R showed that greater than 1,000 transcripts were classified as “loss of rhythm” when MMTV-PyMT mice (both AIN93G-fed and HFD-fed groups) were compared to WT mice fed the AIN93G diet. Eighteen transcripts were classified as “loss of rhythm” in MMTV-PyMT mice when the HFD was compared to AIN93G diet. Hierarchical clustering analysis showed differentially expressed genes that were significantly altered and KEGG enrichment analysis showed the most upregulated and downregulated metabolic pathways in treatment groups than in the control group at each time point over the 24-hour period. These findings indicates that genetic alterations may have a greater effect than dietary effects on transcriptional rhythmicity in mammary glands from pubertal mice.
Citation Format: Lin Yan, Daniel G. Palmer, Huawei Zeng. Alteration to transcriptional rhythmicity in mammary glands from pubertal MMTV-PyMT mice fed a high-fat diet [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 760.
Abstract 7619: Tissue-derived peripheral biomarkers that reflect activity of T-cells, macrophages, and neutrophils in patients with solid tumors
Authors: Willumsen Nicholas , Nissen Neel I. , Karsdal Morten A. 
Published: March 2024

Abstract
Background: A toolbox of tissue-derived peripheral biomarkers that reflect the activity of T-cells, macrophages and neutrophils is a medical need for immuno-oncology drug development allowing non-invasive quantification of immune cell activity before - and during - treatment, both for predictive and pharmacodynamic purposes. By identifying and quantifying specific extracellular matrix fragments with neo-epitopes that are generated by proteases specific for T-cells, macrophages, and neutrophils, respectively, it is possible to develop peripheral biomarkers that reflect the activity of these immune cells. Such biomarkers have previously shown associations with outcome of patients treated with immune checkpoint inhibitors. Here we investigated the distribution of 3 such biomarkers in different cancer indications. Moreover, these data were compared to data from melanoma patients showing associations with response to cancer immunotherapy.
Methods: Tissue-derived biomarkers related to activity of T-cells (C4G: Collagen-4 degraded by Granzyme B), Neutrophils (CPA9-HNE: Calprotectin degraded by neutrophil elastase), Macrophages (VICM: citrullinated and MMP-degraded vimentin) were measured by validated ELISA/ECLIA in serum from patients with various solid tumor types (bladder-, breast- colorectal-, head and neck-, kidney-, lung-, ovarian-, pancreatic, stomach-, prostate- cancer, and melanoma, n=220) and compared to age-matched healthy controls (n=33) by ANOVA. The biomarker levels were compared to historical data.
Results: Median biomarker levels of CPA9HNE (neutrophil activity/NETosis) and VICM (macrophage activity) were significantly increased in all solid tumor types (p&lt;0.001), respectively and with a ~5-fold inter-patient variation as well. Median C4G levels was only slightly elevated in a few indications (p&lt;0.05) and with a 5-10-fold inter-patient variation across tumor types. All biomarker levels were independent of disease stage. Similar biomarkers levels were seen to those found to be associated with objective response rate and overall survival of melanoma patients treated with cancer immunotherapy.
Conclusion: Tissue-derived peripheral biomarkers that reflect the activity of T-cells (C4G), macrophages (VICM) and neutrophils (CPA9HNE) has biomarker potential in solid tumors and may serve as prognostic, predictive and pharmacodynamic biomarkers in clinical trials investigating cancer immunotherapy.
Citation Format: Nicholas Willumsen, Neel I. Nissen, Morten A. Karsdal. Tissue-derived peripheral biomarkers that reflect activity of T-cells, macrophages, and neutrophils in patients with solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7619.
Abstract 7624: DNA checkpoint gene mutation as a biomarker of immune checkpoint inhibitor in advanced biliary tract cancer
Authors: Shin Ji Eun , Kim Seung Tae , Choi Dae-Ho , Lee Junho , Hyeon Jiyeon 
Published: March 2024

Abstract
Introduction: The DNA checkpoint (DNACHK) pathway is engaged in signaling the need for cell cycle arrest. The G1 and S phase checkpoint allows for repair of damaged DNA, preventing damaged DNA from being copied. The G2 and M phase checkpoint prevents transmission of mutated DNA to the next generation. This pathway, along with mismatch repair (MMR), homologous recombination (HR), and base excision repair (BER), is being actively researched to assess its role in cancer immunotherapy.
Methods: Sixty-two patients participated in this study. These patients were treated with immune checkpoint inhibitors (ICIs) for advanced biliary tract cancers (BTCs) from Mar. 2020 to Aug. 2022 at Samsung Medical Center. DNACHK mutations were defined as genomic alterations such as SNVs, MNVs, and short insertion and deletions in seven genes These genes include checkpoint kinase 1 (CHEK1), checkpoint kinase 2 (CHEK2), BRCA1, DNA repair associated (BRCA1), the serine/threonine kinase ATM, the serine/threonine kinase ATR, and mediator of DNA damage checkpoint 1 (MDC1). We analyzed the effect of DNACHK mutations on the efficacy of ICIs in advanced BTCs.
Results: Patient median age at diagnosis was 68.0 years. Ten patients (16.1%) had gall bladder (GB) cancer; the remaining patients (n = 52, 83.9%) were diagnosed with cholangiocarcinoma. Among the 62 patients with advanced BTCs treated with ICIs, 37 (59.7%) were categorized into the DNACHK wild-type (WT) group and 25 (40.3%) into the DNACHK mutated (MT) group. The most observed DNA checkpoint mutations were ATM mutations (n=14). MDC1 mutations were found in seven patients, ATR mutations in three, BRCA1 mutations in four, and CHEK2 mutations in three. Patients in the DNACHK MT group had better disease control rates than patients in the DNACHK WT group (60.0% vs. 48.6%, p=0.53). Median overall survival (OS) was 8.1 months (95% CI, 5.1, 22.8) in the MT group and 5.6 months (95% CI, 3.1, 11.0) in the WT group (p=0.33).
Conclusions: The results of this study suggest that the DNACHK pathway may be a valuable source of biomarkers for ICI and worthy of further study.
Citation Format: Ji Eun Shin, Seung Tae Kim, Dae-Ho Choi, Junho Lee, Jiyeon Hyeon. DNA checkpoint gene mutation as a biomarker of immune checkpoint inhibitor in advanced biliary tract cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7624.
Abstract 7656: Clinicogenomic anlaysis reveals a role for TP53 mutations in distant progression of high-grade glioma
Authors: Kang Byung-Hee , Lee Seungbok , Lee Joo Ho 
Published: March 2024

Abstract
Purpose: High-grade glioma (HGG), the most common form of primary brain tumor, is highly lethal and treatment options remain limited. Despite advances in genomic technologies, there are few molecular biomarkers to guide precision medicine for HGG. Here, we aimed to identify the clinicogenomic features associated with HGG prognosis and recurrence patterns.
Methods: Our single-institution retrospective analysis included 220 patients initially diagnosed with adult HGG (grade 3 or 4) who underwent next-generation sequencing targeting 82 brain tumor-relevant genes. The patients were categorized according to the 2021 WHO classification and their clinical status, survival, genomic profile, and recurrence patterns were analyzed.
Results: At a median follow-up of 23 months (ranges, 2-59 months), 180 patients (82%) showed either progression or recurrence. A total of 15% of patients were reclassified under the 2021 WHO classification, revealing a clear separation of progression-free survival (PFS) and overall survival (OS) curves between grades 3 and 4 gliomas. We found that TP53 mutations were significantly associated with the occurrence of distant progression, especially in grade 4 gliomas. Additionally, TP53 mutations were more common in patients with higher Ki67 index and subependymal/leptomeningeal seeding, indicating an increased risk of distant progression in TP53-mutated grade 4 glioma patients. Following multivariate Cox regression analysis, TP53 mutations were independent predictors of OS (hazard ratio [HR]=1.47, P=0.039) and distant PFS (HR=1.71, P=0.005).
Conclusion: Considering the elevated risk of distant progression in grade 4 gliomas with TP53 mutations, our results underscore the necessity for additional research into the most effective treatment approaches for these patients.
Keywords: high-grade glioma, TP53, pattern of failure, distant progression, next-generation sequencing
Citation Format: Byung-Hee Kang, Seungbok Lee, Joo Ho Lee. Clinicogenomic anlaysis reveals a role for TP53 mutations in distant progression of high-grade glioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7656.
Abstract 7668: Novel pretreatment nomograms based on pan-Immune-inflammation value for predicting clinical outcome in patients with head and neck squamous cell carcinoma
Authors: Chen Qian , Li Xiang , Bai Yanxia , Chen Yue 
Published: March 2024

Abstract
Background: The prognostic value of an effective biomarker, Pan-Immune-Inflammation Value (PIV), for head and neck squamous cell carcinoma (HNSCC) patients after radical surgery or chemoradiotherapy has not been well explored. This study aimed to construct and validate nomograms based on PIV to predict survival outcomes of HNSCC patients.
Methods: 161 HNSCC patients underwent radical surgery and 50 patients received chemoradiotherapy were enrolled retrospectively for development and external validation cohort, respectively. The cut-off of PIV was determined using the maximally selected rank statistics method. Multivariable Cox regression and least absolute shrinkage and selection operator (LASSO) regression analyses were performed to develop two nomograms (Model A and Model B) that predict disease-free survival (DFS).
Results: Patients with higher PIV (≥123.3) experienced a worse DFS (HR: 5.01, 95% CI: 3.25-7.72, p&lt;0.0001) and overall survival (OS) (HR: 5.23, 95% CI: 3.34-8.18, p&lt;0.0001) compared to patients with lower PIV (&lt;123.3), which was also consistent in the external cohort. Predictors of Model A included age, TNM stage, neutrophil-to-lymphocyte ratio (NLR) and PIV, and that of Model B included TNM stage, lymphocyte-to-monocyte ratio (LMR) and PIV. In comparison with TNM stage alone, the concordance index (C-index), receiver operating characteristic (ROC) curves and calibration curves of the nomograms demonstrated good calibration and discrimination, and the decision curve analysis (DCA) also showed satisfactory clinical utility in both internal and external validation.
Conclusions: The nomograms based on PIV, a simple but forceful indicator, can provide intuitive and precise prognosis prediction of individual HNSCC patients after radical surgery or chemoradiotherapy.
Citation Format: Qian Chen, Xiang Li, Yanxia Bai, Yue Chen. Novel pretreatment nomograms based on pan-Immune-inflammation value for predicting clinical outcome in patients with head and neck squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7668.
Abstract 790: Sex and race-dependent variations in the mutational landscape of clonal hematopoiesis
Authors: Dhuri Kanaka , Alachkar Houda 
Published: March 2024

Abstract
Introduction: Clonal hematopoiesis of indeterminate potential (CHIP) has emerged as a significant precursor to hematological malignancies and is associated with several age-related diseases. Recent studies in relatively small disease specific cohorts have suggested that CHIP may exhibit variations among different races and between males and females raising intriguing questions about potential genetic and environmental influences. Understanding the differences in CHIP across races and between males and females may have implications for personalized cancer risk assessment and targeted therapeutic strategies.
Methods: Patient’s data were obtained from the Cancer Therapy and Clonal hematopoiesis via cBioportal. The original study was designed to examine clonal hematopoiesis mutations that were found in blood samples obtained from 24,146 patients with non-hematological cancers and their tumor-blood pairs were analyzed using targeting sequencing data MSK-IMPACT (Memorial Sloan Kettering-IMPACT). The cohort consisted of 45.7% males and 54.3% females; including 6.8% Asians, 6.2% Blacks, and 76.3% Whites. We examined mutation frequencies among these racial groups and between genders, employing the two-sided Fisher's exact test and adjusting p-values for multiple comparisons. Differences were considered significant when both P value and Q values are less than 0.05.
Results: DNMT3A mutations were substantially more prevalent in females than in males (38.94% vs 31.37%, p-value: &lt;10−10, q-value: 6.19e−09), While ASXL1 mutations were more frequent in males than females (5.82% vs 2.69%, p-value: &lt;10−10, q-value: 6.19e−09). In the racial cohorts with sufficient sample sizes, STAT5B and CSF1R mutations were most frequent in Asian (1.40% and 0.84%), followed by Black (0.98% and 0.24%) and White populations (0.29% and 0.09%), (p-value: 8.099e−04 and 7.490e−04, q-value: 0.0234 and 0.0232). Several other CHIP mutations were enriched in Black: RARA, SMAD2, CDKN1B, CENPA, CTLA4, EIF1AX, ELF3, MSI1, MYC, SOX17, AURKA. On the other hand, H3C1, H3C4, MYCL were enriched in the Asian cohort.
Conclusion: Our analysis provides insights into the complex interplay of sex and racial factors in shaping CHIP mutation frequencies. As CHIP continues to gain recognition as a critical precursor to malignancies, understanding these variations contributes to refining our understanding of its underlying mechanisms and clinical implications.
Citation Format: Kanaka Dhuri, Houda Alachkar. Sex and race-dependent variations in the mutational landscape of clonal hematopoiesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 790.
Abstract 791: Evaluation of BCR spike-in controls using DriverMap adaptive immune receptor (AIR) profiling technology
Authors: Chenchik Alex , Liu Tianbing , Makhanov Mikhail , Hu Dongfang , Ghias Khadija , Diehl Paul 
Published: March 2024

Abstract
The DriverMap™ Adaptive Immune Receptor (AIR) repertoire profiling assay employs multiplex RT-PCR for comprehensive profiling of CDR3 or full-length receptor profiling of all variable heavy and light chains of T-cell receptors (TCR) and B-cell receptors (BCR) from either RNA or DNA. In this study, initiated by a U.S. Food and Drug Administration (FDA) consortium to compare performance of different BCR repertoire profiling technologies, we tested spike-ins in peripheral blood mononuclear cell (PBMC) RNA and DNA control mixtures prepared from nine different B-cell lines. We measured the sensitivity, linearity and accuracy of AIR RNA and DNA BCR profiling for the IGH, IGK and IGL chains of the spike-in controls. Our comprehensive analysis, encompassing CDR3 profiling and full-length receptor profiling (CDR1, CDR2, and CDR3) sequencing, revealed a 100X increase in sensitivity of detection of spike-in controls in RNA compared to the DNA assay. The high sensitivity of the full-length DriverMap AIR RNA assay allowed the detection of controls from all nine cell lines, with 8 out of 9 cell lines detected in the DNA assay, which demonstrates the robustness of the DriverMap AIR profiling technology.
This study highlights the remarkable sensitivity of the AIR RNA assay in quantifying transcripts. This approach enables the detection of low-frequency BCR clonotypes, which is particularly advantageous when working with samples containing low numbers of B cells. Furthermore, our AIR DNA assay in combination with spike-in controls offers a quantitative tool for minimal residual disease (MRD) applications, providing accurate insight into cell numbers, which then facilitates tracking clonal expansion of immune cells.
Citation Format: Alex Chenchik, Tianbing Liu, Mikhail Makhanov, Dongfang Hu, Khadija Ghias, Paul Diehl. Evaluation of BCR spike-in controls using DriverMap adaptive immune receptor (AIR) profiling technology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 791.
Abstract 838: Population attributable fraction of occupational carcinogens for cancer incidence among Korean adults in 2020
Authors: Kim Eun Mi , Koh Dong-Hee , Park Sue K , Choi Yoon-Jung , Seo Hong Gwan , Kim Inah , Im Jeong-Soo 
Published: March 2024

Abstract
Assessing the level and scope of exposure to occupational carcinogens on a country-specific basis presents challenges, and as a result, it has been appraised as uncertain when compared with other factors in the estimation of the burden of cancer. The Korean CARcinogen Exposure (K-CAREX) developed in 2021 is utilized to estimate the population at risk in industrial work environments in Korea (Koh et al., 2021). Our goal is to estimate preventable cancer incidence attributable to occupational carcinogens in Korea, utilizing the K-CAREX program and employing appropriate methodology. Among the exposures classified as Group 1 factors by IARC, considering the possibility of occupational exposure. Population attributable fractions (PAFs) were computed using Levin's Formula (1953), considering a latency period of 15 years between exposure and cancer in our assessment. The prevalence of exposure was calculated using K-CAREX program and census data. The relative risk (RR) for incidence was derived from a meta-analysis of literature. It was possible to calculate PAFs for 11 occupational factors linked with 8 cancer types. This estimation was chosen based on a combination of exposure and sufficient evidence of human carcinogenicity. As a result, Population attributable fractions (PAFs) for cancer incidence associated with occupational carcinogens was estimated at 1% in 2020. Lung cancer (approximately 90%) was found to be the most prevalent type of cancer attributable to occupational factors, as widely acknowledged. The prevalence of exposure to occupational carcinogens was 22%, with Diesel engine exhaust being the most significant source for both genders. Since the early 2000s, the exposure levels of asbestos, subject to usage prohibition and restriction measures, were estimated to be at a lower level compared to other countries. It is evident that these estimates reflect the characteristics of the Korean industry. This is anticipated to provide a foundation for the development of methodologies and indicators essential for measuring the burden of occupational cancer in the country.
Citation Format: Eun Mi Kim, Dong-Hee Koh, Sue K Park, Yoon-Jung Choi, Hong Gwan Seo, Inah Kim, Jeong-Soo Im. Population attributable fraction of occupational carcinogens for cancer incidence among Korean adults in 2020 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 838.