tbuckley/cabot-search huggingface dataset:
Abstract 4324: IL6ST increases sorafenib-resistance in hepatocellular carcinoma by regulating BECN1-mediated mitophagic cell death
Authors: Hwan Ma, Yoon-Seok Roh
Journal: Cancer Research (2024)

Abstract Introduction: Sorafenib resistance is often seen in patients with late-stage hepatocellular carcinoma (HCC) and it is a serious concern for the treatment of these patients. Lethal mitophagy plays an important role in anti-tumorigenic mechanisms by inducing mitochondrial dysfunction and mitophagic cell death. Sorafenib resistance is associated with the activation of IL6ST signaling, inhibiting mitochondrial quality. However, how lethal mitophagy regulates sorafenib resistance through IL6ST and mitochondrial dysfunction in HCC is not fully understood. Experimental procedures: Hepatocyte-specific TAK1 deleted (TAK1ΔHep) and TAK1/IL6STΔHep were used for in vivo study. Histology, immunoblots, qPCR, microscopy, FACS, and seahorse bioanalyzer were used for analyzing liver and tumor tissues and Hep3B cells. Results: We identified that sorafenib suppressed IL6ST signaling and that IL6ST signaling was activated in sorafenib-resistant HCC. The number and maximum size of spontaneous HCC in 9-month-old TAK1ΔHep mice were decreased when hepatocyte IL6ST was additionally deleted. Expression of pro-carcinogenic H-19, c-SRC, and MDM2 was increased in 1-month-old TAK1/IL6STΔHep mice compared to TAK1ΔHep mice. An additional IL6ST deletion induced decreases in mitochondrial membrane potential and glycolysis, suggesting that IL6ST protects against mitochondrial dysfunction. Interestingly, IL6ST deletion increases PRKN and BECN1 interaction and translocation to normal mitochondria and subsequent degradation, hereafter referred to as lethal mitophagy. Furthermore, inhibition of BECN1 restores IL6ST deletion-induced lethal mitophagy in HCC, suggesting that IL6ST-mediated lethal mitophagy is dependent on BECN1. Mechanistically, IL6ST inhibited BECN1-lethal mitophagy through STAT3(S705) phosphorylation independently of mTORC1 activation. Notably, enhanced BECN1 through a combination of sorafenib and inhibition of IL6ST increased mitophagic cell death, reducing sorafenib resistance and tumor growth. In addition, enhanced lethal mitophagy through inhibition of GP130 effectively killed sorafenib-resistant HCCs by silencing sorafenib resistance. We further defined the relationship between IL6ST, BECN1, and PRKN expression and sorafenib resistance in terms of HCC patients, RNA sequencing datasets. Conclusion: These results provide the importance of IL6ST in the development of sorafenib resistance and could be an innovative treatment strategy for sorafenib-resistant patients by regulating the IL6ST/STAT3/BECN1 axis-regulated lethal mitophagy. Citation Format: Hwan Ma, Yoon-Seok Roh. IL6ST increases sorafenib-resistance in hepatocellular carcinoma by regulating BECN1-mediated mitophagic cell death [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 4324.
Abstract 821: Uptake of cervical cancer screening services by women living with HIV in Kajiado County Kenya
Authors: Caren Kamau, Alice Njoroge, Francis Makokha, Kimlin T. Ashing
Journal: Cancer Research (2024)

Abstract Background: This project is an African Caribbean Cancer Consortium (AC3) facilitated study: Women living with HIV (WLHIV) are more susceptible to cancer due to their immune-compromised status. The Kenya Ministry of Health recommends that women diagnosed with HIV should be screened for cervical cancer annually by either visual inspection with acetic acid (VIA) or visual inspection with Lugol’s iodine (VILI), cytology and testing for HPV once every two years. Objective: We determined the uptake of cervical cancer screening and HPV testing by women living with HIV (WLHIV) in Kajiado County in 2022. Methodology: The electronic health information system was used to abstract data for WLHIV in Kajiado county. Kajiado county has 57 antiretroviral (ART) facilities. However, our analysis accessed data from 38 facilities whose data is captured in the health information system. Authorized health care workers from the county were requested to abstract redacted data from the health information system. No personal identifiers were collected from the system as a means of protecting the privacy of individuals and abiding with the Kenya’s data protection law. Authorization to access the county was obtained from the county’s department of health while ethical approval was obtained from Mount Kenya University’s Institutional Scientific and Ethics Review Committee. Results: A total of 16,827 people living with HIV were enrolled for care at the 38 ART selected sites in 2022. Out on the total population that was enrolled for care, 11,785 (70%) were women with an age range of 15 to 49 years. A total of 3342 WLHIV, representing 28.36% of the target population, were screened by using visual inspection with acetic acid (VIA). Data for other methods of screening and HPV testing was not available in the health information systems. Of those screened, 3240 (97%) tested negative, 78 (2.3%) had positive results while 24 (0.7%) had suspicious lesions. Conclusion: Our analysis shows low uptake of cervical cancer screening services with only 28.36% of the targeted women being screened in 2022. The only available testing method (VIA) is less robust as compared to cytology and HPV testing. We also found a gap in reporting of HPV testing in the county. We thus recommend implementation science research examining the systemic barriers to HPV testing and reporting to better inform best practice HPV-related cancer prevention and control policy and practice to reduce cancer-related morbidity and mortality among WLHIV. Citation Format: Caren Kamau, Alice Njoroge, Francis Makokha, Kimlin T. Ashing. Uptake of cervical cancer screening services by women living with HIV in Kajiado County Kenya [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 821.
Lipase and pH-responsive diblock copolymers featuring fluorocarbon and carboxyl betaine for methicillin-resistant staphylococcus aureus infections
Authors: Jipeng Xiao, Meihui Yin, Min Yang, Jinghang Ren, Cheng Liu, Jiali Lian, Xinyu Lu, Yuchen Jiang, Yongchao Yao, Jianbin Luo
Journal: Journal of Controlled Release (2024)
Abstract 839: Interaction between solvent exposure and genetic susceptibility and risk for bladder cancer
Authors: Deborah Tadesse, Nathaniel Rothman, Shuai Xie, Lauren Hurwitz, Melissa C. Friesen, Dalsu Baris, Molly Schwenn, Alison Johnson, Margaret Karagas, Debra T. Silverman, Stella Koutros
Journal: Cancer Research (2024)

Abstract Introduction: Recent studies have reported an increased bladder cancer risk with occupational exposure to organic solvents, including exposure to benzene, toluene, and xylene (BTX). The metabolism of solvents is known to be influenced by genetic susceptibility. Here, we evaluated the association between BTX and bladder cancer, stratified by genotype in known bladder cancer susceptibility loci and in variants shown to impact the metabolism of solvents. Methods: We evaluated if single-nucleotide polymorphisms (SNPs) modified the association between BTX exposure and bladder cancer risk in 1182 cases and 1408 controls from a population-based case-control study in New England. Ever and cumulative lifetime exposure to BTX was assessed using occupational histories obtained by personal interviews and exposure-oriented modules in conjunction with a job-exposure matrix. Genotyping was conducted using Illumina arrays and GSTM1 and GSTT1 deletion were determined using melt curve/copy number assays. We used multivariate logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between BTX exposure and bladder cancer, stratified by genotype and to calculate p-values for multiplicative interaction. Results: Ever exposure to BTX was more strongly associated with bladder cancer risk among individuals with the GSTT1 null (deletion) genotype (OR 3.53, 95% CI 1.26-9.89), while exposed individuals with the GSTT1 active genotype had a diminished risk (OR 1.40, 95% CI 0.93-2.10, P-interaction = 0.06). The association between benzene exposure and bladder cancer was similarly modified by GSTT1 genotype (carriers of the deletion: OR 5.19, 95% CI 1.91, 14.13; carriers of one or two copies: OR 1.22, 95% CI 0.79, 1.89, p-interaction=0.008). Conclusion: GSTT1 genotype has been shown to impair the metabolism of solvents, particularly for benzene. Here we show that bladder cancer risk is higher among those exposed to solvents who also harbor a common deletion in GSTT1, adding to the evidence of a plausible link between BTX exposures and bladder cancer risk. Citation Format: Deborah Tadesse, Nathaniel Rothman, Shuai Xie, Lauren Hurwitz, Melissa C. Friesen, Dalsu Baris, Molly Schwenn, Alison Johnson, Margaret Karagas, Debra T. Silverman, Stella Koutros. Interaction between solvent exposure and genetic susceptibility and risk for bladder 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 839.
Abstract 835: Occupational-related exposure to benzene and risk of female genital cancers: Systematic review and meta-analysis
Authors: Darshi Shah, Vincent DeStefano, Veer Shah, Monireh Sadat Seyyedsalehi, Mattia Bonetti, Paolo Boffetta
Journal: Cancer Research (2024)

Abstract Purpose: The IARC monograph has classified benzene as a class I carcinogen, as evidenced by its association with hematological malignancies. However, its association with female genital cancers (ovarian, uterine, cervical) has not been characterized. Therefore, a meta-analysis of cohort studies was performed to determine the possible correlation between occupational benzene exposure and the risk of female genital cancers. Methods: A systematic literature review was conducted that identified 7221 relevant publications. A total of 9 cohort studies detailing occupational exposure to benzene and correlated risk of ovarian, uterine, and cervical cancers were retained, and a meta-analysis (using fixed effects model) was performed. PECOS criteria and STROBE guidelines were followed, and the study protocol was registered in the PROSPERO database (Reg. No. 379720). Study quality was assessed using a modified Newcastle-Ottawa scale (NOS). Results: The summary relative risk (RR) for ever-benzene exposure was 1.22 (95% CI=1.03-1.44, I2&amp;lt;0.001%, n=19); corresponding RR results for female genital cancers incidence and mortality were 1.09 (95% CI=0.92-1.29, I2=5.0%, n=17) and 1.69 (95% CI=1.18-2.4, I2&amp;lt;0.001%, n=9), respectively. These findings were confirmed in sub-analyses by geographical area, industry type, publication year, and levels of benzene exposure. Heterogeneity was detected amongst industries of employment (p-het=0.012) which included petroleum, chemical, printing, and mixed industries categories. Notably, the printing industry (compositors, press operators, and bookbinders) had a summary RR of 2.56 (95% CI=1.45-4.52, I2=35.0%, n=2). However, no heterogeneity was observed for geographical regions (p-het=0.77), duration of benzene exposure (p-het=0.73), publication year (p-het=0.89), or among varying study quality (&amp;lt; or ≥ median NOS score; p-het=0.14). No publication bias was detected (p=0.43). Conclusions: Our meta-analysis identified an association between occupational benzene exposure and the risk of female genital cancers. The association was restricted to the industry of employment. Effects of residual confounding variables cannot be excluded, however, given the present association, there is a potential for causality, especially in workers employed in the printing industry. Citation Format: Darshi Shah, Vincent DeStefano, Veer Shah, Monireh Sadat Seyyedsalehi, Mattia Bonetti, Paolo Boffetta. Occupational-related exposure to benzene and risk of female genital cancers: Systematic review and meta-analysis [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 835.
Abstract 838: Population attributable fraction of occupational carcinogens for cancer incidence among Korean adults in 2020
Authors: Eun Mi Kim, Dong-Hee Koh, Sue K Park, Yoon-Jung Choi, Hong Gwan Seo, Inah Kim, Jeong-Soo Im
Journal: Cancer Research (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.
Abstract 5004: Oncolytic Jurona-driven systemic and intratumoral immunotherapy combined with immune checkpoint blockade boost immune response and survival in hepatocellular carcinoma models
Authors: Mulu Z. Tesfay, Khandoker U. Ferdous, Aleksandra Cios, Randal S. Shelton, Camila C. Simoes, Steven R. Post, Thomas J. Kelly, Martin J. Cannon, Alexei Basnakian, Bolni M. Nagalo
Journal: Cancer Research (2024)

Abstract The members of the vesiculovirus genus have recently become attractive immunotherapeutic agents due to their natural selectivity for tumors and lack of toxicity in humans. Here, the research shows Intratumoral (IT) or Intraperitoneal (IP) injection of JURV was found to induce dynamic tumor regression in human hepatocellular carcinoma (HCC) xenografts and syngeneic models. Furthermore, IT injections of JURV were also shown to recruit and activate cytotoxic T lymphocytes and decrease tumor-associated macrophage infiltration, resulting in the delay of tumor growth in both local and distant murine HCC tumors established in a syngeneic model. Additionally, the concurrent use of JURV and anti-PD-1 antibodies was found to synergistically modulate the tumor microenvironment (TME) via increased tumor-infiltrating CD4+ T cells and depleted CD8+ PD-1+ and NK cells. Furthermore, using RIL-175, an aggressive metastatic HCC tumor mouse model, we show that intraperitoneal (IP) (systemic) administration of JURV and anti-PD1 significantly improved long-term survival (90%) compared to the (20%) JURV or anti-PD1 alone. Through proteogenomic analysis, the activation of different effectors of the immune system was observed to cooperate to alter the TME to a favorable anti-tumor immune state. These findings further support the development of JURV as an immunovirotherapy platform for HCC, with the potential to induce abscopal effects via the activation of several tumor suppressor genes and the mechanism regulating the T helper cell responses. Citation Format: Mulu Z. Tesfay, Khandoker U. Ferdous, Aleksandra Cios, Randal S. Shelton, Camila C. Simoes, Steven R. Post, Thomas J. Kelly, Martin J. Cannon, Alexei Basnakian, Bolni M. Nagalo. Oncolytic Jurona-driven systemic and intratumoral immunotherapy combined with immune checkpoint blockade boost immune response and survival in hepatocellular carcinoma models [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 5004.
Abstract 1036: Development of a comprehensive RNA-based NGS panel for detecting tyrosine kinase fusion genes associated with primary hypereosinophilia
Authors: Bongyong Lee, Andrew Chern, Aiguo Zhang, Chuanyi M. Lu, Michael Y. Sha
Journal: Cancer Research (2024)

Abstract Hypereosinophilia (HE) is a medical condition diagnosed when the count of eosinophils in the blood is greater than 1.5 × 109 per liter. Primary HE is a clonal stem cell disorder manifesting as myeloid and/or lymphoid malignancies and is typically driven by aberrant fusion genes involving a tyrosine kinase (TK) gene (e.g., PDGFRA, PDGFRB, FGFR1, JAK2, FLT3, ABL1). The precise identification of the underlying molecular genetic abnormalities is crucial for timely diagnosing and managing primary HE. There has been no HE-specific assay that can concomitantly detect all known or novel TK fusion genes. We've developed an RNA-based panel for detecting TK fusion genes in HE. This panel, developed using 5' RACE technology, allows for the identification of fusion transcripts in total RNA extracted from whole blood sample. It covers 48 known TK fusion genes and also has the capability of detecting novel gene fusions. We balanced and optimized the panel using an in-house fusion RNA mix containing 11 fusion transcripts. We additionally validated the panel using samples from five patients with hematopoietic neoplasms and two fusion-positive cell lines to ensure its accuracy. The Limit of Detection (LoD) was established by analyzing the in-house RNA mix and normal whole blood RNA. It was found that the minimum RNA input required to detect all 11 fusion transcripts was 3540 copies in the presence of a background of 10 ng normal whole blood RNA. The panel successfully identified two fusion transcripts using 10 ng of total RNA obtained from cancer cell lines. The panel was then used to test five patient RNA samples extracted from whole blood. We successfully confirmed the presence of BCR-ABL1 fusion in 3 patient samples and ETV6-PDGFRB fusion in 1 patient sample, respectively. In summary, we developed HE-specific NGS panel for detecting all known and novel TK fusion genes and demonstrated its analytical accuracy and clinical effectiveness. The next phase of our study is to further validate the tests on a large patient cohort. Citation Format: Bongyong Lee, Andrew Chern, Aiguo Zhang, Chuanyi M. Lu, Michael Y. Sha. Development of a comprehensive RNA-based NGS panel for detecting tyrosine kinase fusion genes associated with primary hypereosinophilia [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 1036.
Abstract 117: Improved PBMC humanized mouse models for immuno-oncology drugs evaluation
Authors: Bin Xie, Xin Hou, Pengfei Yang, Yanbing Zhou, Danyi Wen
Journal: Cancer Research (2024)

Abstract It has been demonstrated that anti-PD(L)1 therapy could significantly improve survival outcomes for patients with metastatic solid cancers, such as melanoma, non-small cell lung cancer and MSI-H colorectal cancer. However, more than half of these patients (NCT02563002, NCT02142738, NCT02563002) do not respond to immune checkpoint blockade (ICB) therapy, and 90% of colorectal cancer patients have MSS/pMMR characteristics and almost no response at all, which drives scientists to design novel drug candidates urgently and integrate tumor and tumor microenvironment (TME) signals systemically to rejuvenate exhausted immune system and overcome ICB resistance. LIDE has developed both traditional PBMC humanized mice model, and human immune cells and cancer co-inoculated model for IO drugs functional evaluation in the last 5-years by using unique PBMC donor selection and standard cancer biobank (PDX patient-derived xenografts, CDX cell derived xenograft) establishment. Cancer biopsies with MDM2 amplification or DNMT3A alternation have been shown resistant to PD1-Ab therapy but sensitive to chemical combo-therapy, and pMMR cancer PDX models seem responsible well to EGFR targeted, CD39-CD73-Adenosine targeted therapy. Human IL15 transgenic mice are used as one useful tool to investigate in vivo function of NK cells, NK engagers/modulators as well as drugs with ADCC (Antibody dependent cell-mediated cytotoxicity) effect. The activated immune cells and cancer co-transfer model, can significantly delay the graft-versus-host-reaction for another month compared with traditional PBMC humanized model, and archives maximal therapeutic effect of the testing drugs by pre-activating T cells with specific tumor antigens. Dendritic cells or macrophages could be successfully introduced into this co-inoculated system to work together with T cells, mimic human tumor tissue complexity, to help determine the overall effect induced by integrated signals. It seems CD40 agonist or CD47 antagonist could well synergies with anti-PD(L)1 to control melanoma and triple negative breast cancer development, respectively. This optimized PBMC humanized cancer-bearing mice models have been tested for various cancer targets, e.g. PD(L)1, Tim3, Lag3, Tigit, PVRIG, TGFβ1, CD73/CD39, CD47/Sirpa, DLL3/CD3, Claudin18.2/4-1BB, B7-H3, GITR, to better understand the interaction between cancer cells and immune cells. Citation Format: Bin Xie, Xin Hou, Pengfei Yang, Yanbing Zhou, Danyi Wen. Improved PBMC humanized mouse models for immuno-oncology drugs evaluation [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 117.