Disease In Population Research Articles

Abstract P46: Small Extracellular Vesicles from Therapy-induced Senescent TNBC Elicit Paracrine Anti-tumour Effects

Abstract Triple-negative breast cancers (TNBC), associated with poor prognosis and high tumour recurrence, are often treated with taxanes. However, cells may bypass treatment-induced cell death via mitotic slippage, resulting in multinucleated polyploid cells and therapy-induced senescence (TIS). TIS cancer cells represent a population of residual disease and may modulate therapy resistance and recurrence through secretion of the senescence-associated secretory phenotype (SASP). While SASP have been heavily linked with pro-tumorigenic behaviour mediated through soluble cytokines, small extracellular vesicles (sEVs) derived from TIS cancer cells represent an underappreciated aspect of the senescent tumour secretome, as its mechanistic role in mediating paracrine effects remains poorly understood. In this study, we uncovered an unexpected role for TIS-derived sEVs within the secretome, which conferred paracrine anti-tumour activity in recipient TNBC cancer cells, in contrast to SASP that support pro-tumorigenic behaviour. SEVs profiling through mass-spectrometry revealed that DKK1, a negative regulator of WNT signalling, is enriched in TIS-derived sEVs. Further investigation into the tumour microenvironment with animal models and neoadjuvant chemo-treated patient samples revealed STING-dependent immune response. Hence, our study suggests that sEVs should be considered as distinct SASP entities within the senescent tumour secretome and provide an additional basis for combinatorial use of senomorphics with taxanes to potentially modulate senescence-associated sEVs while suppressing pro-tumorigenic SASP factors. Citation Format: Matius Robert, Rekha Jakhar, Bijin Veonice Au, Gracie Wee Ling Eng, Alvin Kunyao Gao, You Heng Chuah, Karishma Sachaphibulkij, Lina Hsiu Kim Lim, Derrick Sek Tong Ong, Elaine Hsuen Lim, Yoko Itahana, Koji Itahana, Jit Kong Cheong, John Edward Connolly, Karen Carmelina Crasta. Small Extracellular Vesicles from Therapy-induced Senescent TNBC Elicit Paracrine Anti-tumour Effects [abstract]. In: Proceedings of Frontiers in Cancer Science; 2023 Nov 6-8; Singapore. Philadelphia (PA): AACR; Cancer Res 2024;84(8_Suppl):Abstract nr P46.

Graded exercise with motion style acupuncture therapy for a patient with failed back surgery syndrome and major depressive disorder: a case report and literature review

Effective treatment of failed back surgery syndrome (FBSS) remains challenging despite urgent medical attention requirements. Depression is a contributing factor to the development and poor prognosis of FBSS, and vice versa. We report the case of a patient with FBSS and major depressive disorder (MDD) treated with graded exercise combined with motion-style acupuncture therapy (MSAT). A 53-year-old male veteran who had undergone lumbar discectomy and laminectomy with instrumented fusion was admitted to the hospital with re-current back pain and radiative pain in the left leg. The effects of failed surgery triggered MDD as a comorbidity. After a six-week routine treatment without remarkable improvement, a three-week program of graded exercise with MSAT was applied. The numeric rating scale (NRS) and short form-36 (SF-36) were used to assess low back pain with radiating leg pain, and daily functioning levels, respectively. The voluntary walking distance of the patients was measured. To analyze the therapeutic effects and other applications of the intervention, we surveyed clinical trials using MSAT or graded exercise therapy (GET). Three weeks of graded exercise with MSAT reduced physical and mental functional disabilities (SF-36, physical component: 15.0 to 37.2, mental component: 21.9 to 30.1) as well as the intensity of low back pain and/or radiative leg pain (NRS: 50 to 30). Furthermore, as the therapeutic intensity gradually increased, there was a significant corresponding increase in daily walking distance (mean daily walking distance, the first week vs. baseline, second, and third week, 3.05 ± 0.56: 2.07 ± 0.79, 4.27 ± 0.96, and 4.72 ± 1.04 km, p = 0.04, p = 0.02, and p = 0.003, respectively). Three randomized controlled trials of GET were included, all showing statistically significant antidepressant effects in the diseased population. Graded exercise with MSAT may be an effective rehabilitative therapy for patients with FBSS and MDD who have impaired daily routines.

Dynamical analysis and optimal control of an age‐structured epidemic model with asymptomatic infection and multiple transmission pathways

The diversity of transmission modes and the heterogeneity of populations in the transmission of infectious diseases are issues that have to be faced in the current disease protection. In this paper, an infectious disease model incorporating age structure and horizontal and environmental spread, along with asymptomatic infection, is proposed to describe diversification of disease transmission routes and population heterogeneity. The expression of the basic reproduction number is derived by a linear approximation method, and it is concluded that if , the disease‐free steady state is globally asymptotically stable; if , the model has a unique endemic steady state which is locally asymptotically stable under certain conditions. Further, the uniform persistence of disease is proved using the persistence theory of the infinite‐dimensional dynamical system when . In additional, the issue of optimal control problem according to this model is investigated, and the representation of optimal control with respect to state variables and adjoint variables is obtained which also imply the existence and uniqueness of optimal control. Finally, numerical simulations are carried out to interpret the theoretical results and to discuss the impact of age and control measures in disease transmission.

Improved Tau PET SUVR Quantification in 4-Repeat Tau Phenotypes with [18F]PI-2620.

We used a new data-driven methodology to identify a set of reference regions that enhanced the quantification of the SUV ratio of the second-generation tau tracer 2-(2-([18F]fluoro)pyridin-4-yl)-9H-pyrrolo[2,3-b:4,5-c']dipyridine ([18F]PI-2620) in a group of patients clinically diagnosed with 4-repeat tauopathy, specifically progressive supranuclear palsy or cortical basal syndrome. The study found that SUV ratios calculated using the identified reference regions (i.e., fusiform gyrus and crus-cerebellum) were significantly associated with symptom severity and disease duration. This establishes, for the first time to our knowledge, the suitability of [18F]PI-2620 for tracking disease progression in this 4-repeat disease population. This is an important step toward increased clinical utility, such as patient stratification and monitoring in disease-modifying treatment trials. Additionally, the applied methodology successfully optimized reference regions for automated detection of brain imaging tracers. This approach may also hold value for other brain imaging tracers.

Screening the General Population for Non-Alcoholic Fatty Liver Disease: Model Development and Validation

The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing worldwide. Screening the general population for this may help to select appropriate diagnostic and preventive measures before disease progression. We aimed to develop a screening method to identify patients with NAFLD in the general population. We analyzed cross-sectional data from a large Japanese study of NAFLD. Principal component analysis was used to analyze the data. Candidate predictors were patients' demographic, clinical, and laboratory characteristics. The resulting model was externally validated using three data sets from different populations. Of 15,464 (54.5% men) included patients, 2,741 (17.7%) had NAFLD as determined by ultrasonography. An index was calculated as the arithmetic mean of the scaled body mass index and serum triglyceride levels for both men and women. The area under the receiver operating characteristic curve, sensitivity, specificity, and false positive rate were 0.875, 0.824, 0.770, and 17.6%, respectively. The mean index values were significantly different between the patients with and without non-alcoholic fatty liver disease (p <0.001). The odds ratio of the index cutoff was 15.6 (95% confidence interval [CI]:14.05, 17.39). The model yielded areas under the curve of 0.828, 0.851, and 0.836 for a Chinese (N = 2,319), an Iranian (N = 2,160), and a Brazilian (N = 45,029) data set, respectively. The proposed composite index demonstrated high performance and generalizability, suggesting its potential use as a screening tool for NAFLD in the general population.

Type 2 diabetes mellitus and cardiometabolic outcomes in metabolic dysfunction-associated steatotic liver disease population

The metabolic syndrome, characterized by type 2 diabetes mellitus (T2DM), hypertension, hyperlipidemia, and obesity, collectively increases the risk of cardiovascular diseases. Nonalcoholic fatty liver disease (NAFLD) is a prominent manifestation, affecting over a third of the global population with a concerning annual increase in prevalence. Nearly 70 % of overweight individuals have NAFLD, and NAFLD-related deaths are predicted to rise, especially among young adults. The association of T2DM and NAFLD has led to the proposal of “metabolic dysfunction-associated steatotic liver disease” (MASLD) terminology, encompassing individuals with T2DM, overweight/obesity, hypertension, hypertriglyceridemia, or low HDL-cholesterol. Patients with MASLD will likely have double the risk of developing T2DM, and the combination of insulin resistance, overweight/obesity, and MASLD significantly elevates the risk of T2DM. Cardiovascular diseases remain the leading cause of mortality in the MASLD and T2DM population, with MASLD directly associated with coronary artery disease, compounded by coexisting insulin resistance and T2DM. Urgency lies in early detection of subclinical cardiovascular diseases among patients with T2DM and MASLD. Novel strategies targeting multiple pathways offer hope for effectively improving cardiometabolic health. Understanding and addressing the intertwined factors contributing to these disorders can pave the way towards better management and prevention of cardiometabolic complications.

Multi-Omics Profiling Reveals Phenotypic and Functional Heterogeneity of Neutrophils in COVID-19.

Accumulating evidence has revealed unexpected phenotypic heterogeneity and diverse functions of neutrophils in several diseases. Coronavirus disease (COVID-19) can alter the leukocyte phenotype based on disease severity, including neutrophil activation in severe cases. However, the plasticity of neutrophil phenotypes and their relative impact on COVID-19 pathogenesis has not been well addressed. This study aimed to identify and validate the heterogeneity of neutrophils in COVID-19 and evaluate the functions of each subpopulation. We analyzed public single-cell RNA-seq, bulk RNA-seq, and proteome data from healthy donors and patients with COVID-19 to investigate neutrophil subpopulations and their response to disease pathogenesis. We identified eight neutrophil subtypes: pro-neutrophil, pre-neutrophil, immature neutrophil, and five mature neutrophil subpopulations. The subtypes exhibited distinct features, including diverse activation signatures and multiple enriched pathways. The pro-neutrophil subtype was associated with severe and fatal disease, while the pre-neutrophil subtype was particularly abundant in mild/moderate disease. One of the mature neutrophil subtypes showed consistently large fractions in patients with different disease severity. Bulk RNA-seq dataset analyses using a cellular deconvolution approach validated the relative abundances of neutrophil subtypes and the expansion of pro-neutrophils in severe COVID-19 patients. Cell-cell communication analysis revealed representative ligand-receptor interactions among the identified neutrophil subtypes. Further investigation into transcription factors and differential protein abundance revealed the regulatory network differences between healthy donors and patients with severe COVID-19. Overall, we demonstrated the complex interactions among heterogeneous neutrophil subtypes and other blood cell types during COVID-19 disease. Our work has great value in terms of both clinical and public health as it furthers our understanding of the phenotypic and functional heterogeneity of neutrophils and other cell populations in multiple diseases.

Advancing Wearable Biosensors for Congenital Heart Disease: Patient and Clinician Perspectives: A Science Advisory From the American Heart Association.

Wearable biosensors (wearables) enable continual, noninvasive physiologic and behavioral monitoring at home for those with pediatric or congenital heart disease. Wearables allow patients to access their personal data and monitor their health. Despite substantial technologic advances in recent years, issues with hardware design, data analysis, and integration into the clinical workflow prevent wearables from reaching their potential in high-risk congenital heart disease populations. This science advisory reviews the use of wearables in patients with congenital heart disease, how to improve these technologies for clinicians and patients, and ethical and regulatory considerations. Challenges related to the use of wearables are common to every clinical setting, but specific topics for consideration in congenital heart disease are highlighted.

Comparative evaluation of non-invasive tests for risk stratification for cause specific mortality in at-risk population of hepatic fibrosis

Our study aimed to conduct a comparative evaluation of various noninvasive tests (NITs) for risk stratification in at-risk population for non-alcoholic fatty liver disease (NAFLD), focusing on cardiovascular and liver-related mortality. A total of 21,715 adults aged 40 years and older were enrolled at baseline. The mean follow-up period was 12.39 years. Three types of NITs (fibrosis-4 index [FIB-4], NAFLD fibrosis score [NFS], and steatosis-associated fibrosis estimator [SAFE] score) were used. When using the low cut-off as a 'rule-out' strategy, there were no significant differences in cardiovascular mortality between the 'rule-out' (low-risk) group and the 'rule-in' (intermediate- or high-risk) group based on FIB-4 (aHR = 1.029, P = 0.845) or NFS (aHR = 0.839, P = 0.271) classification. However, the SAFE score exhibited higher sensitivity in predicting cardiovascular mortality compared to FIB-4 or NFS (73.3% in SAFE score vs. 29.6% in FIB-4 or 21.3% in NFS). Only the SAFE score could effectively differentiate the risk between low- and intermediate- or high-risk groups for all types of mortality (all P values for aHR < 0.001). The low cutoff value of the SAFE score discriminated not only liver-related mortality but also identified the cardiovascular high-risk group in the community cohort.

Highlighting the effects of high-intensity interval training on the changes associated with hypertrophy, apoptosis, and histological proteins of the heart of old rats with type 2 diabetes

T2DM is known to cause disturbances in glucose homeostasis and negative changes in the heart muscle, while aging and diabetes are recognized risk factors for CVD. Given this, our study aims to investigate a method for controlling and managing CVDs induced by T2DM in elderly populations. To achieve this, we categorized 40 rats into 5 groups, including HAD (n = 8), HA (n = 8), AD (n = 8), AHT (n = 8), and ADT (n = 8). The exercise protocol consisted of eight weeks of HIIT (three sessions per week) performed at 90–95% of maximal speed. Following cardiac tissue extraction, we assessed the levels of IGF-1, PI3K, and AKT proteins using Western blot technique, and analyzed the histopathological variations of the heart tissue using H&E, Sudan Black, and Masson’s trichrome tissue staining. The histological findings from our study demonstrated that T2DM had a significant impact on the development of pathological hypertrophy and fibrosis in the heart tissue of elderly individuals. However, HIIT not only effectively controlled pathological hypertrophy and fibrosis, but also induced physiological hypertrophy in the AHT and ADT groups compared to the HA and AD groups. Results from Sudan Black staining indicated that there was an increase in lipid droplet accumulation in the cytoplasm of cardiomyocytes and their nuclei in the HA and AD groups, while the accumulation of lipid droplets decreased significantly in the AHT and ADT groups. In both the AHT group and the ADT group, a single HIIT session led to a reduction in collagen fiber accumulation and fibrotic frameworks. Our research also revealed that diabetes caused a significant elevation in the levels of IGF-1, PI3K, and AKT proteins, but after eight weeks of HIIT, the levels of these proteins decreased significantly in the training groups. Overall, our findings suggest that HIIT may be a suitable non-pharmacological approach for improving histological and physiological changes in elderly individuals with T2DM. However, we recommend further research to examine the impact of HIIT training on both healthy and diseased elderly populations.

Abstract 6614: Integrating single-cell RNA-seq and large genome-wide association study data to identify colorectal cancer cell-of-origin populations

Abstract Background: Single-cell RNA sequencing (scRNA-seq) enables the precise identification of distinct cell populations and the measurement of gene expression within each population. Recently, integrating scRNA-seq and genome-wide association study (GWAS) data has shown promise in identifying cell-of-origin populations in human diseases. Colorectal cancer (CRC) progresses through a phenotypic continuum from normal colon to adenoma, and ultimately CRC. However, the specific disease cell-of-origin populations underlying each stage of CRC development at a single-cell resolution have not been well studied. Additionally, while transcriptome-wide association studies (TWAS) have identified more than 200 putative risk genes in CRC, the precise disease cell-of-origin populations associated with these genes remain elusive. Materials and methods: We analyzed scRNA-seq datasets from 31 normal colon, 8 colon serrated polyps, and 15 conventional adenoma tissues of individuals participated the Colorectal Molecular Atlas Project (COLON MAP). We next conducted an integrative analysis of the aforementioned scRNA-seq data, with extensive epigenomics data and summary statistics from a large CRC GWAS conducted among European ancestry populations (78,473 CRC cases and 107,143 controls) using single-cell disease relevance score (scDRS), to investigate cell-of-origin populations underlying the CRC development. We conducted correlation analysis between gene expression and individual cell risk scores derived from scDRS. Additionally, we performed differential expression analysis comparing disease cell-of-origin populations with other cell populations at each stage. Results: We identified multiple cell-of-origin populations associated with CRC, including absorptive cells (ABS) (P &amp;lt; 1 × 10-4) and goblet cells (GOB) (P &amp;lt; 7 × 10-3) in the normal colon, ABS (P &amp;lt; 2 × 10-3), enteroendocrine cells (EE) (P &amp;lt; 0.04), and serrated-specific cells (SSC) (P &amp;lt; 1 × 10-4) in serrated polyps, and ABS (P &amp;lt; 9 × 10-3) and SSC (P &amp;lt; 6 × 10-4) in adenomas. Among the previously reported 205 risk genes from TWAS, a majority show high correlations of their expressions with the risk scores of the single cells (median value R2 = 0.07, 0.14, 0.137 at normal colon, serrated polyps, adenoma, respectively). Moreover, 57 of these TWAS-reported genes (27.8% of 205 genes) exhibited evidence of differential expression in disease cell-of-origin populations compared to other cell populations at a nominal p-value &amp;lt; 0.05 in at least one stage (Binomial test, P &amp;lt; 0.01 for all). Conclusion: This study reveals the cell-of-origin populations that influence the development of CRC, and provides evidence of the role of risk genes in these populations. These findings are crucial for identifying causal genes and understanding the cellular mechanisms that drive the biology and etiology of CRC. Citation Format: Chao Li, Zhishan Chen, Qing Li, Jungyoon Choi, Quanhu Sheng, Wanqing Wen, Xiang Shu, Xiao-ou Shu, Jirong Long, Qiuyin Cai, Bhuminder Singh, Martha J. Shrubsole, Ken Lau, Wei Zheng, Xingyi Guo. Integrating single-cell RNA-seq and large genome-wide association study data to identify colorectal cancer cell-of-origin populations [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 6614.

Abstract 757: Integrating microbiome analysis and multi-modal data to identify high-risk population for esophageal adenocarcinoma

Abstract INTRODUCTION: Esophageal Adenocarcinoma (EAC) represents a pressing public health concern with a rising incidence and a staggering 5-year survival rate of less than 20%, emphasizing the critical need for early detection. Barrett's Esophagus (BE) serves as a well-established precursor to EAC, presenting an opportunity for proactive screening. The salivary microbiome provides a novel opportunity to identify a high-risk population with early-stage esophageal diseases. Here, we assessed whether the oral microbiome, in combination with lifestyle and clinical data, is associated with esophageal disease progression. METHODS: The study included n=23 esophageal adenocarcinoma patients, n=51 with Barrett's Esophagus, and n=32 healthy controls. Saliva samples were collected along with comprehensive lifestyle, dietary intake, and clinical data. Shotgun Metagenomics Sequencing was employed to investigate the microbiome composition of participants. Comprehensive microbiome analyses were performed to evaluate taxonomic profiles, including microbial abundance, microbiome diversity, and functional/metabolic insights. A multi-modal data integration strategy was used to incorporate data from the Diet Health Questionnaire (DHQ) and lifestyle and health records, aiming to utilize these multimodal features to predict esophageal disease formation and progression. RESULTS: A significant difference was observed in the salivary microbiome beta diversity between healthy controls and esophagus disease groups (p= 0.03). Clustering by microbiome taxonomic composition using the Dirichlet Multinomial Mixtures (DMM) framework indicates that some microbial signatures are associated with esophageal diseases (p=0.03). Healthy Eating Index Scores, total score (p=0.01); vegetables (p=0.003); greens, and beans score (p=0.009) were significantly different between study groups. Microbial pathways associated with diet, microbial taxa linked to lifestyle and medications, and supervised classification results reveal group characteristics and diversity variations based on key covariates such as B12 and sugar uptakes. CONCLUSION: The study presents an innovative analytic approach to identify high-risk populations for esophageal diseases by integrating microbiome analysis and multi-modal data, providing insights into early detection and prevention. The potential of this research lies in its ability to revolutionize screening strategies, offering a non-invasive and cost-effective means to identify individuals at risk of EAC at earlier, more treatable stages. Citation Format: Duygu Altinok Dindar, Madeline Krieger, Amy Palma, John Cheney, Fouad Otaki, Jessica Yu, Stephanie Wood, Thomas J. Sharpton, James McGann, Lisa Karstens, Gurkan G. Yardimci, Zhenzhen Zhang. Integrating microbiome analysis and multi-modal data to identify high-risk population for esophageal adenocarcinoma [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 757.

Abstract 4725: Phenotypic single-cell analysis of nuclear stress responses in drug-treated prostate cancer cells

Abstract Chemotherapy with anti-cancer drugs aims to stop the growth of cancer cells either by killing them or by stopping them from dividing. The different specificities in inducing cellular damage responses are incompletely understood currently and may underlie the preferential effectiveness of anti-cancer drugs against different types of cancer cells. Better understanding and tools to measure drug-induced phenotypes in vitro may aid in assessing cellular heterogeneity of responses, determining potential effectiveness, estimating amount and types of adverse effects, and predicting likelihood of surviving populations for residual disease. To measure the types and extent of nuclear stress responses to cancer drugs, we studied nuclear organelle, namely nucleolar and Cajal body, phenotypes to drug-induced stress in prostate cancer cells. We utilized organelle-specific markers NPM, Fibrillarin, Coilin, and SMN1 in immunofluorescence staining to determine suitable markers for nuclear organelle stress. We used three different prostate cancer cells lines representing different biological types of advanced prostate cancer (AR positive, AR negative, and expressing AR transcript variant). Based on initial assessments, NPM and coilin immunostaining were selected for automated phenotypic analysis screening for drug effects. Using AI-assisted nuclear segmentation and feature-based single-cell phenotypic analysis, we demonstrated quantitative effects on nuclear morphology, nucleoli, and Cajal bodies with drug treatments. A proof-of-principle study with platinum-based chemotherapeutic agents in clinical use demonstrated heterologous responses to the platinum drugs that are associated with prostate cancer cell types with different AR status. Further, we have defined the corresponding quantitative responses for androgen deprivation therapy (ADT) drugs enzalutamide and bicalutamide in AR-positive prostate cancer cells. Our findings evidence variability of prostate cancer cells’ response to chemotherapy and have implications in future therapy regimen considerations. Furthermore, we have developed a fluorescence light microscopy-based method to assess nuclear stress response phenotypes in prostate cancer cells that can be used for high throughput drug screening. Citation Format: Enkhzaya Batnasan, Minttu Kärkkäinen, Sonja Koivukoski, Pekka Ruusuvuori, Leena Latonen. Phenotypic single-cell analysis of nuclear stress responses in drug-treated prostate cancer cells [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 4725.

Abstract 6133: Genetic profiling landscape among gynecological and breast cancer patients in the borde city of Tijuana, Mexico: A comprehensive study

Abstract Background: Individuals in Tijuana have been identified as having multicultural and racial diversity. In Baja, California, Mexico, the prevalence and composition of cancer-predisposing germline variants in gynecologic cancers in Tijuana patients have not been evaluated. Aim and Methods: We aimed to evaluate the prevalence of pathogenic variants (PV) using a panel of 84 cancer-predisposing genes in breast, endometrial, and ovarian cancer from the General Hospital of Tijuana during the period of October 2021-October 2023, who were contacted and invited to participate in the evaluation. Pre- and post-test genetic counseling was given, and a questionnaire on personal, gyneco-obstetric, demographic, and lifestyle variables was conducted. Peripheral blood samples were obtained from all patients, and Next-generation sequencing (NGS) was performed on the Illumina commercial platform (Illumina, SD, USA). Variants were classified according to the American College of Medical Genetics and Genomics (ACMG). Data was collected and descriptive statistics was applied to describe the characteristics of the population. Results: A total of 51 patients were included in our cohort; 98.0% (50/51) were females and 2% (1/51) were males. Among study participants (mean age ±standard deviation: 46.1 ± 10.9), 49% reported a personal history of cancer (25/51). Diagnosis of breast cancer was present in 80.3% of the patients (41/51), 9% (5/51) with ovarian cancer, and 3.9% (2/51) with endometrial cancer. Twenty-five percent of participants (13/51) harbor a PV or likely pathogenic (LP) variant distributed among four cancer-risk genes (BRCA1, BRCA2, ATM, and TP53). The distribution by gene in the patients with a PV was: BRCA1 in 61% (8/13), BRCA2 in 23% (3/13), TP53 in 8% (1/13), and ATM in 8% (1/13). Whereas 39.2% (20/51) had variants of uncertain clinical significance in genes with ambiguous or non-well-established risk association for cancer (BARD1, AXIN2, GPC3, NF2, CEBPA, MSH3, ALK, DIS3L2, CDC73, BAP1, RAD51D, NF1, MSH2, BLM, NBN, BRCA2, BARD1, RUNX1, RECQL4, EGFR, PALB2, CASR, and POLD1), and 35.2% (18/51) had negative results for both; PV and VUS. Conclusion: Our findings show a diverse pathogenic variant composition among the recruited individuals of the gynecological cancer population in Tijuana, Mexico, consistent with being a high-risk population for genetic diseases, which warrants further investigation to adequately assess the burden of hereditary cancer and implement appropriate preventative programs. Disparities in access to testing have a significant impact on affected populations, due in part to underrepresentation in surveys of regional cancer etiology and in genomic variant databases. Citation Format: Jorge Alberto Guadarrama-Orozco, Paula Leal-Anaya, Eva Guerrero-Santillan. Genetic profiling landscape among gynecological and breast cancer patients in the borde city of Tijuana, Mexico: A comprehensive study [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 6133.

Abstract 1774: Examination of variants of unknown significance (VUSs) and co-occurring mutations from comprehensive genomic profiling (CGP) results in a cross tumor model

Abstract Data from Comprehensive Genomic Profiling (CGP) generates both actionable and non-actionable results for oncology patients. While the actionable results are included in reports, the non-actionable are less often investigated. This study explored the results of both actionable and non-actionable mutations as well as the co-occurrence of mutations in a pan-tumor model.In this study, we explored data generated from 41 oncology practices where patients (+ 18yo) were tracked within the iKnowMed EHR and had received CGP as part of their care. CGP is defined as a large-scale (300+ genes) NGS-based assay. As part of this study, results between 2017 - present were collected across tumor types and stages.Assessment of the data pool demonstrated that a majority of the 44,769 profiles were generated from Stage IV patients (n=24,545) and NSCLC, colorectal, and breast cancers were the highest representing disease populations in the cohort. The tested gene targets aligned with the diseases that were most represented, with EGFR, PIKC3A, ERBB2, and KRAS genes as the most common genes to have documented results. Exploration of the actionable biomarkers showed the expected pathogenic mutations in the relevant disease context. When exploring the remaining reported variants, it was found that CGP results yield a significant (p&amp;lt;0.05) number of VUSs as well (n=23106). The complexity of mutations was also examined on an intra- and intergenic basis. Intragenic assessment for variants focused on complex mutations, qualified by 2+ mutations including multiple SNV, multiple indels, or SNVs and deletions in the same gene. Trends of co-occurring alterations were not obvious, with TP53 having the most reported occurrences of complex mutations (n=7491). Exploration moved to intergenic assessment and, while disease-bounded exploration did not reveal trends, a disease-agnostic approach revealed co-occurrences of mutations. The top 5 genes with co-existing mutations are TP53, KRAS, APC, PIK3CA, and ATM. Co-occurrence of alterations in any gene with tumor agnostic markers was also explored, notably TMB. The presence of mutation with TMB-high was similar to that of intergenic complex mutations and the same genes had high co-incidence levels. This study has demonstrated that CGP data provide insights beyond actionable biomarkers, and that a pan-tumor approach allows new trends to be observed. Real-world data bias for reported biomarkers skewed the results observed. Taking the results out of disease context allows us to visualize new possibilities for identifying variants implicated in disease processes. Future studies could allow the exploration of unreported data from raw files, overlaid with cellular pathways on complex patient profiles to identify exploitable targets. Inclusion of treatment and outcome data can demonstrate the influence of genetics on a patient journey. Citation Format: Tincy Simon, Rob Oliver, Robyn Harrell, Paul Conkling, Emily Paul. Examination of variants of unknown significance (VUSs) and co-occurring mutations from comprehensive genomic profiling (CGP) results in a cross tumor model [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 1774.

Population-enriched innate immune variants may identify candidate gene targets at the intersection of cancer and cardio-metabolic disease.

Both cancer and cardio-metabolic disease disparities exist among specific populations in the US. For example, African Americans experience the highest rates of breast and prostate cancer mortality and the highest incidence of obesity. Native and Hispanic Americans experience the highest rates of liver cancer mortality. At the same time, Pacific Islanders have the highest death rate attributed to type 2 diabetes (T2D), and Asian Americans experience the highest incidence of non-alcoholic fatty liver disease (NAFLD) and cancers induced by infectious agents. Notably, the pathologic progression of both cancer and cardio-metabolic diseases involves innate immunity and mechanisms of inflammation. Innate immunity in individuals is established through genetic inheritance and external stimuli to respond to environmental threats and stresses such as pathogen exposure. Further, individual genomes contain characteristic genetic markers associated with one or more geographic ancestries (ethnic groups), including protective innate immune genetic programming optimized for survival in their corresponding ancestral environment(s). This perspective explores evidence related to our working hypothesis that genetic variations in innate immune genes, particularly those that are commonly found but unevenly distributed between populations, are associated with disparities between populations in both cancer and cardio-metabolic diseases. Identifying conventional and unconventional innate immune genes that fit this profile may provide critical insights into the underlying mechanisms that connect these two families of complex diseases and offer novel targets for precision-based treatment of cancer and/or cardio-metabolic disease.

Characterization of diseased primary human hepatocytes in an all-human cell-based triculture system

Liver diseases, including NAFLD, are a growing worldwide health concern. Currently, there is a lack of suitable in vitro models that sustain basic primary human hepatocyte (PHH) morphology and functionality while supporting presentation of disease-associated phenotypic characteristics such as lipid accumulation and inflammasome activation. In TruVivo, an all-human triculture system (hTCS), basic metabolic functions were characterized in PHHs isolated from normal or diseased livers during two-weeks of culture. Decreases in albumin and urea levels and CYP3A4 activity were seen in diseased-origin PHHs compared to normal PHHs along with higher CYP2E1 expression. Positive expression of the macrophage markers CD68 and CD163 were seen in the diseased PHH preparations. Elevated levels of the pro-inflammatory cytokines IL-6 and MCP-1 and the fibrotic markers CK-18 and TGF-β were also measured. Gene expression of FASN, PCK1, and G6PC in the diseased PHHs was decreased compared to the normal PHHs. Further characterization revealed differences in lipogenesis and accumulation of intracellular lipids in normal and diseased PHHs when cultured with oleic acid and high glucose. TruVivo represents a promising new platform to study lipogenic mechanisms in normal and diseased populations due to the preservation of phenotypic differences over a prolonged culture period.

Red Yeast Rice and Statin Therapy in Patients with Hypercholesterolemia and the Comorbidities: A Retrospective Cohort Study on Lipid-Lowering Effects and Cardiovascular Outcomes.

Red yeast rice (RYR) is known for its lipid-lowering effects in patients with hypercholesterolemia; however, its comparative efficacy with statins and risk reduction remains uncertain. This retrospective study analyzed data from 337,104 patients with hyperlipidemia in the Chang Gung Research Database cohort, spanning from January 2016 to December 2021. Exclusion criteria were applied to ensure data completeness and compliance, including an age limit of [Formula: see text] years, absence of RYR or statin treatment, and a treatment duration of [Formula: see text] days. Propensity score matching was employed to minimize bias based on baseline factors, with one patient matching with four patients in the comparison group. The study encompassed a total of 5,984 adult hyperlipidemic patients, with 1,197 in the RYR group and 4,787 in the statin group. The patients were also stratified into statin ([Formula: see text]) or combined use ([Formula: see text]) groups for further comparison. Following one year of treatment, both the RYR and statin groups exhibited reductions in total cholesterol and triglyceride levels. Most biochemical parameters showed no significant differences, except for elevated glutamic oxaloacetic transaminase levels in the RYR group ([Formula: see text]) and increased glycohemoglobin levels in the statin group at the three-month mark ([Formula: see text]). In patients with comorbid diabetes, hypertension, kidney, or liver diseases, RYR and statins demonstrated comparable risks for emergency room (ER) visits, stroke, and myocardial infarction (MI). However, the combination of RYR and statins was associated with reduced stroke-related hospitalizations in patients with diabetes, hypertension, and kidney disease, as well as decreased MI-related hospitalizations in patients with hypertension and kidney disease (all [Formula: see text]). In conclusion, both RYR and statins effectively lower blood lipid levels and mitigate related complications. Combining these therapies may lead to fewer ER visits, reduced stroke frequency, and fewer MI hospitalizations in hypertensive and kidney disease patients, and they decreased all-cause mortality in the kidney disease population. Further research on combined therapy is warranted.

Microvascular Function and Exercise Training: Functional Implication of Nitric Oxide Signaling and Ion Channels.

Exercise training elicits indubitable positive adaptation in microcirculation in health and disease populations. An inclusive overview of the current knowledge regarding the effects of exercise on microvascular function consolidates an in-depth understanding of microvasculature. The main physiological function of microvasculature is to maintain optimal blood flow regulation to supply oxygen and nutrition during elevated physical demands in the cardiovascular system. There are several cellular and molecular alterations in resistance vessels in response to exercise intervention, an increase in nitric oxide-mediated vasodilation through the regulation of oxidative stress, inflammatory response, and ion channels in endothelial cells, thus increasing myogenic tone via voltage-gated Ca2+ channels in smooth muscle cells. In the review, we postulate that exercise should be considered a medicine for people with diverse diseases through a comprehensive understanding of the cellular and molecular underlying mechanisms in microcirculation through exercise training.

First ever probable oats (Avena sativa) QTLs mapped on chromosome 1 and 7 for pyrenophora leaf spot resistance in India

An experiment was conducted during 2021–22 at Punjab Agricultural University, Ludhiana, Punjab for the development of linkage map and identification of QTLs for pyrenophora or Helminthosporium leaf spot resistance in oats (Avena sativa L.). A total of 96 F2 plants were used which was derived from the cross EC/0007662 (resistant source) and EC/0131291 (susceptible source). Linkage map was constructed for genotypic data of 96 population lines with 24 polymorphic SSR markers using QTL cartographer. A total of 7 linkage groups (LGs) had been generated from this data. But out of 7 LGs, 5 LGs remained individually at 0 position (unlinked) i.e. belonged to different group each and LG1 and LG7 were grouped. First LG included ABAM232, ABAM493 and ABAM077 from 0 to 66.5 cM. Similarly, 7th LG had two marker position i.e. ABAM342 and ABAM425. Maximum distance between the two markers was found to be 33.4 cM (between the marker interval of ABAM232 and ABAM497. Further QTL analysis was done using cartographer with composite interval mapping to identify the QTLs associated with disease resistance by comparing the phenotypic data of F2 population for disease and genotypic data of the population. The work reported here constitutes a major step toward identification of genetic regions responsible for disease resistance. However, the utility of QTL for marker assisted selection requires that QTLs are localized in a narrow region tightly linked with associated markers. The result of the experiment can be used for marker assisted breeding to transfer such genes identified as part of our research in order to reduce disease severity and yield losses in oats.