Differences In Access Research Articles

Association of household net worth with healthcare costs after radical cystectomy using real-world data.

Financial toxicity of bladder cancer care may influence how patients utilize healthcare resources, from emergency department (ED) encounters to office visits. We aim to examine whether greater household net worth (HHNW) confers differential access to healthcare resources after radical cystectomy (RC). This population-based cohort study examined the association between HHNW and healthcare utilization costs in the 90 days post-RC in commercially insured patients with bladder cancer. Costs accrued from the index hospitalization to 90 days after including health plan costs (HPC) and out-of-pocket costs (OPC). Multivariable logistic regression models were generated by encounter (acute inpatient, ED, outpatient, and office visit). A total of 141,903 patients were identified with HHNW categories near evenly distributed. Acute inpatient encounters incurred the greatest HPC and OPC. Office visits conferred the lowest HPC while ED visits had the lowest OPC. Black patients harbored increased odds of an acute inpatient encounter (OR 1.22, 95% CI 1.16-1.29) and ED encounter (OR 1.20, 95% CI 1.14-1.27) while Asian (OR 0.76, 95% CI 0.69-0.85) and Hispanic (OR 0.74, 95% CI 0.69-0.78, p < 0.001) patients had lower odds of an outpatient encounter, compared to White counterpart. Increasing HHNW was associated with decreasing odds of acute inpatient or ED encounters and greater odds of office visits. Lower HHNW conferred greater risk of costly inpatient encounters while greater HHNW had greater odds of less costly office visits, illustrating how financial flexibility fosters differences in healthcare utilization and lower costs. HHNW may serve as a proxy for financial flexibility and risk of financial hardship than income alone.

Urban public services and fertility intentions of internal migrants in China.

As China continues to implement its progressive fertility promotion policy, there has been a drastic decline in the fertility rate. Given that the migrant population constitutes more than a quarter of China's total population, enhancing the willingness of this demographic to have additional children through policy-guided urban public services is pivotal for optimizing China's population development strategy. This study analyzes the influence of urban public services on the reproductive intentions of the migrant population, utilizing data from 110,667 migrant families with one child, drawn from China's Migrant Population Dynamic Monitoring data in 2016 and 2018. The data analysis reveals several key findings: (1) Urban public services, overall, exhibit a notable positive effect on the willingness of the migrant population to have more children, albeit with limitations and a declining trend. (2) Among urban public services, primary basic education significantly impacts the willingness of the migrant population to expand their families. (3) Large cities have created a 'reverse screening' effect on the migrant population, leading to differential access to public services. This scenario caters effectively to the high human capital migrant individuals while reducing accessibility to livelihood public services for the low human capital migrant population. This paper critically evaluates China's progressively adjusted fertility policy from the perspective of the migrant population. It underscores the necessity of establishing a comprehensive fertility support policy system across China.

Who Captures the Value from Organizational Ratings?: Evidence from Public Schools

Ratings of organizations and firms have become ubiquitous. These ratings, often produced by intermediaries (including private and public organizations), are designed to aid consumers and other stakeholders in their decision making while guiding rated organizations toward performance improvement or compliance. In doing so, these intermediaries introduce new information to markets. However, disparities may exist in the ability to strategically capture the value from such ratings, often due to differential access to complementary assets among stakeholders. Consequently, this differential ability can lead to outcomes contrary to the rating institutions’ intentions. Reflecting on this dynamic, we analyze how widespread access to a prevalent type of rating—school performance information, often produced to enhance transparency and equity in educational access—has affected existing economic and social disparities in America. We leverage the staged rollout of GreatSchools.org school ratings from 2006 to 2015 to answer this question. Across various outcomes and specifications, we find that the availability of school ratings has accelerated the divergence in housing values, income distributions, education levels, and racial and ethnic composition across communities. Affluent and more educated families were better positioned to strategically leverage this new information to capture educational opportunities in communities with top schools. The uneven benefits we observe highlight how ratings can unintentionally deepen existing inequalities, thereby complicating their intended impacts. Supplemental Material: The online appendix is available at https://doi.org/10.1287/stsc.2023.0113 .

Geospatial evaluation of access to otolaryngology care in the United States.

This county-level epidemiological study evaluated the travel distance to the nearest otolaryngologist for continental US communities and identified socioeconomic differences between low- and high-access regions. Geospatial analysis of publicly available 2015-2022 NPI records was combined with US census data to identify geospatial gaps in otolaryngologist distribution. Moran's index geospatial clustering in distance to the nearest county with an otolaryngologist was used as the core metric for differential access determination. Univariate logistic analysis was conducted between low- and high-access counties for 20 socioeconomic and demographic variables. Nationally, the average person was 22 miles from an otolaryngologist. 444 counties were identified as geospatially "low access" with increased travel distance in the Midwest, Great Planes, and Nevada with a median of 47 miles. 1231 counties in the Eastern United States and Western Coast were identified as "high access" with a 3-mile median travel distance. Areas of low access to otolaryngological care had smaller median populations (12,963 vs. 558,306), had smaller percent Black and Asian populations (2% vs. 11%, 1% vs. 5%, respectively), had a greater percent American Indian population (2% vs. 1%), were less densely populated (8 vs. 907 people per square mile), had fewer percent college graduates (20% vs. 34%), and fewer otolaryngologists per county (median: 0.01-20). These findings highlight disparity in otolaryngology care in the United States and the need for otolaryngology funding initiatives in the Midwest and Great Plains regions. Level 3.

Abstract 3: Multiomics analyses reveal functional DNA, methylation pattern changes in clinical transgenic T-cell receptor cell therapy products

Abstract Background: Transgenic T-cell receptor T-cells (TCR-T) directed against tumor-specific antigens are associated with robust initial clinical responses. However, these responses are often not durable, and patients relapse frequently. Therefore, there is a significant need to understand how these cells change at the epigenomic level over time following infusion into the patient. Methods: We analyzed MART-1 TCR-T products from 8 patients treated under a clinical trial at UCLA (NCT00910650). Samples from the baseline infusion product and samples from day +30 recovered from peripheral circulation were sorted for TCR+ cells via flow cytometry, and were then subjected to whole genome bisulfite sequencing (WGBS), ATACseq, and RNAseq in parallel. Differential chromatin accessibility and gene expression by the ATACseq and RNAseq datasets, respectively, were analyzed via DESeq2, with P adjusted less than 0.1. WGBS datasets were analyzed via Metilene, and differentially methylated regions (DMRs) were defined as those regions with CpG loci containing a methylation difference &amp;gt;= 10% and a P adjusted &amp;lt; 0.05. Functional DMRs were defined as those repressed over time (increased DNA methylation with decreased chromatin accessibility/gene expression relative to infusion product), or activated over time (decreased DNA methylation with increased chromatin accessibility/gene expression relative to infusion product). Functional DMRs were then analyzed via EnrichR to evaluate gene ontology and pathways significantly enriched in gene lists. Results: We collectively identified three genes with repressed DMR activity and 49 genes with activated DMR activity compared to baseline infusion products. Our findings revealed that genes associated with repressed DMRs included IL2RA, FBLN7, and ZNRF1. These genes were collectively associated with a decrease in T-cell activation, cytokine signaling, and migration activity, potentially impacting the functional capabilities of T-cells in the post-infusion environment. Conversely, genes associated with activated DMRs included PDCD1 (PD1), FGR, KIR3DL1, KIR2DL4, and KLF3, with pathway enrichment analysis indicating a significant shift in the T-cell landscape towards reduced anti-tumor activity, decreased T-cell proliferation, T-cell aging, and the promotion of immune escape tumor phenotypes. Conclusions: This comprehensive multi-omics approach showcases an atlas of genes in clinical TCR-T cell therapeutics which are subject to functional changes in DNA methylation over time in vivo. These findings shed light on the complex interplay between DNA methylation, chromatin accessibility, and gene expression in the context of TCR-T cell therapy, with implications for the development of more effective immunotherapeutic strategies. Citation Format: Giulia Protti, Cole Peters, Moe Kawakami, Conner Kidd, Varsha Subramanyam, Analynn Lechien, Andrew Dinh, Antoni Ribas, Matteo Pellegrini, Theodore S. Nowicki. Multiomics analyses reveal functional DNA, methylation pattern changes in clinical transgenic T-cell receptor cell therapy products [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 3.

Abstract 4406: Single cell multiomic analysis reveals how genomic, epigenomic and transcriptomic events drive progression of multiple myeloma precursor states

Abstract In this study we have leveraged Moffitt Cancer Center’s cohort of over 1,000 bone marrow (BMBX) aspirates from normal donors, MM precursor diseases (MGUS, SMOL), active therapy naïve disease (NDMM), as well as early (post 1-3 lines of therapy, ERMM) and late-relapse (3+ lines of therapy, LRMM) MM patients, characterized clinically, cytogenetically (FISH), genetically (WES), and transcriptomically (RNA-seq).Transcriptomic analysis identified a subset of cancer hallmarks differentially expressed between MGUS and NDMM samples (e.g. cell identity, adhesion and inflammatory signaling, etc.).Dimensionality reduction analysis, followed by unsupervised segmentation, identified clusters of co-expressing genes across this dataset. Enrichment analysis of aforementioned gene clusters, differentially expressed between MGUS and NDMM states, identified a number of putative transcription factors (GATA1/2, SUZ12, RUNX1, SOX2, TP63, NFE2L2, FOXM1 and NANOG), as well as polycomb complex and H3K27me3 as main drivers. Single cell ATAC-seq in 11 BMBX (4 SMOL, 4 NDMM, 1 ERMM, 2 LRMM) and single cell multiomics (simultaneous scATAC-seq/scRNA-seq) in additional 10 BMBX (2 healthy, 3 MGUS, 3 SMOL and 2 NDMM) confirmed that the H3K27me3 putatively regulated gene clusters were the only ones with significant chromatin accessibility changes. Single cell analysis confirmed differential expression and accessibility of cancer hallmarks identified in larger cohort, as well as putative driver TFs. Correlation between TF expression and motif accessibility produced an additional list of pioneer TFs putatively involved in progression from MM precursor states (ZEB1, EBF1, SPI1, PAX5, etc.).Investigation of scMultiomic data demonstrated that NDMM and SMOL samples contain subpopulations of cells in MGUS and normal “states” (cell clusters in scMultiomics UMAP), confirming intra-sample heterogeneity, and that divergence within the multiomic plane occurs in the transition between MGUS and SMOL. Through pseudotime and single cell copy number analysis (epiAneufinder/scATAC-seq and inferCNV/scRNA-seq) we were able to reconstruct how MM FISH cytogenetic abnormalities alter the multiome of these cells, creating aforementioned intra-sample heterogeneity. Despite different initiating events, all samples shared a common biology putatively regulated by epigenetic dysregulation, suggesting polycomb complex hijacking as a therapeutic opportunity for precursor MM. Citation Format: Rafael Canevarolo, Praneeth Sudalagunta, Maria Silva, Mark Meads, Rachid Baz, Melissa Alsina, Kenneth H. Shain, Ariosto Siqueira Silva. Single cell multiomic analysis reveals how genomic, epigenomic and transcriptomic events drive progression of multiple myeloma precursor states [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 4406.

Abstract 3245: Use of hypomethylating agents to reprogram the epigenome in large granular lymphocyte leukemia

Abstract Large granular lymphocyte (LGL) leukemia is a rare heterogeneous blood cancer that is characterized by the clonal lymphoproliferation of CD8+ T cells (T-LGL leukemia) or, less frequently, natural killer cells (NK-LGL leukemia). These cells evade activation induced cell death, allowing them to accumulate as highly cytotoxic lymphocytes that contribute to autoimmune attacks, neutropenia, and anemia. Frontline treatments are limited to repurposed, nonspecific immunosuppressive agents with limited efficacy and incomplete response rates. As there are no FDA-approved antineoplastic agents for LGL leukemia, our research explores novel therapeutic avenues for this orphan disease. Somatic activating mutations in the transcription factor STAT3 are the most common molecular alteration found in &amp;gt;50% of patients, and STAT3 signaling is dysregulated in almost all LGL leukemia patients. In the largest molecularly profiled LGL leukemia patient cohort to date, we found that STAT3 mutations frequently co-occur with mutations in chromatin and epigenetic modifying genes, suggesting crosstalk and cooperativity between STAT3 activation and epigenetic dysregulation. Moreover, TET2, which promotes DNA demethylation, is frequently inactivated in LGL leukemia via loss-of-function mutations and promoter hypermethylation. As DNA hypermethylation is an emerging hallmark of LGL leukemia, we evaluated the therapeutic potential of two epigenetic agents, azacitidine (AZA) and cladribine (CLAD), that directly and indirectly inhibit DNA hypermethylation, respectively. We hypothesize that AZA and CLAD will 1) exhibit cell intrinsic efficacy, 2) reprogram the epigenome of LGL leukemia through DNA hypomethylation to normalize aberrant gene expression, and 3) induce cytokine-mediated immune responses. AZA and CLAD cytotoxicity was assessed by the Cell Titer Glo viability assay in human LGL leukemia cell lines. Each exhibited potent anti-leukemic effects with IC50 values in the low micromolar and nanomolar ranges. Western blotting analysis demonstrated the decrease in protein expression of DNA methyltransferases and phosphorylated STAT3 levels with treatment in a time- and dose-dependent manner. We also explored the immunomodulatory effects of these hypomethylating agents since LGL leukemia is a pro-inflammatory malignancy with cytotoxic lymphocytes. Preliminary findings using the Isoplexis platform suggest that AZA and CLAD induce production of anti-inflammatory cytokines in LGL leukemia cells. Ongoing studies will identify differential methylation, chromatin accessibility, and gene expression using RRBS, ATAC-seq, and RNA-seq of AZA or CLAD treated samples to define the mechanisms and consequences of DNA demethylation. Uncovering the reprogramming capabilities of AZA and CLAD could allow for the potential repurposing of these inhibitors for treatment of LGL leukemia patients. Citation Format: Ariana Sabzevari, Ipsita Pal, Tess Deddens, Todd Fox, Aakrosh Ratan, David J. Feith, Thomas P. Loughran. Use of hypomethylating agents to reprogram the epigenome in large granular lymphocyte leukemia [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 3245.

Abstract 4339: Chromatin landscapes of colorectal cancer development and cfDNA fragmentation

Abstract Introduction: The stepwise progression of colorectal cancer from healthy epithelium, to premalignant adenoma, to cancer is accompanied by genome-wide epigenetic reprogramming. However, current analyses of these processes have been hampered by complex mixtures of cells in normal, adenoma and cancer tissue samples, as well as absence of suitable adenoma model systems. Cultured colorectal organoids, comprised of pure epithelial cells, could enable insights on the epigenetic changes leading to progression from healthy tissue to cancer. Methods: Using 43 patient-derived colorectal organoids derived from healthy, adenoma, and cancer tissues, we examined the chromatin landscape of tumor progression using transposase accessible chromatin analyses with next generation sequencing. We defined a consensus set of nucleosome depleted regions for each disease stage and used principal component analyses to identify peaks that contributed the most variation across the collection of organoids. Consensus regions were linked to genes they overlapped, and intergenic consensus regions were linked to the nearest gene within 1 Mbp. Subsequently, we performed a gene set enrichment analysis to assess pathways affected by differential chromatin accessibility. To identify the transcription factor drivers of regulatory reprogramming, the DNA sequences within the consensus peaks were analyzed for enrichment of characteristic binding motifs. We analyzed regions of consensus peaks for fragmentation characteristics in the circulating cell-free DNA (cfDNA) of 250 healthy individuals and 51 patients with stage IV colorectal cancer. Results: Across all organoid samples, we identified &amp;gt;35 million nucleosome depleted regions that we coalesced into a consensus set of 61,755 regions. We excluded 13,040 regions that had low variation across the organoid tissues, leaving 48,715 regions that could potentially define tissue-specific signatures of chromatin accessibility. As 78% of these regions could be linked to genes, we assessed whether these signatures identify known pathways involved in colorectal cancer. We identified unique signatures of healthy tissues, adenomas, and cancers comprising genes of known and novel pathways, including those involved in WNT, hippo, and RAS signaling. We found that changes in chromatin accessibility can be detected in circulating cfDNA profiles and were associated with independent circulating tumor DNA abundance by droplet digital PCR (R=0.78, p&amp;lt;0.0001). Conclusions: These analyses highlight important targets of chromatin remodeling in colorectal tumorigenesis and provide an avenue for evaluating these through genome-wide analyses of cfDNA fragmentation. Citation Format: Nicholas A. Vulpescu, Zachariah H. Foda, Pieter H. Wisse, Jamie E. Medina, Vilmos Adleff, Remond J. Fijneman, Robert B. Scharpf, Gerrit A. Meijer, Beatriz Carvalho, Victor E. Velculescu. Chromatin landscapes of colorectal cancer development and cfDNA fragmentation [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 4339.

Abstract 6940: The transcriptional and epigenetic regulation of epithelial-mesenchymal plasticity in patient-derived pancreatic cancer cell lines

Abstract Epithelial-mesenchymal transition (EMT) is a hallmark of pancreatic ductal adenocarcinoma (PDAC) invasion. In general, cellular plasticity is a major contributor to both tumor progression and therapy resistance. The major goals of our study are to 1) directly and quantitatively measure plasticity in PDAC3 cell lines, and 2) identify candidate genes that could alter the plasticity of cancer cells. By understanding the regulation of tumor cell plasticity, we may find ways to perturb cells and prevent the transition towards treatment resistant cell states. A strict definition of plasticity in cancer has yet to be established, however, and is imperative to our understanding of cell state regulation and for identifying vulnerabilities in plastic cells. We argue that in order to prove plasticity occurs within a population of cells, one must either 1) demonstrate that a new cell state has emerged that was previously not present, or 2) trace the lineage of a cell to show it can adopt multiple cell states. For our study, we profile 12 patient-derived PDAC cell lines to find convergent EMT programs and perform lineage tracing on these cell lines using a modified CROP-seq vector, called ClonMapper, to quantitatively measure plasticity. Towards this goal, we perform single-cell RNA-seq (scRNA) and single-cell multiomic measurements of 1000 uniquely barcoded cells expanded over a time course of 2, 3 and 4 weeks. We refer to cells that have the same lineage barcode - originating from the same initial cell - as families. We found that ~50% of families are composed of cells that are epithelial and mesenchymal, thus proving plasticity must exist, as it shows that a given parental cell of unknown state can give rise to progeny that are in multiple states. We then develop mathematical models to show that families have different levels of plasticity, defined by the rates of transition between distinct cell states. We next leverage our barcode-resolution time course data to identify factors at early time points that may influence plasticity at later time points. We show there is differential accessibility of several of these factors across families with different plasticity properties, thus proposing a role for epigenetic regulation of EMT. Importantly, we find that specific factors drive gene regulatory networks important for epithelial and mesenchymal programs, and therefore propose candidates for the modulation of EMT for therapeutic benefit. Citation Format: Deepika Yeramosu, Lynn Bi, Abigail Collins, Mike Bogaev, Martin Jankowiak, Aziz Al’Khafaji, Milan Parikh, Mehrtash Babadi, Alex Bloemendal, Surya Nagaraja, Ray Jones, Jay Shendure, David T. Ting, Andrew Aguirre, Nir Hacohen, Dana Pe’er, Eric S. Lander, Arnav Mehta. The transcriptional and epigenetic regulation of epithelial-mesenchymal plasticity in patient-derived pancreatic cancer cell lines [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 6940.

Abstract P453: Racial Disparities in Early Use of Transcarotid Artery Revascularization Among High-Risk and Symptomatic Black and White Adults With Carotid Artery Stenosis

Introduction: Differential access to new technologies may contribute to racial disparities in health outcomes. We examined the adoption of transcarotid artery revascularization (TCAR) among high-risk Black and white adults undergoing surgery for carotid artery stenosis. Hypothesis: We hypothesized that Black adults would be less likely than white adults to receive TCAR since its introduction to the US market in 2015. Methods: We conducted a retrospective analysis of the prospectively collected Vascular Quality Initiative surgical database from 1/2015 to 12/2021, which includes 100% of the TCAR procedures performed during this period. Non-Hispanic Black and non-Hispanic white adults were included if they met Centers for Medicare &amp; Medicaid Services high-risk criteria due to anatomy, medical comorbidities, and/or recent symptoms (ipsilateral stroke or transient ischemic attack). We used logistic regression to quantify associations of race with receipt of TCAR (versus other surgical procedure for carotid stenosis) overall and by specific high-risk features. Results: There were 119,128 surgical procedures performed for carotid artery stenosis (14.3% TCAR) (mean age 72 years, 5.3% Black, 38.5% female). Black patients were less likely than white patients to receive TCAR after adjustment for patient and disease characteristics (aOR 0.91, 95% CI 0.83, 0.99). Among patients with only one high-risk feature (e.g., only high-risk anatomy), TCAR use did not vary by race. However, Black patients were less likely to receive TCAR in subgroups with multiple high-risk features ( Figure ). Not all hospitals performed TCAR, and Black patients were less likely to be treated at TCAR-capable hospitals (aOR 0.93, 95% CI 0.88, 0.98). TCAR use did not vary by race at TCAR-capable hospitals ( Figure ). Conclusions: Adoption of TCAR was lower among Black compared to white high-risk patients, for whom TCAR offers the most benefit. Differential access to hospitals with newer technology may explain these disparities.

Integrative analysis of chromatin accessibility and transcriptome landscapes in the induction of peritoneal fibrosis by high glucose

BackgroundPeritoneal fibrosis is the prevailing complication induced by prolonged exposure to high glucose in patients undergoing peritoneal dialysis.MethodsTo elucidate the molecular mechanisms underlying this process, we conducted an integrated analysis of the transcriptome and chromatin accessibility profiles of human peritoneal mesothelial cells (HMrSV5) during high-glucose treatment.ResultsOur study identified 2775 differentially expressed genes (DEGs) related to high glucose-triggered pathological changes, including 1164 upregulated and 1611 downregulated genes. Genome-wide DEGs and network analysis revealed enrichment in the epithelial–mesenchymal transition (EMT), inflammatory response, hypoxia, and TGF-beta pathways. The enriched genes included VEGFA, HIF-1α, TGF-β1, EGF, TWIST2, and SNAI2. Using ATAC-seq, we identified 942 hyper (higher ATAC-seq signal in high glucose-treated HMrSV5 cells than in control cells) and 714 hypo (lower ATAC-seq signal in high glucose-treated HMrSV5 cells versus control cells) peaks with differential accessibility in high glucose-treated HMrSV5 cells versus controls. These differentially accessible regions were positively correlated (R = 0.934) with the nearest DEGs. These genes were associated with 566 up- and 398 downregulated genes, including SNAI2, TGF-β1, HIF-1α, FGF2, VEGFA, and VEGFC, which are involved in critical pathways identified by transcriptome analysis. Integrated ATAC-seq and RNA-seq analysis also revealed key transcription factors (TFs), such as HIF-1α, ARNTL, ELF1, SMAD3 and XBP1. Importantly, we demonstrated that HIF-1α is involved in the regulation of several key genes associated with EMT and the TGF-beta pathway. Notably, we predicted and experimentally validated that HIF-1α can exacerbate the expression of TGF-β1 in a high glucose-dependent manner, revealing a novel role of HIF-1α in high glucose-induced pathological changes in human peritoneal mesothelial cells (HPMCs).ConclusionsIn summary, our study provides a comprehensive view of the role of transcriptome deregulation and chromosome accessibility alterations in high glucose-induced pathological fibrotic changes in HPMCs. This analysis identified hub genes, signaling pathways, and key transcription factors involved in peritoneal fibrosis and highlighted the novel glucose-dependent regulation of TGF-β1 by HIF-1α. This integrated approach has offered a deeper understanding of the pathogenesis of peritoneal fibrosis and has indicated potential therapeutic targets for intervention.

Abstract B057: Oncogenic Foxl2 directs enhancer reprogramming and changes in 3D genome structure in ovarian granulosa cell tumors

Abstract Background: Adult-type granulosa cell tumors (aGCTs) are a rare monogenic disease. Nearly all aGCTs carry a missense point mutation in the Forkhead domain containing FOXL2 (Foxl2 p.C134W) transcription factor, but the oncogenic mechanism of this mutation is unknown. Other Forkhead family transcription factors have well-described “pioneer” activity, binding to compacted, nucleosome-bound DNA and increasing accessibility for other regulatory proteins. Objectives: To investigate if oncogenic Foxl2-C134W has pioneering activity and if mutant Foxl2 operates its oncogenic activity through enhancer reprogramming. Methods: CRISPR/Cas9 editing was used to generate isogenic granulosa cell tumor cells lacking either the FOXL2 wild-type allele (single knock-out; SKO) or both the mutant and wild-type FOXL2 alleles (double knock-out; DKO). ATAC-Seq and endogenous Foxl2 ChIP-Seq were performed on these isogenic lines to determine the differential chromatin accessibility at Foxl2-bound regulatory regions across genotypes. Promoter capture HiC was performed using a bespoke genome-wide hybrid capture probe set, CHiCAGO was used to identify significant HiC interactions, and an activity-by-contact model was constructed to identify enhancer elements bound by endogenous Foxl2-C134W and determine their target promoter contact frequency (promoter capture HiC) and enhancer activity (geometric mean of H3K27ac and ATACseq signal. Results: Endogenous ChIP-seq of Foxl2-C134W from the SKO cell line identified 1147 high-confidence peaks. De novo motif discovery identified the canonical Foxl2 binding motif (TGTTTACATT, P = 1.4 × 10−7) in 44.9% of peaks, as well as a novel variant motif (TGTTTTGTCT, P = 6.7 × 10−15) in 68.5% of peaks. Median chromatin accessibility at Foxl2-C134W peak regions, as measured by ATAC-seq, was significantly decreased in the DKO cells compared to either SKO or parental cell lines (P &amp;lt; 2 × 10-16 for both comparisons). Decreased chromatin accessibility at Foxl2-C134W ChIP-seq peaks in the DKO cells was driven by peaks containing the novel variant Foxl2 binding motif. Promoter capture HiC through activity-by-contact model identified promoter-enhancer interactions lost in the DKO cell line involving several genes, including ADAMTS5, FOXF2, and PRICKLE1 (adjusted P &amp;lt; 0.05). Conclusion: Foxl2-C134W exhibits “pioneering” activity, increasing chromatin accessibility at key gene regulatory elements with associated re-programming of promoter-enhancer interactions. The oncogenic mechanism of Foxl2-C134W in granulosa cell tumors may involve changes in DNA binding specificity, re-directing this pioneering function to sites containing a novel variant Foxl2 binding motif. Citation Format: Veena K. Vuttaradhi, Eleonora Khlebus, Thomas Welte, Barrett Lawson, Robert Tyler Hillman. Oncogenic Foxl2 directs enhancer reprogramming and changes in 3D genome structure in ovarian granulosa cell tumors [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr B057.

Access of Urban Poor to Basic Services: Concerns of Sustainability and Equity

Sharp inequality in India’s urban economy, coupled with an increasing reliance on the market system for infrastructure and basic services, has led to inadequate access to and poor quality of amenities for the urban poor. Disparities in welfarist interventions by central and state governments, manifest in changing administrative paradigm, have impacted inequality trends and patterns. Given this macro scenario, this article is designed to achieve two objectives: one, an analysis of the differential access of urban poor to select basic amenities and changes therein over time at the national level. An attempt is also made to bring out the deficits in amenities for households in different asset quintiles within the framework of India’s inclusive development strategy. Two, to analyse the pattern of access to basic services across the states, their changing pattern over time, and probe into their interdependencies with indicators of environmental sustainability. The basic idea is to examine quantitatively the complex relationship between the utilisation of natural resources, environmental degradation, and the provisioning of basic amenities to the poor. The possibility of the poor being forced to use non-renewable resources, posing serious threats to their micro-environment and its long-term implications are discussed using available secondary data and over-viewing empirical research on the subject. The article concludes by proposing broad directions in which solutions to the twin problems of providing a decent living environment to the poor and ensuring ecological sustainability can be sought.

Vision impairment and differential access to eye health services in Aotearoa New Zealand: a scoping review

IntroductionIn Aotearoa New Zealand, Māori and Pacific People experience worse health outcomes compared with other New Zealanders. No population-based eye health survey has been conducted, and eye health services do...

Dossier—Negotiating Urban Spaces: Access, Care and Confinement in Contemporary Gendered Performance

This dossier explores the ways in which theatre and performance practitioners across the globe have addressed the deeply gendered modes of differential access to public spaces, institutional support, and resources through their creative as well as activist work, during the pandemic and its aftermath. In the last three years, the pandemic has transformed experiences of urban space globally. Access to public space has always been gendered as well as shaped by geographical location, race, caste, class and sexual identity. These traditional modes of differential access have been radically reorganized by the isolation and uncertainty engendered by the global pandemic. While ‘working from home’ was certainly not an option for everyone (most notably, care-workers in an overwhelmingly feminized profession), confinement to domestic space also meant escalating incidents of gendered violence for others. Additionally, the lack of sustainable income opportunities meant, as contributions to this dossier will demonstrate, the stripping away of roofs from over the heads of vulnerable citizens, whether impoverished artistes in want of state support or migrant workers on an uncertain daily wage. Staying at home was no longer an option, because ‘home’ often ceased to exist as a viable shelter, whether literally or by implication. For performers and theatre-workers all over the world, it was a time of intensified precarity: not only a loss of employment and income, but also a growing sense of artistic and professional purposelessness. While some were able to reorient this bewilderment through virtual and digital performances, for many grassroots performers, especially in the global South, access to these modes of public engagement were limited. In countries like India, street theatre activists felt unable and unwilling to switch to the digital space, while the prohibition on public assembly struck an irrevocable blow to women's protest movements.

Battery-aware federated learning: Challenges and solutions

Smartphone battery life is a pivotal factor in consumers' purchasing decisions. Recent years have witnessed a surge in studies focusing on smartphone energy management, with data-driven energy management systems offering solutions to prolong battery life. Federated Learning (FL) emerges as a promising distributed learning algorithm, enabling wireless devices to upload locally trained models, fostering collaborative learning without exposing sensitive data. This paper explores the FL process, particularly the Federated Averaging (FedAvg) approach, which excels in scenarios with homogeneous data. In the era of burgeoning data generation, traditional cloud computing systems face limitations, driving the adoption of Edge Computing (EC), which processes data closer to its source, enhancing response times. To make FL efficient for e-commerce, resource constraints must be addressed. This involves techniques like local updates and model compression, which reduce communication overhead. However, FL brings challenges related to data distribution heterogeneity and privacy concerns. Solutions like differential privacy, encryption, and access control are discussed. In conclusion, this paper presents an overview of smartphone battery life, data-driven energy management, and the potential of FL, emphasizing its relevance in the age of EC. By addressing resource limitations and privacy issues, FL holds promise for efficient data processing.

Combination Social Protection Programme as an HIV Prevention Mechanism: Experiences of Youths in Resource-Constrained Settings of Gauteng Province, South Africa

Regardless of the tremendous growth of combination social protection as a human immunodeficiency virus prevention mechanism in South Africa, little is known about the ways in which combination social protection improves prevention outcomes for youths. In this article, we report on the experiences of youths participating in the combination social protection. In the study, which was conducted among Black African youths in the City of Johannesburg township settings of Soweto, Alexandra, and Orange Farm, we adopted a qualitative approach. The aim of the study was to explore the experiences of youths participating in the combination social protection and their views on how the programme changed their risk behaviour and sexual practices. We used a purposively selected sample to identify participants for semi-structured qualitative interviews. In-depth individual interviews were conducted with thirty youths and focus group discussions with six non-governmental organisations practitioners and five Department of Social Development officials. The data were analysed by implementing Creswell and Creswell’s strategy of qualitative thematic analysis. The findings show that when youths are equipped with prevention informational resources, economic capabilities, and social assets, they are empowered with agency and purposefulness that may alter their intentions to engage in risky sexual behaviour. It is also revealed that, by providing space for youths to engage on issues of gender and differential access to health and economic opportunities, the programme advanced the empowerment of female youths. Thus, combination social protection could be part of the country’s comprehensive social work package for empowering youths in poor localities.

Equity of travel to access surgery and radiation therapy for lung cancer in New Zealand

PurposeCentralisation of lung cancer treatment can improve outcomes, but may result in differential access to care for those who do not reside within treatment centres.MethodsWe used national-level cancer registration and health care access data and used Geographic Information Systems (GIS) methods to determine the distance and time to access first relevant surgery and first radiation therapy among all New Zealanders diagnosed with lung cancer (2007–2019; N = 27,869), and compared these outcomes between ethnic groups. We also explored the likelihood of being treated at a high-, medium-, or low-volume hospital. Analysis involved both descriptive and adjusted logistic regression modelling.ResultsWe found that Māori tend to need to travel further (with longer travel times) to access both surgery (median travel distance: Māori 57 km, European 34 km) and radiation therapy (Māori 75 km, European 35 km) than Europeans. Māori have greater odds of living more than 200 km away from both surgery (adjusted odds ratio [aOR] 1.83, 95% CI 1.49–2.25) and radiation therapy (aOR 1.41, 95% CI 1.25–1.60).ConclusionsCentralisation of care may often improve treatment outcomes, but it also makes accessing treatment even more difficult for populations who are more likely to live rurally and in deprivation, such as Māori.

The dynamic landscape of chromatin accessibility and active regulatory elements in the mediobasal hypothalamus influences the seasonal activation of the reproductive axis in the male quail under long light exposure

BackgroundIn cold and temperate zones, seasonal reproduction plays a crucial role in the survival and reproductive success of species. The photoperiod influences reproductive processes in seasonal breeders through the hypothalamic-pituitary-gonadal (HPG) axis, in which the mediobasal hypothalamus (MBH) serves as the central region responsible for transmitting light information to the endocrine system. However, the cis-regulatory elements and the transcriptional activation mechanisms related to seasonal activation of the reproductive axis in MBH remain largely unclear. In this study, an artificial photoperiod program was used to induce the HPG axis activation in male quails, and we compared changes in chromatin accessibility changes during the seasonal activation of the HPG axis.ResultsAlterations in chromatin accessibility occurred in the mediobasal hypothalamus (MBH) and stabilized at LD7 during the activation of the HPG axis. Most open chromatin regions (OCRs) are enriched mainly in introns and distal intergenic regions. The differentially accessible regions (DARs) showed enrichment of binding motifs of the RFX, NKX, and MEF family of transcription factors that gained-loss accessibility under long-day conditions, while the binding motifs of the nuclear receptor (NR) superfamily and BZIP family gained-open accessibility. Retinoic acid signaling and GTPase-mediated signal transduction are involved in adaptation to long days and maintenance of the HPG axis activation. According to our footprint analysis, three clock-output genes (TEF, DBP, and HLF) and the THRA were the first responders to long days in LD3. THRB, NR3C2, AR, and NR3C1 are the key players associated with the initiation and maintenance of the activation of the HPG axis, which appeared at LD7 and tended to be stable under long-day conditions. By integrating chromatin and the transcriptome, three genes (DIO2, SLC16A2, and PDE6H) involved in thyroid hormone signaling showed differential chromatin accessibility and expression levels during the seasonal activation of the HPG axis. TRPA1, a target of THRB identified by DAP-seq, was sensitive to photoactivation and exhibited differential expression levels between short- and long-day conditions.ConclusionOur data suggest that trans effects were the main factors affecting gene expression during the seasonal activation of the HPG axis. This study could lead to further research on the seasonal reproductive behavior of birds, particularly the role of MBH in controlling seasonal reproductive behavior.

Household Livelihood Strategies and Forest Resource Use in Rural West Bengal, India

The economic contributions of forest resources to the well-being of rural households are enormous. However, the level of forest benefits and degree of forest reliance vary across households. Drawing on a sustainable livelihood framework, this article explores how these forest resource uses correlate to the choice of livelihood strategies of rural forest-dependent households with a specific focus on the increased income of households, filling income shortfall, coping with shocks and livelihood diversification. Data were collected from 407 rural forest-dependent households in West Bengal, India. Based on the share of forest income in total household income, households were classified into different livelihood strategy groups. One-way ANOVA was run to test the income differences among these groups. The forest extractive strategy was found least income-generating of all livelihood strategies. Multinomial logit regression was carried out to identify the asset-based explanatory variables that influence livelihood strategy choices and forest dependency of the studied households. Analyses show that households’ differential access to or endowment of livelihood assets determines the choice of a rural household’s livelihood strategy and that forest resource uses of the households are livelihood strategy driven. Asset-poor households should be given opportunities to pursue livelihood activities with higher economic returns. JEL Classifications: Q23, Q56, Q57