tbuckley/cabot-search huggingface dataset:
Burnout Trends Among US Health Care Workers
Authors: David C. Mohr, Shereef Elnahal, Maureen L. Marks, Ryan Derickson, Katerine Osatuke
Journal: JAMA Network Open (2025)

Importance Burnout among health care workers is a widespread concern in health care both before and since the COVID-19 pandemic, yet little is known about health care workers’ burnout levels across occupations and settings. Objective To examine trends in burnout and professional stress reported among health care workers working at the US Veterans Health Administration (VHA) and identify occupations that experienced notable changes and the factors associated with changes. Design, Setting, and Participants This survey study used a retrospective cohort design grouped by key factors associated with burnout and professional stress. Responses to an annual organization-wide survey at 140 medical centers from 2018 to 2023 were used. Exposures Respondents self-reported on 2 burnout items (ie, “I feel burned out from my work” and “I worry that this job is hardening me emotionally”) from the Maslach Burnout Inventory during all study years and professional stress (moderate or lower vs high or extreme) from COVID-19 from 2020 to 2023. Main Outcome and Measures Trends by occupation, telework status, and geographic region were examined, as well as the general pattern over time and the change in burnout and stress rates in the years following the start of the pandemic. Results In 2018, the sample was 71.6% female, with an estimated mean (SD) age of 46.31 (12.11) years, and estimated mean (SD) VA tenure of 8.54 (7.33) years. Totals of health care worker respondents identified from 140 medical centers ranged from 123 271 in 2018 to 169 448 in 2023. Annual burnout rates were 30.4% for 2018, 31.3% for 2019, 30.9% for 2020, 35.4% for 2021, 39.8% for 2022, and 35.4% for 2023. Rates of professional stress from COVID-19 were 32.0% for 2020, 26.9% for 2021, 29.2% for 2022, and 21.4% for 2023. Both measures showed a decrease following the official public health emergency ending in 2023. Primary care physicians reported the highest burnout levels compared with other service areas, ranging from 46.2% in 2018 to 57.6% in 2022. Several service areas saw a relative increase of 10% or more in burnout between 2018 and 2023, with mental health, dental, and rehabilitation service employees reporting the highest increases in burnout rates over this time. Burnout levels for respondents who teleworked most of the time were lower than those for respondents who did not telework. Conclusions and Relevance In this survey study of VHA health care workers, burnout and professional stress decreased on average following the pandemic, but burnout levels remain elevated compared with prepandemic levels. The VHA has made several efforts to reduce burnout and stress, and results showed some promise, but exploration of ways to reduce burnout to prepandemic levels is needed.
Abstract 3913: New insights from transgenic mouse models of PyMT-induced breast cancer: identifying novel long non-coding RNA biomarkers
Authors: Rui Zhang, Jiarong Li, Dunarel Badescu, Jiannis Ragoussis, Richard Kremer
Journal: Cancer Research (2025)

Abstract Metastatic breast cancer with complex molecular mechanisms of progression accounts for most cancer related deaths in women. To improve diagnosis and drug development, it is important to identify novel biomarkers and critical molecular pathways involved in tumor initiation and progression. Here, we profiled and analyzed the expression of lncRNAs from three distinct stages of tumor initiation and progression (hyperplasia, adenoma, and carcinoma) in mammary tumors. We performed RNAseq on tumor and mammary epithelial cells derived from ROSAmT/mG; MMTV-PyMT mice and ROSAmT/mG; non-cancer mice derived from the same strain, respectively. We identified 1913 differentially expressed protein coding genes and 324 lncRNAs in breast cancer cells of all stages compared with normal mammary epithelial cells. Pearson correlation analysis correlated 93 differentially expressed lncRNAs with protein coding genes, providing a comprehensive lncRNA-coding gene co-expression network. Among them, we focused on Gm19303 which was paired with the differentially expressed protein coding gene, Trps1, and identified its human counterpart as LINC00536. Both LINC00536 and human TRPS1 are exclusively overexpressed in breast cancer and correlate with poor patient prognosis from the TCGA and GTEx databases. Single cell RNAseq data from the Atlas of Human breast cancers further confirmed that TRPS1 is upregulated in human breast cancer compared to normal human mammary tissue with highest expression in ER+ subgroup. In summary, our study explored the potential role of lncRNAs in breast cancer initiation and progression, presented the lncRNA-protein coding genes co-expression profiles, and identified human LINC00536/TRPS1 as a potential diagnostic and therapeutic target for breast cancer. Citation Format: Rui Zhang, Jiarong Li, Dunarel Badescu, Jiannis Ragoussis, Richard Kremer. New insights from transgenic mouse models of PyMT-induced breast cancer: identifying novel long non-coding RNA biomarkers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3913.
Abstract 4048: The circadian gene Dec2 promotes pancreatic cancer dormancy by regulating tumor cell antigen presentation to facilitate immune evasion
Authors: Lan Wang, Chris Harris, Orjola Prela, Wade Narrow, Jennifer L. Becker, Juliana Cazarin de Menezes, Darren R. Carpizo
Journal: Cancer Research (2025)

Abstract The mechanisms that regulate cancer dormancy remain poorly understood. Using an orthotopic mouse model of resectable pancreatic adenocarcinoma (PDAC), we identified the transcriptional repressor factor Dec2 (Bhlhe41) as a gene that was upregulated in metastatic dormant tumor cells from the liver. To understand how Dec2 regulates dormancy, we deleted it from the murine pancreatic cancer cells and implanted them in the model. Following resection, mice implanted with Dec2 KO cells demonstrated a striking improvement in survival compared to the mice with Dec2 WT cells. This difference in survival was abrogated when nude mice were used as hosts indicating the survival difference is from an immune mediated mechanism. Pancreatic cancer is a highly immunosuppressive tumor due to both a relatively low expression of major histocompatibility complex class I (MHC-I)-dependent antigen presentation and an abundance of myeloid-derived suppressor cells that lead to poor T cell trafficking and activation. We found that deletion of Dec2 overcame both of these mechanisms to restore anti-tumor immunity that inhibited tumor growth not only in primary tumors as well as metastases. Dec2 suppresses MHC-I antigen presentation by repressing multiple genes in the antigen presentation pathway including H2-k1, H2-d1, Tap1, and B2m as well as the source of tumor antigens from the proteosome by repressing multiple proteasome genes. Loss of Dec2 repolarized the tumor immune microenvironment by decreasing expression of multiple immunosuppressive cytokines such as Cxcl1, Ccl2 and Csf2 in tumors. We conclude that Dec2 facilitates both pancreatic tumor growth and dormancy by regulating tumor cell MHCI antigen presentation. Dec2 is known to function as part of a negative accessory arm of the molecular circadian clock. We found several components of the antigen presentation pathway oscillated in a circadian manner that was lost upon deletion of Dec2. Moreover, T-cell mediated tumor cell killing varied depending on the time of day. We suggest that lowered MHC-I presentation of antigens during rest phase is a natural effect of the circadian clock. Citation Format: Lan Wang, Chris Harris, Orjola Prela, Wade Narrow, Jennifer L. Becker, Juliana Cazarin de Menezes, Darren R. Carpizo. The circadian gene Dec2 promotes pancreatic cancer dormancy by regulating tumor cell antigen presentation to facilitate immune evasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4048.
Abstract 4043: MYB/AKT3 axis is a key driver of ovarian cancer growth and aggressiveness
Authors: Kunwar Somesh Vikramdeo, Orlandric Miree, Shashi Anand, Sanjeev Kumar Srivastava, Seema Singh, Rodney P. Rocconi, Ajay Pratap Singh
Journal: Cancer Research (2025)

Ovarian cancer (OC) is the most common and lethal gynecologic malignancy in the United States, primarily due to late-stage diagnosis and limited treatment options for the advanced disease. It disproportionately affects Black women at every stage, from initial diagnosis to treatment, resulting in higher mortality rates compared to non-Hispanic White women. In an effort to identify novel biomarkers and therapeutic targets for improved clinical management, we discovered MYB as a differentially-expressed gene in OC, exhibiting a race-specific prognostic association. MYB encodes for a transcription factor protein that drives oncogenesis by regulating the expression of a wide array of gene targets. We also found that MYB is expressed in OC cell lines, having elevated levels in aggressive (SKOV3-ip) and chemo-resistant (A2780-Cip) variants compared to their parental counterpart (SKOV3 and A2780) cell lines. Gain- and loss-of-function studies suggested that MYB plays a role in growth, aggressiveness, and chemoresistance. Gene expression profiling of low (SKOV3-Neo) and high (SKOV3-ip-Scr) MYB-expressing cells along with their forced MYB-expressing (SKOV3-MYB) and MYB-silenced (SKOV3-ip-shMYB) derivative lines using the nCounter® PanCancer Progression panel on a nanoString nCounter system, revealed several MYB-driven differentially expressed genes (DEGs). With a 1.5-fold-change cutoff, we identified 164 DEGs in the SKOV3-ip (Scr vs. shMYB) comparison and 87 DEGs in SKOV3 (Neo vs. MYB) comparison. Notably, the majority of DEGs were distinct between these comparisons, suggesting that MYB alters gene expression in a cell-specific manner. Validation of commonly altered genes in additional paired MYB-overexpressing and silenced cell lines by qRT-PCR identified AKT3 as a significant downstream target of MYB. Moreover, KEGG pathway analysis of DEGs in MYB-modulated cells highlighted PI3K pathway as commonly altered. In silico analysis of AKT3 promoter identified seven putative MYB binding regions (P1-P7), and chromatin immunoprecipitation confirmed strong MYB binding to P4 region of the AKT3 promoter. Inhibition of AKT3 through RNA interference resulted in reduced cell proliferation, clonogenicity, migration and invasion, and increased apoptosis in OC cells. These findings suggest that AKT3 serves as a key mediator in driving the oncogenic actions of MYB in ovarian cancer. Citation Format: Kunwar Somesh Vikramdeo, Orlandric Miree, Shashi Anand, Sanjeev Kumar Srivastava, Seema Singh, Rodney P. Rocconi, Ajay Pratap Singh. MYB/AKT3 axis is a key driver of ovarian cancer growth and aggressiveness [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4043.
Abstract 4042: Mitochondrial electron transport chain inhibition suppresses NRF2 expression in NSCLC
Authors: Chang Jiang, Ryan Martin, Yun Huang, Nicolas Prieto, Yun Pyo Kang, Mingxiang Teng, Gina DeNicola
Journal: Cancer Research (2025)

Abstract Lung cancer is the leading cause of cancer-associated death in the US. Non-small cell lung cancer (NSCLC) accounts for 85% of all diagnosed lung cancer cases, which has a high frequency of mutations in the KEAP1/NRF2 circuit (15-34%). NRF2 is a stress-responsive transcription factor that regulates transcriptional programs in response to oxidative stress. KEAP1 directs NRF2 degradation, and accordingly, disruption of KEAP1 increases the abundance and activity of NRF2. KEAP1/NRF2 mutations result in constitutive NRF2 activation and chronic induction of a battery of NRF2 target genes, which confer profound resistance to chemo/radiation therapy. Although direct inhibition of NRF2 holds great therapeutic potential, NRF2 inhibitors have not yet existed in the clinic. Instead, our attempt to address this challenge focuses on targeting upstream NRF2 regulators in NSCLC. To this end, we leveraged CRISPR/Cas9-based genetic screening approaches. We found that electron transport chain (ETC) complex I/III component deletion or pharmacological inhibition results in complete loss of NRF2 protein expression in KEAP1 mutant NSCLC cells. Our results indicate that NRF2 destruction by ETC inhibition is associated with post-translational ubiquitination and degradation facilitated by an alternative E3 ligase within the Cullin complex and is controlled by AMPK. We also translate these findings in vivo using novel NRF2 active genetically engineered lung tumor mouse models LSL-KrasG12D; Lkb1flox/flox ; Nrf2D29H that mimic the common co-occurrence of KRAS and Lkb1 loss-of-function mutations in human lung adenocarcinoma. This work establishes the link between the mitochondria and NRF2 regulation in NSCLC and, more importantly, will lead to the discovery of novel mediators of this signaling, which can be targeted as a therapeutical strategy for NRF2 inhibition. Overall, our research has great implications in reversing the profound resistance of NSCLC with KEAP1/NRF2 mutations to chemo/radiotherapy, which can significantly improve treatment efficacy and patient survival. Citation Format: Chang Jiang, Ryan Martin, Yun Huang, Nicolas Prieto, Yun Pyo Kang, Mingxiang Teng, Gina DeNicola. Mitochondrial electron transport chain inhibition suppresses NRF2 expression in NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4042.
Abstract 1387: Superoxide induces phosphorylation-mediated Mcl-1 stability to promote vresistance in hematologic malignancies
Authors: Stephen J. Chong, Jolin X. Lai, Kartini Iskandar, Chuqi Wang, Yuhan Wang, Romaine Guieze, Deepika Raman, Rachel H. Lim, Catherine J. Wu, Wee Choo Chng, Alice M. Cheung, Charles T. Chuah, Matthew S. Davids, Shazib Pervaiz
Journal: Cancer Research (2025)

Abstract Acquired resistance to Bcl-2 inhibitor, venetoclax, poses a therapeutic challenge in the management of chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML). Venetoclax-resistant cells exhibit increased accumulation of Mcl-1, thereby switching dependence from Bcl-2 to Mcl-1. However, the mechanism behind increased Mcl-1 accumulation upon the acquisition of venetoclax resistance remains elusive. Given that a change in cellular redox state affects cell survival and drug sensitivity, we sought to investigate the interplay between cellular redox state and Mcl-1 accumulation in venetoclax-resistant cells. Our findings reveal that increased Mcl-1 levels in venetoclax-resistant hematologic malignant cells is associated with increased mitochondrial oxygen consumption and intracellular superoxide (O2 .-) levels. Corroborating the link between cellular redox state and Mcl-1 accumulation, increased O2 .- levels in venetoclax sensitive cells was accompanied by enhanced threonine-163 phosphorylation of Mcl-1 (T163pMcl-1), thereby reducing Mcl-1 ubiquitination and degradation. Furthermore, O2 .--induced T163pMcl-1 is mediated by AKT, as evidenced by increased serine-473 phosphorylation. Notably, reducing O2 .- levels or inhibiting AKT decreases T163pMcl-1 and Mcl-1 levels, heightens mitochondrial apoptotic-priming, and restores sensitivity to venetoclax-induced apoptosis. Collectively, our findings unravel redox-dependent mechanism of Mcl-1 stability and accumulation upon the acquisition of venetoclax resistance, which could have implications for the design of novel therapeutic strategy targeting cellular pro-oxidant state or AKT in various venetoclax-resistant hematologic malignancies. Citation Format: Stephen J. Chong, Jolin X. Lai, Kartini Iskandar, Chuqi Wang, Yuhan Wang, Romaine Guieze, Deepika Raman, Rachel H. Lim, Catherine J. Wu, Wee Choo Chng, Alice M. Cheung, Charles T. Chuah, Matthew S. Davids, Shazib Pervaiz. Superoxide induces phosphorylation-mediated Mcl-1 stability to promote vresistance in hematologic malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1387.
Abstract 2080: Whole transcriptome single cell spatial imaging of tumor vs normal tissue microarray
Authors: Wei Yang, Isabel Lee, Michael Patrick, Yi Cui, Shanshan He, Martin Shelton, Haiyan Zhai, Michael Rhodes, Joseph Beechem
Journal: Cancer Research (2025)

Abstract Tissue microarrays (TMAs) are widely used for high-throughput research but present challenges due to variations in tissue fixation, morphology, and cellular composition, which can impact staining, RNA/protein preservation, and segmentation accuracy. Analyzing diverse tissue types, especially when comparing normal and tumor samples, requires advanced imaging and computational tools. The CosMx® Spatial Molecular Imager (SMI) addresses these challenges by enabling accurate definition of single cells with multi-tissue AI segmentation models and high-resolution data extraction from complex TMA samples. We employed the CosMx SMI with the CosMx Human Whole Transcriptome (WTX) panel, which targets approximately 19,000 RNA targets, to analyze human FFPE tissue microarrays. Two FFPE TMAs—one with normal and the other with cancerous tissue—were constructed with cores from multiple organs including breast, skin, lung, colon, liver, prostate, and brain. RNA was detected in its native tissue context, and hematoxylin and eosin (H&amp;E) staining provided histological reference for spatial transcriptomics. Uniform Manifold Approximation and Projection (UMAP) and Leiden clustering were used for dimensionality reduction and cell type identification based on marker gene expression. Differential expression (DE) and pathway analyses identified molecular signatures and biological processes across tissue types. CosMx SMI achieved high cell counts per sample and precise segmentation, enabling reliable analysis of diverse tissue types. H&amp;E staining on the same slide enhanced AI algorithm training, improving tissue structure identification and segmentation accuracy. We identified distinct cell types and tissue-specific biomarkers. DE and pathway analysis revealed potential therapeutic targets and biomarkers, such as PSA, PSMA, AR, PTEN, and ERG fusion in prostate cancer, along with key pathways like AR signaling and DNA damage repair. Transcript profiles localized to specific cell types, demonstrating the platform's robustness in spatial transcriptomics. CosMx SMI significantly enhances single-cell transcriptome studies, providing detailed molecular insights across diverse tissue types. This platform is a powerful tool for tissue analysis, biomarker discovery, and spatial genomics, supporting a wide range of molecular and cellular research applications. -Bruker Confidential- Citation Format: Wei Yang, Isabel Lee, Michael Patrick, Yi Cui, Shanshan He, Martin Shelton, Haiyan Zhai, Michael Rhodes, Joseph Beechem. Whole transcriptome single cell spatial imaging of tumor vs normal tissue microarray [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2080.
Abstract 5275: A dynamic equilibrium of innate immune deaminases and deregulation in hematopoietic malignancies
Authors: Jane Marie Isquith, Inge Van der Werf, Jessica Pham, Thomas Whisenant, Ludmil Alexandrov, Catriona Jamieson
Journal: Cancer Research (2025)

Inflammatory cytokine responsive apolipoprotein B mRNA-editing enzyme, catalytic polypeptide (APOBEC3) cytosine deaminases have been shown to be deregulated during cancer evolution, presenting as gene expression changes and inclusion of distinct C-to-T mutation patterns. However, the exact mechanisms by which APOBEC3 enzymes promote cancer initiation and progression remain to be investigated, especially in hematopoietic malignancies. Building on our advanced sequencing data of healthy, pre-leukemic, and myeloproliferative neoplasm patient samples, we seek to uncover normal and malignant patterns of APOBEC3C overexpression in hematopoietic cells. Overexpression of lentiviral APOBEC3C in normal cord blood, healthy bone marrow, and myeloproliferative neoplasm (MPN) patient hematopoietic stem/progenitor cells (HSPCs) allows us to study the effects of deaminase dysregulation in the hematopoietic niche. These overexpression studies show novel differential gene expression changes, repetitive element alterations, RNA hyper-editing sites, and DNA mutation signatures induced by APOBEC3 mutagenesis. In addition to APOBEC3, we are exploring the upregulation of adenosine deaminase acting on RNA1 (ADAR1), as we have previously shown that these two innate immune deaminases are synchronously upregulated in the high-risk myelofibrosis (MF) stem cell population compared to normal aged bone marrow. We have discovered a co-regulatory relationship dependent on a delicate equilibrium between APOBEC3C and ADAR1, indicating a correlative association between the dysregulation of these essential deaminases and the initiation and progression of hematopoietic malignancies as indicated by survival statistics and gene expression changes. We will use this comprehensive study of innate immune deaminase deregulation to uncover predictive biomarkers and hallmarks of malignant transformation. Citation Format: Jane Marie Isquith, Inge Van der Werf, Jessica Pham, Thomas Whisenant, Ludmil Alexandrov, Catriona Jamieson. A dynamic equilibrium of innate immune deaminases and deregulation in hematopoietic malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5275.