tbuckley/cabot-search huggingface dataset:
Correction to: 2023 Scientific Sessions Abstract 14413
Journal: Circulation (2024)

a correction notice is needed.The Results section read: Of 2,922,522 individuals who met inclusion criteria, 998,234 (34%) were eligible for AOM (mean age, 49 years; 53% female).Of these, 30%, 41%, 18%, and 11% had a BMI (kg/m 2 ) of 27-29.9,30-34.9,35-39.9, and ≥40, respectively.Prior metabolic/bariatric surgery was seen in 2.3%.Musculoskeletal disorders (54%), dyslipidemia/hyperlipidemia (35%), and hypertension (32%) were the most common ORCs, with ≥2 ORCs observed in 58%.Prescription of any FDA-approved AOM was observed in only 1.2% of all eligible patients.Liraglutide 3.0 mg (58% of all AOM) was the most prescribed AOM.AOM prescriptions increased modestly with higher BMI, ORC burden, and number of CVD risk factors (Figure).Among those with prior MACE (11%), 1.5% (1.0% if without T2DM) were prescribed FDAapproved AOM.It has been updated to read: Of 2,469,473 individuals who met inclusion criteria, 1,111,396 (44%) were eligible for AOM (mean age, 54 years; 57% female).Of these, 31%, 41%, 17%, and 11% had a BMI (kg/m 2 ) of 27-29.9,30-34.9,35-39.9, and ≥40, respectively.Prior metabolic/bariatric surgery was seen in 1%.Musculoskeletal disorders (54%), dyslipidemia/hyperlipidemia (36%), and hypertension (35%) were the most common ORCs, with ≥2 ORCs observed in 62%.Prescription of any FDA-approved AOM was observed in only 1.4% of all eligible patients.Liraglutide 3.0 mg (46% of all AOM) was the most prescribed AOM.AOM prescriptions increased modestly with higher BMI, ORC burden, and number of CVD risk factors (Figure).Among those with prior MACE (9%), 1.2% (1.0% if without T2DM) were prescribed FDA-approved AOM.
Oral decitabine and cedazuridine plus venetoclax for older or unfit patients with acute myeloid leukaemia: a phase 2 study
Authors: Alexandre Bazinet, Guillermo Garcia-Manero, Nicholas Short, Yesid Alvarado, Alex Bataller, Tareq Abuasab, Rabiul Islam, Kathryn Montalbano, Ghayas Issa, Abhishek Maiti, Musa Yilmaz, Nitin Jain, Lucia Masarova, Steven Kornblau, Elias Jabbour, Guillermo Montalban-Bravo, Caitlin R Rausch, Sherry Pierce, Courtney D DiNardo, Tapan Kadia, Naval Daver, Marina Konopleva, Xuelin Huang, Hagop Kantarjian, Farhad Ravandi
Journal: The Lancet Haematology (2024)
Abstract B098: Impact of dexamethasone on chemotherapy response in ovarian cancer
Authors: Annapoorna Venkatachalam, Cristina Correia, Cordelia Mcgehee, Sarah Finstuen-Magro, Paula A. Schneider, Rachel Hurley, Kevin L. Peterson, Ethan Heinzen, Melissa C. Larson, Xiaonon Hou, Ann L. Oberg, Saravut Weroha, Scott H. Kaufmann
Journal: Cancer Research (2024)

Abstract Background: Ovarian cancer ranks fifth in cancer deaths among women. The gold standard of care for advanced disease includes cytoreductive surgery along with adjuvant or neoadjuvant platinum/taxane-based chemotherapy. Although response to this treatment is high, chemotherapy-induced nausea and vomiting due to platinum agents and allergic reactions due to both agents are common. For nearly half a century, the glucocorticoid (GC) dexamethasone (DEX) has been administered as part of supportive care. However, there have periodically been questions about the possible deleterious effects of DEX on chemotherapy response, especially in solid tumors. Methods: Platinum-sensitive, glucocorticoid receptor (GRa) expressing ovarian cancer cells were exposed to DEX prior to chemotherapy and clonogenic survival was assessed. The effects of DEX on cell cycle and apoptosis were assessed by flow cytometry. Changes in the tumor cell transcriptome after acute DEX treatment were determined by RNA sequencing. Mice bearing orthotopic ovarian cancer patient-derived xenografts (PDXs) were treated with chemotherapy ± DEX to assess changes in chemotherapy response in vivo. Findings: DEX pre-treatment decreased platinum cytotoxicity in ovarian cancer cell lines in vitro and diminished platinum response in some PDXs analyzed for chemotherapy response ex vivo. RNA-seq analysis revealed changes in transcripts encoding proteins involved in platinum detoxification and TNFa pro-survival signaling. In ovarian cancer PDXs, DEX decreased platinum response in one model and had limited impact on both platinum and platinum/taxane chemotherapy in three distinct studies. Interpretation: DEX appears to modulate chemotherapy response in some settings in vitro and ex-vivo. The impact of DEX on chemotherapy response in vivo appears to be limited. However, further investigation of this question in vivo in non-immunosuppressed murine models appears warranted. Citation Format: Annapoorna Venkatachalam, Cristina Correia, Cordelia Mcgehee, Sarah Finstuen-Magro, Paula A. Schneider, Rachel Hurley, Kevin L. Peterson, Ethan Heinzen, Melissa C. Larson, Xiaonon Hou, Ann L. Oberg, Saravut Weroha, Scott H. Kaufmann. Impact of dexamethasone on chemotherapy response in ovarian cancer [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 B098.
Abstract B097: Image analysis-guided spatial transcriptomics improves recognition of biological features important for outcome in high grade serous carcinoma
Authors: Anna R. Laury, Shuyu Zheng, Niina Aho, Robin Fallegger, Satu M. Hänninen, Julio Saez Rodriguez, Jovan Tanevski, Omar Youssef, Jing Tang, Olli Carpén
Journal: Cancer Research (2024)

Abstract High-grade serous ovarian carcinoma (HGSC) is characterized by late presentation, frequent recurrence, and treatment resistance. Our understanding of this disease is limited, partly due to considerable tumor heterogeneity, which is reflected in the variable tumor morphology. Beyond the diagnosis itself, no particular histologic features have proven sensitive or specific enough for use in clinical practice. Image analysis based deep learning models are now able to extract new information from standard H&amp;E pathology slides, though biological interpretation of the regions detected by artificial intelligence (AI) remains a challenge. In this work, we interrogate the molecular features of tissue regions identified as being highly associated with patient outcome by a deep-learning based AI classification model. We determined the spatial transcriptomic profiles of these regions in 16 patients and compared them to the profiles of background tumor regions not selected by the AI model. We used multiple methods to characterize the regions types, including: differential gene expression, UMAP distances, machine learning-based outcome prediction, pathway enrichment, and spatial organization analyses. We find that regions identified by the AI-based model are significantly different from background tumor regions, and that their transcriptomic profiles are more predictive of patient outcome. We determine the differential signaling pathways and validate a representative transcript using RNA in-situ hybridization. We show that AI-detected regions in poor prognosis tumors have upregulated JUN expression, and are characterized by tumor cell subpopulations with a stress-associated transcriptomic signature. In contrast, spatial pattern analyses show that AI-detected regions in tumors with better outcome are typified by macrophage and plasma cell depleted DNA repair-signature tumor cell subpopulations. The synergy of spatial transcriptomic and image analysis data in our study offers a promising strategy to enhance clinical translation by establishing a more interpretable AI model. Citation Format: Anna R. Laury, Shuyu Zheng, Niina Aho, Robin Fallegger, Satu M. Hänninen, Julio Saez Rodriguez, Jovan Tanevski, Omar Youssef, Jing Tang, Olli Carpén. Image analysis-guided spatial transcriptomics improves recognition of biological features important for outcome in high grade serous carcinoma [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 B097.
Abstract B076: Targeting cancer glycomes sensitizes ovarian tumors to immunotherapy
Authors: Hao Nie, Pratima Saini, Heng Liu, Wei Zhou, Chen Wang, Daniel Claiborne, Nan Zhang, Mohamed Abdel-Mohsen, Rugang Zhang
Journal: Cancer Research (2024)

Abstract Aberrant glycans on tumor cell surface contribute to immune escape. The purpose of this study is to establish novel immunotherapeutic strategies for HGSOC tumors by targeting glycans-mediated immune escape in high-grade serous ovarian cancer (HGSOC). Here, we performed in vivo screens targeting 96 glycan structures among a series of mouse HGSOC tumors with different genotypes. We identified β1, 6-GlcNAc branched N-glycan as a major determinant of immune escape in a homologous recombination (HR)-proficiency dependent manner in HGSOCs. Mechanistically, BRCA1/2 transcriptionally suppresses the expression of MGAT5 that produces β1, 6-GlcNAc branched glycans. Using in vitro T cell killing assay, we observed that removal of β1, 6-GlcNAc branched glycans by a small molecule inhibitor or genetically knocking down MGAT5, sensitizes HR-proficient human HGSOC cells to T cells assault. Consistently, using orthotopic syngeneic mouse models, we observed that inhibition of β1, 6-GlcNAc branched glycans sensitizes and synergizes with anti-PD-L1 in HR-proficient, but not HR-deficient HGSOCs. In summary, we identified β1, 6-GlcNAc branched N-glycan as a key mediator of immune escape in HR-proficient HGSOCs. Our findings indicate that MGAT5 represents a therapeutic target to overcome immune escape in a HR-status dependent manner and inhibition of β1, 6-GlcNAc branched glycans sensitizes HR-proficient HGSOCs to immune checkpoint blockades. Citation Format: Hao Nie, Pratima Saini, Heng Liu, Wei Zhou, Chen Wang, Daniel Claiborne, Nan Zhang, Mohamed Abdel-Mohsen, Rugang Zhang. Targeting cancer glycomes sensitizes ovarian tumors to immunotherapy [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 B076.
Abstract IA009: Epigenetic approaches to endometriosis-associated ovarian cancer
Authors: Rugang Zhang
Journal: Cancer Research (2024)

Abstract The past decade has brought unprecedented progress in understanding the genetics of epithelial ovarian cancer (EOC), but cures remain elusive due to the lack of insights into mechanisms that can be leveraged to develop new therapies. EOC is genetically heterogeneous and, therefore, it is imperative that therapeutic strategies become personalized by targeting distinct molecular subsets of EOC. Despite the importance of epigenetic regulators in EOC, the mechanism of action for these epigenetic regulators and the associated vulnerabilities exposed by their dysregulations have remained elusive for most of them. Here we will discuss our recent work on how to leverage epigenetic mechanisms to address unmet clinical needs in endometriosis-associated ovarian cancer through integrated approaches. Citation Format: Rugang Zhang. Epigenetic approaches to endometriosis-associated ovarian cancer [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 IA009.
Abstract IA008: Rare ovarian cancers: the sequelae of specific interactions between cell contexts mutations and microenvironments
Authors: David Huntsman
Journal: Cancer Research (2024)

Abstract There are many pathologically and clinically distinct types of ovarian cancer and uterine cancers. These are not flavors of the same disease nor can they be solely explained by different mutations or other genomic findings; rather each may be thought to represent distinct interactions between cells of origin, mutations, and the microenvironment in which these cancers occur. Although many know gaps remain this may explain many curious features of these cancers. Fors instance, how endometrioid and clear cell carcinomas have similar mutations yet are distinct biologic and clinical entities. Also, why they occur at similar rates from ovarian endometriomas, yet clear cell cancers are much rarer in the endometrium. As an example of the importance microenvironment, findings will be presented suggesting that expression of Cystathionine gamma-lyase (CTH or CSE), a key enzyme within the transsulfuration pathway, enables CCC precursor cells to survive in endometriotic cysts becoming a defining feature of this cancer, one that may explain its biologic properties, aggressive course and relative chemoresistance. Other cancers will be considered using this model including rare stromal cancers. Citation Format: David Huntsman. Rare ovarian cancers: the sequelae of specific interactions between cell contexts mutations and microenvironments [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 IA008.
Abstract IA003: Advancing novel therapeutics through reverse translation
Authors: Sarah F. Adams
Journal: Cancer Research (2024)

Abstract Background: The established paradigm for cancer drug development was designed to advance cytotoxic agents targeting tumor cells. An increased appreciation of the role of the tumor microenvironment in treatment efficacy and disease outcomes has identified tumor-extrinsic therapeutic targets. The different mechanisms of action employed by anti-angiogenic drugs or immunotherapeutics highlight the need for updated study endpoints to identify the maximally effective dose for clinical applications. These advances, and the translation of novel therapeutics, can be accelerated through reverse translation, a term used to describe research using patient samples to inform mechanistic studies – going from bedside-to-bench. Objective: To present an example of reverse translation in the development of an immune therapy combination for ovarian cancer. Preclinical studies demonstrated therapeutic synergy of CTLA4 immune checkpoint blockade and poly(ADP ribose) polymerase (PARP) inhibition in high grade serous ovarian cancer models. These results were translated to two clinical trials for the treatment of recurrent ovarian cancer. Tumor samples from study subjects have been collected to support ongoing mechanistic investigations and exploratory biomarker studies. Both targeted and unbiased approaches identified candidate biomarkers of response to treatment for further development. Ongoing mechanistic studies are examining the significance of top prognostic markers. Conclusions: Strategies are needed to support the integration of translational studies with clinical research to inform next generation trials and to optimize clinical applications of novel therapeutics. Citation Format: Sarah F. Adams. Advancing novel therapeutics through reverse translation [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 IA003.
Abstract IA005: Regional combating of immunosuppressive forces in the ovarian tumor microenvironment
Authors: Daniel J. Powell
Journal: Cancer Research (2024)

Abstract The accumulation of intraepithelial T cells in ovarian cancer is prognostic for increased survival while the accumulation of immunosuppressive cells, such as tumor associated macrophages, are associated with poor outcomes. These clinical findings provide the rationale for the development of immunotherapeutic approaches that locally augment T cell responses while circumventing immunosuppressive forces. Clinical trials of systemic immunotherapy have shown encouraging clinical responses in a subset of treated patients; however tumor regression does not occur in most treated patients, some patients experience immune related adverse effects and patients with immunologically cold tumors are unlikely to respond. One central objective of researchers is to understand the basis of natural immune recognition and to use this knowledge to rationally bolster anti-tumor immunity. One modality to augment anti-cancer immunity is to administer adoptive T cell therapy (ACT), thereby increasing the net number of tumor-reactive T cells in a patient. While ACT is effective and approved for the treatment of various hematological cancers, there is no approved immunotherapeutic agent for the treatment of ovarian cancer, including ACT. With significant advances in synthetic biology and large-scale cell manufacturing, it is now possible to generate patient-specific T cell products that specifically recognize and kill antigen expressing cancer cells; to outfit those T cells with supraphysiological properties that overcome immunosuppressive forces in the tumor microenvironment; and to safely promote local recruitment of endogenous T cell responses to markedly enhance the overall immune response against ovarian cancer. Using these techniques, overexpressed antigens can be targeted, immunosuppressive tumor associated macrophages can be selectively eliminated, the tumor microenvironment can be polarized to an inflammatory state, endogenous T cell recruited, and T cells made to proliferate robustly at the tumor site in response to tumor recognition. This knowledge and these approaches provide a guidepost and the infrastructure to begin creating safe and effective immunotherapy for ovarian cancer. Citation Format: Daniel J. Powell. Regional combating of immunosuppressive forces in the ovarian tumor microenvironment [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 IA005.
Mental health outcomes in patients with moderate to severe psoriasis treated with bimekizumab: Analysis of phase 2/3 randomized trials
Authors: Andrew Blauvelt, April Armstrong, Joseph F. Merola, Bruce Strober, Dirk de Cuyper, Luke Peterson, Owen Davies, Jeffrey L. Stark, Mark Lebwohl
Journal: Journal of the American Academy of Dermatology (2024)

BackgroundPatients with psoriasis have increased risk of suicidal ideation and behavior (SIB) and depression. Bimekizumab, a biologic that inhibits interleukin (IL)-17A and IL-17F, received Food and Drug Administration approval in 2023 for moderate to severe plaque psoriasis, following 2021 European Medicines Agency approval.ObjectiveTo report SIB and depression in patients with moderate to severe psoriasis treated in bimekizumab clinical trials.MethodsMental health changes, including neuropsychiatric events, were actively monitored across 9 bimekizumab clinical trials in psoriasis phase 2/3 trials. The patient-reported electronic Columbia-Suicide Severity Rating Scale (measuring SIB) and Patient Health Questionnaire-9 (measuring depression) were administered, monitored by an independent Neuropsychiatric Adjudication Committee.ResultsThroughout 7166 patient-years (PY) of bimekizumab exposure, the adjudicated SIB rate was 0.13/100PY; SIB ranges for the general psoriasis population and patients receiving anti-IL-17A/anti-IL-23 therapies are 0.09 to 0.54/100PY and 0.09 to 0.19/100PY, respectively. At week 16, 92.9% vs 81.1% of bimekizumab- vs placebo-treated patients had no/minimal depression. Newonset positive electronic Columbia-Suicide Severity Rating Scale responses and mean Patient Health Questionnaire-9 scores were low for bimekizumab-treated patients.LimitationsPatient exclusion for significant/severe prespecified SIB/depression history.ConclusionThe long-term adjudicated SIB rate with bimekizumab was low and within ranges reported in the general psoriasis patient population and psoriasis patients treated with anti-IL-17A/anti-IL-23 biologics. Screening/monitoring questionnaires reported low SIB and depression levels.
Relationship experiences of transgender and non-binary adults: exploring dating goals, relationship structures, minority stress, sexual fetishization, and relationship victimization
Authors: Jazmine Perez, Christopher A. Pepping
Journal: International Journal of Transgender Health (2024)

Objective Here we investigate the relationship experiences of TNB individuals, with a particular focus on (1) relationship status and structure; (2) dating motivations and dating app use; (3) minority stress in relational contexts, including rates and experiences of fetishization, and minority stress-related difficulties in relationship formation and maintenance; (4) rates of relationship violence, victimization, and online harassment; and (5) relationship outcomes, namely sexual and relationship satisfaction.
The International Association for the Study of Lung Cancer Lung Cancer Staging Project: Proposals for Revision of the TNM Stage Groups in the Forthcoming (Ninth) Edition of the TNM Classification for Lung Cancer
Authors: Ramón Rami-Porta, Katherine K Nishimura, Dorothy J Giroux, Frank Detterbeck, Giuseppe Cardillo, John G Edwards, Kwun M Fong, Meredith Giuliani, James Huang, Kemp H Kernstine, Edith M Marom, Andrew G Nicholson, Paul E Van Schil, William D Travis, Ming S Tsao, Shun-Ichi Watanabe, Valerie W Rusch, Hisao Asamura
Journal: Journal of Thoracic Oncology (2024)
Safety and Efficacy of Efruxifermin in Combination With a GLP-1 Receptor Agonist in Patients With NASH/MASH and Type 2 Diabetes in a Randomized Phase 2 Study
Authors: Stephen A. Harrison, Juan P. Frias, K. Jean Lucas, Gary Reiss, Guy Neff, Sureka Bollepalli, Yan Su, Doreen Chan, Erik J. Tillman, Ali Moulton, Brittany de Temple, Arian Zari, Reshma Shringarpure, Timothy Rolph, Andrew Cheng, Kitty Yale
Journal: Clinical Gastroenterology and Hepatology (2024)

Background & AimsIn phase 2 studies, efruxifermin, an Fc–FGF21 analog, significantly reduced steatohepatitis and fibrosis in patients with non-alcoholic steatohepatitis, now called metabolic dysfunction-associated steatohepatitis (MASH), for which there is no approved treatment. Type 2 diabetes (T2D) and obesity are prevalent among patients with MASH and increasingly treated with glucagon-like peptide-1 receptor agonists (GLP-1RAs). This study evaluated the safety and efficacy of efruxifermin in patients with MASH, fibrosis, and T2D taking a GLP-1RA.MethodsCohort D was a double-blind, placebo-controlled, phase 2b study in adults with T2D and MASH with fibrosis (F1–F3) on stable GLP-1RA therapy randomized (2:1) to receive efruxifermin 50 mg or placebo, once weekly for 12 weeks. The primary endpoint was safety and tolerability of efruxifermin added to a stable dose of GLP-1RA. Secondary endpoints included changes in hepatic fat fraction (HFF), markers of liver injury and fibrosis, and metabolic parameters.ResultsAdults (N = 31) with T2D and MASH fibrosis (F1–F3) on a stable GLP-1RA (semaglutide, 48.4%; dulaglutide, 45.2%; liraglutide, 6.5%) received efruxifermin 50 mg (n = 21) or placebo (n = 10) for 12 weeks. The addition of efruxifermin to a GLP-1RA appeared safe and well-tolerated. The most frequent efruxifermin-related adverse events were mild to moderate gastrointestinal events. One patient receiving efruxifermin discontinued due to nausea, and another withdrew consent. There were no treatment-related serious adverse events. After 12 weeks, efruxifermin reduced HFF by 65% (P < .0001 vs placebo) compared with a 10% reduction for placebo (GLP-1RA alone). Efruxifermin also improved noninvasive markers of liver injury, fibrosis, glucose, and lipid metabolism while maintaining GLP-1RA–mediated weight loss.ConclusionsThe tolerability profile of efruxifermin added to GLP-1RA appeared comparable to that of either drug alone, while also significantly reducing HFF and noninvasive markers of fibrosis in patients with MASH and T2D. Liver health in patients already on a GLP-1RA may be further improved by addition of efruxifermin. Clinicaltrials.gov, Number: NCT05039450.Graphical abstract