bluuebunny/crossref_metadata_2025 huggingface dataset:
Supplementary Figure S14 from Integrated Genomic and Transcriptomic Analysis Improves Disease Classification and Risk Stratification of MDS with Ring Sideroblasts
Authors: Todisco Gabriele , Creignou Maria , Bernard Elsa , Björklund Ann-Charlotte , Moura Pedro Luis , Tesi Bianca , Mortera-Blanco Teresa , Sander Birgitta , Jansson Monika , Walldin Gunilla , Barbosa Indira , Reinsbach Susanne E. , Hofman Isabel Juliana , Nilsson Christer , Yoshizato Tetsuichi , Dimitriou Marios , Chang David , Olafsdottir Svannildur , Venckute Larsson Sigita , Tobiasson Magnus , Malcovati Luca , Woll Petter , Jacobsen Sten Eirik W. , Papaemmanuil Elli , Hellström-Lindberg Eva
Published: October 2023

The proportion of estimated erythroblast-like cells correlate positively with the percentage of RS in BM smears.
Supplementary Figure S13 from Integrated Genomic and Transcriptomic Analysis Improves Disease Classification and Risk Stratification of MDS with Ring Sideroblasts
Authors: Todisco Gabriele , Creignou Maria , Bernard Elsa , Björklund Ann-Charlotte , Moura Pedro Luis , Tesi Bianca , Mortera-Blanco Teresa , Sander Birgitta , Jansson Monika , Walldin Gunilla , Barbosa Indira , Reinsbach Susanne E. , Hofman Isabel Juliana , Nilsson Christer , Yoshizato Tetsuichi , Dimitriou Marios , Chang David , Olafsdottir Svannildur , Venckute Larsson Sigita , Tobiasson Magnus , Malcovati Luca , Woll Petter , Jacobsen Sten Eirik W. , Papaemmanuil Elli , Hellström-Lindberg Eva
Published: October 2023

Digital sorting analysis on bulk CD34+ MNC transcriptome from MDSRS+ cases. Plots refer to unfiltered data, i.e. including hematopoietic stem/progenitor and mature hematopoietic cells. CMP, common myeloid progenitors; EryP, erythroid precursors; GMP, granulocyte–monocyte progenitors; Gran, granulocytes; HSC, hematopoietic stem cells; Lymph, lymphocytes; MK, megakaryocytes; MLP, multi-lymphoid progenitors; MPP, multipotent progenitors; MEP, megakaryocyte-erythroid progenitors). Cases (x-axis) are sorted by decreasing estimated MEP abundance, showing enriched IMP signature in cases with MEP depletion on right-side of the plots.
Supplementary Figure S4 from Neoantigen Targetability in Progressive Advanced Melanoma
Authors: van den Bulk Jitske , Verdegaal Els M.E. , van der Ploeg Manon , Visser Marten , Nunes Joana B. , de Ru Arnoud H. , Tjokrodirijo Rayman T.N. , Ijsselsteijn Marieke E. , Janssen Natasja I. , van der Breggen Ruud , de Bruin Linda , de Kok Pita , Janssen George M.C. , Ruano Dina , Kapiteijn Ellen H.W. , van Veelen Peter A. , de Miranda Noel F.C.C. , van der Burg Sjoerd H.
Published: October 2023

HLA class II expression and recognition of early and later metastatic lesion- derived tumor cells
from patient Mel5 by CD4+ and CD8⁺ T cells.
Supplementary Figure S1 from Neoantigen Targetability in Progressive Advanced Melanoma
Authors: van den Bulk Jitske , Verdegaal Els M.E. , van der Ploeg Manon , Visser Marten , Nunes Joana B. , de Ru Arnoud H. , Tjokrodirijo Rayman T.N. , Ijsselsteijn Marieke E. , Janssen Natasja I. , van der Breggen Ruud , de Bruin Linda , de Kok Pita , Janssen George M.C. , Ruano Dina , Kapiteijn Ellen H.W. , van Veelen Peter A. , de Miranda Noel F.C.C. , van der Burg Sjoerd H.
Published: October 2023

Immunohistochemical staining of proteins involved in T cell recognition and/or inhibition.
Supplementary Table S1 from Patient-Specific Targeting of the T-Cell Receptor Variable Region as a Therapeutic Strategy in Clonal T-Cell Diseases
Authors: Lucero Olivia M. , Lee Ji-Ann , Bowman Jenna , Johnson Kara , Sapparapu Gopal , Thomas John K. , Fan Guang , Chang Bill H. , Thiel-Klare Karina , Eide Christopher A. , Okada Craig , Palazzolo Mike , Lind Evan , Kosaka Yoko , Druker Brian J. , Lydon Nicholas , Bowers Peter M.
Published: October 2023

Supplementary Table S1. (A) List of published datasets used to compile the distribution of TCRVB Gene Usage across T-cell NHL. (B) TCR Vβ usage in 314 patients with T-cell
NHL by disease type. Note that both the IMGT and Wei et al nomenclature are listed.
Supplementary Methods S1 from Patient-Specific Targeting of the T-Cell Receptor Variable Region as a Therapeutic Strategy in Clonal T-Cell Diseases
Authors: Lucero Olivia M. , Lee Ji-Ann , Bowman Jenna , Johnson Kara , Sapparapu Gopal , Thomas John K. , Fan Guang , Chang Bill H. , Thiel-Klare Karina , Eide Christopher A. , Okada Craig , Palazzolo Mike , Lind Evan , Kosaka Yoko , Druker Brian J. , Lydon Nicholas , Bowers Peter M.
Published: October 2023

Supplementary Methods
Table S1 from HDACi-dependent Microenvironmental Normalization Overcomes Tumor Burden–induced T-cell Exhaustion
Authors: Nguyen Andrew , Brown Dominique , Krishnan Ramya , Bastin Donald , Deng Li , Chen Lan , Salem Omar , Walsh Scott R. , Bramson Jonathan L. , Wan Yonghong
Published: October 2023

Table S1: Gene lists of T cell signatures
Supplementary Figure S5 from Patient-Specific Targeting of the T-Cell Receptor Variable Region as a Therapeutic Strategy in Clonal T-Cell Diseases
Authors: Lucero Olivia M. , Lee Ji-Ann , Bowman Jenna , Johnson Kara , Sapparapu Gopal , Thomas John K. , Fan Guang , Chang Bill H. , Thiel-Klare Karina , Eide Christopher A. , Okada Craig , Palazzolo Mike , Lind Evan , Kosaka Yoko , Druker Brian J. , Lydon Nicholas , Bowers Peter M.
Published: October 2023

Supplementary Figure 5. αVβ monoclonal antibodies induce target T-cell activation, characterized by down modulation of the TCR complex
Figure S4 from HDACi-dependent Microenvironmental Normalization Overcomes Tumor Burden–induced T-cell Exhaustion
Authors: Nguyen Andrew , Brown Dominique , Krishnan Ramya , Bastin Donald , Deng Li , Chen Lan , Salem Omar , Walsh Scott R. , Bramson Jonathan L. , Wan Yonghong
Published: October 2023

Figure S4: HAVCR2/DUSP22-pathway correlation
Supplementary Figure S2 from Patient-Specific Targeting of the T-Cell Receptor Variable Region as a Therapeutic Strategy in Clonal T-Cell Diseases
Authors: Lucero Olivia M. , Lee Ji-Ann , Bowman Jenna , Johnson Kara , Sapparapu Gopal , Thomas John K. , Fan Guang , Chang Bill H. , Thiel-Klare Karina , Eide Christopher A. , Okada Craig , Palazzolo Mike , Lind Evan , Kosaka Yoko , Druker Brian J. , Lydon Nicholas , Bowers Peter M.
Published: October 2023

Supplementary Figure S2: The binding specificity of αVβ monoclonal antibodies.
Supplementary Figure S1 from Patient-Specific Targeting of the T-Cell Receptor Variable Region as a Therapeutic Strategy in Clonal T-Cell Diseases
Authors: Lucero Olivia M. , Lee Ji-Ann , Bowman Jenna , Johnson Kara , Sapparapu Gopal , Thomas John K. , Fan Guang , Chang Bill H. , Thiel-Klare Karina , Eide Christopher A. , Okada Craig , Palazzolo Mike , Lind Evan , Kosaka Yoko , Druker Brian J. , Lydon Nicholas , Bowers Peter M.
Published: October 2023

Supplementary Figure S1. Immunophenotype of Patient’s T-LGL cells.
Supplementary Figure 1 from Efficacy and Safety of Stereotactic Body Radiotherapy Combined with Camrelizumab and Apatinib in Patients with Hepatocellular Carcinoma with Portal Vein Tumor Thrombus
Authors: Hu Yue , Zhou Min , Tang Jing , Li Shuang , Liu Hongli , Hu Jianli , Ma Hong , Liu Junli , Qin Tingting , Yu Xiongjie , Chen Yongshun , Peng Jin , Zou Yanmei , Zhang Tao , Xue Jun
Published: October 2023

Supplementary Figure 1. Study time frame.
Supplementary Data 1 from Molecular Results and Potential Biomarkers Identified from the Phase 3 MILO/ENGOT-ov11 Study of Binimetinib versus Physician Choice of Chemotherapy in Recurrent Low-Grade Serous Ovarian Cancer
Authors: Grisham Rachel N. , Vergote Ignace , Banerjee Susana , Drill Esther , Kalbacher Elsa , Mirza Mansoor Raza , Romero Ignacio , Vuylsteke Peter , Coleman Robert L. , Hilpert Felix , Oza Amit M. , Westermann Anneke , Oehler Martin K. , Pignata Sandro , Aghajanian Carol , Colombo Nicoletta , Cibula David , Moore Kathleen N. , del Campo Josep M. , Berger Regina , Marth Christian , Sehouli Jalid , O'Malley David M. , Churruca Cristina , Kristensen Gunnar , Clamp Andrew , Farley John , Iyer Gopa , Ray-Coquard Isabelle , Monk Bradley J.
Published: October 2023

Supplementary Tables and Figures
Supplementary Figure S4 from Anlotinib in Locally Advanced or Metastatic Radioiodine-Refractory Differentiated Thyroid Carcinoma: A Randomized, Double-Blind, Multicenter Phase II Trial
Authors: Chi Yihebali , Zheng Xiangqian , Zhang Yuan , Shi Feng , Cheng Ying , Guo Zhuming , Ge Minghua , Qin Jianwu , Zhang Jiewu , Li Zhendong , Zhou Xiaohong , Huang Rui , Chen Xiaohong , Liu Hui , Cheng Ruochuan , Xu Zhengang , Li Dapeng , Tang Pingzhang , Gao Ming
Published: October 2023

(A) The Kaplan-Meier curve of overall survival (OS) in the per protocol set. (B) The Kaplan-Meier curve of OS adjusted by a two-stage estimation method based on the rank preserving structural failure time (RPSFT) model. The tick marks indicate censored data.
Supplementary Figure S2 from Anlotinib in Locally Advanced or Metastatic Radioiodine-Refractory Differentiated Thyroid Carcinoma: A Randomized, Double-Blind, Multicenter Phase II Trial
Authors: Chi Yihebali , Zheng Xiangqian , Zhang Yuan , Shi Feng , Cheng Ying , Guo Zhuming , Ge Minghua , Qin Jianwu , Zhang Jiewu , Li Zhendong , Zhou Xiaohong , Huang Rui , Chen Xiaohong , Liu Hui , Cheng Ruochuan , Xu Zhengang , Li Dapeng , Tang Pingzhang , Gao Ming
Published: October 2023

The Kaplan-Meier curve of progress-free PFS in the Per-Protocol Set. The tick marks indicate censored data.
Supplementary Figure S5 from Axicabtagene Ciloleucel in Combination with the 4–1BB Agonist Utomilumab in Patients with Relapsed/Refractory Large B-Cell Lymphoma: Phase 1 Results from ZUMA-11
Authors: Jain Michael D. , Miklos David B. , Jacobson Caron A. , Timmerman John M. , Sun Jennifer , Nater Jenny , Fang Xiang , Patel Ankit , Davis Madison , Heeke Darren , Trinh Tan , Mattie Mike , Neumann Frank , Kim Jenny J. , To Christina , Filosto Simone , Reshef Ran
Published: October 2023

Ex vivo Axi-cel Proliferation After Stimulation With Utomilumab
Table S1-S8 from Urinary Tumor DNA MRD Analysis to Identify Responders to Neoadjuvant Immunotherapy in Muscle-invasive Bladder Cancer
Authors: Zhang Ruiyun , Zang Jingyu , Jin Di , Xie Feng , Shahatiaili Akezhouli , Wu Guangyu , Zhang Lu , Wang Lu , Zhang Yue , Zhao Zhixin , Du Pan , Jia Shidong , Fan Jinhai , Zhuang Guanglei , Chen Haige
Published: October 2023

Table S1. Clinicopathological characteristics of 20 patients in our study.
Table S2. Representativeness of study participants.
Table S3. Adverse events associated with toripalimab.
Table S4. SNVs and InDels of therapy-naïve neoplastic tissues detected by whole exome sequencing.
Table S5. SNVs and InDels of basal urine samples detected by whole exome sequencing.
Table S6. SNVs and InDels detected by personalized MRD panel sequencing.
Table S7. SNVs and InDels detected by the fixed actionable/hotspot panel sequencing.
Table S8. Mutational measurements of each urine/plasma sample in our study.
Supplementary Figure S3 from Axicabtagene Ciloleucel in Combination with the 4–1BB Agonist Utomilumab in Patients with Relapsed/Refractory Large B-Cell Lymphoma: Phase 1 Results from ZUMA-11
Authors: Jain Michael D. , Miklos David B. , Jacobson Caron A. , Timmerman John M. , Sun Jennifer , Nater Jenny , Fang Xiang , Patel Ankit , Davis Madison , Heeke Darren , Trinh Tan , Mattie Mike , Neumann Frank , Kim Jenny J. , To Christina , Filosto Simone , Reshef Ran
Published: October 2023

Patient Disposition
Supplementary Table S5 from Targeting Hedgehog Signaling with Glasdegib in Patients with Refractory Sclerotic Chronic GVHD: A Report of Two Phase I/II Trials
Authors: Rodríguez-Arbolí Eduardo , Lee Catherine J. , Caballero-Velázquez Teresa , Martínez Carmen , García-Calderón Clara , Jiménez-León María Reyes , Bermúdez-Rodríguez María Aránzazu , López-Corral Lucía , Triguero Ana , Onstad Lynn , Horwitz Mitchell E. , Sarantopoulos Stefanie , Lee Stephanie J. , Pérez-Simón José Antonio
Published: October 2023

Representativeness of study participants
Supplementary Table S4 from Targeting Hedgehog Signaling with Glasdegib in Patients with Refractory Sclerotic Chronic GVHD: A Report of Two Phase I/II Trials
Authors: Rodríguez-Arbolí Eduardo , Lee Catherine J. , Caballero-Velázquez Teresa , Martínez Carmen , García-Calderón Clara , Jiménez-León María Reyes , Bermúdez-Rodríguez María Aránzazu , López-Corral Lucía , Triguero Ana , Onstad Lynn , Horwitz Mitchell E. , Sarantopoulos Stefanie , Lee Stephanie J. , Pérez-Simón José Antonio
Published: October 2023

Baseline absolute counts and relative distributions of key immune cell subpopulations in patients included in the GETH trial and healthy controls
Supplementary Table S3 from Targeting Hedgehog Signaling with Glasdegib in Patients with Refractory Sclerotic Chronic GVHD: A Report of Two Phase I/II Trials
Authors: Rodríguez-Arbolí Eduardo , Lee Catherine J. , Caballero-Velázquez Teresa , Martínez Carmen , García-Calderón Clara , Jiménez-León María Reyes , Bermúdez-Rodríguez María Aránzazu , López-Corral Lucía , Triguero Ana , Onstad Lynn , Horwitz Mitchell E. , Sarantopoulos Stefanie , Lee Stephanie J. , Pérez-Simón José Antonio
Published: October 2023

Monoclonal antibodies used in the phosphoflow analyses of T-cell activation signaling pathways
Supplementary Figure S3 from Targeting Hedgehog Signaling with Glasdegib in Patients with Refractory Sclerotic Chronic GVHD: A Report of Two Phase I/II Trials
Authors: Rodríguez-Arbolí Eduardo , Lee Catherine J. , Caballero-Velázquez Teresa , Martínez Carmen , García-Calderón Clara , Jiménez-León María Reyes , Bermúdez-Rodríguez María Aránzazu , López-Corral Lucía , Triguero Ana , Onstad Lynn , Horwitz Mitchell E. , Sarantopoulos Stefanie , Lee Stephanie J. , Pérez-Simón José Antonio
Published: October 2023

Fold change from baseline in the absolute count of circulating B cells (C1D1: n=13 responders [R], n=6 non-responders [NR]; C2D1: n=13 R, n=6 NR; C4D1: n=12 R, n=4 NR) (A), naive B cells (C1D1: n=11 R, n=6 NR; C2D1: n=11 R, n=5 NR; C4D1: n=11 R, n=4 NR) (B), unswitched memory B cells cells (C1D1: n=12 R, n=5 NR; C2D1: n=12 R, n=4 NR; C4D1: n=11 R, n=3 NR) (C) and switched memory B cells (C1D1: n=13 R, n=6 NR; C2D1: n=13 R, n=5 NR; C4D1: n=12 R, n=4 NR) (D). E) Fold change in CD268 (BAFF) expression on B cells (C1D1: n=13 R, n=6 NR; C2D1: n=13 R, n=5 NR; C4D1: n=12 R, n=3 NR). MFI normalised ratios were used for expression quantification. MFI, median fluorescence intensity; n.s., non-statistically significant.
Data from Memory-like differentiation, tumor targeting monoclonal antibodies, and chimeric antigen receptors enhance natural killer cell responses to head and neck cancer
Authors: Jacobs Miriam T. , Wong Pamela , Zhou Alice Y. , Becker-Hapak Michelle , Marin Nancy D. , Marsala Lynne , Foster Mark , Foltz Jennifer A. , Cubitt Celia C. , Tran Jennifer , Russler-Germain David A. , Neal Carly , Kersting-Schadek Samantha , Chang Lily , Schappe Timothy , Pence Patrick , McClain Ethan , Zevallos Jose P. , Rich Jason T. , Paniello Randal C. , Jackson Ryan S. , Pipkorn Patrik , Adkins Douglas R. , DeSelm Carl J. , Berrien-Elliott Melissa M. , Puram Sidharth V. , Fehniger Todd A.
Published: October 2023

Abstract
Purpose: Head and neck squamous cell carcinoma (HNSCC) is an aggressive tumor with low response rates to frontline PD-1 blockade. Natural killer (NK) cells are a promising cellular therapy for T cell therapy–refractory cancers, but are frequently dysfunctional in patients with HNSCC. Strategies are needed to enhance NK cell responses against HNSCC. We hypothesized that ML NK cell differentiation, tumor-targeting with cetuximab, and engineering with an anti-EphA2 chimeric antigen receptor (CAR) enhance NK cell responses against HNSCC. Experimental Design: We generated ML NK and conventional (c)NK cells from healthy donors then evaluated their ability to produce IFN-γ, TNF, degranulate, and kill HNSCC cell lines and primary HNSCC cells, alone or in combination with cetuximab, in vitro and in vivo using xenograft models. ML and cNK cells were engineered to express anti-EphA2 CAR-CD8A-41BB-CD3z, and functional responses were assessed in vitro against HNSCC cell lines and primary HNSCC tumor cells. Results: Human ML NK cells displayed enhanced IFN-γ and TNF production and both short- and long-term killing of HNSCC cell lines and primary targets, compared to cNK cells. These enhanced responses were further improved by cetuximab. Compared to controls, ML NK cells expressing anti-EphA2 CAR had increased IFN-γ and cytotoxicity in response to EphA2+ cell lines and primary HNSCC targets. Conclusions: These pre-clinical findings demonstrate that ML differentiation alone or coupled with either cetuximab-directed targeting or EphA2 CAR engineering were effective against HNSCCs and provide the rationale for investigating these combination approaches in early phase clinical trials for HNSCC patients.
Data from Baseline Mutations and ctDNA Dynamics as Prognostic and Predictive Factors in ER-Positive/HER2-Negative Metastatic Breast Cancer Patients
Authors: Pascual Javier , Gil-Gil Miguel , Proszek Paula , Zielinski Christoph , Reay Alistair , Ruiz-Borrego Manuel , Cutts Rosalind , Ciruelos Gil Eva M. , Feber Andrew , Muñoz-Mateu Montserrat , Swift Claire , Bermejo Begoña , Herranz Jesus , Margeli Vila Mireia , Antón Antonio , Kahan Zsuzsanna , Csöszi Tibor , Liu Yuan , Fernandez-Garcia Daniel , Garcia-Murillas Isaac , Hubank Michael , Turner Nicholas C. , Martín Miguel
Published: October 2023

AbstractPurpose:
Prognostic and predictive biomarkers to cyclin-dependent kinases 4 and 6 inhibitors are lacking. Circulating tumor DNA (ctDNA) can be used to profile these patients and dynamic changes in ctDNA could be an early predictor of treatment efficacy. Here, we conducted plasma ctDNA profiling in patients from the PEARL trial comparing palbociclib+fulvestrant versus capecitabine to investigate associations between baseline genomic landscape and on-treatment ctDNA dynamics with treatment efficacy.
Experimental Design:
Correlative blood samples were collected at baseline [cycle 1-day 1 (C1D1)] and prior to treatment [cycle 1-day 15 (C1D15)]. Plasma ctDNA was sequenced with a custom error-corrected capture panel, with both univariate and multivariate Cox models used for treatment efficacy associations. A prespecified methodology measuring ctDNA changes in clonal mutations between C1D1 and C1D15 was used for the on-treatment ctDNA dynamic model.
Results:
201 patients were profiled at baseline, with ctDNA detection associated with worse progression-free survival (PFS)/overall survival (OS). Detectable TP53 mutation showed worse PFS and OS in both treatment arms, even after restricting population to baseline ctDNA detection. ESR1 mutations were associated with worse OS overall, which was lost when restricting population to baseline ctDNA detection. PIK3CA mutations confer worse OS only to patients on the palbociclib+fulvestrant treatment arm. ctDNA dynamics analysis (n = 120) showed higher ctDNA suppression in the capecitabine arm. Patients without ctDNA suppression showed worse PFS in both treatment arms.
Conclusions:
We show impaired survival irrespective of endocrine or chemotherapy-based treatments for patients with hormone receptor–positive/HER2-negative metastatic breast cancer harboring plasma TP53 mutations. Early ctDNA suppression may provide treatment efficacy predictions. Further validation to fully demonstrate clinical utility of ctDNA dynamics is warranted.
Data from Tumor Microenvironment Modifications Induced by Afatinib in Squamous Cell Carcinoma of the Head and Neck: A Window-of-Opportunity Study (EORTC-90111–24111)
Authors: Beyaert Simon P. , Loriot Axelle E. , Huyghe Nicolas D. , Goebbels Rose-Marie , Mendola Antonella , Govaerts Anne-Sophie , Fortpied Catherine , Baldin Pamela , Licitra Lisa F. , Lalami Yassine , Clement Paul M. , Machiels Jean-Pascal H. , Schmitz Sandra
Published: October 2023

AbstractPurpose:
The EORTC-90111–24111 phase II window study evaluated afatinib versus no preoperative treatment in patients with primary squamous cell carcinoma of the head and neck (HNSCC). We investigated afatinib-induced tumor and microenvironment modifications by comparing pre- and posttreatment tumor biopsies.
Patients and Methods:
Thirty treatment-naïve patients with primary HNSCC were randomized. Twenty-five patients received afatinib for 14 days before surgery (40 mg 1×/day) and 5 patients were attributed to the control arm. Biopsies were taken at work-up and during surgery. Good quality RNA samples were used for omics analyses. The control arm was enlarged by samples coming from our previous similar window study.
Results:
IHC analyses of afatinib-treated tumor biopsies showed a decrease in pEGFR (P ≤ 0.05) and pERK (P ≤ 0.05); and an increase in CD3+ (P ≤ 0.01) and CD8+ (P ≤ 0.01) T-cell infiltration, and in CD3+ (P ≤ 0.05) T-cell density. RNA sequencing analyses of afatinib-treated tumor samples showed upregulation of inflammatory genes and increased expression scores of signatures predictive of response to programmed cell death protein 1 blockade (P ≤ 0.05). In posttreatment biopsies of afatinib-treated patients, two clusters were observed. Cluster 1 showed a higher expression of markers and gene sets implicated in epithelial-to-mesenchymal transition (EMT) and activation of cancer-associated fibroblasts (CAF) compared with cluster 2 and controls.
Conclusions:
Short-term treatment with afatinib in primary HNSCC induces CD3+ and CD8+ tumor infiltration and, in some patients, EMT and CAF activation. These results open perspectives to overcome resistance mechanisms to anti-HER therapy and to potentiate the activity of immune checkpoint inhibitors.
Data from Efficacy and safety of stereotactic body radiotherapy combined with Camrelizumab and Apatinib in hepatocellular carcinoma patients with portal vein tumor thrombus
Authors: Hu Yue , Zhou Min , Tang Jing , Li Shuang , Liu Hongli , Hu Jianli , Ma Hong , Liu Junli , Qin Tingting , Yu Xiongjie , Chen Yongshun , Peng Jin , Zou Yanmei , Zhang Tao , Xue Jun
Published: October 2023

Abstract
Purpose: This study aimed to evaluate the efficacy and safety of camrelizumab plus apatinib with or without stereotactic body radiotherapy (SBRT) as first-line therapy for hepatocellular carcinoma (HCC) patients with portal vein tumor thrombus (PVTT). Patients and Methods: This is a multicenter, open-label, non-comparative, randomized trial that recruited HCC patients with type II/III/IV PVTT, who had not previously received systemic therapy. Patients were randomly assigned (2:1) to receive camrelizumab (200 mg, Q3W) and apatinib (250 mg, QD) with or without SBRT (95% PTV, 36 - 40 Gy/6 - 8 Gy). The primary endpoint was overall survival (OS), and the secondary endpoints were progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), duration of response (DOR), time to progression (TTP) and safety. Results: Sixty patients were enrolled and randomly assigned to two prospective cohorts. Median OS were 12.7 months (95% CI, 10.2-NA) and 8.6 months (95% CI, 5.6-NA), and median PFS were 4.6 months (95% CI, 3.3-7.0) and 2.5 months (95% CI, 2.0-7.6) for the SBRT and non-SBRT cohorts, respectively. The ORR and DCR were 47.5% and 72.5% in the SBRT cohort, and 20.0% and 40.0% in the non-SBRT cohort. The most common treatment-related adverse events of any grade were hypertension (55.0%), hand-foot syndrome (51.7%), and leukopenia (50.0%). Grade ≥ 3 was reported in 13 (21.7%) patients. Conclusion: First-line treatment with camrelizumab-apatinib combined with or without SBRT showed clinical benefits in HCC patients with PVTT, with an acceptable safety profile. Thus, these combination regimens may be potential options for such patients.
Data from Safety and Tolerability of Low-Dose Radiation and Stereotactic Body Radiotherapy + Sintilimab for Treatment-Naive Stage IV PD-L1+ Non-Small-Cell Lung Cancer Patients
Authors: Zhou Xiaojuan , Zhou Laiyan , Yao Zhuoran , Huang Meijuan , Gong Youling , Zou Bingwen , Zhu Jiang , Liu Yongmei , Peng Feng , Zhang Yan , Yu Min , Li Yanying , Na Feifei , Wu Yijun , Kang Kai , Xiu Weigang , Zhang Xuanwei , Zhou Lin , Xu Yong , Wang Jin , Wang Yan , Yang Xue , Wu Yuanjun , Li Rui , Zhang Yu , Yang Zhenzhou , Zhou Zhipeng , Bai Jing , Yi Xin , Tong Ruizhan , Yin Limei , Chen Chong , Niedermann Gabriele , Lu You , Xue Jianxin
Published: October 2023

Abstract
Purpose:Low-dose radiation therapy (LDRT) may enhance the synergistic anti-tumor effect of combined immunotherapy and stereotactic body radiation therapy (SBRT). The safety and efficacy of this novel triple-combination therapy were evaluated for the first time as first-line treatment for patients with metastatic non-small-cell lung cancer (NSCLC). Patients and Methods:This prospective phase 1 study enrolled 29 patients and included a dose-escalation and dose-expansion phase. Patients received SBRT (30 Gy/3f) to small lesions and LDRT (2 Gy/1f, 4 Gy/2f, or 10 Gy/5f) to a large lesion concurrently, followed by sintilimab (a PD-1 inhibitor). The primary endpoint was safety and tolerability; secondary endpoints included objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results:No dose-limiting toxicities were observed during the dose-escalation phase; 4 Gy/2f was the recommended LDRT dose. Median follow-up was 15.6 months. Treatment-related adverse events (TRAEs) occurred in 96.6% (28/29) of patients (grade ≥ 3, 20.7% [6/29]); two patients (6.9%) discontinued due to TRAEs. Seven patients experienced pneumonitis (grade 2, n = 6; grade 3, n = 1). Immune-related adverse events were noted in 58.6% (17/29) of patients. In patients with tumor assessment (n = 28), ORR and confirmed ORR were 60.7% and 57.1%, respectively. Median PFS was 8.6 months (95% confidence interval 3.7–16.5), and median OS was not reached. Exploratory analyses suggested both expanded and newly emerging TCR clonotypes were associated with better PFS. Conclusions:The findings indicate that the novel SBRT + LDRT + sintilimab therapy is safe and promising in patients with PD-L1-positive, driver gene-negative primary metastatic NSCLC.
Data from Axicabtagene Ciloleucel in Combination with the 4–1BB Agonist Utomilumab in Patients with Relapsed/Refractory Large B-Cell Lymphoma: Phase 1 Results from ZUMA-11
Authors: Jain Michael D. , Miklos David B. , Jacobson Caron A. , Timmerman John M. , Sun Jennifer , Nater Jenny , Fang Xiang , Patel Ankit , Davis Madison , Heeke Darren , Trinh Tan , Mattie Mike , Neumann Frank , Kim Jenny J. , To Christina , Filosto Simone , Reshef Ran
Published: October 2023

AbstractPurpose:
Chimeric antigen receptor (CAR) T-cell therapies have shown clinical benefit for patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL), yet approximately 60% of patients do not respond or eventually relapse. We investigated the safety and feasibility of the CD19-directed CAR T-cell therapy axicabtagene ciloleucel (axi-cel) in combination with the 4–1BB agonist antibody utomilumab as an approach to improve efficacy of CAR T-cell therapy.
Patients and Methods:
In phase 1 of the single-arm ZUMA-11 trial, patients with R/R LBCL received a single axi-cel infusion (target dose, 2 × 106 cells/kg) plus utomilumab 10 to 200 mg intravenously every 4 weeks for up to 6 months in a dose-escalation design. The primary endpoint was incidence of dose-limiting toxicities (DLT) with utomilumab. Key secondary endpoints were safety, antitumor activity, pharmacokinetics, and pharmacodynamics.
Results:
No DLTs were observed among patients treated with axi-cel and utomilumab (n = 12). Grade ≥3 adverse events occurred in 10 patients (83%); none were Grade ≥3 cytokine release syndrome or neurologic events. The objective response rate was 75% and seven patients (58%) had a complete response. Peak CAR T-cell levels increased in a utomilumab dose-dependent manner up to 100 mg. Patients who received utomilumab 100 mg had persistently increased CAR T cells on days 57 to 168 compared with other dose levels. Utomilumab was associated with dose-dependent increases in IL2, IFNγ, and IL10.
Conclusions:
Utomilumab-mediated 4–1BB agonism combined with axi-cel therapy had a manageable safety profile. Dual 4–1BB and CD28 costimulation is a feasible therapeutic approach that may enhance CAR T-cell expansion in patients with LBCL.
Data from Depth of radiographic response (DpR) and time to tumor regrowth (TTG) predicts overall survival following anti-VEGF therapy in recurrent glioblastoma
Authors: Ellingson Benjamin M. , Hagiwara Akifumi , Morris Connor J. , Cho Nicholas S. , Oshima Sonoko , Sanvito Francesco , Oughourlian Talia C. , Telesca Donatello , Raymond Catalina , Abrey Lauren E. , Garcia Josep , Aftab Dana T. , Hessel Colin , Rachmilewitz Minei Tamar , Harats Dror , Nathanson David A. , Wen Patrick Y. , Cloughesy Timothy F.
Published: October 2023

Abstract
Purpose. Anti-angiogenic therapies are known to cause high radiographic response rates due to reduction in vascular permeability resulting in a lower degree of contrast extravasation. In the current study, we investigate the prognostic ability for model-derived parameters describing enhancing tumor volumetric dynamics to predict survival in recurrent glioblastoma treated with anti-angiogenic therapy. Experimental Design. N=276 patients in two phase II trials were used as training data, including bevacizumab +/- irinotecan (NCT00345163) and cabozantinib (NCT00704288), and N=74 patients in the bevacizumab arm of a phase III trial (NCT02511405) were used for validation. Enhancing volumes were estimated using T1 subtraction maps, and a biexponential model was used to estimate regrowth (g) and regression (d) rates, time to tumor regrowth (TTG), and the depth of response (DpR). Response characteristics were compared to diffusion MR phenotypes previously shown to predict survival. Results: Optimized thresholds occurred at g=0.07months-1 (phase II:HR=0.2579,P=5x10-20; phase III:HR=0.2197, P=5x10-5); d=0.11months-1 (HR=0.3365, P<0.0001; HR=0.3675,P=0.0113); TTG=3.8 months (HR=0.2702,P=6x10-17;HR=0.2061,P=2x10-5); and DpR=11.3% (HR=0.6326,P=0.0028;HR=0.4785, P=0.0206). Multivariable Cox regression controlling for age and baseline tumor volume confirmed these factors as significant predictors of survival. Patients with a favorable pre-treatment diffusion MRI phenotype had a significantly longer TTG and slower regrowth. Conclusions: Recurrent glioblastoma patients with a large, durable radiographic response to anti-angiogenic agents have significantly longer survival. This information is useful for interpreting activity of anti-angiogenic agents in recurrent glioblastoma.
Is the Pentagon-Copying Task More than a Cognitive Feature? Associations with Handgrip Strength, Gait Speed, and Frailty in Older Adults
Authors: Sardella Alberto , Bellone Federica , Mandraffino Giuseppe , Malacarne Fabio , Maltese Giuseppe , Squadrito Giovanni , Quattropani Maria C. , Basile Giorgio
Published: October 2023

Background: The pentagon copy is a sensitive item to the prediction of cognitive decline and dementia. Cognitive and physical/motor decline are able to accelerate the evolution of each other by representing a common pathway toward frailty. Objectives: The objective of the study was to investigate the association of the pentagon-copying task with physical and motor performances and with frailty, in a sample of older adults. Method: This observational, cross-sectional, and single-center study was conducted in a Geriatric Outpatients Clinic. Subjects aged ≥65 years were consecutively recruited, on a voluntary basis. Subjects with positive psychiatric history, with a severe neurocognitive disorder, with severe limitations on the upper limbs and/or reporting sensory deficits were excluded. The pentagon-copying task was scored from the Mini-Mental State Examination; the Qualitative Scoring Pentagon Test (QSPT) was also used. Handgrip strength was measured; a 46-item Frailty Index was calculated; in subjects with autonomous walking, a 4-meter gait speed was also measured. Results: The study included 253 subjects (mean age 80.59 ± 6.89 years). Subjects making a wrong pentagon copy showed greater odds of exhibiting a strength deficit (OR = 3.57; p = 0.001) and of being frail (OR = 4.80; p < 0.001), and exhibited a slower gait. The QSTP score was significantly correlated with handgrip strength (r = 0.388) and gait speed (r = 0.188) and inversely correlated with frailty (r = −0.428); the QSTP score was significantly different between the quartiles of handgrip strength and frailty. Conclusions: The pentagon-copying task might also be confirmed as a quick screening tool of aging trajectories toward frailty by jointly evaluating cognitive and physical performances.
Genetic and Nongenetic Components of Stroke Family History: A Population Study of Adopted and Nonadopted Individuals
Authors: Mayerhofer Ernst , Parodi Livia , Narasimhalu Kaavya , Harloff Andreas , Georgakis Marios K. , Rosand Jonathan , Anderson Christopher D.
Published: October 2023

Background

Genetic and nongenetic factors account for the association of family history with disease risk. Comparing adopted and nonadopted individuals provides an opportunity to disentangle those factors.

Methods and Results

We examined associations between family history of stroke and heart disease with incident stroke and myocardial infarction (MI) in 495 640 UK Biobank participants (mean age, 56.5 years; 55% women) stratified by childhood adoption status (5747 adoptees). We estimated hazard ratios (HRs) per affected family member, and for polygenic risk scores in Cox models adjusted for baseline age and sex. A total of 12 518 strokes and 23 923 MIs occurred over a 13‐year follow‐up. In nonadoptees, family history of stroke and heart disease was associated with increased stroke and MI risk, with the strongest association of family history of stroke for incident stroke (HR, 1.16 [95% CI, 1.12–1.19]) and family history of heart disease for incident MI (HR, 1.48 [95% CI, 1.45–1.50]). In adoptees, family history of stroke associated with incident stroke (HR, 1.41 [95% CI, 1.06–1.86]), but family history of heart disease was not associated with incident MI (
P
>0.5). Polygenic risk scores showed strong disease‐specific associations in both groups. In nonadoptees, the stroke polygenic risk score mediated 6% risk between family history of stroke and incident stroke, and the MI polygenic risk score mediated 13% risk between family history of heart disease and incident MI.

Conclusions

Family history of stroke and heart disease increases risk for their respective conditions. Family history of stroke contains substantial potentially modifiable nongenetic risk, indicating a need for novel prevention strategies, whereas family history of heart disease represents predominantly genetic risk.
Abstract EC.02: Myosin Light Chain Dephosphorylation By Ppp1r12c Promotes Atria Hypocontractility In Atrial Fibrillation
Authors: Gonzalez-Gonzalez Francisco J , perike srikanth , Abu-Taha Issam , Damen Frederick , Lizama Ken S , Aboonabi Anahita , Capote Andrielle , Aguilar-Sanchez Yuriana , Levin Benjamin , Han Zhenbo , Sridhar Arvind , Grand Jacob , Martin Jody C , Akar Joseph , Warren Chad M , Solaro R John , Ong Sang-Ging , Darbar Dawood , Goergen Craig J , Wolska Beata M , Dobrev Dobromir , Wehrens Xander H , McCauley Mark
Published: October 2023

Background:
Atrial fibrillation (AF), the most common sustained cardiac arrhythmia, increases thromboembolic stroke risk five-fold. Although atrial hypocontractility contributes to stroke risk in AF, the molecular mechanisms reducing myofilament contractile function remain unknown. We tested the hypothesis that increased expression of PPP1R12C, the PP1 regulatory subunit targeting atrial myosin light chain 2 (MLC2a), causes hypophosphorylation of MLC2a and results in atrial hypocontractility.

Methods:
Right atrial appendage tissues were isolated from human AF patients versus sinus rhythm (SR) controls. Western blots, co-immunoprecipitation, and phosphorylation studies were performed to examine how the PP1c-PPP1R12C interaction causes MLC2a de-phosphorylation.
In vitro
studies of pharmacologic MRCK inhibitor (BDP5290) in atrial HL-1 cells were performed to evaluate PP1 holoenzyme activity on MLC2a. Cardiac-specific lentiviral PPP1R12C overexpression was performed in mice to evaluate atrial remodeling with atrial cell shortening assays, echocardiography, and AF inducibility with EP studies.

Results:
In human patients with AF, PPP1R12C expression was increased two-fold versus SR controls with > 40% reduction in MLC2a phosphorylation. 12C-PP1c binding and PPP1R12C-MLC2a binding were significantly increased in AF.
In vitro
studies utilizing drug BDP5290, which inhibits T560-PPP1R12C phosphorylation, demonstrated increased PPP1R12C binding with both PP1c and MLC2a, and dephosphorylation of MLC2a. Lenti-12C mice demonstrated a 150% increase in LA size versus controls, with reduced atrial strain and atrial ejection fraction. Pacing-induced AF in Lenti-12C mice was significantly higher than controls.

Conclusions:
AF patients exhibit increased levels of PPP1R12C protein compared to controls. PPP1R12C overexpression in mice increases PP1c targeting to MLC2a and causes MLC2a dephosphorylation, which reduces atrial contractility and increases AF inducibility. These findings suggest that PP1 regulation of sarcomere function at MLC2a is a key regulator of atrial contractility in AF.
Abstract EC.03: Distinct Molecular Signatures Of HCM- And DCM-causing Mutations At The Same Residue In The Transducer Of Cardiac Myosin
Authors: Kawana Masataka , Goluguri Rama Reddy , Dawood Aminah , Spudich James A , Ruppel Kathleen
Published: October 2023

Mutations in cardiac myosin cause both hypertrophic (HCM) and dilated cardiomyopathy (DCM), and the clinical phenotype ultimately depends on the precise effect of the mutation on the function of myosin. Using recombinant human cardiac myosin, we studied the molecular effects of a novel Q222H mutation in MYH7 found in a patient with severe, early-onset DCM, and compared the effects to the Q222K mutation that was previously reported to cause HCM. The Q222 residue is located within the transducer of the head domain near the ATP binding pocket. The Q222H (DCM) mutant myosin exhibited significantly reduced steady-state actin-activated ATPase activity and a decreased rate of ATP binding in transient kinetic studies, while Q222K (HCM) mutant protein showed an increase in ATPase activity and ATP binding kinetics. In vitro motility assays showed 43% reduction and 32% increase in actin gliding velocity in Q222H and Q222K mutations, respectively. Finally, single nucleotide turnover assays revealed that the fraction of myosin with a slow ATP hydrolysis rate (super relaxed state, or SRX) thought to represent myosin in an autoinhibited state was significantly reduced in Q222K and increased in Q222H. Taken together, the Q222H/K mutations exerted contrasting effects on the motor properties of the cardiac myosin catalytic domain. Cellular characterization and molecular dynamic simulations of cardiac myosin to assess the structural impact of mutant residues are underway. These results highlight how subtle structural differences between cardiomyopathy-causing mutations can lead to significant differences in cardiac myosin motor activity and thus phenotypic expression of cardiomyopathy.
Abstract EC.06: Skeletal Muscle Actin Mutation R256H Disrupts Actin Polymerization And Cardiomyocyte Contractility: A Multi-scale Study Of Genetic Dilated Cardiomyopathy
Authors: Garg Ankit , Jansen Silvia , Lavine Kory J , Greenberg Michael
Published: October 2023

Actin is conserved in all eukaryotic cells with six isoforms in humans. Skeletal muscle actin (ACTA1) is the primarily expressed isoform in skeletal muscle; however, it is also expressed at low levels in the heart. ACTA1 mutations are well known to cause skeletal myopathy, but mechanistic insights are incomplete due to difficulties with generating recombinant protein and limited
in vivo
modeling. The impact of ACTA1 mutations on cardiac function is controversial. We previously reported a novel missense heterozygous mutation in ACTA1, R256H, associated with dilated cardiomyopathy (DCM) without overt skeletal myopathy in patients. The objective of this study was to define the mechanistic basis by which ACTA1 R256H contributes to DCM. To establish the pathogenicity of ACTA1 R256H, we generated

Acta1
R256H

mice.

Acta1
R256H/R256H

mice display perinatal mortality. We also observed reduced survival and gross phenotypes in

Acta1
R256H/+

mice over time. To further characterize ACTA1 R256H in human cardiomyocytes, we generated

ACTA1
R256H/+

human induced pluripotent stem cells which we differentiated into cardiomyocytes.

ACTA1
R256H/+

cardiomyocytes generated less force and displayed aberrant sarcomere structure compared to isogenic controls. To biochemically define the consequences of ACTA1 R256H protein, we developed a novel method to generate recombinant wildtype ACTA1 and ACTA1 R256H. Strikingly, ACTA1 R256H demonstrated severely reduced polymerization kinetics possibly accounting for the observed disruption in sarcomere structure. This finding was further supported by molecular dynamic simulations which identified impaired nucleotide binding in ACTA1 R256H compared to wildtype ACTA1 protein. Together, these findings reveal that a mutation in skeletal muscle actin results in increased mortality, cardiomyocyte hypocontractility, sarcomeric disruption, and impaired actin polymerization. Our work defines a cardiac function for skeletal muscle actin and establishes a multiscale approach to studying cardiomyopathy-associated actin mutations.
Abstract EC.07: Tbx5 Maintains Atrial Identity By Regulating An Atrial Enhancer Network
Authors: Sweat Mason E , Cao Yangpo , Zhang Xiaoran , Burnicka-Turek Ozanna , Perez-Cervantes Carlos , Akerberg Brynn , Ma Qing , Wakimoto Hiroko , Gorham Josh , Song Mi-Kyoung , Trembley Michael , Wang Peizhe , Lu Fujian , GIANESELLI MATTEO , Prondzynski Maksymilian K , Bortolin Raul , Seidman Jonathan G , Seidman Christine E , Moskowitz Ivan , Pu William T
Published: October 2023

Atrial cardiomyocytes (aCMs) and ventricular cardiomyocytes (vCMs) are distinct cell types, but the mechanisms underlying these differences are not well understood. By selectively inactivating the transcription factor
Tbx5
in the atrial working myocardium of the neonatal mouse heart, we show that it is required to maintain atrial identity. aCM inactivation of
Tbx5
led to the downregulation of highly chamber specific genes including
Myl7
and
Nppa
, and conversely, increased the expression of ventricular identity genes including
Myl2
. Using concurrent single nucleus RNA- and ATAC- sequencing, we examined genomic accessibility changes underlying the atrial identity expression program, identifying 1846 genomic loci with greater accessibility in control vs KO aCMs. Nearly 70% of the control-enriched ATAC regions were bound by TBX5, demonstrating a novel role for TBX5 in maintaining atrial genomic accessibility. These regions were associated with genes that had higher expression in control aCMs compared to KO aCMs, suggesting they act as TBX5-dependent enhancers. This hypothesis was tested using HiChIP to analyze enhancer chromatin looping and we determined that 510 chromatin loops were sensitive to TBX5 dosage. Of the loops enriched in control aCMs, 73.7% were anchored in control-enriched ATAC regions. Together, these data demonstrate a role for TBX5 in maintaining atrial identity by supporting chamber specific chromatin confirmation required for aCM specificity.
Abstract EC.09: Single Nuclei RNA Sequencing Analysis Of
Mybpc-3-
Associated HCM To Identify Common Pathological Mechanisms In Human, Feline, And Murine Hearts
Authors: Ali Samia , Perera Gayani , Laird Jason , Batorsky Rebecca , Stern Joshua A , Harris Samantha , Chin Michael T
Published: October 2023

Hypertrophic cardiomyopathy (HCM) is a common inherited cardiovascular disease characterized by unexplained hypertrophy, often associated with left ventricular outflow tract (LVOT) obstruction, ventricular tachyarrhythmias, diastolic heart failure, and sudden cardiac death. Mutations in
mybpc3
are the most common genetic mutations associated with human and feline HCM. To understand how mutations in
mybc3
causing sarcomere dysfunction result in the development of non-myocyte phenotypes such as fibrosis, mitral valve anomalies, and microvascular occlusion across species, we generated single nuclei RNA-sequencing datasets from feline, human and murine heart tissue carrying
mybpc3
variants. We analyzed these datasets for differential gene expression by genotype for each cell type and assessed changes in cell-cell communication by ligand-receptor analysis. Gene Ontology (GO) enrichment analysis of differentially expressed genes (DEGs) in feline cardiomyocytes revealed alteration in regulation of calcium ion transmembrane transporter activity, regulation of cation channel activity, and extracellular matrix structure and organization, consistent with known phenotypic aspects of HCM such as calcium dyshomeostasis and fibrosis. DEGs in cardiomyocytes of human tissues revealed novel obstruction of cGMP-mediated signaling, protein O-linked glycosylation and negative regulation of cAMP-mediated signaling. DEGs in murine cardiomyocytes affected cardiac muscle thin filament assembly, CDP-diacylglycerol biosynthesis and cell adhesion molecule production. Analysis of intercellular communication in feline and murine hearts revealed an overall loss of ligands broadcast from all cell types, with notable losses from fibroblast cells and cardiomyocytes. These findings are consistent with recent studies implicating altered intercellular communication between cardiomyocytes and non-myocyte cell types as a potential disease mechanism in human HCM. We will further identify common and species-specific disease-promoting pathways in HCM tissue that will allow identification of conserved disease mechanisms that may be targeted in both human and feline disease and will facilitate an understanding of the relevance of mouse models.
Abstract GS.04: Myocardial Tricarboxylic Acid Cycle Suppression Disrupts The Epigenetic Landscape In Human Heart Failure With Preserved Ejection Fraction
Authors: Yoo Edwin , Keykhaei Mohammad , Jani Vivek , Koleini Navid , Guo Alina , Kim Julie S , Sidoli Simone , Sharma Kavita , Hahn Virginia S , Kass David A
Published: October 2023

Heart Failure with Preserved Ejection Fraction (HFpEF) represents the greatest unmet therapeutic need in cardiology and is intimately related to obesity and metabolic syndrome. Using a bedside-to-bench approach, we investigated the hypothesis that suppressed tricarboxylic acid cycle (TCA) enzymes and metabolic intermediates in HFpEF influence epigenetic histone post-translational modifications (PTMs) that regulate genes involved in mitochondrial OxPhos and fatty acid metabolism. Endomyocardial biopsies were obtained from human HFpEF patients (n=32) and donor controls (n=12) and integrated proteomics, metabolomics, ChIP-seq, and RNAseq analyses were performed. Small molecule histone PTM modulators were screened
in vitro
in neonatal rat ventricular cardiomyocytes (NRVMs) to identify potential therapeutic targets. Proteomics demonstrates reduced TCA cycle enzyme abundance consistent with our recently published metabolomics data showing reduced succinate, fumarate, and malate. Histone PTM profiling found H3K27ac and H3K36me3 upregulated (p<0.001) and inversely correlated with TCA cycle intermediates succinate and fumerate. ChIP-seq promoter gene ontology analysis revealed enrichment of mitochondrial metabolism and fatty acid uptake ontologies (CD36), as well as major cardiac transcription factors such as GATA4. Small-molecule inhibitor proteomics screens of histone writers in neonatal rat ventricular myocytes showed that H3K27ac inhibition upregulates all TCA cycle enzymes 1.5-4 fold and may rescue TCA cycle function. Our multi-omics approach suggests an association between H3K27ac, H3K36me3, and TCA cycle intermediates. Inhibition of myocardial H3K27ac deposition represents a novel therapeutic target for HFpEF.