bluuebunny/crossref_metadata_2025 huggingface dataset:
Supplementary Figure S9 from Phase I/II Study of the Aurora Kinase A Inhibitor Alisertib and Pembrolizumab in Refractory, Rb-Deficient Head and Neck Squamous Cell Carcinomas
Authors: Johnson Faye M. , O’Hara Madison P. , Yapindi Lacin , Jiang Peixin , Tran Hai T. , Reuben Alexandre , Xiao Weihong , Gillison Maura L. , Sun Xiaowen , Khalaf Alexander , Lee J. Jack , Sastry Jagannadha K. , Ghosh Soma
Published: February 2025

Supplementary Figure S9. Plasma concentrations of alisertib on Cycle 1 Day 1 (C1D1) and Cycle 1 Day 7 (C1D7).
Supplementary Figure S8 from Phase I/II Study of the Aurora Kinase A Inhibitor Alisertib and Pembrolizumab in Refractory, Rb-Deficient Head and Neck Squamous Cell Carcinomas
Authors: Johnson Faye M. , O’Hara Madison P. , Yapindi Lacin , Jiang Peixin , Tran Hai T. , Reuben Alexandre , Xiao Weihong , Gillison Maura L. , Sun Xiaowen , Khalaf Alexander , Lee J. Jack , Sastry Jagannadha K. , Ghosh Soma
Published: February 2025

Supplementary Figure S8. Changes in absolute lymphocyte count (ALC) from baseline to 6 weeks of therapy.
Supplementary Figure S3 from Phase I/II Study of the Aurora Kinase A Inhibitor Alisertib and Pembrolizumab in Refractory, Rb-Deficient Head and Neck Squamous Cell Carcinomas
Authors: Johnson Faye M. , O’Hara Madison P. , Yapindi Lacin , Jiang Peixin , Tran Hai T. , Reuben Alexandre , Xiao Weihong , Gillison Maura L. , Sun Xiaowen , Khalaf Alexander , Lee J. Jack , Sastry Jagannadha K. , Ghosh Soma
Published: February 2025

Supplementary Figure S3. Kaplan-Meier curves for progression-free survival (PFS) and overall survival (OS) in phase 2 patients, stratified by PD-L1 CPS score.
Supplementary Figure S8 from Aberrantly Expressed Mitochondrial Lipid Kinase, AGK, Activates JAK2–Histone H3 Axis and BCR Signal: A Mechanistic Study with Implication in CLL Therapy
Authors: Mamidi Murali K. , Sinha Sutapa , Mendez Mariana T. , Sanyal Tapojyoti , Mahmud Hasan , Kay Neil E. , Gupta Mamta , Xu Chao , Vesely Sara K. , Mukherjee Priyabrata , Holter Chakrabarty Jennifer , Ghosh Asish K.
Published: February 2025

Supplementary Figure S8. Impact of fedratinib in combination with ibrutinib/idelalisib on CLL cell survival.
Supplementary Figure S5 from Aberrantly Expressed Mitochondrial Lipid Kinase, AGK, Activates JAK2–Histone H3 Axis and BCR Signal: A Mechanistic Study with Implication in CLL Therapy
Authors: Mamidi Murali K. , Sinha Sutapa , Mendez Mariana T. , Sanyal Tapojyoti , Mahmud Hasan , Kay Neil E. , Gupta Mamta , Xu Chao , Vesely Sara K. , Mukherjee Priyabrata , Holter Chakrabarty Jennifer , Ghosh Asish K.
Published: February 2025

Supplementary Figure S5. JAK2 is not localized in mitochondria.
Data from Safety and Tolerability of Letetresgene Autoleucel (GSK3377794): Pilot Studies in Patients with Advanced Non–Small Cell Lung Cancer
Authors: Altan Mehmet , Lopes Gilberto , Hiltermann T. Jeroen N. , Govindan Ramaswamy , Villaruz Liza C. , Calvo Emiliano , Edelman Martin J. , Furqan Muhammad , Neal Joel , Felip Enriqueta , Carlisle Jennifer W. , Heymach John V. , O’Cearbhaill Róisín Eilish , Zauderer Marjorie , Chisamore Michael , Corigliano Ellie , Eleftheriadou Ioanna , Zajic Stefan , Jenkins Ben , Goodison Sophia , Suchindran Sunil , Ramos-Hernandez Natalia , Tarek Nidale , Schoenfeld Adam J.
Published: February 2025

AbstractPurpose:
The study aims to evaluate the safety, tolerability, and antitumor response of letetresgene autoleucel (lete-cel), genetically modified autologous T cells expressing a T-cell receptor specific for New York esophageal squamous cell carcinoma 1 (NY-ESO-1)/LAGE-1a shared epitope, alone or in combination with pembrolizumab, in HLA-A*02–positive (HLA-A*02:01, HLA-A*02:05, and/or HLA-A*02:06) patients with NY-ESO-1– and/or LAGE-1a–positive non–small cell lung cancer.
Patients and Methods:
Study 208749 was a single-arm study of lete-cel alone. Study 208471 was a multiarm study of lete-cel alone or in combination with pembrolizumab in patients with advanced or recurrent non–small cell lung cancer.
Results:
More than 2,500 patients were screened for target expression. In the multiarm study, 738 (45%) of 1,638 tested patients were HLA-A*02–positive. NY-ESO-1 and LAGE-1a testing was positive in 12% (62/525) and 4% (15/348) of tested patients, respectively. Forty-one patients positive for HLA-A*02 and antigen expression were screened in the single-arm study. Overall, 43 patients underwent leukapheresis and 18 received lete-cel across studies. Lete-cel demonstrated a manageable safety profile. No fatal treatment-related serious adverse events (AE) were reported in either study. Cytopenias and cytokine release syndrome were the most common treatment-emergent AEs. Combining pembrolizumab with lete-cel did not seem to increase toxicity over lete-cel alone. Limited antitumor activity was observed; one of 18 patients had a durable response persisting for 18 months. Pharmacokinetic data showed similar T-cell expansion in all patients.
Conclusions:
Extensive HLA-A*02 and antigen expression testing was performed to identify potential participants. Lete-cel was generally well tolerated and had no unexpected AEs. Antitumor activity was observed in a limited number of patients.
Data from Phase I/II Study of the Aurora Kinase A Inhibitor Alisertib and Pembrolizumab in Refractory, Rb-Deficient Head and Neck Squamous Cell Carcinomas
Authors: Johnson Faye M. , O’Hara Madison P. , Yapindi Lacin , Jiang Peixin , Tran Hai T. , Reuben Alexandre , Xiao Weihong , Gillison Maura L. , Sun Xiaowen , Khalaf Alexander , Lee J. Jack , Sastry Jagannadha K. , Ghosh Soma
Published: February 2025

AbstractPurpose:
Effective therapy for recurrent head and neck squamous cell carcinoma (HNSCC) that is refractory to chemotherapy and immunotherapy is a considerable need. Aurora kinase A inhibition leads to apoptosis and immunogenic cell death in preclinical models of human papilloma virus (HPV)–driven cancers.
Patients and Methods:
Alisertib was administered orally twice daily on days 1–7 and pembrolizumab on day 1 of a 21-day cycle to adults with advanced solid tumors (phase I) or with immunotherapy- and platinum-resistant, HPV-positive HNSCC (phase II).
Results:
The recommended phase II alisertib dose was 40 mg, which had only the expected toxicity including cytopenia that led to dose reductions in two phase II patients at cycles 13 and 16. We saw no objective responses, but the combination led to prolonged stable disease (SD) in several patients, including two of 10 phase I patients (8 and 27 months). Eight of the 15 HPV-positive patients had SD, of which four (heavily pretreated) had ≥6 months, with median overall and progression-free survival durations of 16.8 and 1.4 months, respectively. In circulating immune cells and plasma, patients with SD had markedly higher levels of HLA de novo resistance–expressing NK cells than did progressive disease patients who demonstrated a more immunosuppressive and inflammatory profile. Pharmacokinetics did not indicate any significant drug-drug interactions between pembrolizumab and alisertib.
Conclusions:
The combination of alisertib and pembrolizumab was well tolerated and led to prolonged SD in some immunotherapy-resistant patients, supporting our hypothesis that Aurora kinase A inhibition can reverse immunotherapy resistance of retinoblastoma protein–deficient HNSCC.
Supplementary Table S1 from Alcohol Consumption Does not Modify the Polygenic Risk Score–Based Genetic Risk of Breast Cancer in Postmenopausal Women: Atherosclerosis Risk in Communities Study
Authors: Zhang Minghui , Ru Meng , Zhang Jingning , Wang Ziqiao , Lu Jiayun , Butler Kenneth R. , Chatterjee Nilanjan , Couper David J. , Prizment Anna E. , Soori Mehrnoosh M. , Visvanathan Kala , Zahnow Cynthia A. , Joshu Corinne E. , Platz Elizabeth A.
Published: February 2025

Supplementary Table S1: Baseline characteristics of women in ARIC at Visit 2 (1990-1992)
Supplemental Table 5 from Metabolic Phenotype and Risk of Obesity-Related Cancers in the Women’s Health Initiative
Authors: Karra Prasoona , Hardikar Sheetal , Winn Maci , Anderson Garnet L. , Haaland Benjamin , Shadyab Aladdin H. , Neuhouser Marian L. , Seguin-Fowler Rebecca A. , Thomson Cynthia A. , Coday Mace , Wactawski-Wende Jean , Stefanick Marcia L. , Zhang Xiaochen , Cheng Ting-Yuan David , Karanth Shama , Sun Yangbo , Saquib Nazmus , Pichardo Margaret S. , Jung Su Yon , Tabung Fred K. , Summers Scott A. , Holland William L. , Jalili Thunder , Gunter Marc J. , Playdon Mary C.
Published: February 2025

Supplemental Table 5. Association between metabolic phenotypes defined by high sensitivity C-Reactive Protein (hs-CRP) ≥ 10 mg/L with obesity-related cancer risk in the Women’s Health Initiative cohort (N= 21,245).
Supplemental Figure 5 from Metabolic Phenotype and Risk of Obesity-Related Cancers in the Women’s Health Initiative
Authors: Karra Prasoona , Hardikar Sheetal , Winn Maci , Anderson Garnet L. , Haaland Benjamin , Shadyab Aladdin H. , Neuhouser Marian L. , Seguin-Fowler Rebecca A. , Thomson Cynthia A. , Coday Mace , Wactawski-Wende Jean , Stefanick Marcia L. , Zhang Xiaochen , Cheng Ting-Yuan David , Karanth Shama , Sun Yangbo , Saquib Nazmus , Pichardo Margaret S. , Jung Su Yon , Tabung Fred K. , Summers Scott A. , Holland William L. , Jalili Thunder , Gunter Marc J. , Playdon Mary C.
Published: February 2025

Supplemental Figure 5. Hazard ratios and 95% confidence intervals for the association of metabolic phenotype defined by ATP III criteria with obesity-related cancer risk, stratified by cancer type among postmenopausal women in the Women’s Health Initiative. Model adjusted for demographics (age, education, race/ethnicity, marital status), lifestyle (smoking status, physical activity, alcohol use, fruits and vegetable intake, fiber intake, read meat intake), hormonal factors for female cancers (parity, hormone therapy use), family history of ORC and study ID. MUNW=metabolically unhealthy normal weight; MHO=metabolically healthy overweight/obese; MUO= metabolically unhealthy overweight/obese. Metabolically healthy normal weight (MHNW) is the comparison group.
Table S5 from Setdb1 Loss Induces Type I Interferons and Immune Clearance of Melanoma
Authors: McGeary Meaghan K. , Damsky William , Daniels Andrew J. , Lang Sabine M. , Xu Qingji , Song Eric , Huet-Calderwood Clotilde , Lou Hua Jane , Paradkar Sateja , Micevic Goran , Kaech Susan M. , Calderwood David A. , Turk Benjamin E. , Yan Qin , Iwasaki Akiko , Bosenberg Marcus W.
Published: February 2025

Summary of exonic mutations in YRG cells compared with YMG and WT C57BL6/J cells.
Table S3 from Setdb1 Loss Induces Type I Interferons and Immune Clearance of Melanoma
Authors: McGeary Meaghan K. , Damsky William , Daniels Andrew J. , Lang Sabine M. , Xu Qingji , Song Eric , Huet-Calderwood Clotilde , Lou Hua Jane , Paradkar Sateja , Micevic Goran , Kaech Susan M. , Calderwood David A. , Turk Benjamin E. , Yan Qin , Iwasaki Akiko , Bosenberg Marcus W.
Published: February 2025

Differential expression of SKO vs YRG cells, by RNAseq.
Table S2 from Setdb1 Loss Induces Type I Interferons and Immune Clearance of Melanoma
Authors: McGeary Meaghan K. , Damsky William , Daniels Andrew J. , Lang Sabine M. , Xu Qingji , Song Eric , Huet-Calderwood Clotilde , Lou Hua Jane , Paradkar Sateja , Micevic Goran , Kaech Susan M. , Calderwood David A. , Turk Benjamin E. , Yan Qin , Iwasaki Akiko , Bosenberg Marcus W.
Published: February 2025

Ranked CRISPR screen dropout hits, related to Figure 1. Analysis was performed using MaGeCK.
Figure S5 from Setdb1 Loss Induces Type I Interferons and Immune Clearance of Melanoma
Authors: McGeary Meaghan K. , Damsky William , Daniels Andrew J. , Lang Sabine M. , Xu Qingji , Song Eric , Huet-Calderwood Clotilde , Lou Hua Jane , Paradkar Sateja , Micevic Goran , Kaech Susan M. , Calderwood David A. , Turk Benjamin E. , Yan Qin , Iwasaki Akiko , Bosenberg Marcus W.
Published: February 2025

Figure S5: Evaluation of SETDB1 knockdown in human melanoma cells, related to Figure 4:
Figure S1 from Setdb1 Loss Induces Type I Interferons and Immune Clearance of Melanoma
Authors: McGeary Meaghan K. , Damsky William , Daniels Andrew J. , Lang Sabine M. , Xu Qingji , Song Eric , Huet-Calderwood Clotilde , Lou Hua Jane , Paradkar Sateja , Micevic Goran , Kaech Susan M. , Calderwood David A. , Turk Benjamin E. , Yan Qin , Iwasaki Akiko , Bosenberg Marcus W.
Published: February 2025

Figure S1: Experimental validation of SETDB1 knockout and flow gating schemes, related to Figure 4
Figure S8 from Combination CXCR4 and PD-1 Blockade Enhances Intratumoral Dendritic Cell Activation and Immune Responses Against Hepatocellular Carcinoma
Authors: Morita Satoru , Lei Pin-Ji , Shigeta Kohei , Ando Tomofumi , Kobayashi Tatsuya , Kikuchi Hiroto , Matsui Aya , Huang Peigen , Pittet Mikael J. , Duda Dan G.
Published: February 2025

Supplementary Figure S8
Figure S5 from Combination CXCR4 and PD-1 Blockade Enhances Intratumoral Dendritic Cell Activation and Immune Responses Against Hepatocellular Carcinoma
Authors: Morita Satoru , Lei Pin-Ji , Shigeta Kohei , Ando Tomofumi , Kobayashi Tatsuya , Kikuchi Hiroto , Matsui Aya , Huang Peigen , Pittet Mikael J. , Duda Dan G.
Published: February 2025

Supplementary Figure S5
Figure S1 from Combination CXCR4 and PD-1 Blockade Enhances Intratumoral Dendritic Cell Activation and Immune Responses Against Hepatocellular Carcinoma
Authors: Morita Satoru , Lei Pin-Ji , Shigeta Kohei , Ando Tomofumi , Kobayashi Tatsuya , Kikuchi Hiroto , Matsui Aya , Huang Peigen , Pittet Mikael J. , Duda Dan G.
Published: February 2025

Supplementary Figure S1
Table S6 from Identification and Phenotypic Characterization of Neoantigen-Specific Cytotoxic CD4+ T Cells in Endometrial Cancer
Authors: Fusagawa Minami , Tokita Serina , Murata Kenji , Mariya Tasuku , Umemoto Mina , Sugita Shintaro , Matsuo Kazuhiko , Hirohashi Yoshihiko , Saito Tsuyoshi , Kanaseki Takayuki , Torigoe Toshihiko
Published: February 2025

Table S6
Figure S1 from TBK1 Targeting Is Identified as a Therapeutic Strategy to Enhance CAR T-Cell Efficacy Using Patient-Derived Organotypic Tumor Spheroids
Authors: Sun Yi , Maggs Luke , Panda Apekshya , Wright Samuel J. , Cicerchia Angelina M. , Jenney Anne , Perricone Matthew D. , Mills Caitlin E. , Cattaneo Giulia , Ventin Marco , Chen Feng , Rasmussen Martin Q. , Miranda Alex , Revach Or-Yam , Fang Jacy , Fu Amina , Bowling Peter J. , Sharova Tatyana , Lawless Aleigha , Sorger Peter K. , Bardeesy Nabeel , Wang Xinhui , Flaherty Keith T. , Boland Genevieve M. , Mehta Arnav , Sade-Feldman Moshe , Ferrone Cristina R. , Jenkins Russell W.
Published: February 2025

Supplementary Figure S1 | Supporting data demonstrating B7-H3 expression in melanoma and other cancers.
Fig. S6 from Identification and Phenotypic Characterization of Neoantigen-Specific Cytotoxic CD4+ T Cells in Endometrial Cancer
Authors: Fusagawa Minami , Tokita Serina , Murata Kenji , Mariya Tasuku , Umemoto Mina , Sugita Shintaro , Matsuo Kazuhiko , Hirohashi Yoshihiko , Saito Tsuyoshi , Kanaseki Takayuki , Torigoe Toshihiko
Published: February 2025

Fig. S6 | HLArestriction of neoantigen-specific clones.
Table S4 from The HSP90 Inhibitor Pimitespib Targets Regulatory T Cells in the Tumor Microenvironment
Authors: Tsuge Ayaka , Watanabe Sho , Kawazoe Akihito , Togashi Yosuke , Itahashi Kota , Masuda Mari , Sai Atsuo , Takei Shogo , Muraoka Hiromi , Ohkubo Shuichi , Sugiyama Daisuke , Yan Yue , Fukuoka Shota , Doi Toshihiko , Shitara Kohei , Koyama Shohei , Nishikawa Hiroyoshi
Published: February 2025

Antibodies Used in RPPA Analysis.
Fig. S11 from Identification and Phenotypic Characterization of Neoantigen-Specific Cytotoxic CD4+ T Cells in Endometrial Cancer
Authors: Fusagawa Minami , Tokita Serina , Murata Kenji , Mariya Tasuku , Umemoto Mina , Sugita Shintaro , Matsuo Kazuhiko , Hirohashi Yoshihiko , Saito Tsuyoshi , Kanaseki Takayuki , Torigoe Toshihiko
Published: February 2025

Fig. S11 | Characterization of a neoantigen-specific CD4+ TIL cluster.
Fig. S10 from Identification and Phenotypic Characterization of Neoantigen-Specific Cytotoxic CD4+ T Cells in Endometrial Cancer
Authors: Fusagawa Minami , Tokita Serina , Murata Kenji , Mariya Tasuku , Umemoto Mina , Sugita Shintaro , Matsuo Kazuhiko , Hirohashi Yoshihiko , Saito Tsuyoshi , Kanaseki Takayuki , Torigoe Toshihiko
Published: February 2025

Fig. S10 | Characterization of neoantigen-reactive TCR clonotypes.
Figure S5 from The HSP90 Inhibitor Pimitespib Targets Regulatory T Cells in the Tumor Microenvironment
Authors: Tsuge Ayaka , Watanabe Sho , Kawazoe Akihito , Togashi Yosuke , Itahashi Kota , Masuda Mari , Sai Atsuo , Takei Shogo , Muraoka Hiromi , Ohkubo Shuichi , Sugiyama Daisuke , Yan Yue , Fukuoka Shota , Doi Toshihiko , Shitara Kohei , Koyama Shohei , Nishikawa Hiroyoshi
Published: February 2025

Antitumor efficacy of combined treatment with anti–PD-1 mAb and pimitespib is not observed in CD8+ T cell–depleted mice. (A). Representative flow cytometry staining of PBMCs from C57BL/6 mice. For CD4+ T-cell and CD8+ T-cell depletion, anti-CD4 mAb (0.5 mg/body) or anti-CD8β mAb (0.2 mg/body), respectively, was administered intraperitoneally once weekly. CD4+ T-cell or CD8+ T-cell depletion was confirmed by flow cytometry. (B). Antitumor efficacy of combined treatment with anti–PD-1 mAb and pimitespib in CD4+ or CD8+ T cell–depleted mice. A total of 2 × 106 MC-38 cells were injected subcutaneously, and the cancer size was monitored twice weekly (n = 6). After the cancer volumes reached 100–150 mm3, the mice were randomized, and some mice received intraperitoneal administration of anti–PD-1 mAb (0.05 mg/body) on that day (day 0) and/or oral administration of pimitespib (14 mg/kg/body) five times weekly from day 0. Anti-CD4 mAb or anti-CD8β mAb was administered intraperitoneally every 7 days. All in vivo experiments were performed at least twice. *, P < 0.05; **, P < 0.01; n.s., not significant.
Supplementary Table S1 from T Cells Instruct Immune Checkpoint Inhibitor Therapy Resistance in Tumors Responsive to IL1 and TNFα Inflammation
Authors: Cho Nam Woo , Guldberg Sophia M. , Nabet Barzin Y. , Yu Jie Zeng , Kim Eun Ji , Hiam-Galvez Kamir J. , Yee Jacqueline L. , DeBarge Rachel , Tenvooren Iliana , Ashitey Naa Asheley , Lynce Filipa , Dillon Deborah A. , Rosenbluth Jennifer M. , Spitzer Matthew H.
Published: February 2025

Supplementary Data Table S1
Supplementary R package from Targeting of Tumoral NAC1 Mitigates Myeloid-Derived Suppressor Cell–Mediated Immunosuppression and Potentiates Anti–PD-1 Therapy in Ovarian Cancer
Authors: Dong Shunli , Ye Cong , Li Bin , Lv Fanglin , Zhang Lu , Yang Shumin , Wang Fang , Zhu Mingxian , Zhou Mingxuan , Guo Fanfan , Li Zhenyun , Peng Lei , Ji Cheng , Lu Xialiang , Cheng Yan , Ren Xingcong , Chen Youguo , Zhou Jinhua , Yang Jinming , Zhang Yi
Published: February 2025

Supplementary R package
Supplementary Figure S8 from Targeting of Tumoral NAC1 Mitigates Myeloid-Derived Suppressor Cell–Mediated Immunosuppression and Potentiates Anti–PD-1 Therapy in Ovarian Cancer
Authors: Dong Shunli , Ye Cong , Li Bin , Lv Fanglin , Zhang Lu , Yang Shumin , Wang Fang , Zhu Mingxian , Zhou Mingxuan , Guo Fanfan , Li Zhenyun , Peng Lei , Ji Cheng , Lu Xialiang , Cheng Yan , Ren Xingcong , Chen Youguo , Zhou Jinhua , Yang Jinming , Zhang Yi
Published: February 2025

Figure S8. The levels of CXCR6 mRNA in MDSCs.
Supplementary Figure S7 from Targeting of Tumoral NAC1 Mitigates Myeloid-Derived Suppressor Cell–Mediated Immunosuppression and Potentiates Anti–PD-1 Therapy in Ovarian Cancer
Authors: Dong Shunli , Ye Cong , Li Bin , Lv Fanglin , Zhang Lu , Yang Shumin , Wang Fang , Zhu Mingxian , Zhou Mingxuan , Guo Fanfan , Li Zhenyun , Peng Lei , Ji Cheng , Lu Xialiang , Cheng Yan , Ren Xingcong , Chen Youguo , Zhou Jinhua , Yang Jinming , Zhang Yi
Published: February 2025

Figure S7. NAC1 induces MDSCs recruitment via the CXCL16-CXCR6 axis.
Supplementary Figure S3 from Hyperthermic Intrathoracic Chemotherapy Modulates the Immune Microenvironment of Pleural Mesothelioma and Improves the Impact of Dual Immune Checkpoint Inhibition
Authors: Hao Yameng , Gkasti Aspasia , Managh Amy J. , Dagher Julien , Sifis Alexandros , Tiron Luca , Chriqui Louis-Emmanuel , Marie Damien N. , De Souza Silva Olga , Christodoulou Michel , Peters Solange , Joyce Johanna A. , Krueger Thorsten , Gonzalez Michel , Abdelnour-Berchtold Etienne , Sempoux Christine , Clerc Daniel , Teixeira-Farinha Hugo , Hübner Martin , Meylan Etienne , Dyson Paul J. , Cavin Sabrina , Perentes Jean Y.
Published: February 2025

Supplementary Figure S3: Representative flow cytometry histograms.
Data from TBK1 Targeting Is Identified as a Therapeutic Strategy to Enhance CAR T-Cell Efficacy Using Patient-Derived Organotypic Tumor Spheroids
Authors: Sun Yi , Maggs Luke , Panda Apekshya , Wright Samuel J. , Cicerchia Angelina M. , Jenney Anne , Perricone Matthew D. , Mills Caitlin E. , Cattaneo Giulia , Ventin Marco , Chen Feng , Rasmussen Martin Q. , Miranda Alex , Revach Or-Yam , Fang Jacy , Fu Amina , Bowling Peter J. , Sharova Tatyana , Lawless Aleigha , Sorger Peter K. , Bardeesy Nabeel , Wang Xinhui , Flaherty Keith T. , Boland Genevieve M. , Mehta Arnav , Sade-Feldman Moshe , Ferrone Cristina R. , Jenkins Russell W.
Published: February 2025

Abstract
Novel therapeutic strategies are needed to improve the efficacy of chimeric antigen receptor (CAR) T cells as a treatment of solid tumors. Multiple tumor microenvironmental factors are thought to contribute to resistance to CAR T-cell therapy in solid tumors, and appropriate model systems to identify and examine these factors using clinically relevant biospecimens are limited. In this study, we examined the activity of B7-H3–directed CAR T cells (B7-H3.CAR-T) using 3D microfluidic cultures of patient-derived organotypic tumor spheroids (PDOTS) and then confirmed the activity of B7-H3.CAR T cells in PDOTS. Although B7-H3 expression in PDOTS was associated with B7-H3.CAR-T sensitivity, mechanistic studies revealed dynamic upregulation of co-inhibitory receptors on CAR T-cells following target cell encounter that led to CAR T-cell dysfunction and limited efficacy against B7-H3–expressing tumors. PD-1 blockade restored CAR T-cell activity in monotypic and organotypic tumor spheroids with improved tumor control and upregulation of effector cytokines. Given the emerging role of TANK-binding kinase 1 (TBK1) as an immune evasion gene, we examined the effect of TBK1 inhibition on CAR T-cell efficacy. Similar to PD-1 blockade, TBK1 inhibition restored CAR T-cell activity in monotypic and organotypic tumor spheroids, prevented CAR T-cell dysfunction, and enhanced CAR T-cell proliferation. Inhibition or deletion of TBK1 also enhanced the sensitivity of cancer cells to immune-mediated killing. Taken together, our results demonstrate the feasibility and utility of ex vivo profiling of CAR T cells using PDOTS and suggest that targeting TBK1 could be used to enhance CAR T-cell efficacy by overcoming tumor-intrinsic and -extrinsic resistance mechanisms.
Data from Targeting of Tumoral NAC1 Mitigates Myeloid-Derived Suppressor Cell–Mediated Immunosuppression and Potentiates Anti–PD-1 Therapy in Ovarian Cancer
Authors: Dong Shunli , Ye Cong , Li Bin , Lv Fanglin , Zhang Lu , Yang Shumin , Wang Fang , Zhu Mingxian , Zhou Mingxuan , Guo Fanfan , Li Zhenyun , Peng Lei , Ji Cheng , Lu Xialiang , Cheng Yan , Ren Xingcong , Chen Youguo , Zhou Jinhua , Yang Jinming , Zhang Yi
Published: February 2025

Abstract
Epithelial ovarian cancer is the most common type of ovarian cancer with a low rate of response to immunotherapy such as immune checkpoint blockade therapy. In this study, we report that nucleus accumbens–associated protein 1 (NAC1), a putative driver of epithelial ovarian cancer, has a critical role in immune evasion. We showed in murine ovarian cancer models that depleting or inhibiting tumoral NAC1 reduced the recruitment and immunosuppressive function of myeloid-derived suppressor cells (MDSC) in the tumor microenvironment, led to significant increases of cytotoxic tumor-infiltrating CD8+ T cells, and promoted antitumor immunity and suppressed tumor progression. We further showed that tumoral NAC1 directly enhanced the transcription of CXCL16 by binding to CXCR6, thereby promoting MDSC recruitment to the tumor. Moreover, lipid C20:1T produced by NAC1-expressing tumor cells fueled oxidative metabolism of MDSCs and promoted their immune-suppressive function. We also showed that NIC3, a small-molecule inhibitor of NAC1, was able to sensitize mice bearing NAC1-expressing ovarian tumors to anti–PD-1 therapy. Our study reveals a critical role for NAC1 in controlling tumor infiltration of MDSCs and in modulating the efficacy of immune checkpoint blockade therapy. Thus, targeting of NAC1 may be exploited to sensitize ovarian cancer to immunotherapy.
Data from Inflammatory Stress Determines the Need for Chemotherapy in Patients with HER2-Positive Esophagogastric Adenocarcinoma Receiving Targeted Therapy and Immunotherapy
Authors: Tintelnot Joseph , Paschold Lisa , Goekkurt Eray , Schultheiss Christoph , Matschl Urte , Santos Cruz Mariana , Bauer Marcus , Wickenhauser Claudia , Thuss-Patience Peter , Lorenzen Sylvie , Ettrich Thomas J. , Riera-Knorrenschild Jorge , Jacobasch Lutz , Kretzschmar Albrecht , Kubicka Stefan , Al-Batran Salah-Eddin , Reinacher-Schick Anke , Pink Daniel , Bokemeyer Carsten , Sinn Marianne , Lindig Udo , Hinke Axel , Hegewisch-Becker Susanna , Stein Alexander , Binder Mascha
Published: February 2025

Abstract
Anti–PD-1, trastuzumab, and chemotherapy are used in the treatment of patients with advanced HER2-positive esophagogastric adenocarcinoma, but long-term survival remains limited. In this study, we report extended follow-up data from the INTEGA trial (NCT03409848), which investigated the efficacy of the anti–PD-1 nivolumab, trastuzumab, and FOLFOX chemotherapy (FOLFOX arm) in comparison with a chemotherapy-free regimen involving nivolumab, trastuzumab, and the anti–CTLA-4 ipilimumab (Ipi arm) in the first-line setting for advanced disease. The 12-month overall survival (OS) showed no statistical difference between the arms, with 57% OS (95% confidence interval, 41%–71%) in the Ipi arm and 70% OS (95% confidence interval, 54%–82%) in the FOLFOX arm. Crossing of the survival curves indicated a potential long-term benefit for some patients within the Ipi arm, but early progressors in the Ipi arm underlined the need for biomarker-guided strategies to optimize treatment selection. To this end, metabolomic and cytokine analyses demonstrated elevated levels of normetanephrine, cortisol, and IL6 in immunotherapy-unresponsive patients in the Ipi arm, suggesting a role for systemic inflammatory stress in modulating antitumor immune responses. Patients with this signature also showed an increased neutrophil to lymphocyte ratio that persisted in the Ipi arm, but not in the FOLFOX arm, and strongly correlated with survival. Furthermore, a low neutrophil to lymphocyte ratio characterized patients benefiting from immunotherapy and targeted therapy without the need for additional chemotherapy. These data suggest that patient selection based on inflammatory stress–driven immune changes could help customize first-line treatment in patients with advanced HER2-positive esophagogastric adenocarcinoma to potentially improve long-term survival.
Data from Loss of NF1 Accelerates Uveal and Intradermal Melanoma Tumorigenesis, and Oncogenic GNAQ Transforms Schwann Cells
Authors: Longakit Anne Nathalie , Urtatiz Oscar , Luty Amy , Zhang Christina , Hess Chloe , Yoo Alyssa , Bourget Hannah , Van Raamsdonk Catherine D.
Published: February 2025

Abstract
NF1 encodes the multifunctional tumor suppressor protein, neurofibromin, which is best known for its causative role in neurofibromatosis type 1 and in regulating MAPK signaling. Neurofibromin, in a context-specific manner, is involved in various tumorigenic processes, including those in melanocytes. This study investigated whether NF1 loss can collaborate with oncogenic GNAQ to promote melanoma in the dermis or eyes, in which the Gαq pathway is almost always activated. We found that heterozygous 17q11.2 loss that includes the NF1 locus is a recurrent phenomenon in human intradermal and uveal melanomas described in the literature. We studied the effects of Nf1 haploinsufficiency in mice expressing oncogenic GNAQQ209L in melanocytes and Schwann cells of peripheral nerves using the Plp1-creERT transgene with tamoxifen at 5 weeks of age. Nf1 haploinsufficiency accelerated melanoma formation and/or growth. RNA sequencing analysis found significant pathways related to cAMP signaling and myogenesis. In addition, 20% of the differentially expressed genes were homologous to genes for which expression correlates with prognosis in human uveal melanoma. Unexpectedly, we found that GNAQQ209L alone was sufficient to drive cutaneous nerve sheath tumors, with one GNAQQ209L-expressing Nf1 haploinsufficient mouse also developing a plexiform variant. These tumors strongly resembled neurofibromas. We searched the cBioPortal for Cancer Genomics database and found plexiform neurofibromas with the GNAQT96S hotspot mutation. The Plp1-creERT; GNAQQ209L model with tamoxifen at 5 weeks may be useful as a preclinical model for neurofibroma. Our studies emphasize the importance of GNAQ and NF1 in regulating neural crest–derived cells existing in a dermal-like environment.
Significance:
These results indicate that NF1 loss in intradermal and uveal melanomas is a potentially significant finding. They emphasize the importance of neurofibromin in cAMP signaling. They show for the first time that oncogenic GNAQ can transform Schwann cells in mice. The Plp1-creERT transgene with tamoxifen given at 5 weeks may be a particularly good strategy for modeling cutaneous neurofibroma and plexiform neurofibroma.
Dynamic parameters for Brazilian financial time series
Authors: Francisco Gerson , Paiva Cláudio , Rosenfeld Rogerio
Published: February 2025

In this study we analyse a Brazilian stock index called IBOVESPA using techniques from dynamical systems theory and stochastic processes. We discuss the Lyapunov exponent, the correlation dimension, the LempelZiv complexity, the Hurst exponent and the BDS statistics. We compare this study with other time series including stock prices and deterministic systems. We conclude that the IBOVESPA is a linear stochastic process that exhibits the phenomenon of persistence, thatis, it has long term memory. The stocks are described by nonlinear stochastic processes making it impossible to be simulated with deterministic models such as the usual neural networks architectures.
Efeitos de um programa de condicionamento físico no processo de reabilitação multiprofissional de uma pessoa obesa e amputada: um relato de caso
Authors: Martins Fernanda Maria , Mota Cristiane Gonçalves da , Leite Erica de Castro , Yazbek Junior Paulo , Imamura Marta , Battistella Linamara Rizzo , Sugawara André Tadeu
Published: February 2025

Objetivo: Verificar os efeitos de um programa de condicionamento físico (CF) intensivo sobre a força muscular (FM), capacidade funcional, peso corporal (PC) e índice de massa corporal (IMC) de uma pessoa amputada e com obesidade em processo de reabilitação física multiprofissional para protetização. Métodos: Essa pesquisa é um estudo de caso, de um homem jovem com obesidade que foi submetido a um programa de CF intensivo, 5-6 vezes por semana, durante 10 semanas. A FM, capacidade funcional, PC e IMC foram quantificadas por meio do teste de 7-10 repetições máximas, teste de levantar e sentar da cadeira por 30 segundos e balança antropométrica com estadiômetro acoplado, respectivamente. Resultados: Após a intervenção houve aumento da FM e melhora da capacidade funcional. Além disso, houve redução do PC e IMC após a intervenção. Conclusão: Nossos achados sugerem que um programa de CF intensivo foi eficaz para aumentar a FM, melhorar a capacidade funcional e reduzir o PC e IMC de uma pessoa com amputação de MMII e obesidade durante o processo de reabilitação física multiprofissional para protetização. Além disso, nosso estudo sugere que a realização de um programa de CF intensivo durante o processo de reabilitação física multiprofissional parece ser uma estratégia indispensável para auxiliar na adequação do PC e possibilitar a protetização em pessoas com obesidade.
Challenges of usability and access to a digital tool in a telerehabilitation program for COVID- 19 survivors in a developing country
Authors: Groehs Raphaela Vilar , Bellani Cristiane Aparecida Paião , Jorge Liliana Lourenço , Gaspar Alexandra Passos , Oliveira Isabela Belarmino , Gonçalves Louise Helena Rodrigues , Pereira Elaine Cristina , Matos Luciana Diniz Nagem Janot de
Published: February 2025

Objective: The outbreak of COVID-19 brought many challenges for health system, including for rehabilitation facilities. To supply the high amount of patients with disabilities and functional impairments, telerehabilitation might be a feasible strategy. The aim of this prospective clinical trial is to present a practical experience of a 3-month physical telerehabilitation program, for post COVID-19 patients from a public health system, after hospital discharge. Method: The sample was recruited from a list of 407 patients, to be enrolled up to eight weeks after discharge. Primary outcome measures: Two-minute step test (2MST), Time to Five repetition in the Sit-To-Stand Test, EuroQol (EQ5D). This virtual-wise program consisted of customized videos for respiratory and functional exercises, on a 3-times a week basis. Results: Out of 407 patients, only 19 were enrolled, and 14 completed the program. Main sample losses were due to lack of phone contact, internet and technological constraints and in-person return to work needs. Participants mean age was 56 ± 16.8, 57.9% men; 12 (63.2%) lost weight during hospitalization. Patients increased the 2MST (p= 0.004), a reduction in the five repetitions in the sit and stand test (p= 0.002) and health status score (p= 0.007). Conclusion: Telerehabilitation is a promising option for the treatment of post-discharge COVID-19, physically disabled patients. However, socioeconomical barriers must be taken into account during the development of remote programs for rehabilitation, in order to ensure population access, especially to unequal countries.
Entre biomas e padrões de relevo: diversidade e dinâmica da paisagem da região imediata de Cachoeira do Sul, Rio Grande do Sul
Authors: Weiss Raquel , Zaghetti Ariel , Wilhelm Martiele , Ziani Patrícia , Seefeldt Tainara
Published: February 2025

El objetivo de este trabajo es reconocer y caracterizar la diversidad del paisaje de la Región Inmediata de Cachoeira do Sul (REGICS), entendiéndolo como medio y producto, lugar de condicionantes y transformaciones. Para ello, la investigación se basó en un estudio teórico-metodológico de Ecología del Paisaje; el cruce de datos e información en una interfaz de Sistemas de Información Geográfica (ArcGIS Pro-ESRI) para crear mapas temáticos; y el trabajo de campo. Los resultados incluyen la caracterización de la región, relacionando aspectos morfológicos del paisaje definidos por biomas, patrones de relieve asociados a diferentes tipos de uso y cobertura del suelo y estructura de la propiedad de la tierra, utilizando como base la matriz. A continuación, se generaron datos cuantitativos mediante métricas del paisaje, caracterizando la dinámica y los procesos entre 1985 y 2020, que se resumieron en un cuadro comparativo. A partir del análisis sistémico del paisaje, los resultados encontrados refuerzan la intensificación de las áreas agrícolas como matriz dominante frente a la complejidad paisajística y estructural de REGICS, demostrando ser una importante herramienta para la planificación territorial y ambiental.
Advancing Health Equity in the Cardiovascular Device Life Cycle
Authors: Small Andre M. , Watson Nathan W. , Wadhera Rishi K. , Secemsky Eric A. , Yeh Robert W.
Published: February 2025

Despite advancements in diagnostics and therapeutics for cardiovascular disease, significant health disparities persist among patients from historically marginalized racial and ethnic groups, women, individuals who are socioeconomically under-resourced or underinsured, and those living in rural communities. While transcatheter interventions have revolutionized the treatment landscape in cardiology, populations bearing the greatest burden of disease continue to face inequitable access and poorer outcomes. A notable gap in the literature concerns the role of modern approaches to cardiovascular device innovation in shaping and perpetuating health disparities. Health equity has been declared one of the top strategic initiatives for 2022 to 2025 by the Food and Drug Administration Center for Devices and Radiological Health, underscoring the need for greater attention, dialogue, and targeted interventions in this space. This narrative review uses the cardiovascular device life cycle as a conceptual framework to enhance understanding and guide future efforts to mitigate disparities in the field of interventional cardiology. Drawing on illustrative examples from interventional cardiology, we examine current practices in cardiovascular device regulation and approval, clinical trial evaluation, adoption patterns, and postprocedural outcomes with the aim of uncovering potential mechanisms of disparities and identifying opportunities for targeted interventions.
Sex Differences in Computed Tomography Coronary Stenosis Severity Versus Flow Impairment and Impact on Revascularization, Clinical Events and Health Care Costs: A FORECAST Substudy
Authors: Gabara Lavinia , Hinton Jonathan , Kira Mohamed , Shambrook James , Abbas Ausami , Wilding Sam , Leipsic Jonathon A. , Douglas Pamela S. , Curzen Nick
Published: February 2025

Background

The impact of sex‐related differences in coronary atheroma and flow impairment severity on clinical events and costs remains unclear.

Methods and Results

This is a secondary analysis of patients with stable coronary artery disease who underwent both coronary computed tomography angiography  and fractional flow reserve derived from computed tomography as part of the
FORECAST
(Fractional Flow Reserve Derived From Computed Tomography Coronary Angiography in the Assessment and Management of Stable Chest Pain) trial, investigating (1) the relationship between coronary stenosis severity on coronary computed tomography angiography and fractional flow reserve derived from computed tomography FFR
CT
 by sex and (2) the association with revascularization, resource usage, and adverse clinical events. A total of 212 patients (64 female participants [32.1%]) and 1245 vessels were included. There was no significant sex difference in the frequencies of significant coronary artery disease (38.2% of women versus 51.3% of men;
P
=0.073), but female participants had significantly less coronary flow impairment, according to the presence of at least 1 fractional flow reserve derived from computed tomography≤0.8 (47.0% versus 71.5%;
P
=0.008). Female subjects underwent fewer revascularization procedures (23.5% versus 42.3%;
P
=0.014), less coronary artery bypass graft surgery (2.9% versus 13.1%;
P
=0.025) and were less likely to be on statin treatment (72.0% versus 84.7%;
P
=0.022) by 9‐month follow‐up. This resulted in lower overall health care costs for female participants compared with male counterparts (median total cost, £1276 versus £2051;
P
=0.014). In multivariable Cox analysis the presence of significant coronary artery disease (hazard ratio [
HR],
2.91; 95%
CI
, 1.30–6.51) and having a positive fractional flow reserve derived from computed tomography (
HR,
4.11; 95%
CI,
1.15–14.69) were independent predictors of major adverse cardiovascular events at 9 months, whereas sex was not statistically significant (
p
=0.13).

Conclusions

There are significant sex differences in the anatomico‐functional assessment of coronary artery disease leading to differences in clinical management, costs, and adverse events.
Development and Evaluation of a Deep Learning–Based Pulmonary Hypertension Screening Algorithm Using a Digital Stethoscope
Authors: Guo Ling , Khobragade Nivedita , Kieu Spencer , Ilyas Suleman , Nicely Preston N. , Asiedu Emmanuel K. , Lima Fabio V. , Currie Caroline , Lastowski Emileigh , Choudhary Gaurav
Published: February 2025

Background

Despite the poor outcomes related to the presence of pulmonary hypertension, it often goes undiagnosed in part because of low suspicion and screening tools not being easily accessible such as echocardiography. A new readily available screening tool to identify elevated pulmonary artery systolic pressures is needed to help with the prognosis and timely treatment of underlying causes such as heart failure or pulmonary vascular remodeling. We developed a deep learning–based method that uses phonocardiograms (PCGs) for the detection of elevated pulmonary artery systolic pressure, an indicator of pulmonary hypertension.

Methods

Approximately 6000 PCG recordings with the corresponding echocardiogram‐based estimated pulmonary artery systolic pressure values, as well as ≈169 000 PCG recordings without associated echocardiograms, were used for training a deep convolutional network to detect pulmonary artery systolic pressures ≥40 mm Hg in a semisupervised manner. Each 15‐second PCG, recorded using a digital stethoscope, was processed to generate 5‐second mel‐spectrograms. An additional labeled data set of 196 patients was used for testing. GradCAM++ was used to visualize high importance segments contributing to the network decision.

Results

An average area under the receiver operator characteristic curve of 0.79 was obtained across 5 cross‐validation folds. The testing data set gave a sensitivity of 0.71 and a specificity of 0.73, with pulmonic and left subclavicular locations having higher sensitivities. GradCAM++ technique highlighted physiologically meaningful PCG segments in example pulmonary hypertension recordings.

Conclusions

We demonstrated the feasibility of using digital stethoscopes in conjunction with deep learning algorithms as a low‐cost, noninvasive, and easily accessible screening tool for early detection of pulmonary hypertension.
KLF12 Aggravates Angiotensin II‐Induced Cardiac Remodeling in Male Mice by Transcriptionally Inhibiting SMAD7
Authors: Hu Min , Huang Shi‐Yu , Gao Yi‐Peng , Hu Yu‐Xin , Wang Sha‐Sha , Teng Teng , Zeng Xiao‐Feng , Tang Qi‐Zhu
Published: February 2025

Background

Adverse left ventricular remodeling and subsequent heart failure remain a major cause of patient morbidity and mortality worldwide. The KLF family of transcription factors plays crucial roles in heart injury. KLF12 (Krüppel‐like factor 12) is a transcription factor that regulates multiple disease processes, although the specific role of KLF12 in cardiac remodeling remains unclear.

Methods and Results

In our study, we observed a significant upregulation of KLF12 expression in remodeling hearts. The increased expression of KLF12 primarily originated from cardiac fibroblasts during the fibrotic response induced by angiotensin II. To investigate the effects of KLF12, we performed RNA‐seq and found that KLF12 overexpression significantly upregulated the cardiac remodeling associated pathway. Hence, we generated adult mice with cardiac fibroblast‐specific overexpression of KLF12 using lentivirus or miRNA (miR‐1/133TS) technology. Compared with control mice, KLF12‐miR1/133TS transfected mice exhibited exacerbated cardiac remodeling and function. Mechanistically, we discovered that KLF12 directly binds to the promoter of Smad7, leading to the activation of the TGF‐β (transforming growth factor beta)‐Smad3 pathway.

Conclusions

In conclusion, KLF12 promoted the development of angiotensin II‐induced cardiac remodeling in male mice. Targeting KLF12 may be a promising therapeutic approach to treat cardiac remodeling.
Telomere Length Is Associated With Adverse Atrial Remodeling in Patients With Atrial Fibrillation
Authors: Pradhan Kabita , Neupane Balram , Niehues Paul , Kirschner Martin , Beier Fabian , Kuo Chao‐Chung , Hilbold Erika Anneliese , Bär Christian , Thoma Oana‐Maria , Waldner Maximilian , Vieri Margherita , Brümmendorf Tim H. , Tharmapalan Vithurithra , Wagner Wolfgang , Kleines Michael , Emrani Mahdi , Zink Matthias Daniel , Napp Andreas , Marx Nikolaus , Gramlich Michael
Published: February 2025

Background

Atrial fibrillation (AF) is the most common cardiac arrhythmia with a massive burden on global health. The prevalence of AF increases dramatically with age and can be up to 18% in patients older than 80 years. Telomeres, which are short, repeated DNA sequences at the end of chromosomes, are known to act as a biological aging marker. In this study, we investigated the relation of telomere shortening and AF in the context of atrial remodeling. Furthermore, we assessed changes in the gene expression profiles of patients with AF according to telomere length (TL) and left atrial fibrosis.

Methods

We included 72 patients undergoing catheter ablation for AF. Bipolar voltage maps were obtained to determine left atrial low voltage areas as a surrogate for atrial fibrosis. TL was quantified and correlated to low voltage areas. 3′ mRNA sequencing was performed for gene expression profiling. Clonal hematopoiesis of indeterminate potential was assessed by next generation sequencing. Telomerase reverse transcriptase knockout (
Tert
−/−
) and telomerase RNA component knockout (
Terc
−/−
) mice were used to investigate the mechanistic impact of telomere shortening on atrial remodeling.

Results

Patients with advanced left atrial fibrosis had shorter telomeres compared with patients with healthy left atria. Furthermore, there was a strong correlation between the extent of left atrial low voltage areas, TL, and outcome after catheter ablation of AF. 24 months after ablation, only 26.5% of patients with advanced fibrosis and short TL were in sinus rhythm compared with 62.5% of patients with no/low fibrosis and long TL. Gene expression profiles and clonal hematopoiesis of indeterminate potential frequency differed in patients with AF with short and long telomeres. Finally, atrial tissue of mouse models with shortened telomeres showed marked left atrial fibrosis and over‐expression of fibrosis‐related genes.

Conclusions

Telomere shortening is correlated with left atrial remodeling. Shorter telomeres are associated with a series of molecular events which could eventually lead to cardiac fibrosis and perpetuate AF.
Vascular Contractility Relies on Integrity of Progranulin Pathway: Insights Into Mitochondrial Function
Authors: Singh Shubhnita , Bruder Ariane , Costa Rafael M. , Alves Juliano V. , Bharathi Sivakama , Goetzman Eric S. , Bruder‐Nascimento Thiago
Published: February 2025

Background

The complex interplay between vascular contractility and mitochondrial function is central to cardiovascular disease. The progranulin gene (
GRN
) encodes glycoprotein PGRN (progranulin), a ubiquitous molecule with known anti‐inflammatory property. However, the role of PGRN in cardiovascular disease remains undefined. In this study, we sought to dissect the significance of PGRN in the regulation vascular contractility and investigate the interface between PGRN and mitochondrial quality.

Methods and Results

We used aortae from male and female C57BL6/J wild‐type (PGRN+/+) and B6(Cg)‐Grntm1.1Aidi/J (PGRN−/−) mice. Our results showed suppression of contractile activity in PGRN−/−, followed by reduced α‐smooth muscle actin expression. Mechanistically, PGRN deficiency suppressed mitochondrial respiration, induced mitochondrial fission, and disturbed autophagy process and redox signaling, while restoration of PGRN levels in aortae from PGRN−/− mice via lentivirus delivery ameliorated contractility and boosted mitochondria activity. In addition, in vivo treatment with mitochondrial fission inhibitor restored mitochondrial quality and vascular contractility, while vascular smooth muscle cells overexpressing PGRN displayed higher lysosome biogenesis, accelerated mitophagy flux, and mitochondrial respiration accompanied by vascular hypercontractility. Finally, angiotensin II failed to induce vascular contractility in PGRN−/−, suggesting a key role of PGRN to maintain the vascular tone.

Conclusions

Our findings suggest that PGRN preserves the vascular contractility via regulating mitophagy flux, mitochondrial activity and dynamics, and redox signaling. Therefore, loss of PGRN function appears as a pivotal risk factor in cardiovascular disease.