tbuckley/cabot-search huggingface dataset:
Progranulin AAV gene therapy for frontotemporal dementia: translational studies and phase 1/2 trial interim results
Authors: Jeffrey Sevigny, Olga Uspenskaya, Laura Dean Heckman, Li Chin Wong, Daniel A. Hatch, Ambika Tewari, Rik Vandenberghe, David J. Irwin, Dario Saracino, Isabelle Le Ber, Rebekah Ahmed, Jonathan D. Rohrer, Adam L. Boxer, Sebastian Boland, Patricia Sheehan, Alissa Brandes, Suzanne R. Burstein, Benjamin M. Shykind, Sitharthan Kamalakaran, Carter W. Daniels, E. David Litwack, Erin Mahoney, Jenny Velaga, Ilan McNamara, Patricia Sondergaard, Syed A. Sajjad, Yvonne M. Kobayashi, Asa Abeliovich, Franz Hefti
Journal: Nature Medicine (2024)

Abstract GRN mutations cause progranulin haploinsufficiency, which eventually leads to frontotemporal dementia (FTD-GRN). PR006 is an investigational gene therapy delivering the granulin gene ( GRN ) using an adeno-associated virus serotype 9 (AAV9) vector. In non-clinical studies, PR006 transduced neurons derived from induced pluripotent stem cells of patients with FTD-GRN, resulted in progranulin expression and improvement of lipofuscin, lysosomal and neuroinflammation pathologies in Grn-knockout mice, and was well tolerated except for minimal, asymptomatic dorsal root ganglionopathy in non-human primates. We initiated a first-in-human phase 1/2 open-label trial. Here we report results of a pre-specified interim analysis triggered with the last treated patient of the low-dose cohort ( n = 6) reaching the 12-month follow-up timepoint. We also include preliminary data from the mid-dose cohort ( n = 7). Primary endpoints were safety, immunogenicity and change in progranulin levels in cerebrospinal fluid (CSF) and blood. Secondary endpoints were Clinical Dementia Rating (CDR) plus National Alzheimer’s Disease Coordinating Center (NACC) Frontotemporal Lobar Degeneration (FTLD) rating scale and levels of neurofilament light chain (NfL). One-time administration of PR006 into the cisterna magna was generally safe and well tolerated. All patients developed treatment-emergent anti-AAV9 antibodies in the CSF, but none developed anti-progranulin antibodies. CSF pleocytosis was the most common PR006-related adverse event. Twelve serious adverse events occurred, mostly unrelated to PR006. Deep vein thrombosis developed in three patients. There was one death (unrelated) occurring 18 months after treatment. CSF progranulin increased after PR006 treatment in all patients; blood progranulin increased in most patients but only transiently. NfL levels transiently increased after PR006 treatment, likely reflecting dorsal root ganglia toxicity. Progression rates, based on the CDR scale, were within the broad ranges reported for patients with FTD. These data provide preliminary insights into the safety and bioactivity of PR006. Longer follow-up and additional studies are needed to confirm the safety and potential efficacy of PR006. ClinicalTrials.gov identifier: NCT04408625 .
The aged tumor microenvironment limits T cell control of cancer
Authors: Alex C Y Chen, Sneha Jaiswal, Daniela Martinez, Cansu Yerinde, Keely Ji, Velita Miranda, Megan E Fung, Sarah A Weiss, Maria Zschummel, Kazuhiro Taguchi, Christopher S Garris, Thorsten R Mempel, Nir Hacohen, Debattama R Sen
Journal: Nature Immunology (2024)
Inseparable RNA binding and chromatin modification activities of a nucleosome-interacting surface in EZH2
Authors: Emma H Gail, Evan Healy, Sarena F Flanigan, Natasha Jones, Xiao Han Ng, Michael Uckelmann, Vitalina Levina, Qi Zhang, Chen Davidovich
Journal: Nature Genetics (2024)

Abstract Polycomb repressive complex 2 (PRC2) interacts with RNA in cells, but there is no consensus on how RNA regulates PRC2 canonical functions, including chromatin modification and the maintenance of transcription programs in lineage-committed cells. We assayed two separation-of-function mutants of the PRC2 catalytic subunit EZH2, defective in RNA binding but functional in methyltransferase activity. We find that part of the RNA-binding surface of EZH2 is required for chromatin modification, yet this activity is independent of RNA. Mechanistically, the RNA-binding surface within EZH2 is required for chromatin modification in vitro and in cells, through interactions with nucleosomal DNA. Contrarily, an RNA-binding-defective mutant exhibited normal chromatin modification activity in vitro and in lineage-committed cells, accompanied by normal gene repression activity. Collectively, we show that part of the RNA-binding surface of EZH2, rather than the RNA-binding activity per se, is required for the histone methylation in vitro and in cells, through interactions with the substrate nucleosome.
Analysis of somatic mutations in whole blood from 200,618 individuals identifies pervasive positive selection and novel drivers of clonal hematopoiesis
Authors: Nicholas Bernstein, Michael Spencer Chapman, Kudzai Nyamondo, Zhenghao Chen, Nicholas Williams, Emily Mitchell, Peter J Campbell, Robert L Cohen, Jyoti Nangalia
Journal: Nature Genetics (2024)

Abstract Human aging is marked by the emergence of a tapestry of clonal expansions in dividing tissues, particularly evident in blood as clonal hematopoiesis (CH). CH, linked to cancer risk and aging-related phenotypes, often stems from somatic mutations in a set of established genes. However, the majority of clones lack known drivers. Here we infer gene-level positive selection in whole blood exomes from 200,618 individuals in UK Biobank. We identify 17 additional genes, ZBTB33 , ZNF318 , ZNF234 , SPRED2 , SH2B3 , SRCAP , SIK3 , SRSF1 , CHEK2 , CCDC115 , CCL22 , BAX , YLPM1 , MYD88 , MTA2 , MAGEC3 and IGLL5 , under positive selection at a population level, and validate this selection pattern in 10,837 whole genomes from single-cell-derived hematopoietic colonies. Clones with mutations in these genes grow in frequency and size with age, comparable to classical CH drivers. They correlate with heightened risk of infection, death and hematological malignancy, highlighting the significance of these additional genes in the aging process.
A bioactive nanocomposite integrated specific TAMs target and synergistic TAMs repolarization for effective cancer immunotherapy
Authors: Wei Gu, Wen Guo, Zhishuang Ren, Yimeng Zhang, Meiqi Han, Qinfu Zhao, Yikun Gao, Yuling Mao, Siling Wang
Journal: Bioactive Materials (2024)

Reactive oxygen species (ROS) generated from photosensitizers exhibit great potential for repolarizing immunosuppressive tumor-associated macrophages (TAMs) toward the anti-tumor M1 phenotype, representing a promising cancer immunotherapy strategy. Nevertheless, their effectiveness in eliminating solid tumors is generally limited by the instability and inadequate TAMs-specific targeting of photosensitizers. Here, a novel core-shell integrated nano platform is proposed to achieve a coordinated strategy of repolarizing TAMs for potentiating cancer immunotherapy. Colloidal mesoporous silica nanoparticles (CMSN) are fabricated to encapsulate photosensitizer-Indocyanine Green (ICG) to improve their stability. Then ginseng-derived exosome (GsE) was coated on the surface of ICG/CMSN for targeting TAMs, as well as repolarizing TAMs concurrently, named ICG/CMSN@GsE. As expected, with the synergism of ICG and GsE, ICG/CMSN@GsE exhibited better stability, mild generation of ROS, favorable specificity toward M2-like macrophages, enhancing drug retention in tumors and superior TAMs repolarization potency, then exerted a potent antitumor effect. In vivo, experiment results also confirm the synergistic suppression of tumor growth accompanied by the increased presence of anti-tumor M1-like macrophages and maximal tumor damage. Taken together, by integrating the superiorities of TAMs targeting specificity and synergistic TAMs repolarization effect into a single nanoplatform, ICG/CMSN@GsE can readily serve as a safe and high-performance nanoplatform for enhanced cancer immunotherapy.
Spatial multi-omics at subcellular resolution via high-throughput in situ pairwise sequencing
Authors: Xiaofeng Wu, Weize Xu, Lulu Deng, Yue Li, Zhongchao Wang, Leqiang Sun, Anran Gao, Haoqi Wang, Xiaodan Yang, Chengchao Wu, Yanyan Zou, Keji Yan, Zhixiang Liu, Lingkai Zhang, Guohua Du, Liyao Yang, Da Lin, Junqiu Yue, Ping Wang, Yunyun Han, Zhenfang Fu, Jinxia Dai, Gang Cao
Journal: Nature Biomedical Engineering (2024)
Influence of Pathophysiological Patterns of Coronary Artery Disease on Immediate Percutaneous Coronary Intervention Outcomes
Authors: Carlos Collet, Daniel Munhoz, Takuya Mizukami, Jeroen Sonck, Hitoshi Matsuo, Toshiro Shinke, Hirohiko Ando, Brian Ko, Simone Biscaglia, Fernando Rivero, Thomas Engstrøm, Ketina Arslani, Antonio Maria Leone, Lokien X. van Nunen, William F. Fearon, Evald Høj Christiansen, Stephane Fournier, Liyew Desta, Andy Yong, Julien Adjedj, Javier Escaned, Masafumi Nakayama, Ashkan Eftekhari, Frederik M. Zimmermann, Koshiro Sakai, Tatyana Storozhenko, Bruno R. da Costa, Gianluca Campo, Nick E.J. West, Tom De Potter, Ward Heggermont, Dimitri Buytaert, Jozef Bartunek, Colin Berry, Damien Collison, Thomas Johnson, Tetsuya Amano, Divaka Perera, Allen Jeremias, Ziad Ali, Nico H.J. Pijls, Bernard De Bruyne, Nils P. Johnson
Journal: Circulation (2024)

BACKGROUND: Diffuse coronary artery disease affects the safety and efficacy of percutaneous coronary intervention (PCI). Pathophysiologic coronary artery disease patterns can be quantified using fractional flow reserve (FFR) pullbacks incorporating the pullback pressure gradient (PPG) calculation. This study aimed to establish the capacity of PPG to predict optimal revascularization and procedural outcomes. METHODS: This prospective, investigator-initiated, single-arm, multicenter study enrolled patients with at least one epicardial lesion with an FFR ≤0.80 scheduled for PCI. Manual FFR pullbacks were used to calculate PPG. The primary outcome of optimal revascularization was defined as an FFR ≥0.88 after PCI. RESULTS: A total of 993 patients with 1044 vessels were included. The mean FFR was 0.68±0.12, PPG 0.62±0.17, and the post-PCI FFR was 0.87±0.07. PPG was significantly correlated with the change in FFR after PCI (r=0.65 [95% CI, 0.61–0.69]; P &lt;0.001) and demonstrated excellent predictive capacity for optimal revascularization (area under the receiver operating characteristic curve, 0.82 [95% CI, 0.79–0.84]; P &lt;0.001). FFR alone did not predict revascularization outcomes (area under the receiver operating characteristic curve, 0.54 [95% CI, 0.50–0.57]). PPG influenced treatment decisions in 14% of patients, redirecting them from PCI to alternative treatment modalities. Periprocedural myocardial infarction occurred more frequently in patients with low PPG (&lt;0.62) compared with those with focal disease (odds ratio, 1.71 [95% CI, 1.00–2.97]). CONCLUSIONS: Pathophysiologic coronary artery disease patterns distinctly affect the safety and effectiveness of PCI. PPG showed an excellent predictive capacity for optimal revascularization and demonstrated added value compared with an FFR measurement. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04789317.
N-of-1 Trial of Angina Verification Before Percutaneous Coronary Intervention
Authors: Christopher A. Rajkumar, Michael J. Foley, Fiyyaz Ahmed-Jushuf, Florentina A. Simader, Muhammad Mohsin, Sashiananthan Ganesananthan, Alexandra N. Nowbar, Shayna Chotai, Sayan Sen, Ricardo Petraco, Sukhjinder S. Nijjer, Joban Sehmi, Neil Ruparelia, Jason N. Dungu, Alamgir Kabir, Kare Tang, Reto Gamma, John R. Davies, Tushar Kotecha, Graham D. Cole, James P. Howard, Thomas R. Keeble, Gerald Clesham, Peter D. O’Kane, Frank E. Harrell, Darrel P. Francis, Matthew J. Shun-Shin, Rasha K. Al-Lamee
Journal: Journal of the American College of Cardiology (2024)
The Influence of Epicardial Resistance on Microvascular Resistance Reserve
Authors: Thabo Mahendiran, Dario Bertolone, Michele Mattia Viscusi, Emanuele Gallinoro, Danielle C.J. Keulards, Carlos Collet, Jeroen Sonck, Adriaan Wilgenhof, Nico H.J. Pijls, Bernard De Bruyne
Journal: Journal of the American College of Cardiology (2024)
Glycemic Control and Coronary Stent Failure in Patients With Type 2 Diabetes Mellitus
Authors: Irene Santos-Pardo, Mikael Andersson Franko, Bo Lagerqvist, Viveca Ritsinger, Björn Eliasson, Nils Witt, Anna Norhammar, Thomas Nyström
Journal: Journal of the American College of Cardiology (2024)
A triad between sex, necrosis, and inflammation shapes glioblastoma outcomes
Authors: Brandon Emanuel León, Defne Bayik
Journal: Neuro-Oncology (2024)

Journal Article Accepted manuscript A triad between sex, necrosis, and inflammation shapes glioblastoma outcomes Get access Brandon Emanuel León, Brandon Emanuel León Department of Molecular and Cellular Pharmacology, Miller School of Medicine, University of Miami, Miami, FLSylvester Comprehensive Cancer Center, University of Miami, Miami, FL Search for other works by this author on: Oxford Academic PubMed Google Scholar Defne Bayik Defne Bayik Department of Molecular and Cellular Pharmacology, Miller School of Medicine, University of Miami, Miami, FLSylvester Comprehensive Cancer Center, University of Miami, Miami, FL Corresponding author: defne.bayik@miami.edu https://orcid.org/0000-0002-4740-8869 Search for other works by this author on: Oxford Academic PubMed Google Scholar Neuro-Oncology, noae086, https://doi.org/10.1093/neuonc/noae086 Published: 14 May 2024 Article history Received: 23 April 2024 Published: 14 May 2024
Frailty according to the 2019 HFA‐ESC definition in patients at risk for advanced heart failure: Insights from the HELP‐HF registry
Authors: Alessandro Villaschi, Mauro Chiarito, Matteo Pagnesi, Davide Stolfo, Luca Baldetti, Carlo Mario Lombardi, Marianna Adamo, Ferdinando Loiacono, Antonio Maria Sammartino, Giada Colombo, Daniela Tomasoni, Riccardo Maria Inciardi, Marta Maccallini, Gaia Gasparini, Marco Montella, Stefano Contessi, Daniele Cocianni, Maria Perotto, Giuseppe Barone, Marco Merlo, Cristiana Vitale, Giuseppe Massimo Claudio Rosano, Alberto Maria Cappelletti, Gianfranco Sinagra, Marco Metra, Daniela Pini
Journal: European Journal of Heart Failure (2024)

Abstract Aims Frailty is highly prevalent in patients with heart failure (HF), but a concordant definition of this condition is lacking. The Heart Failure Association of the European Society of Cardiology (HFA‐ESC) proposed in 2019 a new multi‐domain definition of frailty, but it has never been validated. Methods and results Patients from the HELP‐HF registry were stratified according to the number of HFA‐ESC frailty domains fulfilled and to the cumulative deficits frailty index (FI) quintiles. Prevalence of frailty and of each domain was reported, as well as the rate of the composite of all‐cause death and HF hospitalization, its single components, and cardiovascular death in each group and quintile. Among 854 included patients, 37 (4.3%), 206 (24.1%), 365 (42.8%), 217 (25.4%), and 29 (3.4%) patients fulfilled zero, one, two, three, or four domains, respectively, while 179 patients had a FI &lt; 0.21 and were considered not frail. The 1‐year risk of adverse events increased proportionally to the number of domains fulfilled (for each criterion increase, all‐cause death or HF hospitalization: hazard ratio [HR] 1.43, 95% confidence interval [CI] 1.27–1.62; all‐cause death: HR 1.72, 95% CI 1.46–2.02, HF hospitalizations: subHR 1.21, 95% CI 1.04–1.31; cardiovascular death: HR 1.77, 95% CI 1.45–2.15). Consistent results were found stratifying the cohort for FI quintiles. The FI as a continuous variable demonstrated higher discriminative ability than the number of domains fulfilled (area under the curve = 0.68 vs. 0.64, p = 0.004). Conclusion Frailty in patients at risk for advanced HF, assessed via a multi‐domain approach and the FI, is highly prevalent and identifies those at increased risk of adverse events. The FI was found to be slightly more effective in identifying patients at increased risk of mortality.
Finerenone in patients with heart failure with mildly reduced or preserved ejection fraction: Rationale and design of the <scp>FINEARTS‐HF</scp> trial
Authors: Muthiah Vaduganathan, Brian L. Claggett, Carolyn S.P. Lam, Bertram Pitt, Michele Senni, Sanjiv J. Shah, Adriaan A. Voors, Faiez Zannad, Akshay S. Desai, Pardeep S. Jhund, Prabhakar Viswanathan, Antonieta Bomfim Wirtz, Patrick Schloemer, James Lay‐Flurrie, John J.V. McMurray, Scott D. Solomon
Journal: European Journal of Heart Failure (2024)

ABSTRACT Aim Steroidal mineralocorticoid receptor antagonists (MRAs), spironolactone and eplerenone, are strongly recommended in the treatment of patients with chronic heart failure (HF) with reduced left ventricular ejection fraction (LVEF), but the balance of efficacy and safety in those with higher LVEF has not been well established. Broad use of steroidal MRAs has further been limited in part due to safety concerns around risks of hyperkalaemia, gynecomastia, and kidney dysfunction. These risks may be mitigated by the unique pharmacological properties of the non‐steroidal MRA finerenone. The FINEARTS‐HF trial is designed to evaluate the long‐term efficacy and safety of the selective non‐steroidal MRA finerenone among patients with HF with mildly reduced or preserved ejection fraction. Methods FINEARTS‐HF is a global, multicentre, event‐driven randomized trial evaluating oral finerenone versus matching placebo in symptomatic patients with HF with LVEF ≥40%. Adults (≥40 years) with HF with New York Heart Association class II–IV symptoms, LVEF ≥40%, evidence of structural heart disease, and diuretic use for at least the previous 30 days were eligible. All patients required elevated natriuretic peptide levels: for patients in sinus rhythm, N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) ≥300 pg/ml (or B‐type natriuretic peptide [BNP] ≥100 pg/ml) were required, measured within 30 days (in those without a recent worsening HF event) or within 90 days (in those with a recent worsening HF event). Qualifying levels of NT‐proBNP or BNP were tripled if a patient was in atrial fibrillation at screening. Estimated glomerular filtration rate &lt;25 ml/min/1.73 m 2 or serum potassium &gt;5.0 mmol/L were key exclusion criteria. Patients were enrolled irrespective of clinical care setting (whether hospitalized, recently hospitalized, or ambulatory). The primary endpoint is the composite of cardiovascular death and total (first and recurrent) HF events. The trial started on 14 September 2020 and has validly randomized 6001 participants across 37 countries. Approximately 2375 total primary composite events are targeted. Conclusions The FINEARTS‐HF trial will determine the efficacy and safety of the non‐steroidal MRA finerenone in a broad population of hospitalized and ambulatory patients with HF with mildly reduced or preserved ejection fraction. Clinical Trial Registration: ClinicalTrials.gov NCT04435626 and EudraCT 2020‐000306‐29.
Topical versus oral corticosteroids in moderate drug reaction with eosinophilia and systemic symptoms: A multicenter randomized clinical trial
Authors: Saskia Ingen-Housz-Oro, Elie Guichard, Brigitte Milpied, Benoit Bensaid, Evelyne Collet, Annick Barbaud, Florence Le Duff, Florence Tétart, Angèle Soria, Laurent Machet, Vincent Descamps, Sandrine Monestier, Justine Pasteur, Cécile Morice, Guillaume Chaby, Audrey Colin, Laëtitia Grégoire, Laurence Allanore, Bruno Giraudeau, Olivier Chosidow
Journal: Journal of the American Academy of Dermatology (2024)
Long‐term survival outcomes and immune checkpoint inhibitor retreatment in patients with advanced cervical cancer treated with camrelizumab plus apatinib in the phase II CLAP study
Authors: Chunyan Lan, Huaiwu Lu, Lin Zhou, Kunlun Liao, Junxiu Liu, Zhiwen Xie, Haixi Liang, Guorong Zou, Ting Yang, Qin Xu, Xin Huang
Journal: Cancer Communications (2024)

Abstract Background Camrelizumab plus apatinib have demonstrated robust antitumor activity and safety in patients with advanced cervical cancer (CLAP study; NCT03816553). We herein present the updated long‐term results of the CLAP study and explore potential biomarkers for survival. The outcomes of patients who underwent immune checkpoint inhibitor (ICI) retreatment were also reported. Methods In this phase II trial, eligible patients received camrelizumab 200 mg intravenously every two weeks and apatinib 250 mg orally once daily in 4‐week cycles for up to two years. Treatment was continued until disease progression, unacceptable toxicity, or withdrawal of consent. Results Between January 21 and August 1, 2019, a total of 45 patients were enrolled. Data were analyzed as of July 31, 2023, representing &gt; 48 months since treatment initiation for all patients. Nine (20.0%) patients completed the 2‐year study. The median duration of response (DOR) was 16.6 months, and 45.0% of patients achieved a DOR of ≥ 24 months. The 12‐month progression‐free survival (PFS) rate was 40.7% (95% confidence interval [CI], 25.2‐55.6), with an 18‐month PFS rate of 37.8% (95% CI, 22.7‐52.8). The median overall survival (OS) was 20.3 months (95% CI, 9.3‐36.9), and the 24‐month OS rate was 47.8% (95% CI, 31.7‐62.3). Age &gt; 50 years, programmed death‐ligand 1 (PD‐L1) combined positive score (CPS) ≥ 1 (versus [vs.] &lt; 1), CPS ≥ 10 (vs. &lt; 1), high tumor mutational burden, and PIK3CA mutations were associated with improved PFS (hazard ratio [HR] &lt; 1) and longer OS (HR &lt; 1). Eight patients who initially responded in the CLAP trial but later experienced disease progression were retreated with ICIs. Among them, 2 (25.0%) achieved a partial response, while 5 (62.5%) had stable disease. Notably, four patients who received retreatment with ICIs survived for more than 45 months. No new safety signals were identified in the present study. Conclusion Long‐term survival follow‐up data demonstrated that camrelizumab plus apatinib has robust, sustained, and durable efficacy in patients with advanced cervical cancer who progress after first‐line platinum‐based chemotherapy. No new safety signals were noted with long‐term treatment.
Protein tyrosine phosphatases: emerging role in cancer therapy resistance
Authors: Min Zhao, Wen Shuai, Zehao Su, Ping Xu, Aoxue Wang, Qiu Sun, Guan Wang
Journal: Cancer Communications (2024)

Abstract Background Tyrosine phosphorylation of intracellular proteins is a post‐translational modification that plays a regulatory role in signal transduction during cellular events. Dephosphorylation of signal transduction proteins caused by protein tyrosine phosphatases (PTPs) contributed their role as a convergent node to mediate cross‐talk between signaling pathways. In the context of cancer, PTP‐mediated pathways have been identified as signaling hubs that enabled cancer cells to mitigate stress induced by clinical therapy. This is achieved by the promotion of constitutive activation of growth‐stimulatory signaling pathways or modulation of the immune‐suppressive tumor microenvironment. Preclinical evidences suggested that anticancer drugs will release their greatest therapeutic potency when combined with PTP inhibitors, reversing drug resistance that was responsible for clinical failures during cancer therapy. Areas covered This review aimed to elaborate recent insights that supported the involvement of PTP‐mediated pathways in the development of resistance to targeted therapy and immune‐checkpoint therapy. Expert opinion This review proposed the notion of PTP inhibition in anticancer combination therapy as a potential strategy in clinic to achieve long‐term tumor regression. Ongoing clinical trials are currently underway to assess the safety and efficacy of combination therapy in advanced‐stage tumors.