Frontiers in molecular medicine最新文献

{"title":"Editorial: Gene therapy and genome editing for metabolic liver disorders.","authors":"Fanny Collaud, Giulia Bortolussi","doi":"10.3389/fmmed.2024.1543685","DOIUrl":"https://doi.org/10.3389/fmmed.2024.1543685","url":null,"abstract":"","PeriodicalId":73090,"journal":{"name":"Frontiers in molecular medicine","volume":"4 ","pages":"1543685"},"PeriodicalIF":0.0,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11754220/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143029630","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An artificial transcription factor that activates potent interferon-γ expression in human Jurkat T Cells.","authors":"Ashley King, Davis Noblitt, Olivia Sherron, Clara Kjerfve, Lydia Pless, Nicholas L Truex","doi":"10.3389/fmmed.2024.1492370","DOIUrl":"10.3389/fmmed.2024.1492370","url":null,"abstract":"<p><p>Interferon (IFN)-γ is a central regulator of cell-mediated immunity in human health and disease, but reduced expression of the target receptors impairs signaling activity and leads to immunotherapy resistance. Although intracellular expression of IFN-γ restores the signaling and downstream functions, we lack the tools to activate the <i>IFNG</i> gene instead of cell surface receptors. This paper introduces the design and characterization of an artificial transcription factor (ATF) protein that recognizes the <i>IFNG</i> gene with six zinc finger domains, which are dovetailed to a VP64 signaling domain that promotes gene transcription and translation. Biological studies with human Jurkat T cells reveal that the ATF amplifies <i>IFNG</i> gene transcription and translation, and also stimulates gene transcription for multiple class I and II HLA alleles and interferon-stimulated genes (ISGs). Biophysical characterization showed the recombinant ATF protein recognizes the human <i>IFNG</i> gene with nanomolar affinity (K_D = 5.27 ± 0.3 nM), adopts a protein secondary structure associated with the ββα-fold of zinc finger domains, and is resistant to thermal denaturation. These studies demonstrate that transcriptional targeting of cytokine genes, rather than surface receptors, activates cytokine expression and shows significant potential for directing immune function.</p>","PeriodicalId":73090,"journal":{"name":"Frontiers in molecular medicine","volume":"4 ","pages":"1492370"},"PeriodicalIF":0.0,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11751033/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143024817","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immune-checkpoint-inhibitor therapy directed against PD-L1 is tolerated in the heart without manifestation of cardiac inflammation in a preclinical reversible melanoma mouse model.","authors":"Caroline Schoenherr, Stefan Pietzsch, Cristina Barca, Franziska E Müller, Frauke S Bahr, Martina Kasten, Andre Zeug, Sergej Erschow, Christine S Falk, Evgeni Ponimaskin, James T Thackeray, Denise Hilfiker-Kleiner, Melanie Ricke-Hoch","doi":"10.3389/fmmed.2024.1487526","DOIUrl":"10.3389/fmmed.2024.1487526","url":null,"abstract":"<p><p>Immune-checkpoint-inhibitors (ICI) target key regulators of the immune system expressed by cancer cells that mask those from recognition by the immune system. They have improved the outcome for patients with various cancer types, such as melanoma. ICI-based therapy is frequently accompanied by immune-related adverse side effects (IRAEs). The reversible melanoma cancer mouse model (B16F10 cells stably expressing a ganciclovir (GCV)-inducible suicide gene in C57BL/6N mice: B16F10-GCV) allows chemotherapy-free tumor elimination in advanced disease stage and demonstrates almost complete recovery of the mouse heart from cancer-induced atrophy, molecular impairment and heart failure. Thus, enabling the study of anti-cancer-therapy effects. Here, we analyzed potential cardiac side effects of antibody-mediated PD-L1 inhibition in the preclinical B16F10-GCV mouse model after tumor elimination and 2 weeks recovery (50 days after tumor inoculation). Anti-PD-L1 treatment was associated with improved survival as compared to isotype control (Ctrl) treated mice. Surviving anti-PD-L1 and Ctrl mice showed similar cardiac function, dimensions and the expression of cardiac stress and hypertrophy markers. Although anti-PD-L1 treatment was associated with increased troponin I type 3 cardiac (TNNI3) blood levels, cardiac mRNA expression of macrophage markers and elevated cardiac levels of secreted inflammatory factors compared to Ctrl treatment, both groups showed a comparable density of inflammatory cells in the heart (using CXCR4-ligand ⁶⁸Ga-Pentixafor in PET-CT and immunohistochemistry). Thus, anti-PD-L1 therapy improved survival in mice with advanced melanoma cancer with no major cardiac phenotype or inflammation 50 days after tumor inoculation. Without a second hit that triggers the inflammatory response, anti-PD-L1 treatment appears to be safe for the heart in the preclinical melanoma mouse model.</p>","PeriodicalId":73090,"journal":{"name":"Frontiers in molecular medicine","volume":"4 ","pages":"1487526"},"PeriodicalIF":0.0,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11743445/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143017470","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human-specific gene <i>ARHGAP11B</i>-potentially an additional tool in the treatment of neurodegenerative diseases?","authors":"Wieland B Huttner","doi":"10.3389/fmmed.2024.1465647","DOIUrl":"10.3389/fmmed.2024.1465647","url":null,"abstract":"","PeriodicalId":73090,"journal":{"name":"Frontiers in molecular medicine","volume":"4 ","pages":"1465647"},"PeriodicalIF":0.0,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11631617/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142815098","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DeltaRex-G, tumor targeted retrovector encoding a CCNG1 inhibitor, for CAR-T cell therapy induced cytokine release syndrome.","authors":"Grace Haroun, Erlinda M Gordon","doi":"10.3389/fmmed.2024.1461151","DOIUrl":"10.3389/fmmed.2024.1461151","url":null,"abstract":"<p><p>Cytokine release syndrome is a serious complication of chimeric antigen receptor-T cell therapy and is triggered by excessive secretion of inflammatory cytokines by chimeric T cells which could be fatal. Following an inquiry into the molecular mechanisms orchestrating cytokine release syndrome, we hypothesize that DeltaRex-G, a tumor targeted retrovector encoding a cytocidal CCNG1 inhibitor gene, may be a viable treatment option for corticosteroid-resistant cytokine release syndrome. DeltaRex-G received United States Food and Drug Administration Emergency Use Authorization to treat Covid-19-induced acute respiratory distress syndrome, which is due to hyperactivated immune cells. A brief administration of DeltaRex-G would inhibit a certain proportion of hyperactive chimeric T cells, consequently reducing cytokine release while retaining chimeric T cell efficacy.</p>","PeriodicalId":73090,"journal":{"name":"Frontiers in molecular medicine","volume":"4 ","pages":"1461151"},"PeriodicalIF":0.0,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11445129/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142367697","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of epigenetic in cancer biology, in hematologic malignancies and in anticancer therapy.","authors":"Armel Hervé Nwabo Kamdje, Hervet Paulain Dongmo Fogang, Patrice N Mimche","doi":"10.3389/fmmed.2024.1426454","DOIUrl":"10.3389/fmmed.2024.1426454","url":null,"abstract":"<p><p>Major epigenetic changes are associated with carcinogenesis, including aberrant DNA methylations and post-translational modifications of histone. Indeed evidence accumulated in recent years indicates that inactivating DNA hypermethylation preferentially targets the subset of polycomb group (PcG) genes that are regulators of developmental processes. Conversely, activating DNA hypomethylation targets oncogenic signaling pathway genes, but outcomes of both events lead in the overexpression of oncogenic signaling pathways that contribute to the stem-like state of cancer cells. On the basis of recent evidence from population-basedclinical and experimental studies, we hypothesize that factors associated with risk for developing a hematologic malignancy (HM), such as metabolic syndrome and chronic inflammation, may trigger epigenetic mechanisms to increase the transcriptional expression of oncogenes and activate oncogenic signaling pathways. Signaling pathways associated with such risk factors include but are not limited to pro-inflammatory nuclear factor κB (NF-κB) and mitogenic, growth, and survival Janus kinase (JAK) intracellular non-receptor tyrosine kinase-triggered pathways. The latter includes signaling pathways such as transducer and activator of transcription (STAT), Ras GTPases/mitogen-activated protein kinases (MAPKs)/extracellular signal-related kinases (ERKs), phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR), and β-catenin pathways. Recent findings on epigenetic mechanisms at work in the biology of cancer and in HMs and their importance in the etiology and pathogenesis of these diseases are herein summarized and discussed. Furthermore, the role of epigenetic processes in the determination of biological identity, the consequences for interindividual variability in disease clinical profile, and the potential of epigenetic drugs in HMs are also considered.</p>","PeriodicalId":73090,"journal":{"name":"Frontiers in molecular medicine","volume":"4 ","pages":"1426454"},"PeriodicalIF":0.0,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11412843/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142302521","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Editorial: Mitochondrial dysfunction affects mechano-energetic coupling in heart failure","authors":"Jan Dudek, Julia Ritterhoff","doi":"10.3389/fmmed.2024.1433102","DOIUrl":"https://doi.org/10.3389/fmmed.2024.1433102","url":null,"abstract":"","PeriodicalId":73090,"journal":{"name":"Frontiers in molecular medicine","volume":"124 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141682689","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tafazzin deficiency causes substantial remodeling in the lipidome of a mouse model of Barth Syndrome cardiomyopathy.","authors":"Malte Hachmann, Güntas Gülcan, Ranjithkumar Rajendran, Marcus Höring, Gerhard Liebisch, Akash Bachhuka, Michael Kohlhaas, Christoph Maack, Süleyman Ergün, Jan Dudek, Srikanth Karnati","doi":"10.3389/fmmed.2024.1389456","DOIUrl":"10.3389/fmmed.2024.1389456","url":null,"abstract":"<p><p>Barth Syndrome (BTHS) is a rare X-linked disease, characterized clinically by cardiomyopathy, skeletal myopathy, neutropenia, and growth retardation. BTHS is caused by mutations in the phospholipid acyltransferase tafazzin (Gene: TAFAZZIN, TAZ). Tafazzin catalyzes the final step in the remodeling of cardiolipin (CL), a glycerophospholipid located in the inner mitochondrial membrane. As the phospholipid composition strongly determines membrane properties, correct biosynthesis of CL and other membrane lipids is essential for mitochondrial function. Mitochondria provide 95% of the energy demand in the heart, particularly due to their role in fatty acid oxidation. Alterations in lipid homeostasis in BTHS have an impact on mitochondrial membrane proteins and thereby contribute to cardiomyopathy. We analyzed a transgenic TAFAZZIN-knockdown (TAZ-KD) BTHS mouse model and determined the distribution of 193 individual lipid species in TAZ-KD and WT hearts at 10 and 50 weeks of age, using electrospray ionization tandem mass spectrometry (ESI-MS/MS). Our results revealed significant lipid composition differences between the TAZ-KD and WT groups, indicating genotype-dependent alterations in most analyzed lipid species. Significant changes in the myocardial lipidome were identified in both young animals without cardiomyopathy and older animals with heart failure. Notable alterations were found in phosphatidylcholine (PC), phosphatidylethanolamine (PE), lysophosphatidylethanolamine (LPE), lysophosphatidylcholine (LPC) and plasmalogen species. PC species with 2-4 double bonds were significantly increased, while polyunsaturated PC species showed a significant decrease in TAZ-KD mice. Furthermore, Linoleic acid (LA, 18:2) containing PC and PE species, as well as arachidonic acid (AA, 20:4) containing PE 38:4 species are increased in TAZ-KD. We found higher levels of AA containing LPE and PE-based plasmalogens (PE P-). Furthermore, we are the first to show significant changes in sphingomyelin (SM) and ceramide (Cer) lipid species Very long-chained SM species are accumulating in TAZ-KD hearts, whereas long-chained Cer and several hexosyl ceramides (HexCer) species accumulate only in 50-week-old TAZ-KD hearts These findings offer potential avenues for the diagnosis and treatment of BTHS, presenting new possibilities for therapeutic approaches.</p>","PeriodicalId":73090,"journal":{"name":"Frontiers in molecular medicine","volume":"4 ","pages":"1389456"},"PeriodicalIF":0.0,"publicationDate":"2024-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11285559/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141861845","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Editorial: Celebrating the 200th mendel’s anniversary: gene-targeted diagnostics and therapies for cancer","authors":"Noah Federman, Erlinda M. Gordon, S. Chawla, Frederick L. Hall","doi":"10.3389/fmmed.2024.1366963","DOIUrl":"https://doi.org/10.3389/fmmed.2024.1366963","url":null,"abstract":"","PeriodicalId":73090,"journal":{"name":"Frontiers in molecular medicine","volume":"80 8","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140427063","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Current advances in experimental and computational approaches to enhance CAR T cell manufacturing protocols and improve clinical efficacy","authors":"Alfredo Colina, Viren Shah, Ravi K. Shah, Tanya Kozlik, R. K. Dash, Scott S. Terhune, Anthony E. Zamora","doi":"10.3389/fmmed.2024.1310002","DOIUrl":"https://doi.org/10.3389/fmmed.2024.1310002","url":null,"abstract":"Since the FDA’s approval of chimeric antigen receptor (CAR) T cells in 2017, significant improvements have been made in the design of chimeric antigen receptor constructs and in the manufacturing of CAR T cell therapies resulting in increased in vivo CAR T cell persistence and improved clinical outcome in certain hematological malignancies. Despite the remarkable clinical response seen in some patients, challenges remain in achieving durable long-term tumor-free survival, reducing therapy associated malignancies and toxicities, and expanding on the types of cancers that can be treated with this therapeutic modality. Careful analysis of the biological factors demarcating efficacious from suboptimal CAR T cell responses will be of paramount importance to address these shortcomings. With the ever-expanding toolbox of experimental approaches, single-cell technologies, and computational resources, there is renowned interest in discovering new ways to streamline the development and validation of new CAR T cell products. Better and more accurate prognostic and predictive models can be developed to help guide and inform clinical decision making by incorporating these approaches into translational and clinical workflows. In this review, we provide a brief overview of recent advancements in CAR T cell manufacturing and describe the strategies used to selectively expand specific phenotypic subsets. Additionally, we review experimental approaches to assess CAR T cell functionality and summarize current in silico methods which have the potential to improve CAR T cell manufacturing and predict clinical outcomes.","PeriodicalId":73090,"journal":{"name":"Frontiers in molecular medicine","volume":"15 12","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139687814","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}