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The RB protein: more than a sentry of cell cycle entry. RB蛋白：不仅仅是细胞周期进入的哨兵。
IF 12.8 1区 医学
Trends in molecular medicine Pub Date : 2025-04-28 DOI: 10.1016/j.molmed.2025.04.001
Pulari U Thangavelu, Cheng-Yu Lin, Farzaneh Forouz, Kozo Tanaka, Eloïse Dray, Pascal H G Duijf
{"title":"The RB protein: more than a sentry of cell cycle entry.","authors":"Pulari U Thangavelu, Cheng-Yu Lin, Farzaneh Forouz, Kozo Tanaka, Eloïse Dray, Pascal H G Duijf","doi":"10.1016/j.molmed.2025.04.001","DOIUrl":"https://doi.org/10.1016/j.molmed.2025.04.001","url":null,"abstract":"<p><p>Genomic instability is a hallmark of cancer. It fuels cancer progression and therapy resistance. As 'the guardian of the genome', the tumor suppressor protein p53 protects against genomic damage. Canonically, the retinoblastoma protein (RB) is 'the sentry of cell cycle entry', as it dictates whether a cell enters the cell cycle to divide. However, the RB pathway also controls myriad non-canonical cellular processes, including metabolism, stemness, angiogenesis, apoptosis, and immune surveillance. We discuss how frequent RB pathway inactivation and underlying mechanisms in cancers affect these processes. We focus on RB's - rather than p53's - 'guardian of the genome' functions in DNA replication, DNA repair, centrosome duplication, chromosome segregation, and chromatin organization. Finally, we review therapeutic strategies, challenges, and opportunities for targeting RB pathway alterations in cancer.</p>","PeriodicalId":23263,"journal":{"name":"Trends in molecular medicine","volume":" ","pages":""},"PeriodicalIF":12.8,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144047442","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Acquired resistance to immunotherapy in solid tumors. 实体瘤免疫治疗获得性耐药。
IF 12.8 1区 医学
Trends in molecular medicine Pub Date : 2025-04-23 DOI: 10.1016/j.molmed.2025.03.010
Perrine Verdys, Astrid Z Johansen, Anurag Gupta, Mario Presti, Edoardo Dionisio, Daniel H Madsen, Alessandra Curioni-Fontecedro, Marco Donia
{"title":"Acquired resistance to immunotherapy in solid tumors.","authors":"Perrine Verdys, Astrid Z Johansen, Anurag Gupta, Mario Presti, Edoardo Dionisio, Daniel H Madsen, Alessandra Curioni-Fontecedro, Marco Donia","doi":"10.1016/j.molmed.2025.03.010","DOIUrl":"https://doi.org/10.1016/j.molmed.2025.03.010","url":null,"abstract":"<p><p>Acquired resistance to immunotherapy (ARI) is a major challenge in solid tumors, limiting long-term success in up to 65% of patients who initially respond to immunotherapy. Defining ARI clinically remains complex, but ongoing efforts aim to establish standardized criteria. This review describes recent insights into ARI, revealing complex mechanisms involving both tumor-intrinsic mechanisms - such as antigen loss and presentation defects, interferon γ (IFNγ) insensitivity, tumor-mediated T cell exclusion, and metabolic reprogramming - as well as extrinsic factors such as inhibitory molecule upregulation, immunosuppressive cells, extracellular matrix (ECM) remodeling, and dysbiotic microbiota. Understanding the development of ARI is crucial for prevention and effective interventions. The integration of innovative strategies and translational research on appropriately collected samples is key to overcoming ARI and ensuring durable benefits for patients.</p>","PeriodicalId":23263,"journal":{"name":"Trends in molecular medicine","volume":" ","pages":""},"PeriodicalIF":12.8,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144000441","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Fibroproliferative conditions: the 3R approach bridging fibrosis and tumors. 纤维增生性疾病：3R入路桥接纤维化和肿瘤。
IF 12.8 1区 医学
Trends in molecular medicine Pub Date : 2025-04-22 DOI: 10.1016/j.molmed.2025.03.009
Chenyu Huang, Yue Shao, Jianbo Bai, Yi Zhao, Rei Ogawa
{"title":"Fibroproliferative conditions: the 3R approach bridging fibrosis and tumors.","authors":"Chenyu Huang, Yue Shao, Jianbo Bai, Yi Zhao, Rei Ogawa","doi":"10.1016/j.molmed.2025.03.009","DOIUrl":"https://doi.org/10.1016/j.molmed.2025.03.009","url":null,"abstract":"<p><p>Soft-tissue fibroproliferative conditions (FPCs) affect many organs. All demonstrate the accumulation of (myo)fibroblasts and extracellular matrix. Currently, FPCs are classified according to the affected body site/organ. To promote research into the etiological mechanisms that drive pathological FPCs, we propose a new, more clinically grounded, FPC classification that is based on the intent and severity of the fibroproliferation. There are three categories: responsive, replacement, and reconstructive FPCs. Reconstructive FPCs (e.g., keloids) have quasi-neoplastic behaviors, including local invasiveness, and serve as a bridge between fibrosis and cancers. Comparisons of reconstructive FPCs to both cancers and the other FPC categories may help elucidate their pathogenic cellular properties, microenvironmental components, and intracellular-signaling mechanisms. Thus, the new FPC classification may promote research in the fibrosis field.</p>","PeriodicalId":23263,"journal":{"name":"Trends in molecular medicine","volume":" ","pages":""},"PeriodicalIF":12.8,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144038586","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The future of phage therapy in the USA. 噬菌体治疗在美国的未来。
IF 12.8 1区 医学
Trends in molecular medicine Pub Date : 2025-04-22 DOI: 10.1016/j.molmed.2025.03.013
Brandon A Berryhill, Teresa Gil-Gil, Andrew P Smith, Bruce R Levin
{"title":"The future of phage therapy in the USA.","authors":"Brandon A Berryhill, Teresa Gil-Gil, Andrew P Smith, Bruce R Levin","doi":"10.1016/j.molmed.2025.03.013","DOIUrl":"https://doi.org/10.1016/j.molmed.2025.03.013","url":null,"abstract":"<p><p>Fueled by the increasing abundance of antibiotic-resistant pathogens, there has been a resurrection in the use of bacterial viruses (bacteriophages or 'phage') for therapeutic applications. Phage therapy was used in the early 20th century to limited success, which we attribute to its haphazard employment. To avoid repeating the mistakes of the past, this Opinion first evaluates the historical reasons for the failure of phage therapy, analyzes the current state of the field, and ultimately makes recommendations for how to proceed with contemporary phage therapy. Despite many advances in phage biology, crucial gaps in our knowledge persist. Our recommendations require physicians, scientists, and public-policy leaders to cooperate to bridge the outstanding gaps around phage therapy to develop phage into a useful therapeutic tool.</p>","PeriodicalId":23263,"journal":{"name":"Trends in molecular medicine","volume":" ","pages":""},"PeriodicalIF":12.8,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144000443","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Keratinocytes: new perspectives in inflammatory skin diseases. 角质形成细胞：炎症性皮肤病的新视角。
IF 12.8 1区 医学
Trends in molecular medicine Pub Date : 2025-04-16 DOI: 10.1016/j.molmed.2025.03.012
Jiafeng Ye, Yuping Lai
{"title":"Keratinocytes: new perspectives in inflammatory skin diseases.","authors":"Jiafeng Ye, Yuping Lai","doi":"10.1016/j.molmed.2025.03.012","DOIUrl":"https://doi.org/10.1016/j.molmed.2025.03.012","url":null,"abstract":"<p><p>Keratinocytes, the predominant cell type in the epidermis, are indispensable for maintaining skin barrier integrity, mediating host defense, and orchestrating immune responses. Beyond these well-established functions, emerging evidence reveals their dynamic interactions with the nervous system and their capacity to retain inflammatory memory. These discoveries position keratinocytes as key drivers of the onset, progression, and relapse of inflammatory skin diseases. In this review, we delve into the mechanisms underlying keratinocyte crosstalk with immune and neural cells, the metabolic reprogramming, including lactate and other metabolites, that may drive inflammatory memory, and the broader implications for disease pathogenesis and recurrence. Finally, we discuss the challenges to, and therapeutic potential of, targeting keratinocytes for the treatment of chronic inflammatory skin conditions.</p>","PeriodicalId":23263,"journal":{"name":"Trends in molecular medicine","volume":" ","pages":""},"PeriodicalIF":12.8,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144038587","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Vascular cell types in progeria: victims or villains? 早衰症的血管细胞类型：受害者还是恶棍？
IF 12.8 1区 医学
Trends in molecular medicine Pub Date : 2025-04-15 DOI: 10.1016/j.molmed.2025.03.005
Ignacio Benedicto, Magda R Hamczyk, Beatriz Dorado, Vicente Andrés
{"title":"Vascular cell types in progeria: victims or villains?","authors":"Ignacio Benedicto, Magda R Hamczyk, Beatriz Dorado, Vicente Andrés","doi":"10.1016/j.molmed.2025.03.005","DOIUrl":"https://doi.org/10.1016/j.molmed.2025.03.005","url":null,"abstract":"<p><p>Hutchinson-Gilford progeria syndrome (HGPS) is an ultrarare genetic disease caused by progerin, a broadly expressed mutant variant of lamin A protein that accelerates aging and leads to premature death typically in adolescence. Progerin affects many organs and reproduces many characteristics of physiological aging, with the main cause of death in HGPS being atherosclerotic cardiovascular disease (CVD). Due to the rarity of HGPS, advances in understanding the disease and progress toward new therapeutic approaches are crucially dependent on preclinical models. We discuss recent research developments from a variety of HGPS experimental systems, with a special focus on in vivo studies of the role of vascular smooth muscle cells (VSMCs) and endothelial cells (ECs) that are key players in atherosclerosis.</p>","PeriodicalId":23263,"journal":{"name":"Trends in molecular medicine","volume":" ","pages":""},"PeriodicalIF":12.8,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144027881","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Phosphoglycerate kinase 1 as a therapeutic target in neurological disease. 磷酸甘油酸激酶1作为神经系统疾病的治疗靶点。
IF 12.8 1区 医学
Trends in molecular medicine Pub Date : 2025-04-14 DOI: 10.1016/j.molmed.2025.03.008
Harriet McHale-Owen, Kiterie M E Faller, Helena Chaytow, Thomas H Gillingwater
{"title":"Phosphoglycerate kinase 1 as a therapeutic target in neurological disease.","authors":"Harriet McHale-Owen, Kiterie M E Faller, Helena Chaytow, Thomas H Gillingwater","doi":"10.1016/j.molmed.2025.03.008","DOIUrl":"https://doi.org/10.1016/j.molmed.2025.03.008","url":null,"abstract":"<p><p>Phosphoglycerate kinase 1 (PGK1) is a highly conserved enzyme that catalyzes the initial ATP-producing step in glycolysis. Improving cellular energy production by increasing PGK1 activity may be beneficial in multiple neurological conditions where cell metabolism is dysregulated, including Parkinson's disease (PD) and motor neuron disease (MND). This review examines recent evidence that suggests increasing PGK1 activity may be beneficial in multiple neurological conditions and discusses the current challenges surrounding the development of PGK1-focused therapies. PGK1 has considerable therapeutic potential, but novel PGK1 activators are needed to maximize the benefit for patients.</p>","PeriodicalId":23263,"journal":{"name":"Trends in molecular medicine","volume":" ","pages":""},"PeriodicalIF":12.8,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143999240","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
MicroRNAs in the biology and hallmarks of neurodegenerative diseases. 神经退行性疾病的生物学和标志中的microrna。
IF 12.8 1区 医学
Trends in molecular medicine Pub Date : 2025-04-07 DOI: 10.1016/j.molmed.2025.03.006
Shivnarayan Dhuppar, Wolfram C Poller, Gopal Murugaiyan
{"title":"MicroRNAs in the biology and hallmarks of neurodegenerative diseases.","authors":"Shivnarayan Dhuppar, Wolfram C Poller, Gopal Murugaiyan","doi":"10.1016/j.molmed.2025.03.006","DOIUrl":"https://doi.org/10.1016/j.molmed.2025.03.006","url":null,"abstract":"<p><p>A combination of intracellular and extracellular abnormalities of the nervous system, coupled with inflammation and intestinal dysbiosis, form the hallmarks of neurodegenerative diseases (NDDs). While it is difficult to identify the precise order in which these hallmarks manifest in NDDs because of their mutualistic nature, they cumulatively result in nervous or neuronal damage that characterizes neurodegeneration. In this review we discuss the roles of microRNAs (miRNAs) in the maintenance of nervous system homeostasis and their implication for NDDs. We further highlight recent advances in, and limitations of, miRNA therapeutics in NDDs and their future potential.</p>","PeriodicalId":23263,"journal":{"name":"Trends in molecular medicine","volume":" ","pages":""},"PeriodicalIF":12.8,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143812555","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Pushing the boundaries: future directions in the management of spinal muscular atrophy. 突破界限：脊髓性肌萎缩症治疗的未来方向。
IF 12.8 1区 医学
Trends in molecular medicine Pub Date : 2025-04-01 Epub Date: 2025-01-09 DOI: 10.1016/j.molmed.2024.12.006
Fiona Moultrie, Laura Chiverton, Isabel Hatami, Charlotte Lilien, Laurent Servais
{"title":"Pushing the boundaries: future directions in the management of spinal muscular atrophy.","authors":"Fiona Moultrie, Laura Chiverton, Isabel Hatami, Charlotte Lilien, Laurent Servais","doi":"10.1016/j.molmed.2024.12.006","DOIUrl":"10.1016/j.molmed.2024.12.006","url":null,"abstract":"<p><p>Spinal muscular atrophy (SMA) is a devastating, degenerative, paediatric neuromuscular disease which until recently was untreatable. Discovery of the responsible gene 30 years ago heralded a new age of pioneering therapeutic developments. Three disease-modifying therapies (DMTs) have received regulatory approval and have transformed the disease, reducing disability and prolonging patient survival. These therapies - with distinct mechanisms, routes of administration, dosing schedules, side effect profiles, and financial costs - have dramatically altered the clinical phenotypes of this condition and have presented fresh challenges for patient care. In this review article we discuss potential strategies to maximise clinical outcomes through early diagnosis and treatment, optimised dosing, use of therapeutic combinations and state-of-the-art physiotherapy techniques, and the development of innovative therapies targeting alternative mechanisms.</p>","PeriodicalId":23263,"journal":{"name":"Trends in molecular medicine","volume":" ","pages":"307-318"},"PeriodicalIF":12.8,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142967055","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Genetic causes of obesity: mapping a path forward. 肥胖的遗传原因：绘制前进的路径。
IF 12.8 1区 医学
Trends in molecular medicine Pub Date : 2025-04-01 Epub Date: 2025-03-14 DOI: 10.1016/j.molmed.2025.02.002
Ruth J F Loos
{"title":"Genetic causes of obesity: mapping a path forward.","authors":"Ruth J F Loos","doi":"10.1016/j.molmed.2025.02.002","DOIUrl":"10.1016/j.molmed.2025.02.002","url":null,"abstract":"<p><p>Over the past 30 years, significant progress has been made in understanding the genetic causes of obesity. In the coming years, catalogs that map each genetic variant to its genomic function are expected to accelerate variant-to-function (V2F) translation. Given that obesity is a heterogeneous disease, research will have to move beyond body mass index (BMI). Gene discovery efforts for more refined adiposity traits are poised to reveal additional genetic loci, pointing to new biological mechanisms. Obesity genetics research is reaching unprecedented heights and, along with a renewed interest in the development of weight-loss medication, it holds the potential to identify new drug targets. Polygenic scores (PGSs) that predict obesity risk are expected to further improve and will be particularly valuable early in life for timely prevention.</p>","PeriodicalId":23263,"journal":{"name":"Trends in molecular medicine","volume":" ","pages":"319-325"},"PeriodicalIF":12.8,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143634703","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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