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Innate Immunity in Type 1 Diabetes. 1 型糖尿病的先天免疫。
IF 10.1 2区 医学
Cold Spring Harbor perspectives in medicine Pub Date : 2025-08-01 DOI: 10.1101/cshperspect.a041595
Léo Bertrand, Alexander V Chervonsky, Agnès Lehuen
{"title":"Innate Immunity in Type 1 Diabetes.","authors":"Léo Bertrand, Alexander V Chervonsky, Agnès Lehuen","doi":"10.1101/cshperspect.a041595","DOIUrl":"10.1101/cshperspect.a041595","url":null,"abstract":"<p><p>Type 1 diabetes (T1D) results from the destruction of pancreatic β cells by the immune system, to which both pancreatic β-cell dysfunction and pathological activation of the immune system contribute. This paper is focused on understanding the modalities of this activation, and the genetic and environmental factors increasing its risk. Innate immunity has a critical role in the loss of self-tolerance and promotion of inflammation either directly using innate effector mechanisms or by providing activation signals to anti-islet adaptive autoimmunity. We provide an overview of various deleterious and protective roles of innate immunity in T1D inside pancreatic islets, regional lymph nodes, and distant locations such as the gut.</p>","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141792096","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
Ovarian Clear Cell Carcinoma: An Endometriosis-Associated Cancer with Therapeutic Challenges. 卵巢透明细胞癌：子宫内膜异位症相关癌症的治疗难题。
IF 10.1 2区 医学
Cold Spring Harbor perspectives in medicine Pub Date : 2025-08-01 DOI: 10.1101/cshperspect.a041315
Ruby Yun-Ju Huang, Jimmy Jin-Che Lin
{"title":"Ovarian Clear Cell Carcinoma: An Endometriosis-Associated Cancer with Therapeutic Challenges.","authors":"Ruby Yun-Ju Huang, Jimmy Jin-Che Lin","doi":"10.1101/cshperspect.a041315","DOIUrl":"10.1101/cshperspect.a041315","url":null,"abstract":"<p><p>Ovarian clear cell carcinoma (OCCC) is a histological subtype of epithelial ovarian cancer with distinct pathological features, molecular profiles, and biological functions. OCCC has high incidence rates in East Asia compared to the Western hemisphere and Europe and is associated with endometriosis. With its relative resistance to conventional treatment regimens and the worst stage-adjusted prognosis among ovarian cancer subtypes, there is an urgent need to optimize therapeutic options and to improve patient outcomes. To achieve this goal, better patient stratification strategies are required. These strategies could derive from comprehensive and in-depth multidimensional analysis of tumor heterogeneity. Understanding intertumor heterogeneity could assist us in stratifying OCCC patients based on features that are prognostic or predictive. Recent genomic, epigenomic, and transcriptomic profiling analyses allow us to provide an integrative perspective on the diverse heterogeneity in OCCC that could pave the way for novel translational research and clinical development in the future.</p>","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142281435","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
Dopamine Cell-Based Replacement Therapies. 基于多巴胺细胞的替代疗法。
IF 10.1 2区 医学
Cold Spring Harbor perspectives in medicine Pub Date : 2025-08-01 DOI: 10.1101/cshperspect.a041611
Saeed Kayhanian, Roger A Barker
{"title":"Dopamine Cell-Based Replacement Therapies.","authors":"Saeed Kayhanian, Roger A Barker","doi":"10.1101/cshperspect.a041611","DOIUrl":"10.1101/cshperspect.a041611","url":null,"abstract":"<p><p>Parkinson's disease (PD) is a common disorder that has, as part of its core pathology, the loss of the nigral dopaminergic nerve cells that project to the striatum. Replacing this loss with dopaminergic drugs has been the mainstay of therapy in PD for more than 50 years and while offering significant clinical benefit, especially in early-stage disease, leads to side effects over time. A conceptually more effective way to treat this aspect of the PD pathology would be to replace the missing dopaminergic system with grafts of new dopamine cells. This approach has been investigated for nearly 40 years using a variety of different dopamine cell sources. To date, a proof-of-principle has been shown using human fetal dopamine cells in patients with PD, but the more widespread adoption of this approach has been hampered by logistical reasons around tissue supply, the ethics of the cell source, and, most importantly, by the inconsistent results shown across trials, which in some cases have reported worrying side effects. Reasons for all this have been discussed extensively in the literature and one solution may lie in the development of new human stem cell-derived dopamine cells, which are now just entering first in human clinical trials.</p>","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142582429","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
Rebalancing the Immune System to Treat Type 1 Diabetes. 重新平衡免疫系统，治疗 1 型糖尿病。
IF 10.1 2区 医学
Cold Spring Harbor perspectives in medicine Pub Date : 2025-08-01 DOI: 10.1101/cshperspect.a041599
Yannick D Muller, Patrick Ho, Jeffrey A Bluestone, Qizhi Tang
{"title":"Rebalancing the Immune System to Treat Type 1 Diabetes.","authors":"Yannick D Muller, Patrick Ho, Jeffrey A Bluestone, Qizhi Tang","doi":"10.1101/cshperspect.a041599","DOIUrl":"10.1101/cshperspect.a041599","url":null,"abstract":"<p><p>In type 1 diabetes (T1D), the immune system mistakenly attacks the pancreatic islet β cells resulting in the loss of insulin secretion. Insulin-replacement therapy developed more than a century ago provided means to manage the symptoms of diabetes without addressing the root cause of the disease-the faulty immune system. A healthy immune system has built-in mechanisms to limit unwanted, excessive immune activation and prevents damages to self-tissues. These immune self-tolerance mechanisms are often impaired in autoimmune patients including those with T1Ds. Understanding how immune self-tolerance is broken in patients with T1D can inform the design of new curative therapies that correct the immune defects. In this paper, we will summarize the mechanisms of immune tolerance, review their relevance to T1Ds, and discuss novel therapeutic approaches to rebalance the immune system for the treatment of T1Ds.</p>","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142281436","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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 Mitochondrial Connection in Parkinson's Disease. 帕金森病的线粒体关联
IF 10.1 2区 医学
Cold Spring Harbor perspectives in medicine Pub Date : 2025-07-28 DOI: 10.1101/cshperspect.a041891
Eric Schon, Diana Matheoud, Serge Przedborski
{"title":"The Mitochondrial Connection in Parkinson's Disease.","authors":"Eric Schon, Diana Matheoud, Serge Przedborski","doi":"10.1101/cshperspect.a041891","DOIUrl":"https://doi.org/10.1101/cshperspect.a041891","url":null,"abstract":"<p><p>Mitochondria are highly dynamic organelles with complex structural features that perform several essential cellular functions, including energy production by oxidative phosphorylation, regulation of calcium and lipid homeostasis, and control of programmed cell death. Given their critical role, alterations in mitochondrial biology can lead to neuronal dysfunction and death. Defects in mitochondrial respiration, especially in oxidative energy production, have long been thought to be implicated in the etiology and pathogenesis of Parkinson's disease. However, given the multifaceted roles of mitochondria in health and diseases, the putative role of mitochondria in Parkinson's disease likely extends well beyond defective respiration. As such, mitochondrial dysfunction represents a promising target for disease-modifying therapies in Parkinson's disease and related conditions.</p>","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144728435","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
Principles in the Development of Contemporary Treatment of Childhood Malignancies: The First 75 Years. 当代儿童恶性肿瘤治疗发展的原则：前 75 年。
IF 7.8 2区 医学
Cold Spring Harbor perspectives in medicine Pub Date : 2025-07-01 DOI: 10.1101/cshperspect.a041634
Katie A Greenzang, Stephen E Sallan
{"title":"Principles in the Development of Contemporary Treatment of Childhood Malignancies: The First 75 Years.","authors":"Katie A Greenzang, Stephen E Sallan","doi":"10.1101/cshperspect.a041634","DOIUrl":"10.1101/cshperspect.a041634","url":null,"abstract":"<p><p>Over the last 75 years, pediatric cancer has gone from nearly universally fatal, to having a >80% chance of long-term survival. Below we share highlights in this 75-year history, beginning with the \"birth\" of chemotherapy in treating childhood leukemia, through the development of multiagent chemotherapy, risk-stratified therapy, the use of molecular strategies in diagnosis and treatment, and adapting treatment to the needs of particularly vulnerable patient groups such as adolescents and young adults (AYAs). While pediatric leukemia treatment demonstrates the ever-improving cures achieved through iterative incorporation of novel discoveries, this experience is contrasted with that of osteosarcoma, where scientific advances made over recent decades have yet to be translated into meaningful improvements in long-term survival. We conclude with a brief overview of current areas of focus, including precision medicine, immunotherapy, and other treatment advancements, yet describe the need to couple these scientific breakthroughs with consideration of equitable access and evaluation of the long-term impacts of these \"newer\" therapies in survivorship. Substantial further work is needed to achieve our goal of curing all children with cancer as harmlessly as possible.</p>","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":" ","pages":""},"PeriodicalIF":7.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12211995/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141619557","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Technologies for Decoding Cancer Metabolism with Spatial Resolution. 以空间分辨率解码癌症代谢的技术。
IF 7.8 2区 医学
Cold Spring Harbor perspectives in medicine Pub Date : 2025-07-01 DOI: 10.1101/cshperspect.a041553
Walter W Chen, Michael E Pacold, David M Sabatini, Naama Kanarek
{"title":"Technologies for Decoding Cancer Metabolism with Spatial Resolution.","authors":"Walter W Chen, Michael E Pacold, David M Sabatini, Naama Kanarek","doi":"10.1101/cshperspect.a041553","DOIUrl":"10.1101/cshperspect.a041553","url":null,"abstract":"<p><p>It is increasingly appreciated that cancer cells adapt their metabolic pathways to support rapid growth and proliferation as well as survival, often even under the poor nutrient conditions that characterize some tumors. Cancer cells can also rewire their metabolism to circumvent chemotherapeutics that inhibit core metabolic pathways, such as nucleotide synthesis. A critical approach to the study of cancer metabolism is metabolite profiling (metabolomics), the set of technologies, usually based on mass spectrometry, that allow for the detection and quantification of metabolites in cancer cells and their environments. Metabolomics is a burgeoning field, driven by technological innovations in mass spectrometers, as well as novel approaches to isolate cells, subcellular compartments, and rare fluids, such as the interstitial fluid of tumors. Here, we discuss three emerging metabolomic technologies: spatial metabolomics, single-cell metabolomics, and organellar metabolomics. The use of these technologies along with more established profiling methods, like single-cell transcriptomics and proteomics, is likely to underlie new discoveries and questions in cancer research.</p>","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":" ","pages":""},"PeriodicalIF":7.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12211997/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142281437","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Leucine-Rich Repeat Kinase 2: Pathways to Parkinson's Disease. 富亮氨酸重复激酶2：帕金森病的途径。
IF 7.8 2区 医学
Cold Spring Harbor perspectives in medicine Pub Date : 2025-06-30 DOI: 10.1101/cshperspect.a041620
Suzanne R Pfeffer, Dario R Alessi
{"title":"Leucine-Rich Repeat Kinase 2: Pathways to Parkinson's Disease.","authors":"Suzanne R Pfeffer, Dario R Alessi","doi":"10.1101/cshperspect.a041620","DOIUrl":"https://doi.org/10.1101/cshperspect.a041620","url":null,"abstract":"<p><p>The past 10 years have seen tremendous progress in our understanding of leucine-rich repeat kinase 2 (LRRK2) and how mutations activate the kinase and trigger downstream pathology, contributing to Parkinson's disease. A breakthrough came from the identification of key LRRK2 substrates-a subset of small guanosine triphosphatases (GTPases) called Rab proteins. Cryoelectron microscopy has revealed structures of LRRK2 and showed how inhibitors engage and inhibit the kinase. Biochemical experiments have revealed how LRRK2 is recruited to membranes to phosphorylate Rab substrates. LRRK2 activation during lysosomal stress triggers Rab phosphorylation, altering the repertoire of Rab-binding partners. Resulting phospho-Rab-effector complexes have prominent effects in specific cell types, disrupting primary cilia and impairing Hedgehog signaling-effects that can be reversed by LRRK2 inhibitors. This disruption in Hedgehog signaling represents a convergence point linking genetic and idiopathic forms of Parkinson's. Together, these findings support the therapeutic potential of LRRK2 inhibitors in Parkinson's disease.</p>","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":" ","pages":""},"PeriodicalIF":7.8,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144526704","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
Innate Immunity and Parkinson's Disease. 先天免疫和帕金森病。
IF 7.8 2区 医学
Cold Spring Harbor perspectives in medicine Pub Date : 2025-06-16 DOI: 10.1101/cshperspect.a041640
Davina B Oludipe, Xiaoqing Du, Samia Akter, Chen Zhang, R Lee Mosley, Howard E Gendelman, Susmita Sil
{"title":"Innate Immunity and Parkinson's Disease.","authors":"Davina B Oludipe, Xiaoqing Du, Samia Akter, Chen Zhang, R Lee Mosley, Howard E Gendelman, Susmita Sil","doi":"10.1101/cshperspect.a041640","DOIUrl":"https://doi.org/10.1101/cshperspect.a041640","url":null,"abstract":"<p><p>Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of both dopaminergic and non-dopaminergic neurons associated with the accumulation of α-synuclein aggregates and signs of neuroinflammation. This inflammatory aspect of PD neuropathology has led to the hypothesis that the immune system, both adaptive and innate, contributes to the neurodegenerative process. While the adaptive immune system is discussed in detail in another article in this collection, this review focuses on the innate immune system, which includes monocytes, macrophages, microglia, and dendritic cells. We will also discuss the increasingly recognized link between genetic and immune response and the cross talk between peripheral and central immune cells, and its contribution to the overall immune response in PD. Finally, we will propose therapeutic strategies aimed at modulating immunity for neuroprotective and disease-modifying benefits in PD and related disorders.</p>","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":" ","pages":""},"PeriodicalIF":7.8,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144309657","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
Adaptive Immunity and Parkinson's Disease. 适应性免疫和帕金森病
IF 7.8 2区 医学
Cold Spring Harbor perspectives in medicine Pub Date : 2025-06-16 DOI: 10.1101/cshperspect.a041639
Wassim Elyaman
{"title":"Adaptive Immunity and Parkinson's Disease.","authors":"Wassim Elyaman","doi":"10.1101/cshperspect.a041639","DOIUrl":"https://doi.org/10.1101/cshperspect.a041639","url":null,"abstract":"<p><p>Adaptive immunity plays a key role in the pathogenesis of Parkinson's disease (PD) and related conditions. This paper reviews the involvement of CD4<sup>+</sup> and CD8<sup>+</sup> T cells in PD development as well as the effect of PD genetic susceptibility variants and aging. Specifically, the major histocompatibility complex is associated with PD, influencing antigen presentation and, consequently, the T-cell receptor repertoire, believed to contribute to disease susceptibility and progression. Moreover, aging-a major risk factor for PD-also shapes T-cell dynamics, with immunosenescence impacting the adaptive immune system, and potentially exacerbating neuroinflammatory responses in PD. These T-cell-mediated immune responses hold substantial influence over brain physiopathology, dictating the degenerative processes seen in PD. Understanding these interactions offers insights into early immunotherapy intervention during the prodromal phase using engineered regulatory T cells for antigen-specific immunomodulation against pathogenic proteins such as α-synuclein.</p>","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":" ","pages":""},"PeriodicalIF":7.8,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144309656","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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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