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Developmental Modeling of Childhood Cancers. 儿童癌症的发育模型。
IF 7.8 2区 医学
Cold Spring Harbor perspectives in medicine Pub Date : 2024-11-25 DOI: 10.1101/cshperspect.a041711
Kosuke Funato, Viviane Tabar
{"title":"Developmental Modeling of Childhood Cancers.","authors":"Kosuke Funato, Viviane Tabar","doi":"10.1101/cshperspect.a041711","DOIUrl":"https://doi.org/10.1101/cshperspect.a041711","url":null,"abstract":"<p><p>Growing evidence indicates that childhood cancer is a developmental disease and the oncogenic impact of mutations depends on spatiotemporal developmental contexts. This dependency leads to distinct molecular, genetic, and clinical characteristics across various cancer (sub)types. However, the underlying molecular mechanisms of tumorigenesis are not fully understood, and the development of precision medicine for childhood cancers is still an ongoing effort, partially due to their relative rarity. Therefore, it is crucial to develop and use \"developmental models\" that replicate both mutations and specific developmental contexts that determine their impact. In this review, we summarize recent advances in the growing field of developmental modeling of childhood cancers, which enhance our understanding of the pathogenic mechanisms and pave the way for the development of new therapeutic approaches.</p>","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":" ","pages":""},"PeriodicalIF":7.8,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142715441","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
Environmental Factors in Type 1 Diabetes. 1 型糖尿病的环境因素。
IF 7.8 2区 医学
Cold Spring Harbor perspectives in medicine Pub Date : 2024-11-25 DOI: 10.1101/cshperspect.a041590
Heikki Hyöty, Jutta E Laiho, Suvi M Virtanen
{"title":"Environmental Factors in Type 1 Diabetes.","authors":"Heikki Hyöty, Jutta E Laiho, Suvi M Virtanen","doi":"10.1101/cshperspect.a041590","DOIUrl":"https://doi.org/10.1101/cshperspect.a041590","url":null,"abstract":"<p><p>The contribution of environmental factors to the pathogenesis of type 1 diabetes is considered substantial, but their identification has turned out to be challenging. Large prospective studies are crucial for reliable identification of environmental risk and protective factors. However, only few large prospective birth cohort studies have been carried out. Enterovirus infections have shown quite consistent risk association with the initiation of islet autoimmunity (IA) across these studies. Also, certain dietary factors have been consistently associated with IA risk, omega-3 fatty acids inversely, and childhood cow's milk intake directly. However, the mechanisms of these associations are not fully understood, and possible causality has not been confirmed. Clinical trial programs with enterovirus vaccines and antiviral drugs are in progress to evaluate the causality of enterovirus association. The only nutritional primary prevention randomized trial, TRIGR, did not find a difference between weaning to extensively hydrolyzed versus conventional cow's milk-based infant formula.</p>","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":" ","pages":""},"PeriodicalIF":7.8,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142715444","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
Cancer Therapies Targeting Cellular Metabolism. 针对细胞代谢的癌症疗法。
IF 7.8 2区 医学
Cold Spring Harbor perspectives in medicine Pub Date : 2024-11-25 DOI: 10.1101/cshperspect.a041657
Benjamin Morris, Alejandro Gutierrez
{"title":"Cancer Therapies Targeting Cellular Metabolism.","authors":"Benjamin Morris, Alejandro Gutierrez","doi":"10.1101/cshperspect.a041657","DOIUrl":"https://doi.org/10.1101/cshperspect.a041657","url":null,"abstract":"<p><p>Cancer is caused by mutations that drive aberrant growth, proliferation, and invasion, thus overriding regulatory mechanisms that normally link these processes to organismal needs and cellular physiology. This imposes demands for the production of energy and biomass and for survival in microenvironments that are often nonphysiologic and nutrient-poor, which are met by rewiring of cellular metabolism. The resultant dependence of tumor cells on altered metabolism can induce sensitivity to specific metabolic perturbations that can be exploited for cancer therapy. Some cancers are caused by mutations that impart a novel function to metabolic enzymes, leading to the production of a tumor-promoting metabolite that is dispensable in normal cells, representing an ideal therapeutic target. Tumors can also exploit metabolic regulation of cellular immunity to evade antitumor immune responses, and deciphering this biology has revealed potential targets for therapeutic intervention. Here, we discuss a number of illustrative examples highlighting the therapeutic potential and the challenges of targeting metabolism for cancer therapy.</p>","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":" ","pages":""},"PeriodicalIF":7.8,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142715435","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 7.8 2区 医学
Cold Spring Harbor perspectives in medicine Pub Date : 2024-11-05 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":"https://doi.org/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":7.8,"publicationDate":"2024-11-05","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
Cancer Metabolism: Historical Landmarks, New Concepts, and Opportunities. 癌症代谢：历史里程碑、新概念和新机遇》（Cancer Metabolism: Historical Landmarks, New Concepts, and Opportunities）。
IF 7.8 2区 医学
Cold Spring Harbor perspectives in medicine Pub Date : 2024-11-05 DOI: 10.1101/cshperspect.a041814
Navdeep S Chandel, Karen H Vousden, Ralph J DeBerardinis
{"title":"Cancer Metabolism: Historical Landmarks, New Concepts, and Opportunities.","authors":"Navdeep S Chandel, Karen H Vousden, Ralph J DeBerardinis","doi":"10.1101/cshperspect.a041814","DOIUrl":"https://doi.org/10.1101/cshperspect.a041814","url":null,"abstract":"<p><p>Cancer cells undergo changes in metabolism that distinguish them from non-malignant tissue. These may provide a growth advantage by promoting oncogenic signaling and redirecting intermediates to anabolic pathways that provide building blocks for new cellular components. Cancer metabolism is far from uniform, however, and recent work has shed light on its heterogenity within and between tumors. This work is also revealing how cancer metabolism adapts to the tumor microenvironment, as well as ways in which we may capitalize on metabolic changes in cancer cells to create new therapies.</p>","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":" ","pages":""},"PeriodicalIF":7.8,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142582428","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
Epitope Hierarchy in Type 1 Diabetes Pathogenesis. 1 型糖尿病发病机制中的表位层次。
IF 7.8 2区 医学
Cold Spring Harbor perspectives in medicine Pub Date : 2024-11-05 DOI: 10.1101/cshperspect.a041594
Thomas Delong, Maki Nakayama
{"title":"Epitope Hierarchy in Type 1 Diabetes Pathogenesis.","authors":"Thomas Delong, Maki Nakayama","doi":"10.1101/cshperspect.a041594","DOIUrl":"https://doi.org/10.1101/cshperspect.a041594","url":null,"abstract":"<p><p>Type 1 diabetes (T1D) is an autoimmune disease mediated by T cells destroying insulin-producing β cells. Identifying the antigenic epitopes targeted by autoreactive T cells is crucial for understanding pathogenesis, detecting biomarkers, and developing immunotherapies. This paper covers T-cell epitopes in T1D, focusing on pre-proinsulin and hybrid insulin peptides (HIPs) as major autoantigens. Substantial evidence highlights epitopes in the insulin B-chain and C-peptide as dominant targets for pathogenic CD4 and CD8 T cells infiltrating the islets. HIPs, formed by proinsulin fragments ligated to other peptides, constitute a novel class of epitopes detected in human and mouse islets. In addition, the paper also examines neoepitopes arising from posttranslational modifications, splice variants, and defective ribosomal products. A key challenge is differentiating genuinely pathogenic epitopes driving disease from nonpathogenic mimotopes. Identifying any essential, indispensable epitopes among this array could enable the development of antigen-specific immunotherapies targeting the root causative factors underlying T1D.</p>","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":" ","pages":""},"PeriodicalIF":7.8,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142582430","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 Complex Roles of Redox and Antioxidant Biology in Cancer. 氧化还原和抗氧化生物学在癌症中的复杂作用。
IF 7.8 2区 医学
Cold Spring Harbor perspectives in medicine Pub Date : 2024-11-01 DOI: 10.1101/cshperspect.a041546
Makiko Hayashi, Keito Okazaki, Thales Papgiannakopoulos, Hozumi Motohashi
{"title":"The Complex Roles of Redox and Antioxidant Biology in Cancer.","authors":"Makiko Hayashi, Keito Okazaki, Thales Papgiannakopoulos, Hozumi Motohashi","doi":"10.1101/cshperspect.a041546","DOIUrl":"10.1101/cshperspect.a041546","url":null,"abstract":"<p><p>Redox reactions control fundamental biochemical processes, including energy production, metabolism, respiration, detoxification, and signal transduction. Cancer cells, due to their generally active metabolism for sustained proliferation, produce high levels of reactive oxygen species (ROS) compared to normal cells and are equipped with antioxidant defense systems to counteract the detrimental effects of ROS to maintain redox homeostasis. The KEAP1-NRF2 system plays a major role in sensing and regulating endogenous antioxidant defenses in both normal and cancer cells, creating a bivalent contribution of NRF2 to cancer prevention and therapy. Cancer cells hijack the NRF2-dependent antioxidant program and exploit a very unique metabolism as a trade-off for enhanced antioxidant capacity. This work provides an overview of redox metabolism in cancer cells, highlighting the role of the KEAP1-NRF2 system, selenoproteins, sulfur metabolism, heme/iron metabolism, and antioxidants. Finally, we describe therapeutic approaches that can be leveraged to target redox metabolism in cancer.</p>","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":" ","pages":""},"PeriodicalIF":7.8,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11529857/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141075736","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
Restoration of Rod-Derived Metabolic and Redox Signaling to Prevent Blindness. 恢复杆衍生代谢和氧化还原信号以预防失明。
IF 7.8 2区 医学
Cold Spring Harbor perspectives in medicine Pub Date : 2024-11-01 DOI: 10.1101/cshperspect.a041284
Emmanuelle Clérin, Najate Aït-Ali, José-Alain Sahel, Thierry Léveillard
{"title":"Restoration of Rod-Derived Metabolic and Redox Signaling to Prevent Blindness.","authors":"Emmanuelle Clérin, Najate Aït-Ali, José-Alain Sahel, Thierry Léveillard","doi":"10.1101/cshperspect.a041284","DOIUrl":"10.1101/cshperspect.a041284","url":null,"abstract":"<p><p>Vision is initiated by capturing photons in highly specialized sensory cilia known as the photoreceptor outer segment. Because of its lipid and protein composition, the outer segments are prone to photo-oxidation, requiring photoreceptors to have robust antioxidant defenses and high metabolic synthesis rates to regenerate the outer segments every 10 days. Both processes required high levels of glucose uptake and utilization. Retinitis pigmentosa is a prevalent form of inherited retinal degeneration characterized by initial loss of low-light vision caused by the death of rod photoreceptors. In this disease, rods die as a direct effect of an inherited mutation. Following the loss of rods, cones eventually degenerate, resulting in complete blindness. The progression of vision loss in retinitis pigmentosa suggested that rod photoreceptors were necessary to maintain healthy cones. We identified a protein secreted by rods that functions to promote cone survival, and we named it rod-derived cone viability factor (RdCVF). RdCVF is encoded by an alternative splice product of the nucleoredoxin-like 1 (<i>NXNL1</i>) gene, and RdCVF was found to accelerate the uptake of glucose by cones. Without RdCVF, cones eventually die because of compromised glucose uptake and utilization. The <i>NXNL1</i> gene also encodes for the thioredoxin RdCVFL, which reduces cysteines in photoreceptor proteins that are oxidized, providing a defense against radical oxygen species. We will review here the main steps of discovering this novel intercellular signaling currently under translation as a broad-spectrum treatment for retinitis pigmentosa.</p>","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":" ","pages":""},"PeriodicalIF":7.8,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11529851/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41232936","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
α-Synuclein in Parkinson's Disease: 12 Years Later. 帕金森病中的α-突触核蛋白：12 年之后
IF 7.8 2区 医学
Cold Spring Harbor perspectives in medicine Pub Date : 2024-11-01 DOI: 10.1101/cshperspect.a041645
Kostas Vekrellis, Evangelia Emmanouilidou, Maria Xilouri, Leonidas Stefanis
{"title":"α-Synuclein in Parkinson's Disease: 12 Years Later.","authors":"Kostas Vekrellis, Evangelia Emmanouilidou, Maria Xilouri, Leonidas Stefanis","doi":"10.1101/cshperspect.a041645","DOIUrl":"10.1101/cshperspect.a041645","url":null,"abstract":"<p><p>α-Synuclein (AS) is a small presynaptic protein that is genetically, biochemically, and neuropathologically linked to Parkinson's disease (PD) and related synucleinopathies. We present here a review of the topic of this relationship, focusing on more recent knowledge. In particular, we review the genetic evidence linking AS to familial and sporadic PD, including a number of recently identified point mutations in the <i>SNCA</i> gene. We briefly go over the relevant neuropathological findings, stressing the evidence indicating a correlation between aberrant AS deposition and nervous system dysfunction. We analyze the structural characteristics of the protein, in relation to both its physiologic and pathological conformations, with particular emphasis on posttranslational modifications, aggregation properties, and secreted forms. We review the interrelationship of AS with various cellular compartments and functions, with particular focus on the synapse and protein degradation systems. We finally go over the recent exciting data indicating that AS can provide the basis for novel robust biomarkers in the field of synucleinopathies, while at the same time results from the first clinical trials specifically targeting AS are being reported.</p>","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":" ","pages":""},"PeriodicalIF":7.8,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11529858/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142342958","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
Advancing Animal Models of Human Type 1 Diabetes. 推动人类 1 型糖尿病动物模型的发展。
IF 7.8 2区 医学
Cold Spring Harbor perspectives in medicine Pub Date : 2024-10-01 DOI: 10.1101/cshperspect.a041587
David V Serreze, Jennifer R Dwyer, Jeremy J Racine
{"title":"Advancing Animal Models of Human Type 1 Diabetes.","authors":"David V Serreze, Jennifer R Dwyer, Jeremy J Racine","doi":"10.1101/cshperspect.a041587","DOIUrl":"10.1101/cshperspect.a041587","url":null,"abstract":"<p><p>Multiple rodent models have been developed to study the basis of type 1 diabetes (T1D). However, nonobese diabetic (NOD) mice and derivative strains still provide the gold standard for dissecting the basis of the autoimmune responses underlying T1D. Here, we review the developmental origins of NOD mice, and how they and derivative strains have been used over the past several decades to dissect the genetic and immunopathogenic basis of T1D. Also discussed are ways in which the immunopathogenic basis of T1D in NOD mice and humans are similar or differ. Additionally reviewed are efforts to \"humanize\" NOD mice and derivative strains to provide improved models to study autoimmune responses contributing to T1D in human patients.</p>","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":" ","pages":""},"PeriodicalIF":7.8,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11444302/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141418110","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
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