{"title":"Exploring Parkinson's through the Lens of Genomics and Bioinformatics.","authors":"Vilas Menon","doi":"10.1101/cshperspect.a041621","DOIUrl":"https://doi.org/10.1101/cshperspect.a041621","url":null,"abstract":"<p><p>Within the last three decades, revolutions in genomics data generation and bioinformatics analysis techniques have profoundly impacted our understanding of the molecular mechanisms of Parkinson's disease (PD). From the description of the first PD-associated risk gene in 1997 through today, new technologies have revolutionized approaches to identify genetic and molecular mechanisms implicated in human health and disease. Spurred by the dramatically decreasing costs for genotyping, genome sequencing, and transcriptomics approaches, the ability to profile large cohorts of human populations or model organisms has accelerated the understanding of disease susceptibility, pathways, and genes. Thus far, ∼30 genetic loci have been unequivocally linked to the pathogenesis of PD, highlighting essential molecular pathways underlying this common disorder. More recently, the advent of single-cell transcriptomics techniques applied to human brain tissue has implicated cell-type-specific dysregulation and vulnerability (beyond the loss of dopaminergic neurons) in the disease. Herein, we discuss how neurogenomics and bioinformatics are applied to dissect the nature of this complex disease with the overall aim of identifying new targets for therapeutic interventions.</p>","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":" ","pages":""},"PeriodicalIF":7.8,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143390320","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}
Kayla V Hamilton, Akiko Shimamura, Jessica A Pollard
{"title":"Genetic Predisposition to Hematologic Malignancies.","authors":"Kayla V Hamilton, Akiko Shimamura, Jessica A Pollard","doi":"10.1101/cshperspect.a041585","DOIUrl":"https://doi.org/10.1101/cshperspect.a041585","url":null,"abstract":"<p><p>Hematologic malignancies (HMs) have been increasingly recognized in association with an underlying genetic predisposition syndrome (GPS) in individuals of all ages. It is critical for hematology and oncology providers to be aware of the diagnostic findings, physical examination findings, and aspects of family history that raise suspicion for an underlying GPS. Moreover, recognition of how somatic gene panel testing, frequently done at the time of HM diagnosis, may raise suspicion for an underlying germline condition based on the mutation profile reported, is prudent. With knowledge of an underlying germline condition, the chemotherapy used for a given HM may be impacted and the role of hematopoietic stem cell transplant more critically considered. Off-therapy monitoring after HM treatment is completed will also likely be impacted. In this work, we review key features of several GPSs associated with increased risks for HM while also outlining the diagnostic workup to identify GPSs and treatment considerations for affected patients. Armed with this knowledge, treating providers may evaluate the possibility of a GPS in patients with leukemia/lymphoma and modify their treatment plan accordingly.</p>","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":" ","pages":""},"PeriodicalIF":7.8,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143390338","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}
{"title":"Progression in Parkinson's Disease.","authors":"Krithi Irmady, Serge Przedborski","doi":"10.1101/cshperspect.a041641","DOIUrl":"https://doi.org/10.1101/cshperspect.a041641","url":null,"abstract":"<p><p>Parkinson's disease (PD) is a common neurodegenerative disorder characterized by relentlessly progressive motor and nonmotor clinical features. In this paper, we offer a comprehensive overview of progression in PD, covering the heterogeneous symptomatology crucial for monitoring progression from clinical, pathological, and biomarker perspectives. We also discuss prevailing theories concerning the underlying pathobiology driving progression in PD and summarize the literature on emerging biomarkers that are expected to facilitate early prognosis and effective monitoring of disease progression.</p>","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":" ","pages":""},"PeriodicalIF":7.8,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143390340","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}
{"title":"Clinical Immunologic Interventions for the Treatment of Type 1 Diabetes: Challenges, Choice, and Timing of Immunomodulators.","authors":"Danijela Tatovic, Colin Dayan","doi":"10.1101/cshperspect.a041597","DOIUrl":"https://doi.org/10.1101/cshperspect.a041597","url":null,"abstract":"<p><p>Replacement insulin therapy has been the mainstay of type 1 diabetes mellitus (T1D) treatment ever since its introduction into clinical care more than 100 years ago. Despite advances in delivery methods, insulin remains a challenging medication. It is, therefore, not surprising that most people with T1D do not achieve optimal glycemic control and remain at risk of complications. The recent introduction of teplizumab as the first immunotherapy for T1D has ushered in an exciting era where the focus is shifted from metabolic replacement therapy with insulin to proactive disease-modifying treatments that prevent the loss of insulin secretory capacity. At least nine other clinical immunologic interventions have shown phase 2 trial efficacy in preserving β-cell function in T1D. To translate these findings to patient benefit, many changes are required. These include improvements in end points and trial design to accelerate drug development, changing the attitude of healthcare professionals toward novel strategies, and the development of effective screening programs to identify affected individuals in early-stage disease. This will enable a broad portfolio of β-cell preserving therapies to be approved, in turn allowing appropriate selection of immunomodulators tailored to an individual's response with an ultimate goal of \"insulin-free T1D.\"</p>","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":" ","pages":""},"PeriodicalIF":7.8,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143390317","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}
{"title":"A History of Cancer Research: The P53 Pathway.","authors":"Joseph Lipsick","doi":"10.1101/cshperspect.a035931","DOIUrl":"10.1101/cshperspect.a035931","url":null,"abstract":"<p><p>The p53 tumor suppressor was first identified as a cellular protein that bound to the large T antigen in SV40-transformed cells. Initially thought to be the product of an oncogene, p53 turned out to be an anticancer protein whose loss or mutation could promote tumorigenesis. Subsequent work revealed it functions as a DNA-binding transcription factor central to the DNA damage response and cell cycle control. In this excerpt from his forthcoming book on the history of cancer research, Joe Lipsick looks back at the discovery of p53 and the groundbreaking work that revealed its role as \"guardian of the genome.\"</p>","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":"15 2","pages":""},"PeriodicalIF":7.8,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11789935/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143122223","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}
{"title":"Modeling Parkinson's Disease in Primates.","authors":"Erwan Bezard, Margaux Teil, Marie-Laure Arotcarena, Gregory Porras, Qin Li, Benjamin Dehay","doi":"10.1101/cshperspect.a041612","DOIUrl":"10.1101/cshperspect.a041612","url":null,"abstract":"<p><p>Decades of research have identified the pathological and pathophysiological hallmarks of Parkinson's disease (PD): profound deficit in brain dopamine and other monoamines, pathological α-synuclein aggregation, synaptic and neuronal network dysfunction, aberrant proteostasis, altered energy homeostasis, inflammation, and neuronal cell death. The purpose of this contribution is to present the phenocopy aspect, pathogenic, and etiologic nonhuman primate (NHP) models of PD to readers with limited prior knowledge of PD so that they are ready to start working on PD. How NHPs, the closest species to man on which we can model diseases, contribute to the knowledge progress and how these models represent an invaluable translational step in therapeutic development are highlighted.</p>","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":" ","pages":""},"PeriodicalIF":7.8,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11789937/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141300208","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}
{"title":"The Gut-Brain Axis in Parkinson's Disease.","authors":"Virginia Gao, Carl V Crawford, Jacqueline Burré","doi":"10.1101/cshperspect.a041618","DOIUrl":"10.1101/cshperspect.a041618","url":null,"abstract":"<p><p>Parkinson's disease (PD) involves both the central nervous system (CNS) and enteric nervous system (ENS), and their interaction is important for understanding both the clinical manifestations of the disease and the underlying disease pathophysiology. Although the neuroanatomical distribution of pathology strongly suggests that the ENS is involved in disease pathophysiology, there are significant gaps in knowledge about the underlying mechanisms. In this article, we review the clinical presentation and management of gastrointestinal dysfunction in PD. In addition, we discuss the current understanding of disease pathophysiology in the gut, including controversies about early involvement of the gut in disease pathogenesis. We also review current knowledge about gut α-synuclein and the microbiome, discuss experimental models of PD-linked gastrointestinal pathophysiology, and highlight areas for further research. Finally, we discuss opportunities to use the gut-brain axis for the development of biomarkers and disease-modifying treatments.</p>","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":" ","pages":""},"PeriodicalIF":7.8,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11694753/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141075774","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}
{"title":"Developmental Heterogeneity of Rhabdomyosarcoma.","authors":"Bradley T Stevens, Mark E Hatley","doi":"10.1101/cshperspect.a041583","DOIUrl":"10.1101/cshperspect.a041583","url":null,"abstract":"<p><p>Rhabdomyosarcoma (RMS) is a pediatric embryonal solid tumor and the most common pediatric soft tissue sarcoma. The histology and transcriptome of RMS resemble skeletal muscle progenitor cells that have failed to terminally differentiate. Thus, RMS is typically thought to arise from corrupted skeletal muscle progenitor cells during development. However, RMS can occur in body regions devoid of skeletal muscle, suggesting the potential for nonmyogenic cells of origin. Here, we discuss the interplay between RMS driver mutations and cell(s) of origin with an emphasis on driving location specificity. Additionally, we discuss the mechanisms governing RMS transformation events and tumor heterogeneity through the lens of transcriptional networks and epigenetic control. Finally, we reimagine Waddington's developmental landscape to include a plane of transformation connecting distinct lineage landscapes to more accurately reflect the phenomena observed in pediatric cancers.</p>","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":" ","pages":""},"PeriodicalIF":7.8,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11694754/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141075772","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}
{"title":"Corrigendum: Preclinical Modeling of Pathway-Targeted Therapy of Human Lung Cancer in the Mouse.","authors":"Aria Vaishnavi, Conan G Kinsey, Martin McMahon","doi":"10.1101/cshperspect.a041815","DOIUrl":"10.1101/cshperspect.a041815","url":null,"abstract":"","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":" ","pages":""},"PeriodicalIF":7.8,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11696991/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142603599","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}
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