Cold Spring Harbor perspectives in medicine最新文献

{"title":"Models of High-Grade Serous Ovarian Carcinoma.","authors":"Oscar J Pundel, Benjamin G Neel","doi":"10.1101/cshperspect.a041949","DOIUrl":"10.1101/cshperspect.a041949","url":null,"abstract":"<p><p>High-grade serous ovarian carcinoma (HGSC) remains an incompletely understood, highly lethal disease. Historically, a lack of fidelitous in vitro and in vivo models representing HGSC biology and therapy response has been a major barrier to progress. As we discuss below, multiple (if not most) early studies used-and some investigators continue to use-human \"ovarian cancer cell lines\" that lack key genomic/genetic features of HGSC, rendering their conclusions questionable. The frequently deployed ID8 syngeneic mouse model is similarly suspect, as it derives from ovarian surface epithelium (OSE) and is <i>Trp53</i> wild-type. In contrast, most, if not all, HGSC arises in fallopian tube epithelium (FTE), and bona fide HGSC is universally <i>TP53</i> mutant or silenced. Over the past 10 years, attempts have been made to rectify these historical deficiencies, including careful assessment of the genetic composition of standard ovarian cancer cell lines and the development of mouse and human organoids, genetically engineered mouse models (GEMMs), and patient-derived xenografts (PDXs). In this review, we discuss these advances, exploring their differences, strengths, and weaknesses. We also describe \"next-generation\" approaches to more faithfully model HGSC cells in the context of a more realistic tumor microenvironment.</p>","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":" ","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13065344/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238495","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":"Exploring Parkinson's through the Lens of Genomics and Bioinformatics.","authors":"Vilas Menon","doi":"10.1101/cshperspect.a041621","DOIUrl":"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":4.9,"publicationDate":"2026-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13065342/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"From Phagosomes to Niches: Macrophage Biology in Tuberculosis Revisited.","authors":"Pierre Dupuy, Sarah C Monard, Olivier Neyrolles, Geanncarlo Lugo-Villarino","doi":"10.1101/cshperspect.a041819","DOIUrl":"10.1101/cshperspect.a041819","url":null,"abstract":"<p><p><i>Mycobacterium tuberculosis</i> thrives inside macrophages by modulating intracellular pathways and adapting to various lung environments. Here, we first describe how the bacillus alters phagosome maturation, endures intracellular pressure, and obtains essential nutrients. These mechanisms have been primarily defined in cell lines and macrophage models derived from monocytes. However, recent findings regarding macrophage biology suggest that such intracellular processes might differ depending on the origin and surrounding local environment. For this reason, we then examine how different cell origins and lung niches affect infection dynamics, focusing on alveolar and interstitial macrophages, which exhibit unique metabolic and immunological characteristics. Finally, we emphasize newly identified interstitial macrophage subsets related to nerves and blood vessels, whose functions in tuberculosis are mostly unexplored but could signify potential new research opportunities. Altogether, this review highlights that a better understanding of the ontogeny and location of a macrophage is as important as comprehending its microbicidal programs in the fight against tuberculosis, by merging intracellular cellular processes with cell origin and spatial context.</p>","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":" ","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13065343/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145437342","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":"A History of Cancer Research: Proto-Oncogene Activation in Human Cancer.","authors":"Joseph Lipsick","doi":"10.1101/cshperspect.a035790","DOIUrl":"10.1101/cshperspect.a035790","url":null,"abstract":"<p><p>Research in the 1970s showed that while retroviruses had been a key to identification of oncogenes, they were not actually a major cause of human cancer. Moreover, cells contained additional proto-oncogenes that did not necessarily have viral oncogene counterparts. In this excerpt from his forthcoming book, Joe Lipsick remembers the groundbreaking work on DNA transfection, chromosomal rearrangements, and gene amplification that identified the smoking guns responsible for activation of oncogenes such as RAS and revealed how translocations in immune cells produce cancer drivers like the Philadelphia chromosome.</p>","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":"16 4","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13065340/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147607613","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":"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":"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":4.9,"publicationDate":"2026-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13065341/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epigenetic Therapies.","authors":"Wallace Bourgeois, Scott A Armstrong, Emily B Heikamp","doi":"10.1101/cshperspect.a041637","DOIUrl":"10.1101/cshperspect.a041637","url":null,"abstract":"<p><p>Epigenetic therapies are emerging for pediatric cancers. Due to the relatively low mutational burden in pediatric tumors, epigenetic dysregulation and differentiation blockade is a hallmark of oncogenesis in some childhood cancers. By targeting epigenetic regulators that maintain tumor cells in a primitive developmental state, epigenetic therapies may induce differentiation. The most well-studied and clinically advanced epigenetic-targeted therapies include azacitidine and decitabine, which inhibit DNA methylation through competitive inhibition of the enzymatic activity of the DNA methyltransferase family enzymes. These DNA hypomethylating agents are Food and Drug Administration (FDA) approved for hematologic malignancies. The discovery that DNA hypermethylation occurs in patients with isocitrate dehydrogenase (IDH) mutations has led to the development and FDA approval of IDH inhibitors for hematologic and solid tumors. Epigenetic dysregulation in pediatric tumors is also driven by changes in the \"histone code\" that either promote oncogene expression or repress tumor suppressors. Cancers whose chromatin landscape is characterized by such aberrant histone posttranslational modifications may be amenable to targeted therapies that inhibit the chromatin-modifying enzymes that read, write, and erase these histone modifications. Small molecules that inhibit the enzymatic activity of histone deacetylases, acetyltransferases, and methyltransferases have been approved for the treatment of some adult cancers, and these agents are currently under investigation in various pediatric tumors. Chromatin regulatory complexes can be hijacked by oncogenic fusion proteins that are produced by chromosomal translocations, which are common drivers in pediatric cancer. Small molecules that disrupt oncogenic fusion protein activity and their associated chromatin complexes have demonstrated remarkable promise, and this approach has become the standard treatment for a subset of leukemias driven by the PML-RARA oncogenic fusion protein. A deeper understanding of the mechanisms that drive epigenetic dysregulation in pediatric cancer may hold the key to future success in this field, as the landscape of druggable epigenetic targets is also expanding.</p>","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":" ","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12951766/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142853333","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":"Autophagy and Protein Quality Control in Parkinson's Disease.","authors":"Marta Martinez-Vicente, Miquel Vila","doi":"10.1101/cshperspect.a041619","DOIUrl":"10.1101/cshperspect.a041619","url":null,"abstract":"<p><p>Autophagy is a vital cellular process responsible for the degradation of proteins, organelles, and other cellular components within lysosomes. In neurons, basal autophagy is indispensable for maintaining cellular homeostasis and protein quality control. Accordingly, lysosomal dysfunction has been proposed to be associated with neurodegeneration, and with Parkinson's disease (PD) in particular. Aging, dopamine metabolism, and PD-linked genetic mutations are thought to impair the autophagic-lysosomal pathway, disrupt cellular proteostasis, and contribute to PD pathogenesis. These alterations represent an opportunity to identify potential new therapeutic targets and disease biomarkers, thus laying the groundwork for the development of novel disease-modifying strategies for PD that are aimed at restoring cellular proteostasis and quality control systems.</p>","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":" ","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12951769/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142853331","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":"Ovarian Cancer Therapy.","authors":"Diana Miao, Ursula A Matulonis, Rebecca L Porter","doi":"10.1101/cshperspect.a038232","DOIUrl":"10.1101/cshperspect.a038232","url":null,"abstract":"<p><p>Significant advances in basic and translational research have improved our understanding of the molecular alterations and biological vulnerabilities of the different histologic subsets of epithelial ovarian cancer (EOC). This has led to clinical trials that have incorporated novel agents based on molecular aspects into the treatment paradigm for both newly diagnosed and recurrent disease. The past decade has witnessed several regulatory approvals in the United States and Europe for the treatment of EOC, including the antiangiogenic agent, bevacizumab, poly(ADP-ribose) polymerase inhibitors in various therapeutic settings, and the antibody-drug conjugate (ADC), mirvetuximab soravtansine. Immune checkpoint inhibitors do not demonstrate substantial activity as single agents in ovarian cancer, except for the rare entity of microsatellite instability (MSI) high ovarian cancer. Current research is focused on new treatment paradigms such as ADCs, genetically specific therapies, and other novel immunotherapies such as bispecific antibodies, radioligand therapies, cellular therapies, and vaccines. In addition, combination efforts are focused on incorporating conventional chemotherapy, targeted therapies, immune-oncology drugs, and/or novel agents to improve outcomes for patients with newly diagnosed as well as recurrent EOC. This review will focus on the management of high-grade serous ovarian cancer, the most common type of EOC, accounting for ∼75% of cases. Recent advances in the management of rarer histologic subtypes with distinct molecular and clinical characteristics, including clear cell, mucinous, endometrioid, and low-grade serous, will be briefly discussed. Non-EOCs, including germ cell and sex cord stromal tumors and their treatment, have been reviewed elsewhere [see Ray-Coquard et al. (2019) <i>N Engl J Med</i> <b>381:</b> 2416-2428. doi:10.1056/NEJMoa1911361].</p>","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":" ","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12951770/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144101487","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":"Tuberculosis Drug Discovery in the Age of Artificial Intelligence.","authors":"Sean Ekins, Thomas R Lane, Jason T Wong","doi":"10.1101/cshperspect.a041828","DOIUrl":"10.1101/cshperspect.a041828","url":null,"abstract":"<p><p>There is an urgent need to develop additional treatments for tuberculosis (TB) to complement the small panel of approved drugs and to devise shorter treatment regimens. Within the last 20 years, we have seen an increased focus on using cheminformatics-based approaches to understand the properties of <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>) active molecules and machine learning algorithms to subsequently learn from public data sets. We now demonstrate how we have continually used many machine learning approaches that have enabled us to select or synthesize new compounds for testing in vitro to validate our models and to identify new chemical matter. We now put our results into context with studies from other groups to make the case for using machine learning models more widely to aid in finding new <i>Mtb</i> inhibitors. TB research has been slow to adapt to these approaches to increase drug discovery efficiency, but it is better late than never.</p>","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":" ","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12713521/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145437360","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":"Distributed Capability, Shared Vulnerability: International Governance of Biosafety and Biosecurity.","authors":"Filippa Lentzos, Gemma Bowsher","doi":"10.1101/cshperspect.a041627","DOIUrl":"10.1101/cshperspect.a041627","url":null,"abstract":"<p><p>Biological risks are increasingly shaped by globally distributed scientific capability, accelerating technological change and a rapidly evolving information environment. This review examines how these dynamics challenge traditional biosafety and biosecurity governance. It analyzes the internationalization of high-risk life science capacity, the expanding scope of pathogen research, and the implications of digitalization, artificial intelligence (AI)-enabled design tools and cloud laboratories. It then traces the historical foundations of biosafety and biosecurity, highlights the fragmentation across health, environmental and security instruments, and assesses how divergent national systems shape global vulnerability. The article further explores cross-border scientific collaboration, movement of materials and data, and the complexities of ambiguous outbreaks, investigation mechanisms and information integrity. It concludes by identifying strategic gaps and outlining priorities for a more adaptive, interoperable and equitable governance architecture capable of operating in a world where biological capability is widely dispersed and biological risks increasingly dematerialized.</p>","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":" ","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13532519/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146212329","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}