Cold Spring Harbor perspectives in medicine最新文献_第2页

Targeting Hyperactive Ras Signaling in Pediatric Cancer. 靶向小儿癌症中亢进的 Ras 信号

IF 7.8 2区医学

Cold Spring Harbor perspectives in medicine Pub Date : 2025-05-05 DOI: 10.1101/cshperspect.a041572

Anya Levinson, Kevin Shannon, Benjamin J Huang

{"title":"Targeting Hyperactive Ras Signaling in Pediatric Cancer.","authors":"Anya Levinson, Kevin Shannon, Benjamin J Huang","doi":"10.1101/cshperspect.a041572","DOIUrl":"10.1101/cshperspect.a041572","url":null,"abstract":"Somatic RAS mutations are among the most frequent drivers in pediatric and adult cancers. Somatic KRAS, NRAS, and HRAS mutations exhibit distinct tissue-specific predilections. Germline NF1 and RAS mutations in children with neurofibromatosis type 1 and other RASopathy developmental disorders have provided new insights into Ras biology. In many cases, these germline mutations are associated with increased cancer risk. Promising targeted therapeutic strategies for pediatric cancers and neoplasms with NF1 or RAS mutations include inhibition of downstream Ras effector pathways, directly inhibiting the signal output of oncogenic Ras proteins and associated pathway members, and therapeutically targeting Ras posttranslational modifications and intracellular trafficking. Acquired drug resistance to targeted drugs remains a significant challenge but, increasingly, rational drug combination approaches have shown promise in overcoming resistance. Developing predictive preclinical models of childhood cancers for drug testing is a high priority for the field of pediatric oncology.","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":" ","pages":""},"PeriodicalIF":7.8,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12047744/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141619558","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

Neuropathology of Parkinson's Disease and Parkinsonism. 帕金森病和帕金森症的神经病理学。

IF 7.8 2区医学

Cold Spring Harbor perspectives in medicine Pub Date : 2025-05-05 DOI: 10.1101/cshperspect.a041610

Dennis W Dickson

{"title":"Neuropathology of Parkinson's Disease and Parkinsonism.","authors":"Dennis W Dickson","doi":"10.1101/cshperspect.a041610","DOIUrl":"https://doi.org/10.1101/cshperspect.a041610","url":null,"abstract":"Parkinsonism, the clinical term for a disorder with prominent bradykinesia and variably associated extrapyramidal signs and symptoms, is virtually always accompanied by degeneration of the nigrostriatal dopaminergic system, with neuronal loss and gliosis in the substantia nigra at autopsy. Neuronal loss is particularly marked in the ventrolateral cell groups of the substantia nigra, which project to the putamen via the nigrostriatal pathway. Parkinsonism is pathologically heterogeneous, with the most common pathologic substrates related to abnormalities in the presynaptic protein α-synuclein or the microtubule-binding protein tau. In idiopathic Parkinson's disease (PD), α-synuclein accumulates in neuronal perikarya (Lewy bodies) and neuronal processes (Lewy neurites). The disease process is multifocal and involves select central nervous system neurons, as well as neurons in the peripheral autonomic nervous system. The particular set of neurons affected determines nonmotor clinical presentations. Multiple system atrophy (MSA) is the other major α-synucleinopathy. It is also associated with autonomic dysfunction and in some cases with cerebellar signs. The hallmark histopathologic feature of MSA is an accumulation of α-synuclein within glial cytoplasmic inclusions (GCIs). The most common of the Parkinsonian tauopathies is progressive supranuclear palsy (PSP), which is clinically associated with severe postural instability leading to early falls. The tau pathology of PSP also affects both neurons and glia.","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":" ","pages":""},"PeriodicalIF":7.8,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143980467","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 Evolution of Mouse Models of Cancer: Past, Present, and Future. 癌症小鼠模型的演变：过去、现在和未来

IF 7.8 2区医学

Cold Spring Harbor perspectives in medicine Pub Date : 2025-05-05 DOI: 10.1101/cshperspect.a041736

Cory Abate-Shen, Katerina Politi

{"title":"The Evolution of Mouse Models of Cancer: Past, Present, and Future.","authors":"Cory Abate-Shen, Katerina Politi","doi":"10.1101/cshperspect.a041736","DOIUrl":"10.1101/cshperspect.a041736","url":null,"abstract":"In the nearly 50 years since the original models of cancer first hit the stage, mouse models have become a major contributor to virtually all aspects of cancer research, and these have evolved well beyond simple transgenic or xenograft models to encompass a wide range of more complex models. As the sophistication of mouse models has increased, an explosion of new technologies has expanded the potential to both further develop and apply these models to address major challenges in cancer research. In the current era, cancer modeling has expanded to include nongermline genetically engineered mouse models (GEMMs), patient-derived models, organoids, and adaptations of the models better suited for cancer immunology research. New technologies that have transformed the field include the application of CRISPR-Cas9-mediated genome editing, in vivo imaging, and single-cell analysis to cancer modeling. Here, we provide a historical perspective on the evolution of mouse models of cancer, focusing on how far we have come in a relatively short time and how new technologies will shape the future development of mouse models of cancer.","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":" ","pages":""},"PeriodicalIF":7.8,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12047742/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141075737","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

Advances in Islet Transplantation and the Future of Stem Cell-Derived Islets to Treat Diabetes. 胰岛移植的进展和干细胞衍生胰岛治疗糖尿病的未来。

IF 7.8 2区医学

Cold Spring Harbor perspectives in medicine Pub Date : 2025-05-05 DOI: 10.1101/cshperspect.a041624

Timothy J Kieffer, Corinne A Hoesli, A M James Shapiro

{"title":"Advances in Islet Transplantation and the Future of Stem Cell-Derived Islets to Treat Diabetes.","authors":"Timothy J Kieffer, Corinne A Hoesli, A M James Shapiro","doi":"10.1101/cshperspect.a041624","DOIUrl":"10.1101/cshperspect.a041624","url":null,"abstract":"β-Cell replacement for type 1 diabetes (T1D) can restore normal glucose homeostasis, thereby eliminating the need for exogenous insulin and halting the progression of diabetes complications. Success in achieving insulin independence following transplantation of cadaveric islets fueled academic and industry efforts to develop techniques to mass produce β cells from human pluripotent stem cells, and these have now been clinically validated as an alternative source of regulated insulin production. Various encapsulation strategies are being pursued to contain implanted cells in a retrievable format, and different implant sites are being explored with some strategies reaching clinical studies. Stem cell lines, whether derived from embryonic sources or reprogrammed somatic cells, are being genetically modified for designer features, including immune evasiveness to enable implant without the use of chronic immunosuppression. Although hurdles remain in optimizing large-scale manufacturing, demonstrating efficacy, durability, and safety, products containing stem cell-derived β cells promise to provide a potent treatment for insulin-dependent diabetes.","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":" ","pages":""},"PeriodicalIF":7.8,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12047745/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141792094","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

A History of Biosafety: U.S. Perspective. 生物安全的历史：美国视角。

IF 7.8 2区医学

Cold Spring Harbor perspectives in medicine Pub Date : 2025-04-15 DOI: 10.1101/cshperspect.a041625

Robert J Hawley, Joseph P Kozlovac

{"title":"A History of Biosafety: U.S. Perspective.","authors":"Robert J Hawley, Joseph P Kozlovac","doi":"10.1101/cshperspect.a041625","DOIUrl":"https://doi.org/10.1101/cshperspect.a041625","url":null,"abstract":"Over the past thousand years, one can observe a preponderance of evidence demonstrating the emergence and application of safety principles progressing from a crude beginning to the modern era in all human accomplishments. For more than a thousand years, we have seen evidence of the application of safety principles, albeit primitive compared to those of today, for a reasonable approach to accomplish a task. The limited knowledge available in the past, along with a comparative lack of resources, did not deter these early investigators from adapting their thought processes to create solutions to the problems of their day. Notwithstanding their limited knowledge and lack of resources, these early investigators were able to apply their thought processes to reach a goal. Collectively, their practices, experimental results, and findings provided the foundation for the evolution of the disciplines of microbiology, epidemiology, public health, and safety, and eventually biosafety. Many contributions were made in decontamination methodologies and technologies and the use of protective clothing, engineering controls, vaccine development, food preservation, infection control, aseptic practices, and containment. It is wonderful to learn what germs have taught us! This paper provides an overview of historical safety and biosafety events and how they have both influenced and contributed to the development of modern principles and practices.","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":" ","pages":""},"PeriodicalIF":7.8,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143986891","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

Historical Perspectives of Parkinson's Disease: Early Clinical Descriptions and Neurological Therapies. 帕金森病的历史展望：早期临床描述和神经疗法。

IF 7.8 2区医学

Cold Spring Harbor perspectives in medicine Pub Date : 2025-04-01 DOI: 10.1101/cshperspect.a041642

Christopher G Goetz

{"title":"Historical Perspectives of Parkinson's Disease: Early Clinical Descriptions and Neurological Therapies.","authors":"Christopher G Goetz","doi":"10.1101/cshperspect.a041642","DOIUrl":"10.1101/cshperspect.a041642","url":null,"abstract":"Although components of possible Parkinson's disease can be found in earlier documents, the first clear medical description was written in 1817 by James Parkinson. In the mid-1800s, Jean-Martin Charcot was particularly influential in refining and expanding this early description and in disseminating information internationally about Parkinson's disease. He separated the clinical spectrum of Parkinson's disease from multiple sclerosis and other disorders characterized by tremor, and he recognized cases that later would likely be classified among the parkinsonism-plus syndromes. Early treatments of Parkinson's disease were based on empirical observation, and anticholinergic drugs were used as early as the nineteenth century. The discovery of dopaminergic deficits in Parkinson's disease and the synthetic pathway of dopamine led to the first human trials of levodopa. Further historically important anatomical, biochemical, and physiological studies identified additional pharmacological and neurosurgical targets for Parkinson's disease and allow modern clinicians to offer an array of therapies aimed at improving function in this still incurable disease.","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":" ","pages":""},"PeriodicalIF":7.8,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11960689/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141300205","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

The Chicken or the Egg Dilemma: Understanding the Interplay between the Immune System and the β Cell in Type 1 Diabetes. 鸡还是蛋的两难选择：了解 1 型糖尿病中免疫系统与 β 细胞之间的相互作用。

IF 7.8 2区医学

Cold Spring Harbor perspectives in medicine Pub Date : 2025-04-01 DOI: 10.1101/cshperspect.a041591

Maria Skjøtt Hansen, Pravil Pokharel, Jon Piganelli, Lori Sussel

引用次数: 0

Lineage-Selective Dependencies in Pediatric Cancers. 小儿癌症的系谱选择依赖性

IF 7.8 2区医学

Cold Spring Harbor perspectives in medicine Pub Date : 2025-04-01 DOI: 10.1101/cshperspect.a041573

K Elaine Ritter, Adam D Durbin

{"title":"Lineage-Selective Dependencies in Pediatric Cancers.","authors":"K Elaine Ritter, Adam D Durbin","doi":"10.1101/cshperspect.a041573","DOIUrl":"10.1101/cshperspect.a041573","url":null,"abstract":"The quest for effective cancer therapeutics has traditionally centered on targeting mutated or overexpressed oncogenic proteins. However, challenges arise in cancers with low mutational burden or when the mutated oncogene is not conventionally targetable, which are common situations in childhood cancers. This obstacle has sparked large-scale unbiased screens to identify collateral genetic dependencies crucial for cancer cell growth. These screens have revealed promising targets for therapeutic intervention in the form of lineage-selective dependency genes, which may have an expanded therapeutic window compared to pan-lethal dependencies. Many lineage-selective dependencies regulate gene expression and are closely tied to the developmental origins of pediatric tumors. Placing lineage-selective dependencies in a transcriptional network model is helpful for understanding their roles in driving malignant cell behaviors. Here, we discuss the identification of lineage-selective dependencies and how two transcriptional models, core regulatory circuits and gene regulatory networks, can serve as frameworks for understanding their individual and collective actions, particularly in cancers affecting children and young adults.","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":" ","pages":""},"PeriodicalIF":7.8,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11882016/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141161168","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

Zebrafish Models for Drug Discovery and Therapeutic Validation against Non-Tuberculous Mycobacteria. 用于非结核分枝杆菌药物发现和治疗验证的斑马鱼模型。

IF 7.8 2区医学

Cold Spring Harbor perspectives in medicine Pub Date : 2025-03-27 DOI: 10.1101/cshperspect.a041832

Matt D Johansen, Claire Hamela, Yi Ding, Laurent Kremer

引用次数: 0

Developmental Oncology: Principles and Therapy of Cancers of Children and Young Adults. 发展肿瘤学：儿童和青少年癌症的原理和治疗。

IF 7.8 2区医学

Cold Spring Harbor perspectives in medicine Pub Date : 2025-03-17 DOI: 10.1101/cshperspect.a041847

Alex Kentsis, Alejandro Gutierrez

引用次数: 0