Cold Spring Harbor perspectives in medicine最新文献

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.

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.

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.

Type 1 diabetes (T1D) is a progressive T cell-mediated autoimmune disease that results from the breakdown of tolerance mechanisms in β-cell-specific T cells. Although CD8 T cells are primarily responsible for the destruction of insulin-producing β cells, intriguingly, HLA class II allelic polymorphisms confer the greatest genetic risk for the development of T1D, suggesting a critical role of CD4 T cells in disease initiation and progression. Many aspects of autoimmune T cell differentiation remain enigmatic, including where and how autoimmune CD8 and CD4 T cells arise, which molecular programs control autoimmune T cell differentiation, and how CD8 T cells sustain β-cell destruction in the face of persistent self-antigen encounter. In this work, we summarize our current understanding of β-cell-specific CD8 and CD4 T cell differentiation and function, the role of autoimmune stem-like progenitor CD8 T cells in initiating and sustaining disease, and molecular programs and key transcription factors associated with the diabetogenic T cell response.

Patients with relapsed or refractory pediatric solid tumors have limited therapeutic options with little to no appreciable improvements in outcomes in over two decades. Adoptive cell therapy (ACT) is a promising, targeted option for patients with the potential to minimize acute and long-term toxicities. In this review, we (1) characterize the development and manufacture different ACT approaches used for pediatric solid tumors, and (2) discuss the obstacles when targeting and treating solid tumors. The outcomes of the clinical applications of the various cell therapy products are also reviewed along with the future potential, including novel product development and combination therapies. In sum, this review serves as a comprehensive review of the clinical trial results evaluating the safety, feasibility, and efficacy of novel cell therapy products in the clinic for the treatment of pediatric solid tumors and seeks to provide new insights regarding ACT successes, failures, and challenges to benefit a rapidly expanding immunotherapy field.

Type 1 diabetes is an autoimmune condition in which the pancreatic β cells that produce insulin are destroyed by the body's immune system. For 100 years, diet and insulin injections have been the only effective treatment. Recent advances have led to significant progress in our understanding of the pathogenesis of the disease and the interplay between the environment, components of the immune system, and the β cells that are targeted. This has led to new therapies that rebalance the immune system and finally offer the promise of a cure.

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."

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."

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.