Cold Spring Harbor perspectives in medicine最新文献

Over the last 75 years, pediatric cancer has gone from nearly universally fatal, to having a >80% chance of long-term survival. Below we share highlights in this 75-year history, beginning with the "birth" of chemotherapy in treating childhood leukemia, through the development of multiagent chemotherapy, risk-stratified therapy, the use of molecular strategies in diagnosis and treatment, and adapting treatment to the needs of particularly vulnerable patient groups such as adolescents and young adults (AYAs). While pediatric leukemia treatment demonstrates the ever-improving cures achieved through iterative incorporation of novel discoveries, this experience is contrasted with that of osteosarcoma, where scientific advances made over recent decades have yet to be translated into meaningful improvements in long-term survival. We conclude with a brief overview of current areas of focus, including precision medicine, immunotherapy, and other treatment advancements, yet describe the need to couple these scientific breakthroughs with consideration of equitable access and evaluation of the long-term impacts of these "newer" therapies in survivorship. Substantial further work is needed to achieve our goal of curing all children with cancer as harmlessly as possible.

It is increasingly appreciated that cancer cells adapt their metabolic pathways to support rapid growth and proliferation as well as survival, often even under the poor nutrient conditions that characterize some tumors. Cancer cells can also rewire their metabolism to circumvent chemotherapeutics that inhibit core metabolic pathways, such as nucleotide synthesis. A critical approach to the study of cancer metabolism is metabolite profiling (metabolomics), the set of technologies, usually based on mass spectrometry, that allow for the detection and quantification of metabolites in cancer cells and their environments. Metabolomics is a burgeoning field, driven by technological innovations in mass spectrometers, as well as novel approaches to isolate cells, subcellular compartments, and rare fluids, such as the interstitial fluid of tumors. Here, we discuss three emerging metabolomic technologies: spatial metabolomics, single-cell metabolomics, and organellar metabolomics. The use of these technologies along with more established profiling methods, like single-cell transcriptomics and proteomics, is likely to underlie new discoveries and questions in cancer research.

The past 10 years have seen tremendous progress in our understanding of leucine-rich repeat kinase 2 (LRRK2) and how mutations activate the kinase and trigger downstream pathology, contributing to Parkinson's disease. A breakthrough came from the identification of key LRRK2 substrates-a subset of small guanosine triphosphatases (GTPases) called Rab proteins. Cryoelectron microscopy has revealed structures of LRRK2 and showed how inhibitors engage and inhibit the kinase. Biochemical experiments have revealed how LRRK2 is recruited to membranes to phosphorylate Rab substrates. LRRK2 activation during lysosomal stress triggers Rab phosphorylation, altering the repertoire of Rab-binding partners. Resulting phospho-Rab-effector complexes have prominent effects in specific cell types, disrupting primary cilia and impairing Hedgehog signaling-effects that can be reversed by LRRK2 inhibitors. This disruption in Hedgehog signaling represents a convergence point linking genetic and idiopathic forms of Parkinson's. Together, these findings support the therapeutic potential of LRRK2 inhibitors in Parkinson's disease.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of both dopaminergic and non-dopaminergic neurons associated with the accumulation of α-synuclein aggregates and signs of neuroinflammation. This inflammatory aspect of PD neuropathology has led to the hypothesis that the immune system, both adaptive and innate, contributes to the neurodegenerative process. While the adaptive immune system is discussed in detail in another article in this collection, this review focuses on the innate immune system, which includes monocytes, macrophages, microglia, and dendritic cells. We will also discuss the increasingly recognized link between genetic and immune response and the cross talk between peripheral and central immune cells, and its contribution to the overall immune response in PD. Finally, we will propose therapeutic strategies aimed at modulating immunity for neuroprotective and disease-modifying benefits in PD and related disorders.

Adaptive immunity plays a key role in the pathogenesis of Parkinson's disease (PD) and related conditions. This paper reviews the involvement of CD4⁺ and CD8⁺ T cells in PD development as well as the effect of PD genetic susceptibility variants and aging. Specifically, the major histocompatibility complex is associated with PD, influencing antigen presentation and, consequently, the T-cell receptor repertoire, believed to contribute to disease susceptibility and progression. Moreover, aging-a major risk factor for PD-also shapes T-cell dynamics, with immunosenescence impacting the adaptive immune system, and potentially exacerbating neuroinflammatory responses in PD. These T-cell-mediated immune responses hold substantial influence over brain physiopathology, dictating the degenerative processes seen in PD. Understanding these interactions offers insights into early immunotherapy intervention during the prodromal phase using engineered regulatory T cells for antigen-specific immunomodulation against pathogenic proteins such as α-synuclein.

Mounting evidence highlights a role for lipid alterations and defects in lipid signaling in age-related neurodegenerative diseases such as Parkinson's disease (PD) and related conditions (collectively referred to as synucleinopathies). This growing interest is driven by several key findings: (1) lipid membranes are components of Lewy bodies and Lewy neurites, which are prototypical proteinaceous intraneuronal inclusions of PD and other synucleinopathies, primarily composed of α-synuclein (αS); (2) αS shares structural similarities with lipid-binding proteins and has been reported to bind to lipids; (3) glucocerebrosidase, a key enzyme in sphingolipid metabolism, is a major PD risk factor; (4) other enzymes involved in glycolipid and phospholipid regulation, such as diacylglycerol kinase-θ and fatty acid elongase-7, also contribute to PD risk; (5) αS alterations impact lipid homeostasis; (6) αS transiently binds lipid membranes, affecting its conformation. Given these findings, we review what is known about the role of lipids in normal αS biology as well as in the pathogenesis of PD and related conditions. We also highlight areas where further research is warranted.

Parkinson's disease (PD) is a progressive, neurological syndrome that is associated with a plethora of motor and nonmotor symptoms. Recognizing prodromal symptoms and diagnosing PD early and accurately as well as employing timely management strategies targeting motor and nonmotor symptoms across all disease stages will have the potential to improve clinical outcomes. The application of critical advances in the field including the development of biomarkers, pharmacological treatments, exercise, and surgical therapies will be important for clinical practitioners. In this review, we will address differential diagnoses and disease mimics, as well as provide critical updates on clinical diagnosis and management strategies.

Children are surviving cancer in greater numbers than ever. Over the last 50 years, substantial advancements in pediatric cancer treatment have resulted in an 85% 5-year survival rate. Nonetheless, a notable 10%-15% of patients encounter relapse or develop refractory disease, leading to significantly lower survival. Recent attempts to further intensify cytotoxic chemotherapy have failed due to either severe toxicities or ineffectiveness, highlighting the need for new treatment strategies. Immunotherapies are emerging and expanding their clinical application to a wide array of cancers, including those affecting children. In pediatric cancers, monoclonal antibodies targeting GD2 have demonstrated durable radiographic and histologic responses in neuroblastoma (NB), and CD19-targeted bispecific antibodies (BsAbs) and chimeric antigen receptor (CAR) T cells have likewise changed the outlook for refractory acute lymphoblastic leukemia (ALL) in children. This review discusses the clinical development of immunotherapies for pediatric cancers, focusing on pediatric ALL and NB, two major pediatric cancers transformed by immunotherapy, updates on the recent advancements in immunotherapies, and further discusses the future directions of immunotherapy for pediatric cancers.

Type 1 diabetes (T1D) is driven by an immunologically complex, diverse, and self-sustaining immune response directed against tissue autoantigens, leading to loss or dysfunction of β cells. To date, the single approved immune intervention in T1D is based on a strategy that is similar to that used in other related autoimmune diseases, namely, the attenuation of immune cell activation. As a next-generation approach that is more focused on underlying mechanisms of loss of tolerance, antigen-specific immunotherapy is designed to establish or restore bystander immunoregulation in a highly tissue- and target-specific fashion. Here, we describe the basis for this alternative approach, which could also have potential for complementarity if used in combination with more conventional immune modulators, and highlight recent advances, knowledge gaps, and next steps in clinical development.