Cold Spring Harbor perspectives in medicine最新文献

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.

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.

Molecular imaging-the mapping of molecular and cellular processes in vivo-has the unique capability to interrogate cancer metabolism in its spatial contexts. This work describes the usage of the two most developed modalities for imaging metabolism in vivo: positron emission tomography (PET) and magnetic resonance (MR). These techniques can be used to probe glycolysis, glutamine metabolism, anabolic metabolism, redox state, hypoxia, and extracellular acidification. This review aims to provide an overview of the strengths and limitations of currently available molecular imaging strategies.

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). N Engl J Med 381: 2416-2428. doi:10.1056/NEJMoa1911361].

Stable isotope-resolved metabolomics delineates reprogrammed intersecting metabolic networks in human cancers. Knowledge gained from in vivo patient studies provides the "benchmark" for cancer models to recapitulate. It is particularly difficult to model patients' tumor microenvironment (TME) with its complex cell-cell/cell-matrix interactions, which shapes metabolic reprogramming crucial to cancer development/drug resistance. Patient-derived organotypic tissue cultures (PD-OTCs) represent a unique model that retains an individual patient's TME. PD-OTCs of non-small-cell lung cancer better recapitulated the in vivo metabolic reprogramming of patient tumors than the patient-derived tumor xenograft (PDTX), while enabling interrogation of immunometabolic response to modulators and TME-dependent resistance development. Patient-derived organoids (PDOs) are also good models for reconstituting TME-dependent metabolic reprogramming and for evaluating therapeutic responses. Single-cell based 'omics on combinations of PD-OTC and PDO models will afford an unprecedented understanding on TME dependence of human cancer metabolic reprogramming, which should translate into the identification of novel metabolic targets for regulating TME interactions and drug resistance.

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.

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.

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.