Cold Spring Harbor perspectives in medicine最新文献

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.

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.

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.

In this review, we explore the complex interplay between the immune system and pancreatic β cells in the context of type 1 diabetes (T1D). While T1D is predominantly considered a T-cell-mediated autoimmune disease, the inability of human leukocyte antigen (HLA)-risk alleles alone to explain disease development suggests a role for β cells in initiating and/or propagating disease. This review delves into the vulnerability of β cells, emphasizing their susceptibility to endoplasmic reticulum (ER) stress and protein modifications, which may give rise to neoantigens. Additionally, we discuss the role of viral infections as contributors to T1D onset, and of genetic factors with dual impacts on the immune system and β cells. A greater understanding of the interplay between environmental triggers, autoimmunity, and the β cell will not only lead to insight as to why the islet β cells are specifically targeted by the immune system in T1D but may also reveal potential novel therapeutic interventions.

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.

The incidence of non-tuberculous mycobacteria (NTM) is increasing globally, often surpassing the incidence of new tuberculosis (TB) cases in developed countries. Most NTM are environmental organisms; however, there are a number of opportunistic and pathogenic species that can cause severe infections in animals and humans. Many NTM are intrinsically resistant to anti-TB therapies and are incredibly difficult to treat, resulting in poor treatment outcomes for these patients. Recent advances in preclinical animal models such as the zebrafish models have led to the discovery of highly active antimicrobial and host-directed therapies (HDTs) targeting NTM infections that can be applied to treat human infections. Here, we summarize recent progress and technological advancements in the discovery and development of antimicrobial drugs and HDTs that have been applied to NTM zebrafish infection models. We highlight the future directions for this increasingly applicable animal model for the discovery of next-generation therapies to treat NTM diseases.

Children and young adults are affected by a number of different cancers. These are developmental in origin and arise, in particular, in susceptible cell types. Recent advances have led to significant progress in our understanding of the underlying causes and the pathogenetic mechanisms involved. This is informing design of therapeutic approaches that offer new hope for patients.

The tumor microenvironment (TME) is comprised of both cellular and stromal elements and plays an essential role in the growth, survival, and dissemination of malignancies. The TME is an organized program that develops with a growing tumor, using many processes involved in normal tissue development. In multiple solid tumors, developmental pathways are used to recruit immunosuppressive cells, including immunosuppressive monocytes and neutrophils, tumor-associated macrophages, and regulatory T cells to block the antitumor immune response. In addition, stromal cells sustain tumor growth via trophic support, angiogenesis, repair mechanisms, and associated immunosuppression, driven, at least in part, by canonical developmental signaling pathways. The microenvironmental ecosystem shapes tumor progression from its earliest inception by modulating important programs that dictate tumor behavior, necessitating further consideration when studying the developmental origins of malignancy. Here, we review the role of developmental pathways in the formation and modulation of the TME in pediatric and adult solid tumors, including Wnt, Notch, Hippo, Hedgehog, TGF-β, BMP, SOX, and OCT.