Cold Spring Harbor perspectives in medicine最新文献

Host-directed therapies (HDTs) to increase host control of Mycobacterium tuberculosis and limit the pathology caused by tuberculosis (TB) have advanced from the laboratory to the clinic. Several of these HDTs are repurposed drugs, which provide significant advantages over lengthy and costly traditional drug discovery approaches. This review covers the preclinical, retrospective clinical, and randomized controlled trial (RCT) evidence supporting the rapid repurposing of drugs for use as TB HDTs. We explore classes of potential HDTs by preclinical mechanism of action to identify cases where the concept of the therapy is sound, but the current availability of therapeutic agent is lacking. Apart from the drugs that have progressed through to RCTs, we highlight drugs with strong preclinical and retrospective portfolios that may form the next wave of trial candidates. Overall, HDTs are poised to contribute to a reduction in the global burden of TB and posttreatment lung disease.

Epigenetic therapies are emerging for pediatric cancers. Due to the relatively low mutational burden in pediatric tumors, epigenetic dysregulation and differentiation blockade is a hallmark of oncogenesis in some childhood cancers. By targeting epigenetic regulators that maintain tumor cells in a primitive developmental state, epigenetic therapies may induce differentiation. The most well-studied and clinically advanced epigenetic-targeted therapies include azacitidine and decitabine, which inhibit DNA methylation through competitive inhibition of the enzymatic activity of the DNA methyltransferase family enzymes. These DNA hypomethylating agents are Food and Drug Administration (FDA) approved for hematologic malignancies. The discovery that DNA hypermethylation occurs in patients with isocitrate dehydrogenase (IDH) mutations has led to the development and FDA approval of IDH inhibitors for hematologic and solid tumors. Epigenetic dysregulation in pediatric tumors is also driven by changes in the "histone code" that either promote oncogene expression or repress tumor suppressors. Cancers whose chromatin landscape is characterized by such aberrant histone posttranslational modifications may be amenable to targeted therapies that inhibit the chromatin-modifying enzymes that read, write, and erase these histone modifications. Small molecules that inhibit the enzymatic activity of histone deacetylases, acetyltransferases, and methyltransferases have been approved for the treatment of some adult cancers, and these agents are currently under investigation in various pediatric tumors. Chromatin regulatory complexes can be hijacked by oncogenic fusion proteins that are produced by chromosomal translocations, which are common drivers in pediatric cancer. Small molecules that disrupt oncogenic fusion protein activity and their associated chromatin complexes have demonstrated remarkable promise, and this approach has become the standard treatment for a subset of leukemias driven by the PML-RARA oncogenic fusion protein. A deeper understanding of the mechanisms that drive epigenetic dysregulation in pediatric cancer may hold the key to future success in this field, as the landscape of druggable epigenetic targets is also expanding.

Autophagy is a vital cellular process responsible for the degradation of proteins, organelles, and other cellular components within lysosomes. In neurons, basal autophagy is indispensable for maintaining cellular homeostasis and protein quality control. Accordingly, lysosomal dysfunction has been proposed to be associated with neurodegeneration, and with Parkinson's disease (PD) in particular. Aging, dopamine metabolism, and PD-linked genetic mutations are thought to impair the autophagic-lysosomal pathway, disrupt cellular proteostasis, and contribute to PD pathogenesis. These alterations represent an opportunity to identify potential new therapeutic targets and disease biomarkers, thus laying the groundwork for the development of novel disease-modifying strategies for PD that are aimed at restoring cellular proteostasis and quality control systems.

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].

There is an urgent need to develop additional treatments for tuberculosis (TB) to complement the small panel of approved drugs and to devise shorter treatment regimens. Within the last 20 years, we have seen an increased focus on using cheminformatics-based approaches to understand the properties of Mycobacterium tuberculosis (Mtb) active molecules and machine learning algorithms to subsequently learn from public data sets. We now demonstrate how we have continually used many machine learning approaches that have enabled us to select or synthesize new compounds for testing in vitro to validate our models and to identify new chemical matter. We now put our results into context with studies from other groups to make the case for using machine learning models more widely to aid in finding new Mtb inhibitors. TB research has been slow to adapt to these approaches to increase drug discovery efficiency, but it is better late than never.

Biological risks are increasingly shaped by globally distributed scientific capability, accelerating technological change and a rapidly evolving information environment. This review examines how these dynamics challenge traditional biosafety and biosecurity governance. It analyzes the internationalization of high-risk life science capacity, the expanding scope of pathogen research, and the implications of digitalization, artificial intelligence (AI)-enabled design tools and cloud laboratories. It then traces the historical foundations of biosafety and biosecurity, highlights the fragmentation across health, environmental and security instruments, and assesses how divergent national systems shape global vulnerability. The article further explores cross-border scientific collaboration, movement of materials and data, and the complexities of ambiguous outbreaks, investigation mechanisms and information integrity. It concludes by identifying strategic gaps and outlining priorities for a more adaptive, interoperable and equitable governance architecture capable of operating in a world where biological capability is widely dispersed and biological risks increasingly dematerialized.

Mycobacterium tuberculosis (Mtb) induces necrotic cell death of infected macrophages, which contributes to tissue necrosis and the progressive loss of lung function during tuberculosis. Mtb can induce multiple forms of programmed necrosis, including necroptosis, pyroptosis and ferroptosis. Concurrently, Mtb also inhibits apoptosis to prevent a host-beneficial cell death response. This paper will first provide an overview of the programmed cell death pathways relevant to Mtb infection. It will then discuss how Mtb activates and manipulates these pathways under different conditions, including a comparison of the findings across mouse, human, and zebrafish-derived macrophages.

α-Synuclein (α-syn) biomarkers show great promise as diagnostic tools for Parkinson's disease (PD). In recent years, a large body of evidence has validated their efficacy as diagnostic tools for PD and other synucleinopathies and has shown potential for use in patients with isolated prodromal symptoms of PD, such as rapid eye movement (REM) sleep behavior disorder and hyposmia, and further illuminates the pathophysiology of both idiopathic and genetic causes. Various detection methods have been deployed, predominantly immunohistochemistry and α-syn seed amplification assays. α-Syn has been shown to be detectable in many different tissues and biofluids in PD patients, each with benefits and limitations for practical use. α-Syn biomarker studies have shown sensitivities for diagnosis of PD and specificity against healthy controls up to 100%. However, lack of standardization of methods of detection currently limits interlaboratory validation of results. Verification of these assays could lead to more widespread inclusion of these modalities to detect α-syn into biological definitions of PD and provide frameworks for developing disease-modifying therapies. In this review, we discuss the current state of α-syn biomarkers and highlight their potential use in clinical practice and research settings, while identifying further work that is needed in this field.

Growing evidence indicates that childhood cancer is a developmental disease and the oncogenic impact of mutations depends on spatiotemporal developmental contexts. This dependency leads to distinct molecular, genetic, and clinical characteristics across various cancer (sub)types. However, the underlying molecular mechanisms of tumorigenesis are not fully understood, and the development of precision medicine for childhood cancers is still an ongoing effort, partially due to their relative rarity. Therefore, it is crucial to develop and use "developmental models" that replicate both mutations and specific developmental contexts that determine their impact. In this review, we summarize recent advances in the growing field of developmental modeling of childhood cancers, which enhance our understanding of the pathogenic mechanisms and pave the way for the development of new therapeutic approaches.

Effector T cells are central to immune defense against Mycobacterium tuberculosis (Mtb), exerting complex and multifaceted roles that contribute to both protection and immunopathology. CD4⁺ T cells activate macrophages, maintain granulomas, and coordinate broad immune functions through diverse subsets, including cytokine-producing, cytotoxic, and regulatory cells. CD8⁺ T cells target infected cells through cytolytic activity and cytokine secretion, while unconventional T cells provide rapid, innate-like responses, particularly at mucosal sites. Recent advances in single-cell and spatial transcriptomics have revealed heterogeneity, functional plasticity, and spatial compartmentalization among T-cell subsets. Tissue-resident memory T cells in the lung parenchyma have emerged as key predictors of protective immunity. These insights are reshaping our understanding of T-cell-mediated control of Mtb and highlight the limitations of interferon (IFN)-γ-centric vaccine strategies. Future strategies must aim to elicit a broader range of T-cell responses, promote effective tissue localization, enhance polyfunctionality, and overcome regulatory or exhaustion-associated dysfunctions.