Annual Review of Pathology-Mechanisms of Disease最新文献

Research efforts over the past decade have defined the genetic landscape of somatic variation in the brain. Neurons accumulate somatic mutations from development through aging with potentially profound functional consequences. Recent studies have revealed the contribution of somatic mosaicism to various brain disorders including focal epilepsy, neuropsychiatric disease, and neurodegeneration. One notable finding is that the effect of somatic mosaicism on clinical outcomes can vary depending on contextual factors, such as the developmental origin of a variant or the number and type of cells affected. In this review, we highlight current knowledge regarding the role of somatic mosaicism in brain disorders and how biological context can mediate phenotypes. First, we identify the origins of brain somatic variation throughout the lifespan of an individual. Second, we explore recent discoveries that suggest somatic mosaicism contributes to various brain disorders. Finally, we discuss neuropathological associations of brain mosaicism in different biological contexts and potential clinical utility.

I am honored to be asked by the journal to write this personal essay about my career in pediatric neuropathology-a life of immense satisfaction, meaning, and fulfillment. My motivation to enter this discipline is highlighted, as is my decision to perform brain research in the sudden infant death syndrome, the leading cause of postneonatal infant mortality in the United States today. I also touch upon collaborations, mentoring, and experiences along the way-especially with the light microscope. I close with thoughts about the future of the discipline from my perspective as a lifelong devotee.

Over the last two decades, there have been extensive efforts to develop small-molecule inhibitors of protein-protein interactions (PPIs) as novel therapeutics for cancer, including hematologic malignancies. Despite the numerous challenges associated with developing PPI inhibitors, a significant number of them have advanced to clinical studies in hematologic patients in recent years. The US Food and Drug Administration approval of the very first PPI inhibitor, venetoclax, demonstrated the real clinical value of blocking protein-protein interfaces. In this review, we discuss the most successful examples of PPI inhibitors that have reached clinical studies in patients with hematologic malignancies. We also describe the challenges of blocking PPIs with small molecules, clinical resistance to such compounds, and the lessons learned from the development of successful PPI inhibitors. Overall, this review highlights the remarkable success and substantial promise of blocking PPIs in hematologic malignancies.

The immune system plays fundamental roles in maintaining physiological homeostasis. With the increasing prevalence of obesity-a state characterized by chronic inflammation and systemic dyshomeostasis-there is growing scientific and clinical interest in understanding how obesity reshapes immune function. In this review, we propose that obesity is not merely an altered metabolic state but also a fundamentally altered immunological state. We summarize key seminal and recent findings that elucidate how obesity influences immune function, spanning its classical role in microbial defense, its contribution to maladaptive inflammatory diseases such as asthma, and its impact on antitumor immunity. We also explore how obesity modulates immune function within tissue parenchyma, with a particular focus on the role of T cells in adipose tissue. Finally, we consider areas for future research, including investigation of the durable aspects of obesity on immunological function even after weight loss, such as those observed with glucagon-like peptide-1 (GLP-1) receptor agonist treatment. Altogether, this review emphasizes the critical role of systemic metabolism in shaping immune cell functions, with profound implications for tissue homeostasis across various physiological contexts.

Myeloid neoplasms with and without preexisting platelet disorders frequently develop in association with an underlying germline predisposition. Germline alterations affecting ANKRD26, CEBPA, DDX41, ETV6, and RUNX1 are associated with nonsyndromic predisposition to the development of myeloid neoplasms including acute myeloid leukemia and myelodysplastic syndrome. However, germline predisposition to myeloid neoplasms is also associated with a wide range of other syndromes, including SAMD9/9L associated predisposition, GATA2 deficiency, RASopathies, ribosomopathies, telomere biology disorders, Fanconi anemia, severe congenital neutropenia, Down syndrome, and others. In the fifth edition of the World Health Organization (WHO) series on the classification of tumors of hematopoietic and lymphoid tissues, myeloid neoplasms associated with germline predisposition have been recognized as a separate entity. Here, we review several disorders from this WHO entity as well as other related conditions with an emphasis on the molecular pathogenesis of disease and accompanying somatic alterations. Finally, we provide an overview of establishing the molecular diagnosis of these germline genetic conditions and general recommendations for screening and management of the associated hematologic conditions.

This review examines the roles of the choroid plexus (ChP) in central nervous system (CNS) pathology, emphasizing its involvement in disease mechanisms and therapeutic potential. Structural changes in the human ChP have been reported across various diseases in case reports and descriptive work, but studies have yet to pin down the physiological relevance of these changes. We highlight primary pathologies of the ChP, as well as their significance in neurologic disorders, including stroke, hydrocephalus, infectious diseases, and neurodegeneration. Synthesizing recent research, this review positions the ChP as a critical player in CNS homeostasis and pathology, advocating for enhanced focus on its mechanisms to unlock new diagnostic and treatment strategies and ultimately improve patient outcomes in CNS diseases. Whether acting as a principal driver of disease, a gateway for pathogens into the CNS, or an orchestrator of neuroimmune processes, the ChP holds tremendous promise as a therapeutic target to attenuate a multitude of CNS conditions.

The mycobiome plays a key role in the host immune responses in homeostasis and inflammation. Recent studies suggest that an imbalance in the gut's fungi contributes to chronic, noninfectious diseases such as obesity, metabolic disorders, and cancers. Pathogenic fungi can colonize specific organs, and the gut mycobiome has been linked to the development and progression of various cancers, including colorectal, breast, head and neck, and pancreatic cancers. Some fungal species can promote tumorigenesis by triggering the complement system. However, in immunocompromised patients, fungi can also inhibit this activation and establish life-threatening infections. Interestingly, the interaction of the fungi and bacteria can also induce unique host immune responses. Recent breakthroughs and advancements in high-throughput sequencing of the gut and tumor mycobiomes are highlighting novel diagnostic and therapeutic opportunities for cancer. We discuss the latest developments in the field of cancer and the mycobiome and the potential benefits and challenges of antifungal therapies.

The most common form of heart failure is heart failure with preserved ejection fraction (HFpEF). While heterogeneous in origin, the most common form of HFpEF is the cardiometabolic manifestation. Obesity and aging promote systemic inflammation that appears integral to cardiometabolic HFpEF pathophysiology. Accumulation of immune cells within the heart, fueled by an altered metabolome, contribute to cardiac inflammation and fibrosis. In spite of this, broad anti-inflammatory therapy has not shown significant benefit in patient outcomes. Thus, understanding of the nuances to metabolic and age-related inflammation during HFpEF is paramount for more targeted interventions. Here, we review clinical evidence of inflammation in the context of HFpEF and summarize our mechanistic understanding of immunometabolic inflammation, highlighting pathways of therapeutic potential along the way.

Focal segmental glomerulosclerosis (FSGS) is the morphologic manifestation of a spectrum of kidney diseases that primarily impact podocytes, cells that create the filtration barrier of the glomerulus. As its name implies, only parts of the kidney and glomeruli are affected, and only a portion of the affected glomerulus may be sclerosed. Although the diagnosis is based primarily on microscopic features, patient stratification relies on clinical data such as proteinuria and etiological criteria. FSGS affects both children and adults and has an elevated risk of progression to end-stage renal disease. The prevalence of FSGS is rising among various populations, and the efficacy of various therapies is limited. Therefore, understanding the pathophysiology of FSGS and developing targeted therapies to address the complex needs of FSGS patients are topics of great interest that are currently being studied across various clinical trials. We discuss the etiology of FSGS, describe the major contributing pathophysiological pathways, and outline emerging therapeutic strategies along with their pitfalls.

Since its inception, the study of apoptosis has been intricately linked to the field of cancer. The term apoptosis was coined more than five decades ago following its identification in both healthy tissues and malignant neoplasms. The subsequent elucidation of its molecular mechanisms has significantly enhanced our understanding of how cancer cells hijack physiological processes to evade cell death. Moreover, it has shed light on the pathways through which most anticancer therapeutics induce tumor cell death, including targeted therapy and immunotherapy. These mechanistic studies have paved the way for the development of therapeutics directly targeting either pro- or antiapoptotic proteins. Notably, the US Food and Drug Administration (FDA) approved the BCL-2 inhibitor venetoclax in 2016, with additional agents currently undergoing clinical trials. Recent research has brought to the forefront both the anti- and proinflammatory effects of individual apoptotic pathways. This underscores the ongoing imperative to deepen our comprehension of apoptosis, particularly as we navigate the evolving landscape of immunotherapy.