American Journal of Pathology最新文献

Alzheimer disease (AD) is the most common type of dementia and one of the leading causes of death in elderly patients. The number of patients with AD in the United States is projected to double by 2060. Thus, understanding modifiable risk factors for AD is an urgent public health priority. In parallel with the number of patients with AD, the number of cancer survivors is estimated to increase significantly, and up to 80% of cancer patients treated with chemotherapy will develop cognitive deficits, termed chemotherapy-related cognitive impairment. This review discusses biologically plausible pathways underlying both disorders, with the goal of understanding why a proportion of chemotherapy patients may be at higher risk of developing AD. Highlighted are the E4 allele of the apolipoprotein E gene, neuroinflammation, oxidative stress, DNA damage, mitochondrial dysfunction, neuronal and synaptic loss, cellular senescence, brain-derived neurotrophic factor signaling, white matter damage, blood-brain barrier/vascular dysfunction, tau pathology, and transposable element reactivation.

The importance of complex systems has become increasingly evident in recent years. The nervous system is one such example, with neural networks sitting at the intersection of complex networks and biology. A particularly exciting feature is the resilience of complex systems. For example, the ability of the nervous system to perform even in the face of challenges that include neuronal loss, neuroinflammation, protein accumulation, axonal disruptions, and metabolic stress is an intriguing and exciting line of investigation. In neurodegenerative diseases, neural network resilience is responsible for the time between the earliest disease-linked changes and clinical symptom onset and disease diagnosis. In this way, connectivity resilience of neurons within the complex network of cells that make up the nervous system has significant implications. This review provides an overview of relevant concepts related to complex systems with a focus on the connectivity of the nervous system. It discusses the development of the neural network and how a delicate balance determines how this complex system responds to injury, with examples illustrating maladaptive plasticity. The review then addresses the implications of these concepts, methods to understand brain connectivity and neural networks, and recent research efforts aimed at understanding neurodegeneration from this perspective. This study aims to provide foundational knowledge and an overview of current research directions in this evolving and exciting area of neuroscience.

Idiopathic pulmonary fibrosis (IPF) and other progressive fibrotic interstitial lung diseases have limited treatment options. Fibroblasts are key effector cells that sense matrix stiffness through conformation changes in mechanically sensitive receptors, leading to activation of downstream profibrotic pathways. Here, we investigate the role of Piezo2, a mechanosensitive ion channel, in human and mouse lung fibrosis, and its function in myofibroblast differentiation in primary human lung fibroblasts (HLFs). Human samples from patients with IPF and mouse tissue from bleomycin-induced pulmonary fibrosis was assessed. Primary HLFs from nonfibrotic donors were grown on substrates of different stiffness to induce myofibroblast differentiation and treated with a Piezo2 inhibitor. Piezo2 expression is up-regulated in tissue from patients with IPF and in fibrotic mouse lung tissue. Additionally, interrogation of published single-cell RNA-sequencing data showed that Piezo2 is expressed in the profibrotic Cthrc1⁺ fibroblast subpopulation. Myofibroblast differentiation was increased in HLFs grown on substrates with fibrotic levels of stiffness compared with that seen in softer substrates. Piezo2 inhibition reduced stiffness-induced expression α-smooth muscle actin and fibronectin in HLFs. Piezo2 expression is elevated in fibrotic lung disease in both patients and rodents, and its presence is key in the differentiation of fibroblasts to the profibrotic myofibroblasts. Blocking Piezo2 may play a key role in fibrosis and, thus, be a novel therapeutic approach to treat pulmonary fibrosis.

Cellular stress conditions, such as oxidative and endoplasmic reticulum (ER) stresses, contribute to the development of various kidney diseases. Oxidative stress is prompted by reactive oxygen species accumulation and delicately mitigated by glutathione and thioredoxin (Trx) antioxidant systems. Initially identified as a Trx-binding partner, Trx-interacting protein (TXNIP) is significantly up-regulated and activated by oxidative and ER stresses. Function of TXNIP is closely linked to its subcellular localizations. Under normal physiological conditions, TXNIP primarily localizes to the nucleus. When exposed to reactive oxygen species or ER stress, TXNIP relocates to mitochondria and binds to mitochondrial Trx2, which releases Trx-tethered apoptosis signal-regulating kinase 1 and activates apoptosis signal-regulating kinase 1-mediated apoptosis. Oxidative and ER stresses are also closely associated with autophagy. TXNIP can promote or inhibit autophagy depending on different contexts. Although recent studies have highlighted the indispensable role of TXNIP in the etiology and progression of kidney disease, TXNIP-targeted therapy is still missing. This review focuses on the following: i) oxidative and ER stresses; ii) regulation and function of TXNIP during cellular stress; iii) TXNIP in stress-regulated autophagy; iv) TXNIP in kidney diseases (nephrotic syndrome, diabetic nephropathy and chronic kidney disease, acute kidney injury, and kidney aging); and v) novel treatment agents targeting TXNIP in kidney disease. Current advances in chemical compounds and RNA-based therapy suppressing TXNIP are also reviewed.

Duchenne muscular dystrophy (DMD) is a lethal, muscle-wasting, genetic disease that is greatly amplified by an immune response to the diseased muscles. The mdx mouse model of DMD was used to test whether the pathology can be reduced by treatments with a cytotoxic T-lymphocyte-associated protein 4 fused to a modified fragment of IgG1 (CTLA4-Ig) fusion protein that blocks costimulatory signals required for activation of T cells. CTLA4-Ig treatments reduced mdx sarcolemma lesions and reduced the numbers of activated T cells, macrophages, and antigen-presenting cells in mdx muscle and reduced macrophage invasion into muscle fibers. In vitro data showed that CTLA4-Ig acts directly on bone marrow cells and macrophages to modify their function and gene expression. CTLA4-Ig treatments of mdx bone marrow cells diminished their mobility and chemotactic response to chemokine ligand-2. Treating mdx macrophages with CTLA4-Ig reduced their cytolysis of muscle cells in vitro. RNA-sequencing analysis of mdx macrophages showed that CTLA4-Ig reduced expression of genes associated with leukocyte chemotaxis, migration, and extravasation; >90% of those affected genes were tumor necrosis factor-α target genes. Comparison of mdx and wild-type macrophages by RNA sequencing showed that 46% of the genes down-regulated by CTLA4-Ig were genes up-regulated in macrophages by the presence of muscular dystrophy in mice. These findings show that CTLA4-Ig is a promising immunotherapeutic for DMD, and many of its beneficial effects may result from direct actions on macrophages that modify their expression of proinflammatory genes.

Colorectal cancer (CRC) is one of the top three most lethal malignancies worldwide, posing a significant threat to human health. Recently proposed immunotherapy checkpoint blockade treatments have proven effective for CRC, but their use depends on measuring specific biomarkers in patients. Among these biomarkers, tumor mutational burden (TMB) has emerged as a novel indicator, traditionally requiring next-generation sequencing for measurement, which is time-consuming, labor intensive, and costly. To provide an economical and rapid way to predict patients' TMB, we propose the KMeansGraphMIL model based on weakly supervised multiple-instance learning. Compared with previous weakly supervised multiple-instance learning models, KMeansGraphMIL leverages both the similarity of image patch feature vectors and the spatial relationships between patches. This approach improves the model's area under the receiver operating characteristic curve to 0.8334 and significantly increases the recall to 0.7556. Thus, we present an economical and rapid framework for predicting CRC TMB, offering the potential for physicians to quickly develop treatment plans and saving patients substantial time and money.

The tongue facilitates vital activities such as swallowing. Difficulty swallowing (dysphagia) is common in the elderly population and in patients with adult-onset neuromuscular disease. In oculopharyngeal muscular dystrophy (OPMD), dysphagia is often the first symptom. OPMD is an autosomal-dominant myopathy caused by a trinucleotide-expansion mutation in the gene encoding nuclear poly(A)-binding protein (PABPN)-1. Expanded-mutant PABPN1 forms insoluble nuclear aggregates that reduce the levels of the soluble form. Clinical tongue involvement in OPMD has been documented but is poorly understood. Histopathologic analysis of the tongue in an OPMD mouse model was done by light and electron microscopy combined with RNA sequencing. PABPN1 nuclear aggregates were found at moderate levels, whereas deposition of insoluble PABPN1 in blood vessels was prominent already at age 4 months. Muscle wasting of the tongue was age associated. RNA signatures of the OPMD tongue were enriched for mitochondrial and cytoskeletal genes. Electron microscopy revealed abnormalities in sarcomere and mitochondria organization in A17/+ mice, suggesting an energy and contractile deficit in OPMD tongue. This detailed analysis of the histopathology of the tongue in the A17/+ mouse model opens new avenues for understanding the mechanisms of dysphagia.

Grading activity of inflammatory bowel disease (IBD) using standardized histopathological scoring systems remains challenging due to limited availability of pathologists with IBD expertise and interobserver variability. In this study, a deep learning model was developed to classify activity grades in hematoxylin and eosin-stained whole slide images (WSIs) from patients with IBD, offering a robust approach for general pathologists. This study utilized 2077 WSIs from 636 patients who visited Dartmouth-Hitchcock Medical Center in 2018 and 2019, scanned at ×40 magnification (0.25 μm/pixel). Board-certified gastrointestinal pathologists categorized the WSIs into four activity classes: inactive, mildly active, moderately active, and severely active. A transformer-based model was developed and validated using five-fold cross-validation to classify IBD activity. Using HoVer-Net, neutrophil distribution across activity grades was examined. Attention maps from the model highlighted areas contributing to its prediction. The model classified IBD activity with weighted averages of 0.871 (95% CI, 0.860-0.883) for the area under the curve, 0.695 (95% CI, 0.674-0.715) for precision, 0.697 (95% CI, 0.678-0.716) for recall, and 0.695 (95% CI, 0.674-0.714) for F1 score. Neutrophil distribution was significantly different across activity classes. Qualitative evaluation of attention maps by a gastrointestinal pathologist suggested their potential for improved interpretability. The model demonstrates robust diagnostic performance and could enhance consistency and efficiency in IBD activity assessment.

Tumor-infiltrating macrophages, known as tumor-associated macrophages, play a crucial role in the tumor microenvironment. Immunohistochemistry revealed that intratumoral CD68-positive macrophages are associated with poor prognosis and clinicopathologic factors in patients with hepatocellular carcinoma (HCC). Subsequently, an indirect co-culture system involving HCC cells and peripheral blood-derived macrophages was developed. cDNA microarray analysis revealed that chemokine (C-C motif) ligand 2 (CCL2) was highly expressed in HCC cells co-cultured with macrophages. CCL2 neutralization suppressed proliferation, migration, and phosphorylation of extracellular signal-regulated kinase (Erk) in HCC cells and macrophages enhanced through co-culture. In contrast, recombinant human CCL2 (rhCCL2) addition facilitated these malignant phenotypes and increased Erk phosphorylation levels in HCC cells and macrophages. The primary CCL2 receptor, CCR2, was expressed in HCC cells and macrophages and was up-regulated in co-cultured HCC cells. CCR2 inhibition suppressed malignant phenotypes and reduced phosphorylated levels of Erk enhanced by rhCCL2. Additionally, the inhibition of Erk signal suppressed rhCCL2-enhanced malignant phenotypes. Moreover, serum CCL2 levels were higher in patients with HCC than those in healthy donors. On the basis of immunohistochemistry, CCL2-positive cases with high CCR2 expression and phosphorylated Erk-positive cases exhibited poor survival outcomes. Therefore, CCL2 up-regulation through interactions between HCC cells and macrophages contributed to HCC progression, making the CCL2/CCR2/Erk signal a potential target for HCC treatment.