American Journal of Pathology最新文献

Deep learning (DL) models have shown promise in predicting molecular alterations directly from hematoxylin and eosin-stained whole slide images in a variety of solid tumors, offering a rapid alternative to conventional molecular testing. However, these models often offer limited insight into their decision-making process, undermining transparency and eroding clinical trust. Interpreting model predictions is essential for a meaningful application of DL in clinical pathology. This is showcased by interpreting the outputs of a weakly supervised DL model, XpressO-melanoma, that predicts BRAF V600E mutation status from whole slide images of skin cutaneous melanoma. The morphologic plausibility of the model's segmentations of the tumor regions of interest and their prediction of BRAF V600E status were evaluated and compared against the pathologists' annotations for the same. The work resulted into four interpretation categories that associate model's performance (ie, area under the curve of 0.8 and precision and recall of 0.7) with the regions of interest that revealed meaningful diagnostic patterns as well as those that required annotation refinements. The work coheres with the White House's National AI [Artificial Intelligence] Action Plan that identifies interpretability as a national research priority and paves the way for a human-DL collaboration in clinical pathology for a better translation of DL techniques in clinical pathology in the near future.

Psoriasis is a chronic, immune-mediated inflammatory disorder characterized by keratinocyte hyperproliferation and systemic immune dysregulation. The neuroimmune axis, linking sensory nerve activity, neuropeptide signaling, and immune responses, is central to disease pathogenesis. Structural remodeling of sensory nerves enhances the release of neuropeptides such as Substance P, calcitonin gene-related peptide, vasoactive intestinal peptide, and neuropeptide Y, which activate dendritic cells, promote T-cell proliferation, and stimulate keratinocyte cytokine production, sustaining a neurogenic inflammatory loop. Psychological stress exacerbates inflammation through hypothalamic-pituitary-adrenal (HPA) axis dysregulation, altering cortisol signaling and systemic immune responses. Intracellular pathways, including mitogen-activated protein kinase, PI3KAktmTOR, JAKSTAT, and NF-κB, along with epigenetic modifications, integrate neural and immune signals, contributing to disease chronicity and heterogeneity. Targeting neuroimmune interactions through neuropeptide antagonists, neuromodulation, stress management, and precision immunotherapies reduces cutaneous inflammation and addresses systemic comorbidities. This review synthesizes molecular, cellular, and clinical insights into the neuroimmune-HPA axis network in psoriasis, highlighting its therapeutic potential for personalized and multidisciplinary management.

Duchenne muscular dystrophy (DMD) is a severe X-linked disorder with progressive myofiber degeneration and fibrosis from dystrophin deficiency. Current therapies are largely supportive with limited anti-fibrotic benefit, prompting new strategies. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) show emerging anti-fibrotic and anti-inflammatory effects. Open-access proteomic and transcriptomic data sets were integrated for in silico analyses, including differential gene expression, weighted gene co-expression network analysis, and pathway enrichment, to identify dysregulated pathways potentially reversible by SGLT2i. Immune cell composition was estimated using CIBERSORTx in human and murine data sets. Therapeutic effects were tested with empagliflozin (EMPA) in mdx mice (30 mg/kg per day for 4 weeks, starting at 12 weeks) and DMD^mdx rats (10 mg/kg per day for 4 months, starting at 5 months), with vehicle controls. Validation used quantitative RT-PCR, grip-strength testing, and histologic fibrosis staining. Analyses highlighted dysregulated extracellular matrix organization, cytokine signaling, and immune responses. Forty overlapping genes were identified; hub genes included COL3A1, COL5A2, and TGFB1. EMPA reduced Tgfb1 expression in DMD rats and significantly decreased collagen deposition in skeletal muscle. Functional testing showed longer grip duration in EMPA-treated mice. Immune profiling revealed shifts in T cells and macrophages, indicating immunomodulation. Findings were consistent across species and data modalities analyzed. These results demonstrate that EMPA modulates fibrosis, inflammation, and muscle endurance in DMD models. These data support repurposing SGLT2i as a promising therapeutic strategy for DMD.

Hyaluronan (HA)-binding protein involved in HA depolymerization (HYBID), essential for HA degradation, has been reported to promote endochondral ossification in developing bone but to inhibit intramembranous ossification. However, little is known about the role of HYBID in long bone fracture healing, which requires both types of ossification. The role of genetic Hybid depletion in healing was examined in a murine model of femoral diaphyseal fracture. On micro-computed tomography, bridging of fracture gaps was delayed in Hybid-deficient (Hybid^-/-) mice compared to wild-type mice. On histologic analysis, the resorption of cartilaginous callus was retarded due to decreased osteoclasts/chondroclasts and blood vessels at the chondro-osseous junction of cartilaginous and bony callus in Hybid deficiency, with delayed fusion of fracture gaps. At 2 weeks after fracture, Hybid was highly expressed by osteoblasts and hypertrophic chondrocytes in callus of wild-type mice, and Il-6 was overexpressed at 1 week, followed by transforming growth factor β₁ and bone morphogenic protein 2 expression at 2 and 3 weeks. High-molecular-weight HA accumulated in the callus tissue of the Hybid^-/- mice. In both groups, fracture healing was promoted with injections of low-molecular-weight HA around the calluses of the fractured femora. These data suggest that fracture healing is delayed in HYBID deficiency due to impaired endochondral ossification, and that HYBID-mediated HA depolymerization is involved in bone fracture healing.

Angiopoietin-like 4 (Angptl4) is a secreted glycoprotein involved in the regulation of various homeostatic and disease processes. In the intestine, prior studies have suggested protective roles for Angptl4 in inflammation using Angptl4 knockout mouse models; however, phenotypic variability-such as perinatal lethality and intestinal inflammation accompanied by lymphatic defects in only a subset of animals-has complicated the interpretation of its role in intestinal pathogenesis. In this study, the impact of Angptl4 deficiency was examined using a subset of Angptl4 knockout mice that survive postnatally without overt abnormalities. It was found that loss of Angptl4 confers protection against colitis and colitis-associated colorectal tumorigenesis. These protective effects were associated with the alternative activation of anti-inflammatory M2-like macrophages. Similarly, in a genetic model of intestinal tumorigenesis, Angptl4 deficiency resulted in reduced tumor burden and attenuated inflammation, accompanied by increased M2-like macrophages. Analysis of human colorectal cancer data sets further revealed that low ANGPTL4 expression is associated with improved survival outcomes as well as reduced expression of inflammation-related marker genes. Collectively, the findings uncover a previously unrecognized protective effect of Angptl4 deficiency against intestinal pathogenesis via anti-inflammatory mechanisms, suggesting Angptl4 as a potential therapeutic target and prognostic biomarker for colorectal cancer and inflammatory bowel disease.

Pediatric cholestatic liver diseases are rare but serious conditions that frequently progress to liver fibrosis and cirrhosis and often require transplantation. Despite the clinical importance of these diseases, the mechanisms driving disease progression remain poorly understood. Hepatic iron accumulation was identified as a pathologic feature associated with congenital cholestatic liver disease in mice with a liver-specific deletion of Yap, a gene critical for bile duct development. Further hepatic iron overload induced by liver-specific deletion of Fbxl5, a key regulator of cellular iron homeostasis, exacerbated cholestatic liver injury and fibrosis in Yap-deficient mice. Mechanistically, iron overload enhanced the susceptibility to bile acid-induced cytotoxicity via ferroptosis, a form of regulated cell death driven by iron-dependent lipid peroxidation. This ferroptotic process was confirmed by the suppression of bile acid-induced cell death through iron chelation and lipid peroxide scavenging in ex vivo liver slice cultures. Furthermore, both dietary iron restriction and antioxidant treatment mitigated liver injury in vivo. These findings identify iron accumulation as a key driver of disease progression and highlight iron metabolism and ferroptosis as potential therapeutic targets in congenital cholestatic liver disease.