American Journal of Pathology最新文献

Extracellular matrix (ECM) proteins play an important role in the pathological processes of tumor development and progression. Elastic microfibril interface located protein-1 (EMILIN-1), an ECM glycoprotein, has been linked to cell adhesion and migration. It was previously identified from head and neck squamous cell carcinoma (HNSCC) tissues that down-regulated EMILIN-1 is associated with an increased risk of secondary primary malignancy development in HNSCC and hypothesized that EMILIN-1 functions as a tumor suppressor in HNSCC. This study shows EMILIN-1 expression in HNSCC tissues is specific to the stromal area, and secreted-EMILIN-1 level is higher in fibroblasts isolated from HNSCC tissues than in HNSCC cells. EMILIN-1 overexpression decreased cell proliferation, migration, and invasion in FaDu and CAL27 cells. Knockdown of EMILIN-1 in HNSCC cancer-associated fibroblasts induced cell proliferation and migration. The conditioned medium from EMILIN-1 knockdown cancer-associated fibroblasts increased HNSCC cell proliferation, and the co-culture system enhanced cancer cell migration and invasion. RNA-sequencing analysis revealed that the cell cycle and aurora kinase signaling are the most significant enrichment pathways, confirmed at the protein level. Furthermore, using an in ovo chick chorioallantoic membrane model, overexpression of EMILIN-1 in FaDu cells reduced tumor size and Ki-67-positivity and increased cleaved caspase-3-positive cells. These findings suggest that EMILIN-1 suppresses HNSCC growth partly through the down-regulation of cell cycle and aurora kinase signaling pathways.

Cytomegalovirus (CMV)-induced anterior uveitis is linked to increased intraocular pressure, suggesting profibrotic changes in the eye's drainage system. Previous studies on the aqueous humor (AH) of patients with CMV uveitic glaucoma (UG) highlighted the activation of the liver X receptor (LXR) pathway, yet a potential that it has a role in increased intraocular pressure remained unelucidated. Herein, we explored the LXR pathway's role in AH outflow in UG. Global transcriptional analysis revealed that LXR activation primarily induces transforming growth factor-β signaling, with growth differentiation factor 15 (GDF-15), a growth factor in the transforming growth factor-β superfamily, being one of the most up-regulated genes in LXR-agonist-treated trabecular meshwork cells. GDF-15 levels showed a twofold expression in the AH of patients with UG (n = 44) compared with controls (n = 24; P = 0.024) and increased with more anti-glaucoma eyedrops and glaucoma surgeries (P < 0.05). LXRα/β and GDF-15 were found in human outflow tissue and were up-regulated by lipopolysaccharide and CMV infection. In an experimental endotoxin uveitis model, GDF-15 levels were up-regulated by the treatment with LXR agonists and lipopolysaccharide. In human trabecular meshwork cells, LXR agonists triggered actin stress fiber formation and α-smooth muscle actin expression, both reduced by GDF-15 neutralization. These results suggest that the LXR-GDF-15 pathway contributes to profibrotic changes in UG and plays a role in disease pathogenesis.

Preterm birth (PTB; delivery before 37 weeks), the main cause of neonatal death worldwide, can lead to adverse neurodevelopmental outcomes, as well as lung and gut pathology. PTB can be associated with ascending vaginal infection. Previously, it was shown that ascending Escherichia coli infection in pregnant mice induces PTB and reduces pup survival. Here, it is demonstrated that this model recapitulates the pathology observed in human preterm neonates (namely, neuroinflammation, lung injury, and gut inflammation). In neonatal brains, there is widespread cell death, microglial activation, astrogliosis, and reduced neuronal density. The utility of this model is also validated by assessing the efficacy of maternal cervical gene therapy with an adeno-associated viral vector containing human β defensin 3; this improves pup survival and reduces Tnfa mRNA expression in perinatal pup brains exposed to E. coli. This model provides a unique opportunity to evaluate the therapeutic benefit of preterm labor interventions on perinatal pathology.

Tumor cellularity (TC) in lung adenocarcinoma slides submitted for molecular testing is important in identifying actionable mutations, but absent best practice guidelines yield high interobserver variability in TC assessments. An artificial intelligence (AI)-based pipeline developed to assess TC in hematoxylin and eosin (H&E) whole slide images (WSIs) and in tumor areas (TAs) within WSIs includes a new model (CaBeSt-Net) trained to mask cancer cells, benign epithelial cells, and stroma in H&E WSIs using immunohistochemistry-restained slides, and a model to detect all cell nuclei. High masking accuracy (>91%) by CaBeSt-Net computed using 1024 H&E regions of interest and intraclass correlation coefficient >0.97 assessing TC assessments reliability by one pathologist and AI in 20 test regions of interest supported the pipeline's applicability to TC assessment in 50 study H&E WSIs. Using the pipeline, TCs assessed in TAs and WSIs were compared with those by three pathologists. Reliabilities of these ratings by the pathologists supported by the pipeline were good (intraclass correlation coefficient >0.82, P < 0.0001). The consistency of sample categorizations as inadequate or adequate (TC ≤ 20% cut point) for molecular testing among the pathologists assessing TCs without AI support was moderate in TAs (κ = 0.410, P < 0.0001) and slight in WSIs (κ = 0.132, nonsignificant). With AI support, the consistency was substantial in both WSIs (κ = 0.602, P < 0.0001) and TAs (κ = 0.704, P < 0.0001). By visualizing cancer and measuring TC in the sample, this novel AI-based pipeline assists pathologists in selecting samples for molecular testing.

Injuries to the cornea can lead to recurrent corneal erosions, compromising its barrier function and increasing the risk of infection. Vital as corneal integrity is to the eye's optical power and homeostasis, the immune response to corneal erosions remains poorly understood. It is also unknown whether there is coordinated immune activation between the cornea and other regions of the anterior segment to protect against microbial invasion and limit the spread of inflammation when corneal erosions occur. Using a corneal debridement wounding model, we characterized the immune cell phenotypes populating the cornea in response to erosion formation and investigated whether and which immune cells are concurrently recruited to the surface of the lens. Our studies revealed that the formation of corneal erosions induced an influx of myeloid lineage phenotypes, both M2 macrophages associated with tissue healing and wound repair, and Ly6G⁺ Ly6C⁺ myeloperoxidase⁺ cells resembling neutrophils/polymorphonuclear-myeloid-derived suppressor cells (PMN-MDSCs), with few regulatory T cells, into the corneal stroma under erosion sites. This leukocyte migration into the cornea when erosions develop was paralleled by the recruitment of immune cells, predominantly neutrophils/PMN-MDSCs, to the anterior, cornea-facing lens capsule. Both cornea-infiltrating and lens capsule-associated neutrophil/PMN-MDSC-like immune cells produce the anti-inflammatory cytokine IL-10. Our findings suggest a collaborative role for the lens capsule-associated immune cells in preventing infections, controlling inflammation, and maintaining homeostasis of the anterior segment during recurrent corneal erosions.

Ulcerative colitis (UC) is an inflammatory colon and rectum disease affecting approximately 5 million people worldwide. There is no cure available for UC, and approximately 8% of patients with UC develop colorectal cancer (CRC) by gradual acquisition of mutations driving the formation of adenomas and their progression to adenocarcinomas and metastatic disease. CRC constitutes 10% of total cancer cases worldwide and 9% of cancer deaths. Both UC and CRC have an increasing incidence worldwide. Although the epithelium has been well studied in UC and CRC, the contributions of neutrophils are less clear. They are rapidly recruited in excessive amounts from peripheral blood to the colon during UC, and their overactivation in the proinflammatory UC tissue environment contributes to tissue damage. In CRC, the role of neutrophils is controversial, but emerging evidence suggests that their role depends on the evolution and context of the disease. The role of neutrophils in the transition from UC to CRC is even less clear. However, recent studies propose neutrophils as therapeutic targets for better clinical management of both diseases. This review summarizes the current knowledge on the roles of neutrophils in UC and CRC.

Hepatoblastoma (HB), the most common pediatric liver cancer, is associated with dysregulated Wnt/β-catenin, Hippo, and/or nuclear factor erythroid 2 ligand 2/nuclear respiratory factor 2 (NFE2L2/NRF2) pathways. In mice, pairwise combinations of oncogenically active forms of the terminal transcription factors of these pathways, namely, β-catenin (B), Yes-associated protein (YAP; Y), and Nrf2 (N), generated HBs, with the triple combination (B + Y + N) being particularly potent. Each tumor group alters the expression of thousands of B-, Y-, and N-driven unique and common target genes. The identification of those most involved in transformation might reveal mechanisms and opportunities for therapy. Transcription profiling of >60 murine HBs revealed a common set of 22 BYN genes similarly deregulated in all cases. Most were associated with multiple cancer hallmarks, and their expression may correlate with survival in HBs, hepatocellular carcinomas, and other cancers. Among the most down-regulated of these genes was Gas1, which encodes a glycosylphosphatidylinositol-linked outer membrane protein. The restoration of Gas1 expression impaired B + Y + N-driven HB tumor growth in vivo and in HB-derived immortalized BY and BYN cell lines in vitro in a manner that requires membrane anchoring of the protein via its glycosylphosphatidylinositol moiety, implicating Gas1 as a proximal mediator of HB pathogenesis and validating the BYN gene set as deserving of additional scrutiny in future studies.