American Journal of Pathology

Dyslipolysis of adipocytes has played a critical role in various diseases. Adipose triglyceride lipase (ATGL) is a rate-limiting enzyme in adipocyte autonomous lipolysis. However, whether the degree of adipocyte lipolysis relates to the prognoses in acute pancreatitis (AP) and the role of ATGL mediated lipolysis in the pathogenesis of AP remains elusive. The visceral adipose tissue (VAT) consumption rate (VATR) in the acute stage was measured in both AP patients and mouse models. Lipolysis levels and ATGL expression were detected in caerulein (CER)-induced AP models...

The phosphatidylinositol-4,5-bisphosphate 3-kinase delta isoform (Pik3cd), usually considered immune-specific, was unexpectedly identified as a gene potentially related to either regeneration and/or differentiation in animals lacking hepatocellular Integrin Linked Kinase (ILK). Since a specific inhibitor (Idelalisib, or CAL101) for the catalytic subunit encoded by Pik3cd (p110δ) has reported hepatotoxicity when used for treating Chronic Lymphocytic Leukemia and other lymphomas, we aimed to elucidate if there is a role for p110δ in normal liver function...

Melanoma is the deadliest skin cancer, with a poor prognosis in advanced stages. Available treatments have improved the survival, although long-term benefits are still unsatisfactory. The mitogen-activated protein kinase ERK5 promotes melanoma growth, and ERK5 inhibition determines cellular senescence and the senescence-associated secretory phenotype. Here, latent-transforming growth factor β-binding protein 1 (LTBP1) mRNA was found to be upregulated in A375 and SK-Mel-5 BRAFV600E melanoma cells after ERK5 inhibition...

Pulmonary arterial hypertension (PAH) is a sex-biased disease with female gender as a significant risk factor. Recently, we reported that increased expression of the long non-coding (lnc)RNA Xist, as induced by an intersectin-1s protein fragment with proliferative potential (EHITSN ), may explain the sexual dimorphism of female pulmonary artery endothelial cells (ECs) and at least in part, the imbalance sex/ratio of PAH. Xist is essential for X-chromosome inactivation and dosage compensation of X-linked genes...

Acute respiratory distress syndrome (ARDS) is a heterogeneous clinical syndrome that is most commonly triggered by infection-related inflammation. Lung pericytes can respond to infection and act as immune and proangiogenic cells; moreover, these cells can differentiate into myofibroblasts in non-resolving ARDS and contribute to the development of pulmonary fibrosis. Here, we aimed to characterize the role of lung cells which present characteristic of pericytes, such as peri-endothelial location and expression of panel of specific markers...

A considerable number of colon cancer patients with local or local advanced disease suffer from recurrence and there is an urgent need for better prognostic biomarkers in this setting. Here, the transcriptomic landscape of messenger RNAs (mRNAs), long non-coding RNAs (lncRNAs), small nuclear RNAs (snRNAs), small nucleolar RNAs (snoRNAs), small Cajal body-specific RNAs (scaRNAs), pseudogenes and circular RNAs (circRNAs), as well as RNAs denoted as miscellaneous RNAs, was profiled by total RNA sequencing. In addition to well-known coding and non-coding RNAs, differential expression analysis also uncovered transcripts, which have not previously been implicated in colon cancer, such as RNA5SP149, RNU4-2 and SNORD3A...

Adoptive cellular therapy using chimeric antigen receptors (CAR) has transformed immunotherapy by engineering T cells to target specific antigens on tumor cells. As the field continues to advance, pathology laboratories will play increasingly essential roles in the complicated multi-step process of CAR-T therapy. These include the detection of targetable tumor antigens by flow cytometry or immunohistochemistry at the time of disease diagnosis and the isolation and infusion of CAR-T cells. Additional roles include (1) detecting antigen loss or heterogeneity that renders resistance to CAR-T as well as identifying alternative targetable antigens on tumor cells, (2) monitoring the phenotype, persistence and tumor infiltration properties of CAR T-cells and the tumor microenvironment for factors that predict CAR-T success, and (3) evaluating side effects and biomarkers of CAR-T cytotoxicity such as cytokine release syndrome...

Intrahepatic Cholangiocarcinoma (ICC) is highly malignant neoplasm and prone to metastasis. It is unclear if cancer-associated fibroblasts (CAFs) affect the metastasis of ICC. Here, we have established ICC patient-derived CAF lines and related cancerous cell lines and analyzed the effects of CAFs on the tumor progressive properties of the ICC cancerous cells. Results demonstrated that CAFs can be classified into cancer-restraining or promoting categories (rCAFs or pCAFs) based on distinct tumorigenic effects...

Mesothelial cells with reactive hyperplasia are difficult to distinguish from malignant mesothelioma cells on cell morphology. This study aimed to identify and validate potential biomarkers that distinguish mesothelial cells from mesothelioma cells through machine learning combined with immunohistochemistry (IHC) experiments. We integrated the gene expression matrix from three GEO datasets (GSE2549, GSE12345, GSE51024) to analyze the differently expressed gene (DEGs) between normal and mesothelioma tissues...

Since the mechanotransduction by stromal stiffness stimulates the rupture and repair of the nuclear envelope in pancreatic progenitor cells, accumulated genomic aberrations are under selection in the tumor microenvironment. Analysis of cell growth, micronuclei, and γH2AX foci links to mechanotransduction pressure in vivo during serial orthotopic passages of mouse KrasLSL-G12D/+ ;Trp53flox/flox ;Pdx1-Cre (KPC) cancer cells in the tumor and in migrating through the size-restricted 3μm micropores. To search for pancreatic cancer cell-of-origin, analysis of single-cell datasets revealed that the ECM shapes an alternate route of acinar-ductal transdifferentiation of acinar cells into a central hub of elegantly restrained TOP2A-overexpressing cancer cells that spread out as unique cancer clusters with copy number amplifications in MYC-PTK2 locus and PIK3CA...

Mucosal-associated invariant T (MAIT) cells are essential in defending against infection. Sepsis is a systemic inflammatory response to infection and a leading cause of death. The relationship between the overall competency of the host immune response and disease severity is not fully elucidated. This study identified a higher proportion of circulating MAIT17 with expression of IL-17A and RORγt in sepsis patients. The proportion of MAIT17 was correlated with the severity of sepsis. Single-cell RNA sequencing (scRNA-seq) analysis revealed an enhanced expression of lactate dehydrogenase A (LDHA) in MAIT17 in sepsis patients...

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Bronchial premalignant lesions (PMLs) precede the development of invasive lung squamous carcinoma (LUSC), posing a significant challenge in distinguishing those likely to advance to LUSC from those that might regress without intervention. In this context, we present a novel computational approach, the Graph Perceiver Network (GRAPE-Net), leveraging hematoxylin and eosin (H&E) stained whole slide images (WSIs) to stratify endobronchial biopsies of PMLs across a spectrum from normal to tumor lung tissues...

Hepatocyte nuclear factor 4 alpha (HNF4α) is a nuclear factor essential for liver function that regulates the expression of cMyc and plays an important role in proliferation and differentiation during liver regeneration. This study investigated the role of HNF4α-cMyc interaction in regulating liver injury and regeneration using the choline-deficient and ethionine-supplemented (CDE) diet model. WT, hepatocyte-specific HNF4α-KO, cMyc-KO, and HNF4α-cMyc double knockout (DKO) mice were fed a CDE diet for one week to induce subacute liver injury...

The role of the PI3K/Akt pathway in renal cell carcinoma (RCC) progression, metastasis, and resistance to therapies has not been thoroughly investigated. Transcription factor E3 (TFE3) expression is related to poorer prognosis and tumor microenvironment in patients with RCC. We aimed to determine the relationship between TFE3 and the PI3K/Akt pathway. TFE3 downregulation was achieved by transient transfection of small interfering RNA (siRNA) and short hairpin RNA (shRNA) in UOK146 cells. TFE3 overexpression was induced by transient transfection with pcDNA3...

Acute lung injury (ALI) is a devastating clinical disease caused by different factors, with high morbidity and mortality. It has been shown that lung injury and inflammation caused by lipopolysaccharide (LPS) can be modulated by NLRP3 inflammasome activation, yet its exact function within the airway epithelium is still unknown. Meanwhile, glucose transporter protein 1 (GLUT1) has been shown to contribute to a number of inflammatory illnesses, including ALI. The present study was aimed to assess GLUT1's function in NLRP3 inflammasome activation of airway epithelium in LPS-induced acute lung injury...

Two major constituents of exfoliation material (XFM), fibrillin- 1 and lysyl oxidase-like 1 (encoded by FBN1 and LOXL1) are implicated in exfoliation glaucoma (XFG), yet their individual contributions to ocular phenotype are minor. To test the hypothesis that a combination of FBN1 mutation and LOXL1 deficiency exacerbates ocular phenotypes, pan-LOX inhibitor, β-aminopropionitrile (BAPN) was used to treat adult wild-type (wt) and Fbn1C1041G/+ mice for 8 weeks and their eyes were examined. Although intraocular pressure was not changed and XFM not detected in the eyes, BAPN treatment worsened optic nerve and axon expansion in Fbn1C1041G/+ mice, an early sign of axonal damage in rodent models of glaucoma...

Interactions between endothelial cells (EC) and mural pericytes (PC) are critical to maintaining the stability and function of the microvascular wall. Abnormal interactions between these two cell types are a hallmark of progressive fibrotic diseases, such as systemic sclerosis (SSc, scleroderma). However, the role that PCs play in signaling microvascular dysfunction remains underexplored. It is hypothesized that integrin-matrix interactions contribute to PC migration from the vascular wall and conversion into interstitial myofibroblasts...

Hepatocellular carcinoma (HCC) is associated with elevated soluble CD40 levels in our previous study. Here we aimed to investigate CD40's role in liver tumor progression. We examined CD40 levels in HCC patient tissues and various HCC cell lines, studying their interaction with CD4+ T cells. RNA sequencing analysis was performed to explore the mechanisms of CD40 induction. Poorly differentiated HCC tumour tissues exhibited high membrane-bound CD40 (mCD40) expression, in contrast to non-tumour areas. Poorly differentiated HCC cell lines showed high expression of mCD40 with low CD40 promoter methylation which were opposite of well-differentiated ones...

Tumor-infiltrating lymphocytes (TILs) are associated with improved survival in patients with epithelial ovarian cancer. However, the evaluation of TILs has not been applied to routine clinical practice due to reproducibility issues. We developed two convolutional neural network models to detect TILs and to determine their spatial location in whole-slide images, and established a spatial assessment pipeline to objectively quantify intraepithelial and stromal TILs in patients with high-grade serous ovarian carcinoma...