Journal of Pathology

Autoimmune regulator (Aire) and TGF-β signaling play important roles in central tolerance and peripheral tolerance respectively, by eliminating or suppressing the activity of autoreactive T cells. We have previously demonstrated that dnTGFβRII mice develop a defect in peripheral tolerance and a primary biliary cholangitis (PBC) -like disease. We hypothesized that by introducing the Aire gene to this model, we would observe a more severe PBC phenotype. Interestingly, however, we demonstrated that while dnTGFβRII Aire-/- mice do manifest key histologic and serologic features of autoimmune cholangitis, they also develop mild to moderate interface hepatitis and show high levels of alanine transaminase (ALT) and antinuclear antibodies (ANA), characteristics of autoimmune hepatitis (AIH)...

In vitiligo, autoreactive CD8+ T cell is established as the main culprit considering its pathogenic role in mediating epidermal melanocyte-specific destruction. Macrophage migration inhibitory factor (MIF) is a pleiotropic molecular that plays a central role in various immune processes including the activation and proliferation of T cells; but whether MIF is intertwined in vitiligo development and progression and its involvement in aberrantly activated CD8+ T cells remain ill-defined. In the study, we found that MIF was overabundant in vitiligo patients and a mouse model for human vitiligo...

Metastatic uveal melanoma remains incurable at present. We previously demonstrated that loss of BAP1 gene expression in tumour cells triggers molecular mechanisms of immunosuppression in the tumour microenvironment of metastatic uveal melanoma. Adipophilin is a structural protein of lipid droplets involved in fat storage within mammalian cells, and its expression has been identified in uveal melanoma. We comprehensively evaluated adipophilin expression at the RNA (PLIN2) and protein levels of 80 patients of the GDC-TCGA-UM study and in a local cohort of 43 primary uveal melanoma samples, respectively...

Amine oxidase copper-containing 3 (AOC3) is a member of the semicarbazide-sensitive amine oxidase enzyme family. It acts as an ectoenzyme catalysing the oxidative deamination of primary amines and generating hydrogen peroxide (H2 O2 ). While AOC3 is implicated in cardiovascular diseases such as atherosclerosis, its role in cardiac remodelling after myocardial infarction (MI) is unclear. In this study, we first confirmed a long-term upregulation of AOC3 in both cardiac myofibroblasts after MI in vivo and angiotensin II (ANGII)-treated cardiac fibroblasts in vitro...

Benign Prostatic Hyperplasia (BPH) occurs progressively with aging in men and drives deteriorating symptoms collectively known as Lower Urinary Tract Symptoms (LUTS). Age associated changes in circulating steroid hormones, and prostate inflammation have been postulated in the etiology of BPH/LUTS. The link between hormones and inflammation in the development of BPH/LUTS is conflicting because they may occur independently or as sequential steps in disease pathogenesis. This study aimed to decipher the prostatic immune landscape in a mouse model of lower urinary tract dysfunction (LUTD)...

Hepatic angiosarcoma (HAS) is an aggressive mesenchymal malignancy that remains underexplored in its etiology and mutational landscapes. To clarify the association between HAS and end stage end-stage renal disease (ESRD), we exploited nationwide data of the National Health Insurance Research Database (NHIRD) in Taiwan, covering ~99% of the population, from 2001 to 2016. To investigate molecular signatures, we performed whole-exome sequencing (WES) in 27 surgical specimens, including 9 ESRD-associated cases...

The extracellular matrix (ECM) is an integral part of the tumor microenvironment of carcinomas. Even though salivary gland carcinomas (SGC) display a range of tumor cell differentiation and distinct extracellular matrices, their ECM landscape has not been characterized in depth. The ECM composition of 89 SGC primaries, 14 metastases and normal salivary gland tissues was assessed using deep proteomic profiling. Machine learning algorithms and network analysis were used to detect tumor groups and protein modules that explain specific ECM landscapes...

Much of tumour cell biology and the tumour microenvironment may be normal wound healing responses as a consequence of the disruption of tissue structure. This is why tumours resemble wounds, and many features of the tumour microenvironment, such as the epithelial-mesenchymal transition, cancer-associated fibroblasts, and inflammatory infiltrates, may largely be normal responses to abnormal tissue structure, not an exploitation of wound-healing biology. This article is protected by copyright. All rights reserved...

Wnt signaling is a positive regulator of bone formation through the induction of osteoblast differentiation and down-regulation of osteoclast differentiation. We previously reported that muramyl dipeptide (MDP) increases bone volume by increasing osteoblast activity and attenuating osteoclast activity in RANKL-induced osteoporotic model mice. In this study, we investigated whether MDP could alleviate post-menopausal osteoporosis through Wnt signaling regulation through an ovariectomy (OVX)-induced mouse osteoporosis model...

Chronic wounds in diabetic patients are associated with significant morbidity and mortality; however, few therapies are available to improve healing of diabetic wounds. Our group previously reported that low-intensity vibration (LIV) can improve angiogenesis and wound healing in diabetic mice. The purpose of the current study was to begin to elucidate mechanisms underlying LIV-enhanced healing. We first demonstrate that LIV-enhanced wound healing in db/db mice is associated with increased IGF1 protein levels in liver, blood, and wounds...

Multiple Myeloma (MM) remains an incurable haematological malignancy despite substantial advances in therapy. The hypoxic bone marrow induces metabolic rewiring in MM cells contributing to survival and drug resistance. Therefore, targeting metabolic pathways may offer an alternative treatment option. In this study, we re-purpose two FDA-approved drugs, syrosingopine and metformin. Syrosingopine was used as a dual inhibitor of monocarboxylate transporter 1 and 4 (MCT1/4) and metformin as an inhibitor for oxidative phosphorylation (OXPHOS)...

Epstein-Barr virus (EBV) is one of the major drivers of gastric carcinogenesis. EBV infection is established before tumour initiation and is generally maintained throughout tumour development; however, the significance of EBV in tumour maintenance and progression remains to be elucidated. Here, we report eight cases of EBV-associated gastric carcinoma (EBVaGC) with intratumoural heterogenous expression of EBV-encoded small RNA (EBER), a highly expressed latent gene of EBV, and demonstrate clinicopathologic characteristics of these rare cases...

Non-alcoholic fatty liver disease-associated hepatocellular carcinoma (NAFLD-HCC) is an emerging malignancy due to the rising prevalence of NAFLD. However, no drug is available to target NAFLD-HCC. In this study, we aim to unravel novel therapeutic targets of NAFLD-HCC utilizing a high-throughput CRISPR/Cas9 screening strategy. We utilized the Epi-Drug CRISPR/Cas9 library consisting of sgRNAs targeting over 1,000 genes representing the FDA-approved drug targets and epigenetic regulators to perform loss-of-function screening in two NAFLD-HCC cell lines (HKCI2 and HKCI10)...

Platinum resistance is a major obstacle to the treatment of ovarian cancer and is correlated with poor clinical outcomes. Intratumor heterogeneity plays a key role in chemoresistance. Recent studies have emphasized the contributions of genetic and epigenetic factors to the development of intratumor heterogeneity. Although the clinical significance of multisubunit chromatin remodeler, switch/sucrose nonfermenting (SWI/SNF) complexes in cancers has been reported, the impacts of SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4/subfamily A, member 2 (SMARCA4/A2) expression patterns in human cancer tissues have not been fully elucidated...

Neuroendocrine (NE) cells comprise ~1% of epithelial cells in benign prostate and prostatic adenocarcinoma (PCa). However, they become enriched in hormonally-treated and castration-resistant PCa (CRPC). In addition, close to 20% of hormonally-treated tumors recur as small cell neuroendocrine carcinoma (SCNC), composed entirely of NE cells, which may be the result of clonal expansion or lineage plasticity. Since NE cells do not express androgen receptor (AR), they are resistant to hormonal therapy and contribute to therapy failure...

Macropinocytosis is an effective strategy to mitigate nutrient starvation. It can fuel cancer cell growth in nutrient-limited conditions. However, whether and how macropinocytosis contributes to the rapid proliferation of hepatocellular carcinoma cells, which frequently experience an inadequate nutrient supply, remains unclear. Here, we demonstrated that nutrient starvation strongly induced macropinocytosis in some hepatocellular carcinoma cells. It allowed the cells to acquire extracellular nutrients and supported their energy supply to maintain rapid proliferation...

No abstract text is available yet for this article.

Triple-negative breast cancer (TNBC) is known to have relatively poor outcome with variable prognoses, raising the need for more informative risk stratification. We investigated a set of digital, artificial intelligence (AI) based spatial tumour microenvironment (sTME) features and explored their prognostic value in TNBC. After performing tissue classification on digitised Haematoxylin and Eosin (H&E) slides of TNBC cases, we employed a deep learning-based algorithm to segment tissue regions into tumour, stroma, and lymphocytes in order to compute quantitative features concerning the spatial relationship of tumour with lymphocytes and stroma...

Treatment of bladder cancer patients depends on precise diagnosis. Molecular subtyping by gene expression profiling may contribute substantially to subclassification of bladder cancer. Several classification systems have been presented. Most of these base their classification on whole biopsy features, and molecular subtypes are therefore often defined by a combination of features from the cancer cells as well as infiltrating non-cancer cells. This makes the link to what is seen at the cancer cell level unclear...

The aggressive basal/squamous (Ba/Sq) bladder cancer (BLCA) subtype is often diagnosed at the muscle-invasive stage and can progress to the sarcomatoid variant. Identification of molecular changes occurring during progression from non-muscle-invasive BLCA (NMIBC) to Ba/Sq muscle-invasive BLCA (MIBC) is thus challenging in human disease. We used the N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) mouse model of Ba/Sq MIBC to study longitudinally the molecular changes leading to the Ba/Sq phenotype and to the sarcomatoid variant using IHC and microdissection followed by RNA-seq at all stages of progression...