Higher pNRF2, SOCS3, IRF3, and RIG1 Tissue Protein Expression in NASH Patients versus NAFL Patients: pNRF2 Expression Is Concomitantly Associated with Elevated Fasting Glucose Levels.

Non-alcoholic fatty liver disease (NAFLD) embraces simple steatosis in non-alcoholic fatty liver (NAFL) to advanced non-alcoholic steatohepatitis (NASH) associated with inflammation, fibrosis, and cirrhosis. NAFLD patients often have metabolic syndrome and high risks of cardiovascular and liver-related mortality. Our aim was to clarify which proteins play a role in the progression of NAFL to NASH.

Characterization of two types of intranuclear hepatocellular inclusions in NAFLD.

Nuclear inclusions (NI) are a common finding in hepatocytes from patients with liver disease especially in diabetes mellitus and non-alcoholic fatty liver disease (NAFLD) but studies examining the shape and content of these inclusions in detail are lacking. In this study we define two distinct types of NI in NAFLD: inclusions bounded by the nuclear membrane, containing degenerative cell organelles and heterolysosomes (type1) and inclusions with deposits of glycogen but without any kind of organelles and delimiting membrane (type2). NI in 77 paraffin-embedded patients of NAFLD including NAFL and non-alcoholic steatohepatitis (NASH) were analyzed.

[Liver transplantation. Current aspects of pretransplantation diagnosis and rejection].

Liver transplantation is an established treatment option for patients with end-stage liver disease. The therapy management of these patients is interdisciplinary and requires pathologists to have both clinical and immunological knowledge. Continuous advances in treatment and increasing clinical experience are accompanied by the further development of pathological transplant diagnostics.

[Histopathological diagnosis and differential diagnosis of nonalcoholic fatty liver disease].

Fatty liver disease is a rising problem worldwide, particularly due to metabolic syndrome. The current prevalence is 20-30%, but a further increase is expected whereby children will also be increasingly affected. The presence of fat in hepatocytes is known as steatosis or, in the case of nonalcoholic origin, nonalcoholic fatty liver (NAFL).

Hepatocyte KLF6 expression affects FXR signalling and the clinical course of primary sclerosing cholangitis.

Background & Aims: Primary sclerosing cholangitis (PSC) is characterized by chronic cholestasis and inflammation, which promotes cirrhosis and an increased risk of cholangiocellular carcinoma (CCA). The transcription factor Krueppel-like-factor-6 (KLF6) is a mediator of liver regeneration, steatosis, and hepatocellular carcinoma (HCC), but no data are yet available on its potential role in cholestasis. Here, we aimed to identify the impact of hepatic KLF6 expression on cholestatic liver injury and PSC and identify potential effects on farnesoid-X-receptor (FXR) signalling.

New insights into intranuclear inclusions in thyroid carcinoma: Association with autophagy and with BRAFV600E mutation.

Background: Intranuclear inclusions (NI) in normal and neoplastic tissues have been known for years, representing one of the diagnostic criteria for papillary thyroid carcinoma (PTC). BRAF activation is involved among others in autophagy. NI in hepatocellular carcinoma contain autophagy-associated proteins.

Intranuclear inclusions in hepatocellular carcinoma contain autophagy-associated proteins and correlate with prolonged survival.

For decades, intranuclear inclusions in many normal and neoplastic cells have been considered to be mere invaginations of cytoplasm into the nucleus without any notable function or influence on disease. We investigated such inclusions in 75 specimens of hepatocellular carcinoma (HCC). In this context we demonstrate that these inclusions are true inclusions, completely closed and delimited by the nuclear membrane, containing degenerate cell organelles and lysosomal proteins.

Curcumin induces G2/M arrest, apoptosis, NF-κB inhibition, and expression of differentiation genes in thyroid carcinoma cells.

Purpose: The therapy of unresectable advanced thyroid carcinomas shows unfavorable outcome. Constitutive nuclear factor-κB (NF-κB) activation in thyroid carcinomas frequently contributes to therapeutic resistance; the radioiodine therapy often fails due to the loss of differentiated functions in advanced thyroid carcinomas. Curcumin is known for its anticancer properties in a series of cancers, but only few studies have focused on thyroid cancer.

Valproic acid downregulates NF-κB p50 activity and IRAK-1 in a progressive thyroid carcinoma cell line.

Histone deacetylase inhibitor (HDACI) valproic acid (VPA) is a promising drug, currently in clinical phase 2, for the therapy of advanced/poorly differentiated thyroid cancer. The nuclear factor-κB (NF-κB) pathway is constitutively activated in most tumors, including thyroid carcinomas; this often contributes to aggressive tumor growth and therapeutic resistance. We hypothesized that VPA could be useful to decrease NF-κB activity in human thyroid cancer cells.

Hyalinizing trabecular tumour of the thyroid-differential expression of distinct miRNAs compared with papillary thyroid carcinoma.

Aims: To compare the expression pattern of five microRNAs (miRNAs) (146b, -181b, -21, -221, -222) of papillary thyroid carcinoma (PTC) and hyalinizing trabecular tumour of the thyroid (HTT).

Methods And Results: The expression pattern of five miRNAs known to be up-regulated in PTC was retrospectively analysed in 18 HTTs, adjacent normal thyroid tissue, 10 PTCs, 10 follicular adenomas and 10 non-toxic multinodular goitres (MNG) by reverse transcriptase-polymerase chain reaction using the TaqMan miRNA assay. Furthermore, the two common genetic alterations characteristic for PTC, the V600E mutation of the BRAF gene and RET/PTC 1 and 3 rearrangements, were determined in all HTTs.

Differential miRNA expression profiles in variants of papillary thyroid carcinoma and encapsulated follicular thyroid tumours.

Background: Recent studies showed a significant upregulation of distinct microRNAs (miRNAs) in papillary thyroid carcinoma (PTC). The objective of this study was to explore whether this upregulation could also be assigned to distinct histomorphological variants of PTC, especially the follicular variant and other encapsulated follicular thyroid tumours.

Methods: We used total RNA of 113 formalin-fixed paraffin-embedded tissues of 50 PTCs ((10 conventional type (PTC-CT), 10 tall cell variants (PTC-TCVs), 30 follicular variants (PTC-FVs)), 10 follicular adenomas (FAs), 10 multinodular goitres (MNGs), 21 follicular thyroid carcinomas and 22 well-differentiated tumours of unknown malignant potential (WDT-UMP) to analyse the miRNA expression pattern of five selected miRNAs (146b, 181b, 21, 221 and 222) using RT-PCR TaqMan miRNA assay to explore the diagnostic utility of this method.

Analysis of deregulated miRNAs is helpful to distinguish poorly differentiated thyroid carcinoma from papillary thyroid carcinoma.

Poorly differentiated thyroid carcinoma (PDTC) is defined as a malignant follicular cell derived neoplasm, both morphologically and biologically intermediate between well differentiated and anaplastic thyroid carcinoma (ATC). In the present study we investigated the expression levels of two distinct sets of miRNAs ('set 1': miRNA-146b, -181b, -21, -221, -222, all shown to be significantly upregulated in papillary thyroid carcinoma [PTC]; 'set 2': miRNA-30d, -125b, -26a, -30a-5p, and let7c, all downregulated in ATC) in a series of 15 PDTC (including 3 mixed PDTC/PTC), 9 'pure' PTC, and 9 ATC. Compared to normal thyroid tissue all 'set 1' miRNAs were significantly upregulated in PTC (p<0.

Lack of correlation between BRAF V600E mutational status and the expression profile of a distinct set of miRNAs in papillary thyroid carcinoma.

Recent studies demonstrated a significant upregulation of distinct microRNAs (miRNAs), small endogenous RNAs that regulate gene expression, in papillary thyroid carcinoma (PTC). In the pathogenesis of PTC the T1799A (V600E) BRAF mutation is the most common genetic alteration leading to a constitutive activation of the MAPK pathway. The aim of the present study was to elucidate a possible correlation between BRAF mutational status and a distinct miRNA expression profile.

COX-2 expression in highly aggressive thyroid malignancies - indication for a possible therapeutic option?

Both anaplastic thyroid carcinoma (ATC) and angiosarcoma of the thyroid (AST) are highly aggressive malignancies with very limited therapeutic options. Since selective inhibition of COX-2, for example, by celecoxib has been shown to suppress both tumour formation and progression, we investigated COX-2 protein expression in a series of ATC and AST (26 cases each) using immunohistochemistry. COX-2 expression was demonstrated in 13 ATC (50%) and 11 AST (42%); a strong COX-2 expression in more than 50% of vital tumour cells was found in 5 ATC and 5 AST, respectively.

Diffuse sclerosing variant of papillary thyroid carcinoma: lack of BRAF mutation but occurrence of RET/PTC rearrangements.

Diffuse sclerosing variant of papillary thyroid carcinoma (PTC) is a rare tumour with a characteristic morphology as well as a strong preponderance for younger female patients. The T1799A missense mutation in exon 15 of the BRAF gene and RET/PTC rearrangement have been identified as the dominant genetic tumour initiation events in the pathogenesis of PTC leading to a constitutive activation of the RAS-RAF-MAPK pathway. In order to elucidate the pathogenesis of diffuse sclerosing variant of PTC, the prevalence of BRAF mutation and RET/PTC were determined by RT-polymerase chain reaction and DNA-sequence analysis in tumour samples of seven patients with this variant (all female, age range 15-61 years, mean 33.