- Dietary exacerbation of metabolic stress leads to accelerated hepatic carcinogenesis in glycogen storage disease type Ia. [Journal Article]
- JHJ Hepatol 2018 Sep 04
- CONCLUSIONS: The metabolic remodeling in L.G6pc-/- liver generates a preneoplastic status and leads to a loss of cellular defenses and tumor suppressors that facilitates tumor development in GSDI.
- Evaluation of the diagnostic value of emerin and CD56 in papillary thyroid carcinoma - an immunohistochemical study. [Journal Article]
- JIJ Immunoassay Immunochem 2018 Sep 06; :1-17
- Papillary thyroid carcinoma (PTC) is diagnosed in both cytological and histological specimens on the basis of distinct nuclear morphology. These features may not be prominent in some PTC variants and...
Papillary thyroid carcinoma (PTC) is diagnosed in both cytological and histological specimens on the basis of distinct nuclear morphology. These features may not be prominent in some PTC variants and may be seen in some benign conditions. It is necessary to differentiate PTC from other neoplastic and nonneoplastic lesions since it affects treatment strategy and patients' fate. Emerin is a type II integral membrane protein of the inner nuclear membrane that has a characteristic staining pattern in PTC. CD56 is a homophilic membrane glycoprotein that is expressed in thyroid follicular epithelial cells and adrenal glands. The aim of this study was to evaluate the diagnostic value of emerin (positivity, percentage, and highlighting nuclear features) and CD56 (positive versus negative) both singly and in combination for differentiation of PTC from other neoplastic and nonneoplastic mimics. This study was performed on 50 cases of PTC, 9 cases of follicular adenoma (FA), and 12 cases of nonneoplastic thyroid lesions using immunohistochemistry for detection of emerin and CD56. Positive emerin expression was seen in 82% of PTC and in 16.7% of nonneoplastic cases with an absence of expression in FA. CD56 was expressed in 88.9% of FA, 91.7% of nonneoplastic cases and in a minority of PTC cases (6%). Positive emerin revealed 82% sensitivity and 90% specificity, while emerin-highlighted nuclear changes was more specific (95%). Negative CD56 expression revealed 84% sensitivity and 90% specificity. Combined positive emerin (including highlighting nuclear changes) and negative CD56 showed 72% sensitivity and 100% specificity. Positive emerin expression (moderate/strong) and its highlighting nuclear changes combined with negative CD56 could be a very helpful procedure in difficult and overlapping cases with high diagnostic validity (high specificity and positive predictive value).
- Non-functional duodenal neuroendocrine carcinoma: a rare cause of diabetes mellitus. [Journal Article]
- EDEndocrinol Diabetes Metab Case Rep 2018; 2018
- A 40-year-old Caucasian female presented with hyperglycaemia, polyuria, polydipsia and weight loss of 6 kg over a 1-month period. There was no personal or family history of malignancy or diabetes mel...
A 40-year-old Caucasian female presented with hyperglycaemia, polyuria, polydipsia and weight loss of 6 kg over a 1-month period. There was no personal or family history of malignancy or diabetes mellitus. On examination, she was jaundiced with pale mucous membranes and capillary glucose was 23.1 mmol/L. Initial investigations showed iron deficiency anaemia and obstructive pattern of liver function tests. HbA1c was diagnostic of diabetes mellitus at 79 mmol/mol. Malignancy was suspected and CT chest, abdomen and pelvis showed significant dilatation of intra- and extra-hepatic biliary tree including pancreatic duct, with periampullary 30 mm mass lesion projecting into lumen of duodenum. Enlarged nodes were seen around the superior mesenteric artery. This was confirmed on MRI liver. Fasting gut hormones were normal except for a mildly elevated somatostatin level. Chromogranin A was elevated at 78 pmol/L with normal chromogranin B. Duodenoscopy and biopsy showed possible tubovillous adenoma with low-grade dysplasia, but subsequent endoscopic ultrasound and biopsy revealed a grade 1, well differentiated neuroendocrine tumour. The patient was started on insulin, transfused to Hb >8 g/dL and Whipple's pancreatico-duodenectomy was undertaken. This showed a well-differentiated neuroendocrine carcinoma arising in duodenum (Grade G1 with Ki67: 0.5%), with areas of chronic pancreatitis and preservation of pancreatic islet cells. There was complete resolution of diabetes post Whipple's procedure and patient was able to come of insulin treatment. Her last HBA1C was 31 mmol/mol, 4 months post tumour resection.
- Subclassification of hepatocellular adenomas: practical considerations in the implementation of the Bordeaux criteria. [Journal Article]
- PPathology 2018 Aug 24
- Hepatocellular adenomas are benign liver lesions with a risk of rupture and malignant transformation. Various molecular subgroups have been identified which appear to have characteristic morphologica...
Hepatocellular adenomas are benign liver lesions with a risk of rupture and malignant transformation. Various molecular subgroups have been identified which appear to have characteristic morphological and immunohistochemical features. We examined the morphology and immunohistochemical profile of a series of 121 HCA from 97 patients to identify the HCA subtypes present and determine the number at risk for malignant transformation according to the World Health Organization (WHO) criteria for hepatocellular adenomas. There were 34 HNF1α inactivated HCA (28%), 61 inflammatory HCA (50%), 15 β-catenin activated HCA (12%) and 11 unclassified adenomas (9%). This proportion of cases was similar to that seen in other series utilising molecular classification. The morphological features of the adenomas were suggestive but not definite indicators of the subtypes present. Morphological features that showed overlap between the subtypes included steatosis within the lesion, a ductular reaction and focal atypia, so that immunohistochemical typing was required for accurate classification. In conclusion, immunohistochemistry is a clinically useful surrogate for identifying underlying molecular changes in the HCA subtypes.
- BE AWARE OF THE PATIENT WITH BENIGN FOLLICULAR THYROID LESION HISTOLOGY AND RISING THYROGLOBULIN LEVEL. [Journal Article]
- EPEndocr Pract 2018 Aug 14
- CONCLUSIONS: Misclassification of follicular thyroid lesions as benign may lead to progressive disseminated DTC. To minimize the clinical risk of misdiagnosis, especially if a thorough evaluation of the specimens by an experienced pathologist is unfeasible, we suggest long-term follow-up of serum thyroglobulin levels.
- Candidate genes responsible for early key events of phenobarbital-promoted mouse hepatocellular tumorigenesis based on differentiation of regulating genes between wild type mice and humanized chimeric mice. [Journal Article]
- TRToxicol Res (Camb) 2017 Nov 01; 6(6):795-813
- Phenobarbital (PB) is a nongenotoxic hepatocellular carcinogen in rodents. PB induces hepatocellular tumors by activating the constitutive androstane receptor (CAR). Some previous research has sugges...
Phenobarbital (PB) is a nongenotoxic hepatocellular carcinogen in rodents. PB induces hepatocellular tumors by activating the constitutive androstane receptor (CAR). Some previous research has suggested the possible involvement of epigenetic regulation in PB-promoted hepatocellular tumorigenesis, but the details of its molecular mechanism are not fully understood. In the present study, comprehensive analyses of DNA methylation, hydroxymethylation and gene expression using microarrays were performed in mouse hepatocellular adenomas induced by a single 90 mg kg-1 intraperitoneal injection dose of diethylnitrosamine (DEN) followed by 500 ppm PB in the diet for 27 weeks. DNA modification and expression of hundreds of genes are coordinately altered in PB-induced mouse hepatocellular adenomas. Of these, gene network analysis showed alterations of CAR signaling and tumor development-related genes. Pathway enrichment analysis revealed that differentially methylated or hydroxymethylated genes belong mainly to pathways involved in development, immune response and cancer cells in contrast to differentially expressed genes belonging primarily to the cell cycle. Furthermore, overlap was evaluated between the genes with altered expression levels with 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) alterations in mouse hepatocellular adenoma induced by DEN/PB and the genes with altered expression levels in the liver of CD-1 mice or humanized chimeric mice treated with PB for 7 days. With the integration of transcriptomic and epigenetic approaches, we detected candidate genes responsible for early key events of PB-promoted mouse hepatocellular tumorigenesis. Interestingly, these genes did not overlap with genes altered by the PB treatment of humanized chimeric mice, thus suggesting a species difference between the effects of PB in mouse and human hepatocytes.
- HEPATOKIN1 is a biochemistry-based model of liver metabolism for applications in medicine and pharmacology. [Journal Article]
- NCNat Commun 2018 Jun 19; 9(1):2386
- The epidemic increase of non-alcoholic fatty liver diseases (NAFLD) requires a deeper understanding of the regulatory circuits controlling the response of liver metabolism to nutritional challenges, ...
The epidemic increase of non-alcoholic fatty liver diseases (NAFLD) requires a deeper understanding of the regulatory circuits controlling the response of liver metabolism to nutritional challenges, medical drugs, and genetic enzyme variants. As in vivo studies of human liver metabolism are encumbered with serious ethical and technical issues, we developed a comprehensive biochemistry-based kinetic model of the central liver metabolism including the regulation of enzyme activities by their reactants, allosteric effectors, and hormone-dependent phosphorylation. The utility of the model for basic research and applications in medicine and pharmacology is illustrated by simulating diurnal variations of the metabolic state of the liver at various perturbations caused by nutritional challenges (alcohol), drugs (valproate), and inherited enzyme disorders (galactosemia). Using proteomics data to scale maximal enzyme activities, the model is used to highlight differences in the metabolic functions of normal hepatocytes and malignant liver cells (adenoma and hepatocellular carcinoma).
- Inhibition of Glycogen Synthase II with RNAi Prevents Liver Injury in Mouse Models of Glycogen Storage Diseases. [Journal Article]
- MTMol Ther 2018 Jul 05; 26(7):1771-1782
- Glycogen storage diseases (GSDs) of the liver are devastating disorders presenting with fasting hypoglycemia as well as hepatic glycogen and lipid accumulation, which could lead to long-term liver da...
Glycogen storage diseases (GSDs) of the liver are devastating disorders presenting with fasting hypoglycemia as well as hepatic glycogen and lipid accumulation, which could lead to long-term liver damage. Diet control is frequently utilized to manage the potentially dangerous hypoglycemia, but there is currently no effective pharmacological treatment for preventing hepatomegaly and concurrent liver metabolic abnormalities, which could lead to fibrosis, cirrhosis, and hepatocellular adenoma or carcinoma. In this study, we demonstrate that inhibition of glycogen synthesis using an RNAi approach to silence hepatic Gys2 expression effectively prevents glycogen synthesis, glycogen accumulation, hepatomegaly, fibrosis, and nodule development in a mouse model of GSD III. Mechanistically, reduction of accumulated abnormally structured glycogen prevents proliferation of hepatocytes and activation of myofibroblasts as well as infiltration of mononuclear cells. Additionally, we show that silencing Gys2 expression reduces hepatic steatosis in a mouse model of GSD type Ia, where we hypothesize that the reduction of glycogen also reduces the production of excess glucose-6-phosphate and its subsequent diversion to lipid synthesis. Our results support therapeutic silencing of GYS2 expression to prevent glycogen and lipid accumulation, which mediate initial signals that subsequently trigger cascades of long-term liver injury in GSDs.
- Molecular Diagnostics in the Neoplasms of the Pancreas, Liver, Gallbladder, and Extrahepatic Biliary Tract: 2018 Update. [Review]
- CLClin Lab Med 2018; 38(2):367-384
- Pancreatic neoplasms, including ductal adenocarcinoma, solid pseudopapillary neoplasm, pancreatic endocrine neoplasms, acinar cell carcinoma, and pancreatoblastoma, are associated with different gene...
Pancreatic neoplasms, including ductal adenocarcinoma, solid pseudopapillary neoplasm, pancreatic endocrine neoplasms, acinar cell carcinoma, and pancreatoblastoma, are associated with different genetic abnormalities. Hepatic adenomas with beta-catenin exon 3 mutation are associated with a high risk of malignancy. Hepatic adenoma with arginosuccinate synthetase 1 expression or sonic hedgehog mutations are associated with a risk of bleeding. Hepatocellular carcinoma and choangiocarcinoma display heterogeneity at both morphologic and molecular levels Cholangiocellular carcinoma is most commonly associated with IDH 1/2 mutations.
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- Mequindox Induced Genotoxicity and Carcinogenicity in Mice. [Journal Article]
- FPFront Pharmacol 2018; 9:361
- Mequindox (MEQ), acting as an inhibitor of deoxyribonucleic acid (DNA) synthesis, is a synthetic heterocyclic N-oxides. To investigate the potential carcinogenicity of MEQ, four groups of Kun-Ming (K...
Mequindox (MEQ), acting as an inhibitor of deoxyribonucleic acid (DNA) synthesis, is a synthetic heterocyclic N-oxides. To investigate the potential carcinogenicity of MEQ, four groups of Kun-Ming (KM) mice (50 mice/sex/group) were fed with diets containing MEQ (0, 25, 55, and 110 mg/kg) for one and a half years. The result showed adverse effects on body weights, feed consumption, hematology, serum chemistry, organ weights, relative organ weights, and incidence of tumors during most of the study period. Treatment-related changes in hematology, serum chemistry, relative weights and histopathological examinations revealed that the hematological system, liver, kidneys, and adrenal glands, as well as the developmental and reproductive system, were the main targets after MEQ administration. Additionally, MEQ significantly increased the frequency of micronucleated normochromatic erythrocytes in bone marrow cells of mice. Furthermore, MEQ increased the incidence of tumors, including mammary fibroadenoma, breast cancer, corticosuprarenaloma, haemangiomas, hepatocarcinoma, and pulmonary adenoma. Interestingly, the higher incidence of tumors was noted in M25 mg/kg group, the lowest dietary concentration tested, which was equivalent to approximately 2.25 and 1.72 mg/kg b.w./day in females and males, respectively. It was assumed that the lower toxicity might be a reason for its higher tumor incidence in M25 mg/kg group. This finding suggests a potential relationships among the dose, general toxicity and carcinogenicity in vivo, and further study is required to reveal this relationship. In conclusion, the present study demonstrates that MEQ is a genotoxic carcinogen in KM mice.