Podoplanin as a Predictive Marker for Identification of High-Risk Mycosis Fungoides Patients: An Immunohistochemical Study.

BACKGROUND: Podoplanin, an important protein, has been implicated in various cellular processes, including lymphangiogenesis. Podoplanin is a mucin-type transmembrane glycoprotein that is accepted as a novel marker of lymphatic endothelial cells. OBJECTIVES: To study the immunohistochemical expression of podoplanin in the different stages of mycosis fungoides (MF) in comparison to control and to correlate their expression with disease severity and progression. MATERIALS AND METHODS: The study included 50 patients of MF, clinically diagnosed and assessed by World Health Organization/European Organization for Research And Treatment Of Cancer Consensus and 20 normal persons as control. Skin biopsy specimens were taken from all and examined for expression of podoplanin immunohistochemically. RESULTS: Significant upregulation of podoplanin expression was detected in all studied patients of MF in comparison to control group. Podoplanin expression in malignant lymphocytes and also lymph vessel density showed significant upregulation in the aggressive clinical presentations as well as the highest stages regarding TNMB staging of MF. CONCLUSIONS: Evaluation of podoplanin expression may be taken into consideration in the future as a useful tool to identify high-risk MF patients. Furthermore, it may open new therapeutic options for the clinical management of those patients.

Evaluation of the antirheumatic effects of isoflavone-free soy protein isolate and etanercept in rats with adjuvant-induced arthritis.

IMPACT STATEMENT: In view of the partial clinical benefit and significant toxicity of traditional rheumatoid arthritis (RA) treatments, there is a growing trend to use complementary therapy. The antiarthritic activity of soy is related to the effect of soy isoflavones. However, little is known about the antiarthritic activity of soy protein itself. This study demonstrates that soy protein isolate (SPI) and etanercept (ETN), a tumor necrosis factor-α (TNF-α) inhibitor, protect rats against the effects of adjuvant-induced arthritis (AIA) by reducing inflammation (TNF-α and matrix metalloproteinase-3), autoantibody production (anticyclic citrullinated peptide), and lipid peroxidation (malondialdehyde). Only SPI improved dyslipidemia accompanied by RA, giving it the advantage of reducing cardiovascular risk. Additionally, the severity of arthritis-induced pathology, including inflammatory infiltrates, synovial hyperplasia, pannus formation, synovial vascularity, and cartilage erosions, was reduced by both SPI and ETN. This research ascertains the possible antiarthritic effect of SPI, making it a recommended alternative therapy for RA.

Polymeric nano-encapsulation of 5-fluorouracil enhances anti-cancer activity and ameliorates side effects in solid Ehrlich Carcinoma-bearing mice.

Biodegradable PLGA nanoparticles, loaded with 5-fluorouracil (5FU), were prepared using a double emulsion method and characterised in terms of mean diameter, zeta potential, entrapment efficiency and in vitro release. Poly (vinyl alcohol) was used to modify both internal and external aqueous phases and shown have a significant effect on nanoparticulate size, encapsulation efficiency and the initial burst release. Addition of poly (ethylene glycol) to the particle matrix, as part of the polymeric backbone, improved significantly the encapsulation efficiency. 5FU-loaded NPs were spherical in shape and negatively charged with a size range of 185-350 nm. Biological evaluation was performed in vivo using a solid Ehrlich carcinoma (SEC) murine model. An optimised 5FU-loaded formulation containing PEG as part of a block copolymer induced a pronounced reduction in tumour volume and tumour weight, together with an improved percentage tumour growth inhibition. Drug-loaded nanoparticles showed no significant toxicity or associated changes on liver and kidney function in tested animals, whereas increased alanine aminotransferase, aspartate aminotransferase and serum creatinine were observed in animals treated with free 5FU. Histopathological examination demonstrated enhanced cytotoxic action of 5FU-loaded nanoparticles when compared to the free drug. Based on these findings, it was concluded that nano-encapsulation of 5FU using PEGylated PLGA improved encapsulation and sustained in vitro release. This leads to increased anti-tumour efficacy against SEC, with a reduction in adverse effects.

Antifibrotic effect of AT-1 blocker and statin in rats with hepatic fibrosis.

Hepatic fibrosis is an outcome of chronic liver injury. Angiotensin II (ANG II) may play a role in the pathogenesis of hepatic fibrosis. Certain drugs such as ACE inhibitors, ANG II antagonists, and even statins could interfere with the renin angiotensin system and modulate its deleterious effects. This study was carried out to investigate the possible role of losartan and atorvastatin in liver fibrosis. Liver fibrosis was induced in rats by i.p. injection of 50% CCl4 twice per week for 8 weeks. The rats intoxicated with CCl4 were divided into four groups: fibrosis control; losartan group; atorvastatin group; and co-treated group. A fifth group of normal healthy rats served as a control group. The results showed that losartan and atorvastatin, either alone or in combination, significantly decreased ALT, AST, hyaluronic acid and hydroxyproline levels in their groups compared to those of the fibrosis control group. A significant decrease in TGF-ß was found in the losartan and co-treated groups but not in the atorvastatin group. These biochemical data were supported by liver histopathology and α-SMA. The results indicate that the combined treatment with both losartan and atorvastatin produced a greater effect than either drug alone and proved a beneficial role in inhibiting or reversing liver fibrosis.

Biochemical/metabolic changes associated with hepatocellular carcinoma development in mice.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related mortality after lung and stomach cancers. This work was undertaken to investigate some of the biochemical mediators/pathways associated with or implicated in the pathogenesis of HCC. Male albino mice were classified into two groups: normal control group and HCC group. Early stage HCC was induced by injection of diethylnitrosamine (DEN) i.p. 200 mg/kg as a single dose, and after 2 weeks, the mice were given i.p. injection of thioacetamide (TAA) 100 mg/kg twice per week for 4 weeks. Mice were left for further 2 weeks without any treatment, after which, mice were sacrificed; blood and liver samples were collected. Serum was used for determination of activities of glucose-6-phosphate dehydrogenase (G6PDH) and aldolase as well as levels of insulin-like growth factor-1 (IGF-1) and epithelial cadherin (E-cadherin). One portion of the liver was used for histopathological examination and immunohistochemical staining of the tumor suppressor p53 protein. Another portion of the liver was used for determination of citrate synthase activity. Induction of HCC in mice resulted in significant increase in G6PDH and aldolase activities, and E-cadherin level, but significant decrease in IGF-1. HCC mice group showed moderate expression of p53 protein. These results suggest that the molecular pathogenesis of HCC in mice involves reduction of serum level of IGF-1 and increased serum level of E-cadherin accompanied by dysregulation of p53 protein expression. HCC was also associated with reprogrammed metabolic profile shifted toward increased glycolysis and lipogenesis.

Expression of the signal transducer and activator of transcription factor 3 and Janus kinase 3 in colorectal carcinomas, colonic adenomas and ulcerative colitis.

BACKGROUND AND STUDY AIMS: Despite the growing understanding of the involvement of protooncogenes and tumour suppressor genes in the oncogenesis of CRC, the exact biological and molecular mechanisms underpinning this process remain poorly understood. The signal transducer and activator of transcription (STAT3) has been implicated in the regulation of growth and malignant transformation. Accumulating evidences have come to indicate that abnormalities in the Janus kinase (JAK)/STAT pathway are involved in oncogenesis of several cancers. The aim of this study was to investigate the expression of JAK3 and STAT3 in both normal and activated forms by immunohistochemistry in adenomas of the colon, ulcerative colitis and CRC compared to normal colonic mucosa. PATIENTS AND METHODS: Tissues from 30 cases with primary CRC and seven cases with ulcerative colitis (UC), removed by colectomy, were included. In addition, tissues from 10 colonic adenomas, 15 CRC and eight cases with UC, obtained by endoscopic biopsies, were examined histopathologically. Immunohistochemical evaluation of STAT3, p-STAT3, JAK3 and p-JAK3 expression in tissue sections was completed. Statistical analysis and correlation of data were then performed. RESULTS: Normal colonic mucosa showed expression of STAT3 only. Immunoreactivity of p-JAK3 increased significantly (p<0.05) and correlated with the degree of dysplasia in colonic adenomas. Immunoreactivity of p-STAT3 increased significantly (p<0.05) and correlated with the degree of dysplasia in cases with UC. In CRC a significant positive correlation was found between p-STAT3 expression and grading, STAT3, JAK3 and p-JAK3 and TNM or Dukes' staging, and p-STAT3 and nodal status excluding distant metastasis (p<0.05). CONCLUSION: JAK3 and STAT3, and particularly their activated forms, were found to correlate significantly with the degree of dysplasia in adenomas and UC, indicating their potential role in colorectal carcinogenesis. They also correlate with anaplasia and invasion, suggesting a definitive role in progression of CRC.

P63 and cytokeratin8/18 expression in breast, atypical ductal hyperplasia, ductal carcinoma in situ and invasive duct carcinoma.

Background and Purpose : The pattern and distribution of p63 expression as a myoepithelial/basal stem cell marker can be different between atypical ductal hyperplasia (ADH), ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC) and may denote basal phenotype of breast ductal carcinoma. CK8/18 is a luminal marker and may indicate a luminal phenotype of IDC and its expression in ADH and DCIS may refer to a possible precursor lesion to IDC. This work was designed to study and compare the expression of p63 and cytokeratin 8/18 (CK8/18) in some cases of ADH, DCIS and IDC. Materials and Methods : Histopathological evaluation and immunohistochemical study of anti-p63 and anti- CK8/18 was performed on selected archival cases of 7 ADH, 12 DCIS, 30 IDC of known clinicopathological data and previous estrogen receptor status (ER) for IDC. Confirmatory anti-smooth muscle actin (ASMA) expression for positive p63 cases was performed. Results : p63 was expressed in the peripheral rim of the myoepithelial cell layer in ADH and DCIS with occasional gabs in DCIS. It was positive and stained occasional malignant cells in 3/30 (10%) of IDC cases. Confirmatory ASMA staining decorated the same peripheral rim of cells in ADH and DCIS, but was negative in p63 positive IDC cases. CK8/18 was positive in 100% of ADH, 8/12 (66.7%) of DCIS and 22/30 (73%) of IDC cases. Combined p63 and CK8/18 expression was noticed in 3/30 (10%) of IDC. Conclusion : It is concluded from this study that p63 is specific and valuable in differentiating myoepithelial cells and is more specific and valuable than other myoepithelial markers, as ASMA and can differentiate between ADH, DCIS, IDC as it stains peripheral myoepithelial cells in ADH and DCIS with gabs in the latter and does not stain any neoplastic cells. In IDC, it is positive in malignant cells in a minority of cases which may indicate basal/stem cell/myoepithelial cell origin of breast carcinoma. Comparatively, CK8/18 cannot differentiate ADH, DCIS and IDC as there is no difference in its staining pattern among them, which may suggest that they are a continuum or that ADH and DCIS are precursors for the luminal phenotype of IDC. Key Words : p63 -CK8/18 -IDC -ADH -DCIS -Basal/ stem cells.