Circadian variation in expression of G_1 phase cyclins D_1 and E and cyclin-dependent kinase inhibitors p16 and p21 in human bowel mucosa

AIM： To evaluate whether the cellular proliferation rate in the large bowel epithelial cells is characterized by circadian rhythm. METHODS： Between January 2003 and December 2004, twenty patients who were diagnosed as suffering from primary, resectable, non-metastatic adenocarcinoma of the lower rectum, infiltrating the sphincter mechanism, underwent abdominoperineal resection, total mesorectal excision and permanent left iliac colostomy. In formalinfixed and paraffin-embedded biopsy specimens obtained from the colostomy mucosa every six hours （00：00, 06：00, 12：00, 18：00 and 24：00）, we studied the expression of G1 phase cyclins （D1 and E） as well as the expression of the G1 phase cyclin-dependent kinase （CDK） inhibitors p16 and p21 as indicators of cell cycle progres- sion in colonic epithelial cells using immunohistochemical methods. RESULTS： The expression of both cyclins showed a similar circadian fashion obtaining their lowest and highest values at 00：00 and 18：00, respectively （P〈 0.001）. A circadian rhythm in the expression of CDK inhibitor proteins p16 and p21 was also observed, with the lowest levels obtained at 12：00 and 18：00 （P〈0.001）, respectively. When the complexes cyclins D1-p21 and E-p21 were examined, the expression of the cyclins was adversely correlated to the p21 expression throughout the day. When the complexes the cyclins D1-p16 and E-p16 were examined, high levels of p16 expression were correlated to low levels of cyclin expression at 00：00, 06：00 and 24：00. Meanwhile, the highest expression levels of both cyclins were correlated to high levels of p16 expression at 18：00. CONCLUSION： Colonic epithelial cells seem to enter the G1 phase of the cell cycle during afternoon （between 12：00 and 18：00） with the highest rates obtained at 18：00. From a clinical point of view, the present results suggest that G1-phase specific anticancer therapies in afternoon might maximize their anti-tumor effect while minimizing toxicity.

Steatosis and steatohepatitis in postmortem material from Northwestern Greece

AIM: To determine the prevalence of steatosis and steatohepatitis in a series of autopsies in Northwestern Greece. METHODS: Liver biopsy material from a total of 600 autopsies performed over a period of 2 years (2006-2008) to def ine the cause of death was subjected to histological examination. Patient demographic data were also collected. Tissue sections were stained with different dyes for the evaluation of liver architecture, degree of fibrosis and other pathological conditions when necessary. RESULTS: Satisfactory tissue samples for histological evaluation were available in 498 cases (341 male, 157 female) with a mean age of 64.51 ± 17.78 years. In total, 144 (28.9%) had normal liver histology, 156 (31.3%) had evidence of steatosis, and 198 (39.8%) had typical histological findings of steatohepatitis. The most common causes of death were ischemic heart disease with or without myocardial infarction (43.4%), and traffic accidents (13.4%). CONCLUSION: A high prevalence of steatosis and steatohepatitis was detected in postmortem biopsies from Northwestern Greece. Since both diseases can have serious clinical consequences, they should be considered as an important threat to the health of the general population in Greece.

Histone deacetylase inhibitors and pancreatic cancer:Are there any promising clinical trials?

Pancreatic cancer,although not very frequent,has an exceptionally high mortality rate,making it one of the most common causes of cancer mortality in developed countries.Pancreatic cancer is difficult to diagnose,allowing few patients to have the necessary treatment at a relatively early stage.Despite a marginal benefit in survival,the overall response of pancreatic cancer to current systemic therapy continues to be poor,and new therapies are desperately needed.Histone deacetylase(HDAC) enzymes play an important role in the development and progression of cancer and HDAC inhibitors(HDACIs) have been shown to induce differentiation and cell cycle arrest,activate the extrinsic or intrinsic pathways of apoptosis,and inhibit invasion,migration and angiogenesis in different cancer cell lines.As a result of promising preclinical data,various HDACIs are being tested as either monotherapeutic agents or in combination regimens for both solid and hematological malignancies.Vorinostat was the first HDACI approved by the Food and Drug Administration for patients with cutaneous T-cell lymphoma.The use of HDACIs in clinical trials,in pretreated and relapsed patients suffering from advanced pancreatic cancer is discussed.Unfortunately,clinical data for HDACIs in patients with pancreatic cancer are inadequate,because only a few studies have included patients suffering from this type of neoplasm and the number of pancreatic cancer patients that entered HDACIs phase Ⅱ/Ⅲ trials,among others with advanced solid tumors,is very limited.More studies recruiting patients with pancreatic cancer remain to determine the efficiency of these therapies.

Arp2/3 Complex Is Expressed in Oral Squamous Cell Carcinoma: An Immunohistochemical Study of 88 Cases

Background: We investigated the immunohistochemical expression of Arp2/3 complex in 88 oral squamous cell carcinomas (OSCCs) and correlated it with the tumor type and grade. Materials and methods: This is a retrospective study of 88 cases of OSCCs (9 verrucous carcinomas, 4 carcinomas in situ, 37 well differentiated OSCCs, 32 moderately differentiated OSCCs, and 6 poorly differentiated OSCCs), stained with mouse monoclonal antibodies for Arp2 and Arp3. Staining was graded according to the extent of positivity by two observers. Results: Arp2 positivity was seen in 79 (89.77%) cases and Arp3 positivity in 78 (88.63%) cases. In positive cases, Arp2 expression was graded as (+) in 12.5%, (++) in 28.4% and (+++) in 48.86% of the cases;Arp3 was graded as (+) in 36.36%, (++) in 30.68% and (+++) in 21.59% of the cases. Conclusion: Expression of Arp2 and Arp3, indicative of the formation of the Arp2/3 complex, was seen in most OSCCs examined. Although no statistically significant correlation was found between the immunohistochemical expression of Arp2/Arp3 and tumor type or grade, the more common expression in invasive OSCCs than in non-invasive verrucous carcinomas and carcinomas in situ is indicative of its involvement in the biological behaviour of the lesions. The availability of Arp2/3 inhibitors that could be used in clinical practice warrants further study of the expression of Arp2/3 in OSCC.