Recent advances in breast cancer metastasis with special emphasis on metastasis to the brain.

Understanding the underlying mechanisms of breast cancer metastasis is of vital importance for developing treatment approaches. This review emphasizes contemporary breakthrough studies with special focus on breast cancer brain metastasis. Acquired mutational changes in metastatic lesions are often distinct from the primary tumor, suggesting altered mutagenesis pathways. The concept of micrometastases and heterogeneity within the tumors unravels novel therapeutic targets at genomic and molecular levels through epigenetic and proteomic profiling. Several pre-clinical studies have identified mechanisms involving the immune system, where tumor associated macrophages are key players. Expression of cell proteins like Syndecan1, fatty acid-binding protein 7 and tropomyosin kinase receptor B have been implicated in aiding the transmigration of breast cancer cells to the brain. Changes in the proteomic landscape of the blood-brain-barrier show altered permeability characteristics, supporting entry of cancer cells. Findings from laboratory studies pave the path for the emergence of new biomarkers, especially blood-based miRNA and circulating tumor cell markers for prognostic staging. The constantly evolving therapeutics call for clinical trials backing supportive evidence of efficacies of both novel and existing approaches. The challenge lying ahead is discovering innovative techniques to replace use of human samples and optimize small-scale patient recruitment in trials.

Protective effects of madecassoside, a triterpenoid from Centella asiatica, against oxidative stress in INS-1E cells.

Progressive decline in ß cell function and reduction in the ß cell mass is important in type 2 diabetes. Here, we tested the hypothesis that madecassoside's previously demonstrated in vivo protective effects on the ß cell in experimental diabetes were exerted directly. We investigated the effects of madecassoside in protecting a ß cell line (INS-1E) against a variety of agents. INS-1E cells were treated with madecassoside in the presence of high glucose (HG), a cytokine mixture, hydrogen peroxide (H2O2), or streptozotocin (STZ). HG, the cytokine mixture, H2O2 and STZ each produced a significant decrease in cell viability; this was significantly reversed by madecassoside. Pre-treatment with madecassoside reduced the number of apoptotic cells induced by HG, the cytokine mixture, H2O2, and STZ, and concentration-dependently reduced ROS production. Madecassoside also significantly enhanced glucose-induced insulin secretion. The results suggest that madecassoside's in vivo effects are exerted directly on the ß cell.

Effect of madecassoside in reducing oxidative stress and blood glucose in streptozotocin-nicotinamide-induced diabetes in rats.

OBJECTIVES: Madecassoside (MAD) is a triterpenoid constituent of Centella asiatica (L.) Urb., an ethnomedical tropical plant, extracts of which were shown to reduce blood glucose in experimental diabetes. This study examines MAD for its anti-hyperglycaemic effects and tests the hypothesis that it reduces the blood glucose in experimentally induced diabetic rats by protecting the ß-cells. METHODS: Diabetes was induced using streptozotocin (60 mg/kg, i.v.) followed by nicotinamide (210 mg/kg, intraperitoneal (i.p.)). MAD (50 mg/kg) was administered orally for 4 weeks, commencing 15 days after induction of diabetes; resveratrol (10 mg/kg) was used as a positive control. Fasting blood glucose, plasma insulin, HbA1c, liver and lipid parameters were measured, along with antioxidant enzymes and malondialdehyde as an index of lipid peroxidation; histological and immunohistochemical studies were also undertaken. KEY FINDINGS: MAD normalized the elevated fasting blood glucose levels. This was associated with increased plasma insulin concentrations. MAD alleviated oxidative stress by improving enzymatic antioxidants and reducing lipid peroxidation. Histopathological examination showed significant recovery of islet structural degeneration and an increased area of islets. Immunohistochemical staining showed increased insulin content in islets of MAD-treated rats. CONCLUSIONS: The results demonstrate an antidiabetic effect of MAD associated with preservation of ß-cell structure and function.

Quercetin and metformin synergistically reverse endothelial dysfunction in the isolated aorta of streptozotocin-nicotinamide- induced diabetic rats.

The antidiabetic effects of quercetin and metformin are well known. However, their synergistic effect in reversing the symptoms of diabetes-induced endothelial dysfunction remains unknown. In this study, we have investigated their synergistic effect in streptozotocin (STZ)-nicotinamide induced diabetic rats. Seventy-five rats were divided into five groups; normal control, diabetic control, treatment groups (10 mg/kg quercetin, 180 mg/kg metformin, and combined). The plasma glucose and lipid levels, liver enzymes, ex-vivo studies on aortic rings, histology of liver, kidney, pancreas, abdominal aorta and thoracic aorta, and immunohistochemical studies were carried out. The findings revealed that the combination of quercetin and metformin showed a greater antidiabetic effect than either drug, and rendered protection to the endothelium. The combination effectively reversed the hyperglycemia-induced endothelial dysfunction in diabetic rats. Furthermore, it also reversed the dysregulated expression of eNOS, 3-nitrotyrosine, VCAM-1, CD31 and SIRT-1. Overall, the present study's findings demonstrate that quercetin potentiates the activity of metformin to control the complications associated with diabetes.

Student preparedness characteristics important for clinical learning: perspectives of supervisors from medicine, pharmacy and nursing.

BACKGROUND: Student perspectives of clinical preparedness have been studied in the literature, but the viewpoint of supervisors is limited. Hence, the aim was to examine the perspective of supervisors on the characteristics of health professional students important for preparedness for clinical learning. METHODS: This was a descriptive, questionnaire-based, cross-sectional study conducted at three higher education institutions in Malaysia. A previously published questionnaire with 62 characteristics was adopted with modifications after pre-testing. Descriptive analysis was completed for the demographic data. The sample was grouped based on health profession, clinical practice experience and teaching experience for further analysis. Non-parametric Kruskal-Wallis test was selected to evaluate differences in mean ranks to assess the null hypothesis that the medians are equal across the groups. Kruskal-Wallis post-hoc pair wise comparison was performed on samples with significant differences across samples. RESULTS: The sample was comprised of 173 supervisors from medicine (55, 32%), pharmacy (84, 48%) and nursing (34, 20%). The majority (63%) of the supervisors were currently in professional practice. A high percentage (40%) of supervisors had less than 4 years of teaching experience. The highest theme ratings were for willingness (6.00) and professionalism (5.90). There was a significant difference (p < 0.05) in the medians, among medicine, pharmacy and nursing professional speciality for willingness (5.70, 6.00 and 6.00), professionalism (5.70, 5.90 and 6.15), communication and interaction (5.42, 5.67 and 6.00), personal attributes (5.42, 5.71 and 6.02) and the professional and interpersonal skills (5.50, 5.63 and 6.00) themes. Post-hoc analysis showed a significant difference (p < 0.05) between medicine and nursing groups in the willingness (5.70 and 6.00), professionalism (5.70 and 6.15) and personal attributes (5.42 and 6.02) themes. Supervisors who are currently in practice had given high ratings compared to other groups. There were no significant differences observed within groups with different level of teaching experiences. CONCLUSIONS: All supervisors rated professionalism and willingness as the most important characteristics followed by personal attributes. Further strengthening learning opportunities related to these characteristics in the curriculum may improve the students' preparedness in clinical learning.

CD40 polymorphism in cervical carcinoma in a subset of Malaysian population.

AIM: The aim of this study was to determine the allelic frequency of single nucleotide polymorphisms (SNPs) in the human CD40 gene in cervical cancer. METHODS: A total of 200 cases were selected from the records of the Department of Pathology, Hospital Tuanku Jaafar, Seremban, Malaysia. The samples were collected in three separate groups: cervicitis (n = 61), cervical intraepithelial neoplasia (n = 69), and cervical carcinoma (n = 70). The patients' demographic data and the respective paraffin-embedded tissue samples from Hospital Tuanku Jaafar, Seremban were obtained upon consent. The sample tissues were submitted for DNA extraction using G-spin Total DNA Extraction Kit. DNA obtained was then submitted for nested PCR before restriction enzyme digestion. RESULTS: SNP rs1883832 showed higher prevalence of T alleles in the cervical carcinoma group compared to the control groups and in rs3765459, a higher prevalence of G alleles in the cervical carcinoma group was noted. The results of rs1800686 and rs4810485 were insignificant. CONCLUSION: The data from our study indicates a potential association between the rs1883832 and rs3765459 CD40 gene polymorphism and susceptibility to cervical cancer.

The Protective Action of the Aqueous Extract of Auricularia polytricha in Paracetamol Induced Hepatotoxicity in Rats.

Natural antioxidant products are increasingly being used to treat various pathological liver injuries considering the role of oxidative stress in their pathogenesis. Auricularia polytricha has been used as food or medicine due to its antioxidant activity. The aim of the study was to evaluate the protective effect of the aqueous extract of the fruiting bodies of A. polytricha against paracetamol-induced liver toxicity in rats. Liver toxicity was induced in Sprague-Dawley rats by oral administration of 2g/kg paracetamol on the 15th day after the administration of aqueous extract and silymarin 100 mg/kg. Aqueous extract of A. polytricha was administered orally at 250 and 500 mg/kg doses, daily for a period of 14 days. Aspartate aminotransferase (AST), Alanine transaminase (ALT) and Alkaline phosphatase (ALP), Lactate dehydrogenase (LDH), Total bilirubin (TB), Total protein (TP), Triglycerides (TG) and cholesterol were measured to assess the effect of the extract on paracetamol-induced hepatic damage. The patent on Auricularia Polytricha (EP0413052A1) assisted in selecting the extraction procedure. The study also included histopathological examination of liver sections to assess hepatoprotective activity. Paracetamol significantly (P<0.001) increased the serum AST, ALT, ALP, LDH, TB, TG and cholesterol and decreased TP levels. Extract treatment significantly (P<0.001 to P<0.05) attenuated the paracetamol induced increase in AST, ALT, ALP, LDH, TB, TG and cholesterol and increased the diminished TP in a dose dependent manner. The standard drug, silymarin produced significant (P<0.001) decrease in AST, ALT, ALP, LDH, TB, TG and cholesterol and increase in TP. Histopathological examination of animals treated with paracetamol showed large areas of centrilobular necrosis with congestion and dilatation in both central and portal veins. These results indicate that the aqueous extract of A. polytricha has significant protective effect against paracetamol-induced liver toxicity in rats, due to its potent antioxidant activity.

Expression of P16 in high-risk human papillomavirus related lesions of the uterine cervix in a government hospital, Malaysia.

BACKGROUND: Cervical cancer is one of the most common cancers affecting women worldwide. It is well established that human papilloma virus (HPV) infection is the prime risk factor in the development of cervical cancer. The current screening and diagnostic tests have limitations in identifying the range of lesions caused by HPV. The current study aims to evaluate the diagnostic value of p16 immunohistochemical (IHC) investigation in high-risk human papillomavirus (HR-HPV) related lesions of the uterine cervix in Hospital Tuanku Jaafar, Seremban, Malaysia. METHODS: A total of 75 cases were selected from the records of Pathology services, Hospital Tuanku Ja'afar, Seremban. The samples were collected in three separate groups (n=25 per group) as Carcinoma cervix, Carcinoma in situ and Chronic cervicitis. The demographic data of the patients and the representative paraffin blocks were retrieved from Hospital Tuanku Ja'afar, Seremban. The immunohistochemical staining with p16 and HPV 16 L1 were done on all cases. The staining intensity and density were observed and compared among the three groups of cases. RESULTS: Immunohistochemistry of p16INK4A staining shows nil (0/25) expression in the cervicitis patients, 72% (18/25) in CIN patients and 100% (25/25) in cervical carcinoma. HPV 16 L1 was positive in 100% (25/25) of cervicitis patients, 96% (24/25) of CIN patients and 40% (10/25) of cervical cancers patients. A chi square test was used to analyze the result and the obtained p value was <0.05. CONCLUSION: p16 expression was strongly observed in cervical cancer and minimally observed in cervicitis. Thus indicating p16 immunohistochemistry investigations can aid in diagnosing the different categories of cervical lesions into benign, insitu and malignant. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_202.

Comparison of free hand versus ultrasound-guided fine needle aspiration of thyroid with histopathological correlation.

Fine-needle aspiration (FNA) cytology of the thyroid is usually performed on an outpatient basis. The results of FNA are operator dependent and may be affected by the lesion characteristics and the aspiration technique. In current practice ultrasound (US) is widely used to guide the needle for aspiration of nondominant nodules. Our study aimed to compare the free-hand FNA with US-guided FNA in the evaluation of thyroid nodules. A total of 91 cases of thyroid lesions were studied at the Department of Pathology, Karnataka Institute of Medical Sciences, Hubli, India. All the cases underwent free-hand and US-guided FNA. The cytological samples from both procedures were analyzed for adequacy, cytological features, and possible diagnosis. The results were correlated with histopathological diagnosis whenever possible. Of 91 aspirates, 89 were satisfactory and 2 were unsatisfactory on US-guided FNA, whereas 85 were satisfactory and 6 were unsatisfactory in free-hand FNA. Of 91 cases 68 (74.7%) were nonneoplastic lesions and 21 (23.1%) were neoplastic lesions in US-guided FNA, whereas 67 cases (73.6%) were nonneoplastic and 18 cases (19.8%) were neoplastic in free-hand FNA. Histopathological study was possible in 25 patients, among whom 15 lesions were nonneoplastic and 10 were neoplastic. Sensitivity and specificity of US-guided FNA to detect neoplastic lesions were 81.81% and 92.85%, respectively, compared with free-hand FNA, for which the sensitivity and specificity were 54.54% and 92.85%, respectively. The diagnostic accuracy of guided FNA was 88% against the 76% accuracy rate of free-hand FNA. US-guided FNA provides a better representative sample and has a higher diagnostic rate in the evaluation of thyroid lesions.