MicroRNA 3928 Suppresses Glioblastoma through Downregulation of Several Oncogenes and Upregulation of p53.

Glioblastoma (GBM) is the most frequent and lethal primary malignant brain tumor. Despite decades of research, therapeutic advances that significantly prolong life are non-existent. In recent years, microRNAs (miRNAs) have been a focus of study in the pathobiology of cancer because of their ability to simultaneously regulate multiple genes. The aim of this study was to determine the functional and mechanistic effects of miR-3928 in GBM both in vitro and in vivo. To the best of our knowledge, this is the first article investigating the role of miR-3928 in GBM. We measured endogenous miR-3928 expression levels in a panel of patient-derived GBM tissue samples and cell lines. We found that GBM tissue samples and cell lines express lower levels of miR-3928 than normal brain cortex and astrocytes, respectively. Therefore, we hypothesized that miR-3928 is a tumor suppressive microRNA. We verified this hypothesis by showing that exogenous expression of miR-3928 has a strong inhibitory effect on both cell growth and invasiveness of GBM cells. Stable ex vivo overexpression of miR-3928 in GBM cells led to a reduction in tumor size in nude mice xenografts. We identified many targets (MDM2, CD44, DDX3X, HMGA2, CCND1, BRAF, ATOH8, and BMI1) of miR-3928. Interestingly, inhibition of the oncogene MDM2 also led to an upregulation of wild-type p53 expression and phosphorylation. In conclusion, we find that miR-3928, through the downregulation of several oncogenes and upregulation and activation of wild-type p53, is a strong tumor suppressor in GBM. Furthermore, the fact that miR-3928 can target many important dysregulated proteins in GBM suggests it might be a "master" regulatory microRNA that could be therapeutically exploited.

HGF/MET Signaling in Malignant Brain Tumors.

Hepatocyte growth factor (HGF) ligand and its receptor tyrosine kinase (RTK) mesenchymal-epithelial transition factor (MET) are important regulators of cellular processes such as proliferation, motility, angiogenesis, and tissue regeneration. In healthy adult somatic cells, this ligand and receptor pair is expressed at low levels and has little activity except when tissue injuries arise. In cancer cells, HGF/MET are often overexpressed, and this overexpression is found to correlate with tumorigenesis, metastasis, and poorer overall prognosis. This review focuses on the signaling of these molecules in the context of malignant brain tumors. RTK signaling pathways are among the most common and universally dysregulated pathways in gliomas. We focus on the role of HGF/MET in the following primary malignant brain tumors: astrocytomas, glioblastomas, oligodendrogliomas, ependymomas, and embryonal central nervous system tumors (including medulloblastomas and others). Brain metastasis, as well as current advances in targeted therapies, are also discussed.

An appraisal of lymph node ratio in colon and rectal cancer: not one size fits all.

BACKGROUND: Lymph node ratio (LNR) is increasingly accepted as a useful prognostic indicator in colorectal cancer. However, variations in methodology, statistical stringency and cohort composition has led to inconsistency in respect of the optimally prognostic LNR. OBJECTIVE: The aim was to apply a robust regression-based analysis to generate and appraise LNRs optimally prognostic for colon and rectal cancer, both separately and in combination. METHODS: LNR was established for all patients undergoing either a colonic (n = 379) or rectal (n = 160) cancer resection with curative intent. The optimal LNR associated with disease-free and overall survival were established using a classification and regression tree technique. This process was repeated separately for patients who underwent either colonic or rectal resection and for the combined cohort. Survival associated with differing LNR was estimated using the Kaplan-Meier method and compared using a log-rank test. Relationships between LNR, disease-free survival (DFS) and overall survival (OS) were further characterised using Cox regression analysis. All statistical analyses were conducted in the R programming environment, with statistical significance was taken at a level of p < 0.05. RESULTS: Optimal LNRs differed between each cohort, when either overall or disease-free survival was considered. LNRs generated from combined cohorts also differed from those generated by individual cohorts. In relation to DFS, LNR values were obtained and included 0.18 for the colon cancer cohort and 0.19 for the rectal and combined colorectal cancer cohorts. In relation to OS, multiple LNR values were obtained for colon and combined cohorts; however, an optimal LNR was not evident in the rectal cancer cohort. Survival patterns according to LNR closely resembled those associated with standard nodal staging. CONCLUSION: Application of a data-driven approach based on recursive partitioning generates differing lymph node ratios for colon, rectal and combined colorectal cohorts. In each cohort, LNR was similarly prognostic to standard nodal staging in respect to overall and disease-free survival. Overall survival was associated with a multiplicity of LNR values, whilst disease-free survival was associated with a single LNR only. The paper demonstrates the merits of utilising a data-driven approach to determining lymph node ratios from specific patient cohorts. Utilising such an approach enabled the generation of those LNRs that were most associated with particular survival trends in relation to overall and disease-free survival. These differed markedly for colon cancer, rectal cancer and combined cohorts. In general, the survival patterns associated with LNRs generated were similar to those observed with standard nodal staging.

Comparison of microsatellite instability, CpG island methylation phenotype, BRAF and KRAS status in serrated polyps and traditional adenomas indicates separate pathways to distinct colorectal carcinoma end points.

The aim of this study was to compare BRAF and KRAS, CpG island methylator phenotype (CIMP), and microsatellite instability (MSI) status in each of the histologic categories, including end-point carcinomas with residual adenoma, of the serrated polyp neoplasia pathway and the traditional (nonserrated) adenoma-carcinoma sequence. Deoxyribonucleic acid (DNA) was extracted from the selected samples and assayed for BRAF, KRAS2 codon12, 13, CIMP using markers hMLH1, MGMT, MINT1, MINT2, p16, and MSI using an assay for BAT25 and BAT26. A BRAF mutation was present in 82% of serrated carcinomas (SCas), 62% of serrated adenomas (SAs), 83% of serrated polyps with abnormal proliferation (SPAPs-syn. sessile serrated adenoma [SSA]), 76% of microvesicular serrated polyps (MVSPs), and was not found in any of the histologic categories of the traditional adenoma-carcinoma sequence. KRAS2 mutations were found in 43% of the goblet cell serrated polyp (GCSP) category, 13% of MVSPs, 7% of SPAPs, and 24% of SAs; in 26% of large traditional adenoma (lTAs) compared with small traditional adenomas (sTAs) (0/30; P<0.005) and in 37.3% of traditional carcinomas (TCa). CIMP-H (>1 marker positive) was significantly more frequent in SPAP, SA, and SCa compared with MVSP (P<0.05); CIMP-H was present in 10% of sTAs but was found more frequently in lTA (44.4%; OR 7.2; P=0.007) and TCa (38.9%; OR 5.8; P=0.007). Higher CIMP levels (4 or more markers positive) were significantly more frequent in advanced categories of the serrated pathway (SAs [31%] and SCas [30%]) compared with lTAs [0%] and TCAs [3.4%] (OR 12.2; P=0.02). MSI-H was identified only in the adenocarcinoma component of SCas (9/11) or in the contiguous SAs (3/7). The findings indicate that a BRAF mutation is a specific marker for a serrated polyp pathway that has its origin in a hyperplastic polyp (MVSP) and a potential end point as MSI carcinoma. CIMP-High (CIMP-H) develops early in this sequence and MSI-H develops late. The data provided a less complete picture of a second serrated pathway, identified by a KRAS2 mutation in SAs, but showed that the progressive stages of both iterations of the serrated neoplasia pathway are separate and distinct from those of the traditional adenoma-carcinoma sequence.

Prostate cancer metastasis to calcaneus: a solitary lesion at an atypical site, dormant for more than 10 years.

In prostate cancer patients, if bone scan demonstrates a solitary lesion in atypical area, this is possibly an indication of metastatic disease. Therefore, biopsy confirmation is required to determine the nature of the abnormality and therefore dictates further staging investigations and treatment options.

Hyperplastic (serrated) polyps of the colorectum: relationship of CpG island methylator phenotype and K-ras mutation to location and histologic subtype.

We investigated the frequency of promoter region CpG island methylation (CIM) of hMLH1, MGMT, MINT1, MINT2, and p16 and K-ras mutations in a total of 79 hyperplastic (serrated) polyps (HPs) from 75 patients and correlated the molecular profiles to polyp location in the colorectum, histologic variation, and other factors. Methylation-specific PCR (MS-PCR) was used to assay CIM status. HPs that showed CIM of one or more or two or more of the genes assayed were classified as CpG island methylator phenotype (CIMP) and CIMP-high (CIMP-H), respectively. PCR restriction fragment length polymorphism was used to assay K-ras codon 12 and 13 mutations. Logistic regression indicated a statistically significant trend for increasing odds for CIMP (P = 0.002) and CIMP-H (P < 0.001) according to proximity to the cecum or distance from the rectum. Conversely, K-ras codon 12 mutation was present in 13 of 40 (32.5%) distally located HPs compared with 2 of 39 (5.1%) proximal HPs (P = 0.006). Histologic subtype distribution varied by proximal and distal locations. Frequency of CIMP in serrated polyps with abnormal proliferation (SPAPs), differed significantly from goblet cell serrated polyps (GCSPs) (24 of 26, 92.3% vs. 6 of 13, 46.2%) (P = 0.003) and microvesicular serrated polyps (MVSPs) (26 of 38, 68.4%) (P = 0.03). Frequency of K-ras mutation in GCSPs (7 of 13, 54%) differed from that of MVSPs (6 of 38, 16%) (P = 0.01) and SPAPs (2 of 26, 8%) (P = 0.003). Location in the colorectum and histologic subtype were major determinants of the molecular profile of HPs. The molecular findings of CIMP and K-ras mutations appear to encompass most if not all HPs; CIMP profiles suggest that SPAP is the most advanced morphologic variant. We postulate that MVSP and GCSP may be precursor lesions that, if proximally located or larger, can progress to SPAP. Frequent K-ras mutations and infrequent CIMP distinguish the distal GCSP variant.

Ureteric obstruction due to fungus-ball in a chronically immunosuppressed patient.

Candida albicans is a fungus that can cause opportunistic urinary tract infections in immunocompromised patients. Disseminated fungaemia secondary to Candida albicans is associated with considerable mortality and therefore merits aggressive treatment. Diagnostic investigations for urosepsis and disseminated fungaemaia secondary to Candida albicans include positive urine and blood cultures. Herein, we describe an extremely unusual case of disseminated fungaemia associated with an obstructive fungus-ball in the distal ureter of an immunosuppressed patient. We also describe a novel application of an established endourological technique for managing this clinical scenario and discuss appropriate perioperative management strategies.