Background & Aims Genomic instability promotes colon carcinogenesis by inducing genetic mutations, but not all genes affected by this process have been identified. We investigated whether genomic instability in human colorectal cancer (CRC) cells produces mutations in the hepatocyte growth factor (HGF) gene. Methods We genotyped human colon tumor tissues and adjacent non-tumor tissues collected from 78 patients University of Pittsburgh Health Sciences and Veterans hospital, along with 40 human CRC and adjacent non-tumor tissues in a commercial microarray. We used cellular, biochemical, and molecular biological techniques to investigate the factors that alter HGF signaling in colon cancer cells and its effects on cell proliferation and survival. Results All tested human CRC tissues and cell lines that had microsatellite instability (MSI) contained truncations in the regulatory deoxyadenosine tract element (DATE) of the HGF gene promoter. The DATE was unstable in 14% (11/78) of CRC samples; DATE truncation was also polymorphic, and detected in 18% (13/78) of CRC tissues without MSI. In CRC cell lines, truncation of DATE activated expression of HGF, resulting in its autocrine signaling via MET. This promoted cell proliferation and resistance to necroptosis. HGF signaling via MET reduced levels of the receptor-interacting serine-threonine kinase 1 (RIPK1), a mediator of necroptosis, in CRC cells. High levels of HGF protein in tumor tissues correlated with lower levels of RIPK1 and shorter survival times of patients. Conclusions Thirty-one percent of CRC samples contain alterations in the DATE of the HGF promoter. Disruption of the DATE increased HGF signaling via MET and reduced levels of RIPK1 and CRC cell necroptosis. DATE alteration might be used as a prognostic factor or to select patients for therapies that target HGF-MET signaling.

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Objectives:To examine the usefulness of smoothelin -a new immunohistochemical (IHC) marker that is expressed predominantly in visceral smooth muscle -in recognizing muscularis propria (MP) in transurethral resection (TUR) and matched cystectomy specimens and to compare the pattern of its expression in muscularis mucosae (MM) and MP in radical cystectomy specimens. Methods: IHC staining for smoothelin was performed in 49 cases of urothelial carcinoma removed by radical cystectomy (16 had undergone TUR before the cystectomy). Results: In cystectomy specimens, smoothelin staining in the MP was strong (+3), moderate (+2) and weak (+1) in 49%, 44.9% and 6.1% of cases, respectively, whereas smoothelin positivity in the MM was absent and weak in 77.6% and 22.4% of cases, respectively. In TUR specimens, smoothelin immunoreactivity was moderate to strong in 68.8% and weak in 6.3% of cases and all of them proved to have MP invasion in cystectomy specimens. Conclusion:Smoothelin is a useful marker for the detection of MP in TUR specimens. Moderate to strong smoothelin staining of the muscles included in TUR specimens and split by the tumor is a sign of MP invasion. It may be useful in cancer staging and treatment decision making.

Endometriosis is a common disease characterized by the presence of ectopic endometrial tissue. Although the pathogenesis of endometriosis remains unclear, several factors have been implicated, including the dysregulation of homeobox ( HOX) genes. Our objective was to investigate the localization and immunoreactivity of HOXB4 in endometrial tissues from women with or without endometriosis. We studied samples of eutopic endometrium (EE), endometriomas (Eoma), superficial endometriosis (SE), and deep infiltrating endometriosis (DIE) from 34 women with endometriosis, as well as eutopic endometrium from 38 women without endometriosis (EC). HOXB4 localization and immunoreactivity was assessed using immunohistochemistry and histoscore analysis. Data were analyzed with and without stratification by menstrual cycle phase. HOXB4 protein was present in the nuclei of endometrial glandular epithelial cells but not in stromal cells. HOXB4 immunoreactivity was reduced in DIE samples compared to all other groups. A smaller reduction in HOXB4 immunoreactivity was observed in SE samples compared to EC samples. HOXB4 immunoreactivity was significantly greater in proliferative compared to secretory phase samples in the EC group but not in EE, Eoma, or DIE groups. Among only proliferative phase samples, HOXB4 immunoreactivity was reduced in EE, Eoma, and DIE groups compared to EC. Based on these data, we suggest that an impaired capacity of eutopic and ectopic endometrial tissue to upregulate levels of HOXB4 during the proliferative phase may play a role in the pathogenesis of endometriosis and that further downregulation of HOXB4 may enhance ectopic implant invasiveness.

Background: Gliomas represent the most frequent primary tumors of central nervous system (CNS), contributing to more than half of the incidence of brain tumors. Cancer stem cell markers (CSC) identify a group of patients at high risk for progression. Nestin is an intermediate fi lament (IF) protein was fi rst described as a neural stem cell/progenitor cell marker. Nestin-positive neuroepithelial stem cells are detected in the subventricular zone of the human adult brain and they remain mitotically active throughout adulthood. The expression of Nestin in gliomas has been suggested to be related to dedifferentiation, improved cell motility, invasive potential and increased malignancy. This study aims to investigate Nestin immunohistochemical expression in different types of glioma and its correlation with different clinicopathological parameters. Materials and Methods:Nestin immunostaining was studied in 60 specimens of glioma using avidinbiotin peroxidase method.Results: Nestin was strongly expressed in 11/60 (18.33%), moderately expressed in 29/60 (48.33%) and weekly expressed in 15/60 (25%) of studied gliomas. A signifi cant positive correlation was found between Nestin expression and histologic type (p< 0.001) and increasing grade of gliomas (p< 0.001). Conclusion:Increased Nestin expression is correlated with tumor progression, increasing grade, and poor prognostic parameter of glioma. Nestin is a useful marker for detection of CSC in high-grade glioma which is responsible for resistance to chemo-radiotherapy and may serve as a predictor for patient outcomes.