The ubiquitin-proteasome system is a major regulatory pathway of protein degradation and plays an important role in cellular division. Fbxw7 (or hCdc4), a member of the F-box family of proteins, which are substrate recognition components of the multisubunit ubiquitin ligase SCF (Skp1-Cdc53/ Cullin-F-box-protein), has been shown to mediate the ubiquitin-dependent proteolysis of several oncoproteins including cyclin E1, c-Myc, c-Jun, and Notch. The oncogenic potential of Fbxw7 substrates, frequent allelic loss in human cancers, and demonstration that mutation of FBXW7 cooperates with p53 in mouse tumorigenesis have suggested that Fbxw7 could function as a tumor suppressor in human cancer. Here, we carry out an extensive genetic screen of primary tumors to evaluate the role of FBXW7 as a tumor suppressor in human tumorigenesis. Our results indicate that FBXW7 is inactivated by mutation in diverse human cancer types with an overall mutation frequency of f6%. The highest mutation frequencies were found in tumors of the bile duct (cholangiocarcinomas, 35%), blood (T-cell acute lymphocytic leukemia, 31%), endometrium (9%), colon (9%), and stomach (6%). Approximately 43% of all mutations occur at two mutational ''hotspots,'' which alter Arg residues (Arg 465 and Arg 479 ) that are critical for substrate recognition. Furthermore, we show that Fbxw7Arg465 hotspot mutant can abrogate wild-type Fbxw7 function through a dominant negative mechanism. Our study is the first comprehensive screen of FBXW7 mutations in various human malignancies and shows that FBXW7 is a general tumor suppressor in human cancer.

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These findings suggest that indigenous bacteria, particularly lactobacilli, may have an impact on the colonization and growth of H. pylori strains in the stomach of Mongolian gerbils.

Biphasic squamoid alveolar renal cell carcinoma (BSARCC) has been recently described as a distinct neoplasm. Twenty-one cases from 12 institutions were analyzed using routine histology, immunohistochemistry, array comparative genomic hybridization (aCGH) and fluorescence in situ hybridization. Tumors were removed from 11 male and 10 female patients, whose age ranged from 53 to 79 years. The size of tumors ranged from 1.5 to 16 cm. Follow-up information was available for 14 patients (range, 1 to 96 mo), and metastatic spread was found in 5 cases. All tumors comprised 2 cell populations arranged in organoid structures: small, low-grade neoplastic cells with scant cytoplasm usually lining the inside of alveolar structures, and larger squamoid cells with more prominent cytoplasm and larger vesicular nuclei arranged in compact nests. In 9/21 tumors there was a visible transition from such solid and alveolar areas into papillary components. Areas composed of large squamoid cells comprised 10% to 80% of total tumor volume. Emperipolesis was present in all (21/21) tumors. Immunohistochemically, all cases were positive for cytokeratin 7, EMA, vimentin, and cyclin D1. aCGH (confirmed by fluorescence in situ hybridization) in 5 analyzable cases revealed multiple numerical chromosomal changes including gains of chromosomes 7 and 17 in all cases. These changes were further disclosed in 6 additional cases, which were unsuitable for aCGH. We conclude that tumors show a morphologic spectrum ranging from RCC with papillary architecture and large squamoid cells to fully developed BSARCC. Emperipolesis in squamoid cells was a constant finding. All BSARCCs expressed CK7, EMA, vimentin, and cyclin D1. Antibody to cyclin D1 showed a unique and previously not recognized pattern of immunohistochemical staining. Multiple chromosomal aberrations were identified in all analyzable cases including gains of chromosomes 7 and 17, indicating that they are akin to papillary RCC. Some BSARCCs were clinically aggressive, but their prognosis could not be predicted from currently available data. Present microscopic, immunohistochemical, and molecular genetic data strongly support the view that BSARCC is a distinctive and peculiar morphologic variant of papillary RCC.

The aim of the present study was to correlate molecular evidence of the presence of Helicobacter pylori in gastric biopsy samples, based on analysis of 1 6 s rDNA, vacuolating toxin (vacA), urease A (ureA) and cagA genes, with the clinical, histological and serological findings in patients with H. pylori-associated gastritis. Fresh biopsy samples were collected from the gastric antrum and corpus of 22 asymptomatic volunteers with or without H. pylori-associated gastritis. Total DNA was extracted from the biopsy material and subjected to 1 6 s rDNA PCR amplification, Southern blotting and 1 6 s rDNA sequence analysis of the PCR products. The vacA, ureA and cagA genes were characterised by PCR amplification and Southern blot analysis. Based on partial 1 6 s rDNA sequence analysis, DNA belonging to the genus Helicobacter was detected in gastric biopsy samples from 20 of 22 subjects, including seven of nine histologically and serologically normal controls. Six of 20 partial 16s rDNA sequences revealed variations within variable regions V3 and V4 that deviated from those of the H. pylori type strain ATCC 43SOT and, therefore, possibly represented other species of Helicobacter. VacA genes identical with those of the type strain were found predominantly in the subjects with H. pylori gastritis, and all the patients except one were found to be cagA-positive. There was no evidence of false positive PCR reactions. In conclusion, the PCR-based molecular typing methods used here were apparently too sensitive when applied to the detection of H. pylori in human gastric tissues. The lack of quantitative analysis makes them inappropriate as clinical tools for the diagnosis of H. pylori-associated gastritis, despite the fact that they provide a qualitative and sensitive tool for the detection and characterisation of H. pylori in the gastrointestinal tract.

Nasopharyngeal carcinoma (NPC) is an invasive cancer with particularly high incidence in Southern China and Southeast Asia. The study of NPC is greatly hampered by the lack of reliable cell lines due to the loss of EBV genome and HeLa cell contamination. Conditional reprogramming (CR) cell culture technique has been reported for rapid and efficient establishment of patient‐derived normal and tumor cell cultures. The purpose of this study was to assess this method to culture NPC patient‐derived primary tumor cells. Using CR protocol, we demonstrated that epithelial cells could be efficiently cultured from normal (70%) and cancerous nasopharyngeal (46%) biopsies. However, by comparing with original tumors in terms of mutation and methylation profiles, epithelial cells derived from cancerous biopsy represented non‐malignant cells. Further, they exhibited stem‐like characteristics based on their cell surface proteins and could differentiate into pseudostratified epithelium in an air–liquid interface culture system. We conclude that CR method is a highly selective and useful method for growing non‐malignant nasopharyngeal epithelial cells.

Spiradenoma is a benign, morphologically well-defined cutaneous adnexal neoplasm that is closely related to cylindroma. We present the rare occurrence of adenoid cystic carcinoma (ACC)-like areas in 7 spiradenomas and 1 spiradenocylindroma, not described in the English literature to date. The ACC-like areas were a minor but significant component in all lesions and were usually multifocal and blended with the conventionally appearing parts of the neoplasms. The ACC-like areas were typified by cribriform formations of epithelial cells concentrically arranged around gland-like spaces filled with mucin, homogeneous eosinophilic material, or granular basophilic material. In some neoplasms, only mucin occurred in these pseudoglandular structures, whereas in other cases, a combination of all 3 secretory products was encountered. Although well-developed bilayered glands with a demonstrable peripheral myoepithelial cell layer were not recognizable in the ACC-like areas, immunohistochemistry demonstrated myoepithelial differentiation in these portions of the tumors. When present in the ACC-like areas, ductal structures manifested a rather squamoid lining, without a recognizable peripheral myoepithelial cell layer. It is concluded that the ACC-like pattern, although a rare feature and of no clinical consequence, is a distinctive finding in a minority of cases and extends the morphological spectrum of spiradenoma and spiradenocylindroma occurring sporadically or in the setting of Brooke-Spiegler syndrome. It represents a potential diagnostic pitfall, particularly in a limited biopsy specimen where the changes may be misdiagnosed as ACC.