Squamous cell carcinoma of the thyroid: an aggressive tumor associated with tall cell variant of papillary thyroid carcinoma. (17/435)

Squamous cell carcinoma of the thyroid (SCT) is an unusual neoplasm thought to arise as a primary tumor or as a component of an undifferentiated carcinoma. The role of p53 and Ki-67 as prognostic indicators in this type of tumor is not known. We studied eight cases of primary SCT. Three cases were analyzed for Ki-67 by immunohistochemistry and for p53 by immunohistochemistry and loss of heterozygosity. Seven patients were women, and one was a man (age range, 31 to 90 years). SCT were firm, were tan with areas of necrosis, and ranged in size from 2 to 8 cm. Histologically, they had islands of squamous cells with spindle cell areas (two of eight). In four of eight cases, SCT was associated with the tall cell variant of papillary carcinoma (TCV). Positive staining for p53 was seen in two of three cases, and in one of three the TCV was also positive for p53. Mean MIB1 labeling index was 30% and 17% in SCT and TCV, respectively. At the time of presentation, six of eight patients had cervical lymph node metastases. In one case, the primary tumor had SCT and TCV; however, only the SCT component metastasized. After mean follow-up of 48 months, one patient had died of disease, five were alive with recurrent or metastatic tumor, and two were lost to follow-up. Primary SCT is an aggressive neoplasm that may be found in association with TCV. p53 expression and high MIB1 labeling index occur in these tumors and may be useful prognosticators.  (+info)

Molecular genetic changes in metastatic primary Barrett's adenocarcinoma and related lymph node metastases: comparison with nonmetastatic Barrett's adenocarcinoma. (18/435)

Lymph node metastasis is one of the strongest negative prognostic factors for patients with Barrett's adenocarcinoma (BCA). However, despite the importance of the metastatic process in BCA, the molecular basis of it remains poorly understood. To search for cytogenetic events associated with metastasis in regional or distant lymph nodes in BCA, we investigated 8 primary BCA and their lymph node metastases and compared them with 18 nonmetastatic BCA. In metastatic primary BCA, we observed significantly more DNA gains on 3q (P = .013), 17q (P = .019), and 22q (P = .021) compared with nonmetastatic primary BCA. No statistically significant correlation could be observed between DNA copy number changes and the histopathologic stage, grade, or survival (P > .05). The most frequent alteration observed only in lymph node metastases but not in the related primary tumor was loss of 2q (5 of 8). Coamplification of 7p and chromosome 17 was found in 6 of 8 lymph node metastases. A comparison of DNA copy number changes between primary tumors and their corresponding metastases indicated a high degree of genetic heterogeneity. Fluorescence in situ hybridization analysis demonstrated the involvement of the Her-2/neu gene in primary BCA and its related lymph node metastases. Each of the investigated primary tumors and related lymph node metastases also showed striking heterogeneity with respect to Her-2/neu, with several areas displaying different levels of amplification. In summary, our data indicate that DNA copy number changes on 2q, 3q, 7p, 17q, and 22q may be involved in the metastatic process in BCA. Furthermore, the striking genetic heterogeneity that we found between primary BCA and its lymph node metastases may underlie BCA's poor responsiveness to therapy and could help explain why prognostic biomarkers measured exclusively in primary tumors give an incomplete view of the biologic potential of BCA.  (+info)

Topographical distributions of allelic loss in individual non-small-cell lung cancers. (19/435)

Non-small-cell carcinomas of the lung, especially adenocarcinomas, are characterized by a high degree of morphological heterogeneity. As carcinogenesis has been suggested to be a multistep process involving sequential accumulation of multiple genetic alterations, morphological heterogeneity may represent a cross-sectional view of genetic alterations within individual tumors. We therefore examined the topographical distribution of loss of heterozygosity (LOH) events within 10 non-small-cell lung cancers to investigate whether, and which, genetic alterations are accumulated in relation to morphological progression. LOH at the TP53, 17p13.3, and 3p loci was detected in six, eight, and six of 10 informative cases, respectively. In each case, all portions of the tumor shared concordant LOH despite morphological diversity. In contrast, distributions of LOH at 2q, 9p, and 22q, which have been reported to be associated with the advanced stages of tumors, were divergent in two of three, four of eight, and one of one cases with LOH, respectively. In these cases, presence of LOH was mostly related to the morphological tumor grades. These findings suggest the accumulative feature of genetic alterations in particular loci that can be seen even in individual tumors. Furthermore, the present study indicated that cross-sectional examination of individual tumors is also important for better understanding of molecular pathogenesis of lung cancers.  (+info)

Lymphomas with follicular and monocytoid B-cell components. Evidence for a common clonal origin from follicle center cells. (20/435)

We investigated the clonal relationship between follicular center cell and monocytoid B-cell components of non-Hodgkin lymphoma by isolating the components and comparing the nucleotide sequences of the complementarity-determining region (CDR)3 of the rearranged immunoglobulin heavy chain (IgH) gene. Paraffin blocks from 4 cases with amplifiable DNA using the polymerase chain reaction (PCR) were identified. Multiple representative cell clusters of the 2 components were obtained by microdissection, and the IgH CDR3 was amplified using a seminested PCR. Most of the PCR products obtained from both tumor components in each case had identical lengths when analyzed with polyacrylamide gel electrophoresis (PAGE) and identical migratory patterns on denaturing gradient gel electrophoresis (DGGE). These findings indicate sequence identity of the IgH CDR3 of both tumor components. Sequence analysis showed that point mutations were responsible for bands from the same case that had nonidentical migratory patterns by DGGE. The components in each of the 4 cases studied have the same clonal origin. Intraclonal sequence variations in the IgH gene were observed in 2 cases, consistent with the presence of continued somatic hypermutation after establishment of the clone. The expression of CD10 and bcl-2, as well as the detection of bcl-2 rearrangements in 2 cases, indicate that these lymphomas are of follicular center cell origin.  (+info)

Mutations in beta-catenin and APC genes are uncommon in esophageal and esophagogastric junction adenocarcinomas. (21/435)

Beta-catenin plays important roles in both intercellular adhesion and signal transduction. Mutations in the beta-catenin or adenomatous polyposis coli (APC) gene can alter the degradation of beta-catenin and cause aberrant accumulation of beta-catenin result in increased transcription of target genes. The dysregulated APC/beta-catenin pathway has been recently discovered as an important mechanism of tumorigenesis in various cancers, but its role in esophageal adenocarcinomas is not clear. Therefore, we studied the beta-catenin gene mutation, allelic loss of chromosome 5q, and APC gene mutation in esophageal and esophagogastric junction adenocarcinomas. Two (2%) somatic mutations in exon 3 of the beta-catenin gene, encompassing the region for glycogen synthase kinase-3beta phosphorylation, were detected from 109 adenocarcinomas. Chromosomal allelic loss on 5q was frequent in 45.3% (44/97) of tumors. Only one missense mutation in the mutation cluster region of the APC gene was detected from 38 esophageal and esophagogastric junction adenocarcinomas with the 5q allelic loss. Our results based on partial screening mutational analyses indicate that mutations of APC/beta-catenin pathway, unlike in colorectal carcinoma, involve only a small subset of esophageal and esophagogastric junction adenocarcinoma.  (+info)

Most marginal zone B cells in rat express germline encoded Ig VH genes and are ligand selected. (22/435)

The present study was performed to analyze whether marginal zone B (MZ-B) cells in nondeliberately immunized adult rats are selected on basis of the specificity of their B cell receptor, and to determine to what extent memory B cells contribute to the MZ-B cell subset. To this end, the Ig PC7183 V(H) gene repertoire was studied among V(H)DJ(H)-mu transcripts expressed in four sequential stages of B cell development, of two individual untreated adult rats. B cell subsets, i.e., pro/pre-B cells and newly formed B (NF-B) cells from bone marrow, and recirculating follicular B cells and MZ-B cells from spleen were sorted by flow cytometry. In addition, from one these rats, cells were microdissected from follicular and MZ areas of the spleen and productive PC7183 V(H) gene rearrangements were analyzed for the presence of somatic mutations. Sequence analysis reveals that most MZ-B cells in the adult rat, either defined by flow cytometry or by their anatomical location in the spleen, express germline encoded V(H) genes (naive MZ-B cells) and a minor fraction (about 20%) of the MZ-B cells carry somatic mutations (memory MZ-B cells). In addition, we show that naive MZ-B cells are a selected population of cells, both based on PC7183 V(H) gene repertoire and on the length of the Ig heavy (H) chain complementarity-determining region 3 (H-CDR3) region, i.e., PC7183 V(H)DJ(H)-mu transcripts of MZ-B cells carry significantly shorter H-CDR3 regions than other B cell subsets.  (+info)

Stepwise unfolding of titin under force-clamp atomic force microscopy. (23/435)

Here we demonstrate the implementation of a single-molecule force clamp adapted for use with an atomic force microscope. We show that under force-clamp conditions, an engineered titin protein elongates in steps because of the unfolding of its modules and that the waiting times to unfold are exponentially distributed. Force-clamp measurements directly measure the force dependence of the unfolding probability and readily captures the different mechanical stability of the I27 and I28 modules of human cardiac titin. Force-clamp spectroscopy promises to be a direct way to probe the mechanical stability of elastic proteins such as those found in muscle, the extracellular matrix, and cell adhesion.  (+info)

Protein migration into nuclei. II. Frog oocyte nuclei accumulate a class of microinjected oocyte nuclear proteins and exclude a class of microinjected oocyte cytoplasmic proteins. (24/435)

Nuclear contents or cytoplasm from Xenopus oocytes labeled with (35-S)methionine or (3-H)proline (donor oocytes) were reinjected into unlabeled oocytes (recipient oocytes). The radioactivity injected as nuclear contents was found to enter and accumulate in the recipient oocyte nucleus. In contrast, the radioactivity injected as cytoplasm was found to enter but not to accumulate in the recipient oocyte nucleus. Sodium dodecyl sulfate (SDS) gel electrophoresis of the nucleus and cytoplasm of donor oocytes revealed the existence of three classes of labeled proteins in these oocytes: those proteins found predominantly in the nucleus (N proteins), those found predominantly in the cytoplasm (C proteins), and those found in both the nucleus and cytoplasm at similar concentrations (B proteins). SDS gel electrophoresis of the nucleus and cytoplasm of recipient oocytes showed that N proteins entered and accumulated in the nucleus but that B proteins partitioned about equally between the nucleus and cytoplasm. A similar analysis of oocytes injected with labeled cytoplasm showed that C proteins did not enter the nucleus but again B proteins partitioned about equally between the nucleus and cytoplasm.  (+info)