Frequent EGFR mutations in noninvasive bronchioloalveolar carcinoma

Mutations of the epidermal growth factor receptor gene (EGFR) have been reported to be present in a considerable fraction of lung adenocarcinomas showing dramatic response to EGFR tyrosine kinase inhibitors. To clarify pathogenic significance of the mutations for the development of lung adenocarcinoma, we investigated stage I lung adenocarcinomas for the mutations. First, 107 cases of macrodissected stage I adenocarcinomas were examined for mutations in exons 18-21 of the EGFR gene. EGFR mutations were detected in 36 of the 107 cases (34%). In particular, among the stage I cases, the mutations were detected in 17 of 42 small-sized adenocarcinomas (相似文献   

Complete Inhibition of SIVmac Replication by its Capsid Mutants

Mutations were introduced into a genomic region encoding the C-terminal portion of Gag capsid protein of pathogenic simian immunodeficiency virus (SIVmac239). All the mutants generated were defective for virion production and were non-infectious for monkey cells. They all efficiently suppressed the replication of wild type SIVmac in monkey cells. These results were in good agreement with those obtained for human immunodeficiency virus type 1, showing the importance of SIV/monkey model system for studies on Gag. This revised version was published online in July 2006 with corrections to the Cover Date.     

Gag–Pol Region Determines the Tropism of SIVagm for Human Cells

Simian immunodeficiency virus isolated from African green monkeys (SIVagm) does not grow in many of human cell lines such as CEM×174, H9, and MT-4, but could replicate in some human cell lines. Sequence of SIVagm responsible for its narrow host range was determined by making and monitoring growth potential of chimeric clones between SIVagm and human immunodeficiency virus type 1 (HIV-1). The results obtained indicated that the gag–pol region determines the observed narrow host range. By monitoring virus DNA synthesis and progeny virion production, the defect(s) of SIVagm in the replication in the restricted cells was demonstrated to be located at early phase. This revised version was published online in August 2006 with corrections to the Cover Date.     

Rituximab was effective on refractory thrombotic thrombocytopenic purpura but induced a flare of hemophagocytic syndrome in a patient with systemic lupus erythematosus

We report the case of a patient with systemic lupus erythematosus (SLE) who first revealed hemophagocytic syndrome (HPS), which was treated successfully with glucocorticoid and intravenous cyclophosphamide. The patient then demonstrated refractory thrombotic thrombocytopenic purpura (TTP) with normal a disintegrin and metalloprotease with thrombospondin motifs (ADAMTS)-13 activity that responded well to rituximab. After rituximab treatment, the patient showed a flare of HPS that was controlled by additional intravenous cyclophosphamide treatment. This case showed that TTP with normal ADAMTS-13 activity is B-cell dependent and indicated that B-cell depletion might exacerbate some autoimmune conditions in SLE.     

A catalog of genes homozygously deleted in human lung cancer and the candidacy of PTPRD as a tumor suppressor gene

A total of 176 genes homozygously deleted in human lung cancer were identified by DNA array‐based whole genome scanning of 52 lung cancer cell lines and subsequent genomic PCR in 74 cell lines, including the 52 cell lines scanned. One or more exons of these genes were homozygously deleted in one (1%) to 20 (27%) cell lines. These genes included known tumor suppressor genes, e.g., CDKN2A/p16, RB1, and SMAD4, and candidate tumor suppressor genes whose hemizygous or homozygous deletions were reported in several types of human cancers, such as FHIT, KEAP1, and LRP1B/LRP‐DIP. CDKN2A/p16 and p14ARF located in 9p21 were most frequently deleted (20/74, 27%). The PTPRD gene was most frequently deleted (8/74, 11%) among genes mapping to regions other than 9p21. Somatic mutations, including a nonsense mutation, of the PTPRD gene were detected in 8/74 (11%) of cell lines and 4/95 (4%) of surgical specimens of lung cancer. Reduced PTPRD expression was observed in the majority (>80%) of cell lines and surgical specimens of lung cancer. Therefore, PTPRD is a candidate tumor suppressor gene in lung cancer. Microarray‐based expression profiling of 19 lung cancer cell lines also indicated that some of the 176 genes, such as KANK and ADAMTS1, are preferentially inactivated by epigenetic alterations. Genetic/epigenetic as well as functional studies of these 176 genes will increase our understanding of molecular mechanisms behind lung carcinogenesis. © 2010 Wiley‐Liss, Inc.     

Identification of preneoplastic lesions as mucin-depleted foci in patients with sporadic colorectal cancer

In experimental models, mucin-depleted foci (MDF), formed by dysplastic crypts devoid of mucin production have been recognized to be correlated with colorectal carcinogenesis and to serve as preneoplastic lesions of colorectal cancer (CRC). In humans, there is only one report of identification of MDF in patients with familial adenomatous polyposis and CRC; however, the histological characteristics of human MDF are not discussed extensively in the report. In the present study, colonic samples from 53 patients with sporadic CRC were stained with Alcian blue and examined for the presence of MDF. Subsequently, the samples were examined for the presence of aberrant crypt foci (ACF) by methylene blue staining. We classified MDF into two categories: flat-MDF and protruded-MDF (having the characteristics of both ACF and MDF). We found a total of 354, 41 and 19 colonic mucosal lesions with a mean multiplicity of 44, 38.9 and 66.9 crypts (ACF, flat-MDF and protruded-MDF, respectively). The density of MDF was 0.0082 lesions/cm(2) . The ACF identified in sporadic CRC patients corresponded to hyperplastic or non-dysplasic lesions. However, MDF identified in these patients corresponded to low-grade dysplasia. In addition, we found that Paneth cell metaplasia and inflammatory cell infiltration were specific histological features of MDF. These histological characteristics are reported to be associated with the development of CRC. Therefore, our results indicate that MDF might represent preneoplastic lesions in human colorectal carcinogenesis.     

Pre-neoplastic lesion, mucin-depleted foci, reveals de novo high-grade dysplasia in rat colon carcinogenesis

Aberrant crypt foci (ACF) and mucin-depleted foci (MDF) have recently been recognized as pre-neoplastic lesions in the colon of carcinogen-treated rodents. In the present study, we analyzed the sequential development of ACF and MDF histopathologically in the colon of rats from 5 to 40 weeks after DMH treatment. The numbers of ACF per colon increased over time during the experiment, and were much higher than the number in tumors, while the number of MDF per colon remained unchanged from the early stage (the 5th week after carcinogen exposure), and approximate to those in tumors. The incidence of ACF, which was much higher than that of tumors, also increased gradually in a time-dependent manner. The incidence of MDF, however, was similar to that of tumors and did not change significantly during the whole experiment. No lesion as dysplasia with high-grade (DHG) or adenocarcinoma (AC) were found in any large ACF from the 5th to 40th week histopathologically, whereas all of the large MDF showed DHG or AC features. Even at 5 weeks, MDF showed features of DHG. We classified these into two forms of MDF: flat and protruded MDF. At 40 weeks, the number of flat MDF per colon decreased significantly compared with that at 20 weeks (p<0.05), however, the number of protruded MDF per colon increased (p<0.01), and the percentage of DHG in a protruded MDF lesion decreased but that of AC increased remarkably. In conclusion, MDF may develop into cancer through the so-called 'de?novo cancer' pathway.