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Purpose: Lung cancer cells frequently exhibit marked chromosome instability. We postulated that alterations of the double-strand break repair genes (BRCA1, BRCA2, and XRCC5) might be involved in lung cancer. Patients and Methods: We examined the loss of protein and mRNA expression and the 5 ¶CpG hypermethylation and allelic imbalance of the BRCA1, BRCA2, and XRCC5 genes in 98 non^small cell lung cancer (NSCLC) samples. Anchorage-dependent growth after reexpression of these genes was examined in a lung cancer cell line that originally lacked BRCA1and BRCA2 expression. Results: The data indicated that low protein expression of BRCA1 and BRCA2 was frequent in lung adenocarcinomas (42-44%), whereas low XRCC5 protein expression was more prevalent among squamous cell carcinoma (32%). In addition, low BRCA1 expression was significantly associated with low RB expression, especially in lung adenocarcinoma. Concurrent alterations in XRCC5 and p53 were the most frequent profiles in smoking patients. Importantly, low mRNA and protein expressions of BRCA1, BRCA2, and XRCC5 were significantly associated with their promoter hypermethylation. 5-Aza-2 ¶-deoxycytidine treatment of NSCLC cells showed demethylation and reexpression of the BRCA1 and BRCA2 genes and reduced anchorageindependent growth. Conclusions: Our retrospective study provides compelling evidence that low mRNA and protein expression in the BRCA1/BRCA2 and XRCC5 genes occur in lung adenocarcinoma and squamous cell carcinoma, respectively, and that promoter hypermethylation is the predominant mechanism in deregulation of these genes. Alteration of the double-strand break repair pathway, perhaps by interacting with p53 and RB deregulation, is important in the pathogenesis of a subset of NSCLC.Lung cancer is one of the most common malignancies, making it very important to identify the associated gene(s) involved. We previously did a genome-wide loss of heterozygosity (LOH) study in 71 primary surgically resected non -small cell lung cancer (NSCLC) tumors in which a high mean LOH frequency was reported, indicating the presence of chromosome instability in NSCLC (1). Chromosome instability may be caused by failure in the repair of DNA double-strand breaks (DSB; ref. 2). Interestingly, the chromosome regions at 2q33-35 and 13q12.3, which included gene loci encoding the XRCC5 (Ku80) and BRCA2 (breast cancer 2) DSB repair proteins, respectively, showed a high frequency of LOH in NSCLC tumors (1). We therefore postulated that alterations of genes in chromosomal stability control pathways, such as DSB repair genes (BRCA1, BRCA2, and XRCC5), may be involved in NSCLC tumorigenesis.Two distinct and complementary mechanisms, homologous recombination and nonhomologous end joining, are involved in the repair of detrimental DSBs in mammalian cells (2, 3). The breast tumor suppressors BRCA1 and BRCA2 have been shown to interact with DNA damage -induced Rad51 protein to form foci on DSBs (4, 5). Mouse Brca1-and Brca2-deficient embryonic stem cells show a reduced efficiency ...

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Sixty-eight patients with thoracic lesions (48 with lung cancer and 20 with benign lesions) underwent color Doppler ultrasound (US) examinations. Of those, 21 patients (13 with lung cancer and eight with benign lesions) also received resections, and the correlation between color Doppler US signals and resected histologic specimens was evaluated. Our results showed that three patterns of color Doppler US signals could be detected and confirmed: pulsatile flow (artery), constant flow, and triphasic flow (pulmonary vein). Among the 48 patients with lung cancer, pulsatile flow, constant flow, and/or triphasic flow were detected in 34 (71%), 24 (50%), and 14 (29%), respectively. Among the 20 patients with benign lesions, only pulsatile flow and/or triphasic flow were detected in nine (45%) and eight (40%), respectively. From the correlation between color Doppler US signals and histologic specimens, constant flow was representative of the true neovascularity of lung cancers, and it was valuable for differentiating lung cancers from benign lesions (p = 0.00008, sensitivity = 0.50, and specificity = 1.0). Although color Doppler US still had some limitations in detecting blood vessels in thoracic lesions, the correlation between the vascularity represented by color Doppler US signals and histologic specimens was excellent. We conclude that color Doppler US is a valuable method for assessing blood flow in thoracic lesions and differentiating lung cancers from intrapulmonary benign lesions.

An intratracheal instillation technique was developed which permits the repeated administrations of precise volumes of particulate suspension into mouse lungs. Benzo(a)pyrene (BP) adsorbed to ferric oxide was used to test the feasibility of the method. The majority of the animals survived 4 weekly treatments. Histological and fresh tissue sections showed extensive penetration of both chemicals into the lung parenchyma; however, while BP was eliminated from the organ rapidly, the ferric oxide was retained for over a 100 days. These dust particles were observed inside macrophages collected around terminal bronchioles and lymphoid tissues of the lungs.

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With careful patient selection, the hepatitis viral status does not influence the surgical risks of hepatectomy for HCC. After liver resection for HCC, the long-term survival rate of patients seronegative for HBsAg is greater than that of patients seropositive for HBsAg.

Grb2-associated binder 1 (Gab1) is known to play an important role in hepatocyte growth factor (HGF) signaling, which rapidly becomes tyrosine-phosphorylated upon HGF stimulation. In this study, we found that the tyrosine phosphorylation of Gab1 in the cells derived from Src/Yes/Fyn null mouse embryos was ϳ40% lower than that in their wild type counterparts upon HGF stimulation. Increased expression of wild-type Src enhanced HGF-induced phosphorylation of Gab1, and, in contrast, expression of the Src kinase-deficient mutant or treatment of the specific Src inhibitor PP1 suppressed it. Expression of a constitutively active Src mutant (Y527F) or oncogenic v-Src led to a prominent increase in Gab1 phosphorylation independent of HGF stimulation. Moreover, Src interacted with Gab1 via both its Src homology 2 and 3 domains and was capable of phosphorylating purified Gab1 in vitro. Finally, the increased phosphorylation of Gab1 by Src selectively potentiated HGF-induced activation of ERK and AKT. Taken together, our results establish a new role for Src in HGF-induced Gab1 phosphorylation.