Adjuvant chemotherapy with uracil-tegafur improves survival among patients with completely resected pathological stage I adenocarcinoma of the lung.

Although our predetermined criterion for specificity was not statistically confirmed, radiological diagnosis of noninvasive lung cancer with a thin-section computed tomography scan corresponded well with pathological invasiveness. Radiological noninvasive peripheral lung adenocarcinoma could be defined as an adenocarcinoma ≤2.0 cm with ≤0.25 consolidation.

ILD was relatively common in these Japanese patients with NSCLC during therapy with gefitinib or chemotherapy, being higher in the older, smoking patient with preexisting ILD or poor performance status. The risk of developing ILD was higher with gefitinib than chemotherapy, mainly in the first 4 weeks.

Hyperhomocysteinemia, a risk factor for vascular disease, injures endothelial cells through undefined mechanisms. We previously identified several homocysteineresponsive genes in cultured human vascular endothelial cells, including the endoplasmic reticulum (ER)-resident molecular chaperone GRP78/BiP. Here, we demonstrate that homocysteine induces the ER stress response and leads to the expression of a novel protein, Herp, containing a ubiquitin-like domain at the N terminus. mRNA expression of Herp was strongly upregulated by inducers of ER stress, including mercaptoethanol, tunicamycin, A23187, and thapsigargin. The ER stress-dependent induction of Herp was also observed at the protein level. Immunochemical analyses using Herpspecific antibodies indicated that Herp is a 54-kDa, membrane-associated ER protein. Herp is the first integral membrane protein regulated by the ER stress response pathway. Both the N and C termini face the cytoplasmic side of the ER; this membrane topology makes it unlikely that Herp acts as a molecular chaperone for proteins in the ER, in contrast to GRP78 and other ER stress-responsive proteins. Herp may, therefore, play an unknown role in the cellular survival response to stress.

An elevated blood level of homocysteine is associated with arteriosclerosis and thrombosis. The mechanisms by which homocysteine may promote vascular diseases have not been elucidated yet. In the present study, we have applied a modified nonradioactive differential display analysis to evaluate changes in gene expression induced by homocysteine treatment of cultured human umbilical vein endothelial cells (HUVEC). We identified six up-regulated and one down-regulated genes. One upregulated gene was GRP78/BiP, a stress protein, suggesting that misfolded proteins would accumulate in the endoplasmic reticulum because of redox potential changes caused by homocysteine. Another up-regulated gene encoded a bifunctional enzyme with activities of methylenetetrahydrofolate dehydrogenase and methenyltetrahydrofolate cyclohydrolase, which is involved in a homocysteine metabolism. A third up-regulated gene encoded activating transcription factor 4, and a fourth was a gene whose function is not identified yet. The remaining three were novel genes. We isolated a fulllength cDNA of one of the up-regulated genes from a HUVEC library. It encoded a novel protein with 394 amino acids, which was termed reducing agents and tunicamycin-responsive protein (RTP). Northern blot analysis revealed that RTP gene expression was induced in HUVEC after 4 h incubation with homocysteine. RTP mRNA was also observed in unstimulated cells and induced by not only homocysteine but also 2-mercaptoethanol and tunicamycin. The mRNA was ubiquitously expressed in human tissues. These observations indicate that homocysteine can alter the expressivity of multiple genes, including a stress protein and several novel genes. These responses may contribute to atherogenesis.