Retinoic acid imprints gut-homing specificity on T cells

For a preferential homing of T cells to the gut, expression of the integrin alpha4beta7 and the chemokine receptor CCR9 is essential and is induced by antigenic stimulation with dendritic cells from the gut-associated lymphoid organs. Here, we show that the vitamin A (retinol) metabolite, retinoic acid, enhances the expression of alpha4beta7 and CCR9 on T cells upon activation and imprints them with the gut tropism. Dendritic cells from the gut-associated lymphoid organs produced retinoic acid from retinol. The enhanced alpha4beta7 expression on T cells by antigenic stimulation with these dendritic cells was suppressed by the retinal dehydrogenase inhibitor citral and the retinoic acid receptor antagonist LE135. Accordingly, vitamin A deficiency caused a reduction in alpha4beta7(+) memory/activated T cells in lymphoid organs and a depletion of T cells from the intestinal lamina propria. These findings revealed a novel role for retinoic acid in the imprinting of gut-homing specificity on T cells.     

Aberrant methylation and loss of expression of O-methylguanine-DNA methyltransferase in pulmonary squamous cell carcinoma and adenocarcinoma

O(6)-Methylguanine-DNA methyltransferase (MGMT) is a DNA repair protein that protects cells against the carcinogenic effects of alkylating agents. The methylation status of the MGMT gene was investigated by methylation-specific polymerase chain reaction (PCR) and expression status was investigated by immunohistochemistry in 70 cases of pulmonary squamous cell carcinoma (pulmonary SqCC), including 23 cases of the central type and 47 cases of the peripheral type, and in 53 cases of the peripheral type of pulmonary adenocarcinoma (AC). The frequency of MGMT methylation was 36% in SqCC and 42% in AC. Cases with MGMT methylation correlated significantly with T factor in SqCC (P = 0.047) and AC (P = 0.03). In SqCC, the frequency of MGMT methylation was 26% in the central type and 40% in the peripheral type; a significant correlation was not found (P = 0.29). In AC with mixed subtypes showing MGMT methylation, the level of MGMT expression in the bronchioloalveolar carcinoma (BAC) area (non-invasive status) was significantly higher than that in the papillary or acinar AC area (invasive status; P = 0.0002). This trend was not found in AC with mixed subtypes showing no MGMT methylation (P = 0.10). These findings suggest that MGMT inactivation is an event that occurs in the late carcinogenic process in SqCC and AC, and that AC progress from non-invasive status to invasive status with MGMT inactivation induced by the promoter DNA methylation.     

ADAM8 as a novel serological and histochemical marker for lung cancer.

Purpose and EXPERIMENTAL DESIGN: We have been investigating genes involved in pulmonary carcinogenesis by examining gene expression profiles of non-small-cell lung cancers to identify molecules that might serve as diagnostic markers or targets for development of new molecular therapies. A gene encoding ADAM8, a disintegrin and metalloproteinase domain-8, was selected as a candidate for such molecule. Tumor tissue microarray was applied to examine expression of ADAM8 protein in archival lung cancer samples from 363 patients. Serum ADAM8 levels of 105 lung cancer patients and 72 controls were also measured by ELISA. A role of ADAM8 in cellular motility was examined by Matrigel assays. RESULTS: ADAM8 was abundantly expressed in the great majority of lung cancers examined. A high level of ADAM8 expression was significantly more common in advanced-stage IIIB/IV adenocarcinomas than in adenocarcinomas at stages I-IIIA. Serum levels of ADAM8 were significantly higher in lung cancer patients than in healthy controls. The proportion of the serum ADAM8-positive cases defined by our criteria was 63% and that for carcinoembryonic antigen was 57%, indicating equivalent diagnostic power of these two markers. A combined assay using both ADAM8 and carcinoembryonic antigen increased sensitivity because 80% of the lung cancer patients were then diagnosed as positive, whereas only 11% of 72 healthy volunteers were falsely diagnosed as positive. In addition, exogenous expression of ADAM8 increased the migratory activity of mammalian cells, an indication that ADAM8 may play a significant role in progression of lung cancer. CONCLUSIONS: Our data suggest that ADAM8 should be useful as a diagnostic marker and probably as a therapeutic target.     

Various risks of osteoporosis in patients with pituitary adenomas

 Some pituitary adenomas seem to be related to bone loss. It is unknown what kinds of pituitary adenomas affect bone mass. We attempted to determine what kinds of pituitary adenomas caused osteoporosis, and whether hormonal disturbance in pituitary adenoma patients affected bone mass. This study included 53 surgical patients (39 women of premenopausal age and 14 men) aged 21 to 62 years. We measured vertebral bone mineral density (BMD); various bone metabolic parameters, such as serum calcium, phosphorus, alkaline phosphatase, and blood urea nitrogen, parathormone, vitamin D, vitamin K, and hormonal activity in the anterior lobe of the pituitary gland. Comparisons were made of the mean Z scores (the ratio to the mean BMD of age-matched healthy Japanese women and men) among patient groups and controls. Compared with the female controls, the mean Z score was significantly higher in the women with acromegalic adenoma and significantly lower in those with adrenocorticotrophic hormone (ACTH)-secreting adenoma. In male patients, the mean Z scores were significantly decreased in prolactin-secreting adenoma and nonfunctioning adenoma, compared with that in normal controls. Acromegalic adenoma contributes significantly to vertebral bone mass acquisition, although ACTH adenoma may carry a significant risk of osteoporosis in female patients. Male patients with prolactin-secreting and nonfunctioning adenoma have a significant risk of bone decrease. Received: October 9, 2001 / Accepted: August 12, 2002 Offprint requests to: J. Matsuyama     

Concomitant transabdominal MIDCAB and abdominal aortic aneurysm repair

We present 2 patients who underwent transabdominal minimally invasive direct coronary artery bypass with the right gastroepiploic artery combined with abdominal aortic aneurysm repair. The surgical procedures, both performed through a median laparotomy, proved safe and of limited invasiveness. The one-stage surgical intervention prevented catastrophic complications, such as acute myocardial infarction or rupture of abdominal aortic aneurysm. We believe that concomitant transabdominal minimally invasive direct coronary artery bypass and abdominal aortic aneurysm repair should be considered as a single combined surgical strategy in selected patients.     

Usefulness of monitoring the circulating Krebs von den Lungen-6 levels to predict the clinical outcome of patients with advanced nonsmall cell lung cancer treated with epidermal growth factor receptor tyrosine kinase inhibitors

Krebs von den Lungen-6 (KL-6) is a high molecular weight glycoprotein classified in the category of human MUC1 mucin. KL-6 has been reported to serve as a sensitive marker for interstitial pneumonia; however, recent studies have suggested that it can also be used as a tumor marker as its origin shows. To further elucidate the clinicopathological significance of circulating KL-6 in lung cancer, we monitored the circulating KL-6 levels in advanced nonsmall cell lung cancer (NSCLC) patients and analyzed the association between these levels and the clinical outcome of EGFR-TKI treatment. The pretreatment levels of circulating KL-6 were found to be significantly higher in progressive disease (PD) patients than disease-controlled (partial response (PR) and stable disease (SD)) patients. Multivariate analyses revealed the circulating KL-6 level to be an independent prognostic factor for overall survival as well as progression-free survival. In addition to these observations, we found that changes in circulating KL-6 levels at 2 weeks after the start of EGFR-TKI treatment from the baseline could quite precisely discriminate PD cases from PR or SD patients and the clinical outcome of EGFR-TKI in NSCLC patients. These results indicate that the monitoring of circulating KL-6 levels in NSCLC patients is effective for both selecting patients to be treated with EGFR-TKI and predicting the clinical outcome of EGFR-TKI. In addition, the findings suggest that the circulating KL-6 level could be used as a clinically relevant biomarker in patients with NSCLC, particularly those who are candidates for EGFR-TKI treatment.