Mechanism of Macrophage-Derived Chemokine/CCL22 Production by HaCaT Keratinocytes

BackgroundCC chemokine ligand 17 (CCL17) and CCL22 are the functional ligands for CCR4. We previously reported that inhibitors of nuclear factor-kappa B and p38 mitogen-activated protein kinase (p38 MAPK), but not of extracellular signal-related kinase (ERK), inhibited tumor necrosis factor (TNF)-α- and interferon (IFN)-γ-induced production of CCL17 by the human keratinocyte cell line, HaCaT. Further, an inhibitor of epidermal growth factor receptor (EGFR) enhanced the CCL17 production by these keratinocytes.ObjectiveTo identify the mechanism underlying CCL22 production by HaCaT cells.MethodsWe investigated the signal transduction pathways by which TNF-α and IFN-γ stimulate HaCaT cells to produce CCL22 by adding various inhibitors.ResultsTNF-α- and IFN-γ-induced CCL22 production was inhibited by PD98059, PD153035, Bay 11-7085, SB202190, c-Jun N-terminal kinase (JNK) inhibitor II, and Janus kinase (JAK) inhibitor 1.ConclusionOur results indicate that CCL22 production in HaCaT cells is dependent on ERK, EGFR, p38 MAPK, JNK, and JAK and is mediated by different signal pathways from those regulating CCL17 production. Altogether, our previous and present results suggest that EGFR activation represses CCL17 but enhances CCL22 production by these cells.     

Organophosphorus pesticides markedly inhibit the activities of natural killer, cytotoxic T lymphocyte and lymphokine-activated killer: a proposed inhibiting mechanism via granzyme inhibition

We have previously found that diisopropyl methylphosphonate, an organophosphorus by-product generated during sarin synthesis in the Tokyo sarin disaster, significantly inhibited natural killer (NK) and cytotoxic T lymphocyte (CTL) activities. In the present study, to investigate whether organophosphorus pesticides (OPs) also affect NK and CTL activities, we firstly examined the effect of five OPs on human NK activity, and then the effect of Dimethyl 2,2-dichlorovinyl phosphate (DDVP), an OP on murine splenic NK, CTL and lymphokine-activated killer (LAK), and human LAK activities in vitro. To explore the underlying mechanism of decreased NK activity, we also investigated the effect of 4-(2-aminoethyl) benzenesulfonyl fluoride-HCl (p-ABSF), an inhibitor of serine proteases on NK, LAK and CTL activities, and the effect of DDVP on the activity of granzymes (serine proteases). We found that OPs significantly decreased human NK activity in a dose-dependent manner, but the degree of decrease in NK activity differed among the OPs investigated, and that DDVP significantly decreased NK, LAK and CTL activities in a dose-dependent manner, but the degree of decrease in these activities differed. p-ABSF showed a similar inhibitory pattern to DDVP, and had an additive inhibitory effect with DDVP on NK, LAK and CTL activities. We also found that DDVP significantly inhibited granzyme activity in a dose-dependent manner. These findings indicate that OPs significantly decrease NK, LAK and CTL activities in vitro via granzyme inhibition.     

A new medical education using a lung sound auscultation simulator called "Mr. Lung"

We developed a lung sound auscultation simulator "Mr. Lung" in 2001. To improve the auscultation skills of lung sounds, we utilized this new device in our educational training facility. From June 2001 to March 2002, we used "Mr. Lung" for our small group training in which one hundred of the fifth year medical students were divided into small groups from which one group was taught every other week. The class consisted of ninety-minute training periods for auscultation of lung sounds. At first, we explained the classification of lung sounds, and then auscultation tests were performed. Namely, students listened to three cases of abnormal or adventitious lung sounds on "Mr. Lung" through their stethoscopes. Next they answered questions corresponding to the portion and quality of the sounds. Then, we explained the correct answers and how to differentiate lung sounds on "Mr. Lung". Additionally, at the beginning and the end of the lecture, five degrees of self-assessment for the auscultation of the lung sounds were performed. The ratio of correct answers for lung sounds were 36.9% for differences between bilateral lung sounds, 52.5% for coarse crackles, 34.1% for fine crackles, 69.2% for wheezes, 62.1% for rhonchi and 22.2% for stridor. Self-assessment scores were significantly higher after the class than before. The ratio of correct lung sound answers was surprisingly low among medical students. We believe repetitive auscultation of the simulator to be extremely helpful for medical education.     

High-concentration (20 mug/g) tacalcitol ointment therapy on refractory psoriasis vulgaris with low response to topical corticosteroids

The efficacy and safety of the application of high-concentration (20 mug/g) tacalcitol ointment once daily for 12 weeks to psoriasis vulgaris lesions which showed low response to topical corticosteroids, were evaluated in a prospective, multicenter, open-label study. Eighty patients were enrolled in the safety analysis of the test drug, and 54 of the 80 patients in the efficacy analysis. The efficacy rate based on the number of cases graded as "moderate improvement" or better in the final global improvement rating of the 54 cases included in the efficacy analysis, was 88.9% (95% CI: 77.4-95.8%). Significant improvement in erythema, thickness, and scaling was observed from 2 weeks of treatment onward (p < 0.001). Five local adverse reactions (2 events of irritation, 2 events of itching, and 1 event of redness) were observed in 3 of the 80 patients included in the safety analysis. There were no significant changes in mean serum calcium values. Tacalcitol 20 mug/g ointment is concluded to be effective and safe for the treatment of refractory psoriasis vulgaris with low response to topical corticosteroids.     

Lack of consistency in the associations of Helicobacter pylori seropositivity with Se and Le polymorphisms among Japanese

Background: In our previous study, a marked association between Helicobacter pylori seropositivity and functional polymorphisms of the secretor and Lewis genes (odds ratio [OR], 0.32; 95% confidence interval [CI], 0.14–0.70 for se/se genotype relative to Se/Se genotype; and OR, 10.3; 95% CI, 3.16–33.8 for high-risk group defined by the combination of Se and Le relative to low-risk group) had been observed for 239 non-cancer Japanese outpatients of the gastroenterology clinic (OGC) undergoing gastroscopy at Aichi Cancer Center Hospital. Methods: The present study was a confirmatory study to examine the association for 679 first-visit outpatients (FVO) of all clinics at the same cancer hospital and for 465 health checkup examinees (HCE) in the same city. Results: The associations between H. pylori seropositivity and the Se and Le genotypes were nonsignificant or even in the opposite direction among the FVO (OR, 1.52; 95% CI, 1.00–2.32 for se/se genotype relative to Se/Se genotype; and OR, 0.77; 95% CI, 0.43–1.40 for the high-risk group defined similarly to the previous study), and among the HCE (OR, 1.25; 95% CI, 0.75–2.07; and OR, 1.07; 95% CI, 0.50–2.26, respectively). The discrepancy between the previous and present results was not explained by the difference in the distributions of age, sex, smoking, and H. pylori seroprevalence. Conclusion: Even in the same ethnic group, different sources of subjects may demonstrate inconsistent findings due to an unidentified effect modification. Inconsistent findings have rarely been reported by the same research group, but they are very important to understand the whole picture of the association under study. Received: May 9, 2002 / Accepted: July 2, 2002 Acknowledgments This work was supported in part by a Grant-in-Aid for the Second Term Comprehensive 10-Year Strategy for Cancer Control from the Ministry of Health, Labour and Welfare of Japan. The authors are grateful to Ms. Naomi Takeuchi for genotyping. Offprint requests to: N. Hamajima     

Significant growth inhibition of human lung cancer cells both in vitro and in vivo by the combined use of a selective cyclooxygenase 2 inhibitor, JTE-522, and conventional anticancer agents.

This study reports that a selective COX-2 inhibitor JTE-522inhibits both in vitro and in vivo growth of human lung cancer cells as a single agent. Furthermore, the adjunct use of JTE-522 is shown to significantly enhance treatment efficacy of conventional anticancer drugs not only in vitro but also in vivo without causing any noticeable side effects. Indeed, IC(50)s of various anticancer agents in vitro were reduced by up to 70%, whereas the combination therapy of JTE-522 with docetaxel and vinorelbine inhibited tumor growth in vivo by 65 and 55%, respectively. Taken together, these findings suggest that the use of a selective COX-2 inhibitor in the treatment of lung cancer may be promising, especially because of its enhancement of the treatment efficacy of conventional anticancer agents without compromising quality of life.     

Population-based mapping of pulmonary adenoma susceptibility 1 locus

Pulmonary adenoma susceptibility 1 (Pas1), the major locus affecting inherited predisposition to lung tumor development in mice, maps near the Kras2 gene. We previously reported a significant association between a KRAS2/RsaI polymorphism and the risk and prognosis of lung adenocarcinoma (ADCA) in the Italian population. In the present case-control study, we examined 269 lung ADCA patients, 121 squamous cell lung carcinoma patients, and 632 healthy individuals (general population controls) in the Japanese population with genetic markers spanning approximately 1200 kb in the KRAS2 region. Allele-specific oligonucleotide hybridization revealed the same KRAS2/RsaI polymorphism associated with risk and prognosis as in Italian lung ADCA patients; the polymorphism was significantly associated with clinical stage (P < 0.001) and survival rate (log rank = 0.0014), confirming the mapping of PAS1 and pointing to the role of this locus in human lung cancer.     

Comparative study of daily maximum exposure to temperatures during hot summer days in 3 Japanese cities

OBJECTIVES: Health risk assessment and developing measures to deal with global warming (including increased heat waves) have become urgent global issues. In the present study, we measured the personally exposed temperature (Tp) during summer among residents in major Japanese cities to investigate the relation to daily maximum ambient temperature (Tmax), which is generally been used as an index of temperature exposure in epidemiological studies. METHODS: Personal exposures to temperature (Tp) were measured for a week with portable monitors (HOBO H8 Loggers, Onset Computer Corporation) for 194 subjects (101 males and 93 females, aged 21-82 years) in 3 cities, i.e., Sapporo, Tokyo and Naha (Okinawa), from July to September, 2003 (73 days). RESULTS AND DISCUSSION: Even on days with a Tmax of 30-35 degrees C, associated with significantly increased risk of mortality in Tokyo, neither average Tp for 7-19 o'clock nor the value for 13-15 o'clock appeared to rise beyond 30 degrees C in Tokyo and 31 degrees C in Naha. It was, thus, apparent that Tp's are generally controlled to not exceed these values at least during daytime, suggesting that they could be regarded as a threshold for heat stress tolerance. On the other hand, although average Tp's for night time (0-7 o'clock) were also found to be asymptomatic at 29 degrees C in Tokyo and 30 degrees C in Naha, they were generally too high to be free from heat stress including sleep disturbance in both cities as indicated in our questionnaire study. For both cities, in days with the Tmax above 30 degrees C, the average Tmin was 26 degrees C, while average and minimum Tp's during the night time were 28 degrees C and 27 degrees C, respectively. The correlation coefficients with Tmax were generally low; 0.35 for average Tp during daytime, 0.42 for Tmin and 0.27 and 0.19 for average and minimum night time Tp, respectively.     

The clinical strategy for the Barrett's esophagus

The treatment of Barrett's esophagus is controversial. Current treatments include endoscopic therapy, surgical procedures, gastric acid-suppressive therapy with proton pump inhibitors (PPIs), and cancer chemoprevention such as nonsteroidal anti-inflammatory drugs. Endoscopic therapy combined with gastric acid suppressive therapy can result in squamous reepithelialization of the Barrett's mucosa. Antireflux surgery and PPIs therapy are potential options for the treatment of gastroesophageal reflux symptoms in patients with Barrett's esophagus. But there are no prospective studies that support any alternative approach to treatment. Although chemoprevention therapy may reduce cancer risk in Barrett's esophagus, no randomized controlled trials that prove its efficacy have been reported.