Updated overall survival results from a randomized phase III trial comparing gefitinib with carboplatin-paclitaxel for chemo-naïve non-small cell lung cancer with sensitive EGFR gene mutations (NEJ002).

BACKGROUND: NEJ002 study, comparing gefitinib with carboplatin (CBDCA) and paclitaxel (PTX; Taxol) as the first-line treatment for advanced non-small cell lung cancer (NSCLC) harboring an epidermal growth factor receptor (EGFR) mutation, previously reported superiority of gefitinib over CBDCA/PTX on progression-free survival (PFS). Subsequent analysis was carried out mainly regarding overall survival (OS). MATERIALS AND METHODS: For all 228 patients in NEJ002, survival data were updated in December, 2010. Detailed information regarding subsequent chemotherapy after the protocol treatment was also assessed retrospectively and the impact of some key drugs on OS was evaluated. RESULTS: The median survival time (MST) was 27.7 months for the gefitinib group, and was 26.6 months for the CBDCA/PTX group (HR, 0.887; P=0.483). The OS of patients who received platinum throughout their treatment (n=186) was not statistically different from that of patients who never received platinum (n=40). The MST of patients treated with gefitinib, platinum, and pemetrexed (PEM) or docetaxel (DOC, Taxotere; n=76) was around 3 years. CONCLUSIONS: No significant difference in OS was observed between gefitinib and CBDCA/PTX in the NEJ002 study, probably due to a high crossover use of gefitinib in the CBDCA/PTX group. Considering the many benefits and the risk of missing an opportunity to use the most effective agent for EGFR-mutated NSCLC, the first-line gefitinib is strongly recommended.

Association of susceptibility to the development of pneumonia in the older Japanese population with haem oxygenase-1 gene promoter polymorphism.

BACKGROUND: Oxidative stresses including cigarette smoking are implicated in the pathogenesis of cerebrovascular diseases, which are associated with pneumonia because of frequent aspiration. Haem oxygenase-1 (HO-1) acts in cytoprotection against oxidants, provides anti-inflammatory effects, and inhibits atherogenesis. A (GT)(n) dinucleotide repeat in the human HO-1 promoter modulates HO-1 gene expression and shows length polymorphism, which is grouped into three classes: class S (<27 repeats), class M (> or = 27, <33 repeats), and class L (> or = 33 repeats) alleles. OBJECTIVE: To investigate the correlation between the HO-1 gene polymorphism and development of pneumonia in elderly Japanese. METHODS: The length of the (GT)n repeats was analysed in 200 elderly patients with pneumonia and 200 control subjects. The association of the HO-1 gene polymorphism with risk of pneumonia was estimated by logistic regression. RESULTS: The proportion of allele frequencies in class L, and the proportion of genotypic frequencies in the L-allele carriers (L/L, L/M, and L/S), was significantly higher in patients with pneumonia than in controls (20% v 10% in class L, and 34% v 18% in L-allele carriers). After adjustment for potentially confounding factors, both cerebrovascular disorders and HO-1 gene L-allele carriers were significant and independent risk factors for pneumonia. The adjusted odds ratio for L-allele carriers v non-L-allele carrier was 2.1 (95% confidence interval, 1.2 to 3.6). CONCLUSIONS: The large size of a (GT)n repeat in the HO-1 gene promoter may be associated with susceptibility to pneumonia in the older Japanese population.

The monoclonal antibodies TMH-1 and TMH-2 specifically bind to a protein encoded at the murine b-locus, not to the authentic tyrosinase encoded at the c-locus.

Three hybridomas, TMH-1, TMH-2, and TMH-3, were previously reported by Tomita et al to produce monoclonal antibodies against murine and human T4-tyrosinase localized in melanosome for the formation of melanin pigment. However, TMH antibodies were unable to react with K1735 cells transfected with the authentic tyrosinase-cDNA construct, but did react with those transfected with the pMT4-cDNA construct. The cDNA pMT4 was initially cloned as a putative tyrosinase cDNA by Shibahara et al, but it is now known to encode mouse brown (b) locus protein, which was named "tyrosinase-related protein" by Jackson or "b protein" by Hearing and Jimenez. Furthermore, TMH antibodies recognize hair bulbs of C57BL/6J-c2J/c2J mouse (B/B, c/c) lacking tyrosinase activity, but do not recognize hair bulbs of b-locus mutated DBA/2 mouse (b/b, C/C), which have authentic tyrosinase. Considering these observations, we conclude that TMH antibodies specifically recognize the protein encoded at b-locus.

Changes in enzyme activities related to steroidogenesis in human ovaries during the menstrual cycle.

Follicles and corpora lutea were isolated from the ovaries of 25 patients at several stages of the normal menstrual cycle. To measure the steroidogenic enzyme activities, cell-free homogenates of the ovaries were incubated aerobically with 4-14C-labeled pregnenolone, progesterone, 17 alpha-hydroxyprogesterone, androstenedione, and testosterone in the presence of appropriate cofactor(s). The delta 5-3 beta-hydroxysteroid dehydrogenase plus delta 4-delta 5 isomerase activity in the follicle was low during early follicular phase (greater than 11 days before ovulation), but gradually increased toward ovulation and showed maximal values in the corpus luteum at the midluteal phase (6-10 days after ovulation). The activities of 17 alpha-hydroxylase and C-17-C-20 lyase in the follicle reached the highest value at the late follicular phase (within 5 days of ovulation), but markedly decreased after luteinization. 17 alpha-Hydroxylase activity in the corpus luteum increased again during the midluteal phase, whereas the activity of C-17-C-20 lyase remained at a low level throughout the luteal phase. The aromatase activity was low during the follicular phase, but increased markedly with luteinization. These findings are discussed in light of the known plasma steroid concentrations and their changes during the menstrual cycle.

Immunohistochemical localization of pregnancy-associated plasma protein A (PAPP-A) in placentae from normal and pre-eclamptic pregnancies.

An immunohistochemical method was used to locate pregnancy-associated plasma protein A (PAPP-A) in the placenta and uterus. In addition to 10 placentae and basal plates from normal pregnancies, ranging in gestational age from 37 to 40 weeks, the following specimens were studied: three uteri obtained by hysterectomy during early pregnancy; and three placentae from patients with severe hypertensive pre-eclampsia. In early gestation, PAPP-A was localized in the villous cytotrophoblastic cell layer and the endometrial glands but was not found in the villous syncytiotrophoblast, the cytotrophoblastic cell columns or the decidual cells. On histochemical examination of placentae from cases of pre-eclampsia with hypertension, an increased number of villous cytotrophoblastic cells and so-called X-cells was observed. The monospecific antiserum to PAPP-A reacted strongly and evenly with the cytoplasm of these cells. The present study strongly suggests that the active production sites of PAPP-A are the villous cytotrophoblastic cells and the X-cells.

The multiple untranslated first exons and promoters system of the oestrogen receptor gene in the brain and peripheral tissues of the rat and monkey and the developing rat cerebral cortex.

Recent studies on the human oestrogen receptor (ER) gene have revealed the complex system with the multiple untranslated first exons and promoters in the ER gene expression. Little information is however available on the system in the ER gene of the rat or nonhuman primate. The rat genomic library was first screened by the rat ER cDNA (0-1) probe. One of the four positive clones (lambda rEgE1) was subcloned and sequenced. The nucleotide sequence was found to contain the exon 0, the intron 0, and the exon 1 with its 3'-ends. The novel untranslated first exons, the exon ON and the exon OS, were further identified. These results indicated the presence of at least four subtypes of the rat ER mRNAs; the messages transcribed from promoter P-0 (ER mRNA (0-1)), putative promoter P-1 (ER mRNA (1-1)), promoter P-ON (ER mRNA (ON-1)) and promoter P-OS (ER mRNA (OS-1)). The P-O- or P-1 driven message (0-1) or (1-1) appeared to be expressed most strongly in major oestrogen central- (anterior pituitary, AP, hypothalamus-preoptic area, HPOA, and amygdala, AMG) and peripheral targets (uterus and ovary). The message (ON-1) was strongly expressed in the liver and kidney, but not in the HPOA, AMG, cerebral cortex, CC, and cerebellum, Ce. The OS-1 message was expressed variably but generally in the tissues examined except for the CC and Ce. Thus, the region- and tissue specific expression of the rat ER gene is likely to be regulated by the multiple untranslated exons and promoters system. Furthermore, when the ER mRNA subtypes were examined in the rat neonatal CC where the ER protein level rose transiently, considered as a model for the development of the ER or progestin receptor A and B isoforms, the expression of the ER mRNAs seemed to be differential postnatally, implicating some stage dependent usage of the promoters in the development. In the monkey, we identified the untranslated first exon OS, the homologue of the rat exon OS. Interestingly, the exon C was found to consist of two different exons, the exon OK and the exon OG. By the alternative usage of the promoters and the alternative splicing, at least six ER mRNA subtypes, that is, ER mRNAs (0-1), (1-1), (OS-1), (OS-OG-1), (OK-1) and (OK-OG-1) were identified in the monkey tissues. These messages were also differentially distributed in the monkey brain and other tissues. It was noteworthy that the P-OK driven messages were expressed almost exclusively in the monkey liver. These results have suggested that the systems of the multiple untranslated first exons and promoters and the alternative splicing are involved in the regulation of the region- and tissue specific expression of the ER gene in the brain and peripheral tissues of the rat and monkey. Stage-related usage of the promoters was also suggested in the ER gene expression in the CC of the postnatal rat in development.

The role of carbon monoxide in lucigenin-dependent chemiluminescence of rat alveolar macrophages.

We have investigated the role of carbon monoxide (CO) in lucigenin-dependent chemiluminescence of alveolar macrophages from rat lungs. CO (10 nM to 1 microM) decreased chemiluminescence of alveolar macrophages in a concentration-dependent fashion. At a concentration of 1 microM, CO significantly increased intracellular cyclic GMP levels from a control value of 175 +/- 25 fmol/2 x 10(6) cells to 431 +/- 49 fmol/2 x 10(6) cells. Pretreatment of alveolar macrophages with NG-monomethyl-L-arginine (100 microM) failed to inhibit CO (1 microM)-induced decreases in chemiluminescence of alveolar macrophages (3.7 +/- 0.7 cpm x 10(3) in the presence of NG-monomethyl-L-arginine and 3.4 +/- 0.6 cpm x 10(3) in the absence of NG-monomethyl-L-arginine) and CO (1 microM)-induced increases in intracellular cyclic GMP levels (452 +/- 65 fmol/2 x 10(6) cells in the presence of NG-monomethyl-L-arginine and 419 +/- 58 fmol/2 x 10(6) cells in the absence of NG-monomethyl-L-arginine). Decreases in chemiluminescence of alveolar macrophages induced by CO (1 microM) were concentration-dependently inhibited by methylene blue (from 0.1 microM to 10 microM). Dibutyryl cyclic GMP (db cyclic GMP) (1 mM) also reduced chemiluminescence of alveolar macrophages (1.5 +/- 0.3 cpm x 10(3) in the presence of db cyclic GMP and 3.6 +/- 0.6 cpm x 10(3) in the absence of db cyclic GMP). In contrast to CO and db cyclic GMP, zinc protoporphyrin-9 (10nM to microM), an inhibitor of heme oxygenase potentiated chemiluminescence of alveolar macrophages in a concentration-dependent fashion.(ABSTRACT TRUNCATED AT 250 WORDS)

Suppression of macrophage activation by peritoneal fluid from patients with endometriosis.

To investigate the effects of peritoneal fluid from patients with endometriosis on mouse peritoneal macrophages (Mphi), peritoneal fluid from endometriosis patients (n = 15) were added to a monolayer of C3H/HeJ mouse peritoneal Mphi. Tumor necrosis factor-producing activity was measured by the L929 assay activated with FK-23 (a preparation of heat-killed Enterococcus faecalis). Tumor necrosis factor-producing activity of C3H/HeJ mouse peritoneal Mphi incubated with peritoneal fluid was suppressed in 14 endometriosis patients. Interestingly, in nine endometriosis patients, tumor necrosis factor-producing activity was much lower than seen with mouse peritoneal Mphi incubated with corticosterone. Peritoneal fluid contains suppressive properties for the activation of peritoneal Mphi, which might allow the implantation of free endometrial cells or the metaplastic phenomena stimulated by retrograde menstruation.

The role of HMT (histamine N-methyltransferase) in airways: a review.

Histamine N-methyltransferase (HMT) expressed in the epithelial and endothelial cells of the airways is a principal enzyme degrading histamine in the body. This brief review summarizes the recent advances in molecular biology related to the pathophysiological role of HMT in regulating airway functions.

Effect of high-dose progestogen on hemostatic properties of blood in patients with endometrial cancer.

Fifteen cases of endometrial cancer were administered daily doses of 600 mg of MPA after surgery to prevent the recurrence of cancer. The initiation times of coagulation (time necessary for fibrin network formation) were measured with a highly sensitive damped oscillation rheometer and compared with those of 15 control patients who were not administered MPA. Biochemical studies of blood coagulation and fibrinolysis were also done. The initiation times of coagulation were 19.0+/-1.8 minutes (min mean +/- standard deviation) after 3-6 months and 16.0+/-2.0 min after 9-12 months of MPA administration, both times being significantly shorter compared with the controls (24.0+/-2.5 min). Hematocrit values, platelet counts and fibrinogen levels were similar between the two groups. Activated partial thromboplastin time (APTT) was significantly decreased and antithrombin III activity (AT III), thrombin-antithrombin complex (TAT), plasminogen level, plasmin-alpha(2) plasmin inhibitor complex level (PIC) and the fibrin degradation product level (FDP) were significantly increased in the MPA group compared with the control group. Accelerated coagulation of blood was definitely induced by high-dose MPA but antithrombin and fibrinolytic activities were also induced, and, thus, thromboembolic complications were prevented.

Shedding of herpes simplex virus type 1 into tears and saliva in healthy Japanese adults.

It is well known that asymptomatic viral shedding is one of the forms of reactivation of herpes simplex virus type-1 (HSV-1). Although there have been some long-term investigations of viral shedding into tears and saliva in healthy subjects in the U.S.A, there have previously been no investigation study in Japan. Racial differences in the incidence of reactivation of HSV-1 have been pointed out, and it has been considered that reactivation is found less often among Japanese people than among Westerners. In the present study, we selected 10 healthy adults (7 males and 3 females) to isolate HSV-1 from tears and saliva 3 times a week over 6 months, and the results were compared with the results of other studies conducted in the U.S.A. It was found that the virus was isolated in 5 (3 males and 2 females) of 10 subjects and of the 5 subjects, the virus was isolated from saliva in 4 and from tears in 1. The number of specimens was 1,742 for tears and 871 for saliva with isolation of 1 and 4, respectively. The duration of shedding was only 1 day in all of the 5 subjects in whom the virus was isolated. The isolation frequency was significantly lower among Japanese people than among American people when our results were compared with the results of studies conducted in the U.S.A. It was clear that the reactivation rate was lower for Japanese people in terms of asymptomatic shedding.

Comparison of the inpatients admitted during the recent 5 years (January 1994-December 1998) with those admitted during the previous 5 years (January 1989-December 1993): a clinico-statistical study.

As society ages, the composition of the diseases that occur within it changes accordingly. With that in mind, we examined the characteristics and trends in the recent inpatients and compared these recent inpatients with those of a previous report to identify the changes that accompany the aging of society. Subjects were 1,534 cases (men 56.9%, female 43.1%, average age 47.1 years) who were hospitalized at Kurume University Hospital for treatment during the 5-year period from January 1st, 1994 through December 31st, 1998. The ratio of inpatients over 65 years old was about 1.8 times higher than in the previous study, showing a clear trend toward an increased overall age of inpatients. As for the types of disease observed, the most common malignancies were epithelial tumor, followed by other benign tumors, as well as 76 cases which included diseases resembling tumor (epulis and exostosis etc.). A majority of the patients (55.6%) were directed to the Hospital by their dentist, a finding similar to that of the previous report. As for geographical distribution, 93.3% of the inpatients lived within 40 km of the center of Kurume City where our oral surgery is located, an increase of about 10% from the last report. In other words, our results showed a reduction in the sphere of treatment distribution.

[Fundamental and clinical studies on T-1982 (cefbuperazone) in the field of obstetrics and gynecology].

Fundamental and clinical studies on T-1982 (cefbuperazone) in the field of obstetrics and gynecology were carried out. Transfer of T-1982 to various location in uterus tissue was more than 10 micrograms/g over 2 hours after T-1982 1 g intravenous injection. T-1982 was distributed in cervix uteri at the highest concentration followed by ovarium, oviduct, portio vaginalis, endometrium and myometrium. Mean transfer ratio of cervix uteri to uterus arterial blood was 67.6%. Ten cases of gynecological infections receiving T-1982 demonstrated "good" results in 9 cases, except 1 case excluded from the evaluation of efficacy. Neither side effect nor clinical test abnormality was observed. Based on the results of basic and clinical studies, T-1982 is considered to have efficacy in the treatment of gynecological infections.

[Detection of exhaled CO as a simple non-invasive tool for monitoring acute exacerbations of asthma in the elderly].

Exhaled carbon monoxide (CO) concentrations were measured on a CO monitor by vital capacity maneuvers in asthmatic patients either receiving or not receiving inhaled corticosteroids, and in nonsmoking healthy control subjects. CO was detectable and measured reproducibly in the exhaled air of all subjects. The exhaled CO concentrations were higher in asthmatic patients not receiving inhaled corticosteroids and similar in asthmatic patients receiving inhaled corticosteroids and nonsmoking healthy control subjects (Am J Respir Crit Care Med 1997: 156: 1140-1143). All patients with inhaled corticosteroid treatment had reductions in exhaled CO concentration and eosinophil cell counts in sputum that were accompanied by an amelioration of airway obstruction. These results showed that detection of exhaled CO could be a simple non-invasive tool for monitoring airway inflammation and acute exacerbation of asthma.

Comparison of responsiveness of the Japanese Society for Surgery of the Hand version of the carpal tunnel syndrome instrument to surgical treatment with DASH, SF-36, and physical findings.

BACKGROUND: The Japanese Society for Surgery of -the Hand version of the Carpal Tunnel Syndrome Instrument (CTSI-JSSH), which consists of two parts--one for symptom severity (CTSI-SS) and the other for functional status (CTSI-FS)--is a self-administered questionnaire specifically designed for carpal tunnel syndrome. The responsiveness of the CTSI-JSSH was compared with that of the JSSH version of the Disability of Arm, Shoulder, and Hand questionnaire (DASH), the official Japanese version of the 36-Item Short Form Health Survey (SF-36, version 1.2), and physical examinations to elucidate the role of the CTSI-JSSH for evaluating patients with carpal tunnel syndrome. METHODS: Preoperatively, a series of 60 patients with carpal tunnel syndrome completed the CTSI-JSSH, DASH, and SF-36. Results of physical examinations, including grip strength, pulp pinch, and static two-point discrimination of the thumb, index, and long fingers, were recorded. Three months after carpal tunnel release surgery the patients were asked to fill out the same questionnaires, and the physical examinations were repeated. The responsiveness of all the instruments was examined by calculating the standardized response mean (SRM) and effect size (ES). Correlation coefficients were calculated between questionnaire change scores and patient satisfaction scores as well as between the CTSI change scores and those of the DASH and SF-36. RESULTS: The largest responsiveness was observed in the CTSI-SS (SRM/ES: -1.00/-1.08) followed by the CTSI-FS (-0.76/-0.63), and bodily pain subscale of SF-36 (SF-36-BP, 0.45/0.55), and the DASH (-0.46/-0.47). Only the change scores of the CTSI-SS had significant correlation with patient satisfaction (r = 0.34, P < 0.01). An absolute value of Spearman's correlation coefficient of >0.5 was observed between the change scores of the CTSI-SS and the DASH, the CTSI-SS and the SF-36-BP, the CTSI-FS and the DASH, and the DASH and the SF-36-BP. CONCLUSION: The CTSI-JSSH was proven to be more sensitive to clinical changes after carpal tunnel release than the other outcome measures and should be used to evaluate patients with carpal tunnel syndrome who speak Japanese as their native language.

Identification of a nuclear protein that constitutively recognizes the sequence containing a heat-shock element. Its binding properties and possible function modulating heat-shock induction of the rat heme oxygenase gene.

Heme oxygenase is an essential enzyme in heme catabolism, and also known as a 32-kDa heat-shock protein in rat. The rat heme-oxygenase gene promoter contains a functional heat-shock element (HSE) designated as HSE1 (-290 to -276 from the transcriptional initiation site), which consists of three copies of a 5-bp unit (5'-NGAAN-3';-->) in alternating orientation. Here we identified a putative HSE (-221 to -212), designated as HSE2, consisting of an inverted repeat of this 5-bp unit (<==>). Using transient expression assays, we show that HSE1 is sufficient to confer the heat-inducibility (a three fold to fourfold increase) on the reporter gene located downstream from the rat heme-oxygenase gene promoter, but HSE2 alone is not, suggesting that HSE2, a HSE of a tail-to-tail configuration, is not functional in vivo. However, the presence of both HSE1 and HSE2 in the promoter region increased the heat-mediated induction of the reporter-gene expression by more than 15-fold. Gel mobility-shift assays indicate that both HSE1 and HSE2 are recognized by activated heat-shock factor present only in heat-shocked rat glioma cells. Interestingly, the sequence containing HSE2 is also bound by a protein that is present in nuclear extracts prepared from either heat-shocked or non-shocked glioma cells, but this nuclear protein is unable to bind to HSE1. We suggest that a protein binding to the sequence containing HSE2 may be involved in transcriptional regulation of the rat heme oxygenase gene under thermal stress.