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Malignant mesothelioma (MM) shows frequent inactivation of the neurofibromatosis type 2 ( NF2 ) –tumor-suppressor gene. Recent studies have documented that the Hippo signaling pathway, a downstream cascade of Merlin (a product of NF2 ), has a key role in organ size control and carcinogenesis by regulating cell proliferation and apoptosis. We previously reported that MMs show overexpression of Yes-associated protein (YAP) transcriptional coactivator, the main downstream effector of the Hippo signaling pathway, which results from the inactivation of NF2 , LATS2 and/or SAV1 genes (the latter two encoding core components of the mammalian Hippo pathway) or amplification of YAP itself. However, the detailed roles of YAP remain unclear, especially the target genes of YAP that enhance MM cell growth and survival. Here, we demonstrated that YAP-knockdown inhibited cell motility, invasion and anchorage-independent growth as well as cell proliferation of MM cells in vitro . We analyzed genes commonly regulated by YAP in three MM cell lines with constitutive YAP-activation, and found that the major subsets of YAP-upregulating genes encode cell cycle regulators. Among them, YAP directly induced the transcription of CCND1 and FOXM1 , in cooperation with TEAD transcription factor. We also found that knockdown of CCND1 and FOXM1 suppressed MM cell proliferation, although the inhibitory effects were less evident than those of YAP knockdown. These results indicate that constitutive YAP activation in MM cells promotes cell cycle progression giving more aggressive phenotypes to MM cells.

We have previously reported on life span shortening as well as increased incidence rates in several neoplasms in B6C3F1 mice that were continuously exposed to 21 mGy/day of gamma rays for 400 days. To clarify whether the life shortening was due to early appearance of neoplasms (shortened latency) or increased promotion/progression, 8-week-old female specific-pathogen-free B6C3F1 mice were gamma-ray irradiated at a low dose rate of 20 mGy/day for 400 days. At 100 days postirradiation, 60–90 mice were sacrificed, and thereafter every 100 days alongside the age-matched nonirradiated controls, for 700 days. Additional groups were allowed to live out their natural life span. Pathological examination was performed on all mice to identify lesions, non-neoplastic and neoplastic, as well as to determine the cause of death. Body weights were significantly increased in irradiated mice from sacrifice days 200–500. Incidence rates for spontaneously occurring non-neoplastic lesions, such as adrenal subcapsular cell hyperplasia, fatty degeneration of the liver, atrophy and tubulostromal hyperplasia of the ovaries, were significantly increased in irradiated mice. Significantly increased incidence rates with no shortening of latency periods were observed in irradiated mice for malignant lymphomas, hepatocellular adenomas/carcinomas, bronchioloalveolar adenomas, harderian gland adenoma/adenocarcinoma. Shortened latencies with significantly increased incidence rates were observed for adrenal subcapsular cell adenomas and ovarian neoplasms (tubulostromal adenoma, granulosa cell tumors) in irradiated mice. Life span shortening in mice exposed to 20 mGy/day was mostly due to malignant lymphomas. Multiple primary neoplasms were significantly increased in mice exposed to 20 mGy/day from sacrifice days 400–700 and in the life span group. Our results confirm that continuous low-dose-rate gamma-ray irradiation of female B6C3F1 mice causes both cancer induction (shortened latency) and promotion/progression (early death), depending on the neoplasm's organ/tissue of origin.

Background Most organisms have evolved a circadian clock in order to anticipate daily environmental changes and many of these organisms are also capable of sophisticated measurement of daylength (photoperiodism) that is used to regulate seasonal events such as diapause, migration and polymorphism. It has been generally accepted that the same elements are involved in both circadian (daily) and seasonal (annual) rhythms because both rely upon daily light-dark cycles. However, as reasonable as this sounds, there remains no conclusive evidence of such a molecular machinery in insects. We have approached this issue by using RNA interference (RNAi) in Riptortus pedestris . Results The cuticle deposition rhythm exhibited the major properties of circadian rhythms, indicating that the rhythm is regulated by a circadian clock. RNAi directed against the circadian clock genes of period and cycle , which are negative and positive regulators in the circadian clock, respectively, disrupted the cuticle deposition rhythm and distinct cuticle layers were produced by these RNAi. Simultaneously, period RNAi caused the insect to avert diapause under a diapause-inducing photoperiod whereas cycle RNAi induced diapause under a diapause-averting photoperiod. The expression patterns of juvenile hormone-regulated genes and the application of juvenile hormone analogue suggested that neither ovarian development itself nor a downstream cascade of juvenile hormone secretion, were disturbed by period and cycle RNAi. Conclusions This study revealed that the circadian clock genes are crucial not only for daily rhythms but also for photoperiodic diapause. RNAi directed against period and cycle had opposite effects not only in the circadian cuticle deposition rhythm but also in the photoperiodic diapause. These RNAi also had opposite effects on juvenile hormone-regulated gene expression. It is still possible that the circadian clock genes pleiotropically affect ovarian development but, based on these results, we suggest that the circadian clock operated by the circadian clock genes, period and cycle , governs seasonal timing as well as the daily rhythms. See Commentary: http://www.biomedcentral.com/1741-7007/8/115

•The intramuscular adipose tissue content was significantly higher in metabolic syndrome (MetS) than that in non-MetS.•A 10% increase in intramuscular adipose tissue content was positively related to prevalence of MetS.•No significant relation between adjusted skeletal muscle cross-sectional areas and prevalence of MetS.•Inhibiting the accumulation of intramuscular adipose tissue content may effectively prevent MetS. The aim of the present study was to examine the dose–response relationship between trunk tissue composition and prevalence of metabolic syndrome (MetS) in middle-aged Japanese men. The 1026 men (between 35 and 59 y of age) who participated in the present study were divided into two groups: those with metabolic syndrome (MetS) and those without (non-MetS). Intramuscular adipose tissue (IntraMAT) content and the cross-sectional areas (CSAs) of visceral adipose tissue and skeletal muscle tissue were calculated using low-dose computed tomography images acquired at the level of the third lumbar vertebra. Height, body mass, body fat, waist circumference, the presence of MetS, and lifestyle habits were also assessed. IntraMAT content was significantly higher in MetS than in non-MetS men. A 10% increase in IntraMAT content correlated with the prevalence of MetS (odds ratio, 4.197; 95% confidence interval, 3.108–7.088; P < 0.001), even after adjustments for age, height, adjusted skeletal muscle CSA, sleeping time, alcohol consumption, exercise habit, and cigarette smoking. Skeletal muscle CSA did not correlate with the prevalence of MetS after adjustments for IntraMAT content and other cofactors. Increase in IntraMAT content, not in skeletal muscle CSA, significantly correlated with the prevalence of MetS. These results suggest that countermeasures against the accumulation of trunk IntraMAT effectively prevent MetS in middle-aged Japanese men.

Malignant mesothelioma (MM) is one of the most aggressive neoplasms usually associated with asbestos exposure and is highly refractory to current therapeutic modalities. MMs show frequent activation of a transcriptional coactivator Yes-associated protein (YAP), which is attributed to the neurofibromatosis type 2 (NF2)–Hippo pathway dysfunction, leading to deregulated cell proliferation and acquisition of a malignant phenotype. However, the whole mechanism of disordered YAP activation in MMs has not yet been well clarified. In the present study, we investigated various components of the NF2-Hippo pathway, and eventually found that MM cells frequently showed downregulation of LIM-domain protein AJUBA, a binding partner of large tumor suppressor type 2 (LATS2), which is one of the last-step kinases of the NF2-Hippo pathway. Although loss of AJUBA expression was independent of the alteration status of other Hippo pathway components, MM cell lines with AJUBA inactivation showed a more dephosphorylated (activated) level of YAP. Immunohistochemical analysis showed frequent downregulation of AJUBA in primary MMs, which was associated with YAP constitutive activation. We found that AJUBA transduction into MM cells significantly suppressed promoter activities of YAP-target genes, and the suppression of YAP activity by AJUBA was remarkably canceled by knockdown of LATS2. In connection with these results, transduction of AJUBA-expressing lentivirus significantly inhibited the proliferation and anchorage-independent growth of the MM cells that harbored ordinary LATS family expression. Taken together, our findings indicate that AJUBA negatively regulates YAP activity through the LATS family, and inactivation of AJUBA is a novel key mechanism in MM cell proliferation.

Nonsteroidal anti-inflammatory drugs (NSAIDs) induce apoptosis in cancer cells and this effect is involved in their antitumor activity. We recently demonstrated that NSAIDs upregulate GRP78, an endoplasmic reticulum (ER) chaperone, in gastric mucosal cells in primary culture. In the present study, induction of ER chaperones by NSAIDs and the effect of those chaperones on NSAID-induced apoptosis were examined in human gastric carcinoma cells. Celecoxib, an NSAID, upregulated ER chaperones (GRP78 and its cochaperones ERdj3 and ERdj4) but also C/EBP homologous transcription factor (CHOP), a transcription factor involved in apoptosis. Celecoxib also upregulated GRP78 in xenograft tumors, accompanying with the suppression of tumor growth in nude mice. Celecoxib caused phosphorylation of eukaryotic translation initiation factor 2 kinase (PERK) and eukaryotic initiation factor-2 α (eIF2 α ) and production of activating transcription factor (ATF)4 mRNA. Suppression of ATF4 expression by small interfering RNA (siRNA) partially inhibited the celecoxib-dependent upregulation of GRP78. Celecoxib increased the intracellular Ca 2+ concentration, while 1,2-bis(2-aminophenoxy)ethane- N,N,N′N′ -tetraacetic acid, an intracellular Ca 2+ chelator, inhibited the upregulation of GRP78 and ATF4. These results suggest that the Ca 2+ -dependent activation of the PERK-eIF2 α -ATF4 pathway is involved in the upregulation of ER chaperones by celecoxib. Overexpression of GRP78 partially suppressed the apoptosis and induction of CHOP in the presence of celecoxib and this suppression was stimulated by coexpression of either ERdj3 or ERdj4. On the other hand, suppression of GRP78 expression by siRNA drastically stimulated cellular apoptosis and production of CHOP in the presence of celecoxib. These results show that upregulation of ER chaperones by celecoxib protects cancer cells from celecoxib-induced apoptosis, thus may decrease the potential antitumor activity of celecoxib.

Pregnant C57BL/6JJcl mice were exposed to γ rays at low dose rate (20 mGy/day, LDR) or medium dose rate (200 and 400 mGy/day, MDR) from gestation day (GD) 0–18 to total accumulated doses of 360, 3,600 and 7,200 mGy, respectively. An additional group of pregnant mice were acutely exposed to 2 Gy at high dose rate (HDR) of 0.77 Gy/min on GD 11. In experiment 1, fetuses collected via cesarean section on GD 18 were examined for external and skeletal abnormalities. While the results of LDR exposure (20 mGy/day) did not significantly differ from the nonirradiated controls in all parameters examined, MDR (200 and 400 mGy/day) and acute HDR (2 Gy) exposure caused growth retardation and significantly increased incidence of unossified bones. Increased incidence of external abnormalities was observed only in the acute HDR group. In experiment 2, the dams were allowed to give birth and the pups were clinically monitored and weighed periodically until 10 weeks of age when they were sacrificed and subjected to pathological examination. Pups exposed at MDRs of 200 and 400 mGy/dayand at acute HDR of 0.77 Gy/min had lower bodyweights from weaning (3 weeks) to 10 weeks of age except for females exposed to 400 mGy/day MDR. None of the pups exposed to an acute 2 Gy dose on GD 11 survived to 10 weeks of age. Histopathological changes were not significantly different between the nonirradiated control and the 20 mGy/day LDR groups. However, at both MDR exposures of 200 and 400 mGy/day. gonadal (testes and ovary) hypoplasia/atrophy was observed in all the 10-week-old pups. Our results show that in utero LDR exposure to 20 mGy/day for the entire gestation period did not cause any significant effect in pups when compared to the nonirradiated controls up to 10 weeks of age. However, pups exposed in utero to MDRs showed dose-related growth retardation with delayed ossifications (400 mGy/day) and gonadal hypoplasia/atrophy. These findings suggest that increased post-implantation loss in dams exposed at MDR is due to early embryonic deaths resulting in early resorption.

Purpose This study aimed to examine the reliability of extended field-of-view (EFOV) ultrasound imaging to evaluate the cross-sectional area (CSA) and echo intensity of abdominal skeletal muscles. Methods Twenty-seven healthy young males (age 18.6 ± 1.0 years, body mass index 20.9 ± 2.8 kg/m 2 , waist circumference 75.0 ± 7.9 cm, body fat 16.6 ± 5.9%) visited the laboratory on 2 days. EFOV ultrasound images of the rectus abdominis, abdominal oblique, and erector spinae muscles were acquired at the height of the third lumbar vertebra with the subject lying on a bed. We then analyzed CSA and echo intensity using ImageJ software and calculated intra-class correlation coefficients (ICC) and the standard error of measurement (SEM). Results No significant differences ( p  = 0.149–0.679) were observed in CSA or echo intensity values for each skeletal muscle between days. ICC and SEM values in CSA for each skeletal muscle ranged between 0.944 and 0.958 and 4.9% and 7.3%, respectively. The corresponding values for echo intensity were 0.851–0.945 for ICC and 5.3–9.7% for SEM. Conclusions The present results indicate that EFOV ultrasound imaging has high repeatability for measuring CSA and echo intensity of abdominal skeletal muscle groups in healthy college-aged males.

Tanaka, I. B., III, Tanaka, S., Ichinohe, K., Matsushita, S., Matsumoto, T., Otsu, H., Oghiso, Y. and Sato, F. Cause of Death and Neoplasia in Mice Continuously Exposed to Very Low Dose Rates of Gamma Rays. Radiat. Res. 167, 417–437 (2007). Four thousand 8-week-old SPF B6C3F1 mice (2000 of each sex) were divided into four groups, one nonirradiated (control) and three irradiated. The irradiated groups were exposed to 137Cs γ rays at dose rates of 21, 1.1 and 0.05 mGy day−1 for approximately 400 days with total doses equivalent to 8000, 400 and 20 mGy, respectively. All mice were kept until natural death, and pathological examination was performed to determine the cause of death. Neoplasms accounted for >86.7% of all deaths. Compared to the nonirradiated controls, the frequency of myeloid leukemia in males, soft tissue neoplasms and malignant granulosa cell tumors in females, and hemangiosarcoma in both sexes exposed to 21 mGy day−1 were significantly increased. The number of multiple primary neoplasms per mouse was significantly increased in mice irradiated at 21 mGy day−1. Significant increases in body weights were observed from 32 to 60 weeks of age in males and females exposed to 1.1 mGy day−1 and 21 mGy day−1, respectively. Our results suggest that life shortening (Tanaka et al., Radiat. Res. 160, 376–379, 2003) in mice continuously exposed to low-dose-rate γ rays is due to early death from a variety of neoplasms and not from increased incidence of specific neoplasms.

Background and Objectives: Limited information is available on how weight loss intervention programs affect skeletal muscle mass especially in trunk. Methods and Study Design: A total of 235 overweight Japanese men and women aged 40-64 years with a body mass index of 28.0 to 44.8 kg/m2 participated in this randomized controlled intervention study. They were randomly divided into a lifestyle intervention group and control group. Before and after the one-year lifestyle intervention for weight loss an abdominal transverse image was acquired by computed tomography. The cross-sectional areas (CSAs) of visceral fat, subcutaneous fat, and skeletal muscle of rectus abdominis, abdominal oblique, iliopsoas, and erector spinae muscle were calculated. Results: The body weight changed by approximately -5% in the intervention groups. The corresponding values for subcutaneous fat and visceral fat CSAs were -10.8 to -17.5% in both sexes. The reductions observed in skeletal muscle CSAs were significantly less (-6.0% and -7.2% in the men and women intervention groups respectively) than those in fat tissue CSAs. The CSA of each of the four skeletal muscle groups also significantly decreased; however, after adjustments for body weight at each time point, only reductions in the iliopsoas muscle in both sex and abdominal oblique muscles in men remained significant. Conclusions: The lifestyle weight loss intervention might reduce the relative amount of the abdominal skeletal muscles especially in iliopsoas muscle.