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Background: Epithelial-to-mesenchymal transition (EMT) is a fundamental process governing not only morphogenesis in multicellular organisms, but also cancer progression. During EMT, epithelial cadherin (E-cadherin) is downregulated while neural cadherin (N-cadherin) is upregulated, referred to as ‘cadherin switch’. This study aimed to investigate whether cadherin switch promotes cancer progression in cholangiocarcinoma (CC). Methods: CC cell lines were examined for migration, invasion, and morphological changes with typical EMT-induced model using recombinant TGF- β 1. The changes in E-cadherin and N-cadherin expression were investigated during EMT. We also examined E-cadherin and N-cadherin expression in resected specimens from extrahepatic CC patients ( n =38), and the associations with clinicopathological factors and survival rates. Results: TGF- β 1 treatment activated cell migration, invasion, and fibroblastic morphological changes, especially in extrahepatic CC HuCCT-1 cells. These changes occurred with E-cadherin downregulation and N-cadherin upregulation, that is, cadherin switch. Patients with low E-cadherin expression had a significantly lower survival rate than patients with high E-cadherin expression ( P =0.0059). Patients with decreasing E-cadherin and increasing N-cadherin expression had a significantly lower survival rate than patients with increasing E-cadherin and decreasing N-cadherin expression ( P =0.017). Conclusion: Cadherin switch promotes cancer progression via TGF- β -induced EMT in extrahepatic CC, suggesting a target for elucidating the mechanisms of invasion and metastasis in extrahepatic CC.

Wave climate is a primary driver of coastal risk, yet how climate change is altering wave climate is not fully understood. Here we identify transitional wave climate regions, coastlines with a future change in the occurrence frequency of a wave climate, with most of the regions located in south-western and eastern ocean basins. Analysis of the spatio-temporal changes in the atmosphere-driven major wave climates (the easterlies, southerlies and westerlies) under 2 emission scenarios for 2075–2099 and 2081–2099 shows increases in frequency from 5 to 20% for the easterly and southerly wave climates. The projected changes in these regions, in addition to sea-level rise and changes in storminess, can modify the general patterns of the prevailing wave climates and severely alter their coastal risks. Consequently, transitional wave climate regions should be recognized as areas of high coastal climate risk that require focus for adaptation in the near term.Changes in wave climate can pose substantial risk to coastal areas. Here transitional wave climate regions—areas where a wave climate will increase its frequency of occurrence—are identified and classified with implications for understanding future coastal risk.

Historical trends in the direction and magnitude of ocean surface wave height, period, or direction are debated due to diverse data, time-periods, or methodologies. Using a consistent community-driven ensemble of global wave products, we quantify and establish regions with robust trends in global multivariate wave fields between 1980 and 2014. We find that about 30-40% of the global ocean experienced robust seasonal trends in mean and extreme wave height, period, and direction. Most of the Southern Hemisphere exhibited strong upward-trending wave heights (1-2 cm per year) and periods during winter and summer. Ocean basins with robust positive trends are far larger than those with negative trends. Historical trends calculated over shorter periods generally agree with satellite records but vary from product to product, with some showing a consistently negative bias. Variability in trends across products and time-periods highlights the importance of considering multiple sources when seeking robust change analyses.

Recurrence is frequently associated with the acquisition of radioresistance by tumors and resulting failures in radiotherapy. We report, in this study, that long-term fractionated radiation (FR) exposures conferred radioresistance to the human tumor cells, HepG2 and HeLa with cyclin D1 overexpression. A positive feedback loop was responsible for the cyclin D1 overexpression in which constitutively active AKT was involved. AKT is known to inactivate glycogen synthase kinase-3β (GSK3β), which is essential for the proteasomal degradation of cyclin D1. The resulting cyclin D1 overexpression led to the forced progression of S-phase with the induction of DNA double strand breaks. Cyclin D1-dependent DNA damage activated DNA-dependent protein kinase (DNA-PK), which in turn activated AKT and inactivated GSK3β, thus completing a positive feedback loop of cyclin D1 overproduction. Cyclin D1 overexpression led to the activation of DNA damage response (DDR) consisted of ataxia telangiectasia mutated (ATM)- and Chk1-dependent DNA damage checkpoint and homologous recombination repair (HRR). Long-term FR cells repaired radiation-induced DNA damage faster than non-FR cells. Thus, acquired radioresistance of long-term FR cells was the result of alterations in DDR mediated by cyclin D1 overexpression. Inhibition of the AKT/GSK3β/cyclin D1/Cdk4 pathway by the AKT inhibitor, Cdk4 inhibitor or cyclin D1 targeting small interfering RNA (siRNA) suppressed the radioresistance. Present observations give a mechanistic insight for acquired radioresistance of tumor cells by cyclin D1 overexpression, and provide novel therapeutic targets for recurrent radioresistant tumors.

There are numerous global ocean wave reanalysis and hindcast products currently being distributed and used across different scientific fields. However, there is not a consistent dataset that can sample across all existing products based on a standardized framework. Here, we present and describe the first coordinated multi-product ensemble of present-day global wave fields available to date. This dataset, produced through the Coordinated Ocean Wave Climate Project (COWCLIP) phase 2, includes general and extreme statistics of significant wave height (Hs), mean wave period (Tm) and mean wave direction (θm) computed across 1980–2014, at different frequency resolutions (monthly, seasonally, and annually). This coordinated global ensemble has been derived from fourteen state-of-the-science global wave products obtained from different atmospheric reanalysis forcing and downscaling methods. This data set has been processed, under a specific framework for consistency and quality, following standard Data Reference Syntax, Directory Structures and Metadata specifications. This new comprehensive dataset provides support to future broad-scale analysis of historical wave climatology and variability as well as coastal risk and vulnerability assessments across offshore and coastal engineering applications.Measurement(s)Significant wave height • Mean wave period • Mean wave directionTechnology Type(s)Global wave reanalysis and hindcastsSample Characteristic - EnvironmentWind-wavesSample Characteristic - LocationGlobal

Radiotherapy is a well-established treatment for cancer. However, the existence of radioresistant cells is one of the major obstacles in radiotherapy. In order to understand the mechanism of cellular radioresistance and develop more effective radiotherapy, we have established clinically relevant radioresistant (CRR) cell lines, which continue to proliferate under daily exposure to 2 Gray (Gy) of X-rays for >30 days. X-ray irradiation significantly induced autophagic cells in parental cells, which was exiguous in CRR cells, suggesting that autophagic cell death is involved in cellular radiosensitivity. An autophagy inducer, rapamycin sensitized CRR cells to the level of parental cells and suppressed cell growth. An autophagy inhibitor, 3-methyladenine induced radioresistance of parental cells. Furthermore, inhibition of autophagy by knockdown of Beclin-1 made parental cells radioresistant to acute radiation. These suggest that the suppression of autophagic cell death but not apoptosis is mainly involved in cellular radioresistance. Therefore, the enhancement of autophagy may have a considerable impact on the treatment of radioresistant tumor.

Background: Tropomyosin-related receptor kinase B (TrkB) promotes proliferation and invasion, relating to poor prognosis of various malignancies. We examined the role of TrkB at the invasive front of gastric cancer (GC) and its association with tumour cell dedifferentiation and tumour budding. Methods: Immunoreactive TrkB was evaluated at the tumour centre and margin using whole-tissue sections of 320 GC patients. Tumour cell dedifferentiation was defined as higher histologic grade at the tumour margin than the surface or tumour centre. Tumour budding was also scored on cytokeratin-stained sections. Results: Sixty-five patients (20%) showed higher TrkB expression at the invasive front (TrkB expression was higher at the tumour margin than tumour centre). It was significantly associated with several aggressive phenotypes in the full cohort ( n =320). It showed a prognostic significance in test subgroup ( n =98) and was identified as an independent prognostic factor (HR=2.09; 95% CI: 1.26–3.53) by multivariate analysis in validation subgroup ( n =222). Twenty-one patients showed tumour cell dedifferentiation. In predominantly differentiated tumour, higher TrkB at the invasive front was significantly associated with tumour budding rather than tumour cell dedifferentiation. Conclusions: Assessment of immunoreactive TrkB at the invasive front by whole-tissue sections provides prognostic information for GC patients.

Herein we summarize the public health actions taken to mitigate exposure of the public to radiation after the Fukushima accident that occurred on 11 March 2011 in order to record valuable lessons learned for disaster preparedness. Evacuations from the radiation-affected areas and control of the distribution of various food products contributed to the reduction of external and internal radiation exposure resulting from the Fukushima incident. However, risk communication is also an important issue during the emergency response effort and subsequent phases of dealiing with a nuclear disaster. To assist with their healing process, sound, reliable scientific information should continue to be disseminated to the radiation-affected communities via two-way communication. We will describe the essential public health actions following a nuclear disaster for the early, intermediate and late phases that will be useful for radiological preparedness planning in response to other nuclear or radiological disasters.

Radioresistance, which is a major cause of failure of radiotherapy (RT), is proposed as one of the intrinsic characteristics of cancer stem cells (CSCs) whose unique DNA damage response (DDR), efficient DNA repair and resistance to apoptosis are thought to confer the phenotype. We have isolated surviving CSCs by exposure to long-term fractionated radiation for 82 days from HepG2 and A172 cells (82FR-31NR cells). 82FR-31NR cells exhibited CSC properties, such as high expression of CSC marker CD133 and the ABC transporters (MDR1 and BCRP1), and high tumorigenic potential after transplantation into nude mice. The advantage of our isolated CSCs is that they can proliferate in as the same growth medium as that of parental cells without loss of CSC properties. Therefore, we can analyze DDR of non-stem cells and CSCs without any influences caused by different culture conditions. 82FR-31NR cells showed efficient DNA repair of radiation-induced DNA damage and radioresistance with activation of the AKT/cyclin D1 survival signaling pathway. In contrast, DNA damage persisted for a long time after irradiation in parental cells compared with isolated CSCs. Persisted DNA damage induced apoptosis in parental cells without activation of the AKT/cyclin D1 pathway. Therefore, inhibition of the AKT/cyclin D1 pathway by an AKT inhibitor, API-2, or cyclin D1 siRNA resulted in a loss of efficient DNA repair and radiosensitization of 82FR-31NR cells. Furthermore, knockdown of Cdk4 by its siRNA or a Cdk4 inhibitor was sufficient to suppress radioresistance of CSCs. In this study, we present a newly discovered DDR regarding the AKT/cyclin D1/Cdk4 pathway in response to radiation in CSCs. Combination of fractionated RT and reagents targeting the AKT/cyclin D1/Cdk4 pathway to eradicate CSCs would be effective therapeutic modality.