Aberrant Glycogen Synthase Kinase 3β Is Involved in Pancreatic Cancer Cell Invasion and Resistance to Therapy

Background and Purpose: The major obstacles to treatment of pancreatic cancer are the highly invasive capacity and resistance to chemo- and radiotherapy. Glycogen synthase kinase 3β (GSK3β) regulates multiple cellular pathways and is implicated in various diseases including cancer. Here we investigate a pathological role for GSK3β in the invasive and treatment resistant phenotype of pancreatic cancer. Methods: Pancreatic cancer cells were examined for GSK3β expression, phosphorylation and activity using Western blotting and in vitro kinase assay. The effects of GSK3β inhibition on cancer cell survival, proliferation, invasive ability and susceptibility to gemcitabine and radiation were examined following treatment with a pharmacological inhibitor or by RNA interference. Effects of GSK3β inhibition on cancer cell xenografts were also examined. Results: Pancreatic cancer cells showed higher expression and activity of GSK3β than non-neoplastic cells, which were associated with changes in its differential phosphorylation. Inhibition of GSK3β significantly reduced the proliferation and survival of cancer cells, sensitized them to gemcitabine and ionizing radiation, and attenuated their migration and invasion. These effects were associated with decreases in cyclin D1 expression and Rb phosphorylation. Inhibition of GSK3β also altered the subcellular localization of Rac1 and F-actin and the cellular microarchitecture, including lamellipodia. Coincident with these changes were the reduced secretion of matrix metalloproteinase-2 (MMP-2) and decreased phosphorylation of focal adhesion kinase (FAK). The effects of GSK3β inhibition on tumor invasion, susceptibility to gemcitabine, MMP-2 expression and FAK phosphorylation were observed in tumor xenografts. Conclusion: The targeting of GSK3β represents an effective strategy to overcome the dual challenges of invasiveness and treatment resistance in pancreatic cancer. © 2013 Kitano et al

Why Are Outcomes Different for Registry Patients Enrolled Prospectively and Retrospectively? Insights from the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF).

Background: Retrospective and prospective observational studies are designed to reflect real-world evidence on clinical practice, but can yield conflicting results. The GARFIELD-AF Registry includes both methods of enrolment and allows analysis of differences in patient characteristics and outcomes that may result. Methods and Results: Patients with atrial fibrillation (AF) and ≥1 risk factor for stroke at diagnosis of AF were recruited either retrospectively (n = 5069) or prospectively (n = 5501) from 19 countries and then followed prospectively. The retrospectively enrolled cohort comprised patients with established AF (for a least 6, and up to 24 months before enrolment), who were identified retrospectively (and baseline and partial follow-up data were collected from the emedical records) and then followed prospectively between 0-18 months (such that the total time of follow-up was 24 months; data collection Dec-2009 and Oct-2010). In the prospectively enrolled cohort, patients with newly diagnosed AF (≤6 weeks after diagnosis) were recruited between Mar-2010 and Oct-2011 and were followed for 24 months after enrolment. Differences between the cohorts were observed in clinical characteristics, including type of AF, stroke prevention strategies, and event rates. More patients in the retrospectively identified cohort received vitamin K antagonists (62.1% vs. 53.2%) and fewer received non-vitamin K oral anticoagulants (1.8% vs . 4.2%). All-cause mortality rates per 100 person-years during the prospective follow-up (starting the first study visit up to 1 year) were significantly lower in the retrospective than prospectively identified cohort (3.04 [95% CI 2.51 to 3.67] vs . 4.05 [95% CI 3.53 to 4.63]; p = 0.016). Conclusions: Interpretations of data from registries that aim to evaluate the characteristics and outcomes of patients with AF must take account of differences in registry design and the impact of recall bias and survivorship bias that is incurred with retrospective enrolment. Clinical Trial Registration: - URL: http://www.clinicaltrials.gov . Unique identifier for GARFIELD-AF (NCT01090362)

Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362

南九州の火山灰と土器型式 : アカホヤ火山灰以降

名古屋大学タンデトロン加速器質量分析計シンポジウム(1995年度)講演予稿集 ｢南九州の火山噴火と遺跡の年代をさぐる｣ -加速器質量分析計による14C年代測定と考古編年,古環境に関する研究

THE MAIN CAUSE OF “SINKING EVENT” AT A COMPENSATIVE ARTIFICIAL TIDAL FLAT IN OKINOSU, TOKUSHIMA CITY

徳島市沖洲地区にある人工海浜は，埋め立てられる既存海浜の代償措置として造成されたが，既存海浜の底生生物相を再現できていなかった．決定的な違いはホソウミニナの有無であり，その原因は沖洲人工海浜で確認されている「沈み込み現象」によるものと推察された．筆者らは「沈み込み現象」の発生原因として，ニホンスナモグリに着目した．その結果「沈み込み現象」は，ニホンスナモグリの生息域のみで発生していること，加えてニホンスナモグリを排除すると「沈み込み現象」は発生しないことを示した．また，ニホンスナモグリはホソウミニナの生残に負の影響を与えることも分かった．しかしニホンスナモグリを排除することで，底生生物相が貧弱になる結果も示されており，ニホンスナモグリが干潟生態系へ与える影響は極めて複雑であることが示された．An artificial tidal flat was created in 2007, to compensate for the loss of a natural tidal flat, at Okinosu, Tokushima City. However, five years after its creation, it was found that the ecological conditions in the artificial habitat of benthic animals differed vastly from those in the natural habitat. In particular, the mud snail Batillaria cumingi, which dominates natural tidal flats, was rarely found in the artificial habitat.  We tested the hypothesis that the “sinking event” was caused due to bioturbation by the ghost shrimp, Nihonotrypaea japonica. The “sinking event” occurred only at the places where N. japonica was abundant. Therefore, it seemed that bioturbation by N. japonica was the cause of the “sinking event”. Although exclusive treatment with N. japonica led to a low-biodiversity assemblage, N. japonica has both positive and negative effects on the tidal flat ecosystem

CARBON DIOXIDE FLUXS AT WATER AND SEDIMENT IN THE URBAN COASTAL TIDAL FLAT OF OSAKABAY

本研究では大阪湾沿岸部の13地点の干潟を対象に水質項目，底質環境，水面と堆積物のCO2フラックスを定量化し，その関係性を明らかにすることを目的に調査を行った．大阪湾の干潟は全体的に砂質で構成されており，化学的性状から好気的な環境であった．水面におけるCO2フラックスは13地点中8地点で放出を示し，湾奥の河川の影響が強い地点でCO2は放出傾向にあった．堆積物における1日当たりのCO2フラックスは矢倉海岸と男里川を除いてCO2は放出であり，1日当たりのCO2フラックスは水面より高いことから，堆積物では有機物の分解の場としてCO2は放出されていることが推察された．以上のことから，干潟では水面からCO2は放出傾向であり，堆積物は干出することで，有機物の分解が促進されてCO2は放出していることが考えられた．The objective of this study was to quantify the relationships between water surface and sediment CO2 fluxes on 13 tidal flats in the coastal area of Osaka Bay. The tidal flats are generally composed of sandy sediments, and their chemical properties indicate an aerobic environment. CO2 fluxes at the water surface of the tidal flats showed a release at 8 of the 13 sites, and CO2 tended to be released at the sites with strong river influence at inner part of Osaka bay. The daily CO2 flux in the sediments was higher than that in the water surface, suggesting that CO2 is released in the sediments as decomposition of organic matter. These results suggest that CO2 tends to be released from the water surface on tidal flats, and that CO2 at sediments is released by the decomposition of organic matter accelerated in low tide