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Background: This study investigated the usefulness of a novel inflammation-based prognostic system, named the COP-NLR (COmbination of Platelet count and Neutrophil to Lymphocyte Ratio), for predicting the postoperative survival of patients with colorectal cancer (CRC). Methods: The COP-NLR was calculated on the basis of data obtained on the day of admission: patients with both an elevated platelet count (>30 × 10 4  mm −3 ) and an elevated NLR (>3) were allocated a score of 2, and patients showing one or neither were allocated a score of 1 or 0, respectively. Results: Four-hundred and eighty patients were enrolled. Multivariate analysis of clinical characteristics selected by univariate analysis showed that the COP-NLR (1, 2/0) (odds ratio, 0.464; 95% confidence interval, 0.267–0.807; P =0.007) had an association with cancer-specific survival, along with pathology, lymph node metastasis, the serum levels of carcinoembryonic antigen, C-reactive protein and albumin, and the Glasgow Prognostic Score. Kaplan–Meier analysis and log-rank test revealed that the COP-NLR was able to divide such patients into three independent groups ( P <0.001). Conclusion: The COP-NLR is considered to be a useful predictor of postoperative survival in patients with CRC.

Information about the ecotoxicological impacts of surface waters that receive discharges from legacy mines is valuable to infer the ecological impacts on natural environment for managing mine discharges. In this study, we investigated behavioural and reproductive responses of two cladoceran species Ceriodaphnia dubia and Daphnia magna to water samples collected from metal-contaminated and reference rivers near legacy mines in Japan. The toxicity identification evaluation (TIE) of water samples that caused D. magna immobility was conducted to evaluate the key metals causing acute toxicity. The results of our water quality assessment performed using two cladoceran species demonstrated modest to significant adverse effects on their behaviour and reproduction, suggesting the potential for ecotoxicological impacts on natural populations and communities at several contaminated sites that received mine drainage. The results of TIE of water samples that caused D. magna immobility indicated likely contributions of Zn and Cu. These results imply that effect-based water quality assessments such as ours can provide direct and unique evidence of the ecotoxicological impacts of metals in river waters, which will be useful for better understanding and predicting the ecological effects of these metals in the natural environment.

Oligonucleotides are key elements of nucleic acid therapeutics such as small interfering RNAs (siRNAs). Influenza and Ebolaviruses are zoonotic RNA viruses mutating very rapidly, and their sequence changes must be characterized intensively to design therapeutic oligonucleotides with long utility. Focusing on a total of 182 experimentally validated siRNAs for influenza A, B and Ebolaviruses compiled by the siRNA database, we conducted time-series analyses of occurrences of siRNA targets in these viral genomes. Reflecting their high mutation rates, occurrences of target oligonucleotides evidently fluctuate in viral populations and often disappear. Time-series analysis of the one-base changed sequences derived from each original target identified the oligonucleotide that shows a compensatory increase and will potentially become the ‘awaiting-type oligonucleotide’; the combined use of this oligonucleotide with the original can provide therapeutics with long utility. This strategy is also useful for assigning diagnostic reverse transcription-PCR primers with long utility.

Skeletal resistance to parathyroid hormone (PTH) is well known to the phenomenon in chronic renal failure patient, but the detailed mechanism has not been elucidated. In the process of analyzing an animal model of renal failure with low bone turnover, we demonstrated decreased expression of PTH receptor (PTHR) accompanying renal dysfunction in this model. In the present study, we focused on the accumulation of uremic toxins (UTx) in blood, and examined whether indoxyl sulfate (IS), a UTx, is associated with PTH resistance. We established primary osteoblast cultures from mouse calvariae and cultured the cells in the presence of IS. The intracellular cyclic adenosine 3′,5′ monophosphate (cAMP) production, PTHR expression, and free radical production in the primary osteoblast culture were studied. We found that the addition of IS suppressed PTH-stimulated intracellular cAMP production and decreased PTHR expression in this culture system. Free radical production in osteoblasts increased depending on the concentration of IS added. Furthermore, expression of organic anion transporter-3 (OAT-3) that is known to mediate cellular uptake of IS was identified in the primary osteoblast culture. These results suggest that IS taken up by osteoblasts via OAT-3 present in these cells augments oxidative stress to impair osteoblast function and downregulate PTHR expression. These finding strongly suggest that IS accumulated in blood due to renal dysfunction is at least one of the factors that induce skeletal resistance to PTH.

KRAS mutations are one of the most common driver mutations in non-small-cell lung cancer (NSCLC) and finding druggable target molecules to inhibit oncogenic KRAS signaling is a significant challenge in NSCLC therapy. We recently identified epiregulin ( EREG ) as one of several putative transcriptional targets of oncogenic KRAS signaling in both KRAS -mutant NSCLC cells and immortalized bronchial epithelial cells expressing ectopic mutant KRAS . In the current study, we found that EREG is overexpressed in NSCLCs harboring KRAS , BRAF or EGFR mutations compared with NSCLCs with wild-type KRAS / BRAF / EGFR . Small interfering RNAs (siRNAs) targeting mutant KRAS , but not an siRNA targeting wild-type KRAS , significantly reduced EREG expression in KRAS -mutant and EREG -overexpressing NSCLC cell lines. In these cell lines, EREG expression was downregulated by MEK and ERK inhibitors. Importantly, EREG expression significantly correlated with KRAS expression or KRAS copy number in KRAS -mutant NSCLC cell lines. Further expression analysis using 89 NSCLC specimens showed that EREG was predominantly expressed in NSCLCs with pleural involvement, lymphatic permeation or vascular invasion and in KRAS -mutant adenocarcinomas. In addition, multivariate analysis revealed that EREG expression is an independent prognostic marker and EREG overexpression in combination with KRAS mutations was associated with an unfavorable prognosis for lung adenocarcinoma patients. In KRAS -mutant and EREG overexpressing NSCLC cells, siRNA-mediated EREG silencing inhibited anchorage-dependent and -independent growth and induced apoptosis. Our findings suggest that oncogenic KRAS-induced EREG overexpression contributes to an aggressive phenotype and could be a promising therapeutic target in oncogenic KRAS-driven NSCLC.

Connective tissue disease (CTD) associated pulmonary arterial hypertension (PAH) is considered to be an indication for immunosuppressive therapy (IT) except scleroderma associated PAH. However, the response rate defined by improvement of WHO functional class and hemodynamic parameters is reported to be around 50% [1]. Since CTDs are systemic diseases, it may be difficult to evaluate the efficacy of IT by subjective symptoms. Although there are previous studies reporting that the combined use of IT and pulmonary vasodilators significantly improved hemodynamics [2], response to IT without titration of pulmonary vasodilators remains to be elucidated. To examine whether IT is effective for CTD-PAH. We retrospectively examined the medical records of consecutive 13 patients with CTD-PAH (female 13, mean age 47 ± 15 years) treated with methylprednisolone (1 mg/kg/day, oral) and intravenous bolus cyclophosphamide (IVCY) (500 mg/m2) every four weeks for six times. Patient characteristics are described in Table 1. Right heart catheterization (RHC) was done at prior to IT, before adding PAH specific agents, and at the fifth or sixth course of IVCY. In treated cases, the previous vasodilators remained unchanged during the first term of IT. At the first follow up RHC, decrease of mean pulmonary arterial pressure over 5 mmHg was observed in all patients, and decrease of pulmonary vascular resistance (PVR) was observed in twelve out of 13 patients (Figure 1). Over 20% of PVR reduction was observed more in the patients of pulmonary vasodilator naïve and started IT within one year from symptoms than others (6/7 vs 1/6, p=0.03). Although six-minutes walk distance (6MWD) tended to be prolonged between first and second RHC (298 ± 70 m vs 382 ± 81 m; p=0.054; n = 9), 6MWD was shortened in some cases with good hemodynamic improvement (2/5). All patients were prescribed oral PAH specific agents finally, but no one needed parenteral prostanoids. Two patients (15%) died during maintenance therapy for causes other than PAH. Three-year and five-year survival rates were 91.7% and 81.5%, respectively. IT without titration of pulmonary vasodilators significantly improved hemodynamic parameters despite of less improvement in 6MWD in CTD-PAH patients. Considering that CTDs itself might affect the exercise tolerance regardless of PAH, these hemodynamic changes may contribute to better prognosis and IT might be considered especially for patients early in clinical courses and treatment naïve. [1]Jais X, Launay D, Yaici A, et al. Immunosupressive therapy in lupus-and mixed connective tissue disease-associated pulmonary arterial hypertension. ARTHRITIS RHEUM. 2008; 58(2): 521-531. [2]Yamamoto M S, Fukumoto Y, Sugimura K, et al. Intensive immunosuppressive therapy improves pulmonary hemodynamics and long-term prognosis in patients with pulmonary arterial hypertension associated with connective tissue diseasae. Circ J. 2011; 75: 2668-2674. Risa Kishikawa: None declared, Masaru Hatano Speakers bureau: Janssen Pharmaceutical K.K, Bayer Yakuhin, Ltd., Grant/research support from: Janssen Pharmaceutical K.K, Nippon Shinyaku Co., Ltd., MOCHIDA PHARMACEUTICAL CO., LTD., Satoshi Ishii: None declared, Mai Shimbo: None declared, Akihito Saito: None declared, Shun Minatsuki: None declared, Yukiko Iwasaki: None declared, Keishi Fujio Speakers bureau: Tanabe Mitsubishi, Bristol Myers, Eli Lilly, Chugai, Jansen, Pfizer, Ono, AbbVie, Ayumi, Astellas, Sanofi, Novartis, Daiichi Sankyo, Eisai, Asahi Kasei, Japan Blood Products Organization, and Kowa, Grant/research support from: Tanabe Mitsubishi, Bristol Myers, Eli Lilly, Chugai, AbbVie, Ayumi, Astellas, Sanofi, Eisai, Tsumura & Co., and Asahi Kasei., Issei Komuro Speakers bureau: AstraZeneka, Daiichi Sankyo Company, Limited, Takeda Pharmaceutical Company Limited, Bayer Yakuhin, Ltd, Pfizer Japan Inc., and Ono Pharmaceutical Co., Ltd., Grant/research support from: Daiichi Sankyo Company, Ltd, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Ltd, Mitsubishi Tanabe Pharma Corporation, Teijin Pharma Limited, Idorsia Pharmaceuticals Ltd, Otsuka Pharmaceutical Co., Ltd., Bayer Yakuhin, Ltd. Ono Pharmaceutical Co., Ltd. Toa Eiyo Ltd [Display omitted] Table 1Characteristics of patientsPatientAge,yrConnective Tissue DiseaseYears from symptom to immunosuppressive therapyPrevious vasodilatorsvasodilators at final visit147SS1.5PGI2ERA262SS, RA2nonePDE5332SS1noneERA457SS, SSc0.5nonePDE5526SS,MCTD, SLE,SSc0.5nonePDE5670SSc, SS s/o13sGC, ERAsGC, ERA732SS s/o, SLE0.1nonePDE5831MCTD3ERA,PDE5, PGI2ERA,PDE5, PGI2943SSc, SLE0.6ERA, PDE5ERA,PDE5, PGI21067MCTD,PM0nonesGC1141SS0.1noneERA, PDE51269SS0.3nonePDE51344SS, MCTD s/o, SLE s/o0.1noneERA, sGCN.A, not acquired; s/o, suspect of; SS, Sjögren's syndrome; RA, rheumatoid arthritis; SSc systemic sclerosis; SLE, systemic lupus erythematosus; MCTD, mixed connective tissue disease; PM, Polymyositis; PGI2, prostacyclin derivative; sGC, soluble guanylate cyclase stimulator; ERA, endothelin receptor antagonist; PDE5, phosphodiesterase type 5 inhibitor.

Almost 100% of domestic water is covered by groundwater in the Kumamoto region, Japan. However, in recent years, the groundwater recharge area (particularly paddy fields) has been significantly decreasing, and the groundwater level has been gradually dropping in some places. Aside from this, the groundwater level was abnormally changed as an impact of the 2016 Kumamoto earthquake. Our final goal is to build a model to represent the groundwater level change including the abnormal change. For this purpose, we generated a land cover map by using temporal Normalized Difference Vegetation Index (NDVI) changes based on Landsat-8 satellite images and Geographic Information System (GIS) data. Our classification results well expressed the actual land cover especially around rivers, lakes and buildings compared with the existing land cover map. The calculated infiltration and surface runoff amounts from grasslands with the different land uses indicated the importance of understanding not only land covers but also land uses to evaluate infiltration and surface runoff amounts.

Zitterbewegung (ZB; trembling motion) is one of the peculiar phenomena predicted in the Dirac equation in that the velocity and the spatial coordinate cannot be well defined kinetic constant. While the ZB in vacuum is far out of reach, feasibility of observation in solids has been discussed though very few experiments have been reported yet. We here report the ZB in two-dimensional electron gas with strong Rashba-type spin-orbit coupling causes large fluctuation in conductance. Such an experiment was impossible until recent development of point contact injectors with spin-polarised electrons. Numerical calculations on a simple model successfully simulate the experimental observations.

In Minamiaso Village (Kumamoto Prefecture, Japan), land covers of forests, grasslands, and paddy fields play an important role in groundwater recharge. The land covers have been changed in a past few decades by agricultural systems and natural disasters: landslides, slope failures, and damage of irrigation canals caused by the 2016 Kumamoto earthquake in Japan. In this study, we extracted training data for classifying the land covers, and detected the temporal change of NDVI (Normalized Difference Vegetation Index) for each land cover. To quantify the impact of past land cover change on the groundwater recharge, we need to grasp the area of each land cover with the different hydrological parameters such as infiltration capacities. In the case of paddy fields, its distribution also should be known because the infiltration rates that we investigated vary depending on the paddy fields. We attempted to identify the paddy field distribution by the obtained NDVI values, and confirmed that the paddy field areas near the earthquake faults damaged by the earthquake where are still not usable were well distinguished. The paddy field distribution based on NDVI was almost matched with that based on SAR.