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Background: A growing body of evidence suggests that non-viral hepatocellular carcinoma (HCC) might benefit less from immunotherapy. Materials and methods: We carried out a retrospective analysis of prospectively collected data from consecutive patients with non-viral advanced HCC, treated with atezolizumab plus bevacizumab, lenvatinib, or sorafenib, in 36 centers in 4 countries (Italy, Japan, Republic of Korea, and UK). The primary endpoint was overall survival (OS) with atezolizumab plus bevacizumab versus lenvatinib. Secondary endpoints were progression-free survival (PFS) with atezolizumab plus bevacizumab versus lenvatinib, and OS and PFS with atezolizumab plus bevacizumab versus sorafenib. For the primary and secondary endpoints, we carried out the analysis on the whole population first, and then we divided the cohort into two groups: non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) population and non-NAFLD/NASH population. Results: One hundred and ninety patients received atezolizumab plus bevacizumab, 569 patients received lenvatinib, and 210 patients received sorafenib. In the whole population, multivariate analysis showed that treatment with lenvatinib was associated with a longer OS [hazard ratio (HR) 0.65; 95% confidence interval (CI) 0.44-0.95; P = 0.0268] and PFS (HR 0.67; 95% CI 0.51-0.86; P = 0.002) compared to atezolizumab plus bevacizumab. In the NAFLD/NASH population, multivariate analysis confirmed that lenvatinib treatment was associated with a longer OS (HR 0.46; 95% CI 0.26-0.84; P = 0.0110) and PFS (HR 0.55; 95% CI 0.38-0.82; P = 0.031) compared to atezolizumab plus bevacizumab. In the subgroup of non-NAFLD/NASH patients, no difference in OS or PFS was observed between patients treated with lenvatinib and those treated with atezolizumab plus bevacizumab. All these results were confirmed following propensity score matching analysis. By comparing patients receiving atezolizumab plus bevacizumab versus sorafenib, no statistically significant difference in survival was observed. Conclusions: The present analysis conducted on a large number of advanced non-viral HCC patients showed for the first time that treatment with lenvatinib is associated with a significant survival benefit compared to atezolizumab plus bevacizumab, in particular in patients with NAFLD/NASH-related HCC.

AIM To validate the utility of hepatic resection combined with complementary radiofrequency ablation (RFA) compared with resection alone for patients with multiple hepatocellular carcinoma (HCC), and to compare these results with those of a previous report. MATERIALS AND METHODS A total of 78 HCC patients with multiple (≤5) tumours who were initially treated with hepatic resection only (Resection group) or with combined hepatic resection and RFA (Combination group) were included. Overall and disease-free survival were analysed. RESULTS There were 21 women and 57 men with a median age of 72.5 (64.3–76.8) years. Fifty-three patients were treated with resection alone and 25 received combination therapy. The 3-, 5-, and 7-year cumulative overall survival rates were 81.2%, 68.2%, and 57.1%, respectively, in the Resection group, and 81.3%, 59.6%, and 42.4%%, respectively, in the Combination group (hazard ratio [HR], 1.462; 95% confidence interval [CI], 0.682–3.136; p=0.329). The 1-, 3-, and 5-year cumulative disease-free survival rates were 61.4%, 45.7%, and 39.8%, respectively, in the Resection group, and 53.1%, 18.6%, and 0%, respectively, in the Combination group (HR, 2.080; 95% CI, 1.157–3.737; p=0.014). The overall survival rate was not significantly different between the Resection and Combination groups in patients within the up-to-seven HCC criteria (n=56; HR, 2.101; 95% CI, 0.805–5.486; p=0.130) or those beyond these criteria (n=22; HR, 0.804; 95% CI, 0.197–3.286; p=0.761). CONCLUSIONS The combination of hepatic resection and RFA therapy may be an effective strategy for HCC patients with multiple tumours.

Hexavalent chromium [Cr(VI)] is a well-known and widespread environmental contaminant associated with a variety of adverse health effects, in particular lung cancer. The primary route of exposure in humans is through inhalation. Particulate forms of Cr(VI) are the most potent but in vivo studies are difficult. Intratracheal instillation requires highly trained surgical procedures which also limits the number of repeated exposures possible and thus requires high doses. Inhalation studies can deliver lower more chronic doses but are expensive and generate dangerous aerosols. We evaluated an oropharyngeal aspiration exposure route for zinc chromate particles in Wistar rats. Animals were treated once per week for 90 days. We found chromium accumulated in the lungs, blood, and reproductive tissues of all treated animals. Additionally, we found inflammatory indicators in the lung were elevated and circulating lymphocytes had increased chromosomal damage. These results show oropharyngeal aspiration provides a practicable exposure route for chronic and sub-chronic exposures of Cr(VI) particles.

Lung cancer is the leading cause of cancer death; however, the mechanisms of lung carcinogens are poorly understood. Metals, including hexavalent chromium [Cr(VI)], induce chromosome instability, an early event in lung cancer. Failure of homologous recombination repair is a key mechanism for chromosome instability. Particulate Cr(VI) causes DNA double-strand breaks and prolonged exposure impairs homologous recombination targeting a key effector protein in this pathway, RAD51. Reduced RAD51 protein is a key endpoint of particulate Cr(VI) exposure. It is currently unknown how Cr(VI) reduces RAD51 protein. E2F1 is the predominant transcription factor for RAD51. This study sought to identify if E2F1 modulates the RAD51 response to particulate Cr(VI). Particulate Cr(VI) reduced RAD51 protein and mRNA levels but had a minimal effect on RAD51 half-life. E2F1 protein and mRNA were also inhibited by particulate Cr(VI) exposure. To connect these two outcomes, we tested if modulating E2F1 affects RAD51 outcomes after particulate Cr(VI) exposure. E2F1 knockdown inhibited RAD51 nuclear foci formation after acute particulate Cr(VI) exposure. These data indicate reduced RAD51 protein levels after prolonged particulate Cr(VI) exposure are predominantly due to inhibited expression. Particulate Cr(VI) also inhibits E2F1 expression. However, although loss of E2F1 does not modulate RAD51 expression after particulate Cr(VI) exposure, RAD51 nuclear foci formation is inhibited. These findings suggest E2F1 is important for RAD51 localization to double-strand breaks, but not expression after particulate Cr(VI) exposure in human lung cells.

Cultivation management adapted to various environmental changes has been required under changing climate, hence it is necessary to monitor the growth status efficiently. Photosynthesis in crop production is the essential process in crop growth model for forecasting the yield. In this study, we focused on light environment and LAI as important factors in photosynthesis, and conducted the observations to obtain time-series RGB images taken by digital cameras fixed on tower and mounted on UAV in the paddy field and to measure PPFDs at the top (I0) and the bottom (I) of rice canopy during planted period. Three kinds of vegetation color indices (CIs), vegetation coverage (VC) and plant height (PH) derived by processing RGB images were compared with relative PPFD (I/I0) and LAI calculated from relative PPFD. As the results, CIs and VC were basically expressed linear relations with relative PPFD and PH showed the exponential relation with relative PPFD and the linear relation with LAI respectively. Through this study, we clarified that VC and PH would be effective parameters for spatio-temporal monitoring of light environment and LAI.

GaN-on-Diamond high electron mobility transistors were successfully fabricated by surface-activated room-temperature bonding technique. Various diamond substrates were finely polished and bonded to GaN-HEMTs by surface-activated room-temperature bonding. Fabricated devices showed superior characteristics in thermal dissipation compared to the device with conventional structure.

Toward real-time wall conditioning, impurity powder dropping experiments with boron powder were performed in the 22nd experimental campaign of the Large Helical Device. To examine the deposition and desorption process of boron, we focus on boron hydride (BH) molecules which presumably populate near plasma-facing components. We performed spatially-resolved spectroscopic measurements of emission by boron ions and BH molecules. From the measurement, we found that BH and B+ were concentrated on the divertor viewing chord, which suggest boron deposition in the divertor region. By comparing Hγ emissions with and without boron injection, neutral hydrogen shows uniform reduction in the SOL region, whereas less reduction of neutral hydrogen is confirmed in the divertor region. Although emissions from BH and B+ increased linearly, emissions by B0 and B4+ became constant after the middle of the discharge. Continuous reduction of carbon density in the core plasma was confirmed even after B0 and B4+ became constant. The results may show reduction of hydrogen recycling and facilitation of impurity gettering by boron in the divertor region and thus effective real-time wall conditioning.

Hexavalent chromium [Cr(VI)] is a global environmental pollutant and human lung carcinogen. However, the mechanisms of Cr(VI) carcinogenesis are not well defined. Cr(VI)-altered gene expression has been reported in the literature and is implicated in numerous mechanisms of Cr(VI) carcinogenesis. MicroRNAs (miRNAs) play a key role in controlling gene expression and are associated with carcinogenic mechanisms. To date no studies have evaluated global changes in miRNA expression in human cells after Cr(VI) exposure. We used RNA sequencing to evaluate how a particulate Cr(VI) compound (zinc chromate), the most potent form of Cr(VI), alters global miRNA expression after acute (24 h) or prolonged (72 and 120 h) exposure to 0.1, 0.2 and 0.3 ug/cm(2) zinc chromate in an immortalized, non-cancerous human lung cell line (WTHBF-6). Particulate Cr(VI) significantly affected expression of miRNAs at all time points and concentrations tested. We also found the number of significantly downregulated miRNAs increased in a time- and concentration-dependent manner and many miRNAs were upregulated after 24 h exposure at the intermediate concentration tested. Pathway analyses of the differentially expressed miRNAs predicted miRNAs target pathways of Cr(VI) carcinogenesis in a time- and concentration-dependent manner. These data are the first to evaluate global changes in miRNA expression in human lung cells after Cr(VI) exposure and indicate miRNAs may play a key role in pathways of Cr(VI) carcinogenesis.

Background After the advent of new treatment options for advanced hepatocellular carcinoma (HCC), the identification of prognostic factors is crucial for the selection of the most appropriate therapy for each patient. Patients and methods With the aim to fill this gap, we applied recursive partitioning analysis (RPA) to a cohort of 404 patients treated with lenvatinib. Results The application of RPA resulted in a classification based on five variables that originated a new prognostic score, the lenvatinib prognostic index (LEP) index, identifying three groups: low risk [patients with prognostic nutritional index (PNI) >43.3 and previous trans-arterial chemoembolization (TACE)]; medium risk [patients with PNI >43.3 but without previous TACE and patients with PNI, Highlights • This study shows a new prognostic index (LEP index) for patients undergoing systemic therapy for hepatocellular carcinoma. • LEP index is an easy-to-use tool, based on clinical and laboratory features, that identifies three risk groups. • LEP index may be used to stratify hepatocellular carcinoma patients in order to select the most appropriate treatment.

Microplastics are ubiquitous pollutants in the marine environment and a health concern. They are generated directly for commercial purposes or indirectly from the breakdown of larger plastics. Examining a toxicological profile for microplastics is a challenge due to their large variety of physico-chemical properties and toxicological behavior. In addition to their concentration, other parameters such as polymer type, size, shape and color are important to consider in their potential toxicity. Microplastics can adsorb pollutants such as polycyclic aromatic hydrocarbons (PAHs) or metals on their surface and are likely to contain plastic additives that add to their toxicity. The observations of microplastics in seafood increased concern for potential human exposure. Since literature considering microplastics in humans is scarce, using a One Environmental Health approach can help better inform about potential human exposures. Marine mammals and sea turtles are long-lived sentinel species regularly used for biomonitoring the health status of the ocean and share trophic chain and habitat with humans. This review considers the available research regarding microplastic and plastic fiber exposures in humans, marine mammals and turtles. Overall, across the literature, the concentration of microplastics, size, color, shape and polymer types found in GI tract and feces from sea turtles, marine mammals and humans are similar, showing that they might be exposed to the same microplastics profile. Additionally, even if ingestion is a major route of exposure due to contaminated food and water, dermal and inhalation studies in humans have provided data showing that these exposures are also health concerns and more effort on these routes of exposures is needed. In vitro studies looked at a variety of endpoints showing that microplastics can induce immune response, oxidative stress, cytotoxicity, alter membrane integrity and cause differential expression of genes. However, these studies only considered three polymer types and short-term exposures, whereas, due to physiological relevance, prolonged exposures might be more informative., Graphical abstract

The performance of a newly-developed 1D-long atmospheric-pressure microwave plasma, i.e. atmospheric-pressure microwave line plasma (APMLP), is demonstrated. Using vacuum ultraviolet atomic absorption spectroscopy, spatially uniform oxygen radical density along a 50 cm length is observed. With the APMLP using Ar/O2 gas, very fast hydrophilic treatment of polyimide (PI) film within 20 ms is obtained. Using looped-waveguide-type APMLP, fast ashing treatment of PI film at an ashing rate of 20 μm min−1 is demonstrated.

Background & Aims: Hepatocellular carcinoma (HCC) is the leading cause of death in patients with chronic hepatitis. In this international collaboration, we sought to develop a global universal HCC risk score to predict the HCC development for patients with chronic hepatitis. Methods: A total of 17,374 patients, comprising 10,578 treated Asian patients with chronic hepatitis B (CHB), 2,510 treated Caucasian patients with CHB, 3,566 treated patients with hepatitis C virus (including 2,489 patients with cirrhosis achieving a sustained virological response) and 720 patients with non-viral hepatitis (NVH) from 11 international prospective observational cohorts or randomised controlled trials, were divided into a training cohort (3,688 Asian patients with CHB) and 9 validation cohorts with different aetiologies and ethnicities (n = 13,686). Results: We developed an HCC risk score, called the aMAP score (ranging from 0 to 100), that involves only age, male, albumin–bilirubin and platelets. This metric performed excellently in assessing HCC risk not only in patients with hepatitis of different aetiologies, but also in those with different ethnicities (C-index: 0.82–0.87). Cut-off values of 50 and 60 were best for discriminating HCC risk. The 3- or 5-year cumulative incidences of HCC were 0–0.8%, 1.5–4.8%, and 8.1–19.9% in the low- (n = 7,413, 43.6%), medium- (n = 6,529, 38.4%), and high-risk (n = 3,044, 17.9%) groups, respectively. The cut-off value of 50 was associated with a sensitivity of 85.7–100% and a negative predictive value of 99.3–100%. The cut-off value of 60 resulted in a specificity of 56.6–95.8% and a positive predictive value of 6.6–15.7%. Conclusions: This objective, simple, reliable risk score based on 5 common parameters accurately predicted HCC development, regardless of aetiology and ethnicity, which could help to establish a risk score-guided HCC surveillance strategy worldwide. Lay summary: In this international collaboration, we developed and externally validated a simple, objective and accurate prognostic tool (called the aMAP score), that involves only age, male, albumin–bilirubin and platelets. The aMAP score (ranged from 0 to 100) satisfactorily predicted the risk of hepatocellular carcinoma (HCC) development among over 17,000 patients with viral and non-viral hepatitis from 11 global prospective studies. Our findings show that the aMAP score had excellent discrimination and calibration in assessing the 5-year HCC risk among all the cohorts irrespective of aetiology and ethnicity. © 2020 European Association for the Study of the Liver

Distributing codes to specific target sensors in order to fix bugs and/or install a new application is an important management task in WSNs (Wireless Sensor Networks). For the energy efficient dissemination of such codes to specific target sensors, it is required to select the minimum required number of forwarders with the fewest control messages. In this paper, we propose a novel RPL (Routing Protocol for Low-power and lossy networks)-based tree construction scheme for target-specific code dissemination, which is called R-TCS. The main idea of R-TCS is that by leveraging the data collection tree created by a standard routing protocol RPL, it is possible to construct the code dissemination tree with the minimum numbers of non-target sensors and control messages. Since by creating a data collection tree each sensor exchanges RPL messages with the root of the tree, every sensor knows which sensors compose its upwards route, i.e. the route towards the root, and downwards route, i.e. the route towards the leaves. Because of these properties, a target sensor can select the upward route that contains the minimum number of non-target sensors. In addition, a sensor whose downward routes do not contain a target sensor is not required to transmit redundant control messages which are related to the code dissemination operation. In this way, R-TCS can reduce the energy consumption which typically happens in other target-specific code dissemination schemes by the transmission of control messages. In fact, various performance evaluation results obtained by means of computer simulations show that R-TCS reduces by at least 50% energy consumption as compared to the other previous known target-specific code dissemination scheme under the condition where ratio of target sensors is 10% of all sensors. © 2020 The Institute of Electronics.

Background Hexavalent chromium [Cr(VI)] is a human lung carcinogen and global marine pollutant. High Cr concentrations, resembling the ones observed in occupationally exposed workers, have been observed in fin whales (Balaenoptera physalus) in the Gulf of Maine. This outcome suggests Cr might be disrupting the health of fin whale populations. Indeed, Cr in acute (24 h) exposure does cause toxicity in fin whale cells. However, human cell culture data indicate prolonged exposures (120 h) induce a higher amount of toxicity compared to 24 h exposure due to an inhibition of homologous recombination repair. However, whether prolonged exposure causes similar outcomes in fin whale cells is unknown. Objective Due to the importance of assessing prolonged exposure toxicity, this study focuses on characterizing acute and prolonged exposure of Cr(VI) in male and female fin whale cells. Methods Cytotoxicity was measured by the clonogenic assay, also known as colony forming assay, which measures the ability of cells to proliferate and form colonies after the treatment. DNA double strand breaks were analyzed by neutral comet assay. Clastogenicity was measured using the chromosome aberration assay. Intracellular Cr levels were measured with Graphite Furnace Atomic Absorption Spectrometry (GFAAS) with Syngistix Software. Results In this study, we demonstrate that particulate Cr(VI) induces cytotoxicity and genotoxicity in a treatment-dependent manner after 24 h and 120 h exposures. Cytotoxicity levels were generally low with relative survival above 64 %. DNA double strand break data and chromosome aberration data were elevated after a 24 h exposure, but decreased after a 120 h exposure. While cytotoxicity was similar after 24 h and 120 h exposures, less DNA double strand breaks and chromosomal instability occurred with prolonged exposure. Conclusion Particulate Cr(VI) is cytotoxic and genotoxic to fin whale cells after acute and prolonged exposures. The reduction of genotoxicity we have observed after 120 h exposure may be partly explained by lower intracellular Cr levels after 120 h. However, the decrease in intracellular levels is not reflected by a similar decrease in chromosome aberrations suggesting other mechanisms may be at play. Male fin whale cells appear to be more susceptible to the genotoxic effects of particulate Cr(VI) while female cells are less susceptible possibly due to increased cell death of damaged cells, but more work is needed to clarify if this outcome reflects a sex difference or interindividual variability. Overall, the study shows particulate Cr(VI) does induce toxicity at both acute and prolonged exposures in fin whales cells indicating Cr(VI) exposure is a health risk for this species.

The apical buds of lateral rose branches (Rosa hybrida ‘Carl Red’) were asexually propagated by cutting and treatment with chemical mutagens (N-methyl-N’-nitro-N-nitrosoguanidine, ethyl methane sulfonate, 6-azacytidine, and acridine orange), and the growth and differentiation or morphological alterations of the mutagen-treated buds were traced in developed flowers. Variations in size, shape, colour, and the number of petals were detected most frequently in flowers produced from apical buds treated with 100 I¼g/ml N-methyl-N’-nitro-N-nitrosoguanidine. The variant petals were cultured on Murashige and Skoog medium supplemented with I±-naphthalene acetic acid and 6-benzylaminopurine for in vitro isolation and the reproduction of morphologically altered rose plants. Embryogenic calli were obtained from adventitious roots induced from the petals and were successfully differentiated into intact plants. Consequently, the regenerated plants produced flowers that were different from those originally used for tissue culture. The appearance of the flowers in these rose plants was highly consistent through repeated cycles of cutting, suggesting that the present approach is an easy and rapid procedure for mutation breeding in rose in combination with tissue culture techniques for the in situ isolation and propagation of variant plants. This approach is expected to provide an effective method for easily and rapidly inducing variations in rose flowers and for in vitro morphogenesis through their regeneration.

Background: The Japanese ‘BALAD' model offers the first objective, biomarker-based, tool for assessment of prognosis in hepatocellular carcinoma, but relies on dichotomisation of the constituent data, has not been externally validated, and cannot be applied to the individual patients. Methods: In this Japanese/UK collaboration, we replicated the original BALAD model on a UK cohort and then built a new model, BALAD-2, on the original raw Japanese data using variables in their continuous form. Regression analyses using flexible parametric models with fractional polynomials enabled fitting of appropriate baseline hazard functions and functional form of covariates. The resulting models were validated in the respective cohorts to measure the predictive performance. Results: The key prognostic features were confirmed to be Bilirubin and Albumin together with the serological cancer biomarkers, AFP-L3, AFP, and DCP. With appropriate recalibration, the model offered clinically relevant discrimination of prognosis in both the Japanese and UK data sets and accurately predicted patient-level survival. Conclusions: The original BALAD model has been validated in an international setting. The refined BALAD-2 model permits estimation of patient-level survival in UK and Japanese cohorts.

Introduction The usefulness of thoracic damage control (DC) for trauma requiring a thoracotomy is not established. The aim of this study was to clarify the usefulness of thoracic packing as DC surgery. Methods This was a retrospective case series study of 12 patients with thoracic trauma suffering uncontrollable intrathoracic haemorrhage and shock who underwent intrathoracic packing. Our thoracic DC technique consisted of ligation and packing over the bleeding point or filling gauze in the bleeding spaces as well as packing for the thoracotomy wound. The success rates of intrathoracic haemostasis, changes in the circulation and the volume of discharge from the thoracic tubes were evaluated. Results Packing was undertaken for the thoracic wall in five patients, for the lung in four patients, for the vertebrae in two patients and for the descending thoracic aorta in one patient. Haemostasis was achieved successfully in seven cases. Of these, the volume of discharge from the thoracic tube exceeded 400ml/hr within three hours after packing in three patients, decreased to less than 200ml/hr within seven hours in six patients and decreased to 100ml/hr within eight hours in six patients. Systolic pressure could be maintained over 70mmHg by seven hours after packing. Conclusions Intrathoracic packing is useful for some patients, particularly in the space around the vertebrae, at the lung apex, and between the diaphragm and the thoracic wall. After packing, it is advisable to wait for three hours to see whether vital signs can be maintained and then to wait further to see if the discharge from the thoracic tube decreases to less than 200ml/hr within five hours.

We report the first observation of diffractive $J/\psi(\to \mu^+\mu^-)$ production in $\bar pp$ collisions at $\sqrt{s}$=1.8 TeV. Diffractive events are identified by their rapidity gap signature. In a sample of events with two muons of transverse momentum $p_T^{\mu}>2$ GeV/$c$ within the pseudorapidity region $|\eta, Comment: 9 pages, 4 figures, using RevTeX. Submitted to Physical Review Letters

We report a measurement of the strong coupling constant, ${\ensuremath{\alpha}}_{s}({M}_{Z})$, extracted from inclusive jet production in $p\overline{p}$ collisions at $\sqrt{s}\phantom{\rule{0ex}{0ex}}=\phantom{\rule{0ex}{0ex}}1800\mathrm{GeV}$. The QCD prediction for the evolution of ${\ensuremath{\alpha}}_{s}$ with jet transverse energy ${E}_{T}$ is tested over the range $40l{E}_{T}l450\mathrm{GeV}$ using ${E}_{T}$ for the renormalization scale. The data show good agreement with QCD in the region below 250 GeV. The value of ${\ensuremath{\alpha}}_{s}$ at the mass of the ${Z}^{0}$ boson averaged over the range $40l{E}_{T}l250\mathrm{GeV}$ is found to be ${\ensuremath{\alpha}}_{s}({M}_{Z})\phantom{\rule{0ex}{0ex}}=\phantom{\rule{0ex}{0ex}}0.1178\ifmmode\pm\else\textpm\fi{}0.0001(\mathrm{stat}{)}_{\ensuremath{-}0.0095}^{+0.0081}(\mathrm{expt}.\mathrm{syst})$. The associated theoretical uncertainties are mainly due to the choice of renormalization scale $({+6%}{\ensuremath{-}4%})$ and input parton distribution functions $(5%)$.

Hepatitis B Core-Related Antigen: A Possible Indicator for the Termination of Prophylactic Nucleos(t)ide Analogue Therapy in Patients After Immunosuppressive Therapy

BACKGROUND AND PURPOSE The renal sodium-glucose cotransporter 2 (SGLT2) plays an important role in the reuptake of filtered glucose in the proximal tubule and therefore may be an attractive target for the treatment of diabetes mellitus. This study characterizes the pharmacological profile of TS-071 ((1S)-1,5-anhydro-1-[5-(4-ethoxybenzyl)-2-methoxy-4-methylphenyl]-1-thio-d-glucitol hydrate), a novel SGLT2 inhibitor in vitro and in vivo. EXPERIMENTAL APPROACH Inhibition of glucose uptake by TS-071 was studied in CHO-K1 cells stably expressing either human SGLT1 or SGLT2. Single oral dosing studies were performed in rats, mice and dogs to assess the abilities of TS-071 to increase urinary glucose excretion and to lower plasma glucose levels. KEY RESULTS TS-071 inhibited SGLT2 activity in a concentration-dependent manner and was a potent and highly selective inhibitor of SGLT2. Orally administered TS-071 increased urinary glucose excretion in Zucker fatty rats and beagle dogs at doses of 0.3 and 0.03 mg·kg−1 respectively. TS-071 improved glucose tolerance in Zucker fatty rats without stimulating insulin secretion and reduced hyperglycaemia in streptozotocin (STZ)-induced diabetic rats and db/db mice at a dose of 0.3 mg·kg−1. CONCLUSION AND IMPLICATIONS These data indicate that TS-071 is a potent and selective SGLT2 inhibitor that improves glucose levels in rodent models of type 1 and 2 diabetes and may be useful for the treatment for diabetes mellitus.

Mutations in two regions of hepatitis C virus (HCV) have been implicated in influencing response to interferon (IFN) therapy. Substitutions in the NS5A region of HCV have been associated with response to IFN therapy, and this region has been known as the IFN sensitivity-determining region (ISDR). The mutations in the core region of HCV have also been reported to predict IFN response. The aim of this study was to investigate whether amino acid substitutions in the core region and ISDR among patients with HCV genotype 1b affect the response to IFN therapy. A total of 213 patients who completed IFN treatment were randomly selected. All patients received pegylated-IFN-alpha 2b once each week, plus oral ribavirin daily for 48 weeks. Of the 213 patients, 117 (54.9%) showed early virologic response (EVR), with HCV-negativity, at 12 weeks. Factors related to EVR on multivariate analysis were non-Gln70 and Leu91 in the core region, and ISDR mutant-type. One hundred and two (47.9%) showed a sustained virologic response (SVR). SVR occurred more frequently in patients without Gln70 (55.4%) than in those with Gln70 (21.3%) (P < 0.0001). SVR was achieved in 43.6% of patients with wild-type ISDR and 62.5% of patients with mutant-type (P = 0.0227). Of the 34 patients who simultaneously had non-Gln70 and mutant-type ISDR, 26 (76.5%) achieved SVR. Factors related to SVR on multivariate analysis were non-Gln70 and ISDR mutant-type. In conclusion, amino acid substitutions in the core region and ISDR were useful for predicting the response to IFN in patients with HCV genotype 1b.

Summary. Serum ribavirin concentration is an important factor in antiviral therapy in combination with peginterferon (PEG-IFN) and ribavirin for patients with chronic hepatitis C in terms of both beneficial and adverse effects. We evaluated whether the serum ribavirin concentration can be predicted on the basis of renal function estimates. Serum creatinine and cystatin C concentrations were measured at the start of treatment in a total of 148 patients with chronic hepatitis C who underwent combination PEG-IFN and ribavirin therapy. Creatinine clearance (CrCl) and total clearance of ribavirin (CL/F) were calculated on the basis of the serum creatinine level. The glomerular filtration rate was calculated with two different formulae on the basis of the serum cystatin C level. These values were compared with serum ribavirin concentrations 4 weeks after the start of therapy. The cystatin C level increased with the progression of liver fibrosis, whereas the creatinine level was constant regardless of the degree of liver fibrosis. Significant correlation was not observed between the serum ribavirin concentration and serum creatinine level, cystatin C level, or calculated renal function estimates. However, significant correlation was found between the serum ribavirin concentration and CrCl and CL/F in patients who were given ribavirin >800 mg/day. Overall, renal function estimates do not correlate with the serum ribavirin concentration in Japanese patients with chronic hepatitis C who undergo combination PEG-IFN and ribavirin therapy. Serum creatinine-based renal function estimates might be predictive for the serum ribavirin concentration only in patients with a daily ribavirin intake of 800 mg or more.

BACKGROUND AND STUDY AIMS Dieulafoy's lesion is an important cause of upper gastrointestinal bleeding, and the safety and efficacy of endoscopic treatment have been widely accepted. The aim of this study was to evaluate the effectiveness of endoscopic management, including hemoclipping and injection methods, for bleeding Dieulafoy lesions in the upper gastrointestinal tract. PATIENTS AND METHODS Between 1995 and 2003, 61 patients with bleeding Dieulafoy lesions underwent endoscopic treatment. The available hemostatic methods were hemoclipping, hypertonic saline-epinephrine injection, and pure ethanol injection. Clinical data, endoscopic features, and treatment outcome were analyzed retrospectively. RESULTS Comorbid conditions were present in 39 patients (64 %). Active bleeding was noted in 20 patients (33 %). Hemoclipping was a selected treatment in 48 patients (79 %). Initial hemostasis was achieved in 61 patients (100 %). One patient had rebleeding 6 days after the initial procedure but was successfully treated endoscopically. The 30-day mortality was 0 %. During follow-up, for a mean of 47 months, 15 patients (25 %) died of causes unrelated to the Dieulafoy lesion. Two patients had recurrent bleeding due to non-Dieulafoy gastric ulcer, and responded to endoscopic therapy. We encountered no patients who required surgery. CONCLUSIONS Dieulafoy lesion can be successfully managed by endoscopic treatment. The long-term outcome is acceptable.

Energy-controlled and mass-selected beam of fluorocarbon ion (CF3+,CF2+) at energies from 50 to 400 eV are directed at Si and SiO2 surfaces, in order to elucidate etch mechanisms and SiO2/Si etch selectivity. During the ion beam injection, the time evolution of neutral radicals desorbed from the etching surface is measured by appearance mass spectrometry. At the same time, in situ surface analysis is also carried out by x-ray photoelectron spectroscopy. The etching rate of a clean Si surface by CF3+ injection is initially high but decreases with time due to the formation of a thin surface layer containing F and C atoms. Finally, a few-nanometers-thick stationary SixCyFz overlayer is formed on the Si surface for ion fluence >3×1016 cm−2, along with saturation of CF2 and SiF2 radical desorption from the surface. Comparison is made with molecular dynamics simulations of CF3+ interactions with Si surfaces. CF2+ injection on the Si surface yields rapid formation of the SixCyFz layer and lower desorption of the...

The weatherability of PTFE- and PVC-coated fabrics under tropical climate was evaluated based on outdoor exposure test for a period of 2 years. This study is confined to the examination of the surface characteristics of 10 different types of fabric which include dirt repellency, discolouration and coating condition. The results indicate that the dirt repellency of PTFE-coated fabrics is generally more superior. However, the surface treatment for some of the PVC-coated fabrics, do provide excellent dirt repellency as well. Morphological examinations using the scanning electron microscope revealed that cracking and peeling of the coating were more evident on the PVC-coated as compared to the PTFE-coated fabrics. The hot and humid conditions prevalent in a tropical environment were very conducive for the growth of fungi, which adhered on the surface of some of the PVC-coated fabrics. Generally the degree of surface degradation on all the fabrics was more severe due to the much harsher tropical climate in comparison with other exposure tests conducted in the past.

The host range of most poliovirus (PV) strains is restricted to simians. This host range specificity is believed to be determined by the interaction between PV and its receptor molecule. To elucidate the molecular basis of this species-specific infection of PV, we cloned orthologs of the PV receptor (PVR) gene ( pvr) as well as those of PV receptor-related genes 1 and 2 ( prr1 and prr2) from various mammalian species. These three genes are widely present in mammalian genomes including those of non-susceptible species. Comparison of the deduced amino acid sequences of PVR orthologs revealed that the NH(2)-terminal immunoglobulin-like domain (domain 1), which is the virus binding site in the human PVR, is highly variable among species, whereas that of PRR1 is highly conserved. Domain 1 of the PVR orthologs for the ring-tailed lemur and rabbit, which are not susceptible to PV, show only 51 and 61% amino acid sequence identity to that of human PVR, respectively. Chimeric PVR proteins that have the domain 1 of the ring-tailed lemur and rabbit PVRs failed to serve as receptors for PV. These results suggest that rapid changes in the domain 1 sequence during mammalian evolution determined the host range restriction of PV.

BACKGROUND: TT virus (TTV), a novel DNA virus, was originally thought to be transmitted by transfusion. However, nonparenteral transmission is recently suspected to be a major mode of transmission. To investigate the possibility of reinfection with TTV in multiply transfused patients and to evaluate the significance of transfusion transmission of TTV in patients with hemophilia, serial changes in TTV genotype were investigated in three groups. STUDY DESIGN AND METHODS: Serial changes in TTV genotype were investigated in 16 multiply transfused patients with hemophilia, 16 age-matched patients with chronic hepatitis C, and 16 age-matched healthy subjects. RESULTS: Mixed infection with multiple TTV genotypes was common in all groups. However, changes in TTV genotype were frequent in patients with hemophilia (15/16; 93.8%) but rare in patients with chronic hepatitis C and in healthy subjects (each group: 1/16; 6.3%). CONCLUSION: Changes in TTV genotype were frequently observed in multiply transfused patients with hemophilia but not in patients with chronic hepatitis or in healthy subjects without risk of transfusion transmission. This difference may suggest that exposure to TTV or even reinfection occurs frequently in patients with hemophilia, which could be evidence of transfusion transmission of TTV in this population.

We present the results of a search for neutral Higgs bosons produced in association with b quarks in pp-->bb(phi)-->bbb final states with 91+/-7 pb(-1) of pp collisions at sqrt[s] = 1.8 TeV recorded by the Collider Detector at Fermilab. We find no evidence of such a signal and the data are interpreted in the context of the neutral Higgs sector of the minimal supersymmetric extension of the standard model. With basic parameter choices for the supersymmetric scale and the stop-quark mixing, we derive 95% C.L. lower mass limits for neutral Higgs bosons for tan(beta) values in excess of 35.

We have measured the ratio of prompt production rates of the charmonium states {chi}{sub c1} and {chi}{sub c2} in 110 pb{sup -1} of p{ovr p} collisions at sqrt[s] = 1.8 TeV. The photon from their decay into J/{psi}{gamma} is reconstructed through conversion into e{sup +}e{sup -} pairs. The energy resolution this technique provides makes the resolution of the two states possible. We find the ratio of production cross sections {sigma}{sub {chi}{sub c2}}/{sigma}{sub {chi}{sub c1}} = 0.96{+-}0.27(stat){+-}0.11(syst) for events with p{sub {tau}}(J/{psi})>4.0 GeV/c, |{eta}(J/{psi})| 1.0 GeV/c.