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We establish the three-dimensional stratigraphic architecture of the Taipei Basin and its spatiotemporal palaeoenvironmental development during the past 50 kyr by analysing 36 borehole cores and 177 age dates. We calculate the rates of basin subsidence from the borehole data at depths where radiocarbon age dates are available. Our results indicate that, during the eustatic sea level falling period (35–20 ka), low rates of sediment supply and/or rapid basin subsidence controlled sedimentation, leading to a change in the depositional environment from gravelly braided rivers, through sandy braided rivers, to meandering rivers with falling eustatic sea level. During the early stage of eustatic sea level rise (∼20–10.2 ka), balanced rates of sediment supply, eustasy and basin subsidence maintained the meandering river environment. Rapid sea level rise led to the initial appearance of estuarine facies at ∼10.2 ka and widened the distribution of the estuarine environment after 8.5 ka; however, the coeval phases of rapid basin subsidence ∼10.6–10.2 ka and 9–8.5 ka promoted the first appearance and widening of the estuary, respectively. After 7 ka, when the eustatic sea level and rate of basin subsidence remained relatively stable, sufficient sediment supply gradually infilled the estuary. The established stratigraphy improves our understanding of the factors controlling stratigraphic development in marine-influenced inland half grabens, specifically in the Taipei Basin with high rates of sediment supply. Accommodation space in the Taipei Basin was governed by eustatic fluctuations with modulations by basin subsidence and sediment supply since the last glacial period. [ABSTRACT FROM AUTHOR]

Abstract: A new denoising method of milli-meter wave (MMW) image using contourlet and kurtosis based sparse coding (KSC) is proposed in this paper. KSC is a high-order statistical method and can efficiently extract image feature coefficients. Contourlet method has the decomposition property of orientation and the energy variation for images. Further, using the shrinkage threshold that is determined by the sparse prior distribution of feature coefficients extracted in the contourlet transform field, the unknown noise contained in MMW image can be reduced efficiently. In test, an artificial MMW image and a true MMW are respectively used to validate our method, further, compared this method with other denoising methods, the simulation results show this method proposed here can obtain the better quality of image restoration. [Copyright &y& Elsevier]

Abstract: Short digital signatures are always desirable; for instance, when a human is asked to key in the signature manually or it is necessary to work effectively in low-bandwidth communication, low-storage and low-computation environments. We propose a short signature scheme based on knapsack and Gap Diffie–Hellman (GDH) groups whose security is closely related to the discrete logarithm assumption in the random oracle model. Our new scheme offers a better security guarantee than existing signature schemes. Furthermore, our scheme upholds all desirable properties of previous ID-based signature schemes, and requires general cryptographic hash functions instead of MapToPoint hash function that is inefficient and probabilistic. [Copyright &y& Elsevier]

Abstract: For the purpose of analyzing gastric tumor pathologic cell images, a novel method is developed with gray-scale edge detection of mathematical morphology in this study. In combination with texture features of the image under investigation, this paper works on edge detection with various structuring elements (SEs) and gray-scale values. The results of the experiment are presented, and we found several advantages by using the morphological edge detection scheme for the analysis of gastric tumor pathologic cell images. Meanwhile, the results of the binary morphological edge detection are given for comparison. [Copyright &y& Elsevier]

Abstract: Though a lot of public key cryptographic algorithms have been proposed, practically some cryptographic systems’ security will no longer be secure unless the corresponding hard problems are solved in the future. Enhancing security is the major objective for public key cryptosystems on the basis of the hardness of the intractable computational problems. In this paper, we present a new cryptosystem design based on linearly shift knapsack and elliptic curve discrete logarithm problems. Having concatenated Knapsack and ECC hard problems, the presented scheme has solid structure and will hopelessly leave the eavesdropper baffled. The performance analysis has been given to describe the proposed scheme in terms of security level. In addition, the security performance in encryption/decryption complexity is equivalent to related cryptosystems with the nature of security. At the moment, no malicious attacks are capable of “breaking” this scheme in a reasonable amount of time obviously. [Copyright &y& Elsevier]

Abstract: There is no question that knapsack systems still warrant continuous researches, as a result of the NP-completeness nature, the faster speed, and a desire to have a wide variety of available cryptosystems. This paper presents a new knapsack-type public key cryptosystem based on a novel application of the elliptic curve logarithm problem. The difficulty can be made sufficient to frustrate attacks against the survey major knapsack public-key cryptosystems developed in the past more than 20 years, and hope-fully shed some light on the future of the knapsack cryptosystems. The proposed new cryptosystem can be found some theoretic support on confidentiality. [Copyright &y& Elsevier]

Abstract: We present three identification group-oriented (t,n) threshold digital signature schemes based on the elliptic curve discrete logarithm problem, with a view to optimizing these techniques for implementation within a network. By employing these schemes, any t out of n users in a group can represent this group to sign the group signature. This paper has the following five notable advantages: (1) This work demonstrates the feasibility of constructing a fast and extremely secure user identification system. (2) Any group signature can be mutually generated by at least t-group member. (3) The signature verification process is simplified because there is only one group public key required. (4) The group signature can be verified by any outsider. (5) These schemes offer higher speeds, lower power consumption, smaller bandwidth requirements, and smaller certificate sizes than other existing public-key schemes. [Copyright &y& Elsevier]

This paper describes a unified framework to model the floating-body effects of various SOI MOSFET operation modes, including body-contacted mode, partially depleted mode and fully depleted mode. As the operation mode is dimension and bias dependent, different modes can co-exist in a single SOI technology. A smooth transit from one type of operation mode to another is thus essential and has been included in the model. In addition, the floating-body effects can couple to a number of other SOI specific phenomena such as heating assisted impact ionization, gate tunneling induced dynamic behavior, and operation mode dependent small signal output resistance. A methodology to model the overall SOI MOSFET behavior due to the combination of multiple floating-body related effects will also be described. [Copyright &y& Elsevier]

Asia accounts for 60% of the world population, and half the global burden of cancer. The incidence of cancer cases is estimated to increase to 70% by 2030, in part due to a growing aging population, lifestyle and socioeconomic changes. The costs of cancer care can be staggering and Singapore has the challenge of meeting the cancer needs of an aging population while trying to reign in escalating healthcare costs. The challenges faced in delivering optimal cancer care in Singapore is not much different from those experienced by developed countries. [ABSTRACT FROM AUTHOR]

• We examine consumer intentions to switch from fossil fuel scooters to electric scooter-style motorcycles. • We conceptualize a framework of behavioral reasoning theory. • We include context-specific reasons and environmental concern (egoistic, altruistic, biospheric). • We find concerns for the global effects of environmental damage instrumental. • Biospheric concern is most prominent and relates negatively to reasons against the switch. Despite the growing market share of electric scooter-style motorcycles (e-scooters), only limited insight into the role of environmental concern with respect to their adoption is available. The purpose of this study was to investigate the psychological and contextual factors that associate with a switch from fossil fuel scooters to e-scooters. To model these factors, we conducted two studies in Taiwan. In Study 1, we elicited context-specific reasons for and against purchasing an e-scooter in a series of semi-structured interviews. In Study 2, we analyzed data from a survey among consumers (N = 320) using structural equation modelling. We consider the most important reasons from Study 1 together with environmental concerns (egoistic, altruistic, biospheric) in their relationship with intentions to switch to an e-scooter using the framework of Behavioral Reasoning Theory (BRT). In doing so, we provide unique insights for marketers and policymakers who seek to encourage the switch to this more sustainable form of mobility. We found environmental concerns among users of fossil-fueled scooters to be associated with attitude toward as well as reasons for and against switching to an e-scooter. But only a biospheric concern appeared to relate to both reason types and attitude, whereas egoistic and altruistic concerns only associated with reasons for the switch. The study also provides researchers and marketers in the e-scooter industry with a framework for understanding the role of environmental concern and contextual factors on purchase intention for a sustainable mobility product. [ABSTRACT FROM AUTHOR]

We have previously reported benzimidazole-based compounds to be potent inhibitors of FabI for Francisella tularensis ( Ft FabI), making them promising antimicrobial hits. Optically active enantiomers exhibit markedly differing affinities toward Ft FabI. The IC 50 of benzimidazole (−)- 1 is ∼100× lower than the (+)-enantiomer, with similar results for the 2 enantiomers. Determining the absolute configuration for these optical compounds and elucidating their binding modes is important for further design. Electronic circular dichroism (ECD) quantum calculations have become important in determining absolute configurations of optical compounds. We determined the absolute configuration of (−)/(+)- 1 and (−)/(+)- 2 by comparing experimental spectra and theoretical density functional theory (DFT) simulations of ECD spectra at the B3LYP/6-311+G(2d, p) level using Gaussian09. Comparison of experimental and calculated ECD spectra indicates that the S configuration corresponds to the (−)-rotation for both compounds 1 and 2 , while the R configuration corresponds to the (+)-rotation. Further, molecular dynamics simulations and MM-GBSA binding energy calculations for these two pairs of enantiomers with Ft FabI show much tighter binding MM-GBSA free energies for S - 1 and S - 2 than for their enantiomers, R - 1 and R - 2 , consistent with the S configuration being the more active one, and with the ECD determination of the S configuration corresponding to (−) and the R configuration corresponding to (+). Thus, our computational studies allow us to assign (−) to ( S )- and (+) to ( R )- for compounds 1 and 2 , and to further evaluate structural changes to improve efficacy. [ABSTRACT FROM AUTHOR]

Nanoparticles present a promising approach for mitigating cadmium (Cd) uptake in crops. Nevertheless, limited research has been focused on the application nanoparticles to mitigate plant Cd stress through increasing Cd absorption and tolerance of epiphytic microbes. Herein, Methylobacterium currus DSD (Meb) was isolated and identified as the type strain. The application of iron oxide nanoparticles (200 mg L−1 IONPs, including Fe 2 O 3 NPs and Fe 3 O 4 NPs) resulted in considerably enhanced adsorption capacity for Cd by Meb , accompanied by increased surface functional groups, particularly carboxyl and hydroxyl groups. The extracellular polymeric substances (EPS) of Meb -Fe 3 O 4 NPs exhibited the higher contents of proteins and polysaccharides. The introduction of Fe 3 O 4 NPs increased the mole% of ribose, arabinose, and glucose, as well as the contents of most amino acids. Fe 3 O 4 NPs might drive the glycolytic process of converting glucose to amino acids. X-ray photoelectron spectroscopy (XPS) and Fourier transform infrared spectroscopy (FTIR) analyses further confirmed the involvement of C O and C–N groups in proteins, and C–O groups in polysaccharides. Moreover, the presence of IONPs enhanced Meb tolerance to Cd, which was a highlight. This study provides a novel perspective from epiphytic microbes for nanoparticles to reduce the toxicity and accumulation of Cd in crops. [Display omitted] • IONPs enhanced the tolerance and adsorption capacity of Meb DSD to Cd. • IONPs positively regulated the surface chemical properties and EPS components of Meb. • Proteins and polysaccharides in EPS played important roles in complexation with Cd. • Fe 3 O 4 NPs might drive the glycolytic process of converting glucose to amino acids. [ABSTRACT FROM AUTHOR]

This paper investigates and compares the impacts of metal-gate work-function variation on important analog figures-of-merit (FOMs) for TFET and FinFET devices using 3-D atomistic TCAD simulations. Our study indicates that, at 0.6 V supply voltage and 0.2 V gate-voltage overdrive, TFET exhibits superior variation immunity regarding transconductance to drain–current ratio ( g m / I DS ), output resistance ( R out ) and intrinsic gain, and comparable variability in g m and cutoff frequency ( f T ) as compared with the FinFET counterparts. In addition, how the correlations between pertinent parameters (e.g., g m and R out ) impact the variation immunity of important analog FOMs are analyzed. Our study may provide insights for low-voltage analog design using TFET/FinFET technologies. [ABSTRACT FROM AUTHOR]

Abstract: This paper presents a new super-resolution (SR) restoration method of a single millimeter wave image (MMW), based on sparse single representation. A single MMW image is in fact a low-resolution one that is viewed as a downsampled version of a high-resolution image, whose image patches are assumed to be well represented as a sparse linear combination of elements from an appropriately chosen overcomplete dictionary. The theoretical results from compressed sensing ensure that under mild conditions, the sparse representation can be correctly restored from the downsampled signal. Inspired by this idea, a sparse representation for each image path of the MMW image with hardly low-resolution is sought, and then the coefficients of this sparse representation are used to generate the high-resolution output. The high- and low-resolution dictionary pair can be obtained by utilizing the modified fast sparse coding (FSC) algorithm, and it is a more compact representation of the image patch pairs, which hardly reduces the computational cost. In tests, image patches of several high-resolution natural images with different classes and their corresponding low-resolution versions are firstly used to train the dictionary pair. Further, utilizing the learned dictionary pair, the MMW image is restored efficiently. For the restored natural images, the image quality is measured by single noise ratio (SNR), while for the MMW image, it is not suitable to use the SNR criterion because much noise existed in the MMW image. So, the restored MMW image’s quality is measured by the relative SNR (RSNR). Compared with other SR restoration methods of bicubic, Lucy–Richardson (L–R) and neighbor embedding (NE), the simulation experimental results testify that the sparse representation is indeed effective in the super-resolution restoration task of the MMW image. [Copyright &y& Elsevier]

Abstract: Currently, only one drug, sorafenib, is FDA approved for the treatment of advanced hepatocellular carcinoma (HCC), achieving modest objective response rates while still conferring an overall survival benefit. Unlike other solid tumors, no oncogenic addiction loops have been validated as clinically actionable targets in HCC. Outcomes of HCC could potentially be improved if critical molecular subclasses with distinct therapeutic vulnerabilities can be identified, biomarkers that predict recurrence or progression early can be determined and key epigenetic, genetic or microenvironment drivers that determine best response to a specific targeting treatment can be uncovered. Our group and others have examined the molecular heterogeneity of hepatocellular carcinoma. We have developed a panel of patient derived xenograft models to enable focused pre-clinical drug development of rationally designed therapies in specific molecular subgroups. We observed unique patterns, including synergies, of drug activity across our molecularly diverse HCC xenografts, pointing to specific therapeutic vulnerabilities for individual tumors. These efforts inform clinical trial designs and catalyze therapeutic development. It also argues for efficient strategic allocation of patients into appropriate enriched clinical trials. Here, we will discuss some of the recent important therapeutic studies in advanced HCC and also some of the potential strategies to optimize clinical therapeutic development moving forward. [Copyright &y& Elsevier]

Background: Single-agent nivolumab showed durable responses, manageable safety, and promising survival in patients with advanced hepatocellular carcinoma in the phase 1-2 CheckMate 040 study. We aimed to investigate nivolumab monotherapy compared with sorafenib monotherapy in the first-line setting for patients with advanced hepatocellular carcinoma.Methods: In this randomised, open-label, phase 3 trial done at medical centres across 22 countries and territories in Asia, Australasia, Europe, and North America, patients at least 18 years old with histologically confirmed advanced hepatocellular carcinoma not eligible for, or whose disease had progressed after, surgery or locoregional treatment; with no previous systemic therapy for hepatocellular carcinoma, with Child-Pugh class A and Eastern Cooperative Oncology Group performance status score of 0 or 1, and regardless of viral hepatitis status were randomly assigned (1:1) via an interactive voice response system to receive nivolumab (240 mg intravenously every 2 weeks) or sorafenib (400 mg orally twice daily) until disease progression or unacceptable toxicity. The primary endpoint was overall survival assessed in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study drug. This completed trial is registered with ClinicalTrials.gov, NCT02576509.Findings: Between Jan 11, 2016, and May 24, 2017, 743 patients were randomly assigned to treatment (nivolumab, n=371; sorafenib, n=372). At the primary analysis, the median follow-up for overall survival was 15·2 months (IQR 5·7-28·0) for the nivolumab group and 13·4 months (5·7-25·9) in the sorafenib group. Median overall survival was 16·4 months (95% CI 13·9-18·4) with nivolumab and 14·7 months (11·9-17·2) with sorafenib (hazard ratio 0·85 [95% CI 0·72-1·02]; p=0·075; minimum follow-up 22·8 months); the protocol-defined significance level of p=0·0419 was not reached. The most common grade 3 or worse treatment-related adverse events were palmar-plantar erythrodysaesthesia (1 [<1%] of 367 patients in the nivolumab group vs 52 [14%] of patients in the sorafenib group), aspartate aminotransferase increase (22 [6%] vs 13 [4%]), and hypertension (0 vs 26 [7%]). Serious treatment-related adverse events were reported in 43 (12%) patients receiving nivolumab and 39 (11%) patients receiving sorafenib. Four deaths in the nivolumab group and one death in the sorafenib group were assessed as treatment related.Interpretation: First-line nivolumab treatment did not significantly improve overall survival compared with sorafenib, but clinical activity and a favourable safety profile were observed in patients with advanced hepatocellular carcinoma. Thus, nivolumab might be considered a therapeutic option for patients in whom tyrosine kinase inhibitors and antiangiogenic drugs are contraindicated or have substantial risks.Funding: Bristol Myers Squibb in collaboration with Ono Pharmaceutical. [ABSTRACT FROM AUTHOR]

Abstract: We propose a robust first-stop blind signature scheme that will work in any Gap Diffie–Hellman (GDH) group. It can be applied in more critical systems like e-voting, e-commerce and e-payment systems that need higher security against sophisticated attacks and can preserve participants’ anonymity. Untracebility and unlinkability are the two main properties of real coins for successful electronic mimicking. Whenever a user is permitted to spend an e-coin, he must fulfill the blind signature requirements. Because of the GDH group structure and the base scheme, most of our constructions are simpler, more efficient and have more useful properties than similar existing constructions. [Copyright &y& Elsevier]

Abstract: Computer crimes are widely recognized as a significant computer threat. The submission of evidence in any type of legal proceeding is typically challenging, but when computers are involved, the problems are intensified. Special knowledge is required to locate and collect evidence and special care must be taken to preserve and transport the evidence. Evidence of a computer crime differs from conventional types of evidence in that most computer-related evidence is intangible—in the form of electronic pulses or magnetic charges. This paper presents a new scheme that has an analogy in natural immunology. A new method of identifying attackers that involves cryptology is also presented. The proposed method can be applied to various fields in information security, including digital signatures, conference key distribution schemes and on-line broadcasting security. [Copyright &y& Elsevier]

Patients with advanced hepatocellular carcinoma (aHCC) and Child-Pugh B liver function are often excluded from clinical trials. In previous studies, overall survival for these patients treated with sorafenib was ∼3–5 months; thus, new treatments are needed. Nivolumab, alone or in combination with ipilimumab, is conditionally approved in the United States to treat patients with aHCC who previously received sorafenib. We describe nivolumab monotherapy outcomes in patients with Child-Pugh B status. This phase I/II, open-label, non-comparative, multicentre trial (27 centres) included patients with Child-Pugh B (B7–B8) aHCC. Patients received intravenous nivolumab 240 mg every 2 weeks until unacceptable toxicity or disease progression. Primary endpoints were objective response rate (ORR) by investigator assessment (using Response Evaluation Criteria in Solid Tumors v1.1) and duration of response. Safety was assessed using National Cancer Institute Common Terminology Criteria for Adverse Events v4.0. Twenty-five sorafenib-naive and 24 sorafenib-treated patients began treatment between November 2016 and October 2017 (median follow-up, 16.3 months). Investigator-assessed ORR was 12% (95% CI 5–25%) with 6 patients responding; disease control rate was 55% (95% CI 40–69%). Median time to response was 2.7 months (interquartile range, 1.4–4.2), and median duration of response was 9.9 months (95% CI 9.7–9.9). Treatment-related adverse events (TRAEs) were reported in 25 patients (51%) and led to discontinuation in 2 patients (4%). The most frequent grade 3/4 TRAEs were hypertransaminasemia (n = 2), amylase increase (n = 2), and aspartate aminotransferase increase (n = 2). The safety of nivolumab was comparable to that in patients with Child-Pugh A aHCC. Nivolumab showed clinical activity and favourable safety with manageable toxicities, suggesting it could be suitable for patients with Child-Pugh B aHCC. In patients with advanced hepatocellular carcinoma, almost all systemic therapies require very good liver function, i.e. Child-Pugh A status. The evidence from this study suggests that nivolumab shows clinical activity and an acceptable safety profile in patients with hepatocellular carcinoma with Child-Pugh B status who have mild to moderate impairment of liver function or liver decompensation that might rule out other therapies. Further studies are warranted to assess the safety and efficacy of nivolumab in this patient population. NCT01658878. [Display omitted] • This is the first report, to our knowledge, of immune checkpoint inhibitor therapy in patients with advanced HCC and Child-Pugh B liver function status. • Median OS with nivolumab was longer than the historical OS rate for patients treated with sorafenib (7.6 months vs. 2.5–5.4 months, respectively). • Clinically meaningful stabilisation of liver function was observed, as evidenced by maintained or improved Child-Pugh scores and albumin-bilirubin scores. • Nivolumab had a favourable safety profile with manageable toxicities when used in patients with Child-Pugh B advanced HCC and was comparable to that seen in patients with Child-Pugh A HCC. [ABSTRACT FROM AUTHOR]

Encapsulating proteins in polymeric microspheres is a useful mode of drug delivery, but the proteins are subjected to damage in the process of ultrasound emulsion microencapsulation. The objective of this study was to investigate the effects of ultrasound power and duration on the function and structure of trypsin, and the reason of protein denaturation when it was irradiated by 20 kHz ultrasound. The relatively stable enzyme, trypsin, was dissolved in aqueous solution in the presence and absence of additives to study the stability of trypsin during the ultrasound irradiation. The damage of the molecular structure of trypsin was detected via combined high performance liquid chromatogram and electrospray ionization mass spectrometry (HPLC–ESI-MS). The results showed that the activity of trypsin decreased with increasing ultrasound power from 100 to 500 W or extending the irradiation time from 1 to 20 min. This effect could be enhanced via aerating the solution for a duration 10 min at 300 W. Fragments of trypsin were detected in the treatment (300 W, 10 min) by HPLC–ESI-MS. The additives, Tween 80 and mannitol, could protect trypsin against the inactivation caused by ultrasound. The reason of inactivation was partly from the alteration of the molecular conformation and partly from the modification or damage of trypsin''s molecular structure. [Copyright &y& Elsevier]

One water exopolysaccharide, designated G-EPS, was secreted by Rhodopseudomonas palustris GJ-22 culture media. The structure of G-EPS was characterized with HPGPC, GC–MS, methylation, 1D and 2D NMR, along with UV and FT-IR spectrum. The G-EPS molecular weight was 10.026 kilodalton, and is composed of D-mannose (92.8%) and d -glucose (7.2%). The purified G-EPS promoted plant growth and induced systemic resistance against TMV in Nicotiana benthamiana. These results suggested that G-EPS is an important active component of the bio-control capacity of GJ-22. • R. palustris GJ-22 secretes G-EPS, an exopolysaccharide, into culture media. • G-EPS is structurally composed of mannose and glucose. • G-EPS exhibits pro-growth and antiviral activities. • G-EPS induced systemic resistance that involved both the SA and JA/ET two signaling pathways. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitor (ICI) therapy targeting anti-programmed cell death-1 (anti-PD-1) or its ligand (anti-PD-L1) is the backbone of numerous combination regimens aimed at improving the objective response and survival of patients with hepatocellular carcinoma (HCC). Clinical trials of immuno-oncology regimens in other cancer types have shed light on issues of study design, including how to choose candidate regimens based on early-phase trial results, statistical considerations in trials with multiple primary endpoints, and the importance of predictive biomarkers. In this review, the updated data from early-phase trials of combination immunotherapy for HCC are summarised. Since the most extensively tested combination regimens for advanced HCC comprise anti-PD-1/anti-PD-L1 agents plus antiangiogenic agents, the relative benefit and antitumor mechanism of antiangiogenic multikinase inhibitors versus specific VEGF/VEGFR inhibitors are discussed. Other critical issues in the development of combination immunotherapy, including optimal management of immune-related adverse events and the value of ICI therapy in combination with locoregional treatment for HCC, are also explored. [ABSTRACT FROM AUTHOR]

• Objective responses and survival were comparable between intent-to-treat (ITT) overall population and Asian cohort. • Median overall survival in Asian patients was similar across HCC aetiologies. • Nivolumab had a manageable safety profile in both the ITT overall population and Asian cohort. Nivolumab, an immune checkpoint inhibitor, is approved in several countries to treat sorafenib-experienced patients with HCC, based on results from the CheckMate 040 study (NCT01658878). Marked differences exist in HCC clinical presentation, aetiology, treatment patterns and outcomes across regions. This analysis assessed the safety and efficacy of nivolumab in the Asian cohort of CheckMate 040. CheckMate 040 is an international, multicentre, open-label, phase I/II study of nivolumab in adults with advanced HCC, regardless of aetiology, not amenable to curative resection or local treatment and with/without previous sorafenib treatment. This analysis included all sorafenib-experienced patients in the intent-to-treat (ITT) overall population and Asian cohort. The analysis cut-off date was March 2018. There were 182 and 85 patients in the ITT population and Asian cohort, respectively. In both populations, most patients were older than 60 years, had BCLC (Barcelona Clinic Liver Cancer) Stage C disease, and had received previous systemic therapy. A higher percentage of Asian patients had HBV infections, extrahepatic metastases and prior therapies. Median follow-up was 31.6 and 31.3 months for the ITT and Asian patients, respectively. Objective response rates were 14% and 15% in the ITT population and Asian cohort, respectively. In the Asian cohort, patients with HBV, HCV or those who were uninfected had objective response rates of 13%, 14% and 21%, respectively. The median duration of response was longer in the ITT (19.4 months) vs. Asian patients (9.7 months). Median overall survival was similar between the ITT (15.1 months) and Asian patients (14.9 months), and unaffected by aetiology in Asian patients. The nivolumab safety profile was similar and manageable across both populations. Nivolumab safety and efficacy are comparable between sorafenib-experienced ITT and Asian patients. The CheckMate 040 study evaluated the safety and efficacy of nivolumab in patients with advanced hepatocellular carcinoma who were refractory to previous sorafenib treatment or chemotherapy. This subanalysis of the data showed that treatment responses and safety in patients in Asia were similar to those of the overall treatment population, providing support for nivolumab as a treatment option for these patients. Clinical trial number: NCT01658878. [ABSTRACT FROM AUTHOR]

This study aimed to determine the mechanisms of heat-induced oxidative stress in the thymus and spleen of broilers. After 28 d, 30 broilers were randomly divided into the control (25°C ± 2°C; 24 h/d) and heat-stressed (36°C ± 2°C; 8 h/d) groups; the experiment lasted for 1 wk. The broilers in each group were euthanized, and some samples were collected and analyzed at 35 d. The results showed that the birds subjected to heat stress reduced the weight (P < 0.01) and the indices of thymus (P < 0.01), the activities of T-AOC (P < 0.01) and SOD (P < 0.05) of spleen, and levels of IL-10 (P < 0.05) and the GSH-PX (P < 0.05) in thymus and spleen, and increased the IL-6 content of thymus (P < 0.05), the MDA content (P < 0.01), and the reactive oxygen species (ROS) levels (P < 0.01) in thymus and spleen. Moreover, the expression of the IgG gene in the thymus and spleen of heat-stressed broilers was increased (P < 0.05); however, the expression of the IgM gene in the spleen was increased (P < 0.05), with no difference (P > 0.05) in the thymus of heat-stressed broilers compared with the control. Furthermore, the relative expression of adenosine triphosphate-binding cassette subfamily G member 2 (ABCG2) in the thymus and spleen both increased (P < 0.05). The sodium-dependent vitamin C transporter-2 (SVCT-2) (P < 0.01) and mitochondrial calcium uniporter (MCU) (P < 0.01) mRNA levels in the thymus of heat-stressed broilers increased, and the expression of ABCG2 (P < 0.05), SVCT-2 (P < 0.01), and MCU (P < 0.01) proteins in the thymus and spleen of heat-stressed broilers increased compared with the control group. This study confirmed that heat stress-induced oxidative stress in the immune organs of broilers, further reducing immune function. [ABSTRACT FROM AUTHOR]

Background: Curative liver resection is the treatment of choice for both primary and secondary liver malignancies. However, an inadequate future liver remnant (FLR) frequently precludes successful surgery. Portal vein embolization is the gold-standard modality for inducing hypertrophy of the FLR. In recent times, unilobar Yttrium-90 selective internal radiation therapy (SIRT) has been reported to induce hypertrophy of the contralateral, untreated liver lobe. The aim of this study is to review the current literature reporting on contralateral liver hypertrophy induced by unilobar SIRT. Methods: A systematic review of the English-language literature between 2000 and 2014 was performed using the search terms "Yttrium 90" OR "selective internal radiation therapy" OR "radioembolization" AND "hypertrophy". Results: Seven studies, reporting on 312 patients, were included. Two hundred and eighty four patients (91.0%) received treatment to the right lobe. Two hundred and fifteen patients had hepatocellular carcinoma (HCC), 12 had intrahepatic cholangiocarcinoma, and 85 had liver metastases from mixed primaries. Y90 SIRT resulted in contralateral liver hypertrophy which ranged from 26 to 47% at 44 days-9 months. All studies were retrospective in nature, and heterogeneous, with substantial variations relative to pathology treated, underlying liver disease, dosage and delivery of Y90, number of treatment sessions and time to measurement of hypertrophy. Conclusion: Unilobar Y90 SIRT results in significant hypertrophy of the contralateral liver lobe. The rate of hypertrophy seems to be slower than that achieved by other methods. [ABSTRACT FROM AUTHOR]

Francisella tularensis , the causative agent of tularemia, presents a significant biological threat and is a Category A priority pathogen due to its potential for weaponization. The bacterial FASII pathway is a viable target for the development of novel antibacterial agents treating Gram-negative infections. Here we report the advancement of a promising series of benzimidazole FabI (enoyl-ACP reductase) inhibitors to a second-generation using a systematic, structure-guided lead optimization strategy, and the determination of several co-crystal structures that confirm the binding mode of designed inhibitors. These compounds display an improved low nanomolar enzymatic activity as well as promising low microgram/mL antibacterial activity against both F. tularensis and Staphylococcus aureus and its methicillin-resistant strain (MRSA). The improvements in activity accompanying structural modifications lead to a better understanding of the relationship between the chemical structure and biological activity that encompasses both enzymatic and whole-cell activity. [ABSTRACT FROM AUTHOR]

Highlights: [•] We review the impacts of random telegraph noise on FinFET, Ge/Si Nanowire FET, Tunnel FET (TFET) and related circuits. [•] For FinFET, trap in the middle between source/drain and bottom of sidewall interface shows larger impact. [•] The RTN in Ge Nanowire FET exhibits stronger drain bias dependence and may yield current increase. [•] TFET exhibits drastically higher sensitivity to RTN and significant I OFF degradation. [•] The possible RTN combinations due to trapping/detrapping in each device are discussed for SRAM and logic circuits. [ABSTRACT FROM AUTHOR]

Background & Aims: Hepatocellular carcinoma (HCC) is the third leading cause of cancer death. Although sorafenib has been shown to improve survival of patients with advanced HCC, this improvement is modest and patients eventually have refractory disease. This study aims at investigating the antitumor, antiangiogenesis and antimetastatic activities of dovitinib in preclinical models of HCC. Methods: 21-0208 and SK-HEP1 cells as well as patient-derived HCC models were employed to study the antitumor effect of dovitinib. Changes of biomarkers relevant to FGFR/VEGFR/PDGFR pathways were determined by Western blotting. Microvessel density, apoptosis and cell proliferation were analyzed by immunohistochemistry. Results: Treatment of SK-HEP1 cells with dovitinib resulted in G2/M cell cycle arrest, inhibition of colony formation in soft agar and blockade of bFGF-induced cell migration. Dovitinib inhibited basal expression and FGF-induced phosphorylation of FGFR-1, FRS2-α and ERK1/2. In vivo, dovitinib potently inhibited tumor growth of six HCC lines. Inhibition of angiogenesis correlated with inactivation of FGFR/PDGFR-β/VEGFR-2 signaling pathways. Dovitinib also caused dephosphorylation of retinoblastoma, upregulation of p-histone H2A-X and p27, and downregulation of p-cdk-2 and cyclin B1, which resulted in a reduction in cellular proliferation and the induction of tumor cell apoptosis. In an orthotopic model, dovitinib potently inhibited primary tumor growth and lung metastasis and significantly prolonged mouse survival. Conclusions: Dovitinib demonstrated significant antitumor and antimetastatic activities in HCC xenograft models. This study provides a compelling rationale for clinical investigation in patients with advanced HCC. [Copyright &y& Elsevier]

Background & Aims: Hepatocellular carcinoma (HCC) is a particularly vascularized solid tumor where the Raf/MEK/ERK pathway is activated; suggesting that inhibition of this pathway may have therapeutic potential. Methods: We treated patient-derived HCC xenografts with (i) sorafenib, (ii) AZD6244 (ARRY-142886), and (iii) sorafenib plus AZD6244. Western blotting was employed to determine pharmacodynamic changes in biomarkers relevant to both angiogenesis and MEK signaling. Apoptosis, microvessel density, and cell proliferation were analyzed by immunohistochemistry. Results: We report here that sorafenib treatment resulted in suppression of tumor growth, reduction in cell proliferation, induction of apoptosis and inhibition of mTOR targets. Sorafenib-induced elevation of the insulin-like growth factor receptor 1 (IGF-1R), phospho-c-Raf Ser338, phospho-MEK Ser217/221 and phospho-ERK Thr202/Tyr204 was attenuated by co-treating cells with anti-human IGF-1R antibody or over-expression of activated mutant p70S6K. Pharmacological inhibition of the MEK/ERK pathway by AZD6244 enhanced the anti-tumor effect of sorafenib in both orthotopic and ectopic models of HCC. Such inhibition led to a further increase in pro-apoptotic Bim, apoptosis and a profound inhibition of cell proliferation. Conclusion: Our findings underscore the potential of a combined therapeutic approach with sorafenib and MEK inhibitors in the treatment of HCC. [Copyright &y& Elsevier]

Abstract: Aim: To analyze the outcome of elderly patients compared with the younger age group patients who were diagnosed with gastrointestinal stromal tumours (GIST) at our institution. Methods: Patients diagnosed with GISTs were analyzed according to two age groups, those who were at least age 65 and less than age 65. Results: A total of 49 patients were reviewed. Median age at diagnosis was 59. 18 patients (36.7%) were of age at least 65 or above. Of these 11 patients presented with localized disease. Five patients subsequently developed recurrence with metastatic disease. The median recurrence free survival was 18.5 months. This was not significantly different compared to the younger age group patient (P =0.598). On univariate analysis, the presence of co-morbidities was found to be significantly associated with decrease recurrence-free survival (P =0.046). 13 patients (72.2.%) of the elderly age group had metastatic disease. 8 of these patients had metastasis at diagnosis and 5 developed metastasis at recurrence. The median progression-free survival for these patients was 33 months and there was no significant difference compared to the younger age group patient (P =0.887). On univariate analysis, low albumin was associated with low progression survival (P =0.047). The median overall survival for the elderly patients was 37.6 months. There was no significant difference compared to the younger age group patient (P =0.119). Presence of co-morbidity was associated with lower overall survival in the elderly age group in the multivariate analysis (P =0.037). Conclusion: The elderly with GIST can achieve a similar outcome as younger patients. Presence of co-morbidity was found to affect the survival of elderly patients with GIST. [Copyright &y& Elsevier]

Abstract: We investigated the feasibility of two monitoring imaging methods to visualize and evaluate the high intensity focused ultrasound (HIFU) induced lesions in vitro during and after their formation, which were based on differential ultrasonic parameter estimation. Firstly, ultrasonic attenuation slope of tissue sample was estimated based on the spectral analysis of ultrasound RF backscattered signals. The differential attenuation slope maps were acquired, which were interpreted as the differences between the pretreatment image and those obtained in different stages during HIFU therapy. Secondly, ultrasonic integrated backscatter (IBS), defined as the frequency average of the backscatter transfer function over the useful bandwidth, was proposed quantitatively to evaluate the extent of lesions with the same RF signals as the first method. Differential IBS maps were also acquired to visualize temporal evolution of lesion formation. It was found in pig liver in vitro that more precise definition of the treated area was obtained from the differential IBS images than from differential attenuation slope images. Dramatic increase in both attenuation and IBS value was observed during the therapy, which may be related to dramatic enhancement of cavitation due to boiling and accompanying tissue damage. Two methods to obtain one differential image were compared and the cumulative differential image was found to be able to eliminate noises and artifacts to some extent, which was the cumulation of a series of differential images acquired from the differences between the temporally adjacent RF data frames. Moreover, we presented a bidirectional color code for identification of the artifacts due to tissue movements caused by HIFU radiation force. We conclude that cumulative differential IBS images have the potential to monitor the formation of HIFU-induced lesions.(E-mail: mxwan@mail.xjtu.edu.cn) [Copyright &y& Elsevier]

The objective of this study was to investigate the effects of ultrasound on the structure and function of human tumor necrosis factor–alpha (TNF-α) and to study whether TNF-alpha underwent a denaturation process and the molecular structure was damaged when it was irradiated by ultrasound. The samples of TNF-alpha were dissolved in aqueous solution and filled into polystyrene tubes. High intensity ultrasound processor (20 kHz frequency, burst mode, 0.5 duty factor, 100–500 W total electrical power, 0–20 min total treatment time) was used during the treatment. The biologic activity of TNF-alpha was determined by its toxic activity towards TNF-alpha sensitive cell line L929 in the presence of actinomycin D. The methods of sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and matrix-assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF-MS) were used to detect the integrity of TNF-alpha molecule after it was irradiated by ultrasound. The results showed TNF-alpha could keep its biological activity, instead of undergoing a denaturation process, when it is irradiated by ultrasound in the aqueous solution; at the same time, the aggregates of TNF-alpha formed by the recombinant DNA E. coli could be dissociated through the molecular vibration induced by ultrasound energy. The biologic activity of TNF-alpha was not reduced, but small quantities of TNF-alpha molecular structure were damaged during the process of sonication. These features of TNF-α molecule irradiated by ultrasound probably gave TNF-α the advantage in being used in the drug microencapsulation and provided a new drugs formulation for tumor therapy. (mxwan@mail.xjtu.edu.cn) [Copyright &y& Elsevier]

Corrigendum to "Nivolumab in advanced hepatocellular carcinoma: Sorafenib-experienced Asian cohort analysis" [J Hepatol 71 (2019) 543-552] It has come to our attention that there is an error in Table 4 of our manuscript. [Extracted from the article]