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Background: Plant anther development is a systematic and complex process precisely controlled by genes. Regulation genes and their regulatory mechanisms for this process remain elusive. In contrast to numerous researches on anther development with respect to mRNAs or miRNAs in many crops, the association analysis combining both omics has not been reported on cotton anther. Results: In this study, the molecular mechanism of cotton anther development was investigated with the employment of association analysis of transcriptome and small RNA sequencing during the predefined four stages of cotton anther development, sporogenuous cell proliferation (SCP), meiotic phase (MP), microspore release period (MRP) and pollen maturity (PM). Analysis revealed that the differentially expressed genes are increasingly recruited along with the developmental progress. Expression of functional genes differed significantly among developmental stages. The genes related with cell cycle, progesterone-mediated oocyte maturation, and meiosis are predominantly expressed at the early stage of anther development (SCP and MP), and the expression of genes involved in energy metabolism, flavonoid biosynthesis, axon guidance and phospholipase D signaling pathways is mainly enriched at the late stage of anther development (MRP and PM). Analysis of expression patterns revealed that there was the largest number of differentially expressed genes in the MP and the expression profiles of differentially expressed genes were significantly increased, which implied the importance of MP in the entire anther development cycle. In addition, prediction and analysis of miRNA targeted genes suggested that miRNAs play important roles in anther development. The miRNAs ghr-miR393, Dt_chr12_6065 and At_chr9_3080 participated in cell cycle, carbohydrate metabolism and auxin anabolism through the target genes, respectively, to achieve the regulation of anther development. Conclusions: Through the association analysis of mRNA and miRNA, our work gives a better understanding of the preferentially expressed genes and regulation in different developmental stages of cotton anther and the importance of meiotic phase, and also the involvement of miRNAs in precise regulation for this process, which would be valuable for clarifying the mechanism of plant anther development in response to internal and external environments. [ABSTRACT FROM AUTHOR]

Single ferroelectric-FET (FeFET) reconfigurable logic-in-memory is an attractive beyond-von-Neumann scheme for data-centric computing. Different from using body-to-source voltage to tune the operating point of the FeFET for reconfigurability, this brief presents an alternative approach based on the unique ferroelectric minor-loop behavior (which results from the partial switching of domains). Through simulation, we show that the NAND/ NOR reconfigurability can theoretically be achieved by adequately modulating the reference and writing pulses for the FeFET nonvolatile memory (NVM). Our approach may serve as an option when the body-effect capability is lacking for nonplanar FeFETs or 3-D stacked FeFETs which can be crucial to future high-density integration. [ABSTRACT FROM AUTHOR]

Background: Human neutrophil antigen 3 (HNA-3) is encoded by the SLC44A2 gene. Antibodies against HNAs can cause severe, often fatal, transfusion reactions, known as transfusion-related acute lung injury, and neonatal neutropenia. We explored the 2 common HNA-3 variants in 9 ethnic populations residing in Sichuan and Yunnan provinces of China as compared to the Han population.Methods: We genotyped for SLC44A2 (rs2288904) by polymerase chain reaction sequence-based typing among blood donors, for a total of 2206 individuals in Yunnan and 376 in Sichuan.Results: The SLC44A2*02 allele (HNA-3b antigen) frequency varied between 0.24 and 0.33 for all 9 ethnic populations in Yunnan, including Zhuang, Derung, Hani, Lisu, Bai, Miao, Dai, Naxi, and Yi. Specifically, the Yi ethnicity did not present an unusually great SLC44A2*02 frequency at any of the 4 locations examined in Yunnan. Except of the Yi ethnicity in Sichuan (0.40), the Han ethnicity, as the majority population group, had the greatest SLC44A2*02 frequency with 0.39 in Yunnan and 0.35 in Sichuan.Conclusion: The ethnic populations in Southwest China are not at an increased risk for anti-HNA3a compared to the Han population, with the possible exception of Yi in Sichuan. Our data, however, corroborated the known high prevalence of SLC44A2*02 in Han populations. Hence, the Han populations in Yunnan, Sichuan and elsewhere in China are at a comparatively great risk for developing HNA-3a antibodies. [ABSTRACT FROM AUTHOR]

Beauveria bassiana is a well-known insecticidal biocontrol agent. Despite its broad field applications, its survival, colonization, and stability under field conditions remained unclear, mainly due to the lack of a quick and reliable detection method. In this study, we developed a quantitative real-time PCR technology to monitor the stability and population dynamics of B. bassiana in different substrates (water, soil, and on the cotton leaves surface), different spores of B. bassiana applied on Chinese cabbage leaves surface, and the lethality of Pieris rapae spraying with different spores of B. bassiana. Our results showed a decreased concentration of B. bassiana DNA in all three substrates from the 1st day till 9th day of post inoculation (dpi) period, possibly due to the death of B. bassiana. After this decrease, a quick and significant rebound of B. bassiana DNA concentration was observed, starting from the 11th dpi in all three substrates. The B. bassiana DNA concentration reached the plateau at about 13th dpi in water and 17th dpi in the soil. On cotton leaves surface, the B. bassiana DNA concentration reached the highest level at the 17th dpi followed by a small decline and then stabilized. This increase of DNA concentration suggested recovery of B. bassiana growth in all three substrates. We found that the most suitable killing effectiveness of P. rapae was the 1.0 × 107 spores/mL of B. bassiana. In summary, we have established a detection technology that allows a fast and reliable monitoring for the concentration and stability of B. bassiana under different conditions. This technology can benefit and help us in the development of proper management strategies for the application of this biocontrol agent in the field. [ABSTRACT FROM AUTHOR]

Type 3 fimbriae in Klebsiella pneumoniae are important for bacterial colonization on abiotic and biotic surfaces. The major subunit of type 3 fimbriae (MrkA) is increased by overexpression of EtcABC, an EII complex of phosphoenolpyruvate:carbohydrate phosphotransferase systems (PTSs), through cAMP-cAMP receptor protein (cAMP-CRP) in K. pneumoniae STU1. Here, we further characterized the relations between the amount of etcABC mRNA and MrkA in 78 clinical K. pneumoniae isolates incubated in high levels of glucose. By Western blotting, we observed that MrkA of 29 isolates were not decreased much by high levels of glucose (Group A) but MrkA of other 49 isolates were significantly reduced (Group B) in the same condition. The bacterial biofilms on abiotic surfaces and colonization in the Caenorhabditis elegans of representative isolates in the Group A were not affected by high levels of glucose. However, the biofilm and colonization in the worm of clinical isolates in the Group B were much reduced by high levels of glucose. After quantification by real time RT-PCR, 76% of Group A but just 10% of Group B showed high amount of etcA mRNA. In summary, our results suggested that for most of K. pneumoniae clinical isolates, the amount of etcABC mRNA was positively related to their type 3 fimbriae production in a high level of glucose, thereby to their biofilm formation and colonization in the worm. [ABSTRACT FROM AUTHOR]

Background: Approximately 20 % of hepatocellular carcinoma (HCC) patients diagnosed in the early stages may benefit from potentially curative ablative therapies such as surgical resection, transplantation or radiofrequency ablation. For patients not eligible for such options, prognosis is poor. Sorafenib and Selective Internal Radiation Therapy (SIRT) are clinically proven treatment options in patients with unresectable HCC, and this study aims to assess overall survival following either SIRT or Sorafenib therapy for locally advanced HCC patients.Methods: This investigator-initiated, multi-centre, open-label, randomized, controlled trial will enrol 360 patients with locally advanced HCC, as defined by Barcelona Clinic Liver Cancer stage B or stage C, without distant metastases, and which is not amenable to immediate curative treatment. Exclusion criteria include previous systemic therapy, metastatic disease, complete occlusion of the main portal vein, or a Child-Pugh score of >7. Eligible patients will be randomised 1:1 and stratified by centre and presence or absence of portal vein thrombosis to receive either a single administration of SIRT using yttrium-90 resin microspheres (SIR-Spheres®, Sirtex Medical Limited, Sydney, Australia) targeted at HCC in the liver by the trans-arterial route or continuous oral Sorafenib (Nexavar®, Bayer Pharma AG, Berlin, Germany) at a dose of 400 mg twice daily until disease progression, no further response, complete regression or unacceptable toxicity. Patients for both the Sorafenib and SIRT arms will be followed-up every 4 weeks for the first 3 months and 12 weekly thereafter. Overall survival is the primary endpoint, assessed for the intention-to-treat population. Secondary endpoints are tumour response rate, time-to-tumour progression, progression free survival, quality of life and down-staging to receive potentially curative therapy.Discussion: Definitive data comparing these two therapies will help to determine clinical practice in the large group of patients with locally advanced HCC and improve outcomes for such patients.Trial Registration: ClinicalTrials.gov identifier, NCT01135056 , first received 24, May 2010. [ABSTRACT FROM AUTHOR]

This paper investigates the fin-width ($\text{W}_{\textsf {Fin}}$) sensitivity of threshold voltage ($\text{V}_{\textsf {T}}$) for InGaAs and Si channel negative-capacitance FinFETs (NC-FinFETs) using a theoretically derived quantum subthreshold model corroborated with TCAD numerical simulation. Our study indicates that due to the action of negative capacitance, the NC-FinFET possesses smaller $\text{V}_{\textsf {T}}$ sensitivity to $\text{W}_{\textsf {Fin}}$ than the FinFET counterpart. In addition, we point out and demonstrate that a device design with higher internal voltage amplification can be utilized to further reduce the $\text{V}_{\textsf {T}}$ sensitivity to $\text{W}_{\textsf {Fin}}$ for NC-FinFETs. Our study may provide insights for future scaling of FinFETs. [ABSTRACT FROM AUTHOR]

Introduction: Combination therapy with immune checkpoint inhibitor (ICI) and antivascular endothelial growth factor (anti‐VEGF) is currently the first line treatment for advanced hepatocellular carcinoma (aHCC). However, there are many patients who may not be able to receive combination therapy due to underlying comorbidities or resource limitations. For these patients, systemic treatment options include single agent tyrosine kinase inhibitors (TKIs) or ICI monotherapy. However, whether an optimal sequence of systemic therapy exists remains unknown. We aim to explore the impact of sequencing of TKI and ICI therapy in terms of response rates and to examine the safety of their use in sequential order. Methods: Patients with aHCC treated with both ICI and TKI between December 30, 2013 and June 13, 2018 were retrospectively identified. Patients were classified into two groups: those who received TKI in the first‐line (TKI1), followed by ICI (ICI2) and those who received ICI (ICI1) in the first‐line followed by TKI (TKI2). The primary objective of the study was to identify differences in objective response rate (ORR) and disease control rate (DCR), as evaluated based on response evaluation criteria in solid tumor v1.1 for TKI1, TKI2, ICI1, and ICI2. Secondary objectives included comparison of progression free survival (PFS) for each line of therapy, overall survival (OS) and adverse events (AEs). Results: Twenty‐seven and 23 patients were classified into group 1 and 2, respectively. Objective response rates of TKI1 and TKI2 were 3.8% and 17.6%, respectively (p =.28); DCR to TKI1 versus TKI2 was 23.1% versus 35.3% (p =.49). ORRs of ICI1 and ICI2 were 8.7% and 14.3%, respectively (p =.66); DCR to ICI2 versus ICI1 was 56.5% versus 42.9% (p =.37). Median PFS was not significant between TKI1 and TKI2 (PFS 3.06 versus 1.61 months, p =.097) as well as between ICI2 and ICI1 (PFS 1.84 versus 2.37 month, p =.32). Median OS was also not significantly different between both groups (OS 20.63 versus 13.93 months, p =.20) on univariable and multivariable analysis (OS adjusted hazard ratio [HR] 2.07, 95% CI.83–5.18, p =.118). The proportion of patients who experienced adverse events of any grade was similar in both groups (TKI1 59.3% versus TKI2 52.2%; ICI1 78.3% versus ICI2 70.4%). Conclusion: Our study suggests that the sequence of TKI versus ICI therapy in patients with aHCC may not matter, given similar efficacy and toxicity profile when either agent is received in the first or second‐line setting. This finding is of value in the real‐world setting, where patients may be frail or have comorbidities that render them unable to tolerate combination therapy (ICI and TKI/anti‐VEGF). For these patients, sequential exposure to both classes of drugs (ICI and TKI) may be a suitable option. [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]

Despite being a relatively young nation, Singapore has established itself as a leading multifaceted medical hub, both regionally and globally. Although Singapore continues to pursue excellence in oncology care, cancer supportive care and survivorship care remain in the infancy stage. In an effort to advance this important aspect of oncology care in Singapore, the first cancer supportive and survivorship care forum was held in December 2016, involving 74 oncology practitioners. The primary goals of this forum were to raise awareness of the importance of cancer supportive and survivorship care and to provide a platform for oncology practitioners of diverse backgrounds to converge and address the challenges associated with the delivery of cancer supportive and survivorship care in Singapore. Key challenges identified during this forum included, but were not limited to, care fragmentation in an oncologist-centric model of care, poor integration of allied health and rehabilitation services, passive engagement of community partners, lack of specialized skill sets and knowledge in supportive and survivorship care, and patient-related barriers such as poor health literacy. The survivorship care model commonly used in Singapore places an imbalanced emphasis on surveillance for cancer recurrence and second primary cancers, with little attention given to the supportive and survivorship needs of the survivors. In summary, these challenges set the stage for the development and use of a more survivor-centric model, one that focuses not only on cancer surveillance, but also on the broad and unique physical and psychosocial needs of survivors of cancer in Singapore. [ABSTRACT FROM AUTHOR]

The occurrence of neurotrophic tyrosine receptor kinase (NTRK) gene fusions in a wide range of tumor types presents an attractive opportunity for using a tropomyosin receptor kinase (TRK) inhibitor as cancer therapy. Recent clinical studies have demonstrated highly efficacious outcomes associated with the use of TRK inhibitors, such as larotrectinib and entrectinib in NTRK fusion‐bearing cancers, in both adult and pediatric populations. While NTRK gene fusions are commonly found in some uncommon adult and pediatric malignancies, they are also found, albeit rarely, in a wide range of more common malignancies. The potential value of testing for NTRK gene fusions in practically all advanced malignancies is underpinned by the remarkable therapeutic outcomes that TRK inhibitors offer. This requirement presents practical and financial challenges in real‐world oncological practice. Furthermore, different testing platforms exist to detect NTRK gene fusions, each with its advantages and disadvantages. It is, therefore, imperative to develop strategies for NTRK gene fusion testing in an attempt to optimize the use of limited tissue specimen and financial resources, and to minimize the turnaround time. A multidisciplinary task force of Singapore medical experts in both public and private sectors was convened in late 2020 to propose testing algorithms for adult colorectal tumors, sarcomas, non‐small cell lung cancer, and pediatric cancers, with particular adaptation to the Singapore oncological practice. The recommendations presented here highlight the heterogeneity of NTRK‐fusion positive cancers, and emphasize the need to customize the testing methods to each tumor type to optimize the workflow. [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]

To develop new agents against strawberry grey mould and to aid in the development of biological pesticides, we investigated the inhibitory effect of a natural compound, phenazine-1-carboxamide (PCN), against Botrytis cinerea using a growth rate assay. Additionally, indoor toxicity and the in vitro control effect of PCN were further studied to determine its potential mechanisms of action on B. cinerea. PCN was inhibitory against B. cinerea with a 50% effective concentration (EC50) of 108.12 μg/mL; the toxicity of PCN was equivalent to that of carbendazim (CBM). The best in vitro control effect of PCN against grey mould in strawberry (fruit) reached 75.32%, which was slightly higher than that of CBM. The field control effect of PCN against grey mould reached a maximum of 72.31% at a PCN concentration of 700 μg/mL, which was 1.02 times higher than that of CBM. Fungistatic activity was observed at low concentrations of PCN, while high concentrations of PCN resulted in fungicidal activity against B. cinerea. This natural compound strongly inhibited both spore and sclerotium germination of B. cinerea, with the best relative inhibition rates of 77.03% and 82.11%, respectively. The inhibitory effect of PCN on mycelial growth of B. cinerea was significant and reached levels of 87.32%. Scanning electron microscopy observations revealed that after 48 h of PCN treatment, the mycelia appeared loose, locally twisted, and folded, with exudation of contents; the mycelia was withered and twisted, with edge burrs, deformations, ruptures and a sheet-like structure. Transmission electron microscopy observations revealed that after 48 h of PCN treatment, the structure of the cell nucleus was unclear and the vacuoles had ruptured; additionally, various organelles exhibited disordered structures, there were substantial non-membrane transparent inclusions, the cells were plasmolysed, the cell walls were collapsed in some cases, and the hyphal tissue was essentially necrotic. A PCN dosage of 35–140 μg/mL had no effect on the cell membrane permeability of the mycelia, while a PCN dosage of 700 μg/mL resulted in significant permeability. PCN inhibited B. cinerea toxin; the mycotoxin level was approximately 0.41 of the value recorded for the control at a PCN dosage of 700 μg/mL. PCN affected the activity of pectin methylgalacturonase (PMG), polygalacturonase (PG), cellulase (Cx) and β-glucosidase (BG); the lowest activities of PMG, PG, BG and Cx reached 0.3 U/mg, 0.62 U/mg, 0.64 U/mg, and 0.79 U/mg, respectively, after treatment with 700 μg/mL PCN. [ABSTRACT FROM AUTHOR]

Background: Deregulation of FGF19-FGFR4 signaling is found in several cancers, including hepatocellular carcinoma (HCC), nominating it for therapeutic targeting. FGF401 is a potent, selective FGFR4 inhibitor with antitumor activity in preclinical models. This study was designed to determine the recommended phase 2 dose (RP2D), characterize PK/PD, and evaluate the safety and efficacy of FGF401 alone and combined with the anti-PD-1 antibody, spartalizumab. Methods: Patients with HCC or other FGFR4/KLB expressing tumors were enrolled. Dose-escalation was guided by a Bayesian model. Phase 2 dose-expansion enrolled patients with HCC from Asian countries (group1), non-Asian countries (group2), and patients with other solid tumors expressing FGFR4 and KLB (group3). FGF401 and spartalizumab combination was evaluated in patients with HCC. Results: Seventy-four patients were treated in the phase I with single-agent FGF401 at 50 to 150 mg. FGF401 displayed favorable PK characteristics and no food effect when dosed with low-fat meals. The RP2D was established as 120 mg qd. Six of 70 patients experienced grade 3 dose-limiting toxicities: increase in transaminases (n = 4) or blood bilirubin (n = 2). In phase 2, 30 patients in group 1, 36 in group 2, and 20 in group 3 received FGF401. In total, 8 patients experienced objective responses (1 CR, 7 PR; 4 each in phase I and phase II, respectively). Frequent adverse events (AEs) were diarrhea (73.8%), increased AST (47.5%), and ALT (43.8%). Increase in levels of C4, total bile acid, and circulating FGF19, confirmed effective FGFR4 inhibition. Twelve patients received FGF401 plus spartalizumab. RP2D was established as FGF401 120 mg qd and spartalizumab 300 mg Q3W; 2 patients reported PR. Conclusions: At biologically active doses, FGF401 alone or combined with spartalizumab was safe in patients with FGFR4/KLB-positive tumors including HCC. Preliminary clinical efficacy was observed. Further clinical evaluation of FGF401 using a refined biomarker strategy is warranted. Trial registration: NCT02325739. [ABSTRACT FROM AUTHOR]

This paper analyzes the impacts of read-assist and write-assist circuits on GeOI FinFET 6T SRAM cells considering intrinsic random variations, process corner, and temperature variation. The word-line under-drive (WLUD) read-assist is more efficient to improve the read static noise margin and read $V_{{\rm {MIN}}}$ of fast-N slow-P corner GeOI FinFET SRAM cells compared with the Silicon-On-Insulator (SOI) counterparts. GeOI FinFET SRAM cells with WLUD show less cell read access-time degradation compared with the SOI counterparts at both 25 °C and 125 °C. With transient voltage collapse (TVC) write-assist, the write-ability and variation tolerance of GeOI and SOI FinFET SRAM cells are improved. The temperature dependence of data retention time is different between the GeOI and SOI FinFET SRAM cells. The maximum TVC write-assist pulsewidth constrained by the data retention failure is smaller in GeOI FinFET SRAMs at 25 °C and becomes comparable at 125 °C compared with the SOI FinFET SRAMs. [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]

We present a comparative leakage analysis of germanium-on-insulator (GeOI) FinFET and germanium on bulk substrate FinFET (Ge bulk FinFET) at device and circuit levels. Band-to-band tunneling (BTBT) leakage-induced bipolar effect is found to result in an amplified BTBT leakage for GeOI FinFET. Device and circuit designs to mitigate the amplified BTBT leakage of GeOI FinFETs are suggested. The effectiveness of various high threshold voltage technology options including increasing channel doping, increasing gate length and drain-side underlap for leakage reduction is analyzed. [ABSTRACT FROM AUTHOR]

A criticalanalysis of virtual screening results published between2007 and 2011 was performed. The activity of reported hit compoundsfrom over 400 studies was compared to their hit identification criteria.Hit rates and ligand efficiencies were calculated to assist in theseanalyses, and the results were compared with factors such as the sizeof the virtual library and the number of compounds tested. A seriesof promiscuity, druglike, and ADMET filters were applied to the reportedhits to assess the quality of compounds reported, and a careful analysisof a subset of the studies that presented hit optimization was performed.These data allowed us to make several practical recommendations withrespect to selection of compounds for experimental testing, definitionof hit identification criteria, and general virtual screening hitcriteria to allow for realistic hit optimization. A key recommendationis the use of size-targeted ligand efficiency values as hit identificationcriteria. [ABSTRACT FROM AUTHOR]

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]

Using a novel Voronoi method that can provide a more realistic representation of metal-gate granularity, we investigate and compare the impact of work-function variation (WFV) on FinFET and ultrathin body (UTB) silicon-on-insulator (SOI) devices. Our study indicates that, for a given electrostatic integrity and total effective gate area, the FinFET device exhibits better immunity to WFV than its UTB SOI counterpart. We further show that, unlike other sources of random variation, the WFV cannot be suppressed by equivalent oxide thickness scaling. [ABSTRACT FROM PUBLISHER]

Optimized threshold voltage (Vt) design to enhance the variation immunity of high-performance (super-threshold) and low-voltage (near-/sub-threshold) 6 T SRAM cells is presented. For low-voltage SRAM cells operating at low Vdd, low-Vt design shows smaller variability, while the design tradeoff between performance and leakage should be considered. For high-performance SRAM cells operating at high Vdd, ultra-thin-body SOI SRAM cells with high-Vt design show smaller variability while sacrificing performance compared with the low-Vt design. Our study indicates that hetero-channel SRAM cells enable high-Vt design and exhibit improved Read/Write stability and performance, and maintain comparable RSNM variations for the high-performance SRAM applications. [ABSTRACT FROM AUTHOR]

Gastric cancer (GC) constitutes a major cause of cancer deaths worldwide. Recent improvements in both surgical techniques and adjuvant and neoadjuvant radiotherapy and chemotherapy approaches have increased the survival of patients with loco-regional disease. However most patients with GC have advanced disease either at diagnosis or at follow up. Despite recent advances in the treatment of advanced disease, these patients still have poor outcomes. An emerging understanding of the molecular pathways that characterize cell growth, cell cycle, apoptosis, angiogenesis and invasion has provided novel targets in cancer therapy. In this review we describe the current status of targeted therapies in the treatment of GC. These therapeutic strategies include epidermal growth factor receptor inhibitors, antiangiogenic agents, cell cycle inhibitors, apoptosis, promoters and matrix metalloproteinases inhibitors. [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]

Introduction: Immune checkpoint inhibitor (ICI) use in advanced hepatocellular carcinoma (HCC) is increasing. Real‐world data on efficacy and safety, however, are lacking. Methods: We conducted a retrospective review of all patients with advanced HCC seen at our center who received at least one dose of an ICI between May 2015 and June 2018. Data cutoff was December 31, 2018. Responses were evaluated using Response Evaluation Criteria in Solid Tumors version 1.1 criteria. Results: Of 114 patients, 88.6% were male. Median age was 66 years, 96.5% had an Eastern Cooperative Oncology Group of 0–1. 62.3% received monotherapy ICI. 18.4% of patients had Child‐Pugh (CP) B disease on initiation of ICI, and 69.3% had an ALBI grade of 2. 54.4% were known to have chronic hepatitis B (HBV) or were previously infected, and 11.4% had hepatitis C. Baseline HBV viral load (VL) ranged from undetectable to 8 210 000 IU/mL. 35.1% received prior systemic treatment. 28.9% received prior sorafenib. Over a median follow‐up duration of 13.8 months (10.4–15.8), ORR was 18.4%, and DCR was 50.9%. Median progression‐free survival was 2.7 months (1.3–4.0), and median overall survival (OS) was 13.9 months (6.9–16.2). Thirty‐one patients (27.2%) received further systemic therapy after ICI discontinuation. On multivariable analyses, lower albumin level, higher bilirubin level, diuretic‐refractory ascites, and HBV‐associated HCC were associated with poorer OS. 69.3% of patients experienced adverse events (AE) of any grade, 14.9% of these being grade 3–4. No grade 5 AE were observed. Use of antiviral therapy was associated with a lower risk of grade 3 or above hepatic AEs (P = 0.048), whereas high baseline HBV VL was not associated with an increased risk of reactivation or hepatic AE. Discussion: We have demonstrated that the real‐world performance of ICIs in advanced HCC appears comparable to that observed in clinical trials for HCC patients with CP A cirrhosis. While prognosis of patients with advanced HCC and CP B cirrhosis remains poor even with ICI, usage of ICI is likely to be safe. Patients with HBV with a baseline HBV VL ≥100 IU/mL may receive ICI safely, especially if they are on antiviral treatment. [ABSTRACT FROM AUTHOR]

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]

PURPOSE: Precision oncology has transformed the management of advanced cancers through implementation of advanced molecular profiling technologies to identify increasingly defined subsets of patients and match them to appropriate therapy. We report outcomes of a prospective molecular profiling study in a high-volume Asian tertiary cancer center. PATIENTS AND METHODS: Patients with advanced cancer were enrolled onto a prospective protocol for genomic profiling, the Individualized Molecular Profiling for Allocation to Clinical Trials Singapore study, at the National Cancer Center Singapore. Primary objective was to identify molecular biomarkers in patient's tumors for allocation to clinical trials. The study commenced in February 2012 and is ongoing, with the results of all patients who underwent multiplex next-generation sequencing (NGS) testing until December 2018 presented here. The results were discussed at a molecular tumor board where recommendations for allocation to biomarker-directed trials or targeted therapies were made. RESULTS: One thousand fifteen patients were enrolled with a median age of 58 years (range 20-83 years). Most common tumor types were lung adenocarcinoma (26%), colorectal cancer (15%), and breast cancer (12%). A total of 1,064 NGS assays were performed, on fresh tumor tissue for 369 (35%) and archival tumor tissue for 687 (65%) assays. TP53 (39%) alterations were most common, followed by EGFR (21%), KRAS (14%), and PIK3CA (10%). Of 405 NGS assays with potentially actionable alterations, 111 (27%) were allocated to a clinical trial after molecular tumor board and 20 (4.9%) were enrolled on a molecularly matched clinical trial. Gene fusions were detected in 23 of 311 (7%) patients tested, including rare fusions in new tumor types and known fusions in rare tumors. CONCLUSION: Individualized Molecular Profiling for Allocation to Clinical Trials Singapore demonstrates the feasibility of a prospective broad molecular profiling program in an Asian tertiary cancer center, with the ability to develop and adapt to a dynamic landscape of precision oncology. [ABSTRACT FROM AUTHOR]

PURPOSE: Precision oncology has transformed the management of advanced cancers through implementation of advanced molecular profiling technologies to identify increasingly defined subsets of patients and match them to appropriate therapy. We report outcomes of a prospective molecular profiling study in a high-volume Asian tertiary cancer center. PATIENTS AND METHODS: Patients with advanced cancer were enrolled onto a prospective protocol for genomic profiling, the Individualized Molecular Profiling for Allocation to Clinical Trials Singapore study, at the National Cancer Center Singapore. Primary objective was to identify molecular biomarkers in patient's tumors for allocation to clinical trials. The study commenced in February 2012 and is ongoing, with the results of all patients who underwent multiplex next-generation sequencing (NGS) testing until December 2018 presented here. The results were discussed at a molecular tumor board where recommendations for allocation to biomarker-directed trials or targeted therapies were made. RESULTS: One thousand fifteen patients were enrolled with a median age of 58 years (range 20-83 years). Most common tumor types were lung adenocarcinoma (26%), colorectal cancer (15%), and breast cancer (12%). A total of 1,064 NGS assays were performed, on fresh tumor tissue for 369 (35%) and archival tumor tissue for 687 (65%) assays. TP53 (39%) alterations were most common, followed by EGFR (21%), KRAS (14%), and PIK3CA (10%). Of 405 NGS assays with potentially actionable alterations, 111 (27%) were allocated to a clinical trial after molecular tumor board and 20 (4.9%) were enrolled on a molecularly matched clinical trial. Gene fusions were detected in 23 of 311 (7%) patients tested, including rare fusions in new tumor types and known fusions in rare tumors. CONCLUSION: Individualized Molecular Profiling for Allocation to Clinical Trials Singapore demonstrates the feasibility of a prospective broad molecular profiling program in an Asian tertiary cancer center, with the ability to develop and adapt to a dynamic landscape of precision oncology. [ABSTRACT FROM AUTHOR]

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]

Next‐generation sequencing (NGS)‐based diagnostics have demonstrated clinical utility in predicting improved survival benefits with targeted treatment in certain cancer types, and positive cost–benefit in several healthcare systems. However, clinical adoption in Singapore remains low despite commercial availability of these diagnostics. This expert opinion review examines the key challenges to the clinical adoption of NGS‐based diagnostics in Singapore, provides recommendations on impactful initiatives to improve adoption, and also offers practical guidance on specific cancer types in which NGS‐based diagnostics are appropriate for use in Singapore. Limited patient affordability is one major challenge to clinical adoption of NGS‐based diagnostics, which could be improved by enabling patient access to more funds for specific cancer types with clear benefits. Expert opinion based on current evidence and clinical experience supports the upfront use of hotspot panels in advanced non–small cell lung cancer (NSCLC), metastatic colorectal cancer, advanced and recurrent ovarian cancer, and acute myeloid leukemia. Comprehensive genomic profiling could be considered for upfront use in select patients with NSCLC and ovarian cancer, or in refractory patients with the four cancer types. Wider adoption of NGS‐based diagnostics will improve the delivery of cancer care in Singapore and Asia‐Pacific, and thus lead to better patient outcomes. [ABSTRACT FROM AUTHOR]

This paper investigates the temperature dependence of phonon-scattering-limited mobility \muPH for advanced shortchannel strained pMOS devices. By using the split CV method and Matthiessen's rule, surface-roughness-limited mobility \muSR and \muPH are successfully decoupled. This paper indicates that the temperature sensitivity of \muPH is proportional to T^-1.75 for a neutral stressor and becomes higher when compressive strain is applied. It is explained by the higher optical phonon energy induced by uniaxially compressive strain. Our new findings may also explain the previously reported higher temperature sensitivity of drain current present in uniaxial strained pMOSFETs. [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]

Background: In non-small cell lung cancer, response rates to chemotherapy given after immune checkpoint inhibitors has been reported to be higher compared to response rates to chemotherapy given before immune checkpoint inhibitors. However, this phenomenon has not been reported in patients with gastrointestinal cancers nor with the use of multitargeted kinase inhibitors. Case presentation: We present a series of six patients who received multi-targeted kinase inhibitors or chemotherapy after progression on immune checkpoint inhibitors and showed unexpected response. Five of these patients had metastatic hepatocellular carcinoma and received salvage multi-targeted kinase inhibitors. Two of these five patients had no response to initial multi-targeted kinase inhibitors but had unexpected response to re-challenge with multi-targeted kinase inhibitors after immune checkpoint inhibitors exposure. The sixth patient had metastatic rectal cancer and showed response to salvage chemotherapy following immune checkpoint inhibitors. Conclusion: We postulate that the sequencing of immune checkpoint inhibitors prior to other forms of systemic therapy may potentially lead to an immunomodulatory effect in gastrointestinal cancers with potential improvement in response rates. [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: Metastatic gastric cancer has a poor prognosis. We aim to study how clinical features and prognosis differs between different metastatic sites, and to identify prognostic factors for overall survival. Methods: We retrospectively reviewed patients with metastatic gastric adenocarcinoma managed at a tertiary referral cancer center over a 5‐year period. We divided our cohort into three groups based on the site(s) of metastasis at presentation—peritoneal metastasis only (P), distant metastasis only (D), and peritoneal and distant metastases (PD). Results: We studied 470 patients with 175 (37.2%), 193 (41.1%) and 102 (21.7%) patients in the P, D and PD groups, respectively. Patients with peritoneal disease (both P and PD) had higher proportions of patients experiencing chemotherapy disruption due to unplanned hospitalizations, which were also of a longer average duration. The P group had the longest overall median survival of 8.9 months compared to the PD and D groups with 7.4 and 5.5 months, respectively (P < 0.001). On multivariate Cox regression analysis, the presence of ≥1 metastatic site (hazard ratio [HR] 1.67; 95% confidence interval [CI], 1.23–2.28; P  =  0.001) was significantly associated with increased overall mortality, whereas palliative systemic chemotherapy (HR 0.29; 95% CI, 0.22–0.37; P < 0.001) and palliative gastrectomy (HR 0.24; 95% CI, 0.15–0.39; P < 0.001) were significantly associated with decreased overall mortality. Conclusion: Metastatic gastric cancer represents a heterogeneous disease, with specific disease complications and treatment outcomes unique to different metastatic sites. We can consider novel multimodality therapies for patient subgroups with isolated metastatic disease and good prognostic factors in a bid to improve long‐term survival. [ABSTRACT FROM AUTHOR]

Purpose: Utility values are critical for cost-utility analyses that guide healthcare decisions. We aimed to compare the utility values of the 5-level EuroQoL-5Dimension (EQ-5D-5L) health states elicited from members of the general public and patients with heart disease or cancer.Methods: In face-to-face interviews with 157 heart disease patients, 169 cancer patients, and 169 members from the general population, participants valued 10 EQ-5D-5L health states using a composite Time Trade-Off method.Results: Pooling utility values for all health states, heart disease patients and cancer patients had mean utility values lower by 0.11 points (P value = 0.014) and 0.06 points (P value = 0.148), respectively, compared to the general population. Adjusting for sociodemographic characteristics, differences in health state utility values between the patient and the general populations were rendered non-significant, except that heart disease patients gave higher utility values (mean difference = 0.08; P value = 0.007) to mild health states than the general population. Difference in utility values, defined as utility value of a better health state minus that of a poorer health state, was higher among heart disease patients compared to the general population, before and after adjusting for sociodemographic characteristics.Conclusions: Patients may differ from members of the general population in the strength of their preferences for hypothetical health states. Using utility values derived from the general population may under-estimate the comparative effectiveness of healthcare interventions for certain diseases, such as heart diseases. [ABSTRACT FROM AUTHOR]

Background: The majority of patients with hepatocellular carcinoma (HCC) are inoperable and results with conventional chemotherapy are dismal. Many end up with no treatment options and resort to alternative medicine. The authors report the use of Coriolus versicolor (CV) in advanced HCC patients with poor liver function or who were unfit to receive standard therapy. Methods: Fifteen eligible cases were randomized 2:1 to either CV or placebo. The primary endpoint was the median time to progression (TTP) between both arms. Secondary endpoints include evaluating response rates, toxicity, quality of life (QOL), progression-free survival (PFS), and overall survival (OS). Further correlative studies were performed looking at the effect of CV on the immune system. Results: The median treatment duration was 1.5 cycles and 3 cycles on the placebo and CV arm, respectively. Median TTP was 2.5 (1.4-5.3) months compared to 4.2 (0.4-4.2) months in the CV and placebo arm, respectively, hazard ratio (HR) 0.70 (0.16-3.05 p = 0.634). Median PFS was 2.5 (1.4-5.3) months in the CV and 1.1 (0.4-4.2) months in the placebo arm, HR 0.42 (0.13-1.34, p = 0.144). Median OS was 6.5 (3.3-24.1) and 2.2 (0.8-23.3) months, respectively, HR 0.35 (0.10-1.25, p = 0.105). Social and emotional functioning scores were higher in the CV group compared to placebo group on treatment. CV subjects had less appetite loss and pain symptoms compared to placebo subjects during treatment. Conclusions: There was no difference in TTP with use of CV compared to placebo. CV subjects generally had better QOL on treatment compared to placebo subjects. The utility of this supplement in patients whose primary treatment goal is palliation should be further explored. [ABSTRACT FROM AUTHOR]

Background: For patients with advanced hepatocellular carcinoma, sorafenib is the only approved drug worldwide, and outcomes remain poor. We aimed to assess the safety and efficacy of nivolumab, a programmed cell death protein-1 (PD-1) immune checkpoint inhibitor, in patients with advanced hepatocellular carcinoma with or without chronic viral hepatitis.Methods: We did a phase 1/2, open-label, non-comparative, dose escalation and expansion trial (CheckMate 040) of nivolumab in adults (≥18 years) with histologically confirmed advanced hepatocellular carcinoma with or without hepatitis C or B (HCV or HBV) infection. Previous sorafenib treatment was allowed. A dose-escalation phase was conducted at seven hospitals or academic centres in four countries or territories (USA, Spain, Hong Kong, and Singapore) and a dose-expansion phase was conducted at an additional 39 sites in 11 countries (Canada, UK, Germany, Italy, Japan, South Korea, Taiwan). At screening, eligible patients had Child-Pugh scores of 7 or less (Child-Pugh A or B7) for the dose-escalation phase and 6 or less (Child-Pugh A) for the dose-expansion phase, and an Eastern Cooperative Oncology Group performance status of 1 or less. Patients with HBV infection had to be receiving effective antiviral therapy (viral load <100 IU/mL); antiviral therapy was not required for patients with HCV infection. We excluded patients previously treated with an agent targeting T-cell costimulation or checkpoint pathways. Patients received intravenous nivolumab 0·1-10 mg/kg every 2 weeks in the dose-escalation phase (3+3 design). Nivolumab 3 mg/kg was given every 2 weeks in the dose-expansion phase to patients in four cohorts: sorafenib untreated or intolerant without viral hepatitis, sorafenib progressor without viral hepatitis, HCV infected, and HBV infected. Primary endpoints were safety and tolerability for the escalation phase and objective response rate (Response Evaluation Criteria In Solid Tumors version 1.1) for the expansion phase. This study is registered with ClinicalTrials.gov, number NCT01658878.Findings: Between Nov 26, 2012, and Aug 8, 2016, 262 eligible patients were treated (48 patients in the dose-escalation phase and 214 in the dose-expansion phase). 202 (77%) of 262 patients have completed treatment and follow-up is ongoing. During dose escalation, nivolumab showed a manageable safety profile, including acceptable tolerability. In this phase, 46 (96%) of 48 patients discontinued treatment, 42 (88%) due to disease progression. Incidence of treatment-related adverse events did not seem to be associated with dose and no maximum tolerated dose was reached. 12 (25%) of 48 patients had grade 3/4 treatment-related adverse events. Three (6%) patients had treatment-related serious adverse events (pemphigoid, adrenal insufficiency, liver disorder). 30 (63%) of 48 patients in the dose-escalation phase died (not determined to be related to nivolumab therapy). Nivolumab 3 mg/kg was chosen for dose expansion. The objective response rate was 20% (95% CI 15-26) in patients treated with nivolumab 3 mg/kg in the dose-expansion phase and 15% (95% CI 6-28) in the dose-escalation phase.Interpretation: Nivolumab had a manageable safety profile and no new signals were observed in patients with advanced hepatocellular carcinoma. Durable objective responses show the potential of nivolumab for treatment of advanced hepatocellular carcinoma.Funding: Bristol-Myers Squibb. [ABSTRACT FROM AUTHOR]

Introduction:Peritoneal carcinomatosis (PC) is increasingly being treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). We provide a review of a high-volume Asian institute's experience and survival outcomes with this procedure. Methods:Data were prospectively collected from 201 consecutive CRS and HIPEC procedures performed in a single institution between April 2001 and November 2015. Our primary endpoints were overall survival (OS) and disease-free survival (DFS), and secondary endpoints were morbidity and mortality. Results:77% of patients were Chinese, 9% were Malay, 6% were Indian and 8% were other ethnicities. Primary tumours were colorectal (30%), ovarian (32%), appendiceal (20%), primary peritoneal (6.5%), mesothelioma (4.5%) and others (5%). The median peritoneal cancer index (PCI) was 12, and 92% of patients achieved a completeness of cytoreduction score (CC) of 0. High-grade morbidity occurred in 25.8% of cases, and there were no 30-day mortalities. At 5-years, the OS was 55.1% and DFS was 20.3%. Factors associated with improved OS on multivariate analysis were PCI <15 (p < 0.001) and a CC 0 (p = 0.016). Conclusions:The combined treatment of CRS and HIPEC is beneficial and is associated with reasonable morbidity and mortality in Asian patients with PC from colorectal, ovarian, appendiceal, primary peritoneal and mesothelioma primaries. Complete cytoreduction and extent of disease are the most important prognostic factors for survival. [ABSTRACT FROM AUTHOR]

Aim To evaluate the safety and efficacy of the combination therapy of fluorouracil, leucovorin and irinotecan (FOLFIRI) and aflibercept in Asian patients with metastatic colorectal cancer (mCRC), who had progressed after oxaliplatin-based chemotherapy. Methods This is a retrospective analysis of 19 mCRC patients who received FOLFIRI and aflibercept (4 mg/kg intravenously) every 2 weeks via a Named Patient Program (supported by Sanofi Aventis) in Singapore. Treatment was administered until disease progression or unacceptable toxicities. Kaplan-Meier method was used to estimate progression-free survival (PFS) and overall survival (OS). Efficacy and toxicities were summarized using descriptive statistics. Statistical analysis was performed using STATA 12.0 software. Results The majority (84%) of the patients were of chinese ethnicity. The median age was 59 years, with 63.2% of the patients having an Eastern Cooperative Oncology Group status of 1. Four patients (21.1%) achieved partial response and 8 patients (42.1%) achieved stable disease. After a median follow-up of 9.6 months [95% confidence interval (CI), 2.2-13.1 months], the median OS was 11.6 months (95% CI, 6.1 to not-estimable), and median PFS was 4.1 months (95% CI, 2.2-5.9). Majority of the toxicities were grade 1-2, and include leucopenia (84.2%), anemia (73.7%), liver enzyme elevation (68.4%) and fatigue (68.4%). The most frequently reported grade 3 toxicities were neutropenia and neutropenic complications (both 15.8%). All adverse events resolved with supportive management. Conclusion The clinical benefit and safety profile of the combination of FOLFIRI/aflibercept in Asian patients with mCRC are consistent with that of Western population. FOLFIRI/aflibercept may be an appropriate therapeutic option in Asian patients with mCRC previously treated with an oxaliplatin-based regimen. [ABSTRACT FROM AUTHOR]

For the first time, we comprehensively evaluate 6T SRAM stability and performance using monolayer and bilayer transition metal dichalcogenide (TMD) devices based on the ITRS 2028 (5.9 nm) node. Our study indicates that, with excellent device electrostatics and superior stability, the monolayer TMD is favored for low-power SRAM applications, while the bilayer TMD, with higher carrier mobility, is more suitable for relaxed channel length and high-performance SRAM applications. [ABSTRACT FROM AUTHOR]

This paper investigates the impact of quantum capacitance on the intrinsic inversion-capacitance ( C\mathrm{ inv}) characteristics of high-mobility multigate III–V-on-insulator nMOSFETs through a numerical simulation corroborated by the theoretical calculation. Nonmonotonic C\mathrm{ inv} characteristics stemming from the energy dependence of 1-D density-of-states and significant C\mathrm{ inv} degradation due to quantum capacitance have been found in trigate In0.53Ga0.47As and InAs devices based on the ITRS 2018–2024 technology nodes. This paper indicates that, to compensate the excess inversion-charge ( Q\mathrm{ inv} ) loss due to quantum capacitance, the needed mobility gain of the trigate InGaAs and InAs devices (against the Si counterparts) should be at least $\sim 3\times $ and $\sim 4\times $ , respectively. This paper also suggests that the quantum-capacitance-induced Q\mathrm{ inv} loss can be mitigated by raising the fin aspect ratio of the III–V multigate device. [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]

Purpose: The use of trastuzumab, a monoclonal antibody targeting the HER2 protein, in combination with 5-fluorouracil/platinum-based chemotherapy improves survival in patients with HER2-positive advanced gastric cancer. In addition, TS-one (S-1)/platinum is also used as a standard of care in Asian countries. However, little is known about the combination of S-1/cisplatin chemotherapy and trastuzumab in patients with HER2-positive advanced gastric/gastroesophageal junction (GEJ) cancer. Methods: We conducted a single-arm, two-stage, open-label, multicenter phase II study. Trastuzumab was administered intravenously on day 1 of the first cycle at 8 mg/kg and 6 mg/kg on day 1 of subsequent cycles. Cisplatin was administered intravenously at 60 mg/m on day 1 of each cycle after trastuzumab. S-1 was administered orally [based on body surface area (BSA)] twice a day for 14 days in a 3-weekly cycle. Patients with BSA of <1.25 received a total of 80 mg of S-1, those with BSA ≥1.5 received 120 mg, and the remaining received 100 mg daily in two divided doses. Results: All evaluable patients experienced tumor reduction during the trial. The primary end point (overall survival rate) was 59.3 %, with a clinical benefit rate of 66.7 %. Median progression-free survival was 7.4 months; 62.6 % patients were free from disease progression at 6 months. Median overall survival was 14.6 months, and the median time to treatment failure was 6.0 months. Conclusion: The combination of trastuzumab with S-1 and cisplatin demonstrated good activity, was generally well tolerated, and is a feasible treatment option in the first-line treatment of HER2-positive advanced gastric/GEJ cancers. [ABSTRACT FROM AUTHOR]

Background and Aims: Surgery is the primary curative option in patients with hepatocellular carcinoma (HCC). Current prognostic models for HCC are developed on datasets of primarily patients with advanced cancer, and may be less relevant to resectable HCC. We developed a postoperative nomogram, the Singapore Liver Cancer Recurrence (SLICER) Score, to predict outcomes of HCC patients who have undergone surgical resection. Methods: Records for 544 consecutive patients undergoing first-line curative surgery for HCC in one institution from 1992–2007 were reviewed, with 405 local patients selected for analysis. Freedom from relapse (FFR) was the primary outcome measure. An outcome-blinded modeling strategy including clustering, data reduction and transformation was used. We compared the performance of SLICER in estimating FFR with other HCC prognostic models using concordance-indices and likelihood analysis. Results: A nomogram predicting FFR was developed, incorporating non-neoplastic liver cirrhosis, multifocality, preoperative alpha-fetoprotein level, Child-Pugh score, vascular invasion, tumor size, surgical margin and symptoms at presentation. Our nomogram outperformed other HCC prognostic models in predicting FFR by means of log-likelihood ratio statistics with good calibration demonstrated at 3 and 5 years post-resection and a concordance index of 0.69. Using decision curve analysis, SLICER also demonstrated superior net benefit at higher threshold probabilities. Conclusion: The SLICER score enables well-calibrated individualized predictions of relapse following curative HCC resection, and may represent a novel tool for biomarker research and individual counseling. [ABSTRACT FROM AUTHOR]