Arginine depletion is a putative target in hepatocellular carcinoma (HCC). HCC often lacks argininosuccinate synthetase, a citrulline to arginine-repleting enzyme. ADI-PEG 20 is a cloned arginine ...degrading enzyme—arginine deiminase—conjugated with polyethylene glycol. The goal of this study was to evaluate this agent as a potential novel therapeutic for HCC after first line systemic therapy.
Patients with histologically proven advanced HCC and Child-Pugh up to B7 with prior systemic therapy, were randomized 2 : 1 to ADI-PEG 20 18 mg/m2 versus placebo intramuscular injection weekly. The primary end point was overall survival (OS), with 93% power to detect a 4–5.6 months increase in median OS (one-sided α = 0.025). Secondary end points included progression-free survival, safety, and arginine correlatives.
A total of 635 patients were enrolled: median age 61, 82% male, 60% Asian, 52% hepatitis B, 26% hepatitis C, 76% stage IV, 91% Child-Pugh A, 70% progressed on sorafenib and 16% were intolerant. Median OS was 7.8 months for ADI-PEG 20 versus 7.4 for placebo (P = 0.88, HR = 1.02) and median progression-free survival 2.6 months versus 2.6 (P = 0.07, HR = 1.17). Grade 3 fatigue and decreased appetite occurred in <5% of patients. Two patients on ADI-PEG 20 had ≥grade 3 anaphylactic reaction. Death rate within 30 days of end of treatment was 15.2% on ADI-PEG 20 versus 10.4% on placebo, none related to therapy. Post hoc analyses of arginine assessment at 4, 8, 12 and 16 weeks, demonstrated a trend of improved OS for those with more prolonged arginine depletion.
ADI-PEG 20 monotherapy did not demonstrate an OS benefit in second line setting for HCC. It was well tolerated. Strategies to enhance prolonged arginine depletion and synergize the effect of ADI-PEG 20 are underway.
www.clinicaltrials.gov (NCT 01287585).
The performance of graphene-based transistors is often limited by the large electrical resistance across the metal–graphene contact. We report an approach to achieve ultralow resistance metal ...contacts to graphene transistors. Through a process of metal-catalyzed etching in hydrogen, multiple nanosized pits with zigzag edges are created in the graphene portions under source/drain metal contacts while the graphene channel remains intact. The porous graphene source/drain portions with pure zigzag-termination form strong chemical bonds with the deposited nickel metallization without the need for further annealing. This facile contact treatment prior to electrode metallization results in contact resistance as low as 100 Ω·μm in single-layer graphene field-effect transistors, and 11 Ω·μm in bilayer graphene transistors. Besides 96% reduction in contact resistance, the contact-treated graphene transistors exhibit 1.5-fold improvement in mobility. More importantly, the metal-catalyzed etching contact treatment is compatible with complementary metal–oxide–semiconductor (CMOS) fabrication processes, and holds great promise to meet the contact performance required for the integration of graphene in future integrated circuits.
In this study, we apply a multidisciplinary approach to investigate falls in PD patients using clinical, demographic and neuroimaging data from two independent initiatives (University of Michigan and ...Tel Aviv Sourasky Medical Center). Using machine learning techniques, we construct predictive models to discriminate fallers and non-fallers. Through controlled feature selection, we identified the most salient predictors of patient falls including gait speed, Hoehn and Yahr stage, postural instability and gait difficulty-related measurements. The model-based and model-free analytical methods we employed included logistic regression, random forests, support vector machines, and XGboost. The reliability of the forecasts was assessed by internal statistical (5-fold) cross validation as well as by external out-of-bag validation. Four specific challenges were addressed in the study: Challenge 1, develop a protocol for harmonizing and aggregating complex, multisource, and multi-site Parkinson's disease data; Challenge 2, identify salient predictive features associated with specific clinical traits, e.g., patient falls; Challenge 3, forecast patient falls and evaluate the classification performance; and Challenge 4, predict tremor dominance (TD) vs. posture instability and gait difficulty (PIGD). Our findings suggest that, compared to other approaches, model-free machine learning based techniques provide a more reliable clinical outcome forecasting of falls in Parkinson's patients, for example, with a classification accuracy of about 70-80%.
We report an approach to achieve low-resistance contacts to MoS2 transistors with the intrinsic performance of the MoS2 channel preserved. Through a dry transfer technique and a metal-catalyzed ...graphene treatment process, nickel-etched-graphene electrodes were fabricated on MoS2 that yield contact resistance as low as 200 Ω·μm. The substantial contact enhancement (∼2 orders of magnitude), as compared to pure nickel electrodes, is attributed to the much smaller work function of nickel-graphene electrodes, together with the fact that presence of zigzag edges in the treated graphene surface enhances tunneling between nickel and graphene. To this end, the successful fabrication of a clean graphene–MoS2 interface and a low resistance nickel–graphene interface is critical for the experimentally measured low contact resistance. The potential of using graphene as an electrode interlayer demonstrated in this work paves the way toward achieving high performance next-generation transistors.
Annealing is a postprocessing treatment commonly used to improve metal–graphene contacts with the assumption that resist residues sandwiched at the metal–graphene contacts are removed during ...annealing. Here, we examine this assumption by undertaking a systematic study to understand mechanisms that lead to the contact enhancement brought about by annealing. Using a soft shadow-mask, we fabricated residue-free metal–graphene contacts with the same dimensions as lithographically defined metal–graphene contacts on the same graphene flake. Both cases show comparable contact enhancement for nickel–graphene contacts after annealing treatment signifying that removal of resist residues is not the main factor for contact enhancement. It is found instead that carbon dissolves from graphene into the metal at chemisorbed Ni– and Co–graphene interfaces and leads to many end-contacts being formed between the metal and the dangling carbon bonds in the graphene, which contributes to much smaller contact resistance.
The purpose of this replication study was to examine the relationships among life satisfaction, positive youth development and problem behaviour. The respondents were 7,151 Chinese Secondary 2 (Grade ...8) students (3,707 boys and 3,014 girls) recruited from 44 schools in Hong Kong. Validated assessment tools measuring positive youth development, life satisfaction and problem behaviour were used. As predicted, positive youth development was positively correlated with life satisfaction, and positive youth development and life satisfaction were negatively correlated with adolescent problem behaviour. Based on a series of structural equation models, the present findings replicated the previous findings that adolescents with a higher level of positive youth development were more satisfied with life and had lesser problem behaviour, with higher level of life satisfaction and lower level of problem behaviour mutually influencing each other. These replicated findings provide a further advance in the literature on positive youth development, particularly in the Chinese context. Implications for future research and intervention were discussed.
The Pearl River Delta (PRD) region in southeastern China is one of the most polluted industrial and metropolitan areas in the world. We report single‐particle measurements of the refractory black ...carbon (rBC) component in ambient aerosol in the region, and we interpret the results to improve understanding of the importance of rBC for radiative forcing in this region and others like it. A Single‐Particle Soot Photometer (SP2) provided rBC mass loadings, size distributions, and mixing state information. Average rBC loadings are approximately an order of magnitude higher than those measured near Houston, Texas, a major U.S. metropolitan area. The rBC in the PRD is also more often internally mixed with nonrefractory materials than is rBC around Houston. Localized atmospheric heating from rBC solar absorption reached an average rate of 0.4 K d−1. A one‐dimensional discrete ordinates radiative transfer (DISORT) model coupled with the average measured rBC is used to illustrate the potential local contribution of rBC mass and associated scattering aerosol to the radiative forcing. Solar energy deposition rates in the atmosphere at the sampling site due to rBC absorption are estimated to have an average value of 17 W m−2 and be largest in the first 1 km above the ground. These results indicate that rBC has significant potential to influence local meteorology and climate parameters in the PRD region.
Key Points
We performed black carbon measurements in China
A single‐particle soot photometer was used to determine black carbon properties
Solar energy deposition rates due to the black carbon were estimated
This paper examines the relationships among life satisfaction, positive youth development, and problem behaviour. A total of 7,975 Secondary One students (4,169 boys and 3,387 girls; with most aged ...12) of Chinese ethnicity recruited from 48 schools responded tovalidated measures of life satisfaction, positive youth development and problem behaviour. While life satisfaction was positively correlated with different measures of positiveyouth development, these measures were negatively correlated with measures of substance abuse, delinquency and intention to engage in problem behaviour. Based on a series of structural equation models, a non-recursive model was found to best fit the data, which suggests that adolescents having higher levels of positive youth development are more satisfied with life and have fewer problem behaviour, with life satisfaction and problem behaviour negatively reinforcing each other.
The Pearl River Delta (PRD) region in South China is one of the most economically developed regions in China, but it is also noted for its severe air pollution due to industrial/metropolitan ...emissions. In order to continuously improve the understanding and quantification of air pollution in this region, an intensive campaign was executed in PRD during October–November 2008. Here, we report and analyze Aerodyne High-Resolution Aerosol Mass Spectrometer measurements at Kaiping, a rural site downwind of the highly-polluted central PRD area, to characterize the general features of submicron particulate pollution in the regional air. The mean measured PMsub>1 mass concentration was 33.1±18.1 μg m−3 during the campaign and composed of organic matter (33.8%), sulfate (33.7%), ammonium (14.0%), nitrate (10.7%), black carbon (6.7%), and chloride (1.1%), which is characterized by high fractions of inorganic ions due to huge emissions of SO2 and NOx in PRD. The average size distributions of the species (except BC) were all dominated by an accumulation mode peaking at ~450 nm in vacuum aerodynamic diameter. Calculations based on high-resolution organic mass spectra indicate that C, H, O, and N on average contributed 56.6, 7.0, 35.1, and 1.3% to the total organic mass, respectively, corresponding to an organic matter mass to organic carbon mass ratio (OM/OC) of 1.77±0.08. Based on the high-resolution organic mass spectral dataset observed, Positive Matrix Factorization (PMF) analysis differentiated the organic aerosol into three components, i.e., biomass burning (BBOA) and two oxygenated (LV-OOA and SV-OOA) organic aerosols, which on average accounted for 24.5, 39.6 and 35.8% of the total organic mass, respectively. The BBOA showed strong features of biomass burning emissions and has been mainly attributed to the open field burning of crop residues after the harvest in PRD rural areas. The LV-OOA and SV-OOA were found to correspond to more aged (and thus less-volatile) and fresher (and semi-volatile) secondary organic aerosol (SOA), respectively. Analysis of meteorological influence supported that regional transport from the central PRD area was the major origin of the PM1 observed at the Kaiping site.
Increased motility and invasiveness of pancreatic cancer cells are associated with epithelial to mesenchymal transition (EMT). Snai1 and Slug are zinc-finger transcription factors that trigger this ...process by repressing E-cadherin and enhancing vimentin and N-cadherin protein expression. However, the mechanisms that regulate this activation in pancreatic tumors remain elusive. MUC1, a transmembrane mucin glycoprotein, is associated with the most invasive forms of pancreatic ductal adenocarcinomas (PDA). In this study, we show that over expression of MUC1 in pancreatic cancer cells triggers the molecular process of EMT, which translates to increased invasiveness and metastasis. EMT was significantly reduced when MUC1 was genetically deleted in a mouse model of PDA or when all seven tyrosines in the cytoplasmic tail of MUC1 were mutated to phenylalanine (mutated MUC1 CT). Using proteomics, RT-PCR and western blotting, we revealed a significant increase in vimentin, Slug and Snail expression with repression of E-Cadherin in MUC1-expressing cells compared with cells expressing the mutated MUC1 CT. In the cells that carried the mutated MUC1 CT, MUC1 failed to co-immunoprecipitate with β-catenin and translocate to the nucleus, thereby blocking transcription of the genes associated with EMT and metastasis. Thus, functional tyrosines are critical in stimulating the interactions between MUC1 and β-catenin and their nuclear translocation to initiate the process of EMT. This study signifies the oncogenic role of MUC1 CT and is the first to identify a direct role of the MUC1 in initiating EMT during pancreatic cancer. The data may have implications in future design of MUC1-targeted therapies for pancreatic cancer.
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