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).
Fast radio bursts (FRBs) are highly dispersed, millisecond-duration radio bursts1-3. Recent observations of a Galactic FRB4-8 suggest that at least some FRBs originate from magnetars, but the origin ...of cosmological FRBs is still not settled. Here we report the detection of1,863 bursts in 82 h over 54 days from the repeating source FRB 20201124A (ref.9). These observations show irregular short-time variation ofthe Faraday rotation measure (RM), which scrutinizes the density-weighted line-of-sight magnetic field strength, of individual bursts during the first 36 days, followed by a constant RM. We detected circular polarization in more than half of the burst sample, including one burst reaching a high fractional circular polarization of 75%. Oscillations in fractional linear and circular polarizations, as well as polarization angle as a function of wavelength, were detected. All of these features provide evidence for a complicated, dynamically evolving, magnetized immediate environment within about an astronomical unit (au; Earth-Sun distance) ofthe source. Our optical observations of its Milky-Way-sized, metal-rich host galaxy10-12 show a barred spiral, with the FRB source residing in a low-stellar-density interarm region at an intermediate galactocentric distance. This environment is inconsistent with a young magnetar engine formed during an extreme explosion of a massive star that resulted in a long gamma-ray burst or superluminous supernova.
Background. The study aimed to evaluate the risk of hepatitis C virus (HCV) infection on hepatic and extrahepatic deaths. Methods. A cohort of 23 820 adults aged 30—65 years old were enrolled during ...1991—1992. The seromarkers hepatitis B surface antigen (HBsAg), anti-HCV, and serum HCV RNA levels at study entry were tested. The vital status was ascertained through computerized linkage with national death certification profiles from 1991 to 2008. Results. There were 19 636 HBsAg-seronegatives, including 18 541 anti-HCV seronegatives and 1095 anti-HCV seropositives. Among anti-HCV seropositives, 69.4% had detectable serum HCV RNA levels. There were 2394 deaths that occurred during an average follow-up period of 16.2 years. Compared with anti-HCV seronegatives, anti-HCV seropositives had higher mortality from both hepatic and extrahepatic diseases, showing multivariate-adjusted hazard ratio (95% confidence interval) of 1.89 (1.66—2.15) for all causes of death; 12.48 (9.34—16.66) for hepatic diseases; 1.35 (1.15—1.57) for extrahepatic diseases; 1.50 (1.10—2.03) for circulatory diseases; 2.77 (1.49—5.15) for nephritis, nephrotic syndrome, and nephrosis; 4.08 (1.38—12.08) for esophageal cancer; 4.19 (1.18—14.94) for prostate cancer; and 8.22 (1.36—49.66) for thyroid cancer. Anti-HCV seropositives with detectable HCV RNA levels had significantly higher mortality from hepatic and extrahepatic diseases than anti-HCV seropositives with undetectable HCV RNA. Conclusions. Monitoring HCV RNA in anti-HCV seropositives is essential for the prediction of mortality associated with hepatitis C.
Understanding the structure‐activity relationship of catalytic reactions at a molecular level still remains a great challenge. Herein, shell‐isolated nanoparticle‐enhanced Raman spectroscopy ...(SHINERS) is employed to in‐situ study the catalytic hydrogenation of para‐nitrothiophenol (pNTP) on Pt‐based nanocatalysts with different size and composition. The nanocatalysts are assembled on pinhole‐free shell‐isolate nanoparticles (SHINs), which work as Raman amplifiers to enhance the Raman signals of species on the catalysts, allowing the in‐situ monitoring of catalytic reactions carried out on the catalysts. Using this strategy, we find that the catalytic activity of the Pt nanocatalysts shows a volcanic trend with the Pt size, and that PtM (M=Ni or Cu) bimetallic nanocatalysts display much higher performance compared with Pt due to better activation of the nitro group. This work demonstrates that SHINERS is a promising technique for in‐situ study of nanocatalysis thus can deepen the understanding of the behaviors of different catalysts.
Shine like a diamond! Shell‐isolated nanoparticles enhanced Raman spectroscopy (SHINERS) has been employed to reveal the size and composition effect of Pt‐based nanocatalysts towards the hydrogenation of pNTP.
The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of hepatocellular carcinoma (HCC) was published in ...2018, and covered the diagnosis, management, treatment and follow-up of early, intermediate and advanced disease. At the ESMO Asia Meeting in November 2018 it was decided by both the ESMO and the Taiwan Oncology Society (TOS) to convene a special guidelines meeting immediately after the Taiwan Joint Cancer Conference (TJCC) in May 2019 in Taipei. The aim was to adapt the ESMO 2018 guidelines to take into account both the ethnic and the geographic differences in practice associated with the treatment of HCC in Asian patients. These guidelines represent the consensus opinions reached by experts in the treatment of patients with intermediate and advanced/relapsed HCC representing the oncology societies of Taiwan (TOS), China (CSCO), India (ISMPO) Japan (JSMO), Korea (KSMO), Malaysia (MOS) and Singapore (SSO). The voting was based on scientific evidence, and was independent of the current treatment practices, the drug availability and reimbursement situations in the individual participating Asian countries.
Giant Piezoelectricity on Si for Hyperactive MEMS Baek, S. H.; Park, J.; Kim, D. M. ...
Science (American Association for the Advancement of Science),
11/2011, Volume:
334, Issue:
6058
Journal Article
Peer reviewed
Microelectromechanical systems (MEMS) incorporating active piezoelectric layers offer integrated actuation, sensing, and transduction. The broad implementation of such active MEMS has long been ...constrained by the inability to integrate materials with giant piezoelectric response, such as Pb(MG 1/3 Nb 2/3 )O₃-PbTiO₃ (PMN-PT). We synthesized high-quality PMN-PT epitaxial thin films on vicinal (001) Si wafers with the use of an epitaxial (001) SrTiO₃ template layer with superior piezoelectric coefficients (e 31,f = -27 ± 3 coulombs per square meter) and figures of merit for piezoelectric energy-harvesting systems. We have incorporated these heterostructures into microcantilevers that are actuated with extremely low drive voltage due to thin-film piezoelectric properties that rival bulk PMN-PT single crystals. These epitaxial heterostructures exhibit very large electromechanical coupling for ultrasound medical imaging, microfluidic control, mechanical sensing, and energy harvesting.
Background The risk of hepatocellular carcinoma (HCC) increases with increasing level of hepatitis B virus (HBV) in serum (viral load). However, it is unclear whether genetic characteristics of HBV, ...including HBV genotype and specific genetic mutations, contribute to the risk of HCC. We examined the HCC risk associated with HBV genotypes and common variants in the precore and basal core promoter (BCP) regions. Methods From January 5, 1991, to December 21, 1992, baseline blood samples were collected from 2762 Taiwanese men and women who were seropositive for HBV surface antigen but had not been diagnosed with HCC; the samples were tested for HBV viral load by real-time polymerase chain reaction and genotyped by melting curve analysis. Participants who had a baseline serum HBV DNA level greater than 104 copies/mL (n = 1526) were tested for the precore G1896A and BCP A1762T/G1764A mutants by direct sequencing. Incident cases of HCC were ascertained through follow-up examinations and computerized linkage to the National Cancer Registry and death certification profiles. A Cox proportional hazards model was used to estimate the risk of HCC associated with HBV genotype and precore and BCP mutants after adjustment for other risk factors. All statistical tests were two-sided. Results A total of 153 HCC cases occurred during 33 847 person-years of follow-up. The HCC incidence rates per 100 000 person-years for participants infected with HBV genotype B or C were 305.6 (95% confidence interval CI = 236.9 to 388.1) and 785.8 (95% CI = 626.8 to 972.9), respectively. Among participants with a baseline HBV DNA level of at least 104 copies/mL, HCC incidence per 100 000 person-years was higher for those with the precore G1896 (wild-type) variant than for those with the G1896A variant (955.5 95% CI = 749.0 to 1201.4 vs 269.4 95% CI = 172.6 to 400.9) and for those with the BCP A1762T/G1764A double mutant than for those with BCP A1762/G1764 (wild-type) variant (1149.2 95% CI = 872.6 to 1485.6 vs 358.7 95% CI = 255.1 to 490.4). The multivariable-adjusted hazard ratio of developing HCC was 1.76 (95% CI = 1.19 to 2.61) for genotype C vs genotype B, 0.34 (95% CI = 0.21 to 0.57) for precore G1896A vs wild type, and 1.73 (95% CI = 1.13 to 2.67) for BCP A1762T/G1764A vs wild type. Risk was highest among participants infected with genotype C HBV and wild type for the precore 1896 variant and mutant for the BCP 1762/1764 variant (adjusted hazard ratio = 2.99, 95% CI = 1.57 to 5.70, P < .001). Conclusions HBV genotype C and specific alleles of BCP and precore were associated with risk of HCC. These associations were independent of serum HBV DNA level.
Aerosol mixtures composed of coarse mode desert dust combined with fine mode combustion generated aerosols (from fossil fuel and biomass burning sources) were investigated at three locations that are ...in and/or downwind of major global aerosol emission source regions. Multiyear monitoring data at Aerosol Robotic Network sites in Beijing (central eastern China), Kanpur (Indo-Gangetic Plain, northern India), and Ilorin (Nigeria, Sudanian zone of West Africa) were utilized to study the climatological characteristics of aerosol optical properties. Multiyear climatological averages of spectral single scattering albedo (SSA) versus fine mode fraction (FMF) of aerosol optical depth at 675 nm at all three sites exhibited relatively linear trends up to 50% FMF. This suggests the possibility that external linear mixing of both fine and coarse mode components (weighted by FMF) dominates the SSA variation, where the SSA of each component remains relatively constant for this range of FMF only. However, it is likely that a combination of other factors is also involved in determining the dynamics of SSA as a function of FMF, such as fine mode particles adhering to coarse mode dust. The spectral variation of the climatological averaged aerosol absorption optical depth (AAOD) was nearly linear in logarithmic coordinates over the wavelength range of 440-870 nm for both the Kanpur and Ilorin sites. However, at two sites in China (Beijing and Xianghe), a distinct nonlinearity in spectral AAOD in logarithmic space was observed, suggesting the possibility of anomalously strong absorption in coarse mode aerosols increasing the 870 nm AAOD.
To evaluate the refractive outcomes in children treated after intravitreal injection of bevacizumab (IVB) for retinopathy of prematurity (ROP).
A retrospective, bi-centre study of 34 patients (64 ...eyes) was conducted. The patients were divided into three groups, patients received intravitreal IVB (IVB group), patients received combined IVB and laser treatment (IVB + Laser group), or patients received lens-sparing vitrectomy (IVB + LSV group). Cycloplegic refraction and axial length (AXL) were evaluated at 2 years old.
The prevalences of myopia and high myopia were 47.5 and 10.0% in the IVB group, respectively, which were lower than those in the IVB + Laser (82.4 and 29.4%) and IVB + LSV (all 100%) groups (P = 0.001 and P < 0.001). The prevalences of emmetropia in the IVB group, IVB + Laser group, and IVB + LSV group were 50, 5.9, and 0% (P = 0.001). The AXL were similar among all groups.
At the 2-year follow-up, severe ROP patients treated with IVB alone were more likely to remain emmetropic and had lower prevalences of myopia and high myopia. The development of high myopia in severe ROP patients could not be explained by AXL changes but may be associated with abnormalities in the anterior segment.
The purpose of this study was to evaluate the safety and efficacy of hydroxyurea (HU) in spinal muscular atrophy (SMA) in a randomized, double-blind, placebo-controlled trial.
Twenty-eight patients ...with type 2 SMA and 29 patients with type 3 SMA were randomly assigned (2:1) to receive HU or matching placebo for 18 months. HU was initiated at 10 mg/kg/day with an 8-week titration to 20 mg/kg/day. Subjects were assessed at baseline (T0) and monthly for the first 2 months (T1-T2) and then every 2 months throughout treatment (T3-T10) and posttreatment periods (T11-T13). The primary outcome measures were the Gross Motor Function Measure (GMFM), Manual Muscle Test (MMT), and serum full-length survivor motor neuron (flSMN) mRNA. The secondary outcome measures were Modified Hammersmith Functional Motor Scale and forced vital capacity (FVC).
Fifty-five patients completed this trial, which lasted from March 2007 to June 2009. Except for neutropenia, we found no differences in adverse events between the 2 groups. Compared with the placebo group, the HU group had -1.88 for GMFM (p = 0.11), -0.55 for MMT (p = 0.49), and 2.17 for flSMN mRNA (p = 0.13). Similarly, we found no difference in mean improvement of the secondary endpoints. Both groups had a trend toward a decline in FVC with little change in strength and motor function.
Under the current regimen and schedule, HU brought about no improvement in patients with type 2 and 3 SMA, and its main side effect was neutropenia.
This trial provides Class I evidence that HU 20 mg/kg/day does not effectively treat SMA.
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