A Facile Nanodelivery Platform Based on Functionalized Hyperbranched Poly(ether-ester) for Individualized Antitumor Drugs: Pingyangmycin as a Model

Nanodelivery of antitumor drugs is a new treatment mode for cancer. The aim of this investigation was to construct and evaluate a facile nanodelivery platform for individualized antitumor drugs based on functionalized hyperbranched poly(ether-ester)s. Poly(ether-ester)s, as a kind of hyperbranched polymers, have received extensive attention. Three terminal-functionalized (OH–, NH2– and COOH–) hyperbranched poly(ether-ester)s were prepared and characterized by dynamic light scattering and attenuated total reflectance Fourier transform infrared spectroscopy. The relationship between chemical terminal variation and physical surface charges was investigated. Biocompatibility of these polymers was confirmed by methyl tetrazolium assays and scanning electron microscopy. As a model drug, pingyangmycin has antitumor and antiangiogenic effects. In the paper, pingyangmycin was mixed with carboxyl-modified hyperbranched poly(ether-ester) through ionic binding. Polymer-mixed pingyangmycin exhibited significant inhibition of HN-6 head and neck cancer human cells in vitro. These studies demonstrate that functionalized hyperbranched (ether-ester)s can be exploited as a facile nanodelivery platform for antitumor therapy

Association of <i>NUDT15</i> gene polymorphism with adverse reaction, treatment efficacy, and dose of 6-mercaptopurine in patients with acute lymphoblastic leukemia: a systematic review and meta-analysis

6-mercaptopurine (6-MP) serves as the backbone in the maintenance regimens of acute lymphoblastic leukemia (ALL). We aimed to evaluate the influence of NUDT15 gene polymorphism on the risk of myelosupression, hepatotoxicity and interruption of 6-MP, as well as treatment efficacy and dose of 6-MP in ALL patients. A total of 24 studies with 3,374 patients were included in this meta-analysis. We found 9-fold higher risk of 6-MP induced leukopenia (odds ratio [OR] =9.00, 95% confidence interval [CI]: 3.73-21.74) and 2.5-fold higher risk of 6-MP-induced neutropenia (OR=2.52, 95% CI: 1.72-3.69) for NUDT15 c.415C>T variant carriers in the dominant model. Moreover, we found that the dose intensity of 6-MP in ALL patients with one NUDT15 c.415C>T variant alleles (CT) was 19% less than that in wild-type patients (CC) (mean differences: 19.43%, 95% CI: -25.36 to -13.51). The tolerable dose intensity of 6-MP in NUDT15 c.415C>T homozygote variant (TT) and heterozygote variant (CT) carriers was 49% and 15% less than that in wild-type patients, respectively. The NUDT15 c.415C>T variant group (CT+TT) had seven times (OR=6.98, 95% CI: 2.83-17.22) higher risk of developing 6-MP intolerance than the CC group. However, NUDT15 c.415C>T polymorphism did not appear significantly associated with hepatotoxicity, treatment interruption or relapse incidence. We concluded that NUDT15 c.415C>T was a good predictor for 6-MP-induced myelosuppression in ALL patients. The dose intensity of 6-MP in ALL patients with NUDT15 c.415C>T variants was significantly lower than that in wild-type patients. This research provided a basis for further investigation into relations between NUDT15 gene and adverse reaction, treatment efficacy and dose intensity of 6-MP

The impact of zeolite pore structure on the catalytic behavior of CuZnAl/zeolite hybrid catalysts for the direct DME synthesis

[EN] In this work, the influence of the pore structure of 10-ring zeolites used as the methanol dehydration func-tion in CuZnAl(CZA)/zeolite hybrid catalysts was studied for the direct dimethyl ether (DME) synthesis. Tothis purpose, six different 10-ring H-zeolites (ZSM-5, FER, IM-5, TNU-9, MCM-22, ITQ-2) with alike bulkSi/Al ratios (in the 9 14 range) were employed. Additionally, the effect of crystallite size (for ZSM-5) andselective surface dealumination by treatment with oxalic acid (for MCM-22) was also investigated. Whilethe initial activity of the zeolites for methanol dehydration was driven by the concentration of strongBrønsted acid sites, the extent of decay was dictated by the pore structure, which determined the amountand nature of the formed carbon species. When evaluated for direct DME synthesis under methanolsynthesis-controlled conditions, all CZA/zeolite hybrid catalysts (prepared by grinding, CZA:zeolite massratio of 2:1) experienced a decline of CO conversion (and DME yield) with time-on-stream (TOS) due toa gradual loss of the methanol synthesis activity of the Cu-based component. Interestingly, the stabilitywith TOS was the lowest for the hybrid catalysts comprising zeolites with large external surface areas(Sext) such as ITQ-2 and MCM-22. Moreover, for zeolites with similar Sext, the deactivation extent of thehybrid catalysts increased with the concentration of surface Al species (from XPS) in the zeolite. Thus,the delaminated ITQ-2 zeolite (Si/Alsurf= 10.6, Sext= 324 m2/g) produced the less stable hybrid while thatcomprising zeolite TNU-9 (Si/Alsurf= 17.9, Sext= 12 m2/g) displayed the highest stability during the syngas-to-DME experiments. These results suggest that the deterioration of the methanol synthesis activity ofthe CZA catalyst in the hybrid catalysts prepared by grinding is produced by detrimental interactionsbetween zeolitic Al species and Cu sites at the surface-contact between zeolite and CZA particleFinancial support by the Comision Interministerial de Ciencia y Tecnologia (CICYT) of Spain through the Project CTQ2010-17988/PPQ is gratefully acknowledged. A. Garcia-Trenco thanks the Ministerio de Economia y Competitividad (former Ministerio de Ciencia e Innovacion) of Spain for a predoctoral (FPI) scholarship.García Trenco, A.; Valencia Valencia, S.; Martinez Feliu, A. (2013). The impact of zeolite pore structure on the catalytic behavior of CuZnAl/zeolite hybrid catalysts for the direct DME synthesis. Applied Catalysis A General. 468:102-111. doi:10.1016/j.apcata.2013.08.038S10211146

Systems Chemical Genetics-Based Drug Discovery: Prioritizing Agents Targeting Multiple/Reliable Disease-Associated Genes as Drug Candidates

Genetic disease genes are considered a promising source of drug targets. Most diseases are caused by more than one pathogenic factor; thus, it is reasonable to consider that chemical agents targeting multiple disease genes are more likely to have desired activities. This is supported by a comprehensive analysis on the relationships between agent activity/druggability and target genetic characteristics. The therapeutic potential of agents increases steadily with increasing number of targeted disease genes, and can be further enhanced by strengthened genetic links between targets and diseases. By using the multi-label classification models for genetics-based drug activity prediction, we provide universal tools for prioritizing drug candidates. All of the documented data and the machine-learning prediction service are available at SCG-Drug (http://zhanglab.hzau.edu.cn/scgdrug)

Universal phase transitions of B1 structured stoichiometric transition-metal carbides

The high-pressure phase transitions of B1-structured stoichiometric transition metal carbides (TMCs, TM=Ti, Zr, Hf, V, Nb, and Ta) were systematically investigated using ab initio calculations. These carbides underwent universal phase transitions along two novel phase-transition routes, namely, B1\rightarrowdistorted TlI (TlI')\rightarrowTlI and/or B1\rightarrowdistorted TiB (TiB')\rightarrowTiB, when subjected to pressures. The two routes can coexist possibly because of the tiny enthalpy differences between the new phases under corresponding pressures. Four new phases result from atomic slips of the B1-structured parent phases under pressure. After completely releasing the pressure, taking TiC as a representative of TMCs, only its new TlI'-type phase is mechanically and dynamically stable, and may be recovered.Comment: [email protected]

The CDEX-1 1 kg Point-Contact Germanium Detector for Low Mass Dark Matter Searches

The CDEX Collaboration has been established for direct detection of light dark matter particles, using ultra-low energy threshold p-type point-contact germanium detectors, in China JinPing underground Laboratory (CJPL). The first 1 kg point-contact germanium detector with a sub-keV energy threshold has been tested in a passive shielding system located in CJPL. The outputs from both the point-contact p+ electrode and the outside n+ electrode make it possible to scan the lower energy range of less than 1 keV and at the same time to detect the higher energy range up to 3 MeV. The outputs from both p+ and n+ electrode may also provide a more powerful method for signal discrimination for dark matter experiment. Some key parameters, including energy resolution, dead time, decay times of internal X-rays, and system stability, have been tested and measured. The results show that the 1 kg point-contact germanium detector, together with its shielding system and electronics, can run smoothly with good performances. This detector system will be deployed for dark matter search experiments.Comment: 6 pages, 8 figure

A phase 4 multicentre, 2×2 factorial randomised, double-blind, placebo-controlled trial to investigate the efficacy and safety of tobramycin inhalation solution for Pseudomonas aeruginosa eradication in bronchiectasis:Erase

Chronic Pseudomonas aeruginosa (PA) infection significantly contributes to morbidity and mortality in bronchiectasis patients. Initiating antibiotics early may lead to the eradication of PA. Here we outline the design of a trial (ERASE; NCT06093191) assessing the efficacy and safety of inhaled tobramycin, alone or with oral ciprofloxacin, in bronchiectasis patients with a new isolation of PA. This multicentre, 2×2 factorial randomised, double-blind, placebo-controlled, parallel-group trial includes a 2-week screening period, a 12-week treatment phase (with a combination of ciprofloxacin or a placebo at initial 2 weeks) and a 24-week follow-up. 364 adults with bronchiectasis and a new PA isolation will be randomly assigned to one of four groups: placebo (inhaled saline and ciprofloxacin placebo twice daily), ciprofloxacin alone (750 mg ciprofloxacin and inhaled saline twice daily), inhaled tobramycin alone (inhaled 300 mg tobramycin and ciprofloxacin placebo twice daily) or a combination of both drugs (inhaled 300 mg tobramycin and 750 mg ciprofloxacin twice daily). The primary objective of this study is to assess the proportion of patients successfully eradicating PA in each group by the end of the study. Efficacy will be evaluated based on the eradication rate of PA at other time points (12, 24 and 36 weeks), the occurrence of exacerbations and hospitalisations, time to first pulmonary exacerbations, patient-reported outcomes, symptom measures, pulmonary function tests and the cost of hospitalisations. To date no randomised trial has evaluated the benefit of different PA eradication strategies in bronchiectasis patients. The ERASE trial will therefore generate crucial data to inform future clinical guidelines.</p

A phase 4 multicentre, 2×2 factorial randomised, double-blind, placebo-controlled trial to investigate the efficacy and safety of tobramycin inhalation solution for Pseudomonas aeruginosa eradication in bronchiectasis:Erase

Chronic Pseudomonas aeruginosa (PA) infection significantly contributes to morbidity and mortality in bronchiectasis patients. Initiating antibiotics early may lead to the eradication of PA. Here we outline the design of a trial (ERASE; NCT06093191) assessing the efficacy and safety of inhaled tobramycin, alone or with oral ciprofloxacin, in bronchiectasis patients with a new isolation of PA. This multicentre, 2×2 factorial randomised, double-blind, placebo-controlled, parallel-group trial includes a 2-week screening period, a 12-week treatment phase (with a combination of ciprofloxacin or a placebo at initial 2 weeks) and a 24-week follow-up. 364 adults with bronchiectasis and a new PA isolation will be randomly assigned to one of four groups: placebo (inhaled saline and ciprofloxacin placebo twice daily), ciprofloxacin alone (750 mg ciprofloxacin and inhaled saline twice daily), inhaled tobramycin alone (inhaled 300 mg tobramycin and ciprofloxacin placebo twice daily) or a combination of both drugs (inhaled 300 mg tobramycin and 750 mg ciprofloxacin twice daily). The primary objective of this study is to assess the proportion of patients successfully eradicating PA in each group by the end of the study. Efficacy will be evaluated based on the eradication rate of PA at other time points (12, 24 and 36 weeks), the occurrence of exacerbations and hospitalisations, time to first pulmonary exacerbations, patient-reported outcomes, symptom measures, pulmonary function tests and the cost of hospitalisations. To date no randomised trial has evaluated the benefit of different PA eradication strategies in bronchiectasis patients. The ERASE trial will therefore generate crucial data to inform future clinical guidelines.</p

Precision measurement of the branching fractions of J/psi -> pi+pi-pi0 and psi' -> pi+pi-pi0

We study the decays of the J/psi and psi' mesons to pi+pi-pi0 using data samples at both resonances collected with the BES III detector in 2009. We measure the corresponding branching fractions with unprecedented precision and provide mass spectra and Dalitz plots. The branching fraction for J/psi -> pi+pi-pi0 is determined to be (2.137 +- 0.004 (stat.) +0.058-0.056 (syst.) +0.027-0.026 (norm.))*10-2, and the branching fraction for psi' -> pi+pi-pi0 is measured as (2.14 +- 0.03 (stat.) +0.08-0.07 (syst.) +0.09-0.08 (norm.))*10-4. The J/psi decay is found to be dominated by an intermediate rho(770) state, whereas the psi' decay is dominated by di-pion masses around 2.2 GeV/c2, leading to strikingly different Dalitz distributions.Comment: 15 pages, 2 figure

Study of J/ψ→ppˉJ/\psi\to p\bar{p} and J/ψ→nnˉJ/\psi\to n\bar{n}

The decays $J/\psi\to p\bar{p}$ and $J/\psi\to n\bar{n}$ have been investigated with a sample of 225.2 million $J/\psi$ events collected with the BESIII detector at the BEPCII $e^+e^-$ collider. The branching fractions are determined to be $\mathcal{B}(J/\psi\to p\bar{p})=(2.112\pm0.004\pm0.031)\times10^{-3}$ and $\mathcal{B}(J/\psi\to n\bar{n})=(2.07\pm0.01\pm0.17)\times10^{-3}$. Distributions of the angle $\theta$ between the proton or anti-neutron and the beam direction are well described by the form $1+\alpha\cos^2\theta$, and we find $\alpha=0.595\pm0.012\pm0.015$ for $J/\psi\to p\bar{p}$ and $\alpha=0.50\pm0.04\pm0.21$ for $J/\psi\to n\bar{n}$. Our branching-fraction results suggest a large phase angle between the strong and electromagnetic amplitudes describing the $J/\psi\to N\bar{N}$ decay.Comment: 16 pages, 13 figures, the 2nd version, submitted to PR