Pharmacokinetic Study of Di-Phenyl-Di-(2,4-Difluobenzohydroxamato)Tin(IV): Novel Metal-Based Complex with Promising Antitumor Potential

Di-phenyl-di-(2,4-difluobenzohydroxamato)tin(IV)(DPDFT), a new metal-based arylhydroxamate antitumor complex, showed high in vivo and in vitro antitumor activity with relative low toxicity, but no data was reported regarding its pharmacokinetics and dependent toxicity. In this paper, a rapid, sensitive, and reproducible HPLC method in vivo using Diamonsil ODS column with a mixture of methanol and phosphoric acid in water (30 : 70, V/V, pH 3.0) as mobile phase was developed and validated for the determination of DPDFT. The plasma was deproteinized with methanol that contained acetanilide as the internal standard (I.S.). The photodiode array detector was set at a wavelength of 228 nm at room temperature and a linear curve over the concentration range 0.1~25 μg·mL−1 (r = 0.9993) was obtained. The method was used to determine the concentration-time profiles for DPDFT in the plasma after single intravenous administration with doses of 5, 10, 15 mg·kg−1 to rats. The pharmacokinetics parameter calculations and modeling were carried out using the 3p97 software. The results showed that the concentration-time curves of DPDFT in rat plasma could be fitted to two-compartment model

Progress of the satellite laser ranging system TROS1000

AbstractThe mobile satellite laser ranging system TROS1000, successfully developed in 2010, achieves a high repetition rate and enables daytime laser ranging. Its measurement range has reached up to 36000 km with an accuracy as precise as 1 cm. Using recent observations in Wuhan, Jiufeng, Xianning, and Rongcheng, Shandong, we introduce the progress made using this mobile observation system

Pharmacokinetic Study of Di-Phenyl-Di-(2,4-Difluobenzohydroxamato)Tin(IV): Novel Metal-Based Complex with Promising Antitumor Potential

Di-phenyl-di-(2,4-difluobenzohydroxamato)tin(IV)(DPDFT), a new metal-based arylhydroxamate antitumor complex, showed high in vivo and in vitro antitumor activity with relative low toxicity, but no data was reported regarding its pharmacokinetics and dependent toxicity. In this paper, a rapid, sensitive, and reproducible HPLC method in vivo using Diamonsil ODS column with a mixture of methanol and phosphoric acid in water (30 : 70, V/V, pH 3.0) as mobile phase was developed and validated for the determination of DPDFT. The plasma was deproteinized with methanol that contained acetanilide as the internal standard (I.S.). The photodiode array detector was set at a wavelength of 228 nm at room temperature and a linear curve over the concentration range 0.1∼25 μg·mL −1 (r = 0.9993) was obtained. The method was used to determine the concentration-time profiles for DPDFT in the plasma after single intravenous administration with doses of 5, 10, 15 mg·kg −1 to rats. The pharmacokinetics parameter calculations and modeling were carried out using the 3p97 software. The results showed that the concentration-time curves of DPDFT in rat plasma could be fitted to two-compartment model

Muscovy duck reovirus p10.8 protein localizes to the nucleus via a nonconventional nuclear localization signal

BACKGROUND: It was previously report that the first open reading frame of Muscovy duck reocvirus S4 gene encodes a 95-amino-acid protein, designed p10.8, which has no sequence similarity to other known proteins. Its amino acid sequence offers no clues about its function. RESULTS: Subcellular localization and nuclear import signal of p10.8 were characterized. We found that p10.8 protein localizes to the nucleus of infected and transfected cells, suggesting that p10.8 nuclear localization is not facilitated by viral infection or any other viral protein. A functional non-canonical nuclear localization signal (NLS) for p10.8 was identified and mapped to N-terminus residues 1–40. The NLS has the ability to retarget a large cytoplasmic protein to the nucleus. CONCLUSIONS: p10.8 imported into the nucleus might via a nonconventional signal nuclear signal

Extinction and recurrence of multi-group SEIR epidemic

In this paper, we consider a class of multi-group SEIR epidemic models with stochastic perturbations. By the method of stochastic Lyapunov functions, we study their asymptotic behavior in terms of the intensity of the stochastic perturbations and the reproductive number R0R0. When the perturbations are sufficiently large, the exposed and infective components decay exponentially to zero whilst the susceptible components converge weakly to a class of explicit stationary distributions regardless of the magnitude of R0R0. An interesting result is that, if the perturbations are sufficiently small and R0≤1R0≤1, then the exposed, infective and susceptible components have similar behaviors, respectively, as in the case of large perturbations. When the perturbations are small and R0>1R0>1, we construct a new class of stochastic Lyapunov functions to show the ergodic property and the positive recurrence, and our results reveal some cycling phenomena of recurrent diseases. Computer simulations are carried out to illustrate our analytical results

Electrocaloric effect in ferroelectric ceramics with point defects

The electrocaloric effect has drawn much attention due to its potential application in cooling devices. A negative electrocaloric effect is predicted to be induced in defect-doped ferroelectrics by computational results [A. Grunebohm and T. Nishimatsu, Phys. Rev. B 93, 134101 (2016) and Ma et al., Phys. Rev. B 94, 094113 (2016)], but it need to be confirmed by experimental results. In this work, we prepared a 1mol. % Mn-doped Pb(Zr0.2,Ti0.8)O3 ceramics (Pb((Zr0.2,Ti0.8)0.99,Mn0.01)O3), and the electrocaloric effect of the defect-containing ferroelectric ceramics has been investigated by both direct and indirect methods. The indirect method shows a similar negative electrocaloric effect signal as the computational results predicted, while the direct method gives a positive electrocaloric effect. The absence of the negative electrocaloric effect obtained by the direct method may originate from: (a) the unavailability and the improper prediction of the Maxwell relation, (b) an improper assumption of fixed defects in the computational models, and (c) the offset of heat loss due to the application of a large electric field. In addition, we find a giant positive electrocaloric effect of 0.55K at room temperature in the aged ceramics where no phase transition takes place. We attribute this abnormal electrocaloric effect to the restoration force of the defect dipoles. Our results not only provide insights into the origin of the negative electrocaloric effect, but also offer opportunities for the design of electrocaloric materials

Establishing thresholds of handgrip strength based on mortality using machine learning in a prospective cohort of Chinese population

BackgroundThe relative prognostic importance of handgrip strength (HGS) in comparison with other risk factors for mortality remains to be further clarified, and thresholds used for best identify high-risk individuals in health screening are not yet established. Using machine learning and nationally representative data from the China Health and Retirement Longitudinal Study (CHARLS), the study aimed to investigate the prognostic importance of HGS and establish sex-specific thresholds for health screening.MethodsA total of 6,762 participants from CHARLS were enrolled. A random forest model was built using 30 variables with all-cause mortality as outcome. SHapley Additive exPlanation values were applied to explain the model. Cox proportional hazard models and Harrell’s C index change were used to validate the clinical importance of the thresholds.ResultsAmong the participants, 3,102 (45.9%) were men, and 622 (9.1%) case of death were documented follow-up period of 6.78 years. The random forest model identified HGS as the fifth important prognostic variable, with thresholds for identifying high-risk individuals were < 32 kg in men and < 19 kg in women. Low HGS were associated with all-cause mortality [HR (95% CI): 1.77 (1.49–2.11), p < 0.001]. The addition of HGS thresholds improved the predictive ability of an established office-based risk score (C-index change: 0.022, p < 0.001).ConclusionOn the basis of our thresholds, low HGS predicted all-cause mortality better than other risk factors and improved prediction of a traditional office-based risk score. These results reinforced the clinical utility of measurement of HGS in health screening

Genomic Analyses Reveal Mutational Signatures and Frequently Altered Genes in Esophageal Squamous Cell Carcinoma

Esophageal squamous cell carcinoma (ESCC) is one of the most common cancers worldwide and the fourth most lethal cancer in China. However, although genomic studies have identified some mutations associated with ESCC, we know little of the mutational processes responsible. To identify genome-wide mutational signatures, we performed either whole-genome sequencing (WGS) or whole-exome sequencing (WES) on 104 ESCC individuals and combined our data with those of 88 previously reported samples. An APOBEC-mediated mutational signature in 47% of 192 tumors suggests that APOBEC-catalyzed deamination provides a source of DNA damage in ESCC. Moreover, PIK3CA hotspot mutations (c.1624G>A [p.Glu542Lys] and c.1633G>A [p.Glu545Lys]) were enriched in APOBEC-signature tumors, and no smoking-associated signature was observed in ESCC. In the samples analyzed by WGS, we identified focal (<100 kb) amplifications of CBX4 and CBX8. In our combined cohort, we identified frequent inactivating mutations in AJUBA, ZNF750, and PTCH1 and the chromatin-remodeling genes CREBBP and BAP1, in addition to known mutations. Functional analyses suggest roles for several genes (CBX4, CBX8, AJUBA, and ZNF750) in ESCC. Notably, high activity of hedgehog signaling and the PI3K pathway in approximately 60% of 104 ESCC tumors indicates that therapies targeting these pathways might be particularly promising strategies for ESCC. Collectively, our data provide comprehensive insights into the mutational signatures of ESCC and identify markers for early diagnosis and potential therapeutic targets

Actively implementing an evidence-based feeding guideline for critically ill patients (NEED): a multicenter, cluster-randomized, controlled trial

Background: Previous cluster-randomized controlled trials evaluating the impact of implementing evidence-based guidelines for nutrition therapy in critical illness do not consistently demonstrate patient benefits. A large-scale, sufficiently powered study is therefore warranted to ascertain the effects of guideline implementation on patient-centered outcomes. Methods: We conducted a multicenter, cluster-randomized, parallel-controlled trial in intensive care units (ICUs) across China. We developed an evidence-based feeding guideline. ICUs randomly allocated to the guideline group formed a local "intervention team", which actively implemented the guideline using standardized educational materials, a graphical feeding protocol, and live online education outreach meetings conducted by members of the study management committee. ICUs assigned to the control group remained unaware of the guideline content. All ICUs enrolled patients who were expected to stay in the ICU longer than seven days. The primary outcome was all-cause mortality within 28 days of enrollment. Results: Forty-eight ICUs were randomized to the guideline group and 49 to the control group. From March 2018 to July 2019, the guideline ICUs enrolled 1399 patients, and the control ICUs enrolled 1373 patients. Implementation of the guideline resulted in significantly earlier EN initiation (1.20 vs. 1.55 mean days to initiation of EN; difference − 0.40 [95% CI − 0.71 to − 0.09]; P = 0.01) and delayed PN initiation (1.29 vs. 0.80 mean days to start of PN; difference 1.06 [95% CI 0.44 to 1.67]; P = 0.001). There was no significant difference in 28-day mortality (14.2% vs. 15.2%; difference − 1.6% [95% CI − 4.3% to 1.2%]; P = 0.42) between groups. Conclusions: In this large-scale, multicenter trial, active implementation of an evidence-based feeding guideline reduced the time to commencement of EN and overall PN use but did not translate to a reduction in mortality from critical illness. Trial registration: ISRCTN, ISRCTN12233792. Registered November 20th, 2017