LC-MS/MS quantification of ropivacaine and local analgesic and adverse effects of Long-acting Ropivacaine Injection based on pharmacokinetic-pharmacodynamic modelling in Bama minipigs.

The local analgesic efficacy and adverse effects of a new Long-acting Ropivacaine formulation were examined based on pharmacokinetic-pharmacodynamic (PK-PD) modelling in Bama minipigs. 24 Bama minipigs, 12 males and 12 females, were randomly and equally divided into the following treatment groups: normal saline injection, drug vehicle injection, Long-acting Ropivacaine Injection and Ropivacaine Hydrochloride Injection. After routine disinfection, a skin incision about 3 cm long and 3 cm deep was produced in the leg of each pig, and mechanical withdrawal threshold (MWT) measured at various times pre- and post-injection as an index of analgesia against incision pain. Plasma ropivacaine concentrations were also measured at the same times using a novel liquid chromatography-tandem mass spectroscopy (LC-MS/MS) method. Minipigs were sacrificed 24 h post-injection and hearts collected for drug concentration measurements by LC-MS/MS. The LC-MS/MS method demonstrated high sensitivity, linearity and precision. The Long-acting Ropivacaine formulation produced a longer analgesic effect (∼12 h) at a lower plasma concentration than Ropivacaine Hydrochloride (∼4h), suggesting a better side-effects profile. A PK-PD model revealed a direct relationship between plasma ropivacaine concentration and MWT, with peak analgesia at about 1000 ng/mL and behaved good prediction ability. Long-acting Ropivacaine Injection is a superior local anaesthetic-analgesic treatment due to longer-lasting efficacy at lower concentrations compared to Ropivacaine Hydrochloride, which will reduce the risk of side effects such as cardiotoxicity.

Pharmacokinetics and Safety of Single and Multiple Doses of Peficitinib (ASP015K) in Healthy Chinese Subjects.

Objective: To investigate the pharmacokinetics and safety of peficitinib (Janus kinase inhibitor for the treatment of rheumatoid arthritis) in healthy Chinese subjects following single and multiple doses. Methods: This open-label, randomized study was conducted at one site in China. Subjects received peficitinib 50, 100 or 150 mg as a single dose on Day 1 (fasted) and once daily from Days 8 to 13 in the multiple-dose period (fed). Blood samples were collected before administration each day, and up to 72h post administration. Pharmacokinetic assessments included area under the concentration curve (AUC), half-life (t1/2), maximum concentration (Cmax), and time to maximum concentration (tmax) of peficitinib and its metabolites (H1, H2 and H4). Treatment-emergent adverse events (TEAEs) were evaluated. Results: Thirty-six subjects were enrolled (12 per dose group). After a single dose of peficitinib, median tmax was 1.0-1.5h and mean t1/2 was 7.4-13.0h for all doses. In the multiple-dose period, median tmax was 1.5-2.0h. Dose-proportional increases in Cmax and AUC24h were observed for peficitinib and its metabolites following single and multiple doses, with minimal drug accumulation. The major metabolite was H2, with a systemic exposure of >150% of the parent AUC. Drug-related TEAEs were experienced by 5 (13.9%) and 12 (33.3%) subjects in the single- and multiple-dose periods, respectively. Following multiple doses of peficitinib, TEAEs were more frequent in higher than lower dose groups but were mild in severity with no related discontinuation or death. Conclusion: Following single and multiple doses of peficitinib in healthy Chinese subjects, peficitinib demonstrated rapid absorption and was well tolerated at all doses. Clinicaltrialsgov Identifier: NCT04143477.

Homo- and Heterovalent Doping-Mediated Self-Trapped Exciton Emission and Energy Transfer in Mn-Doped Cs2Na1-xAgxBiCl6 Double Perovskites.

Double perovskites exhibit low toxicity, intrinsic thermodynamic stability, and small carrier effective mass. Herein, a novel doping route was adopted to incorporate Mn ions into Cs2Na1-xAgxBiCl6 double perovskites for engineering the band gap and tailoring the energy transfer. The as-prepared Cs2Na1-xAgxBiCl6 (0 < x < 1) exhibited excellent photoluminescence and a broad self-trapped exciton (STE) band from 500 to 900 nm, which exhibited an abnormal emission peak blue shift with increasing temperature. For Mn-doped Cs2Na1-xAgxBiCl6, the two photoluminescence (PL) bands from d-d transition emission of Mn ions and STEs were always observed simultaneously in the PL window. The distinct energy-transfer channel from the Mn2+ ion guest to the double-perovskite host resulted in the dominant Mn2+ emission. Our results will be helpful for further understanding the nature of the photophysics of double perovskites.

Pralatrexate in Chinese Patients with Relapsed or Refractory Peripheral T-cell Lymphoma: A Single-arm, Multicenter Study.

BACKGROUND: Peripheral T-cell lymphoma (PTCL) is associated with poor prognosis, particularly in patients with relapsed/refractory (R/R) disease. Pralatrexate, a folate analogue inhibitor, was the first drug approved to treat R/R PTCL. OBJECTIVE: As the distribution of PTCL subtypes differs between populations and few patients in the pivotal trial of pralatrexate were Asian, this study investigated the safety and efficacy of pralatrexate as monotherapy in Chinese patients with R/R PTCL. PATIENTS AND METHODS: In this single-arm, open-label, multicenter study, 71 patients with R/R PTCL (median [range] 2 [1-14] prior systemic treatments) were recruited from 15 centers in China and received pralatrexate IV 30 mg/m2/week for 6 weeks in 7-week cycles (with vitamin B12/folate). The primary endpoint was objective response rate (ORR) per central review (null hypothesis: ORR < 15%). RESULTS: The study's primary objective was met: ORR (95% CI) was 52% (40-64%) (p < 0.001) and responses were observed across pre-specified patient subgroups. Median (95% CI) duration of response was 8.7 (3.3-14.1) months and first response was observed in Cycle 1 for most (84%) patients. Median (95% CI) progression-free survival and overall survival was 4.8 (3.1-8.1) months and 18.0 (10.4-NA) months, respectively. The most common treatment-emergent adverse events were stomatitis (68% [Grade 3/4: 20%]), anemia (49% [Grade 3/4: 24%]) and alanine aminotransferase increase (41% [Grade 3/4: 4%]). CONCLUSIONS: These results demonstrate that pralatrexate may represent a promising treatment option for Chinese patients with R/R PTCL. The ORR of 52% compared favorably with prior studies of pralatrexate in other populations and there were no unanticipated side effects. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03349333.

Experimental characterization of continuous-variable orbital angular momentum entanglement using Stokes-operator basis.

The continuous-variable (CV) orbital angular momentum (OAM) entanglement is very different to the traditional quadrature entanglement. The Stokes-operators directly reflect the character of OAM light. Here, we report the first direct experimental demonstration the Stokes-operator entanglement of continuous-variable OAM entanglement. Generated by transforming quadrature entanglement in the HG01 mode onto the orbital Stokes-operator basis, the entanglement is measured in the Stokes-operator basis using a self-designed detection scheme. An inseparability of I(O^2,O^3)<1 is achieved over a wide analyzing frequency of 1-10 MHz. Moreover, experimental fluctuations at 5.0 MHz are visualized using the quantum orbital Poincaré sphere representation. The OAM entanglement with Stokes-operators measurement has a promising application in certain nonlocal quantum information protocols and rotational optomechanics by interacting with nanoparticle or atoms.

Measurement of Stokes-operator squeezing for continuous-variable orbital angular momentum.

We demonstrate experimentally a measurement scheme for the Stokes operators for the continuous-variable squeezed states of orbital angular momentum (OAM). An OAM squeezed state is generated by coupling a dim Hermite-Gauss HG01-mode quadrature-squeezed light beam with a bright HG10-mode coherent light beam on a 98/2 beam splitter. Using an asymmetric Mach-Zehnder interferometer with an extra Dove prism in one arm, we measured the three orbital Stokes operators of the OAM squeezed states with a self-homodyne detection and finally characterized their positions and noise on the orbital Poincaré sphere.

Higher order mode entanglement in a type II optical parametric oscillator.

Nonclassical beams in high order spatial modes have attracted much interest but they exhibit much less squeezing and entanglement than the fundamental spatial modes, limiting their applications. We experimentally demonstrate the relation between pump modes and entanglement of first-order Hermite Gauss modes (HG10 entangled states) in a type II OPO and show that the maximum entanglement of high order spatial modes can be obtained by optimizing the pump spatial mode. To our knowledge, this is the first time to report this. Utilizing the optimal pump mode, the HG10 mode threshold can be reached easily without HG00 oscillation and HG10 entanglement is enhanced by 53.5% over HG00 pumping. The technique is broadly applicable to entanglement generation in high order modes.

Direct generation of spatial quadripartite continuous variable entanglement in an optical parametric oscillator.

Multipartite entanglement is used for quantum information applications, such as building multipartite quantum communications. Generally, generation of multipartite entanglement is based on a complex beam-splitter network. Here, based on the spatial freedom of light, we experimentally demonstrated spatial quadripartite continuous variable entanglement among first-order Hermite-Gaussian modes using a single type II optical parametric oscillator operating below threshold with an HG0245° pump beam. The entanglement can be scalable for larger numbers of spatial modes by changing the spatial profile of the pump beam. In addition, spatial multipartite entanglement will be useful for future spatial multichannel quantum information applications.

Experimental generation of continuous-variable hyperentanglement in an optical parametric oscillator.

We report on the generation of continuous-variable hyperentanglement of polarization and orbital angular momentum with a type II optical parametric oscillator. By compensating for the astigmatism between spatial modes, we produce an entangled pair of Hermite-Gauss beams. From correlations measurements, we verify the existence of continuous-variable hyperentanglement by the general entanglement criterion as well as by the continuous-variable version of the Peres-Horodecki criterion visualized on an equivalent Poincaré sphere.

[Research on the influence of urban land use structure and pattern on nitrogen, phosphorus of wetland water environment in Xianlin New Town of Nanjing].

The 10 typical wetlands in Xianlin New Townof Nanjing were classified into three categories, including rural wetland, suburban wetland, and urban wetland according to the influence of urbanization as well as the characteristics of wetland and LUCC of catchment regions. RDA was used to analyse the relationships between nitrogen and phosphorus in urban wetland and various types and patterns of land use. It was found that the water quality of the urban wetlands presented to be worse than that from rural wetlands, followed by sub urban wetlands. Secondly, according to all investigated wetlands, TP and TN turned out to be higher during the wet seasons than dry seasons. In addition, significant differences of TP were observed between wet and dry seasons for rural and suburban wetlands, and it was not so obvious for urban wetlands. However, the differences of TN was opposite to that of TP. Thirdly, factors affecting the water quality of wetlands were comprised of types and patterns of land use, and thus significant positive relationships were found between the concentrations of TN and TP and the impervious land, while negative correlations for meadows, woodlands and wetlands. What's more, higher remarkable differences were found in wetlands than those from meadows and woodlands. Regarding to patterns of land use, TP, TN concentrations were negatively correlated with the average patch shape in the dry and wet seasons, whereas positively relationships were observed for patch density and diversity index; furthermore, with refer to the impact of adjacent landscape, significant relationships were found between the content of TN and the patterns of land use and thus, a negative correlation in the wet season and a positive correlation in the dry season were observed, respectively.

MicroRNA-211 expression promotes colorectal cancer cell growth in vitro and in vivo by targeting tumor suppressor CHD5.

BACKGROUND: Chromodomain-helicase-DNA-binding protein 5 (CHD5) is a newly identified tumor suppressor that is frequently downregulated in a variety of human cancers. Our previous work revealed that the low expression of CHD5 in colorectal cancer is correlated with CHD5 promoter CpG island hypermethylation. In this study, we investigated the effect of microRNA-211 (miR-211)-regulated CHD5 expression on colorectal tumorigenesis. METHODOLOGY/PRINCIPAL FINDINGS: miR-211 was predicted to target CHD5 by TargetScan software analysis. A stably expressing exogenous miR-211 colorectal cancer cell line (HCT-116(miR-211)) was generated using lentiviral transduction and used as a model for in vitro and in vivo studies. The expression level of miR-211 in HCT-116(miR-211) cells was upregulated by 16-fold compared to vector control cells (HCT-116(vector)). Exogenous miR-211 directly binds to the 3'-untranslated region (3'-UTR) of CHD5 mRNA, resulting in a 50% decrease in CHD5 protein level in HCT-116(miR-211) cells. The levels of cell proliferation, tumor growth, and cell migration of HCT-116(miR-211) cells were significantly higher than HCT-116(vector) cells under both in vitro and in vivo conditions, as determined using the methods of MTT, colony formation, flow cytometry, scratch assay, and tumor xenografts, respectively. In addition, we found that enforced expression of miR-211 in HCT-116 cells was able to alter p53 pathway-associated regulatory proteins, such as MDM2, Bcl-2, Bcl-xL, and Bax. CONCLUSION/SIGNIFICANCE: Our results demonstrate that CHD5 is a direct target of miR-211 regulation. Enforced expression of miR-211 promotes tumor cell growth at least in part by downregulating the expression level of the CHD5 tumor suppressor. Our results provide a better understanding of the association of between miR-211-regulated CHD5 expression and CHD5 function in colorectal tumorigenesis.