Developing a psychological care competences framework for nurses in China: a mixed methods study.

BACKGROUND: With social transformation, rapid economic development and deepening awareness of psychological health in China, people's demand for psychological health services is becoming increasingly urgent. A key challenge for Chinese medical organizations is to train enough qualified psychological care nurses. A greater understanding of psychological care competences (PCC) can help in clinical nurse selection, training, and assessment. OBJECTIVE: To develop a PCC framework for Chinese nurses and obtain a consensus on the framework among experts. METHODS: A descriptive mixed methods study was designed consisting of a literature review and semi-structured interviews followed by three Delphi rounds. The experts (n = 16) involved were nurses, nursing managers and educators from nine Chinese provinces with a specific interest in psychological care. Descriptive statistics assisted in data analysis. RESULTS: Using the Iceberg Model as a theoretical foundation, five main dimensions and associated subdomains were integrated from 39 chosen articles. The semi-structured interviews with 24 nursing managers and nurses confirmed all of the themes from the literature review while generating new themes, both of which were incorporated into the initial PCC framework. After three Delphi rounds, the experts reached consensus on the PCC framework, including five domains (knowledge, skills, professional ethics, personal traits, internal motivations) and 22 subdomains with connotations. The response rate (RR) values for the three rounds of consultation were 80.00%, 87.50% and 92.86%, the composite reliability (Cr) values were 0.89-0.90, and the Kendall coordination coefficients were 0.155-0.200 (P < 0.05). CONCLUSIONS: On the basis of the Iceberg Model, literature review and qualitative research methods along with Delphi technique were used to develop a scientific and systematic PCC framework. The research methods were feasible and the results were reliable, thereby providing a basis for adopting this framework into nursing education. A formal assessment tool should be developed to test the PCC of nurses in clinical practice.

Ab initio molecular dynamics calculations on electron ionization induced fragmentations of C4F7N and C5F10O for understanding their decompositions under discharge conditions.

C4F7N and C5F10O are the most promising SF6 alternatives as eco-friendly insulating gaseous mediums in electrical engineering. It is necessary to clarify their electrical stability and decomposition mechanisms. In this work, we first introduced our experimental results for decomposition products of C4F7N/CO2 and C5F10O/synthetic air mixtures under partial discharge and spark discharge conditions. Then, we performed ab initio molecular dynamics (AIMD) simulations on the typical decomposition products. The simulations were performed under standard electron impact mass spectrometry (EI-MS); thus, the statistical results of the mass spectra were compared with those of the experimentally obtained standard mass spectra from the NIST database. The AIMD simulation method in simulating the electron-induced ionization process was verified and found to be reliable. Finally, the calculations were also performed for C4F7N and C5F10O with incident electron energies of 20 eV and 70 eV, respectively. The dominant pathway for both gases is the formation of CF3+ with the fracture of the C-C bond. The AIMD simulation is able to predict the decomposition channels after electron-impact ionization without any preconceived knowledge of fragmentation pathways, which provides a novel insight into understanding the decomposition mechanisms of C4F7N and C5F10O under different discharge conditions with different energies.

Improved measurement method for the Faraday rotation distribution using beam splitting.

In this work, two Faraday channels and one shadow channel are constructed by two non-polarizing beam splitters and one reflector to measure the Faraday rotation distribution. The intensity of the Faraday and shadow images is related to the state of polarization (SOP) of the incident light, thus achieving two-dimensional accurate measurement. The measurement sensitivity is influenced by the settings of two polarization analyzers in the Faraday channels and the parameters of beam splitters, which are explored numerically and verified with experiments. The fluctuation of the probe light is eliminated by using three evaluation indexes. Also, the measurement range and error sources under different experimental settings are discussed.

Measurement of dynamic atomic polarizabilities of Al at 19 wavelengths from 420†nm to 680†nm in electrical exploding wire experiments.

The dynamic polarizabilities of Al atom at 19 wavelengths from 420 nm to 680 nm are measured experimentally for the first time. A 15 µm diameter Al wire is heated to the gas/ microdrop stage using a 3 kA, 25 ns pulsed current, and the energy deposition when the resistive voltage reaches its peak is 4.7 eV·atom-1, which is higher than the atomization enthalpy of Al but much lower than its first ionization potential. Two laser interferometric images of the Al gas are obtained simultaneously using a 532 nm laser and an optical parametric oscillator laser. Then an integrated phase method is used to reconstruct the Al atomic linear density distribution based on the known atomic polarizability at 532 nm, which acts as a bridge between the two interferograms to obtain the relative atomic polarizability value at a specific wavelength with respect to the value at 532 nm. The measured dynamic polarizability of Al atom decreases from 13.5×10-24 cm3 to 9.4×10-24 cm3 as the wavelength increases from 420 nm to 680 nm with a measurement error of approximately ±10%. The experimental result fits well with an uncoupled Hartree-Fock approximation, and the reconstructed static polarizability of 8.13 ± 0.79×10-24 cm3 is well matched with reference measurement results.

Anlotinib Monotherapy for Refractory Metastatic Colorectal Cancer: A Double-Blinded, Placebo-Controlled, Randomized Phase III Trial (ALTER0703).

BACKGROUND: Treatment options for refractory metastatic colorectal cancer (mCRC) were limited. Anlotinib is a novel multitarget tyrosine kinase inhibitor. ALTER0703 study was conducted to assess efficacy and safety of anlotinib for patients with refractory mCRC. MATERIALS AND METHODS: This was a multicenter, double-blinded, placebo-controlled, randomized phase III trial involving 33 hospitals in China. Patients had taken at least two lines of therapies were 2:1 randomized to receive oral anlotinib (12 mg/day; days 1-14; 21 days per cycle) or placebo, plus best supportive care. Randomization was stratified by previous VEGF-targeting treatments and time from diagnosis to metastases. The primary endpoint was overall survival (OS). The secondary endpoints were progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), quality of life (QoL), and safety. RESULTS: A total of 419 patients (anlotinib: 282; placebo: 137) were treated from December 2014 to August 2016. The median PFS was improved in anlotinib group (4.1 months; 95% confidence interval [CI], 3.4-4.5) over placebo group (1.5 months; 95% CI, 1.4-1.5), with a hazard ratio (HR) of 0.34 (95% CI, 0.27-0.43; p < .0001). However, median OS was similar between two groups (8.6 months; 95% CI, 7.8-9.7 vs. 7.2 months; 95% CI, 6.2-8.8; HR, 1.02; p = .870). Improvements of ORR and DCR were observed in anlotinib over placebo. The most common grade ≥ 3 anlotinib related adverse events were hypertension (20.92%), increased γ-GT (7.09%), and hand-foot skin reaction (6.38%). CONCLUSION: Anlotinib was tolerated in Chinese patients with refractory mCRC. Although OS did not reach significant difference, anlotinib still provided clinical benefits by substantially prolonged PFS in these patients. IMPLICATIONS FOR PRACTICE: In this randomized clinical trial that included 419 patients with refractory metastatic colorectal cancer, substantial prolonged in progression-free survival was noted in patients who received anlotinib compared with those given placebo. Improvements on objective response rate and disease control rate was also observed in anlotinib group. However, overall survival was similar between the two groups. In a word, in third-line or above treatment of Chinese patients with refractory metastatic colorectal cancer, anlotinib provided clinical benefit by significantly prolonged progression-free survival.

Comparison of In Vitro to In Vivo Extrapolation Approaches for Predicting Transporter-Mediated Hepatic Uptake Clearance Using Suspended Rat Hepatocytes.

Clearance (CL) prediction remains a significant challenge in drug discovery, especially when complex processes such as drug transporters are involved. The present work explores various in vitro to in vivo extrapolation (IVIVE) approaches to predict hepatic CL driven by uptake transporters in rat. Broadly, two different IVIVE methods using suspended rat hepatocytes were compared: initial uptake CL (PSu,inf) and intrinsic metabolic CL (CLint,met) corrected by unbound hepatocytes to medium partition coefficient (Kpuu). Kpuu was determined by temperature method (Temp Kpuu,ss), homogenization method (Hom Kpuu,ss), and initial rate method (Kpuu,V0). In addition, the impact of bovine serum albumin (BSA) on each of these methods was investigated. Twelve compounds, which are known substrates of organic anion-transporting polypeptides representing diverse chemical matter, were selected for these studies. As expected, CLint,met alone significantly underestimated hepatic CL for all the test compounds. Overall, predicted hepatic CL using PSu,inf with BSA, Hom Kpuu,ss with BSA, and Temp Kpuu,ss showed the most robust correlation with in vivo rat hepatic CL. Adding BSA improved hepatic CL prediction for selected compounds when using the PSu,inf and Hom Kpuu,ss methods, with minimal impact on the Temp Kpuu,ss and Kpuu,V0 methods. None of the IVIVE approaches required an empirical scaling factor. These results suggest that supplementing rat hepatocyte suspension with BSA may be essential in drug discovery research for novel chemical matters to improve CL prediction. SIGNIFICANCE STATEMENT: The current investigation demonstrates that hepatocyte uptake assay supplemented with 4% bovine serum albumin is a valuable tool for estimating unbound hepatic uptake clearance (CL) and Kpuu. Based upon the extended clearance concept, direct extrapolation from these in vitro parameters significantly improved the overall hepatic CL prediction for organic anion-transporting polypeptide substrates in rat. This study provides a practical in vitro to in vivo extrapolation strategy for predicting transporter-mediated hepatic CL in early drug discovery.

Nanoparticle self-assembled technique applied to a whispering-gallery-mode laser.

The low threshold microlaser is the fundamental component of integrated optical circuits. The fabrication method of the microcavity determines the dimension and threshold of lasers, while the doping method limits the available gain materials and emitted wavelength. Here we propose a silica nanoparticles self-assembly technique to fabricate a microlaser with a radius of ∼100 um and Q factor of 2000. The aggregation state of gain molecules is investigated to be J-type dimers with high fluorescence to support the laser generation. The laser can emit a ∼600 nm waveband multimode laser with a low threshold of ∼12 µJ. Such a laser is promising as a coherent light source integrated on the photonic microchips and opens up a new orientation in material science.

Expression of Reg IV and SOX9 and their correlation in human gastric cancer.

BACKGROUND: Reg IV is a member of the regenerating gene family and has been demonstrated to be overexpressed in gastric cancer. However, the functional mechanism of Reg IV in gastric cancer is still unclear. METHODS: Expression of Reg IV and SOX9 were investigated by immunohistochemistry (IHC) and real-time PCR, and the correlation between the expression of Reg IV and SOX9 was analyzed in gastric cancer tissues. Reg IV expression vectors and a siRNA of Reg IV and SOX9 were transfected into human gastric cancer cells and the protein and mRNA levels of Reg IV and SOX9 were investigated by western blot and real-time PCR. The invasion and migration ability of gastric cancer cells with overexpressed Reg IV and with gene silence of Reg IV and SOX9 were examined by transwell chambers and wound healing assay. RESULTS: The Reg IV and SOX9 protein expression levels were both significantly higher in gastric cancer tissues compared with adjacent tissues (p = 0.022, p = 0.003). Reg IV protein expression significantly correlated with tumor invasion depth (p <  0.001), but had no significant correlations with age, clinical stage or lymph node metastasis. SOX9 protein expression also had no significant correlations with age, clinical stage, tumor invasion depth or lymph node metastasis. Reg IV transcript expression demonstrated a significant correlation with invasion depth and lymph node metastasis (p = 0.005, p <  0.001) and no significant correlations with age, clinical stage, tumor tissue differentiation or tumor size. SOX9 transcript expression demonstrated a significant correlation with invasion depth and tumor tissue differentiation (p = 0.044, p = 0.007) and no significant correlations with age, clinical stage or tumor size. The Reg IV expression showed a positive correlation with the SOX9 expression (p <  0.000, p = 0.008). Overexpression of Reg IV could upregulate SOX9 expression and promote invasiveness and migration of tumor cells, and silencing of Reg IV could downregulate SOX9 and inhibit invasiveness and migration of tumor cells in MKN-45 and AGS cells. On the other hand, silencing of SOX9 could upregulate Reg IV protein expression. CONCLUSIONS: Our study demonstrated that Reg IV positively regulates the expression of SOX9 and is involved in tumor cell invasion and migration in gastric cancer.

A simple and economical strategy for obtaining calibration plots for relative quantification of positional isomers of YYX/YXY triglycerides using high-performance liquid chromatography/tandem mass spectrometry.

RATIONALE: Positional analysis of intact triglycerides could provide greater insights into the link between fatty acid position and lipotoxic diseases. However, this methodology has been impeded by lack of commercial availability of positionally pure triglycerides. This work reports on a strategy for defining calibration plots for YXY/YYX triglyceride systems based on the product ion intensities in the collision-induced dissociation spectra of ammoniated precursor ions. METHODS: A set of triglycerides were synthesized and analyzed by electrospray ionization tandem mass spectrometry using an ion trap mass spectrometer. The product ion spectra of the ammoniated precursor ions were collected for 42 triglyceride systems of the form YXY/YYX, where Y represents C16:0 , C18:1(c-9) and C20:4(cccc-5,8,11,14) . Three-point calibration plots were prepared by plotting the relative abundance of the YY+ product ion vs. the relative abundance of the YYX positional isomer. RESULTS: The calibration plots were shown to give relative abundances of positional isomers accurate to within ±0.02 for most systems. Using an ion trap, under a controlled set of collision parameters, the slopes of the calibration plots can be used to compare the sensitivities of the product ion intensities to fatty acid position for various triglyceride systems. The average slopes of the calibration plots for the C16:0 , C18:1(c-9) and C20:4(cccc-5,8,11,14) systems were 0.29 ± 0.05, 0.21 ± 0.05 and 0.045 ± 0.005, respectively. CONCLUSIONS: While the presence of multiple unsaturated fatty acids tends to slightly decrease the slopes of the calibration plots, the data suggest that the sensitivities are sufficient for performing positional analysis of most triglyceride systems. However, the presence of unsaturated fatty acids that contain double bonds close to the carbonyl group, such as arachidonic acid, tends to dramatically decrease positional sensitivity.

Acid sphingomyelinase mediates 50-Hz magnetic field-induced EGF receptor clustering on lipid raft.

Previously, we found that exposure to a 50-Hz magnetic field (MF) could induce epidermal growth factor receptor (EGFR) clustering and phosphorylation on cell surface. In order to explore the possible mechanisms, the roles of acid sphingomyelinase (ASMase) and lipid raft in MF-induced EGFR clustering were investigated in the present study. Human amnion epithelial (FL) cells were exposed to a 50-Hz MF at 0.4 mT for different durations. Intracellular ASMase activity was detected using the Amplex® Red Sphingomyelinase Assay Kit. EGFR clustering, ASMase, and lipid rafts on cell membrane were analyzed using confocal microscopy after indirect immunofluorescence staining. Results showed that disturbing lipid rafts with nystatin could inhibit MF-induced EGFR clustering, indicating that it was dependent on intact lipid raft. Exposure of FL cells to MF significantly enhanced ASMase activity and induced ASMase translocation to membrane that co-localized with lipid rafts. Treatment with imipramine, an ASMase inhibitor, inhibited the MF-induced EGFR clustering. This inhibitory effect could be blocked by the addition of C2-ceramide in the culture medium. It suggested that ASMase mediated the 50-Hz MF-induced EGFR clustering via ceramide which was produced from hydrolyzation on lipid rafts.

ABI1 regulates carbon/nitrogen-nutrient signal transduction independent of ABA biosynthesis and canonical ABA signalling pathways in Arabidopsis.

Plants are able to sense and mediate the balance between carbon (C) and nitrogen (N) nutrient availability to optimize metabolism and growth, described as the C/N response. To clarify the C/N signalling mechanism, C/N-insensitive plants were obtained from an Arabidopsis FOX hunting population, which over-expresses full-length cDNAs for individuals. The resulting cni2-D (carbon/nitrogen insensitive 2-dominant) plant was found to overcome the post-germination growth checkpoint and to expand green cotyledons in disrupted high C/low N stress conditions. The CNI2 gene encodes ABI1, a phosphatase type 2C protein, which negatively regulates abscisic acid (ABA) signal transduction. Over-expressors of ABI1 were found to be insensitive to disrupted C/N stress, whereas the loss-of function mutant abi1-2 was hypersensitive, suggesting that ABI1 plays an essential role in the plant C/N response. By contrast, the C/N-dependent growth phenotype observed in wild-type plants was not associated with endogenous ABA content. Accordingly, the ABA-insensitive mutant abi1-1, which could not bind to the ABA-ABA receptor complex, was not insensitive and restored normal sensitivity to high C/low N stress. The canonical ABA signalling mutants abi4 and abi5 were also sensitive to disrupted C/N stress. Further gene expression analysis demonstrated that several genes in the SnRK2s and SnRK1s pathways are transcriptionally affected by high C/low N stress in wild-type plants regardless of the lack of increased endogenous ABA contents, whereas the expression of these genes were significantly suppressed in ABI1 over-expressors. Taken together, these results suggest direct cross-talk between C/N and non-canonical ABA signalling pathways, regulated by ABI1, in plants.

Differential role of P-glycoprotein and breast cancer resistance protein in drug distribution into brain, CSF and peripheral nerve tissues in rats.

1. This study was designed to evaluate how the absence of P-glycoprotein (Pgp, Mdr1a), breast cancer-resistance protein (Bcrp, Abcg2) or both affects drug distribution into sciatic nerves, brain and cerebrospinal fluid (CSF) in rats. 2. Pgp substrate (loperamide), BCRP substrates (dantrolene and proprietary compound X) and dual substrates (imatinib and proprietary compound Y) were well distributed into sciatic nerves with comparable nerve to plasma concentration ratios between wild-type and knockout (KO) rats. 3. Brain exposure increased substantially in Mdr1a(-/-) rats for loperamide and in Mdr1a(-/-)/Abcg2(-/-) rats for imatinib and compound Y, but minimally to modestly in Abcg2(-/-) rats for dantrolene and compound X. The deletion of Mdr1a or Abcg2 alone had little effect on brain distribution of compound Y. 4. While CSF to unbound brain concentration ratio remained ≥3 in the KO animals for dantrolene, compounds X and Y, it was reduced to 1 in the Mdr1a(-/-)/Abcg2(-/-) rats for imatinib. 5. The data indicate that Pgp and Bcrp do not play significant roles in drug distribution into peripheral nerve tissues in rats, while working in concert to regulate brain penetration. Our results further support that CSF concentration may not be a good surrogate for unbound brain concentration of efflux substrates.

Compact hard x-ray flash radiography device based on wire-shorted low-impedance rod pinch diode.

A rod pinch diode (RPD) is a feasible load configuration to generate a high-brightness, small-size hard x-ray radiation source. In this paper, the radiography performance of a wire-shorted low-impedance RPD on a compactly designed table-top driver (WRPD-1) is demonstrated for the first time. The driver consists of four high-power discharge branches connected in parallel, with each branch consisting of two metal-film capacitors and one multigap field-distortion switch in series. The four branches are triggered synchronously to generate a fast-rising current pulse: the inductance of the load section at the short circuit is ∼10 nH, and the short-circuit current amplitude is ∼325 kA at ±90 kV charging voltage, with a 10%-90% rise time of 110 ns. With a low-impedance RPD shorted by an 18-µm-diameter aluminum wire, a quasi-spherical x-ray focal spot with diameter <0.6 mm (width of the half-maximum grayscale) and a pulse duration of ∼25 ns (half-width of the radiation pulse) is obtained at ±70 kV charging voltage, and the imaging resolution excels 10 lp/mm under 1.56× magnification. According to the transmission-absorption x-ray spectrum estimation, the average emitted photon energy is ∼30 keV with a distinct peak in the 10-15 keV range that corresponds to the L-lines of tungsten, and the total energy of photons >10 keV reaches ∼1.16 J. The present results show that the device can serve well for the flash radiography diagnosis and potentially as an efficient light source for dynamic x-ray diffraction.

Computational pathology: A survey review and the way forward.

Computational Pathology (CPath) is an interdisciplinary science that augments developments of computational approaches to analyze and model medical histopathology images. The main objective for CPath is to develop infrastructure and workflows of digital diagnostics as an assistive CAD system for clinical pathology, facilitating transformational changes in the diagnosis and treatment of cancer that are mainly address by CPath tools. With evergrowing developments in deep learning and computer vision algorithms, and the ease of the data flow from digital pathology, currently CPath is witnessing a paradigm shift. Despite the sheer volume of engineering and scientific works being introduced for cancer image analysis, there is still a considerable gap of adopting and integrating these algorithms in clinical practice. This raises a significant question regarding the direction and trends that are undertaken in CPath. In this article we provide a comprehensive review of more than 800 papers to address the challenges faced in problem design all-the-way to the application and implementation viewpoints. We have catalogued each paper into a model-card by examining the key works and challenges faced to layout the current landscape in CPath. We hope this helps the community to locate relevant works and facilitate understanding of the field's future directions. In a nutshell, we oversee the CPath developments in cycle of stages which are required to be cohesively linked together to address the challenges associated with such multidisciplinary science. We overview this cycle from different perspectives of data-centric, model-centric, and application-centric problems. We finally sketch remaining challenges and provide directions for future technical developments and clinical integration of CPath. For updated information on this survey review paper and accessing to the original model cards repository, please refer to GitHub. Updated version of this draft can also be found from arXiv.

An unexpected but interesting response to a novel therapy for malignant extragastrointestinal stromal tumor of the mesoileum: a case report and review of the literature.

BACKGROUND: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. Extragastrointestinal stromal tumors (eGISTs) of the mesoileum are extremely rare and are usually treated with surgery combined with imatinib therapy. CASE PRESENTATION: We present the case of a 43-year-old man who developed a large eGIST in the mesoileum. Abdominal/pelvic computed tomography revealed a large heterogeneous mass with cystic and solid components that measured 20.0 × 12.0 × 8.0 cm. Three cycles of neoadjuvant chemotherapy with epirubicin, cyclophosphamide and hydroxycamptothecin; en bloc resection; and three more cycles of adjuvant chemotherapy with the same regimen and drugs resulted in five years of disease-free survival without any symptoms. CONCLUSIONS: Although imatinib treatment is usually chosen for eGISTs, resistance to imatinib remains a concern; these patients may receive neoadjuvant or adjuvant chemotherapy. In case of the former, further treatment, that is, surgery or adjuvant chemotherapy, depends on tumor response to the neoadjuvant chemotherapy. In addition, this treatment for eGIST is not only beneficial but also economical for patients compared with imatinib. A novel treatment approach that combined neoadjuvant chemotherapy, surgery and adjuvant chemotherapy resulted in long-term survival in our patient, thus showing promise as a potential therapy for eGISTs.

Hydrothermal Aging Mechanism and Modeling for SCR Catalysts.

Based on the activity evaluation and characterization test, we explored the hydrothermal aging mechanism of a vanadium-based SCR catalyst and constructed a dual-site hydrothermal aging kinetic model in this study. The vanadium-based catalyst contains Brønsted acidic sites and Lewis acidic sites, which show different sensitivities to hydrothermal aging, and the reduction of active sites is the main reason for the NOx conversion efficiency reduction after hydrothermal aging. The ammonia storage capacities of both sites have a high correlation coefficient with the NOx conversion efficiency. Based on the method of NH3-TPD curve peak resolution, we quantified the transformations of the two active sites and established the relationship between the site density, the aging temperature, and the duration to determine the aging factor. Then, a hydrothermal aging kinetic model was constructed, and the parameter identification and verification of the model were carried out through flow reactor experiments. The results show that the model constructed in this study can accurately reflect the catalyst activity after hydrothermal aging.

Experimental study of the mechanism of prepulse current on Z-pinch plasma using Faraday rotation diagnosis.

The prepulse current is an effective way to optimize the load structure and improve the implosion quality of the Z-pinch plasma. Investigating the strong coupling between the preconditioned plasma and pulsed magnetic field is essential for the design and improvement of prepulse current. In this study, the mechanism of the prepulse current on the Z-pinch plasma was revealed by determining the two-dimensional magnetic field distribution of preconditioned and nonpreconditioned single-wire Z-pinch plasma with a high-sensitivity Faraday rotation diagnosis. When the wire was nonpreconditioned, the current path was consistent with the plasma boundary. When the wire was preconditioned, the distributions of current and mass density presented good imploding axial uniformity, and the imploding speed of the current shell was higher than that of the mass shell. In addition, the mechanism of the prepulse current suppressing the magneto-Rayleigh-Taylor instability was revealed, which formed a sharp density profile of the imploding plasma and slowed the shock wave driven by the magnetic pressure. This discovery is essential and instructive for the design of preconditioned wire-array Z-pinch experiments.

The discovery of aminopyrazines as novel, potent Na(v)1.7 antagonists: hit-to-lead identification and SAR.

Herein the discovery of a novel class of aminoheterocyclic Na(v)1.7 antagonists is reported. Hit compound 1 was potent but suffered from poor pharmacokinetics and selectivity. The compact structure of 1 offered a modular synthetic strategy towards a broad structure-activity relationship analysis. This analysis led to the identification of aminopyrazine 41, which had vastly improved hERG selectivity and pharmacokinetic properties.

Discovery and optimization of aminopyrimidinones as potent and state-dependent Nav1.7 antagonists.

Clinical genetic data have shown that the product of the SCN9A gene, voltage-gated sodium ion channel Nav1.7, is a key control point for pain perception and a possible target for a next generation of analgesics. Sodium channels, however, historically have been difficult drug targets, and many of the existing structure-activity relationships (SAR) have been defined on pharmacologically modified channels with indirect reporter assays. Herein we describe the discovery, optimization, and SAR of potent aminopyrimidinone Nav1.7 antagonists using electrophysiology-based assays that measure the ligand-receptor interaction directly. Within this series, rapid functionalization at the polysubstituted aminopyrimidinone head group enabled exploration of SAR and of pharmacokinetic properties. Lead optimized N-Me-aminopyrimidinone 9 exhibited improved Nav1.7 potency, minimal off-target hERG liability, and improved rat PK properties.

Stable and orally bio-available pro-drugs of CPS11.

Stable and orally bio-available pro-drugs of CPS11 were synthesized. They are active on human umbilical vein endothelial cell proliferation assay and tube formation assay. The therapeutic efficacy and safety of 4 as a single agent or combined with Taxol in the treatment of MX-1 human breast cancer xenograft were evaluated. Compound 4 as a single agent failed to produce an anti-tumor activity, while it significantly enhanced antitumor potency of Taxol.