Discrimination of polysorbate 20 by high-performance liquid chromatography-charged aerosol detection and characterization for components by expanding compound database and library.

Analyzing polysorbate 20 (PS20) composition and the impact of each component on stability and safety is crucial due to formulation variations and individual tolerance. The similar structures and polarities of PS20 components make accurate separation, identification, and quantification challenging. In this work, a high-resolution quantitative method was developed using single-dimensional high-performance liquid chromatography (HPLC) with charged aerosol detection (CAD) to separate 18 key components with multiple esters. The separated components were characterized by ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS) with an identical gradient as the HPLC-CAD analysis. The polysorbate compound database and library were expanded over 7-time compared to the commercial database. The method investigated differences in PS20 samples from various origins and grades for different dosage forms to evaluate the composition-process relationship. UHPLC-Q-TOF-MS identified 1329 to 1511 compounds in 4 batches of PS20 from different sources. The method observed the impact of 4 degradation conditions on peak components, identifying stable components and their tendencies to change. HPLC-CAD and UHPLC-Q-TOF-MS results provided insights into fingerprint differences, distinguishing quasi products.

Synthesis of S(IV)-Stereogenic Chiral Thio-Oxazolidinones via Palladium-Catalyzed Asymmetric [3+2] Annulations.

Organic molecules bearing chiral sulfur stereocenters exert a great impact on asymmetric catalysis and synthesis, chiral drugs, and chiral materials. Compared with acyclic ones, the catalytic asymmetric synthesis of thio-heterocycles has largely lagged behind due to the lack of efficient synthetic strategies. Here we establish the first modular platform to access chiral thio-oxazolidinones via Pd-catalyzed asymmetric [3+2] annulations of vinylethylene carbonates with sulfinylanilines. This protocol is featured by readily available starting materials, and high enantio- and diastereoselectivity. In particular, an unusual effect of a non-chiral supporting ligand on the diastereoselectivity was observed. Possible reaction mechanisms and stereocontrol models were proposed.

Dearomatization-Rearomatization Reaction of Metal-Polarized Aza-ortho-Quinone Methides.

Metal-polarized aza-ortho-quinone methides (aza-o-QMs) are a unique and efficient handle for azaheterocycle synthesis. Despite great achievements, the potential of these reactive intermediates has not yet been fully exploited, especially the new reaction modes. Herein, we disclosed an unprecedented dearomatization process of metal-polarized aza-o-QMs, affording transient dearomatized spiroaziridine intermediates. Based on this serendipity, we accomplished three sequential dearomatization-rearomatization reactions of benzimidazolines with aza-sulfur ylides, enabling the divergent synthesis of bis-nitrogen heterocycles with high efficiency and flexibility. Moreover, experimental and theoretical studies were performed to explain the proposed mechanisms and observed selectivity. Further cellular evaluation of the dibenzodiazepine products identified a hit compound for new antitumor drugs.

De Novo Construction of Chiral Aminoindolines by Cu-Catalyzed Asymmetric Cyclization and Subsequent Discovery of an Unexpected Sulfonyl Migration.

Searching for efficient strategies to access structurally novel aminoindolines is of great significance for drug discovery. However, catalytic asymmetric de novo construction of aminoindoline scaffolds with functionality primed for diversification still remains elusive. Here, we report a Cu-catalyzed asymmetric cyclization of ethynyl benzoxazinones with amines, producing chiral 3-aminoindolines in good yield and with high enantioselectivity (up to 97% yield and 98:2 er). Moreover, a radical-mediated sulfonyl migration of these products was unexpectedly found, further affording new chiral 3-aminoindolines bearing alkenyl sulfonyl groups with retained enantiopurity (up to 84% yield and 98:2 er). Bioactivity evaluations indicate that these 3-aminoindolines show notable antitumor activities and chirality is proven to have a significant impact on their antitumor activity.

Stability of Stone-Wales defect in two-dimensional honeycomb crystals.

We have studied the valence effects on the stability of Stone-Wales (SW) defect in some typical two-dimensional honeycomb crystals containing group-IV, V, and VI elements employing density functional theory. The energetics involved in an in-plane formation process of SW defects in pristine and substitutionally doped materials is simulated. The SW defects are stable and have a rotation angle about 90 degree in the group-IV materials. They may become less stable with a smaller rotation angle in the group-V materials and seem difficult to exist in the group-VI materials. Group-VI doping may help eliminate SW defects while group-IV and V doping might introduce SW defects in some group-VI compounds.

[Summary of 61 cases of removable denture restoration in children with congenital tooth deficiency].

PURPOSE: To explore the methods and characteristics of removable denture restoration in children with congenital missing teeth. METHODS: From 1998 to 2018, 61 children aging 3 to 12 years old with congenital dental deficiency were treated with removable dentures. There were 59 males and 2 females. Removable denture prostheses were designed according to the characteristics of the children and the residual teeth in the mouth. There were 42 complete dentures in 21 cases, 40 single jaw complete dentures and maxillary removable partial dentures in 20 cases and 40 removable partial dentures in upper and lower jaw, totally 61 cases and 122 dentures. RESULTS: After wearing the removable denture, the appearance, chewing and pronunciation of the children were improved significantly. CONCLUSIONS: Although the etiology of congenital tooth defect is not completely clear, children can have early denture restoration. It solves the difficulty of eating, improves appearance and pronunciation, and promotes growth and physical and mental health of children.

Integrative analysis of gene expression and DNA methylation through one-class logistic regression machine learning identifies stemness features in medulloblastoma.

Most human cancers develop from stem and progenitor cell populations through the sequential accumulation of various genetic and epigenetic alterations. Cancer stem cells have been identified from medulloblastoma (MB), but a comprehensive understanding of MB stemness, including the interactions between the tumor immune microenvironment and MB stemness, is lacking. Here, we employed a trained stemness index model based on an existent one-class logistic regression (OCLR) machine-learning method to score MB samples; we then obtained two stemness indices, a gene expression-based stemness index (mRNAsi) and a DNA methylation-based stemness index (mDNAsi), to perform an integrated analysis of MB stemness in a cohort of primary cancer samples (n = 763). We observed an inverse trend between mRNAsi and mDNAsi for MB subgroup and metastatic status. By applying the univariable Cox regression analysis, we found that mRNAsi significantly correlated with overall survival (OS) for all MB patients, whereas mDNAsi had no significant association with OS for all MB patients. In addition, by combining the Lasso-penalized Cox regression machine-learning approach with univariate and multivariate Cox regression analyses, we identified a stemness-related gene expression signature that accurately predicted survival in patients with Sonic hedgehog (SHH) MB. Furthermore, positive correlations between mRNAsi and prognostic copy number aberrations in SHH MB, including MYCN amplifications and GLI2 amplifications, were detected. Analyses of the immune microenvironment revealed unanticipated correlations of MB stemness with infiltrating immune cells. Lastly, using the Connectivity Map, we identified potential drugs targeting the MB stemness signature. Our findings based on stemness indices might advance the development of objective diagnostic tools for quantitating MB stemness and lead to novel biomarkers that predict the survival of patients with MB or the efficacy of strategies targeting MB stem cells.

Incidence of metastatic disease and survival among patients with newly diagnosed primary CNS tumors in the United States from 2004-2013.

Background: Population-based estimates of the incidence and prognosis of metastatic disease at the initial diagnosis of primary central nervous system (CNS) tumors are currently lacking. Methods: A total of 43,455 patients diagnosed with a primary CNS tumor were enrolled to evaluate metastatic rates utilizing the data from the Surveillance, Epidemiology, and End Results (SEER) program. We used multivariate logistic regression to analyze the risk factors associated with the presence of metastasis at the first visit of patients with metastatic medulloblastoma (MB), atypical teratoid/rhabdoid tumor (ATRT), glioblastoma multiforme (GBM), or pilocytic astrocytoma (PA). Hazard ratios (HRs) and 95% confidence intervals (CIs) for cancer-specific death (CSD) of patients with these four CNS tumors were analyzed using multivariate Cox regression. Results: In patients with primary CNS embryonal tumors, the metastatic rates of patients with MB and ATRT were 14.51% and 19.25%, respectively. The metastatic rate for MB patients aged 0 to 18 years was 16.69%. In the patients with glioma, the metastatic rates of patients with PA and GBM were 1.55% and 1.39%, respectively. On multivariate logistic regression among patients with glioma, GBM (vs PA; OR, 2.12; 95% CI, 1.37 to 3.30; P=0.001) was associated with greater odds of having metastatic disease at diagnosis. On multivariate logistic regression among patients with GBM, MB, or ATRT, MB (vs GBM; OR, 4.66; 95% CI, 2.81 to 7.72; P<0.001) and ATRT (vs GBM; OR, 5.65; 95% CI, 3.27 to 9.75; P<0.001) were associated with greater odds of having metastatic disease at diagnosis. In the multivariate Cox proportional hazards model for CSD among patients with metastatic GBM or MB at diagnosis, gross total resection/total lobectomy (vs partial resection/partial lobectomy) was not related to a decreased or an increased risk of CSD. In patients with metastatic ATRT, compared to no surgery, gross total resection/total lobectomy or partial resection/partial lobectomy was not associated with a decreased risk of CSD. Conclusions: The findings in this study provide a population-based estimate of the incidence and prognosis of metastatic disease at the initial diagnosis of primary CNS tumors. These survival outcomes are relevant because they will help to prioritize future research directions to improve the treatment strategies of these metastatic CNS tumors.

Synergetic iridium and amine catalysis enables asymmetric [4+2] cycloadditions of vinyl aminoalcohols with carbonyls.

Catalytic asymmetric cycloadditions via transition-metal-containing dipolar intermediates are a powerful tool for synthesizing chiral heterocycles. However, within the field of palladium catalysis, compared with the well-developed normal electron-demand cycloadditions with electrophilic dipolarophiles, a general strategy for inverse electron-demand ones with nucleophilic dipolarophiles remains elusive, due to the inherent linear selectivity in the key palladium-catalyzed intermolecular allylations. Herein, based on the switched regioselectivity of iridium-catalyzed allylations, we achieved two asymmetric [4+2] cycloadditions of vinyl aminoalcohols with aldehydes and ß,γ-unsaturated ketones through synergetic iridium and amine catalysis. The activation of vinyl aminoalcohols by iridium catalysts and carbonyls by amine catalysts provide a foundation for the subsequent asymmetric [4+2] cycloadditions of the resulting iridium-containing 1,4-dipoles and (di)enamine dipolarophiles. The former provides a straightforward route to a diverse set of enantio-enriched hydroquinolines bearing chiral quaternary stereocenters, and the later represent an enantio- and diastereodivergent synthesis of chiral hydroquinolines.

Synthesis of 3,3'-Biindoles through a Copper-Catalyzed Friedel-Crafts Propargylation/Hydroamination/Aromatization Sequence.

A copper-catalyzed Friedel-Crafts propargylation/hydroamination/aromatization sequence is described. In the presence of a catalytic amount of CuI, this sequential reaction can convert ethynyl benzoxazinanones and indoles into a diverse set of 3,3'-biindoles with high efficiency and selectivity. Moreover, the synthesis of other indole-heteroaryl molecules and the catalytic asymmetric formation of axially chiral 3,3'-biindoles are demonstrated.

Copper-catalyzed decarboxylative cyclization via tandem C-P and C-N bond formation: access to 2-phosphorylmethyl indoles.

A novel copper-catalyzed decarboxylative cyclization of ethynyl benzoxazinanones with P(O)H compounds has been developed. This protocol leads to a series of 2-phosphorylmethyl indoles with high efficiency and selectivity (up to 99% yield) through tandem C-P/C-N bond formation under mild conditions.

Divergent Synthesis of Polycyclic Indolines: Copper-Catalyzed Cascade Reactions of Propargylic Carbamates and Indoles.

Polycyclic indolines are the common and core structural motif of many indole alkaloids that usually exhibit biological activities. Here, we describe two copper-catalyzed cascade reactions between propargylic carbamates and indoles. By doing so, one-step and divergent synthesis of structurally distinct polycyclic indolines, quinoline-fused indolines, C(3a)-indolyl furoindolines, and pyrroloindolines was achieved in high synthetic efficiency and selectivity.

Hydrogen Bond Direction Enables Palladium-Catalyzed Branch- and Enantioselective Allylic Aminations and Beyond.

The palladium-catalyzed branch- and enantioselective allylic amination of vinyl benzoxazinones was accomplished through controlling the hydrogen bond direction. This protocol provides a rapid and efficient route for synthesizing an important building block, chiral amino alkene, from widely available aliphatic amines in 64 → 99% yields with up to 99% ee. Furthermore, this transformation and the accompanying products were utilized to develop one-pot reactions through dual catalysis, affording chiral indolines with good synthetic efficiency and excellent enantiocontrol.

Application of Fluorine in Drug Design During 2010-2015 Years: A Mini-Review.

BACKGROUND: The widespread application of fluorine in drug design benefits from distinctive properties. Incorporation of fluorine can positively modulate certain pharmacokinetics properties, including lipophilicity, eletrophilicity, metabolic stability, chemical stability, et al., which were of interest to medicinal chemists. Herein, fluorinated compounds, which have been designed and evaluated for anticancer, antimicrobial, anti-inflammatory and antivirus activity, et al. during the last 6 years (2010-2015) are summarized. CONCLUSION: The emphasis is to highlight the importance of fluorinated compounds and the changes in the properties of compounds when introducing fluorine atom.

Role of MicroRNAs in Malignant Glioma.

OBJECTIVE: This overview seeked to bring together the microRNA (miRNA) researches on biogenesis and bio-function in these areas of clinical diagnosis and therapy for malignant glioma. DATA SOURCES: Using the keyword terms "glioma" and "miRNA," we performed the literature search in PubMed, Ovid, and web.metstr.com databases from their inception to October 2014. STUDY SELECTION: In screening out the quality of the articles, factors such as clinical setting of the study, the size of clinical samples were taken into consideration. Animal studied for verification and reviews article were also included in our data collection. RESULTS: Despite many advance in miRNA for malignant glioma, further studies were still required to focus on the following aspects: (i) Improving the understanding about biogenesis of miRNA and up-down regulation; (ii) utilizing high-throughput miRNA expression analysis to screen out the core miRNA for glioma; (iii) Focusing related miRNAs on the signal transduction pathways that regulate the proliferation and growth of glioma. CONCLUSIONS: We discussed the most promising miRNA, correlative signaling pathway and their relation with gliomas in the way of prompting miRNA target into being a clinical therapeutic strategy.

Design, synthesis and biological evaluation of novel bromophenol derivatives incorporating indolin-2-one moiety as potential anticancer agents.

A series of bromophenol derivatives containing indolin-2-one moiety were designed and evaluated that for their anticancer activities against A549, Bel7402, HepG2, HeLa and HCT116 cancer cell lines using MTT assay in vitro. Among them, seven compounds (4g-4i, 5h, 6d, 7a, 7b) showed potent activity against the tested five human cancer cell lines. Wound-healing assay demonstrated that compound 4g can be used as a potent compound for inactivating invasion and metastasis by inhibiting the migration of cancer cells. The structure-activity relationships (SARs) of bromophenol derivatives had been discussed, which were useful for exploring and developing bromophenol derivatives as novel anticancer drugs.

Crystallin αB acts as a molecular guard in mouse decidualization: regulation and function during early pregnancy.

Although decidualization is crucial for the establishment of successful pregnancy, the molecular mechanism underlying decidualization remains poorly understood. Crystallin αB (CryAB), a small heat shock protein (sHSP), is up-regulated and phosphorylated in mouse decidua. In mouse primary endometrial stromal cells, CryAB is induced upon progesterone treatment via HIF1α. In addition, CryAB is strongly phosphorylated through the p38-MAPK pathway under stress or during in vitro decidualization. Knockdown of CryAB results in the increase of apoptosis of stromal cells and inhibits decidualization under oxidative or inflammatory stress. Our data indicate that CryAB protects decidualization against stress conditions.

Sodium intake, salt taste and gastric cancer risk according to Helicobacter pylori infection, smoking, histological type and tumor site in China.

AIM: The risk factors mostly strongly associated with gastric cancer are gastric bacteria Helicobacter pylori and diet. Using a case-control study among residents in Jinan, we examined the association between the salt taste and gastric cancer according to H. pylori infection, smoking and histological type as well as tumor site. METHODS: This population-based case-control study included 207 cases and 410 controls. Data on potential risk factors of gastric cancer were obtained by interview of cases and controls with a questionnaire, salt taste preference was measured for all subjects, and IgG antibodies to H. pylori were applied to assess infection. Risk measures were determined using unconditional logistic regression. RESULTS: The proportions of salt taste at intervals of 1.8-7.2 g/L and ≥ 7.2 g/L were significantly higher in cases than controls, with ORs of 1.56 (1.23-3.64) and 2.03 (2.12- 4.11), respectively, subjects with high salt intake having an elevated risk for gastric cancer when infected with H. pylori. Significant modification by smoking and tumor site was observed across the different measures of salt intake, the highest salt taste showed higher cancer risk in ever smokers or with non-cardia cancers. CONCLUSION: Our study supports the view that high intake of sodium is an important dietary risk factor for gastric cancer, with a synergistic effect found between salt and H.pylori and smoking, dependent on the tumor site.

[Experimental study on the bonding strength between FCVA film and titanium].

PURPOSE: To study the bonding strength between the FCVA (filtered cathode vacuum arc) film and the titanium substrate. METHODS: According to the Engineer Manual of Germany (VDI3198), the indentation test was applied to evaluate the bonding strength between the FCVA film and the titanium substrate. The structure of the FCVA film and the interface between the film and the substrate were observed by means of scanning electron microscope(SEM). RESULTS: The fracture pattern of the film was classified as HF3 at the load of 400N, the bonding strength was enough between the FCVA film and the titanium substrate. SEM photograph showed the thickness of the FCVA film was about 1.2µm equably and the film bonded to the substrate well. CONCLSION: The bonding strength between the FCVA film and the titanium substrate was enough to meet clinical demand.

[Ribosome display screening of a novel human anti-IgE scFv fragment].

Total mRNA was extracted from lymphocytes separated from the peripheral blood of allergic patients, and then variable region of heavy chain (VH) and variable region of light chain (VL) cDNA library were constructed by RT-PCR. Human scFv templates for rabbit reticulocyte lysate ribosome display were assembled by primers and linker peptide (Gly4Ser)3. mRNA bound in antibody-ribosome-mRNA complexes was recovered using in-situ single primer RT-PCR, and three rounds of anti-IgE scFv DNA were enriched. The target DNA fragments were double enzyme digested and ligated into plasmid pET22b (+), followed by transformation in E. coli Rosseta (DE3). Positive clones were screened using clone PCR, Dot blotting and antigen ELISA. The correct lengths of VH (400 bp) and VL (710 bp) PCR products were obtained. The expected 1,000 bp ribosome display templates were also observed in agarose gel electrophoresis. After three rounds of ribosome display target sequences were effectively enriched, leading to a library of 10(13) members. Antibodies with the highest ELISA value for IgE were generated in the strain pET-IgE-6. A human anti-IgE scFv library was successfully constructed as described herein. Ribosome display using single primer in-situ RT-PCR as the recovery procedure effectively enriched target sequences. Anti-IgE scFv with high affinity and specificity were identified. The prepared human anti-IgE scFv fragment might be self-developed to a lead drug for treating asthma. Our study provides an alternative method for rapid discovery of human antibodies of therapeutic importance.