Lusutrombopag for thrombocytopenia in Chinese patients with chronic liver disease undergoing invasive procedures.

PURPOSE: Probing efficacy and safety of lusutrombopag in Chinese chronic liver disease (CLD) and severe thrombocytopenia (PLT < 50 × 109/L) patients undergoing elective invasive procedures. METHODS: In this double-blind, parallel-group phase 3 study, 66 patients with CLD and severe thrombocytopenia were randomized 2:1 to lusutrombopag or placebo arm treatment regimens for seven days at 9 centers in China. Responders (PLT ≥ 50 × 109/L that increased to ≥ 20 × 109/L from the baseline and not received rescue therapy for bleeding) on Day 8 (the day after seven-day treatment) were assessed. PLT ≥ 50 × 109/L on or after Day 8 and within 2 days before invasive procedure (alternative criteria for not requiring platelet transfusion) were also analyzed. Adverse events (AEs) were recorded. RESULTS: The proportion of responders on Day 8 was evidently higher (p = 0.0011) in the lusutrombopag group (43.2%, 19/44) versus placebo (4.5%, 1/22). And 72.7% (32/44) patients receiving lusutrombopag met the alternative criteria for not requiring platelet transfusion, while 18.2% (4/22) in the placebo group. The median maximum PLT in lusutrombopag group increased to 80.5 × 109/L, and median time to reach maximum was 14.5 days. Compared with placebo, the lusutrombopag group had a lower incidence of bleeding events (6.8% versus 13.6%), and only one patient had thrombotic-related AE. Overall, the incidence of treatment-emergent AEs was comparable between two groups. CONCLUSIONS: Lusutrombopag was effective in raising PLT, diminishing platelet transfusion requirement, and documented a safety profile like the placebo in CLD and severe thrombocytopenia patients in a Chinese cohort undergoing elective invasive procedures. Chinese clinical trial registration number: CTR20192384.

Expression Profiles of Hypoxia-Related Genes of Cancers Originating from Anatomically Similar Locations Using TCGA Database Analysis.

Background: Hypoxia is a well-recognized characteristic of the tumor microenvironment of solid cancers. This study aimed to analyze hypoxia-related genes shared by groups based on tumor location. Methods: A total of 9 hypoxia-related pathways from the Kyoto Encyclopedia of Genes and Genomes database or the Reactome database were selected, and 850 hypoxia-related genes were analyzed. Based on their anatomical locations, 14 tumor types were categorized into 6 groups. The group-specific genetic risk score was classified as high- or low-risk based on mRNA expression, and survival outcomes were evaluated. Results: The risk scores in the Female Reproductive group and the Lung group were internally and externally validated. In the Female Reproductive group, CDKN2A, FN1, and ITGA5 were identified as hub genes associated with poor prognosis, while IL2RB and LEF1 were associated with favorable prognosis. In the Lung group, ITGB1 and LDHA were associated with poor prognosis, and GLS2 was associated with favorable prognosis. Functional enrichment analysis showed that the Female Reproductive group was enriched in relation to cilia and skin, while the Lung group was enriched in relation to cytokines and defense. Conclusions: This analysis may lead to better understanding of the mechanisms of cancer progression and facilitate establishing new biomarkers for prognosis prediction.

[Analysis of clinical features of Craniofacial Langerhans cell histiocytosis in children].

Objective:To investigate the clinical features of craniofacial Langerhans cell histiocytosis（LCH） in children. Method:The clinical data of 11 children with craniofacial LCH confirmed by surgical histopathology were analyzed retrospectively, and their clinical characteristics were compared. Result:Eleven children with craniofacial LCH had a history of misdiagnosis and mistreatment. There were 10 cases aged 1-4 years. 9 cases of LCH occurred in the temporal bone with otorrhea and moderate to severe hearing loss, while 6 cases were binaural involvement. CT of the primary lesions in 7 children showed obvious extensive bone destruction. 2 cases died（both with multiple dangerous organs involved） and 8 cases survived. Conclusion:The craniofacial LCH in children mainly occurs in children under 4 years old, Most of the temporal bone LCH is involved in both ears with otorrhea and severe hearing loss. There is a high rate of misdiagnosis in clinical work due to lack of specific clinical symptoms. Imaging examinations and systemic examinations have important diagnostic value. The cases with dangerous organs involved have a higher mortality rate, while chemotherapy has better clinical effect for children with localized lesions.

Proposal of a rhombohedral-tetragonal phase composition for maximizing piezoelectricity of (K,Na)NbO3 ceramics.

Great progress in the field of piezoelectricity of (K,Na)NbO3 (KNN) lead-free ceramics, driven by emerging rhombohedral-tetragonal (R-T) phase boundary, has instigated research activity regarding elaborate controls of the phase boundary structure. Through phase-microstructure-property mapping in KNN ceramics doped with Bi-containing perovskite oxides, in this study we for the first time report the existence of a certain R-T phase boundary state by which to create maximum piezoelectric response in KNN systems. This phase boundary condition is usually comprised of approximately 15% R phase and 85% T phase, regardless of the choice of dopant material. Any deviation from this phase composition, either by inclusion of orthorhombic (O) phase or by enrichment of R phase, has a negative effect on the value of d33. These findings can provide useful guidance for chemical doping control associated with the type of phase boundary and the phase composition for advanced KNN-based materials.

Multi-functional nano-adhesive releasing therapeutic ions for MMP-deactivation and remineralization.

Restoration of hard tissue in conjunction with adhesive is a globally challenging issue in medicine and dentistry. Common clinical therapies involving application of adhesive and substitute material for functional or anatomical recovery are still suboptimal. Biomaterials with bioactivity and inhibitory effects of enzyme-mediated adhesive degradation can render a solution to this. Here, we designed a novel copper-doped bioactive glass nanoparticles (CuBGn) to offer multifunction: metalloproteinases (MMP) deactivation and remineralization and incorporated the CuBGn in resin-dentin adhesive systems, which showed most common failure of MMP mediated adhesive degradation among hard tissue adhesives, to evaluate proposed therapeutic effects. A sol-gel derived bioactive glass nanoparticles doping 10 wt% of Cu (Cu-BGn) for releasing Cu ions, which were well-known MMP deactivator, were successfully created and included in light-curing dental adhesive (DA), a filler-free co-monomer resin blend, at different concentrations (up to 2 wt%). These therapeutic adhesives (CuBGn-DA) showed enhanced (a)cellular bioactivity, cytocompatibility, microtensile bond strength and MMP deactivation-ability. In conclusion, the incorporation of Cu ions releasing nano-bioactive glass demonstrated multifunctional properties at the resin-dentin interface; MMP deactivation and remineralization, representing a suitable strategy to extend the longevity of adhesive-hard tissue (i.e. resin-dentin) interfaces.

Rapid and direct synthesis of complex perovskite oxides through a highly energetic planetary milling.

The search for a new and facile synthetic route that is simple, economical and environmentally safe is one of the most challenging issues related to the synthesis of functional complex oxides. Herein, we report the expeditious synthesis of single-phase perovskite oxides by a high-rate mechanochemical reaction, which is generally difficult through conventional milling methods. With the help of a highly energetic planetary ball mill, lead-free piezoelectric perovskite oxides of (Bi, Na)TiO3, (K, Na)NbO3 and their modified complex compositions were directly synthesized with low contamination. The reaction time necessary to fully convert the micron-sized reactant powder mixture into a single-phase perovskite structure was markedly short at only 30-40 min regardless of the chemical composition. The cumulative kinetic energy required to overtake the activation period necessary for predominant formation of perovskite products was ca. 387 kJ/g for (Bi, Na)TiO3 and ca. 580 kJ/g for (K, Na)NbO3. The mechanochemically derived powders, when sintered, showed piezoelectric performance capabilities comparable to those of powders obtained by conventional solid-state reaction processes. The observed mechanochemical synthetic route may lead to the realization of a rapid, one-step preparation method by which to create other promising functional oxides without time-consuming homogenization and high-temperature calcination powder procedures.

Novel Angiogenic Activity and Molecular Mechanisms of ZYZ-803, a Slow-Releasing Hydrogen Sulfide-Nitric Oxide Hybrid Molecule.

AIMS: Revascularization strategies and gene therapy for treatment of ischemic diseases remain to be fully optimized for use in human and veterinary clinical medicine. The continued evolution of such strategies must take into consideration two compounds, which act as critical effectors of angiogenesis by endothelial cells. Nevertheless, the nature of interaction between hydrogen sulfide (H2S) and nitric oxide (NO) remained undefined at the time of this writing. RESULTS: The present study uses ZYZ-803, a novel synthetic H2S-NO hybrid molecule, which, under physiological conditions, slowly decomposes to release H2S and NO. This is observed to dose dependently mediate cell proliferation, migration, and tube-like structure formation in vitro along with increased angiogenesis in rat aortic rings, Matrigel plug in vivo, and a murine ischemic hind limb model. The effects of ZYZ-803 exhibited significantly greater potency than those of H2S and/or NO donor alone. The compound stimulated cystathionine γ-lyase (CSE) expression and endothelial NO synthase (eNOS) activity to produce H2S and NO. Blocking CSE and/or eNOS suppressed both H2S and NO generation as well as the proangiogenic effect of ZYZ-803. Sirtuin-1 (SIRT1), CSE, and/or eNOS small interfering RNA (siRNA) suppressed the angiogenic effect of ZYZ-803-induced SIRT1 expression, VEGF, and cyclic guanosine 5'-monophosphate (cGMP) levels. These gasotransmitters cooperatively regulated angiogenesis through an SIRT1/VEGF/cGMP pathway. INNOVATION AND CONCLUSION: H2S and NO exert mutual influence on biological functions mediated by both compounds. Functional convergence occurs in the SIRT1-dependent proangiogenic processes. These two gasotransmitters are mutually required for physiological regulation of endothelial homeostasis. These ongoing characterizations of mechanisms by which ZYZ-803 influences angiogenesis provide expanding insight into strategies for treatment of ischemic diseases. Antioxid. Redox Signal. 25, 498-514.

The novel analogue of hirsutine as an anti-hypertension and vasodilatary agent both in vitro and in vivo.

In this paper, an analogue of hirsutine (compound 1) has been synthesized and evaluated as an anti-hypertension agent, which exhibits extraordinary effects on the contractile response of thoracic aorta rings from male SD rats in vitro (IC50 = 1.129×10(-9)±0.5025) and the abilities of reducing the systolic blood pressure (SBP) and heart rate (HR) of SHR in vivo. The mechanism investigation reveals that the vasodilatation induced by compound 1 is mediated by both endothelium-dependent and -independent manners. The relaxation in endothelium-intact aortic rings induced by compound 1 can be inhibited by L-NAME (1×10(-6) mol•L(-1)) and ODQ (1×10(-6) mol•L(-1)). Moreover, compound 1 can also block Ca2+ influx through L-type Ca2+ channels and inhibit intracellular Ca2+ release while no effect on K+ channel has been observed. All these data demonstrated that the NO/cyclic GMP pathway can be involved in endothelium-dependent manner induced by compound 1. Meanwhile the mechanism on the vasodilatation of compound 1 probably also related to blockade of Ca2+ influx through L-type Ca2+ channels and inhibition of intracellular Ca2+ release may have no relationship with K+ channels.

Prevalence and associated risk factors of allergic rhinitis in preschool children in Beijing.

OBJECTIVES/HYPOTHESIS: To investigate the prevalence of allergic rhinitis (AR) and its associated risk factors in preschool children in Beijing. STUDY DESIGN: Two-stage, clustered, stratified random sample study. METHODS: Parents of 4,075 children aged 3, 4, and 5 years in urban and suburban areas were surveyed using a questionnaire. A random subgroup of 1,067 children was examined by otolaryngologists with skin prick test (SPT). RESULTS: The survey response rate was 98.3%. Based on the criteria published by ARIA document, the prevalence of epidemiologic AR was 48% (53.2% in urban areas; 43.4% in suburban areas). Among 795 children with epidemiologic AR, sensitization to common inhalant allergens was confirmed by a positive SPT in 248 children (31.2%). Thus, the adjusted prevalence of clinical AR was 14.9% (19.5% in urban areas; 10.8% in suburban areas). In these AR children, 166 (67.1%) were intermittent and 82 (32.9%) persistent, with moderate/severe symptoms in 103 (41.5%). The most common inhalant allergens were Alternaria tenuis (55.7%), followed by Dermatophagoides farina (39.4%), and Dermatophagoides pteronyssinus (38.6%). Both asthma (adjusted OR 4.88, 95% CI: 3.48-6.86) and eczema (adjusted OR: 1.49, 95% CI: 1.15-1.94) appear to be significant concomitant risk factors for AR. CONCLUSIONS: The prevalence of AR in young children can be overestimated using epidemiologic criteria. AR is a common disease in Asian preschool children, with an increasing trend as children get older, and is higher in urban than suburban areas--suggesting an important role for environmental risk factors in AR.

Taraxerone enhances alcohol oxidation via increases of alcohol dehyderogenase (ADH) and acetaldehyde dehydrogenase (ALDH) activities and gene expressions.

The present study, taraxerone (d-friedoolean-14-en-3-one) was isolated from Sedum sarmentosum with purity 96.383%, and its enhancing effects on alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase (ALDH) activities were determined: EC(50) values were 512.42 ± 3.12 and 500.16 ± 3.23 µM for ADH and ALDH, respectively. In order to obtain more information on taraxerone related with the alcohol metabolism, 40% ethanol (5 mL/kg body weight) with 0.5-1mM of taraxerone were administered to mice. The plasma alcohol and acetaldehyde concentrations of taraxerone-treated groups were significantly lowered than those of the control group (p<0.01): approximately 20-67% and 7-57% lowered for plasma alcohol and acetaldehyde, respectively. Compare to the control group, the ADH and ALDH expressions in the liver tissues were abruptly increased in the taraxerone-treated groups after ethanol exposure. In addition, taraxerone prevented catalase, superoxide dismutase, and reduced glutathione concentrations from the decrease induced by ethanol administration with the concentration dependent manner.

[Three cases of eosinophilichyperplastic lymphogranuloma in children's parotid area].

From March 2009 to October 2009, three pediatric patients with parotid tumor were cured. Preoperative physical examination showed regional swelling in parotid area, the surface skin was in moderate reddish purple, the border was vague, and the swelling was inactive. The patients' IgE were significantly increased. B ultrasound examination demonstrated the focus was an isoecho with ringlike dark band around, which was concluded as bull's-eye sign. Magnetic resonance imaging (MRI) examination indicated a cystic mass between the skin and parotid. Preoperative diagnosis was eosinophilichyperplastic lymphogranuloma (Kimura's disease) and the granuloma was excised by operation. Pathological examination revealed the capillary vessel hyperplasia in local tissue with a plenty of eosinophils and lymphocytes infiltrating. The disease was confirmed. Although the disease is rare, the diagnosis still could be made by preoperative physical examination, laboratory and imaging examinations.