Safety of selinexor as the only exportin 1 (XPO1) inhibitor so far: a post-marketing study based on the world Health Organization pharmacovigilance database (Vigibase).

BACKGROUND: Exportin 1 (XPO1) inhibitors are being developed as a new agent for anti-cancer therapies. This study aimed to broadly portray the adverse event (AE) profile of selinexor, an XPO1 inhibitor, in actual clinical practice. RESEARCH DESIGN AND METHODS: Disproportionality analyses were conducted by calculating the information component and reporting odds ratio in VigiBase over different reporting periods. All selinexor-related AEs were classified by system organ class (SOC) and preferred term (PT) according to the Medical Dictionary for Regulatory Activities. RESULTS: A total of 116,443 AEs were identified in 2,608 patients that received selinexor. Patients with cardiac disorders had a higher propensity for death. Thirteen SOCs and 125 PTs were identified as having a potential connection with selinexor. Notably, 29 suspected signals detected in our study were defined as significant AEs by the European Medicines Agency, including febrile neutropenia, pancytopenia, and acute kidney injury. Attention should be paid to these AEs, despite most toxicities being manageable and reversible. CONCLUSIONS: This study highlights a number of AEs associated with selinexor. Most toxicities are reversible but require careful management. The benefit of selinexor still outweighs the potential risks, indicating XPO1 inhibitors as promising agents.

Advances on Axial Coordination Design of Single-Atom Catalysts for Energy Electrocatalysis: A Review.

Single-atom catalysts (SACs) have garnered increasingly growing attention in renewable energy scenarios, especially in electrocatalysis due to their unique high efficiency of atom utilization and flexible electronic structure adjustability. The intensive efforts towards the rational design and synthesis of SACs with versatile local configurations have significantly accelerated the development of efficient and sustainable electrocatalysts for a wide range of electrochemical applications. As an emergent coordination avenue, intentionally breaking the planar symmetry of SACs by adding ligands in the axial direction of metal single atoms offers a novel approach for the tuning of both geometric and electronic structures, thereby enhancing electrocatalytic performance at active sites. In this review, we briefly outline the burgeoning research topic of axially coordinated SACs and provide a comprehensive summary of the recent advances in their synthetic strategies and electrocatalytic applications. Besides, the challenges and outlooks in this research field have also been emphasized. The present review provides an in-depth and comprehensive understanding of the axial coordination design of SACs, which could bring new perspectives and solutions for fine regulation of the electronic structures of SACs catering to high-performing energy electrocatalysis.

Heterostructured α-Fe2 O3 @ZnO@ZIF-8 Core-Shell Nanowires for a Highly Selective MEMS-Based ppb-Level H2 S Gas Sensor System.

Highly selective and sensitive H2 S sensors are in high demand in various fields closely related to human life. However, metal oxide semiconductors (MOSs) suffer from poor selectivity and single MOS@metal organic framework (MOF) core-shell nanocomposites are greatly limited due to the intrinsic low sensitivity of MOF shells. To simultaneously improve both selectivity and sensitivity, heterostructured α-Fe2 O3 @ZnO@ZIF-8 core-shell nanowires (NWs) are meticulously synthesized with the assistance of atomic layer deposition. The ZIF-8 shell with regular pores and special surface functional groups is attractive for excellent selectivity and the heterostructured α-Fe2 O3 @ZnO core with an additional electron depletion layer is promising with enhanced sensitivity compared to a single MOS core. As a result, the heterostructured α-Fe2 O3 @ZnO@ZIF-8 core-shell NWs achieve remarkable H2 S sensing performance with a high response (Rair /Rgas  = 32.2 to 10 ppm H2 S), superior selectivity, fast response/recovery speed (18.0/31.8 s), excellent long-term stability (at least over 3 months), and relatively low limit of detection (down to 200 ppb) at low operating temperature of 200 °C, far beyond α-Fe2 O3 @ZIF-8 or α-Fe2 O3 @ZnO core-shell NWs. Furthermore, a micro-electromechanical system-based H2 S gas sensor system with low power consumption is developed, holding great application potential in smart cities.

Methane Alleviates Lung Injury through the IL-10 Pathway by Increasing T Regulatory Cells in a Mouse Asthma Model.

Allergic asthma is associated with allergen-induced airway hyperresponsiveness and inflammatory cell infiltration. While moderate-to-severe asthma with refractory symptoms is difficult to treat, methane is protective against organ damage. In this study, an asthmatic mouse model was established. Airway resistance under acetylcholine stimulation in asthmatic mice and histology of lung tissue injury were determined. EOS infiltration was determined by flow cytometry. Enzyme-linked immunosorbent assays (ELISAs) were performed for the determination of relevant cytokine levels in asthmatic mice with or without methane treatment. The potential mechanisms of methane under anti-IL-10 antibody intraperitoneal intervention were assessed by ELISA and flow cytometry. Pulmonary T regulatory cells (Tregs) were analyzed by flow cytometry, and anti-CD25 antibody was used to block them. Immunoblot analysis was performed to evaluate if methane played a role in the asthmatic lungs via the NF-κB and MAPKs pathways. The results showed that methane significantly improved airway compliance, relieved asthma-induced lung injury, and reduced EOS accumulation and inflammatory mediators in the lungs of ovalbumin-treated asthmatic mice. Anti-IL-10 treatment diminished the ameliorating effect of methane on asthma. In addition, methane enhanced pulmonary Tregs in asthma, which could be blocked by the anti-CD25 antibody. Further analysis revealed that methane decreased p-p65/p65 and p-p38/p38 expression. In conclusion, methane is a readily available and inexpensive molecule potentially suitable for human use, which can alleviate asthma-induced lung injury and EOS infiltration through the IL-10 pathway by increasing Tregs and decreasing NF-κB and p38 MAPK in a mouse model.

Highly sensitive and stable MEMS acetone sensors based on well-designed α-Fe2O3/C mesoporous nanorods.

Highly sensitive and stable acetone gas sensors based on MEMS substrate supported carbon nanoparticles decorated mesoporous α-Fe2O3 (C-d-mFe2O3) nanorods (NRs) derived from Fe-MIL-88B-NH2 NRs were first synthesized via a sequential process including a facile hydrothermal reaction and one-step pyrolysis at a moderate temperature in air. The MEMS architecture ensures low power consumption, small size, and high integration of the sensor. The obtained C-d-mFe2O3 NRs exhibit good thermal stability and superior acetone sensing performance with excellent response (Ra/Rg = 5.2 to 2.5 ppm) and selectivity, fast response/recovery speed (10/27 s), and low detection limit of 500 ppb at 225 °C. Furthermore, the acetone sensor exhibits remarkable long-term stability and repeatability even after being stored in air for over 10 months. The enhanced acetone sensing performance could be attributed to the large specific surface area of mesoporous α-Fe2O3 NRs, highly conductive carbon nanoparticles on the surface, and the formation of α-Fe2O3/C heterojunction. Density functional theory (DFT) calculations help to further confirm the superior acetone sensing performance. The competitive performance makes C-d-mFe2O3 NRs gas sensor a great potential for practical application in environmental harmful acetone gas monitoring.

An in vitro study of pcDNA 3.0-hVEGF165 gene transfection in endothelial progenitor cells derived from peripheral blood of rabbits.

The present study investigated the effect of the VEGF165 gene on adhesion, migration, and proliferation of endothelial progenitor cells (EPCs) derived from peripheral blood of rabbits. Peripheral blood mononuclear cells were isolated from rabbits by density gradient centrifugation with Ficoll-Plaque Plus. EPCs were characterized by immunofluorescence and immunostaining. A pcDNA 3.0-hVEGF165 expression vector was constructed and EPCs were transfected with the pcDNA 3.0-hVEGF165 gene. The EPCs derived from peripheral blood of rabbits were successfully transfected with pcDNA 3.0-hVEGF165. ELISA showed that the expression of VEGF165 increased significantly in the EPCs transfected with the hVEGF165 gene compared to control cells. Compared to control EPCs, EPCs transfected with the hVEGF165 gene had significantly enhanced adhesion, migration, and proliferative ability in vitro.

An evaluation of intrathecal bupivacaine combined with intrathecal or intravenous clonidine in children undergoing orthopedic surgery: a randomized double-blinded study.

BACKGROUND: Propofol is a popular agent for providing intraoperative sedation in pediatric population during lumbar puncture and spinal anesthesia. Adjuvant-like clonidine is used increasingly in pediatric anesthesia to provide postoperative analgesia with a local anesthetic agent. The aim of this study was to assess the effects of intrathecal and intravenous clonidine on postoperative analgesia/sedation and intraoperative requirements of propofol after intrathecal bupivacaine for orthopedic surgery in children. METHODS: Fifty-nine ASA I and II children aged 6-8 year undergoing orthopedic surgery were randomized to receive intrathecal 0.5% bupivacaine 0.2-0.4 mg·kg(-1) and intravenous 2 ml saline (Group B), intrathecal 0.5% bupivacaine 0.2-0.4 mg·kg(-1) plus 1 µg·kg(-1) clonidine and intravenous 2 ml saline (Group BCit), and 0.5% bupivacaine 0.2-0.4 mg·kg(-1) and intravenous 1 µg·kg(-1) clonidine in 2 ml of saline (Group BCiv). Intraoperative sedation was maintained with 20-50 µg·kg(-1)·min(-1) of propofol infusion. The requirements of propofol, time to first rescue analgesia, and postoperative pain or sedation scores were assessed. The duration of motor and sensory blocks and perioperative adverse events were determined. RESULTS: Clonidine significantly prolonged the time to first rescue analgesia and reduced the requirements of propofol sedation whether administered intravenously or intrathecally. The mean Children and Infants Postoperative Pain Scale scores of children were significantly lower in groups BCit and BCiv than in group B. Postoperative sedation scores were higher in groups BCit and BCiv than in group B. Intrathecal clonidine significantly prolonged the time to regression of the sensory block and recovery of motor block. There were no significant differences among the three groups regarding the incidence of perioperative adverse events. CONCLUSION: Intrathecal or intravenous clonidine similarly provided better postoperative analgesia and sedation and reduced the requirements of propofol. Only intrathecal clonidine prolonged the duration of sensory and motor blocks.

Effects of premedication of midazolam or clonidine on perioperative anxiety and pain in children.

The aim of the present study was to compare clinical effects of oral midazolam and clonidine premedication in children. In a prospective randomized double blind trial, 45 children between 2-8 years old received either oral midazolam 0.5 mg/kg (group M) or clonidine at 2 microg/kg (group C 2) or 4 microg/kg (group C4). The level of sedation, quality of parental separation, mask acceptance and thermodynamics were recorded. Postoperative analgesia, and perioperative side effects were assessed. In comparison to group M, the scores of sedation, parental separation and mask acceptance were significantly higher in group C2 and group C4 (p < 0.05). Also the level of sedation was significantly better in group C 4 than in group C 2 (p < 0.05). However, the rate of postoperative analgesia decreased significantly in group C 2 and C 4 compared to group M. The incidence of shivering was significantly increased in group M compared to group C 2 and C 4 . Oral clonidine premedication can therefore provide better preoperative sedation and postoperative analgesia with few adverse effects.

Protective effect of anti-intercellular adhesion molecule-1 antibody on global cerebral ischemia/reperfusion injury in the rat.

The present study aimed to clarify the protective effect of administration of an antiintercellular adhesion molecule-1 (ICAM-1) antibody (1A29) on neurological damage after global cerebral ischemia/reperfusion in rats. Global cerebral ischemia/reperfusion was produced by four-vessel occlusion for 30 min followed by reperfusion for 24 h. Animals were randomly divided into four groups: PC group (n = 10), PI group (n = 10), PR group (n = 10), and PM group (n = 10). Rats in the PC group were administered isotype-matched control antibody at a dose of 1 mg/kg IV. Rats in the PI group, PR group, and PM group were infused with 1A29 at a dose of 1 mg/kg IV before ischemia, upon reperfusion, and 4 h into reperfusion, respectively. All animals were sacrificed after reperfusion for 24 h. Cerebral sections were stained with hematoxylin and eosin for histological evaluation. The brain wet-to-dry ratio and neurological deficits were evaluated. In comparison to the PC group, the counts of polymorphonuclear leukocytes (PMNLs) and macrophages (MPhi) decreased significantly in the PI, PR, and PM groups (P < 0.01). In comparison to the control antibody group, the brain wet-to-dry ratio and the percent infarct volume were significantly reduced in rats receiving 1A29 antibody (P < 0.05 and P < 0.01, respectively). In comparison to the PC group, with a median neurological score of 2.5, mild deficits were noted in the PI, PR, and PM groups (median neurological scores were 1.6 to 1.8) (P < 0.05). 1A29 antibody decreased the counts of PMNLs and MPhi and the neurological score and it reduced the brain wet-to-dry ratio and the infarct volume, suggesting that anti-ICAM-1 antibody provides neuroprotection after global cerebral ischemia/reperfusion injury in rats.