Cardiovascular events of Bruton's tyrosine kinase inhibitors: A real-world study based on the United States Food and Drug Administration Adverse Event Reporting System database.

AIMS: Bruton's tyrosine kinase inhibitors (BTKIs), including first-generation ibrutinib, second-generation acalabrutinib and zanubrutinib, may be involved in the mechanisms of action related to adverse events (AEs) of the cardiovascular system. We aimed to characterize the cardiovascular AEs of BTKIs reported in the US Food and Drug Administration (FDA) Adverse Event Reporting System, and to compare the cardiovascular risks of BTKIs. METHODS: Across all indications of three FDA-approved BTKIs, primary suspect drugs were extracted over two periods: from January 2013 to December 2022 (after the approval of the first BTKI), and from January 2020 to December 2022 (all three BTKIs on the market). Disproportionality was measured by reporting odds ratios (RORs) and information components. Additional analyses were performed without incorporating patients with underlying cardiovascular disease (CVD). RESULTS: A total of 10 353 cases included the uses of ibrutinib, acalabrutinib and zanubrutinib. Ibrutinib was significantly associated with 47 cardiovascular AEs. Acalabrutinib was associated with new signals, including cardiac failure (ROR = 1.82 [1.13-2.93]), pulmonary oedema (ROR = 2.15 [1.19-3.88]), ventricular extrasystoles (ROR = 5.18 [2.15-12.44]), heart rate irregular (ROR = 3.05 [1.53-6.11]), angina pectoris (ROR = 3.18 [1.71-5.91]) and cardiotoxicity (ROR = 25.22 [17.14-37.10]). In addition, cardiovascular events had an earlier onset in acalabrutinib users. Zanubrutinib was only associated with atrial fibrillation. Acalabrutinib and zanubrutinib had lower ROR values than ibrutinib. The AE signals were generally consistent between the population receiving and not receiving CVD medications. CONCLUSIONS: Potential cardiovascular risks identified in this study were not clearly noted on the label of marketed acalabrutinib. Caution should be paid to the cardiovascular risks of BTKIs having been or being developed.

[Chemical Composition of VOCs from Service Stations Vapor Processing Device and Associated Contributions to Secondary Pollution].

Vapor processing device is a device that can control the headspace pressure in the underground storage tanks and recover the vapor. By analyzing the chemical composition of volatile organic compounds (VOCs) at the inlet and outlet of the vapor processing device, the ozone formation potential (OFP) and secondary organic aerosol formation potential (SOAP) were estimated by maximum incremental reaction (MIR) and fractional aerosol coefficients (FAC), and the secondary pollution formation contribution of VOCs were quantitatively evaluated. The results showed that:① the ρ(total volatile organic compounds, TVOC) at the inlet and outlet of the vapor processing device were 436-706 g·m-3 and 4.98-10.04 g·m-3, respectively. Alkanes (72%±4%), oxygenated organics (14%±2%), and olefins (11%±5%) were the dominant components of VOCs emissions. There were little differences in VOCs emissions from the different vapor processing devices; the key species were i-pentane (approximately 25%), followed by n-butane, i-butane, and n-pentane. ② The ozone source reactivity (SR) of VOCs emissions from the outlet of the vapor processing device was 2.6-3.3 g·g-1, and the OFP was 3.5-25.6 g·m-3. Olefins contributed the most (43%-69%), followed by alkanes (20%-35%) and oxygenated organics (10%-22%). Butene, cis-2-butene, trans-2-butene, i-pentane, and propionaldehyde were the species that highly contributed to OFP. ③ Aromatics in VOCs emissions contributed the most to SOAP (80%-92%), and the main active species were toluene, 1, 2, 4-trimethylbenzene, 1, 3, 5-trimethylbenzene, and p-diethylbenzene. The research showed that different VOCs species emitted by the vapor processing device contributed obvious differences to the secondary atmospheric pollution, and butene species and aromatics such as toluene were the focus of VOCs emission control of vehicle gasoline and vapor processing device.

In-situ synthesized porphyrin polymer/TiO2 composites as high-performance Z-scheme photocatalysts for CO2 conversion.

The promising photocatalytic conversion of CO2 into valuable fuel promotes the development of photocatalyst through various methods. In this work, TiO2 nanoparticle was composited with covalent porphyrin polymers (COP-Ps) to fabricate composite photocatalysts. The resultant COP-Ps/TiO2 composites by in situ hydrothermal method exhibit much improved photocatalytic activity for the conversion of CO2 into CO relative to two components, and it is attributable to improved charge transfer between two moieties led by strong interaction. Especially, TiO2 is composited more evenly with the sulfonated hollow COP-P (sh-COP-P). The resultant composite sh-COP-P/TiO2 performs best with a CO production rate of 5.70 µmol·g-1·h-1, which is approximately 20.4 times as high as that of pure TiO2 and 2.3 times of sh-COP-P polymer. For comparison, the simple physical mixture of sh-COP-P and TiO2 (sm-sh-COP-P/TiO2) was fabricated, and it performs more badly due to poor mixing uniformity. A Z-scheme photocatalytic mechanism was proposed for sh-COP-P/TiO2 composite on the basis of energy band analysis and hydroxyl radical test. This study provides a new in situ strategy to fabricate organic polymer/metal oxide composites of high photocatalytic activity for CO2 reduction.

A rapid UPLC-MS/MS method for the determination of oleanolic acid in rat plasma and liver tissue: application to plasma and liver pharmacokinetics.

A reliable high-throughput ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for oleanolic acid (OA) determination in rat plasma and liver tissue using glycyrrhetic acid as the internal standard (IS). Plasma and liver homogenate samples were prepared using solid-phase extraction. Chromatographic separation was achieved on a C18 column using an isocratic mobile phase system. The detection was performed by multiple reaction monitoring mode via positive electrospray ionization interface. The calibration curves showed good linearity (R(2) > 0.9997) within the tested concentration ranges. The lower limit of quantification for plasma and liver tissue was ≤0.75 ng/mL. The intra- and inter-day precision and accuracy deviations were within ±15% in plasma and liver tissue. The mean extraction recoveries ranged from 80.8 to 87.0%. In addition, the carryover, matrix effect, stability and robustness involved in the method were also validated. The method was successfully applied to the plasma and hepatic pharmacokinetics of OA after oral administration to rats.

Interaction between HIV-1 Tat and DNA-PKcs modulates HIV transcription and class switch recombination.

HIV-1 tat targets a variety of host cell proteins to facilitate viral transcription and disrupts host cellular immunity by inducing lymphocyte apoptosis, but whether it influences humoral immunity remains unclear. Previously, our group demonstrated that tat depresses expression of DNA-PKcs, a critical component of the non-homologous end joining pathway (NHEJ) of DNA double-strand breaks repair, immunoglobulin class switch recombination (CSR) and V(D)J recombination, and sensitizes cells to ionizing radiation. In this study, we demonstrated that HIV-1 Tat down-regulates DNA-PKcs expression by directly binding to the core promoter sequence. In addition, Tat interacts with and activates the kinase activity of DNA-PKcs in a dose-dependent and DNA independent manner. Furthermore, Tat inhibits class switch recombination (CSR) at low concentrations (≤ 4 µg/ml) and stimulates CSR at high concentrations (≥ 8 µg/ml). On the other hand, low protein level and high kinase activity of DNA-PKcs promotes HIV-1 transcription, while high protein level and low kinase activity inhibit HIV-1 transcription. Co-immunoprecipitation results revealed that DNA-PKcs forms a large complex comprised of Cyclin T1, CDK9 and Tat via direct interacting with CDK9 and Tat but not Cyclin T1. Taken together, our results provide new clues that Tat regulates host humoral immunity via both transcriptional depression and kinase activation of DNA-PKcs. We also raise the possibility that inhibitors and interventions directed towards DNA-PKcs may inhibit HIV-1 transcription in AIDS patients.

Bio-inspired nacre-like composite films based on graphene with superior mechanical, electrical, and biocompatible properties.

Bio-inspired multifunctional composite films based on reduced poly(vinyl alcohol)/graphene oxide (R-PVA/GO) layers are prepared by a facile solution casting method followed by a reduction procedure. The resulting films with nacre-like, bricks-and-mortar microstructure have excellent mechanical properties, electrical conductivity, and biocompatibility.

HIV-1 Tat impairs cell cycle control by targeting the Tip60, Plk1 and cyclin B1 ternary complex.

HIV-1 Tat triggers intrinsic and extrinsic apoptosis pathways in both infected and uninfected cells and plays an important role in the pathogenesis of AIDS. Knocking down Tip60, an interactive protein of Tat, leads to the impairment of cell cycle progression, indicating a key role of Tip60 in cell cycle control. We found that Tip60 interacts with Plk1 through its ZnFMYST domain, and that this interaction is enhanced in the G 2/M phase. In addition, cyclin B1 was confirmed to interact with the ZnF domain of Tip60. Immunofluorescence imaging showed that Tip60 co-localizes with both Plk1 and cyclin B1 at the centrosome during the mitotic phase and to the mid-body during cytokinesis. Further experiments revealed that Tip60 forms a ternary complex with Plk1 and cyclin B1 and acetylates Plk1 but not cyclin B1. HIV-1 Tat likely forms a quaternary complex with Tip60, cyclin B1 and Plk1. Fluorescent microscopy showed that Tat causes an unscheduled nuclear translocation of both cyclin B1 and Plk1, causing their co-localization with Tip60 in the nucleus. Tat, Tip60, cyclin B1 and Plk1 interactions provide new a mechanistic explanation for Tat-mediated cell cycle dysregulation and apoptosis.