LC-MS/MS methods for simultaneous determination of youkenafil and its metabolite M1 in human seminal plasma and plasma: Application to evaluate the acute effect of youkenafil on semen quality and its pharmacokinetics in human.

Youkenafil is a novel Phosphodiesterase type 5 inhibitor used for treating erectile dysfunction. N-desethyl compound of youkenafil (M1) is its main active metabolite. In this study, two methods were developed and validated for the simultaneous determination of youkenafil and M1 by HPLC-MS/MS in human matrices including seminal plasma and plasma, in which the multiple reaction monitoring and electrospray ionization in positive mode were adopted, and the deuterated youkenafil (youkenafil-d5) was selected as the internal standard. The collected semen sample was kept at room temperature for approximately 30 min until fully liquefied. The volume of the liquefied semen was measured and then divided into two parts. One part was centrifuged to obtain the seminal plasma for the content detection of youkenafil and M1, while the other part was used for routine semen analysis. The chromatographic separation was accomplished with the column of Poroshell 120 EC-C18 (5 × 2.1 mm, 2.7 µm, Agilent). Protein precipitation with methanol was used for the pretreatment of seminal plasma and plasma. The intra-run and inter-run precisions were less than 6.4 % (relative standard deviation) and accuracies were all within -4.7 %-6.8 % (relative error) in both matrices. All other validated bioanalytical parameters were within the acceptance criteria set by the FDA. The methods were successfully applied to different clinical studies of youkenafil. In the clinical study of the acute effect of youkenafil on semen quality in healthy males, the content of youkenafil in seminal plasma was extremely low. Concentrations of youkenafil and M1 in seminal plasma were lower than those in plasma, at 20.7 % and 4.49 % of the plasma concentration, respectively. There was no significant acute effect of youkenafil on semen quality. In the pharmacokinetic study of youkenafil after single dose-escalation administration, the exposure to youkenafil and M1 was non-linear with the dose in the range of 100-400 mg.

An Encapsulation-Free and Hierarchical Porous Triboelectric Scaffold with Dynamic Hydrophilicity for Efficient Cartilage Regeneration.

Tissue engineering and electrotherapy are two promising methods to promote tissue repair. However, their integration remains an underexplored area, because their requirements on devices are usually distinct. Triboelectric nanogenerators (TENGs) have shown great potential to develop self-powered devices. However, due to their susceptibility to moisture, TENGs have to be encapsulated in vivo. Therefore, existing TENGs cannot be employed as tissue engineering scaffolds, which require direct interaction with surrounding cells. Here, the concept of triboelectric scaffolds (TESs) is proposed. Poly(glycerol sebacate), a biodegradable and relatively hydrophobic elastomer, is selected as the matrix of TESs. Each hydrophobic micropore in multi-hierarchical porous TESs efficiently serves as a moisture-resistant working unit of TENGs. Integration of tons of micropores ensures the electrotherapy ability of TESs in vivo without encapsulation. Originally hydrophobic TESs are degraded by surface erosion and transformed into hydrophilic surfaces, facilitating their role as tissue engineering scaffolds. Notably, TESs seeded with chondrocytes obtain dense and large matured cartilages after subcutaneous implantation in nude mice. Importantly, rabbits with osteochondral defects receiving TES implantation show favorable hyaline cartilage regeneration and complete cartilage healing. This work provides a promising electronic biomedical device and will inspire a series of new in vivo applications.

High Performance and Reprocessable In Situ Generated Nanofiber Reinforced Composites Based on Liquid Crystal Polyarylate.

Polymers are playing important roles in the rapid development of triboelectric nanogenerators (TENGs); However, most polymers cannot meet the high requirements of thermomechanical performance; Thus, various polymeric composites are developed for triboelectric layer. These composites are hardly recycled since their reinforcements are unevenly distributed after reprocessing, which limits the sustainable development of TENGs. To solve the above challenges, in situ generated nanofiber reinforced composites (NFRCs) based on single-component liquid crystal polyarylate (LCP) are designed and prepared via a one-step polycondensation. Nonlinear naphthalene (NDA) widens the processing window of LCP without destabilizing the liquid crystal phase. The NDA-rich domains act as a matrix while the NDA-poor domains with higher rigidity form oriented nanofibers to achieve self-reinforcement. The resultant NFRCs possess high glass transition temperature (Tg > 220 °C) and storage modulus (E' = 0.1 GPa at 350 °C), which are far beyond existing triboelectric polymers, typically Tg < 110 °C and E' < 0.1 MPa (flowable) at 350 °C. Furthermore, NFRC-based TENG exhibits superior electrical output performance and retention rate (>90%) after reprocessing; Overall, this work offers a new design principle to prepare self-reinforced composites, which paves a way to explore high performance materials.

The metabolite profiling of YR-1702 injection in human plasma, urine and feces by HPLC-Q-TOF-MS/MS.

YR-1702, a hybrid µ/κ/δ receptor agonist, is modified from the traditional opioid analgesic dezocine. It had shown both excellent analgesic effect and lower addiction in phase I clinical trial in China, however, the metabolic pathway of YR-1702 in humans remains unelucidated.The goals of this study are to characterise the metabolism of YR-1702 in human liver microsomes (HLMs) and patients with chronic non-cancer pain by high performance liquid chromatography-coupled with quadrupole-time-of-flight mass spectrometry (HPLC-Q-TOF-MS/MS).The results showed that a total of twelve metabolites were identified in HLMs, in which 7, 6 and 5 metabolites were also found in human plasma, urine and feces, respectively. And the major metabolic pathways include mono-hydroxylation, di-hydroxylation, dehydrogenation and glucuronidation. The locations of hydroxylation and dehydrogenation were identified by the signature fragments of the metabolites.The relative contents of the metabolites in human plasma were also evaluated, in which the main metabolite M1 notably accounting for more than 14% of the total drug exposure. This study would contribute to the understanding of the in vivo metabolite profile of YR-1702 injection for future use.

Pure-Phase, Large-Grained Wide-Band-Gap Perovskite Films for High-Efficiency, Four-Terminal Perovskite/Silicon Tandem Solar Cells.

High-quality, stable perovskite films with a wide band gap between 1.65 and 1.80 eV are highly suitable for efficient and cost-competitive silicon-based tandem solar cells. Herein, we demonstrate that the combined strategies of the Pb(SCN)2 additive and air annealing can enable the Cs0.22FA0.78Pb(I0.85Br0.15)3 films with a wide band gap of 1.65 eV and favored properties including pure composition, high crystallinity, micro-sized grains, and reduced defects. With these desired films, the average efficiencies of semitransparent perovskite solar cells (PSCs) are boosted from (18.13 ± 0.31) to (20.35 ± 0.28)%. Further, the semitransparent PSC is used to assemble the four-terminal perovskite/TOPCon tandem solar cell. Benefiting from its excellent performance and preferred optical properties, the obtained tandem solar cell yields a milestone efficiency of 30.32%.

Clinical efficacy of PD-1 inhibitor combined with radiotherapy in a multi-drug resistant patient with liver metastasis from gastric cancer.

A 54-year-old male was diagnosed with extensive liver metastasis and small nodule metastasis in the lungs from gastric adenocarcinoma [Her-2 (-)]. The patient achieved significant partial response (PR) after chemotherapy combined with anti-angiogenesis therapy but developed progressive disease (PD) after 5 months. Then, the chemotherapeutic and anti-angiogenic drugs were replaced. Meanwhile, the delivery route of some chemotherapeutic drugs was changed, and some chemotherapeutic drugs were given via transcatheter arterial chemoembolization (TACE) to achieve PR, and PD developed after 3 months of remission maintenance. During chemotherapy combined with anti-angiogenesis, the application of programmed cell death-1 (PD-1) inhibitor achieved PR again and maintained for 5 months before disease progression. The progression of the lesions in the left lobe of the liver and the hepatic hilar lymph nodes was significant. Hence, chemotherapy was terminated and gamma stereotactic body radiation therapy (SBRT) was performed on left lobe lesions and hilar lymph nodes. The lesions both inside and outside the radiation field regressed significantly, reaching PR and abscopal effects. The immune-related adverse events (irAEs) occurred, including erythema and black and luster hair. The abscopal effects of lesion reduction in the radiation field and the enhancement of the immune function stimulated by radiation are a highlight of the combination of radiation and immunotherapy. In the end, the patient died of gastrointestinal failure, with overall survival of 18 months.

Pharmacokinetics, metabolite profiling, safety and tolerability of YZJ-4729 tartrate, a novel G protein-biased µ-opioid receptor agonist, in healthy Chinese subjects.

Objective: YZJ-4729 is a novel G protein-biased µ-opioid receptor agonist for the treatment of acute pain in adult patients who require intravenous opioid analgesic therapy. The aim of this study was to assess the pharmacokinetics, metabolite profiling, safety and tolerability of YZJ-4729 in healthy Chinese subjects following the single intravenous doses ranged from 0.2 mg to 6 mg. Methods: This single-center, randomized, double-blind, placebo-controlled clinical study was conducted in 54 healthy male and female Chinese subjects after single ascending doses of YZJ-4729 tartrate (0.2, 0.5, 1.5, 3, 4.5, and 6 mg). Subjects in each cohort were assigned randomly to receive a single intravenous dose of YZJ-4729 tartrate injection or placebo at a ratio of 4:1. Pharmacokinetic characteristics, metabolite profiling, safety and tolerability profiles of the study drug were evaluated. Results: Overall, YZJ-4729 was safe and well tolerated in healthy Chinese subjects. The study drug reached peak plasma concentrations nearly at the end of the infusion. After administration, YZJ-4729 was eliminated rapidly with a terminal elimination half-life of 0.862-2.50 h, and excreted little in human excreta. The maximum drug concentration and area under the plasma concentration-time curve increased with dose escalation across the entire dose range. YZJ-4729 experienced extensive metabolism in human body. A total of 19 metabolites were identified and the characteristic metabolic pathways involved hydroxylation, ketone formation, N-dealkylation and glucuronide conjugation. Metabolite M10 was the most abundant circulating metabolite, and represented over 10% of total drug-related systemic exposure. Further PK and safety evaluation of M10 was necessary. Conclusion: The clinical study results laid a foundation for the further clinical studies of YZJ-4729 in patients. Clinical Trial Registration: http://www.chinadrugtrials.org.cn, identifier CTR20222574.

Effect Evaluation of Bronchial Artery Embolization for Hemoptysis of Lung Cancer and Changes in Serum Tumor Markers and miR-34 Levels.

The clinical efficacy, serum tumor markers, and miR-34 expression levels of bronchial artery embolization (BAE) in patients with lung cancer with hemoptysis are investigated. 92 patients with lung cancer hemoptysis treated in our hospital from January 2019 to December 2021 are randomly selected, and 92 patients are randomly divided into the conservative group and the BAE group according to the number table method, with 46 patients in each group. The efficacy, overall survival (OS) rate, coagulation function, hemoptysis volume, serum tumor markers, and miR-34 expression are compared among all groups at different time points. The experimental results show that the BAE treatment can promote the expression of miR-34 and inhibit the expression of tumor markers, so it can improve the efficacy of patients with lung cancer hemoptysis, improve the symptoms of hemoptysis and coagulation function, and prolong the life cycle of patients.

Biodegradable Elastomers and Gels for Elastic Electronics.

Biodegradable electronics are considered as an important bio-friendly solution for electronic waste (e-waste) management, sustainable development, and emerging implantable devices. Elastic electronics with higher imitative mechanical characteristics of human tissues, have become crucial for human-related applications. The convergence of biodegradability and elasticity has emerged a new paradigm of next-generation electronics especially for wearable and implantable electronics. The corresponding biodegradable elastic materials are recognized as a key to drive this field toward the practical applications. The review first clarifies the relevant concepts including biodegradable and elastic electronics along with their general design principles. Subsequently, the crucial mechanisms of the degradation in polymeric materials are discussed in depth. The diverse types of biodegradable elastomers and gels for electronics are then summarized. Their molecular design, modification, processing, and device fabrication especially the structure-properties relationship as well as recent advanced are reviewed in detail. Finally, the current challenges and the future directions are proposed. The critical insights of biodegradability and elastic characteristics in the elastomers and gel allows them to be tailored and designed more effectively for electronic applications.

Self-Healing and Elastic Triboelectric Nanogenerators for Muscle Motion Monitoring and Photothermal Treatment.

Owing to wearing and unpredictable damage, the working lifetime of triboelectric nanogenerators (TENGs) is largely limited. In this work, we prepared a single-electrode multifunctional TENG (MF-TENG) that exhibits fast self-healing, human health monitoring capability, and photothermal properties. The device consists of a thin self-healing poly(vinyl alcohol)-based hydrogel sandwiched between two self-healing silicone elastomer films. The MF-TENG exhibits a short-circuit current, short-circuit transfer charge, and open-circuit voltage of 7.98 µA, 78.34 nC, and 38.57 V, respectively. Furthermore, owing to the repairable networks of the dynamic imine bonds in the charged layer and the borate ester bonds in the electrodes, the prepared device could recover its original state after mechanical damage within 10 min at room temperature. The MF-TENG can be attached to different human joints for self-powered monitoring of personal health information. Additionally, the MF-TENG under near-infrared laser irradiation can provide a photothermal therapy for assisting the recovery of human joints motion. It is envisaged that the proposed MF-TENG can be applied to the fields of wearable electronics and health-monitoring devices.

Thermally Conductive Elastomer Composites with Poly(catechol-polyamine)-Modified Boron Nitride.

Effective heat dissipation has become a major concern with the rapid development of microelectronic devices. In general, thermally conductive fillers are incorporated into the polymeric matrix to increase the thermal conductivity of polymer composites. Herein, poly(catechol-polyamine) (PCPA) is employed to modify boron nitride (BN) platelets, referred to as BN-PCPA, and improves the interfacial compatibility between a thermally conductive filler and elastomer matrix, resulting in carboxylated acrylonitrile-butadiene rubber (XNBR) composites filled with BN-PCPA platelets with enhanced thermal conductivity. The influence of PCPA thickness on the mechanical properties, thermal conductivity, and dielectric properties of BN-PCPA/XNBR composites is systematically studied. Briefly, the interfacial compatibility between the BN-PCPA filler and XNBR matrix increases with increasing PCPA thickness, leading to enhanced thermal conductivity. The maximum thermal conductivity of 0.399 W/(m·K) has been rendered by the BN-PCPA-12h/XNBR composite, which is about 2.5 times of pure XNBR. This work provides an easy route to develop polymer composites with a relatively high thermal conductivity and high dielectric constant for potential application in practical electronic packaging.

Improved Mechanical and Electrochemical Properties of XNBR Dielectric Elastomer Actuator by Poly(dopamine) Functionalized Graphene Nano-Sheets.

In this work, graphene nano-sheets (GNS) functionalized with poly(dopamine) (PDA) (denoted as GNS-PDA) were dispersed in a carboxylated nitrile butadiene rubber (XNBR) matrix to obtain excellent dielectric composites via latex mixing. Because hydrogen bonds were formed between ⁻COOH groups of XNBR and phenolic hydroxyl groups of PDA, the encapsulation of GNS-PDA around XNBR latex particles was achieved, and led to a segregated network structure of filler formed in the GNS-PDA/XNBR composite. Thus, the XNBR composite filled with GNS-PDA showed improved filler dispersion, enhanced dielectric constant and dielectric strength, and decreased conductivity compared with the XNBR composite filled with pristine GNS. Finally, the GNS-PDA/XNBR composite displayed an actuated strain of 2.4% at 18 kV/mm, and this actuated strain was much larger than that of pure XNBR (1.3%) at the same electric field. This simple, environmentally friendly, low-cost, and effective method provides a promising route for obtaining a high-performance dielectric elastomer with improved mechanical and electrochemical properties.

Enhancement of Dielectric Performance of Polymer Composites via Constructing BaTiO3-Poly(dopamine)-Ag Nanoparticles through Mussel-Inspired Surface Functionalization.

We demonstrate the synthesis of a novel core-satellite-structured BaTiO3-poly(dopamine)-silver (BT-PDA-Ag) nanoparticle for improving dielectric properties of nitrile-butadiene rubber (NBR) nanocomposites. The BT-PDA-Ag nanoparticles are synthesized by dopamine oxidative polymerization and electroless plating of silver. The Ag nanoparticles decorated on the BT nanoparticles enhanced the dielectric constant of NBR nanocomposites due to the increased conductivity of the filler/matrix interlayer and nanocapacitor structure. In addition, the incorporation of the BT nanoparticles prevented the continuous connection of Ag nanoparticles and suppressed the formation of a conductive path in the NBR matrix. Moreover, the ultrasmall Ag nanoparticles trapped the carriers by Coulomb blockade and quantum confinement effects, which results in low dielectric loss and electrical conductivity of nanocomposites. The proposed method with simplicity and scalability can be adapted to process high-dielectric polymer nanocomposites.

MiR-199a suppresses the hypoxia-induced proliferation of non-small cell lung cancer cells through targeting HIF1α.

Deregulated microRNAs (miRNAs) are small noncoding RNAs that are involved in the carcinogenesis of various cancers, including lung cancer. HIF1a has been suggested to be a master regulator of hypoxia-induced cell proliferation. The relationship between HIF1a expression and the progression of non-small cell lung cancer (NSCLC) is not fully understood, and whether HIF1a expression is regulated by miRNAs in this process remains unclear. In this study, we found that the upregulation of HIF1a expression and the reduction in miR-199a levels were highly associated with NSCLC progression. NSCLC cells derived from cancer tissues with low miR-199a levels showed high HIF1a expression and high proliferation capacity. Moreover, HIF1a and glycolysis inhibitors suppress the proliferation of NSCLC cells. MiR-199a overexpression suppressed the hypoxia-induced proliferation of NSCLC cells through targeting elevated HIF1a and blocking the downstream upregulation of PDK1 without affecting AKT activation. Together, these results indicate that downregulation of miR-199a is essential for hypoxia-induced proliferation through derepressing the expression of HIF1a expression and affecting HIF1a mediated glycolytic pathway in NSCLC progression.

Comprehensive assessment of the association between DNA repair gene XRCC3 rs861539 C/T polymorphism and lung cancer risk.

A few case-control studies were performed to assess the association between X-ray repair cross-complementing group 3 (XRCC3) rs861539 C/T polymorphism and lung cancer susceptibility, but no consistent finding was reported. In the present study, we performed a meta-analysis of 14 case-control studies with a total of 7,869 lung cancer cases and 10,778 controls to provide a comprehensive assessment of the association between XRCC3 rs861539 C/T polymorphism and lung cancer risk. Pooled odds ratios (ORs) and corresponding 95 % confidence intervals (95 % CIs) were calculated to assess the strength of the association. Overall, there was no significant association between XRCC3 rs861539 C/T polymorphism and lung cancer risk under all genetic models [OR (95 % CI) for T versus C, 1.00 (0.89-1.13), P = 0.99; OR (95 % CI) for TT versus CC, 1.07 (0.81-1.41), P = 0.62; OR (95 % CI) for TT/CT versus CC, 0.95 (0.84-1.07), P = 0.39; OR (95 % CI) for TT versus CT/CC, 1.10 (0.86-1.39), P = 0.62]. In the subgroup analyses of both Asians and Caucasians, there was still no significant association between XRCC3 rs861539 C/T polymorphism and lung cancer risk under all genetic models (All P values were more than 0.05). However, there was an obvious association between XRCC3 rs861539 C/T polymorphism and decreased risk of lung cancer in the subgroup analysis of the mixed population (All P values were less than 0.05). In addition, there was some risk of publication bias in the meta-analysis, and there was obvious discrepancy in the findings between studies with large sample size and studies with small sample size in the meta-analysis. The meta-analysis indicates that the association between XRCC3 rs861539 C/T polymorphism and lung cancer risk is still uncertain owing to the obvious discrepancy in the findings between studies with large sample size and studies with small sample size. More studies with large sample size are needed to further assess the association.