Pretreatment and analysis techniques development of TKIs in biological samples for pharmacokinetic studies and therapeutic drug monitoring.

Tyrosine kinase inhibitors (TKIs) have emerged as the first-line small molecule drugs in many cancer therapies, exerting their effects by impeding aberrant cell growth and proliferation through the modulation of tyrosine kinase-mediated signaling pathways. However, there exists a substantial inter-individual variability in the concentrations of certain TKIs and their metabolites, which may render patients with compromised immune function susceptible to diverse infections despite receiving theoretically efficacious anticancer treatments, alongside other potential side effects or adverse reactions. Therefore, an urgent need exists for an up-to-date review concerning the biological matrices relevant to bioanalysis and the sampling methods, clinical pharmacokinetics, and therapeutic drug monitoring of different TKIs. This paper provides a comprehensive overview of the advancements in pretreatment methods, such as protein precipitation (PPT), liquid-liquid extraction (LLE), solid-phase extraction (SPE), micro-SPE (µ-SPE), magnetic SPE (MSPE), and vortex-assisted dispersive SPE (VA-DSPE) achieved since 2017. It also highlights the latest analysis techniques such as newly developed high performance liquid chromatography (HPLC) and high-resolution mass spectrometry (HRMS) methods, capillary electrophoresis (CE), gas chromatography (GC), supercritical fluid chromatography (SFC) procedures, surface plasmon resonance (SPR) assays as well as novel nanoprobes-based biosensing techniques. In addition, a comparison is made between the advantages and disadvantages of different approaches while presenting critical challenges and prospects in pharmacokinetic studies and therapeutic drug monitoring.

Synergistically optimized electron and phonon transport in high-performance copper sulfides thermoelectric materials via one-pot modulation.

Optimizing thermoelectric conversion efficiency requires the compromise of electrical and thermal properties of materials, which are hard to simultaneously improve due to the strong coupling of carrier and phonon transport. Herein, a one-pot approach realizing simultaneous second phase and Cu vacancies modulation is proposed, which is effective in synergistically optimizing thermoelectric performance in copper sulfides. Multiple lattice defects, including nanoprecipitates, dislocations, and nanopores are produced by adding a refined ratio of Sn and Se. Phonon transport is significantly suppressed by multiple mechanisms. An ultralow lattice thermal conductivity is therefore obtained. Furthermore, extra Se is added in the copper sulfide for optimizing electrical transport properties by inducing generating Cu vacancies. Ultimately, an excellent figure of merit of ~1.6 at 873 K is realized in the Cu1.992SSe0.016(Cu2SnSe4)0.004 bulk sample. The simple strategy of inducing compositional and structural modulation for improving thermoelectric parameters promotes low-cost high-performance copper sulfides as alternatives in thermoelectric applications.

A meta-analysis of the efficacy and safety of the traditional Chinese medicine formula Kaixinsan decoction for depression.

BACKGROUND: Kaixinsan (KXS) decoction is a traditional Chinese herbal formulation commonly used to treat depression. This study aimed to evaluate the efficacy and safety of KXS, which is widely used, alone and in combination with other therapies, for the treatment of depression. The main objective was to assess the efficacy and safety of KXS in the treatment of depression as a single agent or in combination with other methods. METHODS: Randomized controlled trials of KXS in the treatment of depression were systematically searched from several Chinese and English databases with no language restriction. Patients in these studies met the relevant diagnostic criteria for depression. Data on HAMD, SDS, practical situations, and occurrence of side effects in the studies were extracted. Finally, the methodological quality and risk of bias of the included studies were assessed using the Jadad scale and Cochrane bias evaluation tool. RESULTS: Twelve studies with 1034 patients were included after screening. The Jadad scale and Cochrane bias evaluation tool indicated that the quality of the studies ranged from fair to good, with 41.7% categorized as good and 58.3% as poor. Egger test and funnel plots showed that the publication bias remain low. CONCLUSION: The results showed that the frequency of side effects in the control group was higher than that in the treatment group, and there was a statistically significant difference. KXS was comparable or superior to antidepressants in treating depression and has fewer side effects. The data analysis showed that effectiveness and other indicators differed significantly by geographic area and dosage form, which has implications for future clinical work.

Pseudopolymorphic Phase Engineering for Improved Thermoelectric Performance in Copper Sulfides.

Polymorphism (and its extended form - pseudopolymorphism) in solids is ubiquitous in mineralogy, crystallography, chemistry/biochemistry, materials science, and the pharmaceutical industries. Despite the difficulty of controlling (pseudo-)polymorphism, the realization of specific (pseudo-)polymorphic phases and associated boundary structures is an efficient route to enhance material performance for energy conversion and electromechanical applications. Here, this work applies the pseudopolymorphic phase (PP) concept to a thermoelectric copper sulfide, Cu2- x S (x ≤ 0.25), via CuBr2 doping. A peak ZT value of 1.25 is obtained at 773 K in Cu1.8 S + 3 wt% CuBr2 , which is 2.3 times higher than that of a pristine Cu1.8 S sample. Atomic-resolution scanning transmission electron microscopy confirms the transformation of pristine Cu1.8 S low digenite into PP-engineered high digenite, as well as the formation of (semi-)coherent interfaces between different PPs, which is expected to enhance phonon scattering. The results demonstrate that PP engineering is an effective approach for achieving improved thermoelectric performance in Cu-S compounds. It is also expected to be useful in other materials.

Non-steroidal anti-inflammatory drugs (NSAIDs) in the environment: Recent updates on the occurrence, fate, hazards and removal technologies.

Non-steroidal Anti-inflammatory Drugs (NSAIDs) are extensively utilized pharmaceuticals worldwide. However, owing to the improper discharge and disposal practices, they have emerged as significant contaminants that are widely distributed in water, soils, and sewage sediments. This ubiquity poses a substantial threat to the ecosystem and human health. Consequently, it is imperative to develop rapid, cost-effective, efficient and reliable approaches for containing these substance in order to mitigate the deleterious impact of NSAIDs. This research provides a comprehensive review of the occurrence, fate, and hazards associated with NSAIDs in the general environment. Additionally, various removal technologies, including advanced oxidation processes, biodegradation, and adsorption, were systematically summarized. The study also presents a comparative analysis of the benefits and drawbacks of different removal technologies while interpreting challenges related to NSAIDs' removal and proposing strategies for future development.

Enrichment of biofertilizer-type hydrogen-oxidizing bacteria on urea containing Cu(II).

With the utilization of pesticides and fertilizers (e.g. urea), the presence of nitrogen and heavy metals (e.g. copper) can enter and pollute the environment. Biofertilizers can be used to replace chemical fertilizers to increase crop yields and reduce environmental stress. The utilization of hydrogen-oxidizing bacteria (HOB) to be biofertilizers has recently attracted more attention. However, the enrichment of HOB on urea and the effect of copper are undetermined. HOB were successfully enriched using urea in this investigation. The average urea conversion rate (AUCR) was 180.08 mgN/L/d with a hydraulic retention time of 10 h. Microbial community (R1) was dominated by Hydrogenophaga (83.92%), a biofertilizer-type HOB. After addition of 5.47 mg/L Cu2+, the AUCR was decreased by 16%-151.18 mgN/L/d, and the growth of HOB was inhibited by 48%. Meanwhile, inhibition was also reflected by the increase of polysaccharide content (20.27 ± 0.57 to 33.45 ± 2.53 mg/gVSS) and protein content (106.19 ± 19.39 to 125.14 ± 24.73 mg/gVSS) of extracellular polymeric substances in the HOB. The resulting microbial community (R2) was changed to Azospiralium-dominated flora (91.33%). Both enriched microbial communities (R1 and R2) exhibited the abilities of ACC degradation and phosphate solubilization. This study demonstrates that employing urea can directly enrich biofertilizer-type HOB and copper-tolerant HOB can be obtained in a 5.47 mg/L Cu2+ environment. The results provide potential methods to obtain biofertilizer from copper-containing urea wastewater via HOB.

High-density lipoprotein regulates angiogenesis by long non-coding RNA HDRACA.

Normal high-density lipoprotein (nHDL) can induce angiogenesis in healthy individuals. However, HDL from patients with coronary artery disease undergoes various modifications, becomes dysfunctional (dHDL), and loses its ability to promote angiogenesis. Here, we identified a long non-coding RNA, HDRACA, that is involved in the regulation of angiogenesis by HDL. In this study, we showed that nHDL downregulates the expression of HDRACA in endothelial cells by activating WW domain-containing E3 ubiquitin protein ligase 2, which catalyzes the ubiquitination and subsequent degradation of its transcription factor, Kruppel-like factor 5, via sphingosine 1-phosphate (S1P) receptor 1. In contrast, dHDL with lower levels of S1P than nHDL were much less effective in decreasing the expression of HDRACA. HDRACA was able to bind to Ras-interacting protein 1 (RAIN) to hinder the interaction between RAIN and vigilin, which led to an increase in the binding between the vigilin protein and proliferating cell nuclear antigen (PCNA) mRNA, resulting in a decrease in the expression of PCNA and inhibition of angiogenesis. The expression of human HDRACA in a hindlimb ischemia mouse model inhibited the recovery of angiogenesis. Taken together, these findings suggest that HDRACA is involved in the HDL regulation of angiogenesis, which nHDL inhibits the expression of HDRACA to induce angiogenesis, and that dHDL is much less effective in inhibiting HDRACA expression, which provides an explanation for the decreased ability of dHDL to stimulate angiogenesis.

Benzodiazepines in complex biological matrices: Recent updates on pretreatment and detection methods.

Benzodiazepines (BDZs) are used in clinics for anxiolysis, anticonvulsants, sedative hypnosis, and muscle relaxation. They have high consumptions worldwide because of their easy availability and potential addiction. They are often used for suicide or criminal practices such as abduction and drug-facilitated sexual assault. The pharmacological effects of using small doses of BDZs and their detections from complex biological matrices are challenging. Efficient pretreatment methods followed by accurate and sensitive detections are necessary. Herein, pretreatment methods for the extraction, enrichment, and preconcentration of BDZs as well as the strategies for their screening, identification, and quantitation developed in the past five years have been reviewed. Moreover, recent advances in various methods are summarized. Characteristics and advantages of each method are encompassed. Future directions of the pretreatment and detection methods for BDZs are also reviewed.

Diuretics in Different Samples: Update on the Pretreatment and Analysis Techniques.

Diuretics are drugs that promote the excretion of water and electrolytes in the body and produce diuretic effects. Clinically, they are often used in the treatment of edema caused by various reasons and hypertension. In sports, diuretics are banned by the World Anti-Doping Agency (WADA). Therefore, in order to monitor blood drug concentration, identify drug quality and maintain the fairness of sports competition, accurate, rapid, highly selective and sensitive detection methods are essential. This review provides a comprehensive summary of the pretreatment and detection of diuretics in various samples since 2015. Commonly used techniques to extract diuretics include liquid-liquid extraction, liquid-phase microextraction, solid-phase extraction, solid-phase microextraction, among others. Determination methods include methods based on liquid chromatography, fluorescent spectroscopy, electrochemical sensor method, capillary electrophoresis and so on. The advantages and disadvantages of various pretreatment and analytical techniques are elaborated. In addition, future development prospects of these techniques are discussed.

HIGHLIGHTSPretreatment and determination methods of diuretics in diverse samples are reviewed.Applications of novel materials and technologies for SPE and sensors are highlighted.Pros and cons of recent pretreatment and analysis techniques used for diuretics are discussed.Applications of high-resolution mass spectrometry are described in detail.

Advances in Photoelectric Therapy for the Early Intervention and Treatment of Traumatic Scars.

Traumatic scar is a disease that affected approximately tens of millions of patients worldwide. According to the histological and morphological properties of scars, the traumatic scar typically includes superficial scar, atrophic scar, hypertrophic scar, and keloid. Its formation is a natural consequence of wound healing, regardless of whether the wound was caused by trauma or surgery. However, the production of scars has considerable impacts on the physical and mental health of patients, even causing substantial aesthetic and functional impairments. Prevention or early treatment of scars is the most suitable therapeutic method, including surgical and non-surgical procedures; nevertheless, the benefits of non-operative therapies for scars are quite limited, and surgical treatments are always hard to achieve satisfying outcomes. Through the application of innovative technologies such as lasers, intense pulsed light, and radiofrequency, significant progress has been made in the treatment of traumatic scars. This review highlights the current advancements of photoelectric therapy for the prevention and treatment of various traumatic scars, which may throw light on innovative therapeutic options for scar therapies.

Breaking the Minimum Limit of Thermal Conductivity of Mg3 Sb2 Thermoelectric Mediated by Chemical Alloying Induced Lattice Instability.

Thermal properties strongly affect the applications of functional materials, such as thermal management, thermal barrier coatings, and thermoelectrics. Thermoelectric (TE) materials must have a low lattice thermal conductivity to maintain a temperature gradient to generate the voltage. Traditional strategies for minimizing the lattice thermal conductivity mainly rely on introduced multiscale defects to suppress the propagation of phonons. Here, the origin of the anomalously low lattice thermal conductivity is uncovered in Cd-alloyed Mg3 Sb2 Zintl compounds through complementary bonding analysis. First, the weakened chemical bonds and the lattice instability induced by the antibonding states of 5p-4d levels between Sb and Cd triggered giant anharmonicity and consequently increased the phonon scattering. Moreover, the bond heterogeneity also augmented Umklapp phonon scatterings. Second, the weakened bonds and heavy element alloying softened the phonon mode and significantly decreased the group velocity. Thus, an ultralow lattice thermal conductivity of ≈0.33 W m-1 K-1 at 773 K is obtained, which is even lower than the predicated minimum value. Eventually, Na0.01 Mg1.7 Cd1.25 Sb2 displays a high ZT of ≈0.76 at 773 K, competitive with most of the reported values. Based on the complementary bonding analysis, the work provides new means to control thermal transport properties through balancing the lattice stability and instability.

Identification and degradation of structural extracellular polymeric substances in waste activated sludge via a polygalacturonate-degrading consortium.

By maintaining the cell integrity of waste activated sludge (WAS), structural extracellular polymeric substances (St-EPS) resist WAS anaerobic fermentation. This study investigates the occurrence of polygalacturonate in WAS St-EPS by combining chemical and metagenomic analyses that identify ∼22% of the bacteria, including Ferruginibacter and Zoogloea, that are associated with polygalacturonate production using the key enzyme EC 5.1.3.6. A highly active polygalacturonate-degrading consortium (GDC) was enriched and the potential of this GDC for degrading St-EPS and promoting methane production from WAS was investigated. The percentage of St-EPS degradation increased from 47.6% to 85.2% after inoculation with the GDC. Methane production was also increased by up to 2.3 times over a control group, with WAS destruction increasing from 11.5% to 28.4%. Zeta potential and rheological behavior confirmed the positive effect which GDC has on WAS fermentation. The major genus in the GDC was identified as Clostridium (17.1%). Extracellular pectate lyases (EC 4.2.2.2 and 4.2.2.9), excluding polygalacturonase (EC 3.2.1.15), were observed in the metagenome of the GDC and most likely play a core role in St-EPS hydrolysis. Dosing with GDC provides a good biological method for St-EPS degradation and thereby enhances the conversion of WAS to methane.

Cloning and rational modification of a cold-adapted esterase for phthalate esters and parabens degradation.

Phthalate esters (PAEs) and parabens are environmental pollutants that can be toxic to human health. Herein, a cold-adapted esterase from the Mao-tofu metagenome named Est1260 was screened for its PAE-hydrolyzing potential in cold temperatures. The results showed that purified Est1260 could degrade a variety of PAEs and parabens at temperatures as low as 0 °C. After careful analysis of the structural information and molecular docking, site-saturation mutation was conducted at the identified hotspots. Protein expression of variant A1B6 doubled, and its thermal stability significantly improved (24 times) without sacrificing activity at low temperatures. In addition, Est1260 and its variants were activated by NaCl and demonstrated resistance to high concentrations of saline (up to 5 M), making it a potential biocatalyst for bioremediation of PAE and paraben-polluted environments.

Piezo1 channel activation stimulates ATP production through enhancing mitochondrial respiration and glycolysis in vascular endothelial cells.

BACKGROUND AND PURPOSE: Piezo1 channels are mechanosensitive cationic channels that are activated by mechanical stretch or shear stress. Endothelial Piezo1 activation by shear stress caused by blood flow induces ATP release from endothelial cells; however, the link between shear stress and endothelial ATP production is unclear. EXPERIMENTAL APPROACH: The mitochondrial respiratory function of cells was measured by using high-resolution respirometry system Oxygraph-2k. The intracellular Ca2+ concentration was evaluated by using Fluo-4/AM and mitochondrial Ca2+ concentration by Rhod-2/AM. KEY RESULTS: The specific Piezo1 channel activator Yoda1 or its analogue Dooku1 increased [Ca2+ ]i in human umbilical vein endothelial cells (HUVECs), and both Yoda1 and Dooku1 increased mitochondrial oxygen consumption rates (OCRs) and mitochondrial ATP production in HUVECs and primary cultured rat aortic endothelial cells (RAECs). Knockdown of Piezo1 inhibited Yoda1- and Dooku1-induced increases of mitochondrial OCRs and mitochondrial ATP production in HUVECs. The shear stress mimetics, Yoda1 and Dooku1, and the Piezo1 knock-down technique also demonstrated that Piezo1 activation increased glycolysis in HUVECs. Chelating extracellular Ca2+ with EGTA or chelating cytosolic Ca2+ with BAPTA-AM did not affect Yoda1- and Dooku1-induced increases of mitochondrial OCRs and ATP production, but chelating cytosolic Ca2+ inhibited Yoda1- and Dooku1-induced increase of glycolysis. Confocal microscopy showed that Piezo1 channels are present in mitochondria of endothelial cells, and Yoda1 and Dooku1 increased mitochondrial Ca2+ in endothelial cells. CONCLUSION AND IMPLICATIONS: Piezo1 channel activation stimulates ATP production through enhancing mitochondrial respiration and glycolysis in vascular endothelial cells, suggesting a novel role of Piezo1 channel in endothelial ATP production.

The synergistic effect of chemical oxidation and microbial activity on improving volatile fatty acids (VFAs) production during the animal wastewater anaerobic digestion process treated with persulfate/biochar.

Improving volatile fatty acid (VFA) production, rather than producing methane from the anaerobic digestion (AD) of waste, has become a new strategy of resource utilization. In regard to animal wastewater, the effectiveness of persulfate/biochar (potassium peroxodisulfate, PDS/BC) on the hydrolysis and acidogenesis stages and the reaction mechanisms are still unclear. In this study, the AD process on cow wastewater was controlled at the hydrolysis and acidification stages by setting the hydraulic retention time (HRT) at 25 days. The results showed that the contents of total solids (TS) and volatile solids (VS) were further reduced by PDS/BC treatment with 0.15 gPDS/gTS of PDS added. The VFAs production increased by 12.4 % from day 0 to 25 compared to the blank set. Based on our molecular analysis, the rate of increase for the dissolved organic matter with low molecular weight (0-10 kDa) was 699.5 mg/(L·d) in the first 10 days. The change rate increased nearly 2.1 times, leading to higher VFAs yield. Moreover, the activities of fermentative bacteria were enhanced and Anaerocella was determined to be the specific and critical genus. However, excessive PDS (0.3 gPDS/gTS) prolonged the acidification period and caused the inactivation of fermentative bacteria. Structural equation modeling demonstrated that PDS can directly affect VFAs yield and also had an indirect effect by influencing the decomposition of particulate matter and microbial activities. Therefore, the enhancement of VFAs production using the PDS/BC method could be due to synergistic chemical and microbial effects. Findings from this study can provide a practical strategy to enhance the VFAs production of AD technology for livestock wastewater and help reveal the reaction mechanism of PDS/BC treatment.

Repurposing nitazoxanide as a novel anti-atherosclerotic drug based on mitochondrial uncoupling mechanisms.

BACKGROUND AND PURPOSE: The anthelmintic drug nitazoxanide has a mitochondrial uncoupling effect. Mitochondrial uncouplers have been proven to inhibit smooth muscle cell proliferation and migration, inhibit NLRP3 inflammasome activation of macrophages and improve dyslipidaemia. Therefore, we aimed to demonstrate that nitazoxanide would protect against atherosclerosis. EXPERIMENTAL APPROACH: The mitochondrial oxygen consumption of cells was measured by using the high-resolution respirometry system, Oxygraph-2K. The proliferation and migration of A10 cells were measured by using Edu immunofluorescence staining, wound-induced migration and the Boyden chamber assay. Protein levels were measured by using the western blot technique. ApoE (-/-) mice were fed with a Western diet to establish an atherosclerotic model in vivo. KEY RESULTS: The in vitro experiments showed that nitazoxanide and tizoxanide had a mitochondrial uncoupling effect and activated cellular AMPK. Nitazoxanide and tizoxanide inhibited serum- and PDGF-induced proliferation and migration of A10 cells. Nitazoxanide and tizoxanide inhibited NLRP3 inflammasome activation in RAW264.7 macrophages, the mechanism by which involved the AMPK/IκBα/NF-κB pathway. Nitazoxanide and tizoxanide also induced autophagy in A10 cells and RAW264.7 macrophages. The in vivo experiments demonstrated that oral administration of nitazoxanide reduced the increase in serum IL-1ß and IL-6 levels and suppressed atherosclerosis in Western diet-fed ApoE (-/-) mice. CONCLUSION AND IMPLICATIONS: Nitazoxanide inhibits the formation of atherosclerotic plaques in ApoE (-/-) mice fed on a Western diet. In view of nitazoxanide being an antiprotozoal drug already approved by the FDA, we propose it as a novel anti-atherosclerotic drug with clinical translational potential.

Total autologous breast reconstruction with the Kiss Latissimus Dorsi Flap.

INTRODUCTION: Patients presenting breast actinic damage or implant-related complications require an autologous approach to breast reconstruction. However, when they are not good candidates for microsurgical procedures, alternative solutions must be sought. Latissimus dorsi (LD) is a workhorse flap in breast reconstruction, but often the amount of skin and volume achievable are insufficient. Taking inspiration from the Kiss flap concept, the authors hereby describe the "Kiss" LD flap to achieve totally autologous breast reconstruction. PATIENTS AND METHODS: A prospective service evaluation of all patients who underwent breast reconstruction with Kiss LD flap between 2018 and 2020 was performed. Patient demographics and operative variables were recorded, together with early and late complications. Patient satisfaction and quality of life were registered using the latest BREAST-Q reconstruction module, which includes specific LD scales. The questionnaire was administered to patients preoperatively and six months postoperatively. RESULTS: Thirty patients underwent total autologous breast reconstruction with Kiss LD flap. Breast cancer and breast sarcoma resection were followed by reconstruction. The timing of reconstruction was immediate in 3 cases and delayed in 27 cases. No major complications nor total flap loss were registered. BREAST-Q scores postoperatively were significantly higher than the preoperative ones in every domain (p<0.0001) except for the physical well-being of back and shoulder, where the scores differed slightly and non-significantly (p=0.05). CONCLUSIONS: The Kiss LD flap allows to harvest a large amount of skin to restore the breast envelope and a considerable volume to reconstruct the breast mound in a completely autologous procedure.

Synthesis and Biological Evaluation of 3-(Pyridine-3-yl)-2-Oxazolidinone Derivatives as Antibacterial Agents.

In this research, a series of 3-(pyridine-3-yl)-2-oxazolidinone derivatives was designed, synthesized, and evaluated for in vitro antibacterial activity, which included bacteriostatic, morphological, kinetic studies, and molecular docking. The results demonstrated that compounds 21b, 21d, 21e and 21f exhibited strong antibacterial activity similar to that of linezolid toward five Gram-positive bacteria. After observing the effect of the drug on the morphology and growth dynamics of the bacteria, the possible modes of action were predicted by molecular docking. Furthermore, the antibiofilm activity and the potential drug resistance assay was proceeded. These compounds exhibited universal antibiofilm activity and compound 21d showed significant concentration-dependent inhibition of biofilm formation. Compound 21d also showed a stable effect on S. pneumoniae (ATCC 49619) with less drug resistance growth for 15 days, which is much longer than that of linezolid. Overall, these results can be used to guide further exploration of novel antimicrobial agents.