GSDMD/Drp1 signaling pathway mediates hippocampal synaptic damage and neural oscillation abnormalities in a mouse model of sepsis-associated encephalopathy.

BACKGROUND: Gasdermin D (GSDMD)-mediated pyroptotic cell death is implicated in the pathogenesis of cognitive deficits in sepsis-associated encephalopathy (SAE), yet the underlying mechanisms remain largely unclear. Dynamin-related protein 1 (Drp1) facilitates mitochondrial fission and ensures quality control to maintain cellular homeostasis during infection. This study aimed to investigate the potential role of the GSDMD/Drp1 signaling pathway in cognitive impairments in a mouse model of SAE. METHODS: C57BL/6 male mice were subjected to cecal ligation and puncture (CLP) to establish an animal model of SAE. In the interventional study, mice were treated with the GSDMD inhibitor necrosulfonamide (NSA) or the Drp1 inhibitor mitochondrial division inhibitor-1 (Mdivi-1). Surviving mice underwent behavioral tests, and hippocampal tissues were harvested for histological analysis and biochemical assays at corresponding time points. Haematoxylin-eosin staining and TUNEL assays were used to evaluate neuronal damage. Golgi staining was used to detect synaptic dendritic spine density. Additionally, transmission electron microscopy was performed to assess mitochondrial and synaptic morphology in the hippocampus. Local field potential recordings were conducted to detect network oscillations in the hippocampus. RESULTS: CLP induced the activation of GSDMD, an upregulation of Drp1, leading to associated mitochondrial impairment, neuroinflammation, as well as neuronal and synaptic damage. Consequently, these effects resulted in a reduction in neural oscillations in the hippocampus and significant learning and memory deficits in the mice. Notably, treatment with NSA or Mdivi-1 effectively prevented these GSDMD-mediated abnormalities. CONCLUSIONS: Our data indicate that the GSDMD/Drp1 signaling pathway is involved in cognitive deficits in a mouse model of SAE. Inhibiting GSDMD or Drp1 emerges as a potential therapeutic strategy to alleviate the observed synaptic damages and network oscillations abnormalities in the hippocampus of SAE mice.

Unique gap-related SERS behaviors ofp-aminothiophenol molecules absorbed on TiO2surface in periodic TiO2/Ni nanopillar arrays.

We observed a unique interpillar gap-related surface-enhanced Raman scattering (SERS) behavior ofp-aminothiophenol (PATP) molecules from periodic TiO2nanopillar arrays with three gap sizes of 191, 297 and 401 nm, which is completely different from that on Ag and Ni nanopillar arrays. Especially, the gap-size-dependent charge-transfer (CT) resonance enhancement from TiO2/Ni has been indicated through comparisons of variation trend of SERS intensities with inter-pillar gap size between TiO2/Ni and Ag/TiO2/Ni as well as Ni nanoarrays, and been confirmed by spectra of ultraviolet-visible absorption and photoluminescence. Results demonstrate that the CT resonance enhancement is more susceptible to the change of the gap size compared with the surface plasmon resonance (SPR) enhancement in TiO2/Ni nanoarrays. Hence, SPR and CT enhancement showing different variation trend and rate with the gap size that leads to a different relative contribution of CT resonance to the overall SERS enhancement as gap size changes, and consequently results in a unique gap-related SERS behavior for TiO2/Ni nanoarrays. The present study is not only helpful for investigating SERS mechanism for semiconductors but also providing a method to design and optimize periodic metal/semiconductor SERS substrates in a controllable way.

Association of hepatitis B virus DNA levels with efficacy and safety outcomes in patients with hepatitis B virus-associated advanced hepatocellular carcinoma receiving tyrosine kinase inhibitor plus anti-PD-1 antibody: a multicenter propensity-matched study.

BACKGROUND: The efficacy and safety of tyrosine kinase inhibitors (TKIs) combined with anti-PD-1 antibodies (α-PD-1) in advanced hepatocellular carcinoma (HCC) with high hepatitis B virus (HBV) DNA levels (>500 IU/mL) remain unclear. METHODS: We retrospectively assessed patients from seven medical institutions diagnosed with HBV-related HCC, undergoing treatment with TKIs and α-PD-1 in conjunction with antiviral therapies. Based on HBV-DNA levels, patients were categorized into either high (HHBV-DNA, >500 IU/mL) or low HBV-DNA (LHBV-DNA, ≤500 IU/mL) cohorts Propensity score matching (PSM) was used to minimize baseline imbalance between groups. RESULTS: 149 patients were included, with 66 patients exhibiting HBV-DNA > 500 IU/mL and 83 patients presenting HBV-DNA ≤ 500 IU/mL. Compared with the LHBV-DNA cohort, the HHBV-DNA cohort had a greater incidence of serum HBeAg positivity, tumor diameter ≥ 10 cm, and vascular invasion. Following PSM, 57 individuals were enrolled in each group. Oncological outcomes were comparable between HHBV-DNA and LHBV-DNA cohorts before and after PSM. Before PSM, the median PFS and OS were 6.1 months and 17.5 months in the HHBV-DNA cohort and 6.7 months and 19.3 months in the LHBV-DNA cohort (all P > 0.05). After PSM, the median PFS and OS were 6.0 months and 19.5 months in the HHBV-DNA cohort and 6.0 months and 17.1 months in the LHBV-DNA cohort, respectively (all P > 0.05). Safety profiles were equivalent across cohorts with no fatal incidents reported. Seven patients (4.7 %) had HBV reactivation. 1 (0.7 %) from HHBV-DNA and 6 (4.0 %) from LHBV-DNA (P = 0.134). Only one patient developed HBV-related hepatitis. CONCLUSIONS: The effectiveness and safety of TKIs plus α-PD-1 in advanced HCC with HBV-DNA > 500 IU/mL were not compromised in the context of concomitant antiviral therapy.

Gene polymorphisms affect postoperative imatinib plasma levels and edema in adults with gastrointestinal stromal tumor.

Aim: To assess the role of genetic polymorphisms in postoperative imatinib concentrations and edema in patients with gastrointestinal stromal tumor. Methods: The relationships between genetic polymorphisms, imatinib concentrations and edema were explored. Results: Carriers of the rs683369 G-allele and rs2231142 T-allele had significantly higher imatinib concentrations. Grade ≥2 periorbital edemas were related to the carriership of two C-alleles in rs2072454 with an adjusted odds ratio of 2.85, two T-alleles in rs1867351 with an adjusted odds ratio of 3.42 and two A-alleles in rs11636419 with an adjusted odds ratio of 3.15. Conclusion: rs683369 and rs2231142 affect the metabolism of imatinib; rs2072454, rs1867351 and rs11636419 are related to grade ≥2 periorbital edemas.

Personalized Dose of Adjuvant Imatinib in Patients with Gastrointestinal Stromal Tumors: Results from a Population Pharmacokinetic Analysis.

Purpose: Imatinib is the first-line treatment for patients with gastrointestinal stromal tumors (GIST) after surgery. However, its pharmacokinetic profile varies remarkably between individuals and has not been well characterized in postoperative Chinese patients with GIST. Therefore, this study aimed to develop a population pharmacokinetic (PPK) model and recommend appropriate doses for different patients to achieve the target trough concentration in such a population. Patients and Methods: A total of 110 surgically treated GIST patients were enrolled, of which 85 were applied to conduct a PPK analysis with a nonlinear mixed-effect model and 25 for external validation of the model. Demographic and biomedical covariates, as well as six single nucleotide polymorphisms were tested to explore the sources of variation in pharmacokinetic parameters of imatinib. Monte Carlo simulations were performed to establish the initial dosing regimens. Results: A one-compartment model was established in postoperative GIST patients. The red blood cell count (RBC) and ABCG2 rs2231142 were observed to have a significant effect on the clearance of imatinib. The typical values estimated by the final model were 9.72 L/h for clearance (CL/F) and 229 L for volume of distribution (V/F). Different from the fixed dose regimen of 400 mg each day, patients carrying rs2231142 heterozygous type and with a lower level of RBC (2.9 × 1012/L), 300 mg imatinib daily is enough to achieve the target trough concentration. When RBC rises to 4.9 × 1012/L, 500 mg daily is recommended. For patients with rs2231142 GG genotype, 500 mg a day is required at RBCs of 3.9 × 1012/L and 4.9 × 1012/L. Conclusion: RBC and rs2231142 contribute to the pharmacokinetic variation of imatinib and personalized dose recommendations based on patient characteristics may be necessary.

Dexpramipexole ameliorates cognitive deficits in sepsis-associated encephalopathy through suppressing mitochondria-mediated pyroptosis and apoptosis.

OBJECTIVES: This study was aimed at evaluating the effects of dexpramipexole (DPX) - a mitochondrial protectant that sustains mitochondrial function and energy production - on cognitive function in a mouse model of sepsis-associated encephalopathy (SAE) induced by peripheral administration of lipopolysaccharide (LPS) and examining the potential mechanisms. METHODS: C57BL/6 male mice were randomized into one of four treatment protocols: Con+Sal, Con+DPX, LPS+Sal or LPS+DPX. The mice were intraperitoneally (i.p.) injected with LPS or equivalent volumes of normal saline once daily for 3 consecutive days. To evaluate the protective effects of DPX, we administered DPX or normal saline i.p. to the mice once daily for 6 consecutive days. Six mice in each group were decapitated on day 7, and each brain was rapidly removed and separated into two halves for biochemical and histochemical analysis. The remaining surviving mice in each group were subjected to behavioral tests from days 7 to 10. RESULTS: Peripheral administration of LPS to mice led to learning and memory deficits in behavioral tests, which were associated with mitochondrial impairment and ATP depletion in the hippocampus. Repeated DPX treatment protected the mitochondria against LPS-induced morphological and functional impairment; inhibited the activation of the Nod-like receptor pyrin domain-containing 3 (NLRP3) inflammasome-caspase-1-dependent pyroptosis pathway and cytochrome c (Cyt-c)-caspase-3-dependent apoptosis pathway; and attenuated LPS-induced neuroinflammation and cell death in the hippocampus in SAE mice. CONCLUSIONS: Mitochondria-mediated pyroptosis and apoptosis are involved in the pathogenesis of cognitive deficits in a mouse model of SAE and DPX protects mitochondria and suppresses the mitochondria-medicated pyroptosis and apoptosis pathways, and ameliorates LPS-induced neuroinflammation and cognitive deficits. This study provides theoretical evidence supporting DPX for the treatment of SAE.

Huangqi Decoction, a compound Chinese herbal medicine, inhibits the proliferation and activation of hepatic stellate cells by regulating the long noncoding RNA-C18orf26-1/microRNA-663a/transforming growth factor-ß axis.

OBJECTIVE: Huangqi Decoction (HQD), a classical traditional Chinese medicine formula, has been used as a valid treatment for alleviating liver fibrosis; however, the underlying molecular mechanism is still unknown. Although our previous studies showed that microRNA-663a (miR-663a) suppresses the proliferation and activation of hepatic stellate cells (HSCs) and the transforming growth factor-ß/small mothers against decapentaplegic (TGF-ß/Smad) pathway, whether long noncoding RNAs (lncRNAs) are involved in HSC activation via the miR-663a/TGF-ß/Smad signaling pathway has not yet reported. The present study aimed to investigate the roles of lncRNA lnc-C18orf26-1 in the activation of HSCs and the mechanism by which HQD inhibits hepatic fibrosis. METHODS: The expression levels of lnc-C18orf26-1, miR-663a and related genes were measured by quantitative reverse transcription-polymerase chain reaction. HSCs were transfected with the miR-663a mimic or inhibitor and lnc-C18orf26-1 small interfering RNAs. The water-soluble tetrazolium salt-1 assay was used to assess the proliferation rate of HSCs. Changes in lncRNA expression were evaluated in miR-663a-overexpressing HSCs by using microarray to identify miR-663a-regulated lncRNAs. RNA hybrid was used to predict the potential miR-663a binding sites on lncRNAs. Luciferase reporter assays further confirmed the interaction between miR-663a and the lncRNA. The expression levels of collagen α-2(I) chain (COL1A2), α-smooth muscle actin (α-SMA) and TGF-ß/Smad signaling pathway-related proteins were determined using Western blotting. RESULTS: Lnc-C18orf26-1 was upregulated in TGF-ß1-activated HSCs and competitively bound to miR-663a. Knockdown of lnc-C18orf26-1 inhibited HSC proliferation and activation, downregulated TGF-ß1-stimulated α-SMA and COL1A2 expression, and inhibited the TGF-ß1/Smad signaling pathway. HQD suppressed the proliferation and activation of HSCs. HQD increased miR-663a expression and decreased lnc-C18orf26-1 expression in HSCs. Further studies showed that HQD inhibited the expression of COL1A2, α-SMA, TGF-ß1, TGF-ß type I receptor (TGF-ßRI) and phosphorylated Smad2 (p-Smad2) in HSCs, and these effects were reversed by miR-663a inhibitor treatment. CONCLUSION: Our study identified lnc-C18orf26-1 and miR-663a as promising therapeutic targets for hepatic fibrosis. HQD inhibits HSC proliferation and activation at least partially by regulating the lnc-C18orf26-1/miR-663a/TGF-ß1/TGF-ßRI/p-Smad2 axis.

Huangqi Decoction, a compound Chinese herbal medicine, inhibits the proliferation and activation of hepatic stellate cells by regulating the long noncoding RNA-C18orf26-1/microRNA-663a/transforming growth factor-β axis / 中西医结合学报

OBJECTIVE@#Huangqi Decoction (HQD), a classical traditional Chinese medicine formula, has been used as a valid treatment for alleviating liver fibrosis; however, the underlying molecular mechanism is still unknown. Although our previous studies showed that microRNA-663a (miR-663a) suppresses the proliferation and activation of hepatic stellate cells (HSCs) and the transforming growth factor-β/small mothers against decapentaplegic (TGF-β/Smad) pathway, whether long noncoding RNAs (lncRNAs) are involved in HSC activation via the miR-663a/TGF-β/Smad signaling pathway has not yet reported. The present study aimed to investigate the roles of lncRNA lnc-C18orf26-1 in the activation of HSCs and the mechanism by which HQD inhibits hepatic fibrosis.@*METHODS@#The expression levels of lnc-C18orf26-1, miR-663a and related genes were measured by quantitative reverse transcription-polymerase chain reaction. HSCs were transfected with the miR-663a mimic or inhibitor and lnc-C18orf26-1 small interfering RNAs. The water-soluble tetrazolium salt-1 assay was used to assess the proliferation rate of HSCs. Changes in lncRNA expression were evaluated in miR-663a-overexpressing HSCs by using microarray to identify miR-663a-regulated lncRNAs. RNA hybrid was used to predict the potential miR-663a binding sites on lncRNAs. Luciferase reporter assays further confirmed the interaction between miR-663a and the lncRNA. The expression levels of collagen α-2(I) chain (COL1A2), α-smooth muscle actin (α-SMA) and TGF-β/Smad signaling pathway-related proteins were determined using Western blotting.@*RESULTS@#Lnc-C18orf26-1 was upregulated in TGF-β1-activated HSCs and competitively bound to miR-663a. Knockdown of lnc-C18orf26-1 inhibited HSC proliferation and activation, downregulated TGF-β1-stimulated α-SMA and COL1A2 expression, and inhibited the TGF-β1/Smad signaling pathway. HQD suppressed the proliferation and activation of HSCs. HQD increased miR-663a expression and decreased lnc-C18orf26-1 expression in HSCs. Further studies showed that HQD inhibited the expression of COL1A2, α-SMA, TGF-β1, TGF-β type I receptor (TGF-βRI) and phosphorylated Smad2 (p-Smad2) in HSCs, and these effects were reversed by miR-663a inhibitor treatment.@*CONCLUSION@#Our study identified lnc-C18orf26-1 and miR-663a as promising therapeutic targets for hepatic fibrosis. HQD inhibits HSC proliferation and activation at least partially by regulating the lnc-C18orf26-1/miR-663a/TGF-β1/TGF-βRI/p-Smad2 axis.

Significance of detecting the levels of miR-29a, survivin and interferon gamma release assay in patients with lung cancer and tuberculosis.

BACKGROUND: When lung cancer is combined with concurrent tuberculosis (TB), it increases the difficulty of diagnosis and treatment, leading to missed and/or misdiagnosed cases. OBJECTIVES: To provide reference markers for the clinical diagnosis of patients with lung cancer complicated by active pulmonary TB (APT). MATERIAL AND METHODS: The concentration of survivin in diseased tissue, and miR-29a and IGRAs interferon gamma (IFN-γ) in serum were evaluated in 25 patients with non-small cell lung carcinoma (NSCLC) complicated by APT, 32 patients with NSCLC and 30 patients with APT. RESULTS: The expression of miR-29a in serum of patients with APT was higher than in patients with NSCLC complicated by APT (least significant difference (LSD)-t = 4.724, p < 0.001), and the NSCLC group (LSD-t = 6.619, p < 0.001). Furthermore, patients with NSCLC complicated by APT had higher miR-29a concentration than the NSCLC group. The rate of positive survivin expression in NSCLC (χ2 = 23.418, p < 0.001) and NSCLC combined with APT group (χ2 = 17.160, p < 0.001) was significantly higher than in patients with APT. The concentration of IFN-γ in serum of the NSCLC complicated by APT group (LSD-t = 2.912, p = 0.004) and the APT group (LSD-t = 4.452, p < 0.001) was higher than in the NSCLC group. The level of IFN-γ in serum of the NSCLC complicated by APT group were higher than in the APT group, but there was no statistical difference. CONCLUSIONS: The levels of MiR-29a, Survivin and IFN-γ was helpful for differential diagnosis of lung cancer and tuberculosis.

Hematologic toxicities of sunitinib in patients with gastrointestinal stromal tumors: a systematic review and meta-analysis.

PURPOSE: Sunitinib offers a significant survival benefit to patients with imatinib-resistant gastrointestinal stromal tumors (GIST). However, the incidence and risk of sunitinib-induced hematologic toxicities in such a population are often overlooked and have not been well characterized. This meta-analysis was performed to assess the summary incidence and risk of hematologic toxicities secondary to sunitinib in patients with GIST. METHODS: Searches were performed in PubMed, Embase, Cochrane Library, and Web of Science as well as ClinicalTrials.gov to identify relevant studies up to April 2022. Studies with adequate safety profile, including anemia, neutropenia, and thrombocytopenia, were included to calculate the pooled incidence, relative risk (RR), and corresponding 95% confidence intervals (CIs). This study was registered with PROSPERO under number CRD42022328202. RESULTS: A total of 2593 patients from 13 studies were included in the present meta-analysis. For patients with GIST assigned to sunitinib, the overall incidences of all-grade anemia, neutropenia, and thrombocytopenia were 26.2% (95% CI, 14.9-39.4%), 41.8% (95% CI, 29.0-55.1%), and 36.4% (95% CI, 22.8-51.1%), respectively. Regarding high-grade (grades 3 and 4) events, there were 4.7% (95% CI, 3.8-5.6%) for anemia, 9.3% (95% CI, 5.6-13.7%) for neutropenia and 5.0% (95% CI, 2.9-7.3%) for thrombocytopenia. Compared to placebo arms, sunitinib was related to an increased risk of high-grade neutropenia with an RR of 10.39 (95% CI, 1.53-70.72; p = 0.017). CONCLUSIONS: Sunitinib carries a relatively high incidence of hematologic toxicities and a substantial increased risk of high-grade neutropenia in patients with GIST. Appropriate prevention and management seem to be inevitable.

TiO2 Thickness-Dependent Charge Transfer in an Ordered Ag/TiO2/Ni Nanopillar Arrays Based on Surface-Enhanced Raman Scattering.

In this study, an ordered Ag/TiO2/Ni nanopillar arrays hybrid substrate was designed, and the charge transfer (CT) process at the metal-semiconductor and substrate-molecule interface was investigated based on the surface-enhanced Raman scattering (SERS) spectra of 4-Aminothiophenol (PATP) absorbed on the composite system. The surface plasmon resonance (SPR) absorption of Ag changes due to the regulation of TiO2 thickness, which leads to different degrees of CT enhancement in the system. The CT degree of SERS spectra obtained at different excitation wavelengths was calculated to study the contribution of CT enhancement to SERS, and a TiO2 thickness-dependent CT enhancement mechanism was proposed. Furthermore, Ag/TiO2/Ni nanopillar arrays possessed favorable detection ability and uniformity, which has potential as a SERS-active substrate.

Machine learning-based method for tacrolimus dose predictions in Chinese kidney transplant perioperative patients.

WHAT IS KNOWN AND OBJECTIVES: Tacrolimus (TAC), a first-line immunosuppressant in solid-organ transplant, has a narrow therapeutic window and large inter-individual variability, which affects its use in clinical practice. Successful predictions using machine learning algorithms have been reported in several fields. However, a comparison of 10 machine learning model-based TAC pharmacogenetic and pharmacokinetic dosing algorithms for kidney transplant perioperative patients of Chinese descent has not been reported. The objective of this study was to screen and establish an appropriate machine learning method to predict the individualized dosages of TAC for perioperative kidney transplant patients. METHODS: The records of 2551 patients were collected from three transplant centres, 80% of which were randomly selected as a 'derivation cohort' to develop the dose prediction algorithm, while the remaining 20% constituted a 'validation cohort' to validate the final algorithm selected. Important features were screened according to our previously established population pharmacokinetic model of tacrolimus. The performances of the algorithms were evaluated and compared using R-squared and the mean percentage in the remaining 20% of patients. RESULTS AND DISCUSSION: This study identified several factors influencing TAC dosage, including CYP3A5 rs776746, CYP3A4 rs4646437, haematocrit, Wuzhi capsules, TAC daily dose, age, height, weight, post-operative time, nifedipine and the medication history of the patient. According to our results, among the 10 machine learning models, the extra trees regressor (ETR) algorithm showed the best performance in the training set (R-squared: 1, mean percentage within 20%: 100%) and test set (R-squared: 0.85, mean percentage within 20%: 92.77%) of the derivation cohort. The ETR model successfully predicted the ideal TAC dosage in 97.73% of patients, especially in the intermediate dosage range (>5 mg/day to <8 mg/day), whereby the ideal TAC dosage could be successfully predicted in 99% of the patients. WHAT IS NEW AND CONCLUSION: The results indicated that the ETR algorithm, which was chosen to establish the dose prediction model, performed better than the other nine machine learning models. This study is the first to establish ETR algorithms to predict TAC dosage. This study will further promote the individualized medication of TAC in kidney transplant patients in the future, which has great significance in ensuring the safety and effectiveness of drug use.

Bismuth Nanoparticles Confined in Carbonaceous Nanospheres as Anodes for High-Performance Potassium-Ion Batteries.

Bismuth (Bi) has been considered as a promising alloying-type anode for potassium-ion batteries (PIBs), owing to its high theoretical capacity and suitable working voltage plateaus. However, Bi suffers from dramatic volume fluctuation and significant pulverization during the discharge/charge processes, resulting in fast capacity decay. Herein, we synthesize Bi nanoparticles confined in carbonaceous nanospheres (denoted as Bi@C) for PIBs by first utilizing BiOCl nanoflakes as a hard template and a Bi precursor. The construction of the loose structure buffers the mechanical stresses resulting from the volume expansion of Bi during the alloying reaction and avoids the fracture of the electrode structure, thus improving the cycling performance. Moreover, the carbonaceous layers increase the electronic conductivity and disperse the Bi nanoparticles, enhancing the charge transportation and ionic diffusion, which further promotes the rate capability of Bi@C. It exhibits a superior capacity (389 mAh g-1 at 100 mA g-1 after 100 cycles), excellent cycling stability (206 mAh g-1 at 500 mA g-1 over 1000 cycles), and an improved rate capability (182 mAh g-1 at 2.0 A g-1). This work provides a new structuring strategy in alloying materials for boosting reversible and stable potassium-ion storage.

Effect of exogenous methyl jasmonate on physiological and carotenoid composition of yellow maize sprouts under NaCl stress.

Carotenoid content in maize sprouts can be increased by NaCl stress, although high NaCl concentrations negatively impact plant growth. The effects of exogenous methyl jasmonate (MeJA) on contents of carotenoid and antioxidant capacity of yellow maize sprouts under NaCl stress were investigated. Our results showed that treatments of NaCl both alone and combined with MeJA enhanced the carotenoid accumulation in maize sprouts. Moreover, the carotenoid biosynthesis related genes showed different expression patterns under addition of MeJA treatment. Additionally, the combined treatment led to significantly higher content of most carotenoids profiles and the addition of MeJA could alleviate the harmful effect caused by NaCl stress. Furthermore, the combined treatment improved antioxidant enzyme activities and radical scavenging capacity. The results implied that MeJA is kind of effective plant growth regulator for enhancing carotenoid accumulation in maize sprouts by up-regulating the expression levels of key genes involved in carotenoid biosynthetic pathway.

Population pharmacokinetic analysis and dosing guidelines for tacrolimus co-administration with Wuzhi capsule in Chinese renal transplant recipients.

WHAT IS KNOWN AND OBJECTIVES: Tacrolimus (TAC) is a first-line immunosuppressant which is used to prevent transplant rejection after solid organ transplantation (SOT). However, it has a narrow therapeutic index and high individual variability in pharmacokinetics (PK) and pharmacogenomics (PG). It has been reported that the metabolism of TAC can be affected by genetic factors, leading to different rates of metabolism in different subjects. Wuzhi Capsule (WZC) is a commonly used TAC-sparing agent in Chinese SOT to reduce TAC dosing due to its inhibitory effect on TAC metabolism by enzymes of the CYP3A subfamily. The aims of this study were to assess the effect of TAC+WZC co-administration and genetic polymorphism on the pharmacokinetics of TAC, by using a population pharmacokinetic (PPK) model. A dosing guideline for individualized TAC dosing is proposed based on the PPK study. METHODS: The medical records of 165 adult patients with kidney transplant and their 824 TAC concentrations from two kidney transplantation centres were reviewed. The genotypes of four single-nucleotide polymorphisms (SNPs) in CYP3A5*3 and ABCB1 (rs1128503, rs2032582 and rs1045642) were tested by MASSARRAY. A PPK model was constructed by nonlinear mixed effect model (NONMEM® , Version 7.3). Finally, Monte Carlo simulations were employed to design initial dosing regimens based on the final model. RESULTS AND DISCUSSION: The one-compartmental PPK model with first-order absorption and elimination of TAC was established in kidney transplant recipients (KTRs). CYP3A5*3 had significant impact on the PPK model. The haematocrit (HCT), postoperative time (POD) and CYP3A5*3 genotypes had a significant influence on TAC clearance when combined with WZC. The model was expressed as 23.4 × (HCT/0.3)-0.729  × 0.837 (combination with WZC) × e-0.0875(POD/12.6) ×1.18 (CYP3A5 expressors). For patients carrying the CYP3A5*3/*3 allele and with 30% HCT, the required TAC dose to achieve target trough concentrations of 10-15 ng/ml was 4 mg twice daily (q12h). For patients with the CYP3A5*3/*3 allele, the required dose was 3 mg TAC q12h when combined with WZC, and for patients with the CYP3A5*1/*1 or *1/*3 allele, the required dose was 4 mg of TAC q12h when co-administered with WZC. WHAT IS NEW AND CONCLUSION: Wuzhi Capsule co-administration and CYP3A5 variants affect the PK of TAC Dosing guidelines are made based on the PPK model to allow individualized administration of TAC, especially when co-administered with WZC.

Comparison of the Detection Rates of Different Diagnostic Methods for Primary Peripheral Lung Cancer.

Objective: The present study aims to compare the detection rates of different diagnostic methods for primary peripheral lung cancer (PPLC). Methods: The detection rate and patient information were collected from a total of 359 cases of PPLC or a suspected diagnosis of lung cancer; among these, 186 cases were simultaneously treated with fibreoptic bronchoscopy, brush inspection and flush inspection, and 173 cases underwent a computed tomography (CT)-guided percutaneous lung biopsy (PNB). The positive detection rates of the different methods were compared. Results: In the detection of peripheral lesions (diameter of <5 cm), the CT-PNB had the significantly highest detection rate, followed by the combined basic method (fibreoptic bronchoscopy + brushing + flushing). The independent use of the three basic sampling methods showed a significantly lower detection rate compared with the combined use. Conclusion: In the diagnosis of peripheral lung cancer, the CT-PNB had the best detection rate; hence, it could be used in clinical practice for the diagnosis of such lesions.

Inhibiting NLRP3 inflammasome with MCC950 ameliorates perioperative neurocognitive disorders, suppressing neuroinflammation in the hippocampus in aged mice.

Perioperative neurocognitive disorders (PND) are characterized by deficits in cognitive functions in the elderly following anesthesia and surgery. Effective clinical interventions for preventing this disease are limited. Growing evidence demonstrates that activation of NOD-like receptor protein3 (NLRP3) inflammasome is involved in neurodegenerative diseases. We therefore hypothesized that activation of NLRP3 inflammasome is linked to neuroinflammation and the subsequent cognitive impairments that occurred in an animal model of PND. In this study, 18-month-old C57BL/6 mice were subjected to an exploratory laparotomy under isoflurane anesthesia to mimic clinical human abdominal surgery. For interventional studies, mice received NLRP3 specific inhibitor MCC950 (10 mg/kg) or the vehicle only intraperitoneally. Behavioral studies were performed at 6 and 7 d after surgery using open field and fear conditioning tests, respectively. Interleukin-1ß (IL-1ß), interleukin-18 (IL-18), tumor necrosis factor-α (TNF-α), ionized calcium-binding adaptor molecule-1 (IBA1) positive cells, glial fibrillary acidic protein (GFAP) positive cells, NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC), and cleaved caspase-1 were measured at 3 days post-surgery. Brain-derived neurotrophic factor (BDNF) and postsynaptic density protein 95 (PSD95) were measured at 7 days post-surgery. Our data indicates that surgery-induced cognitive impairments were associated with significant increases in IL-1ß, IL-18, TNF-α, NLRP3, ASC, cleaved caspase-1, IBA1-positive cells and GFAP-positive cells, and decreases in BDNF and PSD95 expression in the hippocampus. Notably, administration with MCC950 attenuated inflammatory changes and rescued surgery-induced cognitive impairments. Our study suggests that surgery induces neuroinflammation and cognitive deficits that are partly attributed to the activation of NLRP3 inflammasome in the hippocampus of aged mice.

An efficient nanopatterning strategy for controllably fabricating ultra-small gaps as a highly sensitive surface-enhanced Raman scattering platform.

The realization of large-scale and high-density gaps with sizes as small as possible is crucial for designing ultra-sensitive surface-enhanced Raman scattering (SERS) substrates. As known, the ultrathin alumina mask (UTAM) surface nanopatterning technique allows the fabrication of periodic nanoparticle (NP) arrays with 5 nm gaps among the NPs, however, it still faces a significant challenge in realizing the reliable distribution of nanogaps over a large area, because of the unavoidable collapse of the UTAM pore wall during the traditional one-step homothermal pore-widening process. Herein, an efficient two-step poikilothermal pore-widening process was developed to precisely control the pore wall etching of a UTAM, enabling effectively avoiding the fragmentation of the UTAM and finally obtaining a large-scale UTAM with a pore wall thickness of about 5 nm. As a result, large-scale NP arrays with high-density sub-5 nm and even smaller gaps between the neighboring NPs have been realized through applying the as-prepared UTAM as the nanopatterning template. These NP arrays with sub-5 nm gaps show ultrahigh SERS sensitivity (signal enhancement improved by an order of magnitude compared with NP arrays with 5 nm gaps) and good reproducibility, which demonstrates the practical feasibility of this promising two-step pore-widening UTAM technique for the fabrication of high-performance active SERS substrates with large-scale ultra-small nanogaps.

Bismuth oxychloride nanoflake assemblies as a new anode for potassium ion batteries.

This work reports the first demonstration of bismuth oxyhalides as anode materials in potassium-ion batteries. BiOCl nanoflake assemblies deliver high capacities of 367 mA h g-1 at 50 mA g-1 and 175 mA h g-1 at 1 A g-1. The formation of K-Bi alloys at an early stage of potassiation is observed.

Insights into the Crystallinity of Layer-Structured Transition Metal Dichalcogenides on Potassium Ion Battery Performance: A Case Study of Molybdenum Disulfide.

Layer-structured transition metal dichalcogenides (LS-TMDs) are being heavily studied in K-ion batteries (KIBs) owing to their structural uniqueness and interesting electrochemical mechanisms. Synthetic methods are designed primarily focusing on high capacities. The achieved performance is often the collective results of several contributing factors. It is important to decouple the factors and understand their functions individually. This work presents a study focusing on an individual factor, crystallinity, by taking MoS2 as a demonstrator. The performance of low and high-crystallized MoS2 is compared to show the function of crystallinity is dependent on the electrochemical mechanism. Lower crystallinity can alleviate diffusional limitation in 0.5-3.0 V, where intercalation reaction takes charge in storing K-ions. Higher crystallinity can ensure the structural stability of the MoS2 layers and promote surface charge storage in 0.01-3.0 V, where conversion reaction mainly contributes. The low-crystallized MoS2 exhibits an intercalation capacity (118 mAh g-1 ), good cyclability (85% over 100 cycles), and great rate capability (41 mAh g-1 at 2 A g-1 ), and the high-crystallized MoS2 delivers a high capacity of 330 mAh g-1 at 1 A g-1 and retains 161 mAh g-1 at 20 A g-1 , being one of the best among the reported LS-TMDs in KIBs.