Exploring the anti-ferroptosis mechanism of Kai-Xin-San against Alzheimer's disease through integrating network pharmacology, bioinformatics, and experimental validation strategy in vivo and in vitro.

ETHNOPHARMACOLOGICAL RELEVANCE: Kai Xin San (KXS), first proposed by Sun Simiao during the Tang Dynasty, has been utilized to treat dementia by tonifying qi and dispersing phlegm. AIM OF THE STUDY: This study aimed to elucidate the mechanism by which KXS exerts its therapeutic effects on Alzheimer's disease (AD) by targeting ferroptosis, using a combination of network pharmacology, bioinformatics, and experimental validation strategies. MATERIALS AND METHODS: The active target sites and the further potential mechanisms of KXS in protecting against AD were investigated through molecular docking, molecular dynamics simulation, and network pharmacology, and combined with the validation of animal experiments. RESULTS: Computational and experimental findings provide the first indication that KXS significantly improves learning and memory defects and inhibits neuronal ferroptosis by repairing mitochondria damage and upregulating the protein expression of ferroptosis suppressor protein 1 (FSP1) in vivo APP/PS1 mice AD model. According to bioinformatics analysis, the mechanism by which KXS inhibits ferroptosis may involve SIRT1. KXS notably upregulated the mRNA and protein expression of SIRT1 in both vivo APP/PS1 mice and in vitro APP-overexpressed HT22 cells. Additionally, KXS inhibited ferroptosis induced by APP-overexpression in HT22 cells through activating the SIRT1-FSP1 signal pathway. CONCLUSIONS: Collectively, our findings suggest that KXS may inhibit neuronal ferroptosis through activating the SIRT1/FSP1 signaling pathway. This study reveals the scientific basis and underlying modern theory of replenishing qi and eliminating phlegm, which involves the inhibition of ferroptosis. Moreover, it highlights the potential application of SIRT1 or FSP1 activators in the treatment of AD and other ferroptosis-related diseases.

Abnormalities of the Serum proteomic in thrombosis after CVC catheterization in patients with end-stage renal disease.

INTRODUCTION: This study utilized serum proteomics with tandem mass tags (TMT) to investigate potential biomarkers associated with femoral central venous catheter (CVC) thrombosis in endstage kidney disease (ESKD) patients. TMT proteomics analysis on serum samples was conducted to identify proteins with distinct expression levels that may be linked to thrombosis. The findings have important implications for enhancing anticoagulant procedures, catheter closure techniques, and determining optimal intervention timing for post-catheterization dialysis. METHODS: Thirty ESKD patients with CVC receiving hemodialysis between May 2021 and October 2022 at the First Affiliated Hospital of Chengdu Medical College were included in the study, and grouped according to vascular color Doppler ultrasound results, including 23 patients in the thrombo-positive group and 7 patients in the thrombo-negative group. Selection criteria were: 1) Patients with ESKD candidate for hemodialysis initiation; 2) no dialysis access has been placed previously, and CVC needs to be inserted as a temporary access; 3) patients volunteered to participate in this clinical study. Clinical data, blood tests, coagulation function, and biochemical parameters were collected and analyzed on the 14th day after catheterization. Color ultrasonography was conducted on the same day to categorize patients into two groups: those with thrombus-positive results and those with thrombus-negative results. RESULTS: TMT proteomics analysis identified twenty-eight differently expressed proteins, including 16 upregulated and 12 downregulated proteins. Enrichment analysis demonstrated nine proteins that were significantly enriched in four pathways within the thrombus-positive group after CVC insertion. Enzyme-linked immunosorbent assay (ELISA) test confirmed the TMT proteomics findings, specifically highlighting significant differences in human plasma kallikrein B1 (KLKB1) and angiopoietin-like protein 3 (ANGPTL3) levels on the 14th day after CVC insertion. Additionally, KLKB1, fibrinogen (FIB), D-dimer, and fibrinogen degradation products (FDP) levels were significantly elevated, while ANGPTL3 levels were decreased on the 14th day after CVC insertion in the thrombus-positive ESKD patient group. CONCLUSION: Monitoring coagulation status post-CVC catheterization and evaluating potential biomarkers like KLKB1 and ANGPTL3 can contribute to the development of personalized treatment plans, improving the quality of hemodialysis and the overall quality of life for ESKD patients.  DOI: 10.52547/ijkd.7671.

Fan beam CT-guided online adaptive external radiotherapy of uterine cervical cancer: a dosimetric evaluation.

PURPOSE: To discuss the dosimetric advantages and reliability of the accurate delivery of online adaptive radiotherapy(online ART) for uterine cervical cancer(UCC). METHODS AND MATERIALS: Six UCC patients were enrolled in this study. 95% of the planning target volume (PTV) reached 100% of the prescription dose (50.4 Gy/28fractions/6weeks) was required. The patients were scanned with uRT-Linac 506c KV-FBCT then the target volume (TV) and organs at risk (OARs) were delineated by doctors. The dosimeters designed and obtained a routine plan (Plan0). KV-FBCT was used for image guidance before subsequent fractional treatment. The online ART was processed after registration, which acquired a virtual nonadaptive radiotherapy plan (VPlan) and an adaptive plan (APlan). VPlan was the direct calculation of Plan0 on the fractional image, while APlan required adaptive optimization and calculation. In vivo dose monitoring and three-dimensional dose reconstruction were required during the implementation of APlan. RESULTS: The inter-fractional volumes of the bladder and rectum changed greatly among the treatments. These changes influenced the primary gross tumor volume (GTVp) and the position deviation of GTVp and PTV and positively affected the prescription dose coverage of TV. GTVp decreased gradually along with dose accumulation. The Dmax, D98, D95, D50, and D2 of APlan were superior to those of VPlan in target dose distribution. APlan had good conformal index, homogeneity index and target coverage. The rectum V40 and Dmax, bladder V40, the small bowel V40 and Dmax of APlan were better than that of VPlan. The APlan's fractional mean γ passing rate was significantly higher than the international standard and the mean γ passing rate of all cases after the three-dimensional reconstruction was higher than 97.0%. CONCLUSION: Online ART in external radiotherapy of UCC significantly improved the dose distribution and can become an ideal technology to achieve individualized precise radiotherapy.

Analysis of patient medication compliance and quality of life of physician-pharmacist collaborative clinics for T2DM management in primary healthcare in China: A mixed-methods study.

Background: Physician-pharmacist collaboration is a well-established care mode for the management of type 2 diabetes mellitus (T2DM) in developed countries, but no study has been conducted in primary healthcare in China. This study aims to evaluate the effects of physician-pharmacist collaborative clinics to manage T2DM in primary healthcare in China, and to better understand the factors influencing the implementation of physician-pharmacist collaborative clinics. Methods: Two hundred and sixty-seven patients involved in a 12-month randomized controlled trial were assigned to physician-pharmacist collaborative clinics and usual clinics, completing surveys regarding medication compliance, quality of life (QoL) and care-seeking behavior at the baseline, 3rd, 6th, 9th and 12th month respectively, and diabetes knowledge at baseline and 12th month. A sample of twenty-two Patients, nine physicians and twelve pharmacists participated in semi-structured face-to-face interviews. The quantitative and qualitative data was integrated by triangulation. Results: Patients in physician-pharmacist collaborative clinics had significant improvements in medication compliance (p = 0.009), QoL (p = 0.036) and emergency visits (p = 0.003) over the 12-month. Pairwise comparison showed the medication compliance score in the intervention group had been significantly improved at 3rd month (p = 0.001), which is more rapidly than that in the control group at 9th month (p = 0.030). Factors influencing the implementation of physician-pharmacist collaborative clinics were driven by five themes: pharmaceutical service, team-base care, psychological support, acceptability of care and barriers to implementation. Conclusion: Integration of quantitative and qualitative findings showed the effectiveness of physician-pharmacist collaborative clinics in patient medication compliance and QoL in primary healthcare. The qualitative study uncovered barriers in insufficient clinical experience and understaffing of pharmacist. Therefore, the professional training of the primary pharmacist team should be improved in the future. Clinical Trial Registration: clinicaltrials.gov, identifier ChiCTR2000031839.

Optimization of polymyxin B regimens for the treatment of carbapenem-resistant organism nosocomial pneumonia: a real-world prospective study.

BACKGROUND: Polymyxin B is the first-line therapy for Carbapenem-resistant organism (CRO) nosocomial pneumonia. However, clinical data for its pharmacokinetic/pharmacodynamic (PK/PD) relationship are limited. This study aimed to investigate the relationship between polymyxin B exposure and efficacy for the treatment of CRO pneumonia in critically ill patients, and to optimize the individual dosing regimens. METHODS: Patients treated with polymyxin B for CRO pneumonia were enrolled. Blood samples were assayed using a validated high-performance liquid chromatography-tandem mass spectrometry method. Population PK analysis and Monte Carlo simulation were performed using Phoenix NLME software. Logistic regression analyses and receiver operating characteristic (ROC) curve were employed to identify the significant predictors and PK/PD indices of polymyxin B efficacy. RESULTS: A total of 105 patients were included, and the population PK model was developed based on 295 plasma concentrations. AUCss,24 h/MIC (AOR = 0.97, 95% CI 0.95-0.99, p = 0.009), daily dose (AOR = 0.98, 95% CI 0.97-0.99, p = 0.028), and combination of inhaled polymyxin B (AOR = 0.32, 95% CI 0.11-0.94, p = 0.039) were independent risk factors for polymyxin B efficacy. ROC curve showed that AUCss,24 h/MIC is the most predictive PK/PD index of polymyxin B for the treatment of nosocomial pneumonia caused by CRO, and the optimal cutoff point value was 66.9 in patients receiving combination therapy with another antimicrobial. Model-based simulation suggests that the maintaining daily dose of 75 and 100 mg Q12 h could achieve ≥ 90% PTA of this clinical target at MIC values ≤ 0.5 and 1 mg/L, respectively. For patients unable to achieve the target concentration by intravenous administration, adjunctive inhalation of polymyxin B would be beneficial. CONCLUSIONS: For CRO pneumonia, daily dose of 75 and 100 mg Q12 h was recommended for clinical efficacy. Inhalation of polymyxin B is beneficial for patients who cannot achieve the target concentration by intravenous administration.

Insight into autophagy in platinum resistance of cancer.

Platinum drugs, as a class of widely used chemotherapy agents, frequently appear in the treatment of cancer at different phrases. However, platinum resistance is the major bottleneck of platinum drugs for exerting anti-tumor effect. At present, the mechanism of platinum resistance has been thoroughly explored in terms of drug delivery methods, DNA damage repair function, etc., but it has not yet been translated into an effective weapon for reversing platinum resistance. Recently, autophagy has been proved to be closely related to platinum resistance, and the involved molecular mechanism may provide a new perspective on platinum resistance. The aim of this review is to sort out the studies related to autophagy and platinum resistance, and to focus on summarizing the relevant molecular mechanisms, so as to provide clues for future studies related to autophagy and platinum resistance.

Higher incidence of neurotoxicity and skin hyperpigmentation in renal transplant patients treated with polymyxin B.

BACKGROUND: Toxicity is a major concern related to the clinical use of polymyxin B, and available safety data for renal transplant patients are limited. AIMS: We investigated the safety of polymyxin B and toxicity risk factors in renal transplant patients. METHODS: A prospective study was performed on a group of renal transplant patients who received intravenous polymyxin B between January 2018 and August 2021. Polymyxin B treatment was monitored to evaluate toxicity and risk factors. RESULTS: A total of 235 courses of polymyxin B were administered to 213 patients. Of these, 121 (51.5%) developed skin hyperpigmentation (SH), 149 (63.4%) developed neurotoxicity and 10 (5.5%) developed acute kidney injury of which 80% was reversible. Risk factors for developing SH included a high total dose by weight (odds ration [OR] 1.31, 95% confidence interval [CI] 1.08-1.60, P = .008) and the presence of neurotoxicity (OR 2.86, 95% CI 1.56-5.26, P = .001). Neurotoxicity manifested during the first 2 days of treatment. Neurotoxicity occurred most commonly in women (OR 3.84, 95% CI 1.82-8.10, P < .0001), and the presence of SH (OR 1.98, 95% CI 1.13-3.46, P = .016) was also an independent risk factor. CONCLUSIONS: Neurotoxicity and SH are the two major adverse effects of polymyxin B in renal transplant patients, which may limit its clinical use.

Establishing and evaluating physician-pharmacist collaborative clinics to manage patients with type 2 diabetes in primary hospitals in Hunan province: study protocol of a multi-site randomized controlled trial in the era of COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic has exerted an unprecedented and universal impact on global health system, resulting in noticeable challenges in traditional chronic disease care, of which diabetes was reported to be most influenced by the reduction in healthcare resources in the pandemic. China has the world's largest diabetes population, and current diabetes management in China is unsatisfactory, particularly in rural areas. Studies in developed countries have demonstrated that physician-pharmacist collaborative clinics are efficient and cost-effective for diabetes management, but little is known if this mode could be adapted in primary hospitals in China. The aim of this proposed study is to develop and evaluate physician-pharmacist collaborative clinics to manage type 2 diabetes mellitus (T2DM) in primary hospitals in Hunan province. METHODS: A multi-site randomized controlled trial will be conducted to evaluate the effectiveness and cost-effectiveness of the physician-pharmacist collaborative clinics compared with usual care for Chinese patients with T2DM. Six primary hospitals will participate in the study, which will recruit 600 eligible patients. Patients in the intervention group will receive services from both physicians and pharmacists in the collaborative clinics, while the control group will receive usual care from physicians. Patients will be followed up at the 3rd, 6th, 9th and 12th month. Comparison between the two groups will be conducted by assessing the clinical parameters, process indicators and costs on diabetes. A satisfaction survey will also be carried out at the end of the study. DISCUSSION: If effective, the physician-pharmacist collaborative clinics can be adapted and used in primary hospitals of China to improve glycemic control, enhance medication adherence, decrease incidence of complications and reduce patients' dependence on physicians. Findings from the present study are meaningful for developing evidence-based diabetes care policy in rural China, especially in the COVID-19 pandemic era. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR2000031839 , Registered 12 April 2020.

Analysis of the clinical application of ceftazidime-avibactam in China.

BACKGROUND: The efficacy and safety of ceftazidime-avibactam were mainly reported in phase II and phase III clinical trials, rarely in the real-world study. The limited real-world study which evaluated the clinical response of this drug shown inconsistent results. This study aimed to investigate the rationality of the clinical use of ceftazidime-avibactam and to evaluate its clinical response in the treatment of multidrug-resistant gram-negative bacteria (MDR-GNB) infections in China. METHODS: This retrospective study evaluated the outcomes of adult patients with MDR-GNB infections treated with ceftazidime-avibactam during September 2018 to August 2020. Patients' characteristics, comorbidities, microbes, laboratory indicators and medication information were collected. The rationality of ceftazidime-avibactam clinical use, and its clinical response in the treatment of MDR-GNB infections were analyzed. RESULTS: A total of 30 patients were included in this study, of which, 66.6% received target treatment, 26.7% received empirical treatment, and 6.7% received treatment with no indication. Only 50.0% (11/22) of patients were administrated the recommended dose according to the drug instruction or guidelines, at a median treatment duration of 10 days (range: 2-74 days). The most common source of infection was pneumonia (53.6%, 15/28). Carbapenem-resistant Klebsiella pneumoniae was the predominant pathogen (65%, 13/20). A total of 16 patients (61.5%) achieved clinical response. Patients received target treatment had higher clinical response rate than that of patients received empirical treatment (77.8% vs 25.0%, P = 0.026). A total of 11 patients (61.1%) achieved microbiological response. One patient occurred gastrointestinal adverse reactions. CONCLUSIONS: It is necessary to strengthen the monitor of the clinical application of ceftazidime-avibactam, such as the appropriate indication, reasonable dosage and duration, to improve its clinical outcome. Our results showed that ceftazidime-avibactam might be a potencial choice for the MDR-GNB infections. However, further research are still needed to identify its efficacy and safety in the real world.

Cerebral aspergillosis after heart-lung transplantation in a child: Case report with 3-year follow-up and literature review.

There are limited cases of heart-lung transplantation (HLT) in children worldwide owing to lack of donors, demanding surgical teamwork, and arduous post-operative management. Post-transplant management difficulties stem from the possible development of several post-operative complications, with infection being a common complication. Intracranial fungal infections are difficult to diagnose and prone to treatment delays because of their relatively insidious onset and atypical clinical presentation. Here, we present a case of a cerebral infection developed 3 months after HLT in a 10-year-old child, showing no positive results on conventional imaging or cerebrospinal fluid (CSF) examination and culture. On metagenomic next-generation sequencing of the cerebrospinal fluid, the causative organism was finally determined as Aspergillus. After administering 1-year anti-Aspergillus treatment, no recurrence of intracranial fungal infection was noted during the 3-year follow-up. This case illustrates the multifaceted diagnostic techniques for cerebral aspergillosis after HLT and shows the significance of dynamic monitoring of symptoms, such as headache, and of metagenomic sequencing results, trends in intracranial pressure and (1-3)-ß-D-glucan levels for guiding diagnosis and treatment.

Population Pharmacokinetics of Polymyxin B and Dosage Optimization in Renal Transplant Patients.

Currently, polymyxin B has been widely used in the treatment of multidrug-resistant Gram-negative pathogen infections. Due to the limited pharmacokinetic/pharmacodynamic data, the optimal dosage regimen for the recently proposed therapeutic target of the area under the concentration-time curve over 24 h in steady state divided by the minimum inhibitory concentration 50-100 mg⋅h/L has not yet been established. Moreover, most studies have focused on critically ill patients, yet there have been no studies in the field of renal transplantation. To optimize the dosage strategy and reduce the risk of toxicity, a population pharmacokinetics model of polymyxin B with the Phoenix NLME program was developed in our study. A total of 151 plasma samples from 50 patients were collected in the present study. Polymyxin B plasma concentrations were measured by high-performance liquid chromatography-tandem mass spectrometry. A one-compartment model adequately described the data, and the clearance and volume of distribution were 1.18 L/h and 12.09 L, respectively. A larger creatinine clearance was associated with increased clearance of polymyxin B (p < 0.01). Monte Carlo simulation showed that a regimen of a 75 mg loading dose with a 50 mg maintenance dose was a better option to achieve an optimal therapeutic effect (minimum inhibitory concentration ≤1 mg/L) and to reduce the incidence of side effects for patients with renal impairments. The developed model suggested that dosing adjustment should be based on renal function in renal transplant patients.

Incidence of chemotherapy-induced nausea and vomiting among cancer patients receiving moderately to highly emetogenic chemotherapy in cancer centers in Sichuan, China.

PURPOSE: Nausea and vomiting are the most painful and feared side effects for patients during chemotherapy. Currently, most studies focus on the occurrence of CINV during the risk phase. We initiated this real-world study to understand the actual occurrence of CINV throughout all phases, to provide a basis to prevent CINV in patients during chemotherapy and improve their quality of life. METHODS: This prospective real-world study was conducted at 17 major cancer centers in Sichuan, China. Cancer patients who were about to receive moderately/highly emetogenic chemotherapy were included in the study. Occurrences of nausea and vomiting were recorded using patient diaries, and physicians are responsible for recording patient clinical data. RESULTS: A total of 1,139 patients were included in this study between August 2018 and April 2019. In this study, the incidence of acute CINV was 55.3%, delayed CINV was 62.3%, and CINV beyond the risk period was 36%. All phases overall, the overall complete control (CC) rate of CINV was 30.1 and 32.1% for highly and moderately emetogenic chemotherapy regimens, respectively. The median CC time for CINV was 7 days, but only 21.5% of these patients used antiemetic regimens according to the NCCN guideline. CONCLUSION: In the real world, the incidence of CINV is high in patients receiving chemotherapy, and nausea and vomiting may occur beyond the risk period; the low level of standardized antiemetic treatment in compliance with the guideline might have been the main reason for unsatisfactory prevention and control of CINV in this study.

Population pharmacokinetics and exposure-response analysis of tigecycline in patients with hospital-acquired pneumonia.

BACKGROUND: Tigecycline has been widely used to treat hospital-acquired pneumonia (HAP) off-label since it is effective against a wide range of multidrug-resistant bacteria. However, no recommended dosage for this indication has been evaluated, resulting in possible inadequate treatment. AIMS: The aims of this study are to establish the population pharmacokinetic (PPK) model of tigecycline in Chinese patients with HAP, as well as to evaluate the exposure-response relationship for the treatment of HAP with multidrug-resistant gram-negative bacteria. METHODS: A PPK analysis of tigecycline was conducted on pooled data from 328 blood samples obtained from 89 patients with HAP. Tigecycline plasma concentrations were measured by a two-dimensional liquid chromatographic system and the data were analysed using Phoenix NLMETM software. Exposure-response analyses for efficacy were performed based on the data from 79 HAP patients with multidrug-resistant gram-negative infections. Classification and regression tree and logistic regression analyses were employed to identify which pharmacokinetic-pharmacodynamic (PK-PD) indices and magnitudes were the significant predictors of tigecycline efficacy. RESULTS: A two-compartment model with zero-order absorption and first-order elimination adequately described the data. A larger body weight was associated with increased central volume of distribution and clearance (P < .005), and increased age, baseline creatinine concentration and aspertate aminotransferase were associated with decreased clearance (P < .005). The AUC0-12h  × V/MIC ratio, APACHEII score and combined Pseudomonas aeruginosa infection are the strong predictors for tigecycline clinical response. Classification and regression tree analyses indicated that the combination of APACHEII score < 24 and AUC0-12h  × V/MIC ratio ≥ 100 was associated with clinical success. CONCLUSIONS: The proposed PPK model may serve as the basis for estimating tigecycline exposure for PK-PD analyses, and the PK-PD index and magnitude found in this study could be used for designing proper dosage regimens of tigecycline.

The efficacy and toxicity of metronomic oral vinorelbine monotherapy in patients with non-small cell lung cancer: a meta-analysis.

PURPOSE: To evaluate the efficacy and toxicity of metronomic oral vinorelbine monotherapy in patients with stage IIIB/IV and advanced non-small cell lung cancer (NSCLC). METHODS: The PubMed, Embase, Cochrane library, Wanfang, and CNKI databases were searched for relevant studies. The overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and incidence of severe adverse events (grade ≥ 3 adverse events; grade 3/4 AEs) were calculated using the methods of merging ratios and means. Merged ratios and means and their 95% confidence intervals (CIs) were used to descriptively analyze the efficacy and toxicity of metronomic oral vinorelbine monotherapy in patients with stage IIIB/IV and advanced NSCLC. RESULTS: The ORR and DCR achieved with metronomic oral vinorelbine monotherapy were 12% (95% CI 5-20) and 48% (95% CI 38-59), respectively. Median PFS and OS were 3.46 months (95% CI 2.49-4.43) and 8.22 months (95% CI 7.21-9.24), respectively. The incidence of grade 3/4 AEs was 16% (95% CI 10-22). The more common grade 3/4 AEs were neutropenia 9% (95% CI 2-20) and leukopenia 8% (95% CI 1-19). CONCLUSION: Metronomic oral vinorelbine monotherapy has a certain effect on patients with stage IIIB/IV and advanced NSCLC, especially for untreated elderly patients. It offers the advantages of convenience, lower cost and acceptable incidence of severe adverse events.

MicroRNA-1246 regulates the radio-sensitizing effect of curcumin in bladder cancer cells via activating P53.

OBJECTIVES: Radiotherapy is the primary option for bladder cancer patients, but it does not have obvious curative effects. This study was to investigate how to increase radiosensitivity in bladder cancer. MATERIALS AND METHODS: The curcumin and irradiation treated T24 cells were used for analysis of microRNA expression (miRNA microarray), cell viability (Cell Proliferation Assay Kit), colony formation, apoptosis (Annexin V-FITC/7-AAD flow cytometry), miR-1246 and p53 mRNA (real-time PCR) and protein (Western blot) expression. RESULTS: Microarray assay identified 17 differentially expressed miRNAs (twofold change) in curcumin treated cells compared to control cells. Among them, miR-1246 was the miRNA with the largest change in expression after curcumin treatment. Curcumin significantly decreased T24 cell viability and colony formation in a concentration-dependent manner compared to control cells. miR-1246 expression was significantly higher in T24 cells than in SV-HUC-1 cells and the higher concentrations (10 or 20 µM) of curcumin significantly down-regulated miR-1246 expression in T24 and HT-1376 cells. The combination of 10 µM curcumin and irradiation was more effective in decreasing miR-1246 expression, cell viability and colony formation than curcumin or irradiation alone. Inhibition of miR-1246 significantly decreased cell viability and colony formation in T24 and HT-1376 cells. Transfection with antagomiR-1246 significantly increased the G0/G1-phase of T24 cells and induced apoptosis compared to cells transfected with antagomiR-NC. Luciferase reporter assay showed that the overexpression of miR-1246 suppressed the luciferase activity of the P53 3'-UTR reporter genes. CONCLUSION: miR-1246 is involved in the anti-cancer effects of curcumin and irradiation through targeting the inhibition of p53 gene translation in bladder cancer cells.

Clinical experience with tigecycline in the treatment of hospital-acquired pneumonia caused by multidrug resistant Acinetobacter baumannii.

BACKGROUND: Tigecycline, with broad in vitro antibacterial activity, has been widely used off-label for nosocomial pneumonia caused by multi-drug resistant Acinetobacter baumannii (MDRAB). However, many concerns have been raised about the efficacy of tigecycline treatment as the inconsistent results from previous clinical studies. METHODS: This retrospective study evaluated the outcome of adult patients with monomicrobial MDRAB nosocomial pneumonia treated with tigecycline between 2015 and 2017. RESULTS: A total of 77 patients was eligible for this study, and the overall clinical success and 30-day survival rates were 70.03 and 70.13%, respectively, however, the microbiological eradication rate was relatively low (48%). Multivariate analysis indicated that shorter duration of tigecycline use associated with increased clinical failure, whereas higher CURB65 scores, mechanical ventilation and tigecycline resistant to MDRAB have significant association with 30-day mortality. CONCLUSIONS: Our results suggest that tigecycline is one of the potential choices for the treatment of hospital-acquired pneumonia caused by MDRAB, especially with a MIC≤2 mg/L. In addition, a longer duration of tigecycline treatment may be required to insure better clinical outcomes.

Paliperidone, a relatively novel atypical antipsychotic drug, is a substrate for breast cancer resistance protein.

Paliperidone (PAL) is a relatively novel atypical antipsychotic drug for schizophrenia that induces markedly varying responses. Breast cancer resistance protein (BCRP) is a recently discovered member of the ATP-binding cassette superfamily that has been used to control drug absorption, distribution and elimination, and especially to impede drug entry into the brain. To the best of our knowledge, the present study is the first to investigate the possibility of using PAL as a BCRP substrate. The intracellular accumulation and bidirectional transport were investigated using transfected 293 cell/BCRP and porcine renal endothelial cell (LLC-PK1)/BCRP cell monolayers and BCRP overexpression was confirmed by reverse transcription-quantitative polymerase chain reaction and western blot analysis. The in vitro affinity to BCRP was assessed in human BCRP (Arg482) membranes. The intracellular accumulation and bidirectional transport investigations demonstrated that BCRP can efflux PAL from cells and significantly decrease its cellular concentration over a concentration range of 0.1-50 µM. The in vitro affinity experiments indicated that PAL has a moderate affinity to BCRP at 0.1-100 µM. These results together suggest that PAL is a substrate for BCRP and that it can affect the blood-brain barrier penetration of PAL at therapeutic dosages.

Diclofenac--Acetaminophen Combination Induced Acute Kidney Injury In Postoperative Pain Relief.

PURPOSE: The objective of this study was to determine: 1) the incidence and the risk factors of diclofenac/acetaminophen combination as a single agent induced Acute Kidney Injury (AKI) in postoperative pain relief 2) the average cost and length of hospital stay for patients in AKI group and non-AKI group. METHODS: All patients with no prior history of chronic kidney disease (CKD) and normal serum creatinine [44~130 µmol /l] who received diclofenac and acetaminophen combination as a single agent intramuscularly (IM) between January and December 2015 in The Second Xiangya Hospital, Changsha, Hunan, China were included in this retrospective own-control study. Baseline serum creatinine (SCr) and SCr during NSAID use were collected. AKI is defined as an increased of Scr over 1.5 times the baseline. Multivariate analyses were performed with a logistic regression model to assess the significant risk factors of AKI. RESULTS: A total of 821 patients were included in the study with 63 [7.7%] patients had diclofenac/acetaminophen combination single agent induced AKI. Multivariate analysis confirmed that using diclofenac/acetaminophen combination after surgeries within 24 h were significantly associated with AKI [odds ratio, OR, 2.173; 95% CI, 1.113-4.243; P=0.023]. The average cost and length of hospitalization in AKI group was 1.87 times [p=0.000] and 1.2 times [p=0.043] comparison than non-AKI group, respectively. CONCLUSIONS: The incidence of diclofenac/acetaminophen combination single agent induced AKI in postoperative pain relief was 7.7%. Patients with hypertension or liver cirrhosis was more likely to develop AKI and using diclofenac/acetaminophen combination after surgeries within 24 h was significant risk factors for AKI. AKI prolonged the cost and length of hospitalization. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Association Between Vancomycin Blood Brain Barrier Penetration and Clinical Response in Postsurgical Meningitis.

PURPOSE: This study investigated the association between vancomycin blood brain barrier penetration and clinical response in patients with postsurgical meningitis. METHODS: Adult patients with postsurgical meningitis were recruited. Eligible patients received vancomycin 500 mg every 6 h for at least 5 days. On day 3 or 4, cerebrospinal fluid (CSF) and simultaneous serum samples were obtained to determine CSF minimum concentrations (Cmin), serum Cmin and CSF to serum Cmin ratio. RESULTS: Twenty-two patients (14 men and 8 women; mean age of 52.6± 12.1 years) were recruited. The vancomycin Cmin was 3.63 ± 1.64 mg/L in CSF and 13.38 ± 5.36 mg/L in serum, with the CSF to serum Cmin ratio of 0.291 ± 0.118. The Cmin in serum and in CSF showed a significant correlation (p=0.005, r =0.575). The vancomycin CSF Cmin had a significant correlation with the decline of white blood cell counts (WBCs) in CSF (p=0.003, r =0.609). CSF Cmin, serum Cmin and CSF to serum Cmin ratio all showed no significant correlation with clinical response (p=0.335, 0.100, 0.679, respectively). CONCLUSIONS: There was a positive correlation between serum Cmin and CSF Cmin. However, only CSF Cmin is positively correlated with WBCs improvement in CSF. All other parameters such as serum Cmin, CSF Cmin and CSF to serum Cmin ratio had no correlation with clinical response. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Meta-analysis of polymorphism rs6311 and rs6313 in the 5-HT2AR gene and schizophrenia.

BACKGROUND: rs6311 and rs6313 polymorphism of 5-hydroxytryptamine 2A receptor has been widely studied regarding association with susceptibility to schizophrenia, but the results remained inconsistent. AIMS: This study aimed to assess the association between rs6311 and rs6313 polymorphism and schizophrenia using a meta-analysis. METHODS: Pubmed, Web of Science, and Embase databases were searched for all articles linking rs6311 and rs6313 polymorphism and schizophrenia. All studies which met the inclusion and exclusion criteria were included in this meta-analysis. Pooled odds ratio and 95% confidence intervals were used to evaluate the association between rs6311 and rs6313 polymorphism and schizophrenia risk. Sub-group analysis was also performed by different ethnic studies (Asian and Caucasian) and different minor allelic studies (rs6311: minor allele = A and minor allele = G; rs6313: minor allele = T and minor allele = C). RESULTS: Forty articles, including 50 case-control studies, were included in this meta-analysis. Specifically, 12 studies with 4100 cases and 4541 controls involved rs6311, 38 studies with 8960 cases and 9729 controls involved rs6313. The results showed that rs6311 and rs6313 were not associated with schizophrenia. Moreover, no associations were found between rs6311 and schizophrenia in different sub-groups, rs6313 was found to associated with schizophrenia among studies in which C is the minor allele. CONCLUSIONS: This meta-analysis indicates that rs6311 and rs6313 polymorphisms of 5-HT2AR are not associated with schizophrenia. However, the rs6313 polymorphism is associated with schizophrenia in studies in which the minor allele is C.