Immune checkpoint inhibitors in cancer: the increased risk of atherosclerotic cardiovascular disease events and progression of coronary artery calcium.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have contributed to a significant advancement in the treatment of cancer, leading to improved clinical outcomes in many individuals with advanced disease. Both preclinical and clinical investigations have shown that ICIs are associated with atherosclerosis and other cardiovascular events; however, the exact mechanism underlying this relationship has not been clarified. METHODS: Patients diagnosed with stages III or IV non-small cell lung cancer (NSCLC) at the Wuhan Union Hospital from March 1, 2020, to April 30, 2022, were included in this retrospective study. Coronary artery calcium (CAC) volume and score were assessed in a subset of patients during non-ECG-gated chest CT scans at baseline and 3, 6, and 12 months after treatment. Propensity score matching (PSM) was performed in a 1:1 ratio to balance the baseline characteristics between the two groups. RESULTS: Overall, 1458 patients (487 with ICI therapy and 971 without ICI therapy) were enrolled in this cardiovascular cohort study. After PSM, 446 patients were included in each group. During the entire period of follow-up (median follow-up 23.1 months), 24 atherosclerotic cardiovascular disease (ASCVD) events (4.9%) occurred in the ICI group, and 14 ASCVD events (1.4%) in the non-ICI group, before PSM; 24 ASCVD events (5.4%) occurred in the ICI group and 5 ASCVD events (1.1%) in the non-ICI group after PSM. The CAC imaging study group comprised 113 patients with ICI therapy and 133 patients without ICI therapy. After PSM, each group consisted of 75 patients. In the ICI group, the CAC volume/score increased from 93.4 mm3/96.9 (baseline) to 125.1 mm3/132.8 (at 12 months). In the non-ICI group, the CAC volume/score was increased from 70.1 mm3/68.8 (baseline) to 84.4 mm3/87.9 (at 12 months). After PSM, the CAC volume/score was increased from 85.1 mm3/76.4 (baseline) to 111.8 mm3/121.1 (12 months) in the ICI group and was increased from 74.9 mm3/76.8 (baseline) to 109.3 mm3/98.7 (12 months) in the non-ICI group. Both cardiovascular events and CAC progression were increased after the initiation of ICIs. CONCLUSIONS: Treatment with ICIs was associated with a higher rate of ASCVD events and a noticeable increase in CAC progression.

Long-term Radiological and Pulmonary Function Abnormalities at 3-year post COVID-19 Hospitalization: A Longitudinal Cohort Study.

BACKGROUND: This study aimed to evaluate the longitudinal progression of residual lung abnormalities (ground-glass opacities, reticulations, and fibrotic-like changes) and pulmonary function, three years following coronavirus disease 2019(COVID-19). METHODS: This prospective, longitudinal cohort study enrolled COVID-19 survivors who exhibited residual lung abnormalities upon discharge from two hospitals. Follow-up assessments were conducted at 6 months, 12 months, 2 years, and 3 years post-discharge, and included pulmonary function tests, 6-minute walk distance (6MWD), chest CT scans, and symptom questionnaires. Non-COVID-19 controls were retrospectively recruited for comparative analysis. RESULTS: 728 COVID-19 survivors and 792 controls were included. From 6 months to 3 years, there was a gradual improvement in reduced diffusing capacity of the lungs for carbon monoxide (DLCO＜80% predicted, 49% versus 38%, p=0.001), 6MWD (496 m versus 510 m, p=0.002) and residual lung abnormalities(46% versus 36%, p<0.001), regardless of the disease severity. Patients with residual lung abnormalities at 3 years more commonly had respiratory symptoms (32% versus 16%, p<0.001), lower 6MWD (494 m versus 510 m, p=0.003), and abnormal DLCO (57% versus 27%, p<0.001) compared to those with complete resolution. Compared to the controls, the proportion of DLCO impairment (38% versus 17%, p<0.001) and respiratory symptoms (23% versus 2.2%, p<0.001) were significantly higher in the matched COVID-19 survivors at the 3-year follow-up. CONCLUSIONS: Most patients exhibited improvement in radiological abnormalities and pulmonary function over time following COVID-19. However, more than one-third continued to have persistent lung abnormalities at the 3-year mark, which were associated with respiratory symptoms and reduced diffusion capacity.

Serum tumor marker and CT body composition scoring system predicts outcomes in colorectal cancer surgical patients.

OBJECTIVE: To investigate the prognostic value of preoperative body composition and serum tumor markers (STM) in patients undergoing surgical treatment for colorectal cancer (CRC) and to establish the prognostic score for patients with CRC. METHODS: This study enrolled 365 patients (training set 245, validation set 120) with CRC who underwent surgical resection. The predictive value of various body composition features and STM for determining CRC prognosis were compared. A novel index score based on the independent risk factors from Cox regression for CRC patients was established and evaluated for its usefulness. RESULTS: Multivariate Cox regression showed that low skeletal muscle radiodensity (SMD) (p = 0.020), low subcutaneous fat area (SFA) (p = 0.029), high carcinoembryonic antigen (CEA) (p = 0.008), and high alpha-fetoprotein (AFP) (p = 0.039) were all independent prognostic factors for poor overall survival (OS). The multifactorial analysis indicated that high intermuscular fat area (IMFA) (p = 0.033) and high CEA (p = 0.009) were independent prognostic factors for poor disease-free survival (DFS). Based on these findings, two scoring systems for OS and DFS were established in the training datasets. CRC patients who scored higher on the new scoring systems had lower OS and DFS (both p < 0.001) as shown in the Kaplan-Meier survival curves in the training and validation datasets. CONCLUSION: In predicting the prognosis of CRC patients, SFA and SMD are superior to other body composition measurements. A scoring system based on body composition and STM can have prognostic value and clinical applicability. CLINICAL RELEVANCE STATEMENT: This scoring system, combining body composition and serum tumor markers, may help predict postoperative survival of CRC patients and help clinicians make well-informed decisions regarding the treatment of patients. KEY POINTS: Colorectal cancer prognosis can be related to body composition. High intermuscular fat area and CEA were independent prognostic factors for poor disease-free survival. This scoring system, based on body composition and tumor markers, can prognosticate for colorectal cancer patients.

In vivo pharmacodynamic study of contezolid acefosamil, a prodrug of contezolid for oral and intravenous administration.

OBJECTIVES: Contezolid acefosamil is a novel O-acyl phosphoramidate prodrug of contezolid. In the current study, we aimed to systemically evaluate the efficacy of contezolid acefosamil against infections caused by multiple Gram-positive pathogens, and compare the efficacy of the prodrug by oral and intravenous administrations. METHODS: The in vivo pharmacodynamic efficacy of contezolid acefosamil was evaluated in mouse models of systemic (with five S. aureus, three S. pneumoniae and two S. pyogenes bacterial isolates) and thigh (with two S. aureus isolates) infections using linezolid as the reference agent. RESULTS: In both models, contezolid acefosamil administrated either orally or intravenously, demonstrated high antibacterial efficacy similar to linezolid, and the antibacterial efficacy of oral and intravenous contezolid acefosamil were comparable. CONCLUSIONS: The high aqueous solubility and great efficacy of contezolid acefosamil support its clinical development as an injectable and oral antibiotic suitable for serious Gram-positive infections.

Changes of energy metabolism in failing heart and its regulation by SIRT3.

Heart failure (HF) is the leading cause of hospitalization in elderly patients and a disease with extremely high morbidity and mortality rate worldwide. Although there are some existing treatment methods for heart failure, due to its complex pathogenesis and often accompanied by various comorbidities, there is still a lack of specific drugs to treat HF. The mortality rate of patients with HF is still high, highlighting an urgent need to elucidate the pathophysiological mechanisms of HF and seek new therapeutic approaches. The heart is an organ with a very high metabolic intensity, mainly using fatty acids, glucose, ketone bodies, and branched-chain amino acids as energy substrates to supply energy for the heart. Loss of metabolic flexibility and metabolic remodeling occurs with HF. Sirtuin3 (SIRT3) is a member of the NAD+-dependent Sirtuin family located in mitochondria, and can participate in mitochondrial physiological functions through the deacetylation of metabolic and respiratory enzymes in mitochondria. As the center of energy metabolism, mitochondria are involved in many physiological processes. Maintaining stable metabolic and physiological functions of the heart depends on normal mitochondrial function. The damage or loss of SIRT3 can lead to various cardiovascular diseases. Therefore, we summarize the recent progress of SIRT3 in cardiac mitochondrial protection and metabolic remodeling.

Spatiotemporal variation of hydrological connectivity and its threshold effects on flood dynamics: An examination in the arid and semi-arid regions, China.

Hydrological connectivity, a critical indicator of underlying surface changes, plays a pivotal role in the generation and evolution of floods. This study focuses on examining hydrological connectivity and its significant impact on flood dynamics. The Hekou-Longmen section (HL) is used as a case area because of its frequent flooding, which is typical of arid and semi-arid zone. By employing the modified hydrological connectivity index (IC), this study evaluated the hydrological connectivity and examined its spatiotemporal variation of the HL. Based on 1131 Annual Maximum Instantaneous Streamflow (AMS) data of 21 sub-basins in the HL, a panel threshold regression model was used to reveal threshold effect of IC on flood dynamics. The results showed that the annual mean IC showed a decreasing trend, with spatial variation dominated by significant decreases and no change. Furthermore, it was found that the magnitude of the effect of extreme precipitation (EP) on AMS increased with increasing IC thresholds. The threshold effect of EP on AMS were found to exist during the 1990s, 2000s, and 2010s, with thresholds of 2.84, 3.27, and 3.37, respectively. This research established a quantitative framework for comprehensively evaluating the impact of underlying surface changes on flood, providing important reference for the study of flood mechanisms in similar arid and semi-arid regions globally.

The promotion of fatty acid ß-oxidation by hesperidin via activating SIRT1/PGC1α to improve NAFLD induced by a high-fat diet.

Reducing fat deposits in hepatocytes is a direct treatment for nonalcoholic fatty liver disease (NAFLD) and the fatty acid metabolic processes mediated by fatty acid ß-oxidation are important for the prevention of NAFLD. In this study, we established high-fat-diet models in vitro and in vivo to investigate the mechanism by which hesperidin (HDN) prevents NAFLD by modulating fatty acid ß oxidation. Based on LC-MS screening of differential metabolites, many metabolites involved in phospholipid and lipid metabolism were found to be significantly altered and closely associated with fatty acid ß-oxidation. The results from COIP experiments indicated that HDN increased the deacetylation of PGC1α by SIRT1. In addition, the results of CETSA and molecular docking experiments suggest that HDN targeting of SIRT1 plays an important role in their stable binding. Meanwhile, it was found that HDN reduced fatty acid uptake and synthesis and promoted the expression of SIRT1/PGC1α and fatty acid ß-oxidation, and the latter process was inhibited after transfection to knockdown SIRT1. The results suggest that HDN improves NAFLD by promoting fatty acid ß-oxidation through activating SIRT1/PGC1α. Thus, the findings indicate that HDN may be a potential drug for the treatment of NAFLD.

Analysis of the evolution of water culture and water security in the Weihe River Basin over a 100 year-period.

The significance of water culture in addressing water crises and ensuring water security has garnered considerable attention, emerging as a focal point in global change and water science research. Water culture is a societal adaptation to changes in hydrological systems. However, this needs to be acknowledged within contemporary discourse on water security governance. This study utilized historical policy document data from many sources, including local municipal records from Shaanxi and Gansu, and water conservancy records. It aimed to identify the significant nodes and stages of policy transformation in the Weihe River Basin (WRB) during the last century (1949-2020). This study employed a content analysis method to elucidate the evolutionary patterns of water culture in the study region during the previous century. Drawing on the co-evolution framework, our investigation delved into the reciprocal relationship between changes in water culture and the evolution of water security in the WRB. Our findings indicated that water culture transformation in the WRB has undergone four significant stages: the Disaster-Resistant Hydraulic (1949-1966), Irrigation Hydraulic (1967-1998), Resources Hydraulic (1999-2010), and Ecological Hydraulic (2011-2020) phases. Water security assessment showed that policy attention varied across the different stages. The disaster-resistant hydraulic phase primarily addressed water-related disaster concerns, whereas the irrigation hydraulic phase emphasized the scarcity of water resources. The resource hydraulic phase focused on ensuring the security of the water environment, while the ecological hydraulic phase placed emphasis on safeguarding water sustainability. Moreover, we found that prevailing water policies prioritize resolving isolated issues; however, water security is a multifaceted systemic matter that requires a comprehensive approach. This study has the potential to offer policy makers a more comprehensive and systematic perspective, enabling them to enhance their understanding of the underlying nature of the problems. Additionally, this study can assist in developing future water security policies.

New insight into mycotoxins and bacterial toxins: Toxicity assessment, molecular mechanism and food safety (preface to the special issue of food and chemical toxicology on the outcomes of Myco & bacterial toxin).

The special issue "New Insight into Mycotoxins and Bacterial Toxins: Toxicity Assessment, Molecular Mechanism and Food Safety" in Food and Chemical Toxicology contains 19 articles on current hot topics in mycotoxins and bacterial toxins. Dietary exposure to mycotoxins and risk assessments are reported in this issue. Molecular mechanisms of multiple mycotoxins and emerging mechanisms of toxicity are especially concerned by researchers. Moreover, mycotoxin-detoxifying substances and antimicrobial agents are also fully investigated in the context. This special issue will help to further understand the mycotoxins and bacterial toxins, casting new light for the control of food safety.

Influence of skeletal muscle and intermuscular fat on postoperative complications and long-term survival in rectal cancer patients.

BACKGROUND: The body composition of patients with rectal cancer potentially affects postoperative outcomes. This study explored the correlations between skeletal muscle and adipose tissue quantified by computed tomography (CT) with postoperative complications and long-term prognosis in patients with rectal cancer after surgical resection. METHODS: This retrospective cohort study included patients with rectal cancer who underwent surgical resection at the Wuhan Union Hospital between 2014 and 2018. CT images within 3 months prior to the surgery were used to quantify the indices of skeletal muscle and adipose tissue at the levels of the third lumbar vertebra (L3) and umbilicus. Optimal cut-off values for each index were defined separately for males and females. Associations between body composition and postoperative complications, overall survival (OS), and disease-free survival (DFS) were evaluated using logistic and Cox proportional hazards models. RESULTS: We included 415 patients (240 males and 175 females; mean age: 57.8 ± 10.5 years). At the L3 level, a high skeletal muscle density (SMD; hazard ratio [HR]: 0.357, 95% confidence interval [CI]: 0.191-0.665, P = 0.001; HR: 0.571, 95% CI: 0.329-0.993, P = 0.047) and a high skeletal muscle index (SMI; HR: 0.435, 95% CI 0.254-0.747, P = 0.003; HR: 0.568, 95% CI: 0.359-0.897, P = 0.015) were independent prognostic factors for better OS and DFS. At the umbilical level, a large intermuscular fat area (IMFA; HR: 1.904, 95% CI: 1.068-3.395, P = 0.029; HR: 2.064, 95% CI: 1.299-3.280, P = 0.002) was an independent predictive factor for worse OS and DFS, and a high SMI (HR: 0.261, 95% CI: 0.132-0.517, P < 0.001; HR: 0.595, 95% CI: 0.387-0.913, P = 0.018) was an independent prognostic factor for better OS and DFS. The models combining body composition and clinical indicators had good predictive abilities for OS. The receiver operating characteristic areas under the curve were 0.848 and 0.860 at the L3 and umbilical levels, respectively (both P < 0.05). CONCLUSIONS: No correlations existed between CT-quantified body composition parameters and postoperative complications. However, a high SMD and high SMI were significantly associated with longer OS and DFS at the L3 level, whereas a large IMFA and low SMI were associated with worse OS and DFS at the umbilical level. Combining CT-quantified body composition and clinical indicators could help physicians predict the prognosis of patients with rectal cancer after surgery.

Identification of suitable areas for African swine fever occurrence in china using geographic information system-based multi-criteria analysis.

African swine fever (ASF) is a hemorrhagic and fatal disease of domestic pigs and wild boars caused by the African swine fever virus (ASFV). There is neither effective treatment nor vaccine at present, and thus this disease has led to major economic losses and adverse impacts on the livelihoods of stakeholders involved in the pork food system in China. In this study, a multi-criteria decision analysis (MCDA) method based on a geographic information system (GIS) was used to identify suitable areas for ASF occurrence in China. Ten spatial risk factors regarding ASF epidemic in China were identified from literature reviews, and the relative importance between them was evaluated by experts based on a pairwise comparison matrix. A numerical weight was calculated for each risk factor using an analytic hierarchy process (AHP) based on the evaluated results. The corresponding geographic data were collected, according to the hypothetical relationship between each factor and the suitability for ASF occurrence, risk factors were converted to standardized geographical layers using suitability relationship and then were combined using a weighted linear combination (WLC) method to produce a map of suitability for ASF occurrence. The results showed that our map has good accuracy in predicting the hot- spots of ASF in China (AUC =0.791; 95% CI [0.741-0.852]). In conclusion, our study provides decision-making aid support for Chinese veterinary services to implement African swine fever surveillance and control measures.

Hesperidin attenuates hepatic lipid accumulation in mice fed high-fat diet and oleic acid induced HepG2 via AMPK activation.

AIMS: In recent years, more and more people are suffering from lifestyle-related disease such as nonalcoholic fatty liver disease (NAFLD) because of unhealthy diet and lack of physical exercise. Hesperidin (HDN) is a flavonoid found in high concentrations in citrus fruits. In this study, we investigated the effect of HDN on NAFLD, providing information to develop dietary supplements for NAFLD treatment and prevention. MATERIALS AND METHODS: Testing kits, hematoxylin-eosin staining, oil red O staining, western blot, immunofluorescence, cck-8 assay, and blood biochemical analysis were carried out during the experiments in vivo and in vitro. KEY FINDINGS: The current study revealed that HDN significantly reduced liver index and serum lipid levels, and protected against liver steatosis and injury induced by HFD. In addition, HDN suppressed oil acid induced intracellular lipid accumulation in HepG2 cells. Moreover, HDN increased the expression level of pAMPK and downregulated SREBP-1C, ACC and FAS expression in vivo and in vitro. SIGNIFICANCE: In summary, HDN attenuates lipid accumulation in vivo and in vitro via AMPK activation, suggesting that HDN may serve as a potential therapeutic agent for treating NAFLD.

Effect-directed analysis of estrogenic chemicals in sediments from an electronic-waste recycling area.

Electronic waste (e-waste) pollution is of great concern due to the release of hazardous chemicals during the improper e-waste disposal. Many chemicals leached from e-waste were reported to pose estrogenic effects. To date, little is known regarding the occurrence and biological effects of estrogenic chemicals in sediments near an e-waste area. In this study, an effect-directed analysis (EDA) is applied to determine the estrogenic chemicals in sediments of four sites collected from a typical e-waste recycling city in China. Following screening with the ER-CALUX assay, the extract of sample with the most potent effect was subjected in fractionation using reverse phase liquid chromatography. Based on a target analysis for the active fractions, four compounds, including estrone, 17ß-estradiol, 17α-ethinylestradiol and bisphenol A, were identified, and these contributed to 17% of the total toxic effects in the sample. A further nontarget analysis screened four candidates, namely diethylstilbestrol (DES), hexestrol (HES), nandrolone and durabolin, and the total contribution was found to be 48% from the active sample. Specifically, DES and HES were only detected in the active sample and were found to be the primary drivers of estrogenic effects. An examination of the identified chemicals in the four sites indicated that these estrogenic chemicals may originate from e-waste recycling, livestock excretion and domestic waste. These findings uncovered the estrogenic pollutants in sediments from an e-waste area. Considering single endpoint in biological assay is not abundant to screen chemicals with different toxic effects, further EDA studies with multiple endpoints are required to better understand the occurrence of representative or unknown chemicals in e-waste-polluted areas.

Effect-directed analysis for revealing aryl hydrocarbon receptor agonists in sediment samples from an electronic waste recycling town in China.

Exposure to electronic and electrical waste (e-waste) has been related to a few adverse health effects. In this study, sediment samples from an e-waste recycling town in China were collected, and aryl hydrocarbon receptor (AhR) agonists in the samples were identified using an effect-directed analysis (EDA) strategy. The CBG2.8D cell line reporter gene bioassay was used as a toxicity test, while suspect screening against chemical databases was performed for potential AhR agonist identification where both gas chromatography- and liquid chromatography-high resolution mass spectrometry analyses were run. When the original sample extract showed high AhR-mediated activity, sample fractionation was performed, and fractions exhibiting high bioactivity were chemically analyzed again to reveal the corresponding AhR agonists. In total, 23 AhR agonists were identified, including 14 commonly known ones and 9 new ones. Benzo [k]fluoranthene and 6-nitrochrysene were the dominant AhR agonists, covering 16-71% and 2.7-12%, respectively, of the AhR activation effects measured in the parent extracts. The newly identified AhR-active chemicals combined explained 0.13-0.20% of the parent extracts' effects, with 7,12-dimethylbenz [a]anthracene and 8,9,11-trimethylbenz [a]anthracene being the major contributors. A diagnostic isomer ratio analysis of polycyclic aromatic hydrocarbons suggested that the major source of AhR agonists identified in these e-waste related sediment samples were probably petroleum product combustion and biomass combustion. In the future, for a more comprehensive AhR agonist investigation, in-house chemical synthesis and purification, and, when necessary, a secondary sample fractionation, would be beneficial.

Rg3 regulates myocardial pyruvate metabolism via P300-mediated dihydrolipoamide dehydrogenase 2-hydroxyisobutyrylation in TAC-induced cardiac hypertrophy.

The failing heart is characterized by an increase in glucose uptake and glycolytic rates that is not accompanied by a concomitant increase in glucose oxidation. Lower coupling of glucose oxidation to glycolysis possibly owes to unchanged or reduced pyruvate oxidation in mitochondria. Therefore, increasing pyruvate oxidation may lead to new therapies for heart disease. Dihydrolipoamide dehydrogenase (DLD) is a component of the pyruvate dehydrogenase complex (PDH). DLD mutations or defects are closely associated with metabolic diseases. However, few studies explore the effects of DLD mutants or acylation status on PDH activity and pyruvate metabolism. P300 is protein 2-hydroxyisobutyryltransferases in cells, and P300-dependent lysine 2-hydroxyisobutyrylation of glycolytic enzymes affects glucose metabolism. However, there are no relevant reports on the effect of 2-hydroxyisobutyrylation on the energy metabolism of heart failure, and it is worth further in-depth study. In this study, we showed that 2-hydroxyisobutyrylation is an essential protein translational modification (PTM) that regulates the activity of pyruvate dehydrogenase complex (PDHc). In a mouse model of transverse aortic constriction (TAC)-induced cardiac hypertrophy, the 2-hydroxyisobutylation of DLD was significantly increased, related to the decrease in PDH activity. In addition, our data provide clear evidence that DLD is a direct substrate of P300. As one of the main active ingredients of ginseng, ginsenoside Rg3 (Rg3) can reduce the 2-hydroxyisobutylation levels of DLD and restore the PDH activity by inhibiting the acyltransferase activity of P300, thereby producing beneficial effects whenever the heart is injured. Therefore, this study suggests a novel strategy for reversing myocardial hypertrophy.

Enhancement of Fe-C micro-electrolysis in water by magnetic field: Mechanism, influential factors and application effectiveness.

Fe-C micro-electrolysis system has been widely used in filters, or as an advanced treatment process in some water treatment plants to treat various wastewater. In this study, Fe-C micro-electrolysis process was enhanced by an economical and environmentally friendly method, applied magnetic field. Batch kinetic experiments and scanning electron micrographs demonstrated a more effective micro-electrolysis and more severely corroded on the surface of Fe-C after applying a magnetic field at pH 3.0. An applied magnetic field reduced the charge-transfer resistance and increased the current density in micro-electrolysis system and Fe-C became more prone to electrochemical corrosion. Corrosion products were proved to be Fe2+, Fe3O4, and C-O, moreover, the formation of them were also increased in the presence of a magnetic field. Base on that, some influential factors like magnetic field flux intensity, Fe-C particle size, pH, Fe-C dosage and its reusability were investigated in this paper. Since Fe2+ release was accelerated in micro-electrolysis system by an applied magnetic field, combination of various advanced oxidation processes were designed to explore the application effectiveness of the system. The degradation rate of target contaminant was significantly improved in the presence of a magnetic field, suggesting it could be a reliable method for wastewater treatment.

Clinical and microbiological characteristics of hypervirulent Klebsiella pneumoniae (hvKp) in a hospital from North China.

INTRODUCTION: The clinical and molecular characteristics of hypervirulent Klebsiella pneumoniae (hvKp) in various provinces of China have been reported, however, there have been few reports in Hebei Province, North China. METHODOLOGY: The hvKp was identified by PCR amplification of hypervirulence-related genes, the hypermucoviscous phenotype was determined by the "string test", the drug susceptibility analysis was performed using the VITEK® 2 Compact Bacterial Identification and Monitoring System. Logistic regression was used to identify risk factors for hvKp infection. The molecular epidemiological characteristics of the strains were analyzed by pulsed-field gel electrophoresis (PFGE), and the capsular serotype of hvKp strain was detected by PCR. RESULTS: Overall, 52.21% (59/113) of K. pneumoniae isolates were hvKp, and the ratios of patients with older ages or a higher PMN cell count among hvKp infection were higher than those among classical Klebsiella pneumoniae (cKp) infection. hvKp are more susceptible to antibacterial drugs than cKp, and one ESBLs-producing hvKp strain was detected. The main capsular serotype of hvKp were K2, K57 and K1. PFGE indicated that the 59 strains of hvKp could be classified into 51 PFGE band types, forming 6 PFGE clusters. CONCLUSIONS: In this study, the detection rate of hvKp was 52.21% (59/113) identified by virulence genes. People with older ages or a higher PMN cell count are more likely to gain hvKp infection. ESBLs-producing hvKp is emerging, indicating the importance of epidemiologic surveillance and clinical awareness of this pathogen in this region.

Development and validation of a sensitive LC-MS/MS method for the quantitation of IMB-YH-4py5-2H, an antituberculosis candidate, and its application to the pharmacokinetic study.

(E)-N,N-dimethyl-4-oxo-4-(4-(pyridin-4-yl)phenyl)but-2-enamide hydrochloride (IMB-YH-4py5-2H) is a novel Protein Kinase B (PknB) inhibitor with potent activity against Mycobacterium tuberculosis strains. In the present study, a sensitive and specific liquid chromatography/tandem mass spectrometry (LC-MS/MS) method was developed and validated to determine IMB-YH-4py5-2H in rat plasma. Sample pretreatment was achieved by liquid-liquid extraction with ethyl acetate, and separation was performed on an XTerra MS C18 column (2.1×50 mm, 3.5 µm) with gradient elution (methanol and 0.1% formic acid) at a flow rate of 0.3 mL/min. Detection was performed in multiple reaction monitoring (MRM) mode. Linear calibration curves were obtained over a concentration range of 1-100 ng/mL. The intra-day and inter-day precisions were lower than 8.46%, and the accuracies ranged from -8.71% to 12.36% at all quality control levels. The extraction recoveries were approximately 70%, and the matrix effects were negligible. All quality control samples were stable under different storage conditions. The validated method was successfully applied to a preclinical pharmacokinetic study in Sprague-Dawley rats. IMB-YH-4py5-2H demonstrated improved pharmacokinetic properties (higher exposure level) compared with its leading compound. IMB-YH-4py5-2H was also distributed throughout the lung pronouncedly, especially inside alveolar macrophages, indicating its effectiveness against lower respiratory infections.

Microdialysis combined with liquid chromatography-tandem mass spectrometry for the quantitation of gemifloxacin and its application to a muscle penetration study in healthy and MRSA-infected rats.

Pharmacological efficacy is based on the drug concentration in target tissues, which usually cannot be represented by the plasma concentration. The purpose of this study was to compare the pharmacokinetic characteristics of gemifloxacin in plasma and skeletal muscle and evaluate its tissue penetration in both healthy and MRSA (methicillin-resistant Staphylococcus aureus)-infected rats. A microdialysis (MD) combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated to determine free gemifloxacin concentrations in rat plasma and skeletal muscle simultaneously. The in vivo recoveries of MD were 23.21% ± 3.42% for skeletal muscle and 20.62% ± 3.19% for plasma, and were concentration independent. We provided evidence that the method developed here meets FDA requirements. Additionally, this method was successfully applied to the determination of free gemifloxacin in rats. Muscle and blood dialysates were collected after an 18 mg/kg intravenous bolus dose. The mean areas under the concentration-time curves (AUCs) from 0 to 9 h for skeletal muscle and plasma were 3641.50 ± 915.65 h*ng/mL and 7068.32 ± 1964.19 h*ng/mL in MRSA-infected rats and 3774.72 ± 700.36 h*ng/mL and 6927.49 ± 1714.86 h*ng/mL in healthy rats, respectively. There was no significant difference (P>0.05) in gemifloxacin exposure between healthy rats and MRSA-infected rats for plasma or muscle. The low ratio of AUC0-9 muscle to AUC0-9 plasma suggested lower drug exposure in skeletal muscle than in plasma for both healthy and MRSA-infected rats. Our study suggested that the administration of gemifloxacin according to drug levels in plasma to treat local infection is unreasonable and might result in an inadequate dose regimen.

Synthesis and Bioactivity Investigation of the Individual Components of Cyclic Lipopeptide Antibiotics.

In this paper, 26 natural polymyxin components and a new derivative S2 were synthesized, and their differences in efficacy and toxicity have been investigated. Almost all of the synthesized components showed strong activity against both susceptible and resistant strains of E. coli, K. pneumoniae, P. aeruginosa, and A. baumannii. The toxicities were obviously different between the components. Only some of the components were tested for toxicity in vivo. Compounds E2, E2-Val, A2, M2, D2, and S2 showed obviously lower renal cytotoxicity and acute toxicity than polymyxins B and E. The in vivo nephrotoxicity of E2, M2, and S2 was similar to that of polymyxin E. Compound S2, with four positive charges, was especially interesting as it possessed both increased efficacy and decreased toxicity. The SAR and toxicity studies indicated that further structural modification could concentrate on polymyxin S. The results also indicated that S2 could be a new drug candidate.