Equilibrative nucleotide transporter ENT3 (SLC29A3): A unique transporter for inherited disorders and cancers.

As a crucial gene associated with diseases, the SLC29A3 gene encodes the equilibrative nucleoside transporter 3 (ENT3). ENT3 plays an essential regulatory role in transporting intracellular hydrophilic nucleosides, nucleotides, hydrophilic anticancer and antiviral nucleoside drugs, energy metabolism, subcellular localization, protein stability, and signal transduction. The mutation and inactivation of SLC29A3 are intimately linked to the occurrence, development, and prognosis of various human tumors. Moreover, many hereditary human diseases, such as H syndrome, pigmentary hypertrichosis and non-autoimmune insulin-dependent diabetes mellitus (PHID) syndrome, Faisalabad histiocytosis (FHC), are related to SLC29A3 mutations. This review explores the mechanisms of SLC29A3 mutations and expression alterations in inherited disorders and cancers. Additionally, we compile studies on the inhibition of ENT3, which may serve as an effective strategy to potentiate the anticancer activity of chemotherapy. Thus, the synopsis of genetics, permeant function and drug therapy of ENT3 provides a new theoretical and empirical foundation for the diagnosis, prognosis of evaluation and treatment of various related diseases.

Development and validation of an automatic machine learning model to predict abnormal increase of transaminase in valproic acid-treated epilepsy.

Valproic acid (VPA) is a primary medication for epilepsy, yet its hepatotoxicity consistently raises concerns among individuals. This study aims to establish an automated machine learning (autoML) model for forecasting the risk of abnormal increase of transaminase levels while undergoing VPA therapy for 1995 epilepsy patients. The study employed the two-tailed T test, Chi-square test, and binary logistic regression analysis, selecting six clinical parameters, including age, stature, leukocyte count, Total Bilirubin, oral dosage of VPA, and VPA concentration. These variables were used to build a risk prediction model using "H2O" autoML platform, achieving the best performance (AUC training = 0.855, AUC test = 0.789) in the training and testing data set. The model also exhibited robust accuracy (AUC valid = 0.742) in an external validation set, underscoring its credibility in anticipating VPA-induced transaminase abnormalities. The significance of the six variables was elucidated through importance ranking, partial dependence, and the TreeSHAP algorithm. This novel model offers enhanced versatility and explicability, rendering it suitable for clinicians seeking to refine parameter adjustments and address imbalanced data sets, thereby bolstering classification precision. To summarize, the personalized prediction model for VPA-treated epilepsy, established with an autoML model, displayed commendable predictive capability, furnishing clinicians with valuable insights for fostering pharmacovigilance.

Neonatal exposure to low-dose X-ray causes behavioral defects and abnormal hippocampal development in mice.

Development of the hippocampus is critical for its normal maturation. However, there is no systematic study on the effects of low-dose (≤2 Gy) neonatal X-ray exposure on different cells at different developmental stages of the mouse hippocampus. The present study demonstrated that irradiation with 2 Gy at postnatal day (PD) 3 in mice induced anxiety and impairment of spatial learning and memory in adult mice. Neuroinflammatory cells were observed in the dentate gyrus (DG) and CA3 areas of the hippocampus at PD3 + 1. X-ray irradiation impaired neuronal complexity and neurogenesis. However, the number of astrocytes and microglia in the hippocampus was increased the first day after irradiation, and then decreased 21 days later. The protein expression levels of NF-κB, C/EBP homologous protein (CHOP), and γH2 A histone family member X (γH2 AX) increased from 7 to 21 days after irradiation, or till 90 days after irradiation for IL-1ß, whereas those of hippocampal sirtuin1 (SIRT1) decreased after 21 days of irradiation at PD3. These results suggest that neonatal X-ray irradiation-induced neuroinflammation impaired neuroplasticity and neurogenesis in the hippocampus, leading to the anxiety and spatial memory disorder during adulthood. The mechanisms involved in the induction of developmental neurotoxicity following low-dose irradiation may involve the inflammation-mediated signaling pathway IL-1ß/ SIRT1/CHOP.

Discovery of pyrazolones as novel carboxylesterase 2 inhibitors that potently inhibit the adipogenesis in cells.

Carboxylesterase 2 (CES2) is one of the most important Phase I drug metabolizing enzymes in the carboxylesterase family. It plays crucial roles in the bioavailability of oral ester prodrugs and the therapeutic effect of some anticancer drugs such as irinotecan (CPT11) and capecitabine. In addition to the well-known roles of CES2 in xenobiotic metabolism, the enzyme also participates in endogenous metabolism and the production of lipids. In this study, we synthesized a series of pyrazolones and assayed their inhibitory effects against CES2 in vitro. Structure-activity relationship analysis of these pyrazolones reveals that the introduction of 4-methylphenyl unit (R1), 4-methylbenzyl (R2) and cyclohexyl (R3) moieties are beneficial for CES2 inhibition. Guided by these SARs results, 1-cyclohexyl-4-(4-methylbenzyl)-3-p-tolyl-1H- pyrazol-5(4H)-one (27) was designed and synthesized. Further investigations demonstrated that the compound 27 exhibited stronger CES2 inhibition activity with a lower IC50 value (0.13 µM). The inhibition kinetic study demonstrated that compound 27 inhibited the hydrolysis of CES2-fluorescein diacetate (FD) through non-competitive inhibition. In addition, the molecular docking showed that the core of pyrazolone, the cyclohexane moiety, 4-methylbenzyl and 4-methylphenyl groups in compound 27 all played important roles with the amino acid residues of CSE2. Also, compound 27 could inhibit adipocyte adipogenesis induced by mouse preadipocytes. In brief, we designed and synthesized a novel pyrazolone compound with a strong inhibitory ability on CES2 and could inhibit the adipogenesis induced by mouse preadipocytes, which can be served as a promising lead compound for the development of more potent pyrazolone-type CES2 inhibitors, and also used as a potential tool for exploring the biological functions of CES2 in human being.

Valproic acid concentration and biochemical indexes in epilepsy outpatients during monotherapy or combination therapy. / ä¸™æˆŠé ¸æµ“åº¦ä¸Žå•è¯æˆ–è”ç”¨æ²»ç–—é—¨è¯Šç™«ç—«æ‚£è€ ç”ŸåŒ–æŒ‡æ ‡çš„ç›¸å ³æ€§.

OBJECTIVES: Due to the narrow therapeutic window of valproic acid (VPA), grievous adverse reactions such as hepatotoxicity, nephrotoxicity may occur in patients with epilepsy for a long time. This study aimed to explore the effect of VPA concentration on biochemical and routine blood test related to liver, renal, and hematology in epileptic outpatients treated with VPA alone or combined with other antiepileptic drugs. METHODS: A total of 3 194 Chinese epileptic outpatients from Xiangya Hospital, were analyzed in a crude analysis after stratifying through dosage regimens. The plasma VPA concentration was detected by gas chromatography method and then standardized through dosage and body weight. Ten biochemical indexes related to liver, renal, and hematology were evaluated. RESULTS: Of all patients, blood urea nitrogen (BUN), serum creatinine (SCr) level, and erythrocyte count (RBC) showed positive correlations with standardized VPA concentration (r=0.494, r=0.157, r=0.596, respectively), while platelet specific volume (PCT) and blood platelet (PLT) showed negative correlations with standardized VPA concentration (r=-5.500, r=-0.086, respectively). After stratifying through dosage regimens, significantly positive associations between SCr and standardized VPA concentration were found in the juvenile patients from the monotherapy group and combination therapy group (r=1.800, r=0.352, respectively). In addition, PLT and leukocyte count (WBC) in the juvenile patients from the combination therapy group were negatively correlated with standardized VPA concentration (r=-1.463, r=-0.079, respectively), while RBC showed a positive association with standardized VPA concentration in the juvenile patients from the monotherapy group (r=0.068). CONCLUSIONS: SCr level is significantly associated with plasma VPA concentration. Drug combination and age are important factors leading to hematological disorders. The finding provides potential theoretical guidance for the rational and safe clinical use of VPA.

Pharmacist impact on adherence of valproic acid therapy in pediatric patients with epilepsy using active education techniques.

There is limited information on the impact of active education by a pharmacist in the population of pediatric patients with epilepsy (PWE) in China. The objective of this study was to assess the effect of education by pharmacists on medication adherence and percentage of valproic acid (VPA) samples reaching therapeutic reference range in these patients. This study was conducted at two teaching hospitals in Changsha, China. Patients were retrospectively identified from January 2016 to December 2017. Active education by a pharmacist in both oral and written formats was provided at the intervention hospital whereas standard passive pharmacist service (dispensing and answering questions) was provided at the control hospital. Medication adherence was assessed by the simplified medication adherence questionnaire (SMAQ), and serum concentrations of VPA were collected. The correlation between pharmacist education and medication adherence and percentage of VPA samples reaching therapeutic reference range were analyzed. A total of 2165 patients and 4343 serum VPA concentrations were included in the analysis. For the first therapeutic drug monitoring (TDM) measurement, there was no statistical difference between the two hospitals: 41.3% of VPA samples reached therapeutic range at the intervention hospital compared with 45.4% at the control hospital (χ2 = 3.686, P > 0.05). After pharmacist intervention at the intervention hospital, however, there were significant differences in the percentage of therapeutic VPA samples reaching therapeutic range between the first and the second, third, fourth, and fifth TDM measurements (χ2 = 9.756, P < 0.01; χ2 = 22.840, P < 0.01; χ2 = 15.816, P < 0.01; χ2 = 27.613, P < 0.01). Based on the SMAQ adherence assessment, adherence increased from a minimum of 56.0% to a maximum of 73.9% with stabilization during the last six months of follow-up at the intervention hospital. Both the medication adherence rate and the percentage of VPA samples reaching therapeutic range increased as the result of active education by a pharmacist, suggesting that continuous pharmacist intervention had a positive impact in outpatient pediatric PWE.

Vascular Endothelial Growth Factor-D (VEGF-D) is Elevated in Bronchoalveolar Lavage Fluid of Patients with Lung Squamous Carcinoma.

BACKGROUND: Previous studies have found that vascular endothelial growth factor (VEGF) is associated with lung cancer, yet little is known about vascular endothelial growth factor-D (VEGF-D) in bronchoalveolar lavage fluid (BALF) of lung cancer patients. In this study, we aim to investigate the expression and evaluation of VEGF-D in BALF for lung cancer diagnosis. METHODS: BALF samples were acquired from 81 patients: 40 with benign diseases and 41 with lung cancer. The expression of VEGF-D in BALF was measured using sandwich enzyme-linked immune sorbent assays (ELISA), and the evaluation of VEGF-D in BALF for lung cancer diagnosis was also investigated. RESULTS: In the BALF samples, the levels of VEGF-D in the lung cancer group were higher than in the benign disease group; however, there was no statistical significance between the two groups (p > 0.05). In the pathological classification of lung cancer, the levels of VEGF-D in the BALF differed significantly between the lung squamous carcinoma group and the benign disease group (p < 0.05). The diagnostic accuracies of VEGF-D in BALF for discrimination between patients with squamous cell carcinoma and benign disease were reasonable based on receiver operating characteristic (ROC curve) analysis, with a corresponding sensitivity of 64.7% and specificity of 60%, respectively. CONCLUSIONS: This study demonstrated that the detection of VEGF-D levels in BALF is a valuable diagnostic tool for lung squamous carcinoma.

[Inhibitory effect of flavonoids from Scutellariae Radix on human cytochrome P450 1A].

This study investigated the inhibitory effect of eight natural flavonoids in Chinese herb Scutellariae Radix on huamn cytochrome P450 1 A(CYP1 A), a key cancer chemo-preventive target. In this study, phenacetin was used as a probe substrate for CYP1 A, while human liver microsomes and recombinant human CYP1 A enzymes were used as enzyme sources. Liquid chromatography-tandem mass spectrometry was used to monitor the formation rates of acetaminophen, the O-deethylated metabolite of phenacetin. The dose-dependent inhibition curves were depicted based on the changes of the formation rates of acetaminophen, while the IC_(50) were determined. Inhibition kinetic analyses and docking simulations were used to investigate the inhibition modes and mechanism of wogonin(the most potent CYP1 A inhibitor in this herb), while the inhibition constants(K_i) of wogonin against both CYP1 A1 and CYP1 A2 were determined. Among all tested flavonoids, wogonin, 7-methoxyflavanone and oroxylin A displayed a strong inhibitory effect on CYP1 A(IC_(50)<1 µmol·L~(-1)), baicalein exhibited a moderate inhibitory effect on CYP1 A(IC_(50) between 1-10 µmol·L~(-1)), and baicalin, scutellarein and wogonoside displayed a very weak inhibitory effect on CYP1 A(IC_(50) between 10-25 µmol·L~(-1)), but scutellarin displayed a negligible inhibitory effect on CYP1 A(IC_(50)>100 µmol·L~(-1)). Further investigations demonstrated that wogonin had a weak inhibitory effect on other human CYP enzymes, suggesting that it could be used as a lead compound for the development of specific inhibitors of CYP1 A. Furthermore, the inhibition kinetic analyses clearly demonstrated that wogonin could strongly inhibit phenacetin O-deethylation in both CYP1 A1 and CYP1 A2 in a competitive manner, with K_i values at 0.118 and 0.262 µmol·L~(-1), respectively. Molecular docking demonstrated that wogonin could strongly interact with CYP1 A1 and CYP1 A2 via hydrophobic and π-π interactions, as well as Ser120 and Ser116 in CYP1 A1 via hydrogen-bonding. In conclusion, this study found that some flavonoids in Scutellariae Radix displayed a strong inhibitory effect on CYP1 A, while wogonin is the most potent CYP1 A inhibitor with a relatively high selectivity towards CYP1 A over other human CYPs.

Association of valproic acid and 2-propyl-4-pentenoic acid concentrations with adverse reaction in 254 Chinese patients with epilepsy.

OBJECTIVE: To investigate the correlation of the concentrations of valproic acid (VPA) and 2-propyl-4-pentenoic acid (4-ene-VPA) with their adverse reactions, and to guide the clinical safety and rational use of VPA.
 Methods: We collected 254 epilepsy outpatients who took long-term use of sodium valproate oral solution single or combined with other antiepileptic drugs from Xiangya Hospital. The plasma concentrations of VPA and 4-ene-VPA in patients were determined by gas chromatography-mass spectrometry (GC-MS). The double variable correlation analysis was performed to analyze the effect of plasma 4-ene-VPA and VPA concentrations on adverse reactions.
 Results: The correlations between the PLT level and the dosage of VPA (P<0.01 and P<0.05, respectively), and the RBC level and the concentration of VPA (All P<0.01) were significant negatively. The concentrations of 4-ene-VPA, VPA, ALT, and AST in the polytherapy group were much higher than those in the monotherapy group (All P<0.05). In the monotherapy group, the ALT and AST levels in patients younger than or equal to 2 years old were significantly higher than those over 2 years old (P<0.001). In the polytherapy group, the levels of AST, WBC, and PLT in patients younger than or equal to 2 years old were higher than those over 2 years old (P<0.05). The levels of AST did not show positive correlation with the concentrations of 4-ene-VPA and VPA (r=0.031, r=0.035, all P>0.05), and the levels of ALT also did not show positive correlation with the concentrations of 4-ene-VPA and VPA (r=-0.064, r=-0.089, all P>0.05).
 Conclusion: VPA may affect blood routine indexes. Age and combination therapy with the non-enzyme-induced anti-epileptic drugs are risk factors for VPA-related liver dysfunctions and renal impairment. The determination of VPA and 4-ene VPA is not a suitable tool for early warning of the VPA-induced liver dysfunction.

A PRRT2 variant in a Chinese family with paroxysmal kinesigenic dyskinesia and benign familial infantile seizures results in loss of interaction with STX1B.

OBJECTIVE: To identify the causative gene of autosomal dominant paroxysmal kinesigenic dyskinesia and benign familial infantile seizures (PKD/BFIS) in a large Chinese family and explore the potential pathogenic mechanism of a PRRT2 (proline-rich transmembrane protein 2) variant. METHODS: Genetic testing was performed via whole exome sequencing. Western blotting and immunofluorescence were used to analyze the protein expression level and subcellular localization of the PRRT2 mutant in HeLa cells and N2A cells. Coimmunoprecipitation was conducted to investigate the interaction of the PRRT2 mutant with syntaxin 1B (STX1B). RESULTS: In a large Chinese family with autosomal dominant PKD/BFIS showing wide phenotypic heterogeneity, including patients suffering from PKD, BFIS, or epilepsy and asymptomatic variant carriers, a c.621dupA variant in PRRT2 was identified in the proband and was shown to cosegregate with the phenotype in this family. This variant results in premature termination at codon 224, producing a truncated protein (p.Ser208Ilefs*17) in which the two conserved hydrophobic segments and the cytoplasmic loop are missing. Both the expression and subcellular localization of PRRT2 are strongly affected by the c.621dupA variant. In addition, we found that PRRT2 directly interacts with STX1B, a SNARE protein critical for neurotransmitter release, whereas the truncated variant p.Ser208Ilefs*17 lacking the helix-loop-helix domain fails to bind to STX1B. SIGNIFICANCE: Our findings identified a PRRT2 variant in a family with PKD/BFIS and confirmed STX1B as a new binding partner of PRRT2, which suggested that the loss of the interaction between PRRT2 and STX1B may contribute to the pathogenesis of PKD/BFIS.

[Research progress of human cytochrome P450 2J2 and its ligands].

Cytochrome P4502J2 (CYP2J2) is widely distributed in various human tissues and takes a part in the metabolism of endogenous compounds and drugs. CYP2J2 can convert arachidonic acid (AA) to expoxyeicosatrienoic acids (EETs), which have various biological effects, implying the important role of CYP2J2 in the regulation of cardiovascular system and promotion of tumor progression and metastasis. Additionally, CYP2J2 plays an indispensable role in the intestinal metabolism of various drugs, such as astemizole, terfenadine and ebastine. In this review, the metabolic function, characteristic of catalysis and tissue distribution of CYP2J2 are discussed with the latest literatures both in China and abroad. The state-of-the-art methods for characterization of CYP2J2 and current trend of substrate discovery as well as its relationship with disease are highlighted. This review gives in-depth understanding of the function of CYP2J2 and its role in disease advance. The information of ligand (substrate and inhibitor) will provide the theoretical guidance and reference to the development of novel drugs for CYP2J2.

The relationship between the variants in the 5'-untranslated regions of equine chorionic gonadotropin genes and serum equine chorionic gonadotropin levels.

OBJECTIVE: An experiment was conducted to study the association between the single nucleotide polymorphisms (SNPs) in 5'-untranslated regions (5'-UTR) of equine chorionic gonadotropin (eCG) genes and the serum eCG levels. METHODS: SNPs in 5'-UTR of eCG genes were screened across 10 horse breeds, including 7 Chinese indigenous breeds and 3 imported breeds using iPLEX chemistry, and the association between the serum eCG levels of 174 pregnant Da'an mares and their serum eCG levels (determined with ELISA) was analyzed. RESULTS: Four SNPs were identified in the 5'-UTR of the eCGα gene, and one of them was unique in the indigenous breeds. There were 2 SNPs detected at the 5' end of the eCGß subunit gene, and one of them was only found in the Chinese breeds. The SNP g.39948246T>C at the 5'-UTR of eCGα was associated significantly with eCG levels of 75-day pregnant mare serum (p<0.05) in Da'an mares. Prediction analysis on binding sites of transcription factors showed that the g.39948246T>C mutation causes appearance of the specific binding site of hepatocyte nuclear factor 3 forkhead homolog 2 (HFH-2), which is a transcriptional repressor belonging to the forkhead protein family of transcription factors. CONCLUSION: The SNP g.39948246T>C at the 5'-UTR of eCGα is associated with eCG levels of 75-day pregnant mare serum (p<0.05).

Gain-of-function mutations in SCN11A cause familial episodic pain.

Many ion channel genes have been associated with human genetic pain disorders. Here we report two large Chinese families with autosomal-dominant episodic pain. We performed a genome-wide linkage scan with microsatellite markers after excluding mutations in three known genes (SCN9A, SCN10A, and TRPA1) that cause similar pain syndrome to our findings, and we mapped the genetic locus to a 7.81 Mb region on chromosome 3p22.3-p21.32. By using whole-exome sequencing followed by conventional Sanger sequencing, we identified two missense mutations in the gene encoding voltage-gated sodium channel Nav1.9 (SCN11A): c.673C>T (p.Arg225Cys) and c.2423C>G (p.Ala808Gly) (one in each family). Each mutation showed a perfect cosegregation with the pain phenotype in the corresponding family, and neither of them was detected in 1,021 normal individuals. Both missense mutations were predicted to change a highly conserved amino acid residue of the human Nav1.9 channel. We expressed the two SCN11A mutants in mouse dorsal root ganglion (DRG) neurons and showed that both mutations enhanced the channel's electrical activities and induced hyperexcitablity of DRG neurons. Taken together, our results suggest that gain-of-function mutations in SCN11A can be causative of an autosomal-dominant episodic pain disorder.

Long-Term Alcohol-Induced Activation of Mammalian Target of Rapamycin is a Key Risk Factor of Epilepsy.

BACKGROUND The aim of this study was to determine whether activation of mammalian target of rapamycin (mTOR) is a key epileptogenic mechanism in the development of alcohol-related seizure. MATERIAL AND METHODS C57BL/6 mice were administered 10% ethanol in drinking water for 9 weeks. Video-electroencephalography (EEG) monitoring was then used to assess seizure frequency after alcohol and rapamycin treatment. In addition, mouse neuroblastoma NG108-15 cells were treated ethanol for 3 days and subsequently treated with AKT inhibitor LY294002 for 2-12 h. The in vitro kinase assay was performed for determining mTOR activity. Western blot analysis was used to determine the expression of P-AKT, P-S6K, and P-S6. RESULTS Long-term ethanol treatment markedly increased the seizure frequency of C57/BL6 mice over time. Moreover, ethanol treatment increased the expression level of P-S6 over time. Ethanol-induced seizure can be reversed by rapamycin. In addition, the in vitro kinase assay showed mTOR activity was activated by ethanol. Compared with NG108-15 cells treated without both ethanol and LY294002, ethanol increased the expression level of P-AKT, P-S6K, and P-S6, whereas LY294002 had opposite effects on expression levels of these proteins. CONCLUSIONS Our findings indicate that long-term alcohol intake increases the risk of epilepsy via activation of mTOR signaling. Moreover, ethanol-induced mTOR activation may be dependent on the AKT-mTOR signaling pathway. The key molecules involved in AKT-mTOR signaling pathway may serve as potential targets in the treatment of epilepsy.

First Analysis of the Association Between CYP3A4/5, ABCB1 Genetic Polymorphisms and Oxcarbazepine Metabolism and Transport in Chinese Epileptic Patients with Oxcarbazepine Monotherapy and Bitherapy.

PURPOSE: Oxcarbazepine (OXC) is widely used in anti-epileptic treatment. Cytochrome P450 3A4 (CYP3A4), cytochrome P450 3A5(CYP3A5), and ATP-binding cassette sub-family B member 1 (ABCB1) are potential genes involved in OXC metabolisms and transport in vivo. This study aims to examine the genetic effects of CYP3A4, CYP3A5, and ABCB1 on OXC metabolism and transport in Chinese epileptic patients using OXC as monotherapy and bitherapy with lamotrigine (LTG), levetiracetam (LEV), or valproic acid (VPA). METHODS: Sixty-six Chinese epileptic patients were recruited from Xiangya Hospital Central South University, of whom 40 patients were receiving OXC monotherapy, 11 patients were placed in the OXC bitherapy group combined with one enzyme-inducing anti-epileptic drugs (LTG or LEV), and 15 patients were placed in the OXC bitherapy group combined with VPA. Oxcarbazepine and its main metabolite 10-hydrocarbazepine (MHD) plasma concentrations were measured using high performance liquid chromatography (HPLC)-UV method. In addition, eight single nucleotide polymorphisms (SNPs) in CYP3A4, CYP3A5, ABCB1 gene were genotyped by polymerase chain reaction-improved multiple ligase detection reaction (PCR-iMLDR). RESULTS: In the OXC+VPA group, ABCB1 rs2032582 and rs2032582-rs10234411-rs1045642 TAG haplotype were associated with MHD and MHD+OXC plasma concentration before permutation test. In OXC monotherapy and OXC+ LTG/LEV groups, no significant association between genetic polymorphisms in CYP3A4/5, ABCB1 gene and OXC plasma concentration parameters were observed. CONCLUSION: CYP3A4/5 and ABCB1 genetic variants might not take part in the metabolism and transport of MHD and OXC among epileptic patients using OXC monotherapy and bitherapy in combination with LEV, LTG or VPA.

Novel pH-sensitive nanoformulated docetaxel as a potential therapeutic strategy for the treatment of cholangiocarcinoma.

BACKGROUND: Cholangiocarcinoma (CC) is one of the fatal malignant neoplasms with poor prognosis. The traditional chemotherapy has been resistant to CC and does not improve the quality of life. The aim of the present study is to investigate the potential of chondroitin sulphate (CS)-histamine (HS) block copolymer micelles to improve the chemotherapeutic efficacy of docetaxel (DTX). RESULTS: pH-responsive property of CS-HS micelles was utilized to achieve maximum therapeutic efficacy in CC. In the present study, docetaxel-loaded CS-HS micelles (CSH-DTX) controlled the release of drug in the basic pH while rapidly released its cargo in the tumor pH (pH 5 and 6.8) possibly due to the breakdown of polymeric micelles. A nanosize of <150 nm will allow its accumulation in the tumor interstitial spaces via EPR effect. CSH-DTX effectively killed the cancer kills in a time- and concentration-dependent manner and showed pronounced therapeutic action than that of free drug at all-time points. CSH-DTX resulted in higher apoptosis of cancer cells with ~30% and ~50 of cells in early apoptosis quadrant when treated with 100 and 1000 ng/ml of equivalent drug. The micellar formulations showed remarkable effect in controlling the tumor growth and reduced the overall tumor volume to 1/5(th) to that of control and half to that of free drug treated group with no sign of drug-related adverse effects. Immunohistochemical analysis of tumor sections showed that fewer number of Ki-67 cells were present in CSH-DTX treated group comparing to that of free DTX treated group. CONCLUSION: Our data suggests that nanoformulation of DTX could potentially improve the chemotherapy treatment in cholangiocarcinoma as well as in other malignancies.

Vascular endothelial growth factor -634G/C and vascular endothelial growth factor -2578C/A polymorphisms and lung cancer risk: a case-control study and meta-analysis.

Vascular endothelial growth factor (VEGF) is a major regulator of angiogenesis in the process of tumor growth and metastasis. In present study, we conducted a case-control study and meta-analysis to evaluate the genetic effects of VEGF -634G/C and VEGF -2578C/A polymorphisms and risk of lung cancer. A total of 175 subjects were recruited for case-control study and seven studies were included in the meta-analysis. Our case-control study showed that VEGF -634G/C polymorphism had no association with lung cancer risk (CC vs. GG: OR = 0.88, 95% CI = 0.37-2.11), whereas there was an association between VEGF -2578CC genotype and decrease in lung cancer risk (CC vs. CA/AA: OR = 0.52, 95% CI = 0.28-0.96). A meta-analysis was further performed and statistically similar results were obtained (CC vs. GG: OR = 0.91, 95% CI = 0.60-1.39 for VEGF -634; CC vs. AA: OR = 0.53, 95% CI = 0.32-0.89 for VEGF -2578). Our study showed that the variant genotypes of the VEGF -2578C/A polymorphism, but not the VEGF -634G/C polymorphism, was associated with lung cancer risk. More studies are needed to detect VEGF -634G/C and VEGF -2578 polymorphisms and their association with lung cancer in different ethnic populations incorporated with environmental exposures.

[Combination of narrow band imaging (NBI) and autofluorescence bronchoscopy (AFB) in the assessment of central lung cancer].

OBJECTIVE: To assess the diagnostic value of narrow-band imaging(NBI) in the diagnosis of central lung cancer. METHODS: Patients (n = 153) suspected of having lung cancer underwent white light bronchoscopy(WLB), NBI and autofluorescence bronchoscopy(AFB) in turn. At least 3 biopsies in each case were taken from sites visualized as lesions. The sensitivity and specificity of NBI, AFB and combination of NBI and AFB were compared. RESULTS: There were 106 male (69.3%) and 47 female patients (30.7%). By NBI, 91 and 62 cases were positive and negative respectively. The sensitivity and specificity of NBI were 63.5% (87/137) and 75.0% (12/16) respectively. By AFB, 140 and 13 cases were positive and negative respectively. The sensitivity and specificity of AFB were 94.2% (129/137) and 87.5% (5/16) respectively. By NBI combined with AFB, 133 and 20 cases were positive and negative respectively, the sensitivity and specificity being 95.6% (131/137) and 87.5% (14/16) respectively. The difference of specificity between NBI plus AFB and AFB alone was significant (P < 0.01), but the difference of sensitivity between NBI plus AFB and AFB alone(P > 0.05) was not. The difference of specificity between NBI plus AFB and NBI alone was significant (P < 0.01), but the P value of specificity between NBI plus AFB and NBI was 0.03. CONCLUSION: Combination of NBI and AFB could increase the specificity of lung cancer diagnosis compared to AFB alone.

Relationship between morning blood pressure variability and cerebral microbleed burden in patients with hypertension.

Cerebral microbleeds (CMBs) can be understood as a type of target organ damage caused by hypertension. We aimed to explore the association of the CMB burden with morning blood pressure (BP) variability in patients with hypertension. We divided patients with hypertension into two groups: a group with 1-10 CMBs and a group with more than 10 CMBs. The duration, grade, medication, and control of hypertension were recorded in all patients. Morning home BP measurements were performed every 3 days for a month. A total of 791 patients were recruited. Full factor model analysis showed that higher morning home diastolic BP variability (standard deviation [SD], OR = 1.080, 95% CI: 1.024-1.140, P = .005; coefficient of variation [CV], OR = 1.076, 95% CI: 1.028-1.128, P = .002) was associated with more than 10 CMBs. Morning home systolic and diastolic blood pressure variability (SD, CV, average real variability) in more than 10 non-lobar CMBs group was significantly higher than that in 1-10 non-lobar CMBs group (P < .05).The multivariate analysis showed higher morning home diastolic blood pressure variability (SD, OR = 1.124, 95% CI: 1.031-1.224, P = .008; CV, OR = 1.099, 95% CI: 1.019-1.186, P = .015; average real variability, OR = 1.055, 95% CI: 0.995-1.120, P = .075) was associated with more than 10 non-lobar CMBs. There was no significant relationship between morning home systolic blood pressure variability and more than 10 non-lobar CMBs (P > .05). Higher morning home diastolic blood pressure variability was associated with more than 10 CMBs and more than 10 non-lobar CMBs.

Bacterial community analysis of the skin microbiota of cultured Chinese giant salamander infected with Ranavirus.

Skin microorganisms are an important component of host innate immunity and serve as the first line of defense against pathogenic infections. The relative abundance of bacterial species, microbial community assembly, and secretion of specific bacterial metabolites are closely associated with host health. In this study, we investigated the association between the skin microbiome and Ranavirus, and compared the bacterial community assemblage, alpha and beta diversity, and functional predictions of the skin bacterial assemblage in cultured healthy Chinese giant salamanders (Andrias davidianus) and individuals infected with Chinese giant salamander iridovirus (GSIV or ADRV). To achieve this, we employed 16S rRNA amplicon sequencing. The results identified Proteobacteria, Firmicutes, Bacteroidota, and Actinobacteriota as the dominant phyla in the diseased and healthy groups. Alpha diversity analysis indicated that the skin bacterial community in the diseased group exhibited no significant differences in bacterial species diversity and lower species richness compared to the healthy group. Beta diversity suggested that the two group bacterial community was quite different. Kyoto encyclopedia of genes and genomes (KEGG) pathway analyze and clusters of orthologous groups of proteins (COG) function predictions revealed that changes and variations occurred in the metabolic pathways and function distribution of skin bacterial communities in two groups.