[Effect of omeprazole on plasma concentration and adverse reactions of capecitabine in patients with colon cancer].

Objective: To investigate the effect of omeprazole on plasma concentration, efficacy and adverse reactions of capecitabine in patients with colon cancer. Methods: Seventy-two patients with colon cancer treated with capecitabine were analysed retrospective. The patients treated with capecitabine combined with omeprazole were identified as experimental group and the capecitabine treatment alone as control group.The differences of blood concentration and the side effects of capecitabine between these two groups were compared. Results: The plasma concentration of 5-Fluorouracilum in experimental group was (126.25±50.59) µg/ml, without significant difference of (123.09±56.70) µg/ml in control group (P=0.121). The incidence of Ⅲ to Ⅳ degree bone marrow suppression, nausea, vomiting, diarrhea and hand-foot syndrome in experimental group were 13.8%, 0%, 0% and 19.4%, respectively. In control group, the incidence of Ⅲ to Ⅳ degree bone marrow suppression, nausea, vomiting, diarrhea and the hand-foot syndrome were 11.1%, 0%, 0% and 19.4%, respectively, without significant difference of experimental group (P>0.05). The incidence of acid reflux and heartburn in the control group was 72.2%, significantly higher than 44.4% of the experimental group (P<0.05). The objective response rate (ORR) and progression-free survival time (PFS) in these two groups were 30.6% and 33.3%, and 8.0 month and 8.5 month, respectively, without significant difference (P>0.05). Conclusion: The intravenous omeprazole attenuates reflux and heartburn of colon cancer patients treated with capecitabine, without affecting its plasma concentration and side effects and has no impact on the PFS of these patients.

Elevated PT, APPT and PT/INR possibly associated with doxycycline and cefoperazone co-administration: A case report.

WHAT IS KNOWN AND OBJECTIVE: Little is known regarding changes in blood coagulation parameters associated with tetracycline antibiotics. We report a possible case of elevated PT, APPT and PT/INR associated with doxycycline and cefoperazone co-administration. CASE SUMMARY: An 83-year-old Chinese male inpatient with severe pneumonia, chronic renal insufficiency and malnutrition experienced elevated PT, APPT and PT/INR which occurred within a few days of doxycycline added to his cefoperazone treatment and returned to normal after removal of it. WHAT IS NEW AND CONCLUSION: Very close monitoring of coagulation parameters might be advisable in those subjects when administering doxycycline and cefoperazone concomitantly.

Human ß-defensin-3 induces IL-8 release and apoptosis in airway smooth muscle cells.

BACKGROUND: Human airway smooth muscle cells (ASMCs) may have a pro-inflammatory role through the release of inflammatory mediators. Increasing evidence indicates that human ß-defensins (HBDs) are related to pathogenesis of asthma. OBJECTIVES: To examine the plasma level of HBD-1, HBD-2 and HBD-3 in asthmatic patients and the expression of their mouse orthologues in the lung tissue of a mouse model of chronic severe asthma. Further to investigate the effect of HBD-3 on the release of the pro-inflammatory cytokine IL-8 and to explore the mechanisms. METHODS: The plasma levels of HBD-1, HBD-2 and HBD-3 from 34 healthy controls and 25 asthmatic patients were determined by ELISA. The expression of mouse ß-defensins MBD-1, MBD-3 and MBD-14 in the lung tissue of asthmatic mice was detected by Western blot. The ASMCs were cultured with HBD-3 for 24 hour, and then the supernatant level of IL-8 was evaluated by ELISA and the cell viability was examined by WST-1 assay. The signalling pathway was investigated with blocking antibodies or pharmacological inhibitors. RESULTS: The plasma levels of HBD-1 and HBD-3 were elevated in asthmatic patients, and the expression of MBD-14, the mouse orthologue for HBD-3, was increased in asthmatic mice. HBD-3-induced IL-8 production in a CCR6 receptor-specific manner and was dependent on multiple signalling pathways. Moreover, HBD-3-induced cell apoptosis concurrently, which was dependent on the ERK1/2 MAPK pathway. Mitochondrial ROS regulated both HBD-3-induced IL-8 production and cell apoptosis. CONCLUSIONS AND CLINICAL RELEVANCE: These observations provide clear evidence of an important new mechanism for the promotion of airway inflammation and tissue remodelling with potential relevance for the treatment of asthma.

Relationship between estrogen receptor 1 gene polymorphisms and postmenopausal osteoporosis of the spine in Chinese women.

The purpose of this study was to evaluate single nucleotide polymorphism (SNP) variants of the estrogen receptor 1 gene (ESR1) at rs2234693 and rs9340799, as well as to investigate the relationship between ESR gene polymorphisms and postmenopausal osteoporosis (OP) of the spine in Chinese women. We recruited 198 postmenopausal women with OP and 276 healthy women between May 2012 and September 2015 in Zhongshan Hospital. Dual energy x-ray absorptiometry was used to measure the bone mineral density (BMD) of the lumbar vertebrae in all subjects. In addition, PCR-restriction fragment length polymorphism based analysis was conducted to identify the genotypes of ESR1. The distribution of ESR1 in the osteoporosis group and the control group was determined; the relationship between ESR polymorphisms and BMD was analyzed. The distributions of BMD were: TT < TC < CC, GG < AG < AA. The TT, TTGG, and TCGG genotypes were found to be lower as compared to the other genotypes. Stratified analysis suggested that the TT genotype and the combined genotypes TTGG and TCGG were significantly higher in the OP group as compared to the control group (P < 0.01). Therefore, ESR1 polymorphisms at rs2234693 and rs9340799 may be associated with OP, and could be used as markers to screen those with high risks to postmenopausal OP in Chinese women.

Docetaxel enhances apoptosis and G2/M cell cycle arrest by suppressing mitogen-activated protein kinase signaling in human renal clear cell carcinoma.

Tremendous efforts have been made in renal cell carcinoma (RCC) patients' research; however, clinical findings in patients have been disappointing. The aims of our study were to identify better or alternative therapeutic methods that can reverse chemotherapy resistance and to enhance sensitivity to docetaxel (DOX)-based chemotherapy drugs. We evaluated the anti-proliferative effect of DOX against RCC cells. DOX was found to suppress proliferation of RCC cells under in vitro and in vivo settings. Flow cytometric analysis revealed that DOX suppressed cell growth by induction of both apoptosis and G2/M cell cycle arrest in a dose-dependent manner. Various patterns of gene expression were observed by cluster analysis. In addition, based on network analysis using the ingenuity pathway analysis software, DOX was found to suppress phosphorylation of extracellular signal-regulated kinase 1/2 and p38, suggesting that the mitogen-activated protein kinase signaling pathway plays a vital role in the anti-proliferative effect of DOX against RCC.

Lactic acid bacteria protect human intestinal epithelial cells from Staphylococcus aureus and Pseudomonas aeruginosa infections.

Staphylococcus aureus and Pseudomonas aeruginosa are opportunistic pathogens that cause nosocomial and food-borne infections. They promote intestinal diseases. Gastrointestinal colonization by S. aureus and P. aeruginosa has rarely been researched. These organisms spread to extra gastrointestinal niches, resulting in increasingly progressive infections. Lactic acid bacteria are Gram-positive bacteria that produce lactic acid as the major end-product of carbohydrate fermentation. These bacteria inhibit pathogen colonization and modulate the host immune response. This study aimed to investigate the effects of Lactobacillus acidophilus and Lactobacillus rhamnosus on enteric infections caused by the paradigmatic human pathogens S. aureus ATCC25923 and P. aeruginosa ATCC27853. The effect of whole cells and neutralized cell-free supernatant (CFS) of the lactobacilli on LoVo human carcinoma enterocyte (ATCC CCL-229) infection was analyzed by co-exposure, pre-exposure, and post-exposure studies. Simultaneous application of whole cells and CFS of the lactobacilli significantly eradicated enterocyte infection (P < 0.05); however, this effect was not seen when the whole cells and CFS were added after or prior to the infection (P > 0.05). This result could be attributed to interference by extracellular polymeric substances and cell surface hydrophobicity, which resulted in the development of a pathogen that did not form colonies. Furthermore, results of the plate count and LIVE/ DEAD BacLight bacterial viability staining attributed this inhibition to a non-bacteriocin-like substance, which acted independently of organic acid and H2O2 production. Based on these results, the cell-free supernatant derived from lactobacilli was concluded to restrain the development of S. aureus and P. aeruginosa enteric infections.

The Elimination Rate after Clozapine Overdose in Chinese Schizophrenia Patients: A Population Pharmacokinetics Model Study.

INTRODUCTION: The prescribing of clozapine in China is common because of its outstanding efficacy and low price. There have been many cases of clozapine overdose in China. However, studies about the pharmacokinetics after overdose in the Chinese have rarely been reported. Population pharmacokinetics (PopPK) can analyze sparse data, and it is appropriate to compute clozapine pharmacokinetics after overdose. METHODS: There were 47 clozapine overdose cases. We constructed a single-compartment first-order elimination PopPK model. We also considered some covariates that can influence the pharmacokinetics parameters. RESULTS: 21 cases were included in the analysis. When the reported toxic dosage was 3,740 mg, the elimination rate constant of the population was 0.0258(h(-1)). The elimination half-life was 26.9 h. The coefficient of random variation was 17%. DISCUSSION: PopPK can solve the problem of sparse data after overdose. The area under the concentration-time curve after clozapine overdose exhibited the "two peaks phenomenon." The reported toxic dosage could impact clozapine elimination after overdose. Delayed absorption of clozapine is the best explanation for this finding.

Acute cholecystitis associated with infection of Enterobacteriaceae from gut microbiota.

Acute cholecystitis (AC) is one of the most common surgical diseases. Bacterial infection accounts for 50% to 85% of the disease's onset. Since there is a close relationship between the biliary system and the gut, the aims of this study were to characterize and determine the influence of gut microbiota on AC, to detect the pathogenic microorganism in the biliary system, and to explore the relationship between the gut and bile microbiota of patients with AC. A total of 185 713 high-quality sequence reads were generated from the faecal samples of 15 patients and 13 healthy controls by 16S rRNA gene pyrosequencing. Patients' samples were significantly enriched in Akkermansia, Enterobacter and Escherichia/Shigella group. The healthy controls, however, showed significant enrichment of Clostridiales, Coprococcus, Coprobacillaceae, Paraprevotella, Turicibacter and TM7-3 in their faecal samples. Escherichia coli was the main biliary pathogenic microorganism, among others such as Klebsiella spp., Clostridium perfringens, Citrobacter freundii and Enterobacter cloacae in the bile of the patients. Additionally, the amount of bile endotoxin significantly correlated with the number of Enterobacteriaceae, especially E. coli. Our data indicate that Enterobacteriaceae might play essential role in the pathogenesis and/or progress of AC. This was verified in an in vivo model using a pathogenic E. coli isolated from one of the patients in guinea pigs and observed marked gallbladder inflammation and morphologic changes. This study thus provides insight which could be useful for the prevention, diagnosis and treatment of AC and related diseases by controlling the growth of Enterobacteriaceae to alleviate the infection.

Geometrical differences in target volumes based on 18F-fluorodeoxyglucose positron emission tomography/computed tomography and four-dimensional computed tomography maximum intensity projection images of primary thoracic esophageal cancer.

The objective of the study was to compare geometrical differences of target volumes based on four-dimensional computed tomography (4DCT) maximum intensity projection (MIP) and 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) images of primary thoracic esophageal cancer for radiation treatment. Twenty-one patients with thoracic esophageal cancer sequentially underwent contrast-enhanced three-dimensional computed tomography (3DCT), 4DCT, and 18F-FDG PET/CT thoracic simulation scans during normal free breathing. The internal gross target volume defined as IGTVMIP was obtained by contouring on MIP images. The gross target volumes based on PET/CT images (GTVPET ) were determined with nine different standardized uptake value (SUV) thresholds and manual contouring: SUV≥2.0, 2.5, 3.0, 3.5 (SUVn); ≥20%, 25%, 30%, 35%, 40% of the maximum (percentages of SUVmax, SUVn%). The differences in volume ratio (VR), conformity index (CI), and degree of inclusion (DI) between IGTVMIP and GTVPET were investigated. The mean centroid distance between GTVPET and IGTVMIP ranged from 4.98 mm to 6.53 mm. The VR ranged from 0.37 to 1.34, being significantly (P<0.05) closest to 1 at SUV2.5 (0.94), SUV20% (1.07), or manual contouring (1.10). The mean CI ranged from 0.34 to 0.58, being significantly closest to 1 (P<0.05) at SUV2.0 (0.55), SUV2.5 (0.56), SUV20% (0.56), SUV25% (0.53), or manual contouring (0.58). The mean DI of GTVPET in IGTVMIP ranged from 0.61 to 0.91, and the mean DI of IGTVMIP in GTVPET ranged from 0.34 to 0.86. The SUV threshold setting of SUV2.5, SUV20% or manual contouring yields the best tumor VR and CI with internal-gross target volume contoured on MIP of 4DCT dataset, but 3DPET/CT and 4DCT MIP could not replace each other for motion encompassing target volume delineation for radiation treatment.

Comparison of patient-specific internal gross tumor volume for radiation treatment of primary esophageal cancer based separately on three-dimensional and four-dimensional computed tomography images.

To compare the target volume, position and matching index of the patient-specific internal gross tumor volume (IGTV) based on three-dimensional (3D) and four-dimensional (4D) computed tomography (CT) images for primary esophageal cancer. Twenty-nine patients with primary thoracic esophageal cancer underwent 3DCT and 4DCT scans during free breathing. IGTVs were constructed using three approaches: combining the gross target volumes from the 10 respiratory phases of the 4DCT dataset to produce IGTV10 ; IGTV2 was acquired by combining the two extreme phases; and IGTV3D was created from the 3DCT-based gross target volume by enlarging the 95th percentile of motion in each direction measured by the 4DCT. 0.16 cm lateral (LR), 0.14 cm anteroposterior (AP) and 0.29 cm superoinferior (SI) in the upper; 0.18 cm LR, 0.10 cm AP and 0.63 cm SI in the middle; and 0.40 cm LR, 0.58 cm AP and 0.82 cm in the lower thoracic esophagus could account for 95% of respiratory-induced tumor motion. The centroid position shift between IGTV10 and IGTV2 was all below 0.10 cm, and less than 0.20 cm between IGTV10 and IGTV3D . IGTV10 was bigger than IGTV2 ; the mean value of matching index for IGTV2 to IGTV10 was 0.87 ± 0.05, 0.85 ± 0.06 and 0.83 ± 0.05 for upper, middle and distal thoracic esophageal tumors, respectively, and just 0.57 ± 0.11, 0.56 ± 0.13 and 0.40 ± 0.03 between IGTV3D and IGTV10 . 4DCT-based IGTV10 is a reasonable patient-specific IGTV for primary thoracic esophageal cancer, and IGTV2 is considered as an acceptable alternative to IGTV10 . However, it seems unreasonable to use IGTV3D substitute IGTV10 .

Relative bioequivalence evaluation of two oral atomoxetine hydrochloride capsules: a single dose, randomized, open-label, 2-period crossover study in healthy Chinese volunteers under fasting conditions.

To evaluate the bioequivalence of a new formulation of atomoxetine hydrochloride (CAS 82248-59-7) capsules (test) and an available branded capsules (reference) after administration of a single 40 mg dose, randomized, open-label, 2-period crossover study was conducted in 22 healthy male Chinese subjects with a 1-week wash-out period. This study was designed for/the Honglin Pharmaceutical Co. Ltd and contracted to be done by the Beijing Anding Hospital in order to satisfy Chinese regulatory requirements to allow marketing of this generic product and performed according to the criteria of SFDA. Blood samples were collected before and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, 16 and 24 h after drug administration. Plasma concentrations were determined by high-performance liquid chromatography (HPLC) with UV detection. A non-compartmental method was used to calculate the pharmacokinetic parameters and evaluate bioequivalence of the 2 formulations. The 90% confidence interval (CI) of the ratios (test/reference) of atomoxetine for AUC0-24, AUC0-∞ and Cmax were 100.9% (93.6-108.8%), 103.1% (95.1-111.7%) and 105.2% (92.8-119.4%), respectively, which fell within the interval of 80-125% and 75-133%. No clinically significant changes or abnormalities were noted in laboratory data and vital signs. From these results it can be concluded that the test formulation of atomoxetine capsules met the regulatory criterion for bioequivalence to the reference formulation.

Gradual electroforming and memristive switching in Pt/CuO(x)/Si/Pt systems.

We report a memristive switching effect in Pt/CuOx/Si/Pt devices prepared by the rf sputtering technique at room temperature. Differently from other Cu-based metal filament switching systems, a gradual electroforming process, marked by a gradual increase of the device resistance and a gradual decrease of the device capacitance, was observed in the current-voltage and capacitance characteristics. After the gradual electroforming, the devices show a uniform memristive switching behavior. By Auger electron spectroscopy analysis, a model based on the thickness change of the SiOx layer at the CuOx/Si interface and Cu ion migration is proposed for the gradual electroforming and uniform memristive switching, respectively. This work should be meaningful for the preparation of forming-free and homogeneous memristive devices.

Chemical fingerprinting of naphthenic acids and oil sands process waters-A review of analytical methods for environmental samples.

This article provides a review of the routine methods currently utilized for total naphthenic acid analyses. There is a growing need to develop chemical methods that can selectively distinguish compounds found within industrially derived oil sands process affected waters (OSPW) from those derived from the natural weathering of oil sands deposits. Attention is thus given to the characterization of other OSPW components such as oil sands polar organic compounds, PAHs, and heavy metals along with characterization of chemical additives such as polyacrylamide polymers and trace levels of boron species. Environmental samples discussed cover the following matrices: OSPW containments, on-lease interceptor well systems, on- and off-lease groundwater, and river and lake surface waters. There are diverse ranges of methods available for analyses of total naphthenic acids. However, there is a need for inter-laboratory studies to compare their accuracy and precision for routine analyses. Recent advances in high- and medium-resolution mass spectrometry, concomitant with comprehensive mass spectrometry techniques following multi-dimensional chromatography or ion-mobility separations, have allowed for the speciation of monocarboxylic naphthenic acids along with a wide range of other species including humics. The distributions of oil sands polar organic compounds, particularly the sulphur containing species (i.e., OxS and OxS2) may allow for distinguishing sources of OSPW. The ratios of oxygen- (i.e., Ox) and nitrogen-containing species (i.e., NOx, and N2Ox) are useful for differentiating organic components derived from OSPW from natural components found within receiving waters. Synchronous fluorescence spectroscopy also provides a powerful screening technique capable of quickly detecting the presence of aromatic organic acids contained within oil sands naphthenic acid mixtures. Synchronous fluorescence spectroscopy provides diagnostic profiles for OSPW and potentially impacted groundwater that can be compared against reference groundwater and surface water samples. Novel applications of X-ray absorption near edge spectroscopy (XANES) are emerging for speciation of sulphur-containing species (both organic and inorganic components) as well as industrially derived boron-containing species. There is strong potential for an environmental forensics application of XANES for chemical fingerprinting of weathered sulphur-containing species and industrial additives in OSPW.

Investigation of the role of tryptophan residues in cationic antimicrobial peptides to determine the mechanism of antimicrobial action.

AIMS: To understand the effects of Trp residues in linear antimicrobial peptides with α-helical conformations on cell permeation ability and membrane transduction efficacy. METHODS AND RESULTS: A series of L-K6 analogues were designed and synthesized by replacing Ile or Leu with Trp at different positions on the hydrophobic face of L-K6. The antimicrobial and haemolytic activity and secondary structure of the designed Trp-containing peptides were assessed. In addition, the role of Trp in membrane disruption for these designed peptides was investigated. I1W, I4W and L5W demonstrated stronger activity than the other peptides against both Gram-positive and Gram-negative bacteria. All of the tested peptides preferentially interacted with negatively charged vesicles composed of phosphatidylglycerol (PG)/cardiolipin (CL) or PG/CL/phosphatidylethanolamine, and, to a lesser extent, with zwitterionic vesicles. I1W, I4W and L5W caused calcein release at 2·5 µmol l(-1) . CONCLUSIONS: The position of Trp, rather than the number of Trp residues, in these peptides was an important factor in the antimicrobial activity. Trp residues were deeply inserted into negatively charged membranes but were largely exposed in aqueous buffer solution. SIGNIFICANCE AND IMPACT OF THE STUDY: These Trp-containing peptides may represent good candidates for new antibiotic agents and for use in new therapeutic approaches.

Elevated PLGF contributes to small-cell lung cancer brain metastasis.

Brain metastasis (BM) is a major cause of mortality in small-cell lung cancer (SCLC) patients; however, the molecular pathway of SCLC BM remains largely unknown because of a lack of investigation. Here we screen the levels of some candidate-soluble factors in the serum of SCLC patients and find that SCLC patients with high levels of placental growth factor (PLGF) are prone to BM. Using in vitro blood-brain barrier model, we show that PLGF derived from SCLC cells triggers vascular endothelial growth factor receptor-1-Rho-extracellular regulated protein kinase 1/2 signaling axis activation, results in disassembly of tight junction in brain endothelial cells and promotes SCLC cell transendothelial migration. Furthermore, the downregulation of PLGF suppresses SCLC cell metastasis to the brain in an experimental BM model. These data suggest that PLGF is a potential signature of SCLC BM and a prospective therapeutic target for SCLC BM.