Paraoxonase 1 Phenotype and Mass in South Asian versus Caucasian Renal Transplant Recipients

South Asian renal transplant recipients have a higher incidence of cardiovascular disease compared with Caucasian renal transplant recipients. We carried out a study to determine whether paraoxonase 1, a novel biomarker for cardiovascular risk, was decreased in South Asian compared with Caucasian renal transplant recipients. Subjects were matched two to one on the basis of age and sex for a total of 129 subjects. Paraoxonase 1 was measured by mass, arylesterase activity, and two-substrate phenotype assay. Comparisons were made by using a matched design. The frequency of PON1 QQ, QR and RR phenotype was 56%, 37%, and 7% for Caucasian subjects versus 35%, 44%, and 21% for South Asian subjects (χ2 = 7.72, P = 0.02). PON1 mass and arylesterase activity were not significantly different between South Asian and Caucasian subjects. PON1 mass was significantly associated with PON1 phenotype (P = 0.0001), HDL cholesterol (P = 0.009), LDL cholesterol (P = 0.02), and diabetes status (P < 0.05). Arylesterase activity was only associated with HDL cholesterol (P = 0.003). Thus the frequency of the PON1 RR phenotype was higher and that of the QQ phenotype was lower in South Asian versus Caucasian renal transplant recipients. However, ethnicity was not a significant factor as a determinant of PON1 mass or arylesterase activity, with or without analysis including PON1 phenotype. The two-substrate method for determining PON1 phenotype may be of value for future studies of cardiovascular complications in renal transplant recipients

Validation of a multiplexed immunoassay for immunological analysis of pre erythrocytic malaria vaccines

The primary immunological readout for clinical trials of R21/MatrixM™ malaria vaccine, is total IgG antibody specific to the central four amino acid NANP repeat region of the circumsporozoite protein. A multiplexed assay, which includes NANP, was developed and validated for four antigens representing components of the R21 immunogen. Initial assay optimisation included validation of the HBsAg international standard. Further validation performed in Oxford covered intra and inter-assay, and inter-operator variability, accuracy of QC and standard curve material, and included bridging to a singleplex NANP6 ELISA. The assay was shown to be robust and specific, with a broad dynamic range. We report a strong linear relationship between NANP6 IgG as measured by the singleplex ELISA and the multiplexed assay with rho values of 0.89 and 0.88 for two separate clinical trials (both p < 0.0005). This assay can be used to measure antibodies specific to the CSP NANP repeat region, CSP C-term region, full length R21 and HBsAg

A phase 1b clinical trial to determine the safety, tolerability and immunogenicity of simian adenovirus and poxvirus vectored vaccines against Mycobacterium avium complex subspecies in patients with active Crohn's disease

BACKGROUND: Crohn's Disease (CD) is a chronic, debilitating condition hypothesised to be associated with Mycobacterium avium ssp paratuberculosis (MAP) infection. It is the causative pathogen of the granulomatous inflammatory enteritis in ruminants, Johne's Disease. A developing treatment approach is utilising heterologous prime-boost viral vectored vaccines. We report a Phase 1b dose-escalation trial to determine the safety, tolerability and immunogenicity of candidate recombinant ChAdOx2 and MVA vectored vaccines against MAP in patients with CD.METHODS: 28 patients with mild to moderate CD, aged 18-50, were randomly allocated into 5 groups. Group 1 and 2 were vaccinated with ChAdOx2 HAV, Groups 3 and 4 with MVA HAV and Group 5 with both vaccines in a prime-boost regimen. A 112-day follow-up period assessed safety and tolerability by recording adverse events (AEs) and serious adverse events (SAEs). Secondary objectives of immunogenicity were assessed by ELISpot (enzyme-linked immunosorbent spot) and clinical response by Crohn's Disease Activity Index (CDAI) and Simple Endoscopic Score for Crohn's Disease (SES-CD).FINDINGS: 28 participants received either a single dose of ChAdOx2 HAV (n = 12), a single dose of MVA HAV (n = 6) or a prime dose of ChAdOx2 HAV (n = 10) followed by an MVA HAV (n = 9) boost. Solicited AEs were 196 in all participants, one AE was graded as severe but resolved within 24 h. The majority of solicited AEs were graded as mild (149/196; 76%, 95% CI 69%-82%) or moderate (45/196; 23%, 95% CI 17%-29%). ELISpot responses increased in Groups 1 and 2 and significantly more after boosting with MVA HAV.INTERPRETATION: Candidate vaccines ChAdOx2 HAV and MVA HAV were safe, well-tolerated and immunogenic in patients with active CD. A heterologous prime-boost schedule induces a T cell-mediated immune response. Further studies are required to determine the efficacy and optimal regime of the vaccines.FUNDING: HAV Vaccines Limited funded the trial and acted as trial sponsor. The Sponsor was involved in protocol development, trial conduct, including data monitoring and analysis, and the preparation of this manuscript in line with the Medicines for Human Use (Clinical Trials) Regulations 2004 and amendments.</p

R21/Matrix-M malaria vaccine drives diverse immune responses in pre-exposed adults: insights from a phase IIb controlled human malaria infection trial

Introduction: The recently licenced R21/Matrix-M vaccine induces a protective antibody response. In this study, we examined vaccine-induced responses in semi-immune adults in a controlled human malaria infection (CHMI) Phase IIb clinical trial. Methods: Plasma and peripheral blood mononuclear cells from healthy adult volunteers living in coastal Kenya were analysed following vaccination with R21/Matrix-M (n = 19) and CHMI challenge with Plasmodium falciparum (PfSPZ NF54) sporozoites (n = 17). Humoral immunity was evaluated by quantifying antigen specific antibody subtypes and subclasses via ELISA, alongside functional antibody properties including avidity and complement fixation elicited by vaccination and challenge. Antigen-specific memory B cells were characterised using FluoroSpot assays to detect concurrent secretion of multiple antibody isotypes and the frequency and phenotypes of circulating Tfh (cTfh) cells were assessed using multiparametric flow cytometry. Results: Vaccination increased antibody titres across IgA, IgM, and IgG isotypes and IgG1 and IgG3 subclasses but not IgG2 or IgG4 subclasses, targeting different vaccine antigens (full-length R21, NANP, and C-terminus), indicating a broad and heterogeneous response. The responses were maintained over time and, importantly, they demonstrated complement-fixing capabilities. IgG+ and IgA+ antigen-specific memory B cells were boosted but were short-lived for IgA. We observed an increase in total CXCR5+/PD1+ cTfh cells following vaccination and challenge with the predominant Th2/Th17 population. Discussion: We provide insights into the diverse immune responses induced by R21/Matrix-M vaccination and their potential contribution to protection against malaria. These findings highlight the potential of the R21/Matrix-M vaccination and protection in adults with varying levels of prior malaria exposure

Long-term cultivation of colorectal carcinoma cells with anti-cancer drugs induces drug resistance and telomere elongation: an in vitro study

BACKGROUND: The role of telomerase activation in the expression and/or maintenance of drug resistance is not clearly understood. Therefore, we investigated the relationships, among the telomerase activity, telomere length and the expression of multidrug resistance genes in colorectal cancer cell lines cultivated with anti-cancer drugs. METHODS: LoVo and DLD-1 cells were continuously grown in the presence of both CDDP and 5-FU for up to 100 days. Cell proliferation, telomerase activity, telomere length and the expression of multidrug resistance genes were serially monitored as the PDL increased. RESULTS: The expression of multidrug resistance genes tended to increase as the PDL increased. However, an abnormal aneuploid clone was not detected as far as the cells were monitored by a DNA histogram analysis. Tumor cells showing resistance to anti-cancer drugs revealed a higher cell proliferation rate. The telomere length gradually increased with a progressive PDL. The telomerase activity reached a maximum level at 15 PDL in LoVo cells and at 27 PDL in DLD-1 cells. An increase in the mRNA expression of the telomerase components, especially in hTERT and in hTR, was observed at the same PDLs. CONCLUSIONS: These results suggest that a high telomerase activity and an elongation of telomeres both appear to help maintain and/or increase drug resistance in colorectal cancer cells. Cancer cells with long telomeres and a high proliferative activity may thus be able to better survive exposure to anti-cancer drugs. This is presumably due to an increased chromosome stability and a strong expression of both mdr-1 and MRP genes

Sensing and Tactile Artificial Muscles from Reactive Materials

Films of conducting polymers can be oxidized and reduced in a reversible way. Any intermediate oxidation state determines an electrochemical equilibrium. Chemical or physical variables acting on the film may modify the equilibrium potential, so that the film acts as a sensor of the variable. The working potential of polypyrrole/DBSA (Dodecylbenzenesulfonic acid) films, oxidized or reduced under constant currents, changes as a function of the working conditions: electrolyte concentration, temperature or mechanical stress. During oxidation, the reactive material is a sensor of the ambient, the consumed electrical energy being the sensing magnitude. Devices based on any of the electrochemical properties of conducting polymers must act simultaneously as sensors of the working conditions. Artificial muscles, as electrochemical actuators constituted by reactive materials, respond to the ambient conditions during actuation. In this way, they can be used as actuators, sensing the surrounding conditions during actuation. Actuating and sensing signals are simultaneously included by the same two connecting wires

Effect of knowledge management on performance: A case study at PT. Eastern Pearl Flour Mills Makassar

Abstract This study aims to determine the effect of Knowledge Management on the performance of maintenance department employees at PT. Makassar Eastern Pearl Flour Mills and to find out which Knowledge Management indicators are most influential on employee performance. This study uses the statistical application IBM SPSS 21. The population in this study is employees at PT. Eastern Pearl Flour Mills Makassar, amounting to 78 people. The collection of data is done by using a questionnaire. 78 questionnaire were handed out with 65 questionnaire are valid. The data were processed using multiple linear regression analysis technique. The results of the study indicate that there is the influence of the variable Knowledge Management which consists of Personal Knowledge (X1), Job Procedure (X2), and Technology (X3) against the performance of the employee (Y) with the value of the coefficient of determination of 0.286. Analysis of the data do indicate that the variable Personal Knowledge of the results of the t test for 0.3562 is the most giving effect compared with other variables.</jats:p

Serum Apolipoprotein B and A1 Concentrations Predict Late-Onset Posttransplant Diabetes Mellitus in Prevalent Adult Kidney Transplant Recipients

Background: Glucose metabolism links closely to cholesterol metabolism. Posttransplant diabetes mellitus (PTDM) adversely affects posttransplant outcomes, but its risk factors in relation to cholesterol metabolism have not been fully delineated. The apolipoprotein B/A1 (Apo B/A1) ratio, which is associated with insulin resistance, has not been evaluated in kidney transplant recipients as a risk factor for PTDM. Objective: The objective of this study was to determine whether serum apolipoprotein profiles predict late PTDM, defined as a new onset diabetes occurring greater than 3 months posttransplant. Design: Retrospective chart review of a prevalent population of kidney transplant recipients. Setting: Large transplant center in Ontario, Canada. Patients: We identified 1104 previously nondiabetic adults who received a kidney transplant between January 1, 1998, and December 1, 2015, and were followed at 1 transplant center. Measurements: Recipients provided testing for serum apolipoprotein B (Apo B) and apolipoprotein A1 (Apo A1) concentrations from 2010, either at 3 months posttransplant for new transplant recipients or the next clinic visit for prevalent recipients. Late PTDM defined using Canadian Diabetes Association criteria as occurring ≥3 months posttransplant was recorded until May 1, 2016. Methods: All analyses were conducted with R, version 3.4.0 (The R Foundation for Statistical Computing). Comparisons were made using Student t test, Fisher exact test or chi-square test, Kaplan-Meier methodology with the logrank test, or Cox proportional hazards analysis as appropriate. Covariates for the multivariate Cox proportional hazards models of PTDM as the outcome variable were selected based on significance of the univariate associations and biological plausibility. Results: There were 53 incident late PTDM cases, or 1.71 cases per 100 patient-years. Incident late PTDM differed between the highest and lowest quartiles for Apo B/A1 ratio, 2.47 per 100 patient-years vs 0.88 per 100 patient-years ( P = .005 for difference). In multiple Cox regression analysis, first measured serum Apo B/A1 concentration better predicted subsequent PTDM than low-density lipoprotein cholesterol (LDL-C; hazard ratio [HR] = 7.80 per unit increase, P = .039 vs HR = 1.05 per unit increase, P = .774). Non-high-density lipoprotein cholesterol (HDL-C) concentrations also did not predict PTDM ( P = .136). By contrast to Apo B, Apo A1 was protective against PTDM in statin users (HR = 0.17 per unit increase, P = .016). Limitations: Posttransplant diabetes mellitus cases occurring before apolipoprotein testing was implemented were not included in the analysis. Conclusions: Apolipoproteins B and A1 better predict late PTDM than conventional markers of cholesterol metabolism