Evolving epidemiology of poliovirus serotype 2 following withdrawal of the serotype 2 oral poliovirus vaccine.

Although there have been no cases of serotype 2 wild poliovirus for more than 20 years, transmission of serotype 2 vaccine-derived poliovirus (VDPV2) and associated paralytic cases in several continents represent a threat to eradication. The withdrawal of the serotype 2 component of oral poliovirus vaccine (OPV2) was implemented in April 2016 to stop VDPV2 emergence and secure eradication of all serotype 2 poliovirus. Globally, children born after this date have limited immunity to prevent transmission. Using a statistical model, we estimated the emergence date and source of VDPV2s detected between May 2016 and November 2019. Outbreak response campaigns with monovalent OPV2 are the only available method to induce immunity to prevent transmission. Yet our analysis shows that using monovalent OPV2 is generating more paralytic VDPV2 outbreaks with the potential for establishing endemic transmission. A novel OPV2, for which two candidates are currently in clinical trials, is urgently required, together with a contingency strategy if this vaccine does not materialize or perform as anticipated.

Prospective computational design and in vitro bio-analytical tests of new chemical entities as potential selective CYP17A1 lyase inhibitors.

The development and advancement of prostate cancer (PCa) into stage 4, where it metastasize, is a major problem mostly in elder males. The growth of PCa cells is stirred up by androgens and androgen receptor (AR). Therefore, therapeutic strategies such as blocking androgens synthesis and inhibiting AR binding have been explored in recent years. However, recently approved drugs (or in clinical phase) failed in improving the expected survival rates for this metastatic-castration resistant prostate cancer (mCRPC) patients. The selective CYP17A1 inhibition of 17,20-lyase route has emerged as a novel strategy. Such inhibition blocks the production of androgens everywhere they are found in the body. In this work, a three dimensional-quantitative structure activity relationship (3D-QSAR) pharmacophore model is developed on a diverse set of non-steroidal inhibitors of CYP17A1 enzyme. Highly active compounds are selected to define a six-point pharmacophore hypothesis with a unique geometrical arrangement fitting the following description: two hydrogen bond acceptors (A), two hydrogen bond donors (D) and two aromatic rings (R). The QSAR model showed adequate predictive statistics. The 3D-QSAR model is further used for database virtual screening of potential inhibitory hit structures. Density functional theory (DFT) optimization provides the electronic properties explaining the reactivity of the hits. Docking simulations discovers hydrogen bonding and hydrophobic interactions as responsible for the binding affinities of hits to the CYP17A1 Protein Data Bank structure. 13 hits from the database search (including five derivatives) are then synthesized in the laboratory as different scaffolds. Ultra high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) in vitro experiments reveals three new chemical entities (NCEs) with half maximal inhibitory concentration (IC50) values against the lyase route at mid-micromolar range with favorable selectivity to the lyase over the hydroxylase route (one of them with null hydroxylase inhibition). Thus, prospective computational design has enabled the design of potential lead lyase-selective inhibitors for further studies.

Basic fibroblast growth factors as a biomarker of focal segmental glomerulosclerosis in HIV-positive and HIV-negative children

Background. HIV infection can lead to the development of HIV-associated nephropathy (HIVAN) with the majority of patients progressing to end-stage kidney disease. Previous studies have recognised basic fibroblast growth factor (bFGF) as a biomarker for HIVAN, since significant levels of bFGF low-affinity receptors have been found in the kidneys of HIV-infected children.Objective. To assess the association between bFGF and kidney disease in the development of focal segmental glomerulosclerosis (FSGS) in HIV-positive and negative children.Methods. The study group consisted of 31 children; HIVAN (n=11) and idiopathic FSGS (n=20). The control group consisted of both HIV-positive (n=20) and HIV-negative (n=20) children with no kidney disease. Serum samples from all patients in both the study and control groups were analysed for bFGF.Results. The concentration of bFGF was higher, in comparison with idiopathic FSGS children, in HIVAN children (p=0.0167). There was also a significant elevation of serum bFGF levels in children with HIVAN when compared with HIV-positive (p=0.0288) and HIV-negative (p=0.0043) control groups.Conclusion. This study demonstrated statistically significant differences between bFGF levels in children with HIVAN and a control group, although it failed to distinguish significant differences in bFGF levels between HIVAN and idiopathic FSGS children

Experimental-like affinity constants and enantioselectivity estimates from flexible docking.

Experimental-like affinity constants and enantioselectivity estimates, not predicted so far computationally, were obtained using a novel flexible modeling/docking combined strategy. The S- and R-warfarin-human serum albumin (HSA, site I) complexes were used as an interaction model. The process for a verified estimation includes the following: (i) ionized open chain forming at physiological pH (a recent focus); (ii) conformational search (molecular mechanics and Monte Carlo methods); (iii) rigid protein-flexible ligand docking (GlideXP) generating low energy paired S- and R-poses; (iv) graphical comparison against the X-ray crystal structure (unsatisfactory verification step); (v) quantum polarized ligand docking (insufficient verification step); (vi) induced fit docking (one pose satisfying the verification criterion; selection step); (vii) converting docking scores to affinity and enantioselectivity estimates (log K(S) = 5.43, log K(R) = 5.34, ES = K(S)/K(R) = 1.23) and numerical comparison against equivalent literature data from bioanalytical techniques (validation step); (viii) intermolecular forces explaining ES (hydrogen bonding and π-π interactions).

Determination of lead and cadmium in seawater by differential pulse anodic stripping voltammetry: fit-for-purpose partial validation and internal quality aspects.

The main thrust of this work involves method validation, quality control and sample uncertainty estimations related to the determination of cadmium and lead in marine water by anodic stripping voltammetry. We have followed a step-by-step protocol to evaluate and harmonize the internal quality aspects of this method. Such protocol involves a statement of the method's scope (analytes, matrices, concentration level) and requisites (external and/or internal); selection of the method's (fit-for-purpose) features; prevalidation and validation of the intermediate accuracy (under intermediate precision conditions) and its assessment (by Monte Carlo simulation); validation of other required features of the method (if applicable); and a validity statement in terms of a "fit-for-purpose" decision, harmonized validation-control-uncertainty statistics (the "u-approach") and short-term routine work (with the aim of proposing virtually "ready-to-use" methods).