Design and optimization of electrochemical microreactors for continuous electrosynthesis

The study focuses on the design and construction, as well as the theoretical and experimental optimization of electrochemical filter press microreactors for the electrosynthesis of molecules with a high added value. The main characteristics of these devices are firstly a high-specific electrochemical area to increase conversion and selectivity, and secondly the shape and size of themicrochannels designed for a uniform residence time distribution of the fluid. A heat exchanger is integrated into the microstructured electrode to rapidly remove (or supply) the heat required in exo- or endothermic reactions. The microreactors designed are used to perform-specific electrosynthesis reactions such as thermodynamically unfavorable reactions (continuous NADH regeneration), or reactions with high enthalpy changes

Week 96 efficacy and safety results of the phase 3, randomized EMERALD trial to evaluate switching from boosted-protease inhibitors plus emtricitabine/tenofovir disoproxil fumarate regimens to the once daily, single-tablet regimen of darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) in treatment-experienced, virologically-suppressed adults living with HIV-1

Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg was investigated through 96 weeks in EMERALD (NCT02269917). Virologically-suppressed, HIV-1-positive treatment-experienced adults (previous non-darunavir virologic failure [VF] allowed) were randomized (2:1) to D/C/F/TAF or boosted protease inhibitor (PI) plus emtricitabine/tenofovir-disoproxil-fumarate (F/TDF) over 48 weeks. At week 52 participants in the boosted PI arm were offered switch to D/C/F/TAF (late-switch, 44 weeks D/C/F/TAF exposure). All participants were followed on D/C/F/TAF until week 96. Efficacy endpoints were percentage cumulative protocol-defined virologic rebound (PDVR; confirmed viral load [VL] >= 50 copies/mL) and VL = 50 copies/mL (VF) (FDA-snapshot analysis). Of 1141 randomized patients, 1080 continued in the extension phase. Few patients had PDVR (D/C/F/TAF: 3.1%, 24/763 cumulative through week 96; late-switch: 2.3%, 8/352 week 52-96). Week 96 virologic suppression was 90.7% (692/763) (D/C/F/TAF) and 93.8% (330/352) (late-switch). VF was 1.2% and 1.7%, respectively. No darunavir, primary PI, tenofovir or emtricitabine resistance-associated mutations were observed post-baseline. No patients discontinued for efficacy-related reasons. Few discontinued due to adverse events (2% D/C/F/TAF arm). Improved renal and bone parameters were maintained in the D/C/F/TAF arm and observed in the late-switch arm, with small increases in total cholesterol/high-density-lipoprotein-cholesterol ratio. A study limitation was the lack of a control arm in the week 96 analysis. Through 96 weeks, D/C/F/TAF resulted in low PDVR rates, high virologic suppression rates, very few VFs, and no resistance development. Late-switch results were consistent with D/C/F/TAF week 48 results. EMERALD week 96 results confirm the efficacy, high genetic barrier to resistance and safety benefits of D/C/F/TAF

Enabling large-scale design, synthesis and validation of small molecule protein-protein antagonists

Although there is no shortage of potential drug targets, there are only a handful known low-molecular-weight inhibitors of protein-protein interactions (PPIs). One problem is that current efforts are dominated by low-yield high-throughput screening, whose rigid framework is not suitable for the diverse chemotypes present in PPIs. Here, we developed a novel pharmacophore-based interactive screening technology that builds on the role anchor residues, or deeply buried hot spots, have in PPIs, and redesigns these entry points with anchor-biased virtual multicomponent reactions, delivering tens of millions of readily synthesizable novel compounds. Application of this approach to the MDM2/p53 cancer target led to high hit rates, resulting in a large and diverse set of confirmed inhibitors, and co-crystal structures validate the designed compounds. Our unique open-access technology promises to expand chemical space and the exploration of the human interactome by leveraging in-house small-scale assays and user-friendly chemistry to rationally design ligands for PPIs with known structure. © 2012 Koes et al

Prognostic value and kinetics of circulating endothelial cells in patients with recurrent glioblastoma randomised to bevacizumab plus lomustine, bevacizumab single agent or lomustine single agent. A report from the Dutch Neuro-Oncology Group BELOB trial

Background:Angiogenesis is crucial for glioblastoma growth, and anti-vascular endothelial growth factor agents are widely used in recurrent glioblastoma patients. The number of circulating endothelial cells (CECs) is a surrogate marker for endothelial damage. We assessed their kinetics and explored their prognostic value in patients with recurrent glioblastoma.Methods:In this side study of the BELOB trial, 141 patients with recurrent glioblastoma were randomised to receive single-agent bevacizumab or lomustine, or bevacizumab plus lomustine. Before treatment, after 4 weeks and after 6 weeks of treatment, CECs were enumerated.Results:The number of CECs increased during treatment with bevacizumab plus lomustine, but not during treatment in the single-agent arms. In patients treated with lomustine single agent, higher absolute CEC numbers after 4 weeks (log 10 CEC hazard ratio (HR) 0.41, 95% CI 0.18-0.91) and 6 weeks (log 10 CEC HR 0.16, 95% CI 0.05-0.56) of treatment were associated with improved overall survival (OS). Absolute CEC numbers in patients receiving bevacizumab plus lomustine or bevacizumab single agent were not associated wit

Antiretroviral-naive and -treated HIV-1 patients can harbour more resistant viruses in CSF than in plasma

Objectives The neurological disorders in HIV-1-infected patients remain prevalent. The HIV-1 resistance in plasma and CSF was compared in patients with neurological disorders in a multicentre study. Methods Blood and CSF samples were collected at time of neurological disorders for 244 patients. The viral loads were >50 copies/mL in both compartments and bulk genotypic tests were realized. Results On 244 patients, 89 and 155 were antiretroviral (ARV) naive and ARV treated, respectively. In ARV-naive patients, detection of mutations in CSF and not in plasma were reported for the reverse transcriptase (RT) gene in 2/89 patients (2.2%) and for the protease gene in 1/89 patients (1.1%). In ARV-treated patients, 19/152 (12.5%) patients had HIV-1 mutations only in the CSF for the RT gene and 30/151 (19.8%) for the protease gene. Two mutations appeared statistically more prevalent in the CSF than in plasma: M41L (P = 0.0455) and T215Y (P = 0.0455). Conclusions In most cases, resistance mutations were present and similar in both studied compartments. However, in 3.4% of ARV-naive and 8.8% of ARV-treated patients, the virus was more resistant in CSF than in plasma. These results support the need for genotypic resistance testing when lumbar puncture is performe

Week 48 resistance analyses of the once-daily, single-tablet regimen darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) in adults living with HIV-1 from the Phase III Randomized AMBER and EMERALD Trials

Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg is being investigated in two Phase III trials, AMBER (NCT02431247; treatment-naive adults) and EMERALD (NCT02269917; treatment-experienced, virologically suppressed adults). Week 48 AMBER and EMERALD resistance analyses are presented. Postbaseline samples for genotyping/phenotyping were analyzed from protocol-defined virologic failures (PDVFs) with viral load (VL) >= 400 copies/mL at failure/later time points. Post hoc analyses were deep sequencing in AMBER, and HIV-1 proviral DNA from baseline samples (VL = 3 thymidine analog-associated mutations (24% not fully susceptible to tenofovir) detected at screening. All achieved VL <50 copies/mL at week 48 or prior discontinuation. D/C/F/TAF has a high genetic barrier to resistance; no darunavir, primary PI, or tenofovir RAMs were observed through 48 weeks in AMBER and EMERALD. Only one postbaseline M184I/V RAM was observed in HIV-1 of an AMBER participant. In EMERALD, baseline archived RAMs to darunavir, emtricitabine, and tenofovir in participants with prior VF did not preclude virologic response

Clinical and Virological Factors Influencing the Performance of a NS1 Antigen-Capture Assay and Potential Use as a Marker of Dengue Disease Severity

Dengue is the most prevalent arthropod-borne disease in tropical regions. The clinical manifestation may vary from asymptomatic to potentially fatal dengue shock syndrome. Early laboratory confirmation of dengue diagnosis is essential since many symptoms are not specific. Dengue non-structural protein 1 (NS1) may be used in simple antigen-capture ELISA for early detection of dengue virus infection. Our result demonstrated that the Platelia NS1 antigen detection kit had a quite low overall sensitivity. However, sensitivity rises significantly when used in combination with MAC-ELISA. When taking into account the various forms of dengue infection, the NS1 antigen detection was found relatively high in patients sampled during the first 3 days of fever onset, in patients with primary infection, DENV-1 infection, with high level of viremia and in mild form of dengue fever. In asymptomatically infected individuals, RT-PCR assay has proved to be more sensitive than NS1 antigen detection. Moreover, the NS1 antigen level correlated significantly with high viremia and low level of NS1 antigen was associated with more severe disease

Dengue in Thailand and Cambodia: An Assessment of the Degree of Underrecognized Disease Burden Based on Reported Cases

Dengue is a major public health problem especially in tropical and subtropical countries of Asia and Latin-America. An effective dengue vaccine is not yet available, but several vaccine candidates are currently being evaluated in clinical trials. Accurate country-level incidence data are crucial to assess the cost-effectiveness of such vaccines and will assist policy-makers in making vaccine introduction decisions. Existing national surveillance systems are often passive and are designed to monitor trends and to detect disease outbreaks. Our analyses of data from prospectively followed cohorts with laboratory confirmation of dengue cases show that, in Thailand and Cambodia, dengue incidence is underrecognized by more than 8-fold. The magnitude of the outpatient burden caused by dengue is not assessed or reflected by the national surveillance data. We estimate that a median of more than 340,000 symptomatic dengue virus infections occurred annually in children less than 15 years of age in Thailand in Cambodia between 2003 and 2007