Biotinylated non-ionic amphipols for GPCR ligands screening.

We present herein the synthesis of biotin-functionalized polymers (BNAPols) that have been developed for the fixation of membrane proteins (MPs) onto surfaces. BNAPols were synthesized by free-radical polymerization of a tris(hydroxymethyl)acrylamidomethane (THAM)-derived amphiphilic monomer in the presence of a thiol-based transfer agent with an azido group. Then a Huisgen-cycloaddition reaction was performed with Biotin-(PEG)8-alkyne that resulted in formation of the biotinylated polymers. The designed structure of BNAPols was confirmed by NMR spectroscopy, and a HABA/avidin assay was used for estimating the percentage of biotin grafted on the polymer end chain. The colloidal characterization of these biotin-functionalized polymers was done using both dynamic light scattering (DLS) and small angle X-ray scattering (SAXS) techniques. BNAPols were used to stabilize a model G protein-coupled receptor (GPCR), the human Growth Hormone Secretagogue Receptor (GHSR), out of its membrane environment. Subsequent immobilization of the BNAPols:GHSR complex onto a streptavidin-coated surface allowed screening of ligands based on their ability to bind the immobilized receptor. This opens the way to the use of biotinylated NAPols to immobilize functional, unmodified, membrane proteins, providing original sensor devices for multiple applications including innovative ligand screening assays.

Hydrogenated Diglucose Detergents for Membrane-Protein Extraction and Stabilization.

We report herein the design and synthesis of a novel series of alkyl glycoside detergents consisting of a nonionic polar headgroup that comprises two glucose moieties in a branched arrangement (DG), onto which octane-, decane-, and dodecanethiols were grafted leading to ODG, DDG, and DDDG detergents, respectively. Micellization in aqueous solution was studied by isothermal titration calorimetry, 1H NMR spectroscopy, and surface tensiometry. Critical micellar concentration values were found to decrease by a factor of ∼10 for each pair of methylene groups added to the alkyl chain, ranging from ∼0.05 to 9 mM for DDDG and ODG, respectively. Dynamic light scattering and analytical ultracentrifugation sedimentation velocity experiments were used to investigate the size and composition of the micellar aggregates, showing that the aggregation number significantly increased from ∼40 for ODG to ∼80 for DDDG. All new compounds were able to solubilize membrane proteins (MPs) from bacterial membranes, insect cells, as well as the Madin-Darby canine kidney cells. In particular, native human adenosine receptor (A2AR) and bacterial transporter (BmrA) were solubilized efficiently. Striking thermostability improvements of +13 and +8 °C were observed when ODG and DDG were, respectively, applied to wild-type and full-length A2AR. Taken together, this novel detergent series shows promising detergent potency for solubilization and stabilization of membrane proteins (MPs) and thus makes a valuable addition to the chemical toolbox available for extracting and handling these important but challenging MP targets.

Hybrid Double-Chain Maltose-Based Detergents: Synthesis and Colloidal and Biochemical Evaluation.

Four hybrid double-chain surfactants with a maltose polar head were synthesized. The apolar domain consists of a hydrogenated chain, and a partially fluorinated chain made of a propyl hydrogenated spacer terminated by a perfluorinated core of various lengths. Their water solubility was found to be lower than 1 g/L irrespective of the length of both chains. The self-assembling properties of pure hybrids in water were studied by dynamic light scattering and transmission electron microscopy, which revealed the formation of two populations of aggregates with diameters of 8-50 nm and 80-300 nm. When mixed with the classical detergent n-dodecylmaltoside (DDM), the four hybrids were well soluble and formed small mixed micelles. DDM/hybrid mixtures were further evaluated for the extraction of the full-length, wild-type human GPCR adenosine receptor (A2AR), and the bacterial transporter AcrB. The solubilization of A2AR showed extraction efficiencies ranging from 40 to 70%, while that of AcrB reached 60-90%. Finally, three of the hybrids exhibited significant thermostabilization when present as additives. The derivative with a C12-hydrogenated chain and a C4F9-fluorinated chain emerged as the most potent additive exhibiting both good extraction yields of A2AR and AcrB and thermostabilization of A2AR by ∼7 °C.

Fluorinated diglucose detergents for membrane-protein extraction.

Fluorinated surfactants have scarcely been explored for the direct extraction of proteins from membranes because fluorination is believed to abrogate detergency. However, we have recently shown that a commercially available fluorinated surfactant readily solubilizes lipid membranes, thereby suggesting that fluorination per se does not interfere with detergent activity. In this work, we developed new fluorinated surfactants that exhibit detergency in terms of both lipid-vesicle solubilization and membrane-protein extraction. The compounds made and tested contain two glucose moieties as polar headgroup, a hydrogenated thioether linker, and a perfluorinated alkyl tail with either 4, 6, or 8 carbon atoms. The physicochemical properties of the micelles formed by the three fluorinated surfactants were evaluated by NMR spectroscopy, surface tensiometry, isothermal titration calorimetry, dynamic light scattering, small-angle X-ray scattering, and analytical ultracentrifugation. At 25 °C, micellization was mainly entropy-driven, and the CMC values were found to decrease with chain length of the fluorinated tail, whereas the aggregation number increased with chain length. Remarkably, all three surfactants were found to solubilize lipid vesicles and extract a broad range of proteins from Escherichia coli membranes. These findings demonstrate, for the first time, that nonionic fluorinated surfactants could be further exploited for the direct extraction and solubilization of membrane proteins.

Divalent Amino-Acid-Based Amphiphilic Antioxidants: Synthesis, Self-Assembling Properties, and Biological Evaluation.

We report herein the synthesis of a divalent amphiphilic carrier onto which α-phenyl-N-tert-butyl nitrone (PBN) and 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox) antioxidants were grafted to give the divalent derivative called FATxPBN. The divalent carrier consists of two lysine amino acids as a scaffold upon which the antioxidant moieties are grafted, a perfluorinated chain that supplies hydrophobicity, and a sugar-based polar headgroup that ensures water solubility. For the sake of comparison, a divalent PBN derivative called FADiPBN was also synthesized. The self-aggregation properties of FATxPBN and FADiPBN were studied by means of surface tension, dynamic light scattering, and transmission electron microscopy methods, and showed they form small micelles (i.e., 12 and 6 nm diameter, respectively) at submillimolar concentrations (i.e., 0.01 and 0.05 mM, respectively), in agreement with partition coefficient values. The superior antioxidant properties of FATxPBN over FADiPBN and the parent compounds PBN and Trolox were demonstrated using in vitro ABTS(•+) reduction (98%) and soybean lipoxygenase inhibition (94%) assays. Finally, FATxPBN was found to significantly inhibit hyperglycemia-induced toxicity on an ex-vivo rat model, demonstrating its potency as a bioactive antioxidant against oxidative stress-induced damage.

Hybrid Fluorinated and Hydrogenated Double-Chain Surfactants for Handling Membrane Proteins.

Two hybrid fluorinated double-chain surfactants with a diglucosylated polar head were synthesized. The apolar domain consists of a perfluorohexyl main chain and a butyl hydrogenated branch as a side chain. They were found to self-assemble into small micelles at low critical micellar concentrations, demonstrating that the short branch increases the overall hydrophobicity while keeping the length of the apolar domain short. They were both able to keep the membrane protein bacteriorhodopsin stable, one of them for at least 3 months.

Cetuximab versus methotrexate in first-line treatment of older, frail patients with inoperable recurrent or metastatic head and neck cancer (ELAN UNFIT): a randomised, open-label, phase 3 trial.

BACKGROUND: At present, there is no established standard treatment for frail older patients with recurrent or metastatic head and neck squamous cell carcinoma. We aimed to compare the efficacy and safety of cetuximab to those of methotrexate (the reference regimen) in this population. METHODS: This randomised, open-label, phase 3 trial was done at 20 hospitals in France. Patients aged 70 years or older, assessed as frail by the ELAN Geriatric Evaluation, with recurrent or metastatic head and neck squamous cell carcinoma in the first-line setting and with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 were eligible for inclusion. Patients were randomly assigned (1:1) to receive cetuximab 500 mg/m2 intravenously every 2 weeks or methotrexate 40 mg/m2 intravenously every week, with minimisation by ECOG performance status, type of disease evolution, Charlson Comorbidity Index score, serum albumin concentration, and geriatrician consultation. To avoid deterministic minimisation and assure allocation concealment, patients were allocated with a probability of 0·80 to the treatment that most reduced the imbalance. Treatment was continued until disease progression or unacceptable toxicity, whichever occurred first. The primary endpoint was failure-free survival (defined as the time from randomisation to disease progression, death, discontinuation of treatment, or loss of 2 or more points on the Activities in Daily Living scale, whichever occurred first) and was analysed in the intention-to-treat population. 151 failures expected out of 164 patients were required to detect a hazard ratio (HR) of 0·625 with 0·05 alpha error, with 80% power. A futility interim analysis was planned when approximately 80 failures were observed, based on failure-free survival. Safety analyses included all patients who received at least one dose of the study drug. This study is registered on ClinicalTrials.gov (NCT01884623) and was stopped for futility after the interim analysis. FINDINGS: Between Nov 7, 2013, and April 23, 2018, 82 patients were enrolled (41 to the cetuximab group and 41 to the methotrexate group); 60 (73%) were male, 37 (45%) were aged 80 years or older, 35 (43%) had an ECOG performance status of 2, and 36 (44%) had metastatic disease. Enrolment was stopped for futility at the interim analysis. At the final analysis, median follow-up was 43·3 months (IQR 30·8-52·1). At data cutoff, all 82 patients had failure; failure-free survival did not differ significantly between the groups (median 1·4 months [95% CI 1·0-2·1] in the cetuximab group vs 1·9 months [1·1-2·6] in the methotrexate group; adjusted HR 1·03 [95% CI 0·66-1·61], p=0·89). The frequency of patients who had grade 3 or worse adverse events was 63% (26 of 41) in the cetuximab group and 73% (30 of 41) in the methotrexate group. The most common grade 3-4 adverse events in the cetuximab group were fatigue (four [10%] of 41 patients), lung infection (four [10%]), and rash acneiform (four [10%]), and those in the methotrexate group were fatigue (nine [22%] of 41), increased gamma-glutamyltransferase (seven [17%]), natraemia disorder (four [10%]), anaemia (four [10%]), leukopenia (four [10%]), and neutropenia (four [10%]). The frequency of patients who had serious adverse events was 44% (18 of 41) in the cetuximab group and 39% (16 of 41) in the methotrexate group. Four patients presented with a fatal adverse event in the cetuximab group (sepsis, decreased level of consciousness, pulmonary oedema, and death of unknown cause) as did two patients in the methotrexate group (dyspnoea and death of unknown cause). INTERPRETATION: The study showed no improvement in failure-free survival with cetuximab versus methotrexate. Patients with an ECOG performance status of 2 did not benefit from these systemic therapies. New treatment options including immunotherapy should be explored in frail older patients with recurrent or metastatic head and neck squamous cell carcinoma, after an initial geriatric evaluation, such as the ELAN Geriatric Evaluation. FUNDING: French programme PAIR-VADS 2011 (sponsored by the National Cancer Institute, the Fondation ARC and the Ligue Contre le Cancer), GEMLUC, GEFLUC, and Merck Santé. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Adapted EXTREME regimen in the first-line treatment of fit, older patients with recurrent or metastatic head and neck squamous cell carcinoma (ELAN-FIT): a multicentre, single-arm, phase 2 trial.

BACKGROUND: A standard treatment for fit, older patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) is yet to be established. In the previous EXTREME trial, few older patients were included. We aimed to evaluate the efficacy and tolerance of an adapted EXTREME regimen in fit, older patients with recurrent or metastatic HNSCC. METHODS: This single-arm, phase 2 study was done at 22 centres in France. Eligible patients were aged 70 years or older and assessed as not frail (fit) using the ELAN Geriatric Evaluation (EGE) and had recurrent or metastatic HNSCC in the first-line setting that was not eligible for local therapy (surgery or radiotherapy), and an Eastern Cooperative Oncology Group performance status of 0-1. The adapted EXTREME regimen consisted of six cycles of fluorouracil 4000 mg/m2 on days 1-4, carboplatin with an area under the curve of 5 on day 1, and cetuximab on days 1, 8, and 15 (400 mg/m2 on cycle 1-day 1, and 250 mg/m2 subsequently), all intravenously, with cycles starting every 21 days. In patients with disease control after two to six cycles, cetuximab 500 mg/m2 was continued once every 2 weeks as maintenance therapy until disease progression or unacceptable toxicity. Granulocyte colony-stimulating factor was systematically administered and erythropoietin was recommended during chemotherapy. The study was based on the two-stage Bryant and Day design, combining efficacy and toxicity endpoints. The primary efficacy endpoint was objective response rate at week 12 after the start of treatment, assessed by central review (with an unacceptable rate of ≤15%). The primary toxicity endpoint was morbidity, defined as grade 4-5 adverse events, or cutaneous rash (grade ≥3) that required cetuximab to be discontinued, during the chemotherapy phase, or a decrease in functional autonomy (Activities of Daily Living score decrease ≥2 points from baseline) at 1 month after the end of chemotherapy (with an unacceptable morbidity rate of >40%). Analysis of the coprimary endpoints, and of safety in the chemotherapy phase, was based on the per-protocol population, defined as eligible patients who received at least one cycle of the adapted EXTREME regimen. Safety in the maintenance phase was assessed in all patients who received at least one dose of cetuximab as maintenance therapy. The study is registered with ClinicalTrials.gov, NCT01864772, and is completed. FINDINGS: Between Sept 27, 2013, and June 20, 2018, 85 patients were enrolled, of whom 78 were in the per-protocol population. 66 (85%) patients were male and 12 (15%) were female, and the median age was 75 years (IQR 72-79). The median number of chemotherapy cycles received was five (IQR 3-6). Objective response at week 12 was observed in 31 patients (40% [95% CI 30-51]) and morbidity events were observed in 24 patients (31% [22-42]). No fatal adverse events occurred. Four patients presented with a decrease in functional autonomy 1 month after the end of chemotherapy versus baseline. During chemotherapy, the most common grade 3-4 adverse events were haematological events (leukopenia [22 patients; 28%], neutropenia [20; 26%], thrombocytopenia [15; 19%], and anaemia [12; 15%]), oral mucositis (14; 18%), fatigue (11; 14%), rash acneiform (ten; 13%), and hypomagnesaemia (nine; 12%). Among 44 patients who received cetuximab during the maintenance phase, the most common grade 3-4 adverse events were hypomagnesaemia (six patients; 14%) and acneiform rash (six; 14%). INTERPRETATION: The study met its primary objectives on objective response and morbidity, and showed overall survival to be as good as in younger patients treated with standard regimens, indicating that the adapted EXTREME regimen could be used in older patients with recurrent or metastatic HNSCC who are deemed fit with use of a geriatric evaluation tool adapted to patients with head and neck cancer, such as the EGE. FUNDING: French programme PAIR-VADS 2011 (sponsored by the National Cancer Institute, the Fondation ARC, and the Ligue Contre le Cancer), Sandoz, GEFLUC, and GEMLUC. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Non-ionic cholesterol-based additives for the stabilization of membrane proteins.

We report herein the synthesis of two non-ionic amphiphiles with a cholesterol hydrophobic moiety that can be used as chemical additives for biochemical studies of membrane proteins. They were designed to show a high similarity with the planar steroid core of cholesterol and small-to-medium polar head groups attached at the C3 position of ring-A on the sterol skeleton. The two Chol-Tris and Chol-DG have a Tris-hydroxymethyl and a branched diglucose polar head group, respectively, which provide them sufficient water solubility when mixed with the "gold standard" detergent n-Dodecyl-ß-D-Maltoside (DDM). The colloidal properties of these mixed micelles were investigated by means of surface tension (SFT) measurements and dynamic light scattering (DLS) experiments and showed the formation of globular micelles of about 8 nm in diameter with a critical micellar concentration of 0.20 mM for DDM:Chol-DG and 0.22 mM for DDM:Chol-Tris. We showed that mixed micelles do not alter the extraction potency of a G-protein coupled receptor (GPCR): the human adenosine A2A receptor (A2AR). The thermostabilizing effect of the mixed micelles was confirmed on two GPCRs, A2AR and the growth hormone secretagogue receptor (GHSR). Finally, these two mixed micelles were found suitable for the purification of an active form of A2AR which remained able to bind two ligands of different class i.e. the specific agonist CGS-21680 and the specific inverse agonist ZM-241385. This suggests that Chol-Tris and Chol-DG may be used as a non-ionic alternative to the cholesteryl hemisuccinate (CHS) stabilizing agent.

Highly ordered conjugated polymer nanoarchitectures with three-dimensional structural control.

Conductive polymers are a class of materials with vast potential for tomorrow's ultra-large-scale technologies as they combine structural and functional diversity with flexible synthesis and processing approaches. A missing component, with their subtle chemical structure, is reliable building at nanoscale. Here we report on the patterning of polyaniline, a prototypical conjugated polymer, with an unprecedented areal patterning order and density exceeding 0.25 teradot/inch(2). With template-confined growth, through platinum-surface-catalyzed polymerization of aniline, highly ordered arrays of distinct polyaniline nanowires are produced with a typical diameter

Linear and Nonlinear Dynamic Behavior of Polymer Micellar Assemblies Connected by Metallo-Supramolecular Interactions.

The linear and nonlinear rheology of associative colloidal polymer assemblies with metallo-supramolecular interactions is herein studied. Polystyrene-b-poly(tert-butylacrylate) with a terpyridine ligand at the end of the acrylate block is self-assembled into micelles in ethanol, a selective solvent for the latter block, and supramolecularly connected by complexation to divalent metal ions. The dependence of the system elasticity on polymer concentration can be semi-quantitatively understood by a geometrical packing model. For strongly associated (Ni2+, Fe2+) and sufficiently concentrated systems (15 w/v%), any given ligand end-group has a virtually 100% probability of being located in an overlapping hairy region between two micelles. By assuming a 50% probability of intermicellar crosslinks being formed, an excellent prediction of the plateau modulus was achieved and compared with the experimental results. For strongly associated but somewhat more dilute systems (12 w/v%) that still have significant overlap between hairy regions, the experimental modulus was lower than the predicted value, as the effective number of crosslinkers was further reduced along with possible density heterogeneities. The reversible destruction of the network by shear forces can be observed from the strain dependence of the storage and loss moduli. The storage moduli of the Ni2+ and Zn2+ systems at a lower concentration (12 w/v%) showed a rarely observed feature (i.e., a peak at the transition from linear to nonlinear regime). This peak disappeared at a higher concentration (15 w/v%). This behavior can be rationalized based on concentration-dependent network stretchability.

PREDOMOS study, impact of a social intervention program for socially isolated elderly cancer patients: update to the study protocol for a randomized controlled trial.

BACKGROUND: Social isolation potentiates the risk of death by cancer in the older cancer patient population. The PREDOMOS study investigates the impact of establishing a Program of Social intervention associated with techniques of Domotic and Remote assistance on the improvement of quality of life of older isolated patients, treated for locally advanced or metastatic cancer. This paper updates the pilot trial protocol. METHODS/DESIGN: The original protocol was published in Trials, accessible at https://trialsjournal.biomedcentral.com/articles/10.1186/s13063-017-1894-7 . This update reports on the eligibility criteria expansion and on the adjunction of a cost-utility analysis. We widened the eligible population to patients with locally advanced or metastatic cancer including malignant hemopathies (except acute myeloid leukemia) and to patients in the first and second lines of oncologic treatment. We restricted the inclusion to patients with a Mini Mental State Examination score strictly over 24. In addition to the secondary outcomes outlined in the protocol, a medico-economic analysis has been added to evaluate both the health benefits and costs of the two strategies and calculate the incremental cost-utility ratio of the innovative program assessed, compared to the standard practice. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02829762 . Registered on 29 June 2016.

Induction Chemotherapy Followed by Cetuximab Radiotherapy Is Not Superior to Concurrent Chemoradiotherapy for Head and Neck Carcinomas: Results of the GORTEC 2007-02 Phase III Randomized Trial.

PURPOSE: Both concurrent chemoradiotherapy (CT-RT) and cetuximab radiotherapy (cetux-RT) have been established as the standard of care for the treatment of locally advanced squamous cell carcinoma of the head and neck. It was not known whether the addition of induction chemotherapy before cetux-RT could improve outcomes compared with standard of care CT-RT. PATIENTS AND METHODS: The current trial was restricted to patients with nonmetastatic N2b, N2c, or N3 squamous cell carcinoma of the head and neck and fit for taxotere, cisplatin, fluorouracil (TPF). Patients were randomly assigned to receive three cycles of TPF followed by cetux-RT versus concurrent carboplatin fluorouracil and RT as recommended in National Comprehensive Cancer Network guidelines. The trial was powered to detect a hazard ratio (HR) of 0.66 in favor of TPF plus cetux-RT for progression-free survival at 2 years. The inclusion of 180 patients per arm was needed to achieve 80% power at a two-sided significance level of .05. RESULTS: Between 2009 and 2013, 370 patients were included. All patients and tumors characteristics were well balanced between arms. There were more cases of grade 3 and 4 neutropenia in the induction arm, and the induction TPF was associated with 6.6% treatment-related deaths. With a median follow-up of 2.8 years, 2-year progression-free survival was not different between both arms (CT-RT, 0.38 v TPF + cetux-RT, 0.36; HR, 0.93 [95% CI, 0.73 to 1.20]; P = .58). HR was 0.98 (95% CI, 0.74 to 1.3; P = .90) for locoregional control and 1.12 (95% CI, 0.86 to 1.46; P = .39) for overall survival. These effects were observed regardless of p16 status. The rate of distant metastases was lower in the TPF arm (HR, 0.54 [95% CI, 0.30 to 0.99]; P = .05). CONCLUSION: Induction TPF followed by cetux-RT did not improve outcomes compared with CT-RT in a population of patients with advanced cervical lymphadenopathy.

Spectrum of metabolic-based resistance to DDT and pyrethroids in Anopheles gambiae s.l. populations from Cameroon.

Some populations of Anopheles gambiae s.l. from Cameroon were reported to develop resistance to DDT or pyrethroids but were free of the kdr mutation "Leucine-Phenylalanine" (Leu-Phe). This study reports on the metabolic activity of non-specific esterases (NSEs), mixed function oxidases (MFOs), and glutathione S-transferases (GSTs), three enzyme systems commonly involved in insecticide resistance. Biochemical assays were performed in DDT or pyrethroid-resistant populations of An. gambiae s.l. from Douala, Mbalmayo, Pitoa, and Simatou neighborhoods. Enzyme activity was compared to the Kisumu-susceptible reference strain using the Mann-Whitney test. Most of the tested samples had elevated NSE activity (P < 0.02). The Douala sample evenly displayed elevated GST activity (P < 0.001), while high MFO level was recorded in the Pitoa sample (P < 0.001). MFO or GST levels were sometimes lower or similar to that of the Kisumu strain. These results suggest metabolic detoxification is a major DDT or pyrethroid resistance mechanism and emphasize the need for further investigations on An. gambiae s.l. resistance mechanisms in Cameroon.

PREDOMOS study, impact of a social intervention program for socially isolated elderly cancer patients: study protocol for a randomized controlled trial.

BACKGROUND: Cancer incidence and social isolation increase along with advanced age, and social isolation potentiates the relative risk of death by cancer. Once spotted, social isolation can be averted with the intervention of a multidisciplinary team. Techniques of automation and remote assistance have already demonstrated their positive impact on falls prevention and quality of life (QoL), though little is known about their impact on socially isolated elderly patients supported for cancer. The primary objective of the PREDOMOS study is to evaluate the impact of establishing a Program of Social intervention associated with techniques of Domotic and Remote assistance (PS-DR) on the improvement of QoL of elderly isolated patients, treated for locally advanced or metastatic cancer. The secondary objectives include treatment failure, tolerance, survival, and autonomy. METHODS/DESIGN: This trial is a multicenter, prospective, randomized, placebo-controlled, open-label, two-parallel group study. The setting is 10 French oncogeriatric centers. Inclusion criteria are patients aged at least 70 years with a social isolation risk and a histological diagnosis of cancer, locally advanced or metastatic disease. The groups are (1) the control group, receiving usual care; (2) the experimental group, receiving usual care associating with monthly social assistance, domotic, and remote assistance. Participants are randomized in a 1:1 allocation ratio. Evaluation times involve inclusion (randomization) and follow-up (12 months). The primary endpoint is QoL at 3 months (via European Organization for Research and Treatment of Cancer (EORTC) QLQ C30); secondary endpoints are social isolation, time to treatment failure, toxicity, dose response-intensity, survival, autonomy, and QoL at 6 months. For the sample size, 320 individuals are required to obtain 90% power to detect a 10-point difference (standard deviation 25) in QoL score between the two groups (20% loss to follow-up patients expected). DISCUSSION: The randomized controlled design is the most appropriate design to demonstrate the efficacy of a new experimental strategy (Evidence-Based Medicine Working Group classification). National and international recommendations could be updated based on the findings of this study. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02829762 . Registered on 29 June 2016.

Inhibition of adult emergence of Aedes aegypti in simulated domestic water-storage containers by using a controlled-release formulation of pyriproxyfen.

Concrete domestic water-storage jars are a common larval habitat of the dengue vector Aedes aegypti in countries of Southeast Asia. The efficacy of a novel controlled-release formulation of the insect growth regulator pyriproxyfen, designed to inhibit adult emergence for 6 months (the approximate duration of the main dengue transmission season in many endemic countries) was tested in Cambodia against a local strain of Ae. aegypti in 200-liter jars. The resin-based formulation contained 4.8% active ingredient (AI). At target dosages of 18, 27, and 36 ppb of AI, inhibition of adult emergence remained above 95% for at least 2 months. After 3 months at 18 ppb AI, the residual efficacy was significantly lower than for the higher dosages (P < 0.05). At the higher dosages, inhibition of adult emergence was > or = 87% for 6 months. At a dosage of 27 ppb AI, monthly removal and replacement of two thirds of the water did not reduce efficacy (P > 0.05). Potential operational advantages and challenges of using the formulation are discussed. Larger-scale efficacy studies are recommended in community settings.

Protective efficacy of lambda-cyhalothrin treated nets in Anopheles gambiae pyrethroid resistance areas of Côte d'Ivoire.

The efficacy of nets treated with lambda-cyhalothrin, a pyrethroid insecticide, on malaria infection and disease was assessed for the first time at the community level in Anopheles gambiae pyrethroid resistance areas. The study was carried out in northern Côte d'Ivoire, which is an area of kdr resistance. Four pairs of villages were selected and matched according to demographic, sociological, and ecological criteria. Among each pair, a village was randomly allocated to receive mosquito nets. More than 80% of beds were covered with nets treated with lambda-cyhalothrin and retreated after 6 months. In each village, 54 children aged 0-59 months were randomly selected and clinically monitored for 8 periods of 7 days throughout the year. Results showed that the efficacy of treated nets was maintained with a reduction of the prevalence of asymptomatic malaria infection by 12% and an estimated protective efficacy against malaria disease of 56%.

FFCD-1004 Clinical Trial: Impact of Cytidine Deaminase Activity on Clinical Outcome in Gemcitabine-Monotherapy Treated Patients.

PURPOSE: Because cytidine deaminase (CDA) is the key enzyme in gemcitabine metabolism, numerous studies have attempted to investigate impact of CDA status (i.e. genotype or phenotype) on clinical outcome. To date, data are still controversial because none of these studies has fully investigated genotype-phenotype CDA status, pharmacokinetics and clinical outcome relationships in gemcitabine-treated patients. Besides, most patients were treated with gemcitabine associated with other drugs, thus adding a confounding factor. We performed a multicenter prospective clinical trial in gemcitabine-treated patients which aimed at investigating the link between CDA deficiency on the occurrence of severe toxicities and on pharmacokinetics, and studying CDA genotype-phenotype relationships. EXPERIMENTAL DESIGN: One hundred twenty patients with resected pancreatic adenocarcinoma eligible for adjuvant gemcitabine monotherapy were enrolled in this study promoted and managed by the Fédération Francophone de Cancérologie Digestive. Toxicities were graded according to National Cancer Institute's Common Terminology Criteria for Adverse Events Version 4. They were considered severe for grade ≥ 3, and early when occurring during the first eight weeks of treatment. CDA status was evaluated using a double approach: genotyping for 79A>C and functional testing. Therapeutic drug monitoring of gemcitabine and its metabolite were performed on the first course of gemcitabine. RESULTS: Five patients out of 120 (i.e., 4.6%) were found to be CDA deficient (i.e., CDA activity <1.3 U/mg), and only one among them experienced early severe hematological toxicity. There was no statistically significant difference in CDA activity between patients experiencing hematological severe toxicities (28.44%) and patients who tolerated the treatment (71.56%). CDA genetic analysis failed in evidencing an impact in terms of toxicities or in CDA activity. Regarding pharmacokinetics, a wide inter-individual variability has been observed in patients. CONCLUSION: This study, which included only 4.6% of CDA-deficient patients, failed in identifying CDA status as a predictive marker of toxicities with gemcitabine. A lack of statistical power because of smoothing effect of CDA variability as compared with real life conditions could explain this absence of impact. TRIAL REGISTRATION: ClinicalTrials.gov NCT01416662.

Alternative insecticides: an urgent need.

Most insecticides used against pests and vectors of human disease (e.g. fleas, flies and mosquitoes) are spin-offs from agrochemical research and development. The arsenal of safe and cost-effective public health insecticides is being depleted by restrictions for various reasons (e.g. insecticide resistance, unacceptable side effects and non re-registration) and the number of new products launched is dwindling. Mobilizing public resources and establishment of partnerships to support research and development of public health insecticides is crucial in the post-DDT and post-pyrethroid era.

Combating malaria vectors in Africa: current directions of research.

Vector control remains an important component of malaria control, particularly in Africa where most infant deaths occur. Among the different methods, insecticide-treated bednets seem to be a suitable way to reduce morbidity and child mortality in endemic areas. To facilitate their large-scale use and to investigate alternative vector control methods, the authors propose these current directions of research that are already being explored in Africa through a collaborating network involving several African countries: (1) vector genetics, (2) insecticide resistance and (3) vector control strategies.