Publications by authors named "Patrick Saulnier"

108 Publications

Characterization of Biological Material Adsorption to the Surface of Nanoparticles without a Prior Separation Step: a Case Study of Glioblastoma-Targeting Peptide and Lipid Nanocapsules.

Pharm Res 2021 Apr 7. Epub 2021 Apr 7.

University of Angers, Inserm, CNRS, MINT, SFR ICAT, F-49000, Angers, France.

Purpose: Current preclinical therapeutic strategies involving nanomedicine require increasingly sophisticated nanosystems and the characterization of the complexity of such nanoassemblies is becoming a major issue. Accurate characterization is often the factor that can accelerate the translational approaches of nanomedicines and their pharmaceutical development to reach the clinic faster. We conducted a case study involving the adsorption of the NFL-TBS.40-63 (NFL) peptide (derived from neurofilaments) to the surface of lipid nanocapsules (LNCs) (a combined nanosystem used to target glioblastoma cells) to develop an analytical approach combining the separation and the quantification in a single step, leading to the characterization of the proportion of free peptide and thus the proportion of peptide adsorbed to the lipid nanocapsule surface.

Methods: LNC suspensions, NFL peptide solution and LNC/NFL peptide mixtures were characterized using a Size-Exclusion Chromatography method (with a chromatographic apparatus). In addition, this method was compared to centrifugal-filtration devices, currently used in literature for this case study.

Results: Combining the steps for separation and characterization in one single sequence improved the accuracy and robustness of the data and led to reproducible results. Moreover the data deviation observed for the centrifugal-filtration devices demonstrated the limits for this increasingly used characterization approach, explained by the poor separation quality and highlighting the importance for the method optimization. The high potential of the technique was shown, proving that H-bond and/or electrostatic interactions mediate adsorption of the NFL peptide to the surface of LNCs.

Conclusions: Used only as a characterization tool, the process using chromatographic apparatus is less time and solvent consuming than classical Size-Exclusion Chromatography columns only used for separation. It could be a promising tool for the scientific community for characterizing the interactions of other combinations of nanosystems and active biological agents.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11095-021-03034-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026175PMC
April 2021

Lipid Nanoparticles Vectorized with NFL-TBS.40-63 Peptide Target Oligodendrocytes and Promote Neurotrophin-3 Effects After Demyelination In Vitro.

Neurochem Res 2020 Nov 10;45(11):2732-2748. Epub 2020 Sep 10.

MINT, UNIV Angers, INSERM 1066, CNRS 6021, Université Bretagne Loire, Angers, France.

Promoting remyelination in multiple sclerosis is important to prevent axon degeneration, given the lack of curative treatment. Although some growth factors improve this repair, unspecific delivery to cells and potential side effects limit their therapeutic use. Thus, NFL-TBS.40-63 peptide (NFL)-known to enter specifically myelinating oligodendrocytes (OL)-was used to vectorize 100 nm diameter lipid nanoparticles (LNC), and the ability of NFL-LNC to specifically target OL from newborn rat brain was assessed in vitro. Specific uptake of DiD-labeled NFL-LNC by OL characterized by CNP and myelin basic protein was observed by confocal microscopy, as well as DiD colocalization with NFL and with Rab5-a marker of early endosomes. Unvectorized LNC did not significantly penetrate OL and there was no uptake of NFL-LNC by astrocytes. Canonical maturation of OL which extended compacted myelin-like membranes was observed by transmission electron microscopy in cells grown up to 9 days with NFL-LNC. Endocytosis of NFL-LNC appeared to depend on several pathways, as demonstrated by inhibitors. In addition, vectorized NFL-LNC adsorbed on neurotrophin-3 (NT-3) potentiated the proremyelinating effects of NT-3 after demyelination by lysophosphatidyl choline, allowing noticeably decreasing NT-3 concentration. Our results if they were confirmed in vivo suggest that NFL-vectorized LNC appear safe and could be considered as putative carriers for specific drug delivery to OL in order to increase remyelination.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11064-020-03122-yDOI Listing
November 2020

Carboplatin plus etoposide versus topotecan as second-line treatment for patients with sensitive relapsed small-cell lung cancer: an open-label, multicentre, randomised, phase 3 trial.

Lancet Oncol 2020 09;21(9):1224-1233

Service de Pneumologie, CHI Créteil, Créteil, France; Institut Mondor de Recherche Biomédicale, U955 Inserm-Université Paris Est Créteil, Créteil, France. Electronic address:

Background: Topotecan is currently the only drug approved in Europe in a second-line setting for the treatment of small-cell lung cancer. This study investigated whether the doublet of carboplatin plus etoposide was superior to topotecan as a second-line treatment in patients with sensitive relapsed small-cell lung cancer.

Methods: In this open-label, randomised, phase 3 trial done in 38 hospitals in France, we enrolled patients with histologically or cytologically confirmed advanced stage IV or locally relapsed small-cell lung cancer, who responded to first-line platinum plus etoposide treatment, but who had disease relapse or progression at least 90 days after completion of first-line treatment. Eligible patients were aged 18 years or older and had an Eastern Cooperative Oncology Group performance status 0-2. Enrolled patients were randomly assigned (1:1) to receive combination carboplatin plus etoposide (six cycles of intravenous carboplatin [area under the curve 5 mg/mL per min] on day 1 plus intravenous etoposide [100 mg/m from day 1 to day 3]) or oral topotecan (2·3 mg/m from day 1 to day 5, for six cycles). Randomisation was done using the minimisation method with biased-coin balancing for ECOG performance status, response to the first-line chemotherapy, and treatment centre. The primary endpoint was progression-free survival, which was centrally reviewed and analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02738346.

Findings: Between July 18, 2013, and July 2, 2018, we enrolled and randomly assigned 164 patients (82 in each study group). One patient from each group withdrew consent, therefore 162 patients (81 in each group) were included in the intention-to-treat population. With a median follow-up of 22·7 months (IQR 20·0-37·3), median progression-free survival was significantly longer in the combination chemotherapy group than in the topotecan group (4·7 months, 90% CI 3·9-5·5 vs 2·7 months, 2·3-3·2; stratified hazard ratio 0·57, 90% CI 0·41-0·73; p=0·0041). The most frequent grade 3-4 adverse events were neutropenia (18 [22%] of 81 patients in the topotecan group vs 11 [14%] of 81 patients in the combination chemotherapy group), thrombocytopenia (29 [36%] vs 25 [31%]), anaemia (17 [21%] vs 20 [25%]), febrile neutropenia (nine [11%] vs five [6%]), and asthenia (eight [10%] vs seven [9%]). Two treatment-related deaths occurred in the topotecan group (both were febrile neutropenia with sepsis) and no treatment-related deaths occurred in the combination group.

Interpretation: Our results suggest that carboplatin plus etoposide rechallenge can be considered as a reasonable second-line chemotherapy option for patients with sensitive relapsed small-cell lung cancer.

Funding: Amgen and the French Lung Cancer Group (Groupe Français de Pneumo-Cancérologie).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1470-2045(20)30461-7DOI Listing
September 2020

Systemic short chain fatty acids limit antitumor effect of CTLA-4 blockade in hosts with cancer.

Nat Commun 2020 05 1;11(1):2168. Epub 2020 May 1.

Université Paris-Saclay, Institut Gustave Roussy, Inserm, CNRS, Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse, Laboratoire d'Immunomonitoring en Oncologie, F-94805, Villejuif, France.

Gut microbiota composition influences the clinical benefit of immune checkpoints in patients with advanced cancer but mechanisms underlying this relationship remain unclear. Molecular mechanism whereby gut microbiota influences immune responses is mainly assigned to gut microbial metabolites. Short-chain fatty acids (SCFA) are produced in large amounts in the colon through bacterial fermentation of dietary fiber. We evaluate in mice and in patients treated with anti-CTLA-4 blocking mAbs whether SCFA levels is related to clinical outcome. High blood butyrate and propionate levels are associated with resistance to CTLA-4 blockade and higher proportion of Treg cells. In mice, butyrate restrains anti-CTLA-4-induced up-regulation of CD80/CD86 on dendritic cells and ICOS on T cells, accumulation of tumor-specific T cells and memory T cells. In patients, high blood butyrate levels moderate ipilimumab-induced accumulation of memory and ICOS + CD4 + T cells and IL-2 impregnation. Altogether, these results suggest that SCFA limits anti-CTLA-4 activity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-020-16079-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7195489PMC
May 2020

Association of TERT, OGG1, and CHRNA5 Polymorphisms and the Predisposition to Lung Cancer in Eastern Algeria.

Pulm Med 2020 20;2020:7649038. Epub 2020 Mar 20.

Laboratoire de Biologie Moléculaire et Cellulaire, University Frères Mentouri Constantine 1, Constantine 25000, Algeria.

Lung cancer remains the most common cancer in the world. The genetic polymorphisms (rs2853669 in TERT, rs1052133 in OGG1, and rs16969968 in CHRNA5 genes) were shown to be strongly associated with the risk of lung cancer. Our study's aim is to elucidate whether these polymorphisms predispose Eastern Algerian population to non-small-cell lung cancer (NSCLC). To date, no study has considered this association in the Algerian population. This study included 211 healthy individuals and 144 NSCLC cases. Genotyping was performed using TaqMan probes and Sanger sequencing, and the data were analyzed using multivariate logistic regression adjusted for covariates. The minor allele frequencies (MAFs) of TERT rs2853669, CHRNA5 rs16969968, and OGG1 rs1052133 polymorphisms in controls were C: 20%, A: 31%, and G: 29%, respectively. Of the three polymorphisms, none shows a significant association, but stratified analysis rs16969968 showed that persons carrying the AA genotype are significantly associated with adenocarcinoma risk (pAdj = 0.03, ORAdj = 2.55). Smokers with an AA allele have a larger risk of lung cancer than smokers with GG or GA genotype (pAdj = 0.03, ORAdj = 3.91), which is not the case of nonsmokers. Our study suggests that CHRNA5 rs16969968 polymorphism is associated with a significant increase of lung adenocarcinoma risk and with a nicotinic addiction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2020/7649038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7109590PMC
March 2020

Renin aldosterone vasopressin and copeptin kinetics in patients with septic shock, a post-hoc Hyper2S randomized trial analysis.

Intensive Care Med 2020 04 19;46(4):808-810. Epub 2020 Feb 19.

Département de Médecine Intensive-Réanimation et Médecine Hyperbare, CHU d'Angers, France, 4 Rue Larrey, 49 993, Angers Cedex 9, France.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00134-019-05912-7DOI Listing
April 2020

New Intravenous Calcimimetic Agents: New Options, New Problems. An Example on How Clinical, Economical and Ethical Considerations Affect Choice of Treatment.

Int J Environ Res Public Health 2020 02 14;17(4). Epub 2020 Feb 14.

Nephrology Department, Fondazione Policlinico Universitario A. Gemelli, IRCCS, 00168 Roma, Italy.

Background: Dialysis treatment is improving, but several long-term problems remain unsolved, including metabolic bone disease linked to chronic kidney disease (CKD-MBD). The availability of new, efficacious but expensive drugs (intravenous calcimimetic agents) poses ethical problems, especially in the setting of budget limitations.

Methods: Reasons of choice, side effects, biochemical trends were discussed in a cohort of 15 patients (13% of the dialysis population) who stared treatment with intravenous calcimimetics in a single center. All patients had previously been treated with oral calcimimetic agents; dialysis efficacy was at target in 14/15; hemodiafiltration was employed in 10/15. Median Charlson Comorbidity Index was 8. The indications were discussed according to the principlist ethics (beneficience, non maleficience, justice and autonomy). Biochemical results were analyzed to support the clinical-ethical choices.

Results: In the context of a strict clinical and biochemical surveillance, the lack of side effects ensured "non-maleficence"; efficacy was at least similar to oral calcimimetic agents, but tolerance was better. Autonomy was respected through a shared decision-making model; all patients appreciated the reduction of the drug burden, and most acknowledged better control of their biochemical data. The ethical conflict resides in the balance between the clinical "beneficience, non-maleficience" advantage and "justice" (economic impact of treatment, potentially in attrition with other resources, since the drug is expensive and included in the dialysis bundle). The dilemma is more relevant when a patient's life expectancy is short (economic impact without clear clinical advantages), or when non-compliance is an issue (unclear advantage if the whole treatment is not correctly taken).

Conclusions: In a context of person-centered medicine, autonomy, beneficence and non-maleficence should weight more than economic justice. While ethical discussions are not aimed at finding "the right answer" but asking "the right questions", this example can raise awareness of the importance of including an ethical analysis in the choice of "economically relevant" drugs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijerph17041238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7068561PMC
February 2020

Retinoic acid-loaded NFL-lipid nanocapsules promote oligodendrogenesis in focal white matter lesion.

Biomaterials 2020 02 2;230:119653. Epub 2019 Dec 2.

Université catholique de Louvain, Louvain Drug Research Institute, Advanced Drug Delivery and Biomaterials, Avenue E. Mounier 73, 1200, Brussels, Belgium. Electronic address:

Neural stem cells (NSC) are located in restricted areas of the central nervous system where they self-renew or differentiate into neurons, astrocytes or oligodendrocytes. The stimulation of endogenous NSC differentiation is one of the most promising therapeutic approaches to restore neurological function in patients affected by neurodegenerative diseases. Endogenous NSC of the subventricular zone (SVZ) can be selectively targeted by lipid nanocapsules (LNC) coated with the peptide NFLTBS.40-63 (NFL-LNC) after intra-lateral ventricular injection in the brain. NFL-LNC can potentially deliver active compounds to SVZ-NSC and thus promote their differentiation to treat neurodegenerative diseases. The aim of this work was to induce endogenous NSC differentiation by specifically delivering retinoic acid (RA) to SVZ-NSC via NFL-LNC. RA was successfully encapsulated into NFL-LNC and RA-NFL-LNC were incubated with primary rat SVZ-NSC. In vitro, RA-NFL-LNC decreased the number of nestin (NSC marker) cells and neurospheres compared to controls and increased the number of GalC (oligodendrocytic marker) cells. Then, RA-NFL-LNC were injected in the right lateral ventricle of a lysolecithin-induced rat focal white matter lesion model to evaluate their impact on oligodendrocyte repopulation and remyelination. RA-NFL-LNC significantly increased the percentage of mature oligodendrocytes, stimulating oligodendrogenesis, nearly to the pre-lesion levels. Thus, RA-NFL-LNC represent a promising nanomedicine to be further investigated in the treatment of demyelinating diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.biomaterials.2019.119653DOI Listing
February 2020

Risk of Preeclampsia and Adverse Pregnancy Outcomes after Heterologous Egg Donation: Hypothesizing a Role for Kidney Function and Comorbidity.

J Clin Med 2019 Oct 28;8(11). Epub 2019 Oct 28.

Nephrology, Centre Hospitalier Le Mans, Le Mans 72000, France.

Background And Objectives: Preeclampsia (PE) is a risk factor for kidney diseases; egg-donation (ED) increasingly used for overcoming fertility reduction, is a risk factor for PE. CKD is also a risk factor for PE. However, kidney function is not routinely assessed in ED pregnancies. Objective of the study is seeking to assess the importance of kidney function and maternal comorbidity in ED pregnancies.

Design, Setting, Participants And Measurements:

Design: retrospective observational study from clinical charts.

Setting: Sant'Anna Hospital, Turin, Italy (over 7000 deliveries per year).

Selection: cases: 296 singleton pregnancies from ED (gestation > 24 weeks), who delivered January 2008-February 2019. Controls were selected from the TOrino Cagliari Observational Study (1407 low-risk singleton pregnancies 2009-2016).

Measurements: Standard descriptive analysis. Logistic multiple regression analysis tested: PE; pregnancy-induced hypertension; preterm delivery; small for gestational age; explicatory variables: age; BMI; parity; comorbidity (kidney diseases; immunologic diseases; thyroid diseases; other). Delivery over time was analyzed according to Kaplan Meier; ROC (Relative Operating Characteristic) curves were tested for PE and pre-term delivery, employing serum creatinine and e-GFR as continuous variables. The analysis was performed with SPSS v.14.0 and MedCalc v.18.

Results: In keeping with ED indications, maternal age was high (44 years). Comorbidity was common: at least one potential comorbid factor was found in about 40% of the cases (kidney disease: 3.7%, immunologic 6.4%, thyroid disease 18.9%, other-including hypertension, previous neoplasia and all other relevant diseases-10.8%). No difference in age, parity and BMI is observed in ED women with and without comorbidity. Patients with baseline renal disease or "other" comorbidity had a higher risk of developing PE or preterm delivery after ED. PE was recorded in 23% vs. 9%, OR: 2.513 (CI 1.066-5.923; = 0.039); preterm delivery: 30.2% vs. 14%, OR 2.565 (CI: 1.198-5.488; = 0.044). Limiting the analysis to 124 cases (41.9%) with available serum creatinine measurement, higher serum creatinine (dichotomised at the median: 0.67 mg/dL) was correlated with risk of PE (multivariate OR 17.277 (CI: 5.125-58.238)) and preterm delivery (multivariate OR 2.545 (CI: 1.100-5.892).

Conclusions: Within the limits of a retrospective analysis, this study suggests that the risk of PE after ED is modulated by comorbidity. While the cause effect relationship is difficult to ascertain, the relationship between serum creatinine and outcomes suggests that more attention is needed to baseline kidney function and comorbidity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/jcm8111806DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6912476PMC
October 2019

Importance of Combining Advanced Particle Size Analysis Techniques To Characterize Cell-Penetrating Peptide-Ferrocifen Self-Assemblies.

J Phys Chem Lett 2019 Nov 15;10(21):6613-6620. Epub 2019 Oct 15.

Micro et Nanomédecines Translationnelles, MINT , UNIV Angers , UMR INSERM 1066, UMR CNRS 6021, 49000 Angers , France.

The design of a simple platform to target the delivery of notably hydrophobic drugs into cancer cells is an ultimate goal. Here, three strategies were combined in the same nanovector, in limiting the use of excipients: cell-penetrating peptides, an amphiphilic prodrug, and self-assembly. Light scattering and cryogenic transmission electron microscopy revealed one size population of objects around 100 nm with a narrow size distribution. However, in-depth analysis of the suspension by nanoparticle tracking analysis, small-angle X-ray scattering, and nuclear magnetic resonance (NMR) diffusometry demonstrated the presence of another population of small objects (<2 nm). It has been shown that these small self-assemblies represented >99% of the matter! This presence was clearly and unambiguously demonstrated by NMR diffusometry experiments. The study highlights the importance and the complementary contribution of each characterization method to reflect the reality of the studied nanoassembly.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jpclett.9b01493DOI Listing
November 2019

Is multidetector CT-scan able to detect T3a renal tumor before surgery?

Scand J Urol 2019 Oct 12;53(5):350-355. Epub 2019 Oct 12.

Department of Radiology, Angers University Hospital, Angers, France.

To evaluate the diagnostic accuracy of multidetector Computed Tomography (MDCT) in predicting T3a renal cell carcinoma (RCC). Preoperative MDCT of 96 patients with 100 pathologically proven RCC were assessed by two radiologists focusing on the presence of peritumoral fat, sinus fat or venous invasion for cT3a staging. Nature of tumor margins and the presence of peritumoral neovessels were also evaluated, as the influence of perinephric soft-tissue stranding in the interpretation of peritumoral fat. Sensitivity for the identification of peritumoral fat, sinus fat or renal vein invasion was 77%, 86% and 86%, and specificity was 72%, 88% and 97%, respectively. Sensitivity and specificity in the prediction of T3a tumors were 72% and 70% respectively ( score = 0.38 (0.29-0.47)). Among the 38 pT3 tumors, 6 (16%) were under-staged, and the neovessels and irregular tumor edge as secondary CT signs did not significantly increase the accuracy of the prediction of local invasion. Among the 62 confined tumors, 17 (27%) were over-staged as cT3 and among these 17 false positives cases, perinephric soft-tissue stranding was present in 14 cases. MDCT provides good results in detecting sinus fat, venous invasion and kidney-confined tumors, but evaluation of perinephric fat remains a difficult task, leading to reduced accuracy in T3a staging.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/21681805.2019.1675756DOI Listing
October 2019

Positron Emission Tomography Can Support the Diagnosis of Dialysis-Related Amyloidosis.

J Clin Med 2019 Sep 19;8(9). Epub 2019 Sep 19.

Néphrologie, Centre Hospitalier du Mans, 72037 Le Mans, France.

Background: The improvements in dialysis have not eliminated long-term problems, including dialysis-related amyloidosis (DRA), caused by Beta-2 microglobulin deposition. Several types of scintigraphy have been tested to detect DRA, none entered the clinical practice. Aim of the study was to assess the potential of PET-FDG scan in the diagnosis of DRA.

Methods: Forty-six dialysis patients with at least one PET scan (72 scans) were selected out 162 patients treated in 2016-2018. Subjective global assessment (SGA), malnutrition inflammation score (A), Charlson Comorbidity Index (CCI), were assessed at time of scan; 218 age-matched cases with normal kidney function were selected as controls. PET scans were read in duplicate. Carpal tunnel syndrome was considered a proxy for DRA. A composite "amyloid score" score considered each dialysis year = 1 point; carpal tunnel-DRA = 5 points per site. Logistic regression, ROC curves and a prediction model were built.

Results: The prevalence of positive PET was 43.5% in dialysis, 5% in controls ( < 0.0001). PET was positive in 14/15 (93.3%) scans in patients with carpal tunnel. PET sensitivity for detecting DRA was 95% (specificity 64%). Carpal tunnel was related to dialysis vintage and MIS. A positive PET scan was significantly associated with dialysis vintage, MIS and amyloid score. A prediction model to explain PET positivity combined clinical score and MIS, allowing for an AUC of 0.906 (CI: 0.813-0.962; < 0.001).

Conclusions: PET-FDG may identify DRA, and may be useful in detecting cases in which inflammation favours B2M deposition. This finding, needing large-scale confirmation, could open new perspectives in the study of DRA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/jcm8091494DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6781261PMC
September 2019

Dietary satisfaction and quality of life in chronic kidney disease patients on low-protein diets: a multicentre study with long-term outcome data (TOrino-Pisa study).

Nephrol Dial Transplant 2020 05;35(5):790-802

Nephrology, Department of Medicine, University of Pisa, Pisa, Italy.

Background: Concerns about adherence and quality of life (QoL) limit the diffusion of low-protein diets (LPDs) as a way to slow chronic kidney disease (CKD) progression and postpone dialysis. The aim of this multicentre study is to assess dietary satisfaction in stable CKD patients.

Methods: This was a multicentre cross-sectional study with long-term follow-up data. Prevalent patients on LPD for at least 6 months were selected in four Italian centres. QoL was assessed using the World Health Organization Quality of Life questionnaire, and diet satisfaction with the Modification of Diet in Renal Disease satisfaction questionnaire. Comorbidity was assessed by Charlson Comorbidity Index, estimated glomerular filtration rate (eGFR) was calculated by the CKD Epidemiology Collaboration equation and protein intake by Maroni-Mitch formula. Survival was analysed with Kaplan-Meier curves and Cox Proportional Hazard Model.

Results: Four hundred and twenty-two CKD Stages 3-5 patients were enrolled. Over 95% were on moderately restricted diets (0.6 g/kg/day). Compliance was good (protein intake: 0.59 g/kg/day at baseline, 0.72 at the end of follow-up). Median dietary satisfaction was 4 on a 1-5 scale. QoL was not affected by the type of diet, but was influenced by age, comorbidity and setting of care. Two years later, at the end of follow-up, 66.6% of the patients were still on a diet; the main causes of discontinuation were dialysis and death. The dropout rate was low (5.5%); in Cox analysis, patient and renal survival were influenced by age and eGFR, but not by QoL, setting of care or type of diet.

Conclusions: LPDs are compatible with high dietary satisfaction and minimal dropout, at least in patients who are able to follow such a diet for at least 6 months.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ndt/gfz147DOI Listing
May 2020

A comparison of different strategies for antimicrobial peptides incorporation onto/into lipid nanocapsules.

Nanomedicine (Lond) 2019 07 11;14(13):1647-1662. Epub 2019 Jul 11.

Micro & Nanomédecines Translationelles-MINT, UNIV Angers, INSERM U1066, CNRS UMR 6021, UBL Universite Bretagne Loire, Angers F-49933, France.

Over the last decade, antimicrobial peptides (AMPs) have emerged as a promising alternative for the treatment of various infections. The aim of this work is to explore the potential of lipid nanocapsules for the delivery of AMPs. Three approaches were compared in terms of encapsulation efficiency, peptide activity and protection against proteases: peptide encapsulation, surface adsorption or covalent attachment of three selected AMPs. A potentiation of the antimicrobial activity and a partial protection of the peptides after adsorption were demonstrated compared with native peptides. Conversely, encapsulation allowed better peptide stability, correlated with higher encapsulation efficiencies and a preservation of the activity. Finally, the covalent attachment strategy turned out to be less conclusive due to peptide inactivation. In brief, a lipid nanocapsule-based platform appears suitable to deliver AMPs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2217/nnm-2018-0337DOI Listing
July 2019

A mathematical model to predict mean time to delivery following cervical ripening with dinoprostone vaginal insert.

Sci Rep 2019 07 9;9(1):9910. Epub 2019 Jul 9.

Department of Obstetrics and Gynecology, Angers University Hospital, Angers, France.

The main objective of our study was to analyze the mean time to delivery following cervical ripening with a 10 mg dinoprostone vaginal insert. We performed a retrospective observational study at the level III maternity ward of Angers university hospital. We included all women who had cervical ripening with dinoprostone between January 1, 2015 and September 30, 2016. Overall, 405 patients were included, and 59.3% (240/405) were nulliparous. The mean time to delivery was 20h39 min ± 10h49 min. 21% of deliveries (86/405) occurred between midnight and 6 h a.m., and the cesarean section rate was 33% (132/405). Multiple regression analysis showed that nulliparity, overweight (BMI ≥ 25), a closed cervix on initial examination and the absence of premature rupture of membranes (PRM) all significantly increased the mean time to delivery. We developed a mathematical model integrating the aforementioned factors and their impact to help predict the mean time to delivery following cervical ripening with dinoprostone vaginal insert: Y = 961.188-80.346 × parity + 21.437 × BMI-165.263 × cervical dilation-241.759 × PRM. This equation allows obstetricians to calculate a personalized time to delivery for each patient, allowing a precise scheduling of dinoprostone insert placement, and thus improving the organization in busy maternity wards.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-019-46101-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6616328PMC
July 2019

Characterization of the , and Efficacy of the Antimicrobial Peptide DPK-060 Used for Topical Treatment.

Front Cell Infect Microbiol 2019 28;9:174. Epub 2019 May 28.

Promore Pharma AB, Solna, Sweden.

Antimicrobial peptides, also known as host defense peptides, have recently emerged as a promising new category of therapeutic agents for the treatment of infectious diseases. This study evaluated the preclinical , and antimicrobial activity, as well as the potential to cause skin irritation, of human kininogen-derived antimicrobial peptide DPK-060 in different formulations designed for topical delivery. We found that DPK-060 formulated in acetate buffer or poloxamer gel caused a marked reduction of bacterial counts of (minimum microbicidal concentration <5 μg/ml). We also found that DPK-060 in poloxamer gel significantly suppressed microbial survival in an wound infection model using pig skin and in an mouse model of surgical site infection (≥99 or ≥94% reduction in bacterial counts was achieved with 1% DPK-060 at 4 h post-treatment, respectively). Encapsulation of DPK-060 in different types of lipid nanocapsules or cubosomes did not improve the bactericidal potential of the peptide under the applied test conditions. No reduction in cell viability was observed in response to administration of DPK-060 in any of the formulations tested. In conclusion, the present study confirms that DPK-060 has the potential to be an effective and safe drug candidate for the topical treatment of microbial infections; however, adsorption of the peptide to nanocarriers failed to show any additional benefits.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fcimb.2019.00174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6548878PMC
January 2020

Lipid nanocapsules as in vivo oxygen sensors using magnetic resonance imaging.

Mater Sci Eng C Mater Biol Appl 2019 Aug 2;101:396-403. Epub 2019 Apr 2.

Micro et Nanomedecines translationnelles, MINT, UNIV Angers, INSERM 1066, CNRS 6021, 4 rue Larrey, Angers, France; PRISM, UNIV d'Angers, 4 rue Larrey, Angers F-49933, France. Electronic address:

Hypoxia is common occurrence of the tumour microenvironment, wherein heterogeneous gradients of O give rise to tumoural cells which are highly malignant, metastatic, and resistant to therapeutic efforts. Thus, the assessment and imaging of hypoxia is essential for tumour diagnosis and treatment. Magnetic resonance imaging and, more specifically, the quantitative assessment of longitudinal relaxation time enhancement, was shown to enable the mapping of oxygen in tumours with increased sensitivity for lipids as compared to water signal. Unfortunately, this can only be applied to tumours with high lipid content. To overcome this issue, we propose the use of lipid nanocapsules (LNCs). LNCs have been demonstrated as excellent core-shell nanocarriers, wherein the lipidic-core is used for lipophilic drug encapsulation, enabling treatment of highly malignant tumours. Herein, however, we exploited the lipidic-core of the LNCs to develop a simple but effective technique to increase the lipidic content within tissues to enable the assessment and mapping of pO. LNCs were prepared using the phase-inversion technique to produce 60 nm sized nanoparticles, and in vitro studies demonstrated the permeability and responsiveness of LNCs to O. To evaluate the ability of LNCs to respond to changes in pOin vivo, after a hyperoxic challenge, three animal models, namely a normal tissue model (gastrocnemius muscle tissue) and two tumour tissue models (subcutaneous fibrosarcoma and intracerebral glioblastoma) were explored. LNCs were found to be responsive to variation of Oin vivo. Moreover, the use of MRI enabled the mapping of oxygen gradients and heterogeneity within tumours.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.msec.2019.03.104DOI Listing
August 2019

Contribution of the OC Sensor immunoassay in comparison to the Hemoccult II guaiac-test in organized colorectal cancer screening.

Eur J Epidemiol 2019 Feb 8;34(2):163-172. Epub 2018 Dec 8.

Service d'Hépato-gastro-entérologie, CHU Angers, 4, rue Larrey, 49933, Angers Cedex 09, France.

Colorectal cancer (CRC) is a major cause of cancer-related death of worldwide with high incidence and mortality rate, accessible to a screening program in France, first with guaiac- based fecal occult blood test (g-FOBT) then with fecal immunochemical tests (FIT), since 2015, because of better accuracy. The aim of our study was to compare the characteristics of screen-detected lesions in two successive CRC screening campaigns, using two different tests (Hemoccult II and OC Sensor) in the department of Maine-et-Loire, and to precise the performance of these tests [participation rate, detection rates (DR), positive predictive value (PPV)]. Participants, invited by CAP SANTE 49, with polyps or cancer at the colonoscopy after a positive screening test between 01/01/2013 and 31/12/2016 were included. A guaiac-based fecal occult blood test (g-FOBT) was used from January 2013 to December 2014 and a FIT was used from June 2015 to December 2016). 2575 participants, 642 in g-FOBT group and 1933 in FIT group had lesions. Participation rate was not different between tests (p = 0.104), whereas DR and PPV were statistically higher in FIT for all lesions (2.61, 95% CI [2.50-2.70] vs 0.93, 95% CI [0.90-1.00], p < 0.0001 and 64.84, 95% CI [63.10-66.60], 50.00, 95% CI [47.30-52.70], p < 0.0001 respectively). FIT detects more precancerous lesions (adenomas, p < 0.001, and advanced adenomas, p < 0.001) than g-FOBT but g-FOBT detects more serrated polyps (p = 0.025). AAs were more in right colon in FIT than g-FOBT (p = 0.035). No different participation rate was detected between FIT and g-FOBT but DR and PPV of all lesions was higher with FIT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10654-018-0471-zDOI Listing
February 2019

Reverse micelle-lipid nanocapsules: a novel strategy for drug delivery of the plectasin derivate AP138 antimicrobial peptide.

Int J Nanomedicine 2018 15;13:7565-7574. Epub 2018 Nov 15.

Micro & Nanomédecines Translationelles-MINT, UNIV Angers, INSERM U1066, CNRS UMR 6021, UBL Universite Bretagne Loire, Angers, France.

Introduction: Resistance to traditional antibiotics is an increasingly serious problem. Antimicrobial peptides (AMPs) have emerged as a new therapeutic class with great potential against infectious diseases, as they are less prone to induce resistance. Nanotechnology-based delivery strategies can improve the efficiency and stability of AMPs, particularly against proteolytic degradation. Lipid nanocapsules (LNCs) are a new generation of biomimetic nanocarriers and were used in this study to deliver peptides.

Methods: AMP-loaded reverse micelles (RM) were developed and incorpo rated into LNCs by the phase inversion process and the antimicrobial activity of the AMPs-loaded LNC was evaluated by the minimum inhibitory concentration method. We studied the activity of AMP solutions and AMP-loaded LNCs against Gram-positive and Gram-negative bacterial strains and then evaluated the encapsulation of a new cationic AMP called AP138. Finally, we analyzed the effect of enzymatic attack on AP138 and AP138-RM-LNCs after incubation with trypsin.

Results: AP138 was efficiently encapsulated in the LNCs (encapsulation efficiency = 97.8% at a drug loading of 0.151%), resulting in protection against degradation by proteases and the preservation of antimicrobial activity against , including .

Conclusion: This study shows that RM-LNCs are an excellent candidate system to deliver AMPs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2147/IJN.S180040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6241861PMC
January 2019

The origin of neural stem cells impacts their interactions with targeted-lipid nanocapsules: Potential role of plasma membrane lipid composition and fluidity.

J Control Release 2018 12 5;292:248-255. Epub 2018 Nov 5.

Université catholique de Louvain, UCLouvain, Louvain Drug Research Institute, Advanced Drug Delivery and Biomaterials, Avenue E. Mounier 73, 1200 Brussels, Belgium. Electronic address:

The adsorption of a peptide (NFL-TBS.40-63 peptide (NFL)) known to induce neural stem cells (NSC) differentiation in vitro, at the surface of lipid nanocapsules (LNC) provides a targeting drug delivery system (NFL-LNC) that penetrates subventricular zone-neural stem cells (SVZ-NSC) but not central canal-NSC (CC-NSC). We hypothesized preferential interactions could explaine, at least partially, the different properties of SVZ- and CC-NSC plasma membranes. The objective of this work was to compare SVZ- and CC-NSC plasma membrane lipid composition, fluidity and permeability. Plasma membranes of SVZ- and CC-NSC were isolated and analyzed by LC-MS for their lipid content. Membrane fluidity was evaluated by measuring the generalized polarization (GP) of Laurdan and membrane permeability by fluorescent dextran penetration. Liposomes with different lipid compositions and steady state fluidities were prepared. ΔGP was measured after incubation with NFL-LNC. A significantly higher proportion of cholesterol, ceramides, sphingomyelins, phosphatidylethanolamines and a lower proportion of phosphatidylcholines and sulfatides were observed in SVZ- compared to CC-NSC. Fluidity, probably more than lipid composition, drove NFL-LNC and NSC interactions, and SVZ-NSC were more sensitive to NFL permeabilization than CC-NSC. We demonstrated that NSC membrane lipid composition and fluidity depended of NSC origin and that these features could play a role in the specific interactions with NFL-LNC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jconrel.2018.11.005DOI Listing
December 2018

Preparation and evaluation of trityl-loaded lipid nanocapsules as oxygen sensors for electron paramagnetic resonance oximetry.

Int J Pharm 2019 Jan 3;554:87-92. Epub 2018 Nov 3.

Biomedical Magnetic Resonance Unit (REMA), Louvain Drug Research Institute, Université catholique de Louvain, Avenue Mounier 73 bte B1.73.08, 1200 Brussels, Belgium. Electronic address:

Oxygen is essential in physiology and pathophysiology. Electron paramagnetic resonance (EPR) oximetry, using oxygen sensitive paramagnetic materials, could be attractive for measuring oxygen in tissues. The aim of the present study was to assess the properties of lipid nanocapsules (LNCs) loaded with the nitroxide tempo-benzoate (TB) or tetrathiatriarylmethyl (TAM) radicals. LNCs loaded with the EPR probes were successfully prepared by the phase inversion process leading to nanocapsules of about 60 nm. LNCs protected the TB radical against reduction in vitro. The calibration of the EPR line width (LW) as a function of the pO showed a two-fold increase in sensitivity with TAM-LNC compared to hydrophilic trityl radical. The TAM-LNCs were evaluated in vivo. Contrarily to unencapsulated TAM, for which a rapid decrease in EPR signal was observed, the half-life of TAM-LNCs administered in muscles or in tumours exceeded an hour. Carbogen-challenges in mice demonstrated that the TAM-LNCs responded well to changes in oxygen environment. However, the apparent pO values acquired were higher than the expected physiological values. These results warrant further investigation in the formulation of stable nano-objects encapsulating EPR oxygen sensitive probes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijpharm.2018.11.007DOI Listing
January 2019

Synergistic Effect of Combinations Containing EDTA and the Antimicrobial Peptide AA230, an Arenicin-3 Derivative, on Gram-Negative Bacteria.

Biomolecules 2018 10 23;8(4). Epub 2018 Oct 23.

MINT, UNIV Angers, INSERM 1066, CNRS 6021, Université Bretagne Loire, F-49933 Angers, France.

The worldwide occurrence of resistance to standard antibiotics and lack of new antibacterial drugs demand new strategies to treat complicated infections. Hence, the aim of this study was to examine the antibacterial activities of an antimicrobial peptide, arenicin-3 derivative AA230, and ethylenediaminetetraacetic acid (EDTA) as well as the two compounds in combination against Gram-negative bacteria. AA230 showed strong antibacterial activity against all of the studied standard strains and clinical isolates, with minimum inhibitory concentrations ranging between 1 µg/mL and 8 µg/mL. AA230 exhibited a bactericidal mode of action. EDTA inhibited the growth of at 500⁻1000 µg/mL. Strains of were found to be more susceptible to EDTA than or . The antibacterial effects of both AA230 and EDTA were independent of the antibiotic resistance patterns. Indifference to synergistic activity was observed for AA230 and EDTA combinations using checkerboard titration. In time-kill studies, a substantial synergistic interaction between AA230 and EDTA was detected against all of the tested strains. The addition of EDTA enabled a 2⁻4-fold decrease in the AA230 dose. In conclusion, AA230 could have potential applications in the treatment of infections caused by Gram-negative organisms, and its effect can be potentiated by EDTA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/biom8040122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6315934PMC
October 2018

HIBISCUS: Hydroxychloroquine for the secondary prevention of thrombotic and obstetrical events in primary antiphospholipid syndrome.

Autoimmun Rev 2018 Dec 12;17(12):1153-1168. Epub 2018 Oct 12.

Istituto Auxologico Italiano, IRCCS, Laboratory of Immunorheumatology, Milan, Italy.

The relapse rate in antiphospholipid syndrome (APS) remains high, i.e. around 20%-21% at 5 years in thrombotic APS and 20-28% in obstetrical APS [2, 3]. Hydroxychloroquine (HCQ) appears as an additional therapy, as it possesses immunomodulatory and anti-thrombotic various effects [4-16]. Our group recently obtained the orphan designation of HCQ in antiphospholipid syndrome by the European Medicine Agency. Furthermore, the leaders of the project made the proposal of an international project, HIBISCUS, about the use of Hydroxychloroquine in secondary prevention of obstetrical and thrombotic events in primary APS. This study has been launched in several countries and at now, 53 centers from 16 countries participate to this international trial. This trial consists in two parts: a retrospective and a prospective study. The French part of the trial in thrombosis has been granted by the French Minister of Health in December 2015 (the academic trial independent of the pharmaceutical industry PHRC N PAPIRUS) and is coordinated by one of the members of the leading consortium of HIBISCUS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.autrev.2018.05.012DOI Listing
December 2018

Primary antiphospholipid syndrome and antiphospholipid syndrome associated to systemic lupus: Are they different entities?

Autoimmun Rev 2018 Aug 6;17(8):739-745. Epub 2018 Jun 6.

Coagulation Laboratory, Department of Clinical Biology, Immunology and Microbiology, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium.

Primary antiphospholipid syndrome (PAPS) and antiphospholipid syndrome associated to lupus (SAPS) have several overlapping characteristics. As systemic manifestations are also reported in patients with PAPS, and as a subgroup of PAPS patients could evaluate to a SAPS, the differentiation between the two types of APS could be performed based on the clinical experience of the medical teams and is related to a variety of clinical, biological, histological and genetic features. Several data are available in the literature with respect to the identification of distinctive features between these two entities. However, there are some limitation in the interpretation of results issued from studies performed prior to updated Sydney criteria. Based on recent data, a certain number of features more frequent in one type of APS as compared to the other could be distinguished. The major differentiation between these two entities is genetical. New genetic data allowing the identification of specific subgroups of APS are ongoing.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.autrev.2018.01.027DOI Listing
August 2018

Antibacterial activity of antipsychotic agents, their association with lipid nanocapsules and its impact on the properties of the nanocarriers and on antibacterial activity.

PLoS One 2018 3;13(1):e0189950. Epub 2018 Jan 3.

MINT, UNIV Angers, INSERM 1066, CNRS 6021, Université Bretagne Loire, Angers, France.

Bacterial antibiotic resistance is an emerging public health problem worldwide; therefore, new therapeutic strategies are needed. Many studies have described antipsychotic compounds that present antibacterial activity. Hence, the aims of this study were to evaluate the in vitro antibacterial activity of antipsychotics belonging to different chemical families, to assess the influence of their association with lipid nanocapsules (LNCs) on their antimicrobial activity as well as drug release and to study the uptake of LNCs by bacterial cells. Antibacterial activity was evaluated against Gram-positive Staphylococcus aureus and Gram negative Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae and Acinetobacter baumannii by minimum inhibitory concentration (MIC) assay, and the capability of killing tested microorganisms was evaluated by time kill assay. LNCs were prepared by phase inversion method, and the antipsychotic agents were incorporated using pre-loading and post-loading strategies. Only phenothiazines and thioxanthenes showed antibacterial activity, which was independent of antibiotic-resistance patterns. Loading the nanocarriers with the drugs affected the properties of the former, particularly their zeta potential. The release rate depended on the drug and its concentration-a maximum of released drug of less than 40% over 24 hours was observed for promazine. The influence of the drug associations on the antibacterial properties was concentration-dependent since, at low concentrations (high nanocarrier/drug ratio), the activity was lost, probably due to the high affinity of the drug to nanocarriers and slow release rate, whereas at higher concentrations, the activity was well maintained for the majority of the drugs. Chlorpromazine and thioridazine increased the uptake of the LNCs by bacteria compared with blank LNCs, even below the minimum inhibitory concentration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0189950PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5752010PMC
January 2018

Absence of lung fibrosis after a single pulmonary delivery of lipid nanocapsules in rats.

Int J Nanomedicine 2017 8;12:8159-8170. Epub 2017 Nov 8.

Unité Micro et Nanomédecines Biomimétiques (MINT), Université d'Angers, INSERM 1066, CNRS 6021, Université Bretagne Loire.

Lipid nanocapsules (LNCs) are potential drug carriers for pulmonary delivery since they can be nebulized without any structural or functional changes, and the aerosols produced are highly compatible with pulmonary drug delivery in human beings. The alveolar surface tension, in vitro cytotoxicity, biodistribution and pulmonary toxicity in rats of a single endotracheal spray of LNCs or paclitaxel-loaded LNCs were studied. In vitro cytotoxicity of LNCs after a spray remained unchanged. Biodistribution study showed a homogeneous repartition in the lungs in rats with an improvement in lung retention of the radiolabeled tracer loaded in LNCs compared to the absence of LNCs with a lung half-time of 8.8±0.7 hours. Bronchoalveolar fluid analysis revealed transient 7-day alveolar inflammation, reaching a maximum between days 2 and 4, characterized by a peak of granulocytes at day 1 followed by a peak of lymphocytes at day 3. Alveolar protein levels were increased at days 3 and 7. Acute inflammation was increased with paclitaxel-loaded LNCs in comparison with blank LNCs but dropped out at day 7. No histological pulmonary lesion was observed at day 60. LNCs lowered surface tension to a greater degree than Curosurf in a physicochemical model of the pulmonary alveolus. A single pulmonary delivery of LNCs induces a short-term alveolar inflammation with no residual lesions in rats at day 60. These data permit to start the study of LNCs in surfactant replacement therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2147/IJN.S146740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5687496PMC
March 2018

NMR diffusometry data sampling optimization for mixture analysis.

J Pharm Biomed Anal 2018 Jan 2;148:156-162. Epub 2017 Oct 2.

MINT, UNIV Angers, INSERM 1066, CNRS 6021, Université Bretagne Loire, IBS-CHU Angers, 4 rue Larrey, 49933 Angers Cedex 9, France. Electronic address:

NMR diffusometry is a powerful but challenging method to analyze complex mixture. Each component diffuses differently, from the faster small species to the slower large species, corresponding to different signal attenuation. However, the method is highly sensitive to the quality of the acquired data and the performance of the processing used to resolve multiexponential signals influences. Adapting the signal decay sampling to the mixture composition is one way to improve the precision of the measure. In this work, we propose a prediction tool, based on the calculation of the Cramér-Rao lower bound to minimize the variance of diffusion coefficient estimation in order to determine the optimal number of diffusion gradient steps, the best diffusion gradient sampling (among linear, exponential, quadratic and sigmoidal ones) and the optimal maximum diffusion factor. The tool was validated experimentally on a unimer/micelle solution of sodium dodecyl sulfate and on Caelyx, a commercial liposomal preparation containing a mixture of pegylated-liposomes and sucrose.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jpba.2017.09.028DOI Listing
January 2018

Nationwide French Study of RET Variants Detected from 2003 to 2013 Suggests a Possible Influence of Polymorphisms as Modifiers.

Thyroid 2017 12 3;27(12):1511-1522. Epub 2017 Nov 3.

3 Réseau TenGen , France .

Background: The presence of single nucleotide polymorphisms (SNPs) in the REarranged during Transfection (RET) gene has been investigated with regard to their potential role in the development or progression of medullary thyroid cancer or pheochromocytomas (PHEO) in patients with the multiple endocrine neoplasia type 2 (MEN2) syndrome. The aim of this study was to evaluate the spectrum of RET variants in France between 2003 and 2013, and to evaluate the impact of SNPs on the MEN2 A phenotype.

Methods: In this retrospective cohort study, RET variants were screened in 5109 index cases, and RET pathogenic variants were screened in 2214 relatives. Exons 5, 8, 10, 11, 13, 14, 15, and 16 were characterized by Sanger sequencing. RET pathogenic variants, RET variants with unknown functional significance (VUS), and four RET SNP variants-G691S (rs1799939), L769L (rs1800861), S836S (rs1800862), and S904S (rs1800863)-were characterized and are reported in index cases. In silico analysis and classification following the recommendation of the American College of Medical Genetics and Genomics was performed for RET VUS. Each patient's age at the time of diagnosis, sex, and the endocrine neoplasias present at molecular diagnosis were recorded.

Results: Twenty-six single VUS in RET without any well-defined risk profiles were found in 33 patients. Nine of these were considered probably pathogenic, 11 of uncertain significance, and six as probably benign. Three double pathogenic variants found in three patients were classified as pathogenic. A study of the entire cohort showed that patients carrying pathogenic variants or VUS in RET together with PHEO were diagnosed earlier than the others. The presence of the G691S SNP, or a combination of SNPs, increased the risk of developing PHEO but did not modify the date of the diagnosis. No association was found between SNPs and medullary thyroid cancer or hyperparathyroidism.

Conclusions: The findings propose a classification of 15 of the 26 VUS in RET without any well-defined risk profiles and suggest that the G691S SNP, or a combination of SNPs, may be associated with the development of PHEO.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/thy.2016.0399DOI Listing
December 2017

Synergistic interactions between antimicrobial peptides derived from plectasin and lipid nanocapsules containing monolaurin as a cosurfactant against .

Int J Nanomedicine 2017 8;12:5687-5699. Epub 2017 Aug 8.

MINT, UNIV Angers, INSERM 1066, CNRS 6021, Université Bretagne Loire, Angers, Cedex, France.

Development of effective antibacterial agents for the treatment of infections caused by Gram-positive bacteria resistant to existing antibiotics, such as methicillin-resistant (MRSA), is an area of intensive research. In this work, the antibacterial efficacy of two antimicrobial peptides derived from plectasin, AP114 and AP138, used alone and in combination with monolaurin-lipid nanocapsules (ML-LNCs) was evaluated. Several interesting findings emerged from the present study. First, ML-LNCs and both plectasin derivatives showed potent activity against all 14 tested strains of , independent of their resistance phenotype. Both peptides displayed a considerable adsorption (33%-62%) onto ML-LNCs without having an important impact on the particle properties such as size. The combinations of peptide with ML-LNC displayed synergistic effect against , as confirmed by two methods: checkerboard and time-kill assays. This synergistic interaction enables a dose reduction and consequently decreases the risk of toxicity and has the potential of minimizing the development of resistance. Together, these results suggest that ML-LNCs loaded with a plectasin derivative may be a very promising drug delivery system for further development as a novel antibacterial agent against , including MRSA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2147/IJN.S139625DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5557623PMC
February 2018

Tissue oxygenation mapping by combined chemical shift and T magnetic resonance imaging.

Magn Reson Med 2018 04 21;79(4):1981-1991. Epub 2017 Aug 21.

Micro & Nanomédecines Translationelles-MINT, UNIV Angers, INSERM U1066, CNRS UMR 6021, UBL Universite Bretagne Loire, Angers, France.

Purpose: To propose a method for determining tissue oxygenation via the measurement of fat T . The method is based on a 2D fat/water chemical shift-encoded and T -weighted acquisition.

Theory And Methods: A 2D data set was acquired with a fast spin echo sequence with several echo asymmetries and repetition times, wherein one dimension is related to the fat/water phase modulation and the other to the T saturation recovery. A joint magnitude-based process of phase modulation and T evolution allowed for the collection of the fat fraction and T maps with resolved fat or water dominance ambiguity while avoiding the phased error problem.

Results: In vitro imaging allowed for the attribution of fat content for different water/oil emulsions that demonstrated longitudinal relaxation rate (R ) sensitivity to the oxygenated emulsion environment. The fat R values were subsequently compared to reference values, which were measured using low receiver bandwidth acquisition to enhance water and fat signal separations. In vivo feasibility of tissue oxygenation assessment was demonstrated by investigating interscapular brown adipose tissue modifications during an air/carbogen challenge in rats.

Conclusion: The proposed method offers a precise and robust estimate of tissue oxygenation illustrated by the method's ability to detect-brown adipose tissue oxygenation modifications. Magn Reson Med 79:1981-1991, 2018. © 2017 International Society for Magnetic Resonance in Medicine.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mrm.26857DOI Listing
April 2018