Nephrectomy for kidney tumour increases the risk of de novo arterial hypertension.

OBJECTIVE: To evaluate prospectively the effects of surgical excision of renal tumours on blood pressure (BP). PATIENTS AND METHODS: In a multicentre prospective study, we evaluated 200 patients who underwent nephrectomy for renal tumour between 2018 and 2020 at seven departments of the French Network for Kidney Cancer, the UroCCR. All patients had localized cancer without pre-existing hypertension (HTN). Blood pressure was measured the week before nephrectomy, and at 1 month and 6 months after nephrectomy, according to the recommendations for home BP monitoring. Plasma renin was measured 1 week before surgery and 6 months after surgery. The primary endpoint was the occurrence of de novo HTN. The secondary endpoint was clinically significant increase in BP at 6 months, defined by an increase in systolic and/or diastolic ambulatory BP ≥10 mmHg or requirement for medical antihypertensive treatment. RESULTS: Blood pressure and renin measurements were available for 182 (91%) and 136 patients (68%), respectively. We excluded from the analysis 18 patients who had undeclared HTN detected on preoperative measurements. At 6 months, 31 patients (19.2%) had de novo HTN and 43 patients (26.3%) had a significant increase in their BP. Type of surgery was not associated with an increased risk of HTN (21.7% partial nephrectomy [PN] vs 15.7% radical nephrectomy [RN]; P = 0.59). There was no difference between plasmatic renin levels before and after surgery (18.5 vs 16; P = 0.46). In multivariable analysis, age (odds ratio [OR] 1.07, 95% confidence interval [CI] 1.02-1.12; P = 0.03) and body mass index (OR 1.14, 95% CI 1.03-1.26; P = 0.01) were the only predictors of de novo HTN. CONCLUSION: Surgical treatment of renal tumours is associated with significant changes in BP, with de novo HTN occurring in almost 20% of the patients. These changes are not impacted by the type of surgery (PN vs RN). Patients who are scheduled to undergo kidney cancer surgery should be informed of these findings and have their BP closely monitored after the operation.

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.

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.

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.

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/m2 from day 1 to day 3]) or oral topotecan (2·3 mg/m2 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).

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

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.

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).

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.

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

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.

Tissue oxygenation mapping by combined chemical shift and T1 magnetic resonance imaging.

PURPOSE: To propose a method for determining tissue oxygenation via the measurement of fat T1 . The method is based on a 2D fat/water chemical shift-encoded and T1 -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 T1 saturation recovery. A joint magnitude-based process of phase modulation and T1 evolution allowed for the collection of the fat fraction and T1 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 (R1 ) sensitivity to the oxygenated emulsion environment. The fat R1 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.

ERCC1 isoform expression and DNA repair in non-small-cell lung cancer.

BACKGROUND: The excision repair cross-complementation group 1 (ERCC1) protein is a potential prognostic biomarker of the efficacy of cisplatin-based chemotherapy in non-small-cell lung cancer (NSCLC). Although several ongoing trials are evaluating the level of expression of ERCC1, no consensus has been reached regarding a method for evaluation. METHODS: We used the 8F1 antibody to measure the level of expression of ERCC1 protein by means of immunohistochemical analysis in a validation set of samples obtained from 494 patients in two independent phase 3 trials (the National Cancer Institute of Canada Clinical Trials Group JBR.10 and the Cancer and Leukemia Group B 9633 trial from the Lung Adjuvant Cisplatin Evaluation Biology project). We compared the results of repeated staining of the entire original set of samples obtained from 589 patients in the International Adjuvant Lung Cancer Trial Biology study, which had led to the initial correlation between the absence of ERCC1 expression and platinum response, with our previous results in the same tumors. We mapped the epitope recognized by 16 commercially available ERCC1 antibodies and investigated the capacity of the different ERCC1 isoforms to repair platinum-induced DNA damage. RESULTS: We were unable to validate the predictive effect of immunostaining for ERCC1 protein. The discordance in the results of staining for ERCC1 suggested a change in the performance of the 8F1 antibody since 2006. We found that none of the 16 antibodies could distinguish among the four ERCC1 protein isoforms, whereas only one isoform produced a protein that had full capacities for nucleotide excision repair and cisplatin resistance. CONCLUSIONS: Immunohistochemical analysis with the use of currently available ERCC1 antibodies did not specifically detect the unique functional ERCC1 isoform. As a result, its usefulness in guiding therapeutic decision making is limited. (Funded by Eli Lilly and others.).

Diagnosis of HPV-driven head and neck cancer with a single test in routine clinical practice.

Accurate screening of HPV-driven head and neck squamous cell carcinoma is a critical issue. Although there are commercial direct and indirect assays for HPV-related head and neck squamous cell carcinoma, none are ideal. Recently, a novel RNA in situ hybridization test (the RNAscope HPV-test) has been developed for the detection of high-risk HPV E6/E7 mRNA in formalin-fixed paraffin-embedded tissue. However, validation of this assay against the 'gold standard' (identification of high-risk HPV E6/E7 mRNA in fresh-frozen tissue by quantitative real-time (qRT)-PCR) has only been reported by one team. Formalin-fixed paraffin-embedded samples from 50 patients with tonsil or tongue base carcinoma were tested using the RNAscope HPV-test, p16 immunohistochemistry, and chromogenic in situ hybridization for high-risk HPV-DNA. The results were compared with those of qRT-PCR on matched fresh-frozen samples. Compared with the reference test, the sensitivity, specificity, positive, and negative predictive values of the RNAscope HPV-test and of p16 immunohistochemistry were 93%, 94%, 96%, 88% and 96%, 93%, 96%, and 93%, respectively. Five cases were discrepant between the RNAscope HPV-test and p16-immunohistochemisrty. The RNAscope HPV-test demonstrated excellent analytical performance against the 'gold standard' and is easier to interpret than chromogenic in situ hybridization. p16-immunohistochemistry also performed very well, however its main weakness is that it is an indirect marker of the presence of HPV. These data suggest that the RNAscope HPV-test is a promising test that could be developed as a clinical standard for the precise identification of HPV-driven oropharyngeal squamous cell carcinoma.

Histone H3F3A and HIST1H3B K27M mutations define two subgroups of diffuse intrinsic pontine gliomas with different prognosis and phenotypes.

Diffuse intrinsic pontine glioma (DIPG) is the most severe paediatric solid tumour, with no significant therapeutic progress made in the past 50 years. Recent studies suggest that diffuse midline glioma, H3-K27M mutant, may comprise more than one biological entity. The aim of the study was to determine the clinical and biological variables that most impact their prognosis. Ninety-one patients with classically defined DIPG underwent a systematic stereotactic biopsy and were included in this observational retrospective study. Histone H3 genes mutations were assessed by immunochemistry and direct sequencing, whilst global gene expression profiling and chromosomal imbalances were determined by microarrays. A full description of the MRI findings at diagnosis and at relapse was integrated with the molecular profiling data and clinical outcome. All DIPG but one were found to harbour either a somatic H3-K27M mutation and/or loss of H3K27 trimethylation. We also discovered a novel K27M mutation in HIST2H3C, and a lysine-to-isoleucine substitution (K27I) in H3F3A, also creating a loss of trimethylation. Patients with tumours harbouring a K27M mutation in H3.3 (H3F3A) did not respond clinically to radiotherapy as well, relapsed significantly earlier and exhibited more metastatic recurrences than those in H3.1 (HIST1H3B/C). H3.3-K27M-mutated DIPG have a proneural/oligodendroglial phenotype and a pro-metastatic gene expression signature with PDGFRA activation, while H3.1-K27M-mutated tumours exhibit a mesenchymal/astrocytic phenotype and a pro-angiogenic/hypoxic signature supported by expression profiling and radiological findings. H3K27 alterations appear as the founding event in DIPG and the mutations in the two main histone H3 variants drive two distinct oncogenic programmes with potential specific therapeutic targets.

Development of 2D and 3D mucus models and their interactions with mucus-penetrating paclitaxel-loaded lipid nanocapsules.

PURPOSE: To study, diffusion through mucus (3D model) of different formulations of paclitaxel loaded lipid nanocapsules (Ptx-LNCs), to interpret the results in the light of LNC behavior at air-mucus interface (2D model). METHODS: LNC surface properties were modified with chitosan or poly(ethylene glycol) (PEG) coatings of different size (PEG 2,000 to 5,000 Da) and surface charges. LNC diffusion through 446 µm pig intestinal mucus layer was studied using Transwell(®). LNCs were spread at the air-water-mucus interface then interfacial pressure and area changes were monitored and the efficiency of triglyceride (TG) inclusion was determined. RESULTS: Ptx-LNCs of surface charges ranging from -35.7 to +25.3 mV were obtained with sizes between 56.2 and 75.1 nm. The diffusion of paclitaxel in mucus was improved after encapsulation in neutral or positively charged particles (p < 0.05 vs Taxol(®)). No significative difference was observed in the 2,000-5,000 PEG length for diffusion both on the 2D or 3D models. On 2D model positive or neutral LNCs interacted less with mucus. Highest efficiency of TG inclusion was observed for particles with smallest PEG length. CONCLUSIONS: The results obtained with 2D and 3D model allowed us to select the best candidates for in vivo studies (neutral or positive LNCs with smaller PEG length).

Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy.

Conventional cancer treatments rely on radiotherapy and chemotherapy. Such treatments supposedly mediate their effects via the direct elimination of tumor cells. Here we show that the success of some protocols for anticancer therapy depends on innate and adaptive antitumor immune responses. We describe in both mice and humans a previously unrecognized pathway for the activation of tumor antigen-specific T-cell immunity that involves secretion of the high-mobility-group box 1 (HMGB1) alarmin protein by dying tumor cells and the action of HMGB1 on Toll-like receptor 4 (TLR4) expressed by dendritic cells (DCs). During chemotherapy or radiotherapy, DCs require signaling through TLR4 and its adaptor MyD88 for efficient processing and cross-presentation of antigen from dying tumor cells. Patients with breast cancer who carry a TLR4 loss-of-function allele relapse more quickly after radiotherapy and chemotherapy than those carrying the normal TLR4 allele. These results delineate a clinically relevant immunoadjuvant pathway triggered by tumor cell death.

HPV-related oropharyngeal squamous cell carcinomas: a comparison between three diagnostic approaches.

PURPOSE: HPV-related oropharyngeal squamous cell carcinomas clearly represent a growing entity in the head and neck with distinct carcinogenesis, clinico-pathological presentation and survival profile. We aimed to compare the HPV prevalence rates and clinico-pathological correlations obtained with three distinct commonly used HPV detection methods. MATERIALS AND METHODS: p16-immunohistochemistry (IHC), HPV DNA viral load by real-time PCR (qPCR), and HPV genotyping by a reverse hybridization-based line probe assay (INNO-LiPA) were performed on pretreatment formalin-fixed paraffin-embedded tumor samples from 46 patients treated for single primary oropharyngeal carcinomas. RESULTS: Twenty-eight patients (61%) had a p16 overexpression in IHC. Twenty-nine patients (63%) harbored HPV DNA on qPCR. Thirty-four patients (74%) harbored HPV DNA on INNO-LiPA. The concordance analysis revealed a good agreement between both HPV DNA detection methods (κ=0.65); when both tests were positive, the depicted HPV subtypes were always concordant (HPV16 in 27 cases, HPV18 in 1 case). Agreement was moderate between IHC and qPCR (κ=0.59) and fair between IHC and INNO-LiPA (κ=0.22). CONCLUSIONS: Certain highly sensitive methods are able to detect the mere presence of HPV without any carcinogenetic involvement while other more specific tests provide proof of viral transcriptional activity and thus evidence of clinically relevant infections. The use of a stepwise approach allows reducing false positives; p16-immunostaining seems to be an excellent screening test and in situ hybridization may overcome some of the PCR limitations.

Effects of high-intensity inspiratory muscle training on systemic inflammatory response in cardiac surgery - A randomized clinical trial.

PURPOSE: Preoperative inspiratory muscle training reduces the incidence of postoperative pulmonary complications after cardiac surgery, but training protocols vary widely in terms of intensity. Currently, the mechanisms underlying the effectiveness of this practice are not known. The purpose of the present study is to determine whether preoperative high-intensity inspiratory muscle training (HI-IMT) modulates the perioperative systemic inflammatory response in cardiac surgery patients. METHODS: Participants awaiting surgical aortic valve replacement were randomized to 3 to 6 weeks preoperative home-based HI-IMT or same duration low-intensity inspiratory muscle training (LI-IMT). The primary outcome was the preoperative value of the soluble tumor necrosis factor receptor 1 (sTNFR1). Secondary outcomes assessed perioperative evolution of the cytokines: sTNFR1, Tumor necrosis factor-α, Interleukin (IL)-6, IL-8, IL10, IL1ß, and their combined z-score; reflecting post-training and postoperative inflammatory response. Perioperative pulmonary function and postoperative clinical outcomes were collected. RESULTS: Between February 2018 and March 30, 2019 patients were randomized, to HI-IMT or LI-IMT. There were no differences between the groups in terms of baseline characteristics. The median (IQR) training duration was 34 (28-44) days. After training, the median (IQR) predicted maximal inspiratory pressure was higher in the HI-IMT vs LI-IMT group (119 (96-142%) vs 97 (81-107%); p = .04) Levels of the sTNFR1 cytokine increased during training in the HI-IMT group, pre vs post training (Median (IQR) 1073 (920; 1219) vs 1172 (965; 1368) ng/L; p = .03). The 24-h postoperative global inflammatory score was lower in the HI-IMT than in the LI-IMT group (Median (IQR), -0.37 (-0.62, 0.03) vs -0.10 (-0.17, 0.49), p = .04). Global inflammatory scores were not different at other time points. There were no significant differences between the groups in post-operative pulmonary function and postoperative clinical outcome. CONCLUSION: High intensity inspiratory muscle training shows immunomodulatory properties. These properties could explain why preoperative inspiratory muscle training can lead to lung protection after cardiac surgery.

Elimination study of intact lipid nanocapsules after intravenous rat administration.

Aim: The present study investigated renal elimination after intravenous administration of four different formulations of lipid nanocapsules (LNCs) containing dyes adapted to Förster resonance energy transfer (FRET-LNCs). Materials & methods: FRET-LNCs of 85 or 50 nm with or without a pegylated surface were injected and collected in the blood or urine of rats at different time points. Quantitative analysis was performed to measure intact FRET-LNCs. Results & conclusion: No intact LNCs were found in urine (0 particles/ml) for all formulations. The 50-nm pegylated LNCs were eliminated faster from the blood, whereas 85-nm pegylated LNCS were eliminated slower than nonpegylated LNCs. Elimination of FRET-LNCs was mainly due to liver tissue interaction and not renal elimination.

Aqueous core nanocapsules: a new solution for encapsulating doxorubicin hydrochloride.

In this study, we propose a new solution for the nanoencapsulation of hydrophilic anticancer drug, doxorubicin hydrochloride (DOX). The drug molecules are solubilized in the core of aqueous nanoreservoirs, so-called aqueous core nanocapsules (ACN) recently developed by our team, and dispersed in aqueous bulk media. Since it is well acknowledged that the nanoencapsulation of DOX has many advantages, like reducing the sides effects (e.g. cardiac toxicity), we propose through the present study a novel formulation solution for this purpose. After focusing on the formulation process for optimizing the drug encapsulation yield, the DOX-release profiles were followed up and analyzed. Different physicochemical and in vitro characterization were performed, and complement activation experiments. ACN were shown efficient to encapsulate DOX reaching yields as high as 80%, followed by a sustained release governed by a diffusion-controlled mechanism. The loaded nanocarriers showed low levels of complement activation, compatible with stealth properties. To summarize, this study brings out a new tool for the nanoencapsulation of hydrophilic anticancers and could open new doors for the administration of this particular class of drugs.

Protein corona formation on lipidic nanocapsules: Influence of the interfacial PEG repartition.

The parameters currently used for characterization of nanoparticles, such as size and zeta potential, were not able to reflect the performance of a nanocarrier in the biological environment. Therefore, more thorough in vitro characterization is required to predict their behavior in vivo, where nanoparticles acquire a new biological identity due to interactions with biomolecules. In this present study, we performed in vitro characterization in biological fluids for lipid nanocapsules (LNCs) with varying means sizes (50 nm and 100 nm), different electrical surface charges and different Poly Ethylene Glycol (PEG) compositions. Then, different methods were applied to show the impact of the protein corona formation on LNCs. Even if all formulations attached to plasmatic proteins, a higher thickness of corona and highest protein binding was observed for certain LNC50 formulations. A better knowledge of the phenomenon of protein adsorption over NPs in the plasmatic media is a cornerstone of clinical translation. In fact, after short blood circulation time, it is not the initially designed nanoparticle but the complex nanoparticle bearing its protein corona which circulates to reach its target.

Waiting for a kidney transplant, a source of unavoidable but reversible anxiety: a prospective pilot study investigating a psychological intervention.

BACKGROUND: Kidney transplantation is the treatment of choice for end-stage renal disease. Psychological problems and the presence of high anxiety have been described at various times over the course of transplantation, starting early at inclusion on the waiting-list. The objective of this study was to investigate anxiety symptoms among patients waiting for a transplant and the efficacy of a psychological intervention in the management of the anxiety. METHODS: In this prospective trial, 30 patients waiting for a first kidney transplantation were included. Medico-psycho-sociodemographic data were collected. Anxiety symptoms were assessed at inclusion using the State-Trait Anxiety Inventory self-assessment questionnaire for state anxiety (Spielberger and Vagg in Inventaire d'anxiété état-trait, forme Y (STAI-Y) Paris, 1993). A second assessment was carried out after the psychological intervention, which consisted of three sessions conducted by a clinical psychologist. RESULTS: Anxiety scores were considerably higher in females compared to males (47.5 versus 33.0, p < 0.023) and among those who had a psychological treatment history (60 versus 37, p = 0.003). We found a correlation between the level of anxiety and the length of time spent on the waiting-list (r = 0.552, p = 0.002). Importantly, anxiety scores decreased significantly (44 versus 32, p < 0.0001) after the psychological intervention. CONCLUSION: This study suggests that early psychological support allows improving anxiety symptoms in patients wait-listed for a kidney transplant. TRIAL REGISTRATION: Clinical trial NCT02690272.

Glioblastoma-targeted, local and sustained drug delivery system based on an unconventional lipid nanocapsule hydrogel.

The objective of this work was to develop an implantable therapeutic hydrogel that will ensure continuity in treatment between surgery and radiochemotherapy for patients with glioblastoma (GBM). A hydrogel of self-associated gemcitabine-loaded lipid nanocapsules (LNC) has shown therapeutic efficacy in vivo in murine GBM resection models. To improve the targeting of GBM cells, the NFL-TBS.40-63 peptide (NFL), was associated with LNC. The LNC-based hydrogels were formulated with the NFL. The peptide was totally and instantaneously adsorbed at the LNC surface, without modifying the hydrogel mechanical properties, and remained adsorbed to the LNC surface after the hydrogel dissolution. In vitro studies on GBM cell lines showed a faster internalization of the LNC and enhanced cytotoxicity, in the presence of NFL. Finally, in vivo studies in the murine GBM resection model proved that the gemcitabine-loaded LNC with adsorbed NFL could target the non-resected GBM cells and significantly delay or even inhibit the apparition of recurrences.

Dedifferentiated cells obtained from glioblastoma cell lines are an easy and robust model for mesenchymal glioblastoma stem cells studies.

Glioblastoma is an aggressive brain tumor with a poor prognosis. Glioblastoma Stem Cells (GSC) are involved in glioblastoma resistance and relapse. Effective glioblastoma treatment must include GSC targeting strategy. Robust and well defined in vitroGSC models are required for new therapies evaluation. In this study, we extensively characterized 4 GSC models obtained by dedifferentiation of commercially available glioblastoma cell lines and compared them to 2 established patient derived GSC lines (Brain Tumor Initiating Cells). Dedifferentiated cells formed gliospheres, typical for GSC, with self-renewal ability. Gene expression and protein analysis revealed an increased expression of several stemness associated markers such as A2B5, integrin α6, Nestin, SOX2 and NANOG. Cells were oriented toward a mesenchymal GSC phenotype as shown by elevated levels of mesenchymal and EMT related markers (CD44, FN1, integrin α5). Dedifferentiated GSC were similar to BTIC in terms of size and heterogeneity. The characterization study also revealed that CXCR4 pathway was activated by dedifferentiation, emphasizing its role as a potential therapeutic target. The expression of resistance-associated markers and the phenotypic diversity of the 4 GSC models obtained by dedifferentiation make them relevant to challenge future GSC targeting therapies.