Improved organotypic skin model with reduced quantity of monounsaturated ceramides by inhibiting stearoyl-CoA desaturase-1

Full thickness models (FTM) are 3D in vitro skin cultures that resemble the native human skin (NHS) to a great extent. However, the barrier function of these skin models is reduced. The skin barrier is located in the stratum corneum (SC) and consists of corneocytes embedded in a lipid matrix. In this matrix, deviations in the composition of the FTMs lipid matrix may contribute to the impaired skin barrier when compared to NHS. One of the most abundant changes in lipid composition is an increase in monounsaturated lipids for which stearoyl-CoA desaturase-1 (SCD-1) is responsible. To improve the SC lipid composition, we reduced SCD-1 activity during the generation of the FTMs. These FTMs were subsequently assessed on all major aspects, including epidermal homeostasis, lipid composition, lipid organization, and barrier functionality. We demonstrate that SCD-1 inhibition was successful and resulted in FTMs that better mimic the lipid composition of FTMs to NHS by a significant reduction in monounsaturated lipids. In conclusion, this study demonstrates an effective approach to normalize SC monounsaturated lipid concentration and may be a valuable tool in further optimizing the FTMs in future studies.Drug Delivery Technolog

Lesional skin of seborrheic dermatitis patients is characterized by skin barrier dysfunction and correlating alterations in the stratum corneum ceramide composition

Drug Delivery Technolog

The effect of PPAR isoform (de)activation on the lipid composition in full-thickness skin models

Human skin equivalents (HSEs) are 3D-cultured human skin models that mimic many aspects of native human skin (NHS). Although HSEs resemble NHS very closely, the barrier located in the stratum corneum (SC) is impaired. This is caused by an altered lipid composition in the SC of HSEs compared with NHS. One of the most pronounced changes in this lipid composition is a high level of monounsaturation. One key enzyme in this change is stearoyl-CoA desaturase-1 (SCD1), which catalyses the monounsaturation of lipids. In order to normalize the lipid composition, we aimed to target a group of nuclear receptors that are important regulators in the lipid synthesis. This group of receptors are known as the peroxisome proliferating activating receptors (PPARs). By (de)activating each isoform (PPAR-alpha, PPAR-delta and PPAR-gamma), the PPAR isoforms may have normalizing effects on the lipid composition. In addition, another PPAR-alpha agonist Wy14643 was included as this supplement demonstrated normalizing effects in the lipid composition in a more recent study. After PPAR (ant)agonists supplementation, the mRNA of downstream targets, lipid synthesis genes and lipid composition were investigated. The PPAR downstream targets were activated, indicating that the supplements reached the keratinocytes to trigger their effect. However, minimal impact was observed on the lipid composition after PPAR isoform (de) activation. Only the highest concentration Wy14643 resulted in strong, but negative effects on CER composition. Although the novel tested modifications did not result in an improvement, more insight is gained on the nuclear receptors PPARs and their effects on the lipid barrier in full-thickness skin models.Drug Delivery Technolog

What Makes Polysorbate Functional? Impact of Polysorbate 80 Grade and Quality on IgG Stability During Mechanical Stress.

Polysorbate 80 (PS80) is a commonly used surfactant in therapeutic protein formulations to mitigate adsorption and interface-induced protein aggregation. Several PS80 grades and qualities are available on the market for parenteral application. The role of PS80 grade on protein stability remains debatable, and the impact of (partially) degraded PS on protein aggregation is not yet well understood. In our study, a monoclonal antibody (IgG) was subjected to 3 different mechanical stress conditions in the presence of multicompendial (MC) and Chinese pharmacopeia (ChP) grade PS80. Furthermore, IgG formulations were spiked with (partly) hydrolyzed PS80 to investigate the effect of PS80 degradants on protein stability. PS80 functionality was assessed by measuring the extent of protein aggregation and particle formation induced during mechanical stress by using size-exclusion chromatography, dynamic light scattering, backgrounded membrane imaging, and flow imaging microscopy. No distinguishable differences in PS80 functionality between MC and ChP grade were observed in the 3 stress tests. However, with increasing degree of PS80 hydrolysis, higher counts of subvisible particles were measured after stress. Furthermore, higher levels of PS80 degradants at a constant PS80 concentration may destabilize the IgG. In conclusion, MC and ChP grade PS80 are equally protective, but PS80 degradants compromise IgG stability.Drug Delivery Technolog

Soil moisture monitoring over wetland areas using GNSS signals

International audienceDuring summer 2015, two experimental campaigns in the framework of the Mistrale Project have been carried. In those campaigns a complete GNSS-R sensor was installed on an ultralight aircraft, allowing gathering polarimetric GNSS-R data. The flights were done in France over the Camargue area (flooded areas, marshlands and water salinity changes), and Pech Rouge area (agricultural plots).The estimated reflection coefficients acquired during the flights, have been computed and geo-referenced on ground, showing that the reflection coefficients are sensible to terrain changes. Main results are presented in this work

The effect of PPAR isoform (de)activation on the lipid composition in full-thickness skin models

Human skin equivalents (HSEs) are 3D-cultured human skin models that mimic many aspects of native human skin (NHS). Although HSEs resemble NHS very closely, the barrier located in the stratum corneum (SC) is impaired. This is caused by an altered lipid composition in the SC of HSEs compared with NHS. One of the most pronounced changes in this lipid composition is a high level of monounsaturation. One key enzyme in this change is stearoyl-CoA desaturase-1 (SCD1), which catalyses the monounsaturation of lipids. In order to normalize the lipid composition, we aimed to target a group of nuclear receptors that are important regulators in the lipid synthesis. This group of receptors are known as the peroxisome proliferating activating receptors (PPARs). By (de)activating each isoform (PPAR-α, PPAR-δ and PPAR-γ), the PPAR isoforms may have normalizing effects on the lipid composition. In addition, another PPAR-α agonist Wy14643 was included as this supplement demonstrated normalizing effects in the lipid composition in a more recent study. After PPAR (ant)agonists supplementation, the mRNA of downstream targets, lipid synthesis genes and lipid composition were investigated. The PPAR downstream targets were activated, indicating that the supplements reached the keratinocytes to trigger their effect. However, minimal impact was observed on the lipid composition after PPAR isoform (de) activation. Only the highest concentration Wy14643 resulted in strong, but negative effects on CER composition. Although the novel tested modifications did not result in an improvement, more insight is gained on the nuclear receptors PPARs and their effects on the lipid barrier in full-thickness skin models

Impact of metastasectomy on cancer specific and overall survival in metastatic renal cell carcinoma: Analysis of the REMARCC registry

Introduction & Objectives: As treatment paradigms for management of metastatic renal cell carcinoma (mRCC) have shifted, the role of surgical metastasectomy in management of mRCC has been in similar flux. We examined impact on survival of surgical metastatectomy stratified in the setting of different mRCC risk groups. Materials & Methods: Multicenter retrospective analysis of patients from the REMARCC (REgistry of MetAstatic RCC) database. The cohort was subdivided utilizing Motzer RCC criteria (low, intermediate, and high risk), and impact of metastasectomy was analyzed via multivariable analysis (MVA) and Kaplan Meier analysis within each Motzer subgroup (KMA). Primary outcome was overall survival (OS) and secondary outcome was cancer specific mortality (CSM). Results: 431 patients (59 low risk, 274 intermediate risk, 98 high risk) with median follow-up of 19.2 months were analyzed. Metastasectomy was performed in 22 (37%), 66 (24%), and 32 (16%) of low, intermediate and high risk groups (p=0.012). Risk groups differed significantly with respect to ECOG performance status (p<0.001) and number of metastases at diagnosis (low 2, intermediate 3.4, high 5.1, p<0.001). MVA for CSM revealed male sex (OR 1.77, p=0.015), number of metastases at diagnosis (OR 1.18, p<0.001), and higher risk category [low (referent) vs. intermediate OR 2.16, p=0.046, high OR 2.44, p=0.002] to be independent risk factors. MVA for OS demonstrated increasing number of metastases at diagnosis (OR 1.78, p<0.001) and higher risk category [low (referent) vs. intermediate OR 2.37, p=0.03, high OR 2.61, p=0.001] to be independent risk factors. KMA for CSM demonstrated that metastasectomy was associated with longer cancer-specific survival in low (32.78 vs. 76.09 months, p=0.004) but not intermediate (p=0.060) and high risk (p=0.595) groups. KMA for OS demonstrated that metastasectomy was associated with longer median OS in the low (25.8 vs. 92.7 months, p=0.003) and intermediate risk (20.1 vs. 26.3, p=0.038), but not high risk (p=0.911) groups (Figure). Conclusions: Metastasectomy was not associated with benefit in high risk mRCC patients, but was associated with improved CSM in low risk and improved OS in low and intermediate risk mRCC patients. Further investigation is requisite to refine criteria for employment of metastasectomy

Lesional skin of seborrheic dermatitis patients is characterized by skin barrier dysfunction and correlating alterations in the stratum corneum ceramide composition

Seborrheic dermatitis (SD) is a chronic inflammatory skin disease characterized by erythematous papulosquamous lesions in sebum rich areas such as the face and scalp. Its pathogenesis appears multifactorial with a disbalanced immune system, Malassezia driven microbial involvement and skin barrier perturbations. Microbial involvement has been well described in SD, but skin barrier involvement remains to be properly elucidated. To determine whether barrier impairment is a critical factor of inflammation in SD alongside microbial dysbiosis, a cross-sectional study was performed in 37 patients with mild-to-moderate facial SD. Their lesional and non-lesional skin was comprehensively and non-invasively assessed with standardized 2D-photography, optical coherence tomography (OCT), microbial profiling including Malassezia species identification, functional skin barrier assessments and ceramide profiling. The presence of inflammation was established through significant increases in erythema, epidermal thickness, vascularization and superficial roughness in lesional skin compared to non-lesional skin. Lesional skin showed a perturbed skin barrier with an underlying skewed ceramide subclass composition, impaired chain elongation and increased chain unsaturation. Changes in ceramide composition correlated with barrier impairment indicating interdependency of the functional barrier and ceramide composition. Lesional skin showed significantly increased Staphylococcus and decreased Cutibacterium abundances but similar Malassezia abundances and mycobial composition compared to non-lesional skin. Principal component analysis highlighted barrier properties as main discriminating features. To conclude, SD is associated with skin barrier dysfunction and changes in the ceramide composition. No significant differences in the abundance of Malassezia were observed. Restoring the cutaneous barrier might be a valid therapeutic approach in the treatment of facial SD

Open versus minimally invasive cytoreductive nephrectomy (CN) for metastatic renal cell carcinoma (mRCC): Results from a multicenter retrospective study

Aim of the study: Recent evidence outlined that not all patients with mRCC might benefit from CN. However, there is lack of data on perioperative morbidity after this procedure. We aimed to investigate the impact of surgical approach on perioperative outcomes and surgical complications relying on a multicenter international registry. Materials and methods: Clinical data of 681 patients with mRCC undergoing CN at 11 centers included in the REgistry of MetAstatic RCC (REMARCC) from January 2014 to December 2017 were retrospectively collected. Patients with complete data on demographics and comorbidity profiles were included in final analysis. Study endpoints were: a) postoperative complications, assessed and graded using the modified Clavien-Dindo scale, and b) 30th day readmission rate. Results: Overall, 369 (54.2%) patients (247 open CN [OCN] and 122 minimally-invasive CN [MICN]) were considered. Patients treated with OCN had a significantly higher cT stage (p = 0.01), tumor size (p < 0.0001) and cN stage (p = 0.04). Conversely, there was no difference in terms of gender, age, Charlson comorbidity index, body mass index, site of metastasic lesions and baseline hemoglobin level, LDH level, glomerular filtration rate and calcemia. Lymph node dissection (LND) rate and renal vein/vena cava thrombectomy were significantly higher in the OCN compared to the MICN (p < 0.0001 and p = 0.001, respectively). Median estimated blood loss was significantly lower in the MICN compared to the OCN group (100 vs 450 cc, p < 0.0001). The rate of removal of adjacent organs beyond the tumorbearing kidney was not significantly different among the two groups. Patients with MICN compared to OCN had a significantly lower intraoperative (10% vs 22.6%, p = 0.004), overall postoperative (18% vs 38.6%, p < 0.0001) and major postoperative (2.5 vs 8.2%, p = 0.03) complications and lower median length of stay (5 vs 8 days, p < 0.0001). Perioperative mortality was reported in 3 patients in the OCN group. Readmission rate was 7.1% in both groups. Discussion: MICN was feasible and achieved acceptable perioperative morbidity in selected patients with mRCC. The main study limitation is the retrospective design with risk of selection and attrition bias