Nuclear receptor peroxisome proliferator activated receptor (PPAR) beta/delta in skin wound healing and cancer

We review the functions of peroxisome proliferator activated receptor (PPAR) beta/delta in skin wound healing and cancer. In particular, we highlight the roles of PPAR beta/delta in inhibiting keratinocyte apoptosis at wound edges via activation of the PI3K/PKB alpha/Akt1 pathway and its role during re-epithelialization in regulating keratinocyte adhesion and migration. In fibroblasts, PPAR beta/delta controls IL-1 signalling and thereby contributes to the homeostatic control of keratinocyte proliferation. We discuss its therapeutic potential for treating diabetic wounds and inflammatory skin diseases such as psoriasis and acne vulgaris. PPAR beta/delta is classified as a tumour growth modifier; it is activated by chronic low-grade inflammation, which promotes the production of lipids that, in turn, enhance PPAR beta/delta transcription activity. Our earlier,work unveiled a cascade of events triggered by PPAR beta/delta that involve the oncogene Src, which promotes ultraviolet-induced skin cancer in mice via enhanced EGFR/Erk1/2 signalling and the expression of epithelial-to-mesenchymal transition (EMT) markers. Interestingly, PPAR beta/delta expression is correlated with the expression of SRC and EMT markers in human skin squamous cell carcinoma. Furthermore, there is a positive interaction between PPAR beta/delta, SRC, and TGF beta 1 at the transcriptional level in various human epithelial cancers. Taken together, these observations suggest the need for evaluating PPAR beta/delta modulators that attenuate or increase its activity, depending on the therapeutic target.

Nuclear Symmetry Energy Probed by Neutron Skin Thickness of Nuclei

We describe a relation between the symmetry energy coefficients csym(ρ) of nuclear matter and asym(A) of finite nuclei that accommodates other correlations of nuclear properties with the low-density behavior of csym(ρ). Here, we take advantage of this relation to explore the prospects for constraining csym(ρ) of systematic measurements of neutron skin sizes across the mass table, using as example present data from antiprotonic atoms. The found constraints from neutron skins are in harmony with the recent determinations from reactions and giant resonances.

Multiple Myeloma with primary manifestation in the mandible: a case report

Multiple myeloma is a monoclonal malignant proliferation of plasma cells that causes osteolytic lesions in the vertebrae, ribs, pelvic bone, skull and jaw. We report on a clinical case of an 81-year-old male patient who presented with a tumefaction in the mandibular symphysis region, which had evolved over the previous seven months. In the radiographic examination, an extensive osteolytic lesion was observed in the region mentioned above. An incisional biopsy was performed and a histopathological study revealed a malignant hematopoietic neoplasm formed by plasmacytoid cells. During the bone gammagraphy a dissemination of the disease was detected in the scapula, clavicle and ribs. The diagnosis was multiple myeloma. Knowledge about the maxillofacial manifestations of multiple myeloma is important for the early diagnosis of the disease, since its primary form can manifest itself in the jaw. In the clinical case presented here, we highlight the interdisciplinarity needed to obtain a diagnosis and treatment of multiple myeloma

Analysis of bulk and surface contributions in the neutron skin of nuclei

The neutron skin thickness of nuclei is a sensitive probe of the nuclear symmetry energy and has multiple implications for nuclear and astrophysical studies. However, precision measurements of this observable are difficult to obtain. The analysis of the experimental data may imply some assumptions about the bulk or surface nature of the formation of the neutron skin. Here we study the bulk or surface character of neutron skins of nuclei following from calculations with Gogny, Skyrme, and covariant nuclear mean-field interactions. These interactions are successful in describing nuclear charge radii and binding energies but predict different values for neutron skins. We perform the study by fitting two-parameter Fermi distributions to the calculated self-consistent neutron and proton densities. We note that the equivalent sharp radius is a more suitable reference quantity than the half-density radius parameter of the Fermi distributions to discern between the bulk and surface contributions in neutron skins. We present calculations for nuclei in the stability valley and for the isotopic chains of Sn and Pb.

Soft tissue artifact distribution on lower limbs during treadmill gait: Influence of skin markers' location on cluster design.

Segment poses and joint kinematics estimated from skin markers are highly affected by soft tissue artifact (STA) and its rigid motion component (STARM). While four marker-clusters could decrease the STA non-rigid motion during gait activity, other data, such as marker location or STARM patterns, would be crucial to compensate for STA in clinical gait analysis. The present study proposed 1) to devise a comprehensive average map illustrating the spatial distribution of STA for the lower limb during treadmill gait and 2) to analyze STARM from four marker-clusters assigned to areas extracted from spatial distribution. All experiments were realized using a stereophotogrammetric system to track the skin markers and a bi-plane fluoroscopic system to track the knee prosthesis. Computation of the spatial distribution of STA was realized on 19 subjects using 80 markers apposed on the lower limb. Three different areas were extracted from the distribution map of the thigh. The marker displacement reached a maximum of 24.9mm and 15.3mm in the proximal areas of thigh and shank, respectively. STARM was larger on thigh than the shank with RMS error in cluster orientations between 1.2° and 8.1°. The translation RMS errors were also large (3.0mm to 16.2mm). No marker-cluster correctly compensated for STARM. However, the coefficient of multiple correlations exhibited excellent scores between skin and bone kinematics, as well as for STARM between subjects. These correlations highlight dependencies between STARM and the kinematic components. This study provides new insights for modeling STARM for gait activity.

Neutron skin of 208Pb, nuclear symmetry energy, and the parity radius experiment

A precise determination of the neutron skin thickness of a heavy nucleus sets a basic constraint on the nuclear symmetry energy (the neutron skin thickness is the difference of the neutron and proton rms radii of the nucleus). The parity radius experiment (PREX) may achieve it by electroweak parity-violating electron scattering (PVES) on 208Pb. We investigate PVES in nuclear mean field approach to allow the accurate extraction of the neutron skin thickness of 208Pb from the parity-violating asymmetry probed in the experiment. We demonstrate a high linear correlation between the parity-violating asymmetry and the neutron skin thickness in successful mean field forces as the best means to constrain the neutron skin of 208Pb from PREX, without assumptions on the neutron density shape. Continuation of the experiment with higher precision in the parity-violating asymmetry is motivated since the present method can support it to constrain the density slope of the nuclear symmetry energy to new accuracy.

New cationic nanovesicular systems containing lysine-based surfactants for topical administration: Toxicity assessment using representative skin cell lines

Many strategies for treating diseases require the delivery of drugs into the cell cytoplasm following internalization within endosomal vesicles. Thus, compounds triggered by low pH to disrupt membranes and release endosomal contents into the cytosol are of particular interest. Cationic nanovesicles have attracted considerable interest as effective carriers to improve the delivery of biologically active molecules into and through the skin. In this study, lipid-based nanovesicles containing three different cationic lysine-based surfactants were designed for topical administration. We used representative skin cell lines and in vitro assays to assess whether the cationic compounds modulate the toxic responses of these nanocarriers. The nanovesicles were characterized in both water and cell culture medium. In general, significant agglomeration occurred after 24 h incubation under cell culture conditions. We found different cytotoxic responses among the formulations, which depended on the surfactant,cell line (3T3, HaCaT, and THP-1) and endpoint assayed (MTT, NRU, and LDH). Moreover, no potential phototoxicity was detected in fibroblast or keratinocyte cells, whereas only a slight inflammatory response was induced, as detected by IL-1a and IL-8 production in HaCaT and THP-1 cell lines, respectively. A key finding of our research was that the cationic charge position and the alkyl chain length of the surfactants determine the nanovesicles resulting toxicity. The charge on the a-amino group of lysine increased the depletion of cell metabolic activity, as determined by the MTT assay, while a higher hydrophobicity tends to enhance the toxic responses of the nanovesicles. The insights provided here using different cell lines and assays offer a comprehensive toxicological evaluation of this group of new nanomaterials.

Estimations of topographically correct regeneration to nerve branches and skin after peripheral nerve injury and repair.

Peripheral nerve injury is typically associated with long-term disturbances in sensory localization, despite nerve repair and regeneration. Here, we investigate the extent of correct reinnervation by back-labeling neuronal soma with fluorescent tracers applied in the target area before and after sciatic nerve injury and repair in the rat. The subpopulations of sensory or motor neurons that had regenerated their axons to either the tibial branch or the skin of the third hindlimb digit were calculated from the number of cell bodies labeled by the first and/or second tracer. Compared to the normal control side, 81% of the sensory and 66% of the motor tibial nerve cells regenerated their axons back to this nerve, while 22% of the afferent cells from the third digit reinnervated this digit. Corresponding percentages based on quantification of the surviving population on the experimental side showed 91%, 87%, and 56%, respectively. The results show that nerve injury followed by nerve repair by epineurial suture results in a high but variable amount of topographically correct regeneration, and that proportionally more neurons regenerate into the correct proximal nerve branch than into the correct innervation territory in the skin

Précarité et problèmes cutanés [Skin problems associated with poor living conditions].

Les personnes vivant dans une situation de précarité sont susceptibles de développer un large éventail de problèmes médicaux et les atteintes cutanées sont très fréquentes. Nous présentons quatre situations cliniques de problèmes cutanés fréquemment retrouvés au sein des populations précaires. Leurs diagnostic et prise en charge précoces sont essentiels pour en prévenir l'ultérieure dissémination dans des contextes de promiscuité. People living in poor conditions are at high risk of developing different medical diseases of which dermatological diseases are very common. We present 4 clinical cases of skin diseases, which are the most prevalent amongst the majority of socially and economically vulnerable patients. Early diagnosis and appropriate treatment are of paramount importance, in order to avoid their spread in close- knit communities where these patients often live.

Nrf2 Activation Promotes Keratinocyte Survival during Early Skin Carcinogenesis via Metabolic Alterations.

Pharmacologic activation of the transcription factor NRF2 has been suggested to offer a strategy for cancer prevention. In this study, we present evidence from murine tumorigenesis experiments suggesting there may be limitations to this possibility, based on tumorigenic effects of Nrf2 in murine keratinocytes that have not been described previously. In this setting, Nrf2 expression conferred metabolic alterations in keratinocytes that were protumorigenic in nature, affecting enzymes involved in glutathione biosynthesis or in the oxidative pentose phosphate pathway and other NADPH-producing enzymes. Under stress conditions, coordinate increases in NADPH, purine, and glutathione levels promoted the survival of keratinocytes harboring oncogenic mutations, thereby promoting tumor development. The protumorigenic activity of Nrf2 in keratinocytes was particularly significant in a mouse model of skin tumorigenesis that did not rely upon chemical carcinogenesis. In exploring the clinical relevance of our findings, we confirm that NRF2 and protumorigenic NRF2 target genes were activated in some actinic keratoses, the major precancerous lesion in human skin. Overall, our results reveal an unexpected tumor-promoting activity of activated NRF2 during early phases of skin tumorigenesis. Cancer Res; 75(22); 4817-29. ©2015 AACR.

A new alternative method for testing skin irritation using a fresh human skin model

La dermatite irritative est décrite comme une réaction réversible, non immunologique caractérisée par des lésions d'aspect très variable, allant de la simple rougeur jusqu'à la formation de bulles voire d'une nécrose, accompagnée de prurit ou d'une sensation de brûlure suite à I' application d'une substance chimique. Le teste de prédiction d'irritation cutanée est traditionnellement depuis les années 1940 le Test de Draize. Ce test consiste en l'application d'une substance chimique sur une peau rasée de lapin pendant 4h et de regarder à 24h si des signes cliniques d'irritations sont présents. Cette méthode critiquable autant d'un point de vue éthique que qualitative reste actuellement le teste le plus utilisé. Depuis le début des années 2000 de nouvelles méthodes in vitro se sont développées tel que le model d'épiderme humain recombiné (RHE). Il s agit d'une multicouche de kératinocyte bien différencié obtenu depuis une culture de don d'ovocyte. Cependant cette méthode en plus d'être très couteuse n'obtient au mieux que 76% de résultat similaire comparé au test in vivo humain. Il existe donc la nécessité de développer une nouvelle méthode in vitro qui simulerait encore mieux la réalité anatomique et physiologique retrouvée in vivo. Notre objectif a été de développer cette nouvelle méthode in vitro. Pour cela nous avons travaillé avec de la peau humaine directement prélevée après une abdominoplastie. Celle ci après préparation avec un dermatome, un couteau dont la lame est réglable pour découper l'épaisseur souhaitée de peau, est montée dans un système de diffusion cellulaire. La couche cornée est alors exposée de manière optimale à 1 ml de la substance chimique testée pendant 4h. L'échantillon de peau est alors fixé dans du formaldéhyde pour permettre la préparation de lames standards d'hématoxyline et éosine. L'irritation est alors investiguée selon des critères histopathologiques de spongioses, de nécroses et de vacuolisations cellulaires. Les résultats de ce.tte première batterie de testes sont plus que prometteurs. En effet, comparé au résultat in vivo, nous obtenons 100% de concordance pour les 4 même substances testes irritantes ou non irritantes, ce qui est supérieur au model d épiderme humain recombiné (76%). De plus le coefficient de variation entre les 3 différentes séries est inférieur à 0.1 ce qui montre une bonne reproductibilité dans un même laboratoire. Dans le futur cette méthode va devoir être testée avec un plus grand nombre de substances chimiques et sa reproductibilité évaluée dans différents laboratoires. Mais cette première evaluation, très encourageante, ouvre des pistes précieuses pour l'avenir des tests irritatifs.

Study of the skin anatomy with high-frequency (22 MHz) ultrasonography and histological correlation

AbstractThe present essay is aimed at getting the radiologist familiar with the basic histological skin structure, allowing for a better correlation with sonographic findings. A high-frequency (22 MHz) ultrasonography apparatus was utilized in the present study. The histological analysis was performed after the skin specimens fixation with formalin, inclusion in paraffin blocks and subsequent staining with hematoxylin-eosin. The authors present a literature review showing the relationship between sonographic and histological findings in normal cutaneous tissue, and discuss the technique for a better performance of the sonographic scan. High-frequency ultrasonography is an excellent tool for the diagnosis of different skin conditions. However, as this method is operator-dependent, it is crucial to understand the normal skin structure as well as the correlation between histological and sonographic findings.

Analysis of TRIP expression in different types of skin tumor

TRAF-interacting protein (TRIP) is a ubiquitously expressed nucleolar E3 ubiquitin ligase. Ubiquitination of proteins is a post-translational modification, which decides on the cellular fate of the protein. TRIP in vivo substrate has not been yet identified. However, TRIP has been shown to play an important role in cellular proliferation, especially in keratinocytes. TRIP was found to be up-regulated in basal cell carcinoma (BCC) at the mRNA level. This prompted us to elucidate its role in skin proliferative diseases such as cancer by analyzing its expression in BCCs at protein level and in squamous cell carcinoma (SCC) at mRNA and protein level. To that purpose, we performed a real-time PCR (qPCR) analysis followed by an immunohistochemistry (IHC) on formalin-fixed, paraffin-embedded (FFPE) biopsies. The real-time PCR was performed on 12 RNA samples of which 6 were extracted from SCC biopsies and 6 from normal human skin. The results were statistically insignificant. Further analyses are needed on new RNA samples. The IHC assay was performed on 20 biopsies from BCCs, 21 biopsies from SCCs and on 5 tissues from normal human skin. The results obtained showed an extensive expression of TRIP in keratinocytes nuclei. Due to various limitations related to the technique and to doubts about preservation of the antigens in the tissues from normal human skin, we could not highlight a clear difference in TRIP expression between the different tissues. In conclusion, further analyses are needed on new RNA samples (qPCR) and on better preserved FFPE tissues from normal skin (IHC) to assess TRIP relative expression in BCCs and SCCs versus normal human skin.