History and Prospects of Drug Discovery and Development Collaboration between Industry and Academia.

Research collaborations and licensing deals are critical for the discovery and development of life-saving drugs. This practice has been ongoing since the inception of the pharmaceutical industry. The current process of drug discovery and development is complex, regulated, and highly regimented, having evolved over time. Academia excels in the discovery of fundamental scientific concepts and biological processes, while industry excels in translational science and product development. Potential for collaboration exists at every step of the drug discovery and development continuum. This perspective walks through such collaborative activities, provides examples, and offers tips for potential collaborations.

Ultraviolet transmission microscopy for the imaging of topical sunscreen emulsions.

OBJECTIVE: Microscopy is widely used during the development and testing of topical formulations; however, it often lacks the ability to be chemically specific with regard to what is being imaged. This article describes how moving outside of the visible light region and into different parts of the ultraviolet (UV) spectrum enables differently UV absorbing components in topical emulsions to be directly visualized using optical transmission microscopy. METHODS: Optical transmission microscopy of different sunscreen emulsions was carried out using a custom-built microscope, imaging in the UVB (313 nm), UVA (365 nm) and visible light (546 nm) and with different magnifications. RESULTS: By using light of different wavelengths, direct visualization of different UV absorbing ingredients within the product emulsion using optical transmission microscopy has been performed and the locations of the UV absorbing actives in the formulations imaged. CONCLUSIONS: Microscopy has long been a valuable tool for the skin researcher, providing structural information about the products and how they perform. By moving outside of the spectral region of visible light and into the UV, it has been possible for the first time to directly image different SPF ingredients within topical formulations using optical microscopy.

OBJECTIF: La microscopie est largement utilisée dans le processus de développement et d'analyse des formulations topiques; cependant, elle ne parvient pas souvent à être chimiquement spécifique en ce qui concerne l'objet de l'imagerie. Le présent article décrit comment le déplacement au-delà de la zone de lumière visible et dans différentes parties du spectre ultraviolet (UV) permet aux ingrédients qui absorbent différemment les UV dans les émulsions topiques, d'être directement visualisés grâce à la microscopie à transmission optique. MÉTHODES: La microscopie à transmission optique de différentes émulsions de crème solaire a été réalisée à l'aide d'un microscope sur mesure, de l'imagerie dans les UVB (313 nm), les UVA (365 nm) et la lumière visible (546 nm) et à différents grossissements. RÉSULTATS: En utilisant la lumière de différentes longueurs d'onde, une visualisation directe des différents ingrédients absorbant les UV dans l'émulsion du produit grâce à la microscopie à transmission optique a été réalisée et les emplacements des substances actives absorbant les UV dans les formulations ont fait l'objet d'imagerie. CONCLUSIONS: La microscopie a été depuis longtemps un outil précieux pour les spécialistes de la peau, en fournissant des informations structurelles sur les produits et leurs performances. En se déplaçant au-delà de la région spectrale de la lumière visible, dans les UV, il a été possible pour la première fois d'obtenir directement une imagerie des différents ingrédients du facteur de protection solaire dans des formulations topiques à l'aide de la microscopie optique.

Ultraviolet Fluorescence Photography-Choosing the Correct Filters for Imaging.

Ultraviolet (UV) fluorescence is a valuable tool for the imaging of a wide range of subjects. Like all imaging techniques, the key to success depends on the correct choice of equipment and approach used. In fluorescence photography, a filter is placed in front of the camera lens to block unwanted short-wavelength light from entering the camera, which would compromise the image. However, some filters exhibit fluorescence under UV light and can therefore have the potential to produce a color cast on the image. Filters also vary in how well they block unwanted light. A range of commonly used optical filters was assessed for fluorescence under UV light, and their optical transmission between 250 nm and 800 nm was measured. Finally, a simple method to enable the researcher to determine the fluorescence of the filters that they are using or wish to use for their work is described. The results indicate that the filters tested demonstrated a wide range of fluorescence under UV light and varying degrees of UV blocking. Some filters tested had equivalent or reduced fluorescence compared to Schott KV-418, which is a widely used, but, unfortunately, no longer manufactured UV blocking filter commonly used for fluorescence photography.

Monochrome Camera Conversion: Effect on Sensitivity for Multispectral Imaging (Ultraviolet, Visible, and Infrared).

Conversion of standard cameras to enable them to capture images in the ultraviolet (UV) and infrared (IR) spectral regions has applications ranging from purely artistic to science and research. Taking the modification of the camera a step further and removing the color filter array (CFA) results in the formation of a monochrome camera. The spectral sensitivities of a range of cameras with different sensors which were converted to monochrome were measured and compared with standard multispectral camera conversions, with an emphasis on their behavior from the UV through to the IR regions.

Topical emollient therapy with sunflower seed oil alters the skin microbiota of young children with severe acute malnutrition in Bangladesh: A randomised, controlled study.

BACKGROUND: Topical emollient therapy with sunflower seed oil (SSO) reduces risk of sepsis and mortality in very preterm infants in low- or middle-income countries (LMICs). Proposed mechanisms include modulation of skin and possibly gut barrier function. The skin and gut microbiota play important roles in regulating barrier function, but the effects of emollient therapy on these microbiotas are poorly understood. METHODS: We characterised microbiota structure and diversity with 16S rRNA gene amplicon sequence data and ecological statistics in 20 children with severe acute malnutrition (SAM) aged 2-24 months, at four skin sites and in stool, during a randomised, controlled trial of emollient therapy with SSO in Bangladesh. Microbes associated with therapy were identified with tree-based sparse discriminant analysis. RESULTS: The skin microbiota of Bangladeshi children with SAM was highly diverse and displayed significant variation in structure as a function of physical distance between sites. Microbiota structure differed between the study groups (P = 0.005), was more diverse in emollient-treated subjects-including on the forehead which did not receive direct treatment-and changed with each day (P = 0.005) at all skin sites. Overall, Prevotellaceae were the most differentially affected by emollient treatment; several genera within this family became more abundant in the emollient group than in the controls across several skin sites. Gut microbiota structure was associated with sample day (P = 0.045) and subject age (P = 0.045), but was not significantly affected by emollient treatment (P = 0.060). CONCLUSIONS: Emollient therapy altered the skin microbiota in a consistent and temporally coherent manner. We speculate that therapy with SSO enhances skin barrier function in part through alterations in the microbiota, and through systemic mechanisms. Strategies to strengthen skin and gut barrier function in populations at risk, such as children in LMICs like Bangladesh, might include deliberate manipulation of their skin microbiota. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02616289.

Understanding humectant behaviour through their water-holding properties.

OBJECTIVE: Humectants perform essential roles in the formulation of topical moisturizing products in terms of delivery of active ingredients, consumer experience and biophysical behaviour. How they retain and release water is key to understanding their behaviour. METHODS: Dynamic vapour sorption (DVS) was used to monitor the dehydration kinetics of three humectants widely used in topical formulations-glycerine, dexpanthenol and urea. Model aqueous solutions with concentrations of 20% w/w were tested and compared against pure deionized water. RESULTS: The three humectants varied in their ability to retain water during the dehydration process. Dexpanthenol was able to retain water most efficiently during the latter stages of dehydration. Urea demonstrated evidence of crystallization during the final stage of water loss, which was not shown by glycerine or dexpanthenol. CONCLUSIONS: Humectants perform vital roles in the formulation of consumer acceptable topical products including the delivery of actives to the skin. Their ability to influence water movement in the skin is also essential for the maintenance of stratum corneum flexibility. DVS assessment of aqueous solutions has demonstrated how the behaviour of three commonly used humectants differs. Knowledge of the mechanisms by which these humectants operate enables the formulator to develop topical products optimized for the roles for which they are intended.

OBJECTIF: Les agents humectants jouent un rôle essentiel dans la formulation des produits hydratants topiques en termes de délivrance des principes actifs, d'expérience client et de comportement biophysique. La façon dont ils retiennent et libèrent l'eau est essentielle pour comprendre leur comportement. MÉTHODES: La gravimétrie d'adsorption de vapeur d'eau (Dynamic Vapour Sorption, DVS) a été utilisée pour surveiller la cinétique de déshydratation de trois humectants largement utilisés dans les formulations topiques : glycérine, dexpanthénol et urée. Des solutions aqueuses modèles avec des concentrations de 20 % p/p ont été testées et comparées à de l'eau pure déionisée. RÉSULTATS: Les trois humectants ont varié dans leur capacité à retenir l'eau pendant le processus de déshydratation. Le dexpanthénol a été capable de retenir l'eau plus efficacement pendant les dernières étapes de la déshydratation. L'urée a démontré des signes de cristallisation pendant la perte d'eau au stade final qui n'a pas été démontrée par la glycérine ou le dexpanthénol CONCLUSIONS: Les agents humectants jouent un rôle essentiel dans la formulation des produits topiques acceptables pour les consommateurs, y compris l'administration de principes actifs sur la peau. Leur capacité à influencer le mouvement de l'eau dans la peau est également essentielle pour maintenir la flexibilité de la couche cornée. L'évaluation DVS des solutions aqueuses a démontré comment le comportement de trois humectants couramment utilisés diffère. La connaissance des mécanismes par lesquels fonctionnent ces humectants permet au formulateur de développer des produits topiques optimisés pour les rôles auxquels ils sont destinés.

Effect of topical applications of sunflower seed oil on systemic fatty acid levels in under-two children under rehabilitation for severe acute malnutrition in Bangladesh: a randomized controlled trial.

BACKGROUND: Children with severe acute malnutrition (SAM) have inadequate levels of fatty acids (FAs) and limited capacity for enteral nutritional rehabilitation. We hypothesized that topical high-linoleate sunflower seed oil (SSO) would be effective adjunctive treatment for children with SAM. METHODS: This study tested a prespecified secondary endpoint of a randomized, controlled, unblinded clinical trial with 212 children with SAM aged 2 to 24 months in two strata (2 to < 6 months, 6 to 24 months in a 1:2 ratio) at Dhaka Hospital of icddr,b, Bangladesh between January 2016 and December 2017. All children received standard-of-care management of SAM. Children randomized to the emollient group also received whole-body applications of 3 g/kg SSO three times daily for 10 days. We applied difference-in-difference analysis and unsupervised clustering analysis using t-distributed stochastic neighbor embedding (t-SNE) to visualize changes in FA levels in blood from day 0 to day 10 of children with SAM treated with emollient compared to no-emollient. RESULTS: Emollient therapy led to systematically higher increases in 26 of 29 FAs over time compared to the control. These effects were driven primarily by changes in younger subjects (27 of 29 FAs). Several FAs, especially those most abundant in SSO showed high-magnitude but non-significant incremental increases from day 0 to day 10 in the emollient group vs. the no-emollient group; for linoleic acid, a 237 µg/mL increase was attributable to enteral feeding and an incremental 98 µg/mL increase (41%) was due to emollient therapy. Behenic acid (22:0), gamma-linolenic acid (18:3n6), and eicosapentaenoic acid (20:5n3) were significantly increased in the younger age stratum; minimal changes were seen in the older children. CONCLUSIONS: SSO therapy for SAM augmented the impact of enteral feeding in increasing levels of several FAs in young children. Further research is warranted into optimizing this novel approach for nutritional rehabilitation of children with SAM, especially those < 6 months. TRIAL REGISTRATION: ClinicalTrials.gov : NCT02616289 .

Loss of 9p21 Regulatory Hub Promotes Kidney Cancer Progression by Upregulating HOXB13.

Loss of chromosome 9p21 is observed in one-thirds of clear-cell renal cell carcinoma (ccRCC) and is associated with poorer patient survival. Unexpectedly, 9p21 LOH does not lead to decreased expression of the 9p21 tumor suppressor genes, CDKN2A and CDKN2B, suggesting alternative mechanisms of 9p-mediated tumorigenesis. Concordantly, CRISPR-mediated 9p21 deletion promotes growth of immortalized human embryonic kidney epithelial cells independently of the CDKN2A/B pathway inactivation. The 9p21 locus has a highly accessible chromatin structure, suggesting that 9p21 loss might contribute to kidney cancer progression by dysregulating genes distal to the 9p21 locus. We identified several 9p21 regulatory hubs by assessing which of the 9p21-interacting genes are dysregulated in 9p21-deleted kidney cells and ccRCCs. By focusing on the analysis of the homeobox gene 13 (HOXB13) locus, we found that 9p21 loss relieves the HOXB13 locus, decreasing HOXB13 methylation and promoting its expression. Upregulation of HOXB13 facilitates cell growth and is associated with poorer survival of patients with ccRCC. IMPLICATIONS: The results of our study propose a novel tumor suppressive mechanism on the basis of coordinated expression of physically associated genes, providing a better understanding of the role of chromosomal deletions in cancer.

Targeted dry skin treatment using a multifunctional topical moisturizer.

OBJECTIVE: The development of dry skin is a complex process, with a wide variety of factors each playing different roles in its evolution. Given this, it is important when designing a formulation to tackle dry skin that these varied aspects of skin behaviour are addressed. Presented here are the results of a 3-week moisturization study carried out on dry legs. A wide range of traditional and more recently developed biophysical measurement methods have been combined with visual assessment of skin condition to enable multiple aspects of skin function to be determined. The observed changes in the skin are discussed in terms of the ingredients used in the moisturizing formulation. METHODS: A range of novel and traditional skin assessment methods and techniques were used to assess the effects of an oil in water-based moisturizing product compared to an untreated site during a 3-week in vivo study on dry lower leg skin. RESULTS: Statistically significant improvements were observed in a range of skin parameters as a result of product usage. Skin hydration assessed using Corneometer®, Epsilon® and visual dry skin grading all increased after 3 weeks of use. Skin barrier function measured using transepidermal water loss also improved. Levels of cholesterol, free fatty acids and Ceramide NH increased, as well as the average length of the stratum corneum (SC) lipid lamella bilayers, and the ratio of lipid to protein increased (measured using Lipbarvis® and in vivo Confocal Raman Spectroscopy). Increases in the levels of Ceramide EOS and NP were also observed, along with an improvement in corneocyte maturity, although these were not statistically significant. CONCLUSIONS: Using a variety of traditional and novel skin assessment techniques, a wide range of factors associated with the evolution of dry skin have been assessed upon treatment with a new topical moisturizer. Product usage resulted in significant improvements to skin hydration and barrier function, the levels and morphology of SC barrier lipids, and overall epidermal differentiation. As a result there was a significant reduction in the characteristics associated with the development of dry skin after use of the test product.

OBJECTIF: le développement de la sécheresse cutanée est un processus complexe, une grande variété de facteurs jouant chacun des rôles différents dans son évolution. De ce fait, il est important d'aborder ces différents aspects du comportement de la peau lors de la conception d'une formulation pour lutter contre la sécheresse cutanée. Les résultats d'une étude de 3 semaines sur l'hydratation des jambes sèches sont présentés ci-dessous. Un large éventail de méthodes de mesure biophysiques traditionnelles et plus récemment développées ont été combinées à une évaluation visuelle de l'état de la peau pour permettre de déterminer de multiples aspects de la fonction cutanée. Les changements observés sur la peau sont abordés en termes des ingrédients utilisés dans la formulation hydratante. MÉTHODES: une série de méthodes et de techniques nouvelles et traditionnelles d'évaluation de la peau ont été utilisées pour évaluer les effets d'un produit hydratant à base d'émulsion huile dans eau par comparaison à un site non traité au cours d'une étude in vivo de 3 semaines sur la peau sèche de la partie inférieure des jambes. RÉSULTATS: des améliorations statistiquement significatives ont été observées au niveau d'une gamme de paramètres cutanés suite à l'utilisation du produit. L'hydratation cutanée évaluée à l'aide de Corneometer®, Epsilon® et de la cotation visuelle de la sécheresse cutanée s'est améliorée selon toutes ces méthodes après 3 semaines d'utilisation. La fonction de barrière cutanée mesurée d'après la perte d'eau transépidermique s'est également améliorée. Les taux de cholestérol, d'acides gras libres et de céramides NH ont augmenté, ainsi que la longueur moyenne des bicouches des lamelles lipidiques de la couche cornée (CC), et il en a été de même pour le rapport lipide/protéine (mesuré à l'aide du Lipbarvis® et de la spectroscopie confocale de Raman in vivo). Des augmentations des taux de céramides EOS et NP ont également été observées, ainsi qu'une amélioration de la maturité des cornéocytes, bien qu'elles n'aient pas été statistiquement significatives. CONCLUSION: à l'aide d'une gamme de techniques d'évaluation de la peau traditionnelles et nouvelles, un large éventail de facteurs associés à l'évolution de la sécheresse cutanée a été évalué lors du traitement avec un nouveau produit hydratant topique. L'utilisation du produit a entraîné une amélioration significative de l'hydratation et de la fonction de barrière de la peau, des taux et de la morphologie des lipides de la barrière SC , et de la différenciation épidermique globale. Cela a entraîné une amélioration significative des facteurs associés au développement de la sécheresse cutanée.

Topical emollient therapy in the management of severe acute malnutrition in children under two: A randomized controlled clinical trial in Bangladesh.

BACKGROUND: Topical emollient therapy can improve neonatal health and growth and potentially provides an additional avenue for augmenting the provision of nutrition to children with severe acute malnutrition (SAM). We hypothesised that topical treatment of hospitalised children with SAM using sunflower seed oil (SSO), in addition to standard-of-care for SAM, would improve skin barrier function and weight gain, reduce risk of infection, and accelerate clinical recovery. METHODS: We conducted a randomised, two-arm, controlled, unblinded clinical trial in 212 subjects aged 2 to 24 months who were admitted for care of SAM at the 'Dhaka Hospital' of icddr,b during January 2016 to November 2017. Enrollment was age-stratified into 2 to <6 months and 6 to 24 months age groups in a 1:2 ratio. All children received SAM standard-of-care, and the SSO group was also treated with 3 g of SSO per kg body weight three times daily for 10 days. Primary outcome was rate of weight gain over the 10-day study period. Secondary endpoints included rate of nosocomial infection, time to recovery from acute illness, skin condition score, rate of transepidermal water loss (TEWL) and C-reactive protein (CRP) level. RESULTS: Rate of weight gain was higher in the SSO than the control group (adjusted mean difference, AMD = 0.90 g/kg/d, 95% confidence interval (CI) = -1.22 to 3.03 in the younger age stratum), but did not reach statistical significance. Nosocomial infection rate was significantly lower in the SSO group in the older age stratum (adjusted odds ratio (OR) = 0.41, 95% CI = 0.19 to 0.85; P = 0.017), but was comparable in the younger age stratum and overall. Skin condition score improved (AMD = -14.88, 95% CI = -24.12 to -5.65, P = 0.002) and TEWL was reduced overall (AMD = -2.59, 95% CI = -3.86 to -1.31, P < 0.001) in the SSO group. Reduction in CRP level was significantly greater in the SSO group (median: -0.28) than the control group (median 0.00) (P = 0.019) in the younger age stratum. CONCLUSIONS: Topical therapy with SSO was beneficial for children with SAM when applied as adjunctive therapy. A community-based trial with a longer intervention period is recommended to validate these results. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02616289.

A Preliminary Investigation of Additive Manufacture to Fabricate Human Nail Plate Surrogates for Pharmaceutical Testing.

In vitro permeation studies using nail clippings or nail plates are commonly used in the development of transungual formulations. However, there are ethical, safety and cost issues associated with sourcing such tissues. Herein, we describe a preliminary approach is described for the design and manufacture of a human nail model surrogate based on 3D printing. To evaluate these 3D printed constructs, nails were mounted in conventional glass Franz cells and a commercial antifungal lacquer formulation containing ciclopirox olamine was applied daily to the surrogate printed surfaces for a period of 14 days. On days 8 and 14, the surfaces of the 3D printed nails were washed with ethanol to remove excess formulation. Confocal Raman spectroscopy (CRS) was used to profile the drug in the 3D printed nail. At the end of the Franz cell studies, no drug was observed in the receptor phase. CRS studies confirmed penetration of the active into the model nails with reproducible depth profiles. Our ongoing work is focused on synthesising commercial and non-commercial printable resins that can replicate the physical and chemical characteristics of the human nail. This will allow further evaluation of actives for ungual therapy and advance the development of the surrogate nail tissue model.

Optimised detection of mitochondrial DNA strand breaks.

Intrinsic and extrinsic factors that induce cellular oxidative stress damage tissue integrity and promote ageing, resulting in accumulative strand breaks to the mitochondrial DNA (mtDNA) genome. Limited repair mechanisms and close proximity to superoxide generation make mtDNA a prominent biomarker of oxidative damage. Using human DNA we describe an optimised long-range qPCR methodology that sensitively detects mtDNA strand breaks relative to a suite of short mitochondrial and nuclear DNA housekeeping amplicons, which control for any variation in mtDNA copy number. An application is demonstrated by detecting 16-36-fold mtDNA damage in human skin cells induced by hydrogen peroxide and solar simulated radiation.

Spectrophotometry of Thin Films of Light-Absorbing Particles.

Thin films of dispersions of light-absorbing solid particles or emulsions containing a light-absorbing solute all have a nonuniform distribution of light-absorbing species throughout the sample volume. This results in nonuniform light absorption over the illuminated area, which causes the optical absorbance, as measured using a conventional specular UV-vis spectrophotometer, to deviate from the Beer-Lambert relationship. We have developed a theoretical model to account for the absorbance properties of such films, which are shown to depend on the size and volume fraction of the light-absorbing particles plus other sample variables. We have compared model predictions with measured spectra for samples consisting of emulsions containing a dissolved light-absorbing solute. Using no adjustable parameters, the model successfully predicts the behavior of nonuniform, light-absorbing emulsion films with varying values of droplet size, volume fraction, and other parameters.

In vitro permeation and disposition of niacinamide in silicone and porcine skin of skin barrier-mimetic formulations.

Niacinamide (NIA) is an amide form of vitamin B3 which is used in cosmetic formulations to improve various skin conditions and it has also been shown to increase stratum corneum thickness following repeated application. In this study, three doses (5, 20 and 50µL per cm2) of two NIA containing oil-in-water skin barrier-mimetic formulations were evaluated in silicone membrane and porcine ear skin and compared with a commercial control formulation. Permeation studies were conducted over 24h in Franz cells and at the end of the experiment membranes were washed and niacinamide was extracted. For the three doses, retention or deposition of NIA was generally higher in porcine skin compared with silicone membrane, consistent with the hydrophilic nature of the active. Despite the control containing a higher amount of active, comparable amounts of NIA were deposited in skin for all formulations for all doses; total skin absorption values (permeation and retention) of NIA were also comparable across all formulations. For infinite (50µL) and finite (5µL) doses the absolute permeation of NIA from the control formulation was significantly higher in porcine skin compared with both test formulations. This likely reflects differences in formulation components and/or presence of skin penetration enhancers in the formulations. Higher permeation for the 50 and 20µL dose was also evident in porcine skin compared with silicone membrane but the opposite is the case for the finite dose. The findings point to the critical importance of dose and occlusion when evaluating topical formulations in vitro and also the likelihood of exaggerated effects of excipients on permeation at infinite and pseudo-finite dose applications.

Evaluation of the ROS Inhibiting Activity and Mitochondrial Targeting of Phenolic Compounds in Fibroblast Cells Model System and Enhancement of Efficiency by Natural Deep Eutectic Solvent (NADES) Formulation.

PURPOSE: Many phenolics have already been tested for their antioxidant activities using in vitro methods. However, such assays do not consider the complexity of real cellular systems, and most of the phenolics characterized with such assays shows disappointing results when evaluated in cells. Accordingly, there is a need to develop effective screening methods. METHODS: Antioxidants were first evaluated by CAT assay and then, evaluated for their ability (i) to reduce the level of ROS using fluorescent probe, (ii) to cross fibroblast cell membranes using confocal microscopy, and (iii) to target mitochondria. Antioxidants were also formulated in NADES. RESULTS: Correlation was obtained when comparing CAT results with short term inhibition (2 h) in the fibroblast cells. On the contrary, it was difficult to anticipate ROS inhibiting efficiency at long term (24 h) from both the CAT assay and the short term inhibition measurements. Indeed, some molecules displayed activity rapidly but lost it over time. In contrast, other molecules were better for long term. The comparable efficiency at long term of Bis-Ethylhexyl Hydroxydimethoxy Benzylmalonate (Bis-EHBm) and decyl rosmarinate, prompted us to further investigate the potential mitochondrial targeting of the former. Using mitochondrial probes, our results confirmed its mitochondrial location. Finally, the formulation of antioxidants in NADES could greatly improve their activity. CONCLUSIONS: Combinations of fast acting and slow acting molecules could be promising strategies to identify a performant antioxidant system. Bis-EHBm behaves as decyl rosmarinate with a confirmed mitochondrial location. Finally, the formulation of antioxidants in NADES could greatly improve their activity for ROS inhibition.

Evaporation of Particle-Stabilized Emulsion Sunscreen Films.

We recently showed (Binks et al., ACS Appl. Mater. Interfaces, 2016, DOI: 10.1021/acsami.6b02696) how evaporation of sunscreen films consisting of solutions of molecular UV filters leads to loss of UV light absorption and derived sun protection factor (SPF). In the present work, we investigate evaporation-induced effects for sunscreen films consisting of particle-stabilized emulsions containing a dissolved UV filter. The emulsions contained either droplets of propylene glycol (PG) in squalane (SQ), droplets of SQ in PG or droplets of decane in PG. In these different emulsion types, the SQ is involatile and shows no evaporation, the PG is volatile and evaporates relatively slowly, whereas the decane is relatively very volatile and evaporates quickly. We have measured the film mass and area, optical micrographs of the film structure, and the UV absorbance spectra during evaporation. For emulsion films containing the involatile SQ, evaporation of the PG causes collapse of the emulsion structure with some loss of specular UV absorbance due to light scattering. However, for these emulsions with droplets much larger than the wavelength of light, the light is scattered only at small forward angles so does not contribute to the diffuse absorbance and the film SPF. The UV filter remains soluble throughout the evaporation and thus the UV absorption by the filter and the SPF remain approximately constant. Both PG-in-SQ and SQ-in-PG films behave similarly and do not show area shrinkage by dewetting. In contrast, the decane-in-PG film shows rapid evaporative loss of the decane, followed by slower loss of the PG resulting in precipitation of the UV filter and film area shrinkage by dewetting which cause the UV absorbance and derived SPF to decrease. Measured UV spectra during evaporation are in reasonable agreement with spectra calculated using models discussed here.

Loss of Chromosome 8p Governs Tumor Progression and Drug Response by Altering Lipid Metabolism.

Large-scale heterozygous deletions are a hallmark of cancer genomes. The concomitant loss of multiple genes creates vulnerabilities that are impossible to reveal through the study of individual genes. To delineate the functional outcome of chromosome 8p loss of heterozygosity (LOH), a common aberration in breast cancer, we modeled 8p LOH using TALEN-based genomic engineering. 8p LOH alters fatty acid and ceramide metabolism. The shift in lipid metabolism triggers invasiveness and confers tumor growth under stress conditions due to increased autophagy. The resistance of 8p-deleted cells to chemotherapeutic drugs concurs with poorer survival rates of breast cancer patients harboring an 8p LOH. The autophagy dependency of 8p-deleted cells provides the rational basis for treatment of 8p LOH tumors with autophagy inhibitors.

Evaporation of Sunscreen Films: How the UV Protection Properties Change.

We have investigated the evaporation of thin sunscreen films and how the light absorption and the derived sun protection factor (SPF) change. For films consisting of solutions of common UV filters in propylene glycol (PG) as solvent, we show how evaporation generally causes three effects. First, the film area can decrease by dewetting leading to a transient increase in the average film thickness. Second, the film thins by evaporative loss of the solvent. Third, precipitation of the UV filter occurs when solvent loss causes the solubility limit to be reached. These evaporation-induced changes cause the UV absorbance of the film to decrease with resultant loss of SPF over the time scale of the evaporation. We derive an approximate model which accounts semiquantitatively for the variation of SPF with evaporation. Experimental results for solutions of different UV filters on quartz, different skin mimicking substrates, films with added nanoparticles, films with an added polymer and films with fast-evaporating decane as solvent (instead of slow evaporating PG) are discussed and compared with model calculations. Addition of either nanoparticles or polymer suppress film dewetting. Overall, it is hoped that the understanding gained about the mechanisms whereby film evaporation affects the SPF will provide useful guidance for the formulation of more effective sunscreens.

OTUB1 triggers lung cancer development by inhibiting RAS monoubiquitination.

Activation of the RAS oncogenic pathway, frequently ensuing from mutations in RAS genes, is a common event in human cancer. Recent reports demonstrate that reversible ubiquitination of RAS GTPases dramatically affects their activity, suggesting that enzymes involved in regulating RAS ubiquitination may contribute to malignant transformation. Here, we identified the de-ubiquitinase OTUB1 as a negative regulator of RAS mono- and di-ubiquitination. OTUB1 inhibits RAS ubiquitination independently of its catalytic activity resulting in sequestration of RAS on the plasma membrane. OTUB1 promotes RAS activation and tumorigenesis in wild-type RAS cells. An increase of OTUB1 expression is commonly observed in non-small-cell lung carcinomas harboring wild-type KRAS and is associated with increased levels of ERK1/2 phosphorylation, high Ki67 score, and poorer patient survival. Our results strongly indicate that dysregulation of RAS ubiquitination represents an alternative mechanism of RAS activation during lung cancer development.

Bacterial biofilm development on hydroxyapatite-coated glass.

Glass plates are frequently used as the substratum in flow cell experiments to allow continuous non-destructive observations of biofilm development via microscopy. The aim of this study was to evaluate hydroxyapatite-coated glass as a substratum for flow cell experiments, in comparison to plain glass, for modelling primary colonization of the tooth surface by Streptococcus sanguis. Glass plates were magnetron sputter coated with hydroxyapatite, producing a thin transparent layer. Biofilm development in the flow cell was recorded using image capture from a microscope, and images were analyzed to determine percentage coverage of the substratum over 24 h. Removal of biofilm by increasing the flow rate was also assessed. No statistically significant differences were detected between S. sanguis biofilms grown on the two different substratum materials. Hence, this work supports the proposal that the conditioning film reduces the influence of substratum surface properties.