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Intrinsic and acquired resistance to mitogen-activated protein kinase inhibitors (MAPKi) in melanoma remains a major therapeutic challenge. Here, we show that the clinical development of resistance to MAPKi is associated with reduced tumor expression of the melanoma suppressor Autophagy and Beclin 1 Regulator 1 (AMBRA1) and that lower expression levels of AMBRA1 predict a poor response to MAPKi treatment. Functional analyses show that loss of AMBRA1 induces phenotype switching and orchestrates an extracellular signal-regulated kinase (ERK)-independent resistance mechanism by activating focal adhesion kinase 1 (FAK1). In both in vitro and in vivo settings, melanomas with low AMBRA1 expression exhibit intrinsic resistance to MAPKi therapy but higher sensitivity to FAK1 inhibition. Finally, we show that the rapid development of resistance in initially MAPKi-sensitive melanomas can be attributed to preexisting subclones characterized by low AMBRA1 expression and that cotreatment with MAPKi and FAK1 inhibitors (FAKi) effectively prevents the development of resistance in these tumors. In summary, our findings underscore the value of AMBRA1 expression for predicting melanoma response to MAPKi and supporting the therapeutic efficacy of FAKi to overcome MAPKi-induced resistance. [ABSTRACT FROM AUTHOR]

Brazilian green propolis is a well-known product that is consumed globally. Its major component, Artepillin C, showed potential as an antitumor product. This study explored the impact of Artepillin C on fibroblast and glioblastoma cell lines, used as healthy and very aggressive tumor cell lines, respectively. The focus of the study was to evaluate the pH-dependence of Artepillin C cytotoxicity, since tumor cells are known to have a more acidic extracellular microenvironment compared to healthy cells, and Artepillin C was shown to become more lipophilic at lower pH values. Investigations into the pH-dependency of Artepillin C (6.0–7.4), through viability assays and live cell imaging, revealed compelling insights. At pH 6.0, MTT assays showed the pronounced cytotoxic effects of Artepillin C, yielding a notable reduction in cell viability to less than 12% among glioblastoma cells following a 24 h exposure to 100 µM of Artepillin C. Concurrently, LDH assays indicated significant membrane damage, affecting approximately 50% of the total cells under the same conditions. Our Laurdan GP analysis suggests that Artepillin C induces autophagy, and notably, provokes a lipid membrane packing effect, contributing to cell death. These combined results affirm the selective cytotoxicity of Artepillin C within the acidic tumor microenvironment, emphasizing its potential as an effective antitumor agent. Furthermore, our findings suggest that Artepillin C holds promise for potential applications in the realm of anticancer therapies given its pH-dependence cytotoxicity. [ABSTRACT FROM AUTHOR]

Hepatic lipid metabolism is highly dynamic, and disruption of several circadian transcriptional regulators results in hepatic steatosis. This includes genetic disruption of the glucocorticoid receptor (GR) as the liver develops. To address the functional role of GR in the adult liver, we used an acute hepatocyte-specific GR knockout model to study temporal hepatic lipid metabolism governed by GR at several preprandial and postprandial circadian timepoints. Lipidomics analysis revealed significant temporal lipid metabolism, where GR disruption results in impaired regulation of specific triglycerides, nonesterified fatty acids, and sphingolipids. This correlates with increased number and size of lipid droplets and mildly reduced mitochondrial respiration, most noticeably in the postprandial phase. Proteomics and transcriptomics analyses suggest that dysregulated lipid metabolism originates from pronounced induced expression of enzymes involved in fatty acid synthesis, β-oxidation, and sphingolipid metabolism. Integration of GR cistromic data suggests that induced gene expression is a result of regulatory actions secondary to direct GR effects on gene transcription. [ABSTRACT FROM AUTHOR]

Cellular engulfment and uptake of macromolecular assemblies or nanoparticles via endocytosis can be associated to both healthy and disease-related biological processes as well as delivery of drug nanoparticles and potential nanotoxicity of pollutants. Depending on the physical and chemical properties of the system, the adsorbed particles may remain at the membrane surface, become wrapped by the membrane, or translocate across the membrane through an endocytosis-like process. In this paper, we address the question of how the wrapping of colloidal particles by lipid membranes can be controlled by the shape of the particles, the particle–membrane adhesion energy, the membrane phase behavior, and the membrane-bending rigidity. We use a model system composed of soft core–shell microgel particles with spherical and ellipsoidal shapes, together with phospholipid membranes with varying composition. Confocal microscopy data clearly demonstrate how tuning of these basic properties of particles and membranes can be used to direct wrapping and membrane deformation and the organization of the particles at the membrane. The deep-wrapped states are more favorable for ellipsoidal than for spherical microgel particles of similar volume. Theoretical calculations for fixed adhesion strength predict the opposite behavior— wrapping becomes more difficult with increasing aspect ratio. The comparison with the experiments implies that the microgel adhesion strength must increase with increasing particle stretching. Considering the versatility offered by microgels systems to be synthesized with different shapes, functionalizations, and mechanical properties, the present findings further inspire future studies involving nanoparticle–membrane interactions relevant for the design of novel biomaterials and therapeutic applications. [ABSTRACT FROM AUTHOR]

Chemical fine‐tuning of fluorophores is a pivotal step towards development of next generation fluorescent dyes for microscopy. With the advent of high‐resolution two‐photon excitation fluorescence imaging, there is a growing demand for very sensitive laser dyes that can be efficiently excited using commercial Ti:sapphire laser sources in the first near‐infrared window (NIR‐I, 780–1020 nm). Using the fluorescent dye Nile Red as the lead structure, we report a robust and concise Suzuki coupling approach for the synthesis of 14 new Nile Red analogues that feature extended π ring systems and diverse functionalities. For this set, we gauged their two‐photon excitation efficiency in NIR‐I as well as evaluated their general fluorescent properties (emission wavelength, Stokes shift, quantum yield and solvatochromism). Several of the new fluorophores were found to display very favorable characteristics. In particular, the derivative featuring a 4‐aminophenyl group in the 2‐position of Nile Red exhibited extreme solvent sensitivity, and the thien‐2‐yl substituted Nile Red derivative showed significantly redshifted emission, large Stokes shift and high two‐photon brightness. [ABSTRACT FROM AUTHOR]

Focused ion beams have recently emerged as a powerful tool for ultrastructural imaging of biological samples. In this article, we show that helium ion microscopy (HIM), in combination with ion milling, can be used to visualize the inner structure of both major and minor ampullate silk fibers of the orb-web weaving spider Nephila madagascariensis. The internal nanofibrils were imaged in pristine silk fibers, with little or no damage to the sample structure observed. Furthermore, a method to cut/rupture the fibers using He+ ions combined with internal sample tension is presented. This showed that the stretching and rupturing of spider silk is a highly dynamic process with considerable material reorganization. [ABSTRACT FROM AUTHOR]

Introduction: Regional anesthesia has long been used in a perioperative setting for the treatment of both pre- and postoperative pain. Recently, this skill has been brought into the emergency department (ED) as a modality for treating acute pain as the pendulum shifts away from an opioid-based armamentarium and toward a multimodal future. In this case series, we describe a way to use the pectoralis nerve block I and II in the treatment of pain with regard to breast abscesses and/or breast cellulitis managed in the ED. Case Series: This paper describes three cases, all of which consist of a painful complaint in the thoracic region. The first was a patient diagnosed with a breast abscess. The second patient was diagnosed with breast cellulitis. Finally, the third patient was diagnosed with a large breast abscess that extended into the axilla. All three sustained immense relief with the pectoralis block. Conclusion: While further research is needed on a larger scale, preliminary data suggests that the ultrasound-guided pectoralis nerve block is an effective and safe modality of acute pain control in regard to breast and axillary abscesses along with breast cellulitis. [Clin Pract Cases Emerg Med. [ABSTRACT FROM AUTHOR]

In this work using Coherent anti‐Stokes Raman Scattering microscopy, it was possible to directly measure the time dependent, spatially resolved change in concentration of water (D2O) in intact skin tissue with a spatial resolution of under 1 μm, and combined with a multilayer diffusion model, diffusion coefficients at different depths in the tissue were extracted. The results show that the diffusion varies at different layers throughout the Stratum Corneum (SC), indicating that the SC is not a homogeneous barrier but a complicated heterogeneous structure. Interestingly, averaging over the diffusion at the different depths and samples gave a relatively constant value of 0.047 ± 0.01 μm2/second. Treating the skin with acetone or tape stripping led to an increased diffusion coefficient of 0.064 ± 0.02 μm2/second and 0.079 ± 0.03 μm2/second, respectively. The combined method and model presented here shows potential for wide applications for measuring spatially resolved diffusion of different substances in a variety of different samples. [ABSTRACT FROM AUTHOR]

A variety of human skin models have been developed for applications in regenerative medicine and efficacy studies. Typically, these employ matrix molecules that are derived from non‐human sources along with human cells. Key limitations of such models include a lack of cellular and tissue microenvironment that is representative of human physiology for efficacy studies, as well as the potential for adverse immune responses to animal products for regenerative medicine applications. The use of recombinant extracellular matrix proteins to fabricate tissues can overcome these limitations. We evaluated animal‐ and non‐animal‐derived scaffold proteins and glycosaminoglycans for the design of biomaterials for skin reconstruction in vitro. Screening of proteins from the dermal‐epidermal junction (collagen IV, laminin 5, and fibronectin) demonstrated that certain protein combinations when used as substrates increase the proliferation and migration of keratinocytes compared to the control (no protein). In the investigation of the effect of components from the dermal layer (collagen types I and III, elastin, hyaluronic acid, and dermatan sulfate), the primary influence on the viability of fibroblasts was attributed to the source of type I collagen (rat tail, human, or bovine) used as scaffold. Furthermore, incorporation of dermatan sulfate in the dermal layer led to a reduction in the contraction of tissues compared to the control where the dermal scaffold was composed primarily of collagen type I. This work highlights the influence of the composition of biomaterials on the development of complex reconstructed skin models that are suitable for clinical translation and in vitro safety assessment. [ABSTRACT FROM AUTHOR]

Background: While sunbathing of performing outdoor sport activities, sunscreens are important for protection of uncovered skin against ultraviolet (UV) radiation. However, perspiration negatively affects the performance of a sunscreen film by weakening its substantivity and uniformity through the activation of two mechanisms, namely sunscreen wash‐off and sunscreen redistribution. Material and methods: We used a perspiring skin simulator to investigate the effect of sunscreen formulation on its efficiency upon sweating. Specifically, we modified the sunscreen formulation by incorporating a hydrophobic film former and adding water‐absorbing particles. Sunscreen performance before and after perspiration is assessed by in vitro sun protection factor measurements, direct detection of changes in the sunscreen distribution using UV reflectance imaging, and by coherent anti‐Stokes Raman scattering (CARS) microscopy for microscopic characterization of the UV filter relocation. Results: The results show that incorporating a hydrophobic film former can decrease sunscreen wash‐off due to sweating, while an excessive amount of film former might negatively affect the sunscreen distribution. The addition of water‐absorbing particles, on the other hand, had either a negative or positive impact on the sunscreen substantivity, depending on the particle properties. While the addition of large water‐absorbing particles appeared to increase sunscreen redistribution, smaller particles that could form a gel‐like structure upon contact with water, appeared to change sunscreen wetting and sweat droplet spreading, thereby decreasing sunscreen wash‐off and sunscreen redistribution. Conclusions: We find that using a combination of hydrophobic film formers, which increase water resistance, and small water‐absorbing particles, which change the wetting behavior, can make sunscreen formulations more sweat‐resistant and less runny. [ABSTRACT FROM AUTHOR]

Point of care ultrasound (POCUS) allows for rapid, real-time evaluation of cardiovascular and respiratory pathology. The advent of portable, handheld devices and increased recognition by accrediting bodies of the importance of POCUS in guiding clinical decision making has expanded its use across the hospital setting and within medical training programs. POCUS allows clinicians to begin immediate investigation into their differential diagnoses without waiting for a formal imaging study, enhancing the speed of clinical interpretation. In addition to its diagnostic utility, POCUS can also inform clinicians of patients' response to interventions when serial exams are obtained. This review examines the role of POCUS in the context of frequently encountered patients and highlights the key clinical questions that can be readily answered by POCUS. [ABSTRACT FROM AUTHOR]

This document is a response to clarifications on the nomenclature and applications of regional anesthesia techniques for pectoralis blocks. The authors of the response address the use of terms "Pecs I and Pecs II" in their study, explaining that they chose to use these terms for simplicity and because they are commonly used by anesthesiologists. They also acknowledge the importance of using more descriptive nomenclature in the future. The authors agree that careful attention must be paid to the sensory coverage of each block and recognize the limitations of their case series. They mention a contraindication to the block in the presence of infection and discuss the potential of a modified block called "Pecs Zero." The authors also compare the pectoralis block to the erector spinae plane block and highlight the goal of introducing a novel technique for acute pain control in the emergency department. They express gratitude for the contribution and healthy discussion from the author of the original letter and emphasize the importance of continued research and application in emergency medicine. [Extracted from the article]

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