The Acute and Short-Term Inhalation of Carbon Nanofiber in Sprague-Dawley Rats.

The inhalation toxicity of carbon nanofibers (CNFs) is not clearly known due to relatively few related studies reported. An acute inhalation study and short-term inhalation study (5 days) were therefore conducted using Sprague-Dawley rats. In the acute inhalation study, the rats were grouped and exposed to a fresh air control or to low (0.238 ± 0.197), moderate (1.935 ± 0.159), or high (24.696 ± 6.336 mg/m3) CNF concentrations for 6 h and thereafter sacrificed at 14 days. For the short-term inhalation study, the rats were grouped and exposed to a fresh air control or low (0.593 ± 0.019), moderate (2.487 ± 0.213), or high (10.345 ± 0.541 mg/m3) CNF concentrations for 6 h/day for 5 days and sacrificed at 1, 3, and 21 days post-exposure. No mortality was observed in the acute inhalation study. Thus, the CNF LC50 was higher than 25 mg/m3. No significant body or organ weight changes were noted during the 5 days short-term inhalation study or during the post-exposure period. No significant effects of toxicological importance were observed in the hematological, blood biochemical, and coagulation tests. In addition, the bronchoalveolar lavage (BAL) fluid cell differential counts and BAL inflammatory markers showed no CNF-exposure-relevant changes. The histopathological examination also found no CNF-exposure-relevant histopathological lesions. Thus, neither acute nor 5 days inhalation exposure to CNFs induced any noticeable toxicological responses.

Single-cell analysis of human basal cell carcinoma reveals novel regulators of tumor growth and the tumor microenvironment.

How basal cell carcinoma (BCC) interacts with its tumor microenvironment to promote growth is unclear. We use singe-cell RNA sequencing to define the human BCC ecosystem and discriminate between normal and malignant epithelial cells. We identify spatial biomarkers of tumors and their surrounding stroma that reinforce the heterogeneity of each tissue type. Combining pseudotime, RNA velocity-PAGA, cellular entropy, and regulon analysis in stromal cells reveals a cancer-specific rewiring of fibroblasts, where STAT1, TGF-ß, and inflammatory signals induce a noncanonical WNT5A program that maintains the stromal inflammatory state. Cell-cell communication modeling suggests that tumors respond to the sudden burst of fibroblast-specific inflammatory signaling pathways by producing heat shock proteins, whose expression we validated in situ. Last, dose-dependent treatment with an HSP70 inhibitor suppresses in vitro vismodegib-resistant BCC cell growth, Hedgehog signaling, and in vivo tumor growth in a BCC mouse model, validating HSP70's essential role in tumor growth and reinforcing the critical nature of tumor microenvironment cross-talk in BCC progression.

Transcriptomic Repositioning Analysis Identifies mTOR Inhibitor as Potential Therapy for Epidermolysis Bullosa Simplex.

Expression-based systematic drug repositioning has been explored to predict novel treatments for a number of skin disorders. In this study, we utilize this approach to identify, to our knowledge, previously unreported therapies for epidermolysis bullosa simplex (EBS). RNA sequencing analysis was performed on skin biopsies of acute blisters (<1 week old) (n = 9) and nonblistered epidermis (n = 11) obtained from 11 patients with EBS. Transcriptomic analysis of blistered epidermis in patients with EBS revealed a set of 1,276 genes dysregulated in EBS blisters. The IL-6, IL-8, and IL-10 pathways were upregulated in the epidermis from EBS. Consistent with this, predicted upstream regulators included TNF-α, IL-1ß, IL-2, IL-6, phosphatidylinositol 3-kinase, and mTOR. The 1,276 gene EBS blister signature was integrated with molecular signatures from cell lines treated with 2,423 drugs using the Connectivity Map CLUE platform. The mTOR inhibitors and phosphatidylinositol 3-kinase inhibitors most opposed the EBS signature. To determine whether mTOR inhibitors could be used clinically in EBS, we conducted an independent pilot study of two patients with EBS treated with topical sirolimus for painful plantar keratoderma due to chronic blistering. Both individuals experienced marked clinical improvement and a notable reduction of keratoderma. In summary, a computational drug repositioning analysis successfully identified, to our knowledge, previously unreported targets in the treatment of EBS.

The Sunscreen for Kindergarteners (SKIN) Study trial protocol.

BACKGROUND: Exposure to ultraviolet radiation (UVR) is the major modifiable risk factor for skin cancers. The majority of lifetime UVR exposure occurs before age 20, underscoring an important window for risk reduction. Incorporation of skills-based sunscreen education into school health curricula may foster the development of consistent and effective use of sunscreen among children and youth. We describe the study protocol for a first-of-its-kind study that examined the feasibility of bringing skills-based sunscreen education into kindergarten classrooms. METHODS: Participants were 96 kindergarten students across four classrooms in a single elementary school. A single-blind open-label trial design was used to evaluate the feasibility of incorporating a song-based, video-guided intervention for independent application of sunscreen into the kindergarten curriculum. Students first completed a 10-day no-intervention baseline period, followed by a 10-day intervention period, and then a 10-day randomized follow-up period where students were randomly assigned to continue with the intervention or to revert to the no-intervention condition. OUTCOMES: Feasibility metrics associated with study process, resources, management, scientific outcomes and safety were gathered. The primary outcome was pre-to-post intervention changes in student engagement in the sunscreen task. The secondary outcome was pre-to-post intervention changes in the proportion of exposed skin to which a student applies sunscreen. Teacher and student perceptions of intervention value and utility were also evaluated. DISCUSSION: This is the study protocol for a clinical trial designed to determine the feasibility of implementing a skills-based sunscreen curriculum in kindergarten classrooms. Next steps include evaluation of the intervention for efficacy and effectiveness. CLINICAL TRIAL REGISTRATION: NCT03752736.

Using Visual Arts Education in Dermatology to Benefit Resident Wellness and Clinical Communication.

Introduction: Art education interventions improve observation skills among dermatology residents, but there is limited data regarding their benefits to wellness and clinical communication. Methods: Residents in the Stanford dermatology residency program participated in an arts-based education session, repeated in the fall of 2018 and 2019, that included a rotation of observational exercises adapted from the Artful Thinking program through Harvard Project Zero. The 2018 session featured exercises on identification and understanding of visual observation, while the 2019 session featured exercises on perspectives and objectivity of visual observation. Participants completed preintervention, postintervention, and 3-month follow-up surveys in fall 2018 and a postintervention survey in fall 2019. Results: Twenty-one residents participated in the 2018 education session and produced an adequate response rate (62%-90%) across surveys. At 3 months, five of 13 residents (39%) reported new use of art for mindfulness and stress reduction, 12 of 13 (92%) could recall an example of use of observation to improve patient communication, and four of 13 (31%) confirmed and described adjustments to their handoff technique. In 2019, 13 out of 18 participants (72%) completed the postintervention survey. Responses reinforced themes from the prior iteration but focused on perspective, objectivity, context, and uncertainty in observations. Respondents also identified additional arenas of communication to benefit from these observational techniques. Discussion: Dermatology residents increased use of art for personal wellness and adjusted clinical communication strategies after a single arts-based education session. Annual repetition with novel exercises maintained engagement and yielded additional participant insights.

Highly efficient oxygen evolution reaction via facile bubble transport realized by three-dimensionally stack-printed catalysts.

Despite highly promising characteristics of three-dimensionally (3D) nanostructured catalysts for the oxygen evolution reaction (OER) in polymer electrolyte membrane water electrolyzers (PEMWEs), universal design rules for maximizing their performance have not been explored. Here we show that woodpile (WP)-structured Ir, consisting of 3D-printed, highly-ordered Ir nanowire building blocks, improve OER mass activity markedly. The WP structure secures the electrochemically active surface area (ECSA) through enhanced utilization efficiency of the extended surface area of 3D WP catalysts. Moreover, systematic control of the 3D geometry combined with theoretical calculations and various electrochemical analyses reveals that facile transport of evolved O2 gas bubbles is an important contributor to the improved ECSA-specific activity. The 3D nanostructuring-based improvement of ECSA and ECSA-specific activity enables our well-controlled geometry to afford a 30-fold higher mass activity of the OER catalyst when used in a single-cell PEMWE than conventional nanoparticle-based catalysts.

Simulation and Fabrication of Nanoscale Spirals Based on Dual-Scale Self-Assemblies.

Archimedean spirals in nanometer scale have shown remarkable plasmonic responses derived from their linear and rotational asymmetry. Despite the unique optical properties of nanoscale spirals, their applications have been limited due to the difficulty in fabricating large-scale arrays with uniform and systematic control of the morphology. Here, we report simulation results of spiral morphologies, which are used to design a scalable fabrication process for nanoscale spirals and predict their plasmonic responses. First, self-consistent field theory (SCFT) simulations were performed to design optimal templates to guide self-assembly into spiral morphologies. Using the SCFT results, we developed a scalable fabrication process, which is based on the micron-scale assembly of microspheres combined with glancing angle deposition and nanoscale assembly of block copolymers, to induce the formation of uniform nanospirals with diverse size, handedness, orientation, and winding number. Finally, finite-difference time-domain simulation results show linear dichroism and electric field intensity enhancement effects of these nanospirals, which are highly dependent on the winding number of the spirals, indicating the importance of precise control of the structural parameters.

Genetic disease and intellectual disability as contraindications to transplant listing in the United States: A survey of heart, kidney, liver, and lung transplant programs.

Discrimination based on disability is prohibited in organ transplantation, yet studies suggest it continues in listing practices for intellectual disability and genetic diseases. It is not known if this differs between adult and pediatric programs, or by organ type. We performed an online, forced-choice survey of psychosocial listing criteria for adult and pediatric heart, kidney, liver, and lung transplant programs in the United States. Of 650 programs contacted, 343 (52.8%) submitted complete. A minority of programs had formal listing guidelines for any condition considered (Down Syndrome, Duchenne Muscular Dystrophy, Becker Muscular Dystrophy, DiGeorge Syndrome, and Wolf Hirschhorn Syndrome; and mild [IQ < 70] and severe [IQ < 35] intellectual disability), although a majority had encountered most. Pediatric programs were significantly (P < .02) more lenient in the level of contraindication to listing for all genetic conditions considered except Duchenne Muscular Dystrophy, and for mild and severe intellectual disability. Level of contraindication differed significantly by organ type (heart, lung, liver, and kidney) for Duchenne Muscular dystrophy (P = <.001), Becker Muscular Dystrophy (P < .001), DiGeorge Syndrome (P < .001), Wolf-Hirschhorn syndrome (P = .0012), and severe intellectual disability (P < .001). There is significant variation among transplant programs in availability of guidelines for as well as listing practices regarding genetic diseases and intellectual disability, differing by both adult vs pediatric program, and organ type. Programs with absolute contraindications to listing for specific genetic diseases or intellectual disability should reframe their approach, ensuring individualized assessments and avoiding elimination of patients based on membership in a particular group.

Fluorescent Polymer-MoS2-Embedded Microgels for Photothermal Heating and Colorimetric Monitoring.

Photothermal heating with accurate monitoring of local temperature in complex biological fluids is crucial for therapeutic accuracy. Herein, photothermal microgels are developed to heat microscopic volumes through photothermal conversion and report the local temperature with a colorimetric response. The microgels consist of poly(ethylene glycol)-based hydrogels, which integrate temperature-responsive block-copolymer-grafted MoS2 nanosheets (BCP-grafted MoS2 NSs). The MoS2 NSs are used as a fluorescence quencher as well as an efficient photothermal agent, with their surface decorated with three distinct temperature-responsive BCPs containing blue-, green-, and red-fluorescent dyes. Upon irradiation of near-infrared light, MoS2 NSs convert the radiation into heat, and the BCPs change their conformation depending on the local temperature, selectively activating Förster resonance energy transfer of the three dyes. The use of three distinct BCPs and dyes enables the measurement of temperature in a wide range (i.e., from 25 to 50 °C). Importantly, the hydrogel matrix excludes molecules larger than the limiting mesh size so that BCP-grafted MoS2 NSs remain free from contamination against large adhesive proteins such as albumin, thus maintaining their sensitivity even in complex fluids.

Brn3a/Pou4f1 Functions as a Tumor Suppressor by Targeting c-MET/STAT3 Signaling in Thyroid Cancer.

BACKGROUND: Brn3a/Pou4f1 is a class IV POU domain-containing transcription factor and has been found to be expressed in a variety of cancers. However, the mechanism and action of Brn3a in thyroid cancer has not been investigated. PURPOSE: To investigate the role of Brn3a in thyroid cancer progression and its clinical implication. METHODS: We examined Brn3a expression status in patients with thyroid cancer and analyzed relationships between Brn3a expression and clinicopathological findings using The Cancer Genome Atlas (TCGA) database. For functional in vitro analysis, proliferation, migration, invasion assay, and Western blotting were performed after overexpression or suppression of Brn3a. RESULTS: The promoter hypermethylation of Brn3a was found in patients with aggressive thyroid cancer and Brn3a was downregulated in tissues of patients with thyroid cancer. In TCGA database, the low-Brn3a-expression group revealed a more aggressive phenotype, including T stage and extrathyroid extension when compared with the high-Brn3a-expression group. Overexpression of Brn3a suppressed cell migration and invasion via regulation of epithelial-mesenchymal transition (EMT)-associated proteins in thyroid cancer cell lines. Brn3a overexpression also downregulated signal transducer and activator of transcription 3 (STAT3) signaling through suppression of tyrosine-protein kinase Met (c-MET). In contrast, knockdown of Brn3a by small interfering ribonucleic acid (siRNA) significantly increased cell migration and invasion through upregulation of c-MET/STAT3. These results imply that Brn3a suppresses tumor metastasis via c-MET/STAT3 inhibition and EMT suppression in thyroid cancer. CONCLUSIONS: Our findings show that Brn3a is a potential tumor suppressor that leads to reduced cancer cell migration and invasion in thyroid cancer. Elucidation of the Brn3a-regulated cancer pathways may therefore provide novel therapeutic strategies to control thyroid cancer metastasis.

Interfacial Assembly of Amphiphilic Tiles for Reconfigurable Photonic Surfaces.

Nature has created photonic structures in cells and assembled them to make photonic layers for a living. Inspired from nature, we design amphiphilic photonic tiles and assemble them at air-water interface to compose highly reconfigurable photonic layers. The photonic tiles are prepared by photolithographically defining the shape of the disc using a photocurable dispersion of repulsive particles. The tiles are further treated by directional dry etching to selectively render top and side surfaces of the discs hydrophobic. The amphiphilic photonic tiles deform the air-water interface by gravity, which causes a strong attractive force driven by capillarity. Therefore, the tiles form two-dimensional (2D) dense-packing, which rapidly adapts dynamic fluctuation and shape change of the interface, providing highly reconfigurable photonic layers. In addition, the assembly can be transferred into target solid surfaces through the Langmuir-Blodgett method to make photonic coatings. Moreover, the amphiphilic tiles can be assembled on the surface of water drops, forming a photonic shell on liquid marbles which resembles photonic structures in nature. We believe that our strategy based on a 2D tile assembly at the free interface will provide a simple yet useful means to create photonic layers on various purposes.

Medical Contraindications to Transplant Listing in the USA: A Survey of Adult and Pediatric Heart, Kidney, Liver, and Lung Programs.

INTRODUCTION: Listing practices for solid organ transplantation are variable across programs in the USA. To better characterize this variability, we performed a survey of psychosocial listing criteria for pediatric and adult heart, lung, liver, and kidney programs in the USA. In this manuscript, we report our results regarding listing practices with respect to obesity, advanced age, and HIV seropositivity. METHODS: We performed an online, forced-choice survey of adult and pediatric heart, kidney, liver, and lung transplant programs in the USA. RESULTS: Of 650 programs contacted, 343 submitted complete responses (response rate = 52.8%). Most programs have absolute contraindications to listing for BMI > 45 (adult: 67.5%; pediatric: 88.0%) and age > 80 (adult: 55.4%; pediatric: not relevant). Only 29.5% of adult programs and 25.7% of pediatric programs consider HIV seropositivity an absolute contraindication to listing. We found that there is variation in absolute contraindications to listing in adult programs among organ types for BMI > 45 (heart 89.8%, lung 92.3%, liver 49.1%, kidney 71.9%), age > 80 (heart 83.7%, lung 76.9%, liver 68.4%, kidney 29.2%), and HIV seropositivity (heart 30.6%, lung 59.0%, kidney 16.9%, liver 28.1%). CONCLUSIONS: We argue that variability in listing enhances access to transplantation for potential recipients who have the ability to pursue workup at different centers by allowing different programs to have different risk thresholds. Programs should remain independent in listing practices, but because these practices differ, we recommend transparency in listing policies and informing patients of reasons for listing denial and alternative opportunities to seek listing at another program.

Photonic Microcapsules Containing Single-Crystal Colloidal Arrays with Optical Anisotropy.

Colloidal particles with a repulsive interparticle potential spontaneously form crystalline lattices, which are used as a motif for photonic materials. It is difficult to predict the crystal arrangement in spherical volume as lattices are incompatible with a spherical surface. Here, the optimum arrangement of charged colloids is experimentally investigated by encapsulating them in double-emulsion drops. Under conditions of strong interparticle repulsion, the colloidal crystal rapidly grows from the surface toward the center of the microcapsule, forming an onion-like arrangement. By contrast, for weak repulsion, crystallites slowly grow and fuse through rearrangement to form a single-crystal phase. Single-crystal structure is energetically favorable even for strong repulsion. Nevertheless, a high energy barrier to colloidal rearrangement kinetically arrests the onion-like structure formed by heterogeneous nucleation. Unlike the isotropic onion-shaped product, the anisotropic single-crystal-containing microcapsules selectively display-at certain orientations but not others-one of the distinct colors from the various crystal planes.

Structural Coloration with Nonclose-Packed Array of Bidisperse Colloidal Particles.

Colloidal crystals and glasses have their own photonic effects. Colloidal crystals show high reflectivity at narrowband, whereas colloidal glasses show low reflectivity at broadband. To compromise the opposite optical properties, a simple means is suggested to control the colloidal arrangement between crystal and glass by employing two different sizes of silica particles with repulsive interparticle potential. Monodisperse silica particles with repulsive potential spontaneously form crystalline structure at volume fraction far below 0.74. When two different sizes of silica particles coexist, the arrangement of silica particles is significantly influenced by two parameters: size contrast and mixing ratio. When the size contrast is small, a long-range order is partially conserved in the entire mixing ratio, resulting in a pronounced reflectance peak and brilliant structural color. When the size contrast is large, the long-range order is rapidly reduced along with mixing ratio. Nevertheless, a short-range order survives, which causes low reflectivity at a broad wavelength, developing faint structural colors. These findings offer an insight into controlling the colloidal arrangements and provide a simple way to tune the optical property of colloidal arrays for structural coloration.

Evidence-based, Skin-directed Treatments for Cutaneous Chronic Graft-versus-host Disease.

Chronic graft-versus host disease (cGVHD) occurs in 30% to 70% of patients undergoing allogeneic hematopoietic cell transplantation (HCT). Cutaneous cGVHD affects 75% of cGVHD patients, causing discomfort, limiting the range of movement, and increasing the risk of wound infections. Furthermore, systemic immunosuppression is often needed to treat cGVHD and long-term use can lead to adverse events. Optimal use of skin-directed therapies is integral to the management of cutaneous cGVHD and may decrease the amount of systemic immunosuppression required. This study reviewed English-language articles published from 1990 to 2017 that evaluated the effect of skin-directed treatments for cutaneous cGVHD. A total of 201 papers were identified, 164 articles were screened, 46 were read, and 18 publications were utilized in the review. Skin-directed treatments for cGVHD included topical steroids, topical calcineurin inhibitors, psoralen with ultraviolet A (PUVA) irradiation, ultraviolet A1 (UVA1) irradiation, and ultraviolet B (UVB) irradiation. We report the number of complete remissions, partial remissions, and systemic immunosuppression reduction in each study, as available. Twenty-two out of 30 (73.3%) patients experienced overall improvement with topical calcineurin inhibitors. At least 26 out of 76 patients (34.2%) receiving PUVA experienced complete remission, and 30 out of 76 patients (39.5%) experienced partial remission. In UVA1 studies, 44 out of 52 (84.6%) patients experienced overall improvement. In UVB studies, nine out of 14 patients (64.3%) experienced complete remission and four out of 14 patients (28.6%) experienced partial remission. As more HCTs are performed, more individuals will develop cGVHD. Awareness and optimal use of skin-directed therapies for cutaneous cGVHD may help improve patient outcomes and quality of life.

Photonic Capsule Sensors with Built-In Colloidal Crystallites.

Technologies to monitor microenvironmental conditions and its spatial distribution are in high demand, yet remain unmet need. Herein, photonic microsensors are designed in a capsule format that can be injected, suspended, and implanted in any target volume. Colorimetric sensors are loaded in the core of microcapsules by assembling core-shell colloids into crystallites through the depletion attraction. The shells of the colloids are made of a temperature-responsive hydrogel, which enables the crystallites to rapidly and widely tune the structural color in response to a change in temperature while maintaining close-packed arrays. The spherical symmetry of the microcapsules renders them optically isotropic, i.e., displaying orientation-independent color. In addition, as a solid membrane is used to protect the delicate crystallites from external stresses, their high stability is assured. More importantly, each microcapsule reports the temperature of its microenvironment so that a suspension of capsules can provide information on the spatial distribution of the temperature.

Transferrable Plasmonic Au Thin Film Containing Sub-20 nm Nanohole Array Constructed via High-Resolution Polymer Self-Assembly and Nanotransfer Printing.

The fabrication and characterization of nanoscale hole arrays (NHA) have been extensively performed for a variety of unique characteristics including extraordinary optical transmission phenomenon observed for plasmonic NHAs. Although the size miniaturization and hole densification are strongly required for enhancement of high-frequency optical responses, from a practical point-of-view, it is still not straightforward to manufacture NHA using conventional lithography techniques. Herein, a facile, cost-effective, and transferrable fabrication route for high-resolution and high-density NHA with sub-50 nm periodicity is demonstrated. Solvent-assisted nanotransfer printing with ultrahigh-resolution combined with block copolymer self-assembly is used to fabricate well-defined Si nanomesh master template with 4-fold symmetry. An Au NHA film on quartz substrate is then obtained by thermal-evaporation on the Si master and subsequent transfer of the sample, resulting in NHA structure having a hole with a diameter of 18 nm and a density over 400 holes/µm2. A resonance peak at the wavelength of 650 nm, which is not present in the transmittance spectrum of a flat Au film, is observed for the Au NHA film. Finite-difference time-domain (FDTD) simulation results propose that the unexpected peak appears because of plasmonic surface guiding mode. The position of the resonance peak shows the sensitivity toward the change of the refractive index of surrounding medium, suggesting it as a promising label-free sensor application. In addition, other types of Au nanostructure arrays such as geometry-controlled NHA and nanoparticle arrays (NPAs) shows the outstanding versatility of our approach.

Chameleon-Inspired Mechanochromic Photonic Films Composed of Non-Close-Packed Colloidal Arrays.

Chameleons use a non-close-packed array of guanine nanocrystals in iridophores to develop and tune skin colors in the full visible range. Inspired by the biological process uncovered in panther chameleons, we designed photonic films containing a non-close-packed face-centered-cubic array of silica particles embedded in an elastomer. The non-close-packed array is formed by interparticle repulsion exerted by solvation layers on the particle surface, which is rapidly captured in the elastomer by photocuring of the dispersion medium. The artificial skin exhibits a structural color that shifts from red to blue under stretching or compression. The separation between inelastic particles enables tuning without experiencing significant rearrangement of particles, providing elastic deformation and reversible color change, as chameleons do. The simple fabrication procedure consists of film casting and UV irradiation, potentially enabling the continuous high-throughput production. The mechanochromic property of the photonic films enables the visualization of deformation or stress with colors, which is potentially beneficial for various applications, including mechanical sensors, sound-vision transformers, and color display.