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.

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.

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.

Exposure monitoring of graphene nanoplatelets manufacturing workplaces.

Graphenes have emerged as a highly promising, two-dimensional engineered nanomaterial that can possibly substitute carbon nanotubes. They are being explored in numerous R&D and industrial applications in laboratories across the globe, leading to possible human and environmental exposures to them. Yet, there are no published data on graphene exposures in occupational settings and no readily available methods for their detection and quantitation exist. This study investigates for the first time the potential exposure of workers and research personnel to graphenes in two research facilities and evaluates the status of the control measures. One facility manufactures graphene using graphite exfoliation and chemical vapor deposition (CVD), while the other facility grows graphene on a copper plate using CVD, which is then transferred to a polyethylene terephthalate (PET) sheet. Graphene exposures and process emissions were investigated for three tasks - CVD growth, exfoliation, and transfer - using a multi-metric approach, which utilizes several direct reading instruments, integrated sampling, and chemical and morphological analysis. Real-time instruments included a dust monitor, condensation particle counter (CPC), nanoparticle surface area monitor, scanning mobility particle sizer, and an aethalometer. Morphologically, graphenes and other nanostructures released from the work process were investigated using a transmission electron microscope (TEM). Graphenes were quantified in airborne respirable samples as elemental carbon via thermo-optical analysis. The mass concentrations of total suspended particulate at Workplaces A and B were very low, and elemental carbon concentrations were mostly below the detection limit, indicating very low exposure to graphene or any other particles. The real-time monitoring, especially the aethalometer, showed a good response to the released black carbon, providing a signature of the graphene released during the opening of the CVD reactor at Workplace A. The TEM observation of the samples obtained from Workplaces A and B showed graphene-like structures and aggregated/agglomerated carbon structures. Taken together, the current findings on common scenarios (exfoliation, CVD growth, and transfer), while not inclusive of all graphene manufacturing processes, indicate very minimal graphene or particle exposure at facilities manufacturing graphenes with good manufacturing practices.

Overexpression of malic enzyme in the larval stage extends Drosophila lifespan.

Metabolic modifications during the developmental period can extend longevity. We found that malic enzyme (Men) overexpression during the larval period lengthened the lifespan of Drosophila. Men overexpression by S106-GeneSwitch-Gal4 driver increased pyruvate content and NADPH/NADP(+) ratio but reduced triglyceride, glycogen, and ATP levels in the larvae. ROS levels increased unexpectedly in Men-overexpressing larvae. Interestingly, adults exposed to larval Men-overexpression maintained ROS tolerance with enhanced expression levels of glutathione-S-transferase D2 and thioredoxin-2. Our results suggest that metabolic changes mediated by Men during development might be related to the control of ROS tolerance and the longevity of Drosophila.

Microfluidic Design of Magnetoresponsive Photonic Microcylinders with Multicompartments.

Colloidal photonic structures have been designed to have granular format to use them for paint pigments, encoded carriers, and display pixels. However, conventional approaches only provide spherical or discoid shapes, restricting their applications. Cylindrical granules with fan-shaped compartments in the cross section are appealing for microcarriers with abundant optical codes and active display pigments for color switching. In this work, a stratified laminar flow of concentrated silica particles is employed, formed in a cylindrical microchannel, to produce cylindrical photonic microparticles with multiple compartments. To accomplish this, a microfluidic device is designed to have one cylindrical main channel connected with four branch channels. Four different photocurable suspensions are independently injected through the branches to form quarter-cylindrically compartmentalized streams in the main channel. Local ultraviolet irradiation on the main channel polymerizes the suspension, thereby forming cylindrical microparticles with four compartments. In each compartment, silica particles form ordered array which develops particle size-dependent structural color. Therefore, different colors can be incorporated into single microcylinder by employing different sizes of silica particles. Moreover, one of the compartments can be rendered to be magnetoresponsive by embedding aligned magnetic particles, which enables the remote control of microcylinder orientation and therefore the switching of structural colors.

In vivo genotoxicity evaluation of lung cells from Fischer 344 rats following 28 days of inhalation exposure to MWCNTs, plus 28 days and 90 days post-exposure.

Despite their useful physico-chemical properties, carbon nanotubes (CNTs) continue to cause concern over occupational and human health due to their structural similarity to asbestos. Thus, to evaluate the toxic and genotoxic effect of multi-wall carbon nanotubes (MWCNTs) on lung cells in vivo, eight-week-old rats were divided into four groups (each group = 25 animals), a fresh air control (0 mg/m(3)), low (0.17 mg/m(3)), middle (0.49 mg/m(3)), and high (0.96 mg/m(3)) dose group, and exposed to MWCNTs via nose-only inhalation 6 h per day, 5 days per week for 28 days. The count median length and geometric standard deviation for the MWCNTs determined by TEM were 330.18 and 1.72 nm, respectively, and the MWCNT diameters ranged from 10 to 15 nm. Lung cells were isolated from five male and five female rats in each group on day 0, day 28 (only from males) and day 90 following the 28-day exposure. The total number of animals used was 15 male and 10 female rats for each concentration group. To determine the genotoxicity of the MWCNTs, a single cell gel electrophoresis assay (Comet assay) was conducted on the rat lung cells. As a result of the exposure, the olive tail moments were found to be significantly higher (p < 0.05) in the male and female rats from all the exposed groups when compared with the fresh air control. In addition, the high-dose exposed male and middle and high-dose exposed female rats retained DNA damage, even 90 days post-exposure (p < 0.05). To investigate the mode of genotoxicity, the intracellular reactive oxygen species (ROS) levels and inflammatory cytokine levels (TNF-α, TGF- ß, IL-1, IL-2, IL-4, IL-5, IL-10, IL-12 and IFN-γ) were also measured. For the male rats, the H2O2 levels were significantly higher in the middle (0 days post-exposure) and high- (0 days and 28 days post-exposure) dose groups (p < 0.05). Conversely, the female rats showed no changes in the H2O2 levels. The inflammatory cytokine levels in the bronchoalveolar lavage (BAL) fluid did not show any statistically significant difference. Interestingly, the short-length MWCNTs deposited in the lung cells were persistent at 90 days post-exposure. Thus, exposing lung cells to MWCNTs with a short tube length may induce genotoxicity.

Comparison of dilatation & curettage and endometrial aspiration biopsy accuracy in patients treated with high-dose oral progestin plus levonorgestrel intrauterine system for early-stage endometrial cancer.

OBJECTIVE: To compare the diagnostic accuracy of dilatation & curettage (D&C) vs. endometrial aspiration biopsy in follow-up evaluation of patients treated with high-dose oral progestin plus levonorgestrel intrauterine system (LNG-IUS) for early-stage endometrial cancer (EC). METHOD: A prospective observational study was conducted with 11 patients with FIGO grade 1 or 2, clinical stage IA endometrioid adenocarcinoma. Patients were aged up to 40 years wishing to preserve fertility treated with high-dose oral progestin plus LNG-IUS. Treatment response assessment was done at three month intervals. Endometrial tissues were obtained via endometrial aspiration biopsy with LNG-IUS in place and D&C after removal of LNG-IUS. We identified 28 cases; the histologic results were compared. Kappa statistics were used to assess the agreement of two methods. RESULTS: Diagnostic concordance between examinations was assessed for 9 out of 28 cases examined (32.1%). These consisted of three cases with both examination results of normal, 3 cases with endometrioid adenocarcinoma, 1 case with complex endometrial hyperplasia, 2 cases with material insufficient for diagnosis. Endometrioid adenocarcinoma on D&C was diagnosed in 9 out of 28 cases, but from endometrial aspiration biopsy, only 3 of these 9 cases were diagnosed with endometrioid adenocarcinoma, giving the diagnostic concordance at 33% (kappa value=0.27). From endometrial aspiration biopsy, 17 out of 28 cases (60.7%) had material insufficiency for diagnosis. CONCLUSION: In patients treated with high-dose oral progestin plus LNG-IUS for early-stage EC, endometrial aspiration biopsy with LNG-IUS in place may be not reliable as a follow-up evaluation method.

Regulatory role of osteopontin in malignant transformation of endometrial cancer.

Osteopontin (OPN) involves in the tumor-promoting or metastasis in human endometrial cancer. Depletion of OPN gene expression in endometrial cancer cells was significantly decreased in cell viability and the cells undergo apoptotic cell death. The status of OPN in THESC, RL95, Hec1A and Ishikawa cell lines were analyzed by RT-PCR and western blot. After OPN-siRNA transfection, mRNA and protein expression levels of OPN were determined in Hec1A and Ishikawa cells. Cell proliferation and cell cycle distribution were observed by MTT and flow cytometry analysis. DNA fragmentation assay was used to measure cell apoptosis. Cell migration was assessed by wound healing assay. Depletion of OPN gene expression in endometrial cancer cell lines (Hec1A and Ishikawa cells) reproducibly changed their ability of proliferation. Concomitant changes were seen in the expression of OPN binding cell surface receptors, cell cycle-regulatory genes, cell invasion and colony formation nature of the tumor cells. Decreased colonizing potential in the absence of OPN was reversed in the presence of recombinant OPN. Inhibition of anchorage-independent growth was observed in the presence of metabolic inhibitors of the PI3K, Src and integrin signaling cascades, which was ameliorated in the presence of exogenously added OPN. Our result showed the role of OPN in endometrial cancer, in particular on the malignancy-promoting aspects of OPN that may pave way for new approaches to the clinical management of endometrial cancer.

Pattern of expression of cyclooxygenase-2 in malignant transformation of sinonasal inverted papilloma.

OBJECTIVE: Cyclooxygenases (COXs) are enzymes that catalyze the conversion of arachidonic acid to prostaglandins. Many studies have suggested that COX-2, the inducible form of COX, is important in carcinogenesis. However, little is known about the pattern of expression of COX-2 in a multistep process of malignant transformation of sinonasal inverted papilloma (IP). In this study, we investigated COX-2 expression in IPs, IPs with dysplasia, IPs with squamous cell carcinoma (SCC), and primary SCCs of sinonasal tract. STUDY DESIGN: A retrospective study was conducted. SETTING: The setting was a tertiary care referral center. SUBJECTS AND METHODS: The expression of COX-2 was evaluated by immunohistochemistry in 56, 7, 18, and 17 cases of IPs, IPs with dysplasia, IPs with SCC, and primary SCCs, respectively. Furthermore, we investigated the possible correlation between the expression of COX-2 and clinicopathologic variables in patients with IPs with SCC and primary SCC patients. RESULTS: Positive immunoreactivity for COX-2 was observed in 3 (5.4%) of 56 IPs, 7 (38.9%) of 18 IPs with SCC, and 7 (41.2%) of 17 primary SCCs, whereas it was not observed in IPs with dysplasia. The percentage of tumors with COX-2-positive immunostaining was significantly higher in IPs with SCC and primary SCCs compared with benign IPs. There was no significant correlation between the expression of COX-2 and clinicopathologic variables, such as tumor stage, histologic differentiation, and the proportion of malignant areas in patients with IPs with SCC. CONCLUSION: Cyclooxygenase-2 may play an important role in the process of malignant transformation from IP to SCC.

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 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.

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.

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.

Prophylactic lymphadenectomy of neck level II in clinically node-positive papillary thyroid carcinoma.

BACKGROUND: The purpose of this study was to examine the frequency, pattern, and predictive factors associated with occult level II lymph node (LN) metastases in papillary thyroid carcinoma (PTC) patients with clinically metastatic lymph nodes in the lateral neck (level III, IV, and/or V) by preoperative ultrasonography. METHODS: We retrospectively reviewed the medical records of 52 PTC patients with clinically positive neck lymph nodes in level III, IV, and/or V based on preoperative ultrasonography, who underwent therapeutic lateral neck dissection (ND) (level II-V) between March 2004 and October 2009. All patients had no suspicion of clinically positive neck nodes in level II. Histopathological analysis of neck specimens according to each node level of the neck was performed, with special attention given to level II. RESULTS: Forty-two (81%), 41 (79%), and 6 (12%) patients had histologically positive lymph nodes in level III, IV, and V, respectively. Occult metastases in level II were observed in ten (19%) patients. Patients without suspicious positive LNs in both neck level III and IV by preoperative ultrasonography, and patients without pathologic LN metastases in level III, had no occult LN metastases occurrence to level II. Based on multivariate analysis, presence of more than four metastatic LNs was an independent predictive factor for occult level II metastases [P = 0.022, odds ratio (OR) = 7.738]. CONCLUSIONS: Prophylactic level II LN dissection may be omitted in PTC patients with clinically positive neck nodes if suspicious positive lymph nodes in level III are absent during preoperative ultrasonography.

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.

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.