Pharmacokinetics-Based Safety Evaluation in Half-Dose Verteporfin Photodynamic Therapy.

INTRODUCTION: This study was conducted to assess the systemic pharmacokinetic profiles of half-dose verteporfin photodynamic therapy (PDT) using concentration data from a previous clinical trial and to subsequently suggest safety precaution guidelines. METHODS: Coefficients for the bi-exponential model were obtained from published data on post-infusion plasma verteporfin concentrations within a period of 0.17-4 h. Using the extrapolative forecasting method, we plotted the 48-h post-verteporfin plasma concentration model. The time required to achieve a comparable level of verteporfin 48 h after a conventional dose (6 mg/m2 body surface area, BSA) infusion was calculated for a half-dose infusion (3 mg/m2 BSA). RESULTS: At 24 and 48 h post-verteporfin infusion, the plasma concentration following the conventional dose was 1.28 × 10-4 µg/mL and 5.06 × 10-8 µg/mL, compared to 3.57 × 10-5 µg/mL and 7.54 × 10-9 µg/mL for the half-dose PDT, representing concentrations that were 3.6 times and 6.7 times higher, respectively. The estimated time required to attain the same level of verteporfin 48 h after a conventional dose was calculated as 42-h post-half-dose PDT. CONCLUSIONS: The results of this study indicate that precautionary measures should be taken to avoid sunlight following both half and conventional doses of PDT during the similar post-treatment periods of two days. Nevertheless, given the substantially higher plasma concentration levels associated with conventional-dose PDT compared with the half-dose, systemic safety should be carefully considered when administering conventional-dose PDT.

Lipid-coated gold nanorods for photoimmunotherapy of primary breast cancer and the prevention of metastasis.

Nanomedicines hold promise for the treatment of various diseases. However, treating cancer metastasis remains highly challenging. In this study, we synthesized gold nanorods (AuNRs) containing (α-GC), an immune stimulator, for the treatment of primary cancer, metastasis, and recurrence of the cancer. Therefore, the AuNR were coated with lipid bilayers loaded with α-GC (α-LA). Upon irradiation with 808 nm light, α-LA showed a temperature increase. Intra-tumoral injection of α-LA in mice and local irradiation of the 4T1 breast cancer tumor effectively eliminated tumor growth. We found that the presence of α-GC in α-LA activated dendritic cells and T cells in the spleen, which completely blocked the development of lung metastasis. In mice injected with α-LA for primary breast cancer treatment, we observed antigen-specific T cell responses and increased cytotoxicity against 4T1 cells. We conclude that α-LA is promising for the treatment of both primary breast cancer and its metastasis.

Risk compensation after COVID-19 vaccination: Evidence from vaccine rollout by exact birth date in South Korea.

We utilize the phased rollout of COVID-19 vaccines by exact birth date in South Korea as a natural experiment for testing risk compensation. People may resume face-to-face social activities following vaccination because they perceive lower risk of infection. Applying a regression discontinuity design based on birth date cutoffs for vaccine eligibility, we find no evidence of risk-compensating behaviors, as measured by large, high-frequency data from credit card and airline companies as well as survey data. We find some evidence of self-selection into vaccine take-up based on perception toward vaccine effectiveness and side effects, but the treatment effects do not differ between compliers and never-takers.

Selection and behavioral responses of health insurance subsidies in the long run: Evidence from a field experiment in Ghana.

We study the effects of a health insurance subsidy in Ghana, where mandates are not enforceable. We randomly provide different levels of subsidy (1/3, 2/3, and full) and evaluate the impact at 7 months and 3 years after the intervention. We find that a one-time subsidy increased insurance enrollment for all groups in both the short and long runs, but health care utilization in the long run increased only for the partial subsidy group. We find supportive evidence that ex-post behavioral responses rather than ex-ante selective enrollment explain the long-run health care utilization results.

Broken Inversion Symmetry in Van Der Waals Topological Ferromagnetic Metal Iron Germanium Telluride.

Inversion symmetry breaking is critical for many quantum effects and fundamental for spin-orbit torque, which is crucial for next-generation spintronics. Recently, a novel type of gigantic intrinsic spin-orbit torque is established in the topological van der Waals (vdW) magnet iron germanium telluride. However, it remains a puzzle because no clear evidence exists for interlayer inversion symmetry breaking. Here, the definitive evidence of broken inversion symmetry in iron germanium telluride directly measured by the second harmonic generation (SHG) technique is reported. The data show that the crystal symmetry reduces from centrosymmetric P63/mmc to noncentrosymmetric polar P3m1 space group, giving the threefold SHG pattern with dominant out-of-plane polarization. Additionally, the SHG response evolves from an isotropic pattern to a sharp threefold symmetry upon increasing Fe deficiency, mainly due to the transition from random defects to ordered Fe vacancies. Such SHG response is robust against temperature, ensuring unaltered crystalline symmetries above and below the ferromagnetic transition temperature. These findings add crucial new information to the understanding of this interesting vdW metal, iron germanium telluride: band topology, intrinsic spin-orbit torque, and topological vdW polar metal states.

Development of exosome membrane materials-fused microbubbles for enhanced stability and efficient drug delivery of ultrasound contrast agent.

Lipid-coated microbubbles are widely used as an ultrasound contrast agent, as well as drug delivery carriers. However, the two main limitations in ultrasound diagnosis and drug delivery using microbubbles are the short half-life in the blood system, and the difficulty of surface modification of microbubbles for active targeting. The exosome, a type of extracellular vesicle, has a preferentially targeting ability for its original cell. In this study, exosome-fused microbubbles (Exo-MBs) were developed by embedding the exosome membrane proteins into microbubbles. As a result, the stability of Exo-MBs is improved over the conventional microbubbles. On the same principle that under the exposure of ultrasound, microbubbles are cavitated and self-assembled into nano-sized particles, and Exo-MBs are self-assembled into exosome membrane proteins-embedded nanoparticles (Exo-NPs). The Exo-NPs showed favorable targeting properties to their original cells. A photosensitizer, chlorin e6, was loaded into Exo-MBs to evaluate therapeutic efficacy as a drug carrier. Much higher therapeutic efficacy of photodynamic therapy was confirmed, followed by cancer immunotherapy from immunogenic cell death. We have therefore developed a novel ultrasound image-guided drug delivery platform that overcomes the shortcomings of the conventional ultrasound contrast agent and is capable of simultaneous photodynamic therapy and cancer immunotherapy.

Dual-color space network with global priors for photo retouching.

There have been growing trends using deep learning-based approaches for photo retouching which aims to enhance unattractive images and make them visually appealing. However, the existing methods only considered the RGB color space, which limited the available color information for editing. To address this issue, we propose a dual-color space network that extracts color representations from multiple color spaces to provide more robust color information. Our approach is based on the observation that converting an image to a different color space generates a new image that can be further processed by a neural network. Hence, we utilize two separate networks: a transitional network and a base network, each operating in a different color space. Specifically, the input RGB image is converted to another color space (e.g., YCbCr) using color space converter (CSC). The resulting image is then passed through the transitional network to extract color representations from the corresponding color space using color prediction module (CPM). The output of the transitional network is converted back to the RGB space and fed into the base network, which operates in RGB space. By utilizing global priors from each representation in different color spaces, we guide the retouching process to produce natural and realistic results. Experimental results demonstrate that our proposed method outperforms state-of-the-art methods on the MIT-Adobe FiveK dataset, and an in-depth analysis and ablation study highlight the advantages of our approach.

Micro-syringe chip-guided intratumoral administration of lipid nanoparticles for targeted anticancer therapy.

BACKGROUND: Nano-sized drug delivery system has been widely studied as a potential technique to promote tumor-specific delivery of anticancer drugs due to its passive targeting property, but resulting in very restricted improvements in its systemic administration so far. There is a requirement for a different approach that dramatically increases the targeting efficiency of therapeutic agents at targeted tumor tissues. METHODS: To improve the tumor-specific accumulation of anticancer drugs and minimize their undesirable toxicity to normal tissues, a tumor-implantable micro-syringe chip (MSC) with a drug reservoir is fabricated. As a clinically established delivery system, six liposome nanoparticles (LNPs) with different compositions and surface chemistry are prepared and their physicochemical properties and cellular uptake are examined in vitro. Subsequently, MSC-guided intratumoral administration is studied to identify the most appropriate for the higher tumor targeting efficacy with a uniform intratumoral distribution. For efficient cancer treatment, pro-apoptotic anticancer prodrugs (SMAC-P-FRRG-DOX) are encapsulated to the optimal LNPs (SMAC-P-FRRG-DOX encapsulating LNPs; ApoLNPs), then the ApoLNPs are loaded into the 1 µL-volume drug reservoir of MSC to be delivered intratumorally for 9 h. The tumor accumulation and therapeutic effect of ApoLNPs administered via MSC guidance are evaluated and compared to those of intravenous and intratumoral administration of ApoLNP in 4T1 tumor-bearing mice. RESULTS: MSC is precisely fabricated to have a 0.5 × 4.5 mm needle and 1 µL-volume drug reservoir to achieve the uniform intratumoral distribution of LNPs in targeted tumor tissues. Six liposome nanoparticles with different compositions of 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine (PC), 1,2-dioleoyl-sn-glycero-3-phospho-L-serine (PS), 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy (polyethylene glycol)2000] (PEG2000-DSPE) are prepared with average sizes of 100-120 nm and loaded into the 1 µL-volume drug reservoir in MSC. Importantly negatively charged 10 mol% of PS-containing LNPs are very slowly infused into the tumor tissue through the micro-syringe of the MSC over 6 h. The intratumoral targeting efficiency of MSC guidance is 93.5%, effectively assisting the homogeneous diffusion of LNPs throughout the tumor tissue at 3.8- and 2.7-fold higher concentrations compared to the intravenous and intratumoral administrations of LNPs, respectively. Among the six LNP candidates 10 mol% of PS-containing LNPs are finally selected for preparing pro-apoptotic SMAC-P-FRRG-DOX anticancer prodrug-encapsulated LNPs (ApoLNPs) due to their moderate endocytosis rate high tumor accumulation and homogenous intratumoral distribution. The ApoLNPs show a high therapeutic effect specifically to cathepsin B-overexpressing cancer cells with 6.6 µM of IC50 value while its IC50 against normal cells is 230.7 µM. The MSC-guided administration of ApoLNPs efficiently inhibits tumor growth wherein the size of the tumor is 4.7- and 2.2-fold smaller than those treated with saline and intratumoral ApoLNP without MSC, respectively. Moreover, the ApoLNPs remarkably reduce the inhibitor of apoptosis proteins (IAPs) level in tumor tissues confirming their efficacy even in cancers with high drug resistance. CONCLUSION: The MSC-guided administration of LNPs greatly enhances the therapeutic efficiency of anticancer drugs via the slow diffusion mechanism through micro-syringe to tumor tissues for 6 h, whereas they bypass most hurdles of systemic delivery including hepatic metabolism, rapid renal clearance, and interaction with blood components or other normal tissues, resulting in the minimum toxicity to normal tissues. The negatively charged ApoLNPs with cancer cell-specific pro-apoptotic prodrug (SMAC-P-FRRG-DOX) show the highest tumor-targeting efficacy when they are treated with the MSC guidance, compared to their intravenous or intratumoral administration in 4T1 tumor-bearing mice. The MSC-guided administration of anticancer drug-encapsulated LNPs is expected to be a potent platform system that facilitates overcoming the limitations of systemic drug administration with low delivery efficiency and serious side effects.

Strontium-90 levels in seawater southeast of Jeju Island during 2021-2023.

This study introduces an efficient method for determining 90Sr activity levels in seawater, reducing the processing time to <3 h for 50 L of seawater. The key feature of the proposed method is the chemical separation of 90Y when it is in equilibrium with 90Sr, which is achieved by utilizing custom-made sample-loading equipment and an automated radionuclide separation instrument. As a result, the procedure consistently yields a recovery rate > 90 % for 90Y. Investigations of 90Sr levels were conducted in the ocean southeast of Jeju Island from November 2021 to January 2023. Owing to the regional ocean circulation, this region was among the first within the Korean Peninsula to experience the impact of the Fukushima-accident-derived radionuclides. Throughout the investigation period, the observed 90Sr activity concentration ranged from 0.57 to 1.0 Bq m-3. No distinct temporal variation of 90Sr was observed in the selected area during the investigation.

Development of Polymersomes Co-Delivering Doxorubicin and Melittin to Overcome Multidrug Resistance.

Multidrug resistance (MDR) is one of the major barriers in chemotherapy. It is often related to the overexpression of efflux receptors such as P-glycoprotein (P-gp). Overexpressed efflux receptors inhibit chemotherapeutic efficacy by pumping out intracellularly delivered anticancer drugs. In P-gp-mediated MDR-related pathways, PI3K/Akt and NF-kB pathways are commonly activated signaling pathways, but these pathways are downregulated by melittin, a main component of bee venom. In this study, a polymersome based on a poly (lactic acid) (PLA)-hyaluronic acid (HA) (20k-10k) di-block copolymer and encapsulating melittin and doxorubicin was developed to overcome anticancer resistance and enhance chemotherapeutic efficacy. Through the simultaneous delivery of doxorubicin and melittin, PI3K/Akt and NF-κB pathways could be effectively inhibited, thereby downregulating P-gp and successfully enhancing chemotherapeutic efficacy. In conclusion, a polymersome carrying an anticancer drug and melittin could overcome MDR by regulating P-gp overexpression pathways.

Development of a Polymersome-Based Nanomedicine for Chemotherapeutic and Sonodynamic Combination Therapy.

In anticancer therapy, combination therapy has been suggested as an alternative to the insufficient therapeutic efficacy of single therapy. Among combination therapies, combination chemo- and photodynamic therapy are actively investigated. However, photodynamic therapy shows a limitation in the penetration depth of the laser. Therefore, sonodynamic therapy (SDT), using ultrasound instead of a laser as a trigger, is an upcoming strategy for deep tumors. Additionally, free drugs are easily degraded by enzymes, have difficulty in reaching the target site, and show side effects after systemic administration; therefore, the development of drug delivery systems is desirable for sufficient drug efficacy for combination therapy. However, nanocarriers, such as microbubbles, and albumin nanoparticles, are unstable in the body and show low drug-loading efficiency. Here, we propose polylactide (PLA)-poly (ethylene glycol) (PEG) polymersomes (PLs) with a high drug loading rate of doxorubicin (DOX) and verteporfin (VP) for effective combination therapy in both in vitro and in vivo experiments. The cellular uptake efficiency and cytotoxicity test results of VP-DOX-PLs were higher than that of single therapy. Moreover, in vivo biodistribution showed the accumulation of the VP-DOX-PLs in tumor regions. Therefore, VP-DOX-PLs showed more effective anticancer efficacy than either single therapy in vivo. These results suggest that the combination therapy of SDT and chemotherapy could show novel anticancer effects using VP-DOX-PLs.

Cell proliferation effect of deep-penetrating microcavity tandem NIR OLEDs with therapeutic trend analysis.

Long wavelengths that can deeply penetrate into human skin are required to maximize therapeutic effects. Hence, various studies on near-infrared organic light-emitting diodes (NIR OLEDs) have been conducted, and they have been applied in numerous fields. This paper presents a microcavity tandem NIR OLED with narrow full-width half-maximum (FWHM) (34 nm), high radiant emittance (> 5 mW/cm2) and external quantum efficiency (EQE) (19.17%). Only a few papers have reported on biomedical applications using the entire wavelength range of the visible and NIR regions. In particular, no biomedical application studies have been reported in the full wavelength region using OLEDs. Therefore, it is worth researching the therapeutic effects of using OLED, a next-generation light source, and analyzing trends for cell proliferation effects. Cell proliferation effects were observed in certain wavelength regions when B, G, R, and NIR OLEDs were used to irradiate human fibroblasts. The results of an in-vitro experiment indicated that the overall tendency of wavelengths is similar to that of the cytochrome c oxidase absorption spectrum of human fibroblasts. This is the first paper to report trends in the cell proliferation effects in all wavelength regions using OLEDs.

Ultra-Sensitive Determination of Particulate, Gaseous Inorganic and Organic Iodine-129 and Iodine-127 in Ambient Air.

Atmospheric iodine cycling is of significance in climate change and environmental and health impacts. To better explore speciation transformation of atmospheric stable and radioactive iodine, an ultra-sensitive analytical method was established for determination of 129I and 127I in particulate, gaseous inorganic, and gaseous organic species, which was conducted with a self-designed cascade sampling apparatus, followed by their separation with a pyrolysis system and accelerator mass spectrometry and ICP-MS measurements. Combustion protocols for three sampling matrices and NaOH concentration for iodine trapping were optimized to achieve a safe analytical procedure with a high chemical yield of iodine. Based on the lowest concentrations of 129I and 127I, a suitable activated carbon product for adsorption of gaseous organic iodine was carefully selected. The detection limits of the three species were 0.30-2.21 ng m-3 for 127I and 0.05-0.22 × 105 atoms m-3 for 129I. This newly established method was successfully applied to analyze the levels and species of 129I and 127I in ambinet air from Xi'an, China, from May to August, 2020. Gaseous organic iodine was found to be the dominant species of 127I and 129I, accounting for about half of total iodine, and gaseous inorganic iodine and particulate iodine accounted for one-quarter each during the whole sampling period. Speciation variation of 129I and 127I indicates that speciation transformation apparently occurred at the turn of spring and summer, mainly between particulate and gaseous organic iodine. This study has implications on delicate tracing of the atmospheric behavior of iodine with long-lived anthropogenic 129I.

Changes in the ozone chemical regime over the contiguous United States inferred by the inversion of NOx and VOC emissions using satellite observation.

To investigate changes in the ozone (O3) chemical production regime over the contiguous United States (CONUS) with accurate knowledge of concentrations of its precursors, we applied an inverse modeling technique with Ozone Monitoring Instrument (OMI) tropospheric nitrogen dioxide (NO2) and total formaldehyde (HCHO) retrieval products in the summers of 2011, 2014, and 2017, years in which United States National Emission Inventory were based. The inclusion of dynamic chemical lateral boundary conditions and lightning-induced nitric oxide emissions significantly account for the contribution of background sources in the free troposphere. Satellite-constrained nitrogen oxide (NOx) and non-methane volatile organic compounds (NMVOCs) emissions mitigate the discrepancy between satellite and modeled columns: the inversion suggested 2.33-2.84 (1.07-1.34) times higher NOx over the CONUS (over urban regions) and 0.28-0.81 times fewer NMVOCs emissions over the southeastern United States. The model-derived HCHO/NO2 column ratio shows gradual spatial changes in the O3 production regime near urban cores relative to previously defined threshold values representing NOx and VOC sensitive conditions. We also found apparent shifts from the NOx-saturated regime to the transition regime (or the transition regime to the NOx-limited regime) over the major cities in the western United States. In contrast, rural areas, especially in the east-southeastern United States, exhibit a decreased HCHO/NO2 column ratio by -1.30 ± 1.71 with a reduction in HCHO column primarily driven by meteorology, becoming sensitive to VOC emissions. Results show that incorporating satellite observations into numerical modeling could help policymakers implement appropriate emission control policies for O3 pollution.

The Roles of Nutrition Education and Food Vouchers in Improving Child Nutrition: Evidence from a Field Experiment in Ethiopia.

Mothers' lack of knowledge about child nutrition and limited resources lead to poor diets among children in developing countries, increasing their risk of chronic undernutrition. We implemented a cluster randomized control trial that randomly provides four-month-long Behavior Change Communication (BCC) and food vouchers in Ethiopia. We find improvements in child-feeding practices and a reduction in chronic child undernutrition only when BCC and vouchers are provided together. BCC or voucher alone had limited impacts. Our results highlight the importance of adding an effective educational component to existing transfer programs.

Simultaneous removal of radioactive cesium and strontium from seawater using a highly efficient Prussian blue-embedded alginate aerogel.

Radioactive cesium (137Cs) and strontium (90Sr) contaminants in seawater have been a serious problem since the Fukushima accident in 2011 due to their long-term health risks. For the effective and simultaneous removal of radioactive cesium (137Cs) and strontium (90Sr) from seawater, a Prussian blue (PB)-immobilized alginate aerogel (PB-alginate aerogel) was fabricated and its adsorption performance was evaluated. PB nanoparticles were homogeneously dispersed in the three-dimensional porous alginate aerogel matrix, which enabled facile contact with seawater. The PB-alginate aerogel exhibited Cs+ and Sr2+ adsorption capacities of 19.88 and 20.10 mg/g, respectively, without substantial interference because Cs+ and Sr2+ adsorption occurred at different adsorption sites on the composite. The Cs+ and Sr2+ adsorption onto the PB-alginate aerogel was completed within 3 h due to the highly porous morphology of the aerogel. The Cs+ and Sr2+ adsorption behaviors on the PB-alginate aerogel were systematically investigated under various conditions. Compared with Cs+ adsorption, Sr2+ adsorption onto the PB-alginate aerogel was more strongly influenced by competing cations (Na+, Mg2+, Ca2+, and K+) in seawater. 137Cs and 90Sr removal tests in real seawater demonstrated the practical feasibility of the PB-alginate aerogel as an adsorbent.

Permeability of the Retina and RPE-Choroid-Sclera to Three Ophthalmic Drugs and the Associated Factors.

In this study, Retina-RPE-Choroid-Sclera (RCS) and RPE-Choroid-Sclera (CS) were prepared by scraping them off neural retina, and using the Ussing chamber we measured the average time-concentration values in the acceptor chamber across five isolated rabbit tissues for each drug molecule. We determined the outward direction permeability of the RCS and CS and calculated the neural retina permeability. The permeability coefficients of RCS and CS were as follows: ganciclovir, 13.78 ± 5.82 and 23.22 ± 9.74; brimonidine, 15.34 ± 7.64 and 31.56 ± 12.46; bevacizumab, 0.0136 ± 0.0059 and 0.0612 ± 0.0264 (×10-6 cm/s). The calculated permeability coefficients of the neural retina were as follows: ganciclovir, 33.89 ± 12.64; brimonidine, 29.83 ± 11.58; bevacizumab, 0.0205 ± 0.0074 (×10-6 cm/s). Between brimonidine and ganciclovir, lipophilic brimonidine presented better RCS and CS permeability, whereas ganciclovir showed better calculated neural retinal permeability. The large molecular weight drug bevacizumab demonstrated a much lower permeability than brimonidine and ganciclovir. In conclusion, the ophthalmic drug permeability of RCS and CS is affected by the molecular weight and lipophilicity, and influences the intravitreal half-life.

Health Surveillance of Penguins in the Barton Peninsula on King George Island, Antarctica.

Samples from 29 adult Gentoo (Pygoscelis papua), Chinstrap (Pygoscelis antarcticus), and Adélie Penguins (Pygoscelis adeliae) at the King Sejong Station on NarÌ¢ ebski Point, King George Island, Antarctica, were investigated to detect antibodies to avian influenza, Newcastle disease virus, infectious bursal disease virus, infectious bronchitis virus, Mycoplasma, and Salmonella. Antibodies were identified from one Gentoo Penguin and one Chinstrap Penguin against infectious bronchitis virus; from one Gentoo Penguin against Newcastle disease virus; from one Gentoo Penguin against Mycoplasma synoviae; and from two Chinstrap Penguins against Salmonella pullorum. Thirty-three dead penguin chicks were collected from the breeding colony for necropsy, histopathological examination, and polymerase chain reaction. Pulmonary hemorrhage and congestion were the main necropsy findings.

Lysosome-Instructed Self-Assembly of Amino-Acid-Functionalized Perylene Diimide for Multidrug-Resistant Cancer Cells.

Multidrug resistance (MDR) of cancer cells reduces chemotherapeutic efficacy by preventing drug accumulation in the cells through a drug efflux pump and lysosomal sequestration/exocytosis. Herein, to overcome such anticancer resistance, lysosome-targeted self-assembly of perylene diimide (PDI) derivatives is presented as a powerful strategy for effective and selective anticancer therapy. Stimulated by the lysosomal low pH, the amphiphilic PDI derivatives functionalized with amino acids (PDI-AAs) construct fibrous self-assembled structures inside the lysosomes, causing cancer cell apoptosis by lysosomal rupture. In contrast, negligible apoptosis was observed from normal cells by PDI-AA. The agglomerated fibrous assemblies were not removed by lysosomal exocytosis, thereby displaying a 10.7-fold higher anticancer efficacy on MDR cancer cells compared to a doxorubicin chemotherapeutic agent. The MDR-circumventing capability, along with high selectivity toward cancer cells, supports PDI-AAs as potential candidates for the treatment of MDR cancer cells by lysosome-targeted self-assembly.