Optimization of micelle-encapsulated extremely small sized iron oxide nanoparticles as a T1 contrast imaging agent: biodistribution and safety profile.

BACKGROUND: Iron oxide nanoparticles (IONPs) have been cleared by the Food and Drug Administration (FDA) for various clinical applications, such as tumor-targeted imaging, hyperthermia therapy, drug delivery, and live-cell tracking. However, the application of IONPs as T1 contrast agents has been restricted due to their high r2 values and r2/r1 ratios, which limit their effectiveness in T1 contrast enhancement. Notably, IONPs with diameters smaller than 5 nm, referred to as extremely small-sized IONPs (ESIONs), have demonstrated potential in overcoming these limitations. To advance the clinical application of ESIONs as T1 contrast agents, we have refined a scale-up process for micelle encapsulation aimed at improving the hydrophilization of ESIONs, and have carried out comprehensive in vivo biodistribution and preclinical toxicity assessments. RESULTS: The optimization of the scale-up micelle-encapsulation process, specifically employing Tween60 at a concentration of 10% v/v, resulted in ESIONs that were uniformly hydrophilized, with an average size of 9.35 nm and a high purification yield. Stability tests showed that these ESIONs maintained consistent size over extended storage periods and dispersed effectively in blood and serum-mimicking environments. Relaxivity measurements indicated an r1 value of 3.43 mM- 1s- 1 and a favorable r2/r1 ratio of 5.36, suggesting their potential as T1 contrast agents. Biodistribution studies revealed that the ESIONs had extended circulation times in the bloodstream and were primarily cleared via the hepatobiliary route, with negligible renal excretion. We monitored blood clearance and organ distribution using positron emission tomography and magnetic resonance imaging (MRI). Additionally, MRI signal variations in a dose-dependent manner highlighted different behaviors at varying ESIONs concentrations, implying that optimal dosages might be specific to the intended imaging application. Preclinical safety evaluations indicated that ESIONs were tolerable in rats at doses up to 25 mg/kg. CONCLUSIONS: This study effectively optimized a scale-up process for the micelle encapsulation of ESIONs, leading to the production of hydrophilic ESIONs at gram-scale levels. These optimized ESIONs showcased properties conducive to T1 contrast imaging, such as elevated r1 relaxivity and a reduced r2/r1 ratio. Biodistribution study underscored their prolonged bloodstream presence and efficient clearance through the liver and bile, without significant renal involvement. The preclinical toxicity tests affirmed the safety of the ESIONs, supporting their potential use as T1 contrast agent with versatile clinical application.

The PIN1-YTHDF1 axis promotes breast tumorigenesis via the m6A-dependent stabilization of AURKA mRNA.

The post-transcriptional processing of N6-methyladenosine (m6A)-modified mRNA by YTH domain-containing family protein 1 (YTHDF1) plays a crucial role in the regulation of gene expression. Although YTHDF1 expression is frequently upregulated in breast cancer, the regulatory mechanisms for this remain unclear. In this study, we examined the role of peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1) in regulating YTHDF1 stability in breast cancer cells. The WW domain of PIN1 interacted with YTHDF1 in a phosphorylation-dependent manner. Additionally, PIN1 overexpression increased YTHDF1 stability by preventing ubiquitin-dependent proteasomal degradation. Furthermore, using the MS2-tagged RNA pull-down assay, we identified Aurora kinase A (AURKA) mRNA as a bona fide substrate of YTHDF1. PIN1-mediated YTHDF1 stabilization increased the stability of AURKA mRNA in an m6A-dependent manner. Furthermore, YTHDF1 knockout reduced AURKA protein expression levels, resulting in anticancer effects in breast cancer cells, including decreased cell proliferation, cell cycle arrest at the G0/G1 phase, apoptotic cell death, and decreased spheroid formation. The anticancer effects induced by YTHDF1 knockout were reversed by AURKA overexpression. Similarly, the knockout of PIN1 produced comparable anticancer effects to those observed in YTHDF1-knockout cells, and these effects were reversed upon overexpression of YTHDF1. In conclusion, the findings of our study suggest that increased YTHDF1 stability induced by PIN1 promotes breast tumorigenesis via the stabilization of AURKA mRNA. Targeting the PIN1/YTHDF1 axis may represent a novel therapeutic strategy for breast cancer.

Nutrition Intervention through Interdisciplinary Medical Treatment in Hospice Patients: From Admission to Death.

The demand for hospice services as well as for 'well-dying' of terminal patients is increasing as patient financial burden is decreasing due to National Health Insurance coverage for hospice care. Hospice institutions utilize interdisciplinary teams comprising doctors, nurses, dietitians, and other health staffs to provide comprehensive patient management. This report examined the nutritional status of a hospice patient from admission to death as well as the nutrition management of this patient in the hospice ward through nutrition interventions performed by a dietitian in the interdisciplinary team. The patient in the present case was a 74-year-old man diagnosed with pancreatic head cancer who died after 26 days of hospice care following transfer from the general ward. During hospice care, the dietitian monitored the patient's nutritional status and performed 8 nutrition interventions, but his oral intake decreased as the patient's symptoms worsened. The average energy intake rates were 30% and 17% of required rates for oral and artificial nutrition, respectively. In line with a report suggesting that the main focus of nutrition in palliative care should be on improving the quality of life and reducing worry in patients, rather than aggressive nutritional management, there is a need for nutrition interventions that are personalized to individual patients by monitoring progress and offering continuous counseling from the time of admission. In addition, further studies such as comparative analysis of nutritional management in Korean hospice ward will be needed for better nutrition management for terminally ill patients.

Enhanced DC-Operated Electroluminescence of Forwardly Aligned   p/MQW/n InGaN Nanorod LEDs via DC Offset-AC Dielectrophoresis.

We introduce an orientation-controlled alignment process of p-GaN/InGaN multiquantum-well/n-GaN (p/MQW/n InGaN) nanorod light-emitting diodes (LEDs) by applying the direct current (DC) offset-alternating current (AC) or pulsed DC electric fields across interdigitated metal electrodes. The as-forwardly aligned p/MQW/n InGaN nanorod LEDs by a pulsed DC dielectrophoresis (DEP) assembly process improve the electroluminescence (EL) intensities by 1.8 times compared to the conventional AC DEP assembly process under DC electric field operation and exhibit an enhanced applied current and EL brightness in the current-voltage and EL intensity-voltage curves, which can be directly used as the fundamental data to construct DC-operated nanorod LED devices, such as LED areal surface lightings, scalable lightings (micrometers to inches) and formable surface lightings. The enhancement in the applied current, the improved EL intensity, and the increased number of forwardly aligned p/MQW/n InGaN nanorods in panchromatic cathodoluminescence images confirm the considerable enhancement of forwardly aligned one-dimensional nanorod LEDs between two opposite electrodes using DC offset-AC or a pulsed DC electric field DEP assembly process. These DC offset-AC or pulsed DC electric field DEP assembly processes suggest that designing for these types of interactions could yield new ways to control the orientation of asymmetric p/MQW/n InGaN diode-type LED nanorods with a relatively low aspect ratio.

Droplet-Guiding Superhydrophobic Arrays of Plasmonic Microposts for Molecular Concentration and Detection.

Droplet-guiding superhydrophobic SERS substrates are created by a combinatorial lithographic technique. Photolithography defines the pattern of a micropillar array with a radial density gradient, whereas colloidal lithography features a nanotip array on the top surface of each micropillar. The nanotip array renders the surface superhydrophobic, and the pattern of micropillars endows the radial gradient of the contact angle, enabling the spontaneous droplet migration toward the center of the pattern. Water droplets containing target molecules are guided to the center, and the molecules dissolved in the droplets are concentrated at the surface of the central micropillar during droplet evaporation. Therefore, the molecules can be analyzed at the predefined position by Raman spectra without scanning the entire substrate. At the same time, the SERS-active nanotip array provides high sensitivity of Raman measurement.

Tumor Necrosis Factor dynamically regulates the mRNA stabilome in rheumatoid arthritis fibroblast-like synoviocytes.

During rheumatoid arthritis (RA), Tumor Necrosis Factor (TNF) activates fibroblast-like synoviocytes (FLS) inducing in a temporal order a constellation of genes, which perpetuate synovial inflammation. Although the molecular mechanisms regulating TNF-induced transcription are well characterized, little is known about the impact of mRNA stability on gene expression and the impact of TNF on decay rates of mRNA transcripts in FLS. To address these issues we performed RNA sequencing and genome-wide analysis of the mRNA stabilome in RA FLS. We found that TNF induces a biphasic gene expression program: initially, the inducible transcriptome consists primarily of unstable transcripts but progressively switches and becomes dominated by very stable transcripts. This temporal switch is due to: a) TNF-induced prolonged stabilization of previously unstable transcripts that enables progressive transcript accumulation over days and b) sustained expression and late induction of very stable transcripts. TNF-induced mRNA stabilization in RA FLS occurs during the late phase of TNF response, is MAPK-dependent, and involves several genes with pathogenic potential such as IL6, CXCL1, CXCL3, CXCL8/IL8, CCL2, and PTGS2. These results provide the first insights into genome-wide regulation of mRNA stability in RA FLS and highlight the potential contribution of dynamic regulation of the mRNA stabilome by TNF to chronic synovitis.

Lithographically Encrypted Inverse Opals for Anti-Counterfeiting Applications.

Colloidal photonic crystals possess inimitable optical properties of iridescent structural colors and unique spectral shape, which render them useful for security materials. This work reports a novel method to encrypt graphical and spectral codes in polymeric inverse opals to provide advanced security. To accomplish this, this study prepares lithographically featured micropatterns on the top surface of hydrophobic inverse opals, which serve as shadow masks against the surface modification of air cavities to achieve hydrophilicity. The resultant inverse opals allow rapid infiltration of aqueous solution into the hydrophilic cavities while retaining air in the hydrophobic cavities. Therefore, the structural color of inverse opals is regioselectively red-shifted, disclosing the encrypted graphical codes. The decoded inverse opals also deliver unique reflectance spectral codes originated from two distinct regions. The combinatorial code composed of graphical and optical codes is revealed only when the aqueous solution agreed in advance is used for decoding. In addition, the encrypted inverse opals are chemically stable, providing invariant codes with high reproducibility. In addition, high mechanical stability enables the transfer of the films onto any surfaces. This novel encryption technology will provide a new opportunity in a wide range of security applications.

Liquid-impermeable inverse opals with invariant photonic bandgap.

Omniphobic inverse opals are created by structurally and chemically modifying the surface of inverse opals through reactive ion etching. During the etching, void arrays of the inverse opal surface evolves to a triangular post array with re-entrant geometry. The elaborate structure can efficiently pin the air-liquid interface and retain air cavities against water and oil, thereby providing liquid-impermeable inverse opals with invariant photonic bandgap.

Colloidal assembly in Leidenfrost drops for noniridescent structural color pigments.

Noniridescent structural color pigments have great potential as alternatives to conventional chemical color pigments in many coloration applications due to their nonbleaching and color-tunable properties. In this work, we report a novel method to create photonic microgranules composed of glassy packing of silica particles and small fraction of carbon black nanoparticles, which show pronounced structural colors with low angle-dependency. To prepare isotropic random packing in each microgranule, a Leidenfrost drop, which is a drop levitated by its own vapor on a hot surface, is employed as a template for fast consolidation of silica particles. The drop randomly migrates over the hot surface and rapidly shrinks, while maintaining its spherical shape, thereby consolidating silica particles to granular structures. Carbon black nanoparticles incorporated in the microgranules suppress incoherent multiple scattering, thereby providing improved color contrast. Therefore, photonic microgranules in a full visible range can be prepared by adjusting the size of silica particles with insignificant whitening.

Bio-inspired nanotadpoles with component-specific functionality.

We report a new class of bio-inspired nanotadpoles (NTPs) with component-specific functionalities. The plasmonic NTPs with a gold-coated head and a reactive ion etching-treated tail showed the tail length dependence of their cellular uptake, enabling the photothermal treatment of cancer cells with high efficacy.

Durable plasmonic cap arrays on flexible substrate with real-time optical tunability for high-fidelity SERS devices.

Active tunable plasmonic cap arrays were fabricated on a flexible stretchable substrate using a combination of colloidal lithography, lift-up soft lithography, and subsequent electrostatic assembly of gold nanoparticles. The arrangement of the plasmonic caps could be tuned under external strain to deform the substrate in reversible. Real-time variation in the arrangement could be used to tune the optical properties and the electromagnetic field enhancement, thereby a proving a promising mechanism for optimizing the SERS sensitivity.