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Hee Ji Shin,1,* Min Jeong Jo,1,* Ik Sup Jin,1 Chun-Woong Park,1 Jin-Seok Kim,2 Dae Hwan Shin1 1College of Pharmacy, Chungbuk National University, Cheongju, 28160, Republic of Korea; 2Drug Information Research Institute (DIRI), College of Pharmacy, Sookmyung Women’s University, Seoul, 04310, Republic of Korea*These authors contributed equally to this workCorrespondence: Dae Hwan ShinCollege of Pharmacy, Chungbuk National University, Osongsaengmyeong 1-ro, Osong-eup, Heungdeok-gu, Cheongju, 28160, Republic of KoreaTel +82 43 261 2820Fax +82 43 268 2732Email dshin@chungbuk.ac.krPurpose: We aimed to develop a nanocarrier formulation incorporating fenbendazole (FEN) and rapamycin (RAPA) with strong efficacy against A549 cancer cells. As FEN and RAPA are poorly soluble in water, it is difficult to apply them clinically in vivo. Therefore, we attempted to resolve this problem by encapsulating these drugs in polymeric micelles.Methods: We evaluated drug synergy using the combination index (CI) values of various molar ratios of FEN and RAPA. We formed and tested micelles composed of different polymers. Moreover, we conducted cytotoxicity, stability, release, pharmacokinetic, and biodistribution studies to investigate the antitumor effects of FEN/RAPA-loaded mPEG-b-PCL micelles.Results: We selected mPEG-b-PCL-containing FEN and RAPA at a molar ratio of 1:2 because these particles were consistent in size and had high encapsulation efficiency (EE, %) and drug loading (DL, %) capacity. The in vitro cytotoxicity was assessed for various FEN, RAPA, and combined FEN/RAPA formulations. After long-term exposures, both the solutions and the micelles had similar efficacy against A549 cancer cells. The in vivo pharmacokinetic study revealed that FEN/RAPA-loaded mPEG-b-PCL micelles had a relatively higher area under the plasma concentration–time curve from 0 to 2 h (AUC0– 2 h) and 0 to 8 h (AUC0– 8 h) and plasma concentration at time zero (Co) than that of the FEN/RAPA solution. The in vivo biodistribution assay revealed that the IV injection of FEN/RAPA-loaded mPEG-b-PCL micelles resulted in lower pulmonary FEN concentration than the IV injection of the FEN/RAPA solution.Conclusion: When FEN and RAPA had a 1:2 molar ratio, they showed synergism. Additionally, using data from in vitro cytotoxicity, synergism between a 1:2 molar ratio of FEN and RAPA was observed in the micelle formulation. The FEN/RAPA-loaded mPEG-b-PCL micelle had enhanced bioavailability than the FEN/RAPA solution.Keywords: combination therapy, drug interaction, cytotoxicity, biodistribution, bioavailability

Insufficient efficacy of current single drug therapy of cancers have led to the advancement of combination drug-loaded formulations. Specifically, polymeric micelles have been focused on as efficient injectable vehicles for the delivery of several anticancer drugs simultaneously to cancer cells. These nano delivery systems have evolved with advancements in the area of nanotechnology. The current review presents a summary of the past events that have led to the procession of nanomicelles and novel nanotechnologies for combinatorial drug delivery. It also focuses on the advantages, disadvantages, and considerations for the design of nanotechnologies for combinatorial drug delivery systems. The opportunities and challenges of nanotechnologies in drug delivery to overcome current disadvantages are also discussed. Furthermore, we have added findings regarding the trends and perspectives regarding nanotechnologies for combinatorial anticancer drug delivery.

Assembly of neuronal SNARE protein complexes is essential for fusion of synaptic vesicles with the presynaptic plasma membrane, which releases neurotransmitters into the synaptic cleft and mediates neurotransmission. However, despite the potential of pharmacological regulation of this process for the treatment of various neurological disorders, only a few reagents, including botulinum neurotoxins, are currently available. Here, we report that buforin-1, an antimicrobial peptide from the Asian toad Bufo gargarizans, inhibits neuronal SNARE complex assembly, resulting in neuronal SNARE-mediated membrane fusion in vitro via its direct association with neuronal t-SNAREs syntaxin-1 and SNAP-25. Consistently, buforin-1 significantly inhibited neuronal-SNARE-mediated exocytosis in PC-12 cells. Thus, buforin-1 has potential for the treatment of neurological disorders caused by dysregulated neurotransmission.

Fenbendazole (FEN), a broad-spectrum benzimidazole anthelmintic, suppresses cancer cell growth through various mechanisms but has low solubility and achieves low blood concentrations, which leads to low bioavailability. Solubilizing agents are required to prepare poorly soluble drugs for injections, however, these are toxic. To overcome this problem, we designed and fabricated low-toxicity Soluplus&reg, polymeric micelles encapsulating FEN and conducted toxicity assays in vitro and in vivo. FEN-loaded Soluplus&reg, micelles had an average particle size of 68.3 &plusmn, 0.6 nm, a zeta potential of &minus, 2.3 &plusmn, 0.2 mV, a drug loading of 0.8 &plusmn, 0.03%, and an encapsulation efficiency of 85.3 &plusmn, 2.9%. MTT and clonogenic assays were performed on A549 cells treated with free FEN and FEN-loaded Soluplus&reg, micelles. The in vitro drug release profile showed that the micelles released FEN more gradually than the solution. Pharmacokinetic studies revealed lower total clearance and volume of distribution and higher area under the curve and plasma concentration at time zero of FEN-loaded Soluplus&reg, micelles than of the FEN solution. The in vivo toxicity assay revealed that FEN-loaded Soluplus&reg, micelle induced no severe toxicity. Therefore, we propose that preclinical and clinical safety and efficacy trials on FEN-loaded Soluplus&reg, micelles would be worthwhile.

Despite a lot of efforts to respond flood hazards with remote sensing data, it is still difficult to generate an accurate flood map using solely optical or radar imagery. While optical data is relatively high-resolution and does not suffer from speckle noise compared to radar data, it is very likely to be impacted by cloud and shadow. On the other hand, radar imagery can be used in all weather conditions due to its capability of penetrating clouds. Although a significant improvement of flood monitoring capability is achieved by using radar data, it is still challenging to map urban floods because of strong backscattering by man-made structures. Therefore, complementary use of optical and radar imagery in flood response is required, particularly in urban areas. In this study, we have adopted the Bayesian Joint Probability function to combine two different flood products generated from SAR and optical imagery. Flood detection with SAR data relies on the difference of backscatter signals between standing water and rougher land surface, while a Normalized Difference Water Index (NDWI) approach is used for optical data. Specifically, Planet Dove data with its 3m spatial resolution is used with higher weight values to detect flood extent in urban areas.

Land subsidence on landfill parks needs to be consistently and periodically measured because the landfill areas tend to subside unexpectedly. Although in-situ measurements have been adopted in gene...

Multiple-aperture SAR interferometry (MAI) is an advanced technique that is used to retrieve actual surface motions by complementing missing components of InSAR measurements. Despite the wide use of the MAI method in the geosciences, X-band SAR has rarely been applied in MAI-based studies due to the relatively shorter decorrelation periods involved. Thus, we need to evaluate the MAI measurements from X-band SAR for the use in the geosciences. In this paper, an assessment of the MAI performance for TerraSAR-X system was carried out at the test site, Kīlauea Volcano, Hawaii, focusing on the Kamoamoa fissure eruption episode that occurred on March 6–10, 2011. The root-mean-square (RMS) errors of single MAI interferograms were 3.26 ± 1.32 cm and 2.95 ± 0.77 cm for descending and ascending datasets, respectively. Multi-stacked MAI interferograms showed reduced error levels of 1.77 and 2.04 cm for descending and ascending datasets, respectively. In addition, empirical uncertainty models of the MAI measurements were generated with respect to the interferometric coherence of single- and multi-stacked MAI measurements, and these regression models enabled us to confirm the difference between the theoretical and practical accuracies of the MAI measurements. Moreover, the MAI-based 3D model based on high accuracy 3D maps showed some possibilities of new findings and interpretations of the geologic sources.

Cascading hazard processes refer to a primary trigger such as heavy rainfall, seismic activity, or snow melt, followed by a chain or web of consequences that can cause subsequent hazards influenced by a complex array of preconditions and vulnerabilities. These interact in multiple ways and can have tremendous impacts on populations proximate to or downstream of these initial triggers. High Mountain Asia (HMA) is extremely vulnerable to cascading hazard processes given the tectonic, geomorphologic, and climatic setting of the region, particularly as it relates to glacial lakes. Given the limitations of in situ surveys in steep and often inaccessible terrain, remote sensing data are a valuable resource for better understanding and quantifying these processes. The present work provides a survey of cascading hazard processes impacting HMA and how these can be characterized using remote sensing sources. We discuss how remote sensing products can be used to address these process chains, citing several examples of cascading hazard scenarios across HMA. This work also provides a perspective on the current gaps and challenges, community needs, and view forward towards improved characterization of evolving hazards and risk across HMA.

Alpinumisoflavone, a major compound in unripe Cudrania tricuspidata fruit is reported to exhibit numerous beneficial pharmacological activities, such as osteoprotective, antibacterial, estrogenic, anti-metastatic, atheroprotective, antioxidant, and anticancer effects. Despite its medicinal value, alpinumisoflavone is poorly soluble in water, which makes it difficult to formulate and administer intravenously (i.v.). To overcome these limitations, we used methoxy poly(ethylene glycol)-b-poly(d,l-lactide) (mPEG-b-PLA) polymeric micelles to solubilize alpinumisoflavone and increase its bioavailability, and evaluated their toxicity in vivo. Alpinumisoflavone-loaded polymeric micelles were prepared using thin-film hydration method, and their physicochemical properties were characterized for drug release, particle size, drug-loading (DL, %), and encapsulation efficiency (EE, %). The in vitro drug release profile was determined and the release rate of alpinumisoflavone from mPEG-b-PLA micelles was slower than that from drug solution, and sustained. Pharmacokinetic studies showed decreased total clearance and volume of distribution of alpinumisoflavone, whereas area under the curve (AUC) and bioavailability were significantly increased by incorporation in mPEG-b-PLA micelles. In vivo toxicity assay revealed that alpinumisoflavone-loaded mPEG-b-PLA micelles had no severe toxicity. In conclusion, we prepared an intravenous (i.v.) injectable alpinumisoflavone formulation, which was solubilized using mPEG-b-PLA micelles, and determined their physicochemical properties, pharmacokinetics, and toxicity profiles.

Docetaxel (DTX), a taxane-based anticancer drug, and osthol (OTH), a coumarin-derivative compound, have shown anticancer effects against different types of cancers through various mechanisms. However, these drugs have low solubility in water and low oral bioavailability, and thus their clinical application is difficult. To overcome these problems, we encapsulated DTX and OTH in methoxy poly(ethylene glycol)-b-poly(caprolactone) (mPEG-b-PCL) and conducted studies in vitro and in vivo. We selected a 1:4 ratio as the optimal ratio of DTX and OTH, through combination index analysis in A549 cancer cells, and prepared micelles to evaluate the encapsulation efficiency, drug loading, particle size, and zeta potential. The in vitro drug-release profile showed that DTX/OTH-loaded mPEG-b-PCL micelles could slowly release DTX and OTH. In the clonogenic assay, DTX/OTH-loaded mPEG-b-PCL micelles showed 3.7 times higher inhibitory effect than the DTX/OTH solution. Pharmacokinetic studies demonstrated that micelles in combination with DTX and OTH exhibited increased area under curve and decreased clearance values, as ​​compared with single micelles.

Three-dimensional (3D) surface deformation is retrieved for the March 6–10, 2011 (UTC dates), Kamoamoa fissure eruption along the East Rift Zone of Kīlauea Volcano, Hawai'i, through the integration of multi-temporal synthetic aperture radar (SAR) interferometry (InSAR) and multiple-aperture interferometry (MAI) measurements from the COSMO-SkyMed X-band SAR. The measurement accuracies of 1) the individual and multi-stacked MAI interferograms and 2) the 3D deformation, which is measured from COSMO-SkyMed data, are assessed using continuous GPS stations. The root-mean-square (RMS) errors of individual MAI interferograms for descending and ascending data are 2.97 ± 0.6 cm and 3.20 ± 0.62 cm, respectively. The MAI interferograms stacked from multi-temporal observations can produce better results by emphasizing surface deformation signals, with the RMS errors of 1.06 and 1.24 cm for descending and ascending data, respectively. The empirical equations for measurement uncertainties are determined with respect to interferometric coherence for individual and stacked MAI interferograms. An assessment of the 3D components of deformation was performed as well, and RMS errors of 0.75, 0.83, and 0.68 cm were estimated in the east, north, and up directions. A performance test of magma source model parameter estimations was carried out by using the InSAR and 3D measurements. From the 3D deformation field, we found that the magma chamber source at the Kīlauea caldera should be modeled by the spheroid source rather than the simple point source. The performance comparison between the InSAR and 3D modeled results showed that the 3D deformation field allows for precise model parameter estimation.

To develop novel functional ingredients, a polysaccharide called BF-E2-P was purified from fermented barley and its antitumor activity was investigated. In the experimental lung metastasis model of colon 26-M3.1 carcinoma cells, intravenous administration of BF-E2-P (500 μg/mouse) 2 days before inoculation resulted in inhibition of metastasis by about 76%, and the extent of inhibition was dose-dependent. To demonstrate the anti-metastatic activity of BF-E2-P, we tested whether BF-E2-P could activate the innate immune system. Stimulation of macrophages by BF-E2-P resulted in cytokine production. In a co-culture of macrophages and cancer cells, BF-E2-P altered the pattern of cytokine production, suggesting that BF-E2-P affects the polarization of macrophages. In addition, intravenous administration of BF-E2-P augmented the natural killer (NK) cell-mediated cytotoxicity against cancer cells. It also increased the production of IFN- γ and granzyme B. In conclusion, BF-E2-P activates NK cells and macrophages, resulting in the enhancement of host-defense against tumor growth.

North Korea conducted the sixth nuclear test in Punggye-ri on 3 September 2017. An artificial earthquake of Mw 6.3 was reported near North Korea's Punggye-ri nuclear test site. Several minutes later, a second smaller earthquake followed the initial event, and it was characterized as a collapse of the cavity. The large and complex deformations related to the earthquakes occurred in the ground surface. It is very important to measure the artificial earthquake-related deformations, because it enables us to estimate the location, depth and cavity radius of the nuclear test. We observed the three-dimensional surface deformations related to the sixth North Korea nuclear test using the ascending and descending ALOS-2 PALSAR-2 radar offset-tracking. We used the multi-kernel offset tracking method to improve the precision of the offset-tracking measurement. The maximum deformation of more than 3 m was observed in the horizontal direction. We estimated the location, depth and cavity radius using the Mogi model. The estimated depth and cavity radius are about 600 m and about 52 m, respectively. The satellite offset-tracking observation will contribute to the nuclear test monitoring and characterization.

Synthetic Aperture Radar Interferometry (InSAR) provides one-dimensional measurements on ground displacement in the radar line-of-sight (LOS) direction. Multiple-Aperture Interferometry (MAI) technique has been successfully used to measure along-track ground displacement. However, the technique occasionally shows filtering boundary artifacts along the boundary of incoherent areas and a loss of MAI coherence in the presence of large and complex LOS deformation. In this study, we propose an efficient MAI processing method to mitigate them and improve computational efficiencies as well. We validated the performance of the proposed MAI method using ALOS PALSAR interferometric pair acquired from the ascending orbits on June 12, 2007 and August 2, 2009. The test pair includes large and complex LOS deformation signals accumulated from several dike intrusions and fissure eruptions. Through the proposed MAI processing method, we have generated the InSAR and MAI interferograms with the pixel spacing of about 45 and 40 m in ground range and azimuth directions, respectively. Close to surface rupture, we found that our proposed method improved the MAI coherence from 0.33 to 0.96 and reduced the filtering boundary artifacts from 0.068 to 0.040 rad. The results demonstrate the potential of the proposed method to measure along-track ground displacement in regions of decorrelation.

Multiple-aperture SAR interferometry (MAI) has demonstrated outstanding measurement accuracy of along-track displacement when compared to pixel-offset-tracking methods; however, measuring slow-moving (cm/year) surface displacement remains a challenge. Stacking of multi-temporal observations is a potential approach to reducing noise and increasing measurement accuracy, but it is difficult to achieve a significant improvement by applying traditional stacking methods to multi-temporal MAI interferograms. This paper proposes an efficient MAI stacking method, where multi-temporal forward- and backward-looking residual interferograms are individually stacked before the MAI interferogram is generated. We tested the performance of this method using ENVISAT data from Kīlauea Volcano, Hawai‘i, where displacement on the order of several centimeters per year is common. By comparing results from the proposed stacking methods with displacements from GPS data, we documented measurement accuracies of about 1.03 and 1.07 cm/year for the descending and ascending tracks, respectively—an improvement of about a factor of two when compared with that from the conventional stacking approach. Three-dimensional surface-displacement maps can be constructed by combining stacked InSAR and MAI observations, which will contribute to a better understanding of a variety of geological phenomena.

The somatostatin analog octreotide has recently been introduced in the treatment of infants with chylothorax. The safety profile of octreotide has not been fully evaluated. Octreotide reduces the splanchnic blood flow in a dose-dependent manner, affecting the entire gastrointestinal tract. Some concern has been recently raised regarding the potential implications of this effect in the development of necrotizing enterocolitis in neonates receiving octreotide for congenital hyperinsulinism or chylothorax. To our knowledge, there is no case report linking the use of octreotide with necrotizing enterocolitis in Korea. We report a case of serious necrotizing enterocolitis in a neonate treated with octreotide for congenital idiopathic chylothorax.

We reconstructed the three-dimensional (3D) surface displacement field of the 24 August 2014 M6.0 South Napa earthquake using SAR data from the Italian Space Agency’s COSMO-SkyMed and the European Space Agency’s Sentinel-1A satellites. Along-track and cross-track displacements produced with conventional SAR interferometry (InSAR) and multiple-aperture SAR interferometry (MAI) techniques were integrated to retrieve the east, north, and up components of surface deformation. The resulting 3D displacement maps clearly delineated the right-lateral shear motion of the fault rupture with a maximum surface displacement of approximately 45 cm along the fault’s strike, showing the east and north components of the trace particularly clearly. These maps also suggested a better-constrained model for the South Napa earthquake. We determined a strike of approximately 338° and dip of 85° by applying the Okada dislocation model considering a single patch with a homogeneous slip motion. Using the distributed slip model obtained by a linear solution, we estimated that a peak slip of approximately 1.7 m occurred around 4 km depth from the surface. 3D modelling using the retrieved 3D maps helps clarify the fault’s nature and thus characterize its behaviour.

The San Andreas Fault (SAF) is a continental transform fault that exists as a consequence of the relative motion of the Pacific and North American Plates. Differential SAR interferometry (DInSAR) particularly with a time-series analysis is an effective tool for long-term monitoring of the SAF. Radar interferometric phase, however, contains unwanted noises originated from atmosphere as well as observation system. For studying characteristics of interferometric phase at the southern end of the SAF zone, ERS-1/2 data, acquired from 1992 to 1999, and ENVISAT data, from 2003 to the present, were utilized. Troposphere interference and orbit error were the most significant sources of errors. Since the phase noise highly correlates with topographic elevation, a simulated interferogram from topographic elevation was utilized to compensate for the tropospheric signal delay. After subtracting the simulated phase from each DInSAR interferogram, more reliable results were obtained. These results are supported by comparison with the geodetic GPS data set.

Despite several studies using the multiple-aperture interferometry (MAI) technique, X-band SAR has rarely been applied to MAI-based studies due to their shorter decorrelation timescale. However, the relatively short antenna length and high temporal resolution of the COSMO-SkyMed X-band SAR system provides an opportunity to measure the precise displacement in the along-track direction. In this study, we have assessed the MAI performance in comparison with GPS and established an empirical uncertainty model of MAI measurements with respect to interferometric coherence. It enables us to confirm the difference between theoretical and practical uncertainties of the MAI method. Moreover, this study will be helpful for evaluating the reliability of MAI measurements where GPS data are unavailable.