Exploring the Tumor-Associated Risk of Mesenchymal Stem Cell Therapy in Veterinary Medicine.

Mesenchymal stem cell (MSC) therapy has been actively applied in veterinary regenerative medicine to treat various canine and feline diseases. With increasing emphasis on safe cell-based therapies, evaluations of their tumorigenic potential are in great demand. However, a direct confirmation of whether tumors originate from stem cells or host cells is not easily achievable. Additionally, previous studies evaluating injections of high doses of MSCs into nude mice did not demonstrate tumor formation. Recent research focused on optimizing MSC-based therapies for veterinary patients, such as MSC-derived extracellular vesicles in treating different diseases. This progress also signifies a broader shift towards personalized veterinary medicine, where treatments can be tailored to individual pets based on their unique genetic profiles. These findings related to different treatments using MSCs emphasize their future potential for veterinary clinical applications. In summary, because of lower tumor-associated risk of MSCs as compared to embryonic and induced pluripotent stem cells, MSCs are considered a suitable source for treating various canine and feline diseases.

Exceptional Repositioning of Dog Dewormer: Fenbendazole Fever.

Fenbendazole (FZ) is a benzimidazole carbamate drug with broad-spectrum antiparasitic activity in humans and animals. The mechanism of action of FZ is associated with microtubular polymerization inhibition and glucose uptake blockade resulting in reduced glycogen stores and decreased ATP formation in the adult stages of susceptible parasites. A completely cured case of lung cancer became known globally and greatly influenced the cancer community in South Korea. Desperate Korean patients with cancer began self-administering FZ without their physician's knowledge, which interfered with the outcome of the cancer treatment planned by their oncologists. On the basis of presented evidence, this review provides valuable information from PubMed, Naver, Google Scholar, and Social Network Services (SNS) on the effects of FZ in a broad range of preclinical studies on cancer. In addition, we suggest investigating the self-administration of products, including supplements, herbs, or bioactive compounds, by patients to circumvent waiting for long and costly FZ clinical trials.

Superior therapeutic activity of TGF-ß-induced extracellular vesicles against interstitial cystitis.

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic disease characterized by incapacitating pelvic pain. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) are considered key mediators of the paracrine action of MSCs and show better biological activities than the parent MSCs, especially in the bladder tissue, which may be unfavorable for MSC survival. Here, we produced MSC-EVs using advanced three-dimensional (a3D) culture with exogenous transforming growth factor-ß3 (TGF-ß3) (T-a3D-EVs). Treatment with T-a3D-EVs led to significantly enhanced wound healing and anti-inflammatory capacities. Moreover, submucosal layer injection of T-a3D-EVs in chronic IC/BPS animal model resulted in restoration of bladder function, superior anti-inflammatory activity, and recovery of damaged urothelium compared to MSCs. Interestingly, we detected increased TGF-ß1 level in T-a3D-EVs, which might be involved in the anti-inflammatory activity of these EVs. Taken together, we demonstrate the excellent immune-modulatory and regenerative abilities of T-a3D-EVs as observed by recovery from urothelial denudation and dysfunction, which could be a promising therapeutic strategy for IC/BPS.

Double Repositioning: Veterinary Antiparasitic to Human Anticancer.

Drug repositioning, the approach of discovering different uses for existing drugs, has gained enormous popularity in recent years in the anticancer drug discovery field due to the increasing demand for anticancer drugs. Additionally, the repurposing of veterinary antiparasitic drugs for the treatment of cancer is gaining traction, as supported by existing literature. A prominent example is the proposal to implement the use of veterinary antiparasitics such as benzimidazole carbamates and halogenated salicylanilides as novel anticancer drugs. These agents have revealed pronounced anti-tumor activities and gained special attention for "double repositioning", as they are repurposed for different species and diseases simultaneously, acting via different mechanisms depending on their target. As anticancer agents, these compounds employ several mechanisms, including the inhibition of oncogenic signal transduction pathways of mitochondrial respiration and the inhibition of cellular stress responses. In this review, we summarize and provide valuable information about the experimental, preclinical, and clinical trials of veterinary antiparasitic drugs available for the treatment of various cancers in humans. This review suggests the possibility of new treatment options that could improve the quality of life and outcomes for cancer patients in comparison to the currently used treatments.

Effects of carrier solutions on the viability and efficacy of canine adipose-derived mesenchymal stem cells.

BACKGROUND: Mesenchymal stem cells (MSCs) have favorable characteristics that render them a potent therapeutic tool. We tested the characteristics of MSCs after temporal storage in various carrier solutions, such as 0.9% saline (saline), 5% dextrose solution (DS), heparin in saline, and Hartmann's solution, all of which are approved by the U.S. Food and Drug Administration (FDA). Phosphate-buffered saline, which does not have FDA approval, was also used as a carrier solution. We aimed to examine the effects of these solutions on the viability and characteristics of MSCs to evaluate their suitability and efficacy for the storage of canine adipose-derived MSCs (cADMSCs). RESULTS: We stored the cADMSCs in the test carrier solutions in a time-dependent manner (1, 6, and 12 h) at 4 °C, and analyzed cell confluency, viability, proliferation, self-renewability, and chondrogenic differentiation. Cell confluency was significantly higher in 5% DS and lower in phosphate-buffered saline at 12 h compared to other solutions. cADMSCs stored in saline for 12 h showed the highest viability rate. However, at 12 h, the proliferation rate of cADMSCs was significantly higher after storage in 5% DS and significantly lower after storage in saline, compared to the other solutions. cADMSCs stored in heparin in saline showed superior chondrogenic capacities at 12 h compared to other carrier solutions. The expression levels of the stemness markers, Nanog and Sox2, as well as those of the MSC surface markers, CD90 and CD105, were also affected over time. CONCLUSION: Our results suggest that MSCs should be stored in saline, 5% DS, heparin in saline, or Hartmann's solution at 4 °C, all of which have FDA approval (preferable storage conditions: less than 6 h and no longer than 12 h), rather than storing them in phosphate-buffered saline to ensure high viability and efficacy.

Identification of a multi-stack structure of graphene electrodes doped layer-by-layer with benzimidazole and its implication for the design of optoelectronic devices.

Optical properties of benzimidazole (BI)-doped layer-by-layer graphene differ significantly from those of intrinsic graphene. Our study based on transmission electron microscopy and X-ray photoelectron spectroscopy depth profiling reveals that such a difference stems from its peculiar stratified geometry formed in situ during the doping process. This work presents an effective thickness and optical constants that can treat these multi-stacked BI-doped graphene electrodes as a single equivalent medium. For verification, the efficiency and angular emission spectra of organic light-emitting diodes with the BI-doped graphene electrode are modeled with the proposed method, and we demonstrate that the calculation matches experimental results in a much narrower margin than that based on the optical properties of undoped graphene.

Metal-Organic Framework as a Functional Analyte Channel of Organic-Transistor-Based Air Pollution Sensors.

Air pollution sensors based on organic transistors have attracted much interest recently; however, the devices suffer from low responsivity and slow response and recovery rates for gas analytes. These shortcomings are attributed to the low charge-carrier mobility of organic semiconductors and to a structural limitation resulting from the use of a thick and continuous active layer. In the present work, we investigated the material properties of a multiscale porous zeolitic imidazolate framework, [Zn(2-methylimidazole)2]n (ZIF-8), and examined its potential as an analyte channel material inserted at an organic-transistor active layer. A series of carbonized zeolitic imidazolate frameworks (ZIFs) were prepared by thermal conversion of ZIF-8 and also studied for comparison. The microstructures, morphologies, and optical/electrical characteristics of polythiophene/ZIF-8 hybrid films were systematically investigated. Organic-transistor-type nitrogen dioxide sensors based on the polythiophene/ZIF-8 hybrid films showed substantially improved sensing properties, including responsivity, response rate, and recovery rate. The electrical conductivity of the carbonized ZIF-8s enhanced the field-effect mobility of the organic transistors; however, the sensing performance was not improved, because of the closed pore structures resulting from the carbonization. These results provide invaluable information and useful insights into the design of transistor-type gas sensors based on organic semiconductor/metal-organic framework hybrid films.

Solvent-assisted strongly enhanced light-emitting electrochemiluminescent devices for lighting applications.

Rubrene-based electrochemiluminescence (r-ECL) cells with two different solvent systems is prepared, one in a co-solvent system with a mixture of 1,2-dichlorobenzene and propylene carbonate (DCB : PC, v/v 3 : 1) and another in a single solvent system of tetrahydrofuran (THF), as the medium to form a liquid-electrolyte (L-El). By simply changing the solvent systems, from the co-solvent DCB : PC (v/v 3 : 1) to the single solvent THF, with the same amount of electrochemiluminescent rubrene (5 mM) and Li-based salt, a dramatically enhanced brightness of over 30 cd m-2 is observed for the r-ECL cell in L-ElTHF which is approximately 7-times higher than the brightness of 5 cd m-2 observed for the r-ECL in L-ElDCB:PC(v/v 3:1).

Ginseng Gintonin Contains Ligands for GPR40 and GPR55.

Gintonin, a novel ginseng-derived glycolipoprotein complex, has an exogenous ligand for lysophosphatidic acid (LPA) receptors. However, recent lipid analysis of gintonin has shown that gintonin also contains other bioactive lipids besides LPAs, including linoleic acid and lysophosphatidylinositol (LPI). Linoleic acid, a free fatty acid, and LPI are known as ligands for the G-protein coupled receptors (GPCR), GPR40, and GPR55, respectively. We, herein, investigated whether gintonin could serve as a ligand for GPR40 and GPR55, using the insulin-secreting beta cell-derived cell line INS-1 and the human prostate cancer cell line PC-3, respectively. Gintonin dose-dependently enhanced insulin secretion from INS-1 cells. Gintonin-stimulated insulin secretion was partially inhibited by a GPR40 receptor antagonist but not an LPA1/3 receptor antagonist and was down-regulated by small interfering RNA (siRNA) against GPR40. Gintonin dose-dependently induced [Ca2+]i transients and Ca2+-dependent cell migration in PC-3 cells. Gintonin actions in PC-3 cells were attenuated by pretreatment with a GPR55 antagonist and an LPA1/3 receptor antagonist or by down-regulating GPR55 with siRNA. Taken together, these results demonstrated that gintonin-mediated insulin secretion by INS-1 cells and PC-3 cell migration were regulated by the respective activation of GPR40 and GPR55 receptors. These findings indicated that gintonin could function as a ligand for both receptors. Finally, we demonstrated that gintonin contained two more GPCR ligands, in addition to that for LPA receptors. Gintonin, with its multiple GPCR ligands, might provide the molecular basis for the multiple pharmacological actions of ginseng.

Ultraflexible and transparent electroluminescent skin for real-time and super-resolution imaging of pressure distribution.

The ability to image pressure distribution over complex three-dimensional surfaces would significantly augment the potential applications of electronic skin. However, existing methods show poor spatial and temporal fidelity due to their limited pixel density, low sensitivity, or low conformability. Here, we report an ultraflexible and transparent electroluminescent skin that autonomously displays super-resolution images of pressure distribution in real time. The device comprises a transparent pressure-sensing film with a solution-processable cellulose/nanowire nanohybrid network featuring ultrahigh sensor sensitivity (>5000 kPa-1) and a fast response time (<1 ms), and a quantum dot-based electroluminescent film. The two ultrathin films conform to each contact object and transduce spatial pressure into conductivity distribution in a continuous domain, resulting in super-resolution (>1000 dpi) pressure imaging without the need for pixel structures. Our approach provides a new framework for visualizing accurate stimulus distribution with potential applications in skin prosthesis, robotics, and advanced human-machine interfaces.

Locating the Instant Center of Rotation in the Subaxial Cervical Spine with Biplanar Fluoroscopy during In Vivo Dynamic Flexion-Extension.

BACKGROUND: Recently, biplanar fluoroscopy is used to evaluate the cervical kinematics, especially to locate the instant center of rotation (ICR) during in vivo motion. This study aims to ascertain the ICR at each cervical segment in the sagittal plane during dynamic motion and assess the differences from previous studies. METHODS: While three healthy subjects were performing full flexion-extension, two oblique views aligned horizontally and angled at approximately 55° were obtained by biplanar fluoroscopy. The minimum degree to detect significant movement in a helical axis model was set at 2°, and anterior-posterior and superior-inferior locations of each ICR were defined. To evaluate the possible distribution area and overlapping area of the ICR with disc space, we drew a circle by using the calculated distance between each coordination and the mean coordination of ICR as the radius. RESULTS: During flexion-extension motion, the mean superior-inferior location of the ICR became progressively more superior, except the C5-6 segment (p = 0.015), and the mean anterior-posterior location of the ICR became progressively more anterior without exception from C2-3 to C6-7 segments, but anterior-posterior ICR locations were not significantly different among segments. The overlapping area with the distribution circle of ICR was mainly located in the posterior half in the C3-4 segment, but the overlapping area was about 80% of the total disc space in C4-5 and C6-7 segments. The overlapping was more noticeable in the lower cervical segments after exclusion of the outlier data of the C5-6 segment in subject 1. CONCLUSIONS: The ICR in the cervical spine showed a trend of moving progressively more superiorly and anteriorly and the disc space overlapping the distribution circle of ICR increased along the lower motion segments except the C5-6 segment. These findings could provide a good basis for level-specific cervical arthroplasty designs.

Translational assessment of a genetic engineering methodology to improve islet function for transplantation.

BACKGROUND: The functional quality of insulin-secreting islet beta cells is a major factor determining the outcome of clinical transplantations for diabetes. It is therefore of importance to develop methodological strategies aiming at optimizing islet cell function prior to transplantation. In this study we propose a synthetic biology approach to genetically engineer cellular signalling pathways in islet cells. METHODS: We established a novel procedure to modify islet beta cell function by combining adenovirus-mediated transduction with reaggregation of islet cells into pseudoislets. As a proof-of-concept for the genetic engineering of islets prior to transplantation, this methodology was applied to increase the expression of the V1b receptor specifically in insulin-secreting beta cells. The functional outcomes were assessed in vitro and in vivo following transplantation into the anterior chamber of the eye. FINDINGS: Pseudoislets produced from mouse dissociated islet cells displayed basic functions similar to intact native islets in terms of glucose induced intracellular signalling and insulin release, and after transplantation were properly vascularized and contributed to blood glucose homeostasis. The synthetic amplification of the V1b receptor signalling in beta cells successfully modulated pseudoislet function in vitro. Finally, in vivo responses of these pseudoislet grafts to vasopressin allowed evaluation of the potential benefits of this approach in regenerative medicine. INTERPRETATION: These results are promising first steps towards the generation of high-quality islets and suggest synthetic biology as an important tool in future clinical islet transplantations. Moreover, the presented methodology might serve as a useful research strategy to dissect cellular signalling mechanisms of relevance for optimal islet function.

Current Status of Canine Umbilical Cord Blood-Derived Mesenchymal Stem Cells in Veterinary Medicine.

Stem cell therapy has prompted the expansion of veterinary medicine both experimentally and clinically, with the potential to contribute to contemporary treatment strategies for various diseases and conditions for which limited or no therapeutic options are presently available. Although the application of various types of stem cells, such as bone marrow-derived mesenchymal stem cells (BM-MSCs), adipose tissue-derived mesenchymal stem cells (AT-MSCs), and umbilical cord blood-derived mesenchymal stem cells (UCB-MSCs), has promising potential to improve the health of different species, it is crucial that the benefits and drawbacks are completely evaluated before use. Umbilical cord blood (UCB) is a rich source of stem cells; nonetheless, isolation of mesenchymal stem cells (MSCs) from UCB presents technical challenges. Although MSCs have been isolated from UCB of diverse species such as human, equine, sheep, goat, and canine, there are inherent limitations of using UCB from these species for the expansion of MSCs. In this review, we investigated canine UCB (cUCB) and compared it with UCB from other species by reviewing recent articles published from February 2003 to June 2017 to gain an understanding of the limitations of cUCB in the acquisition of MSCs and to determine other suitable sources for the isolation of MSCs from canine. Our review indicates that cUCB is not an ideal source of MSCs because of insufficient volume and ethical issues. However, canine reproductive organs discarded during neutering may help broaden our understanding of effective isolation of MSCs. We recommend exploring canine reproductive and adipose tissue rather than UCB to fulfill the current need in veterinary medicine for the well-designed and ethically approved source of MSCs.

Mechanistic Understanding of Improved Performance of Graphene Cathode Inverted Organic Light-Emitting Diodes by Photoemission and Impedance Spectroscopy.

Modification of multilayer graphene films was investigated for a cathode of organic light-emitting diodes (OLEDs). By doping the graphene/electron transport layer (ETL) interface with Li, the driving voltage of the OLED was reduced dramatically from 24.5 to 3.2 V at a luminance of 1000 cd/m2. The external quantum efficiency was also enhanced from 3.4 to 12.9%. Surface analyses showed that the Li doping significantly lowers the lowest unoccupied molecular orbital level of the ETL, thereby reducing the electron injection barrier and facilitating electron injection from the cathode. Impedance spectroscopy analyses performed on electron-only devices (EODs) revealed the existence of distributed trap states with a well-defined activation energy, which is successfully described by the Havriliak-Negami capacitance functions and the temperature-independent frequency dispersion parameters. In particular, the graphene EOD showed a unique high-frequency feature as compared to the indium tin oxide one, which could be explained by an additional parallel capacitance element.

Optical Analysis of Power Distribution in Top-Emitting Organic Light Emitting Diodes Integrated with Nanolens Array Using Finite Difference Time Domain.

Recently, we have addressed that a formation mechanism of a nanolens array (NLA) fabricated by using a maskless vacuum deposition is explained as the increase in surface tension of organic molecules induced by their crystallization. Here, as another research using finite difference time domain simulations, not electric field intensities but transmitted energies of electromagnetic waves inside and outside top-emitting blue organic light-emitting diodes (TOLEDs), without and with NLAs, are obtained, to easily grasp the effect of NLA formation on the light extraction of TOLEDs. Interestingly, the calculations show that NLA acts as an efficient light extraction structure. With NLA, larger transmitted energies in the direction from emitting layer to air are observed, indicating that NLAs send more light to air otherwise trapped in the devices by reducing the losses by waveguide and absorption. This is more significant for higher refractive index of NLA. Simulation and measurement results are consistent. A successful increase in both light extraction efficiency and color stability of blue TOLEDs, rarely reported before, is accomplished by introducing the highly process-compatible NLA technology using the one-step dry process. Blue TOLEDs integrated with a N, N'-di(1-naphthyl)- N, N'-diphenyl-(1,1'-biphenyl)-4,4'-diamine NLA with a refractive index of 1.8 show a 1.55-times-higher light extraction efficiency, compared to those without it. In addition, viewing angle characteristics are enhanced and image blurring is reduced, indicating that the manufacturer-adaptable technology satisfies the requirements of highly efficient and color-stable top-emission displays.

Graphene Electrode Enabling Electrochromic Approaches for Daylight-Dimming Applications.

For environmental reason, buildings increasingly install smart windows, which can dim incoming daylight based on active electrochromic devices (ECDs). In this work, multi-layered graphene (MLG) was investigated as an ECD window electrode, to minimize carbon dioxide (CO2) emissions by decreasing the electricity consumption for building space cooling and heating and as an alternative to the transparent conductor tin-doped indium oxide (ITO) in order to decrease dependence on it. Various MLG electrodes with different numbers of graphene layers were prepared with environmentally friendly poly(3,4-ethylenedioxythiophene):poly(styrene-sulfonate) (PEDOT:PSS) to produce ECD cells. Tests demonstrated the reproducibility and uniformity in optical performance, as well as the flexibility of the ECD fabrication. With the optimized MLG electrode, the ECD cells exhibited a very fast switching response for optical changes from transparent to dark states of a few hundred msec.

Overcoming the efficiency limit of organic light-emitting diodes using ultra-thin and transparent graphene electrodes.

We propose an effective way to enhance the out-coupling efficiencies of organic light-emitting diodes (OLEDs) using graphene as a transparent electrode. In this study, we investigated the detrimental adsorption and internal optics occurring in OLEDs with graphene anodes. The optical out-coupling efficiencies of previous OLEDs with transparent graphene electrodes barely exceeded those of OLEDs with conventional transparent electrodes because of the weak microcavity effect. To overcome this issue, we introduced an internal random scattering layer for light extraction and reduced the optical absorption of the graphene by reducing the number of layers in the multilayered graphene film. The efficiencies of the graphene-OLEDs increased significantly with decreasing the number of graphene layers, strongly indicating absorption reduction. The maximum light extraction efficiency was obtained by using a single-layer graphene electrode together with a scattering layer. As a result, a widened angular luminance distribution with a remarkable external quantum efficiency and a luminous efficacy enhancement of 52.8% and 48.5%, respectively, was achieved. Our approach provides a demonstration of graphene-OLED having a performance comparable to that of conventional OLEDs.

Unraveled Face-Dependent Effects of Multilayered Graphene Embedded in Transparent Organic Light-Emitting Diodes.

With increasing demand for transparent conducting electrodes, graphene has attracted considerable attention, owing to its high electrical conductivity, high transmittance, low reflectance, flexibility, and tunable work function. Two faces of single-layer graphene are indistinguishable in its nature, and this idea has not been doubted even in multilayered graphene (MLG) because it is difficult to separately characterize the front (first-born) and the rear face (last-born) of MLG by using conventional analysis tools, such as Raman and ultraviolet spectroscopy, scanning probe microscopy, and sheet resistance. In this paper, we report the striking difference of the emission pattern and performance of transparent organic light-emitting diodes (OLEDs) depending on the adopted face of MLG and show the resolved chemical and physical states of both faces by using depth-selected absorption spectroscopy. Our results strongly support that the interface property between two different materials rules over the bulk property in the driving performance of OLEDs.

DC-SIGN expression in Hofbauer cells may play an important role in immune tolerance in fetal chorionic villi during the development of preeclampsia.

Immune tolerance at feto-maternal interfaces is a complex phenomenon. Although maternal decidual macrophages are well-known immune cells, little is known about fetal-derived macrophages (Hofbauer cells) within chorionic villi. Preeclampsia (PE) is a major cause of maternal mortality in the field of obstetrics, and the innate immunological role of maternal decidual macrophages is well known. In this study, we assessed the differential phenotypes and marker expression in fetal macrophages, known as dendritic cell-specific ICAM-grabbing non-integrin (DC-SIGN)-positive Hofbauer cells. We compared Hofbauer cell properties between normal and PE placenta chorionic villi and performed sequential staining of DC-SIGN, CD14, and CD68 to evaluate the existence of Hofbauer cells. Furthermore, to evaluate the immunological function of these cells, we stained the cells for CD163, a marker of immunoregulatory type 2 (M2) macrophages. Additionally, we examined the expression of the immunosuppressive cytokine interleukin (IL)-10, which is known to be produced by M2 macrophages. DC-SIGN+/CD14+, DC-SIGN+/CD68+, and CD163+/DC-SIGN+ cells were quantified based on photomicrographs. The results showed that CD14, CD163, DC-SIGN, and IL-10 levels were significantly downregulated in PE compared with normal. Additionally, CD163+/DC-SIGN+ Hofbauer cells were significantly less frequent in PE than in normal. DC-SIGN Hofbauer cells produced IL-10 at lower levels in the PE than in the normal. Thus, we speculate that fetal-derived Hofbauer cells may play an important role in normal pregnancy with immunosuppressive effects based on their M2 macrophage characteristics to maintain immune tolerance during pregnancy. Additionally, in PE, these functions were defective, supporting the roles of these macrophages in PE development.