Efficacy of 3D-printed simulation models of unruptured intracranial aneurysms in patient education and surgical simulation.

OBJECTIVE: The purpose of this study was to determine the efficacy of a 3D-printed aneurysm simulation model (3DPM) in educating patients and improving physicians' comprehension and performance. METHODS: This prospective study involved 40 patients who were diagnosed with unruptured intracranial aneurysms (UIAs) and scheduled for surgical clipping or endovascular coiling and randomly divided into two groups (the 3DPM group and the non-3DPM group). The 3DPM was used in preoperative consultation with patients and intraoperatively referenced by surgeons. The patients, 7 neurosurgical residents, and 10 surgeons completed questionnaires (5-point Likert scale) to determine the usefulness of the 3DPM. RESULTS: Patients in the 3DPM group had significantly higher scores in terms of their understanding of the disease (mean 4.85 vs. 3.95, p<0.001) and the treatment plan (mean 4.85 vs. 4.20, p=0.005) and reported higher satisfaction during consultation (5.0 vs. 4.60, p=0.036) than patients in the non-3DPM group. During patient consultation, 3DPMs were most useful in improving doctor-patient communication (mean 4.57, range 4-5). During clipping surgery, the models were most useful in assessing adjacent arteries (mean 4.9, range 4-5); during endovascular coiling, they were especially helpful in microcatheter shaping (mean 4.7, range 4-5). CONCLUSIONS: In general, 3DPMs are beneficial in educating patients and improving the physician's performance in terms of surgical clipping and endovascular coiling of UIAs.

A Novel Biosensor and Algorithm to Predict Vitamin D Status by Measuring Skin Impedance.

The deficiency and excess of vitamin D cause various diseases, necessitating continuous management; but it is not easy to accurately measure the serum vitamin D level in the body using a non-invasive method. The aim of this study is to investigate the correlation between vitamin D levels, body information obtained by an InBody scan, and blood parameters obtained during health checkups, to determine the optimum frequency of vitamin D quantification in the skin and to propose a vitamin D measurement method based on impedance. We assessed body composition, arm impedance, and blood vitamin D concentrations to determine the correlation between each element using multiple machine learning analyses and an algorithm which predicted the concentration of vitamin D in the body using the impedance value developed. Body fat percentage obtained from the InBody device and blood parameters albumin and lactate dehydrogenase correlated with vitamin D level. An impedance measurement frequency of 21.1 Hz was reflected in the blood vitamin D concentration at optimum levels, and a confidence level of about 75% for vitamin D in the body was confirmed. These data demonstrate that the concentration of vitamin D in the body can be predicted using impedance measurement values. This method can be used for predicting and monitoring vitamin D-related diseases and may be incorporated in wearable health measurement devices.

Photobiomodulation (660 nm) therapy reduces oxidative stress and induces BDNF expression in the hippocampus.

Photobiomodulation therapy (PBMT) effects an important role in neural regeneration and function enhancement, such as expression of nerve growth factor and nerve regeneration, in neuronal tissues, and inhibition of cell death by amyloid beta in neurons is inhibited by PBMT. However, there no studies evaluated the effects of PBMT on oxidative stress in the hippocampus. The aim of this study is to evaluate the effects of PBMT on oxidative stress in the hippocampus. This study assessed the anti-oxidative effect, the expression of BDNF and antioxidant enzymes, as well as the activation of cAMP response element binding (CREB) and extracellular signal-regulated kinase (ERK) signal transduction pathways assess using a hippocampal cell line (HT-22) and mouse organotypic hippocampal tissues by PBMT (LED, 660 nm, 20 mW/cm2). PBMT inhibited HT-22 cell death by oxidative stress and increased BDNF expression via ERK and CREB signaling pathway activation. In addition, PBMT increased BDNF expression in hippocampal organotypic slices and the levels of phosphorylated ERK and CREB, which were reduced by oxidative stress, as well as the expression of the antioxidant enzyme superoxide dismutase. These data demonstrate that PBMT inhibits hippocampal damage induced by oxidative stress and increases the expression of BDNF, which can be used as an alternative to treat a variety of related disorders that lead to nerve damage. Activation and redox homeostasis in neuronal cells may be a notable mechanism of the 660-nm PBMT-mediated photobioreactivity.

Novel smart clothing with dry electrode biosensor for real-time automatic diagnosis of cardiovascular diseases.

The incidence of heart disease increases with age. The typical method of monitoring arrhythmia is to use a body patch type sensor with a wet electrode. Even though this sensor is easy to use, it has several disadvantages such as problems caused by wet electrodes in tissues when they are monitored for long periods. Thus, a monitoring sensor integrated into clothes with a dry electrode is proposed. In this study, we developed a smart outdoor shirt equipped with a dry electrode electrocardiogram (ECG) sensor for a cardiac arrhythmia computer-aided diagnosis system. The sensor can be inserted in a console close to the chest, charged, used to communicate wirelessly, and can be connected to a smartphone application. According to experiments, the ECG signals measured by the smart shirt indicated that 97.5 ± 1% of the signals could be measured in an immobile state and at least 85.2 ± 2% of the signals could be measured during movement. In addition, we propose a computer-aided diagnosis system for detecting cardiac arrhythmia. It was determined through experiments that the system can detect arrhythmia with an accuracy of 98.2 ± 2%.

Induction of Inflammation In Vivo by Electrocardiogram Sensor Operation Using Wireless Power Transmission.

Prolonged monitoring by cardiac electrocardiogram (ECG) sensors is useful for patients with emergency heart conditions. However, implant monitoring systems are limited by lack of tissue biocompatibility. Here, we developed an implantable ECG sensor for real-time monitoring of ventricular fibrillation and evaluated its biocompatibility using an animal model. The implantable sensor comprised transplant sensors with two electrodes, a wireless power transmission system, and a monitoring system. The sensor was inserted into the subcutaneous tissue of the abdominal area and operated for 1 h/day for 5 days using a wireless power system. Importantly, the sensor was encapsulated by subcutaneous tissue and induced angiogenesis, inflammation, and phagocytosis. In addition, we observed that the levels of inflammation-related markers increased with wireless-powered transmission via the ECG sensor; in particular, levels of the Th-1 cytokine interleukin-12 were significantly increased. The results showed that induced tissue damage was associated with the use of wireless-powered sensors. We also investigated research strategies for the prevention of adverse effects caused by lack of tissue biocompatibility of a wireless-powered ECG monitoring system and provided information on the clinical applications of inflammatory reactions in implant treatment using the wireless-powered transmission system.

Computer aided diagnosis sensor integrated outdoor shirts for real time heart disease monitoring.

The typical method of monitoring arrhythmia is to use a body patch type sensor with a wet electrode. It has several problems caused by wet electrodes for long-term monitoring. Thus, a monitoring sensor integrated into clothes with a dry electrode is proposed. In this study, we develop a smart outdoor shirt equipped with a dry electrode electrocardiogram (ECG) sensor for a cardiac arrhythmia computer aided diagnosis system. The sensor can be inserted in a console close to the chest, charged, used to communicate wirelessly, and connected with a smartphone application. The ECG signals measured by the smart shirt indicated that 97.5 ± 1% of the signals could be measured in an immobile state and at least 85.2 ± 2% of the signals could be measured during movement. We propose a computer aided diagnosis system for detecting cardiac arrhythmia. It was determined through experiments that the system can detect arrhythmia with an accuracy of 98.2 ± 2%. This study suggests that smart shirt which can diagnose arrhythmia will provide information that can quickly recognize arrhythmia in daily life or exercise.

The solid-state fermentation of Artemisia capillaris leaves with Ganoderma lucidum enhances the anti-inflammatory effects in a model of atopic dermatitis.

Artemisia capillaris, which belongs to the Asteraceae family and the genus Artemisia, has been reported to exert inhibitory effects on diabetes, cancer and inflammation. In this study, in order to enhance the bioactivity potential of the leaves of Artemisia by Ganoderma lucidum mycelium, we prepared aqueous samples of Artemisia capillaris (Ac) leaves, Ganoderma lucidum (Gl) and aqueous fractions produced by the solid fermentation of Ganoderma lucidum on Artemisia capillaris leaves (afAc/Gl). Thereafter, we evaluated whether these samples have potential to attenuate inflammation-related symptoms in an amimal model of 2,4-dinitrofluorobenzene (DNFB)-induced atopic dermatitis. We found that afAc/Gl exhibited enhanced anti-inflamamatory activity following the solid fermentation process when compared with Ac or Gl on ear thickness, ear epidermal thickness and eosinophil infiltration in the skin tissues. The expression of nitric oxide (NO) synthases (NOSs) was measured by immunohistochemical staining. The results revealed that afAc/Gl decreased endothelial NOS and inducible NOS expression compared with the DNFB group, while neuronal NOS expression was not altered. By comparing NO production, we found that as opposed to Ac, afAc/Gl has potential to inhibit atopic dermatitis-related symptoms during the inflammatory event. As regards matrix metalloproteinase (MMP) expression patterns, afAc/Gl exerted potent inhibitory activity on the mRNA expression of MMP-2, -7, -9, -12, -14 and -19. Taken together, these results suggest that the solid state fermentation of Ac by Gl is an effective strategy to obtaining useful ingredients which are converted into valuable compounds during an atopic inflammatory insult.

Different characteristics of mesenchymal stem cells isolated from different layers of full term placenta.

BACKGROUND: The placenta is a very attractive source of mesenchymal stem cells (MSCs) for regenerative medicine due to readily availability, non-invasive acquisition, and avoidance of ethical issues. Isolating MSCs from parts of placenta tissue has obtained growing interest because they are assumed to exhibit different proliferation and differentiation potentials due to complex structures and functions of the placenta. The objective of this study was to isolate MSCs from different parts of the placenta and compare their characteristics. METHODS: Placenta was divided into amniotic epithelium (AE), amniotic membrane (AM), chorionic membrane (CM), chorionic villi (CV), chorionic trophoblast without villi (CT-V), decidua (DC), and whole placenta (Pla). Cells isolated from each layer were subjected to analyses for their morphology, proliferation ability, surface markers, and multi-lineage differentiation potential. MSCs were isolated from all placental layers and their characteristics were compared. FINDINGS: Surface antigen phenotype, morphology, and differentiation characteristics of cells from all layers indicated that they exhibited properties of MSCs. MSCs from different placental layers had different proliferation rates and differentiation potentials. MSCs from CM, CT-V, CV, and DC had better population doubling time and multi-lineage differentiation potentials compared to those from other layers. CONCLUSIONS: Our results indicate that MSCs with different characteristics can be isolated from all layers of term placenta. These finding suggest that it is necessary to appropriately select MSCs from different placental layers for successful and consistent outcomes in clinical applications.

No Association of the rs17822931 Polymorphism in ABCC11 with Breast Cancer Risk in Koreans.

ABCC11 is reported to be associated with breast cancer. However, whether ABCC11 polymorphisms relate to breast cancer risk remains unclear. This study aimed to evaluate any association of a single nucleotide polymorphism (SNP), rs17822931, in ABCC11 with breast cancer in Koreans. Genomic DNA samples of 170 women with breast cancer and 100 controls were assessed for SNP rs17822931 of ABCC11 by single-strand conformation polymorphism (SSCP) and DNA sequencing. A 27-bp deletion (Δ27) of ABCC11 was analyzed by PCR amplification. The genotype of SNP rs17822931 was confirmed to be AA in all samples from breast cancer patients and Δ27 was found in none of the samples. Our finding indicated that the SNP rs17822931 in ABCC11 is not associated with breast cancer. However, this study does provide information on fundamental genetic aspects of ABCC11 with regard to breast cancer risk in Koreans.

Effect of bexarotene on differentiation of glioblastoma multiforme compared with ATRA.

Glioblastoma multiforme (GBM) is the most aggressive malignant brain tumor. Since differentiation can attenuate or halt the growth of tumor cells, an image-based phenotypic screening was performed to find out drugs inducing morphological differentiation of GBMs. Bexarotene, a selective retinoid X receptor agonist, showed strong inhibition of neurospheroidal colony formation and migration of cultured primary GBM cells. Bexarotene treatment reduced nestin expression, while significantly increasing glial fibrillary acidic protein (GFAP) expression. The effect of bexarotene on gene expression profile was compared with the activity of all-trans retinoic acid (ATRA), a well-known differentiation inducer. Both drugs largely altered the gene expression pattern into a tumor-ameliorating direction. These drugs increased the gene expression levels of Krüppel-like factor 9 (KLF9), regulator of G-protein signaling 4 (RGS4), growth differentiation factor 15 (GDF15), angiopoietin-like protein 4 (ANGPTL4), and lowered the level of chemokine receptor type 4 (CXCR4). However, transglutaminase 2 (TG2) induction, an adverse effect of ATRA, was much weaker in bexarotene treated primary GBM cells. Consistently, the TG2 enzymatic activity was negligibly affected by bexarotene treatment. It is important to control TG2 overexpression since its upregulation is correlated with tumor transformation and drug resistance. Bexarotene also showed in vivo tumoricidal effects in a GBM xenograft mouse model. Therefore, we suggest bexarotene as a more beneficial differentiation agent than ATRA for GBM.

Discovery of potent and selective cytotoxic activity of new quinazoline-ureas against TMZ-resistant glioblastoma multiforme (GBM).

Herein, we report new quinazoline-urea based compounds with potent cytotoxic activities against TMZ-resistant glioblastoma multiforme (GBM) cells. Low micromolar IC50 values were exhibited over a panel of three primary GBM patient-derived cell cultures belonging to proneural (GBM-1), mesenchymal (GBM-2), and classical (GBM-3) subtypes. Eight compounds showed excellent selectivity indices for GBM cells comparing to a normal astrocyte cell line. In JC-1 assay, analogues 11, 12, 20, 22, and 24 exerted promising rates of mPTP opening induction towards proneural GBM subtype. Compounds 11, 20, and 24 bound to the translocator protein 18 kDa (TSPO) in submicromolar range using [(3)H] PK-11195 binding affinity assay. A homology model was built and docked models of 11, 12, 20, 22 and 24 were generated for describing their plausible binding modes in TSPO. In 3D clonogenic assay, compound 20 manifested potent tumoricidal effects on TMZ-resistant GBM cells even at submicromolar concentrations. In addition, CYP450 and hERG assays presented a safe toxicity profile of 20. Taken as a whole, this report presents compound 20 as a potent, selective and safe GBM cytotoxic agent which constitutes a promising direction against TMZ-resistant GBM.

Effect of chondrocyte-derived early extracellular matrix on chondrogenesis of placenta-derived mesenchymal stem cells.

The extracellular matrix (ECM) surrounding cells contains a variety of proteins that provide structural support and regulate cellular functions. Previous studies have shown that decellularized ECM isolated from tissues or cultured cells can be used to improve cell differentiation in tissue engineering applications. In this study we evaluated the effect of decellularized chondrocyte-derived ECM (CDECM) on the chondrogenesis of human placenta-derived mesenchymal stem cells (hPDMSCs) in a pellet culture system. After incubation with or without chondrocyte-derived ECM in chondrogenic medium for 1 or 3 weeks, the sizes and wet masses of the cell pellets were compared with untreated controls (hPDMSCs incubated in chondrogenic medium without chondrocyte-derived ECM). In addition, histologic analysis of the cell pellets (Safranin O and collagen type II staining) and quantitative reverse transcription-PCR analysis of chondrogenic markers (aggrecan, collagen type II, and SOX9) were carried out. Our results showed that the sizes and masses of hPDMSC pellets incubated with chondrocyte-derived ECM were significantly higher than those of untreated controls. Differentiation of hPDMSCs (both with and without chondrocyte-derived ECM) was confirmed by Safranin O and collagen type II staining. Chondrogenic marker expression and glycosaminoglycan (GAG) levels were significantly higher in hPDMSC pellets incubated with chondrocyte-derived ECM compared with untreated controls, especially in cells precultured with chondrocyte-derived ECM for 7 d. Taken together, these results demonstrate that chondrocyte-derived ECM enhances the chondrogenesis of hPDMSCs, and this effect is further increased by preculture with chondrocyte-derived ECM. This preculture method for hPDMSC chondrogenesis represents a promising approach for cartilage tissue engineering.

Repositioning Potential of PAK4 to Osteoclastic Bone Resorption.

Drug repositioning is a rational approach for expanding the use of existing drugs or candidate drugs to treat additional disorders. Here we investigated the possibility of using the anticancer p21-activated kinase 4 (PAK4)-targeted inhibitor PF-3758309 to treat osteoclast-mediated disorders. PAK4 was highly expressed in bone marrow cells and was phosphorylated during their differentiation into osteoclasts, and osteoclast differentiation was significantly inhibited by the dominant negative form of PAK4 and by PF-3758309. Specifically, PF-3758309 significantly inhibited the fusion of preosteoclasts, the podosome formation, and the migration of preosteoclasts. PF-3758309 also had in vivo antiresorptive activity in a lipopolysaccharide-induced bone erosion model and in vitro antiosteoclastogenic activity in the differentiation of human bone marrow-derived cells and peripheral blood mononuclear cells into osteoclasts. These data demonstrate the relevance of PAK4 in osteoclast differentiation and the potential of PAK4 inhibitors for treating osteoclast-related disorders.

Cinnamomum cassia bark produced by solid-state fermentation with Phellinus baumii has the potential to alleviate atopic dermatitis-related symptoms.

In order to evaluate whether the aqueous fraction of Cinnamomum cassia produced by solid-state fermentation with Phellinus baumii (afCc/Pb) inhibits atopic symptoms in vivo, its efficacy was evaluated in an animal model of 2,4-dinitrofluorobenzene (DNFB)-induced atopic dermatitis. Immune-related cells were quantified using hematoxylin and eosin staining, and phenotypic cytokines, enzymes and the expression of other proteins in the animal model were evaluated. The data revealed that afCc/Pb (100 µg/ml) exhibited strong anti-atopic activity, causing a significant 40% reduction in immune response, as shown by the extent of ear swelling, resulting from a decrease in the number of eosinophils in the skin tissues due to decreased matrix metalloproteinase-2 and interleukin-31 expression. These results collectively suggest that afCc/Pb has the potential to alleviate the symptoms of atopic dermatitis in a mouse model of DNFB-induced atopic dermatitis, and that it may be a valuable bioresource for the cosmetic/cosmeceutical industry.

Natural polyamines inhibit the migration of preosteoclasts by attenuating Ca2+-PYK2-Src-NFATc1 signaling pathways.

Natural polyamines have numerous biological activities. Several studies have reported their beneficial role in bone metabolism, but their mode of action is not fully understood. Bone diseases such as osteoporosis, which is characterized by impaired bone structure and low bone mass, are caused by an increased number of osteoclasts and/or overactivation of osteoclastogenesis. Osteoclast differentiation is a multi-complex procedure involving the following sequential steps: differentiation-migration-fusion-resorption. In this study, we found that putrescine, spermidine or spermine inhibited the RANKL-mediated migration of preosteoclasts. Furthermore, the RANKL-mediated activation of the Src-PYK2 signaling axis and of transcription factors such as NF-κB and NFATc1 was prevented by each polyamine. Anti-osteoclastogenic and anti-migration activities of polyamines were confirmed by evaluating their potential to downregulate the mRNA expression levels of osteoclastogenesis-related genes such as OSCAR, TRAP, cathepsin K and c-Src, and genes related to fusion and/or migration of preosteoclasts. Moreover, ATP-mediated elevation of cytosolic free Ca(2+) concentration ([Ca(2+)]i) was strongly inhibited by each polyamine, indicating the involvement of [Ca(2+)]i in the anti-fusion activities of polyamines. In conclusion, polyamines could exhibit anti-osteoclastogenic activity by inhibiting the migration of preosteoclasts via the Ca(2+)-PYK2-Src-NFATc1 signaling axis.

Indatraline inhibits Rho- and calcium-mediated glioblastoma cell motility and angiogenesis.

Glioblastoma multiforme (GBM) is the most common and lethal primary brain tumor of the central nervous system (CNS). As an attempt to identify drugs for GBM therapeutics, phenotypic assays were used to screen 1000 chemicals from a clinical compound library. GBM subtypes exhibited different capabilities to induce angiogenesis when cultured on Matrigel; proneural cells migrated and formed a tube-like structure without endothelial cells. Among the compounds screened, indatraline, a nonselective monoamine transporter inhibitor, suppressed these morphological changes; it dose dependently inhibited cell spreading, migration, and in vitro/in vivo tube formation. In addition to intracellular calcium concentration, indatraline increased the level of Rho GTPase and its activity. Moreover, indatraline downregulated angiogenesis-related genes such as IGFBP2, PTN, VEGFA, PDGFRA, and VEGFR as well as nestin, a stem cell marker. These findings collectively suggest that the activation of Rho GTPase and the suppression of angiogenesis-related factors mediate the antiangiogenic activity of indatraline in proneural GBM culture.

Alleviation of asthma-related symptoms by a derivative of L-allo threonine.

Chronic asthma is characterized by inflammatory cell infiltration and tissue remodeling, leading to subepithelial inflammation. In order to evaluate the anti-asthmatic activity of LX519290, a derivative of L-allo threonine, we performed several in vitro and in vivo anti-asthmatic assays. Using ovalbumin (OVA)-sensitized C57BL/6 mice, the effects of LX519290 on lung inflammation and cytokine expression in the asthmatic animals were analyzed. Treatment with this compound increased IFN-γ and decreased IL-10 mRNA expression. LX519290 potently decreased, not only immune cell infiltration in the lung, but also IL-4 and IL-13 cytokine levels in the serum of OVA-treated mice. The results demonstrated that LX519290 decreased the pathogenesis of chronic airway injury. Evidence from our model of OVA-induced asthma demonstrated that LX519290 inhibits immune cell infiltration, mucus hypersecretion, and inflammatory cytokine production. Collectively, our findings suggest that LX519290 has the potential to ameliorate asthmatic symptoms by treating inflammatory factors in the lung.

A derivative of L-allo threonine alleviates 2,4-dinitrofluorobenzene-induced atopic dermatitis indications.

LX519290, a synthetic derivative from a combinatorial chemistry library, has been screened for anti-atopic activity, but its biological activities have not yet been elucidated. To assess whether LX519290 has the potential to lessen 2,4-dinitrofluorobenzene-induced atopic dermatitis symptoms in mice, first we sensitized the skin in the dorsal neck of C57BL/6 mice and re-sensitized the ear skin to determine the ear thickness. Then, we tested to determine whether LX519290 affect atopic dermatitis symptoms in vivo. The results indicate that LX519290 significantly mitigated inflammation indications including ear thickness, total T-cell numbers, and eosinophils. Moreover, the treatment drastically inhibited the levels of mediators such as interleukin-17E and histamine by 52% and 37% of control, respectively. Taken together, the data suggest that LX519290 can alleviate atopic parameters in mice.

Mitigation of 2,4-dinitrofluorobenzene-induced atopic dermatitis-related symptoms by Terminalia chebula Retzius.

To evaluate whether an aqueous seed extract of Terminalia chebula Retzius inhibited development of atopy in vivo, we used a 2,4-dinitrofluorobenzene (DNFB)-induced animal model of atopic symptoms to investigate the effects of the extract. We measured CD4+ cell numbers by hematoxylin and eosin (H&E) staining, and determined the expression levels of matrix metalloproteinase (MMP)-9, interleukin (IL)-31, and T-bet genes, in this animal model. The data showed that a Terminalia chebula extract (100 µg/ml) exhibited strong anti-atopic activity, mediating a 52% reduction in the immune response, as measured by thickness of ear swelling, and resulting in decreased eosinophil levels in adjacent skin tissue. Collectively, the results indicate that a Terminalia chebula seed extract has potential for alleviation of atopy-like symptoms induced by DNFB in the mouse.

Alleviation of atopic dermatitis-related symptoms by Perilla frutescens Britton.

To ascertain whether an aqueous fraction of Perilla frutescens Britton (PfB/af) has advantageous anti-atopic dermatitis activity, we used a 2,4-dinitrofluorobenzene (DNFB)-induced animal model of atopic dermatitis symptoms to investigate the effects of the extract. We performed an ear swelling assay by comparing thickness of the DNFB-induced ear, and measured the numbers of eosinophils as well as total immune cells. We analyzed the expression levels of matrix metalloproteinase (MMP)-9, interleukin (IL)-31 and of the T-bet transcription factor. The results revealed that PfB/af (100 µg/ml) exhibited strong anti-atopic dermatitis activity, interceding drastic reduction (35%) of the immune response, as measured by the thickness of ear epidermis swelling, and resulting in decreased eosinophil levels (73.7%) in adjacent skin tissues. Collectively, the present results suggest that PfB/af has potential for mitigation of atopic dermatitis-like symptoms induced by DNFB in the mouse.