Preclinical Therapeutic Evaluation of Lenvatinib-Eluting Microspheres for Transcatheter Arterial Chemoembolization of Hepatocellular Carcinoma.

PURPOSE: To evaluate the preclinical in vivo therapeutic response of Lenvatinib-eluting microspheres (LEN-EM) transcatheter arterial chemoembolization (LEN-TACE) in an hepatocellular carcinoma (HCC) rat model. METHODS: Magnetic resonance imaging (MRI) visible LEN-EM was fabricated with poly(lactide-co-glycolide) and iron oxide nanoparticles by a double-emulsion method. The morphology, LEN loading/release kinetics, and MRI contrast effect of LEN-EM were evaluated. For in vivo study, N1S1 HCC rats were treated with LEN-TACE (LEN: 2.4 mg/kg, n = 5) using LEN-EM, systemic LEN (LEN: 0.4 mg/kg, oral gavage daily for 7 days, n = 5), control (intra-arterial (IA) saline infusion, n = 5), and non-tumor control (n = 3). Tumor size changes were measured for 2 weeks. Histology, comparative LEN plasma concentration, hematologic markers, liver profile, and serum chemistry among the groups were measured. RESULTS: LEN-EM with 33 µm in average size was prepared in an optimized emulsion process. LEN loading efficiency was 58.7%. LEN was continuously released for 500 h. LEN-TACE showed the delivered LEN-EM surrounding tumor tissue in MRI-T2* images. The LEN-TACE group demonstrated a statistically significant larger tumor volume reduction compared to the other groups at 2 weeks post-procedure. Quantification data of Terminal deoxynucleotidyl transferase dUTP nick end labeling positive cells confirmed increased cancer cell death in the LEN-TACE group compared to control groups. Additional histology, hematologic markers, and liver profiles showed minimal side effects of LEN-TACE. CONCLUSION: LEN-TACE using IA delivery of LEN-EM demonstrated an effective therapeutic efficacy in an HCC rat animal model.

Magneto-Activation and Magnetic Resonance Imaging of Natural Killer Cells Labeled with Magnetic Nanocomplexes for the Treatment of Solid Tumors.

Natural killer (NK) cell-based immunotherapy has been considered a promising cell-based cancer treatment strategy with low side effects for early tumors and metastasis. However, the therapeutic efficacy is generally low in established solid tumors. Ex vivo activation of NK cells with exogenous cytokines is often essential but ineffective to generate high doses of functional NK cells for cancer treatment. Image-guided local delivery of NK cells is also suggested for the therapy. However, there is a lack of noninvasive tools for monitoring NK cells. Herein, magnetic nanocomplexes are fabricated with clinically available materials (hyaluronic acid, protamine, and ferumoxytol; HAPF) for labeling NK cells. The prepared HAPF-nanocomplexes effectively attach to the NK cells (HAPF-NK). An exogenous magnetic field application effectively achieves magneto-activation of NK cells, promoting the generation and secretion of lytic granules of NK cells. The magneto-activated HAPF-NK cells also allow an MR image-guided NK cell therapy to treat hepatocellular carcinoma (HCC) solid tumors via transcatheter intra-arterial infusion. Suppressed tumor growth after the treatment of IA infused magneto-activated NK cells demonstrated a potential enhanced therapeutic efficacy of image guided local delivery of magneto-activated HAPF-NK cells. Given the potential challenges of NK cell cancer immunotherapy against established solid tumors, the effective NK cell labeling with HAPF, magneto-activation, and MRI contrast effect of NK cells will be beneficial to enhance the NK cell-therapeutic efficacy in various cancers.

Neuroanatomical correlates of poststroke complex regional pain syndrome: a voxel-based lesion symptom-mapping study.

Complex regional pain syndrome (CRPS) is a common poststroke complication. However, the neural substrates associated with CRPS remain unclear. We investigated the neural correlates associated with poststroke CRPS using voxel-based lesion‒symptom mapping (VLSM) analysis. Among 145 patients with ischemic stroke, 35 were diagnosed with CRPS and categorized into the poststroke CRPS group, and the remaining 110 into the control group. We compared the clinical characteristics between the groups. VLSM analysis was performed to identify the brain region associated with the development of poststroke CRPS. The clinical findings suggested that the poststroke CRPS group had lower muscle strength; lower scores on Fugl‒Meyer assessment, Manual Function Test, Mini-Mental Status Examination; and higher incidence of absent somatosensory evoked potentials in the median nerve than the control group. The head of the caudate nucleus, putamen, and white matter complexes in the corona radiata were significantly associated with poststroke CRPS development in ischemic stroke patients. These results facilitate an understanding of poststroke CRPS pathophysiology. Monitoring patients with lesions in these structures may aid the prevention and early treatment of poststroke CRPS.

Astrocytes Control Sensory Acuity via Tonic Inhibition in the Thalamus.

Sensory discrimination is essential for survival. However, how sensory information is finely controlled in the brain is not well defined. Here, we show that astrocytes control tactile acuity via tonic inhibition in the thalamus. Mechanistically, diamine oxidase (DAO) and the subsequent aldehyde dehydrogenase 1a1 (Aldh1a1) convert putrescine into GABA, which is released via Best1. The GABA from astrocytes inhibits synaptically evoked firing at the lemniscal synapses to fine-tune the dynamic range of the stimulation-response relationship, the precision of spike timing, and tactile discrimination. Our findings reveal a novel role of astrocytes in the control of sensory acuity through tonic GABA release.

Ultrasonographic Thyroid Nodule Classification Using a Deep Convolutional Neural Network with Surgical Pathology.

Ultrasonography with fine-needle aspiration biopsy is commonly used to detect thyroid cancer. However, thyroid ultrasonography is prone to subjective interpretations and interobserver variabilities. The objective of this study was to develop a thyroid nodule classification system for ultrasonography using convolutional neural networks. Transverse and longitudinal ultrasonographic thyroid images of 762 patients were used to create a deep learning model. After surgical biopsy, 325 cases were confirmed to be benign and 437 cases were confirmed to be papillary thyroid carcinoma. Image annotation marks were removed, and missing regions were recovered using neighboring parenchyme. To reduce overfitting of the deep learning model, we applied data augmentation, global average pooling. And 4-fold cross-validation was performed to detect overfitting. We employed a transfer learning method with the pretrained deep learning model VGG16. The average area under the curve of the model was 0.916, and its specificity and sensitivity were 0.70 and 0.92, respectively. Positive and negative predictive values were 0.90 and 0.75, respectively. We introduced a new fine-tuned deep learning model for classifying thyroid nodules in ultrasonography. We expect that this model will help physicians diagnose thyroid nodules with ultrasonography.

Solution processable formation of a few nanometer thick-disordered overlayer on the surface of open-ended TiO2 nanotubes.

Herein, we designed vertically aligned TiO2 nanotube arrays, in which a very thin disordered overlayer approximately a few nm thick was formed via a room-temperature solution process. At the optimal overlayer thickness, the TiO2 nanotube arrays yielded a photocurrent density of up to ∼1.75 mA cm-2 at 1.23 V vs. RHE, approximately twice that of the pristine one.

Evaluation of Bacillus spp. as dough starters for Adhirasam - A traditional rice based fermented food of Southern India.

Adhirasam is a cereal based, doughnut shaped, deep fried dessert consumed in the southern regions of India. The dough used to prepare adhirasam is fermented and contains rice flour and jaggery. The aim of the present study was to characterize the cultivable bacteria associated with this fermented dough and to identify a suitable starter culture for the production of quality adhirasam. In total, one hundred and seventy bacterial isolates were recovered from de Man Rogosa Sharp (MRS) agar, nutrient agar, lysogeny agar and tryptic soy agar media. Out of the 170 bacterial isolates, sixteen isolates were selected based on their ability to tolerate glucose and sucrose. All the bacterial isolates tolerated 15% glucose and 30% sucrose. Analyses of 16S rDNA gene sequences of the bacterial isolates showed that the dominant cultivable bacteria were members of the genus Bacillus. These strains were further used as starters and tested for their ability to ferment rice flour with jaggery to produce adhirasam dough. Organoleptic evaluation was carried out to choose the best starter strain. Adhirasam prepared from Bacillus subtilis isolates S4-P11, S2-G2-A1 and S1-G15, Bacillus tequilensis isolates S2-H16, S3-P9, S3-G10 and Bacillus siamensis isolate S2-G13 were highly acceptable to consumers. Adhirasam prepared using these starter cultures had superior product characteristics such as softness in texture, flavor and enhanced aroma and sweet taste.

Evaluation of Bacillus spp. as dough starters for Adhirasam - A traditional rice based fermented food of Southern India

Abstract Adhirasam is a cereal based, doughnut shaped, deep fried dessert consumed in the southern regions of India. The dough used to prepare adhirasam is fermented and contains rice flour and jaggery. The aim of the present study was to characterize the cultivable bacteria associated with this fermented dough and to identify a suitable starter culture for the production of quality adhirasam. In total, one hundred and seventy bacterial isolates were recovered from de Man Rogosa Sharp (MRS) agar, nutrient agar, lysogeny agar and tryptic soy agar media. Out of the 170 bacterial isolates, sixteen isolates were selected based on their ability to tolerate glucose and sucrose. All the bacterial isolates tolerated 15% glucose and 30% sucrose. Analyses of 16S rDNA gene sequences of the bacterial isolates showed that the dominant cultivable bacteria were members of the genus Bacillus. These strains were further used as starters and tested for their ability to ferment rice flour with jaggery to produce adhirasam dough. Organoleptic evaluation was carried out to choose the best starter strain. Adhirasam prepared from Bacillus subtilis isolates S4-P11, S2-G2-A1 and S1-G15, Bacillus tequilensis isolates S2-H16, S3-P9, S3-G10 and Bacillus siamensis isolate S2-G13 were highly acceptable to consumers. Adhirasam prepared using these starter cultures had superior product characteristics such as softness in texture, flavor and enhanced aroma and sweet taste.

Large-scale graphene micropatterns via self-assembly-mediated process for flexible device application.

We report on a method for the large-scale production of graphene micropatterns by a self-assembly mediated process. The evaporation-induced self-assembly technique was engineered to produce highly ordered graphene patterns on flexible substrates in a simplified and scalable manner. The crossed stripe graphene patterns have been produced over a large area with regions consisting of single- and two-layer graphene. Based on these graphene patterns, flexible graphene-based field effect transistors have been fabricated with an ion-gel gate dielectric, which operates at low voltages of < 2 V with a hole and electron mobility of 214 and 106 cm(2)/V·s, respectively. The self-assembly approach described here may pave the way for the nonlithographic production of graphene patterns, which is scalable to large areas and compatible with roll-to-roll system.

Species belonging to genus protodaedalea in Korea.

One rare and interesting species collected from Seorak-san, Inje-gun; Yeonyeop-san, Hongcheon-gun; Daeam-san, Yanggu-gun, Gangwon-do; Pocheon-gun, Gyeonggi-do; Songni-san, Boeun-gun; Joryeong-san, Goesan-gun, Chungcheongbuk-do and Sobaeksan, Yeongju-si, Gyeongsangbuk-do is described and illustrated in detail. The species "Protodaedalea hispida Imazeki" and genus "Protodaedalea Iamzeki" has not been previously recorded in Korean fungal flora. The specimens have been deposited in the Herbarium Conservation Center of the National Academy of Agricultural Sciences.

Notes on some new species of psathyrella.

This study contains descriptions and illustrations of three new and noteworthy taxa of the genus Psathyrella from Korea. Among them, Psathyrella pervelatoid, P. koreana, and P. utriformcystis are new to science. All collections cited here are deposited in the Herbarium Conservation Center of National Academy of Agricultural Sciences.

Birefringent waveguide sensor using a polarizer rotating technique.

A birefringence measurement system is introduced to get high phase resolution for detection of low contents of biochemicals. By using a fixed quarter-wave plate and a rotating polarizer, the phase difference between two orthogonal polarizations is transformed into phase delay of output sinusoidal signal. Analyzing the output phase, birefringence change could be detected with a phase noise of 0.14 degrees. As well as the birefringence measurement system, an optical evanescent waveguide sensor was developed. A rib-type silica waveguide overlaid with TiO2 film was fabricated, and a developed birefringence measurement technique was employed in evaluating a refractive index change on waveguide surface. For the fabricated waveguide with a 40-nm-thick TiO2 film, experiment results showed that the minimum detectable index change was 5.9x10(-7).

Integrated optical modulator for signal up-conversion over radio-on-fiber link.

An integrated optical modulator, which consists of a dual-sideband suppressed carrier (DSB-SC) modulator cascaded with a single-sideband (SSB) modulator, is proposed for signal up-conversion over Radio-on-Fiber. Utilizing a single-drive domain inverted structure in both modulators, balanced modulations were obtained without complicated radio frequency (RF) driving circuits and delicate RF phase adjustments. Intermediate frequency (IF) band signal was up-conversed to 60GHz band by using the fabricated device and was transmitted over optical fiber. Experiment results show that the proposed device enables millimeter wave generation and signal transmission without any power penalty caused by chromatic dispersion.

Diarctigenin, a lignan constituent from Arctium lappa, down-regulated zymosan-induced transcription of inflammatory genes through suppression of DNA binding ability of nuclear factor-kappaB in macrophages.

Diarctigenin was previously isolated as an inhibitor of nitric oxide (NO) production in macrophages from the seeds of Arctium lappa used as an alternative medicine for the treatment of inflammatory disorders. However, little is known about the molecular basis of these effects. Here, we demonstrated that diarctigenin inhibited the production of NO, prostaglandin E(2), tumor necrosis factor-alpha, and interleukin (IL)-1beta and IL-6 with IC(50) values of 6 to 12 miciroM in zymosan- or lipopolysaccharide-(LPS) activated macrophages. Diarctigenin attenuated zymosan-induced mRNA synthesis of inducible NO synthase (iNOS) and also inhibited promoter activities of iNOS and cytokine genes in the cells. Because nuclear factor (NF)-kappaB plays a pivotal role in inflammatory gene transcription, we next investigated the effect of diarctigenin on NF-kappaB activation. Diarctigenin inhibited the transcriptional activity and DNA binding ability of NF-kappaB in zymosan-activated macrophages but did not affect the degradation and phosphorylation of inhibitory kappaB (IkappaB) proteins. Moreover, diarctigenin suppressed expression vector NF-kappaB p65-elicited NF-kappaB activation and also iNOS promoter activity, indicating that the compound could directly target an NF-kappa-activating signal cascade downstream of IkappaB degradation and inhibit NF-kappaB-regulated iNOS expression. Diarctigenin also inhibited the in vitro DNA binding ability of NF-kappaB but did not affect the nuclear import of NF-kappaB p65 in the cells. Taken together, diarctigenin down-regulated zymosan- or LPS-induced inflammatory gene transcription in macrophages, which was due to direct inhibition of the DNA binding ability of NF-kappaB. Finally, this study provides a pharmacological potential of diarctigenin in the NF-kappaB-associated inflammatory disorders.

21-Methylmelianodiols from Poncirus trifoliata as inhibitors of interleukin-5 bioactivity in Pro-B cells.

Interleukin (IL)-5 plays an important role in the progression of allergic inflammation. Here, we have isolated 21alpha-methylmelianodiol and 21beta-methylmelianodiol from Poncirus trifoliata (L.) Raf., a plant of the Rutaceae family, as the inhibitors of IL-5-dependent growth of Y16 pro-B cells by bioassay-guided fractionation. 21alpha-Methylmelianodiol and 21beta-methylmelianodiol inhibited IL-5-dependent growth of Y16 cells in a dose-dependent manner with IC (50) values of 17 microM and 15 microM, respectively. A positive control, tyrphostin AG-490, exhibited an IC (50) value of 23 microM on IL-5 bioactivity. Further, we have documented that 21alpha-methylmelianodiol and 21beta-methylmelianodiol cause G1 arrest of IL-5-induced cell cycle progression of Y16 cells, and also reduce IL-5-dependent survival of the cells by apoptosis. This study could provide a pharmacological potential for P. trifoliata in treatment of IL-5-associated inflammatory disorders.

Antitumor activity of cytokine-induced killer cells against human lung cancer.

Lung cancer is the leading cause of cancer-related death among men and women in the world. Despite the aggressive treatment with surgery, radiation and chemotherapy, the long term survival for lung cancer patients remains low. In this study, the anti-tumor activity of cytokine-induced killer (CIK) cells against human lung cancer was evaluated in vitro and in vivo. Although CD3(+)CD56(+) CIK cells were rare in fresh human peripheral blood mononuclear cells, they could expand more than 1000-fold on day 14 in the presence of anti-CD3 antibody plus IL-2. At an effector-target cell ratio of 30:1, CIK cells destroyed 98% of NCI-H460 human lung cancer cells, which was determined by the (51)Cr-release assay. In addition, CIK cells at doses of 3 and 30 million cells per mouse inhibited 57% and 77% of NCI-H460 tumor growth in nude mouse xenograft assay, respectively. This study suggests that CD3(+)CD56(+) CIK cells may be used as an adoptive immunotherapy for patients with lung cancer.