Exploiting an Intermediate Latent Space between Photo and Sketch for Face Photo-Sketch Recognition.

The photo-sketch matching problem is challenging because the modality gap between a photo and a sketch is very large. This work features a novel approach to the use of an intermediate latent space between the two modalities that circumvents the problem of modality gap for face photo-sketch recognition. To set up a stable homogenous latent space between a photo and a sketch that is effective for matching, we utilize a bidirectional (photo → sketch and sketch → photo) collaborative synthesis network and equip the latent space with rich representation power. To provide rich representation power, we employ StyleGAN architectures, such as StyleGAN and StyleGAN2. The proposed latent space equipped with rich representation power enables us to conduct accurate matching because we can effectively align the distributions of the two modalities in the latent space. In addition, to resolve the problem of insufficient paired photo/sketch samples for training, we introduce a three-step training scheme. Extensive evaluation on a public composite face sketch database confirms superior performance of the proposed approach compared to existing state-of-the-art methods. The proposed methodology can be employed in matching other modality pairs.

Subretinal transplantation of human embryonic stem cell-derived retinal pigment epithelium (MA09-hRPE): A safety and tolerability evaluation in minipigs.

This study aimed to determine the safety and tolerability of the subretinal injection of hESC-derived RPE cells at higher doses than the established clinical dose (5 × 104 cells/150 µL) by using minipigs. The hESC-derived RPE cells (60 or 120 × 104 cells/150 µL) were injected in subretinal region, and minipigs were sacrificed at Weeks 4, 8, and 12 post-surgery. Time-course examination was performed by using fundus photography, optical coherence tomography (OCT), histopathology, and fluorescence in situ hybridization (FISH). After surgery, retinal bleb and pigmentation were seen and retinal bleb became smaller gradually. In histopathology, cell clusters consisting of a uniform population of the round to oval cells were seen at the subretinal injection site. In immunohistochemistry, most of the cells were positive for anti-CD3 and CD45 antibodies but negative for anti-human nuclei antibody; transplanted cells were not detectable by DNA probe in FISH assay. Cell clusters were thought to be a host immune response to trauma or transplanted cells. There were no other changes related to subretinal RPE cell injection. These results suggested that subretinal injection of hESC-derived RPE cells (60 and 120 × 104 cells/150 µL) in minipigs is well-tolerated and safe.

Drug repurposing screening identifies bortezomib and panobinostat as drugs targeting cancer associated fibroblasts (CAFs) by synergistic induction of apoptosis.

Cancer associated fibroblasts (CAFs) are the most abundant components of cancer-microenvironment. They play important roles in cancer initiation, progression, and metastasis. In addition, CAFs can confer drug-resistance to cancer cells. Considering their pro-tumorigenic roles, it is recommended to remove CAFs to prevent cancer recurrence after chemotherapy. Despite their clinical significance, few anti-CAF drugs have been developed. The objective of this study was to find a drug that could suppress the viability of patient-derived CAFs through repurposed screening of 51 drugs that were in clinical trials or received FDA approval. As a result, bortezomib (BTZ), carfilzomib (CFZ), and panobinostat (PST) were identified as anti-CAF drug candidates. It was confirmed that BTZ and PST could decrease the viability of various patients derived CAFs through inducing of caspase-3 mediated apoptosis. Interestingly, combination therapy with BTZ and PST showed better efficacy of inhibiting CAFs than single treatment. The synergistic effect between BTZ and PST on viability of CAFs was observed both in vitro CAF culture and in vivo mouse model. Furthermore, combination therapy with BTZ/PST and conventional anticancer compound docetaxel strongly inhibited tumor growth in xenografts of mouse breast cancer cells with mouse CAFs. In conclusion, our present study revealed that BTZ and PST could significantly reduce the viability of CAFs. Therefore, a combination therapy with BTZ/PST and anticancer drugs might be considered as a new rational for the development of anticancer therapy.

Evaluation of Circulating MicroRNA Biomarkers in the Acute Pancreatic Injury Dog Model.

This study aimed to evaluate the usefulness of four microRNAs (miRNAs) in an acute pancreatic injury dog model. Acute pancreatitis was induced by infusion of cerulein for 2 h (7.5 µg/kg/h). The levels of well-known miRNAs, microRNA-216a (miR-216a) and microRNA-375 (miR-375), and new candidates microRNA-551b (miR-551b), and microRNA-7 (miR-7), were measured at 0, 0.5, 1, 2, 6, 12, and 24 h with serum amylase and lipase, and histopathological examination was performed. Among the four miRNAs, miR-216a and miR-375, and serum enzymes were significantly increased by cerulein treatment. The expression levels of miRNAs and serum enzymes peaked at 2⁻6 h with a similar pattern; however, the overall increases in miR-216a and miR-375 levels were much higher than those of the serum enzyme biomarkers. Increased levels of miR-216a and miR-375 were most highly correlated to the degree of individual histopathological injuries of the pancreas, and showed much greater dynamic response than serum enzyme biomarkers. Twenty-four-hour time-course analysis in this study revealed time-dependent changes of miRNA expression levels, from initial increase to decrease by predose level in acute pancreatitis. Our findings demonstrate that, in dogs, miR-216a and miR-375 have the potential to sensitively detect pancreatitis and reflect well the degree of pancreatic injury, whereas miR-551b and miR-7 do not.

Development of a Mouse Model of Prostate Cancer Using the Sleeping Beauty Transposon and Electroporation.

The Sleeping Beauty (SB) transposon system is non-viral and uses insertional mutagenesis, resulting in the permanent expression of transferred genes. Although the SB transposon is a useful method for establishing a mouse tumor model, there has been difficulty in using this method to generate tumors in the prostate. In the present study, electroporation was used to enhance the transfection efficiency of the SB transposon. To generate tumors, three constructs (a c-Myc expression cassette, a HRAS (HRas proto-oncogene, GTPase) expression cassette and a shRNA against p53) contained within the SB transposon plasmids were directly injected into the prostate. Electroporation was conducted on the injection site after the injection of the DNA plasmid. Following the tumorigenesis, the tumors were monitored by animal PET imaging and identified by gross observation. After this, the tumors were characterized by using histological and immunohistochemical techniques. The expression of the targeted genes was analyzed by Real-Time qRT-PCR. All mice subjected to the injection were found to have prostate tumors, which was supported by PSA immunohistochemistry. To our knowledge, this is the first demonstration of tumor induction in the mouse prostate using the electroporation-enhanced SB transposon system in combination with c-Myc, HRAS and p53. This model serves as a valuable resource for the future development of SB-induced mouse models of cancer.

Antitumor activity, pharmacokinetics, tumor-homing effect, and hepatotoxicity of a species cross-reactive c-Met antibody.

The receptor tyrosine kinase c-Met plays critical roles in promoting tumor growth, invasion, metastasis, and angiogenesis in various types of cancer and is a promising therapeutic target. The development of a species cross-reactive therapeutic antibody could provide useful to comprehensive preclinical assessment in animal models. Towards this goal, we developed human/mouse cross-reactive c-Met antibodies using an antibody phage library. IRCR201, a c-Met antibody with species cross-reactivity, successfully inhibited the HGF/c-Met signaling pathway via degradation of c-Met and disruption of the binding with its partners, and demonstrated strong in vivo antitumor activity. In pharmacokinetic analysis, IRCR201 exhibited a nonlinear pharmacokinetic profile and showed rapid serum clearance at low dosage. Ex vivo fluorescence imaging and immunohistochemistry demonstrated strong tumor accumulation of IRCR201. Hepatotoxicity analysis revealed that IRCR201 does not significantly affect primary human and mouse hepatocytes. Serum chemistry analysis demonstrated that the alanine aminotransferase serum level was elevated in mice treated with 30 mg/kg IRCR201 than in PBS-treated mice, whereas the levels of aspartate aminotransferase and blood urea nitrogen did not significantly differ. Thus, IRCR201 is a potent therapeutic antibody that can disrupt the HGF/c-Met signaling axis and its species cross-reactivity would enable to evaluate precise biological activity in animal models.

Tumor Inhibitory Effect of IRCR201, a Novel Cross-Reactive c-Met Antibody Targeting the PSI Domain.

Hepatocyte growth factor receptor (HGFR, c-Met) is an essential member of the receptor tyrosine kinase (RTK) family that is often dysregulated during tumor progression, driving a malignant phenotypic state and modulating important cellular functions including tumor growth, invasion, metastasis, and angiogenesis, providing a strong rationale for targeting HGF/c-Met signaling axis in cancer therapy. Based on its protumorigenic potentials, we developed IRCR201, a potent antagonistic antibody targeting the plexin-semaphorin-integrin (PSI) domain of c-Met, using synthetic human antibody phage libraries. We characterized and evaluated the biochemical properties and tumor inhibitory effect of IRCR201 in vitro and in vivo. IRCR201 is a novel fully-human bivalent therapeutic antibody that exhibits cross-reactivity against both human and mouse c-Met proteins with high affinity and specificity. IRCR201 displayed low agonist activity and rapidly depleted total c-Met protein via the lysosomal degradation pathway, inhibiting c-Met-dependent downstream activation and attenuating cellular proliferation in various c-Met-expressing cancer cells. In vivo tumor xenograft models also demonstrated the superior tumor inhibitory responsiveness of IRCR201. Taken together, IRCR201 provides a promising therapeutic agent for c-Met-positive cancer patients through suppressing the c-Met signaling pathway and tumor growth.

Usefulness of optical coherence tomography to detect central serous chorioretinopathy in monkeys.

Many systemic drugs can induce ocular toxicity and several ocular side-effects have been identified in clinical studies. However, it is difficult to detect ocular toxicity in preclinical studies because of the lack of appropriate evaluation methods. Optical coherence tomography (OCT) is useful because it can provide real-time images throughout a study period, whereas histopathology only provides images of sacrificed animals. Using OCT alongside histopathology, attempts were made to find effective approaches for screening of drug-induced ocular toxicity in monkeys. Such approaches could be used in preclinical studies prior to human trials. Six male cynomolgus monkeys (Macaca fascicularis Raffles) were orally administered one of six candidate MAPK/ERK kinase (MEK) inhibitors. Central serous chorioretinopathy, a known side-effect of such inhibitors, was identified in four monkeys by OCT. Artifacts generated during tissue processing meant that histopathology could not detect edematous changes. Thus, OCT is a useful tool to detect ocular toxicity which cannot be detected by histopathology in preclinical studies.

Carcinogenicity of metamifop, a novel herbicide, in Wistar rats following oral administration for 104 weeks.

Metamifop is a novel herbicide with as yet undetermined properties. To assess its carcinogenicity, metamifop was mixed into standard rodent chow and fed to male and female Wistar rats at doses of 10, 100 and 750ppm for 104weeks. The viability/mortality of these rats was not affected by treatment with metamifop. Treatment had no significant effects on clinical parameters, and food consumption. Males and females fed 750ppm of metamifop for 104weeks showed decreases in body weight and body weight gain. Histopathological examination revealed that treatment with metamifop reduced non-neoplastic findings (chronic progressive nephropathy, tubular basophilia, tubular casts, glomerulosclerosis, basophilic and clear cell foci, senile atrophy, and mesothelial hyperplasia) and reduced neoplastic findings (thymoma, pituitary adenoma, and mammary fibroadenoma and adenocarcinoma in females, and mesenteric lymph node hemangioma in males) compared with control groups. Benign granulosa cell tumors were increased in a dose-dependent manner. As metamifop did not show any genotoxic potential, and there was no correlation between ovarian cancer and increased gonadal hormone levels in humans, the granulosa cell tumors observed in female rats fed a high dose of metamifop were considered not relevant to humans.

Carcinogenicity study of CKD-501, a novel dual peroxisome proliferator-activated receptors α and γ agonist, following oral administration to Sprague Dawley rats for 94-101 weeks.

CKD-501 is a peroxisome proliferator-activated receptor (PPAR) agonist. The current study was conducted in Sprague Dawley (SD) rats for 94-101 weeks to investigate the carcinogenic potential of CKD-501. 60 males received 0, 0.03, 0.12, or 1.0mg/kg/day, which was changed after 66 weeks to 0.24 mg/kg/day due to increased mortality, while 60 females received 0, 0.03, 0.06, or 0.12 mg/kg/day throughout the study period. After switching the dosage, no significant changes in the survival rates were observed. Non-neoplastic lesions such as bladder transitional cell hyperplasia and a diminished corpus luteum were observed in females administered 0.12 mg/kg/day and the right chamber dilation and left ventricular hypertrophy were increased dose dependently in both males and females. Non-neoplastic lesions such as bone marrow hypoplasia and fat cell proliferation and neoplastic lesions such as lipomas and liposarcomas observed in males and/or females were considered expected pharmacological effects for this compound. Compared to rosiglitazone, CKD-501 had a 4.4-fold higher margin of safety for tumor induction and did not cause bladder carcinoma as was observed with pioglitazone.

CKD-501, a novel selective PPARγ agonist, shows no carcinogenic potential in ICR mice following oral administration for 104 weeks.

CKD-501 is a peroxisome proliferator-activated receptor gamma (PPARγ) agonist that is effective for the treatment of diabetes. However, its carcinogenic potential remains controversial. The current carcinogenicity study was conducted over a period of 104 weeks in ICR mice. Three groups, each consisting of 60 male and 60 female mice, received oral CKD-501 dosages of 0.2, 1.0 or 6.0 mg kg(-1) day(-1). The mortality rates of the male control, 0.2, 1.0 and 6.0 mg kg(-1) day(-1) treated groups were 60%, 68%, 58% and 67%, respectively and 57%, 68% and 67% in the female control, 0.2 and 1.0 mg kg(-1) day(-1) treated groups. It was 67% in the female 6.0 mg kg(-1) day(-1) treated group, which was terminated at week 98 due to its increased mortality rate. No significant treatment-related effects were observed on the survival rates, with the exception of females in the 6.0 mg kg(-1) day(-1) group. Body weights increased in females receiving 1.0 and 6.0 mg kg(-1) day(-1) due to the class effects of the PPARγ agonist. Differences were not found in hematology parameters between the CKD-501-treated groups and their corresponding controls, but the histopathological evidence did not reveal any findings attributed to CKD-501. Treated animals exhibited non-neoplastic findings (adipocyte proliferation, bone marrow hypoplasia cardiomyopathy), but all of these were expected changes for this class of compound. There were no treatment-related neoplastic changes in this study. The results of this study therefore demonstrate a lack of carcinogenicity following oral administration of CKD-501 to ICR mice for 104 weeks.

Analysis of diffuse reflectivity of a highly disordered GaN nanostructure as an antireflection coating.

A highly disordered GaN nanostructure was grown by using hydride vapor phase epitaxy on an Si(100) substrate, and its diffuse reflectivity was measured in the 200-1200 nm spectral range by using an integrating sphere. A modified multiple-scattering-based model successfully explained the spectral distribution of diffuse reflectivity of this highly disordered GaN nanostructure.

Growth of high quality ZnO nanowires on graphene.

We report growth of the ZnO nanowires on graphene/SiO2/Si substrates using a chemical vapor deposition method. The length of nanowires varies from 1 microm to 10 microm with increasing the growth time from 30 min to 90 min. X-ray diffraction and high-resolution transmission electron microscopy investigations predict the high structural quality of the c-axis grown single crystalline ZnO nanowires. Temperature dependent photoluminescence spectra from the nanowires reveal excellent optical quality and excitonic behavior in the single crystalline ZnO nanowires. A well-resolved free exciton emission at 3.375 eV, indicates high crystalline quality nanowires and a strong PL peak at 3.370 eV is assigned to neutral-donor bound excitons (D0X).

Control of electronic structure of graphene by various dopants and their effects on a nanogenerator.

It is essential to control the electronic structure of graphene in order to apply graphene films for use in electrodes. We have introduced chemical dopants that modulate the electronic properties of few-layer graphene films synthesized by chemical vapor deposition. The work function, sheet carrier density, mobility, and sheet resistance of these films were systematically modulated by the reduction potential values of dopants. We further demonstrated that the power generation of a nanogenerator was strongly influenced by the choice of a graphene electrode with a modified work function. The off-current was well quenched in graphene films with high work functions (Au-doped) due to the formation of high Schottky barrier heights, whereas leakage current was observed in graphene films with low work functions (viologen-doped), due to nearly ohmic contact.

Virtual-reality Cataract Surgery Simulator Using Haptic Sensory Substitution in Continuous Circular Capsulorhexis.

Cataract is one of the most common geriatric diseases, and surgery is known to be the best treatment. Despite the increasing demand for cataract surgery, the opportunity for novice residents to practice cataract surgery is gradually diminishing as the patient and animal ethics become strict. Therefore, there have been many attempts to overcome the lack of experience by using virtual reality training system. So far, most of the surgical training simulation devices so far focused on visual training, and when they have a haptic sense, they are tethered to a fixed station, which is different from the feeling of moving the actual surgical tool. In this study, we have developed a haptic surgical training tool with sensory substitution and virtual-reality-based cataract surgery simulator. To assess and reproduce the tactile senses during surgery, we prepared viscoelastic lens dummies and measured vibrations in contact and motion required during Continuous Circular Capsulorhexis (CCC). Based on measurement we designed vibration models for haptic sensory substitution and applied them to virtual reality simulator. With complete virtual reality training system, the contact vibration was successfully implemented for virtual contacts to reproduced realistic haptic senses.

EZH2 Expression in Naturally Occurring Canine Tumors.

Enhancer of zeste homolog 2 (EZH2) shows upregulated expression in tumors and is an important driver of tumor development and progression. However, the mechanism underlying the mediation of tumor aggressiveness by EZH2 remains unclear. We here investigated the levels of EZH2 in various normal and tumorous dog tissues and compared these patterns with those of the corresponding human tissues. Immunohistochemical analysis showed positive staining for EZH2 in 76 of 82 cases of canine tumors, whereas low or negligible staining occurred in normal tissues and other canine tumors, including hepatocellular adenoma and lipoma. In particular, canine lymphoma, melanoma, basal cell tumors, squamous cell carcinoma, and prostate cancer all show EZH2 overexpression, as do their human counterparts. Given the similarities of spontaneous canine tumors to human cancers, we believe that these canine tumors can be used as animal models in future research and clinical trials in the development of EZH2 inhibitors.

Pressure Insensitive Strain Sensor with Facile Solution-Based Process for Tactile Sensing Applications.

Tactile sensors that can mechanically decouple, and therefore differentiate, various tactile inputs are highly important to properly mimic the sensing capabilities of human skin. Herein, we present an all-solution processable pressure insensitive strain sensor that utilizes the difference in structural change upon the application of pressure and tensile strain. Under the application of strain, microcracks occur within the multiwalled carbon nanotube (MWCNT) network, inducing a large change in resistance with gauge factor of ∼56 at 70% strain. On the other hand, under the application of pressure to as high as 140 kPa, negligible change in resistance is observed, which can be attributed to the pressure working primarily to close the pores, and hence minimally changing the MWCNT network conformation. Our sensor can easily be coated onto irregularly shaped three-dimensional objects (e.g., robotic hand) via spray coating, or be attached to human joints, to detect bending motion. Furthermore, our sensor can differentiate between shear stress and normal pressure, and the local strain can be spatially mapped without the use of patterned electrode array using electrical impedance tomography. These demonstrations make our sensor highly useful and important for the future development of high performance tactile sensors.

Characterization of a bimorph deformable mirror using stroboscopic phase-shifting interferometry.

The static and dynamic characteristics of a bimorph deformable mirror (DM) for use in an adaptive optics system are described. The DM is a 35-actuator device composed of two disks of lead magnesium niobate (PMN), an electrostrictive ceramic that produces a mechanical strain in response to an imposed electric field. A custom stroboscopic phase-shifting interferometer was developed to measure the deformation of the mirror in response to applied voltage. The ability of the mirror to replicate optical aberrations described by the Zernike polynomials was tested as a measure of the mirror's static performance. The natural frequencies of the DM were measured up to 20 kHz using both stroboscopic interferometry as well as a commercial laser Doppler vibrometer (LDV). Interferometric measurements of the DM surface profile were analyzed by fitting the surface with mode-shapes predicted using classical plate theory for an elastically supported disk. The measured natural frequencies were found to be in good agreement with the predictions of the theoretical model.

Metformin inhibits early stage diethylnitrosamine­induced hepatocarcinogenesis in rats.

Antitumor effects of metformin have recently emerged despite its original use for type II diabetes. In the present study, the effects of metformin on the development and recurrence of hepatocellular carcinoma (HCC) were investigated using the diethylnitrosamine (DEN)­induced rat model of HCC. Tumor foci were characterized by gross examination and by histopathological characteristics, including proliferation, hepatic progenitor cell content and the expression of hepatocarcinoma­specific molecular markers. Potential target molecules of metformin were investigated to determine the molecular mechanism underlying the inhibitory effects of metformin on chemically induced liver tumorigenesis. The antitumor effects of metformin were increased by the reduction of surface nodules and decreased the incidence of altered hepatocellular foci, hepatocellular adenoma and carcinoma. Also, decreased expression levels of glutathione S­transferase placental form, proliferating cell nuclear antigen and cytokeratin 8 described the inhibitory effects of metformin on HCC. In the present study, Wistar rats receiving treatment with DEN were administered metformin for 16 weeks. In addition, metformin suppressed liver tumorigenesis via an AMPK­dependent pathway. These results suggested that metformin has promising effects on the early stage of HCC in rats. Therefore, metformin may be used for the prevention of HCC recurrence following primary chemotherapy for HCC and/or for high­risk patients, including chronic hepatitis and cirrhosis.

Time-course changes in the expression levels of miR-122, -155, and -21 as markers of liver cell damage, inflammation, and regeneration in acetaminophen-induced liver injury in rats.

Drug-induced liver injury (DILI) is a significant threat to patient health and a major concern during drug development. Recently, multiple circulating microRNAs (miRNAs) have been reported to be potential biomarkers for DILI. To adapt and validate miRNAs for clinical use, we investigated the time-course changes in miR-122 expression levels in an acetaminophen-induced liver injury model in rats. In addition, miR-155 and miR-21 were evaluated as makers of inflammation and regeneration, respectively, to characterize liver status. Our results revealed that miR-122 is an early and sensitive biomarker of hepatocellular injury at a stage when alanine transaminase, aspartate transaminase, and total bilirubin were not detectable. However, no significant differences in the expression levels of other miRNAs (miR-155 and -21) were observed between treatment and vehicle groups. Collectively, these time-course changes in the expression levels of miRNAs may be useful as markers for clinical decision-making, in the diagnosis and treatment of DILI.