Natural killer group 2D-major histocompatibility complex class I polypeptide-related sequence A activation enhances natural killer cell-mediated immunity against hepatocellular carcinoma: A review.

The recent clinical introduction of immune checkpoint inhibitors has improved therapeutic outcomes in patients with advanced hepatocellular carcinoma. However, these therapies targeting CD8+ T lymphocytes have a response rate of approximately 30%. In addition to CD8+ T lymphocytes, natural killer (NK) cells represent promising therapeutic targets for hepatocellular carcinoma, because they comprise 30%-50% of all lymphocytes in the liver and contribute to antitumor immunity. A recent meta-analysis revealed that the percentage of infiltrating NK cells in hepatocellular carcinoma correlates with a better patient outcome. Similarly, our previous genome-wide association study on chronic viral hepatitis showed that a single-nucleotide polymorphism of major histocompatibility complex class I polypeptide-related sequence A (MICA), a ligand to the NK activating receptor, plays a critical role in hepatocarcinogenesis. In this review, we summarize the mechanisms underlying the regulation of MICA and NK group 2D expression in chronic hepatitis. Furthermore, we describe recent reports on MICA single-nucleotide polymorphism-driven hepatocarcinogenesis. The suppression of MICA shedding could represent a promising approach for immunosurveillance, as increased expression of membrane-bound MICA achieved through the use of a MICA shedding inhibitor also enhances NK cell-mediated cytotoxicity.

Prophylactic use of a self-assembling peptide hydrogel for preventing delayed bleeding after endoscopic sphincterotomy: A propensity score-matched analysis.

BACKGROUND AND AIM: Delayed endoscopic sphincterotomy-related bleeding (ES bleeding) is an unavoidable adverse event (AE) that can have serious ramifications. Intraoperative ES bleeding, which stops spontaneously in most cases, is a known risk factor for delayed bleeding. This study aimed to examine the preventive effect of a novel self-assembling peptide (SAP) for delayed ES bleeding in patients who attained spontaneous hemostasis after intraoperative ES bleeding. METHODS: A total of 1507 patients met the eligibility criteria for inclusion in this study. The rates of delayed ES bleeding and AE besides bleeding were compared between patients administered the SAP (SAP group) and those who were simply observed after spontaneous hemostasis of intraoperative ES bleeding (control group). Propensity score matching was performed to adjust for differences between the groups. RESULTS: The rate of delayed ES bleeding was significantly lower in the SAP group than that in the control group (0.9% vs 3.8%, P = 0.044). The rates of AEs other than bleeding were 2.4% and 3.8% in the SAP and control groups, respectively, and the difference lacked statistical significance (P = 0.481). Multivariate analysis revealed that the use of SAP was significantly associated with a lower frequency of delayed ES bleeding (odds ratio, 0.35; 95% confidence interval, 0.13-0.98; P = 0.047). CONCLUSIONS: Self-assembling peptide may be a simple, safe, and useful way to reduce the risk of delayed ES bleeding in patients who experienced intraoperative ES bleeding and obtained subsequent spontaneous hemostasis.

Sedanolide Activates KEAP1-NRF2 Pathway and Ameliorates Hydrogen Peroxide-Induced Apoptotic Cell Death.

Sedanolide is a bioactive compound with anti-inflammatory and antitumor activities. Although it has been recently suggested that sedanolide activates the nuclear factor E2-related factor 2 (NRF2) pathway, there is little research on its effects on cellular resistance to oxidative stress. The objective of the present study was to investigate the function of sedanolide in suppressing hydrogen peroxide (H2O2)-induced oxidative damage and the underlying molecular mechanisms in human hepatoblastoma cell line HepG2 cells. We found that sedanolide activated the antioxidant response element (ARE)-dependent transcription mediated by the nuclear translocation of NRF2. Pathway enrichment analysis of RNA sequencing data revealed that sedanolide upregulated the transcription of antioxidant enzymes involved in the NRF2 pathway and glutathione metabolism. Then, we further investigated whether sedanolide exerts cytoprotective effects against H2O2-induced cell death. We showed that sedanolide significantly attenuated cytosolic and mitochondrial reactive oxygen species (ROS) generation induced by exposure to H2O2. Furthermore, we demonstrated that pretreatment with sedanolide conferred a significant cytoprotective effect against H2O2-induced cell death probably due to preventing the decrease in the mitochondrial membrane potential and the increase in caspase-3/7 activity. Our study demonstrated that sedanolide enhanced cellular resistance to oxidative damage via the activation of the Kelch-like ECH-associated protein 1 (KEAP1)-NRF2 pathway.

High-resolution 3D display using time-division light ray quadruplexing technology.

We propose a flicker-reduced time-division light ray quadruplexing technology to improve both the spatial and angular resolutions of three-dimensional (3D) images. The proposed method uses an image-shift optical device with polarization gratings. By optimizing the design of the image-shift optical device and incorporating it into the display system, we confirmed that the resolution characteristics of 3D images displayed at a depth of 30 mm or more can be improved by up to 1.58 times. Furthermore, by developing the display system using a 120 Hz 8K projector with wobbling device and a wavelength-selective λ/2 plate for reducing flicker, we achieved high-resolution 3D image display with deeper depth.

Pixel-density enhanced integral three-dimensional display with two-dimensional image synthesis.

Integral three-dimensional (3D) displays can display naturally viewable 3D images. However, displaying 3D images with high pixel density is difficult because the maximum pixel number is restricted by the number of lenses of a lens array. Therefore, we propose a method for increasing the maximum pixel density of 3D images by optically synthesizing the displayed images of an integral 3D display and high-definition two-dimensional display using a half mirror. We evaluated the improvements in 3D image resolution characteristics through simulation analysis of the modulation transfer function. We developed a prototype display system that can display 3D images with a maximum resolution of 4K and demonstrated the effectiveness of the proposed method.

Baseline soluble MICA levels act as a predictive biomarker for the efficacy of regorafenib treatment in colorectal cancer.

BACKGROUND: To evaluate the effect of regorafenib on soluble MHC class I polypeptide-related sequence A (MICA) (sMICA) level in vitro. In addition, we clinically examined whether its plasma levels were associated with regorafenib activity in terms of progression-free survival (PFS) in patients with CRC. METHODS: Human CRC cell line HCT116 and HT29 cells were treated with regorafenib and its pharmacologically active metabolites, M2 or M5 at the same concentrations as those in sera of patients. We also examined the sMICA levels and the area under the plasma concentration-time curve of regorafenib, M2 and M5. RESULTS: Regorafenib, M2, and M5 significantly suppressed shedding of MICA in human CRC cells without toxicity. This resulted in the reduced production of sMICA. In the clinical examination, patients with CRC who showed long median PFS (3.7 months) had significantly lower sMICA levels than those with shorter median PFS (1.2 months) (p = 0.045). CONCLUSIONS: MICA is an attractive agent for manipulating the immunological control of CRC and baseline sMICA levels could be a predictive biomarker for the efficacy of regorafenib treatment.

Leukotriene receptor antagonists enhance HCC treatment efficacy by inhibiting ADAMs and suppressing MICA shedding.

In our previous genome-wide association study, we demonstrated the association between MHC class I-related chain A (MICA) and hepatocellular carcinoma (HCC) development in patients with chronic hepatitis C. Increasing membrane-bound MICA (mMICA) in cancer cells by reducing MICA sheddases facilitates natural killer (NK) cell-mediated cytotoxicity. Our recent study clarified that A disintegrin and metalloproteases (ADAM), including ADAM9, are MICA sheddases in HCC, and that the suppression of ADAMs increases mMICA, demonstrating the rationality of mMICA-NK targeted therapy. Furthermore, we showed that regorafenib suppresses ADAM9 transcriptionally and translationally. A library of FDA-approved drugs was screened for more efficient inhibitors of ADAM9. Flow cytometry evaluation of the expression of mMICA after treatment with various candidate drugs identified leukotriene receptor antagonists as potential ADAM9 inhibitors. Furthermore, leukotriene receptor antagonists alone or in combination with regorafenib upregulated mMICA, which was in turn downregulated by leukotriene C4 and D4 via ADAM9 function. Our study demonstrates that leukotriene receptor antagonists could be developed as novel drugs for immunological control and suppression of ADAM9 in HCC. Further, leukotriene receptor antagonists should be explored as combination therapy partners with conventional multi-kinase inhibitors for developing therapeutic strategies with enhanced efficacies for HCC management and treatment.

Pneumococcal capsular phase shift is associated with invasion into cell-to-cell junctions and is inhibited by macrolides.

Streptococcus pneumoniae frequently colonizes the human nasopharynx beginning in the early childhood. Pneumococci exhibit a spontaneous and reversible phase shift between opaque and transparent allowing them to adapt to different environments. This is the first report of the dynamics of pneumococcal phase shift during the course of adhesion and subsequent invasion into epithelial cell monolayers by bacteria-cell co-culture assay with a time-lapse microscopy. The invasion of an inoculum between the human epithelial cells was dependent on the transparent phenotype, but successful replication of the cells within the cell layer was strongly associated with its transformation into an opaque-like variant. We also observed that sub-MIC levels of clarithromycin inhibited the spontaneous pneumococcal phase shift. Our results show that the pneumococcus can modulate its fitness in part because it can switch phenotype in response to the environment during not only inflammation but also during the establishment of colonization. Our current findings provide a more in depth understanding not only of how the pneumococcal phase shift acts to protect pneumococci from commensal flora and the immune status of the host, but also illustrate a novel strategy for antimicrobial treatments to interfere with pneumococcal colonization.

Roadmap on 3D integral imaging: sensing, processing, and display.

This Roadmap article on three-dimensional integral imaging provides an overview of some of the research activities in the field of integral imaging. The article discusses various aspects of the field including sensing of 3D scenes, processing of captured information, and 3D display and visualization of information. The paper consists of a series of 15 sections from the experts presenting various aspects of the field on sensing, processing, displays, augmented reality, microscopy, object recognition, and other applications. Each section represents the vision of its author to describe the progress, potential, vision, and challenging issues in this field.

Function of PoLAE2, a laeA homolog, in appressorium formation and cAMP signal transduction in Pyricularia oryzae.

A novel homolog of laeA, a global regulatory gene in filamentous fungi, was identified from Pyricularia oryzae. A deletion mutant of the homolog (PoLAE2) exhibited lowered intracellular cAMP levels, and decreased appressorium formation on non-host surface; the decrease was recovered using exogenous cAMP and IBMX, indicating that PoLAE2 deletion affected the cAMP signaling pathway.

Three cases of histologically proven hepatic epithelioid hemangioendothelioma evaluated using a second-generation microbubble contrast medium in ultrasonography: case reports.

BACKGROUND: Hepatic epithelioid hemangioendothelioma (HEH) is rare; it is reported in < 1 person in 1,000,000 individuals. For accurate diagnosis, information regarding multiple graphic modalities in HEH is required. However, there is very little information concerning Sonazoid® contrast enhanced ultrasonography (CEUS) in HEH. CASE PRESENTATION: The present report describes the histologically proven three HEH cases evaluated using Sonazoid® CEUS. Case 1 was a 33-year-old female patient with no relevant past medical history, who experienced right upper quadrant pain. Conventional abdominal US revealed multiple low echoic liver nodules with vague borderlines. In CEUS, the vascularity of the nodules was similar to that seen in the neighboring normal liver. Later in the portal venous and late phases (PVLP) and post vascular phase, washout of Sonazoid® was detected in the nodules. Case 2 was a 93-year-old female patient with a previous medical history including operations for breast cancer and ovary cancer in her 50's. Conventional abdominal US revealed multiple low echoic nodules, some of which contained cystic lesions. In the early vascular phase of CEUS, nodules excluding the central anechoic regions were enhanced from peripheral sites. Although the enhancement inside the nodules persisted in both the PVLP and post vascular phase, anechoic areas in the center of some nodules were not enhanced at all. Case 3 was a 39-year-old male patient presented with right upper-quadrant pain, without any relevant past medical history. Conventional abdominal US revealed multiple low echoic liver nodules. In the early vascular phase of CEUS, nodules were gradually enhanced from the peripheral sites as ringed enhancement. Sonazoid®was washed out from the nodules in the PVLP and post vascular phase. CONCLUSIONS: The most important feature was peripheral enhancement in the early vascular phase. In case 2, the enhancement of the parenchyma of liver nodules persisted even in the PVLP; indicating the lower degree of malignant potential than others. Actually, the tumors did not extend without any treatment in case 2. Since case 2 is the first case report of HEH with cystic lesions, in patients with liver nodules including cystic lesions, HEH is a potential diagnosis.

CD4+ T cells from patients with primary biliary cholangitis show T cell activation and differentially expressed T-cell receptor repertoires.

AIM: Primary biliary cholangitis (PBC) is an autoimmune liver disease with unknown pathogenesis. In PBC, activation of T-cell receptor (TCR) signaling is associated with inflammatory cytokine production through N-Ras upregulation. Although the CD4+ T cell TCR repertoire could be associated with PBC pathogenesis, it has not been evaluated. Thus, we analyzed the PBC-CD4+ T cell TCR repertoire using next generation sequencing (NGS). METHODS: Four PBC patients (one treatment-naïve and three receiving ursodeoxycholic acid) and three healthy individuals were enrolled. NRAS expression in CD4+ T cells was assessed by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). N-Ras dynamics in CD4+ T cells were assessed by qRT-PCR and GTP-N-Ras activation assay. The TCR α- (TRA) and ß-chain (TRB) repertoires on CD4+ T cells were analyzed by NGS and profiled using hierarchical analysis. Motif analysis was undertaken to elucidate the structure of PBC-specific TCRs. RESULTS: NRAS was upregulated in PBC relative to control CD4+ T cells (P < 0.05), and N-Ras enhanced T cell activation in CD4+ T cells. Among 2668 TRAs and 841 TRBs, 20 and 11, respectively, were differentially expressed in PBC compared to that in controls (P < 0.05, fold-change >2). Among them, TRAV29/J22, TRBV6-5/J2-6, and TRBV10-1/J2-1 were expressed in PBC but the expression was negligible in the controls, with more mature and longer forms observed in PBC-CD4+ T cells. CONCLUSIONS: N-Ras was upregulated in PBC-CD4+ T cells, and it enhanced TCR activation, indicating that PBC-CD4+ T cells were activated by N-Ras upregulation with differentially expressed TCR repertoires on their surfaces.

Enzymatic inhibition of MICA sheddase ADAM17 by lomofungin in hepatocellular carcinoma cells.

In our previous study on hepatocellular carcinoma (HCC) susceptibility genes in chronic hepatitis patients, we identified the MHC class I polypeptide-related sequence A (MICA). Natural killer cells eliminate various cancer cells, including HCC, by suppressing MICA shedding. Therefore, we investigated MICA sheddases and inhibitors for HCC immunotherapy. In this study, HepG2, PLC/PRF/5, and Hep3B were treated with the siRNA of a disintegrin and metalloproteases (ADAMs) and matrix metalloproteases to measure the concentration of soluble MICA (sMICA) by ELISA to detect the therapeutic target. Furthermore, an FDA-approved drug library was tested for the enzymatic inhibition of the targeted enzyme in an in vitro drug screening assay system. ADAM17 knockdown reduced sMICA levels and increased membrane-bound MICA (mMICA) expression in HCC cells. In an in vitro drug screen using an FDA-approved drug library, lomofungin, an antifungal drug, was found to strongly decrease ADAM17 activity. In HCC cells, mMICA expression was induced and sMICA production was inhibited in a dose-dependent manner. These effects were cancelled upon ADAM17 knockdown, suggesting that lomofungin targeted ADAM17. Analysis of lomofungin analogs revealed the responsible functional groups. In summary, we suggest lomofungin to be an attractive agent for the immunological control of HCC, via the suppression of ADAM17.

Enhanced B-cell differentiation driven by advanced cirrhosis resulting in hyperglobulinemia.

BACKGROUND AND AIM: The mechanism underlying hyperglobulinemia in cirrhosis, a long appreciated phenomenon, has never been clearly understood. The aim of this study is to investigate the basis for changes in humoral immunity observed in cirrhosis. METHODS: We retrospectively reviewed our medical record to analyze serum immunoglobulin (Ig) levels in patients with liver disease. We also prospectively analyzed peripheral blood mononuclear cells and sera from liver disease patients. Peripheral blood mononuclear cell surface marker expressions were measured by flow cytometry and serum B-cell-activating factor was measured by enzyme-linked immunosorbent assay. Expression of specific gene expression in magnetically separated B cells was also analyzed by real-time polymerase chain reaction. RESULTS: In retrospective analysis, we found that advancing cirrhosis, irrespective of underlying etiology or hepatocellular carcinoma, resulted in progressively increasing levels of serum IgG and IgA. In prospective analysis using clinical samples, we demonstrated that advancing cirrhosis stage was associated with increased toll-like-receptor (TLR)9 expression in CD27+ B cell and serum B-cell-activating factor levels but decreased CD27+ memory B-cell frequency. The remaining CD27+ B cells in peripheral blood exhibited increased activation-induced cytidine deaminase mRNA expression. Finally, we also demonstrated isolated B cells from advanced cirrhosis were more reactive to TLR9 stimulation that drove antibody secreting cells differentiation leading to hyperimmunoglobulinemia in vitro. CONCLUSIONS: Enhanced TLR9-induced differentiation into antibody secreting cell may explain peripheral reductions of circulating CD27+ memory B cells as well as increased serum Ig levels in cirrhosis.

Predominance of regorafenib over sorafenib: Restoration of membrane-bound MICA in hepatocellular carcinoma cells.

BACKGROUND AND AIM: The multi-kinase inhibitor regorafenib (REG) was recently demonstrated to be effective in patients with sorafenib (SOR)-resistant hepatocellular carcinoma (HCC). Interestingly, SOR is known to enhance the accumulation of membrane-bound MHC class I polypeptide-related sequence A (mMICA) in HCC cells and to block the production of soluble MICA (sMICA), an immunological decoy. In addition, MICA is associated with HCC in patients with chronic hepatitis C. We have now compared the impact of REG and SOR on MICA in HCC cells, as well as the immunotherapeutic implications thereof. METHODS: HepG2 and PLC/PRF/5 cells were exposed to REG and SOR, and levels of sMICA and mMICA were measured by ELISA and flow cytometry, respectively. The drugs were also tested in vitro for inhibitory activity against recombinant human A disintegrin and metalloprotease 9 (ADAM9), a sheddase that releases MICA from the membrane. RESULTS: To a greater extent than SOR, but without marked difference in cytotoxicity, REG significantly suppressed mRNA and protein expression of ADAM9 and ADAM10, thereby decreasing production of sMICA and boosting accumulation of mMICA. Accumulation of mMICA in response to REG was reversed by siRNA against ADAM9. However, the drugs did not inhibit the enzymatic activity of ADAM9 in vitro. CONCLUSIONS: The clinical superiority of REG over SOR is partially attributable to reduced MICA shedding via transcriptional suppression of ADAM9 and ADAM10.

Measurement of static convergence and accommodation responses to images of integral photography and binocular stereoscopy.

Static convergence and accommodation responses were measured by comparing integral photography images, binocular stereoscopic images, and real objects in a measurement range from 450 to 900 mm. The experimental results were evaluated with a multiple comparison test. It was found that six of the ten observers did not have an accommodation-convergence conflict in viewing integral photography in the range. Moreover, the required resolution was found to be 0.7 or more and less than 1.4 cycles per degree for inducing accommodation. In conclusion, integral photography can provide a natural 3D image that looks like a real object.

Integral 3D display using multiple LCD panels and multi-image combining optical system.

We present a method to display an integral three-dimensional (3D) image without gaps between multiple display active areas by using multiple liquid crystal display (LCD) panels and multi-image combining optical systems (MICOS). We designed a MICOS to improve the resolution characteristics and decrease the luminance unevenness corresponding to the viewpoint. Furthermore, we developed a method for correcting the distortion of the integral 3D image by using image processing. We prototyped an integral 3D display using four 8K dual-green (8KDG) LCD panels and the improved MICOSs. The prototype display achieved to magnify the display area about 5.66 times more than when a single LCD panel was used.

Retraction: 'Effect of blonanserin on cognitive function in antipsychotic-naïve first-episode schizophrenia'.

The above article from Human Psychopharmacology, first published on 25 January 2012 in Wiley OnlineLibrary (onlinelibrary.wiley.com), and in Volume 90, pp. 90-100, has been retracted by agreement between the authors, the journal Editor in Chief, David Baldwin, and John Wiley & Sons Ltd. The retraction has been agreed following an investigation by the St Marianna University Ethics Committee which determined that the paper was not as originally designed and approved. REFERENCES: Tenjin, T., Miyamoto, S., Miyake, N., Ogino, S., Kitajima, R., Ojima, K., … Yamaguchi, N. (2012). Effect of blonanserin on cognitive function in antipsychotic-naïve first-episode schizophrenia. Hum. Psychopharmacol Clin Exp, 27, 90-100. https://doi.org/10.1002/hup.1276.

Isomeric iodinated analogs of nimesulide: Synthesis, physicochemical characterization, cyclooxygenase-2 inhibitory activity, and transport across Caco-2 cells.

Isomeric iodinated derivatives of nimesulide, with an iodine substituent on the phenoxy ring, were prepared with the aim of identifying potential candidate compounds for the development of imaging agents targeting cyclooxygenase-2 (COX-2) in the brain. Both the experimental logP7.4 and pKa values for these iodinated analogs were in the acceptable range for passive brain penetration. The para-iodo-substituted analog was a more potent and selective COX-2 inhibitor than nimesulide, with a potency that was comparable to the reference drug, celecoxib. Iodination at the ortho- or meta-position of the phenoxy ring was associated with a substantial loss of COX-2 inhibitory activity. Transport studies across Caco-2 cell monolayers in the presence and absence of a P-glycoprotein (P-gp) inhibitor, verapamil, indicated that the para-iodo-substituted analog was not a P-gp transport substrate; this feature is a prerequisite for potential in vivo brain imaging compounds. The para-iodo-substituted analog of nimesulide appears to be an attractive candidate for the development of radioiodine-labeled tracers for in vivo brain imaging of COX-2 levels.