Search

Background: Squamous cell lung cancer (SqCLC) is a distinct histologic subtype of non-small cell lung cancer (NSCLC). Although the discovery of driver mutations and their targeted drugs has remarkably improved the treatment outcomes for lung adenocarcinoma, currently no such molecular target is clinically available for SqCLC. The CDKN2A locus at 9p21 encodes two alternatively spliced proteins, p16 INK4a (p16) and p14 ARF (p14), which function as cell cycle inhibitors. The Cancer Genome Atlas (TCGA) project revealed that CDKN2A is inactivated in 72% of SqCLC cases. In addition, it was found that CDKN2A mutations are significantly more common in SqCLC than in adenocarcinoma. Down-regulation of p16 and p14 by CDKN2A gene inactivation leads to activation of cyclin-dependent kinases (CDKs), thereby permitting constitutive phosphorylation of Rb and subsequent cell cycle progression. Here, we hypothesized that CDK inhibition may serve as an attractive strategy for the treatment of CDKN2A-defective SqCLC., Methods: We investigated whether the CDK inhibitors flavopiridol and dinaciclib may exhibit antitumor activity in CDKN2A-defective SqCLC cells compared to control cells. The cytotoxic effect of the CDK inhibitors was evaluated using cell viability assays, and the induction of apoptosis was assessed using TUNEL assays and Western blot analyses. Finally, anti-tumor effects of the CDK inhibitors on xenografted cells were investigated in vivo., Results: We found that flavopiridol and dinaciclib induced cytotoxicity by enhancing apoptosis in CDKN2A-defective SqCLC cells, and that epithelial to mesenchymal transition (EMT) decreased and autophagy increased during this process. In addition, we found that autophagy had a cytoprotective role., Conclusion: Our data suggest a potential role of CDK inhibitors in managing CDKN2A-defective SqCLC.

Citrus pomace (CP) is a by-product occurred during juice or other products processing. The enormous amount of CP caused serious environmental issues. However, CP is rich in a variety of bioactive compounds. In the present study, a water extract of CP (CPW) was prepared from the by-product and the in vitro and in vivo antioxidant activities of CPW were investigated. The in vitro antioxidant activities of CPW were evaluated by measuring the free radical scavenging activity and protective effects against 2,2-azobis(2-amidinopropane) hydrochloride (AAPH)-induced oxidative stress in Vero cells. CPW scavenges 1,1-diphenyl-2-picrylhydrazyl, alkyl, and hydroxyl radicals at IC 50 of 0.16±0.00, 0.31±0.01, and 0.86±0.02 mg/mL, respectively. In addition, CPW improved cell viability and scavenged intracellular reactive oxygen species (ROS) in AAPH-stimulated Vero cells in a dose-dependent manner. The in vivo antioxidant activities of CPW were investigated in a model of AAPH-induced zebrafish embryos. CPW significantly improved the survival rates and reduced heartbeat rates in AAPH-stimulated zebrafish. Furthermore, the intracellular ROS and cell death levels were remarkably decreased in CPW-treated zebrafish. Therefore, the present results indicated that CPW possesses potent in vitro and in vivo antioxidant properties and could be a potential ingredient used in food, pharmaceutical, and cosmetic industries., Competing Interests: AUTHOR DISCLOSURE STATEMENT The authors declare no conflict of interest.

Background: There are limitations to current colorectal cancer (CRC)-specific diagnostic methods and therapies. Tumorigenesis proceeds because of interaction between cancer cells and various surrounding cells; discovering new molecular mediators through studies of the CRC secretome is a promising approach for the development of CRC diagnostics and therapies., Materials and Methods: A comparative secretomic analysis was performed using primary and metastatic human isogenic CRC cells. Proliferation was determined by MTT and thymidine incorporation assay, migration was determined by wound-healing assay (ELISA). The level of palmitoleoyl-protein carboxylesterase (NOTUM) in plasma from patients with CRC was determined by enzyme-linked immunosorbent assay., Results: NOTUM expression was increased in metastatic cells. Proliferation was suppressed by inhibiting expression of NOTUM. Knockdown of NOTUM genes inhibited proliferation as well as migration, with possible involvement of p38 and c-JUN N-terminal kinase in this process. The result was verified in patients with CRC., Conclusion: NOTUM may be a new candidate for diagnostics and therapy of CRC., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Dry eyes are caused by highly increased osmolarity of tear film, inflammation, and apoptosis of the ocular surface. In this study, we investigated the effect of Polygonum cuspidatum (PCE) aqueous extract in in vivo and in vitro dry eye models. Dry eye was induced by excision of the lacrimal gland and hyperosmotic media. In vivo, oral administration of PCE in exorbital lacrimal gland-excised rats recovered tear volume and Mucin4 (MUC4) expression by inhibiting corneal irregularity and expression of inflammatory cytokines. In vitro, hyperosmotic media induced human corneal epithelial cell (HCEC) cytotoxicity though increased inflammation, apoptosis, and oxidative stress. PCE treatment significantly inhibited expression of cyclooxygenase-2 and inflammatory cytokines (interleukin-6 and tumor necrosis factor-α), and activation of NF-κB p65 in hyperosmolar stress-induced HCECs. Hyperosmolarity-induced increase in Bcl-2-associated X protein (BAX) expression and activation of cleaved poly (ADP-ribose) polymerase and caspase 3 were attenuated in a concentration-dependent manner by PCE. PCE treatment restored anti-oxidative proteins such as heme oxygenase-1 (HO-1), superoxide dismutase-1 (SOD-1), and glutathione peroxidase (GPx) in hyperosmolar stress-induced HCECs. These data demonstrate that PCE prevents adverse changes in the ocular surface and tear fluid through inhibition of hyperosmolar stress-induced inflammation, apoptosis, and oxidation, suggesting that PCE may have the potential to preserve eye health.

Recently, we reported that orphan nuclear receptor small heterodimer partner (SHP) is involved in neutrophil recruitment through the regulation of C-X-C motif chemokine ligand 2 (CXCL2) expression in a concanavalin A (ConA)-induced hepatitis model. In the present study, we examined the mechanisms underlying CXCL2 regulation by SHP and the cell types involved in liver inflammation. To this end, either Shp knockout (KO) or wild-type (WT) bone marrow cells were transferred into sublethally-irradiated WT (KO → WT or WT → WT) or Shp KO (KO → KO or WT → KO) recipients, followed by intravenous injection of ConA (20-30 mg/kg) 8 weeks later. The KO recipient groups showed higher ConA-induced lethality than the WT recipient groups. Accordingly, plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, and inflammatory cytokine expressions were significantly higher in the KO recipients than in the WT recipients regardless of donor genotype. Massively increased hepatocyte death in KO recipients, as determined by H&E and TUNEL staining, was observed after ConA challenge. Bone marrow chimera experiments and in vitro chemotaxis assay also showed that SHP-deficient hepatocytes have an enhanced ability to recruit neutrophils to the injured liver. In vitro promoter assays showed that SHP is a negative regulator of Cxcl2 transcription by interfering with c-Jun binding to the AP-1 site within the Cxcl2 promoter. Collectively, SHP regulates Cxcl2 transcription in hepatocytes, playing a pivotal role in the recruitment of neutrophils. SHP-targeting strategies may represent alternative approaches to control fulminant hepatitis.

Time-of-flight secondary ion mass spectrometry (ToF-SIMS) imaging is an analytical technique rapidly expanding in use in biological studies. This technique is based on high spatial resolution (50-100 nm), high surface sensitivity (1-2 nm top-layer), and statistical analytic power. In mass spectrometry imaging (MSI), sample preparation is a crucial step to maintaining the natural state of the biomolecules and providing accurate spatial information. However, a number of problems associated with temperature changes in tissue samples such as loss of original distribution due to undesired molecular migration during the sample preparation or reduced ionization efficiency make it difficult to accurately perform MSI. Although frozen hydrate analysis is the ideal sample preparation method to eliminate the effects of temperature, this approach is hindered by mechanical limitations. Alternatively, an adhesive-tape-supported mounting and freeze-drying preparation has been proposed. This paper provides a concise review of the sample preparation procedures, a review of current issues, and proposes efficacious solutions for ToF-SIMS imaging in biological research.

The melanocortin-4 receptor (MC4R) belongs to the G protein-coupled receptor (GPCR) family and plays an essential role in the control of energy homeostasis. Here, we identified a novel MC4R-interacting protein, glucose-regulated protein 78 (GRP78), from a pulldown assay using hypothalamic protein extracts and the third intracellular loop of MC4R. We found that MC4R interacted with GRP78 in both the cytosol and at the cell surface and that this interaction increased when MC4R was internalized in the presence of the agonist melanotan-II (MTII). Downregulation of GRP78 using a short interfering RNA approach attenuated MTII-mediated receptor internalization. Reduction in GRP78 expression during tunicamycin-induced endoplasmic reticulum stress also suppressed MTII-mediated internalization of MC4R and cAMP-mediated transcriptional activity. Furthermore, lentiviral-mediated short hairpin RNA knockdown of endogenous GRP78 in the paraventricular nucleus (PVN) of the hypothalamus resulted in an increase in body weight in mice fed a high-fat diet. These results suggest that GRP78 in the PVN binds to MC4R and may have a chaperone-like role in the regulation of MC4R trafficking and signaling.

Localized surface plasmon resonance (LSPR) biosensors have attracted much interest due to their capacity for multiplexing, miniaturization, and high performance, which offers the potential for their integration into lab-on-a-chip platforms for point-of-care (POC) diagnostics. The need for microRNA (miRNA)-sensing platforms is particularly urgent because miRNAs are key regulators and biomarkers in numerous pathological processes and diseases. Unfortunately, however, development of such miRNA-sensing platforms has not yet been achieved. In order to realize the detection of these important biomarkers, there has been an increasing demand for POC-sensing platforms that enable label-free quantification with low sample consumption, good sensitivity, real-time responsiveness, and high throughput. Here, we developed a highly specific, sensitive LSPR miRNA-sensing platform on a flexible, scalable plasmonic nanostructure to enable single-base mismatch discrimination and attomole detection of miRNAs in clinically relevant samples. The hairpin probe contained a locked nucleic acid (LNA) that enabled the discrimination of single base mismatches based on differences in melting temperatures of perfectly matched or single base mismatched miRNAs when they formed base pairs with probes. In addition, through hybridization induced signal amplification based on precipitate formation on the gold surface through the enzyme reaction, we observed a dramatic LSPR peak shift, which enabled attomole detection. Additionally, our LSPR miRNA sensor enabled the detection of miR-200a-3p in total RNA extracts from primary cancer cell lines without purification or labeling of the miRNA. This label-free and highly specific miRNA sensing platform may have applications in POC cancer diagnostics without the need for gene amplification., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Acetaminophen (APAP) overdose is a leading cause of drug-induced acute liver failure. Prolonged c-Jun N-terminal kinase (JNK) activation plays a central role in APAP-induced liver injury; however, growth arrest and DNA damage-inducible 45 beta (GADD45β) is known to inhibit JNK phosphorylation. The orphan nuclear receptor small heterodimer partner (SHP, NR0B2) acts as a transcriptional co-repressor of various genes. The aim of the present study was to investigate the role of SHP in APAP-evoked hepatotoxicity. We used lethal (750 mg/kg) or sublethal (300 mg/kg) doses of APAP-treated wild-type (WT), Shp knockout (Shp -/- ), hepatocyte-specific Shp knockout (Shp hep-/- ), and Shp and Gadd45β double knockout (Shp -/- Gadd45β -/- ) mice for in vivo studies. Primary mouse hepatocytes were used for a comparative in vitro study. SHP deficiency protected against APAP toxicity with an increased survival rate, decreased liver damage, and inhibition of prolonged hepatic JNK phosphorylation in mice, which was independent of APAP metabolism regulation. Furthermore, Shp hep-/- mice showed diminished APAP hepatotoxicity compared with WT mice. SHP-deficient primary mouse hepatocytes also showed decreased cell death and inhibition of sustained JNK phosphorylation following toxic APAP treatment. While SHP expression declined, GADD45β expression increased after APAP treatment in WT mice. In Shp -/- mice, APAP-evoked GADD45β induction was significantly enhanced. Notably, the ameliorative effects of SHP deficiency on APAP-induced liver injury were abolished in Shp -/- Gadd45β -/- mice. The current study is the first to demonstrate that hepatocyte-specific SHP deficiency protects against APAP overdose-evoked hepatotoxicity in a JNK signaling regulation and GADD45β dependent manner. SHP is suggested to be a novel therapeutic target for APAP overdose treatment.

Colorectal large-cell neuroendocrine carcinomas (NECs) are extremely rare and have very poor prognosis compared to adenocarcinomas. A 74-year-old man presented with abdominal pain, diarrhea and hematochezia. The histopathologic report of colonoscopic biopsy performed at a local clinic was a poorly differentiated carcinoma. An abdominopelvic computed scan revealed irregularly enhanced wall thickening at the sigmoid colon with regional fat stranding and lymphnode enlargement. He underwent a laparoscopic high anterior resection with selective peritonectomy for peritoneal carcinomatosis, intraoperative peritoneal irrigation chemotherapy, and early postoperative intraperitoneal chemotherapy for 5 days. The tumor had a high proliferation rate (mitotic count > 50/10 HPFs and 90% of the Ki-67 index) and lymph-node metastases had occurred. On immunohistochemistry, the tumor cells expressed CD56 and synaptophysin. Large-cell NEC was confirmed. Systemic chemotherapy with cisplatin/etoposide was done. The patient is still alive after 3 years with no evidence of recurrence.

Background: Sacral neuromodulation is an effective therapy for overactive bladder, urinary retention, and fecal incontinence. Infection after sacral neurostimulation is costly and burdensome. Determining optimal perioperative management strategies to reduce the risk of infection is important to reduce this burden., Objective: We sought to identify risk factors associated with sacral neurostimulator infection requiring explantation, to estimate the incidence of infection requiring explantation, and identify associated microbial pathogens., Study Design: This is a multicenter retrospective case-control study of sacral neuromodulation procedures completed from Jan. 1, 2004, through Dec. 31, 2014. We identified all sacral neuromodulation implantable pulse generator implants as well as explants due to infection at 8 participating institutions. Cases were patients who required implantable pulse generator explantation for infection during the review period. Cases were included if age ≥18 years old, follow-up data were available ≥30 days after implantable pulse generator implant, and the implant was performed at the institution performing the explant. Two controls were matched to each case. These controls were the patients who had an implantable pulse generator implanted by the same surgeon immediately preceding and immediately following the identified case who met inclusion criteria. Controls were included if age ≥18 years old, no infection after implantable pulse generator implant, follow-up data were available ≥180 days after implant, and no explant for any reason <180 days from implant. Controls may have had an explant for reasons other than infection at >180 days after implant. Fisher exact test (for categorical variables) and Student t test (for continuous variables) were used to test the strength of the association between infection and patient and surgery characteristics. Significant variables were then considered in a multivariable logistic regression model to determine risk factors independently associated with infection., Results: Over a 10-year period at 8 academic institutions, 1930 sacral neuromodulator implants were performed by 17 surgeons. In all, 38 cases requiring device explant for infection and 72 corresponding controls were identified. The incidence of infection requiring explant was 1.97%. Hematoma formation (13% cases, 0% controls; P = .004) and pocket depth of ≥3 cm (21% cases, 0% controls; P = .031) were independently associated with an increased risk of infection requiring explant. On multivariable regression analysis controlling for significant variables, both hematoma formation (P = .006) and pocket depth ≥3 cm (P = .020, odds ratio 3.26; 95% confidence interval, 1.20-8.89) remained significantly associated with infection requiring explant. Of the 38 cases requiring explant, 32 had cultures collected and 24 had positive cultures. All 5 cases with a hematoma had a positive culture (100%). Of the 4 cases with a pocket depth ≥3 cm, 2 had positive cultures, 1 had negative cultures, and 1 had a missing culture result. The most common organism identified was methicillin-resistant Staphylococcus aureus (38%)., Conclusion: Infection after sacral neuromodulation requiring device explant is low. The most common infectious pathogen identified was methicillin-resistant S aureus. Demographic and health characteristics did not predict risk of explant due to infection, however, having a postoperative hematoma or a deep pocket ≥3 cm significantly increased the risk of explant due to infection. These findings highlight the importance of meticulous hemostasis as well as ensuring the pocket depth is <3 cm at the time of device implant., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Metformin is a medication that is widely prescribed for the management of type 2 diabetes. In addition to its anti-diabetic uses, metformin has been proposed as a therapeutically effective drug candidate in various central nervous system disorders, including Parkinson's disease (PD). PD is characterized by severe movement defects and is commonly treated with the dopamine (DA) precursor 3,4-dihydroxyphenyl-l-alanine (L-DOPA). However, prolonged use of L-DOPA can lead to the development of L-DOPA-induced dyskinesia (LID). Here, we hypothesized that metformin co-treatment would improve LID in the 6-hydroxydopamine (6-OHDA)-lesioned mouse model of PD. Metformin did not interfere the pharmacotherapeutic effects of L-DOPA in the cylinder test. Furthermore, metformin co-treatment with L-DOPA attenuated the development of LID in unilaterally 6-OHDA-lesioned mice. Metformin showed a long-lasting effect on axial, limb, and orofacial abnormal involuntary movement scores for up to 20 days after treatment initiation. Interestingly, persistent enhancement of the mammalian target of rapamycin, dopamine D1 receptor, and extracellular signaling-regulated kinase 1/2 signaling was maintained in the DA-denervated striatum during metformin treatment. Metformin globally normalized the increased glycogen synthase kinase 3β activity induced by chronic treatment of L-DOPA in a manner associated with Akt activation in unilaterally 6-OHDA-lesioned mice. These findings suggest that metformin may have therapeutic potential for the suppression or management of L-DOPA-induced motor complications in patients with PD.

Although detailed pathophysiological mechanisms of fulminant hepatitis remain elusive, immune cell recruitment with excessive cytokine production is a well-recognized hallmark of the disease. We determined the function of orphan nuclear receptor small heterodimer partner (SHP) in concanavalin A (ConA)-induced hepatitis model. Male C57BL/6 J mice were injected intravenously with either a lethal dose (25 mg/kg) or a sub-lethal dose (15 mg/kg) of ConA. For the C-X-C motif chemokine ligand (CXCL) 2 neutralization study, mice were intravenously administered anti-mouse CXCL2 antibody (100 μg/mouse). Thirty-six hours following lethal dose of ConA administration, 47% wild type (WT) mice were alive, whereas >85% of Shp knockout (KO) were dead. Shp KO mice were highly susceptible to ConA-induced liver injury and exhibited increased liver necrosis upon sub-lethal dose of ConA administration. FACS analysis and immunohistochemical staining showed significantly higher neutrophil infiltration in Shp KO mice, as compared with WT mice. We found that also in the WT situation, Shp expression gradually decreased, while Cxcl2 expression increased until 6 h, and vice versa at 24 h upon ConA-treatment, indicating an inverse correlation between Shp and Cxcl2 expression during ConA-induced hepatitis. Furthermore, in vivo neutralization of CXCL2 with neutralizing antibody reduces ConA-induced plasma ALT and AST levels, hepatocyte death and neutrophil infiltration in Shp KO mice. Collectively, these results confirm that lacking of SHP results in CXCL2-dependent neutrophil infiltration in ConA-induced liver damage. SHP plays a protective, anti-inflammatory role in liver during acute liver inflammation.

Background: Folliculotropic mycosis fungoides (FMF) is a variant of mycosis fungoides (MF) that is characterized clinically by variable types of skin eruptions, including plaques, acneiform lesions, and alopecic patches. Histopathologically, FMF is characterized by folliculotropic infiltrates., Objective: This study was conducted to scrutinize the clinical and histopathologic features of FMF in Koreans and the responses to phototherapy., Methods: Twenty Koreans diagnosed with MF who had histopathologic evidence of folliculotropism were enrolled., Results: Eighteen patients had head-and-neck-region infiltration, while five had solitary lesion. In all patients, the atypical lymphocytic infiltrate had a perifollicular distribution. Twelve patients were treated with ultraviolet A (UVA)-1. Eleven of these 12 patients with early-stage FMF experienced >80% improvement (8: complete remission; 3: partial remission). Four patients, including 2 who relapsed after UVA-1, were treated with photodynamic therapy (PDT), reaching complete remission after PDT., Conclusion: As FMF has variable clinical presentations, skin biopsy is required to confirm the diagnosis. And both UVA-1 and methyl aminolevulinate-PDT are clinically effective in treatment of early-stage FMF., Competing Interests: CONFLICTS OF INTEREST: The authors have nothing to disclose.

Time-of-flight secondary ion mass spectrometry (ToF-SIMS) imaging elucidates molecular distributions in tissue sections, providing useful information about the metabolic pathways linked to diseases. However, delocalization of the analytes and inadequate tissue adherence during sample preparation are among some of the unfortunate phenomena associated with this technique due to their role in the reduction of the quality, reliability, and spatial resolution of the ToF-SIMS images. For these reasons, ToF-SIMS imaging requires a more rigorous sample preparation method in order to preserve the natural state of the tissues. The traditional thaw-mounting method is particularly vulnerable to altered distributions of the analytes due to thermal effects, as well as to tissue shrinkage. In the present study, the authors made comparisons of different tissue mounting methods, including the thaw-mounting method. The authors used conductive tape as the tissue-mounting material on the substrate because it does not require heat from the finger for the tissue section to adhere to the substrate and can reduce charge accumulation during data acquisition. With the conductive-tape sampling method, they were able to acquire reproducible tissue sections and high-quality images without redistribution of the molecules. Also, the authors were successful in preserving the natural states and chemical distributions of the different components of fat metabolites such as diacylglycerol and fatty acids by using the tape-supported sampling in microRNA-14 (miR-14) deleted Drosophila models. The method highlighted here shows an improvement in the accuracy of mass spectrometric imaging of tissue samples.

The C-type lectin-like domain of CLEC14a (CLEC14a-C-type lectin-like domain [CTLD]) is a key domain that mediates endothelial cell-cell contacts in angiogenesis. However, the role of CLEC14a-CTLD in pathological angiogenesis has not yet been clearly elucidated. In this study, through complementarity-determining region grafting, consecutive deglycosylation, and functional isolation, we generated a novel anti-angiogenic human monoclonal antibody that specifically targets CLEC14a-CTLD and that shows improved stability and homogeneity relative to the parental antibody. We found that this antibody directly inhibits CLEC14a-CTLD-mediated endothelial cell-cell contact and simultaneously downregulates expression of CLEC14a on the surface of endothelial cells. Using various in vitro and in vivo functional assays, we demonstrated that this antibody effectively suppresses vascular endothelial growth factor (VEGF)-dependent angiogenesis and tumor angiogenesis of SNU182 human hepatocellular carcinoma, CFPAC-1 human pancreatic cancer, and U87 human glioma cells. Furthermore, we also found that this antibody significantly inhibits tumor angiogenesis of HCT116 and bevacizumab-adapted HCT116 human colorectal cancer cells. These findings suggest that antibody targeting of CLEC14a-CTLD has the potential to suppress VEGF-dependent angiogenesis and tumor angiogenesis and that CLEC14a-CTLD may be a novel anti-angiogenic target for VEGF-dependent angiogenesis and tumor angiogenesis., (© 2018 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.)

Brain imaging using time-of-flight secondary ion mass spectrometry (ToF-SIMS) has been reported to produce the distorted biomolecular distributions due to the cholesterol-induced matrix effect when cholesterol migrates to the surface, particularly in white matter, which contains a high level of cholesterol. Frozen-hydrated analysis has been used to inhibit the movement of cholesterol in the brain. In this paper, the authors propose new sample preparation and drying methods that can be used to obtain accurate biomolecular images at room temperature, instead of frozen-hydrated analysis using liquid-nitrogen, which must be continuously supplied to maintain the sample at -160 °C during the experiment. The rat brain prepared by the tape-supporting method on a precooled (-20 °C) stainless steel plate was freeze-dried in a load-lock chamber of ToF-SIMS for about an hour and moved directly to the main chamber. Using this preparation method, the authors found that cholesterol did not migrate to the surface in the corpus callosum (white matter) of the rat brain and sulfatide-related signals obtained from the cerebellum were not reduced in white matter. Our tape-supporting and freeze-drying sampling method for brain tissues could be a useful tool to study important metabolites of neurodegenerative diseases.

Optical-resolution photoacoustic microscopy (OR-PAM), which has been widely used and studied as a noninvasive and in vivo imaging technique, can yield high-resolution and absorption contrast images. Recently, metallic nanoparticles and dyes, such as gold nanoparticles, methylene blue, and indocyanine green, have been used as contrast agents of OR-PAM. This study demonstrates real-time functional OR-PAM images with high-speed alternating illumination at 2 wavelengths. To generate 2 wavelengths, second harmonic generation at 532 nm with an LBO crystal and a pump wavelength of 1064 nm is applied at a pulse repetition rate of 300 kHz. For alternating illumination, an electro-optical modulator is used as an optical switch. Therefore, the A-line rate for the functional image is 150 kHz, which is half of the laser repetition rate. To enable fast signal processing and real-time displays, parallel signal processing using a graphics processing unit (GPU) is performed. OR-PAM images of the distribution of blood vessels and gold nanorods in a BALB/c-nude mouse's ear can be simultaneously obtained with 500 × 500 pixels and real-time display at 0.49 fps., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Highly sensitive and reproducible surface enhanced Raman spectroscopy (SERS) requires not only a nanometer-level structural control, but also superb uniformity across the SERS substrate for practical imaging and sensing applications. However, in the past, increased reproducibility of the SERS signal was incompatible with increased SERS sensitivity. This work presents multiple silver nanocrystals inside periodically arrayed gold nanobowls (SGBs) via an electrochemical reaction at an overpotential of -3.0 V (vs. Ag/AgCl). The gaps between the silver nanocrystals serve as hot spots for SERS enhancement, and the evenly distributed gold nanobowls lead to a high device-to-device signal uniformity. The SGBs on the large sample surface exhibit an excellent SERS enhancement factor of up to 4.80 × 10 9 , with excellent signal uniformity (RSD < 8.0 ± 2.5%). Furthermore, the SGBs can detect specific microRNA (miR-34a), which plays a widely acknowledged role as biomarkers in diagnosis and treatment of diseases. Although the small size and low abundance of miR-34a in total RNA samples hinder their detection, by utilizing the advantages of SGBs in SERS sensing, reliable and direct detection of human gastric cancer cells has been successfully accomplished.

Background: Tsutsugamushi disease is an acute, febrile, infectious disease caused by Orientia tsutsugamushi . Several studies investigating the histopathologic findings of eschars in tsutsugamushi disease reported leukocytoclastic vasculitis and neutrophil infiltration as the major findings. However, these findings may result from secondary changes following tissue necrosis. The histopathologic findings of perieschar lesions may be important to understand the primary changes associated with tsutsugamushi disease., Objective: To investigate characteristic histopathologic features of perieschar lesions and suppose the mechanism of vascular pathophysiological changes associated with tsutsugamushi disease., Methods: We analyzed histopathological slides of perieschar lesions in 12 patients diagnosed with tsutsugamushi disease., Results: In the epidermis, exocytosis of mononuclear cells (75.0%) and basal vacuolar changes (66.7%) were frequent. In the dermis, perivascular, interstitial, and perineural mononuclear cell infiltration (100.0%, 83.3%, and 83.3%, respectively), as well as thrombosis (83.3%), atypical lymphocyte infiltration (91.7%), and mitotic figures (83.3%) were commonly seen. Lymphocytic vasculitis and mononuclear cell infiltration around eccrine glands were found in all cases, but eosinophil infiltration was only found in one patient (8.3%). However, the characteristic findings of eschar lesions, such as leukocytoclastic vasculitis and neutrophil infiltration, were not found in perieschar lesions., Conclusion: The major histopathologic findings in the perieschar lesions of tsutsugamushi disease were lymphocytic vasculitis and atypical lymphocytic infiltration, mimicking lymphoma. Therefore, we suggest that this lesion should be added to the list of pseudolymphomas. To observe these characteristic histopathologic features, we also recommend that skin biopsies should be performed on perieschar lesions, not eschar lesions., Competing Interests: CONFLICTS OF INTEREST: The authors have nothing to disclose.

The development of analytical tools for accurate and sensitive detection of intracellular metabolites associated with mutated metabolic enzymes is important in cancer diagnosis and staging. The gene encoding the metabolic enzyme isocitrate dehydrogenase 1 (IDH1) is mutated in various cancers, and mutant IDH1 could represent a good biomarker and potent target for cancer therapy. Owing to a mutation in an important arginine residue in the catalytic pocket, mutant IDH1 catalyzes the production of 2-hydroxyglutarate (2-HG) instead of its wild type product α-ketoglutarate (α-KG), which is involved in multiple cellular pathways involving the hydroxylation of proteins, ribonucleic acid, and deoxyribose nucleic acid (DNA). Since 2-HG is an α-KG antagonist, inhibiting normal α-KG-dependent metabolism, high intracellular levels of 2-HG result in abnormal histone and DNA methylation. Therefore, accurate and sensitive analytical tools for the direct detection of 2-HG in cancer cells expressing mutant IDH1 would benefit this field, as it would minimize the need both for complicated experimental procedures and for large amounts of biological samples. Here, the authors describe a useful analytical method for the direct detection of 2-HG in lysates from a mutant IDH1-expressing cell line by time-of-flight secondary ion mass spectrometry (TOF-SIMS) analysis, a powerful surface analysis tool. In addition, the authors verified the efficacy of the specific mutant IDH1 inhibitor AGI-5198 by tracking the intracellular 2-HG concentration, which decreased in a dose-dependent manner. Our results demonstrate the large potential of TOF-SIMS as an analytical tool for the simple, direct detection of oncometabolites during cancer diagnosis, and for verifying the efficiency of the targeted cancer drugs.

Upon single treatment against Staphylococus aureus, quercetin-pivaloxymethyl conjugate (Q-POM) had antibacterial activities with minimum inhibitory concentrations (MICs) of 16-32 mg/L. Q-POM showed MIC of 32 mg/L against vancomycin-resistant Enterococcus faceium (VRE), which is remarkably lower than other antibiotics investigated (≥256 mg/L). Under sub-MIC concentrations, Q-POM potentiated the activity of ampicillin, cefepime, and vancomycin against S. aureus and Enterococcus (including highly resistant strains such as hetero-resistant vancomycin-intermediate S. aureus (hVISA), vancomycin-intermediate S. aureus (VISA), and VRE), by decreasing the MICs of these antibiotics by 4-128 folds. Q-POM was found to be partially synergistic with ampicillin and cefepime against S. aureus and Enterococcus, while it was strongly synergistic with vancomycin. Q-POM at 5 mg/L inhibited the formation of biofilms of S. aureus by 24-83% and VRE by 70%. Additionally, Q-POM inhibited the hemolytic activity of S. aureus in a dose-dependent manner. Cytotoxic activity was evaluated in human liver epithelial cells (HepG2), and the 50% cytotoxicity concentration (CC 50 ) value of Q-POM was higher than 50 mg/L. These results indicate the potential use of Q-POM in treatment of methicillin-resistant Staphylococcus aureus (MRSA) and VRE infections.

The aim of this study was to assess the potential application of activated carbon (AC) and nonwoven fabric mats (NWFM) for thin-layer capping in remediation of sediments containing high amounts of carbon, nitrogen, and phosphorus. Laboratory column incubation experiments were performed to analyze the efficiencies of AC and NWFM for blocking nutrients. Under uncapped conditions, dissolved oxygen (DO) was exhausted within three days but under NWFM/AC capping conditions (with NWFM above the AC capping layer), the presence of DO was prolonged until Day 33. Chemical oxygen demand (COD) was lower under all capped conditions than under uncapped conditions, with lowest COD observed with NWFM/AC capping. NH 4 -N occupied the highest percentage of total nitrogen in the overlying water and its percentage increased as the DO concentration decreased. The capping efficiencies for NH 4 -N, T-N, and PO 4 -P with NWFM/AC capping were (66.0, 54.2, and 73.1) %, respectively, which were higher than for other capping conditions. In the case of T-P, capping efficiencies under all capping conditions were almost 100%, indicating that both AC and NWFM effectively interrupted phosphorus release from sediments. Placing NWFM above the AC capping layer was more effective than the opposite arrangement. It can be concluded that NWFM and AC can be successfully used for remediation of lake sediments with high amounts of nitrogen and phosphorus., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Purpose: A suture line placed with the same direction as the relaxed skin tension line leads to good healing, but a suture line with over 30 degrees of angle from the relaxed skin tension line leads to longer healing time and more prominent scarring. W-plasty is widely used to change the direction of the scar or to divide it into several split scars. In this study, we applied W-plasty to patients with facial lacerations in the emergency department., Methods: From June 2012 to December 2014, 35 patients underwent simple repair or W-plasty for facial lacerations. Patients in the simple repair group underwent resection following a thermal margin, and the W-plasty group was resected within a pre-designed margin of W-shaped laceration. We assessed prognosis using the Stony Brook Scar Evaluation Scale (SBSES) after 10 days (short-term) and six months (long-term), respectively, following suture removal., Results: Among 35 patients, 15 (42.9%) underwent simple debridement and 20 (57.1%) underwent W-plasty. In the W-plasty group, there was no difference between short-term and long-term follow-up showing high SBSES, but in the simple debridement group, long-term follow-up SBSES significantly decreased. W-plasty SBSES was higher than simple debridement at short-term as well as long-term follow-up., Conclusion: We experienced good results of direct W-plasty application at six-month long-term follow-up. Therefore, W-plasty application is more effective in reducing scar appearance than a simple debridement method for facial laceration patients with an angle of 30 degrees or more to the relaxed skin tension line., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The surface protein hemagglutinin (HA) mediates the attachment of influenza virus to host cells containing sialic acid and thus facilitates viral infection. Therefore, HA is considered as a good target for the development of diagnostic tools for influenza virus. Previously, we reported the isolation of single-stranded aptamers that can distinguish influenza subtype H1 from H5. In this study, we describe a method for the selective electrical detection of H1 using the isolated aptamer as a molecular probe. After immobilization of the aptamer on Si wafer, enzyme-linked immunosorbent assay (ELISA) and field emission scanning electron microscopy (FE-SEM) showed that the immobilized aptamer bound specifically to the H1 subtype but not to the H5 subtype. Assessment by cyclic voltammetry (CV) also demonstrated that the immobilized aptamer on the indium thin oxide-coated surface was specifically bound to the H1 subtype only, which was consistent with the ELISA and FE-SEM results. Further measurement of CV using various amounts of H1 subtype provided the detection limit of the immobilized aptamer, which showed that a nanomolar scale of target protein was sufficient to produce the signal. These results indicated that the selected aptamer can be an effective probe for distinguishing the subtypes of influenza viruses by monitoring current changes.

Intensive study of the organic extract of the marine-derived bacterium Saccharomonospora sp. CNQ-490 has yielded three new α-pyrones, saccharomonopyrones A-C ( 1 - 3 ). The chemical structures of these compounds were assigned from the interpretation of 1D, 2D NMR and mass spectrometry data. Saccharomonopyrone A ( 1 ) is the first α-pyrone microbial natural product bearing the ethyl-butyl ether chain in the molecule, while saccharomonopyrones B and C possess unusual 3-methyl and a 6-alkyl side-chain within a 3,4,5,6-tetrasubstituted α-pyrone moiety. Saccharomonopyrone A exhibited weak antioxidant activity using a cation radical scavenging activity assay with an IC 50 value of 140 μM., Competing Interests: The authors declare no conflict of interest.

Corn seed tissue sections were prepared by the tape support method using an adhesive tape, and mass spectrometry imaging (MSI) was performed. The effect of heat generated during sample preparation was investigated by time-of-flight secondary mass spectrometry (TOF-SIMS) imaging of corn seed tissue prepared by the tape support and the thaw-mounted methods. Unlike thaw-mounted sample preparation, the tape support method does not cause imaging distortion because of the absence of heat, which can cause migration of the analytes on the sample. By applying the tape-support method, the corn seed tissue was prepared without structural damage and MSI with accurate spatial information of analytes was successfully performed. Graphical Abstract ᅟ.

Non-small cell lung cancers harboring somatic gain-of-function mutations in the epidermal growth factor receptor (EGFR) tyrosine kinase domain respond well to treatment with EGFR tyrosine kinase inhibitors (TKIs) including gefitinib and erlotinib. However, all patients who experience a marked improvement with these drugs eventually develop disease progression due to the acquisition of drug resistance. Approximately half of the cases with acquired resistance to EGFR TKIs can be accounted for by a second-site mutation in exon 20 of the EGFR kinase domain (T790M). However, the changes of gene expression involved in EGFR TKI resistance due to the T790M mutation remain poorly defined. The present study established lung cancer cell lines that were resistant to gefitinib or erlotinib, and these cell lines were verified to contain the EGFR T790M mutation. The differential expression of genes associated with acquired resistance was verified in the present study by mRNA microarray analysis. Among the genes whose expression was significantly altered, genes whose expression was altered in gefitinib- and erlotinib-resistant cells were focused on. Notably, a total of 1,617 genes were identified as being differentially expressed in gefitinib- and erlotinib-resistant cells. Indeed, Gene ontology analysis revealed altered expression of genes involved in the regulation of cellular proliferation, apoptosis, and the cell cycle in EGFR TKI-resistant cells. The present results demonstrate distinctive gene expression patterns of EGFR TKI-resistant lung cancer cells with the EGFR T790M mutation. The present study can provide key insights into gene expression profiles involved in conferring resistance to EGFR TKI therapy in lung cancer cells.

Background: Construction of an esophagojejunostomy is still a challenging procedure in totally laparoscopic total gastrectomy (TLTG), and there is no standard anastomosing method. The aims of this study were to describe our TLTG with the overlap method using a linear stapler and report surgical outcomes., Methods: From January 2015 to April 2016, 50 patients underwent TLTG using the overlap method for gastric cancer. The procedures were performed by a single surgeon, and the patients' medical records were reviewed. Their clinicopathologic characteristics, operation time, date of flatus, hospital stay, morbidity, and mortality were analyzed., Results: The median age and body mass index were 56 years and 23.5, respectively. Stage 1A tumors were the most common. Mean operating time was 144.6 min, and no cases required changing to open laparotomy during surgery. On average, flatus occurred 3.5 days after surgery, and patients were discharged 6.8 days after surgery. No patient experienced anastomosis leakage, stricture, duodenal stump leakage, luminal bleeding, pancreatic fistula, or wound problems. There were two cases of intra-abdominal bleeding that required additional surgery. Intra-abdominal fluid collection and mechanical ileus occurred in two patients, respectively, and were successfully managed with conservative treatment., Conclusions: We reported favorable surgical outcomes of TLTG using the overlap method. It is a feasible and safe option for treatment of gastric cancer.

Bare gold nanospheres have been shown to have anti-angiogenic effects but are optically unfavorable because their resonant wavelength lies in the visible spectrum. Here, we design gold nanodisks with a higher scattering capability than gold nanorods and with a resonant wavelength at near-infrared region - the area where the source of light utilized by optical coherence tomography (OCT) lies. With a physical synthesis system, we then fabricate 160-nm-sized gold nanodisks exhibiting resonant wavelength at 830 nm. The synthesized nanoparticles were successfully visualized in in vivo OCT at concentrations as low as 1 pM. After demonstrating their binding ability to vascular endothelial growth factor (VEGF), we show that they suppress VEGF-induced migration of endothelial cells. Finally, we demonstrate that intravitreally injected gold nanodisks attenuate neovascularization of oxygen-induced retinopathy in mice, in a dose dependent manner, such that they are cleared from the vitreous within 2 weeks without histologic or electrophysiologic toxicity., (Copyright © 2017 Elsevier Inc. All rights reserved.)

A novel chemically bonded phosphate ceramic (CBPC) binder was developed for the simultaneous treatment of the top five most toxic heavy metals (Hg, Pb, As, Cr, and Cd). Various CBPC binders were synthesized and tested, and their toxicity characteristic leaching procedure (TCLP) values were obtained. A magnesium/calcium-potassium phosphate ceramic binder with FeCl 2 (M/C-KP-FeCl 2 ) simultaneously stabilized multiple heavy metals. The TCLP value of the final product for industrial waste (IW) treatment using the M/C-KP-FeCl 2 technology was well below the Universal Treatment Standard (UTS). Additionally, the compressive strength of the final product was below the US Nuclear Regulatory Commission Standard., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Herein, we report on biological imaging nanoprobes: physically synthesized gold nanodisks that have inherent optical advantages-a wide range of resonant wavelengths, tunable ratio of light absorption-to-scattering, and responsiveness to random incident light-due to their two-dimensional circular nanostructure. Based on our proposed physical synthesis where gold is vacuum deposited onto a prepatterned polymer template and released from the substrate in the form of a nanodisk, monodisperse two-dimensional gold nanodisks were prepared with independent control of their diameter and thickness. The optical benefits of the Au nanodisk were successfully demonstrated by the measurement of light absorbance of the nanodisks and the application of stacked nanodisks, where a smaller sized Au nanodisk was laid atop a larger nanodisk, as bimodal contrast agents for photoacoustic microscopy and optical coherence tomography.

The direct in situ synthesis of cadmium sulfide (CdS) nanowires (NWs) was presented by direct synthesis of CdS NWs on the gold surface of an interdigitated electrode (IDE). In this work, we investigated the effect of a strong oxidant on the surfaces of the CdS NWs using X-ray photoelectron spectroscopy, transmission electron microscopy, and time-of-flight secondary ion mass spectrometry. We also fabricated a parylene-C film as a surface passivation layer for in situ-synthesized CdS NW photosensors and investigated the influence of the parylene-C passivation layer on the photoresponse during the coating of parylene-C under vacuum using a quartz crystal microbalance and a photoanalyzer. Finally, we used the in situ-synthesized CdS NW photosensor with the parylene-C passivation layer to detect the chemiluminescence of horseradish peroxidase and luminol and applied it to medical detection of carcinoembryonic antigen., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: All nasal bone fractures have the potential for worsening of olfactory function. However, few studies have studied the olfactory outcomes following reduction of nasal bone fractures. This study evaluates posttraumatic olfactory dysfunction in patients with nasal bone fracture before and after closed reduction., Methods: A prospective study was conducted for all patients presenting with nasal bone fracture (n=97). Each patient consenting to the study underwent the Korean version of Sniffin' Sticks test (KVSS II) before operation and at 6 month after closed reduction. The nasal fractures were divided according to the nasal bone fracture classification by Haug and Prather (Types I-IV). The olfactory scores were compared across fracture types and between preoperative and postoperative settings., Results: Olfactory dysfunction was frequent after nasal fracture (45/97, 46.4%). Our olfactory assessment using the KVSS II test revealed that fracture reduction was not associated with improvements in the mean test score in Type I or Type II fractures. More specifically, the mean posttraumatic Threshold, discrimination and identification score decreased from 28.8 points prior to operation to 23.1 point at 6 months for Type II fracture with septal fracture., Conclusion: Our study has revealed two alarming trends regarding post-nasal fracture olfactory dysfunction. First, our study demonstrated that almost half (46.4%) of nasal fracture patients experience posttraumatic olfactory dysfunction. Second, closed reduction of these fractures does not lead to improvements olfaction at 6 months, which suggest that olfactory dysfunction is probably due to factors other than the fracture itself. The association should be further explored between injuries that lead to nasal fracture and the mechanism behind posttraumatic olfactory dysfunction., Competing Interests: No potential conflict of interest relevant to this article was reported.

Inactivation of the fragile histidine triad (Fhit) gene has been reported in the majority of human cancers, particularly in lung cancer. The role of Fhit as a tumor suppressor gene has been well documented, and restoration of Fhit expression suppresses tumorigenicity in tumor cell lines and in mouse models by inducing apoptosis and inhibiting proliferation of tumor cells. Autophagy is a catabolic pathway, whereby cytoplasmic proteins and organelles are sequestered in vacuoles and delivered to lysosomes for degradation and recycling. Although autophagy is necessary for cell survival under stress conditions, recent studies have shown that autophagy can also promote cell death. Due to the fact that both autophagy induction and Fhit expression are commonly associated with nutrient starvation, we hypothesized that Fhit expression may be related to autophagy induction. In the present study, we assessed whether Fhit overexpression by gene transfer induces autophagy in Fhit-deficient non-small cell lung cancer (NSCLC) cells. The results of our study indicate that Fhit protein induces autophagy in NSCLC cells, and that this autophagy prevents apoptotic cell death in vivo and in vitro in a 14-3-3τ protein-dependent manner. To the best of our knowledge, this is the first report to describe Fhit-induced autophagy. Suppressing autophagy might be a promising therapeutic option to enhance the efficacy of Fhit gene therapy in NSCLC.

Carbon nanotube/polytetrafluoroethylene composite polymer targets are proposed for use in the fabrication of fluorocarbon thin films using the mid-frequency sputtering process. Fluorocarbon thin films deposited using carbon nanotube/polytetrafluoroethylene composite targets exhibit an amorphous phase with a smooth surface and show a high water contact angle, optical transmittance, and surface hardness. X-ray photoelectron spectroscopy and Fourier transform infrared spectroscopy studies reveal that as the carbon nanotube concentration increased in the composite target, a carbon cross-linked structure was formed, which enhanced the film hardness and the modulus of the fluorocarbon thin film. Large-area fluorocarbon thin films with a substrate width of 700 mm were successfully fabricated by a pilot-scale roll-to-roll sputtering system using a carbon nanotube/polytetrafluoroethylene composite target.

Purpose: To evaluate the 3-month natural course of recurrent macular edema secondary to branch retinal vein occlusion (BRVO) treated with intravitreal bevacizumab., Methods: This retrospective, observational study included 36 eyes with macular edema secondary to BRVO. All patients were initially treated with intravitreal bevacizumab for macular edema. Recurrence of macular edema was either not treated (untreated group) or treated with a single intravitreal bevacizumab injection (treated group). Central foveal thickness (CFT) and best-corrected visual acuity (BCVA) were compared at the time of recurrence and 3 months later., Results: At the time of recurrence, the mean CFT and logarithm of the minimum angle of resolution BCVA were 484.9 ± 124.1 µm and 0.58 ± 0.26 in the untreated group (n = 19) and 456.3 ± 126.8 µm and 0.51 ± 0.21 in the treated group (n = 17), respectively. Three months later, the mean CFT and BCVA had changed to 493.7 ± 123.9 µm and 0.62 ± 0.29 in the untreated group and 294.7 ± 104.4 µm and 0.40 ± 0.24 in the treated group, respectively. The differences in CFT and BCVA between the two time points were not significant in the untreated group ( p = 0.106 and p = 0.687, respectively), whereas statistically significant differences were noted in the treated group ( p = 0.002 and p < 0.001, respectively)., Conclusions: Unlike the first episode of macular edema following BRVO, recurrent macular edema following intravitreal bevacizumab therapy did not spontaneously resolve, suggesting the potential benefit of prompt treatment., Competing Interests: Conflict of Interest: No potential conflict of interest relevant to this article was reported.

We investigated the temperature-dependent locomotion of Caenorhabditis elegans by using the mobile phone-based microscope. We developed the customized imaging system with mini incubator and smartphone to effectively control the thermal stimulation for precisely observing the temperature-dependent locomotory behaviours of C. elegans. Using the mobile phone-based microscope, we successfully followed the long-term progress of specimens of C. elegans in real time as they hatched and explored their temperature-dependent locomotory behaviour. We are convinced that the mobile phone-based microscope is a useful device for real time and long-term observations of biological samples during incubation, and can make it possible to carry out live observations via wireless communications regardless of location. In addition, this microscope has the potential for widespread use owing to its low cost and compact design., (© 2017 The Authors Journal of Microscopy © 2017 Royal Microscopical Society.)

Toxoplasmic encephalitis (TE) is an opportunistic infection found in immunocompromised patients and TE related cerebral mass lesion is often reported in acquired immunodeficiency acquired immunodeficiency syndrome (AIDS) patients. However, incidence of TE related AIDS in Korea is still rare and is unfamiliar to neurosurgeons. Differential diagnosis is needed to rule out other brain lesions. A 39-year-old man visited the emergency room with rapid progressive left hemiparesis. Magnetic resonance imaging showed a ring-enhanced mass lesion in his right frontal lobe. Human immunodeficiency virus and Toxoplasma gondii immunoglobulin G were tested positive by a serologic test. We report here a rare case of patient with TE related AIDS., Competing Interests: Conflicts of Interest: The authors have no financial conflicts of interest.

Background/aims: 18 F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) has been used for preoperative staging of colorectal cancer (CRC). However, the diagnostic accuracy of FDG-PET/CT for detection of lymph node or distant metastasis and its prognostic role have not been well established. We therefore evaluated the diagnostic and prognostic value of FDG-PET/CT in comparison with conventional CT for CRC., Methods: We investigated 220 patients who underwent preoperative FDG-PET/CT and CT, followed by curative surgery for CRC. The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of FDG-PET/CT and CT for detection of lymph node metastasis and distant metastasis were evaluated. In addition, we assessed the findings of FDG-PET/CT and CT according to outcomes, including cancer recurrence and cancer-related death, for evaluation of prognostic value., Results: For detection of lymph node metastasis, FDG-PET/CT had a sensitivity of 44%, a specificity of 84%, and an accuracy of 67%, compared with 59%, 65%, and 62%, respectively, for CT ( P =0.029, P =0.000, and P =0.022). For distant metastasis, FDG-PET/CT had a sensitivity of 79%, a specificity of 94%, and an accuracy of 93%, compared with 79%, 87%, and 86%, respectively, for CT ( P =1.000, P =0.004, and P =0.037). In addition, positive findings of lymph node metastasis and distant metastasis on FDG-PET/CT were associated significantly with cancer recurrence or cancer-related death ( P =0.009, P =0.001, respectively)., Conclusions: Preoperative FDG-PET/CT had a higher specificity and accuracy compared to CT for detection of lymph node metastasis and distant metastasis of CRC. In addition, FDG-PET/CT could be a valuable prognostic tool for CRC., Competing Interests: Conflict of interest: None.

Importance: Pelvic organ prolapse is a common condition, the prevalence of which is likely to increase with the aging of our population. Also changing are parameters by which outcomes are assessed, shifting toward patient-centered care., Objective: To review vaginal obliterative procedures for surgical treatment of advanced pelvic organ prolapse historically and to discuss evidence on indications for colpocleisis, outcomes, and complications, as well as review pros and cons for concomitant vaginal hysterectomy and anti-incontinence procedures., Evidence Acquisition: Review predominantly of the English language literature on issues associated with obliterative vaginal surgery for advanced pelvic organ prolapse from LeFort's and Neugebauer's original description in the late 1800s to now., Results: LeFort and total colpocleisis are effective procedures for surgical treatment of advanced pelvic organ prolapse with relatively low complication rates. Patient satisfaction is high. Loss of coital function is rarely a reason for regret. Hysterectomy is not required in most patients with procidentia. Anti-incontinence procedures can be performed at time of colpocleisis for patients with coexisting stress incontinence. Evidence is conflicting with regard to occult stress urinary incontinence., Conclusions and Relevance: Colpocleisis are valuable procedures for women with severe pelvic organ prolapse who do not wish to retain coital function. Results are maintained in women with recurrent prolapse after prior failed reconstructive surgery. Considering a patient's goals for surgery and comprehensive presurgical counseling are important determinants of patient satisfaction., Target Audience: Obstetricians and gynecologists, family physicians., Learning Objectives: After completing this activity, the learner should be better able to list indications and contraindications for vaginal obliterative procedures, discuss risks and benefits of sling placement at time of colpocleisis, list perioperative complications, and discuss perioperative workup for LeFort colpocleisis.

Mercury (Hg)-containing waste from various industrial facilities is commonly treated by incineration or stabilization/solidification and retained in a landfill at a managed site. However, when highly concentrated Hg waste is treated using these methods, Hg is released into the atmosphere and soil environment. To eliminate these risks, Hg recovery technology using thermal treatment has been developed and commercialized to recover Hg from Hg-containing waste for safe disposal. Therefore, we developed Hg recovery equipment to treat Hg-containing waste under a vacuum of 6.67kPa (abs) at 400°C and recover the Hg. In addition, the dust generated from the waste was separated by controlling the temperature of the dust filtration unit to 230°C. Additionally, water and Hg vapors were condensed in a condensation unit. The Hg removal rate after waste treatment was 96.75%, and the Hg recovery rate as elemental Hg was 75.23%., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Protein kinases are enzymes that are important targets for drug discovery because of their involvement in regulating the essential cellular processes. For this reason, the changes in protein kinase activity induced by each drug candidate (the inhibitor in this case) need to be accurately determined. Here, an on-chip secondary ion mass spectrometry (SIMS) imaging technique of the peptides was developed for determining protein kinase activity and inhibitor screening without a matrix. In our method, cysteine-tethered peptides adsorbed onto a gold surface produced changes in the relative peak intensities of the phosphorylated and unphosphorylated substrate peptides, which were quantitatively dependent on protein kinase activity. Using mass spectrometry imaging of multiple compartments on the gold surface in the presence of a peptide substrate, we screened 13,727 inhibitors, of which seven were initially found to have inhibitor efficiencies that surpassed 50%. Of these, we were able to identify a new breakpoint cluster region-abelson (BCR-ABL) T315I kinase inhibitor, henceforth referred to as KR135861. KR135861 showed no cytotoxicity and was subsequently confirmed to be superior to imatinib, a commercial drug marketed as Gleevec. Moreover, KR135861 exhibited a greater inhibitory effect on the BCR-ABL T315I tyrosine kinase, with an IC 50 value as low as 1.3 μM. In in vitro experiments, KR135861 reduced the viability of both Ba/F3 cells expressing wild-type BCR-ABL and BCR-ABL T315I , in contrast to imatinib's inhibitory effects only on Ba/F3 cells expressing wild-type BCR-ABL. Due to the surface sensitivity and selectivity of SIMS imaging, it is anticipated that our approach will make it easier to validate the small modifications of a substrate in relation to enzyme activity as well as for drug discovery. This mass spectrometry imaging analysis enables efficient screening for protein kinase inhibitors, thus permitting high-throughput drug screening with high accuracy, sensitivity, and specificity.

This study aimed to develop a mercury (Hg) adsorption trap, which can be used to measure the concentration of elemental Hg in emissions from a Hg discharge facility, and evaluate its adsorption efficiency. The Hg spiking efficiency was compared by impregnating metallic and halogen materials that have high affinity for Hg into activated carbon (AC) to determine an accurate spiking method for Hg on AC. The Hg spiking efficiency was compared according to the type and content of the impregnated substances. AC impregnated with Cl and Au had a 15-20% higher Hg spiking efficiency compared to virgin AC. For Au impregnation at weight ratios of 0-20 wt% of adsorbent, spiking efficiencies of over 97% were observed under certain conditions. The Hg adsorption properties of the above adsorbent were determined experimentally, and the results were used to test the adsorption performance of Hg adsorption traps., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Purpose: To compare, in neovascular age-related macular degeneration (AMD) patients, short-term choroidal thickness changes in eyes treated using ranibizumab with those in eyes treated using aflibercept., Methods: This retrospective, observational study included 240 eyes from 240 patients who had been diagnosed with treatment-naive neovascular AMD and treated using three monthly injections of either ranibizumab (ranibizumab group) or aflibercept (aflibercept group). The choroidal thickness change between the time of diagnosis and 3 months later was compared between the two groups. Eyes were then classified into three disease groups: typical neovascular AMD, polypoidal choroidal vasculopathy (PCV) and retinal angiomatous proliferation (RAP). Within each disease group, choroidal thickness change was again compared between the two treatment groups., Results: In the ranibizumab group (n=155), the mean choroidal thicknesses at diagnosis and at 3 months were 255.3±103.9 μm and 242.9±104.8 μm, respectively. In the aflibercept group (n=85), the values were 277.5±119.1 μm and 254.7±114.5 μm, respectively. The decrease was significantly greater in the aflibercept group (p<0.001). In the PCV group, the decrease was greater in the aflibercept group (p=0.001), whereas the difference was not significant in either the typical neovascular AMD group or the RAP group., Conclusions: A greater decrease in choroidal thickness was noted in eyes treated with aflibercept than in eyes treated with ranibizumab. This difference was more marked in PCV than in other subtypes of neovascular AMD., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Nanoparticles adsorb biomolecules to form corona upon entering the biological environment. In this study, tissue-specific corona formation is provided as a way of controlling protein interaction with nanoparticles in vivo. In the vitreous, the composition of the corona was determined by the electrostatic and hydrophobic properties of the associated proteins, regardless of the material (gold and silica) or size (20- and 100-nm diameter) of the nanoparticles. To control protein adsorption, we pre-incubate 20-nm gold nanoparticles with 5 selectively enriched proteins from the corona, formed in the vitreous, to produce nanoparticle-protein complexes. Compared to bare nanoparticles, nanoparticle-protein complexes demonstrate improved binding to vascular endothelial growth factor (VEGF) in the vitreous. Furthermore, nanoparticle-protein complexes retain in vitro anti-angiogenic properties of bare nanoparticles. In particular, priming the nanoparticles (gold and silica) with tissue-specific corona proteins allows nanoparticle-protein complexes to exert better in vivo therapeutic effects by higher binding to VEGF than bare nanoparticles. These results suggest that controlled corona formation that mimics in vivo processes may be useful in the therapeutic use of nanomaterials in local environment., (Copyright © 2016 Elsevier Ltd. All rights reserved.)