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Background: The risk of mortality due to serious complications associated with hepatectomy for biliary tract cancer remains high. We aimed to investigate the significance of preoperative functional liver volume in predicting and preventing serious morbidity following hepatectomy with bile duct resection (BDR)., Methods: Seventy-one patients who underwent hepatectomy with BDR for biliary tract cancer were included. Functional future remnant liver volume (fFRLV) was calculated using future liver remnant (FLR) volume and functional score measured using EOB-MRI. Patients with unsatisfactory fFRLV values underwent portal or sequential portal/hepatic vein embolization (PVE/HVE). We assessed relationship between variables for liver-related morbidity (LRM), including posthepatectomy liver failure, bile leakage, and persistent ascites. Additionally, we assessed Clavien-Dindo grade IV complications (CD ≥ IV) as indicators of serious morbidity., Results: LRM and CD ≥ IV occurred in 20 (28.2 %) and 6 (8.5 %) cases, respectively. Preoperative FLR volume (p = 0.021), FLR ratio (p = 0.004), fFRLV (p = 0.008), and ICGK-F (p = 0.023) were associated with LRM. fFRLV (p = 0.017) was predictive for LRM but not independent (AUC:0.704). Preoperative FLR volume (p = 0.005), FLR ratio (p = 0.008), and fFRLV (p < 0.001) were associated with CD ≥ IV. fFRLV (p = 0.017) was an independent predictive factor for CD ≥ IV(AUC:0.914), showing greater predictive power compared to other factors., Conclusion: fFRLV predicts CD ≥ IV in patients undergoing hepatectomy with BDR. A sufficient fFRLV, enhanced by PVE/HVE if necessary, may prevent serious morbidity and mortality., Competing Interests: Conflicts of interest None declared., (Copyright © 2024 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Background/purpose: Post-pancreatectomy hemorrhage (PPH) is a fatal complication of pancreatoduodenectomy. When complicated by a pancreatic fistula, pancreatic juice contacting the artery may form a pseudoaneurysm and cause arterial bleeding. We used Hem-o-lok® clips to prevent damage to the outer wall of the gastroduodenal artery (GDA). This study evaluated the usefulness of using Hem-o-lok® clips to ligate the GDA stump to prevent PPH., Methods: Overall, 468 patients who underwent PD at our hospital were included. Before July 2020, we ligated the GDA stump using the knot-tying method, which involves double ligation. After July 2020, the GDA stump was double clipped using a 10-mm Hem-o-lok® clip to the residual side without tension on the GDA. Propensity score matching was used to compare cases of pancreatic fistulas that underwent clipping vs. knot-tying., Results: Propensity score matching resulted in 37 patients in each group. PPH occurred in 12 (16.4%) and 4 (6.9%) patients in the knot-tying and clipping groups, respectively. PPH from the GDA stump occurred in eight (11.0%) and one (1.7%) patient in the knot tying and clipping groups, respectively (P = 0.044)., Conclusions: Hem-o-lok® clips are safe to apply on the GDA stump during pancreatoduodenectomy to prevent PPH., (Copyright © 2024 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Multinucleation occurs in various types of advanced cancers and contributes to their malignant characteristics, including anticancer drug resistance. Therefore, inhibiting multinucleation can improve cancer prognosis; however, the molecular mechanisms underlying multinucleation remain elusive. Here, we introduced a genetic mutation in cervical cancer cells to induce cell fusion-mediated multinucleation. The olfactory receptor OR1N2 was heterozygously mutated in these fused cells; the same OR1N2 mutation was detected in multinucleated cells from clinical cervical cancer specimens. The mutation-induced structural change in the OR1N2 protein activated protein kinase A (PKA), which, in turn, mediated the non-canonical olfactory pathway. PKA phosphorylated and activated furin protease, resulting in the cleavage of the fusogenic protein syncytin-1. Because this cleaved form of syncytin-1, processed by furin, participates in cell fusion, furin inhibitors could suppress multinucleation and reduce surviving cell numbers after anticancer drug treatment. The improved anticancer drug efficacy indicates a promising therapeutic approach for advanced cervical cancers., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: We previously developed a site-specific transvascular drug delivery system (DDS) based on photomechanical waves (PMWs) or laser-induced stress/shock waves (LISWs). In this study, we investigated the validity of this method to deliver a clinical photosensitizer, talaporfin sodium (TS), to subcutaneous tumors in mice and to enhance the efficacy of photodynamic therapy (PDT)., Methods: TS solution (2.5 mg/kg) was intravenously injected into mice. Immediately thereafter, PMWs were applied to the tumor by irradiating a laser target with a Q-switched ruby laser pulse (0.8 J/cm 2 ). Five hours after TS administration, some tumors were excised to evaluate the depth distribution of the delivered TS under a fluorescence microscope. Other tumors were subjected to PDT by irradiating the tissues with a 665 nm continuous-wave laser diode (75 mW/cm 2 , 667 s) at this timepoint. The effects of PDT were evaluated on the basis of the two primary therapeutic mechanisms of TS-mediated PDT: i) damage to tumor cells and ii) damage to endothelial cells of tumor vessels, i.e., the vascular shutdown effect on tumors., Results: PMW application significantly increased the accumulation of TS in the tumor parenchyma but not in the tumor vessel walls; the endothelial cell junctions of tumor vessels should be the route of TS delivery enhanced by PMWs. Thus, as a result of PMW application followed by PDT, while the vascular shutdown effect on the tumors was not enhanced, direct damage to the tumor cells was increased, resulting in significant tumor growth retardation without body weight loss for 7 days after treatment., Competing Interests: Declaration of Competing Interest Hitoshi Tsuda received grants from Roche Diagnostics and a scholarship donation from Chugai Pharmaceutical. However, neither of these funding sources are related to this study., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The metabolites in the plasma serve as potential biomarkers of disease. We previously established an early-onset diabetes mouse model, Ins2 +/Q104del Kuma mice, under a severe immune-deficient (Rag-2/Jak3 double-deficient in BALB/c) background. Here, we revealed the differences in plasma amino acid profiles between Kuma and the wild-type mice. We observed an early reduction in glucogenic and ketogenic amino acids, a late increase in branched-chain amino acids (BCAAs) and succinyl CoA-related amino acids, and a trend of increasing ketogenic amino acids in Kuma mice than in the wild-type mice. Kuma mice exhibited hyperglucagonemia at high blood glucose, leading to perturbations in plasma amino acid profiles. The reversal of blood glucose by islet transplantation normalized the increases of the BCAAs and several aspects of the altered metabolic profiles in Kuma mice. Our results indicate that the Kuma mice are a unique animal model to study the link between plasma amino acid profile and the progression of diabetes for monitoring the therapeutic effects., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The TFDP1 gene codes for the heterodimeric partner DP1 of the transcription factor E2F. E2F, principal target of the tumor suppressor pRB, plays central roles in cell proliferation by activating a group of growth-related genes. E2F also mediates tumor suppression by activating tumor suppressor genes such as ARF, an upstream activator of the tumor suppressor p53, when deregulated from pRB upon oncogenic changes. Among 8 E2F family members (E2F1∼E2F8), expression of activator E2Fs (E2F1∼E2F3a) is induced at the G1/S boundary of the cell cycle after growth stimulation by E2F itself. However, mechanisms regulating DP1 expression are not known. We show here that over-expression of E2F1 and forced inactivation of pRB, by adenovirus E1a, induced TFDP1 gene expression in human normal fibroblast HFFs, suggesting that the TFDP1 gene is a target of E2F. Serum stimulation of HFFs also induced TFDP1 gene expression, but with different kinetics from that of the CDC6 gene, a typical growth-related E2F target. Both over-expression of E2F1 and serum stimulation activated the TFDP1 promoter. We searched for E2F1-responsive regions by 5' and 3' deletion of the TFDP1 promoter and by introducing point mutations in putative E2F1-responsive elements. Promoter analysis identified several GC-rich elements, mutation of which reduced E2F1-responsiveness but not serum-responsiveness. ChIP assays showed that the GC-rich elements bound deregulated E2F1 but not physiological E2F1 induced by serum stimulation. These results suggest that the TFDP1 gene is a target of deregulated E2F. In addition, knockdown of DP1 expression by shRNA enhanced ARF gene expression, which is specifically induced by deregulated E2F activity, suggesting that activation of the TFDP1 gene by deregulated E2F may function as a failsafe feedback mechanism to suppress deregulated E2F and maintain normal cell growth in the event that DP1 expression is insufficient relative to that of its partner activator E2Fs. a maximum of 6 keywords: E2F, DP1, TFDP1 gene, pRB, gene expression., Competing Interests: Declaration of competing interest All authors have no conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: Evaluation of a severity grade (SG) is important to classify patients for efficient use of limited medical resources. This study validates two existing evaluation systems for the prevention of the coronavirus disease 2019 (COVID-19) in Japan: a criterion of SG and a list of 14 specialized underlying diseases (SUDs)., Methods: A retrospective cohort was created using electronic medical records from 18 research institutes. The cohort includes 6,050 COVID-19 patients with two types of diagnosis information as follows: SG at hospitalization among mild, moderate I, moderate II, and severe and aggravation after hospitalization., Results: A crude mortality rate and an aggravation rate increased by the worsening of SG in the COVID-19 cohort. The transition of the aggravation rate was notable for COVID-19 patients with SUD. A conditional probability of the mortality given the aggravation in the COVID-19 cohort was 87.4% compared to mild or moderate patients (approximately 21%-45%) who have the possibility of the aggravation. An odds ratio of the mortality and aggravation information about the SUD list was higher than other variables., Conclusions: We demonstrated the possibility of improving the criteria of SG by including the SUD list for more effective operation of the criteria of SG. Furthermore, we demonstrated the importance of the prevention of the aggravation based on the conditional probability, and the possibility of predicting the aggravation using the risk factors., Competing Interests: Declaration of competing interest HF has no competing interests. KA received a research fund as the director of the Japan Medical Network Association from the Kyoto University., (Copyright © 2022 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: Several carbapenemases have been identified globally in Enterobacteriaceae. In Japan, IMP-type carbapenemase is the most prevalent, although cases of carbapenemase-producing Enterobacteriaceae (CPE) bacteremia are still scarce. The present case series and literature review aimed to elucidate the clinical characteristics and treatment strategies for IMP-type CPE bacteremia., Methods: Clinical data on pediatric cases of IMP-type CPE bacteremia at the Tokyo Metropolitan Children's Medical Center between 2010 and 2020 were collected, and a review of past studies of IMP-type CPE bacteremia has been provided., Results: Five pediatric episodes of IMP-type CPE bacteremia were identified. Our review of previous literature on IMP-type CPE bacteremia revealed 24 adult patients, but no pediatric patients. All 29 cases had underlying diseases, and 23 (79%) received combination therapy. The median duration of antibiotic therapy was 14 days (interquartile range: 9-14 days). The overall mortality rate was 38% (11/29). The mortality rates associated with monotherapy and combination therapy were 67% (4/6) and 30% (7/23), respectively., Conclusions: We report the first case series of IMP-type CPE bacteremia in children. Our review of past studies suggests that combination therapy might lead to better survival outcomes in patients with IMP-type CPE bacteremia. Further research is needed to establish an optimal treatment strategy for IMP-type CPE bacteremia., Competing Interests: Declaration of competing interest The authors have no conflict., (Copyright © 2022 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

We identified a functional SNP in the 3' untranslated region of Pak1 that is responsible for the skin tumor modifier of MSM 1a locus. Candidate SNPs in the 3' untranslated region of Pak1 from resistance strain MSM/Ms were introduced into susceptible strain FVB/N using CRISPR/Cas9. The 7,12-dimethylbenz(a)anthracene/12-O-tetradecanoylphorbol-13-acetate skin carcinogenesis experiments revealed an SNP (Pak1-3' untranslated region-6 C>T : rs31627325) that strongly suppressed skin tumors. Furthermore, MBNL1 bound more strongly to FVB-allele (6 C/C ) and regulated the transcript length in the 3' untranslated region of Pak1 and tumorigenesis through polyadenylation. Therefore, the alternative polyadenylation of Pak1 is cis-regulated by rs31627325., Competing Interests: Conflict of Interest The authors state no conflict of interest., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Control of gut microbes is crucial for not only local defense in the intestine but also proper systemic immune responses. Although intestinal epithelial cells (IECs) play important roles in cytokine-mediated control of enterobacteria, the underlying mechanisms are not fully understood. Here we show that deletion of IκBζ in IECs in mice leads to dysbiosis with marked expansion of segmented filamentous bacteria (SFB), thereby enhancing Th17 cell development and exacerbating inflammatory diseases. Mechanistically, the IκBζ deficiency results in decrease in the number of Paneth cells and impairment in expression of IL-17-inducible genes involved in IgA production. The decrease in Paneth cells is caused by aberrant activation of IFN-γ signaling and a failure of IL-17-dependent recovery from IFN-γ-induced damage. Thus, the IL-17R-IκBζ axis in IECs contributes to the maintenance of intestinal homeostasis by serving as a key component in a regulatory loop between the gut microbiota and immune cells., (© 2022. The Author(s).)

Background: Preoperative portal vein embolization (PVE) stimulates liver hypertrophy and improves the safety of major hepatectomy. It is essential to predict the future remnant liver volume (FRLV) and resection limit following PVE. Previously, we reported that evaluating functional FRLV (fFRLV) using EOB-MRI could predict post-hepatectomy liver failure. In this study, we investigated the usefulness of fFRLV in predicting the achieving of adequate resection limit for safe hepatectomy following PVE., Methods: We included 55 patients who underwent PVE and were scheduled for major hepatectomy. We calculated the liver-to-muscle ratio in the remnant liver and fFRLV using EOB-MRI. We investigated the pre-PVE variables in determining the nonachievement of the resection limit., Results: The median observation period between PVE and the first evaluation was 21 days, and the median growth rate of FRLV was 26.4%. In 54.5% of patients, the resection limit of fFRLV (615 mL/m 2 ) was achieved. In logistic regression and receiver-operating characteristic analyses, pre-PVE fFRLV (p < 0.001, area under the curve: 0.852) was the reliable predictor of achieving the resection limit; the cutoff value of pre-PVE fFRLV was 446 mL/m 2 ., Conclusion: Pre-PVE fFRLV can be useful in predicting the achievement of adequate resection limit following PVE., (Copyright © 2021 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Intracellular modifications caused by two metal-based antitumor compounds were assessed by confocal Raman imaging assisted by multivariate curve resolution method, a very powerful deconvolution tool that can be used to extract the characteristic spectral profile of the individual or "purest" components from an image dataset. The use of this Raman methodology has the advantage of being non-invasive and totally label-free. Four main different intracellular processes were observed under the Raman imaging and multivariate approach combination, and even, significant differences could be identified between the treatments with both metallodrugs. Leakage of the nucleus and nucleolus content into the cytoplasm, along with releasing of cytochrome c were observed for the treatment with the Cu-based complex. At the same time, changes of hydrogen-bonding network were also evidenced, indicating an apoptotic cellular death process, consistent with complementary Total Reflection X-Ray fluorescence (TXRF) and fluorescence experiments attesting mitochondria and DNA as main targets after uptake of the complex by cells. For treatment with the Zn-based complex, changes associated with cytochrome c were not detected, neither a rapid leakage of nucleus content upon 24 h treatment. The hydrogen-bonding network also followed a quite different pattern, suggesting that with this metallodrug, the cellular death follows a different mechanism., Competing Interests: Declaration of competing interest The authors declare no competing financial interest. Competing financial interests The University of São Paulo and FAPESP have a Brazilian patent based on the antitumor activity of oxindolimine-metal complexes studied in our lab (PI 0600985-9, granted at March 24th, 2020)., (Copyright © 2020 Elsevier B.V. All rights reserved.)

"Neisseria skkuensis" is a gram-negative coccus that is endemic in the human oral cavity, with only few reports of infection in humans. Herein, we report a case of a male patient in his sixties presenting with infective endocarditis (IE) caused by "N. skkuensis". To our knowledge, this is the second case of IE confirmed using 16S rRNA gene to have been caused by "N. skkuensis". The accurate diagnosis of rare or difficult-to-identify pathogens is a major challenge for clinical microbiological laboratories. Although Neisseria spp. are common in the oral cavity and are often seen in routine tests, identification of their biochemical properties and mass spectrometric analysis are difficult. In this case report, we describe the accurate identification of "N. skkuensis" by 16S rRNA gene sequencing analysis compared to other identification methods. Further cases of "N. skkuensis" are needed to fully evaluate the clinical approach of this detection method., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2020 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Objective: Second-hand smoke (SHS) is considered a risk factor for a number of oral diseases. However, its influence on tooth loss, which is the final consequence of periodontal disease and caries, remains unknown. We aimed to evaluate the association between SHS experience and the number of remaining teeth among non-smoking older Japanese individuals., Methods: Cross-sectional data from the Japan Gerontological Evaluation Study (JAGES) 2013 were used. From the 27,561 people ≥65 years of age who responded to a self-reported questionnaire (response rate = 71.1%), data of 18,865 respondents who had never smoked were analysed. Multinomial logistic regression with multiple imputations was applied to estimate the odds ratio of the frequency of SHS exposures on the number of remaining teeth., Results: The prevalence of participants with ≥20 teeth, 10-19 teeth, 5-9 teeth, 1-4 teeth, and no teeth were 53.2%, 20.4%, 9.9%, 6.6%, and 9.9%, respectively. The proportion of participants with SHS was 37.5%. After adjusting for sex, the SHS experience tended to be associated with a lower risk of having the fewer number of remaining teeth (P < 0.05). However, after being adjusted for age and sex, participants with SHS exposure at "a few times a week" and "almost every day" were significantly associated with the fewer number of teeth. After adding all other covariates, compared to the participants without any exposure to SHS, the odds ratio for having no teeth rather than having ≥20 teeth among the participants with daily exposure to SHS was 1.35 (P < 0.01)., Conclusion: Daily second-hand smoke was significantly associated with fewer remaining teeth based on the self-reported survey among older Japanese people., (© 2020 FDI World Dental Federation.)

Although reference intervals (RIs) and clinical decision limits (CDLs) are vital laboratory information for supporting the interpretation of numerical clinical pathology results, there is evidence that RIs and CDLs vary in certain contexts as well as other evidence that RIs and CDLs are flawed. We propose a random forest algorithm-based exploration methodology by using phenotype transformation of independent variables in relation to dependent variables to capture latent decision variables and their cutoff values. We denote certain CDLs within the RIs estimated by an indirect method that affect some diagnostics or outcomes in the context of specific patients' conditions as latent CDLs. We then apply the proposed methodology to clinical laboratory data regarding bodily fluids, such as blood, urine at the admission of patients for the exploration of latent CDLs of hospital length of stay (HLOS) for each patients' condition identified by diseases of patients who undergoing surgeries. From the exploration results, we found that free Thyroxine (T4) above five unique cutoff values: 1.16 ng/dL, 1.19 ng/dL, 1.2 ng/dL, 1.23 ng/dL and 1.25 ng/dL for tachyarrhythmia predicted longer HLOS, though these cutoff values fall within the estimated RIs as well as the hospital-determined RIs. In addition to the evidence that higher free Thyroxine (T4) levels within the RIs have an association with the corresponding disease, on the whole, the cutoff values except 1.16 ng/dL tended to affect long HLOS with the significant differences. The cutoff values could be taken up for discussion among clinical experts whether it is meaningful to alert the risk of patients' conditions and the long HLOS at the admission of patients. If clinical experts appreciate its meaningfulness in clinical practice, the alerts could be embedded in electronic medical records for handling those risks at the admission of patients., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: The epithelial-mesenchymal transition (EMT) is a key process in tumor progression and metastasis and is also associated with drug resistance. Thus, controlling EMT status is a research of interest to conquer the malignant tumors., Materials and Methods: A drug repositioning analysis of transcriptomic data from a public cell line database identified monensin, a widely used in veterinary medicine, as a candidate EMT inhibitor that suppresses the conversion of the EMT phenotype. Using TGF-β-induced EMT cell line models, the effects of monensin on the EMT status and EMT-mediated drug resistance were assessed., Results: TGF-β treatment induced EMT in non-small cell lung cancer (NSCLC) cell lines and the EGFR-mutant NSCLC cell lines with TGF-β-induced EMT acquired resistance to EGFR-tyrosine kinase inhibitor. The addition of monensin effectively suppressed the TGF-β-induced-EMT conversion, and restored the growth inhibition and the induction of apoptosis by the EGFR-tyrosine kinase inhibitor., Conclusion: Our data suggested that combined therapy with monensin might be a useful strategy for preventing EMT-mediated acquired drug resistance., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Eikenella corrodens is a facultatively anaerobic gram-negative rod bacterium in the oropharynx and respiratory tract. It is a member of HACEK (Haemophilus spp., Aggregatibacter spp., Cardiobacterium hominis, E. corrodens, and Kingella kingae) group commonly associated with endocarditis and craniofacial infections. It is usually susceptible to penicillin, second and third-generation cephalosporins, and carbapenem, but has variable susceptibility to first-generation cephalosporin. We herein provide a description of the first case of pediatric acute dacryocystitis caused by E. corrodens. The patient did not respond to oral cephalexin and required surgical drainage followed by intravenous cefotaxime. Also provided is a brief review of the current literature., Competing Interests: Declaration of Competing Interest None., (Copyright © 2019 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: Gd-EOB-DTPA-enhanced magnetic resonance imaging (EOB-MRI) can be used for evaluating liver functional reserve. We assessed whether functional remnant liver volumetry (FRLV) using EOB-MRI predicted post-hepatectomy liver failure (PHLF) in resection of more than one segment., Methods: We retrospectively analyzed 155 cases of hepatectomy of more than one segment. For assessment of FRLV, signal intensity (SI) of remnant liver was measured in T1-weighted images. Functional remnant liver score was derived by division of SI of liver by SI of muscle (or spleen), resulting in liver-to-muscle ratio (LMR) and liver-to-spleen ratio (LSR). FRLV were calculated by multiplying LMR (or LSR) and remnant liver volume. We investigated preoperative factors predicting PHLF (≥grade B) in study cohort (all cases except for portal vein embolization [PVE], n = 129) and validation cohort (PVE cases, n = 26)., Results: In study cohort, PHLF occurred in 5 patients (3.9%). In multivariate analysis, FRLV (LMR) was the most reliable predictor of PHLF (P = 0.013). The cutoff value of FRLV (LMR) predicting PHLF was 615 mL/m 2 (AUC: 0.939). In validation cohort (n = 26), the cutoff value of FRLV (LMR) indicated reliable results, sensitivity (100%), specificity (77.3%), and accuracy (80.8%)., Conclusions: FRLV using LMR could precisely predict PHLF of more than one segment, and was useful even in patients who underwent PVE., (Copyright © 2019 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

The effect of the ligand shell on the cellular uptake efficiency was evaluated by a systematic study using fully dispersed 6 nm diameter superparamagnetic iron oxide nanoparticles (SPIONs), mono and bis-conjugated with glycerol phosphate (glyc), dopamine (dopa), 4,5-dihydroxy-1,3-benzenedisulfonic acid (tiron) and phosphorylethanolamine (pea). Negatively charged SPION-glyc was more efficiently incorporated than positively charged SPION-pea and SPION-dopa clearly evidencing that there are strong enough short-range interactions in addition to the long-range electrostatic interactions, as measured by the zeta potential, to reverse our expectation on cellular uptake. Those effects were pursued by correlating the nanoparticles incorporation efficiency as a function of the respective zeta potentials and the molar fractions of glyc and pea ligands co-conjugated on the SPION surface. The possibility of associating different ligands to modulate the physicochemical properties and biological events was demonstrated, showing promising perspectives for the development of multifunctional nanosystems for biomedical applications., Competing Interests: Declaration of Competing Interest None., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Tuning the electrocatalytic properties of high surface area porous metallic frameworks like Nanoporous Gold (NPG) by tailoring the structure is a convenient strategy to design electrochemical sensors. Accordingly, an NPG-based sensitive, selective and robust electroanalytical platform was designed for the detection of ascorbic acid (AA) in acidic extracts of Aspergillus fumigatus fungus and Arabidopsis thaliana leaves. NPG films were electrodeposited on a gold microelectrode by potentiostatic electrodeposition and characterized by electron microscopy techniques, which confirmed the morphology and highly porous structure resembling nanowires-type pure gold fractals. The electrodeposition parameters, particularly deposition potential and time, were optimized to achieve large and selective amperometric detection of AA on the NPG modified electrodes. Faster electron transfer kinetics was manifested on the 0.3 V shift in overpotential and remarkable enhancement of the oxidation peak current as compared with bare gold electrode. Amperometric measurements were performed at 0.3 V vs. Ag/AgCl (sat. KCl) in the highly acidic electrolyte solution employed to extract ascorbate from biological samples and minimize its autoxidation. The sensitivity of conventional Au-microelectrodes was increased about one thousand-fold upon modification with NPG film, reaching 2 nA μmol -1  L -1 . The detection limit for AA based on a linear current-concentration calibration plot was found to be 2 μmol L -1 . The NPG-based microsensor was demonstrated to be selective, reproducible and stable, and was employed for determinations of AA concentration in highly acidic biological extracts., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Aspergillus fumigatus is the commonest cause of pulmonary aspergillosis; however, a recently developed molecular genetic technique identified A. lentulus as a sibling species. Most of the isolates were found in solid organ recipients, often associated with a fatal outcome. Moreover, there is concern that A. lentulus has low susceptibility to multiple antifungal agents. Herein, we report an adult immunocompromised patient with proven invasive pulmonary aspergillosis (IPA) caused by A. lentulus, which was identified through molecular genetic analysis. The patient was diagnosed with IPA by bronchoscopy 3 weeks after initiating systemic corticosteroid therapy for anti-neutrophil cytoplasmic antibody-associated vasculitis. The clinical course of IPA due to A. lentulus showed improvement after treatment with the antifungal agent voriconazole. In summary, we report an adult immunocompromised patient without a history of transplantation who was diagnosed with IPA due to A. lentulus successfully treated with voriconazole, and we also report the findings of a literature review on IPA caused by A. lentulus., (Copyright © 2019 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Identification of the specific genetic variants responsible for the increased susceptibility to familial or sporadic cancers is important. Using a forward genetics approach to map such loci in a mouse skin cancer model, we previously identified a strong genetic locus, Stmm3, conferring resistance to chemically induced skin papillomas on chromosome 4. Here, we report the cyclin-dependent kinase inhibitor gene Cdkn2a/p19 Arf as a major responsible gene for the Stmm3 locus. We provide evidence that the function of Stmm3 is dependent on p53 and that p19 ArfMSM confers stronger resistance to papillomas than p16 Ink4aMSM in vivo. In addition, we found that genetic polymorphism in p19 Arf between a resistant strain, MSM/Ms (Val), and a susceptible strain, FVB/N (Leu), alters the susceptibility to papilloma development, malignant conversion, and the epithelial-mesenchymal transition. Moreover, we demonstrated that the p19 ArfMSM allele more efficiently activates the p53 pathway than the p19 ArfFVB allele in vitro and in vivo. Furthermore, we found polymorphisms in CDKN2A in the vicinity of a polymorphism in mouse Cdkn2a associated with the risk of human cancers in the Japanese population. Genetic polymorphisms in Cdkn2a and CDKN2A may affect the cancer risk in both mice and humans., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Indocyanine green lactosome (ICG-lactosome) is an attractive new-generation agent for photodynamic therapy (PDT) that is characterized by a near-infrared excitation wavelength and high stability in the bloodstream. Fluorescence imaging has been used to examine its pharmacokinetics in vivo, but no depth-resolved information can be obtained with this method. In this study, we applied photoacoustic (PA) imaging to visualize the depth distribution of ICG-lactosome in a mouse subcutaneous tumor model. With this method, the depth distribution of blood vessels can also be visualized, enabling detection of vascular shutdown effects due to PDT. We performed PA imaging of both the distributions of ICG-lactosome and blood vessels in a tumor before and after PDT, and we found that PA signals originating from ICG-lactosome were greatly increased at 18 h after drug injection but rapidly decreased after PDT. These results indicate efficient accumulation of ICG-lactosome and rapid photobleaching due to the PDT reaction in the tumor, respectively. After PDT, PA amplitudes of hemoglobin were significantly decreased, being attributable to vascular shutdown effects. These results show the usefulness of PA imaging for monitoring not only photosensitizer accumulation and bleaching but also vascular responses in PDT with ICG-lactosome. This method can be applied to the diagnosis of many types of PDT processes., (Copyright © 2019. Published by Elsevier B.V.)

Antibody drugs have been important therapeutic agents for treating various diseases, such as cancer, rheumatism, and hypercholesterolemia, for the last three decades. Despite showing excellent therapeutic efficacy with good safety in vivo, they require high doses. We have developed a ∼30-nm bio-nanocapsule (ZZ-BNC) consisting of hepatitis B virus envelope L protein fused with the tandem form of protein A-derived IgG Fc-binding Z domain (ZZ-L protein), for tethering antibodies in an oriented immobilization manner. In this study, antibody drugs were spontaneously conjugated to ZZ-BNC, which displayed the IgG Fv regions outwardly. The anti-human epidermal growth factor receptor IgG conjugated to ZZ-BNC (α-hEGFR-ZZ-BNC) was endocytosed by the human epidermoid carcinoma A431 cells, with increases in cellular uptake by ∼1.5 fold, compared that of α-hEGFR IgG alone. The amount of α-hEGFR IgG in the late endosomes and lysosomes was increased from 4% to 33% by the conjugation to ZZ-BNC. The in vitro cytotoxicity of α-hEGFR-ZZ-BNC was higher by ∼10-fold than that of α-hEGFR IgG alone. Furthermore, in vivo tumor growth was significantly reduced by α-hEGFR-ZZ-BNC than by α-hEGFR IgG alone. Taken together, since endosomal EGFR, not cell surface EGFR, played a pivotal role in the EGFR-mediated signaling cascade, ZZ-BNC increased α-hEGFR IgG avidity by efficiently repressing the activation of hEGFR not only on the cell surface, but presumably also in the endosomes. These results strongly suggested that ZZ-BNC is a promising nano-scaffold for enhancing the therapeutic efficacy and reducing the dose of antibody drugs. STATEMENT OF SIGNIFICANCE: Antibody drugs are widely used for treating severe diseases, such as cancer, rheumatism, and hypercholesterolemia. These drugs are composed of naturally occurring biomaterials with low immunogenicity and toxicity, as well as long in vivo serum half-life. To achieve sufficient therapeutic efficacy, the dose of antibody drugs are unavoidably higher than those of conventional drugs. The present study shows an innovative way to reduce the dose of antibody drugs by using a nanocarrier-conjugated antibody. Oriented immobilization of the antibody enhanced its avidity, endocytosis efficiency, and therapeutic efficacy., (Copyright © 2019 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Background: While the middle hepatic vein (MHV) guides parenchymal transection during right hepatectomy, its most proximal tributaries can be difficult to identify, and injury to its tributaries can be a source of major bleeding., Method: Following simulation modeling of right hepatectomy, reconstructed MHV data was pooled from 40 patients. MHV-tributaries and MHV-relationship to the portal pedicle were mapped out to facilitate their identification from the beginning of parenchymal transection., Results: Hotspots for injury were identified: A median of 1 (1-3) tributaries draining segment 5 (V5) were within 45-90mm from the MHV termination, and 16mm above and 22mm caudal to the portal trunk. Simulation demonstrated a constant anatomic relationship between portal pedicle and the proximal MHV. A median of 2 (0-4) tributaries draining segment 8 (V8) were located 9-35mm from the MHV termination. This information was compiled into an "MHV-road-map" demonstrating 86% of the MHV tributaries at risk for significant bleeding are within 15mm of the MHV, while only thin tributaries are located in the outer area., Conclusions: The MHV-road-map led to a peripheral-to-central parenchymal transection approach to minimize the risk of MHV-injury thereby reducing bleeding during open and minimally invasive right hepatectomy., (Copyright © 2018. Published by Elsevier Ltd.)

Defects in DNA polymerase Eta (Polη) cause the sunlight-sensitivity and skin cancer-propensity disorder xeroderma pigmentosum variant. The extent to which Polη function depends on the upstream E3 ubiquitin ligase Rad18 is controversial and has not been investigated using mouse models. Therefore, we tested the role of Rad18 in UV-inducible skin tumorigenesis. Because Rad18 deficiency leads to compensatory DNA damage signaling by Chk2, we also investigated genetic interactions between Rad18 and Chk2 in vivo. Chk2 -/- Rad18 -/- mice were prone to spontaneous lymphomagenesis. Both Chk2 -/- and Chk2 -/- Rad18 -/- mice were prone to UV-B irradiation-induced skin tumorigenesis when compared with wild-type (WT) animals, but unexpectedly Rad18 -/- mice did not recapitulate the skin tumor propensity of Polη mutants. UV-irradiated Rad18 -/- cells were more susceptible to G1/S arrest and apoptosis than WT cultures. Chk2 deficiency alleviated both UV-induced G1/S phase arrest and apoptosis of WT and Rad18 -/- cells, but led to increased genomic instability. Taken together, our results demonstrate that the tumor-suppressive role of Polη in UV-treated skin is Rad18 independent. We also define a role for Chk2 in suppressing UV-induced skin carcinogenesis in vivo. This study identifies Chk2 dysfunction as a potential risk factor for sunlight-induced skin tumorigenesis in humans., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

The Raman spectral profile of p-methylcarbohydrazonethioamide (MCHT) is completely changed due to strong SERS effects upon bonding onto gold nanoparticles surface, but some vibrational modes are further enhanced in the presence of Hg(II) ions. The lack of SERS response for most common metal ions indicates that the coordinating groups are interacting with the gold nanoparticles surface and not available for binding metal ions in solution, except for mercury ions. The selective enhancement of some vibrational modes is consistent with significant conformational changes upon binding of Hg(II) ion onto the AuNP@MCHT hybrid, as confirmed by TEM/EDS measurements, demonstrating its potentiality as a highly selective and sensitive SERS substrate., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Interleukin (IL)-11 belongs to the members of the IL-6 family of cytokines and is involved in a variety of biological responses, including hematopoiesis, bone development, and carcinogenesis. However, the cellular sources of IL-11 and regulation of IL-11 expression under physiological and pathological conditions are not fully understood. One of the causes to prevent characterization of IL-11 in vivo is due to the lack of reliable antibodies that detect IL-11 by immunohistochemistry. Moreover, although mice lacking Il11ra have been generated and extensively characterized, Il11-deficient mice have not been characterized yet. Here we generated two anti-IL-11 antibodies that blocked biological activities of IL-11 and detected IL-11 by immunohistochemistry, respectively. One clone of anti-IL-11 antibodies blocked IL-11-, but not IL-6-induced cell proliferation and IL-11-induced phosphorylation of STAT3 of an IL-11-dependent cell line. Moreover, we used recently established Il11-deficient mice to test the specificity of anti-IL-11 antibodies for immunohistochemistry. Another clone of anti-IL-11 antibodies stained stromal cells surrounding tumors of the colon of wild-type, but not Il11-deficient mice following treatment with Azoxymethane plus dextran sulfate sodium. Together, these newly developed anti-IL-11 antibodies provide a better understanding of the functions of IL-11 in vivo under various physiological and pathological conditions., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Introduction: Although eribulin and nab-paclitaxel are chemotherapy agents widely used for locally advanced or metastatic breast cancer (MBC), their predictive factors remain unknown. Because the absolute neutrophil-to-lymphocyte ratio (NLR) is a significant prognostic factor for early-stage breast cancer, we investigated its usefulness in terms of the eribulin or nab-paclitaxel treatment efficacy for MBC., Patients and Methods: A total of 85 patients with MBC treated with eribulin (n = 59) or nab-paclitaxel (n = 26) were recruited. NLR values were collected at baseline, after 1 cycle, after 2 cycles, and at the end of treatment. The NLR cutoff value was set at 3., Results: The progression-free survival (PFS) of patients with an NLR < 3 at baseline (median, 242 days; n = 24) was significantly better than that of patients with an NLR of ≥ 3 (median, 98 days; n = 35; hazard ratio, 0.37, 95% confidence interval, 0.18-0.71; P = .0032). Similarly, the overall survival was marginally significantly better in patients with an NLR < 3 who were treated with eribulin (P = .058). However, the NLR was not significantly associated with PFS or overall survival for patients treated with nab-paclitaxel. No significant association was found between the NLR during treatment and PFS in the eribulin group. The significance of the NLR for the efficacy of eribulin was consistent, irrespective of estrogen receptor status, previous anthracycline or endocrine use, and the number of previous chemotherapy regimens., Conclusion: A low NLR at baseline was significantly associated with improved PFS in patients treated with eribulin but not in those treated with nab-paclitaxel. Therefore, the baseline NLR might be clinically useful for selecting patients who would benefit from eribulin., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: To evaluate the antibacterial effects, cytotoxicity and microtensile bond strength of an adhesive containing low concentrations of silver nanoparticles (NAg)., Methods: Various concentrations of NAg (50, 100, 150, 200 and 250 ppm) were incorporated into the primer of the Scotchbond Multi-Purpose adhesive system (SBMP). Antibacterial activity was examined using a broth microdilution assay to determine minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC), agar diffusion assay and the MTT assay was used to examine the biofilm metabolic activity (S. mutans). The Microtensile Bond Test (μTBS) was performed after 24 h, followed by 6-months storage in distilled water. Cytotoxicity was assessed with an MTT reduction assay in human dental pulp stem cells viability after exposure to Nag-conditioned culture media during 0, 24, 48, and 72 h. The results were statistically analyzed (α ≤ 0.05)., Results: MIC was found between NAg 25 and 50 ppm MBC was determined at 50 ppm of NAg. Bacterial activity inhibition was higher than control in all NAg groups compared to control in agar diffusion assay. Biofilm inhibition was statistically higher in 250 ppm NAg than control. All NAg groups and SBMP presented similar cytotoxicity in each period. Adhesives with NAg 200 and 250 ppm and SBMP (control) presented the highest μTBS values, similar to that of SBMP control, in both instances (24 h and 6 months) (p > 0.05)., Conclusions: The commercial primer containing NAg 250 ppm showed both antibacterial effect and reliable bond strength with no cytotoxicity increase. The addition of NAg to primers seems promising for the improvement of conventional dental adhesives efficacy., Clinical Significance: The addition of low concentrations of NAg (250 ppm) to primers were effective to improve antibacterial effect preserving the bond strength and the biocompatibility of the commercial product. NAg/primer association could protect the tooth-adhesive interface increasing dental restoration longevity., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Purpose: The purpose of this study was to evaluate the quality of image in abdominopelvic late phase computed tomography (CT) with a low tube voltage plus low dose contrast medium (CM) protocol (80-kVp, 60% CM). A compared with the conventional protocol (120-kVp, 100% CM) B in the same patients., Material and Methods: This study included with 22 patients {36 to 77 kg (mean: 55.5 kg)} who had renal insufficiency and had experience of performance conventional CT without renal insufficiency during pre-18 months. The CT value of the portal vein, liver parenchyma, abdominal aorta, psoas muscle was measured. The estimated mean CNR (contrast-to-noise ratios), FOM (figure of merit), DLP (dose length product) and ED (effective dose) were compared between protocol A and B. Moreover, two radiologists assessed the visual quality of the CT images., Results: The mean DLP and ED in the protocol B was about 50% lower than that in the protocol A (p < 0.01). The mean CT value of the portal vein and abdominal aorta in the protocol B were significantly higher than that in the protocol A (p < 0.01). All of the FOM in the protocol B was significantly higher than that in the protocol A (p < 0.01). However, there was no significant difference in the mean CNR and visual quality between protocol A and B., Conclusion: Performance of abdominopelvic CT using a low tube voltage plus reduced CM dose (80-kVp, 60% CM) achieved reduction of the radiation dose without impairing image quality in relatively light weight group., Clinical Relevance/application: In abdominopelvic CT, protocol of low tube voltage (80-kVp) plus iodine dose reduction (60%) is able to provide the same quality of traditional protocols, also able to reducing radiation exposure (50%)., (Copyright © 2018 Elsevier Inc. All rights reserved.)

This study reports the preparation and characterization of nickel/lead hydroxide nanoparticles used to construct electrochemical sensors, which were investigated for amperometric quantification of N-acetylcysteine (NAC). The newly synthesised material presents good uniformity, with the lead (II) ions homogenously incorporated into the alpha nickel hydroxide crystal structure, confirmed by X-ray diffraction, transmission electron microscopy and X-ray photoelectron spectroscopy analyses. Films of nanoparticles (3 nm in size) were prepared on conductive fluorine-doped tin oxide-coated glass slides and used connected to a specially built batch injection analysis (BIA) cell with a capacity of only 4 mL and the electrode positioned in the bottom. To attain optimal analytical performance, the main parameters for BIA measurements (volume injected, different velocities of injection and best distance of the pipette from the electrode) were evaluated, as was the working potential, to determine the optimal conditions. Linear responses were obtained for the concentration range from 20 to 220 μmol L -1 , and the limits of detection (3σ/slope) and quantification (10σ/slope) were calculated as 0.23 μmol L -1 and 0.70 μmol L -1 , respectively. The new NAC sensor does not exhibit a memory effect and has enormous potential utility in the quantitative determination of N-acetylcysteine in drugs. The results of the analysis of NAC obtained using BIA presented good concordance with those obtained by chromatography. The analytical frequency attained using BIA (120 analysis h -1 ) compares very favourably with the one obtained using chromatography (6 analysis h -1 )., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Heat shock protein 47 kDa (HSP47), an ER-resident and collagen-specific molecular chaperone, recognizes collagenous hydrophobic amino acid sequences (Gly-Pro-Hyp) and assists in secretion of correctly folded collagen. Elevated collagen production is correlated with HSP47 expression in various diseases, including fibrosis and keloid. HSP47 knockdown ameliorates liver fibrosis by inhibiting collagen secretion, and inhibition of the interaction of HSP47 with procollagen also prevents collagen secretion. Therefore, a high-throughput system for screening of drugs capable of inhibiting the interaction between HSP47 and collagen would aid the development of novel therapies for fibrotic diseases. In this study, we established a straightforward method for rapidly and quantitatively measuring the interaction between HSP47 and collagen in solution using fluorescence correlation spectroscopy (FCS). The diffusion rate of HSP47 labeled with Alexa Fluor 488 (HSP47-AF), a green fluorescent dye, decreased upon addition of type I or III collagen, whereas that of dye-labeled protein disulfide isomerase (PDI) or bovine serum albumin (BSA) did not, indicating that specific binding of HSP47 to collagen could be detected using FCS. Using this method, we calculated the dissociation constant of the interaction between HSP47 and collagen. The binding ratio between HSP47-AF and collagen did not change in the presence of sodium chloride, confirming that the interaction was hydrophobic in nature. In addition, we observed dissociation of collagen from HSP47 at low pH and re-association after recovery to neutral pH. These observations indicate that this system is appropriate for detecting the interaction between HSP47 and collagen, and could be applied to high-throughput screening for drugs capable of suppressing and/or curing fibrosis., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Pazopanib, one of the antiangiogenic drugs, has recently become a first-line treatment for metastatic renal cell carcinoma. The most common adverse effects of pazopanib include diarrhea, fatigue, and nausea, but neuropathic complication has not been documented. Here, we report the first case of a patient with metastatic renal cell carcinoma who developed acute neuropathy mimicking Guillain-Barré syndrome following the first course of pazopanib therapy. A 75-year-old man with a metastatic renal cell carcinoma was admitted for rapidly progressive weakness and numbness in the extremities after the first course of pazopanib therapy. Neurological examination revealed symmetrical distal limb weakness, sensory disturbance, and areflexia. Based on the clinical pictures, conduction slowing on the nerve conduction studies of the extremities and albuminocytologic dissociation on the cerebrospinal fluid examination, a diagnosis of Guillain-Barré syndrome was made. After discontinuation of pazopanib and a subsequent high-dose intravenous immunoglobulin therapy, symptoms rapidly resolved and the patient became ambulatory with a cane. Serological and neuroradiological examinations failed to reveal any possible causes for the neuropathy other than pazopanib. While the benefits of pazopanib for metastatic renal cell carcinoma far outweigh this neurotoxic effect, physicians prescribing this drug should be aware of this rare complication of neuropathy., (Copyright © 2017 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: The efficacy and safety of continuing multiple anti-HER2 therapies in advanced breast cancer (ABC) patients remains unclear. This study investigated eribulin in combination with pertuzumab and trastuzumab for both taxane- and trastuzumab-pretreated HER2-positive ABC patients., Methods: In a single-institute, single-arm, open-label, phase II trial, HER2-positive ABC patients who had previously received taxanes and trastuzumab were treated with eribulin in combination with pertuzumab and trastuzumab. The pharmacokinetics of eribulin in this combination were assessed in 6 patients. Tumor assessments were conducted every 6 weeks for the first 6 cycles and every 12 weeks thereafter. The primary endpoint was objective response rate (ORR)., Results: A total of 30 patients (median age, 58 years; range, 31-76) were enrolled, with a median number of previous chemotherapy regimens of 3.5 (range: 1-9) in the metastatic setting. Pharmacokinetic parameters of eribulin in this combination were similar to previous reports of eribulin monotherapy. ORR was 34.8% (95% CI: 16.4-57.3, n = 23), and median progression-free survival was 42.6 weeks (95% CI: 20.3-51.9, n = 30). Clinical benefit rate was 60.9% (95% CI: 16.4-57.3). The most common grade 3/4 adverse event was neutropenia in 20 patients (66.7%). A dose reduction of eribulin was required in 27 patients due to adverse events, particularly grade 3 neutropenia., Conclusions: Eribulin in combination with pertuzumab and trastuzumab was well tolerated in heavily pretreated patients. Eribulin may be a viable treatment option when used in combination with pertuzumab and trastuzumab for HER2-positive ABC patients (UMIN Clinical Trial Registry identification number, UMIN000012375)., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

MicroRNAs (miRNAs) are small noncoding RNAs that regulate protein translation by binding to complementary target mRNAs. We previously identified two mature members of the miR-142 family, miR-142-5p and miR-142-3p, as inflammation-related miRNAs with potential roles in wound healing. Here, we demonstrated that these two miRNAs are prominently expressed in wound-infiltrated neutrophils and macrophages and play central roles in wound healing. We generated miR-142 -/- mice using the exchangeable gene-trap method and showed that healing of Staphylococcus aureus-infected skin wounds was significantly delayed in miR-142 -/- mice compared with that in wild-type mice. MiR-142 -/- mice exhibited abnormal abscess formation at S. aureus-infected skin wound sites and were also more susceptible to horizontal transmission of wound infections. MiR-142 -/- neutrophils showed altered phagocytosis as a consequence of chemotactic behavior, including enhanced F-actin assembly, disturbed cell polarity, and increased cell motility. We showed that these changes were linked to cytoskeletal regulation, and that expression of the small GTPases was markedly increased in miR-142 -/- neutrophils. Collectively, our data demonstrate that the miR-142 family is indispensable for protection against S. aureus infection and its clearance at wound sites. MiR-142-3p and miR-142-5p play nonredundant roles in actin cytoskeleton regulation by controlling small GTPase translation in neutrophils at wound sites., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

CD99 is a crucial regulator of the transmigration (diapedesis) of leukocytes through the blood vessel wall. Here, we report that CD99 acts at 2 different steps in the extravasation process. In agreement with previous antibody-blocking experiments, we found that CD99 gene inactivation caused neutrophil accumulation between venular endothelial cells and the basement membrane in the inflamed cremaster. Unexpectedly, we additionally found that leukocyte attachment to the luminal surface of the venular endothelium was impaired in the absence of CD99. Intravital video microscopy revealed that CD99 supported rapid chemokine-induced leukocyte arrest. Inhibition of leukocyte attachment and extravasation were both solely due to the absence of CD99 on endothelial cells, whereas CD99 on leukocytes was irrelevant. Therefore, we searched for heterophilic ligands of endothelial CD99 on neutrophils. We found that endothelial cells bind to the paired immunoglobulinlike receptors (PILRs) in a strictly CD99-dependent way. In addition, endothelial CD99 was coprecipitated with PILRs from neutrophils that adhered to endothelial cells. Furthermore, soluble CD99 carrying a transferable biotin tag could transfer this tag covalently to PILR when incubated with intact neutrophils. Binding of neutrophils under flow to a surface coated with P-selectin fragment crystallizable (Fc) and intercellular adhesion molecule 1 (ICAM-1) Fc became more shear resistant if CD99 Fc was coimmobilized. This increased shear resistance was lost if neutrophils were preincubated with anti-PILR antibodies. We concluded that endothelial CD99 promotes leukocyte attachment to endothelium in inflamed vessels by a heterophilic ligand. In addition, CD99 binds to PILRs on neutrophils, an interaction that leads to increased shear resistance of the neutrophil attachment to ICAM-1., (© 2017 by The American Society of Hematology.)

Thiol-based redox control is among the most important mechanisms for maintaining cellular redox homeostasis, with essential participation of cysteine thiols of oxidoreductases. To explore cellular redox regulatory networks, direct interactions among active cysteine thiols of oxidoreductases and their targets must be clarified. We applied a recently described thiol-ene crosslinking-based strategy, named divinyl sulfone (DVSF) method, enabling identification of new potential redox relay partners of the cytosolic oxidoreductases thioredoxin (TXN) and thioredoxin domain containing 17 (TXNDC17). Applying multiple methods, including classical substrate-trapping techniques, will increase understanding of redox regulatory mechanisms in cells., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Intracranial carotid sympathetic plexus schwannoma (CSPS) is extremely rare; thus differential diagnostic criteria, optimal surgical strategies, and even a precise definition are lacking. Here we describe a case of CSPS and propose a definition and classification for previously reported cases., Case Description: A 54-year-old man presented with hypacusis and abducens nerve palsy. Radiologic examinations revealed a well-enhanced mass at the right medial temporal base with erosion of the petrous apex and intact perilesional cortical bone. Preoperative findings, such as spontaneous improvement of diplopia, absence of xerophthalmia or facial palsy, and laterally displaced internal carotid artery (ICA), suggested the atypical origins of the petrous apex schwannoma. The tumor was exposed using the subtemporal extradural approach and completely resected. Intact foramen ovale, rostrolateral displacement of the greater superficial petrosal nerve within the outer membrane of the tumor, eroded petrous apex and carotid canal, superolaterally displaced ICA, and lack of an obvious tumor attachment to any of the suspected nerves suggested that the tumor originated from the carotid sympathetic plexus of the petrous ICA. The patient fully recovered without neurological complications., Conclusions: Preoperative diagnosis of petrous apex schwannoma is difficult: characteristic findings such as diplopia, hypacusis, and laterally displaced ICA may help. In addition, assessment of the relationship between the tumor and cavernous sinus could be useful in the determination of the surgical approach. Complete resection with good clinical outcome could be expected using Dolenc's approach (type A) and by the middle fossa extradural approach (type B) for intracavernous and extracavernous CSPS, respectively., (Copyright © 2016 Elsevier Inc. All rights reserved.)

In cancer treatment, specifically targeting cancer cells is important for optimal therapeutic efficacy. One strategy is to utilize a cancer specific promoter to express a cytotoxic gene or a viral gene required for replication. In this approach, the therapeutic window is dependent on the relative promoter activity in cancer cells versus normal cells. Therefore, a promoter with optimal cancer cell-specificity should be used. The tumor suppressor ARF promoter, which specifically responds to deregulated E2F activity, is a potent candidate. Defects in the RB pathway resulting in deregulated E2F activity are observed in almost all cancers. Furthermore, the ARF promoter exhibits greater cancer cell specificity than the E2F1 promoter and consequently, adenovirus expressing HSV-TK under the control of the ARF promoter (Ad-ARF-TK) has more selective cytotoxicity in cancer cells than the analogous E2F1 construct. Ideally, cancer specific gene expression driven by the ARF promoter could be enhanced for optimal therapeutic efficacy, with minimal side effects. We show here that ectopic expression of the CDK inhibitor p21 Cip1 enhanced deregulated E2F activity and pro-apoptotic E2F target gene expression in cancer cells. Moreover, ectopic expression of p21 Cip1 augmented cancer specific cytotoxicity of Ad-ARF-TK, and apoptosis induced by p21 Cip1 was dependent on deregulated E2F activity. These results suggest that p21 Cip1 specifically enhances deregulated E2F activity and that a combination of the CDK inhibitor with Ad-ARF-TK could be effectively employed for cancer therapy., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The transcription factor E2F plays crucial roles in tumor suppression by activating pro-apoptotic genes such as the tumor suppressor ARF. The regulation of the ARF gene is distinct from that of growth-related E2F targets, in that it is specifically activated by deregulated E2F activity, induced by over-expression of E2F or forced inactivation of pRB, but not by physiological E2F activity induced by growth stimulation. The phosphatidyl inositol 3 kinase (PI3K) pathway was reported to suppress expression of some atypical pro-apoptotic genes by over-expressed E2F1. However, the effects of the PI3K pathway on the distinct regulation of typical pro-apoptotic E2F targets have not been elucidated. We examined whether the PI3K pathway suppressed activation of the typical pro-apoptotic E2F targets ARF and BIM. Activation of the PI3K pathway by growth stimulation or introduction of a constitutively active Akt/PKB did not reduce induction of ARF or BIM gene expression or activation of their promoters by over-expressed E2F1. These results suggest that the PI3K pathway does not suppress induction of typical pro-apoptotic genes that are selectively activated by deregulated E2F1., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Molecular organization of the eukaryote chaperonin known as CCT/TRiC complex was recently clarified. Eight distinct subunits are uniquely organized, providing a favorable folding cavity for specific client proteins such as tubulin and actin. Because of its heterogeneous subunit composition, CCT complex has polarized inner faces, which may underlie an essential part of its chaperonin function. In this study, we structurally characterized the closed and open states of CCT complex, using molecular dynamics analyses. Our results showed that the inter-subunit interaction energies were asymmetrically distributed and were remodeled during conformational changes of CCT complex. In addition, exploration of redox related characteristics indicated changes in inner surface properties, including electrostatic potential, pK a and exposure of inner cysteine thiol groups, between the closed and open states. Cysteine activation events were experimentally verified by interaction analyses, using tubulin as a model substrate. Our data highlighted the importance of dynamics-based structural profiling of asymmetrically oriented chaperonin function., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The heterodimeric transcription factor E2F1-DP1 plays crucial roles in coordinating gene expression during G 1 /S cell cycle progression. For transcriptional activation, the transactivation domain (TAD) of E2F1 is known to interact with the TATA-binding protein of TFIID and the p62 subunit of TFIIH. It is generally believed that DP1 facilitates E2F1 binding to target DNA and does not possess a TAD. Here, we show that an acidic region of DP1, whose function has remained elusive, binds to the plekstrin homology (PH) domain of p62 with higher affinity than that of E2F1 and contributes to transcriptional activation. The structure of the complex revealed that DP1 forms a twisted U-shaped, string-like conformation and binds to the surface of the PH domain by anchoring Phe403 into a pocket in the PH domain. The transcriptional activity of E2F1-DP1 was reduced when Phe403 of DP1 was mutated. These findings indicate that the acidic region of DP1 acts as a TAD by contacting TFIIH., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Herein, the design and syntheses of two new mononuclear oxindolimine-copper(II) (1 and 2) and corresponding heterobinuclear oxindolimine Cu(II)Pt(II) complexes (3 and 4), are described. All the isolated complexes were characterized by spectroscopic techniques (UV/Vis, IR, EPR), in addition to elemental analysis and mass spectrometry. Cyclic voltammetry (CV) measurements showed that in all cases, one-electron quasi-reversible waves were observed, and ascribed to the formation of corresponding copper(I) complexes. Additionally, waves related to oxindolimine ligand reduction was verified, and confirmed using analogous oxindolimine-Zn(II) complexes. The Pt(IV/II) reduction, and corresponding oxidation, for complexes 3 and 4 occurred at very close values to those observed for cisplatin. By complementary fluorescence studies, it was shown that glutathione (GSH) cannot reduce any of these complexes, under the experimental conditions (room temperature, phosphate buffer 50mM, pH7.4), using an excess of 20-fold [GSH]. All these complexes showed characteristic EPR spectral profile, with parameters values g ǁ >g ⊥ suggesting an axially distorted environment around the copper(II) center. Interactions with calf thymus-DNA, monitored by circular dichroism (CD), indicated different effects modulated by the ligands. Finally, the cytotoxicity of each complex was tested toward different tumor cells, in comparison to cisplatin, and low values of IC 50 in the range 0.6 to 4.0μM were obtained, after 24 or 48h incubation at 37°C. The obtained results indicate that such complexes can be promising alternative antitumor agents., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Cellular FLICE-inhibitory protein (cFLIP) is a catalytically inactive homolog of the initiator caspase, caspase 8 and blocks apoptosis through binding to caspase 8. Human CFLAR gene encodes two proteins, a long form cFLIP (cFLIP L ) and a short form cFLIP (cFLIPs) due to an alternative splicing. Recent studies have shown that expression of cFLIPs, but not cFLIP L promotes programmed necrosis (also referred to as necroptosis) in an immortalized human keratinocyte cell line, HaCaT. Here, we found that expression of cFLIPs similarly promoted necroptosis in immortalized fibroblasts. To further expand this observation and exclude the possibility that immortalization process of keratinocytes or fibroblasts might affect the phenotype induced by cFLIPs expression, we generated human CFLARs transgenic (Tg) mice. Primary fibroblasts derived from CFLARs Tg mice were increased in susceptibility to TNFα-induced necroptosis, but not apoptosis compared to wild-type (WT) fibroblasts. Moreover, hallmarks of necroptosis, such as phosphorylation of receptor-interacting protein kinase (RIPK)1 and RIPK3, and oligomer formation of mixed lineage kinase domain-like (MLKL) were robustly induced in CFLARs Tg fibroblasts compared to wild-type fibroblasts following TNFα stimulation. Thus, cFLIPs-dependent promotion of necroptosis is not unique to immortalized keratinocytes or fibroblasts, but also to generalized to primary fibroblasts., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Blunt abdominal aortic injury (BAAI) is very rare. In general, BAAI occurs in high-energy accidents. Here, we present a case of BAAI in a low-energy accident. A 70-year-old female was injured after falling 3 m. Her vital signs were stable. She had lumbar fractures (L1, L2) and BAAI associated with a fragment of the fractured L2 vertebral body. On the fifth posttrauma day, we performed an operation because computed tomography showed a bone fragment of the lumbar fractures (L1, L2) threatening the abdominal aorta. The aortic injury site was transected, and the fragment of the L2 vertebral body was removed. Even in low-energy accidents, BAAI should be considered. BAAI with stable vital signs can be electively treated., (Copyright © 2016 Elsevier Inc. All rights reserved.)