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Inferior vena cava (IVC) anomalies, such as the absence of an intra-hepatic IVC or IVC hypoplasia, are rare. Usually, these anomalies are asymptomatic and cause few clinical issues. We herien report a 53-year-old woman with IVC anomalies who demonstrated both azygos and portal vein system continuation. Over time, this resulted in gradually progressive portal hypertension due to abnormal hemodynamics. The increased inflow from the IVC to the portal vein system for an extended time may contribute to the development of portal hypertension without liver cirrhosis.

By the emergence and worldwide spread of multi-drug-resistant Gram-negative bacteria, there have been growing demands for efficacious drugs to cure these resistant infections. The key mechanism for resistance to β-lactam antibiotics is the production of β-lactamases, which hydrolyze and deactivate β-lactams. Diazabicyclooctane (DBO) analogs play an important role as one of the new classes of β-lactamase inhibitors (BLIs), and several compounds such as avibactam (AVI) have been approved by the FDA, along with many derivatives under clinical or preclinical development. Although these compounds have a similar amide substituent at the C2 position, we have recently reported the synthesis of novel DBO analogs which possess a thio functional group. This structural modification enhances the ability to restore the antimicrobial activities of cefixime (CMF) against pathogens producing classes A, C, and D serine β-lactamases compared with AVI and expands the structural tolerance at the six position. Furthermore, some of these analogs showed intrinsic microbial activities based on multipenicillin binding protein (PBP) inhibition. This is the unique feature which has never been observed in DBOs. One of our DBOs had a pharmacokinetic profile comparable to that of other DBOs. These results indicate that the introduction of a thio functional group into DBO is a novel and effective modification to discover a clinically useful new BLI.

Purpose: Although HER2-positive (HER2+) invasive breast carcinomas (BC) have a different clinical therapeutic responsiveness according to estrogen and progesterone receptor expression, the relationship with androgen receptors (AR), which are the same family of steroid hormones, is poorly understood. We investigated the relationship between AR expression in HER2 BCs and therapeutic responsiveness and prognosis in this study., Methods: We evaluated patients with HER2 (H) + invasive BC undergoing surgery after neoadjuvant chemotherapy (± HER2-targeted therapies) from 2007-2017, classified as hormone receptor-positive (Allred score: 2-8) (luminal B: LH) and receptor-negative groups (Allred: score 0) (non-luminal: NLH). AR expression was assessed by immunostaining pre-neoadjuvant chemotherapy biopsy specimens, positive with Allred score ≥ 4. The pathological complete response, disease-free survival, and overall survival rates were compared between AR-positive and AR-negative groups., Results: We classified 82 patients with HER2 + invasive BC into LH (n = 45, 54.9%) and NLH groups (n = 37, 45.1%), and AR + was observed in 43 patients (52.4%) (LH: 23, 51.1%; NLH: 20, 54.1%; p = 0.79). Quasi-pathological complete response was observed in 40 patients (48.8%) (LH: 18, 40%; NLH: 22, 59.5%; p = 0.08) overall, and in 31 AR + patients (72.1%) (LH: 15, 34.9%; NLH: 16, 37.2%), significantly higher than in the AR - group for both subgroups (p < 0.001). Regarding prognosis, disease-free survival was relatively better in the AR + group in all HER2 + BCs (p = 0.085), and overall survival was significantly better in the AR + group for NLH (p = 0.029)., Conclusions: High AR expression may be a useful predictor of therapeutic effects and prognosis in both subgroups of HER2 + BCs.

Nonalcoholic fatty liver disease (NAFLD) is based on the concept of pathological morphology as well as clinical findings, and is broadly categorized into nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). The differential diagnosis between NAFL and NASH is important because NASH has the potential to progress to cirrhosis and hepatocellular carcinoma. NAFL is simple hepatic steatosis without hepatocellular injury, while NASH is characterized by macrovesicular steatosis, inflammation, and ballooning hepatocytes with a predominantly centrilobular (zone 3) distribution. Liver biopsy is a useful test for diagnosing NAFLD, but it is invasive. Therefore, various noninvasive methods including diagnostic imaging have been developed in recent years. To verify their usefulness, it is necessary to clarify in detail how the pathological findings are reflected in the image findings as imaging and histopathological findings are closely related. We describe the main histological features of NAFLD, i.e., steatosis, inflammation, ballooning hepatocytes, Mallory-Denk bodies, and fibrosis, as well as the evolutional process to liver cirrhosis.

Identification of the complete set of translated genes of viruses is important to understand viral replication and pathogenesis as well as for therapeutic approaches to control viral infection. Here, we use chemical proteomics, integrating bio-orthogonal non-canonical amino acid tagging and high-resolution mass spectrometry, to characterize the newly synthesized herpes simplex virus 1 (HSV-1) proteome in infected cells. In these infected cells, host cellular protein synthesis is shut-off, increasing the chance to preferentially detect viral proteomes. We identify nine previously cryptic orphan protein coding sequences whose translated products are expressed in HSV-1-infected cells. Functional characterization of one identified protein, designated piUL49, shows that it is critical for HSV-1 neurovirulence in vivo by regulating the activity of virally encoded dUTPase, a key enzyme that maintains accurate DNA replication. Our results demonstrate that cryptic orphan protein coding genes of HSV-1, and probably other large DNA viruses, remain to be identified.

Background: Device underexpansion is associated with late adverse outcomes after bioresorbable vascular scaffold (BVS) implantation. This study, representing official IVUS results of the ABSORB Japan trial, aimed to characterize IVUS findings, focusing specifically on acute device expansion, and to investigate its impact on late lumen loss (LLL) with Absorb-BVS compared with cobalt-chromium everolimus-eluting stents (CoCr-EES)., Methods: ABSORB Japan enrolled 148 patients (2:1 randomization) in the IVUS cohort. Serial IVUS was prescheduled at post-procedure and 3 years. Acute device expansion was evaluated with respect to the degree and uniformity of the implanted device., Results: Overall, Absorb-BVS showed smaller and more nonuniform device expansion at post-procedure, compared with CoCr-EES, which was particularly prominent in small-vessel lesions. In serial analysis, Absorb-BVS showed unique associations of smaller device expansion (r = 0.40, p = 0.001) and more nonuniformity (r = 0.29, p = 0.007) at post-procedure with greater LLL at 3 years, primarily attributable to greater negative remodeling (r = 0.39, p = 0.006). In contrast, acute device expansion showed no relation with subsequent lumen change in CoCr-EES. In Absorb-BVS, ischemic-driven target lesion or vessel revascularization (ID-TLR or ID-TVR) at 3 years occurred more frequently in small- versus large-vessel lesions (12.5% vs. 0%, p = 0.04 for ID-TLR and 15.6% vs. 2.3%, p = 0.08 for ID-TVR). Conversely, Absorb BVS had no target lesion nor vessel failure, even in small-vessel lesions, when adequate device expansion was achieved at post-procedure., Conclusions: Unlike CoCr-EES, underexpansion was associated with greater negative remodeling and LLL in Absorb-BVS. This may in part account for the poorer outcomes of Absorb-BVS than CoCr-EES when under-expanded., Competing Interests: T.K., and J.J.P. are members of Advisory Board of Abbott Vascular; T.K. is a member of Advisory Board of Abbott Vascular Japan; K.S., H.K., and W-F.C. are employees of Abbott Vascular; P.G.Y., and P.J.F received institutional research grant from Abbott Vascular; the other authors report no conflicts of interest with regards to this manuscript., (© 2020 The Authors.)

Several recent clinical and epidemiological studies have suggested inhibitory effects of light-to-moderate alcohol consumption on nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH); however, these effects have not been confirmed in experimental studies. Therefore, in this study, we examined the effects of small amounts of ethanol consumption on a mouse model of NASH. Nine-week-old male obese mice (db/db mice) were divided into the following groups: control, high-fat, and low-ethanol groups. The control group was provided ad libitum access to a control liquid diet, the high-fat group was provided access to a high-fat liquid diet, and the low-ethanol group was provided access to the high-fat liquid diet supplemented with 0.1% (w/w) ethanol. Eight weeks later, the mice were sacrificed and serum biochemical, histopathological, and molecular analyses were performed. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were significantly lower in the low-ethanol group than in the high-fat group (p = 0.033 and 0.037, respectively). Liver histopathological analysis showed that intralobular and portal inflammation was significantly milder in the low-ethanol group than in the high-fat group (p = 0.018 and 0.041, respectively). However, no significant differences were observed among the groups in serum insulin and adiponectin levels, hepatic 4-hydroxynonenal (oxidative injury marker) levels, and hepatic cytokine and receptor gene expression levels. In conclusion, the serum transaminase levels and hepatic inflammation in NASH model mice improved after administration of small amounts of ethanol. This study directly demonstrated inhibitory effects of small amounts of ethanol on NASH in mice. The mechanisms underlying these inhibitory effects remain to be elucidated., Competing Interests: Declarations of interest None., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Lithospermum erythrorhizon is a medicinal plant that produces shikonin, a red lipophilic naphthoquinone derivative that accumulates exclusively in roots. The biosynthetic steps required to complete the naphthalene ring of shikonin and its mechanism of secretion remain unclear. Multiple omics studies identified several candidate genes involved in shikonin production. The functions of these genes can be evaluated using virus-induced gene silencing (VIGS) systems, which have been shown advantageous in introducing iRNA genes into non-model plants. This study describes the development of a VIGS system using an apple latent spherical virus (ALSV) vector and a target gene, phytoene desaturase (LePDS1). Virus particles packaged in Nicotiana benthamiana were inoculated into L. erythrorhizon seedlings, yielding new leaves with albino phenotype but without disease symptoms. The levels of LePDS1 mRNAs were significantly lower in the albino plants than in mock control or escape plants. Virus-derived mRNA was detected in infected plants but not in escape and mock plants. Quantitative PCR and deep sequencing analysis indicated that transcription of another hypothetical PDS gene (LePDS2) also decreased in the defective leaves. Virus infection, however, had no effect on shikonin production. These results suggest that virus-based genetic transformation and the VIGS system silence target genes in soil-grown L. erythrorhizon.

Approval of avibactam by the FDA has led to the recognition of 1,6-diazabicyclo[3.2.1]octane (DBO) derivatives as attractive compounds for β-lactamase inhibition. We achieved a concise and collective synthesis of 2-thio-substituted DBO derivatives. The synthesis involves diastereoselective photo-induced Barton decarboxylative thiolation, which can be applied to large-scale synthesis. The DBO analogues exhibited strong inhibitory activities against serine β-lactamases and acceptable solution stabilities for clinical development.

Geant4 Monte Carlo simulations were carried out to investigate the possible shielding materials of aluminum, polyethylene, hydrides, complex hydrides and composite materials for radiation protection in spacecraft by considering two physical parameters, stopping power and fragmentation cross section. The dose reduction with shielding materials was investigated for Fe ions with energies of 500 MeV/n, 1 GeV/n and 2 GeV/n which are around the peak of the GCR energy spectrum. Fe ions easily stop in materials such as polyethylene and hydrides as opposed to materials such as aluminum and complex hydrides including high Z metals with contain little or no hydrogen. Attenuation of the primary particles in the shielding and fragmentation into more lightly charged and therefore more penetrating secondary particles are competing factors: attenuation acts to reduce the dose behind shielding while fragmentation increases it. Among hydrogenous materials, 6 Li 10 BH 4 was one of the more effective shielding materials as a function of mass providing a 20% greater dose reduction compared to polyethylene. Composite materials such as carbon fiber reinforced plastic and SiC composite plastic offer 1.9 times the dose reduction compared to aluminum as well as high mechanical strength. Composite materials have been found to be promising for spacecraft shielding, where both mass and volume are constrained., Competing Interests: Declaration of Competing Interest The authors declare that there are no potential conflicts of interest., (Copyright © 2020 The Committee on Space Research (COSPAR). Published by Elsevier Ltd. All rights reserved.)

Background/aim: Assessment of the biological behavior of tumors is important for choosing an appropriate cancer therapy. In hepatocellular carcinoma (HCC), the biological behaviour can be assessed by tumor morphology and molecular biology. This study investigated the usefulness of tumor tissue biopsy for predicting the biological behavior of HCC., Patients and Methods: We studied 43 patients who underwent hepatectomy and preoperative liver tumor biopsy for HCC. We performed clinicopathological and immunohistochemical (IHC) analyses. The expression of the following molecules was examined: regulator of G-protein signaling 5 (RGS5), glypican-3 (GPC3), keratin 19 (K19), epithelial cell adhesion molecule (EpCAM), protein induced by vitamin K absence or antagonist-II (PIVKA-II), β-Catenin, and p53., Results: There was an overall 83.7% agreement regarding tumor differentiation between the preoperative biopsy specimens and the resected specimens. The accuracy of IHC analysis was more than 70% for all molecules between the preoperative biopsy specimens and the resected specimens. The RGS5-positive biopsy cases had higher serum α-fetoprotein levels (p=0.04), a higher rate of moderately or poorly differentiated tumors (p=0.02) and portal vein invasion (p=0.0003) than the RGS5-negative biopsy cases. The GPC3-positive biopsy cases were younger (p=0.04), had higher serum PIVKA-II levels (p=0.01), and a higher rate of portal vein invasion (p=0.03) than the GPC3-negative biopsy cases. The PIVKA-II-positive biopsy cases had significantly higher serum PIVKA-II levels than the PIVKA-II-negative biopsy cases (p=0.02). The other molecular markers showed no significantly different clinical findings between the positive and negative cases., Conclusion: In HCC, there was a high agreement rate of both the histopathological and IHC findings between preoperative biopsy specimens and resected specimens. In the biopsy specimens of HCC, RGS5 and GPC3 expression were useful molecular makers for predicting portal vein invasion. Liver tumor biopsy is useful for predicting the biological behavior of HCC through histopathological and immunohistochemical findings., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Hepatoblastoma (HB) is the leading primary hepatic malignancy in children and likely emerges due to failure of hepatic progenitor cells to properly differentiate. The peroxiredoxin (PRDX) family is frequently linked to cancer. In our previous study, we demonstrated that expression of the only secreted family member, PRDX4, was correlated with hepatocellular carcinoma. The aim of this new study was to investigate PRDX4's role in HB. We collected 87 HB specimens and performed PRDX4 immunohistochemistry staining. Clinical analysis was conducted and the effect of PRDX4 overexpression on two HB cell lines (Huh6 and HepG2) was also examined. Clinical data revealed elevated PRDX4 expression in embryonal component was correlated with advanced stage (IV) and metastasis. In comparison, increased PRDX4 expression in fetal component was associated with well differentiation. In vitro experiments showed PRDX4 overexpression enhanced migration in embryonal-like HB cells (Huh6), which was accompanied by epithelial-mesenchymal transition (EMT). By contrast, PRDX4 overexpression inhibited proliferation, decreased stemness markers, and increased hepatic markers in fetal-like HB cells (HepG2), which indicated induction of tumor cell differentiation. In conclusion, PRDX4 promotes embryonal hepatoblastoma cell migration but induces fetal cell differentiation. It can be adopted as an important marker for HB prognosis and a potential treatment target., Competing Interests: None., (AJTR Copyright © 2020.)

Background: Bioresorbable vascular scaffolds (BVS) are promising alternatives to metallic drug-eluting stents (DES) in percutaneous coronary interventions. Absorb BVS was comparable to XIENCE (DES) for patient- and device-oriented composite endpoints through 1 year post-procedure. Mid-term results showed increased rates of device-oriented events with Absorb. The objective of this study was to evaluate the long-term safety and effectiveness of Absorb BVS compared with XIENCE metallic DES when implanted in patients in Japan with de novo coronary artery lesions., Methods and results: ABSORB Japan randomized 400 patients into either Absorb (n=266) or XIENCE (n=134) treatment arm. Through 5-year follow-up, the composite endpoints of DMR (death, myocardial infarction [MI], and all revascularization), target vessel failure (TVF), major adverse cardiac events (MACE), target lesion failure (TLF), and cardiac death/all MI were evaluated. Individual endpoints included death, MI, coronary revascularization, and scaffold/stent thrombosis. There were no significant differences in the composite or individual endpoint outcomes between the Absorb and XIENCE arms through 5 years or between 3 and 5 years. Numerically lower TVF, MACE, and all MI rates were observed for the Absorb vs. XIENCE arm after 3 years. No scaffold/stent thrombosis was reported beyond 3 years. Post-procedure imaging subgroups showed comparable event rates., Conclusions: Following resorption of the scaffold, between 3 and 5 years post-procedure, the Absorb BVS performed comparably to XIENCE in all patient- and device-oriented endpoints (ClinicalTrials.gov, #NCT01844284).

Crop plants accumulate a large amount of storage starch and storage proteins in the endosperm. Genes involved in the biosynthesis of these substances work in concert during development of the rice endosperm. The rice flo2 mutant produces aberrant seeds with reduced grain quality. FLOURRY ENDOSPERM 2 (FLO2) , the causative gene of the flo2 mutant, is considered to be a regulatory protein that controls the biosynthesis of seed storage substances. FLO2 contains tetratricopeptide repeat (TPR) motifs that may mediate protein-protein interactions. In this study, we identified the protein that interacts with the TPR motif of FLO2. We generated a transformant that produced the FLAG-tagged fusion FLO2 protein in the flo2 mutant and used this in the shotgun proteomic analysis. A protein, which we named FLOC1, interacted with FLO2. In vitro pull-down assays indicated that the TPR motif was involved in this interaction. A knock-down transformant of FLOC1 showed significantly reducted fertility and generation of seeds with abnormal features. These findings suggest that FLOC1 is involved not only in seed fertility but also in seed quality. These phenotypes were also observed on the RNAi transformants of the flo2 mutant although the effect of the flo2 mutation remained. these findings imply that there is a difference in the functions of FLO2 and FLOC1 although both of appear to be involved in the control of seed quality during seed formation., (© 2020 The Japanese Society for Plant Cell and Molecular Biology.)

Aims: HER2-positive (HER2+) breast carcinoma (BC) cases are often treated similarly; however, they can be classified as either luminal B (LH) or non-luminal type (NLH) BC, which have different prognoses. In this study, we investigated the clinicohistomorphological features of each HER2+ BC subgroup., Methods and Results: We classified 166 patients with HER2+ invasive BC into LH (n = 110, 66.3%) and NLH groups (n = 56, 33.7%). We further subclassified LH into patients with carcinomas expressing high levels of hormone receptors [LH-high; Allred score, oestrogen receptor (ER) and/or progesterone receptor (PgR) 4-8, n = 89, 53.6%] or low levels (LH-low; Allred score, ER and/or PgR 2 or 3, n = 21, 12.7%) for clinicohistomorphological characterisation. Morphological review showed that NLH included a percentage of patients with comedo necrosis, while LH patients had significantly more central scarring. In terms of immune responsiveness, NLH showed significantly higher rates of tumour-infiltrating lymphocytes and healing. The LH-high and NLH groups showed distinct characteristics (by both models, P < 0.05) and the LH-low group appeared to demonstrate intermediate characteristics according to multinomial analyses using covariates reflecting tumour morphology and immune response outcomes., Conclusions: These results support the classification of HER2+ BC into two major subgroups, LH-high and NLH, based on tumour morphology and immune response; LH-high proliferates via scirrhous and/or spiculated growth with a central scar, while the primary proliferation pattern of NLH is based on in-situ carcinomas containing comedo necrosis with noticeable TILs and healing., (© 2019 John Wiley & Sons Ltd.)

Objectives: The aim of this study was to investigate the vascular responses and fates of the scaffold after bioresorbable vascular scaffold (BVS) implantation using multimodality imaging., Background: Serial comprehensive image assessments after BVS implantation in the context of a randomized trial have not yet been reported., Methods: In the ABSORB Japan trial, 400 patients were randomized to a BVS (n = 266) or a cobalt-chromium everolimus-eluting stent (n = 134). Through 3 years, patients underwent serial angiography and intravascular ultrasound or optical coherence tomography (OCT)., Results: Luminal dimension at 3 years was consistently smaller with the BVS than with the cobalt-chromium everolimus-eluting stent (mean angiographic minimal luminal diameter 2.04 ± 0.63 mm vs. 2.40 ± 0.56 mm, mean difference -0.37 mm [95% confidence interval: -0.50 to -0.24 mm]; p < 0.001), mainly because of smaller device area (6.13 ± 2.03 mm 2 vs. 7.15 ± 2.16 mm 2 , mean difference -1.04 mm 2 [95% confidence interval: -1.66 to -0.42 mm 2 ]; p < 0.001), and larger neointimal area (2.10 ± 0.61 mm 2 vs. 1.86 ± 0.64 mm 2 , mean difference 0.24 mm 2 [95% confidence interval: 0.06 to 0.43 mm 2 ]; p = 0.01) by OCT. BVS-treated vessels did not show previously reported favorable vessel responses, such as positive vessel remodeling, late luminal enlargement, and restoration of vasomotion, although the OCT-based healing score was on average zero (interquartile range: 0.00 to 0.00). At 3 years, intraluminal scaffold dismantling (ISD) was observed in 14% of BVS. On serial OCT, ISD was observed in 6 lesions at 2 years, where the struts had been fully apposed at post-procedure, while ISD was observed in 12 lesions at 3 years, where 8 lesions were free from ISD on 2-year OCT. In 5 cases of very late scaffold thrombosis, strut discontinuities were detected in all 4 cases with available OCT immediately before reintervention., Conclusions: In this multimodality serial imaging study, luminal dimension at 3 years was smaller with the BVS than with the cobalt-chromium everolimus-eluting stent. ISD, suspected to be one of the mechanisms of very late BVS thrombosis, was observed in a substantial proportion of cases at 3 years, which developed between post-procedure and 2 years and even beyond 2 years. (AVJ-301 Clinical Trial: A Clinical Evaluation of AVJ-301 [Absorb™ BVS] in Japanese Population [ABSORB JAPAN]; NCT01844284)., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Aim: Cholangiolocellular carcinoma (CLC) is classified as a subtype of combined hepatocellular cholangiocarcinoma with stem-cell features (CHC-SC) in the latest World Health Organization classification. This subclassification of CHC-SCs is controversial and the relevance of such classification is unclear., Methods: We analyzed a series of CHC-SCs and intrahepatic cholangiocarcinoma (iCCA) to clarify the clinicopathological features and mutational status of each tumor., Results: Background liver disease, fibrosis stage, microvascular invasion, nodal metastasis, and IDH1/2 mutation status were associated with their histology. Compared with the intermediate cell subtype of CHC-SC (CHCs-SC-int), CLCs were less frequently associated with chronic viral hepatitis, and showed lower levels of serum alpha-fetoprotein. Compared with iCCAs, CLCs showed lower levels of serum carbohydrate antigen 19-9 (CA19-9) and a lower frequency of expression of S100P. Patients with iCCA showed worse overall survival than those with CLC or CHC-SC-int. In patients with iCCA, CLC, or CHC-SC-int, a histology of iCCA, microvascular invasion, and serum CA19-9 value of >100 U/mL were significant poor prognostic factors for overall survival in univariate analysis. Multivariate analysis showed that a high serum CA19-9 value was an independent poor prognostic factor for overall survival., Conclusions: Patients with CLC are likely to have a different etiology and mutational background from those with CHC-SC-int. Their clinicopathological manifestations are also different from those with classic iCCA. Our results suggest that CLC might be a distinct entity among primary liver carcinomas., (© 2019 The Japan Society of Hepatology.)

A 69-year-old woman underwent extended cholecystectomy for gallbladder cancer[T2N0M0, fStage Ⅱ(UICC 7th edition)]. She was then administered adjuvant S-1 and was treated for drug-induced neutropenia. One year later, recurrent lesions were detected in liver S4 and S5. We treated the patient with hepatectomy and hepatic arterial infusion adjuvant chemotherapy by cisplatin, along with the systemic administration of gemcitabine for 10 months. The patient is now doing well without any sign of recurrence 29 months after the initial operation and 16 months after the secondary liver resection.

Background: The Japan post-marketing surveillance (PMS) for the Absorb GT1 bioresorbable vascular scaffold (BVS) mandated an intracoronary imaging-guided implantation technique., Methods and results: We enrolled 135 patients who were planned to undergo PCI with THE Absorb GT1. Adequate lesion preparation, imaging-guided appropriate sizing, and high-pressure post-dilatation using a noncompliant balloon to minimize final diameter stenosis were recommended. The primary endpoint was the scaffold thrombosis rate at 3 months. All patients successfully received at least 1 Absorb GT1 at the index procedure and completed 1-year follow-up. All 139 lesions were predilatated: cutting/scoring balloon and noncompliant balloon were used in 48 (34.5%) and 58 (41.7%) lesions, respectively. Post-dilatation was performed in 137 (98.5%) lesions with mean high pressure of 18.8 atm. Optical coherence tomography (OCT) was used in 127 of 139 (91.4%) lesions, and revealed 56.7% of lesions had incomplete scaffold apposition (ISA) but only in 1.89% in the per strut analysis. All patients received adenosine diphosphate receptor antagonist at discharge, and 132 (97.8%) patients continued therapy through the year. No definite/probable scaffold thrombosis, cardiac death, myocardial infarction, or ischemia-driven target lesion revascularization was reported up to 1 year follow-up., Conclusions: Appropriate OCT-guided BVS implantation may prevent incomplete strut apposition, thereby reducing the risk of target lesion failure and scaffold thrombosis.

Objective: To retrospectively compare the efficacy of suprascapular nerve block (SSNB) versus interscalene block (ISB) for analgesia after arthroscopic rotator cuff repair (ARCR)., Methods: Ninety-seven patients who underwent ARCR were retrospectively divided into three groups. Group S comprised 33 patients who received SSNB, group I comprised 52 patients who received ISB, and group C comprised 12 patients who received a glenohumeral injection as a control. SSNB and ISB were performed with 20 ml of 0.375% ropivacaine before surgery, while glenohumeral injection was performed after surgery. The Visual analog scale (VAS) pain scores were recorded at 1,3, and 6 h and 1, 3, and 6 days postoperatively. The total number of additional analgesic administrations was also counted for 6 days postoperatively., Results: Compared with group C, the VAS pain score was significantly lower in group S at 1 h and 6 days postoperatively, and in group I at 1 and 3 h postoperatively. There were no significant differences between groups S and I in the VAS pain scores, or the administration of additional analgesia. There were no major complications associated with SSNB or ISB., Conclusion: There were no significant differences between SSNB and ISB in the duration of analgesia and the VAS pain scores after ARCR., Competing Interests: None., (© 2019 Published by Elsevier B.V. on behalf of Professor P K Surendran Memorial Education Foundation.)

Progressive familial intrahepatic cholestasis (PFIC), a rare inherited disorder, progresses to liver failure in childhood. We have shown that sodium 4-phenylbutyrate (NaPB), a drug approved for urea cycle disorders (UCDs), has beneficial effects in PFIC. However, there is little evidence to determine an optimal regimen for NaPB therapy. Herein, a multicenter, open-label, single-dose study was performed to investigate the influence of meal timing on the pharmacokinetics of NaPB. NaPB (150 mg/kg) was administered orally 30 min before, just before, and just after breakfast following overnight fasting. Seven pediatric PFIC patients were enrolled and six completed the study. Compared with postprandial administration, an approved regimen for UCDs, preprandial administration significantly increased the peak plasma concentration and area under the plasma concentration-time curve of 4-phenylbutyrate by 2.5-fold (95% confidential interval (CI), 2.0-3.0;P = 0.003) and 2.4-fold (95% CI, 1.7-3.2;P = 0.005). The observational study over 3 years in two PFIC patients showed that preprandial, but not prandial or postprandial, oral treatment with 500 mg/kg/day NaPB improved liver function tests and clinical symptoms and suppressed the fibrosis progression. No adverse events were observed. Preprandial oral administration of NaPB was needed to maximize its potency in PFIC patients.

Background/aim: Therapeutic targeting of receptor protein tyrosine kinases (PTKs) has proven successful in treating cancer. However, reports about PTKs in treating prostate cancer are few. Elevated expression of the erythropoietin-producing hepatocellular receptor A2 (EPHA2) receptor tyrosine kinase, a transmembrane protein, is associated with poor prognosis of certain cancer types when the enzyme is dephosphorylated. This study investigated whether EPHA2 is useful in predicting the biochemical recurrence of prostate cancer., Patients and Methods: Data from 241 patients who had undergone total prostatectomy between 2007 and 2011 were used. EPHA2 protein expression was categorized as high or low by two pathologists. The relationship was examined between EPHA2 expression level (high vs. low) and clinicopathological factors including biochemical recurrence. Correlations were examined between EPHA2, low-molecular-weight protein tyrosine phosphatase (LMW-PTP), E-cadherin, and Ki-67., Results: EPHA2 expression was high in 121 (50.2%) and low in 120 (49.8%) patients. A log-rank test revealed early biochemical recurrence in the high-expression group. Gleason score, Ki-67 labeling index, and biochemical recurrence were more frequent in the high-expression group. Furthermore, multivariate analyses revealed that high EPHA2 expression was an independent prognostic factor for biochemical recurrence (hazard ratio=3.62, 95% confidence interval=2.39-5.61). Correlations between EPHA2 and both LMW-PTP and Ki-67 labeling index were positive, whereas EPHA2 and E-cadherin were negatively correlated., Conclusion: EPHA2 overexpression is predictive of aggressive prostate cancer behavior. EPHA2 may be a powerful prognostic biomarker for decision-making in postoperative follow-up after total prostatectomy, and regarding the need for palliative treatment. Additionally, it may be an important therapeutic target., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Lenvatinib is a potent inhibitor of receptor tyrosine kinases, targeting vascular endothelial growth factor receptors (VEGFR1-3), fibroblast growth factor receptors (FGFR1-4), KIT, and RET. Here, we investigated the antiproliferative effects of lenvatinib in liver cancer cells in vitro and in vivo., Materials and Methods: Eleven hepatocellular carcinoma cell lines and two combined hepatocellular/cholangiocarcinoma cell lines were treated with 0-30 μM lenvatinib. Cell growth, apoptosis and the expression of FGFR1-4, FGF19, fibroblast growth factor receptor substrate (FRS)2α and RET were examined. Two HCC cell lines were subcutaneously implanted on nude mice and mice were treated with 3, 10, 30 mg/kg/day of lenvatinib or vehicle for 14 consecutive days. Tumor volume was measured every 3 days. Mice were sacrificed on day 15 and tumors were processed for histological examination. Blood vessels, microvessel density, necrosis, and apoptosis were also examined., Results: Lenvatinib dose- and time-dependently inhibited growth of all cell lines; however, sensitivity to lenvatinib varied. Apoptosis was not observed in any cell line, and expression of FGFR1, -2, -3 and -4, FGF19, FRS2α, and RET were observed in these cell lines. Cell lines with high expression of these factors showed higher response to lenvatinib. In mice, lenvatinib dose-dependently suppressed tumor growth. Blood vessels and microvessel density were significantly reduced and the rate of necrosis was significantly increased by lenvatinib; apoptosis was not observed., Conclusion: Antiproliferative effects of lenvatinib on liver cancer cells were observed in vitro and in vivo. Lenvatinib may suppress tumor formation by inhibiting angiogenesis, and via an additional direct antiproliferative effect in some liver cancer cells., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Aim: Combined hepatocellular cholangiocarcinoma, subtype with stem-cell features, intermediate-cell subtype (INT) shows various histological appearances and could be misdiagnosed as intrahepatic cholangiocarcinoma (iCCA). In the present study, we aimed to identify specific histological diagnostic markers of INT., Methods: We extracted RNA from FFPE sections of six INT, five iCCA, and five hepatocellular carcinoma (HCC) cases and compared gene expression between INT, iCCA, and HCC by microarray analysis. We then undertook immunohistochemical (IHC) staining of potential key molecules identified by microarray analysis, the conventional hepatocytic marker, hepatocyte paraffin (HepPar)-1, and the cholangiocytic markers, keratin (K) 7 and K19, on 35 INT, 25 iCCA, and 60 HCC cases., Results: Microarray analysis suggested that malic enzyme 1 (ME1) was significantly upregulated in INT. Immunohistochemical analysis revealed that the positive rates of ME1 in INT, iCCA, and HCC were 77.1% (27/35), 28.0% (7/25), and 61.7% (37/60), respectively. Analysis of classification and regression trees based on IHC scores indicated that HepPar-1 could be a good candidate for discriminating HCC from the others with high sensitivity (93.3%) and high specificity (96.7%). A multiple logistic regression model and receiver operating characteristic curve analysis based on the IHC scores of ME1, K7, and K19 generated a composite score that can discriminate between INT and iCCA. Using this composite score, INT could be discriminated from iCCA with high sensitivity (88.6%) and high specificity (88.0%)., Conclusions: We propose that ME1 is a useful diagnostic marker of INT when used in combination with other hepatocytic and cholangiocytic markers., (© 2019 The Japan Society of Hepatology.)

Borderline resectable pancreatic head cancer (BR-PHC) has low resectability due to vascular invasion. Although the clinical effects of neoadjuvant chemoradiotherapy (NAC-RT) for BR-PHC have been examined, few studies have reported its pathological aspects. The present study retrospectively investigated the effect of NAC-RT on the histological features of BR-PHC. A total of 29 patients with BR-PHC who underwent NAC-RT, and 55 controls with resectable PHC, who underwent pancreaticoduodenectomy at the Kurume University Hospital. Tumor staging, lymphovascular invasion (LVI), and microvessel invasion (MVI) were evaluated. The median tumor size in the NAC-RT group was 2.0 cm, and it was smaller than that of the control group (P=0.006). The rates of lymph node metastasis, LVI, and MVI were significantly lower in the NAC-RT group (P<0.001, 0.002, and 0.015, respectively). Overall survival in the NAC-RT group was comparable to that in the control group, although patients with BR-PHC generally had a poorer prognosis than those with resectable PHC. Patients in the NAC-RT group without portal vein invasion (PVI) had a significantly better prognosis than those with PVI in the control group (P=0.002). NAC-RT may be beneficial for patients with BR-PHC by inhibiting local invasion and metastasis as prognosis following resection could be equivalent to that of patients with conventional ductal adenocarcinoma.

Sulfite oxidase (SUOX) is a metalloenzyme that plays a role in ATP synthesis via oxidative phosphorylation in mitochondria and has been reported to also be involved in the invasion and differentiation capacities of tumor cells. Here, we performed a clinicopathological investigation of SUOX expression in prostate cancer and discussed the usefulness of SUOX expression as a predictor of biochemical recurrence following surgical treatment in prostate cancer. This study was conducted using Tissue Micro Array specimens obtained from 97 patients who underwent radical prostatectomy at our hospital between 2007 and 2011. SUOX staining was used to evaluate cytoplasmic SUOX expression. In the high-expression group, the early biochemical recurrence was significantly more frequent than in the low-expression group (p = 0.0008). In multivariate analysis, high SUOX expression was found to serve as an independent prognostic factor of biochemical recurrence (hazard ratio = 2.33, 95% confidence interval = 1.32-4.15, p = 0.0037). In addition, Ki-67-labeling indices were significantly higher in the high-expression group than in the low-expression group (p = 0.0058). Therefore, SUOX expression may be a powerful prognostic biomarker for decision-making in postoperative follow-up after total prostatectomy and with regard to the need for relief treatment.

Background: Osteochondritis dissecans of the humeral capitellum (capitellar OCD) is a common injury among adolescent throwing athletes. Some younger patients with incomplete maturity of the epiphysis and early-stage capitellar OCD are good candidates for nonoperative treatment. However, during initial examination, predicting the need for surgical treatment in patients with capitellar OCD is difficult., Purpose: To perform multivariate ordered logistic regression analysis of data obtained from patients' medical records and images on initial examination and identify the predictors of unsuccessful nonoperative management of capitellar OCD., Study Design: Cohort study (prognosis); Level of evidence, 2., Methods: This study included 245 elbows with capitellar OCD (all male; mean age, 14 years [range, 10-27 years]). Patients were divided into 3 groups comprising 148 elbows requiring an immediate operation on initial examination, 48 requiring nonsurgical treatment, and 49 requiring an operation after nonoperative management. Baseline data and radiographic parameters, such as lesion location, lesion size, modified Minami classification, radial head size, skeletal age difference between both elbows on initial examination, lesion size on computed tomography, and staging on magnetic resonance imaging, were retrospectively reviewed. Univariate and multivariate ordered logistic regression analyses of spontaneous healing of the lesion were conducted., Results: Univariate logistic regression analysis showed that radial head enlargement and skeletal age difference were significantly associated with spontaneous healing. In multivariate ordered logistic regression analysis, radial head enlargement (anteroposterior and lateral) and skeletal age difference were significant predictors of lack of spontaneous healing (odds ratio [OR], 2.76, P =.025; OR, 7.92, P =.026; and OR, 1.84, P =.0089, respectively)., Conclusion: To predict spontaneous healing in the moderate stage, plain radiographs would be important to evaluate radiocapitellar congruity and skeletal age. This study showed that preoperative radiographic findings of radial head enlargement and advanced skeletal age of the throwing side compared with that of the nonthrowing side were predictors of advanced-stage capitellar OCD. Despite several limitations, the statistical significance and correlations herein provide important information on preoperative surgical planning to surgeons.

Root hairs protruding from epidermal cells increase the surface area for water absorption and nutrient uptake. Various environmental factors including light, oxygen concentration, carbon dioxide concentration, calcium and mycorrhizal associations promote root hair formation in Arabidopsis thaliana. Light regulates the expression of a large number of genes at the transcriptional and post-transcriptional levels; however, there is little information linking the light response to root hair development. In this study, we describe a novel mutant, light-sensitive root-hair development 1 (lrh1), that displays enhanced root hair development in response to light. Hypocotyl and root elongation was inhibited in the lrh1 mutant, which had a late flowering phenotype. We identified the gene encoding the p14 protein, a putative component of the splicing factor 3b complex essential for pre-mRNA splicing, as being responsible for the lrh1 phenotype. Indeed, regulation of alternative splicing was affected in lrh1 mutants and treatment with a splicing inhibitor mimicked the lrh1 phenotype. Genome-wide alterations in pre-mRNA splicing patterns including differential splicing events of light signaling- and circadian clock-related genes were found in lrh1 as well as a difference in transcriptional regulation of multiple genes including upregulation of essential genes for root hair development. These results suggest that pre-mRNA splicing is the key mechanism regulating root hair development in response to light signals., (� The Author(s) 2019. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The aim of the present study was to study the pathological prognostic factor of initial hepatocellular carcinoma (HCC) after archiving sustained virologic response (SVR) for hepatitis C virus (HCV) infection. A single-center retrospective analysis was performed for patients who underwent hepatectomy between 2003 and 2017. We studied clinico-pathological findings of resected liver tissues in 35 patients with HCC after SVR treated by interferon (IFN group) and 13 patients with HCC after SVR treated by direct acting antivirals (DAA group). We also performed immunohistochemical staining using antibodies against programmed death-ligand 1 (PD-L1), cytokeratin 19, epithelial cell adhesion molecule (EpCAM) and regulator of G-protein signaling 5 (RGS5). PD-L1 positive HCC was observed in 6 cases of the IFN group and 4 cases of the DAA group. In the IFN group, in univariate analysis of recurrence free survival after surgery (RFS), the PD-L1 expression had a statistically significant impact (HR=6.01; P=0.02). In the multivariate analysis of RFS, PD-L1 expression significantly remained (HR=5.01; P=0.03). For both RFS and overall survival, Kaplan-Meier curves confirmed that patients with PD-L1 expression showed significantly worse prognosis (log-rank test P<0.01). Nuclear grade, RGS5 expression, and EpCAM expression were significantly higher in the PD-L1-positive HCC group compared with the PD-L1-negative HCC group (P<0.05). Therefore, PD-L1 expression may be an independent prognostic factor of surgically resected HCC after achieving SVR.

Purine permeases (PUPs) mediate the proton-coupled uptake of nucleotide bases and their derivatives into cytosol. PUPs facilitate uptake of adenine, cytokinins and nicotine. Caffeine, a purine alkaloid derived from xanthosine, occurs in only a few eudicot species, including coffee, cacao, and tea. Although caffeine is not an endogenous metabolite in Arabidopsis and rice, AtPUP1 and OsPUP7 were suggested to transport caffeine. In this study, we identified 15 PUPs in the genome of Coffea canephora . Direct uptake measurements in yeast demonstrated that CcPUP1 and CcPUP5 facilitate adenine - but not caffeine - transport. Adenine uptake was pH-dependent, with increased activity at pH 3 and 4, and inhibited by nigericin, a potassium-proton ionophore, suggesting that CcPUP1 and CcPUP5 function as proton-symporters. Furthermore, adenine uptake was not competitively inhibited by an excess amount of caffeine, which implies that PUPs of C. canephora have evolved to become caffeine-insensitive to promote efficient uptake of adenine into cytosol.

Pyrethroid-resistance in onion thrips, Thrips tabaci, has been reported in many countries including Japan. Identifying factors of the resistance is important to correctly monitoring the resistance in field populations. To identify pyrethroid-resistance related genes in T. tabaci in Japan, we performed RNA-Seq analysis of seven T. tabaci strains including two pyrethroid-resistant and five pyrethroid-susceptible strains. We identified a pair of single point mutations, T929I and K1774N, introducing two amino acid mutations, in the voltage-gated sodium channel gene, a pyrethroid target gene, in the two resistant strains. The K1774N is a newly identified mutation located in the fourth repeat domain of the sodium channel. Genotyping analysis of field-collected populations showed that most of the T. tabaci individuals in resistant populations carried the mutation pair, indicating that the mutation pair is closely associated with pyrethroid-resistance in Japan. Another resistance-related mutation, M918L, was also identified in part of the resistant populations. Most of the individuals with the mutation pair were arrhenotokous while all individuals with the M918L single mutation were thelytokous. The result of differentially expressed gene analysis revealed a small number of up-regulated detoxification genes in each resistant strain which might be involved in resistance to pyrethroid. However, no up-regulated detoxification genes common to the two resistant strains were detected. Our results indicate that the mutation pair in the sodium channel gene is the most important target for monitoring pyrethroid-resistance in T. tabaci, and that pyrethroid-resistant arrhenotokous individuals with the mutation pair are likely to be widely distributed in Japan., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Plant specialized metabolism emerged from the land colonization by ancient plants, becoming diversified along with plant evolution. To date, more than 1 million metabolites have been predicted to exist in the plant kingdom, and their metabolic processes have been revealed on the molecular level. Previous studies have reported that rates of evolution are greater for genes involved in plant specialized metabolism than in primary metabolism. This perspective introduces topics on the enigmatic molecular evolution of some plant specialized metabolic processes. Two transferase families, BAHD acyltransferases and aromatic prenyltransferases, which are involved in the biosynthesis of paclitaxel and meroterpenes, respectively, have shown apparent expansion. The latter family has been shown to beinvolved in the biosynthesis of a variety of aromatic substances, including prenylated coumarins in citrus plants and shikonin in Lithospermum erythrorhizon . These genes have evolved in the development of each special subfamily within the plant lineage. The broadness of substrate specificity and the exon-intron structure of their genes may provide hints to explain the evolutionary process underlying chemodiversity in plants.

Background: First-rib stress fracture is considered a potential cause of nonspecific atraumatic chronic shoulder pain in adolescent athletes. However, the etiology in throwing athletes with first-rib fracture is still unknown. The purpose of this retrospective study was to investigate the characteristic clinical features and radiographic findings of overhead throwing athletes with first-rib fracture., Methods: Twenty-four first-rib stress fractures in 23 players were studied retrospectively. Clinical features, including age, initial symptom, sports, pain-related activity, diagnostic method, treatment method, and final follow-up, were reviewed., Results: The following characteristic clinical features were identified: mean age of 16.8 years (range, 13 to 25 years), 19 dominant arm injuries and 5 non-dominant arm injuries, and an acute increase in pain while swinging the bat or pitching the ball. Sixteen fractures presented with posterior shoulder or upper thoracic back pain. At a mean time of 7.5 months after the initiation of conservative treatment, 17 healing fractures (71%) and 7 nonunion fractures (29%) among throwing athletes with first-rib stress fracture were identified. On image analysis, first-rib stress fractures were classified into 3 types depending on the direction and location of fracture lines: groove, intrascalene, and posterior types. Three symptomatic patients underwent first-rib resection due to thoracic outlet syndrome. On average, 46% of the first rib was visible on the shoulder radiographs and 97% was visible on the cervical spine radiographs. The Cohen kappa coefficient for the above percentages was 0.87 and the percent agreement was 89.4% for the shoulder, and the Cohen kappa coefficient was 0.80 and the percent agreement was 99.0% for the cervical spine., Conclusions: First-rib stress fracture should be considered when adolescent overhead throwing athletes have acute-onset posterior shoulder pain while swinging the bat or pitching the ball. Anteroposterior radiography of the cervical spine is available for initial diagnosis. Although 71% of the patients healed at a mean follow-up of 7.5 months with conservative treatment, some patients may have symptoms consistent with thoracic outlet syndrome., Level of Evidence: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Plant growth is strictly controlled by cell division, elongation, and differentiation for which adequate supplies of intracellular ATP are required. However, it is unclear how changes in the amount of intracellular ATP affect cell division and growth. To reveal the specific pathway dependent on ATP concentration, we performed analyses on the Arabidopsis mitochondria mutation sd3 . The mutant is tiny, a result of a low amount of ATP caused by the disruption of Tim21, a subunit of the TIM23 protein complex localized in the inner membrane of the mitochondria. Loss of function of suppressor of gamma response 1 ( SOG1 ) also restored the dwarf phenotype of wild type treated with antimycin A, a blocker of ATP synthesis in mitochondria. The sd3 phenotype is partially restored by the introduction of sog1, suppressor of gamma response 1 , and kin10 / kin11 , subunits of Snf1-related kinase 1 (SnRK1). Additionally, SOG1 interacted with SnRK1, and was modified by phosphorylation in planta only after treatment with antimycin A. Transcripts of several negative regulators of the endocycle were up-regulated in the sd3 mutant, and this high expression was not observed in sd3sog1 and sd3kin11 . We suggest that there is a novel regulatory mechanism for the control of plant cell cycle involving SnRK1 and SOG1, which is induced by low amounts of intracellular ATP, and controls plant development.

Mixed carcinoma of the pancreas is defined as the concurrent existence of pancreatic ductal carcinoma, acinar cell carcinoma, and/or islet cell carcinoma within the same neoplasm. We herein report a rare case of mixed ductal-acinar cell carcinoma in a 74-year-old man who was undergoing treatment for hypertension and diabetes at another hospital. After an abrupt worsening of his blood glucose control, the patient was referred to our hospital for further evaluation. Abdominal contrast-enhanced computed tomography and magnetic resonance imaging revealed a tumor with a multilocular cystic lesion in the head of the pancreas. Endoscopic retrograde cholangiopancreatography revealed obstruction of the main pancreatic duct and dilation of the dorsal pancreatic duct; in addition, adenocarcinoma was detected in the pancreatic juice cytology. Based on the abovementioned findings, the patient was diagnosed with carcinoma of the pancreatic head and underwent subtotal stomach-preserving pancreaticoduodenectomy. Based on the histopathological and immunohistochemical findings, the patient was diagnosed with mixed ductal-acinar cell carcinoma. The patient was prescribed TS-1 as postoperative adjuvant chemotherapy upon discharge. However, treatment was discontinued 2 months later due to marked general malaise, and the patient succumbed to tumor recurrence in the residual pancreas 12 months after the surgery.

Background/aim: For prostate cancer, positive surgical margins are considered an important predictor of biochemical recurrence. However, biochemical recurrence is observed in approximately 20% of cases, even with negative surgical margins, and some cases require salvage therapy. The elevated expression of low-molecular-weight protein tyrosine phosphatase (LMW-PTP, MW 18 kDa) is associated with a poor prognosis of certain cancers. In this study, we investigated whether the LMW-PTP expression levels could be used as a biomarker of recurrence in prostate cancer with negative surgical margins., Materials and Methods: The subjects of this retrospective study were 119 patients who underwent total prostatectomy with negative resection margins. LMW-PTP expression was categorized either as a high-expression group or as a low-expression group bye two pathologists. Subsequently, we examined the relationship between LMW-PTP expression levels and clinicopathological factors including biochemical recurrence., Results: Evaluation of the immunostained samples by two pathologists was highly reliable, with an Intraclass correlation (ICC) score for two distinct measurements of 0.77 and 0.98, respectively. Seventy-three patients (61.3%) were placed in the LMW-PTP high expression group; and 46 patients (38.7%) were placed in the low expression group. The log-rank test revealed early biochemical recurrence in the high LMW-PTP expression group (p=0.0001). In addition, pathological T stage (p=0.004), lymphatic invasion (p=0.0456), Ki-67 labeling index (p=0.0002), and biochemical recurrence (p<0.0001) were more frequently identified in the LMW-PTP high expression group. Furthermore, multivariate analyses revealed that a high LMW-PTP expression level was an independent prognostic factor for biochemical recurrence (HR=3.14, 95% CI=1.37-8.07, p=0.0057). In addition, Ki-67 labeling indices were significantly higher in the high-expression group compared to the low-expression group (p<0.0001)., Conclusion: LMW-PTP can be assessed using a single immunostaining protocol in a highly reproducible fashion. Tt may, thus, be applied clinically to establish the required postoperative follow-up period and determine the necessity for salvage therapy in cases of prostate cancer with negative surgical margins. LMW-PTP has the potential to be a highly useful prognostic biomarker and a therapeutic target in conjunction with other factors, such as the Gleason Score, the pathological T stage and the PSA level., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Liver is a common location of colorectal metastasis, but intrabiliary growth of liver metastasis is not well recognized. Furthermore, intrabiliary metastasis that discovered over 10 years after excision has rarely been described., Case Presentation: An 80-year-old man was admitted due to the presence of a liver mass in segment 5 (S5) concomitant with elevated carcinoembryonic antigen (CEA), and carbohydrate antigen (CA) 19-9. He underwent right hemicolectomy for colon cancer 12 years prior. Enhanced computed tomography (CT) showed dilated bile ducts with periductal enhancement in S5; hence, cholangiocarcinoma was suspected. Upon anterior segmentectomy, we observed that the cut surface of the specimen exhibited a yellowish-white tumor within the bile ducts. Histologically, the tumor formed within the papillary process, extended along the lumen, and replaced the normal bile duct epithelium. Immunohistochemical studies showed that the liver tumor and primary colon cancer were negative for cytokeratin (CK) 7 and positive for CK20 and Caudal-type homeobox transcription factor 2 (CDX-2). In addition, both tumors showed a same KRAS mutation. We diagnosed the liver tumor as liver metastasis recurrence from colon cancer., Conclusion: Intrabiliary growth type of metastasis (IGM) is difficult to distinguish from cholangiocarcinoma, and sometimes develops long after surgery; thus, careful examination of a patient's history is needed in such cases.

Background: Hermansky-Pudlak syndrome (HPS) is a rare, genetically heterogeneous disorder that manifests oculocutaneous albinism together with bleeding diatheses that reflect a platelet storage pool deficiency. Ten genetic subtypes of this autosomal recessive condition have been described to date. Some patients with Hermansky-Pudlak syndrome type 1, 4, or 6 develop Crohn's-like inflammatory bowel disease at any age including early childhood, but most often in adolescence or young adulthood. Here we report infantile-onset of inflammatory bowel disease in a patient with Hermansky-Pudlak syndrome type 1 who responded to infliximab., Case Presentation: A Japanese boy, the second child of non-consanguineous healthy parents, was born with chalky white skin, silvery-white hair, and gray eyes, representing oculocutaneous albinism. He developed frequent diarrhea and fever accompanied by weight loss at 6 months, and was diagnosed with Crohn's-like inflammatory bowel disease based on the endoscopic finding of longitudinal ulcerations in the colon and the histopathologic finding of nonspecific chronic inflammation without granulomas at the age of 11 months. Treatment with an elemental diet, salazosulfapyridine, and corticosteroids failed to improve clinical or laboratory abnormalities, and the diarrhea became bloody. At 13 months he began treatment with infliximab, which produced marked improvement followed by clinical remission. Endoscopy at 20 months demonstrated healing of the colonic mucosa. At 22 months he is in sustained clinical remission receiving only infliximab. Because albinism with inflammatory bowel disease suggested Hermansky-Pudlak syndrome, we performed genetic screening using next-generation sequencing in a targeted gene panel analysis for primary immunodeficiency disease and/or inflammatory bowel disease. The patient proved to have a compound heterozygous mutation of the HPS1 gene resulting in Hermansky-Pudlak syndrome type 1., Conclusions: We consider this report to be the first account of type 1 Hermansky-Pudlak syndrome with infantile-onset of inflammatory bowel disease. Early administration of infliximab was effective. We recommend next-generation sequencing for patients with very early-onset inflammatory bowel disease suspected to be monogenic.

Biallelic mutations in the neuroblastoma amplified sequence ( NBAS ) gene have been reported to cause two different clinical spectra: short stature with optic nerve atrophy and Pelger-Huët anomaly (SOPH) syndrome and infantile liver failure syndrome 2 (ILFS2). Here, we describe a case of a 3-year-old Japanese boy who presented with fever-triggered recurrent acute liver failure (ALF). The clinical characteristics were considerable elevation of liver enzymes, severe coagulopathy, and acute renal failure. In addition to the liver phenotype, he had short stature and Pelger-Huët anomaly in the peripheral granulocytes. Whole-exome and Sanger sequencing of the patient and his parents revealed that he carried novel compound heterozygous missense mutations in NBAS , c.1018G>C (p.Gly340Arg) and c.2674 G>T (p.Val892Phe). Both mutations affect evolutionarily conserved amino acid residues and are predicted to be highly damaging. Immunoblot analysis of the patient's skin fibroblasts showed a normal NBAS protein level but a reduced protein level of its interaction partner, p31, involved in Golgi-to-endoplasmic reticulum retrograde vesicular trafficking. We recommend NBAS gene analysis in children with unexplained fever-triggered recurrent ALF or liver dysfunction. Early antipyretic therapy may prevent further episodes of ALF., Competing Interests: The authors declare that they have no conflict of interest.

The Cobalt Chromium Everolimus-Eluting Stent (CoCr-EES) Post Marketing Surveillance (PMS) Japan study is a prospective multicenter registry designed to evaluate the safety and efficacy of XIENCE V/PROMUS everolimus-eluting stents in routine clinical practice at 47 centers representative of the clinical environment in Japan. We enrolled 2010 consecutive patients (2649 lesions) who underwent percutaneous coronary intervention using CoCr-EES. Clinical outcomes were evaluated through 5 years. Mean age was 68.8 years, 41.9% had diabetes, 4.9% received hemodialysis. Five-year clinical follow up was available for 1704 (84.8%) patients. Major adverse cardiovascular events (MACE) occurred in 10.7% of patients, including cardiac death (3.8%), myocardial infarction (1.8%), and clinically driven target lesion revascularization (TLR) (6.0%). Beyond 1 year, annual incidence of clinically driven TLR was 0.5-0.8%. Definite or probable stent thrombosis occurred in 9 (0.5%) patients at 5 years. After 1 year, definite stent thrombosis occurred in only 1 patient. Significant predictors for MACE were dialysis (ODDs ratio 4.58, 95% CI 2.75-7.64), prior cardiac intervention (ODDs ratio 2.47, 95% CI 1.75-3.49), total stent length (ODDs ratio 1.01, 95% CI 1.01-1.02), and number of diseased vessels (ODDs ratio 1.66, 95% CI 1.08-2.55). Five-year clinical outcomes from the CoCr-EES PMS Japan study demonstrated a low incidence of clinical events in the daily practice up to 5 years.Clinical Trial Registration Information: https://clinicaltrials.gov/ct2/show/NCT01086228 .

Rice flo2 mutation produces grains showing a reduced amount of storage proteins. Using Nipponbare and the flo2 mutant, we created rice transformants that showed defective production of major allergen proteins RA14 and RA33 (14-16 kDa and 33 kDa allergen proteins, respectively) by RNAi introduction. The knock-down transformant generated using Nipponbare showed greatly reduced accumulation of both allergen proteins, normal growth, and production of a sufficient amount of normal-shaped seeds. F 1 seeds were obtained by crossing between the transformants containing RNAi genes to RA14 and RA33, and showed decreased accumulation of both proteins. However, a peculiar phenotype was observed in the flo2 transformants that lacked accumulation of RA14 or RA33. They showed significantly reduced fertility. A wrinkled grain feature was found on the transformant lacking accumulation of RA14. F 1 seeds obtained by crossing these transformants showed significantly lower fertility. F 2 seeds showed decreases in both allergen proteins but morphological abnormality with small and severely wrinkled features. These results indicated that it is hard to obtain any transformant lacking accumulation of these allergen proteins using the flo2 mutant, whereas a knock-down transformant of both allergen protein genes was obtained when a wild-type Nipponbare was used as a host. These facts strongly suggest that RA14 and RA33 have some roles in rice seeds., (© 2019 The Japanese Society for Plant Cell and Molecular Biology.)

We report a case of endocrine cell carcinoma (ECC) of the esophagus with long term survival after chemoradiotherapy. The patient had a complete response and remains without any recurrence. A 69-year-old woman visited our hospital because of progressive dysphagia. The patient was diagnosed by computed tomography and histology examination of biopsy specimens with small cell ECC of the esophagus, cT2N1M0, cStage II based on the Classification of Esophageal Carcinoma. She was treated with chemoradiotherapy comprising 45Gy of irradiation and four courses of cisplatin and etoposide chemotherapy. After completion of the treatment, she was found to have a complete response. She remains alive to date without evidence of any recurrence after 7 years. This case suggests that chemoradiotherapy is an effective treatment for ECC of the esophagus.

Transcription activator-like effector nuclease (TALEN) is an artificial nuclease that causes DNA cleavage at the target site and induces few off-target reactions because of its high sequence specificity. Powerful and variable tools using TALENs can be used in practical applications and may facilitate the molecular breeding of many plant species. We have developed a convenient construction system for a plant TALEN vector named the Emerald Gateway TALEN system. In this study, we added new properties to this system, which led to an increase in the efficiency of targeted mutagenesis. Rice dMac3 is a translational enhancer that highly increases the efficiency of translation of the downstream ORF. We inserted dMac3 into the 5' untranslated region of the TALEN gene. In the cultured rice cells to which the TALEN gene was introduced, the frequency of targeted mutagenesis was highly increased compared with those altered using the conventional system. Next, the promoter for the TALEN gene was replaced with iPromoter, and its expression was stringently controlled by a GVG transcription factor that was activated in the presence of glucocorticoid. This conditional expression system worked effectively and led to a higher frequency of targeted mutagenesis than that by the constitutive expression system, while no mutagenesis was detected without glucocorticoid treatment. These results suggest that our system can be applied to genome editing to create the desired mutation., Competing Interests: This study was partly supported by a grant within the scope of Bayer Crop Science’s initiative "Grants4Traits - Novel solutions to increase crop productivity" to HS. This does not alter our adherence to PLOS ONE policies on sharing data and materials. All other authors declare that no competing interests exist.

Aim: We examined the programmed death-ligand 1 (PD-L1) expression in surgically resected pancreatic adenosquamous carcinoma (PASC) samples. Furthermore, the detection rate was also assessed using biopsy cases obtained from endoscopic ultrasound-guided fine needle aspiration (EUS-FNA)., Methods: Fifteen cases of PASC (six resected and nine EUS-FNA biopsied) from the Kurume University Hospital between 2009 and 2016 were used for the evaluation of PD-L1 expression. As a control group, 34 cases of pancreatic ductal adenocarcinomas (PDACs) were selected. To compare　the positivity and intensity of PD-L1, two types of clones (SP263, E1L3N) were examined for immunostaining. Only the membrane expression of PD-L1 was regarded as positive. The PD-L1 expressions in the squamous cell carcinoma component (SCc), adenocarcinoma component (ACc), and immune cells were assessed separately. The ratio of PD-L1 expression was calculated by counting the positive tumor cells, and tumor proportion score (TPS) was applied (TPS; Null < 1%, low expression; 1 ≤ TPS ≤ 49% and high expression; ≥ 50%)., Results: PD-L1 expression was observed in five surgical PASC samples (83%). This shows that SCc presented a high expression in these cases. However, the overall TPS indicated a low expression. In contrast, only one case (3%) was positive for PD-L1 in PDACs, and the TPS indicated a low expression. No differences in PD-L1 expression were observed between the two clones, SP263 and E1L3N. High PD-L1 expression in the EUS-FNA sample was found in only one case (11%)., Discussion: Although assessment using the tumor cells of PASC samples obtained from EUS-FNA was difficult, this study suggests the selective expression of PD-L1 in the SCc of PASC. Furthermore, it was considered that immune checkpoint inhibitors could provide therapeutic effects selectively on the SCc for the entire range of TPSs, though the PD-L1 expression was low., (Copyright © 2018 Elsevier GmbH. All rights reserved.)

Dihydrosphingosine C4 hydroxylase (DSH), a diiron-binding membrane enzyme, catalyzes the hydration of dihydrosphingosine and acyl-sphinganine to produce phytosphingosine and phytoceramide, respectively. Rice has two types of DSH homologs: general DSHs, namely DSH1, DSH2 and DSH4, and others that show spatial expression profiles, namely DSH3 and DSH5. The general DSHs exist in many plant species. These DSHs showed similarity in their functions and complemented the yeast sur2D mutation. In contrast, homologs of DSH3 and DSH5 were found only in monocot plants. Phylogenetic analysis placed these DSHs in different clades that are evolutionarily divergent from those of the general DSHs. DSH3 and DSH5 showed low-level expression. DSH5 expression was specifically in vascular bundle tissues. Ectopic expression of DSH5 induced a dwarf phenotype characterized by severe growth inhibition and an increase in the thickness of the leaf body caused by enlargement of bulliform cells in the leaves. However, no significant difference was observed in the amount of sphingolipid species. DSH5 did not complement the yeast sur2D mutation, implying that DSH5 has little effect on sphingolipid metabolism. These findings suggested that DSH3 and DSH5 originated and diverged in monocot plants.

Aim: Spleen stiffness is increased in liver cirrhosis (LC). We attempted to characterize the pathological features of spleen in LC., Methods: We compared pathological findings of resected spleen tissues of 28 LC patients and those of six healthy controls. In addition, we measured spleen stiffness before splenectomy by shear wave elastography in nine LC patients. After splenectomy, we examined the relationship between spleen stiffness and pathological findings., Results: Passive congestion of the spleen was more frequently observed in LC patients than in controls (P < 0.01). The sinus was wider in LC patients than in controls (P < 0.01). In the spleens of the LC patients, diffuse α-smooth muscle actin (αSMA) expression of sinusoidal mesenchymal cells and deposition of collagen fibers on the perisinusoidal wall were observed. In nine LC patients whose spleen stiffness was examined, the width of the sinus increased along with spleen stiffness (r = 0.89, P < 0.01). Spleen stiffness was higher in the spleen tissues with diffuse αSMA expression of sinusoidal mesenchymal cells than in those with partial αSMA expression of sinusoidal mesenchymal cells (P = 0.01). The degree of fibrosis was higher in the LC patients with diffuse αSMA expression of the red pulp than in those with partial αSMA expression of the red pulp (P = 0.03)., Conclusion: In the LC patients, spleen tissues showed passive congestion with a dilated sinus, diffuse αSMA expression of sinusoidal mesenchymal cells, and deposition of collagen fibers on the perisinusoidal wall. This contributed to spleen stiffness., (© 2018 The Japan Society of Hepatology.)

Aims: Blooming artefacts limit accurate coronary assessment by multislice computed tomography (MSCT) in metallic stents. We sought to investigate whether bioresorbable vascular scaffolds (BVS) could be better assessed by MSCT., Methods and Results: Among 400 patients in the randomised ABSORB Japan trial, a pre-specified MSCT substudy was performed in 98 patients (103 lesions) in the BVS arm and 49 patients (49 lesions) in the cobalt-chromium everolimus-eluting stent (CoCr-EES) arm at 13 months prior to follow-up angiography. The assessability of BVS by MSCT was superior to that of CoCr-EES (94% versus 67%, p<0.001). Blooming artefacts were the main reason CoCr-EES could not be analysed (29%), while marker artefacts precluded analysis in 1.1% of BVS. In the CoCr-EES arm, non-assessable lesions were more prevalent in segments with 2.5 mm stents compared to 3.0 or 3.5 mm stents (75.0% versus 23.5%, p=0.01), while in the BVS arm image quality was good regardless of the diameter. The in-device minimal lumen diameter by MSCT was smaller than that by QCA with a difference of 0.61 mm in the CoCr-EES arm, vs. only 0.026 mm in the BVS arm., Conclusions: The feasibility of MSCT assessment of BVS-treated lesions was greater than that for lesions with CoCr-EES.

Coronary calcification (CCA) is one of the independent predictors for major adverse cardiac events (MACEs) in coronary intervention. Post-marketing surveillance study Japan is a prospective registry designed to evaluate the safety and efficacy of the everolimus-eluting stent (EES, XIENCE V/PROMUS Stent) in routine clinical practice at 47 centers. In this study, 1848 lesions (1546 patients) were assessed using quantitative coronary angiography. In these 1546 patients, renal function data were unknown in 26 patients. Three patients in 70 patients with dialysis and 56 patients in 1450 patients with no dialysis were excluded, because they had multiple lesions with mixed calcification lesions. We evaluated the effects of CCA on 8-month angiographic and 3-year clinical outcomes in dialysis and non-dialysis patients. Moderate-to-severe (Ca group) and none-to-mild CCA (non-Ca group) were observed in 33 lesions (30 patients) and 48 lesions (37 patients) in dialysis patients, and these were observed in 306 lesions (286 patients) and 1303 lesions (1108 patients) in non-dialysis patients, respectively. In non-dialysis patients, the ischemic-driven target lesion revascularization (ID-TLR) and MACE rate over the 3 years were significantly higher in the Ca group than in the non-Ca group (5.8 vs. 3.1%, p = 0.025 and 10.0 vs. 5.0%, p = 0.0011). In dialysis patients, ID-TLR and MACE rates were high in both groups (14.3 vs. 17.9%, p = 0.85 and 17.5 vs. 36.1%, p = 0.16). In non-dialysis patients, 8-month angiographic and 3-year clinical outcomes were worse in the Ca group. However, in dialysis patients, both outcomes were worse regardless of CCA.Clinical Trial registration https://clinicaltrials.gov/ct2/show/NCT01086228 .

CRISPR/Cas9 is a programmable nuclease composed of the Cas9 protein and a guide RNA (gRNA) molecule. To create a mutant potato, a powerful genome-editing system was required because potato has a tetraploid genome. The translational enhancer dMac3, consisting of a portion of the OsMac3 mRNA 5'-untranslated region, greatly enhanced the production of the protein encoded in the downstream ORF. To enrich the amount of Cas9, we applied the dMac3 translational enhancer to the Cas9 expression system with multiple gRNA genes. CRISPR/Cas9 systems targeting the potato granule-bound starch synthase I (GBSSI) gene examined the frequency of mutant alleles in transgenic potato plants. The efficiency of the targeted mutagenesis strongly increased when the dMac3-installed Cas9 was used. In this case, the ratio of transformants containing four mutant alleles reached approximately 25% when estimated by CAPS analysis. The mutants that exhibited targeted mutagenesis in the GBSSI gene showed characteristics of low amylose starch in their tubers. This result suggests that our system may facilitate genome-editing events in polyploid plants.

The structure-activity relationship (SAR) for a novel series of catechol conjugated siderophore cephalosporins is described with their in vitro activities against multi-drug resistant Gram-negative pathogens including Pseudomonas aeruginosa, Acinetobacter baumannii, Stenotrophomonas maltophilia and Enterobacteriaceae. Cefiderocol (3) was one of the best molecules which displayed well-balanced and potent activities against multi-drug resistant Gram-negative pathogens including carbapenem resistant bacteria among the prepared compounds with the modified C-7 side chain and the modified C-3 side chain. Cefiderocol (3) is a highly promising parenteral cephalosporin for the treatment of multi-drug resistant Gram-negative infection., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)