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An enantioselective aldol reaction of aryl methyl ketones with aryl trifluoromethyl ketones catalyzed by tertiary amino thiourea has been established. Under mild conditions, the corresponding β-trifluoromethyl-β-hydroxy ketone products were obtained with up to 89% ee.

T–lymphokine-activated killer cell–originated protein kinase (TOPK) and maternal embryonic leucine zipper kinase (MELK) have been reported to play critical roles in cancer cell proliferation and maintenance of stemness. In this study, we investigated possible roles of TOPK and MELK in kidney cancer cells and found their growth promotive effect as well as some feedback mechanism between these two molecules. Interestingly, the blockade of either of these two kinases effectively caused downregulation of forkhead box protein M1 (FOXM1) activity which is known as an oncogenic transcriptional factor in various types of cancer cells. Small molecular compound inhibitors against TOPK (OTS514) and MELK (OTS167) effectively suppressed the kidney cancer cell growth, and the combination of these two compounds additively worked and showed the very strong growth suppressive effect on kidney cancer cells. Collectively, our results suggest that both TOPK and MELK are promising molecular targets for kidney cancer treatment and that dual blockade of OTS514 and OTS167 may bring additive anti-tumor effects with low risk of side effects.

// Suyoun Chung 1 , Kyoko Kijima 1 , Aiko Kudo 1 , Yoshiko Fujisawa 1 , Yosuke Harada 1 , Akiko Taira 1 , Naofumi Takamatsu 1 , Takashi Miyamoto 1 , Yo Matsuo 1 and Yusuke Nakamura 2 1 OncoTherapy Science, Inc., Kawasaki, Kanagawa, Japan 2 Department of Medicine and Surgery, The University of Chicago, Chicago, IL, USA Correspondence to: Yusuke Nakamura, email: // Keywords : MELK, xenograft model, kinase inhibitor, molecular pharmacology, biomarker Received : December 22, 2015 Accepted : February 08, 2016 Published : February 24, 2016 Abstract MELK is upregulated in various types of human cancer and is known to be associated with cancer progression, maintenance of stemness, and poor prognosis. OTS167, a MELK kinase inhibitor, shows potent growth-suppressive effect on human tumors in a xenograft model, but the detailed mode of action has not been fully elucidated. In this study, we demonstrate the molecular mechanism of action of MELK inhibitor OTS167 in a preclinical model. OTS167-treated cells caused morphological transformation, induced the differentiation markers, and reduced stem-cell marker expression. Furthermore, we identified DEPDC1, known as an oncogene, as an additional downstream molecule of the MELK signaling pathway. MELK enhanced DEPDC1 phosphorylation and its stability. The expression of MELK and downstream molecules was decreased in OTS167-treated xenograft tumor tissues, which revealed central necrosis and significant growth suppression. Our data should further shed light on the mechanism of action how OTS167 suppresses tumor growth through the inhibition of the MELK signaling pathway and suggest the possibility of biomarkers for the assessment of clinical efficacy.

Diverse lines of evidence suggest that amyloid-β (Aβ) peptides causally contribute to the pathogenesis of Alzheimer disease (AD), the most frequent neurodegenerative disorder. However, the mechanisms by which Aβ impairs neuronal functions remain to be fully elucidated. Previous studies showed that soluble Aβ oligomers interfere with synaptic functions by depleting NMDA-type glutamate receptors (NMDARs) from the neuronal surface and that overexpression of the receptor tyrosine kinase EphB2 can counteract this process. Through pharmacological treatments and biochemical analyses of primary neuronal cultures expressing wild-type or mutant forms of EphB2, we demonstrate that this protective effect of EphB2 depends on its PDZ-binding motif and the presence of neuronal activity but not on its kinase activity. We further present evidence that the protective effect of EphB2 may be mediated by the AMPA-type glutamate receptor subunit GluA2, which can become associated with the PDZ-binding motif of EphB2 through PDZ domain-containing proteins and can promote the retention of NMDARs in the membrane. In addition, we show that the Aβ-induced depletion of surface NMDARs does not depend on several factors that have been implicated in the pathogenesis of Aβ-induced neuronal dysfunction, including aberrant neuronal activity, tau, prion protein (PrP(C)), and EphB2 itself. Thus, although EphB2 does not appear to be directly involved in the Aβ-induced depletion of NMDARs, increasing its expression may counteract this pathogenic process through a neuronal activity- and PDZ-dependent regulation of AMPA-type glutamate receptors.

Our previous study has shown that plasminogen activator inhibitor 1 (PAI-1) gene expression and secretion from bone marrow adipocytes increased markedly with dexamethasone administration. The purpose of the present study was to measure the secretion of various adipokines from human bone marrow and blood, and investigate how adipokine secretion changes in a steroid environment. Human blood and bone marrow fluid were collected from a steroid treatment group and a control group during hip replacement surgery, and an enzyme-linked immunosorbent assay (ELISA) was used to measure the adiponectin, leptin, and PAI-1 levels. Adiponectin and leptin showed no significant differences between bone marrow and blood levels, but PAI-1 was significantly higher in bone marrow. The steroid treatment group had higher levels of leptin and PAI-1 in both the blood and bone marrow than the control group. PAI-1 was present at high concentrations in the bone marrow and increased by steroid treatment. High levels of PAI-1 in bone marrow may influence intraosseous hemodynamics and may induce necrotic bone disorders.

Left pulmonary artery sling (LPAS) is a rare vascular anomaly. The left pulmonary artery arises distally from the right pulmonary artery on the right side of the trachea and passes between the trachea and esophagus towards the left lung, compressing the lower trachea. LPAS is associated with congenital tracheal stenosis, which frequently requires early surgical intervention and has a poor prognosis due to severe airway obstruction after birth. Therefore, LPAS should be prenatally diagnosed to prepare for surgical intervention for tracheal stenosis. To the best of our knowledge, there are few reports on prenatal echocardiographic findings in LPAS. We report three prenatal cases of LPAS, which resulted in respiratory symptoms. We discuss fetal ultrasound findings and highlight the abnormal rotation of the fetal cardiac axis to the right as a useful sign in the prenatal screening of LPAS.

644 Background: The radiographic diagnosis of tumor infiltration into the periarterial plexus in pancreatic cancer is important because it is related to the classification, however, it is difficult to distinguish the abnormal shadow along the artery caused by inflammation or cancer infiltration. The aim of this study is to investigate CT values of the abnormal shadow along artery could distinguish between inflammation and tumor invasion. Methods: Study 1: Of 26 patients who underwent DP-CAR between 2009 and 2018, we analyzed 19 patients who had dynamic CT and obtained sagittal slice taken 120 seconds after injection with less than 2.5 mm slice thickness. At first, we measured CT values at upper and lower point of CeA and CHA each sagittal slice using CT. Next, we evaluated tumor invasion at the upper and lower plexus of CeA and CHA in each section of the pathological specimen, and evaluated the relationship between the tumor invasion and the CT value. Study 2: Using these 19 patients and 40 patients who underwent DP for PDAC between 2010 and 2014, we analyzed the relation between CT value and long-term states. Results: Study 1: CT value was totally measured at the 606 points using 19 patients who underwent DP-CAR. At the 490 points, we did not observe cancer infiltration and fibrosis. At the 70 points, we observed fibrosis without cancer cells. At the 46 points, we observed cancer infiltration. CT value was significantly higher in the tumor infiltration group than that in the without cancer infiltration and fibrosis group (P < 0.01). Study 2: The best cut-off of CT value of the presence of cancer infiltration was 44.9 HU using ROC curve (AUC = 0.861). The median survival time of patients who had the points of CT value > 44.9 HU around arteries was significantly shorter than that of patients who did not have the points of CT value > 44.9 HU (2.17 vs. 4.55 years, p = 0.03). Conclusions: The CT value around the arteries was significantly higher in the points of pathological tumor infiltration than that in the points of fibrosis without cancer cells. The best cut-off CT value of the presence of cancer infiltration around arteries was 44.9 HU, and the presence of the point of CT value > 44.9 HU around arteries was associated with poor survival.

Summary In this case-control study, we concluded that women with distal radial fractures who were surgically treated showed lower grip strength and dynamic body balancing than those of controls. These results suggest that measurements of grip strength and dynamic body balance may be useful screening tools to assess future fracture risk. Introduction Patients with distal radial fractures (DRFs) are at risk of future fragility fractures. However, their physical characteristics and tendencies for falls remain unclear. We aimed to compare the physical characteristics of women with and without distal radial fractures. Methods We included 128 women with a DRF as their first fragility fracture (fracture group) who underwent surgical treatment. Concurrently, 128 age- and sex-matched participants without a history of fragility fractures were selected as controls (control group). The participants underwent assessments of grip strength and the body balancing ability test. Measurements were taken twice in the fracture group, at 2 weeks and 6 months postoperatively, and once in the control group. The body balancing ability test included the Functional Reach Test, Timed Up and Go test (TUG), 2-Step test (2ST), and Timed Uni-pedal Stance test. The participants also completed questionnaires about their health. Results There were no significant differences (p > 0.05) in patient characteristics between the groups. The fracture group showed lower grip strength across all age groups. In the DRF group, prolonged TUG time was observed at 2 weeks postoperatively in all age groups and at 6 months in participants aged 55–74 years; the 2ST score was significantly lower in participants aged between 65 and 74 years. Conclusions Women with DRF demonstrated lower grip strength and dynamic body balancing ability. Lower grip strength and dynamic body balancing ability were identified as significant risk factors in women with DRF, suggesting that these may be useful screening tools to assess fracture risk. Electronic supplementary material The online version of this article (10.1007/s00198-018-04816-4) contains supplementary material, which is available to authorized users.

Background: The volar locking plate is frequently used in the fixation of unstable distal radius fractures, but despite this there is a paucity of mid to long term outcome studies. The purpose of this study was to investigate the mid-term functional outcomes of elderly patients treated with a volar locking plate for unstable distal radius fractures. Methods: Thirty-two patients with a mean age of 74.1 (range, 65–85) years were followed for a mean of 39.1 (range, 30–81) months. Patients with follow-up periods of < 24 months were excluded from this study to investigate the mid-term clinical outcomes. The Mayo wrist score (MWS), grip strength and wrist range of motion were retrospectively reviewed at 12 months, 24 months and the latest follow-up (mean 39.1 months). Osteoarthritis status according to the system of Knirk and Jupiter was assessed at 24 months. Results: Significant improvements in MWS and grip strength were observed between 12 and 24 months but not between 24 months and the final follow-up. There was no significant difference in wrist range of motion between 12 and 24 months. The MWS of 14 patients with radiographic signs of osteoarthritis was not significantly different from that of 18 patients without radiographic signs of osteoarthritis. Conclusions: Elderly patients treated with the volar locking plate showed improved MWS and grip strength postoperatively after 12 months. Improvement in grip strength was slower than range of motion.

Case We report a rare case of complete rupture of the right femoral nerve at the pelvic level, which was caused by a self-inflicted stab wound. The nerve was surgically reconstructed with use of an autologous sural nerve cable graft. Postoperatively, the patient's sensorimotor function returned to near normal. Conclusion Femoral nerve rupture caused by a laceration is very unusual. A bilateral sural nerve cable graft performed in collaboration with surgeons from other specialties achieved a good outcome in this otherwise healthy young patient.

Background Although conventional Bankart repair has been the accepted procedure for traumatic anterior glenohumeral instability, the humeral avulsion of the glenohumeral ligament or an elongation of the capsule remains challenging to decide the appropriate treatment. The anatomical knowledge regarding the whole capsule of glenohumeral joint is necessary to accurately treat for the capsular disorders. The aims of the current study were to investigate the anatomical features of capsular attachment and thickness in a whole capsule of glenohumeral joint. Methods We used 13 shoulders in the current study. In 9 shoulders, we macroscopically measured the attachment widths of the capsulolabrum complex on the scapular glenoid, and the attachment widths of the capsule on the humerus in reference to the scapular origin of the long head of triceps brachii, and the humeral insertion of the rotator cuff tendons. We additionally used 4 cadaveric shoulders, which were embalmed using Thiel’s method, for the analysis of the thickness in a whole capsule by using micro-CT. Results The glenoidal attachment of the articular capsule appeared to have a consistent width except for the superior part of the origin of the long head of triceps brachii. On the humerus, the articular capsule was widely attached to areas without overlying rotator cuffs, with the widest width (17.3 ± 0.9 mm) attached to the axillary pouch. The inferior part of the capsule, which was consistently thicker than the superior part, continued to the superior part along the glenoid and humeral side edge. Conclusions The current study showed that the inferior part of the glenohumeral capsule had a wide humeral attachment from the inferior edge of the subscapularis insertion to the inferior edge of the teres minor insertion via the anatomical neck of the humerus, and the thickness of it was thicker than the superior part of the capsule.

Gain-of-function mutations of FLT3 (FLT3-ITD), comprises up to 30% of normal karyotype acute myeloid leukemia (AML) and is associated with an adverse prognosis. Current FLT3 kinase inhibitors have been tested extensively, but have not yet resulted in a survival benefit and novel therapies are awaited. Here we show that T-LAK cell-originated protein kinase (TOPK), a mitotic kinase highly expressed in and correlated with more aggressive phenotype in several types of cancer, is expressed in AML but not in normal CD34+ cells and that TOPK knockdown decreased cell viability and induced apoptosis. Treatment of AML cells with TOPK inhibitor (OTS514) resulted in a dose-dependent decrease in cell viability with lower IC50 in FLT3-mutated cells, including blasts obtained from patients relapsed after FLT3-inhibitor treatment. Using a MV4-11-engrafted mouse model, we found that mice treated with 7.5 mg/kg IV daily for 3 weeks survived significantly longer than vehicle treated mice (median survival 46 vs 29 days, P < 0.001). Importantly, we identified TOPK as a FLT3-ITD and CEBPA regulated kinase, and that modulating TOPK expression or activity resulted in significant decrease of FLT3 expression and CEBPA phosphorylation. Thus, targeting TOPK in FLT3-ITD AML represents a novel therapeutic approach for this adverse risk subset of AML.

The cost-effectiveness according to primary disease or dialysis duration has never been analyzed with respect to maintenance hemodialysis (MHD). Study candidates were > 20 years of age and had received hemodialysis for at least 6 months. Hemodialysis patients were prospectively observed for 36 months, and patient utility was assessed based on the Euro-QOL 5-dimensions (EQ-5D), from which the quality adjusted life years (QALYs) were estimated. Medical costs were calculated based on medical service fees. The cost-effectiveness defined as the incremental cost utility ratio (ICUR) was analyzed from a social perspective. A total of 29 patients (mean age; 59.9 ± 13.1 years) undergoing 437 dialysis sessions were analyzed. Utility based upon the EQ-5D score was 0.75 ± 0.21, and the estimated total medical cost for one year of MHD treatment was 4.52 ± 0.88 US$10 000. ICUR was 6.88 ± 4.47 US$10 000/QALY on average, and when comparing ICUR based on the causes of kidney failure, the value for diabetic nephropathy was found to be higher than that for glomerulonephritis (8.17 ± 6.28 vs. 6.82 ± 4.07). ICUR after 36 months observation increased mainly in the patients below 65 years of age (All; P

We investigated biofilm formation and time of vancomycin (VCM) resistance expression after adhesion to a metal surface inStaphylococcus epidermidis. Biofilm-formingStaphylococcus epidermidiswith a VCM MIC of 1 μg/mL was used. The bacteria were made to adhere to a stainless steel washer and treated with VCM at different times and concentrations. VCM was administered 0, 2, 4, and 8 hours after adhesion. The amount of biofilm formed was evaluated based on the biofilm coverage rates (BCRs) before and after VCM administration, bacterial viability in biofilm was visually observed using the fluorescence staining method, and the viable bacterial count in biofilm was measured. The VCM concentration required to decrease BCR significantly compared with that of VCM-untreated bacteria was 4 μg/mL, even in the 0 hr group. In the 4 and 8 hr groups, VCM could not inhibit biofilm growth even at 1,024 μg/mL. In the 8 hr group, viable bacteria remained in biofilm at a count of 104CFU even at a high VCM concentration (1,024 μg/mL). It was suggested that biofilm-formingStaphylococcus epidermidisexpresses resistance to VCM early after adhesion to a metal surface. Resistance increased over time after adhesion as the biofilm formed, and strong resistance was expressed 4–8 hours after adhesion.

Tau ablation, knockdown, and reconstitution studies in primary mouse neurons show that tau enables amyloid β oligomers to inhibit axonal transport through activation of GSK3β and through functions of tau that do not depend on its microtubule binding activity., Axonal transport deficits in Alzheimer’s disease (AD) are attributed to amyloid β (Aβ) peptides and pathological forms of the microtubule-associated protein tau. Genetic ablation of tau prevents neuronal overexcitation and axonal transport deficits caused by recombinant Aβ oligomers. Relevance of these findings to naturally secreted Aβ and mechanisms underlying tau’s enabling effect are unknown. Here we demonstrate deficits in anterograde axonal transport of mitochondria in primary neurons from transgenic mice expressing familial AD-linked forms of human amyloid precursor protein. We show that these deficits depend on Aβ1–42 production and are prevented by tau reduction. The copathogenic effect of tau did not depend on its microtubule binding, interactions with Fyn, or potential role in neuronal development. Inhibition of neuronal activity, N-methyl-d-aspartate receptor function, or glycogen synthase kinase 3β (GSK3β) activity or expression also abolished Aβ-induced transport deficits. Tau ablation prevented Aβ-induced GSK3β activation. Thus, tau allows Aβ oligomers to inhibit axonal transport through activation of GSK3β, possibly by facilitating aberrant neuronal activity.

A 12-month-old boy weighing 5.2 kg underwent surgical repair for a ventricular septal defect (VSD) combined with airway obstruction resulting from pectus excavatum. His right atrium and left main bronchus were extremely compressed by the sternum. To repair the VSD, we performed a sternal closure for pectus excavatum that used a mesh-shaped bioresorbable device (Super Fixsorb MX40; Takiron Co, Ltd, Osaka, Japan) made of hydroxyapatite/poly-L-lactide composites. After the operation, the cardiac and tracheal compression caused by the sternum was alleviated.

Of the five human senses, vision is said to account for 80% of the information acquired. The presentation of light is an effective way to convey visual information. A blinking presentation especially attracts attention. A low-vision person acquires peripheral information through residual vision. In this case, light effectively supports the travel of low-vision persons. A blinking light stimulates more than a continuous light. However, a blinking light is not sufficiently compatible with the surrounding environment. This research investigates an environmentally friendly blinking pattern to arouse attention.

Background Hyperexcitability of neuronal networks can lead to excessive release of the excitatory neurotransmitter glutamate, which in turn can cause neuronal damage by overactivating NMDA-type glutamate receptors and related signaling pathways. This process (excitotoxicity) has been implicated in the pathogenesis of many neurological conditions, ranging from childhood epilepsies to stroke and neurodegenerative disorders such as Alzheimer’s disease (AD). Reducing neuronal levels of the microtubule-associated protein tau counteracts network hyperexcitability of diverse causes, but whether this strategy can also diminish downstream excitotoxicity is less clear. Methods We established a cell-based assay to quantify excitotoxicity in primary cultures of mouse hippocampal neurons and investigated the role of tau in exicitotoxicity by modulating neuronal tau expression through genetic ablation or transduction with lentiviral vectors expressing anti-tau shRNA or constructs encoding wildtype versus mutant mouse tau. Results We demonstrate that shRNA-mediated knockdown of tau reduces glutamate-induced, NMDA receptor-dependent Ca2+ influx and neurotoxicity in neurons from wildtype mice. Conversely, expression of wildtype mouse tau enhances Ca2+ influx and excitotoxicity in tau-deficient (Mapt −/−) neurons. Reconstituting tau expression in Mapt −/− neurons with mutant forms of tau reveals that the tau-related enhancement of Ca2+ influx and excitotoxicity depend on the phosphorylation of tau at tyrosine 18 (pY18), which is mediated by the tyrosine kinase Fyn. These effects are most evident at pathologically elevated concentrations of glutamate, do not involve GluN2B–containing NMDA receptors, and do not require binding of Fyn to tau’s major interacting PxxP motif or of tau to microtubules. Conclusions Although tau has been implicated in diverse neurological diseases, its most pathogenic forms remain to be defined. Our study suggests that reducing the formation or level of pY18-tau can counteract excitotoxicity by diminishing NMDA receptor-dependent Ca2+ influx. Electronic supplementary material The online version of this article (doi:10.1186/s13024-017-0176-x) contains supplementary material, which is available to authorized users.

Objectives: We evaluated the efficacy of balloon dilatation after bilateral pulmonary artery banding for the treatment of severe congenital heart disease that depends on patent ductus arteriosus for systemic circulation. Background: Neonatal cardiopulmonary bypass can cause brain injury, which may result in a severely impaired neurodevelopmental outcome. Hence, we perform bilateral pulmonary artery banding combined with postoperative percutaneous trans catheter angioplasty with balloon dilatation as first-stage palliation. Methods: From October 2007 to December 2013, 27 consecutive patients underwent bilateral pulmonary artery banding at our institution. We retrospectively obtained their diagnostic, clinical, and catheter examination data from the medical records. Results: Bilateral pulmonary artery banding was performed at a median of 7 days. Among the 27 patients, 16 underwent expansive angioplasty using a balloon catheter at each banding site to increase pulmonary blood flow. The mean age at dilatation was 53.4 ± 25.9 days, and the mean pulmonary artery index significantly increased from 130.6 mm2/m2 ± 51.1 mm2/m2 before dilatation to 243.6 mm2/ m2 ± 93.5 mm2/m2 after dilatation (p

How we sense touch remains fundamentally unknown. The Merkel cell-neurite complex is a gentle touch receptor in the skin that mediates slowly adapting responses of Aβ sensory fibres to encode fine details of objects. This mechanoreceptor complex was recognized to have an essential role in sensing gentle touch nearly 50 years ago. However, whether Merkel cells or afferent fibres themselves sense mechanical force is still debated, and the molecular mechanism of mechanotransduction is unknown. Synapse-like junctions are observed between Merkel cells and associated afferents, and yet it is unclear whether Merkel cells are inherently mechanosensitive or whether they can rapidly transmit such information to the neighbouring nerve. Here we show that Merkel cells produce touch-sensitive currents in vitro. Piezo2, a mechanically activated cation channel, is expressed in Merkel cells. We engineered mice deficient in Piezo2 in the skin, but not in sensory neurons, and show that Merkel-cell mechanosensitivity completely depends on Piezo2. In these mice, slowly adapting responses in vivo mediated by the Merkel cell-neurite complex show reduced static firing rates, and moreover, the mice display moderately decreased behavioural responses to gentle touch. Our results indicate that Piezo2 is the Merkel-cell mechanotransduction channel and provide the first line of evidence that Piezo channels have a physiological role in mechanosensation in mammals. Furthermore, our data present evidence for a two-receptor-site model, in which both Merkel cells and innervating afferents act together as mechanosensors. The two-receptor system could provide this mechanoreceptor complex with a tuning mechanism to achieve highly sophisticated responses to a given mechanical stimulus.

Background: Although the effects of the trauma center(TC) were researched in several studies, there have been few studies on changes in the regional mortality due to the implementation of a TC.An emergency medical center (EMC) and TC were implemented at Nagasaki University Hospital (NUH) for the first time in the Nagasaki medical region of Japan in April 2010 and October 2011, respectively, and they have cooperated with each other in treating trauma patients. The purpose of this study was to investigate the effects on the early mortality at population level of a TC working in cooperation with an EMC. Methods: This is a retrospective study using standardized regional data (ambulance service record) in Nagasaki medical region from April 2007 through March 2017. We included 19,045 trauma patients directly transported from the scene. The outcome measures were prognosis for one week. To examine the association between the implementation of the EMC and TC and mortality at a region, we fit adjusted logistic regression models. Results: The number of patients of each fiscal year increased from 1492 in 2007 to 2101 in 2016.The number of all patients transported to NUH decreased until 2009 to 70, but increased after implementation of the EMC and TC. Overall mortality of all patients in the region improved from 2.3% in 2007 to 1.0% in 2016.In multivariate logistic regression model, odds ratio of death was significantly smaller at 2013 and thereafter if the data from 2007 to 2011 was taken as reference. Conclusions: Implementation of the EMC and TC was associated with early mortality in trauma patients directly transported from the scene by ambulance. Our analysis suggested that the implementation of EMC and TC contributed to the improvement of the early mortality at a regional city with 500000 populations. Level of evidence: Level III., Trauma Surgery and Acute Care Open, 4(1), art.no.e00029; 2019

The article Lower grip strength and dynamic body balance in women with distal radial fractures, written by. K. Fujita, H. Kaburagi, A. Nimura, T. Miyamoto, Y. Wakabayashi, Y. Seki, H. Aoyama, H. Shimura, R. Kato, A. Okawa was originally published electronically on the publisher's internet portal.

Purpose – The purpose of this study is to compare revenue guarantee programs in a build-operation-transfer project (BOT). Two types of revenue guarantee programs are formulated: a payment-based annual revenue guarantee program and a period-extension-based cumulative revenue guarantee program. Design/methodology/approach – Monte Carlo simulation is used to model the real option approach. This method is applied to a toll road project in the Philippines wherein the expected payoffs of the government and the concessionaire are simulated over an evaluation period that includes the concession period. The condition under which the expected government return in one program is equal to that in the other program is shown. These programs are then evaluated by incorporating a project risk factor into the project return. Findings – The results show that the cumulative revenue guarantee program is preferred to the annual revenue guarantee program. However, the optimal solution depends on the government's return-risk preference. Research limitations/implications – The simulation was implemented with limited cases of discrete input with respect to the cost-sharing parameter, the annual guarantee rate, and the guaranteed cumulative revenue. A simulation with more input values should be performed to achieve results that are more general and sophisticated. Practical implications – It is indicated that the simple reduction of risk does not necessarily mean that government expected payoff will increase. Originality/value – It is expected that this method contributes to the proper decisions made by the governments with respect to the choice of a revenue guarantee mechanism in BOT projects.

Here, we describe a case of total anomalous pulmonary venous return with coarctation of the aorta that was diagnosed as pulmonary alveolar proteinosis at autopsy in a male infant. Surgical repair was performed at 1 day of age, but the infant died on postoperative day 51 due to respiratory insufficiency without any evidence of pulmonary venous obstruction. He had been unexpectedly diagnosed with pulmonary alveolar proteinosis and pulmonary hypoplasia on autopsy. Congenital pulmonary alveolar proteinosis is a serious condition with a high mortality rate, which should be considered in the differential diagnosis in patients with a clinical picture of pulmonary venous obstruction, because most patients are unable to survive without proper treatment. In this report, we address specific issues that should be discussed in such cases based on our recent experience.

This study conducted large-eddy simulations (LES) of fully developed turbulent flow within and above explicitly resolved buildings in Tokyo and Nagoya, Japan. The more than 100 LES results, each covering a 1,000 $$\times $$ 1,000 m $$^{2}$$ area with 2-m resolution, provide a database of the horizontally-averaged turbulent statistics and surface drag corresponding to various urban morphologies. The vertical profiles of horizontally-averaged wind velocity mostly follow a logarithmic law even for districts with high-rise buildings, allowing estimates of aerodynamic parameters such as displacement height and roughness length using the von Karman constant $$=$$ 0.4. As an alternative derivation of the aerodynamic parameters, a regression of roughness length and variable Karman constant was also attempted, using a displacement height physically determined as the central height of drag action. Although both the regression methods worked, the former gives larger (smaller) values of displacement height (roughness length) by 20–25 % than the latter. The LES database clearly illustrates the essential difference in bulk flow properties between real urban surfaces and simplified arrays. The vertical profiles of horizontally-averaged momentum flux were influenced by the maximum building height and the standard deviation of building height, as well as conventional geometric parameters such as the average building height, frontal area index, and plane area index. On the basis of these investigations, a new aerodynamic parametrization of roughness length and displacement height in terms of the five geometric parameters described above was empirically proposed. The new parametrizations work well for both real urban morphologies and simplified model geometries.

// Suyoun Chung 1 , Hanae Suzuki 2 , Takashi Miyamoto 2 , Naofumi Takamatsu 2 , Ayako Tatsuguchi 3 , Koji Ueda 3 , Kyoko Kijima 2 , Yusuke Nakamura 1,4 and Yo Matsuo 2 1 Department of Medicine and Surgery, The University of Chicago, Chicago, IL, USA 2 OncoTherapy Science, Inc., Kawasaki, Kanagawa, Japan 3 Laboratory for Biomarker Development, RIKEN, Yokohama, Japan 4 Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan Correspondence: Yusuke Nakamura, email: // Yo Matsuo, email: // Keywords : oncogene, drug discovery, kinase inhibitor, cancer stem cell Received : December 05, 2012, Accepted : December 20, 2012, Published : December 21, 2012 Abstract We previously reported MELK (maternal embryonic leucine zipper kinase) as a novel therapeutic target for breast cancer. MELK was also reported to be highly upregulated in multiple types of human cancer. It was implied to play indispensable roles in cancer cell survival and indicated its involvement in the maintenance of tumor-initiating cells. We conducted a high-throughput screening of a compound library followed by structure-activity relationship studies, and successfully obtained a highly potent MELK inhibitor OTSSP167 with IC 50 of 0.41 nM. OTSSP167 inhibited the phosphorylation of PSMA1 (proteasome subunit alpha type 1) and DBNL (drebrin-like), which we identified as novel MELK substrates and are important for stem-cell characteristics and invasiveness. The compound suppressed mammosphere formation of breast cancer cells and exhibited significant tumor growth suppression in xenograft studies using breast, lung, prostate, and pancreas cancer cell lines in mice by both intravenous and oral administration. This MELK inhibitor should be a promising compound possibly to suppress the growth of tumor-initiating cells and be applied for treatment of a wide range of human cancer.

We have repaired a unilateral absent pulmonary artery(UAPA) using a prosthetic graft with a ring. Case 1 was a 1-month old girl. The right pulmonary artery(RPA) was anti-anatomically reconstructed with a 4 mm ePTFE graft. In postoperative year 1, however, the graft became stenosed due to compression by the ascending aorta. We reversed the stenosis with a 6 mm stent by percutaneous transluminal angioplasty. Case 2 was 6-year old boy. His RPA was anatomically reconstructed with a ringed 5 mm ePTFE graft when he was 5-months old. In postoperative year 6, he needed the graft exchanged because of the relatively decreased pulmonary flow due to body growth. Therefore, we exchanged the graft with an anti-anatomically ringed 12 mm ePTFE graft. No graft stenosis was observed during the perioperative course. Using a prosthetic graft with a ring may be a good solution to avoid compression from the ascending aorta.

Pulmonary tumor embolism (PTE) and intravascular lymphoma cause rapidly progressive deterioration and an antemortem diagnosis is difficult. The usefulness of pulmonary microvascular cytology (PMC) in the diagnosis of these disorders has been reported in sporadic case reports. We retrospectively evaluated the records of 7 patients with tumor cells in the pulmonary microvasculature (4 with PTE and 3 with malignant lymphoma) who underwent pulmonary microvascular cytology. Two of the 4 patients with PTE and 2 of the 3 patients with malignant lymphoma (all 3 had intravascular metastasis) had positive PMC results. These findings suggested that PMC may be useful in the diagnosis of these disorders.

We describe the rare case of a 1-year-old girl who had large muscular ventricular defect (VSD) nearby the moderator band. We experienced the patch closure using sandwich method. A 1-month-old girl was referred to our institution for treatment of muscular VSD. At the age of 2 month, she underwent the pulmonary artery banding to control the pulmonary high flow. After follow up, the patient have reached 70 cm tall and weighed 7 kg. One year after the "sandwich operation", cardiac catheterization revealed the tiny residual shunt. Nevertheless, the cardiac function was good and the growth was in fine fettle. Sandwich method is a useful surgical technique to close the muscular VSD without resect the right ventricular trabeculation.

Our previous study has shown that plasminogen activator inhibitor 1 (PAI-1) gene expression and secretion from bone marrow adipocytes increased markedly with dexamethasone administration. The purpose of the present study was to measure the secretion of various adipokines from human bone marrow and blood, and investigate how adipokine secretion changes in a steroid environment. Human blood and bone marrow fluid were collected from a steroid treatment group and a control group during hip replacement surgery, and an enzyme-linked immunosorbent assay (ELISA) was used to measure the adiponectin, leptin, and PAI-1 levels. Adiponectin and leptin showed no significant differences between bone marrow and blood levels, but PAI-1 was significantly higher in bone marrow. The steroid treatment group had higher levels of leptin and PAI-1 in both the blood and bone marrow than the control group. PAI-1 was present at high concentrations in the bone marrow and increased by steroid treatment. High levels of PAI-1 in bone marrow may influence intraosseous hemodynamics and may induce necrotic bone disorders.

An enantioselective aldol reaction of aryl methyl ketones with aryl trifluoromethyl ketones catalyzed by tertiary amino thiourea has been established. Under mild conditions, the corresponding β-trifluoromethyl-β-hydroxy ketone products were obtained with up to 89% ee.

Aggregates of human plasma-derived intravenous immunoglobulins (IVIGs) carries a risk of severe adverse events after nonspecific complement activation induced in humans administrated. Therefore, the anti-complementary activity (ACA) test is legally required in every batch of IVIGs in Japan. However, due to the intrinsic nature of this bioassay, there might be large differences in the results of ACA tests from laboratories, even when the same batch of IVIGs was measured. Our six laboratories evaluated whether there were such differences and argued for establishment of a reference material (RM) for standardization of the ACA test. Our results revealed inter-laboratory differences in ACA values, indicating a need to establish an RM. Therefore, after ACA values in candidate RMs were measured collaboratively, one RM was selected from two candidates and unit value-assigned. The RM in fact normalized the ACA test values for samples measured in parallel at almost all the laboratories, when the values were calculated relative to the assigned unit value of the RM. Thus, we established a first RM to standardize the ACA test in Japan, which enabled each laboratory to normalize ACA values constantly for IVIGs. This indicates that the establishment of an RM can contribute to quality control of IVIGs.

Background: We aimed to clarify the clinical significance of TOPK (T-lymphokine–activated killer cell–originated protein kinase) expression in ovarian cancer and evaluate the possible effect of TOPK inhibitors, OTS514 and OTS964, on ovarian cancer cells. Methods: TOPK expression was examined by immunohistochemistry using 163 samples with epithelial ovarian cancer (EOC). TOPK protein level and FOXM1 transcriptional level in ovarian cancer cell lines were examined by Western blot and RT-PCR, respectively. Half-maximum inhibitory concentration (IC50) values against TOPK inhibitors were examined by the MTT assay. Using the peritoneal dissemination model of ES-2 ovarian cancer cells, we examined the in vivo efficacy of OTS514. In addition, the cytotoxic effect of OTS514 and OTS964 on 31 patient-derived primary ovarian cancer cells was examined. Results: TOPK was expressed very highly in 84 (52%) of 163 EOC tissues, and high TOPK expression was significantly associated with poor progression-free survival and overall survival in early-stage cases of EOC (P = 0.008 and 0.006, respectively). Both OTS514 and OTS964 showed significant growth-inhibitory effect on ovarian cancer cell lines with IC50 values of 3.0 to 46 nmol/L and 14 to 110 nmol/L, respectively. TOPK protein and transcriptional levels of FOXM1 were reduced by TOPK inhibitor treatment. Oral administration of OTS514 significantly elongated overall survival in the ES-2 abdominal dissemination xenograft model, compared with vehicle control (P < 0.001). Two drugs showed strong growth-inhibitory effect on primary ovarian cancer cells regardless of tumor sites or histological subtypes. Conclusions: Our results demonstrated the clinical significance of high TOPK expression and potential of TOPK inhibitors to treat ovarian cancer. Clin Cancer Res; 22(24); 6110–7. ©2016 AACR.

Ciliated muconodular papillary tumor (CMPT) is a rare papillary tumor that arises in the peripheral lung fields and is associated with the proliferation of ciliate d and goblet cells and increased mucin production. We report a case of CMPT involving the rearrangement of the anaplastic lymphoma kinase (ALK) gene. The patient was an 84-year-old Japanese female who had exhibited a small nodular shadow on chest computed tomography during a regular checkup 10 years ago. She underwent a partial resection of segment S10 of the right lung. The cut surface of the surgical specimen revealed a well-circumscribed, jelly-like mass measuring 8 × 8 × 10 mm. Histologically, the tumor was composed of a mixture of ciliated, goblet, and basal cells arranged in a papillary pattern together with pools of mucin. A diagnosis of CMPT was made. The lung tumor cells were subjected to fluorescent in situ hybridization and highly sensitive immunohistochemical staining for the ALK protein, both of which produced positive results. CMPT usually follows a favorable course, but the exact nature of this tumor; i.e., whether it is benign or malignant, has not been established. This is the first reported case of an ALK-positive CMPT.

The purpose of this paper is to introduce five martingale Orlicz-Hardy spaces and to establish the atomic decomposition theorem. As applications we show the relation among five martingale Orlicz-Hardy spaces and the duality, namely, the dual of martingale Orlicz-Hardy spaces are generalized martingale Campanato spaces. Further, we prove a John-Nirenberg type inequality for generalized martingale Campanato spaces when the stochastic basis is regular.

Maternal embryonic leucine zipper kinase (MELK), that plays a critical role in maintenance of cancer stem cells (CSCs), is predominantly expressed in various types of human cancer including small cell lung cancer (SCLC). SCLC usually acquires resistance to anti-cancer drugs and portends dismal prognosis. We have delineated roles of MELK in development/progression of SCLC and examined anti-tumor efficacy of OTS167, a highly potent MELK inhibitor, against SCLC. MELK expression was highly upregulated in both SCLC cell lines and primary tumors. siRNA-mediated MELK knockdown induced significant growth inhibition in SCLC cell lines. Concordantly, treatment with OTS167 exhibited strong cytotoxicity against eleven SCLC cell lines with IC50 of < 10 nM. As similar to siRNA knockdown, OTS167 treatment induced cytokinetic defects with intercellular bridges, and in some cell lines we observed formation of neuronal protrusions accompanied with increase of a neuronal differentiation marker (CD56), indicating that the compound induced differentiation of cancer cells to neuron-like cells. Furthermore, the MELK inhibition decreased its downstream FOXM1 activity and Akt expression in SCLC cells, and led to apoptotic cell death. OTS167 appeared to be more effective to CSCs as measured by the sphere formation assay, thus MELK inhibition might become a promising treatment modality for SCLC.

Objective: Continuous veno-venous hemodiafiltration (CVVH) is used as one of the modalities of continuous renal replacement therapy (CRRT) in pediatric intensive units. The aim of our study was to investigate the use of CVVH in small children with acute renal failure (ARF) after cardiac surgery.Patient and Methods: Between June 2005 and June 2008, 7 patients who required dialysis after pediatric cardiac surgery without ECMO underwent CVVH with polymethylmethacrylate membrane (PMMA) treatment. The definition of ARF was based on a 100% rise in serum creatinine (Cr) concentration, oliguria. On the other hand, PMMA-CVVH was weaned in patients with satisfactory urine output, stable biochemical markers of renal function and adequate fluid balance.Results: All patients treated with PMMA-CVVH alone (4 boys, 3 girls) had a median age of 36 months and a median body weight of 11kg. The averaged established time from cardiac operation to CVVH was 2.6 days. There was a significant decrease in the post-filter compared with pre-filter levels of BUN, Cr, potassium concentration. There were no significant changes in systolic blood pressure, lactate level and CRP; however, it was unnecessary for all patients to use epinephrine.Conclusions: Continuous veno-venous hemodiafiltration with PMMA-CVVH without ECMO achieved a surprisingly Zero mortality.

We have performed bilateral pulmonary artery banding operations combined with planned percutaneous balloon dilatation at banding sites for patients with hypoplastic left heart syndrome and related anomalies. Here, we report a case of Fontan completion in a patient who underwent aortic arch repair and a bidirectional Glenn procedure following flowadjustable bilateral pulmonary artery banding. The patient had a double-inlet left ventricle, a hypoplastic right ventricle, a hypoplastic aortic arch, and coarctation of the aorta. She underwent banding at 9 days of age and balloon dilatation at 2 months. The Damus-Kaye-Stansel anastomosis, aortic arch repair, and bidirectional Glenn procedure were performed at 5 months of age, and the extracardiac Fontan procedure was performed at 1.5 years.

Mass spectrometry-based untargeted metabolomics often results in the observation of hundreds to thousands of features that are differentially regulated between sample classes. A major challenge in interpreting the data is distinguishing metabolites that are causally associated with the phenotype of interest from those that are unrelated but altered in downstream pathways as an effect. To facilitate this distinction, here we describe new software called metaXCMS for performing second-order ("meta") analysis of untargeted metabolomics data from multiple sample groups representing different models of the same phenotype. While the original version of XCMS was designed for the direct comparison of two sample groups, metaXCMS enables meta-analysis of an unlimited number of sample classes to facilitate prioritization of the data and increase the probability of identifying metabolites causally related to the phenotype of interest. metaXCMS is used to import XCMS results that are subsequently filtered, realigned, and ultimately compared to identify shared metabolites that are up- or down-regulated across all sample groups. We demonstrate the software's utility by identifying histamine as a metabolite that is commonly altered in three different models of pain. metaXCMS is freely available at http://metlin.scripps.edu/metaxcms/.

Background: The anterior cruciate ligament-deficient (ACLD) knee requires appropriate treatment for the patient to return to sports. The purpose of this study was to clarify the kinematics of the anterior cruciate ligament-deficient knee in squatting motion before and after double-bundle anterior cruciate ligament reconstruction (DB-ACLR) using a 2D/3D registration technique. Methods: The subjects of this study were 10 men with confirmed unilateral ACL rupture who underwent DB-ACLR. Computed tomography (CT) of the knee joints was performed before DB-ACLR. Fluoroscopic imaging of the knee motion in squatting before and after DB-ACLR was also performed. The 2D/3D registration technique is a method of calculating positional relationships by projecting the 3D bone model created from the CT data onto the image extracted from the fluoroscopic images. The tibial anteroposterior (AP) and rotational positions were analyzed with reference to the femur. Results: The tibial AP position of the ACLD knees was significantly anterior to the contralateral knees (p = 0.015). The tibial rotational position of the ACLD knees was significantly internally rotated compared to the contralateral knees (p < 0.001). Both tibial AP and rotational positions improved after DB-ACLR (p < 0.001), with no significant differences compared to the contralateral knees. Conclusion: DB-ACLR improved not only tibial AP instability but also tibial rotational instability at knee flexion with weight-bearing. DB-ACLR appears to be a useful technique for normalizing the knee joint kinematics of ACLD knees., Journal of Orthopaedic Surgery and Research, 13(1), 111; 2018