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Supplementary Figures 1-6 from Mechanisms Involved in Synergistic Anticancer Immunity of Anti-4-1BB and Anti-CD4 Therapy

Anti-4-1BB–mediated anticancer effects were potentiated by depletion of CD4+ cells in B16F10 melanoma-bearing C57BL/6 mice. Anti-4-1BB induced the expansion and differentiation of polyclonal tumor-specific CD8+ T cells into IFN-γ–producing CD11c+CD8+ T cells. The CD4+ cell depletion was responsible for facilitating immune cell infiltration into tumor tissues and removing some regulatory barriers such as T regulatory and indoleamine-2,3-dioxygenase (IDO)+ dendritic cells. Both monoclonal antibodies (mAb) contributed to the efficient induction of MHC class I molecules on the tumor cells in vivo. The effectors that mediated the anti-4-1BB effect were NKG2D+KLRG1+CD11c+CD8+ T cells that accumulated preferentially in the tumor tissues. Blocking NKG2D reduced the therapeutic effect by 20% to 26%, which may indicate that NKG2D contributes partially to tumor killing by the differentiated CD8+ T cells. Our results indicate that the combination of the two mAbs, agonistic anti-4-1BB and depleting anti-CD4, results in enhanced production of efficient tumor-killing CTLs, facilitation of their infiltration, and production of a susceptible tumor microenvironment. [Cancer Res 2007;67(18):8891–9]

Background: We have demonstrated that TBX18 suffices to reprogram postnatal ventricular cardiomyocytes (CMs) to induced pacemaker cells. Cell-cell interactions and cell-extracellular matrix (ECM) are important regulators of microtissue organization and assembly. Here, we sought to gain a finer understanding of self-organization and assembly of pacemaker microtissue with myocytes and non-myocytes driven by TBX18. Methods: 2D monolayer of neonatal rat ventricular myocytes (NRVMs) were transduced with Adeno- GFP and Adeno-TBX18 in vitro model. AAV9-TBX18 was delivered via tail vein injection of Hcn4 (+/eGFP) transgenic mice to track the induced pacemaker myocytes. Result: TBX18-NRVMs showed more compact nodal-like aggregates with a higher density of CMs and surrounded by nonmyocytes. The number of alpha smooth muscle actin (αSMA) + myofibroblasts producing specific ECM and facilitating cell motility was increased by 190% in TBX18-NRVMs as well. Systemic delivery of AAV9-TBX18 via tail vein of mice created aggregation of de novo Hcn4+ induced pacemaker myocytes (iPMs) surrounded by αSMA+ myofibroblasts in vivo. Then, we treated pre-plated neonatal rat ventricular cells (NRVCs, including CMs and nonmyocytes) to explore the potential role of cell-cell communication and cell-ECM interaction in the formation of nodal-like aggregates through scRNA-seq. The data indicated that TBX18+ CM (28.6% % of all CMs) and TBX18-negative CMs (71.4% of all CMs) presented highly consistent transcriptomic profiles at day 3. No significant difference in Hcn4 transcript levels and the ratio of iPMs (defined as Hcn4+, Gja1 low , Nkx2.5 low , Tnni3 high , Actn2 high CM) was observed between them, as well as other pacemaker genes, suggesting cross-communication between them. Despite of TBX18+ fibroblasts (FBs) accounting for only 5% of all FBs, a higher proportion of activated myofibroblasts (39.3% vs. 25.4%) and lower proportion of quiescent FBs were observed in TBX18-NRVCs compared to control. Enrichment analysis revealed that TBX18-CMs lost ventricular specific electrical coupling and sarcomere organization (down-regulated Gja1, Cdh2, Irx3 ), but reconstructed hemidesmosome assembly and cell-ECM interaction enriched in sinoatrial node myocytes (Upregulated Lamc1, Itgb1, Plec, Des, Actn1, and Acta2 ) and activated Tgfβ signaling. Furthermore, treatment with gap junction inhibitor palmitoleic acid as well as Tgfβ receptor inhibitor A83-01 significantly suppressed the activation of quiescent fibroblasts to αSMA+ myofibroblasts and the formation of nodal-like aggregation of TBX18-NRVMs. Conclusion: TBX18 drives self-organization and nodal-like assembly of pacemaker microtissue with myocytes and non-myocytes through cell-cell communication of gap junction and Tgfβ signal.

In this study, we investigated the antibacterial and anti-inflammatory properties of

The cavities of metallosupramolecular cages can be used to mimic the central spaces of naturally occurring proteins and bind a wide variety of molecular guests. A range of potential applications have arisen from this capacity for host-guest chemistry. However, to truly harness the opportunities thus afforded, methodologies to controllably allow the release and reuptake of guests from the cavities of metallosupramolecular cages are required. Methods to accomplish this have centered upon reversibly altering the character of either the guest or host. This minireview outlines the current approaches used to carry out the binding and release of guests from metallosupramolecular hosts using important examples from the field.

Four planar tripyridyl ligands (Ltripy), 1,3,5-tris(pyridin-3-ylethynyl)benzene 1 a, 1,3,5-tris[4-(3-pyridyl)phenyl]benzene 2 a, and the hexyloxy chain functionalized derivatives 1,3,5-tris[(3-hexyloxy-5-pyridyl)ethynyl]benzene 1 b, and 1,3,5-tris[4-(3-hexyloxy-5-pyridyl)phenyl]benzene 2 b, were synthesized and used to generate a family of [Pd6(Ltripy)8](BF4)12 octahedral cages (Ltripy=1 a, b or 2 a, b). The ligands and cages were characterized using a combination of 1H, 13C, and DOSY nuclear magnetic resonance (NMR) spectroscopy, high resolution electrospray mass spectrometry (HR-ESI-MS), infrared (IR) spectroscopy, elemental analysis, and in three cases, X-ray crystallography. The molecular recognition properties of the cages with neutral and anionic guests were examined, in dimethyl sulfoxide (DMSO), using NMR spectroscopy, mass spectrometry and molecular modeling. No binding was observed with simple aliphatic and aromatic guest molecules. However, anionic sulfonates were found to interact with the octahedral cages and the binding interaction was size selective. The smaller [Pd6(1 a, b)8]12+ cages were able to interact with three p-toluenesulfonate guest molecules while the larger [Pd6(2 a, b)8]12+ systems could host four of the anionic guest molecules. To probe the importance of the hydrophobic effect, a mixed water–DMSO (1:1) solvent system was used to reexamine the binding of the neutral organic guests adamantane, anthracene, pyrene and 1,8-naphthalimide within the cages. In this solvent system all the guests except adamantane were observed to bind within the cavities of the cages. NMR spectroscopy and molecular modeling indicated that the cages bind multiple copies of the individual guests (between 3–6 guest molecules per cage).

BACKGROUND: Predicting severe acute pancreatitis (AP) in the early clinical stage is important for low morbidity and mortality. Delta neutrophil index (DNI) is used to detect infection and inflammation, but no previous studies have evaluated the usefulness of DNI as an early predictor of progression to severe AP (SAP). METHODS: The medical records of patients who were diagnosed with AP at the emergency department (ED) of Wonju Severance Christian Hospital from January 2012 to August 2016 were retrospectively reviewed. The initial DNI obtained in the ED was compared with other inflammatory markers to predict SAP. Multivariate logistic regression was used for statistical analysis. RESULTS: Of the 209 cases included in the analysis, 13 were classified as SAP. Compared to the DNI of the mild to moderately SAP group, that in the SAP group was considerably higher. The DNI showed a positive correlation with the Atlanta classification and bedside index of severity in AP. Using multivariate logistic regression analysis, DNI was an independent predictor of early SAP detection (odds ratio 1.122, 95% CI 1.045–1.205, p = 0.001). Among the biomarkers, DNI had the highest predictive value for SAP. CONCLUSIONS: The DNI measured in the ED at presentation is a potentially useful adjunctive marker to predict SAP.

Propranolol has been used as prophylaxis for variceal bleeding in patients with cirrhosis. More recent data suggest that carvedilol may be more effective for reducing the hepatic venous pressure gradient (HVPG) than propranolol. The primary aim of this study was to evaluate the hemodynamic response to carvedilol compared with propranolol.A total of 110 patients with a baseline HVPG value12 mm Hg were allocated randomly to receive either carvedilol or propranolol. The HVPG measurement was repeated after 6 weeks of daily medication. The primary end point was a ≥20% fall in HVPG compared with baseline or12 mm Hg.The difference in the proportion of responders in the carvedilol (49.1%) vs. propranolol (30.9%) groups did not reach statistical significance in the intention-to-treat analysis (P=0.08). However, among patients with a model for end-stage liver disease (MELD) score ≥15, carvedilol resulted in a significantly greater response than that of propranolol (7/12, 58.3% vs. 0/10, 0%; P=0.005). Similarly, carvedilol was superior to propranolol in patients with Child-Pugh score ≥9 (46.2 vs. 0%; P=0.046). The presence of ascites also had a significant influence on the response rate (51.5 vs. 24.2%; P=0.042). A MELD score ≥15 was the only significant predictor of response among these post hoc groups after adjusting for multiple comparisons (P=0.005). Severe adverse events were higher in the carvedilol group although drug-associated adverse events were not different.Overall, carvedilol offered no clear advantage over propranolol but it may be more effective in advanced cirrhotic patients with a MELD score≥15 in reducing the portal pressure gradient. However, this potential benefit may come with a cost of increased risk of side-effects and outcome data over a longer term is needed to understand the relative risk benefit.

Limited data are available on the efficacy of anti-IGF-1R agents in KRAS mutant colorectal cancer (CRC). We analysed outcome of 69 chemorefractory, KRAS exon 2 mutant CRC patients who were enrolled in a double-blind, randomised, phase II/III study of irinotecan and cetuximab plus dalotuzumab 10 mg/kg once weekly (arm A), dalotuzumab 7.5 mg/kg every second week (arm B) or placebo (arm C). Objective response rate (5.6% vs. 3.1% vs. 4.8%), median progression-free survival (2.7 vs. 2.6 vs. 1.4 months) and overall survival (7.8 vs. 10.3 vs. 7.8 months) were not statistically significantly different between treatment groups. Most common grade ≥3 treatment-related toxicities included neutropenia, diarrhoea, hyperglycaemia, fatigue and dermatitis acneiform. Expression of IGF-1R, IGF-1, IGF-2 and EREG by quantitative real-time polymerase chain reaction was assessed in 351 patients from the same study with available data on KRAS exon 2 mutational status. Median cycle threshold values for all biomarkers were significantly lower (i.e., higher expression, p

Solid electrolytes (SE) are key components for the safe and continuous operation of high-energy lithium metal batteries. Metal oxide SEs, which are stable under ambient conditions, are used as separators in the form of thick and heavy plates; however, this reduces the specific energy of practical battery cells. Despite considerable efforts, the development of thin SE separators with high ionic conductivities has remained a significant challenge. This paper reports the scalable production of a thin membrane comprising single-crystal SE particles that are bicontinuously embedded in a polymer matrix to form ion-conducting channels. The membrane exhibits a high ionic conductivity of 6.0 × 10−4 S cm−1 with remarkably low activation energy (20-times greater than that of current membranes with polycrystalline SE particles), eliminating large grain boundary resistances. The high conductivity enables stable lithium metal stripping and plating, producing a homogeneous ion flow to the lithium metal. Furthermore, a lithium metal–air battery cell using the membrane demonstrates a high specific energy of 700 Wh kg−1.

Four planar tripyridyl ligands (L

We propose a multiferroic tri-layer structure in which two magnetic layers are epitaxially constrained on a bottom piezoelectric substrate. In this structure, the exchange bias is observed due to interface spin coupling between the two magnetic layers. We also show that the exchange bias is significantly modulated by the application of an external electric field at room temperature, and the modulation in exchange bias is reproducible and reversible.

A family of electronically tuned fac-Re(CO)3Cl pyridyl-1,2,3-triazole complexes have been synthesized by refluxing methanol solutions of [Re(CO)5Cl] and the substituted 2-(1-R-1H-1,2,3-triazol-4-yl)pyridine ligands (pytri-R). The resulting rhenium(I) complexes were characterised by elemental analysis, HR-ESMS, IR, 1H and 13C NMR and in one case the molecular structure was confirmed by X-ray crystallography. The electronic structure of this family of fac-[(pytri-R)Re(CO)3Cl] complexes was probed using UV–Vis, Raman and emission spectroscopy and cyclic voltammetry techniques. The complexes show intense absorptions in the visible region, comprising strong π → π∗ and metal-to-ligand charge-transfer (MLCT) transitions, which were modelled using time-dependent density functional theory (TD-DFT). Interestingly, the MLCT transition energy and the emission maxima are unaffected by the nature of the R substituent on the 2-(1-R-1H-1,2,3-triazol-4-yl)pyridine ligand indicating that the 1,2,3-triazoyl unit is acting as an electronic insulator. The emission lifetimes of the complexes are modestly dependent on the nature of the 1,2,3-triazole substituent, with the conjugated complexes displaying longer lifetimes than the non-conjugated ones. The shorter lifetimes for complexes with non-conjugated ligands are attributed to the “free-rotor” effect which allows molecules to relax through non-radiative pathways. In this case, the freely rotating CH2 group located between the triazole and the R group causes the decrease in excited lifetime. The electrochemistry of all examples is defined by irreversible Re oxidation and triazole based ligand reduction processes. The nitro substituted complexes show additional nitrobenzene type reduction features. Similarly, the ferrocenyl substituted complex displays the expected reversible one electron oxidation process. Consistent with the spectroscopic data, the position of the oxidation and reduction processes are essentially unaffected by the electronic nature of the 2-(1-R-1H-1,2,3-triazol-4-yl)pyridine substituent.

Sex is a key function of human beings. Its physical, emotional, psychological, and social aspects permeate into many parts of our lives. Therefore, it is a major contributor to “Quality of life” (QoL). This chapter covers defining and measuring sexual QoL, and then details sex and QoL in nonclinical populations covering a variety of demographic groups. A detailed review follows for QoL in clinical populations of medical/surgical, psychiatric disorders, and sexual disorders before and after treatment. The chapter concludes with a discussion of ways to enhance QoL by detailing interventions to improve QoL in general and in sex in particular.

The antiproliferative effect of simvastatin on tumor cells has been speculated to be by intracellular signal inhibition through 3-hydroxy-3-methylglutaryl acetyl coenzyme A reductase. We examined the killing effect of simvastatin on imatinib-sensitive and resistant chronic myelogenous leukemia (CML) cells (three kinds of CML cell lines representative of each hematopoietic lineage: K562, KCL22, and LAMA84) and T315I and E255K site-directed mutant cells (Ba/F3). The in-vivo effect of simvastatin was determined in K562-xenografted nude mice. Cotreatment with imatinib and simvastatin in imatinib-resistant CML cells showed a synergistic killing effect in K562-R, KCL22-R, LAMA84-R, and E255K mutant cells, but only an additive effect in the T315I mutant cell, although a single treatment of simvastatin strongly inhibited T315I mutant cells. Mechanisms of killing were an induction of apoptosis and cell cycle arrest, through inhibition of tyrosine phosphorylation, and activated STAT5 and STAT3. Simvastatin suppressed the growth of K562-transplanted tumors, and cotreatment with imatinib was more effective in reducing tumor size. Simvastatin also killed primary CD34 cells from patients with CML more efficiently, compared with CD34 CML cells. Our study shows a synergic effect of imatinib and simvastatin both in imatinib-sensitive and imatinib-resistant cells, but more effective synergism in resistant cells. On the basis of these findings, we suggest that a combination of simvastatin and imatinib may be a potential candidate for the treatment of imatinib-resistant CML.

Limited data are available on the efficacy of anti-IGF-1R agents in KRAS mutant colorectal cancer (CRC). We analysed the outcome of 69 chemorefractory, KRAS exon 2 mutant CRC patients who were enrolled in a double-blind, randomised, phase II/III study of irinotecan and cetuximab plus dalotuzumab 10 mg/kg once weekly (arm A), dalotuzumab 7.5 mg/kg every second week (arm B) or placebo (arm C). Objective response rate (5.6% vs. 3.1% vs. 4.8%), median progression-free survival (2.7 vs. 2.6 vs. 1.4 months) and overall survival (7.8 vs. 10.3 vs. 7.8 months) were not statistically significantly different between treatment groups. Most common grade ≥3 treatment-related toxicities included neutropenia, diarrhoea, hyperglycaemia, fatigue and dermatitis acneiform. Expression of IGF-1R, IGF-1, IGF-2 and EREG by quantitative real-time polymerase chain reaction was assessed in 351 patients from the same study with available data on KRAS exon 2 mutational status. Median cycle threshold values for all biomarkers were significantly lower (i.e., higher expression, p 0.05) among patients with KRAS wild-type compared to those with KRAS exon 2 mutant tumours. No significant changes were found according to location of the primary tumour with only a trend towards lower expression of IGF-1 in colon compared to rectal cancers (p = 0.06). Albeit limited by the small sample size, this study does not appear to support a potential role for anti-IGF-1R agents in KRAS exon 2 mutant CRC. Data on IGF-1R, IGF-1 and IGF-2 expression here reported may be useful for patient stratification in future trials with inhibitors of the IGF pathway.

Anti-4-1BB–mediated anticancer effects were potentiated by depletion of CD4+ cells in B16F10 melanoma-bearing C57BL/6 mice. Anti-4-1BB induced the expansion and differentiation of polyclonal tumor-specific CD8+ T cells into IFN-γ–producing CD11c+CD8+ T cells. The CD4+ cell depletion was responsible for facilitating immune cell infiltration into tumor tissues and removing some regulatory barriers such as T regulatory and indoleamine-2,3-dioxygenase (IDO)+ dendritic cells. Both monoclonal antibodies (mAb) contributed to the efficient induction of MHC class I molecules on the tumor cells in vivo. The effectors that mediated the anti-4-1BB effect were NKG2D+KLRG1+CD11c+CD8+ T cells that accumulated preferentially in the tumor tissues. Blocking NKG2D reduced the therapeutic effect by 20% to 26%, which may indicate that NKG2D contributes partially to tumor killing by the differentiated CD8+ T cells. Our results indicate that the combination of the two mAbs, agonistic anti-4-1BB and depleting anti-CD4, results in enhanced production of efficient tumor-killing CTLs, facilitation of their infiltration, and production of a susceptible tumor microenvironment. [Cancer Res 2007;67(18):8891–9]

The glucocorticoid-induced tumour necrosis factor receptor family related gene (GITR) has been reported to be expressed on the activated T and CD4(+)CD25(+) regulatory T cells (Treg). Signalling triggered by GITR not only neutralizes the suppressive effect of Treg cells, but also augments activation, proliferation and cytokine production of effector T cells. To test the role of GITR in 2,4,6-trinitrobenzene sulphonic acid (TNBS)-induced colitis - a murine model of mucosal inflammation - TNBS-injected Balb/c mice were treated with agonistic anti-GITR monoclonal antibody (mAb). Anti-GITR treatment increased the death rate compared to rat IgG-treated mice. Typically, death occurred within 4 days after the TNBS injection when the mice were treated with anti-GITR. The mice that survived anti-GITR treatment suffered from severe inflammation in their entire intestines. CD4(+) T-depletion protected the mice from colitis; even an anti-GITR effect was not apparent. In contrast, CD8(+) T depletion showed less protective than did CD4(+) T depletion. Stimulation of GITR enhanced the production of proinflammatory cytokines including interferon (IFN)-gamma, tumour necrosis factor (TNF)-alpha, interleukin (IL)-6 and IL-12. It also enhanced the humoral response such as serum levels of IgG(2b) and IgA, which was completely dependent on CD4(+) T cells. Taken together, this study demonstrated that GITR signalling on CD4(+) T cells is involved in the development and progress of colitis by enhancing both T helper type 1 (Th1) and Th2 type responses.

A diaryl-linked tripyridyl ligand (L), 2,6-bis[4-(3-pyridinyl)phenyl]-4-(hydroxymethyl)pyridine, was synthesised in good yield (57%) exploiting the Pd-catalysed Suzuki cross-coupling method and used to assemble a new [Pd2L4]4+ metallosupramolecular cage architecture. These systems have been characterised by NMR, IR and UV–vis spectroscopies, mass spectrometry, elemental analysis and by X-ray crystallography. It was shown using NMR spectroscopy and X-ray crystallography that the cage acts as a host for BF4− anions. However, efforts to bind the anticancer drug cisplatin within the central cavity of the cage were unsuccessful. This appears to be connected to steric effects caused by the aryl spacer units of the ligands forming the cage.

This article focuses on the concept of trust and its implications for democratic governance in South Korea. Trust is an elusive concept that is often discussed using such synonyms as confidence, trustworthy, reliance, or anticipation of goodwill. Trust in interpersonal relations is different from trust in institutions. The case of South Korean politics and administration shows that the absence of trust hampers the process of building a mature democratic society and hinders the development of democratic governance. The article concludes by stressing the need to enhance trust in society, government, policy‐makers, and public administrators.

Most edge detection methods have parameters (threshold values or standard deviation of Gaussian operator for smoothing) to be set, and these parameters make much influence on the outputs of the detectors. In this paper we propose an objective parameter evaluation measure. We evaluate parameters based on the edge ambiguity measures of existence, location and formation. The existence and location ambiguity measures are derived from comparing fuzzy memberships of edgeness with detected edges, and the formation ambiguity measure assesses the connectedness and the total number of edge point in an edge image with respect to the image size. The parameters which produce the least ambiguous edges of a detection method for an image are selected as significant ones. No iterative visual interaction or prior knowledge of edges are needed for these evaluation measures. The effectiveness of the measures is demonstrated by applying the ambiguity measures to synthetic and real images.

Pressure half-time (PHT) method is usually unreliable for accurate determination of mitral valve area (MVA) immediately after surgical intervention of mitral stenosis (MS). The planimetry method using three-dimensional (3D) transesophageal echocardiography (3D-planimetery method) could enhance accurate determination of the intraoperative MVA. Authors investigated the efficacy of 3D-planimetry method in determining MVA immediately after mitral valve repair procedure (MVRep) for severe mitral stenosis (MS).In severe MS patients undergoing elective MVRep (N.=41), intraoperative MVAs were determined by using PHT-method and 3D-planimetry method before and immediately after cardiopulmonary bypass (pre- and post-MVAPHT, and -MVA3D-planimetry). MVAs were also determined by using multi-detector computed tomographic scan (MDCT) before MVRep and within 7 days after MVRep (pre- and post-MVACT). MVAs determined by using three different methods were analysed.Mitral inflow pressure gradient (median [25th-75th percentile]) was significantly reduced after MVRep (3.0 [2.0-4.0] vs. 7.0 [6.0-9.0] mmHg; P0.001). Pre-MVAPHT, pre-MVA3D-planimetry and preop-MVACT (mean [95% confidence interval]) did not differ significantly (1.08 [1.00-1.05], 1.08 [0.98-1.08], and 1.14 [1.07-1.22] cm2, respectively), but post-MVA3D-planimetry and post-MVACT (2.22 [2.07-2.36] and 2.31 [2.07-2.36] cm2, respectively) were significantly larger than post-MVAPHT (1.98 [1.83-2.13] cm2; P=0.007 and P0.001, respectively). The correlation coefficient between post-MVA3D-planimetry and post-MVACT (0.59, P0.01) was greater than that between post-MVAPHT and post-MVACT (0.39, P=0.01).These results support the clinical efficacy of 3D-planimetry for accurate evaluation of the MVA immediately after MVRep for severe MS, as a valuable alternative to PHT-method which usually underestimates MVA during this period.

IntroductionChildren are particularly vulnerable during disasters and mass-casualty incidents. Coordinated multi-hospital training exercises may help health care facilities prepare for pediatric disaster victims.ProblemThe purpose of this study was to use mixed methods to assess the disaster response of three hospitals, focusing on pediatric disaster victims.MethodsA full-functional disaster exercise involving a simulated 7.8-magnitude earthquake was conducted at three Los Angeles (California USA) hospitals, one of which is a freestanding designated Level I Pediatric Trauma Center. Exercise participants provided quantitative and qualitative feedback regarding their perceptions of pediatric disaster response during the exercise in the form of surveys and interviews. Additionally, trained observers provided qualitative feedback and recommendations regarding aspects of emergency response during the exercise, including communication, equipment and supplies, pediatric safety, security, and training.ResultsAccording to quantitative participant feedback, the disaster exercise enhanced respondents’ perceived preparedness to care for the pediatric population during a mass-casualty event. Further, qualitative feedback from exercise participants and observers revealed opportunities to improve multiple aspects of emergency response, such as communication, equipment availability, and physician participation. Additionally, participants and observers reported opportunities to improve safety and security of children, understanding of staff roles and responsibilities, and implementation of disaster triage exercises.ConclusionConsistent with previous investigations of pediatric disaster preparedness, evaluation of the exercise revealed several opportunities for all hospitals to improve their ability to respond to the needs of pediatric victims. Quantitative and qualitative feedback from both participants and observers was useful for comprehensively assessing the exercise's successes and obstacles. The present study has identified several opportunities to improve the current state of all hospitals’ pediatric disaster preparedness, through increased training on pediatric disaster triage methods and additional training on the safety and security of children. Regular assessment and evaluation of supplies, equipment, leadership assignments, and inter-hospital communication is also suggested to optimize the effectiveness and efficiency of response to pediatric victims in a disaster.BurkeRV, KimTY, BachmanSL, IversonEI, BergBM. Using mixed methods to assess pediatric disaster preparedness in the hospital setting. Prehosp Disaster Med. 2014;29(6): 1-7.

Background Insulin-like growth factor type 1 receptor (IGF-1R) mediates resistance to epidermal growth factor receptor (EGFR) inhibition and may represent a therapeutic target. We conducted a multicenter, randomized, double blind, phase II/III trial of dalotuzumab, an anti-IGF-1R monoclonal antibody, with standard therapy in chemo-refractory, KRAS wild-type metastatic colorectal cancer. Methods Eligible patients were randomly assigned to dalotuzumab 10mg/kg weekly (arm A), dalotuzumab 7.5mg/kg every alternate week (arm B), or placebo (arm C) in combination with cetuximab and irinotecan. Primary endpoints were progression-free survival (PFS) and overall survival (OS). Secondary endpoints included exploratory biomarker analyses. All statistical tests were two-sided. Results The trial was prematurely discontinued for futility after 344 eligible KRAS wild-type patients were included in the primary efficacy population (arm A = 116, arm B = 117, arm C = 111). Median PFS was 3.9 months in arm A (hazard ratio [HR] = 1.33, 95% confidence interval [CI] = 0.98 to 1.83, P = .07) and 5.4 months in arm B (HR = 1.13, 95% CI = 0.83 to 1.55, P = .44) compared with 5.6 months in arm C. Median OS was 10.8 months in arm A (HR = 1.41, 95% CI = 0.99 to 2.00, P = .06) and 11.6 months in arm B (HR = 1.26, 95% CI = 0.89 to 1.79, P = .18) compared with 14.0 months in arm C. Grade 3 or higher asthenia and hyperglycaemia occurred more frequently with dalotuzumab compared with placebo. In exploratory biomarker analyses, patients with high IGF-1 mRNA tumors in arm A had numerically better PFS (5.6 vs 3.6 months, HR = 0.59, 95% CI = 0.28 to 1.23, P = .16) and OS (17.9 vs 9.4 months, HR = 0.67, 95% CI = 0.31 to 1.45, P = .31) compared with those with high IGF-1 mRNA tumors in arm C. In contrast, in arm C high IGF-1 mRNA expression predicted lower response rate (17.6% vs 37.3%, P = .04), shorter PFS (3.6 vs 6.6 months, HR = 2.15, 95% CI = 1.15 to 4.02, P = .02), and shorter OS (9.4 vs 15.5 months, HR = 2.42, 95% CI = 1.21 to 4.82, P = .01). Conclusions Adding dalotuzumab to irinotecan and cetuximab was feasible but did not improve survival outcome. IGF-1R ligands are promising biomarkers for differential response to anti-EGFR and anti-IGF-1R therapies.

Our purpose was to evaluate the usefulness of early diastolic notch depth in predicting adverse perinatal outcome.Uterine artery Doppler velocimetry is widely applied in predicting pregnancy outcomes. Recent studies of uterine artery early diastolic notch have demonstrated its usefulness as a marker for fetal well-being. The early diastolic notch represents the reflected blood flow of uteroplacental circulation. This study was carried out under the hypothesis that when early diastolic notch is present evaluating its depth plays a significant role in predicting poor pregnancy outcomes. Its ability to predict adverse perinatal outcomes was evaluated in 198 pregnant women with early diastolic notch after 28 weeks' gestation.The incidence of adverse perinatal outcome (5-minute Apgar score7, cesarean delivery because of fetal distress, admission to neonatal intensive care unit, fetal growth restriction, or perinatal death) was 90.5% when the notch index was/=0.70. When the notch index range was 0.70 to 0.79, 0.80 to 0.89, and/=0.90, the respective incidences were 72.3%, 46. 9%, and 28.1%.This study suggests that evaluating notch depth in the presence of early diastolic notch on uterine artery velocimetry during the third trimester would be a useful method for predicting adverse perinatal outcomes.

A new series of geldanamycin derivatives were synthesized using a semi-synthetic approach involving genetically engineered biosynthetic intermediates. These analogues were then evaluated for anti-proliferation activity in human cancer cell lines, SK-Br3 and SK-Ov3. Most of the synthesized compounds exhibited potent in vitro anti-proliferation activity toward both cell lines. Such compounds potently inhibited the expression of the Hsp90 client protein ErbB2.

In image formation, we usually consider two things: the intensity and the location of a pixel. Because of several reasons, there could be uncertainty in the image brightness and also in the location of a pixel. We consider the cases where the observed image data or entities computed from it are inherently fuzzy. Based on this idea, we have considered shape detection methods and representation of edges using fuzzy set theory. In shape detection method, an image point is considered as a fuzzy data. By combining this concept and the Hough transform algorithm, a fuzzy Hough transform algorithm is introduced. More general shape detection paradigm is given by defining the cardinality of a shape. Edges, which is one of the basic entities of an image, is generalized using the fuzzy set theory. An edge evaluation criteria for the edges are also presented.