External Domain Research Articles

MUC1 (VPM654 and EPR1023) Expression in Mucosa of Fallopian Tubes With Ectopic Pregnancy is Altered.

MUC1 is a surface glycoprotein that has an external and an internal domain. A recent report has shown that 1 segment of the external domain is reduced in ectopic pregnancy, suggesting that MUC1 may provide a protective mechanism against ectopic pregnancy. The objective of this study was to analyze the protein expression of 4 antibodies against MUC1 in fallopian tubes with or without ectopic pregnancy. Tissue sections of ectopic pregnancies (n=10) and normal tubes (n=16) derived from surgery were analyzed for the intensity of the staining with 3,3'-diaminobenzidine (DAB). Paraffin sections were submitted to immunohistochemical analysis using 4 different antibodies against different epitopes for MUC1: 214D4, EPR1023, HMFG1, and VPM654. Intensity of the immunostaining (DAB) was measured with ImageJ software. Statistical analysis was performed using Student unpaired t test, Mann-Whitney U test, and ANCOVA. The mean intensity of MUC1 [mean±SD, or median (interquartile)] in the mucosa of fallopian tubes with ectopic pregnancy was higher for EPR1023 (23.73±13.63 vs. 8.5±5.1, P=0.006), and reduced for VPM654 [13.7 (13-16.2) vs. 22.5 (19.5-29.7), P=0.005] compared with normal tubes. No difference was found for 214D4 and HMFG1. The immunoexpression of different epitopes (external and cytoplasmic) of MUC1 expression are altered in tubes with ectopic pregnancy compared with normal tubes, suggesting an association to explain its etiology.

Harnessing proteins to control crystal size and morphology, for improved delivery performance of hydrophobic bioactives, using genistein as a model

Protein-surface and protein-crystal interactions are important in many areas of technology including drug and nutraceutical delivery, as many bioactives are highly hydrophobic and tend to crystallize, resulting in poor bioavailability. The improved ability to control lipophilic bioactive nanocrystal formation and dispersibility can increase colloidal stability, and open new ways to control the release of incorporated bioactives and their bioavailability.Herein we compared three model proteins: β-casein, hydrophobin, and β-lactoglobulin, representing different structural groups of proteins, and assessed their functionality in preventing crystal growth, using genistein as a model hydrophobic crystallizing bioactive.Dynamic light scattering, polarized light microscopy and cryo-TEM showed that β-lactoglobulin, hydrophobin and β-casein, respectively inhibit genistein crystal growth in aqueous solution in increasing order of efficacy. Protein structure determines the mechanism and the efficacy by which it affects crystal growth and morphology: β-lactoglobulin, a rigid globular protein with an inward facing hydrophobic domain, indirectly suppresses crystallization by binding and reducing concentration of free hydrophobic compound molecules. Hydrophobin, a rigid globular protein with a flat external hydrophobic domain, adheres to the surface of certain crystal faces, limiting growth in the perpendicular directions. β-casein, a rheomorphic protein with an external hydrophobic domain, adheres to different crystal faces nonspecifically, thereby blocking growth in all directions. Consequently, an inverse correlation was observed between nanocrystal size and in vitro bioavailability. Based on this study, amphiphilic proteins can be more effectively selected and applied to control crystal growth and morphology of hydrophobic bioactives to improve their delivery and bioavailability in food and drug systems.

Use of the "Exposome" in the Practice of Epidemiology: A Primer on -Omic Technologies.

The exposome has been defined as the totality of exposures individuals experience over the course of their lives and how those exposures affect health. Three domains of the exposome have been identified: internal, specific external, and general external. Internal factors are those that are unique to the individual, and specific external factors include occupational exposures and lifestyle factors. The general external domain includes sociodemographic factors such as educational level and financial status. Eliciting information on the exposome is daunting and not feasible at present; the undertaking may never be fully realized. A variety of tools have been identified to measure the exposome. Biomarker measurements will be one of the major tools in exposomic studies. However, exposure data can also be obtained from other sources such as sensors, geographic information systems, and conventional tools such as survey instruments. Proof-of-concept studies are being conducted that show the promise of exposomic investigation and the integration of different kinds of data. The inherent value of exposomic data in epidemiologic studies is that they can provide greater understanding of the relationships among a broad range of chemical and other risk factors and health conditions and ultimately lead to more effective and efficient disease prevention and control.

Analysis of internal and external thermal resistances of heat pipes including fins using a three-dimensional numerical simulation

A complete thermal network analysis for a cylindrical heat pipe is presented and the dominant thermal resistances are identified. The proposed numerical model was developed to simulate heat pipe operation and has been verified for both low and high applications including heat sources and sinks as a single-domain conjugate problem. Steady-state and transient solution methods were performed for a three-dimensional heat pipe with a compressible vapor core and a wick governed by pure conduction. The numerical model accounts for the full external coolant domain, with and without external fins on the condenser, to investigate their influence on the thermal resistance network. The numerical results indicate that the overall heat pipe thermal resistances can be predicted with as little as 1%–28% variation from empirical correlations, based on the choice of heat pipe dimensions, materials and operating conditions. It was found that the vapor core thermal resistance can become significant as the operating temperature increases, however, the largest thermal resistances are those corresponding to the external heat transfer fluids.

Tetraspanin 7 autoantibodies in type 1 diabetes.

Autoantibodies to pancreatic beta cell proteins are markers of asymptomatic type 1 diabetes. The aim was to determine whether autoantibodies to the beta cell protein tetraspanin 7 would improve the ability to identify autoimmunity against pancreatic beta cells. Full length and external domain fragments of tetraspanin 7 were expressed as luciferase-tagged fusion proteins and used in immunoprecipitation assays to measure autoantibodies in samples from 363 patients with type 1 diabetes at onset of disease, 503 beta cell autoantibody negative first-degree relatives of patients, and 212 relatives with autoantibodies to insulin, glutamic acid decarboxylase, insulinoma antigen 2 or zinc transporter 8. Antibody binding was observed against the full length and external domains of tetraspanin 7, and was strongest against the full length protein. Autoantibodies that could be inhibited by untagged tetraspanin 7 were detected in 5 (1%) of 503 autoantibody negative relatives, 3 (3.2%) of 94 autoantibody negative patients, 95 (35.3%) of 269 autoantibody positive patients, 1 (1%) of 98 single autoantibody positive relatives and 25 (21.9%) of 114 multiple autoantibody positive relatives. Progression to diabetes did not differ between multiple autoantibody positive relatives with and without tetraspanin 7 autoantibodies. Tetraspanin 7 is an autoantigen in type 1 diabetes. Tetraspanin 7 autoantibodies are a marker of type 1 diabetes, but provide minor additional value to existing autoantibodies in identifying beta cell autoimmunity.

Recovery of humoral immunity in patients with durable complete responses following chimeric antigen receptor modified t cells directed against CD19 (CTL019).

7564Background: Autologous T cells genetically modified to express a chimeric antigen receptor with an external anti-CD19 antibody domain, and CD3ζ and 4-1BB signaling domains (CTL019) can achieve remissions in patients (pts) with relapsed/refractory (r/r) CD19+ non-Hodgkin lymphomas (NHL). We studied the effect of this therapy on humoral immunity. Methods: Serial immunoglobulin (Ig) levels were measured in pts with complete response (CR) to CTL019 on a phase II trial. Pts had r/r CD19+ follicular lymphoma (FL), diffuse large B cell lymphoma (DLBCL), or mantle cell lymphoma (MCL). After collection of lymphocytes, pts received lymphodepleting chemotherapy followed 1 - 4 days later by 1 - 5 x 108CTL019 cells intravenously. Response was assessed every 3 months (mo) for 24 mo. Enrollment is reported from Feb 2014 – Nov 2015, survival analyses through Jan 2016. Results: 43 pts enrolled: median age 56 years (range 25-77); female: male ratio 17:26; median prior therapies 4 (range 1-19); prior ASCT 14 (33%). 30 p...

In vitro responses of chicken macrophage-like monocytes following exposure to pathogenic and non-pathogenic E. coli ghosts loaded with a rational design of conserved genetic materials of influenza and Newcastle disease viruses

Avian influenza virus (AIV) and Newcastle disease virus (NDV) are two important viral diseases in the poultry industry. Therefore, new disease-fighting strategies, especially effective genetic vaccination, are in high demand. Bacterial Ghost (BG) is a promising platform for delivering genetic materials to macrophages, cells that are among the first to encounter these viruses. However, there is no investigation on the immune response of these macrophage-targeted treatments.Here, we investigated the effect of genetic materials of AIV and NDV on the gene expression profile of important pro-inflammatory cytokines, a chemokine, a transcription factor, major histocompatibility complexes, and the viability of the chicken macrophage-like monocyte cells (CMM). Our genetic construct contained the external domain of matrix protein 2 and nucleoprotein gene of AIV, and immunodominant epitopes of fusion and hemagglutinin-neuraminidase proteins of NDV (hereinafter referred to as pAIV-Vax), delivered via the pathogenic and non-pathogenic BGs (Escherichia coli O78K80 and E. coli TOP10 respectively).The results demonstrated that both types of BGs were able to efficiently deliver the construct to the CMM, although the pathogenic strain derived BG was a significantly better stimulant and delivery vehicle. Both BGs were safe regarding LPS toxicity and did not induce any cell death. Furthermore, the loaded BGs were more powerful in modulating the pro-inflammatory cytokines’ responses and antigen presentation systems in comparison to the unloaded BGs. Nitric oxide production of the BG-stimulated cells was also comparable to those challenged by the live bacteria.According to the results, the combination of pAIV-Vax construct and E. coli O78K80 BG is promising in inducing a considerable innate and adaptive immune response against AIV-NDV and perhaps the pathogenic E. coli, provided that the current combination be a potential candidate for in vivo testing regarding the development of an effective trivalent DNA vaccine against avian influenza and Newcastle disease, as well as a bacterial ghost vaccine against avian pathogenic E. coli (APEC).

Everyday Understandings of Happiness, Good Life, and Satisfaction: Three Different Facets of Well-being

The need for increasing conceptual clarity within well-being research has been stressed by social scientists as well as policymakers and international organizations. The present study aimed to identify and compare conceptual structures of the everyday terms happiness, a good life, and satisfaction, based on a semi-stratified sample of Norwegian adults. Findings indicate that these terms share certain conceptual similarities, as used in everyday Norwegian language. For each term, it was possible to identify an underlying structure of conceptual configuration, articulated into external life domain components and internal, psychological dimensions. Relationship themes were prominent among the external domains for all three terms. Findings indicated that in Norwegian participants’ understanding, happiness and good life were highly inclusive of external life domains, whereas satisfaction primarily evoked associations to internal, psychological states and experiences. Latent class analyses highlighted differences among socio-demographic groups as concerns the degree to which different conceptualizations of the three terms were endorsed. Findings raise questions about the practice, relatively common in the applied social sciences, of treating happiness, good life and satisfaction as highly similar concepts, and the assumption that each term carries the same meaning for everyone.

Cardiotoxicity Associated with Trastuzumab Therapy in Taiwan: A Single Medical Center's 5-Year Experience

IntroductionTrastuzumab, a recombinant humanized monoclonal antibody, targets the external domain of HER2 to improve the efficacy of HER2-positive breast cancer treatment and inhibit carcinoma cellular proliferation. The purpose of this study was to identify early changes in cardiac function and dimensional changes in heart size in patients treated with trastuzumab. Materials and MethodsSeventy three female patients with Her2/neu overexpression (IHC 3+/Fish +) in breast cancer underwent echocardiography before and after trastuzumab therapy. ResultsCardiac complications developed in 14 patients (19.2%), including asymptomatic left ventricle systolic dysfunction (n = 12), symptomatic heart failure (n = 2), new asymptomatic left bundle branch block (n = 1), new negative T waves on electrocardiogram (n = 2), pericardial effusion (n = 1), and death (n = 1). No significant deterioration in diastolic function was noted, and right heart diameters and function did not change significantly. Most patients remained in an asymptomatic stage of cardiac disease. A significant decrease in left ventricular ejection fraction (LVEF) was observed in 14 patients (19.2%), and new mitral regurgitation (≥ grade 1) was noted after 3 months of trastuzumab therapy in 7 patients (9.6%). ConclusionsTrastuzumab led to measurable decreases in LVEF (but only 2.7% was symptomatic heart failure) and new mitral regurgitation. Therefore, regular follow-up with echocardiography is essential for early detection and prevention of trastuzumab-induced cardiomyopathy.

Revitalising mathematics classroom teaching through Lesson Study (LS): a Malaysian case study

This paper discusses how implementation of Lesson Study (LS) has brought about evolving changes in the quality of mathematics classroom teaching in one Chinese primary school. The Japanese model of LS was adapted as a teacher professional development to improve mathematics teachers’ teaching practices. The LS group consisted of five mathematics teachers. Data were collected through video recording of lesson observations, reflection and interviews with the teachers and selected pupils. Altogether five lessons were recorded: one each before and after commencing the Lesson Study; as well as one research lesson for each of the three Lesson Study cycles. In this study, the well-known Interconnected Model of Teacher Growth was used as the analytical framework to observe teacher change in the iterative processes of enactment and reflection between the four domains: external domain, teachers’ personal domain, the domain of practice and the domain of consequence. Analysis of the results show five observed changes in teaching practices: (a) innovative use of teaching materials; (b) choice and sequencing of learning tasks; (c) empowering pupils to create questions; (d) resizing the group; and (e) better teacher engagement. These results showed that there were connections among the four domains; and the dynamic enactment and reflection shared by the most to the least experienced teachers was evident of teacher growth.

Ammonite assemblages and chronostratigraphy of the uppermost Bajocian–Callovian (Middle Jurassic) of the Murcia Region (Betic Cordillera, south-eastern Spain)

In this paper the stratigraphy and biostratigraphy of the Bathonian–Callovian rocks of the Murcia Region, based on high-resolution sampling yielding good ammonite dating, is reported. All the ammonites analysed are from four sections located on a pelagic swell (External Subbetic palaeogeographic domain) of the External Zones of the Betic Cordillera, Murcia Region, southern Spain. These represent characteristic Bathonian–Callovian sections of the Subbetic epipelagic swells in the Betic Cordillera. The lithology consists mainly of both nodular limestones and marly limestones. Discontinuities with hiatuses of variable duration, submarine hardgrounds, Fe–Mn macrooncoids, limonite crusts, neptunian dykes, etc., occur in the Middle Bathonian–Callovian interval. Extreme condensation episodes are common, but abundant ammonite faunal records have enabled a consistent and accurate chronostratigraphy. The Parkinsoni Zone, Daubenyi and Dimorphus subzones (uppermost Bajocian), the Zigzag and Aurigerus zones (Lower Bathonian), the Sofanus and Costatus zones (Middle Bathonian), the Orbis Zone (Upper Bathonian), and the Bullatus and Gracilis Zones (Lower Callovian) are recognised and characterised. The ammonite fauna shows a typical Mediterranean character. Phylloceratina and Lytoceratina are the predominant elements within the ammonite fauna, but Lytoceratina is dominant in the Lower Bathonian whereas Phylloceratina predominates in the rest of the Bathonian and in the Callovian. Other ammonites, such as Oppeliidae, Lissoceratidae, Stephanoceratidae, Perisphinctidae, Tulitidae, and Reineckeiidae, are also common throughout the uppermost Bajocian to Lower Callovian interval. Strigoceratidae are present, but scarce.

Psychoanalysis and Palestine-Israel: A personal angle

Identifications with or against Israel are widespread and powerful, and through them we are drawn into the conflict between Israel and the Palestinians. Psychoanalysts tend to see such identifications as involving a regressive pull, which fuels a view of the conflict as belonging exclusively in the external domain, placing the issues involved beyond the reach of psychoanalysis. This paper describes work done in the “Nazareth conferences”, involving staff members’ Jewish and Muslim identifications, which mobilised powerful feelings. It is suggested that containing these is a necessary prelude to acknowledging the experience of the other – an alternative to the on-going enactment of violent conflict.

Earth Dams in Near-fault Areas: From the Regional to the Site Model

The seismic response of large embankments in near-source conditions may be investigated by a multi-scale and multidisciplinary approach, where the seismological and geological aspects of the problem are firstly studied on a regional scale while the local and geotechnical aspects are studied on a detailed scale, including the structure of interest. A detailed knowledge of the basic seismological aspects of the area on a regional scale is necessary to properly simulate the seismic source and the wave propagation pattern within the rock basement to get the input motion at the bedrock formation for the reference site. The proper characterization of the motion at the bedrock level is crucial for large earth-dams or embankments for which a strong variability of the input motion may be dangerous, since differential settlements and fractures of the embankment may be promoted, with the consequent reduction of structure safety. Worth mentioning is the case-history of Conza Dam (AV) during the 1980 Irpinia earthquake: the embankment was partially jeopardized by the seismic event, being the dam site very close to the Irpinia source (≈10km). To merge the different scales of analysis (macro and micro) the mathematical formulation of the Domain Reduction Method (DRM), initially proposed by [1], has been recently implemented [14] in a FDM commercial code. One of the main advantage of the DRM procedure is the possibility of sub-structuring the real problem, dealing the generation and propagation of the seismic waves (model on a regional scale) separately from the seismic response of the specific site and structure, carried out on a reduced and detailed model (site model). According to the DRM approach, the dam is inserted in the refined internal domain and will receive the seismic motion from the external domain (which contains the source and propagation medium) through an interface boundary. To quantitatively evaluate the variability of the ground motion at the bedrock of the reference site, synthetic parameters were selected and suitable represented.

Block Topology Generation for Structured Multi-block Meshing with Hierarchical Geometry Handling

Multi-block structured mesh generation remains one of the most popular meshing techniques because of its superior simulation quality but it is difficult to apply when dealing with complex three dimensional (3D) domains. To this end, a hybrid blocking approach, combining the medial axis based method with level set isosurface is presented and applied to mesh complex 3D external flow domains. Secondly, a hierarchical geometry handling approach is demonstrated which makes use of the lower order modeling, overset meshes and zonal blocking to reduce the meshing and modeling effort. Typical external aerodynamics cases have been showcased to describe how such techniques can be used for efficiently addressing modern industrial meshing challenges.

Image-Based Analysis to Predict the Activity of Tariquidar Analogs as P-Glycoprotein Inhibitors: The Importance of External Validation.

Permeability glycoprotein (P-gp) is involved in the pathology of various diseases including cancer and epilepsy, mainly through the translocation of some medicines across the cell membrane. Here, we employed image-based quantitative structure-activity relationship (QSAR) models to predict the P-gp inhibitory activity of some Tariquidar derivatives. The structures of 65 Tariquidar derivatives and their P-gp inhibition activities were collected from the literature. For each compound, the pixels of bidimensional images and their principal components (PCs) were calculated using MATLAB software. Various statistical methods including principal component regression, artificial neural networks, and support vector machines were employed to investigate the correlation between the PCs and the activity of the compounds. The predictability of the models was investigated using external validation and applicability domain analysis. An artificial neural network-based model demonstrated the best prediction results for the test set. Moreover, external validation analysis of the developed models supports the idea that R(2) cannot assure the validity of QSAR models and another criterion, i.e., the concordance correlation coefficient (CCC) parameter, should be involved to evaluate the validity of the QSAR models. The results of this study indicate that image analysis could be as suitable as descriptors calculated by commercial software to predict the activity of drug-like molecules.

Teachers’ professional growth through engagement with lesson study

Lesson study is highly regarded as a model for professional learning, yet remains under-theorised. This article examines the professional learning experiences of teachers and numeracy coaches from three schools in a local network of schools, participating in a lesson study project over two research cycles in 2012. It maps the interconnections between their experiences and their beliefs and practices, using Clarke and Hollingsworth’s (Teach Educ 18(8):947–967, 2002)Interconnected Model of Professional Growth. Analysis of interview data and video-recordings of planning meetings, research lessons, and post-lesson discussions reveals the development of teachers’ collaborative planning skills, increased attention to students’ mathematical thinking, use of orchestrated whole-class discussion based on anticipated student solutions and focused questioning, and the enhancement of collaborative practices for teacher inquiry. Our findings illuminate the interplay between the External Domain, the Personal Domain, the Domain of Practice, and the Domain of Consequence, in the teaching and learning change environment, and the mediating processes of enactment and reflection. Changes in the domains across the period of the lesson study provide evidence of teachers’ professional growth, with the iterative processes of enactment and reflection being critical in mediating this professional growth.

Sustained Remissions Following Chimeric Antigen Receptor Modified T Cells Directed Against CD19 (CTL019) in Patients with Relapsed or Refractory CD19+ Lymphomas

BACKGROUND: Autologous T cells genetically modified to express a chimeric antigen receptor consisting of an external anti-CD19 single chain antibody domain with CD3ζ and 4-1BB signaling domains (CTL019 cells) can mediate potent anti-tumor effects in patients (pts) with relapsed or refractory chronic lymphocytic and acute lymphoblastic leukemias. We are conducting a phase IIa clinical trial to evaluate the safety and efficacy of CTL019 cells in pts with relapsed or refractory CD19+ non-Hodgkin lymphomas (NHL).METHODS: Pts with CD19+ diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), or mantle cell lymphoma (MCL) with no available curative treatment options, a limited prognosis (<2 years anticipated survival), and responsive or stable disease with most recent therapy are eligible. Pts with DLBCL have residual disease after primary and salvage therapies and are not eligible for autologous stem cell transplant (ASCT) or have relapsed or residual disease after ASCT; FL pts have progression of lymphoma <2 years after second or higher line of therapy (not including single agent monoclonal antibody therapy); MCL pts have relapsed, residual, or progressive disease after rituximab-chemotherapy combination therapy and are not appropriate for transplant or have relapsed after transplant. After steady state apheresis to collect peripheral blood leukocytes, pts receive lymphodepleting chemotherapy based on disease burden, histology, and past therapies. One to 4 days after chemotherapy, pts receive a single dose of CTL019 cells by intravenous infusion. Peripheral blood and marrow samples are collected for immunophenotypic, cytokine, and molecular studies at pre-specified times after T cell infusion. Initial tumor response assessment is performed 3 months after T cell infusion using International Working Group response criteria. Enrollment started in February 2014; data reported here are through July 26, 2015.RESULTS: To date, 38 pts have enrolled (DLBCL 21; FL 14; MCL 3). The median age is 56 years (range: 25-77), male: female ratio is 22:16, median number of prior therapies is 4 (range: 1-10), and number of pts with prior transplant is 12 (32%; 11 ASCT, 1 allotransplant). Ann Arbor stages at enrollment are: Stage IV 23 pts (61%), Stage III 7 pts (18%), Stage II 6 pts (16%), Stage 1E 2 pts (5%); 11 pts (29%) had bone marrow involvement. LDH was increased in 28 pts (74%). ECOG PS was 0 in 16 pts (42%) and 1 in 22 pts (58%). As of July 26, 2015, 24 patients have received the protocol-specified dose of CTL019 cells (13 DLBCL; 9 FL; 2 MCL). Lymphodepleting chemotherapy regimens were bendamustine (6 pts), cyclophosphamide (11 pts), cyclophosphamide-fludarabine (1 pt), modified EPOCH (3 pts), and radiation-cyclophosphamide (3 pts). Median total CTL019 cell dose is 5.00e8 (range: 1.79e8 - 5.00e8); median CTL019 cell dose/kg is 5.84e6 (range: 3.08e6-8.87e6). Median peak CTL019 cell expansion in blood occurred 7 days after infusion (range: 2-14 days); there was no difference in peak expansion between responders and non-responders. Cytokine release syndrome (CRS) occurred in 16 pts (14 grade 2; 1 grade 3; 1 grade 4) and did not predict response. Neurologic toxicity occurred in 3 pts: 2 episodes of delirium (1 grade 2, 1 grade 3) and one possibly related grade 5 encephalitis. 22 pts are evaluable for response (DLBCL 13, FL 7, MCL 2). Overall response rate (ORR) at 3 months is 68% (15/22): DLBCL 54% (7/13); FL 100% (7/7); MCL 50% (1/2). At the median follow-up 11.7 months, progression-free survival (PFS) from CTL019 infusion is 62% (DLBCL 43%; FL 100%). For responders at median follow up, response duration is 83% for DLBCL and 100% for FL.CONCLUSIONS: These results demonstrate that CTL019 cells can be prepared from extensively pretreated pts with active NHL and can induce durable responses with toxicity that is less than reported for chronic lymphocytic and acute lymphoblastic leukemias. [Display omitted] DisclosuresSchuster:Phamacyclics: Consultancy, Research Funding; Novartis: Research Funding; Gilead: Research Funding; Janssen: Research Funding; Nordic Nanovector: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Research Funding; Genentech: Consultancy; Hoffman-LaRoche: Research Funding. Svoboda:Seattle Genetics: Research Funding; Celgene: Research Funding; Celldex: Research Funding; Immunomedics: Research Funding. Dwivedy Nasta:BMS: Research Funding; Millenium Takeda: Research Funding. Porter:Genentech: Other: Spouse Employment; Novartis: Patents & Royalties, Research Funding. Mato:Celgene Corportation: Consultancy, Research Funding; Genentech: Consultancy; Pharmacylics: Consultancy, Research Funding; Pronai Pharmaceuticals: Research Funding; AbbVie: Consultancy, Research Funding; Janssen: Consultancy; TG Therapeutics: Research Funding; Gilead: Consultancy, Research Funding. Lacey:Novartis: Research Funding. Melenhorst:Novartis: Research Funding. Chew:Novartis: Patents & Royalties. Hasskarl:Novartis: Employment, Equity Ownership. Shah:Novartis: Employment, Equity Ownership. Wasik:Janseen and Novartis: Research Funding. Zheng:Novartis: Patents & Royalties. Levine:Novartis: Patents & Royalties, Research Funding. June:Novartis: Patents & Royalties, Research Funding.

Task-positive Functional Connectivity of the Default Mode Network Transcends Task Domain.

The default mode network (DMN) was first recognized as a set of brain regions demonstrating consistently greater activity during rest than during a multitude of tasks. Originally, this network was believed to interfere with goal-directed behavior based on its decreased activity during many such tasks. More recently, however, the role of the DMN during goal-directed behavior was established for internally oriented tasks, in which the DMN demonstrated increased activity. However, the well-documented hub position and information-bridging potential of midline DMN regions indicate that there is more to uncover regarding its functional contributions to goal-directed tasks, which may be based on its functional interactions rather than its level of activation. An investigation of task-related changes in DMN functional connectivity during a series of both internal and external tasks would provide the requisite investigation for examining the role of the DMN during goal-directed task performance. In this study, 20 participants underwent fMRI while performing six tasks spanning diverse internal and external domains in addition to a resting-state scan. We hypothesized that the DMN would demonstrate "task-positive" (i.e., positively contributing to task performance) changes in functional connectivity relative to rest regardless of the direction of task-related changes in activity. Indeed, our results demonstrate significant increases in DMN connectivity with task-promoting regions (e.g., anterior insula, inferior frontal gyrus, middle frontal gyrus) across all six tasks. Furthermore, canonical correlation analyses indicated that the observed task-related connectivity changes were significantly associated with individual differences in task performance. Our results indicate that the DMN may not only support a "default" mode but may play a greater role in both internal and external tasks through flexible coupling with task-relevant brain regions.

Expression patterns of human epidermal growth factor receptor proteins in early gastric cancer

Introduction Stomach cancer is the 3rd commonest cause of death by cancer worldwide. As many as 60% of these gastric tumours express the Human Epidermal Growth Factor receptor (HER 1–4), which play a role in cell proliferation and survival. Endoscopic submucosal dissection (ESD) is a minimally invasive surgical technique used to resect early gastric neoplasias. The purpose of this study was to establish a relationship between HER family expression in early gastric cancers, their clinical utility as a diagnostic or prognostic adjunct and how over-expression of the HER receptor affects the curative rate of ESD. Method Formalin fixed paraffin embedded tissue from 22 early gastric ESD resection specimens were sectioned. Normal gastric resections were used as a control. Immunohistochemical staining for the HER family receptors were optimised and staining performed against EGFR external (ED) and internal domain (ID), HER2 (ED and ID), HER3 (ID) and HER4 (ID). Scoring was performed by two independent observers and confirmed by diagnostic software. Results 2/22 (9%), 2/22 (9%) and 3/22 (13%) of cases were positive for EGFR ID, HER2 ID and HER2 ED respectively. 1/22 (4.5%) of cases showed co-expression of EGFR ID, HER2 ID and HER2 ED. 1 showed HER2 ED and ID co-expression. EGFR ED, HER3 and HER4 were all negative for overexpression. Over-expression of HER2 ID (p = 0.047) and HER2 ED (p = 0.0045) correlated positively with cancer aggressiveness. 10/20 (50%) cases showing no over-expression treated with ESD had reoccurrence of dysplasia, compared to 3/3 (100%) in the over-expressed group (p = 0.21). Conclusion Though small, our study showed a positive relationship between EGFR and HER2 expression, a potential target for therapeutic treatment. HER3 and HER4 expression did not correlate with any other antibody, in contrast to reported relationships. Repeats with different antibody clones would confirm the reliability of these results. The prognostic utility EGFR and HER2 co-expression to predict an aggressive early gastric cancer phenotype warrants further investigation. Although insignificant, the negative correlation between HER over-expression and ESD curative rates should be followed up with a larger cohort. Disclosure of interest None Declared.

The external domains of the HIV-1 envelope are a mutational cold spot.

In RNA viruses, mutations occur fast and have large fitness effects. While this affords remarkable adaptability, it can also endanger viral survival due to the accumulation of deleterious mutations. How RNA viruses reconcile these two opposed facets of mutation is still unknown. Here we show that, in human immunodeficiency virus (HIV-1), spontaneous mutations are not randomly located along the viral genome. We find that the viral mutation rate experiences a threefold reduction in the region encoding the most external domains of the viral envelope, which are strongly targeted by neutralizing antibodies. This contrasts with the hypermutation mechanisms deployed by other, more slowly mutating pathogens such as DNA viruses and bacteria, in response to immune pressure. We show that downregulation of the mutation rate in HIV-1 is exerted by the template RNA through changes in sequence context and secondary structure, which control the activity of apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 (A3)-mediated cytidine deamination and the fidelity of the viral reverse transcriptase.