Interactions between hypoxia and epidermal growth factor receptor in non-small-cell-lung cancer

Tumor hypoxia has been recognized to confer resistance to anticancer therapy since the early 20th century. More recently, its fundamental role in tumorigenesis has been established. Hypoxia-inducible factor (HIF)-1 has been identified as an important transcription factor that mediates the cellular response to hypoxia, promoting both cellular survival and apoptosis under different conditions. Increased tumor cell expression of this transcription factor promotes tumor growth In vivo and is associated with a worse prognosis in patients with non-small-cell lung cancer (NSCLC) undergoing tumor resection. The epidermal growth factor receptor (EGFR) promotes tumor cell proliferation and anglogenesis and inhibits apoptosis. Epidermal growth factor receptor expression increases in a stepwise manner during tumorigenesis and is overexpressed in > 50% of NSCLC tumors. This review discusses the reciprocal relationship between tumor cell hypoxia and EGFR. Recent studies suggest that hypoxia induces expression of EGFR and its ligands. In return, EGFR might enhance the cellular response to hypoxia by increasing expression of HIF-1α, and so act as a survival factor for hypoxic cancer cells. Immunohistochemical studies on a series of resected NSCLC tumors add weight to this contention by demonstrating a close association between expression of EGFR, HIF-1α, and:1 of HIF-1's target proteins, carbonic anhydrase IX. In this article we discuss emerging treatment strategies for NSCLC that target HIF-1, HIF-1 transcriptional targets, and EGFR.

Choroidal thickness in myopic and non-myopic children assessed with enhanced depth imaging optical coherence tomography

Purpose To examine choroidal thickness (ChT) and its topographical variation across the posterior pole in myopic and non-myopic children. Methods One hundred and four children aged 10-15 years of age (mean age 13.1 ± 1.4 years) had ChT measured using enhanced depth imaging optical coherence tomography (OCT). Forty one children were myopic (mean spherical equivalent -2.4 ± 1.5 D) and 63 non-myopic (mean +0.3 ± 0.3 D). Two series of 6 radial OCT line scans centred on the fovea were assessed for each child. Subfoveal ChT and ChT across a series of parafoveal zones over the central 6mm of the posterior pole were determined through manual image segmentation. Results Subfoveal ChT was significantly thinner in myopes (mean 303 ± 79 µm) compared to non-myopes (mean 359 ± 77 µm) (p<0.0001). Multiple regression analysis revealed both refractive error (r = 0.39, p<0.001) and age (r = 0.21, p = 0.02) were positively associated with subfoveal ChT. ChT also exhibited significant topographical variations, with the choroid being thicker in more central regions. The thinnest choroid was typically observed in nasal (mean 286 ± 77 µm) and inferior-nasal (306 ± 79 µm) locations, and the thickest in superior (346 ± 79 µm) and superior-temporal (341 ± 74 µm) locations. The difference in ChT between myopic and non-myopic children was significantly greater in central foveal regions compared to more peripheral regions (>3 mm diameter) (p<0.001). Conclusions Myopic children have significantly thinner choroids compared to non-myopic children of similar age, particularly in central foveal regions. The magnitude of difference in choroidal thickness associated with myopia appears greater than would be predicted by a simple passive choroidal thinning with axial elongation.

Gelatine methacrylamide-based hydrogels : an alternative three-dimensional cancer cell culture system

Modern cancer research requires physiological, three-dimensional (3-D) cell culture platforms, wherein the physical and chemical characteristics of the extracellular matrix (ECM) can be modified. In this study, gelatine methacrylamide (GelMA)-based hydrogels were characterized and established as in vitro and in vivo spheroid-based models for ovarian cancer, reflecting the advanced disease stage of patients, with accumulation of multicellular spheroids in the tumour fluid (ascites). Polymer concentration (2.5-7% w/v) strongly influenced hydrogel stiffness (0.5±0.2kPa to 9.0±1.8kPa) but had little effect on solute diffusion. The diffusion coefficient of 70kDa fluorescein isothiocyanate (FITC)-labelled dextran in 7% GelMA-based hydrogels was only 2.3 times slower compared to water. Hydrogels of medium concentration (5% w/v GelMA) and stiffness (3.4kPa) allowed spheroid formation and high proliferation and metabolic rates. The inhibition of matrix metalloproteinases and consequently ECM degradability reduced spheroid formation and proliferation rates. The incorporation of the ECM components laminin-411 and hyaluronic acid further stimulated spheroid growth within GelMA-based hydrogels. The feasibility of pre-cultured GelMA-based hydrogels as spheroid carriers within an ovarian cancer animal model was proven and led to tumour development and metastasis. These tumours were sensitive to treatment with the anti-cancer drug paclitaxel, but not the integrin antagonist ATN-161. While paclitaxel and its combination with ATN-161 resulted in a treatment response of 33-37.8%, ATN-161 alone had no effect on tumour growth and peritoneal spread. The semi-synthetic biomaterial GelMA combines relevant natural cues with tunable properties, providing an alternative, bioengineered 3-D cancer cell culture in in vitro and in vivo model systems.

Remote sensing utility expansion through Earth Portal internet browser

A modular, graphic-oriented Internet browser has been developed to enable non-technical client access to a literal spinning world of information and remotely sensed. The Earth Portal (www.earthportal.net) uses the ManyOne browser (www.manyone.net) to provide engaging point and click views of the Earth fully tessellated with remotely sensed imagery and geospatial data. The ManyOne browser technology use Mozilla with embedded plugins to apply multiple 3-D graphics engines, e.g. ArcGlobe or GeoFusion, that directly link with the open-systems architecture of the geo-spatial infrastructure. This innovation allows for rendering of satellite imagery directly over the Earth's surface and requires no technical training by the web user. Effective use of this global distribution system for the remote sensing community requires a minimal compliance with protocols and standards that have been promoted by NSDI and other open-systems standards organizations.

Adipose differentiation of bone marrow-derived mesenchymal stem cells using Pluronic F-127 hydrogel in vitro

Due to increasing clinical demand for adipose tissue, a suitable scaffold for engineering adipose tissue constructs is needed. In this study, we have developed a three-dimensional (3-D) culture system using bone marrow-derived mesenchymal stem cells (BM-MSC) and a Pluronic F-127 hydrogel scaffold as a step towards the in vitro tissue engineering of fat. BM-MSC were dispersed into a Pluronic F-127 hydrogel with or without type I collagen added. The adipogenic differentiation of the BM-MSC was assessed by cellular morphology and further confirmed by Oil Red O staining. The BM-MSC differentiated into adipocytes in Pluronic F-127 in the presence of adipogenic stimuli over a period of 2 weeks, with some differentiation present even in absence of such stimuli. The addition of type I collagen to the Pluronic F-127 caused the BM-MSC to aggregate into clumps, thereby generating an uneven adipogenic response, which was not desirable.

Myoepithelial molecular markers in human breast carcinoma PMC42-LA cells are induced by extracellular matrix and stromal cells

The microenvironment plays a key role in the cellular differentiation of the two main cell lineages of the human breast, luminal epithelial, and myoepithelial. It is not clear, however, how the components of the microenvironment control the development of these cell lineages. To investigate how lineage development is regulated by 3-D culture and microenvironment components, we used the PMC42-LA human breast carcinoma cell line, which possesses stem cell characteristics. When cultured on a two-dimensional glass substrate, PMC42-LA cells formed a monolayer and expressed predominantly luminal epithelial markers, including cytokeratins 8, 18, and 19; E-cadherin; and sialomucin. The key myoepithelial-specific proteins α-smooth muscle actin and cytokeratin 14 were not expressed. When cultured within Engelbreth-Holm- Swarm sarcoma-derived basement membrane matrix (EHS matrix), PMC42-LA cells formed organoids in which the expression of luminal markers was reduced and the expression of other myoepithelial-specific markers (cytokeratin 17 and P-cadherin) was promoted. The presence of primary human mammary gland fibroblasts within the EHS matrix induced expression of the key myoepithelial-specific markers, α-smooth muscle actin and cytokeratin 14. Immortalized human skin fibroblasts were less effective in inducing expression of these key myoepithelial-specific markers. Confocal dual-labeling showed that individual cells expressed luminal or myoepithelial proteins, but not both. Conditioned medium from the mammary fibroblasts was equally effective in inducing myoepithelial marker expression. The results indicate that the myoepithelial lineage is promoted by the extracellular matrix, in conjunction with products secreted by breast-specific fibroblasts. Our results demonstrate a key role for the breast microenvironment in the regulation of breast lineage development.

Design and modification of three-component randomly incorporated copolymers for high performance organic photovoltaic applications

In this study we report the molecular design, synthesis, characterization, and photovoltaic properties of a series of diketopyrrolopyrrole (DPP) and dithienothiophene (DTT) based donor-acceptor random copolymers. The six random copolymers are obtained via Stille coupling polymerization using various concentration ratios of donor to acceptor in the conjugated backbone. Bis(trimethylstannyl)thiophene was used as the bridge block to link randomly with the two comonomers 5-(bromothien-2-yl)-2,5-dialkylpyrrolo[3,4-c]pyrrole-1, 4-dione and 2,6-dibromo-3,5-dipentadecyl-dithieno[3,2-b;2′,3′-d] thiophene. The optical properties of these copolymers clearly reveal a change in the absorption band through optimization of the donor-acceptor ratio in the backbone. Additionally, the solution processability of the copolymers is modified through the attachment of different bulky alkyl chains to the lactam N-atoms of the DPP moiety. Applications of the polymers as light-harvesting and electron-donating materials in solar cells, in conjunction with PCBM as acceptor, show power conversion efficiencies (PCEs) of up to 5.02%.

Future perfect

"Future Perfect" is a solo artist exhibition featuring a 9 channel video installation, which is comprised of looped computer animation projections. In the first room, the big one, there are nine projections of looped computer animations. Many of these look like representations of gallery spaces containing sculptures, including rotating interpenetrating discs, bouncing coloured coffins, and jostling cardboard cubes (the cubes are blank, then covered in drawings, then covered in photographic imagery). In one video, a man and a woman walk towards one another but never get together. In the second room, an animated video on a flatscreen suggests an origin story. The subtitles tell how, in Russia, my great-grandfather made a joke about Stalin's child bride that cost him his life. That one isn’t a loop; it has a beginning, middle, and end. Lying on the floor, in front of the video, are two slightly crumpled mural prints of photographs of the ocean. There's also a clear Perspex cloud shape on a wall. Viewers will see themselves reflected in it, as if it were a distant hovering mirage. The first room of the exhibition, where objects are set in perpetual motion, is about departure. The second room registers some sense of arrival. The future perfect implies looking back on something that hasn't happened yet; future and past are conflated and the present is somehow deferred. The future perfect combines anticipation and reflection, and it relates to my interest in combining 3-D animation with other mediums like drawing, painting, and shot video. In my work, the virtual and actual coexist in tension, just like experience and expectation in the future perfect.

Deformation of a three-dimensional red blood cell in a stenosed micro-capillary

Red blood cells (RBCs) exhibit different types of motions and deformations when the blood flows through capillaries. Interestingly, due to the complex three-dimensional structure of the RBC membrane, RBCs show three-dimensional motions and deformations in the blood flow. These motions and deformations of the RBCs highly depend on the stiffness of the RBC membrane and on the geometrical parameters of the capillary through which blood flows. However, capillaries always do not have uniform cross sections and some capillaries have stenosed segments, where cross sectional area suddenly reduces. Further, some diseases can alter the stiffness of the RBC membrane drastically. In this study, the deformation behaviour of a single three-dimensional RBC is examined, when it moves through a stenosed capillary. A three-dimensional spring network is used to model the RBC membrane. The RBC’s inside and outside fluids are discretized into a finite number of mass points and treated by smoothed particle hydrodynamics (SPH) method. The capillary is considered as a rigid tube with a stenosed section. The deformation index, mean velocity and total energy of the RBC are analysed when it flows through the stenosed capillary. Further, motion and deformation of the RBCs with different membrane stiffness (KB) are compared when they flow through the stenosed segment of the capillary. The simulation results demonstrate the RBCs are subjected to a larger deformation when they move through the stenosed part of the capillary and the RBCs with lower KBvalues easily pass through the stenosed segment of the capillary. Further, RBCs having higher KBvalues have a lower mean velocity and it leads to slow down the overall blood flow rate

Dietary intake in Australian children aged 4–24 months: Consumption of meat and meat alternatives

Meat/meat alternatives (M/MA) are key sources of Fe, Zn and protein, but intake tends to be low in young children. Australian recommendations state that Fe-rich foods, including M/MA, should be the first complementary foods offered to infants. The present paper reports M/MA consumption of Australian infants and toddlers, compares intake with guidelines, and suggests strategies to enhance adherence to those guidelines. Mother–infant dyads recruited as part of the NOURISH and South Australian Infants Dietary Intake studies provided 3 d of intake data at three time points: Time 1 (T1) (n 482, mean age 5·5 (SD 1·1) months), Time 2 (T2) (n 600, mean age 14·0 (SD 1·2) months) and Time 3 (T3) (n 533, mean age 24 (SD 0·7) months). Of 170 infants consuming solids and aged greater than 6 months at T1, 50 (29 %) consumed beef, lamb, veal (BLV) or pork on at least one of 3 d. Commercial infant foods containing BLV or poultry were the most common form of M/MA consumed at T1, whilst by T2 BLV mixed dishes (including pasta bolognaise) became more popular and remained so at T3. The processed M/MA increased in popularity over time, led by pork (including ham). The present study shows that M/MA are not being eaten by Australian infants or toddlers regularly enough; or in adequate quantities to meet recommendations; and that the form in which these foods are eaten can lead to smaller M/MA serve sizes and greater Na intake. Parents should be encouraged to offer M/MA in a recognisable form, as one of the first complementary foods, in order to increase acceptance at a later age.

A nonconservative Lagrangian framework for statistical fluid registration - SAFIRA

In this paper, we used a nonconservative Lagrangian mechanics approach to formulate a new statistical algorithm for fluid registration of 3-D brain images. This algorithm is named SAFIRA, acronym for statistically-assisted fluid image registration algorithm. A nonstatistical version of this algorithm was implemented, where the deformation was regularized by penalizing deviations from a zero rate of strain. In, the terms regularizing the deformation included the covariance of the deformation matrices Σ and the vector fields (q). Here, we used a Lagrangian framework to reformulate this algorithm, showing that the regularizing terms essentially allow nonconservative work to occur during the flow. Given 3-D brain images from a group of subjects, vector fields and their corresponding deformation matrices are computed in a first round of registrations using the nonstatistical implementation. Covariance matrices for both the deformation matrices and the vector fields are then obtained and incorporated (separately or jointly) in the nonconservative terms, creating four versions of SAFIRA. We evaluated and compared our algorithms' performance on 92 3-D brain scans from healthy monozygotic and dizygotic twins; 2-D validations are also shown for corpus callosum shapes delineated at midline in the same subjects. After preliminary tests to demonstrate each method, we compared their detection power using tensor-based morphometry (TBM), a technique to analyze local volumetric differences in brain structure. We compared the accuracy of each algorithm variant using various statistical metrics derived from the images and deformation fields. All these tests were also run with a traditional fluid method, which has been quite widely used in TBM studies. The versions incorporating vector-based empirical statistics on brain variation were consistently more accurate than their counterparts, when used for automated volumetric quantification in new brain images. This suggests the advantages of this approach for large-scale neuroimaging studies.

New insights from IODP Expedition 340 offshore Montserrat: First drilling of large volcanic island landslides

Montserrat now provides one of the most complete datasets for understanding the character and tempo of hazardous events at volcanic islands. Much of the erupted material ends up offshore, and this offshore record may be easier to date due to intervening hemiplegic sediments between event beds. The offshore dataset includes the first scientific drilling of volcanic island landslides during IODP Expedition 340, together with an unusually comprehensive set of shallow sediment cores and 2-D and 3-D seismic surveys. Most recently in 2013, Remotely Operated Vehicle (ROV) dives mapped and sampled the surface of the main landslide deposits. This contribution aims to provide an overview of key insights from ongoing work on IODP Expedition 340 Sites offshore Montserrat.Key objectives are to understand the composition (and hence source), emplacement mechanism (and hence tsunami generation) of major landslides, together with their frequency and timing relative to volcanic eruption cycles. The most recent major collapse event is Deposit 1, which involved ~1.8 km cubed of material and produced a blocky deposit at ~12-14ka. Deposit 1 appears to have involved not only the volcanic edifice, but also a substantial component of a fringing bioclastic shelf, and material locally incorporated from the underlying seafloor. This information allows us to test how first-order landslide morphology (e.g. blocky or elongate lobes) is related to first-order landslide composition. Preliminary analysis suggests that Deposit 1 occurred shortly before a second major landslide on the SW of the island (Deposit 5). It may have initiated English's Crater, but was not associated with a major change in magma composition. An associated turbidite-stack suggests it was emplaced in multiple stages, separated by at least a few hours and thus reducing the tsunami magnitude. The ROV dives show that mega-blocks in detail comprise smaller-scale breccias, which can travel significant distances without complete disintegration. Landslide Deposit 2 was emplaced at ~130ka, and is more voluminous (~8.4km cubed). It had a much more profound influence on the magmatic system, as it was linked to a major explosive mafic eruption and formation of a new volcanic centre (South Soufriere Hills) on the island. Site U1395 confirms a hypothesis based on the site survey seismic data that Deposit 2 includes a substantial component of pre-existing seafloor sediment. However, surprisingly, this pre-existing seafloor sediment in the lower part of Deposit 2 at Site U1395 is completely undeformed and flat lying, suggesting that Site U1395 penetrated a flat lying block. Work to date material from the upper part of U1396, U1395 and U1394 will also be summarised. This work is establishing a chronostratigraphy of major events over the last 1 Ma, with particularly detailed constraints during the last ~250ka. This is helping us to understand whether major landslides are related to cycles of volcanic eruptions.

STEM learning through engineering design: fourth-grade students' investigations in aerospace

Background: Internationally, there is a growing concern for developing STEM education to prepare students for a scientifically and technologically advanced society. Despite educational bodies lobbying for an increased focus on STEM, there is limited research on how engineering might be incorporated especially in the elementary school curriculum. A framework of five comprehensive core engineering design processes (problem scoping, idea generation, design and construction, design evaluation, redesign), adapted from the literature on design thinking in young children, served as a basis for the study. We report on a qualitative study of fourth-grade students’ developments in working an aerospace problem, which took place during the first year of a 3-year longitudinal study. Students applied design processes together with their mathematics and science knowledge to the design and redesign of a 3-D model plane. Results: The study shows that through an aerospace engineering problem, students could complete initial designs and redesigns of a model plane at varying levels of sophistication. Three levels of increasing sophistication in students’ sketches were identified in their designs and redesigns. The second level was the most prevalent involving drawings or templates of planes together with an indication of how to fold the materials as well as measurements linked to the plane’s construction. The third level incorporated written instructions and calculations. Students’ engagement with each of the framework’s design processes revealed problem scoping components in their initial designs and redesigns. Furthermore, students’ recommendations for improving their launching techniques revealed an ability to apply their mathematics knowledge in conjunction with their science learning on the forces of flight. Students’ addition of context was evident together with an awareness of constraints and a consideration of what was feasible in their design creation. Interestingly, students’ application of disciplinary knowledge occurred more frequently in the last two phases of the engineering framework (i.e., design evaluation and redesign), highlighting the need for students to reach these final phases to enable the science and mathematics ideas to emerge. Conclusions: The study supports research indicating young learners’ potential for early engineering. Students can engage in design and redesign processes, applying their STEM disciplinary knowledge in doing so. An appropriate balance is needed between teacher input of new concepts and students’ application of this learning in ways they choose. For example, scaffolding by the teacher about how to improve designs for increased detail could be included in subsequent experiences. Such input could enhance students’ application of STEM disciplinary knowledge in the redesign process. We offer our framework of design processes for younger learners as one way to approach early engineering education with respect to both the creation of rich problem experiences and the analysis of their learning.

Regional changes in choroidal thickness associated with accommodation

Purpose. To characterize the changes occurring in choroidal thickness (ChT) across the posterior pole during accommodation using enhanced-depth imaging optical coherence tomography (OCT). Methods. Forty participants (mean age 21 ± 2 years) had measures of ChT and ocular biometry taken during accommodation to 0, 3, and 6 diopter (D) stimuli, with the Spectralis OCT and Lenstar biometer. A Badal optometer and cold mirror system was mounted on both instruments, allowing measurement collection while subjects viewed an external fixation target at varying accommodative demands. Results. The choroid exhibited significant thinning during accommodation to the 6 D stimulus in both subfoveal (mean change, −5 ± 7 μm) and parafoveal regions (P < 0.001). The magnitude of these changes varied by parafoveal meridian, with the largest changes seen in the temporal (−9 ± 12 μm) and inferotemporal (−8 ± 8 μm) meridians (P < 0.001). Axial length increased with accommodation (mean change, +5 ± 11 μm at 3 D, +14 ± 13 μm at 6 D), and these changes were weakly negatively associated with the choroidal changes (r2 = 0.114, P < 0.05). Conclusions. A small, but significant thinning of the choroid was observed at the 6 D accommodation demand, which was greatest in the temporal and inferotemporal parafoveal choroid, and increased with increasing eccentricity from the fovea. The regional variation in the parafoveal thinning corresponds to the distribution of the nonvascular smooth muscle within the uvea, which may implicate these cells as the potential mechanism by which the choroid thins during accommodation.

Evolution of electronic structure with dimensionality in divalent nickelates

We investigate the evolution of electronic structure with dimensionality (d) of Ni-O-Ni connectivity in divalent nickelates, NiO (3-d), La2NiO4, Pr2NiO4 (2-d), Y2BaNiO5 (1-d) and Lu2BaNi5 (0-d), by analyzing the valence band and the Ni 2p core-level photoemission spectra in conjunction with detailed many-body calculations including full multiplet interactions. Experimental results exhibit a reduction in the intensity of correlation-induced satellite features with decreasing dimensionality. The calculations based on the cluster model, but evaluating both Ni 3d and O 2p related photoemission processes on the same footing, provide a consistent description of both valence-band and core-level spectra in terms of various interaction strengths. While the correlation-induced satellite features in NiO is dominated by poorly screened d(8) states as described in the existing literature, we find that the satellite features in the nickelates with lower dimensional Ni-O-Ni connectivity are in fact dominated by the over-screened d(10)L(2) states. It is found that the changing electronic structure with the dimensionality is primarily driven by two factors: (i) a suppression of the nonlocal contribution to screening; and (ii) a systematic decrease of the charge-transfer energy Delta driven by changes in the Madelung potential. [S0163-1829(99)09619-8].