Exploiting inflammation for therapeutic gain in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy associated with <5% 5-year survival, in which standard chemotherapeutics have limited benefit. The disease is associated with significant intra- and peritumoral inflammation and failure of protective immunosurveillance. Indeed, inflammatory signals are implicated in both tumour initiation and tumour progression. The major pathways regulating PDAC-associated inflammation are now being explored. Activation of leukocytes, and upregulation of cytokine and chemokine signalling pathways, both have been shown to modulate PDAC progression. Therefore, targeting inflammatory pathways may be of benefit as part of a multi-target approach to PDAC therapy. This review explores the pathways known to modulate inflammation at different stages of tumour development, drawing conclusions on their potential as therapeutic targets in PDAC

Adolescent standing postural response to backpack loads: a randomised controlled experimental study

BACKGROUND: Backpack loads produce changes in standing posture when compared with unloaded posture. Although 'poor' unloaded standing posture has been related to spinal pain, there is little evidence of whether, and how much, exposure to posterior load produces injurious effects on spinal tissue. The objective of this study was to describe the effect on adolescent sagittal plane standing posture of different loads and positions of a common design of school backpack. The underlying study aim was to test the appropriateness of two adult 'rules-of-thumb'-that for postural efficiency, backpacks should be worn high on the spine, and loads should be limited to 10% of body weight. METHOD: A randomised controlled experimental study was conducted on 250 adolescents (12–18 years), randomly selected from five South Australian metropolitan high schools. Sagittal view anatomical points were marked on head, neck, shoulder, hip, thigh, knee and ankle. There were nine experimental conditions: combinations of backpack loads (3, 5 or 10% of body weight) and positions (backpack centred at T7, T12 or L3). Sagittal plane photographs were taken of unloaded standing posture (baseline), and standing posture under the experimental conditions. Posture was quantified from the x (horizontal) coordinate of each anatomical point under each experimental condition. Differences in postural response were described, and differences between conditions were determined using Analysis of Variance models. RESULTS: Neither age nor gender was a significant factor when comparing postural response to backpack loads or conditions. Backpacks positioned at T7 produced the largest forward (horizontal) displacement at all the anatomical points. The horizontal position of all anatomical points increased linearly with load. CONCLUSION: There is evidence refuting the 'rule-of-thumb' to carry the backpack high on the back. Typical school backpacks should be positioned with the centre at waist or hip level. There is no evidence for the 10% body weight limit

A DNA Sequence Directed Mutual Transcription Regulation of HSF1 and NFIX Involves Novel Heat Sensitive Protein Interactions

BACKGROUND: Though the Nuclear factor 1 family member NFIX has been strongly implicated in PDGFB-induced glioblastoma, its molecular mechanisms of action remain unknown. HSF1, a heat shock-related transcription factor is also a powerful modifier of carcinogenesis by several factors, including PDGFB. How HSF1 transcription is controlled has remained largely elusive. METHODOLOGY/PRINCIPAL FINDINGS: By combining microarray expression profiling and a yeast-two-hybrid screen, we identified that NFIX and its interactions with CGGBP1 and HMGN1 regulate expression of HSF1. We found that CGGBP1 organizes a bifunctional transcriptional complex at small CGG repeats in the HSF1 promoter. Under chronic heat shock, NFIX uses CGGBP1 and HMGN1 to get recruited to this promoter and in turn affects their binding to DNA. Results show that the interactions of NFIX with CGGBP1 and HMGN1 in the soluble fraction are heat shock sensitive due to preferential localization of CGGBP1 to heterochromatin after heat shock. HSF1 in turn was found to bind to the NFIX promoter and repress its expression in a heat shock sensitive manner. CONCLUSIONS/SIGNIFICANCE: NFIX and HSF1 exert a mutual transcriptional repressive effect on each other which requires CGG repeat in HSF1 promoter and HSF1 binding site in NFIX promoter. We unravel a unique mechanism of heat shock sensitive DNA sequence-directed reciprocal transcriptional regulation between NFIX and HSF1. Our findings provide new insights into mechanisms of transcription regulation under stress

Effect of defects on reaction of NiO surface with Pb-contained solution

In order to understand the role of defects in chemical reactions, we used two types of samples, which are molecular beam epitaxy (MBE) grown NiO(001) film on Mg(001) substrate as the defect free NiO prototype and NiO grown on Ni(110) single crystal as the one with defects. In-situ observations for oxide-liquid interfacial structure and surface morphology were performed for both samples in water and Pb-contained solution using high-resolution X-ray reflectivity and atomic force microscopy. For the MBE grown NiO, no significant changes were detected in the high-resolution X-ray reflectivity data with monotonic increase in roughness. Meanwhile, in the case of native grown NiO on Ni(110), significant changes in both the morphology and atomistic structure at the interface were observed when immersed in water and Pb-contained solution. Our results provide simple and direct experimental evidence of the role of the defects in chemical reaction of oxide surfaces with both water and Pb-contained solution.ope

Near-infrared sensitivity enhancement of photorefractive polymer composites by pre-illumination

Among the various applications for reversible holographic storage media, a particularly interesting one is time-gated holographic imaging (TGHI). This technique could provide a noninvasive medical diagnosis tool, related to optical coherence tomography. In this technique, biological samples are illuminated within their transparency windowwith near-infrared light, and information about subsurface features is obtained by a detection method that distinguishes between reflected photons originating from a certain depth and those scattered from various depths. Such an application requires reversible holographic storage media with very high sensitivity in the near-infrared. Photorefractive materials, in particular certain amorphous organic systems, are in principle promising candidate media, but their sensitivity has so far been too low, mainly owing to their long response times in the near-infrared. Here we introduce an organic photorefractive material—a composite based on the poly(arylene vinylene) copolymer TPD-PPV—that exhibits favourable near-infrared characteristics. We show that pre-illumination of this material at a shorter wavelength before holographic recording improves the response time by a factor of 40. This process was found to be reversible. We demonstrate multiple holographic recording with this technique at video rate under practical conditions

Activation of Akt by the Bacterial Inositol Phosphatase, SopB, is Wortmannin Insensitive

Salmonella enterica uses effector proteins translocated by a Type III Secretion System to invade epithelial cells. One of the invasion-associated effectors, SopB, is an inositol phosphatase that mediates sustained activation of the pro-survival kinase Akt in infected cells. Canonical activation of Akt involves membrane translocation and phosphorylation and is dependent on phosphatidyl inositide 3 kinase (PI3K). Here we have investigated these two distinct processes in Salmonella infected HeLa cells. Firstly, we found that SopB-dependent membrane translocation and phosphorylation of Akt are insensitive to the PI3K inhibitor wortmannin. Similarly, depletion of the PI3K regulatory subunits p85α and p85ß by RNAi had no inhibitory effect on SopB-dependent Akt phosphorylation. Nevertheless, SopB-dependent phosphorylation does depend on the Akt kinases, PDK1 and rictor-mTOR. Membrane translocation assays revealed a dependence on SopB for Akt recruitment to Salmonella ruffles and suggest that this is mediated by phosphoinositide (3,4) P2 rather than phosphoinositide (3,4,5) P3. Altogether these data demonstrate that Salmonella activates Akt via a wortmannin insensitive mechanism that is likely a class I PI3K-independent process that incorporates some essential elements of the canonical pathway

Imaging Magnetic Focusing of Coherent Electron Waves

The magnetic focusing of electrons has proven its utility in fundamental studies of electron transport. Here we report the direct imaging of magnetic focusing of electron waves, specifically in a two-dimensional electron gas (2DEG). We see the semicircular trajectories of electrons as they bounce along a boundary in the 2DEG, as well as fringes showing the coherent nature of the electron waves. Imaging flow in open systems is made possible by a cooled scanning probe microscope. Remarkable agreement between experiment and theory demonstrates our ability to see these trajectories and to use this system as an interferometer. We image branched electron flow as well as the interference of electron waves. This technique can visualize the motion of electron waves between two points in an open system, providing a straightforward way to study systems that may be useful for quantum information processing and spintronics

The postural effects of load carriage on young people – a systematic review

BACKGROUND: Spinal pain in young people is a significant source of morbidity in industrialised countries. The carriage of posterior loads by young people has been linked with spinal pain, and the amount of postural change produced by load carriage has been used as a measure of the potential to cause tissue damage. The purpose of this review was to identify, appraise and collate the research evidence regarding load-carriage related postural changes in young people. METHODS: A systematic literature review sought published literature on the postural effects of load carriage in young people. Sixteen databases were searched, which covered the domains of allied health, childcare, engineering, health, health-research, health-science, medicine and medical sciences. Two independent reviewers graded the papers according to Lloyd-Smith's hierarchy of evidence scale. Papers graded between 1a (meta-analysis of randomised controlled trials) and 2b (well-designed quasi-experimental study) were eligible for inclusion in this review. These papers were quality appraised using a modified Crombie tool. The results informed the collation of research evidence from the papers sourced. RESULTS: Seven papers were identified for inclusion in this review. Methodological differences limited our ability to collate evidence. CONCLUSIONS: Evidence based recommendations for load carriage in young people could not be made based on the results of this systematic review, therefore constraining the use of published literature to inform good load carriage practice for young people