c-Src and cooperating partners in human cancer

AbstractThe proto-oncogene c-src is rarely mutated in human cancers, and when overexpressed in normal cells is non- or weakly oncogenic. These observations have raised doubts about the involvement of c-src in the etiology of human tumors. However, recent studies have shown that c-Src, a non-receptor tyrosine kinase, exhibits elevated protein levels and activity in numerous types of human cancers. Furthermore, it has been found to be a critical component of multiple signaling pathways that regulate proliferation, survival, metastasis, and angiogenesis. Because of its important role in these oncogenic processes, it represents a therapeutic target ripe for exploitation

Preserved singing in aphasia: A case study of the efficacy of melodic intonation therapy

This study examined the efficacy of Melodic Intonation Therapy (MIT) in a male singer (KL) with severe Broca’s aphasia. Thirty novel phrases were allocated to one of three experimental conditions: unrehearsed, rehearsed verbal production (repetition), and rehearsed verbal production with melody (MIT). The results showed superior production of MIT phrases during therapy. Comparison of performance at baseline, 1 week, and 5 weeks after therapy revealed an initial beneficial effect of both types of rehearsal; however, MIT was more durable, facilitating longer-term phrase production. Our findings suggest that MIT facilitated KL’s speech praxis, and that combining melody and speech through rehearsal promoted separate storage and/or access to the phrase representation

p190RhoGAP is cell cycle regulated and affects cytokinesis

p190RhoGAP (p190), a Rho family GTPase-activating protein, regulates actin stress fiber dynamics via hydrolysis of Rho-GTP. Recent data suggest that p190 also regulates cell proliferation. To gain insights into the cellular process(es) affected by p190, we altered its levels by conditional or transient overexpression. Overexpression of p190 resulted in a multinucleated phenotype that was dependent on the GTPase-activating protein domain. Confocal immunofluorescence microscopy revealed that both endogenous and exogenous p190 localized to the newly forming and contracting cleavage furrow of dividing cells. However, overexpression of p190 resulted in abnormal positioning of the furrow specification site and unequal daughter cell partitioning, as well as faulty furrow contraction and multinucleation. Furthermore, levels of endogenous p190 protein were transiently decreased in late mitosis via an ubiquitin-mediated degradation process that required the NH2-terminal GTP-binding region of p190. These results suggest that a cell cycle–regulated reduction in endogenous p190 levels is linked to completion of cytokinesis and generation of viable cell progeny

Centroacinar cells are progenitors that contribute to endocrine pancreas regeneration

Diabetes is associated with a paucity of insulin-producing β-cells. With the goal of finding therapeutic routes to treat diabetes, we aim to find molecular and cellular mechanisms involved in β-cell neogenesis and regeneration. To facilitate discovery of such mechanisms, we use a vertebrate organism where pancreatic cells readily regenerate. The larval zebrafish pancreas contains Notch-responsive progenitors that during development give rise to adult ductal, endocrine, and centroacinar cells (CACs). Adult CACs are also Notch responsive and are morphologically similar to their larval predecessors. To test our hypothesis that adult CACs are also progenitors, we took two complementary approaches: 1) We established the transcriptome for adult CACs. Using gene ontology, transgenic lines, and in situ hybridization, we found that the CAC transcriptome is enriched for progenitor markers. 2) Using lineage tracing, we demonstrated that CACs do form new endocrine cells after β-cell ablation or partial pancreatectomy. We concluded that CACs and their larval predecessors are the same cell type and represent an opportune model to study both β-cell neogenesis and β-cell regeneration. Furthermore, we show that in cftr loss-of-function mutants, there is a deficiency of larval CACs, providing a possible explanation for pancreatic complications associated with cystic fibrosis

Are DNA repair factors promising biomarkers for personalized therapy in gastric cancer?

Chronic inflammation is a driving force for gastric carcinogenesis. Reactive oxygen species (ROS) generated during the inflammatory process generates DNA damage that is processed through the DNA repair pathways. In this study, we profiled key DNA repair proteins (single-strand-selective monofunctional uracil-DNA glycosylase 1 [SMUG1], Flap endonuclease 1 [FEN1], X-ray repair cross-complementing gene 1 [XRCC1], and Ataxia telangiectasia mutated [ATM]) involved in ROS-induced oxidative DNA damage repair in gastric cancer and correlated to clinicopathological outcomes. High expression of SMUG1, FEN1, and XRCC1 correlated to high T-stage (T3/T4) (p-values: 0.001, 0.005, and 0.02, respectively). High expression of XRCC1 and FEN1 also correlated to lymph node-positive disease (p-values: 0.009 and 0.02, respectively). High expression of XRCC1, FEN1, and SMUG1 correlated with poor disease-specific survival (DSS) (p-values: 0.001, 0.006, and 0.05, respectively) and poor disease-free survival (DFS) (p-values: 0.001, 0.001, and 0.02, respectively). Low expression of ATM correlated to lymph node positivity (p=0.03), vascular invasion (p=0.05), and perineural invasion (p=0.005) and poor DFS (p=0.001) and poor DSS (p=0.003). In the multivariate Cox model, high XRCC1 and low ATM were independently associated with poor survival (p=0.008 and 0.011, respectively). Our observation supports the hypothesis that DNA repair factors are promising biomarkers for personalized therapy in gastric cancer. Antioxid. Redox Signal. 18, 2392–2398

Dexamethasone Administration During Definitive Radiation and Temozolomide Renders a Poor Prognosis in a Retrospective Analysis of Newly Diagnosed Glioblastoma Patients

BACKGROUND: Dexamethasone (DXM) is commonly used in the management of cerebral edema in patients diagnosed with glioblastoma multiforme (GBM). Bevacizumab (BEV) is FDA-approved for the progression or recurrence of GBM but has not been shown to improve survival when given for newly diagnosed patients concurrently with radiation (RT) and temozolomide (TMZ). Both DXM and BEV reduce cerebral edema, however, DXM has been shown to induce cytokine cascades which could interfere with cytotoxic therapy. We investigated whether DXM would reduce survival of GBM patients in the setting of concurrent TMZ and BEV administration. METHODS: We reviewed the treatment of all 73 patients with GBM who received definitive therapy at our institution from 2005 to 2013 with RT (60 Gy) delivered with concurrent daily TMZ (75 mg/m2). Of these, 34 patients also were treated with concurrent BEV (10 mg/kg every two weeks). Patients received adjuvant therapy (TMZ or TMZ/Bev) until either progression, discontinuation due to toxicity, or 12 months after radiation completion. All patients who had GBM progression with TMZ were offered BEV for salvage therapy, with 19 (56 %) receiving BEV. RESULTS: With a median follow-up of 15.6 months, 67 (91.8 %) patients were deceased. The OS for the entire cohort was 15.9 months, while the PFS was 7.7 months. The extent of resection was a prognostic indicator for OS (p  = .0044). The median survival following gross tumor resection (GTR) was 22.5 months, subtotal resection (STR) was 14.9 months, and biopsy was 12.1 months. The addition of BEV to TMZ with RT was borderline significantly associated with increased PFS (9.4 vs. 5.1 months, p = 0.0574) although was not significantly associated with OS (18.1 vs. 15.3 months respectively, p  = 0.3064). In patients receiving TMZ, DXM use concurrent with RT was a poor prognostic indicator of both OS (12.7 vs. 22.6 months, p = 0.003) and PFS (3.6 vs. 8.4 months, p p = 0.4818). On multivariable analysis, DXM use predicted an unfavorable OS hazard ratio (HR) = 1.72, p = 0.045). CONCLUSIONS: Our results with TMZ, BEV, and RT are similar to previous studies in terms of PFS and OS. DXM use during RT with concurrent TMZ correlated with reduced OS and PFS unless BEV was administered

Emergency ambulance service involvement with residential care homes in the support of older people with dementia : an observational study

© 2014 Amador et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.BACKGROUND: Older people resident in care homes have a limited life expectancy and approximately two-thirds have limited mental capacity. Despite initiatives to reduce unplanned hospital admissions for this population, little is known about the involvement of emergency services in supporting residents in these settings.METHODS: This paper reports on a longitudinal study that tracked the involvement of emergency ambulance personnel in the support of older people with dementia, resident in care homes with no on-site nursing providing personal care only. 133 residents with dementia across 6 care homes in the East of England were tracked for a year. The paper examines the frequency and reasons for emergency ambulance call-outs, outcomes and factors associated with emergency ambulance service use. RESULTS: 56% of residents used ambulance services. Less than half (43%) of all call-outs resulted in an unscheduled admission to hospital. In addition to trauma following a following a fall in the home, results suggest that at least a reasonable proportion of ambulance contacts are for ambulatory care sensitive conditions. An emergency ambulance is not likely to be called for older rather than younger residents or for women more than men. Length of residence does not influence use of emergency ambulance services among older people with dementia. Contact with primary care services and admission route into the care home were both significantly associated with emergency ambulance service use. The odds of using emergency ambulance services for residents admitted from a relative's home were 90% lower than the odds of using emergency ambulance services for residents admitted from their own home. CONCLUSIONS: Emergency service involvement with this vulnerable population merits further examination. Future research on emergency ambulance service use by older people with dementia in care homes, should account for important contextual factors, namely, presence or absence of on-site nursing, GP involvement, and access to residents' family, alongside resident health characteristics.Peer reviewedFinal Published versio

The human papillomavirus E7 proteins associate with p190RhoGAP and alter its function

Using mass spectrometry, we identified p190RhoGAP (p190) as a binding partner of human papillomavirus 16 (HPV16) E7. p190 belongs to the GTPase activating protein (GAP) family and is one of the primary GAPs for RhoA. GAPs stimulate the intrinsic GTPase activity of the Rho proteins, leading to Rho inactivation and influencing numerous biological processes. RhoA is one of the best-characterized Rho proteins and is specifically involved in formation of focal adhesions and stress fibers, thereby regulating cell migration and cell spreading. Since this is the first report that E7 associates with p190, we carried out detailed interaction studies. We show that E7 proteins from other HPV types also bind p190. Furthermore, we found that conserved region 3 (CR3) of E7 and the middle domain of p190 are important for this interaction. More specifically, we identified two residues in CR3 of E7 that are necessary for p190 binding and used mutants of E7 with mutations of these residues to determine the biological consequences of the E7-p190 interaction. Our data suggest that the interaction of E7 with p190 dysregulates this GAP and alters the actin cytoskeleton. We also found that this interaction negatively regulates cell spreading on a fibronectin substrate and therefore likely contributes to important aspects of the HPV life cycle or HPV-induced tumorigenesis. © 2014, American Society for Microbiology

Inclusive research in education: contributions to method and debate

Education is not necessarily associated with inclusive research and the label of inclusive research is little used in our discipline. It is an umbrella term encompassing participatory, emancipatory and community/peer-led research. This is research in which those (such as learners and teachers) who tend to be the objects of other people’s research become agents in the conduct of research, ensuring that such research addresses issues that are important to them and includes their views and experiences (see Walmsley & Johnson, 2003 and Nind, 2014 for more on definitions). Conceptualising some research as inclusive is part of a concern with the democratization of the research process and with social justice - in and through - research; it represents an interest in the people outside of academia being active and credible producers of knowledge

Current- and wave- generated bedforms on mixed sand-clay intertidal flats : a new bedform phase diagram and implications for bed roughness and preservation potential

Funding: This work was supported by the United Kingdom’s Natural Environment Research Council (NERC) under Grant NE/I027223/1 (COHBED). JM, Julie Hope, and Daniel Parsons were partially funded by a Horizon 2020 European Research Council Consolidator Award (GEOSTICK, Grant 725955). The GEOSTICK project also kindly contributed the article processing fees. Andrew Manning’s contribution toward this research was partly supported by the National Science Foundation grants OCE-1924532 and OCE-1736668, TKI-MUSA project 11204950-000-ZKS-0002, and the HR Wallingford company research project FineScale (Grant Nos. ACK3013_62). DP received funding from the MASTS pooling initiative (The Marine Alliance for Science and Technology for Scotland) and their support is gratefully acknowledged. MASTS is funded by the Scottish Funding Council (Grant reference HR09011) and contributing institutions.The effect of bedforms on frictional roughness felt by the overlying flow is crucial to the regional modelling of estuaries and coastal seas. Bedforms are also a key marker of palaeoenvironments. Experiments have shown that even modest biotic and abiotic cohesion in sand inhibits bedform formation, modifies bedform size, and slows bedform development, but this has rarely been tested in nature. The present study used a comprehensive dataset recorded over a complete spring–neap cycle on an intertidal flat to investigate bedform dynamics controlled by a wide range of wave and current conditions, including the effects of wave–current angle and bed cohesion. A detailed picture of different bedform types and their relationship to the flow, be they equilibrium, non-equilibrium, or relict, was produced, and captured in a phase diagram that integrates wave-dominated, current-dominated, and combined wave–current bedforms. This bedform phase diagram incorporates a substantially wider range of flow conditions than previous phase diagrams, including bedforms related to near-orthogonal wave–current angles, such as ladderback ripples. Comparison with laboratory-derived bedform phase diagrams indicates that washed-out ripples, lunate interference ripples and upper-stage plane beds replace the subaqueous dune field; such bedform distributions may be a key characteristic of intertidal flats. The field data also provide a means of predicting the dimensions of these bedforms, which can be transferred to other areas and grain sizes. We show that an equation for the prediction of equilibrium bedform size is sufficient to predict the roughness, even though the bedforms are highly variable in character and only in equilibrium with the flow for approximately half the time. Whilst the effect of cohesive clay is limited under more active spring conditions, clay does play a role in reducing the bedform dimensions under more quiescent neap conditions. We also investigated which combinations of waves, currents, and bed clay contents in the intertidal zone have the highest potential for bedform preservation in the geological record. This shows that combined wave–current bedforms have the lowest preservation potential and equilibrium current ripples have the highest preservation potential, even in the presence of moderate and storm waves. Hence, the absence of wave ripples and combined-flow bedforms and their primary stratification in sedimentary successions cannot be taken as evidence that waves were absent at the time of deposition.Publisher PDFPeer reviewe