Melatonin attenuates pulmonary hypertension in chronically hypoxic rats

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Structural basis of N-Myc binding by Aurora-A and its destabilization by kinase inhibitors

Myc family proteins promote cancer by inducing widespread changes in gene expression. Their rapid turn-over by the ubiquitin-proteasome pathway is regulated through phosphorylation of Myc Box I and ubiquitination by SCFFbxw7. However, N-Myc protein is stabilized in neuroblastoma by Aurora-A kinase in a manner that is sensitive to certain Aurora-A-selective inhibitors. Here we identify a direct interaction between the catalytic domain of Aurora-A and a site flanking Myc Box I that also binds SCFFbxw7. We determine the crystal structure of the complex between Aurora-A and this region of N-Myc to 1.72 Å resolution. The structure indicates that the conformation of Aurora-A induced by compounds such as alisertib and CD532 is not compatible with binding of N-Myc, explaining the activity of these compounds in neuroblastoma cells and providing a rational basis for the design of cancer therapeutics optimized for destabilization of the complex. We also propose a model for the stabilization mechanism in which binding to Aurora-A alters how N-Myc interacts with SCFFbxw7 to disfavor the generation of Lys48-linked poly-Ub chains

Yttrium-90 radioembolization for advanced inoperable hepatocellular carcinoma

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Improved Cell Survival and Paracrine Capacity of Human Embryonic Stem Cell-Derived Mesenchymal Stem Cells Promote Therapeutic Potential for Pulmonary Arterial Hypertension.

Although transplantation of adult bone marrow mesenchymal stem cells (BM-MSCs) holds promise in the treatment for pulmonary arterial hypertension (PAH), the poor survival and differentiation potential of adult BM-MSCs have limited their therapeutic efficiency. Here, we compared the therapeutic efficacy of human embryonic stem cell-derived MSCs (hESC-MSCs) with adult BM-MSCs for the treatment of PAH in an animal model. One week following monocrotaline (MCT)-induced PAH, mice were randomly assigned to receive phosphate-buffered saline (MCT group); 3.0×106 human BM-derived MSCs (BM-MSCs group) or 3.0 ×106 hESC-derived MSCs (hESC-MSCs group) via tail vein injection. At 3 weeks posttransplantation, the right ventricular systolic pressure (RVSP), degree of RV hypertrophy, and medial wall thickening of pulmonary arteries were lower=, and pulmonary capillary density was higher in the hESC-MSC group as compared with BM-MSC and MCT groups (all p < 0.05). At 1 week posttransplantation, the number of engrafted MSCs in the lungs was found significantly higher in the hESC-MSC group than in the BM-MSC group (all p < 0.01). At 3 weeks posttransplantation, implanted BM-MSCs were undetectable whereas hESC-MSCs were not only engrafted in injured pulmonary arteries but had also undergone endothelial differentiation. In addition, protein profiling of hESC-MSC- and BM-MSC-conditioned medium revealed a differential paracrine capacity. Classification of these factors into bioprocesses revealed that secreted factors from hESC-MSCs were preferentially involved in early embryonic development and tissue differentiation, especially blood vessel morphogenesis. We concluded that improved cell survival and paracrine capacity of hESC-MSCs provide better therapeutic efficacy than BM-MSCs in the treatment for PAH. © 2012 Cognizant Comm. Corp.published_or_final_versio

Potential roles of cytoskeletal protein in glioblastoma chemoresistance

Conference Theme: Brain Attack: A New EraPosters: no. P-14INTRODUCTION: Glioblastoma is a highly malignant neoplasm for which temozolomide is currently the standard chemotherapeutic agent. Adducin 3 (ADD3) is a cytoskeletal protein associated with chemoresistance but its role in glioblastoma has not been investigated ...postprin

Inhibition of NUCKS Facilitates Corneal Recovery Following Alkali Burn

Corneal wound healing involves a complex cascade of cytokine-controlled cellular events, including inflammatory and angiogenesis responses that are regulated by transcriptional chromatin remodeling. Nuclear Ubiquitous Casein and cyclin-dependent Kinase Substrate (NUCKS) is a key chromatin modifier and transcriptional regulator of metabolic signaling. In this study, we investigated the role of NUCKS in corneal wound healing by comparing its effects on corneal alkali burn in NUCKS knockout (NKO) and NUCKS wild-type (NWT) mice. Our data showed that following alkali-injury, inhibition of NUCKS (NKO) accelerated ocular resurfacing and suppressed neovascularization; the cytokine profile of alkali burned corneas in NKO mice showed suppressed expression of inflammation cytokines (IL1A &IL1B); upregulated expression of antiangiogenic factor (Pigment Epithelium-derived Factor; PEDF); and downregulated expression of angiogenic factor (Vascular Endothelial Growth Factor, VEGF); in vitro, following LPS-induced NFκB activation, NKO corneal cells showed reduced expression of IL6, IP10 and TNFα. In vitro, corneal epithelial cells showed reduced NF-κb activation on silencing of NUCKS and corresponding NFκB-mediated cytokine expression was reduced. Here, we illustrate that inhibition of NUCKS played a role in cytokine modulation and facilitated corneal recovery. This reveals a potential new effective strategy for ocular burn treatment.published_or_final_versio

Endoplasmic reticulum chaperone prolyl 4-hydroxylase, beta polypeptide (P4HB) promotes malignant phenotypes in glioma via MAPK signaling

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Factors related with the university degree selection in Spanish public university system. An structural equation model analysis

The final publication is available at Springer via http://dx.doi.org/10.1007/s11135-014-0008-9Students take into account different factors in their choice of university studies and college. Some are global, as the quality of the degree (ratio available places/firstchoice places in, cut-off grade, etc.), and others are subjective factors (e.g.: my friends are also taking this degree). In this work we present a partial multivariate model that takes into account the weight of the different variables shown by different works linked to this decision. We have studied three samples (n = 372 from the Universidad Pablo de Olavide; n = 2,244 from the Universitat Politécnica de Valencia, and n = 543 from the Universitat de Barcelona) from several degrees in the 2010 2011 and 2011 2012 academic years, all of them new students, coming from high school, and who had choosen these universities as first choice. The global effect shows that the structural model fits reasonably well in the three universities studied. Similarly, university and specialty models show different intensity effects, and we found that, in the case of Universitat Politécnica de Valencia (UPV) and Universitat de Barcelona (UB), they show higher intensity than in Universidad Pablo de Olavide (UPO). This makes us think that in most urban universities with a clear and regular offer of degrees (engineering in the case of UPV, and Health and Social Sciences in the case of UB), personal and social factors are more important than in the case of universities, as is the case of UPO, with an offer and dimension not yet completely defined.Guàrdia Olmos, J.; Peró Cebollero, M.; Hervás Jorge, A.; Capilla Lladró, R.; Soriano Jiménez, PP.; Porras Yañez, M. (2014). Factors related with the university degree selection in Spanish public university system. An structural equation model analysis. Quality and Quantity. March(2014):1-19. doi:10.1007/s11135-014-0008-9S119March2014Baker, S., Brown, B.: Images of excellence: constructions of institutional prestige and reflections in the university choice process. Br. J. Sociol. Educ. 28(3), 377–391 (2007)Browne, M.W., Cudeck, R.: Alternative ways of assessing model fit. Sociol. Methods Res. 21, 230–258 (1992)Capilla, R.: Análisis estratégico de los estudios TIC en la Universidad Politécnica de Valencia. Tesis Doctoral no Publicada. Valencia: Universitat Politécnica de Valéncia. (2009). http://riunet.upv.es/handle/10251/5767 . Retrieved 11 Mar 2014Ford, D.Y.: The underrepresentation of minority students in gifted education: problems and promises in recruitment and retention. J. Spec. Educ. 31(1), 4–14 (2008)Guàrdia, J., Peró, M., Hervás, A., Capilla, R., Soriano, P.P., Porras, M.: Factores asociados con la decisión de cursar estudios universitarios de Psicología. Una aproximación mediante modelos de ecuaciones estructurales. Anuario de Psicologia 42(1), 87–104 (2012)Guerra, C., & Rueda, E.M.: Estudio longitudinal de los jóvenes en el tránsito de la enseñza secundaria a la universidad: orientación, expectativas, toma de decisiones y acogida de los nuevos estudiantes en la universidad. Dirección General de Universidades. Estudios y Análisis (2005)Hu, L., Bentler, P.M.: Cutoff criteria for fit indexes in covariance structure analysis: conventional criteria versus new alternatives. Struct. Equ. Model. 6, 1–55 (1999)Huang, Sh, Fang, N.: Predicting student academic performance in an enginnering dynamics course: a comparison for four types of predictive mathematical models. Comput. Educ. 61, 133–145 (2013)Leppel, K., Williams, M.L., Waldauer, C.: The impact of parental occupation and socioeconomic status on choice of college major. J. Fam. Econ. Issues 22(4), 373–394 (2001)Maringe, F.: University and course choice Implications for positioning, recruitment and marketing. Int. J. Educ. Manage. 20(6), 466–479 (2006)Muñiz, J.: Utilización de los test. En J. Muñiz, A.M. Fidalgo, E. García-Cueto, R. Martínez y R. Moreno (Eds.). Análisis de los ítems, (pp. 133–172). Madrid: La Muralla, S.A (2005)Murphy, P.E., McGarrity, R.A.: Marketing universities: a survey of student recruitment activities. Coll. Univ. 53(3), 249–261 (1978)Ory, D.T., Mokhtarian, P.L.: The impact of non-normality, sample size and estimation technique on goodness-of-fit measures in structural equation modeling: evidence from ten empirical models of travel behavior. Qual. Q. 44(3), 427–445 (2010)Palomo, J., Dunson, D.B., Bollen, K.: Bayesian structural equation modeling. In: Lee, S.Y. (ed.) Handbook of Latent Variable and Related Models, pp. 163–179. Elsevier, New York (2007)Perna, L.W., Titus, M.A.: Understanding differences in the choice of college attended: the role of state public policies. Rev. High. Educ. 27(4), 501–525 (2004)Poon, W.Y., Lee, S.Y.: A Distribution Free Approach for Analysis of Two-level Structural Equation Model. Elsevier, New York (1994)Price, I., Matzdorf, F., Smith, L., Agahi, H.: The impact of facilities on student choice of university. Facilities 21(10), 212–222 (2003)Raymond, S.: Predicting academic succes of first-year engineering students from standardized test scores and psychological variables. Int. J. Eng. Educ. 17(1), 75–80 (2001)Turner, C.S.V., Thompson, J.R.: Socializing women doctoral students: minority and majority experiences. Rev. High. Educ. 6, 232–241 (1993)Veenstra, C.P., Dey, E.L., Herrin, G.D.: Is modeling of freshman engineering succes different from modeling of non-engineering succes? J. Eng. Educ. 97, 467–479 (2008)Yurtseven, T.: How does the image of engineering affect student recruitment and retention? A perspective from the USA. Glob. J. Eng. Educ. 6(2), 267 (2002

Disease control and functional outcome in three modern combined organ preserving regimens for locally advanced squamous cell carcinoma of the head and neck (SCCHN)

<p>Abstract</p> <p>Purpose</p> <p>To report our experience on disease control and functional outcome using three modern combined-modality approaches for definitive radiochemotherapy of locally advanced SCCHN with modern radiotherapy techniques: radiochemotherapy (RChT), radioimmunotherapy (RIT) with cetuximab, or induction chemotherapy with docetaxel, cisplatin, and 5-FU (TPF) combined with either RChT or RIT.</p> <p>Methods</p> <p>Toxicity and outcome was retrospectively analysed in patients receiving definitive RChT, RIT, or induction chemotherapy followed by RChT or RIT between 2006 and 2009. Outcome was estimated using Kaplan-Meier analyses, toxicity was analysed according to CTCAE v 3.0.</p> <p>Results</p> <p>Thirty-eight patients were treated with RChT, 38 patients with RIT, 16 patients received TPF followed by either RChT or RIT. Radiotherapy was mostly applied as IMRT (68%). Long-term toxicity was low, only one case of grad III dysphagia requiring oesophageal dilatation, no case of either xerostomia ≥ grade II or cervical plexopathy were observed. Median overall survival (OS) was 25.7 months (RChT) and 27.7 months (RIT), median locoregional progression-free survival (PFS) was not reached yet. Subgroup analysis showed no significant differences between TPF, RChT, and RIT despite higher age and co-morbidities in the RIT group. Results suggested improved OS, distant and overall PFS for the TPF regimen.</p> <p>Conclusion</p> <p>Late radiation effects in our cohort are rare. No significant differences in outcome between RChT and RIT were observed. Adding TPF suggests improved progression-free and overall survival, impact of TPF on locoregional PFS was marginal, therefore radiotherapeutic options for intensification of local treatment should be explored.</p