MCL-1 inhibition provides a new way to suppress breast cancer metastasis and increase sensitivity to dasatinib.

BACKGROUND: Metastatic disease is largely resistant to therapy and accounts for almost all cancer deaths. Myeloid cell leukemia-1 (MCL-1) is an important regulator of cell survival and chemo-resistance in a wide range of malignancies, and thus its inhibition may prove to be therapeutically useful. METHODS: To examine whether targeting MCL-1 may provide an effective treatment for breast cancer, we constructed inducible models of BIMs2A expression (a specific MCL-1 inhibitor) in MDA-MB-468 (MDA-MB-468-2A) and MDA-MB-231 (MDA-MB-231-2A) cells. RESULTS: MCL-1 inhibition caused apoptosis of basal-like MDA-MB-468-2A cells grown as monolayers, and sensitized them to the BCL-2/BCL-XL inhibitor ABT-263, demonstrating that MCL-1 regulated cell survival. In MDA-MB-231-2A cells, grown in an organotypic model, induction of BIMs2A produced an almost complete suppression of invasion. Apoptosis was induced in such a small proportion of these cells that it could not account for the large decrease in invasion, suggesting that MCL-1 was operating via a previously undetected mechanism. MCL-1 antagonism also suppressed local invasion and distant metastasis to the lung in mouse mammary intraductal xenografts. Kinomic profiling revealed that MCL-1 antagonism modulated Src family kinases and their targets, which suggested that MCL-1 might act as an upstream modulator of invasion via this pathway. Inhibition of MCL-1 in combination with dasatinib suppressed invasion in 3D models of invasion and inhibited the establishment of tumors in vivo. CONCLUSION: These data provide the first evidence that MCL-1 drives breast cancer cell invasion and suggests that MCL-1 antagonists could be used alone or in combination with drugs targeting Src kinases such as dasatinib to suppress metastasis

Cortisol secretion after adrenocorticotrophin (ACTH) and Dexamethasone tests in healthy female and male dogs

<p>Abstract</p> <p>Background</p> <p>For the conclusive diagnosis of Cushing's Syndrome, a stimulating ACTH test or a low suppressive Dexamethasone test is used. Reports in other species than the dog indicate that plasma cortisol concentration after ACTH administration is affected by gender. We investigated the effect of gender on the cortisol response to ACTH and Dexamethasone tests in dogs.</p> <p>Methods</p> <p>Seven healthy adult Cocker Spaniels (4 females and 3 males) were assigned to a two by two factorial design: 4 dogs (2 females and 2 males) received IV Dexamethasone 0.01 mg/kg, while the other 3 dogs received an IV saline solution (control group). Two weeks later the treatments were reversed. After one month, ACTH was given IV (250 μg/animal) to 4 dogs (2 female and 2 males) while the rest was treated with saline solution (control group). Cortisol concentrations were determined by a direct solid-phase radioimmunoassay and cholesterol and triglycerides by commercial kits.</p> <p>Results and Discussion</p> <p>No effect of treatment was observed in metabolite concentrations, but females presented higher cholesterol concentrations. ACTH-treated dogs showed an increase in cortisol levels in the first hour after sampling until 3 hours post injection. Cortisol concentrations in Dexamethasone-treated dogs decreased one hour post injection and remained low for 3 hours, thereafter cortisol concentrations increased. The increase in cortisol levels from one to two hours post ACTH injection was significantly higher in females than males. In Dexamethasone-treated males cortisol levels decreased one hour post injection up to 3 hours; in females the decrease was more pronounced and prolonged, up to 5 hours post injection.</p> <p>Conclusion</p> <p>We have demonstrated that cortisol response to ACTH and Dexamethasone treatment in dogs differs according to sex.</p

Strongly magnetized pulsars: explosive events and evolution

Well before the radio discovery of pulsars offered the first observational confirmation for their existence (Hewish et al., 1968), it had been suggested that neutron stars might be endowed with very strong magnetic fields of $10^{10}$-$10^{14}$G (Hoyle et al., 1964; Pacini, 1967). It is because of their magnetic fields that these otherwise small ed inert, cooling dead stars emit radio pulses and shine in various part of the electromagnetic spectrum. But the presence of a strong magnetic field has more subtle and sometimes dramatic consequences: In the last decades of observations indeed, evidence mounted that it is likely the magnetic field that makes of an isolated neutron star what it is among the different observational manifestations in which they come. The contribution of the magnetic field to the energy budget of the neutron star can be comparable or even exceed the available kinetic energy. The most magnetised neutron stars in particular, the magnetars, exhibit an amazing assortment of explosive events, underlining the importance of their magnetic field in their lives. In this chapter we review the recent observational and theoretical achievements, which not only confirmed the importance of the magnetic field in the evolution of neutron stars, but also provide a promising unification scheme for the different observational manifestations in which they appear. We focus on the role of their magnetic field as an energy source behind their persistent emission, but also its critical role in explosive events.Comment: Review commissioned for publication in the White Book of "NewCompStar" European COST Action MP1304, 43 pages, 8 figure

Reaction rates and transport in neutron stars

Understanding signals from neutron stars requires knowledge about the transport inside the star. We review the transport properties and the underlying reaction rates of dense hadronic and quark matter in the crust and the core of neutron stars and point out open problems and future directions.Comment: 74 pages; commissioned for the book "Physics and Astrophysics of Neutron Stars", NewCompStar COST Action MP1304; version 3: minor changes, references updated, overview graphic added in the introduction, improvements in Sec IV.A.

Mathematical properties of weighted impact factors based on measures of prestige of the citing journals

The final publication is available at Springer via http://dx.doi.org/10.1007/s11192-015-1741-0An abstract construction for general weighted impact factors is introduced. We show that the classical weighted impact factors are particular cases of our model, but it can also be used for defining new impact measuring tools for other sources of information as repositories of datasets providing the mathematical support for a new family of altmet- rics. Our aim is to show the main mathematical properties of this class of impact measuring tools, that hold as consequences of their mathematical structure and does not depend on the definition of any given index nowadays in use. In order to show the power of our approach in a well-known setting, we apply our construction to analyze the stability of the ordering induced in a list of journals by the 2-year impact factor (IF2). We study the change of this ordering when the criterium to define it is given by the numerical value of a new weighted impact factor, in which IF2 is used for defining the weights. We prove that, if we assume that the weight associated to a citing journal increases with its IF2, then the ordering given in the list by the new weighted impact factor coincides with the order defined by the IF2. We give a quantitative bound for the errors committed. We also show two examples of weighted impact factors defined by weights associated to the prestige of the citing journal for the fields of MATHEMATICS and MEDICINE, GENERAL AND INTERNAL, checking if they satisfy the increasing behavior mentioned above.Ferrer Sapena, A.; Sánchez Pérez, EA.; González, LM.; Peset Mancebo, MF.; Aleixandre Benavent, R. (2015). Mathematical properties of weighted impact factors based on measures of prestige of the citing journals. 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In: Proceedings of MDAI 2012 modeling decisions for artificial intelligence. Lecture Notes in Computer Science, Vol. 7647, pp. 35–44.Beliakov, G., & James, S. (2011). Citation-based journal ranks: The use of fuzzy measures. Fuzzy Sets and Systems, 167, 101–119.Buela-Casal, G. (2003). Evaluating quality of articles and scientific journals. Proposal of weighted impact factor and a quality index. Psicothema, 15(1), 23–25.Dorta-Gonzalez, P., & Dorta-Gonzalez, M. I. (2013). Comparing journals from different fields of science and social science through a JCR subject categories normalized impact factor. Scientometrics, 95(2), 645–672.Dorta-Gonzalez, P., Dorta-Gonzalez, M. I., Santos-Penate, D. R., & Suarez-Vega, R. (2014). Journal topic citation potential and between-field comparisons: The topic normalized impact factor. Journal of Informetrics, 8(2), 406–418.Egghe, L., & Rousseau, R. (2002). A general frame-work for relative impact indicators. Canadian Journal of Information and Library Science, 27(1), 29–48.Gagolewski, M., & Mesiar, R. (2014). Monotone measures and universal integrals in a uniform framework for the scientific impact assessment problem. Information Sciences, 263, 166–174.Garfield, E. (2006). The history and meaning of the journal impact factor. JAMA, 295(1), 90–93.Habibzadeh, F., & Yadollahie, M. (2008). Journal weighted impact factor: A proposal. Journal of Informetrics, 2(2), 164–172.Klement, E., Mesiar, R., & Pap, E. (2010). A universal integral as common frame for Choquet and Sugeno integral. IEEE Transaction on Fuzzy System, 18, 178–187.Leydesdorff, L., & Opthof, T. (2010). Scopus’s source normalized impact per paper (SNIP) versus a journal impact factor based on fractional counting of citations. Journal of the American Society for Information Science and Technology, 61, 2365–2369.Li, Y. R., Radicchi, F., Castellano, C., & Ruiz-Castillo, J. (2013). Quantitative evaluation of alternative field normalization procedures. Journal of Informetrics, 7(3), 746–755.Moed, H. F. (2010). Measuring contextual citation impact of scientific journals. Journal of Informetrics, 4, 265–277.NISO. (2014). Alternative metrics initiative phase 1. White paper. http://www.niso.org/apps/group-public/download.php/13809/Altmetrics-project-phase1-white-paperOwlia, P., Vasei, M., Goliaei, B., & Nassiri, I. (2011). Normalized impact factor (NIF): An adjusted method for calculating the citation rate of biomedical journals. Journal of Biomedical Informatics, 44(2), 216–220.Pinski, G., & Narin, F. (1976). Citation influence for journal aggregates of scientific publications: Theory, with application to the literature of physics. Information Processing and Management, 12, 297–312.Pinto, A. C., & Andrade, J. B. (1999). Impact factor of scientific journals: What is the meaning of this parameter? Quimica Nova, 22, 448–453.Raghunathan, M. S., & Srinivas, V. (2001). Significance of impact factor with regard to mathematics journals. Current Science, 80(5), 605.Ruiz Castillo, J., & Waltman, L. (2015). Field-normalized citation impact indicators using algorithmically constructed classification systems of science. Journal of Informetrics, 9, 102–117.Saha, S., Saint, S., & Christakis, D. A. (2003). Impact factor: A valid measure of journal quality? Journal of the Medical Library Association, 91, 42–46.Torra, V., & Narukawa, Y. (2008). The h-index and the number of citations: Two fuzzy integrals. IEEE Transaction on Fuzzy System, 16, 795–797.Torres-Salinas, D., & Jimenez-Contreras, E. (2010). Introduction and comparative study of the new scientific journals citation indicators in journal citation reports and scopus. El Profesional de la Información, 19, 201–207.Waltman, L., & van Eck, N. J. (2008). Some comments on the journal weighted impact factor proposed by Habibzadeh and Yadollahie. Journal of Informetrics, 2(4), 369–372.Waltman, L., van Eck, N. J., van Leeuwen, T. N., & Visser, M. S. (2013). Some modifications to the SNIP journal impact indicator. Journal of Informetrics, 7, 272–285.Zitt, M. (2011). Behind citing-side normalization of citations: some properties of the journal impact factor. Scientometrics, 89, 329–344.Zitt, M., & Small, H. (2008). Modifying the journal impact factor by fractional citation weighting: The audience factor. Journal of the American Society for Information Science and Technology, 59, 1856–1860.Zyczkowski, K. (2010). Citation graph, weighted impact factors and performance indices. Scientometrics, 85(1), 301–315

Cellular Mechanisms Underlying the Laxative Effect of Flavonol Naringenin on Rat Constipation Model

BACKGROUND & AIMS: Symptoms of constipation are extremely common, especially in the elderly. The present study aim to identify an efficacious treatment strategy for constipation by evaluating the secretion-promoting and laxative effect of a herbal compound, naringenin, on intestinal epithelial anion secretion and a rat constipation model, respectively. METHODS/PRINCIPAL FINDINGS: In isolated rat colonic crypts, mucosal addition of naringenin (100 microM) elicited a concentration-dependent and sustained increase in the short-circuit current (I(SC)), which could be inhibited in Cl- free solution or by bumetanide and DPC (diphenylamine-2-carboxylic acid), but not by DIDS (4, 4'- diisothiocyanatostilbene-2, 2'-disulfonic acid). Naringenin could increase intracellular cAMP content and PKA activity, consisted with that MDL-12330A (N-(Cis-2-phenyl-cyclopentyl) azacyclotridecan-2-imine-hydrochloride) pretreatment reduced the naringenin-induced I(SC). In addition, significant inhibition of the naringenin-induced I(SC) by quinidine indicated that basolateral K+ channels were involved in maintaining this cAMP-dependent Cl- secretion. Naringenin-evoked whole cell current which exhibited a linear I-V relationship and time-and voltage- independent characteristics was inhibited by DPC, indicating that the cAMP activated Cl- conductance most likely CFTR (cystic fibrosis transmembrane conductance regulator) was involved. In rat constipation model, administration of naringenin restored the level of fecal output, water content and mucus secretion compared to loperamide-administrated group. CONCLUSIONS: Taken together, our data suggest that naringenin could stimulate Cl- secretion in colonic epithelium via a signaling pathway involving cAMP and PKA, hence provide an osmotic force for subsequent colonic fluid secretion by which the laxative effect observed in the rat constipation model. Naringenin appears to be a novel alternative treatment strategy for constipation

Demographic variation in incidence of adult glioma by subtype, United States, 1992-2007

<p>Abstract</p> <p>Background</p> <p>We hypothesized that race/ethnic group, sex, age, and/or calendar period variation in adult glioma incidence differs between the two broad subtypes of glioblastoma (GBM) and non-GBM. Primary GBM, which constitute 90-95% of GBM, differ from non-GBM with respect to a number of molecular characteristics, providing a molecular rationale for these two broad glioma subtypes.</p> <p>Methods</p> <p>We utilized data from the Surveillance, Epidemiology, and End Results Program for 1992-2007, ages 30-69 years. We compared 15,088 GBM cases with 9,252 non-GBM cases. We used Poisson regression to calculate adjusted rate ratios and 95% confidence intervals.</p> <p>Results</p> <p>The GBM incidence rate increased proportionally with the 4^thpower of age, whereas the non-GBM rate increased proportionally with the square root of age. For each subtype, compared to non-Hispanic Whites, the incidence rate among Blacks, Asians/Pacific Islanders, and American Indians/Alaskan Natives was substantially lower (one-fourth to one-half for GBM; about two-fifths for non-GBM). Secondary to this primary effect, race/ethnic group variation in incidence was significantly less for non-GBM than for GBM. For each subtype, the incidence rate was higher for males than for females, with the male/female rate ratio being significantly higher for GBM (1.6) than for non-GBM (1.4). We observed significant calendar period trends of increasing incidence for GBM and decreasing incidence for non-GBM. For the two subtypes combined, we observed a 3% decrease in incidence between 1992-1995 and 2004-2007.</p> <p>Conclusions</p> <p>The substantial difference in age effect between GBM and non-GBM suggests a fundamental difference in the genesis of primary GBM (the driver of GBM incidence) versus non-GBM. However, the commonalities between GBM and non-GBM with respect to race/ethnic group and sex variation, more notable than the somewhat subtle, albeit statistically significant, differences, suggest that within the context of a fundamental difference, some aspects of the complex process of gliomagenesis are shared by these subtypes as well. The increasing calendar period trend of GBM incidence coupled with the decreasing trend of non-GBM incidence may at least partly be due to a secular trend in diagnostic fashion, as opposed to real changes in incidence of these subtypes.</p

What zinc supplementation does and does not achieve in diarrhea prevention: a systematic review and meta-analysis

<p>Abstract</p> <p>Background</p> <p>Prevention of diarrhea has presented indomitable challenges. A preventive strategy that has received significant interest is zinc supplementation. Existing literature including quantitative meta-analyses and systematic reviews tend to show that zinc supplementation is beneficial however evidence to the contrary is augmenting. We therefore conducted an updated and comprehensive meta-analytical synthesis of the existing literature on the effect of zinc supplementation in prevention of diarrhea.</p> <p>Methods</p> <p>EMBASE^®, MEDLINE ^®and CINAHL^®databases were searched for published reviews and meta-analyses on the use of zinc supplementation for the prevention childhood diarrhea. Additional RCTs published following the meta-analyses were also sought. Effect of zinc supplementation on the following five outcomes was studied: incidence of diarrhea, prevalence of diarrhea, incidence of persistent diarrhea, incidence of dysentery and incidence of mortality. The published RCTs were combined using random-effects meta-analyses, subgroup meta-analyses, meta-regression, cumulative meta-analyses and restricted meta-analyses to quantify and characterize the role of zinc supplementation with the afore stated outcomes.</p> <p>Results</p> <p>We found that zinc supplementation has a modest beneficial association (9% reduction) with incidence of diarrhea, a stronger beneficial association (19% reduction) with prevalence of diarrhea and occurrence of multiple diarrheal episodes (28% reduction) but there was significant unexplained heterogeneity across the studies for these associations. Age, continent of study origin, zinc salt and risk of bias contributed significantly to between studies heterogeneity. Zinc supplementation did not show statistically significant benefit in reducing the incidence of persistent diarrhea, dysentery or mortality. In most instances, the 95% prediction intervals for summary relative risk estimates straddled unity.</p> <p>Conclusions</p> <p>Demonstrable benefit of preventive zinc supplementation was observed against two of the five diarrhea-related outcomes but the prediction intervals straddled unity. Thus the evidence for a preventive benefit of zinc against diarrhea is inconclusive. Continued efforts are needed to better understand the sources of heterogeneity. The outcomes of zinc supplementation may be improved by identifying subgroups that need zinc supplementation.</p

The Spread of Tomato Yellow Leaf Curl Virus from the Middle East to the World

The ongoing global spread of Tomato yellow leaf curl virus (TYLCV; Genus Begomovirus, Family Geminiviridae) represents a serious looming threat to tomato production in all temperate parts of the world. Whereas determining where and when TYLCV movements have occurred could help curtail its spread and prevent future movements of related viruses, determining the consequences of past TYLCV movements could reveal the ecological and economic risks associated with similar viral invasions. Towards this end we applied Bayesian phylogeographic inference and recombination analyses to available TYLCV sequences (including those of 15 new Iranian full TYLCV genomes) and reconstructed a plausible history of TYLCV's diversification and movements throughout the world. In agreement with historical accounts, our results suggest that the first TYLCVs most probably arose somewhere in the Middle East between the 1930s and 1950s (with 95% highest probability density intervals 1905–1972) and that the global spread of TYLCV only began in the 1980s after the evolution of the TYLCV-Mld and -IL strains. Despite the global distribution of TYLCV we found no convincing evidence anywhere other than the Middle East and the Western Mediterranean of epidemiologically relevant TYLCV variants arising through recombination. Although the region around Iran is both the center of present day TYLCV diversity and the site of the most intensive ongoing TYLCV evolution, the evidence indicates that the region is epidemiologically isolated, which suggests that novel TYLCV variants found there are probably not direct global threats. We instead identify the Mediterranean basin as the main launch-pad of global TYLCV movements

Cannabidiol Reduces Aβ-Induced Neuroinflammation and Promotes Hippocampal Neurogenesis through PPARγ Involvement

Peroxisome proliferator-activated receptor-γ (PPARγ) has been reported to be involved in the etiology of pathological features of Alzheimer's disease (AD). Cannabidiol (CBD), a Cannabis derivative devoid of psychomimetic effects, has attracted much attention because of its promising neuroprotective properties in rat AD models, even though the mechanism responsible for such actions remains unknown. This study was aimed at exploring whether CBD effects could be subordinate to its activity at PPARγ, which has been recently indicated as its putative binding site. CBD actions on β-amyloid-induced neurotoxicity in rat AD models, either in presence or absence of PPAR antagonists were investigated. Results showed that the blockade of PPARγ was able to significantly blunt CBD effects on reactive gliosis and subsequently on neuronal damage. Moreover, due to its interaction at PPARγ, CBD was observed to stimulate hippocampal neurogenesis. All these findings report the inescapable role of this receptor in mediating CBD actions, here reported