Anti-proliferative but not anti-angiogenic tyrosine kinase inhibitors enrich for cancer stem cells in soft tissue sarcoma.

BackgroundIncreasing studies implicate cancer stem cells (CSCs) as the source of resistance and relapse following conventional cytotoxic therapies. Few studies have examined the response of CSCs to targeted therapies, such as tyrosine kinase inhibitors (TKIs). We hypothesized that TKIs would have differential effects on CSC populations depending on their mechanism of action (anti-proliferative vs. anti-angiogenic).MethodsWe exposed human sarcoma cell lines to sorafenib, regorafenib, and pazopanib and assessed cell viability and expression of CSC markers (ALDH, CD24, CD44, and CD133). We evaluated survival and CSC phenotype in mice harboring sarcoma metastases after TKI therapy. We exposed dissociated primary sarcoma tumors to sorafenib, regorafenib, and pazopanib, and we used tissue microarray (TMA) and primary sarcoma samples to evaluate the frequency and intensity of CSC markers after neoadjuvant therapy with sorafenib and pazopanib. Parametric and non-parametric statistical analyses were performed as appropriate.ResultsAfter functionally validating the CSC phenotype of ALDHbright sarcoma cells, we observed that sorafenib and regorafenib were cytotoxic to sarcoma cell lines (P < 0.05), with a corresponding 1.4 - 2.8 fold increase in ALDHbright cells from baseline (P < 0.05). In contrast, we observed negligible effects on viability and CSC sub-populations with pazopanib. At low doses, there was progressive CSC enrichment in vitro after longer term exposure to sorafenib although the anti-proliferative effects were attenuated. In vivo, sorafenib improved median survival by 11 days (P < 0.05), but enriched ALDHbright cells 2.5 - 2.8 fold (P < 0.05). Analysis of primary human sarcoma samples revealed direct cytotoxicity following exposure to sorafenib and regorafenib with a corresponding increase in ALDHbright cells (P < 0.05). Again, negligible effects from pazopanib were observed. TMA analysis of archived specimens from sarcoma patients treated with sorafenib demonstrated significant enrichment for ALDHbright cells in the post-treatment resection specimen (P < 0.05), whereas clinical specimens obtained longitudinally from a patient treated with pazopanib showed no enrichment for ALDHbright cells (P > 0.05).ConclusionsAnti-proliferative TKIs appear to enrich for sarcoma CSCs while anti-angiogenic TKIs do not. The rational selection of targeted therapies for sarcoma patients may benefit from an awareness of the differential impact of TKIs on CSC populations

Applicability of the Theory of Planned Behavior for Predicting Alcohol Use in Spanish Early Adolescents

According to the theory of planned behavior (TPB), intentions to perform a specific behavior are the result of attitudes, norms, and perceived control, and in turn, intentions and perceived control are the main predictors of the behavior. This study aimed to test the applicability of TPB in predicting alcohol use in normative pre-adolescents. The sample was composed of 755 Spanish adolescents aged 11 to 15 (M = 12.24; SD = 0.56), 47.1% females, from 12 state secondary schools in Spain. The results of path analysis indicate that positive attitudes towards alcohol, favorable norms towards alcohol, and offer vulnerability (perceived control) are significantly positively related to intentions to use alcohol as well as negatively related to actual behavioral control (i.e., actual strategies to avoid alcohol use). In turn, intentions to use and actual control predict higher alcohol frequency and heavy drinking. Significant indirect effects of these antecedents were found on alcohol outcomes through the mediation of intentions and actual control. The findings suggest that the validity and applicability of the TPB in normative pre-adolescents depend on the severity of alcohol use and point to a need to consider negative social influence in decision making processes in early adolescenceThis research was funded by the Global Center for Applied Health Research (GCAHR; Arizona State University) and supported by the Programa de Axudas á etapa posdoutoral da Xunta de Galicia (Consellería de Cultura, Educación e Ordenación Universitaria) and by FEDER/Ministerio de Ciencia, Innovación y Universidades—Agencia Estatal de Investigación (Grant PSI2015-65766-R)—under the Axuda para a consolidación e estruturación de unidades de investigación competitivas e outras accións de fomento nas universidades do SUG (GRC, 2018)S

Pennsylvania Folklife Vol. 26, No. 2

• Battalion Day: Militia Exercise and Frolic in Pennsylvania Before the Civil War • Folklore in the Library: Cherished Memories of Old Lancaster • Widows\u27 Wills for Philadelphia County, 1750-1784: A Study of Pennsylvania German Folklife • Forest County Lore • The Big Valley Amish of Central Pennsylvania: A Community of Cultural Contrasts • Maurice A. Mook (1904-1973): An Appreciation • Collectanea: Ore-Mining and Basket-Making in Maxatawny ; The Sharadin Tannery at Kutztown ; Occult Lore Recorded in Cumberland County • German Immigrants in America as Presented in Travel Accounts • The Pie and Related Forms in Pennsylvania Cuisine: Folk-Cultural Questionnaire No. 46https://digitalcommons.ursinus.edu/pafolklifemag/1071/thumbnail.jp

Rehabilitation: A crucial component in the future of HIV care and support

Provision of antiretroviral therapy (ART) is not an end in itself but a means to achieving improved wellness for people living with HIV. Rehabilitation, broadly defined, is another key contributor to wellness within this context. Understanding the potential for rehabilitation requires that one is able to consider HIV not only within a biomedical model that focuses on body systems, diagnoses and symptoms, but also within a rehabilitation framework that focuses on how these diagnoses and symptoms affect people’s lives more broadly. Furthermore, rehabilitation is a human rights imperative, which deserves the energetic attention enjoyed by other aspects of HIV treatment and care. In particular, the United Nations Convention on the Rights of Persons with Disabilities (UNCRPD) is shining a long-overdue spotlight on the human rights imperatives associated with disability. For South Africa and other countries, proactively and meaningfully engaging rehabilitation in the HIV response will require major shifts on several fronts, including practice, education, policy and research. We argue that in settings where ART delivery is now widespread, HIV should be understood not only as a medical issue, but as a rehabilitation and disability concern. Whereas medicine adds years to life, it is rehabilitation that aims to add life to years

Anti-proliferative but not anti-angiogenic tyrosine kinase inhibitors enrich for cancer stem cells in soft tissue sarcoma

The templated zeolite-analogue GaPO-34 (CHA structure type) crystallises from a gel precursor Ga2O3:2H3PO4:1HF:1.7SDA:70H2O (where SDA = structure directing agent), treated hydrothermally for 24 hours at 170 °C using either pyridine or 1-methylimizadole as SDA and one of either poorly crystalline ε-Ga2O3 or γ-Ga2O3 as gallium precursor. If the same gels are stirred for periods shorter than 2 hours but treated under identical hydrothermal conditions, then a second phase crystallises, free of GaPO-34. If β-Ga2O3 is used as a reagent only the second phase is found to crystallise, irrespective of gel aging time. The competing phase, which we denote GaPO-34A, has been structurally characterised using synchrotron powder X-ray diffraction for the pyridine material, GaPO-34A(pyr), and using single-crystal X-ray diffraction for the 1-methylimiazole material, GaPO-34A(mim). The structure of GaPO-34A(pyr), P1 @#x0305;, a = 10.22682(6) Å, b = 12.09585(7) Å, c = 13.86713(8) Å, α = 104.6531(4) °, β = 100.8111(6) °, γ = 102.5228(6) °, contains 7 unique gallium sites and 6 phosphorus sites, with empirical formula [Ga7P6O24(OH)2F3(H2O)2].2(C5NH6). GaPO-34A(mim) is isostructural but is modelled as a half volume unit cell, P1 @#x0305;, a = 5.0991(2) Å, b = 12.0631(6) Å, c = 13.8405(9) Å, α = 104.626(5) °, β = 100.346(5) °, γ = 101.936(4) °, with a gallium and a bridging fluoride partially occupied and two partially occupied SDA sites. Solid-state 31P and 71Ga NMR spectroscopy confirms the structural complexity of GaPO-34A with signals resulting from overlapping lineshapes from multiple Ga and P sites, while 1H and 13C solid-state NMR spectra confirm the presence of the protonated SDA and provide evidence for disorder in the SDA. The protonated SDA is located in 14-ring one-dimensional channels with hydrogen bonding deduced from the SDA nitrogens to framework oxygen distances. Upon thermal treatment to investigate SDA removal, structure collapse occurs, which may be due the large number of bridging hydroxides and fluorides in the as-made material, and the unequal amounts of gallium and phosphorus present

Global timber investments, 2005 to 2017

We estimated timber investment returns for 22 countries and 54 species/management regimes in 2017, for a range of global timber plantation species and countries at the stand level, using capital budgeting criteria, without land costs, at a real discount rate of 8%. Returns were estimated for the principal plantation countries in the Americas-Brazil, Argentina, Uruguay, Chile, Colombia, Venezuela, Paraguay, Mexico, and the United States-as well as New Zealand, Australia, South Africa, China, Vietnam, Laos, Spain, Finland, Poland, Scotland, and France. South American plantation growth rates and their concomitant returns were generally greater, at more than 12% Internal Rates of Return (IRRs), as were those in China, Vietnam, and Laos. These IRRs were followed by those for plantations in southern hemisphere countries of Australia and New Zealand and in Mexico, with IRRs around 8%. Temperate forest plantations in the U.S. and Europe returned less, from 4% to 8%, but those countries have less financial risk, better timber markets, and more infrastructure. Returns to most planted species in all countries except Asia have decreased from 2005 to 2017. If land costs were included in calculating the overall timberland investment returns, the IRRs would decrease from 3 percentage points less for loblolly pine in the U.S. South to 8 percentage points less for eucalypts in Brazil.Peer reviewe

Experiencias del Espacio Multidisciplinario de Interacción SocioAmbiental (EMISA) –Plaguicidas

El CIMA posee una trayectoria de más de 20 años en el estudio de la contaminación ambiental, siendo los agrotóxicos una de sus líneas de investigación principales. A principios del año 2010 se comenzaron a recibir consultas de distintos pueblos respecto al impacto de las prácticas agrícolas. Esta situación llevó a investigadores y estudiantes del CIMA a vincularse con movimientos de vecinos organizados y médicos de pueblos fumigados. Inicialmente se realizaron monitoreos ambientales en distintas regiones del territorio dirigidas a evaluar la presencia de agrotóxicos en muestras de suelos, aguas y aire. La gran demanda social, el vacío de información y el avance de los sistemas agro-productivos promovieron estrategias integradas de trabajo con la comunidad. Esta creciente construcción de un espacio de multivoces permitió pensar y discutir los problemas ambientales en un contexto tanto técnico como social y político. Surge entonces el Espacio Multidisciplinario de Interacción Socio Ambiental-EMISA en permanente retroalimentación socio-colectiva, aportando resultados objetivos, de base científica y por demanda social para la defensa de la salud y el ambiente.Centro de Investigaciones del Medioambient

A first AFLP-based genetic linkage map for brine shrimp Artemia franciscana and its application in mapping the sex locus

We report on the construction of sex-specific linkage maps, the identification of sex-linked markers and the genome size estimation for the brine shrimp Artemia franciscana. Overall, from the analysis of 433 AFLP markers segregating in a 112 full-sib family we identified 21 male and 22 female linkage groups (2n = 42), covering 1,041 and 1,313 cM respectively. Fifteen putatively homologous linkage groups, including the sex linkage groups, were identified between the female and male linkage map. Eight sex-linked AFLP marker alleles were inherited from the female parent, supporting the hypothesis of a WZ-ZZ sex-determining system. The haploid Artemia genome size was estimated to 0.93 Gb by flow cytometry. The produced Artemia linkage maps provide the basis for further fine mapping and exploring of the sex-determining region and are a possible marker resource for mapping genomic loci underlying phenotypic differences among Artemia species

Sex-specific effects of the local social environment on juvenile post-fledging dispersal in great tits

An individual’s decision to disperse from the natal habitat can affect its future fitness prospects. Especially in species with sex-biased dispersal, we expect the cost–benefit balance for dispersal to vary according to the social environment (e.g., local sex ratio and density). However, little is known about the social factors affecting dispersal decisions and about the temporal and spatial patterns of the dispersal process. In our study, we investigated experimentally the effects of the social environment on post-fledging dispersal of juvenile great tits by simultaneously manipulating the density and sex ratio of fledglings within forest plots. We expected young females in the post-fledging period mainly to compete for resources related to food and, as they are subordinate to males, we predicted higher female dispersal from male-biased plots. Juvenile males compete for vacant territories already in late summer and autumn; thus, we predicted increased male dispersal from high density and male-biased plots. We found that juvenile females had a higher probability to leave male-biased plots and had dispersed further from male-biased plots in the later post-fledging phase when juvenile males start to become territorial and more aggressive. Juvenile males were least likely to leave male-biased plots and had smallest dispersal distances from female-biased plots early after fledging. The results suggest that the social environment differentially affected the costs and benefits of philopatry for male and female juveniles. The local sex ratio of individuals is thus an important social trait to be considered for understanding sex-specific dispersal processes