A highly invasive human glioblastoma pre-clinical model for testing therapeutics

Animal models greatly facilitate understanding of cancer and importantly, serve pre-clinically for evaluating potential anti-cancer therapies. We developed an invasive orthotopic human glioblastoma multiforme (GBM) mouse model that enables real-time tumor ultrasound imaging and pre-clinical evaluation of anti-neoplastic drugs such as 17-(allylamino)-17-demethoxy geldanamycin (17AAG). Clinically, GBM metastasis rarely happen, but unexpectedly most human GBM tumor cell lines intrinsically possess metastatic potential. We used an experimental lung metastasis assay (ELM) to enrich for metastatic cells and three of four commonly used GBM lines were highly metastatic after repeated ELM selection (M2). These GBM-M2 lines grew more aggressively orthotopically and all showed dramatic multifold increases in IL6, IL8, MCP-1 and GM-CSF expression, cytokines and factors that are associated with GBM and poor prognosis. DBM2 cells, which were derived from the DBTRG-05MG cell line were used to test the efficacy of 17AAG for treatment of intracranial tumors. The DMB2 orthotopic xenografts form highly invasive tumors with areas of central necrosis, vascular hyperplasia and intracranial dissemination. In addition, the orthotopic tumors caused osteolysis and the skull opening correlated to the tumor size, permitting the use of real-time ultrasound imaging to evaluate antitumor drug activity. We show that 17AAG significantly inhibits DBM2 tumor growth with significant drug responses in subcutaneous, lung and orthotopic tumor locations. This model has multiple unique features for investigating the pathobiology of intracranial tumor growth and for monitoring systemic and intracranial responses to antitumor agents

The Interplay of Variants Near LEKR and CCNL1 and Social Stress in Relation to Birth Size

Background We previously identified via a genome wide association study variants near LEKR and CCNL1 and in the ADCY5 genes lead to lower birthweight. Here, we study the impact of these variants and social stress during pregnancy, defined as social adversity and neighborhood disparity, on infant birth size. We aimed to determine whether the addition of genetic variance magnified the observed associations. Methodology/Principal Findings We analyzed data from the Northern Finland Birth Cohort 1986 (n = 5369). Social adversity was defined by young maternal age (<20 years), low maternal education (<11 years), and/or single marital status. Neighborhood social disparity was assessed by discrepancy between neighborhoods relative to personal socio-economic status. These variables are indicative of social and socioeconomic stress, but also of biological risk. The adjusted multiple regression analysis showed smaller birth size in both infants of mothers who experienced social adversity (birthweight by −40.4 g, 95%CI −61.4, −19.5; birth length −0.14 cm, 95%CI −0.23, −0.05; head circumference −0.09 cm 95%CI −0.15, −0.02) and neighborhood disparity (birthweight −28.8 g, 95%CI −47.7, −10.0; birth length −0.12 cm, 95%CI −0.20, −0.05). The birthweight-lowering risk allele (SNP rs900400 near LEKR and CCNL1) magnified this association in an additive manner. However, likely due to sample size restriction, this association was not significant for the SNP rs9883204 in ADCY5. Birth size difference due to social stress was greater in the presence of birthweight-lowering alleles. Conclusions/Significance Social adversity, neighborhood disparity, and genetic variants have independent associations with infant birth size in the mutually adjusted analyses. If the newborn carried a risk allele rs900400 near LEKR/CCNL1, the impact of stress on birth size was stronger. These observations give support to the hypothesis that individuals with genetic or other biological risk are more vulnerable to environmental influences. Our study indicates the need for further research to understand the mechanisms by which genes impact individual vulnerability to environmental insults

Importance of proximity to resources, social support, transportation and neighborhood security for mobility and social participation in older adults: results from a scoping study

ABSTRACT: Background: Since mobility and social participation are key determinants of health and quality of life, it is important to identify factors associated with them. Although several investigations have been conducted on the neighborhood environment, mobility and social participation, there is no clear integration of the results. This study aimed to provide a comprehensive understanding regarding how the neighborhood environment is associated with mobility and social participation in older adults.Methods: A rigorous methodological scoping study framework was used to search nine databases from different fields with fifty-one keywords. Data were exhaustively analyzed, organized and synthesized according to the International Classification of Functioning, Disability and Health (ICF) by two research assistants following PRISMA guidelines, and results were validated with knowledge users.Results: The majority of the 50 selected articles report results of cross-sectional studies (29; 58 %), mainly conducted in the US (24; 48 %) or Canada (15; 30 %). Studies mostly focused on neighborhood environment associations with mobility (39; 78 %), social participation (19; 38 %), and occasionally both (11; 22 %). Neighborhood attributes considered were mainly 'Pro ducts and technology' (43; 86) and 'Services, systems and policies' (37; 74 %), but also 'Natural and human- made changes' (27; 54 %) and 'Support and relationships' (21; 42 %). Mobility and social participation were both positively associated with Proximity to resources and recreational facilities, Social support, Having a car or driver's license, Public transportation and Neighborhood security, and negatively associated with Poor user-friendliness of the walking environment and Neighborhood insecurity. Attributes of the neighborhood environment not covered by previous research on mobility and social participation mainly concerned 'Attitudes', and 'Services, systems and policies'.Conclusion: Results from this comprehensive synthesis of empirical studies on associations of the neighborhood environment with mobility and social participation will ultimately support best practices, decisions and the development of innovative inclusive public health interventions including clear guidelines for the creation of age-supportive environments. To foster mobility and social participation, these interventions must consider Proximity to resources and to recreational facilities, Social support, Transportation, Neighborhood security and User-friendliness of the walking environment. Future studies should include both mobility and social participation, and investigate how they are associated with 'Attitudes', and 'Services, systems and policies' in older adults, including disadvantaged older adults