Mice lacking the vascular endothelial growth factor (VEGF) receptor flt-1 die of vascular overgrowth, and we are interested in how flt-1 normally prevents this outcome. Our results support a model whereby aberrant endothelial cell division is the cellular mechanism resulting in vascular overgrowth, and they suggest that VEGF-dependent endothelial cell division is normally finely modulated by flt-1 to produce blood vessels. Flt-1 ؊/؊ embryonic stem cell cultures had a 2-fold increase in endothelial cells by day 8, and the endothelial cell mitotic index was significantly elevated before day 8. . Some of the mitogenic signals that promote division of endothelial cells and their precursors are known, but how these signals are modulated to initiate cell divisions only when and where they are needed is not known in detail. After blood vessels initially form, maturation and remodeling steps involve the recruitment of ancillary cells, such as smooth muscle and pericytes. These cells and the extracellular matrix that is also produced can negatively modulate endothelial cell division. [4][5][6][7][8] However, modulators of endothelial cell mitogenesis at the earliest stages of blood vessel formation have not been identified.The vascular endothelial growth factor (VEGF) signaling pathway is clearly critical to both early endothelial cell division and morphogenesis, and its regulation is complex (reviewed in Ferrara & Davis-Smyth 9 and Neufeld et al 10 ). Mouse embryos lacking even one copy of the VEGF gene die in utero with severe vascular defects, and vascular development in differentiating embryonic stem (ES) cells is compromised in VEGF-A ϩ/Ϫ and VEGF-A Ϫ/Ϫ ES cells in a dose-dependent manner. [11][12][13] Moreover, even modestly elevated levels of VEGF lead to vascular abnormalities, 14 and large doses of VEGF invariably severely compromise both vascular development and neovascularization in adult organisms. [15][16][17] These findings suggest that VEGF signaling must be precisely controlled during vascularization to result in proper vessels. The location and duration of VEGF expression provide the first level of control, [18][19][20][21] but other components of the pathway are likely to be involved in fine-tuning the signal.Two high-affinity receptors, flk-1 and flt-1, participate in VEGF signal transduction and are candidates to be involved in fine-tuning mechanisms. Both receptors are membrane-spanning receptor tyrosine kinases that bind VEGF with high affinity, 22-26 but their effects on VEGF signaling are very different. Mice or ES cells lacking flk-1 have little or no blood vessel formation, suggesting that many downstream effects of VEGF on endothelial cells are mediated through flk-1. 27,28 Specifically, numerous studies show that VEGF signaling through flk-1 produces a strong mitogenic signal for endothelial cells. [29][30][31][32] In contrast, VEGF binding to flt-1 does not produce a strong mitogenic signal, and flt-1 Ϫ/Ϫ mice die at mid-gestation with vascular overgrowth and disorganization. 23,29,33 This ph...
OBJECTIVES Parents and caregivers’ responses to their child’s gender identity or expression play a pivotal role in their mental health. Despite increasing visibility of transgender and gender diverse (TGD) children, few scientific resources exist to advise their parents and caregivers. METHODS We used an online Delphi study to generate expert consensus. Expert adult participants (N = 93; 55% cisgender women, 12% cisgender men, 33% gender minority; 83% White race or ethnicity) rated statements describing parenting strategies compiled from a systematic search of community-generated online literature. Participants represented 3 distinct “panels” of expertise: parents and caregivers of a TGD child, TGD persons, and/or professionals working with TGD populations. Statements rated as essential or important by 80% to 100% of each panel were endorsed as a guideline. Three rounds of surveys were used with iterative feedback to develop consensus. RESULTS Of 813 total statements, only 125 were endorsed by all 3 panels. Key domains of consensus included: supportive strategies for parents (eg, open communication, listening), behaviors to avoid (eg, pressuring a child into a gender transition), strategies for navigating healthcare and school systems, and common responses for parents (eg, confusion). Areas of disagreement, in which professional and TGD panels concurred but the parent panel did not, included whether to allow gender identity experimentation during childhood, the value of providing access to gender diverse media, and how to avoid misgendering a child. CONCLUSIONS These consensus-based guidelines offer a unique and needed resource for parents and caregivers and clinicians and can be used to promote the mental health and well-being of TGD children.
Adolescent relationship abuse (ARA) has well-documented detrimental health effects. Adolescence is a window of opportunity to promote development of healthy relationship behaviors. Although peer-led interventions have a history of use in the health education field, there are few rigorously evaluated peer-led interventions targeting ARA. Start Strong leverages peer support by training adolescents to deliver ARA prevention curriculum to younger peers. Although the program has shown positive results in recipients, little is known about the impact on the peer leaders themselves. This qualitative study describes the impact of being an ARA prevention peer leader on former peer leaders’ relationships and trajectories in emerging adulthood. Specific objectives include: (a) how being a peer leader shaped participants’ norms around romantic relationships and ARA, and (b) the impact of participating in a peer leadership program on their emerging adult lives. Researchers conducted semi-structured interviews with former peer leaders and coded transcripts using thematic analysis. Fourteen former peer leaders aged 18–26 participated. Most participants (99%) identified as Black or Afro-Latinx. Participants described a lasting impact on their relationships, identity formation, future orientation, and professional lives. Participants highlighted the skills they use to avoid unhealthy relationships and help friends and family navigate their relationships. They identified unexpected challenges, including a sense of isolation around how their relationship expectations differ from same-aged peers, and trepidation about dating partners without advanced healthy relationship knowledge. Participants highlighted positive impacts beyond those pertaining to relationships, including their identity development and expanded sense of opportunity. Finally, they identified tangible skills gained from program participation and relevance to their professional paths. This study suggests that peer-led ARA prevention programs have a far-reaching impact on participants’ lives that lasts into adulthood. Future studies may examine how professional development within peer-led interventions can influence future orientation and thus bolster protective factors against ARA.
Focal Adhesion Kinase (FAK) is a key regulator of cancer cell migration and invasion and overexpression of FAK and Src has been associated with resistance to current anticancer therapies. Thus, inhibition of FAK may represent a promising therapeutic approach to anti-cancer treatment. We investigated the anti-cancer activity of the FAK inhibitor (GSK2256098) in a panel of 26 human glioblastoma (GBM) cell lines. GBM is one of the most aggressive and lethal forms of cancer, characterized by exponential growth and diffuse invasiveness. Herein, we report that 8/26 GBM cell lines displayed sensitivity to FAK inhibition in both migration and Matrigel invasion assays. GSK2256098 had minimal effect on 2D cell proliferation. Integrated genomic and proteomic analyses revealed up-regulation of the PI3K and MAPK pathways in the FAK inhibitor-resistant GBM cell lines, suggesting possible drug combination strategies. To test this hypothesis, we assessed the effects of combining GSK2256098 with a PI3K inhibitor and a MEK inhibitor in the FAK inhibitor-resistant GBM cell lines. Our results suggest that multi-agent inhibition of FAK and MEK or PI3K may provide an attractive therapeutic strategy for GBM. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3714. doi:1538-7445.AM2012-3714
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