Sickle-cell disease plays a disproportionately high role in childhood stroke when a biracial population is surveyed.
Melanoma is one of the most devastating malignances with a rising incidence and lack of effective treatments for advanced disease. Constitutive activation of the mitogen-activated protein kinase (MAPK) pathway and altered expression of A v B 3 integrin are critical for melanoma development and progression. Ras-associated protein-1 (Rap1), a Ras family member of the small GTPases, has emerged as a key mediator in these two important processes. In this study, we have shown Rap1 activation in cells derived from two human metastatic melanomas and also in three of seven cutaneous metastatic melanoma tissues. We found increased extracellular signalregulated kinase (ERK) activity in the tumors with detected Rap1 activity that interestingly harbored neither BRAF nor N-Ras mutation, suggesting a role for Rap1 in ERK activation in vivo. We also showed Rap1 and ERK activation by both hepatocyte growth factor (HGF) and 8CPT-2Me-cAMP (an activator of Epac, a Rap1 guanine nucleotide exchange factor) in two human melanoma cell lines. In addition, the activation of ERK by HGF was reduced, at least in part, by small interfering RNAs against Rap1 and a dominant-negative Rap1. Finally, a functional role for Rap1 activation was shown by Rap1-induced A v B 3 integrin activation and consequent increased melanoma cell migration in vitro. Taken together, these results show that Rap1 is involved in the activation of MAPK pathway and integrin activation in human melanoma and suggest a potential role for Rap1 in melanoma tumorigenesis and metastasis. (Cancer Res 2006; 66(16): 7880-8)
SummaryPulmonary hypertension (PHT) is an important co‐morbidity in sickle cell disease (SCD). Despite increasing research in adults, the prevalence and implication of this condition in children is unknown. Charts of 362 SCD patients followed at the Children's Hospital & Research Center Oakland were reviewed to determine clinical variables associated with obtaining echocardiographic screening for PHT, clinical associations of PHT, and associated mortality following diagnosis in adults and children with SCD. In this cohort, patients with underlying lung abnormalities or those on chronic transfusions were more likely to have echocardiograms, however the diagnosis of PHT was often unrecognized. A different clinical phenotype for PHT in adults versus children was identified. Associations with PHT for adults included age, renal and lung disease, hepatitis C, chronic transfusions, and a history of acute chest syndrome (ACS), with ACS being protective. Surprisingly, for children, a history of sepsis, along with a history of ACS, or obstructive lung disease were associated with PHT. Survival analysis found significant mortality for PHT, with a hazard ratio of 17·3 (95% confidence interval 4·9–60·4). The divergent clinical spectrum for PHT between adults and children may point to different age‐specific mechanisms or biological expression of PHT.
Tyro3, a member of the Tyro3/Axl/Mer (TAM) family of receptor tyrosine kinases, has emerged as a potential oncogene in melanoma. Here, we confirm that Tyro3 is specifically overexpressed in primary melanoma samples and show that Tyro3 is expressed at varying levels in numerous melanoma cell lines. Short hairpin RNA-mediated knockdown of Tyro3 led to significant cell death via apoptotic mechanisms in nearly all melanoma cell lines tested, regardless of the BRAF or NRAS mutation status or co-expression of Axl and/or Mer. We generated soluble and monomeric versions of the human Tyro3 extracellular domain and human Gas6 for affinity measurements and correlated these values with the level of Gas6 required to induce Tyro3 signaling in cellular assays. Calcium was critical for the correct folding of Gas6 and its binding to Tyro3. In melanoma cell lines, Gas6 induced Tyro3 phosphorylation and downstream Akt phosphorylation without apparent effects on Erk. We generated monoclonal antibodies (mAbs) against Tyro3 to examine their effect on survival signaling in melanoma cell lines. The mAbs generated against Tyro3 included nonligand blockers, partial blockers, and competitive ligand blockers. A number of weak and partial ligand blockers (all recognizing the Tyro3 Ig domains) were the most effective at blocking ligand-mediated downstream signaling of Tyro3. Overall, these data indicate that Tyro3 may confer increased survival signals in melanoma cells and can be stymied using inhibitory mAbs. These mAbs may be useful for further investigations of the role of Tyro3 in melanoma.
BackgroundThe built environment plays a critical role in promoting physical activity and health. The association between parks, as a key attribute of the built environment, and physical activity, however, remains inconclusive. This project leverages a natural experiment opportunity to assess the impact of the Community Parks Initiative (CPI), a citywide park redesign and renovation effort in New York City, on physical activity, park usage, psychosocial and mental health, and community wellbeing.MethodsThe project will use a longitudinal design with matched controls. Thirty intervention park neighborhoods are socio-demographically matched to 20 control park neighborhoods. The study will investigate whether improvements in physical activity, park usage, psychosocial and mental health, and community wellbeing are observed from baseline to 3 years post-renovation among residents in intervention vs. control neighborhoods.DiscussionThis study represents a rare opportunity to provide robust evidence to further our understanding of the complex relationship between parks and health. Findings will inform future investments in health-oriented urban design policies and offer evidence for addressing health disparities through built environment strategies.
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