Co-targeting HGF/cMET Signaling with MEK Inhibitors in Metastatic Uveal Melanoma.

Patients with metastatic uveal melanoma usually die within 1 year of diagnosis, emphasizing an urgent need to develop new treatment strategies. The liver is the most common site of metastasis. Mitogen-activated protein kinase kinase (MEK) inhibitors improve survival in V600 BRAF-mutated cutaneous melanoma patients but have limited efficacy in patients with uveal melanoma. Our previous work showed that hepatocyte growth factor (HGF) signaling elicits resistance to MEK inhibitors in metastatic uveal melanoma. In this study, we demonstrate that expression of two BH3-only family proteins, Bim-EL and Bmf, contributes to HGF-mediated resistance to MEK inhibitors. Targeting HGF/cMET signaling with LY2875358, a neutralizing and internalizing anti-cMET bivalent antibody, and LY2801653, a dual cMET/RON inhibitor, overcomes resistance to trametinib provided by exogenous HGF and by conditioned medium from primary hepatic stellate cells. We further determined that activation of PI3Kα/γ/δ isoforms mediates the resistance to MEK inhibitors by HGF. Combination of LY2801653 with trametinib decreases AKT phosphorylation and promotes proapoptotic PARP cleavage in metastatic uveal melanoma explants. Together, our data support the notion that selectively blocking cMET signaling or PI3K isoforms in metastatic uveal melanoma may break the intrinsic resistance to MEK inhibitors provided by factors from stromal cells in the liver

Anti-phospholipid human monoclonal antibodies inhibit CCR5-tropic HIV-1 and induce β-chemokines

Traditional antibody-mediated neutralization of HIV-1 infection is thought to result from the binding of antibodies to virions, thus preventing virus entry. However, antibodies that broadly neutralize HIV-1 are rare and are not induced by current vaccines. We report that four human anti-phospholipid monoclonal antibodies (mAbs) (PGN632, P1, IS4, and CL1) inhibit HIV-1 CCR5-tropic (R5) primary isolate infection of peripheral blood mononuclear cells (PBMCs) with 80% inhibitory concentrations of <0.02 to ∼10 µg/ml. Anti-phospholipid mAbs inhibited PBMC HIV-1 infection in vitro by mechanisms involving binding to monocytes and triggering the release of MIP-1α and MIP-1β. The release of these β-chemokines explains both the specificity for R5 HIV-1 and the activity of these mAbs in PBMC cultures containing both primary lymphocytes and monocytes

Oxidative stress in children late after Kawasaki disease: relationship with carotid atherosclerosis and stiffness

Background: Persistent arterial dysfunction in patients with a history of Kawasaki disease (KD) and an integral role of oxidative stress in the development of cardiovascular disease are increasingly recognized. We sought to test the hypothesis that oxidative stress is increased in KD patients and related to carotid atherosclerotic changes and stiffness. Methods: We compared the serum levels of oxidative stress biomarkers, carotid intima-media thickness (IMT), and carotid stiffness index among KD patients with coronary aneurysms (n = 32), those without coronary complications (n = 19), and controls (n = 32). Results: Compared with controls, patients with coronary aneurysms had significantly higher serum levels of malonaldehyde (2.62 ± 0.12 μM vs 2.22 ± 0.07 μM, p = 0.014) and hydroperoxides (26.50 ± 1.13 μM vs 22.50 ± 0.62 μM, p = 0.008). A linear trend of the magnitude of oxidative stress in relation to inflammatory damage was observed for malonaldehyde (p = 0.018) and hydroperoxides (p = 0.014) levels. Serum malonaldehyde and hydroperoxide levels correlated positively with carotid IMT (p < 0.001 and p = 0.034, respectively) and stiffness index (p = 0.001 and p = 0.021, respectively). Multiple linear regression analysis identified serum malonaldehyde level as a significant determinant of carotid IMT (β = 0.31, p = 0.006) and stiffness (β = 0.27, p = 0.008). Conclusion: Our findings suggestoxidative stress is increased in KD patients with coronary aneurysms and is associated with carotid intima-media thickening and stiffening. © 2008 Cheung et al; licensee BioMed Central Ltd.published_or_final_versio

Engaging students globally without leaving the comforts of home

To meet the needs of and preparing graduates to enter the 21st century business environment, higher education institutions have realized global learning is now an essential part of the knowledge and skill sets needed by business graduates. Global competency is no longer a luxury. This article describes how a regional higher education institution has implemented active learning projects and assessments which integrate global competency in the core and elective courses. Students can complete these projects and assessments without leaving the comforts of their homes, the campus, or the U.S. and still be exposed to a global experience. The purpose of the study was to examine the global competency students acquire through active learning projects and assessments in different classes. Specifically, the study sought to determine the students’ perceived satisfaction level with these global active learning experiences, and to determine if they perceived their global competency had increased. Data analysis suggests the students were gaining global competencies using active learning projects and assessments. Also, from seven of the specific courses, the students indicated they were satisfied or very satisfied with their acquired global competency in six courses. Additionally, the students’ perceived global competence increased after taking the courses which implemented these projects and assessments. Therefore, it appears students can gain global competency through active learning projects and assessments used in courses without leaving the comforts of home

Thrombopoietin Receptor Agonist Mitigates Hematopoietic Radiation Syndrome and Improves Survival after Whole-Body Ionizing Irradiation Followed by Wound Trauma

Ionizing radiation combined with trauma tissue injury (combined injury, CI) results in greater mortality and H-ARS than radiation alone (radiation injury, RI), which includes thrombocytopenia. The aim of this study was to determine whether increases in numbers of thrombocytes would improve survival and mitigate H-ARS after CI. We observed in mice that WBC and platelets remained very low in surviving RI animals that were given 9.5 Gy 60Co-γ-photon radiation, whereas only lymphocytes and basophils remained low in surviving CI mice that were irradiated and then given skin wounds. Numbers of RBC and platelets, hemoglobin concentrations, and hematocrit values remained low in surviving RI and CI mice. CI induced 30-day mortality higher than RI. Radiation delayed wound healing by approximately 14 days. Treatment with a thrombopoietin receptor agonist, Alxn4100TPO, after CI improved survival, mitigated body-weight loss, and reduced water consumption. Though this therapy delayed wound-healing rate more than in vehicle groups, it greatly increased numbers of platelets in sham, wounded, RI, and CI mice; it significantly mitigated decreases in WBC, spleen weights, and splenocytes in CI mice and decreases in RBC, hemoglobin, hematocrit values, and splenocytes and splenomegaly in RI mice. The results suggest that Alxn4100TPO is effective in mitigating CI