196,063 research outputs found
Proteomic characterization of the antiangiogenic activity of PF4-DLR in glioblastomas
No full textnon disponibileThe prognosis of the most common glial tumors, the glioblastoma (GBM; World
Health Organization grade IV), remains poor with 2-year survival rates at less than
20% despite significant advances in therapeutic options available to patients. The
dependence of tumor growth and metastasis on angiogenesis has provided powerful
rationale for anti-angiogenic approaches to cancer therapy (Folkman J. 1971;
Carmeliet P. et al. 2000). One of the most important negative regulators of
angiogenesis is platelet factor-4 (PF-4). In a previous study Hagedorn M. et al.
demonstrated that PF4-DLR inhibits tumor growth in an intracranial glioma model.
In this study we use a proteomic approach to better understand the molecular
mechanisms involved in PF4-DLR response. Experiments were performed on
gliomas treated for 10 and 20 days with PF4-DLR. Two–dimensional SDSpolyacrylamide
gel elecrophoresis technique (2D-SDS-PAGE) was use to compare
protein expression pattern between treated and untreated tumors. In tumors treated
with PF4-DLR for 10 days we identified 24 proteins that were differentially
expressed (p<0.05) in response to the treatment. In mice treated with PF4-DLR for
20 days we identified 30 proteins to be differentially expressed (p<0.05)
subsequently to the treatment.
A bioinformatics analysis of the identified proteins revealed the complexity of the
pathway modulated by PF4-DLR treatment and suggest that two different protein
populations is regulated by the treatment: one involved in growth inhibition
mediated by PF4-DLR and one involved in tumor escape. Most of the proteins we
have identified at 20 days of treatment seem to be functionally involved in
regulating tumor growth and escape.
Interestingly we detected in tumors from animals treated with PF4-DLR for 10 days
a significant decrease of ILK levels compared with untreated tumors while in mice
treated with PF4-DLR for 20 days we detected a significant increase of ILK levels
compared with untreated tumors.
We also analyzed the ILK levels in human low grade gliomas compared with
human high grade gliomas. We found a significant increase of ILK in high grade
gliomas compared to low grade. Consequently ILK can represent a new molecular
target for gliomas therapy. Thus, as first approach, we have identified specific ILK
siRNA that are able to reduce glioma cell proliferation.
Our data taken together indicate that the combinatorial administration of compounds
that simultaneously inhibit angiogenesis and tumor cell proliferation by targeting
specific signaling pathways might results in a significant increase in the therapeutic
efficacy
Capturing Value by Extending the End of Life of a Machining Department Through Data Analytics: An Industrial Use Case
No full textThe neuropeptide PACAP38 induces dendritic spine remodeling through ADAM10-N-cadherin signaling pathway
No full textThe neuropeptide pituitary adenylate cyclase-activating polypeptide 38 (PACAP38) has been implicated in the induction of synaptic plasticity at the excitatory glutamatergic synapse. In particular, recent studies have shown that it is involved in the regulation of Nmethyl-D-aspartate (NMDA) and a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor activation. Here we demonstrate the effect of PACAP38 on the modulation of dendritic spine morphology through a disintegrin and metalloproteinase 10 (ADAM10)-N-cadherin-AMPA receptor signaling pathway. Treatment of primary hippocampal neurons with PACAP38 induced an accumulation of ADAM10 at the postsynaptic membrane. This event led to a significant decrease of dendritic spine head width and to a concomitant reduction of GluR1 colocalization with postsynaptic markers. The PACAP38-induced effect on dendritic spine head width was prevented by either treatment with the ADAM10-specific inhibitor or transfection of a cleavage-defective N-cadherin construct mutated in the ADAM10 cleavage site. Overall, our findings reveal that PACAP38 is involved in the modulation of dendritic spine morphology in hippocampal neurons, and assign to the ADAM10-N-cadherin signaling pathway a crucial role in this modification of the excitatory glutamatergic synaps
Combined targeting of interleukin-6 and vascular endothelial growth factor potently inhibits glioma growth and invasiveness
No full textInterleukin-6 (IL6) and vascular endothelial growth factor (VEGFA) are abundantly produced by glioma cells and contribute to malignancy by promoting angiogenesis, cell proliferation and resistance to apoptosis. We compared the effect of inhibiting IL6 and VEGF on U87-derived experimental glioma grown on the chick chorio-allantoic membrane (CAM) or in the brain of xenografted mice. Tumor growth was monitored by biomicroscopy and immunohistology. In vitro, IL6 knockdown had no effect on proliferation but substantially enhanced invasion. In the CAM experimental glioma, IL6 or VEGF knockdown reduced growth and vascularization of the tumors with a comparable efficiency, but increased invasion of residual tumor cells. In contrast, combined IL6/VEGF knockdown not only showed enhanced reduction of tumor growth and angiogenesis but also significantly prevented invasion of residual tumor cells. In mice, combining IL6 knockdown and Avastin treatment completely abrogated tumor development and infiltration. Molecular response of tumor cells to single or combined treatment was studied by transcriptomic profiling. Many cell cycle promoting genes and chromatin components were silenced in the double knockdown. In addition, specific migratory signatures detected in tumors under single IL6 or VEGF knockdown were partially erased in combined IL6/VEGF knockdown tumors. Our results show that treatment with a combination of IL6 and VEGF inhibitors brings synergistic antitumoral benefit and reduces global activity of major pathways of cell survival, proliferation and invasiveness in remaining tumor cells that may be induced by using VEGF or IL6 inhibitors alone
Dr. Duane M. Jackson, Morehouse College, July 2011
No full textThis video is a conversation with Dr. Duane M. Jackson. Dr. Jackson talks about his paper, "Recall and the Serial Position Effect: The Role of Primacy and Recency on Accounting Students' Performance." Jackie Daniel, AUC Woodruff Library, is the interviewer
Elongation factor-2 phosphorylation in dendrites and the regulation of dendritic mRNA translation in neurons
No full textNeuronal activity results in long lasting changes in synaptic structure and function by regulating mRNA translation in dendrites. These activity dependent events yield the synthesis of proteins known to be important for synaptic modifications and diverse forms of synaptic plasticity. Worthy of note, there is accumulating evidence that the eukaryotic Elongation Factor 2 Kinase (eEF2K)/eukaryotic Elongation Factor 2 (eEF2) pathway may be strongly involved in this process. Upon activation, eEF2K phosphorylates and thereby inhibits eEF2, resulting in a dramatic reduction of mRNA translation. eEF2K is activated by elevated levels of calcium and binding of Calmodulin (CaM), hence its alternative name calcium/CaM-dependent protein kinase III (CaMKIII). In dendrites, this process depends on glutamate signaling and N-methyl-D-aspartate receptor (NMDAR) activation. Interestingly, it has been shown that eEF2K can be activated in dendrites by metabotropic glutamate receptor (mGluR) 1/5 signaling, as well. Therefore, neuronal activity can induce local proteomic changes at the postsynapse by altering eEF2K activity. Well-established targets of eEF2K in dendrites include brain-derived neurotrophic factor (BDNF), activity-regulated cytoskeletal-associated protein (Arc), the alpha subunit of calcium/CaM-dependent protein kinase II (αCaMKII), and microtubule-associated protein 1B (MAP1B), all of which have well-known functions in different forms of synaptic plasticity. In this review we will give an overview of the involvement of the eEF2K/eEF2 pathway at dendrites in regulating the translation of dendritic mRNA in the context of altered NMDAR- and neuronal activity, and diverse forms of synaptic plasticity, such as metabotropic glutamate receptor-dependent-long-term depression (mGluR-LTD). For this, we draw on studies carried out both in vitro and in vivo
The GluR2 subunit inhibits proliferation by inactivating Src-MAPK signalling and induces apoptosis by means of caspase 3/6-dependent activation in glioma cells
No full textGlioblastoma multiforme (GBM) is the most invasive and undifferentiated type of brain tumour, and so surgical interventions are ineffective. We found that GluR2 is absent in fast-growing GBM-derived tumour stem cells and high-grade glioma specimens, but is expressed in slow-growing stem cells and low-grade glioma specimens. More remarkably, GluR2 overexpression in U-87MG cells inhibits proliferation by inactivating extracellular signal-regulated kinase (ERK)1/2-Src phosphorylation and induces apoptosis. Mechanistically, we observed that the scaffold protein GRIP is essential for the effect of GluR2 on ERK-Src inactivation. These findings indicate that the absence of the GluR2 subunit favours malignancy
"Reflections on the subject of Emigration from Europe with a view to Settlement in the United States" By M. Carey.
No full text"Reflections on the subject of Emigration from Europe with a view to Settlement in the United States: containing bried sketches of the moral and political character of those states.
By M. Carey, member of the American philosophical, and of the American Antiquarian Society, and author of The Olive Branch, Cindiciae Hibernicae, essays on banking, on political economy, and on internal improvement.
To which are now added the English editor's comments on the subject; together with Important Advice to Emigrants, and Cautions Against Impositions Practiced in the Outports
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