RasGRP3 Mediates MAPK Pathway Activation in GNAQ Mutant Uveal Melanoma

Constitutive activation of Gαq signaling by mutations in GNAQ or GNA11 occurs in over 80% of uveal melanomas (UMs) and activates MAPK. Protein kinase C (PKC) has been implicated as a link, but the mechanistic details remained unclear. We identified PKC δ and ɛ as required and sufficient to activate MAPK in GNAQ mutant melanomas. MAPK activation depends on Ras and is caused by RasGRP3, which is significantly and selectively overexpressed in response to GNAQ/11 mutation in UM. RasGRP3 activation occurs via PKC δ- and ɛ-dependent phosphorylation and PKC-independent, DAG-mediated membrane recruitment, possibly explaining the limited effect of PKC inhibitors to durably suppress MAPK in UM. The findings nominate RasGRP3 as a therapeutic target for cancers driven by oncogenic GNAQ/11

No relationship between 2',3'-cyclic nucleotide 3'-phosphodiesterase and schizophrenia in the Chinese Han population: an expression study and meta-analysis

<p>Abstract</p> <p>Background</p> <p>2',3'-Cyclic nucleotide 3'-phosphodiesterase (<it>CNP</it>), one of the promising candidate genes for schizophrenia, plays a key part in the oligodendrocyte function and in myelination. The present study aims to investigate the relationship between <it>CNP </it>and schizophrenia in the Chinese population and the effect of different factors on the expression level of <it>CNP </it>in schizophrenia.</p> <p>Methods</p> <p>Five <it>CNP </it>single nucleotide polymorphisms (SNPs) were investigated in a Chinese Han schizophrenia case-control sample set (n = 180) using direct sequencing. The results were included in the following meta-analysis. Quantitative real-time polymerase chain reaction (PCR) was conducted to examine <it>CNP </it>expression levels in peripheral blood lymphocytes.</p> <p>Results</p> <p>Factors including gender, genotype, sub-diagnosis and antipsychotics-treatment were found not to contribute to the expression regulation of the <it>CNP </it>gene in schizophrenia. Our meta-analysis produced similar negative results.</p> <p>Conclusion</p> <p>The results suggest that the <it>CNP </it>gene may not be involved in the etiology and pathology of schizophrenia in the Chinese population.</p

A prospective study of preoperative computed tomographic angiography for head and neck reconstruction with anterolateral thigh flaps

Background: During anterolateral thigh flap harvest, inadequate perforators may necessitate modification of the flap design, exploration of the contralateral thigh, or additional flap harvest. Computed tomographic angiography may facilitate perforator mapping and optimize flap design. The authors performed this pilot study to determine the predictive power of computed tomographic angiography in anterolateral thigh flap planning and execution. Methods: Sixteen consecutive computed tomographic angiography-mapped anterolateral thigh flaps for head and neck reconstruction were studied. Perforator location, origin, caliber, and course were compared between computed tomographic angiography and intraoperative findings. The relationship of patient characteristics, imaging studies, and intraoperative factors to flap design and surgical outcomes was analyzed. Results: Among the 16 anterolateral thigh flaps, 40 of 54 perforators identified intraoperatively were visible on computed tomographic angiography, resulting in 74 percent sensitivity. Intraoperative perforator location averaged 0.35 cm from the computed tomographic angiography-predicted location. The overall ability of computed tomographic angiography to predict perforator size was 67.5 percent. Its overall accuracy in predicting whether a perforator took a septocutaneous or intramuscular course before perforating the deep fascia was 77.5 percent. Preoperative angiography resulted in surgeons modifying the operative plan in 37 percent of cases and 57 percent of double-island flap cases. All flaps were elevated successfully and survived. Conclusions: Computed tomographic angiography identified larger perforators better than smaller ones and proximal perforators better than distal ones. It accurately predicted the location and origin of visible perforators and less accurately predicted the size and course of visible perforators. Most importantly, the information it provided influenced surgeons to modify their reconstructive strategy, resulting in a higher level of recipient-site specificity. Copyright © 2011 by the American Society of Plastic Surgeons