Joseph R Testa

..In addition, we review recent literature documenting the various ways the AKT signaling pathway is activated in human cancers and consequences for molecularly targeted therapies...

..Using the MEK1/2 inhibitor, U0126 and stably transfected shERK1 and shERK2 MM cell lines, we show that inhibition of both ERK1 and 2 sensitizes MM cells to Dox...

..We hypothesize that other cancers may also be involved and that mesothelioma predominates upon asbestos exposure. These findings will help to identify individuals at high risk of mesothelioma who could be targeted for early intervention...

..Additional articles discuss current approaches to identify selective inhibitors of the AKT pathway...

..These findings also suggest that mouse models of MM may be useful for future preclinical studies of pharmaceuticals targeting the PI3K/AKT pathway...

..Collectively, our findings are consistent with a working model in which AKT activation regulates FAS expression, at least in part, whereas FAS activity modulates AKT activation...

..The broad long-term objective of this project was to use preclinical cancer models with precisely defined genetic lesions to elucidate the efficacy of targeting Akt with GSK690693...

..In addition, DLX5 was found to cooperate with HRAS in the transformation of human ovarian surface epithelial cells. Together, these data suggest that DLX5 plays a significant role in the pathogenesis of some ovarian cancers...

..These findings suggest that activation of the Akt pathway can act as the initial hit to promote cell survival and genomic instability, whereas the acquisition of T-cell-specific overexpression of Dlx5 or Myc leads to lymphomagenesis...

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..Because DLX5 has a restricted pattern of expression in adult tissues, it may serve as a potential therapeutic target for the treatment of cancers that overexpress DLX5...

..Furthermore, while inactivation of Arf appears to be crucial for MM pathogenesis, the inactivation of both p16(Ink4a) and p19(Arf) cooperate to accelerate asbestos-induced tumorigenesis...

..We examined whether mTOR inhibition by RAD001 (everolimus) is therapeutically efficacious in the treatment of ovarian cancer as a single agent and in combination with cisplatin...

..However, there may be additional or alternative mechanism(s) of action...

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..Collectively, our findings indicate that Appl1 is dispensable for Akt signaling in vivo and T-cell differentiation...

..Collectively, these findings indicate that active AKT and downstream mTOR represent potentially important therapeutic and/or chemopreventive targets in ovarian cancer...

..Our studies suggest that Appl1 is dispensable for development and only participate in Akt signaling under certain conditions...

..Conventional cytogenetics and FISH demonstrated loss of chromosomes Y and 1 and gains of chromosome 7. We postulate that the PRCC represents a neoplastic progression by the gain of chromosome 7 oncocytoma with -Y and -1...

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..Ornithine decarboxylase is a key enzyme in the regulation of polyamine metabolism. The aim of this study is to analyze MTAP and ornithine decarboxylase (ODC) expression in primary pancreatic tumor specimens...

..These results suggest that GISTs without activating kinase mutations, whether pediatric or adult, generally exhibit a much lower level of cytogenetic progression than that observed in mutant GISTs...

..We also review various pathogenic mechanisms contributing to activation of the AKT pathway in human malignancy as well as current pharmacologic strategies to target therapeutically components of this pathway...

..Thus, AKT represents a potentially important target for chemoprevention in individuals at high risk of NSCLC...

..In addition, DLX5, but not DLX6, was found to be abundantly expressed in three of seven human T-cell lymphomas tested. These findings suggest that the Dlx5 can act as an oncogene by cooperating with Akt2 to promote lymphomagenesis...

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..These findings also suggest that the 5q duplication/3p deficiency resulting from unbalanced 3;5 translocations conveys a proliferative advantage of particular importance in ccRCC tumorigenesis...

..Detectable effects of "one-hit" represent early molecular changes in tumorigenesis that may serve as targets for chemopreventive intervention...

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..A case of the rare, benign, Wilms' tumor (WT) variant, metanephric adenofibroma (MAF), is presented...

..These findings demonstrate the utility of SNP-based mapping arrays for high-resolution analysis of genomic imbalances in cancer cells...

..Taken together, our data suggest that the addition of MTA to anti-purine-based chemotherapy may greatly increase the therapeutic index of this class of drugs if used specifically to treat MTAP (-) tumors...

..Here, we highlight FAF1's role in NFkappaB signaling and postulate that this pathway has critical connotations for the pathogenesis and treatment of human cancers...

..Collectively, these data suggest that pharmacologic inhibition of group I PAKs may have therapeutic efficacy in tumors characterized by PAK activation...

..In addition, the patient had no evidence of a renal angiomyolipoma at autopsy and therefore demonstrated for the first time that somatic TSC2 mutations cause LAM in patients without angiomyolipomas...

..We propose that p53 causes transactivation-independent growth inhibition of ALT cells by perturbing telomeric recombination...

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..Our finding that Rpl22 inactivation promotes transformation by inducing expression of Lin28B provides the first insight into the mechanistic basis by which mutations in Rpl22, and perhaps some other RP genes, increases cancer risk...

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..To our knowledge, this is the first report of the genetic and cytogenetic findings in oncocytosis not related to BDH syndrome and may suggest a possible model of progression from oncocytoma to chromophobe renal cell carcinoma...

..The molecular implications of consistent chromosome imbalances found in lung cancer to date are also discussed...

..The results demonstrate that the C-terminal domain of NHERF functions as an intramolecular switch that regulates the binding capability of PDZ2, and thus controls the stoichiometry of NHERF to assemble protein complexes...

..Both mutation as well as copy number changes can be used as predictive markers for this purpose...

..In this review, we summarize the involvement of NF2 inactivation in tumorigenesis. We also discuss observations implicating merlin in cell motility and cell proliferation, with a focus on recent findings linking merlin to Rac signaling...

..Overall, these data suggest that upstream perturbations of the PI3K/AKT pathway contribute to frequent activation of AKT2 in pancreatic cancer, which may contribute to the pathogenesis of this highly aggressive form of human malignancy...

..These biochemical investigations provide insights into the regulation of merlin function and establish a framework for elucidating tumorigenic mechanisms involved in neoplasms associated with merlin inactivation...

..These data indicate that ArgBP2gamma is a physiological substrate of Akt, functions as an adaptor for Akt and PAK1, and plays a role in Akt/PAK1 cell survival pathway...

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..These observations suggest that AKT signaling augments resistance to stress-induced apoptosis in breast cancer cells overexpressing HER-2/neu...

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..These results support the concept that the recently identified alpha-catulin protein may modulate Rho pathway signaling in vivo by providing a scaffold for the Lbc Rho guanine nucleotide exchange factor...

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..Induction of telomerase activity by SV40 may be related to the very high rate of mesothelial cell immortalization that is characteristically associated with SV40 infection of mesothelial cells...

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..The finding that Nef induces phosphorylation of the key signaling molecule merlin suggests several possible roles for PAK2 activation in HIV pathogenesis...

..These mechanistic approaches offer new hope for early detection and treatment of these devastating tumors...

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..Data suggest that HGF-induced effects in some MM cells are mediated via activation of a novel PI3K/ERK5/Fra-1 feedback pathway that might explain tumor-specific effects of c-Met inhibitors on MM and other tumors...

..3-q21.2. Taken together, these studies provide insight into the molecular pathways involved in the regulation of ALT and reveal several loci that might be exploited either as prognostic markers or targets of chemotherapeutic intervention...

..Collectively, these findings indicate that NGB is a tumor suppressor that regulates and requires merlin to suppress cell proliferation...

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..PI3K activity, but not mTOR, may regulate transcriptional activity of myogenin. Our data also suggest that Akt1 and Akt2 play distinct roles in myogenic differentiation...

..Mesothelioma appears to have a complex etiology in which environmental carcinogens (asbestos and erionite), ionizing radiation, viruses, and genetic factors act alone or in concert to cause malignancy...