Phosphatidylinositol 3-kinase (PI3K) is a key player in cell-growth signaling in a number of lymphoid malignancies, but its role in diffuse large B-cell lymphoma (DLBCL) has not been fully elucidated. Therefore, we investigated the role of the PI3K/AKT pathway in a panel of 5 DLBCL cell lines and 100 clinical samples. Inhibition of PI3K by a specific inhibitor, LY294002, induced apoptosis in SUDHL4, SUDHL5, and SUDHL10 (LY-sensitive) cells, whereas SUDHL8 and OCI-LY19 (LYresistant) cells were refractory to LY294002-induced apoptosis. AKT was phosphorylated in 5 of 5 DLBCL cell lines and inhibition of PI3K caused dephosphorylation/inactivation of constitutively active AKT, FOXO transcription factor, and GSK3 in LY-sensitive cell lines. In addition, there was a decrease in the expression level of inhibitory apoptotic protein, XIAP, in the DLBCL cell lines sensitive to LY294002 after treatment. However, no effect was observed in XIAP protein levels in the resistant DLBCL cell lines following LY294002 treatment. Finally, using immunohistochemistry, p-AKT was detected in 52% of DLBCL tumors tested. Furthermore, in univariate analysis, high p-AKT expression was associated with short survival. In multivariate analysis, this correlation was no longer significant. Altogether, these results suggest that the PI3K/AKT pathway may be a potential target for therapeutic intervention in DLBCL. IntroductionB-cell lymphoma represents the malignant counterpart of normal B cells arrested at specific maturational stages. Diffuse large B-cell lymphoma (DLBCL) is considered to be the most common type of lymphoma in adults, accounting for 30% to 40% of cases of non-Hodgkin lymphoma. 1 Although patients with DLBCLs are potentially curable with combination chemotherapy, the disease proves fatal in approximately 50% of patients. 2 The cause of most DLBCLs remains unknown; however, dysregulation of apoptosis or defective repair plays a role in lymphogenesis. 3 A number of constitutively activated growth signaling pathways have frequently been observed in DLBCL including protein kinase AKT and nuclear factor B (NF-B) transcription factor. [4][5][6] Protein kinases have been implicated as having crucial roles in regulating cell growth, metabolic responses, cell proliferation, migration, and apoptosis, which altogether contribute to tumorigenesis. Constitutive activation of these protein kinases, mainly by phosphorylation, has been implicated as contributing to malignant phenotypes in a number of human cancers. [7][8][9] AKT is a serine threonine kinase that gets activated on growth factor and cytokine stimulation. When phosphoinositide-3,4,5-triphosphate (PIP 3 ) is generated by phosphatidylinositol 3Ј-kinase (PI3K) in response to an intracellular signal, it binds to the PH domain of AKT and translocates to the plasma membrane resulting in the activation of phosphoinositidedependent protein kinases (PDK1 and PDK2). Activated PDK1 and PDK2 phosphorylate at the Thr308 and Ser473 residues of the AKT kinase domain, resulting in its activation. ...

Context: Genetic aberration in phosphatidylinositol 3-kinase (PI3K)/AKT pathway has been detected in numerous and diverse human cancers. PIK3CA, which encodes for the catalytic subunit of p110␣ of PI3K, is amplified in some cases of papillary thyroid cancer (PTC). Mutations in the PIK3CA have also been identified in thyroid cancers and, although relatively common in anaplastic thyroid carcinoma, are uncommon in PTC.Objective: The objective of the study was to investigate genetic alterations like PIK3CA gene mutation, PIK3CA amplification, RAS, and RAF mutations and to further explore the relationship of these genetic alterations with various clinicopathological characteristics in Middle Eastern PTC. Design:We used the fluorescence in situ hybridization technique for analysis of PIK3CA amplification from 536 PTC cases, and selected amplified samples were further validated by real-time quantitative PCR. Mutation analysis was done by direct DNA sequencing of PIK3CA, N2-RAS, and BRAF genes.Results: PIK3CA amplification was seen in 265 of 499 PTC cases analyzed (53.1%); PIK3CA gene mutations in four of 207 PTC (1.9%); N2-RAS mutations in 16 of 265 PTC (6%); and BRAF mutations in 153 of 296 PTC (51.7%). N-RAS mutations were-associated with an early stage (P ϭ 0.0465) and lower incidence of extrathyroidal extension (P ϭ 0.027), whereas BRAF mutations were-associated with metastasis (P ϭ 0.0274) and poor disease-free survival (P ϭ 0.0121) in PTCs. P apillary thyroid carcinoma (PTC) is the most common malignant thyroid tumor, representing 80 -90% of all thyroid malignancies. PTC is usually well differentiated; however, the clinical behavior of PTC varies widely. For example, incidental microcarcinomas grow very slowly and are noninvasive or minimally invasive. On the other hand, invasive PTC with metastasis can be lethal. PTC often recurs many years after surgical removal. The prognosis for PTC is often favorable; however, approximately 20% of PTC tumors recur, and some reach advanced stages (1). Several clinicopathological variables including stage, cancer invasion, and distant metastasis are used for prognostication and treatment selection for PTC (2, 3). A better understanding of the factors and mechanisms determining the aggressive behavior of some papillary carcinomas is critical in developing new treatment. Conclusion

Activation of the phosphatidylinositol 3 0 -kinase (PI3K)/ AKT pathway results in an increase in cell proliferation and survival. Somatic mutations within the PI3K catalytic subunit, PIK3CA are common cause of increasing PI3K activity and are believed to be oncogenic in many cancer types. Few reports addressed the association between PIK3CA mutations and tumor progression specifically in microsatellite instable (MSI) colorectal cancer (CRC). In the present study, we have evaluated PIK3CA mutational status in a series of 410 Middle Eastern CRC and 13 colon cell lines to study the prevalence of PIK3CA mutations in MSI cases, PTEN expression in CRC and possibility of therapeutic targeting of this set of patients. PIK3CA mutations were found in four of the cell lines tested and 51 colorectal carcinomas (12.2%). Three of these four mutated cell lines were MSI. PTEN was inactivated in 66.1% of the CRC. Furthermore, we observed a strong association between PIK3CA mutations and MSI status (P ¼ 0.0046) while PTEN loss was more frequent in microsatellite stable (MSS) CRC (P ¼ 0.043). A high prevalence of genetic alterations in PI3K/AKT pathway in Saudi cohort of CRC, predominance of PIK3CA mutations in the MSI subgroup and their possible involvement in development/progression of this subset of CRC are some of the significant findings of our study.

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The putative role of leptin and its receptor (Ob-R) in the pathogenesis of various primary human malignancies has been reported; however, their role in papillary thyroid cancer (PTC) has not yet been evaluated. We investigated the role of Ob-R in a large tissue microarray cohort of PTC followed by in vitro studies using a panel of PTC cell lines. Ob-R overexpression was seen in 80% PTCs and was significantly associated with poor disease-free survival (PZ0.0235). PTCs that overexpressed Ob-R showed a aggressive phenotype characterized by older age, extrathyroid extension, larger tumor size, nodal metastasis, advanced stage, tall cell variant histological subtype, and a poor disease-free survival (PZ0.0005, PZ0.0006, PZ0.0398, PZ0.0004, PZ0.0111, PZ0.0003, and PZ0.0235 respectively). However, Ob-R expression was not an independent prognostic marker to predict disease-free survival in multivariate analysis. PTCs with overexpression of Ob-R showed a significant direct association with overexpression of XIAP (P!0.0001) and Bcl-XL (P!0.0001). In vitro analysis showed that leptin stimulated cell proliferation and inhibited apoptosis via activation of phosphatidylinisitol 3 0 kinase (PI3K)/protein kinase B (AKT) signaling pathway. Inhibition of PI3K activity by its inhibitor LY294002 abrogated leptin-mediated PI3K/AKT signaling. Gene silencing of Ob-R in PTC cells resulted in downregulation of phospho-AKT, Bcl-XL, and XIAP expression suggesting that leptin-mediated pathogenesis of PTC occurs via involvement of these downstream targets. Altogether, these data show that leptin plays an important role in PTC pathogenesis through PI3K/AKT pathway via Ob-R and is a potential prognostic marker associated with an aggressive phenotype and poor diseasefree survival.

Cyclooxygenase-2 (COX-2) expression contributes to tumor growth and invasion in epithelial ovarian cancer (EOC). COX-2 inhibitors exhibit important anticarcinogenic potential against EOC, but the molecular mechanisms underlying this effect and relation with PI3-kinase/AKT signaling remain the subject of intense investigations. Therefore, the role of COX-2 in EOC and its cross talk with PI3-kinase/AKT pathway were investigated using a large series of EOC tissues in a tissue micro array (TMA) format followed by in vitro and in vivo studies using EOC cell lines and NUDE mice. Clinically, COX-2 was overexpressed in 60.3% of EOC and was significantly associated with activated AKT (p < 0.0001). Cox-1 expression was seen in 59.9% but did not associate with AKT. Our in vitro data using EOC cell line showed that inhibition of COX-2 by aspirin, selective inhibitor NS398 and gene silencing by COX-2 specific siRNA impaired phosphorylation of AKT resulting decreased downstream signaling leading to cell growth inhibition and induction of apoptosis. Finally, treatment of MDAH2774 cell line xenografts with aspirin resulted in growth inhibition of tumors in NUDE mice via down-regulation of COX-2 and AKT activity. These data identify COX-2 as a potential biomarker and therapeutic target in distinct molecular subtypes of ovarian cancer.More than 85% of human ovarian cancers are epithelial ovarian carcinomas (EOCs), which originate from ovarian surface epithelial (OSE) cells.

We report an unusual case of multifocal leiomyosarcoma involving the thyroid gland, liver, and right lung in a child with congenital immunodeficiency disease. The smooth muscle nature of these neoplasms was confirmed by immunohistochemistry and electron microscopic studies. In situ hybridization showed large amounts of Epstein-Barr virus messenger RNA within the tumor cells. Although Epstein-Barr virus-associated smooth muscle tumors have been reported in children with AIDS and after organ transplantation, we are unaware of any case report in congenital immunodeficiency disease.