Abstract. The most common therapeutic approach for many cancers is chemotherapy. However, many patients relapse after treatment due to the development of chemoresistance. Recently, targeted therapies represent novel approaches to destroy cancer cells. The PI3K/PTEN/AKT pathway is a key signaling pathway involved in the regulation of cell growth. Dysregulated signaling of this pathway may be associated with activating mutations of PI3K-related genes. Analyses of these mutations reveal that they increase the PI3K signal, stimulate downstream Akt signaling, promote growth factor-independent growth and increase cell invasion and metastasis. In this review, we summarize the PI3K/PTEN/AKT pathway genetic alterations in cancer and their potential clinical applications. IntroductionPhosphatidylinositol 3-kinases (PI3Ks) are lipid kinases that phosphorylate phoshoinositides at the D-3 position of the inositol ring generating second messengers that govern cellular activities and promote various biological properties including proliferation, survival, motility and morphology changes. Members of the PI3K family are grouped into three classes according to sequence homology, substrate preference and tissue distribution (1). In terms of regulating cell division and tumorigenesis, the most important PI3K proteins are those that belong to class IA, the catalytic subunit p110α and its associated regulatory subunit p85. In quiescent cells, the regulatory subunit p85 maintains the p110α catalytic subunit in a lowactivity state. Upon growth factor stimulation, the SH2 domain [Rous-sarcoma (src) oncogene homology-2 domain] of the p85 subunit binds to phosphorylated tyrosine in receptor tyrosine kinases or their substrate adaptor proteins. This binding relieves the inhibition of p110α subunit and mediates recruitment of this subunit to the plasma membrane (2). Activation of p110α leads to the production of phosphatidylinositol 3,4,5-triphosphate (PIP3), which recruits adaptor and effector proteins containing a pleckstrin homology domain (PH domain) to cellular membranes including the protein kinase B (PKB/Akt), phosphoinositide-dependent kinase 1 (PDK-1) (3). Once at the membrane PKB/Akt is phosphorylated at Thr308 and Ser473 by PDK1 and the mTORC2 complex, respectively. Once activated PKB/Akt phosphorylates and actives target proteins involved in many different cellular functions, which span cell cycle progression, cell survival, metabolism, ribosome biogenesis, protein translation, RNA transcription and cell motility (4,5

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Brevin, an actin-severing protein present in serum from numerous mammals, has been purified to homogeneity from bovine serum, using hydrophobic chromatography as the last purification step. The physicochemical parameters of brevin have been established and some of them studied in the absence and presence of Ca2+. Brevin exhibits an apparent Stokes radius, R,, of 3.4 nm, an intrinsic sedimentation coefficient s&,,, of 4.8 S and 4.4 S in the absence and presence of Ca2 + respectively, indicative of calcium-induced conformational change. The native molecular mass of brevin was found to be 68 kDa and the hydrodynamic data suggest that the protein is an asymmetric molecule. Sedimentation equilibrium studies demonstrated that Ca2 ' affects the shape (asymmetry) of brevin without altering its molecular mass. Limited tryptic and chymotryptic digestion of brevin distinguishes the Ca2 -induced conformation from the EGTA one. No change in the electrophoretic migration of brevin was seen upon CaZ + addition. Several isoforms were detected by two-dimensional gel electrophoresis. Brevin increases the rate of nucleation of actin but decreases the rate of elongation of the filaments and the steady-state viscosity of F-actin in substo'ichiometric amounts, as measured by viscometric assays under high shear conditions. Electron microscopic examination documents these effects. Brevin produces shorter actin filaments and binds to the 'barbed' end of filaments to which monomers add preferentially during elongation, as demonstrated by indirect immunogold staining of antibodies against brevin. Filament elongation occurs only at the slowly growing end. An enzyme-linked immunosorbent assay was developed and used to detect and quantify brevin and related proteins in extracts of different bovine cells and tissues. Liver and smooth muscles were found to contain the highest amounts of the severing protein.Recent years have seen rapid progress in studies on the composition of various filaments within cells. Their spatial organization and possible functions have focused much interest on the cytoskeleton, and particularly on the microfilament system.Actin is a contractile and structural protein widely distributed in all eukaryotic cells [l, 21. Besides its structural role and maintenance of cell shape, in non-muscle cells actin is constantly being reorganized according to the physiological state of the cell [3] and in response to functional demands. These dynamic events 11, 41 are related to a spatial and a temporal control of actin assembly and diassembly.The study of the molecular mechanisms underlying these events has led to the discovery within various cells of numerous proteins which modulate the assembly state of actin. Three major classes of actin binding proteins have been identified [5] : (a) actin cross-linking proteins, (b) severing and capping proteins, (c) G-actin stabilizing proteins.Several proteins which interact with F-actin in a calciumregulated way have been identified in a wide variety of cell types: gelsolin from rabbit mac...

The addition of anti-CD20 monoclonal antibody (rituximab) to chemotherapy has significantly improved survival in B-cell lymphoma. However, a substantial number of patients relapse after treatment with rituximab. Understanding of anti-CD20 antibody molecular function may facilitate the development of pharmacologic strategies to overcome resistance. Cell death have been demonstrated to be caused by rituximab binding to CD20 throughout direct and indirect mechanisms. The direct mechanism comprises growth inhibition, induction of apoptosis and sensitization of cells to chemotherapy. While, the indirect mechanisms to Rituximab include complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC). However, these mechanisms are still poorly understood. To shed light on this issue, we have analyzed the most significant results showing the role of Rituximab as a signal-inducing antibody and as a chemosensitizing agent through negative regulation of major survival pathways. Mechanisms of resistance to Rituximab are also discussed. Additionally, studies here reported show that, cellular targets are modified after treatment with Rituximab and may become useful for novel therapeutic strategies in the treatment of patients resistant to standard therapy.

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disease of motile cilia. Even though PCD is widely studied, North‐African patients have been rarely explored. In this study, we aim at confirming the clinical diagnosis and explore the genetic spectrum of PCD in a cohort of Tunisian patients. Forty clinically diagnosed patients with PCD belonging to 34 families were recruited from Tunisian pediatric departments. In each proband, targeted capture PCD panel sequencing of the 40 PCD genes was performed. PCD panel sequencing identified bi‐allelic mutations in 82% of the families in eight PCD genes. Remarkably, 23.5% of patients carried the same c.2190del CCDC39 mutation. Single nucleotide polymorphism profiling in six unrelated patients carrying this mutation has revealed a founder effect in North‐African patients. This mutation is estimated to date back at least 1,400–1,750 years ago. The identification of this major allele allowed us to suggest a cost‐effective genetic diagnostic strategy in North‐African patients with PCD.