Activated-PAK4 predicts worse prognosis in breast cancer and promotes tumorigenesis through activation of PI3K/AKT signaling.

The p21-activated kinase 4 (PAK4) is sufficient to transform noncancerous mammary epithelial cells and to form tumors in the mammary glands of mice. The accumulated information suggests that PAK4 might be an oncogenic protein in breast cancer. In this study, we sought to identify the role for PAK4 in breast cancer progression. Immunohistochemical study revealed that high PAK4 expression is associated with larger tumor size, lymph node metastasis, and advanced stage cancer in 93 invasive breast carcinoma patients. Moreover, high PAK4 expression was significantly associated with poor overall and disease-free survival. PAK4 remained an independent adverse prognosticator after univariate and multivariate analysis. Ectopic expression of wild-type PAK4 in MDA-MB-231 cells activated PI3K/AKT signaling and resulted in the enhancement of the cell proliferation, migration, and invasion, whereas PAK4-induced effects were blocked by the PAK4 kinase inhibitor PF- 3758309, PAK4 siRNAs or the PI3K inhibitor LY294002. Furthermore, a kinase-active PAK4 (S474E) strongly induced PI3K/AKT activation, and promoted proliferation, migration and invasion in breast cancer cells. A kinase-inactive PAK4 KD (K350A/K351A) did partially upregulate PI3K/AKT, and promoted invasive phenotype. Taken together, these findings suggest that PAK4-activated PI3K/AKT signaling is both kinase-dependent and -independent, which contributes to breast cancer progression. Thus, our results imply that dual inhibition of PAK4 and PI3K/AKT signaling might be a potential therapeutic approach for breast cancer therapy.

The expression of cytoglobin as a prognostic factor in gliomas: a retrospective analysis of 88 patients.

BACKGROUND: Evidence suggests that cytoglobin (Cygb) may function as a tumor suppressor gene. METHODS: We immunohistochemically evaluated the expression of Cygb, phosphatidylinositol-3 kinase (PI-3K), phosphorylated (p)-Akt, Interleukin-6 (IL-6), tumor necrosis factor-α (TNFα) and vascular endothelial growth factor (VEGF) in 88 patients with 41 high-grade gliomas and 47 low-grade gliomas. Intratumoral microvessel density (IMD) was also determined and associated with clinicopathological factors. RESULTS: Low expression of Cygb was significantly associated with the higher histological grading and tumor recurrence. A significant negative correlation emerged between Cygb expression and PI3K, p-Akt, IL-6, TNFα or VEGF expression. Cygb expression was negatively correlated with IMD. There was a positive correlation between PI3K, p-Akt, IL-6, TNFα and VEGF expression with IMD.High histologic grade, tumor recurrence, decreased Cygb expression, increased PI3K expression, increased p-Akt expression and increased VEGF expression correlated with patients' overall survival in univariate analysis. However, only histological grading and Cygb expression exhibited a relationship with survival of patients as independent prognostic factors of glioma by multivariate analysis. CONCLUSIONS: Cygb loss may contribute to tumor recurrence and a worse prognosis in gliomas. Cygb may serve as an independent predictive factor for prognosis of glioma patients.

Methyl (R)-2-(2-chloro-phen-yl)-2-(3-nitro-phenyl-sulfon-yloxy)acetate.

The reaction between methyl (R)-2-(2-chloro-phen-yl)-2-hy-droxy-acetate and 3-nitro-benzene-sulfonyl chloride gave the title compound, C(15)H(12)ClNO(7)S, which is a promising inter-mediate for the synthesis of Clopidrogel, an anti-platelet drug used in the prevention of strokes and heart attacks. In the crystal, mol-ecules are linked through C-H⋯O interactions, and there is also a short Cl⋯O contact present [Cl⋯O = 3.018 (2) Å].

Bis[4-(2-hydr-oxy-3-methoxy-benzyl-ideneamino)phen-yl] ether.

The title compound, C(28)H(24)N(2)O(5), a flexible Schiff base ligand, was prepared in high yield by a Schiff base condensation of 3-methoxy-salicylaldehyde and bis-(4-amino-phen-yl) ether in methanol. The mol-ecule lies on a twofold rotation axis, and each half exhibits an imine E configuration and an O-H⋯N hydrogen bond. The dihedral angle between the two benzene rings attached to the central O atom is 69.22 (6)°, and that between each of these rings and the other benzene ring in the same half of the mol-ecule is 24.29 (11)°, illustrating the degree of twisting of the flexible mol-ecule.

Copper(II)-mediated resolution of alpha-halo carboxylic acids with chiral O,O'-dibenzoyltartaric acid: spontaneous racemization and crystallization-induced dynamic resolution.

Herein we present a new example of coordination-mediated resolution of racemic acids by a chiral acid. The reaction of copper(II) acetate monohydrate, optically pure O,O'-dibenzoyltartaric acid (DBTA) and racemic alpha-bromo-2-chlorophenylacetic acid (HL1) in acetonitrile solution afforded a binuclear copper(II) complex with D-DBTA dianion, alpha-bromo-2-chlorophenylacetate and acetate as ligands. After decomposition of the complex with acid, the optically active acid ((R)-HL1) was obtained. Similarly, alpha-bromo-2-fluorophenylacetic acid (HL2), alpha-bromo-2-bromophenylacetic acid (HL3), alpha-chloro-2-chlorophenylacetic acid (HL4), alpha-chloro-2-fluorophenylacetic acid (HL5), alpha-bromophenylacetic acid (HL6), alpha-bromo-4-chlorophenylacetic acid (HL7), 2-bromopropionic acid (HL8) and 2-chloropropionic acid (HL9) were resolved by the same method. Satisfactory results were obtained for HL2 to HL5. For HL6 and HL7, only racemic acids were obtained. For the two alpha-halo aliphatic acids (HL8 and HL9), poor enantioselectivity was obtained. It is more interesting that three acids (HL1, HL2 and HL3) could spontaneously racemize in acetonitrile solution, which resulted in crystallization-induced dynamic resolution (CIDR) with greater than 50% yield.

Self-assembly luminescent heteroheptanuclear complexes with metal diphosphine and metal thiolate as components.

Self-assembly between the building blocks [M2(mu-dppm)2(MeCN)2]2+ (M = Cu or Ag; dppm = bis(diphenylphosphino)methane) and M'(aet)2 (aet = 2-aminoethanethiolate) afforded luminescent heterohepta-nuclear complexes [Cu4M'3(mu-dppm)3(mu 3-aet)4(mu-aet)2]4+ (M' = Ni 1; Pd 2) or heterotrinuclear complexes [Ag2M'(mu-dppm)2(mu-aet)2]2+ (M' = Ni 3, Pd 4).