Constitutive phosphatidylinositol 3-kinase (PI3K)-AKT activation has a causal role in adult T-cell leukaemia-lymphoma (ATLL) and other cancers. ATLL cells do not harbour genetic alterations in PTEN and PI3KCA but express high levels of PTEN that is highly phosphorylated at its C-terminal tail. Here we report a mechanism for the N-myc downstream-regulated gene 2 (NDRG2)-dependent regulation of PTEN phosphatase activity via the dephosphorylation of PTEN at the Ser380, Thr382 and Thr383 cluster within the C-terminal tail. We show that NDRG2 is a PTEN-binding protein that recruits protein phosphatase 2A (PP2A) to PTEN. The expression of NDRG2 is frequently downregulated in ATLL, resulting in enhanced phosphorylation of PTEN at the Ser380/Thr382/Thr383 cluster and enhanced activation of the PI3K-AKT pathway. Given the high incidence of T-cell lymphoma and other cancers in NDRG2-deficient mice, PI3K-AKT activation via enhanced PTEN phosphorylation may be critical for the development of cancer.

Acute myeloid leukemia with high ecotropic viral integration site-1 expression (EVI1(high) AML) is classified as a refractory type of leukemia with a poor prognosis. To provide new insights into the prevention and treatment of this disease, we identified the high expression of EVI1-regulated G protein-coupled receptor 56 (GPR56), and the association of high cell adhesion and antiapoptotic activities in EVI1(high) AML cells. Knockdown of GPR56 expression decreased the cellular adhesion ability through inactivation of RhoA signaling, resulting in a reduction of cellular growth rates and enhanced apoptosis. Moreover, in Gpr56(-/-) mice, the number of hematopoietic stem cells (HSCs) was significantly decreased in the bone marrow (BM) and, conversely, was increased in the spleen, liver and peripheral blood. The number of Gpr56(-/-) HSC progenitors in the G0/G1-phase was significantly reduced and was associated with impaired cellular adhesion. Finally, the loss of GPR56 function resulted in a reduction of the in vivo repopulating ability of the HSCs. In conclusion, GPR56 may represent an important GPCR for the maintenance of HSCs by acting as a co-ordinator of interactions with the BM osteosteal niche; furthermore, this receptor has the potential to become a novel molecular target in EVI1(high) leukemia.

The development of oral squamous cell carcinoma (OSCC) is a multistep process that requires the accumulation of genetic alterations. To identify genes responsible for OSCC development, we performed high-density single nucleotide polymorphism array analysis and genome-wide gene expression profiling on OSCC tumors. These analyses indicated that the absent in melanoma 2 (AIM2) gene and the interferon-inducible gene 16 (IFI16) mapped to the hematopoietic interferon-inducible nuclear proteins. The 200-amino-acid repeat gene cluster in the amplified region of chromosome 1q23 is overexpressed in OSCC. Both AIM2 and IFI16 are cytoplasmic double-stranded DNA sensors for innate immunity and act as tumor suppressors in several human cancers. Knockdown of AIM2 or IFI16 in OSCC cells results in the suppression of cell growth and apoptosis, accompanied by the downregulation of nuclear factor kappa-light-chain-enhancer of activated B cells activation. Because all OSCC cell lines have reduced p53 activity, wild-type p53 was introduced in p53-deficient OSCC cells. The expression of wild-type p53 suppressed cell growth and induced apoptosis via suppression of nuclear factor kappa-light-chain-enhancer of activated B cells activity. Finally, the co-expression of AIM2 and IFI16 significantly enhanced cell growth in p53-deficient cells; in contrast, the expression of AIM2 and/or IFI16 in cells bearing wild-type p53 suppressed cell growth. Moreover, AIM2 and IFI16 synergistically enhanced nuclear factor kappa-light-chain-enhancer of activated B cells signaling in p53-deficient cells. Thus, expression of AIM2 and IFI16 may have oncogenic activities in the OSCC cells that have inactivated the p53 system. (Cancer Sci 2012; 103: 782-790) O ral squamous cell carcinoma is commonly found in lowincome communities. This cancer mainly affects older men; 90% of cases are in men over 45 years old who have been exposed to risk factors including tobacco and/or alcohol (International Agency for Research on Cancer [IARC] 2004). OSCC is the sixth most common cancer worldwide and affects approximately 270 000 people each year.(1) The incidence and rate of mortality from OSCC are rising in several regions of Europe, Australia and Asia, including Japan. Despite recent progress in OSCC diagnosis and therapy, the 5-year survival rate has not improved in more than two decades. Oral carcinogenesis is a multifactorial cascade involving numerous genetic changes that affect the activity of oncogenes, tumor suppressor genes and other classes of diseaserelated genes. Chronic exposure to carcinogens, such as tobacco, causes genetic changes in the epithelial cells of the oral mucosa. The activation of the COX-2,epidermal growth factor receptor, (4) and cyclin D1 oncogenes and the inactivation of the p16 and p53 tumor suppressor genes have also been reported in OSCC.(5-7) In addition to tobacco smoke exposure, chronic alcohol use and chronic inflammation can both induce genetic alterations.(3) The causative agent of cervical cancer, HPV is also reportedly associa...

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A lattice study of the equation of state for pure SU͑3͒ gauge theory using a renormalization-group ͑RG͒ improved action is presented. The energy density and pressure are calculated on a 16 3 ϫ4 and a 32 3 ϫ8 lattice employing the integral method. Extrapolating the results to the continuum limit, we find the energy density and pressure to be in good agreement with those obtained with the standard plaquette action within the error of 3-4 %. ͓S0556-2821͑99͒07819-4͔

The present 3D reconstruction technique was useful for determining the 3D vascular anatomical pattern including the relative positions of the IMA, SCA, and IMV during laparoscope-assisted left-side colorectal surgery.

We explore application of the domain wall fermion formalism of lattice QCD to calculate the K → ππ decay amplitudes in terms of the K + → π + and K 0 → 0 hadronic matrix elements through relations derived in chiral perturbation theory. Numerical simulations are carried out in quenched QCD using domain-wall fermion action for quarks and an RG-improved gauge action for gluons on a 16 3 × 32 × 16 and 24 3 × 32 × 16 lattice at β = 2.6 corresponding to the lattice spacing 1/a ≈ 2 GeV. Quark loop contractions which appear in Penguin diagrams are calculated by the random noise method, and the ∆I = 1/2 matrix elements which require subtractions with the quark loop contractions are obtained with a statistical accuracy of about 10%. We investigate the chiral properties required of the K + → π + matrix elements. Matching the lattice matrix elements to those in the continuum at µ = 1/a using the perturbative renormalization factor to one loop order, and running to the scale µ = mc = 1.3 GeV with the renormalization group for N f = 3 flavors, we calculate all the matrix elements needed for the decay amplitudes.With these matrix elements, the ∆I = 3/2 decay amplitude ReA2 shows a good agreement with experiment after an extrapolation to the chiral limit. The ∆I = 1/2 amplitude ReA0, on the other hand, is about 50-60% of the experimental one even after chiral extrapolation. In view of the insufficient enhancement of the ∆I = 1/2 contribution, we employ the experimental values for the real parts of the decay amplitudes in our calculation of ε ′ /ε. The central values of our result indicate that the ∆I = 3/2 contribution is larger than the ∆I = 1/2 contribution so that ε ′ /ε is negative and has a magnitude of order 10 −4 . We discuss in detail possible systematic uncertainties, which seem too large for a definite conclusion on the value of ε ′ /ε.