NK/T-cell lymphoma (NKTL) is strongly associated with latent Epstein-Barr virus (EBV) infection. Recently, latent membrane protein 1 (LMP1), an EBV oncoprotein, was reported to activate the phosphatidylinositol-3 kinase (PI3K)/Akt pathway for cell survival. Because geldanamycin (GA) and its derivative, 17-allylamino-17-demethoxygeldanamycin (17-AAG), exhibit anti-tumour activity by degrading HSP90 client proteins, including Akt, we investigated the effect of GA and 17-AAG on the survival of NKTL cell lines. EBV-positive NKTL cell lines, Hank-1 and NK-YS, and an EBV-negative NK leukaemia cell line, NK-L, were treated with PI3K and Akt inhibitors, GA, and 17-AAG, and were subjected to apoptosis and cell viability assays, and immunoblot analysis. EBV-positive B-lymphoblastoid cell lines IM9 and LMP1-transfected IM9 (IM9-LMP1) were also included. Hank-1 and NK-YS cell viability was compromised and apoptosis was induced by LY294002 (PI3K inhibitor) or Akt inhibitor II. GA or 17-AAG administration resulted in the apoptosis of NKTL cells, accompanied by Akt and pAkt down-regulation, caspase 3 activation, and mitochondrial membrane potential disruption. The intrinsic level of pAkt was higher in EBV-positive NKTL cells than in EBV-negative NK-L, and GA or 17-AAG decreased the viability of NKTL cells more efficiently than NK-L. Moreover, IM9-LMP1 was more sensitive to Akt inhibitor II or HSP90 inhibitors than IM9. Importantly, GA showed little effect on the viability of normal peripheral NK cells as non-neoplastic counterparts for comparison. In conclusion, this study suggests that the PI3K/Akt pathway is frequently activated in EBV-positive NKTL and that therapeutic modalities based on targeting the PI3K/Akt pathway with HSP90 inhibitors could be useful for achieving NKTL control.

Cellular plasticity in adipose tissue involves adipocyte death, its clearance, and de novo adipogenesis, enabling homeostatic turnover and adaptation to metabolic challenges; however, mechanisms regulating these serial events are not fully understood. The present study investigated the roles of arachidonate 15-lipoxygenase (Alox15) in the clearance of dying adipocytes by adipose tissue macrophages. First, upregulation of Alox15 expression and apoptotic adipocyte death in gonadal white adipose tissue (gWAT) were characterized during adipose tissue remodeling induced by β3-adrenergic receptor stimulation. Next, an in vitro reconstruction of adipose tissue macrophages and apoptotic adipocytes recapitulated adipocyte clearance by macrophages and demonstrated that macrophages co-cultured with apoptotic adipocytes increased the expression of efferocytosis-related genes. Genetic deletion and pharmacological inhibition of Alox15 diminished the levels of adipocyte clearance by macrophages in a co-culture system. Gene expression profiling of macrophages isolated from gWAT of Alox15 knockout (KO) mice demonstrated distinct phenotypes, especially downregulation of genes involved in lipid uptake and metabolism compared to wild-type mice. Finally, in vivo β3-adrenergic stimulation in Alox15 KO mice failed to recruit crown-like structures, a macrophage network clearing dying adipocytes in gWAT. Consequently, in Alox15 KO mice, proliferation/differentiation of adipocyte progenitors and β3-adrenergic remodeling of gWAT were impaired compared to wild-type control mice. Collectively, our data established a pivotal role of Alox15 in the resolution of adipocyte death and in adipose tissue remodeling.

Background: Adult onset Still's disease (AOSD) is a rare systemic inflammatory disorder of unknown aetiology, frequently accompanying multiple lymphadenopathy. It often mimics malignant lymphoma, and immunohistochemical and molecular studies are needed for definite diagnosis. Aims: To aid in diagnosis and understand the pathogenesis of the disease by clarifying lymph node (LN) pathology in AOSD. Methods: Thirteen biopsies (one follow up biopsy) and medical records of 12 patients were reviewed. Immunohistochemistry, polymerase chain reaction for T cell receptor c chain (TCRc) and immunoglobulin heavy chain gene rearrangement, and Epstein-Barr virus in situ hybridisation were performed. Results: Histologically, LN lesions were classified into four patterns. The most common (six biopsies) showed paracortical hyperplasia, with prominent vascular proliferation, scattered large B/T immunoblasts, and infiltration by reactive lymphocytes and inflammatory cells. In the second pattern (two biopsies), paracortical hyperplasia was accompanied by massive sinus histiocytosis and S-100 positive histiocyte aggregates. The third pattern (three patients) showed an exuberant immunoblastic reaction, in the form of patchy/diffuse infiltration of large T immunoblasts with high mitotic activity, although clonal rearrangement of the TCRc gene was not detected. The fourth pattern showed distinct follicular hyperplasia (two cases). One patient with a follow up biopsy showed a pattern change from pronounced follicular hyperplasia to atypical paracortical hyperplasia. Conclusions: AOSD LN lesions show a dynamic histological spectrum, including atypical paracortical hyperplasia, burnt out histiocytic reaction, exuberant immunoblastic reaction, and follicular hyperplasia. During the course of disease, LN reactivity changes and mixed B and T cells are involved in the pathogenesis.

A343diseases, age at first pap smear, pap smear frequency, use of oral contraceptives and the number of pregnancies. Results: Overall, 600 respondents were eligible for the analysis, consisting of 465 patients (44.0±16.3 years) and 135 controls (44.0±13.2 years). More than 5 sexual partners increased the risk of acquiring HPV infections up to 2.52-fold (95%CI: 1.34-4.74), while smoking or an early sexual debut (≤ 18 years) raised it by about a factor of 1.62. Higher levels of education were associated with a protective effect. The overall rate of individuals at high risk with more than 5 sexual partners and at least another additional factor corresponded to 26.3% (158 out of 600). The proportion of subjects with an average risk (respondents with less than 5 partners and at least another additional factor) amounted to 53.2% (319 out of 600). ConClusions: Analysis of risk factors can be used as part of the economic assessment of other effective HPV vaccination strategies, including an immunization programme for pre-adolescents of both sexes in Italy. PIN16A Study of A.

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