Optimal HIV testing and earlier care: the way forward in Europe

The articles in this supplement were developed from a recent pan-European conference entitled 'HIV in Europe 2007: Working together for optimal testing and earlier care', which took place on 26–27 November in Brussels, Belgium. The conference, organized by a multidisciplinary group of experts representing advocacy, clinical and policy areas of the HIV field, was convened in an effort to gain a common understanding on the role of HIV testing and counselling in optimizing diagnosis and the need for earlier care. Key topics discussed at the conference and described in the following articles include: current barriers to HIV testing across Europe, trends in the epidemiology of HIV in the region, problems associated with undiagnosed infection and the psychosocial barriers impacting on testing. The supplement also provides a summary of the World Health Organization's recommendations for HIV testing in Europe and an outline of an indicator disease-guided approach to HIV testing proposed by a committee of experts from the European AIDS Clinical Society (EACS). We hope that consideration of the issues discussed in this supplement will help to shift the HIV field closer towards our ultimate goal: provision of optimal HIV testing and earlier care across the whole of the European region.     

The PML/RAR alpha oncoprotein is a direct molecular target of retinoic acid in acute promyelocytic leukemia cells

Acute promyelocytic leukemia (APL) is characterized by the translocation, t(15;17) and the expression of a PML/RAR alpha fusion protein that is diagnostic of the disease. There is evidence that PML/RAR alpha protein acts as a dominant negative inhibitor of normal retinoid receptor function and myeloid differentiation. We now show that the PML/RAR alpha fusion product is directly downregulated in response to retinoic acid (tRA) treatment in the human APL cell line, NB4. tRA treatment induces loss of PML/RAR alpha at the protein level but not at the level of mRNA, as determined by Northern blots, by Western blots, and by ligand binding assays and in binding to RA- responsive DNA elements. We present evidence that this regulation is posttranslational. This evidence suggests that tRA induces synthesis of a protein that selectively degrades PML/RAR alpha. We further show that this loss of PML/ RAR-alpha is not limited to the unique APL cell line. NB4, because PML/RAR alpha protein is selectively downregulated by tRA when expressed in the transfected myeloid cell line U937. The loss of PML/RAR alpha may be directly linked to tRA-induced differentiation, because in a retinoid-resistant subclone of NB4, tRA does not decrease PML/RAR alpha protein expression. In NB4 cells, the specific downregulation of the fusion protein decreases the ratio of PML/RAR alpha to wild-type RAR alpha. Because the ratio of expression of PML/RAR alpha to wild-type RAR alpha and PML may be important in maintaining the dominant negative block of myelocytic differentiation, these data suggest a molecular mechanism for restoration by tRA normal myeloid differentiation in APL cells.     

Malignant lymphoma of the head and neck

Oral Diseases (2010) 16 , 119–128 Malignant lymphomas represent approximately 5% of all malignant neoplasms of the head and neck area. They are classically divided into two subgroups, Hodgkin’s lymphomas (HLs) and non‐Hodgkin’s lymphomas (NHLs). We describe the clinical characteristics of head and neck lymphomas and the methods to establish the diagnosis. The World Health Organization classification of lymphoid tissues describes more than 50 different histological types, and we analyse the most common staging system for lymphomas, the Ann Arbor staging system. Finally, the different therapeutic approaches are discussed.     

Induction of trefoil factor (TFF)1, TFF2 and TFF3 by hypoxia is mediated by hypoxia inducible factor-1: implications for gastric mucosal healing

Background and purpose:

Mucosal microcirculation is compromised during gastric damage induced by non-steroidal anti-inflammatory drugs, such as aspirin. Consequently, oxygen supply to epithelial cells is decreased. The trefoil factor (TFF) peptides are involved in mechanisms of defence and repair in the gastrointestinal tract but their regulation at sites of gastric injury is unknown.

Experimental approach:

Hypoxia and expression of TFF genes and peptides were measured in the damaged stomach of aspirin-treated rats. In a human gastric cell line (AGS cells), the effects of hypoxia and of hypoxia inducible factor (HIF)-1 (through transient transfection of HIF-1α siRNA or over-expression of HIF-1α) on TFF gene expression were evaluated.

Key results:

Hypoxyprobe immunostaining, up-regulation of TFF2 (1.9-fold) and TFF3 (1.8-fold) and a non-significant increase of TFF1 (1.5-fold) mRNA were observed in the damaged stomach of aspirin-treated rats, compared with control animals. Hypoxia (3% O₂, 16 h) induced mRNA for TFF1 (5.8-fold), TTF2 (9.1-fold) and TFF3 (9.3-fold) in AGS cells, an effect mediated by HIF-1, as transient transfection of HIF-1α siRNA reduced the effects of hypoxia. Over-expression of HIF-1α by transfection in non-hypoxic epithelial cells produced a similar pattern of TFF induction to that observed with hypoxia and transactivated a TFF1 reporter construct.

Conclusions and implications:

Hypoxia inducible factor-1 mediated the induction of TFF gene expression by hypoxia in gastric epithelial cells. Low oxygen levels and up-regulation of TFF gene expression in the damaged stomach of aspirin-treated rats suggest that hypoxia induced expression of TFF genes at sites of gastric injury.     

Enhanced oxidative stress and increased mitochondrial mass during Efavirenz-induced apoptosis in human hepatic cells

BACKGROUND AND PURPOSE

Efavirenz (EFV) is widely used in the treatment of HIV-1 infection. Though highly efficient, there is growing concern about EFV-related side effects, the molecular basis of which remains elusive.

EXPERIMENTAL APPROACH

In vitro studies were performed to address the effect of clinically relevant concentrations of EFV (10, 25 and 50 µM) on human hepatic cells.

KEY RESULTS

Cellular proliferation and viability were reduced in a concentration-dependent manner. Analyses of the cell cycle and several cell death parameters (chromatin condensation, phosphatidylserine exteriorization, mitochondrial proapoptotic protein translocation and caspase activation) revealed that EFV triggered apoptosis via the intrinsic pathway. In addition, EFV directly affected mitochondrial function in a reversible manner, inducing a decrease in mitochondrial membrane potential and an increase in mitochondrial superoxide production, followed by a reduction in cellular glutathione content. The rapidity of these actions rules out any involvement of mitochondrial DNA replication, which, until now, was thought to be the main mechanism of mitochondrial toxicity of antiretroviral drugs. Importantly, we also observed an increase in mitochondrial mass, manifested as an elevated cardiolipin content and enhanced expression of mitochondrial proteins, which was not paralleled by an increase in the mtDNA/nuclear DNA copy number ratio. The toxic effect of EFV was partially reversed by antioxidant pretreatment, which suggests ROS generation is involved in this effect.

CONCLUSION AND IMPLICATIONS

Clinically relevant concentrations of EFV were shown to be mitotoxic in human hepatic cells in vitro, which may be pertinent to the understanding of the hepatotoxicity associated with this drug.     

The Discovery of Pyridone and Pyridazone Heterocycles as γ-Secretase Modulators

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