Overexpression of the anti-apoptotic protein AVEN contributes to increased malignancy in hematopoietic neoplasms.

AVEN has been identified as an inhibitor of apoptosis, which binds to the adaptor protein, APAF-1, and thereby prevents apoptosome formation and mitochondrial apoptosis. Recent data have demonstrated high expression levels of AVEN messenger RNA in acute leukemias as well as a positive correlation between AVEN mRNA overexpression and poor prognosis in childhood acute lymphoblastic leukemia. On the basis of these data, we investigated the potential involvement of AVEN in tumorigenesis. First, we confirmed the overexpression of AVEN in T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) patient samples. We then established a transgenic mouse model with T-cell-specific overexpression of AVEN, with which we demonstrated the oncogenic cooperation of AVEN with heterozygous loss of p53. Finally, we used a subcutaneous xenograft mouse model to show that AVEN knockdown in the T-ALL cell lines, MOLT-4 and CCRF-CEM, and in the acute myeloblastic leukemia cell line, Kasumi-1, leads to a halt in tumor growth owing to the increased apoptosis and decreased proliferation of tumor cells. Collectively, our data demonstrate that the anti-apoptotic molecule, AVEN, functions as an oncoprotein in hematopoietic neoplasms.

Effects of an acute exposure to toluene on the DNA repair activity of the human 8-oxoguanine DNA glycosylase 1 (hOGG1) in healthy subjects.

The structure and previous studies on the biotransformation of toluene lead to the suspicion that metabolites may be formed which preferentially react with strongly nucleophilic partners such as sulfhydryl groups of cysteines in proteins. Human 8-oxoguanine DNA glycosylase 1 removes the major oxidative DNA damage and possesses eight cysteines. Its potential inactivation may lead to accumulation of DNA damage by reactive oxygen species formed by exogenous agents or by ubiquitous endogenous processes. The goal of the present investigation was to study the in vivo effect in humans of an acute toluene exposure on hOGG1 activity. Twenty healthy, non-smoking males were exposed to 50 ppm toluene and to filtered air in an exposure chamber for 270 min, using a cross-over design. Before and 30 min after the end of exposure, blood samples were taken and toluene concentrations and the hOGG1 activity were measured. hOGG1 activity was determined in peripheral mononuclear blood cells. Thirty minutes after exposure to toluene, we found a median blood concentration of 0.25 mg toluene/l. Compared with the activity before exposure, upon exposure to toluene a statistically insignificant median increase of hOGG1 activity by +0.4% and upon exposure to air by +2.3% was determined. Thus, no reduction of the hOGG1 repair activity after acute exposure to 50 ppm toluene was observed.

[Thrombotic microangiopathy under an effective treatment with gemcitabine]. / Thrombotische Mikroangiopathie unter einer effektiven Therapie mit Gemcitabin.

A 67-year-old male patient with a pancreatic carcinoma and hepatic metastases was admitted with progressive dyspnea and anuria. Previously he had received five cycles of a palliative chemotherapy with gemcitabine and responded well with a reduction of the tumor mass. The laboratory results showed a distinct anemia, thrombocytopenia, an increase in creatinine and lactate dehydrogenase levels. With an additional finding of 21 per mille fragmentocytes in the periphery blood smear, we diagnosed a thrombotic microangiopathy (TMA). Until now the literature lacks well-defined therapy standards for this known but rare condition of gemcitabine. In a few case reports addressing the related microangiopathy of thrombotic thrombocytopenic purpura (TTP), which is characterised by a significant reduction of the von Willebrand factor (vWF) cleaving serum protease ADAMTS-13, encouraging results have been achieved by an immediate plasma exchange. Though ADAMTS-13 activity was not relevantly reduced in our patient, we still observed a rapid improvement of the clinical features as well as of LDH, thrombocytes and fragmentocytes under plasma exchange. The patient was discharged after one month in good clinical condition. Interestingly, during follow-up for further 21 months we found a continued stable status of the pancreatic carcinoma without any cytostatic therapy. In summary, this case provides evidence that the use of plasma exchange therapy in gemcitabine-associated TMA is justified.