25 research outputs found

    Selective inactivation of hypomethylating agents by SAMHD1 provides a rationale for therapeutic stratification in AML.

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    Hypomethylating agents decitabine and azacytidine are regarded as interchangeable in the treatment of acute myeloid leukemia (AML). However, their mechanisms of action remain incompletely understood, and predictive biomarkers for HMA efficacy are lacking. Here, we show that the bioactive metabolite decitabine triphosphate, but not azacytidine triphosphate, functions as activator and substrate of the triphosphohydrolase SAMHD1 and is subject to SAMHD1-mediated inactivation. Retrospective immunohistochemical analysis of bone marrow specimens from AML patients at diagnosis revealed that SAMHD1 expression in leukemic cells inversely correlates with clinical response to decitabine, but not to azacytidine. SAMHD1 ablation increases the antileukemic activity of decitabine in AML cell lines, primary leukemic blasts, and xenograft models. AML cells acquire resistance to decitabine partly by SAMHD1 up-regulation. Together, our data suggest that SAMHD1 is a biomarker for the stratified use of hypomethylating agents in AML patients and a potential target for the treatment of decitabine-resistant leukemia

    Effects of new beta-type Ti-40Nb implant materials, brain-derived neurotrophic factor, acetylcholine and nicotine on human mesenchymal stem cells of osteoporotic and non osteoporotic donors.

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    Treatment of osteoporotic fractures is still challenging and an urgent need exists for new materials, better adapted to osteoporotic bone by adjusted Young's modulus, appropriate surface modification and pharmaceuticals.Titanium-40-niobium alloys, mechanically ground or additionally etched and titanium-6-aluminium-4-vanadium were analyzed in combination with brain-derived neurotrophic factor, acetylcholine and nicotine to determine their effects on human mesenchymal stem cells in vitro over 21 days using lactate dehydrogenase and alkaline phosphatase assays, live cell imaging and immunofluorescence microscopy.Cell number of human mesenchymal stem cells of osteoporotic donors was increased after 14 d in presence of ground titanium-40-niobium or titanium-6-aluminium-4-vanadium, together with brain-derived neurotrophic factor. Cell number of human mesenchymal stem cells of non osteoporotic donors increased after 21 d in presence of titanium-6-aluminium-4-vanadium without pharmaceuticals. No significant increase was measured for ground or etched titanium-40-niobium after 21 d. Osteoblast differentiation of osteoporotic donors was significantly higher than in non osteoporotic donors after 21 d in presence of etched, ground titanium-40-niobium or titanium-6-aluminium-4-vanadium accompanied by all pharmaceuticals tested. In presence of all alloys tested brain-derived neurotrophic factor, acetylcholine and nicotine increased differentiation of cells of osteoporotic donors and accelerated it in non osteoporotic donors.We conclude that ground titanium-40-niobium and brain-derived neurotrophic factor might be most suitable for subsequent in vivo testing

    Obesity is associated with an impaired survival in lymphoma patients undergoing autologous stem cell transplantation

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    Autologous hematopoietic stem cell transplantation (auto-HSCT) provides a potentially curative treatment option for relapsed and refractory lymphomas. Obesity displays an emerging epidemic risk factor for global mortality and is associated with an increased mortality in cancer patients. To date, the impact of obesity on the outcome of lymphoma patients undergoing auto-HSCT is understudied. We conducted a retrospective single-center study assessing 119 lymphoma patients who underwent auto-HSCT. Overall survival (OS) served as the primary endpoint whereas progression free survival (PFS), cumulative incidence of non-relapse related mortality (NRM) and cumulative incidence of relapse were analyzed as secondary endpoints. Obese patients (Body mass index, BMI≥30) had significantly lower OS (45.3% vs. 77.9%; p = 0.005) and PFS (29.8% vs. 67.2%; p<0.001) compared to non-obese patients at 48 months post-transplantation. The cumulative incidence of NRM displayed no significant differences while the cumulative incidence of relapse was significantly increased in patients with BMI≥30 (66.2% vs. 21.5%; p<0.001). Patients with a BMI<25 and overweight patients (BMI 25–30; 76.1% vs. 80.9%; p = 0.585), showed no significant difference in OS, whereas patients with BMI≥30 exhibited significant lower OS when compared to either of both groups (76.1% vs. 45.3%; p = .0.021 and 80.9% vs. 45.3%; p = 0.010). Furthermore, in a multivariate analysis, obesity was identified as an independent risk factor for death (Hazard ratio 2.231; 95% CI 1.024 to 4.860; p = 0.043). Further studies are needed to evaluate the reasons for the higher relapse rate causing higher mortality in obese patients

    Profiling of bacterial bloodstream infections in hematological and oncological patients based on a comparative survival analysis

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    Bloodstream infections (BSI) are a frequent complication in patients with hematological and oncological diseases. However, the impact of different bacterial species causing BSI and of multiple BSI remains incompletely understood. We performed a retrospective study profiling 637 bacterial BSI episodes in hematological and oncological patients. Based on the 30-day (30d) overall survival (OS), we analyzed different types of multiple BSI and grouped BSI-associated bacteria into clusters followed by further assessment of clinical and infection-related characteristics. We discovered that polymicrobial BSI (different organisms on the first day of a BSI episode) and sequential BSI (another BSI before the respective BSI episode) were associated with a worse 30d OS. Different bacterial groups could be classified into three BSI outcome clusters based on 30d OS: favorable (FAV) including mainly common skin contaminants, Escherichia spp. and Streptococcus spp.; intermediate (INT) including mainly Enterococcus spp., vancomycin-resistant Enterococcus spp., and multidrug-resistant gram-negative bacteria (MDRGN); and adverse (ADV) including MDRGN with an additional carbapenem-resistance (MDRGN+CR). A polymicrobial or sequential BSI especially influenced the outcome in the combination of two INT cluster BSI. The presence of a polymicrobial BSI and the assignment into the BSI outcome clusters were identified as independent risk factors for 30d mortality in a Cox multivariate regression analysis. The assignment to a BSI outcome cluster and the differentiated perspective of multiple BSI open new insights into the prognosis of patients with BSI and should be further validated in other patient cohorts

    Live cell images of hMSCs number after 21 days <i>in vitro</i>.

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    <p>Shown are hMSCs of osteoporotic (left) and non osteoporotic (right) donors in presence of etched (1<sup>st</sup> row) or ground Ti-40Nb (2<sup>nd</sup> row), Ti-6Al-4V (3<sup>rd</sup> row) or without Ti (4<sup>th</sup> row) in presence of BDNF (A), ACh (B), Nic (C) or without pharmaceuticals serving as controls (D). White arrows indicate RS cells. The images show cells of different donors as typical representative of 4 independent experiments. Black regions at the margin of pictures show Ti alloys. Scale bar shown in A applies to all photographs in this figure.</p

    Live cell images of hMSCs after 21 days of differentiation in osteogenic medium <i>in vitro</i>.

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    <p>Shown are hMSCs of osteoporotic (left) and non osteoporotic (right) donors in presence of etched (1<sup>st</sup> row) or ground Ti-40Nb (2<sup>nd</sup> row), Ti-6Al-4V (3<sup>rd</sup> row) or without Ti (4<sup>th</sup> row) in presence of BDNF (A), ACh (B), Nic (C) or without pharmaceuticals serving as controls (D). White arrows indicate mineral. The images show cells of different donors as typical representative of 4 independent experiments. Black regions at the margin of pictures show Ti alloys. Scale bar shown in A applies to all photographs in this figure.</p

    Live cell images of hMSCs number after 7 days <i>in vitro</i>.

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    <p>Shown are hMSCs of osteoporotic (left) and non osteoporotic (right) donors in presence of etched (1<sup>st</sup> row) or ground Ti-40Nb (2<sup>nd</sup> row), Ti-6Al-4V (3<sup>rd</sup> row) or without Ti (4<sup>th</sup> row) in presence of BDNF (A), ACh (B), Nic (C) or without pharmaceuticals serving as controls (D). The images show cells of different donors as typical representative of 4 independent experiments. Black regions at the margin of pictures show Ti alloys. Scale bar shown in A applies to all photographs in this figure.</p

    Live cell images of hMSCs after 14 days of differentiation in osteogenic medium <i>in vitro</i>.

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    <p>Shown are hMSCs of osteoporotic (left) and non osteoporotic (right) donors in presence of etched (1<sup>st</sup> row) or ground Ti-40Nb (2<sup>nd</sup> row), Ti-6Al-4V (3<sup>rd</sup> row) or without Ti (4<sup>th</sup> row) in presence of BDNF (A), ACh (B), Nic (C) or without pharmaceuticals serving as controls (D). White arrows indicate mineral. The images show cells of different donors as typical representative of 4 independent experiments. Black regions at the margin of pictures show Ti alloys. Scale bar shown in A applies to all photographs in this figure.</p

    Relative cell number of hMSCs of osteoporotic (grey boxplots) and non osteoporotic (white boxplots) donors in presence of etched or ground Ti-40Nb, Ti-6Al-4V as well as without Ti with or without pharmaceuticals.

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    <p>Shown is the effect of Ti alloys on cell number after 14 d (A) and 21 d (B) of <i>in vitro</i> incubation. The grey line represents cells at time point 0 d without Ti and without pharmaceuticals. A value of p ≤ 0.05 was considered to be significant and is indicated with one asterisk.</p
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