Combining Simvastatin with the Farnesyltransferase Inhibitor Tipifarnib Results in an Enhanced Cytotoxic Effect in a Subset of Primary CD34 +

Purpose: To show whether the inhibitory effects of the cholesterol synthesis inhibitor simvastatin on human CD34(+) acute myeloid leukemia (AML) cells can be further promoted by combining it with the farnesyltransferase inhibitor tipifarnib. Experimental Design: Normal CD34(+), AML CD34(+), and CD34(-) sorted subfractions, and AML cell lines (TF-1 and KG1A) were exposed to simvastatin and tipifarnib. Results: Both simvastatin and tipifarnib showed a cytotoxic effect on AML cell lines, which was additive when used in combination. In primary sorted CD34(+) AML cells, a heterogeneous response pattern was observed upon treatment with simvastatin when analyzing cell survival. A group of normal (n = 12) and abnormal (n = 10) responders were identified within the AML CD34(+) subfraction when compared with normal CD34(+) cells. This distinction was not observed within the AML CD34(-) cell fraction. When the CD34(+) AML cells were exposed to simvastatin and tipifarnib, a significant enhanced inhibitory effect was shown exclusively in the normal AML responder group, whereas the AML CD34(-) cell fractions all showed an enhanced inhibitory effect. The observed heterogeneity in AML responsiveness could not be explained by differences in effects on cholesterol metabolism genes or extracellular signal-regulated kinase phosphorylation in response to simvastatin and tipifarnib treatment. Conclusion: The results suggest that combined treatment with statins and farnesyltransferase inhibitors may be beneficial for a subset of AML patients that can be defined by studying the AML CD34(+) fraction

Combining Simvastatin with the Farnesyltransferase Inhibitor Tipifarnib Results in an Enhanced Cytotoxic Effect in a Subset of Primary CD34(+) Acute Myeloid Leukemia Samples

Purpose: To show whether the inhibitory effects of the cholesterol synthesis inhibitor simvastatin on human CD34(+) acute myeloid leukemia (AML) cells can be further promoted by combining it with the farnesyltransferase inhibitor tipifarnib. Experimental Design: Normal CD34(+), AML CD34(+), and CD34(-) sorted subfractions, and AML cell lines (TF-1 and KG1A) were exposed to simvastatin and tipifarnib. Results: Both simvastatin and tipifarnib showed a cytotoxic effect on AML cell lines, which was additive when used in combination. In primary sorted CD34(+) AML cells, a heterogeneous response pattern was observed upon treatment with simvastatin when analyzing cell survival. A group of normal (n = 12) and abnormal (n = 10) responders were identified within the AML CD34(+) subfraction when compared with normal CD34(+) cells. This distinction was not observed within the AML CD34(-) cell fraction. When the CD34(+) AML cells were exposed to simvastatin and tipifarnib, a significant enhanced inhibitory effect was shown exclusively in the normal AML responder group, whereas the AML CD34(-) cell fractions all showed an enhanced inhibitory effect. The observed heterogeneity in AML responsiveness could not be explained by differences in effects on cholesterol metabolism genes or extracellular signal-regulated kinase phosphorylation in response to simvastatin and tipifarnib treatment. Conclusion: The results suggest that combined treatment with statins and farnesyltransferase inhibitors may be beneficial for a subset of AML patients that can be defined by studying the AML CD34(+) fraction

Variability in responsiveness to lovastatin of the primitive CD34(+) AML subfraction compared to normal CD34(+) cells

International audienceIn the present study, we questioned whether the cholesterol synthesis inhibitor lovastatin potentiates the cytotoxicity of chemotherapeutic agents in the primitive CD34 subpopulation of acute myeloid leukemia (AML) cells. AML mononuclear cells ( = 17) were sorted in CD34 and CD34 fractions and compared to normal CD34 cells ( = 7). The percentage of surviving cells upon exposure to lovastatin (25–100 μM) and/or chemotherapeutics (cytarabin or daunorubicin) was determined with a luminescent cell viability assay. The results demonstrate that the primitive CD34 subpopulation of normal and AML cells displayed a higher sensitivity to lovastatin than the more mature CD34 subpopulation. The combination of lovastatin and chemotherapeutics resulted in a more pronounced inhibitory effect on both subpopulations. In contrast to the homogeneous results in normal CD34 cells, a distinct heterogeneity in lovastatin sensitivity was found in AML samples. Therefore, a group of normal ( = 11) and abnormal ( = 6) responders were identified based on a reduced or increased cell survival compared to normal CD34 cells. This distinction was not only observed in the CD34 AML subfraction but also in CD34CD38AML cells. In the abnormal responder group, 50% of patients presented with unfavorable cytogenetics and significant higher peripheral blast cell counts, which coincided with poor treatment results. In summary, the findings indicate that the primitive subfraction of CD34 AML cells is in the majority of cases affected by lovastatin treatment, which is potentiated when combined with chemotherapeutics. Heterogeneity of the response observed in AML patients allowed identification of a subgroup with poor prognosis

HLA-DQB1 6672G > C (rs113332494) is associated with clozapine-induced neutropenia and agranulocytosis in individuals of European ancestry

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked DownloadThe atypical antipsychotic clozapine is the only effective medication for treatment-resistant schizophrenia. However, it can also induce serious adverse drug reactions, including agranulocytosis and neutropenia. The mechanism by which it does so is largely unknown, but there is evidence for contributing genetic factors. Several studies identified HLA-DQB1 variants and especially a polymorphism located in HLA-DQB1 (6672G>C, rs113332494) as associated with clozapine-induced agranulocytosis and neutropenia. We analysed the risk allele distribution of SNP rs113332494 in a sample of 1396 controls and 178 neutropenia cases of which 60 developed agranulocytosis. Absolute neutrophil counts of 500/mm3 and 1500/mm3 were used for defining agranulocytosis and neutropenia cases, respectively. We also performed association analyses and analysed local ancestry patterns in individuals of European ancestry, seeking replication and extension of earlier findings. HLA-DQB1 (6672G>C, rs113332494) was associated with neutropenia (OR = 6.20, P = 2.20E-06) and agranulocytosis (OR = 10.49, P = 1.83E-06) in individuals of European ancestry. The association signal strengthened after including local ancestry estimates (neutropenia: OR = 10.38, P = 6.05E-08; agranulocytosis: OR = 16.31, P = 1.39E-06), with effect sizes being considerably larger for agranulocytosis. Using local ancestry estimates for prediction, the sensitivity of rs113332494 increased from 11.28 to 55.64% for neutropenia and from 16.67 to 53.70% for agranulocytosis. Our study further strengthens the evidence implicating HLA-DQB1 in agranulocytosis and neutropenia, suggesting components of the immune system as contributing to this serious adverse drug reaction. Using local ancestry estimates might help in identifying risk variants and improve prediction of haematological adverse effects.European Union's Seventh Framework Programme for research, technological development and demonstration UK Research & Innovation (UKRI) Medical Research Council UK (MRC) "Springboard" award from the Academy of Medical Sciences Takeda Pharmaceutical Company Ltd US National Institute of Mental Health via the American Recovery and Reinvestment Act of 2009 National Science Foundation (NSF

White paper for grassland opportunities : Discussion document

Grassland is an important type of land use in Europe, covering a large area and providing ecosystem services such as carbon sequestration, enhancing biodiversity and protecting water. To boost the development of a bio-based economy and contribute to the EU’s goal of achieving net zero emissions by 2050, there is a need for business models that can be replicated in a variety of locations and contexts, with relatively low levels of investment, risk and technical sophistication. A wider range of rural entrepreneurs need to get involved in the emerging bio-based business sector, including farmers and forest owners (and their associations), policy makers, small rural businesses, and advisors. This is key to diversifying and revitalising the rural economies and creating quality jobs in rural areas