Predicting the cell death responsiveness and sensitization of glioma cells to TRAIL and temozolomide.

Genotoxic chemotherapy with temozolomide (TMZ) is a mainstay of treatment for glioblastoma (GBM); however, at best, TMZ provides only modest survival benefit to a subset of patients. Recent insight into the heterogeneous nature of GBM suggests a more personalized approach to treatment may be necessary to overcome cancer drug resistance and improve patient care. These include novel therapies that can be used both alone and with TMZ to selectively reactivate apoptosis within malignant cells. For this approach to work, reliable molecular signatures that can accurately predict treatment responsiveness need to be identified first. Here, we describe the first proof-of-principle study that merges quantitative protein-based analysis of apoptosis signaling networks with data- and knowledge-driven mathematical systems modeling to predict treatment responsiveness of GBM cell lines to various apoptosis-inducing stimuli. These include monotherapies with TMZ and TRAIL, which activate the intrinsic and extrinsic apoptosis pathways, respectively, as well as combination therapies of TMZ+TRAIL. We also successfully employed this approach to predict whether individual GBM cell lines could be sensitized to TMZ or TRAIL via the selective targeting of Bcl-2/Bcl-xL proteins with ABT-737. Our findings suggest that systems biology-based approaches could assist in personalizing treatment decisions in GBM to optimize cell death induction

Activation of executioner caspases is a predictor of progression-free survival in glioblastoma patients: a systems medicine approach.

Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults. GBM cells are highly resistant to apoptosis induced by antitumor drugs and radiotherapy resulting in cancer progression. We assessed whether a systems medicine approach, analysing the ability of tumor cells to execute apoptosis could be utilized to predict the response of GBM patients to treatment. Concentrations of the key proapoptotic proteins procaspase-3, procaspase-9, Smac and Apaf-1 and the antiapopotic protein XIAP were determined in a panel of GBM cell lines and GBM patient tumor resections. These values were used as input for APOPTO-CELL, a systems biological based mathematical model built to predict cellular susceptibility to undergo caspase activation. The modeling was capable of accurately distinguishing between GBM cells that die or survive in response to treatment with temozolomide in 10 of the 11 lines analysed. Importantly the results obtained using GBM patient samples show that APOPTO-CELL was capable of stratifying patients according to their progression-free survival times and predicted the ability of tumor cells to support caspase activation in 16 of the 21 GBM patients analysed. Calculating the susceptibility to apoptosis execution may be a potent tool in predicting GBM patient therapy responsiveness and may allow for the use of APOPTO-CELL in a clinical setting

Матеріали міжнародної науково-практичної конференції „Маркетинговий інструментарій управління попитом на товари та послуги“

Матеріали міжнародної науково-практичної конференції є результатом наукових досліджень авторів з проблем розроблення концептуальних засад маркетингового інструментарію управління попитом на товари і послуги України

Correlation Analysis of Treatment Sensitivity and Protein Expresson of pro- and anti-apoptotic Proteins & the Role of the BH3-only Protein Bim during Apoptosis of malignant Gliomas

GBM (Glioblastoma multiforme) is the most aggressive form of primary brain tumour, with dismal patient outcome. Treatment failure is often associated with intrinsic or acquired apoptosis resistance and aberrant signalling of survival pathways. In this work, we analysed apoptosis resistance in gliomas in order to improve treatment predictions and the accuracy of prognosis for patients suffering from GBM. We successfully correlated protein expression profiles of 21 pro- and anti-apoptotic proteins in glioma cell lines with chemotherapeutic sensitivity to mono-therapy with TMZ or TRAIL and to combined therapy with TMZ and TRAIL in these cell lines, using single protein analysis, the multivariate principal component analysis and the computational model APOPTO CELL. We found that sensitivity to TMZ was sufficiently predicted by analysing the components involved in the late steps of apoptosis after the release of cytochrome c. Sensitivity to TRAIL or a combination of TMZ and TRAIL was best explained by the analysis of all 21 apoptotic proteins, which are involved in an interactive network in extrinsic and intrinsic apoptotic pathways. Our results also revealed a high predictive value of the anti-apoptotic proteins XIAP and B c1-x l and the pro-apoptotic protein procaspase-3 in the determination of apoptosis resistance in glioblastomas. The BH3-only protein Bim was extensively downregulated in most glioma cell lines and all GBM patient samples. Additionally, a glioma cell line with high intrinsic expression of Bim showed further upregulation of Bim levels during treatment, which was also associated with an enhanced cell death following combination therapy with TMZ and TRAIL. Our results suggest that Bim is transcriptionally regulated during TMZ- and TRAIL-induced apoptosis by the transcription factor Fox03a, which itself is posttranscriptionally controlled by phosphorylation mediated through the Ras/ RAF/ ERK1/2 survival signalling pathway. Thus, we hypothesise that the repression of Bim activity is a pivotal step during tumourigenesis, which is conferred by both the dysregulation of the apoptotic pathway and aberrant survival signalling.</p

Sunlight-induced carbon dioxide emissions from inland waters

The emissions of carbon dioxide (CO2) from inland waters are substantial on a global scale. Yet, the fundamental question remains open which proportion of these CO2 emissions is induced by sunlight via photochemical mineralization of dissolved organic carbon (DOC), rather than by microbial respiration during DOC decomposition. Also, it is unknown on larger spatial and temporal scales how photochemical mineralization compares to other C fluxes in the inland water C cycle. We combined field and laboratory data with atmospheric radiative transfer modeling to parameterize a photochemical rate model for each day of the year 2009, for 1086 lakes situated between latitudes from 55 to 69°N in Sweden. The sunlight-induced production of dissolved inorganic carbon (DIC) averaged 3.8 ± 0.04 g C m-2 yr-1, which is a flux comparable in size to the organic carbon burial in the lake sediments. Countrywide, 151 ± 1 kt C yr-1 was produced by photochemical mineralization, corresponding to about 12% of total annual mean CO2 emissions from Swedish lakes. With a median depth of 3.2 m, the lakes were generally deep enough that incoming, photochemically active photons were absorbed in the water column. This resulted in a linear positive relationship between DIC photoproduction and the incoming photon flux, which correspond to the absorbed photons. Therefore, the slope of the regression line represents the wavelength- and depth-integrated apparent quantum yield of DIC photoproduction. We used this relationship to obtain a first estimate of DIC photoproduction in lakes and reservoirs worldwide. Global DIC photoproduction amounted to 13 and 35 Mt C yr-1 under overcast and clear sky, respectively. Consequently, these directly sunlight-induced CO2 emissions contribute up to about one tenth to the global CO2 emissions from lakes and reservoirs, corroborating that microbial respiration contributes a substantially larger share than formerly thought, and generate annual C fluxes similar in magnitude to the C burial in natural lake sediments worldwide.</p

Hourly, daily, and seasonal variability in the absorption spectra of chromophoric dissolved organic matter in a eutrophic, humic lake

The short-term (hourly and daily) variation in chromophoric dissolved organic matter (CDOM) in lakes is largely unknown. We assessed the spectral characteristics of light absorption by CDOM in a eutrophic, humic shallow mixed lake of temperate Sweden at a high-frequency (30 min) interval and during a full growing season (May to October). Physical time series, such as solar radiation, temperature, wind, and partial pressures of carbon dioxide in water and air, were measured synchronously. We identified a strong radiation-induced summer CDOM loss (25 to 50%) that developed over 4 months, which was accompanied by strong changes in CDOM absorption spectral shape. The magnitude of the CDOM loss exceeded subhourly to daily variability by an order of magnitude. Applying Fourier analysis, we demonstrate that variation in CDOM remained largely unaffected by rapid shifts in weather, and no apparent response to in-lake dissolved organic carbon production was found. In autumn, CDOM occasionally showed variation at hourly to daily time scales, reaching a maximum daily coefficient of variation of 15%. We suggest that lake-internal effects on CDOM are quenched in humic lake waters by dominating effects associated with imported CDOM and solar exposure. Since humic lake waters belong to one of the most abundant lake types on Earth, our results have important implications for the understanding of global CDOM cycling

Predicting the cell death responsiveness and sensitization of glioma cells to TRAIL and temozolomide.

Genotoxic chemotherapy with temozolomide (TMZ) is a mainstay of treatment for glioblastoma (GBM); however, at best, TMZ provides only modest survival benefit to a subset of patients. Recent insight into the heterogeneous nature of GBM suggests a more personalized approach to treatment may be necessary to overcome cancer drug resistance and improve patient care. These include novel therapies that can be used both alone and with TMZ to selectively reactivate apoptosis within malignant cells. For this approach to work, reliable molecular signatures that can accurately predict treatment responsiveness need to be identified first. Here, we describe the first proof-of-principle study that merges quantitative protein-based analysis of apoptosis signaling networks with data- and knowledge-driven mathematical systems modeling to predict treatment responsiveness of GBM cell lines to various apoptosis-inducing stimuli. These include monotherapies with TMZ and TRAIL, which activate the intrinsic and extrinsic apoptosis pathways, respectively, as well as combination therapies of TMZ+TRAIL. We also successfully employed this approach to predict whether individual GBM cell lines could be sensitized to TMZ or TRAIL via the selective targeting of Bcl-2/Bcl-xL proteins with ABT-737. Our findings suggest that systems biology-based approaches could assist in personalizing treatment decisions in GBM to optimize cell death induction.</p

Modulation of Mcl-1 sensitizes glioblastoma to TRAIL-induced apoptosis.

Glioblastoma (GBM) is the most aggressive form of primary brain tumour, with dismal patient outcome. Treatment failure is associated with intrinsic or acquired apoptosis resistance and the presence of a highly tumourigenic subpopulation of cancer cells called GBM stem cells. Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) has emerged as a promising novel therapy for some treatment-resistant tumours but unfortunately GBM can be completely resistant to TRAIL monotherapy. In this study, we identified Mcl-1, an anti-apoptotic Bcl-2 family member, as a critical player involved in determining the sensitivity of GBM to TRAIL-induced apoptosis. Effective targeting of Mcl-1 in TRAIL resistant GBM cells, either by gene silencing technology or by treatment with R-roscovitine, a cyclin-dependent kinase inhibitor that targets Mcl-1, was demonstrated to augment sensitivity to TRAIL, both within GBM cells grown as monolayers and in a 3D tumour model. Finally, we highlight that two separate pathways are activated during the apoptotic death of GBM cells treated with a combination of TRAIL and R-roscovitine, one which leads to caspase-8 and caspase-3 activation and a second pathway, involving a Mcl-1:Noxa axis. In conclusion, our study demonstrates that R-roscovitine in combination with TRAIL presents a promising novel strategy to trigger cell death pathways in glioblastoma.</p

Activation of executioner caspases is a predictor of progression-free survival in glioblastoma patients: a systems medicine approach.

Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults. GBM cells are highly resistant to apoptosis induced by antitumor drugs and radiotherapy resulting in cancer progression. We assessed whether a systems medicine approach, analysing the ability of tumor cells to execute apoptosis could be utilized to predict the response of GBM patients to treatment. Concentrations of the key proapoptotic proteins procaspase-3, procaspase-9, Smac and Apaf-1 and the antiapopotic protein XIAP were determined in a panel of GBM cell lines and GBM patient tumor resections. These values were used as input for APOPTO-CELL, a systems biological based mathematical model built to predict cellular susceptibility to undergo caspase activation. The modeling was capable of accurately distinguishing between GBM cells that die or survive in response to treatment with temozolomide in 10 of the 11 lines analysed. Importantly the results obtained using GBM patient samples show that APOPTO-CELL was capable of stratifying patients according to their progression-free survival times and predicted the ability of tumor cells to support caspase activation in 16 of the 21 GBM patients analysed. Calculating the susceptibility to apoptosis execution may be a potent tool in predicting GBM patient therapy responsiveness and may allow for the use of APOPTO-CELL in a clinical setting.</p