Patient-derived glioblastoma cells show significant heterogeneity in treatment responses to the inhibitor-of-apoptosis-protein antagonist birinapant.

BACKGROUND: Resistance to temozolomide (TMZ) greatly limits chemotherapeutic effectiveness in glioblastoma (GBM). Here we analysed the ability of the Inhibitor-of-apoptosis-protein (IAP) antagonist birinapant to enhance treatment responses to TMZ in both commercially available and patient-derived GBM cells. METHODS: Responses to TMZ and birinapant were analysed in a panel of commercial and patient-derived GBM cell lines using colorimetric viability assays, flow cytometry, morphological analysis and protein expression profiling of pro- and antiapoptotic proteins. Responses in vivo were analysed in an orthotopic xenograft GBM model. RESULTS: Single-agent treatment experiments categorised GBM cells into TMZ-sensitive cells, birinapant-sensitive cells, and cells that were insensitive to either treatment. Combination treatment allowed sensitisation to therapy in only a subset of resistant GBM cells. Cell death analysis identified three principal response patterns: Type A cells that readily activated caspase-8 and cell death in response to TMZ while addition of birinapant further sensitised the cells to TMZ-induced cell death; Type B cells that readily activated caspase-8 and cell death in response to birinapant but did not show further sensitisation with TMZ; and Type C cells that showed no significant cell death or moderately enhanced cell death in the combined treatment paradigm. Furthermore, in vivo, a Type C patient-derived cell line that was TMZ-insensitive in vitro and showed a strong sensitivity to TMZ and TMZ plus birinapant treatments. CONCLUSIONS: Our results demonstrate remarkable differences in responses of patient-derived GBM cells to birinapant single and combination treatments, and suggest that therapeutic responses in vivo may be greatly affected by the tumour microenvironment

Do Two Machine-Learning Based Prognostic Signatures for Breast Cancer Capture the Same Biological Processes?

The fact that there is very little if any overlap between the genes of different prognostic signatures for early-discovery breast cancer is well documented. The reasons for this apparent discrepancy have been explained by the limits of simple machine-learning identification and ranking techniques, and the biological relevance and meaning of the prognostic gene lists was questioned. Subsequently, proponents of the prognostic gene lists claimed that different lists do capture similar underlying biological processes and pathways. The present study places under scrutiny the validity of this claim, for two important gene lists that are at the focus of current large-scale validation efforts. We performed careful enrichment analysis, controlling the effects of multiple testing in a manner which takes into account the nested dependent structure of gene ontologies. In contradiction to several previous publications, we find that the only biological process or pathway for which statistically significant concordance can be claimed is cell proliferation, a process whose relevance and prognostic value was well known long before gene expression profiling. We found that the claims reported by others, of wider concordance between the biological processes captured by the two prognostic signatures studied, were found either to be lacking statistical rigor or were in fact based on addressing some other question

ICAR: endoscopic skull‐base surgery

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On a biophysical and mathematical model of pgp-mediated multidrug resistance: understanding the “space–time” dimension of MDR

Multidrug resistance (MDR) is explained by drug transporters with a drug-handling activity. Despite much work, MDR remains multifaceted, and several conditions are required to generate drug resistance. The drug pumping was conceptually described using a kinetic, i.e., temporal, approach. The re-emergence of physical biology has allowed us to take into account new parameters focusing on the notion of space. This, in turn, has given us important clues regarding the process whereby drug and transporter interact. We will demonstrate that the likelihood of drug-transporter meeting (i.e., the affinity) and thus interaction are also driven by the mechanical interaction between drug molecular weight (MW) and the membrane mechanical properties. This should allow us to mechanically control drug delivery

Association between exposure to traumatic events and anxiety disorders in a post-conflict setting: a cross-sectional community study in South Sudan

Background The negative effect of exposure to traumatic events on mental health is well known. Most studies of the effects of trauma on mental health in war-affected populations have focused on post-traumatic stress disorder (PTSD) and depression. Although some studies confirm the existence of anxiety symptoms in war-affected populations, the extent to which exposure to traumatic events is independently associated with anxiety diagnoses (other than PTSD) has received less attention. The study aimed to determine whether having an anxiety diagnosis, other than PTSD, was associated with experiencing traumatic events in a post-conflict setting, across genders and after controlling for demographic and socio-economic variables. Methods In this cross-sectional community study (n = 1200), we applied the Harvard Trauma Questionnaire (HTQ) to investigate the extent of trauma exposure and PTSD. The Mini-International Neuropsychiatric Interview (MINI) was used to investigate the prevalence of anxiety disorders: generalized anxiety disorder (GAD), panic disorder (PD), social phobia, obsessive-compulsive disorder (OCD), and agoraphobia. Multinomial logistic regression analyses were conducted to examine the association between these disorders, previous trauma exposure, and socio-economic factors. Results The participants were 56.4% male and 43.6% female. The age ranged between 18 and 73 years old (Mean 34.63, SD = 12.03). The estimated rates of GAD-only and PD-only (without comorbidity with PTSD) were 5.5% and 3.1%, respectively. Exposure to traumatic events and socio-economic disadvantage were significantly associated with having one or more anxiety diagnoses. After controlling for age, sex, rural/urban setting, and socio-economic disadvantage, exposure to trauma was independently associated with anxiety diagnosis. There were gender differences in the pattern of risk factors for having PTSD, GAD or PD. Conclusion In individuals with a history of war-related trauma exposure, attention should be given to symptoms of GAD and PD, in addition to PTSD symptoms