Targeting acute myeloid leukemia by drug-induced c-MYB degradation

Despite advances in our understanding of the molecular basis for particular subtypes of acute myeloid leukemia (AML), effective therapy remains a challenge for many individuals suffering from this disease. A significant proportion of both pediatric and adult AML patients cannot be cured and since the upper limits of chemotherapy intensification have been reached, there is an urgent need for novel therapeutic approaches. The transcription factor c-MYB has been shown to play a central role in the development and progression of AML driven by several different oncogenes, including mixed lineage leukemia (MLL)-fusion genes. Here, we have used a c-MYB gene expression signature from MLL-rearranged AML to probe the Connectivity Map database and identified mebendazole as a c-MYB targeting drug. Mebendazole induces c-MYB degradation via the proteasome by interfering with the heat shock protein 70 (HSP70) chaperone system. Transient exposure to mebendazole is sufficient to inhibit colony formation by AML cells, but not normal cord blood-derived cells. Furthermore, mebendazole is effective at impairing AML progression in vivo in mouse xenotransplantation experiments. In the context of widespread human use of mebendazole, our data indicate that mebendazole-induced c-MYB degradation represents a safe and novel therapeutic approach for AML

Small heat shock proteins, ClpB and the DnaK system form a functional triade in reversing protein aggregation.

Small heat shock proteins (sHsps) can efficiently prevent the aggregation of unfolded proteins in vitro. However, how this in vitro activity translates to function in vivo is poorly understood. We demonstrate that sHsps of Escherichia coli, IbpA and IbpB, co-operate with ClpB and the DnaK system in vitro and in vivo, forming a functional triade of chaperones. IbpA/IbpB and ClpB support independently and co-operatively the DnaK system in reversing protein aggregation. A delta ibpAB delta clpB double mutant exhibits strongly increased protein aggregation at 42 degrees C compared with the single mutants. sHsp and ClpB function become essential for cell viability at 37 degrees C if DnaK levels are reduced. The DnaK requirement for growth is increasingly higher for delta ibpAB, delta clpB, and the double delta ibpAB delta clpB mutant cells, establishing the positions of sHsps and ClpB in this chaperone triade

Abnormal directed connectivity of resting state networks in focal epilepsy

Objective: Epilepsy diagnosis can be difficult in the absence of interictal epileptic discharges (IED) on scalp EEG. We used high-density EEG to measure connectivity in large‐scale functional networks of patients with focal epilepsy (Temporal and Extratemporal Lobe Epilepsy, TLE and ETLE) and tested for network alterations during resting wakefulness without IEDs, compared to healthy controls. We measured global efficiency as a marker of integration within networks. Methods: We analysed 49 adult patients with focal epilepsy and 16 healthy subjects who underwent high-density-EEG and structural MRI. We estimated cortical activity using electric source analysis in 82 atlas-based cortical regions based on the individual MRI. We applied directed connectivity analysis (Partial Directed Coherence) on these sources and performed graph analysis: we computed the Global Efficiency on the whole brain and on each resting state network. We tested these features in different group of patients. Results: Compared to controls, efficiency was increased in both TLE and ETLE (p < 0.05). The somato-motor-network, the ventral-attention-network and the default-mode-network had a significantly increased efficiency (p < 0.05) in both TLE and ETLE as well as TLE with hippocampal sclerosis. Significance: During interictal scalp EEG epochs without IED, patients with focal epilepsy show brain functional connectivity alterations in the whole brain and in specific resting-state-networks. This higher integration reflects a chronic effect of pathological activity within these structures and complement previous work on altered information outflow. These findings could increase the diagnostic sensitivity of scalp EEG to identify epileptic activity in the absence of IED

Effects of deep brain stimulation on prepulse inhibition in obsessive-compulsive disorder

Owing to a high response rate, deep brain stimulation (DBS) of the ventral striatal area has been approved for treatment-refractory obsessive-compulsive disorder (tr-OCD). Many basic issues regarding DBS for tr-OCD are still not understood, in particular, the mechanisms of action and the origin of side effects. We measured prepulse inhibition (PPI) in treatment-refractory OCD patients undergoing DBS of the nucleus accumbens (NAcc) and matched controls. As PPI has been used in animal DBS studies, it is highly suitable for translational research. Eight patients receiving DBS, eight patients with pharmacological treatment and eight age-matched healthy controls participated in our study. PPI was measured twice in the DBS group: one session with the stimulator switched on and one session with the stimulator switched off. OCD patients in the pharmacologic group took part in a single session. Controls were tested twice, to ensure stability of data. Statistical analysis revealed significant differences between controls and (1) patients with pharmacological treatment and (2) OCD DBS patients when the stimulation was switched off. Switching the stimulator on led to an increase in PPI at a stimulus-onset asynchrony of 200 ms. There was no significant difference in PPI between OCD patients being stimulated and the control group. This study shows that NAcc-DBS leads to an increase in PPI in tr-OCD patients towards a level seen in healthy controls. Assuming that PPI impairments partially reflect the neurobiological substrates of OCD, our results show that DBS of the NAcc may improve sensorimotor gating via correction of dysfunctional neural substrates. Bearing in mind that PPI is based on a complex and multilayered network, our data confirm that DBS most likely takes effect via network modulation