Decoy receptor DcR1 is induced in a p50/Bcl3-dependent manner and attenuates the efficacy of temozolomide

Temozolomide is used widely to treat malignant glioma but the overall response to this agent is generally poor. Resistance to DNA damaging drugs such as temozolomide has been related to the induction of anti-apoptotic proteins. Specifically, the transcription factor NF-κB has been suggested to participate in promoting the survival of cells exposed to chemotherapy. To identify factors that modulate cytotoxicity in the setting of DNA damage, we used an unbiased strategy to examine the NF-κB-dependent expression profile induced by temozolomide. By this route, we defined the decoy receptor DcR1 as a temozolomide response gene induced by a mechanism relying upon p50/NF-κB1. A conserved NF-κB binding sequence (κB-site) was identified in the proximal promoter and demonstrated to be required for DcR1 induction by temozolomide. Loss-of-function and gain-of-function studies reveal that the atypical IκB protein, Bcl3, is also required for induction of DcR1 by temozolomide. Mechanistically, DcR1 attenuates temozolomide efficacy by blunting activation of the Fas receptor pathway in p53+/+ glioma cells. Intracranial xenograft studies show that DcR1 depletion in glioma cells enhances the efficacy of temozolomide. Taken together, our results show how DcR1 upregulation mediates temozolomide resistance, and provide a rationale for DcR1 targeting as a strategy to sensitize gliomas to this widely used chemotherapy

Decoy receptor DcR1 is induced in a p50/Bcl3-dependent manner and attenuates the efficacy of temozolomide

Temozolomide is used widely to treat malignant glioma but the overall response to this agent is generally poor. Resistance to DNA damaging drugs such as temozolomide has been related to the induction of anti-apoptotic proteins. Specifically, the transcription factor NF-κB has been suggested to participate in promoting the survival of cells exposed to chemotherapy. To identify factors that modulate cytotoxicity in the setting of DNA damage, we used an unbiased strategy to examine the NF-κB-dependent expression profile induced by temozolomide. By this route, we defined the decoy receptor DcR1 as a temozolomide response gene induced by a mechanism relying upon p50/NF-κB1. A conserved NF-κB binding sequence (κB-site) was identified in the proximal promoter and demonstrated to be required for DcR1 induction by temozolomide. Loss-of-function and gain-of-function studies reveal that the atypical IκB protein, Bcl3, is also required for induction of DcR1 by temozolomide. Mechanistically, DcR1 attenuates temozolomide efficacy by blunting activation of the Fas receptor pathway in p53+/+ glioma cells. Intracranial xenograft studies show that DcR1 depletion in glioma cells enhances the efficacy of temozolomide. Taken together, our results show how DcR1 upregulation mediates temozolomide resistance, and provide a rationale for DcR1 targeting as a strategy to sensitize gliomas to this widely used chemotherapy

Convection enhanced delivery and \u3ci\u3ein vivo\u3c/i\u3e imaging of polymeric nanoparticles for the treatment of malignant glioma

A major obstacle to the management of malignant glioma is the inability to effectively deliver therapeutic agent to the tumor. In this study, we describe a polymeric nanoparticle vector that not only delivers viable therapeutic, but can also be tracked in vivo using MRI. Nanoparticles, produced by a non-emulsion technique, were fabricated to carry iron oxide within the shell and the chemotherapeutic agent, temozolomide (TMZ), as the payload. Nanoparticle properties were characterized and subsequently their endocytosis-mediated uptake by glioma cells demonstrated. Convection enhanced delivery (CED) can disperse nanoparticles through the rodent brain and their distribution is accurately visualized by MRI. Infusion of nanoparticles does not result in observable animal toxicity relative to control. CED of TMZ bearing nanoparticles prolongs the survival of animals with intracranial xenografts compared to control. In conclusion, the described nanoparticle vector represents a unique multifunctional platform that can be used for image-guided treatment of malignant glioma

Behavioural economics, motivating psycho-education improvements; a mobile technology initiative in South Africa

Here we report on a health behavioural support project, using incentivised behaviour on a mobile platform through M4JAM. This was a proof of concept study to support further developments, more specifically targeted at the management of Tuberculosis and Human Immunodeficiency Virus. The study reported here examines the impact of financial rewards and app towards improving mental health outcomes in South Africa. 136 participants were recruited from a database and dichotomized into self-determined and heteronomous groups based on self-report scores. Overall the findings highlighted that personal financial incentives have a role in motivating behaviour and that individuals with higher levels of self-determinate motivation. The findings are discussed in light of the usefulness of an incentivized mobile platform in real-world practice to encourage mental health improvements in a low to middle-income countries

Alzheimer\u27s Therapeutics Targeting Amyloid Beta 1–42 Oligomers II: Sigma-2/PGRMC1 Receptors Mediate Abeta 42 Oligomer Binding and Synaptotoxicity

Amyloid beta (Abeta) 1-42 oligomers accumulate in brains of patients with Mild Cognitive Impairment (MCI) and disrupt synaptic plasticity processes that underlie memory formation. Synaptic binding of Abeta oligomers to several putative receptor proteins is reported to inhibit long-term potentiation, affect membrane trafficking and induce reversible spine loss in neurons, leading to impaired cognitive performance and ultimately to anterograde amnesia in the early stages of Alzheimer\u27s disease (AD). We have identified a receptor not previously associated with AD that mediates the binding of Abeta oligomers to neurons, and describe novel therapeutic antagonists of this receptor capable of blocking Abeta toxic effects on synapses in vitro and cognitive deficits in vivo. Knockdown of sigma-2/PGRMC1 (progesterone receptor membrane component 1) protein expression in vitro using siRNA results in a highly correlated reduction in binding of exogenous Abeta oligomers to neurons of more than 90%. Expression of sigma-2/PGRMC1 is upregulated in vitro by treatment with Abeta oligomers, and is dysregulated in Alzheimer\u27s disease patients\u27 brain compared to age-matched, normal individuals. Specific, high affinity small molecule receptor antagonists and antibodies raised against specific regions on this receptor can displace synthetic Abeta oligomer binding to synaptic puncta in vitro and displace endogenous human AD patient oligomers from brain tissue sections in a dose-dependent manner. These receptor antagonists prevent and reverse the effects of Abeta oligomers on membrane trafficking and synapse loss in vitro and cognitive deficits in AD mouse models. These findings suggest sigma-2/PGRMC1 receptors mediate saturable oligomer binding to synaptic puncta on neurons and that brain penetrant, small molecules can displace endogenous and synthetic oligomers and improve cognitive deficits in AD models. We propose that sigma-2/PGRMC1 is a key mediator of the pathological effects of Abeta oligomers in AD and is a tractable target for small molecule disease-modifying therapeutics

An upper limit for ice in Shackleton crater as revealed by LRO Mini-RF orbital

[1] Although diverse measurements have indicated H + , OH À , or H 2 O species in the lunar polar regions, pinpointing its location, form, and abundance in specific reservoirs has proven elusive. Here we report on the first orbital radar measurements of Shackleton crater near the lunar south pole. Mini-RF observations indicate a patchy, heterogeneous enhancement in CPR (circular polarization ratio) on the crater walls whose strength decreases with depth toward the crater floor, a result that is most consistent with a roughness effect due to less mature regolith present on the crater wall slopes. However, the results do not rule out a modest ice contribution, and an upper limit of $5-10 wt% H 2 O ice (up to 30 vol.%) present in the uppermost meter of regolith is also consistent with the observations

Constitutivism

A brief explanation and overview of constitutivism