Inhibition of TXNRD or SOD1 overcomes NRF2-mediated resistance to β-lapachone

Alterations in the NRF2/KEAP1 pathway result in the constitutive activation of NRF2, leading to the aberrant induction of antioxidant and detoxification enzymes, including NQO1. The NQO1 bioactivatable agent β-lapachone can target cells with high NQO1 expression but relies in the generation of reactive oxygen species (ROS), which are actively scavenged in cells with NRF2/KEAP1 mutations. However, whether NRF2/KEAP1 mutations influence the response to β-lapachone treatment remains unknown. To address this question, we assessed the cytotoxicity of β-lapachone in a panel of NSCLC cell lines bearing either wild-type or mutant KEAP1. We found that, despite overexpression of NQO1, KEAP1 mutant cells were resistant to β-lapachone due to enhanced detoxification of ROS, which prevented DNA damage and cell death. To evaluate whether specific inhibition of the NRF2-regulated antioxidant enzymes could abrogate resistance to β-lapachone, we systematically inhibited the four major antioxidant cellular systems using genetic and/or pharmacologic approaches. We demonstrated that inhibition of the thioredoxin-dependent system or copper-zinc superoxide dismutase (SOD1) could abrogate NRF2-mediated resistance to β-lapachone, while depletion of catalase or glutathione was ineffective. Interestingly, inhibition of SOD1 selectively sensitized KEAP1 mutant cells to β-lapachone exposure. Our results suggest that NRF2/KEAP1 mutational status might serve as a predictive biomarker for response to NQO1-bioactivatable quinones in patients. Further, our results suggest SOD1 inhibition may have potential utility in combination with other ROS inducers in patients with KEAP1/NRF2 mutations

GATE simulation for medical physics with genius Web portal

présenté par C. ThiamPCSV team of the LPC laboratory in Clermont-Ferrand is involved in the deployment of biomedical applications on the grid architecture. One of these applications deals with the deployment of GATE (Geant4 Application for Tomographic Emission) for medical physics application. The aim of the developments actually performed is to enable an application of the GATE platform in clinical routine. However, this perspective is only possible if the computing time and user time are highly reduced. The new grid architecture, developed within the framework of the European project Enabling Grid for E-sciencE (EGEE) is there to answer this requirement. The use of the grid resources must be transparent easy and rapid for the medical physicists. For this perpose, we adapted the GENIUS web portal in order to facilitate the GATE simulations planning on the grid. We will present a demonstration of the GENIUS portal which integrates all the functionalities of EGEE: to create, to submit and manage GATE jobs on the grid architecture. Our GATE activities for dosimetry application entered in to direct phase of evaluation by the cancer treatment center of Clermont Ferrand (Centre Jean perrin).A work station is currently available in this center to test the use of GATE application on the grid through GENIUS. This portal will allow in a long term to use GATE application in brachytherapy and radiotherapy treatment planning using medical data (medical images, DICOM, binary data dose calculation in the heterogeneous mediums) and to analyze the results obtained in visual form. Other functionalities are under development and will make possible to register medical data on grid storages elements and to manage them. However, these data must be anonymised before their recording on the grid. Their access via the GENIUS portal must be made safe and fast (compared simulation computing time). In order to be sure that the medical data are accessible for calculations, their replication on various storage element (SE) should be possible. The grid services give the possibility of managing this information in a free way and transparently. Operations of data handling and catalogues on the grid are ensured by the Replica Manager system which integrates all tools making it possible to manage data on the grid. The computing grid give promising results and meet a definite need: reach acceptable computing time for a future use of Monte Carlo simulations for treatment planning in brachytherapy and radiotherapy

Dopamine D 4 Receptor-Deficient Mice Display Cortical Hyperexcitability

The dopamine D(4) receptor (D(4)R) is predominantly expressed in the frontal cortex (FC), a brain region that receives dense input from midbrain dopamine (DA) neurons and is associated with cognitive and emotional processes. However, the physiological significance of this dopamine receptor subtype has been difficult to explore because of the slow development of D(4)R agonists and antagonists the selectivity and efficacy of which have been rigorously demonstrated in vivo. We have attempted to overcome this limitation by taking a multidimensional approach to the characterization of mice completely deficient in this receptor subtype. Electrophysiological current and voltage-clamp recordings were performed in cortical pyramidal neurons from wild-type and D(4)R-deficient mice. The frequency of spontaneous synaptic activity and the frequency and duration of paroxysmal discharges induced by epileptogenic agents were increased in mutant mice. Enhanced synaptic activity was also observed in brain slices of wild-type mice incubated in the presence of the selective D(4)R antagonist PNU-101387G. Consistent with greater electrophysiological activity, nerve terminal glutamate density associated with asymmetrical synaptic contacts within layer VI of the motor cortex was reduced in mutant neurons. Taken together, these results suggest that the D(4)R can function as an inhibitory modulator of glutamate activity in the FC.Fil: Rubinstein, Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Cepeda, Carlos. University of California at Los Angeles; Estados UnidosFil: Hurst, Raymond S.. University of California at Los Angeles; Estados UnidosFil: Flores Hernandez, Jorge. University of California at Los Angeles; Estados UnidosFil: Ariano, Marjorie A.. The Chicago Medical School; Estados UnidosFil: Falzone, Tomas Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Kozell, Laura B.. Oregon Health Sciences University; Estados UnidosFil: Meshul, Charles K.. Oregon Health Sciences University; Estados UnidosFil: Bunzow, James R.. Oregon Health Sciences University; Estados UnidosFil: Low, Malcolm J.. Oregon Health Sciences University; Estados UnidosFil: Levine, Michael S.. University of California at Los Angeles; Estados UnidosFil: Grandy, David K.. Oregon Health Sciences University; Estados Unido

Carboxyhaemoglobin levels in water-pipe and cigarette smokers

Water-pipe smoking is growing in popularity, especially among young people, because of the social nature of the smoking session and the assumption that the effects are less harmful than those of cigarette smoking. It has however been shown that a single water-pipe smoking session produces a 24-hour urinary cotinine level equivalent to smoking 10 cigarettes per day.Aim. We aimed to measure carboxyhaemoglobin (COHb) blood levels before and after water-pipe and cigarette smoking sessions.Method. Self-confessed smokers older than 18 years (N=30)volunteered to smoke a water-pipe or a cigarette andhave their blood COHb levels measured under controlledconditions.Results. Mean baseline COHb levels were 2.9% for the 15 cigarette smokers and 1.0% for the 15 water-pipe smokers. Levels increased by a mean of 481.7% in water-pipe smokers as opposed to 39.9% in cigarette smokers.Conclusion. The study demonstrated that water-pipe smokers had significantly higher increases in blood COHb levels than cigarette smokers during a single smoking session

Carboxyhaemoglobin levels in water-pipe and cigarette smokers

Water-pipe smoking is growing in popularity, especially among young people, because of the social nature of the smoking session and the assumption that the effects are less harmful than those of cigarette smoking. It has however been shown that a single water-pipe smoking session produces a 24-hour urinary cotinine level equivalent to smoking 10 cigarettes per day. Aim. We aimed to measure carboxyhaemoglogin (COHb) blood levels before and after water-pipe and cigarette smoking sessions. Method. Self-confessed smokers older than 18 years (N=30) volunteered to smoke a water-pipe or a cigarette and have their blood COHb levels measured under controlled conditions. Results. Mean baseline COHb levels were 2.9% for the 15 cigarette smokers and 1.0% for the 15 water-pipe smokers. Levels increased by a mean of 481.7% in water-pipe smokers as opposed to 39.9% in cigarette smokers. Conclusion. The study demonstrated that water-pipe smokers had significantly higher increases in blood COHb levels than cigarette smokers during a single smoking session

Targeted radionuclide therapy in combined-modality regimens

Targeted radionuclide therapy (TRT) is a branch of cancer medicine concerned with the use of radioisotopes, radiolabelled molecules, nanoparticles or microparticles that either naturally accumulate in or are designed to home to tumours. They combine the specificity of molecular and, sometimes, physical targeting with the potent cytotoxicity of ionising radiation. Targeting vectors for TRT include antibodies, antibody fragments, proteins, peptides, and small molecules. The diversity of available carrier molecules together with the large panel of suitable radioisotopes with unique physicochemical properties allows vector-radionuclide pairings to be matched to the molecular, pathological and physical characteristics of a tumour. Some agents are designed for dual therapeutic and diagnostic (“theranostic”) applications. TRT use has increased with the introduction of agents that are indicated for common oncological conditions, including 90Y-microspheres for the treatment of hepatic tumours and 223RaCl2 for bone metastases. This raises the question of how best to integrate TRT into multi-modality protocols. Achievements in this area and future prospects are reviewed here