Combined Inactivation of MYC and K-Ras oncogenes reverses tumorigenesis in lung adenocarcinomas and lymphomas

Background

Conditional transgenic models have established that tumors require sustained oncogene activation for tumor maintenance, exhibiting the phenomenon known as “oncogene-addiction.” However, most cancers are caused by multiple genetic events making it difficult to determine which oncogenes or combination of oncogenes will be the most effective targets for their treatment.

Methodology/Principal Findings

To examine how the MYC and K-ras^G12D oncogenes cooperate for the initiation and maintenance of tumorigenesis, we generated double conditional transgenic tumor models of lung adenocarcinoma and lymphoma. The ability of MYC and K-ras^G12D to cooperate for tumorigenesis and the ability of the inactivation of these oncogenes to result in tumor regression depended upon the specific tissue context. MYC-, K-ras^G12D- or MYC/K-ras^G12D-induced lymphomas exhibited sustained regression upon the inactivation of either or both oncogenes. However, in marked contrast, MYC-induced lung tumors failed to regress completely upon oncogene inactivation; whereas K-ras^G12D-induced lung tumors regressed completely. Importantly, the combined inactivation of both MYC and K-ras^G12D resulted more frequently in complete lung tumor regression. To account for the different roles of MYC and K-ras^G12D in maintenance of lung tumors, we found that the down-stream mediators of K-ras^G12D signaling, Stat3 and Stat5, are dephosphorylated following conditional K-ras^G12D but not MYC inactivation. In contrast, Stat3 becomes dephosphorylated in lymphoma cells upon inactivation of MYC and/or K-ras^G12D. Interestingly, MYC-induced lung tumors that failed to regress upon MYC inactivation were found to have persistent Stat3 and Stat5 phosphorylation.

Conclusions/Significance

Taken together, our findings point to the importance of the K-Ras and associated down-stream Stat effector pathways in the initiation and maintenance of lymphomas and lung tumors. We suggest that combined targeting of oncogenic pathways is more likely to be effective in the treatment of lung cancers and lymphomas.     

Rational Design of Core@shell Structured CoSx@Cu2MoS4 Hybridized MoS2/N,S‐Codoped Graphene as Advanced Electrocatalyst for Water Splitting and Zn‐Air Battery

A novel hybrid of small core@shell structured CoS_x@Cu₂MoS₄ uniformly hybridizing with a molybdenum dichalcogenide/N,S‐codoped graphene hetero‐network (CoS_x@Cu₂MoS₄‐MoS₂/NSG) is prepared by a facile route. It shows excellent performance toward the oxygen reduction reaction (ORR), oxygen evolution reaction (OER), and hydrogen evolution reaction (HER) in alkaline medium. The hybrid exhibits rapid kinetics for ORR with high electron transfer number of ≈3.97 and exciting durability superior to commercial Pt/C. It also demonstrates great potential with remarkable stability for HER and OER, requiring low overpotential of 118.1 and 351.4 mV, respectively, to reach a current density of 10 mA cm^?2. An electrolyzer based on CoS_x@Cu₂MoS₄‐MoS₂/NSG produces low cell voltage of 1.60 V and long‐term stability, surpassing a device of Pt/C + RuO₂/C. In addition, a Zn‐air battery using cathodic CoS_x@Cu₂MoS₄‐MoS₂/NSG catalyst delivers a high cell voltage of ≈1.44 V and a power density of 40 mW cm^?2 at 58 mA cm^?2, better than the state‐of‐the‐art Pt/C catalyst. These achievements are due to the rational combination of highly active core@shell CoS_x@Cu₂MoS₄ with large‐area and high‐porosity MoS₂/NSG to produce unique physicochemical properties with multi‐integrated active centers and synergistic effects. The outperformances of such catalyst suggest an advanced candidate for multielectrocatalysis applications in metal‐air batteries and hydrogen production.     

Serum sphinganine and the sphinganine to sphingosine ratio as a biomarker of dietary fumonisins during chronic exposure in ducks

Sphinganine concentration (Sa) and sphinganine to sphingosine ratio (Sa/So) are sensitive biomarkers of fumonisin B1 (FB1) exposure in animals and have been proposed to reveal FB1 exposure in humans. They correlate with liver and kidney toxicity and often precede signs of toxicity. However, the use of Sa and Sa/So is confusing during chronic exposure. Indeed, some authors report altered sphingolipids metabolism, whereas others fail to demonstrate significant effect. The aim of this study was to investigate the kinetics of Sa and Sa/So in the serum of ducks over a 77-day exposure to 0, 2, 8, 32 and 128 mg FB1/kg feeds. Serum biochemistry was also investigated to reveal hepatotoxicity. The results obtained indicate that the kinetics of sphingolipids and serum biochemistry are closely linked with the duration of the exposure. After a strong and rapid increase Sa and Sa/So decrease then stabilize. The lowest investigated dose able to determine a detectable effect is 2 mg/kg feeds, the Sa/So ratio being the most sensitive biomarker of FB1 exposure.     

Concentrations of high-mobility-group proteins in the nucleus and cytoplasm of several rat tissues

Nuclear and cytoplasmic fractions were isolated from various tissues of the rat by a nonaqueous technique. The high-mobility-group (HMG) proteins were extracted from these fractions with acid and separated by one- and two-dimensional PAGE. The concentrations of high-mobility-group proteins HMG1, HMG2, and HMG17 in the nucleus and cytoplasm were then estimated from the staining intensities of the electrophoretic bands. The cytoplasmic concentrations of these proteins were very low--usually less than 1/30 of those present in the corresponding nuclear fractions. For the tissues studied (liver, kidney, heart, and lung), the concentrations of HMG proteins in the nucleus did not differ significantly from one tissue to another. Averaged over the four tissues investigated, there were 0.28 molecule of HMG1, 0.18 molecule of HMG2, and 0.46 molecule of HMG17 per nucleosome. These values are considerably higher than those that have been reported previously.     

Design and optimisation of orally active TLR7 agonists for the treatment of hepatitis C virus infection

The synthesis and structure-activity relationships of a series of novel interferon inducers are described. Pharmacokinetic studies and efficacy assessment of a series of 8-oxo-3-deazapurine analogues led to the identification of compound 33, a potent and selective agonist of the TLR7 receptor with an excellent in vivo efficacy profile in a mouse model.     

Sequestration of DROSHA and DGCR8 by Expanded CGG RNA Repeats Alters MicroRNA Processing in Fragile X-Associated Tremor/Ataxia Syndrome

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Highlights? DGCR8 binds to CGG RNA repeats, cause of the neurodegenerative FXTAS disease ? DGCR8 and its partner, DROSHA, are sequestered within CGG RNA aggregates ? DGCR8 rescues the neuronal cell death induced by expanded CGG RNA repeats ? MicroRNA processing is impaired in patients with FXTAS     

LPS Unmasking of Shigella flexneri Reveals Preferential Localisation of Tagged Outer Membrane Protease IcsP to Septa and New Poles

The Shigella flexneri outer membrane (OM) protease IcsP (SopA) is a member of the enterobacterial Omptin family of proteases which cleaves the polarly localised OM protein IcsA that is essential for Shigella virulence. Unlike IcsA however, the specific localisation of IcsP on the cell surface is unknown. To determine the distribution of IcsP, a haemagglutinin (HA) epitope was inserted into the non-essential IcsP OM loop 5 using Splicing by Overlap Extension (SOE) PCR, and IcsP^HA was characterised. Quantum Dot (QD) immunofluorescence (IF) surface labelling of IcsP^HA was then undertaken. Quantitative fluorescence analysis of S. flexneri 2a 2457T treated with and without tunicaymcin to deplete lipopolysaccharide (LPS) O antigen (Oag) showed that IcsP^HA was asymmetrically distributed on the surface of septating and non-septating cells, and that this distribution was masked by LPS Oag in untreated cells. Double QD IF labelling of IcsP^HA and IcsA showed that IcsP^HA preferentially localised to the new pole of non-septating cells and to the septum of septating cells. The localisation of IcsP^HA in a rough LPS S. flexneri 2457T strain (with no Oag) was also investigated and a similar distribution of IcsP^HA was observed. Complementation of the rough LPS strain with rmlD resulted in restored LPS Oag chain expression and loss of IcsP^HA detection, providing further support for LPS Oag masking of surface proteins. Our data presents for the first time the distribution for the Omptin OM protease IcsP, relative to IcsA, and the effect of LPS Oag masking on its detection.