Dual blockage of STAT3 and ERK1/2 eliminates radioresistant GBM cells.

Radiotherapy (RT) is the major modality for control of glioblastoma multiforme (GBM), the most aggressive brain tumor in adults with poor prognosis and low patient survival rate. To improve the RT efficacy on GBM, the mechanism causing tumor adaptive radioresistance which leads to the failure of tumor control and lethal progression needs to be further elucidated. Here, we conducted a comparative analysis of RT-treated recurrent tumors versus primary counterparts in GBM patients, RT-treated orthotopic GBM tumors xenografts versus untreated tumors and radioresistant GBM cells versus wild type cells. The results reveal that activation of STAT3, a well-defined redox-sensitive transcriptional factor, is causally linked with GBM adaptive radioresistance. Database analysis also agrees with the worse prognosis in GBM patients due to the STAT3 expression-associated low RT responsiveness. However, although the radioresistant GBM cells can be resensitized by inhibition of STAT3, a fraction of radioresistant cells can still survive the RT combined with STAT3 inhibition or CRISPR/Cas9-mediated STAT3 knockout. A complementally enhanced activation of ERK1/2 by STAT3 inhibition is identified responsible for the survival of the remaining resistant tumor cells. Dual inhibition of ERK1/2 and STAT3 remarkably eliminates resistant GBM cells and inhibits tumor regrowth. These findings demonstrate a previously unknown feature ofSTAT3-mediated ERK1/2 regulation and an effective combination of two targets in resensitizing GBM to RT

Experimental Study on Anisotropic Strength and Deformation Behavior of a Coal Measure Shale under Room Dried and Water Saturated Conditions

This paper presents an experimental investigation of anisotropic strength and deformation behavior of coal measure shale. The effect of two factors (i.e., anisotropy and water content) on shale strength and deformation behavior was studied. A series of uniaxial and triaxial compression tests were conducted on both room dried and water saturated samples for different lamination angles. The test results indicate that (1) the compressive strength, cohesion, internal friction angle, tangent Young’s modulus, and axial strain corresponding to the peak and residual strengths of room dried specimens exhibit anisotropic behavior that strongly depends on the orientation angle ; (2) in comparison to the room dried samples, the compressive strength and Young’s modulus as well as the anisotropy are all reduced for water saturated specimens; and (3) the failure mechanism of the samples can be summarized into two categories: sliding along lamination and shearing of rock material, with the type occurring in a particular situation depending strongly on the lamination orientation angles with respect to the major principal stress. According to the findings, it is strongly recommended that the effect of anisotropy and water content on the strength and deformation behavior of the rock must be considered in ground control designs

Characterization of a synthetic human LINE-1 retrotransposon ORFeus-Hs

Long interspersed elements, type 1(LINE-1, L1) are the most abundant and only active autonomous retrotransposons in the human genome. Native L1 elements are inefficiently expressed because of a transcription elongation defect thought to be caused by high adenosine content in L1 sequences. Previously, we constructed a highly active synthetic mouse L1 element (ORFeus-Mm), partially by reducing the nucleotide composition bias. As a result, the transcript abundance of ORFeus-Mm was greatly increased, and its retrotransposition frequency was > 200-fold higher than its native counterpart. In this paper, we report a synthetic human L1 element (ORFeus-Hs) synthesized using a similar strategy. The adenosine content of the L1 open reading frames (ORFs) was reduced from 40% to 27% by changing 25% of the bases in the ORFs, without altering the amino acid sequence. By studying a series of native/synthetic chimeric elements, we observed increased levels of full-length L1 RNA and ORF1 protein and retrotransposition frequency, mostly proportional to increased fraction of synthetic sequence. Overall, the fully synthetic ORFeus-Hs has > 40-fold more RNA but is at most only ~threefold more active than its native counterpart (L1RP); however, its absolute retrotransposition activity is similar to ORFeus-Mm. Owing to the elevated expression of the L1 RNA/protein and its high retrotransposition ability, ORFeus-Hs and its chimeric derivatives will be useful tools for mechanistic L1 studies and mammalian genome manipulation

A regional nuclear conflict would compromise global food security

A limited nuclear war between India and Pakistan could ignite fires large enough to emit more than 5 Tg of soot into the stratosphere. Climate model simulations have shown severe resulting climate perturbations with declines in global mean temperature by 1.8 °C and precipitation by 8%, for at least 5 y. Here we evaluate impacts for the global food system. Six harmonized state-of-the-art crop models show that global caloric production from maize, wheat, rice, and soybean falls by 13 (±1)%, 11 (±8)%, 3 (±5)%, and 17 (±2)% over 5 y. Total single-year losses of 12 (±4)% quadruple the largest observed historical anomaly and exceed impacts caused by historic droughts and volcanic eruptions. Colder temperatures drive losses more than changes in precipitation and solar radiation, leading to strongest impacts in temperate regions poleward of 30°N, including the United States, Europe, and China for 10 to 15 y. Integrated food trade network analyses show that domestic reserves and global trade can largely buffer the production anomaly in the first year. Persistent multiyear losses, however, would constrain domestic food availability and propagate to the Global South, especially to food-insecure countries. By year 5, maize and wheat availability would decrease by 13% globally and by more than 20% in 71 countries with a cumulative population of 1.3 billion people. In view of increasing instability in South Asia, this study shows that a regional conflict using <1% of the worldwide nuclear arsenal could have adverse consequences for global food security unmatched in modern history

A Regional Nuclear Conflict Would Compromise Global Food Security

A limited nuclear war between India and Pakistan could ignite fires large enough to emit more than 5 Tg of soot into the stratosphere. Climate model simulations have shown severe resulting climate perturbations with declines in global mean temperature by 1.8 C and precipitation by 8%, for at least 5 y. Here we evaluate impacts for the global food system. Six harmonized state-of-the-art crop models show that global caloric production from maize, wheat, rice, and soybean falls by 13 (1)%, 11 (8)%, 3 (5)%, and 17 (2)% over 5 y. Total single-year losses of 12 (4)% quadruple the largest observed historical anomaly and exceed impacts caused by historic droughts and volcanic eruptions. Colder temperatures drive losses more than changes in precipitation and solar radiation, leading to strongest impacts in temperate regions poleward of 30N, including the United States, Europe, and China for 10 to 15 y. Integrated food trade network analyses show that domestic reserves and global trade can largely buffer the production anomaly in the first year. Persistent multiyear losses, however, would constrain domestic food availability and propagate to the Global South, especially to food-insecure countries. By year 5, maize and wheat availability would decrease by 13% globally and by more than 20% in 71 countries with a cumulative population of 1.3 billion people. In view of increasing instability in South Asia, this study shows that a regional conflict using <1% of the worldwide nuclear arsenal could have adverse consequences for global food security unmatched in modern history

A Protective Role by Interleukin-17F in Colon Tumorigenesis

Interleukin-17F (IL-17F), produced by Th17 cells and other immune cells, is a member of IL-17 cytokine family with highest homology to IL-17A. IL-17F has been shown to have multiple functions in inflammatory responses. While IL-17A plays important roles in cancer development, the function of IL-17F in tumorigenesis has not yet been elucidated. In the current study, we found that IL-17F is expressed in normal human colonic epithelial cells, but this expression is greatly decreased in colon cancer tissues. To examine the roles of IL-17F in colon cancer, we have used IL-17F over-expressing colon cancer cell lines and IL-17F-deficient mice. Our data showed decreased tumor growth of IL-17F-transfected HCT116 cells comparing to mock transfectants when transplanted in nude mice. Conversely, there were increased colonic tumor numbers and tumor areas in Il-17f−/− mice than those from wild-type controls after colon cancer induction. These results indicate that IL-17F plays an inhibitory role in colon tumorigenesis in vivo. In IL-17F over-expressing tumors, there was no significant change in leukocyte infiltration; instead, we found decreased VEGF levels and CD31+ cells. While the VEGF levels were increased in the colon tissues of Il-17f−/− mice with colon cancer. Together, our findings demonstrate a protective role for IL-17F in colon cancer development, possibly via inhibiting tumor angiogenesis

Comparison of phase structures and surface free energy values for the coatings synthesised from linear polyurethanes and from waterborne polyurethane cationomers

WAXS, DSC and AFM methods were employed to compare phase structures of the coatings obtained from waterborne polyurethane cationomers which had been synthesised in the reaction of some diisocyanates (MDI, IPDI, TDI and HDI) with polyoxyethylene glycols (M = 600 and 2,000) and butane1,4-diol or N-methyl- or N-butyldiethanolamine and 2,2,3,3-tetrafluoro-1,4-butanediol. The structures were also analysed of the coatings derived from linear polyurethanes which had been synthesised on the basis of similar raw materials. Better rigidity was found for generally amorphous cationomer coats. Changes were discussed in the surface free energy (SFE) values and in their components, as calculated independently with the use of the van Oss–Good and Owens–Wendt methods. Polyurethane coats turned out more hydrophobic as compared to cationomer ones. In both coat types, fluorine incorporated into cationomers contributed to lower SFE values: from 50 down to about 30 mJ/m2

The B7 family member B7-H6 is a tumor cell ligand for the activating natural killer cell receptor NKp30 in humans

Cancer development is often associated with the lack of specific and efficient recognition of tumor cells by the immune system. Natural killer (NK) cells are lymphocytes of the innate immune system that participate in the elimination of tumors. We report the identification of a tumor cell surface molecule that binds NKp30, a human receptor which triggers antitumor NK cell cytotoxicity and cytokine secretion. This previously unannotated gene belongs to the B7 family and, hence, was designated B7-H6. B7-H6 triggers NKp30-mediated activation of human NK cells. B7-H6 was not detected in normal human tissues but was expressed on human tumor cells, emphasizing that the expression of stress-induced self-molecules associated with cell transformation serves as a mode of cell recognition in innate immunity

The unfolded protein response in immunity and inflammation.

The unfolded protein response (UPR) is a highly conserved pathway that allows the cell to manage endoplasmic reticulum (ER) stress that is imposed by the secretory demands associated with environmental forces. In this role, the UPR has increasingly been shown to have crucial functions in immunity and inflammation. In this Review, we discuss the importance of the UPR in the development, differentiation, function and survival of immune cells in meeting the needs of an immune response. In addition, we review current insights into how the UPR is involved in complex chronic inflammatory diseases and, through its role in immune regulation, antitumour responses.This work was supported by the Netherlands Organization for Scientific Research Rubicon grant 825.13.012 (J.G.); US National Institutes of Health (NIH) grants DK044319, DK051362, DK053056 and DK088199, and the Harvard Digestive Diseases Center (HDDC) grant DK034854 (R.S.B.); National Institutes of Health grants DK042394, DK088227, DK103183 and CA128814 (R.J.K.); and European Research Council (ERC) Starting Grant 260961, ERC Consolidator Grant 648889, and the Wellcome Trust Investigator award 106260/Z/14/Z (A.K.).This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/nri.2016.6