ΔNp63α silences a microRNA program to aberrantly initiate a wound healing program that promotes TGFβ-induced metastasis.

Primary cancer cell dissemination is a key event during the metastatic cascade, but context-specific determinants of this process remain largely undefined. Multiple reports have suggested that the p53 (TP53) family member p63 (TP63) plays an anti-metastatic role through its minor epithelial isoform containing the N-terminal transactivation domain (TAp63). However, the role and contribution of the major p63 isoform lacking this domain, ΔNp63α, remain largely undefined. Here, we report a distinct and TAp63-independent mechanism by which ΔNp63α-expressing cells within a TGFβ-rich microenvironment become positively selected for metastatic dissemination. Orthotopic transplantation of ΔNp63α-expressing human osteosarcoma cells into athymic mice resulted in larger and more frequent lung metastases than transplantation of control cells. Mechanistic investigations revealed that ΔNp63α repressed miR-527 and miR-665, leading to the upregulation of two TGFβ effectors, SMAD4 and TβRII (TGFBR2). Furthermore, we provide evidence that this mechanism reflects a fundamental role for ΔNp63α in the normal wound healing response. We show that ΔNp63α-mediated repression of miR-527/665 controls a TGFβ-dependent signaling node that switches off anti-migratory miR-198 by suppressing the expression of the regulatory factor, KSRP (KHSRP). Collectively, these findings reveal that a novel microRNA network involved in the regulation of physiological wound healing responses is hijacked and suppressed by tumor cells to promote metastatic dissemination

Emerging Roles of PAR-1 and PAFR in Melanoma Metastasis

Melanoma growth, angiogenesis and metastatic progression are strongly promoted by the inflammatory tumor microenvironment due to high levels of cytokine and chemokine secretion by the recruited inflammatory and stromal cells. In addition, platelets and molecular components of procoagulant pathways have been recently emerging as critical players of tumor growth and metastasis. In particular, thrombin, through the activity of its receptor protease-activated receptor-1 (PAR-1), regulates tumor cell adhesion to platelets and endothelial cells, stimulates tumor angiogenesis, and promotes tumor growth and metastasis. Notably, in many tumor types including melanoma, PAR-1 expression directly correlates with their metastatic phenotype and is directly responsible for the expression of interleukin-8, matrix metalloproteinase-2 (MMP-2), vascular endothelial growth factor, platelet-derived growth factor, and integrins. Another proinflammatory receptor–ligand pair, platelet-activating factor (PAF) and its receptor (PAFR), have been shown to act as important modulators of tumor cell adhesion to endothelial cells, angiogenesis, tumor growth and metastasis. PAF is a bioactive lipid produced by a variety of cells from membrane glycerophospholipids in the same reaction that releases arachidonic acid, and can be secreted by platelets, inflammatory cells, keratinocytes and endothelial cells. We have demonstrated that in metastatic melanoma cells, PAF stimulates the phosphorylation of cyclic adenosine monophosphate response element-binding protein (CREB) and activating transcription factor 1 (ATF-1), which results in overexpression of MMP-2 and membrane type 1-MMP (membrane type 1-MMP). Since only metastatic melanoma cells overexpress CREB/ATF-1, we propose that metastatic melanoma cells are better equipped than their non-metastatic counterparts to respond to PAF within the tumor microenvironment. The evidence supporting the hypothesis that the two G-protein coupled receptors, PAR-1 and PAFR, contribute to the acquisition of the metastatic phenotype of melanoma is presented and discussed

CREB Inhibits AP-2α Expression to Regulate the Malignant Phenotype of Melanoma

The loss of AP-2alpha and increased activity of cAMP-responsive element binding (CREB) protein are two hallmarks of malignant progression of cutaneous melanoma. However, the molecular mechanism responsible for the loss of AP-2alpha during melanoma progression remains unknown.Herein, we demonstrate that both inhibition of PKA-dependent CREB phosphorylation, as well as silencing of CREB expression by shRNA, restored AP-2alpha protein expression in two metastatic melanoma cell lines. Moreover, rescue of CREB expression in CREB-silenced cell lines downregulates expression of AP-2alpha. Loss of AP-2alpha expression in metastatic melanoma occurs via a dual mechanism involving binding of CREB to the AP-2alpha promoter and CREB-induced overexpression of another oncogenic transcription factor, E2F-1. Upregulation of AP-2alpha expression following CREB silencing increases endogenous p21(Waf1) and decreases MCAM/MUC18, both known to be downstream target genes of AP-2alpha involved in melanoma progression.Since AP-2alpha regulates several genes associated with the metastatic potential of melanoma including c-KIT, VEGF, PAR-1, MCAM/MUC18, and p21(Waf1), our data identified CREB as a major regulator of the malignant melanoma phenotype

Lipid profile, cardiovascular disease and mortality in a Mediterranean high-risk population: the ESCARVAL-RISK study

The potential impact of targeting different components of an adverse lipid profile in populations with multiple cardiovascular risk factors is not completely clear. This study aims to assess the association between different components of the standard lipid profile with all cause mortality and hospitalization due to cardiovascular events in a high-risk population. Methods This prospective registry included high risk adults over 30 years old free of cardiovascular disease (2008±2012). Diagnosis of hypertension, dyslipidemia or diabetes mellitus was inclusion criterion. Lipid biomarkers were evaluated. Primary endpoints were all-cause mortality and hospital admission due to coronary heart disease or stroke. We estimated adjusted rate ratios (aRR), absolute risk differences and population attributable risk associated with adverse lipid profiles. Results 51,462 subjects were included with a mean age of 62.6 years (47.6% men). During an average follow-up of 3.2 years, 919 deaths, 1666 hospitalizations for coronary heart disease and 1510 hospitalizations for stroke were recorded. The parameters that showed an increased rate for total mortality, coronary heart disease and stroke hospitalization were, respectively, low HDL-Cholesterol: aRR 1.25, 1.29 and 1.23; high Total/HDL-Cholesterol: aRR 1.22, 1.38 and 1.25; and high Triglycerides/HDL-Cholesterol: aRR 1.21, 1.30, 1.09. The parameters that showed highest population attributable risk (%) were, respectively, low HDL-Cholesterol: 7.70, 11.42, 8.40; high Total/HDL-Cholesterol: 6.55, 12.47, 8.73; and high Triglycerides/ HDL-Cholesterol: 8.94, 15.09, 6.92. Conclusions In a population with cardiovascular risk factors, HDL-cholesterol, Total/HDL-cholesterol and triglycerides/HDL-cholesterol ratios were associated with a higher population attributable risk for cardiovascular disease compared to other common biomarkers

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

ON THE GREAT FLOOD OF 1954 OF THE YANGTZEKIANG

1954年の夏, 揚子江の全流域にわたって.大洪水が発生し, 8月18日15時には漢口の水位が呉瀬基準面(ほぼ上海の最低低潮面, 以下高度の基準はすべてこれによる)上29.73mに達した。漢口における過去の最高水位28.27m(1931年8月19日)を遙かに破る記録である。漢口において揚子江の水位観測が開始されたのは1865年であるから, 1954年の最高水位は過去ほとんど100年間の最高記録であるGこれに匹敵する洪水がそれ以前にも果して起ぎたか, どうか, については記録がないからわからないが, 恐らく800年に一回位の洪水てあろうと推定されている。この洪水については当時わが国の新聞にも報道されたが, 詳しいことは知るすべもなかった。わたくしは昨秋, 中国科学院の招聘による訪中水利科学代表団に参加して中国を訪れた際, この洪水について若干の資料を得たので, これを一応とりまとめてここに報告いたしたい。もとより, 甚だ断片的であって, これから洪水の全貌をうかがうことはできないけれども, なんらかの参考資料ともなれば幸である。In this paper some aspects of the great flood of 1954 of the Yangtze-kiang which is estimated to have occurred probably once in eight hundred years aredescribed. After introductory remarks in the first chapter, the rainfall of China, especially that in 1954, is outlined in the next chapter. Basing on some records ofthe river stage, flood conditions in and around the Poyang and Tungting Lakes areexamined in the succeeding chapters. In the last chapter. The effect of the recentlyestablished Chinkiang diversion project on this flood is analysed and its success isconfirmed.1954年の夏,揚子江の全流域にわたって.大洪水が発生し,8月18日15時には漢口の水位が呉瀬基準面(ほぼ上海の最低低潮面,以下高度の基準はすべてこれによる)上29.73mに達した。漢口における過去の最高水位28.27m(1931年8月19日)を遙かに破る記録である。漢口において揚子江の水位観測が開始されたのは1865年であるから,1954年の最高水位は過去ほとんど100年間の最高記録であるGこれに匹敵する洪水がそれ以前にも果して起ぎたか,どうか,については記録がないからわからないが,恐らく800年に一回位の洪水てあろうと推定されている。この洪水については当時わが国の新聞にも報道されたが,詳しいことは知るすべもなかった。わたくしは昨秋,中国科学院の招聘による訪中水利科学代表団に参加して中国を訪れた際,この洪水について若干の資料を得たので,これを一応とりまとめてここに報告いたしたい。もとより,甚だ断片的であって,これから洪水の全貌をうかがうことはできないけれども,なんらかの参考資料ともなれば幸である。In this paper some aspects of the great flood of 1954 of the Yangtze-kiang which is estimated to have occurred probably once in eight hundred years aredescribed. After introductory remarks in the first chapter, the rainfall of China,especially that in 1954, is outlined in the next chapter. Basing on some records ofthe river stage, flood conditions in and around the Poyang and Tungting Lakes areexamined in the succeeding chapters. In the last chapter. The effect of the recentlyestablished Chinkiang diversion project on this flood is analysed and its success isconfirmed

Structural, magnetic, multiferroic and electronic properties of sr2timno6 double perovskite

We report structural analysis, magnetic ordering, ferroelectric behavior and electronic structure of Sr2TiMnO6 complex perovskite. Samples were produced by the solid state reaction recipe. Crystallographic analysis was performed by Rietveld refinement of experimental x-ray diffraction patterns. Results show that this material crystallizes in a perovskite tetragonal structure which corresponds to the space group I4/mmm. We obtain a matching of 99 % between structural properties predicted by Density Functional Theory and structural ordering, found from the Rietveld refinement method. From Field Cooling measurements of susceptibility as a function of temperature, we determine the occurrence of a magnetic ordering for a critical temperature of 44.8 K. From the fitting with the Molecular Field Theory of ferrimagnetism we establish that the ordering corresponds to a paramagnetic-ferrimagnetic transition, which is corroborated by the behavior of the inverse of susceptibility as a function of temperature. The Curie constant permitted to obtain an effective magnetic moment of 3.5 uB. The result of magnetization as a function of applied field, measured at T=40 K, shows a ferromagnetic-hysteretic behavior. The curve of polarization as a function of applied voltage evidences a ferroelectric character. It is experimentally showed that below 44.8 K this perovskite material evidences a multiferroic feature. Ab initio calculations of density of states and band structure for this manganite-like material were carried out by means of the Density Functional Theory and the Linearized Augmented Plane Waves method for both spin orientations. For calculations, the exchange and correlation potentials were included through the local density LDA+U approximation. Density of states study was carried out considering both up and down spin polarizations by the Generalized Gradient Approximation (GGA). Results of total and partial density of states reveal the insulator character of this material with effective magnetic moment 3.3 uB

The expression of the long NEAT1_2 isoform is associated with human epidermal growth factor receptor 2-positive breast cancers

The long non-coding RNA NEAT1 locus is transcribed into two overlapping isoforms, NEAT1_1 and NEAT1_2, of which the latter is essential for the assembly of nuclear paraspeckles. NEAT1 is abnormally expressed in a wide variety of human cancers. Emerging evidence suggests that the two isoforms have distinct functions in gene expression regulation, and recently it was shown that NEAT1_2, but not NEAT1_1, expression predicts poor clinical outcome in cancer. Here, we report that NEAT1_2 expression correlates with HER2-positive breast cancers and high-grade disease. We provide evidence that NEAT1_1 and NEAT1_2 have distinct expression pattern among different intrinsic breast cancer subtypes. Finally, we show that NEAT1_2 expression and paraspeckle formation increase upon lactation in humans, confirming what has previously been demonstrated in mice