RASSF2 Is a Novel K-Ras-specific Effector and Potential Tumor Suppressor

Ras proteins regulate a wide range of biological processes by interacting with a broad assortment of effector proteins. Although activated forms of Ras are frequently associated with oncogenesis, they may also provoke growth-antagonistic effects. These include senescence, cell cycle arrest, differentiation, and apoptosis. The mechanisms that underlie these growth-inhibitory activities are relatively poorly understood. Recently, two related novel Ras effectors, NORE1 and RASSF1, have been identified as mediators of apoptosis and cell cycle arrest. Both of these proteins exhibit many of the properties normally associated with tumor suppressors. We now identify a novel third member of this family, designated RASSF2. RASSF2 binds directly to K-Ras in a GTP-dependent manner via the Ras effector domain. However, RASSF2 only weakly interacts with H-Ras. Moreover, RASSF2 promotes apoptosis and cell cycle arrest and is frequently down-regulated in lung tumor cell lines. Thus, we identify RASSF2 as a new member of the RASSF1 family of Ras effectors/tumor suppressors that exhibits a specificity for interacting with K-Ras

Ras-mediated Loss of the Pro-apoptotic Response Protein Par-4 Is Mediated by DNA Hypermethylation through Raf-independent and Raf-dependent Signaling Cascades in Epithelial Cells

The apoptosis-promoting protein Par-4 has been shown to be down-regulated in Ras-transformed NIH 3T3 fibroblasts through the Raf/MEK/ERK MAPK pathway. Because mutations of the ras gene are most often found in tumors of epithelial origin, we explored the signaling pathways utilized by oncogenic Ras to down-regulate Par-4 in RIE-1 and rat ovarian surface epithelial (ROSE) cells. We determined that constitutive activation of the Raf, phosphatidylinositol 3-kinase, or Ral guanine nucleotide exchange factor effector pathway alone was not sufficient to down-regulate Par-4 in RIE-1 or ROSE cells. However, treatment of Ras-transformed RIE-1 or ROSE cells with the MEK inhibitors U0126 and PD98059 increased Par-4 protein expression. Thus, although oncogenic Ras utilizes the Raf/MEK/ERK pathway to down-regulate Par-4 in both fibroblasts and epithelial cells, Ras activation of an additional signaling pathway(s) is required to achieve the same outcome in epithelial cells. Methylation-specific PCR showed that the par-4 promoter is methylated in Ras-transformed cells through a MEK-dependent pathway and that treatment with the DNA methyltransferase inhibitor azadeoxycytidine restored Par-4 mRNA transcript and protein levels, suggesting that the mechanism for Ras-mediated down-regulation of Par-4 is by promoter methylation. Support for this possibility is provided by our observation that Ras transformation was associated with up-regulation of Dnmt1 and Dnmt3 DNA methyltransferase expression. Finally, ectopic Par-4 expression significantly reduced Ras-mediated growth in soft agar, but not morphological transformation, highlighting the importance of Par-4 down-regulation in specific aspects of Ras-mediated transformation of epithelial cells

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

Kültürel Bellek 2016

Hacettepe Üniversitesi Tarihi ve Kültürel Mirası Araştırma Merkezi HÜTKAM olarak kültürel bellek çalışmalarına katkıda bulunmayı görevimiz kabul ediyoruz. 2016 yılında, yönetim kurulu olarak bu serüvene başlamaya karar verdik. Güvendiğimiz dostlarımız, arkadaşlarımız ve elbette hocalarımız çağrımızı yanıtsız bırakmadı. Birbirinden değerli araştırmalarla zenginleştik ve tarihe not düşmek adına kültürel bellek çalışmalarına biz de katıldık. Kültürel mirasın evrensel olduğu, oralı/buralı, sizden/bizden, uzak/yakın ayırmadan, hepimizin olduğu fikrinden yola çıktık. Bizi biz yapan, toplumları oluşturan, birleştiren kültürel belleğimizdir. Kimi zaman insan eliyle, cehaletle, yıkıcılıkla bazen adamsendecilikle, bilinçsizlikle tahrip edilen, yok edilen tarihi ve kültürel miras, belleğimizin önemli, çok önemli bir parçasıdır. Her zaman önünden geçtiğimiz bir yapı bir gecede yıkıldıysa, çocukluk anılarımızı biriktirdiğimiz mahallemiz yok olduysa, sokağımızın, meydanımızın adı değiştiyse eksiliriz. Bizi büyüten oyunlar kaybolduysa, bir tekerleme artık hatırlanmıyorsa, çocukluğumuzun sanatçıları göçmüşse, eski şarkılar plaklarda bile yoksa eksiliriz. Hafızamızı tetikleyen imgeler, kokular, sesler, tatlar değişirse bireysel belleğimiz, yaşadığımız kentin ve toplumun belleği zarar görür, eksiliriz. Bireysel tarihimizde, belleğimizdeki insanları yitirdikçe nasıl azalıyorsak tarihi ve kültürel mirası, ortak belleği yitirdikçe de öyle zayıflar ve giderek yok oluruz. İşte bu nedenle biz hatırlamayı, öğrenmeyi, görmeyi, araştırmayı seçiyoruz. Unutmamak için, unutulduysa hatırlamak ve hatırlatmak için, bilmeyenlere göstermek, anlatmak ve belleğimize sahip çıkmak için başladığımız bu serüvende çağrımızı kırmayan değerli araştırmacılara şükranlarımızı sunuyoruz. Unutmayalım ki kültürel bellek, hepimizi birleştiren güçtür