Extracellular Superoxide Dismutase: Growth Promoter or Tumor Suppressor?

Extracellular superoxide dismutase (SOD3) gene transfer to tissue damage results in increased healing, increased cell proliferation, decreased apoptosis, and decreased inflammatory cell infiltration. At molecular level, in vivo SOD3 overexpression reduces superoxide anion (O2-) concentration and increases mitogen kinase activation suggesting that SOD3 could have life-supporting characteristics. The hypothesis is further strengthened by the observations showing significantly increased mortality in conditional knockout mice. However, in cancer SOD3 has been shown to either increase or decrease cell proliferation and survival depending on the model system used, indicating that SOD3-derived growth mechanisms are not completely understood. In this paper, the author reviews the main discoveries in SOD3-dependent growth regulation and signal transduction

An analysis of prehospital critical care events and management patterns from 97 539 emergency helicopter medical service missions : A retrospective registry-based study

BACKGROUND It is largely unknown how often physicians in emergency helicopter medical services (HEMS) encounter various critical care events and if HEMS exposure is associated with particular practice patterns or outcomes. OBJECTIVES This study aimed: to describe the frequency and distribution of critical care events; to investigate whether HEMS exposure is associated with differences in practice patterns and determine if HEMS exposure factors are associated with mortality. DESIGN A retrospective registry-based study. SETTING Physician-staffed HEMS in Finland between January 2012 and August 2019. PARTICIPANTS Ninety-four physicians who worked at least 6 months in the HEMS during the study period. Physicians with undeterminable HEMS exposure were excluded from practice pattern comparisons and mortality analysis, leaving 80 physicians. MAIN OUTCOME MEASURES The primary outcome measure was a physician's average annual frequencies for operational events and clinical interventions. Our secondary outcomes were the proportion of missions cancelled or denied, time onsite (OST) and proportion of unconscious patients intubated. Our tertiary outcome was adjusted 30-day mortality of patients. RESULTS The physicians encountered 62 [33 to 98], escorted 31 [17 to 41] and transported by helicopter 2.1 [1.3 to 3.5] patients annually, given as median [interquartile range; IQR]. Rapid sequence intubation was performed 11 [6.2 to 16] times per year. Physicians were involved in out-of-hospital cardiac arrest (OHCA) 10 [5.9 to 14] and postresuscitation care 5.5 [3.1 to 8.1] times per year. Physicians with longer patient intervals had shorter times onsite. Proportionally, they cancelled more missions and intubated fewer unconscious patients. A short patient interval [odds ratio (OR); 95% confidence interval (CI)] was associated with decreased mortality (0.87; 95% CI, 0.76 to1.00), whereas no association was observed between mortality and HEMS career length. CONCLUSION Prehospital exposure is distributed unevenly, and some physicians receive limited exposure to prehospital critical care. This seems to be associated with differences in practice patterns. Rare HEMS patient contacts may be associated with increased mortality.Peer reviewe

SOD3 Reduces Inflammatory Cell Migration by Regulating Adhesion Molecule and Cytokine Expression

Inflammatory cell migration characteristic of ischemic damages has a dual role providing the tissue with factors needed for tissue injury recovery simultaneously causing deleterious development depending on the quality and the quantity of infiltrated cells. Extracellular superoxide dismutase (SOD3) has been shown to have an anti-inflammatory role in ischemic injuries where it increases the recovery process by activating mitogen signal transduction and increasing cell proliferation. However, SOD3 derived effects on inflammatory cytokine and adhesion molecule expression, which would explain reduced inflammation in vascular lesions, has not been properly characterized. In the present work the effect of SOD3 on the inflammatory cell extravasation was studied in vivo in rat hind limb ischemia and mouse peritonitis models by identifying the migrated cells and analyzing SOD3-derived response on inflammatory cytokine and adhesion molecule expression. SOD3 overexpression significantly reduced TNFα, IL1α, IL6, MIP2, and MCP-1 cytokine and VCAM, ICAM, P-selectin, and E-selectin adhesion molecule expressions in injured tissues. Consequently the mononuclear cell, especially CD68+ monocyte and CD3+ T cell infiltration were significantly decreased whereas granulocyte migration was less affected. According to our data SOD3 has a selective anti-inflammatory role in ischemic damages preventing the migration of reactive oxygen producing monocyte/macrophages, which in excessive amounts could potentially further intensify the tissue injuries therefore suggesting potential for SOD3 in treatment of inflammatory disorders

SOD3 Decreases Ischemic Injury Derived Apoptosis through Phosphorylation of Erk1/2, Akt, and FoxO3a

Extracellular superoxide dismutase (SOD3), which dismutates superoxide anion to hydrogen peroxide, has been shown to reduce the free radical stress derived apoptosis in tissue injuries. Since both superoxide anion and hydrogen peroxide have a marked impact on signal transduction pathways and could potentially explain a number of apoptosis and survival -related phenomena in different pathological conditions, we clarified the impact of SOD3 on Akt and Erk1/2 cell survival pathways in rat hind limb injury model. Based on our data, the hind limb ischemic rats treated with virally delivered sod3 have milder injury and less apoptosis than control animals that could be due to parallel activation of pro-proliferative and anti-apoptotic Erk1/2 and Akt pathways. The common downstream factor of both signaling pathways, the apoptosis related forkhead box protein O3a (FoxO3a), was phosphorylated and translocated to the cytoplasm in sod3 treated tissues and cell line. Additionally, we obtained increased mRNA production of elk-1, ets-1, and microRNA 21 (miR-21), whereas synthesis of bim mRNA was decreased in sod3 overexpressing tissues. We further showed that overexpression of sod3 modulated redox related gene expression by downregulating nox2 and inos when compared to injured control animals. The study shows the complexity of SOD3-derived effects on tissue injury recovery that are not limited to the reduction of superoxide anion caused cellular stress but highlights the impact of SOD3 related signal transduction on tissue functions and suggests an important role for SOD3 in attenuating cell stress effects in different pathological conditions

The Interplay between Colon Cancer Cells and Tumour-Associated Stromal Cells Impacts the Biological Clock and Enhances Malignant Phenotypes

Cancer cells interrelate with the bordering host microenvironment that encompasses the extracellular matrix and a nontumour cellular component comprising fibroblasts and immune-competent cells. The tumour microenvironment modulates cancer onset and progression, but the molecular factors managing this interaction are not fully understood. Malignant transformation of a benign tumour is among the first crucial events in colorectal carcinogenesis. The role of tumour stroma fibroblasts is well-described in cancer, but less well-characterized in benign tumours. In the current work we utilized fibroblasts isolated from tubulovillous adenoma, which has high risk for malignant transformation, to study the interaction between benign tumour stroma and the circadian clock machinery. We explored the role of the biological clock in this interplay taking advantage of an experimental model, represented by the co-culture of colon cancer cells with normal fibroblasts or tumour-associated fibroblasts, isolated from human colorectal tumour specimens. When co-cultured with tumour-associated fibroblasts, colon cancer cells showed alterations in their circadian and metabolic parameters, with decreased apoptosis, increased colon cancer cell viability, and increased resistance to chemotherapeutic agents. In conclusion, the interactions among colon cancer cells and tumour-associated fibroblasts affect the molecular clockwork and seem to aggravate malignant cell phenotypes, suggesting a detrimental effect of this interplay on cancer dynamics

Epigenetic Regulation of miR-212 Expression in Lung Cancer

Many studies have shown that microRNA expression in cancer may be regulated by epigenetic events. Recently, we found that in lung cancer miR-212 was strongly down-regulated. However, mechanisms involved in the regulation of miR-212 expression are unknown. Therefore, we addressed this point by investigating the molecular mechanisms of miR-212 silencing in lung cancer. We identified histone modifications rather than DNA hypermethylation as epigenetic events that regulate miR-212 levels in NSCLC. Moreover, we found that miR-212 silencing in vivo is closely associated with the severity of the disease

ESABALT - Improvement of Situational Awareness in the Baltic with the Use of Crowdsourcing

This paper presents the key assumptions and preliminary research on an integrated system called ESABALT, for enhancing maritime safety, which incorporates the latest technological advances in positioning, e-Navigation, Earth observation systems and multi-channel cooperative communications. The most novel part of the ESABALT concept, however, is a focus on user-driven crowdsourcing techniques for information gathering and integration. The system will consist of a situational awareness solution for real-time maritime traffic monitoring via utilizing various positioning technologies; an observation system of the marine environment relevant to transportation and accidents including assessing the sea ice, oil spread, waves, wind etc.; and a methodology for context-aware maritime communication with cooperative, multi-channel capabilities. The paper presents the intelligent, novel, user-driven solution and associated services developed in ESABALT for enhancing the maritime safety in the whole Baltic area

FLIM reveals alternative EV-mediated cellular up-take pathways of paclitaxel

In response to physiological and artificial stimuli, cells generate nano-scale extracellular vesicles (EVs) by encapsulating biomolecules in plasma membrane-derived phospholipid envelopes. These vesicles are released to bodily fluids, hence acting as powerful endogenous mediators in intercellular signaling. EVs provide a compelling alternative for biomarker discovery and targeted drug delivery, but their kinetics and dynamics while interacting with living cells are poorly understood. Here we introduce a novel method, fluorescence lifetime imaging microscopy (FLIM) to investigate these interaction attributes. By FLIM, we show distinct cellular uptake mechanisms of different EV subtypes, exosomes and microvesicles, loaded with anti-cancer agent, paclitaxel. We demonstrate differences in intracellular behavior and drug release profiles of paclitaxel-containing EVs. Exosomes seem to deliver the drug mostly by endocytosis while microvesicles enter the cells by both endocytosis and fusion with cell membrane. This research offers a new real-time method to investigate EV kinetics with living cells, and it is a potential advancement to complement the existing techniques. The findings of this study improve the current knowledge in exploiting EVs as next-generation targeted drug delivery systems.Peer reviewe