Complement C5b-9 and Cancer: Mechanisms of Cell Damage, Cancer Counteractions, and Approaches for Intervention

The interactions of cancer cells with components of the complement system are highly complex, leading to an outcome that is either favorable or detrimental to cancer cells. Currently, we perceive only the “tip of the iceberg” of these interactions. In this review, we focus on the complement terminal C5b-9 complex, known also as the complement membrane attack complex (MAC) and discuss the complexity of its interaction with cancer cells, starting with a discussion of its proposed mode of action in mediating cell death, and continuing with a portrayal of the strategies of evasion exhibited by cancer cells, and closing with a proposal of treatment approaches targeted at evasion strategies. Upon intense complement activation and membrane insertion of sufficient C5b-9 complexes, the afflicted cells undergo regulated necrotic cell death with characteristic damage to intracellular organelles, including mitochondria, and perforation of the plasma membrane. Several pro-lytic factors have been proposed, including elevated intracellular calcium ion concentrations and activated JNK, Bid, RIPK1, RIPK3, and MLKL; however, further research is required to fully characterize the effective cell death signals activated by the C5b-9 complexes. Cancer cells over-express a multitude of protective measures which either block complement activation, thus reducing the number of membrane-inserted C5b-9 complexes, or facilitate the elimination of C5b-9 from the cell surface. Concomitantly, cancer cells activate several protective pathways that counteract the death signals. Blockage of complement activation is mediated by the complement membrane regulatory proteins CD46, CD55, and CD59 and by soluble complement regulators, by proteases that cleave complement proteins and by protein kinases, like CK2, which phosphorylate complement proteins. C5b-9 elimination and inhibition of cell death signals are mediated by caveolin and dynamin, by Hsp70 and Hsp90, by the mitochondrial stress protein mortalin, and by the protein kinases PKC and ERK. It is conceivable that various cancers and cancers at different stages of development will utilize distinct patterns of these and other MAC resistance strategies. In order to enhance the impact of antibody-based therapy on cancer, novel precise reagents that block the most effective protective strategies will have to be designed and applied as adjuvants to the therapeutic antibodies

Interactive film scenes for tutor training in problem-based learning (PBL): dealing with difficult situations

<p>Abstract</p> <p>Background</p> <p>In problem-based learning (PBL), tutors play an essential role in facilitating and efficiently structuring tutorials to enable students to construct individual cognitive networks, and have a significant impact on students' performance in subsequent assessments. The necessity of elaborate training to fulfil this complex role is undeniable. In the plethora of data on PBL however, little attention has been paid to tutor training which promotes competence in the moderation of specific difficult situations commonly encountered in PBL tutorials.</p> <p>Methods</p> <p>Major interactive obstacles arising in PBL tutorials were identified from prior publications. Potential solutions were defined by an expert group. Video clips were produced addressing the tutor's role and providing exemplary solutions. These clips were embedded in a PBL tutor-training course at our medical faculty combining PBL self-experience with a non-medical case. Trainees provided pre- and post-intervention self-efficacy ratings regarding their PBL-related knowledge, skills, and attitudes, as well as their acceptance and the feasibility of integrating the video clips into PBL tutor-training (all items: 100 = completely agree, 0 = don't agree at all).</p> <p>Results</p> <p>An interactive online tool for PBL tutor training was developed comprising 18 video clips highlighting difficult situations in PBL tutorials to encourage trainees to develop and formulate their own intervention strategies. In subsequent sequences, potential interventions are presented for the specific scenario, with a concluding discussion which addresses unresolved issues.</p> <p>The tool was well accepted and considered worth the time spent on it (81.62 ± 16.91; 62.94 ± 16.76). Tutors considered the videos to prepare them well to respond to specific challenges in future tutorials (75.98 ± 19.46). The entire training, which comprised PBL self-experience and video clips as integral elements, improved tutor's self-efficacy with respect to dealing with problematic situations (pre: 36.47 ± 26.25, post: 66.99 ± 21.01; p < .0001) and significantly increased appreciation of PBL as a method (pre: 61.33 ± 24.84, post: 76.20 ± 20.12; p < .0001).</p> <p>Conclusions</p> <p>The interactive tool with instructional video clips is designed to broaden the view of future PBL tutors in terms of recognizing specific obstacles to functional group dynamics and developing individual intervention strategies. We show that this tool is well accepted and can be successfully integrated into PBL tutor-training. Free access is provided to the entire tool at <url>http://www.medizinische-fakultaet-hd.uni-heidelberg.de/fileadmin/PBLTutorTraining/player.swf</url>.</p

Increased compensatory kidney workload results in cellular damage in a short time porcine model of mixed acidemia – Is acidemia a ‘first hit’ in acute kidney injury?

Acute kidney injury (AKI) corrupts the outcome of about 50% of all critically ill patients. We investigated the possible contribution of the pathology acidemia on the development of AKI. Pigs were exposed to acidemia, acidemia plus hypoxemia or a normal acid-base balance in an experimental setup, which included mechanical ventilation and renal replacement therapy to facilitate biotrauma caused by extracorporeal therapies. Interestingly, extensive histomorphological changes like a tubular loss of cell barriers occurred in the kidneys after just 5 hours exposure to acidemia. The additional exposure to hypoxemia aggravated these findings. These 'early' microscopic pathologies opposed intra vitam data of kidney function. They did not mirror cellular or systemic patterns of proinflammatory molecules (like TNF-α or IL 18) nor were they detectable by new, sensitive markers of AKI like Neutrophil gelatinase-associated lipocalin. Instead, the data suggest that the increased renal proton excretion during acidemia could be an 'early' first hit in the multifactorial pathogenesis of AKI

Разработка и проектирование устройств для мобилизации людей в аэропортах

Объектом исследования выступает организация обслуживания авиапассажиров в аэропортах. Цель работы: проектирование устройства для мобилизации людей в аэропортах и разработка программного обеспечения на базе ОС Android для использования авиапассажирами в качестве управления транспортным средством. В процессе исследования проводится анализ организации предполетного обслуживания авиапассажиров в аэропортах. Основные характеристики: работа состоит из введения, трёх глав, заключения, списка использованных источников и ряда приложений. В результате исследования было разработано и спроектировано инновационное устройство для мобилизации людей в аэропортах и мобильное приложение на базе операционной системы Android, позволяющее осуществлять управление транспортным средством в помещении.The object of the research is the organization of the service of air passengers at airports. Objective: to design a device for mobilizing people at airports and developing Android-based software for use by air passengers as a means of driving a vehicle. In the course of the study, an analysis of the organization of pre-flight service of air passengers at airports is carried out. Main characteristics: the work consists of an introduction, three chapters, conclusion, list of references and a number of applications. As a result of the study, an innovative device for mobilizing people at airports and a mobile application based on the Android operating system were developed and designed to control the vehicle indoors

Efficacy of eculizumab in a patient with immunoadsorption- dependent catastrophic antiphospholipid syndrome: A case report

Catastrophic antiphospholipid syndrome (CAPS) is a rare but devastating complication in patients with antiphospholipid syndrome (APS) with a high morbidity and mortality. We describe a case of a 30-year old female patient with immunoglobulin A (IgA) deficiency who underwent splenectomy because of idiopathic thrombocytopenic thrombocytopenia. Subsequently, an APS and finally systemic lupus erythematosus was diagnosed. After an uncomplicated pregnancy that was terminated by cesarean section, the patient developed severe CAPS with cerebral, myocardial, renal, and pulmonary involvement. Because of IgA deficiency, standard therapy consisting of plasmapheresis and intravenous immunoglobulins in addition to steroids was not tolerated. After 8 sessions of immunoadsorption (IAS), massive pulmonary hemorrhage was controlled but relapsed twice whenever IAS was terminated. As other immunosuppressive agents were considered dangerous because of the risk of infections in the face of severe hypogammaglobulinemia, we administered eculizumab, an inhibitor of the terminal complement pathway, which led to a persistent control of her disease. Interestingly, eculizumab therapy was associatedwith a further decline of complement C3 and C4 serumlevels. The patient developed a subsequent flare of her systemic lupus erythematosus, potentially indicating that complement inhibition by eculizumab is not effective in preventing lupus flares. Taken together, we describe a unique case of life-threatening and difficult-to-treat CAPS with a good clinical response after terminal complement complex inhibition with eculizumab. Further controlled trials are necessary to investigate the value of eculizumab in patients with CAPS

Системы подготовки топлива на угольных ТЭС

РЕФЕРАТ Выпускная квалификационная работа 65 с., 12 рис., 16 табл., ____20______источников, 2 прил. Ключевые слова:ШБМ, ТОПЛИВО,УГОЛЬ,ПЫЛЕПРИГОТОВЛЕНИЕ . Объектом исследования является (ются): СИСТЕМЫ ПОДГОТОВКИ ТОПЛИВА НА УГОЛЬНЫХ ТЭС Цель работы – исследовать систему топливоприготовления на пылеугольной ТЭЦ В процессе исследования проводились Системный анализ топливного хозяйства и функциональный анализ В результате расчетов пришли к выводу, что топливоприготовление на буром угле значительно больше отбирает собственных нужд чем на каменном Основные конструктивные, технологические и технико-эксплуатационные характеристики: За основу реальные данный Бийской ТЭЦ Степень внедрения: исследование Область применения: Из-за устаревшего оборудования и износа теплосетей, главная задача проекта улуABSTRACT Final qualifying work 65 p., 12 fig., 16 tab., 20 ____ ______ sources, 2 adj. Keywords: SHBM, fuel, coal, coal pulverization. The object of this study is (are): SYSTEM OF PREPARATION OF FUEL IN COAL TPP Purpose - to investigate toplivoprigotovleniya system for pulverized coal thermal power station The study conduct a systematic analysis of the fuel economy and functional analysis The calculations concluded that toplivoprigotovlenie lignite significantly more seeds of their own needs than stone main constructive, technological and technical and operational characteristics: the basis of the actual active Biysk CHP implementation degree: research applications: due to outdated equipment and depreciation of heating systems, the main objective of the project to improve the quality of heat supply and electrification, instead of obsolete equipment Cost-effectiveness / relevance The study of the efficiency of the work planned for the future reconstruction of Biysk TPP is pulverizing syste

European Society for Immunodeficiencies (ESID) and European Reference Network on Rare Primary Immunodeficiency, Autoinflammatory and Autoimmune Diseases (ERN RITA) Complement Guideline : Deficiencies, Diagnosis, and Management

This guideline aims to describe the complement system and the functions of the constituent pathways, with particular focus on primary immunodeficiencies (PIDs) and their diagnosis and management. The complement system is a crucial part of the innate immune system, with multiple membrane-bound and soluble components. There are three distinct enzymatic cascade pathways within the complement system, the classical, alternative and lectin pathways, which converge with the cleavage of central C3. Complement deficiencies account for similar to 5% of PIDs. The clinical consequences of inherited defects in the complement system are protean and include increased susceptibility to infection, autoimmune diseases (e.g., systemic lupus erythematosus), age-related macular degeneration, renal disorders (e.g., atypical hemolytic uremic syndrome) and angioedema. Modern complement analysis allows an in-depth insight into the functional and molecular basis of nearly all complement deficiencies. However, therapeutic options remain relatively limited for the majority of complement deficiencies with the exception of hereditary angioedema and inhibition of an overactivated complement system in regulation defects. Current management strategies for complement disorders associated with infection include education, family testing, vaccinations, antibiotics and emergency planning.Peer reviewe

A novel multiplex detection array revealed systemic complement activation in oral squamous cell carcinoma

Oral squamous cell carcinoma (OSCC) is one of the most common tumors within the oral cavity. Early diagnosis and prognosis tools are urgently needed. This study aimed to investigate the activation of the complement system in OSCC patients as potential biomarker. Therefore, an innovative complement activation array was developed. Characterized antibodies detecting the complement activation specific epitopes C3a, C5a and sC5b-9 along with control antibodies were implemented into a suspension bead array. Human serum from a healthy (n = 46) and OSCC patient (n = 57) cohort were used to investigate the role of complement activation in oral tumor progression. The novel multiplex assay detected C3a, C5a and sC5b-9 from a minimal sample volume of human tears, aqueous humor and blood samples. Limits of detection were 0.04 ng/mL for C3a, 0.03 ng/mL for C5a and 18.9 ng/mL for sC5b-9, respectively. Biological cut-off levels guaranteed specific detections from serum. The mean serum concentration of a healthy control cohort was 680 ng/mL C3a, 70 ng/mL C5a and 2247 ng/mL sC5b-9, respectively. The assay showed an intra-assay precision of 2.9-6.4% and an inter-assay precision of 9.2-18.2%. Increased systemic C5a (p < 0.0001) and sC5b-9 (p = 0.01) concentrations in OSCC patients were determined using the validated multiplex complement assay. Higher C5a concentrations correlated with tumor differentiation and OSCC extension state. Systemic sC5b-9 determination provided a novel biomarker for infiltrating tumor growth and C3a levels were associated with local tumor spreading. Our study suggests that systemic complement activation levels in OSCC patients may be useful to assess disease progression