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Most metastatic cancers remain incurable due to the emergence of apoptosis-resistant clones, fuelled by intratumour heterogeneity and tumour evolution. To improve treatment, therapies should not only kill cancer cells but also activate the immune system against the tumour to eliminate any residual cancer cells that survive treatment. While current cancer therapies rely heavily on apoptosis — a largely immunologically silent form of cell death — there is growing interest in harnessing immunogenic forms of cell death such as necroptosis. Unlike apoptosis, necroptosis generates second messengers that act on immune cells in the tumour microenvironment, alerting them of danger. This lytic form of cell death optimizes the provision of antigens and adjuvanticity for immune cells, potentially boosting anticancer treatment approaches by combining cellular suicide and immune response approaches. In this Review, we discuss the mechanisms of necroptosis and how it activates antigen-presenting cells, drives cross-priming of CD8+T cells and induces antitumour immune responses. We also examine the opportunities and potential drawbacks of such strategies for exposing cancer cells to immunological attacks.

Das starke Wachstum des E‑Commerce stellt bedeutende Herausforderungen an die Betreiber von Fahrzeugflotten, um den kostenintensiven Fahrzeugeinsatz in einem digital getriebenen Transportmarkt zu optimieren. Innovative Fahrzeug- und Datentechnologien bieten dabei neue Möglichkeiten für die serviceorientierte Gestaltung digitaler Ökosysteme mit weiteren Stakeholdern durch cloudbasierte Infrastrukturen. Bei genauerer Betrachtung der Transportkette wurde ein durchgehendes, automatisiertes und vernetztes Flottenmanagement in einem gemeinsamen Datenraum bisher nicht realisiert. In diesem Beitrag stellen die Autoren das Konzept „Smart Managed Freight Fleet“ vor, das im Rahmen des vom BMWK geförderten Konsortialprojekts „GAIA-X 4 ROMS“ (Remote Operation for Automated and Connected Mobility Services) entwickelt werden soll. Dazu zeigen die Autoren zunächst die bestehenden Informations- und Fahrzeugtechnologien für ein vernetztes Flottenmanagement auf. Anschließend wird ein innovativer multiagentenbasierter Flottenmanagementansatz beschrieben, der insbesondere Telematik-gestützte „intelligente Wechselbrücken- und Trailer (iWT)“ mit neuartigen „autonom navigierenden Paketstationen (ANP)“ auf der ersten bzw. letzten Meile verknüpft. Ein sicherer und souveräner Datenaustausch zwischen den Akteuren, Softwareagenten und weiteren Diensten wird dabei durch ein Gaia-X-konformes Datenökosystem erfolgen. Im Anschluss werden die hieraus entstehenden wissenschaftlichen und praktischen Implikationen für ein datenbasiertes Flottenmanagement beschrieben. Abschließend gibt der Artikel einen Ausblick auf die nächsten Entwicklungsschritte zur Gestaltung frei nutzbarer Flottenmanagementdienste in einem interoperablen Datenökosystem.

Cell death and inflammation are closely linked arms of the innate immune response to combat infection and tissue malfunction. Recent advancements in our understanding of the intricate signals originating from dying cells have revealed that cell death serves as more than just an end point. It facilitates the exchange of information between the dying cell and cells of the tissue microenvironment, particularly immune cells, alerting and recruiting them to the site of disturbance. Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is emerging as a critical stress sentinel that functions as a molecular switch, governing cellular survival, inflammatory responses and immunogenic cell death signalling. Its tight regulation involves multiple layers of post-translational modifications. In this Review, we discuss the molecular mechanisms that regulate RIPK1 to maintain homeostasis and cellular survival in healthy cells, yet drive cell death in a context-dependent manner. We address how RIPK1 mutations or aberrant regulation is associated with inflammatory and autoimmune disorders and cancer. Moreover, we tease apart what is known about catalytic and non-catalytic roles of RIPK1 and discuss the successes and pitfalls of current strategies that aim to target RIPK1 in the clinic.

Apoptosis is a form of regulated cell death (RCD) that involves proteases of the caspase family. Pharmacological and genetic strategies that experimentally inhibit or delay apoptosis in mammalian systems have elucidated the key contribution of this process not only to (post-)embryonic development and adult tissue homeostasis, but also to the etiology of multiple human disorders. Consistent with this notion, while defects in the molecular machinery for apoptotic cell death impair organismal development and promote oncogenesis, the unwarranted activation of apoptosis promotes cell loss and tissue damage in the context of various neurological, cardiovascular, renal, hepatic, infectious, neoplastic and inflammatory conditions. Here, the Nomenclature Committee on Cell Death (NCCD) gathered to critically summarize an abundant pre-clinical literature mechanistically linking the core apoptotic apparatus to organismal homeostasis in the context of disease.

The DrosophilaIAP protein, Diap2, is a key mediator of NF-κB signalling and innate immune responses. Diap2 is required for both local immune activation, taking place in the epithelial cells of the gut and trachea, and for mounting systemic immune responses in the cells of the fat body. We have found that transgenic expression of Diap2 leads to a spontaneous induction of NF-κB target genes, inducing chronic inflammation in the Drosophilamidgut, but not in the fat body. Drice is a Drosophilaeffector caspase known to interact and form a stable complex with Diap2. We have found that this complex formation induces its subsequent degradation, thereby regulating the amount of Diap2 driving NF-κB signalling in the intestine. Concordantly, loss of Drice activity leads to accumulation of Diap2 and to chronic intestinal inflammation. Interestingly, Drice does not interfere with pathogen-induced signalling, suggesting that it protects from immune responses induced by resident microbes. Accordingly, no inflammation was detected in transgenic Diap2 flies and Drice-mutant flies reared in axenic conditions. Hence, we show that Drice, by restraining Diap2, halts unwanted inflammatory signalling in the intestine.

Abstract:This paper examines whether sports betting markets are semi-strong form efficient—i.e., whether new information is rapidly and completely incorporated into betting prices. We use news on ghost games in the top European football leagues due to the COVID-19 pandemic as a clean arrival of new public information. Because spectators are absent during ghost games, the home advantage is reduced, and we test whether this information is fully reflected in betting prices. Our results show that bookmakers and betting exchanges systematically overestimated a home team’s winning probability during the first period of the ghost games, which suggests that betting markets are, at least temporally, not semi-strong form efficient. Examining different leagues, we find that our main results are driven by the German Bundesliga, which was the first league to resume operations. We exploit a betting strategy that yields a positive net payoff over more than one month.

The receptor-interacting serine/threonine protein kinase 1 (RIPK1) is a key mediator of regulated cell death and inflammation. Recent studies suggest that RIPK1 inhibition would fundamentally improve the therapy of RIPK1-dependent organ damage in stroke, myocardial infarction, kidney failure, and systemic inflammatory response syndrome. Additionally, it could ameliorate or prevent multi-organ failure induced by cytokine release in the context of hyperinflammation, as seen in COVID-19 patients. Therefore, we searched for a RIPK1 inhibitor and present the aromatic antiepileptic and FDA-approved drug primidone (Liskantin®) as a potent inhibitor of RIPK1 activation in vitro and in a murine model of TNFα-induced shock, which mimics the hyperinflammatory state of cytokine release syndrome. Furthermore, we detected for the first time RIPK1 activation in the respiratory tract epithelium of hospitalized patients who tested positive for SARS-CoV-2 infection. Our data provide a strong rationale for evaluating the drug primidone in conditions of hyperinflammation in humans.

Different forms of regulated cell death-like apoptosis and necroptosis contribute to the pathophysiology of clinical conditions including ischemia-reperfusion injury, myocardial infarction, sepsis, and multiple sclerosis. In particular, the kinase activity of the receptor-interacting serine/threonine protein kinase 1 (RIPK1) is crucial for cell fate in inflammation and cell death. However, despite its involvement in pathological conditions, no pharmacologic inhibitor of RIPK1-mediated cell death is currently in clinical use. Herein, we screened a collection of clinical compounds to assess their ability to modulate RIPK1-mediated cell death. Our small-scale screen identified the anti-epilepsy drug Phenhydan®as a potent inhibitor of death receptor-induced necroptosis and apoptosis. Accordingly, Phenhydan®blocked activation of necrosome formation/activation as well as death receptor-induced NF-κB signaling by influencing the membrane function of cells, such as lipid raft formation, thus exerting an inhibitory effect on pathophysiologic cell death processes. By targeting death receptor signaling, the already FDA-approved Phenhydan®may provide new therapeutic strategies for inflammation-driven diseases caused by aberrant cell death.

Cardiovascular disease is one of the main causes of morbidity and mortality worldwide. Despite the availability of highly effective treatments, the contemporary burden of disease remains huge. Digital health interventions hold promise to improve further the quality and experience of cardiovascular care. This position paper provides a brief overview of currently existing digital health applications in different cardiovascular disease settings. It provides the reader with the most relevant challenges for their large-scale deployment in Europe. The potential role of different stakeholders and related challenges are identified, and the key points suggestions on how to proceed are given. This position paper was developed by the European Society of Cardiology (ESC) e-Cardiology working group, in close collaboration with the ESC Digital Health Committee, the European Association of Preventive Cardiology, the European Heart Rhythm Association, the Heart Failure Association, the European Association of Cardiovascular Imaging, the Acute Cardiovascular Care Association, the European Association of Percutaneous Cardiovascular Interventions, the Association of Cardiovascular Nursing and Allied Professions and the Council on Hypertension. It relates to the ESC's action plan and mission to play a pro-active role in all aspects of the e-health agenda in support of cardiovascular health in Europe and aims to be used as guiding document for cardiologists and other relevant stakeholders in the field of digital health.

Disease activity in Interleukin-10-deficient (Il10−/−) mice, a model for IBD, depends on genetic background and microbiome composition. B6.129P2/JZtm-Il10tm1Cgn(B6-Il10−/−) mice are partially resistant to colitis, whereas mice carrying the Cdcs1C3Birhaplotype on chromosome 3, B6.Cg-Il10tm1CgnMMU3(D3Mit11-D3Mit348)/JZtm (BC-R3-Il10−/−), are susceptible. This study was performed to clarify Cdcs1and candidate gene effects on the colitogenic potential of hematopoietic cells using bone marrow (BM) and T-cell transfer models. Acute and chronic graft versus host reaction was excluded by high-density genotyping, in vitro and in vivo approaches. BM-chimeras were created with animals housed in two barriers (I and II) with distinct microbiota composition as identified by sequencing. BM-chimeras of all groups developed comparable moderate-to-severe colitis in Barrier I, however, in Barrier II only recipients of BC-R3-Il10−/−BM. Subsequent adoptive T cell transfers pointed to a new subcongenic interval within Cdcs1affecting their colitogenic potential. Transfers excluded Larp7and Alpk1but highlighted Ifi44as potential candidate genes. In this model-system, colitis development after cell transfer heavily depends on microbiome, though Cdcs1acts mainly independently in hematopoietic cells. A new subcongenic interval, provisionally named Cdcs1.4, modifies colitogenic T cell function. Within this locus, Ifi44represents an important candidate gene for colitis expression.

Disease activity in Interleukin-10-deficient (Il10−/−) mice, a model for IBD, depends on genetic background and microbiome composition. B6.129P2/JZtm-Il10tm1Cgn(B6-Il10−/−) mice are partially resistant to colitis, whereas mice carrying the Cdcs1C3Birhaplotype on chromosome 3, B6.Cg-Il10tm1CgnMMU3(D3Mit11-D3Mit348)/JZtm (BC-R3-Il10−/−), are susceptible. This study was performed to clarify Cdcs1and candidate gene effects on the colitogenic potential of hematopoietic cells using bone marrow (BM) and T-cell transfer models. Acute and chronic graft versus host reaction was excluded by high-density genotyping, in vitro and in vivo approaches. BM-chimeras were created with animals housed in two barriers (I and II) with distinct microbiota composition as identified by sequencing. BM-chimeras of all groups developed comparable moderate-to-severe colitis in Barrier I, however, in Barrier II only recipients of BC-R3-Il10−/−BM. Subsequent adoptive T cell transfers pointed to a new subcongenic interval within Cdcs1affecting their colitogenic potential. Transfers excluded Larp7and Alpk1but highlighted Ifi44as potential candidate genes. In this model-system, colitis development after cell transfer heavily depends on microbiome, though Cdcs1acts mainly independently in hematopoietic cells. A new subcongenic interval, provisionally named Cdcs1.4, modifies colitogenic T cell function. Within this locus, Ifi44represents an important candidate gene for colitis expression.

Lung squamous cell carcinoma (LSCC) and adenocarcinoma (LADC) are the most common lung cancer subtypes. Molecular targeted treatments have improved LADC patient survival but are largely ineffective in LSCC. The tumor suppressor FBW7 is commonly mutated or down-regulated in human LSCC, and oncogenic KRasG12D activation combined with Fbxw7 inactivation in mice (KF model) caused both LSCC and LADC. Lineage-tracing experiments showed that CC10+, but not basal, cells are the cells of origin of LSCC in KF mice. KF LSCC tumors recapitulated human LSCC resistance to cisplatin-based chemotherapy, and we identified LUBAC-mediated NF-κB signaling as a determinant of chemotherapy resistance in human and mouse. Inhibition of NF-κB activation using TAK1 or LUBAC inhibitors resensitized LSCC tumors to cisplatin, suggesting a future avenue for LSCC patient treatment.

Tumor necrosis factor (TNF) is an inflammatory cytokine that can signal cell survival or cell death. The mechanisms that switch between these distinct outcomes remain poorly defined. Here, we show that the E3 ubiquitin ligase Mind Bomb-2 (MIB2) regulates TNF-induced cell death by inactivating RIPK1 via inhibitory ubiquitylation. Although depletion of MIB2 has little effect on NF-κB activation, it sensitizes cells to RIPK1- and caspase-8-dependent cell death. We find that MIB2 represses the cytotoxic potential of RIPK1 by ubiquitylating lysine residues in the C-terminal portion of RIPK1. Our data suggest that ubiquitin conjugation of RIPK1 interferes with RIPK1 oligomerization and RIPK1-FADD association. Disruption of MIB2-mediated ubiquitylation, either by mutation of MIB2’s E3 activity or RIPK1’s ubiquitin-acceptor lysines, sensitizes cells to RIPK1-mediated cell death. Together, our findings demonstrate that Mind Bomb E3 ubiquitin ligases can function as additional checkpoint of cytokine-induced cell death, selectively protecting cells from the cytotoxic effects of TNF.

Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field.

Im Zuge des demografischen Wandels und der Urbanisierung stehen ländliche Regionen vor großen Herausforderungen. Der Trend zum städtischen Leben („Landflucht“) ist insbesondere bei jüngeren Menschen ungebrochen. Für die alternden und schrumpfenden Regionen wird es zunehmend schwieriger, die erforderliche Infrastruktur sowie Nahversorgung zu gewährleisten. Der Bevölkerungsrückgang in ländlichen Regionen kann in eine Abwärtsspirale münden: Wo weniger Menschen leben, sinkt die Kaufkraft, wodurch privatwirtschaftliche Angebote wie zum Beispiel Dorfläden an Rentabilität verlieren und schließlich aus Altersgründen von den Inhabern ganz aufgegeben werden müssen, da die Suche nach einem Nachfolger oftmals erfolglos bleibt. Zudem wird in diesen Regionen oftmals auch weniger Geld in moderne Infrastruktur investiert, was wiederum den Negativtrend verstärkt. In diesem Beitrag wird ein Vorgehensmodell vorgestellt, das ländlichen Regionen bei der Entwicklung und Erneuerung von Dorfläden Hilfestellung bietet. Zudem wird eine Übersicht verschiedener Technologien zur Realisierung einer Digital Customer Experience für multifunktionale Dorfläden mit einem Omnichannel-Erlebniseinkauf vorgestellt. Die mittels partizipatorischer Designprozesse entwickelten Artefakte werden anhand einer Fallstudie zur Dorfladenerneuerung im Zuge des vom BMBF-geförderten Demografieprojektes „Dorfgemeinschaft 2.0“ in einer der ältesten Siedlungen im westlichen Niedersachsen veranschaulicht und erprobt. In the course of demographic change and urbanisation, rural areas are faced with major challenges. Especially amongst the young generation, the trend to migrate into cities is unbroken. For ageing and shrinking regions it is becoming increasingly difficult to provide the necessary infrastructure and local supply. Further, this ongoing population decrease might lead to a downward spiral: The purchasing power in sparsely populated areas declines, which leads to a reduced profitability of commercial offers, e. g. village shops, and induces shop owners to finally give up due to old age and lack of a successor. Moreover, less money is invested in infrastructure in these areas, which further strengthens the negative trend. With the procedure model presented in this contribution, rural areas are supported in the development and renewal of village shops. Furthermore, an overview of various technologies to realise a digital customer experience for multi-functional village shops with an omni-channel shopping experience is given. The artefacts developed with participatory design processes are illustrated and tested by means of a case study that focusses on a village shop renewal as part of the BMBF funded demography project “Dorfgemeinschaft 2.0” which takes place in one of the oldest villages in Western Lower Saxony.

Formation of the death-inducing signaling complex (DISC) initiates extrinsic apoptosis. Caspase-8 and its regulator cFLIP control death signaling by binding to death-receptor-bound FADD. By elucidating the function of the caspase-8 homolog, caspase-10, we discover that caspase-10 negatively regulates caspase-8-mediated cell death. Significantly, we reveal that caspase-10 reduces DISC association and activation of caspase-8. Furthermore, we extend our co-operative/hierarchical binding model of caspase-8/cFLIP and show that caspase-10 does not compete with caspase-8 for binding to FADD. Utilizing caspase-8-knockout cells, we demonstrate that caspase-8 is required upstream of both cFLIP and caspase-10 and that DISC formation critically depends on the scaffold function of caspase-8. We establish that caspase-10 rewires DISC signaling to NF-κB activation/cell survival and demonstrate that the catalytic activity of caspase-10, and caspase-8, is redundant in gene induction. Thus, our data are consistent with a model in which both caspase-10 and cFLIP coordinately regulate CD95L-mediated signaling for death or survival.

Receptor tyrosine kinases exhibit a variety of activation mechanisms despite highly homologous catalytic domains. Such diversity arises through coupling of extracellular ligand-binding portions with highly variable intracellular sequences flanking the tyrosine kinase domain and specific patterns of autophosphorylation sites. Here, we show that the juxtamembrane (JM) segment enhances RET catalytic domain activity through Y687. This phospho-site is also required by the JM region to rescue an otherwise catalytically deficient RET activation-loop mutant lacking tyrosines. Structure-function analyses identified interactions between the JM hinge, αC helix, and an unconventional activation-loop serine phosphorylation site that engages the HRD motif and promotes phospho-tyrosine conformational accessibility and regulatory spine assembly. We demonstrate that this phospho-S909 arises from an intrinsic RET dual-specificity kinase activity and show that an equivalent serine is required for RET signaling in Drosophila. Our findings reveal dual-specificity and allosteric components for the mechanism of RET activation and signaling with direct implications for drug discovery.

In triple-negative breast cancer, the kinase PIM1, which is highly expressed, functions through the transcription factor c-MYC to promote tumor cell survival and growth.

The innate immune system needs to distinguish between harmful and innocuous stimuli to adapt its activation to the level of threat. How Drosophila mounts differential immune responses to dead and live Gram-negative bacteria using the single peptidoglycan receptor PGRP-LC is unknown. Here we describe rPGRP-LC, an alternative splice variant of PGRP-LC that selectively dampens immune response activation in response to dead bacteria. rPGRP-LC-deficient flies cannot resolve immune activation after Gram-negative infection and die prematurely. The alternative exon in the encoding gene, here called rPGRP-LC, encodes an adaptor module that targets rPGRP-LC to membrane microdomains and interacts with the negative regulator Pirk and the ubiquitin ligase DIAP2. We find that rPGRP-LC-mediated resolution of an efficient immune response requires degradation of activating and regulatory receptors via endosomal ESCRT sorting. We propose that rPGRP-LC selectively responds to peptidoglycans from dead bacteria to tailor the immune response to the level of threat.

IMPORTANCE: Intracoronary pressure wire–derived measurements of fractional flow reserve (FFR) and intravascular ultrasonography (IVUS) provide functional and anatomical information that can be used to guide coronary stent implantation. Although these devices are widely used and recommended by guidelines, limited data exist about their effect on clinical end points. OBJECTIVE: To determine the effect on long-term survival of using FFR and IVUS during percutaneous coronary intervention (PCI). DESIGN AND SETTING: Cohort study based on the pan-London (United Kingdom) PCI registry. In total, 64 232 patients are included in this registry covering the London, England, area. PARTICIPANTS: All patients (n = 41 688) who underwent elective or urgent PCI in National Health Service hospitals in London between January 1, 2004, and July 31, 2011, were included. Patients with ST-segment elevation myocardial infarction (n = 11 370) were excluded. INTERVENTIONS: Patients underwent PCI guided by angiography (visual lesion assessment) alone, PCI guided by FFR, or IVUS-guided PCI. MAIN OUTCOMES AND MEASURES: The primary end point was all-cause mortality at a median of 3.3 years. RESULTS: Fractional flow reserve was used in 2767 patients (6.6%) and IVUS was used in 1831 patients (4.4%). No difference in mortality was observed between patients who underwent angiography-guided PCI compared with patients who underwent FFR-guided PCI (hazard ratio, 0.88; 95% CI, 0.67-1.16; P = .37). Patients who underwent IVUS had a slightly higher adjusted mortality (hazard ratio, 1.39; 95% CI, 1.09-1.78; P = .009) compared with patients who underwent angiography-guided PCI. However, this difference was no longer statistically significant in a propensity score–based analysis (hazard ratio, 1.33; 95% CI, 0.85-2.09; P = .25). The mean (SD) number of implanted stents was lower in the FFR group (1.1 [1.2] stents) compared with the IVUS group (1.6 [1.3]) and the angiography-guided group (1.7 [1.1]) (P < .001). CONCLUSIONS AND RELEVANCE: In this large observational study, FFR-guided PCI and IVUS-guided PCI were not associated with improved long-term survival compared with standard angiography-guided PCI. The use of FFR was associated with the implantation of fewer stents.

Recent innovations in interventional cardiology have dramatically expanded the therapeutic options for patients with cardiac conditions. Interventional cardiology is no longer limited to the treatment of coronary artery disease but allows also treatment of valvular disease, stroke prevention, hypertension, etc. One of the most important new treatment options is the percutaneous treatment for aortic valve stenosis (transcatheter aortic valve implantation), since aortic valve disease is a rather common problem in elderly patients, with many of them at high risk for surgery. Similarly, mitral regurgitation is often associated with comorbidities which make surgery high risk. The MitraClip is a promising percutaneous alternative to surgical valve repair or replacement. Other procedures discussed in this review are the percutaneous left atrial appendage closure as a non-pharmacologic therapy to prevent strokes, and renal denervation for resistant hypertension. This review explains the basic principles of these procedures, the most important clinical evidence, and also provides additional recent clinical data on each of them.

Traditional cardiovascular risk factors, particularly hypertension and diabetes, are common in the disease processes of both renal and cardiac pathology. Unfortunately the coexistence of renal impairment is not an innocent bystander in cardiovascular disease; it disorder not only increases the prevalence and severity of cardiovascular disease, but also negatively affects prognostic outcomes and the safety and efficacy of cardiac interventions. This article discusses the role and impact of kidney disease in the cardiac patient in 3 key common cardiovascular processes: coronary artery disease, arrhythmia, and heart failure.

In 1669, anastomoses between the right and left coronary artery were first documented by Richard Lower of Amsterdam. Using post-mortem imaging, a debate followed on the existence of structural inter-coronary anastomoses, which was not resolved before the first half of the 20ieth century in case of the presence of coronary artery disease (CAD), and not before the early 1960ies in case of the normal human coronary circulation by William Fulton. Functional coronary collateral measurements during coronary interventions were first performed only in the 1970ies, respectively in the early 1980ies. In humans, the existence of functional coronary collaterals in the absence of CAD has not been documented before 2003. Though the coronary collateral circulation has been recognized as an alternative source of blood supply to ischemic myocardium, its prognostic significance for the CAD population as a whole has been controversial until recently. The debate was due to different populations examined (acute versus chronic CAD, varying severity of CAD), to variable definitions of the term “prognosis”, to insufficient statistical power of the investigation with rare occurrence of prognostic endpoints, to short duration of follow-up and to blunt instruments employed for collateral assessment. Individually, it has been acknowledged that a well functioning collateral supply to a myocardial area at risk for necrosis reduces infarct size, preserves ventricular function, prevents ventricular remodelling and aneurysm formation. Collectively, evidence has accumulated only recently that an extensive coronary collateral circulation is a beneficial prognosticator quoad vitam. In a recent meta-analysis on the topic, the risk ratio to die from any cause for high vs low or absent collateralization in patients with subacute myocardial infarction was 0.53 (95% confidence interval 0.15–1.92; p=0.335), and for patients with acute myocardial infarction, it was 0.63 (95% confidence interval 0.29–1.39; p=0.257)¸ the relative risk to die from any cause for well vs poorly developed collaterals in patients with stable CAD was 0.59 (95% confidence interval 0.39–0.89), p=0.012.

Unstable coronary artery plaque is the most common underlying cause of acute coronary syndromes (ACS) and can manifest as unstable angina, non-ST segment elevation infarction (NSTE-ACS), and ST elevation myocardial infarction (STEMI), but can also manifest as sudden cardiac arrest due to ischaemia induced tachyarrhythmias. ACS mortality has decreased significantly over the last few years, especially from the more extreme manifestations of ACS, STEMI, and cardiac arrest. This trend is likely to continue based on recent therapeutic progress which includes novel antiplatelet agents such as prasugrel, ticagrelor, and cangrelor.

Out-of-hospital cardiac arrest (OHCA) has attracted increasing attention over the past years because outcomes have improved impressively lately. The changes for neurological intact outcomes has been poor but several areas have achieved improving survival rates after adjusting their cardiac arrest care. The pre-hospital management is certainly key and decides whether a cardiac arrest patient can be brought back into a spontaneous circulation. However, the whole chain of resuscitation including the in-hospital care have improved also. This review describes aetiologies of OHCA, risk and potential protective factors and recent advances in the pre-hospital and in-hospital management of these patients.

The field of interventional cardiology continues to progress quickly. The efficacy of percutaneous interventions with newer generation drug-eluting stents has advanced a lot over the last decade. This improvement in stent performance has broadened the level of indication towards more complex interventions such as left main and multi-vessel PCI. Major improvements continue in the field of medical co-therapy such as antiplatelet therapies (bivalirudin, prasugrel, and ticagrelor) and this will further improve outcomes of PCI. The same is true for intravascular imaging such as ultrasound IVUS and optical coherence tomography OCT. However, interventional cardiology has become a rather broad field, also including alcohol septal ablation for hypertrophic obstructive cardiomyopathy, etc. At the moment, the fastest growing area is the structural interventions, especially for aortic valve stenosis (transcatheter aortic valve implantation TAVI) and for mitral regurgitation (mitral clipping). This review covers recent advances in all these different fields of interventional cardiology.

Uncontrolled complement activation is central to the occurrence of atypical hemolytic uremic syndrome (aHUS) and can result in thrombotic microangiopathies (TMAs).These terms encompass a group of heterogenic inherited or acquired diseases that recent research suggests may be triggered by the complement cascade. Pathogenetic triggers of complement activation include immunologic disorders, genetics, infections, systemic diseases, pregnancy, drug administration, metabolic diseases, transplantation, or triggers of mixed cause. Hallmarks of aHUS and other TMAs include increased vascular endothelium thromboresistance, leukocyte adhesion to damaged endothelium, complement consumption, coagulation abnormalities, and vascular shear stress, whereas common end points of these mechanisms include hemolytic anemia, thrombocytopenia with microvascular infarction, and predisposition for decreased kidney function and other organ involvement. The central role of the complement cascade as a disease trigger suggests a possible therapeutic target. Eculizumab, a first-in-class humanized monoclonal anti-C5 antibody that has been successful in the treatment of paroxysmal nocturnal hemoglobinuria, a disorder of complement-induced hemolytic anemia, received approval for the treatment of aHUS in the United States and Europe in late 2011. We review the treatment of aHUS and other TMAs, focusing on the role of eculizumab, including its pharmacology, mechanism of action, and approved dosing recommendations and health economic considerations. Finally, the potential for future indications for eculizumab use in other complement-driven diseases is discussed.

Aims: Recent data have demonstrated the feasibility of therapeutic induction of coronary collateral growth (arteriogenesis); however, mechanisms of action of such therapeutic collateral stimulation in humans are unknown. The aim of this study was to evaluate potential mechanisms, especially the involvement of arteriogenesis-relevant genes. Methods and Results: A total of 52 patients were randomized into two groups: subcutaneous G-CSF (10g/kg; n26) or placebo (n26). Before and after this 2-week treatment, collateral-flow index (CFI) was determined by simultaneous measurement of mean aortic, distal coronary occlusive and central venous pressure. CD34 endothelial progenitor cells (EPC) and monocytes were quantified before, during and after treatment; gene-expression analysis of monocytes was performed with real-time polymerase chain reaction (RT-PCR). G-CSF lead to a significant increase of EPC and monocytes (4.8 and 2.6 fold, p<0.05); for both cell types, the extent of increase correlated with CFI increase (r0.23 and 0.14, p<0.05). G-CSF also induced a change in gene expression of pro-and anti-arteriogenic genes in monocytes. Among nine assessed genes, three were found to be differentially regulated (IL8, JAK2, and PNPLa4; p<0.05). Conclusions: The mechanism of induction of collateral growth by G-CSF is related to an increase of EPC and of peripheral monocytes. It also leads to a change toward a pro-arteriogenic gene expression in peripheral monocytes.

Atherosclerotic renal artery stenosis (ARAS) usually occurs in patients at high risk of vascular disease, and is associated with increased mortality. The primary goals of ARAS treatment include the control of blood pressure (BP), the improved renal function, and the benefit on cardiovascular events. Although medical therapy remains the standard approach to the management of ARAS, percutaneous transluminal renal angioplasty (PTRA) revascularization can be a therapeutic option under certain conditions.