Traditional models of appetite control have emphasised the role of parallelhomeostatic and hedonic systems, but more recently the distinction betweenindependent homeostatic and hedonic systems has been abandoned in favour of aframework that emphasises the cross talk between the neurochemical substrates ofthe two systems. In addition, evidence has emerged more recently, that higherlevel cognitive functions such as learning, memory and attention play animportant role in everyday appetite control and that homeostatic signals alsoplay a role in cognition. Here, we review this evidence and present acomprehensive model of the control of appetite that integrates cognitive,homeostatic and reward mechanisms. We discuss the implications of this model forunderstanding the factors that may contribute to disordered patterns of eatingand suggest opportunities for developing more effective treatment approaches foreating disorders and weight management. Greater understanding of the mechanisms underlying appetite control is crucial toaddress the health problems that are associated with poor dietary choices andoverconsumption of food . MoreoveThe neural control of eating involves activity in brain circuits that process signalsof nutritional state and food reward value. The ingestion of food reduces theincentive value of food, which is reflected in decreased activity in reward-relatedbrain areas . HoweverTraditionally, appetite has been investigated by two parallel lines of researchfocusing on the homeostatic and hedonic systems. Research on the neurobehaviouralcontrol of appetite, by homeostatic mechanisms, has focused for many years on therole of nutrient sensing processes coordinated in the brain by the hypothalamus. This reAppetite is also known to be responsive to hormones such as the pancreatic hormoneinsulin and the adipokine leptin that are secreted in proportion to the amount offat stored in adipocytes . The arcFrom a hedonic system perspective, research has focused on the importance of rewardprocesses in motivated behaviours, including eating. This research has elucidatedhow cues associated with the consumption of tasty foods can promote food seeking andintake .When weThe neurobiology of food reward circuitry has been well studied: coordinated activityin a network of opioidergic and cannabinoidergic hedonic hotspots in the nucleusaccumbens (NAcc), ventral pallidum and brainstem is thought to mediate ‘liking’responses e.g. . On the More recently, the idea that there are independent homeostatic and hedonic systemshas been abandoned in favour of a framework that emphasises the crosstalk betweenthe neurochemical substrates of the two systems . This apExtensive evidence has now accumulated that neural systems of food reward interactwith homeostatic networks, thus providing a mechanism by which food deprivation orsatiation affects food attractiveness. For example, food deprivation increases theincentive value of food, which is reflected in enhanced responses to appetitivestimuli in reward-related brain areas in humans  whereas 2C receptor agonist lorcaserin  reduced consumption of a palatable energydense snack eaten after a satiating meal in healthy volunteers. Using functionalmagnetic resonance imaging (fMRI) we further observed that mCPP caused a markedreduction in activity across reward-related brain regions in response to the sightof food pictures. These data suggest a role for 5-HT2C receptormechanisms in inhibiting food-reward, especially after eating.Investigations of the role of 5-HT in the control of appetite have focused on bothhomeostatic and hedonic mechanisms . Neurobircaserin , whichhthe VTA  modulatethe VTA .These pIn addition to direct links between metabolic signalling and the mesolimbic dopaminesystem, there are indirect links via the lateral hypothalamus (LH) .It is wThe effects of metabolic signals on food reward go some way to explaining why food isusually more attractive when we are hungry and less attractive when we are full. Butindividuals do not always respond to the presence of food cues by initiating eating,and eating may continue even when someone has already consumed a large amount offood. Eating is a complex behaviour that can be initiated or brought to a closedepending on a multitude of influences that include taste and smell as well ascontextual factors and prior experiences . IndividThe view that motivation to eat depends on cognitive modulation of reward processesis gaining traction and it has been argued that everyday control of appetiteinvolves cognitive processes such as learning, attention and memory . For exaThe sight of a tasty food can elicit appetitive behaviours, such as food seeking anda desire to eat, and it will also evoke cognitive expectations about how the foodwill taste, how satiating it is and whether eating it will be consistent with ourlonger-term health goals . These eHowever, one’s ability to maintain goal-directed behaviour will be affected byseveral factors including: whether the longer-term consequences of behaviour areretrieved from memory and are then a focus of attention ;the extThere are also individual differences in the ability to adhere to longer-term goalsin the face of immediate rewards. The conflict between the delayed rewards of goodhealth versus the immediate reward of a tasty food is a dilemma modelled in thedelay discounting task . In thisThe desire to eat may be triggered by the sight of food, but also by thoughts of foodthat come spontaneously to mind, especially if one is hungry . WhetherThoughts of food may guide attention to food and stimulate appetitive behaviour butwe may also experience food cravings and emotional responses if an initial thoughtis embellished in memory . For exaIn the later phases of a meal, there is a decline in the perceived pleasantness offood that contributes to the cessation of eating . The redCognitive processes are also important for the inhibition of food intake that occursafter an eating episode (satiety). There is considerable experimental evidence thatmemory of a recent eating episode inhibits eating . A strikUntil recently, research on the cognitive control of eating had not been wellintegrated with research on metabolic control. An emerging literature is documentingthe broader effects of metabolic signals on higher-level cognitive processes such asattention and learning and memory. This literature suggests that some effects ofmetabolic signals on eating may be mediated by their effects on cognition, althoughresearch specifically linking cognitive effects of metabolic signals with appetiteis in its infancy.A high density of insulin receptors is expressed in the cerebral cortex, olfactorybulb, hippocampus, cerebellum and hypothalamus .IntraceIn relation to the effects of enhanced brain-insulin signalling on food intake ,it is uLeptin receptors are located in the cerebral cortex, hippocampus, basal ganglia,hypothalamus, brainstem and cerebellum  and therInterestingly, while leptin’s effects on cognition have not been directly linked tofood intake in humans, leptin replacement has been reported to reduce neuronalactivity to food images in the insular, parietal and temporal cortex but increaseactivation in the prefrontal cortex , suggestActivation of either peripheral or central GLP-1 receptors (GLP-1Rs) in thehypothalamus and NTS reduces food intake . GLP-1RsA link between the anorectic and cognitive effects of GLP-1 receptor activation isprovided by the observation that injection of the GLP-1R agonist exendin-4 into theventral hippocampus of rats reduces meal size and lever pressing for palatable food.In cont1A receptors,5-HT3 receptors and, more recently, 5-HT6 receptors ,which showed promising results in preclinical studies and early Phase 2 clinicaltrials for Alzheimer’s disease, subsequently failed in large Phase 3 trials might act to decrease food intake via enhancement of meal memories ,and is highly expressed in the ARC and in the hippocampus . GhrelinIn summary, activity in multiple metabolic signalling pathways is associated withalterations in cognition. While the effects of metabolic signals on cognitiveperformance and eating behaviour have traditionally been considered separately, itis increasingly apparent that an integrated approach may be more successful inadvancing our understanding of this complex area of research e.g. . InaddiThere is a growing appreciation that obesity is associated with alterations to brainstructure and function that are linked with neurocognitive problems, particularly inthe domains of learning and memory and decision-making .There iOne approach would be to develop cognitive training programmes that strengthen theability to inhibit responses to food. A number of such training programmes have beendeveloped and are currently in the early stages of testing . There iGiven that weight loss is difficult to achieve, and maintain, by changes to diet andexercise patterns alone, the use of approved pharmacotherapy, along with lifestylechanges, can be useful for chronic weight management . At pres2C receptor agonist lorcaserin. New drugs couldbe developed that target the cognitive processes involved in appetite control.Interestingly, lisdexamphetamine (Vyvanse) has been marketed for a number of yearsfor the treatment of cognitive symptoms of attention deficit hyperactivity disorder(ADHD) and has recently been approved by the FDA for treatment of binge eatingdisorder. It is unclear how lisdexamphetamine reduces binge eating but one potentialmechanism relates to its effects on attentional processes. Future consideration innovel drug therapy for weight management could be given to combiningcognitive-enhancing drugs with ligands that have complementary actions on metabolictargets.The effects of pharmacotherapies might be enhanced by cognitive interventions,especially if the mechanism of action to reduce food intake is at least in partexplained by cognitive modulation, as may be the case for the GLP-1 receptor agonistliraglutide and the 5-HTAnother approach to overcome problems with cognitive control in obesity would be totarget pathologies in the brain areas that underlie those functions or target theneural mechanisms underlying cognitive control with non-invasive neuromodulationtechniques. For example, transcranial direct current stimulation (tDCS) andrepetitive transcranial magnetic stimulation (rTMS), or the non-invasiveneurotherapeutic tool real-time fMRI (rt-fMRI) neurofeedback . The RDoC encourages research on dimensions ofobservable behaviour and neurobiology rather than a categorical, symptom-basedapproach to the study of mental health . Our proWe have reviewed the evidence that signals relating to the ingestion of food arisingfrom the GI tract  modulate the neural homeostatic and rewardprocesses in the brain that determine how much a food is desired. Food is lessattractive when we have eaten for this reason. We have also reviewed recent evidenceindicating that cognitive processes such as attention and memory underpin everydayeating behaviours. Finally, we have integrated an emerging literature on cognitiveeffects of metabolic signals with their effects on eating and argued that metabolicsignals are likely to affect eating behaviours at least in part via modulation ofhigher cognitive functions. Further investigation in this area is required, inparticular, to elucidate how metabolic signals influence complex food-relateddecision-making processes in humans. Such work will be important in fleshing out acomprehensive model of the control of appetite that integrates cognitive mechanismswith homeostatic and reward mechanisms see . There a


It is well known that regular exercise can benefit health by enhancing antioxidant defenses in the body. However, unaccustomed and/or exhaustive exercise can generate excessive reactive oxygen species (ROS), leading to oxidative stress-related tissue damages and impaired muscle contractility. ROS are produced in both aerobic and anaerobic exercise. Mitochondria, NADPH oxidases and xanthine oxidases have all been identified as potential contributors to ROS production, yet the exact redox mechanisms underlying exercise-induced oxidative stress remain elusive. Interestingly, moderate exposure to ROS is necessary to induce body's adaptive responses such as the activation of antioxidant defense mechanisms. Dietary antioxidant manipulation can also reduce ROS levels and muscle fatigue, as well as enhance exercise recovery. To elucidate the complex role of ROS in exercise, this review updates on new findings of ROS origins within skeletal muscles associated with various types of exercises such as endurance, sprint and mountain climbing. In addition, we will examine the corresponding antioxidant defense systems as well as dietary manipulation against damages caused by ROS. Therefore, this review aims to provide a timely update on the sources of ROS in different types of exercise, as well as the paradoxical role of ROS in acute and chronic exercise.2+) release and muscle contractions during exercise , have been shown to stimulate NOX to produce ROS. PLA2 also facilitates phospholipid turnover and releases arachidonic acid (a substrate for lipoxygenases), leading to further ROS formation and lipid peroxidation related damage  and the intensity of anaerobic exercise is described by repetition maximum (% RM). The extents and sources of ROS production can be influenced by the intensity, type, and duration of exercise, in which details will be discussed in latter paragraphs.In skeletal muscle, both enzymatic  and catalase) and non-enzymatic  antioxidants function as a unified complex to scavenge ROS  of 5% of O2•In static positions, isometric exercise is common in daily activities such as holding weighted objects. A variety of oxidative stress biomarkers have been examined in response to isometric exercise; yet mixed results can be produced. For instance, isometric contractions result in increased levels of hydroperoxide and elevations in blood protein carbonyls. However, there is no change in plasma malondialdehyde (a useful indicator of lipid peroxidation) . The activated NF-κB then binds to a specific DNA binding domain and upregulates the corresponding antioxidant gene expression   (Jin et al., Growing evidence on exercise-induced oxidative damage and impaired muscle performance has prompted intensive research into the efficacy of antioxidant supplementation in exercising individuals (Gomes et al., Most commonly known antioxidants are vitamins, which can be obtained readily through natural foods such as vegetables and fruits (Trapp et al., Despite beneficial effects mentioned above, a thorough understanding on the application of vitamin and antioxidant supplements such as effective dosage and administration method is necessary to avoid undesirable effects. Some studies have indicated that antioxidant supplements fail to protect against the damaging effects of oxidative stress such as exercise-induced lipid peroxidation and inflammation, both of which hinder muscle recovery (Teixeira et al., Collectively, mixed results from antioxidant intervention studies may be interpreted by the variances in participants' baseline redox status, the dose and length of the antioxidant supplementation, and the choice of oxidative stress markers. Instead of antioxidant supplements, a balanced diet consisting natural antioxidants from fruits and vegetables is sufficient to meet the dietary requirement for physically active individuals (Bloomer et al., In the past decades, exercise-induced oxidative stress and its effects have been largely studied. Despite the increasingly sophisticated approaches on the study of ROS in skeletal muscle, inconsistency in the results of several studies remains, which is likely associated with different methodology of ROS measurements and exercise protocols. It is therefore essential to determine an appropriate measuring module for various types of exercises and muscles in order to obtain reliable and valid data (Zuo et al., LZ, FH designed the outline, FH, JL, ZL, CC, WY, LZ wrote the paper.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive neuromodulation technique, which has brain network-level effects in healthy individuals and is also used to treat many neurological and psychiatric conditions in which brain connectivity is believed to be abnormal. Despite the fact that rTMS is being used in a clinical setting and animal studies are increasingly identifying potential cellular and molecular mechanisms, little is known about how these mechanisms relate to clinical changes. This knowledge gap is amplified by non-overlapping approaches used in preclinical and clinical rTMS studies: preclinical studies are mostly invasive, using cellular and molecular approaches, while clinical studies are non-invasive, including functional magnetic resonance imaging (fMRI), TMS electroencephalography (EEG), positron emission tomography (PET), and behavioral measures. A non-invasive method is therefore needed in rodents to link our understanding of cellular and molecular changes to functional connectivity changes that are clinically relevant. fMRI is the technique of choice for examining both short and long term functional connectivity changes in large-scale networks and is becoming increasingly popular in animal research because of its high translatability, but, to date, there have been no reports of animal rTMS studies using this technique. This review summarizes the main studies combining different rTMS protocols with fMRI in humans, in both healthy and patient populations, providing a foundation for the design of equivalent studies in animals. We discuss the challenges of combining these two methods in animals and highlight considerations important for acquiring clinically-relevant information from combined rTMS/fMRI studies in animals. We believe that combining rTMS and fMRI in animal models will generate new knowledge in the following ways: functional connectivity changes can be explored in greater detail through complementary invasive procedures, clarifying mechanism and improving the therapeutic application of rTMS, as well as improving interpretation of fMRI data. And, in a more general context, a robust comparative approach will refine the use of animal models of specific neuropsychiatric conditions. An exciting approach for the treatment of neuropsychiatric conditions is to use neuronal activity itself to encourage repair and improve brain function. This method can be used as an adjuvant with other interventions and might prove to be more effective and specific than a pharmacological approach, which often has side-effects and might not induce lasting changes. Several lines of evidence suggest that dysfunctional connectivity within specific neural networks may underpin many neurological and psychiatric conditions  delivers trains of closely spaced pulses to the brain to induce transient modulation of neural excitability and brain function. Although transient, the modulation can outlast the stimulation period leading to long-term changes in synaptic plasticity and behavior . These results suggested the presence of rTMS-induced plasticity in prefrontally connected networks downstream of the stimulation site  provides information about connectivity between brain regions at rest, i.e., when no specific stimulus or task is presented. Rs-fMRI detects brain regions whose patterns of spontaneous blood oxygen level dependent (BOLD) contrast fluctuations are temporally correlated when the subject is at rest. These brain regions with coherent spontaneous fluctuations in activity form an organized network called the resting-state network  and extent of this modulation depend on the rTMS protocol used, as we review below  rTMS has long-term synaptic depression (LTD) like effects and thereby decreases brain excitability  rTMS has long-term synaptic potentiation (LTP) like effects and increases brain excitability  uses a composite stimulation pattern, consisting of repeating bursts of stimuli  (e.g., Jonckers et al., a priori knowledge, and thus is a less biased approach (Cole et al., Two of the popular methods for rs-fMRI data are seed-based connectivity analysis (e.g., Hutchison et al., inter alia have permitted the characterization of corrupted networks in diseased states, as well as intriguing glimpses into how alterations in functional connectivity patterns after rTMS are correlated with improvements in symptoms. There is also exciting evidence that functional connectivity can be used to predict responses to rTMS treatment with high reliability.Considered together, the human studies discussed in this review demonstrate the broad relevance and significance of the results from combined rTMS/fMRI protocols. Results from human studies to date Although methodological challenges remain in the use of brain imaging techniques in rodents, we anticipate that the use of fMRI to study rTMS in animal models will not only permit more detailed characterizations of how different rTMS protocols affect network dynamics and connectivity but will also elucidate how these changes reflect the manifestation of symptoms in preclinical models. Linking these functional changes to the molecular and cellular changes currently known in rodents will provide new insights into the fundamental mechanisms of brain plasticity and how to use rTMS therapeutically.BJS: Wrote and edited the manuscript; SE: Provided feedback, structured and edited the manuscript; KWF: Provided feedback, structured and edited the manuscript; JR: Conceived the idea and approach of the review, structured and edited the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Radiation-induced late brain injury consisting of vascular abnormalities, demyelination, white matter necrosis, and cognitive impairment has been described in patients subjected to cranial radiotherapy for brain tumors. Accumulating evidence suggests that various degrees of cognitive deficit can develop after much lower doses of ionizing radiation, as well. The pathophysiological mechanisms underlying these alterations are not elucidated so far. A permanent deficit in neurogenesis, chronic microvascular alterations, and blood–brain barrier dysfunctionality are considered among the main causative factors. Chronic neuroinflammation and altered immune reactions in the brain, which are inherent complications of brain irradiation, have also been directly implicated in the development of cognitive decline after radiation. This review aims to give a comprehensive overview on radiation-induced immune alterations and inflammatory reactions in the brain and summarizes how these processes can influence cognitive performance. The available data on the risk of low-dose radiation exposure in the development of cognitive impairment and the underlying mechanisms are also discussed. Cellular and molecular mechanisms leading to radiation-induced brain injury are far from being understood. Currently, the concomitant involvement of multiple processes is thought to contribute to the development of several pathologies. Such processes are damage at the level of microvessels leading to blood–brain barrier (BBB) leakage, increased neuronal stem, and progenitor cell death as a consequence of direct cytotoxic effect of radiation, perturbations in the energy production due to mitochondrial damage, as well as direct (activation of microglia cells) and consequential (increased infiltration of immune and inflammatory cells through the damaged BBB) inflammatory and immune reactions. Although these processes are often discussed separately for didactic purposes, they are tightly interrelated where inflammation constitutes a major link. This review will focus on the role of inflammatory and immune reactions in the development of radiation-induced cognitive deficits Figure .Physiologically inflammation and subsequent immune reactions are protective mechanisms of the body by which foreign pathogens and damaged cells are eliminated and homeostasis is restored. During an inflammatory reaction, cellular and tissue damage of various extents takes place, which in the case of a tissue with a good regenerative capacity does not normally lead to functional deficit. Brain, however, is an organ with a very poor regenerative capacity. Thus, in order to minimize inflammation-induced neuronal damage, the interaction between the central nervous system (CNS) and the immune system is in several aspects different from other organs. This leads to a privileged immune status of the brain maintained by certain structural and functional features: 1) the BBB and the blood–cerebrospinal fluid barrier (BCSFB) are well-structured barrier systems that tightly control the free penetration of immune cells into the brain parenchyma. 2) Antigen presentation within the brain and at the regional lymph nodes is restricted due to (i) the absence of constitutive expression of major histocompatibility I molecules on neurons of the adult brain  receptors able to sense various danger signals from their environment, such as infectious agents, molecular toxins, and cellular damage and by which they can trigger innate immune processes , 5. MicrConventional DCs are also present in certain well-defined brain regions in varying numbers. These are the juxtavascular spaces of the brain parenchyma, brain regions that physiologically lack an intact BBB, brain parenchyma in close contact with the cerebrospinal fluid (CSF)  and the choroid plexus (CP) . A possi+ T cells and rare CD8+ T cells. A significant fraction of these lymphocytes are CD4+ memory cells. They can be found in the CSF, in the meningeal spaces, and in the stroma of the CP  where they continuously screen APCs presenting their cognate antigens  and by endogenous factors (cellular damage within the brain parenchyma). Ionizing radiation, by causing various extent of cellular damage in the brain, is an important endogenous factor in inducing neuroinflammation.The first step in mounting an acute inflammatory reaction within the brain consists of microglia and astrocyte activation, which sense neuronal damage in their environment. It has been already mentioned that neurons express soluble factors that inhibit microglia activation Figure . It is mvia the altered barrier systems. A certain level of lymphocyte infiltration within the brain parenchyma during the acute phase of a neuroinflammation is needed for a quick resolution of the inflammatory process and for rapid neuroregeneration. The immunological profile of the immune cells penetrating the brain parenchyma is an immune suppressive one, consisting of Th2 lymphocytes, regulatory T cells, and M2 macrophages, which produce IL-10 and TGFβ  leads to further neuronal damage and cell death, which maintains microglial cells in their activated status. Interestingly, systemic immune suppressive strategies for resolving neuroinflammation are often counterproductive because they inhibit CD4ed above .+ cells with a Th2 phenotype and elevated T cell anergy  is delivered in multiple fractions of approximately 1.8–2 Gy either to the whole brain or to restricted brain regions. Despite the fact that treatment schedules are planned in a way to avoid or minimize toxic side effects in healthy tissues, they still occur in a certain number of sensitive patients.Classically, radiation-induced brain damage can be divided into acute, early delayed, and late injury based on the time of onset and includes both morphologic and functional deficits . Acute dRadiation-induced late brain injuries develop more than 6 months after irradiation and are mostly irreversible changes. Morphological damage consists of vascular abnormalities, demyelination, gliosis, and in extreme cases white matter necrosis. Functionally, it is associated with two main alterations: endocrinopathy and cognitive impairment. Endocrinopathy develops mainly after higher radiation doses delivered to the hypothalamic–pituitary axis. Its most frequent manifestations are hypothyroidism (due to direct radiation damage on the thyroid or to decreased production of the thyroid-stimulating hormone or TSH as a consequence of radiation damage to the hypophysis), growth retardation (due to growth hormone deficiency), and gonadal dysfunction (due to gonadotropin deficiency). Several comprehensive reviews have been published in this topic –45. SincCertain patient cohorts can be used to study radiation-induced cognitive impairment. Long-term survivors of glioma constitute an important group; however, in this case, a number of confounding factors  make the correct evaluation of radiotherapy effects on the cognitive performance more difficult. Within this group, low-grade glioma patients’ follow-up is of particular interest due to their much better prognosis in terms of overall survival. Most studies agree that radiotherapy poses a significant risk of late cognitive impairment in adult patients with low-grade gliomas , 48, butThe brain can be exposed to substantial doses of irradiation during the radiotherapy of various head and neck tumors as well. However, in these cases, radiation exposure is restricted to certain brain regions only. Various trials demonstrated an increased risk of cognitive impairment in these patients . Meyers per se was not a toxic agent for cognitive outcome. Waber et al. reported slightly different findings in a study conducted 15 years later at the Dana Farber Cancer Institute. In this study, cranial irradiation could not be directly linked with cognitive damage, most probably because the applied average total dose was much lower (18 Gy)  .It is very important to note that all of these cohorts were treated with conventional X-ray or gamma ray techniques. While major technical improvements were done to reduce irradiation of healthy tissues (such as the development of different intensity-modulated radiotherapy techniques), due to the energy deposition characteristics of these radiation types it is impossible to completely spare non-tumorous tissues. Proton radiation therapy has emerged as a novel therapeutic modality that is beginning to be largely applied for the treatment of various brain tumors. Protons are charged particles, which deposit their energy over a narrow range, and have little lateral scatters in the tissues. Due to these properties, the proton beam focuses on the tumor and doses delivered to surrounding normal tissues are much lower than in the case of X-ray-based techniques. While proton beam therapy (PBT) is a relatively new technology, and there are no large patient cohorts yet which allow a thorough evaluation of the developing side effects in the brain, the already available data indicate its suitability to reduce late toxicities. This is especially important in children whose brain is very sensitive to irradiation (as discussed above). An essential dose reduction by using PBT compared to conformal radiotherapy was shown particularly in contralaterally located critical neuronal structures . DiffereAll the abovementioned clinical studies demonstrate that cognitive impairment is a relatively frequent consequence of high-dose therapeutic brain irradiation. While the severity of the damage is influenced by multiple factors, the most important ones are the young age at irradiation and the irradiated brain region. The exquisite sensitivity of the hippocampus to irradiation, where the neuronal stem cells are located has been shown by numerous animal experiments –69 and cvia microglia and endothelial cell activation , as the precursor of adult murine microglia in the peripheral blood and showed that microglia engraftment during postnatal life was enhanced by various degenerative brain disorders. However, these monocytes were preferentially recruited to the brain and differentiated into microglia only if the brain was “preconditioned” by irradiation. The authors explained this enhanced cell engraftment primarily by a radiation-induced production of CCL2 in the brain, which attracted blood-derived CCR2-expressing monocytes and by an inactivation of the repository signals and to a lesser extent by a radiation-induced damage in BBB integrity, although they admitted that subtle BBB alterations might have been present , which is an endotoxin released by bacterial cells during an infection. On the other hand, the endogenous LPS-like molecule high-mobility group protein 1 (HMGB1) is a danger signal , which is released in the extracellular medium under cellular stress. It was shown that HMGB1 by binding to the TLR4 receptor could promote microglia activation under stress conditions associated with neuronal damage such as traumatic brain injury, ischemic injury, and methamphetamine treatment , though they did not exclude the possibility of minor BBB alterations . These alterations were relatively long lasting and were accompanied by increased permeability for both low- and high-molecular weight proteins. Morphologically, a rarefaction of the endothelial layer was seen, which could lead to the opening of the endothelial tight junctions, despite the fact that no gross alterations were observed in the immunolabelling of a panel of tight junction proteins   .in vitro and in vivo studies demonstrated endothelial cell apoptosis as an early event after irradiation. However, it was induced only by high doses of irradiation and was accompanied by strong inhibition of endothelial cell proliferation capacity . Recent epidemiological data pose serious concerns regarding long-term health consequences of these low doses. It was shown by several epidemiological studies that cranial CT exposure increased the risk of brain tumors in children –128. SimVery interesting data start to emerge regarding the impact of low-dose or low-dose rate irradiation on endothelial cell integrity. A premature senescence was observed in human umbilical vein endothelial cells exposed to low-dose rate irradiation delivered by 2.4 or 4.1 mGy/h dose rates. Transcriptomic and proteomic studies revealed the activation of signaling pathways related to cell–cell communication, adhesion, and inflammation in these cells with a special involvement of the insulin-like growth factor-binding protein 5 in this process , 144. EnExposition of astronauts to cosmic rays during deep space flights represents another source of low-dose irradiation to the brain. Cosmic rays are mainly composed of high-atomic number and energy charged particles (high-energy protons and fully ionized atomic nuclei). These are densely ionizing radiations, which differ from main terrestrial radiation types (X and γ-rays) in terms of biological damage. The density of ionizing events deposited in tissues by charged particles produces a track of biological damage (mostly complex DNA double-strand breaks), which is very difficult to be repaired through the cellular repair processes. Exposure to heavy ion irradiation as low as 0.5 Gy was supposed to induce impaired neurogenesis with a very poor or no recovery . A long-Very few studies investigated the effect of low doses of proton and heavy ion irradiation on inflammatory and immune parameters in the brain. Vlkolinsky et al. showed that LPS treatment of mice in the absence of (56)Fe-particle irradiation induced a reduction in the hippocampal long-term potentiation capacity, while this inhibition was abolished and a reversal effect was registered after irradiation of the brain with (56)Fe ions. This phenomenon persisted for months, indicating that heavy ion irradiation stably altered hippocampal reactivity to immunological stressors . RegardiIn this review, we presented data proving a direct link between ionizing radiation-induced neuroinflammation and the development of late neurodegenerative disorders and cognitive deficit. It has been shown that the most common radiation-related alterations after brain irradiation are various forms of cognitive deficit. Some of the most representative epidemiological cohorts presenting an elevated risk for late cognitive sequela have been reviewed highlighting the increased sensitivity of the developing brain (and thus children) for radiation damage. The second part of the review focused on the description of the mechanisms on how IR can induce inflammatory reactions and can perturb brain immune homeostasis. IR-induced neuroinflammation develops as a result of a complex signaling between various cellular components residing in the brain  as well as the peripheral immune system. These data clearly prove that immune reactions in the brain are in many aspects similar to systemic immune reactions. Finally, we have discussed the long-term risk of low-dose radiation on the brain and presented the already available epidemiological and experimental data supporting this increased risk. These findings showed that molecular and cellular mechanisms within the low-dose range are often different from those elicited by high-dose irradiation. The relevance of these data is huge, since this means that even doses in the range used for diagnostic purposes might have long-lasting consequences and might contribute to the development of radiation-induced late cognitive impairment.Although much progress has been made in the field, the mechanisms that govern IR-induced inflammatory and immune reactions in the brain, their relationship with IR-related functional deficit and consequently the optimal therapeutic countermeasures are far from being elucidated. While formerly research work focused almost exclusively on therapeutic radiation doses, new and accumulating data regarding the risk of low-dose radiation highlight the importance of studies within this dose range as well.KL designed the review. KL, TS, and GS wrote the review.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


In-patient suicide prevention is a high priority in many countries, but its practice remains poorly understood. Patients in a suicidal crisis who receive psychiatric care can provide valuable insight into understanding and improving patient safety. The aim of this paper was therefore to summarize the qualitative literature regarding suicidal patients’ in-patient care experiences. The following question guided the review: How can we describe suicidal patients’ experiences regarding safety during psychiatric in-patient care?Systematic searches were conducted in the MEDLINE, Academic Search Premier, CINAHL, SOCINDEX and PsycINFO databases, identifying 20 qualitative studies on suicidal patients and their psychiatric in-patient care experiences. These studies were systematically reviewed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, synthesized via thematic analysis and subjected to quality appraisals.Patients described safety as “feeling safe”, and three components, i.e., connection, protection and control, were vital to their experiences of safety. Fulfilling these needs was essential to patients recovering from suicidal crises, feeling safe during encounters with health care professionals and feeling safe from suicidal impulses. Unmet needs for connection, protection and control left patients feeling unsafe and increased their suicidal behaviour.Our review addresses the importance of adopting a wider perspective of patient safety than considering safety solely in technical and physical terms. Safety for the suicidal patient is highly dependent on patients’ perceptions of their psychological safety and the fulfilment of their needs. The three patient-identified factors mentioned above – connection, protection and control – should be considered an integral part of patient safety practices and should form the basis of future efforts to understand the safety of suicidal patients during psychiatric in-patient care.The online version of this article (doi:10.1186/s12913-017-2023-8) contains supplementary material, which is available to authorized users. Suicide is a particular concern in mental health settings because of its strong association with mental illness . AlthougThe ethical and pragmatic problems posed by including suicidal patients in research have contributed to the currently limited research regarding the treatment of high-risk and hospitalized suicidal patients . To undeQualitative studies of patient experiences with psychiatric in-patient care have been reviewed within certain areas, such as involuntary hospitalizations , physicaA literature review was conducted to answer the following review question: How can we describe suicidal patients’ experiences regarding safety during psychiatric in-patient care?The selected studies were systematically reviewed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines ; the artType of study: Qualitative peer-reviewed studies in English with empirical data on patients’ experiences regarding safety were eligible. Participants: Studies examining a sample of suicidal in-patients who were interviewed during their hospitalizations or after discharge were eligible. “Suicidal in-patients” included patients hospitalized after a recent suicide attempt, described as suicidal during hospitalization or with serious suicidal thoughts or ideations; self-harming behaviour was excluded. The final criteria related to Setting: Experiences regarding care in psychiatric hospital wards, including psychiatric emergency wards and psychiatric long-term in-patient care, were eligible. Studies in multiple hospital settings were included if information regarding psychiatric in-patient care experiences could be extracted. Patient experiences pertaining to outpatient clinics, community mental health care, home care, forensic psychiatric services, emergency care and medical care were excluded. Studies describing patient experiences with adverse side effects from pharmacological treatment were excluded. Studies with mixed patient samples and studies involving health care professionals’ experiences were included if information regarding patient experiences could be extracted.The eligibility criteria for inclusion in the review pertained to the following three characteristics: To increase sensitivity, limitations on publication date were not imposed during the database search. The selection of databases, search terms and search methodology were determined in collaboration with a university librarian. The databases included in the systematic search were MEDLINE and the Academic Search Premier, CINAHL, SocINDEX with Full-Text and PsycINFO Ovid databases. Systematic database searches were conducted between June and December 2014 and in July 2016.Search terms were identified in relevant studies during the planning of the systematic review. The terms were selected from qualitative studies of patient experiences in mental health care and from qualitative studies of suicidal patients’ experiences. All identified search terms were included to increase search sensitivity. The full electronic search strategy for PsycINFO is outlined in Additional file We systematically searched all of the above databases using the following terms: patient* satisfaction*, patient* preference*, in-patient* experience*, patient* experience*, patient* perception*, patient* view*, patient* perspective*, patient* opinion*, user* experience*, consumer* experience*, consumer participation, suicide, suicidal, feeling safe and feeling unsafe.The study selection process was conducted according to the eligibility criteria displayed in the flow diagram in Fig. Thematic analysis, as proposed by Thomas and Harden  and BrauTwo authors (SHB and KR) independently assessed the methodological quality of the included studies and rated the studies based on Malterud’s  checklisThe study selection process utilized the PRISMA guidelines  Fig. 1)1) and idThe review consisted of 20 articles published between 1999 and 2016. The patients’ ages ranged from 16 to 63 years. The most frequently occurring diagnoses in the sample were affective disorders, of which major depression was the most prevalent, followed by schizophrenia spectrum diagnoses and personality disorders. Patients reported different experiences and needs depending on their symptoms and level of functioning; however, these parameters could not be analysed because of the presence of mixed samples. All patients had experienced suicidal crises, and the majority had attempted suicide prior to hospitalization. The studies originated primarily from Western mental health care settings, with the exception of studies by Sun et al. , 25, whiThe results of the 20 studies were synthesized and organized under analytical and descriptive themes Table . The resmeeting someone who cares; to feel understood by receiving a confirmation of feelings; and to feel respected and trusted by being acknowledged as a human being.The “Connection” theme illustrates how connections with health care professionals were vital for patient recovery and feelings of safety. A lack of connection was also experienced by the patients and had potentially fatal consequences. The sample of suicidal patients included in this review reported multiple and diverse causes of their suicidal crises , 27, butSuicidal patients expressed feeling lonely, being alone with their despair, being separated from the external world and feeling a need to be connected with others –30, 34. Some patients felt that their health care providers had neither time nor compassion for them , 34, 37,Patients indicated that they needed someone who could listen to and understand their story and situation , 32, 34 Patients experienced a lack of confirmation when health care professionals denied their feelings, neglected their illness, diverged from topics that the patients wanted to address, did not address difficult feelings –35, merePatients stated that it was important for providers to meet them on equal ground in order for them to feel acknowledged as a human being , 33, 34.Not being seen as a human being was related to feelings of inequality , 34, e.gprotected from death during constant observation. Receiving support from the observers was the most important aspect during constant observation, as patients lacking these relationships felt detached and objectified, and their anxiety and symptoms worsened [The “Protection” theme pertained to patients’ experiences when under constant observation and their struggles to feel safe from themselves and their invasive suicidal impulses , 40. Patworsened , 40.During constant observation, some patients experienced a state of mind in which they continually searched for available means to attempt suicide. Some experienced feeling powerless against their suicidal thoughts, whereas others experienced command hallucinations related to suicide . PatientHowever, one patient explained that not being able to end his life actually increased his suffering, as he believed that being able to end his suffering in the event that it became unbearable was a source of comfort that helped him cope with his situation . PatientCardell and Pitula  concludeSome patients experienced a lack of acknowledgement and a lack of interpersonal engagement under constant observation, in which the observers appeared disinterested or distant or behaved as though their patients were a burden , 40. Whegain insight and cope with difficulties and symptoms were able to regain control of themselves. This sense of control was important for attaining discharge readiness and feeling safe from themselves. Patients without this sense of control experienced increased suicidal thoughts.The “Control” theme involved patients’ need to re-establish a feeling of control over their lives . SuicidaGaining insight into their illnesses enabled patients to regain control after their suicide attempt , 31, 41;Patients felt that a sense of control could be achieved by being able to manage difficulties and by learning new problem-solving and help-seeking skills, as well as by receiving adequate treatment for mental health problems and obtaining assistance for social and economic problems. Patients who were able to manage difficulties were able to visualize a way back to their lives , 36, 37.Patients expressed the expectation that their admission would result in a cure for or solution to their problems; this belief represented a major disconnect between patients’ expectations and the treatment provided during short-term hospitalization . At discPatients’ sense of control was strengthened by having a post-discharge support plan and by being able to contact the ward after discharge if necessary , 35, 41,This paper posed the following review question: “How can we describe suicidal patients’ experiences regarding safety during psychiatric in-patient care?” Suicidal patients’ experiences with safety during psychiatric in-patient care were described in 20 studies that addressed whether their needs were met during their hospitalization. This review argues that patients define safety in terms of “feeling safe” and that connection, protection and control play vital roles in their safety-related experiences. Fulfilment of these needs are experienced as essential for recovery from their suicidal crises, in addition to the ability to feel safe during their encounters with health care professionals and to feel safe from their suicidal impulses. When experiencing unmet needs, the patients not only felt unsafe but also exhibited increased suicidal thoughts and feelings. For some patients, these experiences were characterized as triggers for another suicide attempt.connection and protection components discussed herein emphasize the importance of the therapeutic relationship in not only establishing feelings of safety but also optimizing patient outcomes, such as those related to increases or decreases in patient suicidality. The suicidal patients in this review addressed the vital importance of the therapeutic relationship in helping patients both feel safe and be safe. These findings are consistent with those of studies highlighting the therapeutic alliance in effective suicidal patient assessments and management [The patient experiences discussed in our review are related to the relational and emotional aspects of hospital care and are consistent with the findings of other studies regarding patient experiences , 13. Ournagement –47 and snagement , 48, 49.nagement .control component demonstrates the importance of supporting external and internal processes that help suicidal patients feel a sense of control and of understanding the individual from an ideographic point of view. Consistent the results of this review, Connell [This review highlights the importance of addressing the control component to enable suicidal patients to feel and be safe after discharge from the hospital ward. The  Connell  found thUndrill  stated tThere were a few limitations to this review. There is a risk of missed studies due to a lack of common nomenclature. To address this limitation, the search terms and strategy were designed to increase the sensitivity to relevant literature. Furthermore, the systematic search included only published peer-reviewed studies, resulting in the exclusion of possibly valuable grey literature and unpublished papers. Although there is a risk of reviewer bias, efforts were made to minimize this bias by applying systematic search methods and by following the PRISMA guidelines for systematic reviews.The review was limited to studies regarding psychiatric in-patient care. Studies examining the experiences of suicidal patients when receiving emergency care and outpatient treatment were excluded, as were studies regarding the experiences of patients without access to psychiatric care. These types of studies should be included in future reviews that aim to explore patient pathways and continuity of care, as poor continuity of psychiatric care has been associated with preventable suicides .The literature included a diverse group of patients characterized by suicidal behaviour. These different patient groups may present distinct experiences, thus limiting the general understanding of suicidal patients as a group. To account for the diversity of patients in suicidal crises, more studies involving the elderly, youths, low-income countries and non-Western health care settings are necessary. There is also a need to explore the experiences of suicidal patients in different diagnostic groups, such as suicidal in-patients with/without psychotic symptoms and patients with/without chronic suicidality or borderline personality disorder. The similarities and differences between the experiences of suicidal patients and non-suicidal patients must be elucidated to identify the generic versus group-specific characteristics that determine patient safety in psychiatric care. Additionally, patients may have different needs during different stages of their suicidal crises. For example, Rise et al.  observedPatient experiences should be considered an integral part of suicidal patients’ safety to guide clinical practice and the design of patient safety measures.Suicidal patients’ need for connection with health care personnel indicate that the relational component of patient safety is considered the most vital aspect of care and should thus be integrated into measures such as constant observation, suicide risk assessments, clinical supervision, ward therapeutic environments and encounters with health care personnel groups.Suicidal patients’ need for protection highlights the importance of constant observation in suicidal crises and the need for skilled professionals in close proximity to patients.Suicidal patients’ need for control emphasizes the need for therapeutic interventions that increases the patient’s insight and problem-solving skills as well as shared decision making regarding treatment plans, crisis plans, support systems and post-discharge follow-up activities.We recommend the following changes regarding in-patient care practices for suicidal patients based on the results of our systematic review:connections with health care professionals; they must be protected against their suicidal impulses and they must have a sense of control over their lives. These components should serve as the basis of future efforts designed to understand the ontology of safety for suicidal patients during in-patient psychiatric care.Our review addresses the importance of having a broader view of safety for suicidal patients rather than merely understanding safety in technical terms. When considering suicidal patients’ experiences, safety appears to be related to more than the absence of suicide risk and the need for physical protection. Safety for the suicidal patient is highly dependent on patients’ perceptions of their connections with health care professionals, the fulfilment of their needs during care and their psychological safety. To be safe, patients must feel safe through their


The publication of the first tick sialome  heralded a new era of research of tick protease inhibitors, which represent important constituents of the proteins secreted via tick saliva into the host. Three major groups of protease inhibitors are secreted into saliva: Kunitz inhibitors, serpins, and cystatins. Kunitz inhibitors are anti-hemostatic agents and tens of proteins with one or more Kunitz domains are known to block host coagulation and/or platelet aggregation. Serpins and cystatins are also anti-hemostatic effectors, but intriguingly, from the translational perspective, also act as pluripotent modulators of the host immune system. Here we focus especially on this latter aspect of protease inhibition by ticks and describe the current knowledge and data on secreted salivary serpins and cystatins and their role in tick-host-pathogen interaction triad. We also discuss the potential therapeutic use of tick protease inhibitors. Ixodes scapularis nymphs was attenuated upon infection with Anaplasma phagocytophilum, as seen in the transcriptomic data  are ubiquitous enzymes that cleave proteins to smaller peptides and amino acids. Proteases participate in a range of physiological processes including extracellular digestion, protein degradation, and tissue development  inhibitors, and serpins. Inhibitors with 1–7 Kunitz domains mostly act as anti-hemostatic proteins and form a large multigenic family of secreted salivary proteins in ticks that have probably played a crucial role in the development of tick hematophagy  are also notable serpins that act as major transport proteins for glucocorticoids and progesterone   experiments  is upregulated during first 3 days of feeding and is likely to be injected into the host during feeding; however, RNAi did not affect tick feeding ability  have been characterized thus far in AAS19 is an anti-coagulant that was shown to inhibit five of the eight serine protease blood clotting factors. AAS19 inhibited thrombin—but not ADP—and cathepsin G-activated platelet aggregation and delayed clotting in re-calcification and thrombin time assays   possesses a signal sequence and seems to be secreted by hemocytes into the haemolymph but not by the salivary glands or midgut   and lack a signaling peptide, suggesting intracellular rather than extracellular function. However, Iris has been detected in tick saliva using a polyclonal serum raised against recombinant protein  was the second serpin to be characterized in I. ricinus. IRS-2 has tryptophan in its P1 site, confirmed by its resolved crystal structure  and two putatively intracellular (RAS-1 and RAS-2), were identified in and isolated from the salivary glands of R. haemaphysaloides  have been identified and characterized from R. microplus displayed anti-elastase and anti-chymotrypsin inhibitory activities  from Cystatins form a superfamily of tight-binding reversible inhibitors of papain-like cysteine proteases and legumains and, similar to serpins, they are present in all organisms including prokaryotes , suggesting a role in regulating tick embryogenesis  were identified in the cattle tick A. americanum ticks  and stages  of tick development. The only exception was absence of JpIpcys2c transcripts in unfed larvae. Furthermore, vaccination of hamsters with a structurally similar BrBmcys2c cystatin from R. microplus did not show any cross-reactivity and did not lead to impaired I. persulcatus feeding or reproduction   were thought to be strictly limited to intracellular protein degradation and cellular metabolism. Recently, many cathepsins have been shown to be involved in multiple pathological processes. For example, increased serum levels of cathepsin L are associated with metastatic stage of different cancer types and poor patient prognosis  either by inhibiting the IFN-β production  or by inhibiting STAT3 phosphorylation downstream from IFN-β  (Lieskovska et al., JC and JK wrote the manuscript, JK prepared the tables, JC prepared the figures, HL and MK edited and revised the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


There has long been interest in innovating an approach by which tumor cells can be selectively and specifically targeted and destroyed. The discovery of viruses that lyse tumor cells, termed oncolytic viruses (OVs), has led to a revolution in the treatment of cancer. The potential of OVs to improve the therapeutic ratio is derived from their ability to preferentially infect and replicate in cancer cells while avoiding destruction of normal cells surrounding the tumor. Two main mechanisms exist through which these viruses are reported to improve outcomes: direct lysis of tumor cells and indirect augmentation of host anti-tumor immunity. With these factors in mind, viruses are chosen or modified to selectively target tumor cells, decrease pathogenicity to normal cells, decrease the antiviral immune response , and increase the antitumor immune response. While only one OV has been approved for the treatment of cancer in the United States, and only two other OVs have been approved worldwide, a wide spectrum of OVs are in various stages of preclinical development and in clinical trials. These viruses are being studied as alternatives and adjuncts to more traditional cancer therapies including surgical resection, chemotherapy, radiation, hormonal therapies, targeted therapies, and other immunotherapies. Here, we review the natural characteristics and genetically engineered modifications that enhance the effectiveness of OVs for the treatment of cancer. Observations of spontaneous tumor regression after naturally occurring viral infections gave rise to the notion that OVs can be incorporated as treatments . AlthougAs our understanding of cancer biology and virus–host cell interactions improves in concert with genetic engineering, the ability to manipulate the viral genome gains importance. For example, talimogene laherparepvec (T-VEC) is a herpes simplex virus (HSV) type 1 (HSV-1) that is the first OV to be approved by the FDA for the treatment of advanced melanoma , 18. AltThis review will describe a series of OVs used in clinical trials and care settings, as well as, in testing and development. It will especially focus on mechanisms underlying the oncolysis of naturally occurring OVs and the genetic modifications that have been made to improve the therapeutic ratio provided by OVs. A number of important considerations exist in terms of choosing a virus for potential use as a therapeutic oncolytic agent. These include targeting the OV to the appropriate tissue or cell type and mechanisms of action (including specific lysis of tumor cells and the activation of an effective immune response) Figure . These aIn the development of cancer therapeutics, targeting may be the most difficult obstacle to overcome. Targeting can be achieved by choosing viruses with natural tropisms to specific tissues or cell types or by engineering these tropisms Figure . While rCell permissivity for viral infection begins with the ability of the virus to identify and enter its cellular target. This is mediated primarily through the expression of cell surface receptors. Several OVs in use have been chosen based on their inherent ability to use cell surface molecules for entry that are abnormally upregulated in cancer cells. An example of this is the use of HVEM, nectin-1, and nectin-2 by T-VEC . This auCancer cells use more than aberrant cell surface receptor expression to fuel carcinogenesis. Specifically, they manipulate the transcriptional and signaling networks of cells to increase survival, proliferation, immune evasion, and metastasis. Viruses use many of these same pathways to propagate and infect cells. These parallels lead to cancer cells being more permissible to viral infections based on the overlaps between carcinogenesis and viral infection. An example is cancer’s resistance to cell death, often achieved by increased expression of antiapoptotic molecules such as those of the Bcl family. This increase in antiapoptotic molecules increases the targeting of cancer cells by certain OVs. Newcastle disease virus, for example, specifically targets cancer cells overexpressing Bcl-xL, a protein that inhibits apoptosis. This gives the virus time to incubate, multiply, and form syncytia, which is imperative to the survival and spread of Newcastle disease virus . The RasFurther, a number of viruses have been identified and taken to clinical trial that are oncolytic through preferentially targeting transformed cells by mechanisms that have not yet been fully elucidated. For example, Seneca valley virus is being clinically evaluated for its therapeutic efficacy against neuroendocrine tumors based on its natural tropism for cancer cells with neuroendocrine features , 32. Onevia cancer-specific promoters, and deletion of viral proteins that prevent apoptosis in healthy cells.Advances in molecular biology have afforded the OV field an opportunity to alter the DNA sequences of viruses and thus engineer viruses that are more specific for cancer cells than their normal counterparts. Currently, in clinical trials and in preclinical development, such viruses employ multiple mechanisms, including expression of modified receptors for cellular entry, restriction of critical viral protein expression vβ3 and αvβ5  protein motif so that it could bind to αand αvβ5  since thand αvβ5 . Similarand αvβ5 . This esCancer cells inherently have altered signaling pathways that allow for uncontrolled proliferation. Molecular biology is allowing viruses to be modified and provided tropisms that take advantage of protein regulation and signaling in cancer cells. One technique used is the manipulation of viral genes so they are under the control of modified promoters. Adenoviruses are commonly engineered in this manner based on their large viral genome, which allows for the incorporation of long DNA sequences thus permitting multiple modifications to be made to the native virus. E1A is an adenoviral protein that inhibits retinoblastoma (Rb)-mediated cell cycle arrest, allowing for sustained viral replication. It has been manipulated in various ways to allow for selective viral tropism in tumor cells. In an engineered virus specific to prostate cancer, for example, this gene has been modified to be under a prostate-specific antigen (PSA) promoter. PSA is a protein that is created specifically in normal and malignant prostate cells. This modification leads to E1A expression, and therefore, viral proliferation and oncolysis, that only occurs in prostate cells . In otheIn addition to restricting viral replication to tumor cells, adenoviruses have been engineered to use targeted delivery of suicide genes with promoters that have increased activity. One example is the placement of the HSV-1 thymidine kinase (TK) suicide gene under the control of an osteocalcin promoter. Osteocalcin is overexpressed in patients with bone metastases. This modification restricts the toxicity of the suicide gene to cells with an active osteocalcin promoter and increases susceptibility of cancer cells with overactive osteocalcin promoters . This stTo promote tumorigenesis, cancer cells disrupt natural immune system antiviral defenses and thus do not function like normal cells. This allows for the engineering of viruses to induce proliferation and lysis of cancer cells while inducing apoptosis in normal cells. Adenoviruses, for example, normally act to prevent abortive apoptosis in normal cells through the E1B protein, which binds to and inactivates the p53 protein. OVs ONYX-15 and H101 have been engineered to prevent expression of E1B . While tOther viruses, including oncolytic herpesvirus have been likewise engineered to take advantage of the disruption of standard antiviral responses that are inherent to cancer cells. Cancer cells commonly have overactive Ras-MAPK signaling which blocks phosphorylation of PKR. Such PKR blockade permits cellular proliferation. The HSV JS1 strain (the backbone of T-VEC) has been engineered with deletions of ICP 34.5 and US11. ICP34.5 acts as a neurovirulence factor required for viral replication that works by interacting with PCNA, and the US11 gene product downregulates expression of PKR. These virulence factors are required in normal infection, but since tumor cells undergo aberrant division and frequently downregulate PKR, this attenuated virus is able to preferentially infect cancer cells .The first-line mechanism of action of OVs is their direct lysis of cancer cells Figure . Some OVOther OVs have been engineered to induce cell death through mechanisms involving both virolysis and the introduction of suicide genes. Some adenoviruses have been modified to express HSV-1 TK. Once the virus targets the cancer cell using its specific natural or engineered tropism, it allows for a unique mechanism of cell killing when combined with thymidine analogs . Unlike normal human TK, the HSV-1 TK can activate these thymidine analogs by converting them into monophosphates . These mBeyond using the inherent lytic potential of OVs to provide direct killing of the cancer cell, viral infection of cancer cells elicits the standard antiviral immune response to clear the viral infection Figure . In thisMechanisms that some malignancies use to subvert the host immune system, in turn make them more susceptible to OVs. An example of this is interference with the type I IFN signaling pathway, which acts systemically to heighten antiviral and antitumor immune responses and locally to decrease cellular proliferation and increase p53, thereby activating the host apoptotic pathways . A numbeAdditional factors have to be considered for oncolytic viral treatments. These include understanding the ability of a virus to hide from the immune system as well as possible antibodies generated against a virus since immunity may already exist to certain viruses. Some OVs are ones that humans are commonly exposed to, including adenovirus and poxviruses. Therefore, neutralizing antibodies may be present in the serum prior to treatment and further antibodies produced more rapidly based on immunological memory . HoweverIn addition to the immune-mediated mechanism of action for OVs that is a result of standard antiviral responses, OVs have been specifically engineered to further potentiate the immune response Figure . To imprNatural serotype switching provides an advantageous method of treatment for viruses that possess multiple serotypes such as VSV and adenoviruses. However, serotype switching can also be mimicked through engineering of a virus to aid in immune system evasion and has been successfully done in measles virus . Other mDespite the immense progress evident in the development of OVs, it is important to note that substantial work remains in regards to understanding the mechanics and the ultimate potential of OVs. Genetic engineering to augment therapeutic efficacy still needs to be studied. Further, the proper administration and doses of different viruses should be investigated. As more information arises describing the use of new OVs, increases in biosafety procedures and protocols will also be a factor to consider. Clinical implications regarding the correct cancers to target and appropriate patients for whom to use oncolytic therapies will also be important to understand.Oncolytic viruses used in therapy have had modest clinical success as stand-alone treatments for cancer. While efforts are being made to improve the overall efficacy of these viruses as individual therapies (including by engineering better OVs), combining OVs with currently approved cancer treatments may drastically improve therapy. Because of their unique mechanism of action, specific ability to target cancer cells, and good safety profile, OVs have been combined with many standard cancer therapies including surgery NCT02714374), chemotherapy (NCT02779855), radiation therapy (NCT02453191), hormone modulators (NCT01867333), targeted therapies (NCT03088176), and even other immunotherapies (NCT02978625) , 65–71.4374, cheIn addition, OVs have been combined with other OVs to enhance cancer cell lysis, improve targeting, and overcome immunity developed against multiple administrations of the same virus. Herpes virus combined with adenovirus in a pancreatic tumor model has been shown to improve the lytic release of adenovirus . EchovirFurther, OVs have been combined with recently FDA-approved immunotherapies to enhance the immune-mediated mechanisms associated with tumor clearance. Specifically, talimogene laherparepvec (T-VEC), a herpes virus encoding GM-CSF, is being assessed for its ability to be combined with the immune checkpoint blockers ipilimumab (an antibody against CTLA-4) (NCT01740297) and pembrolizumab (an antibody against PD-1) (NCT02263508). Similarly, adenoviruses have been combined with checkpoint inhibitors in several ongoing studies in various malignancies including melanoma NCT03003676), lung cancer (NCT02879760), and breast cancer (NCT03004183). The potential synergy from initiating immune responses with OVs and then blocking tumor immune suppression with immune checkpoint blockade represents an attractive therapy to generate effective antitumor responses. Such responses may be achieved in greater proportions of patients than either therapy has delivered alone. The emergence and imminent regulatory approval of chimeric antigen receptor (CAR)-modified T cells will lead to yet another potential combination therapy. CAR-T cells have been limited in their ability to treat solid tumors, likely secondary to poor trafficking to the immunosuppressive microenvironment , lung ca. Given tClinical trials have demonstrated that OVs are tolerable and their common side effects include those present in natural viral infections  , 79. ImpOverall, OVs have shown the potential to be a very effective method of immunotherapy that efficiently and preferentially kills cancer cells. OVs have shown great successes as a treatment modality that both directly lyses cancer cells and elicits strong antitumor immune responses. With T-VEC producing significant results in terms of tumor regression in the United States, and with H101 approval in China, the use of OVs as an immunotherapeutic strategy has the potential to change the way we treat our patients. Numerous viruses exist as future therapeutic candidates allowing various cancers to be targeted for treatment. OVs have thus emerged as a fascinating approach to combat cancer and will only continue to improve with increased funding, preclinical studies, and clinical trials.All authors contributed to writing and/or providing feedback on the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


A systemic activation of blood coagulation is usually present in many clinical conditions including the infectious or inflammatory ones and malignant disease as well. Depending upon circumstances, patients suffering from acute decompensated disseminated intravascular coagulation may be managed by a medical oncologist and either an internist or a physician working in an emergency and/or intensive care unit. In some cases, for example, the indolent ones, the activation of coagulation might not be easily detected by routine laboratory tests and not lead to clinical manifestations. Such a chronically activated intravascular coagulation can progress toward an overt decompensated disseminated intravascular coagulation. Traditional therapy of decompensated disseminated intravascular coagulation is based on reversing the underlying triggering disease and providing patients with adequate supportive treatment. The dilemma for the oncologist is whether or not the trigger cause can be treated and amended with a specific antineoplastic treatment, without worsening the consumption of platelets and the risk of bleeding. In light of the availability of new targeted therapies, the main criteria that should drive the strategy against solid cancer–related disseminated intravascular coagulation will be discussed. Occurrence of decompensated disseminated intravascular coagulation is a major management challenge posed by cancer patients, particularly in the case of those suffering from solid tumors. The authors searched medical literature in their institutional libraries and PubMed. A number of peer reviewed articles deemed of relevant interest and published from 1983 to 2017 were taken into account for completion of this article. Medical oncologists are well aware that decompensated DIC is a potentially fatal complication often associated with the most aggressive types of tumor. Identification of patients who may be more likely to respond to a given anticancer drug should be the mainstay of treatment of cancer-related DIC. Whenever possible, a close cooperation between oncologist, hematologist and internist would be desirable.Although the manuscript often highlights the personal authors’ point of view, the search of a link with evidence issued by several scientific papers published on the topic was constantly pursued. Therefore, this article may be considered a contribution to overcome a possible too pessimistic physicians’ attitude toward the treatment of solid tumor–related DIC.2 Therefore, cancer patients suffering of such a disease may be initially admitted to hospitals under the care of physicians who belong to a division of Internal Medicine or of Clinical Oncology as well as an Emergency Care Unit and Intensive Care Unit. Physicians focusing their attention on these aspects may improve and hasten the diagnosis and start the best treatment. There is undoubted evidence that an interaction among coagulation/fibrinolysis pathways and cancer tissues exists.35 The interaction is mediated by an amount of molecules/enzymes such as cancer procoagulant (CP), tumor cell surface tissue factor (TF), microparticles carrying tissue factor, urokinase plasminogen activators (uPAs), plasminogen activator inhibitor-1 (PAI-1).58 Thus, cancer cells possess prothrombotic and fibrinolytic properties at once, and a thrombophilic state is present in almost all cancer patients.9 Accordingly, thromboembolic events and DIC, or coagulation consumption coagulopathy, can occur as result of the cancer-related prothrombotic tendency. Decompensated DIC is often present in patients who suffer from solid tumors or from hematological malignancy but with some different peculiarities. In fact, decompensated DIC frequently appears in early stage of some hematological malignancies while it mostly characterizes advanced or late stages of metastatic solid tumors.10 Among the solid tumor patients those harboring disseminated carcinomatosis of the bone marrow (DCBM) seem to be more susceptible to develop DIC.1113 When decompensated DIC occurs in patients suffering from solid cancer, it is often associated with an indolent course: only a borderline or slowly dropping platelet count and a normal or slightly deranged level of other coagulation parameters such as prothrombin time (PT), activated partial thromboplastin time (APTT) and fibrinogen level.14 On the contrary, in most cases of hematologic malignancies, decompensated DIC presents itself as an acute consumption coagulopathy with rapid platelet count drop and coagulation factors exhaustion potentially leading to dramatic and fatal bleeding.15 However, bleeding is not the only life-threatening complication affecting DIC patients. Furthermore, widespread deposition of fibrin-rich thrombi in microvasculature and subsequent ischemia are both factors able to cause a fatal multiple organ dysfunction syndrome (MODS).1618 The above type of thrombotic microangiopathy (TMA) observed in DIC course has a different pathogenesis in comparison with other TMAs as thrombotic thrombocytopenic purpura (TTP) or hemolytic uremic syndrome (HUS) which are usually not associated with coagulation factors consumption at least in their early stage despite presenting with thrombocytopenia.20 In clinical practice, many blood tests and a number of diagnostic guidelines are helpful to reveal and monitor the consumption coagulopathy associated with DIC along with its evolution and complications.2125Decompensated DIC may occur as the first sign of an underlying malignant disease or a late complication of a previously diagnosed and heavily treated cancer.21 In any case, the main question that needs to be answered, especially in cancer patients, is whether or not the triggering cause can be amended; otherwise, every effort may be in vain. DIC is a clinicopathological syndrome characterized by a consumption coagulopathy potentially causing a decreased level of procoagulant proteins and platelets. For practical clinical application, DIC is classically divided into two stages: overt DIC (decompensated DIC) and non-overt DIC (not decompensated DIC).22 When decompensation occurs (overt DIC), it can manifest itself with different clinical and laboratory features depending on variable speed of platelets and coagulation factors depletion. In this regard, the efficiency of compensatory mechanisms (i.e. fibrinolysis activation or liver and bone marrow production of coagulation factors and platelets) along with the intensity of the underlying trigger conditions also affects the severity of the coagulopathy.23 A variety of pathological conditions, including solid tumors, play a causal role in initiating this coagulation disorder. Among solid tumors, especially adenocarcinomas are more prone to trigger both thromboembolic complications and consumption coagulopathy.21 Prevalence of overt DIC is estimated to be up to 7% in patients suffering from solid tumors.2 The course of an overt DIC can be unruly (acute DIC), dramatically translating to a serious thrombocytopenia and hypofibrinogenemia along with diffuse thrombosis within microvasculature or larger vessels, potentially leading to bleeding and MODS.17 However, in the case of solid tumors, the coagulopathy has, most often, an indolent presentation and chronic course that may also be defined as low intensity decompensated DIC or mild DIC. It is less commonly associated with hemorrhagic complications and characterized by minimally deranged blood coagulation parameters. Therefore, DIC can produce laboratory signs alone or in conjunction with clinical symptoms.15 In general, treatment of the underlying disease is the instrumental key in reversing the consumption coagulopathy and, in addition, supportive therapy based on blood component infusion and/or low dose heparin and/or antifibrinolytics could be started simultaneously.21 The administration of heparin should be considered in non-symptomatic DIC, namely without bleeding, and low molecular weight heparin should be preferred over unfractionated heparin.25 Unfortunately, the removal of the trigger cause of DIC was and still is often impossible when physicians deal with metastatic and/or heavily pretreated solid tumors. In fact, cancer is not a self-limiting disease and is not always successfully manageable. Current available guidelines provide recommendations for optimal use of blood components such as fresh frozen plasma (FFP) and platelet concentrate, and, where appropriate, heparin and/or antifibrinolytics-based therapy in DIC irrespectively of its causal factors.25 FFP infusion aims to correct alterations of coagulation parameters resulting from plasma coagulation factors depletion; heparin is commonly used in order to inhibit or slow down the coagulation cascade; antifibrinolitics might have a role in treating DIC with hyperfibrinolysis and bleeding dominant complication.25 Administration of blood components is mandatory in the event of active bleeding and platelet count of <50 × 109/L, or if the perceived risk of bleeding is increased , decreased fibrinogen and a platelet count of <20 × 109/L or sometimes higher).25 It is interesting to note that supportive therapy other than and in addition to traditional treatments can be considered for patients with both DIC and DCBM. Bisphosphonates (i.e. zoledronic acid) or denosumab based supportive treatment is considered able to inhibit or slow down tumor-related bone resorption and can benefit patients with DCBM.13 Basically, in the context of solid tumors, the main controversy is not so much the appropriate indication for using blood component therapy but whether the treatment of the tumor triggering the coagulopathy is worth being undertaken or not. In fact, the blood component administration alone or in conjunction with heparin or, if it is the case, with antifibrinolytics is usually not able to stop and/or reverse DIC in cancer patients in the absence of an effective treatment of the underlying malignant disease.26 Two key issues should be addressed when the oncologists/physicians are dealing with patients affected from cancer-related DIC:The approach to decompensated DIC varies from watchful waiting to active treatment according to the severity of clinical presentation. The treatment of the trigger causes at once with restoring (as necessary) coagulation factors and platelet count has a pivotal role in influencing the course of decompensated DIC.Should we only treat the clinical and laboratory manifestations of the coagulopathy or the tumor (that is the trigger cause) as well? In other words, when is a given tumor causing DIC worth being treated?In addition, should the malignant disease not be suitable for an effective treatment, what would the aim of administering blood component therapy be?25 Conversely, when DIC has an indolent/chronic course, the clinical picture is essentially oligo or asymptomatic and no urgent treatments may be required over a long period of time.25 As to anticancer treatments, a large amount of data regarding the toxicity and response rate of any anticancer drug are usually published in several scientific papers and can be easily used in clinical practice. The term terminally ill cancer patients essentially identify a population whose clinical conditions progressively worsen with a life expectancy of 6 months or less and no treatments are able to restore their health.27 Regarding the approach to the clinical and/or laboratory manifestations of DIC, the choice of starting supportive measures  is mainly based on the course (indolent/chronic or acute) of the consumption coagulopathy. If no effective therapy should be available to ensure an effective treatment of underlying malignancy, this is for example the case of terminally ill cancer patients, the above-mentioned supportive therapies would have an essential role in preventing patients from uncomfortable physical and psychological clinical complications such as external bleeding.28 Of course, the current general guidelines can help in deciding which supportive measures are more appropriate for the patients.25 Decompensated DIC usually, but not always, occurs in the advanced or later stages of solid cancer.29 At the opposite, it is well known that most hematological malignancies are remarkably chemosensitive and, at least in the early cancer stage, the related DIC is more successfully treated than when it occurs in the solid ones.30 Accordingly, the DIC occurring during hematological diseases can regress more easily than expected in the course of solid tumors. Thus, only a small percentage of patients suffering from solid cancer and decompensated DIC are suitable candidates for and take advantage of chemotherapy. This is the case of some histotypes, that is, gastric cancer or breast cancer, considered very chemoresponsive.32 As a result, over the past decades, the oncologists who treat solid tumors developed an almost defeatist approach to cancer-related DIC. Sallah et al. had already pointed out the relevance of “patient’s performance status and prior therapy” to make the right decision whether or not to treat the underlying malignancy.2 To date, in addition, other factors should be taken into account before deciding to start a therapy specifically directed to the cancer in patients with DIC. For example, tumor’s histotype in conjunction with additional biological characteristics has to be considered among the main factors influencing the “expected tumor response to anticancer therapy.” Fortunately, at present, many genotype-driven and/or targeted therapies, often less myelotoxic and more effective than chemotherapy, are taking place in the therapeutic armamentarium of the oncologists.3335 In this regard, the effectiveness of some of the new anticancer drugs is very impressive. The oncologists have now the option of targeted therapies with fast response as B-raf/MEK inhibitors in malignant cutaneous melanoma or epidermal growth factor receptor (EGFR) inhibitors in EGFR exon 19 and 21 gene mutation or anaplastic lymphoma kinase (ALK) inhibitors in EML4-ALK gene re-arrangement in patients affected from non-small cell lung cancer.36 These new anticancer drugs may reconcile a low myelotoxicity with high specificity and response rate even against aggressive tumors often involved in triggering DIC.37 The above characteristics might make them attractive for the oncologists when approaching frail cancer patients even if affected from tumor-related decompensated DIC and subsequent thrombocytopenia. Some authors recently reported a really remarkable regression of acute DIC and cancer dissemination in poor performance status patients with non-small cell lung cancer who were administered erlotinib (an EGFR inhibitor) and crizotinib (an ALK inhibitor).39 Overall, In essence, the decision whether to treat the cancer or not is mainly influenced by two factors: one lies in the cancer potential responsiveness to a specific therapy and another in the expected therapy-related myelotoxicity. Additional key factors are listed in The single patients’ and tumors’ characteristics, along with DIC course, are the main criteria to dictate a therapeutic choice possibly including specific anticancer drugs. The current availability of a number of targeted therapies may open out new opportunities of effectively treating the cause of the cancer-related consumption coagulopathy. As a result, the outcome of DIC might be improved even in rapidly progressive tumors. Accordingly, a comprehensive approach to a consumption coagulopathy should include an as much as possible accurate biological characterization of the tumor and the choice of the most specific and less myelotoxic anticancer treatment if any. Of course, a close multidisciplinary cooperation among oncologist, hematologist, and internist should be required in most cases and the best treatment option discussed on an individual basis.