Interest in tumor cell mitochondria as a pharmacological target has been rekindled in recent years. This attention is due in part to new publications documenting heterogenous characteristics of solid tumors, including anoxic and hypoxic zones that foster cellular populations with differentiating metabolic characteristics. These populations include tumor-initiating or cancer stem cells, which have a strong capacity to adapt to reduced oxygen availability, switching rapidly between glycolysis and oxidative phosphorylation as sources of energy and metabolites. Additionally, this cell subpopulation shows high chemo- and radioresistance and a high capacity for tumor repopulation. Interestingly, it has been shown that inhibiting mitochondrial function in tumor cells affects glycolysis pathways, cell bioenergy, and cell viability. Therefore, mitochondrial inhibition may be a viable strategy for eradicating cancer stem cells. In this context, medicinal chemistry research over the last decade has synthesized and characterized “vehicles” capable of transporting novel or existing pharmacophores to mitochondrial tumor cells, based on mechanisms that exploit the physicochemical properties of the vehicles and the inherent properties of the mitochondria. The pharmacophores, some of which have been isolated from plants and others, which were synthesized in the lab, are diverse in chemical nature. Some of these molecules are active, while others are prodrugs that have been evaluated alone or linked to mitochondria-targeted agents. Finally, researchers have recently described drugs with well-proven safety and efficacy that may exert a mitochondria-specific inhibitory effect in tumor cells through noncanonical mechanisms. The effectiveness of these molecules may be improved by linking them to mitochondrial carrier molecules. These promising pharmacological agents should be evaluated alone and in combination with classic chemotherapeutic drugs in clinical studies. Mitochondria, often called the “powerhouses of the cell”, are essential organelles that play a well-recognized role in cell bioenergy, producing ATP via oxidative phosphorylation (OXPHOS). Mitochondria and the biochemical reactions that take place within them occupy a central position in many metabolic processes, such as the Krebs cycle, the urea cycle, and fatty acid oxidation . These oRecent findings have shown that tumor cell survival in nutritionally compromised microenvironments depends critically on efficient energy production  . WarburgThe structure and function of the mitochondria in tumor cells differ from those of normal cells in several ways . Tumor cMitochondrial structure in tumor cells is also distinct from that of normal cells. Cholesterol and cardiolipin content are present in the inner mitochondrial membrane (IMM) of tumor cell mitochondria, reducing proton permeability and significantly elevating mitochondrial transmembrane potential (∆Ψm) . This diIt is well known that solid tumor cells have vastly heterogenous genetic and metabolic characteristics. This heterogeneity is due not only to clonal expansion of cells with different genetic compositions but also to microenvironmental variance. The microenvironment of tumor cells adjacent to blood vessels is rich in nutrients and oxygen . As the Studies on cell lineage in solid tumors have confirmed the existence of cellular subpopulations called CSCs, as noted above. These CSCs, located inside the tumor mass, have an intrinsic capacity for self-renewal, aberrant differentiation, and tumor regrowth, thus contributing to tumor heterogeneity. These CSCs reside in a microenvironment with scant oxygen levels of 1–5%. This hypoxic phenomenon underlies the growth of this population, through a mechanism related to expression of the hypoxia-inducible factor-1α (HIF-1α) . As CSCsAvascular zones of solid tumors are also characterized by nutrient deprivation. Mean glucose concentration in colon and stomach carcinoma tissues, for instance, has been measured at only a fraction of plasma concentrations . Tumor cGiven the apparently crucial role of tumor mitochondria, medicinal chemistry research over the last decade has endeavored to isolate, design, synthesize, and characterize a broad number of molecules capable of selectively transporting novel or known pharmacophore groups that disturb mitochondrial function in tumor cells . Many ofAmong the diverse molecules postulated as antitumor drugs, this review will analyze the mitochondrial and cellular effects of polyphenols, delocalized lipophilic cations, and old drugs that have demonstrated interesting results in terms of inducing tumor cell death (some in CSCs) both in vitro and in vivo. Polyphenols are plant-derived compounds with complex chemical structures. These compounds can be classified into two main groups: flavonoids  and non-flavonoids  . PolypheTumor cells have high reactive oxygen species (ROS) levels. To compensate, these cells increase expression of proteins involved in antioxidant pathways. Overexpression of these antioxidant enzymes, along with elevated ROS levels, likely underlies many of the typical features of cancer cells, including high rates of cell proliferation, metastasis, and angiogenesis, as well as resistance to chemotherapy . DisruptThe catechin family of polyphenols is among the most well-known of these molecules. Catechins obtained from cacao exert pro-oxidant effects and induce apoptosis in epithelial ovarian carcinoma cell lines . Other pAs antioxidant molecules, polyphenols act as ROS scavengers, transition metal chelators, and regulators of the activity and/or expression of enzymes that participate in signaling pathways related to oxidative stress. Luteolin, a flavonoid present in apple peels, carrots, and broccoli, has been evaluated in vivo and in vitro using various breast and pancreatic cancer cell lines. In these models, luteolin induced cell apoptosis and inhibited metastasis, as well as reducing proliferation and tumor formation ,46,47. A2•−), which generate H2O2 and hydroxyl radicals. For example, EGCG , a green tea catechin, can markedly increase ROS production and positively regulate expression of CTR1 (cationic transporter receptor type 1), a relevant transporter for cisplatin intake . Ba. Ba98]. Lately, interest in another DLC has been renewed—the cyanine dye derivative D112, discovered in the 1970s, which shows toxicity against colon cancer cell lines . RecentlIn recent decades, there has been a growing interest in identifying possible antitumoral effects of drugs previously approved for other clinical indications. Consequently, we will review the most relevant drugs with mitochondrial activity.Several classes of existing drugs used to treat inflammation, infections, metabolic diseases, and other problems have been shown to exert antitumor effects, especially as mitochondrial target agents. Many of these agents induce severe energy stress by targeting the mitochondria, eventually triggering cell death  86]. Wi. Wi86]. Antibiotics are one such promising pharmacological group. Many of these drugs have a singular chemical structure that allows the agents to target mitochondria and induce a pharmacological effect, often inhibiting mitochondrial protein translation. These effects may also occur in mitochondria due to similarities between this organelle and bacteria ,105. The+ positivity, a CSC marker, suggesting the possible efficacy of this drug in resistant breast cancers [+ positivity in breast cancer cells, accompanied by reduced numbers of CSCs and subsequent inhibition of cell proliferation [The antibiotic most widely known as an antitumor agent is doxycycline. This drug is mainly used to either disrupt mitochondrial protein generation through accumulation in the mitochondrial matrix of human cells or to inhibit the 28S mitoribosomal subunit. Recently, Protasoni et al.  reported cancers . Zhang eferation .Tigecycline, a glycylcycline from a new group of antibiotics, has been approved for intravenous administration. Similar to tetracyclines, this drug has been described as an antineoplastic agent that acts by inhibiting the 28S mitoribosomal subunit in many types of cell lines. Tigecycline was shown to inhibit cellular respiration in thyroid cancer, reducing mtCOX1 and mtCOX2 translation, lowering ATP levels, and inducing cell death due to energy stress in a manner comparable to doxycycline . SimilarAnother group of drugs with potential as antineoplastic agents are non-steroidal anti-inflammatory drugs (NSAIDs). NSAIDs have been investigated extensively, with many studies describing mechanisms that might inhibit cell proliferation. There is some evidence that NSAIDs act on the mitochondria to induce antineoplastic effects. The classic mechanism of NSAIDs as anti-inflammatory agents occurs through inhibition of the enzyme cyclooxygenase, which blocks production of inflammatory prostaglandins and thromboxane . The antOther mitochondria-targeting agents with antineoplastic effects include drugs used to treat metabolic diseases, such as diabetes and hyperlipidemia medications. Antilipemic agents such as fibrates and statins first showed a capacity to trigger cell death by acting on the mitochondria. Fibrates can activate the nuclear peroxisome proliferator-activated receptor α (PPAR-α), reducing triglyceride-type fatty acid levels in adipocytes and muscles, to exert an antineoplastic action through a mitochondrial mechanism . FenofibStatins are another type of antilipemic drug with proven antitumor effects. These drugs inhibit the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, which is the rate-limiting step for cholesterol synthesis in the mevalonate pathway. Normally, statins act on the muscle by provoking mitochondrial oxidative stress, affecting the function of the organelle. These effects may cause myalgia or rhabdomyolysis—well-documented and characteristic side effects of these drugs . It has + breast cancer in a phase III clinical study [Metformin is a hypoglycemic drug with proven antitumor activity. This biguanide has been shown to act on various types of tumors as described in several epidemiological, preclinical, and clinical studies . The comal study , suggestal study . It shouMitochondria have emerged over the past decade as a promising target for new and old drugs known to selectively disturb the function of this organelle. Numerous tumor models, including in vivo and in vitro studies, have demonstrated the potential of this approach. Various molecules with diverse chemical properties have also been identified as potential pharmacophore groups or vehicles to deliver drugs to mitochondrial targets. Polyphenols, largely derived from plants, are of particular interest, as these molecules may induce mitochondrial dysfunction. Furthermore, several old drugs have been repositioned as mitochondriotropic molecules. Finally, some promising data have emerged regarding new lipophilic cations, such as F16. This fluorescent probe shows interesting cytotoxic activity, but F16 has not yet been sufficiently explored as a vehicle for novel pharmacophores.We now know that metabolic changes triggered by the tumor microenvironment elicit the presence of troublesome cell subpopulations, including CSCs. These cell populations pose significant challenges for medicinal chemistry, along with all of the previously identified metabolic characteristics of cancer cells that confer them with resistance to chemotherapy. The cytotoxic effects of many mitochondria-targeting anticancer agents have been demonstrated using normoxia models, in which CSC subpopulations tend to be small. In the years ahead, it will be important to confirm whether these agents are also effective against CSCs, which typically emerge in greater numbers as oxygen becomes scarcer. It may be especially useful to develop mitocans that can block induction of resistance mechanisms, as these molecules may be capable of inducing energy stress that inhibits mitochondrial function, provoking tumor cell death through autophagy or other processes.Another crucial task will be to research the effectiveness of mitocans in clinical trials and to explore drug combinations that improve antineoplastic activity without increasing adverse effects. New F16 fluorescent derivatives or other DLCs may enhance the cytotoxic activity of these drugs, even against CSCs. If such agents can be linked to potent mitochondria-targeting molecules found to exert antineoplastic effects in clinical trials, mitocans may become an applied therapy for patients with various types of cancers.Finally, in addition to the search for better and safer mitocans, it will be equally important to seek new combinations of drugs already approved for clinical use that produce synergistic antineoplastic effects.


This research investigated the effect of sprouting on wheat bran. Bran from un-sprouted (BUW) and sprouted (BSW) wheat were characterized in terms of chemical composition, enzymatic activities, and hydration properties. In addition, the rheological properties  and bread-making performance  of wheat doughs enriched in bran at 20% replacement level were assessed. Sprouting process caused a significant decrease in phytic acid (~20%), insoluble dietary fiber (~11%), and water holding capacity (~8%), whereas simple sugars (~133%) and enzymatic activities significantly increased after processing. As regards the gluten aggregation kinetics, the BSW-blend profile was more similar to wheat than BUW-blend, indicating changes in the fiber and gluten interactions. BSW led to a worsening of the mixing and leavening properties, instead, no significant changes in extensibility were observed. Finally, BSW improved bread volume (~10%) and crumb softness (~52%). Exploiting bran from sprouted wheat might be useful to produce bread rich in fiber with enhanced characteristics. Fiber-enrichment of food products has become increasingly important as a means to increase their nutritional properties. In this context, bran from cereals-with a total dietary fiber content of 30%–50%—is one of the most important source of dietary fiber used in the bread-making industry . HoweverThe detrimental effect of bran addition on bread-making cannot be solely attributed to the dilution of gluten proteins and to the physical disruption of gluten network, but the physical, chemical, and biochemical properties of bran should be also considered . BesidesSeveral pre-treatments have been proposed to counter these negative effects, such as: (i) particle size reduction, which significantly influences the rheological properties of dough in terms of mixing time, stability and dough resistance to extension , (ii) apIn this context, sprouting (or germination) can be proposed as a bio-technological process able to promote the accumulation of enzymatic activities. A recent study reported that wholegrain flour from sprouted wheat could be used to produce bread with improved characteristics  compared to conventional wholegrain flours ,11. EnhaConsidering the potential use of flour from sprouted wheat, it remains to elucidate the physical, chemical, and structural aspects of the wheat milling by-products  and how these characteristics might affect the baking performance of bran-enriched wheat bread. Indeed, although in the literature there is a large amount of study available on the enrichment of baked products in bran, no information is available on the use of bran from sprouted wheat in bread-making. Starting from this point, the purpose of this research was to investigate the features of bran obtained from sprouted wheat and how this ingredient affects both dough rheological properties and bread characteristics.Triticum aestivum L.) were kindly supplied by Molino Quaglia . A part of kernels (10 tons) was sprouted at industrial scale for 48 h, and then dried at 60 °C for 12 h, as previously reported by Marti et al. . Th. Thk valing time . In conclusion, this research provides information about the effects induced by sprouting process on the chemical and physical properties of bran and how these features affect its interaction with water and gluten in both slurry (using the GlutoPeak test) and dough systems. Last but not least, the effect on bread were considered. Unlike the numerous studies present in the literature, where the enzymatic treatments were conducted directly on bran, isolated after milling , in this study the bio-technological treatment was performed directly on the wheat kernels. Using bran from sprouted wheat in bread-making has led to positive effects in terms of gluten aggregation kinetic, bread volume and crumb softness, compared to the use of conventional bran. Thus, bran from sprouted wheat might represent a valid strategy to produce staple foods rich in fiber with high quality traits. Moreover, the use of milling by-products is a good approach to decrease food losses. Finally, results from this study might encourage the use of bran from sprouted wheat in small amount in bread formulations to replace the use of exogenous enzymatic improvers and create clean-label products.


Many of our theories for the generation and maintenance of diversity in nature depend on the existence of specialist biotic interactions which, in host–pathogen systems, also shape cross-species disease emergence. As such, niche breadth evolution, especially in host–parasite systems, remains a central focus in ecology and evolution. The predominant explanation for the existence of specialization in the literature is that niche breadth is constrained by trade-offs, such that a generalist is less fit on any particular environment than a given specialist. This trade-off theory has been used to predict niche breadth (co)evolution in both population genetics and eco-evolutionary models, with the different modelling methods providing separate, complementary insights. However, trade-offs may be far from universal, so population genetics theory has also proposed alternate mechanisms for costly generalism, including mutation accumulation. However, these mechanisms have yet to be integrated into eco-evolutionary models in order to understand how the mechanism of costly generalism alters the biological and ecological circumstances predicted to maintain specialism. In this review, we outline how population genetics and eco-evolutionary models based on trade-offs have provided insights for parasite niche breadth evolution and argue that the population genetics-derived mutation accumulation theory needs to be better integrated into eco-evolutionary theory. At a fundamental level, this question underpins most of our theories for why there is so much genetic, phenotypic and species diversity in nature ,2. The piversity ,11 and aiversity .niche breadth  or multiple (coarse grained) specialists [Levins  used modcialists .3.niche breadth evolution, but this theory began to be questioned as groups started explicitly trying to measure trade-offs in traits underlying adaptation to different environments . Theiewed in ,28. Indeiewed in ,29).et al. [Pareto front) defining a region of inaccessible no-cost generalist parameter space. They also showed that many genotypes can exist below the Pareto front. In this case, no-cost generalist alleles could advance the fitness of these maladapted genotypes to Pareto front, but evolution would be determined by the trade-off afterwards [Some of this failure to find trade-offs may be because they are difficult to measure . To testet al.  showed tterwards ,34. Accoterwards  show thaRegardless of these difficulties in measuring trade-offs, measurements of the correlation between viral fitness on different hosts have ranged from negative, to neutral, to positive ,29. Ther4.(a)fitness landscape that can be a simple peak or more rugged depending on the genetic architecture of the system and the number of possible strategies to respond to an environmental pressure [Population genetics models of pathogen evolution focus on how the availability of mutations and the ability of selection to act on them together determine fitness outcomes . Fitnesspressure ,43. Popupressure .Figure genetic drift, can lead to the purging, balancing or fixation of such new mutations [genetic hitchhiking and clonal interference [These models consider mutational fitness effects and the selection pressures on them that, depending on their strength relative to utations . They alrference ,55 and hrference ,57. Thro(b)SIR type compartmental models which follow the infection, recovery, birth and death of host individuals [Eco-evolutionary models incorporate explicit ecological feedbacks into evolutionary models to consider how invading phenotypes reshape the ecological equilibrium of a system and therefore potentially change the optimal fitness strategy ,59. For ividuals . This meividuals .evolutionarily and coevolutionarilystable strategies, branching or cycling [Generally, these models consider quantitative trait phenotypes (or strategies) and their trade-offs rather than explicitly including complex genetic or mutational processes, and follow frameworks where the invasion of any new strategy affects the equilibrium population sizes of each organism in the system ,62,63. T cycling ,65.5.antagonistic pleiotropy, where mutations conferring fitness on one environment hinder fitness on others [niche breadth and diversity dynamics.Modern trade-off theory assumes that costs to generalism are owing to n others . In both(a)niche breadth is determined by the collection of virulence and resistance alleles [In population genetics theory, the main model for host range in host–pathogen systems is the gene-for-gene (GfG) model, where  alleles . In this alleles ,69. Thes alleles ,69.However, classic GfG models only allow fluctuations in range breadth (i.e. the number of hosts that a parasite infects or the number of parasites that the host resists) . This is(b)In the eco-evolutionary theory on infectious diseases, trade-offs have been extensively applied by combining evolutionary trade-off models and epidemiological  models ,20,21,76niche breadth in heterogeneous host environments can be determined by a combination of the shape of the trade-off and the contact structure between the between host types.Other models have also used mixing matrices to show that higher between host type (versus within-host type) transmission selects more for generalists, even when generalism is costly ,20. Takeet al. [stable strategy for the parasites, but an unstable one for the hosts. This leads to hosts branching into higher resistance (lower infection) and lower resistance (higher reproduction) strains, which the parasites subsequently partition. In other words, a host whose resistance breadth exactly overlaps with a parasite's infectivity breadth should either evolve further costly resistance to prevent infection from that parasite or evolve less resistance to reproduce faster, as it is susceptible anyway. Furthermore, Boots et al. [It is also clear that hosts commonly evolve pathogen resistance and that different ecological dynamics between host and pathogen populations are likely to create varying selection pressures for resistance evolution and, therefore, coevolutionary feedbacks . Best etet al.  show thas et al.  show how6.antagonistic pleiotropy , or in longer experiments (versus ones that have been evolved for fewer generations). These factors all suggest that trade-offs exist, but that they are most consistently evolved when populations adapt to selective environments that allow them to experience one environment. Meanwhile, populations experiencing selective environments where they are forced to replicate on both environments often find mechanisms of adaptation that do not include trade-offs. The trend of trade-offs being found more often in longer experiments suggests that mutation accumulation might be a common driver of costs to generalism, that short-term evolution may be dominated by mutations below Pareto fronts or that selection from standing variation is likely to select for less pleiotropic alleles than selection from novel mutation [In a meta-analysis, Bono et al.  concludemutation .7.niche breadths, while mutation accumulation models propose additional explanations for mediocre generalism. In a 2005 review, Maclean [antagonistic pleiotropy. Theory needs to be developed to determine whether models based upon these two mechanisms (trade-offs and mutation accumulation) differ in ways that would affect how different population structures select for niche breadth evolution, how coevolution shapes these traits, and how niche breadths selected by these two mechanisms may impact population-level dynamics and diversification processes. Thus, these models' separate insights could be combined to generate integrated theory of niche breadth evolution.While trade-off and mutation accumulation theories for the evolution of specialization have often been presented as in conflict with each other, they both start with the observable phenomenon that specialists exist and that generalists are often less adapted to any one environment. Fundamentally, trade-off models start with the observation that there is a cost to generalism and explain how ecological processes may select for different  Maclean  briefly niche breadth. In this combined model, any trade-off curves may emerge through the balance between mutational and purging pressures rather than underlying assumptions of antagonistic pleiotropy. Such models would need to rely heavily on simulation but should be tractable and allow clear insights as population genetic and eco-evolutionary theoretical frameworks have already been developed. More generally, similar approaches should be developed to better integrate population genetics and eco-evolutionary theory insights across evolutionary biology.Comparing these classes of models is obviously complicated by the different underlying assumptions of modelling methods. A combined theoretical framework would have to allow a trade-off that is shaped by population genetics models of mutation and selection to feed into an eco-evolutionary model similar to those based on trade-offs to predict selection for Box 3.Recently, much attention has been turned to integrating theory across scales of biological organization . Both ecEco-evolutionary models have not yet well explained how selective strategies maintained by population-level ecological feedbacks are actually maintained in the face of high mutation rates and short-term evolution ,94. In tdrift promoting bottlenecks of many natural transmission events [On the other hand, many theoretical and experimental treatments of population genetic processes in viruses consider within-host processes or selection through cell culture . Howevern events ,95–97. TTherefore, better integrating these two fields may help us better understand how population genetics strategies function at the level of between host transmission and lineage-level selection and how eco-evolutionary feedbacks are selected through shorter term mutational and selection processes.8.Niche breadth evolution in parasites is an important problem that a large body of empirical work and theory has attempted to explain. Both population genetics and eco-evolutionary theory have important insights on the topic, but these have not yet been well integrated to produce a unifying theory of how both genetic and ecological processes might interact with pathogen biology to shape niche breadth evolution. We argue that further theoretical work is needed to unify these perspectives to predict how niche breadth evolves and how various ecological conditions may bias selection towards generalism or specialism. Unifying these perspectives to explore how non-trade-off costs of generalism shape the coevolution of hosts and pathogens in eco-evolutionary models would allow us to determine whether the mechanism of costly generalism shapes niche breadth coevolutionary dynamics in ways that alter our understandings about the ecological conditions predicted to drive spillover and maintain diversity. It is likely that differences, if they arise, are likely to depend on temporal scale and open up further avenues of research regarding the role of temporal scale and habitat instability in niche breadth diversification dynamics [dynamics ,92.niche breadth evolution. A wider consideration of the exact nature of trade-offs could help understand how selective pressures are maintained across scales (. In general, a better consideration of the nature of trade-offs in the light of constant mutation pressure and ecological feedbacks should help us better understand ecological and evolutionary processes.Finally, the lack of unification across population genetics and eco-evolutionary perspectives is not limited to s scales . For exa


Endometrial cancer is the most common female genital tract cancer in developed countries. We systematically reviewed the current health-economic evidence on early detection and prevention strategies for endometrial cancer based on a search in relevant databases (Medline/Embase/Cochrane Library/CRD/EconLit). Study characteristics and results including life-years gained (LYG), quality-adjusted life-years (QALY) gained, and incremental cost-effectiveness ratios (ICERs) were summarized in standardized evidence tables. Economic results were transformed into 2019 euros using standard conversion methods . Seven studies were included, evaluating (1) screening for endometrial cancer in women with different risk profiles, (2) risk-reducing interventions for women at increased or high risk for endometrial cancer, and (3) genetic testing for germline mutations followed by risk-reducing interventions for diagnosed mutation carriers. Compared to no screening, screening with transvaginal sonography (TVS), biomarker CA-125, and endometrial biopsy yielded an ICER of 43,600 EUR/LYG  in women with Lynch syndrome at high endometrial cancer risk. For women considering prophylactic surgery, surgery was more effective and less costly than screening. In obese women, prevention using Levonorgestrel as of age 30 for five years had an ICER of 72,000 EUR/LYG; the ICER for using oral contraceptives for five years as of age 50 was 450,000 EUR/LYG. Genetic testing for mutations in women at increased risk for carrying a mutation followed by risk-reducing surgery yielded ICERs below 40,000 EUR/QALY. Based on study results, preventive surgery in mutation carriers and genetic testing in women at increased risk for mutations are cost-effective. Except for high-risk women, screening using TVS and endometrial biopsy is not cost-effective and may lead to overtreatment. Model-based analyses indicate that future biomarker screening in women at increased risk for cancer may be cost-effective, dependent on high test accuracy and moderate test costs. Future research should reveal risk-adapted early detection and prevention strategies for endometrial cancer. Endometrial cancer is the sixth most common cancer in women and the most common female genital tract cancer in the developed world with rising incidences since 1990 . North AGermline mutations such as Lynch syndrome may increase the lifetime risk for endometrial cancer. Women with Lynch syndrome have a 40–60% chance of developing endometrial cancer and a 3–14% chance of developing ovarian cancer ,9. LynchUnlike breast and cervical cancer, for which screening programs are available to the general population, endometrial cancer is most commonly diagnosed after endometrial biopsy in symptomatic patients  ,13. In wIdentifying women at increased risk for endometrial cancer is crucially important for cancer prevention. Risk-tailored early detection and prevention strategies may have the potential to lower endometrial cancer incidence and mortality at reasonable costs. Benefits of screening and prevention need to be carefully balanced against both the clinical harms and the economic burden as health care resources are limited. Thus, it is critical to evaluate the evidence on cost-effectiveness of potential prevention or early detection strategies.The purpose of this semi-quantitative systematic review was to identify and summarize current evidence on the long-term effectiveness and cost-effectiveness of different early detection and prevention strategies for endometrial cancer in various population subgroups.Out of 125 identified publication hits, seven studies ,19,20,21The included studies were published between 2008 and 2017. All studies were performed for the health care system of the United States of America. No European study was found evaluating early detection or prevention strategies for endometrial cancer. The included studies showed heterogeneity regarding target population, study perspective, analytic approach, and compared intervention strategies.We distinguished between (1) screening for endometrial cancer, (2) preventive interventions and (3) genetic screening for germline mutations. If studies reported more than one type of intervention, we separated the interventions and sorted them into these three categories. We found four studies reporting screening strategies for four different risk groups, five studies reporting risk-reducing interventions targeting women with high risk, and one study on genetic screening. Key characteristics of the included studies are summarized in In the following paragraphs, the overall health-economic results are summarized for each category and target group presenting incremental cost-effectiveness ratios (ICERs) and incremental cost-utility ratios (ICURs) compared to the next non-dominated strategy.In total, four studies ,18,19,20Of those, two studies ,20 evaluTwo studies ,18 evaluAnnual screening using the hypothetical serum biomarker panel in women older than 60 years with a breast cancer history at increased risk for endometrial cancer (6% lifetime risk), who had been using tamoxifen for up to five years, achieved an ICER of about 23,000 EUR/LYG compared with no screening . Annual Five studies ,19,20,21Two of these studies ,20 evaluOne study  evaluateTwo other studies ,18 evaluApplication of oral contraceptives for five years in 30-year-old obese women  to prevent endometrial cancer was not cost-effective with an ICER of 458,800 EUR/LYG compared with no intervention . HoweverOnly one study  evaluateThe ICURs varied widely depending on the age of the individual and the risk threshold for carrying a mutation, that was considered for genetic testing, with a range from 8200 EUR/QALY for performing genetic testing in populations with a risk of at least 10% to carry a mismatch repair gene mutation in individuals as of age 40, to over 7.4 million EUR/QALY for universal genetic testing in individuals as of age 20. The authors concluded that genetic testing for mismatch repair gene mutations in women age 25–35 years with a pretest risk of carrying a mutation higher than 5% may be cost-effective with an ICUR below 43,300 EUR/QALY gained compared with current practice.While decision-making should be based on the incremental cost-effectiveness ratios reported above , determiThe risk of developing endometrial cancer in the target population and the impact of interventions on the quality of life are the most important influence factors for cost-effectiveness results. The cost-effectiveness results of the different endometrial cancer early detection and prevention strategies depend mainly on the overall risk for developing endometrial cancer in the target populations, and on the intervention’s impact on the quality of life. In women at high risk for endometrial cancer , risk-reducing prophylactic hysterectomy and PBSO compared with no intervention were highly cost-effective achieving ICERs and ICURs below the threshold of once the per capita GDP . AlthougGenetic testing for mutations in women at increased or high risk for carrying a mutation followed by risk-reducing surgery for mutation carriers compared with no intervention were highly cost-effective, achieving ICERs and ICURs even below the threshold of once the per capita GDP .In women at increased risk for endometrial cancer , intrauterine devices with Levonorgestrel for five years at age 50 achieved an ICER below twice the per capita GDP, which can be considered cost-effective . WhereasAn analysis assuming a hypothetical future screening test with high test accuracy  reported this screening test to be highly cost-effective (once the per capita GDP) in women at increased risk for endometrial cancer  and to be cost-effective (twice the per capita GDP) in postmenopausal women from the general population or in obese women as of age 45 years .We conducted a systematic literature search with the objective to give an overview of the current evidence on the effectiveness and cost-effectiveness of screening and prevention strategies for endometrial cancer. According to our study, the cost-effectiveness is influenced strongly by the risk level in the chosen target population. It also depends to a large extent on the intervention’s impact on quality of life and finally on the willingness-to-pay threshold of the specific country or health care system.Study results suggest that preventive surgery, for example, hysterectomy plus PBSO, may be considered highly cost-effective in women at high risk  for developing endometrial cancer. In women at increased risk, younger age at intervention  results in very low ICERs, but in higher ICURs when including quality of life. This points to the importance of including quality of life in the evaluation in addition to mortality reductions and remaining life expectancy. As prophylactic surgery may have severe side effects, which strongly impact the quality of life of the individual woman , the age at which the prophylactic surgery is offered should be chosen wisely. For women at high risk for endometrial cancer not willing to undergo prophylactic surgery, annual screening with TVS, CA-125, and endometrial biopsy may also be a cost-effective alternative. One study on genetic testing for mutations in women with familial risk found a 5% threshold for pre-test risk of carrying a mutation above which genetic testing is highly cost-effective if followed by risk-reducing surgery for mutation carriers. In obese women at increased risk for endometrial cancer, Levonorgestrel to prevent endometrial cancer may be considered cost-effective when treating women as of age 50 for five years. In contrast, treating obese women as of age 30 with oral contraceptives for five years cannot be considered cost-effective, neither can be screening approaches with annual TVS or endometrial biopsy.In women at average risk for endometrial cancer, no reliable early detection, and no prevention strategy are currently available. In our review, one study reported that annual screening with a high-performing hypothetical test (98% sensitivity and 98% specificity) may be effective and cost-effective to early detect endometrial cancer in women from the general population as well as in women at increased cancer risk. These results emphasize that a future screening test for endometrial cancer not only needs to detect malignancies at a very high rate, but also needs to be very accurate in order to avoid unnecessary treatment associated with false-positive results.Current evidence advises against endometrial cancer screening in asymptomatic women in the general population. Presently applied screening tests such as TVS or endometrial biopsy have not yet demonstrated to reduce endometrial cancer mortality. Controversies still exist on what endometrial thickness threshold to apply when deciding on biopsy. Using the same threshold for asymptomatic women as is used for women with abnormal vaginal bleeding (4 mm cut-off)  will leaToday’s guidelines recommend either prophylactic surgery or annual screening with TVS and endometrial biopsy as of age 35 years for women with Lynch syndrome. In modeling studies, both screening and preventive surgery in women as of age 30 years were shown to be cost-effective, but only when quality of life was not considered. Consideration of quality of life is of high importance though as each early detection or prevention strategy might have possible implications for the physical and psychological health of women. Invasive interventions such as an endometrial biopsy or a prophylactic surgery  often have moderate to severe side effects. Preventive surgeries may lead to infertility and artificial menopause in women at childbearing age. Preventive surgeries may affect body image negatively, cause disturbances in sexual relationships, and generate psychological distress . For womTo our best knowledge, this is the first study systematically summarizing current evidence on the cost-effectiveness of early detection or preventive strategies for endometrial cancer for women with different risk profiles. Our study has particular strengths. One specific strength of our review is that we performed additional calculations with the published data such as the incremental cost-effectiveness ratios based on the reported effects and cost of the individual studies. All ICERs/ICURs are consistently calculated in the step-wise manner considering dominance and extended dominance as is necessary to be relevant for decision-making ,28. To fDecision-analytic models, as a simplification of reality, have their limitations. Analyses outcomes will depend greatly on the model assumptions, methodology, and structure of the model . First, the studies varied significantly in the study perspective, time horizon, and in the evaluated interventions, which makes comparison between studies difficult. Compared interventions in different studies for the same population subgroup differ greatly in the type and frequency of the interventions. Three studies reported to adopt a societal perspective but included only direct medical costs. Incomplete cost assessments  may lead either to underestimated or overestimated ICERs and ICURs. Thus, these study findings may be biased or rather considered as findings adopting a payer’s perspective. Second, an important limitation of most of the studies was a lack of reporting model validations. International guidelines for modeling recommend that the “validation of a model should include an evaluation of face validity of the structure, evidence, problem formulation, and results of the model.” Models that are not validated may bear a potential risk of bias .One study  used a dThird, not all studies considered quality of life, and none of the included studies considered the anxiety that women might experience when they receive a positive test result. While in some studies the impact of a preventive intervention such as surgery on quality of life was considered, the impact of receiving a positive test result itself was not incorporated in any of the analyses. Studies not including quality of life measures in women receiving a positive test result and/or undergoing surgery might not be able to thoroughly evaluate the trade-off between clinical benefits and psychological harms of screening.Fourth, in modeling studies evaluating screening strategies, false-positive test results leading to unnecessary surgeries  could potentially have a positive effect if they prevent endometrial cancer in women who would have developed it later in life (and in the model) without the surgery. Studies neglecting the effect on quality of life caused by positive test results and necessary or unnecessary surgery may overestimate benefits and underestimate cost-effectiveness ratios. Both may lead to falsely favoring strategies with lower specificity and therefore more false-positive results and unnecessary surgeries. A similar effect may occur in modeling studies when not all downstream costs of positive test results are carefully included.Finally, it is crucial that all relevant strategies  are included as comparators in the analysis and that cost-effectiveness ratios are reported for each non-dominated strategy and always in comparison to the next best non-dominated strategy . This prBesides the limitations of individual studies, our review has limitations of its own. Our search for studies was focused on cost-effectiveness studies based on a decision-analytic model, evaluating screening and prevention for endometrial cancer in asymptomatic women. We may have missed evidence from effectiveness studies not reporting costs. In addition, our results may be not representative for women presenting with symptoms such as abnormal bleeding . While we searched in a range of relevant electronic databases, we may have missed further studies in the gray literature. Publications in languages other than English or German were also not considered. Future research should consider all of the issues discussed above and may also focus on risk-adapted strategies to early detect and prevent endometrial cancer considering genomics, epigenetics, and lifestyle information, including individual characteristics . To date, only a few endometrial cancer prediction models have been developed especially for asymptomatic women . LikewisThis review can guide further research into risk-adapted, personalized early detection and prevention strategies for endometrial cancer and provide guidance for informed decisions in health care resource allocation. This semi-quantitative systematic review consists of several steps. In the first step, we systematically searched for studies evaluating both the clinical long-term effectiveness and cost-effectiveness of early detection and prevention strategies for endometrial cancer in the electronic databases Medline (Ovid and PubMed), Embase (Ovid), the Cochrane Library, CRD databases , and EconLit (last update: January 2020). The search codes were developed separately for each database using medical subject headings (MeSH) and search term combinations for endometrial cancer, detection or prevention, effectiveness, costs, and modeling . AdditioWe included decision-analytic modeling studies assessing both the long-term effectiveness and the cost-effectiveness of different early detection and prevention strategies for endometrial cancer, reporting outcome measures such as quality-adjusted life-years gained (QALY), life-years gained (LYG), incremental cost-utility ratios , or incremental cost-effectiveness ratios . We included studies with a time horizon sufficiently long to reflect that cancer and preventive interventions affect life expectancy and overall costs ,36. We eIn the second step, we systematically extracted and summarized the following information in standardized evidence tables: model analytic framework and characteristics , clinical effectiveness, and cost-effectiveness results of compared strategies. In cases where ICER or ICUR were not reported in the included study, we calculated ICER and ICUR based on the reported study data if possible. The third step served the comparison across countries, currencies, and study years. We converted all costs into 2019 euros using the gross domestic product (GDP) purchasing power parities (PPP) to adjust for the country-specific purchasing power and the consumer price index (CPI) of Europe to adjust for inflation ,38,39. In the fourth step, in order to quantitatively compare cost-effectiveness measures across studies, we calculated ICER or ICUR compared to the next non-dominated strategy, if necessary and if data were available. Strategies are considered dominated if they provide less health benefit at higher costs when compared with any other strategy ,41. SimiIn the fifth step, we performed the judgment of cost-effectiveness. We did not use a global willingness-to-pay (WTP) threshold for incremental cost-effectiveness ratios, as these thresholds vary across different countries . In thisFinally, we calculated the ICER or ICUR compared to no intervention or standard of care as a simple descriptive point of reference for all included studies, if data were available. This step served to visualize the cost-effectiveness measures across different risk groups, interventions, studies, and countries. Only for this visualization, we used the World Health Organization (WHO) recommended willingness-to-pay threshold of one to three times the GDP per capita for a specific country ,44 to shAll abbreviations used are summarized in Based on study results, genetic testing in women at increased risk for mutations followed by preventive surgery in mutation carriers as well as preventive surgery in known mutation carriers can be considered effective and cost-effective. Except for women with diagnosed Lynch syndrome, screening strategies using transvaginal sonography or endometrial biopsy are likely not cost-effective. Screening with transvaginal sonography or endometrial biopsy in women at average risk may lead to overtreatment and cannot be considered cost-effective. Promising model-based results suggest that future biomarker screening in asymptomatic women at increased risk for cancer may be cost-effective if the test accuracy is sufficiently high and test costs are moderate. Future research is needed on risk-adapted early detection and prevention strategies for endometrial cancer, integrating harms of intervention and considering overdiagnosis. Future trials may investigate new biomarkers for preventive strategies based on genomics, epigenetics, and lifestyle information.


Linear regression was used to assess the moderation effect of parenting practices (both adolescent- and parent-reported) on the relationship between reward sensitivity, and diet using SPSS 25.0. Results: In the main analysis (adolescent-reported), no significant moderation effects were found for parenting practices on the relationship between reward sensitivity and diet. However, the sensitivity analysis (parent-reported) showed a moderation effect for health-reducing parenting practices on the association between reward sensitivity and unhealthy snack intake . Conclusion: Given the difference in the effect of parenting practices between the adolescent- and parent-reported data, our inconclusive findings warrant more research in larger adolescent-parent dyad samples.Background: Reward sensitivity has been associated with adolescents’ intake of unhealthy snacks and sugar-sweetened beverages. However, so far, there are no studies published describing the impact of parenting practices on this relationship. The present study will, therefore, investigate whether food parenting practices can moderate the association between reward sensitivity and diet intakes. Method: A cross-sectional research study was conducted among 14- to 16-year old Flemish adolescents ( Adolescents’ eating pattern is characterized by a high intake of energy-dense snacks and sugar-sweetened beverages (SSBs) ,2. ReseaAt the individual level, some adolescents seem to be more vulnerable to increase their food intake when they are faced with highly palatable (or reinforcing) foods like energy-dense snacks or SSBs . More spImportantly, adolescents’ food choices may not only be explained by individual characteristics but also by environmental factors . DecadesPast research often focuses on how food parenting practices influence dietary intake in toddlers and elementary school-aged children, and to date, far less studies have been carried out in samples of adolescents. Although adolescence is a developmental period that is characterized by an increased strive for autonomy, at the same time, adolescent boys and girls are still dependent on their parents, and the quality of the parent-child relationship remains important for determining food intake . In adolIn recent developmental models such as the goodness of fit model , it is ghttp://www.rewardstudy.be). The overall aim of this project was to provide evidence for a new public health framework to improve the eating patterns of children and adolescents by focusing on individual differences in reward sensitivity. Data were collected between September and December 2013 in a representative sample of adolescents recruited in the third and fourth grades of 20 secondary schools in Flanders (Belgium). Additionally, parents of the participating adolescents were also invited to fill out the parent questionnaire (one parent per adolescent). Parents’ passive consent and adolescents’ active consent were obtained prior to participation of the adolescents, and parents’ active consent was given for their own participation. Of the 1210 selected adolescents, 6% were absent or not allowed to participate, and 3% returned a questionnaire of unsatisfactory quality (defined as more than 33% of the questions not completed or straight-lining responses) for further use. More detailed information on the study procedure and used materials can be found elsewhere [The present study was a secondary data analysis on data from the REWARD project  consumption was assessed using a Food Frequency Questionnaire (FFQ) for adolescents , based oReward Sensitivity (RS) was indexed by the BAS-scale of a Dutch age-downward version one of Carver and White’s BIS/BAS scale . ThirteeThe food parenting practices were assessed separately in both adolescents (adolescent-reported) and their parents (parent-reported) by 21 items  from the adolescent and parent version of the Child Feeding Questionnaire  and the The following a-priori defined covariables were considered as potential confounders due to a known association with diet ). AdolesDescriptive statistics were produced see . AnalyseSensitivity analyses were performed to evaluate the robustness of the findings see  by rerunOne-thousand one-hundred and four adolescents (and 158 parents) completed the questionnaires. The complete-cases analysis sample was comprised of 867 adolescents (and 131 parents). In the sensitivity analyses, we did find a moderation effect for parent-reported health-reducing parenting practices on the relationship between reward sensitivity and unhealthy snack intake. The present study investigated whether the influence of reward sensitivity, a known determinant of snack and SSB intake in adolescents , might bHowever, when diet outliers were removed, these effects were no longer significant. In contrast, the effects of parenting practices were more robust and survived all sensitivity analyses. Increased use of health-promoting parenting practices was associated with reduced SSB consumption and increased healthy snack intake, while increased use of health-reducing parenting practices was associated with increased unhealthy snack intake. These results are in line with previous studies ,23 and sParent-reported data on parenting practices; however, did provide evidence for their interactive role with reward sensitivity in explaining adolescents’ unhealthy snack intake. More specifically, results demonstrate that health-reducing parenting practices strengthen the association between adolescents’ reward sensitivity and unhealthy snack intake. In other words, in line with the assumptions of the goodness of fit model , unhealtThe present study has several strengths. First of all, the divergence of the results obtained through adolescent and parent report point to the relevance of multi-informant assessment. Although considered best practice in developmental psychopathology research , this apA large sample is necessary to have enough power to detect small effects. We assumed that the effect sizes of the determinants under study would be small because eating behavior has multiple determinants that act together on different levels ,14. TherSome limitations have to be noted, as well. First, parenting practices were assessed through a purpose-built questionnaire, using a selection of relevant items borrowed from several instruments on food parenting practices, being the Child Feeding Questionnaire , and theTo conclude, the present study investigated whether health-promoting or health-reducing food parenting practices could impact the relationship between reward sensitivity and dietary intake in adolescents. The main analysis on the adolescent-reported data did not show any moderating effect of food parenting practices. This finding indicates that, although reward sensitivity and parenting practices were uniquely associated with dietary intake, they do not seem to interact based on adolescent-reported data. Other—for example, observational—measures and multiple informants are needed to investigate further whether and how parenting practices impact the relation between temperamental traits and adolescents’ dietary intake. Especially since the sensitivity analysis using the small sample of parent-reported data showed an interactive role with reward sensitivity in explaining adolescents’ unhealthy snack intake. This finding indicates that health-reducing parenting practices seemed to strengthen the association between adolescents’ reward sensitivity and unhealthy snack intake. Nevertheless, more longitudinal and intervention research in larger samples of adolescent-parent dyads is necessary to further investigate the impact of both health-promoting and health-reducing parenting practices on the relationship between reward sensitivity and diet intakes of adolescents.


Together with its dominant immunological and bone remodeling involvement, RRO axis, comprising of receptor activator of nuclear factor-κB (RANK), RANK ligand (RANKL), and osteoprotegerin (OPG) signaling, is as well-implicated in CNS functioning and corresponding pathologies. The CNS aspects of RANKL/RANK/OPG (RRO) axis were systematically reviewed. With search 10 databases, and 7 additional resources from first article publication to July 2019, resulted in total 2,222 hits, from which 33 relevant articles were selected. The elements of RRO axis in CNS include cells involved in neuroinflammation, predominantly in microglia, but as well in resident macrophages and inflammatory cells migrating across the blood-brain barrier. The expression in neurons and oligodendrocytes is mainly confined to processes of differentiation and cell death. RRO axis tunes the neuroinflammatory response, depending on the molecular, cellular and pathological context. RANK/RANKL signaling is neuroprotective in TLR-mediated inflammation, while OPG seems detrimental in stroke, but beneficial in multiple sclerosis. The levels of RRO axis elements can serve as biomarkers in the blood and cerebrospinal fluid. They act as neuroprotectant after brain damage even being implicated in body weight- and thermo-regulation. As derivatives of RRO axis already exist as therapeutic agents in bone remodeling, it would be intriquing to see if these or new RRO-based pharmaceuticals would appear effective in CNS therapies. The receptor activator of nuclear factor-κB (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) (RRO axis) was originally discovered through parallel investigations in the late 1990's within the immune and bone systems . This siThe RRO axis involves the interactions between three members of the tumor necrosis factor (TNF) superfamily (TNFSF), RANK , its cognate ligand RANKL  and a decoy receptor OPG . RANKL, a member of the TNF ligand superfamily binds to RANK and a decoy receptor OPG, both from the TNF receptor (TNFR) superfamily . RANKL, In addition to the immune system, the RRO axis is well-characterized in the context of bone remodeling. RANKL, secreted by osteoblasts, osteocytes, hypertrophying chondrocytes, and bone marrow stromal cells, stimulates the responsive RANK-bearing osteoclast precursors, to differentiate into active bone-resorbing osteoclasts. This negative feedback-loop is important for physiological bone remodeling, and the equilibrium between bone formation and bone resorption. OPG is secreted by osteoblasts, bone marrow stromal cells, B cells, and dendritic cells. It acts as a decoy receptor for RANKL, preventing its interaction with RANK and, consequently, blocking osteoclast maturation Moreover, the imbalance in RANKL/RANK signaling may lead to a number of bone disorders, such as rheumatoid, arthritis and osteoporosis –13.2+ ions, which interact with the calcium sensing receptors and simulate proinflammatory mediators  and developed detailed search strategies, based on the strategy for MEDLINE (using MeSH terms and text keywords) but revised appropriately for each resource, and used English language while searching the entire database.We searched the following databases:Cochrane Central Register of Controlled Trials MEDLINE (via Ovid)ScopusWeb of Science Core Collection (via Web of Science)Current Contents (via Web of Science)SciELO Citation Index (via Web of Science)KCI-Korean Journal Database (via Web of Science)Russian Science Citation Index (via Web of Science)BIOSIS Citation Index (via Web of Science)Data Citation Index (via Web of Science).We searched additional resources including:ProQuest Dissertations & Theses GlobalOpenGreyAfrican Index MedicusIndMEDClinicalTrials.govWHO International Clinical Trials Registry Platform (WHO ICTRP)CenterWatch.Our search strategy is described in detail in Relatively low number of references on this topic , due to the risk of bias, may indicate an insufficient number of studies whose results could directly and undoubtedly be used for further research or some other application in practice.The RRO axis and osteoclast paradigm is applicable to microglial cells as both osteoclasts and microglia share some developmental and functional properties, including hematopoietic origin, phagocytosis, and immunomodulation . MoreoveRecent studies have demonstrated that members of the RRO axis are expressed by several types of cells within neural tissue; this includes microglia, other resident macrophages, neurons and oligodendrocyte precursor cells –30. It hIn vitro studies showed that, in certain conditions of cellular stress, OPG can be expressed by neurons and oligodendrocyte progenitors, protecting the neurons from apoptosis caused by death receptor stimulation  , 37. MorIn vitro activated microglia polarizes into either pro-inflammatory  or anti-inflammatory (mediating phagocytosis of tissue debris and regeneration) subtype, a concept adapted from polarization of peripheral tissue macrophages  which serve as pathogen recognition receptors . RANK exThe RRO axis has been studied in both, a variety of experimental animal models, and humans with different pathological conditions. These studies suggest that RRO triad may be a novel target for diagnostic and therapeutic approaches. Some research groups have developed RRO axis modifiers applicable to neurological setting and are working toward their application in clinic, some of these will be discussed below.Recent studies of the RANKL/RANK/OPG signaling pathway indicate its involvement in ischemic brain injury in particular in microglial activation. The relevance of microglia in ischemic injury is highlighted by its contribution to the reparative processes during the latter stages of CNS damage , 51.In vitro studies using recombinant (r)RANKL confirmed this neuroprotective effect. However, it was seen only in mixed neuron/glia cell cultures, but not in cell cultures comprised only of cortical neurons. In peri-infarction areas, OPG is also overexpressed, but its exact cellular source is still under debate , OPG deficient mice were found to have reduced infarction volume compared to wild-type (WT) controls. Administration of anti-RANKL neutralizing antibody increased the infarction volume in both OPG –/– and WT mice, although the effect was less pronounced in WT than in OPG –/– mice. These data imply that RANKL/RANK signaling has a protective role in ischaemic brain injury, whereas OPG exterts an opposite effect .Based on the available data, it is proposed that blockade of TLR signal would reduce the extent of post-ischaemic brain injury. In such context, activation of the RANKL/RANK axis could be considered as an “anti-TLR” agent . HoweverThese results collectively suggest that blockade of the RRO axis may lead to overstimulation of microglial cells, and in turn may exacerbate neural damage following tissue injury. In contrast, activation of RANK-signaling cascade ameliorates the unwanted inflammatory response, thus protecting the brain tissue from further damage.Autoimmune-mediated neuroinflammatory processes damage the integrity of the BBB and this results in a loss of immune privilege , 58. BesAutoimmune disorders of the CNS, such as multiple sclerosis (MS), are associated with myelin sheath damage mainly caused by aberrant T cell response. The RRO axis has been found to potentially play a role in murine experimental autoimmune encephalomyelitis (EAE) as a model of human MS , 65, 66.In relation to possible biomarkers, the concentrations of RANKL and OPG are found to be higher in the blood of MS patients. Primary progressive (PP)-MS is in particular associated with the highest levels of RANKL in parallel with other inflammatory makers  . AnotherThrough the parallel profiling of peripheral blood and cerebrospinal fluid (CSF), our group was the first to compare the levels of RANKL and OPG in control subjects and MS patients at clinical onset . It is iIn conclusion, RRO axis has potential as both a disease biomarker and therapeutic target in certain autoimmune diseases of the CNS such as MS.Primary CNS tumors account for a significant proportion of morbidity and mortality up to 29.9 per 100,000 persons , 76. Sevin vivo xenograft study, in which human glioma cells were stereotactically injected into mouse brain, revealed that GBM cells expressing high level of endogenous RANKL resulted in a more invasive tumor form compared to GBM cells expressing relatively low endogenous RANKL. Furthermore, the number of activated astrocytes was markedly increased in the periphery of RANKL-abundant invasive tumors, suggesting that RANKL is able to activate astrocytes through NF-κB signaling. These astrocytes have been shown to secrete various factors that regulate glioma cell invasion (Glioma cell lines and murine glioblastoma multiforme (GBM) models have demonstrated that GBM has employed immune escape mechanism that involve secretion of CCL20 and OPG, which acts directly and indirectly on microglia cells triggering their production of CCL2. This chemokine gradient attracts CCR4-expressing Tregs and CCR2-expressing monocytic myeloid-derived suppressor cells to the site of GBM, which in turn reduces the inflammatory response to tumor cells –80. One invasion .RANKL expression has also been examined in pituitary adenoma cell lines, in the context of death receptor activation. The cytotoxic agent containing the fused tripeptide sequence Arg-Gly-Asp (RGD) (interacting with transmembrane integrins) and Fas ligand was used for targeted activation of receptor Fas in several adenoma cell lines. In parallel to the increase in caspase expression, administration of RGD-Fas ligand stimulated the expression of RANKL, indicating that the RRO axis and its mediators are functionally linked to pro-apoptotic members of the TNF superfamily , 83.The RRO axis may be implicated in neurological conditions not directly related to ischaemic injury, neuroinflammation or tumorigenesis, indicating a general biological role within the CNS. A recent study of prednisolone-induced neurotoxicity in rat brain demonstrated that it is associated with the attenuation of RRO signaling through modulation of OPG and RANK expression . This stThere is also evidence that RANKL reduces food intake and causes weight loss via modulating the hypothalamic neuropeptide Y(NPY)/cocaine- and amphetamine-regulated transcript (CART) peptide pathways , 87. RANThree studies suggest the involvement of RRO axis in thermoregulation. It seems that RANKL may activate brain regions involved in thermoregulation and induce fever via COX2-prostaglandin E2/EP3 receptor pathway in neurons and astrocytes. RANK mutation in both rodents and humans results in an abrogated fever response compared to controls –90.The increasing evidence is accumulated that RRO axis has an important role in neural tissue pathophysiology and could be a common functional link between different inflammatory processes within the CNS.in vivo by RRO mediators and their functional interactions with other cytokines and growth factors still need to be fully elucidated.The elements of RRO axis in CNS include immune cells, predominantly microglia, but also other resident and infiltrating macrophages, mediating homeostatic and neuroinflammatory mechanisms. The expression in neurons and oligodendrocytes is mainly confined to differentiation and apoptotic processes. RRO axis tunes the neuroinflammatory response, highly depending on the tissue context. Research into RRO signaling has demonstrated apparent contradictory effects and suggests that RRO signaling is beneficial in ischemic lesions and deleterious in autoimmune reactions. We propose that this paradox may be explained by the stimulation of different microglial subtypes and the induction of diverse downstream effector functions . HoweverTo date most studies involving RRO mediators in human samples have focused on the peripheral blood biomarkers. Future research is needed to identify their specific effects within brain tissue and to develop novel agents that can modulate RRO signaling. Several such modulators are presently in clinical use for different conditions, including RANKL agonists as well as OPG-mediated axial antagonists. We believe that modulation of the RRO axis may complement current treatment strategies for certain neurological disorders providing novel therapeutic and diagnostic targets.The original contributions presented in the study are included in the article/supplementary materials, further inquiries can be directed to the corresponding author/s.AG, NO'M, DG, and SG: conception and design of the study. AG, NO'M, NK, DG, and SG: agreement to be accountable for all aspects of the work, final approval of the version to be submitted, critical revision of the manuscript for important intellectual content, drafting of the manuscript, analysis, and interpretation of the data. All authors contributed to the article and approved the submitted version.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.


Physical functioning is essential for independent living and aging in place among older adults. Although older adults show a general trend of increasing functional disability, it was unclear how cancer diagnosis, which also has an increased incidence rate among older adults, may potentially aggravate the progress of functional decline at the within- and between-person levels. Using 3 waves of the China Health and Retirement Longitudinal Study , the current study examined the trajectory of functional disability and associated factors over 5 years among older adults with (n = 139) and without cancer (n = 212), who were matched on key demographic characteristics. We considered four contributing factors to disability as specified in the Disablement Process model as covariates, in the context of cancer diagnosis timing at both the within- and between-person levels. These factors were psychological , physical limitations , cognitive impairment , and environmental constraints . Consistent with the literature, there was a general trend of increasing functional disability among all participants over time. At the within-person level, although cancer diagnosis timing was associated with higher levels of functional difficulty, we found a slower increasing rate over time. At the between-person level, functional disability trajectory was not associated with cancer diagnosis timing. These findings suggest that maintenance of physical functioning should be considered at the within-person level, and personalized care is recommended for Chinese older adults with cancer.


Among antioxidants in the human body, bilirubin has been recognized over the past 20 years to afford protection against different chronic conditions, including inflammation and cardiovascular disease. Moderate increases in plasma concentration and cellular bilirubin generation from metabolism of heme via heme oxygenase (HMOX) in virtually all tissues can modulate endothelial and vascular function and exert antioxidant and anti-inflammatory roles. This review aims to provide an up-to-date and critical overview of the molecular mechanisms by which bilirubin derived from plasma or from HMOX1 activation in vascular cells affects endothelial function. Understanding the molecular actions of bilirubin may critically improve the management not only of key cardiovascular diseases, but also provide insights into a broad spectrum of pathologies driven by endothelial dysfunction. In this context, therapeutic interventions aimed at mildly increasing serum bilirubin as well as bilirubin generated endogenously by endothelial HMOX1 should be considered. Bilirubin is widely known as an end-product of the degradation of heme which occurs in the spleen primarily as part of red blood cell removal. Senescent or damaged red blood cells are degraded and the heme groups derived from hemoglobin are converted into biliverdin by the activity of heme oxygenases (HMOX1 and HMOX2) , and thein vitro even at relatively low concentrations, e.g., 0.5 μM UCB is toxic to primary cells and acts to enhance glutamate-induced toxicity  increases and can cause toxicity in the nervous system in particular, a serious condition known as bilirubin encephalopathy which has been the focus of excellent reviews . It is itoxicity . Moreovetoxicity .Nonetheless, different beneficial aspects linked to mild elevations of plasma bilirubin (up to 12 mg/dl) have been recognized. The anti-inflammatory effect of jaundice was already observed by 2+) and CO  is the first, rate-limiting enzyme in heme degradation pathway, with two major isoforms of HMOX identified. HMOX1 is inducible, expressed only under oxidative stress or when heme concentration increases; HMOX2 is constitutively present mainly in testis and neuronal cells  but has ) and CO . The act) and CO . CO has ) and CO , both in) and CO  of blood) and CO . The gen) and CO . This adfunction . Finallyfunction . Moreovefunction . Indeed,function , e.g., ifunction . Notablyfunction .de novo synthesis of heme occurs with the specific purpose of bilirubin generation in order to provide cytoprotection  of UCB . In addiex vivo platelets, opening the possibility of screening the actions of acute BRT treatment to improve platelets storage and function  has been widely documented and ascribed to its antioxidant properties . Thus, afunction .in vitro or HMOX1 overexpression via gene transfer in VSMC  have been reported to preserve flow-mediated vasodilation compared to subjects with low levels of plasma bilirubin (0.40 ± 0.08 mg/dl) . As receFurthermore, HMOX1 derived UCB protects endothelial cells against nitrosative stress, induced by hemin pre-treatment, which is able to further increase HMOX1 dependent bilirubin generation to reduce endothelial apoptosis induced by peroxynitrite . Indeed,Moreover, the increased availability of NO due to UCB, positively affects the rate of glomerular filtration improving renal hemodynamics . HoweverThe role played by UCB in preventing endothelial dysfunction in chronic sequaele of diabetes has been widely demonstrated . Indeed,Furthermore, in diabetic rats, up-regulation of HMOX1 increases serum bilirubin, reduces superoxide anion and endothelial sloughing induced by hyperglycemia . MoreoveBilirubin has been shown to be protective against the development of ischemic damage associated with ischemic/reperfusion injury and endothelial activation . A recenex vivo heart perfusion with BRT improves post-ischemic outcomes by reducing oxidative damage (in vivo or ex vivo evaluate whole tissue without considering the specific role played by endothelial cells, it is conceivable that bilirubin supplementation can directly protect the endothelium. It is important to note that UCB induces HMOX1 up-regulation in aortic endothelial cells, generating a positive loop that increases endothelial resistance to oxidative stress (In different models of cardiac ischemia/reperfusion damage, bilirubin administration protects against tissue damage. Indeed, e damage . Moreovee damage . More ree damage . Furthere damage . Furthere damage . Even the stress . The speMoreover, protection afforded by bilirubin against rejection of kidney transplantation has been demonstrated, and its antioxidant activity in preventing ischemia/reperfusion damage as well as its anti-inflammatory action that favors organ acceptance has been reviewed, highlighting the positive impact on renal hemodynamics .The first evidence for the anti-inflammatory properties of bilirubin stems from Philip Hench who in 1938 described the remission of rheumatoid arthritis in the 94% of patients who developed jaundice . Even thThe ability of UCB to modulate immunoglobulin production, native or acquired immunity as well as complement activity has been reviewed by others , highligEndothelial dysfunction and inflammation characterize the development and progression of obesity, and mild hyperbilirubinemia contributes to a reduction of obesity especially during aging. These findings were particularly significant when abdominal obesity, triglyceridemia and hip and waist circumference were considered . The samFurthermore, a positive effect of CoPPIX-induced HMOX1 activation on reduction of body weight has been reported by Endothelial activation and recruitment of inflammatory cells are two pivotal steps in the development of atherosclerotic lesions . The negIn vitro studies demonstrated that UCB prevents TNFα-induced leukocyte adhesion to endothelial cells by reducing the expression of E-selectin, VCAM and ICAM (–/– mice prevents atherosclerotic plaque formation by inhibiting leukocyte infiltration in vessel wall. These authors also confirmed in vitro that both exogenous bilirubin and HMOX1 derived bilirubin are highly efficient in reducing VCAM and ICAM dependent signals by quenching NOX4- and XO-derived ROS.UCB has been shown to impair leukocyte migration by affecting endothelial adhesion molecules. The activation of endothelial cells induced by pro-inflammatory cytokines such as TNFα leads to the expression of adhesion molecules . In vitrand ICAM  by impaiand ICAM . Howeverand ICAM , 2002. VIt has clearly been shown that UCB mimics the hypolipidemic activity of fenofibrate . In addiAs recently reviewed, bilirubin prevent platelets aggregation due its ability to interfere with the surface expression of adhesion molecules and its antioxidant activity, thereby supporting a role played in the prevention of hypercoagulability and thrombosis . Even thAs mentioned before, the beneficial role of UCB in autoimmune and chronic inflammatory diseases is widely accepted. Indeed, there is clinical evidence that higher total serum bilirubin levels reduce the risk of rheumatoid arthritis , GilbertFocusing on the role played by endothelial cells in the context of chronic inflammation, it has been shown that bilirubin impairs the expression and the activity of adhesion molecules as documented in animal models of airways inflammation and inflammatory colitis. Indeed, intraperitoneal administration of bilirubin blocks the influx of leukocytes into the lungs of mice with OVA-induced asthma , and bilPro-angiogenetic activity of bilirubin has been demonstrated and related both to vascular activation of HMOX1 and to an increased plasma concentration of UCB. Favorable or detrimental actions can be associated with increased angiogenesis, depending on the different pathological conditions involved. Indeed, pro-angiogenetic activity can be desirable in repairing tissue damage or in preventing placental dysfunction  but becoIn vivo and in vitro studies have shown that exogenous bilirubin promotes angiogenesis in response to ischemia via direct modulation of the PI3K/AKT pathway, which favors eNOS activation (At a molecular level, pro-angiogenetic activity of bilirubin is achieved by the modulation of different pathways, some of which are not directly related to its antioxidant activity. tivation . The acttivation .Furthermore, vascular HMOX1 induction favors the production of angiogenic factors, such as VEGF and IL-8, and decreases antiangiogenic factors such as VEGF soluble receptor , with alFurthermore, constitutive HMOX2 has been proposed to play an important role in angiogenesis. In HMOX2 null mice, an increase in corneal angiogenesis has been observed, which is paralleled by a down-regulation of HMOX1 . Howeverin vitro and in vivo, avoiding the potential toxic effects due to iron overload (The process of wound healing is strictly dependent on tightly regulated angiogenesis. The role played by both HMOX1  and HMOXoverload . In thisoverload . The invoverload . Furtheroverload , 2016. Ooverload .The involvement of HMOX1 in placental development and pathology has been reviewed by In general, bilirubin is associated with anti-proliferative and anti-neoplastic activity. In fact, specific polymorphisms in UGT1A1 gene and the consequent hyperbilirubinemia are correlated positively with an increased overall survival in cancer patients , particuAt molecular level, an antigenotoxic activity of bilirubin has been hypothesized and a negative correlation between bilirubin concentration and DNA damage in epithelial cells has been documented  even thoThus, bilirubin not unlike other antioxidants, can counteract cancer onset and development by preventing DNA damage and the oxidative stress which plays a central role in carcinogenesis .in vitro experiments showing that bilirubin concentrations >25μM exert pro-apoptotic activity whereas concentrations <25μM have no effect on cell viability or proliferation.Moreover, the anti-cancer proprieties of bilirubin have been documented, with bilirubin administration i.p. in mice increasing plasma bilirubin up to 40μM and drastically reducing colon cancer growth via activation of ERK1/2 . These fin loco generation of bilirubin.Nonetheless, it is important to note that once a tumor mass has developed, cancer cells can take advantage of antioxidants, especially when they derived from the activation of intrinsic adaptive pathways, and can be used for their growth and survival, favoring resistance to therapies and disease progression . This haMoreover, the involvement of HMOX1 in physiological angiogenesis in pregnancy and pathological angiogenesis in cancer has been proposed, since both share a necessity for a permissive microenvironment in which cell invasion, cytoprotection, angiogenesis and immune-escape are favored . HoweverDifferent therapeutic approaches aimed at elevating plasma bilirubin concentration as well as modulating cellular HMOX1 activity have been proposed for the treatment of many disorders, as widely reviewed by others . Here, win vitro preconditioning of cells significantly suppresses the immune response and favors tolerance improving the outcomes (Elevating bilirubin plasma concentration needs to be considered carefully due to bilirubin’s well-known toxic effects. As discussed, bilirubin supplementation significantly decreases infarct size in animal models of ischemia damage  as does outcomes . Furtheroutcomes  and to routcomes . Notablyoutcomes .In humans, elevated plasma bilirubin levels, as side effects of drugs such as HIV PIs, have been proposed to improve endothelial function. For instance, 3-day atazanavir treatment in type II diabetes patients significantly ameliorates endothelial dysfunction . Notablyin vivo and in vitro (Importantly, therapeutic approaches leading to induce iatrogenic GS and to improve bioavailability of bilirubin might represent a valid strategy to prevent and ameliorate oxidative stress-related diseases, and in vitro .Spirulina platensis, exert in vitro and in vivo actions including antiproliferative effects in cancer cells (Furthermore, bilirubin analogs or related compounds can exert anti-proliferative effects as discussed earlier. In this context it is important to note that administration of natural tetrapyrrolic compounds structurally related to bilirubin, such as molecules extracted from er cells . In addier cells .in vitro and in animals to activate HMOX1, the use of the heme analogs such as heme arginate or hematin remains potentially toxic at the vascular level (The role of HMOX1 activity in protection of endothelial cells against oxidative stress has been already highlighted  as has tar level . Howeverar level , statinsar level  and fenoar level  have beear level .in vitro and improve recovery from ischemia/reperfusion injury in vivo (Finally, to achieve a more efficient up-regulation of HMOX1 and to avoid its pathological overexpression a molecular approach has been proposed: the use a hypoxia-regulated plasmid coding for HMOX1 to enhance vascular cell resistance  in vivo .As far as tumor therapy is concerned, it has been reported that chlorophyll is able to inhibit HMOX1 expression and activity, exerting antiproliferative and antioxidative effects toward pancreatic cancer and inducing a significant reduction of pancreatic tumor size . HoweverBilirubin, far from being just a waste product highly toxic for neurons, has been recognized as a powerful antioxidant and anti-inflammatory molecule. The potential application of bilirubin for the treatment of human diseases is driven by its ability to prevent endothelial dysfunction, thus affecting not only the treatment and prevention of CVDs , but alsAs both increasing plasma levels of bilirubin and up-regulating HMOX1 could lead to toxic effects, the discovery of new strategies to reduce its toxic potential to maintain therapeutic effectiveness will be key for the treatment/prevention of endothelial dysfunction. Finally, it is worth noting that senescence and aging processes, strongly associated with accumulation of oxidative damage, are reduced/slowed by bilirubin. Notably, has been recently highlighted the negative relationship among bilirubin concentration and cancer mortality, even though the relationship is missing among bilirubin and CVD mortality . It is cin vitro and in aged mice via the generation of both CO and bilirubin (Nonetheless, it has been proved that in Gilbert subjects and in Gunn rats both mitochondrial and cytosolic ROS production is reduced leading to a decrease of chronic inflammation markers and better anthropometric parameters . Furtherilirubin . Thus, tAll authors conceived and wrote the manuscript, and revised the literature. MN and GM provided financial support.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.