Even though there are several synthetic or natural occurring species of zeolites, the most widespread and studied is the naturally occurring zeolite clinoptilolite (ZC). ZC is an excellent detoxifying, antioxidant and anti-inflammatory agent. As a result, it is been used in many industrial applications ranging from environmental remediation to oral applications/supplementation in vivo in humans as food supplements or medical devices. Moreover, the modification as micronization of ZC (M-ZC) or tribomechanically activated zeolite clinoptilolite (TMAZ) or furthermore as double tribomechanically activated zeolite clinoptilolite (PMA-ZC) allows improving its benefits in preclinical and clinical models. Despite its extensive use, many underlying action mechanisms of ZC in its natural or modified forms are still unclear, especially in humans. The main aim of this review is to shed light on the geochemical aspects and therapeutic potentials of ZC with a vision of endorsing further preclinical and clinical research on zeolites, in specific on the ZC and its modified forms as a potential agent for promoting human brain health and overall well-being.Zeolites are porous minerals with high absorbency and ion-exchange capacity. Their molecular structure is a dense network of AlO The teren atoms . Clinopten atoms . Thanks en atoms . At presen atoms . The oraen atoms . Preclinen atoms . This coen atoms .In order to gain a better understanding of natural zeolite minerals and their therapeutic action and some side effects, it is essential to study their geological origin, chemical composition, and structure. This review will focus on exploring the geo-chemical aspects of naturally occurring zeolite clinoptilolite (ZC) without any modification—referred to either as ZC or “natural zeolite” or “zeolite” in this article. Furthermore, the focus will be on the modified forms of ZC  by highlighting its therapeutic aspects and with the aim of promoting further research on ZC for overall human well-being and as a potential preventive agent in Alzheimer disease and other neurological disorders.4 and SiO4 joined by shared oxygen atoms [The geological formation of natural zeolite indifference to synthetic zeolite involves different rock species, in particular, physio-chemical conditions of temperature and pressure. These rock species could vary from volcanic to plutonic rocks ,10. Beloen atoms   or two times (PMA) with PMA technology (PMA-ZC) showed some preclinical and clinical evidences ,5,44,45.In this section, the characteristics of different modified ZCs and their therapeutic applications will be discussed.The micronization of zeolite clinoptilolite (M-ZC) is a procedure that breaks down the ZC into small parts accentuating its detoxifying characteristics . This miMost of the clinical positive effects of ZC and modified ZC have been attributed to its reversible ion exchange and adsorption capacity. The first detoxifying effects of ZC in a modified form were observed in murine models. In lead poisoned mice, the modified ZC reduced the accumulation of lead in the intestine by more than 70% with a protective effect on the brain tissue . In ratsDifferent hypotheses and recently published reports have explained the anti-inflammatory effects of ZC, some of these reports highlighting the relationship between PMA-ZC and the site of action at the intestinal level. The mucosa-associated lymphoid tissue (MALT) and the gut-associated lymphoid tissue (GALT) are the sites where the main intestinal cell-mediated inflammatory responses are modulated . These tThe enzymatic systems that regulate the homeostasis of the redox system in the body are the superoxide dismutase (SOD), catalase, peroxiredoxin, thioredoxin and glutathione (GSH) enzymes . An exceGiven the existence of the gut-brain interconnection, it has been hypothesized that an indirect action of ZC exists at the level of the central nervous system. In this regard, some recent hypotheses are discussed below.In the pharmacological field, there are so many treatments which have beneficial effects but their underlying molecular mechanisms are still unknown . The samAlzheimer disease (AD) is a progressive neurodegenerative disorder and the most prevalent form of dementia affecting millions of people worldwide with no potential cure or treatment in sight . As all The physical–chemical properties of ZC are essential for the absorbing characteristics or ion-exchange, and therefore, for its therapeutic potential. Indeed, the rock mixtures that constitute the natural mineral form complexes of aluminum and silicon which allow the formation of cavities inside where inorganic and organic polar or metal ions are deposited or exchanged. This exceptional ion-exchange capacity, as well as the surface area, are improved with micronization processes, in particular with the tribomechanical micronization processes used for TMAZ or PMA-ZC. In particular, thanks to PMA technology, ZC is activated and its absorbing capacities increase. ZC, in general, is known as an environmental decontaminant and specific TMAZ and PMA-ZC have found multiple applications in the last 20 years. The most important is its oral use for supplementation in humans. Environment decontamination from heavy metals derived from industrial waste or from organic molecules derived from intensive farming is essential for biological ecosystems. Due to the binding capacities, ZC has been generally used in the zootechnical field for water purification and decontamination, contributing to the improvement of livestock health. Furthermore, environmental contaminants accumulate throughout the food chain and are therefore part of foodstuff. For this reason, PMA-ZC is studied and used for oral supplementation to bind toxic substances such as ammonia or heavy metals in the milieu of the gastro-intestinal tract. Furthermore, PMA-ZC is capable of improving the ecosystem of intestinal microbial flora. Based on the data collected on animal models and on a few clinical trials, it can be speculated that the general state of wellbeing generated by ZC, and in particular by TMAZ and PMA-ZC, is due to its detoxifying, anti-inflammatory and antioxidant action in the intestine. Indeed, recent findings of the importance of the gut microbiome in the regulation of immunity and its interconnection with the central nervous system could at least partially explain the results obtained using animal models treated with PMA-ZC. ZC could purify the internal environment of our body, maintain gut microbiota homeostasis for healthy brain activity, improve the antioxidant and endogenous anti-inflammatory activities thereby improving the overall wellbeing of the patient. Despite all this, still, only a few studies have defined the molecular mechanisms underlying the positive effects of all ZC. Furthermore, several important questions are still unanswered: What is the molecular mechanism that increases the antioxidant activity of SOD and GSH in experimental models treated with ZC? What is the translational value of the action of ZC on β-amyloid levels? Is there risk of reducing the contribution of mineral salts due to the ion exchange action of ZC? Finally, is there remote danger of ZC crossing the intestinal wall?In conclusion, preclinical research on zeolites was not aimed at finding a new drug, but a food supplement that can improve lifestyle and be combined with traditional pharmacological treatment. In fact, recent evidenced suggested a promising detoxifying role of ZC in the removal of toxic metabolites produced by drugs chronically administered during chemotherapy, diabetes, or cardiovascular diseases. However, new and extensive research will be needed to explore all the potential benefits that ZC and other specific modified ZC can produce on human health.


Colorectal cancer (CRC), a multi-step malignancy showing increasing incidence in today’s societies, represents an important worldwide health issue. Exogenous factors, such as lifestyle, diet, nutrition, environment and microbiota, contribute to CRC pathogenesis, also influencing non neoplastic cells, including immune cells. Several immune dysfunctions were described in CRC patients at different disease stages. Many studies underline the role of microbiota, obesity-related inflammation, diet and host reactive cells, including dendritic cells (DC), in CRC pathogenesis. Here, we focused on DC, the main cells linking innate and adaptive anti-cancer immunity. Variations in the number and phenotype of circulating and tumor-infiltrating DC have been found in CRC patients and correlated with disease stages and progression. A critical review of DC-based clinical studies and of recent advances in cancer immunotherapy leads to consider new strategies for combining DC vaccination strategies with check-point inhibitors, thus opening perspectives for a more effective management of this neoplastic disease. Colorectal cancer (CRC) is one of the major leading cause of cancer-associated mortality worldwide, thus representing an important public health issue, with a great impact in terms of human suffering and costs for the clinical management of patients . The ratThe pathogenesis of CRC exhibits a great level of complexity, being characterized by several multi-step disease events, associated with the accumulation of both genetic and epigenetic alterations of the genome. In fact, the development of CRC is a long process taking several years to progress from barely detectable small neoplastic foci to adenomas and subsequently to malignant carcinomas endowed with metastatic behavior .CRC is characterized by a high heterogeneity given the remarkable genomic instability . MoreoveHost immune dysfunctions are important factors contributing to CRC development. Indeed, a significant impairment of the host anti-tumor immunity has been reported during initiation of CRC mostly relying on escape mechanisms adopted by transformed cells to create a favorable growth environment ,8,9. DurToday, an ensemble of data support the statement that inflammation plays an important role in CRC pathogenesis and progression . The lowInformation stemming from both mouse models and studies in patients points to a key role of immune cells and soluble factors with immunosuppressive activity in the CRC disease process . Among t+ T cells and clinical outcome [The clinical management of CRC is firstly based on surgical resection, but the optimal treatments in patients with advanced metastatic disease is still matter of debate. Different protocols of chemotherapy and immunotherapy, including combination therapies, have been used in metastatic patients with variable success . Of note outcome , thus su outcome . However outcome ,18, pati outcome ,21. This outcome . In thishttps://www.wcrf.org continuous-update-project 2017). Obese subjects have a 1.5–3.5-fold increased risk of developing CRC compared with lean individuals, and epidemiologic evidence indicates that abdominal rather than overall obesity may be more predictive of CRC risk [Excess adiposity is associated with increased incidence of several cancers and represents an important indicator of survival, prognosis, recurrence and response to therapy in CRC. Notably, patterns and trends in CRC incidence and mortality correlate with geographical location, societal and economic changes and their increase may reflect the obesity epidemic and the adoption of more Western lifestyles. Both genetic and a range of environmental, largely modifiable, lifestyle factors play an important role in CRC etiology. Among these, the links between body weight, dietary patterns and CRC risk are some of the strongest for any type of cancer with profound implications for prevention strategies. It is now well-recognized that CRC risk is highly modifiable through lifestyle, particularly diet and physical activity; recent reports suggest that up to 47% of CRC cases could be prevented by staying physically active, maintaining a healthy body weight and eating a healthy diet . Nevertheless, the exact microbial signature of a healthy or an obese gut microbiota is still matter of debate. Dysbiosis is associated with a large array of diseases including cancer, where it is implicated in different ways . In addil tumors  and hepal tumors . Interesl tumors . In addil tumors ,42.In the following chapters, we provide a brief overview of the role of DC in the regulation of inflammatory and immune responses, of their functional changes in CRC patients and of their exploitation in immunotherapy protocols against CRC.+ and CD8+ T lymphocytes.DC represent a heterogeneous group of innate immune cells endowed with the unique capacity to initiate and coordinate the immune response. They are professional antigen presenting cells (APC) and comprise a variety of subsets, of both myeloid and lymphoid origin, as either resident or migrating cells, in lymphoid and non-lymphoid organs. They are able to recognize, capture and process antigens and to present them to naïve T lymphocytes. DC are nowadays recognized as a family comprising several subtypes that differ in ontogeny, gene expression profile, anatomical location, phenotypic and functional features . In thisIt is currently thought that DC play an important role in presenting tumor antigens to T cells and in shaping an antitumor immune response, which may result in an effective control of tumor growth ,44. Howe+/CD141+DC is the same in lean with respect to obese subjects, the number of CD11c+/CD1c+ cells positively correlates with the body mass index (BMI). This accumulation parallels an enhanced presence of Th17 lymphocytes in AT, suggesting a role of DC infiltrating AT in the regulation of tissue inflammation and Th17 cell expansion [+ DC in the AT of lean mice can be important for the local expansion of T regulatory cells providing anti-inflammatory signals to maintain AT homeostasis [Dietary habits and excessive adiposity can not only influence cancer growth but also shape host immune response . Myeloidxpansion . Of noteeostasis . Intereseostasis . Furthereostasis .+ mature DC was lower in the tumor stroma of patients in an advanced disease stage. In general, we can state that negative correlations between the detection of these tumor infiltrating DC and the number of lymph node metastases as well as the survival time of CRC patients were frequently documented [Several groups have described qualitative as well as quantitative changes of DC in the blood as well as in the tumor microenvironment of CRC patients at different stages of disease and their possible correlation with the clinical response of patients . The intcumented ,50,51. Ncumented . Of intecumented ,54. Of ncumented  reportedcumented ,21. Somecumented ,57,58,59A useful in vitro model to investigate the biology of DC and the mediators and mechanisms important in shaping their functions is represented by MoDC, generated from monocytes by in vitro treatments with GM-CSF and various cytokines, such as IL-4, IFN and other activation/maturation factors. Thus, some published studies where the phenotype and functions of MoDC from CRC patients were compared to those detectable in control subjects are available ,60,61,62Since the early study by William Coley in cancer patients treated with killed bacterial vaccine in 1891, for more than 120 years, the history of cancer immunotherapy has been characterized by alternate cycles of optimism and discouragement. The clinical use of certain cytokines , the subsequent identification of the first set of human tumor antigens, the progress on cancer vaccines and in the development of protocols based on adoptive cell therapy have all represented important milestones in the field of cancer immunotherapy. However, it is only in recent years that we have registered a fundamental progress, which today leads to consider cancer immunotherapy as the latest revolution in cancer therapy. This is mainly due to the impressive results achieved in patients with different type of malignancies after treatment with CPI . With reIn view of their crucial role in linking innate and adaptive antitumor immunity, DC have extensively been used in cancer immunotherapy clinical trials over the last two decades ,65. NotaIn considering new and potentially more effective DC types to be used in cancer immunotherapy protocols, we may consider to use DC generated by monocytes by a short-term in vitro exposure to IFN-α and GM-CSF . In factOne of the major reason for the limited response of CRC to the immunotherapy is thought to be represented by the immunosuppressive tumor microenvironment which generally occurs in patients with advanced disease. As a matter of fact, the major challenge for developing an effective protocol of cancer immunotherapy is indeed to counteract the several and complex immunosuppressive mechanisms activated in the tumor microenvironment of cancer patients. The role of several cancer-induced immunosuppressive mediators in CRC prognosis and treatment response has been reviewed elsewhere ,10,11. T+ and CD4+ T-cell-mediated responses against the colon tumor antigen-1 in CRC patients at different stages of the disease [Today, in the new era of CPI, major research challenges are to fully understand the mechanisms of the response and how to increase the clinical efficacy in poorly responding patients by designing more sounded combination therapies, which may also include DC. Of interest, a recent study showed that an effective antitumor response to anti-PD1 mAbs strictly requires the occurrence of intratumoral DC . Likewis disease . Thus, o disease ,72,89,90 disease ,72, or aCRC represents one of the human malignancies where promotion of prevention strategies can play a major role in reducing cancer development and tumor burden and progression. In fact, primary prevention, based on special attention to reduce exposure to environmental and lifestyle risk factors  is indeed of great importance for reducing CRC incidence, with enormous impact in terms of public health and reduction of costs for the national health services. In addition, in view of the long and multi-step processes involved in CRC development, strategies of secondary prevention, including the promotion of the use of early diagnostic platforms, can be very important for prevention and control of CRC. In spite of all this, the optimal therapeutic management of patients with metastatic CRC remains an important issue in clinical oncology. While surgery and chemo-radiotherapy interventions continue to represent essential therapeutic options depending on the stage of the disease and the clinical settings, immunotherapy has recently emerged as a powerful tool for tertiary immune prevention.Recently, we have learned new rationales and modalities for combining different immunotherapy regimens with both conventional and target therapies. Likewise, we have recently started to understand the importance of sex- and gender-specific differences in several pathologies including cancer. In fact, gender disparities have been reported in different aspects that can collectively influence CRC pathogenesis and therapy . Thus, CHow to reverse DC dysfunctions occurring at different disease stages and in various tissues in CRC patients still remains a complex issue deserving further research efforts. In principle, intervention strategies for restoring DC functions in the very early stages of the disease could also be considered, but we need to reach a better knowledge of the role of this highly heterogeneous cell population in the pathogenesis and progression of CRC. The recent advances on the cross-talk between gut microbiota and human health and on the potential of lifestyle, food components and/or dietary patterns to modulate this functional interplay has opened new perspectives for diet-based interventions in the modulation of the antitumor immune response .With regard to the still critical issue of implementing the management of advanced metastatic CRC, a great importance is currently given to combination therapies, since we now have a much better knowledge on how different therapeutic tools and strategies should be associated. With the advent of next-generation sequencing methodologies, we have now the unprecedented ability to identify tumor, host, and microbial genomes. The growing application of these novel technologies to finely characterize patient’s tumor and driver mutations as well as the immune repertoire for evaluating genetic responses to current immunotherapies has opened new ways to maximize patient benefits through cancer precision medicine strategies. We conclude by stating that, taking into account some recent findings ,87,88, n


Ruminant meat flavor is an important quality and sensory parameter which relays mainly on the organoleptic characteristics of meat. Meat flavor is vital factor for the palatability and acceptability of meat by the consumers. There are various intrinsic and extrinsic factors that influence eating quality of meat. Among these factors, flavor is the major contributor. Fat and low-molecular-weight water-soluble compounds are the most important precursor components in meat, responsible for the meat flavor. The present review focus on the different pre and post-harvest factors that influences the ruminant meat flavor. Raw meat has little flavor but cooking adds value in flavor due to different temperature and cooking methods. The volatile flavoring compounds which are responsible for cooked meat flavor are produced thermally by the Maillard’s reaction itself or interaction with lipid oxidation products and vitamin degradation. In nutshell, this review provides perception into previous literature on flavor that affected by various factors particularly the fatty acids and cooking methods. Flavor is a very important sensory characteristic of the overall acceptability of ruminant meat products. Volatile flavor compounds have a strong impact on the sensory properties of ruminant meat. Intramuscular fat (IMF) in meat depends on various factors and impacts meat quality and flavor. There is a higher proportion of IMF in ruminants that are fed on grains, and their meat is more tender in comparison with meat from ruminants fed on grass –4. The rMeat flavor produced by the thermal reaction of non-volatile compounds to produce volatiles which are the major characteristics of flavor . The lipThe Maillard reaction is important for formation of meat flavor. This reaction helps to explain carbonyl and amine reactions. Normally, meat cooked at a high temperature shows browning because when a free amino acid links with a carbonyl group forming glycosylamine, and when the latter is dehydrated and rearranged, it produces furanone derivatives, furfural, dicarbonyl compounds, and hydroxyketones . These cIn the Maillard reaction, the first step is the dehydration reaction or removal of water. A dry atmosphere is needed to support the first reaction. Strecker degradation of amino acids is linked with the Maillard reaction by a dicarbonyl compound that is produced by the Maillard reaction . AldehydThe flavor of prepared foods is humanity’s greatest universal behavior, experienced by individuals of all ages in the course of daily life. Also, the flavor perception is one of complex behavior in human that involves nearly all senses especially sense of smell which engage odorous compounds generated in the olfactory pathway. It also engages the complex facial, swallowing and respiratory motor systems   and disgust (bitter), which are not learned; they are hard-wired in the brainstem from birth Similarly, in human brain, the perceptual systems are closely linked to systems for learning, memory, emotion and language, so distributed neural mechanisms contribute to food preference   meat in cattle. PSS occurred due to a number of exogenous and endogenous factors that affects the post-mortem biochemical changes that may cause the conversion of muscle into meat. The PSS in cattle may cause the formation of DFD meat due to lessening the muscle glycogen reserves and lactic acid accumulation that alters the normal process for acidification of meat during post-mortem and affects the meat quality like tenderness, juiciness and flavor , 52. TheThe most important factors affecting meat preference is the flavor of meat. Flavor involves two sensations: taste and aroma. The perception of flavor is often more about texture than flavor molecules. Texture changes as a result of protein coagulation, fat melting, collagen turning into gelatin, when moisture is driven off from the surface, and when starches turn stiff and crunchy . These aFat is the major contributor to the flavor development in meat. There is variation among species in flavor development. Different flavors of breeds result from the fatty components. Fatty tissues give the meat specific flavor attributes. Fat is one of originators of flavor due to different kinds of fatty acids. As the fat melts, it produces flavors . It is gPolyphenols or vitamin E supplements that are consumed by grain-fed animals act as antioxidants during the finishing period. Lipids play an important role in flavor development. Shahidi  reportedPalatability, including flavor, is affected by fat content. Most United States consumers prefer increased IMF as well as fat flavor. For the United States consumer, the lowest acceptable level of IMF is approximately 3% in beef . There iVia the partial biohydrogenation of conjugated fatty acids, CLAs are formed in the rumen, because in the meat of ruminant animals, they are found at high concentrations, e.g., in sheep. The chief features affecting biohydrogenation are the concentrate ratio, the forage, ruminal pH, and the kind and level of fatty-acid intake. For instance, linoleic and linolenic acids significantly contribute to low ruminal pH. Increasing CLA cis-9, trans-11 content in meat and meat products is a strategy to enhance C18:1 trans-11 uptake in the duodenum. Miller  reportedThe marbling and the types of muscles and muscle fibers affect the meat quality and alternatively affect the flavor of meat. There are four types of muscle fiber present in the skeletal muscle of adult animals, which include fast oxido-glycolytic or type II A, slow-oxidative or type I, fast glycolytic IIB, and IIX. Fibers of these types are present commonly in meat muscles, and their proportions can determine most of the muscle’s metabolic properties in different muscles. Therefore, postmortem metabolism of muscle is an important parameter to analyze; quality of fresh meat may or may not be affected by cross-sectional area of muscle fibers, and depends on the total fiber number and proportions of fiber types. The characteristics of muscle fiber are affected by different factors including hormones, muscle location, breed, gender, growth performance selection, and diet , 66.In addition, in many countries, the meat industry showed interest in promotion of different types of muscles. Nonetheless, the quality characteristics and factors of individual muscles are mostly unknown. Skeletal muscles contain different types of fiber, which are influenced by various factors including muscle type, breed, hormones, and age. Meat quality is affected by characteristics of muscle fiber including marbling, water-holding capacity, texture of meat, and color. Generally, marbling strongly affects meat quality. Mainly, marbling is a significant feature in the meat industry, whereby consumers judge the quality of meat, and may also affect the flavor. The effects of muscle fiber characteristics on meat quality are studied broadly in ruminants, although there are some reports regarding poultry and swine .Muscle fiber  characteristics affect marbling and flavor in meat. The rate of Mb oxidation and Mb content are unique for each muscle type; manufactures maintain the fraction of red muscle fibers high, which results in an increase in Mb content and redness of meat. As the ratio of Type I fiber increases, the stability of color decreases, resulting in shifting of the meet muscle fiber color to brownish. In young bull muscle, the fast-twitch glycolytic (IIB) fiber content correlates with lower water-holding capacity and higher lightness. Hypertrophy of fast-twitch oxido-glycolytic fibers (IIA) is significantly disadvantageous for the water-holding capacity. Size of the fiber bundle and muscle growth potential are affected by the size of muscle fibers; big size results in noticeable coarseness of cross-sections of meat .Connective tissues and their proportion together with IMF also affect the characteristics of muscle fiber . In porcFTC of muscle is linked to glycolysis, the pH decline rate, and protein metabolism (proteolytic degradation). Highly glycolytic fibers are fast-twitch IIB fibers, and their metabolism results in high-speed metabolism in the early protein-metabolic period. Rapid glycolysis is enhanced in muscles if they contain fast-twitch glycolytic fibers as a major component, and this situation results in a rapid decline of pH in muscles. Therefore, the proportion of type IIB fiber positively correlates with the R-value and negatively correlates with muscle pH (adenine/inosine ratio); this phenomenon allows for evaluation of ATP reduction during the early postmortem period. Nevertheless, an increase in the ratio of fibers of type I in muscle reduces the extent and rate of decline of postmortem pH. FTCs are the cause of variation in postmortem muscle properties, hence affecting meat tenderness. In addition, fast fibers of type II are more vulnerable as compared to type I slow fibers in the case of early postmortem proteolytic degradation. Some researchers stated, however, that tenderness increases with the increasing ratio of fiber of type I, while it decreases with the increasing ratio of type IIB fibers in the muscles of cattle , 70.The effects of muscle fiber characteristics on postmortem aging have also been suggested as a chief determinant of meat quality. Fast-twitch glycolytic fiber positively correlates with postmortem aging in cattle and with tenderness. In slow-twitch oxidative muscles, the rate of aging is slower as compared to fast-twitch muscles. The ratio calpain/calpastatin is lower in slow-switch oxidative muscles than in fast-twitch glycolytic muscles. To some extent, these phenomena could explain the faster rate of aging in glycolytic muscles. Fast-twitch fibers are believed to have a more widely developed transverse tubule system, sarcoplasmic reticulum, and slim Z-band in comparison with slow-twitch fibers. The protein responsible for the Z-band in fast twitching fibers is more prone to early postmortem protein degradation as compared to slow twitch fibers. IMF content strongly affects the juiciness and flavor of meat, which is positively related to the proportion of type I fibers in muscles. Phospholipids are the chief determinant of cooked-meat flavor, and the level of type I fiber is linked with it. Meat juiciness also positively correlates with type I fibers, even though one study has clarified the notion that more IMF is present in red oxidative muscles as compared to white glycolytic muscles .There are many cooking methods that have an impact on meat flavor. There are many volatile compounds produced during cooking.The high-heat treatment involves production of volatile flavoring compounds due to the Maillard reaction . The effWarm-off flavor means undesirable flavors that result from flavor changes and deterioration in reheated, precooked, or chilled-stored meat. There are different kinds of tastes and odors of warm-off flavors such as rancid, bitter, stale, cardboardlike, painty, and liverlike off-flavor. These flavors are the main factors that affect the sensory and eating quality of meat. Oxidation of membrane phospholipids is the major cause of warm-off flavor found in cooked meat. Byrne et al. , reporteThere are many dry-heat cooking methods that affect the flavor of meat. In broiling and grilling, the cooking time is very crucial during preparation of products like streaks; kababs are cooked at higher temperatures. Studies show that during roasting, many of the flavoring compounds are lost as compared to boiling, which preserves many flavoring compounds such as heterocyclic compounds, e.g., pyrazines, thiazoles, and oxazoles . Frying During prolonged exposure to smoke, the meat surface will acquire a smoky flavor. The strength of the flavor depends upon the time and density of the smoke [Moist-heat cooking methods are also helpful for flavor preservation. In these methods, a liquid is used in varied quantities to preserve flavor at various high temperatures and with varying duration. Braising is slow and gentle cooking in a liquid. The moist-heat methods involve low heat in a tightly covered pan, to which liquid has been added. The moist heat methods solubilize the collagen and produce natural meat flavors in less tender cuts, and the steam produced by the liquid converts the tough collagen into tender gelatin. Sometimes, the meat flavor compounds leach into the cooking liquid creating delicately flavored meat during long, slow cooking in moist heat. The quantity of water makes a big difference between cooking by braising/pot roasting and liquid/stewing . Smokinghe smoke , 74.The high-pressure treatment is very useful for preserving the sensory quality, especially flavor and taste of meat products . reporteMeat cooking plays a crucial role in affecting the health of an individual. As discussed earlier, different cooking methods have different types of health effects. The temperature and the time of the cooking  are the important parameters. Lower temperature of cooking is beneficial as it require less energy consumption but for the safety of meat, it require final internal temperature of 65–80 °C . RoastinThere are many factors which influenced the formation of HAAs in meat during cooking including, cooking methods, cooking time, animal flesh type, and contents of amino acids as well as fat. When meat cooked at higher temperature for long time, the concentration of HAAs were found to be higher . There aSeasonings are the plant parts used as food flavoring and the development of processed spices has resulted an important support industry for food processing enterprises to meet consumer demands. The seasoning mixtures are formulated to serve as flavoring agents for processed meat products and the major groups of seasonings include natural spices, herbs and vegetable bulbs. Natural spices includes dried rootstocks, barks, flowers or their parts and fruits or seeds of different plants. The most important natural spices used in processed meat products are pepper, paprika, nutmeg, mace, cloves, ginger, cinnamon, cardamom, chilli, coriander, cumin and pimento . SeasoniVarious studies reported that role of different seasonings to improve the flavor profile of the meat along with preservation and quality retention of the product. A study by  documentFew studies reported the role of seasonings addition on beef flavor that can affect the consumer choices for the meat products. The personal predisposition of the food especially meat and meat based products varied around the globe as US consumers like beef products with higher initial flavor impact, brown/roasted, and salty characteristics than other countries peoples. In this regard, a study was to determine the most popular beef seasonings used in Argentina, United States (US), and Spain. After establishing the typical cooking methods and seasonings, descriptive analysis was used to determine the differences in the main flavor attributes, particularly the impact on beef characteristics. Findings indicated average US consumers would prefer beef products with more initial flavor impact, brown/ roasted and salty characteristics than Argentinian or Spanish consumers. They also reported that seasonings addition influenced major attributes but the major attributes were affected by cooking method. This study also indicated the personal predisposition of the consumers regarding the likelihood as well as acceptability for the meat products .Meat flavor is a combination of taste and aroma and is one of the major parameters that affects acceptance of meat by the consumer. Several factors affect the meat flavor. The Maillard reaction plays a vital role in the development of meat flavor mediated by volatile and nonvolatile precursors. The conditions and methods of meat cooking are crucial for flavor development because due to thermal reactions, many volatiles are produced that contribute to flavor. It has been demonstrated that high temperature produces a better aroma and flavor due to Maillard products. The high temperatures induce synthesis of compounds that favor mechanisms involved in the inflammatory response and oxidative stress. These processes involved in the development of disease. The pre- and postharvest factors are highly influential for meat flavor, but for many of these factors, clarification is needed regarding their effects on meat flavor. Thus, further research is needed on the chemistry and formation of compounds via Maillard reaction products that affect meat flavor.


Personalized, precision, and risk-based medicine are becoming increasingly important in medicine. These involve the use of information about the prognosis of a patient, to make individualized treatment decisions. This has led to an accumulating amount of literature available on prognosis studies. To summarize and evaluate this information overload, high-quality systematic reviews are essential, additionally helping us to facilitate interpretation and usability of prognosis study findings and to identify gaps in literature. Four types of prognosis studies can be identified: overall prognosis, prognostic factors, prognostic models, and predictors of treatment effect. Methodologists have focussed on developing methods and tools for every step of a systematic review for reviews of all four types of prognosis studies, from formulating the review question and writing a protocol to searching for studies, assessing risk of bias, meta-analysing results, and interpretation of results. The growing attention for prognosis research has led to the introduction of the Cochrane Prognosis Methods Group (PMG). Since 2016, reviews of prognosis studies are formally implemented within Cochrane. With these recent methodological developments and tools, and the implementation within Cochrane, it becomes increasingly feasible to perform high-quality reviews of prognosis studies that will have an impact on clinical practice. Clinical practice roughly consists of diagnosis, prognosis, and treatment. Treatment selection used to be driven mostly by the diagnosis that was made, but prognosis has become increasingly important to inform evidence-based decisions about healthcare. Clinical trials mainly focused on estimating a single overall effect, while decisions are being made on an individual level. Some patients benefit more (or less) than average; therefore, identifying those subgroups with different effects of an intervention has become very important to guide evidence-informed decision making. This personalized, precision, and risk-based medicine all involves the use of prognostic and predictive characteristics to make individualized treatment decisions for patients. The shift to personalized medicine has led to an accumulating amount of evidence available from prognosis studies. Reviews of prognosis studies make this information overload informative and usable. They summarize and evaluate the available evidence and guide the interpretation of results, in order to facilitate optimal use of all existing evidence. Reviews of high quality provide trusted evidence for stakeholders, like clinicians and guideline developers, to help them deciding which prognostic model or factor to use in clinical practice or implement in evidence-based guidelines. In addition, reviews identify gaps and redundant or unnecessary studies in the scientific literature, highlight flaws in conduct and reporting of primary studies, and identify and indicate which further studies are needed –5. TherePrimary prognosis studies are presented as four types in the PROGnosis RESearch Strategy (PROGRESS) partnership series –9: overaAll types of primary prognosis studies can be summarized, evaluated, and interpreted in different types of systematic reviews, following the broad range of aims and objectives of the included prognosis studies. Reviews are, for example, helpful to give an overview of all available prognostic factors or models , to study the prognostic value of a certain externally validated prognostic model (e.g. the predictive (prognostic) performance of the Revised Cardiac Risk Score for cardiac outcomes after noncardiac surgery ), or theMethodological guidance for most steps of conducting a systematic review is currently developed. Amongst others, to facilitate searching and reduce the number of references to be screened, methodological search filters are available –18, and The growing attention for prognosis research and the increasing emphasis on the importance of prognostic information in clinical practice have led to the introduction of the Cochrane Prognosis Methods Group (PMG) in 2007 . Over thIn summary, systematic reviews are urgently needed to summarize the growing amount of prognostic evidence, to evaluate the available evidence and guide the interpretation of results, in order to facilitate optimal use of existing evidence for medical practice and policy making. With the recent methodological developments and tools for systematic reviews of prognosis studies, it becomes increasingly feasible to perform these reviews. With the implementation within Cochrane, it is ensured that reviews of high quality will be produced that will have an impact on clinical practice.


Cancer is a major cause of morbidity, disability, and mortality worldwide, and breast cancer is the most common cause of death in women. Different modalities of cancer treatment can have adverse effects that reduce the quality of life of patients and lead to treatment interruptions, if not managed properly. The use of mobile technologies has brought innovative possibilities for improving health care. Mobile apps can help individuals manage their own health and well-being and may also promote healthy lifestyles and information access.The aim of this study was to identify available evidence on the use of mobile apps to provide information and facilitate communication regarding self-care management related to the adverse effects of toxicities owing to breast cancer therapy.This systematic review includes studies which were identified using a search strategy adapted for each electronic database: CINAHL, Cochrane Library, LILACS, LIVIVO, PubMed, SCOPUS, and Web of Science. In addition, a gray literature search was performed using Google Scholar. All the electronic database searches were conducted on April 17, 2019. Two investigators independently reviewed the titles and abstracts of the studies identified and then read the full text of all selected papers. The quality of the included studies was analyzed by the Cochrane Collaboration Risk of Bias Tool and the Methodological Index for Non-Randomized Studies.A total of 9 studies which met the eligibility criteria—3 randomized clinical trials and 6 nonrandomized studies published in English from 2010 to 2018—were considered for this systematic review; 396 patients with breast cancer, as well as 40 experts in the medical and nursing fields, and 3 software engineers were included.The evidence from the studies included in this systematic review is currently limited but suggests that mobile apps for women with breast cancer might be an acceptable information source that can improve patient well-being; they can also be used to report symptoms and adverse treatment-related effects and promote self-care. There is a need to test more evidence-based apps in future randomized clinical trials. Cancer is a major cause of morbidity, disability, and mortality worldwide, affecting more than 18 million people each year .The different modalities of cancer treatment can have adverse effects that may reduce the quality of life of patients and lead to treatment interruptions if not managed properly . ConsideThe landscape of mobile app usage has been growing and evolving. Apps can be used to offer services related to entertainment, media, education, shopping, finances, travel, health, and so on . The useConsidering the important role they can play in patient education, disease self-management, and remote monitoring of patients, the use of smartphones is receiving more attention in the health domain every day. A systematic review investigating smartphone-based health care technologies concluded that many medical apps have been developed and are widely used by health professionals and patients alike .In a study evaluating 185 mobile apps related to breast disease in the main app stores , the authors found that most (n=139) concerned breast cancer . A recenA systematic review of apps targeting patients with breast and prostate cancer involved 5 studies and a total of 644 patients. The purposes of the apps were related to the main psychological variables in psycho-oncological care: quality of life and anxiety and depression symptoms . AnotherNone of these recent reviews exclusively evaluated apps for women with breast cancer during cancer treatment. Therefore, given the magnitude of the disease burden, the needs of this population, the increasing use of mobile apps in the health domain, and the need to identify quality apps, it is necessary to enhance knowledge about the mobile apps available to provide information and improve the course of treatment of women with breast cancer.This systematic review aimed to identify available evidence on the use of mobile apps to provide information and facilitate communication regarding self-care management related to the adverse effects of toxicities owing to breast cancer therapy.This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Checklist . The proIn this systematic review, we included the following: (1) studies about mobile apps, defined as any computer programs or software installed on mobile electronic devices to provide information and facilitate communication regarding self-care management and adverse effects related to toxicities owing to breast cancer therapy, (2) studies that performed validation of content or evaluated the usability or effectiveness of apps, and (3) studies that collected the opinions of patients, clinicians, or experts about apps developed for patients with breast cancer. There were no restrictions on the year of publication or language.Studies were excluded for the following reasons: (1) if they focused on mobile apps related to other types of cancer, (2) if they focused on electronic technologies, but not mobile apps, such as telephone services, text messages, videotapes, audiotapes, audiovisual materials in DVDs, websites, games, or online programs for desktop computers, (3) if they concerned the post-treatment period, (4) if their objective was to evaluate mobile apps intended for health professionals but not patients, (5) if they focused on emotional, cognitive, and behavioral strategies, and (6) if they took the form of reviews, letters, conference summaries, book chapters, or studies that only described the development of mobile apps.Studies were identified using an individual search strategy for each of the following electronic databases: CINAHL, Cochrane Library, LILACS, LIVIVO, PubMed, SCOPUS, and Web of Science . The refDuplicated references were removed by using appropriate software . All the electronic database searches were conducted on April 17, 2019.Study selection was completed in 2 phases by using an online app . In phase 1, 2 investigators (FOAMC and PEDR) independently screened the titles and abstracts of all citations retrieved from electronic databases and identified papers that appeared to meet the inclusion criteria. In phase 2, the same investigators independently read the full text of all selected papers and excluded studies that did not meet the inclusion criteria. Any disagreements in the first or second phases were resolved by discussion and consensus between the 2 reviewers. In case a consensus could not be reached, a third investigator (EBF) became involved to make a final decision. Studies that were excluded after full-text assessment and the reasons for their exclusion are listed in Two investigators (FOAMC and PEDR) independently collected data from the selected papers: population characteristics , study characteristics (author(s), country and year of publication, and objective), intervention characteristics , and outcome characteristics (primary outcomes and main conclusions). Any disagreement was resolved by discussion and mutual agreement. A third author (EBF) was involved when required to make a final decision. If the required data were not complete, attempts were made to contact the authors to retrieve any pertinent information.Two investigators (FOAMC and PEDR) independently conducted the risk of bias assessment for the selected papers. Again, any disagreement was resolved by discussion and mutual agreement. A third author (EBF) was involved when required to make a final decision.To assess the risk of bias of the included randomized controlled trials, including judgments about sequence generation, allocation concealment, blinding of participants, personnel and outcome assessors, incomplete outcome data, and selective reporting, the Cochrane Collaboration Risk of Bias Tool  was usedThe heterogeneity across studies was evaluated by considering clinical (treatment-related differences), methodological (design and risk of bias), and statistical (outcome measures) characteristics. Therefore, owing to the heterogeneity among the included studies, a quantitative synthesis was not undertaken. Congruent with the review objectives, the results of the included studies were analyzed and reported according to the characteristics of the mobile apps, their assessment, and satisfaction with their use.The literature search initially yielded 3416 papers from 7 electronic databases. After duplicate removal, the titles and abstracts of 2396 papers were screened, and 25 potentially relevant studies were selected for full-text reading; 16 papers were excluded  and 9 paAll studies were published in English from 2010 to 2018 and evaluated mobile apps for women with breast cancer during treatment. In total, 4 studies included patients undergoing chemotherapy , 1 conceIn this systematic review, 396 patients with breast cancer were included, as well as 40 medical and nursing experts and 3 software engineers. The clinical nursing experts’ average career length was 17.0 years, with the duration ranging from 7 to 36 years in one of the studies . One stuA study measured health literacy through a validated instrument, showing that 72.5% of participants had high health literacy . RegardiThe main characteristics of the studies included are presented in On the basis of the methodological quality assessment using MINORS , the totOn the basis of the methodological quality assessment using the Cochrane Collaboration Risk of Bias Tool , one of All the analyzed studies carried out the evaluation of mobile apps for women during the treatment of breast cancer. On the basis of the objective, different types of apps were developed. In general, all involved the provision of useful and quality information to patients as a way of improving management of adverse treatment effects through the promotion of self-care at home.P<.05) during the intervention and reported higher drug adherence than those who did not opt for this feature  [Some studies reported the importance of using the specific app under the supervision of health professionals, either online ,22,25 orP<.05), as the app allows the professional to conduct an electronic consultation if necessary, avoiding complications. Almost all e-monitoring patients felt that the app led to improved care (95%) and would recommend it to a friend or colleague (90%).Another study reported a significantly lower number of unexpected medical consultations, including hospital readmissions and visits to the emergency department, in the e-monitoring group than the conventional follow-up control group , symptom interference , and quality of life  compared with participants who received usual care [Through qualitative interviews, it emerged that the participants considered the app to be useful for improving knowledge and promoting emotional well-being and would recommend it to other women undergoing chemotherapy . In addiual care .Another study reported the importance of an app for patients who require face-to-face follow-up with health care professionals on scheduled visits. Through the app, the patient can make a recording of the perceived symptoms at home, improving the report of the adverse effects management for the health care professional during consultation .The focus of some studies was on using mobile apps to improve the retention of information about the management of adverse effects and, consequently, to improve self-care and patient well-being. One study evaluated an app with a module dedicated to the latest research findings, technologies, and methods for breast cancer care, thereby helping patients obtain up-to-date information .Moreover, one study assessed a mobile app that, in addition to offering patient guidance through the provision of knowledge, includes a calendar to highlight important dates related to events, treatments, and consultations. This app incorporates texts, photos, and audio, making it possible for patients to capture and store important information related to their care. This app allows greater interaction between the patient and the app, a fact that was valued by the study participants .However, this was not the only study on an app enabling the inclusion of audio. In another study, all patients (n=15) used the audio recording function to record consultations with their nurses and physicians, and 14 (93%) patients found this feature useful. Patients considered the audio aspect and the personalization of information about disease and treatment as the most useful features of the app. Almost all physicians and nurses (90%) also found the recording function useful and would recommend the app to their patients . Figure This is a systematic review about the available evidence regarding women’s use of mobile apps during breast cancer treatment. A total of 9 papers, which covered the development of various types of mobile apps, were included -26. The While there is growing interest in using patient reporting tools to improve symptom monitoring during cancer treatment, there is a lack of evidence about the impact of this strategy on clinical outcomes ,27. A moElectronic follow-up via apps may help avoid unplanned visits to the emergency room and hospital readmissions, reducing health care costs . These rWeb-based self-management support systems and apps involving health professionals are important to ensure the communication of high-quality information between patients and the health team empowering the patients to increase their self-care and improve their own health  and alsoCalendar events, photos, messages, and audio are a few of the mechanisms that can increase the usability of apps and improve the acquisition of information related to illness and treatment ,24,26. TCharacteristics related to communication and interaction were also demonstrated by a recent study that aimed to investigate the behavior of patients with prostate cancer when using a mobile app during radiation therapy . As founIn this context, health apps are increasingly being used in clinical care and might have significant informative potential. However, they are often inserted into clinical care before the necessary research to confirm the benefits for patients and health professionals has been conducted .Some methodological limitations of this systematic review should be taken into account. Most studies validated apps for mobile devices during their development, focusing on their content and functionality. More data from randomized clinical trials are needed to assess the effects of using mobile apps during the treatment of women with breast cancer, as is being done with the Breast Cancer e-Support program. In addition, the evaluated apps have different functionalities and are geared toward different treatments. Therefore, their heterogeneity prevents the data from being satisfactorily grouped, hindering a quantitative analysis.The evidence from the studies included in this systematic review is currently limited but suggests that mobile apps for women with breast cancer might be an acceptable information source and lead to improved patient well-being. They can also be used to report symptoms and adverse treatment-related effects and promote self-care. However, the real utility of mobile apps for women undergoing breast cancer treatment is still uncertain. More evidence-based apps must be tested in future randomized clinical trials.


The industrial production of chondroitin sulfate (CS) uses animal tissue sources as raw material derived from different terrestrial or marine species of animals. CS possesses a heterogeneous structure and physical-chemical profile in different species and tissues, responsible for the various and more specialized functions of these macromolecules. Moreover, mixes of different animal tissues and sources are possible, producing a CS final product having varied characteristics and not well identified profile, influencing oral absorption and activity. Finally, different extraction and purification processes may introduce further modifications of the CS structural characteristics and properties and may lead to extracts having a variable grade of purity, limited biological effects, presence of contaminants causing problems of safety and reproducibility along with not surely identified origin. These aspects pose a serious problem for the final consumers of the pharmaceutical or nutraceutical products mainly related to the traceability of CS and to the declaration of the real origin of the active ingredient and its content. In this review, specific, sensitive and validated analytical quality controls such as electrophoresis, eHPLC (enzymatic HPLC) and HPSEC (high-performance size-exclusion chromatography) able to assure CS quality and origin are illustrated and discussed. N-acetyl-d-galactosamine  [N-acetyl-d-glucosamine (GlcNAc) or GalNAc [Hyaluronic acid (HA), keratan sulfate (KS), chondroitin sulfate (CS)/dermatan sulfate (DS) and heparan sulfate (HS)/heparin are natural macromolecules and the main complex heteropolysaccharides belonging to the class of glycosaminoglycans (GAGs) ,2. Apart , the bacr GalNAc . KS, CS/r GalNAc ,2,3,4.CS with different disaccharides and overall carbohydrate backbones may be biosynthesized possessing various number and position of sulfate groups  Figure . ConsequBesides the above-illustrated CS structures, a peculiar CS polysaccharide known as CSB or DS is known in nature, formed of disaccharide units of IdoA and GalNAc mainly sulfated in position C4 with a minor and variable content of the disulfated disaccharide in position C4 of GalNAc and C2 of IdoUA ,2.CS is a natural biomacromolecule abundantly distributed in virtually all invertebrates and vertebrates (and consequently in humans) and involved in many biological processes ,5,7,8. BThe biological effects of CS are related to its ability to interact with a wide variety of other bio(macro)molecules including (but not limited to) matrix molecules, growth factors, protease inhibitors, cytokines, chemokines, adhesion molecules and pathogen virulence factors via aspecific/specific sulfated saccharide domains within the chains ,12,13. IOsteoarthritis (OA) is a global issue affecting all known countries and ethnicities with huge incidence and economic impact . OA partCS, according to its nature, must be extracted from animal sources and submitted to purification processes for commercial purposes ,6. ActuaBesides the source material, manufacturing processes, the presence of contaminants and other natural biomolecules, as well as many other factors, contribute to the quality, structure and properties of the final product influencing CS overall biological, nutraceutical and pharmacological capacities. In fact, as well known, CS possesses a complex structure strictly depending on the tissue, organ and species but also on the age of the animals ,6. MoreoCS from various sources has a carbohydrate backbone formed of disaccharides with sulfate groups in different percentages and positions see  producinExtraction and purification processes may further produce CS preparations having different structures introducing modifications of the macromolecular characteristics and chemical properties by controlled as well as undesired depolymerization, desulfation and/or chemical modifications .Another key point is related to the accurate evaluation of the CS content and purity when the preparation is produced for therapeutic or nutraceutical applications. In fact, the CS content and purity may change according to the manufacturing processes and/or tissue sources. Depending on the purification protocols, the extracts may have a variable content and purity of CS due to the presence of polluting inorganic or organic side-products .All the above-mentioned aspects pose a serious problem for the pharmaceutical or nutraceutical Companies having the necessity to declare the real origin of the active ingredients and the label traceability of CS from the raw material up to the finished products. Moreover, an accurate label indication of the CS content is of paramount importance to assure to the final consumer a real dose administration also considering the possible intentional adulteration by potentially dangerous (macro)molecules (see below) mimicking CS structure and properties.As already mentioned, commercial CS produced from animal sources requires long and complex procedures of extraction and purification with the aim to eliminate or reduce the content of the other (macro)molecules present as natural contaminants  Figure . At the Depending on the animal source and on the extraction and purification procedures that generally are complex and require long time, CS extracts and final products for commercial purposes are also polluted with variable percentages of other polysaccharides that are co-extracted with CS during its preparation .HA in particular, and DS with its carbohydrate backbone made of iduronic acid, have been detected in raw materials and formulations and reported in scientific papers  due to tThe presence of these natural polymers in CS products, also in high percentages, alerts the manufacturers for improved isolation procedures as well as the supervisory agencies for better audits. In addition, this finding also compromises the desired amounts of the real ingredient specified on the label claims and forewarns the pharmacopeias to update their monographs. In fact, general non-specific analytical methods such as CPC (cetylpyridinium chloride) titration and carbazole assay are unable to detect the presence of other polysaccharides in CS products due to their quite similar properties and chemical structures . Finally, the presence of variable amounts of the immunogenic KS poses serious problems related to the possible development of immunogenic adverse reactions .Other (macro)molecules possessing similar properties of CS are copurified during CS extraction from tissues, such as nucleic acids  and protThe animal origin of CS may pose safety problems due to the possible presence of pathogen contamination and transmissible infective agents such as bacteria residues, viruses and prions potentially causing spongiform encephalopathy in bovines (BSE), foot-and-mouth disease, influenza spread in birds and other animal diseases . The posAnother key point is the adoption of specific and selective analytical assays to detect the possible presence of the different infective agents in the final products. In fact, the presence of prions may be easily demonstrated with a diagnostic test. However, the current available analytical assays are characterized by high costs and limited to specialized laboratories . FinallyBesides the presence of natural contamination, finished CS preparations may also be adulterated by the voluntary addition of cheaper polysaccharides and organic derivatives unable to be determined with usual analytical controls utilized in the nutraceutical industry . In factApproximately 80–90% of the CS supplied to the US and Europe markets is produced in China and intentional adulteration is possibly practiced by nutraceutical manufacturers globally with the aim to reduce ingredient costs by using cheaper substances . The priThe application of specific analytical methods such as eHPLC (enzymatic HPLC), HPSEC (high-performance size-exclusion chromatography) and electrophoresis . These sCS for pharmaceutical applications is strictly evaluated for quality, content, structural characterization and parameters (such as charge density and molecular mass) by means of sensitive, specific, validated and published analytical approaches . These fEuropean and USA pharmacopoeias require some analytical tests for CS identification such as infrared spectroscopy, specific optical rotation, intrinsic viscosity, electrophoresis and CPC titration ,47. SomeBesides the low title, also origin of CS has the been reported to be a puzzle and in general not declared on product labels . The oriThe use of animal-derived sources to produce commercial CS also represents a concern for vegetarians and people with dietary restrictions related to religious and supply issues. In fact, religious reasons and/or the practice of abstaining from the use of animal products have precluded the introduction of CS dietary supplements both in key emerging markets, such as Middle East and Asia, and in consolidated markets.www.bioiberica.com/) and possessing a purity greater than 98% and approved in 2004 as Chemical Reference Substance (CRS) by the European Pharmacopeia Commission [https://www.sigmaaldrich.com/) or the CS sodium salt from shark cartilage .The application of the above-illustrated multi-analytical techniques, electrophoresis, HPSEC and eHPLC requires highly qualified laboratories equipped with dedicated instrumentation and qualified technicians with specific analytical know-how producing very expensive activity and elevated costs for high quality CS management . Moreovemmission . FurtherIn 2008, heparin manufactured in China was intentionally adulterated with an oversulfated CS polymer having a very high charge density quite similar to natural heparin, which provoked hundreds of deaths in Europe and USA after intravenous administration . As for Even if specific and high-level analytical methods are generally able to distinguish from various sources, the detection of the presence of small amounts of different raw material remains very difficult. Additionally, CS structure can vary with environmental factors, animal subspecies, age and/or tissues providing additional difficulties for its quality and properties standardization. Moreover, the missing guidelines allow manufacturers of finished products to often change the sources of supply of the animal tissues or CS raw materials for competitive advantages. Consequently, the urgent solution to this scenario is the introduction and utilization in the current market of validated, specific, scientifically sound and largely published analytical controls. Manufacturers should ensure traceability of raw material right through to the finished product, with analytical evaluation made of each lot supplied to guarantee same quality, reproducibility and safety, as well as avoid misleading label information on finished products as reported in the literature.In conclusion, specific and accurate analytical procedures should be enforced for the control of high-quality products and applied by quality control laboratories to confirm the purity and label claims of CS in raw materials and finished products for food and nutraceutical applications. Finally, there are no definite regulations and common acceptance governing the origin of the ingredients in these supplements and the origin of the ingredients in products of natural and extractive origin is one of the most important factors ensuring quality, safety and efficacy.


Celiac disease (CD) is an immunogenic disorder that affects the small intestine. It is caused by the ingestion of gluten, a protein network formed by prolamins and glutelins from cereals such as wheat, barley, rye and, possibly, oats. For predisposed people, gluten presents epitopes able to stimulate T-cells causing symptoms like nausea, vomiting, diarrhea, among others unrelated to the gastrointestinal system. The only treatment for CD is to maintain a gluten-free diet, not exceeding 20 mg/kg of gluten, what is generally considered the safe amount for celiacs. Due to this context, it is very important to identify and quantify the gluten content of food products. ELISA is the most commonly used method to detect gluten traces in food. However, by detecting only prolamins, the results of ELISA tests may be underestimated. For this reason, more reliable and sensitive assays are needed to improve gluten quantification. Because of high sensitivity and the ability to detect even trace amounts of peptides in complex matrices, the most promising approaches to verify the presence of gluten peptides in food are non-immunological techniques, like liquid chromatography coupled to mass spectrometry. Different methodologies using this approach have been developed and described in the last years, ranging from non-targeted and exploratory analysis to targeted and specific methods depending on the purpose of interest. Non-targeted analyses aim to define the proteomic profile of the sample, while targeted analyses allow the search for specific peptides, making it possible to quantify them. This review aims to gather and summarize the main proteomic techniques used in the identification and quantitation of gluten peptides related to CD-activity and gluten-related allergies. Cereals are one of the main food sources in the world. The nutrients provided by this group represent about 50% of the recommended daily intake (RDI) of carbohydrates and one third of the RDI for proteins. Cereal grains are also considered a good source of minerals and vitamins, especially complex B vitamins . AccordiWheat is one of the most important cereals in the world for human consumption, and is considered the most suitable raw material for bread and pasta making. Its production has remained constant over the years, currently only behind maize and followed by rice . In receThe search for practical ways in the preparation and consumption of meals combined with the promotion of healthier eating habits, sparked an increase in research for new processes for products . Grain pTriticeae subtribe  contain significantly higher levels of Q and P, being the main cereal grains responsible for triggering the immune response in celiacs  and glutelins (maintenance of the elasticity and strength of the gluten). Gluten proteins have common structural characteristics. Their primary structure is subdivided into distinct domains that may exhibit repetitive sequences rich in the amino acids proline (P) and glutamine (Q) , but low celiacs . Cystein celiacs .The disorders associated to gluten consumption are known as GRD (gluten-related diseases) and are classified into three types according to the response triggered in the body: autoimmune, allergic, and neither autoimmune nor allergic . Examplee.g. sausages, nuggets, meatballs)  .Triticum aestivum landraces, which were not subjected to breeding practices. Despite the advances in the study of genetic variability of wheat toxicity, at present there is no common hexaploid wheat that might be safe for CD patients. Furthermore, considering the wide range of in vivo immunoresponse between celiac patients and the limitation of the immunological techniques for quantifying gluten proteins, the quantification and identification of cereal reactive proteins and peptides has been a complex task requiring constant analytical improvements.Some authors indicated the natural genetic variability as a strategy to be further exploited for the development of wheat varieties with lower levels of immunogenic epitopes . By usinCurrently, the gold standard method to detect and quantify gluten in foods is the R5 ELISA and it is recommended by the in tandem tools, proteomics can undoubtedly provide additional information to ELISA results, such as the confirmation of specific proteins by unraveling the peptide sequences  and denaturing agents (e.g. SDS or urea)  . The enzor urea) . After tde novo sequencing (LC coupled to mass spectrometry (LC-MS) is the most important tool for the identification and quantification of immunoreactive cereal proteins . One of quencing .Other aspects, such as ionization source and type of MS analyzer, also influence the analysis and consequently the identification and quantification of the proteins. All of these topics will be briefly covered in this review. With the use of this information, significant advances in the understanding of GRD mechanisms, such as aspects related to resistance to proteolysis of these proteins and influence of cereal processing can be clarified, contributing to various aspects from the development of peptide detection and quantification methods to the selection of less reactive genotypes for better tolerability of these cereals.For LC-MS/MS analysis is important to define and use a well-curated gluten protein sequence database to improve the identification of immunogenic peptides. For this, it may be necessary to build a custom database based on an existing general database.www.uniprot.org/). The UniProt Knowledgebase (UniProtKB), the main product of this consortium, combines UniProtKB/Swiss-Prot  and UniProtKB/TrEMBL  , the European Bioinformatics Institute (EBI), and the Protein Information Resource (PIR) group have joined forces and created the UniProt consortium in 2002 (o wheat) . Besideso wheat) . All knoViridiplantae).To customize a database, other softwares should be applied. Clustal Omega  and Jalvin silico digestions and specific epitopes that are responsible for wheat-related food disorders. Accordingly, is provided 667,402 unique digestion events, but also including redundant protein–peptide connections due to the simultaneous presence of some protein sequences in many genotypes and the frequency of the same peptide within a protein. Besides to be highly specific in the identification of protein sequences, this database provides specific information, such as the possible disease associated with the sequence.e.g. not available in FASTA format).Developed in 2005, Allergen Online database provides a updated peer reviewed allergen list and sequence searchable dataset to offer a risk assessment tool for evaluating the potential allergenicity of new food proteins produced by genetically modified organisms (GMO) and novel protein ingredients in processed foods . The maiThe “omic” suffix means collectively considering all constituents. Proteomics consists of the analysis of the set of proteins encoded by the genome and its component molecules responsible for the control of almost all biological processes . The usevia an ion source; the ions are separated according to their mass-to-charge ratios (m/z) and monitored by a mass analyzer prior to detection. In tandem MS (MS/MS) these precursor ions are then introduced into a collision cell where they undergo specific fragmentation through collision-induced dissociation (CID) by an inert gas, usually nitrogen or argon, resulting in the formation of product ions , they can also be combined to improve the sensitivity of the method , IT (ion trap), Orbitrape method .The variability of cereal protein composition caused by the different species and varieties (genetic variability) and by growing conditions  leads to methodological difficulties for the analysis of immunoreactive peptides and also for the selection of genotypes . In addiE allow minimizing data loss   analyzer  . In MSE analyzer . In DIA analyzer .E method, takes advantage of a data collection approach that focuses on maximizing peptide fragmentation and then improving the identification and proteome coverage  has appeared as an analytical separation technique, especially important to the analysis of primary structures with a high degree of homology, such as gluten proteins. The IMS consists of an orthogonal separation technique, where for each value of -section . Thus, tproaches .E and IMS, called UDMSE (Ultra Definition Mass Spectrometry). Collectively, about 5,900 proteins and 45,000 peptides  have also been reported and identified by MS . Samplespeptides  were idepeptides .Following the same approach, de novo sequencing to assemble wheat gluten gene sequences   or also This methodology was used by T. spelta), but it was absent in tetraploid and diploid wheat flours. No obvious cluster formation between modern and old wheat cultivars and no correlations between contents of 33-mer and those of α-gliadins, gliadins, gluten, or crude protein were observed. Indeed, the harvest year had a higher influence on 33-mer contents than the cultivar. It is important to highlight that this was the first study that accurately quantitated the 33-mer peptide in wheat flours.Recent studies use the combination of untargeted and targeted methods as a strategy to quantify gluten marker peptides in cereals and determine gluten concentrations in different types of samples . Schalk One of the most important considerations when using targeted LC-MS/MS is the careful selection of gluten marker peptides, because only these pre-defined peptides will be monitored. Even a single amino acid substitution, deletion, insertion, or post-translational modification will result in that marker peptide not being detected anymore, even if the sample may still contain other gluten-derived and possibly immunogenic peptides. While it is possible to use stable isotope labeled peptides or concatamers as internal standards to precisely quantify the selected peptides, the conversion of gluten peptide contents to gluten contents is far from being trivial. Legislation requires the result to be expressed as mg gluten/kg of the food, so that the correspondence between the amount of gluten and the resulting peptides needs to be established by careful calibration, also considering the whole sample preparation procedure. One of the most important points to verify is the extent of enzymatic hydrolysis. Matrix-matched calibration has been applied in many cases , but theA quantitative approach was also used to compare the relative abundance of 12 allergens in the albumins/globulins fraction in seven wheat varieties . AllergeEven with all the benefits of LC-MS/MS, such as the identification and quantification of specific proteins and peptides, new techniques have also been highlighted, such as the use of biosensors. In addition to the shortest analysis time, biosensors also have high sensitivity at low detection limits and low cost. LC-MRM/MS analysis can also be linked to genomics to improve our understanding of the genes responsible for expressing allergenic proteins, culminating in the development of wheat varieties with a lower allergenic potential , increasThe use of LC-MS/MS strategies is the most useful and promising path to improve the identification and quantification of immunogenic peptides. Despite the methodological difficulties, it proves to be a fast, sensitive, and reproducible method. In addition, it can be extended to several other allergenic food matrices, like dairy, nuts, and seafood. Thus, knowing the profile of allergenic proteins of cereals is necessary as a basis, not only for future applications of MS in the quantification of gluten in food, but also to ensure the safety of consumers regarding food labeled cereal- or gluten-free.Although the declaration of gluten-containing cereals on products labeled gluten-free is mandatory worldwide, there is no certified reference material available for gluten. The available reference material contains only gliadins that underestimate the gluten content, besides the problem of reproducing a new batch with similar properties and composition. The majority of MS-based studies have been conducted with the final objective to establish a reference material for gluten analysis starting from the study of specific grain peptide markers. Therefore, targeted high-resolution MS/MS methods allowed the quantification of low levels of specific marker peptides from different species and protein types.When comparing LC-MS/MS methods to ELISA for gluten detection, ELISA still remains the method of choice in most cases, because it is fast, comparatively cheap, suitable for routine analyses, and does not require highly specialized equipment. However, several studies have shown that ELISA may underestimate gluten contents especially in processed foods that have been extensively heat-treated or hydrolyzed. Untargeted LC-MS/MS is recommended to screen for the presence of gluten-derived peptides in products such as beer, malt vinegar, and fermented sauces. However, there are some points that will equally all analytical methods, because gluten extractability has been shown to be reduced substantially in heat-treated foods and processing-induced post-translational protein modifications will lead to reduced gluten detectability irrespective of the analytical method used.The use of modern MS-based techniques, combining orthogonal separations with high sensitivity and reliable certified references materials will hopefully help to better comprehend the effect of food processing or plant breeding on gluten immunogenicity. Continued efforts in this area will also help to solve the questions about the selection of relevant target epitopes and even antibodies, taking account the high protein polymorphism and the fact that patients react individually to different proteins and present variable sensitivities.TA organized and wrote the manuscript and the summarized table, CD’A complemented the writing and designed the figure, KS reviewed the manuscript, and MF supervised and reviewed the manuscript.This work was funded by Federal University of State of Rio de Janeiro (UNIRIO), FAPERJ (E-26/202.709/2018), CNPq (427116/2018-0), and in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior—Brasil (CAPES)—Finance Code 001.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 therapy is one of the most important treatment modalities for thoracic tumors. Despite significant advances in radiation techniques, radiation-induced lung injury (RILI) still occurs in up to 30% of patients undergoing thoracic radiotherapy, and therefore remains the main dose-limiting obstacle. RILI is a potentially lethal clinical complication of radiotherapy that has 2 main stages: an acute stage defined as radiation pneumonitis, and a late stage defined as radiation-induced lung fibrosis. Patients who develop lung fibrosis have a reduced quality of life with progressive and irreversible organ malfunction. Currently, the most effective intervention for the treatment of lung fibrosis is lung transplantation, but the lack of available lungs and transplantation-related complications severely limits the success of this procedure. Over the last few decades, advances have been reported in the use of mesenchymal stem cells (MSCs) for lung tissue repair and regeneration. MSCs not only replace damaged lung epithelial cells but also promote tissue repair through the secretion of anti-inflammatory and anti-fibrotic factors. Here, we present an overview of MSC-based therapy for radiation-induced lung fibrosis, focusing in particular on the molecular mechanisms involved and describing the most recent preclinical and clinical studies carried out in the field. Despicapacity . Currentcapacity . In factcapacity . Among tcapacity . Howevercapacity ,11. OverRadiation-induced lung fibrosis is characterized by different kinds of lung alterations that lead to progressive and irreversible organ malfunction . The desThe effects of radiation on the lungs are, from a clinical point of view, considered as a continuous and complex process characterized by an initial latent and asymptomatic phase starting immediately after radiation treatment, followed by an acute phase (radiation pneumonitis), and a late phase (radiation-induced pulmonary fibrosis) that normally occurs 1–2 years post-treatment . RadiatiThe lung is one of the most sensitive organs to the direct and indirect damage caused by ionizing radiation which frequently overcomes the intrinsic repair capacity of the lung, resulting in a permanent injury. The exact mechanisms involved in the development of RILI are still not known. Radiation disrupts epithelial and endothelial integrity in different areas of lung parenchyma from bronchi to alveolar capillary complexes, leading to a cascade of biomolecular events that modify the microenvironment, thereby inducing inflammation and oxidative stress . One hypMany types of cells composing lung tissue are affected by radiation treatment and each can potentially contribute to the development of fibrosis. The airway epithelium comprises multiple cell types constituting a mucosal barrier that mechanically and physically protects it from environmental insults and infections and orchestrates innate and adaptive immune response . The psel-proline, an amino acid required for the production of collagen by activated myofibroblasts [Radiation-induced damage in lung tissue leads to the activation of the immune system. Radiation-damaged epithelial and endothelial cells release a variety of chemotactic factors that promote the recruitment of inflammatory myeloid cells at the site of injury involved in chronic inflammation-induced fibrosis . Monocytroblasts . M2 macrroblasts ,57. It rroblasts .The adaptive immunity response plays an important role in the fibrotic process, in particular Th2 response involving IL-4, IL-5 and IL-13 , thus reMesenchymal stromal cells were first identified in 1968  as a fibhttps://clinicaltrials.gov), there were 910 clinical studies on MSCs registered as of April 28th, 2019, the majority focusing on MSCs as a potential therapy for nervous system disorders and bone and cartilage diseases. In contrast, only a handful of clinical trials are currently evaluating the regenerative and therapeutic role of MSCs in inflammatory lung disease. Most are phase I or II studies and their aim is to test the feasibility, safety and efficacy of MSC-based therapy, thus indicating that any hopes for its implementation in clinical practice are still a long way off [MSCs display high potential for the treatment of both immunological and non-immunological diseases , MSC-bas way off . The therapeutic potential of MSCs is a result of unique proprieties such as their ability to migrate to the site of an injury, their secretion of soluble factors required for cell death or survival and for the modulation of the immunological response, their capacity to differentiate into several cell lineages, their low immunogenicity, and the simplicity of their isolation and culture ,110,111.In adult tissues, cells are hierarchically organized and only a small proportion are endowed with self-renewal ability and multi-potential properties which are responsible for the maintenance of tissue homeostasis, balancing stem cell self-renewal and cell differentiation ,148. TheThe therapeutic potential of MSCs in the treatment of RILI derives mainly from their ability to reach the injured lung tissue after systemic administration and to secrete factors that act on the lung microenvironment ,170 Fig. Severalhttps://clinicaltrials.gov: NCT02277145), indicating that there is still a long way to go before MSCs-based therapy can be implemented in clinical practice for RILI (Despite in vitro and in vivo evidence of the effectiveness of MSC-based therapy for RILI, clinical trials are still lacking . Up to nfor RILI .Lung pneumonitis and fibrosis remain the major clinical complications of radiotherapy in patients with thoracic tumors, as they reduce the chances of survival and quality of life. The lack of effective therapeutic strategies and the recent advances in MSC-based therapy have induced researchers to investigate the role of MSCs in the treatment of RILI, but several concerns have been raised about their safety. For example, the lack of standardized methods for MSC harvesting and the little or no information available on the optimal dosage, timing and route of administration make it difficult to envisage using MSC-based therapy in clinical practice in the near future. Numerous other questions remain to be answered: What is the best source of MSCs? The best administration route? Are MSCs completely safe? How can MSCs be modified to increase their efficacy and safety? These and many other issues must be addressed before moving forward.


Collective violence in the context of armed conflict impacts the economy, health systems, and social stability of affected countries. This is considered a complex phenomenon with interwoven biological, psychological, social, cultural, and political factors. However, most of the research on this topic still lacks suitable established integrative approaches to assess multilevel perspectives. Social, cognitive and affective mental processes (SCAMP) are critical factors that should be considered in multilevel approaches. In this article, we critically discuss some of the classically isolated approaches used in violence research, the absence of successful interventions for ex-combatants reintegration, and the specific neglect of SCAMP in these interventions. We present the case of post-conflict Colombia as a unique opportunity to study the different roots of collective violence, and we call for a more robust and situated approach to understanding of and intervention in this multifaceted phenomenon. In addition, we suggest a two-stage approach for addressing ex-combatants’ reintegration programs, which considers the situated nature of post-conflict scenarios and the urgent need for evidence-based interventions. This approach focuses on the comprehensive scientific assessment of specific factors involved in violence exposure and the subsequent design of successful interventions. The implementation of this approach will contribute to the effective reintegration of individuals who have been exposed to extreme violence for more than 50 years. Collective violence within the context of armed conflicts is a scourge with great impacts on human society. Numerous civil wars and armed conflicts across the globe  exemplify the pervasive and ubiquitous nature of human violence . CollectThe Colombian conflict is a great example of the inherent complexity of the sources, actors and effects of violence. Across more than 50 years of army conflict, Colombia has nearly 363,374 victims of violence. This includes 363,374 victims of threats, 22,915 victims of sexual offenses, 167,809 victims of enforced disappearance, 7,265,072 victims of forced displacement and 11,140 victims of anti-personnel mines . DiffereThe government and the Revolutionary Armed Forces of Colombia (FARC) reached a peace agreement in 2016 to end their 52-year armed conflict. In 2017, the United Nations mission in Colombia verified that the FARC had handed over its weapons and demobilized. However, a minority of dissident guerrilla fighters rejected the terms of the peace agreement, have not disarmed, and continue to commit violent acts. Currently, civilians continue to face death threats and violence from National Liberation Army (ELN) guerrillas and paramilitary successor groups that emerged after a demobilization process that occurred a decade ago . Thus, pEx-combatants usually display abnormal and exacerbated expressions of aggression and violent behavior , which cthe mind of ex-combatants is not currently considered a critical component of reintegration. Mental health and SCAMP have not been considered to be core topics for Colombian disarmament, demobilization, and reintegration (DDR) programs. Indeed, the effects of violence- and conflict-exposure on the mental health of ex-combatants have not been investigated in a rigorous and comprehensive manner. In addition, social cognition abilities have been proposed as important variables in relation to violent profiles  consequentialist violence: violence committed by utilitarian reasons following the principle of the end justify means ; (b) appInterdisciplinary efforts are urgently needed to build novel strategies for violence research that incorporate inclusive approaches regarding violence origins, individual differences in SCAMP and mental health, and other factors that perpetuate violence and their consequences. Similarly, it is crucial to assess the background, including the cultural, social, and political context where reintegration interventions will be implemented. Specifically, new research approaches should consider the assessment of both contextual  and individual or person-centered  factors that could be associated with different domains of violence. For instance, contextual factors include the presence of threatening social experiences  Contextual assessment should include experiences and factors present at different stages of subjects’ life: before the subjects entered to the armed group, during the time they were part of the armed group, and after they leaved the armed group and accepted the reintegration processes.The assessment of person-centered factors should include mental disorders symptoms, personality traits, basic cognitive abilities, social cognition skills and quality of life aspects. The last one involves the environment adaptation skills, social and emotional skills , determinants of psychical integrity and health ; and the self-projection skills.Research approaches including a comprehensive assessment of both contextual and person-centered factors associated with different violence dimensions in ex-combatants, would contribute to the understanding of the specific interplay multidimensional factors involved in specific violent behaviors. Additionally, personalized assessments should identify both protective and risk factors for successful reintegration. Finally, more studies that anticipate the factors that may challenge successful reintegration and social participation processes are of critical relevance. This information is crucial for designing specific interventions within reintegration programs.The second stage involves the design of evidence-based interventions grounded in the knowledge accumulated during the first stage. Given the scarcity of interventions designed specifically for ex-combatants, successful interventions employed in other populations may be considered examples for future designs.For instance, some research in healthy non-offender populations  has showNew technologies and advances in data analysis should also be considered for designing interventions. For instance, recent research has revealed the utility of machine learning and data-mining methods to develop statistical models that aim to predict the risk for reoffense in violent criminals. These methods have the capacity to empirically discover patterns in the data and to construct suitably complex decision boundaries by using conventional predictors and a large sample size . In thisIn addition, insights from neuroscience could contribute to the understanding and  the prediction of violence and other forms of antisocial behavior present in ex-combatants. Cognitive neuroscience may contribute to the understanding of the neural basis of basic cognitive and social functions associated to violent behaviors. Besides, basic neuroscience could provide insights on aspects of brain function, structure, chemistry, or connectivity related to violence dimensions . In addiSpecifically, our approach proposes the designing of long-term (at least 9 months) interventions that integrates individual, group and community strategies, matching aims with individual needs. Regarding individual interventions, it is worth to highlight that personalized interventions considering the individualized prescription of specific therapeutics  have beeFor instance, the proposed approach includes the adaptation of successful mental training interventions  for diffGroup interventions should be complemented with individual sessions considering the ex-combatants personal needs. These individual interventions may be based in previous protocols implemented in ex-combatants populations e.g., . HoweverGiven that only a few studies  have attFinally, the preparation of the receiving communities which are willing and able to accept ex-combatants is of particular importance to the success of social reintegration . ReintegPost-conflict Colombia represents a unique opportunity to study the different roots of violence. The implementation of the proposed approach would contribute to the understanding of the multidimensional factors involved in violence and the efficiency of these interventions to change violent behaviors. The situated perspective supported by a comprehensive scientific assessment and the designing of evidence-based interventions constitute the major strengthens of this proposal. However, some limitations and challenges should also be acknowledged. First, the implementation of the two-stage approach critically demand long-term funding from governmental and non-governmental agencies. Second, this proposal demands a concerted effort from academics, social science and mental health professionals, as well as communities and governments. Third, as any long-term intervention, high rates of drop out or withdrawal may be present. To circumvent this issue, the adherence of ex-combatants to interventions should be closely controlled.The proposed two-stage approach involves long-term interventions that critically demand funding from governmental and non-governmental agencies. The implementation of an established evidence-based intervention in post-conflict Colombia demands a concerted effort from academics, social science and mental health professionals, and communities and governments, accompanied by economic and social support. Long-term, evidence-based and established interventions would contribute to the successful reintegration and rehabilitation of individuals and communities that have been exposed to extreme violence for more than 50 years.SB and HS-G wrote the first draft. All authors designed the proposal, searched the literature, participated in discussing the contents of the paper, contributed to editing and approved the final version of 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.