Plasmodium species, or by blood-feeding parasites, such as the soil-transmitted helminths (STHs) The main cause of anemia is iron deficiency, which, in turn, can result from a wide range of factors. Iron intake may be insufficient because of a low dietary iron content, less bioavailable  iron, or because of poor absorption of iron due to concurrent ingestion of inhibitors such as cereals and grain Normal hemoglobin distributions vary by age and sex and so do anemia thresholds  concentrations below which individuals are considered anemic). Among women of reproductive age, this threshold is 11 g/dL for pregnant women and 12 g/dL for nonpregnant women The association between hookworm infection and anemia is well known. Hookworm infection is recognized as a risk factor for anemia, both in pregnant women Trichuris trichiura, with anemia is less clear. Most studies of Hb/anemia in pregnant women compared Trichuris-infected and non-Trichuris-infected women, and found no statistically significant associations Trichuris infection intensity categories. Of the single study which had examined Trichuris infection intensity categories, results showed that pregnant women with moderate or heavy Trichuris infection in their second trimester of pregnancy had statistically significantly lower Hb levels compared to those with no or light Trichuris infection, despite all of the women receiving iron supplementation Trichuris infection and increasing Trichuris intensity, as well as an increased risk of anemia—and this despite iron supplementation.The evidence linking the whipworm, Trichuris with hookworm, the risk of anemia increases with increasing intensity of either Trichuris infection or hookworm infection Moreover, there is limited evidence demonstrating that, in cases where there is co-infection of Trichuris infection and lower Hb levels, or anemia Trichuris infection precluded analyses by infection intensity categories. In contrast, studies that showed an association between Trichuris and lower Hb levels included sufficient numbers of infected subjects to divide them into intensity categories, and found associations between higher infection intensity categories and lower Hb levels Similar patterns have been observed in children. Some studies have shown an association between The effectiveness of anthelminthic treatment to reduce anemia during pregnancy has been examined in three randomized controlled trials (RCTs) to date. These were, in turn, examined in two systematic reviews and meta-analyses, concluding that anthelminthics do not significantly increase Hb levels or decrease the prevalence of anemia during pregnancy T. trichiura. Indeed, a recent meta-analysis of RCTs showed that commonly used single-dose treatments with albendazole (400 mg) or mebendazole (500 mg) are of limited efficacy against Trichuris infection, while albendazole is more effective than mebendazole against hookworms The apparent lack of deworming effectiveness can be explained, in part, by the low prevalence of STH infection in two of the three study populations. Consequently, these studies likely had insufficient power to detect a statistically significant effect, if one existed. Another partial explanation may be the limited effectiveness of anthelminthics against Ascaris lumbricoides, T. trichiura, and hookworms Anthelminthic agents, while essential in endemic areas, may not be sufficient, alone, to achieve sustained elimination of STHs and, consequently, of related STH-attributable anemia. This suggests a need for a shift “from morbidity control to transmission control” It is clear that a sustainable reduction in STH-attributable maternal anemia would benefit from both short-term and long-term prevention and control strategies. Efforts to address the Millennium Development Goals (MDGs), in particular MDG 5  and MDG 7 , would contribute to achieving such a reduction. With global attention increasingly focused on alleviating the inequities resulting from Neglected Tropical Diseases, now is the time to ensure an evidence-informed, comprehensive, and integrated strategy to both deworm infected individuals and prevent infections by deploying sanitation and hygiene interventions.


An increasingly asked question is 'can we confidently link bats with emergingviruses?'. No, or not yet, is the qualified answer based on the evidence available.Although more than 200 viruses - some of them deadly zoonotic viruses - have beenisolated from or otherwise detected in bats, the supposed connections between bats,bat viruses and human diseases have been raised more on speculation than on evidencesupporting their direct or indirect roles in the epidemiology of diseases (except forrabies). However, we are convinced that the evidence points in that direction andthat at some point it will be proved that bats are competent hosts for at least a fewzoonotic viruses. In this review, we cover aspects of bat biology, ecology andevolution that might be relevant in medical investigations and we provide ahistorical synthesis of some disease outbreaks causally linked to bats. We provideevolutionary-based hypotheses to tentatively explain the viral transmission routethrough mammalian intermediate hosts and to explain the geographic concentration ofmost outbreaks, but both are no more than speculations that still require formalassessment. These characteristics and the ecosystemservices they provide set them apart from all other mammals. Other aspects of their naturalhistory, ecology, biology and evolution also distinguish them from other mammals, but nonehas been more emphasised recently than their potential link with human diseases,particularly those caused by zoonotic viruses , the second smallest mammal known] to 1 kgin some flying-foxes [Pteropus spp (Pteropodidae)], whose wingspans canreach 2 m , crevices and foliage as day roosts  and manyBat reproduction is similar to that of other mammals, but mating and duration ofbreeding season are strongly influenced by hibernation and migration. In hibernatingbats of various species, copulation generally occurs in the fall, either with ovulationand fertilisation occurring immediately, followed by a slow development of the fetusthroughout the winter and birth in the spring, or with sperm storage until spring, afterwhich ovulation, fertilisation and foetal development occurs. In migratory bats, matingis generally concentrated in the early spring, after they reach their summer roosts.These bats and several others that do not need to migrate or hibernate, but that live inareas with food availability varying seasonally, reproduce once a year (monoestrus),whereas others facing less marked seasonal variation or having food resources availableyear-round generally reproduce twice or more a year (polyestrus). The former pattern ischaracteristic of most insectivorous bats from temperate regions, whereas the latter iscommon in most frugivorous bats living in tropical regions. Gestation averages about twomonths and bats of most species produce a single young per litter, but a few producetwins and a very few produce three or four young at a time . Halpin Myotis brandtii (Vespertilionidae)] from Siberia wasrecaptured 41 years after the first capture ] form the largest warm-blooded non-humanvertebrate colony in the world.Bats of some species also form large aggregations and a few of them form the largestaggregations of mammals in the world. Old World fruit bats (Pteropodidae) of variousspecies constitute colonies of hundreds of thousands to millions of bats that aggregateon exposed tree branches . InBracAlthough bats are outnumbered by rodents in species richness, they are first amongmammals (and probably among vertebrates) in dietary diversity  which inEvolutionary history - Chiroptera is a middle Paleocene or early Eocenelineage of placentals ,the prevention of diseases and the expanded studies of bats for one reason or anotherlikely will provide more information about the bats themselves and, in the long run,help us protect bat populations from further decline.Summary of viruses from bats - More than 200 viruses have been isolatedfrom or detected in bats. Represented are bats of both suborders, 11 families and 37genera . Classical rabies virus (street rabies) is the prototype virus of a complex ofviruses that have been detected in bats, dogs and other mammals. This negative sense,single-stranded RNA virus has been classified in the virus order Mononegavirales, familyRhabdoviridae  and genus Lyssavirus .Canis lupus ], now domesticated asdogs (C. lupus familiaris). Even as far back as 2300 BC dog owners inthe Babylonian city of Eshnunna were fined for deaths caused by their dogs having bittenpeople. In 500 BC, the Greek philosopher Democritus described a case of canine rabies.In 400 BC, Aristotle wrote 'dogs suffer from the madness. This causes them to becomevery irritable and all animals they bite become diseased', In the first century, Romanwriter Cardanus described the saliva from a rabid dog as a 'virus' . In 1804, a German scientist, Georg Gottfried Zinke,demonstrated that rabies could be passed through saliva from rabid dogs.Rabies may be the oldest human infectious disease known. Its origin has been associatedwith wolves  in 1931 ] in Kyrghyzstan, Central Asia, Australian bat lyssavirus, from black, gray-headed , little red (Pteropus scapulatus) andspectacled (Pteropus conspicillatus) flying-foxes (Pteropodidae) andyellow-bellied pouched bats [Saccolaimus flaviventris], in Australia, Bokeloh virus from a Natterer's myotis [Myotisnattereri (Vespertilionidae)] in Germany, Duvenhage virus, from Schreibers'slong-fingered bat [Miniopterus schreibersii (Miniopteridae)] andEgyptian slit-faced bat [Nycteris thebaica (Nycteridae)] in SouthAfrica, European bat lyssavirus 1, from common serotines [Eptesicusserotinus (Vespertilionidae)], European bat lyssavirus 2, from Daubenton'sbats [Myotis daubentonii (Vespertilionidae)], Irkut virus, from greatertube-nosed bats [Murina leucogaster (Vespertilionidae)] in Russia andChina, Khujand virus, from a whiskered myotis [Myotis mystacinus(Vespertilionidae)] in Tajikistan, Lagos bat virus, first isolated from a Africanstraw-coloured fruit bat [Eidolon helvum (Pteropodidae)] in Nigeria,Lleida bat lyssavirus, from Schreibers's long-fingered bat in Spain, Shimoni bat virus,from a Commerson's leaf-nosed bat [Hipposideros commersoni(Hipposideridae)] in Kenya and West Caucasian bat virus, from a Schreibers'slong-fingered bat in Russia. Mokola virus, although not isolated from bats, also is amember of the rabies-virus related virus group and has been isolated from shrews[Crocidura spp ] and domestic cats inNigeria. Since the initial detections of these viruses, with the exception of Mokolavirus, most have been detected in bats of species other than those mentioned above.Among those mentioned above, only pteropodids feed on plants, whereas all others feed onanimals, including insects, other invertebrates or vertebrates. rom bats . AravanSevere rabies-like disease in humans has led to additional studies of flying-foxes,resulting in a greater understanding of the epidemiology and geographic distribution ofAustralian bat lyssavirus. Based on this evidence, Hendra, Nipah and other paramyxovirus diseases - Hendra and Nipahviruses are both highly pathogenic zoonotic paramyxoviruses  that have been detected in pteropodid bats within the last decades ,responsible for a 1997 zoonotic disease affecting pigs and humans in New South Wales,Australia. Antibodies capable of neutralising Menangle virus were detected inflying-foxes, providing provisional evidence of a bat origin for this virus; the viruslater was isolated from black flying-foxes . SamplesIn 1998 yet another paramyxovirus, this one named Nipah virus, was recognised as theetiologic agent of a fatal disease of humans and pigs in Malaysia and Singapore . By JunePteropushypomelanus) and in fruits partially eaten by them, confirming these bats asnatural hosts of the virus (Pteropuslylei (Pteropodidae)] in Cambodia ] and viaperson-to-person route. Nipah virus RNAs detected in Bangladesh are variable in theirsequences, suggesting multiple introductions via Indian flying-foxesPteropus giganteus (Pteropodiae), which migrate long distances andare found in the Maldives, India, Bangladesh, China, Nepal, Pakistan and Sri Lanka.In contrast to transmission of Nipah virus from bats elsewhere, transmission inBangladesh was found to be Mustela putorius furo ] anddomesticated guinea pigs [Cavia porcellus ], bothsusceptible to infection and disease with known henipaviruses, confirmed virusreplication and production of neutralising antibodies, but no clinical disease. Also,the major genetic difference between Cedar virus and Hendra and Nipah viruses lieswithin the coding strategy of the P gene, known to play an important role in evading thehost innate immune system. Preliminary studies indicated that Cedar virus infection ofhuman cells induces a more robust interferon-β response than does Hendra virus. Cedarvirus is one that might be studied to develop a human and livestock vaccine.RNA of Cedar virus, another henipavirus, was detected in urine of pteropodid bats inAustralia in 2009, but little is yet known about this virus . ChallenIntriguing evidence for infection with a henipavirus in African bats was presented bySevere acute respiratory syndrome (SARS) - The hundreds of human casenotifications of SARS in Guangdong Province, People's Republic of China in late 2002,then elsewhere in the world, moved bat virus recognition from unanticipated andoccasional to well-planned and more methodical. Thereafter the World Health Organization(WHO) put the entire world on alert. SARS cases soon were diagnosed in patients not onlyin Vietnam, but also in Hong Kong and Canada, and cases were diagnosed in health careworkers and household members who had cared for patients with the disease. Many of thecases were traced back through chains of transmission to a health care worker fromGuangdong Province who had visited Hong Kong, where he was hospitalised with pneumoniaand died. By late April 2003, more than 4,000 SARS cases and 250 SARS-related deathswere reported to the WHO from more than 25 countries. Most of these cases occurred afterexposure to SARS patients in health care or household settings.in nature had not been determined at that time,but knowing it was a CoV made the search easier.The WHO coordinated a massive international collaborative effort that included clinical,epidemiologic and laboratory investigations and simultaneously initiated efforts tocontrol the spread of the disease. Attempts to identify the causative agent of theoutbreak were successful during 2003, when laboratories in the United States of America(USA), Canada, Germany and Hong Kong isolated a novel CoV (SARS CoV) from SARS patients.Classified as a virus in the order Nidovirales, family Coronaviridae and genus CoV,unlike other human CoVs, this one can be isolated in Vero cells. SARS CoV RNA hasfrequently been detected in respiratory secretions and convalescent-phase serumspecimens from SARS patients contain antibodies that react with SARS CoV, altogetherproviding evidence that it was a newly recognised virus and associated with the disease.The source of the virus CoVs comprise a diverse group of large, enveloped, positive-stranded RNA viruses thatcause respiratory and enteric diseases in humans and other animals. Their genomes arethe largest  of any RNA virus known. A great deal is knownabout CoVs, nicely summarised by Paguma larvata ] andraccoon dogs [Nyctereutes procyonoides ] in livemarkets of wild animals in mainland China - were proposed, but were more confusing thanhelpful to our understanding of the origin and spread of the virus. Many possible natural history scenarios - among others, human infections originatingwith masked palm civets [Middle East respiratory syndrome (MERS) - MERS is caused by a CoVcalled MERS CoV. Cases of this disease were first reported from Saudi Arabia by ProMEDand formally published soon after  (Neoromiciacf. zuluensis (Vespertilionidae)] by Camelus dromedarius ] may be a primary source of this virus in nature (on after . MERS afnuridae) ] in Saudn nature  and expen nature . MERS CoMarburg and ebolavirus haemorrhagic fevers - Marburg and ebolaviruses -, genera Marburgvirus and Ebolavirus, respectively, the'filoviruses' - were discovered because they cause severe, often fatal, haemorrhagicdiseases in humans and other primates.Marburgvirus disease - In late summer of 1967, an haemorrhagic feveroutbreak was observed in laboratory workers in Serbia, at the time part of Yugoslaviaand in Germany. It was soon shown that the disease was transmitted from green monkeys[Chlorocebus sabaeus ] consigned fromUganda to Europe, but the origin of the disease was unknown, other than that it wascaused by a hitherto unrecognised virus, named Marburg virus for the city in Germanywhere the disease was first recognised. Another infection with this virus occurred in atraveller in Africa in 1975 and cases of Marburg haemorrhagic fever have been documentedwith some frequency in various parts of Africa since then. Although a great deal waslearned about this virus from pathologic and laboratory studies, its epidemiologyremained undetermined. Nonetheless, bits and pieces of evidence suggested that batsmight be associated with Marburg virus. It was not until 1999 that Rhinolophus eloquens(Rhinolophidae)] and a greater long-fingered bat [Miniopterus inflatus(Vespertilionidae)] captured in the Democratic Republic of the Congo and Ebolavirus diseases - In 1976, a series of severe and often fatalhaemorrhagic fevers occurred in southern Sudan. Almost immediately after those caseswere recognised, a similar disease was observed in humans in Zaire, now known as theDemocratic Republic of the Congo, nearly 1,000 km away. A virus, originally termed'Ebola virus', named after the Ebola River near the epidemic site in Zaire, was isolatedfrom patients in Zaire and partially characterised ]imported from a commercial source in the Philippines to a primate holding site inReston, Virginia, USA. No human illnesses among animal handlers were recognised ] in the Taï Forest ofCôte d'Ivoire resulted in an accidental infection and non-fatal illness of aninvestigator performing a necropsy on one of these primates. Virus isolation from thispatient was successful and the virus named Taï Forest ebolavirus. The cause of deaths ofthe members of the chimpanzee group was later shown to be infection with this virus.This was the first time that a human ebolavirus infection had been connected tonaturally-infected non-human primates in Africa , was detected during the investigation of bat die-offs in Cueva del Lloviuin Spain in 2002. Lloviu virus is genetically distinct from marburgviruses andebolaviruses and is the first filovirus detected in Europe that was not imported from anendemic area in Africa. Whereas infections of bats with marburgviruses and ebolavirusesdo not appear to be associated with disease in the bats, Lloviu virus was detected in adead Schreibers's long-fingered bat.Epomophorus wahlbergi (Pteropodidae)], little free-tailed bats[Chaerephon pumilus (Molossidae)] and Angolan free-tailed bats[Mops condylurus (Molossidae)] as potential hosts for Zaireebolavirus. In addition, from 2001 and 2003, Hypsignathus monstrosus),Franquet's epauletted fruit bats (Epomops franqueti) and littlecollared fruit bats (Myonycteris torquata). These RNA sequences werequite similar to those of the ebolavirus isolated from humans during the 1976 outbreakin Zaire. Other investigations led to antibody detections in bats of the same species.Survival of bats from experimental infections led Based on the work of Eptesicus fuscus(Vespertilionidae)] experimentally infected with Japanese encephalitis virus atvarious environmental temperatures and then tested them for both virus and neutralisingantibody. Viraemias were demonstrable in most of these bats within two-three days afterinfection and persisted for one-two weeks. However, not all viraemic bats producedantibody to the virus, a few others had equivocal and then delayed (nearly 2 months)antibody responses and some that had produced antibody soon after being infected nolonger had detectable antibody three months later.In addition to their other well-known uniquenesses, it may be asked whether bats haveunique responses to virus infections. That is, why (or how) do bats survive infectionswith viruses and other agents that are pathogenic for other vertebrates? Or do they?These questions have not been answered satisfactorily and data accumulated thus far havenot definitively answered them, but have led to speculation, much of which isfascinating. Serologic studies demonstrated that bats have antibody to many viruses, butit was not determined whether their antibody isotypes were similar to those of othermammals. Nearly 50 years ago, for example, Carolliaperspicillata (Phyllostomidae)], whereas little brown myotis [Myotislucifugus (Vespertilionidae)] have five IgG subclasses ] differs somewhat from that of In an effort to provide a foundation for understanding adaptations by bats that mightallow them to at least somewhat peacefully coexist with viruses that infect them, Other studies of bat genomes have indicated differences in genes associated with earlyimmune responses, which might allow virus to replicate in the absence of a primary andhearty immunological response. It is further reasonable to assume that this in turnmight allow at least low-level virus replication over an extended period. There is someevidence that these genes may be evolving more rapidly in bats than in vertebrates ofother taxa, which would suggest that the genes are co-evolving with the bats in responseto viral and other infections. An additional note of caution: when studying viruses frombats in order to understand their effects, it is clearly more appropriate to use bats ortheir cells in culture, rather than other hosts or cells from other hosts. That is,simply because a virus or other pathogen might interfere with or activate a gene productin one host, there is no certainty that it does the same in another host; thus theextrapolatory and speculatory nature of many available publications. A recent paper byHumans and most other mammals respond to infections by activating their immune systemsat the time they are infected, usually producing type I and type III interferons, whichare temporising responses activated prior to humoral antibody responses. The immunesystems of bats of at least one species (black fling-fox), on the contrary, appear to beperpetually switched on at a low level, thus allowing them to respond quickly to aninfectious agent .AlternaPseudogymnoascus destructans , maybring about a severe immune reconstitution inflammatory syndrome . Because bats represent such a largeproportion of mammals (about 20%) and are so diversified in their biology, habitats andnatural history, it seems reasonable to assume that they have many hundreds moreviruses, just as do other diversified groups of life forms. A few hypotheses have beenraised to explain so many viruses in bats ( in bats .HoweverArtibeus lituratus) and little yellow-shoulderedbats (Sturnira lilium) had circulating virus levels high enough toinfect culicid mosquitoes  that may serve as vectors for the virus,whereas great spear-nosed bats [Phyllostomus hastatus (Phyllostomidae)]did not develop sufficient viraemia to infect subsequently feeding mosquitoes  also figure among the mammals in which viruses apparently circulate. Except forhumans, these mammals are from groups that have evolved within the superorderLaurasiatheria. Horses are representatives of the order Perissodactyla, pigs and camelsare in the order Artiodactyla and ferrets, palm civets and raccoon dogs are in the orderCarnivora; all are members of the superorder Laurasiatheria.Although bats have been distinct from other mammals for more than 52 million years,bats, carnivores perissodactyls and artiodactyls share part of their evolutionaryhistory that is not shared with other mammals and their ancestors may have co-evolvedwith ancient lineages of certain viruses. This suggests that they may sharephysiological characteristics that could facilitate circulation of these viruses. The taxonomic and geographic distribution of bats whose viruses have potentially jumpedto humans is also noteworthy. Except for rabies, all episodes are in the Old World andpteropodid, hipposiderid and rhinolophid bats - representatives of families in thesuborder Yinpterochiroptera - have been mostly involved . To dateFuture investigations - We still know comparatively little about theimmunological and physiological systems of wild mammals of different orders. With batsbeing potential reservoirs of a long list of viruses ] are potential models for research in South America.They are widely distributed on the continent, adapt well to human constructions and feedon insects  that have continental distributions as potential models to testenzootic (or endemic) viruses. As an example, Pallas's mastiff bats [ insects , making In addition, fieldwork is necessary to continually searching for new pathogens and tounderstand the mechanisms underlying the dynamics of zoonotic diseases. It is importantto design field studies to understand the role of different biotic and abiotic factorsaffecting bat populations and pathogen circulation in bats and how these factors mayfavour spillovers to humans .Joining expertise from bat biologists and medical investigators, this scenario canquickly move forward to a new one in which the role of bats in the circulation ofzoonotic viruses and other pathogenic agents will be at least minimally understood.After understanding the role of bats  in the maintenance andcirculation of pathogens and the mechanisms underlying the emergence of zoonoticdiseases, wildlife biologists and epidemiologists should work together to developappropriate management plans to control virus circulation and minimise risks of humaninfection without causing significant biases against specific animal populations. Wecannot ignore the potential role of bats in the maintenance, circulation andtransmission of pathogens to humans and we cannot ignore the important ecosystemservices provided by these animals. Thus, the only possible approach is to developresponsible research to avoid the obstacles and keep safe both human and batpopulations. In addition, wildlife biologists and medical investigators should worktogether to provide expertise to wildlife epidemiologists. This training could beprovided by graduate programs in public health.Finally, can we confidently link bats with emerging viruses? No, or not yet, is thequalified answer based on the evidence available. Only integrative and organised fieldand laboratory research, using ecological and epidemiological approaches conducted bybat biologists and medical researchers, will provide a useful and satisfactorysolution.


Eosinophilic esophagitis (EoE) is a chronic inflammatory disorder of the esophagus and commonly classified as a Th2-type allergy. Major advances in our understanding of the EoE pathophysiology have recently been made, but clinicians struggle with highly unpredictable therapy responses indicative of phenotypic diversity within the patient population. Here, we summarize evidences for the existence of EoE subpopulations based on diverse inflammatory characteristics of the esophageal tissue in EoE. Additionally, clinical characteristics of EoE patients support the concept of disease subtypes. We conclude that clinical and experimental evidences indicate that EoE is an umbrella term for conditions that are unified by esophageal eosinophilia but that several disease subgroups with various inflammatory esophageal patterns and/or different clinical features exist. We further discuss strategies to study the pathophysiologic differences as observed in EoE patients in murine experimental EoE. Going forward, models of EoE that faithfully mimic EoE subentities as defined in humans will be essential because mechanistic studies on triggers which regulate the onset of diverse EoE subpopulations are not feasible in patients. Understanding how and why different EoE phenotypes develop will be a first and fundamental step to establish strategies that integrate individual variations of the EoE pathology into personalized therapy. The large number of recent reviews on eosinophilic esophagitis (EoE) illustrates the importance of research on this disease and underlines the great interest that allergists, immunologists, and gastroenterologists have in this condition. Several of the world-leading experts, including  Drs. Aceves, Cianferoni, Dellon, Furuta, Liacouras, Oyoshi, Rothenberg, and Spergel, have recently provided detailed overviews on the state of the art in EoE research –12. To aEoE is classified as a primary eosinophilic gastrointestinal disorder (EGID) . EGIDs cEoE is a clinicopathological disease. Quantification of esophageal tissue eosinophils combined with assessment of clinical symptomatology suggestive of esophageal dysfunction remains the gold standard in identifying patients with EoE , 17, 18.In daily practice, distinguishing between EoE and reflux-associated eosinophil infiltration of the esophagus as seen in gastroesophageal reflux disease (GERD) remains particularly difficult, especially since the recent recognition of a new entity: PPI-responsive esophageal eosinophilia (PPI-REE). PPI-REE has similar clinicopathological characteristics to EoE but resolves following high-dose PPI therapy , 28–30. Elevated serum IgE is found and used to identify allergen-sensitized EoE individuals that suffer from an IgE-mediated/allergen-driven disease phenotype. However, up to 50 % of EoE patients have normal serum IgE levels and, as defined by consensus using standard serum diagnostic approach, show no evidence for allergic sensitization in serum. In a conclusive opinion piece, it was recently argued that the pathogenesis of EoE is rather distinct from IgE-mediated food allergy . The autClinicians treat EoE to reduce, or ideally resolve, esophageal inflammation and to resolve symptoms. The most commonly used therapeutic strategies for EoE are proton-pump inhibitors, which are also important in the diagnostic phase; topical corticosteroids, most often in the form of swallowed fluticasone or liquid budesonide; and/or dietary interventions. Several dietary strategies are used, such as the six-food elimination diet, targeted food elimination based off allergy testing, and elemental diet therapy. Dilatation of esophageal strictures is also a treatment strategy used to relieve EoE associated symptoms, such as dysphagia; however, it has no effect on inflammation . The repGenerally, it is important to stress that the concept of differential disease subphenotypes and subgroups is not new to allergy research. For asthma, the most common allergic disease, disease subtypes and individualized therapy have, in fact, already been integrated in clinical practice and are known to be beneficial in guiding therapy –54. BasiClinical presentation of EoE is highly age dependent. Infants tend to suffer from feeding difficulties and failure to thrive. Children typically experience abdominal pain, nausea, vomiting, and heartburn, whereas adolescents and adults tend to present with dysphagia and episodes of food impaction , 56. RecProton pump inhibitor-responsive esophageal eosinophilia (PPI-REE) has recently been described  and may Another recently described phenotype of EoE consists of EoE patients with an extreme narrow-caliber esophagus. This patient group is characterized by a longer symptom duration and a disease phenotype that is rather refractory to steroid treatment .EoE is more prevalent in patients suffering from other disorders. For example, an association between EoE and celiac disease has been suggested. However, contradicting reports are found in the literature, and no mechanistic studies have been performed –64. AddiEsophageal tissue inflammation is described to be highly variable within the EoE patient group , 24. OurAnother EoE subgroup is defined by low transcript levels of LTC4S but elevated IL23 transcripts . IL23 iIn an independent study, we described another EoE subtype that is associated with an increased CD1d-restricted, invariant chain natural killer T (iNKT) cell compartment . JyonouThe distribution analysis of mRNA expression levels of the mast cell marker carboxypeptidase3 , 74 alsoDefining clinical subtypes in EoE patients is a first essential step towards establishing novel treatment strategies that take individual variations of the EoE pathology into account. Going forward, human cohorts might be less useful here because mechanistic studies are hardly feasible in patients.One perfect example for the problem of doing functional studies that define cause and effect in EoE pathology are studies on the role of the microbial signals for EoE development. Such studies are highly important in view of the recent description of the EoE specific microbiome  and the Experimental strategies to understand pathophysiologic differences of EoE as seen in patients require murine disease models that phenocopy human EoE and its subtypes in vivo as closely as possible. Using a variety of allergens, diverse types of sensitization, and different types of challenges, several murine models of experimental EoE have been described in the literature. For a conclusive review on the established experimental models of EoE, we refer to Mishra et al .Aspergillus in a sensitization/challenge type of model [Aspergillus model might be well suited to study MC-EoE. Since Aspergillus is also a common antigen in asthma, this strategy could also be useful for studying subtypes of EoE that are associated with asthma. In contrast, the combination of peanut antigen and sensitization with aluminum hydroxide as adjuvant  has been established for inducing iNKT cell infiltration in EoE [The most commonly used experimental EoE model uses intranasal application of of model , 94. Then in EoE , 94. It n in EoE .Following the established concept that EoE is, at least in a considerable number of patients, a manifestation of an IgE-mediated allergy, one has to consider that experimental murine EoE needs to be studied in models that faithfully mimic the human IgE network . ImportaR-TG mice [R-TG strains are characterized in detail and have been published by our group as well as others.As corroborated by studies from our own laboratory, allergic Th2-type diseases such as EoE are on the list of human conditions that are not fully modeled by the murine immune system in their complexity . For man-TG mice , 107–109-TG mice , 110. ItR-TG mice has provided surprising insights into the physiological role of FcεRI-bound IgE in allergy. None of the IgER-TG strains developed a spontaneous allergic phenotype, implying that the presence of cell-bound IgE on DCs does not drive the development of allergies, including EoE. Using three independently generated IgER-TG strains on two different backgrounds, less severe Th2-type allergic inflammation was found in the TG animals than in their wild-type counterparts, which did not have DC-bound IgE. Experiments with human DCs confirmed that IgE-crosslinking dampens the TLR-ligand-induced production of Th2-promoting cytokines, validating that experiments in the IgER-TG mice yield results that are directly relevant for human allergy [R-TG mice should be used as an improved model for studying mechanisms that regulate allergic IgE-mediated inflammation in EoE and the development of EoE disease subtypes.Research applying IgE allergy . Further allergy , substan allergy , 102. HoCumulative evidences support the existence of subtypes of EoE. Inflammatory tissue mRNA pattern analysis might be a feasible approach to define certain EoE patient subpopulations, but more studies are required to validate the approach. Currently, the development of experimental strategies that aim at providing mechanistic insights into cellular and molecular pathways that regulate the development of EoE subtypes are highly important. New insights into mechanisms responsible for the manifestation of diverse pathologies are a prerequisite to establish the concept of different EoE subtypes more convincingly. Research efforts along this line will lead to improved understanding of causative triggers for EoE, in general, and more specifically of factors that define individual EoE subtypes. A better understanding of diverse EoE pathologies, in turn, has the potential to direct the development of new therapeutic approaches with a focus on individualized patient therapy.R-TG, FcεRI transgenic; iNKT, invariant natural killer T cell; MC, mast cells; PPI-REE, PPI-responsive esophageal eosinophiliaCTDs, connective tissue diseases; DCs, dendritic cells; EGID, eosinophilic gastrointestinal disorder; EoE, eosinophilic esophagitis; FcεRI, high affinity IgE Fc receptor; GERD, gastroesophageal reflux disease; IgE


Phthalate exposure is prevalent in populations worldwide, including pregnant women. Maternal urinary metabolite concentrations have been associated with adverse reproductive outcomes, but underlying mechanisms remain unclear. Here we investigate inflammation as a possible pathway by examining phthalates in association with inflammation biomarkers, including C-reactive protein (CRP) and a panel of cytokines  in a repeated measures analysis of pregnant women (N = 480). Urinary phthalate metabolites and plasma inflammation biomarkers were measured from samples collected at up to four visits per subject during gestation . Associations were examined using mixed models to account for within-individual correlation of measures. Few statistically significant associations or clear trends were observed, although in full models mono-carboxypropyl phthalate (MCPP) was significantly , and mono-benzyl phthalate (MBzP) was suggestively  associated with IL-6. Overall these findings show little evidence of an association between phthalate exposure and peripheral inflammation in pregnant women. To investigate inflammation as a mechanism of phthalate effects in humans, biomarkers from target tissues or fluids, though difficult to measure in large-scale studies, may be necessary to detect effects. Exposure to phthalates diesters occurs ubiquitously in the United States and elsewhere through continual human contact with phthalate-containing materials, particularly flexible plastics, used in vinyl flooring, shower curtains, and food packaging containers, as well as personal care products such as perfumes, deodorants, and nail polish . PhthalaPhthalate metabolites are also readily detected in pregnant women –5, and tWe investigated whether phthalate exposure during pregnancy was associated with maternal inflammation in a study with repeated measures of exposure and outcome biomarkers. We examined concentrations of urinary phthalate metabolites collected at up to four time points per subject during pregnancy in association with plasma C-reactive protein (CRP), pro-inflammatory cytokines , and an anti-inflammatory cytokine (IL-10). We previously identified associations between urinary phthalate metabolites and the same panel of inflammation biomarkers in a small study of pregnant women in Puerto Rico . The prePregnant women included in the present analysis were part of a nested-case control study designed to assess the relationship between maternal phthalate exposure during pregnancy and preterm birth . SubjectUrine samples were analyzed for a panel of 9 metabolites, including mono (2-ethylhexyl) phthalate (MEHP), mono (2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono (2-ethyl-5-oxohexyl) phthalate (MEOHP), mono (2-ethyl-5-carboxypentyl) phthalate (MECPP), mono-benzyl phthalate (MBzp), mono-n-butyl phthalate (MBP), mono-iso-butyl phthalate (MiBP), mono-ethyl phthalate (MEP), and mono (3-carboxypropyl) phthalate (MCPP). Concentrations were measured via mass spectrometry at NSF International  using methods adapted from the Centers for Disease Control and Prevention procedures, described in detail by Lewis et al.  At the tSG = P[(1.015-1)/(SG-1)], where PSG represents the specific gravity corrected phthalate concentration, P represents the raw phthalate concentration, 1.015 is the median urinary specific gravity concentration in all samples measured, and SG is the specific gravity of that particular sample [For examining population distributions, phthalate metabolites were standardized to urinary specific gravity concentrations using the following equation: Pr sample . For staPlasma CRP was analyzed using a DuoSet enzyme-linked immunosorbent assay . Cytokines were assayed using a premixed Milliplex MAP High Sensitivity Human Cytokine Magnetic Bead Panel  and measured using a Luminex 200 instrument . All plasma biomarkers were analyzed by the University of Michigan Cancer Center Immunological Monitoring Core . Both methods and detection limits have been described in detail elsewhere . As withth and 75th percentiles of plasma inflammation biomarkers and specific gravity corrected phthalate metabolites for each study visit. To test for significant differences in biomarker concentrations by study visit we created linear mixed effect models (LME), adjusting for subject-specific random intercepts and slopes, with ln-transformed phthalate or inflammation biomarker concentration predicted by study visit as a factor  or as a numeric variable (to test for significant linear trends from visits 1–4).R version 3.1.0 was used for all statistical analysis . Unless 2, 25 to <30 kg/m2, or >30 kg/m2), and parity (nulliparous or parous). Additionally, we examined time of day of urine sample collection (before vs. after 1pm) as a covariate as this variable can improve the estimation of phthalate concentration. Beta coefficients from crude and full models corresponding to the fixed effects were converted to percent change of inflammation biomarker in association with an interquartile range (IQR) increase in urinary phthalate metabolite for comparison across metabolites and with other studies.LME were also created to test associations between each inflammation biomarker and each phthalate metabolite measured. Prior to model building, we tested whether to include subject specific random slopes by conducting a likelihood ratio test using restricted maximum likelihood. We also compared Akaike Information Criterion (AIC) values for models with and without inclusion of the random slope. Crude models were adjusted for urinary specific gravity to account for urine dilution. Full models were built by adding covariates one at a time and including in the model if they altered effect estimates by greater than 10 percent. Covariates considered for inclusion as fixed effects were those that were significantly associated with inflammation biomarkers, as previously published . These iWe performed several sensitivity analyses as well. First, we examined full statistical models in cases of preterm birth  as well as controls separately . We also created models stratified by gender of the fetus, as phthalates have been shown to have gender-specific effects in other studies , 27 and For the present analysis, subjects were included if they had both urinary exposure and plasma inflammation biomarkers from 1 or more study visits, and time points were excluded if they did not have both measurements. Additionally, one sample was excluded because of an extremely low and influential (changed LME model effect estimates by >10%) CRP concentration for all results presented . Weighted maternal demographic characteristics varied only slightly from those previously published on the overall population studied, and are presented in Percentiles of plasma inflammation biomarkers and urinary phthalate metabolite concentrations standardized to urinary specific gravity are shown in Results from crude and fully adjusted LME models for the associations between phthalate metabolites and inflammation biomarkers are presented in In sensitivity analyses, results stratified by preterm case status, fetal gender, and study visit were largely similar to the results presented in Finally, when stratified by visit associations between MCPP and IL-6 appeared to be stronger at visit 1  and visit 2  compared to visits 3  and 4 .We additionally examined the validity of the linearity assumption by using GAMMs. All but one of the associations were linear, as indicated by straight lines and intersecting confidence intervals in GAMM plots of the residuals. As an example, plots of IL-6 with MBzP and MCPP are displayed in In a large study of repeated biomarkers of phthalate exposure and inflammation in pregnant women, we observed few associations. The strongest associations observed were between MCPP levels and increased IL-6, and this association was strongest early compared to late in pregnancy. However, MCPP was not significantly associated with other cytokines indicative of inflammation, and even showed a suggestive inverse association with CRP. Associations between MBzP and MiBP and all inflammation biomarkers were positive, but few reached statistical significance. In general, we found largely null associations between urinary phthalate metabolites and systemic markers of inflammation during gestation.in vitro studies using various cell lines have demonstrated that some phthalates have a pro-inflammatory effect. One study showed that neonatal neutrophils treated with MEHP had increased IL-1β production, and that adult neutrophils treated similarly had increased IL-8 production [in vitro and animal studies of phthalate exposure and inflammatory responses, the preponderance of research has explored effects of DEHP or its metabolite MEHP; evidence for consequences of other phthalate exposure is minimal. An adjuvant effect of phthalates may also explain our findings of larger effect estimates for associations between exposure and inflammation biomarkers in mothers who went on to deliver preterm compared to term. Women who deliver prematurely are more likely to have higher levels of other inflammatory stimuli, as this is a well-recognized pathway to preterm birth, and thus phthalate exposure may act to exacerbate the effects of those stimuli.This evidence is somewhat contrary to previous studies, which suggest that phthalates can cause inflammation in biological systems. Several oduction . In anotoduction . Howeveroduction . These soduction , animal oduction –36, althoduction , and resCross-sectional human studies have also suggested associations between urinary phthalate metabolites and biomarkers of inflammation. In a large study from the National Health and Nutrition Examination Survey (NHANES), we previously observed significant positive associations between MiBP and MBzP and CRP in a population of male and female children and adults . While iDevelopment of asthma and allergies is the primary endpoint of interest in research devoted to phthalates and inflammation, as apparent from the animal research described above, and by a number of studies in human populations . One repWe previously published findings from a pilot analysis with repeated measures of urinary phthalate metabolites and this same panel of inflammation biomarkers in pregnant women from an ongoing birth cohort in Puerto Rico . That stin vitro studies, inflammatory consequences may be very specific to the target cells; effects in the periphery  may not be occurring in peripheral cells, and changes in the placenta may not be detectable in maternal circulation. This latter point is supported by research showing that inflammatory cytokines transfer minimally through the fully developed placental barrier [There are several explanations for the generally null findings observed in the present study. First, we utilized peripheral (plasma) biomarkers of inflammation. As shown by  barrier . For inv barrier . However barrier .Elements of the study design could have contributed to our null findings as well. Such elements include biomarkers selected for assessing inflammation or the timing and stability of exposure and outcome measurements. CRP and the panel of plasma cytokines measured were selected because of their observed associations with preterm birth in previous epidemiologic studies , and theOur study had a number of strengths which provide credence to these results. First, we had a large study both in terms of number of subjects and number of repeated measurements of both exposure and outcome biomarkers, which provided ample power for detecting these associations. Second, we used a panel of inflammation biomarkers to encompass multiple potential effects consequences .Third, the assays used to measure markers of both phthalates and inflammation were highly sensitive and thus we had excellent detection rates , 22. Finn-octyl) phthalate, which is still used commonly in plastic products while others like DEHP are being phased out. While we observed few associations overall between other phthalate metabolites and biomarkers of inflammation in peripheral plasma samples, future studies should aim to be more specific to cell type and site. Previous hypotheses argued that maternal inflammation may be a mechanism for the association between phthalate exposure and preterm birth, which we have previously established in this population [Of the phthalate metabolites measured in the present study, MCPP had the clearest associations with inflammation biomarkers, and these associations are in concordance with other epidemiologic studies. Animal and cellular studies should be expanded to examine effects of this metabolite and its parent compound, di (pulation . HoweverS1 Table(DOCX)Click here for additional data file.


In March 2012, a Salvadoran-American boy aged 7 years living in Maryland developed three slightly painful, well-demarcated, flat, gray-brown patches on his torso. A dermatologist in Washington, DC, suspected a fixed drug eruption (an erythema multiforme-like adverse drug reaction that occurs in the same location each time the person uses a particular medication). The child had recently taken a cough and cold remedy, Baczol Antigripal, which was made in El Salvador and purchased in a Maryland suburb of Washington, DC, without a prescription. The Baczol Antigripal ingredients included the sulfonamide-containing antibiotic trimethoprim-sulfamethoxazole (TMP/SMX), which is a common cause of fixed drug eruption. In June 2013, another Salvadoran-American child, a girl aged 14 years living in northern Virginia, was evaluated for a similar fixed drug eruption likely caused by a Baczol product purchased near her home. In August 2013, staff members from the Children’s National Medical Center investigated the availability of Baczol products in grocery stores in Salvadoran neighborhoods of Washington, DC, and neighboring suburbs. TMP/SMX-containing products were found in seven of 19 stores.Four Baczol products were identified; two listed TMP/SMX as an ingredient and were labeled for sale in El Salvador only. TMP/SMX is a known cause of fixed drug eruptions and other adverse drug reactions and cannot be legally dispensed in the United States without a prescription. On August 20, the Food and Drug Administration (FDA) issued a Safety Alert in English and Spanish.The dermatologist who diagnosed the first case and learned of the sale of Baczol Antigripal in Maryland notified Maryland’s Department of Health and Mental Hygiene that an antibiotic was being sold without a prescription. In April 2012, the department issued an alert regarding Baczol, which is sold in El Salvador as an over-the-counter remedy for the common cold and cough in children. The FDA has issued import refusals for those Baczol formulations that contain TMP/SMX , Virginia , and Maryland (Wheaton and Silver Spring). Search terms used included “Latino market,” “Latino grocery,” “Latin American market,” and “Latin American grocery.” The investigators identified areas within each neighborhood that appeared to have several Latino grocery stores in close proximity. They visited identified stores and conducted scripted questioning for Baczol. Latino grocery stores nearby that had not been found via the Internet search also were assessed with the same scripted materials. The investigators also searched the medical literature but found no cases of fixed drug eruption attributed to sulfonamide-containing drugs sold without prescription.TMP/SMX-containing products were found in three of seven stores in Washington, DC, one of six stores in Virginia, and three of six stores in Maryland. Two products, Baczol Antigripal  and BaczTwo additional products, also called Baczol Antigripal  and BaczA survey in South Carolina showed that 20% of Latino immigrants have obtained or purchased oral antibiotics without a prescription in the United States . In mostSelf-medication with antibiotics for viral illnesses is not consistent with prudent use of antibiotics. TMP/SMX is a known cause of fixed drug eruptions and other rare but potentially serious adverse drug reactions, such as Stevens-Johnson syndrome, toxic epidermal necrolysis, and bone marrow suppression . CompareWhat is already known on this topic?Self-medication with oral antibiotics obtained without a prescription has been observed among substantial numbers of persons in U.S. Latino communities.What is added by this report?Following reports of severe skin conditions in youths, approximately one third of Latino grocery stores surveyed in the greater Washington, DC, area were found to be selling illegally imported sulfonamide antibiotic preparations.What are the implications for public health practice?Clinicians should be aware that patients with severe skin conditions might have consumed nonprescribed antibiotics and should specifically ask about over-the-counter cold and flu remedies, especially when there is a suspicion of an adverse drug reaction. Health-care professionals and consumers are encouraged to report adverse events related to Baczol Antigripal and Baczol Expectorante to the Food and Drug Administration’s MedWatch Safety Information and Adverse Event Reporting Program.One Baczol formulation also contained metamizole (or dipyrone), a nonsteroidal antiinflammatory drug formerly widely prescribed outside the United States  as an analgesic and antipyretic, and banned by the FDA in 1977 because of its association with agranulocytosis . The druThis investigation showed that medications containing TMP/SMX are readily available from many Latino grocery stores in Washington, DC, and its suburbs. These products, Baczol Antigripal and Baczol Expectorante, might be confused with similar products legally sold in the United States. The legal formulations have the same names and nearly identical packaging as their TMP/SMX-containing counterparts. In response to this investigation, the FDA issued a Safety Alert in English and Spanish on August 20, 2013, advising consumers who have purchased one of these products to immediately stop taking it and consult a health care professional. Clinicians should be aware that patients might consume nonprescribed antibiotics and should specifically ask about over-the-counter cold and flu remedies, especially when there is a suspicion of an adverse drug reaction. Health-care professionals and consumers are encouraged to report any adverse events related to Baczol Antigripal and Baczol Expectorante to FDA’s MedWatch Safety Information and Adverse Event Reporting Program.†


For a long time, the stem cell regenerative paradigm has been based on the assumption that progenitor cells play a critical role in tissue repair by means of their plasticity and differentiation potential. However, recent works suggest that the mechanism underlying the benefits of stem cell transplantation might relate to a paracrine modulatory effect rather than the replacement of affected cells at the site of injury. Therefore, mounting evidence that stem cells may act as a reservoir of trophic signals released to modulate the surrounding tissue has led to a paradigm shift in regenerative medicine. Attention has been shifted from analysis of the stem cell genome to understanding the stem cell “secretome”, which is represented by the growth factors, cytokines and chemokines produced through paracrine secretion. Insights into paracrine-mediated repair support a new approach in regenerative medicine and the isolation and administration of specific stem cell-derived paracrine factors may represent an extremely promising strategy, introducing paracrine-based therapy as a novel and feasible clinical application. In this review, we will discuss the regenerative potential of fetal and adult stem cells, with particular attention to their secretome. Stem cell therapy has been shown to promote a substantial regenerative effect on damaged tissues and organs in several animal models. A large number of studies have provided strong evidence that stem cells  can mediate tissue repair through the modulation of the local environment, influencing the immune/inflammatory response, sustaining angiogenesis and establishing co-operative effects with the resident cells, overall resulting in a significant cytoprotective and pro-survival beneficial influence ,2. The min vivo has been demonstrated by a consistent body of studies on cardiovascular, renal, liver and lung injury, as well as in neurodegenerative disease models [Direct evidence that stem cell-derived secretome plays a key role in mediating the regenerative effects observed e models ,4,5,6,7.In this scenario, microvesicles have been described as key regulators of the stem cell paracrine activity. The term of extracellular microvesicles (MVs) was first introduced to indicate nano-sized bodies released as shedding vesicles by various cell types into the extracellular environment. They include: (i) Exosomes, which are 30–100 nm diameter vesicles of endocytic origin obtained upon fusion of multivesicular bodies (MVB) with the cell membrane; (ii) Ectosomes (shedding vesicles), which are 100 nm–1 μm diameter vesicles directly shed from the cell membrane; and (iii) Apoptotic blebs, 1–5 μm diameter vesicles secreted by cells undergoing apoptosis . Some coIn this review, we will discuss the latest and more relevant findings on the paracrine potential of the fetal and adult stem cells’ secretome for tissue regeneration and repair.Stem cells are undifferentiated cells characterized by the capability of producing new cells with equal stem functionality  or with restricted more specialized features via the expression of a specific committed phenotype (by differentiation) . AccordiThe possibility of deriving multi- and pluripotent cells from fetal tissues, with properties intermediate between embryonic and adult stem cells, has recently been described by several groups . Fetal tin vitro differentiation into adipogenic, osteogenic, myogenic, endothelial, neural and hepatic lineages; furthermore, they were recently demonstrated to give rise to induced pluripotent stem cells (iPS) via non-viral methods [in vivo in a limb ischemia-reperfusion rmouse model, by enhancing vasculogenesis via chemo-attraction of host endothelial precursor cells [in vitro co-culture system with human amniotic mesenchymal stem cells and primary fibroblasts from a patient affected by cystinosis with a lysosomal cystine transporter mutation (CTNS −/−). In this study, the amount of altered cell cystine detected in culture was significantly reduced, suggesting a paracrine effect of the amniotic stem cells on the mutant fibroblasts, which was mediated by the microvesicles derived from the stem cells and transferring wild type cystinosin and CTNS transcript to the affected target cells [Along with fetal tissue, amniotic fluid (AF) is another source of stem cells with suitable potential for therapeutic applications . Amnioti methods ,47. Rece methods . The humor cells . These ror cells . Moreoveor cells . The cytor cells ,54,55,56et cells . in vitro self-renewal properties, these stem cells may represent an ideal candidate for paracrine therapy, in order to isolate and scale-up putative drug-like formulation from their secretome for future regenerative medicine applications. In light of these considerations, fetal stem cells possess a promising paracrine capacity which may be the principal mechanism contributing to tissue repair, in addition to their multipotent differentiation potential. Considering their remarkable in vitro potential to give rise to adipogenic, chondrogenic and osteogenic lineages [in vivo low level of differentiation in the long term. Such a therapeutic effect seems to be mediated by the MSC paracrine potential to secrete trophic factors, which sustain local neovascularization, inhibit cell death with modulation of the immune response and mobilization and survival of host cells [in vitro proliferation and migration of endothelial cells in a dose-dependent manner with VEGF and bFGF being the key factors implicated in this process. Likewise, in a murine model of hindlimb ischemia, the factors released into the adult MSC-conditioned medium enhanced collateral flow recovery and remodeling, thus attenuating muscle atrophy [Adult stem cells are involved in the maintenance of homeostasis and physiological repair of somatic tissues and organs through a fine balance between self-renewal and differentiation; they reside in specialized niches, a term used to describe the complex interaction of different cells, matrix components and biological factors in distinct tissue locations . After alineages . Neverthst cells ,63. In ast cells . The carst cells ; in part atrophy . An addi atrophy . In ligh atrophy . in vitro specific MSC subpopulations with potential to induce the host regenerative response in vivo. Implantation of constructs seeded with bFGF-selected MSC led to formation of bone of host origin through the activation of an endochondral ossification process, whereas an intramembranous ossification directly performed by the seeded cells was observed in implanted constructs with unselected MSC [It has also been recently demonstrated that the intrinsic capacity of MSC to activate endogenous regenerative mechanisms and to induce the mobilization of host cells is critically dependent on their commitment level, highlighting the importance of carefully investigating the differences in the soluble morphogens used in the culture conditions. The addition of basic-fibroblast growth factor (bFGF or FGF-2) to primary bone marrow-derived MSC cultures proved to be a key element in order to select cted MSC . Moreovected MSC . A similcted MSC . Moreovected MSC . It is well known that the extracellular microenvironment contains solutions of proteins, polysaccharides as well as vesicles containing proteins, mRNA, and micro-RNA . Recent MVs and exosomes released by MSC are currently being tested in several other preclinical injury models, such as stroke , liver fVarious adult and fetal progenitor cells have been demonstrated to exert cytoprotective, pro-survival, anti-inflammatory, anti-apoptotic and angiogenetic effects on injured cells by secreting and delivering regenerative factors within MVs/exosomes. More recently, another mechanism underlying the paracrine hypothesis has been proposed, suggesting that the bioactive factors secreted by the exogenous transplanted stem cells, and contained in their conditioned medium, might act not only on the injured host cells, but also by targeting an endogenous progenitor population residing in the tissue, in order to recruit and activate them to initiate/sustain the repair process, overall improving the functional outcome by autocrine effects. This synergistic result, which is based on the intercellular crosstalk via paracrine signalling between the exogenous stem cells and the host endogenous progenitors, has been described in different cell therapy preclinical studies, in particular in cardiovascular, neural, bone and revascularization models. The restoration of cardiac progenitor cell (CPC) populations and the activation of the molecular pathways within their repair programme have been recently described following the paracrine effect mediated by transplanted adult bone marrow-derived stem cells in the setting of myocardial ischemic injury ,83,84,85Hence, these observations support the developing idea that harnessing the stem cell secretome can lead to a double beneficial influence on the injured tissue (1) by direct modulation of the local environment, thus providing an immediate cytoprotective, angiogenic and anti-inflammatory effect during the acute phase following injury and (2) by boosting the local resident stem/progenitor cells, with the aim of achieving a more pronounced tissue-specific repair programme and instructing the stimulation of resident endogenous progenitors as a critical mechanism for future development of pharmacological paracrine therapy.An additional feature of the paracrine therapy is represented by the characterization of the signalling mechanisms that orchestrate the activity of the stem cell secretome, and in this scenario, MV/exosome secretion represents a crucial aspect. Microvesicles and exosomes currently represent a very intriguing and timely focus in stem cell biology, as they are considered the key component mediating stem cell-derived paracrine effects on target cells via cell-to-cell signalling. Different studies have described them as active components of the pro-angiogenic and regenerative effects exerted by stem cells in animal models of myocardial ischemia/reperfusion injury or corneal assay ,92,93,94In the last few years, significant effort has been invested in stem cell-based therapy for tissue regeneration following injury, trauma and chronic disease. However, much scepticism still surrounds cell transplantation- and tissue engineering-based methods, due to their poor clinical feasibility, namely limitations associated with safety, immunogenicity, and, in many cases, limited efficacy of the injected cells. A strong limiting factor to stem cell-base therapy is also represented by the high cost of the procedure to treat each patient that precludes application to a large number of people within public and private health social systems. In this scenario, isolation and administration of specific stem cell-derived regenerative factors for future paracrine pharmacological therapy may represent an extremely promising strategy with the clinical advantage of limiting many of the safety concerns associated with the transplantation of viable replicating cells. Indeed, this approach represents a more tractable model to still obtain stem cell-mediated regenerative effects but through the cell-free delivery of soluble molecules, shifting attention from cell therapy to paracrine pharmacological treatment. Insights into paracrine-mediated repair support a new approach for regenerative medicine, via the identification of suitable cocktails of stem cell-derived trophic factors to trigger endogenous tissue repair mechanisms, thus introducing paracrine therapy as a novel and feasible clinical read-out for patients suffering from injuries and traumas. In addition, patients suffering from diseases such as ischemic injuries and/or traumas need prompt therapeutic intervention. Therefore, it would be ideal to have access to “off-the-shelf” products ready for administration on demand, and by taking advantage of our knowledge of the stem cell secretome, we could envisage the use of stem cells as “drug-stores” to produce specific soluble paracrine factors, which can ultimately be administered orally or systemically. As well, this strategy removes the invasive or additional surgical procedures generally required for cell-therapy or tissue engineering methods, together with the risks associated with them. in vivo stability of such molecules. Therefore, it is crucial to optimize the stem cell culture protocols in vitro, in order to produce the right amount, concentration and combination of paracrine factors and to obtain the required therapeutic effect once administrated in vivo [While paracrine therapy may represent a novel “cell-free” approach for tissue regeneration, it is worth considering that cytokine therapy strategies, based on the delivery of multiple/high doses of a single trophic factor, have not yet met expectations, due to problems related to appropriate delivery, pharmacokinetics and  in vivo .in vivo targeting of specific tissues. As a matter of fact, exosomes show several features of the ideal drug carrier, such as membrane penetration potential, intrinsic homing ability, long circulating half-life and the possibility of undergoing membrane modifications in order to enhance targeting of specific cell types [In this scenario, MVs and exosomes may represent an ideal vehicle for paracrine therapy, since they can be used as immunologically inert nano-carriers with the intrinsic capacity to carry a significant amount of stem cell-derived bioactive molecules , while protecting these from the degradative enzymes/chemicals and bypassing biological barriers for the ll types . Despitell types . mRNA anll types . One of ll types . In a sill types . Due to ll types . With thll types .in vitro and are referred to as preconditioning methods [ex vivo rat aortic and in a chick chorioallantoic membrane angiogenesis assay [in vivo ischemic environment, in which transplanted stem cells are likely to exert their beneficial effect, hypoxia preconditioning has been broadly used by subjecting MSC to physiological conditions of low oxygen tension (<5%) in vitro. This strategy induced adult and fetal MSC to secrete higher levels of pro-angiogenic and pro-survival cytokines, such as VEGF and bFGF, to counteract hypoxic effects, while activating survival pathways with genes like Akt, HO-1 and Hsp70 [in vitro. Preconditioning MSC with pro-inflammatory cytokines such as TGF-α, TNF-α and lipopolysaccharide (LPS) resulted in an increased production of VEGF, IL-6, IL-8 and MCP-1 [in vitro using different cocktails of signalling cues in order to mimick the injury setting might differ from the actual situation in vivo. A further relevant point to be considered for future stem cell-derived paracrine therapy regards the use of primary stem cells to isolate specific therapeutic factors. As a matter of fact, adult and fetal MSC  are characterised by significant, yet limited, proliferative and self-renewal potential. Thus, a scale-up production of MSC-derived paracrine factors for future applications would involve the use of repeated isolation of cells with the risk of batch-to-batch variation [MYC gene to demonstrate that, once immortalized, they can increase their proliferative rate, while maintaining the production of exosomes therapeutically effective in reducing the infarct size in a mouse model of cardiac I/R injury [Another crucial aspect to be evaluated, when harnessing the stem cell secretome for therapeutic purposes, is defining suitable strategies to stimulate the cells to release significant amounts of the desired paracrine factors in their conditioned medium or microvesicles, in order to provide tissue regeneration, as represented in  methods . Serum d methods . Moreoveis assay . To mimind Hsp70 ,109,110.nd Hsp70 . To imprnd Hsp70 ,114,115.nd MCP-1 ,118,119,nd MCP-1 . Similarnd MCP-1 . Neverthariation . In ordeR injury .® methodology, have been recently developed in order to simultaneously measure several hundreds of compounds in multiple samples, with the possibility of detecting cytokine concentration less than 1 picogram/mL [Lastly, the technology available to analyse the stem cell secretome will be an instrumental role for future paracrine therapy, since the cell culture medium conditioned by adult and fetal MSC is a subject of intensive characterization in the search for specific released factors and MVs/exosomes that might be used for regenerative medicine purposes. In this scenario, the techniques applicable to stem cell secretomics mainly focus both on proteomic analysis and microarrays for small RNAs screening, coupled with bioinformatic computational approaches . Proteomogram/mL . ® Systems), Bioinformatic Harvester and the Panther  have been recently developed to provide clusterings of groups, maps of signalling pathways and entries for possible interacting proteins in order to predict the putative roles of the stem cell secreted factors in metabolism, inflammation, immune response, development, tissue repair and regeneration [As for the proteomic characterization of the stem cell-derived MVs and exosomes, their profiling is based on the same techniques as for the measurement of soluble secreted peptides, such as one dimensional sodium dodecyl sulphate—polyacrylamide gel electrophoresis (1D SDS PAGE), liquid chromatography and mass spectrometry; at present, only a few studies have been published so far, such as those involving neural stem cells, adipose tissue and human embyonic stem cell-derived MSC ,124,125.neration . AlthougOver the past few years, we have witnessed scientists and physicians expressing increasing enthusiasm for the therapeutic potential of stem cells. Traditional cell therapy is based on the belief that, when healthy cells are injected into patients, they can stimulate the body’s own healing process. Recent data available on database about clinical studies of human participants conducted around the world  showed that more of 4600 stem cell-based therapeutic approaches are globally active, and 300 of those are MSC-related. Based on advanced cell technology, promising curative effects and ethical issues, MSC have become the most common cell source in cell-based treatment. In light of these considerations, many biotechnology companies are supporting stem cell therapy and focusing on producing and commercializing human cell technology to treat degeneration of tissue and organs. i.e., skin repair following burns or cornea regeneration), many concerns still exist related to the clinical application of stem cells for the repair of mesodermal tissue and organs with many researchers currently suggesting that the use of MSCs should be reconsidered. The clinical potential offered by MSC for therapeutic applications includes diverse clinical targets, and in most of the current ongoing clinical trials, stem cells seem to mostly contribute in modelling the in vivo regenerative microenvironment by secreting bioactive molecules acting on angiogenesis, inflammatory and local immune response. Although much effort has been invested into preclinical research, several concerns and risks associated with the direct use of stem cells still need to be addressed. As well, many questions remain unanswered, such as the potential of the transplanted stem cells to generate fully functional new cells in the patient’s damaged organ. In addition, we also need to consider a manufacturing risk: Stem cell therapy requires Good Manufacturing Practice (GMP facility) with a consequent drastic increase in the costs of cellular technology. Thus, despite the extensive research developed in the last 20 years and the encouraging results obtained with cell therapy for the regeneration of tissue such as the epithelium  are isolated from biopsy obtained by surgical procedures, fetal stem cells  can be harvested from leftover samples from prenatal diagnosis or discarded tissue collected at birth, avoiding all the surgical risks associated with the first source, which might retain some level of morbidity. At the same time, despite the fact that fetal stem cells retain a more immature potential and higher self-renewal properties compared to progenitor cells from adult sources, the characterisation of their secretome is incomplete and further studies need to be performed.Furthermore, to establish the basis of a future paracrine pharmacological therapy, it is of crucial relevance to identify the most suitable stem cell font. The ideal stem cell source should be selected upon consideration of their paracrine potential and the feasibility of their isolation, together with their in vivo must be performed and evaluated accurately [in vitro studies, thus it has to be considered that the secretome of cells cultured under specific controlled conditions might be quite different in terms of composition, concentration and timing from that in vivo, where stem cells can modulate their paracrine potential in response to the stimuli released by the injured microenvironment. Hence, it will be particularly important to profile the MSC secretome in vivo and to develop more sensitive techniques in order to characterise the dynamic expression of MSC-secreted factors and their qualitative and quantitative changes in response to the local milieu.Finally, although stem cell-derived paracrine therapy may represent an extremely exciting and novel therapeutic strategy, several aspects are yet to be addressed before clinical use of their secreted factors and MVs is considered. The large-scale production of specific paracrine molecules  obtained from cultured stem cells needs to be defined in detail; the regenerative potential of different preparations of stem cell-derived MVs and trophic factors has to be investigated and experiments to assess the long-term safety, bio-distribution and persistency of the therapeutic effects curately . FurtherIn this review, we discussed how the number of studies exploiting fetal and adult MSC therapeutic potential based on the release of regenerative trophic factors, rather than their direct trans-differentiation capacity, is rapidly evolving including several clinical applications, such as graft versus host disease (GVHD), myocardial infarct, stroke, acute kidney, lung failure, wound healing, rheumatoid arthritis, and multiple sclerosis . It is reasonable to conclude that the protective and restorative benefits mediated by adult and fetal stem cells are partially due to paracrine effects obtained by the release of specific cytokine, chemokine andgrowth factors, which are likely exerted via exosome and microvesicles secretion. At the same time, the advantage of using cell-based therapy relies on the possibility of providing the physiological concentrations of trophic factors to injured tissue at the appropriate timing; these synergistic effects may provide a regenerative microenvironment in the damaged tissue as well as recruit resident progenitor cells for tissue repair.The paracrine potential of adult and fetal stem cells might be then considered as a new regenerative medicine approach for future clinical use, in order to cure specific disease or congenital defects.


Our conceptualization of brain changes across the lifespan is evolving . First, they can provide valuable translatable physiologic biomarkers of the state of cortical reactivity, brain network connectivity and dynamics, and mechanisms of brain plasticity  techniques like transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) are well-suited to explore brain plasticity across the lifespan Young-Bernier et al. hypothesize that measures of short-latency afferent inhibition (SAI), reflecting cortical cholinergic activity, mediate age-related individual differences to the plasticity-inducing effects of theta burst stimulation (TBS). While their results confirm high inter-individual variability to TBS, no association could be observed with responsiveness to SAI. Particular sample characteristics or unexplored specific responses to the stimulation protocols on aged individuals could account for these results, and further research is needed. Puri et al. investigated the role of the Val66Met BDNF polymorphism (encoding for a synaptic potentiation related neurotrophine) in motor cortical plasticity following tDCS. After 20, but not 10 min of stimulation, they observed greater motor plasticity responses to tDCS in the Met allele carriers, along with marked reduction in inter-individual variability. Hence, BDNF may modulate the time-course of motor plastic responses in elders and may be important to stratify sample selection where more homogeneous responses to NIBS are required . Finally, Dickins et al. showed that the intermanual transfer of training simple motor skills is preserved in elders. However, for complex motor tasks, cortical excitability of the untrained hemisphere did only correlate with performance of the untrained hand in young individuals.A first set of studies focus on motor cortex plasticity. Chan et al. stress the relevance of obesity in advanced age as a condition aggravating age-related cognitive decline. As this effect is mediated through brain regions thought to sustain a relevant plastic role, the authors emphasize the need to promote plasticity, such as engaging in physical exercise. In a related study Arenaza-Urquijo et al. propose a theoretical perspective on brain and cognitive reserve postulates: amongst healthy aged subjects, exposure to lifetime enriched environments would mainly act through “neuroprotection,” leading to preserved brain function and structure. However, when considering patients at various stages of disease, higher reserve might translate to “compensatory” plasticity, providing greater capacity to minimize the clinical impact of pathology.Moving to the realm of cognitive function, Li et al. studied the effect of multimodal training , whereas Lampit et al. investigated the impact of computerized cognitive training. In both reports significant behavioral improvements were observed that were related to changes in brain connectivity. Moreover Lampit et al. showed that cognitive-training induced functional brain changes preceded structural modifications, providing new evidences about the dynamics of the neurobiological underpinnings subtending cognitive training responses in elders.The last set of studies aims to enhance cognitive function in aging through the use of non-invasive interventions. Sandrini et al. investigated the effects of NIBS on reactivation of consolidated memories . Compared to sham stimulation, tDCS with the anode over the dorsolateral prefrontal cortex (DLPFC) decreased the forgetting rate tested after 48 h and 1 month of initial memory encoding. However, combining brain stimulation with reconsolidation did not lead to better long-term memory performance. Following this pioneer work, further investigation is needed to determine if specific particular adaptations of the experimental reconsolidation designs are needed in elders. Fertonani et al. also applied tDCS targeting the DLPFC to investigate the time-course of plasticity effects on picture-naming tasks. They observed that young individuals benefited from stimulation when anodal tDCS was applied both during  and after task performance , whereas for elder individuals the benefit was only observed during online stimulation. These results revealing an age-dependent timing of stimulation response may be considered in further cognitive neurorehabilitation studies. Also, the work suggest novel insights about neuromodulatory approaches to age-related cognitive dysfunction, by showing that online stimulation, thought to be associated with changes in membrane potential, was more effective in elders than effects primarily linked to synaptic potentiation (offline stimulation).Three studies examined the efficacy of tDCS to enhance cognitive functions in elders. Meinzer et al. used anodal tDCS to enhance activity of M1 and investigated the impact on a word-generation task. The authors observed better performance both during anodal left M1 stimulation as well as during dual anodal left M1 and cathodal right M1, as compared to sham. Further, functional imaging data reflected that brain activity in premotor linguistic regions was enhanced, without effects in motor cortices. The findings hence, suggest that tDCS may have been acting as facilitating switching costs of two tasks that are engaging partially overlapping networks. They further show that tDCS can improve linguistic functions in aging by targeting brain sites  functionally linked to the language system, but avoiding the typical perilesional stimulation sites in stroke patients.Finally, In conclusion, the studies gathered in this Research Topic highlight the suitability of NIBS approaches to investigate the mechanisms and the consequences of plasticity associated to the aging process. From a methodological point of view, the findings contribute to our understanding of how major characteristics of the aging brain interact with stimulation parameters, hence stressing the need to consider distinct approaches when NIBS is to be applied to aged- as compared to young-populations. From a fundamental perspective, these studies provide novel insights into inter-individual differences in neuroplasticity, their relevance to the aging process and to behavioral and cognitive well-being in elders. In this regard, NIBS might even offer a novel intervention to promote cognitive function across the lifespan.DBF wrote a first draft of the text. SR and APL reviewed it and provided corrections and conceptual inputs.DBF was partially by research grant from the Spanish Ministerio de Economía y Competitividad (MINECO) ref. PSI2012-38257. APL was partly supported by the Sidney R. Baer Jr. Foundation, the NIH , the Football Players Health Study at Harvard University, and Harvard Catalyst; The Harvard Clinical and Translational Science Center .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.


Obesity is increasing at an alarming rate, with significant negative health, social, and economic consequences. While its impact on metabolism is manifest in the development of insulin resistance and type 2 diabetes, there are also connections between obesity and several chronic inflammatory diseases. Indeed, obese individuals are at higher risk of cancer, asthma, as well as intestinal and pulmonary diseases and their overall mortality is higher. Chronic low-grade inflammation in the expanding white adipose tissue (WAT) may mediate the association between excessive body fat accumulation and inflammatory diseases. The exact trigger of WAT inflammation is unknown, however, several mechanisms have been proposed such as e.g. hypoxia, endoplasmic reticular stress, and excess saturated fatty acids. Furthermore, WAT macrophages and T lymphocytes have also important roles in the inflammatory process: proinflammatory macrophages (M1 macrophages) accumulated in the obese WAT while in contrast the numbers and frequencies of anti-inflammatory regulatory T cells (Tregs) and group 2 innate lymphoid cells (ILC2) are reduced. Finally, alterations in gut microbiota composition and diversity were recently suggested to play a key role in the development of obesity-related inflammatory diseases. Our talk will provide an update on the mechanistic aspects of the pathogenesis of adipose tissue inflammation, insulin resistance and chronic inflammatory diseases such as those resulting from pulmonary infections. We will also suggest some new therapeutic strategies that could be derived in order to prevent and/or reverse these processes; such as the development of immunological or dietary interventions.


P = .005). School policy restricting student access to sports drinks at school may contribute to decreasing consumption of sport drinks among school-aged youth and improving student weight outcomes in this population.This ecologic study evaluated the association between school policy allowing students to purchase sports drinks from school vending machines and school stores and student body mass index (BMI). Data were from surveillance surveys of Minnesota secondary schools (n = 238) and students , administered in 2012 and 2013, respectively. We used generalized linear models to assess the association between policies and mean age- and sex-adjusted BMI percentile. In adjusted multivariate analysis, school policy was positively associated with BMI percentile ( Sugar-sweetened beverages (SSBs) are typically defined as some combination of regular soda, sports drinks, energy drinks, or fruit drinks. Considerable data support a link between the consumption of SSBs and weight gain and obesity . Policy Although several studies have examined the link between school policy allowing student access to SSBs at school and student weight outcomes , albeit The School Obesity-Related Policy Evaluation study uses existing state and national surveillance data to examine school obesity prevention policies in Minnesota secondary schools . School-Student-level data were obtained from the 2013 Minnesota Student Survey, administered in public schools every 3 years by the Minnesota Department of Education . In 2013School-level demographic characteristics were obtained from the National Center for Educational Statistics (NCES) common core data and included percentage minority enrollment and free- or reduced-price lunch eligibility, both assessed as continuous variables. School location, categorized as city, suburb, or town or rural, was constructed using a combination of NCES and Rural–Urban Commuting Areas classification schemes . This stThe analysis was restricted to schools that completed the 2012 Profiles principals survey (n = 238) and whose students participated in the 2013 Minnesota Student Survey . Consistent with an ecologic study design, school-level analyses were performed with individual student responses averaged within each school. Generalized linear models were used to assess the association between policy that allowed students to purchase sports drinks from VMSS and mean school-level BMI percentile. The model was adjusted for school-level demographics and policies allowing student purchase of soda pop/fruit drinks and snack foods. All analyses were conducted using SAS version 9.4, 2013 .P = .005).Characteristics of the sample are in the Sports drinks are a recognized source of added sugars. School policy that restricts student access to sports drinks at school may contribute to decreasing consumption of sports drinks among school-aged youth and improving student weight outcomes. Recent evidence suggests that, among adolescents, the frequency of consuming sports drinks is associated with greater increases in BMI .This study has several limitations. School and student surveys were cross-sectional. However, school policy data were collected 1 year before the student data, providing a reasonable time lag between policy implementation and assessment of student BMI. School-level associations may not reflect student-level associations. Other limitations were use of self-report data and a school sample that was mostly rural and white.The Smart Snacks in School standards may contribute to a changed school food environment in which a healthy choice is the usual choice. However, a decade of school policy research suggests that the makeover will not occur overnight and that gains seen today may be lost tomorrow, especially in high schools. The popularity of sports drinks merits continued attention and further study. Empirical evidence is needed to support the advancement and institutionalization of food policy that promotes healthy food choices at school.


We highlight recent data reporting that treatments particularly those genotoxic can induce highly conserved damage responses in non-cancerous constituents of the tumor microenvironment (TMEN). Master regulators, including but not limited to NF-kB and C/EBP-β, are implicated and their signal cascades culminate in a robust, chronic and genome-wide secretory program, forming an activated TMEN that releases a myriad of soluble factors. The damage-elicited but essentially off target and cell non-autonomous secretory phenotype of host stroma causes adverse consequences, among which is acquired resistance of cancer cells. Harnessing signals arising from the TMEN, a pathophysiological niche frequently damaged by medical interventions, has the potential to promote overall efficacy and improve clinical outcomes provided that appropriate actions are ingeniously integrated into contemporary therapies. Thereby, anticancer regimens should be well tuned to establish an innovative clinical avenue, and such advancement will allow future oncological treatments to be more specific, accurate, thorough and personalized.Cancer is a highly aggressive and devastating disease, and impediments to a cure arise not just from cancer itself. Targeted therapies are difficult to achieve since the majority of cancers are more intricate than ever imagined. Mainstream methodologies including chemotherapy and radiotherapy as routine clinical regimens frequently fail, eventually leading to pathologies that are refractory and incurable. One major cause is the gradual to rapid repopulation of surviving cancer cells during intervals of multiple-dose administration. Novel stress-responsive molecular pathways are increasingly unmasked and show promise as emerging targets for advanced strategies that aim at both  There are obstacles in clinical cancer therapies. For years, solid tumors account for the major burden to human health, and epithelial cancers arising in tissues including lung, breast, prostate, colon, ovary and pancreas constitute approximately 80% of all cancers , unexpectedly, trigger prosurvival signaling in a neoplastic or pre-neoplastic context by providing a micro-reservoir of various pathophysiological conditions that harbor occult arsenals and subsequently fuels tumor relapse. How to overcome these obstacles to successful anticancer treatments remains an increasingly hot topic and requires intelligent inputs from both basic and translational perspectives.in vitro by a range of biochemically unrelated DNA damaging anticancer moieties, such as DNA topoisomerase I inhibitor camptothecin, the topoisomerase II inhibitor doxorubicin, the cross-linking agent cisplatin, or to a lesser extent, the anti-metabolite cytarabin. In contrast, some anti-microtubule agents that do not damage DNA such as docetaxel, vincristine or vinblastine basically cause senescence but fail to produce a secretory phenotype (unpublished). It is conceivable that cancer cells in a senescence-like state might remain as “dormant” tumor cells and therefore represent a dangerous potential for tumor relapse   family members are upregulated in senescent fibroblasts in particular stromelysin-1 and -2  and collagenase-1 (MMP-1)  production, where increased functional mitochondria are involved  and inhibits their therapeutic actions through inhibition of AP-1 activity. Vice versa, forced expression of miR-335 resulted in early senescence-like alterations in hMSCs, including increased SA-β-gal activity and cell size, reduced cell proliferation capacity, augmented p16 expression, and more importantly, the development of a DDSP phenotype, indicating that miR-335 plays a key function in the regulation of reparative activities of hMSCs and that it not only mediates senescence/DDSP signaling but might be considered a marker for the therapeutic potency of these cells in clinical applications , negatively regulate the senescence-associated secretion of IL-6 and IL-8  polymerase 1 (PARP-1) detects DNA lesions and promotes DNA repair, but can also mediate NF-κB activation upon genotoxic stress, as suppression of NF-κB activity and CCL2 secretion by the PARP-1 inhibitor 3-AB diminishes a secretome in senescent melanoma cells . Once approved to enter clinical trials, they will demonstrate the values in circumventing the side-effects of DNA-damaging treatments. In a long term, it benefits to develop medication that enhances DNA damage but sever the signaling pathway arising from DDR events to the downstream consequence, DDSP program development, thereby depriving cancer of acquired resistance and reducing disease incidence, progression and mortality.Recently immunotherapeutics have entered clinics, largely on the basis of the recognition that several types of immune activities are correlated with tumor development. Although resistance-augmenting microenvironments represent a major barrier to effective elimination of multiple malignancies, combination regimens including synergistic chemoimmunotherapeutic approach that involves anti-CD20 (or anti-CD52) turns out to be a potent strategy for using conventional anticancer agents to alter the TMEN and promote the efficacy of targeted treatments  and have the capacity to regenerate the tumor, occurs during a course of fractionated radiotherapy or chemotherapy. As a result of influence from the TMEN that not only limits drug distribution but exerts multiple anti-treatment forces, repopulation often has a dominant and limiting effect on therapeutic index, and accelerated repopulation during successive therapy can lead to an initial response followed by tumor regrowth in the absence of intrinsic sensitivity change of cancer cells (Yu and Tannock, Upon chemotherapy tumor growth will follow a Gompertzian curve, and the rate of regrowth would be faster after shrinkage induced by treatment (Norton and Simon, Repopulation depends on the activation of specific signaling pathways to promote cancer cell proliferation. In clinical trials, agents including small molecule inhibitors and antibody-based pharmaceuticals can be given concurrently or continually with conventional therapy (Hallek et al., On the other hand, despite tremendous resources being exploited in cancer biology and clinical oncology, there are progressively increasing failure rates, high cost, low bioavailability, poor safety, limited efficacy, and a lengthy design and testing process associated with cancer drug discovery and development. Exploring established non-cancer drugs for anticancer activity provides an opportunity to rapidly advance therapeutic strategies into clinical trials (Gupta et al., Considerable progress is made in elucidating the underlying mechanisms of cancer resistance, with expected innovation in therapeutic design, both conceptually and practically. However, much is still in dark and many blanks remain unfilled. By nature, cancer is caused not just by bad cells or bad genes, but also by good ones not doing the right thing—an aspect of the disease that is highly complicated to study and to combat Bourzac, . The keyPreclinical trials are ongoing to evaluate strategies to manipulate the distinct phenotype of DNA-damaged cells, and a promising methodology is to combine the use of cytotoxic agents which shrink tumor mass by selectively inhibiting cell proliferation and that of novel drugs to diminish the development of DDSP of damaged TMEN during treatment intervals, a combined and integral approach. Although for new trials prudential scheduling of multiple agents between courses of therapy is not only necessary but essential, priority should be given to experimental and clinical studies of the process, which may be more complicated than thought. Last, but not least, translation of most scientific findings from laboratories to clinics has the potential and holds promise to improve the safety and efficacy of anticancer therapies, by successfully cutting the lifeline of cancer cell populations.