Extracellular vesicles (EVs), including exosomes, microvesicles, and apoptotic bodies, are cell-derived membranous structures that were originally catalogued as a way of releasing cellular waste products. Since the discovery of their function in intercellular communication as carriers of proteins, lipids, and DNA and RNA molecules, numerous therapeutic approaches have focused on the use of EVs, in part because of their minimized risk compared to cell-based therapies. The skin is the organ with the largest surface in the body. Besides the importance of its body barrier function, much attention has been paid to the skin in regenerative medicine because of its cosmetic aspect, which is closely related to disorders affecting pigmentation and the presence or absence of hair follicles. The use of exosomes in therapeutic approaches for cutaneous wound healing has been reported and is briefly reviewed here. However, less attention has been paid to emerging interest in the potential capacity of EVs as modulators of hair follicle dynamics. Hair follicles are skin appendices that mainly comprise an epidermal and a mesenchymal component, with the former including a major reservoir of epithelial stem cells but also melanocytes and other cell types. Hair follicles continuously cycle, undergoing consecutive phases of resting, growing, and regression. Many biomolecules carried by EVs have been involved in the control of the hair follicle cycle and stem cell function. Thus, investigating the role of either naturally produced or therapeutically delivered EVs as signaling vehicles potentially involved in skin homeostasis and hair cycling may be an important step in the attempt to design future strategies towards the efficient treatment of several skin disorders. Due to Extracellular vesicles (EVs) comprise a heterogeneous variety of membrane-enclosed structures in terms of size, mechanisms of biogenesis, composition, cargo, and functions. They contain transmembrane proteins and enclose components derived from the donor cell that may include proteins, lipids, and DNA and RNA molecules ,5,6. MosAccording to their route of biogenesis, EVs are generally classified into three subtypes, namely, exosomes, microvesicles, and apoptotic bodies, with the former having been more frequently connected to skin regenerative processes. Exosomes are 30–150 nm vesicles which originate via the endocytic pathway. Normally, inward budding of the plasma membrane or fusion of vesicles gives rise to early endosomes, which in turn can undergo inward budding, forming so-called multivesicular bodies (MVBs). The intraluminal vesicles created by this process can either be directed to degradation in late endosomes, involving lysosomes, or can be secreted to the extracellular space by exocytosis, which is mediated by the fusion of MVBs with the plasma membrane ,10. SincThe skin wound healing process comprises four stages: (1) hemostatic, (2) inflammatory, (3) proliferative, and (4) remodeling ,18. DuriAdditionally, it has been suggested that multipotent neural SCs obtained from HFs can serve as exosome producers, based on the beneficial effects of a conditioned medium for the treatment of ischemia-reperfusion-induced lung injury in a rat model . Hence, However, robust conclusions and defined clinical protocols are still hard to define because of the lack of consensus regarding the source of EVs used in different studies, the models chosen to test EV treatments, and the methods used for EV delivery. Additionally, the technical procedures used to isolate, purify, and quantify exosomes and microvesicles, which have been fairly extensively reviewed , are indThe cell population of melanocytes, which are resident in the skin but originate at the neural crest during embryonic development , accountImportantly, not only can the exosomes potentially secreted by melanocytes affect the pigmentation process, but also signaling molecules carried by exosomes originating in other cell types resident in the skin could affect melanocytes. In this regard, one sophisticated study has compared the effects of exosomes obtained from human keratinocytes of different skin phototypes to stimulate melanocyte function, as well as the potential of ultraviolet B (UVB) light to modulate this capacity. Interestingly, the expression of key proteins participating in the pigmentation process, such as the enzyme tyrosinase, the melanocyte isoform of microphthalmia-associated transcription factor (MITF), which is the master transcriptional regulator of melanogenesis, and the Rab27a protein, involved in the mobilization of melanosomes, were proven to be increased in melanocytes in the presence of exosomes either obtained from Caucasian donors and treated with UVB, or obtained from black donors . This grOne previous study focused on rodent incisors found evidence of exosomes mediating epithelium-mesenchyme molecular crosstalk . Since tDrosophila [Bone morphogenetic proteins (BMP), which emanate from dermal cells and adipocytes, maintain SC quiescence during telogen . Interesosophila .MicroRNAs (miRNAs) are small noncoding RNA molecules which are capable of altering gene expression post transcriptionally and are typically transported in EVs ,57. ThesSeveral important signaling pathways involved in key cellular processes such as cell migration, proliferation, and survival are activated by epidermal growth factor (EGF) ligands binding their receptors on the plasma membrane. Among these, the routes involving Pi3K/AKT, MAPK/ERK, STAT3, and IGF1 have been connected with exosome-mediated effects on skin wound healing or hair growth ,27,28,53Although only a few studies have focused on the use of exosomes to stimulate hair growth, the findings in this field are promising. A patented study has provided the first evidence of exosomes obtained from MSCs being a central component of a pharmaceutical composition directed at enhancing hair growth . The indOverall, these observations suggest that since EV cargo has the potential to target a wide range of molecular processes and recipient cells, EVs emerge as both natural mediators potentially participating in the control of the hair cycle and promising delivery vehicles for the improvement of skin and hair regeneration. More work needs to be done in order to determine both the physiological contribution of exosomes to the HF cycle in vivo and the therapeutic potential of the use of exosomes in the clinics in order to modulate hair growth.Different types of EVs have been implicated by a myriad of studies in interactions that involve and affect immune cells ,72. ConcThe importance of the crosstalk between immune cells and skin and HF cells has also been highlighted by the classification of alopecia areata as an autoimmune disorder involving a switch of mast cells towards a proinflammatory phenotype . Mast ceIn this context, the use of exosomes as carriers of danger-associated molecular patterns (DAMPs) and molecules that regulate T-cell function can exert either a direct effect on HF SCs or an indirect effect through the activation of immune cells involved in the inflammatory response. This can mimic molecular signals that participate in the activation of skin SCs in response to skin damage, although it remains unknown whether exosomes are involved in this type of mechanism during physiological skin homeostasis and repair. Strikingly, exosomes enriched in telomeric repeat-containing RNA (TERRA), which are non-coding RNAs that contribute to telomere function, have been identified . These TThe emergent role of EVs in HF dynamics is likely to become a high-impact tool in cosmetic and skin regenerative biomedicine. In line with recent work revisiting the isolation and purification methods of different types of EVs ,45,85, t


The adoption and implementation of best practices in cancer screening, and timely research to address new questions, holds great potential to reduce morbidity and mortality from cancer around the globe. Sharing knowledge and experiences across different cancer screening programs and different settings can accelerate more effective screening implementation and evaluation and identify research opportunities to advance cancer prevention and control. In October 2019, two publications in this journal described the value of international research networks and, more specifically, the International Cancer Screening Network (ICSN).3 This seemingly straightforward task was, in fact, a very ambitious one. Comparing outcomes of programs without country-specific contexts, such as differences in health care systems, organization of screening activities, screening policies, and follow-up results, leads to comparisons that may mischaracterize program effectiveness and obscure strengths and potential development opportunities. At the same time, the process of trying to understand these differences and how they might affect outcomes of screening is extremely helpful to establish a standardized approach in comparisons of screening programs.The ICSN began with an initiative of Prof Sam Shapiro to create a common database for the evaluation of breast cancer screening programs.4 The ICSN has become even more expansive in recent years, including sessions at its biennial meetings on prostate cancer screening, lung cancer screening, and oral cancer screening. Inclusion of the latter cancer site also reflects the growing aspiration of the ICSN to reach out and include screening professionals from low- and middle-income countries (LMICs). As LMICs are increasingly affected by growing numbers of patients with cancer, the opportunity to learn from experiences of the countries with more established screening programs may accelerate effective implementation and evaluation of their cancer control programs. At the same time, learning from the experiences of LMICs may also encourage re-evaluation of cancer screening programs in high-income settings.With support from the US National Cancer Institute (NCI), the ICSN started as the International Breast Cancer Screening Network (IBSN). The inaugural meeting of the IBSN was held in 1988 with representatives from 11 countries. By 2005, IBSN membership had grown to 27 countries. In May 2006, the scope of the network was expanded to include additional cancer sites, spurred by the fact that many IBSN members were already becoming involved in cervical and colorectal cancer screening programs. Consequently, the network was renamed to the ICSN.2 of ICSN participants showed that the distribution of years of experience in the field of cancer screening, work activities, and workplace affiliations differed between HICs and LMICs. HIC respondents had more years of experience in the cancer screening field, were more likely to be engaged with research, and worked primarily in academic settings. In contrast, LMIC respondents spent more time directly involved with various aspects of implementation and management of screening programs and worked primarily in government agencies. Differences were also observed with regard to cancer site of interest. HIC respondents were interested in colorectal, lung, and prostate cancers, whereas LMIC respondents were more interested in cervical cancer. As the authors note, these differences are consistent with the distribution of cancer burden between HICs and LMICs and the emergence of screening programs in LMICs in recent years. Respondents from both HICs and LMICs reported that the ICSN, through its biennial meetings and scientific working groups, fosters collaboration and facilitates networking and knowledge sharing. Notably, LMIC respondents reported that the ICSN particularly facilitated the receipt of technical assistance for screening implementation in their settings.2Broadly, results from the 2018 survey by Puricelli Perin et alThese survey results illuminate the many contributions of the ICSN. However, as the network has grown and the field of cancer screening has enlarged to include more cancer sites, meeting the needs and interests of members across programs and settings has become more challenging, particularly for setting biennial meeting agendas. What began as a small, collaborative group of breast cancer screening researchers has expanded to encompass a much larger and more diverse group of dedicated professionals representing different aspects of research, implementation, monitoring, and evaluation. The spirit of knowledge sharing and networking remains, as evidenced by the survey results, but we believe that the ICSN could be further strengthened through increased focus on the efforts of the scientific working groups at future meetings and support of their continued work between meetings. Historically, ICSN working group initiatives with support from the NCI have resulted in the publication of 21 papers comparing outcomes of cancer screening programs across participating countries and have advanced other collaborative research efforts. Future working group efforts could support early-career researchers interested in screening by providing opportunities to actively engage in collaborative projects, define relevant research topics, and further facilitate knowledge sharing and networking across settings.5 By providing an inclusive forum for dedicated screening professionals to collaborate in cancer screening research and evaluation, engage in knowledge sharing, and mentor the next generation of screening professionals, the ICSN is uniquely positioned to play an important role in global cancer control.The mission of the ICSN is to reduce the burden of cancer by promoting dialogue and collaborative cancer screening research and evaluation regarding the effectiveness of context-specific evidence-based cancer screening programs, including promotion, recruitment and follow-up, among other relevant topics. Recent evidence suggests that cancer will surpass cardiovascular disease as the leading cause of death in many HICs and some middle-income countries.


Epilepsy is a neurological disorder characterized by a long term propensity to produce unprovoked seizures and by the associated comorbidities including neurological, cognitive, psychiatric, and impairment the quality of life. Despite the clinic availability of several novel antiepileptic drugs (AEDs) with different mechanisms of action, more than one-third of patients with epilepsy suffer with pharmacoresistant epilepsy. Until now, no AEDs have been proven to confer the efficacy in alteration of disease progression or inhibition of the development of epilepsy. The ketogenic diet, the high-fat, low-carbohydrate composition is an alternative metabolic therapy for epilepsy, especially for children with drug-resistant epilepsy. Recently clinical and experimental results demonstrate its efficacy in ameliorating both seizures and comorbidities associated with epilepsy, such as cognitive/psychiatric concerns for the patients with refractory epilepsy. Of importance, ketogenic diet demonstrates to be a promising disease-modifying or partial antiepileptogenesis therapy for epilepsy. The mechanisms of action of ketogenic diet in epilepsy have been revealed recently, such as epigenetic mechanism for increase the adenosine level in the brain and inhibition of DNA methylation. In the present review, we will focus on the mechanisms of ketogenic diet therapies underlying adenosine system in the prevention of epileptogenesis and disease modification. In addition, we will review the role of ketogenic diet therapy in comorbidities associated epilepsy and the underlying mechanisms of adenosine. Possible implications of the ketogenic diet (KD), a high-fat, low-carbohydrate diet, have been demonstrated in neurological fields, for instance: cognitive decline and dementia , 2, ParkThe term epileptogenesis refers to a complex processes that happens prior to the initial epileptic seizure appears to translate the epileptic brain with higher propensity of recurrent seizures and processes that aggravate seizures to drug resistant , which iThe high-fat, low-carbohydrate KD has been regarded as a palliative therapy for pharmacoresistant epilepsy in children and adults. The 30% of children with pharmacoresistant epilepsy on the diet had more than 90% seizure reduction, and 52% of the children had more than 50% seizure reduction at 3 months . Even inIn addition, experimental research also indicated that KD therapy prevented disease progression in two different typical animal models of epilepsy induced by electrical kindling and chemicoconvulsants . In the Recent evidence demonstrated that KD treatment also confers antiepileptogenesis efficacy in genetic models of epilepsy with kcna1-null mutant mice , 33. KcnHowever, there exist controversies on whether KD therapy has the role of antiepileptogenesis or disease modification. In the post-traumatic epilepsy model, a good model to test antiepileptogenic therapies , no evidIn addition, the adverse effects of the KD had been reported in extensive studies . The chi+ channels  promote sleep and downregulation of adenosine (decrease adenosine level or inactivation of adenosine receptors) induce wakefulness . It is hThe overall review design was conceived and supervised by TL. FC, XH, and GL helped in the writing different parts of the review. All authors read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The participation of recreational runners in sport events ranging from 5 km to ultra-endurance races have increased dramatically during the last decades and this phenomenon has attracted scientific interest. Most research has focused on the physiological characteristics of these runners and less in their psychological characteristics. Therefore, the aim of the present study was to review the existing knowledge with regards to the personality of recreational endurance runners and the role of sex, age and performance. It was concluded that limited information was available with regards to the personality of recreational marathon runners. So far, our knowledge on the personality of marathon runners relied on studies conducted a few decades ago, mostly on competitive marathon runners, highlighting the need for original research on recreational runners. The beneficial role of endurance exercise for health might explain partially the increase of participation in marathon races during the last decades . With reTo the best of our knowledge, no review has been even conducted on the personality of marathon runners. Information from a review on this topic would be of great practical importance for strength and conditioning coaches, and sport psychologists working with marathon runners, especially considering the increased number of finishers and races during the last years. The recent trends in participation and performance were that relatively more women and older runners participated compared to the past, and overall race times became slower ,9, highlA general overview of the psychological profile of marathon runners has been derived from studies comparing them with general population. The cognitive anxiety, arousal, self-confidence, motivation and perception of physical state were the most representative variables of marathon runners psychological state . The psyConsidering the limited existing data on marathon runners, the psychological profile of ultra-marathon and other sports was examined, too. For instance, a study on triathletes indicated low levels of anxiety and high levels of self-confidence . It has Several studies investigated the prevalence of menstrual irregularity and anorexia nervosa in women endurance and ultra-endurance runners. Menstrual irregularity has been experienced by ~40% of ultra-marathon runners during periods of intensive training due to emotional stresses of competitive ultra-marathon running, and menstrual patterns normalised once these stresses were removed . In womeRunners participate in marathon races usually classified in 5-year age groups . As the rate of participation and performance has been shown to vary by age group . The samThe increased rates of participation in marathon during the last decades were attributed mostly to the entry of relatively old age groups of recreational runners rather than to competitive runners . TherefoOn the contrary, other studies did observe a similar personality between marathon runners and other athletes. For instance, no difference was found between women marathon and non-marathon runners in anxiety, self-esteem, family/spouse relationships and addictive behaviours . CompareRace time in marathon was related to and repression-sensitization (faster runners being more sensitized), but not to locus of control . In addiThe personality traits of marathon runners might have changed across time. The increased number of participants, especially of women and master athletes, in marathon races during the last decades resulted in a more recreational and less competitive profile of marathon runner nowadays compared to the past. Accordingly, the race time lowered, e.g., by 47 min from 1980 to 2014 in a USA marathon race and the age increased . Thus, cIn summary, limited information was available with regards to the personality of recreational marathon runners. So far, our knowledge on the personality of marathon runners relied on studies conducted a few decades ago, mostly on competitive marathon runners, highlighting the need for original research on recreational runners.


To compare the effectiveness of exercise therapy with surgery for lumbar spinal stenosis.Five English databases PubMed, the Cochrane Library, Web of science, OVID and PEDro database were searched for randomized controlled trials comparing surgical procedures with exercise therapy for lumbar spinal stenosis. Information on patients, study design, inclusion criteria, intervention and follow-up, outcomes, treatment details and adverse events were extracted. Meta-analysis was performed using Review Manager Version 5.3.Two randomized controlled trials and one mixed design trial with a total of 897 patients were included. The pooled results showed a significant difference between exercise and surgery in Oswestry Disability Index at two years , but no significant difference at six months  and one year . In terms of physical function of 36 Items Short Form Health Survey, there were no significant differences between exercise and surgery at six months , one year  and two years .In brief, the current evidence demonstrated a trend that exercise therapy had a similar effect for lumbar spinal stenosis compared with decompressive laminectomies. However, for the small sample size and low methodology quality of the included trials, some rigorously designed and large-scaled RCTs need to be performed to confirm the conclusion. Lumbar spinal stenosis (LSS) is one of the most prevalent and disabling conditions in people older than 65 years, which may lead to pain in low back, buttocks or lower extremities as well as neurogenic claudication2As one of the conservative modalities, exercise therapy can play an important role in the treatment of LSS. In a study of forty-five patients with LSS, Ahmet found that the leg pain and disability scores significantly decreased in patients treated using three-week therapeutic exercises compared with those without treatment.6In addition, patients with severe spinal stenosis are usually treated using surgical procedures, and subsequently it is important to evaluate the effectiveness of exercise therapy versus surgery. In a systematic review, JarrettTherefore, we performed this systematic review and meta-analysis, and our purpose was to evaluate the evidence of the effectiveness of exercise therapy versus surgery.A medical literature search was carried out in the following databases from their inception through June 15, 2017: PubMed, the Cochrane Library, Web of science, OVID and PEDro database. The language of these studies was restricted in English. The searching was performed using medical subject headings (MeSH) and keywords. The search terms were  and  and  and (lumbar or lumbar spine or lumbar vertebra). Two investigators performed the search independently to confirm the consistency of the search. Two investigators independently reviewed the titles and abstracts of articles and chose the potential ones, then checked full texts of the selected articles according to inclusion and exclusion criteria, in which the third person checked the divergent articles.Trials were included based on the following criteria:Randomized controlled trials (RCTs)Trials comparing surgical procedure with exercise therapy of any types for LSSTrials in which exercise therapy was the sole treatment or part of treatment package in exercise group, while surgery was the sole treatment in surgery groupTrials published in EnglishTrials in which LSS was diagnosed by symptoms, signs and imaging examinationThe exclusion criteria consisted:Non-RCTsLiterature reviewDuplicate studiesCase reports or expert opinionsStudies comparing different types of exercise therapies or surgical proceduresStudies without integrated dataTwo reviewers independently participated in the data extraction, and collected the following information:Basic characteristics, including author name, study type and design, sample size, inclusion criteria, intervention measures, outcomes, treatment duration and adverse events.Outcome measurementsFollow-up period.Quality assessment was independently performed according to the Cochrane Risk of Bias Tool by two reviewers. Disagreements were checked by the third reviewer. Risk of bias included the items of random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting and other bias, in which blinding of participants and personnel were disregarded, as it was not applicable when comparing surgery with exercise therapies.A meta-analysis was carried out using Review Manager Version 5.3. Continuous variables were analyzed using the mean differences (MD) with its 95% confidence interval (CI), and the dichotomous data using the risk ratio (RR) and its 95% CI. The heterogeneity was quantified by calculating the value of I², and I984 articles were identified in our initial search, from which 180 were excluded for duplications, 747 were excluded by reading titles and abstracts. The full text of the remaining 57 articles were obtained to check eligibility, in which 6 were excluded because of failing to meet the inclusion criteria, 26 were excluded for review articles, six were excluded for protocols and 15 were excluded for non-RCTs. In the remaining 4 full texts, two reported the same trial with different follow-up period, so only three trialsThe included trials were all published in English. The trials involved 897 patients who included 504 males and 393 females, and the sample sizes ranged from 94 to 654 cases. The baseline characteristics of included studies are presented in The risk of bias assessment was performed based on the Cochrane criterion. The patients in two RCTsAll the trialsTwo trialsAll trials reported side effects. In Weinstein’s trialIn this systematic review and meta-analysis, the efficacy of exercise therapy versus surgery for LSS was evaluated, which may help physicians better make treatment strategies in the treatment of LSS.In the included trials, ODI and physical function of SF-36 were primary outcome measurements. The pooled results in physical function of SF-36 demonstrated no significant difference between exercise therapy and surgery group at every follow-up time point. Also, at most of follow-up time points the pooled results of ODI showed no significant differences. However, at two years the pooled result of ODI showed a favorable effectiveness of surgery. The difference may be attributed to Malmivaara’s trial, in which most of outcome measurements presented with a better efficacy of surgery.10In terms of the mechanism of exercise therapy for LSS, it may be attributed to its effect on lumbar alignment. Exercises can increase the activation of paravertebral muscles, improve the stability and coordination of lumbar spine, improve lumbar lordosis angle and adjust the lumbar alignment and subsequently it can result in the relief of nerve compression, and the symptoms including pain and disability are improved in patients with LSS.First, the included trials evaluating exercise therapy interventions versus surgery for patients with LSS were few, and one trial lacked details in the domains of randomization sequence generation and allocation concealment, and one trial had small sample size, which may affect the quality of evidence and strength of recommendation. Second, exercise therapy programs, including session number, session duration, program duration and other details, were not provided in some trials, which may affect the interpretation of study results and replication in future studies. Third, in the analysis of ODI at six months and one year, the heterogeneity is high, which may be attributed to the difference of intervention measures, such as different types of exercise therapies or physical therapies were used in trials.In view of the above-mentioned limitations, more RCTs evaluating the effect of exercise therapy versus surgery for LSS with large-scaled sample size should be performed to provide higher quality evidence. Moreover, the methodology quality of trials should be paid high attention to, and the details of interventions such as exercise type, time spent on intervention and program duration should be provided in future trials. In addition, considering the heterogeneity between exercise therapy and some cointerventions, in future RCTs exercise therapy should be used as unique intervention measure in exercise group.In brief, the current evidence demonstrated a trend that exercise therapy had a similar effect for LSS as decompressive laminectomies. However, as the quantity was small and methodology quality was low in the included trials, some rigorously designed and large-scaled RCTs need to be performed to confirm the current conclusion.SJT conceived, designed and did statistical analysis & editing of manuscript.ZMM, RWZ, MMC did data collection and manuscript writing.SJT did review and final approval of manuscript.


Restricted drug entry to the brain that is closely associated with the existence of the blood brain barrier (BBB) has limited the accessibility of most potential active therapeutic compounds to the brain from the systemic circulation. Recently, evidences for the presence of direct nose-to-brain drug transport pathways have been accumulated by several studies and an intranasal drug administration route has gained attention as a promising way for providing direct access to the brain without the needs to cross to the BBB. Studies aiming for developing nanoparticles as an intranasal drug carrier have shown considerable promise in overcoming the challenges of intranasal drug delivery route. This review gives a comprehensive overview of works having investigated liposomes as a potential vehicle to deliver drugs to the brain through nose-to-brain route while considering the excellent biocompatibility and high potential of liposomes for clinical development. Herein, studies are reviewed with special emphasis on the impact of formulation factors, such as liposome composition and surface modification of liposomes with targeting moieties, in addition to intranasal environmental factors that may affect the extent/site of absorption of intranasally administered, liposome-encapsulated drugs. A number of patients suffering from neurodegenerative diseases and other central nervous system (CNS) disorders has shown a continuous increase that is associated with the aging population during the last decade. Alzheimer’s disease (AD), Parkinson’s disease, schizophrenia, migraine, malignant glioma, vestibular schwannoma, meningitis, and multiple sclerosis are representative CNS-related diseases . HoweverRestricted drug entry to the brain is closely associated with the existence of the blood brain barrier (BBB), the network of blood vessels that is comprised of tightly packed endothelial cells that separates the brain  from the systemic circulation . BBB hasNumerous attempts have been made to improve the drug delivery to the brain . StrategThe intranasal administration route has gained interest as a promising alternative, providing direct access to the brain circumventing needs to cross the BBB ,5. EvideRecent progress in nanotechnology has brought the development of nanoparticles as an advanced carrier delivering drugs ,20,21,22The present review summarizes the transport mechanisms by which nasally administered drugs gain access to the brain first, followed by a comprehensive overview of the latest progress in the field of liposome formulation as an intranasally administered carrier. Finally, implications and future perspectives will be given to better understand and give insight in developing liposomal formulations for nose-to-brain drug delivery. Despite growing interest, the mechanisms underlying the direct nose-to brain pathway of drug transport are not yet fully elucidated. Nevertheless, it is generally believed that there are direct and indirect pathways for drug transport from the intranasal cavity into the brain ,41: one 2 . Int. Int2]. As depicted in One of major factors determining the effectiveness of nose-to-brain drug transport is the physiological and environmental condition of intranasal cavity. The presence/activity of metabolic enzymes, including epoxide hydrolase, aldehyde hydrogenase, carboxylesterase, and glutathione S-transferase, in the nasal mucosa may affect drug metabolism ,49. IncoThe effectiveness of nose-to-brain drug transport mainly depends on the physicochemical properties of drugs, such as the size, lipophilicity, and degree of ionization . Drug prAmong varying transport routes, the predominance of one pathway over the others principally depends on the physicochemical properties of drugs. The transcellular route is mainly responsible for the transport of lipophilic molecules. The extracellular route is suitable for the transport of hydrophilic drugs/substances, including proteins and peptides, allowing for the prompt onset of action, and it does not require the drugs’ binding to any receptors or undergoing axonal internalization. Small hydrophilic drugs (<1000 Da) may have rapid access to cerebral fluid compared to lipophilic drugs, since the former is less likely to be transported via the neuronal and supporting cells of the olfactory epithelium after nasal application. Several formulation approaches have been made to address the limitations of intranasal delivery. The limited drug absorption across the nasal epithelium and low transport to the brain tissues can be improved with permeation enhancers . HoweverNanotechnology-based formulations have the advantage of protecting the therapeutic cargo, in addition to improving and/or extending its interaction with the olfactory region ,44. NanoNanoparticle-based formulations can be combined with enzymatic inhibitor, nasal absorption enhancers, and mucoadhesive polymers. Liposomes are spherical vesicle structures with an internal aqueous core that is surrounded by a single or multiple lamellar lipid bilayer . Among dLiposomes for the intranasal administration have been developed for both hydrophilic and lipophilic drugs since hydrophilic drugs can be entrapped in the aqueous core of liposomes while lipophilic drugs inserted into the phospholipid bilayer surround the core . After imax was similar (1-h post-administration) in both groups. Ovalbumin level in the brain remained higher up to 24-h, which thereby resulted in eight-fold higher AUC0–infinity in rats receiving liposomes. Authors speculated that liposomes, particularly cationic liposomes, increased the residence time of ovalbumin at the olfactory epithelium, resulting in higher brain uptake. This research group also investigated the nasal delivery of glial-derived neurotrophic factor (GDNF)-encapsulated liposomes /[AUCbrain/AUCplasmaIV]) of three liposome formulations [max of intranasally administered liposomal celecoxib was higher than that of free drug (aqueous suspension) administered by the same route. The increased celecoxib concentration by liposome encapsulation seems likely to be at least partly due to the improvement of the solubility limitation of celecoxib by liposomal encapsulation. When the brain level of intranasally administered celecoxib was determined by fluorescence analysis of celecoxib-quantum dot (CB-QD) conjugate or by LC-mass analysis of celecoxib, liposomal drug was detected at much higher levels, from the earlier time points and for the longer period as compared to free drug. The liposome group and free drug group both exhibited the faster Tmax in the brain when compared to that in the systemic circulation. Importantly, the neuronal uptake of celecoxib was found, regardless of formulations and separate experiments that were done with cultured neuronal cells demonstrated that the liposome encapsulation facilitates the intraneuronal uptake of CB-QD. Collectively, the increased brain transport of celecoxib by liposomal encapsulation appears to involve increased nose-to-brain transport via intraneuronal pathway. In accordance with the brain pharmacokinetic data, the aggregation of amyloid β protein in the brain of disease model mice was more effectively reduced by three-month administration of liposomes than that of free drugs, which demonstrates the more potent therapeutic effect of liposome formulations [Narayan and coworkers  investigulations . The DTEulations  studied ulations . The plaulations . 99mTc and liposome-entrapped 99mTc exhibited higher brain accumulation when compared to free 99mTc dispersion. When the quetiapine level in the brain homogenate was determined by HPLC analysis, it was found that liposomal drug was detected at much higher levels, from the later time points and for the longer period as compared to free drug, which indicates increased brain bioavailability of quetiapine by liposome encapsulation. Based on data, the authors proposed the gain of an alternative brain entry pathway for the intranasally administered liposomal quetiapine . Liposomal formulation of quetiapine fumarate, a schizophrenia drug, for the intranasal administration, was studied in a mice model . The bra0–360min, lower Cmax, and faster clearance of olanzapine in the systemic circulation as compared to intranasally administered free drug solution. Plasma Tmax and Cmax of drug obtained in intranasally administered SDC-containing liposome group was slower and much lower, while those of the Span60-containing liposome group were similar to those of the free drug group. In the brain, all three formulations exhibited similar Tmax and mean residence times, but the intravenously administered free drug group exhibited the highest AUC0–360min and Cmax. Between two liposome formulations, Span60 liposomes showed higher Cmax and AUC0–360min than SDC liposomes. In combination with in vitro liposome deformability data, the authors speculated that the liposomes with better deformability, by being able to be squeezed through the nasal mucosa easier, showing higher bioavailability in both the plasma and the brain. The authors also speculated that the minimal effectiveness of liposomal formulation of olanzapine might be due to the intrinsic high permeability of free drug crossing the nasal layer and BBB easily [In other study, olanzapine was encapsulated in liposomes . SDC or B easily .max, prolonged drug distribution in the brain and longer duration of therapeutic effects by liposomal encapsulation [max by liposomal encapsulation of olanzapine shown by Salama [Most works listed in sulation ,76,77,79sulation ,75,77,78sulation , therebysulation ,75,76,77y Salama ,76,77,79y Salama ,76,78. Ay Salama ,75,76,79y Salama ,81 and tIt is well known that the physicochemical characteristics of nanoparticles  are a critical factor affecting the various properties of nanoparticles as a drug carrier . In a reFrom literatures, the sizes of nanoparticles should be smaller than 50 nm to penetrate the nasal epithelium via extracellular routes ,75. AnotSurface modification of liposomes is known to increase the liposome binding to target sites or the systemic circulation half-life of encapsulated drugs ,49. SurfIn a study that was performed with positively- or negatively charged polymeric nanoparticles, anionic nanoparticles showed a preference for the olfactory pathway, whereas cationic ones did for trigeminal pathways , which sEarlier literatures have demonstrated that the addition of permeation enhancers in the drug solution is effective in increasing the nasal absorption of poorly permeable drugs by transiently inducing tight junction opening between epithelial cells . HoweverStudies for developing nanoparticle formulations aiming at enhancing the nose-to-brain drug delivery have shown considerable promise for the future. Among various nanoparticles, liposomes have gained attraction as a formulation to deliver drugs to the brain by the nasal route due to the high potential of liposomes for clinical development. However, a limited number of works has still been reported in the field of liposomal formulations for the nose-to-brain delivery. Nevertheless, works that were reported over the last years indicate the effectiveness of liposomes as a nose-to-brain carrier of drugs, particularly hydrophilic and macromolecular ones. Works suggest that the optimization of formulations parameters, such as phospholipid composition, insertion of edge activators, PEGylation, surface modification of liposomes with targeting moieties, and/or combination of liposomes with other carrier systems, such as in-situ gelling hydrogel, would contribute to further enhancing the drug bioavailability in the brain. In doing optimization studies, the impacts of environment liposomes would meet after nasal administration should be simultaneously considered. For example, the changes of the tonicity of the nasal environment may considerably affect the liposomal formulation stability and the drug-releasing rate . Formula


Chemokines are a family of small protein cytokines that act as chemoattractants to migrating cells, in particular those of the immune system. They are categorized functionally as either homeostatic, constitutively produced by tissues for basal levels of cell migration, or inflammatory, where they are generated in association with a pathological inflammatory response. While the extravasation of leukocytes via blood vessels is a key step in cells entering the tissues, the lymphatic vessels also serve as a conduit for cells that are recruited and localized through chemoattractant gradients. Furthermore, the growth and remodeling of lymphatic vessels in pathologies is influenced by chemokines and their receptors expressed by lymphatic endothelial cells (LECs) in and around the pathological tissue. In this review we summarize the diverse role played by specific chemokines and their receptors in shaping the interaction of lymphatic vessels, immune cells, and other pathological cell types in physiology and disease. Chemokiovement) , 5. Theyovement)  that canovement) .Chemokines act by establishing gradients to direct random or directed migration of cells bearing cognate receptors from lower to higher concentrations of ligands. These gradients are often formed through the interaction with proteoglycans attached to the cell surface or extracellular matrix. Diversity within the chemokine system is generated both structurally and functionally through an array of different receptors and ligands with precise or promiscuous binding affinity, where splice variants, post-translational modifications including nitrosylation, citullination, and many forms of proteolytic cleavage  can all The movement of cells in normal and pathological situations is highly dependent on the circulatory system, which allows long and short range transport, and exit and entry from all tissues. Previous studies have shown the critical role of blood vessels in chemokine action, in particular directing key cellular effectors of the immune response . Blood ain vitro has provided a more in-depth understanding of their unique biological function and differences to blood vascular endothelium  signaling  exhibit defects in lymphatic development, typified by precocious development of lymph sacs and hyperplasia . This phArguably the best-characterized chemokine-mediated functions involving the lymphatics are those that regulate trafficking of leukocytes in physiological homeostasis and during inflammation and immune responses. Leukocytes in the peripheral interstitium typically enter initial lymphatics in the first instance, and subsequently migrate through the local plexus of pre-collecting lymphatics before entering the large collecting lymphatic vessels that pump lymph and cells over long distances to LNs, where encounters between antigen-presenting cells and cognate T and B lymphocytes are coordinated , 85, 86.CCL21, constitutively expressed by peripheral LECs, has a prominent role in trafficking CCR7-expressing dendritic cells (DCs) through afferent lymphatic vessels to LNs along with other CCR7-expressing cells such as T cell subsets and neutrophils –24. NotaAlthough low levels of cellular trafficking occur under homeostatic conditions, this increases dramatically during immune responses , 86. Accin vivo  , 93. HerHeligmosomoides polygyrus, lymphangiogenesis driven by VEGF-A and VEGF-C from B lymphocytes results in a sustained expansion of LN LECs   where enin vitro analyses examining chemokines and receptors upregulated in LECs by specific stimuli (Lymphatic vessels, like blood vessels, are a highly interactive surface for cells of the immune system, and through the use of chemokines and their receptors can coordinate key interactions. These pathways can control the entry and function of particular immune subsets in a number of pathological conditions. Nonetheless LECs have distinct patterns of chemokine secretion and expression of chemokine receptors that distinguish them from the blood vessel system and mediate distinct roles and responses. The abundance and diversity of the chemokine family point to the likelihood that a plethora of novel chemokine functions and interactions remain to be discovered. Of note, several recent studies have undertaken differential expression profiling of LECs by microarray in a range of different pathologies, revealing multiple chemokines with as-yet undefined roles in disease . These s stimuli , 60, 88.RF and SS conceived the review. RF, TK, SiM, ScM, and SS wrote and edited the manuscript.SS has ownership interest in Opthea Ltd. that develops therapeutics in vascular biology. The remaining 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.


The pancreas is a bulky gland, with mixed secretion, exocrine and endocrine, attached to the duodenum, participating through its secretions in carbohydrates digestion and metabolism. For a long time, it was considered a mysterious organ, with an inaccessible, examining and exploring due to its deep retroperitoneal position.We intend to make a comparative analysis of pancreatic microanatomy, between the examination of the necroptic-collected pieces and the ex vivo pieces, intraoperatively, with the patient’s prior consent. We aimed to deepen the qualitative micro anatomic study on the pancreas parts of dissection, and quantitative study of the vessels micro anatomic normal pancreatic body.The methods and techniques used were the anatomical study through dissection and intraoperative and qualitative micro anatomic study by making blades of pathological sample products taken from patients: extemporaneous and microscope examination. The exocrine pancreas occupies most of the gland [5] (The pancreas is a mixed gland (amphicrania) with double secretion, having two components .The exocrine pancreas (pars exocrina pancreatis) is mostly present at the level of the gland (97-99%) .The interlobular ducts are joined together, then open into the channels of a higher caliber in Wirsung's pancreatic duct (ductus pancreaticus), as well as in the Santorini's accessory pancreatic duct (ductus pancreaticus accesorius) [6].The endocrine pancreas (pars endocrina pancreatis) (1-3%) or insular pancreas is composed of islands of pancreatic cells (insula pancreatica), called the islets of Langerhans scattered among glandular acini, being reduced in number at the level of the head and body of pancreas and more numerous in the tail of the pancreas (6] and the cells C (1%) are clear, agranular cells [6].The islets of Langerhans are separated by a reticulo-capillary network. Prismatic cell cords are anastomose to one another, being composed of α cells and β cells. The islets are surrounded by a very fine network of connective tissue, do not contain ducts and have several capillaries, called fenestrated capillaries. In terms of cytological aspects: alpha cells / A (20%) are to be found on the periphery of the islets and secret glucagon [The micro anatomical study was performed on pancreatic tissue fragments collected from the main body segments during the first 24 hours of death. Legislation and methodology did not allow carrying out necroptic tests on more freshly collected samples. For this reason, the micro-anatomical study will be completed later, in another phase of the research, with pancreatic tissue harvested intraoperatively. The tissue fragments were processed by paraffin technique, stained by usual and special methods, the slides being qualitatively examined afterwards for the overall look and in order to detect any pathological lesions. Among the specific methods, quite useful is the Novelli technique, using Ewans blue which highlights the vascular device that can be easily computer quantified during the next phase of the study (In five cases, the organ has been specifically processed for the study of micro-vascularization: the fresh sample has been injected within the main arteries using a solution of Chinese ink and gelatin (1. Micro-anatomical aspects of quality.The microscopic examination of fragments taken from different segments of the pancreas did not reveal various qualitative aspects of pancreatic tissue.Thus, in all cases, the conjunctive capsule is thin, consisting of dense connective semi-ordered tissue.In all its parts, the stroma of the organ is composed of loose connective tissue that separates the parenchyma elements of the lobules. There are numerous conjunctive vascular nervous septa originating from the capsule, which are distributed in all organ parts. In cases of elderly people, over 60 years old, the stroma is denser, the connective tissue more abundant, further studies having to stereologically determine the percentage they occupy (The exocrine parenchyma is composed of pancreatic acini separated from each other by a loose connective tissue, through which blood vessels, lymph, nerves and excretion ducts pass, continued by the interlobular septal tissue (The pancreatic acini are formed by the pyramidal secretory acinar cells (2. The micro-irrigation of the pancreasWithin the pancreas, arteries branch off successively at the level of the septa into interlobular branches, out of which further intralobular branches get loose. These branches pass through the connective tissue between the acini, creating arterioles and a rich capillary periacinar network (Within the pancreas, arteries create arteriolar branches (Arterioles, in turn, create a special network of capillaries, dilated, dispersed among the cellular cords, showing vascular glomeruli. Insular capillaries have a larger size larger as compared with the rest of the gland. Through them, the pancreatic hormones such as glucagon and insulin, go directly into the blood, which gives the islets their endocrine character.portvas and portduct structures that create pathways and directs the movement and progression of tumor cells.The micro-anatomical structure of the pancreas favours the dissemination of a tumor due to fibrocollagenous system well represented throughout the body, making up the


Cancer Letters [Allogeneic hematopoietic stem cell transplantation  is the only curative treatment for many patients with hematologic malignancies. However, relapse after allo-HSCT remains a major challenge, and patients with relapsed disease usually have a dismal prognosis. Recently, on behalf of the HSCT working group of the Chinese Society of Hematology and Chinese Medical Association, experts from major transplant centers in China came together and produced the Chinese consensus on the management of post-HSCT leukemia relapse, which was published in  Letters . In thisOperational recommendations for minimal residual disease cut-off levels and the detection time-point for Chinese patient populations, such as the combination of quantitative WT1 expression and multiparameter flow cytometry assay for leukemia-associated aberrant immunophenotypesNovel immunologic interventions developed by Chinese groups; for example, the modified donor lymphocyte infusion (DLI) protocol introduced by Huang in 2003 , which iAn individualized, risk-adapted strategy for prophylaxis, pre-emptive intervention, and treatment of leukemia relapse post-HSCT.Compared to the recommendations made by the National Cancer Institute of the United States , 3 and tThese consensus recommendations will help standardize the transplant practices in China, where 6601 allo-HSCT procedures were performed in 2017 [The modified DLI protocol and the large number of patients treated with this protocol (now part of a consensus recommendation) also provide a unique opportunity to investigate the mechanisms of disease relapse after allo-HSCT, which is a major cause of morbidity and mortality in patients with leukemia. For example, how do different donor types, conditioning regimens, post-transplant therapies, or immunomodulatory interventions affect the malignant stem cells and their microenvironment in different disorders? What are the mechanisms for normal/malignant cell competition, especially during the early stage of disease relapse?It is anticipated that the implementation of such consensus recommendations will not only improve the care of many patients with leukemia and other hematologic malignancies in China, but also lead to a better understanding of these disorders through bench to bedside to bench research, which is essential for the development of novel, more effective therapeutic strategies for our patients. However, a cautious approach towards implementation is warranted. As discussed by Wang et al. , most ofThe diagnosis and management of Chinese cancer patients has mostly been adopted from foreign guidelines. Recent studies have illustrated that the different genetic background in the Asian population has significant consequences in cancer diagnosis, treatment, and prognosis . For bet


Moderate to severe diarrhea caused by Shigella is a global health concern due to its substantial contribution to morbidity and mortality in children aged <5 years in low- and middle-income countries. Although antibiotic treatment can be effective, emerging antimicrobial resistance, limited access, and cost affirm the role of vaccines as the most attractive countermeasure. Controlled human infection models (CHIMs) represent a valuable tool for assessing vaccine efficacy and potentially accelerating licensure. Currently, immunological analysis during CHIM studies is customized based on vaccine type, regimen, and administration route. Additionally, differences in type of immunoassays and procedures used limit comparisons across studies. In November 2017, an expert working group reviewed Shigella CHIM studies performed to date and developed consensus guidelines on prioritization of immunoassays, specimens, and collection time points. Immunoassays were ranked into 3 tiers, with antibodies to Shigella lipopolysaccharide (LPS) being the highest priority. To facilitate comparisons across clinical studies, a second workshop was conducted in December 2017, which focused on the pathway toward a recognized enzyme-linked immunosorbent assay (ELISA) to determine serum immunoglobulin G titers against Shigella LPS. The consensus of the meeting was to establish a consortium of international institutions with expertise in Shigella immunology that would work with the National Institute for Biological Standards and Control to establish a harmonized ELISA, produce a reference sera, and identify a reliable source of Shigella LPS for global utilization. Herein we describe efforts toward establishing common procedures to advance Shigella vaccine development, support licensure, and ultimately facilitate vaccine deployment and uptake. Shigella CHIM studies. These assays will best facilitate assessing vaccine immunogenicity in the context of vaccine efficacy and provide a higher-level understanding of vaccine-induced immune responses, mechanistic principles of protection, and correlates of immunity. The second objective focused on establishing a pathway toward the harmonization and validation of an internationally recognized enzyme-linked immunosorbent assay (ELISA) to determine serum immunoglobulin G (IgG) directed to the O-antigen of several Shigella serotypes anticipated for inclusion in future vaccine formulations  using well-characterized antigens, serum controls, and reference standards for data normalization.In November and December 2017, workshops were held in Washington, District of Columbia, and London, United Kingdom, by the Bill & Melinda Gates Foundation. The topics discussed focused on immunological assays in support of vaccine efficacy studies and controlled human infection models (CHIMs). Working groups of clinicians and scientists focused on 2 primary objectives during these meetings. The first objective was to reach a consensus on the most appropriate panel of assays to conduct on clinical samples from Shigella immunology were joined by leaders of recent Shigella vaccine development efforts and representatives from the National Institute for Biological Standards and Control (NIBSC) and others involved with conducting immunological investigations.Several institutions have been involved with assessment of immune responses in CHIMs and field efficacy studies. The Walter Reed Army Institute of Research (WRAIR), the Center for Vaccine Development (CVD) at the University of Maryland, and Tel Aviv University all have extensive history and experience in the field. Investigators from these 3 institutions conducting Shigella clinical studies, the timing of sample collection for these assays, and prioritization of the immunoassays. Clinical study designs are highly customized to the vaccine product being evaluated with generally accepted intervals between prime and booster immunizations specific for administration route and vaccine type . A consensus immunological sampling schedule was developed based on the clinical study design previously used for Shigella conjugate vaccines (a 2-dose regimen separated by 28 days) as a framework  were thought to be the most essential measurement, as several previous studies have clearly indicated that protective immunity, either vaccine-induced or originating from natural infection, is largely serotype-specific [Shigella serotype is determined by the differences in structure and sugars present in the O-antigen of Shigella LPS. There were additional discussions regarding the importance of measuring antibodies in both systemic circulation (serum) and in mucosal intestinal compartments, as either direct  or indirect  measurements. The consensus of the group was that both serum antibodies  and mucosal responses were important.The group discussed immunoassays to evaluate both humoral and cellular immune responses in the context of vaccine immunogenicity and efficacy studies, but with a primary focus on antibody-related assays. Antibodies directed to the O-antigen of specific , and theShigella serotypes, whereas the number of PBMCs required to measure ASC frequency to the same number of LPS serotypes would be prohibitive. ALS are also easier to perform and less expensive, and lymphocyte supernatants from multiple time points can be batched to reduce assay variability. Therefore, there was a clear preference to conduct ALS rather than ASC assays, especially after bridging studies have been completed for a vaccine program.One portion of the discussion focused on the advantages and disadvantages of ALS and ASCs as indirect measurements of mucosal immunity. ALS assays using antigen-stimulated peripheral blood mononuclear cells (PBMCs) or enriched/purified B cells bearing mucosal homing markers, such as α4β7, would allow for a broader assessment of antibodies directed to multiple Shigella bactericidal assay (SBA) or opsonophagocytic killing assay, the avidity and affinity of Shigella antigen-specific antibodies, and the generation of memory B cells were important parameters necessary to more fully understand immune responses. In addition, the group discussed the value of evaluating the serum antibody response postchallenge by utilizing protein microarrays, which may provide additional insight into antigens recognized after natural infection and potentially allow the identification of novel vaccine targets for improved, next-generation vaccine formulations. In a recent study, a newly developed Shigella proteome microarray enabled the identification of novel immune-reacting antigens following oral vaccination and experimental challenge, and a defined type III secretion protein immune profile associated with clinical protection against shigellosis [Other attributes of the humoral immune response postvaccination or challenge were also discussed. The consensus was that antibody functionality, either in a gellosis .In relation to the contributions of T cells to a protective immune response, the group consensus was that evaluating T follicular helper (Tfh) cells, in addition to other T-cell phenotypes, by traditional flow cytometry (fluorescence-activated cell sorting) or mass cytometry (CyTOF) would add significant value to the immune assessments. Tfh cells generated shortly after induction of the adaptive immune response have been correlated with memory B-cell generation , which iShigella CHIM assessments as well as culture-based methods to evaluate shedding of the challenge strain. The group consensus was to also conduct quantitative polymerase chain reaction (qPCR) to quantitate Shigella organisms in stool as well as to measure inflammatory markers, such as calprotectin and myeloperoxidase, during the inpatient challenge phase of the CHIM. Elevated levels of fecal inflammatory markers have been associated with physical and cognitive stunting in children [Shigella vaccination and/or infection on the microbiome was also determined to have value; therefore, collection and processing of fecal samples for eventual microbiome and transcriptome analysis were prioritized.In addition to the direct measurements of antibodies in stool, several additional parameters surrounding stool samples were discussed by the group. Stool grading is one hallmark measurement that has been incorporated into children , and theShigella conjugate vaccine as the example , type of vaccine , and whether samples are being collected after a priming or booster immunization. Work conducted in the context of oral immunization or challenge suggests that peak IgA ASC responses occur between 5 and 9 days postintervention , 15. How example .Direct measurements of mucosal immune responses in the intestine are traditionally performed in stool. However, stool samples are susceptible to multiple factors that may confound accurate and reproducible results. For example, transit time through the intestine and volume is individually based, and the temperature and time elapsed from stool production to processing can significantly affect the overall quality of the samples. During the inpatient phase of a CHIM, stool samples can be rapidly transported to the laboratory and processed to prevent degradation, but this is not possible during a typical outpatient vaccination phase. The consistency of specimens can significantly influence results, thus requiring additional specimen treatment  or measurement of total IgA for normalization. In terms of blood collection for PBMC isolation during the CHIM phase, 7 days postintervention is typically utilized to capture peak antibody responses, but also to capture mucosally primed B cells homing to different anatomical compartments. Tfh cells, on the other hand, peak around 3 days postintervention. The inpatient phase of CHIMs facilitates the collection of multiple specimens on a daily basis, which may be essential for measurements of inflammation markers, qPCR analysis, and grading of stool samples. PBMC isolation and serum separation from whole blood may only be necessary at 3 and 7 days postchallenge to adequately evaluate the adaptive immune response induced. Regardless of the availability of immediate funding for immunological analysis, a sampling plan should be developed to effectively collect sufficient samples during the vaccination and CHIM phases of the study for proper processing and archiving, with the intention to secure funding for additional analyses at a later time point as warranted by the clinical study results.A portion of the workshop focused on building consensus surrounding the prioritization of immunological assays that should be considered when establishing a CHIM study considering that sample types and volumes, subject recruitment, and funding can be limiting factors. The type of specimens obtained from consented subjects largely fell into 3 categories: stool, blood, and others. Stool collections are necessary for multiple immunoassays, but also for bacteriology, microbiome, transcriptome, and inflammatory markers. Blood is typically separated to obtain serum for antibody testing and PBMCs to investigate immunity at a cellular level. In addition to stool samples, various levels of success have also been achieved with saliva, urine, and tear collection, although there is not a general consensus in the field regarding their utility and therefore they were not included in the final recommendations.After discussion, the working group agreed on a prioritization of immunoassays and placed them into first-, second-, and third-priority analysis tiers . ImmunoaThe focus of the meeting held in London during December 2017 was ELISA protocols to measure LPS-specific serum IgG. Subject matter experts from the CVD, WRAIR, and Tel Aviv University presented details of their assay procedures and discussed common elements, as well as areas that were unique to each site. The protocols were all generally comparable, but several differences were highlighted, including data analysis, antigen and key reagent sources, and reference or control samples utilized in the assays. The protocols utilized by WRAIR and Tel Aviv University both started from a common protocol and therefore only differed in minor technical aspects, whereas the protocols from WRAIR and Tel Aviv University were less aligned with the protocol from the CVD. One of the major differentiators of the CVD ELISA protocol and those used by WRAIR and Tel Aviv was the utilization of a standard curve to interpolate titers as compared to the WRAIR protocol, which determines endpoint titers by diluting the samples until a negative signal is achieved. Both procedures have their advantages and disadvantages and could be reconciled with minimal effort.Shigella vaccine studies conducted over the past 10 years, although both Institut Pasteur and Tel Aviv University have also contributed antigen in the context of the STOPENTERICS European Union FP7 program.WRAIR outlined their program to produce, qualify, and maintain key ELISA reagents. Purified LPS is isolated from wild-type bacteria using hot phenol extraction methods adapted from Westphal and Jann , and quaShigella clinical studies, including the International Centre for Diarrhoeal Disease Research (Bangladesh), LimmaTech Biologics Inc, Cincinnati Children's Hospital Medical Center, Johns Hopkins University, the CVD, and the Armed Forces Research Institute of Medical Sciences, Thailand. The consensus from the working group was that LPS antigens were critical reagents necessary for the harmonization of the ELISA and suggested that the product should be made under good laboratory practice or good manufacturing practice conditions, in sufficient quantity to be used globally for a decade or more, and be readily available to all laboratories that will conduct immunoassays on samples collected in support of clinical studies.WRAIR also described control sera, reference sera, and proficiency panels that have been utilized to deploy the assay across several international laboratories conducting Shigella immunoassays, with a focus on S. flexneri 2a and S. sonnei to precede S. flexneri 3a, 6, and 1b.The workshop attendees discussed next steps in the process of establishing an internationally recognized ELISA. Presentations by representatives from the NIBSC outlined the mission, capacity, expertise, and experience with establishing and distributing immunoassays and the necessary reference samples, controls, and protocols based on their existing relationship with the World Health Organization (WHO) on numerous projects. The NIBSC has recently conducted a collaborative study involving multiple international laboratories, which confirmed the suitability and assigned unitage to a newly prepared WHO Anti-Vi Reference Serum Standard, and compared the performance of different Vi ELISA formats across multiple sites . The conShigella-specific ELISAs.A consortium will be created including WRAIR, CVD, Tel Aviv University, Johns Hopkins University, and GSK Vaccines for Global Health, with logistic support and organizational efforts led by the NIBSC. Each consortium member will provide the NIBSC with standard operating procedures (SOPs) of their in-house ELISA and sera with low, medium, and high anti-LPS IgG titers. These materials will be confirmed to be free of blood-borne pathogens, freeze-dried, and distributed in coded format, along with essential reagents and components of the assay, within the consortium. Each consortium laboratory will test the study samples in their in-house assay, in the first instance, and provide data sets to the NIBSC for statistical analysis including intralaboratory and interlaboratory reproducibility, repeatability, and accuracy using appropriate statistical methodology. The objective is to achieve a protocol for a harmonized ELISA and the production of adequate supplies for LPS antigen for plate coating, reference and control serum, and other key reagents for the global deployment of the harmonized assay. The NIBSC will work with consortium members to establish a detailed SOP of the harmonized LPS ELISA, guidelines for data analysis, endpoint titer calculation, and data reporting, and will facilitate central distribution of reagents and tools to further ensure consistency across multiple laboratories conducting Shigella vaccines by establishing consensus in the field regarding specimen collection, prioritization of Shigella-specific immunoassays, and harmonization of procedures to evaluate serum IgG responses directed to Shigella LPS. A Shigella vaccine remains a top priority for the global community, both for travelers and for children who live in endemic areas of the world. As Shigella vaccine candidates progress through the clinical pipeline, establishing a well-thought-out framework to guide immunological investigations will facilitate the comparison of vaccine-induced immunity and assist in the selection and advancement of effective Shigella vaccine candidates. While work progresses toward the establishment of a harmonized ELISA, members of the consortium will work with the NIBSC to ensure global access to the necessary protocols, procedures, reagents, and tools required to generate results that can be used across multiple efforts focused on the common goal of producing an effective Shigella vaccine for the world.The overall objective of the 2 workshops organized by the Bill & Melinda Gates Foundation was to help advance second-generation O-antigen–based


The brain is an important organ that controls all sensory and motor actions, memory, and emotions. Each anatomical and physiological modulation in various brain centers, results in psychological, behavioral, and sensory-motor changes. Alcohol and addictive drugs such as opioids and amphetamines have been shown to exert a great impact on brain, specifically on the hippocampus. Emerging evidence has indicated that altered hippocampal neurogenesis is associated with the pathophysiology of neuropsychological disorders including addiction. The addictive drugs impair neurogenesis and undermine the function of neural stem/progenitor cells in hippocampus. This feature was claimed to be one of the underlying mechanisms of behavioral changes in patients with addiction. As the impairment of stem cells’ function has been proven to be the underlying cause of pathologic neuroadaptations in the brain, the administration of stem cell populations has shown promising results for re-modulating of neuronal status in the brain and especially in the hippocampus. Among the different types of stem cells, bone marrow derived mesenchymal stem cells are the most proper candidates for stem cell therapies. In this review article, the recent studies on the effects of addictive drugs on brain neurogenesis, and also the promising potential effects of stem cells in curing addiction related hippocampal damages are discussed. Addiction is defined as a chronic disease with obligation to take drugs or alcohol, no control on restraining intake, and having negative emotional feeling during withdrawal period. Addiction does not just affect the addict’s life, but also it has a huge burden on the society and economy. It was revealed that the addictive agents have a great anatomical and physiological impact on the brain centers, resulting in psychological, behavioral, and sensory-motor changes. It was Brain has the ability to produce new neural stem/ progenitor cells (NSPCs) during adulthood. Hippocampus might be the most plastic region of the brain, where granular cells in the dentate gyrus are born in adulthood. The precursors of these cells are placed in the subgranular zone (SGZ), the tissue between hilus and granule cell layer , 4. The Addictive drugs and alcohol can regulate NSPCs by a variety of mechanisms. Some of these mechanisms are shared among them . For exaSome signaling molecules and pathways such as the mitogen-activated protein kinase (MAPK) signaling pathway, cell cycle regulatory molecules, and microRNAs (miRNAs) which may function independently or act in conjunction with one another have been identified to play important roles in these modulations .Although neurons are the principal targets of drug addiction, it has recently been shown that nearly all drugs of abuse also affect glial cells . AstrocyGLT-1, leading to excessive accumulation of glutamate in synaptic cleft. Excess glutamate massively stimulates N-methyl-D-aspartate receptors (NMDARs). Massive stimulation of NMDARs leads to an excessive cellular influx of ions, particularly calcium, causing the activation of proteases, phospholipases, and endonucleases that end in cellular death , leading to the release of pro-inflammatory cytokines, and reactive oxygen species which in turn, promote neuronal death in hippocampus and other brain regions .In the first part of this review, the effects of drug and alcohol abuse on neurogenesis are discussed, then we provide an overview of the promising effects of bone marrow derived mesenchymal stem cells (BM-MSCs) for the treatment of addiction related hippocampal damages.The principal centers that are directing the feelings and are affected by addictive drugs are hippocampus and medial prefrontal cortex. It has been indicated that the behaviors of drug seeking and relapsing to drug abuse are mediated by these centers , 34.Animal studies showed that self-administration of drugs attenuates neurogenesis in dentate gyrus , 35-43. Methamphetamines as another drug have non-linear effect on the dentate gyrus stem cells. In the case of daily self-administration of methamphetamine, the survival, proliferation, and differentiation of progenitors are decreasing. However, intermittent access raises proliferation and differentiation, but this type of increase in the population of immature neuronal cells does not alter survival and neurogenesis of hippocampal progenitors, perhaps because of opposing effects on proliferation of late progenitors and differentiation of post-mitotic neurons . MethampNeuroinflammation is also associated with the chronic use of addictive drugs including cocaine, opiates, marijuana, and methamphetamine .It is vital to indicate that all above studies show a correlation between daily drug intake and alteration in neurogenesis. As the amount of drug intake increases, the pathologic effects are more on the dentate gyrus neurogenesis.Alcohol abuse often leads to the alcohol use disorder (AUD) that has great deteriorating impacts on the brain. Excessive use of alcohol results in progressive neurodegeneration in brain that also accelerates AUD . AlcoholWithdrawal from ethanol exposure enhanced cell proliferation in the hippocampus, resulting in initial microglial proliferation followed by the production of immature neurons and eventual neurogenesis , 67. TheWhat we summarized in above topics are brief description of the effects of drugs and alcohol in addicted patients on adult neurogenesis. The NSPCs are introduced as the main affected cell population in addiction. In this part, the potential of BM-MSCs for treating injuries to the brain with focus on addiction-derived alterations is discussed.Stem cells are primary cells with self-renewal and differentiation ability . The mosin vivo and in vitro , and basic fibroblast growth factor (bFGF). These neuro-regenerative effects were accompanied by the improvement in animals’ memory and motor behavior . It was em cells . Secretiem cells . Conditiem cells .Besides soluble growth factors and cytokines, MSCs also secrete microvesicles and exosomes containing mRNAs and/or miRNAs, which are believed to mediate cell-to-cell communication . ExosomeMSCs have shown therapeutic effects on the brain pathologies. A crucial finding in mental illnesses like bipolar disorder, major depression, and schizophrenia is the disturbance of neurotrophic factors and immunomodulatory systems in the brain. The pro- inflammatory cytokines such as TNF-α, IL-6, and IL- 2 are increasing and BDNF is decreasing in such disorders -94. FurtA brief description of the effects of drug on brain and the benefits of stem cell injection on addicted brains is represented in Yang et al. transplanted labeled BM-MSCs into the hippocampus of alcohol-associated dementia animal model. Evaluation of the behavior and hippocampus structure of the injected rats revealed that their learning and memory function were enhanced, alcohol-induced hippocampal injures were inhibited in histological examinations, the number of apoptotic neural cells was decreased, and the activity of total superoxide dismutase was increased in the hippocampus. Transplantation of BM-MSCs also increased the level of BDNF protein .MCP1 expression in the hippocampus, suggesting a potent anti-inflammatory effect of BM-MSC-spheroids. Furthermore, oxidative stress was normalized by MSC- spheroid administration . The results showed that injected MSCs survived and became attached to cerebral ventricles. Transplanted MSCs reduced 24-h alcohol intake and also blocked alcohol relapse-like drinking induced in the alcohol deprivation effect condition . Ezquer stration .Therapeutic promises of BM‐MSCs have been overshadowed by concerns regarding their limited homing potential or migration to non-target sites , 106. AlSeveral studies indicated the damaging effects of drug and/or alcohol abuse on the brain neuroanatomy and function. Experiments have revealed that addiction leads to impairment in adult neurogenesis in behavioral centers of brain including hippocampus and medial prefrontal cortex. Numerous experiments on animal models have shown the effects of addictive drugs such as morphine, cocaine, methamphetamines, and alcohol on the proliferation, survival and differentiation of progenitor cells in the hippocampus. Animal studies showed promising results after hippocampal transplantation of BM-MSCs in psychological disorders e.g. depression and alcohol abuse. More studies on the stem cell therapy of psychological defects related to addiction are required.The authors declare no conflict of interest.


Currently, there are no approved pharmacotherapies for addiction to cocaine and other psychostimulant drugs. Several studies have proposed that cannabidiol (CBD) could be a promising treatment for substance use disorders. In the present work, the authors describe the scarce preclinical and human research about the actions of CBD on the effects of stimulant drugs, mainly cocaine and methamphetamine (METH). Additionally, the possible mechanisms underlying the therapeutic potential of CBD on stimulant use disorders are reviewed. CBD has reversed toxicity and seizures induced by cocaine, behavioural sensitization induced by amphetamines, motivation to self-administer cocaine and METH, context- and stress-induced reinstatement of cocaine and priming-induced reinstatement of METH seeking behaviours. CBD also potentiated the extinction of cocaine- and amphetamine-induced conditioned place preference (CPP), impaired the reconsolidation of cocaine CPP and prevented priming-induced reinstatement of METH CPP. Observational studies suggest that CBD may reduce problems related with crack-cocaine addiction, such as withdrawal symptoms, craving, impulsivity and paranoia . The potential mechanisms involved in the protective effects of CBD on addiction to psychostimulant drugs include the prevention of drug-induced neuroadaptations , the erasure of aberrant drug-memories, the reversion of cognitive deficits induced by psychostimulant drugs and the alleviation of mental disorders comorbid with psychostimulant abuse. Further, preclinical studies and future clinical trials are necessary to fully evaluate the potential of CBD as an intervention for cocaine and methamphetamine addictive disorders. Cocaine and methamphetamine (METH) are addictive psychostimulant drugs that are commonly abused and cause significant morbidity and mortality ,2. AbuseCannabidiol (CBD) is the second most abundant phytocannabinoid component of the cannabis plant, behind delta-9-tetrahydrocannabinol (THC) ,7,8,9. HCBD also acts on a number of receptors of different neurotransmitters systems. CBD has agonistic properties at 5-HT1A receptors ,21. On tn = 2409) recruited through social media showed that almost 62% of them reported using this drug to treat a medical condition, mainly pain, anxiety, depression and sleep disorders  through activation of mTOR with subsequent reduction in glutamate release” . In anotPreclinical studies have demonstrated that drugs of abuse induce neuroinflammatory effects and disrupt glutamate homeostasis through their interaction with microglia and astrocytes. Due to this, glial modulators, anti-oxidants and anti-inflammatory drugs show therapeutic potential in animal models of substance use disorders ,96. NeurIn models of ischemia, neurodegenerative disorders (Alzheimer’s disease and multiple sclerosis), sciatic nerve injury, epilepsy and schizophrenia, CBD reduces proinflammatory effects and the increased activity in astrocytes that characterises these disorders . HoweverOther studies have also demonstrated that CBD exerted a neuroprotective effect against the adverse consequences of alcohol in the hippocampus  and reduThe release of DA induced by cocaine, METH and other drugs of abuse, in addition to underlying their rewarding effects, strengthens the association between the pleasant effects of these drugs and the contextual cues present when such effects are experienced by the subjects. Thus, drugs of abuse induce the creation of aberrant memories related to the drug experience. Even after long-term abstinence, exposure to drug-associated environmental cues activates the recalling of drug-related memories, thereby inducing craving and frequently leading to a relapse into drug use. Several studies have demonstrated that the manipulation of the reconsolidation process may be therapeutically used to erase pathological emotional memories such as fear- and drug-related memories ,102. In Different studies have confirmed that CBD regulates the processing of emotional memories ,102. HowChronic consumption of psychostimulant drugs is associated with cognitive deficits in attention, memory and executive functions ,110. TheAn open-label clinical trial with frequent cannabis users treated with 200 mg of daily oral CBD treatment for 10 weeks, while continuing to use cannabis, reported improvements in attention, verbal learning, and memory . In cigaCBD has been shown to have a potential therapeutic value for a wide range of disorders, including stress, anxiety, psychosis, depression, as well as for problems related to sleep and appetite ,114,116.Stress is an environmental variable clearly associated with initiation, maintenance and relapse into drug abuse and is a challenge for the treatment of substance use disorders. According to Greenwald , CBD canImpulsive and compulsive behaviour have also been related with an enhanced propensity to develop substance-related disorders. Using a delay-discounting task, it has been observed that CBD prevented the development of high impulsivity in rats with a history of alcohol dependence . HoweverThere is a clear association between psychostimulant abuse and psychosis . CBD hasFinally, there is an association between drug addiction and depression and it could be expected that the improvement of depressive symptoms, such as helplessness and anhedonia, may be accompanied by a reduction of drug use. In experimental rodents, CBD had anti-depressive effects in the forced swim test ,134,135,A limited number of preclinical studies indicate that CBD could have therapeutic properties on cocaine and METH addiction and some preliminary data suggest that CBD may be beneficial in cocaine-crack addiction in humans. CBD has shown promising results in reducing the inflammation and seizures induced by cocaine ,52 and iDrug addiction is characterized by the compulsive desire to use drugs and a loss of control over consumption. For this reason, in the preclinical field, the effects of CBD need to be evaluated in experimental models of drug-escalation, which translate more readily to drug abusers searching treatment, who have initiated and progressed their drug use until developing a compulsive pattern of consumption. Future preclinical studies should evaluate the effects of CBD on priming- and stress-induced reinstatement of cocaine CPP as well as on the negative consequences of withdrawal after repeated exposure to cocaine and METH. Some of these issues are currently being researched in the authors’ laboratory. Further studying of the mechanisms of action underlying CBD’s therapeutic potential for psychostimulant addiction will be also necessary. The reversion of psychostimulant-induced alterations in the DA mesolimbic system and the minimization of inflammatory injury promoted by cocaine or METH seem to be important mechanisms. Moreover, the protracted behavioural effects of CBD suggest that this compound has a long-term impact on synaptic plasticity, which is mediated by the endocannabinoid system  and alteThe FDA has approved a purified form of CBD (Epidiolex) to treat rare, severe forms of epilepsy. However, there are no other FDA-approved drug products that contain CBD for the treatment of any other diseases. The cause of this lies in the FDA’s priority to protect and promote public health and, consequently, this Agency is committed to science-based decision-making. The FDA recognizes CBD’s potential benefits, but also maintains that questions remain regarding its safety, including the potential for liver injury (identified during the review of the marketing application for Epidiolex). Currently, CBD is the subject of substantial clinical research on its potential medical uses, including the treatment of addiction to drugs of abuse, but there remain many open questions that need to be considered before CBD may be more widely available. For example, what is the maximal dose of CBD that is safe to consume daily? How does CBD’s safety depend on the method of administration? What are the risks of long-term exposure? Are there drug interactions? How does CBD impact special populations (such as adolescents or pregnant women) and people with chronic diseases? In addition to the safety issues, the effectiveness of CBD for treating addiction to psychostimulant drugs has not yet been proven. The paucity of preclinical findings and the lack of results derived from clinical trials greatly hinder the FDA’s approval of CBD to treat addiction to cocaine or METH. From the case of Epidiolex, the FDA only supports a drug’s approval after careful review of the evidence obtained in scientifically valid research and the conclusion that CBD is safe and effective for its intended use. Thus, a priority of research is to demonstrate the usefulness of CBD as a novel pharmacotherapy for psychostimulant dependence in clinical trials. These future clinical trials should include randomised controlled samples of individuals with the diagnosis of cocaine or METH dependence (without or with comorbid neuropsychiatric conditions) to investigate the specific effects of CBD on these disorders, the specific mechanism of action of CBD and the safe and ideal therapeutic doses of this compound. Biological measures must also be included in these clinical trials in order to correlate the therapeutic effects of CBD to changes in neurotransmitters, intracellular signalling, neuroinflammatory markers, and structural and functional cerebral changes . It is nIn conclusion, there is currently limited evidence of the potential therapeutic benefits of CBD for cocaine and METH use disorders and commonly related adverse symptoms. A clear limitation of the literature is the paucity of human research and the lack of clinical trials. Given the absence of abuse liability of CBD and its general tolerability, this compound appears to be a promising candidate for pharmacotherapy of psychostimulant drug-use disorders. Further preclinical studies and future clinical trials are clearly necessary to fully evaluate the potential of CBD as an intervention for cocaine and METH addictive disorders. The validation of the safety and efficacy of CBD in reducing craving and relapse in preclinical and clinical trials will be necessary for the translation of research findings into clinical settings.


After damage, axons in the peripheral nervous system (PNS) regenerate and regrow following a process termed Wallerian degeneration, but the regenerative process is often incomplete and usually the system does not reach full recovery. Key steps to the creation of a permissive environment for axonal regrowth are the trans-differentiation of Schwann cells and the remodeling of the extracellular matrix (ECM). In this review article, we will discuss how proteases and secretases promote effective regeneration and remyelination. We will detail how they control neuregulin-1 (NRG-1) activity at the post-translational level, as the concerted action of alpha, beta and gamma secretases cooperates to balance activating and inhibitory signals necessary for physiological myelination and remyelination. In addition, we will discuss the role of other proteases in nerve repair, among which A Disintegrin And Metalloproteinases (ADAMs) and gamma-secretases substrates. Moreover, we will present how matrix metalloproteinases (MMPs) and proteases of the blood coagulation cascade participate in forming newly synthetized myelin and in regulating axonal regeneration. Overall, we will highlight how a deeper comprehension of secretases and proteases mechanism of action in Wallerian degeneration might be useful to develop new therapies with the potential of readily and efficiently improve the regenerative process. In the peripheral nervous system (PNS), nerves can be damaged following various events such as traumatic injuries, metabolic alterations and genetic peripheral neuropathies. All these events significantly impact the quality of life of both patients and caregivers. Regardless of the nature of the triggering cause, after injury both Schwann cells and neurons are compromised as their reciprocal interdependence determines that damaging one cell type will eventually influence the other. Unlike the central nervous system, the PNS possesses the intrinsic capability to regenerate, as axons can regrow over long distances to reach their final target and Schwann cells are able to remyelinate them. Nonetheless, the regenerative process often remains incomplete, due to the inability of the repair machinery to maintain an extended growth promoting response -like growth factors Falls, . They siAmong the various types of Neuregulins, we will focus on NRG1 type I and type III, which are the main isoforms thus far investigated in PNS development and regeneration. NRG1 type I is a single-pass membrane protein and presents an Immunoglobulin-like domain at the N-terminus, while NRG1 type III, in addition to the transmembrane domain, possesses a cysteine-rich domain in the N-terminal portion that further anchors the protein to the plasma membrane  are membrane-anchored metalloproteinases involved in the proteolytic processing of several transmembrane proteins and in the consequent regulation of the cleaved substrates’ activity  are a multi-subunit protease complex responsible for the intramembrane cleavage of transmembrane proteins, mostly known for the generation of the β-amyloid peptide in Alzheimer’s disease  mechanism . After bp75NTR regulates a variety of cellular function in the nervous system, from programmed cell death, axonal growth and degeneration, to cell proliferation, myelination and synaptic plasticity  are a family of zinc-dependent enzymes, which can degrade all components of the ECM , namely tissue PA (tPA) and urokinase PA (uPA), are key enzymes of the blood coagulation cascade implicated in several biological processes, including vascular and tissue remodeling, tumor development and progression (Mekkawy et al., In addition to the PA system, thrombin, another key enzyme of the blood coagulation system, and its inhibitor Nexin-1, are potently induced after sciatic nerve injury. In the blood coagulation cascade, thrombin converts fibrinogen into fibrin, its insoluble derivative (Weisel and Litvinov, Collectively, these studies indicate that the proteases of the blood coagulation system and their regulators are essential to stimulate recovery in injured PNS and a precise balance between activation and inhibition of their proteolytic activity is required to correctly modulate nerve repair.In the present review article, we presented a selected range of molecules and pathways involved in injured PNS. We specifically focused on extra cellular matrix and tissue modifiers and on growth factors’ processing. Several studies have demonstrated how crucial is the role of these enzymes in tissue remodeling in response to damage. Nonetheless, despite the extensive studies conducted thus far, additional work is required to better define both the cell autonomy and the time frame in which these molecules and pathways are mostly active. We thus think that clarifying these aspects could be beneficial to define new therapeutic strategies that, together with the development of conduit devices, could efficiently improve the regenerative process and prompt full functional recovery.MP and CT searched PubMed for articles published up until August 2018. Both MP and CT discussed the topics, decided the outline of the review and wrote the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.