Pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD) is a common type of pulmonary arterial hypertension (PAH) and a frequent complication of congenital heart disease (CHD). PAH-CHD represents a heterogeneous patient population and it is important to distinguish between the underlying cardiac defects considering the prognostic and therapeutic implications. Improved interventional techniques have enabled repair or palliation of most cardiac defects, though a substantial number of patients remain at high risk for PAH after closure. Traditionally, the treatment and management of PAH-CHD patients has been limited to palliative and supportive care, and based on expert opinion rather than clinical trials. Recently, however, the availability of advanced PAH-specific treatment has opened up a new field for the clinical management of this condition. Nevertheless, there is limited evidence on the optimal therapeutic approach for PAH-CHD. Herein, we discuss the current and novel therapeutic options for PAH-CHD as well as highlight several challenges in the clinical management at present. Any congenital heart disease (CHD) with intra- or extracardiac shunting that allows for persistent exposure to increased pressure and volume overload of the pulmonary circulation may lead to the development of pulmonary arterial hypertension (PAH). PAH may develop at any stage of the disease and when it does, it is characterized by poor exercise tolerance and quality-of-life as well as high morbidity and mortality . DespiteThe demographics of CHD and subsequently PAH-CHD are changing. Over the last decades, major advances in pediatric cardiovascular medicine and surgery have led to a marked increase in survival of CHD patients—more than 90% now reach adulthood . The remInterestingly, some CHD patients are at higher risk for developing PAH and with rapid disease progression despite similar underlying cardiac defects. Aside from environmental factors, genetic predisposition may play an important role in the phenotypic variability of PAH in CHD. It may be useful to screen for PAH gene mutations in case of discrepancy between severity of PAH and CHD. Multiple mutations have been identified in hereditary PAH. Some of which, like the bone morphogenetic protein receptor type 2 mutation, were also observed in PAH-CHD patients, though considerably less than in hereditary or idiopathic PAH patients  refers to diseases with increased pulmonary pressures, defined as mean pulmonary arterial pressure (PAP) ≥ 25mmHg at rest. PH is not synonymous with PAH, which specifies either obstructive or vasoconstrictive PH characterized by elevated pulmonary vascular resistance (PVR) and normal pulmonary venous pressure . The cliPAH-CHD is distinctly different from other PAH etiologies regarding underlying cause and clinical outcome. In general, PAH-CHD has a slower disease progression and better life expectancy compared to other PAH etiologies . SurvivaAs indicated in Transthoracic echocardiography is the most commonly used diagnostic test in the initial evaluation on PAH-CHD to determine the underlying cardiac defect, image the effects of PAH on the heart and provide an estimate of the PAP with continuous wave Doppler measurements . AdditioInternational consensus guidelines recommend that PAH-CHD patients should undergo periodic assessment at specialized centers for both PAH and CHD ,15. A coSeveral supportive measures should be considered in management of PAH-CHD. PAH-CHD patients, especially those with ES, are at particular risk for hemodynamic complications during general anesthesia and surgery. For ES patients, a multidisciplinary approach is imperative and surgery should preferably be performed only at centers with expertise in the management of such patients, or in case of emergent or urgent situations, caregivers should seek consultation with expert centers throughout care. Pregnancy is still associated with a significant risk of both maternal and fetal mortality even though recent reports show better outcome than previously described as specialized care during pregnancy and delivery is now available ,31. HoweAfter recent successes in clinical trials, advanced therapy is now widely used for the treatment of PAH. Most pivotal trials have included a small number of patients with closed defects—because of the similarities with idiopathic PAH—and were underpowered for formal subgroup analyses, thereby limiting the generalizability to the overall PAH-CHD population. Nevertheless, increasing evidence from observational studies and several randomized controlled trials in mainly ES support the benefit of pulmonary vasodilator therapies in PAH-CHD. To date, three major pathways have been identified in the pathophysiology of PAH and serve as target for PAH-specific treatment: (i) endothelin pathway, (ii) nitric-oxide pathway, and (iii) prostacyclin pathway .Endothelin receptor antagonists (ERAs) include bosentan, macitentan , and ambrisentan . Currently, the strongest evidence for the use of ERAs in PAH-CHD is from the Bosentan Randomized Trial of Endothelin Antagonist Therapy-5 (BREATHE-5) and its 40-week open-label extension study. In this RCT with 54 ES patients, bosentan significantly improved exercise capacity, hemodynamics, and functional class ,59, indeEvidence supporting the use of ambrisentan in PAH-CHD is limited to one uncontrolled, single-center study with 17 ES patients  reportinMacitentan has been granted approval based on the Study with an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome (SERAPHIN) trial, a RCT including 62 PAH-CHD patients with closed defects (8% of the study population) demonstrating a reduced morbity and mortality with macitentan . The resCurrently, no studies on direct comparison have been performed to assess the superiority of one ERA over the other. Interestingly, however, a recent trial in which 40 PAH-CHD patients were switched from bosentan to macitentan, showed improved World Health Organization (WHO) functional class, NT-proBNP levels, and echocardiographic RV measures but noted no difference in events such as syncope and hospitalization for heart failure .To date, fewer studies on phosphodiesterase-5 inhibitors (PDE-5i), such as sildenafil and tadalafil, have been conducted in PAH-CHD compared to ERAs. One small randomized trial  with silSimilar favorable results of tadalafil have been reported in subgroup analyses of the Pulmonary Arterial Hypertension and Response to Tadalafil (PHIRST) trial , a preliA novel class of drugs targeting the nitric-oxide (NO) pathway are the soluble guanylate cyclase (sGC) stimulators, with riociguat as its first approved drug. The Pulmonary Arterial Hypertension Soluble Guanylate Cyclase–Stimulator Trial 1 (PATENT-1) included 35 PAH-CHD patients with closed defects (8% of the study population), and evaluated riociguat in treatment-naïve patients and patients on background therapy . After 1Despite the lack of supportive data, the efficacy and safety of sildenafil, tadalafil and riociguat seem comparable, though tadalafil does have the advantage of a once-daily dose intake compared to a three-time daily dose of sildenafil and riociguat. Also, riociguat requires a two weekly dose uptitration, whereas sildenafil and tadalafil do not require an uptitration phase.Intravenous prostacyclin analogues were the first pulmonary vasodilators. In several small, open-label studies, intravenous epoprostenol led to favorable effects on functional class, hemodynamics and exercise capacity in PAH-CHD patients ,72,73, bIn a randomized trial with subcutaneous treprostinil , a subgrIn general, oral therapies are preferred in PAH-CHD patients as opposed to intravenous drug given its potential risks of paradoxical embolism and infectious complications or inhaled drugs requiring frequent utilization. Recently, selexipag, the first oral selective non-prostanoid IP-receptor agonist, was approved for the treatment of PAH after the Prostacyclin Receptor Agonist In Pulmonary Arterial Hypertension Study (GRIPHON) trial . In the Over the last years, the experience with combination therapy—using two or more classes of drugs simultaneously—in PAH is increasing. Similar to treatment of systemic hypertension and heart failure, the rationale is to evoke additional and synergic therapeutic effects by acting on separate pathways at once. The general approach in PAH has been to start combination therapy when patients deteriorate or have suboptimal response to monotherapy. A recent meta-analysis of 18 RCTs including 4162 PAH patients showed that combination therapy reduced the risk of clinical worsening and was associated with improved functional status, exercise tolerance, and hemodynamics compared to monotherapy . DespiteSeveral RCTs provide evidence for favorable effects of sequential combination therapy in PAH ,78,79,80Upfront combination therapy, i.e., initiating with two or more PAH-specific therapies in treatment-naïve patients, is becoming increasingly commonplace in clinical practice. First-Line Ambrisentan and Tadalafil Combination Therapy in Subjects With Pulmonary Arterial Hypertension (AMBITION) was the first large-scale trial with 500 PAH patients to demonstrate that upfront combination therapy with ambrisentan and tadalafil resulted in a significantly lower risk for clinical failure events compared with monotherapy with either of these drugs . In a piMore research is required to guide management decision as to whether upfront combination therapy is superior to sequential combination therapy, and if so, which combinations of drugs are preferred. Also, more data are urgently needed on the potential safety and efficacy of advanced therapies for PAH-CHD patients, beyond those with ES or closed defects.Recent advances in surgical and percutaneous techniques have enabled repair or palliation of most cardiac defects, with low periprocedural risks. Timing of repair is crucial in the avoidance of development of PAH, as early changes in the pulmonary vascular bed are likely reversible if the shunt is repaired. In general, patients with prevalent systemic-to-pulmonary shunts and normal PVR may safely undergo shunt closure. Hemodynamically insignificant shunts do not require closure. In case of raised PVR and mean PAP and predominantly systemic-to-pulmonary shunting, repair may be considered, whereas in case of predominantly pulmonary-to-systemic shunting repair of the defect is contraindicated as the shunt facilitates RV decompression.Clinical decision making for patients with borderline hemodynamics is more difficult and expert consensus guidelines propose remarkably different criteria for shunt closure ,15,83 T. It is r2 and PVR/systemic vascular resistance ratio ≥ 0.33 are common in these patients [Of note, a significant proportion of CHD patients who have undergone seemingly successful repair during childhood may develop PAH years after closure—estimated 15% lifetime risk of those with closed defects in the Dutch CONgenital CORvitia registry . Accordipatients , though In ES patients, the shunt should never be closed, as it may act as a “relief” valve for the excess pressure in the RV. In fact, the principle of a “relief” valve has been successfully used in idiopathic PAH patients with severe or drug-refractory PAH, by atrial septosomy  or creatReversibility of PAH remains difficult to predict and data on markers for reversibility are scarce, though urgently required for the purpose of assessing operability. So far, the number of circulating endothelial cells might be a promising candidate as it was shown to be increased in CHD patients with irreversible PAH compared with those with reversible PAH . Animal Unfortunately, many CHD patients have been lost-to-follow-up or discharged after repair ,99 and cRisk stratification is becoming increasingly important for refining prognostication of disease progression, treatment response and timing of intervention. In recent years, numerous predictors of mortality in PAH  have been identified and implemented in PAH guidelines for risk stratification and guidance of treatment. Given the distinct differences between PAH-CHD and other PAH etiologies, a modification of the widely used ESC/ERS guidelines table on disease severity, stability and prognostic parameters to PAH-CHD patients is necessary and one has been proposed by Gatzoulis et al. for ES patients , though Management of some CHD subgroups with elevated PVR is particularly challenging. Patients with Down syndrome are more prone to develop PAH earlier . In factAnother challenging subgroup is the Fontan population—who strictly speaking does not meet the diagnostic criteria for PAH but may suffer from elevated PVR. As their pulmonary circulation is passively driven in the absence of a subpulmonary ventricle, even a mild increase in PVR may limit pulmonary blood flow and thus cardiac output. The introduction of advanced therapies in this population is an area of active investigation. Bosentan for six months had no favorable effects on exercise capacity, NT-proBNP levels, or quality-of-life in a randomized trial , whereasOngoing studies are addressing whether there is a role for classic heart failure therapies in the treatment of PAH. Spironolactone is being evaluated in two RCTs, as monotherapy or sequential therapy to ambrisentan . Another trial is assessing the effect of adding beta-blockers to background therapy .l-citrulline, a NO-independent stimulator, was evaluated in 20 idiopathic PAH and five ES patients, and showed significant improvement in exercise capacity, hemodynamics, and quality-of-life after two weeks [The current PAH-specific drugs are able to slow disease progression, but cannot be considered a cure. Although over the last decades many drugs belonging to the same classes have been developed, we perhaps should consider pursuing the development of truly novel therapies—that could potentially reverse or cure PAH—rather than reinvesting in the same classes of drugs or their combinations. There is no shortage of such new candidate therapies for PAH that target alternative pathobiological pathways like metabolic or inflammatory approaches or explore new treatment strategies like regenerative medicine. wo weeks . Imatiniwo weeks ,113, butSome of the limitations discussed in the prior randomized trials, such as including one subgroup of PAH-CHD  and limited power for subgroup analyses, are applicable to these ongoing trials. Still, these trials with new candidate drugs may potentially transform the therapeutic approach of PAH-CHD.Identifying the optimal treatment for the heterogeneous population with PAH-CHD demands a thorough and expert approach. Over the past years, considerable progress has been made in the field of PAH with the introduction of advanced PAH-specific therapies. Cumulative evidence now supports the introduction of these therapies in PAH-CHD patients including patients with ES or closed defects—though less research has focused on other types of PAH-CHD. Although many challenges regarding the clinical management of PAH-CHD still remain, ongoing studies are likely to complement current insights and some may revolutionize the treatment of PAH in CHD. Research on risk stratification and the impact of genetic background may further enhance our understanding of the pathophysiology and help to determine the best therapeutic and management approaches. These aforesaid developments are bound to improve quality-of-life and survival prospects for PAH-CHD patients.


The vertebrate gut teems with a large, diverse, and dynamic bacterial community that has pervasive effects on gut physiology, metabolism, and immunity. Under natural conditions, these microbes share their habitat with a similarly dynamic community of eukaryotes , many of which are well-known parasites. Both parasites and the prokaryotic microbiota can dramatically alter the physical and immune landscape of the gut, creating ample opportunities for them to interact. Such interactions may critically alter infection outcomes and affect overall host health and disease. For instance, parasite infection can change how a host interacts with its bacterial flora, either driving or protecting against dysbiosis and inflammatory disease. Conversely, the microbiota can alter a parasite's colonization success, replication, and virulence, shifting it along the parasitism-mutualism spectrum. The mechanisms and consequences of these interactions are just starting to be elucidated in an emergent transdisciplinary area at the boundary of microbiology and parasitology. However, heterogeneity in experimental designs, host and parasite species, and a largely phenomenological and taxonomic approach to synthesizing the literature have meant that common themes across studies remain elusive. Here, we use an ecological perspective to review the literature on interactions between the prokaryotic microbiota and eukaryotic parasites in the vertebrate gut. Using knowledge about parasite biology and ecology, we discuss mechanisms by which they may interact with gut microbes, the consequences of such interactions for host health, and how understanding parasite-microbiota interactions may lead to novel approaches in disease control. Toxoplasma, Giardia, and Entamoeba only cause disease in a subset of cases, with many carriers remaining asymptomatic  tract by a parasite markedly alters physical aspects of the gut ecosystem and hence the landscape in which the microbiota reside. Infection can alter epithelial barrier function by affecting mucus production and composition, tight junctions, as well as epithelial cell turnover. Since the outer mucus layer houses and feeds many gut microbial taxa, and barrier function mediates access to and interaction with host immune cells, changes at the epithelial interface represent a key arena for parasite-microbiota interactions Table .T. muris, there is a switch in colonic mucin expression from MUC2 to MUC5AC, which is believed to change biochemical properties of the mucus in a way that aids helminth expulsion  (Box Nippostrongyloides brasiliensis infection upregulates angiogenin 4 (Ang4) and downregulates regenerating islet-derived protein 3 gamma (RegIIIγ) and lysozymes (Lyz1 and Lyz2), all of which have bactericidal activity against a range of Gram-positive and Gram-negative bacteria  involved in host defense against bacterial infections  Box , a cytokF-β) Box . This maF-β) Box . Nippostzymes Lyz and Lyz2Fasciola hepatica secretes a peptide (FhHDM-1) that inhibits NLRP3 inflammasomes  products lead to the activation of NLRP3 inflammasomes  immune responses , apparently driving stronger intestinal IL-17A  by E. histolytica induces a switch to virulence in the parasite, allowing it to invade the host epithelium and cause dysentery , both positive and negative. For instance, Wescott, , T. spirCrytosporidium  accompanied by gut microbial compositional changes, including a reduction in diversity and a switch from Gram-positive to Gram-negative bacteria  Box  refers tT. muris infection reduces microbiota diversity in wild-type mice , the growing number of studies showing that parasites alter microbiota composition  amplicon sequencing. 16S rRNA sequencing is a PCR-based method in which primers targeting highly variable gene regions are used to amplify bacterial DNA in a sample, and the resultant pool of sequences analyzed to assess taxon relative abundance. While this method provides an important first step toward understanding parasite-microbiota interactions, we now need to look beyond the broad taxonomic changes it can reveal to probe mechanisms further and better predict infection outcomes. For example, an increase in the genus The current literature on parasite-microbiota interactions often describes heterogeneous findings even on the same or similar host-parasite systems. This can result from variation in the host or parasite strain used, experimental design, sampling types and time points, and analysis pipelines. Heterogeneity in a host's baseline microbiota, for example across mouse vendors, can also lead to contrasting immune responses  benefit from the observed effects of parasites on the microbiota? Do parasites benefit such that microbiota changes might reflect a manipulation by the parasite, do hosts benefit such that microbiota changes represent a part of the host's defenses, or are the changes simply a non-adaptive by-product of co-infection?To what extent are parasite and microbe behaviors  fixed versus plastic ?Do parasites and gut microbes interact through overlapping resource requirements, for example competing for the same nutrients or cross-feeding?How frequently do parasites  feed directly on microbes such that their ecological relationship is better understood as predator-prey rather than as competitors?Do different stages of parasite infection alter the microbiota differently?Is the impact of parasitic infection on the microbiota similar across all host ages, or is there a “critical window” during development when parasite-microbiota interactions are more influential in terms of host health?To what extent is malnutrition associated with parasite infection a result of parasite-driven changes to the gut microbiota?Which probiotic species can best improve protective host immune responses to parasite infection?Can administration of prebiotics reduce susceptibility to parasite infection? If so, what microbial taxa are altered with prebiotics leading to this effect?JL and SK: contributed to the conception of the work, reviewed and analyzed the primary literature, and wrote the paper; AG: revised it critically for important content.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.


Interest in the ecology of sponges on coral reefs has grown in recent years with mounting evidence that sponges are becoming dominant members of reef communities, particularly in the Caribbean. New estimates of water column processing by sponge pumping activities combined with discoveries related to carbon and nutrient cycling have led to novel hypotheses about the role of sponges in reef ecosystem function. Among these developments, a debate has emerged about the relative effects of bottom-up (food availability) and top-down (predation) control on the community of sponges on Caribbean fore-reefs. In this review, we evaluate the impact of the latest findings on the debate, as well as provide new insights based on older citations. Recent studies that employed different research methods have demonstrated that dissolved organic carbon (DOC) and detritus are the principal sources of food for a growing list of sponge species, challenging the idea that the relative availability of living picoplankton is the sole proxy for sponge growth or abundance. New reports have confirmed earlier findings that reef macroalgae release labile DOC available for sponge nutrition. Evidence for top-down control of sponge community structure by fish predation is further supported by gut content studies and historical population estimates of hawksbill turtles, which likely had a much greater impact on relative sponge abundances on Caribbean reefs of the past. Implicit to investigations designed to address the bottom-up vs. top-down debate are appropriate studies of Caribbean fore-reef environments, where benthic communities are relatively homogeneous and terrestrial influences and abiotic effects are minimized. One recent study designed to test both aspects of the debate did so using experiments conducted entirely in shallow lagoonal habitats dominated by mangroves and seagrass beds. The top-down results from this study are reinterpreted as supporting past research demonstrating predator preferences for sponge species that are abundant in these lagoonal habitats, but grazed away in fore-reef habitats. We conclude that sponge communities on Caribbean fore-reefs of the past and present are largely structured by predation, and offer new directions for research, such as determining the environmental conditions under which sponges may be food-limited  and monitoring changes in sponge community structure as populations of hawksbill turtles rebound. Xestospongia muta), mirroring abundance gains across its range, with this species now likely the dominant organism on Caribbean reefs in terms of biomass , the author concluded that sponge-eating fishes actively alternate feeding on various sponge species  to avoid sponge defenses, and therefore have no particular impact on any one sponge species. These conclusions were reported without reference to bottom-up processes.Yes, top-down control: Using laboratory and field manipulative experiments, it was demonstrated that sponge-eating fishes have clear preferences among sponge species, particularly based on chemical defenses  and detritus . Since tstigated . It may stigated , as rate species .Ircinia felix at three Caribbean sites ranged from 1.94 to 68.27 μmol C L−1 and the standard deviation of estimates surpassed the mean at each site . Sponges are generally thought to feed on the labile, rather than refractory, fraction of DOC . Recent X. muta  were reduced to less than 1% of their former population  in feeding arrays on the fore-reef , respectively, with four additional highest-ranked sponge species, all palatable species, making up 44% and 35% of the total volume, so that only five species of palatable sponges constituted 66% and 62% of the diet, respectively  grow on hard-bottom in a few meters of water depth  but much more difficult in others (deep sea), because they would require sufficient replication, caging to exclude predators, and most importantly, appropriate measurement of sponge growth (wet mass determination of whole sponges rather than volume approximations based on linear measurements or the linear extension of sponge tubes; see Regarding top-down control, as indicated in a previous review , the bes2 fore-reef study area (Should the populations of hawksbill turtles continue to rebound, their impacts on sponge communities would be predictable, beginning with a reduction in palatable sponge species on Caribbean reefs . Decadesudy area . Time-seudy area , a trendLargely unexplored is whether top-down control of sponge communities on Caribbean fore-reefs changes as a function of depth. One study has reported reduced levels of chemical defenses in a common sponge species across a depth gradient from shallow water to the mesophotic , suggest


Cardiac arrest (CA) is a well-known cause of global brain ischemia. After CA and subsequent loss of consciousness, oxygen tension starts to decline and leads to a series of cellular changes that will lead to cellular death, if not reversed immediately, with brain edema as a result. The electroencephalographic activity starts to change as well. Although increased intracranial pressure (ICP) is not a direct result of cardiac arrest, it can still occur due to hypoxic-ischemic encephalopathy induced changes in brain tissue, and is a measure of brain edema after CA and ischemic brain injury. In this review, we will discuss the pathophysiology of brain edema after CA, some available techniques, and methods to monitor brain oxygen, electroencephalography (EEG), ICP , and microdialysis on its measurement of cerebral metabolism and its usefulness both in clinical practice and possible basic science research in development. With this review, we hope to gain knowledge of the more personalized information about patient status and specifics of their brain injury, and thus facilitating the physicians’ decision making in terms of which treatments to pursue. Cardiac arrest (CA) has a yearly incidence of approximately 50–110 per 100,000 people worldwide . Due to Explosive growth of technology and information has occurred over the years and clinicians approach their daily practice differently compared to previous generations of medical practice. A reasonable explanation takes into consideration the fact that advances in pre-mortem non-invasive diagnostic methods are available for doctors, with less need to perform pre-mortem biopsies. Advances in imaging, clinical laboratory studies, and surgical and nonsurgical tissue sampling techniques over the past several decades provide the tools needed to better diagnose and detect pre mortem pathologies, thus yielding a greater number of ante mortem diagnoses and shifting physicians’ attitude away from needing to perform a detailed autopsy to acquire information . In addiThe PubMed search for this review focused on original articles, review papers and clinical trials published in peer-reviewed journals; however, there are several challenges in identifying the exact intracranial events after cardiac arrest. Major problems regarding this issue include inadequate pre-mortem tissue sampling, difficulties in brain tissue acquisition and analysis after cardiac arrest, challenges in establishing a representative in vivo experimental model that directly projects and describes either molecular or gross events following cardiac arrest, and the existence of population heterogeneity in post cardiac arrest clinical research. In order to minimize and exclude these effects in this review, we primarily focused on stroke-models like global hypoxia-ischemia and oxygen deprived cell line studies. In this review, we also involved and cited the clinical trials whose targeted population has a diagnosis of cardiac arrest with various etiologies.For this review, multiple searches were conducted in order to find the appropriate articles for each subsection. In the section entitled Pathophysiology, a PubMed Boolean search was performed using “cardiac arrest and pathophysiology and brain”, 1820 articles were found. Another Boolean search was performed using “global brain ischemia and pathophysiology”, and 1852 articles were found. Forty-three sources were used. In the section entitled Electrophysiologic Monitoring of Brain Injury after Cardiac Arrest, PubMed search criteria included “EEG and cardiac arrest”. These keywords were used to find review papers and original articles in last ten years and 437 articles were found, and 19 papers were selected. In the section entitled Intracranial Pressure Monitoring and Cerebral Autoregulation, PubMed research database was searched using the following keywords: “Cerebral edema and cardiac arrest” and found 382 results. Review papers were avoided, and this narrowed down the search to 3 papers of interest based on criteria of clinical study and use of experimental animal models. “Intracranial pressure monitoring” search found 4872 results. Review papers were avoided, and this narrowed down the search to 10 papers based on criteria of clinical studies and experimental animal models. “Cerebral autoregulation and cardiac arrest” search found 210 results. Review papers were avoided, and this narrowed down the search to one paper based on criteria of clinical study. The total number of citations used for “Intracranial Pressure Monitoring and Cerebral Autoregulation” was 14. In the section entitled Brain Oxygen Monitoring, several searches were performed. A search using keywords “Near-infrared spectroscopy and Cerebral Oximetry” yielded 700 results, and 4 were selected. A search using keywords “Cerebral ischemia and oximetry” found 340 articles, and 3 were selected. A search using keywords “mean arterial pressure and cardiac arrest” found 1478 articles, and 2 were selected. Lastly, a search using keywords “cerebral oximetry and cardiac arrest” yielded 121 results and 6 were selected. Categories for inclusion included clinically relevant and translatable, including animal studies, monitoring methods already being implemented in the clinical setting, measured or was involved in continuous measurement of brain tissue oxygen content/saturation, and more recent publications took priority. In the section entitled Metabolic Imaging Modalities for Cardiac Arrest Brain Injury, PubMed search used the following keywords, “metabolic imaging and cardiac arrest and brain” and 44 search results were found. An additional set of keywords included “molecular imaging and cardiac arrest and brain” and 16 search results were found. Total number of citations used for this section was 6. In the section entitled Microdialysis, a PubMed Boolean search was conducted using the keywords “Microdialysis and cardiac arrest”. Eighty-five articles were found. Excluding papers except for those published in last five years left 70 articles. Inclusion criteria also included using reviews for background information and then focusing on clinical trials. Fourteen papers were utilized in this section.+ concentration rapidly increases, membrane depolarization and a large influx of Na+, Cl− and water into cells, constituting cytotoxic edema .,17.+ conal (OH−) . It overal (OH−) . Other hal (OH−) .2)/waste exchange, eventually leading to loss of tissue function [The initial cell swelling (cytotoxic edema) is a translocation of interstitial water into intracellular compartment following the disturbance of ionic hemostasis ; only affunction . The mecfunction .If global ischemia endures without resuscitation, severe cerebral ischemia renders the mitochondria completely dysfunctional for ATP production, leading to necrotic cell death . AlthougAn important feature of global ischemia reperfusion injury after CA and resuscitation is a substantial delay between the end of short insult and cell death. This “delayed apoptotic neuronal death” generally occurs several days and is most evident in the CA1 region of the hippocampus. It also occurs within the parts of the CA3 region of hippocampus, striatum and layers 2 and 5 in cerebral cortex ,32. The Inflammation plays an important role in global brain ischemia. The post-resuscitation diseases have been suggested as a sepsis-like syndrome, involving a systemic inflammatory response in a cardiac arrest patient . After CIn the next sections, we will review the tracing methods that monitor brain injury and edema, facilitating the understanding of some of the pathophysiological mechanism above. In addition, we will discuss the methods available to monitor brain function after CA and their application and updates in research and clinical practice.EEG, an electrical phenomenon of the brain, was discovered more than one century ago, and has lasted several decades. Scientists are trying to use EEG as a prognostic predictor and find out its advantages after CA and human brain injury. Currently, the most useful method of Electrophysiological Monitoring of Brain Injury after CA is an EEG. Most patients succumb due to hypoxic brain damage; even after successful cardiopulmonary resuscitation following CA, prediction of brain injury during or after CA remains an important issue guiding the decision to continue or withdrawal treatment, and organ donation. The prognostic prediction of EEG is an important diagnostic criterion of brain injury, such as clinical symptoms and biochemical markers. Technical advantages of EEG recording including continuous EEG, quantitative EEG, and amplitude-integrated EEG are used to predict patient outcomes after CA. Moreover, somatosensory, motor, auditory, and visual evoked potentials in EEG provide information about degree of functional damage of brain after CA .Human and animal studies have shown that EEG is a well-described method to monitor acute brain injury after CA. The studies demonstrated that EEG is a useful monitor for seizure and ischemia detection and, has a well-described role for EEG in convulsive status epilepticus after CA . RecentlThe absence or discontinuation of reactivity in continuous EEG is a strong predictor of outcome independent of temperature and sedatives . BilaterCellular electrophysiology, such as multi-unit activity and local field potentials, has strong potential for improving prognostication after CA, but they still require further investigation before being translated into in vivo studies and clinical practice . StudiesMore comparable studies are recommended for scientific evidence to accurately describe EEG characterization after CA with and without therapeutic hypothermia. They also need to describe outcomes after CA that are altered under hypothermic conditions. Several limitations should be considered in the further studies. As a diagnostic tool, waveform-based EEG analysis is subjective and laborious, with results depending on the interpreter’s expertise . Most stCerebral edema is an important cause of secondary brain injury following CA and must be carefully monitored in order to decrease the risk of coma and chance of mortality amongst individuals that experience such a devastating event ,29.Increased intracerebral pressure (ICP) is not a direct result of cardiac arrest, as evidenced by a clinical study conducted by Sakabe and colleagues who found that ICP persistently remained below 20 mmHg in five out of six patients following cardiopulmonary resuscitation . NonetheThe most commonly used ICP monitoring devices are categorized based on their location of placement: parenchymal and ventricular. Both types are minimally associated with infection and bleeding with greater risk of complications typically seen in use of extra cranial ventricular drain ICP monitors . In ordeBesides the obvious danger of cerebral herniation, the other concern associated with having increased ICP is a decrease in cerebral perfusion pressure , which is derived from mean arterial pressure (MAP)—ICP. In a non-pathologic state, cerebral autoregulation is responsible for maintenance of cerebral blood flow (CBF) in light of the constantly fluctuating MAP. While conducting a clinical study, Sundgreen and colleagues found that in a majority of patients in the acute phase of cardiac arrest, cerebral autoregulation was either absent or right-shifted, thereby suggesting that MAP should be maintained at higher levels to maintain proper cerebral perfusion, which was measured via transcranial Doppler ultrasonography .However, the aforementioned advances in ICP monitoring and understanding of cerebral autoregulation would have never seen the light of day unless results from animal studies were translated into clinical trials, interventions and innovations.Experimental studies are often a required precursor to clinical trials that test differences in intervention therapies’ effectiveness in a clinical setting. Mirski and colleagues questioned the difference in effectiveness between administration of mannitol and hypertonic saline in reduction and control of ICP, the latter of which was found to be more effective in rats, at least in the first 8 h . While oWhile methods exist for monitoring cerebral oxygen content perioperatively, no standardized method of continuous cerebral oxygen monitoring currently exists for patients undergoing an out-of-hospital (OHCA) or in-hospital CA (IHCA). Parnia and colleagues state that the ability to detect and quantify cerebral ischemia in real-time, during CPR is of vital clinical importance . Patient2) are unavailable to out-of-hospital patients [2) is unavailable to those experiencing OHCA [Many of the more established methods of continuous cerebral oxygen monitoring are invasive, such as monitoring catheters, and or unfeasible  for both out-of-hospital and in-hospital CA patients. In addition, neuromonitoring such as transcranial Doppler sonography and jugular oxygen content (SjvOpatients . In addiing OHCA . For insing OHCA . Despite2) content via near-infrared spectroscopy (NIRS) showed an association between a high CVP (>20 mmHg) and a decrease in SctO2 content [2 [2 with respect to MAP and CVP may be of an increased benefit to IHCA patients.A non-invasive method of accessing cerebral oxygen content may come from determining mean arterial pressure (MAP). Kilgannon and colleagues postulated whether an association between mean arterial pressure (MAP) and neurological outcome could be found . In the  content . Additiontent [2 . UnfortuStudies have emerged regarding the feasibility and accuracy of near-infrared spectroscopy (NIRS) for non-invasive cerebral oximetry . NIRS utThere are pitfalls with cerebral oximetry with near-infrared spectroscopy. Meng and colleagues  suggestsPotential prediction of neurologic outcome after CA induced brain injury has been one of the main aims of advanced neuroimaging techniques. Evidence from clinical studies has pointed out the first 72 h after cardiopulmonary resuscitation to be a poor prediction for cerebral prognosis. Thus, reducing the lack of certainty in neurologic prognosis prediction should be the leading purpose of advanced molecular imaging techniques where maintenance and modulation of cellular pathways causing brain injury can improve neurologic outcomes as well .Brain injury following CA involves periods of global hypoxia-ischemia, reperfusion recovery, glutamate consumption, and GABA-induced pathways . Yi Zhan1H-proton spectroscopy (H-MRS) and perfusion-weighted imaging (PWI) in an experimental cat study and monitored the variations of regional cerebral blood flow after cerebral recirculation along with lactate and creatinine measurements during the first 6 h after CA. Despite the favorable results, the lower statistical power and inadequate model standardization through the experiment are the main restricted factors for their results [Clinically, David KH and colleagues reported a broad literature review in order to correlate the association between levels of evidence and quality of previous studies for predicting the accurate neurologic outcomes with molecular neuroimaging techniques in post-CA patients. This review discussed the pros and cons of Positron Emission Tomography (PET) and Single-Photon Emission Computed Tomography (SPECT) in prognostication. However, limited sample sizes, variability in imaging times, and inadequate standardization methods in previous clinical research were present . Krep an results .N-acetyl aspartate (NAA)-to-creatine ratio) and NAA/Cho (reduced N-acetyl aspartate (NAA)-to-Cho ratio) at 6 h after spontaneous recirculation although Cho/Cr levels was found increased. Furthermore, in that study, hypothermia has a lessening effect on NAA/Cr decrease and Cho/Cr increase after CA. Parallel to their study, Su and colleagues used single voxel proton magnetic resonance spectroscopy in CA pig model and found lactic acid production was reduced in hypothermia group [Magnetic resonance spectroscopy (MRS) is a favorable advanced neuroimaging technique for assessing metabolite concentration alterations in ischemic brain injury. In means of CA brain injury, Tang and colleagues  analyzedia group . Chan K ia group . More ania group .Microdialysis is a method of neuromonitoring consisting of a probe covered in a semi-permeable membrane, which is inserted into the interstitial tissue of the brain. A solution, usually normal saline or artificial cerebral spinal fluid, is perfused through the probe and into the tissue, allowing cerebral fluid, along with some small molecules, to passively diffuse into the membrane where the extracellular concentration of solute is measured. Common solutes of interest include free ions, neurotransmitters, and other biomarkers and metabolites .CA often leads to a cessation of blood flow to the brain, creating areas of ischemia and consequently brain damage. Reperfusion is typically the first in the line of treatments administered; yet it is not without risk. Reperfusion injury includes a broad description of damages that can occur with restoration of cerebral blood flow. Although these molecular events are largely unknown, research in this field is quickly growing. During ischemia, cellular function is altered and one of the known pathways of damage is that of mitochondrial dysfunction. The downstream cascade is believed to begin in the mitochondria, the lack of oxygen results in anaerobic respiration, and in time, cell death . When trAlthough it has been used extensively as a research tool, further developments of microdialysis allow it to be used in clinical settings to better monitor patients who have suffered severe brain injury. Changes in levels of lactate, pyruvate, glycerol and glutamate act as biomarkers and allow clinicians to determine the current state of a patient’s brain, as well to possibly aid in the intervention of secondary injury such as hypoxia, glucose depravation  edema, aHosmann and colleagues used rodents to create a microdialysis CA model, using microdialysis as a neuro-monitor to determine cerebral metabolism during baseline, CA, cardiopulmonary resuscitation, reperfusion, and death. Significant results include the possible distinction between survivors and non-survivors. Non-survivors demonstrated with a marked increase in glutamate compared to surviving rodents within 8 min of CPR. On the other hand, survivors were characterized with higher cerebral and peripheral lactate and glucose concentrations. According to the authors, the usefulness of microdialysis outweighed its invasiveness, as it is able to detail the metabolic time course, as well giving unique insight into chemical changes in the brain .A Viennese pilot trial used microdialysis to examine metabolic changes during ventricular fibrillation CA (VF-CA), to compare two different treatments  and cardiopulmonary resuscitation (CPR)), as well as to monitor resuscitation and the return of spontaneous circulation. There were no significant differences between the extracorporeal life support and cardiopulmonary resuscitation treatment groups; all metabolic changes during each step were consistent between the groups. Glucose, glutamate and lactate-pyruvate ratios were the biomarkers used in this study. During CA, glucose decreased dramatically, and after resuscitation, increased back to normal levels. LPR had a five-fold increase from baseline levels, and peaked 8 min after return of spontaneous circulation. Glutamate also had a marked increase (3.5-fold) after CA .Overall, microdialysis has proven useful in clinical settings to monitor cerebral metabolism in critically ill neurological and neurosurgical patients, enabling physicians to provide more effective treatment depending on which biochemical signals are present . HoweverWith the challenges faced by the limitations that each method has, there is a strong need to stimulate research towards brain monitoring after CA that can generate enough robust data to support the use of brain monitoring and be able to predict in hospital and long term prognosis in patients affected by brain injury after CA . Notwith


Anorexia nervosa (AN) is among the most pernicious of psychiatric disorders, demonstrating a mortality rate six times greater than the general population, and a crude mortality rate of 5–6% . Even inAs treatment development studies aim to illustrate and engage specific mechanisms of AN psychopathology, a crucial endeavor lies in precisely indexing the mechanisms of existing treatments, as they relate to the array of symptoms encompassed by AN, including physiological, cognitive and behavioral symptoms. However, existing methods for reporting treatment and course-of-illness outcomes in AN research may have precluded a thorough investigation of both treatment efficacy and mechanisms. Here we outline several important challenges relating to conceptualizations of outcome in AN, which must be considered as we advance towards the development of novel interventions with precise, targeted mechanisms.The symptom profile in AN comprises both physiological and cognitive features, although the central distinction between weight-based versus cognitive symptomatology has historically been underreported in AN treatment trials and long-term course-of-illness studies, with weight status alone being the most widely favoured index of recovery. In studies adopting weight as an exclusive or primary metric of outcome, potentially important differences may go undetected, as may their implications for our understanding of both disorder- and treatment-specific mechanisms. Without question, an essential first step in the treatment of AN is the reversal of the acute effects of starvation, which may be most readily indexed by weight status. However, inferring from positive increments in our patients’ weight that we have effectively engaged the target mechanism of treatment and achieved change in corresponding broader symptom domains, belies the complex and interwoven network of maintaining factors that underpin AN. Moreover, the implicit assumption that weight-based recovery is a proxy for broader cognitive recovery is not supported by evidence, as the constellation of cognitive and affective challenges facing those with AN, including the fear of weight gain, body dissatisfaction, emotional dysregulation, and an ongoing fear of calorie-dense foods, frequently persist after significant weight gain has been achieved . Thus, rand cognitive AN psychopathology, yielding categorical outcome groupings. For instance, “full” remission is typically achieved by attaining both (i) 95% of expected body weight plus (ii) a score within 1 standard deviation of community norms on gold standard measures of cognitive and behavioural ED psychopathology; “partial” remission can be defined by meeting either of those criteria, but not both; and no remission would reflect an absence of the two criteria. While this approach represents an improvement over exclusively weight-based outcomes, there are potential discrepancies between these component dimensions. Conflating weight-based and cognitive symptom status into unitary outcome measures represents a missed opportunity to elucidate their distinct pathways, which in turn can stymie ongoing attempts to locate precise mechanisms of treatment. Moreover, varying definitions of what constitutes a ‘good outcome’, even when applied to a single clinical trial, yields remission rates ranging from 2% - 96% [More recently, an increasing number of clinical trials have begun to report treatment outcomes as an aggregated function of both weight status 2% - 96% , which hAccurate indices of potentially differential treatment dimensions, rather than conflated unitary outcomes, are necessary to more closely understand treatment mechanisms. We contest that such delineated outcomes ought to be deemed equally primary to the results and discussion of controlled treatment trials as conflated categorical outcomes, which offer a broad snapshot of outcome. For instance, an RCT may find a significant superiority of one treatment over another in terms of categorical outcomes, yet fail to demonstrate any significant differences across the same treatments in delineated indices of weight or cognitive symptomatology . InterprFully delineating indices of weight- versus cognitive AN symptomatology may not only foster a more nuanced understanding of their respective and combined patterns of change, but also the temporal relationship between them. For instance, examining the latency between nutritional rehabilitation and cognitive relief as a function of moderators, such as duration of illness, will direct our understanding of the intersection between chronicity, the biological effects of starvation, and the mechanistic underpinnings of cognitive AN symptomatology. Alongside these delineated outcomes, incorporating behavioural indicators and parent-report observations of cognitive symptoms will be critical to avoid false negatives in this type of research involving child and adolescent AN populations with ego syntonic presentations .Finally, rigorous, detailed reporting of longer-term outcomes, as well as treatment engagement during follow up, will allow for more controlled tracking of symptom trajectories and pathways over time. Approximately half of RCTs for AN have reported long-term follow-up data, and of those that do, few have reported whether participants were engaged in ongoing treatment further to completion of the clinical trial, and whether ongoing treatment was concordant or discrepant from the intervention received during the RCT. Ongoing treatment-seeking will by definition be correlated with end-of-treatment symptom status; this means it does not occur at random, and thus represents a confound that compromises the validity of the field’s sparse longer-term data on AN.Clearly, the development of novel treatments for AN is indicated, although a shift in our conceptualization of treatment outcomes may help identify precise targets for novel interventions. Notably, this may extend beyond weight status and diagnostic cognitive symptoms, i.e., shape and weight disturbance, to include other more transdiagnostic mechanisms such as intolerance of uncertainty and even purported endophenotypic features such as cognitive rigidity , 13. To


As previously observed for other types of tumor ablation technologies, however, this ablation-induced enhanced infiltration alone appears insufficient to generate consistent protective antitumor immunity. Therapies combining ablation with immune stimulation are therefore expected to be key to boost HIFU-induced immune effects and to achieve systemic, long-lasting, antitumor immunity.Tumor ablation technologies, such as radiofrequency-, cryo- or high-intensity focused ultrasound (HIFU) ablation will destroy tumor tissue in a minimally invasive manner. Ablation generates large volumes of tumor debris in situ, releasing multiple bio-molecules like tumor antigens and damage-associated molecular patterns. To initiate an adaptive antitumor immune response, antigen-presenting cells need to take up tumor antigens and, following activation, present them to immune effector cells. The impact of the type of tumor ablation on the precise nature, availability and suitability of the tumor debris for immune response induction, however, is poorly understood. In this review, we focus on immune effects after HIFU-mediated ablation and compare these to findings using other ablation technologies. HIFU can be used both for thermal and mechanical destruction of tissue, inducing coagulative necrosis or subcellular fragmentation, respectively. Preclinical and clinical results of HIFU tumor ablation show increased infiltration and activation of CD4 These cells then perform their effector functions in a concerted manner to eliminate pathogen-infected cells or tumor cells.The immune system is able to detect a wide variety of pathogens and tumor cells, and to distinguish them from healthy host cells. Induction of an adaptive immune response starts with phagocytosis of a pathogen by antigen-presenting cells (APCs), such as dendritic cells (DCs). The phagocytosed antigens are processed into small peptides and presented in major histocompatibility complex (MHC) receptors on their membranes, after which DCs migrate toward lymph nodes (LNs). Further activation signals are required for the establishment of a potent immune response, for instance via recognition of pathogen-associated molecular patterns by pattern recognition receptors ). DCs subsequently upregulate co-stimulatory molecules, including CD40 and CD80, and present the foreign antigen to T lymphocytes for recognition by their T cell receptors, inducing differentiation of effector and memory CD4+ cytotoxic T lymphocytes (CTLs) or CD4+ T helper cells. Over the last few years, however, boosting the immune system through T cell checkpoint blockade, adoptive T cell transfer or vaccination is emerging as an effective treatment modality with clinical benefit for cancer patients [In cancer patients, lymphocyte-mediated immunity has failed to prevent primary tumor development. Poor recognition of tumor cells by APCs and the lack of proper activation of these APCs by tumor cells hamper the generation of effective immune effector cells. Also, the presence of immunosuppressive cytokines and that of suppressive tumor-associated cells are common mechanisms by which tumors block the induction and establishment of effective CD8patients .Surgical resection of the primary tumor is still the mainstay of treatment for many cancer patients. However, depending on the tumor type and location of the tumor in the body, this procedure can have severe risks for the patient. During the last few decades, there has been widespread interest in the development and refinement of ablation techniques for local treatment of tumors in a minimally invasive manner. In addition, due to the development of imaging modalities and devices, image-guided tumor ablation is increasingly used for curative treatment, as well as palliative pain treatment. Ablation in its many forms is an attractive alternative treatment option, including for patients otherwise ineligible for surgical resection , 3. FurtThe majority of tumor ablation modalities apply energy to cause spatially localized necrosis of tumor cells. Radiofrequency ablation (RFA), microwave ablation (MWA), laser ablation (LA) and high-intensity focused ultrasound (HIFU) employ different sources of energy to rapidly (in seconds or minutes) heat the target region, while cryoablation uses longer (in minutes) cycles of freezing to cause cell death. Complete destruction of the tumor by ablation techniques has several technical difficulties, such as loss of accuracy by respiratory motion or insufficient detection of the tumor borders with different imaging modalities. Incomplete destruction may also occur due to tissue inhomogeneities and asymmetrical heat conduction (heat sink effect). Specifically for HIFU, the presence of gas or bone in the acoustic field results in scattering or absorption of acoustic waves at these interfaces.HIFU is the only completely noninvasive ablation technique available to date and has been applied for the treatment of uterine fibroids and prostate, breast, liver, kidney, bone and brain tumors , 7. HIFUIn addition to thermal destruction, HIFU can be used to generate non-thermal effects for disruption of tissue, known as (boiling) histotripsy . HistotrPoor detection of tumor borders using current imaging techniques and/or outgrowth of micrometastases present prior to ablation elsewhere in the body can lead to incomplete elimination of tumor cells. Local recurrence and distant metastases are currently also major limitations of ablation modalities , 15, andNext to lowering the general tumor burden, ablation releases tumor antigens and multiple bioactive molecules such as damage-associated molecular patterns (DAMPs). Combined with general inflammation and immune-regulatory processes of the wound healing response following ablation, this will result in different innate and adaptive immune effects. However, without co-exposure of antigen-loaded APCs to potent stimulation signals, responses generally remain weak. Potent antitumor immunity therefore is rarely generated, as also evidenced by scarce reports of spontaneous regression following ablation , 19. ComHIFU is a relatively new treatment modality with high potential. This review aims to summarize the immune effects after thermal and mechanical HIFU tumor ablation. Furthermore, we will describe parallels with other ablation methods and discuss the future perspectives of combination treatments with ablation to generate effective antitumor immunity.HIFU ablation of tumor cells will lead to either coagulative necrosis  or subcellular fragmentation . The resulting depot of damaged tumor cells will remain in situ, and tumor antigens present in this depot can be captured by tissue-resident phagocytic cells, such as DCs, that subsequently migrate toward tumor-draining lymph nodes (TDLNs). Alternatively, tumor antigens may passively enter the circulation or lymphatics and be transported to LNs where they can be taken up by LN-resident DCs. The in situ tumor debris will contain all tumor antigens in a  denatured or non-denatured state, depending on the temperatures reached in the focal zone. It has been shown in a cryoablation model that the presence of the depot is essential for the creation of tumor-specific immune responses. There, protection against a rechallenge with the same tumor was attenuated when the tumor debris was excised shortly after ablation, indicating the importance of release of antigens from the depot . Additio+ tumor-infiltrating lymphocytes reactive to clonal tumor neoantigens were identified in early stage non-small cell lung cancers. More strikingly, T cells recognizing clonal neoantigens were detected in patients with good clinical outcomes, while poor responders showed enrichment of T cells recognizing only subclonal neoantigens. These data suggest that immune cells targeting clonal neoantigens play a key role in antitumor protection [The goal of personalized cancer therapy hinges on the discovery of suitable antigens giving rise to epitopes present in an individual tumor for the creation of tumor vaccines, recently coined as the HLA ligandome . These votection . In prinFew studies have investigated the presence of tumor antigens in HIFU-generated tumor debris by making use of mAbs recognizing tumor antigens. One such study demonstrated that in several breast cancer patients, some tumor markers, such as CD44v6 and matrix metalloproteinase-9, were completely absent in immunohistochemically stained tumor biopsies after thermal HIFU ablation, while other tumor antigens could be detected to varying degrees in the HIFU-induced lesion . A commoAfter thermal ablation, a lesion of coagulative necrosis is formed, as well as a transition zone of cells undergoing apoptosis at a slower rate due to heat stress , 34. On So far only a limited number of studies have investigated the release of immune stimulatory signals following HIFU ablation. Thermal or mechanical HIFU treatment of MC-38 colon adenocarcinoma cells in vitro resulted in a rapid release of endogenous DAMPs, such as HSP-60 and ATP, from the damaged tumor cells , from whIn conclusion, tumor ablation will lead to formation of an in situ antigen depot containing all tumor antigens, including mutated neoantigens, which can be processed and presented by APCs. Furthermore, ablation will lead to the release of DAMPs that potentially could activate cells from the innate immune system, such as DCs. However, the kinetics of release of tumor antigens and DAMPs from the depot after thermal or mechanical HIFU require further investigation. In current HIFU literature, however, comparisons between different HIFU treatments are complicated by lack of details in the treatment description, as well as classification of the acoustic field generated and the temperature in the lesion . For thiewed in . This obTaken together, these data suggest that HIFU ablation alone does significantly influence the immune system, but that the overall antitumor immune response is insufficient. Therefore, it has been suggested that different immune stimuli can help boost ablation-induced immune effects. For cryoablation, it is known that in vivo proximity of tumor antigen and immune stimulus  in place and time is essential for optimal immune activation. Efficacy of cancer immunotherapy was strongly increased only when CpG-ODN was administered peritumorally immediately after cryoablation , 57. Fur+ and CD8+ T cells, as well as an increase in effector T cell/regulatory T cell ratio in secondary tumors [+ DCs in TDLNs, enhanced cross-presentation and activation, compared to cryoablation alone [In the B16 model, RFA and cryoablation have also been combined with a checkpoint blockade antibody directed against CTLA-4, resulting in increased numbers of tumor-specific T cells with increased IFN-γ secretion potential, and protection against outgrowth of tumor rechallenges . Later, y tumors . Analysey tumors . The daton alone .+/CD8+ T cell ratio prior to HIFU treatment, had their CD4+/CD8+ ratio revert to normal 1 week after ablation [+ and CD4+ cells in peripheral blood was observed [+, CD4+ and CD8+ lymphocytes in the margins of induced lesions in breast tumors, compared with untreated tumors [As shown in Table ablation , 60. In observed . Thermald tumors , 63. TheEvaluation of immune-related cytokines showed increases in the Th2 cytokines, IL-6 and IL-10, in serum after ablation, although it was not determined what cell type secretes these cytokines , 65. TheIn conclusion, immune effects after tumor ablation alone consist mostly of increased infiltration of immune cells, including innate and adaptive immune cells, in the destroyed tumor tissue, which is observed in experimental and clinical setup. In several murine tumor models, enhanced DC and CTLs activities are observed. In man, the results revealed mainly changes in the secretion of inflammatory, as well as immunosuppressive cytokines. Systemic protection after HIFU has not been observed frequently, which is in line with studies using cryoablation or RFA. There, systemic effects were only achieved when ablation was combined with immune adjuvants, including checkpoint blockade antibodies.HIFU is an important development toward a completely noninvasive ablation treatment. Thermal and mechanical HIFU ablation is being used in various pre-clinical settings for different solid malignancies. Thermal HIFU ablation is applied in various clinical settings, while for mechanical ablation the first clinical trial is being performed. Although preliminary data do suggest that immune effects occur after HIFU ablation, such as increased infiltration and cytotoxicity of CTLs, no potent tumor-specific immunity has yet been convincingly demonstrated. Despite the obviously changing immunological parameters, the minor decreases in tumor growth after rechallenge, and inconsistent decrease in metastasis formation after HIFU alone, do not support the induction of strong antitumor immune responses. Data retrieved from HIFU studies so far are in line with other ablation technologies and strengthen the notion that ablation should be combined with immunomodulatory adjuvants to boost antitumor immune responses. Combination strategies could lead to an in situ tumor vaccine, where tumor antigens are released from the tumor debris and taken up by APCs, while the immunotherapeutic compound helps activate immune cells and overcome immunosuppression. Only in such a scenario, long-lasting systemic immunity against the tumor can be expected. Further studies will elucidate by what mechanism HIFU induces or enhances immune responses and what immunomodulatory adjuvants synergizes best with each type of ablation in different cancer types. Selecting the best ablation-immune stimulation combination will be key to boost HIFU-induced immune effects and to achieve consistent protective antitumor immunity.The effects of tumor ablation are multifold: 1) the destruction of tumor mass, lowering tumor burden and (2) the release of tumor antigens, making them available for uptake by APCs. The treatment itself will lead to (3) the release of DAMPs and (4) the induction of a physiological wound healing response. Ablation will lead to creation of an in situ antigen depot containing all types of tumor proteins. Ablation of tumors at temperatures above 65 °C leads to denaturation of proteins. This can affect immune responses in opposing ways as high temperatures denature immune activating signals, such as danger signals like HSPs, as well as immune suppressive signals such as TGF-β or IL-10. Depending on the tumor microenvironment, it may be more important to remove immune suppressive signals or maintain danger signals using, respectively, thermal ablation or mechanical ablation. Furthermore, availability of tumor antigens from the tumor debris may be different between thermal and mechanical HIFU. The state of blood vessels in/near the treated area should be considered as well, since the majority of immune cells will reach the induced lesion via the circulation. More experiments looking closely at the optimal treatment regime for a given cancer patient are needed to achieve this. In current literature, however, the treatment description, as well as classification of the acoustic field generated, is often lacking details (see also Table  the destIn clinical practice, local recurrence of the primary tumor and/or emergence of pre-existing metastases are the main limitations of successful curative treatment using tumor ablation methods. Recent clinical results with current ablation treatments have shown that these problems persist with HIFU , 15. To


Gastrointestinal (GI) side-effects of chemotherapy are a debilitating and often overlooked clinical hurdle in cancer management. Chemotherapy-induced constipation (CIC) and Diarrhea (CID) present a constant challenge in the efficient and tolerable treatment of cancer and are amongst the primary contributors to dose reductions, delays and cessation of treatment. Although prevalence of CIC is hard to estimate, it is believed to affect approximately 16% of cancer patients, whilst incidence of CID has been estimated to be as high as 80%. Despite this, the underlying mechanisms of both CID and CIC remain unclear, but are believed to result from a combination of intersecting mechanisms including inflammation, secretory dysfunctions, GI dysmotility and alterations in GI innervation. Current treatments for CIC and CID aim to reduce the severity of symptoms rather than combating the pathophysiological mechanisms of dysfunction, and often result in worsening of already chronic GI symptoms or trigger the onset of a plethora of other side-effects including respiratory depression, uneven heartbeat, seizures, and neurotoxicity. Emerging treatments including those targeting the enteric nervous system present promising avenues to alleviate CID and CIC. Identification of potential targets for novel therapies to alleviate chemotherapy-induced toxicity is essential to improve clinical outcomes and quality of life amongst cancer sufferers. Cancer is a leading cause of death worldwide  with appTable 1), incidences as high as 40% in patients receiving standard dose chemotherapy and 100% in patients receiving high dose chemotherapy have been reported   .Chemotherapy-induced diarrhea severely interferes with anti-cancer treatment, resulting in treatment alterations in approximately 60% of patients, dose reductions in 22% of patients, dose delays in 28% of patients and complete termination of treatment in 15% of patients . MoreoveFor over 30% of CID sufferers it interferes with their daily activities , with deTable 1), most basic research into the mechanisms underlying CID has focused on irinotecan and its active metabolite SN38  and subsequent up-regulation of pro-inflammatory cytokines including interleukin 1 , which cBifidobacterium spp. toward Salmonella spp. and Escherichia coli following irinotecan administration  or complicated (grade 3–4 with one or more complicating signs or symptoms), early onset (<24 h after administration) or late onset (>24 h after administration) and may be categorized as persistent (present for >4 weeks) or non-persistent (present for <4 weeks) according to the National Cancer Institute’s Common Terminology Criteria for Adverse Effects grading system . AlthougLoperamide is a non-analgesic agonist that acts at μ-opioid receptors at the level of the myenteric plexus to decrease intestinal motility . High doOctreotide is a synthetic somatostatin analog that promotes absorption by inhibiting specific gut hormones to increase intestinal transit time  as well Deodorized tincture of opium (DTO) is another widely used antidiarrheal agent, despite the absence of literature to support its use in CID treatment . SimilarConstipation is a frequent, and underestimated, complication in patients with advanced cancer . As consThe mechanisms underlying CIC are poorly defined with minimal clinical studies existing. Distinguishing true CIC from secondary constipation from drugs given to control other chemotherapy or cancer-induced symptoms (such as anti-emetics for nausea and vomiting and opioids for pain) is a major issue hindering investigation . Given tConstipation is not deemed to be of clinical importance until it causes physical risks or impairs quality of life. Constipation can cause a number of significant symptoms. Severely constipated patients experience abdominal distension usually accompanied by severe abrupt episodes of abdominal pain . FurtherNormal bowel function requires the coordination of motility, mucosal transport, and defecation reflexes . BroadlyThough little clinical research has been undertaken to elucidate the underlying pathology in CIC, it has been hypothesized that CIC may result from effects of chemotherapy on nerve endings in the gut . The GI Subtle changes to the ENS, not evident in conventional histological examination, have been suggested as a potential underlying mechanism for abnormal colonic motor function leading to constipation . For insAs previously mentioned, a major limitation in the estimation and evaluation of true CIC is the onset of secondary constipation, namely opioid-induced constipation produced by opioid analgesia. Whilst opioid analgesics are the gold standard in pain relief for cancer patients, adverse effects such as opioid-induced bowel dysfunction (OIBD) and opioid-induced constipation (OIC) severely compromise their therapeutic potential . IncidenWhilst administration of laxatives remains the first-line treatment option for OIC, this intervention alone is frequently ineffective . SelectiThe management of constipation can be divided into general interventions and therapeutic measures. The general interventions involve increasing physical exercise, fluid intake and fiber consumption, availability of comfort, privacy and convenience during defecation as well as elimination of medical factors that may be contributing to constipation . TherapeBulk-forming laxatives such as methylcellulose, psyllium, and polycarbophil most closely mimic the physiologic mechanisms involved in promoting GI evacuation. Available as natural or semisynthetic hydrophilic polysaccharides, cellulose derivatives, or polyacrylic resins, bulk forming laxatives work by either dissolving or swelling in the intestines to form a viscous liquid that provides mechanical distension. This facilitates the passage of intestinal contents by stimulating peristalsis and reducing GI transit time. Although typically recommended as initial therapy for most forms of mild constipation , bulk-foOsmotic laxatives such as lactulose, sorbitol, polyethylene glycol compounds, and saline laxatives (magnesium hydroxide), attract and retain fluid within GI tract . OsmoticEmollient laxatives, also known as stool softeners, are anionic surfactants increasing efficiency of intestinal fluids and facilitating the mixing of aqueous and fatty substances within the feces; this softens the feces allowing them to move more easily through the GI tract . Stool sStimulant laxatives such as diphenylmethane derivatives , ricinoleic acid (castor oil), and surface-acting agents directly stimulate myenteric neurons to increase peristalsis resulting in reduced net absorption of water and electrolytes from the intraluminal contents . StimulaLubricant laxatives emulsify themselves into the fecal mass, coating the feces and rectum for easier passage whilst retarding colonic water absorption to simultaneously soften stool . Liquid Rectal laxatives such as bisacodyl (stimulant), sodium phosphate , glycerin (osmotic), and mineral oil (lubricant)  generallAs current therapies for CID and CIC have limited efficacy and a plethora of adverse effects, a search for and use of novel anti-diarrheal and laxative agents is essential to improve quality of life and chemotherapeutic efficacy for cancer patients. Several emerging and already existing therapies used for treatment of other conditions such as diarrhea predominant irritable bowel syndrome (IBS-D), constipation predominant irritable bowel syndrome (IBS-C) and chronic idiopathic diarrhea and constipation could be employed for the treatment of CID and CIC.Chloride is an essential ion in intestinal secretion and absorption. Secretory diarrhea, such as that experienced in irinotecan-treated patients, results from a combination of excessive secretion and reduced absorption in the intestinal lumen . ExcessiConversely, chloride channel activation has been used in the management of chronic idiopathic constipation and constipation related to irritable bowel syndrome (IBS-C). Lubiprostone is a bicyclic fatty acid derived from prostaglandin E1 that specifically activates chloride channels in the intestine, whilst having no effect on smooth muscle contraction . The und1 and CB2, widely expressed in the GI tract (1 receptors coupled to cholinergic motor neurons has been found to inhibit excitatory neuromuscular transmission in human colonic circular muscle (1 receptor inverse agonist, taranabant, has been shown to improve symptoms related to slow GI motility and abdominal pain when administered in vivo in mice (Cannabinoids mediate their effects via binding to two main G-protein coupled receptors, CBGI tract . Althougr muscle  and inhir muscle . In recer muscle , 2007 anr muscle . Convers in mice . Taranab in mice . It has  in mice .E. coli-induced secretory diarrhea (Guanylate cyclase C is the principal receptor for heat-stable enterotoxins and plays a major role in diarrhea . Enterotdiarrhea . In phasdiarrhea . Linaclodiarrhea , but no Lactobacillus rhamnosus and fiber has been found to reduce the severity of grade 3/4 5-fluorouracil/leucovorin-induced diarrhea by 15% in a randomized study of patients treated for colorectal cancer (With the recognition that intestinal microbiota play key roles in the pathophysiology of mucositis and development of CID/CIC, both antibiotics and probiotics have emerged as promising therapeutic options. Administration of probiotics have been shown to prevent CID in both 5-fluorouracil and irinotecan-treated animals . Similarl cancer . Adminisl cancer .The selective inhibition of bacterial β-glucuronidase has recently been shown to alleviate drug-induced GI toxicity in mice . A low-pChemotherapy-induced diarrhea and CIC are amongst the most common chemotherapy-induced GI toxicities, heavily contributing to treatment delays, dose reductions and in some cases cessation of anti-cancer treatment, greatly effecting management and clinical outcomes. Current treatments for CID and CIC are limited and come with a profuse amount of concomitant symptoms; however, novel therapies present a promising avenue of treatment for CID and CIC. Identification of potential targets and the development of novel treatments alleviating chemotherapy-induced toxicity are essential to improve clinical outcomes and quality of life amongst cancer sufferers.RM: conception and manuscript writing; VS, RA, JB, and KN: critical revision of the manuscript. All authors approved final version of the manuscript to be published and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.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 reviewer HA and handling Editor declared their shared affiliation, and the handling Editor states that the process nevertheless met the standards of a fair and objective review.


Non-native plants reach novel environments with hidden fungal hitchhikers. Some remain on their hosts, often contributing to invasiveness while others move beyond and naturalise and some cause epidemics on native trees. Among the three main types of fungal associations, pathotroph, symbiotroph or saprotroph, there are many categories reflecting either the part of the plant with which the fungus forms an association, the type of association, or the type of disease symptom it causes. The likelihood of non-native fungi forming novel host associations in a new environment is dependent upon the type of association. When non-native plants reach novel environments, they typically arrive with hidden microbiomes. In general, most of these hitchhikers remain on their co-evolved hosts, some contribute to the invasiveness of their hosts, and a small number can undergo host shifts and move onto native hosts. Invasion success can vary depending upon the different categories of fungal associates. When an invader tree relies on a fungal mutualism to survive in the new environment, there is a fundamentally lower likelihood of either the tree, or the fungus, establishing novel associations. In contrast, parasitic hitchhikers could merely use their host plants to move through the landscape and to become established on new hosts (host shifts). Evidence suggests the frequency of these host shifts is low and depends upon the fungal functional group. However, epidemics caused by invasive pathogens in native ecosystems have occurred globally. Thus, elucidating the potential for hidden non-native fungi to form novel host associations in a new environment is important for biodiversity conservation. The negative consequences of plant invasions to ecosystem integrity are well recognized . The inaLargely ignored in the global transportation of plants are the hidden microorganisms, within seed, the plants themselves, or the soil in which the plants were grown. These so-called hitchhikers include those beneficial to their hosts, those detrimental, those that may become naturalized without causing harm, and those negatively impacting native plants via host shift events . As discApplying eco-evolutionary experience (EEE) principles to novel host-microbe interactions sensu  can helpFungi can be classified into three broad trophic levels: (1) pathotrophs which receive nutrition by harming host cells, (2) symbiotrophs which receive nutrition by exchanging resources with host cells and (3) saprotrophs which obtain nutrient by breaking down dead host cells , do not Endophytic fungi exist within host tissues without causing any obvious symptoms . Althougvisa versa. For example, in Uruguay, the known Australian eucalypt endophyte, Neofusicoccum eucalyptorum, has been isolated from both introduced eucalypts and native Myrtales  were most diverse in locations where the tree species had been introduced centuries ago and not in the area of its natural distribution, as it had acquired many associates from the new environment  have broad hosts’ ranges . In factMany ectomycorrhizal fungi (EMF) display a degree of specificity . In foreTeratosphaeria nubilosa, has been distributed globally with its hosts, but has never moved onto native vegetation  pathogen, the honey fungus Heterobasidium annosum was original thought to have a broad distribution across the northern hemisphere until, as with Armillaria mellea, molecular systematics and detailed mating studies revealed there were several species with distinct continental distributions , where it caused more damage on the native Pinus pinea (stone pine) than the closely related local pathogenic species, H. annosum. The continuous spore release by the invasive species compared with seasonal release by the native H. annosum contributes to its success , and the South African National Research Foundation (DVGR Grant no. 98182). Murdoch University through the Sir Walter Murdoch Scheme (awarded to M.W.) supported the travel of T.B. to attend the workshop.This paper had its origin at a workshop on “Evolutionary dynamics of tree invasions’’ hosted by the DST-NRF Centre of Excellence for Invasion Biology (C•I•B) in Stellenbosch, South Africa, in November 2015. Funding for the workshop was provided by All authors contributed to discussions and subsequent writing of the manuscript.None declared.


Extracellular vesicles are a heterogeneous population of microparticles released by virtually all living cells which have been recently widely investigated in different biological fields. They are typically composed of two primary types (exosomes and microvesicles) and are recently commanding increasing attention as mediators of cellular signaling. Indeed, these vesicles can affect recipient cells by carrying and delivering complex cargos of biomolecules , protected from enzymatic degradation in the environment. Their importance has been demonstrated in the pathophysiology of several organs, in particular in kidney, where different cell types secrete extracellular vesicles that mediate their communication with downstream urinary tract cells. Over the past few years, evidence has been shown that vesicles participate in kidney development and normal physiology. Moreover, EVs are widely demonstrated to be implicated in cellular signaling during renal regenerative and pathological processes. Although many EV mechanisms are still poorly understood, in particular in kidney, the discovery of their role could help to shed light on renal biological processes which are so far elusive. Lastly, extracellular vesicles secreted by renal cells gather in urine, thus becoming a great resource for disease or recovery markers and a promising non-invasive diagnostic instrument for renal disease. In the present review, we discuss the most recent findings on the role of extracellular vesicles in renal physiopathology and their potential implication in diagnosis and therapy. Cell-to-cell communication is a very complex and finely regulated system which ensures proper signaling among different cell types in tissues. Aside from soluble factors, cell-derived extracellular vesicles (EVs) were described as a new mechanism of communication between cells  reflects their cells of origin, with specific proteins  reaching target organs such us kidney. Using a mouse model infected with l et al.  showed tl et al. .in vitro hypoxic damage promoted proliferation, α-smooth muscle actin expression, F-actin expression, and type I collagen production in fibroblasts. Among the complex EV content, the authors highlighted the importance of TGF-β1 mRNA, a profibrotic growth factor  showed to protect renal tubular basement membrane through EVs in a mouse model of renal tubule-interstitial fibrosis induced by unilateral ureteral obstruction. This molecule fostered bone marrow cells to release EV-containing miR-144, which was able to inhibit tPA/MMP9-mediated proteolytic network and MMP9 into the mouse kidney  represents more than 2% of tumors in humans worldwide and renal biopsy is still the gold standard diagnostic procedure, though it is invasive and not suitable for all patients   in animal models as well as in patients affected by chronic glomerular pathologies  and represents a putative marker for disease progression  decrease after treatment with a vasopressin receptor 2 antagonist  is an inherited kidney disease very common worldwide. The leading causes are mutations in genes encoding for proteins essential to the functioning of primary cilia, including polycystin1 (PC1), polycystin 2 (PC2), and fibrocystin  showed to reduce the accumulation of cystine in vitro and silence the specific gene transcription (Greco et al., in vivo model of unilateral ureteral obstruction and downregulated several pro-fibrotic genes (Wang et al., A final possible therapeutic application comprehends the use of EVs as a drug carrier. Drugs, proteins or RNAs can be loaded into EVs with several methods, such as electroporation, coincubation, transfection, and delivered to recipient cells for cancer and regenerative therapy (Barile and Vassalli, Altogether, these studies underline the multifaceted applications of the EVs and support increasing interest for their full understanding.All authors listed have made substantial, direct and intellectual contribution in writing the paper.BB and GC are named as inventors in EV-related patents. The other 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.


Stem cells residing in the epidermis and skin appendages are imperative for skin homeostasis and regeneration. These stem cells also participate in the repair of the epidermis after injuries, inducing restoration of tissue integrity and function of damaged tissue. Unlike epidermis-derived stem cells, comprehensive knowledge about skin appendage-derived stem cells remains limited. In this review, we summarize the current knowledge of skin appendage-derived stem cells, including their fundamental characteristics, their preferentially expressed biomarkers, and their potential contribution involved in wound repair. Finally, we will also discuss current strategies, future applications, and limitations of these stem cells, attempting to provide some perspectives on optimizing the available therapy in cutaneous repair and regeneration. Skin as a barrier for resisting external invasion is distributed to every part of the body, which concludes the epidermis and dermis . MorpholThis review aimed primarily to introduce the skin appendage-derived progenitor/stem cells, including their characteristics, functions, therapeutic potentials, and limitations as therapeutic tools for wound healing. In the following sections, we defined skin appendage-derived progenitor/stem cells and summarized some of the biomarkers used for their identification based on reported researches, and discussed their potentials in wound healing and limitations.Skin appendages develop during the embryonic period following a precise spatiotemporal pattern involving complex interactions between the cells from primitive epidermis, and ectodermic origin, as well as the underlying mesenchymal cells from mesodermic origin Fig. . EpithelSweat gland as a crucial skin appendage widely exists in the human skin surface, while only distributed on the palm of mice, which plays a pivotal role in the process of temperature regulation and homeostasis , 8. In h+) during fetal life. After stratification, K18 expression is increased and K14 expression reduced, which generates a transient but proliferative suprabasal layer of progenitors (K14low/K18+) [Knowledge of the eccrine sweat gland is relatively unified, which is differentiated from epithelial-derived stem cells and its progenitors. Recently, Lu et al. and Van Keymeulen et al. found the existence of two populations of stem cells in the sweat ducts of postnatal mice and four populations in the paw skin of adult mice , 12. Sweow/K18+) . Finallyow/K18+) , 13. In ow/K18+) , 14.Whether in human or in mice, these cells of sweat glands express a number of characterized markers. Luminal cells of a mature sweat gland express K8 and K18 . NKAα, AThe morphology of hair follicle begins at the early period of embryo and signals from the epithelium inducing the formation of dermal condensates . The firHair follicle stem cells are likely persistent throughout the lifetime of the organism . There aIn mice, the bugle cells of hair follicle express K15, CD34, and SRY box 9 –27. StemSebaceous gland as an integral philosebaceous unit resides above the bugle and under the hair shaft orifice at the skin surface and secretes sebum to lubricate the skin and keeps the waterproof property of hair in mammals . In humaExcept for eccrine sweat glands, hair follicle, and sebaceous glands, there are other appendages in the epidermis including melanocytes. Melanocyte stem cells mainly reside in the hair follicle bulge region and hair germ, which express dopachrome tautomerase, Sox10, and paired box 3 . These sSkin as the first barrier of our body resists the encroachment. Thus the rapid repair is crucial to maintain its function. Previous studies using lineage tracing and mouse models indicated that stem cells of both the epidermis and its appendages contribute to skin wound healing.To search decisional assessment of the source of stem cells in wound healing process, Lu et al. marked four stem cell populations and established new models . They reBoth clinical and experimental evidence suggest that hair follicle and sebaceous gland progenitor cells contribute to the re-epithelialization of wounds . Some reSome researchers confirmed that the stem cells of the root sheath and bugle can repair not only the hair follicle but also the sebaceous gland on the process of wound healing , 23. SweSkin appendages or appendage-derived stem cells have thrilled so many biomedical researchers over the last 10 years. PubMed, in 2015, collected over 867 references for “skin appendage” and more than 7725 for “skin appendage-derived stem cells.” Part of them are comprehensive recent reviews on skin appendages and skin appendage-derived stem cells. However, studies treating wound healing with these stem cells are rare. We summarized limitations and difficulties from different points of view about skin appendage-derived stem cells on wound healing.The cell source is certainly limited. Lu et al. found four types stem cells of the eccrine sweat gland at 2012 , while tMice were the most commonly used animal mode for researches of skin appendage-derived stem cells, but it is difficult to establish the identical wound. We usually established chronic non-healing wounds mice model through burns or diabetes mellitus wounds, while the changes were not only involved in wound region. For example, a burn patient would not only develop a series of metabolic changes in wound site but also have significant change of homeostasis of the whole body, such as water and salt balance. In chronic non-healing wounds caused by diabetes in patients usually with elder age, they might have diseases including hypertension, hyperlipidemia, and renal involvement generally. The complex symptom is difficult to completely reproduce in animal models. Stem cell therapy is usually directly injected to the specific site or intravenous injection, but the exact number of cells that arrived at the wound site and the interaction time could not be determined. Hence, a suitable approach to study the role of stem cells in the wound site is in urgent need. Not to mention, there are some problems that blocked the transformation of basic experiments to clinical trials.In this review, we have discussed the characteristics and functions of eccrine sweat gland-, hair follicle-, and sebaceous gland-derived progenitor/stem cells as well as summarized the relationship, potential, and limits of these stem cells on wound healing. We mainly elucidated the roles of skin appendage-derived progenitor/stem cells in wound healing, associated with their development and molecular mechanisms. Chronic non-healing wounds are common and need to be paid attention. Skin appendage-derived progenitor/stem cells could reduce the immune response and promote repair. To figure out the comprehensive cellular interactions and stem cell behavior would facilitate wound healing. With the knowledge of skin appendage-derived progenitor/stem cells recently showed that choosing the right stem cell type for fully functional skin regeneration in vivo is extremely important. Furthermore, identifying and isolating pure skin appendage-derived progenitor/stem cell populations, exploring the underlying mechanisms, and optimizing protocols for cell delivering to appropriate portion need to be further explored. Moreover, we need more clinical trials to further explore the long-term effects with these cells and ultimately provide safer and more effective therapies for future clinical applications.