Several chromatographic approaches have been established over the last decades for the production of pharmaceutically relevant viruses. Due to the large size of these products compared to other biopharmaceuticals, e.g., proteins, convective flow media have proven to be superior to bead-based resins in terms of process productivity and column capacity. One representative of such convective flow materials is membranes, which can be modified to suit the particular operating principle and are also suitable for economical single-use applications. Among the different membrane variants, affinity surfaces allow for the most selective separation of the target molecule from other components in the feed solution, especially from host cell-derived DNA and proteins. A successful membrane affinity chromatography, however, requires the identification and implementation of ligands, which can be applied economically while at the same time being stable during the process and non-toxic in the case of any leaching. This review summarizes the current evaluation of membrane-based affinity purifications for viruses and virus-like particles, including traditional resin and monolith approaches and the advantages of membrane applications. An overview of potential affinity ligands is given, as well as considerations of suitable affinity platform technologies, e.g., for different virus serotypes, including a description of processes using pseudo-affinity matrices, such as sulfated cellulose membrane adsorbers. The production of viruses and virus-like particles (VLPs) for biopharmaceutical uses, such as vaccines or viral vector applications, requires an extensive product purification to reduce safety risks for patients. Depending on the production system of the particular product, the composition of contaminants in the starting material can vary ,2. In geWhen focusing on chromatographic approaches, a variety of techniques are available that allow for a tailored method development depending on the characteristics of the target product. Possible approaches include charge- and pH-driven principles using ion exchange chromatography ,9,10,11,Here, we summarize the modern membrane-based affinity and pseudo-affinity purifications of viruses and VLPs while also briefly covering the history of bead-based resin affinity purifications for these products in general. We also provide a brief overview of the methods, which are used to identify affinity ligands as well as the relevant decision criteria for their selection. In addition, we indicate which types of ligands are suitable for use with membranes and give a brief outlook on the future prospects of affinity chromatography using membranes.Originally, affinity purifications were established for biopharmaceutical proteins, especially for antibodies, and were based on a classical antibody–antigen interaction, where the antigen is immobilized on a stationary phase. A technology that has been established as a platform purification approach for various antibody purifications are the Protein A, G, or L affinity resins, which represent the most widely used affinity matrix materials on the market, taking into account several modifications and optimizations of the ligand composition over the years . For virFor various viruses, individual ligands have been identified and immobilized onto a stationary phase backbone, often consisting of resin particle beads of silica, cellulose, or dextran. Reports of various applications have been reviewed in previous publications ,25. A rePichia pastoris as a production host. [As variations in the composition of the product  can alter its binding interaction with the column, it is desirable to use ligands that are suitable for a wider range of targets. With this in mind, it is possible to select viral surface structures that are present on all viruses of the same class regardless of the viral genotype, such as the gp64 protein found on many different baculoviruses , or the on host. . While tAnother approach to avoid heparin and to, nevertheless, use an affinity platform purification approach is to use ligands that mimic the properties of heparin, namely the highly sulfated polysaccharide chain . For resIn addition to bead-based particle resins, monolithic backbones are often used for an affinity and pseudo-affinity purification of viruses. Examples from recent years include the preparation of monolithic hydrogel columns with heparin ligands for the DSP of the enterovirus 71 , the purThe advantages of membrane processes over classical bead-based resins and also as an alternative to monolithic columns for the chromatographic purification of biological nanoplexes have been widely discussed in previous reviews ,44. In sAn overview of previous studies, focusing on affinity purifications using membranes as stationary phases, is shown in While sulfated cellulose membrane adsorbers have been rigorously evaluated, a further expansion of the membranes’ product portfolio, in terms of pore size distribution and ligand densities, would increase the attractiveness of this pseudo-affinity method for the purification of a diversity of viruses on varying scales. A different approach to broad platform applications could be a focus on individual viruses that are currently of high pharmaceutical relevance, such as the adeno viruses and AAV, retroviruses, herpes simplex viruses, or hepatitis viruses, to name a few. It would be highly desirable to promote the development of scalable affinity membranes for these viruses as has been done recently for lentiviral vectors using a bead-based resin . A compaIn principle, the use of membrane materials supports the implementation of single-use applications, which reduce cleaning and validation efforts as well as potential cross-contamination ,54,119. The only commercially available membrane material suitable for a purification platform is the heparin-mimicking sulfated cellulose membrane adsorber, which allows for a pseudo-affinity purification of various viruses and VLPs. However, the possible implementation in a DSP process is limited not only by the requirement for the product affinity but also by the size of the product due to the rather narrow pore size (about 0.8 µm) of these membranes.Currently, many chromatographic applications for an affinity purification of viruses and VLPs using affinity ligands are based on resin or gel column backbones, and several different column types are commercially available. However, due to the limited process productivity of these columns as a result of diffusion-limited mass transport, convective flow materials such as monoliths and membranes are a promising choice for a wide range of these applications.To enable the robust single-use affinity membrane purification of large biopharmaceuticals, such as viruses, further research is essential and will become increasingly important in the future due to the rising number of medical applications of virus-based pharmaceuticals and the need for flexible and, at the same time, specific purification approaches. Ideal ligands for such pseudo-affinity purifications must (i) be specific enough to separate the target from contaminating DNA and proteins, as well as from other particles; (ii) be unaffected by variations in the composition of the targets and ideally suitable for a range of different virus types or at least for genotypic variations of individual  viruses (platform application); (iii) allow for mild elution conditions to not affect the viral activity or the stability of the virus-like particles; and (iv) allow for an economic production and immobilization on the membrane surface. The last point, in particular, is crucial, as otherwise single-use applications are not financially feasible, thus severely compromising one of the major advantages of membrane chromatography applications.


The development of different transportation systems, especially land transportation, has contributed to the mobility, accessibility and development of societies. Great economic and technological benefits are derived from this flow of goods and people. However, at the same time and together with all the benefits derived from it, the most pernicious aspects appear, such as environmental pollution, visual and acoustic intrusion, congestion and the worsening of habitability in cities, among other elements.Of all these problems, traffic accidents have the greatest social impact. This problem represents a real pandemic since official figures indicate that every year, about 1,300,000 people die on the roads, and 50 million are injured [World Health Organization (WHO), Consequently, this Research Topic deals with the human factor in the field of traffic, mobility, transportation and road safety, and the relationship with other major factors such as roads, environment, signaling, vehicles and enforcement.Flor et al. analyzed the impact of the expansion of new transport services, such as Uber or Cabify, on urban mobility. Specifically, the study aimed to assess whether ridesharing platforms substitute or complement public transport to reduce accident rates, considering the two basic transport zones of Madrid. Data were collected from the 21 districts of Madrid for the period 2013–2019. The results suggest that since the arrival of Uber and Cabify, the number of deaths and serious injuries in traffic accidents has been reduced, as well as the number of traffic accidents on weekends and holidays. However, the number of minor injuries has increased in the central districts of Madrid. In addition, the results suggest that these services are replacing urban buses as an alternative mode of transport, especially for some users.Yuen et al. investigate how technology and health belief factors influence consumer acceptance of autonomous delivery robots. Five hundred valid responses were collected through an online questionnaire in Singapore, and structural equation modeling was performed to examine the data. The results revealed that perceived ease of use, perceived usefulness, perceived susceptibility, perceived severity, self-efficacy, and cues to action have a positive and significant influence on consumers' perceptions of the value of autonomous delivery robots.Useche et al. conducted a systematic review to determine the number and type of studies investigating the behavioral perceptions of different groups of road users, contrasting self-reported behavioral data with those reported by other users and their results. The review used the PRISMA methodology, obtaining a final selection of 19 articles that directly address the topic. Thus, it is indicated that road users perceive themselves as “safer” than other road users in terms of their knowledge of traffic rules and their performance on the road.Grasso and Tagliabue analyzed the relationship between self-reported aberrant behaviors and actual driving performance during a virtual simulation, focusing particularly on speeding. The experiment was conducted on an Italian sample of 79 people who had to drive through virtual road environments. The integrated use of the driving simulator and the Driver Behavior Questionnaire instrument with reference to driving behavior allowed supporting previous theoretical considerations on the relationships between aberrant on-road behaviors and speeding behaviors.Zhang et al. identify the influence of external factors in promoting customer behavioral intention for electric vehicles. Data from 203 customers in China were analyzed. The results indicated that perceived ease of use and perceived usefulness have a serial mediating relationship between external factors and behavioral intention.Von Beesten and Bresges studied the effectiveness of a road safety training program applied to high school students (Crash Curs NRW). The results evidenced that a structured follow-up training is adequate to obtain a reactive behavior of the scenic event. The follow-up intervention successfully addressed knowledge deficits about the cause and outcome of crashes.Antoñanzas and Salavera conducted the validation of the Metacognitive Skills Questionnaire for Drivers of Vehicles (CHMC), which assesses the metacognitive skills used by drivers of vehicles at three points in time . The results show the existence of three factors, a planning factor, a self-realization factor and a third evaluation factor.Cuentas et al. analyzed data from the Naturalistic Engagement in Second Tasks (NEST). The results confirm that the road traffic environment influences distracted driving behavior among automobile drivers; driving uphill compared to driving downhill, in low-density traffic scenarios compared to high-density traffic scenarios, and during afternoon periods compared to morning periods.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.


Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) are considered part of a common clinical and neuropathological continuum, with the hallmarks of both diseases being present within the same person in the so-called ALS-frontotemporal spectrum disorder (ALS-FTSD). Over the last decades, a growing amount of research has led to a better characterization of the ALS-FTSD, considering the common genetic, molecular, neuroradiological and neuropathological signatures and the significant inter-individual heterogeneity in clinical presentation and evolution. So, the potential of available markers for ALS diagnosis and prognostic estimation continues to improve. However, to date, no specific markers for the definition or prediction of motor disability or cognitive/behavioral dysfunction have been validated. For example, the current Strong criteria define ALS-FTSD from a clinical and neuropsychological standpoint but will soon need the support of wet biomarkers (both on CSF and plasma) and translational approaches provided by neuroimaging and neurophysiology at different levels of complexity. For this reason, many research efforts in this area are dedicated to the search for translational markers able to define this neurodegenerative spectrum better.In this Frontiers Research Topic, the four published articles will help the researchers to be updated on the main innovations in this area, speeding up the applicability of these findings. In this Volume, most studies focused mainly on ALS, where the underlying pathological mechanisms are even more obscure, but translatable to the whole spectrum.Starting from the diseases' risk, we know that in FTD a positive family history for dementia is reported in roughly 40% of cases, although a clear autosomal dominant transmission accounts for only 10% of cases. On the contrary, non-genetic risk factors are yet to be identified, although traumatic brain injury, bipolar disorder, diabetes mellitus and thyroid diseases are associated with an increased risk of disease . Subgroup analysis also clarified that current smoking significantly increased the risk of ALS, compared with previous smoking, suggesting that lifestyle modifications might impact the individual risk of disease development. Moreover, the significant protective associations that were found with high BMI and the use of antidiabetic drugs strongly support the potential importance of metabolic and nutritional interventions for a protective effect on ALS, in line with previous suggestions  alterations in the clinical evolution of ALS, highlighting the need further to investigate brain structures traditionally unexplored in the disease to get a deeper understanding of its underlying pathophysiology. In particular, the up-to-date overview of structural and functional Magnetic Resonance Imaging studies in the field provided converging evidence from different imaging modalities on the association between BG degeneration and motor and cognitive symptoms of the disease.Besides risk factors, research focuses on previously unexplored pathological mechanisms possibly involved in disease onset and evolution. In this context, the review by Recent important updates are not confined to risk factors and newly discovered pathological processes but include disabling symptoms relatively underestimated in ALS and new reworkings of the classical electromyographic diagnostic process, possibly leading to novel neurophysiological markers.An et al. extensively discussed this topic in their paper. First, the authors confirmed the high frequency of pain in this large cohort of Chinese ALS patients. Surprisingly, the pain did not affect the quality of life, assessed with an innovatively multidimensional scale evaluating different—often ignored—domains. Conversely, anxiety, depression, and spinal burden can affect the quality of life in ALS patients. The social beliefs and ethics of the country of origin could have affected the impact of pain on the quality of life, resulting from complex and heterogeneous mechanisms (Ciećwierska et al., Zoccolella et al. described current evidence regarding the split-hand and split-leg phenomena in a concise and easily consultable mini-review, focusing on the possible associated neurophysiological findings and their clinical implications. The authors' findings supported the role of these signs as reliable markers for motor neuron disease differentiation and prognosis estimation. In fact, although the exact underlying mechanisms related to the split indexes are yet unclear, the authors support the idea on an involvement of both cortical and spinal pathways for their genesis.Pain is a frequently underrated ALS symptom that has been largely investigated in recent works (Chiò et al., In conclusion, the present Frontier Research Topic focused on research updates in ALS-FTSD, ranging from risk factors to imaging and clinical disease markers, consolidating concepts already well-known in the literature, and hypothesizing new underlying paths to investigate. All these reported detecting points will help improve diagnosis, staging, and prognosis, heading toward a path to precision medicine that needs to be implemented soon.FD conceived and wrote the manuscript with great scientific input from PF, AI, and ES. All authors contributed to the article and approved the submitted version.


The compliance of conventional granular jamming universal grippers is limited due to the increasing friction among particles when enveloping an object. This property limits the applications of such grippers. In this paper, we propose a fluidic-based approach for universal gripper which has a much higher compliance compared to conventional granular jamming universal grippers. The fluid is made of micro-particles suspended in liquid. Jamming transition of the dense granular suspension fluid from a fluid (hydrodynamic interactions) to solid-like state  in the gripper is achieved by external pressure from the inflation of an airbag. The basic jamming mechanism and theoretical analysis of the proposed fluid is investigated, and a prototype universal gripper based on the fluid is developed. The proposed universal gripper exhibits advantageous compliance and grasping robustness in sample grasping of delicate objects, such as plants and sponge objects, where the traditional granular jamming universal gripper fails. To grasp objects of various sizes and shapes, robotic grippers based on different design principles have been developed by researchers. Compared with rigid humanoid grippers, soft universal grippers possess unique merits because of their brilliant compliance with the environment, which leads to fewer requests on structure design, control algorithms, and sensory feedback. In 2010, based on granular jamming   and multThe basic principle behind the proposed research is based on shear thickening fluids, whose viscosity increases with the shear rate or shear stress and can recover spontaneously after the removal of external impact. Because of this unique property, shear thickening fluids have a wide variety of applications, such as shock absorption ,11, huma jamming ,17. In sobserved ,19,20. Iarticles . For a graction) . Becauseraction) ,24. HoweThe complete grasping process of a conventional universal gripper involves approaching the object, deforming around the object, gripper solidification, and object manipulation . Though The phenomenon of a person being able to run on a dense corn starch suspension is long-documented . Under iAs mentioned above, the dense granular suspension of volume fraction es model , which nThe fraction of frictional contacts In Equation (2), ssure Pa . The airHolding force From Equation (6), we can see major factors that have effects on holding force or performance of the proposed universal gripper in solid state, such as dimension of the airbag, roughness of membrane (coefficient of friction), the input airbag pressure, and contact area with the object. Additionally, for object grasping with interlock mechanism, the gripper must deform before an object is pulled off; thus, the force inducing gripper deformation is considered as a part of the holding force. The force required for gripper deformation is related to gripper stiffness, which is generally associated with particle friction coefficient To characterize the performance of the proposed universal gripper, a number of experiments have been conducted using the experimental platform as shown in From Finally, to demonstrate the capability of the proposed gripper in grasping soft and delicate objects, sample object grasping operations as shown in ectively ,30. For A universal gripper based on the jamming of a dense granular suspension fluid for soft and delicate object grasping is proposed and investigated in this study. We demonstrate that the positive-pressure-induced jamming transition of a dense granular suspension enables the proposed universal gripper to exhibit an obvious advantage in compliance. The mechanism of the jamming process of a dense granular suspension is also illustrated, and the required input pressure for the onset of fully jamming is estimated. For the proposed universal gripper, the combination of friction and geometrical interlocking mechanism contributes to the gripper holding force. The gripper holding force is dependent on several factors, such as air input pressure, gripper construction (the volume of suspension and the airbag covering surface area), size of object (contact area), and surface roughness (friction coefficient). Moreover, experimental studies, including pull-off force test and applied force test, are conducted to evaluate and investigate the gripper performance. From the results, the proposed universal gripper exhibits good performance that conforms to our expectations.Compared with the traditional universal gripper, the universal gripper based on the jamming of a dense granular suspension may have a variety of applications that have requirements for high adaptability, such as grasping soft objects of different sizes and shapes. Though the proposed universal gripper shows promising performance and application prospects, some problems still need to be further studied for practical use. The adverse effect of the membrane elasticity on the gripper compliance should be minimized. Problems associated with the inherent properties of dense granular suspensions, such as dehydration in a non-hermetic environment and particle settlement for suspensions like the corn starch suspension still cause degrading performance over time. Vibration or adjunction of cesium chloride may solve or retard the settlement of corn starch suspension, and thus may partly solve these problems ,22. Furt


Eosinophilic esophagitis (EoE) is a chronic esophageal disease that needs lifelong management and follow-up. The diagnosis requires an upper endoscopy with at least one esophageal biopsy demonstrating >15 eosinophils/high-power field, and often occurs with a diagnostic delay of up to ten years, partly due to the absence of valid non-invasive screening tools. In addition, serial upper endoscopies with esophageal biopsies are mandatory to assess the efficacy of any ongoing treatment in patients with EoE. These procedures are invasive, costly, and, when performed without sedation, are often poorly tolerated by patients. Therefore, there is the clinical need to identify reliable non-invasive or minimally invasive biomarkers that could be used to assess disease activity in clinical practice as a surrogate of peak eosinophil counts on esophageal biopsies. This review summarizes evidence on investigational non-invasive or minimally invasive biomarkers for the diagnosis and follow-up of EoE to report on the state of the art in the field and support future research. We discussed eosinophil-derived mediators including eosinophil cationic protein (ECP), eosinophil-derived neurotoxin , eosinophil peroxidase (EPO), and major basic protein (MBP) as well as other promising non-eosinophil-derived biomarkers. Although several studies have shown the utility of most biomarkers collected from the serum, esophageal luminal secretions, and feces of EoE patients, numerous limitations currently hamper the integration of such biomarkers in clinical practice. Future studies should aim at validating the utility of non-invasive and minimally invasive biomarkers using rigorous protocols and updated consensus criteria for EoE. Eosinophilic esophagitis (EoE) is a chronic, lifelong esophageal disease, characterized by symptoms of esophageal dysfunction and an eosinophil-predominant esophageal infiltrate . AlthougMost EoE-related health care costs derive from the cumbersome follow-up of patients and assessment of disease activity . In thisEosinophils are pleiotropic leukocytes involved in the physiological immune defense against pathogens . HoweverECP is a single-chain, zinc-containing protein with a molecular weight ranging from 16 to 22 kilo Dalton (kDa) . In matuSeveral studies have investigated the potential role of ECP in the diagnosis and follow-up of EoE when assessed in the serum, on esophageal luminal secretions, and in stool specimens. In a prospective observational study conducted on 15 patients, Schlag and colleagues  investigMost of the available studies on the use of serum ECP as a biomarker have included a small number of patients and were conducted prior to current consensus criteria for the diagnosis of EoE ,10. TherIn a recent randomized controlled trial, the levels of ECP identified with immunofluorescence on esophageal biopsies had excellent correlation with tissue eosinophil counts, showing a promising role of esophageal ECP in monitoring EoE . In thisp = 0.008. Based on these promising results, further studies should aim at validating the performance of fecal ECP in the clinical management of EoE.With regards to fecal testing, there is a lack of studies investigating normative concentrations of fecal ECP in both adults and children with eosinophilic gastrointestinal diseases (EGIDs) ,66,67. NEDN, also known as eosinophil protein X, is a neurotoxic protein of around 18 kDa that has 89% homology with ECP . The namDellon and colleagues  assessedIt has also been shown that marked tissue deposition of extracellular EDN is present in the esophagus of patients with EoE . AccordiThere are no studies investigating the accuracy of fecal EDN in the diagnosis or monitoring of EoE. However, at a mucosal and molecular level, EoE and food allergies share similar pathophysiological mechanisms , and stuEPO is a two-chain heme-binding protein with one heavy chain of about 52 kDa and one light chain of about 14 kDa , which iWith regard to serum EPO in EoE, Wright and colleagues  investigIt has also been shown that the EPO staining area at immunostaining on esophageal biopsies strongly correlates with tissue eosinophilia in EoE . AccordiGiven the significant tissue deposition of EPO in active EoE patients compared to EoE in remission and controls, EPO could be a promising fecal biomarker in the management of EoE patients. However, studies on fecal EPO in patients with EoE are lacking.MBP is a basic protein of 13.8 kDa that is produced as a much larger inactive protein named proMBP to protect cellular structures from the cytotoxic activity of MBP. Upon storage into the eosinophil granules, an acidic portion of the proMBP is cleaved off, and the active form of MBP is stored within eosinophil granules . AlthougWith regard to the utility of MBP as a biomarker in EoE, Dellon and colleagues  found thSeveral studies have shown that there is a deposition of MBP in the esophagus of patients with EoE. Dellon and colleagues  comparedAlthough esophageal inflammation in EoE is predominantly eosinophil-driven, several other cells and cytokines are involved in the chronic esophageal inflammatory process . A growiChronic food antigen exposure may lead to the development and deposition of IgG4s . AccordiPeriostin is another player in the esophageal inflammation in patients with EoE and is involved in esophageal remodeling . PeriostOn a final note, the role of the microbiome in health and disease is being increasingly recognized ,82, and EoE is a chronic esophageal disease that requires lifelong treatment and follow-up for the monitoring of the safety and efficacy of any ongoing treatment ,83. AccoRecent randomized controlled trials have questioned the utility of peak eosinophil counts as a clinically meaningful endpoint in EoE ,90. In tHere, we performed a literature review to summarize evidence on potential non-invasive and minimally invasive biomarkers for the diagnosis and follow-up of EoE. We found that several studies have shown that biomarkers in the serum, esophageal luminal secretions, and feces could be useful in the management of patients with EoE, as shown in


Acute pancreatitis is a complex inflammatory disease with significant morbidity and mortality. Despite advances in its management, the role of antibiotics in the prophylaxis and treatment of acute pancreatitis remains controversial. The aim of this comprehensive review is to analyze current evidence on the use of antibiotics in acute pancreatitis, focusing on prophylactic and therapeutic strategies. Prophylactic use aims to prevent local and systemic infections. However, recent studies have questioned the routine use of antibiotics for prophylaxis and highlighted the potential risks of antibiotic resistance and adverse effects. In selected high-risk cases, such as infected necrotizing pancreatitis, prophylactic antibiotic therapy may still be beneficial. As for therapeutic use, antibiotics are usually used to treat infected pancreatic necrosis and extrapancreatic infections. When selecting an antibiotic, the microbiologic profile and local resistance patterns should be considered. Combination therapy with broad-spectrum antibiotics is often recommended to cover both Gram-positive and Gram-negative pathogens. Recent research has highlighted the importance of individualized approaches to antibiotic use in acute pancreatitis and underscored the need for a tailored approach based on patient-specific factors. This review also highlights the potential role of new antimicrobial agents and alternative strategies, such as probiotics, in the management of acute pancreatitis. Acute pancreatitis (AP) is a serious inflammatory process that can range from a mild, self-limiting condition to a life-threatening disease with significant morbidity and mortality. The exact mechanisms that trigger the onset of AP are not yet fully understood but are thought to involve a complex interaction of genetic, environmental, and lifestyle factors. The initial event in the development of AP is the inappropriate activation of pancreatic enzymes within the acinar cells; under pathological conditions, such as bile reflux, alcohol abuse, or gallstones, the activation of pancreatic enzymes occurs prematurely within the pancreas itself. Once activated, they can directly damage acinar cells, leading to their necrosis. The release of pro-inflammatory cytokines, such as interleukin-1β (IL-1β) and tumor necrosis factor-alpha (TNF-α), further amplifies the inflammatory response. These cytokines recruit and activate immune cells, including neutrophils and macrophages, which infiltrate the pancreas and release additional inflammatory mediators, exacerbating tissue damage and promoting the production of reactive oxygen species (ROS), resulting in oxidative stress .Another crucial pathophysiological mechanism underlying AP is bacterial translocation, which refers to the migration of bacteria and their products from the gastrointestinal tract to extraintestinal sites; possible disruption of the intestinal barrier allows gut bacteria to migrate into the systemic circulation and reach the pancreas, triggering local and systemic inflammatory responses .The Atlanta criteria, first established in 1992 and revised in 2012, are widely used to standardize the diagnosis and classification of AP . AccordiIn addition to the Revised Atlanta Classification, several scoring systems have been developed to assess the severity and prognosis of AP: the Ranson criteria, which evaluate clinical and laboratory parameters at admission and within 48 h to predict the severity of the disease ; the AcuAdvancements in imaging techniques have also contributed to classification. CT scans are routinely used to assess the extent of pancreatic inflammation and detect complications such as necrosis, abscess formation, and pseudocysts. The Balthazar scoring system, based on CT findings, categorizes acute pancreatitis into several grades ranging from A to E, depending on the severity and extent of pancreatic involvement .In this heterogeneous clinical setting, the indications and timing for antibiotic therapy have been the main controversial topics in recent decades. The results of the first meta-analyses indicated a beneficial effect of antibiotic prophylaxis , while the second group did not receive antibiotic therapy and was considered the control group (n = 371). The study did not identify significant differences in the incidence of infected pancreatic necrosis, surgical intervention, and mortality when comparing the two groups. Interestingly, antibiotic prophylaxis was associated with a statistically significant decrease in the incidence of nonpancreatic infections. A subsequent meta-analysis [Prophylaxis is the administration of antibiotics to patients who do not have a clinical infection with the goal of preventing pancreatic infection . Accordianalysis   ,32 and pDespite its possible clinical benefits, antibiotic prophylaxis is also correlated with risks, including increased prevalence of multi-drug-resistant bacteria and incidence of fungal infection, among other effects ,28. FungAlthough antibiotic prophylaxis is not recommended by international guidelines, the clinical use of prophylactic antibiotics in SAP has become widespread; a retrospective study conducted in the United Kingdom in 2018  showed hSeveral guidelines clearly recommend antibiotics for the treatment of infected severe acute pancreatitis ,25. An iHistorically, surgical intervention, such as open necrosectomy, was the primary treatment modality of IPN . HoweverThe American Gastroenterological Association Institute guidelines state that carbapenems, quinolones, and metronidazole, which are known to penetrate pancreatic necrosis, may be helpful in individuals with infected necrosis and may be useful to delay or sometimes avoid surgical intervention and reduce morbidity and mortality . The optNonpancreatic infections mainly include pneumonia, bacteremia, central venous catheter infections, urinary tract infections, and cholangitis . In the In SAP, pancreatic or peripancreatic necrosis is initially aseptic and may develop into infected necrosis if contaminated with intestinal bacteria. Translocation of intestinal bacteria is facilitated by intestinal barrier disruption, immunosuppression, and bacterial dysbiosis in combination ,57 Figu. Most ofA recent study  found thAs analyzed earlier, in SAP, pancreatic or peripancreatic necrosis is initially aseptic and may develop into infected necrosis if infected with intestinal bacteria. Several factors contribute to the development of bacterial translocation in AP. Firstly, the increased pancreatic duct pressure and obstruction, characteristic of this condition, may result in the retrograde flow of pancreatic secretions into the common bile duct and duodenum. This retrograde flow can facilitate the migration of bacteria from the gut into the pancreatic tissue. Additionally, the inflammatory response triggered by the release of pancreatic enzymes can cause local tissue damage and compromise the integrity of the intestinal barrier. This disruption allows gut bacteria, including both commensal and potentially pathogenic organisms, to translocate into the systemic circulation and reach distant organs. Moreover, the release of inflammatory mediators, such as interleukins and TNF-α, can impair intestinal barrier function by disrupting tight junctions and reducing the production of protective mucus. The translocated bacteria can elicit an immune response, leading to the release of pro-inflammatory cytokines, the activation of immune cells, and the amplification of the systemic inflammatory cascade ,57,58,59In this context, the gut microbiome is potentially a promising target for AP treatment because it undergoes disruption during the disease’s etiology. Several studies have identified a dysbiosis of the gut microbiota during AP ,61,62,63According to the latest guidelines, antimicrobials are indicated in AP only when infection is either confirmed or strongly suspected. In recent decades, several RCTs and meta-analyses have been performed to evaluate the efficacy of antibiotic prophylaxis in reducing mortality and incidence of pancreatic and other organ infections in patients with SAP. Unfortunately, the results are inconclusive, likely due to differences in the class of antibiotics administered, timing of therapy, treatment outcomes, and study design. For these reasons, no conclusive judgments can be made about the overall efficacy of prophylactic antibiotics in acute pancreatitis. Future RCTs are urgently required to determine which subgroups may benefit from prophylactic antibiotics. Several studies have shown that antibiotic prophylaxis should be administered early, within 72 h of symptom onset or 48 h of hospitalization, underscoring the importance of timing of antibiotic initiation. The monitoring of blood levels of PCT and CRP can be useful in predicting the likelihood of developing IPN and can help identify patients who will benefit from early antibiotic therapy. Antibiotic prophylaxis is also correlated with risks, including increased prevalence of multi-drug-resistant bacteria and incidence of fungal infection; antimicrobial stewardship is needed in order to optimize the application of antibiotics to obtain the best therapeutic outcomes while avoiding side effects and decreasing the selective pressure that cause resistance emergence. Antibiotics play a critical role in the treatment of IPN and its associated complications. Early initiation of antibiotic therapy has been shown to improve treatment outcomes by reducing infection-related morbidity and mortality. Typically, broad-spectrum antibiotics, which are known to penetrate pancreatic necrosis, are used to cover both Gram-positive and Gram-negative pathogens, with adjustments based on local resistance patterns and microbiologic data. Nevertheless, alternative strategies such as probiotics may offer potential benefits. The gut microbiome is likely a potential target for treatment of AP, as dysbiosis and bacterial translocation play a pivotal role in the pathogenesis of AP and in the development of pancreatic and peri-pancreatic infections. Several studies have identified a dysbiosis of the gut microbiota during AP, characterized by an increase in the abundance of harmful bacteria  and a decrease in the abundance of bacteria producing short-chain fatty acids (SCFAs), which are thought to have anti-inflammatory properties . Because the evidence on the modulation of the gut microbiota by probiotics remains controversial to date, the use of probiotics is not recommended in severe AP.


The extracellular matrix (ECM) is a complex assembly of hundreds of proteins forming the architectural scaffold of multicellular organisms. In addition to its structural role, the ECM conveys signals orchestrating cellular phenotypes. Alterations of ECM composition, abundance, structure, or mechanics have been linked to diseases and disorders affecting all physiological systems, including fibrosis and cancer. Deciphering the protein composition of the ECM and how it changes in pathophysiological contexts is thus the first step toward understanding the roles of the ECM in health and disease and toward the development of therapeutic strategies to correct disease-causing ECM alterations. Potentially, the ECM also represents a vast, yet untapped reservoir of disease biomarkers. ECM proteins are characterized by unique biochemical properties that have hindered their study: they are large, heavily and uniquely posttranslationally modified, and highly insoluble. Overcoming these challenges, we and others have devised mass-spectrometry–based proteomic approaches to define the ECM composition, or “matrisome,” of tissues. This first part of this review provides a historical overview of ECM proteomics research and presents the latest advances that now allow the profiling of the ECM of healthy and diseased tissues. The second part highlights recent examples illustrating how ECM proteomics has emerged as a powerful discovery pipeline to identify prognostic cancer biomarkers. The third part discusses remaining challenges limiting our ability to translate findings to clinical application and proposes approaches to overcome them. Lastly, the review introduces readers to resources available to facilitate the interpretation of ECM proteomics datasets. The ECM was once thought to be impenetrable. Mass spectrometry–based proteomics has proven to be a powerful tool to decode the ECM. In light of the progress made over the past decade, there are reasons to believe that the in-depth exploration of the matrisome is within reach and that we may soon witness the first translational application of ECM proteomics.  •ECM alterations cause or accompany diseases and disorders of all organ systems.•Proteomics is a method of choice to profile the composition of the ECM of tissues.•ECM proteomics can identify novel prognostic and diagnostic biomarkers.•ECM proteomics can uncover proteins playing functional roles in disease etiology.•Further technical advances are needed to capture the diversity of ECM proteoforms The extracellular matrix (ECM) is a complex assembly of hundreds of proteins forming the architectural organizer of multicellular organisms. Over the past decade, bottom-up proteomics has become the method of choice to profile the composition of the ECM. This article reviews the state of the art in ECM proteomics research and illustrates how ECM proteomics has emerged as a powerful discovery pipeline for cancer biomarkers. This review also introduces resources available to facilitate the study of the ECM using proteomics. Antegrins , syndecantegrins ) that orntegrins , 11, 12.e.g., Ehlers–Danlos syndrome  or families of proteins  of the ECM have been extensively studied, the ECM as a whole, remained, until recently, largely underexplored , the casyndrome ), the resyndrome ), and thfibrosis , 23), tofibrosis  and cancfibrosis , 26, 27.fibrosis , 29. Ninfibrosis  are ECM fibrosis , 32, 33 fibrosis , 35, 36.fibrosis , 41, 42.explored  and unchexplored .via hydrogen bonds , including glycosylation, lysine and proline hydroxylation for collagens and collagen-domain-containing proteins that contribute to the stabilization of the triple-helical structure of collagens , din dimers ), and co elastin , collage elastin ). These The second challenge limiting the comprehensive characterization of the ECM is its broad dynamic range in terms of protein abundance. The ECM is comprised of very large and highly abundant structural ECM components, which can generate many peptides , and also smaller secreted factors, such as ECM-remodeling enzymes, growth factors, or morphogens, present in much lower abundance. This limitation is not unique to the ECM, and advances in instrumentations and methods to fractionate protein and peptide samples, that will not be discussed here, have been key to capture the complexity of different subproteomes and are now being applied to ECM proteomics (see below).The first attempts at profiling the protein composition of the ECM of ECM-rich tissues, like the cartilage, or following ECM enrichment for other tissues, employed SDS-PAGE or 2D gel electrophoresis to separate the subsets of ECM proteins that could be solubilized, followed by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). These studies reported the detection of up to a few dozen structural ECM proteins. At the time, this was no small feat and these early studies have been instrumental in helping shape the field of ECM proteomics , 55, 56.However, for most studies, known ECM proteins, expected to be detected in those tissues, were not identified. One may then ask: how can we ensure capturing potential novel ECM proteins or proteins not known to be present in these tissues? And indeed, the third challenge our field faced when attempting to characterize, in an unbiased manner, the protein composition of the ECM of tissues, was the lack of a defined parts list to systematically annotate experimental output. As a result, in the early days of ECM proteomics, many proteins listed as “ECM” proteins were in fact intracellular proteins involved in cell–ECM adhesions or secreted proteins but not incorporated in the ECM. Conversely, proteins for which no prior knowledge existed would fail to be annotated as belonging to the ECM. This represented a significant limitation to any attempt aiming to identify biomarkers of diseased states. It thus became obvious that tailored experimental and analytical approaches would be needed to decipher the complexity of the ECM.This review will discuss the latest developments in ECM proteomics, from enhancement in sample preparation and analytical methods to the application of ECM proteomics for the purpose of biomarker and therapeutic target discovery with a focus on cancer. As part of the Special Issue on Clinical Proteomics, this article will highlight selected studies performed on clinical samples or rodent models of human diseases that show translational promise. Of note, ECM proteomics is also applied to study the ECM of many multicellular organisms, for example, zebrafish , 60, 61,In 2012, we published in this journal an article describing a two-pronged approach to define the protein composition of the ECM of tissues . While pi.e., the “core matrisome” including collagens, noncollagen ECM glycoproteins, and proteoglycans. The “matrisome” also included proteins not directly contributing to the structure of the ECM meshwork but are involved in ECM homeostasis and signaling functions, such as ECM remodeling enzymes and growth factors capable of interacting with ECM proteins , easy-to-follow step-by-step protocols and videos . Orthogonal validation, for example, using tissue staining, is thus necessary to gain information on protein localization, which, in turn, will provide crucial information on protein function.The Amorim lab has proposed a simpler two-step fractionation approach using commercially available MS-compatible reagents and separating tissue lysates into two pools of protein: detergent soluble and detergent insoluble . Similare.g., sialidase, O-glycosidase, galactosidase). Recent protocols have reported other deglycosylation methods using trifluoromethanesulphonic acid or enzymes to cleave the glycosaminoglycan (GAG) moieties of proteoglycans such as chondroitinase ABC, heparin lyase, heparanase, and keratanase. While deglycosylation may enhance the release of peptides and thus protein discovery and quantification, it is worth noting that not capturing the glycosylation profile of ECM components only results in a partial view of this compartment (see below).ECM protein deglycosylation plays a key role in enhancing trypsin accessibility. Common protocols employ PNGaseF, an enzyme that cleaves N-linked glycans. However, some peptides may be resistant to PNGase F , and PNGIn conclusion, there is no “best” or no “right” sample preparation method. Different methods will yield different results. It is thus important to consider the strengths and limitations of each protocol available, as well as more practical considerations like ease of use, reagent availability, time, and cost. Ultimately, researchers should opt for the method that is best suited to investigate the one facet of the multifaceted ECM they are interested in, for example, identifying the largest number of proteins, focusing on the more insoluble components of the ECM to understand the mechanisms of assembly of the ECM meshwork, or detecting ECM remodeling enzymes present in differential abundance between healthy and diseased tissue for the purpose of drug target discovery.Over the past decade, ECM proteomics has adopted methods broadly used for global proteomics such as tandem-mass labels  for accurate determination of protein abundance or the inclusion of peptide fractionation using high-pH reversed-phase liquid chromatography . While dFor accurate protein identification and estimation of protein abundance, it is imperative to maximize peptide-to-spectrum matching, which requires prior knowledge, in particular on the nature of the posttranslational modifications that can affect proteins of interest. For collagens and collagen-domain-containing proteins, these include oxidation (or hydroxylation) of lysines and prolines. These variable modifications are typically not selected by default for database searches, since they increase the search time for global proteomic studies and have limited impact on the output. However, we and others have shown that omitting lysine and proline oxidation results in the underestimation of the number and abundance of matrisome proteins present in samples , 96.To overcome the limitation posed by the large dynamic range of matrisome protein abundance, we attempted to implement a custom dynamic exclusion approach to “ignore” all peptides derived from the most abundant proteins detected in our samples . To do sHaving overcome inherent challenges in studying the ECM and having established the feasibility of analyzing the protein composition of the ECM using bottom-up proteomics, the question became: can we derive meaningful biological and clinical information from ECM proteomic studies?e.g., clinical biopsies, tissues from mouse models of human diseases, tissue interstitial fluid or serum, ECM produced by cells in culture) and in the context of diverse diseases and disorders. Excellent reviews have recently discussed the application of proteomics to study the ECM of the skin , readers are invited to refer to our previous review .LTBP3 and SNED1 negatively correlated with breast cancer patient prognosis  or a vehicle control . The autPancreatic cancers accounted for close to 60,000 new cancer cases diagnosed in the United States in 2022 . With onMore recently, Tian and collaborators profiled the ECM composition of early-stage human pancreatic intraepithelial neoplasia and advanced PDAC samples using TMT proteomics and identified a subset of 136 matrisome proteins, including collagen type I, fibronectin, fibrillin 1, and periostin, present in high abundance in pancreatic intraepithelial neoplasias as compared with healthy pancreatic tissue, and in even higher abundance in PDAC samples . Moreovevia the systemic circulation  of different human glioblastoma subtypes with the goal of identifying potential GBM biomarkers  and derive the matrisome profile of each sample. The study identified a total of 146 matrisome components and revealed differences in the nature of the GAGs detected, in the nature and abundance of ECM proteins detected, and also, interestingly, in the nature and abundance of certain types of posttranslational modifications  between the different GBM subtypes. Since the study was conducted on intact tissue samples, the team was also able to detect changes in the abundance of intracellular enzymes responsible for the PTMs of ECM proteins , something that cannot be captured when working on decellularized samples.Tumors arising in a given organ can originate from different cell types and/or in different regions in that organ and hence may contain a different ECM. Proteomics has been applied to study the ECM composition of two of the main common types of brain tumors, medulloblastomas and glioblastomas (GBMs), and has revealed that, in addition to unique ECM signatures distinguishing medulloblastomas and glioblastomas, a subset of ECM proteins was detected in higher abundance in both tumor types as compared with control brain tissues . In a reomarkers . This stIn summary, ECM-focused proteomics is now broadly adopted to study the composition of tumor microenvironments and to identify proteins characteristic of disease stages. As recent studies have shown, matrisome proteins whose change in abundance correlates with disease progression can serve as prognostic markers or be used to monitor treatment efficiency. Interestingly, certain ECM proteins or families of proteins  are consistently altered across different cancer types, opening the possibility of the existence of common ECM-dependent mechanisms being at play during tumor progression. This is of paramount importance as we think about ways to exploit the ECM to develop new anticancer strategies.Once challenging, the characterization of the protein composition of the ECM of tissues is now broadly accessible. But ECM proteins, beyond their identity, have much more to reveal. For example, to what extent are they posttranslationally modified? Do ECM PTMs vary during the time course of disease progression or with aging? How are ECM proteins folded? With which other proteins do they interact? Addressing these questions will contribute to increasing our knowledge of ECM protein functions and of the fundamental mechanisms orchestrated by cell–ECM interactions. MS-based proteomics has the potential to help address these questions.P11276) is 20.6% in healthy liver samples or 11.5% in primary metastatic colorectal tumor samples, and that of thrombospondin1 (UniProt P07996) 10.9% in the ECM of normal saphenous vein samples.The recognition of proteoform diversity is not recent , neitherin situ to invasive ductal carcinoma , as well as the enrichment of protein databases used to search LC-MS/MS output with patient-specific sequences derived from the large body of RNA-Seq studies, and broader or even open search strategies, should contribute to enhance our ability to detect and quantify ECM proteoforms. As a community, we will also need novel analytical methods to interpret LC-MS/MS output. For example, Merl-Pham and colleagues have reported the development of a pipeline aimed at mapping and quantifying proline and lysine hydroxylations and lysine glycosylations for 15 collagen chains produced in vitro by primary lung fibroblasts isolated from patients with idiopathic lung fibrosis   , the proersican) , 179. Thersican)  and haveersican) .versus altered states . IMS is commonly applied to the study of lipids, glycans, and metabolites  but has ., CODEX ). Signif., CODEX  or the p., CODEX . ECM proThe emergence of MS-based proteomics as the method of choice to study the ECM has been concurrent to the emergence of principles dictating “Findability, Accessibility, Interoperability, and Reuse” (FAIR) of -omic datasets . This hahttps://matrisomedb.org/), the ECM protein knowledge database, which included curated ECM datasets from 17 published studies reprocessed using unified search parameters and available through an interface allowing multiple query inputs   . The latspecies) . Novel fspecies)  and the species)  to facilspecies) .https://www.manchesterproteome.manchester.ac.uk/#/MPLF) allows the user to query preanalyzed datasets with the goal of identifying structural alterations of ECM proteins, resulting in differential peptide yields in proteomic datasets, across pathophysiological conditions (The Manchester Peptide Location Fingerprinting developed by the laboratory of Dr Michael Sherratt at the University of Manchester (nditions .https://topfind.clip.msl.ubc.ca/)  is a database of protease cleavage sites, protein termini, and protein terminus modifications (ubc.ca/) . While thttp://matrixdb.univ-lyon1.fr/), a database reporting ECM protein–ECM protein and ECM protein–glycan interactions validated experimentally in vitro and allowing the building of interaction networks. However, to interact, proteins need to be present in the same tissue with precise stoichiometry. To account for this, we integrated the content of MatrisomeDB to the 2019 release of the MatrixDB, allowing users to build tissue-specific interaction networks  was developed by the Izzi laboratory at the University of Oulu to study the ECM connectome and ECM networks in normal and cancerous tissues (MatriNet ( tissues . Originahttps://bmbase.manchester.ac.uk/) is a knowledgebase jointly developed by the University of Manchester and Duke University that provides information on the composition of the specialized basement membrane ECM in development, life, and disease and across multiple species (Basement membraneBASE ( species . It alsoA better understanding of the biochemical properties of ECM proteins has led, over the past decade, to the development of MS-based strategies capable of decoding the compositional complexity of the ECM of tissues. The democratization of such strategies has resulted in the definition of the matrisome of many tissues, across diverse pathophysiological states, and in the identification of ECM signatures characteristics of these states, leading, in some cases, to the discovery of novel biomarkers of human diseases such as cancer. The ECM holds the promise to be an important reservoir of novel biomarkers and therapeutic targets , 206. InThis article contains A. N. has sponsored research agreements with Boehringer-Ingelheim.


Drug-induced nephrotoxicity (DIN) is a big concern for clinical medication, but the clinical use of certain nephrotoxic drugs is still inevitable. Current testing methods make it hard to detect early renal injury accurately. In addition to understanding the pathogenesis and risk factors of drug-induced nephrotoxicity, it is crucial to identify specific renal injury biomarkers for early detection of DIN. Urine is an ideal sample source for biomarkers related to kidney disease, and urinary exosomes have great potential as biomarkers for predicting DIN, which has attracted the attention of many scholars. In the present paper, we will first introduce the mechanism of DIN and the biogenesis of urinary exosomes. Finally, we will discuss the changes in urinary exosomes in DIN and compare them with other predictive indicators to enrich and boost the development of biomarkers of DIN. The kidney is an essential organ for drug metabolism and excretion. Due to its unique structure and function, the kidney is particularly susceptible to drug damage and is the target organ of drug toxicity . Drug-inUrine samples are easy to collect but are susceptible to external environmental factors that can affect the urinalysis results. For example, free urinary RNA is easily degraded by urinary RNase, while urinary protein is easily contaminated. Urinary exosomes are a kind of extracellular vesicles (VEs) with 40–200 nm size secreted by various cells in the urinary system and released into the urine . In genePrevious studies have observed changes in urinary exosomes during drug-induced nephrotoxicity, indicating that drug toxicity will affect the biogenesis of urinary exosomes. The pathogenesis of DIN may determine the correlation between changes in urinary exosomal contents and DIN. In the present paper, we will first introduce the mechanism of DIN and the biogenesis of urinary exosomes. Then we will discuss the changes in urinary exosomes in DIN and compare them with other predictive indicators to enrich and boost the development of biomarkers of DIN.In 2015, Mehta et al. proposed four phenotypes of renal diseases caused by DIN in the expert consensus of phenotypic standardization of drug-induced nephropathy: AKI, glomerular disorder, nephrolithiasis/crystalluria, and renal tubular disorder .Drug-related toxic effects: the excretion of drugs is mainly through urine. The kidney can concentrate urine leading to high concentrations of drugs or their metabolite solutions in renal tubules that may damage the cell membrane of renal tubules and cause renal tubular transport dysfunction . Some coAlteration in glomerular hemodynamics: Glomerular filtration is closely related to the arterial blood volume and vascular resistance of afferent and efferent arterioles in the glomerulus. The relaxation of the afferent arterioles and the contraction of the efferent arterioles also are contributed to the maintenance and regulation of glomerular pressure. Some studies have found that prostaglandins and angiotensin II regulate the relaxation or contraction of the afferent arterioles and efferent arterioles, respectively . Some drβ- Lactam drugs, and antiviral drugs. Patients may even experience typical symptoms of hypersensitivity after medication, such as fever, rash, and eosinophilia : TMA is the thrombosis and ischemic injury of capillaries and arterioles in renal parenchyma caused by the severe damage of vascular endothelial cells . TMA is Urine contains exosomes and other EVs  that originate from several parts of the urogenital tract, such as kidneys, bladder, prostate , and even uterovaginal tract . In 1986 Wiggins and colleagues first observed these membrane-bound vesicles by transmission electron microscopy (TEM) . Until 22+, ROS, and hypoxia) are closely related to the biogenesis pathways of exosomes. Lysosomes, endoplasmic reticulum, and mitochondria organize into a dynamic network through some crosstalk. Defects in one or two organelles can cause damage to the other, resulting in a change in Intracellular homeostasis  and the intracellular and extracellular environment , and cystatin C (CysC)  , 88. CluC (CysC) . In receC (CysC) . So far,C (CysC) –106. TheC (CysC) . UrinarySoluble biomarkers in urine are easier to obtain, but sample and biological complexity may lead to some limitations in gaining valuable information efficiently. In contrast, urine exosomes around a lipid bilayer protect their content and offer the specific bio information of DIN with the ease and safety of urine collection for noninvasive tests. The Isolation and purification of exosomes from urine samples are essential to avoid potential differences in different quantitative and compositional analysis protocols. Street and colleagues introduced each step of the protocols for detecting urinary exosomal biomarkers, from ultracentrifugation/isolation/purification, quantitation, composition/constituent analysis, normalization, storage and processing, and data analysis in their published review . In shorGlycyrrhiza glabra, and so on), indicating that the use of natural Chinese herbs does not equate to their clinical medication safety  TheZZ and YJ had the idea for the review. ZZ and CL wrote the first draft of the manuscript. LW and YY wrote the sections of the manuscript. YJ and XX proofread the manuscript. All the authors contributed to manuscript revision and approved the submitted version.


Wound healing is characterized by the formation of a granulation tissue consisting of inflammatory cells, newly formed blood vessels, and fibroblasts embedded in a loose collagenous extracellular matrix. Tumors behave as wounds that fail to heal. Neuronal loss in neurodegenerative disease is associated with the synthesis and release of new components of the extracellular matrix by activated fibroblasts and astrocytes. This condition is responsible for a perpetuation of the wound healing state and constitutes a condition very similar to that which occurs during tumor progression. The aim of this article is to emphasize and compare the role of wound healing in two different pathological conditions, namely tumor growth and central nervous system neurodegenerative diseases. Both are conditions in which wounds fail to heal, as occurs in physiological conditions. Wound healing is a physiological process which involves cellular activation and proliferation, leading to tissue matrix remodeling. In this context, the reactive capacity of different organs is heterogeneous: skin and gut epithelia and hematopoietic cells have highly active regenerative capacities; the liver and pancreas have intermediate capacities; and the heart and central nervous system (CNS) have low or absent capacities .In wound healing after injury, several different phases have been described. These include an inflammation phase involving different inflammatory cells, as well as proliferation and re-epithelization, angiogenesis, and remodeling phases, which lead to the formation of a granulation tissue. This product contains inflammatory cells, newly formed blood vessels, and fibroblasts embedded in a loose collagenous extracellular matrix ,3 Figur. PrimariAngiogenesis, i.e., the formation of new vessels from pre-existing ones, is required to oxygenate the new tissue and dispose of the waste products of metabolism. This mechanism is rapidly stimulated after injury, a process which ceases when wound healing is complete. Among the extracellular matrix proteins, fibronectin, a glycoprotein secreted by proliferating endothelial cells, forms the provisional extracellular matrix of wounds and promotes the migration of endothelial cells over the wound .Neutrophils are the first inflammatory cells to move to the wound tissues. Neutrophils kill pathogens, and macrophages phagocytose neutrophils while infiltrating T cells produce interleukin (IL)-17 and IL-22 and tumor necrosis factor alpha (TNFα) to amplify the host defense response. IL-17 contributes to further recruiting neutrophils, establishing a positive loop [The aim of this article is to emphasize and compare the role of wound healing in two different pathological conditions, namely tumor growth and CNS neurodegenerative diseases, both conditions in which wounds fail to heal, as occurs in physiological conditions.Tumor growth is characterized by an angiogenic response in the tumor stroma, allowing the growth of the primary tumor and favoring metastatic spread. Studying the dynamic aspects of this process the pathologist Harold F. Dvorak demonstrated similarities between tumor stroma generation and wound healing . Dvorak In skin wounds, within 24 h of wounding, VEGF mRNA expression increases in epidermal keratinocytes at the wound edge , reachesFibrin and collagen I constitute the provisional extracellular matrix during wound healing in vivo ,12 and, CNS fibrotic scar formation is a response to injury and other damage and contributes to a large degree to the pathology of CNS disorders ,16. For Following injury, the initial phases of healing involve a response starting with an inflammatory reaction, macrophage infiltration, and secretion factors, triggering extracellular matrix deposition by fibroblasts.Following acute injury of the CNS, the initial phases of healing are very similar . The celIn the adult healthy CNS, fibroblasts are localized in the meninges, perivascular space, and choroid plexus . When anConcerning chronic injuries of the CNS, including those associated with neurodegenerative diseases, the main difference with acute injuries is the gradual accumulation of the damage and the production of an interspersed set of small individual lesions, exhibiting the above-mentioned general features in terms of cell response and extracellular matrix deposits ,21. ReceDuring normal wound healing in various tissues, unwanted cells undergo apoptosis, and the extracellular matrix is reorganized to allow for tissue regeneration . In thisHowever, the persistence of reactive macrophages/microglia and fibroblasts for a quite long time at the core of the lesion, with a disproportionate deposition of extracellular matrix proteins to form the mesenchymal scar, may lead to an obstacle to axonal growth in different CNS injuries and diseases . ExtraceOn the other side, however, in vivo obtained evidence also exists, indicating that the glial scar, formed by astrocytes around the mesenchymal one, may help axonal growth by creating permissive bridges  which allow growing axons to cross the fibrotic scar in response to different growth factors ,44.Thus, both the promotion of tissue protection and the inhibition of repair take place in the healing process of the CNS ,21 and tA crucial event in tumor growth progression is the nonsolution of the wound healing-like process, which leads and contributes to the perpetuation of the disease and to the establishment of an altered tumor microenvironment ,7.The CNS displays both poor wound healing and low regenerative potential for new neurons, with the wound healing process leaving a persistent scar that impedes tissue function. The CNS scar comprises two compartmentalized cellular structures: the fibrotic scar, which is made up of fibroblasts originating from a perivascular source and infiltrating monocytes/macrophages; and the glial scar, which is composed of resident glial cell types that encase the fibrotic scar ,46. In a


Editorial on the Research TopicRecent advances in vascular neurosurgeryVascular pathology is one of the most complex branches of neurosurgery. The most common diseases for which neurosurgical treatment is performed are cerebral aneurysms (ruptured and un-ruptured), arteriovenous malformations (AVMs), carotid cavernous fistulas (CCF), brachiocephalic artery stenosis (narrowing of the vessels supplying the brain) . Like noThe successes of endovascular neurosurgery over the past thirty years are based on the emergence of new polymers and metal alloys, on the rapid introduction of electronics into medicine, on the development of unprecedented implantable devices. Endovascular neurosurgery has evolved along with improvements in endovascular materials and improved techniques for applying these materials to the target. At the same time, the introduction of new materials led to improved treatment results . For exaIn addition, endovascular therapy can complement open surgery, as in the case of carotid disease. Combined use of endovascular technique with open surgery, as in the case of tumor resections, AVM treatments or complex aneurysms, has become common . BasilarEndovascular modalities also have limitations mostly relating to its durability: Coiled aneurysms show a higher recurrence rates than clipped aneurysms and we see a higher number of incompletely treated aneurysms and AVMs after endovascular treatment. However, as technology advances, so will the applications of endovascular techniques, and the boundaries between medical disciplines such as neurology, neurosurgery, and radiology will continue to blur. For these reasons, neurosurgery remains the ideal discipline for understanding when and how to use endovascular techniques to treat all cerebrovascular diseases. For instance, even before the early 2000s, ischemic stroke was a non-surgical disease in which the best medical treatment with systemic intravenous thrombolysis was only marginally effective. However, the persistence of vascular surgeons in the surgical treatment of mechanical obstruction of large vessel occlusion (LVO) has led to one of the most profound paradigm shifts in modern medicine and neurosurgery in particular .Unfortunately, within the framework of one editorial article it is impossible to cover all areas of development of the still young specialty—endovascular neurosurgery. Nevertheless, only the specialist who has mastered the management of modern angiographic complexes and clearly understands their capabilities, programs and control functions will be able to know, be able to and master the methods of endovascular surgery. Another important rule for the safe and effective performance of endovascular operations is to correctly navigate the instruments—catheters, guidewires, sheaths, implantable devices, stents and embolisms. Endovascular treatment methods are actively introduced into neurosurgery. These are high-tech, minimally invasive, organ-preserving technologies, which are a system of methods for the refined diagnosis and treatment of cerebrovascular diseases, and in some cases, provide an alternative to traditional surgical interventions.