The progress in biomarker research is characterized by the perpetual quest for parameters that fulfill the strict criteria of sensitivity, specificity, ease and speed in performance and cost-effectiveness. The expectations towards the range of functions the ideal index should deal with are increasing too. Lack of differentiation between biomarkers useful in the assessment of risk, prediction, prevention, diagnosis, progression or recovery raises the probability of functional overlap. Although unintentionally, such striving for perfection and versatility may lead to a dead end if there is no translation between sophisticated parameters and their use in clinical practice.The example of acute kidney injury (AKI) clearly shows how difficult such implementation to the bedside can be. Despite years of research and subsequent recommendations, no internationally recognized definition of AKI has introduced any biomarker of damage so far . Thus, oThe problem seems even more serious in the pediatric field, where both physiological processes and pathological conditions largely depend on age and anthropometric data, extending presumed normal range values of biomarkers from prematures and neonates to adolescents . MoreoveOn the other hand, the assessment of biomarkers in specific panels seems superior to the evaluation of single parameters . Last, bPediatric nephrology seems to take on this challenge, tailoring parameters to various specific demands, including those of the neonatal period, rare diseases, inherited disorders or peritoneal dialysis ,8,9,10.However, with their specificity and multiplicity of topics, kidney diseases of childhood and adolescence don’t make the search for ideal biomarkers easy. On the whole, understanding pediatric kidney meanders requires screening through the plethora of genetically conditioned, age-related, disease-specific and renal tissue-originating potential biomarkers. The pathology they illustrate is either restricted to clearly defined cells/milieu within the kidney, or to intrarenal interactions, or it triggers systemic engagement through interorgan crosslinks. Changes limited to the kidney are characteristic for the early phase of any renal pathology, then the systemic influence becomes the rule. However, it is usually challenging, because the dilemma whether the kidney is the culprit or the victim can remain unresolved. Not unexpectedly, the kidney may also play both roles at the same time, as it occurs in the case of proteinuria in the course of chronic kidney disease.Meanwhile, the examples of cardiorenal and hepatorenal syndromes unravel the truth of complex links between hemodynamic, metabolic, oxidative, inflammatory and neurohormonal conditions originating from distant organs ,12. TheyThe most recent example of a systemic approach towards the disease is the COVID-19-related pulmonary-renal crosstalk, placing the kidney as the second most frequently affected organ during SARS-CoV-2 infection. The existence of the lung-kidney axis has underlined the complexity and dynamism of interactions between the two organs and has given stimulus to new discoveries in the area of biomarkers predicting the development of complications and the patients’ outcome ,15.In order to highlight the pathological background of a newly discovered disease, the molecular mechanisms of SARS-CoV-2 toxicity were analyzed within the clinical context. The first reports on the increased chemokine concentration, complement and coagulation overactivity stimulated a search for the molecular background of symptoms such as acute respiratory distress syndrome, thrombotic events or acute kidney injury ,17. TracThus, the turnover of candidate biomarkers, as well as their diagnostic/prognostic/therapeutic potentials during COVID-19 infection, were analyzed from bedside to bench and back again, and also in children . Such atThe special issue entitled “Pediatric and adolescent nephrology facing the future: diagnostic advances and prognostic biomarkers in everyday practice” contains articles written in the era when COVID-19 had not yet been a major clinical problem in children. Now that we know its multifaceted clinical course, complications concerning the kidneys, and childhood-specific post-COVID pediatric inflammatory multisystem syndrome (PIMS), the value of diagnostic and prognostic biomarkers in the pediatric area should be appreciated, and their importance ought to increase .The readers will have the opportunity to get acquainted with the spectrum of all major aspects of biomarker use in pediatric nephrology: from neonatal to adolescent perspectives, from rare genetic disorders to civilization diseases such as obesity, diabetes, and hypertension, from transient acute kidney injury to fibrosis and irreversible end-stage kidney disease, as well as from in situ sources to systemic manifestations.The content should convince both the scientists and clinicians that re-shaping the attitude towards biomarkers is the only way to build up a de novo strategy, first based on in-depth analysis of the changeable clinical picture, then bridging clinical to molecular data, and coming back to the patient with molecular solutions to clinical challenges. No matter how far we reach, the patient remains in focus and gives the final answer to the question of the potential usefulness of tested biomarkers. Therefore, let these articles give us courage to come back to the bedside and start using biomarkers in everyday practice for the patients’ good.


Tumor development is frequently accompanied by abnormal expression of multiple genomic genes, which can be broadly viewed as decreased expression of tumor suppressor genes and upregulated expression of oncogenes. In this process, epigenetic regulation plays an essential role in the regulation of gene expression without alteration of DNA or RNA sequence, including DNA methylation, RNA methylation, histone modifications and non-coding RNAs. Therefore, drugs developed for the above epigenetic modulation have entered clinical use or preclinical and clinical research stages, contributing to the development of antitumor drugs greatly. Despite the efficacy of epigenetic drugs in hematologic caners, their therapeutic effects in solid tumors have been less favorable. A growing body of research suggests that epigenetic drugs can be applied in combination with other therapies to increase efficacy and overcome tumor resistance. In this review, the progress of epigenetics in tumor progression and oncology drug development is systematically summarized, as well as its synergy with other oncology therapies. The future directions of epigenetic drug development are described in detail. Cancers are the second leading cause of human death, second only to cardiovascular disease . The oriDue to the heterogeneity of tumor cells, tumor recurrence and drug resistance frequently occur, which are the main reasons for the high mortality of cancer. In the early stage of tumor development, numbers of epigenetic changes occur in tumor cells . TherefoAlthough epigenetic drugs have made great progress in the treatment of hematological tumors, they are less effective in solid tumors. With the proposal of drug combination regimens, the combination of epigenetic drugs and other therapies has achieved good efficacy in several solid tumors, such as radiation therapy, chemotherapy, hormone therapy, targeted therapy and immunotherapy. Numerous completed and ongoing clinical trials have been conducted to evaluate the plausibility of combination schemes integrating epigenetic drugs.It is of great significance to analyze the mechanism of gene irregulation in cancer cells and to identify agents that could modify the abnormal expression of genes. In this review, we reviewed the recent progress of epigenetics in tumor progression and anticancer therapeutics development. In addition, the combination of epigenetic drugs and other oncology therapies are specially reviewed.via TSGs silencing, such as BRCA1  family, which contains DNMT1, DNMT2, DNMT3A, DNMT3B and DNMT3L . DNMT1 ihylation . Abnormahylation . The relvia blocking the binding of SRSF2 at RNA splice sites  could regulate the metabolism of RNA, such as splice, transport, degradation, translation and miRNA modulation . Recent ce sites . Many FTvia upregulating the expression of oncogenes or inhibiting the expression of tumor suppressor genes. On the contrary, the m6A modification could also inhibit the expression of oncogenes and elevate the expression of tumor suppressor genes  the readers which identify the modifications of histone, (II) the writers which regulate the modifications of histone, (III) the erasers which remove the modifications of histone (Histone Modifications could regulate the accessibility and conformation of chromatin thereby modulating gene expression . The pos histone .via histone deacetylases (HDACs) and histone acetyltransferases (HATs) in a reversible and dynamic way (3CO) to lysine residues which are related to the activation of gene transcription. On the contrary, the HDACs are erasers which are responsible for removal of the acetyl groups  will be recruited for activation of gene transcription . In contBromodomain and extraterminal domain (BET) proteins are readers of the acetylated proteins, which contains a couple of tandem bromodomains, a C-terminal domain and an extra-terminal domain. The BRD family includes BRD2, BRD3, BRD4 and BRDT. The first three are commonly distributed in tissues, and BRDT is only expressed in the testis . The BETvia the histone methyl transferases (HMTs), whereas the histone demethylases (HDMs) regulate the elimination of methylation. The consequence of histone methylation can be repression or activation of transcription, depending on the methylated residues  could be generally characterized to small and large ncRNAs  . These nccupancy .in vivo  was proved as an effective inhibitor of KDM4E and its derivative IOX1 was also demonstrated to inhibit various types of HDMs . In partin vitro and in vivo  cells . The iso in vivo . The ant in vivo .The application of inhibitors of HDAC (HDACis) was successfully proved in the treatment of cancer in clinical practice. The HDACis are able to inhibit the proliferation of cancer cells through inducing cell apoptosis and suppressing the process of EMT by inhibiting the expression related to the cell migration and angiogenesis .The derivative of hydroxamic acid Vorinostat was the first HDACi authorized by the Food and Drug Administration (FDA) for the therapeutic of cutaneous T cell lymphoma (CTCL) . Since tin vitro and tacedinaline will exert better effect when it with combined with other anticancer agents, like docetaxel and gemcitabine . Entinostat was effectively examined without severe toxic effects in breast cancer , melanomcitabine . Howevercitabine .In vitro studies have suggested that phenylbutyrate is able to inhibit the proliferation of glioblastomas cells  and phenylbutyrate, which belongs to the short chain fatty acid type, are also found to inhibit the activity of HDAC with anti-cancer activity. VPA was effectively demonstrated in the neuroendocrine tumors . In vitras cells . Variousas cells  . Using BETs remarkably upregulated the sensitivity of head and neck squamous cell cancer (HNSCC) to anti-EGFR antibody  and the In addition, numerous clinical trials have demonstrated that the combination of anti-angiogenic therapeutics and HDAC inhibitors could remarkably improve the efficacy of the treatment for various cancers with favorable safety profile. The drug combinations have achieved good efficacy and safety, such as sorafenib and resminostat (HDACi) in treatment of hepatocellular cancer , bevacizThe epigenetic regulation was found to overcome drug resistance of the immune-checkpoint blockade (ICB). The combinations of epigenetic drugs and immune-checkpoint inhibitors were demonstrated effective for the treatment of cancers which were refractory or resistant to ICB, both in preclinical and clinical studies. The combinations of HDACi and ICB have received favorable clinical effect in the clinical trials, such as vorinostat and pembrolizumab (anti-PD-1 antibody) for the treatment of ICB-resistant metastatic NSCLC , entinosNonetheless, extended application of epigenetic drugs could induce harmful influence in the antitumor immunity. For instance, the BETi could cause severe depletion of T cells in the tumor environment . Therefoin vitro that azacytidine and decitabine use different human nucleoside transporters (hNTs), and that cytotoxicity is dependent on hNT presence. These observations suggest that hNTs may be useful biomarkers for the efficacy of DNMTis, but clinical data are still not available (Epigenetic biomarkers are able to provide relevant information for diagnosis, prognosis and therapy optimization in routine clinical treatment and drug discovery. Epigenetic biomarkers may provide a rationale for patient stratification and precision medicine, thus maximizing the chances of treatment success while minimizing unwanted effects. Epigenetic biomarkers can also provide extra advantages, including low patient invasiveness. For example, variations in DNA methylation can be detected in body fluids and liquid biopsies . The devvailable . Unfortuvailable . The appAlthough epigenetic drugs have made great progress in cancer drug development, the problems that arise are not to be underestimated. The first and most serious problem is that the low selectivity of epigenetic drugs leads to serious adverse reactions, such as the HDACi. Therefore, the search for epigenetic drugs with better selectivity that can target more elaborate isoform of epigenetic target may be one of the significant development directions in the future. In addition, monotherapy of epigenetic drugs presented favorable efficacy in hematologic cancer rather than in solid tumor. Therefore, the combination of epigenetic drugs and other antitumor therapies in the treatment of insensitive solid tumors and drug-resistant recurrent tumors is in active development. Unfortunately, the occurrence of serious toxic effects is still the main reason that disturbs the application of combined therapy. Hence, the exploration of optimizing the combination regimen and reducing the administered dosage may be promising directions for the extensive application of epigenetic drugs in the future. In summary, this review systematically concluded the recent progress of the epigenetic therapeutics in the treatment of cancers  and the


Following publication of the original article , the autThe incorrect author name is: Neil ShahThe correct author name is: Niel ShahThe sentence currently reads: These include, but are not limited to, the investigation of possible renal and vascular pathologies, endocrine issues, or drug side effects .The sentence should read: These include multiple investigations to evaluate for possible renal and vascular pathologies, endocrine issues, or drug side effects .The author group and the wording of a sentence in the first paragraph of the Background section have been updated. The original article  has been


This review article represents the proceedings from the expert panel discussions at the WSES congress and was designed to provide an international perspective on optimizing teamwork and non-technical skills in emergency general surgery.The assurance of patient safety in emergency general surgery remains challenging due to the patients’ high-risk underlying conditions and the wide variability in emergency surgical care provided around the globe. The authors of this article convened as an expert panel on patient safety in surgery at the 8 The congress was designed as a “hybrid” meeting with the options of in-person and virtual attendance. The congress was hosted by the University of Edinburgh and sponsored by the Royal College of Surgeons of Edinburgh (RCSEd). The challenges of organizing an international hybrid meeting during the resurgence of the COVID-19 pandemic cannot be understated. In spite of the logistic obstacles, the congress had a record number of submissions for both oral and poster presentations, attracting delegates from 42 countries from all continents. The local organizing committee had the pleasure of welcoming more than 100 delegates in person at the McEwan Hall. The Chair of Behavioural Sciences at the University of Edinburgh has been leading cutting-edge research in the field of non-technical skills, surgical sabermetrics, coaching, global surgery, and space medicine. Furthermore, the MSc in Patient Safety & Clinical Human Factors (www.edinburghsurgeryonline.com/courses), run in partnership with the RCSEd, further added to the distinguished expertise of the patient safety panel in attendance at WSES. This forum allowed for a unique opportunity of international experts to convene in a variety of panels that focused around human factors, non-technical skills, and other pertinent aspects related to surgical patient safety. This review article evolved from an expert panel discussion at the 8th International WSES Congress in Edinburgh and was designed to provide an international consensus opinion on the role of team dynamics and non-technical skills in improving patient safety and patient outcomes in emergency surgery.The World Society of Emergency Surgery (WSES) was founded in 2007 with the mission of promoting research, education, clinical quality and patient safety, interdisciplinary networking, and ultimately the global advancement of emergency surgery . The WSEMore than 200 million surgeries are performed worldwide each year . HoweverIn spite of the multitude of patient safety initiatives designed to protect surgical patients, the current regulatory mandates and safety checklists continue to fall short of protecting surgical patients from suffering preventable harm . Two recThe context of emergency and trauma surgery is complicated and characterized by high pressure, stress, and time restraints. Lack of knowledge about the trauma causes, the identity of the patients, and their existing circumstances or conditions can negatively affect surgical decision making, leading to less effective clinical choices. Moreover, the situation may not allow the engagement with the patients or their families in order to understand their treatment preferences or wishes. While shared decision making and co-production dynamics in a multistakeholder scenario stand today among the most relevant pillars of the patient-centric healthcare system, such processes may appear particularly challenging or even not be possible at all –21. FurtStarting from this premise, the “Team Dynamics” initiative , 25, endStarting from the Team Dynamics initiative, some takeaways emerge. Two relevant topics, namely the importance of shared-decision making and the adoption of advanced technological tools to empower surgical decision-making, should be on the agenda of the scientific societies to support the surgical community in ensuring the best possible outcomes for their patients . MoreoveHuman Factors for Health & Social Care . Th. Th57]. automate human tasks, but rather augments human capabilities by avoiding mundane errors due to distractions and cognitive overload [A systematic review revealed that poor wellbeing and the presence of burnout among healthcare professionals was associated with a threat to patient safety, including a higher rate of medication errors . In the overload . A classThe teaching of non-technical skills for medical students and trainees remains a challenge on a global scale. The total number and distribution of medical schools worldwide is not matched with existing physician numbers and distribution. India, Brazil, USA, and China, make up more than one-third of the world’s total number of medical schools . In manyThe “European Trauma Course” (ETC) brings together different specialists like surgeons, emergency physicians, anaesthetists, intensivists, and others engaged in the initial evaluation of major trauma patients to learn and teach together as a team, including the technical and non-technical skills . The ETCThe adherence to evidence-based practice protocols and patient safety checklists represents a global trend in EGS . The 19-


In the fight against climate change, achieving carbon neutrality has become a severe test and task for global society. Meanwhile, this is also a great opportunity for decarbonization, mitigating climate risks and supporting the transition to a renewable energy future. Hopefully, a variety of future-oriented ‘black technologies’ will emerge and grow immediately. In particular, the birth and development of solar energy conversion products has been entering contemporary society, and has become an indispensable key link of low-carbon cycle and green development. Enormous effort has been dedicated to building a comprehensive sustainable system based on solar energy conversion, and it has been a consensus that developing advanced materials is the basis of realizing high-efficiency, low-cost solar energy conversion and utilization.In recent years, photovoltaic and artificial photosynthetic systems with traditional materials and structures have become increasingly mature, and solar energy conversion systems represented by silicon-based semiconductors have been widely used all over the world. However, due to the serious pollution caused by crystalline silicon modules in the production process, and the relatively low theoretical conversion efficiency of silicon-based semiconductors, a variety of new photovoltaic materials and devices based on novel materials have been proposed. In particular, organic and perovskite solar cells have attracted wide attention. In addition, since the responsive range of the solar spectrum spread from ultraviolet to the visible region at the beginning of the 21st century, solar photosynthetic processes have obtained extensive attention in the fields of physics, chemistry, materials and energy. Photosynthesis has become an important branch of catalytic chemistry and energy materials because of the continuous development of the catalytic theory, the increasing number of material systems, the improvement of quantum efficiency and the expanding of the application range. All this progress expedites the delivery of this special issue.2 production, respectively, expanding the potential application of state-of-the-art solar energy conversion devices. Professor Zhiyong Jason Ren, Professors Ding-Jiang Xue, Yuan Lin and Jing-Song Hu, Professors Xiao Wang and Jiangyu Li, Professors Zhiliang Ku, Jianfeng Lu and Fuzhi Huang, Professor Junbai Li, and the professors of my research team systematically reviewed and highlighted the recent progress made with perovskite solar cells and artificial photosynthesis, ranging from fundamental science to application. All the above together presented an overview of solar energy conversion materials research in China.On this topic, some outstanding and dedicated scientists provided their views on advanced materials for photovoltaics and artificial photosynthesis, especially the opportunities and challenges of the future. I believe this will inspire the development of solar energy conversion both at home and abroad. The Perspective article from Professor Yingping Zou on the research progress and future direction of the electron acceptor Y6 and its derivatives provides important guidelines for future research into high-performance organic solar cells. Professor Jinglong Gong, Professors Fujun Zhang and Han Young Woo, and Professors Jianhui Hou and Shaoqing Zhang introduced their material research on organic solar cells and photocatalytic HI would like to thank the members of the editorial office of NSR  for their diligent work. In addition, without the support and help from invited experts and contributors, I would not be able to complete my guest editing work. I hope that all the papers in this special topic will be beneficial to the readers, from general readers and new learners such as graduate students, to experts in this field.


Aim: To explore the relationship between the use of aspirin and the incidence of hepatocellular carcinoma (HCC).Methods: MEDLINE, EMBASE, Web of Science and Cochrane CENTRAL databases were searched systematically from the earliest available date to 13 March 2020. The primary outcome was incidence of HCC, and the secondary outcomes were recurrence and mortality of HCC. The results were expressed as the Hazard Ratio (HR) and 95% confidence interval (CI). Based on the heterogeneity evaluated with the I2 statistic, a meta-analysis was performed using either a random- or fixed-effects model.Results: A total of sixteen articles (2781100 participants) were included. There was lower incidence of HCC in aspirin users than those in non-aspirin users . Subgroup analysis further showed that the incidence of liver cancer in patients with alcoholic cirrhosis  and virus hepatitis  who use aspirin was lower than that of patients who do not use aspirin. In addition, aspirin was found to associate with decreased risk of HCC mortality , not HCC recurrence .Conclusions: Aspirin use is significantly associated with the low incidence rate of liver cancer. Hepatocellular carcinoma (HCC) accounts for a large proportion of cancer deaths worldwide , and thAspirin is a COX inhibitor frequently used to reduce the risk of cardiovascular and cerebrovascular disease-related death, owing to its antiplatelet effect. Moreover, aspirin has been shown to play a role in preventing lung cancer, colorectal cancer and prostate cancer . It hasGiven the evidence of aspirin’s chemopreventive effect, it may potentially be prevent HCC. Recent articles have indicated that due to anti-inflammation and immune modulation effect of aspirin , numberThe meta-analysis was performed based on the Meta-analysis of Observational Studies in Epidemiology guidelines and the protocol of this study in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) checklist . And thThe inclusion criteria of this study are as follows : they enThe inclusion criteria of this study are as follows : they enThese articles were first extracted based on the inclusion criteria by two investigators; after that, the differences between them were determined by another investigator. The articles that were included into this study contain the following information: first author’s name, year of publication, area where the study was conducted, study design, study period, total number of aspirin/no-aspirin users, HCC number of aspirin/no-aspirin users, liver disease status, primary and secondary outcomes, definition of aspirin user, aspirin dose, adjusted variables. We show these in We included thirteen cohort studies and three case-control studies in this meta-analysis. The Newcastle Ottawa scale (NOS) was used to assess the risk of bias for each outcome in all included studies . AccordThe main study outcome of this meta-analysis was incidence of HCC, and the secondary outcomes were recurrence and mortality of HCC.2 and I2 test, in which the percentage of variability was determined (not sampling error) . Differences for which p < 0.05 (two-sided) were considered statistically significant.Heterogeneity between articles was presented as HRs and 95% CIs, and were determined using a random or fixed effect model. Heterogeneity was further assessed by Chig error) . Articlestudies . DissymA total of 915 relevant articles were searched, among which 191 articles were duplicates and were removed. After the initial search, 64 articles that discuss problems related to the main goal of this study were selected. Finally, 16 articles , in whiThe included articles were observational studies that reported the relationship between aspirin and HCC. Among which, twelve articles reported the relationship between aspirin and incidence of HCC, two arI2 = 92.5%, 68.7%, respectively), and fixed-effects model was used to perform in this meta-analysis for mortality due to mild heterogeneity (I2 = 26.4%) between studies. The pooled results from these studies showed that aspirin is associated with lower incidence of HCC .We employed the funnel plots  and the Evaluation of studies that enrolled 2781100 participants demonstrated that the incidence of HCC was lower in patients with alcoholic cirrhosis and virus hepatitis who use aspirin than that of patients who do not use aspirin, but also the mortality of HCC was lower in aspirin users than those in non-aspirin users. This finding suggests that the use of aspirin was associated with decreased risk of HCC and the risk of HCC mortality. However, clinical trials should be further conducted to confirm this suggestion.+ lymphocytes to secret many inflammatory factors involving in the dealing with infection; inability to timely clear the virus can lead to failure of the liver. Although numerous articles have demonstrated that aspirin users has a significantly lower incidence of HCC compared with non-aspirin users , which has been reported to have chemo-protective effects, according to epidemiological researches. Studies , in whin users ; Second, aspirin dose and period of use were varied in the original studies, which may affect the results shown in this study and may be the source of heterogeneity; therefore, further researches are needed; Third, the small included studies for aspirin use and incidence of HCC in alcoholic cirrhosis patients may lead to the in-reliable result. However, it is clear that use of aspirin has a significant reduction in the incidence of HCC in patients with alcoholic cirrhosis and virus hepatitis. Fourth, this study evaluate only the preventive or therapeutic effect of aspirin on HCC patients, not its safety, administration initiation or continuation; Finally, more importantly, although the included articles have a low risk of bias, this study did not include randomized controlled trials, which may be one of the most important disadvantages.This article presents the first meta-analysis that elaborate on the beneficial effect of aspirin on HCC incidence in patients with or without virus hepatitis and alcoholic cirrhosis. The analysis indicated that aspirin could decrease the incidence risk of HCC including virus hepatitis, especially for patients with alcoholic cirrhosis, and also the mortality of HCC. However, further clinical trials are encouraged to be conducted to support the present results.


Traditional medicines (TMs) have made a great contribution to the human healthcare over thousands of years. Therefore, it is of great importance to effectively assess the quality of TMs, which is necessary to ensure their clinical therapeutical effect. With the natural origin, TMs contain a complex chemical composition with numerous unknown components, bringing inevitable difficulties in quality control by chemical approaches (the identification or determination of components). Besides, chemical approaches are insufficient to provide an evidence of the relationship between components and bioactivities. Thus, bioassay, a qualitative or quantitative evaluation of the specific biological effects of tested drugs on biological systems  under specific experimental conditions, is proposed to comprehensively control the quality of TMs. Importantly, the methodology for TM bioassay still needs further development, and some key issues including biochemical principle, experimental system, application scope, and the limitation of bioassays in the quality control of TMs need to be elucidated. Accordingly, this Research Topic serves as a forum to solve the above-mentioned problems by publishing researches on establishing experimental systems, developing novel techniques or data processing models, elucidating mechanisms, or proposing perspectives and so forth, with the purpose of better improvement of the safety and effectiveness of TMs.Gao et al. conducted a bioassay for the quality control of Lianhua Qingwen capsule, a traditional Chinese medicine formula used in the treatment of influenza A virus infection. As the formula effectively improved influenza-like symptoms in the mice infected with influenza A virus, it also obviously changed the metabolic profiling, as suggested by the metabolomic study. Using serum metabolomics analysis, prostaglandin F2α and arachidonic acid and their metabolic pathway, arachidonic acid metabolism, were identified as the key feature strongly involved in the treatment of influenza A virus infection by the formula. Consistently, the transcriptomics study highlighted the prominent role of cyclooxygenase-2 as the major rate-limiting enzyme in the arachidonic acid metabolism pathway, of which expressions in the lung tissues were validated by RT-qPCR. More importantly, the discovery of cyclooxygenase-2 as a key target in treating influenza pneumonia with the formula by metabolomics and transcriptomics analysis is successfully applied to the bioassay of the formula. Using a cyclooxygenase-2 inhibitor screening kit, it was observed that the biological potency of denatured samples was remarkably lower than that of commercial samples, which suggested that this multiomics-based bioassay was sensitive to distinguish the quality of different Lianhua Qingwen samples. Associated with therapeutic effect and quality evaluation, this study established a good example of systematic methodology in the bioassay, which is theoretically and commercially profound in the quality control of TMs. Additionally, metabolomics combined with chemometrics could be applied to screen the key component panel as the discriminatory quality markers of TMs. Guo et al. proposed an LC-MS-based metabolomics coupled with chemometrics to distinguish the crude and salt-fired Eucommiae Cortex, which came from Eucommia ulmoides Oliv. In the family of Eucommiaceae. The combinatorial markers filtered by orthogonal partial least-squares discriminant analysis, random forest, and partial least squares regression were eventually quantified, and their ability to differentiate crude and salt-fired Eucommiae Cortex was validated by discriminant analysis. Thus, this study established a method in screening discriminatory markers to distinguish different processed TMs. As the different processed TMs exert different biofunctions, this study might provide an insight on the improvement of the specificity of the bioassay. Apart from omics, the classic pharmacological study can also provide direct evidence of the bioactivity of TMs, which forms a solid basis for bioassays. It was demonstrated by Qiu et al. that Buxin Yishen decoction was able to improve heart function and delay the progress of renal fibrosis in the myocardial infarction-induced type 2 cardiorenal syndrome. Several targets, including connective tissue growth factor, α-smooth muscle actin, and low-density lipoprotein receptor-related protein, were strongly involved in the underlying mechanism of Buxin Yishen decoction. Hence, a bioassay for the quality control of Buxin Yishen decoction or other related medical products can be designated based on these key targets in the treatment of type 2 cardiorenal syndrome. Besides, as TMs contain various components with multiple targets, the study on the chemical composition or bioactivity might be time consuming and cost intensive. Thus, researches based on big data retrieval, computer simulation, or virtual screening can be a wonderful assistant during the discovery of the biofunctions of TMs. Guo et al. proposed a clinical prescription-protein-small molecule-disease strategy, namely, the CPSD. It was suggested that the classical prescriptions could be used as the source of potential drugs to screen small molecules that regulate specific targets for the drug development. Exemplified by Linggui Zhugan decoction, a library of chemical components was constructed, and the compound–protein interaction was analyzed by semi-flexible docking, which successfully identified the potential targets of Linggui Zhugan decoction in the treatment of arrhythmia. Conveniently and quickly, such strategy could be an alternative to explore the bioactivity of TMs, providing rich information for the bioassay methodology development.Given that TMs have apparent characteristics of multiple components and targets, it is essential to use proper approaches matching with the characteristics of TMs in bioassay. Noteworthy, the application of multiomics has contributed greatly to the overall description of the homeostatic intervention by TMs, markedly coincident with the characteristics of TMs that work as a holistic system in the treatment of diseases. Importantly, the multiomics is potent to reflect the integrative characteristics of both pathophysiological status and pharmacological effect, which plays an essential role as a bridge connecting efficacy indicator, syndrome feature, drug action, and biological mechanism. Hence, the strategy based on multiomics has been paid closed attention due to its strong capability to elucidate the mechanism of the action of TMs and find appropriate candidates for bioassay. Following this strategy, Angelicae Sinensis Radix from Angelica sinensis (Oliv.). Diels with functions of both blood circulation activation and hemostasis when different parts of the plant are used) or those with ambiguous bioactivities  The studies in this Research Topic undoubtably promote the establishment of bioassay methodology. It has been declared by the US Food and Drug Administration that the biological assay is an essential part of the registration and evaluation of new botanical medicines in the quality control, clinical pharmacology, evidence to ensure therapeutic consistency, and postmarketing consideration, which suggests that the ideology and methodology in the bioassay has achieved a consistency in the development of TMs. With the integration of clinical efficacy confirmation, bioactive component clarification, and underlying mechanism elucidation, the improved bioassay system could promote the modernization and internationalization of TMs, gaining more attention from the world community.It is well accepted that TMs are difficult to comprehensively characterize by only chemical approaches because of their diverse components and various targets. Bioassay is considered as a useful approach to understand the properties of TMs with biostatistics as a tool, which would be more suitable for evaluating complex systems like TMs, with more practical value and advantages than conventional chemical approaches. Notably, the improvement of methodology is critical to the development of bioassay. Basically, the design of bioassay should follow the basic principles of pharmacological studies to be random, controlled, and repeatable. Clear background information, well-controlled interferences, sensitive indicators, and low detection cost should be taken into consideration when choosing experimental systems  in bioassays. The detection of biopotency using reasonable group sets of different dosages is recommended in bioassays, as well as the negative control and the positive control with similar mechanisms for better experiment system reliability and stability. To be subjective, clear, and specific, the indicators selected in bioassays should have rationality and representativeness, with closed relationship to the clinical efficacy or safety of TMs. The selection of qualitative, semi-quantitative, and quantitative techniques as well as the suitable biostatistical method is also a key scientific issue in the methodology of TM bioassay. Besides, novel strategies should be proposed for the bioassay methodology establishment of some TMs with opposite clinical efficacy (e.g.,


The cementoblastoma is a rare odontogenic tumor occurring in the mandibular molar and premolar of the patients in the second and third decades of life. Despite its typical benign behavior, this tumor may promote local destruction by perforating the cortical bone and displacing the mandibular canal. This case report shows a 31-year-old man with an aggressive cementoblastoma attached to the apex of the mandibular first molar. Cone-beam computed tomography revealed a hyperdense mass connected to the root of mandibular molar surrounded by a hypodense area. Multiplanar reconstructions showed rupture of buccal bone plate and tumor invasion of the mandibular canal roof. The surgical planning included enucleation of tumor with the first and second molars extractions and the diagnosis of cementoblastoma was confirmed by histopathology. This case report emphasizes the contribution of cone-beam computed tomography on diagnosis and appropriate surgical planning of the cementoblastoma. Key words:Cone-Beam computed tomography, odontogenic tumors, diagnosis. The cementoblastoma remains as a rare odontogenic tumor with less than 300 cases reported in the literature . This tuDespite of typical benign behavior, the cementoblastoma can also behave aggressively. The tumor may promote local destruction by expanding and perforating the adjacent cortical bone, leading to resorption of the surrounding teeth, and, less commonly, displacing the mandibular canal -4.A detailed three-dimensional analysis by cone-beam computed tomography (CBCT) of cementoblastoma might provide the determination of the tumor size, density, presence of root resorption, cortical bone expansion and perforation, in addition to the relationship of the tumor mass with the adjacent anatomic structures ,6. AccorThis case report shows a 31-year-old man with an aggressive cementoblastoma attached to the apex of the mandibular first molar and causing its resorption and perforation of the buccal bone plate. The importance of cone-beam computed tomography on diagnosis and appropriate surgical planning of the cementoblastoma is discussed.A 31-year-old man was referred to the Oral and Maxillofacial surgeon complaining about a persistent and spontaneous pain in the left mandibular first molar (tooth 36). Intraoral examination revealed a hard swelling in the buccal aspect of the referred tooth. The radiographic analysis showed endodontic treatment of the left mandibular first molar. A radiopaque mass was also attached to the apex of the tooth surrounded by radiolucent halo and extending to the mandibular second molar Fig. A. MultipThe cementoblastoma is a rare benign odontogenic tumor with clinical/radiographic and microscopic well established characteristics. This tumor has a high prevalence in the mandibular first molar root of the young patients in the second/third decade of life ,3,4. AllUntil the 1990s, prior to advent of computed tomography scan, most of the cementoblastomas were diagnosed based on radiographic findings, i.e. rounded radiopaque or mixed-density mass attached to the root of vital tooth causing radicular resorption and obliterating the periodontal ligament space ,6,12. InThe clinical diagnosis of cementoblastoma based in radiographic findings can be challenging. In early stage, the tumor can be confused with other benign lesions of inflammatory origin that occur in the dental apex such as focal sclerosing osteitis and osteomyelitis . ConsideDue to the continuous tumor growth associated with pain and expansion of bone cortical, our patient was referred to an Oral and Maxillofacial surgeon and a CBCT of the mandibular lesion was requested. The CBCT images obtained in different planes  and 3D reconstruction played a critical role on diagnosis of the cementoblastoma, in its extension in relation to adjacent mandibular second molar, root resorption, and in the detection of bone cortical rupture Fig. . As the Additionally, as observed in other cases reported of cementoblastoma ,7, the tThe histopathologic analysis of the present case showed distinctive and classical characteristics of the cementoblastoma, according to World Health Organization and described by others ,8,10,12.Concluding, this case report emphasizes that CBCT contributed for accurate diagnosis of the cementoblastoma enhancing the detailed view of the size, extension, density, the relationship of tumor with adjacent mandibular structures as well as for adequate surgical planning reducing the risk of tumor relapse.


Parathyroid hormone disorders are a group of diseases in which secretion of parathormone (PTH) is impaired. The disorders that result are characterized by signs and symptoms associated with the persistent presence of high blood calcium levels  related to hyperparathyroidism (PHPT), or reduced blood calcium levels  associated with hypoparathyroidism (HypoPT). In addition to the resulting alteration in bone microarchitecture and mass for both pathologies, patients also report problems with skeletal muscle due to a decrease in muscular strength, muscular dysfunction, and myopathies, which can be responsible for an increased risk of instability and fracture. Although the effect of PTH on bone is well established, and numerous studies suggest that PTH has an effect on skeletal muscle, knowledge about cellular e molecular mechanisms of action on skeletal muscle is very limited. Skeletal muscle is a tissue well known for its structural and mechanical actions and is endowed with an extraordinary ability to adapt to physiological changes. Research in skeletal muscle has increased over the last decade, its importance as an endocrine tissue also emerging, becoming itself a target of numerous substances and hormones. Parathyroid hormone disorders represent a starting point to understand whether PTH may have an effect on skeletal muscle. This review analyzes the basic research data reported to date on PTH and skeletal muscle, highlighting the importance of increasing our knowledge in this field of research. Skeletal muscle is one of the most dynamic tissues of the human body, fundamental for vital functions like locomotion, postural support, breathing, and thermogenesis . It comp0 phase) and transcriptionally inactive; after injury or degeneration, quiescent SCs rapidly re-enter the cell cycle, become activated, and proliferate to supply myoblasts. After activation and the proliferation phase, the expression of PAX-7 decreases, myoblasts exit the cell cycle and differentiate into mature muscle cells, fusing into existing myofibers to repair, or fuse together, to generate large numbers of new multinucleated myofibers within just few days , located between the plasma membrane of the myofibers and the basement membrane (sarcolemma) . SCs canfew days .Skeletal muscle regeneration  is a higResearch focused on skeletal muscle has greatly increased over the last decade. Skeletal muscle is also considered a secretory organ, capable of producing several substances of protein nature, called myokines, which can act in an autocrine, paracrine or endocrine fashion, on the muscle itself, on nearby tissues, or distant organs . These fConsidering the importance of healthy skeletal muscle to provide stability and strength for all the body, any alteration in its function leads to some degree of instability and/or impairment. Therefore, factors that influence skeletal muscle structure and function are a subject of great scientific and clinical interest.Parathyroid hormone diseases, characterized by alteration of parathyroid hormone levels in the blood, are disorders that feature bone abnormalities and decreased skeletal muscle strength. This review will consider these disorders and take into consideration the current knowledge on the effects of PTH on skeletal muscle.Disorders of the parathyroid glands, 4 endocrine glands located on the dorsal part of the thyroid, most typically present with abnormalities of serum calcium concentration. The disorders that result are characterized by signs and symptoms associated with the persistent presence of high blood calcium levels  related to primary hyperparathyroidism (PHPT), or reduced blood calcium levels  associated with hypoparathyroidism (HypoPT) .PHPT is an endocrine disorder, characterized by hypercalcemia combined with inappropriately normal or elevated parathyroid hormone (PTH) levels, which are associated with serious skeletal and renal complications. It is caused by excessive synthesis and secretion of PTH by one or more of the four parathyroid glands and leads to a reduction of bone mineral density (BMD), deterioration of bone microarchitecture, and increased risk of fractures, given the catabolic action of high levels of PTH on bone. Patients also present complex symptoms of muscular fatigue, myopathy, various neuropsychiatric and cardiovascular manifestations, and kidney stones , 14. In HypoPT, instead, is a rare endocrine disorder caused by chronic deficiency or absence of PTH. The most common etiology of the disorder is the removal of, or injury to, the parathyroid glands during a complication of anterior neck surgery, for example total thyroidectomy or radical neck dissection for head and neck malignancies. Other etiologies include autoimmune, genetic and, very rarely, infiltrative disorders (such as hemochromatosis) , 22. HypMyopathy of the skeletal muscle, characterized by increased serum levels of creatine kinase (CK) and histological abnormalities in muscle biopsies, is also seen in HypoPT, and seems to relate to the severity of hypocalcemia , 24. IncCalcium supplement and active vitamin D are the conventional treatment of HypoPT and can control the serum calcium levels, but high doses may be required, exposing patients to the risk of long-term soft tissue calcifications.Replacement therapy with recombinant human PTH (1–84) represents a major step in the therapies of this disease . In factClinical trials demonstrating the efficacy of PTH for the treatment of HypoPT have led to the 2015 approval by the FDA in the United States of full-length recombinant human PTH [rhPTH (1–84)] for the management of hypoparathyroidism. Many clinical studies regarding its impact on QoL and effect on long-term complications are still ongoing , 30–32.The parathyroid glands control extracellular calcium homeostasis by secreting PTH. In the parathyroid cells, PTH is synthetized as a precursor peptide of 115 amino-acids (pre–pro-PTH), which later matures and is cleaved into full-length PTH, a single-chain polypeptide of 84 amino-acids, and stored in granules that can be secreted by the parathyroid glands when circulating ionized calcium concentrations are reduced. The biological activity of the intact PTH is associated to the 1–34 amino-terminal portion .Changes in serum calcium levels are detected by the Calcium-Sensing Receptor (CaSR), a G-protein-coupled receptor that is highly expressed on parathyroid cell membrane. A decrease of extracellular ionized calcium concentration  induces a marked increase in PTH synthesis and secretion from the parathyroid glands. The secreted PTH circulates in the bloodstream and acts on bone and kidneys to increase serum calcium levels, which leads to feedback inhibition of PTH secretion from the parathyroid glands . MoreovePTH also regulates circulating phosphate levels. In fact, it inhibits the tubular phosphate reabsorption by the kidney, thereby decreasing serum phosphate concentrations . Therefos-mediated activation of the adenylyl cyclase/cyclic AMP (cAMP)/protein kinase A (PKA) signaling pathway. The PTHR1 is also coupled to Gαq-mediated activation of the Gα12/13-phospholipase D/RhoA pathway, the phospho-lipase/protein kinase C (PKC) signaling cascade, and the extracellular signal-regulated kinase 1/2 (ERK1/2) / mitogen-activated protein kinase (MAPK) signaling cascade, the latter via G protein–dependent and G protein–independent/β-arrestin–dependent mechanisms (PTH receptor type 1 (PTHR1) is a G-protein-coupled receptor through which PTH (1–84) mediates its classical actions. This receptor is expressed in bone, on osteoblast and osteocyte surfaces, and in tubular cells in the kidney, but it is also present in other tissues, such as mammary glands and intestine . Stimulachanisms .PTHR1 is also activated by PTH-related peptide (PTHrP), first isolated in 1987 in the search for the causative agent of hypercalcemia of malignancy . The amiAlthough both PTH and PTHrP signal via the same receptor, the biological functions of the two ligands are distinct, as PTH acts in an endocrine manner on bone and kidney cells to regulate blood levels of calcium and phosphate, enhancing bone remodeling, as evidenced by slow bone turnover in individuals with PTH deficiency , whereasIn humans, PTH potently activates a second PTH receptor, called PTHR2, leading to cAMP accumulation, whereas PTHrP is almost inactive. This receptor is abundantly expressed in the central nervous system , but also in placenta and pancreas .Moreover, a third PTH-recognizing receptor has been identified in zebrafish and broadly shares the same pharmacological profile with PTH1R .Bone and skeletal muscle interact anatomically and biochemically with each other, and they are considered to be a single functional system whose relationship is essential for the physiology of the entire body. PTH is fundamental for the maintenance of calcium homeostasis through its actions to regulate bone remodeling, and the catabolic and anabolic actions that PTH exerts on the skeleton are well known and reported. This hormone can promote both bone formation and bone resorption by direct effects on osteoblasts and indirect actions on osteoclasts. The final effect on bone mass depends on the duration and periodicity of PTH exposure; bone resorption predominates when continuous exposure to high levels of PTH persists, whereas administration of low and intermittent doses of PTH leads to a net increase in bone mass , 42.Since muscle is functionally linked to bone, it is likewise important to investigate the effects of PTH treatment on muscle tissue. It is indeed conceivable that variation in serum calcium concentration can affect skeletal muscle tissue, also considering the well-known involvement of calcium in muscle contraction .It has been reported that both intact PTH and its amino-terminal fragment carry out their action by enhancing proteolysis and increasing the release of alanine and glutamine; these activities lead to an alteration of amino-acid metabolism and consequently affect muscle protein metabolism . MoreoveExcess of PTH appears to have detrimental effects of skeletal muscle metabolism, since it has been shown that PHPT is associated with muscle dysfunctions, such as muscular weakness, myopathy and postural stability –48. PattLevels of PTH increase with age, and it has been hypothesized that the age-related change in hormone concentration may be responsible for the loss of muscle strength and muscle mass, characteristic in sarcopenia . EvidencAlthough bone and kidney are the classical PTH targets, associated with calcium homeostasis, where mRNAs of PTH receptors have been found to be highly expressed, numerous reports demonstrate a wide tissue distribution of the PTH receptors in non-traditional targets for the hormone, such as heart, liver, brain, pancreas, and others. In these tissues, it has been demonstrated that PTH can affect cell function, since acute exposure of the hormone results in cAMP accumulation, suggesting that their response to PTH involves an interaction between the hormone and its receptors , 53.Research on skeletal muscle in recent years has evidenced the importance of this tissue as a secretory organ, which, thanks to the production and release of myokines into the blood stem, can interact with other organs and tissues , 54, 55.Skeletal muscle is a target organ for several hormones, such as insulin and estrogens. PTH may be one of these hormones, mediating its actions, which are distinct from the hormone's traditional function as regulator of mineral homeostasis , 57 Fig. This hyThe identification of PTHR1 and PTHR2 mRNAs in the brain may indicate that a lack/excess of PTH stimulation within in this organ can explain some of the neuropsychiatric manifestations, cognitive disorders, and reduced QoL in patients with HypoPT and PHPT .in vitro studies on the effect of this hormone on the skeletal muscle. In particular, in vitro human cell models represent a valuable tool to contribute to the comprehension, at cellular and molecular levels, of the effects of PTH on skeletal muscle cells, in order to identify new mechanisms of action that may control skeletal muscle differentiation.Although abundant clinical evidence suggests an effect of PTH on skeletal muscle tissue, there has been little basic research done regarding A recent article by Sato et al. reports the effects of the human recombinant PTH (1–34) on bone and skeletal muscle in a rat model of osteoporosis and muscle atrophy. Data showed that monotherapy with PTH (1–34), dosage of 30 μg/kg body weight three times per week, significantly increases the proximal and distal femoral bone mineral density (BMD) and the percentage of skeletal muscle mass in the ovariectomized, tail-suspended rats . AnotherKimura et al.  reportedin vitro study reports that the presence of PTH receptors was demonstrated by immunohistochemistry and by western blot in differentiated myotubes and on muscle fibers. Moreover, PTH (1–34) modulates the uptake and retention of 25-hydroxyvitamin D in the mouse C2C12 skeletal muscle cells differentiated in myotubes (in vitro studies on C2C12 treated with PTH (1–34) significantly downregulated the expression of fibronectin type III domain-containing protein 5 (FNDC5), the precursor of irisin, suggesting an inverse interplay between the metabolism of these two important molecules (Another myotubes . Moreoveolecules .in vivo/in vitro studies on the role of PTH on skeletal muscle.In in vitro model of skeletal muscle cells isolated from human biopsies of healthy donors who underwent reconstructive plastic surgery not attributable to endocrine diseases, to characterize skeletal muscle endocrine machinery and its hormonal regulation. The established myogenesis model used for the analysis has allowed us to highlight significant increases in PTHR1 gene expression during satellite cell differentiation, supporting the possible involvement of PTH in skeletal muscle regeneration and function, and confirming the utility of myogenesis models as a crucial factor for the development of possible new therapies (Our research group recently developed an herapies .in vitro analysis at the molecular and cellular levels, are therefore necessary for better and more specific comprehension of the effects of PTH on skeletal muscle cell proliferation and differentiation.Considering the presence of PTH receptors in many non-traditional target organs for the hormone, even skeletal muscle, it is evident how important it is to increase efforts to understand how PTH acts, not only on the regulation of bone and kidney cells, but also on skeletal myogenesis. Numerous studies have shown that the proliferation and differentiation of satellite cells during muscle regeneration are profoundly influenced by innervation, vasculature, hormones, nutrition, and extent of tissue injury . Future Furthermore, since the bone and skeletal muscle units are in a close relationship, the study of the actions of PTH on the muscle compartment could open new windows to understanding the interactions between these two important tissues and enable the development of a PTH therapy for the diseases characterized by skeletal muscle degeneration, such as HypoPT.CR and MB contributed equally to the writing of the manuscript. Both authors have read and agreed to the published version of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


According to the World Health Organization (WHO), cardiovascular disorders are one of the main causes of death worldwide. The prognosis and the mortality rate are directly related to the vascular damage favoring the progression toward heart failure. One pathogenic mechanism and common nexus of chronic pathologies and chronic inflammation is oxidative stress characterized by a biochemical imbalance between the production of reactive oxygen species (ROS) and the endogenous antioxidant defense system. In metabolic process, oxygen undergoes a series of reduction steps leading to the production of free radicals represented by Superoxide (O·-2), Oxygen radical (O··2), Hydroxyl (OH·), Alkoxyradical (RO·), and Peroxyl radical (ROO·). Under physiological conditions, small quantities of ROS are intracellular produced which act in cell signaling, and can be readily reduced by the antioxidant defense system. The unbalance between the oxidant species and the antioxidant compounds may increase harmful species that induce structure modification and functional modulation of proteins, lipids and nucleic acids. These alterations disturb homeostasis of the organism due to the damage produced at cellular, tissue, and systemic levels. Oxidative damage has been implicated in the etiology or pathology of cardiovascular diseases including endothelial dysfunction, atherosclerosis, hypertension, heart failure, and is involved in metabolic syndrome and obesity, responsible for a rise in stroke incidence among young adults. On vascular wall, ROS modulate cell growth, apoptosis, migration, inflammation, secretion, and extracellular matrix production, acting through various mechanisms: (1) damaging direct action on the endothelium and the vascular smooth muscle cells; (2) decrease in nitric oxide bioavailability due to oxidative inactivation; (3) formation of peroxynitrite, a radical with powerful lipid oxidizing and constricting action; (4) changes in the endothelial metabolism of eicosanoids  and (5) oxidative modifications of LDL.The properties of plant products as antioxidants have been of worldwide interest. Since ancient times, they have been used to mitigate or cure diseases and the analysis of the ability of their components to counteract oxidative stress has been increasing noticeably.In plant organisms, evolution has defined and selected numerous strategies to defense, attack, adapt and communicate, generating an immense number of bioactive molecules. Given their wide structural and biological diversity, natural products (NP) represent the most abundant source of identified chemical structures, making them ideal as a basis for the rational design of drugs. In this context, NP chemistry plays an especially important role as the majority of drugs currently approved for human use (60%) are being isolated or derived from NP. In recent years, the study of the beneficial effect on human health of the consumption of antioxidants contained in NP has become very relevant. Among the components of these products with greater antioxidant capacity are polyphenols and flavonoids. There are more than thousands of species for which folk medicine describes different uses in the care and preservation of health. Studies have been carried out on the potential properties of the flora, leaves, roots, and their aqueous and/or ethanolic extracts, describing antioxidant, anti-lipidic, anti-atherosclerotic, anti-glycemic, and anti-mitogenic effects.The Research Topic present in this issue offers the opportunity to revise the importance of compounds derivate from natural plants with antioxidant and anti-inflammatory properties on cardiovascular diseases. The main goal is to offer a collection of high quality papers that increase the knowledge about the effect of bioactive compounds present in plants on vascular biology.In this collection you would find an interesting review about the influence of flavonoids on the gut microbiota, and the mechanism of new bioactive molecules derived from this interaction, in the occurrence and development of atherosclerosis, myocardial infarction, heart failure, and hypertension. Flavonoids show a potential value in the prevention and treatment of cardiovascular disease following their transformation through gut microbiota metabolism.In order to provide new ideas for the prevention and treatment of cardiovascular diseases, the molecular mechanisms of different antioxidants, extracted from native plants, are included in this Research Topic. First, novel data of anti-restenotic properties of Jujuboside B (JB), one of the main biologically active ingredients extracted from the seeds of Zizyphus jujube, is presented. JB antagonizes PDGF-BB-induced phenotypic switch, proliferation and migration of vascular smooth muscle cells partly through AMPK/PPAR-γ pathway.Then, cardioprotective therapy is presented with a strong antioxidant extracted from Chinese herbal medicine, the astragalus, called astragaloside IV (ASIV), which showed the ability to alleviate myocardial ischemia-reperfusion (I/R) injury, caused by autophagosome accumulation. Finally, new data is presented about the beneficial effects of two South American origin shrubs, Prosopis strombulifera (Ps), and Tessaria absinthioides (Ta). Consumption of aqueous extract of Ps or Ta produces anti-oxidant/anti-mitogenic/anti-atherosclerotic effects and the use of these plants may be beneficial as a complementary strategy regarding cardiovascular therapies.The increasingly frequent use of phytochemicals determines the importance of running studies with the purpose of evaluating their properties, which facilitates the enrichment of the cultural interpretation of the popular use of different plants when investigating possible biological effects. The use of natural antioxidants for the treatment of different pathologies is based on a long popular tradition, with empirical evidence, but with little scientific backup to support it from the point of view of basic or clinical studies. The study of the traditional use of medicinal plants applying biological tests provides information, with scientific bases, about the efficacy and safety of potential therapeutic agents obtained from plants.The author confirms being the sole contributor of this work and has approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The rising prevalence of Autism Spectrum Disorders (ASD) has led to a quickly increasing need for effective interventions. Several criteria and measures have been developed to critically assess these interventions with particular focus on the evaluation of the efficacy. Given the huge diversity of ASD symptoms and the different levels of severity across individuals, identifying a one size fits all intervention approach is challenging, and the question What works and for whom? Remains still unanswered. Why do we seem to be dragging our feet on this fundamental issue? The main aim of this paper is to answer this question through four non-alternative points. First, there are a scarce number of studies with a solid methodology. Secondly, most trials on intervention efficacy for ASD are designed exclusively in terms of behavioral outcomes. Thirdly, there is a reduced use of biologically oriented outcome measures. Fourthly, in most clinical trials, appropriate practices emerging from research evidence are not systematically applied. A strong effort to improve the methodology of clinical trials is mandatory for the future of autism research. The development of a research-based intervention (RBI) perspective aimed at better integrating: (a) evidence-based approaches; (b) more sensitive behavioral outcome measures; and (c) biomarkers, with the aim of increasing a more detailed clustering of phenotypes, may strongly improve our approach to a precision medicine. The rising prevalence of Autism Spectrum Disorders (ASD)  has led Given the huge diversity of ASD symptoms and the different levels of severity across individuals, identifying a “one size fits all” intervention approach is challenging, and the question “What works and for whom?”  remains First, as previously reported, there are a scarce number of studies with a solid methodology, and this issue strongly limits the generalization of the findings . These lSecondly, (a) most trials on intervention efficacy for ASD are designed exclusively in terms of behavioral outcomes. Despite the wide range of psychometric measures providing useful information , they cannot assess subtle changes in the quality of the core symptomatology of the disorder ; (b) the differences in the behavioral outcome measures used by studies do not allow for comparison between trials.Over the years, the low reliability of outcome measures and the lack of objective markers to identify subgroups of young children with different levels of response to specific interventions has prompted researchers to develop more sensitive methodological designs. The systematic adoption of instruments aimed at studying subtle changes in children and in parent–child interactions may be helpful at further improving current outcome measures. Among the well-conducted research in ASD ,21 the AThe findings of a seminal research carried out by Green et al. in 2010, replicated in 2016 , showed Thirdly, a reliable response to the question about what works and for whom is difficult, given the reduced use of biologically oriented outcome measures. In recent years, biomarker research has become an increasing goal in the field of ASD. Although much effort is being made, there are still no reliable and valid biological or brain imaging markers that would allow us to study subtle changes more objectively during the intervention ,31,32.To address the question, it would be essential to implement studies including, alongside behavioral outcome measures, also biologically oriented outcome measures, such as EEG, eye-tracking, f-MRI, and wearable devices for neurovegetative parameters. Integrating the results of biological and behavioral outcome measures using artificial intelligence may help to identifying subtypes of ASD with different responses to specific interventions, with the aim to develop and monitor specific biological therapies .In terms of biological-oriented outcome measures, the research has shown that visual patterning, explored through eye-tracking, could be a promising measure to monitor subtle response to the intervention, to predict outcomes, and to determine unique features of the child’s performance that fit with the proposed mechanisms of change . Over thSince the literature has identified unordinary models of functional brain connectivity in young children with ASD based on electrophysiological measures ,45,46, tFollowing the wave of atypical connectivity, postmortem studies have revealed increased density of excitatory synapses in the brain of individuals with ASD, with a putative link to aberrant mTORdependent synaptic pruning ,47. ThesIn 2012, a trial by Dawson et al.  showed tIn 2016, Yang et al. demonstrated that functional MRI may predict responses to evidence-based behavioral intervention . In theiFourthly, in most clinical trials, appropriate practices emerging from research evidence are not systematically applied. Following the advices of Zwaigenbaum et al. , effectiIn addition to the above suggestions, another best practice aimed to capture subtle changes in children and their interacting families is the technique of video-feedback ,50. It tAlthough substantial advancement continues to be made within the past decade in the study of ASD, the translational research about the efficacy and effectiveness of interventions is hampered by extreme heterogeneity in models, as well as in outcome measures. These limits do not allow for an adequate generalization of findings and a significant progress in precision medicine. The lack of a systematic integration of behavioral and biomarker outcomes in clinical trials targeting the core symptomatology of ASD decrease our potential for new knowledge  . A stronThe development of a research-based intervention (RBI) perspective aimed at better integrating: (a) evidence-based approaches; (b) more sensitive behavioral outcome measures; and (c) biomarkers, with the aim of increasing a more detailed clustering of phenotypes, may strongly improve our approach to a precision medicine. This target could help us to better identify the most effective intervention solution for children and improve and accelerate the development of effective treatments (including innovative drugs) for the core deficits of ASD.


Photothermal therapy (PTT), which converts light energy to heat energy, has become a new research hotspot in cancer treatment. Although researchers have investigated various ways to improve the efficiency of tumor heat ablation to treat cancer, PTT may cause severe damage to normal tissue due to the systemic distribution of photothermal agents (PTAs) in the body and inaccurate laser exposure during treatment. To further improve the survival rate of cancer patients and reduce possible side effects on other parts of the body, it is still necessary to explore PTAs with high selectivity and precise treatment. In this review, we summarized strategies to improve the treatment selectivity of PTT, such as increasing the accumulation of PTAs at tumor sites and endowing PTAs with a self-regulating photothermal conversion function. The views and challenges of selective PTT were discussed, especially the prospects and challenges of their clinical applications. Cancer therapy is one of the most significant challenges facing the health care industry today . AccordiIncreasingly, researchers have recognized the advantages of selective killing of tumor cells in PTT and developed a variety of strategies to achieve selective killing by PTT Scheme , such asThe process of PTT is the delivery of PTAs to tumor tissue, which is then radiated to raise the local temperature , 16. The4)xWO3 nanocubes, which indicated through in vivo and in vitro studies that (NH4)xWO3 nanocubes have an excellent ability to suppress breast cancer under the second near-infrared window xWO3 naVia intratumoral injection, nanoparticles enter the tumor. These nanoparticles usually remain at the injection site and have poor permeability in the tumor, leading to incomplete ablation and recurrence . Thus, cd-Phe7-α-melanocyte-stimulating hormone (NDP-MSH) is an effective receptor agonist of melanocortintype-1, which is overexpressed in many melanoma cells and combines with the melanocortintype-1 receptor with high affinity . A. A13]. ABy the same stimuli-responsive principle, Zhiyong Qian et al. prepared a nanosystem (NLG919/IR780 micelle) with the characteristics of both photothermal conversion and regulation of the tryptophan metabolism pathway to inhibit tumor growth . NLG919/However, metallic nanoparticles and organic dyes have disadvantages, such as poor water solubility, limited tumor accumulation, and bioavailability. In addition, although the stimulus–response system has realized the self-regulating photothermal conversion ability of PTAs in vitro and animal experiments, the complexity of the in vivo environments of the body is still a major challenge for the precisely controlled photothermal conversion capability of PTAs. Therefore, researchers must conduct further studies to prove the practicality of the materials in clinical practice.Since the concept of “precision medicine” was proposed, tumor treatment has gradually developed toward the direction of individualization and precision. The multi-subject crossing, combination, and arrival of the nanotechnology revolution have extensively promoted the application of PTT in tumor therapy , 76. DueThe photothermal conversion ability of most PTAs is in direct proportion to the concentration. Hence, increasing the concentration of photothermal nanomaterials at tumor sites is an effective method for improving the PTT accuracy. Intratumoral injection, targeting systems, biomimetic systems, and programmed targeting systems aim to increase the PTAs concentration in tumors. Although intratumoral injection can effectively cause the concentration difference between normal tissue and tumor tissue to selectively increase the temperature of the tumor site, this method cannot be directly employed for metastatic and deep tissue tumors in vivo. Additionally, many times intratumoral injections may cause to tumor metastasis. Intelligent transportation systems  enhance the uptake of tumor cells. Nevertheless, most PTAs are filtered from the body before entering tumor cells, which makes the amount of enrichment in tumor sites is far from expected. Therefore, although the method increases the concentration difference between the tumor site and normal tissue, which is feasible in theory, actual results will not materialize unless the nano-drug delivery system achieves rapid progress.Assume that PTAs have weak photothermal conversion ability in normal tissue and strong photothermal conversion ability in the tumor site. In this case, the temperature of the tumor site will selectively increase after the same enrichment amount and infrared laser irradiation, with either minimal or no damage to normal cells. Therefore, endowing PTAs with a self-regulating photothermal conversion capability through the responsive activation of PTAs at the tumor site can achieve a better precision killing effect on tumors. Although the self-regulating photothermal conversion ability of PTAs has been realized by stimulus–response systems (such as the self-assembly of gold nanoparticles or dye molecules) in vitro and animal experiments, the complexity of the in vivo environments of the body is still a significant challenge for the precisely controlled.As a non-invasive and spatiotemporally controllable tumor treatment method, PTT is still in the preliminary clinical research stage and has proven excellent anticancer efficacy in the laboratory and clinic , 77. AllAlthough the complete clinical application of PTT has not fully emerged, it offers new hope for the clinical treatment of cancer. Highly selective PTT will render the construction of clinical PTT more refined and intelligent and become a new opportunity to develop clinical cancer therapy. With rational technological innovation and strategic improvements, there is a considerable scope for clinical expansion of the new PTT platform. Simultaneously, we hope that this review will provide valuable information and insights for future research into selective PTT.


We analyzed the COVID-19 Open Research Dataset (CORD-19) to understand leading research institutions, collaborations among institutions, major publication venues, key research concepts, and topics covered by pandemic-related research.We conducted a descriptive analysis of authors' institutions and relationships, automatic content extraction of key words and phrases from titles and abstracts, and topic modeling and evolution. Data visualization techniques were applied to present the results of the analysis.The BMJ, PLOS One, Journal of Virology, and The Lancet. Key research concepts included the coronavirus, acute respiratory impairments, health care, and social distancing. The ten most popular topics were identified through topic modeling and included human metapneumovirus and livestock, clinical outcomes of severe patients, and risk factors for higher mortality rate.We found that leading research institutions on COVID-19 included the Chinese Academy of Sciences, the US National Institutes of Health, and the University of California. Research studies mostly involved collaboration among different institutions at national and international levels. In addition to bioRxiv, major publication venues included journals such as Data analytics is a powerful approach for quickly processing and understanding large-scale datasets like CORD-19. This approach could help medical librarians, researchers, and the public understand important characteristics of COVID-19 research and could be applied to the analysis of other large datasets. COVID-19 is an extremely dangerous disease due to its high infection and death rates and the damage it has caused to the world's economy. The COVID-19 epidemic started as a series of unidentified pneumonia cases reported in Wuhan, China, in late December 2019. On January 30, 2020, the World Health Organization (WHO) officially characterized the disease as a “public health emergency of international concern” or pandemic [A Coordinated Global Research Roadmap (herein abbreviated as GRRM) on March 2, 2020 [To accelerate COVID-19 research and unite the research community in focusing on key knowledge gaps, the WHO in collaboration with the Global Research Collaboration for Infectious Disease Preparedness and Response released In the meantime, the global research community is investing continuous efforts into pandemic-related research areas. Many research studies in transmission, therapeutics, vaccines, and health care have been published since the outbreak. The newly available CORD-19 dataset , which iThe CORD-19 dataset is a valuable resource for scientists to discover patterns of viral spread, improve diagnostic speed and accuracy, and develop novel effective therapeutic approaches to fight against this novel virus . It is uFor information professionals and medical librarians, understanding this dataset is valuable for seeing the big picture of COVID-19 research to better assist users in finding and using relevant information.The purpose of this study was to understand existing research efforts combating COVID-19 through a large-scale analysis of CORD-19. Specifically, we aimed to answer the following three questions:What are the major characteristics of COVID-19 literature as reflected in the CORD-19 dataset?What are the major research topics or areas of focus investigated by research communities?How have these research topics evolved over time?To answer these questions, we conducted descriptive analysis and a series of automatic data analysis of metadata records, including key word extraction, Latent Dirichlet Allocation (LDA) topic modeling, and topic evolution.There are several ways to analyze a collection of text data depending on the purpose of the analysis . ManuallWe performed data integration, segmentation, and cleaning to prepare the data for processing.We extracted affiliation information, which was not available in the metadata file, from the set of JSON-formatted files. This attribute was then integrated as a feature in the metadata file.To understand how research areas evolved over time, we segmented the whole data collection into seven subsets based on monthly publication dates as described in For data cleaning, as suggested by Almuhaideb and Menai , we loweDescriptive analysis of the dataset focused on determining the research institutions of authors, geographical distribution of institutions, and collaboration among institutions from different countries and regions. Also, we identified the leading publication venues and disciplines.To build an affiliation collaboration network, we counted all collaborations (no duplicates) if there were two or more different affiliations within the same papers. However, the large dimensions of the network made it challenging to visualize all institutions and collaborations. To maximize the visual effect of the network, we set a threshold of thirty-seven collaborations, meaning that only institutions that collaborated with at least thirty-seven other distinct institutions would be included in the network visualization. We compared two popular tools—Python's NetworkX package  and GephMultiple methods, such as key word or concept extraction and topic modeling, are applied to discover topics covered in publications. Moreover, topic evolution is performed to investigate how topics change over time.We considered key words or concepts to be English words or phrases. Many techniques and tools can be used for automatic key word extraction –16; howeTopic modeling is an unsupervised learning model for generating topics from many documents. This method enables us to rapidly generate a comprehensive overview of the content of documents in our huge dataset. Latent Semantic Analysis (LSA) and Latent Dirichlet Allocation (LDA) are the most popular techniques for topic modeling. Compared to LSA, LDA can improve the mixture models that capture the exchangeability of both words and documents from the former method produced by LSA . TherefoOne of the most important steps for applying topic modeling is to select an appropriate number of topics contained by the corpus. This is difficult sometimes because choosing too few topics will produce results that are overly broad, while choosing too many will result in overclustering, which means the documents in the corpus are classified into many small and overlapping topics . We applTopic evolution refers to changes in the topics and their popularity over time. Here, we examined key word evolution and dynamic topic modeling (DTM)  in the sBased on the affiliations of authors, we found that 2,082 institutions contributed at least 10 papers related to COVID-19. The top 20 institutions involved in COVID-19 research are presented in The Chinese Academy of Sciences, the US National Institutes of Health, and the University of California were the three most active institutions. As one of the largest research organizations in the world, the Chinese Academy of Sciences has many branches or subinstitutions in different fields that can conduct COVID-19 research from multiple aspects. Similarly, the National Institutes of Health plays an important role in medical research. The University of California was the leading academic site in the fight against COVID-19. Our analysis also indicates that among the top 100 institutions involved in COVID-19 research, 40 were from the United States and 27 were from China, which aligns with the fact that the pandemic started in China and has hit hardest in the United States. Moreover, both the United States and China are well-known around the world for their large medical research resources . Among tWe constructed a collaboration network to illustrate collaborations or coauthorship relations among institutions. In Nature, Science Report, and Science, which have general scopes covering multiple fields, the remainder belonged to the medical and biology fields, more specifically virology. In addition, by referring to the list of bioinformatics journals at bioinformatics.org [Our analysis showed that research in the CORD-19 dataset covered about 18,569 publication venues, the majority of which were medical and biology journals. tics.org , we fountics.org .To understand the most important research concepts in the publications, we extracted a list of key words  using YAKE!  from theThe topics/research areas of the publications may not be fully represented by the extracted key words due to their low frequency counts in the dataset. We therefore decided to complement the key word extraction approach with topic modeling. The topic modeling results indicate that the research community focused on learning about the disease at three levels: (1) characteristics of the disease, including gene mutation, transmission, and human-animal interface; (2) how it affects the human body, such as risk factors, susceptible populations, symptoms, and effects on human mechanisms; and (3) therapeutics and vaccines for the disease. Still, topics such as behaviors and education among the public and ethical issues in pandemic response have not been explored much in the literature, although GRRM recommends investigation of these topics.As listed in Using NEViewer  and DTM By performing affiliation and publication venue analysis, we identified some basic characteristics of the whole CORD-19 dataset –29 to anThe second research question regarding the major research topics or areas of focus was addressed by applying several methods to determine research areas and extract topics and key words from the COVID-19 literature. We found that while the major research areas were biology and medicine, COVID-19-related research was also published in social science journals. However, social science–related issues were not among the ten most prominent global topics of COVID-19. Topics extracted from the entire dataset mainly covered biological characteristics of the SARS-CoV-2 virus, such as genetics, testing, therapeutics, transmission, and symptoms. By contrast, visualization of the six time-sliced segments presents more multi-faceted topics of the pandemic than topic modeling. In addition to the biological features of the disease, topic evolution analysis discovered topics such as psychological impacts, environmental outcomes, and the effects of wearing masks.For the third research question, we found that research focuses changed substantially over time slices, probably based on the current situation and progress of COVID-19 research. Some prioritized research topics recommended by the GRRM were highly concerted and investigated by the research community, such as treatment, vaccine, infection prevention, and diagnostics. However, a few important aspects of the COVID-19 pandemic have not received enough attention: virus origin, health care worker protection, human-animal interface, and ethical issues. Our findings could benefit the research community by helping it adjust future research focuses and thereby fight the pandemic more effectively.This study is innovative as we combined multiple methods to answer each research question to account for the strengths and weaknesses of each of the automatic methods applied. Python programming language was used to run most of the analytic tasks in combination with other tools, and multiple visualization tools were used to save time and maximize the visual effect of the results. For example, Gephi and NEViewer were used to visualize our outputs. Tools with a good user interface, available color palettes, and integrated algorithms were hereby deemed to have higher usability and proved to be timesaving. However, the selection of tools depends on the analytic tasks; for example, though NEViewer software allows users the capability to interact with data, color, and other attributes, the graph generated to visualize topic and key word evolutions was less interpretable. Our analytic experience with these tools can be applied for analyzing comparable datasets or solving similar analytic problems.We believe health sciences librarians and information professionals could benefit in multiple ways from this study. First, we identified and applied effective data analytic tools, such as YAKE!, LDA, DTM, and Gephi. These tools can be learned and used by health sciences information professionals to analyze large text collection automatically. Second, health sciences information professionals can adjust their research directions by focusing on urgent but not well-studied topics based on our findings. Moreover, top institutions and publication venues for COVID-19-related research discovered in this study may help health sciences information professionals identify potential collaborators and target publication venues for their services and collection development.This study has its limitations. As the CORD-19 dataset is continuously updated every day, the results may not be accurate in the future. However, our methods can be replicated to investigate future growth of datasets. Furthermore, the dataset is very large, so for some methods, such as YAKE! key word extraction, we were not able to run the program on the entire dataset but only a random sample of the dataset. Although the sample was randomly selected, the results might not represent the true findings for the entire dataset.In conclusion, this study provides a comprehensive understanding of the continuous efforts of the research community to defeat the global pandemic. It shows that the current COVID-19 research direction partly aligns with the research roadmap released by the WHO ; some reIn the future, we will continue to track the progress in COVID-19 research. For example, we are working on developing a knowledge graph of diseases based on the same dataset, which will provide an effective approach to organize knowledge included in the dataset for better information access and use.


Dear Editor:We completely agree with the reader’s comments and share the same perspective. In the case of category III exposure, administration of rabies immunoglobulin is formally indicated, and patients undergoing post-exposure prophylaxis should be monitored until the entire regimen is completed. Unfortunately, of the 63 patients with rabies occurring over 50 years, as described in our paper, only 14 (22%) sought medical care before the onset of symptoms, and most patients did not receive the post-exposure prophylaxis regimen, according to the World Health Organization (WHO) guidelines; several patients failed to complete the treatment regimen. This highlights challenges faced by the population in accessing the health system, especially in rural areas, and insufficient knowledge among the population and healthcare professionals, mainly from the 1970s to the 1990s. Although there has been substantial improvement in precise clinical management over the past years, there is an ongoing need for continuous medical education, considering that several healthcare professionals remain unfamiliar with WHO guidelines regarding post-exposure prophylaxis