bluuebunny/crossref_metadata_2025 huggingface dataset:
Adaptive Radiation Therapy in the Treatment of Lung Cancer: An Overview of the Current State of the Field
Authors: Piperdi Huzaifa , Portal Daniella , Neibart Shane S. , Yue Ning J. , Jabbour Salma K. , Reyhan Meral
Published: December 2021

Lung cancer treatment is constantly evolving due to technological advances in the delivery of radiation therapy. Adaptive radiation therapy (ART) allows for modification of a treatment plan with the goal of improving the dose distribution to the patient due to anatomic or physiologic deviations from the initial simulation. The implementation of ART for lung cancer is widely varied with limited consensus on who to adapt, when to adapt, how to adapt, and what the actual benefits of adaptation are. ART for lung cancer presents significant challenges due to the nature of the moving target, tumor shrinkage, and complex dose accumulation because of plan adaptation. This article presents an overview of the current state of the field in ART for lung cancer, specifically, probing topics of: patient selection for the greatest benefit from adaptation, models which predict who and when to adapt plans, best timing for plan adaptation, optimized workflows for implementing ART including alternatives to re-simulation, the best radiation techniques for ART including magnetic resonance guided treatment, algorithms and quality assurance, and challenges and techniques for dose reconstruction. To date, the clinical workflow burden of ART is one of the major reasons limiting its widespread acceptance. However, the growing body of evidence demonstrates overwhelming support for reduced toxicity while improving tumor dose coverage by adapting plans mid-treatment, but this is offset by the limited knowledge about tumor control. Progress made in predictive modeling of on-treatment tumor shrinkage and toxicity, optimizing the timing of adaptation of the plan during the course of treatment, creating optimal workflows to minimize staffing burden, and utilizing deformable image registration represent ways the field is moving toward a more uniform implementation of ART.
Reirradiation of Whole Brain for Recurrent Brain Metastases: A Case Report of Lung Cancer With 12-Year Survival
Authors: Li Minmin , Song Yanbo , Li Longhao , Qin Jian , Deng Hongbin , Zhang Tao
Published: December 2021

Whole brain radiotherapy (WBRT) for brain metastases (BMs) was considered to be dose limited. Reirradiation of WBRT for recurrent BM has always been challenged. Here, we report a patient with multiple BMs of non-small-cell lung cancer (NSCLC), who received two courses of WBRT at the interval of 5 years with the cumulative administration dose for whole brain as 70 Gy and a boost for the local site as 30 Gy. Furthermore, after experiencing relapse in the brain, he underwent extra gamma knife (GK) radiotherapy for local brain metastasis for the third time after 5 years. The overall survival was 12 years since he was initially diagnosed with NSCLC with multiple brain metastases. Meanwhile, each time of radiotherapy brought a good tumor response to brain metastasis. Outstandingly, during the whole survival, he had a good quality of life (QoL) with Karnofsky Performance Score (KPS) above 80. Even after the last GK was executed, he had just a mild neurocognitive defect. In conclusion, with the cautious evaluation of a patient, we suggest that reirradiation of WBRT could be a choice, and the cumulative radiation dose of the brain may be individually modified.
Advancements in 3D Cell Culture Systems for Personalizing Anti-Cancer Therapies
Authors: Law Andrew M. K. , Rodriguez de la Fuente Laura , Grundy Thomas J. , Fang Guocheng , Valdes-Mora Fatima , Gallego-Ortega David
Published: December 2021

Over 90% of potential anti-cancer drug candidates results in translational failures in clinical trials. The main reason for this failure can be attributed to the non-accurate pre-clinical models that are being currently used for drug development and in personalised therapies. To ensure that the assessment of drug efficacy and their mechanism of action have clinical translatability, the complexity of the tumor microenvironment needs to be properly modelled. 3D culture models are emerging as a powerful research tool that recapitulatesin vivocharacteristics. Technological advancements in this field show promising application in improving drug discovery, pre-clinical validation, and precision medicine. In this review, we discuss the significance of the tumor microenvironment and its impact on therapy success, the current developments of 3D culture, and the opportunities that advancements thatin vitrotechnologies can provide to improve cancer therapeutics.
Influence of Family Integrated Care on the Intestinal Microbiome of Preterm Infants With Necrotizing Enterocolitis and Enterostomy: A Preliminary Study
Authors: Yang Mengyang , Du Juan , Yang Qin , Dou Wenyan , Jiang Min , Hei Mingyan
Published: December 2021

The aim of this study was to investigate the influence of family integrated care (FICare) on the intestinal microbiome of preterm infants with necrotizing enterocolitis and enterostomy. This was a prospective pilot study at Beijing Children's Hospital. Premature infants with an enterostomy who met the enrollment criteria were divided into the 2-week FICare and non-FICare groups (non-randomly). We collected their fecal samples and subjected the intestinal microbiomes to 16S rRNA gene sequencing. Operational taxonomic units (OTU) were analyzed to assess the intestinal microbiome richness, and we then carried out α-diversity, β-diversity, and species clustering analyses and a linear discriminant analysis (LDA) effect size (LEfSe) analysis to identify the differences in the microbial communities between the two groups. There were 12 patients enrolled in the study (FICare, n = 7; non-FICare, n = 5). There were no significant between-group differences in demographic characteristics, or in the relative abundances of phyla and genera. The major bacterial phyla were Proteobacteria, Firmicutes, and Actinobacteria, and Serratia, Enterococcus, Cronobacter, and Bifidobacterium dominated at the genus level. The α-diversity analysis indicated that the intestinal flora was more diverse in the non-FICare group than the FICare group (p < 0.05). However, most of the other indicators did not suggest a difference between the two groups. There was a high proportion of shared OTUs between the two groups, and the PCoA and clustering analyses indicated that the two groups were difficult to distinguish, indicating that the intestinal microbiomes were relatively similar between the groups. In summary, short-term FICare had no significant positive effect on the establishment of intestinal flora diversity in premature infants with necrotizing enterocolitis and enterostomy. The trial was registered in the Chinese Clinical Trial Registry (ChiCTR-OPN-17011801).
Human Milk-Based or Bovine Milk-Based Fortifiers Differentially Impact the Development of the Gut Microbiota of Preterm Infants
Authors: Aguilar-Lopez Miriam , Wetzel Christine , MacDonald Alissa , Ho Thao T. B. , Donovan Sharon M.
Published: December 2021

Background: Preterm infants are exposed to different dietary inputs during their hospitalization in the neonatal intensive care unit (NICU). These include human milk (HM), with a human milk-based (HMF) or a bovine milk-based (BMF) fortifier, or formula. Milk consumption and the type of fortification will cause changes in the gut microbiota structure of preterm infants. This study aimed to characterize the gut microbiota of PT infant according to the type of feeding and the type of HM fortification and its possible association with infant's growth.

Methods: Ninety-seven infants born ≤33 wks of gestation or <1,500 g were followed during the hospitalization period in the NICU after birth until discharge. Clinical and dietary information was collected, including mode of delivery, pregnancy complications, mechanical ventilation, use of antibiotics, weight, and type and amount of milk consumed. To characterize the gut microbiota composition, weekly stool samples were collected from study participants. The V3–V4 region of the 16S rRNA bacterial gene was Sequenced using Illumina MiSeq technology.

Results: After birth, black maternal race, corrected gestational age (GA) and exposure to pregnancy complications, had a significant effect on gut microbial diversity and the abundance of Enterococcus, Veillonella, Bifidobacterium, Enterobacter, and Bacteroides. Over the course of hospitalization, corrected GA and exposure to chorioamnionitis remained to have an effect on gut microbial composition. Two different enterotypes were found in the gut microbiota of preterm infants. One enriched in Escherichia-Shigella, and another enriched in uncharacterized Enterobacteriaceae, Klebsiella and Clostridium sensu stricto 1. Overall, HM and fortification with HMF were the most common feeding strategies. When consuming BMF, PT infants had higher growth rates than those consuming HMF. Milk and type of fortification were significantly associated with the abundance of Clostridium sensu stricto 1, Bifidobacterium and Lactobacillus.

Conclusions: This observational study shows the significant association between milk consumption and the exposure to HMF or BMF fortification in the fecal microbiota composition of preterm infants. Additionally, these results show the effect of other perinatal factors in the establishment and development of PT infant's gut microbiota.
Diagnosis of Peanut Allergy in Preschool Children: The Impact of Skin Testing With a Novel Composition of Peanuts
Authors: Kidon Mona I. , Yahia Soad Haj , Machnes-Maayan Diti , Levy Yael , Frizinsky Shirli , Maoz-Segal Ramit , Offenganden Irena , Kenett Ron S. , Agmon-Levin Nancy , Hovav Ran
Published: December 2021

Peanut allergy is an increasing concern in younger children. Available bedside diagnostic tools, i.e., prick tests with commercial extracts or peanut-containing foods have only limited predictive values. In a cohort of preschoolers with both a history of allergic reactions and sensitization to peanut proteins, we aimed to characterize the impact of skin tests with a novel composition of peanuts LPP-MH. Almost one quarter (27/110) of preschool children, with a history of allergic reactions to peanuts and positive standard IgE-mediated tests for peanut allergy, can tolerate the reintroduction of peanut proteins into their diet after resolving their allergy and, thus, can avoid adverse health outcomes associated with the false diagnosis. In the younger age group, a quarter of peanut allergic children, display a relatively high threshold, potentially enabling an easier and safer oral immunotherapy protocol in this window of opportunity in childhood. The use of the novel diagnostic skin test, LPP-MH, significantly improves the predictive value of outpatient evaluation for the outcomes of peanut challenge as well as the expected threshold at which the PA child will react, thus, making for a better informed decision of how, when, and where to challenge.
A Novel Homozygous Variant of TMEM231 in a Case With Hypoplasia of the Cerebellar Vermis and Polydactyly
Authors: Wang Tao , Liu Yu-Xing , Luo Fang-Mei , Dong Yi , Li Ya-Li , Fan Liang-Liang
Published: December 2021

Background: Transmembrane protein 231 (TMEM231) is a component of the B9 complex that participates in the formation of the diffusion barrier between the cilia and plasma membrane. Mutations in TMEM231 gene may contribute to the Joubert syndrome (JBTS) or Meckel–Gruber syndrome (MKS). However, reports on JBTS or MKS caused by TMEM231 mutations are comparatively rare.

Method: We describe a Chinese fetus with unexplained hypoplasia of the cerebellar vermis and polydactyly, detected by ultrasound imaging. The fetus was primarily diagnosed with JBTS/MKS. The parents of this fetus were non-consanguineous and healthy. Whole-exome sequencing (WES) and bioinformatics strategies were employed to explore the genetic lesion of this family.

Results: An unknown missense variant (c.19C>T;p.R7W) of TMEM231 gene was detected. The variant was predicted as pathogenic and was absent in our 200 healthy controls.

Conclusion: WES was employed to explore the genetic lesion of a fetus with unexplained hypoplasia of the cerebellar vermis and polydactyly. A novel variant in TMEM231 gene was identified. Our study not only provided data for genetic counseling and prenatal diagnosis to this family but also broadened the spectrum of TMEM231 mutations.
Transarterial Embolization in Neonatal Kasabach–Merritt Syndrome
Authors: Wang Yinghao , Wang Song , Wang Lili , Bi Shaohua , Zhang Jian , Zha Ping , Dai Liying
Published: December 2021

Background: Kasabach–Merritt syndrome (KMS) is characterized by large hemangiomas and persistent thrombocytopenia, which may result in visceral hemorrhage and disseminated intravascular coagulation. This study aimed to evaluate the value of transarterial embolization (TAE) in neonatal KMS patients.

Patients and Methods: The clinical course of 11 neonates with KMS who underwent TAE in the Department of Neonatology, Anhui Provincal Children's Hospital, Anhui Medical University, China, were reviewed retrospectively.

Results: Eleven neonates with KMS (nine male and two female) were admitted to our hospital between the age of 1 h and 6 days. All were born with progressively enlarged hemangiomas and persistent thrombocytopenia. The largest lesion had its maximum size reached at 15 × 8 × 8 cm. Eight patients had cutaneous hemangiomas (1 right face, one oropharynx, one left upper arm, two back, one left lumbar, one right lower leg, and one right thigh), and three patients had liver hemangiomas. All 11 patients underwent TAE. Nine patients underwent two TAEs, and two patients underwent only one embolization procedure. They all obtained >80% devascularization of their lesions without a major complication. The platelet count increased at 2–5 days after treatment and reached normal count and coagulation profile at 18–28 days after the TAE.

Conclusions: TAE is a safe and effective alternative therapy for neonatal KMS patients.
Exploring the Critical Components and Therapeutic Mechanisms of Perilla frutescens L. in the Treatment of Chronic Kidney Disease via Network Pharmacology
Authors: Yong Chen , Zhang Zhengchun , Huang Guoshun , Yang Yang , Zhu Yiye , Qian Leilei , Tian Fang , Liu Li , Wu Qijing , Xu Zhongchi , Chen Chong , Zhao Jing , Gao Kun , Zhou Enchao
Published: December 2021

Chronic kidney disease (CKD) is a chronic progressive disease that seriously threatens human health. Some patients will continue to progress into the CKD stage 3–5 (also called chronic renal failure), which is mainly manifested by a decline in renal function and multi-system damage. Perilla frutescens (L.) Britton. (Lamiaceae) is one of the most widely used traditional Chinese medicine (TCM) herbs in CKD, especially in CKD stage 3–5. But its active components and mechanisms are still unclear. In this study, we used network pharmacology to analyze the active components of P. frutescens and the main therapeutic targets for intervention in CKD stage 3–5. Then, the key components were selected for enrichment analysis and identified by high performance liquid chromatograph (HPLC). Finally, we verified the critical components through molecular docking, and in vitro experiments. The results show that 19 main active components of P. frutescens were screened, and 108 targets were intersected with CKD stage 3–5. The PPI network was constructed and found that the core nodes AKT1, TP53, IL6, TNF, and MAPK1 may be key therapeutic targets. Enrichment analysis shows that related targets may be involved in regulating various biological functions, and play a therapeutic role in CKD stage 3–5 by regulating apoptosis, T cell receptor, and PI3K-AKT signaling pathways. Molecular docking indicates that the key active components were well docked with its corresponding targets. Five active components were identified and quantified by HPLC. According to the results, luteolin was selected as the critical component for further verification. In vitro experiments have shown that luteolin can effectively alleviate adriamycin (ADR)-induced renal tubular apoptosis and suppress AKT and p53 phosphorylation. The effects of luteolin to reduce apoptosis may be mediated by inhibiting oxidative stress and downregulating the mitogen-activated protein kinase (MAPK) and p53 pathways. In general, we screened and analyzed the possible active components, therapeutic targets and pathways of P. frutescens for treating CKD. Our findings revealed that luteolin can reduce renal tubular epithelial cell apoptosis and may be the critical component of P. frutescens in the treatment of CKD. It provides references and direction for further research.
Induction of PI3K/Akt-Mediated Apoptosis in Osteoclasts Is a Key Approach for Buxue Tongluo Pills to Treat Osteonecrosis of the Femoral Head
Authors: Wang Dan , Liu Yicheng , Tang Dandan , Wei Shujun , Sun Jiayi , Ruan Lvqiang , He Lin , Li Ruolan , Ren Qiang , Tian Xiaoping , Chen Yunhui
Published: December 2021

The Buxue Tongluo pill (BTP) is a self-made pill with the functions of nourishing blood, promoting blood circulation, dredging collaterals, and relieving pain. It consists of Angelica sinensis (Oliv.) Diels, Pheretima aspergillum (E.Perrier), Panax notoginseng (Burk.) F. H. Chen, Astragalus membranaceus (Fisch.) Bge, and Glycyrrhiza uralensis Fisch. Various clinical practices have confirmed the therapeutic effect of BTP on osteonecrosis of the femoral head (ONFH), but little attention has been paid to the study of its bioactive ingredients and related mechanisms of action. In this study, UPLC/MS-MS combined with GEO data mining was used to construct a bioactive ingredient library of BTP and a differentially expressed gene (DEG) library for ONFH. Subsequently, Cytoscape (3.7.2) software was used to analyze the protein–protein interaction between BTP and DEGs of ONFH to screen the key targets, and functional annotation analysis and pathway enrichment analysis were carried out. Finally, 34 bioactive compounds were screened, which acted on 1,232 targets. A total of 178 DEGs were collected, and 17 key genes were obtained after two screenings. By bioinformatics annotation on these key genes, a total of 354 gene ontology (GO) functional annotation analyses and 42 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were obtained. The present study found that GO and KEGG enrichment were mainly related to apoptosis, suggesting that BTP may exert an anti-ONFH effect by promoting osteoclast apoptosis. Experiments in vitro demonstrated that BTP could increase the mitochondrial membrane potential (MMP) and induce remarkable apoptosis in osteoclasts. Furthermore, we determined the apoptosis marker of cleaved(C)-caspase-3, bcl-2, and bax and found that BTP could upregulate the C-caspase-3 and bax expression in osteoclasts and decrease the expression of bcl-2, p-Akt, and p-PI3K in a dose-dependent manner, indicating that BTP could induce PI3K/Akt-mediated apoptosis in osteoclasts to treat ONFH. This study explored the pharmacodynamic basis and mechanism of BTP against ONFH from the perspective of systemic pharmacology, laying a foundation for further elucidating the therapeutic effects of BTP against ONFH.
Study on the Chemical Constituents and Anti-Migraine Activity of Supercritical CO2 Extracts of Zanthoxylum schinifolium
Authors: Yuan Ruifang , Shi Yunzhen , Zhang Jinming , Hu Qi , Wei Xichuan , Luo Chuanhong , Wu Yi , Yang Jinhui , Yang Ming , Wang Fang , Zheng Chuan , Zhang Dingkun
Published: December 2021

Background:Zanthoxylum schinifolium is a common herbal medicine in Southwest China. It is also a condiment commonly used in many families. In Chinese folk medicine, Z. schinifolium is considered to have the effect of relieving migraine, but there is no modern evidence on its anti-migraine mechanism.

Objective: The aim of this study was to investigate the chemical constituents of the supercritical carbon dioxide extracts of Z. schinifolium (CO2-ZSE) and its effects on migraine animals.

Materials and Methods: Supercritical CO2 extraction technology was applied to extract the dried fruit of Z. schinifolium, and the chemical components were determined by gas chromatography–mass spectrometry (GC-MS). Two migraine animal models were established by subcutaneous injection of nitroglycerin (NTG) and reserpine, respectively, to further evaluate the therapeutic effect of CO2-ZSE and explore its mechanism. On the basis of the experimental results, the therapeutic effects of linalool in different dosages and different ways of administration on NTG-induced migraine rats have been further investigated.

Results: About 125 peaks were detected in CO2-ZSE, and the relative content of linalool was 74.16%. CO2-ZSE decreased the number of head-scratching significantly and the levels of serum nitric oxide (NO), endothelin-1 (ET-1), calcitonin gene–related peptide (CGRP), interleukin-1β (IL-1β), nuclear factor kappa B (NF-κB) p65, and inhibitor of kappa B alpha (IκBα), and increased the level of 5-hydroxytryptamine (5-HT). Linalool has the potential to reduce the frequency of scratching the head and the expressions of NO, ET-1, and CGRP in NTG-induced migraine rats.

Conclusion: CO2-ZSE has a definite therapeutic effect on migraine by affecting the expression of vasomotor factors and the inflammatory pathway. Linalool has been proven to be the main effective substance against migraine. These findings provide scientific basis for the development of effective and simple migraine therapy.
An Integrated Gut Microbiota and Network Pharmacology Study on Fuzi-Lizhong Pill for Treating Diarrhea-Predominant Irritable Bowel Syndrome
Authors: Zhen Zhang , Xia Lin , You Huang , Jingwei Zhou , Shasha Yang , Xinyi Wei , Wenjing Lai , Xin Zhang , Chaomei Fu
Published: December 2021

Diarrhea-predominant irritable bowel syndrome (IBS-D) is one of the most common chronic functional gastrointestinal diseases with limited treatments. Gut microbiota play an important role in chronic gastrointestinal diseases. In traditional Chinese medicine (TCM), Spleen–Yang deficiency (SYD) is one of the root causes of IBS-D. Fuzi-Lizhong pill (FLZP) is well known for its powerful capacity for treating SYD and has a good clinical effect on IBS-D. However, the mechanism of FLZP on the gut microbiota of IBS-D has not been fully clarified. Our present study aimed to reveal the mechanism of FLZP regulating gut microbiota of IBS-D. The body mass, CCK, MTL, and Bristol fecal character score were used to verify the establishment of the IBS-D model. IL-6, TNF, IL-1β, and IFN-γ were crucial targets screened by network pharmacology and preliminarily verified by ELISA. Eighteen gut microbiota were important for the treatment of IBS-D with FLZP. Bacteroidetes, Blautia, Turicibacter, and Ruminococcus_torques_group were the crucial gut microbiota that FLZP inhibits persistent systemic inflammation in the IBS-D model. Lactobacillus is the crucial gut microbiota that FLZP renovates intestinal immune barrier in the IBS-D model. In summary, FLZP can affect bacterial diversity and community structures in the host and regulate inflammation and immune system to treat IBS-D.
Probiotics and Vitamin D/Vitamin D Receptor Pathway Interaction: Potential Therapeutic Implications in Inflammatory Bowel Disease
Authors: Pagnini Cristiano , Di Paolo Maria Carla , Graziani Maria Giovanna , Delle Fave Gianfranco
Published: December 2021

Inflammatory bowel diseases (IBD) are chronic conditions of unknown etiology and immunomediated pathogenesis. In the last years, the comprehension of the complex mechanisms involved in the intestinal mucosal homeostasis, and the analysis of the alterations potentially leading to inflammatory pathologic states, has consistently increased. Specifically, the extraordinary impulse in the field of research of the intestinal microbiome has opened the door to the investigation of possible novel approaches to the diagnosis, management and therapeutic applications in IBD. In line with that, administration of probiotic bacteria has been intensely evaluated, leading to much more exciting results in experimental models than in clinical practice. Considering the consistent heterogeneity of the available studies on probiotics, the increased knowledge of the properties of the single bacterial species would ideally lead to unravel potential mechanisms of action that may bring therapeutic applications in specific pathologic condition. Among the relevant molecular pathways for mucosal homeostasis maintenance, the vitamin D/vitamin D receptor (VDR) pathway has been intensely studied in the very last years. In fact, besides osteometabolic functions, the vitamin D exerts important homeostatic effects in the organism at multiple levels, such as immunomodulation, inflammation control, and microbiota regulation, which are likely to play a relevant role in intestinal mucosa protection. In the present review, recent findings about probiotic applications in IBD and mechanisms of action linking vitamin D/VDR pathway to IBD are reported. Available evidence for probiotic effect on vitamin D/VDR are reviewed and potential future application in IBD patients are discussed. At present, many aspects of IBD pathogenesis are still obscure, and current therapeutic options for IBD treatment are at best suboptimal. The increasing comprehension of the different pathways involved in IBD pathogenesis will lead to novel findings ideally leading to potential clinical applications. Microbiota manipulation and vitamin/VDR pathway appear a promising field for future research and therapeutic developments.
Phytomedicine in Disease Management: In-Silico Analysis of the Binding Affinity of Artesunate and Azadirachtin for Malaria Treatment
Authors: Okoh Michael P. , Singla Rajeev K. , Madu Chijioke , Soremekun Opeyemi , Adejoh Johnson , Alli Lukman A. , Shen Bairong
Published: December 2021

In the rural communities of sub-Saharan African (sSA) countries, malaria is being managed using phytocompounds. Artesunate is reported to inhibit Gephyrin E, a central, multi-domain scaffolding protein of inhibitory post-synapses. Neem plant and its metabolites like azadirachtin are being indicated for management of malaria by traditional healers. The present study was aimed to cheminformatically analyse the binding potential of artesunate and azadirachtin with various reactive moieties of Gephyrin E, to reduce malaria scourge. With molecular dynamics (MD), binding free energy estimation and binding affinity of artesunate and azadirachtin to Gephyrin E was done. GRIP docking was done to study the interactions of these test ligands with Gephyrin E (6FGC). MD simulation gave insights to structural changes upon binding of artesunate and azadirachtin in the ligand-binding pocket of Gephyrin E. Root mean square deviation (RMSD) and root mean square fluctuation (RMSF) were calculated. From the estimation, azadirachtin had a total binding energy of −36.97 kcal/mol; artesunate had a binding energy of −35.73 kcal/mol. The GRIP docking results provided a clearer evidence that artesunate has comparatively better binding affinity to Gephyrin E than azadirachtin, and the critical binding sites (in activity order) were cavity 3, 2, 8, and 6 for artesunate while for azadirachtin, it was cavity 6, 3, 8, and 2. The GRIP docking provided detailed interactions at the atomic levels, providing evidence; both compounds have chances to overcome the drug resistance problem, albeit higher for artesunate. Our findings added another piece of evidence that azadirachtin may be effective as an anti-malarial agent. The results herein may provide impetus for more studies into bioactive components of plant origin towards the effective management of malaria disease phenotype.
The Role of Brain-Derived Neurotrophic Factor in Epileptogenesis: an Update
Authors: Wang Xinyi , Hu Zhe , Zhong Kai
Published: December 2021

Epilepsy, which is characterized by spontaneous recurrent seizures, is one of the most common and serious chronic neurological diseases in the world. 30% patients failed to control seizures with multiple anti-seizure epileptic drugs, leading to serious outcomes. The pathogenesis of epilepsy is very complex and remains unclear. Brain-derived neurotrophic factor (BDNF), as a member of the neurotrophic factor family, is considered to play an important role in the survival, growth and differentiation of neurons during the development of the central nervous system. Recent years, a series of studies have reported that BDNF can maintain the function of the nervous system and promotes the regeneration of neurons after injury, which is believed to be closely related to epileptogenesis. However, two controversial views (BDNF inhibits or promotes epileptogenesis) still exist. Thus, this mini-review focuses on updating the new evidence of the role of BDNF in epileptogenesis and discussing the possibility of BDNF as an underlying target for the treatment of epilepsy.
ERα-Targeting PROTAC as a Chemical Knockdown Tool to Investigate the Estrogen Receptor Function in Rat Menopausal Arthritis
Authors: Duan Li , Xu Xiao , Xu Limei , Wen Caining , Ouyang Kan , Li Zigang , Liang Yujie
Published: December 2021

Proteolytic targeting chimeras (PROTACs) is a rapid and reversible chemical knockout method. Compared with traditional gene-editing tools, it can avoid potential genetic compensation, misunderstandings caused by spontaneous mutations, or gene knockouts that lead to embryonic death. To study the role of estrogen receptor alpha (ERα) in the occurrence and progression of menopausal arthritis, we report a chemical knockout strategy in which stable peptide-based (PROTACs) against ERα to inhibit their function. This chemical knockdown strategy can effectively and quickly inhibit ERα protein in vivo and in vitro. In the rat menopausal arthritis model, this study showed that inhibiting estrogen function by degrading ERα can significantly interfere with cartilage matrix metabolism and cause menopausal arthritis by up-regulating matrix metalloproteinase (MMP-13). The results of this study indicate that ERα is a crucial estrogen receptor for maintaining cartilage metabolism. Inhibition of ERα function by PROTACs can promote the progression of osteoarthritis.
Examining Sex Differences in Conditioned Place Preference or Aversion to Methamphetamine in Adolescent and Adult Mice
Authors: Cullity Ellen R. , Guerin Alexandre A. , Perry Christina J. , Kim Jee Hyun
Published: December 2021

Adolescence marks a particularly vulnerable period to developing substance use disorders. Human and rodent studies suggest that hypersensitivity to reward may contribute towards such vulnerability when adolescents are exposed to casual drug use. Methamphetamine is a popular illicit substance used by male and female youths. However, age- and sex-specific research in methamphetamine is scarce. The present study therefore aimed to examine potential sex differences in methamphetamine-conditioned place preference in adolescent and adult mice. Mice (n = 16–24/group) were conditioned to methamphetamine (0.1 mg/kg). We observed that regardless of age, females were more hyperactive compared to males. Individually normalized score against baseline preference indicated that on average, adolescents formed stronger preference compared to adults in both sexes. This suggests that adolescents are more sensitive to the rewarding effects of methamphetamine compared to adults. Surprisingly, individual data showed that some mice formed a conditioned place aversion instead of preference, with females less likely to form an aversion compared to males. These results suggest that adolescents may be hypersensitive to methamphetamine’s rewarding effects. In addition, female resistance to the aversive effects of methamphetamine may relate to the sex-specific findings in humans, including quicker transition to regular methamphetamine use observed in females compared to males.
Enhancing Fatty Acids Oxidation via L-Carnitine Attenuates Obesity-Related Atrial Fibrillation and Structural Remodeling by Activating AMPK Signaling and Alleviating Cardiac Lipotoxicity
Authors: Zhang Yudi , Fu Yuping , Jiang Tiannan , Liu Binghua , Sun Hongke , Zhang Ying , Fan Boyuan , Li Xiaoli , Qin Xinghua , Zheng Qiangsun
Published: December 2021

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in clinical setting. Its pathogenesis was associated with metabolic disorder, especially defective fatty acids oxidation (FAO). However, whether promoting FAO could prevent AF occurrence and development remains elusive. In this study, we established a mouse model of obesity-related AF through high-fat diet (HFD) feeding, and used l-carnitine (LCA, 150 mg/kg⋅BW/d), an endogenous cofactor of carnitine palmitoyl-transferase-1B (CPT1B; the rate-limiting enzyme of FAO) to investigate whether FAO promotion can attenuate the AF susceptibility in obesity. All mice underwent electrophysiological assessment for atrial vulnerability, and echocardiography, histology and molecular evaluation for AF substrates and underlying mechanisms, which were further validated by pharmacological experiments in vitro. HFD-induced obese mice increased AF vulnerability and exhibited apparent atrial structural remodeling, including left atrial dilation, cardiomyocyte hypertrophy, connexin-43 remodeling and fibrosis. Pathologically, HFD apparently leads to defective cardiac FAO and subsequent lipotoxicity, thereby evoking a set of pathological reactions including oxidative stress, DNA damage, inflammation, and insulin resistance. Enhancing FAO via LCA attenuated lipotoxicity and lipotoxicity-induced pathological changes in the atria of obese mice, resulting in restored structural remodeling and ameliorated AF susceptibility. Mechanistically, LCA activated AMPK/PGC1α signaling both in vivo and in vitro, and pharmacological inhibition of AMPK via Compound C attenuated LCA-induced cardio-protection in palmitate-treated primary atrial cardiomyocytes. Taken together, our results demonstrated that FAO promotion via LCA attenuated obesity-mediated AF and structural remodeling by activating AMPK signaling and alleviating atrial lipotoxicity. Thus, enhancing FAO may be a potential therapeutic target for AF.
Anti-Osteogenic Effect of Danshensu in Ankylosing Spondylitis: An in Vitro Study Based on Integrated Network Pharmacology
Authors: Li Jiaxiao , Chen Zexin , Liao Hongbo , Zhong Yanting , Hua Junying , Su Miaoling , Li Jiahao , Xu Jinrong , Cui Liao , Cui Yang
Published: December 2021

Ankylosing spondylitis (AS) is a chronic inflammatory disease characterized by abnormal bone metabolism, with few effective treatments available. Danshensu [3-(3,4-dihydroxy-phenyl) lactic acid) is a bioactive compound from traditional Chinese medicine with a variety of pharmacologic effects. In the present study, we investigated the pharmacologic effect and molecular mechanism of Danshensu in AS. Potential targets of Danshensu were identified in four drugs-genes databases; and potential pharmacologic target genes in AS were identified in three diseases-genes databases. Differentially expressed genes related to AS were obtained from the Gene Expression Omnibus database. Overlapping targets of Danshensu and AS were determined and a disease–active ingredient–target interaction network was constructed with Cytoscape software. Enrichment analyses of the common targets were performed using Bioconductor. To test the validity of the constructed network, an in vitro model was established by treating osteoblasts from newborn rats with low concentrations of tumor necrosis factor (TNF)-α. Then, the in vitro model and AS fibroblasts were treated with Danshensu (1–10 μM). Osteogenesis was evaluated by alkaline phosphatase staining and activity assay, alizarin red staining, quantitative PCR, and western blotting. We identified 2944 AS-related genes and 406 Danshensu targets, including 47 that were common to both datasets. The main signaling pathways associated with the targets were the c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) pathways. A low concentration of TNF-α (0.01 ng/ml) promoted the differentiation of osteoblasts; this was inhibited by Danshensu, which had the same effect on AS fibroblasts but had the opposite effect on normal osteoblasts. Danshensu also decreased the phosphorylation of JNK and ERK in AS fibroblasts. There results provide evidence that Danshensu exerts an anti-osteogenic effect via suppression of JNK and ERK signaling, highlighting its therapeutic potential for the treatment of AS.
Methodological Characteristics of Clinical Trials Supporting the Marketing Authorisation of Advanced Therapies in the European Union
Authors: Iglesias-Lopez Carolina , Agustí Antònia , Vallano Antonio , Obach Merce
Published: December 2021

Several advanced therapy medicinal products (ATMPs) have been approved in the European Union (EU). The aim of this study is to analyse the methodological features of the clinical trials (CT) that supported the marketing authorization (MA) of the approved ATMPs in the EU. A systematic review of the characteristics of pivotal CT of ATMPs approved in the EU until January 31st, 2021 was carried out. A total of 17 ATMPs were approved and 23 CT were conducted to support the MA (median, 1, range, 1–3). Of those studies, 8 (34.78%) were non-controlled and 7 (30.43%) used historical controls. Only 7 (30.4%) were placebo or active-controlled studies. Among all CT, 21 (91.3%) were open-label and 13 (56.52%) had a single-arm design. To evaluate the primary endpoint, 18 (78.26%) studies used an intermediate and single variable. The median (IQR) number of patients enrolled in the studies was 75 (22–118). To date, ATMPs’ approval in the EU is mainly supported by uncontrolled, single-arm pivotal CT. Although there is a trend toward an adaptive or a life cycle approach, a switch to more robust clinical trial designs is expected to better define the benefit and the therapeutic added value of ATMPs.
Discovery of a Novel MyD88 Inhibitor M20 and Its Protection Against Sepsis-Mediated Acute Lung Injury
Authors: Song Jiali , Chen Daoxing , Pan Yingqiao , Shi Xueqin , Liu Qian , Lu Xiaoyao , Xu Ximing , Chen Gaozhi , Cai Yuepiao
Published: December 2021

Myeloid differentiation factor 88 (MyD88) is a hub protein in the Toll-like receptor signaling pathway, which acts as a master switch for numerous inflammatory diseases, including acute lung injury (ALI). Although this protein is considered as a crucial therapeutic target, there are currently no clinically approved MyD88-targeting drugs. Based on previous literature, here we report the discovery via computer-aided drug design (CADD) of a small molecule, M20, which functions as a novel MyD88 inhibitor to efficiently relieve lipopolysaccharide-induced inflammation both in vitro and in vivo. Computational chemistry, surface plasmon resonance detection (SPR) and biological experiments demonstrated that M20 forms an important interaction with the MyD88-Toll/interleukin-1 receptor domain and thereby inhibits the protein dimerization. Taken together, this study found a MyD88 inhibitor, M20, with a novel skeleton, which provides a crucial understanding in the development and modification of MyD88 inhibitors. Meanwhile, the favorable bioactivity of the hit compound is also conducive to the treatment of acute lung injury or other more inflammatory diseases.
Effect of Anti-Inflammatory and Antimicrobial Cosupplementations on Sepsis Prevention in Critically Ill Trauma Patients at High Risk for Sepsis
Authors: Kamel Noha A. , Soliman Moetaza M. , Abo-Zeid Maha A. , Shaaban Mona I.
Published: December 2021

Background: Sepsis development in patients with trauma is associated with bad prognosis. This study investigated the effect of immunomodulatory interventions in major trauma patients at high risk for sepsis.

Methods: In a randomized, double-blinded, controlled design, severe trauma patients were stratified by leukocyte anti-sedimentation rate (LAR) test into high risk (HR) and low risk (LR) for sepsis. The HR patients were randomly allocated into intravenous vitamin C plus vitamin B1 (HR-CB), intramuscular vitamin D plus oral Lactobacillus probiotics (HR-DP), or control (HR-C) groups. The clinical trial was registered at clinicaltrials.gov (https://clinicaltrials.gov/show/NCT04216459).

Outcomes: The primary outcome was Acute Physiologic Assessment and Chronic Health Evaluation score II (APACHE II) score. Secondary outcomes included sepsis incidence, changes in Sequential Organ Failure Assessment (SOFA) score, and serum monocyte chemoattractant protein-1 (MCP-1) on day 6 from baseline, 28-day mortality, intensive care unit (ICU), and hospital discharge.

Results: The HR-DP, HR-CB, and LR groups showed a significantly lower incidence of sepsis development (20%, 20%, and 16%, respectively, versus 60% in the HR-C group, p-value = 0.004). The three groups also showed a significant improvement in APACHE II and SOFA scores. Besides, MCP-1 levels were significantly decreased in HR-DP and HR-CB groups compared to the HR-C group (p-value ≤ 0.05). Significantly decreased mortality (10% and 16% versus 60% in the HR-C group) and increased ICU discharge (95% and 84% versus 45% in the HR-C group) were observed in HR-CB and LR groups (p-value = 0.001).

Conclusion: Both combinations of interventions improved APACHE II scores and reduced sepsis incidence in trauma patients. The LAR combined with injury severity score were good sepsis predictors.
Review of a Decade of Research on Disordered Anderson Localizing Optical Fibers
Authors: Mafi Arash , Ballato John
Published: December 2021

Nearly a decade ago, transverse Anderson localization was observed for the first time in an optical fiber with a random transverse refractive index profile. This started the development of a whole new class of optical fibers that guide light, not in a conventional core-cladding setting based on total internal reflection, but utilizing Anderson localization, where light can guide at any location across the transverse profile of the fiber. These fibers have since been used successfully in high-quality endoscopic image transport. They also show interesting nonlinear and active (lasing) properties with promising applications. This review will cover a brief history of these fibers with personal accounts of the events that led to their development in our research groups. It will then follow with recent progress and future perspectives on science and applications of these fibers.
Pulsatile Flow Measurement by a Speckle Triangle Assessment
Authors: Yuan Yuan , Bi Yong , Gao Xiao Cao , Gao Wei Nan
Published: December 2021

The blood flow in the coronary artery (CA) is pulsatile and much higher than that measured in the brain, retina, and skin before. Its quantitative measurement is medically significant in the coronary artery bypass grafting (CABG). Here, to the best of our knowledge, we first detect the pulsatile flow using the laser speckle contrast imaging technique. Since the factors influencing the flow rate in the CA are complex, we developed a comprehensive model, a speckle triangle assessment (STA), to assess the characteristics of the flow: the speckle flow index (SFI), mean flow index (MFI), and pulsatility index (PI). The phantom experiment was performed and found that our customized setup possessed high dynamic range of the velocity measurement with good sensitivity. It also indicated that the pulsatile flow estimated by the speckle triangle assessment is promising to obtain a more accurate assessment of a coronary artery’s patency in the CABG.
Behavior Individuality: A Focus on Drosophila melanogaster
Authors: Mollá-Albaladejo Rubén , Sánchez-Alcañiz Juan A.
Published: December 2021

Among individuals, behavioral differences result from the well-known interplay of nature and nurture. Minute differences in the genetic code can lead to differential gene expression and function, dramatically affecting developmental processes and adult behavior. Environmental factors, epigenetic modifications, and gene expression and function are responsible for generating stochastic behaviors. In the last decade, the advent of high-throughput sequencing has facilitated studying the genetic basis of behavior and individuality. We can now study the genomes of multiple individuals and infer which genetic variations might be responsible for the observed behavior. In addition, the development of high-throughput behavioral paradigms, where multiple isogenic animals can be analyzed in various environmental conditions, has again facilitated the study of the influence of genetic and environmental variations in animal personality. Mainly, Drosophila melanogaster has been the focus of a great effort to understand how inter-individual behavioral differences emerge. The possibility of using large numbers of animals, isogenic populations, and the possibility of modifying neuronal function has made it an ideal model to search for the origins of individuality. In the present review, we will focus on the recent findings that try to shed light on the emergence of individuality with a particular interest in D. melanogaster.
Response of Bone Metabolism Markers to Ice Swimming in Regular Practitioners
Authors: Mu Shuai , Xia Yang , Wu Qijun , Ji Chao , Dai Huixu , Zhang Ming , Jiao Jiao , Shi Feng , Liu Shengye , Wang Guangbin , Shen Tao , Tian Ye , Yang Liqing , Fu Qin , Zhao Yuhong
Published: December 2021

Objective: Both exercise and cold exposure cause physiological stress and they often occur in combination. However, the effects of exercise during severe cold on variation in bone metabolism in humans have remained elusive. The aim of this study was to investigate the variations in circulating bone metabolism markers after ice swimming (IS).

Methods: Eighty-seven women and men aged 42–84 years old were recruited to perform regular IS activities. Serum parathyroid hormone (PTH), total calcium (Ca2+), total phosphorus (Pi), total magnesium (Mg2+), N-terminal osteocalcin (N-MID), total propeptide of procollagen 1 (TPINP), and C-terminal telopeptide of type 1 collagen (β-CTX) were measured 30 min before and 30 min after IS. Bone mineral content (BMC) and bone mineral density (BMD) were assessed at lumbar spine 1–4 (L1–L4) and femoral neck (FN). The IS habits were obtained from questionnaires and the 10-year probability of osteoporotic fracture was calculated using the FRAX® tool with and without a BMD value of the FN.

Results: There were significant increases in PTH (median, 40.120–51.540 pg/mL), Ca2+ (median, 2.330–2.400 mmol/L), and Pi (median, 1.100–1.340 mmol/L) and significant decreases in TPINP (median, 38.190–36.610 ng/mL) and β-CTX (median, 0.185–0.171 ng/mL), while there was a trend for increased serum Mg2+ (P = 0.058) but no significant change in N-MID (P = 0.933) after IS in all subjects. The increases in the proportions of cases of hyperparathyroidemia, hypercalcemia, and hyperphosphatemia in those performing IS were statistically significant. The baseline levels and the changes of bone metabolism markers had associations with osteoporosis and bone status, but these may be age and sex dependent. Finally, there were significant correlations among the bone metabolism markers.

Conclusion: IS caused significant alterations in bone metabolic markers, specifically, increases in PTH, Ca2+ and Pi should raise concerns about potential cardiovascular health risks in severe cold exercise. Additionally, a divergence between PTH elevation and a decline in bone turnover, which shown a special change of bone metabolism after IS and may suggest potential therapeutic implications of cold exercise in PTH and bone metabolic disorders.