Search

ObjectivesTo evaluate the changes in distal vascular morphology and hemodynamics in patients with extremely severe aortic coarctation (CoA) after covered palliative (CP) stent dilation with different surgical strategies.Materials and methodsPerioperative computed tomography angiography and digital subtraction angiography were utilized to construct three aortic models with varying stenosis rates and one follow-up model in a patient with extremely severe CoA. The models included: an idealized non-stenosed model (A: 0%), a model post initial stent deployment (B: 28%), a model post balloon expansion (C: 39%), and a model 18 months after post-balloon expansion (D: 39%). Consistent boundary conditions were applied to all models, and hemodynamic simulation was conducted using the pure fluid method.ResultsThe narrowest and distal diameter of the stent increased by 34.71% and 59.29%, respectively, from model B to C. Additionally, the distal diameter of the stent increased by −13.80% and +43.68% compared to the descending aorta diameter, respectively. Furthermore, the ellipticity of the maximum cross-section of the aneurysm region in model A to D continued to increase. The oscillatory shear index at the stenosis to the region of the aneurysm were found to be higher in Models A and B, and lower in Models C and D. At the moment of maximum flow velocity, the blood flow distribution in models A and B was more uniform in the widest section of the blood vessels at the distal end of the stenosis, whereas models C and D exhibited disturbed blood flow with more than 2 eddy currents. The time-averaged wall shear stress (TAWSS) decreased in the distal and basal aneurysms, while it significantly increased at the step position. The aneurysmal region exhibited an endothelial cell activation potential value lower than 0.4 Pa−1.ConclusionIn patients with extremely severe CoA, it is crucial to ensure that the expanded diameter at both ends of the CP stent does not exceed the native vascular diameter during deployment. Our simulation results demonstrate that overdilation leads to a decrease in the TAWSS above the injured vessel, creating an abnormal hemodynamic environment that may contribute to the development and enlargement of false aneurysms in the early postoperative period. Clinical Trial RegistrationClinicalTrials.gov, (NCT02917980).

BackgroundUlcerative colitis (UC) is a lifelong inflammatory disease affecting the rectum and colon with numerous treatment options that require an individualized treatment plan. Histone modifications regulate chromosome structure and gene expression, resulting in effects on inflammatory and immune responses. However, the relationship between histone modification-related genes and UC remains unclear.MethodsTranscriptomic data from GSE59071 and GSE66407 were obtained from the Gene Expression Omnibus (GEO), encompassing colonic biopsy expression profiles of UC patients in inflamed and non-inflamed status. Differentially expressed gene (DEG) analyses, functional enrichment analyses, weighted gene co-expression network analysis (WGCNA), and random forest were performed to identify histone modification-related core genes associated with UC inflammation. Features were screened through the least absolute shrinkage and selection operator (LASSO) and support vector machine‐recursive feature elimination (SVM‐RFE), establishing a molecular inflammatory predictive model using logistic regression. The model was validated in the GSE107499 dataset, and the performance of the features was assessed using receiver operating characteristic (ROC) and calibration curves. Immunohistochemistry (IHC) staining of colonic biopsy tissues from UC patients treated with infliximab was used to further confirm the clinical application value. Univariate logistic regression on GSE14580 highlighted features linked to infliximab response.ResultsA total of 253 histone modification-related DEGs were identified between inflammatory and non-inflammatory patients with UC. Seven key genes (IL-1β, MSL3, HDAC7, IRF4, CAMK2D, AUTS2, and PADI2) were selected using WGCNA and random forest. Through univariate logistic regression, three core genes (CAMK2D, AUTS2, and IL-1β) were further incorporated to construct the molecular inflammatory predictive model. The area under the curve (AUC) of the model was 0.943 in the independent validation dataset. A significant association between CAMK2D protein expression and infliximab response was observed, which was validated in another independent verification set of GSE14580 from the GEO database.ConclusionThe molecular inflammatory predictive model based on CAMK2D, AUTS2, and IL-1β could reliably distinguish the mucosal inflammatory status of UC patients. We further revealed that CAMK2D was a predictive marker of infliximab response. These findings are expected to provide a new evidence base for personalized treatment and management strategies for UC patients.

BackgroundPancreatic cancer is renowned for its elevated incidence and mortality rates on a global scale. The disease burden of pancreatic cancer is anticipated to increase, particularly in Asia, due to its vast and rapidly aging population.MethodsData from the Global Burden of Disease 2019 were analyzed for pancreatic cancer burden across 52 countries in Asia, including the incidence, mortality, and disability-adjusted life years (DALY) for pancreatic cancer, with a focus on risk factors such as high body mass index (BMI), elevated fasting plasma glucose, and smoking. We applied the Estimated Annual Percentage Change, the Age–Period–Cohort model, and decomposition analysis to evaluate incidence trends and effects.ResultsFrom 1990 to 2019, both incidence and mortality rates of pancreatic cancer in Asia significantly increased, with an average annual standardized incidence rate change of 1.73%. Males consistently exhibited higher rates than females, with smoking as a key risk factor. Central Asia reported the highest rates, and South Asia the lowest. The incidence rose with age, peaking in those aged 70~74. The disease burden increased in all age groups, particularly in populations aged 55 and above, representing 84.41% of total cases in 2019, up from 79.01% in 1990. Pancreatic cancer ranked the fifth in incidence among six major gastrointestinal tumors but presented a significant growth rate of mortality and DALY.ConclusionWith the growing, aging population in Asia, the pancreatic cancer burden is projected to escalate, bringing a significant public health challenge. Hence, comprehensive public health strategies emphasizing early detection, risk modification, and optimized treatment of pancreatic cancer are imperative.

Although the role of METTL3 has been extensively studied in many cancers, its role in isoform switching in prostate cancer (PCa) has been poorly explored. To investigate its role, we applied standard RNA-sequencing and long-read direct RNA-sequencing from Oxford Nanopore to examine how METTL3 affects alternative splicing (AS) in two PCa cell lines. By dissecting genome-wide METTL3-regulated AS events, we noted that two PCa cell lines (representing two different PCa subtypes, androgen-sensitive or resistant) behave differently in exon skipping and intron retention events following METTL3 depletion, suggesting AS heterogeneity in PCa. Moreover, we revealed that METTL3-regulated AS is dependent on N6-methyladenosine (m6A) and distinct splicing factors. Analysis of the AS landscape also revealed cell type specific AS signatures for some genes (e.g., MKNK2) involved in key functions in PCa tumorigenesis. Finally, we also validated the clinical relevance of MKNK2 AS events in PCa patients and pointed to the possible regulatory mechanism related to m6A in the exon14a/b region and SRSF1. Overall, we characterize the role of METTL3 in regulating PCa-associated AS programs, expand the role of METTL3 in tumorigenesis, and suggest that MKNK2 AS events may serve as a new potential prognostic biomarker.

Introduction: Growth plate injury is a significant challenge in clinical practice, as it could severely affect the limb development of children, leading to limb deformity. Tissue engineering and 3D bioprinting technology have great potential in the repair and regeneration of injured growth plate, but there are still challenges associated with achieving successful repair outcomes.Methods: In this study, GelMA hydrogel containing PLGA microspheres loaded with chondrogenic factor PTH(1–34) was combined with BMSCs and Polycaprolactone (PCL) to develop the PTH(1–34)@PLGA/BMSCs/GelMA-PCL scaffold using bio-3D printing technology.Results: The scaffold exhibited a three-dimensional interconnected porous network structure, good mechanical properties, biocompatibility, and was suitable for cellchondrogenic differentiation. And a rabbit model of growth plate injury was appliedto validate the effect of scaffold on the repair of injured growth plate. The resultsshowed that the scaffold was more effective than injectable hydrogel in promotingcartilage regeneration and reducing bone bridge formation. Moreover, the addition ofPCL to the scaffold provided good mechanical support, significantly reducing limbdeformities after growth plate injury compared with directly injected hydrogel.Discussion: Accordingly, our study demonstrates the feasibility of using 3D printed scaffolds for treating growth plate injuries and could offer a new strategy for the development of growth plate tissue engineering therapy.

Introduction: The repair and regeneration of growth plate injuries using tissue engineering techniques remains a challenge due to large bone bridge formation and low chondrogenic efficiency.Methods: In this study, a bilayer drug-loaded microspheres was developed that contains the vascular endothelial growth factor (VEGF) inhibitor, Bevacizumab, on the outer layer and insulin-like growth factor-1 (IGF-1), a cartilage repair factor, on the inner layer. The microspheres were then combined with bone marrow mesenchymal stem cells (BMSCs) in the gelatin methacryloyl (GelMA) hydrogel to create a composite hydrogel with good injectability and biocompatibility.Results: The in vitro drug-release profile of bilayer microspheres showed a sequential release, with Bevacizumab released first followed by IGF-1. And this hydrogel simultaneously inhibited angiogenesis and promoted cartilage regeneration. Finally, in vivo studies indicated that the composite hydrogel reduced bone bridge formation and improved cartilage regeneration in the rabbit model of proximal tibial growth plate injury.Conclusion: This bilayer microsphere-based composite hydrogel with sequential controlled release of Bevacizumab and IGF-1 has promising potential for growth plate injury repair.

BackgroundDue to the effectiveness and safety, acupuncture, one of the traditional therapies of Chinese medicine, has been widely used in clinical practice globally. A few systematic review or meta-analyses have proved its effectiveness and safety towards patients with cancer pain, while there are no syntheses among those evidence. The aim of this scoping review is to summarize the evidence from systematic reviews of acupuncture for the treatment of cancer pain and evaluate the breadth and methodological quality of these evidence as well.MethodsThe scoping review process was guided by the methodology framework of Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for scoping reviews (PRISMA ScR) and “Arkseyand O’Malley six-stage framework”. Electronic searches were carried out in several online databases from inception to Jan 2022. Systematic reviews and meta-analyses that involve any type of acupuncture for patients with cancer pain will be included. A pair of reviewers independently screened full texts. Moreover, review characteristics were extracted, and methodological quality was assessed using the AMSTAR 2 tool.ResultsTwenty-five systematic reviews and meta-analyses were included. Manual acupuncture is the most frequently included types of test group intervention (48%), followed by acupuncture + medicine (28%), and auricular acupuncture (12%). All the reviews have declared that acupuncture is an effective method for cancer pain treatment. Eleven reviews (44%) aiming at evaluating the safety also have confirmed that acupuncture is safe for treating cancer pain. However, most included studies were conducted in China. With certain geographical limitations, the findings were not representative within the region. The results of our review may owe to the synthesis of all kinds of cancer pain, and only 2 reviews described the type of cancer pain in detail.ConclusionsThis scoping review synthesizes and evaluates existing evidence of acupuncture for cancer pain. From this scoping review of systematic reviews and meta-analyses, there are clear recommendations for future studies: expanding the region of research in the world and trying to conduct the study of different types of cancer pain in details as much as possible. Evidences of acupuncture for cancer pain can inform clinical decision-making. Systematic review registrationhttps://inplasy.com/inplasy-2022-1-0073/, identifier INPLASY202210073.

Observational studies revealed altered gut microbial composition in patients with allergic diseases, which illustrated a strong association between the gut microbiome and the risk of allergies. However, whether such associations reflect causality remains to be well-documented. Two-sample mendelian randomization (2SMR) was performed to estimate the potential causal effect between the gut microbiota and the risk of allergic diseases. 3, 12, and 16 SNPs at the species, genus, and family levels respectively of 15 microbiome features were obtained as the genetic instruments of the exposure dataset from a previous study. GWAS summary data of a total of 17 independent studies related to allergic diseases were collected from the IEU GWAS database for the outcome dataset. Significant causal relationships were obtained between gut microbiome features including Ruminococcaceae, Eggerthella, Bifidobacterium, Faecalibacterium, and Bacteroides and the risk of allergic diseases. Furthermore, our results also pointed out a number of putative associations between the gut microbiome and allergic diseases. Taken together, this study was the first study using the approach of 2SMR to elucidate the association between gut microbiome and allergic diseases.

Energy is an internal variable during rock deformation and failure, and its dissipation and conversion law can reflect the rock’s internal damage and deterioration state. Analysis of rock deformation and failure process from the perspective of energy is helpful to deeply understand the mechanism of rock damage, fracture and instability failure, and has important theoretical and practical significance for the stability evaluation and support control of surrounding rock. In this study, through single cyclic loading and unloading (SCLU) experiments, cyclic triaxial loading and unloading (CTLU) experiments and conventional triaxial compression (CTC) experiments, the equivalent elastic modulus method based on elastic strain energy is proposed to analyze the energy conversion of rock. The results show that the error of the elastic strain energy calculated by the strain energy formula method is generally higher than 10% with the secant and tangent modulus of the loading and unloading curve as input parameters. Taking the equivalent elastic modulus proposed in this study as an input parameter, more accurate elastic strain energy can be obtained by the strain energy formula. During the rock failure process, the equivalent elastic modulus shows a three-stage characteristic of increase, steady and decrease. The equivalent elastic modulus can be estimated by the quadratic function between the equivalent elastic modulus and confining pressure and axial strain. Under the same deformation and deviatoric stress, the elastic strain energy stored in rock increases with increasing confining pressure. The local maximum energy dissipation rate corresponds to stress drop, and the peak energy dissipation rate appears near the peak strength. High energy dissipation mainly occurs in a short time after peak strength, and energy release and dissipation are more sudden and severe under high confining pressure.

ObjectiveTo systematically evaluate the risk factors of lower respiratory tract infection caused by Stenotrophomonas maltophilia for better clinical treatment.MethodsPubMed, Embase, the Cochrane Library, Web of Science, China Journal full-text Database (CNKI), Wanfang Database (WanFang Data), VIP (VIP), and China Biomedical Literature Database (CBM) were selected and published by June 2022 about the risk factors of lower respiratory tract infection of S. maltophilia. Two researchers independently screened the literature, extracted data, and quality evaluation according to the inclusion and exclusion criteria. RevMan 5.4 software was used for meta-analysis.ResultsA total of 18 articles were included, including 10 in English and 8 in Chinese. Meta analysis showed that the risk factors of lower respiratory tract infection caused by S. maltophilia included disease severity, hospitalization days, use of glucocorticoids, invasive procedures, use of broad-spectrum antibiotics and use of more than 3 Antibiotics. The OR values of patients with hospitalization, mechanical ventilation, use of more than 3 Antibiotics, endotracheal intubation and tracheotomy were the highest. Specific hospitalization days (OR = 14.56, 95% CI: 6.12~23.01), mechanical ventilation (OR = 14.16, 95% CI: 5.85~34.3), use of more than 3 Antibiotics (OR = 6.21, 95% CI: 1.24~31.14), tracheal intubation (OR = 6.07, 95% CI: 1.97~3.64), tracheotomy (OR = 3.77, 95% CI: 1.09~13.04).ConclusionThere are many risk factors for lower respiratory tract infection of S. maltophilia, which can occur in patients with severe illness, high APACHE-II score, invasive procedures, and the need for broad-spectrum antibiotics. In terms of the host, these patients are characterized by impaired immune function, severe illness and long-term hospitalization, which objectively leads to the infection of S. maltophilia. Therefore, strengthening the monitoring, prevention and control of patients with risk factors of S. maltophilia infection is conducive to reducing the risk of infection and death.

ObjectivePelvic injuries refer to the disruption of the inherent structural and mechanical integrity of the pelvic ring. Sacroiliac screw fixation technique is often used for the treatment of posterior pelvic ring injury, which is prone to the iatrogenic injury. Various attempts were proposed to avoid iatrogenic injuries, while the executing processes are usually too cumbersome. The patient-personalized guide template based on 3D printing technology has been considered as a promising method, which can achieve lower deviation and higher accuracy in a simple and convenient way. We reported the first case of posterior pelvic ring injury using 3D printing personalized guide template with the verification of intraoperative CT.MethodsThe subject was a 74-year-old female with posterior pelvic ring injury. Two patient-specific guide templates were customized based on 3D printing technology, one for S1 and the other for S2. We used the guide templates for navigation to place the sacroiliac screws. The placement of screws was verified by intraoperative CT. Intraoperative and postoperative variables were collected.ResultsThe technique helped us successfully insert the sacroiliac screws into the safe zone. The intraoperative blood loss was 23.03 ml, and the duration of operation was 62 min. The exposure dose during CT scanning was 7.025 mSv. The assessment of screws position was excellent. Furthermore, there was no sign of any functional impairment postoperatively.ConclusionSacroiliac screws fixation with the assistance of 3D printing personalized guide template under the verification of intraoperative CT may be a promising method to treat posterior pelvic ring injuries.

ContextRepetitive sub-concussive head impacts (RSHIs) are common in American football and result in changes to the microstructural integrity of white matter. Both docosahexaenoic acid (DHA) and eicosapentaoic acid (EPA) supplementation exerted neuroprotective effects against RSHIs in animal models and in a prior study in football players supplemented with DHA alone.ObjectiveHere, we present exploratory neuroimaging outcomes from a randomized controlled trial of DHA + EPA supplementation in American football players. We hypothesized that supplementation would result in less white matter integrity loss on diffusion weighted imaging over the season.Design, setting, participantsWe conducted a double-blind placebo-controlled trial in 38 American football players between June 2019 and January 2020.InterventionParticipants were randomized to the treatment (2.442 g/day DHA and 1.020 g/day EPA) or placebo group for five times-per-week supplementation for 7 months. Of these, 27 participants were included in the neuroimaging data analysis (n = 16 placebo; n = 11 DHA + EPA).Exploratory outcome measuresChanges in white matter integrity were quantified using both voxelwise diffusion kurtosis scalars and deterministic tractography at baseline and end of season. Additional neuroimaging outcomes included changes in regional gray matter volume as well as intra-regional, edge-wise, and network level functional connectivity. Serum neurofilament light (NfL) provided a peripheral biomarker of axonal damage.ResultsNo voxel-wise between-group differences were identified on diffusion tensor metrics. Deterministic tractography using quantitative anisotropy (QA) revealed increased structural connectivity in ascending corticostriatal fibers and decreased connectivity in long association and commissural fibers in the DHA+EPA group compared to the placebo group. Serum NfL increases were correlated with increased mean (ρ = 0.47), axial (ρ = 0.44), and radial (ρ = 0.51) diffusivity and decreased QA (ρ = −0.52) in the corpus callosum and bilateral corona radiata irrespective of treatment group. DHA + EPA supplementation did preserve default mode/frontoparietal control network connectivity (g = 0.96, p = 0.024).ConclusionsThese exploratory findings did not provide strong evidence that DHA + EPA prevented or protected against axonal damage as quantified via neuroimaging. Neuroprotective effects on functional connectivity were observed despite white matter damage. Further studies with larger samples are needed to fully establish the relationship between omega-3 supplementation, RSHIs, and neuroimaging biomarkers.Trial registrationClinicalTrials.gov-NCT04796207

Traditional studies using cancer cell lines are often performed on a two-dimensional (2D) cell culture model with a low success rate of translating to Phase I or Phase II clinical studies. In comparison, with the advent of developments three-dimensional (3D) cell culture has been championed as the latest cellular model system that better mimics in vivo conditions and pathological conditions such as cancer. In comparison to biospecimens taken from in vivo tissue, the details of gene expression of 3D culture models are largely undefined, especially in mesothelioma – an aggressive cancer with very limited effective treatment options. In this study, we examined the veracity of the 3D mesothelioma cell culture model to study cell-to-cell interaction, gene expression and drug response from 3D cell culture, and compared them to 2D cell and tumor samples. We confirmed via SEM analysis that 3D cells grown using the spheroid methods expressed highly interconnected cell-to-cell junctions. The 3D spheroids were revealed to be an improved mini-tumor model as indicated by the TEM visualization of cell junctions and microvilli, features not seen in the 2D models. Growing 3D cell models using decellularized lung scaffold provided a platform for cell growth and infiltration for all cell types including primary cell lines. The most time-effective method was growing cells in spheroids using low-adhesive U-bottom plates. However, not every cell type grew into a 3D model using the the other methods of hanging drop or poly-HEMA. Cells grown in 3D showed more resistance to chemotherapeutic drugs, exhibiting reduced apoptosis. 3D cells stained with H&E showed cell-to-cell interactions and internal architecture that better represent that of in vivo patient tumors when compared to 2D cells. IHC staining revealed increased protein expression in 3D spheroids compared to 2D culture. Lastly, cells grown in 3D showed very different microRNA expression when compared to that of 2D counterparts. In conclusion, 3D cell models, regardless of which method is used. Showed a more realistic tumor microenvironment for architecture, gene expression and drug response, when compared to 2D cell models, and thus are superior preclinical cancer models.

A total of nine immature–low maturity oil shale samples from Fushun and Maoming, the main oil shale producing areas in China, and three mature shale samples from the Jiyang Depression, China, were selected for use in hydrocarbon generation thermal simulation experiments in an open system and a closed system. The parallel first–order reaction kinetic model and the overall nth–order reaction kinetic model were used to calibrate the pyrolysis kinetic parameters of the samples. This comparative study revealed following conclusion. The generation period of the gaseous hydrocarbons (C1–5) was the longest, and the generation period of the heavy hydrocarbon (C14+) was the shortest. The activation energy of the hydrocarbon generation reaction was closely related to the maturity of the organic matter, i.e., the higher the maturity of the sample, the higher the activation energy of the reaction, which indicates that oil shale/shale oil conversion requires higher temperature conditions. The parallel first–order reaction model regards the hydrocarbon generation reaction as a series of first–order reactions, and it has a better fitting effect for the longer hydrocarbon generation period reactions, such as generating gaseous hydrocarbons (C1–5) and light components (C6–14) from organic matter. The overall nth–order reaction treats the reaction as a nth–order reaction, and the nth–order reaction has a better fitting effect for reactions with a narrow hydrocarbon generation window, such as generating heavy components from organic matter. In the process of generating hydrocarbons from organic matter, the order of the reaction is the sum of the orders of the sub–reactions. The more hydrocarbon–generating parent material, the higher order of hydrocarbon–generating reaction. The reaction order sequence of the generation of different hydrocarbons from organic matter is as follows: generation of gaseous hydrocarbons > generation of light hydrocarbons > generation of heavy hydrocarbons.

ObjectiveThis study aimed to compare limited open reduction and transepiphyseal intramedullary fixation with Kirschner wire (LOR-TIKW) versus open reduction and internal fixation with plate and screw (ORIF-PS) for treatment of irreducible distal radius diaphyseal–metaphyseal junction (DMJ) fracture in older children.MethodsData of children (aged 10–14 years) treated in our hospital for distal radius DMJ fractures with LOR-TIKW or ORIF-PS from January 2018 to December 2019 were retrospectively analyzed. Follow-up was until radiographic union. Demographic, clinical, and radiographic data; treatment cost; healing time; functional outcome (by Price criteria); complications; and postoperative angulation and displacement were compared between children treated by the two methods. Statistical analysis was performed with alpha set at P < 0.05.ResultsA total of 26 children were included: 14 treated with LOR-TIKW and 12 with ORIF-PS. Operation time was less (22.1 min vs. 46.7 min, P < 0.0001), surgical incision smaller (2.43 cm vs. 5.00 cm, P < 0.0001), cost of internal fixation lower (US$, 40.6 vs. 2020, P < 0.0001), and healing time shorter (4.79 weeks vs. 5.64 weeks, P = 0.03) with LOR-TIKW; however, postoperative fracture angulation was slightly larger (1.07° vs. 0.83°, P = 0.85) and displacement slightly more (0.86 mm vs. 0.58 mm, P = 0.44) in the LOR-TIKW group. Rate of union, functional outcome, and complications were not significantly different between the groups.ConclusionFor irreducible DMJ fracture of distal radius in older children, LOR-TIKW appears to be a promising method with several advantages over ORIF-PS.

Epstein-Barr virus (EBV)-associated hemophagocytic lymphohistiocytosis (EBV-HLH) is a life-threatening syndrome, which is caused by EBV infection that is usually refractory to treatment and shows relapse. The development of new biomarkers for the early diagnosis and clinical treatment of EBV-HLH is urgently needed. Exosomes have been shown to mediate various biological processes and are ideal non-invasive biomarkers. Here, we present the differential plasma exosomal proteome of a patient with EBV-HLH before vs. during treatment and with that of his healthy twin brother. A tandem mass tag-labeled LC-MS technique was employed for proteomic detection. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses indicated that differential proteomic profiles were related to virus infection, coagulopathy, nervous system dysfunction, imbalance of immune response, and abnormal liver function. The candidate biomarkers were first identified in the patient’s plasma exosomes at different treatment and follow-up time points. Then, 14 additional EBV-HLH exosome samples were used to verify six differentially expressed proteins. The upregulation of C-reactive protein, moesin, galectin three-binding protein, and heat shock cognate 71 kDa protein and the downregulation of plasminogen and fibronectin 1 could serve as potential biomarkers of EBV-HLH. This plasma exosomal proteomic analysis provides new insights into the diagnostic and therapeutic biomarkers of EBV-HLH.

Carbonizing by stir-frying (CSF) is the most common technology in botanical folk medicines to enhance the convergence, hemostasis, and antidiarrheal effects. Sanguisorbae Radix (SR), a well-known herbal medicine in China, has extensive therapeutic functions, while charred SR is known as an additional product obtained from SR after CSF. In this study, mass spectrometry was used to investigate the effect of charring on tannins transformation of SR. The findings showed that the content level of tannins in SR decreased significantly after carbonizing process, while their three categories, gallotannins, ellagitannins, and procyanidins, had downward trends in general. Moreover, CSF also induced the polyphenol in SR to release relevant monomers from its origins. Significant amount of hydrolyzable tannins were detected by mass spectrometry, including gallotannins and ellagitannins, suggesting that hydrolysis during CSF yielded gallic and ellagic acid and their derivatives, in addition to sugar moieties. Subsequently, gallic and ellagic acid can further polymerize to form sanguisorbic acid dilactone. The amount of proanthocyanidins, the oligomers of catechin, including procyanidin, procyanidin C2, procyanidin B3, and 3-O-galloylprocyanidin B3, decreased to form catechin and its derivatives, which may further degrade to protocatechualdehyde. Quantitative analysis illustrated that the amount of gallic, pyrogallic, and ellagic acid and methyl gallate, the essential effectors in SR, significantly increased after CSF, with increased ratios of 1.36, 4.28, 10.33, and 4.79, respectively. In contrast, the contents of cathechin and epigallocatechin dropped remarkably with increased ratios of 0.04 and 0.02. Tannins exhibit moderate absorption, while their relevant monomers have a higher bioavailability. Therefore, CSF is proved here to be an effective technique to the release of active monomers from the original polyphenol precursor. This study explored the mechanism by which tannins are transformed upon CSF of SR.

Deubiquitylating enzymes (DUBs) are proteases that crack the ubiquitin code from ubiquitylated substrates to reverse the fate of substrate proteins. Recently, DUBs have been found to mediate various cellular biological functions, including antiviral innate immune response mediated by pattern-recognition receptors (PRRs) and NLR Family pyrin domain containing 3 (NLRP3) inflammasomes. So far, many DUBs have been identified to exert a distinct function in fine-tuning antiviral innate immunity and are utilized by viruses for immune evasion. Here, the recent advances in the regulation of antiviral responses by DUBs are reviewed. We also discussed the DUBs-mediated interaction between the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and antiviral innate immunity. The understanding of the mechanisms on antiviral innate immunity regulated by DUBs may provide therapeutic opportunities for viral infection.

Background: Circumferential trabeculotomy have evolved from ab externo to ab interno approach. Both procedures may lower IOP, but it is unclear which maybe a superior approach.Purpose: To compare the outcomes of ab interno and ab externo circumferential trabeculotomy in patients with primary open-angle glaucoma.Design: Retrospective, comparative case series.Participants: Primary open angle glaucoma patients undergoing ab interno (40 patients in Group 1) or ab externo (54 patients in Group 2) circumferential trabeculotomy, with about one half of them having prior incisional glaucoma surgery.Methods: Outcomes including intraocular pressure (IOP), glaucoma medications and surgical complications were analyzed.Main Outcome Measures: IOP, medications and surgical success defined as an IOP of ≤ 21 mmHg and a reduction of IOP ≥20% from baseline (criterion A) or IOP ≤ 18 mmHg and a reduction of IOP 20% from baseline (criterion B) with (qualified success) or without (complete success) medications.Results: At 1 year, IOP decreased by 37.1% (26.0–14.8 mmHg) in Group 1 and 39.5% (28.5–15.1 mmHg) in Group 2. Medications decreased from 3.5 in Group 1 and 3.6 in Group 2 pre-operatively to 0.6 ± 1.0 and 0.3 ± 0.6 post-operatively, respectively. Success rates did not differ significantly between groups based on criterion A (complete and qualified success: 68.7 and 81.9% in Group 1, and 75.3 and 90.4% in Group 2, respectively) or criterion B (complete and qualified success: 58.2 and 79.3%in Group 1, and 69.5 and 88.4% in Group 2, respectively). For eyes with prior filtration surgeries, the mean percent reduction of IOP (41.7 ± 32.7% in Group 1, 39.7 ± 27.8% in Group 2, P = 0.724) and the mean medication reduction (2.9 ± 1.6 in Group 1, 3.4 ± 1.0 in Group 2, P = 0.454) were not significantly different.Conclusions: Ab interno circumferential trabeculotomy achieved comparable outcomes to ab externo trabeculotomy and may be an effective surgical option for patients with primary open-angle glaucoma.

Type 1 diabetes (T1D) is a disorder of impaired glucoregulation due to lymphocyte-driven pancreatic autoimmunity. Mobilizing dendritic cells (DC) in vivo to acquire tolerogenic activity is an attractive therapeutic approach as it results in multiple and overlapping immunosuppressive mechanisms. Delivery of agents that can achieve this, in the form of micro/nanoparticles, has successfully prevented a number of autoimmune conditions in vivo. Most of these formulations, however, do not establish multiple layers of immunoregulation. all-trans retinoic acid (RA) together with transforming growth factor beta 1 (TGFβ1), in contrast, has been shown to promote such mechanisms. When delivered in separate nanoparticle vehicles, they successfully prevent the progression of early-onset T1D autoimmunity in vivo. Herein, we show that the approach can be simplified into a single microparticle formulation of RA + TGFβ1 with surface decoration with the T1D-relevant insulin autoantigen. We show that the onset of hyperglycemia is prevented when administered into non-obese diabetic mice that are at the mid-stage of active islet-selective autoimmunity. Unexpectedly, the preventive effects do not seem to be mediated by increased numbers of regulatory T-lymphocytes inside the pancreatic lymph nodes, at least following acute administration of microparticles. Instead, we observed a mild increase in the frequency of regulatory B-lymphocytes inside the mesenteric lymph nodes. These data suggest additional and potentially-novel mechanisms that RA and TGFβ1 could be modulating to prevent progression of mid-stage autoimmunity to overt T1D. Our data further strengthen the rationale to develop RA+TGFβ1-based micro/nanoparticle “vaccines” as possible treatments of pre-symptomatic and new-onset T1D autoimmunity.

Sini Decoction (SND), as a classic prescription of Traditional Chinese Medicine (TCM), has been proved to be clinically useful in cardiomyopathy and inflammatory bowel diseases. However, the role and mechanism of SND in colitis-associated cancer remains unclear. This study aims to evaluate the effect of SND on colorectal cancer(CRC) symptoms and further explore the changes of gut microbes mediated by SND extract in azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced CRC mice through 16 S rRNA sequencing. Our results indicated that treatment with SND extract could ameliorate the tumors' malignant degree by decreasing tumor number and size. Also, the expression levels of Cyclooxygenase 2 and Mucin-2, which are typical CRC biomarkers, were reduced compared to the CRC group. In the meantime, SND extract can upregulate CD8+ T lymphocytes' expression and Occludin in the colonic mucosal layer. Besides, SND inhibited the expression of CD4+ T cells and inflammatory cytokines in CRC tissue. According to bioinformatics analysis, SND extract was also suggested could modulate the gut microbial community. After the SND treatment, compared with the CRC mice model, the number of pathogenic bacteria showed a significant reduction, including Bacteroides fragilis and Sulphate-reducing bacteria; and SND increased the relative contents of the beneficial bacteria, including Lactobacillus, Bacillus coagulans, Akkermansia muciniphila, and Bifidobacterium. In summary, SND can effectively intervene in colorectal cancer development by regulating intestinal immunity, protecting the colonic mucosal barrier, and SND can change the intestinal microbiota composition in mice.

Capsule networks (CapsNets), a new class of deep neural network architectures proposed recently by Hinton et al., have shown a great performance in many fields, particularly in image recognition and natural language processing. However, CapsNets have not yet been applied to drug discovery-related studies. As the first attempt, we in this investigation adopted CapsNets to develop classification models of hERG blockers/nonblockers; drugs with hERG blockade activity are thought to have a potential risk of cardiotoxicity. Two capsule network architectures were established: convolution-capsule network (Conv-CapsNet) and restricted Boltzmann machine-capsule networks (RBM-CapsNet), in which convolution and a restricted Boltzmann machine (RBM) were used as feature extractors, respectively. Two prediction models of hERG blockers/nonblockers were then developed by Conv-CapsNet and RBM-CapsNet with the Doddareddy's training set composed of 2,389 compounds. The established models showed excellent performance in an independent test set comprising 255 compounds, with prediction accuracies of 91.8 and 92.2% for Conv-CapsNet and RBM-CapsNet models, respectively. Various comparisons were also made between our models and those developed by other machine learning methods including deep belief network (DBN), convolutional neural network (CNN), multilayer perceptron (MLP), support vector machine (SVM), k-nearest neighbors (kNN), logistic regression (LR), and LightGBM, and with different training sets. All the results showed that the models by Conv-CapsNet and RBM-CapsNet are among the best classification models. Overall, the excellent performance of capsule networks achieved in this investigation highlights their potential in drug discovery-related studies.

Perineural invasion (PNI) has guiding significances for nerve preservation in cervical cancer, but there is no definite marker indicating PNI. Two cervical cancer cell lines (HeLa and ME-180) showed significant abilities to migrate along neurites in vitro and in vivo. Morphological observation revealed that Schwann cells (SC) arrived at the sites of cervical cancer cells before the onset of cancer metastasis. We used high-throughput antibody array to screen the signals mediating the interaction of nerve cells and cancer cells and found the high expression of CCL2 in dorsal root ganglion (DRG). Meanwhile, serum CCL2 showed a notable raise especially in cervical adenocarcinoma. SC-derived CCL2 bound to its receptor CCR2 and promoted the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of cervical cancer cells. In turn, cancer cell-derived signals triggered the expression of metalloproteinases (MMPs) including MMP2, MMP9, and MMP12 in SCs, promoting SCs to dissolve matrix. These data demonstrated that the cancer-nerve crosstalk formed a tumor microenvironment (TME) that facilitated to PNI. We identified the CCL2/CCR2 axis as a potential marker to predict the PNI and affect the nerve preservation for cervical cancer.

Recent research has revealed that uncontrolled chronic neuroinflammation is closely associated with diverse neurodegenerative diseases, by impairing blood-brain barrier (BBB) function and astrocytic reaction. Endoplasmic reticulum (ER) stress is conventionally linked to the loss of neuronal structure and function and should be widely attenuated. This notion has been questioned by recent experimental studies, which have shown that non-harmful levels of ER stress had numerous beneficial roles against neurodegeneration, including neuroprotection and inhibition of cytokine production. Here, we investigated the mild ER stress-based regulation of LPS-induced inflammatory responses in astrocytes. Primary astrocytes were exposed to tunicamycin (TM), a compound that activates ER stress, with or without the ER-stress inhibitor sodium 4-phenylbutyrate (4-PBA) before LPS treatment. Astrocytic activation, proinflammatory factor production, and the extent of ER stress were assessed. In addition, the effect of mild ER stress on astrocytes and BBB function was determined in vivo. Male Sprague-Dawley rats received intracerebroventricular injections of TM with or without intraperitoneal 4-PBA before LPS administration. The levels of astrocytic activation and BBB permeability were measured after treatment. Our results showed that lower doses of TM resulted in a mild ER-stress response without inducing cytotoxicity and tissue toxicity. Non-toxic ER-stress preconditioning ameliorated LPS-induced overactivation and inflammatory responses in astrocytes. Moreover, pre-exposure to non-lethal doses of TM improved LPS-induced BBB impairment and cognitive ability dysfunction in rats. However, 4-PBA, reversed the protective effect of TM preconditioning in vitro and in vivo. We conclude that mild ER stress (“preconditioning”) can alleviate LPS-induced astrocytic activation and BBB disruption. Our findings provide a better understanding for the regulatory role of ER stress in neuroinflammation and indicate that mild ER stress might have therapeutic value for the treatment of neurodegenerative diseases.

The dermis of human skin contains large numbers of fibroblasts that are responsible for the production of the extracellular matrix (ECM) that supporting skin integrity, elasticity and wound healing. Previously, an in vivo study demonstrated that dermal fibroblasts siting in the lower dermis are capable to convert into skin adipose layer and hence fibroblast lipogenesis may vary the structure and elasticity of dermis. In the present study, Hs68 human dermal fibroblasts were utilized as an in vitro model to study the lipogenesis via using adipogenic differentiation medium (ADM). Baicalein, isolated from Scutellaria baicalensis, is one of the flavonoids to inhibit adipocyte differentiation due to high antioxidant activity in vitro. In order to develop a suitable formulation for baicalein (a poorly water-soluble drug), soybean phosphatidylcholine (SPC) was used to prepare baicalein-loaded liposomes to enhance drug bioavailability. Our results demonstrated that liposome-encapsulated baicalein protected cell viability and increased cellular uptake efficiency of Hs68 fibroblasts. Lipid accumulation, triglyceride synthesis and gene expressions of lipogenesis enzymes (FABP4 and LPL) were significantly increased in ADM-stimulated Hs68 fibroblasts but subsequently suppressed by liposome-encapsulated baicalein. In addition, ADM-induced TNF-α expression and related inflammatory factors was down-regulated by liposome-encapsulated baicalein. Through ADM-induced lipogenesis, the protein expression of elastin, type I and type III collagens increased remarkably, whereas liposome-encapsulated baicalein can down-regulate ADM-induced ECM protein synthesis. Taken together, we found that liposome-encapsulated baicalein can inhibit ADM-induced lipid accumulation and ECM formation in Hs68 fibroblasts through the suppression of lipogenesis enzymes and inflammatory responses. Liposome-encapsulated baicalein may have the potential to improve wound healing and restore skin structure after skin injury.

The brain is the most energetically demanding organ of the body, and is thus vulnerable to even modest decline in ATP generation. Multiple neurodegenerative diseases are associated with decline in mitochondrial function e.g. Alzheimer’s, Parkinson’s, multiple sclerosis and multiple neuropathies. Genetic variances in the mitochondrial genome can modify bioenergetic and respiratory phenotypes, at both the cellular and system biology levels. Mitochondrial haplotype can be a key driver of mitochondrial efficiency. Herein, we focus on the association between mitochondrial haplotype and risk of late onset Alzheimer’s disease (LOAD). Evidence for the association of mitochondrial genetic variances/haplotypes and the risk of developing late onset Alzheimer’s disease are explored and discussed. Further, we provide a conceptual framework that suggests an interaction between mitochondrial haplotypes and two demonstrated risk factors for Alzheimer’s disease, apolipoprotein E genotype and chromosomal sex. We posit herein that mitochondrial haplotype, and hence respiratory capacity, plays a key role in determining risk of late onset Alzheimer’s and other age-associated neurodegenerative diseases. Further, therapeutic design and targeting that involve mitochondrial haplotype would advance precision medicine for Alzheimer’s disease and other age related neurodegenerative diseases.

Context: Repetitive sub-concussive head impacts (RSHIs) are common in American football and result in changes to the microstructural integrity of white matter. Both docosahexaenoic acid (DHA) and eicosapentaoic acid (EPA) supplementation exerted neuroprotective effects against RSHIs in animal models and in a prior study in football players supplemented with DHA alone. Objective: Here, we present exploratory neuroimaging outcomes from a randomized controlled trial of DHA + EPA supplementation in American football players. We hypothesized that supplementation would result in less white matter integrity loss on diffusion weighted imaging over the season. Design, setting, participants: We conducted a double-blind placebo-controlled trial in 38 American football players between June 2019 and January 2020. Intervention: Participants were randomized to the treatment (2.442 g/day DHA and 1.020 g/day EPA) or placebo group for five times-per-week supplementation for 7 months. Of these, 27 participants were included in the neuroimaging data analysis (n = 16 placebo; n = 11 DHA + EPA). Exploratory outcome measures: Changes in white matter integrity were quantified using both voxelwise diffusion kurtosis scalars and deterministic tractography at baseline and end of season. Additional neuroimaging outcomes included changes in regional gray matter volume as well as intra-regional, edge-wise, and network level functional connectivity. Serum neurofilament light (NfL) provided a peripheral biomarker of axonal damage. Results: No voxel-wise between-group differences were identified on diffusion tensor metrics. Deterministic tractography using quantitative anisotropy (QA) revealed increased structural connectivity in ascending corticostriatal fibers and decreased connectivity in long association and commissural fibers in the DHA+EPA group compared to the placebo group. Serum NfL increases were correlated with increased mean (ρ = 0.47), axial (ρ = 0.44), and radial (ρ = 0.51) diffusivity and decreased QA (ρ = -0.52) in the corpus callosum and bilateral corona radiata irrespective of treatment group. DHA + EPA supplementation did preserve default mode/frontoparietal control network connectivity (g = 0.96, p = 0.024). Conclusions: These exploratory findings did not provide strong evidence that DHA + EPA prevented or protected against axonal damage as quantified via neuroimaging. Neuroprotective effects on functional connectivity were observed despite whitematter damage. Further studies with larger samples are needed to fully establish the relationship between omega-3 supplementation, RSHIs, and neuroimaging biomarkers. [ABSTRACT FROM AUTHOR]