Search

Abstract Objective To examine the role of animal models in tumor research, the ethical issues surrounding their use, and the potential of artificial intelligence technology in improving animal welfare and addressing ethical concerns. Methods This paper reviews the role of animal models in cancer research and considers the ethical issues surrounding their use. The various types and applications of animal models used in cancer research, as well as the controversy surrounding the use of experimental animals and the potential and feasibility of AI in improving animal welfare and addressing ethical issues, were examined in detail. Results Tumor animal models are a valuable research tool for advancing our understanding of tumor formation and for evaluating the efficacy of therapeutic approaches. The implementation of AI has the potential to diminish or supplant the necessity for animal experimentation, enhance the precision and credibility of research outcomes, and address ethical concerns. Conclusion Animal models are very important in tumor research, and they should be combined with the development of science and technology to improve animal welfare and relieve ethical pressure.

Abstract Microfluidic-engineered hydrogel microspheres have emerged as a promising avenue for advancements in tissue engineering and regenerative medicine, particularly through the precise manipulation of fluids to achieve personalized composite biomaterials. In this study, we employed microfluidic technology to fabricate hydrogel microspheres (HMs) using Chinese herbal Bletilla striata polysaccharide (BSP) as the primary material. Concurrently, the natural active ingredient 20(S)-protopanaxadiol (PPD) was encapsulated within the HMs in the form of liposomes (PPD-Lipo), resulting in the formation of nanocomposite hydrogel microspheres (PPD-Lipo@HMs) intended for diabetic wound tissue repair. PPD-Lipo@HMs are characterized by the expansive specific surface area, adjustable mechanical properties, and exceptional biocompatibility. PPD-Lipo@HMs can stimulate the production of vascular endothelial factors, which in turn enhances the migration of endothelial cells, the creation of tubes, angiogenesis, and tissue repair. Moreover, the PPD-Lipo@HMs accumulation produces a microsphere scaffold that effectively covers damaged tissues, promoting the attachment, spread, and multiplication of fibroblast and endothelial cells. The polysaccharide material BSP within PPD-Lipo@HMs can modulate the immune microenvironment of the damaged tissue, reducing inflammation, encouraging re-epithelialization and granulation tissue formation, accelerating angiogenesis and collagen deposition, ultimately leading to tissue repair. The findings highlight the superior therapeutic efficacy of the microfluidic-engineered PPD-Lipo@HMs in addressing the complex challenges of diabetic wound tissue repair, thereby affirming the significant potential of microfluidic engineering technology in tissue repair applications.

Abstract Apoptotic vesicles (apoVs) play a vital role in various physiological and pathological conditions. However, we have yet to fully understand their precise biological effects in rescuing impaired mesenchymal stem cells (MSCs). Here, we proved that systemic infusion of MSCs derived from wild-type (WT) mice rather than from ovariectomized (OVX) mice effectively improved the osteopenia phenotype and rescued the impaired recipient MSCs in osteoporotic mice. Meanwhile, apoVs derived from WT MSCs (WT apoVs) instead of OVX apoVs efficiently restored the impaired biological function of OVX MSCs and their ability to improve osteoporosis. Mechanistically, the reduced miR-145a-5p expression hindered the osteogenic differentiation and immunomodulatory capacity of OVX MSCs by affecting the TGF-β/Smad 2/3-Wnt/β-catenin signaling axis, resulting in the development of osteoporosis. WT apoVs directly transferred miR-145a-5p to OVX MSCs, which were then reused to restore their impaired biological functions. The differential expression of miR-145a-5p is responsible for the distinct efficacy between the two types of apoVs. Overall, our findings unveil the remarkable potential of apoVs, as a novel nongenetic engineering approach, in rescuing the biological function and therapeutic capability of MSCs derived from patients. This discovery offers a new avenue for exploring apoVs-based stem cell engineering and expands the application scope of stem cell therapy, contributing to the maintenance of bone homeostasis through a previously unrecognized mechanism.

Abstract Background Postoperative time to extubation plays a role in prognosis after heart valve surgery; however, its exact impact has not been clarified. This study compared the postoperative outcomes of minimally invasive surgery and conventional sternotomy, focusing on early extubation and factors influencing prolonged mechanical ventilation. Methods Data from 744 patients who underwent heart valve surgery at the Zhejiang Provincial People’s Hospital between August 2019 and June 2022 were retrospectively analyzed. The outcomes in patients who underwent conventional median sternotomy (MS) and minimally invasive (MI) video-assisted thoracoscopic surgery were compared using inverse probability of treatment weighting (IPTW) and Kaplan–Meier curves. Clinical data, including surgical data, postoperative cardiac function, postoperative complications, and intensive care monitoring data, were analyzed. Results After propensity score matching and IPTW, 196 cases of conventional MS were compared with 196 cases of MI video-assisted thoracoscopic surgery. Compared to patients in the conventional MS group, those in the MI video-assisted thoracoscopic surgery group in the matched cohort had a higher early postoperative extubation rate (P

Abstract Over 50 billion cells undergo apoptosis each day in an adult human to maintain tissue homeostasis by eliminating damaged or unwanted cells. Apoptotic deficiency can lead to age-related diseases with reduced apoptotic metabolites. However, whether apoptotic metabolism regulates aging is unclear. Here, we show that aging mice and apoptosis-deficient MRL/lpr (B6.MRL-Faslpr/J) mice exhibit decreased apoptotic levels along with increased aging phenotypes in the skeletal bones, which can be rescued by the treatment with apoptosis inducer staurosporine (STS) and stem cell-derived apoptotic vesicles (apoVs). Moreover, embryonic stem cells (ESC)-apoVs can significantly reduce senescent hallmarks and mtDNA leakage to rejuvenate aging bone marrow mesenchymal stem cells (MSCs) and ameliorate senile osteoporosis when compared to MSC-apoVs. Mechanistically, ESC-apoVs use TCOF1 to upregulate mitochondrial protein transcription, resulting in FLVCR1-mediated mitochondrial functional homeostasis. Taken together, this study reveals a previously unknown role of apoptotic metabolites in ameliorating bone aging phenotypes and the unique role of TCOF1/FLVCR1 in maintaining mitochondrial homeostasis.

Introduction Elderly stable chronic obstructive pulmonary disease (COPD) patients frequently experience walking dysfunction. Research indicates that balance training holds promise for enhancing walking stability in these individuals, whereas respiratory therapy (RT) can enhance walking endurance effectively. However, existing balance training regimens tailored for COPD are intricate and lack specificity, and the impact of combined RT on patients’ walking function remains uncertain. This study aims to assess the influence of core training (CT) integrated with RT on walking function among elderly stable COPD patients.Methods and analysis This randomised, assessment-blinded, routine rehabilitation-controlled trial will be carried out at the Department of Respiratory and Critical Care Rehabilitation, the Second Rehabilitation Hospital of Shanghai. A total of 42 elderly patients diagnosed with stable COPD will be randomly allocated to either the study group (SG) or the control group in a 1:1 ratio. Both groups will undergo 6 weeks of standard rehabilitation training. Additionally, patients in the SG will receive CT based on RT. The primary outcome of the study is the 6 min walk test. Secondary outcomes encompass ultrasound indicators of the diaphragm and multifidus, pulmonary function tests, Berg balance scale test, trunk impairment scale test, COPD assessment test and St. George’s Respiratory Questionnaire.Ethics and dissemination Ethical approval was obtained from the Ethics Committee of the Second Rehabilitation Hospital of Shanghai (2023-01-01, see online supplemental file 1). All patients will provide written informed consent before participation. The results of the trial are intended for publication in a peer-reviewed journal.Trial registration number ChiCTR2400080276.

Abstract Background Tuberculosis is a chronic infectious disease that endangers people’s health, and China is a country with a high burden of tuberculosis. To accelerate the progress towards ending TB, the Chinese government implemented the End TB Action Plan (2019–2022), which consists of six actions. Among the End TB Action Plan, health promotion was conducted to improve the awareness of TB knowledge among Chinese people. The purpose of this study is to evaluate the effectiveness of implementing TB health promotion activities outlined in the End TB Action Plan, and to provide recommendations for future TB prevention and control plan. Methods A cross-sectional study was conducted in nine Chinese provinces in 2022. A total of 11,920 Chinese people filled out the questionnaire. Logistic regression analysis was used to explore that overall awareness of TB core information is associated with whether they received TB health education. Results The study involved 11,920 Chinese participants. The overall awareness rate of the core information of TB was 84.2%, which does not reach the 85% goal of the End TB Action Plan. The single awareness rate that TB is a chronic infectious disease and that the vast majority of TB patients can be cured were 75.3% and 76.0%. Participants who received TB health education had a higher awareness rate of TB core information. Participants who were elderly, retired or had a primary school education or below had poor awareness of the core information of TB. Participants who were elderly, lived in urban areas, were equipment operators or had a primary school education or below received less TB health education. Participants mainly received TB health education through TV (44.6%) and Internet (37.8%), preferred TV, broadcasts or movies (58.9%) and Internet advertising (54.7%). Participants preferred illustrated (46.2%) and audio-visual (44.8%) advertising materials. The common sources used to answer health-related questions on the internet were We-Medias (48.3%) and search engines (38.9%). Participants preferred to use short-form videos (66.8%) and illustrations (53.1%) to answer health-related questions. Conclusions Health promotion action for TB had a positive effect in China, but the awareness of TB was inadequate among Chinese people, and it is necessary to strengthen TB health education for those people. Moreover, TB prevention and control institutions should advertise TB more in audio-visual and illustrated forms on the Internet and audio-visual media. Health-related questions should be published in short-form video and illustrated forms in the We-Media and search engine more.

Abstract Background Pilomatricoma (PM) is a cutaneous benign neoplasm derived from the hair matrix. It clinically presents as a solitary and firm nodule overlying normal epidermis and is usually not easy to be noticed at early stage. Nevertheless, when special bullous lesion occurs in a short time or even ulcerates, preoperative diagnosis by a dermatologist is often challenging especially when the pediatric patients refuse biopsy. Case presentation We present six bullous PM cases and particularly conduct correlation analysis on the dermotoscopy and histopathology detection data. The basic information, medical history, symptoms and lesion morphology results of the patients were also provided. We found that the incidence of bullous PM was higher in females than in males, and most patients were adolescents and the predilection location seem to be consistent in the vaccine injection site. The dermatoscopic features of bullous PM reported were luminous yellow structure below, with gray-blue homogeneous areas and branched capillary. The histological features were consistent with PM, and evident epidermis bullae were above the tumor with extraordinary dilation of lymphangion in the upper dermis. The patients described in this study were Chinese patients in Han population included 4 females and 2 males, coincidentally, they are almost teen-age, respectively are 5,11,17,19,21,22 year-old. Conclusions This study reported and analyzed the dermotoscopy and clinical characteristics of bullous PM, dermotoscopy may guide as a rapid and reliable technique in bullous PM diagnosis.

Abstract Mitochondrial dysfunction and oxidative stress are important mechanisms for secondary injury after traumatic brain injury (TBI), which result in progressive pathophysiological exacerbation. Although the Fibronectin type III domain-containing 5 (FNDC5) was reported to repress oxidative stress by retaining mitochondrial biogenesis and dynamics, its possible role in the secondary injury after TBI remain obscure. In present study, we observed that the level of serum irisin (the cleavage product of FNDC5) significantly correlated with the neurological outcomes of TBI patients. Knockout of FNDC5 increased the lesion volume and exacerbated apoptosis and neurological deficits after TBI in mice, while FNDC5 overexpression yielded a neuroprotective effect. Moreover, FNDC5 deficiency disrupted mitochondrial dynamics and function. Activation of Sirtuin 3 (SIRT3) alleviated FNDC5 deficiency-induced disruption of mitochondrial dynamics and bioenergetics. In neuron-specific SIRT3 knockout mice, FNDC5 failed to attenuate TBI-induced mitochondrial damage and brain injuries. Mechanically, FNDC5 deficiency led to reduced SIRT3 expression via enhanced ubiquitin degradation of transcription factor Nuclear factor erythroid 2-related factor 2 (NRF2), which contributed to the hyperacetylation and inactivation of key regulatory proteins of mitochondrial dynamics and function, including OPA1 and SOD2. Finally, engineered RVG29-conjugated nanoparticles were generated to selectively and efficiently deliver irisin to the brain of mice, which yielded a satisfactory curative effect against TBI. In conclusion, FNDC5/irisin exerts a protective role against acute brain injury by promoting SIRT3-dependent mitochondrial quality control and thus represents a potential target for neuroprotection after TBI.

Abstract Camellia reticulata Lindl., also known as Yunnan Camellia, is an important ornamental plant in China, especially for its large and stunning flowers. A comprehensive understanding of their coloration mechanisms can aid breeders in developing new cultivars and improving their ornamental value; however, it is still unclear in Yunnan Camellia, especially in mixed-color flowers. In this study, we conducted metabolic and transcriptomic comparison analyses to investigate the coloration differences in three Yunnan Camellia cultivars: C. reticulata ‘Shizitou’ (SZT), C. reticulata ‘Damanao’ (MN), and C. reticulata ‘Tongzimian’ (TZM). Our results revealed that the initial flowering stage may play a critical role in the color change of MN. Metabolome analysis demonstrated that cyanidin was the primary anthocyanin in SZT and MN’s red region, while its content was low in TZM and MN’s white region. According to the transcriptome analysis, the anthocyanins biosynthesis pathway was reconstructed in Yunnan Camellia, and the low expression of CHS was detected in TZM and MN’s white region, while ANR maintained a high expression level, which may lead to the low content of cyanidin in them. Transcription factors MYBs, bHLH, and bZIP may play a key role in regulating anthocyanin-structural genes. The co-expression analysis showed that the meristem tissue may play a crucial role in the formation of the mixed white-red color in MN. Our study enriched the genetic basis of flower coloration differences in Yunnan Camellia which will be a valuable genomic resource to understanding the biology of coloration formation and for breeding the Camellia cultivars.

Abstract Background The VHL-HIF pathway and lipid droplet accumulation are the main characteristics of clear cell renal cell carcinoma (ccRCC). However, the connection between the two features is largely unknown. Methods We used transcriptional sequencing and TCGA database analysis to identify APOL1 as a novel therapeutic target for ccRCC. The oncogenic functions of APOL1 were investigated by cell proliferation, colony formation, migration and invasion assays in ccRCC cells in vitro and xenografts derived from ccRCC cells in vivo. Oil red O staining and quantification were used to detect lipid droplets. Chromatin immunoprecipitation (ChIP) assays and luciferase reporter assays were carried out to identify HIF-2α bound to the promoter of APOL1 and lncRNA LINC02609. RNA-FISH and luciferase reporter assays were performed to determine that LncRNA LINC02609 functions as a competing endogenous RNA to regulate APOL1 expression by sponging miR-149-5p. Findings RNA-seq data revealed that HIF2α can regulate APOL1 and lncRNA LINC02609 expression. We also found that HIF-2α can bind to the promoter of APOL1 and lncRNA LINC02609 and transcriptionally regulate their expression directly. We further demonstrated that LncRNA LINC02609 functions as a competing endogenous RNA to regulate APOL1 expression by sponging miR-149-5p in ccRCC. Mechanistically, APOL1-dependent lipid storage is required for endoplasmic reticulum (ER) homeostasis and cell viability and metastasis in ccRCC. We also showed that high APOL1 expression correlated with worse clinical outcomes, and knockdown of APOL1 inhibited tumor cell lipid droplet formation, proliferation, metastasis and xenograft tumor formation abilities. Together, our studies identify that HIF2α can regulate the expression of the lipid metabolism related gene APOL1 by direct and indirect means, which are essential for ccRCC tumorigenesis. Interpretation Based on the experimental data, in ccRCC, the HIF-2α/LINC02609/APOL1 axis can regulate the expression of APOL1, thus interfering with lipid storage, promoting endoplasmic reticulum homeostasis and regulating tumor progression in ccRCC. Together, our findings provide potential biomarkers and novel therapeutic targets for future studies in ccRCC.

Meconopsis integrifolia is an endangered Tibetan medicinal plant with significant medicinal and ornamental value. Understanding its genetic diversity and structure is crucial for its sustainable utilization and effective conservation. Here, we develop a set of SSR markers based on transcriptome data to analyze the genetic diversity and structure of 185 individuals from 16 populations of M. integrifolia. The results indicate that M. integrifolia exhibits relatively high genetic diversity at the species level (the percentage of polymorphic bands PPB = 91.67%, Nei’s genetic diversity index He = 0.2989, Shannon’s information index I = 0.4514) but limited genetic variation within populations (PPB = 12.08%, He = 0.0399, I = 0.0610). The genetic differentiation among populations is relatively high (the coefficient of gene differentiation GST = 0.6902), and AMOVA analysis indicates that 63.39% of the total variation occurs among populations. This suggests that maintaining a limited number of populations is insufficient to preserve the overall diversity of M. integrifolia. Different populations are categorized into four representative subclusters, but they do not cluster strictly according to geographical distribution. Limited gene flow (Nm = 0.2244) is likely the main reason for the high differentiation among these populations. Limited seed and pollen dispersal abilities, along with habitat fragmentation, may explain the restricted gene flow among populations, highlighting the necessity of conserving as many populations in the wild as possible.

Abstract Background To construct and validate a risk assessment model for acute kidney injury (AKI) in patients with acute pancreatitis (AP) in the intensive care unit (ICU). Methods A total of 963 patients diagnosed with acute pancreatitis (AP) from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database was included. These patients were randomly divided into training set (N = 674) and validation set (N = 289) at a ratio of 7:3. Clinical characteristics were utilized to establish a nomogram for the prediction of AKI during ICU stay. These variables were selected by the least absolute shrinkage and selection operation (LASSO) regression and included in multivariate logistic regression analysis. Variables with P-values less than 0.05 were included in the final model. A nomogram was constructed based on the final model. The predicted accuracy of the nomogram was assessed by calculating the receiver operating characteristic curve (ROC) and the area under the curve (AUC). Moreover, calibration curves and Hosmer-Lemeshow goodness-of-fit test (HL test) were performed to evaluate model performance. Decision curve analysis (DCA) evaluated the clinical net benefit of the model. Results A multivariable model that included 6 variables: weight, SOFA score, white blood cell count, albumin, chronic heart failure, and sepsis. The C-index of the nomogram was 0.82, and the area under the receiver operating characteristic curve (AUC) of the training set and validation set were 0.82 (95% confidence interval:0.79–0.86) and 0.76 (95% confidence interval: 0.70–0.82), respectively. Calibration plots showed good consistency between predicted and observed outcomes in both the training and validation sets. DCA confirmed the clinical value of the model and its good impact on actual decision-making. Conclusion We identified risk factors associated with the development of AKI in patients with AP. A risk prediction model for AKI in ICU patients with AP was constructed, and improving the treatment strategy of relevant factors in the model can reduce the risk of AKI in AP patients.

Abstract Background Metastases within liver or the brain are the most common causes of mortality from lung cancer (LC). Predicting liver or brain metastases before having evidence from imaging of the tumors is challenging but important for early patient intervention. According to mounting evidence, exosomes circulating within blood may facilitate cancer spread by transporting certain proteins for target cells. Methods Using liquid chromatography–MS/MS, we investigated the plasma exosomes’ proteomic profiles derived from 42 metastatic LC patients [16 solitary liver metastasis (LM), together with 26 solitary brain metastasis (BM)] and 25 local advanced (LA) lung cancer cases without metastasis, together with five healthy controls (HC), assessing the LM and BM pathogenesis and find potential novel organ-designated proteomic biomarkers. Using ELISA assay, we verified the expression levels of three plasma exosomal protein biomarkers in 110 LC patients, including 40 solitary LM, 32 solitary BM and 38 LA, and 25 HC. Results In total, 143 and 120 differentially expressed exosome-based proteins (DEEPs) were found to be dysregulated in LM and BM of lung cancer (LM-DEEPs, BM-DEEPs), compared for LA lung cancer samples, respectively. The bioinformatics analyses indicated the heterogeneity and homogeneity in LM-DEEPs and BM-DEEPs. They were primarily engaged within proteomic triggering cascade, ECM-receptor interaction, and the collagen-containing extracellular matrix. Regarding heterogeneity, LM-DEEPs primarily consisted of proteoglycans, lipoprotein, integrin, and heat shock protein, whereas the BM-DEEPs consisted of calcium-dependent/S100 proteins. Furthermore, small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC)-plasma-stemming exosome proteomics showed heterogeneity, which helped to explain some of the differences between SCLC and NSCLC's metastatic features. We also found that SELL and MUC5B could be used as diagnostic markers of BM, while APOH, CD81, and CCT5 could help diagnose LM in LC patients. Additionally, we demonstrated in a validation cohort that MUC5B and SELL could serve as biomarkers for diagnosing BM, and APOH could be a novel potential diagnostic biomarker of LM. Conclusion We presented the comprehensive and comparative plasma-stemming exosomes’ proteomic profiles from cases of LC who had isolated liver and brain metastases for the first time. We also suggested several possible biomarkers and pathogenic pathways that might be a great starting point for future research on LC metastasis.

Objective: Immune checkpoint inhibitors (ICIs) targeting programmed cell death-1/ligand-1 (PD-1/PD-L1), cytotoxic T lymphocyte antigen-4 (CTLA-4), and lymphocyte-activation gene-3 (LAG-3) have been widely studied and applied throughout the course of cancer treatment. This study aimed to provide a comprehensive profile of ICI-associated toxicity and elucidate the toxicity patterns of ICIs across different treatment lines. Methods: In total, 155 cohorts comprising 24 539 eligible patients were included in the safety analysis. Trial name, registration number, cancer type, trial phase, clinical setting, trial design, regimen, dosing schedule, age, sex and ethnicity distributions, number of patients, number of treatment-related adverse events (trAEs), and number of treatment-related death were extracted. We defined a timeline from the neoadjuvant setting to the third-line setting. We also introduced a synthesizing principle for adverse event rates (SPAER) of immunotherapy to ensure the comparability and reliability across different treatment lines. The study protocol was registered and approved by the PROSPERO protocol review committee (CRD42021242368). Results: After excluding the neoadjuvant setting group, we observed a distinct reduction in the incidence of treatment-related adverse events (trAEs) with an advancement of the line of ICI treatment. The incidence of trAEs was negatively correlated with the line of treatment, irrespective of whether monotherapy or dual-ICI combination therapy was administered. Sensitivity analyses also confirmed the coincident negative correlations. Conclusion: In summary, using a timeline-based concept centered around treatment lines, we revealed the dynamic landscape of ICI-associated toxicity and found that patients treated with ICIs during later lines of therapy may have a lower risk of trAEs.

Abstract It is well known that DNA damage can cause apoptosis. However, whether apoptosis and its metabolites contribute to DNA repair is largely unknown. In this study, we found that apoptosis‐deficient Fasmut and Bim−/− mice show significantly elevated DNA damage and premature cellular senescence, along with a significantly reduced number of 16,000 g apoptotic vesicles (apoVs). Intravenous infusion of mesenchymal stromal cell (MSC)‐derived 16,000 g apoVs rescued the DNA damage and premature senescence in Fasmut and Bim−/− mice. Moreover, a sublethal dose of radiation exposure caused more severe DNA damage, reduced survival rate, and loss of body weight in Fasmut mice than in wild‐type mice, which can be recovered by the infusion of MSC‐apoVs. Mechanistically, we showed that apoptosis can assemble multiple nuclear DNA repair enzymes, such as the full‐length PARP1, into 16,000 g apoVs. These DNA repair components are directly transferred by 16,000 g apoVs to recipient cells, leading to the rescue of DNA damage and elimination of senescent cells. Finally, we showed that embryonic stem cell‐derived 16,000 g apoVs have superior DNA repair capacity due to containing a high level of nuclear DNA repair enzymes to rescue lethal dose‐irradiated mice. This study uncovers a previously unknown role of 16,000 g apoVs in safeguarding tissues from DNA damage and demonstrates a strategy for using stem cell‐derived apoVs to ameliorate irradiation‐induced DNA damage.

Background: Studies have been inconclusive on the risk for hemorrhage in patients with a history of aspirin use who underwent emergency external ventricular drainage (EVD)/intracranial pressure (ICP) probe placement. The aim of this study was to explore hemorrhage-related risk factors in order to reduce the risk for hemorrhage in these patients. Methods: Between July 2014 and July 2020, patients were retrospectively divided into EVD/ICP-related hemorrhage and non-hemorrhage groups. The collected data included age, gender, major diagnosis, medical history, imaging examinations, conventional coagulation test data, thromboelastography with platelet mapping (TEG-PM), surgical procedures and discharge conditions. Results: In total 94 patients, 21 in the hemorrhage group (15 males, 6 females) and 73 in the non-hemorrhage group (52 males, 21 females) were included. The majority of hemorrhages were recorded in EVD patients (19/21; 90.5%). Platelet AA pathway inhibition rate of ≥75% (sensitivity: 79.45% specificity: 52.38%) (P = 0.014) and SBP ≥125 mmHg (P = 0.006) were significantly related to hemorrhage. When the platelet AA pathway inhibition rate was ≥75% and the during-procedure SBP was ≥125 mmHg, the hemorrhage rate was significantly higher (83.3%) than with SBP 0.05). Multivariate logistic regression analysis revealed that a platelet AA pathway inhibition rate ≥75% (OR = 5.183, 95% CI: 1.683–15.960) and during-procedure SBP ≥125 mmHg (OR = 4.609, 95% CI: 1.466–14.484) were independent risk factors for EVD/ICP-related hemorrhage. Conclusion: Patients with long-term aspirin therapy, a platelet AA pathway inhibition rate ≥75% and during-procedure SBP ≥125 mmHg had a significantly higher risk of hemorrhage, which could be reduced by adjusting the SBP to

Abstract Pivotal roles of extracellular vesicles (EVs) in the pathogenesis of central nervous system (CNS) disorders including acute brain injury are increasingly acknowledged. Through the analysis of EVs packaged miRNAs in plasma samples from patients with intracerebral hemorrhage (ICH), it is discovered that the level of EVs packaged miR‐143‐3p (EVs‐miR‐143‐3p) correlates closely with perihematomal edema and neurological outcomes. Further study reveals that, upon ICH, EVs‐miR‐143‐3p is robustly secreted by astrocytes and can shuttle into brain microvascular endothelial cells (BMECs). Heightened levels of miR‐143‐3p in BMECs induce the up‐regulated expression of cell adhesion molecules (CAMs) that bind to circulating neutrophils and facilitate their transendothelial cell migration (TEM) into brain. Mechanism‐wise, miR‐143‐3p directly targets ATP6V1A, resulting in impaired lysosomal hydrolysis ability and reduced autophagic degradation of CAMs. Importantly, a VCAM‐1–targeting EVs system to selectively deliver miR‐143‐3p inhibitor to pathological BMECs is created, which shows satisfactory therapeutic effects in both ICH and traumatic brain injury (TBI) mouse models. In conclusion, the study highlights the causal role of EVs‐miR‐143‐3p in BMECs’ dysfunction in acute brain injury and demonstrates a proof of concept that engineered EVs can be devised as a potentially applicable nucleotide drug delivery system for the treatment of CNS disorders.

Acne vulgaris is a common inflammatory skin disease associated with Propionibacterium acnes (P. acnes), with serious physical and psychological effects on patients. Conventional topical use of antibiotics is not effective due to the skin barrier and oral administration can adversely affect the intestinal flora. Microneedle is a novel type of localized drug delivery system that noninvasively breaks through the stratum corneum barrier and effectively enhances the transdermal absorption of drugs. Here, Bletilla striata polysaccharide (BSP)/Hyaluronic acid (HA) loaded Epigallocatechin gallate (EGCG) was used as the microneedle body to easily penetrate the epidermis and enhance antibacterial ability. Polyvinyl alcohol (PVA) and Diatomaceous earth (DE) are used as the microneedle backing to absorb pus and bacterial debris, prevent re-infection of bacteria and promote skin healing. Compared to traditional antibiotics, the excellent skin permeability of EGCG@BSP/HA MNs studied here can improve the efficacy and solve side effects and drug resistance. In vivo studies in mice models induced by P. acnes showed that this microneedle could effectively reduce skin swelling, inhibit bacterial growth and reduce the levels of TNF-α, IL-8 and MMP-2. In summary, this study provides an ideal antimicrobial drug delivery system for the treatment of acne vulgaris.

Abstract Background Osimertinib is the first‐line treatment for patients with epidermal growth factor receptor (EGFR) mutations, but the treatment options after drug resistance are limited. Previous studies have suggested that EGFR is in an immunosuppressive tumor immune microenvironment (TIME). However, the evolution of TIME after osimertinib resistance and whether this resistance can be overcome by targeting TIME needs to be further investigated. Methods The remodeling process and mechanism of TIME during the treatment with osimertinib were studied. Results The proportion of EGFRL858R+T790M mutant tumor immune infiltrating cells was extremely low. Osimertinib treatment transiently triggered inflammatory cells, but several immunosuppressive cells infiltrated after drug resistance and formed a myeloid‐derived suppressor cell (MDSC)‐enriched TIME. The programmed cell death protein‐1 monoclonal antibody was not able to reverse the MDSC‐enriched TIME. Further analysis revealed that the activation of nuclear factor‐kappa B (NF‐κB) and mitogen‐activated protein kinase (MAPK) pathways recruited a large number of MDSCs via cytokines. Finally, MDSC secreted high levels of interleukin‐10 and arginase‐1 and created an immunosuppressive TIME. Conclusions Thus, our findings lay the foundation for the evolution of TIME in osimertinib treatment, establish the mechanism of immunosuppressive TIME after osimertinib resistance, and propose potential solutions.

Triple-negative breast cancer (TNBC) due to lack of clear target and notorious “cold” tumor microenvironment (TME) is one of the most intractable and lethal malignancies. Tuning “cold” TME into “hot” becomes an emerging therapeutic strategy to TNBC. Herewith, we report that integrin-targeting micellar gemcitabine and paclitaxel (ATN-mG/P, ATN sequence: Ac-PhScNK-NH2) cooperating with polymersomal CpG (NanoCpG) effectively “heated up” and treated TNBC. ATN-mG/P exhibited greatly boosted apoptotic activity in 4T1 cells, induced potent immunogenic cell death (ICD), and efficiently stimulated maturation of bone marrow-derived dendritic cells (BMDCs). Remarkably, in a postoperative TNBC model, ATN-mG/P combining with NanoCpG promoted strong anti-cancer immune responses, showing a greatly augmented proportion of mature DCs and CD8+ T cells while reduced immune-suppressive myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Treg), which led to complete inhibition of lung metastasis and 60% mice tumor-free. The co-delivery of gemcitabine and paclitaxel at desired ratio in combination with NanoCpG provides a unique platform for potent chemoimmunotherapy of “cold” tumors like TNBC.

This research tackles the challenge of ice-induced vibrations in fixed-bottom offshore wind turbines, particularly the risk of frequency lock-in (FLI), a critical loading condition arising from slow ice movement against structures. We introduce an innovative FLI analysis process grounded in the ductile damage–collapse (DDC) mechanism, which offers a more accurate and significantly lower probability of FLI occurrence than conventional methods. Through dynamic evaluations employing a time-domain ice load model and FLI displacement analyses, we demonstrate that FLI can lead to higher structural vibrations than those caused by continuous brittle ice crushing. A case study of a 5 MW monopile wind turbine tower utilising Abaqus confirms the necessity for incorporating FLI considerations into structural design to ensure safety and performance in ice-prone environments. Comparing the DDC mechanism with the ISO method, our study reveals that the DDC approach predicts higher displacement and acceleration values during FLI, nearly an order of magnitude greater than those induced by ice loads with a 50-year return period. The research underscores the importance of robust ice-load integration in design strategies for offshore wind turbines, especially in regions susceptible to ice. It highlights the DDC mechanism as a novel strategy for enhancing structural resilience against ice-induced hazards.

ABSTRACTObjective The currently employed red blood cell reagents have a short shelf life. Some hospitals with a small number of specimens will be unable to utilize them within the validity period, resulting in a substantial increase in the purchase price. Therefore, the method of developing long-term red blood cell reagents is a problem worthy of further study.Methods In this experiment, the type and concentration of the red blood cell reagent treatment solution were evaluated based on the red blood cell antigen concentration 24 h after treatment. In addition, the qualified glutaraldehyde/paraformaldehyde reagent was stored for six months, and five red blood cell indices were measured every month. At the same time, the detection indices of treated red blood cell reagents and untreated red blood cell reagents were compared.Results It was discovered that treated red blood cells containing 0.005% GA and 0.05% PFA were more suitable for the preservation of red blood cells than other treated concentrations, and the preservation time could reach six months. The test tube method (n = 24) and microcolumn gel card (n = 35) were used to determine the accuracy of the treated blood cells containing 0.005% glutaraldehyde +0.05% paraformaldehyde, with an accuracy of 100%.Conclusion This experiment resulted in the development of a novel reagent for treating red blood cells with glutaraldehyde/paraformaldehyde fixed solution that can effectively prolong its storage time by two to three times that of red blood cell reagents currently on the market.

Abstract Glioma is the most common type of primary malignant tumor in the central nervous system with limited treatment satisfaction. Finding new therapeutic targets has remained a major challenge. Ferroptosis is a novel and distinct type of programmed cell death, playing a regulatory role in the progression of tumors. However, the role of ferroptosis or ferroptosis-related genes (FRGs) in glioma progression has not been extensively studied. In our study, a novel ferroptosis-related prognostic model, including 7 genes, was established, in which patients classified into the high-risk group had more immuno-suppressive status and worse prognosis. Among these 7 genes, we screened solute carrier family 1 member 5 (SLC1A5), an FRG, as a possible new target for glioma treatment. Our results showed that the expression of SLC1A5 was significantly upregulated in glioblastoma tissues compared with the low-grade gliomas. In addition, SLC1A5 knockdown could significantly inhibit glioma cell proliferation and invasion, and reduce the sensitivity of ferroptosis via the GPX4-dependent pathway. Furthermore, SLC1A5 was found to be related to immune response and SLC1A5 knockdown decreased the infiltration and M2 polarization of tumor-associated macrophages. Pharmacological inhibition of SLC1A5 by V9302 was confirmed to promote the efficacy of anti-PD-1 therapy. Overall, we developed a novel prognostic model for glioma based on the seven-FRGs signature, which could apply to glioma prognostic and immune status prediction. Besides, SLC1A5 in the model could regulate the proliferation, invasion, ferroptosis and immune state in glioma, and be applied as a prognostic biomarker and potential therapeutic target for glioma.

Abstract Background Postoperative fever is one of the common complications in neurosurgery, and intracranial aseptic inflammation and infection are important risk factors. Continuous drainage of cerebrospinal fluid (CSF) via lumbar drainage (LD) is often used in the treatment of postoperative intracranial infection or aseptic inflammation. Compared with the previously reported placement of LD after the onset of meningitis symptoms, we designed this randomized controlled trial (RCT) to evaluate the effectiveness and safety of early drainage (1st day postoperation) of CSF using the preset lumbar cistern to prevent delayed fever (fever occurred after the third day postoperation) or reduce its treatment time after cerebellopontine angle (CPA) tumour surgery. Methods Patients suffering from CPA tumours and who underwent resection of the tumour with an intraoperative dura opening time > 4 h are recruited for this study. The study is a 2-arm RCT to compare the early LD group and the no early LD group. Postoperative duration and rate of delayed fever and postoperative length of stay (LOS), as the main outcomes, will be compared in the two groups. Discussion Here, we present the study design of a prospective RCT to evaluate the safety and efficacy of using preoperative preset LD to treat or reduce postoperative delayed fever. Trial registration China Clinical Trial Registry ChiCTR2100049057. Registered on July 20, 2021.

BackgroundCollege students, especially those in the lower grades, constitute the main high-risk population for tuberculosis (TB). Insufficient knowledge about TB among college students contributes to an increased risk of TB infection. In Zhejiang Province, China, limited research has been conducted recently on the awareness of TB in schools among college students. Therefore, this study aims to gain insight into TB knowledge among low-grade college students in Zhejiang Province and develop effective strategies for TB education targeted at this specific population.MethodsA cross-sectional survey was conducted between 1st and 20th May 2022 in 20 colleges in Zhejiang Province, southeastern China. The survey aimed to assess the level of TB awareness among 1st and 2nd-year college students. Chi-square tests were performed to compare the rates, while multivariate logistic regression was used to identify the factors influencing the overall awareness level of students' regarding key knowledge about TB.ResultsA total of 4,414 lower-grade students participated in the study. The total awareness rate and entire awareness rate of key TB knowledge were 81.6 and 25.3%, respectively. Participants who demonstrated a relatively poor understanding of the definition were (51.0%), curable outcomes (75.7%), and preventive measures of TB (76.1%). Female participants [adjusted odds ratio (aOR):1.44; 95% confidence interval (CI):1.25–1.65], medical students (aOR:2.00; 95%CI:1.63–2.64), had a high level of monthly expenditures (aOR:2.50; 95%CI:1.49–4.19), had prior TB health education (aOR:1.95; 95%CI:1.68–2.25) and previous exposure to TB patients (aOR:2.13; 95% CI:1.48–3.08) indicating a better level of awareness of key knowledge about TB. Among the students, 58.5% expressed their willingness to acquire TB knowledge through “broadcasting, television, films, and audiovisual materials.”ConclusionsThe total awareness rate of key knowledge among low-grade college students in Zhejiang did not meet the national requirements. To effectively prevent TB in schools, it is crucial to develop a comprehensive understanding of the disease among college students. Therefore, it is necessary to enhance TB awareness through theoretical and practical education, starting from the early semesters of college.

BackgroundGlioma is the most common primary brain tumor. Traditional treatments for glioma include surgical resection, radiotherapy, chemotherapy, and bevacizumab therapy, but their efficacies are limited. Immunotherapy provides a new direction for glioma treatment. This study aimed to summarize the knowledge structure and research hotspots of glioma immunotherapy through a bibliometric analysis.MethodPublications pertaining to glioma immunotherapy published during the period from 1st January 1990 to 27th March 2023 were downloaded from the Web of Science Core Collection (WoSCC). Bibliometric analysis and visualization were performed using the CiteSpace, VOSviewer, Online Analysis Platform of Literature Metrology, and R software. The hotspots and prospects of glioma immunotherapy research were illustrated via analyzing the countries, institutions, journals, authors, citations and keywords of eligible publications.ResultsA total of 1,929 publications pertaining to glioma immunotherapy in 502 journals were identified as of 27th March 2023, involving 9,505 authors from 1,988 institutions in 62 countries. Among them were 1,285 articles and 644 reviews. Most of publications were produced by the United States. JOURNAL OF NEURO-ONCOLOGY published the majority of publications pertaining to glioma immunotherapy. Among the authors, Lim M contributed the largest number of publications. Through analyzing keyword bursts and co-cited references, immune-checkpoint inhibitors (ICIs) were identified as the research focus and hotspot.ConclusionUsing a bibliometric analysis, this study provided the knowledge structure and research hotspots in glioma immunotherapy research during the past 33 years, with ICIs staying in the current and future hotspot. Our findings may direct the research of glioma immunotherapy in the future.

IntroductionEffective management and therapies for the motor complications of Parkinson’s disease (PD) require appropriate clinical evaluation. The Parkinson’s KinetiGraph™ (PKG) is a wearable biosensor system that can record the motion characteristics of PD objectively and remotely.ObjectiveThe study aims to investigate the value of PKG in identifying and quantitatively assessing motor complications including motor fluctuations and dyskinesia in the Chinese PD population, as well as the correlation with the clinical scale assessments.MethodsEighty-four subjects with PD were recruited and continuously wore the PKG for 7 days. Reports with 7-day output data were provided by the manufacturer, including the fluctuation scores (FS) and dyskinesia scores (DKS). Specialists in movement disorders used the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale-IV (MDS-UPDRS IV), the wearing-off questionnaire 9 (WOQ-9), and the unified dyskinesia rating scale (UDysRS) for the clinical assessment of motor complications. Spearman correlation analyses were used to evaluate the correlation between the FS and DKS recorded by the PKG and the clinical scale assessment results. Receiver operating characteristic (ROC) curves were generated to analyze the sensitivity and specificity of the FS and DKS scores in the identification of PD motor complications.ResultsThe FS was significantly positively correlated with the MDS-UPDRS IV motor fluctuation (items 4.3–4.5) scores (r = 0.645, p < 0.001). ROC curve analysis showed a maximum FS cut-off value of 7.5 to identify motor fluctuation, with a sensitivity of 74.3% and specificity of 87.8%. The DKS was significantly positively correlated with the UDysRS total score (r = 0.629, p < 0.001) and the UDysRS III score (r = 0.634, p < 0.001). ROC curve analysis showed that the maximum DKS cut-off value for the diagnosis of dyskinesia was 0.7, with a sensitivity of 83.3% and a specificity of 83.3%.ConclusionThe PKG assessment of motor complications in the PD population analyzed in this study has a significant correlation with the clinical scale assessment, high sensitivity, and high specificity. Compared with clinical evaluations, PKG can objectively, quantitatively, and remotely identify and assess motor complications in PD, providing a good objective recording for managing motor complications.

Grassland management affects soil respiration (Rs, consists of heterotrophic respiration and autotrophic respiration) through soil micro-ecological processes, such as hydrothermal, plant root, organic carbon decomposition and microbial activity. Flooding, an irregular phenomenon in grasslands, may strongly regulate the response of soil respiration and its components to grassland management, but the regulatory mechanism remains unclear. We conducted a 3-year experiment by grassland management (fencing and grazing) and flooding conditions (no flooding (NF), short-term flooding (STF) and long-term flooding (LTF)) to study their effects on Rs and its components in a meadow steppe in the Hui River basin of Hulunbuir. We found differences in the patterns of Rs and its components under grassland management and flooding conditions. In 2021–2023, the temporal trends of Rs, heterotrophic respiration (Rh) and autotrophic respiration (Ra) were generally consistent, with peaks occurring on days 190–220, and the peaks of grazing were higher than that of fencing. In NF, Rs of grazed grassland was significantly higher than that of fenced grassland in 2021–2022 (p < 0.05). In STF and LTF, there was no significant difference in Rs between fenced and grazed grassland (p > 0.05). The dependence of Rs on soil temperature (ST) decreased with increasing flooding duration, and the dependence of Rs on ST of grazed grassland was higher than fenced grassland under NF and STF, but there was no difference between fenced grassland and grazed grassland under LTF. In addition, Rh was more sensitive to ST than Ra. This may be due to the different pathways of ST effects on Rs under grazing in different flooding conditions. Our study indicates that the effect of flooding on Rs is the key to the rational use of grassland under future climate change. To reduce regional carbon emissions, we recommend grazing on flooding grassland and fencing on no-flooding grassland.

Cyclic dinucleotides (CDNs) as stimulator of interferon genes (STING) agonists capable of inducing strong antitumor innate immune response are highly promising for tumor immunotherapy. The efficacy of these CDNs is, however, reduced greatly by their fast clearance, poor cell uptake and inefficient cytosolic transportation. Here, we report that reduction-responsive biodegradable chimaeric polymersomes (CPs) markedly enhance tumor retention and cytosolic delivery of a synthetic CDN, ADU-S100, and bolster STING pathway activation in the tumor microenvironment and tumor draining lymph nodes, giving significantly better tumor repression and survival of B16F10 melanoma-bearing mice compared with free CDN control. The superiority of CPs-mediated CDN delivery is further verified in combination therapy with low-dose fractionated radiation, which brings about clearly stronger and longer-term immunotherapeutic effects and protection against tumor re-challenge. The development of nano-STING agonists that are able to overcome the delivery barriers of CDNs represents an effective strategy to potentiate cancer immunotherapy.

Abstract. Meningiomas are the most common primary intracranial neoplasm with diverse pathological types and complicated clinical manifestations. The fifth edition of the WHO Classification of Tumors of the Central Nervous System (WHO CNS5), published in 2021, introduces major changes that advance the role of molecular diagnostics in meningiomas. To follow the revision of WHO CNS5, this expert consensus statement was formed jointly by the Group of Neuro-Oncology, Society of Neurosurgery, Chinese Medical Association together with neuropathologists and evidence-based experts. The consensus provides reference points to integrate key biomarkers into stratification and clinical decision making for meningioma patients. Registration:. Practice guideline REgistration for transPAREncy (PREPARE), IPGRP-2022CN234

Intracranial hemangiopericytoma is a rare invasive tumor originating from mesenchymal fibroblasts and is prone to local recurrence and distant metastasis. This study reports a case of a 27-year-old woman who presented with severe headache, nausea and vomiting for two weeks at thirty-three weeks of gestation. Cranial magnetic resonance imaging (MRI) demonstrated a giant lesion in the bilateral parietal lobe with a size of 5.12x9.19x6.03 cm and severe edema in the surrounding brain tissue. The patient underwent four operations and 3 gamma knife radiosurgery procedures and is recovering well now. The histopathology findings showed hemangiopericytoma and STAT6 and CD34 positivity after the first and second surgeries. Because of tumor progression, the patient received gamma knife radiosurgery at 1, 3, and 4 years after the first operation. Total tumor resection was achieved in the fourth surgery. Nevertheless, the patient showed malignant transformation to from low-grade to high-grade hemangiopericytoma.

ObjectiveTraumatic brain injury (TBI) is a global social, economic, and health challenge that is associated with premature death and long-term disability. In the context of rapid development of urbanization, the analysis of TBI rate and mortality trend could provide abundant diagnosis and treatment suggestions, which helps to form future reference on public health strategies.MethodsIn this study, as one of major neurosurgical centers in China, we focused on the regime shift of TBI based on 18-year consecutive clinical data and evaluated the epidemiological features. In our current study, a total of 11,068 TBI patients were reviewed.ResultsThe major cause of TBI was road traffic injuries (44.%), while the main type of injury was cerebral contusion (n = 4,974 [44.94%]). Regarding to temporal changes, a decreasing trend in TBI incidence for patients under 44 years old was observed, while an increasing trend for those aged over 45 years was indicated. Incidences of RTI and assaults decreased, while ground level fall presented increasing incidences. The total number of deaths was 933 (8.43%), with a decreasing trend in overall mortality since 2011. Age, cause of injury, GCS at admission, Injury Severity Score, shock state at admission, trauma-related diagnoses and treatments were significantly associated with mortality. A predictive nomogram model for poor prognosis was developed based on patient's GOS scores at discharge.ConclusionsThe trends and characteristics of TBI patients changed with rapid development of urbanization in the past 18 years. Further larger studies are warranted to verify its clinical suggestions.

Crops are commonly subjected to freeze-thaw and salt stress factors simultaneously in Qinghai-Tibet Plateau. In the agricultural field, potassium fulvic acid can not only promote plant growth and increase crop yield but also enhance plant resistance to stress. In this study, the changes of osmotic adjustment substances, antioxidant enzyme activities and photosynthetic characteristics of barley seedlings under alkaline salt and freeze-thaw stress were investigated by laboratory simulation. The results showed that under single alkaline salt stress, the soluble protein content increased significantly (P < 0.05), and the malondialdehyde (MDA) content of seedlings increased by 63.1%; however, antioxidant enzymes activities and photosynthetic rate of barley seedlings decreased. Under combined stresses of alkaline salt and freeze-thaw, the soluble protein content, antioxidant enzyme activities, and photosynthetic rate of barley seedlings decreased; in contrast, the MDA content of seedlings increased. With the addition of potassium fulvic acid, the soluble protein content of seedlings increased, MDA content decreased significantly (P < 0.05), and enzyme activities tended to be stable. This study revealed that the addition of a proper amount of potassium fulvic acid could mitigate the damage of alkali salt and freeze-thaw stress on barley seedlings.

Abstract Background Pulmonary metastasis is the main cause of poor prognosis in osteosarcoma. Sialic acid-bound immunoglobulin lectin 15 (Siglec-15) has been demonstrated to be obviously correlated with pulmonary metastasis in osteosarcoma patients. However, the effect of Siglec-15 on autophagy in osteosarcoma remains unclear, while the role and mechanism of Siglec-15-related autophagy in lung metastasis also remain unknown. Methods The expression levels of Siglec-15 and Beclin-1 were detected in osteosarcoma tissues using immunohistochemistry (IHC). The effect of Siglec-15 on metastasis was investigated using Transwell, wound healing and animal experiments with osteosarcoma cells. Corresponding proteins were confirmed using Western blotting when Siglec-15 or Beclin-1 was silenced or overexpressed. Changes in autophagy and the cytoskeleton were detected using immunofluorescence and transmission electron microscopy. Results Siglec-15 and Beclin-1 expression was evaluated both in lung metastases and in patients who presented with pulmonary metastasis of osteosarcoma. Immunoprecipitation experiments revealed that Siglec-15 interacts directly with Beclin-1, an important autophagic protein. Moreover, loss of Siglec-15 distinctly inhibited autophagy and reduced Beclin-1/ATG14 expression. The decreased invasion and migration caused by Siglec-15 silencing could be reversed by Beclin-1 overexpression. Additionally, autophagy can promote the epithelial–mesenchymal transition (EMT) and affect cytoskeletal rearrangement, which was confirmed by overexpression or silencing of Beclin-1. Conclusions These findings confirmed the role of Siglec-15 in the regulation of autophagy and elaborated the relationship and mechanisms between autophagy and the metastasis of osteosarcoma cells.

Abstract Mesenchymal stem cells (MSCs) are a type of immunosuppressive stromal cell found in multiple tissues and organs. However, whether MSCs possess immunosupportive characteristics remains unclear. In this study, we showed that the lymph nodes contain immunosupportive MSCs. They produce and secrete a high level of MCP-1 to promote T-cell proliferation and differentiation, in contrast to bone marrow MSCs (BMMSCs), which repress T-cell activation. Unlike BMMSCs, lymph node MSCs (LNMSCs) fail to respond to activated T-cell-induced production of PD-L1 to induce T-cell apoptosis. Mechanistically, MCP-1 activates phospho-Erk to sustain T-cell proliferation and activation while it represses NF-κB/PD-L1 pathway to avoid induction of T-cell apoptosis. Interestingly, inflammatory lymph node-derived LNMSCs abolish their immunosupportive function due to reduction of MCP-1 expression. Finally, we show that systemic infusion of LNMSCs rescues immunosuppression in cytoxan (CTX)-treated mice. This study reveals a previously unrecognized mechanism underlying MSC-based immunoregulation using the MCP-1/PD-L1 axis to energize T cells and suggests a potential to use MSCs to treat immunosuppressive disorders.

Abstract Background Previous cluster-randomized controlled trials evaluating the impact of implementing evidence-based guidelines for nutrition therapy in critical illness do not consistently demonstrate patient benefits. A large-scale, sufficiently powered study is therefore warranted to ascertain the effects of guideline implementation on patient-centered outcomes. Methods We conducted a multicenter, cluster-randomized, parallel-controlled trial in intensive care units (ICUs) across China. We developed an evidence-based feeding guideline. ICUs randomly allocated to the guideline group formed a local "intervention team", which actively implemented the guideline using standardized educational materials, a graphical feeding protocol, and live online education outreach meetings conducted by members of the study management committee. ICUs assigned to the control group remained unaware of the guideline content. All ICUs enrolled patients who were expected to stay in the ICU longer than seven days. The primary outcome was all-cause mortality within 28 days of enrollment. Results Forty-eight ICUs were randomized to the guideline group and 49 to the control group. From March 2018 to July 2019, the guideline ICUs enrolled 1399 patients, and the control ICUs enrolled 1373 patients. Implementation of the guideline resulted in significantly earlier EN initiation (1.20 vs. 1.55 mean days to initiation of EN; difference − 0.40 [95% CI − 0.71 to − 0.09]; P = 0.01) and delayed PN initiation (1.29 vs. 0.80 mean days to start of PN; difference 1.06 [95% CI 0.44 to 1.67]; P = 0.001). There was no significant difference in 28-day mortality (14.2% vs. 15.2%; difference − 1.6% [95% CI − 4.3% to 1.2%]; P = 0.42) between groups. Conclusions In this large-scale, multicenter trial, active implementation of an evidence-based feeding guideline reduced the time to commencement of EN and overall PN use but did not translate to a reduction in mortality from critical illness. Trial registration: ISRCTN, ISRCTN12233792 . Registered November 20th, 2017.

Ischemic stroke is the most common cerebrovascular disease, and vascular obstruction is an important cause of this disease. As the main method for the management of carotid artery stenosis, carotid endarterectomy (CEA) is an effective and preventive treatment measure in ischemic cerebrovascular disease. This study aims to propose the application of a new enhanced recovery after surgery (ERAS) nutritional support regimen in CEA, which can significantly improve the perioperative nutritional status of patients. A total of 74 patients who underwent CEA were included and randomly divided into two groups: 39 patients received nutritional therapy with the ERAS protocol (ERAS group) and 35 patients received routine perioperative nutritional support (control group). Our results showed that the levels of major clinical and biochemical parameters (albumin, hemoglobin, creatinine, calcium and magnesium levels, etc.) in the ERAS group were significantly higher than those in the control group after surgery (p

Osteoarthritis (OA) is a disabling disease with significant morbidity worldwide. OA attacks the large synovial joint, including the peripheral joints and temporomandibular joint (TMJ). As a representative of peripheral joint OA, knee OA shares similar symptoms with TMJ OA. However, these two joints also display differences based on their distinct development, anatomy, and physiology. Extracellular vesicles (EVs) are phospholipid bilayer nanoparticles, including exosomes, microvesicles, and apoptotic bodies. EVs contain proteins, lipids, DNA, micro-RNA, and mRNA that regulate tissue homeostasis and cell-to-cell communication, which play an essential role in the progression and treatment of OA. They are likely to partake in mechanical response, extracellular matrix degradation, and inflammatory regulation during OA. More evidence has shown that synovial fluid and synovium-derived EVs may serve as OA biomarkers. More importantly, mesenchymal stem cell-derived EV shows a therapeutic effect on OA. However, the different function of EVs in these two joints is largely unknown based on their distinct biological characteristic. Here, we reviewed the effects of EVs in OA progression and compared the difference between the knee joint and TMJ, and summarized their potential therapeutic role in the treatment of OA.

ObjectiveLumbar cistern blockage is a common complication of continuous lumbar cistern drainage. This paper analyzes the risk factors for lumbar cistern blockage drainage due to various causes and proposes a series of prevention and intervention measures to reduce blockage or improve recanalization after blockage.MethodsThe clinical data of 637 patients with various lesions who underwent lumbar cistern drainage in our hospital were retrospectively collected and analyzed. Perioperative clinical and imaging data were assessed. Variates were analyzed using univariate and multivariate logistic regression analyses.ResultsA total of 13.7% (87/637) of patients had lumbar cistern blockage. Multivariate analysis revealed that drainage time (≥7 days), CSF volume

Objective: Study the repair effect of tilapia collagen on acute wounds, and the effect on the expression level of related genes and its metabolic direction in the repair process.Materials and methods: After the full-thickness skin defect model was constructed in standard deviation rats, the wound healing effect was observed and evaluated by means of characterization, histology, and immunohistochemistry. RT-PCR, fluorescence tracer, frozen section and other techniques were used to observe the effect of fish collagen on the expression of related genes and its metabolic direction in the process of wound repair.Results: After implantation, there was no immune rejection reaction, fish collagen fused with new collagen fibers in the early stage of wound repair, and was gradually degraded and replaced by new collagen in the later stage. It has excellent performance in inducing vascular growth, promoting collagen deposition and maturation, and re-epithelialization. The results of fluorescent tracer showed that fish collagen was decomposed, and the decomposition products were involved in the wound repair process and remained at the wound site as a part of the new tissue. RT-PCR results showed that, without affecting collagen deposition, the expression level of collagen-related genes was down-regulated due to the implantation of fish collagen.Conclusion: Fish collagen has good biocompatibility and wound repair ability. It is decomposed and utilized in the process of wound repair to form new tissues.

BackgroundThe clinical features and therapeutic measures of vestibular schwannoma (VS) radiation-related aneurysm (RRA) have not been well described. We reported the first VS RRA case admitted for acute anterior inferior cerebella artery (AICA) ischemic symptoms. Literature was reviewed to present the research fruits about VS RRAs, and some therapeutic advices were given.Materials and methodsA 54-year-old woman who had undergone GKS 10 years previously for a right VS was admitted to our hospital in 2018 because of sudden onset of severe vertigo and vomiting, accompanied with unsteady gait. During tumor resection, a dissecting aneurysm arose from the main trunk of AICA was encountered accidently within the tumor. The aneurysm was successfully treated with direct clip ligation, sparing the parent vessel. Data about this case were combined with those of other 11 radiation-related AICA aneurysm cases retrieved from the current literature. The following parameters were evaluated: Age, Sex, Diagnostic method, Location of aneurysm, Age of radiotherapy (Years)/Latency, Rupture, x-ray dosage, Type of radiotherapy, History of surgical resection of VS, Aneurysm Type, Morphology, Number, Treatment, Operative complications, Sequela, Outcome. VS RRAs mainly occurred in women (75%) with a median age of 62.5 years and were mainly located on AICA. Ruptured aneurysms accounted for 75.0% of the total cases. This paper reported the first VS case admitted with acute AICA ischemic symptoms. Cases with sacciform-like, irregular and fusiform-shaped aneurysms accounted for 50.0%, 25.0% and 25.0% of the total, respectively. After surgical treatment, 75.0% patients recovered, except for 3 patients who developed new ischemic consequence.ConclusionPatients should be informed of the risk of RRAs after receiving radiotherapy for VS. In these patients, RRAs should be suspected when subarachnoid hemorrhage or AICA ischemic symptoms occurred. Active intervention should be conducted considering the high instability and bleeding rate of VS RRAs.

The repair of wounds is essential for overcoming injuries, but the process often leads to scars, and the formation mechanism is unclear. Interestingly, Bletilla striata polysaccharide (BSP) is a procoagulant and has anti-inflammatory properties to promote wound healing, which has great research value for scarless wound healing. Herein, we developed a transdermal drug delivery system of BSP/chitosan (CS) composite bilayer dissolvable microneedles (CS-AS-BSP MNs) containing asiaticoside (AS) based on a centrifugation method with a polydimethylsiloxane mould that fulfilled the requirements of wound healing and achieved a scar-free effect. The drug release results showed that this system improved the solubility of AS and maintained the stable release of the drug for a long time. Further experiments indicated that CS-AS-BSP MNs had a good antibacterial effect and reduced the proliferation of human scar fibroblasts. The wound healing effect of CS-AS-BSP MNs was evaluated in an experimental full-thickness-wound rat model, which demonstrated that the covered wound healed completely without scars within 3 weeks. Furthermore, CS-AS-BSP MNs downregulated TGF-β1 and COL Ⅰ, which are fibrosis-related genes, to inhibit scarring. In brief, this study provides a new strategy for meeting the clinical requirements of effective scarless wound dressings.

Abstract Background Chronic subdural haematoma (CSDH) is a common condition in the elderly that often requires neurosurgical management. For small CSDH, evidence has emerged that statins may reduce haematoma volume and improve outcomes, presumably by reducing local inflammation and promoting vascular repair. We wish to extend this evidence in a study that aims to determine the efficacy and safety of atorvastatin combined with low-dose dexamethasone in patients with CSDH. Methods The second ATorvastatin On Chronic subdural Hematoma (ATOCH-II) study is a multi-centre, randomized, placebo-controlled, double-blind trial which aims to enrol 240 adult patients with a conservative therapeutic indication for CSDH, randomly allocated to standard treatment with atorvastatin 20 mg combined with low-dose dexamethasone (or matching placebos) daily for 28 days, and with 152 days of follow-up. The primary outcome is a composite good outcome defined by any reduction from baseline in haematoma volume and survival free of surgery at 28 days. Secondary outcomes include functional outcome on the modified Rankin scale (mRS) and modified Barthel Index at 28 days, surgical transition and reduction in haematoma volumes at 14, 28 and 90 days. Discussion This multi-centre clinical trial aims to provide high-quality evidence on the efficacy and safety of the combined treatment of atorvastatin and low-dose dexamethasone to reduce inflammation and enhance angiogenesis in CSDH. Trial registration ChiCTR, ChiCTR1900021659 . Registered on 3 March 2019, http://www.chictr.org.cn/showproj.aspx?proj=36157 .

IntroductionChemokine-like factor (CKLF)-like MARVEL transmembrane domain containing 6 (CMTM6) is a protein localized to the cell membrane and is known for its ability to co-localize with PD-L1 on the plasma membrane, prevent PD-L1 degradation, and maintain PD-L1 expression on the cell membrane. CMTM6 is highly expressed and plays an important role in various tumors such as oral squamous cell carcinoma (OSCC) and colorectal cancer (CRC), however, its role in Glioblastoma multiforme (GBM) is unclear.MethodsIn this paper, to investigate the role of CMTM6 in GBM, we analyzed the expression of CMTM6 in GBM, the interaction with CMTM6 and the associated genes by bioinformatics. Importantly, we analyzed the expression of CMTM6 in GBM in relation to tumor-infiltrating lymphocytes (TILs), immunoinhibitors, immunostimulators, chemokines and chemokine receptors. We further analyzed the function of CMTM6 and performed in vitro experiments to verify it. Finally, the sensitivity of CMTM6 to drugs was also analyzed and the relationship between CMTM6 and the anticancer drug Piperlonguminine (PL) was verified in vitro.ResultsThe results showed that CMTM6 was highly expressed in GBM and correlated with multiple genes. Furthermore, CMTM6 is closely related to the immune microenvironment and inflammatory response in GBM. Bioinformatic analysis of CMTM6 correlated with the function of GBM, and our experiments demonstrated that CMTM6 significantly promoted the migration of GBM cells and epithelial-mesenchymal transition (EMT), but had no significant effect on other functions. Interestingly, we found that in GBM, PL promotes the expression of CMTM6.DiscussionIn this paper, we have performed a detailed analysis and validation of the role of CMTM6 in GBM using bioinformatics analysis and in vitro experiments to demonstrate that CMTM6 may be a potential target for glioma therapy.