40 Hz light flickering facilitates the glymphatic flow via adenosine signaling in mice.

The glymphatic-lymphatic system is increasingly recognized as fundamental for the homeostasis of the brain milieu since it defines cerebral spinal fluid flow in the brain parenchyma and eliminates metabolic waste. Animal and human studies have uncovered several important physiological factors regulating the glymphatic system including sleep, aquaporin-4, and hemodynamic factors. Yet, our understanding of the modulation of the glymphatic system is limited, which has hindered the development of glymphatic-based treatment for aging and neurodegenerative disorders. Here, we present the evidence from fluorescence tracing, two-photon recording, and dynamic contrast-enhanced magnetic resonance imaging analyses that 40 Hz light flickering enhanced glymphatic influx and efflux independently of anesthesia and sleep, an effect attributed to increased astrocytic aquaporin-4 polarization and enhanced vasomotion. Adenosine-A2A receptor (A2AR) signaling emerged as the neurochemical underpinning of 40 Hz flickering-induced enhancement of glymphatic flow, based on increased cerebrofluid adenosine levels, the abolishment of enhanced glymphatic flow by pharmacological or genetic inactivation of equilibrative nucleotide transporters-2 or of A2AR, and by the physical and functional A2AR-aquaporin-4 interaction in astrocytes. These findings establish 40 Hz light flickering as a novel non-invasive strategy of enhanced glymphatic flow, with translational potential to relieve brain disorders.

Novel magnetic compression technique for the treatment of postoperative anastomotic stenosis in rectal cancer: A case report.

BACKGROUND: The treatment of postoperative anastomotic stenosis after excision of rectal cancer is challenging. Endoscopic balloon dilation and radial incision are not effective in all patients. We present a new endoscopy-assisted magnetic compression technique (MCT) for the treatment of rectal anastomotic stenosis. We successfully applied this MCT to a patient who developed an anastomotic stricture after radical resection of rectal cancer. CASE SUMMARY: A 50-year-old man had undergone laparoscopic radical rectal cancer surgery at a local hospital 5 months ago. A colonoscopy performed 2 months ago indicated that the rectal anastomosis was narrow due to which ileostomy closure could not be performed. The patient came to the Magnetic Surgery Clinic of the First Affiliated Hospital of Xi'an Jiaotong University after learning that we had successfully treated patients with colorectal stenosis using MCT. We performed endoscopy-assisted magnetic compression surgery for rectal stenosis. The magnets were removed 16 d later. A follow-up colonoscopy performed after 4 months showed good anastomotic patency, following which, ileostomy closure surgery was performed. CONCLUSION: MCT is a simple, non-invasive technique for the treatment of anastomotic stricture after radical resection of rectal cancer. The technique can be widely used in clinical settings.

Strategies used to detect and mitigate system-related errors over time: A qualitative study in an Australian health district.

BACKGROUND: Electronic medical record (EMR) systems provide timely access to clinical information and have been shown to improve medication safety. However, EMRs can also create opportunities for error, including system-related errors or errors that were unlikely or not possible with the use of paper medication charts. This study aimed to determine the detection and mitigation strategies adopted by a health district in Australia to target system-related errors and to explore stakeholder views on strategies needed to curb future system-related errors from emerging. METHODS: A qualitative descriptive study design was used comprising semi-structured interviews. Data were collected from three hospitals within a health district in Sydney, Australia, between September 2020 and May 2021. Interviews were conducted with EMR users and other key stakeholders (e.g. clinical informatics team members). Participants were asked to reflect on how system-related errors changed over time, and to describe approaches taken by their organisation to detect and mitigate these errors. Thematic analysis was conducted iteratively using a general inductive approach, where codes were assigned as themes emerged from the data. RESULTS: Interviews were conducted with 25 stakeholders. Participants reported that most system-related errors were detected by front-line clinicians. Following error detection, clinicians either reported system-related errors directly to the clinical informatics team or submitted reports to the incident information management system. System-related errors were also reported to be detected via reports run within the EMR, or during organisational processes such as incident investigations or system enhancement projects. EMR redesign was the main approach described by participants for mitigating system-related errors, however other strategies, like regular user education and minimising the use of hybrid systems, were also reported. CONCLUSIONS: Initial detection of system-related errors relies heavily on front-line clinicians, however other organisational strategies that are proactive and layered can improve the systemic detection, investigation, and management of errors. Together with EMR design changes, complementary error mitigation strategies, including targeted staff education, can support safe EMR use and development.

Gut microbes on the risk of advanced adenomas.

BACKGROUND: More than 90% of colorectal cancer (CRC) arises from advanced adenomas (AA) and gut microbes are closely associated with the initiation and progression of both AA and CRC. OBJECTIVE: To analyze the characteristic microbes in AA. METHODS: Fecal samples were collected from 92 AA and 184 negative control (NC). Illumina HiSeq X sequencing platform was used for high-throughput sequencing of microbial populations. The sequencing results were annotated and compared with NCBI RefSeq database to find the microbial characteristics of AA. R-vegan package was used to analyze α diversity and ß diversity. α diversity included box diagram, and ß diversity included Principal Component Analysis (PCA), principal co-ordinates analysis (PCoA), and non-metric multidimensional scaling (NMDS). The AA risk prediction models were constructed based on six kinds of machine learning algorithms. In addition, unsupervised clustering methods were used to classify bacteria and viruses. Finally, the characteristics of bacteria and viruses in different subtypes were analyzed. RESULTS: The abundance of Prevotella sp900557255, Alistipes putredinis, and Megamonas funiformis were higher in AA, while the abundance of Lilyvirus, Felixounavirus, and Drulisvirus were also higher in AA. The Catboost based model for predicting the risk of AA has the highest accuracy (bacteria test set: 87.27%; virus test set: 83.33%). In addition, 4 subtypes (B1V1, B1V2, B2V1, and B2V2) were distinguished based on the abundance of gut bacteria and enteroviruses (EVs). Escherichia coli D, Prevotella sp900557255, CAG-180 sp000432435, Phocaeicola plebeiuA, Teseptimavirus, Svunavirus, Felixounavirus, and Jiaodavirus are the characteristic bacteria and viruses of 4 subtypes. The results of Catboost model indicated that the accuracy of prediction improved after incorporating subtypes. The accuracy of discovery sets was 100%, 96.34%, 100%, and 98.46% in 4 subtypes, respectively. CONCLUSION: Prevotella sp900557255 and Felixounavirus have high value in early warning of AA. As promising non-invasive biomarkers, gut microbes can become potential diagnostic targets for AA, and the accuracy of predicting AA can be improved by typing.

Comparison of the Medium-term Outcomes of Anterior Lumbar Discectomy and Fusion with Minimally Invasive Transforaminal Lumbar Interbody Fusion: A Retrospective Cohort Study.

OBJECTIVE: Lumbar degenerative diseases (LDDs) with huge herniation in the left lateral recess or central canal present challenges for oblique lateral lumbar interbody fusion (OLIF) or endoscope-assisted OLIF procedures. Currently, minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF) is the primary approach for this issue. This study aims to provide a standardized technical description of the anterior lumbar discectomy and fusion (ALDF) and evaluate the medium-term clinical effectiveness of both ALDF and MIS-TLIF techniques. METHODS: A retrospective review was performed on LDDs who underwent ALDF and MIS-TLIF surgery from January 2018 to January 2020. The evaluation encompassed various clinical outcomes, such as the visual analogue scale (VAS) scores for back pain and leg pain (VAS-back, VAS-leg), the Oswestry disability index (ODI), the 36-item short-form health survey mental component summary (SF-36 MCS), and the physical component summary (SF-36 PCS). Additionally, radiological parameters, including disc height (DH), segmental disk angle (SDA), lumbar lordosis (LL), and cross-sectional area (CSA), were assessed. Data including radiculopathy, estimated blood loss, operation time, time of getting out of bed, fusion rate, and complications were recorded. Student's independent samples t test and Pearson's chi-square test were used to compare the differences between groups. RESULTS: In total, 47 patients were treated by ALDF and 48 patients were treated by MIS-TLIF. The ALDF group exhibited statistically significant lower estimated blood loss and earlier time of getting out of bed compared to the MIS-TLIF group (p < 0.05). The ALDF group demonstrated lower VAS-back scores and a higher remission rate of low back pain 3 years after the surgery (p < 0.05). During the entire follow-up period, the ALDF group exhibited higher increases in DH and SDA compared to the MIS-TLIF group (p < 0.05). At 6 months, the fusion rate in the ALDF group was significantly higher than in the MIS-TLIF group (p < 0.05). The comparison revealed no statistically significant differences in complication rates between the two groups (p > 0.05). CONCLUSION: The ALDF could be considered as a viable surgical alternative for the treatment of LDDs that necessitate ventral neural direct decompression. ALDF exhibited favorable medium-term outcomes in patients with LDDs, displaying advantages in facilitating expedited recovery, enhancing radiographic outcomes, and elevating the remission rate of low back pain. Although ALDF presents slightly higher complication rates compared to MIS-TLIF, it does not adversely affect clinical outcomes.

Autocrine phosphatase PDP2 inhibits ferroptosis by dephosphorylating ACSL4 in the Luminal A Breast Cancer.

Phosphatases can dephosphorylate phosphorylated kinases, leading to their inactivation, and ferroptosis is a type of cell death. Therefore, our aim is to identify phosphatases associated with ferroptosis by analyzing the differentially expressed genes (DEGs) of the Luminal A Breast Cancer (LumABC) cohort from the Cancer Genome Atlas (TCGA). An analysis of 260 phosphatase genes from the GeneCard database revealed that out of the 28 DEGs with high expression, only the expression of pyruvate dehydrogenase phosphatase 2 (PDP2) had a significant correlation with patient survival. In addition, an analysis of DEGs using gene ontology, Kyoto Encyclopedia of Genes and Genomes and gene set enrichment analysis revealed a significant variation in the expression of ferroptosis-related genes. To further investigate this, we analyzed 34 ferroptosis-related genes from the TCGA-LumABC cohort. The expression of long-chain acyl-CoA synthetase 4 (ACSL4) was found to have the highest correlation with the expression of PDP2, and its expression was also inversely proportional to the survival rate of patients. Western blot experiments using the MCF-7 cell line showed that the phosphorylation level of ACSL4 was significantly lower in cells transfected with the HA-PDP2 plasmid, and ferroptosis was correspondingly reduced (p < 0.001), as indicated by data from flow cytometry detection of membrane-permeability cell death stained with 7-aminoactinomycin, lipid peroxidation, and Fe2+. Immunoprecipitation experiments further revealed that the phosphorylation level of ACSL4 was only significantly reduced in cells where PDP2 and ACSL4 co-precipitated. These findings suggest that PDP2 may act as a phosphatase to dephosphorylate and inhibit the activity of ACSL4, which had been phosphorylated and activated in LumABC cells. Further experiments are needed to confirm the molecular mechanism of PDP2 inhibiting ferroptosis.

Gankyrin inhibits ferroptosis through the p53/SLC7A11/GPX4 axis in triple-negative breast cancer cells.

Gankyrin is found in high levels in triple-negative breast cancer (TNBC) and has been established to form a complex with the E3 ubiquitin ligase MDM2 and p53, resulting in the degradation of p53 in hepatocarcinoma cells. Therefore, this study sought to determine whether gankyrin could inhibit ferroptosis through this mechanism in TNBC cells. The expression of gankyrin was investigated in relation to the prognosis of TNBC using bioinformatics. Co-immunoprecipitation and GST pull-down assays were then conducted to determine the presence of a gankyrin and MDM2 complex. RT-qPCR and immunoblotting were used to examine molecules related to ferroptosis, such as gankyrin, p53, MDM2, SLC7A11, and GPX4. Additionally, cell death was evaluated using flow cytometry detection of 7-AAD and a lactate dehydrogenase release assay, as well as lipid peroxide C11-BODIPY. Results showed that the expression of gankyrin is significantly higher in TNBC tissues and cell lines, and is associated with a poor prognosis for patients. Subsequent studies revealed that inhibiting gankyrin activity triggered ferroptosis in TNBC cells. Additionally, silencing gankyrin caused an increase in the expression of the p53 protein, without altering its mRNA expression. Co-immunoprecipitation and GST pull-down experiments indicated that gankyrin and MDM2 form a complex. In mouse embryonic fibroblasts lacking both MDM2 and p53, this gankyrin/MDM2 complex was observed to ubiquitinate p53, thus raising the expression of molecules inhibited by ferroptosis, such as SLC7A11 and GPX4. Furthermore, silencing gankyrin in TNBC cells disrupted the formation of the gankyrin/MDM2 complex, hindered the degradation of p53, increased SLC7A11 expression, impeded cysteine uptake, and decreased GPX4 production. Our findings suggest that TNBC cells are able to prevent cell ferroptosis through the gankyrin/p53/SLC7A11/GPX4 signaling pathway, indicating that gankyrin may be a useful biomarker for predicting TNBC prognosis or a potential therapeutic target.

Top 100 cited classical articles in sentinel lymph nodes biopsy for breast cancer.

Background: The sentinel lymph node biopsy (SLNB) takes on a critical significance in breast cancer surgery since it is the gold standard for assessing axillary lymph node (ALN) metastasis and determining whether to perform axillary lymph node dissection (ALND). A bibliometric analysis is beneficial to visualize characteristics and hotspots in the field of sentinel lymph nodes (SLNs), and it is conducive to summarizing the important themes in the field to provide more insights into SLNs and facilitate the management of SLNs. Materials and methods: Search terms relating to SLNs were aggregated and searched in the Web of Science core collection database to identify the top 100 most cited articles. Bibliometric tools were employed to identify and analyze publications for annual article volume, authors, countries, institutions, keywords, as well as hotspot topics. Results: The period was from 1998 to 2018. The total number of citations ranged from 160 to 1925. LANCET ONCOLOGY and JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION were the top two journals in which the above articles were published. Giuliano, AE was the author with the highest number of articles in this field with 15. EUROPEAN INST ONCOL is the institution with the highest number of publications, with 35 articles. Hotspots include the following 4 topics, false-negative SLNs after neoadjuvant chemotherapy; prediction of metastatic SLNs; quality of life and postoperative complications; and lymphography of SLNs. Conclusion: This study applies bibliometric tools to analyze the most influential literature, the top 100 cited articles in the field of SLNB, to provide researchers and physicians with research priorities and hotspots.

A2AR antagonist treatment for multiple sclerosis: Current progress and future prospects.

Emerging evidence suggests that both selective and non-selective Adenosine A2A receptor (A2AR) antagonists could effectively protect mice from experimental autoimmune encephalomyelitis (EAE), which is the most commonly used animal model for multiple sclerosis (MS) research. Meanwhile, the recent FDA approval of Nourianz® (istradefylline) in 2019 as an add-on treatment to levodopa in Parkinson's disease (PD) with "OFF" episodes, along with its proven clinical safety, has prompted us to explore the potential of A2AR antagonists in treating multiple sclerosis (MS) through clinical trials. However, despite promising findings in experimental autoimmune encephalomyelitis (EAE), the complex and contradictory role of A2AR signaling in EAE pathology has raised concerns about the feasibility of using A2AR antagonists as a therapeutic approach for MS. This review addresses the potential effect of A2AR antagonists on EAE/MS in both the peripheral immune system (PIS) and the central nervous system (CNS). In brief, A2AR antagonists had a moderate effect on the proliferation and inflammatory response, while exhibiting a potent anti-inflammatory effect in the CNS through their impact on microglia, astrocytes, and the endothelial cells/epithelium of the blood-brain barrier. Consequently, A2AR signaling remains an essential immunomodulator in EAE/MS, suggesting that A2AR antagonists hold promise as a drug class for treating MS.

Targeted Knockdown of Genes in the Choroid Plexus.

The choroid plexus (ChP) serves as a critical gateway for immune cell infiltration into the central nervous system (CNS) under both physiological and pathological conditions. Recent research has shown that regulating ChP activity may offer protection against CNS disorders. However, studying the biological function of the ChP without affecting other brain regions is challenging due to its delicate structure. This study presents a novel method for gene knockdown in ChP tissue using adeno-associated viruses (AAVs) or cyclization recombination enzyme (Cre) recombinase protein consisting of TAT sequence (CRE-TAT). The results demonstrate that after injecting AAV or CRE-TAT into the lateral ventricle, the fluorescence was exclusively concentrated in the ChP. Using this approach, the study successfully knocked down the adenosine A2A receptor (A2AR) in the ChP using RNA interference (RNAi) or Cre/locus of X-overP1 (Cre/LoxP) systems, and showed that this knockdown could alleviate the pathology of experimental autoimmune encephalomyelitis (EAE). This technique may have important implications for future research on the ChP's role in CNS disorders.

Mesenchymal Stem Cell Therapy for Huntington Disease: A Meta-Analysis.

Objective: Mesenchymal stem cell (MSC) therapy has been explored in Huntington disease (HD) as a potential therapeutic approach; however, a complete synthesis of these results is lacking. We conducted a meta-analysis to evaluate the effects of MSCs on HD. Method: Eligible studies published before November 2022 were screened from Embase, PubMed, Web of Science, Medline, and Cochrane in accordance with PRISMA guidelines. ClinicalTrial.gov and the World Health Organization International Clinical Trials Registry Platform were also searched for registered clinical trials. The outcomes in rodent studies evaluated included morphological changes (striatal volume and ventricular volume), motor function (rotarod test, wire hang test, grip strength test, limb-clasping test, apomorphine-induced rotation test, and neuromuscular electromyography activity), cognition (Morris water maze test), and body weight. Result: The initial search returned 362 records, of which 15 studies incorporating 346 HD rodents were eligible for meta-analysis. Larger striatal and smaller ventricular volumes were observed in MSC-treated animals compared to controls. MSCs transplanted before the occurrence of motor dysfunction rescued the motor incoordination of HD. Among different MSC sources, bone marrow mesenchymal stem cells were the most investigated cells and were effective in improving motor coordination. MSC therapy improved muscle strength, neuromuscular electromyography activity, cortex-related motor function, and striatum-related motor function, while cognition was not changed. The body weight of male HD rodents increased after MSC transplantation, while that of females was not affected. Conclusion: Meta-analysis showed a positive effect of MSCs on HD rodents overall, as reflected in morphological changes, motor coordination, muscle strength, neuromuscular electromyography activity, cortex-related motor function, and striatum-related motor function, while cognition was not changed by MSC therapy.

Lateral septum adenosine A2A receptors control stress-induced depressive-like behaviors via signaling to the hypothalamus and habenula.

Major depressive disorder ranks as a major burden of disease worldwide, yet the current antidepressant medications are limited by frequent non-responsiveness and significant side effects. The lateral septum (LS) is thought to control of depression, however, the cellular and circuit substrates are largely unknown. Here, we identified a subpopulation of LS GABAergic adenosine A2A receptors (A2AR)-positive neurons mediating depressive symptoms via direct projects to the lateral habenula (LHb) and the dorsomedial hypothalamus (DMH). Activation of A2AR in the LS augmented the spiking frequency of A2AR-positive neurons leading to a decreased activation of surrounding neurons and the bi-directional manipulation of LS-A2AR activity demonstrated that LS-A2ARs are necessary and sufficient to trigger depressive phenotypes. Thus, the optogenetic modulation (stimulation or inhibition) of LS-A2AR-positive neuronal activity or LS-A2AR-positive neurons projection terminals to the LHb or DMH, phenocopied depressive behaviors. Moreover, A2AR are upregulated in the LS in two male mouse models of repeated stress-induced depression. This identification that aberrantly increased A2AR signaling in the LS is a critical upstream regulator of repeated stress-induced depressive-like behaviors provides a neurophysiological and circuit-based justification of the antidepressant potential of A2AR antagonists, prompting their clinical translation.

The Fusion Rate of Cortical Bone Trajectory Screw Fixation and Pedicle Screw Fixations in L4-5 Interbody Fusion: A Retrospective Cohort Study.

OBJECTIVE: Although cortical bone trajectory (CBT) screw fixation has been used for several years, the number of studies on its fusion effects is limited. Furthermore, several studies report conflicting outcomes. We aimed to compare the fusion rates and clinical efficacy of CBT screw fixation and pedicle screw (PS) fixation for L4-L5 interbody fusion. METHODS: This study was a retrospective cohort control study. Patients with lumbar degenerative disease who underwent L4-L5 oblique lumbar interbody fusion (OLIF) or posterior decompression using CBT screws between February 2016 and February 2019 were included. Patients in whom PS was used were matched for age, sex, height, weight, and BMI. Record the operation time, blood loss. All enrolled patients underwent lumbar CT imaging at one-year follow-up to evaluate the fusion rate. At the two-year follow-up the visual analogue scale (VAS), Oswestry disability index (ODI), and Japanese Orthopaedic Association scores (JOA) were used to identify symptom improvement. Independent t-test was used for the comparison, and score data were analyzed using the χ2 and exact probability tests. RESULTS: A total of 144 patients with were included. All patients were followed-up postoperatively for 25-36 months (average 32.42 ± 10.55 months). Twenty-eight patients underwent OLIF and CBT screw fixation, 36 underwent OLIF and PS fixation, 32 underwent posterior decompression and CBT screw fixation, and 48 underwent posterior decompression and PS fixation. The fusion rates following CBT screw and PS fixations in OLIF were 92.86% (26/28) and 91.67% (33/36), respectively (P = 1). The fusion rates following CBT screw and PS fixations in posterior decompression were 93.75% (30/32) and 93.75% (45/48), respectively (P > 0.05). Regardless of OLIF or posterior decompression, there were no significant differences in the VAS, ODI, and JOA scores between patients treated with CBT and PS (P > 0.05). CONCLUSION: CBT screw fixation can achieve a satisfactory interbody fusion rate with a clinical efficacy similar to that of PS in patients with lumbar degenerative disease, regardless of whether OLIF or posterior decompression was performed.

Correlation between Sonographic Features and Central Neck Lymph Node Metastasis in Solitary Solid Papillary Thyroid Microcarcinoma with a Taller-Than-Wide Shape.

Purpose: This study aimed to investigate the correlation between sonographic features and central neck lymph node metastasis (CNLM) in solitary solid papillary thyroid microcarcinoma (PTMC) with a taller-than-wide shape. Methods: A total of 103 patients with solitary solid PTMC with a taller-than-wide shape on ultrasonography who underwent surgical histopathological examination were retrospectively selected. Based on the presence or absence of CNLM, patients with PTMC were divided into a CNLM (n = 45) or nonmetastatic (n = 58) group, respectively. Clinical findings and ultrasonographic features, including a suspicious thyroid capsule involvement sign (STCS, which is defined as PTMC abutment or a disrupted thyroid capsule), were compared between the two groups. Additionally, postoperative ultrasonography was performed to assess patients during the follow-up period. Results: Significant differences were observed in sex and the presence of STCS between the two groups (p < 0.05). The specificity and accuracy of the male sex for predicting CNLM were 86.21% (50/58 patients) and 64.08% (66/103 patients), respectively. The sensitivity, specificity, positive predictive value (PPV), and accuracy of STCS for predicting CNLM were 82.22% (37/45 patients), 70.69% (41/58 patients), 68.52% (37/54 patients), and 75.73% (78/103 patients), respectively. The specificity, PPV, and accuracy of the combination of sex and STCS for predicting CNLM were 96.55% (56/58 patients), 87.50% (14/16 patients), and 67.96% (70/103 patients), respectively. A total of 89 (86.4%) patients were followed up for a median of 4.6 years, with no patient having recurrence as detected on ultrasonography and pathological examination. Conclusions: STCS is a useful ultrasonographic feature for predicting CNLM in patients with solitary solid PTMC with a taller-than-wide shape, especially in male patients. Solitary solid PTMC with a taller-than-wide shape may have a good prognosis.

Circ0005654 as a new biomarker of thyroid cancer interacting with SP1 to influence the prognosis: A case-control study.

Circular RNAs (CircRNAs) have been reported to play key roles in the progression of various cancers, including thyroid cancer (TC). Transcription factor 1 (SP1) promotes the development of thyroid cancer. This study aims at investigating the expression level of Circ0005654 in combination with Transcription factor1 (SP1) in patients with TC for diagnostic and therapeutic purposes. A total of 76 patients with thyroid cancer underwent radical surgery. Intraoperatively, thyroid cancer tissues and paired adjacent tissues and the corresponding clinicopathological data were collected. The expression of SP1 and ß-catenin in thyroid cancer and adjacent tissues was determined by immunohistochemistry (IHC) while the Circ0005654 expression level was measured by semiquantitative real-time polymerase chain reaction (sqRT-PCR). Then, we compared the variability of Circ0005654, SP1, and Wnt/ß-catenin expression in cancerous and adjacent tissues and determined the relationship between the correlation analysis and the clinicopathological features of the thyroid cancer patients. The diagnostic value of Circ0005654 in thyroid cancer tissues was analyzed with the help of the receiver operating characteristic (ROC) curve, counting the 3-year postoperative survival rate, and analyzing the effect of Circ0005654 and SP1 protein levels on the 3-year survival rate of the patients. sqRT-PCR showed that the expression level of Circ0005654 in thyroid cancer tissue was significantly higher than that of adjacent tissues. The area under the ROC of Circ0005654 was 0.9553, 95% confidence interval: (0.9211-0.9895) with a cutoff value of 0.7895, a sensitivity of 92.11%, and a specificity of 86.84%. The IHC results showed that the expression level of SP1, ß-catenin, and Wnt was higher in cancer tissues than in adjacent tissues; Circ0005654, SP1, Wnt/ß-catenin expression levels were associated with tumor diameter, lymph node metastasis, TNM stage, and envelope invasion (all P < .05). According to the Circ0005654 expression level in thyroid cancer tissue, the 3-year survival rate of the high expression group was 77.5% and 94.4% in the low expression group with a statistically significant difference; the 3-year survival rate of SP1 positive and negative patients was 78.6% and 100%, respectively, with the data being significantly different. Circ0005654 may serve as a potential biomarker for thyroid cancer diagnosis and may be involved in the development of thyroid cancer.

3'-epi-12ß-hydroxyfroside-mediated autophagy degradation of RIPK1/RIPK3 necrosomes leads to anergy of immunogenic cell death in triple-negative breast cancer cells.

Increasing studies have suggested that some cardiac glycosides, such as conventional digoxin (DIG) and digitoxin, can induce immunogenic cell death (ICD) in various tumors. We previously found that 3'-epi-12ß-hydroxyfroside (HyFS), a novel cardenolide compound isolated by our group, could induce cytoprotective autophagy through inactivation of the Akt/mTOR pathway. However, whether HyFS can induce ICD remains unknown. In this study, we extend our work to further investigate whether HyFS could induce both autophagy and ICD, and we investigated the relationship between autophagy and ICD in three TNBC cell lines. Unexpectedly, compared to DIG, we found that HyFS could induce complete autophagy flux but not ICD in three human triple-negative breast cancer (TNBC) cell lines and one murine TNBC model. Inhibition of HyFS-induced autophagy resulted in the production of ICD in TNBC MDA-MB-231, MDA-MB-436, and HCC38 cells. A further mechanism study showed that formation of RIPK1/RIPK3 necrosomes was necessary for ICD induction in DIG-treated TNBC cells, while HyFS treatment led to receptor-interacting serine-threonine kinase (RIPK)1/3 necrosome degradation via an autophagy process. Additionally, inhibition of HyFS-induced autophagy by the autophagy inhibitor chloroquine resulted in the reoccurrence of ICD and reversion of the tumor microenvironment, leading to more significant antitumor effects in immunocompetent mice than in immunodeficient mice. These findings indicate that HyFS-mediated autophagic degradation of RIPK1/RIPK3 necrosomes leads to inactivation of ICD in TNBC cells. Moreover, combined treatment with HyFS and an autophagy inhibitor may enhance the antitumor activities, suggesting an alternative therapeutic for TNBC treatment.

Adenosine A2A receptor controls the gateway of the choroid plexus.

The choroid plexus (CP) is one of the key gateways regulating the entry of peripheral immune cells into the CNS. However, the neuromodulatory mechanisms of maintaining its gateway activity are not fully understood. Here, we identified adenosine A2A receptor (A2AR) activity as a regulatory signal for the activity of CP gateway under physiological conditions. In association with a tightly closed CP gateway, we found that A2AR was present at low density in the CP. The RNA-seq analysis revealed that the A2AR antagonist KW6002 affected the expression of the cell adhesion molecules' (CAMs) pathway and cell response to IFN-γ in the CP. Furthermore, blocking or activating A2AR signaling in the CP resulted in a decreased and an increased, respectively, expression of lymphocyte trafficking determinants and disruption of the tight junctions (TJs). Furthermore, A2AR signaling regulates the CP permeability. Thus, A2AR activity in the CP may serve as a therapeutic target for remodeling the immune homeostasis in the CNS with implications for the treatment of neuroimmunological disorders.

Hemorrhagic, hypovolemic shock resuscitated with Ringer's solution using bicarbonate versus lactate: A CONSORT-randomized controlled study comparing patient outcomes and blood inflammatory factors.

BACKGROUND: Isotonic crystalloids are the preferred solution for the initial clinical management of patients with multiple trauma, among which lactated Ringer's solution and normal saline are the most widely used, but both have clinical limitations. Bicarbonated Ringer's solution (BRS), which provides physiological levels of bicarbonate ions and electrolyte ions, can be used to supplement missing extracellular fluid and correct metabolic acidosis. METHODS: A prospective, randomized controlled study enrolled 63 patients with traumatic hepatic rupture and hemorrhagic shock. They were randomly assigned to the Bicarbonated group (n = 33) or the Control group (n = 30), which received restrictive fluid resuscitation with sodium bicarbonate Ringer's solution or sodium lactate Ringer's solution, respectively. The levels of interleukin (IL)-6, tumor necrosis factor (TNF)-α, arterial blood lactic acid and potential of hydrogen (pH) were measured prior to, 1, 3, 24, and 72 hours following resuscitation. The primary outcomes were patient survival, shock-related complications, and comparison of the inflammatory factors. RESULTS: The incidence of complications in the Bicarbonated group was significantly lower than in the Control group (15.15% vs 40.0%; P < .05). The intensive care unit length of stay and mechanical ventilation time in the Bicarbonated group were significantly shorter than in the Control group (all P < .01). The levels of IL-6 and TNF-α in the Bicarbonated group were significantly lower 1 hour following resuscitation than prior to resuscitation (P < .01), whereas these levels in the Control group were increased following 1h of resuscitation as compared with before resuscitation (P < .01). Following resuscitation, the levels of IL-6, TNF-α and lactate in the Bicarbonated group were significantly lower than in the Control group (P < .01). Moreover, in the Bicarbonated group, the lactic acid level decreased and the pH value increased significantly following resuscitation, whereas there was no difference in lactic acid levels and pH value between pre- and 1 hour post-resuscitation in the Control group (P > .05). CONCLUSION: The shock-related complications were dramatically reduced from using BRS in these patients. Additionally, the BRS was found to better inhibit the expression of inflammatory factors in their peripheral blood and could correct acidosis.

Inhibiting uptake of extracellular vesicles derived from senescent bone marrow mesenchymal stem cells by muscle satellite cells attenuates sarcopenia.

Objective: Osteoporosis is associated with senescence of bone marrow mesenchymal stem cells (BMSCs). Extracellular vesicles derived from senescent BMSCs (BMSC-EVs) could be uptaken by muscle satellite cells (SCs). We hypothesized that inhibiting the uptake of harmful BMSC-EVs by SCs could prevent patients with osteoporosis complicated with sarcopenia. Methods: Bioinformatics analysis was used to analyze senescent SCs. Myogenic potential of SCs was measured using myogenesis assay and immunofluorescence while muscle atrophy was measured using histological evaluation. And the interaction of cluster of differentiation (CD) 81 and the membrane proteins of SCs was verified using biotin pulldown assay.. CD81-specific siRNA (si-CD81) was used to knockdown CD81 and anti-CD81 antibody (anti-CD81 Ab) was used to block CD81. Results: Differentially expressed genes in senescent SCs were enriched in muscle cell differentiation. The myogenic potential of senescent SCs was significantly decreased. Senescent BMSC-EVs impaired myogenesis of SCs. CD81 on the surface of BMSC-EVs could bind to membrane proteins of SCs. Both knockdown of CD81 and blocking CD81 prevented the uptake of senescent BMSC-EVs by SCs, thus relieving harmful effects of senescent BMSC-EVs on muscle atrophy. Conclusion: Blocking CD81 on the surface of senescent BMSC-EVs attenuates sarcopenia in aged mice, which could be useful for prevention of sarcopenia in patients with osteoporosis in clinical practice. Translational potential of this article: Inhibiting uptake of extracellular vesicles derived from senescent bone marrow mesenchymal stem cells by muscle satellite cells can prevent muscle atrophy in aged mice and has potential for application in treating sarcopenia.

Immunotherapy combining tumor and endothelium cell lysis with immune enforcement by recombinant MIP-3α Newcastle disease virus in a vessel-targeting liposome enhances antitumor immunity.

BACKGROUND: Several agents for oncolytic immunotherapy have been approved for clinical use, but monotherapy is modest for most oncolytic agents. The combination of several therapeutic strategies through recombinant and nanotechnology to engineer multifunctional oncolytic viruses for oncolytic immunotherapy is a promising strategy. METHODS: An endothelium-targeting iRGD-liposome encapsulating a recombinant Newcastle disease virus (NDV), which expresses the dendritic cell (DC) chemokine MIP-3α (iNDV3α-LP), and three control liposomes were constructed. MIP-3α, HMGB1, IgG, and ATP were detected by western blotting or ELISA. The chemotaxis of DCs was examined by Transwell chambers. The phenotypes of the immune cells were analyzed by flow cytometry. The antitumor efficiency was investigated in B16 and 4T1 tumor-bearing mice. Immunofluorescence and immunohistochemistry were used to observe the localization of liposomes, molecular expression and angiogenesis. Synergistic index was calculated using the data of tumor volume, tumor angiogenesis and tumor-infiltrating lymphocytes. RESULTS: Compared with NDV-LP, treatment with iNDV3α-LP and NDV3α-LP induced stronger virus replication and cell lysis in B16 and 4T1 tumor cells and human umbilical vein endothelial cells (HUVECs) with the best response observed following iNDV3α-LP treatment. B16 and 4T1 cells treated with iNDV3α-LP produced more damage-associated molecular pattern molecules, including secreted HMGB1, ATP, and calreticulin. Moreover, iNDV3α-LP specifically bound to αvß3-expressing 4T1 cells and HUVECs and to tumor neovasculature. Tumor growth was significantly suppressed, and survival was longer in iNDV3α-LP-treated B16-bearing and 4T1-bearing mice. A mechanism study showed that iNDV3α-LP treatment initiated the strongest tumor-specific cellular and humoral immune response. Moreover, iNDV3α-LP treatment could significantly suppress tumor angiogenesis and reverse the tumor immune suppressive microenvironment in both B16-bearing and 4T1-bearing mice. CONCLUSIONS: In this study, iNDV3α-LP had several functions, such as tumor and vessel lysis, MIP-3α immunotherapy, and binding to αvß3-expressing tumor and its neovasculature. iNDV3α-LP treatment significantly suppressed tumor angiogenesis and reversed the tumor immunosuppressive microenvironment. These findings offer a strong rationale for further clinical investigation into a combination strategy for oncolytic immunotherapy, such as the formulation iNDV3α-LP in this study.