Antibiotic prophylaxis for surgical wound infections in clean and clean-contaminated surgery: an updated systematic review and meta-analysis.

BACKGROUND: The efficacy and necessity of prophylactic antibiotics in clean and clean-contaminated surgery remains controversial. METHODS: The studies were screened and extracted using databases including PubMed, Embase, Cochrane Library, Web of Science, and Clinical Trials.gov according to predefined eligibility criteria. Randomized controlled trials (RCTs) comparing the effect of preoperative and postoperative prophylactic antibiotic use on the incidence of surgical site infections (SSIs) in patients undergoing any clean or clean-contaminated surgery. RESULTS: A total of 16,189 participants in 48 RCTs were included in the primary meta-analysis following the eligibility criteria. The pooled odds ratio (OR) for SSI with antibiotic prophylaxis versus placebo was 0.60 (95% CI: 0.53-0.68). The pooled OR among gastrointestinal, oncology, orthopedics, neurosurgery, oral, and urology surgery was 3.06 (95% CI: 1.05-8.91), 1.16 (95% CI: 0.89-1.50), 2.04 (95% CI: 1.09-3.81), 3.05 (95% CI: 1.25-7.47), 3.55 (95% CI: 1.78-7.06), and 2.26 (95% CI: 1.12-4.55), respectively. Furthermore, the summary mean difference (MD) for patients' length of hospitalization was -0.91 (95% CI: -1.61, -0.16). The results of sensitivity analyses for all combined effect sizes showed good stability. CONCLUSION: Antibiotics are both effective, safe, and necessary in preventing surgical wound infections in clean and clean-contaminated procedures, attributed to their reduction in the incidence of surgical site infections as well as the length of patient hospitalization.

Fc-Fc interactions and immune inhibitory effects of IgG4: implications for anti-PD-1 immunotherapies.

BACKGROUND: The majority of anti-programmed cell-death 1 (PD-1) monoclonal antibodies (mAbs) use S228P mutation IgG4 as the structural basis to avoid the activation of immune cells or complement. However, little attention has been paid to the Fc-Fc interactions between IgG4 and other IgG Fc fragments that could result in adverse effects. Fc-null IgG1 framework is a potential safer alternative to avoid the undesirable Fc-Fc interactions and Fc receptor binding derived effects observed with IgG4. This study provides a comprehensive evaluation of anti-PD-1 mAbs of these two frameworks. METHODS: Trastuzumab and rituximab (both IgG1), wildtype IgG1 and IgG4 were immobilized on nitrocellulose membranes, coated to microplates and biosensor chips, and bound to tumor cells as targets for Fc-Fc interactions. Wildtype IgG1 and IgG4, anti-PD-1 mAb nivolumab (IgG4 S228P), penpulimab (Fc-null IgG1), and tislelizumab (Fc-null IgG4 S228P-R409K) were assessed for their binding reactions to the immobilized IgG proteins and quantitative kinetic data were obtained. To evaluate the effects of the two anti-PD-1 mAbs on immune responses mediated by trastuzumab and rituximab in the context of combination therapy, we employed classic immune models for antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, and complement dependent cytotoxicity. Tumor-bearing mouse models, both wildtype and humanized, were used for in vivo investigation. Furthermore, we also examined the effects of IgG1 and IgG4 on diverse immune cell populations RESULTS: Experiments demonstrated that wildtype IgG4 and nivolumab bound to immobilized IgG through Fc-Fc interactions, diminishing antibody-dependent cell-mediated cytotoxicity and phagocytosis reactions. Quantitative analysis of kinetic parameters suggests that nivolumab and wildtype IgG4 exhibit comparable binding affinities to immobilized IgG1 in both non-denatured and denatured states. IgG4 exerted inhibitory effects on various immune cell types. Wildtype IgG4 and nivolumab both promoted tumor growth in wildtype mouse models. Conversely, wildtype IgG1, penpulimab, and tislelizumab did not show similar adverse effects. CONCLUSIONS: Fc-null IgG1 represents a safer choice for anti-PD-1 immunotherapies by avoiding both the adverse Fc-Fc interactions and Fc-related immune inhibitory effects of IgG4. Fc-null IgG4 S228P-R409K and Fc-null IgG1 displayed similar structural properties and benefits. This study contributes to the understanding of immunotherapy resistance and the advancement of safer immune therapies for cancer.

Ferritin Nanoparticle Delivery of the E2 Protein of Classical Swine Fever Virus Completely Protects Pigs from Lethal Challenge.

Classical swine fever (CSF), caused by the classical swine fever virus (CSFV), results in significant economic losses to the swine industry in many countries. Vaccination represents the primary strategy to control CSF and the CSFV E2 protein is known as the major protective antigen. However, the E2 protein expressed or presented by different systems elicits distinct immune responses. In this study, we established a stable CHO cell line to express the E2 protein and delivered it using self-assembled ferritin nanoparticles (NPs). Subsequently, we compared the adaptive immune responses induced by the E2-ferritin NPs and the monomeric E2 protein produced by the CHO cells or a baculovirus expression system. The results revealed that the NP-delivered E2 protein elicited higher titers of neutralizing antibodies than did the monomeric E2 protein in pigs. Importantly, only the NP-delivered E2 protein significantly induced CSFV-specific IFN-γ-secreting cells. Furthermore, all the pigs inoculated with the E2-ferritin NPs were completely protected from a lethal CSFV challenge infection. These findings demonstrate the ability of the E2-ferritin NPs to protect pigs against the lethal CSFV challenge by eliciting robust humoral and cellular immune responses.

OLFM4 promotes the progression of intestinal metaplasia through activation of the MYH9/GSK3ß/ß-catenin pathway.

BACKGROUND: Intestinal metaplasia (IM) is classified into complete intestinal metaplasia (CIM) and incomplete intestinal metaplasia (IIM). Patients diagnosed with IIM face an elevated susceptibility to the development of gastric cancer, underscoring the critical need for early screening measures. In addition to the complexities associated with diagnosis, the exact mechanisms driving the progression of gastric cancer in IIM patients remain poorly understood. OLFM4 is overexpressed in several types of tumors, including colorectal, gastric, pancreatic, and ovarian cancers, and its expression has been associated with tumor progression. METHODS: In this study, we used pathological sections from two clinical centers, biopsies of IM tissues, precancerous lesions of gastric cancer (PLGC) cell models, animal models, and organoids to explore the role of OLFM4 in IIM. RESULTS: Our results show that OLFM4 expression is highly increased in IIM, with superior diagnostic accuracy of IIM when compared to CDX2 and MUC2. OLFM4, along with MYH9, was overexpressed in IM organoids and PLGC animal models. Furthermore, OLFM4, in combination with Myosin heavy chain 9 (MYH9), accelerated the ubiquitination of GSK3ß and resulted in increased ß-catenin levels through the Wnt signaling pathway, promoting the proliferation and invasion abilities of PLGC cells. CONCLUSIONS: OLFM4 represents a novel biomarker for IIM and could be utilized as an important auxiliary means to delimit the key population for early gastric cancer screening. Finally, our study identifies cell signaling pathways involved in the progression of IM.

In vitro and in silico analyses reveal the toxicity of metolachlor to grass carp hepatocytes and the antagonism of melatonin.

Due to the widespread use of metolachlor (MET), the accumulation of MET and its metabolites in the environment has brought serious health problems to aquatic organisms. At present, the toxicity of MET on the physiological metabolism of aquatic animals mainly focused on the role of enzymes. There is still a lack of research on the molecular mechanisms of MET hepatotoxicity, especially on antagonizing MET toxicity. Therefore, this study focuses on grass carp hepatocytes (L8824 cells) closely related to toxin accumulation. By establishing a MET exposed L8824 cells model, it is determined that MET exposure induces pyrolytic inflammation of L8824 cells. Subsequent mechanistic studies found that MET exposure induces pyroptosis in L8824 cells through mitochondrial dysfunction, and siCaspase-1 inhibits the MET induced ROS production, suggesting a regulation of ROS-NLRP3- Caspase-1 pyroptotic inflammation cycling center in MET induced injury to L8824 cells. Molecular docking revealed a strong binding energy between melatonin (MT) and Caspase-1. Finally, a model of L8824 cells with MT intervention in MET exposure was established. MT can antagonize the pyroptosis induced by MET exposure in L8824 cells by targeting Caspase-1, thereby restoring mitochondrial function and inhibiting the ROS-pyroptosis cycle. This study discovered targets and mechanisms of MT regulating pyroptosis in MET exposed-L8824 cells, and the results are helpful to provide new targets for the design of MET antidotes.

Structure-guided Evolutionary Analysis of Interactome Network Rewiring at Single Residue Resolution in Yeasts.

Protein-protein interactions (PPIs) are known to rewire extensively during evolution leading to lineage-specific and species-specific changes in molecular processes. However, the detailed molecular evolutionary mechanisms underlying interactome network rewiring are not well-understood. Here, we combine high-confidence PPI data, high-resolution three-dimensional structures of protein complexes, and homology-based structural annotation transfer to construct structurally-resolved interactome networks for the two yeasts S. cerevisiae and S. pombe. We then classify PPIs according to whether they are preserved or different between the two yeast species and compare site-specific evolutionary rates of interfacial versus non-interfacial residues for these different categories of PPIs. We find that residues in PPI interfaces evolve significantly more slowly than non-interfacial residues when using lineage-specific measures of evolutionary rate, but not when using non-lineage-specific measures. Furthermore, both lineage-specific and non-lineage-specific evolutionary rate measures can distinguish interfacial residues from non-interfacial residues for preserved PPIs between the two yeasts, but only the lineage-specific measure is appropriate for rewired PPIs. Finally, both lineage-specific and non-lineage-specific evolutionary rate measures are appropriate for elucidating structural determinants of protein evolution for residues outside of PPI interfaces. Overall, our results demonstrate that unlike tertiary structures of single proteins, PPIs and PPI interfaces can be highly volatile in their evolution, thus requiring the use of lineage-specific measures when studying their evolution. These results yield insight into the evolutionary design principles of PPIs and the mechanisms by which interactions are preserved or rewired between species, improving our understanding of the molecular evolution of PPIs and PPI interfaces at the residue level.

Indomethacin Combined with Ciprofloxacin Improves the Prognosis of Mice under Severe Traumatic Infection via the PI3K/Akt Pathway in Macrophages.

The prevention and treatment strategies for traumatic infection often focus on the use of antibiotics, while eschew the combined treatment of the bacteria, their toxins, and inflammatory mediators. This might be a main reason the prognosis of wound victims has not improved. Although our previous work found that the combination of indomethacin (IND) and ciprofloxacin (CIP) could promote skin wound repair and enhance the immune function, the efficacy and safety of this strategy for severe traumatic infection-mediated complications remain unknown. Additionally, there is no study on the relevant target cells and molecular mechanisms. In this study, C57BL/6 adult male mice were modeled for severe traumatic infection, and the optimal doses of IND and CIP alone were determined. After that, the efficacy and safety of IND plus CIP in traumatic infection mice were explored. Then the differentially expressed genes of activated macrophages in this process were analysed and verified by transcriptomic methods and conventional experimental techniques. The role of a candidate signalling pathway (PI3K/Akt) in regulating macrophage function and drug combination therapy was evaluated. The results showed that IND plus CIP increased the survival rate, reduced the degree of inflammatory response, and enhanced the bacteriostatic effect in mice under traumatic infection. This combined therapy did not cause significant damage to the functions of important organs (liver, kidney, heart). In addition, IND combined with CIP induced macrophages to significantly change their expression levels of several cytokines, including interleukin (IL) -1ß, IL-6, IL-10, IL-22, IL-23A, IL-17A, IL-17F, cluster of differentiation (CD) 11b and other genes/encode proteins. Further study showed that intervention with the PI3K inhibitor LY294002 modulated the secretion function of the above-mentioned macrophages and Akt activation (phosphorylation at serine 473). IND plus CIP can regulate macrophage function through the PI3K/Akt signalling pathway and improve the prognosis of severe traumatic infected mice. This may be a new therapeutic strategy for the prevention and treatment of severe traumatic infection.

Roles of Thermosensitive Transient Receptor Channels TRPV1 and TRPM8 in Paclitaxel-Induced Peripheral Neuropathic Pain.

Paclitaxel, a microtubule-stabilizing chemotherapy drug, can cause severe paclitaxel-induced peripheral neuropathic pain (PIPNP). The roles of transient receptor potential (TRP) ion channel vanilloid 1 (TRPV1, a nociceptor and heat sensor) and melastatin 8 (TRPM8, a cold sensor) in PIPNP remain controversial. In this study, Western blotting, immunofluorescence staining, and calcium imaging revealed that the expression and functional activity of TRPV1 were upregulated in rat dorsal root ganglion (DRG) neurons in PIPNP. Behavioral assessments using the von Frey and brush tests demonstrated that mechanical hyperalgesia in PIPNP was significantly inhibited by intraperitoneal or intrathecal administration of the TRPV1 antagonist capsazepine, indicating that TRPV1 played a key role in PIPNP. Conversely, the expression of TRPM8 protein decreased and its channel activity was reduced in DRG neurons. Furthermore, activation of TRPM8 via topical application of menthol or intrathecal injection of WS-12 attenuated the mechanical pain. Mechanistically, the TRPV1 activity triggered by capsaicin (a TRPV1 agonist) was reduced after menthol application in cultured DRG neurons, especially in the paclitaxel-treated group. These findings showed that upregulation of TRPV1 and inhibition of TRPM8 are involved in the generation of PIPNP, and they suggested that inhibition of TRPV1 function in DRG neurons via activation of TRPM8 might underlie the analgesic effects of menthol.

Penpulimab, an anti-PD-1 antibody, for heavily pretreated metastatic nasopharyngeal carcinoma: a single-arm phase II study.

Penpulimab is an anti-programmed cell death-1 (PD-1) IgG1 antibody with no Fc gamma receptor (FcγR) binding activity, and thus theoretically reduced immune-related adverse events (irAEs) while maintaining efficacy. This single-arm, phase II trial conducted across 20 tertiary care centers in China enrolled adult patients with metastatic nasopharyngeal carcinoma (NPC) who had failed two or more lines of previous systemic chemotherapy. Patients received 200-mg penpulimab intravenously every 2 weeks (4 weeks per cycle) until disease progression or intolerable toxicities. The primary endpoint was objective response rate (ORR) per RECIST (version 1.1), as assessed by an independent radiological review committee. The secondary endpoints included progression-free survival (PFS) and overall survival (OS). One hundred thirty patients were enrolled and 125 were efficacy evaluable. At the data cutoff date (September 28, 2022), 1 patient achieved complete response and 34 patients attained partial response. The ORR was 28.0% (95% CI 20.3-36.7%). The response was durable, with 66.8% still in response at 9 months. Thirty-three patients (26.4%) were still on treatment. The median PFS and OS were 3.6 months (95% CI = 1.9-7.3 months) and 22.8 months (95% CI = 17.1 months to not reached), respectively. Ten (7.6%) patients experienced grade 3 or higher irAEs. Penpulimab has promising anti-tumor activities and acceptable toxicities in heavily pretreated metastatic NPC patients, supporting further clinical development as third-line treatment of metastatic NPC.

Impact of perceived value in virtual brand communities on purchase intention of domestic electric vehicles.

The consumption value seems to be insufficient to explain consumers' domestic electric vehicle purchase behaviour, especially in a highly competitive global environment. This study aims to investigate how consumer ethnocentrism and perceived interactivity influence consumption value and pro-environmental value, subsequently affecting attitude and intention. A total of 353 valid questionnaires were collected through convenience sampling in Xuzhou, China, and the partial least square (PLS) path modelling approach was performed to test the hypotheses. The results show that consumer ethnocentrism and perceived interactivity positively influence function value, emotional value, and social value; perceived interactivity also positively influences altruistic value, biospheric value, and collectivistic value. Function value, social value, and collectivistic value positively influence attitude; however, emotional value, altruistic value and biospheric value did not find a correlation with attitude. Furthermore, attitude positively influences intention to adopt domestic electric vehicles. Finally, the theoretical and practical implications, as well as limitations were discussed accordingly.

No increase of soil wind erosion with the establishment of center pivot irrigation system in Mu-Us sandy land.

Center Pivot Irrigation system (CPIs) is widely used in newly exploited arable land in sandy lands. These sandy lands are currently stable because of climate change and ecological restoration efforts since the beginning of the 21st century in northern China. The exploitation of these fixed sandy lands to arable land with CPIs may affect the soil wind erosion, yet it remains unknown. The temporal changes of CPIs and its effect on wind erosion module were analyzed and modeled from 2000 to 2020 in Mu-Us sandy land using satellite images and Revised Wind Erosion Equation (RWEQ). The establishment of CPIs started from 2010, boomed in 2015 and peaked in 2020. They were mainly transformed from woodland, grassland, and barren land near rivers in east and southeast, and from cropland in inter-dunes in west and southwest of Mu-Us sandy land. The temporal and spatial pattern of CPIs well aligns with the land consolidation and requisition-compensation balance policies. In most of the Mu-Us sandy land, the annual erosion module is <25 t ha-1 a-1. Despite great variation, the annual, Winter and Spring erosion module of the Mu-Us sandy land or in Otog Qian and Yuyang, the CPIs concentrated counties, all decreased during 2000-2019. Although, wind erosion module in CPIs was lower than the surrounding area, it increased in 2019 given the same climate conditions as in 2010. Our results suggest 1) the establishment of CPIs in Mu-Us sandy land greatly depends on the local policy and natural endowment, and 2) although the set-up of CPIs showed no impact on the wind erosion with CPIs accounting for <1 % of Mu-Us sandy land, post-harvest of CPIs should be carefully concerned to prevent soil wind erosion.

Comparison of Therapeutic Effects Between Conventional 2D Laparoscopy and 3D Laparoscopy in the Treatment of Colorectal Cancer: A Systematic Review and Meta-Analysis.

BACKGROUND: This study aimed to evaluate the effectiveness and safety of 2D laparoscopy vs 3D laparoscopy for the treatment of colorectal cancer. METHODS: A literature search was conducted through PubMed, Web of Science, and Embase from their inception to January 2024. Studies investigating different outcomes of colorectal surgery were included. Results are presented as odds ratios (ORs) or mean differences (MDs) with 95% confidence intervals (CIs). The protocol for this review has been registered on PROSPERO (CRD42024504902). RESULTS: A total of 10 publications were retrieved in this article. The 3D group is associated with a significant improvement in intraoperative blood loss (MD = -8.04, 95% CI = -14.18 to -1.89, P = 0.01, I2 = 55%), operative time (MD = -17.33, 95% CI = -29.15 to -5.51, P = 0.004, I2 = 90%), and postoperative hospital stay (MD = -0.23, 95% CI = -0.43 to -0.04, P = 0.02, I2 = 48%) compared to that of patients treated in the 2D group, particularly for rectal cancer patients above three results (MD = -10.36, 95% CI = -15.00 to -5.73, P < 0.001, I2 = 0%), (MD = -18.85, 95% CI = -34.88 to -2.82, P = 0.02, I2 = 57%), and (MD = -0.93, 95% CI = -1.53 to -0.34, P = 0.002, I2 = 0%), respectively. There was no significant statistical difference in the time of pass flatus (MD = -0.14, 95% CI = -0.49 to 0.21, P = 0.44, I2 = 79%) and the number of dissected lymph nodes (MD = 0.36, 95% CI = -0.49 to 1.21, P = 0.41, I2 = 45%), but the 3D group had an earlier postoperative pass flatus for rectal cancer patients (MD = -0.46, 95% CI = -0.66 to -0.27, P<0.001, I2 = 0%) and the more number of dissected lymph nodes for colon cancer patients (MD = 1.54, 95% CI = 0.05 to 3.03, P = 0.04, I2 = 69%) than the 2D group. There was no significant difference in postoperative overall complication (OR = 0.94, 95% CI = 0.67 to 1.31, P = 0.71, I2 = 0%) and anastomotic leakage (OR = 0.93, 95% CI = 0.48 to 1.80, P = 0.83, I2 = 0%) in the two groups, regardless of rectal cancer and colon surgery patients. CONCLUSION: This meta-analysis demonstrates that 3D laparoscopy could reduce the amount of blood loss, accelerate postoperative pass flatus, and shorten the operation time and postoperative hospital stay over 2D for radical rectal cancer surgery, without obvious advantage for radical colon cancer surgery. Moreover, 3D laparoscopy increases the number of dissected lymph nodes for radical colon cancer surgery but may not be observed in rectal cancer surgery.

Deep profiling of plasmalogens by coupling the Paternò-Büchi derivatization with tandem mass spectrometry.

Plasmalogens are a special class of glycerophospholipids characterized by a vinyl ether bond (-C = C-O-) at the sn-1 position of the glycerol backbone. Altered plasmalogen profiles have been observed in neurodegenerative diseases and cancers. Profiling of plasmalogens requires specifying the vinyl ether bond and differentiating them from various types of isobars and isomers. Herein, by coupling C = C derivatization via offline Paternò-Büchi reaction with liquid chromatography-tandem mass spectrometry, we have developed a sensitive workflow for analysis of plasmalogens from biological samples. Using bovine heart lipid extract as a model system, we profiled more than 100 distinct structures of plasmenylethanolamines (PE-Ps) and plasmenylcholines (PC-Ps) at the C = C location level, far exceeding previous reports. Analysis of human glioma and normal brain tissue samples revealed elevated n-10 C = C isomers of PE-Ps in the glioma tissue samples. These findings suggest that the developed workflow holds potential in aiding the study of altered metabolism of plasmalogens in clinical samples.

A Strong Supramolecular Mechanophore with Controlled Mechanical Strength.

Supramolecular mechanophores typically exhibit much lower mechanical strengths than covalent counterparts, with strengths usually around 100 pN, which is significantly lower than the nN-scale strength of covalent bonds. Inspired by the slow dissociation kinetics of the cucurbit[7]uril (CB[7])-hexanoate-isoquinoline (HIQ) complex, we discovered that charge-dipole repulsion can be utilized to create strong supramolecular mechanophores. When activated at its -COO- state, the CB[7]-HIQ complex exhibits a high mechanical strength of ~700 pN, comparable to weak covalent bonds such as Au-S bonds or a thiol-maleimide adducts. The strength of the CB[7]-HIQ complex can also be tuned with pH in a gradual manner, with a minimum value of ~150 pN at its -COOH state, similar to an ordinary supramolecular conjugate. This research may pave the way for the development of supramolecular architectures that combine the advantages of covalent and supramolecular systems.

Hydrogen-rich saline upregulates the Sirt1/NF-κB signaling pathway and reduces vascular endothelial glycocalyx shedding in sepsis-induced acute kidney injury.

ABSTRACT: Sepsis causes dysfunction in different organs, but the pathophysiological mechanisms behind it are similar and mainly involve complex haemodynamic and cellular dysfunction. The importance of microcirculatory dysfunction in sepsis is becoming increasingly evident, in which endothelial dysfunction and glycocalyx degradation play a major role. This study aimed to investigate the effects of hydrogen-rich saline (HRS) on renal microcirculation in septic renal failure, and whether Sirt1 was involved in the renoprotective effects of HRS. Rats model of sepsis was established by cecal ligation and puncture, and septic rats were intraperitoneal injected with HRS (10 ml/kg). We found that in sepsis, the degree of glycocalyx shedding was directly proportional to the severity of sepsis. The seven-day survival rate of rats in the HRS + CLP group (70%) was higher than that of the CLP group (30%). HRS improved acidosis and renal function and reduced the release of inflammatory factors (TNF, IL-1ßand IL-6). The endothelial glycocalyx of capillaries in the HRS + CLP group (115 nm) was observed to be significantly thicker than that in the CLP group (44 nm) and EX527 (67.2 nm) groups by electron microscopy, and fewer glycocalyx metabolites (SDC-1, HS, HA, and MMP9) were found in the blood. Compared with the CLP group, HRS reduced renal apoptosis and upregulated Sirt1 expression, and inhibited the NF-κB/MMP9 signalling pathway. In addition, HRS did not damage immune function in septic rats as well. Generally speaking, our results suggest that HRS can alleviate the inflammatory response, inhibit glycocalyx shedding, improve septic kidney injury, and enhance survival rate.

Research progress on astrocyte-derived extracellular vesicles in the pathogenesis and treatment of neurodegenerative diseases.

Neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD), pose significant global health risks and represent a substantial public health concern in the contemporary era. A primary factor in the pathophysiology of these disorders is aberrant accumulation and aggregation of pathogenic proteins within the brain and spinal cord. Recent investigations have identified extracellular vesicles (EVs) in the central nervous system (CNS) as potential carriers for intercellular transport of misfolded proteins associated with neurodegenerative diseases. EVs are involved in pathological processes that contribute to various brain disorders including neurodegenerative disorders. Proteins linked to neurodegenerative disorders are secreted and distributed from cell to cell via EVs, serving as a mechanism for direct intercellular communication through the transfer of biomolecules. Astrocytes, as active participants in CNS intercellular communication, release astrocyte-derived extracellular vesicles (ADEVs) that are capable of interacting with diverse target cells. This review primarily focuses on the involvement of ADEVs in the development of neurological disorders and explores their potential dual roles - both advantageous and disadvantageous in the context of neurological disorders. Furthermore, this review examines the current studies investigating ADEVs as potential biomarkers for the diagnosis and treatment of neurodegenerative diseases. The prospects and challenges associated with the application of ADEVs in clinical settings were also comprehensively reviewed.

The molecular signature and prognosis of glioma with preoperative intratumoral hemorrhage: a retrospective cohort analysis.

BACKGROUND: Intratumoral hemorrhage, though less common, could be the first clinical manifestation of glioma and is detectable via MRI; however, its exact impacts on patient outcomes remain unclear and controversial. The 2021 WHO CNS 5 classification emphasised genetic and molecular features, initiating the necessity to establish the correlation between hemorrhage and molecular alterations. This study aims to determine the prevalence of intratumoral hemorrhage in glioma subtypes and identify associated molecular and clinical characteristics to improve patient management. METHODS: Integrated clinical data and imaging studies of patients who underwent surgery at the Department of Neurosurgery at Peking Union Medical College Hospital from January 2011 to January 2022 with pathological confirmation of glioma were retrospectively reviewed. Patients were divided into hemorrhage and non-hemorrhage groups based on preoperative magnetic resonance imaging. A comparison and survival analysis were conducted with the two groups. In terms of subgroup analysis, we classified patients into astrocytoma, IDH-mutant; oligodendroglioma, IDH-mutant, 1p/19q-codeleted; glioblastoma, IDH-wildtype; pediatric-type gliomas; or circumscribed glioma using integrated histological and molecular characteristics, according to WHO CNS 5 classifications. RESULTS: 457 patients were enrolled in the analysis, including 67 (14.7%) patients with intratumoral hemorrhage. The hemorrhage group was significantly older and had worse preoperative Karnofsky performance scores. The hemorrhage group had a higher occurrence of neurological impairment and a higher Ki-67 index. Molecular analysis indicated that CDKN2B, KMT5B, and PIK3CA alteration occurred more in the hemorrhage group (CDKN2B, 84.4% vs. 62.2%, p = 0.029; KMT5B, 25.0% vs. 8.9%, p = 0.029; and PIK3CA, 81.3% vs. 58.5%, p = 0.029). Survival analysis showed significantly worse prognoses for the hemorrhage group (hemorrhage 18.4 months vs. non-hemorrhage 39.1 months, p = 0.01). In subgroup analysis, the multivariate analysis showed that intra-tumoral hemorrhage is an independent risk factor only in glioblastoma, IDH-wildtype (162 cases of 457 overall, HR = 1.72, p = 0.026), but not in other types of gliomas. The molecular alteration of CDK6 (hemorrhage group p = 0.004, non-hemorrhage group p < 0.001), EGFR (hemorrhage group p = 0.003, non-hemorrhage group p = 0.001), and FGFR2 (hemorrhage group p = 0.007, non-hemorrhage group p = 0.001) was associated with shorter overall survival time in both hemorrhage and non-hemorrhage groups. CONCLUSIONS: Glioma patients with preoperative intratumoral hemorrhage had unfavorable prognoses compared to their nonhemorrhage counterparts. CDKN2B, KMT5B, and PIK3CA alterations were associated with an increased occurrence of intratumoral hemorrhage, which might be future targets for further investigation of intratumoral hemorrhage.