A facile strategy for the preparation of polylactide nano-microspheres with enhanced stereo-complexations.

Stereo-complexed polylactide (sc-PLA) nano-microspheres were separated by adding poor solvent to the poly(l-lactide) (PLLA)/poly(d-lactide) (PDLA) blend solution. The effects of different process parameters (concentration, processing method, ratio of PLLA/PDLA blend solution to poor solvent) on the microsphere particle size were investigated. The microscopic morphology, crystallinity, and thermal properties were investigated by Fourier transform infrared spectroscopy, differential scanning calorimetry, two-dimensional wide-angle X-ray diffraction, transmission electron microscopy and scanning electron microscopy. The results indicated that when the concentration reached 10 wt% and the PLLA/PDLA blend solution to poor solvent ratio was 1 : 5, the sc-PLA nano-microspheres exhibited more regular shape, good sphericity and uniform particle size, and the highest crystallinity. Additionally, the degree of crystallinity of the stereo-complexed crystals was as high as 39.60%, the rate of stereo-complexation was 99.65%, and the melting temperature reached 220 °C, indicating notable improvement in the crystallization and thermal properties. The sc-PLA nano-microspheres obtained in this research could be used as a nucleating agent for fibers and drug delivery carrier, and the sc-PLA nano-microspheres have broad application prospects in the textile and biomedical fields.

Monolithic Nitrogen-Doped Carbon Electrode with Hierarchical Porous Structure for Efficient Electrochemical CO2 Reduction.

N-doped carbon materials have garnered extensive development in electrochemical CO2 reduction due to their abundant sources, high structural plasticity, and excellent catalytic performance. However, the use of powder carbon materials for electrocatalytic reactions limits their current density and mechanical strength, which pose challenges for industrial applications. In this study, we synthesized a monolithic N-doped carbon electrode with high mechanical strength for efficient electrochemical reduction of CO2 to CO through a simple pyrolysis method, using phenolic resin as the precursor and ZIF-8 as the sacrificial template. At 900 °C, the decomposition of ZIF-8 and the volatilization of Zn atoms promote the formation of a hierarchical porous structure in the carbon matrix, characterized by macropores with extended mesoporous channels. Simultaneously, N active species derived from ZIF-8 are effectively generated around the pores and fully exposed. The efficient mass transfer facilitated by the hierarchical porous structure and high activity of exposed nitrogen species enables efficient conversion of CO2 to CO. When the ZIF-8 content is 30%, the catalyst achieves a Faradaic efficiency of 88.9% for CO at a low potential of -0.7 V (vs RHE), with a CO production rate of 244.05 µmol h-1 cm-2. After 50 h of potentiostatic electrolysis, the current density and FECO remain stable. This work not only provides a strategy for the synergistic effects of hierarchical porous structures and nitrogen doping but also offers an effective method to avoid using powder binders and prepare integrated, stable monolithic electrodes.

Study on the Metabolic Basis of the Color Formation of Two Color-Presenting Types of Jujube Fruits.

Jujube is a plant of the genus Ziziphus in the family Rhamnaceae; its fruit has high nutritional value, and it is rich in polyphenols, flavonoids, and other secondary metabolites. The color of its peel is an important indicator for evaluating the appearance of the fruit. However, the mechanism of the difference in color presentation between the seedling offspring of the 'Red Fruit' (TLHH) and the 'Green Fruit' (TLHL) of the fresh jujube cultivar 'Tailihong' is not clear. Therefore, this study used targeted metabolomics techniques to accurately and quantitatively analyze the metabolic pathways of carotenoid and anthocyanin metabolites during the ripening process of two color-presenting types of jujube fruits. Through the analysis of the dynamic changes in the pigment content of the jujube peel, it was found that 30 DAP (days after pollination), 80 DAP, and 110 DAP were the key periods for the development of the color of the peel of 'TLHL' and 'TLHH' jujube and that the substances responsible for the main differences were chlorophyll, carotenoids, and anthocyanins. Furthermore, we used an LC-MS/MS metabolic analysis to compare the differences in the carotenoids and anthocyanin metabolites between the two color-presenting types of jujube peels at the key periods of 30 DAP, 80 DAP, and 110 DAP. We detected 32 carotene metabolites and 75 anthocyanin metabolites, respectively, among which lutein had the highest content of carotenoids; it reached the maximum value (93.05 µg/g) and was higher than that of 'TLHH' (74.14 µg/g) at 30 DAP of 'TLHL'. Both showed a decreasing trend with fruit ripening. The anthocyanin with the highest content was cyanidin-3-O-(tartaryl)rhamnoside-5-O-glucoside, which reached the maximum value (258.32 µg/g) at 30 DAP of 'TLHH' and was 51.6 times that of 'TLHL'; similarly, both showed a decreasing trend with fruit ripening. These results elucidate the main metabolites of carotenoids and anthocyanins in the two types of jujube peel and their accumulation characteristics, suggesting that the key metabolites of the difference in color between 'TLHL' and 'TLHH' jujube fruits were lutein and cyanidin-3-O-(tartaryl)rhamnoside-5-O-glucoside, increasing the understanding of the color mechanism of jujube peel and providing a reference for targeted genetic breeding of jujube peel color.

Associations between sensitivity to thyroid hormones and insulin resistance in euthyroid adults with obesity.

Background: Impaired sensitivity to thyroid hormones (TH) was associated with metabolic syndrome. The study aimed to explore the association between central TH sensitivity indices and insulin resistance (IR) in euthyroid adults with obesity. Methods: This cross-sectional study enrolled 293 euthyroid outpatients with obesity in Beijing Chao-Yang Hospital. We used the thyroid feedback quantile-based index (TFQI), thyroid stimulating hormone index (TSHI), and thyrotrophic T4 resistance index (TT4RI) to indicate central TH sensitivity. IR was assessed by homeostasis model assessment of insulin resistance (HOMA-IR), hepatic insulin resistance index (hepatic-IR), the Matsuda index, and the adipose tissue insulin resistance index (Adipo-IR). Participants were categorized according to tertiles of TH sensitivity indices. We used multiple linear regressions to explore the associations. Results: There was a significant stepwise increase in HOMA-IR and Adipo-IR from the lowest to the highest tertiles of TH sensitivity indices (all P<0.05). After adjustment for age, sex, body mass index, hypertension, hyperlipidemia, and diabetes, only Adipo-IR was significantly associated with TH sensitivity indices. On average, each unit increased in TFQI, TSHI, and TT4RI was associated with 1.19 (P=0.053), 1.16 (P=0.04), and 1.01 (P=0.03) units increased in Adipo-IR, respectively. There was no significant association between TH sensitivity indices and HOMA-IR, hepatic-IR, and the Matsuda index after adjustment for other risk factors. Conclusions: Reduced central TH sensitivity was associated with increased adipose tissue insulin resistance in euthyroid adults with obesity. The results further confirmed the importance of TH sensitivity on metabolic diseases.

Low Remnant Cholesterol and In-Hospital Bleeding Risk After Ischemic Stroke or Transient Ischemic Attack.

BACKGROUND: Bleeding risk brought by intensive lipid-lowering therapy and low low-density lipoprotein cholesterol is concerning, while evidence regarding the relationship between remnant cholesterol and bleeding is frightening. This study aimed to investigate the association between remnant cholesterol at admission and an in-hospital bleeding event after acute ischemic stroke or transient ischemic attack (TIA). METHODS AND RESULTS: A total of 3222 eligible patients admitted to Shanghai Huashan Hospital between 2015 and 2021 with complete lipid data were analyzed. Patients were classified into low (<20.0 mg/dL), moderate (20.0-29.9 mg/dL), and high (≥30 mg/dL) groups by remnant cholesterol. The mean age of patients was 63.0± 13.1 years, including 2301 (71.4%) men and 651 (20.2%) with TIA. The median (interquartile range) of remnant cholesterol was 18.6 (13.5-25.9) mg/dL. After adjustment for confounding variables, patients with low remnant cholesterol had a higher risk of bleeding events (odds ratio, 2.56 [95% CI, 1.12-6.67]) than those with moderate remnant cholesterol. The high remnant cholesterol group was not significantly associated with bleeding risk. Combined assessment of low-density lipoprotein cholesterol and remnant cholesterol further identified patients with the highest risk of bleeding events. CONCLUSIONS: Low remnant cholesterol levels were associated with bleeding events during the acute stage of ischemic stroke and TIA. The assessment of remnant cholesterol could inform the bleeding risk during hospitalization both for patients and physicians in clinical practice.

Atomically Dispersed Iron-Copper Dual-Metal Sites Synergistically Boost Carbonylation of Methane.

The direct liquid-phase oxidative carbonylation of methane, utilizing abundant natural gas, offers a mild and straightforward alternative. However, most catalysts proposed for this process suffer from low acetic acid yields due to few active sites and rapid C1 oxygenate generation, impeding their industrial feasibility. Herein, we report a highly efficient 0.1Cu/Fe-HZSM-5-TF (TF denotes template-free synthesis) catalyst featuring exclusively mononuclear Fe and Cu anchored in the ZSM-5 channels. Under optimized conditions, the catalyst achieved an unprecedented acetic acid yield of 40.5 mmol gcat -1 h-1 at 50 °C, tripling the previous records of 12.0 mmol gcat -1 h-1. Comprehensive characterization, isotope-labeled experiments and density functional theory (DFT) calculations reveal that the homogeneous mononuclear Fe sites are responsible for the activation and oxidation of methane, while the neighboring Cu sites play a key role in retarding the oxidation process, promoting C-C coupling for effective acetic acid synthesis. Furthermore, the methyl-group carbon in acetic acid originates solely from methane, while its carbonyl-group carbon is derived exclusively from CO, rather than the conversion of other C1 oxygenates. The proposed bimetallic catalyst design not only overcomes the limitations of current catalysts but also generalizes the oxidative carbonylation of other alkanes, demonstrating promising advancements in sustainable chemical synthesis.

Ziprasidone population pharmacokinetics and co-medication effects in Chinese patients.

Ziprasidone is widely used in the treatment of psychiatric disorders. Despite its prevalence, there is a notable lack of population pharmacokinetics (PPK) studies on ziprasidone in serum, both domestically and internationally. This study aimed to comprehensively investigate the various factors influencing the PPK characteristics of Ziprasidone, thereby providing a scientific basis for personalized treatment strategies in clinical settings. This is a retrospective study. A non-linear mixed-effects modeling method was used for data analysis, with the ziprasidone PPK model established using the Phoenix NLME 8.1 software. Model evaluation employed goodness-of-fit plots, visual predictive checks, and Bootstrap methods to ensure reliability and accuracy. To further validate the model's applicability, data from an additional 30 patients meeting the same inclusion criteria but not included in the final model were collected for external validation. Simulations were performed to explore the personalized dosage regimens. This retrospective analysis collected 547 drug concentration data points from 185 psychiatric disorder patients, along with related medical records. The data included detailed demographic information (such as age, gender, weight), dosing regimens, laboratory test results, and concomitant medication details. In the final model, Ka was fixed at 0.5 h-1 based on literature, and the population typical values for ziprasidone clearance (CL) and volume of distribution (V) were 18.74 L/h and 110.24 L, respectively. Co-administration of lorazepam and valproic acid significantly influenced the clearance of ziprasidone. Moreover, the model evaluation indicated good stability and predictive accuracy. A simple to use dosage regimen table was derived based on the results of simulations. This study successfully established and validated a PPK model for ziprasidone in Chinese patients with psychiatric disorders. The model provides a scientific reference for individualized dosing of ziprasidone and holds the potential to optimize treatment strategies, thereby enhancing therapeutic efficacy and safety.

Development and validation of individualized tacrolimus dosing software for Chinese pediatric liver transplantation patients: a population pharmacokinetic approach.

OBJECTIVE: We aim to describe the population pharmacokinetics (PPK) of tacrolimus in Chinese pediatric patients under 4 years old after liver transplantation and to develop individualized tacrolimus dosing software. METHODS: A total of 663 blood concentrations from 85 patients aged 4.57 months to 3.97 years were collected in this study. PPK analysis was performed using a nonlinear mixed effects modeling approach with the software, Phoenix. Using C#, an individualized tacrolimus dosing software was created. The software was then used to predict the concentrations of another ten pediatric liver transplantation patients to verify the accuracy of said software. The predictive error (PE) and the absolute predictive error (APE) for each predicted time point were computed. RESULTS: A one-compartment model with first-order elimination best fitted the data. The apparent volume of distribution (V/F) and apparent clearance (CL/F) were 198.65 L and 2.41 L/h. Postoperative days (POD), total bilirubin (TBIL), and the use of voriconazole significantly influenced tacrolimus apparent clearance. The incorporation of an increasing number of actual blood drug concentrations into the prediction resulted in a decrease in both PE (72%, 17%, 7%) and APE (87%, 53%, 26%). CONCLUSIONS: A qualified PPK model of tacrolimus was developed in Chinese pediatric patients. The individualized tacrolimus dosing software could be used as a suitable tool for the personalization of tacrolimus dosing for pediatric patients after liver transplantation.

Population pharmacokinetics of fluconazole for prevention or treatment of invasive candidiasis in Chinese young infants.

The dosing of fluconazole for young infants remains empirical because of the limited pharmacokinetic (PK) data. We aimed to establish a population PK model and assess the systematic exposure-response of commonly used regimens of fluconazole in Chinese infants. We included infants with a postnatal age of less than 120 days and received intravenous fluconazole. Both scheduled and scavenged plasma samples were collected, and fluconzaole concentration was determined by a validated ultra-performance liquid chromatography-tandem mass spectrometry assay. Population PK analysis was conducted using Phoenix NLME, and then Monte Carlo simulation was conducted to predict the probability of target attainment (PTA) of empirically used regimens of both prophylactic and therapeutic purposes. Based on 304 plasma samples from 183 young infants, fluconazole concentration data was best described by a one-compartment model with first-order elimination. Gestational Age (GA), postnatal age (PNA), and body weight (BW) were included in the final model as CL = 0.02*(GA/214)2.77*(PNA/13)0.24*exp(nCL); V = 1.56*(BW/1435)0.90*exp(nV). Model validation revealed the final model had qualified stability and acceptable predictive properties. Monte Carlo simulation indicated that under the same minimum inhibitory concentration (MIC) value and administration regimen, PTA decreased with GA and PNA. The commonly used prophylactic regimens can meet the clinical need, while higher doses might be needed for treatment of invasive candidiasis. This population PK model of fluconazole discriminated the impact of GA and PNA on CL and BW on V. Dosing adjustment was needed according to the GA and PNA of infants to achieve targeted exposures.

Stimulation of tumoricidal immunity via bacteriotherapy inhibits glioblastoma relapse.

Glioblastoma multiforme (GBM) is a highly aggressive brain tumor characterized by invasive behavior and a compromised immune response, presenting treatment challenges. Surgical debulking of GBM fails to address its highly infiltrative nature, leaving neoplastic satellites in an environment characterized by impaired immune surveillance, ultimately paving the way for tumor recurrence. Tracking and eradicating residual GBM cells by boosting antitumor immunity is critical for preventing postoperative relapse, but effective immunotherapeutic strategies remain elusive. Here, we report a cavity-injectable bacterium-hydrogel superstructure that targets GBM satellites around the cavity, triggers GBM pyroptosis, and initiates innate and adaptive immune responses, which prevent postoperative GBM relapse in male mice. The immunostimulatory Salmonella delivery vehicles (SDVs) engineered from attenuated Salmonella typhimurium (VNP20009) seek and attack GBM cells. Salmonella lysis-inducing nanocapsules (SLINs), designed to trigger autolysis, are tethered to the SDVs, eliciting antitumor immune response through the intracellular release of bacterial components. Furthermore, SDVs and SLINs administration via intracavitary injection of the ATP-responsive hydrogel can recruit phagocytes and promote antigen presentation, initiating an adaptive immune response. Therefore, our work offers a local bacteriotherapy for stimulating anti-GBM immunity, with potential applicability for patients facing malignancies at a high risk of recurrence.

Doping heteroatoms to form multiple hydrogen bond sites for enhanced interfacial reconstruction and separations.

Interfacial challenges in unconventional oil extraction include heavy oil-water-solid multiphase separation and corrosion inhibition. Herein, a novel strategy based on interfacial hydrogen bonding reconstruction is proposed for constructing multifunctional interfacially active materials (MIAMs) to address multi-interfacial separation needs. A simple one-pot method is applied to successfully synthesize four different MIAM varieties, integrating site groups (-NH2, OSO, -COOH, and Si-O-Si) with multiple hydrogen bonds (HBs) into allyl polyether chains. The results indicate that all synthesized MIAMs excel in demulsification, detergency, and corrosion inhibition simultaneously, even at 25 °C. Their dehydration efficiency for different water-in-oil emulsions (even heavy oil emulsion) surpasses 99.9 % even at 16 °C, showing their excellent energy-saving potential for field applications. Furthermore, they demonstrate effective, nondestructive static cleaning (up to 86 %) of adhered oil from solid surfaces at 25 °C and provide corrosion inhibition effects (up to 92.09 %) on mild steel immersed in saturated brine. Mechanistic tests reveal that incorporating multiple HB sites in MIAMs dramatically enhances their effectiveness in interfacial separations. Based on these findings, an HB-dominated noncovalent interaction reconstruction strategy is tentatively proposed to develop advanced materials for low-carbon, efficient interfacial separations.

A Guanidinobenzol-Rich Polymer Overcoming Cascade Delivery Barriers for CRISPR-Cas9 Genome Editing.

The efficient cytosolic delivery of the CRISPR-Cas9 machinery remains a challenge for genome editing. Herein, we performed ligand screening and identified a guanidinobenzol-rich polymer to overcome the cascade delivery barriers of CRISPR-Cas9 ribonucleoproteins (RNPs) for genome editing. RNPs were stably loaded into the polymeric nanoparticles (PGBA NPs) by their inherent affinity. The polymer facilitated rapid endosomal escape of RNPs via a dynamic multiple-step cascade process. Importantly, the incorporation of fluorescence in the polymer helps to identify the correlation between cellular uptake and editing efficiency, increasing the efficiency up to 70% from the initial 30% for the enrichment of edited cells. The PGBA NPs efficiently deliver RNPs for in vivo gene editing via both local and systemic injections and dramatically reduce PCSK9 level. These results indicate that PGBA NPs enable the cascade delivery of RNPs for genome editing, showing great promise in broadening the therapeutic potential of the CRISPR-Cas9 technique.

Targeting the molecular chaperone CCT2 inhibits GBM progression by influencing KRAS stability.

Proper protein folding relies on the assistance of molecular chaperones post-translation. Dysfunctions in chaperones can cause diseases associated with protein misfolding, including cancer. While previous studies have identified CCT2 as a chaperone subunit and an autophagy receptor, its specific involvement in glioblastoma remains unknown. Here, we identified CCT2 promote glioblastoma progression. Using approaches of coimmunoprecipitation, mass spectrometry and surface plasmon resonance, we found CCT2 directly bound to KRAS leading to increased stability and upregulated downstream signaling of KRAS. Interestingly, we found that dihydroartemisinin, a derivative of artemisinin, exhibited therapeutic effects in a glioblastoma animal model. We further demonstrated direct binding between dihydroartemisinin and CCT2. Treatment with dihydroartemisinin resulted in decreased KRAS expression and downstream signaling. Highlighting the significance of CCT2, CCT2 overexpression rescued the inhibitory effect of dihydroartemisinin on glioblastoma. In conclusion, the study demonstrates that CCT2 promotes glioblastoma progression by directly binding to and enhancing the stability of the KRAS protein. Additionally, dihydroartemisinin inhibits glioblastoma by targeting the CCT2 and the following KRAS signaling. Our findings overcome the challenge posed by the undruggable nature of KRAS and offer potential therapeutic strategies for glioblastoma treatment.

Liver kinase B-1 modulates the activity of dopamine neurons in the ventral tegmental area and regulates social memory formation.

Social memory is the ability to discriminate between familiar and unknown conspecifics. It is an important component of social cognition and is therefore essential for the establishment of social relationships. Although the neural circuit mechanisms underlying social memory encoding have been well investigated, little focus has been placed on the regulatory mechanisms of social memory processing. The dopaminergic system, originating from the midbrain ventral tegmental area (VTA), is a key modulator of cognitive function. This study aimed to illustrate its role in modulating social memory and explore the possible molecular mechanisms. Here, we show that the activation of VTA dopamine (DA) neurons is required for the formation, but not the retrieval, of social memory. Inhibition of VTA DA neurons before social interaction, but not 24 h after social interaction, significantly impaired social discrimination the following day. In addition, we showed that the activation of VTA DA neurons was regulated by the serine/threonine protein kinase liver kinase B1 (Lkb1). Deletion of Lkb1 in VTA DA neurons reduced the frequency of burst firing of dopaminergic neurons. Furthermore, Lkb1 plays an important role in regulating social behaviors. Both genetic and virus-mediated deletions of Lkb1 in the VTA of adult mice impaired social memory and subsequently attenuated social familiarization. Altogether, our results provide direct evidence linking social memory formation to the activation of VTA DA neurons in mice and illustrate the crucial role of Lkb1 in regulating VTA DA neuron function.

Effectiveness and Safety of Different Oral Anticoagulants with P-glycoprotein/ CYP3A4 Inhibitors: A Network Meta-analysis.

BACKGROUND: Metabolism of oral anticoagulants (OAC) is affected by P-glycoprotein (P-gp)/ CYP3A4 enzyme. However, the P-gp/CYP3A4 inhibitors are unavoidably used with OACs. METHODS: Medline, Cochrane, and Embase were systematically searched for randomized controlled trials and cohort studies from inception till 23rd November, 2022 to assess the safety and effectiveness of OACs when concomitantly used with P-gp/CYP3A4 inhibitors. The primary outcomes were major bleeding and gastrointestinal (GI) bleeding. Secondary outcomes were stroke/systemic embolism (SE), all-cause mortality, any bleeding as well as intracranial hemorrhage (ICH). We estimated summary odds ratios (OR) with 95% credible intervals (CI) using pairwise and network meta-analysis with random effects. RESULTS: A total of 11 studies involving 37,973 patients were included. When concomitantly used with P-pg/ CYP3A4 inhibitors, network meta-analysis indicated that dabigatran, apixaban, and edoxaban were associated with significantly lower risk of major bleeding compared to rivaroxaban, with ORs of 0.56, 0.51 and 0.48, respectively. Rivaroxaban and dabigatran were associated with a significantly increased risk of GI bleeding than warfarin, apixaban and edoxaban. Dabigatran and apixaban were linked with significantly lower risk of any bleeding compared with warfarin (ORs were 0.75 and 0.68, respectively) or rivaroxaban (ORs were 0.67 and 0.60, respectively). Apixaban (OR 0.32) and edoxaban (OR 0.35) were associated with a lower risk of ICH compared with warfarin. There was no difference between any OACs in terms of stroke/SE or all-cause mortality. CONCLUSION: When concomitantly used with P-gp/CYP3A4 inhibitors, apixaban and edoxaban were associated with a lower risk of bleeding, though no significant difference in effectiveness was observed among all OACs.

Deep brain stimulation of the subthalamic nucleus increases the risk of sialorrhea in patients with advanced Parkinson's disease.

INTRODUCTION: Sialorrhea is a common neurological manifestation of Parkinson's disease (PD). No specifically designed prospective study has tested the effects of deep brain stimulation of the subthalamic nucleus (STN-DBS) on sialorrhea in patients with advanced PD. We focused on the effect of STN-DBS on the incidence of sialorrhea in patients with PD. METHODS: This multicenter, prospective, non-randomized concurrent clinical trial analyzed the incidence of sialorrhea during long-term follow-up in 170 patients with advanced PD (84 patients with STN-DBS and 86 patients with medication therapy). RESULTS: After STN-DBS, 58.1% of patients presented with sialorrhea (Drooling Rating Scale (DRS) > 5) compared with 39.3% of patients with medication therapy (P < 0.001). STN-DBS stimulation demonstrated a significant increase in DRS and Drooling Severity and Frequency Scale (DSFS) compared with the patients with medication therapy (P < 0.001). At follow-up, the onabotulinumtoxin-A (BTX-A) injection ratio was significantly higher in the STN-DBS group (29.8% vs. 11.9%, P = 0.0057) compared with the patients with medication therapy. CONCLUSIONS: STN-DBS increased the risk of sialorrhea in patients with advanced PD. TRIAL REGISTRATION: clinicaltrials. gov (NCT06090929).

Blood-Brain Barrier Penetrating Nanovehicles for Interfering with Mitochondrial Electron Flow in Glioblastoma.

Glioblastoma multiforme (GBM) is the most aggressive and lethal form of human brain tumors. Dismantling the suppressed immune microenvironment is an effective therapeutic strategy against GBM; however, GBM does not respond to exogenous immunotherapeutic agents due to low immunogenicity. Manipulating the mitochondrial electron transport chain (ETC) elevates the immunogenicity of GBM, rendering previously immune-evasive tumors highly susceptible to immune surveillance, thereby enhancing tumor immune responsiveness and subsequently activating both innate and adaptive immunity. Here, we report a nanomedicine-based immunotherapeutic approach that targets the mitochondria in GBM cells by utilizing a Trojan-inspired nanovector (ABBPN) that can cross the blood-brain barrier. We propose that the synthetic photosensitizer IrPS can alter mitochondrial electron flow and concurrently interfere with mitochondrial antioxidative mechanisms by delivering si-OGG1 to GBM cells. Our synthesized ABBPN coloaded with IrPS and si-OGG1 (ISA) disrupts mitochondrial electron flow, which inhibits ATP production and induces mitochondrial DNA oxidation, thereby recruiting immune cells and endogenously activating intracranial antitumor immune responses. The results of our study indicate that strategies targeting the mitochondrial ETC have the potential to treat tumors with limited immunogenicity.

Feasibility and efficiency of a new classification based on high-resolution MRI for carotid artery pseudo-occlusion and occlusion: Hybrid revascularization pilot study.

BACKGROUND AND PURPOSE: Studies on changes in the distal internal carotid artery based on high resolution magnetic resonance imaging (HRMRI) are scarce. Herein, we propose a histological classification system for patients with carotid artery pseudo-occlusion or occlusion based on preoperative HRMRI, for which we evaluated the feasibility and clinical implications. MATERIALS AND METHODS: From January 2017 to June 2021, 40 patients with Doppler ultrasound, CTA or MRA suggesting carotid artery occlusion were enrolled in this study. A new classification system based on HRMRI was established and subsequently verified by postoperative specimens. We recorded and analyzed patient characteristics, HRMRI data, recanalization rate, requirements of additional endovascular procedures, complications, and outcomes. RESULTS: Four histological classifications (type Ⅰ-Ⅳ) were identified. According to our classification system, 20 patients (50.00%) were type I, nine (22.50%) were type II, 7 (17.50%) were type III, and four (10.00%) were type Ⅳ. The success rate of recanalization was 88.89% (32/36) in type I-III patients. Four (44.44%) type Ⅱ patients and five (71.43%) type Ⅲ patients suffered from intraoperative dissection. CONCLUSION: Patients identified as types I (pseudo-occlusion) and II (thrombotic-occlusion) were able to be treated via hybrid revascularization with relatively low risk, while patients identified as type III (fibrous-occlusion) required more careful treatment. Recanalization is not suitable for patients identified as type Ⅳ. Our proposed classification system based on HRMRI data can be used as an adjunctive guide to predict the technical feasibility and success of revascularization via a hybrid technique.

HTRA1 promotes EMT through the HDAC6/Ac-α-tubulin pathway in human GBM cells.

BACKGROUND: The infiltrative nature of human gliomas renders complete surgical removal of tumors futile. Thus, illuminating mechanisms of their infiltrative properties may improve therapies and outcomes of glioma patients. METHODS: Comprehensive bioinformatic analyses of PRSS family were undertaken. Transfection of HTRA1 siRNAs was used to suppress HTRA1 expression. CCK-8, EdU, and colony formation assay were employed to assess cell viability, and cell migration/invasion was detected by transwell, wound healing, and 3D tumor spheroid invasion assays. Immunoprecipitation was applied to study the mechanism that HTRA1 affected cell migration. In addition, in situ xenograft tumor model was employed to explore the role of HTRA1 in glioma growth in vivo. RESULTS: HTRA1 knockdown could lead to suppression of cell viability, migration and invasion, as well as increased apoptosis. Immunoprecipitation results indicates HTRA1 might facilitate combination between HDAC6 and α-tubulin to enhance cell migration by decreasing α-tubulin acetylation. Besides, HTRA1 knockdown inhibited the growth of xenografts derived from orthotopic implantation of GBM cells and prolonged the survival time of tumor-bearing mice. CONCLUSION: Our results indicate that HTRA1 promotes the proliferation and migration of GBM cells in vitro and in vivo, and thus may be a potential target for treatment in gliomas.