Tumor habitat-based MRI features assessing early response in locally advanced nasopharyngeal carcinoma.

OBJECTIVE: The early response to concurrent chemoradiotherapy in patients with locally advanced nasopharyngeal carcinoma (LA-NPC) is closely correlated with prognosis. In this study, we aimed to predict early response using a combined model that combines sub-regional radiomics features from multi-sequence MRI with clinically relevant factors. METHODS: A total of 104 patients with LA-NPC were randomly divided into training and test cohorts at a ratio of 3:1. Radiomic features were extracted from subregions within the tumor area using the K-means clustering method, and feature selection was performed using LASSO regression. Four models were established: a radiomics model, a clinical model, an Intratumor Heterogeneity (ITH) score-based model and a combined model that integrates the ITH score with clinical factors. The predictive performance of these models was evaluated using receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA). RESULTS: Among the models, the combined model incorporating the ITH score and clinical factors exhibited the highest predictive performance in the test cohort (AUC=0.838). Additionally, the models based on ITH score showed superior prognostic value in both the training cohort (AUC=0.888) and the test cohort (AUC=0.833). CONCLUSION: The combined model that integrates the ITH score with clinical factors exhibited superior performance in predicting early response following concurrent chemoradiotherapy in patients with LA-NPC.

Predictive value of peripheral blood biomarkers in patients with non-small-cell lung cancer responding to anti-PD-1-based treatment.

BACKGROUND: The introduction of the anti-PD-1 antibody has greatly improved the clinical outcomes of patients with non-small cell lung cancer (NSCLC). In this study, we retrospectively analyzed the efficacy of PD-1 antibody-based therapy in patients with locally advanced inoperable or metastatic NSCLC and reported an association between peripheral blood biomarkers and clinical response in these patients. METHODS: This single-center study included medical record data of patients with NSCLC treated with the PD-1 antibody as a first-line or subsequent line of treatment, either as monotherapy or in combination with chemotherapy. The patients were enrolled from 2020 to 2022. We dynamically evaluated multiple Th1 and Th2 cytokines in the blood serum and analyzed the phenotype of T cells from the peripheral blood to explore the correlation between cytokine levels, T cell phenotypes, and clinical response. RESULTS: A total of 88 patients with stage IIIA-IV NSCLC were enrolled, out of which 60 (68.18%) achieved a partial response (PR), 13 (14.77%) had stable disease (SD), and 15 (17.05%) experienced disease progression (PD). The disease control rate was 82.95%. Our results suggested a significant reduction (P = 0.002, P < 0.005) in lymphocyte absolute counts after treatment in patients with PD. Higher levels of IFN-γ (P = 0.023, P < 0.05), TNF-α (P = 0.00098, P < 0.005), IL-4 (P = 0.0031, P < 0.005), IL-5 (P = 0.0015, P < 0.005), and IL-10 (P = 0.036, P < 0.05) were detected in the peripheral blood before treatment in the PR group compared to the PD group. Moreover, patients with high levels of IL-5, IL-13, IL-4, IL-6, IFN-γ, and TNF-α (> 10 ng/mL) had superior progression-free survival compared to those with low levels (< 10 ng/mL). Furthermore, PD-1 expression on CD8+ T cells was higher in patients who showed a PR than in those who did not show a response (SD + PD; P = 0.042, P < 0.05). CONCLUSIONS: The findings of this study imply that the decrease in absolute blood lymphocyte counts after treatment is correlated with disease progression. Serum cytokine levels may predict the effectiveness and survival rates of anti-PD-1 blockade therapy in patients with NSCLC. In addition, PD-1 expression on CD8+ T cells was positively associated with better clinical response. Our findings highlight the potential of peripheral blood biomarkers to predict the effectiveness of PD-1-targeted treatments in patients with NSCLC. Larger prospective studies are warranted to further clarify the value of these biomarkers.

Membrane Trafficking-Related Genes Predict Tumor Immune Microenvironment and Prognosis in Colorectal Cancer.

Colorectal cancer (CRC) is a heterogeneous disease with varying clinical outcomes. The identification of distinct subgroups of CRC patients based on molecular profiling can aid in better understanding the disease and improving patient outcomes. This study aimed to investigate the potential of membrane trafficking-related genes (MTRGs) in sub-grouping colorectal cancer patients based on their overall survival and immune microenvironments. Consensus clustering analysis identified two distinct clusters with different expression profiles of membrane trafficking-related genes. The patients in cluster 1 had a significantly better overall survival than those in cluster 2. Furthermore, the immune microenvironments in the two clusters were also found to be significantly different, with cluster 1 having a higher immune score and more immune cells present. Functional analysis of differentially expressed genes between the two clusters revealed that MTRGs were involved in immune response and metabolic processes, and a risk signature model based on MTRGs was established to predict the prognosis of CRC patients. These findings suggest that MTRGs play a crucial role in the immune microenvironment and overall survival of CRC patients and may provide a potential target for personalized therapy.

Exploring the Expression and Prognosis of Mismatch Repair Proteins and PD-L1 in Colorectal Cancer in a Chinese Cohort.

Purpose: Exploring the expression and prognosis of mismatch repair proteins and PD-L1 in colorectal cancer. Patients and Methods: A total of 272 patients with surgically resected CRC were enrolled in the study from January 2018 to May 2022 at Nanjing Drum Tower Hospital (The Affiliated Hospital of Nanjing University Medical School). Surgically resected samples were collected from patients along with general, clinicopathological, and imaging data for each patient. Immunohistochemistry (IHC) was used to detect expression of MSH2, MSH6, MLH1, and PMS2 proteins in tumor tissue. X-squared (X2) testing was performed to investigate the correlation between expression of MMR proteins and PD-L1 in CRC tumor tissues and clinicopathological characteristics. Correlation analysis was also used to compare the deletion of four MMR proteins in CRC tumor tissues. A survival curve and Log rank test were used to investigate the relationship between the expression of MMR proteins and PD-L1 with regard to CRC patient prognosis and survival. Results: MMR protein expression deletion was correlated with tumor location, the degree of tissue differentiation, and TNM stage (P<0.05). PD-L1 expression was correlated with TNM stage (P<0.05). Correlation analysis of deletion of MMR protein isoform expression found that PMS2 deletion was significantly correlated with MLH1 deletion (P<0.05). Similarly, MSH2 deletion was significantly correlated with MSH6 deletion (P<0.05). PMS2 deletion was also found to be correlated with PD-L1 expression (P<0.05). Progression-free survival was found to be significantly longer in mismatch repair-proficient (pMMR) patients compared with mismatch repair-deficient (dMMR) patients. Conclusion: Deletion of MMR proteins and expression of PD-L1 are closely related to clinicopathological characteristics and overall prognosis of CRC patients. This suggests the relevance of MMR and PD-L1 as potential biomarkers for treatment of CRC patients.

Multicenter, single-arm, phase II study (CAP) of radiotherapy plus liposomal irinotecan followed by camrelizumab and anti-angiogenic treatment in advanced solid tumors.

Introduction: Combination therapeutic mode is likely to be the key to enhance the efficacy of immunotherapy in a wider range of cancer patients. Herein, we conducted an open-label, single-arm, multicenter, phase II clinical trial that enrolled patients with advanced solid tumors who had progressed after standard treatments. Methods: Radiotherapy of 24 Gy/3 fractions/3-10 days was given to the targeted lesions. Liposomal irinotecan (80mg/m2, dose could be adjusted to 60 mg/m2 for intolerable cases) was intravenously (IV) administered once within 48 hours after radiotherapy. Then, camrelizumab (200mg IV, q3w) and anti-angiogenic drugs were given regularly until disease progression. The primary endpoint was objective response rate (ORR) in the target lesions evaluated by investigators per RECIST 1.1. The secondary endpoints were disease control rate (DCR) and treatment-related adverse events (TRAEs). Results: Between November 2020 and June 2022, 60 patients were enrolled. The median follow-up was 9.0 months (95% confidence interval (CI) 5.5-12.5). Of 52 evaluable patients, the overall ORR and DCR were 34.6% and 82.7%, respectively. Fifty patients with target lesions were evaluable, the ORR and DCR of the target lesions were 35.3% and 82.4%, respectively. The median progression-free survival was 5.3 months (95% CI 3.6, 6.2), and the median overall survival was not reached. TRAEs (all grades) occurred in 55 (91.7%) patients. The most common grade 3-4 TRAEs were lymphopenia (31.7%), anemia (10.0%), and leukopenia (10.0%). Conclusion: The combination of radiotherapy, liposomal irinotecan, camrelizumab, and anti-angiogenesis therapy demonstrated promising anti-tumor activity and well tolerance in various advanced solid tumors. Clinical trial registration: https://clinicaltrials.gov/ct2/home, identifier NCT04569916.

SLAMF8, a potential new immune checkpoint molecule, is associated with the prognosis of colorectal cancer.

Recently, immune checkpoint inhibitors (ICIs), such as programmed cell death 1 (PD-1) monoclonal antibodies (mAbs), have revolutionized the treatment of malignant tumors. Therefore, the number of studies aiming to screen and identify new immune checkpoint molecules for antitumor immunotherapy is increasing. Signaling lymphocytic activation molecule (SLAM) family members are mainly expressed by and regulate the functions of immune cells. Recent studies have shown that several SLAM family members are involved in the regulation of the tumor immune microenvironment and are promising targets for antitumor immunotherapy. Signaling lymphocytic activation molecule family member 8 (SLAMF8) is a type I cell surface glycoprotein and is encoded on chromosome 1q21. To further illustrate the clinical value of SLAMF8 in colorectal cancer (CRC), we retrospectively analyzed the relationship between SLAMF8 expression and the prognosis of CRC patients and the associations between SLAMF8 expression and the expression levels of other SLAM family members and other classic immune checkpoint molecules using The Cancer Genome Atlas (TCGA) data, RNA sequencing data, tissue immunohistochemistry staining, and systematic follow-up analysis. Here, high SLAMF8 expression was associated with poor overall survival (OS) in CRC. The mRNA expression level of SLAMF8 was positively correlated with the expression levels of multiple classic immune checkpoints and other SLAM family members. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis suggested that the pathways enriched in CRC tissues with high SLAMF8 expression were associated with the regulation of the tumor immune microenvironment.

Novel Fluorescent Probe Based on Rare-Earth Doped Upconversion Nanomaterials and Its Applications in Early Cancer Detection.

In this paper, a novel rare-earth-doped upconverted nanomaterial NaYF4:Yb,Tm fluorescent probe is reported, which can detect cancer-related specific miRNAs in low abundance. The detection is based on an upconversion of nanomaterials NaYF4:Yb,Tm, with emissions at 345, 362, 450, 477, 646, and 802 nm, upon excitation at 980 nm. The optimal Yb3+:Tm3+ doping ratio is 40:1, in which the NaYF4:Yb,Tm nanomaterials have the strongest fluorescence. The NaYF4:Yb, Tm nanoparticles were coated with carboxylation or carboxylated protein, in order to improve their water solubility and biocompatibility. The two commonly expressed proteins, miRNA-155 and miRNA-150, were detected by the designed fluorescent probe. The results showed that the probes can distinguish miRNA-155 well from partial and complete base mismatch miRNA-155, and can effectively distinguish miRNA-155 and miRNA-150. The preliminary results indicate that these upconverted nanomaterials have good potential for protein detection in disease diagnosis, including early cancer detection.

Berberine induces non-small cell lung cancer apoptosis via the activation of the ROS/ASK1/JNK pathway.

Background: Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancers. Berberine (BBR), an isoquinoline alkaloid, is commonly used in traditional Chinese medicine. Previous studies have shown that BBR has a potential anti-tumor effect. However, the mechanisms of BBR on mitochondrial function in anti-lung cancer remain unknown. The aim of this study was to explore mitochondrial function in anti-tumor mechanisms of BBR in NSCLC. Methods: The NSCLCs were cultured and treated with various doses (40, 80, 120 µg/mL) of BBR for 24 and 48 h. Cell viability was evaluated using Cell Counting Kit-8 (CCK-8). Cell apoptosis, reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) were detected by flow cytometry. Relative protein expression was examined by western blot and immunohistochemical (IHC) analysis. Results: BBR potently suppressed NSCLC cells growth by inducing apoptosis in a dose-and time-dependent manner. BBR induced apoptosis in NSCLC cells as evidenced by caspase-3 cleavage, cytochrome c release, and mitochondrial membrane depolarization. BBR-induced, dose-dependent induction of apoptosis was accompanied by sustained phosphorylation of c-jun-NH2-kinase (JNK) and the JNK inhibitor (SP600125) significantly suppressed BBR-induced apoptosis, N-acetyl cysteine (NAC), a ROS scavenger, was sufficient to both suppress apoptosis signal-regulating kinase 1 (ASK1) and JNK activation and disrupt apoptotic induction. Conclusions: The results suggest that BBR induces apoptosis of NSCLC cells via ROS-mediated ASK1/JNK activation and the mitochondrial pathway.

The exploration of quantum dot-molecular beacon based MoS2 fluorescence probing for myeloma-related Mirnas detection.

Highly sensitive and reliable detection of multiple myeloma remains a major challenge in liquid biopsy. Herein, for the first time, quantum dot-molecular beacon (QD-MB) functionalized MoS2 (QD-MB @MoS2) fluorescent probes were designed for the dual detection of multiple myeloma (MM)-related miRNA-155 and miRNA-150. The results indicate that the two probes can effectively detect miRNA-155 and miRNA-150 simultaneously with satisfactory recovery rates, and the limit of detections (LODs) of miRNA-155 and miRNA-150 in human serum are low to 7.19 fM and 5.84 fM, respectively. These results indicate that our method is the most sensitive detection so far reported and that the designed fluorescent probes with signal amplification strategies can achieve highly sensitive detection of MM-related miRNAs for MM diagnosis.

SLAMF8 expression predicts the efficacy of anti-PD1 immunotherapy in gastrointestinal cancers.

OBJECTIVES: Epstein-Barr virus (EBV) infection is associated with a better response to anti-PD1 immunotherapy. We hypothesised that genetic alterations induced by EBV infection are responsible for the activation of key immune responses and hence are predictive of anti-PD1 efficacy. METHODS: With transcriptome data of gastric cancer (GC), we explored differentially expressed genes (DEGs) specific for EBV infection and performed coexpression network analysis using the DEGs to identify the consistent coexpression genes (CCGs) between EBV-positive and EBV-negative GC tissues. We selected the tag genes of the CCGs and validated them using RNA sequencing and immunohistochemistry. We established murine models and collected tissues from clinical patients to test the value of SLAMF8 in predicting anti-PD1 treatment. The location and expression of SLAMF8 were characterised by multiplex immunofluorescence and quantitative PCR. Moreover, exogenous overexpression and RNA-sequencing analysis were used to test the potential function of SLAMF8. RESULTS: We identified 290 CCGs and validated the tag gene SLAMF8 in transcriptome data of gastrointestinal cancer (GI). We observed that the T-cell activation pathway was significantly enriched in high-expression SLAMF8 GI cancers. Higher SLAMF8 expression was positively associated with CD8 expression and a better response to anti-PD1 treatment. We further observed dynamically increased expression of SLAMF8 in murine models relatively sensitive to anti-PD1 treatment. SLAMF8 was mainly expressed on the surface of macrophages. Exogenous overexpression of SLAMF8 in macrophages resulted in enrichment of positive regulation of multiple immune-related pathways. CONCLUSION: Higher SLAMF8 expression may predict better anti-PD1 immunotherapy efficacy in GI cancer.

α-Lipoic Acid Targeting PDK1/NRF2 Axis Contributes to the Apoptosis Effect of Lung Cancer Cells.

As an antioxidant, α-lipoic acid (LA) has attracted much attention to cancer research. However, the exact mechanism of LA in cancer progression control and prevention remains to be unclear. In this study, we demonstrated that α-lipoic acid has inhibitory effects on the proliferation, migration, and proapoptotic effects of non-small-cell lung cancer (NSCLC) cell lines A549 and PC9. LA-induced NSCLC cell apoptosis was mediated by elevated mitochondrial reactive oxygen species (ROS). Further study confirmed that it is by downregulating the expression of PDK1 (the PDH kinase), resulted in less phospho-PDH phenotype which could interact with Keap1, the negative controller of NRF2, directly leading to NRF2 decrease. Thus, by downregulating the NRF2 antioxidant system, LA plays a role in promoting apoptosis through the ROS signaling pathway. Moreover, LA could enhance other PDK inhibitors with the proapoptosis effect. In summary, our study shows that LA promotes apoptosis and exerts its antitumor activity against lung cancer by regulating mitochondrial energy metabolism enzyme-related antioxidative stress system. Administration of LA to the tumor-bearing animal model further supported the antitumor effect of LA. These findings provided new ideas for the clinical application of LA in the field of cancer therapy.

Highly Sensitive Detection of miRNA-155 Using Molecular Beacon-Functionalized Monolayer MoS2 Nanosheet Probes with Duplex-Specific Nuclease-Mediated Signal Amplification.

MicroRNA-155 (miRNA-155) as a characteristic myeloma-associated biomarker exhibits significant potential application in the diagnosis of multiple myeloma (MM). In this paper, a novel type of molecular beacon (MB)-functionalized monolayer MoS2 nanosheet probe was proposed as fluorescent probe for high-sensitive assays of miRNA-155that uses a duplexspecificnuclease (DSN) enzyme to amplify the fluorescence signal. The preparation and detection conditions of the fluorescent probes were optimized in some aspects, such as the concentration of MoS2 (0.80 µM) and DSN (0.2 U), and the incubation time of DSN (30 min). The probesexhibited a sensitive fluorescence response to miRNA-155 and the fluorescence signal of the assay was significantly amplified by the cleavage of DSN. The relationship between F/F0 and logC miRNA follows a linear calibration curve, and the limit of detection (LOD) of miRNA-155 in 10% human serum is calculated to be 10.96 fM based on this relationship. The good performance and fluorescence amplification effect of the fluorescent probe were confirmed by studying the recovery of miRNA-155 in 10% human serum, which was ranged from 98.32% to 106.3% with a relative standard deviation of less than 4.14%. Besides, the high expression of miRNA-155 in clinic blood of MM patients was sensitively distinguished from healthy peoples by using the proposed probes. The proposed novel fluorescent probe based on the DSN can be used to detect miRNA-155 in human serum and provide a potential, convenient and reliable tool for diagnosis of MM.

Treatment strategy of unstable atlas fracture: A retrospective study of 21 patients.

At present, the posterior cervical approach with open reduction and internal fixation (ORIF) remains a commonly effective treatment for unstable Atlas fracture. However, the inserted screws into the C1 lateral mass of some unstable atlas fracture are very difficult, so that the operation is forced to change into C0 to C2 fusion. In order to improve the successful rate of lateral mass screw placement, we introduced a method of fixing lateral mass with a towel clamp in posterior transpedicular fixation, and explore the efficacy and feasibility.Twenty-one consecutive patients with unstable atlas fracture were treated via this method from October 2012 to July 2017. All cases had neck pain and restricted motion of neck movement on admission. Electronic medical records and pre- and postoperative radiographs were reviewed. Screw and rod placement, bone fusion, and spinal cord integrity were assessed via long-term follow-up with anteroposterior and lateral radiographs and computed tomography. Follow-up included clinical assessment of neurological function, assessment of pain using the visual analog scale (VAS), and assessment of the activities of daily living using the neck disability index (NDI).The mean follow-up duration was 22.1 months (range: 12-54 months). No screw loosening or breakage, plate displacement, neurovascular injury, and severe complications occurred during follow-up. The mean operative time was 112.4 ±â€Š14.9 min (range: 82-135 min), and mean blood loss was 386.2 ±â€Š147.9 mL (range: 210-850 mL). One patient experienced continuous neck pain postoperatively, but this gradually disappeared with analgesic administration. At final follow-up, all patients had bone fusion, the VAS scores and NDI were significantly improved compared with preoperatively.Fixing the C1 lateral mass with a towel clamp during posterior transpedicular fixation for unstable atlas fracture appears to be a safe and reliable method, with the advantages of being a simple technique with few complications.

Comprehensive analysis of the long noncoding RNA expression profile and construction of the lncRNA-mRNA co-expression network in colorectal cancer.

Long noncoding RNAs (lncRNAs) have been shown to play important roles in various tumors including colorectal cancer (CRC). Here, we obtained data from RNA-sequencing analysis using 3 paired of CRC tissues and corresponding normal tissues. Through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses, the biological functions of these dysregulated genes were identified. Moreover, we analyzed the expression levels of lncRNA PGM5-AS1 and B3GALT5-AS1 by quantitative real-time PCR (qRT-PCR) assay. To evaluate the accuracy of the lncRNA-mRNA co-expression network we built, we also detected PGM5 expression and analyzed the relationship between PGM5-AS1 and PGM5 in CRC. In addition, we explored the potential function of PGM5-AS1 in vitro and in vivo. In conclusion, we identified dysregulated lncRNAs and constructed the lncRNA-mRNA co-expression network in CRC. Then, we showed that the expression levels of PGM5-AS1, B3GALT5-AS1 and PGM5 were significantly downregulated in CRC tissues compared with corresponding normal tissues. Besides, PGM5-AS1 expression was positively associated with PGM5 expression. These findings were consistent with our RNA-sequencing data. Functionally, overexpression of PGM5-AS1 could induce cell apoptosis and cell cycle arrest in CRC. Animal study indicated that PGM5-AS1 overexpression inhibited CRC growth in vivo. This work provides dysregulated lncRNAs as candidates for further study in CRC. The lncRNA-mRNA co-expression network brings novel insights into further function research. More importantly, PGM5-AS1 is a critical tumor suppressor in CRC.

Berberine induces apoptosis in non-small-cell lung cancer cells by upregulating miR-19a targeting tissue factor.

BACKGROUND: Berberine (BBR) from the widely used Chinese herbal medicine Huanglian has an array of pharmacological and biochemical properties, including anti-neoplastic activity. However, the specific mechanisms underlying these properties are unknown. The aim of this study was to explore the anti-tumor mechanisms of BBR in non-small cell lung cancer (NSCLC). METHODS: The effects of BBR on NSCLC tumor development and programmed cell death were investigated both in vivo and in vitro. Luciferase reporter assays were used to determine whether tissue factor (TF) was a target of miR-19a. RESULTS: BBR suppressed NSCLC growth and promoted apoptosis in NSCLC cells by modulating miR-19a and TF expression. Luciferase assays showed that TF was a direct inhibitory target of miR-19a in NSCLC cells. BBR induced apoptosis through the miR-19a/TF/MAPK axis. CONCLUSION: The results suggest that BBR induces apoptosis of NSCLC cells via the miR-19a/TF/MAPK signaling pathway.

Dihydromyricetin induces apoptosis and cytoprotective autophagy through ROS-NF-κB signalling in human melanoma cells.

Dihydromyricetin (DHM), a Rattan tea extract, has recently been shown to have anti-cancer activity in mammalian cells. In this study, we investigated the effect of DHM on human melanoma cells. Apart from induction of apoptosis, we demonstrated that DHM induced an autophagic response. Moreover, pharmacological inhibition or genetic blockade of autophagy enhanced DHM-induced cell death and apoptosis, indicating the cytoprotective role of autophagy in DHM-treated human melanoma cells. Further study suggested that the nuclear factor kappa B (NF-κB) signalling pathway was involved in DHM-induced autophagy. Moreover, N-acetyl-cysteine (NAC), an ROS scavenger, abrogated the effects of DHM on NF-κB-dependent autophagy. Taken together, this evidence demonstrates that a strategy of blocking ROS-NF-κB-dependent autophagy to enhance the activity of DHM warrants further attention for the treatment of human melanoma.

Neuroprotective effects of (S)-N-[4-[4-[(3,4-Dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1-piperazinyl]phenyl]-2-thiophenecarboximid-amide (BN 80933), an inhibitor of neuronal nitric-oxide synthase and an antioxidant, in model of transient focal cerebral ischemia in mice.

Nitric oxide (NO) and reactive oxygen species are both implicated in neuronal death due to cerebral ischemia. BN 80933, an original compound associating an inhibitor of neuronal NO synthase with an antioxidant, has been shown to reduce functional and histological damage in rat submitted to cerebral ischemia. The aim of the present study was to confirm these results in mice and to further examine the effects of BN 80933 on inflammatory response, including blood-brain barrier (BBB) disruption, brain edema, and neutrophil infiltration after transient middle cerebral artery occlusion (MCAO). Intravenous administration of BN 80933 at 3 and 10 mg/kg 3 h after MCAO significantly reduced by 26 to 36% the infarct volume evaluated 24 and 48 h after ischemia, and improved the neurological score. Furthermore, BN 80933 at both dosages decreased by 42 to 75% the extravasation of Evans blue in brain parenchyma observed 24 h after ischemia. This reduction in BBB disruption was associated with decreased brain edema as demonstrated by the 37% reduction in brain water content induced by BN 80933 at 3 mg/kg 24 h after MCAO. Neutrophil infiltration in brain parenchyma, evaluated by the myeloperoxidase activity, was also reduced by 45 to 56% in animals treated with BN 80933 at 3 and 10 mg/kg. Together, these results extend the protective capacity of BN 80933 against brain ischemic injury and confirm that BN 80933 represents a promising treatment for stroke.