Naringenin Alleviates Radiation-Induced Intestinal Injury by Inhibiting TRPV6 in Mice.

SCOPE: Naringenin (NAR) possesses unique anti-inflammatory, antiapoptosis effects and various bioactivities; however, its role against radiation-induced intestinal injury (RIII) remains unclear. This study aims to investigate whether NAR has protective effects against radiation-induced intestinal injury and the underlying mechanisms. METHODS AND RESULTS: C57BL/6J mice are exposed to a single dose of 13 Gy X-ray total abdominal irradiation (TAI), then gavaged with NAR for 7 days. NAR treatment prolongs the survival rate, protects crypts and villi from damage, alleviates the level of radiation-induced inflammation, and mitigates intestinal barrier damage in the irradiated mice. Additionally, NAR reduces immune cell infiltration and intestinal epithelial cell apoptosis. NAR also shows radioprotective effects in human colon cancer cells (HCT116) and human intestinal epithelial cells (NCM460). It reduces cell damage by reducing intracellular calcium ion levels and reactive oxygen species (ROS) levels. NAR-mediated radioprotection is associated with the downregulation of transient receptor potential vanilloid 6 (TRPV6), and inhibition of apoptosis pathway. Notably, treatment with NAR fails to further increase the protective effects of the TRPV6 inhibitor 2-APB, indicating that TRPV6 inhibition is essential for NAR activity. CONCLUSION: NAR inhibits the apoptosis pathway by downregulating TRPV6 and reducing calcium ion level, thereby alleviating RIII. Therefore, NAR is a promising therapeutic drug for RIII.

Time and Influencing Factors to Chronic Subdural Hematoma Resolution After Middle Meningeal Artery Embolization.

OBJECTIVE: We sought to describe the resolution time of chronic subdural hematoma (CSDH) after middle meningeal artery embolization (MMAE) and potential variables that may affect hematoma resolution. METHODS: A retrospective analysis was performed on CSDH patients between December 2018 and December 2021. Patient characteristics, radiologic manifestations, and data of hematoma resolution were recorded. Univariate and multivariate analyses were conducted to identify predictors of CSDH resolution time. RESULTS: A total of 53 patients were enrolled including 53 hematomas. Only 1 participant relapsed and did not require surgical evacuation. Hematoma resolution was observed in 27 (50.9%) at 4 months and 48 (90.6%) cases at the last radiologic follow-up. The median MMAE-to-resolution time was 19 weeks (interquartile range: 8-24). The burr-hole irrigation + MMAE group showed faster hematoma resolution than MMAE alone during early follow-up periods, but no significant difference was found at 6 months. Increased thickness of residual hematoma, excessive postoperative midline shift, high-density hematoma, mixed-density hematoma, separated hematoma, and anticoagulant or antiplatelet agents used were predictive of nonresolution at 4 months as determined by univariate analysis, whereas anticoagulant or antiplatelet agents used and high-density hematoma were not significant on multivariate analysis. No significant association was noted between hematoma resolution and comorbidities or other hematoma radiologic features. CONCLUSIONS: MMAE is an effective and minimally invasive treatment for CSDH with a lower recurrence rate. The median resolution time of CSDH following MMAE was 19 weeks (interquartile range: 8-24). Burr-hole irrigation contributed to early hematoma resolution but had no significant effect at 6 months. In addition, residual hematoma thickness, postoperative midline shift, and specific type of hematoma were associated with delayed hematoma resolution at 4 months.

Metformin Alleviates Delayed Hydrocephalus after Intraventricular Hemorrhage by Inhibiting Inflammation and Fibrosis.

Intraventricular hemorrhage (IVH) is a subtype of intracerebral hemorrhage (ICH) with high morbidity and mortality. Posthemorrhagic hydrocephalus (PHH) is a common and major complication that affects prognosis, but the mechanism is still unclear. Inflammation and fibrosis have been well established as the major causes of PHH after IVH. In this study, we aimed to investigate the effects of metformin on IVH in adult male mice and further explored the underlying molecular mechanisms of these effects. In the acute phase, metformin treatment exerted dose-dependent neuroprotective effects by reducing periependymal apoptosis and neuronal degeneration and decreasing brain edema. Moreover, high-dose metformin reduced inflammatory cell infiltration and the release of proinflammatory factors, thus protecting ependymal structure integrity and subependymal neurons. In the chronic phase, metformin administration improved neurocognitive function and reduced delayed hydrocephalus. Additionally, metformin significantly inhibited basal subarachnoid fibrosis and ependymal glial scarring. The ependymal structures partially restored. Mechanically, IVH reduced phospho-AMPK (p-AMPK) and SIRT1 expression and activated the phospho-NF-κB (p-NF-κB) inflammatory signaling pathway. However, metformin treatment increased AMPK/SIRT1 expression and lowered the protein expression of p-NF-κB and its downstream inflammation. Compound C and EX527 administration reversed the anti-inflammatory effect of metformin. In conclusion, metformin attenuated neuroinflammation and subsequent fibrosis after IVH by regulating AMPK /SIRT1/ NF-κB pathways, thereby reducing delayed hydrocephalus. Metformin may be a promising therapeutic agent to prevent delayed hydrocephalus following IVH.

Gut microbiota and its metabolites in non-small cell lung cancer and brain metastasis: from alteration to potential microbial markers and drug targets.

Background: The elevated mortality rate associated with non-small-cell lung cancer (NSCLC) is a well-established global concern. Considerable attention has been directed toward exploring the association between gut microbiota and various malignant tumors. We herein investigated the associations between the intestinal microbiome and its metabolites, particularly short-chain fatty acids (SCFAs), in patients with NSCLC at different stages, including early and brain metastasis (BM) stages. The findings aim to offer a fresh perspective on the diagnosis and management of NSCLC. Methods: Fecal samples were collected from 115 participants, comprising healthy controls (n = 35) and patients with treatment-naive NSCLC at the early stage (ELC, n = 40) and the BM stage (n = 40). Characterization of the intestinal microbiome and fecal SCFA levels was performed using 16S rRNA gene sequencing and gas chromatography. Results: The microbial diversity in patients with NSCLC was found to be less abundant and uniform, particularly in the BM stage. Significant alterations in the community structure of the gut microbiota were observed in patients with NSCLC, with an increase in pathogens in Fusobacteria and Proteobacteria and a decrease in SCFA-producing bacteria in Firmicutes and Actinobacteria, particularly in the BM stage. Meanwhile, microbial communities displayed intricate associations in patients with NSCLC. A biomarker panel (Faecalibacterium, Bifidobacterium, Butyricicoccus, Klebsiella, Streptococcus, and Blautia) successfully distinguished patients in the ELC and BM stages from healthy controls (area under the curve: 0.884). The overall concentration of fecal SCFAs was significantly lower in patients with BM compared to patients with ELC and healthy controls. Subgroup analysis of acetate and butyrate yielded similar results. Moreover, multiple disrupted pathways in the NSCLC group were identified using the Kyoto Encyclopedia of Genes and Genomes annotation, including lipid metabolism and genetic information processing, specifically in the BM stage. Conclusion: Compared with healthy controls, distinct host-microbe interactions were evident in different phases of patients with NSCLC. Furthermore, specific forms of the gut microbiome and SCFAs may serve as valuable biomarkers and therapeutic targets in the diagnosis and treatment of NSCLC.

Interleukin-7-loaded oncolytic adenovirus improves CAR-T cell therapy for glioblastoma.

BACKGROUND: T cell with chimeric antigen receptors (CAR-T) has presented remarkable efficacy for blood cancer as an emerging immunotherapy. However, for solid tumors, the therapeutic efficacy is much impaired due to the lack of infiltration and persistence of CAR-T in tumor tissue. Thus, we constructed an interleukin-7-loaded oncolytic adenovirus and combined the use of oncolytic virus and CAR-T to improve the therapeutic outcome. METHODS: We constructed an interleukin-7-loaded oncolytic adenovirus (oAD-IL7) and a B7H3-targeted CAR-T and explored the efficacy of the single use of oAD-IL7, B7H3-CAR-T, or the combined therapy for glioblastoma in vitro and in vivo. The improved CAR-T anti-tumor efficacy was evaluated according to the proliferation, survival, persistence, exhaustion of T cells, and tumor regression. RESULTS: Constructed oAD-IL7 and B7H3-CAR-T presented moderate cytotoxicity during in vitro study, but failed to induce a thorough and persistent anti-tumor therapeutic efficacy in vivo. The combination of oAD-IL7 and B7H3-CAR-T in vitro resulted in enhanced T cell proliferation and reduced T cell apoptosis. The joint efficacy was further confirmed using tumor-bearing xenograft mice. During in vivo study, the mice treated with both oAD-IL7 and B7H3-CAR-T showed prolonged survival and reduced tumor burden. According to the ex vivo study, oAD-IL7 improved the proliferation and persistence of tumor-infiltrating B7H3-CAR-T, but failed to reverse the exhaustion. CONCLUSIONS: Our results indicated that oAD-IL7 is a promising auxiliary therapy to improve the therapeutic efficacy of B7H3-CAR-T in glioblastoma by providing the activating signals for tumor-infiltrating T cells. Our results also lay the basis for the future clinical trials for the combination of IL7-loaded oncolytic adenovirus and CAR-T therapy for glioblastoma.

Compared with conventional procedures, an intraoperative navigation system for ventriculoperitoneal shunting via the occipital horn improves outcomes in patients with hydrocephalus.

BACKGROUND: Ventriculoperitoneal shunting (VPS) is a common neurosurgical procedure used to treat hydrocephalus. Although the use of a navigation system in VPS achieves superior results compared with conventional surgery, the relationships among clinical symptoms, ventricular catheter placement, catheter obstruction, and the postoperative Evans index have not been clearly reported. METHODS: We performed a retrospective study of 40 patients with VPS (the navigation surgery group) and 31 patients with VPS (the conventional surgery group). Clinical data, follow-up times, catheterization accuracy, postoperative outcomes, cumulative survival times, and correlations between catheter placement and obstruction, symptom grade and the postoperative Evans index were analyzed. RESULTS: Thirty-seven patients experienced optimal ventricular catheter placement (grade 1), three experienced suboptimal placements (grade 2), and none experienced poor ventricular catheter placement (grade 3) in the navigation surgery group. Greater improvement in postoperative symptoms (p < 0.001), including less catheter readjustment (p < 0.001), was observed in the navigation surgery group. A Kaplan-Meier analysis showed that the cumulative catheter obstruction-free survival time was longer in the navigation surgery group (p = 0.016). Moreover, catheter placement was significantly correlated with catheter obstruction (p < 0.001). Additionally, catheter obstruction was significantly correlated with the symptom grade (p < 0.001) and postoperative Evans index (p = 0.002). CONCLUSION: VPS for hydrocephalus via the occipital horn with a navigation system is superior to the conventional surgical procedure in terms of clinical outcomes, the precision of ventricular catheterization, and the occurrence of complications. Catheter obstruction-free survival times were longer in the navigation surgery group and catheter placement was significantly correlated with catheter obstruction.

Infantile Giant Intracranial Aneurysm Resection and In Situ Anastomosis.

BACKGROUND: Infantile intracranial aneurysms (IAs) are extremely rare. IA clipping and embolization have been the most common treatment options. Infantile giant IAs treated by surgical resection and in situ anastomosis have rarely been reported. CASE DESCRIPTION: A 43-day-old female infant was admitted to our hospital because of abnormal crying and vomiting. Multimodal images showed a right temporal hematoma and a giant dissecting IA. With comprehensive preoperative management, IA resection and in situ anastomosis were successfully performed. Furthermore, intraoperative and postoperative multimodal images demonstrated that the parent vessel was patent. Pathological examination showed chronic inflammation of this IA wall. The infant had a favorable outcome during the 3-month follow-up period. CONCLUSIONS: Infantile giant IAs are extremely rare. Chronic inflammation might be involved in the pathogenesis of infantile dissecting IAs. IA resection and in situ anastomosis could be a reasonable choice in the management of infantile giant IAs that cannot be completely clipped or embolized.

A machine learning model to precisely immunohistochemically classify pituitary adenoma subtypes with radiomics based on preoperative magnetic resonance imaging.

PURPOSE: The type of pituitary adenoma (PA) cannot be clearly recognized with preoperative magnetic resonance imaging (MRI) but can be classified with immunohistochemical staining after surgery. In this study, a model to precisely immunohistochemically classify the PA subtypes by radiomic features based on preoperative MR images was developed. METHODS: Two hundred thirty-five pathologically diagnosed PAs, including t-box pituitary transcription factor (Tpit) family tumors (n = 55), pituitary transcription factor 1 (Pit-1) family tumors (n = 110), and steroidogenic factor 1 (SF-1) family tumors (n = 70), were retrospectively studied. T1-weighted, T2-weighted and contrast-enhanced T1-weighted images were obtained from all patients. Through imaging acquisition, feature extraction and radiomic data processing, 18 radiomic features were used to train support vector machine (SVM), k-nearest neighbors (KNN) and Naïve Bayes (NBs) models. Ten-fold cross-validation was applied to evaluate the performance of these models. RESULTS: The SVM model showed high performance (balanced accuracy 0.89, AUC 0.9549) whereas the KNN (balanced accuracy 0.83, AUC 0.9266) and NBs (balanced accuracy 0.80, AUC 0.9324) models displayed low performance based on the T2-weighted images. The performance of the T2-weighted images was better than that of the other two MR sequences. Additionally, significant sensitivity (P = 0.031) and specificity (P = 0.012) differences were observed when classifying the PA subtypes by T2-weighted images. CONCLUSIONS: The SVM model was superior to the KNN and NBs models and can potentially precisely immunohistochemically classify PA subtypes with an MR-based radiomic analysis. The developed model exhibited good performance using T2-weighted images and might offer potential guidance to neurosurgeons in clinical decision-making before surgery.

Case report: neonatal giant forehead hemangiopericytoma with a 5-year follow-up.

RATIONALE: Hemangiopericytoma (HPC) is a rare pediatric neoplasm with a high risk of bleeding, aggressive growth and high early relapse rates. Surgical excision remains the mainstream treatment, while the functions of chemotherapy and radiotherapy remain controversial. In particular, an infantile giant extracranial HPC located in the forehead has never been reported. PATIENT CONCERNS: A 3-day-old girl was delivered normally with a giant tumor localized mainly in the right frontal region. The surface of the mass was filled with vascularity. DIAGNOSIS: According to the results of imaging and pathological examinations, the diagnosis was HPC grade II. INTERVENTIONS: Gross total resection of the tumor and the invading partial frontal bone followed by skin scalp reconstruction was carried out without any blood transfusion. OUTCOMES: No recurrence was identified during 5 years of follow-up. And better outcomes can be achieved without adjuvant therapy. LESSONS: Multimodality imaging and a collaborative multidisciplinary approach are indispensable for the successful surgical management of infantile HPC, especially for giant tumors and their potential risk of life-threatening bleeding. Gross total resection is the optimal option for infantile HPC, and even without adjuvant therapy, it achieves better outcomes.

The expanding family of noncanonical regulatory cell subsets.

The overwhelming body of research on regulatory lymphocytes has focused on CD4+ CD25+ Foxp3+ T cells (regulatory T cells); however, the last 5 years have witnessed inspiring progress in our understanding of regulatory B cells, regulatory CD8+ T cells, regulatory γδ cells, and, more recently, regulatory innate lymphoid cells(ILCregs). This review focuses on these so-called noncanonical regulatory cell subsets. We primarily survey existing information on the phenotype, function, sustaining factors, and clinical value of the 4 best-characterized non-CD4 + Foxp3+ T regulatory cells. We then take a brief journey into the advances and challenges associated with next-generation sequencing technologies and the application of sequencing to the study of noncanonical regulatory cell subsets.

Atorvastatin ameliorates early brain injury through inhibition of apoptosis and ER stress in a rat model of subarachnoid hemorrhage.

Aneurysmal subarachnoid hemorrhage (SAH) is a severe cerebrovascular disease with very poor prognosis. The aim of the present study was to evaluate the protective effects of atorvastatin on early brain injury (EBI) after SAH using a perforation SAH model. Male Sprague-Dawley rats were randomly divided into four groups: the sham group, the SAH group (model group), SAH + 10 mg.kg-1day-1 atorvastatin (low atorvastatin group), and SAH + 20 mg.kg-1day-1 atorvastatin (high atorvastatin group). Atorvastatin was administered orally by gastric gavage for 15 days before operation. At 24 h after SAH, we evaluated the effects of atorvastatin on brain water content, apoptosis by TUNEL assay and scanning electron microscope (SEM), and the expression of apoptosis-related proteins by immunofluorescence and Western blotting analysis. Compared with the sham group, we observed increased brain water content, significant apoptosis, and elevated levels of apoptosis-related proteins including caspase-3, CCAAT enhancer-binding protein homologous protein (CHOP), the 78-kDa glucose-regulated protein (GRP78), and aquaporin-4 (AQP4) in the SAH group. Atorvastatin administration under all doses could significantly reduce brain water content, apoptosis, and the expression levels of caspase-3, CHOP, GRP78, and AQP4 at 24 h after SAH. Our data show that early treatment with atorvastatin effectively ameliorates EBI after SAH through anti-apoptotic effects and the effects might be associated inhibition of caspase-3 and endoplasmic reticulum (ER) stress related proteins CHOP and GRP78.

Fibrinolytic Therapy Improves Outcomes in Patients with Epidural Hematomas Following Cranioplasty: A Pilot Study.

BACKGROUND AND STUDY AIMS: Cranioplasty is a cosmetic procedure utilized to reconstruct cranial defects in patients following decompressive craniectomy. Epidural hematomas are a common complication of cranioplasty and often require surgical drainage. However, repeated surgery compromises patient safety and delays recovery. MATERIAL AND METHODS: We investigated the development of epidural hematomas among 131 patients who underwent cranioplasty. Then we explored the efficacy of urokinase (UK) injection for the noninvasive treatment of epidural hematomas. We observed that 15 patients presented with epidural hematoma following cranioplasty. UK (30,000 IU/3 mL) was injected into the hematoma cavity twice every 12 hours in the first postoperative day. Next we closed the subgaleal drain for 1.5 hours and connected it with a negative-pressure ball on full vacuum to allow drainage. Binary logistic regression analysis was used to evaluate the risk factors associated with the development of epidural hematomas. RESULTS: Our findings demonstrated that a sunken skin flap was a risk factor for epidural hematoma formation (p = 0.006). The decrease in epidural hematoma volume was 35.27 ± 7.27 mL in the first 12 hours on postoperative day 1 after UK treatment. All treated patients whose Glasgow Coma Scale score did not significantly change despite the epidural hematoma had an uneventful recovery without additional complications and were discharged from the hospital, except for one patient. CONCLUSION: Fibrinolytic therapy can be considered an optional treatment for postoperative epidural hematoma associated with cranioplasty, especially in patients who refused further operative treatment or who are not optimal candidates for a second surgery.