m6A methyltransferase WTAP regulates myocardial ischemia reperfusion injury through YTHDF1/FOXO3a signaling.

N6-methyladenosine (m6A) is emerging as an essential regulator in the progression of myocardial ischemia reperfusion (I/R) injury. However, the in-depth functions and mechanisms for m6A are still unclear. This work aimed to explore the potential functions and mechanisms for myocardial I/R injury. In this study, m6A methyltransferase WTAP and m6A modification level elevated in the hypoxia/reoxygenation (H/R) induced rat cardiomyocytes (H9C2) and I/R injury rat model. Bio-functional cellular experiments demonstrated that knockdown of WTAP remarkably released the proliferation and reduced the apoptosis and inflammatory cytokines induced by H/R. Moreover, exercise training alleviated WTAP level in exercise-trained rats. Mechanistically, methylated RNA immunoprecipitation sequencing (MeRIP-Seq) revealed that a remarkable m6A modification site was found in the 3'-UTR of FOXO3a mRNA. Moreover, WTAP triggered the installation of m6A modification on FOXO3a mRNA through m6A reader YTHDF1, thereby enhancing the stability of FOXO3a mRNA. Collectively, WTAP/YTHDF1/m6A/FOXO3a axis regulates the myocardial I/R injury progression, which provides new insights for the treatment of myocardial injury.

Predictive value of white blood cell to hemoglobin ratio for 30-day mortality in patients with severe intracerebral hemorrhage.

Aim: To explore the predictive value of white blood cell to hemoglobin ratio (WHR) for 30-day mortality in patients with intracerebral hemorrhage (ICH). Methods: In this cohort study, 2,848 patients with ICH were identified in the Medical Information Mart for Intensive Care (MIMIC)-III and MIMIC-IV. Least absolute shrinkage and selection operator (LASSO) regression screened covariates of 30-day mortality of ICH patients. COX regression analysis was used to study the association of different levels of WHR, white blood cell (WBC), and hemoglobin (Hb) with 30-day mortality. The median follow-up time was 30 (20.28, 30.00) days. Results: In total, 2,068 participants survived at the end of the follow-up. WHR was negatively correlated with the Glasgow Coma Score (GCS) (spearman correlation coefficient = -0.143, p < 0.001), and positively associated with the Sepsis-related Organ Failure Assessment (SOFA) score (spearman correlation coefficient = 0.156, p < 0.001), quick SOFA (qSOFA) score (spearman correlation coefficient = 0.156, p < 0.001), and Simplified Acute Physiology Score II (SAPS-II) (spearman correlation coefficient = 0.213, p < 0.001). After adjusting for confounders, WHR >0.833 (HR = 1.64, 95%CI: 1.39-1.92) and WBC >10.9 K/uL (HR = 1.49, 95%CI: 1.28-1.73) were associated with increased risk of 30-day mortality of patients with ICH. The area under the curve (AUC) value of the prediction model based on WHR and other predictors was 0.78 (95%CI: 0.77-0.79), which was higher than SAPSII (AUC = 0.75, 95%CI: 0.74-0.76), SOFA score (AUC = 0.69, 95%CI: 0.68-0.70) and GCS (AUC = 0.59, 95%CI: 0.57-0.60). Conclusion: The level of WHR was associated with 30-day mortality in patients with severe ICH, and the WHR-based prediction model might provide a tool to quickly predict 30-day mortality in patients with ICH.

Trigone ventricular glioblastoma multiforme with trapped temporal horn: A case report.

Background: Intraventricular glioblastoma multiforme (GBM) is extremely rare, especially in the trigone region. This report presents a case of trigone ventricular GBM with trapped temporal horn (TTH). Case presentation: A 59-year-old woman was admitted to our department with a 1-month history of rapidly progressive headache, nausea, and weakness in the right lower extremity. Head non-contrast computed tomography and enhanced magnetic resonance imaging (MRI) revealed a trigone ventricular mass lesion with TTH and heterogeneous enhancement. The lesion was found 18 months ago as a small asymptomatic tumor mimicking ependymoma. This neoplasm was removed subtotally through the right parieto-occipital approach guided by neuroendoscopy. A ventriculoperitoneal shunt was subsequently performed to relieve TTH. The final pathological diagnosis was GBM. Unfortunately, 36 days after the first surgery, the patient died due to her family's decision to refuse therapy. Conclusion: This rare case shows that GBM should be considered in the differential diagnosis of trigonal tumors. In this case, the tumor possibly originated from the neural stem cells in the subventricular zone. Patients with intraventricular GBM have a worse prognosis, and careful follow-up and early surgery for small intraventricular tumors are necessary, even for those with ependymoma-like radiological findings.

Treatment and prognostic factors of pituicytoma: a single-center experience and comprehensive literature review.

PURPOSE: Preoperative diagnosis of pituicytomas is difficult, and management and prognostic factors remain ambiguous. The purpose of this study was to elucidate the radiological characteristics of pituicytoma, to assess the risk factors affecting tumor progression, and to propose the optimal treatment regimen based on comprehensive analysis. METHODS: We reviewed the clinical data of 22 patients with pituicytoma confirmed pathologically in our institution. In addition, 93 cases of pituicytoma in the previous literature were recruited. The individual data of 115 patients were analyzed to evaluate the adverse factors affecting pituicytoma progression. RESULTS: In the combined cohort, 3 of 61 patients who underwent gross-total resection (GTR) developed recurrence (4.9%); of the 54 patients who received non-GTR, 19 progressed (35.2%). Univariate and multivariate Cox regression analysis verified male gender (HR 2.855, 95% CI 1.008-8.089; p = 0.048), TS (transsphenoidal surgery; HR 3.559, 95% CI 1.015-12.476; p = 0.047), and non-GTR (HR 4.388, 95%CI 1.240-15.521; p = 0.022) were independent unfavorable factors for pituicytoma progression. A multivariate logistic regression model verified that tumor diameter ≥ 1.85 cm (OR 4.859, 95% CI 1.335-17.691; p = 0.016) was independent adverse factors for GTR. Compared with TS, OT (open transcranial) is more likely to have postoperative complications (OR 3.185, 95% CI 1.020-9.944; p = 0.046), especially vision deterioration (OR 37.267, 95% CI 4.486-309.595; p = 0.001). CONCLUSION: Based on our findings, GTR was advocated as an optimal treatment for pituicytomas. However, in order to avoid damage to important structures, partial resection is acceptable. After that, adjuvant radiotherapy is recommended for male patients with high Ki-67 index, and the remaining patients can be followed up closely. When the tumor recurs or progresses, it is recommended to re-operate and remove the lesion completely as far as possible. If GTR is still not possible, postoperative radiotherapy for the residual tumor is recommended.

Single-cell transcriptome and genome analyses of pituitary neuroendocrine tumors.

BACKGROUND: Pituitary neuroendocrine tumors (PitNETs) are the second most common intracranial tumor. We lacked a comprehensive understanding of the pathogenesis and heterogeneity of these tumors. METHODS: We performed high-precision single-cell RNA sequencing for 2679 individual cells obtained from 23 surgically resected samples of the major subtypes of PitNETs from 21 patients. We also performed single-cell multi-omics sequencing for 238 cells from 5 patients. RESULTS: Unsupervised clustering analysis distinguished all tumor subtypes, which was in accordance with the classification based on immunohistochemistry and provided additional information. We identified 3 normal endocrine cell types: somatotrophs, lactotrophs, and gonadotrophs. Comparisons of tumor and matched normal cells showed that differentially expressed genes of gonadotroph tumors were predominantly downregulated, while those of somatotroph and lactotroph tumors were mainly upregulated. We identified novel tumor-related genes, such as AMIGO2, ZFP36, BTG1, and DLG5. Tumors expressing multiple hormone genes showed little transcriptomic heterogeneity. Furthermore, single-cell multi-omics analysis demonstrated that the tumor had a relatively uniform pattern of genome with slight heterogeneity in copy number variations. CONCLUSIONS: Our single-cell transcriptome and single-cell multi-omics analyses provide novel insights into the characteristics and heterogeneity of these complex neoplasms for the identification of biomarkers and therapeutic targets.

Comparative efficacy of antiangiogenic treatment for newly diagnosed glioblastoma: A protocol for systematic review and network meta-analysis.

BACKGROUND: Glioblastoma is the most common malignant primary brain tumor which has highly expressed vascular endothelial growth factor. To date, various antiangiogenic drugs have been investigated in clinical trials but with no overall conclusion, especially for newly diagnosed glioblastoma (nGBM). In this study, Bayesian network meta-analysis will be used to conduct a comprehensive analysis of the results of different clinical trials, and assess the efficacy of different antiangiogenic drugs on nGBM. METHODS: In order to find more comprehensive information about the application of antiangiogenic drugs in nGBM patients, we searched the MEDLINE, EMBASE, Web of Science, and Cochrane Central Register of Controlled Trials for relevant randomized controlled trials. We also reviewed their reference lists to avoid omissions. Cochrane risk of bias tool (V.1.4.3) and Stata (V.15.0) will be used to assess the methodological quality of this review. RESULTS: This study will provide reliable evidence for different antiangiogenic therapies in nGBM patients. CONCLUSION: We will evaluate the relative effectiveness of different antiangiogenic drugs and rank each intervention in nGBM patients through prognosis to provide decision-making reference on which method to choose for clinicians. PROTOCOL REGISTRATION NUMBER: CRD42019146537.

Predicting short-term recurrence in pituitary adenomas: Phosphohistone-H3 (Ser 10) proves an effective biomarker.

AIMS: This research sought to assess the effectiveness of the phosphohistone-H3 (PHH3) mitotic index (MI) as a biomarker to predict early recurrence and inform treatment options and follow-up intervals. MATERIALS AND METHODS: Quantitative immunohistochemical analysis was performed to assess H & E, PHH3, and MIB-1/Ki-67 expression in samples of 141 PAs. Next, the correlation between mitotic figures on H & E (mitotic figures), PHH3 MI, Ki-67 labeling index (LI) and clinical variables was analyzed. The difference among primary- and repeated-surgery groups, nonrecurrent and recurrent groups, and tumor subtypes of PHH3 MI and Ki-67 LI were also assessed. Finally, survival analysis was performed to test the predictive capacity of the biomarkers. RESULTS: The results showed that the group with Ki-67 LI > 2.6% was more prone to short-term recurrence (p < 0.05). Ki-67 LI also correlated with tumor size and Knosp grades (p < 0.05); Ki-67 LI was higher in PAs with Knosp grades III and IV. However, PHH3-positive tumor cells were strongly correlated with the mitosis observed by hematoxylin-eosin staining. Significantly, the PHH3 MI showed stronger short-term prognostic capacity than Ki-67 LI. With a cut-off value of 0.5%, PHH3 MI predicted recurrence with a sensitivity and specificity of 61.5 and 92.1%, respectively. Multivariate survival analysis found that only PHH3 MI was found to be an independent prognostic factor with a hazard ratio of 2.884, compared with 1.076 for Ki-67 LI. CONCLUSION: Phosphohistone-H3 is shown to be an effective prognostic biomarker for short-term recurrence of PAs. This suggests that it should be used alongside Ki-67 as a predictor for prognosis.