Oncogenic lncRNA MALAT-1 recruits E2F1 to upregulate RAD51 expression and thus promotes cell autophagy and tumor growth in non-small cell lung cancer.

INTRODUCTION: LncRNA MALAT-1 expression is involved in regulating activities of non-small-cell lung cancer (NSCLC) cells. This study aimed to investigate the effects of lncRNA MALAT-1 on chemosensitivity of NSCLC cells by regulating autophagy. METHODS: We first validated the expression of lncRNA MALAT-1 in NSCLC cell lines. NSCLC cell lines with high lncRNA MALAT-1 expression were exposed to doxorubicin (DOX) to assess chemosensitivity. Further LncMAP database retrieval and ChIP, RIP and luciferase activity assays were conducted to explore interplay between lncRNA MALAT-1, RAD51, and E2F1. Immunofluorescence staining was performed to evaluate formation of autophagosomes in NSCLC cells. Ectopic expression and knockdown methods were used for in vitro mechanism experiments and in vivo substantiation. RESULTS: LncRNA MALAT-1 was overexpressed in NSCLC cells, and could promote NSCLC cell autophagy and inhibit its chemosensitivity. In vitro cell mechanism verification experiments showed that lncRNA MALAT-1 could recruit transcription factor E2F1 to bind to the promoter of RAD51, so as to promote the transcriptional expression of RAD51. In addition, cell function experiments in vitro showed that ectopically expressed lncRNA MALAT-1 promoted NSCLC cell autophagy and inhibited its chemosensitivity, while RAD51 knockdown negated its effect. Finally, in vivo animal experiments confirmed that lncRNA MALAT-1 silencing could impede the tumor growth. CONCLUSIONS: Taken together, this study revealed that silencing lncRNA MALAT-1 enhanced chemosensitivity of NSCLC cells by promoting autophagy, highlighting a feasible approach to prevent chemoresistance in NSCLC treatment.

Iron-Dependent Autophagic Cell Death Induced by Radiation in MDA-MB-231 Breast Cancer Cells.

In radiation oncology, ionizing radiation is used to kill cancer cells, in other words, the induction of different types of cell death. To investigate this cellular death and the associated iron accumulation, the transfer, release, and participation of iron after radiation treatment was analyzed. We found that radiation-induced cell death varied in different breast cancer cells and autophagy was induced in MDA-MB-231 and BT549 cells (triple negative breast cancer cell line) rather than in MCF-7 and zr-75 cells. Iron chelator deferoxamine (DFO), the autophagy inhibitor 3MA, silencing of the autophagy-related genes ATG5, and Beclin 1 could decrease radiation induced cell death in MDA-MB-231 cells, while inhibitors of apoptosis such as Z-VAD-FMK, ferroptosis inhibitor ferrostatin-1 (Fer-1), and necroptosis inhibitor Necrostatin-1 showed no change. This suggests the occurrence of autophagic cell death. Furthermore, we found that iron accumulation and iron regulatory proteins, including transferrin (Tf), transferrin receptor (CD71), and Ferritin (FTH), increased after radiation treatment, and the silencing of transferrin decreased radiation-induced cell death. In addition, radiation increased lysosomal membrane permeabilization (LMP) and the release of lysosomal iron and cathepsins, while cathepsins silencing failed to change cell viability. Radiation-induced iron accumulation increased Reactive oxygen species (ROS) generation via the Fenton reaction and increased autophagy in a time-dependent manner. DFO, N-acetylcysteine (NAC), and overexpression of superoxide dismutase 2 (SOD2) decreased ROS generation, autophagy, and cell death. To summarize, for the first time, we found that radiation-induced autophagic cell death was iron-dependent in breast cancer MDA-MB-231 cells. These results provide new insights into the cell death process of cancers and might conduce to the development and application of novel therapeutic strategies for patients with apoptosis-resistant breast cancer.

Prognostic value of the neutrophil-to-lymphocyte ratio in acute organophosphorus pesticide poisoning.

This study investigates the ability of blood neutrophil-to-lymphocyte ratio (NLR) to predict acute organophosphorus pesticide poisoning (AOPP). Clinical data of 385 patients with AOPP were obtained within 24 h of admission, and NLR values were calculated based on neutrophil and lymphocyte counts. The patients were divided into two groups - good and poor - based on prognosis. Poor prognosis included in-hospital death and severe poisoning. The factors affecting prognosis were analyzed by logistic regression analysis, and the prognostic value of NLR was evaluated using the area under the receiver operating characteristic curve (AUC). Univariate logistic regression analysis showed that NLR levels, serum cholinesterase, and creatinine levels were good predictors of AOPP. Multivariate logistic regression analysis showed that high NLR was an independent risk factor for severe poisoning (adjusted odds ratio [AOR], 1.13; 95% CI, 1.10-1.17; p < 0.05) and in-hospital mortality (AOR, 1.07; 95% CI, 1.03-1.11; p < 0.05). NLR values >13 and >17 had a moderate ability to predict severe poisoning and in-hospital mortality, respectively (AUC of 0.782 [95% CI, 0.74-0.824] and 0.714 [95% CI, 0.626-0.803], respectively). Our results show that high NLR at admission is an independent indicator of poor prognosis in AOPP and can be used to optimize treatment and manage patients.

Nonconvulsive status epilepticus manifesting as rapidly progressive dementia and infarction in the splenium of the corpus callosum: A case report.

RATIONALE: Nonconvulsive status epilepticus (NCSE) is a heterogeneous disease with multiple subtypes. NCSE poses great diagnostic and therapeutic challenges due to the lack of typical symptoms. Here, we report a case of NCSE manifesting as rapidly progressive dementia (RPD) and infarction in the splenium of the corpus callosum. Additionally, the relevant literature was reviewed. PATIENT CONCERNS: A 63-year-old man presented with RPD. Electroencephalogram (EEG) revealed NCSE, and brain magnetic resonance imaging (MRI) showed an isolated infarction in the splenium of the corpus callosum. Mini-mental state examination showed moderate cognitive impairment (14/30 points). DIAGNOSIS: A diagnosis of NCSE with RPD and infarction in the splenium of the corpus callosum was made. INTERVENTIONS: The patient was treated with intravenous diazepam (10 mg), oral levetiracetam (1.0g twice daily), oral sodium valproate (0.2g twice daily), and intramuscular phenobarbital sodium (0.2g once daily). OUTCOMES: After the treatment, the symptoms were improved. The patient could answer questions. Repeated EEG showed that the background a rhythm was slightly overdeveloped, and no clinical or electrical seizures were observed. After discharge, the patient was treated with oral levetiracetam (1.0g twice daily) and oral sodium valproate (0.2g twice daily) for 6 months. At the last follow-up, the patient had clear consciousness, sensitive response, and fluent answering ability. Repeated mini-mental state examination showed that his cognitive function was significantly improved (28/30 points); nevertheless, the lesion in the splenium of corpus callosum remained unchanged on MRI. LESSONS: NCSE manifesting as RPD and infarction in the splenium of the corpus callosum is extremely rare. Epileptic events and focal infarction are usually overlooked in patients with dementia, and the diagnostic value of MRI and EEG should be highlighted.

Social anxiety is associated with poor quality of life in adults with epilepsy in Northeast China: A cross-sectional study.

OBJECTIVE: This study aimed to investigate the factors influencing the level of social anxiety in patients with epilepsy (PWE) in Northeast China. We also identified the effect of social anxiety on the quality of life in these patients. METHODS: A consecutive cohort of 148 adult PWE from The First Hospital of Jilin University were recruited. In this sample, 116 patients had focal epilepsy, 20 had generalized epilepsy, and 12 had unclassified epilepsy. Depressive symptoms, social anxiety, and quality of life were evaluated using the Chinese version of the Patient Health Questionnaire 9 (PHQ-9), 20-item Social Phobia Scale (SPS), 20-item Social Interaction Anxiety Scale (SIAS), and Quality-of-Life Inventory in Epilepsy-31 (QOLIE-31), respectively. Multivariate linear regression analyses were employed to identify independent factors influencing SPS scores and SIAS scores. RESULTS: Correlation analysis suggested that sex, age at onset, seizure frequency over the last year, AED treatment model, >50% nocturnal seizures, PHQ-9 score, and QOLIE-31 score had a significant correlation with the SPS score. The age at onset, seizure frequency over the last year, AED treatment model, PHQ-9 score, and QOLIE-31 score correlated with the SIAS score. Multiple linear regression analysis showed that the total QOLIE-31 score (ß = - 0.481; p = 0.001) was inversely associated with the SPS score in PWE. Additionally, earlier age of onset (ß = -0.156; p = 0.022) and low total QOLIE-31 score (ß = -0.457; p = 0.001) were risk factors for high SIAS scores. CONCLUSION: We found that social anxiety was independently associated with poor quality of life. Earlier age of onset was also a risk factor for social anxiety. Future studies with large sample sizes are required to confirm our findings.

D-serine and NMDA Receptor 1 Expression in Patients with Intractable Epilepsy.

AIM: To investigate the expression patterns of D-serine and N-methyl-D-aspartate (NMDA) receptor 1 in the temporal lobes of patients with intractable epilepsy. MATERIAL AND METHODS: Cortical temporal lobe brain tissue samples were collected from 20 patients with intractable epilepsy and 6 patients with brain trauma. The expression patterns of D-serine and NMDA receptor 1 were detected by immunofluorescence staining and western blot analysis. RESULTS: A total of 20 patients (11 males, 9 females) were included in the present study. D-serine expression was significantly higher in the neurons and glial cells of patients with intractable epilepsy than in control individuals. The mean integrated optical density (IOD) value for the intractable epilepsy group (13.37 ± 1.88) was significantly higher than that for the control group (9.27 ± 0.62, p < 0.05). The mean absorbance value of the NMDA receptor 1 protein strip obtained from intractable epileptic patients was 0.4175 ± 0.2321, which was significantly higher than the value of 0.2402 ± 0.1458 for the control group (p < 0.05). CONCLUSION: D-serine and NMDA receptor 1 expressions increased significantly in patients with intractable epilepsy compared with control patients. Therefore, the D-serine signaling pathway may represent a potential neurochemical target for epilepsy treatment.

Development and Validation of a New Prognostic Scoring System for COVID-19.

This study aimed to develop and validate a bedside risk analysis system for predicting the clinical severity and prognosis of patients with coronavirus disease 2019 (COVID-19). In total, 444 COVID-19 patients were included and randomly assigned in a 2:1 ratio to 2 groups: derivation group and validation group. The new scoring system comprised of the following 8 variables: history of malignant diseases, history of diabetes mellitus, dyspnea, respiratory rate >24 breaths/min, C-reactive protein level >14 mg/L, white blood cell count >8×109/L, platelets count <180 × 1012/L, and lymphocyte count <1 × 109/L. The sensitivity analysis revealed that this new scoring system was more efficient than the sequential organ failure assessment scoring system on the first day of admission. The receiver characteristic curve analysis revealed that the new risk scoring predicted the severe cases of COVID-19 infection with an area under the curve of 0.831 (95% confidence interval [CI]: 0.783-0.879) and 0.798 (95% CI: 0.727-0.869) in the derivation and validation groups, respectively. This proposed risk score system is a fairly reliable and robust tool for evaluating the severity and prognosis of patients with COVID-19. This may help in the early identification of severe COVID-19 patients with poor prognosis, requiring more intense interventions.

Pre-clinical toxicity and immunogenicity evaluation of a MUC1-MBP/BCG anti-tumor vaccine.

Mucin 1 (MUC1), as an oncogene, plays a key role in the progression and tumorigenesis of many human adenocarcinomas and is an attractive target in tumor immunotherapy. Our previous study showed that the MUC1-MBP/BCG anti-tumor vaccine induced a MUC1-specific Th1-dominant immune response, simulated MUC1-specific cytotoxic T lymphocyte killing activity, and could significantly inhibit MUC1-expression B16 cells' growth in mice. To help move the vaccine into a Phase I clinical trial, in the current study, a pre-clinical toxicity and immunogenicity evaluation of the vaccine was conducted. The evaluation was comprised of a single-dose acute toxicity study in mice, repeat-dose chronic toxicity and immunogenicity studies in rats, and pilot toxicity and immunogenicity studies in cynomolgus monkeys. The results showed that treatment with the MUC1-MBP/BCG anti-tumor vaccine did not cause any organ toxicity, except for arthritis or local nodules induced by BCG in several rats. Furthermore, the vaccine significantly increased the levels of IFN-γ in rats, indicating that Th1 cells were activated. In addition, the results showed that the MUC1-MBP/BCG anti-tumor vaccine induced a MUC1-specific IgG antibody response both in rats and cynomolgus monkeys. Collectively, these data are beneficial to move the MUC1-MBP/BCG anti-tumor vaccine into a Phase I clinical trial.