MiR-23b-3p Improves Brain Damage after Status Epilepticus by Reducing the Formation of Pathological High-Frequency Oscillations via Inhibition of cx43 in Rat Hippocampus.

In order to investigate the effectiveness and safety of miR-23b-3p in anti-seizure activity and to elucidate the regulatory relationship between miR-23b-3p and Cx43 in the nervous system, we have established a lithium chloride-pilocarpine (PILO) status epilepticus (SE) model. Rats were randomly divided into the following groups: seizure control (PILO), valproate sodium (VPA+PILO), recombinant miR-23b-3p overexpression (miR+PILO), miR-23b-3p sponges (Sponges+PILO), and scramble sequence negative control (Scramble+PILO) (n = 6/group). After experiments, we got the following results. In the acute phase, the time required for rats to reach stage IV after PILO injection was significantly longer in VPA+PILO and miR+PILO. In the chronic phase after SE, the frequency of spontaneous recurrent seizures (SRSs) in VPA+PILO and miR+PILO was significantly reduced. At 10 min before seizure cessation, the average energy expression of fast ripples (FRs) in VPA+PILO and miR+PILO was significantly lower than in PILO. After 28 days of seizure, Cx43 expression in PILO was significantly increased, and Beclin1expression in all groups was significantly increased. After 28 days of SE,the number of synapses in the CA1 region of the hippocampus was significantly higher in the VPA+PILO and miR+PILO groups compared to that in the PILO group. After 28 days of SE ,hippocampal necrotic cells in the CA3 region were significantly lower in the VPA+PILO and miR+PILO groups compared to those in the PILO group. There were no significant differences in biochemical indicators among the experimental group rats 28 days after SE compared to the seizure control group. Based on the previous facts, we can reach the conclusion that MiR-23b-3p targets and blocks the expression of hippocampal Cx43 which can reduce the formation of pathological FRs, thereby alleviating the severity of seizures, improving seizure-induced brain damage.

Concomitant genomic features stratify prognosis to patients with advanced EGFR mutant lung cancer.

This study aimed to explore the clinical significance of genomics features including tumor mutation burden (TMB) and copy number alteration (CNA) for advanced EGFR mutant lung cancer. We retrospectively identified 1378 patients with advanced EGFR mutant lung cancer and next-generation sequencing tests from three cohorts. Multiple co-occurring genomics alternations occurred in a large proportion (97%) of patients with advanced EGFR mutant lung cancers. Both TMB and CNA were predictive biomarkers for these patients. A joint analysis of TMB and CNA found that patients with high TMB and high CNA showed worse responses to EGFR-TKIs and predicted worse outcomes. TMBhighCNAhigh, as a high-risk genomic feature, showed predictive ability in most of the subgroups based on clinical characteristics. These patients had larger numbers of metastatic sites, and higher rates of EGFR copy number amplification, TP53 mutations, and cell-cycle gene alterations, which showed more potential survival gain from combination treatment. Furthermore, a nomogram based on genomic features and clinical features was developed to distinguish prognosis. Genomic features could stratify prognosis and guide clinical treatment for patients with advanced EGFR mutant lung cancer.

Identification of common genetic variants in KCNQ family genes associated with gastric cancer survival in a Chinese population.

KCNQ family genes ( KCNQ1-5), encoding voltage-gated K + (Kv) channels, have been revealed to have potential pathophysiological roles in cancers. However, the associations between genetic variants located in KCNQ family genes and gastric cancer survival remain unclear. A large-scale cohort comprising 1,135 Chinese gastric cancer patients was enrolled to identify genetic variants in KCNQ family genes associated with overall survival (OS). Based on the survival evaluation of all five members, KCNQ1 was selected for subsequent genetic analysis. Cox regression models and stepwise Cox regression models were conducted to evaluate survival-related genetic variants. We found that KCNQ1 rs10832417 was associated with increased OS in gastric cancer patients (adjusted hazard ratio (HR) = 0.84, 95% confidence interval (CI): 0.72-0.98, P = 0.023). Subsequently, a nomogram was generated to support the prognostic capacity and clinical translation of rs10832417 variants. The rs10832417 T allele was predicted to increase the minimum free energy (MFE) of the secondary structure. Furthermore, we observed that gastric cancer patients with downregulation of KCNQ1 had poor survival in multiple public datasets. The present study found that KCNQ1 rs10832417 could serve as an independent prognostic predictor of gastric cancer, yielding novel insight into the progression and survival of gastric cancer.

Mixed-Mode Mindfulness-based cognitive therapy for psychological resilience, Self Esteem and Stigma of patients with schizophrenia: a randomized controlled trial.

BACKGROUND: People with schizophrenia often face challenges such as lower psychological resilience, reduced self-worth, and increased social stigma, hindering their recovery. Mindfulness-Based Cognitive Therapy (MBCT) has shown promise in boosting psychological resilience and self-esteem while diminishing stigma. However, MBCT demands professional involvement and substantial expenses, adding to the workload of professionals and the financial strain on patients. Mixed-mode Mindfulness-Based Cognitive Therapy (M-MBCT) integrates both "face-to-face" and "self-help" approaches to minimize staff effort and costs. This study aims to assess the impact of M-MBCT on the psychological resilience, self-esteem, and stigma in schizophrenia patients. METHODS: This randomized, controlled, parallel-group, assessor-blinded clinical trial enrolled 174 inpatients with schizophrenia. Participants were randomly assigned to either the experimental or control group. The experimental group underwent an 8-week M-MBCT intervention, while the control group received standard treatment. Data collection employed the Connor-Davidson Resilience Scale (CD-RISC), Internalized Stigma of Mental Illness Scale (ISMI), and Rosenberg Self-Esteem Scale (RSES) before and after the intervention. Post-intervention, significant differences in ISMI, CD-RISC, and RSES scores were observed between the experimental and control groups. RESULTS: In the experimental group, ISMI scores notably decreased, while CD-RISC and RSES scores significantly increased (P < 0.05). Multiple linear regression analysis identified age, education, and family history of mental illness as significant factors related to stigma (P < 0.05). Additionally, correlation analysis indicated a significant negative relationship between the reduction in CD-RISC scores and the reduction in ISMI scores (P < 0.05). CONCLUSION: M-MBCT effectively enhanced psychological resilience and self-esteem while diminishing stigma in individuals with schizophrenia. M-MBCT emerges as a promising treatment option for schizophrenia sufferers. TRIAL REGISTRATION: The trial was registered at the Chinese Clinical Trial Registry on 03/06/2023 ( www.chictr.org.cn ; ChiCTR ID: ChiCTR2300069071).

Guided self-help mindfulness-based intervention for increasing psychological resilience and reducing job burnout in psychiatric nurses: A randomized controlled trial.

AIMS: The present study aimed to explore the effects of a guided self-help mindfulness intervention on psychological resilience and job burnout among psychiatric nurses. BACKGROUND: Psychiatric nurses work in challenging and potentially high stress settings. Mindfulness interventions can improve psychological resilience and reduce job burnout of nurses. However, face-to-face delivery of mindfulness interventions may be inconvenient for individuals. Guided self-help interventions may be more accessible. METHODS: This randomized controlled trial was conducted from January to August 2022. One hundred and eighteen psychiatric nurses were randomized into the intervention and control groups. The individuals in the intervention group received an 8-week guided self-help mindfulness intervention, while the individuals in the control group received a psycho-educational brochure. The Five Facet Mindfulness Questionnaire, the Connor-Davidson Resilience Scale and the Maslach Burnout Inventory-Human Services Survey were used to evaluate the levels of mindfulness, psychological resilience and job burnout, respectively. RESULTS: After an 8-week intervention, compared with the control group, the levels of mindfulness and psychological resilience were higher, while the level of job burnout was lower in the intervention group. CONCLUSIONS: The guided self-help mindfulness intervention can improve psychological resilience and reduce job burnout among psychiatric nurses.

A clinical decision support system to predict the efficacy for EGFR-TKIs based on artificial neural network.

BACKGROUND: The efficacy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) was affected by numerous factors. In the study, we developed and validated an artificial neural network (ANN) system based on clinical characteristics and next-generation sequencing (NGS) to support clinical decisions. METHODS: A multicenter retrospective non-interventional study was conducted. 240 patients from three hospitals with advanced non-small cell lung cancer (NSCLC) and EGFR mutation were tested by NGS before the first treatment. All patients received formal EGFR-TKIs treatment. Five different models were individually trained to predict the efficacy of EGFR-TKIs based on one medical center with 188 patients. Two independent cohorts from other medical centers were collected for external validation. RESULTS: Compared with logistic regression, four machine learning methods showed better predicting abilities for EGFR-TKIs. The inclusion of NGS tests improved the predictive power of models. ANN performed best on the dataset with mutations TP53, RB1, PIK3CA, EGFR mutation sites, and tumor mutation burden (TMB). The prediction accuracy, recall and AUC were 0.82, 0.82, and 0.82, respectively in our final model. In the external validation set, ANN still showed good performance and differentiated patients with poor outcomes. Finally, a clinical decision support software based on ANN was developed and provided a visualization interface for clinicians. CONCLUSION: This study provides an approach to assess the efficacy of NSCLC patients with first-line EGFR-TKI treatment. Software is developed to support clinical decisions.

Pemetrexed induces ROS generation and cellular senescence by attenuating TS-mediated thymidylate metabolism to reverse gefitinib resistance in NSCLC.

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) are strongly recommended for non-small-cell lung cancer (NSCLC) patients harbouring active EGFR mutations, while drug resistance makes exploring resistance mechanisms and seeking effective therapeutic strategies urgent endeavours. Thymidylate synthetase (TYMS or TS) is a dominant enzyme in thymidylate nucleotide metabolism. In this study, we found a positive correlation between TS expression and overall survival (OS) and disease-free survival (DFS) in lung adenocarcinoma. The examination of gene sets from 140 NSCLC patients received EGFR-TKI therapy demonstrated a negative correlation between high TS expression and the efficacy of EGFR-TKI therapy. 24 tissue specimens from NSCLC patients exhibited upregulated TS mRNA expression in NSCLC patients resistant to gefitinib. The NSCLC cell PC9 and HCC827 sensitive to gefitinib and relatively resistant PC9/GR and HCC827/GR cells were used to demonstrate the knockdown of TS restored the sensitivity of resistant cells to gefitinib. Furthermore, pemetrexed effectively suppressed TS-mediated thymidylate metabolism and induced ROS generation, DNA damage and cellular senescence, thereby hampering cancer progression and restoring sensitivity to gefitinib. Our findings illuminate the potential mechanism of TS-triggered gefitinib resistance and indicate inhibition of TS by pemetrexed can potentiate the effect of gefitinib in NSCLC. Pemetrexed combined with gefitinib has potent anti-progression potential in gefitinib-resistant NSCLC. This study suggests that NSCLC patients with both high TS expression and EGFR-driving mutations might benefit more from a combination strategy of EGFR-TKI and pemetrexed-based chemotherapy than EGFR-TKI monotherapy, which has profound clinical implications and therapeutic value.

B4GALT1 promotes immune escape by regulating the expression of PD-L1 at multiple levels in lung adenocarcinoma.

BACKGROUND: Invasive adenocarcinoma (IAC), which is typically preceded by minimally invasive adenocarcinoma (MIA), is the dominant pathological subtype of early-stage lung adenocarcinoma (LUAD). Identifying the molecular events underlying the progression from MIA to IAC may provide a crucial perspective and boost the exploration of novel strategies for early-stage LUAD diagnosis and treatment. METHODS: Transcriptome sequencing of four pairs of MIA and IAC tumours obtained from four multiple primary lung cancer patients was performed to screen out beta-1,4-galactosyltransferase1 (B4GALT1). Function and mechanism experiments in vitro and in vivo were performed to explore the regulatory mechanism of B4GALT1-mediated immune evasion by regulating programmed cell death ligand 1 (PD-L1). RESULTS: B4GALT1, a key gene involved in N-glycan biosynthesis, was highly expressed in IAC samples. Further experiments revealed that B4GALT1 regulated LUAD cell proliferation and invasion both in vitro and in vivo and was related to the impaired antitumour capacity of CD8 + T cells. Mechanistically, B4GALT1 directly mediates the N-linked glycosylation of PD-L1 protein, thus preventing PD-L1 degradation at the posttranscriptional level. In addition, B4GALT1 stabilized the TAZ protein via glycosylation, which activated CD274 at the transcriptional level. These factors lead to lung cancer immune escape. Importantly, inhibition of B4GALT1 increased CD8 + T-cell abundance and activity and enhanced the antitumour immunity of anti-PD-1 therapy in vivo. CONCLUSION: B4GALT1 is a critical molecule in the development of early-stage LUAD and may be a novel target for LUAD intervention and immunotherapy.

LncRNA LINC00969 promotes acquired gefitinib resistance by epigenetically suppressing of NLRP3 at transcriptional and posttranscriptional levels to inhibit pyroptosis in lung cancer.

Epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) treatment prolongs the survival of lung cancer patients harbouring activating EGFR mutations. However, resistance to EGFR-TKIs is inevitable after long-term treatment. Molecular mechanistic research is of great importance in combatting resistance. A comprehensive investigation of the molecular mechanisms underlying resistance has important implications for overcoming resistance. An accumulating body of evidence shows that lncRNAs can contribute to tumorigenesis and treatment resistance. By bioinformatics analysis, we found that LINC00969 expression was elevated in lung cancer cells with acquired gefitinib resistance. LINC00969 regulated resistance to gefitinib in vitro and in vivo. Mechanistically, gain of H3K4me1 and H3K27Ac led to the activation of LINC00969 expression. LINC00969 interacts with EZH2 and METTL3, transcriptionally regulates the level of H3K27me3 in the NLRP3 promoter region, and posttranscriptionally modifies the m6A level of NLRP3 in an m6A-YTHDF2-dependent manner, thus epigenetically repressing NLRP3 expression to suppress the activation of the NLRP3/caspase-1/GSDMD-related classical pyroptosis signalling pathways, thereby endowing an antipyroptotic phenotype and promoting TKI resistance in lung cancer. Our findings provide a new mechanism for lncRNA-mediated TKI resistance from the new perspective of pyroptosis via simultaneous regulation of histone methylation and RNA methylation. The pivotal role of LINC00969 gives it the potential to be a novel biomarker and therapeutic target for overcoming EGFR-TKI resistance in lung cancer.

Carbonic Anhydrase IX Controls Vulnerability to Ferroptosis in Gefitinib-Resistant Lung Cancer.

Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI, such as gefitinib) in lung cancer continues to be a major problem. Recent studies have shown the promise of ferroptosis-inducing therapy in EGFR-TKI resistant cancer, but have not been translated into clinical benefits. Here, we identified carbonic anhydrase IX (CA9) was upregulated in gefitinib-resistant lung cancer. Then we measured the cell viability, intracellular reactive oxygen species (ROS) levels, and labile iron levels after the treatment of ferroptosis inducer erastin. We found that CA9 confers resistance to ferroptosis-inducing drugs. Mechanistically, CA9 is involved in the inhibition of transferrin endocytosis and the stabilization of ferritin, leading to resistance to ferroptosis. Targeting CA9 promotes iron uptake and release, thus triggering gefitinib-resistant cell ferroptosis. Notably, CA9 inhibitor enhances the ferroptosis-inducing effect of cisplatin on gefitinib-resistant cells, thus eliminating resistant cells in heterogeneous tumor tissues. Taken together, CA9-targeting therapy is a promising approach to improve the therapeutic effect of gefitinib-resistant lung cancer by inducing ferroptosis.

Efficacy and safety of antiangiogenic agents or chemotherapy plus EGFR-TKIs in advanced non-small cell lung cancer: A systematic review and network meta-analysis.

BACKGROUND: The combination of antiangiogenic agents with epidermal growth factor receptor inhibitors (EGFR-TKIs) and chemotherapy with EGFR-TKIs are the most common combination treatment options in epidermal growth factor receptor (EGFR) positive non-small cell lung cancer (NSCLC). This network meta-analysis was performed to evaluate the differences between them. METHODS: We searched the PubMed, EMBASE and the Cochrane Controlled Trials Register up to August 2022. The primary outcomes were progression-free survival (PFS) and objective response rate (ORR). The secondary endpoints were overall survival (OS), disease control rate (DCR) and adverse events (AEs). The data of hazard ratio (HR) or risk ratio (RR) with their corresponding 95% confidence intervals (CIs) were extracted in the studies. A network meta-analysis (NMA) was used to indirectly compare the efficacy and safety of antiangiogenic agents plus EGFR-TKIs and chemotherapy plus EGFR-TKIs. RESULTS: Pooled data of included studies were demonstrated that chemotherapy plus EGFR-TKIs had a benefit in ORR compared to antiangiogenic agents plus EGFR-TKIs in patients with EGFR mutated NSCLC (RR = 1.1, 95% CI: 1.0-1.2). However, there were no significant differences in PFS, OS and DCR between in the two group (PFS: HR = 1.0, 95% CI: 0.74-1.6; OS: HR = 0.78, 95% CI: 0.45-1.5; DCR: RR = 1.0, 95% CI: 0.94-1.1). The common treatment-related AEs in the two groups were relatively manageable. CONCLUSION: Based on the efficacy and safety, the combination of chemotherapy with EGFR-TKIs is considered the best combination treatment options in advanced NSCLC with EGFR mutation.

Clinical implications of ctDNA for EGFR-TKIs as first-line treatment in NSCLC.

PURPOSE: This study aimed to explore the clinical implications of ctDNA for epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) as the first-line treatment in EGFR-mutated (EGFRm) non-small cell lung cancer (NSCLC) in real-world settings. METHODS: A total of 122 patients with NSCLC who underwent tissue and liquid next generation sequencing (NGS) tests were included. 66 patients with detected EGFR mutation in both tumor-tissue and plasma were included into the EGFRt+, p+ group, and 56 patients with EGFR mutation detected only in tumor-tissue were included into the EGFRt+, p- group. The differences in clinical characteristics, concomitant mutations and prognosis between the two groups were compared. RESULTS: The detection rate of the EGFRt+, p+ group was 54.1% (66/122). EGFRt+, p+ in the NGS test was particularly relevant to the size of tumors, liver metastasis, bone metastasis and TP53 mutation. In patients with TP53 mutation in ctDNA, the detection rate of EGFR mutation in ctDNA was up to 91.3%. EGFRt+, p+ could be an independent prognostic factor for first-line EGFR-TKIs treatment. Combination therapy seems to be a promising approach to improve the outcome for EGFRt+, p+ (P = 0.017, HR 0.509 [95% CI 0.288-0.897]). Moreover, the combination of TP53 mutated status and EGFRm status in plasma showed a better completion of risk stratification for PFS (Log-rank P < 0.001). CONCLUSIONS: Co-detection of EGFR mutation in tumor tissue and plasma is an independent prognostic factor for first-line EGFR-TKIs treatment. Moreover, combination therapy could be a promising approach to improve the outcome for these patients.

Analysis of color vision and cognitive function in first-episode schizophrenia before and after antipsychotic treatment.

BACKGROUND: A large body of recent research has demonstrated that patients with schizophrenia exhibit significant changes in visual function and ocular tissue structure in the early stages of onset. It is therefore possible to explore a novel scientific breakthrough in the etiology of schizophrenia by transforming the traditional study of brain structure and function with a view to examining the potential field of eye tissue and function. However, few studies have investigated the correlation between iris characteristics and schizophrenia, and evidence is lacking in this regard. Thus, further exploration is needed. PURPOSE: This study was designed to analyze the characteristics of iris structure, color vision function and cognitive function, as well as the changes therein in patients with the first-episode drug-free schizophrenia before and after antipsychotic treatment. It aimed to preliminarily identify easily-measurable biomarkers for early clinical screening and diagnosis of schizophrenia. METHODS: This study recruited 61 patients (22 males) with first-episode schizophrenia. Prior to the commencement of treatment with antipsychotic drugs, the Montreal Cognitive Assessment (MoCA) and Farnsworth-Munsell Dichotomous (D-15 Hue Test) were used as assessment tools to evaluate cognitive function and color vision function, respectively. Over a 6-week period, patients received a second-generation antipsychotic treatment (all converted to olanzapine equivalent dose) as prescribed by the doctor, and the Positive and Negative Syndrome Scale (PANSS) was applied to evaluate the clinical treatment effects before treatment (baseline), as well as at the 2nd, 4th, and 6th weeks after drug treatment. On the basis of iris characteristics, the patients were divided into groups. The observed differences in drug treatment effects between the groups were then compared and analyzed to further clarify the relationship between treatment efficacy and iris characteristics. Finally, changes in the cognitive function and color vision function of patients at baseline and at the 6th week after drug treatment were compared, and the effects of antipsychotic drug treatment on the above-mentioned functions were analyzed. RESULTS: On the basis of structural iris characteristics, 61 patients were classified as follows: 28 patients without iris crypts and 33 with iris crypts; 35 without iris pigment dots and 26 with iris pigment dots; 42 without iris wrinkles and 19 with iris wrinkles. No significant difference was observed in the PANSS scores of all of the patients at baseline; however, significant differences were found in patients with iris crypts and iris pigment dots at each follow-up timepoint (i.e., at the 2nd, 4th, and 6th week). Moreover, it is noteworthy that, compared with other patients, the PANSS scores of patients without specific iris structure characteristics (iris crypts and pigment dots) decreased significantly (P<0.05), which indicated that the drug therapy was highly effective. Excluding the interference of drug factors, a significant correlation was found between the results of the D-15 (color vision function) and MoCA (cognitive function) in first-episode untreated patients (r = -0.401, P < 0.05). In addition, the MoCA scores (mean difference = 2.36, t = 10.05, P ˂ 0.01) were significantly higher after 6 weeks of antipsychotic drug treatment compared to conditions at baseline. CONCLUSIONS: The findings of this study demonstrated that color vision function of patients with schizophrenia improved with the improvement of cognitive function. The structural characteristics of the iris with crypts and pigment dots could have a significant impact on the drug treatment effect of schizophrenia and could be considered as a potential biomarker for detecting and recognizing schizophrenia.

Study on the Correlation Between Iris Characteristics and Schizophrenia.

Background: Recently, researchers have conducted many studies on the potential contribution of the retina and other eye structures on schizophrenia. This study aimed to evaluate differences in iris characteristics between patients with schizophrenia and healthy individuals so as to find more easily accessible and easily measurable biomarkers with a view to improving clinical assessments and furthering our understanding of the disease. Methods: Overall, 80 patients with schizophrenia and 52 healthy individuals were included in the case group and the control group, respectively. Iris images were collected from all subjects to compare differences in the structure and color of the iris. The Positive and Negative Symptom Scale (PANSS) and the Modified Overt Aggression Scale (MOAS) were used to evaluate the clinical symptoms and characteristics of 45 first-episode untreated schizophrenics, and analyzed correlations between iris characteristics and schizophrenia symptoms. Results: There were significant differences in iris crypts (P<0.05) and pigment spots (P<0.01) between the case and control group, but no significant difference was found in iris wrinkles (P<0.05). The logistic regression analysis demonstrated that the total iris crypts [odds ratio (OR) 1.166, 95% confidence interval (CI) 1.022-1.330] and total iris pigment spots (OR 1.815, 95% CI 1.186-2.775) increased the risk of suffering from schizophrenia. Furthermore, it was demonstrated that the number of iris crypts was positively associated with the MOAS score (r=0.474, P<0.01). Moreover, the number of the iris pigment spots (r=0.395, P<0.01) and wrinkles (r=0.309, P<0.05) were positively correlated with the subjects' negative symptom scores, respectively. Conclusion: Iris crypts and pigment spots were identified as potential biomarkers for detecting schizophrenia. In patients with first-episode untreated schizophrenia, iris characteristics may help psychiatrists to identify the illness and its severity, and to detect characteristic clinical symptoms.

Does environmental information disclosure affect the financial performance of commercial banks? Evidence from China.

The article uses hand-collected data regarding environmental information disclosure for Chinese 30 listed banks from 2009 to 2019 to investigate the effect of environmental information disclosure on banks' financial performance. Results show that the improvement in the quality of environmental information disclosure enhances the financial performance of banks, and this effect is intertemporal. In terms of the bank heterogeneity, national banks have a more significant effect of environmental information disclosure on their financial performance compared to regional banks. Furthermore, we provide evidence that the regional green development environment moderates the relationship between environmental information disclosure and banks' financial performance. The findings of our study add impetus for commercial banks to improve their environmental information disclosure.

Deleterious AHNAK2 Mutation as a Novel Biomarker for Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer.

Immune checkpoint inhibitors (ICIs) have exhibited promising efficacy in non-small cell lung cancer (NSCLC), but the response occurs in only a minority of patients. In clinic, biomarkers such as TMB (tumor mutation burden) and PD-L1 (programmed cell death 1 ligand 1) still have their limitations in predicting the prognosis of ICI treatment. Hence, reliable predictive markers for ICIs are urgently needed. A public immunotherapy dataset with clinical information and mutational data of 75 NSCLC patients was obtained from cBioPortal as the discovery cohort, and another immunotherapy dataset of 249 patients across multiple cancer types was collected as the validation. Integrated bioinformatics analysis was performed to explore the potential mechanism, and immunohistochemistry studies were used to verify it. AHNAK nucleoprotein 2 (AHNAK2) was reported to have pro-tumor growth effects across multiple cancers, while its role in tumor immunity was unclear. We found that approximately 11% of the NSCLC patients harbored AHNAK2 mutations, which were associated with promising outcomes to ICI treatments (ORR, p = 0.013). We further found that AHNAK2 deleterious mutation (del-AHNAK2 mut) possessed better predictive function in NSCLC than non-deleterious AHNAK2 mutation (PFS, OS, log-rank p < 0.05), potentially associated with stronger tumor immunogenicity and an activated immune microenvironment. This work identified del-AHNAK2 mut as a novel biomarker to predict favorable ICI response in NSCLC.

PBRM1 mutation as a predictive biomarker for immunotherapy in multiple cancers.

Background: There has been evidence that Polybromo-1 (PBRM1) mutation was closely associated with immunotherapy response in clear cell renal cell carcinoma (ccRCC). However, it remains incompletely unclear whether PBRM1 mutations correlate with ICI response in pan-cancer. Methods: The clinical data and whole exome sequencing (WES) data were collected from seven published immunotherapy studies to evaluate the association between PBRM1 mutation and ICIs efficacy in the discovery cohort. In order to provide further insight into the relationship between PBRM1 and immunity, we analyzed a relatively large sample as a validation cohort. Moreover, we also collected the clinical data and mutation information of 134 non-small cell lung cancer (NSCLC) patients from the First Affiliated Hospital of Nanjing Medical University to verify the findings. Gene set enrichment analysis (GSEA) was used to evaluate the relationship between PBRM1 and immune-related pathway. Results: Our results found that PBRM1 mutation were associated with immune response in the discovery cohort (Progression free survival [PFS]: hazard ratio (HR) = .51, 95% CI: .28-.95, p = .030; objective response rate [ORR]: 47.92% vs. 28.21%, p = .0044; disease control rate [DCR]: 72.92% vs. 47.53%, p = .0008). In the validation cohort, the patients with PBRM1 mutation had a longer overall survival (OS) (hazard ratio = .69, 95% CI: .53-.91, p = .006). In our non-small cell lung cancer cohort, PFS, objective response rate and disease control rate had obvious superiority in the patients with PBRM1 mutation than those without PBRM1 mutation (PFS: HR = .268, 95% CI: 084-.854, p = .04, ORR: 55.56% vs. 20.00%, p = .027, DCR: 100% vs. 75.20%). Using the Gene set enrichment analysis (GSEA) in TCGA cohorts, PBRM1 mutation was closely related to immune efficacy and immune microenvironment, including killer cell mediated immunity regulation, cell cytokine production, CD8+ T-cell activation and MHC protein binding process. Conclusion: There is a strong correlation between PBRM1 mutation and prognosis and immune response. Based on the findings, PBRM1 mutation may be a promising immunotherapeutic signature that could guide clinical management and personalized immunotherapy.

Overexpression of PELP1 in Lung Adenocarcinoma Promoted E2 Induced Proliferation, Migration and Invasion of the Tumor Cells and Predicted a Worse Outcome of the Patients.

The expression of Proline-, glutamic acid-, and leucine-rich protein 1 (PELP1) has been reported to be dysregulated in non-small cell lung carcinoma, especially in lung adenocarcinoma (LUAD). Therefore, we aimed to investigate the functional and prognostic roles of PELP1 in LUAD in this study. We first immunolocalized PELP1 in 76 cases of LUAD and 17 non-pathological or tumorous lung (NTL) tissue specimens and correlated the findings with the clinicopathological parameters of the patients. We then performed in vitro analysis including MTT, flow cytometry, wound healing, and transwell assays in order to further explore the biological roles of PELP1 in 17-ß-estradiol (E2) induced cell proliferation, migration, and invasion of LUAD cells. We subsequently evaluated the prognostic significance of PELP1 in LUAD patients using the online survival analysis tool Kaplan-Meier Plotter. The status of PELP1 immunoreactivity in LUAD was significantly higher than that in the NTL tissues and significantly positively correlated with less differentiated features of carcinoma cells, positive lymph node metastasis, higher clinical stage as well as the status of ERα, ERß, and PCNA. In vitro study did reveal that E2 promoted cell proliferation and migration and elevated PELP1 protein level in PELP1-high A549 and H1975 cells but not in PELP1-low H-1299 cells. Knock down of PELP1 significantly attenuated E2 induced cell proliferation, colony formation, cell cycle progress as well as migration and invasion of A549 and H1975 cells. Kaplan-Meier Plotter revealed that LUAD cases harboring higher PELP1 expression had significantly shorter overall survival. In summary, PELP1 played a pivotal role in the estrogen-induced aggressive transformation of LUAD and could represent adverse clinical outcome of the LUAD patients.

Based on a Decision Tree Model for Exploring the Risk Factors of Smartphone Addiction Among Children and Adolescents in China During the COVID-19 Pandemic.

Background: Smartphone addiction has emerged as a major concern among children and adolescents over the past few decades and may be heightened by the outbreak of COVID-19, posing a threat to their physical and mental health. Then we aimed to develop a decision tree model as a screening tool for unrecognized smartphone addiction by conducting large sample investigation in mainland China. Methods: The data from cross-sectional investigation of smartphone addiction among children and adolescents in mainland China (n = 3,615) was used to build models of smartphone addiction by employing logistic regression, visualized nomogram, and decision tree analysis. Results: Smartphone addiction was found in 849 (23.5%) of the 3,615 respondents. According to the results of logistic regression, nomogram, and decision tree analyses, Internet addiction, hours spend on smartphone during the epidemic, levels of clinical anxiety symptoms, fear of physical injury, and sex were used in predictive model of smartphone addiction among children and adolescents. The C-index of the final adjusted model of logistic regression was 0.804. The classification accuracy, sensitivity, specificity, positive predictive value, negative predictive value, and AUC area of decision tree for detecting smartphone addiction were 87.3, 71.4, 92.1, 73.5, 91.4, and 0.884, respectively. Conclusions: It was found that the incidence of smartphone addiction among children and adolescents is significant during the epidemic. The decision tree model can be used to screen smartphone addiction among them. Findings of the five risk factors will help researchers and parents assess the risk of smartphone addiction quickly and easily.

The Mediating Roles of Emotional Regulation on Negative Emotion and Internet Addiction Among Chinese Adolescents From a Development Perspective.

Previous researches indicated that emotional regulation can be associated with depression and anxiety, which may be an important mediating factor between emotional regulation and internet addiction. However, the mechanism between these associations has received little attention and it is still unclear. This study has examined 716 Chinese adolescents, 341 were males (47.6%), aged 13 to 18(Mean = 14.58, SD = 1.50), using a cross-sectional survey involving Young's Diagnostic Questionnaire for Internet Addiction, the nine-item Patient Health Questionnaire (PHQ-9), the seven-item Generalized Anxiety (GAD-7) scale, and the Emotion Regulation Questionnaire (ERQ). Correlation analysis, multiple-group analysis and structural equation modeling were carried out in SPSS Statistics version 23 (IBM, Armonk, NY) and AMOS version 21. Cognitive reappraisal had a significantly negative direct effect on Internet addiction (ß = -0.118, p < 0.05). Furthermore, negative emotions mediated the relationships between expression suppression and Internet addiction [ß = 0.149, 95% CI = (0.099, 0.212)] and the relationship between cognitive reappraisal and Internet addiction [ß = -0.101, 95% CI = (-0.147, -0.065)]. The differences in the structure path coefficients for different development stages demonstrated that recognitive reappraisal showed more protective roles for negative emotion (p < 0.01), and negative emotion also predict Internet addiction more effectively in high school students (p < 0.001). However, cognitive reappraisal directly predicted negative Internet addiction in junior high school students. Therefore, the intervention on adolescents for internet addiction should not only focus on emotional regulation and negative emotion, but also development stages of adolescents.