Transition of allele-specific DNA hydroxymethylation at regulatory loci is associated with phenotypic variation in monozygotic twins discordant for psychiatric disorders.

BACKGROUND: Major psychiatric disorders such as schizophrenia (SCZ) and bipolar disorder (BPD) are complex genetic mental illnesses. Their non-Mendelian features, such as those observed in monozygotic twins discordant for SCZ or BPD, are likely complicated by environmental modifiers of genetic effects. 5-Hydroxymethylcytosine (5hmC) is an important epigenetic mark in gene regulation, and whether it is linked to genetic variants that contribute to non-Mendelian features remains largely unexplored. METHODS: We combined the 5hmC-selective chemical labeling method (5hmC-seq) and whole-genome sequencing (WGS) analysis of peripheral blood DNA obtained from monozygotic (MZ) twins discordant for SCZ or BPD to identify allelic imbalances in hydroxymethylome maps, and examined association of allele-specific hydroxymethylation (AShM) transition with disease susceptibility based on Bayes factors (BF) derived from the Bayesian generalized additive linear mixed model. We then performed multi-omics integrative analysis to determine the molecular pathogenic basis of those AShM sites. We finally employed luciferase reporter, CRISPR/Cas9 technology, electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation (ChIP), PCR, FM4-64 imaging analysis, and RNA sequencing to validate the function of interested AShM sites in the human neuroblastoma SK-N-SH cells and human embryonic kidney 293T (HEK293T) cells. RESULTS: We identified thousands of genetic variants associated with AShM imbalances that exhibited phenotypic variation-associated AShM changes at regulatory loci. These AShM marks showed plausible associations with SCZ or BPD based on their effects on interactions among transcription factors (TFs), DNA methylation levels, or other epigenomic marks and thus contributed to dysregulated gene expression, which ultimately increased disease susceptibility. We then validated that competitive binding of POU3F2 on the alternative allele at the AShM site rs4558409 (G/T) in PLLP-enhanced PLLP expression, while the hydroxymethylated alternative allele, which alleviated the POU3F2 binding activity at the rs4558409 site, might be associated with the downregulated PLLP expression observed in BPD or SCZ. Moreover, disruption of rs4558409 promoted neural development and vesicle trafficking. CONCLUSION: Our study provides a powerful strategy for prioritizing regulatory risk variants and contributes to our understanding of the interplay between genetic and epigenetic factors in mediating SCZ or BPD susceptibility.

Multimodal Emotion Recognition in Response to Oil Paintings.

Most previous affective studies use facial expression pictures, music or movie clips as emotional stimuli, which are either too simplified without contexts or too dynamic for emotion annotations. In this work, we evaluate the effectiveness of oil paintings as stimuli. We develop an emotion stimuli dataset with 114 oil paintings selected from subject ratings to evoke three emotional states (i.e., negative, neutral and positive), and acquire both EEG and eye tracking data from 20 subjects while watching the oil paintings. Furthermore, we propose a novel affective model for multimodal emotion recognition by 1) extracting informative features of EEG signals from both the time domain and the frequency domain, 2) exploring topological information embedded in EEG channels with graph neural networks (GNNs), and 3) combining EEG and eye tracking data with a deep autoencoder neural network. From the exper-iments, our model obtains an averaged classification accuracy of 94.72 % ± 1.47 %, which demonstrates the feasibility of using oil paintings as emotion elicitation material.

PEP-sNASP Peptide Alleviates LPS-Induced Acute Lung Injury Through the TLR4/TRAF6 Axis.

Acute lung injury (ALI) is a severe inflammatory lung disease associated with macrophages. Somatic nuclear autoantigenic sperm protein (sNASP) is a negative regulator of Toll-like receptor (TLR) signaling that targets tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) in macrophages, which is required to maintain homeostasis of the innate immune response. In the present study, we generated a cell permeable PEP-sNASP peptide using the sNASP protein N-terminal domain, and examined its potential therapeutic effect in a mouse model of ALI induced by the intranasal administration of lipopolysaccharide (LPS) and elucidated the underlying molecular mechanisms in RAW 264.7 cells. In vivo, PEP-sNASP peptide treatment markedly ameliorated pathological injury, reduced the wet/dry (W/D) weight ratio of the lungs and the production of proinflammatory cytokines (interleukin (IL)-1ß, IL-6, and TNF-α). In vitro, we demonstrated that when the PEP-sNASP peptide was transduced into RAW 264.7 cells, it bound to TRAF6, which markedly decreased LPS-induced proinflammatory cytokines by inhibiting TRAF6 autoubiquitination, nuclear factor (NF)-κB activation, reactive oxygen species (ROS) and cellular nitric oxide (NO) levels. Furthermore, the PEP-sNASP peptide also inhibited NLR family pyrin domain containing 3 (NLRP3) inflammasome activation. Our results therefore suggest that the PEP-sNASP may provide a potential protein therapy against oxidative stress and pulmonary inflammation via selective TRAF6 signaling.

Surgery for advanced-stage non-small cell lung cancer: lobectomy or sub-lobar resection?

BACKGROUND: Metastatic non-small cell lung cancer (NSCLC) has many comorbidities, such as chronic obstructive pulmonary disease, coronary heart disease, and older age-related comorbidities. A survival benefit was observed in such patients who underwent surgery for selected oligometastatic disease. However, to the best of our knowledge, there is no evidence to support whether lobectomy (compared with sub-lobar resection) would further prolong these patients' lives. METHODS: Patients with metastatic NSCLC who underwent primary tumor resection were identified from the Surveillance, Epidemiology, and End Results (SEER) database and then divided into lobectomy and sub-lobar resection groups. Propensity score matching (PSM, 1:1) was performed to match the baseline characteristics of the two groups. Cancer-specific survival (CSS) was estimated. RESULTS: In total, 24,268 patients with metastatic NSCLC were identified; 4,114 (16.95%) underwent primary tumor surgery, and of these, 2,045 (49.71%) underwent lobectomy and 1,766 (42.93%) underwent sub-lobar resection. After PSM, 644 patients in each group were included. Lobectomy was independently correlated with longer median CSS time [hazards ratio (HR): 0.70, 95% confidence interval (CI): 0.61-0.80, P<0.001]. The 1, 2, and 3-year survival rates after PSM also favored the lobectomy group. However, no significant survival difference was found for wedge resection and segmentectomy (HR: 0.96, 95% CI: 0.70-1.31, P=0.490). The 1-, 2-, and 3-year survival rates after PSM also exhibited no difference within the sub-lobar group. We explored whether lymph node dissection would provide additional survival benefits for stage IV NSCLC patients. According to the multivariate Cox analysis of the matched population, lymph node dissection was independently associated with better CSS (HR: 0.76, 95% CI: 0.66-0.88, P<0.001) and overall survival (OS) (HR: 0.74, 95% CI: 0.65-0.86, P<0.001). We confirmed this result in the different types of surgery and found that the lymph node dissection group consistently had better survival outcomes both in the lobectomy group and sub-lobar resection population. According to the subgroup analysis, with the exception of stage T4 and brain metastatic patients, all of the patient subtypes exhibited greater benefit from lobectomy than sub-lobar resection. CONCLUSIONS: Lobectomy has a greater survival benefit in metastatic NSCLC patients compared with sub-lobar resection when radical treatment of primary site was indicated.

Spontaneous ventilation video-assisted thoracic surgery for mediastinal tumor resection in patients with pulmonary function deficiency.

BACKGROUND: Whether non-intubated spontaneous ventilation video-assisted thoracoscopic surgery (SV-VATS) is a safe procedure remains controversial for mediastinal tumor patients with impaired lung function. Herein, we assessed feasibility of SV-VATS in lung function deficiency patients underwent mediastinal tumor resection. METHODS: From December 2015 to February 2020, 32 mediastinal tumor patients with impaired lung function (preoperative forced expiratory volume in 1 second <70% of the predicted value) were retrospectively collected. Patients were divided into two groups: SV-VATS group and mechanical ventilation VATS (MV-VATS) group. Intraoperative and postoperative variables were compared between two cohorts. RESULTS: Fifteen patients (46.88%) underwent SV-VATS and 17 patients (53.12%) were performed with MV-VATS. The most common causes of lung function deficiency were smoking (81.25%) and COPD (71.88%). Patients in the SV-VATS group had similar blood loss (20.63 vs. 18.76 mL, P=0.417) with MV-VATS group. The anesthesia time (217.51 vs. 197.76 min; P=0.343) and surgery time (141.23 vs. 132.36 min; P=0.209) were also similar between groups. Five people suffered postoperative complications in each group, in which 1 patient underwent MV-VATS was transferred to intensive care unit (ICU) because of prolonged extubation owing to hypoxia. There was no difference on chest tube removal time (2.6 vs. 2.3 days; P=0.172) or hospital duration (5.03 vs. 4.74 days; P=0.297) in patients underwent SV-VATS and MV-VATS. CONCLUSIONS: SV-VATS is safe and provides similar short-term results to MV-VATS for mediastinal tumor resection in patients with limited pulmonary function.

Comparison of different surgical approaches for anterior mediastinal tumor.

BACKGROUND: Different video-assisted thoracoscopic surgery (VATS) approaches may related to heterogeneous clinical outcomes in anterior mediastinal tumor surgery. Herein, we assessed the comparison between the subxiphoid and intercostal approach, and also compare the left versus the right incision in the intercostal approach for anterior mediastinal tumor patients. METHODS: Clinical data of patients receiving thoracoscopic anterior mediastinal tumor resection were retrospectively collected. Patients were divided into two groups according to the approaches: subxiphoid and the intercostal group. The intercostal group was further subdivided into two groups according to different sides: left and right incision group. Intraoperative and postoperative variables were compared between subgroups. RESULTS: A total of 238 patients were consecutively included in this analysis; 198 (83.2%) patients received intercostal procedure and 40 (16.8%) patients received subxiphoid approach. After 1:1 propensity score matching, all baseline characters were well balanced between intercostal and subxiphoid approach, left and right intercostal approach. The visual analogue scale (VAS) pain score was lower in patients underwent subxiphoid approach than intercostal group at first post-operative evaluation in 12-24 h (4.36 vs. 2.23; P=0.03). According to left and right approach, postoperative drainage time (1.9 vs. 1.2 days, P=0.016), postoperative drainage volume (312.1 vs. 193.9 mL, P=0.041) and hospitalization time (5.3 vs. 4.1 days, P=0.043) were significantly increased in the left thoracic approach group compared with the right thoracic approach. CONCLUSIONS: Subxiphoid approach is associated with less pain compared with intercostal approach. The right intercostal thoracic approach may offer better clinical effect of short-term postoperative recovery.

Feasibility and safety of PD-1/L1 inhibitors for non-small cell lung cancer in front-line treatment: a Bayesian network meta-analysis.

BACKGROUND: This Bayesian network meta-analysis (NMA) was conducted to compare efficacy and safety of programmed death 1/ligand 1 (PD-1/L1) inhibitors in previous untreated advanced non-small cell lung cancer (NSCLC) patients. METHODS: Eligible studies evaluating first-line anti-PD-1/L1 based regimens in advanced NSCLC patients were included. Overall survival (OS), progression free survival (PFS), objective response rate (ORR), as well as treatment-related severe adverse events (tr-SAE) were synthesized within the Bayesian framework. Subgroup analysis was conducted according to PD-L1 expression. RESULTS: Twelve studies including 7,490 patients and 9 treatment strategies were enrolled in this study. For the PD-L1 expression non-selective patients, all chemo-immunotherapies were significantly better than chemotherapy for prolonging OS and PFS, except for caremlizumab plus chemotherapy (HR =0.72) failed to show advantages for OS. In addition, pembrolizumab plus chemotherapy showed better PFS than nivolumab plus ipilimumab (HR =0.66). In PD-L1 ≥50% patients, all immunotherapy was better than chemotherapy for OS, except for nivolumab (HR =0.83) and nivolumab plus ipilimumab (HR =0.70). For PFS, pembrolizumab plus chemotherapy (HR =0.39), atezolizumab plus chemotherapy (HR =0.47) and pembrolizumab (HR =0.67) were significantly better than chemotherapy. In PD-L1 1-49% patients, pembrolizumab plus chemotherapy (HR =0.52) and atezolizumab plus chemotherapy (HR =0.70) were better than chemotherapy for PFS. In the PD-L1 positive or negative group, all included corresponding regimens were equivalence according to OS and PFS. CONCLUSIONS: We conducted a systematic comparison of first line immunotherapy for advanced NSCLC. Chemo-immunotherapies were better than chemotherapy and mono-immunotherapies in most patients. Pembrolizumab might have better efficacy than other PD-1/L1 inhibitors.