How to Improve People's Intentions Regarding COVID-19 Vaccination in China: A Randomized Controlled Trial.

BACKGROUND: The global COVID-19 pandemic has impaired the health and living conditions of millions of people. For governments to formulate policies promoting vaccination behavior, it is important to understand individuals' intentions to vaccinate. This study explores the effectiveness of a brief online intervention based on the Health Action Process Approach (HAPA) in improving individuals' COVID-19 vaccination intention, as well as considering the reasons for their unwillingness to get vaccinated. METHOD: A total of 1,258 participants were assessed using a questionnaire to determine their phase of vaccination intention (pre-intention, intention, and action). Subsequently, focused on the underlying factors in the pre-intention phase (i.e., task self-efficacy, outcome expectation, and risk perception), a 7-day randomized controlled HAPA intervention (n intervention = 57, n control = 49) was conducted online for individuals who were not willing to get vaccinated. The measurement points included pre- (T1), post- (T2), and 30-day follow-up (T3). RESULTS: The intervention may effectively improve participants' COVID-19 vaccination intentions; however, it had no impact on their planning and actions involved in taking the vaccine. CONCLUSIONS: This study provides relevant reference data for government stakeholders to use in developing public awareness campaigns and policies to encourage COVID-19 vaccination.

Regulation of craving training to support healthy food choices under stress: A randomized control trial employing the hierarchical drift-diffusion model.

Stress increases the likelihood of consuming unhealthy food in some individuals. Previous research has demonstrated that the Regulation of Craving - Training (ROC-T) intervention can reduce unhealthy food intake. However, its effectiveness under stress and the underlying mechanism remained uncertain. This study aimed to assess the efficacy of the ROC-T intervention in improving healthy food choices and to explore the intervention mechanism through computational modeling employing the hierarchical drift-diffusion model (HDDM). This study adopted a 2 (ROC-T intervention vs. control) * 2 (stress vs. no-stress) between-subject experimental design. A total of 118 employees (72 women, Mage  = 28.74) participated in the online experiment. Results show that the ROC-T intervention increases healthy food choices under stress and no-stress conditions. The HDDM results reveal a significant two-way interaction for non-decision time (Bayes factor, BF = 32.722) and initial bias (BF = 27.350). Specifically, in the no-stress condition, the ROC-T intervention resulted in lower non-decision time and higher initial bias compared with the control group. The findings validated the negative impact of stress on healthy food choices, and that the ROC-T intervention promotes healthy food choices both under stress and no-stress conditions.

MiR-302a-3p reduces cisplatin resistance of esophageal squamous cell carcinoma cells by targeting EphA2.

Platinum-based chemotherapy is a common clinical treatment for esophageal squamous cell carcinoma (ESCC), and chemoresistance is a major leading reason for cancer treatment failure. MiR-302a-3p is involved in the development of many diseases. Here, we investigated the role of miR-302a-3p in the cisplatin resistance of ESCC cells and explored its potential mechanism via molecular techniques. The expression of miR-302a-3p was significantly reduced, while the expressions of EphA2 were increased in ESCC tumor tissues and cells. EphA2 was one target gene of miR-302a-3p, and was negatively regulated by miR-302a-3p. By regulating EphA2, miR-302a-3p reduced the viability and promoted the apoptosis of ECA109 cells treated with cisplatin, suggesting that miR-302a-3p could enhance the sensitivity of ECA109 cells to cisplatin treatment by targeting EphA2. MiR-302a-3p plays an important role in reducing cisplatin resistance by inhibiting EphA2, suggesting that it may be a promising therapeutic strategy for cisplatin resistance in ESCC in the future.

COVID-19 risk perception and negative emotional symptoms: Mediating role of self-control and moderating role of life history strategy.

The coronavirus disease 2019 (COVID-19) has emerged as a significant public health crisis, posing threats to physical health and mental well-being. This study, grounded in the Risk-Resilience Model, sought to elucidate how COVID-19 risk perception impacts negative emotional symptoms. Specifically, we examined the mediating role of self-control and the moderating role of life history strategies. We conducted a two-wave longitudinal survey in October 2020 (N = 334) and November 2020 (N = 249), targeting residents across 14 provinces (24 cities) in China. After controlling for sex and age, the results supported the moderated mediation model, illustrating that (1) self-control mediated the relationship between COVID-19 risk perception and negative emotional symptoms, (2) life history strategy moderated the first segment of the mediation process, and (3) life history strategies also moderated the mediating effect of self-control on the link between COVID-19 risk perception and negative emotional symptoms. Furthermore, compared to a fast life history strategy, a slow life history strategy mitigated the effect of COVID-19 risk perception on self-control, thereby reducing negative emotional symptoms. This study sheds light on how COVID-19 risk perception affects negative emotional symptoms and identifies potential targets (i.e., self-control and life history strategy) for addressing emotional distress during pandemics.

Bufalin suppresses esophageal squamous cell carcinoma progression by activating the PIAS3/STAT3 signaling pathway.

Background: Esophageal cancer, especially esophageal squamous cell carcinoma (ESCC), is a common malignant tumor of the digestive tract. Bufalin is an effective anti-tumor compound. However, little is known about the regulatory mechanisms of Bufalin in ESCC. To investigate the effect and molecular mechanism of Bufalin on the proliferation, migration and invasion of ESCC cells will provide a more reliable basis for the application of Bufalin in clinical tumor therapy. Methods: First, the half-inhibitory concentration (IC50) of Bufalin was evaluated by Cell Counting Kit-8 (CCK-8) assays. In vitro, the effects of Bufalin on the proliferation of the ECA109 cells was measured using CCK-8 and 5-ethynyl-2'-deoxyuridine assays. Wound-healing and transwell assays were used to evaluate the effects of Bufalin on the migration and invasion of the ECA109 cells. Further, to determine the mechanisms underlying the Bufalin-mediated suppression of cell progression in ESCC, total RNA was extracted from negative control (NC) and Bufalin treated cells to perform RNA-sequencing (RNA-seq) to screen for abnormally expressed genes. In vivo, the ECA 109 cells were subcutaneously injected into BALB/c nude mice to determine the effects of Bufalin on tumor cell proliferation. The protein inhibitor of activated signal transducer and activator of transcription 3 (PIAS3), signal transducer and activator of transcription 3 (STAT3), and phosphorylated STAT3 (p-STAT3) protein expression levels in the ECA109 cells were detected by Western blot. Results: The CCK-8 assays showed that the IC50 of Bufalin was 200 nM. The proliferation, migration, and invasion ability of the ECA109 cells was significantly inhibited in the Bufalin group in a concentration-dependent manner. In vivo, the Xenograft tumor model showed that Bufalin decreased the tumor volume and weight of the subcutaneous tumors. The RNA-seq results showed that the expression of PIAS3 was upregulated in the Bufalin group. Additionally, down-regulation of PIAS3 decreased the inhibition of STAT3, thereby increasing p-STAT3 expression. Finally, PIAS3 knockdown reversed the inhibitory effects of Bufalin on the proliferation, migration, and invasion of the ECA109 cells. Conclusions: Bufalin may inhibit the proliferation, migration, and invasion of the ECA109 cells through the PIAS3/STAT3 signaling pathway.

Relationship between body composition and upper limb physical fitness among Chinese students: 4-Year longitudinal follow-up and experimental study.

Background: Recently, students' fitness has been declining, and high physical fitness level is crucial in establishing optimal physical/mental health and academic performance. The purpose of this study was to explore the relationship between body composition and upper limb physical fitness and the specific aspects of low physical fitness level in Chinese students. Exploring the development and impact factors for upper limb physical fitness can provide a theoretical basis for the health management strategy of students. Methods: Study 1 collected data from 183 male students over 4 years and used Hierarchical Linear Model (HLM) to explore the quadratic predictive role of body composition on upper limb physical fitness. To further explored which aspects of upper limb physical fitness were affected by body composition, study 2 conducted an experimental investigation among 42 male students, comparing different kinds of upper limb physical fitness within two different body composition groups. Results: Studies found (1) from 2015 to 2018, students' Body-Mass-Index (BMI) showed an upward trend, and BMI differences were significant from year to year. While the upper limb physical fitness showed a downward trend. There were significant differences in the number of pull-outs between 2015 and 2016, 2015 and 2017, and 2015 and 2018. (2) The quadratic term of BMI could predict the upper body physical fitness in the same year and the following year. That is, when BMI was medium, the upper body fitness of the same year and the following year was the best. (3) Chinese students with excellent body composition had greater grip strength, drape height and anaerobic power than those with average body composition. Conclusion: In recent years, male students' BMI has been increasing, and the upper body physical fitness has been decreasing. Furthermore, body composition can predict the upper body mass in the same year and the second year, and male students with better body composition also had greater grip strength, drape height and anaerobic power in their upper limbs.

Effect of MBSR, DBT and CBT on the hypertension patients with depression/anxiety: Protocol of a systematic review and Bayesian network meta-analysis.

INTRODUCTION: Hypertension, one of the most common chronic diseases worldwide, usually requires lifetime managing blood pressure (BP) with medications. Due to quite large number of hypertension patients co-exist with depression and/or anxiety, and non-cooperated with medical instruction, consequently management of BP is impaired with serious complications, resulting in compromised quality of life. Consequently quality of life of such patients is impaired with serious complications. Therefore, management of depression and/or anxiety is equally important as the treatment of hypertension. Depression and/or anxiety are independent risk factors of hypertension, which is supported by the finding that there is close correlation between hypertension are depression/or anxiety. Psychotherapy (non-drug treatment) maybe useful for hypertensive patients with depression and/or anxiety to improve their negative emotions. We aim to quantify the effective of psychological therapies in the management of hypertension patients with depression or anxiety, by comparing and ranking a network meta-analysis (NMA). MATERIALS AND METHODS: Literature search for randomized controlled trials (RCTs) will be performed in five electronic databases from inception to December 2021, including PubMed, the Cochrane library, Embase, Web of Science, and China Biology Medicine disc (CBM). The search terms mainly include "hypertension", "mindfulness-based stress reduction" (MBSR), "cognitive behavioral therapy" (CBT) and "dialectical behavior therapy" (DBT). Cochrane Collaboration quality assessment tool will be used for the risk of bias assessment. A Bayesian network meta-analysis will be performed, using WinBUGS 1.4.3, and Stata 14 will be applied to draw the network diagram, while RevMan 5.3.5 will be used to produce funnel plot for assessing the risk of publication bias. Recommended rating, development and grade methodology will also be utilized to assess the quality of evidence. RESULTS: Effect of MBSR, CBT and DBT will be evaluated by traditional meta-analysis directly and Bayesian network meta-analysis indirectly. Our study will provide the evidence on the efficacy and safety of psychological treatments in the hypertension patients with anxiety. There is no research ethical requirement because this is a systematic review of published literature. The results of this study will be published in a peer-reviewed journal. TRIAL REGISTRATION: Prospero registration number: CRD42021248566.

The Relationship Between Meaning in Life and Health Behaviors in Adults Aged 55 Years and Over During the COVID-19 Pandemic: the Mediating Role of Risk Perception and the Moderating Role of Powerful Others Health Locus of Control.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has impacted many people's meaning in life and health behaviors. This study aimed to verify the relationship among meaning in life (MIL), epidemic risk perception, health locus of control (HLC), and preventive health behaviors among older adults after the COVID-19 outbreak was declared a pandemic. METHOD: In this longitudinal study, 164 participants aged 55 years and above completed the following measures at time 1 (February 19, 2021) and one month later at time 2 (March 19, 2021): Meaning in Life in the Epidemic Questionnaire, Epidemic Risk Perception Questionnaire, Multidimensional Health Locus of Control Scale, and Health Behaviors Before and After the Epidemic Survey. Hayes' SPSS Process Macro was used to analyze the mediating effect of epidemic risk perception (model 4) and the moderating role of powerful others HLC in the mediation model (model 14). RESULTS: The results showed that after controlling for gender, age, education level, and health behaviors at the baseline, risk perception had a significant mediating effect on the relationship between MIL and preventive health behaviors (ß = .02, SE = .01, 95% CI [.00, .04]). In addition, powerful others HLC had a moderating effect on the second half of the mediating effect (ß = .02, p = .02, 95% CI [.00, .03]). Specifically, compared to the older adults with low powerful others HLC, the risk perception of older adults with high powerful others HLC increased preventive health behaviors. CONCLUSION: Practitioners should adequately cultivate older adults' risk awareness and reinforce the importance of advice from doctors and professionals, thereby effectively enhancing the preventive health behaviors of older adults in China during the COVID-19 pandemic.

Identification and Analysis of Key Barriers of BIM Application for Small- and Medium-Sized Fire Protection Enterprises.

The application of Building Information Modeling (BIM) in fire protection discipline has been sufficiently proved to be useful, but has encountered many barriers in China. Among which, small- and medium-sized enterprises (SMEs), which are considered sensitive to adoption costs and external funding support, play a critical role in the BIM adoption process in fire protection discipline. Therefore, identifying and analyzing the barriers of BIM application are essential to help small- and medium-sized fire protection enterprises to overcome these barriers. In this study, semantic analysis, which includes word frequency analysis and coword analysis, based on literature review was utilized to identify the main barriers. 20 main barriers, which were classified into software, people, organization, and environment group, were obtained. Then, Interpretive Structural Modelling (ISM) approach and Cross-Impact Matrix Multiplication Applied to Classification (MICMAC) analysis were utilized to hierarchically analyze and categorize the main barriers of BIM application in Chinese SMFEs. The findings revealed that the lack of external support and the lack of BIM laws and regulations applicable to fire protection discipline are the key barriers in general for the application of BIM in SMFEs. For the barriers at the enterprise level, through further analysis and discussion based on barriers in the people and organization clusters, the lack of funding support for proper BIM training and the lack of organization culture support were concluded as the key barriers of BIM application inside the scope of SMFEs. According to 80-20 principle, more effort should be focused on the key barriers to gain maximum management effect. The research result categorizes the barriers for easy intervention of fire protection enterprises' managers and policymakers. It contributes to the nascent studies of BIM application and provides guidance for the application of BIM in fire protection discipline.

Single-cell RNA sequencing reveals dysregulation of spinal cord cell types in a severe spinal muscular atrophy mouse model.

Although spinal muscular atrophy (SMA) is a motor neuron disease caused by the loss of survival of motor neuron (SMN) proteins, there is growing evidence that non-neuronal cells play important roles in SMA pathogenesis. However, transcriptome alterations occurring at the single-cell level in SMA spinal cord remain unknown, preventing us from fully comprehending the role of specific cells. Here, we performed single-cell RNA sequencing of the spinal cord of a severe SMA mouse model, and identified ten cell types as well as their differentially expressed genes. Using CellChat, we found that cellular communication between different cell types in the spinal cord of SMA mice was significantly reduced. A dimensionality reduction analysis revealed 29 cell subtypes and their differentially expressed gene. A subpopulation of vascular fibroblasts showed the most significant change in the SMA spinal cord at the single-cell level. This subpopulation was drastically reduced, possibly causing vascular defects and resulting in widespread protein synthesis and energy metabolism reductions in SMA mice. This study reveals for the first time a single-cell atlas of the spinal cord of mice with severe SMA, and sheds new light on the pathogenesis of SMA.

Ten ignored questions for stress psychology research.

Stress psychology is an interesting and important interdisciplinary research field. In this perspective article, we briefly discuss 10 challenges related to the conceptual definition, research methodology, and translation in the field of stress that do not receive sufficient attention or are ignored entirely. Future research should attempt to integrate a comprehensive stress conceptual framework into a multidimensional comprehensive stress model, incorporating subjective and objective indicators as comprehensive measures. The popularity of machine learning, cognitive neuroscience, and gene epigenetics is a promising approach that brings innovation to the field of stress psychology. The development of wearable devices that precisely record physiological signals to assess stress responses in naturalistic situations, standardize real-life stressors, and measure baselines presents challenges to address in the future. Conducting large individualized and digital intervention studies could be crucial steps in enhancing the translation of research.

CD44 deficiency represses neuroinflammation and rescues dopaminergic neurons in a mouse model of Parkinson's disease.

CD44 is a transmembrane protein that transduces extracellular stimuli to immune response. Neuroinflammation is a causative factor in neurodegenerative diseases, such as Parkinson's disease (PD). Owing to its role in inflammation, this study investigated whether CD44 is involved in the pathological progression of PD. Our data showed that CD44 deficiency largely abolished proinflammatory cytokine expression in primary microglia and astrocytes. In PD model mice, CD44 knockout improved behavioral defects, prevented TH loss in the SNpc and striatum, and blocked activation of microglia and astrocytes. Moreover, CD44 neutralization by anti-CD44 antibody recapitulated the phenotypes observed in CD44 knockout mice. Mechanistically, CD44 neutralization blocked TLR4 expression and NF-κB p65 nuclear translocation induced by lipopolysaccharide in BV2 cells. Overall, our results indicate that CD44 deficiency has a beneficial role against PD, which is likely due to repression of the TLR4/NF-κB axis, leading to reduced neuroinflammation. Therefore, CD44 might be a therapeutic target for the development of anti-PD agents.

Value Proposition for Enabling Construction Project Innovation by Applying Building Information Modeling.

Building information modeling (BIM) is evolving as a digital infrastructure model for innovation in the construction field. The innovation-enabling potential of BIM has been highly neglected in the literature. This study explores the innovative potential of BIM, specifically its value in enabling construction innovation (CI). Through reflective research and a literature review, the relationship between BIM and CI is redefined, BIM-CI's value spectrum and underlying mechanisms are mapped and their required resources and activities are illustrated. The results indicate that different BIM applications provide various proinnovation environments wherein CI may flourish. Extra attention should be paid to BIM-enabled systematic collaborative innovation and digital innovation ecosystems with BIM as the core infrastructure that integrates the physical space with cyberspace to accelerate radical innovation. This study extends BIM management research by considering digital innovation and providing a new perspective for CI management theory and practice. The results will provide academics with a solid point of departure for developing relevant research and serve as a reference for practitioners who intend to utilize BIM for efficient innovation in construction projects.

CtBP2 interacts with TGIF to promote the progression of esophageal squamous cell cancer through the Wnt/ß­catenin pathway.

C­terminal­binding protein 2 (CtBP2), a transcriptional co­repressor, plays a main role in tumorigenesis and in the development of multiple tumors. Transforming growth interacting factor (TGIF) is involved in a number of cellular signal transduction pathways and is related to tumor occurrence and development. In the present study, the proteins interacting with CtBP2 were identified and the mechanisms underlying the biological activity of CtBP2 in esophageal squamous cell carcinoma (ESCC) were investigated. The Search Tool for the Retrieval of Interacting Genes (STRING) database was used to search for known proteins interacting with CtBP2, and co­immunoprecipitation (Co­IP) assay was performed to validate the interactions. Reverse transcription­quantitative PCR (RT­qPCR), immunohistochemistry (IHC) and western blot analysis were performed to examine the expression levels of CtBP2 and TGIF in ESCC. The correlation between CtBP2 and TGIF was analyzed using Gene Expression Profiling Interactive Analysis (GEPIA) by Pearson's correlation analysis, and the co­localization of CtBP2 with TGIF in the ECA109 cells was identified using immunofluorescence staining. XAV939 treatment, CCK­8, 5­ethynyl­2'­deoxyuridine (EdU) staining, wound healing and Transwell assays were performed to investigate the signaling pathways involved in the biological activity of CtBP2 in ECA109 cells. According to the results obtained from STRING and Co­IP analysis, an interaction between CtBP2 and TGIF was indicated, and these proteins were co­localized in the nucleus. CtBP2 and TGIF mRNA and protein expression levels were robustly and simultaneously increased in both ESCC tissues and cell lines. There was a direct correlation between CtBP2 and TGIF expression levels in ESCC tissues, and both were significantly associated with metastasis and survival. The TGIF and CtBP2 expression levels were significantly increased or decreased simultaneously, in ECA109 cells transfected with LV­CtBP2 or sh­CtBP2, and vice versa. According to the results of CCK­8 assay, EdU staining and Transwell assay, CtBP2 promoted the proliferation, migration and invasion of ECA109 cells through the Wnt/ß­catenin pathway. On the whole, the present study demonstrates that CtBP2 interacts with TGIF and promotes the malignant progression of ESCC through the Wnt/ß­catenin pathway.

Health Status Stability of Patients in a Medical Rehabilitation Program: What Are the Roles of Time, Physical Fitness Level, and Self-efficacy?

BACKGROUND: Individuals' physical and mental health, as well as their chances of returning to work after their ability to work is damaged, can be addressed by medical rehabilitation. AIM: This study investigated the developmental trends of mental and physical health among patients in medical rehabilitation and the roles of self-efficacy and physical fitness in the development of mental and physical health. DESIGN: A longitudinal design that included four time-point measurements across 15 months. SETTING: A medical rehabilitation center in Germany. POPULATION: Participants included 201 patients who were recruited from a medical rehabilitation center. METHODS: To objectively measure physical fitness (lung functioning), oxygen reabsorption at anaerobic threshold (VO2AT) was used, along with several self-report scales. RESULTS: We found a nonlinear change in mental health among medical rehabilitation patients. The results underscored the importance of medical rehabilitation for patients' mental health over time. In addition, patients' physical health was stable over time. The initial level of physical fitness (VO2AT) positively predicted their mental health and kept the trend more stable. Self-efficacy appeared to have a positive relationship with mental health after rehabilitation treatment. CONCLUSIONS: This study revealed a nonlinear change in mental health among medical rehabilitation patients. Self-efficacy was positively related to mental health, and the initial level of physical fitness positively predicted the level of mental health after rehabilitation treatment. CLINICAL REHABILITATION: More attention could be given to physical capacity and self-efficacy for improving and maintaining rehabilitants' mental health.

RASSF9 promotes NSCLC cell proliferation by activating the MEK/ERK axis.

The RAS-associated domain family 9 (RASSF9), a RAS-associated domain family gene, is expressed in a variety of tissues. However, its roles in tumorigenesis, particularly in non-small cell lung cancer (NSCLC), are still not understood well. In the present study, we aimed to examine the potential roles of RASSF9 in NSCLC and the underlying mechanisms. Our data showed that RASSF9 expression was upregulated in NSCLC tissues and cell lines. Increased expression of RASSF9 promotes NSCLC cell proliferation. On the contrary, knockdown of RASSF9 represses cell proliferation. Moreover, the effects of RASSF9 on NSCLC cell proliferation were further confirmed in vivo by using a subcutaneous tumor model. Mechanistically, pharmacological intervention studies revealed that the MEK/ERK axis is targeted by RASSF9 for transducing its regulatory roles on NSCLC cell proliferation. Collectively, our data indicate that RASSF9 plays a key role in tumorigenesis of NSCLC by stimulating tumor cell proliferation, which relies on activation of the MEK/ERK axis. Thus, RASSF9 might be a druggable target for developing novel agents for treating NSCLC.

MAPK14 over-expression is a transcriptomic feature of polycythemia vera and correlates with adverse clinical outcomes.

BACKGROUND: The transcriptomic signature has not been fully elucidated in PV, as well as mRNA markers for clinical variables (thrombosis, leukemic transformation, survival, etc.). We attempted to reveal and validate crucial co-expression modules and marker mRNAs correlating with polycythemia vera (PV) by weighted gene co-expression network analysis (WGCNA). MATERIAL AND METHODS: The GSE57793/26014/61629 datasets were downloaded from Gene Expression Omnibus (GEO) database and integrated into one fused dataset. By R software and 'WGCNA' package, the PV-specific co-expression module was identified, the pathway enrichment profile of which was obtained by over-representation analysis (ORA). Protein-protein interaction (PPI) network and hub gene analysis identified MAPK14 as our target gene. Then the distribution of MAPK14 expression in different disease/mutation types, were depicted based on external independent datasets. Genome-scale correlation analysis revealed the association of MAPK14 and JAK/STAT family genes. Then gene set enrichment analysis (GSEA) was performed to detect the activated and suppressed pathways associating with MAPK14 expression. Moreover, GSE47018 dataset was utilized to compare clinical variables (thrombosis, leukemic transformation, survival, etc.) between MAPK14-high and MAPK14-low groups. RESULTS: An integrated dataset including 177 samples (83 PV, 35 ET, 17 PMF and 42 normal donors) were inputted into WGCNA. The 'tan' module was identified as the PV-specific module (R2 = 0.56, p = 8e-16), the genes of which were dominantly enriched in pro-inflammatory pathways (Toll-like receptor (TLR)/TNF signaling, etc.). MAPK14 is identified as the top hub gene in PV-related PPI network with the highest betweenness. External datasets validated that the MAPK14 expression was significantly higher in PV than that of essential thrombocytosis (ET)/primary myelofibrosis (PMF) patients and normal donors. JAK2 homozygous mutation carriers have higher level of MAPK14 than that of other mutation types. The expression of JAK/STAT family genes significantly correlated with MAPK14, which also contributed to the activation of oxidated phosphorylation, interferon-alpha (IFNα) response and PI3K-Akt-mTOR signaling, etc. Moreover, MAPK14-high group have more adverse clinical outcomes (splenectomy, thrombosis, disease aggressiveness) and inferior survival than MAPK14-low group. CONCLUSION: MAPK14 over-expression was identified as a transcriptomic feature of PV, which was also related to inferior clinical outcomes. The results provided novel insights for biomarkers and therapeutic targets for PV.

The landscape of gene co-expression modules correlating with prognostic genetic abnormalities in AML.

BACKGROUND: The heterogenous cytogenetic and molecular variations were harbored by AML patients, some of which are related with AML pathogenesis and clinical outcomes. We aimed to uncover the intrinsic expression profiles correlating with prognostic genetic abnormalities by WGCNA. METHODS: We downloaded the clinical and expression dataset from BeatAML, TCGA and GEO database. Using R (version 4.0.2) and 'WGCNA' package, the co-expression modules correlating with the ELN2017 prognostic markers were identified (R2 ≥ 0.4, p < 0.01). ORA detected the enriched pathways for the key co-expression modules. The patients in TCGA cohort were randomly assigned into the training set (50%) and testing set (50%). The LASSO penalized regression analysis was employed to build the prediction model, fitting OS to the expression level of hub genes by 'glmnet' package. Then the testing and 2 independent validation sets (GSE12417 and GSE37642) were used to validate the diagnostic utility and accuracy of the model. RESULTS: A total of 37 gene co-expression modules and 973 hub genes were identified for the BeatAML cohort. We found that 3 modules were significantly correlated with genetic markers (the 'lightyellow' module for NPM1 mutation, the 'saddlebrown' module for RUNX1 mutation, the 'lightgreen' module for TP53 mutation). ORA revealed that the 'lightyellow' module was mainly enriched in DNA-binding transcription factor activity and activation of HOX genes. The 'saddlebrown' module was enriched in immune response process. And the 'lightgreen' module was predominantly enriched in mitosis cell cycle process. The LASSO- regression analysis identified 6 genes (NFKB2, NEK9, HOXA7, APRC5L, FAM30A and LOC105371592) with non-zero coefficients. The risk score generated from the 6-gene model, was associated with ELN2017 risk stratification, relapsed disease, and prior MDS history. The 5-year AUC for the model was 0.822 and 0.824 in the training and testing sets, respectively. Moreover, the diagnostic utility of the model was robust when it was employed in 2 validation sets (5-year AUC 0.743-0.79). CONCLUSIONS: We established the co-expression network signature correlated with the ELN2017 recommended prognostic genetic abnormalities in AML. The 6-gene prediction model for AML survival was developed and validated by multiple datasets.

TAK1 Phosphorylates RASSF9 and Inhibits Esophageal Squamous Tumor Cell Proliferation by Targeting the RAS/MEK/ERK Axis.

TGF-ß-activated kinase 1 (TAK1), a serine/threonine kinase, is a key intermediate in several signaling pathways. However, its role in tumorigenesis is still not understood well. In this study, it is found that TAK1 expression decreases in esophageal tumor tissues and cell lines. In vitro experiments demonstrate that proliferation of esophageal tumor cells is enhanced by knockdown of TAK1 expression and attenuated by elevated expression of TAK1. Using a subcutaneous tumor model, these observations are confirmed in vivo. Based on the results from co-immunoprecipitation coupled with mass spectrometry, Ras association domain family 9 (RASSF9) is identified as a downstream target of TAK1. TAK1 phosphorylates RASSF9 at S284, which leads to reduced RAS dimerization, thereby blocking RAF/MEK/ERK signal transduction. Clinical survey reveals that TAK1 expression is inversely correlated with survival in esophageal cancer patients. Taken together, the data reveal that TAK1-mediated phosphorylation of RASSF9 at Ser284 negatively regulates esophageal tumor cell proliferation via inhibition of the RAS/MEK/ERK axis.

HELQ and EGR3 expression correlate with IGHV mutation status and prognosis in chronic lymphocytic leukemia.

BACKGROUND: IGHV mutation status is a crucial prognostic biomarker for CLL. In the present study, we investigated the transcriptomic signatures associating with IGHV mutation status and CLL prognosis. METHODS: The co-expression modules and hub genes correlating with IGHV status, were identified using the GSE28654, by 'WGCNA' package and R software (version 4.0.2). The over-representation analysis was performed to reveal enriched cell pathways for genes of correlating modules. Then 9 external cohorts were used to validate the correlation of hub genes expression with IGHV status or clinical features (treatment response, transformation to Richter syndrome, etc.). Moreover, to elucidate the significance of hub genes on disease course and prognosis of CLL patients, the Kaplan-Meier analysis for the OS and TTFT of were performed between subgroups dichotomized by the median expression value of individual hub genes. RESULTS: 2 co-expression modules and 9 hub genes ((FCRL1/FCRL2/HELQ/EGR3LPL/LDOC1/ZNF667/SOWAHC/SEPTIN10) correlating with IGHV status were identified by WGCNA, and validated by external datasets. The modules were found to be enriched in NF-kappaB, HIF-1 and other important pathways, involving cell proliferation and apoptosis. The expression of hub genes was revealed to be significantly different, not only between CLL and normal B cell, but also between various types of lymphoid neoplasms. HELQ expression was found to be related with response of immunochemotherapy treatment significantly (p = 0.0413), while HELQ and ZNF667 were expressed differently between stable CLL and Richter syndrome patients (p < 0.0001 and p = 0.0278, respectively). By survival analysis of subgroups, EGR3 expression was indicated to be significantly associated with TTFT by 2 independent cohorts (GSE39671, p = 0.0311; GSE22762, p = 0.0135). While the expression of HELQ and EGR3 was found to be associated with OS (p = 0.0291 and 0.0114 respectively).The Kras, Hedgehog and IL6-JAK-STAT3 pathways were found to be associating with the expression of hub genes, resulting from GSEA. CONCLUSIONS: The expression of HELQ and EGR3 were correlated with IGHV mutation status in CLL patients. Additionally, the expression of HELQ/EGR3 were prognostic markers for CLL associating with targetable cell signaling pathways.