The clinical association of programmed death-1/PD-L1 axis, myeloid derived suppressor cells subsets and regulatory T cells in peripheral blood of stable COPD patients.

Background: Myeloid-derived suppressor cells (MDSCs) have crucial immunosuppressive role in T cell dysfunction in various disease processes. However, the role of MDSCs and their impact on Tregs in COPD have not been fully understood. The aim of the present study is to investigate the immunomodulatory role of MDSCs and their potential impact on the expansion and function of Tregs in COPD patients. Methods: Peripheral blood samples were collected to analyze circulating MDSCs, Tregs, PD-1/PD-L1 expression to assess the immunomodulatory role of MDSC and their potential impact on the expansion and function of Treg in COPD. A total of 54 COPD patients and 24 healthy individuals were enrolled in our study. Flow cytometric analyses were performed to identify granulocytic MDSCs (G-MDSCs), monocytic MDSCs (M-MDSCs), Tregs, and the expression of PD-1/PD-L1(L2) on MDSCs and Tregs in peripheral blood. Results: Our results revealed a significantly higher percentage of G-MDSCs and M-MDSCs (p < 0.001) in COPD patients compared to the healthy controls. Additionally, a significantly higher proportion of peripheral blood Tregs was observed in COPD patients. Furthermore, an increased expression of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) on Tregs (p < 0.01) was detected in COPD patients. The expression of PD-1 on CD4+ Tcells and Tregs, but not CD8+Tcells, was found to be increased in patients with COPD compared to controls. Furthermore, an elevated expression of PD-L1 on M-MDSCs (p < 0.01) was also observed in COPD patients. A positive correlation was observed between the accumulation of M-MDSCs and Tregs in COPD patients. Additionally, the percentage of circulating M-MDSCs is positively associated with the level of PD-1 (r = 0.51, p < 0.0001) and CTLA-4 (r = 0.42, p = 0.0014) on Tregs in COPD. Conclusion: The recruitment of MDSCs, accumulation of Tregs, and up-regulation of CTLA-4 on Treg in COPD, accompanied by an increased level of PD-1/PD-L1, suggest PD-1/PD-L1 axis may be potentially involved in MDSCs-induced the expansion and activation of Treg at least partially in COPD.

Myeloid­derived suppressor cell accumulation induces Treg expansion and modulates lung malignancy progression.

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous family of myeloid cells that suppress T cell immunity in tumor-bearing hosts. The present study aimed to examine roles of T and MDSC subsets in lung malignancy. The study analyzed 102 cases with lung malignancy and 34 healthy individuals. Flow cytometry was performed for identification of T cell and MDSC subsets and their phenotypic characteristics in peripheral blood. The lung malignancy cases exhibited lower frequencies of granulocyte-like MDSCs (G-MDSCs) expressing PD-L2 and PD-L1 than healthy controls (P=0.013 and P<0.001, respectively). Additionally, there was a higher frequency of monocyte-like MDSCs (M-MDSCs) expressing PD-L1 in the peripheral blood of patients with lung malignancy than healthy controls (P<0.001). The frequencies of G-MDSCs and M-MDSCs were positively correlated with proportions of PD-1+ and CTLA-4+ regulatory T cells (Tregs). In vitro co-culture assay demonstrated M-MDSCs of lung malignancy enhanced naive T cell apoptosis and promoted Treg subset differentiation compared with M-MDSCs of healthy controls. The findings suggested accumulation of MDSC subsets in lung malignancy and MDSCs expressing PD-L2 and PD-L1 induced Treg expansion by binding to PD-1 on the surface of Tregs.

The diversity of peripheral blood T cells and myeloid-derived suppressor cells in patients with idiopathic membranous nephropathy.

OBJECTIVE: Membranous nephropathy is a leading cause of adult-onset nephrotic syndrome. Peripheral T cells and myeloid-derived suppressor cells (MDSCs) are closely associated with autoimmune diseases, while their exact roles and interaction in these processes are unclear. Here, we studied the roles of T cells, MDSCs, and their subsets in patients with idiopathic membranous nephropathy (IMN). MATERIALS AND METHODS: 35 IMN patients and 30 healthy controls were included in this retrospective study. Flow cytometry was performed to determine the phenotype of human T cells and MDSCs in peripheral blood mononuclear cells (PBMCs). Anti-PLA2R was measured by ELISA. Values ≥ 20 RU/mL were defined as positive and < 14 RU/mL as negative. RESULTS: A higher ratio of CD4/CD8 T cells with a lower proportion of Tregs, a remarkably lower proportion of G-MDSCs (but not M-MDSCs), lower frequency of PD-L2+G-MDSCs, and higher frequency of PD-L1+M-MDSCs were found in IMN patients compared to healthy controls. The ratio of CD4/CD8 T cells was higher, and the frequencies of PD-1+CD4+ T cells, CTLA-4+CD4+ T cells, PD-1+Tregs, and CTLA-4+Tregs were lower in PBMCs of PLA2R-positive IMN patients compared to PLA2R-negative IMN patients. CONCLUSION: Tregs and G-MDSCs were reduced in the circulation of the IMN patients, which may promote understanding of the crucial functions that are mediated by these cells in the pathogenesis of IMN.

First case report of a novel KIF13A-ALK fusion in a lung adenocarcinoma patient and response to alectinib with a 4-year follow-up.

The prevalence of Anaplastic Lymphoma Kinase gene (ALK) fusion is about 5% among patients with lung adenocarcinoma, underscoring the importance of pinpointing distinct fusion variants for optimizing treatment approaches. This is the first reported case of a 74-year-old female with stage IV lung adenocarcinoma, featuring a novel Kinesin Family Member 13A (KIF13A)-ALK fusion, identified via next-generation sequencing (NGS) and confirmed with fluorescence in situ hybridization (FISH). Initially undergoing chemotherapy and then crizotinib, she achieved a partial response (PR) before progressing with multiple bone metastases. However, subsequent treatment with alectinib as a third-line option yielded positive results. A stable disease state persisted for an impressive 31 months of progression-free survival (PFS), accompanied by minimal toxicity symptoms. Up until now, a remarkable near 4-year span of overall survival (OS) has been consistently observed and monitored. This report of a KIF13A-ALK fusion case benefit significantly from alectinib with extensive follow-up. The case diversifies the array of ALK fusion partners and holds clinical relevance in refining therapeutic choices for KIF13A-ALK fusion-associated lung cancer.

The distribution of myeloid-derived suppressor cells subsets and up-regulation of programmed death-1/PD-L1 axis in peripheral blood of adult CAP patients.

BACKGROUND: Myeloid-derived suppressor cells (MDSCs) have been reported to expand and have a potent ability in the expansion of regulatory T cells in malignant and infectious disease. The current study was performed to investigate the role of MDSCs and possible immune mechanisms in dampening immune responses of community acquired pneumonia (CAP). METHODS: This was a single-center cross-sectional study. The distribution of MDSCs subsets, the PD-1/PD-L1(L2) level of MDSCs subsets and Tregs in the peripheral blood of adult CAP patients and healthy control were measured by flow cytometry analysis. RESULTS: Peripheral blood mononuclear cells (PBMCs) from 63 adult CAP patients contained an elevated frequency of both G-MDSC (4.92±0.30 vs 2.25±0.21,p<0.0001) and M-MDSC (19.40±1.30 vs 9.64±0.57,p<0.001) compared to healthy controls. Treg in the peripheral blood of CAP patients exhibited increased expression of PD-1 and CTLA-4, accompanied by no difference of their frequency. Moreover, up-regulated expression of PD-L1 on MDSC subsets in the peripheral blood of CAP patients was also revealed. Of note, the frequency of circulating MDSCs subset displayed a positive correlation with neutrophil count percentage in blood in CAP patients. CONCLUSIONS: In summary, the significant expansion of circulating MDSCs subsets and the up-regulated expression of PD-1/PD-L1 level in CAP patients may suggest the possible involvement of PD-1/PD-L1axis in MDSCs mediated immune regulation on Treg at least partially in CAP patients.

Recruitment of myeloid­derived suppressor cells and regulatory T­cells is associated with the occurrence of acute myocardial infarction.

The roles of myeloid-derived suppressor cells (MDSCs) and regulatory T-cells (Tregs) in acute myocardial infarction (AMI) remain elusive. The present study aimed to analyze the proportions of the granulocytic and monocytic populations of MDSCs (G-MDSCs and M-MDSCs, respectively), and Tregs in the peripheral blood mononuclear cells (PBMCs) of patients with AMI. The present study recruited 34 patients with AMI and 37 healthy controls without clinical signs of myocardial ischemia. PBMCs were isolated from the peripheral blood samples of patients with AMI within 24 h following admission to the hospital and from those of the healthy controls during a physical examination. Two subsets of MDSCs, G-MDSCs (CD15+CD33+CD11b+CD14-HLA-DRlow) and M-MDSCs (CD14+CD15-CD11b+HLA-DRlow), and Tregs (CD3+CD4+CD25highCD127low T-cells) in the PBMCs derived from the patients with AMI and healthy controls were analyzed using flow cytometry. The effects of MDSCs derived from patients with AMI on naïve CD4+ T-cells were examined in the co-culture system. The results revealed that the proportions of G-MDSCs and M-MDSCs were higher in the peripheral blood of patients with AMI than in that of the healthy controls. The patients with AMI had significantly higher numbers of programmed death-ligand (PD-L)1- and PD-L2-positive G-MDSCs and M-MDSCs compared with the healthy controls (P<0.05). The MDSCs could acquire a granulocytic phenotype following AMI, and the G-MDSCs and M-MDSCs would be more likely to express PD-L2 and PD-L1, respectively. The ratios of Tregs to CD4+ T-cells and PD-1+ Tregs in the peripheral blood of patients with AMI were significantly higher than those in the healthy controls (P<0.05). The results of flow cytometry demonstrated an increase in the numbers of inducible Tregs in the co-culture system with the G-MDSCs derived from patients with AMI compared with the G-MDSCs derived from the healthy controls (P<0.01). On the whole, the findings presented herein demonstrate the accumulation of MDSCs, and the upregulation of PD-L1 and PD-L2 expression on the surface of MDSCs in patients with AMI. MDSCs can induce the expansion of Tregs by binding PD-1 on the surface of Tregs, thus playing a crucial role in AMI.

Decreased programmed cell death ligand 2-positive monocytic myeloid-derived suppressor cells and programmed cell death protein 1-positive T-regulatory cells in patients with type 2 diabetes: implications for immunopathogenesis.

Objectives: The activation of immune cells plays a significant role in the progression of type 2 diabetes. This study aimed to investigate the potential role of myeloid-derived suppressor cells (MDSCs) and T-regulatory cells (Tregs) in type 2 diabetes. Methods: A total of 61 patients diagnosed with type 2 diabetes were recruited. Clinical characteristics were reviewed and peripheral blood samples were collected. We calculated the percentage of different cells. Frequencies of MDSC subsets refered to the percentage of G-MDSCs (CD15+CD33+CD11b+CD14-HLA-DR-/low) in CD45 positive cells and the percentage of M-MDSCs (CD14+CD15-CD11b+CD33+HLA-DR-/low) in lymphocytes plus monocytes. Results: Frequencies of programmed cell death ligand 1-positive granulocytic MDSCs (PD-L1+ G-MDSCs), programmed cell death ligand 2-positive monocytic MDSCs (PD-L2+ M-MDSCs), PD-L2+ G-MDSC, and programmed cell death protein 1-positive Tregs (PD-1+Tregs) were decreased in patients with type 2 diabetes. The frequency of PD-1+ Tregs was positively related to PD-L2+ M-MDSCs (r= 0.357, P = 0.009) and negatively related to HbA1c (r = -0.265, P = 0.042), fasting insulin level (r = -0.260, P = 0.047), and waist circumference (r = -0.373, P = 0.005). Conclusions: Decreased PD-L2+ M-MDSCs and PD-1+ Tregs may promote effector T cell activation, leading to chronic low-grade inflammation in type 2 diabetes. These findings highlight the contribution of MDSCs and Tregs to the immunopathogenesis of type 2 diabetes and suggest their potential as targets for new therapeutic approaches.

IRAK-M Regulates Proliferative and Invasive Phenotypes of Lung Fibroblasts.

Lung fibroblasts play an important role in subepithelial fibrosis, one feature for airway remodeling. IL-1 receptor-associated kinase (IRAK)-M was shown to involve fibrosis formation in airways and lung through regulation of inflammatory responses. IRAK-M is expressed by lung fibroblasts, whether IRAK-M has direct impact on lung fibroblasts remains unclear. In this investigation, we evaluated in vitro effect of IRAK-M on phenotypes of lung fibroblasts by silencing or overexpressing IRAK-M. Murine lung fibroblasts (MLg) were stimulated with house dust mite (HDM), IL-33, and transforming growth factor (TGF) ß1. Techniques of small interfering RNA or expression plasmid were employed to silence or overexpress IRAK-M in MLg fibroblast cells. Proliferation, migration, invasiveness, and fibrosis-related events were evaluated. Significant upregulation of IRAK-M expression in MLg cells was caused by these stimuli. Silencing IRAK-M significantly increased proliferation, migration, and invasiveness of lung fibroblasts regardless of stimulating conditions. By contrast, IRAK-M overexpression significantly inhibited proliferation and motility of MLg lung fibroblasts. IRAK-M overexpression also significantly decreased the expression of fibronectin, collagen I, and α-SMA in MLg cells. Under stimulation with TGFß1 or IL-33, IRAK-M silencing reduced MMP9 production, while IRAK-M overexpression increased MMP9 production. Modulation of IRAK-M expression affected cytokines production, either decreased or increased expression of TNFα and CXCL10 by the cells regardless of stimulation. Our in vitro data reveal that IRAK-M directly impacts on lung fibroblasts through modulation of cellular motility, release of inflammatory, and fibrotic cytokines of lung fibroblasts. These might suggest a new target by regulation of IRAK-M in slowing airway remodeling.

Implementation of early rehabilitation for critically ill children in China: A survey and narrative review of the literature.

Introduction: The focus of this survey was to understand the current status of implementation of early rehabilitation for critically ill children in China. We also reviewed the available literature on this topic for further insights to inform its future development. Materials and methods: We used a cross-sectional study design to survey tertiary hospitals nationwide. Questionnaires were distributed via the social media platform "WeChat Questionnaire Star" within the framework of the Rehabilitation Group of the Pediatrics Branch of the Chinese Medical Association. A narrative literature review on the implementation of the early rehabilitation for critically ill pediatric and/or adult patients was carried out. Results: A total of 202 valid questionnaires were received. About half (n = 105, 52.0%) of respondent hospitals reported that they implement early rehabilitation for critically ill children. Among these 105 hospitals, 28 implemented a continuous chain of early rehabilitation. A total of 24 hospitals had set up permanent specialized centralized early rehabilitation units for critically ill children. Implications and future directions: Early rehabilitation for critically ill children is not widely available in China and only a minority of hospitals implement a continuous chain of early rehabilitation. To improve this undesirable situation, we suggest creating a two-level integrated system comprising centralized early rehabilitation units and surrounding early rehabilitation networks within a region.

Spina Bifida Occulta Is a Risk Factor for Spinal Cord Injury Without Fracture or Dislocation for Children Performing a Backbend During Dance.

Objective: This study aimed to explore the clinical features and outcomes of children with spinal cord injury (SCI) without fracture or dislocation. Methods: The clinical data of children with SCI without fracture or dislocation in this retrospective study were collected in Chongqing, China (January 2010 to December 2021). We collected patient demographics at admission including age, gender, cause, level, and severity of the injury in admission and complications. Reports from radiologic imaging were reviewed to identify spina bifida occulta (SBO). Neurological function was evaluated using the American Spinal Injury Association (ASIA) Impairment Scale (AIS) for an SCI. Results: A total of 74 children with SCI (male, 27%; female, 73%; male-to-female ratio, 1:2.7; average age, 5.7 years) were included. The main cause of injury was backbend during the dance (34 patients, 45.9%, including 2 patients who hugged back falling backward), followed by traffic accidents (17 patients, 23%). Children with backbend-related SCI were older than other children (6.9 vs. 4.9 years old, P < 0.001). When reviewing all radiological images, it was found that 20 (27%) patients with SCI had SBO. The proportion of SCI with SBO caused by backbend was considerably higher than those caused by non-backbend (41.2 vs. 15%, P = 0.012). The AIS were 22 (29.7%), 4 (5.4%), 8 (10.8%), 31 (41.9%), and 9 (12.2%) in A, B, C, D, and E, respectively. The prognosis was poorer in the backbend during dancing than other causes of injury (p = 0.003). Conclusion: This study showed that backbend during the dance was the main cause of children's SCI without fracture or dislocation in Chongqing, China. The prognosis was poorer in those children than in other causes of injury. Meanwhile, we have established an association between SBO and SCI for children performing a backbend during the dance.

Ultrafine cobalt selenide nanowires tangled with MXene nanosheets as highly efficient electrocatalysts toward the hydrogen evolution reaction.

Hydrogen energy has attracted sustainable attention in the exploitation and application of advanced power-generator devices, and electrocatalysts for the hydrogen evolution reaction (HER) have been regarded as one of the core components in the current electrochemical hydrogen production systems. In this work, a facile and cost-effective bottom-up strategy is developed for the construction of 1D ultrafine cobalt selenide nanowires tangled with 2D Ti3C2Tx MXene nanosheets (CoSe NW/Ti3C2Tx) through an in situ stereo-assembly process. Such an architectural design endows the hybrid system not only with a large accessible surface for the rapid transportation of reactants, but also with numerous exposed CoSe edge sites, thereby generating substantial synergic coupling effects. The as-derived CoSe NW/Ti3C2Tx hybrid demonstrates competitive electrocatalytic properties toward the HER with a small onset potential of 84 mV, a low Tafel slope of 56 mV dec-1 and exceptional cycling performance, which are superior to those of bare CoSe and Ti3C2Tx materials. It is believed this promising nanoarchitecture may provide new possibilities for the design and construction of precious-metal-free electrocatalysts with high efficiency and great stability in the energy-conversion field.

Anthocyanins Inhibit Airway Inflammation by Downregulating the NF-κB Pathway via the miR-138-5p/SIRT1 Axis in Asthmatic Mice.

OBJECTIVE: Asthma, caused by chronic inflammation, is a common disease. Anthocyanins are involved in asthma treatment. This study explored the mechanism of anthocyanins on airway inflammation in asthmatic mice by regulating nuclear factor-κB (NF-κB) via the miR-138-5p/sirtuin-1 (SIRT1) axis. METHODS: The asthmatic mouse model was established by ovalbumin (OVA) induction and treated with anthocyanins or simultaneously injected with the lentivirus miR-138-5p mimic, followed by the measurement of lung inflammatory injury and IL-4, IL-5, IL-13, and IFN-γ levels in bronchoalveolar lavage fluid. Human bronchial epithelial (HBE) cells 16HBE14o-160 were induced by OVA to establish an asthmatic cell model, treated with anthocyanins and manipulated with miR-138-5p mimic and pcDNA3.1-SIRT1. The releases of inflammatory cytokines, the nuclear translocation of p-p65/p65 in the NF-κB pathway, and the levels of miR-138-5p and SIRT1 mRNA were detected. RESULTS: In vivo experiments showed that anthocyanins could reduce the OVA-induced airway hyperresponsiveness and airway inflammation, improve the inflammatory infiltration and mucus in lung tissues, and diminish the miR-138-5p level in asthmatic mice. Infection with the miR-138-5p mimic averted the remission effect of anthocyanins in asthmatic mice. In vitro experiments showed that in HBE cells exposed to OVA, anthocyanins reduced the miR-138-5p level, increased the SIRT1 level, inhibited the release of inflammatory factors, and reduced the nuclear translocation of NF-κB p65. miR-138-5p targeted SIRT1. miR-138-5p overexpression partially reversed the therapeutic effect of anthocyanins, while SIRT1 overexpression antagonized the effect of miR-138-5p overexpression. CONCLUSION: Anthocyanins inhibited the NF-κB pathway by regulating the miR-138-5p/SIRT1 axis, thus inhibiting airway inflammation in asthmatic mice.

Functional diversity outperforms taxonomic diversity in revealing short-term trampling effects.

Alpine grasslands harbor diverse groups of flora and fauna, provide important ecosystem functions, and yield essential ecosystem goods and services, especially for the development of nature-based tourism. However, they are experiencing increasing anthropogenic perturbations such as tourist trampling. Although negative effects of tourist trampling on alpine vegetation have been frequently reported, previous studies have focused mainly on changes in taxonomic diversity after trampling, and rarely provide a mechanistic elucidation of trampling effects from a trait-based perspective. The present study evaluates the impacts of simulated trampling on taxonomic and functional diversity of a typical alpine grassland community in Shangri-La, China using a standardized protocol. The results showed that although taxonomic diversity was not statistically significantly affected by trampling, some functional attributes responded rapidly to trampling disturbance. Specifically, functional divergence decreased with an increase in trampling intensity, and characteristics of community-weighted mean trait values changed towards shorter species with reduced leaf area and lower leaf dry matter content. Such strong shifts in functional attributes may further affect ecosystem goods and services provided by alpine grasslands. Our inclusion of functional diversity in the analysis thus adds an important caution to previous studies predominantly focusing on taxonomic diversity, and it is urgent to keep alpine grasslands well managed and ecologically coherent so that their valuable functions and services can be safeguarded.

Design and Integrated Analysis of a Flexible Support Microstructure with a Honeycomb Sandwich for the Optical Window of a Hypersonic Remote Sensor.

In order to reduce the influence of the optical window on the image quality of a hypersonic visible light optical remote sensor, we propose a method of adding a double-layer semicircular honeycomb core microstructure with flexible support of a high temperature elastic alloy between a window glass and a frame to reduce the influence of complex thermal stress on the surface accuracy of the optical window. An equivalent model of a semicircular honeycomb structure was established, the elastic parameters of the semicircular honeycomb sandwich microstructure were derived by an analytical method, and a numerical verification and finite element simulation were carried out. The results show that the equivalent model is in good agreement with the detailed model. The optical-mechanical-thermal integrated simulation analysis of the optical window assembly with flexible supporting microstructure proves that the semicircular honeycomb sandwich flexible supporting structure has a positive effect on stress attenuation of the window glass and ensures the wave aberration accuracy of the transmitted optical path difference of the optical window (PV < 0.665 λ, RMS < 0.156 λ, λ = 632.8 nm). Combined with the actual optical system, the optical performance of the window assembly under the flexible support structure is verified. The simulation results show that the spatial frequency of the modulation transfer function (MTF) of the optical system after focusing is not less than 0.58 in the range of 0-63 cycle/mm and the relative decline of MTF is not more than 0.01, which meet the imaging requirements of a remote sensor. The study results show that the proposed metal-based double-layer semicircular honeycomb sandwich flexible support microstructure ensures the imaging quality of the optical window under ultra-high temperature conditions.

IRAK-M knockout promotes allergic airway inflammation, but not airway hyperresponsiveness, in house dust mite-induced experimental asthma model.

BACKGROUND: IL-1 receptor associated-kinase (IRAK)-M, expressed by airway epithelium and macrophages, was shown to regulate acute and chronic airway inflammation exhibiting a biphasic response in an OVA-based animal model. House dust mite (HDM) is a common real-life aeroallergen highly relevant to asthma pathogenesis. The role of IRAK-M in HDM-induced asthma remains unknown. This study was aimed to investigate the effect of IRAK-M on allergic airway inflammation induced by HDM using IRAK-M knockout (KO) mice and the potential underlying mechanisms. METHODS: IRAK-M KO and wild-type (WT) mice were sensitized and challenged with HDM. The differences in airway inflammation were evaluated 24 hours after the last challenge between the two genotypes of mice using a number of cellular and molecular biological techniques. In vitro mechanistic investigation was also involved. RESULTS: Lung expression of IRAK-M was significantly upregulated by HDM in the WT mice. Compared with the WT controls, HDM-treated IRAK-M KO mice showed exacerbated infiltration of inflammatory cells, particularly Th2 cells, in the airways and mucus overproduction, higher epithelial mediators IL-25, IL-33 and TSLP and Th2 cytokines in bronchoalveolar lavage (BAL) fluid. Lung IRAK-M KO macrophages expressed higher percentage of costimulatory molecules OX40L and CD 80 and exhibited enhanced antigen uptake. However, IRAK-M KO didn't impact the airway hyperreactivity (AHR) indirectly induced by HDM. CONCLUSIONS: The findings indicate that IRAK-M protects allergic airway inflammation, not AHR, by modifying activation and antigen uptake of lung macrophages following HDM stimulation. Optimal regulation of IRAK-M might indicate an intriguing therapeutic avenue for allergic airway inflammation.

Increased Seizure Susceptibility for Rats Subject to Early Life Hypoxia Might Be Associated with Brain Dysfunction of NRG1-ErbB4 Signaling in Parvalbumin Interneurons.

Neuregulin 1 (NRG1)-induced activation of ErbB4 in parvalbumin (PV) inhibitory interneurons is reported to serve as a critical endogenous negative-feedback mechanism to repress brain epileptogenesis. Here, we investigated the seizure susceptibility and the role of NRG1-ErbB4 signaling in PV interneurons in the suppression of epileptic seizures for rats subject to early life hypoxia. Neonatal postnatal day 5 (P5) rats were exposed to intermittent hypoxia (IH) or control (CON) room air for 10 days. In the prefrontal cortex (PFC) of P54 rats, we determined the impact of neonatal IH exposures on the expression of PV, NRG1, ErbB4, and phosphorylated ErbB4 (p-ErbB4) during the seizure induction. Seizure susceptibility tests with the common convulsant agent pentylenetetrazole (PEN) at P54 revealed that rats subject to neonatal hypoxia exposure developed faster and more serious epileptic seizures. Neonatal IH exposures (1) decreased the number of PV cells in the PFC of P54 rats; (2) interrupted the expression of NRG1 gene; and (3) altered the activity of NRG1 on PV interneurons in the PFC after the seizure induction. Intracerebroventricular delivery of exogenous NRG1 before seizure induction by PEN significantly reduced the seizure susceptibility for neonatal IH-exposed rats. The ErbB4 inhibitor AG1478 inhibited the exogenous NRG1's effects on seizure susceptibility. Environmental enrichment (EE) rescued the abovementioned pathophysiological alterations and significantly attenuated the epileptic seizures after the seizure induction for neonatal IH-exposed rats. Our study indicated early life hypoxia exposure might increase the seizure susceptibility for rats and contribute to pathophysiological dysfunction of NRG1-ErbB4 signaling in PV interneurons in the suppression of epileptic seizures. EE might attenuate the increased seizure susceptibility for neonatal IH-exposed rats through rescuing pathophysiological alterations of NRG1-ErbB4 signaling in PV interneurons.

An improved clear cell renal cell carcinoma stage prediction model based on gene sets.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cell carcinoma and accounts for cancer-related deaths. Survival rates are very low when the tumor is discovered in the late-stage. Thus, developing an efficient strategy to stratify patients by the stage of the cancer and inner mechanisms that drive the development and progression of cancers is critical in early prevention and treatment. RESULTS: In this study, we developed new strategies to extract important gene features and trained machine learning-based classifiers to predict stages of ccRCC samples. The novelty of our approach is that (i) We improved the feature preprocessing procedure by binning and coding, and increased the stability of data and robustness of the classification model. (ii) We proposed a joint gene selection algorithm by combining the Fast-Correlation-Based Filter (FCBF) search with the information value, the linear correlation coefficient, and variance inflation factor, and removed irrelevant/redundant features. Then the logistic regression-based feature selection method was used to determine influencing factors. (iii) Classification models were developed using machine learning algorithms. This method is evaluated on RNA expression value of clear cell renal cell carcinoma derived from The Cancer Genome Atlas (TCGA). The results showed that the result on the testing set (accuracy of 81.15% and AUC 0.86) outperformed state-of-the-art models (accuracy of 72.64% and AUC 0.81) and a gene set FJL-set was developed, which contained 23 genes, far less than 64. Furthermore, a gene function analysis was used to explore molecular mechanisms that might affect cancer development. CONCLUSIONS: The results suggested that our model can extract more prognostic information, and is worthy of further investigation and validation in order to understand the progression mechanism.

Developing prognostic gene panel of survival time in lung adenocarcinoma patients using machine learning.

BACKGROUND: Transcriptome data generates massive amounts of information that can be used for characterization and prognosis of patient outcomes for many diseases. The goal of our research is to predict the survival time of lung adenocarcinoma patients and improve the accuracy of classifying the long-survival cohort and short-survival cohort. METHODS: We filtered prognostic features related with survival time of lung adenocarcinoma patients by the method of Relief and predicted whether survival time of the patient is >3 years or not-using eight machine learning algorithms (Support Vector Machines, Random Forests, Logistic Regression, Naïve Bayes, Linear Regression, Support Vector Regression (kernel Poly), Support Vector Regression (kernel Linear), and Ridge Regression). Then the best-performed algorithm was chosen to build a predictive model of survival time of lung adenocarcinoma patients. Further, another dataset was used to verify the stability and suitability of this model. We explored the underlying mechanisms of RNA expression changes with the corresponding DNA mutations and DNA methylation patterns in the 22 selected genetic features. RESULTS: The best machine learning algorithm was Naïve Bayes (accuracy=75%, AUC =0.81) using the top 22 genetic features, and this algorithm had the stable and great performance on another dataset as well. The coupled mutation number of the long-survival group (>6 years) was less than the short-survival group (<1 year) in 22 genes (P=0.031). CONCLUSIONS: The expression of gene panel can predict the survival time of lung adenocarcinoma patients using Naïve Bayes. These 22 genes do affect the survival time of lung adenocarcinoma.