Genetic prediction of asthma increases multiple sepsis risks: A Mendelian randomization study.

Background: Observational epidemiological studies have indicated a potential association between asthma and sepsis, although the causal relationship between these 2 conditions remains uncertain. To further investigate this relationship, the present study utilized Mendelian randomization (MR) analysis approach to explore the potential links between asthma and various types of sepsis. Methods: In a large-scale genome-wide association study, single nucleotide polymorphisms (SNPs) associated with asthma were selected as instrumental variables. Three methods, including inverse-variance weighted (IVW), MR-Egger regression, and weighted median were used to assess the causal relationship between asthma and sepsis. The odds ratio (OR) and 95% confidence interval (CI) were used as the evaluation metrics for causal relationships, and sensitivity analysis was conducted to assess pleiotropy and instrument validity. Finally, a reverse MR analysis was conducted to investigate whether there is a causal relationship between sepsis and asthma. Results: We found a positive association between asthma and an increased risk of sepsis (OR=1.18, P＜0.05), streptococcal sepsis (OR=1.23, P=0.04), pneumonia-related sepsis (OR=1.57, P＜0.05), pneumococcal sepsis (OR=1.58, P=0.01), other sepsis (OR=1.15, P＜0.05), and sepsis in intensive care unit (ICU) settings (OR=1.23, P=0.02). Sensitivity analysis showed consistent results without heterogeneity or pleiotropy. The reverse MR analysis reveals no causal relationship between various types of sepsis and asthma. Conclusion: Our study demonstrates a causal relationship between asthma and different types of sepsis. These findings suggest the importance of healthcare providers paying attention to the potential risk of sepsis in asthma patients and implementing appropriate preventive and intervention measures in a timely manner.

Lama1 upregulation prolongs the lifespan of the dyH/dyH mouse model of LAMA2-related congenital muscular dystrophy.

LAMA2-related congenital muscular dystrophy (LAMA2-CMD), characterized by laminin-α2 deficiency, is debilitating and ultimately fatal. To date, no effective therapy has been clinically available. Laminin-α1, which shares significant similarities with laminin-α2, has been proven as a viable compensatory modifier. To evaluate its clinical applicability, we establish a Lama2 exon-3 deletion mouse model (dyH/dyH). The dyH/dyH mice exhibit early lethality and typical LAMA2-CMD phenotypes, allowing the evaluation of various endpoints. In dyH/dyH mice treated with synergistic activation mediator-based CRISPRa-mediated Lama1 upregulation, a nearly doubled median survival is observed, as well as improvements in weight and grip. Significant therapeutical effects are revealed by MRI, serum biochemical indices, and muscle pathology studies. Treating LAMA2-CMD with LAMA1 upregulation is feasible and that early intervention can alleviate symptoms and extend lifespan. Additionally, we reveal limitations of LAMA1 upregulation, including high-dose mortality and non-sustained expression, which require further optimization in future studies.

Causal relationship between several autoimmune diseases and renal malignancies: A two-sample mendelian randomization study.

OBJECTIVE: Observational studies have shown an association between systemic autoimmune disease (AD) and multiple malignancies. However, due to the difficulty indetermining the temporal nature of the order, their causal relationship remains elusive. Based on pooled data from a large population-wide genome-wide association study (GWAS), this study explores the genetic causality between systemic autoimmune disease and renal malignancy. METHODS: We took a series of quality control steps from a large-scale genome-wide association study to select single nucleotide polymorphisms (SNPs) associated with systemic autoimmune disease as instrumental variables(IVs) to analyze genetic causality with renal malignancies. Inverse variance weighting (IVW), MR- Egger, weighted median, simple model and weighted model were used for analysis. The results were mainly based on IVW (Random Effects), followed by sensitivity analysis. Inverse-Variance Weighted(IVW) and MR-Egger were used to test for heterogeneity. MR- Egger is also used for pleiotropic testing. A single SNP analysis was used to identify single nucleotide polymorphisms (SNPs) with potential impact. Odds ratio (OR) and 95% confidence interval (CI) were used to evaluate causality, and sensitivity analysis was performed to evaluate pleiotropy and instrumental validity. RESULTS: Acute and subacute iridocylitis (P = 0.006, OR = 1.077), Ankylosing spondylitis (P = 0.002, OR = 1.051), and spondyloarthritis (P = 0.009, OR = 1.073) were positively associated with an increased risk of renal malignancy. Coxarthrosis (P = 0.008, OR = 0.483), Juvenile rheumatism (P = 0.011, OR = 0.897), and Systemic lupus erythematosus (P = 0.014, OR = 0.869) were negatively associated with an increased risk of renal malignancy. The results of sensitivity analysis were consistent without heterogeneity or pleiotropy. CONCLUSION: Our study suggests a causal relationship between different systemic autoimmune diseases and renal malignancies. These findings prompt health care providers to take seriously the potential risk of systemic autoimmune disease and provide new insights into the genetics of kidney malignancies.

New perspectives on the potential of tetrandrine in the treatment of non-small cell lung cancer: bioinformatics, Mendelian randomization study and experimental investigation.

BACKGROUND: Although there are numerous treatment methods for NSCLC, long-term survival remains a challenge for patients. The objective of this study is to investigate the role and causal relationship between the target of tetrandrine and non-small cell lung cancer (NSCLC) through transcriptome and single-cell sequencing data, summary-data-based Mendelian Randomization (SMR) and basic experiments. The aim is to provide a new perspective for the treatment of NSCLC. METHODS: We obtained the drug target gene of tetrandrine through the drug database, and then used the GSE19188 data set to obtain the NSCLC pathogenic gene, established a drug-disease gene interaction network, screened out the hub drug-disease gene, and performed bioinformatics and tumor cell immune infiltration analysis. Single-cell sequencing data (GSE148071) to determine gene location, SMR to clarify causality and drug experiment verification. RESULTS: 10 drug-disease genes were obtained from 213 drug targets and 529 disease genes. DO/GO/KEGG analysis showed that the above genes were all related to the progression and invasion of NSCLC. Four drug-disease genes were identified from a drug-disease PPI network. These four genes were highly expressed in tumors and positively correlated with plasma cells, T cells, and macrophages. Subsequent single-cell sequencing data confirmed that these four genes were distributed in epithelial cells, and SMR analysis revealed the causal relationship between CCNA2 and CCNB1 and the development of NSCLC. The final molecular docking and drug experiments showed that CCNA2 and CCNB1 are key targets for tetrandrine in the treatment of NSCLC.

TMSB4X: A novel prognostic marker for non-small cell lung cancer.

Non-small cell lung cancer (NSCLC), as the main type of lung cancer, has a long history of high incidence and mortality. Despite the continuous updates to the American Joint Committee on Cancer (AJCC) staging system, which adapt to evolving treatment modalities and diagnostic advancements, it is evident that patients at the same stage exhibit varying prognoses. The heterogeneity of tumors underscores the need for molecular diagnostics to assume a pivotal role in tumor staging and patient stratification. In our investigation, we meticulously analyzed the data of the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database, incorporating clinical patients and scrutinizing pathological specimens. Through this comprehensive approach, we established a correlation between the expression of the Thymosin beta 4 X-linked (TMSB4X) gene and poorer disease-free survival (DFS) and overall survival (OS) post-surgery. Compared to the TMSB4X positive expression group, patients in the negative expression group had a better prognosis, with longer DFS (median disease-free survival (median DFS): 16.2 months vs. 11.3 months, P = 0.032) and OS (median overall survival (mOS): 29.8 months vs. 18.5 months, P = 0.033). Furthermore, our findings suggest that TMSB4X may facilitate immune evasion in non-small cell lung cancer cells by influencing the activation of infiltrating dendritic cells (DCs) in tumor infiltrating immune cells (TIICs) (R = 0.27, P = 4.8E+08). In summary, TMSB4X emerges as an unfavorable prognostic factor for NSCLC, potentially modulating the tumor immune microenvironment through its regulatory impact on dendritic cell function, thus facilitating tumor immune escape.

17-DMAG ameliorates neuroinflammation and BBB disruption via SOX5 mediated PI3K/Akt pathway after intracerebral hemorrhage in rats.

Intracerebral hemorrhage (ICH) can result in secondary brain injury due to inflammation and breakdown of the blood-brain barrier (BBB), which are closely associated with patient prognosis. The potential of the heat shock protein 90 (Hsp90) inhibitor 17-DMAG in promoting neuroprotection has been observed in certain vascular diseases. However, the precise role of 17-DMAG treatment in ICH is not yet fully understood. In this study, we found that treatment with 17-DMAG (5 mg/kg) effectively reduced hematoma expansion and resulted in improved neurological outcomes. Meanwhile, the injection of 17-DMAG had a positive effect on reducing BBB disruption in rats with ICH. This effect was achieved by increasing the levels of BBB tight junction proteins (TJPs) such as zo-1, claudin-5, and occludin. As a result, the leakage of EB extravasation, brain edema and IgG in the peri-hematoma tissue were reduced. Furthermore, the injection of 17-DMAG decreased the infiltration of neutrophils into the brain tissues surrounding the hematoma in ICH rats and also reduced the production of proinflammatory cytokines IL-6 and TNF-α. Next, we used integrative mass spectrometry (MS) and molecular docking analysis to confirm that sex determining region Y-box protein 5 (SOX5) is a potential direct target of 17-DMAG in ICH. SOX5 encodes a positive regulator of the PI3K/Akt axis, and treatment with 17-DMAG resulted in a noticeable increase in SOX5 accumulation. To further investigate the role of SOX5, we employed virus-regulated SOX5 silencing and found that suppressing SOX5 blocked the ability of 17-DMAG to suppress neutrophil trafficking. Additionally, silencing SOX5 blocked the protective effects of 17-DMAG on the BBB by inhibiting PI3K, p-Akt, and BBB TJPs levels, which led to an increase in EB and IgG leakage in the peri-hematoma tissue after ICH. Similarly, when SOX5 was knocked down, the protective effects of 17-DMAG were lost. Overall, the results of our study indicate that the injection of 17-DMAG has the potential to mitigate neuroinflammation and prevent the disruption of the BBB caused by ICH, resulting in improved neurological outcomes in rats. These positive effects are attributed to the regulation of SOX5 and activation of the PI3K/Akt pathway. These findings highlight the possibility of targeting SOX5 and the PI3K/Akt pathway as a novel therapeutic approach for ICH.

Establishing a prognostic model of chromatin modulators and identifying potential drug candidates in renal clear cell patients.

BACKGROUND: Renal carcinoma is a common malignant tumor of the urinary system. Advanced renal carcinoma has a low 5-year survival rate and a poor prognosis. More and more studies have confirmed that chromatin regulators (CRs) can regulate the occurrence and development of cancer. This article investigates the functional and prognostic value of CRs in renal carcinoma patients. METHODS: mRNA expression and clinical information were obtained from The Cancer Genome Atlas database. Univariate Cox regression analysis and LASSO regression analysis were used to select prognostic chromatin-regulated genes and use them to construct a risk model for predicting the prognosis of renal cancer. Differences in prognosis between high-risk and low-risk groups were compared using Kaplan-Meier analysis. In addition, we analyzed the relationship between chromatin regulators and tumor immune infiltration, and explored differences in drug sensitivity between risk groups. RESULTS: We constructed a model consisting of 11 CRs to predict the prognosis of renal cancer patients. We not only successfully validated its feasibility, but also found that the 11 CR-based model was an independent prognostic factor. Functional analysis showed that CRs were mainly enriched in cancer development-related signalling pathways. We also found through the TIMER database that CR-based models were also associated with immune cell infiltration and immune checkpoints. At the same time, the genomics of drug sensitivity in cancer database was used to analyze the commonly used drugs of renal clear cell carcinoma patients. It was found that patients in the low-risk group were sensitive to medicines such as axitinib, pazopanib, sorafenib, and gemcitabine. In contrast, those in the high-risk group may be sensitive to sunitinib. CONCLUSION: The chromatin regulator-related prognostic model we constructed can be used to assess the prognostic risk of patients with clear cell renal cell carcinoma. The results of this study can bring new ideas for targeted therapy of clear cell renal carcinoma, helping doctors to take corresponding measures in advance for patients with different risks.

miR-183 promotes radioresistance of lung adenocarcinoma H1299 cells via epithelial-mesenchymal transition.

Lung adenocarcinomas are usually sensitive to radiation therapy, but some develop resistance. Radiation resistance can lead to poor patient prognosis. Studies have shown that lung adenocarcinoma cells (H1299 cells) can develop radioresistance through epithelial-mesenchymal transition (EMT), and this process is regulated by miRNAs. However, it is unclear which miRNAs are involved in the process of EMT. In our present study, we found that miR-183 expression was increased in a radioresistant lung adenocarcinoma cell line (H1299R cells). We then explored the regulatory mechanism of miR-183 and found that it may be involved in the regulation of zinc finger E-box-binding homeobox 1 (ZEB1) expression and mediate EMT in lung adenocarcinoma cells. qPCR results showed that miR-183, ZEB1, and vimentin were highly expressed in H1299R cells, whereas no difference was observed in E-cadherin expression. Western blot results showed that ZEB1 and vimentin were highly expressed in H1299R cells, while E-cadherin expression was decreased. When miR-183 expression was inhibited in H1299R cells, radiation resistance, proliferation, and cell migration were decreased. The expression of ZEB1 and vimentin in H1299R cells was decreased, while the expression of E-cadherin was increased. Moreover, miR-183 overexpression in H1299 cells enhanced radiation resistance, proliferative capacity, and cell migration ability. The expression of ZEB1 and vimentin in H1299 cells was increased, while that of E-cadherin was decreased. In conclusion, miR-183 may promote EMT and radioresistance in H1299 cells, and targeting the miR-183-ZEB1 signaling pathway may be a promising approach for lung cancer treatment.

miR-183 promotes radioresistance of lung adenocarcinoma H1299 cells via epithelial-mesenchymal transition

Lung adenocarcinomas are usually sensitive to radiation therapy, but some develop resistance. Radiation resistance can lead to poor patient prognosis. Studies have shown that lung adenocarcinoma cells (H1299 cells) can develop radioresistance through epithelial-mesenchymal transition (EMT), and this process is regulated by miRNAs. However, it is unclear which miRNAs are involved in the process of EMT. In our present study, we found that miR-183 expression was increased in a radioresistant lung adenocarcinoma cell line (H1299R cells). We then explored the regulatory mechanism of miR-183 and found that it may be involved in the regulation of zinc finger E-box-binding homeobox 1 (ZEB1) expression and mediate EMT in lung adenocarcinoma cells. qPCR results showed that miR-183, ZEB1, and vimentin were highly expressed in H1299R cells, whereas no difference was observed in E-cadherin expression. Western blot results showed that ZEB1 and vimentin were highly expressed in H1299R cells, while E-cadherin expression was decreased. When miR-183 expression was inhibited in H1299R cells, radiation resistance, proliferation, and cell migration were decreased. The expression of ZEB1 and vimentin in H1299R cells was decreased, while the expression of E-cadherin was increased. Moreover, miR-183 overexpression in H1299 cells enhanced radiation resistance, proliferative capacity, and cell migration ability. The expression of ZEB1 and vimentin in H1299 cells was increased, while that of E-cadherin was decreased. In conclusion, miR-183 may promote EMT and radioresistance in H1299 cells, and targeting the miR-183-ZEB1 signaling pathway may be a promising approach for lung cancer treatment.

Establishment of an immune-related gene pair model to predict colon adenocarcinoma prognosis.

BACKGROUND: Colon cancer is the most common type of gastrointestinal cancer and has high morbidity and mortality. Colon adenocarcinoma (COAD) is the main pathological type of colon cancer, and much evidence has supported the correlation between the prognosis of COAD and the immune system. The current study aimed to develop a robust prognostic immune-related gene pair (IRGP) model to estimate the overall survival of patients with COAD. METHODS: The gene expression profiles and clinical information of patients with colon adenocarcinoma were obtained from the TCGA and GEO databases and were divided into training and validation cohorts. Immune genes were selected that showed a significant association with prognosis. RESULTS: Among 1647 immune genes, a model with 17 IRGPs was built that was significantly associated with OS in the training cohort. In the training and validation datasets, the IRGP model divided patients into the high-risk group and low-risk group, and the prognosis of the high-risk group was significantly worse (P<0.001). Univariate and multivariate Cox proportional hazard analyses confirmed the feasibility of this model. Functional analysis confirmed that multiple tumor progression and stem cell growth-related pathways were upregulated in the high-risk groups. Regulatory T cells and macrophages M0 were significantly highly expressed in the high-risk group. CONCLUSION: We successfully constructed an IRGP model that can predict the prognosis of COAD, providing new insights into the treatment strategy of COAD.

Study on demulsification and deoiling for O/W emulsion by microbubble pretreated resin.

The microbubble pretreated resin was used for demulsification and deoiling of the simulated O/W emulsion. The demulsification and deoiling performance and the influencing factors were investigated systematically. Experimental results indicate that the microbubble pretreated resin reaches a 97% oil removal within 80 min; on the contrary, oil removals are 90% and 85% for NaOH solution soaked and un-pretreated resins respectively. After five repeated runs, the oil removal of microbubble pretreated resin can be maintained at over 70%. The demulsification mechanism was revealed by comparing zeta potential, surface tension, contact angle of the emulsion in treatment, and the characterization results of the resin before and after use. Three possible pathways of demulsification were concluded and the ranking contributions can be shown below. Pathway 1: Competitive trapping of surfactant. The cationic groups of the resin combine with the anionic groups of the surfactant and drag them away from the oil particle surface. Pathway 2: Distribution equilibrium of surfactant. Free surfactants in the emulsion are captured by resin and reduce the concentration of uncombined surfactant. This results in surfactants on the oil particle partly detaching from the oil surface to maintain the adsorption-desorption equilibrium of the surfactant. Pathway 3: Adsorption coalescence.

[Clinical phenotypes and genetic study of 2 cases with 22q13 deletion syndrome].

OBJECTIVE: To determine the genetic etiology and clinical characteristics of 2 boys featuring development delay (DD). METHODS: Routine chromosomal banding was performed to analyze the karyotypes of the patients and their parents. Single nucleotide polymorphism array (SNP array) analysis was employed to identify pathogenic deletion/duplication of chromosomes, and quantitative real-time PCR (qPCR) was performed to confirm the results. RESULTS: Patient 1 showed a global developmental delay, especially impaired language development, seizures, behavioral problems belonging to the autism spectrum and mild facial dysmorphism. Patient 2 mainly presented with severely delayed speech and moderate intellectual disability, but did not have obvious facial dysmorphism and autistic-like behavior. The diagnosis of 22q13 syndrome was established based on identification of a heterozygous microdeletion at chromosome 22q13.33 in both patients (69 kb and 587 kb, respectively) by the SNP array analysis. Both patients had deletions of SHANK3 and ACR, which are located at the end of 22q. Quantitative real-time PCR verified that the deletion of SHANK3 gene in both patients were de novo in origin. CONCLUSION: Two cases of 22q13 deletion syndrome have been diagnosed by SNP array analysis. Deletion of SHANK3 gene may be the major contributor to the clinical manifestations of the patients. SNP array analysis can facilitate discovery of microdeletions, which has played an important role in the diagnosis and genetic counseling for the family.

Mutations in methionyl-tRNA synthetase gene in a Chinese family with interstitial lung and liver disease, postnatal growth failure and anemia.

Methionyl-tRNA synthetase (MARS) catalyzes the ligation of methionine to tRNA. Heterozygous MARS mutations have been reported to cause Charcot-Marie-Tooth disease, axonal, type 2U (CMT2U). Homozygous or compound heterozygous mutations in MARS gene would cause interstitial lung and liver disease (ILLD), a severe disease onset in infancy or early childhood. Here we report a Chinese ILLD family with two affected boys diagnosed by exome sequencing. They carry novel compound heterozygous MARS mutations (p.Asp145Asn and p.Phe802Ser). Their phenotype is concordant with ILLD description. As ILLD patients were only reported by two studies, we summarized all the reported patients and characterized the principle clinical features as interstitial lung disease, developmental delay, postnatal growth failure, non-life-threatening liver dysfunction and anemia. Genotype-phenotype correlation analysis suggests most of the ILLD mutations locate in the catalytic domain of MARS. ILLD and CMT2U might have different disease mechanism.