Ferroptosis biomarkers predict tumor mutation burden's impact on prognosis in HER2-positive breast cancer.

BACKGROUND: Ferroptosis has recently been associated with multiple degenerative diseases. Ferroptosis induction in cancer cells is a feasible method for treating neoplastic diseases. However, the association of iron proliferation-related genes with prognosis in HER2+ breast cancer (BC) patients is unclear. AIM: To identify and evaluate fresh ferroptosis-related biomarkers for HER2+ BC. METHODS: First, we obtained the mRNA expression profiles and clinical information of HER2+ BC patients from the TCGA and METABRIC public databases. A four-gene prediction model comprising PROM2, SLC7A11, FANCD2, and FH was subsequently developed in the TCGA cohort and confirmed in the METABRIC cohort. Patients were stratified into high-risk and low-risk groups based on their median risk score, an independent predictor of overall survival (OS). Based on these findings, immune infiltration, mutations, and medication sensitivity were analyzed in various risk groupings. Additionally, we assessed patient prognosis by combining the tumor mutation burden (TMB) with risk score. Finally, we evaluated the expression of critical genes by analyzing single-cell RNA sequencing (scRNA-seq) data from malignant vs normal epithelial cells. RESULTS: We found that the higher the risk score was, the worse the prognosis was (P < 0.05). We also found that the immune cell infiltration, mutation, and drug sensitivity were different between the different risk groups. The high-risk subgroup was associated with lower immune scores and high TMB. Moreover, we found that the combination of the TMB and risk score could stratify patients into three groups with distinct prognoses. HRisk-HTMB patients had the worst prognosis, whereas LRisk-LTMB patients had the best prognosis (P < 0.0001). Analysis of the scRNA-seq data showed that PROM2, SLC7A11, and FANCD2 were significantly differentially expressed, whereas FH was not, suggesting that these genes are expressed mainly in cancer epithelial cells (P < 0.01). CONCLUSION: Our model helps guide the prognosis of HER2+ breast cancer patients, and its combination with the TMB can aid in more accurate assessment of patient prognosis and provide new ideas for further diagnosis and treatment.

Genetic prediction of modifiable lifestyle factors for erectile dysfunction.

Background: The causal relationship between certain lifestyle factors and erectile dysfunction (ED) is still uncertain. Aim: The study sought to investigate the causal effect of 9 life factors on ED through 2-sample single-variable Mendelian randomization (SVMR) and multivariable Mendelian randomization (MVMR). Methods: Genetic instruments to proxy 9 risk factors were identified by genome-wide association studies. The genome-wide association studies estimated the connection of these genetic variants with ED risk (n = 223 805). We conducted SVMR, inverse variance-weighting, Cochran's Q, weighted median, MR-Egger, MR-PRESSO (Mendelian Randomization Pleiotropy RESidual Sum and Outlier), and MVMR analyses to explore the total and direct relationship between life factors and ED. Outcomes: The primary outcome was defined as self or physician-reported ED, or using oral ED medication, or a history of surgery related to ED. Results: In SVMR analyses, suggestive associations with increased the risk of ED were noted for ever smoked (odds ratio [OR], 5.894; 95% confidence interval [CI], 0.469 to 3.079; P = .008), alcohol consumption (OR, 1.495; 95% CI, 0.044 to 0.760; P = .028) and body mass index (BMI) (OR, 1.177; 95% CI, 0.057 to 0.268; P = .003). Earlier age at first intercourse was significantly related to reduced ED risk (OR, 0.659; 95% CI, -0.592 to -0.244; P = 2.5 × 10-6). No strong evidence was found for the effect of coffee intake, time spent driving, physical activity, and leisure sedentary behaviors on the incidence of ED (All P > .05). The result of MVMR analysis for BMI (OR, 1.13; 95% CI, 1.01 to 1.25; P = .045) and earlier age at first intercourse (OR, 0.77; 95% CI, 0.56 to 0.99; P = .018) provided suggestive evidence for the direct impact on ED, while no causal factor was detected for alcoholic drinks per week and ever smoked. Clinical implications: This study provides evidence for the impact of certain modifiable lifestyle factors on the development of ED. Strengths and limitations: We performed both SVMR and MVMR to strengthen the causal relationship between exposures and outcomes. However, the population in this study was limited to European ancestry. Conclusion: Ever smoked, alcoholic drinks per week, BMI, and age first had sexual intercourse were causally related to ED, while the potential connection between coffee intake, physical activity, recreational sedentary habits, and increased risk of ED needs to be further confirmed.

Identifying cellular senescence associated genes involved in the progression of end-stage renal disease as new biomarkers.

BACKGROUND: Cellular senescence plays an essential role in the development and progression of end-stage renal disease (ESRD). However, the detailed mechanisms phenomenon remains unclear. METHODS: The mRNA expression profiling dataset GSE37171 was taken from the Gene Expression Omnibus (GEO) database. The cell senescence-associated hub genes were selected by applying protein-protein interaction (PPI), followed by correlation analysis, gene interaction analysis, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. We next explored the relationships of hub genes with miRNAs, TFs, and diseases. The absolute abundance of eight immune cells and two stromal cells were calculated by MCPcount and the correlation of hub genes with these ten cells was analyzed. Lasso was used to selecting for trait genes. ROC curves and DCA decision curves were used to assess the accuracy and predictive power of the trait genes. RESULTS: A total of 65 cellular senescence signature genes were identified among patients and controls. The PPI network screened out ten hub genes. GO and KEGG indicated that ten hub genes were associated with ESRD progression. Transcription factor gene interactions and common regulatory networks of miRNAs were also identified in the datasets. The hub genes were significantly correlated with immune cells and stromal cells. Then the lasso model was constructed to screen out the five most relevant signature genes (FOS, FOXO3, SIRT1, TP53, SMARCA4). The area under the ROC curve (AUC) showed that these five characteristic genes have good resolving power for the diagnostic model. CONCLUSIONS: Our findings suggested that cellular senescence-associated genes played an important role in the development of ESRD and immune regulation.

Causal Association Between mTOR-Dependent Protein Levels and Alzheimer's Disease: A Mendelian Randomization Study.

BACKGROUND: Most previous studies supported that the mammalian target of rapamycin (mTOR) is over-activated in Alzheimer's disease (AD) and exacerbates the development of AD. It is unclear whether the causal associations between the mTOR signaling-related protein and the risk for AD exist. OBJECTIVE: This study aims to investigate the causal effects of the mTOR signaling targets on AD. METHODS: We explored whether the risk of AD varied with genetically predicted AKT, RP-S6K, EIF4E-BP, eIF4E, eIF4A, and eIF4G circulating levels using a two-sample Mendelian randomization analysis. The summary data for targets of the mTOR signaling were acquired from published genome-wide association studies for the INTERVAL study. Genetic associations with AD were retrieved from the International Genomics of Alzheimer's Project. We utilized the inverse variance weighted as the primary approach to calculate the effect estimates. RESULTS: The elevated levels of AKT (OR = 0.910, 95% CI=0.840-0.986, p = 0.02) and RP-S6K (OR = 0.910, 95% CI=0.840-0.986, p = 0.02) may decrease the AD risk. In contrast, the elevated eIF4E levels (OR = 1.805, 95% CI=1.002-1.174, p = 0.045) may genetically increase the AD risk. No statistical significance was identified for levels of EIF4-BP, eIF4A, and eIF4G with AD risk (p > 0.05). CONCLUSION: There was a causal relationship between the mTOR signaling and the risk for AD. Activating AKT and RP-S6K, or inhibiting eIF4E may be potentially beneficial to the prevention and treatment of AD.

Causal association between JAK2 and erectile dysfunction: a Mendelian randomization study.

BACKGROUND: As one of the most critical proteins in the JAK/STAT signaling pathway, Janus kinase 2 (JAK2) is involved in many biological processes and diseases. Several observational studies have reported the role of JAK2 in erectile dysfunction. However, the causal relationship between JAK2 and erectile dysfunction remains unclear. Here we investigated the causal relationship between JAK2 and erectile dysfunction. RESULTS: Genetically predicted JAK2 was causally associated with erectile dysfunction in inverse variance weighting (OR = 1.109, 95% CI = 1.029-1.196, p = 0.007) and weighted median method (OR = 1.117, 95% CI = 1.003-1.245, p = 0.044). No heterogeneity was observed in Cochran Q-test (p = 0.855) and MR-PRESSO (p = 0.866). Pleiotropy was not observed in our study (p = 0.617). CONCLUSIONS: These findings highlighted JAK2 as a risk factor for erectile dysfunction and proved the causal relationship between JAK2 and erectile dysfunction, suggesting that targeting JAK2 signaling might be a novel and promising therapeutic candidate in the treatment of erectile dysfunction.

RéSUMé: CONTEXTE: En tant que l'une des protéines les plus critiques de la voie de signalisation JAK/STAT, Janus kinase 2 (JAK2) est impliquée dans de nombreux processus biologiques et maladies. Plusieurs études observationnelles ont rapporté le rôle de JAK2 dans la dysfonction érectile. Cependant, la relation causale entre JAK2 et la dysfonction érectile reste incertaine. Ici, nous étudions la relation causale entre JAK2 et la dysfonction érectile. RéSULTATS: JAK2 génétiquement prédit était causalement associée à la dysfonction érectile par pondération de variance inverse (OR = 1,109, IC à 95% = 1,029­1,196, p = 0,007) et la méthode médiane pondérée (OR = 1.117, IC à 95% = 1.003-1.245, p = 0.044). Aucune hétérogénéité n'a été observée dans le test Q de Cochran (p = 0,855) et MR-PRESSO (p = 0,866). La pléiotropie n'a pas été observée dans notre étude (p = 0,617). CONCLUSIONS: Ces résultats ont mis en évidence JAK2 comme un facteur de risque de dysfonction érectile et ont prouvé la relation causale entre JAK2 et la dysfonction érectile; ils suggèrent que le ciblage de la signalisation JAK2 pourrait être un candidat thérapeutique nouveau et prometteur dans le traitement de la dysfonction érectile.

Research progress of Müller cells and retinal nerve regeneration / 国际眼科杂志(Guoji Yanke Zazhi)

@#Retinal degenerative diseases, a type of blinding eye diseases in which retinal neuron apoptosis is the main pathological process. Neuronal cells cannot be regenerated after damage, Müller cells are important glial cells of the retina and involved in retinal development, damage, and regeneration process. In recent years, studies have proved that Müller cells are an endogenous alternative source for stimulating damaged retinal neurons and an excellent target for retinal nerve regeneration. This article reviews the related factors of Müller cells and retinal nerve regeneration, and provides a new direction for nerve regeneration research.

Influence of astragalus injection on retina of simulated high altitude hypoxia rat / 国际眼科杂志(Guoji Yanke Zazhi)

·AIM: To investigate the effects of astragalus injection on the metabolic and pathological changes of the retinal free radical metabolism and pathology in high-altitude hypoxic rats. ·METHODS: Sixty healthy SD rats without any eye disease were selected,and the random grouping method was divided into two groups: astragalus injection group (intervention group) and physiological saline group (control group),each group of 30 rats. In each group,6 were randomly selected for injection of astragalus injection (15mL/kg) and physiological saline (15mL/kg) in the pre-simulated chamber. The rats were sacrificed immediately and removed the eyeballs after the rats were taken out of the simulated module. We observed the changes of retinal morphology with the HE staining method, and determine the retinal SOD and MDA content with colorimetry. · RESULTS: HE staining showed no morphological changes in the two groups of retinas at 2h, and as the time of hypoxia was prolonged, the retinal edema gradually increased,but the intervention group was less edema than the control group. The activity of SOD in both groups decreased with the increase of anoxia time of high altitude, and the comparison of different time points in the group was statistically significant(P<0.05). The content of MDA in both groups increased gradually, and the comparison between different time points in the group was statistically significant (P<0.05). The SOD in the two groups of retinas was significantly different at same time point(P<0. 05), except for at 2h without statistical significance. The MDA showed the same situation as SOD. ·CONCLUSION: Astragalus injection can reduce the damage degree of retinopathy in rats under the high altitude hypoxia environment, that the mechanism may be related to free radicals, enhance the activity of SOD, reduce the MDA content of lipid peroxides,and enhance antioxidant capacity.