Ferroptosis-associated gene SLC7A11 is upregulated in NSCLC and correlated with patient’s poor prognosis: An integrated bioinformatics analysis

Objective Ferroptosis is a type of programmed cell death dependent on iron and characterized by the accumulation of lipid peroxides, which was involved in the progression of malignant tumors including non-small cell lung cancer (NSCLC). Material/methods Ferroptosis inhibiting gene solute carrier family 7 member 11 (SLC7A11) mRNA expression was investigated in the database of TCGA and Oncomine and compared between the cancer tissue and the normal corresponding tissue of NSCLC patients. SLC7A11 gene mutation of NSCLC was investigated in the TCGA database by the online data analysis tool of Catalog of Somatic Mutations in Cancer (COSMIC) and cBioPortal. The protein–protein interaction (PPI) network of SLC7A11 and associated genes were constructed with the STRING database. Gene ontology (GO) and the KEGG pathway of genes involved in the PPI network were explored and demonstrated by a bubble plot. Progression-free survival (PFS), overall survival (OS) and postprogression survival (PPS) between SLC7A11high and SLC7A11low expression groups were compared and demonstrated by the survival curve. Results SLC7A11 mRNA was upregulated in cancer tissues compared to paired normal tissues in colorectal adenocarcinoma, esophageal squamous cell carcinoma, lung squamous cell carcinoma rectum adenocarcinoma and uterine corpus endometrial carcinoma. Missense and synonymous substitutions were 66.67% and 16.67% for lung squamous cell carcinoma. For lung adenocarcinoma, the missense and synonymous substitutions were 66.67% and 33.33% respectively. In the case of single nucleotide mutation, A>T, C>G, G>A, G>T for lung squamous cell carcinoma and G>T, C>A, G>A, T> for lung adenocarcinoma were the most common mutations in the SLC7A11 coding strand. Fifty-one genes were included in the PPI network with an edge number of 287, average node degree of 11.3 and local clustering coefficient of 0.694, which demonstrated that the PPI network was enriched significantly (p = 1.0 × 10−16). In terms of the KEGG pathway, the SLC7A11 and PPI-involved genes were mainly enriched in ferroptosis, NSCLC, pathways in cancer, tp53 signaling pathway, etc. The overall survival (OS) in the SLC7A11high group was significantly lower than those of SLC7A11low groups in NSCLC (HR = 1.15, 95% CI: 1.02–1.31, p = 0.027). However, the progression-free survival (PFS) (HR = 1.17, 95% CI: 0.97–1.42, p = 0.098) and postprogression survival (PPS) (HR = 1.00, 95% CI: 0.78–1.29, p = 0.97) between SLC7A11high and SLC7A11low expression groups were not statistically different. Conclusion SLC7A11 was upregulated in NSCLC and correlated with the patient’s poor overall survival. SLC7A11 may be a potential target for NSCLC treatment through the ferroptosis pathway.

Correlation between methylene tetrahydrofolate reductase (MTHFR) gene rs1801133 C>T polymorphisms and risk of osteoporosis

Objective To evaluate the correlation between methylene tetrahydrofolate reductase (MTHFR) gene rs1801133 C>T polymorphisms and risk of osteoporosis. Methods We searched the clinical studies related to MTHFR gene rs1801133 C>T polymorphisms and risk of osteoporosis in the electronic databases of PubMed, Web of Science, EMBASE, China National Knowledge Infrastructure (CNKI), Chinese BioMedical Literature Database (CBM) and included the suitable publications in the present meta-analysis according to the inclusion and exclusion criteria. The data of included studies were extracted and pooled by a random or fixed-effect model. The odds ratio (OR) and 95% confidence interval (95% CI) were applied to demonstrate the correlation between MTHFR gene rs1801133 C>T polymorphisms and the risk of osteoporosis. Publication bias was assessed by Begg’s funnel plot and Egger’s line regression test. Results Seven case–control clinical studies were included and a data combination was made. The data was pooled by the fixed effect model because of no obvious statistical heterogeneity. The pooled results indicated that people with the T allele had increased risk of developing osteoporosis under the homologous gene model (TT vs CC) (OR = 2.36, 95% CI: 1.81–3.08, p < 0.05), dominant gene model (TT + CT) vs CC (OR = 1.47, 95% CI: 1.21–1.77, p < 0.05) and recessive gene model TT vs (CC + CT) (OR = 2.16, 95% CI: 1.71–2.74, p < 0.05). Egger’s line regression test indicated no significant publication bias for the present meta-analysis in the above homologous, dominant, and recessive gene models. Conclusion The MTHFR gene rs1801133 C>T polymorphisms are associated with osteoporosis and subjects with the T allele have an increased risk of developing osteoporosis.

Screening and bioinformatics analysis of key biomarkers in acute myocardial infarction

Acute myocardial infarction (AMI) is the most severe manifestation of coronary artery disease. Considerable efforts have been made to elucidate its etiology and pathology, but the genetic factors that play a decisive role in the occurrence of AMI are still unclear. To determine the molecular mechanism of the occurrence and development of AMI, four microarray datasets, namely, GSE29111, GSE48060, GSE66360, and GSE97320, were downloaded from the Gene Expression Omnibus (GEO) database. We analyzed the four GEO datasets to obtain the differential expression genes (DEGs) of patients with AMI and patients with non-AMI and then performed gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, and Protein-protein interaction (PPI) network analysis. A total of 41 DEGs were identified, including 39 upregulated genes and 2 downregulated genes. The enriched functions and pathways of the DEGs included the inflammatory response, neutrophil chemotaxis, immune response, extracellular space, positive regulation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) transcription factor activity, response to lipopolysaccharide, receptor for advanced glycation end products (RAGE) receptor binding, innate immune response, defense response to bacterium, and receptor activity. The cytoHubba plug-in in Cytoscape was used to select the most significant hub gene from the PPI network. Ten hub genes were identified, and GO enrichment analysis revealed that these genes were mainly enriched in inflammatory response, neutrophil chemotaxis, immune response, RAGE receptor binding, and extracellular region. In conclusion, this study integrated four datasets and used bioinformatics methods to analyze the gene chips of AMI samples and control samples and identified DEGs that may be involved in the occurrence and development of AMI. The study provides reliable molecular biomarkers for AMI screening, diagnosis, and prognosis.

Circulating concentrations of citrulline, neopterin, kynurenine, and tryptophan during chemoradiation in patients with cervical carcinoma

The aim of this study was to investigate the changes in circulating concentrations of citrulline, neopterin, kynurenine, and tryptophan during the course of chemoradiation in patients with cervical cancer. Sixteen patients with histologically confirmed carcinoma of the uterine cervix, aged 53 ± 15 years (range 29–76 years), were included in this study. Plasma neopterin, kynurenine, and tryptophan were determined with an enzyme-linked immunosorbent assay. Plasma citrulline was measured with high-performance liquid chromatography. Compared to baseline, citrulline concentration was markedly and statistically significantly decreased at visits 2, 3, and 4, while returning to pretreatment concentrations at visit 5. A significant increase in serum neopterin concentrations was observed at visits 4 and 5. With the exception of decreased kynurenine/tryptophan ratio at visit 3, no significant changes were observed in the concentrations of kynurenine, tryptophan, and kynurenine/tryptophan ratio throughout the course of the treatment. In conclusion, present data demonstrate that citrulline concentrations decrease early and neopterin concentrations increase late during the course of chemoradiation in patients with cervical carcinoma. Citrulline represents a biomarker of intestinal toxicity in this population.

Lipophilic vs. hydrophilic statins and psychiatric hospitalizations and emergency room visits in US Veterans with schizophrenia and bipolar disorder

Objective Psychiatric hospitalizations and emergency department (ED) visits are costly, stigmatizing, and often ineffective. Given the immune and kynurenine activation in bipolar disorder (BD) and schizophrenia, as well as the immune-modulatory effects of statins, we aimed to compare the relative risk (RRs) of psychiatric hospitalizations and ED visits between individuals prescribed lipophilic vs. hydrophilic statins vs. no statins. We hypothesized (a) reduced rates of hospitalization and ER utilization with statins versus no statins and (b) differences in outcomes between statins, as lipophilia increases the capability to penetrate the blood–brain barrier with potentially beneficial neuroimmune, antioxidant, neuroprotective, neurotrophic, and endothelial stabilizing effects, and, in contrast, potentially detrimental decreases in brain cholesterol concentrations leading to serotoninergic dysfunction, changes in membrane lipid composition, thus affecting ion channels and receptors. Methods We used VA service utilization data from October 1, 2010 to September 30, 2015. The RRs for psychiatric hospitalization and ED visits, were estimated using robust Poisson regression analyses. The number of individuals analyzed was 683,129. Results Individuals with schizophrenia and BD who received prescriptions for either lipophilic or hydrophilic statins had a lower RR of psychiatric hospitalization or ED visits relative to nonstatin controls. Hydrophilic statins were significantly associated with lower RRs of psychiatric hospitalization but not of ED visits, compared to lipophilic statins. Conclusion The reduction in psychiatric hospitalizations in statin users (vs. nonusers) should be interpreted cautiously, as it carries a high risk of confounding by indication. While the lower RR of psychiatric hospitalizations in hydrophilic statins relative to the lipophilic statins is relatively bias free, the finding bears replication in a specifically designed study. If replicated, important clinical implications for personalizing statin treatment in patients with mental illness, investigating add-on statins for improved therapeutic control, and mechanistic exploration for identifying new treatment targets are natural next steps.

Laboratory diagnostic value of neopterin measurements in patients with COVID-19 infection

The new coronavirus SARS-CoV-2 was identified to be responsible for the COVID-19 pandemic. There are striking differences in the response to infection, some people develop no or mild symptoms, while other outcomes are severe of even fatal. For those COVID-19 patients who require hospitalization, prognostic markers could help clinicians to identify patients with a poor outcome early. The serum levels of the immune activation marker neopterin have already been shown to be of prognostic value in patients with SARS-CoV-1 and a similar pattern can be observed for SARS-CoV-2. This comment discusses the biochemical circuits that support the clinical value of neopterin measurements in COVID-19 patients.

The urinary biopterin in autism spectrum disorder

Objective The aim of the study was to determine whether biopterin is present in significantly lower quantities in urine samples of patients with autism spectrum disorder (ASD) compared to healthy individuals. Methods The concentration of biopterin in urine samples was measured by ELISA using commercially available kit. The study involved 53 children aged 3–16 years with ASD and 60 healthy children aged 2–14 years. Results Significantly lower biopterin concentration was observed in autistic patients compared to the control group. However, no significant difference was observed between mild, moderate, and severe ASD. Conclusion One of the potential causes of decrease in urinary biopterin levels may be tetrahydrobiopterin (BH4) deficiency, which has extensive and serious health consequences for the nervous system. The results of measuring biopterin as a fully oxidized form of BH4 may suggest that biosynthesis or regeneration of BH4 may be decreased in children with ASD. On the other hand, decreased urinary biopterin levels in children with ASD may be due to BH4 overuse, a good regeneration process, and decreased urinary excretion; and abnormalities in BH4 metabolism appear to be related to the aetiology of ASD or may be due to ASD.

Norepinephrine was superior in death risk reducing and hemodynamics compared to dopamine in treatment of patients with septic shock

Background To investigate the clinical effects of norepinephrine versus dopamine in treatment of septic shock by pooling the data form open published clinical trials. Material and Methods The clinical trials relevant to norepinephrine versus dopamine in treatment of septic shock were electronically searched in the databases of Pubmed, Embase, the Cochrane Library, Web of Science, Google scholar and CNKI. The original data related to the treatment effects such as death risk, oxygen metabolism and hemodynamics index were extracted from the included original studies. The death risk was pooled by the effect size of relative risk (RR), the oxygen metabolism and hemodynamics index were pooled by standard mean difference (SMD) and the corresponding 95% confidence interval (95%CI). The publication bias was evaluated by Begg's funnel plot and Egger's line regression test. Results Thirteen clinical trials were included in the meta-analysis. The pooled results demonstrated the death risk was significantly decreased (RR=0.89, 95%CI:0.81 to 0.98, p=0.024) in septic shock patients who received norepinephrine compared to those receiving dopamine. The HR (SMD=−1.84, 95%CI: −2.86 to −0.81, p<0.01) and cardiac index (SMD=−0.74, 95%CI: −1.01 to −0.48, p<0.01) were lower in norepinephrine group compared to dopamine group. The systemic vascular resistance index (SMD=1.33, 95%CI:0.62 to 2.04, p<0.01) in norepinephrine group was higher than those of dopamine group with statistical difference. The Begg's funnel plot and Egger's line regression test (t=−0.84, p=0.425) showed no publication bias. Conclusions Based on the present evidence, norepinephrine was superior to dopamine in the aspects of death risk reducing and hemodynamics.

Methylene tetrahydrofolate dehydrogenase 2 (MTHFD2) is overexpressed in head and neck squamous cell carcinoma (HNSCC) and correlated with patient’s poor prognosis

Objective To investigate methylene tetrahydrofolate dehydrogenase 2 (MTHFD2) expression, biological function, and correlation with head and neck squamous cell carcinoma (HNSCC) patient’s prognosis. Methods The relative expression levels of MTHFD2 gene mRNA in tumor tissues of HNSCC and adjacent normal tissues were analyzed in the Cancer Genome Atlas and oncomine database. MTHFD2 protein relative expression in tumor tissue of HNSCC patients was analyzed in human proteome database. Protein–protein interaction (PPI) network of MTHFD2 and correlated genes were constructed in STRING database. Gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway of MTHFD2 and relevant proteins involved in the PPI network was enriched. The Tumor Immune Estimation Resource database was used to analyze the relationship between MTHFD2 expression and immune infiltration. Overall survival (OS) and progression-free survival (PFS) for MTHFD2 high and low expression groups were investigated in the Kaplan–Meier Plotter database. Results In HNSCC, MTHFD2 mRNA relative expression level in tumor tissue was significantly higher than the corresponding normal tissue with statistical difference (p < 0.05). In the PPI network, 21 protein coding genes were involved in the network with 124 edges, which indicated that the enrichment was significant (p < 0.05). MTHFD2 and PPI network involved genes were mainly enriched in tetrahydrofolate metabolic process, one-carbon metabolic process biological process. In KEGG pathway, MTHFD2 and PPI network involved genes were mainly enriched in one-carbon pool by folate, metabolic pathways, glyoxylate, and dicarboxylate metabolism, and carbon metabolism. The relative expression level of MTHFD2 gene was correlated with immune infiltration of macrophage (r = 0.712, p < 0.05), neutrophil (r = 0.158, p < 0.05), dendritic cell (r = 0.1825, p < 0.05), and CD4+ T lymph cell (r = 0.1825, p < 0.05). HNSCC patients with high expression MTHFD2 had low OS compared to low expression cases (hazard ratio = 1.53, 95% CI: 1.16–2.02, p < 0.05). Conclusion MTHFD2 is overexpressed in HNSCC and correlated with patient’s prognosis. MTHFD2 maybe a potential target for HNSCC target treatment and provides a possible direction for the research and development of related targeted drugs.

Clinical significance of serum homocysteine as a biomarker for early diagnosis of diabetic nephropathy in type 2 diabetes mellitus patients

Objective The aim of this study was to investigate the clinical significance of serum homocysteine (Hcy) as a biomarker for early diagnosis of diabetic nephropathy (DN) in type 2 diabetes mellitus (T2DM) patients. Methods Fifty-five T2DM patients with DN and 51 T2DM patients without DN were prospectively recruited from January 2016 to May 2020 in our hospital. The serum Hcy was tested by electrochemiluminescence assay in DN and T2DM groups and compared. The diagnostic efficacy of serum Hcy as a biomarker for early diagnosis of DN was evaluated by calculating the diagnostic sensitivity, specificity and area under the ROC curve (AUC). Results The serum levels of Hcy were 15.49 ± 5.40 and 9.23 ± 3.15 μmol/L for DN and T2DM patients, respectively, with statistical difference (t = 7.21, P < 0.001). In the DN group, the serum Hcy levels for patients with hyperfiltration, intermittent proteinuria, microalbuminuria, macroalbuminuria and uremic were 10.99 ± 2.57, 13.90 ± 2.86, 15.38 ± 4.77, 18.98 ± 4.36 and 23.31 ± 5.22 μmol/L, respectively, which indicated that serum Hcy levels in DN were higher than those of T2DM patients and correlated with patient’s renal damage. Using the serum Hcy level as the reference, the diagnostic sensitivity, specificity and AUC were 84.31 (71.41–92.98)%, 74.55 (61.00–85.33)% and 0.85 (0.78–0.92)%, respectively, with the cutoff value of 12.08 between DN and T2DM. The serum Hcy also had relatively good differential diagnostic efficacy between different DN stages with high sensitivity, specificity and AUC. Conclusion Serum Hcy was obviously elevated in DN compared to T2MD and correlated with the renal damage severity, which can be applied as a potential serological marker for early diagnosis of DN.