Volume 32, Issue 1

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.

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.

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 (BH 4 ) deficiency, which has extensive and serious health consequences for the nervous system. The results of measuring biopterin as a fully oxidized form of BH 4 may suggest that biosynthesis or regeneration of BH 4 may be decreased in children with ASD. On the other hand, decreased urinary biopterin levels in children with ASD may be due to BH 4 overuse, a good regeneration process, and decreased urinary excretion; and abnormalities in BH 4 metabolism appear to be related to the aetiology of ASD or may be due to ASD.

Objective The aim of this study was to investigate the correlation between MTHFR 677C > T polymorphism and response of pemetrexed-based chemotherapy in advanced non-small-cell lung cancer (NSCLC) by pooling the open published relevant studies. Methods Clinical studies associated with MTHFR 677C > T polymorphism and response of pemetrexed-based chemotherapy in advanced NSCLC were systematically searched in databases of Pubmed, Embase, Cochrance Library, China national knowledge infrastructure (CNKI) and Wanfang. The correlation was expressed by odds ratio (OR) and corresponding 95% confidence interval (95% CI). The publication bias of the included studies was evaluated through Begg’s funnel plot and Egger’s line regression test. Results Ten prospective clinical studies relevant to MTHFR 677C > T polymorphism and response of pemetrexed-based chemotherapy in NSCLC were included in the present meta-analysis. The pooled results indicated that the partial response in NSCLC patients with TT or CT genotype was inferior to CC genotype in a dominant gene model (TT + CT vs CC) (OR = 0.16, 95% CI: 0.06–0.41, P = 0.001). NSCLC cases with T genotype were inferior to C genotype in the objective response rate treated with pemetrexed-based chemotherapy for dominant (OR = 0.28, 95% CI: 0.18–0.45, P = 0.001), recessive (OR = 0.43, 95% CI: 0.19–0.94, P = 0.03) and homozygous models (OR = 0.30, 95% CI: 0.13–0.67, P = 0.003). However, there was no statistical difference in disease control rate, progressive disease between different genotypes of different gene models ( P all > 0.05). Conclusion The pemetrexed-based chemotherapy response was decreased in NSCLC cases with T genotype, which can be applied as a potential pemetrexed-based chemotherapy response marker.

Objective The aim of the study is to investigate the correlations among serum homocysteine (Hcy), D-dimer, and the risk of developing deep venous thrombosis (DVT) of the lower extremities in patients who underwent operation for lower limb fracture. Methods Seventy-five cases who underwent operation for lower limb fracture were included and further divided into DVT group ( n = 26) and control group ( n = 49) based on post-DVT diagnostic criteria. The serum Hcy and D-dimer were examined 48 h after operation. The serum Hcy and D-dimer levels were compared between the two groups. The correlation between serum Hcy and D-dimer was investigated by the Pearson correlation test. The receiver-operating characteristic (ROC) curve was applied to evaluate the diagnostic performance of serum Hcy and D-dimer as serological markers for DVT. Results The serum Hcy concentrations were 11.96 ± 3.98 μmol/L and 7.92 ± 3.27 μmol/L for DVT and control groups, respectively, with statistical difference ( t = 4.72, P < 0.01). The serum D-dimer in the DVT group was significantly higher than that of the control group (8.99 ± 4.50 vs 1.70 ± 2.11) μg/mL with statistical difference ( t = 9.56, P < 0.01). Line regression analysis indicated that serum Hcy was positively correlated with serum D-dimer concentration and can be demonstrated by the equation of Y = 0.6651* X + 1.036 for the DVT group. Using serum Hcy as the biomarker for predicting DVT, the prediction sensitivity and specificity were 76.92 and 71.44%, respectively, with the AUC of 0.7804 under the cut-point of 9.54 μmol/L. For serum D-dimer, the prediction sensitivity and specificity were 96.15 and 73.47%, respectively, with the area under the ROC (AUC) of 0.9455 under the cut-point of 1.66 μg/mL. Conclusion Serum Hcy was significantly elevated in DTV patients, and hence, it can be applied as a serological marker for DVT prediction in patients who underwent operation for lower limb fracture. However, the DVT prediction performance of serum Hcy was inferior to D-dimer especially for diagnostic sensitivity.

Objective To explore the expression and genotypes of thymidylate synthase (TS) in patients of non-small cell lung cancer (NSCLC) with different clinicopathological characteristics. Methods The expression profiles of TS were examined by immunohistochemical staining and quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) in 160 patients with NSCLC. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to detect TS-5′UTR tandem repeats, G/C nucleotide polymorphisms, and 3′UTR 6 bp deletion/insertion polymorphisms. The relationships between clinicopathological characteristics and TS expression or genotypes were investigated through χ 2 test. Kaplan–Meier survival analysis was used to analyze the association between TS expression and overall survival (OS) and disease-free survival (DFS) of NSCLC patients. Results The expression levels of TS protein and TS gene in NSCLC tissues were significantly higher than that in paracancerous tissues ( P < 0.05). Furthermore, high expression of TS protein and 5′UTR polymorphism of TS gene showed significant correlation with differentiation, TNM stage, and lymph node metastases. The frequency of −6 bp/−6 bp genotypes in patients with NSCLC was 43.13% (69/160), which was higher than others. In addition, the rate of TS protein overexpression in NSCLC patients with 3R/3R was 79.79%, which was higher than others. Interestingly, high expression of TS protein predicted shorter DFS and OS and lower 3-year DFS rate and 3-year OS rate. Conclusions The expression levels of TS in NSCLC were significantly increased and may help to predict the prognosis of NSCLC, and high expression of TS protein and 5′UTR polymorphism of TS gene were significantly related to differentiation, TNM stage, and lymph node metastases.

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.

The naturally occurring stilbenoid oxyresveratrol was shown to influence inflammatory and metabolic processes. During cellular immune activation, tryptophan breakdown and neopterin formation via the enzymes indoleamine 2,3-dioxygenase-1 (IDO-1) and GTP-cyclohydrolase, respectively, are induced. Neopterin and the kynurenine to tryptophan ratio are reliable and pertinent biomarkers of Th1-type immune response and are also used in vitro to monitor effects of active plant ingredients on peripheral blood mononuclear cells (PBMCs). We investigated the effects of oxyresveratrol on the activity of the above-mentioned pathways in mitogen-stimulated human PBMC and in the myelomonocytic cell line THP-1. Oxyresveratrol exerted suppressive effects on tryptophan breakdown in both stimulated cell models. Of note, in PBMC, tryptophan breakdown was induced at lower concentrations (5–20 µM) and suppressed at higher treatment concentrations only. Neopterin formation was decreased dose-dependently in stimulated PBMC. In unstimulated PBMC similar, albeit lesser effects were observed. Data indicate that oxyresveratrol exerts distinct and concentration-dependent effects on different immune cell types. IDO-1 is targeted by oxyresveratrol and its activity can be modulated in both directions. Detailed investigations of the interactions would be interesting to fully explore the activity of this phytocompound.

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.

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.

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.

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 SLC7A11 high and SLC7A11 low 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 SLC7A11 high group was significantly lower than those of SLC7A11 low 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 SLC7A11 high and SLC7A11 low 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.

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.

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.