Genomic and transcriptomic significance of multiple primary lung cancers detected by next-generation sequencing in clinical settings.

Effective diagnosis and understanding of the mechanism of intrapulmonary metastasis (IM) from multiple primary lung cancers (MPLC) aid clinical management. However, the actual detection panels used in the clinic are variable. Current research on tumor microenvironment (TME) of MPLC and IM is insufficient. Therefore, additional investigation into the differential diagnosis and discrepancies in TME between two conditions is crucial. Two hundred and fourteen non-small cell lung cancer patients with multiple tumors were enrolled and 507 samples were subjected to DNA sequencing (NGS 10). Then, DNA and RNA sequencing (master panel) were performed on the specimens from 32 patients, the TME profiles between tumors within each patient and across patients and the differentially expressed genes were compared. Four patients were regrouped with NGS 10 results. Master panel resolved the classifications of six undetermined patients. The TME in MPLC exhibited a high degree of infiltration by natural killer (NK) cells, CD56dim NK cells, endothelial cells, etc., P < 0.05. Conversely, B cells, activated B cells, regulatory cells, immature dendritic cells, etc., P < 0.001, were heavily infiltrated in the IM. NECTIN4 and LILRB4 mRNA were downregulated in the MPLC (P < 0.0001). Additionally, NECTIN4 (P < 0.05) and LILRB4 were linked to improved disease-free survival in the MPLC. In conclusion, IM is screened from MPLC by pathology joint NGS 10 detections, followed by a large NGS panel for indistinguishable patients. A superior prognosis of MPLC may be associated with an immune-activating TME and the downregulation of NECTIN4 and LILRB4 considered as potential drug therapeutic targets.

Feto-placental endothelial dysfunction in Gestational Diabetes Mellitus under dietary or insulin therapy.

OBJECTIVE: Gestational diabetes mellitus (GDM) is a serious complication in pregnancy. Despite controlling the plasma glucose levels with dietary intervention (GDM-D) or insulin therapy (GDM-I), children born of diabetic mothers suffer more long-term complications from childhood to early adulthood. Placental circulation and nutrient exchange play a vital role in fetal development. Additionally, placental endothelial function is an indicator of vascular health, and plays an important role in maintaining placental circulation for nutrient exchange. This study was conducted to assess changes in fetal endothelial dysfunction in GDM under different interventions during pregnancy. METHODS: The primary human umbilical vein endothelial cells (HUVECs) were obtained from normal pregnant women (n = 11), GDM-D (n = 14), and GDM-I (n = 12) patients. LC-MS/MS was used to identify differentially expressed proteins in primary HUVECs among the three groups, after which Bioinformatics analysis was performed. Glucose uptake, ATP level, apoptosis, and differentially expressed proteins were assessed to investigate changes in energy metabolism. RESULTS: A total of 8174 quantifiable proteins were detected, and 142 differentially expressed proteins were identified after comparing patients with GDM-D/GDM-I and healthy controls. Of the 142, 64 proteins were upregulated while 77 were downregulated. Bioinformatics analysis revealed that the differentially expressed proteins were involved in multiple biological processes and signaling pathways related to cellular processes, biological regulation, and metabolic processes. According to the results from KEGG analysis, there were changes in the PI3K/AKT signaling pathway after comparing the three groups. In addition, there was a decrease in glucose uptake in the GDM-I (P < 0.01) group. In GDM-I, there was a significant decrease in the levels of glucose transporter 1 (GLUT1) and glucose transporter 3 (GLUT3). Moreover, glucose uptake was significantly decreased in GDM-I, although in GDM-D, there was only a decrease in the levels of GLUT1. ATP levels decreased in GDM-I (P < 0.05) and apoptosis occurred in both the GDM-D and GDM-I groups. Compared to the normal controls, the levels of phosphate AKT and phosphate AMPK over total AKT and AMPK were reduced in the GDM-I group. CONCLUSION: In summary, endothelial dysfunction occurred in pregnancies with GDM even though the plasma glucose levels were controlled, and this dysfunction might be related to the degree of glucose tolerance. The energy dysfunction might be related to the regulation of the AKT/AMPK/mTOR signaling pathway.

Turning waste into wealth: nitrogen-doped carbon quantum dots derived from fruits wastes for sensing.

Hydrothermal treatment of m-phenylenediamine and grape seed powder has been adopted to synthesize nitrogen-doped carbon quantum dots (N-CQDs). The prepared N-CQDs possessed outstanding optical properties and high quantum yield. Based on the combined effect of static quenching effect and inner filter effect of permanganate (MnO4 - ) to N-CQDs and the redox reaction that occurred between MnO4 - and l-ascorbic acid (l-AA), an 'off-on' fluorescence strategy with N-CQDs has been proposed for the detection of MnO4 - and l-AA. The proposed fluorescent probe was fast, sensitive and selective to MnO4 - and l-AA under mild conditions. In addition, the satisfactory results of the proposed strategy for the detection of MnO4 - and l-AA in real samples indicated its practicability.

Comparison of submucosal and subserosal approaches toward optimized indocyanine green tracer-guided laparoscopic lymphadenectomy for patients with gastric cancer (FUGES-019): a randomized controlled trial.

BACKGROUND: Application of indocyanine green (ICG) fluorescence imaging is effective in guiding laparoscopic radical lymphadenectomy for gastric cancer. However, the optimal approach for indocyanine green injection is controversial. Therefore, the objective of this study was aimed to compare the efficacy and ICG injection between the preoperative submucosal and intraoperative subserosal approaches for lymph node (LN) tracing during laparoscopic gastrectomy. METHOD: This randomized controlled trial (ClinicalTrials.gov, NCT04219332) included 266 patients with potentially resectable gastric cancer (cT1-T4a, N0/+, M0) enrolled from a tertiary teaching center between December 2019 and October 2020. The primary endpoint was total number of retrieved LNs. RESULTS: In total, 259 patients (n = 130 and n = 129 in the submucosal and subserosal groups, respectively) were included in the per-protocol analysis. There are no significant differences in total number of retrieved LNs between the two groups (49.8 vs. 49.2, P = 0.713). The rate of LN noncompliance in the submucosal group was comparable to that in the subserosal group (32.3% vs. 33.3%, P = 0.860). No significant difference was found between the submucosal and subserosal groups in terms of the incidence (17.7% vs. 16.3%; P = 0.762) or severity of postoperative complications. The mean fluorescence cost in the submucosal group was higher than that in the subserosal group ($335.3 vs. $182.4; P < 0.001). The overall treatment satisfaction score was lower in the submucosal group than in the subserosal group (70.5 vs. 76.1%, P = 0.048). CONCLUSION: ICG administered by subserosal injection was comparable to that administered by submucosal injection for lymph node tracing in gastric cancer. However, the former approach imposed a lower economic and mental burden on patients undergoing laparoscopic D2 lymphadenectomy. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04219332 .

Redox-modulated colorimetric detection of ascorbic acid and alkaline phosphatase activity with gold nanoparticles.

Gold nanoparticles (AuNPs) exhibit characteristic absorption peaks in the ultraviolet visible region due to their special surface plasmon resonance effect. This characteristic absorption peak would change with the relative colour varying from wine red to orange-yellow upon sequential addition of ascorbic acid (AA) into the mixture of AuNPs and Ag(I). Similar observations also could be found when the hydrolysis product of sodium l-ascorbyl-2-phosphate with alkaline phosphatase (ALP) was used as an alternative to AA. Results of structure characterization confirmed that the phenomena were due to the reduction of Ag(I) to Ag(0) on the surface of AuNPs and the formation of core-shell AuNPs@Ag. Therefore, a colorimetric assay for rapid visual detection of AA and ALP based on redox-modulated silver deposition on AuNPs has been proposed. Under the optimal experimental conditions, the absorbance variation ΔA522 nm /A370 nm of AuNPs was proportional to the concentration of AA (5-60 µmol/L) and ALP (3-18 U/L) with the corresponding detection limit of 2.44 µmol/L for AA and 0.52 U/L for ALP. The assay showed excellent selectivity towards AA and ALP. Moreover, the assay has been applied to detect AA and ALP activity in real samples with satisfying results.

Simple and Accurate Quantitative Analysis of 16 Antipsychotics and Antidepressants in Human Plasma by Ultrafast High-Performance Liquid Chromatography/Tandem Mass Spectrometry.

BACKGROUND: In psychopharmacology, treatment with psychotropic drugs is often suboptimal, mainly because of the high interindividual variability in pharmacokinetic properties. Therapeutic drug monitoring (TDM) can be a valuable tool for monitoring the individual effects of a prescribed dosage in a patient, and it facilitates antipsychotic treatment by increasing the effectiveness and safety of drugs and by reducing treatment costs. The aim of this study was to develop and validate an ultrafast liquid chromatography (UFLC) method with tandem mass spectrometric detection for the measurement of 16 antipsychotics and antidepressants in human plasma samples for TDM or other applications. METHODS: The method was developed to replace traditional methods using the solid-phase extraction of proteins precipitated with methanol/acetonitrile containing 0.1% formic acid. Quantitative analysis was performed by UFLC combined with a tandem mass spectrometer using a Synergy 3u-Hydro-RP (2.0 × 50 mm, 3 µm) column with a mobile phase consisting of 0.1% formic acid and acetonitrile. RESULTS: A simple, fast, and sensitive UFLC-tandem mass spectrometry method for the simultaneous measurement of commonly used antipsychotics (aripiprazole, chlorpromazine, paliperidone, quetiapine, risperidone, ziprasidone, clozapine, and olanzapine), antidepressants (citalopram, escitalopram, mirtazapine, fluoxetine, paroxetine, sertraline, venlafaxine plus O-desmethylvenlafaxine, and fluvoxamine) and an antidementia drug (donepezil) has been developed. The total run time of the chromatographic separation was 6.0 minutes. The precision and accuracy varied from 0.90% to 14% and from 88.5% to 118%, respectively. A 6-point standard curve covering the clinically relevant ranges with a power function fit was applied for calibration. Ion suppression due to matrix effects and the internal standards were investigated. Their recoveries varied from 89% to 110%. CONCLUSIONS: This new validated method fulfills all criteria for TDM and was successfully applied in the routine TDM of antipsychotics and antidepressants at the First Affiliated Hospital of Kunming Medical University.

Causal effects of genetic birth weight and gestational age on adult esophageal diseases: Mendelian randomization study.

BACKGROUND: Few studies have investigated the association between gestational age, birth weight, and esophageal cancer risk; however, causality remains debated. We aimed to establish causal links between genetic gestational age and birth weight traits and gastroesophageal reflux disease (GERD), Barrett's esophagus (BE), and esophageal adenocarcinoma (EA). Additionally, we explored if known risk factors mediate these links. AIM: To analyze of the relationship between gestational age, birth weight and GERD, BE, and EA. METHODS: Genetic data on gestational age and birth weight (n = 84689 and 143677) from the Early Growth Genetics Consortium and outcomes for GERD (n = 467253), BE (n = 56429), and EA (n = 21271) from genome-wide association study served as instrumental variables. Mendelian randomization (MR) and mediation analyses were conducted using MR-Egger, weighted median, and inverse variance weighted methods. Robustness was ensured through heterogeneity, pleiotropy tests, and sensitivity analyses. RESULTS: Birth weight was negatively correlated with GERD and BE risk [odds ratio (OR) = 0.78; 95% confidence interval (CI): 0.69-0.8] and (OR = 0.75; 95%CI: 0.60-0.9), respectively, with no significant association with EA. No causal link was found between gestational age and outcomes. Birth weight was positively correlated with five risk factors: Educational attainment (OR = 1.15; 95%CI: 1.01-1.31), body mass index (OR = 1.06; 95%CI: 1.02-1.1), height (OR = 1.12; 95%CI: 1.06-1.19), weight (OR = 1.13; 95%CI: 1.10-1.1), and alcoholic drinks per week (OR = 1.03; 95%CI: 1.00-1.06). Mediation analysis showed educational attainment and height mediated the birth weight-BE link by 13.99% and 5.46%. CONCLUSION: Our study supports the protective role of genetically predicted birth weight against GERD, BE, and EA, independent of gestational age and partially mediated by educational attainment and height.

Comprehensive multi-omics analysis of pyroptosis for optimizing neoadjuvant immunotherapy in patients with gastric cancer.

Background: Pyroptosis plays a crucial role in immune responses. However, the effects of pyroptosis on tumor microenvironment remodeling and immunotherapy in gastric cancer (GC) remain unclear. Patients and Methods: Large-sample GEO data (GSE15459, GSE54129, and GSE62254) were used to explore the immunoregulatory roles of pyroptosis. TCGA cohort was used to elucidate multiple molecular events associated with pyroptosis, and a pyroptosis risk score (PRS) was constructed. The prognostic performance of the PRS was validated using postoperative GC samples from three public databases (n=925) and four independent Chinese medical cohorts (n=978). Single-cell sequencing and multiplex immunofluorescence were used to elucidate the immune cell infiltration landscape associated with PRS. Patients with GC who received neoadjuvant immunotherapy (n=48) and those with GC who received neoadjuvant chemotherapy (n=49) were enrolled to explore the value of PRS in neoadjuvant immunotherapy. Results: GC pyroptosis participates in immune activation in the tumor microenvironment and plays a powerful role in immune regulation. PRS, composed of four pyroptosis-related differentially expressed genes (BATF2, PTPRJ, RGS1, and VCAN), is a reliable and independent biomarker for GC. PRSlow is associated with an activated pyroptosis pathway and greater infiltration of anti-tumor immune cells, including more effector and CD4+ T cells, and with the polarization of tumor-associated macrophages in the tumor center. Importantly, PRSlow marks the effectiveness of neoadjuvant immunotherapy and enables screening of GC patients with combined positive score ≥1 who benefit from neoadjuvant immunotherapy. Conclusion: Our study demonstrated that pyroptosis activates immune processes in the tumor microenvironment. A low PRS correlates with enhanced infiltration of anti-tumor immune cells at the tumor site, increased pyroptotic activity, and improved patient outcomes. The constructed PRS can be used as an effective quantitative tool for pyroptosis analysis to guide more effective immunotherapeutic strategies for patients with GC.

Safety and efficacy of 12-week or longer indacaterol treatment in moderate-to-severe COPD patients: a systematic review.

BACKGROUND: This is a meta-analysis of the safety and efficacy of indacaterol in chronic obstructive pulmonary disease (COPD) with treatment duration of ≥12 weeks. METHODS: Randomized controlled trials (RCTs) reported in English (to September 30, 2012) were identified from PubMed, the Cochrane Library, Embase, websites, reference lists, and manual searches. Two reviewers independently assessed the quality of the trials and extracted information. RESULTS: Five RCTs were eligible. Five involved indacaterol, two salmeterol, one formoterol, and one tiotropium. Four studies had placebos. Using trough forced expiratory volume in 1 s as a measure of therapeutic effect, indacaterol was superior to the other ß2-agonists, tiotropium, and placebo at weeks 12, 26, and 52. Indacaterol had a greater effect on the transition dyspnoea index compared with placebo, formoterol, and salmeterol, but not open-label tiotropium. In reducing the as-needed use of salbutamol, indacaterol were superior to placebo, tiotropium, and formoterol, but not salmeterol (5, 95 % confidence interval (CI), -2.15, 12.15). Indacaterol improved St George's Respiratory Questionnaire scores more than placebo and open-label tiotropium, but not formoterol. Indacaterol seemed to cause more adverse events than placebo only at a dose of 600 µg daily and a duration of 52 weeks (risk ratio 1.15; 95 % CI, 1.04, 1.26). The total and serious adverse events and adverse events leading to discontinuation were comparable with open-label tiotropium and the ß2-agonists. CONCLUSIONS: Indacaterol is effective and well-tolerated as a bronchodilator for the maintenance of moderate to severe COPD.

The predictive implication of programmed cell death ligand 1 expression in extranodal natural killer/T-Cell lymphoma and its correlation with clinicopathological features: a systematic review and meta-analysis.

Background: Although programmed cell death ligand 1 (PD-L1) expression and function in hematologic malignancies have aroused extensive attention, its prognostic value for extranodal natural killer/T-cell lymphoma (ENKTL) is still unknown. Therefore, we conducted this meta-analysis to explore the predictive value of neoplastic PD-L1 expression for ENKTL. Methods: The PubMed, Embase, Web of Science, and CNKI databases were searched to identify eligible observational studies reporting PD-L1 expression and survival outcomes of ENKTL patients. The search was conducted in accordance with the Meta-analyses Of Observative Studies in Epidemiology (MOOSE) guidelines. The pooled hazard ratios (HRs) and 95% confidence intervals (95% CIs) were adopted to analyze survival outcomes, and the odds ratios (ORs) and 95% CIs were adopted for clinicopathological parameters. Review Manager 5.3 and STATA 17.0 were used for statistical analysis. Potential publication bias was evaluated by funnel plot and Egger's test. Results: A total of 433 patients with ENKTL were included across seven studies. The pooled results showed no significant relationship between neoplastic PD-L1 expression and overall survival (OS) (HR =1.35, 95% CI: 0.49-3.75, P=0.559). We also performed subgroup analyses. However, increased PD-L1 expression was associated with a low international prognostic index (IPI) score of 0-1 (OR =2.46; 95% CI: 1.11-5.45, P=0.03), good performance status (OR =1.97; 95% CI: 1.11-3.51, P=0.02), and a good treatment effect (OR =2.61; 95% CI: 1.01-6.70, P=0.05). Conclusions: PD-L1-positive expression in patients with ENKTL was correlated with favorable clinical features. Thus, PD-L1-positive expression appears to be a potential predictor of treatment benefits. Additional large-scale, high-quality studies are needed to further explore its predictive value.

Decoding VaCOLD1 Function in Grapevines: A Membrane Protein Enhancing Cold Stress Tolerance.

In globally cultivated grapevines, low-temperature stress poses a persistent challenge. Although COLD1 is recognized as a cold receptor in rice, its function in grapevine cold signaling is unclear. Here, we identified VaCOLD1, a transmembrane protein from the cold-tolerant Vitis amurensis Rupr, which is primarily located on plasma and endoplasmic reticulum membranes. Broadly expressed across multiple tissues, VaCOLD1 responds to various environmental stresses, particularly to cold. Its promoter contains distinct hormone- and stress-responsive elements, with GUS assays confirming widespread expression in Arabidopsis thaliana. Validation of interaction between VaCOLD1 and VaGPA1, together with their combined expression in yeast and grape calli, notably improved cold endurance. Overexpression of VaCOLD1 enhances cold tolerance in Arabidopsis by strengthening the CBF-COR signaling pathway. This is achieved through shielding against osmotic disturbances and modifying the expression of ABA-mediated genes. These findings emphasize the critical role of the VaCOLD1-VaGPA1 complex in mediating the response to cold stress via the CBF-COR pathway.

A retrospective study of 134 patients with cervical region Kikuchi-Fujimoto disease.

Background: To explore the clinical and laboratory features, therapy and prognosis of Kikuchi-Fujimoto disease (KFD) in the cervical region. Methods: We retrospectively reviewed the medical records of 134 patients who were diagnosed and treated with KFD from January 2000 to May 2022 in Fujian Medical University Union Hospital (Fujian, China). Their clinical characteristics, affected lymph node size, imaging examinations, and laboratory study results were analyzed. Results: The mean patient age was 24.9 years, and the male-female ratio was 1:1.73. Fever (55.2%, n = 74) was the most common clinical manifestation. Leukopenia (49.3%) was the commonest reported laboratory abnormality. A majority (65.7%) of the 134 patients presented with bilateral nodal involvement. Conclusion: KFD should be considered as a possible diagnosis in a female patient under the age of 30 presenting with cervical lymphadenopathy, fever, leukopenia, and elevated LDH. Level of Evidence: 4.

Indocyanine green fluorescence imaging-guided versus conventional laparoscopic lymphadenectomy for gastric cancer: long-term outcomes of a phase 3 randomised clinical trial.

Indocyanine green (ICG) fluorescence imaging-guided lymphadenectomy has been demonstrated to be effective in increasing the number of lymph nodes (LNs) retrieved in laparoscopic gastrectomy for gastric cancer (GC). Previously, we reported the primary outcomes and short-term secondary outcomes of a phase 3, open-label, randomized clinical trial (NCT03050879) investigating the use of ICG for image-guided lymphadenectomy in patients with potentially resectable GC. Patients were randomly (1:1 ratio) assigned to either the ICG or non-ICG group. The primary outcome was the number of LNs retrieved and has been reported. Here, we report the primary outcome and long-term secondary outcomes including three-year overall survival (OS), three-year disease-free survival (DFS), and recurrence patterns. The per-protocol analysis set population is used for all analyses (258 patients, ICG [n = 129] vs. non-ICG group [n = 129]). The mean total LNs retrieved in the ICG group significantly exceeds that in the non-ICG group (50.5 ± 15.9 vs 42.0 ± 10.3, P < 0.001). Both OS and DFS in the ICG group are significantly better than that in the non-ICG group (log-rank P = 0.015; log-rank P = 0.012, respectively). There is a difference in the overall recurrence rates between the ICG and non-ICG groups (17.8% vs 31.0%). Compared with conventional lymphadenectomy, ICG guided laparoscopic lymphadenectomy is safe and effective in prolonging survival among patients with resectable GC.

Tumor Immunophenotyping-Derived Signature Identifies Prognosis and Neoadjuvant Immunotherapeutic Responsiveness in Gastric Cancer.

The effectiveness of neoadjuvant immune checkpoint inhibitor (ICI) therapy is confirmed in clinical trials; however, the patients suitable for receiving this therapy remain unspecified. Previous studies have demonstrated that the tumor microenvironment (TME) dominates immunotherapy; therefore, an effective TME classification strategy is required. In this study, five crucial immunophenotype-related molecules (WARS, UBE2L6, GZMB, BATF2, and LAG-3) in the TME are determined in five public gastric cancer (GC) datasets (n = 1426) and an in-house sequencing dataset (n = 79). Based on this, a GC immunophenotypic score (IPS) is constructed using the least absolute shrinkage and selection operator (LASSO) Cox, and randomSurvivalForest. IPSLow is characterized as immune-activated, and IPSHigh is immune-silenced. Data from seven centers (n = 1144) indicate that the IPS is a robust and independent biomarker for GC and superior to the AJCC stage. Furthermore, patients with an IPSLow and a combined positive score of ≥5 are likely to benefit from neoadjuvant anti-PD-1 therapy. In summary, the IPS can be a useful quantitative tool for immunophenotyping to improve clinical outcomes and provide a practical reference for implementing neoadjuvant ICI therapy for patients with GC.

Loss of ATOH1 in Pit Cell Drives Stemness and Progression of Gastric Adenocarcinoma by Activating AKT/mTOR Signaling through GAS1.

Gastric cancer stem cells (GCSCs) are self-renewing tumor cells that govern chemoresistance in gastric adenocarcinoma (GAC), whereas their regulatory mechanisms remain elusive. Here, the study aims to elucidate the role of ATOH1 in the maintenance of GCSCs. The preclinical model and GAC sample analysis indicate that ATOH1 deficiency is correlated with poor GAC prognosis and chemoresistance. ScRNA-seq reveals that ATOH1 is downregulated in the pit cells of GAC compared with those in paracarcinoma samples. Lineage tracing reveals that Atoh1 deletion strongly confers pit cell stemness. ATOH1 depletion significantly accelerates cancer stemness and chemoresistance in Tff1-CreERT2; Rosa26Tdtomato and Tff1-CreERT2; Apcfl/fl ; p53fl/fl (TcPP) mouse models and organoids. ATOH1 deficiency downregulates growth arrest-specific protein 1 (GAS1) by suppressing GAS1 promoter transcription. GAS1 forms a complex with RET, which inhibits Tyr1062 phosphorylation, and consequently activates the RET/AKT/mTOR signaling pathway by ATOH1 deficiency. Combining chemotherapy with drugs targeting AKT/mTOR signaling can overcome ATOH1 deficiency-induced chemoresistance. Moreover, it is confirmed that abnormal DNA hypermethylation induces ATOH1 deficiency. Taken together, the results demonstrate that ATOH1 loss promotes cancer stemness through the ATOH1/GAS1/RET/AKT/mTOR signaling pathway in GAC, thus providing a potential therapeutic strategy for AKT/mTOR inhibitors in GAC patients with ATOH1 deficiency.

Effect of MTHFRC677 T Gene Polymorphism on Early Morning Blood Pressure in Elderly Female Patients with H-Type Hypertension.

The distribution characteristics of Methylenetetrahydrofolate Reductase (MTHFR) gene C677 T polymorphism and its influence on early morning blood pressure in elderly female patients with H-type hypertension are investigated. A total of 220 elderly female patients with hypertension who received diagnosis and treatment in our hospital from March to September 2021 are selected. All patients received serum index detection in our hospital and are grouped according to blood homocysteine (Hcy) level. Patients with Hcy>10 µmol/L are classified as H-type hypertension and included in H-type hypertension group (n = 166). Patients with Hcy≤10 µmol/L are included in the non-H-type hypertension group (n = 54). Both groups underwent 24-hour ambulatory blood pressure monitoring. Base frequency and allele distribution of MTHFR gene C677 T locus are compared between the two groups, and the relationship between different bases of MTHFR gene C677 T locus and morning blood pressure and Hcy level is analyzed. The risk factors of morning hypertension in patients with H-type hypertension are analyzed by binary logistic regression. Binary logistic regression analysis shows that smoking history, drinking history, high-salt diet, MTHFR gene C677 T genotype, and abnormal 24 h systolic blood pressure are the risk factors for the occurrence of morning hypertension in H-type hypertension patients. The frequency of TT homozygous mutation at the C677 T site of the MTHFR gene is high in patients with H-type hypertension, and the mutation of the C677 T site of the MTHFR gene had an effect on systolic blood pressure and Hcy level.

An immunosuppressive scoring system to predict recurrence and assist in decision regarding postoperative adjuvant treatment in gastric cancer.

Inhibition of the immune microenvironment is the main cause of tumor recurrence after surgery in patients with gastric cancer (GC). In this study, immunohistochemistry and multiple immunofluorescence staining were used to evaluate immunosuppressive indicators and immune biomarkers in 825 patients with gastric cancer from three centers. We constructed an immunosuppressive recurrence score (IRS) using LASSO Cox regression based on the expression of six immunosuppressive indicators and found that the IRS and IRS-based nomogram were significantly accurate and reliable in predicting recurrence. Moreover, an elevated IRS was associated with locoregional recurrence and postoperative adjuvant chemotherapy failure. Furthermore, an increase in IRS indicated inhibition of the antitumor effect of CD8+ tumor-infiltrating lymphocytes in the invasive margin. Thus, we propose that the IRS can predict the recurrence outcome of patients with GC by distinguishing the immunosuppressive status, which is helpful in the selection of individualized adjuvant treatment plans.

m6A methylation mediates LHPP acetylation as a tumour aerobic glycolysis suppressor to improve the prognosis of gastric cancer.

LHPP, a histidine phosphatase, has been implicated in tumour progression. However, its role, underlying mechanisms, and prognostic significance in human gastric cancer (GC) are elusive. Here, we obtained GC tissues and corresponding normal tissues from 48 patients and identified LHPP as a downregulated gene via RNA-seq. qRT-PCR and western blotting were applied to examine LHPP levels in normal and GC tissues. The prognostic value of LHPP was elucidated using tissue microarray and IHC analyses in two independent GC cohorts. The functional roles and mechanistic insights of LHPP in GC growth and metastasis were evaluated in vitro and in vivo. The results showed that LHPP expression was significantly decreased in GC tissues at both the mRNA and protein levels. Multivariate Cox regression analysis revealed that LHPP was an independent prognostic factor and effective predictor in patients with GC. The low expression of LHPP was significantly related to the poor prognosis and chemotherapy sensitivity of gastric cancer patients. Moreover, elevated LHPP expression effectively suppressed GC growth and metastasis in vitro and in vivo. Mechanistically, the m6A modification of LHPP mRNA by METTL14 represses its expression; LHPP inhibits the phosphorylation of GSK3b through acetylation and mediates HIF1A to inhibit glycolysis, proliferation, invasion and metastasis of gastric cancer cells. Together, our findings suggest that LHPP is regulated by m6A methylation and regulates the metabolism of GC by changing the acetylation level. Thus, LHPP is a potential predictive biomarker and therapeutic target for GC.

The Prognostic Significance of APOBEC3B and PD-L1/PD-1 in Nasopharyngeal Carcinoma.

PURPOSE: Apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3B (APOBEC3B) is a recently discovered protein that is considered important in causing mutations in tumor cell genome bases. Whether APOBEC3B is expressed in nasopharyngeal carcinoma (NPC) still remains unknown. Studies have shown that programmed-cell-death receptor-1 ligand (PD-L1) is highly expressed in NPC, but its clinical significance has not been fully elucidated. We aimed to evaluate APOBEC3B and PD-L1 protein expression in NPC and also investigate their prognostic significance. MATERIALS AND METHODS: One hundred and three patients with NPC were retrospectively collected in this study, and were followed-up for 5 years. The expression of APOBEC3B and PD-L1/PD-1 in NPC was detected by immunohistochemical staining. RESULTS: High expression of APOBEC3B was observed in 42.7% of NPC patients. The high expression rate of APOBEC3B was 31.5% in patients without recurrence or metastasis within 5 years, and 55.1% in those patients with recurrence or metastasis, and the difference was statistically significant (P=0.016). There was no significant difference in APOBEC3B expression among patients with different sex, age group, and clinical stage (P>0.05). The positive expression rate of PD-L1 was 55.3% in all patients with NPC. There was no significant difference in PD-L1 expression among patients with different sex, age group, clinical stage, and tumor recurrence or metastasis condition (P> 0.05). There was no significant correlation between the expression of APOBEC3B and PD-L1 in NPC patients. The positive expression rate of PD-1 was 1.9% (2/103) in patients with NPC. CONCLUSIONS: APOBEC3B showed association with aggressive behavior and poor outcome in NPC, and is also considered as a potential marker for predicting NPC recurrence or metastasis. PD-L1 is not associated with the aggressive behavior and poor outcome in NPC.

Neutral Desorption Extractive Electrospray Ionization Mass Spectrometry Analysis Sputum for Non-Invasive Lung Adenocarcinoma Detection.

PURPOSE: Increased use of low-dose spiral computed tomography (LDCT: low-dose computed tomography) screening has contributed to more frequent incidental detection of peripheral lung nodules, part of them were adenocarcinoma, which need to be further evaluated to establish a definitive diagnosis. Here, our primary objective was to evaluate the ambient mass spectrometry (AMS) sputum analysis as a non-invasive lung adenocarcinoma (LAC) diagnosis solution. PATIENTS AND METHODS: Neutral desorption extractive electrospray ionization mass spectrometry (ND-EESI-MS) and collision induced dissociation (CID) were used to detect sputum metabolites from 143 spontaneous sputum samples. Partial least squares-discriminant analysis (PLS-DA) was used to refine the biomarker panel, whereas orthogonal PLS-DA (OPLS-DA) was used to operationalize the enhanced biomarker panel for diagnosis. RESULTS: In this approach, 19 altered metabolites were detected by ND-EESI-MS from 76 cases of LAC and 67 cases of control. Significance testing and receiver operating characteristic (ROC) analysis identified 5 metabolites [hydroxyphenyllactic acid, phytosphingosine, N-nonanoylglycine, sphinganine, S-carboxymethyl-L-cysteine] with p <0.05 and AUC >0.75, respectively. Evaluation of model performance for prediction of LAC resulted in a cross-validation classification accuracy of 87.9%. Metabolic pathway analysis showed that sphingolipid metabolism, fatty acid metabolism, carnitine synthesis and Warburg effect were most impacted in response to disease. CONCLUSION: This study indicates that the application of ND-EESI-MS to sputum analysis can be used as a non-invasive detection of peripheral lung nodules. The use of sputum metabolite biomarkers may aid in the development of a further evaluation program for lung adenocarcinoma.