Purpose: Cancer has become a significant major public health concern, making the discovery of new cancer markers or therapeutic targets exceptionally important. Elevated expression of tumor necrosis factor receptor superfamily member 12A (TNFRSF12A) expression has been observed in certain types of cancer. This project aims to investigate the function of TNFRSF12A in tumors and the underlying mechanisms. Materials and Methods: Various websites were utilized for conducting the bioinformatics analysis. Tumor cell lines with stable knockdown or overexpression of TNFRSF12A were established for cell phenotyping experiments and subcutaneous tumorigenesis in BALB/c mice. RNA-seq was employed to investigate the mechanism of TNFRSF12A. Results: TNFRSF12A was upregulated in the majority of cancers and associated with a poor prognosis. Knockdown TNFRSF12A hindered the colorectal cancer progression, while overexpression facilitated malignancy both in vitro and in vivo. TNFRSF12A overexpression led to increased nuclear factor кB (NF-κB) signaling and significant upregulation of baculoviral IAP repeat containing 3 (BIRC3), a transcription target of the NF-κB member RELA, and it was experimentally confirmed to be a critical downstream factor of TNFRSF12A. Therefore, we speculated the existence of a TNFRSF12A/RELA/BIRC3 regulatory axis in colorectal cancer. Conclusion TNFRSF12A is upregulated in various cancer types and associated with a poor prognosis. In colorectal cancer, elevated TNFRSF12A expression promotes tumor growth, potentially through the TNFRSF12A/RELA/BIRC3 regulatory axis.

Purpose: Cancer has become a significant major public health concern, making the discovery of new cancer markers or therapeutic targets exceptionally important. Elevated expression of tumor necrosis factor receptor superfamily member 12A (TNFRSF12A) expression has been observed in certain types of cancer. This project aims to investigate the function of TNFRSF12A in tumors and the underlying mechanisms. Materials and Methods: Various websites were utilized for conducting the bioinformatics analysis. Tumor cell lines with stable knockdown or overexpression of TNFRSF12A were established for cell phenotyping experiments and subcutaneous tumorigenesis in BALB/c mice. RNA-seq was employed to investigate the mechanism of TNFRSF12A. Results: TNFRSF12A was upregulated in the majority of cancers and associated with a poor prognosis. Knockdown TNFRSF12A hindered the colorectal cancer progression, while overexpression facilitated malignancy both in vitro and in vivo. TNFRSF12A overexpression led to increased nuclear factor кB (NF-κB) signaling and significant upregulation of baculoviral IAP repeat containing 3 (BIRC3), a transcription target of the NF-κB member RELA, and it was experimentally confirmed to be a critical downstream factor of TNFRSF12A. Therefore, we speculated the existence of a TNFRSF12A/RELA/BIRC3 regulatory axis in colorectal cancer. Conclusion TNFRSF12A is upregulated in various cancer types and associated with a poor prognosis. In colorectal cancer, elevated TNFRSF12A expression promotes tumor growth, potentially through the TNFRSF12A/RELA/BIRC3 regulatory axis.

Purpose: Cancer has become a significant major public health concern, making the discovery of new cancer markers or therapeutic targets exceptionally important. Elevated expression of tumor necrosis factor receptor superfamily member 12A (TNFRSF12A) expression has been observed in certain types of cancer. This project aims to investigate the function of TNFRSF12A in tumors and the underlying mechanisms. Materials and Methods: Various websites were utilized for conducting the bioinformatics analysis. Tumor cell lines with stable knockdown or overexpression of TNFRSF12A were established for cell phenotyping experiments and subcutaneous tumorigenesis in BALB/c mice. RNA-seq was employed to investigate the mechanism of TNFRSF12A. Results: TNFRSF12A was upregulated in the majority of cancers and associated with a poor prognosis. Knockdown TNFRSF12A hindered the colorectal cancer progression, while overexpression facilitated malignancy both in vitro and in vivo. TNFRSF12A overexpression led to increased nuclear factor кB (NF-κB) signaling and significant upregulation of baculoviral IAP repeat containing 3 (BIRC3), a transcription target of the NF-κB member RELA, and it was experimentally confirmed to be a critical downstream factor of TNFRSF12A. Therefore, we speculated the existence of a TNFRSF12A/RELA/BIRC3 regulatory axis in colorectal cancer. Conclusion TNFRSF12A is upregulated in various cancer types and associated with a poor prognosis. In colorectal cancer, elevated TNFRSF12A expression promotes tumor growth, potentially through the TNFRSF12A/RELA/BIRC3 regulatory axis.

Background::Arterial stiffening increases with age and blood pressure and is associated with cardiovascular disease (CVD), but the relationship between blood pressure lowering and arterial stiffening is still uncertain, especially in older people. This study aimed to evaluate the effect of intensive blood pressure treatment on the progression of arterial stiffness and risk of CVD in older patients with hypertension.Methods::The Strategy of Blood Pressure Intervention in the Elderly Hypertensive Patients (STEP) trial was a multicenter, randomized, controlled trial performed at 42 clinical centers throughout China, and 8511 patients aged 60–80 years with essential hypertension were enrolled and randomly assigned to systolic blood pressure (SBP) target of 110 mmHg to <130 mmHg (intensive treatment) or 130 mmHg to <150 mmHg (standard treatment). Patients underwent repeated examinations of the brachial-ankle pulse wave velocity (baPWV) and ankle-brachial index (ABI) at baseline, and the arterial stiffness was evaluated at the 3-year follow-up. A total of 5339 patients who had twice repeated measurements were included in this study. Changes in arterial stiffness between the intensive and standard treatment groups were analyzed using a multivariate linear regression model. The Cox proportional hazard regression model was used to evaluate the effect of intensive treatment on primary CVD outcomes.Results::The changes in baPWV were 61.5 cm/s (95% confidence interval [CI]: 49.8–73.2 cm/s) in the intensive treatment group and 98.4 cm/s (95% CI: 86.7–110.1 cm/s) in the standard treatment group ( P <0.001). Intensive treatment significantly delayed the progression of arterial stiffness, with an annual change of 23.1 cm·s –1·year –1vs. 36.7 cm·s –1·year -1 of baPWV in the intensive and standard treatment groups, respectively. During a median follow-up period of 3.36 years, primary CVD outcomes occurred in 77 (2.9%) patients in the intensive treatment group compared with 93 (3.5%) in the standard treatment group. Intensive treatment resulted in a significantly lower CVD risk in patients aged 70–80 years or with SBP <140 mmHg. Conclusion::Intensive blood pressure control with an SBP target of 110 mmHg to <130 mmHg could delay the progression of arterial stiffness and reduce the risk of CVD in older patients with hypertension.Clinical trial registration::http://www.clinicaltrials.gov; No. NCT03015311.

Background::Heterotaxy (HTX) is a thoracoabdominal organ anomaly syndrome and commonly accompanied by congenital heart disease (CHD). The aim of this study was to analyze rare copy number variations (CNVs) in a HTX/CHD cohort and to examine the potential mechanisms contributing to HTX/CHD.Methods::Chromosome microarray analysis was used to identify rare CNVs in a cohort of 120 unrelated HTX/CHD patients, and available samples from parents were used to confirm the inheritance pattern. Potential candidate genes in CNVs region were prioritized via the DECIPHER database, and PNPLA4 was identified as the leading candidate gene. To validate, we generated PNPLA4-overexpressing human induced pluripotent stem cell lines as well as pnpla4-overexpressing zebrafish model, followed by a series of transcriptomic, biochemical and cellular analyses. Results::Seventeen rare CNVs were identified in 15 of the 120 HTX/CHD patients (12.5%). Xp22.31 duplication was one of the inherited CNVs identified in this HTX/CHD cohort, and PNPLA4 in the Xp22.31 was a candidate gene associated with HTX/CHD. PNPLA4 is expressed in the lateral plate mesoderm, which is known to be critical for left/right embryonic patterning as well as cardiomyocyte differentiation, and in the neural crest cell lineage. Through a series of in vivo and in vitro analyses at the molecular and cellular levels, we revealed that the biological function of PNPLA4 is importantly involved in the primary cilia formation and function via its regulation of energy metabolism and mitochondria-mediated ATP production. Conclusions::Our findings demonstrated a significant association between CNVs and HTX/CHD. Our data strongly suggested that an increased genetic dose of PNPLA4 due to Xp22.31 duplication is a disease-causing risk factor for HTX/CHD.

Objective:To explore the relationship between anhedonia and suicidal ideation and the effects of anhedonia on suicidal ideation in patients with first-episode untreated depressive disorder.Methods:Totally 106 in-patients who met the diagnostic criteria for depressive disorder of the Diagnostic and Statistical Manual of Mental Disorders,Fifth Edition(DSM-5)were invited to participate in the study.Anhedonia,depressive symptoms and sui-cidal ideation were assessed with the Snaith-Hamilton Pleasure Scale(SHAPS),Hamilton Depression Scale(HAMD)and Beck Scale for Suicide Ideation(BSI),respectively.If both items 4 and 5 of BSI were 0,it indicated non-suicidal ideation,the subjects were divided into a group of suicidal ideation(n=66)and a group non-suicidal ideation(n=40).Spearman correlation analysis and multivariate binary logistic regression analysis were used for a-nalysis.Results:The correlation between the scores of SHAPS and HAMD was not statistically significant(P＞0.05).The SHAPS scores were positively correlated with the BSI scores(r=0.70,P＜0.01).Meanwhile,binary logistic regression analysis showed that anhedonia was one of a risk factor for suicidal ideation(OR=2.34,95％CI:1.58-3.47,P＜0.001).Conclusion:It suggests that anhedonia maybe partially independent of other depres-sive symptoms and it is one of the risk factors for suicidal ideation in first-episode untreated patients with depressive disorder.

Objective To explore the prognostic value of serum neutrophils/lymphocytes(NLR)for first-line treatment of patients with advanced gastric cancer using programmed cell death receptor 1(PD-1)inhibitors.Methods A total of 168 patients with advanced gastric cancer who were treated with immunotherapy combined with chemotherapy in the Fourth Hospital of Qinhuangdao from January 2018 to January 2021 were selected as study subjects,and the follow-up period was terminated at January 2023.The patients'data were collected,hematological and tumor markers before the combined treatment were analyzed,and the optimal cut-off value of NLR was calculated using X-tile software.The effect of NLR expression on the survival rate of patients with advanced gastric cancer was analysed by the Kaplan-Meier survival curve.Receiver operating curve(ROC)was used to analyze the predictive value of NLR in patients with advanced gastric cancer.The related factors affecting the disease progression of patients with advanced gastric cancer were screened combined with Cox proportional risk model.Results Among 168 patients,the optimal cut-off value of serum NLR before treatment was 2.41.Patients were divided into high NLR group(NLR＞2.41,n=93)and low NLR group(NLR＜2.41,n=75).NLR was related to tumor differentiation,distant metastasis,composite positive scores of PD-L1,carcinoembryonic antigen and cancer antigen 125(P＜0.05);the effective rate in the low NLR group was significantly higher than that in the high NLR group(P＜0.05);the median progression free survival(PFS)and the overall survival(OS)of patients in the low NLR group were both longer than those in the high NLR group(PFS:P=0.006;OS:P=0.023);ROC analysis showed that the area under the curve of NLR for the prognosis of advanced gastric cancer patients was 0.740,sensitivity was 81.50％,and specificity was 69.70％;in multivariate analysis,except initial NLR value,tumor differentiation degree and distant metastasis were also independent predictors of poor prognosis in patients with advanced gastric cancer(P＜0.05).Conclusion Among patients with advanced gastric cancer who received first-line immunotherapy combined with chemotherapy,pretreatment NLR is correlated with efficacy and PFS/OS,and has high value in predicting the prognosis of immunotherapy for advanced gastric cancer.

BACKGROUND:Mesenchymal stem cells are susceptible to senescence during in vitro expansion,which greatly hinders their application in vivo and in vitro.How to improve the replicative senescence of mesenchymal stem cells is an urgent problem to be solved in tissue engineering. OBJECTIVE:To determine whether vascular endothelial growth factor combined with basic fibroblast growth factor can improve the aging of bone marrow mesenchymal stem cells caused by replicative passage. METHODS:Rat bone marrow mesenchymal stem cells were extracted by whole bone marrow adhesion method.Passage 2 cells were selected as normal control group.Passage 7 and later algebraic cells were selected as aging model group.Vascular endothelial growth factor(50 μg/L),basic fibroblast growth factor(10 μg/L),and their combination were administered.Cell proliferation was detected by CCK-8 assay.Cell senescence was observed by β-galactosidase activity staining.Cytoskeleton size and colony formation ability were observed by phalloidine staining and Giemsa staining,respectively,and the levels of senescence-related genes P16,P21,and P53 were detected by qRT-PCR.Gene expression levels of P16,P21,and P53 were tested by qRT-PCR. RESULTS AND CONCLUSION:(1)Vascular endothelial growth factor combined with basic fibroblast growth factor could promote the proliferation of aged bone marrow mesenchymal stem cells,which began to enter the plateau stage on day 9,and the absorbance value of the combined intervention group was significantly higher than that of the model group on day 9(P<0.05).(2)The phenotypic markers of the cells in the combined intervention group did not change,and the cell morphology changed from broad to slender.(3)Compared with the model group,the positive rate of β-galactosidase was significantly decreased(P<0.01);the number of nuclei increased(P<0.001);the total area of cytoskeleton increased(P<0.01);colony formation ability was enhanced(P<0.05);expression level of P16 was decreased(P<0.01)in the combined intervention group.These results indicate that vascular endothelial growth factor combined with basic fibroblast growth factor can improve the senescence of bone marrow mesenchymal stem cells caused by replicative passage without changing the cell phenotype.

Objective:To explore the differences in bacterial community structure between proximal colon cancer (PC), distal colon cancer (DC), and rectal cancer (RC), and the values of featured microbiota in differentiating PC with tumor markers.Methods:This case-control study enrolled 85 newly diagnosed colorectal cancer patients, including 22 PC, 15 DC and 48 RC patients, and 8 colorectal adenoma patients from May 2019 to July 2022 at the Department of General Surgery, Anyang Oncology Hospital. The blood and fecal samples were collected before surgery and then subjected to biochemical tests for tumor markers and 16S rDNA tests, respectively. SPSS (27.0.1) was applied to perform the t-test, one-way ANOVA, Mann-Whitney U test, Kruskal-Wallis H test, and Chi-Squared Test. Also, the receiver operating characteristic curve (ROC) was plotted on tumor markers and/or f_Bacteroidaceae with SPSS software .Results:All groups had significant differences in the CA125 ( F=3.543, P<0.05), CA72-4 ( F=3.596, P<0.05), and serum tumor-associated materials (TAM) levels ( F=5.787, P<0.01). In PC group, the levels of CA125 [PC vs RC, (36.84±6.30) kU/L vs (12.73±4.21) kU/L, P<0.01] and CA72-4 [PC vs RC, (45.56±10.86) kU/L vs (3.30±7.63) kU/L, P<0.01] were significantly higher than that of the RC group, while the level of TAM was remarkably elevated in PC group than in RC group [PC vs RC, (124.84±5.19) U/ml vs (102.44±3.63) U/ml, P<0.001] and CRA group [PC vs CRA, (124.84±5.19) U/ml vs (95.39±8.42) U/ml, P<0.01]. The LEfSe analysis showed that the featured microbiota in the PC group included f_Bacteroidaceae, f_Neisseriaceae, f_Clostridiaceae_1, f_Spirochaetaceae, and so on. The largest area under the ROC belonged to the combination of TAM and f_Bacteroidaceae, which reached 0.845 (95% CI 0.747-0.944), with sensitivity being 0.857 and specificity being 0.815. Conclusions:There is heterogeneity in gut microbiota composition among PC, DC, RC, and CRA. The combination of gut microbiota and tumor biomarkers demonstrated good differentiating effects in proximal colon cancers.

Objective:To investigate the correlation between the neoadjuvant rectal (NAR) score and long-term survival in patients with locally advanced rectal cancer who have undergone neoadjuvant chemoradiotherapy.Methods:Clinical and pathological data of 487 patients diagnosed with rectal adenocarcinoma from October 2004 to April 2014 at Sun Yat-sen University Cancer Center who had received neoadjuvant chemoradiotherapy were retrospectively analyzed and the impact of NAR score on prognosis studied. Disease-free-survival (DFS) was calculated by the Kaplan-Meier method and survivals compared using the log-rank test. Cox models were used for univariate and multivariate analyses. Receiver operating characteristic curves were utilized to evaluate the predictive capability of NAR and tumor regression grade scores for the risk of 10-year postoperative recurrence and metastasis. The Delong test was employed to compare the diagnostic performance of the two scores.Results:Of the 487 patients included in the study, 166 were men (34.1%). The median age was 56 years (interquartile range [IQR]: 46–63). All patients completed adequate preoperative chemoradiotherapy and underwent R0 resection.The median interval between the end of chemoradiotherapy and surgery was 51 days (IQR: 44–58). Post-chemoradiotherapy downstaging occurred in 329 patients (67.6%). Tumor regression grades (TRGs) were 1–2 in 246 patients (50.5%) and 3–4 in 241 patients (49.5%). A total of 394 patients (80.9%) received postoperative chemotherapy. NAR scores were <8 in 182 patients (37.4%), 8–16 in 180 (37.0%), and >16 in 125 (25.6%). The median follow-up time was 111.5 months (IQR: 70.7–133.7 months). One hundred and thirteen patients died of rectal cancer, among whom 13 patients developed local recurrence, 88 patients developed distant metastasis, and 12 patients had unknown recurrence patterns. The 10-year DFS and overall survival rate of f the whole group were 68.9% and 71.5% respectively. The 10-year DFS rates for patients with NAR scores <8, 8–16, and >16 were 85.1%, 80.5%, and 66.4%, respectively ( P<0.001). Multivariate analyses revealed that the Dixon operation (HR=0.606, 95%CI: 0.408–0.902, P=0.014), and >16 (HR=2.569, 95%CI: 1.559–4.233, P<0.001) were independent predictors of the 10-year DFS of patients with locally advanced rectal cancer ( P<0.05 for all). In the entire patient cohort, the AUC of the receiver operating characteristic curve for NAR score predicting 10-year recurrence and metastasis was 0.67 (95%CI: 0.62–0.72), whereas the AUC for TRG score was 0.54 (95%CI: 0.49–0.60). The two scores differed significantly in accuracy ( Z=-4.06, P<0.001), the NAR score being a significantly better predictor of risk of 10-year recurrence and metastasis than the TRG score. Conclusion:The NAR score is a reliable predictor of 10-year DFS in patients with locally advanced rectal cancer who have undergone neoadjuvant chemoradiotherapy followed by curative surgery.