Genome-wide 5-hydroxymethylcytosines in circulating cell-free DNA as noninvasive diagnostic markers for gastric cancer.

BACKGROUND: 5-Hydroxymethylcytosine-enriched gene profiles and regions show tissue-specific and tumor specific. There is a potential value to explore cell-free DNA 5-hydroxymethylcytosine feature biomarkers for early gastric cancer detection. METHODS: A matched case‒control study design with 50 gastric cancer patients and 50 controls was performed to sequence the different 5-hydroxymethylcytosine modification features of cell free DNA. Significantly differential 5-hydroxymethylcytosine modification genes were identified to construct a gastric cancer diagnostic model. Data set from GEO was used as an external testing set to test the robustness of the diagnostic model. RESULTS: Accounting for more than 90% of 5-hydroxymethylcytosine peaks were distributed in the gene body in both the gastric cancer and control groups. The diagnostic model was developed based on five different 5-hydroxymethylcytosine modification genes, FBXL7, PDE3A, TPO, SNTG2 and STXBP5. The model could effectively distinguish gastric cancer patients from controls in the training (AUC = 0.95, sensitivity = 88.6%, specificity = 94.3%), validation (AUC = 0.87, sensitivity = 73.3%, specificity = 93.3%) and testing (AUC = 0.90, sensitivity = 81.9%, specificity = 90.2%) sets. The risk scores of the controls from the model were significantly lower than those of gastric cancer patients in both our own data (P < 0.001) and GEO external testing data (P < 0.001), and no significant difference between different TNM stage patients (P = 0.09 and 0.66). Furthermore, there was no significant difference between the healthy control and benign gastric disease patients in the testing set from GEO (P = 0.10). CONCLUSIONS: The characteristics of 5-hydroxymethylcytosine in cell free DNA are specific to gastric cancer patients, and the diagnostic model constructed by five genes' 5-hydroxymethylcytosine features could effectively identify gastric cancer patients.

The roles of epigallocatechin gallate in the tumor microenvironment, metabolic reprogramming, and immunotherapy.

Cancer, a disease that modern medicine has not fully understood and conquered, with its high incidence and mortality, deprives countless patients of health and even life. According to global cancer statistics, there were an estimated 19.3 million new cancer cases and nearly 10 million cancer deaths in 2020, with the age-standardized incidence and mortality rates of 201.0 and 100.7 per 100,000, respectively. Although remarkable advancements have been made in therapeutic strategies recently, the overall prognosis of cancer patients remains not optimistic. Consequently, there are still many severe challenges to be faced and difficult problems to be solved in cancer therapy today. Epigallocatechin gallate (EGCG), a natural polyphenol extracted from tea leaves, has received much attention for its antitumor effects. Accumulating investigations have confirmed that EGCG can inhibit tumorigenesis and progression by triggering apoptosis, suppressing proliferation, invasion, and migration, altering tumor epigenetic modification, and overcoming chemotherapy resistance. Nevertheless, its regulatory roles and biomolecular mechanisms in the immune microenvironment, metabolic microenvironment, and immunotherapy remain obscure. In this article, we summarized the most recent updates about the effects of EGCG on tumor microenvironment (TME), metabolic reprogramming, and anti-cancer immunotherapy. The results demonstrated EGCG can promote the anti-cancer immune response of cytotoxic lymphocytes and dendritic cells (DCs), attenuate the immunosuppression of myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs), and inhibit the tumor-promoting functions of tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), and various stromal cells including cancer-associated fibroblasts (CAFs), endothelial cells (ECs), stellate cells, and mesenchymal stem/stromal cells (MSCs). Additionally, EGCG can suppress multiple metabolic reprogramming pathways, including glucose uptake, aerobic glycolysis, glutamine metabolism, fatty acid anabolism, and nucleotide synthesis. Finally, EGCG, as an immunomodulator and immune checkpoint blockade, can enhance immunotherapeutic efficacy and may be a promising candidate for antitumor immunotherapy. In conclusion, EGCG plays versatile regulatory roles in TME and metabolic reprogramming, which provides novel insights and combined therapeutic strategies for cancer immunotherapy.

Predictive value of hepatitis B serological indicators for mortality among cancer survivors and validation in a gastric cancer cohort.

Hepatitis B virus (HBV) infection has gradually been considered to associate with cancer development and progression. This study aimed to explore the associations of serological indicators of HBV infection with mortality risk among cancer survivors and further validated using a gastric cancer (GC) cohort from China, where HBV infection is endemic. National Center for Health Statistics' National Health and Nutrition Examination Survey (NHANES) data were used in this study. Individuals with positive results of hepatitis B core antigen (anti-HBc) were considered to have current or past HBV infection. Serological indicators were positive only for hepatitis B surface antibodies (anti-HBs), indicating vaccine-induced immunity, whereas negativity for all serologic indicators was considered to indicate the absence of HBV infection and immunity to HBV. The GC cohort included patients from the First Hospital of Jilin University, China. The median follow-up time of the NHANES was 10 years; during the follow-up, 1505 deaths occurred. The results revealed that anti-HBs-positive cancer survivors had a 39% reduced risk of mortality (hazard ratio [HR] 0.61, 95% confidence interval [CI] 0.44-0.85). Men and individuals aged <65 years old with past exposure to HBV had higher mortality risk (HR 1.52, 95% CI 1.09-2.13; HR 2.07, 95% CI 1.13-3.83). In this GC cohort, individuals who were only anti-HBs-positive showed a reduced risk of mortality (HR 0.77, 95% CI 0.62-0.95). Thus, anti-HBs positivity was a significant factor of decreased mortality among cancer survivors. More rigorous surveillance is necessary for cancer survivors with anti-HBc positivity, particularly men, and younger individuals.

The crosstalk among the physical tumor microenvironment and the effects of glucose deprivation on tumors in the past decade.

The occurrence and progression of tumors are inseparable from glucose metabolism. With the development of tumors, the volume increases gradually and the nutritional supply of tumors cannot be fully guaranteed. The tumor microenvironment changes and glucose deficiency becomes the common stress environment of tumors. Here, we discuss the mutual influences between glucose deprivation and other features of the tumor microenvironment, such as hypoxia, immune escape, low pH, and oxidative stress. In the face of a series of stress responses brought by glucose deficiency, different types of tumors have different coping mechanisms. We summarize the tumor studies on glucose deficiency in the last decade and review the genes and pathways that determine the fate of tumors under harsh conditions. It turns out that most of these genes help tumor cells survive in glucose-deprivation conditions. The development of related inhibitors may bring new opportunities for the treatment of tumors.

Locally advanced head and neck squamous cell carcinoma treatment efficacy and safety: a systematic review and network meta-analysis.

Head and neck squamous cell carcinoma (HNSCC) accounts for approximately 3% of new cancer cases and 3% of all deaths worldwide. Most HNSCC patients are locally advanced (LA) at diagnosis. The combination of radiotherapy (RT), chemotherapy, targeted therapy, and immunotherapy are the primary LA-HNSCC treatment options. Nevertheless, the choice of optimal LA-HNSCC treatment remains controversial. We systematically searched public databases for LA-HNSCC-related studies and assess treatment effectiveness and safety by assessing the objective response rate (ORR), ≥3 adverse events (AEs), overall survival (OS), progression-free survival (PFS), disease-free survival (DFS), local-region control (LRC), and disease-specific survival (DSS). 126 randomized controlled clinical trials (RCTs) were included in this study. We show that concurrent RT with nimotuzumab or conventional concurrent chemo-radiotherapy (CCRT) had significantly better efficacy and long-term survival without increasing AEs than RT alone. Accelerated fractionated radiotherapy (AFRT) showed better efficiency than conventional fractionated RT, although it had higher AEs. In addition, concurrent cetuximab combined with RT failed to show a significant advantage over RT alone. Trial registration: PROSPERO CRD42022352127.

Risk-stratified approach by aMAP score for community population infected with hepatitis B and C to guide subsequent liver cancer screening practice: A cohort study with 10-year follow-up.

The aim of this study was to determine whether the age-Male-ALBI-Platelet (aMAP) score is applicable in community settings and how to maximise its role in risk stratification. A total of thousand five hundred and three participants had an aMAP score calculated at baseline and were followed up for about 10 years to obtain information on liver cancer incidence and death. After assessing the ability of aMAP to predict liver cancer incidence and death in terms of differentiation and calibration, the optimal risk stratification threshold of the aMAP score was explored, based on absolute and relative risks. The aMAP score achieved higher area under curves (AUCs) (almost all above 0.8) within 10 years and exhibited a better calibration within 5 years. Regarding absolute risk, the risk of incidence of and death from liver cancer showed a rapid increase after an aMAP score of 55. The cumulative incidence (5-year: 8.3% vs. 1.3% and 10-year: 20.9% vs. 3.6%) and mortality (5-year: 6.7% vs. 1.1% and 10-year: 17.5% vs. 3.1%) of liver cancer in individuals with an aMAP score of ≥55 were significantly higher than in those with a score of <55 (Grey's test p < .001). In terms of relative risk, the risk of death from liver cancer surpassed that from other causes after an aMAP score of ≥55 [HR = 1.38(1.02-1.87)]. Notably, the two types of death risk had opposite trends between the subpopulation with an aMAP score of ≥55 and < 55. To conclude, this study showed the value of the aMAP score in community settings and recommends using 55 as a new risk stratification threshold to guide subsequent liver cancer screening.

Elder and booster vaccination associates with decreased risk of serious clinical outcomes in comparison of Omicron and Delta variant: A meta-analysis of SARS-CoV-2 infection.

Background: The COVID-19 pandemic brings great pressure to the public health systems. This meta-analysis aimed to compare the clinical outcomes among different virus variants, to clarify their impact on medical resources and to provide evidence for the formulation of epidemic prevention policies. Methods: A systematic literature search was performed in the PubMed, Embase, and Cochrane Library databases using the key words "Omicron" and "Delta." The adjusted Risk ratios (RRs), Odds ratios (ORs) and Hazard ratios (HRs) were extracted, and RRs and Rate difference % (RD%) were used to interpret the risk estimates of the outcomes ultimately. Results: Forty-three studies were included, with 3,812,681 and 14,926,841 individuals infected with SARS-CoV-2 Delta and Omicron variant, respectively. The relative risks of hospitalization, death, ICU admission, and mechanical ventilation use after infection with the Omicron variant were all significantly reduced compared those after infection with the Delta variant (RRhospitalization = 0.45, 95%CI: 0.40-0.52; RRdeath = 0.37, 95%CI: 0.30-0.45; RRICU = 0.35, 95%CI: 0.29-0.42; RRmechanical ventilation = 0.33, 95%CI: 0.25-0.44). The change of both absolute and relative risks for hospitalization was more evident (RR = 0.47, 95%CI: 0.42-0.53；RD% =10.61, 95%CI: 8.64-12.59) and a significant increase was observed for the absolute differences in death in the elderly (RD% = 5.60, 95CI%: 4.65-6.55); the change of the absolute differences in the risk of hospitalization and death were most markedly observed in the patients with booster vaccination (RD%hospitalization = 8.60, 95CI%: 5.95-11.24; RD%death = 3.70, 95CI%: 0.34-7.06). Conclusion: The ability of the Omicron variant to cause severe clinical events has decreased significantly, as compared with the Delta variant, but vulnerable populations still need to be vigilant. There was no interaction between the vaccination doses and different variants.

The prognostic significance of bromodomain protein 4 expression in solid tumor patients: A meta-analysis.

BACKGROUND: Cancer is a leading cause of death worldwide. At present, several inhibitors of bromodomain protein 4 have shown promising anti-tumor responses in clinical trials. Numerous studies have reported the value of bromodomain protein 4 expression in predicting the prognosis of patients with cancers, but their conclusions remain controversial. Therefore, we conducted a meta-analysis to explore the association between bromodomain protein 4 and patient prognosis with the aim to provide new directions for the development of strategies for targeted cancer therapy. METHODS: The meta-analysis was registered in the International Prospective Register of Systematic Reviews (https://www.crd.york.ac.uk/prospero/; Registration No. CRD42020184948) and followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. PubMed Central, PubMed, Cochrane Library and Embase were thoroughly searched to identify eligible studies published through March 31, 2021. Odds ratios with 95% confidence intervals were calculated to demonstrate the relationship between bromodomain protein 4 expression and clinicopathological features. We computed pooled estimated hazard ratios with 95% confidence intervals using Stata 12.0 software to clarify the relationship between bromodomain protein 4 expression and overall survival of various cancers. A quality assessment of the eligible articles was performed based on the Newcastle-Ottawa scale. RESULTS: A total of 974 patients from 10 studies were enrolled in the meta-analysis. Our results revealed that compared to low bromodomain protein 4 expression, high bromodomain protein 4 expression in cancer tissues was significantly associated with lymph node metastasis (Odds ratio = 3.59, 95% confidence interval: 2.62-4.91), distant metastasis (Odds ratio = 4.22, 95% confidence interval: 2.40-7.45), advanced TNM stage (III+IV vs. I+II: Odds ratio = 3.23, 95% confidence interval: 1.29-8.08), and poorly differentiated tumors (Odds ratio = 1.87, 95% confidence interval: 1.33-2.63). In addition, an elevated expression of bromodomain protein 4 tended to shorten survival time (Hazard ratio = 2.23, 95% confidence interval: 1.62-3.07). The subgroup analysis results showed that bromodomain protein 4 upregulation was related to poor prognosis in patients with digestive system cancers (Hazard ratio = 2.54, 95% confidence interval: 1.85-3.50). CONCLUSION: This meta-analysis indicated that bromodomain protein 4 may serve as a promising prognostic biomarker for cancers and a direct effective cancer treatment target.

Dietary inflammatory index, and depression and mortality risk associations in U.S. adults, with a special focus on cancer survivors.

Introduction: A higher risk for depression and mortality is associated with the inflammatory potential of diet measured through the Dietary Inflammatory Index (DII). The roles of DII in the risk of depression and death in cancer survivors were unclear. We aimed to examine the association between energy-adjusted DII (E-DII) score and risk of depression, and mortality using data from the 2007-2018 National Health and Nutrition Examination Survey (NHANES), with a special focus on cancer survivors. Methods: The 24-h dietary recall interview was used as a basis to calculate the E-DII score and the Patient Health Questionnaire-9 (PHQ-9) was used to measure the depressive outcomes. Logistic regression analyses were performed to determine the association between quartiles of E-DII score and depression. Cox proportional hazard regression and competing risk analyses were used to estimate the risks of quartiles of E-DII score or depression on mortality. Results: A total of 27,447 participants were included; including 24,694 subjects without cancer and 2,753 cancer survivors. The E-DII score and depression were not distributed differently between the two groups. However, the E-DII scores were positively associated with within each group's depression (all P trend < 0.001) and participants with higher E-DII scores had a higher risk of depression (subjects without cancer: ORQ4 vs Q1: 2.17, 95% CI: 1.75-2.70; cancer survivors: ORQ4 vsQ1: 1.78, 95% CI: 1.09-2.92). The median follow-up time were 87 person-months, a total of 1,701 (4.8%) and 570 (15.2%) all-cause deaths in subjects without cancer and cancer survivors were identified by the end of 2019. The highest E-DII scores quartile was associated with the highest risk of all-cause (HRQ4 vsQ1: 1.90, 95% CI: 1.54-2.35) and cardiovascular disease (CVD) cause death (HRQ4 vsQ1: 2.50, 95% CI: 1.69-2.3.7) in the subjects without cancer. Moreover, participants with depressive symptoms had higher all-cause mortality (HR: 1.29, 95% CI: 1.04-1.59). No significant correlation was found for E-DII scores or depression with all-cause, cancer-cause or CVD-cause mortality in cancer survivors. Conclusion: Our findings demonstrate that E-DII score was positively associated with depression risk. A higher E-DII score or depressive symptom may increase the risks of all-cause and CVD-cause mortality only among general subjects.

Association of Helicobacter pylori infection with estimated glomerular filtration rate in a Chinese population.

BACKGROUND: Helicobacter pylori (H. Pylori) infection is reported to be associated with extragastric disorders which include kidney diseases. But the association between H. pylori infection and estimated glomerular filtration rate (eGFR) is unclear as far. Thus, we performed the study to investigate the prevalence of H. pylori infection and its association with eGFR in a Chinese population. MATERIALS AND METHODS: We conducted a cross-sectional study in adults who took health examination at the First Hospital of Jilin University in 2019. All the subjects received 14C-labled urea breath test to determine the H. pylori infection, and we analyzed the relationship between prevalence of H. pylori infection and eGFR. RESULTS: Among 3593 participants in the health checkup, the positive rate of H. pylori infection was 37.3%. H. pylori-positive participants had a lower level of eGFR than H. pylori-negative participants. In univariate analysis, we observed that the positive rate of H. pylori infection and RR (relative risk) became larger with eGFR decreased, however, the association was not significant after adjustment for other factors. Further multivariable analysis showed age and sex were the main confounders between eGFR and H. pylori infection. CONCLUSIONS: The correlation between eGFR and positive rate of H. pylori infection was confounded by age and sex.

Efficacy and safety of systemic treatments for patients with recurrent/metastatic head and neck squamous cell carcinoma: A systematic review and network meta-analysis.

A variety of systemic chemotherapy regimens have been used for recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). However, most guidelines have been derived from a single clinical trial, and no studies have comprehensively compared their efficacy and safety. We systematically searched PubMed, Embase, Web of Science, and Cochrane Library databases. Eligible studies reported overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and ≥ 3 adverse events rate (AEs). Eighteen eligible trials involving 4930 patients and 15 treatment regimens were included. The results suggest that patients with R/M HNSCC exhibit better tumor response with the cetuximab/platinum/5-FU, pembrolizumab/platinum/5-FU or pembrolizumab alone, accompanied by a low AE rate. Nivolumab also showed better efficacy than other single agents. Immunotherapy has achieved better efficacy.

Highly efficient ammonia synthesis at low temperature over a Ru-Co catalyst with dual atomically dispersed active centers.

The desire for a carbon-free society and the continuously increasing demand for clean energy make it valuable to exploit green ammonia (NH3) synthesis that proceeds via the electrolysis driven Haber-Bosch (eHB) process. The key for successful operation is to develop advanced catalysts that can operate under mild conditions with efficacy. The main bottleneck of NH3 synthesis under mild conditions is the known scaling relation in which the feasibility of N2 dissociative adsorption of a catalyst is inversely related to that of the desorption of surface N-containing intermediate species, which leads to the dilemma that NH3 synthesis could not be catalyzed effectively under mild conditions. The present work offers a new strategy via introducing atomically dispersed Ru onto a single Co atom coordinated with pyrrolic N, which forms RuCo dual single-atom active sites. In this system the d-band centers of Ru and Co were both regulated to decouple the scaling relation. Detailed experimental and theoretical investigations demonstrate that the d-bands of Ru and Co both become narrow, and there is a significant overlapping of t2g and eg orbitals as well as the formation of a nearly uniform Co 3d ligand field, making the electronic structure of the Co atom resemble that of a "free-atom". The "free-Co-atom" acts as a bridge to facilitate electron transfer from pyrrolic N to surface Ru single atoms, which enables the Ru atom to donate electrons to the antibonding π* orbitals of N2, thus resulting in promoted N2 adsorption and activation. Meanwhile, H2 adsorbs dissociatively on the Co center to form a hydride, which can transfer to the Ru site to cause the hydrogenation of the activated N2 to generate N2H x (x = 1-4) intermediates. The narrow d-band centers of this RuCo catalyst facilitate desorption of surface *NH3 intermediates even at 50 °C. The cooperativity of the RuCo system decouples the sites for the activation of N2 from those for the desorption of *NH3 and *N2H x intermediates, giving rise to a favorable pathway for efficient NH3 synthesis under mild conditions.

Construction of a Pd(PdO)/Co3O4@SiO2 core-shell structure for efficient low-temperature methane combustion.

Catalytic combustion is a promising way to remove trace amounts of CH4 to alleviate serious environmental concerns. However, the reactivity of a catalyst at low temperature is usually limited because of the difficulty to activate the C-H bond of methane. Herein, we design a Pd(PdO)/Co3O4@SiO2 bimetallic oxide core-shell catalyst which shows much higher activity in the methane combustion reaction compared with Pd(PdO)/SiO2 and Co3O4@SiO2 catalysts without a core-shell structure. The T50% and T90% of Pd(PdO)/Co3O4@SiO2 are 357 °C and 445 °C, respectively, which decrease by 67 °C and 55 °C in comparison with those of Pd(PdO)/SiO2. Extensive characterization demonstrates that the bimetallic oxide core-shell structure can effectively enhance the metal interaction between Pd and Co, which can weaken the strength of the Co-O bond in Pd(PdO)/Co3O4@SiO2. The weakening of the Co-O bond could promote the release of more lattice oxygen species to participate in the C-H breaking, resulting in superior catalytic performance in methane combustion at low temperature.

A Practical Model is Equivalent to the BALAD or BALAD-2 Score in Predicting Long-term Survival after Hepatectomy in Chinese Patients with Hepatocellular Carcinoma.

Aim: To evaluate the predictive value of the BALAD and BALAD-2 scores on long-term survival after hepatectomy in Chinese hepatocellular carcinoma (HCC) patients and to attempt to establish a more practical or effective model. Methods: A total of 251 HCC patients underwent hepatectomy were recruited. The BALAD and BALAD-2 scores were calculated with total bilirubin, albumin, alpha-fetoprotein, Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein and des-gamma-carboxyprothrombin. The associations of the two scores and their components with the overall survival were analyzed. Finally, three prediction models were explored and constructed. Results: We observed that HCC patients had 5-year survival rates that worsened with increasement of BALAD and BALAD-2 scores. The BALAD and BALAD-2 scores demonstrated fine value in predicting overall survival with Harrell-C statistics of 0.665 (0.618-0.712) and 0.603 (0.554-0.636). After two variables, largest tumor size and BMI, were included in BALAD [0.720 (0.671-0.769)] or BALAD-2 [0.701 (0.649-0.751)] multivariate models, the Harrell-C statistic increased significantly than BALAD (P=0.048) or BALAD-2 (P<0.001) alone. Taking into account availability and expense, an equivalent BAA-BS model was established based on total bilirubin, albumin, AFP, BMI and largest tumor size. The Harrell-C statistic of BAA-BS model [0.723(0.674-0.772)] was similar to that of BALAD (P=0.820) or BALAD-2 (P=0.209) multivariate model. And, the continuous net reclassification index and integrated discriminatory improvement were not statistically different. Finally, a nomogram of the equivalent BAA-BS model was constructed to assist surgeons and patients in predicting 5-year survival rates. Conclusion: Both BALAD and BALAD-2 scores were highly suitable for predicting long-term survival after hepatectomy in Chinese HCC patients. A significant increase in predictive efficacy was observed after the addition of largest tumor size and BMI to BALAD or BALAD-2 score. Even if AFP-L3 and DCP are not detected, an equivalent BAA-BS model also obtained an excellent discriminatory performance.

Tissue inhibitor of metalloproteinase-1 (TIMP-1) as a prognostic biomarker in gastrointestinal cancer: a meta-analysis.

BACKGROUND: Tissue inhibitor of metalloproteinase 1 (TIMP-1) has recently been shown to be dependent on or independent of Matrix metalloproteinases (MMPs) in its roles in tumorigenesis and progression. This appreciation has prompted various studies assessing the prognostic value of TIMP-1 in patients with gastrointestinal cancer, however, the conclusions were still inconsistent. The aim of this study was to assess the prognostic value of TIMP-1-immunohistochemistry (IHC) staining and pretreatment serum/plasma TIMP-1 level in gastrointestinal cancer survival as well as the association between TIMP-1 and clinicopathologic features. METHODS: The meta-analysis was registered in the International Prospective Register of Systematic Reviews (PROSPERO; Registration NO. CRD42020185407) and followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. A highly sensitive literature search was performed in electronic databases including PubMed, EMBASE and the Cochrane Library. Heterogeneity analysis was conducted using both chi-square-based Q statistics and the I2 test. The pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated to assess the prognostic value of TIMP-1 using the fixed-effects model. Odds ratios (ORs) with 95% CIs were calculated to evaluate the associations between TIMP-1 and clinicopathological characteristics. The meta-analysis was conducted using STATA 12.0 software. RESULTS: A total of 3,958 patients from twenty-two studies were included in the meta-analysis. Elevated TIMP-1 levels were significantly associated with poor survival in gastrointestinal cancer (TIMP-1-IHC staining: HR = 2.04, 95% CI [1.59-2.61], I 2 = 35.7%, P Q = 0.156; pretreatment serum/plasma TIMP-1 levels: HR = 2.02, 95% CI [1.80-2.28], I 2 = 0%, P Q = 0.630). Moreover, clinicopathological parameter data analysis showed that elevated TIMP-1 levels were significantly associated with lymph node metastasis (N1/N2/N3 vs N0: OR = 2.92, 95% CI [1.95-4.38]) and higher TNM stages (III/IV vs I/II: OR = 2.73, 95% CI [1.23-6.04]). CONCLUSION: Both TIMP-1-positive IHC staining and high serum/plasma TIMP-1 levels are poor prognostic factors for the survival of gastrointestinal cancer. In addition, TIMP-1 overexpression was correlated with more advanced clinicopathological features.

Coexpression of Matrix Metalloproteinase-7 and Tissue Inhibitor of Metalloproteinase-1 as a Prognostic Biomarker in Gastric Cancer.

BACKGROUND: Degradation of the extracellular matrix (ECM), an essential step in tumour invasion and metastasis, is mainly dependent on the activities of both matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). This study aimed to explore whether expression of MMP-7 and TIMP-1 alone and in combination can be used as a prognostic marker for gastric cancer (GC). METHOD: A total of 285 patients who had undergone tumourectomy for GC were included. Gastric tumour tissues were stained immunohistochemically to evaluate expression of MMP-7 and TIMP-1. RESULTS: Expression of MMP-7 was associated with tumour N stage and neural invasion. Multivariate Cox regression analysis suggested that expression of MMP-7 or TIMP-1 alone cannot serve as an indicator of patient prognosis; however, coexpression of MMP-7 and TIMP-1 was found to be an independent predictive factor of overall survival in patients with GC (HR = 1.74, 95% CI: 1.08-2.80). The results of stratified analysis also showed that the predictive value of MMP-7 and TIMP-1 coexpression was stronger in patients with N3 stage disease and not receiving chemotherapy. CONCLUSIONS: In conclusion, coexpression of MMP-7 and its inhibitor TIMP-1 in gastric tumour tissues is a potential prognostic marker for GC. Greater knowledge of protein expression will lead to new paradigms and possible improvements in therapeutics.

Evaluation of the Combined Application of AFP, AFP-L3%, and DCP for Hepatocellular Carcinoma Diagnosis: A Meta-analysis.

The role of α-fetoprotein (AFP) in the surveillance and diagnosis of hepatocellular carcinoma (HCC) has been questioned in recent years due to its low sensitivity and specificity. In addition to AFP, several new serum biomarkers, such as lens culinaris agglutinin-reactive fraction of AFP (AFP-L3) and des-gamma-carboxy prothrombin (DCP), have also been identified as useful HCC serological markers. However, the exact diagnostic value of the combinations of these biomarkers for detecting HCC in patients with liver disease remains unclear. Thus, we performed the current meta-analysis to assess performance of AFP+AFP-L3%+DCP for diagnosing HCC. Studies were systematically searched in PubMed, Embase, the Cochrane Library, CNKI, and WanFang Data databases. After full-text evaluation, 13 studies from 11 articles focusing on the combination of the three serum biomarkers for HCC detection were enrolled. Random-effects models were used due to the presence of heterogeneity. The pooled sensitivity and specificity for AFP+AFP-L3%+DCP were 88% and 79%, respectively. The area under the summary receiver operating characteristic (sROC) curve was 0.91, and the diagnostic odds ratio (DOR) was 28.33 (95% CI 16.78-47.83). Subgroup analysis showed that the pooled sensitivity and specificity of AFP+AFP-L3%+DCP in the diagnosis of HCC versus cirrhosis patients were 0.81 and 0.82, respectively. In conclusion, the combination of AFP, AFP-L3%, and DCP may prove to be useful in the diagnosis and screening of HCC.

Effect of prophylactic closure on adverse events after colorectal endoscopic submucosal dissection: A meta-analysis.

BACKGROUND AND AIM: Endoscopic submucosal dissection (ESD) has a high en bloc resection rate and is widely performed for large colorectal lesions. However, colorectal ESD is associated with a high frequency of adverse events (AEs), and the efficacy of prophylactic endoscopic closure after ESD for preventing AEs is still controversial. This meta-analysis was conducted to assess the efficacy of closure on AEs following colorectal ESD. METHODS: We searched PubMed, Embase, and the Cochrane Library for eligible studies. The chi-square-based Q statistics and the I2 test were used to test for heterogeneity. Pooling was conducted using a fixed or random effects model. RESULTS: We identified eight eligible studies that compared the effects of closure vs non-closure with respect to delayed bleeding, delayed perforation, and post-ESD coagulation syndrome. Compared with non-closure (5.2%), closure was associated with a lower incidence (0.9%) of delayed bleeding (pooled odd ratios [ORs]:0.19, 95% CI: 0.08-0.49) following ESD. The pooled ORs showed no significant differences in incidence of delayed perforation (pooled OR: 0.22; 95% CI: 0.05-1.03) or post-ESD coagulation syndrome (pooled OR:0.75; 95% CI: 0.26-2.18) between the closure and non-closure groups. CONCLUSION: Prophylactic endoscopic closure may reduce the incidence of delayed bleeding following ESD of colorectal lesions. Future studies are needed to further illuminate risk factors and stratify high risk subjects for a cost-effective preventive strategy.

Long non-coding RNA polymorphisms on 8q24 are associated with the prognosis of gastric cancer in a Chinese population.

BACKGROUND: Gastric cancer (GC) remains the third leading cause of cancer death in China. Although genome-wide association studies have identified the association between several single nucleotide polymorphisms (SNPs) on 8q24 and the risk of GC, the role of these SNPs in the prognosis of GC in Chinese populations has not yet been fully evaluated. Therefore, this study was conducted to explore the association between long non-coding RNA (lncRNA) polymorphisms on 8q24 and the prognosis of GC. METHODS: We genotyped 726 surgically resected GC patients to explore the association between eight SNPs in the lncRNAs CCAT1 (rs10087719, rs7816475), PCAT1 (rs1026411), PRNCR1 (rs12682421, rs13252298), and CASC8 (rs1562430, rs4871789, rs6983267) transcribed from the 8q24 locus and the prognosis of GC in a Chinese population. RESULTS: We found that the patients carrying rs12682421 AA genotypes survived for a shorter time than those with the GG/GA genotype (HR = 1.39, 95% confidence interval (CI) [1.09-1.78]). Compared with the CC/CT genotype, the TT genotype of rs1562430 was associated with an increased risk of death (HR = 1.38, 95% CI [1.06-1.80]). Furthermore, the results also identified the rs1026411 SNP as an independent prognostic factor for poor survival in GC patients. Patients carrying AA/AG variant genotypes had a 36% increased risk of death compared to those carrying the GG genotype (HR = 1.36, 95% CI [1.06-1.74]). These findings suggested that the rs12682421, rs1026411 and rs1562430 SNPs may contribute to the survival of GC and be prognostic markers for GC.

Reactivation of Atp4a concomitant with intragenic DNA demethylation for cancer inhibition in a gastric cancer model.

Accumulating evidence suggests that aberrant DNA methylation and gene silencing of tumor suppressors are pervasive in gastric malignancies, supporting reactivation of tumor suppressors through DNA demethylation as a potential therapeutic opportunity. Atp4a is an important tumor suppressor gene, encoding H+, K+-ATPase, and mediating gastric acid secretion in the stomach. Using transgenic gastric cancer model K19-Wnt1/C2mE (Gan) mice, by combining the transcriptome and MeDIP (methylated DNA immunoprecipitation) sequencing, together with qRT-PCR, we showed that Atp4a was expressed at low levels in tumor tissues and multiple GC cells, while both 5-aza-CdR and 18ß-glycyrrhetinic acid (GRA) pharmacological treatment triggered Atp4a activation with downregulation of DNMT1. In addition, CpG island (CGI) search showed that the CpG rich region is absent in the promoter region but present in exons 9-14 of Atp4a. Methylation specific PCR (MSP) indicated that Atp4a was fully or partly methylated in multiple GC cells. Further MassArray suggested that the demethylation in the CpG site 75, 183, 196, 262-268 might be responsible for the reactivation of Atp4a. Our research identified that GRA, a bioactive component found in abundance in Radix Glycyrrhiza, reactivated Atp4a expression and inhibited gastric tumorigenesis as a potential demethylation agent.