Circulating tumor cells as potential prognostic biomarkers for early-stage pancreatic cancer: A systematic review and meta-analysis.

BACKGROUND: Pancreatic cancer is difficult to be diagnosed early clinically, while often leads to poor prognosis. If optimal personalized treatment plan can be provided to pancreatic cancer patient at an earlier stage, this can greatly improve overall survival (OS). Circulating tumor cells (CTCs) are a collective term for various types of tumor cells present in the peripheral blood (PB), which are formed by detachment during the development of solid tumor lesions. Most CTCs undergo apoptosis or are phagocytosed after entering the PB, whereas a few can escape and anchor at distal sites to develop metastasis, increasing the risk of death for patients with malignant tumors. AIM: To investigate the significance of CTCs in predicting the prognosis of early pancreatic cancer patients. METHODS: The PubMed, EMBASE, Web of Science, Cochrane Library, China National Knowledge Infrastructure, China Biology Medicine, and ChinaInfo databases were searched for articles published through December 2022. Studies were considered qualified if they included patients with early pancreatic cancer, analyzed the prognostic value of CTCs, and were full papers reported in English or Chinese. Researches were selected and assessed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocol and the Newcastle-Ottawa Scale criteria. We used a funnel plot to assess publication bias. RESULTS: From 1595 publications, we identified eight eligible studies that collectively enrolled 355 patients with pancreatic cancer. Among these original studies, two were carried out in China; three in the United States; and one each in Italy, Spain, and Norway. All eight studies analyzed the relevance between CTCs and the prognosis of patients with early-stage pancreatic cancer after surgery. A meta-analysis showed that the patients that were positive pre-treatment or post-treatment for CTCs were associated with decreased OS [hazard ratio (HR) = 1.93, 95% confidence interval (CI): 1.197-3.126, P = 0.007] and decreased relapse-free/disease-free/progression-free survival (HR = 1.27, 95%CI: 1.137-1.419, P < 0.001) in early-stage pancreatic cancer. Additionally, the results suggest no statistically noticeable publication bias for overall, disease-free, progression-free, and recurrence-free survival. CONCLUSION: This pooled meta-analysis shows that CTCs, as biomarkers, can afford reliable prognostic information for patients with early-stage pancreatic cancer and help develop individualized treatment plans.

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.

Compound erosion effect of snowmelt, wind, and rainfall on sloping farmlands of Chinese typical Mollisol region.

Research on the processes and mechanisms of compound soil erosion by multiple forces can provide scientific guidance for precisely controlling cropland soil erosion. Based on the seasonal alternation of freezing-thawing, snowmelt, wind, and rainfall erosion forces on sloping farmlands under natural conditions from November to next October of each year, we used a set of indoor simulation experiments of multi-force superimpositions to analyze the compound soil erosion processes of snowmelt (1 and 2 L·min-1), wind (12 m·s-1), and rainfall (100 mm·h-1). We further discussed the erosion effects of multi-force superimpositions. The results showed that, under single snowmelt erosion, an increase in snowmelt flow had a greater effect on sloping snowmelt erosion intensity than that of sloping runoff rate. When sloping snowmelt flow increased from 1 L·min-1 to 2 L·min-1, sloping runoff rate and erosion intensity increased by 2.7 and 4.0 times, respectively. Under snowmelt-wind superimposition erosion, previous sloping snowmelt erosion inhibited late wind erosion occurrence. As sloping snowmelt flow increased from 1 L·min-1 to 2 L·min-1, the inhibiting action subsequently increased and wind erosion intensity caused by previous snowmelt reduced by more than 50%. Both wind erosion and snowmelt-wind superimposed erosion intensified late rainfall erosion. The early wind erosion increased rainfall erosion by 24.5%. The snowmelt-wind superimposed effect increased the later slope rainfall erosion by 132.8% and 465.4% under 1 and 2 L·min-1 snowmelt runoff rates, respectively. The compound soil erosion amount driven by multiple force superimposition was not the sum of the corresponding erosion amount caused by single erosion force, with promoting or inhibiting effects of erosion force superimposition. The erosion effect of snowmelt-wind superposition was negative, but that of wind-rainfall superposition and snowmelt-wind-rainfall superpositions were positive.

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.

[Hydrodynamic characteristics of grass swale runoff in Guanzhong area of Loess Plateau, Northwest China.] / é»„åœŸé«˜åŽŸå ³ä¸­åœ°åŒºæ¤è‰æ²Ÿå¾„æµæ°´åŠ›å­¦ç‰¹æ€§.

Grass swale has been widely used in sponge city construction, which can effectively improve the urban ecological environment. To explore the regulation mechanism of runoff in grass swale, runoff scouring experiment was carried out to study the hydrodynamic characteristics of runoff and the distribution of cross-section velocity under the combined conditions of five slopes (1%, 2%, 3%, 4%, 5%) and five scour flows (20, 30, 40, 50, 60 L·min-1). With the increases of flow rate and slope, flow velocity, Reynolds number and Froude number all increased gradually, while the Manning roughness coefficient and Darcy-Weisbach friction coefficient decreased gradually. The velocity (V) could be expressed as a power function V=0.3387Q0.555S0.6601 of flow rate (Q) and slope (S). The variation ranges of Reynolds number and Froude number were 1160.95-6596.82 and 0.17-1.21, respectively. The runoff flow patterns were all turbulent. The flow pattern was greatly affected by the slope. When flow rate and slope were small, they had great influence on friction coefficient. Under the experimental conditions, the Darcy-Weisbach friction coefficient was negatively correlated with Reynolds number. The velocity distribution of cross-section showed symmetrical distribution on both sides of the center. The maximum velocity point was located at the center of water surface. With the increases of flow rate and slope, the velocity contours of cross section gradually became dense and the gradient of the velocity change increased. Our results provide a theoretical basis for the design, application and hydraulic calculation of grass swale in the construction of sponge cities in loess areas, and reveal the runoff regulation mechanism by analyzing the hydraulic characteristics of grass swale runoff.

Hand-assisted laparoscopic resection versus total laparoscopic gastric surgery for primary gastric gastrointestinal stromal tumors (GISTs): an analysis from a high-volume institution.

BACKGROUND: Laparoscopic resection of gastric gastrointestinal stromal tumors (GISTs) is technically feasible and associated with favorable outcomes. We compared the clinical efficacy of hand-assisted laparoscopic surgery (HLS) and total laparoscopic surgery (TLS) for gastric GISTs. METHODS: We retrospectively analyzed the clinical data of 69 consecutive patients diagnosed with a gastric GIST in a tertiary referral teaching hospital from December 2016 to December 2020. Surgical outcomes were compared between two groups. RESULTS: Fifty-three patients (TLS group: n = 36; HLS group: n = 17) were included. The mean age was 56.9 and 58.1 years in the TLS and HLS groups, respectively. The maximum tumor margin was significantly shorter in the HLS group than in the TLS group (2.3 ± 0.9. vs. 3.0 ± 0.8 cm; P = 0.004). The operative time of the HLS group was significantly shorter than that of the TLS group (70.6 ± 19.1 min vs. 134.4 ± 53.7 min; P < 0.001). The HLS group had less intraoperative blood loss, a shorter time to first flatus, and a shorter time to fluid diet than the TLS group (P < 0.05). No significant difference was found between the groups in the incidence or severity of complications within 30 days after surgery. Recurrence or metastasis occurred in four cases (HLS group; n = 1; TLS group; n = 3). CONCLUSIONS: This study demonstrated that compared with TLS, HLS for gastric GISTs has the advantages of simpler operation, shorter operative time, and faster postoperative recovery.

The peroxisome proliferator-activated receptor agonist rosiglitazone specifically represses tumour metastatic potential in chromatin inaccessibility-mediated FABP4-deficient gastric cancer.

Background: Efforts to prevent recurrence in gastric cancer (GC) patients are limited by current incomplete understanding of the pathological mechanisms. The present study aimed to identify novel tumour metastasis-associated genes and investigate potential value of these genes in clinical diagnosis and therapy. Methods: RNA sequencing was performed to identify differentially expressed genes related to GC metastasis. The expression and prognostic significance of fatty acid binding protein 4 (FABP4) were evaluated in two independent cohorts of GC patients. Chromatin immunoprecipitation sequencing, diverse mouse models and assays for transposase-accessible chromatin with high-throughput sequencing were used to investigate the roles and mechanisms of action of FABP4. Results: The results of the present multicentre study confirmed an association between a decrease in the expression of FABP4 and poor outcomes in GC patients. FABP4 inhibited GC metastasis but did not influence tumour growth in vitro and in vivo. Mechanistically, FABP4 binding with peroxisome proliferator-activated receptor γ (PPAR-γ) facilitated the translocation of PPAR-γ to the nucleus. FABP4 depletion suppressed PPAR-γ-mediated transcription of cell adhesion molecule 3 (CADM3), which preferentially governed GC metastasis. Notably, the PPAR-γ agonist rosiglitazone reversed the metastatic properties of FABP4-deficient GC cells in vitro and demonstrated viable therapeutic potential in multiple mouse models. For GC patients with diabetes, low FABP4 portends better prognosis than high FABP4 after receipt of rosiglitazone treatment. Additionally, chromatin inaccessibility induced by HDAC1 reduced FABP4 expression at the epigenetic level. Conclusions: Our findings suggest that chromatin inaccessibility orchestrates a reduction in FABP4 expression, which inhibits CADM3 transcription via PPAR-γ, thereby resulting in GC metastasis. The antidiabetic drug rosiglitazone restores PPAR-γ/CADM3 activation in FABP4-deficient GC and thus has promising therapeutic potential.

[Impacts of seepage flow and soil thaw depth on hillslope snowmelt erosion in Chinese Mollisol region]. / 壤中流和土壤解冻深度对黑土坡面融雪侵蚀的影响.

Snowmelt erosion is an important way of soil loss in Chinese Mollisol region. However, little is known about the effects of seepage flow and soil thaw depth on hillslope snowmelt runoff erosion. An indoor simulated experiment was conducted to analyze the impacts of seepage flow and soil thaw depth on hillslope snowmelt erosion. There were two snowmelt flow rates (1 and 4 L·min-1), two soil thaw depths (5 and 10 cm), and two near-surface hydrological conditions (with and without seepage flow). The results showed that hillslope runoff depth and soil erosion amount in the treatment with seepage flow were 1.1 to 1.2 times and 1.3 to 1.9 times of those in the treatment without seepage flow, respectively. Under two snowmelt flow rates, when soil thaw depth increased from 5 cm to 10 cm, hillslope runoff depth and soil erosion amount increased by 10.0% to 13.5% and 15.4% to 37.1% in the treatment without seepage flow, respectively. In the treatment with seepage flow, when soil thaw depth shifted from 5 cm to 10 cm, hillslope runoff depth increased by 6.5% to 8.5%, and soil erosion amount remained stable. Moreover, hillslope rill development was comprehensively influenced by seepage flow, soil thaw depth, and snowmelt flow rate, with rill erosion amount occupying more than 72% of hillslope snowmelt erosion amount. Compared with the treatment without seepage flow, flow velocity and shear stress under the treatment with seepage flow increased by 20.3% to 23.2% and 37.0% to 51.3%, respectively; but Darcy-Weisbach friction coefficient reduced by 9.0% to 21.4%, which caused an increase of hillslope snowmelt erosion. In addition, seepage flow enhanced rill development, which caused rill erosion amount to increase by 43.6% to 69.9% compared with the treatment without seepage flow, and it further resulted in the increase of hillslope snowmelt erosion amount. The main reason for soil thaw depth enhancing hillslope snowmelt erosion amount under the treatment without seepage flow was that both sloping runoff erosivity and erodible materials increased with increasing soil thaw depth. Furthermore, soil thaw depth had a significant impact on hillslope rill morphology development under the treatment with seepage flow. Rill widening process was dominated when soil thaw depth was 5 cm, whereas rill incision process was dominant when soil thaw depth was 10 cm. This study could improve the understanding of hillslope snowmelt erosion mechanism in Chinese Mollisol region and provide theoretical guidance for the development of water erosion model.

MiR-450a-5p Inhibits Gastric Cancer Cell Proliferation, Migration, and Invasion and Promotes Apoptosis via Targeting CREB1 and Inhibiting AKT/GSK-3ß Signaling Pathway.

Gastric cancer seriously affects human health and research on gastric cancer is attracting more and more attentions. In recent years, molecular targets have become the research focus. Accumulating evidence indicates that miR-450a-5p plays a critical role in cancer progression. However, the biological role of miR-450a-5p in gastric carcinogenesis remains largely unknown. In this study, we explore the effects and mechanisms of miR-450a-5p on the development and progression of gastric cancer. We used gain-of-function approaches to investigate the role of miR-450a-5p on gastric cancer cell proliferation, migration, invasion, and apoptosis using biological and molecular techniques including real-time quantitative PCR (RT-qPCR), CCK-8, colony formation, flow cytometry, Western blot, wound healing, transwell chamber, dual luciferase reporter, and tumor xenograft mouse model. We found that gastric cancer cells have low expression of miR-450a-5p and overexpression of miR-450a-5p inhibited gastric cancer cell proliferation, migration and invasion, and induced apoptosis in vitro. Moreover, we demonstrated that ectopic expression of miR-450a-5p inhibited gastric cancer growth in vivo. At the molecular level, overexpression of miR-450a-5p significantly increased the expression of pro-apoptotic proteins, including caspase-3, caspase-9, and Bax, and inhibited the expression of anti-apoptotic protein Bcl-2. Luciferase reporter experiment suggested that camp response element binding protein 1 (CREB1) had a negative correlation with miR-450a-5p expression, and knockdown of CREB1 alleviated gastric cancer growth. Furthermore, we also found that miR-450a-5p inhibited the activation of AKT/GSK-3ß signaling pathway to inhibit the progression of gastric cancer. Collectively, miR-450a-5p repressed gastric cancer cell proliferation, migration and invasion and induced apoptosis through targeting CREB1 by inhibiting AKT/GSK-3ß signaling pathway. MiR-450a-5p could be a novel molecular target for the treatment of gastric cancer.

Tumor-associated mesenchymal stem cells promote hepatocellular carcinoma metastasis via a DNM3OS/KDM6B/TIAM1 axis.

Tumor-associated mesenchymal stem cells (MSCs) play a critical role in the growth and metastasis of hepatocellular carcinoma (HCC). However, the mechanism underlying the crosstalk between MSCs and HCC cells is not completely understood. Here, HCC cells were treated with or without conditioned medium of MSCs (CM-MSC), and examined for differential expression of long non-coding RNAs (lncRNAs). Knockdown and overexpression experiments were conducted to explore the function of the lncRNA DNM3OS in MSC-induced HCC growth and metastasis. CM-MSC treatment led to a concentration-dependent induction of DNM3OS in HCC cells. DNM3OS was significantly upregulated in HCC compared to adjacent liver tissues. High DNM3OS expression was associated with TNM stage, vascular invasion, and poor prognosis of HCC patients. Silencing of DNM3OS inhibited HCC cell proliferation and invasion in vitro and tumorigenesis and metastasis in vivo. Overexpression of DNM3OS enhanced HCC cell proliferation, invasion, and metastasis. Biochemically, DNM3OS was mainly localized in the nucleus and physically interacted with KDM6B. The association of DNM3OS with KDM6B induced the expression of TIAM1 through reduction of H3K27me3 at the TIAM1 promoter. TIAM1 overexpression restored the proliferation and invasion of DNM3OS-depleted HCC cells. Our data delineate a mechanism by which MSCs accelerate HCC growth and metastasis through a DNM3OS/KDM6B/TIAM1 axis.

Impact of intrauterine hypoxia on adolescent and adult cognitive function in rat offspring: sexual differences and the effects of spermidine intervention.

Intrauterine hypoxia (IUH) affects the growth and development of offspring. It remains unclear that how long the impact of IUH on cognitive function lasts and whether sexual differences exist. Spermidine (SPD) has shown to improve cognition, but its effect on the cognitive function of IUH offspring remains unknown. In the present study we investigated the influence of IUH on body weight and neurological, motor and cognitive function and the expression of APP, BACE1 and Tau5 proteins in brain tissues in 2- and 4-month-old IUH rat offspring, as well as the effects of SPD intervention on these parameters. IUH rat model was established by treating pregnant rats with intermittent hypoxia on gestational days 15-21, meanwhile pregnant rats were administered SPD (5 mg·kg-1·d-1;ip) for 7 days. Neurological deficits were assessed in the Longa scoring test; motor and cognitive functions were evaluated in coat hanger test and active avoidance test, respectively. We found that IUH decreased the body weight of rats in both sexes but merely impaired motor and cognitive function in female rats without changing neurological function in the rat offspring of either sex at 2 months of age. For 4-month-old offspring, IUH decreased body weight in males and impaired neurological function and increased cognitive function in both sexes. IUH did not affect APP, BACE1 or Tau5 protein expression in either the hippocampus or cortex of all offspring; however, it increased the cortical Tau5 level in 2-month-old female offspring. Surprisingly, SPD intervention prevented weight loss. SPD intervention reversed the motor and cognitive decline caused by IUH in 2-month-old female rat offspring. Taken together, IUH-induced cognitive decline in rat offspring is sex-dependent during puberty and can be recovered in adult rats. SPD intervention improves IUH-induced cognitive and neural function decline.

An immune checkpoint score system for prognostic evaluation and adjuvant chemotherapy selection in gastric cancer.

Immunosuppressive molecules are extremely valuable prognostic biomarkers across different cancer types. However, the diversity of different immunosuppressive molecules makes it very difficult to accurately predict clinical outcomes based only on a single immunosuppressive molecule. Here, we establish a comprehensive immune scoring system (ISSGC) based on 6 immunosuppressive ligands (NECTIN2, CEACAM1, HMGB1, SIGLEC6, CD44, and CD155) using the LASSO method to improve prognostic accuracy and provide an additional selection strategy for adjuvant chemotherapy of gastric cancer (GC). The results show that ISSGC is an independent prognostic factor and a supplement of TNM stage for GC patients, and it can improve their prognosis prediction accuracy; in addition, it can distinguish GC patients with better prognosis from those with high prognostic nutritional index score; furthermore, ISSGC can also be used as a tool to select GC patients who would benefit from adjuvant chemotherapy independent of their TNM stages, MSI status and EBV status.

An Intraoperative Model for Predicting Survival and Deciding Therapeutic Schedules: A Comprehensive Analysis of Peritoneal Metastasis in Patients With Advanced Gastric Cancer.

Background and Objective: No specialized prognostic model for patients with gastric cancer with peritoneal metastasis (GCPM) exists for intraoperative clinical decision making. This study aims to establish a new prognostic model to provide individual treatment decisions for patients with GCPM. Method: This retrospective analysis included 324 patients with GCPM diagnosed pathologically by laparoscopy from January 2007 to January 2018 who were randomly assigned to different sets (227 in the training set and 97 in the internal validation set). A nomogram was established from preoperative and intraoperative variables determined by a Cox model. The predictive ability and clinical applicability of the PM nomogram (PMN) were compared with the 15th Japanese Classification of Gastric Carcinoma (JCGC) Staging Guidelines for PM (P1abc). Additional external validation was performed using a dataset (n = 39) from the First Affiliated Hospital of University of Science and Technology of China. Results: The median survival time was 8 (range, 1-90) months. In the training set, each PMN substage had significantly different survival curves (P < 0.001), and the PMN was superior to the P1abc based on the results of time-dependent receiver operating characteristic curve, C-index, Akaike information criterion and likelihood ratio chi-square analyses. In the internal and external validation sets, the PMN was also better than the P1abc in terms of its predictive ability. Of the PMN1 patients, those undergoing palliative resection had better overall survival (OS) than those undergoing exploratory surgery (P < 0.05). Among the patients undergoing exploratory surgery, those who received chemotherapy exhibited better OS than those who did not (P < 0.05). Among the patients who received palliative resection, only PMN1 patients exhibited better OS following chemotherapy (P < 0.05). Conclusion: We developed and validated a simple, specific PM model for patients with GCPM that can predict prognosis well and guide treatment decisions.

m6A modification-mediated BATF2 acts as a tumor suppressor in gastric cancer through inhibition of ERK signaling.

BACKGROUND: BATF2, also known as SARI, has been implicated in tumor progression. However, its role, underlying mechanisms, and prognostic significance in human gastric cancer (GC) are elusive. METHODS: We obtained GC tissues and corresponding normal tissues from 8 patients and identified BATF2 as a downregulated gene via RNA-seq. qRT-PCR and western blotting were applied to examine BATF2 levels in normal and GC tissues. The prognostic value of BATF2 was elucidated using tissue microarray and IHC analyses in two independent GC cohorts. The functional roles and mechanistic insights of BATF2 in GC growth and metastasis were evaluated in vitro and in vivo. RESULTS: BATF2 expression was significantly decreased in GC tissues at both the mRNA and protein level. Multivariate Cox regression analysis revealed that BATF2 was an independent prognostic factor and effective predictor in patients with GC. Low BATF2 expression was remarkably associated with peritoneal recurrence after curative gastrectomy. Moreover, elevated BATF2 expression effectively suppressed GC growth and metastasis in vitro and in vivo. Mechanistically, BATF2 binds to p53 and enhances its protein stability, thereby inhibiting the phosphorylation of ERK. Tissue microarray results indicated that the prognostic value of BATF2 was dependent on ERK activity. In addition, the N6-methyladenosine (m6A) modification of BATF2 mRNA by METTL3 repressed its expression in GC. CONCLUSIONS: Collectively, our findings indicate the pivotal role of BATF2 in GC and highlight the regulatory function of the METTL3/BATF2/p53/ERK axis in modulating GC progression, which provides potential prognostic and therapeutic targets for GC treatment.

Association Between EphA1 and Tumor Microenvironment in Gastric Carcinoma and its Clinical Significance.

BACKGROUND With the growing global burden of gastric carcinoma (GC) and the urgent need for biomolecular targeted therapies, this study aimed to elucidate the relationship between EphA1 and the tumor microenvironment (focusing primarily on the key inflammatory cytokines IL-6 and tumor angiogenic cytokine VEGF) to identify a new potential therapeutic target. MATERIAL AND METHODS IHC and qRT-PCR were performed to quantify the protein and gene expression levels of EphA1, IL-6, and VEGF in normal mucosal tissues, carcinoma tissues, and paracarcinomatous tissues from 57 GC patients. Spearman's rank correlation test was performed to determine the relationship between EphA1, IL-6, and VEGF expression levels. The relationships of EphA1 with clinicopathologic parameter and survival in GC patients were also evaluated. RESULTS The protein and gene expression levels of EphA1 were all attenuated gradually from carcinoma tissues to paracarcinomatous tissues and then to normal mucosal tissues in GC patients. Additionally, significant correlations between the overexpression of EphA1 with aggressive clinicopathological features and shorter survival time of GC patients were verified. In particular, we found a significant positive correlation between the expression of EphA1 and tumor microenvironment hallmark proteins IL-6 and VEGF in carcinoma tissues and paracarcinomatous tissues. CONCLUSIONS EphA1 can promote the occurrence and development of GC by its selective high expression in cancer tissues and its relationship with malignant clinical features and prognosis of GC patients. The underlying potential mechanism appears to involve enhancement of the tumor microenvironment, which via drives the expression of tumor microenvironment hallmark proteins IL-6 and VEGF.

Comparative study of laparoscopic versus open radical gastrectomy in advanced gastric neuroendocrine carcinoma: Analysis from a high-volume institution.

BACKGROUND: Gastric neuroendocrine carcinomas (G-NECs) are rare. This study aimed to explore the feasibility and clinical efficacy of laparoscopic surgery in patients with advanced G-NECs. METHODS: The clinicopathological data of 175 G-NECs patients who underwent radical gastrectomy in a high-volume centre were collected. One hundred fifty-one cases with advanced G-NECs (laparoscopic gastrectomy [LG] = 30, open gastrectomy [OG] = 121) were finally selected for comparison of the short-term outcomes and oncologic efficacy. RESULTS: In the postoperative recovery, when comparing the OG group, the time to ambulation (3.2 d vs. 2.6 d, respectively, p = 0.049), the time to first flatus (4.1 d vs. 3.6 d, respectively, p = 0.050), the time to first soft diet (7.9 d vs. 6.7 d, respectively, p = 0.007), and the postoperative hospital stay (13.1 d vs. 11.4 d, respectively, p = 0.047) of the LG group were shorter. There was no significant difference in the postoperative complication rates between the OG and LG groups (19.8% vs. 23.3%, p = 0.671). The 3-year overall survival (OS) rate was 57.0% in the OG group and 64.4% in the LG group (p = 0.349). The 3-year disease-free survival (DFS) rate was 51.7% in the OG group and 57.4% in the LG group (p = 0.357). There was no significant difference in the 3-year OS and DFS rates between the LG and OG groups at each stage. The recurrence rate was 35.5% in the OG group and 33.0% in the LG group (p = 0.821). CONCLUSIONS: The short-term outcomes and oncologic efficacy of laparoscopic gastrectomy and open gastrectomy for advanced G-NECs are comparable.

Knockdown of AGGF1 inhibits the invasion and migration of gastric cancer via epithelial-mesenchymal transition through Wnt/ß-catenin pathway.

BACKGROUND: Angiogenic factor with G-patch and FHA domain 1 (AGGF1), as a newly identified human angiogenic factor, is overexpressed in some types of malignant tumors and closely associated with patient's prognosis. However, the mechanisms involved in the regulation of AGGF1 in gastric cancer (GC) still remain unclear. METHODS: In this study, AGGF1 level in GC tissues and cell lines was analyzed by western blot and quantitative real-time polymerase chain reaction (qRT-PCR). After knockdown of AGGF expression by RNA interference in GC cell lines MKN-45 and MGC-803, wound healing and transwell assays were conducted to examine the effects of AGGF1 on migration and invasion. Tumor growth was assessed in a mouse xenograft model in vivo. Furthermore, expression levels of epithelial-mesenchymal transition (EMT) biomarkers and involvement of the Wnt/ß-catenin pathway were detected by western blot and qRT-PCR. RESULTS: Compared to those in normal groups, the protein and mRNA of AGGF1 expression levels were significantly higher both in GC tissues and cell lines (all P < 0.05). Knockdown of AGGF1 dramatically inhibited the invasion and migration of MKN-45 and MGC-803 cells (all P < 0.01) in vitro, and suppressed the tumor growth of nude mice xenograft model in vivo. Western blot revealed alterations in EMT biomarkers, suggesting the role of AGGF1 in EMT. Moreover, we found that downregulated expression of AGGF1 attenuated Wnt/ß-catenin related protein expression. CONCLUSIONS: Collectively, knockdown of AGGF1 inhibits the invasion and migration of gastric cancer via epithelial-mesenchymal transition through Wnt/ß-catenin pathway.

Distinct mechanisms in the numerosity processing of random and regular dots.

This study investigated the mechanisms of the numerosity coding of random and regular dot distribution patterns. Experiment 1 revealed that connectedness significantly affected the numerosity perception of randomly distributed dots, and two adjacent dots were considered to be one numeral unit when connected via lines. The connectedness effect was much weaker on the numerosity perception of regularly distributed dots in vertical or horizontal queues and was absent in the perception of dots in diagonal queues. Experiment 2 demonstrated that randomly distributed adaptors induced a stronger effect of adaptation compared with regular adaptors when random dots after adaptation were used to test participants' numerosity perception. Experiment 3 found that the change in stimulus orientation has no effect on adaptation for random patterns. However, for regular patterns, adapting stimuli with an orientation identical to the tests caused stronger aftereffects compared with those with a different orientation. In Experiment 4, when random adaptors were presented in one eye of a participant, the adaptation aftereffect was shown to exist in both the exposed and un-exposed eyes (binocular transfer), whereas the aftereffect of regular adaptors remained only in the exposed eye (monocular transfer). We interpret that distinct mechanisms might control the numerosity processing of randomly and regularly distributed dots. Generic numerosity processing seems to be automatically inhibited based on the coding of regular patterns. The absence of numeral unit individuation, which is coded at a higher visual-processing level, might play an important role in this inhibition.

Ibutilide protects against cardiomyocytes injury via inhibiting endoplasmic reticulum and mitochondrial stress pathways.

Atrial fibrillation (AF) is a complex disease with multiple inter-relating causes culminating in rapid atrial activation and atrial structural remodeling. The contribution of endoplasmic reticulum and mitochondria stress to AF has been highlighted. As the class III antiarrhythmic agent, ibutilide are widely used to AF. This study was designed to explore whether ibutilide could treat AF by inhibiting endoplasmic reticulum stress pathways and mitochondria stress. The neonatal rat cardiomyocytes were isolated and exposed to H2O2, ibutilide was add to the culture medium 12 h. Then the cell viability, oxidative stress levels and apoptotic rate were analyzed. In addition, endoplasmic reticulum stress related protein (GRP78, GRP94, CHOP), mitochondria-dependent protein (Bax, Bcl-2) and caspase-3/9/12 were identified by real-time PCR and western blot analysis. In our results, remarkable decreased cell viability and oxidative stress levels were detected in cardiomyocytes after treating with H2O2. The apoptotic rate and the expression of proteins involved in mitochondrial stress and endoplasmic reticulum stress pathways increased. While ibutilide significantly inhibited these changes. These data suggested that ibutilide serves a protective role against H2O2-induced apoptosis of neonatal rat cardiomyocytes, and the mechanism is related to suppression of mitochondrial stress and endoplasmic reticulum stress.