Research progress on the development of hepatocyte growth factor/c-Met signaling pathway in gastric cancer: A review.

Hepatocyte growth factor (HGF) and its receptor, c-Met, play important roles in the occurrence, development, and treatment of gastric cancer (GC). This review explored the function of the HGF/c-Met signaling pathway in GC and its potential targeted therapeutic mechanisms. As one of the most common malignant tumors worldwide, GC has a complex pathogenesis and limited therapeutic options. Therefore, a thorough understanding of the molecular mechanism of GC is very important for the development of new therapeutic methods. The HGF/c-Met signaling pathway plays an important role in the proliferation, migration, and invasion of GC cells and has become a new therapeutic target. This review summarizes the current research progress on the role of HGF/c-Met in GC and discusses targeted therapeutic strategies targeting this signaling pathway, providing new ideas and directions for the treatment of GC.

Association between calcification and risk stratification in gastric gastrointestinal stromal tumors.

BACKGROUND: Risk assessment of gastric gastrointestinal stromal tumors (GISTs), particularly those with a diameter ≤ 5 cm, remains a clinical challenge. Previous research has primarily focused on tumor size, ulceration, necrosis, and enhancement patterns, with less emphasis on the role of tumor calcification, which remains controversial regarding its correlation with malignancy risk. OBJECTIVE: This study aims to explore the characteristics of calcification in gastric GISTs and its correlation with risk stratification as defined by the National Institutes of Health (NIH), to improve preoperative risk assessment for gastric GISTs ≤ 5 cm. METHODS: A retrospective analysis of 385 pathologically confirmed gastric GIST patients, including 178 with small gastric GISTs (< 2 cm), was conducted. Tumors were categorized into low-risk (very low / low) and high-risk (intermediate / high) groups based on NIH criteria. Variables such as age, gender, tumor long-axis diameter, calcification rates, calcification size, the number and distribution of calcification, calcification to tumor long-axis diameter ratio were analyzed. Logistic regression was used to identify independent predictors of malignancy for gastric GISTs, with predictive values assessed via receiver operating characteristic (ROC) curves. RESULTS: Significant differences were found between high-risk and low-risk groups in treatment methods, tumor long-axis diameter, the ratio of calcification to tumor long-axis, and calcification distribution (P < 0.05). Calcification rates varied across risk categories, with 23.6% in very low-risk, 31.6% in low-risk, 9.8% in intermediate-risk, and 31.7% in high-risk categories (P < 0.05). In GISTs ≤ 5 cm, both tumor long-axis diameter (OR = 3.07, 95% CI: 2.29-4.10) and calcification (OR = 0.36, 95% CI: 0.13-0.97) were independent predictors of malignancy risk (both P < 0.05). ROC curve analysis yielded areas of 0.849 for tumor long-axis diameter, 0.578 for calcification, and 0.862 for their combination. CONCLUSION: The study indicates lower calcification rates in intermediate-risk gastric GISTs and higher rates in other risk categories. Additionally, tumors of different sizes exhibit two distinct calcification patterns, suggesting possible differing mechanisms of calcification in tumors. Calcification in gastric GISTs ≤ 5 cm acts as a protective factor against higher malignancy risk, and when combined with tumor long-axis diameter, significantly enhances predictive accuracy over long-axis diameter alone.

Deep Learning Radiomics Model of Dynamic Contrast-Enhanced MRI for Evaluating Vessels Encapsulating Tumor Clusters and Prognosis in Hepatocellular Carcinoma.

BACKGROUND: Vessels encapsulating tumor cluster (VETC) is a critical prognostic factor and therapeutic predictor of hepatocellular carcinoma (HCC). However, noninvasive evaluation of VETC remains challenging. PURPOSE: To develop and validate a deep learning radiomic (DLR) model of dynamic contrast-enhanced MRI (DCE-MRI) for the preoperative discrimination of VETC and prognosis of HCC. STUDY TYPE: Retrospective. POPULATION: A total of 221 patients with histologically confirmed HCC and stratified this cohort into training set (n = 154) and time-independent validation set (n = 67). FIELD STRENGTH/SEQUENCE: A 1.5 T and 3.0 T; DCE imaging with T1-weighted three-dimensional fast spoiled gradient echo. ASSESSMENT: Histological specimens were used to evaluate VETC status. VETC+ cases had a visible pattern (≥5% tumor area), while cases without any pattern were VETC-. The regions of intratumor and peritumor were segmented manually in the arterial, portal-venous and delayed phase (AP, PP, and DP, respectively) of DCE-MRI and reproducibility of segmentation was evaluated. Deep neural network and machine learning (ML) classifiers (logistic regression, decision tree, random forest, SVM, KNN, and Bayes) were used to develop nine DLR, 54 ML and clinical-radiological (CR) models based on AP, PP, and DP of DCE-MRI for evaluating VETC status and association with recurrence. STATISTICAL TESTS: The Fleiss kappa, intraclass correlation coefficient, receiver operating characteristic curve, area under the curve (AUC), Delong test and Kaplan-Meier survival analysis. P value <0.05 was considered as statistical significance. RESULTS: Pathological VETC+ were confirmed in 68 patients (training set: 46, validation set: 22). In the validation set, DLR model based on peritumor PP (peri-PP) phase had the best performance (AUC: 0.844) in comparison to CR (AUC: 0.591) and ML (AUC: 0.672) models. Significant differences in recurrence rates between peri-PP DLR model-predicted VETC+ and VETC- status were found. DATA CONCLUSIONS: The DLR model provides a noninvasive method to discriminate VETC status and prognosis of HCC patients preoperatively. EVIDENCE LEVEL: 4. TECHNICAL EFFICACY: Stage 2.

Preoperative MRI features for characterization of vessels encapsulating tumor clusters and microvascular invasion in hepatocellular carcinoma.

PURPOSE: This study aimed to analyze imaging features based on preoperative dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) for the identification of vessels encapsulating tumor clusters (VETC)-microvascular invasion (MVI) in hepatocellular carcinoma (HCC), VM-HCC pattern. METHODS: Patients who underwent hepatectomy and preoperative DCE-MRI between January 2015 and March 2021 were retrospectively analyzed. Clinical and imaging features related to VM-HCC (VETC + /MVI-, VETC-/MVI +, VETC + /MVI +) and Non-VM-HCC (VETC-/MVI-) were determined by multivariable logistic regression analyses. Early and overall recurrence were determined using the Kaplan-Meier survival curve. Indicators of early and overall recurrence were identified using the Cox proportional hazard regression model. RESULTS: In total, 221 patients (177 men, 44 women; median age, 60 years; interquartile range, 52-66 years) were evaluated. The multivariable logistic regression analyses revealed fetoprotein > 400 ng/mL (odds ratio [OR] = 2.17, 95% confidence interval [CI] 1.07, 4.41, p = 0.033), intratumor vascularity (OR 2.15, 95% CI 1.07, 4.31, p = 0.031), and enhancement pattern (OR 2.71, 95% CI 1.17, 6.03, p = 0.019) as independent predictors of VM-HCC. In Kaplan-Meier survival analysis, intratumor vascularity was associated with early and overall recurrence (p < 0.05). CONCLUSION: Based on DCE-MRI, intratumor vascularity can be used to characterize VM-HCC and is of prognostic significance for recurrence in patients with HCC.

68Ga-Labeled GX1 Dimer: A Novel Probe for PET/Cerenkov Imaging Targeting Gastric Cancer.

PURPOSE: To synthesize the dimer of GX1 and identify whether its affinity and targeting are better than those of GX1. To prepare 68Ga-DOTA-KEK-(GX1)2 and to apply it to PET and Cerenkov imaging of gastric cancer. METHODS: 68Ga-DOTA-KEK-(GX1)2 was prepared, and the labeling yield and stability were determined. Its specificity and affinity were verified using an in vitro cell binding assay and competitive inhibition test, cell immunofluorescence, and cell uptake and efflux study. Its tumor-targeting ability was determined by nano PET/CT and Cerenkov imaging, standardized uptake value (SUV), signal-to-background ratio (SBR) quantification, and a biodistribution study in tumor-bearing nude mice. RESULTS: 68Ga-DOTA-KEK-(GX1)2 was successfully prepared, and the labeling yield was more than 97%. It existed stably for 90 min in serum. The binding of 68Ga-DOTA-KEK-(GX1)2 to cocultured HUVECs (Co-HUVECs) was higher than that to human umbilical vein endothelial cells (HUVECs), BGC823 cells, and GES cells. It was also higher than that of 68Ga-DOTA-GX1, indicating that the dimer did improve the specificity and affinity of GX1. The binding of KEK-(GX1)2 to Co-HUVECs was significantly higher than that of GX1. Additionally, the uptake of 68Ga-DOTA-KEK-(GX1)2 by Co-HUVECs was higher than that of 68Ga-DOTA-GX1 and reached a maximum at 60 min. Nano PET/CT and Cerenkov imaging showed that the tumor imaging of the nude mice injected with 68Ga-DOTA-KEK-(GX1)2 was clear, and the SUV and SBR value of the tumor sites were significantly higher than those of the nude mice injected with 68Ga-DOTA-GX1, indicating that the probe had better targeting in vivo. Finally, the biodistribution showed quantitatively that when organs such as the kidney and liver metabolized rapidly, the radioactivity of the tumor site of the nude mice injected with 68Ga-DOTA-KEK-(GX1)2 decreased relatively slowly. At the same time, the percentage of injected dose per gram (%ID/g) of the tumor site was higher than that of other normal organs except the liver and kidney at 60 min, which indicated that the tumor had good absorption of the probe. CONCLUSION: GX1 was modified successfully, and the in vivo and in vitro properties of the GX1 dimer were significantly better than those of GX1. The imaging probe, 68Ga-DOTA-KEK-(GX1)2, was successfully prepared, which provides a candidate probe for PET and Cerenkov diagnosis of gastric cancer.

Endovascular treatment of cerebrovascular stenosis with stent for patients with ischemic cerebrovascular disease.

This study aimed to investigate the therapeutic effect of cerebrovascular stent implantation in southwest Chinese patients with ischemic cerebrovascular disease and underlying risk factors for stent restenosis.We made a retrospectively analysis of occurring risk, cerebrovascular lesion, stent implantation, complication treatment, and prognosis of 54 patients with ischemic cerebrovascular disease in our department.A total of 85 stents were implanted into 54 patients, involving 44 of the internal carotid artery system, 34 of the vertebral-basal artery system and 7 of the subclavian artery system. All patients with stenosis were reduced by >70%, with all stenosis complete reduction in 5 (9%) patients and reduction of over 90% in 25 (46%) patients. A total of 50 patients were followed up for 28.5 (21-35) months. The stents in 42 patients exhibited satisfactory shape and location while restenosis occurred in 8 patients. Univariate analysis revealed that hyperlipidemia, hyperuricemia, surgery duration, and total length of hospital stay are significantly correlated with stent restenosis, and hyperlipidemia and hyperuricemia were proven to be independent risk factors for restenosis using logistic regression analysis.Cerebrovascular stent implantation and balloon inflation surgery can assist in abating angiostenosis and improving blood supplement effectively in patients with ischemic cerebrovascular disease. Besides, an overall evaluation, strict care, and regular check-up in perioperative period may reduce the occurrence of complications. Finally, several clinical parameters may need to be highly focused on in surgery for better prognosis.

188Re-labeled GX1 dimer as a novel dual-functional probe targeting TGM2 for imaging and antiangiogenic therapy of gastric cancer.

PURPOSE: The GX1 peptide (CGNSNPKSC) can specifically bind to TGM2 and possesses the ability to target the blood vessels of gastric cancer. This study intends to develop an integrated dual-functional probe with higher affinity, specificity and targeting and to characterize it in vivo and in vitro. METHODS: The dimer and tetramer of GX1 were prepared using cross-linked PEG and labeled with 99mTc. The best targeting probe [PEG-(GX1)2] was selected by gamma camera imaging in nude mouse models of gastric cancer. 188Re-PEG-(GX1)2 was prepared and characterized through cell binding analysis and competitive inhibition experiments, gamma camera imaging, MTT analysis and flow cytometry, BLI, immunohistochemistry, HE staining and biochemical analysis. RESULTS: PEG-(GX1)2 bound specifically to Co-HUVEC with higher affinity than GX1. 188Re-PEG-(GX1)2 had better ability to target gastric cancer in tumor-bearing nude mice and higher T/H ratios than 188Re-GX1. 188Re-PEG-(GX1)2 inhibited the growth of Co-HUVEC and induced apoptosis, and its effects were more robust than those of 188Re-GX1. BLI showed that 188Re-PEG-(GX1)2 inhibited tumor proliferation in vivo with a stronger effect than 188Re-GX1. Compared with 188Re-GX1, 188Re-PEG-(GX1)2 suppressed tumor angiogenesis and tumor cell proliferation and induced tumor cell apoptosis in vivo. The 188Re-PEG-(GX1)2 group did not cause visible changes in liver and kidney morphology and function in vivo. CONCLUSION: The dimer of GX1 was synthesized by using cross-linked PEG, and then 188Re-PEG-(GX1)2 was prepared. This radiopharmaceutical played both diagnostic and therapeutic functions, and gamma camera imaging could be utilized to detect the distribution of drugs in vivo during treatment. Through a series of experiments in vitro and in vivo, the feasibility of the drug was confirmed, and these results laid the foundation for the subsequent development and application of GX1.

Overexpression of LncRNA PSMG3-AS1 Distinguishes Glioblastomas from Sarcoidosis.

In clinical practices, glioblastomas (GBM) in some cases can be misdiagnosed as sarcoidosis. This study aimed to develop a biomarker to distinguish GBM from sarcoidosis. In this study, we found that PSMG3-AS1 was upregulated in plasma of GBM patients in comparison with that in sarcoidosis patients and healthy controls. Receiver operating characteristic (ROC) curve analysis showed that upregulation of PSMG3-AS1 effectively separated GBM patients from sarcoidosis patients and healthy controls. In GBM cells, overexpression of PSMG3-AS1 led to downregulated miR-34a and increased methylation of miR-34a gene. In addition, overexpression of PSMG3-AS1 reduced the inhibitory effects of miR-34a on GBM cell proliferation. In conclusion, overexpression of PSMG3-AS1 distinguishes GBM patients from patients with sarcoidosis, and PSMG3-AS1 may promote GBM cell proliferation by downregulating miR-34a through methylation.

Association of ERCC gene polymorphism with osteosarcoma risk.

BACKGROUND: The relationship between ERCC gene polymorphism and osteosarcoma risk / overall survival of osteosarcoma is still conflicting, and this meta-analysis was performed to assess these associations. MATERIAL AND METHODS: The association studies were identified from PubMed, and eligible reports were included and calculated using meta-analysis method. RESULTS: Four studies were included for the association of ERCC gene polymorphism with osteosarcoma risk, and nine studies were recruited into this meta-analysis for the relationship between ERCC gene polymorphism and overall survival of osteosarcoma. The meta-analysis indicated that ERCC1 rs3212986 (8092 C>A) gene polymorphism, ERCC1 rs11615 (19007 T>C) gene polymorphism, ERCC2 rs1799793 (A>G) gene polymorphism, ERCC2 rs13181 (Lys751Gln) gene polymorphism were not associated with osteosarcoma risk. ERCC1 rs2298881 (C>A) gene polymorphism, ERCC1 rs3212986 (8092 C>A) gene polymorphism, ERCC1 rs11615 (19007 T>C) gene polymorphism, ERCC2 rs1799793 (Asp312Asn) gene polymorphism were not associated with overall survival of osteosarcoma. Interestingly, ERCC2 rs13181 A allele and GG genotype were associated with overall survival of osteosarcoma, but AA genotype not (A allele: OR = 0.78, 95% CI: 0.65-0.93, P = 0.007; GG genotype: OR = 1.32, 95% CI: 1.05-1.65, P = 0.02; AA genotype: OR = 0.69, 95% CI: 0.45-1.04, P = 0.08). CONCLUSION: ERCC2 rs13181 A allele and GG genotype were associated with overall survival of osteosarcoma.

Association of X-ray cross-complementing group 3 Thr241Met gene polymorphism with osteosarcoma risk and its development and prognosis.

AIM OF STUDY: The relationship between X-ray cross-complementing group 3 (XRCC3) Thr241Met gene polymorphism and osteosarcoma risk and its development and prognosis is still debated. This meta-analysis was performed to assess these associations. MATERIALS AND METHODS: The association studies were identified from PubMed, and eligible reports were included and calculated using meta-analysis method. RESULTS: Interestingly, all the included studies were from Asian population. The meta-analysis indicated that XRCC3 Thr241Met gene polymorphism was associated with osteosarcoma risk (T allele: Odds ratio [OR] =1.57, 95% confidence interval [CI]: 1.25-1.98, P = 0.0001; TT genotype: OR = 2.23, 95% CI: 1.40-3.57, P = 0.0008; CC genotype: OR = 0.69, 95% CI: 0.54-0.87, P = 0.002). However, XRCC3 Thr241Met CC genotype was not associated with Enneking stage, tumor location, and tumor metastasis. CONCLUSION: XRCC3 Thr241Met gene polymorphism was associated with osteosarcoma risk, but XRCC3 Thr241Met CC genotype was not associated with Enneking stage, tumor location, and tumor metastasis.

Platelet-activating factor receptor activation promotes prostate cancer cell growth, invasion and metastasis via ERK1/2 pathway.

Platelet-activating factor (PAF) and its receptor (PAFR), have been reported to participate in many cellular processes of cancer. However, little is known about their function in prostate cancer. In the present study, we found that PAFR was overexpressed in prostate cancer cells. PAF stimulation dose-dependently promoted the invasion, migration and growth of prostate cancer cells in vitro, while knockdown of PAFR inhibited the effect of PAF on prostate cancer cells. We further found that PAFR promoted prostate cancer cell growth and metastasis in vivo. Moreover, we found that PAFR activation increased MMP-3 expression and decreased E-cadherin expression of prostate cancer cells in vitro and in vivo. Finally, we found that PAFR time-dependently induced activation of ERK1/2, and ERK1/2 pathway contributed to PAFR-mediated prostate cancer cell invasion, migration and growth. Together, our findings demonstrate that PAFR can activate ERK1/2 pathway, and subsequently increase MMP-3 expression and decrease E-cadherin expression, which finally promote prostate cancer cell growth, invasion and metastasis. Thus, PAFR may act as a potential target for therapeutic use of prostate cancer.

[Effects of ursolic acid in ameliorating insulin resistance in liver of KKAy mice via peroxisome proliferator-activated receptors α and γ].

OBJECTIVE: To explore the effects and mechanism of ursolic acid in improving hepatic insulin resistance in KKAy mice with spontaneous type 2 diabetes. METHODS: Thirty-five KKAy mice were divided into five groups according to the randomized block design, namely, control, rosiglitazone, fenofibrate, and high- and low-dose ursolic acid groups with seven mice in each group. C57BL/6J mice were used as the normal control group. At the end of the 4th week, free fatty acid (FFA), tumor necrosis factor-α (TNF-α) and adiponectin contents in serum were detected by enzyme-linked immunosorbent assay; the protein expressions of phosphoenolpyruvate carboxykinase (PEPCK), insulin receptor substrate-2 (IRS-2) and glucose transport factor-2 (GLUT-2) were detected by Western blot method; the mRNA expressions of PEPCK, IRS-2 and GLUT-2 were detected by real-time polymerase chain reaction; the expressions of peroxisome proliferator-activated receptor α (PPARα) and peroxisome proliferator-activated receptor γ (PPARγ) in liver tissue were detected by immunohistochemical method. RESULTS: After four weeks of intervention, the contents of FFA, TNF-α and adiponectin in serum of the high-dose ursolic acid group had changed, showing statistically significant difference compared to those of the control group (P<0.01); high dose of ursolic acid had depressant effect on the expressions of PEPCK protein and PEPCK mRNA (P<0.01); low dose of ursolic acid depressed the expression of PEPCK mRNA and induced phosphorylation of IRS-2 in the liver (P<0.05); both high and low dose of ursolic acid improved the expression of PPARα in the liver (P<0.01). CONCLUSION: The effects of ursolic acid in improving hepatic insulin resistance in KKAy mice with spontaneous type 2 diabetes may be closely related to affecting the contents of FFA, TNF-α and adiponectin, improving the expression of PPARα protein, regulating transcription of PEPCK protein and inducing phosphorylation of IRS-2.