Delayed Contrast Enhancement in Magnetic Resonance Imaging and Vascular Morphology of Primary Diffuse Large B-Cell Lymphoma (DLBCL) of the Central Nervous System (CNS): A Retrospective Study.

BACKGROUND This study aimed to compare the magnetic resonance imaging (MRI) findings of primary diffuse large B-cell lymphoma (DLBCL) of the central nervous system (CNS) with delayed contrast enhancement and histological microvessel density (MVD). T1-weighted and T2-weighted contrast-enhanced and non-enhanced brain imaging were used. CNS lymphoma tissue was evaluated using primary antibodies to endothelial cells and smooth muscle cells, and histochemical staining for reticulin fibers and basement membrane, which allowed quantification of the MVD. MATERIAL AND METHODS Twenty-one patients with histologically confirmed primary DLBCL of the CNS underwent pre-contrast-enhanced and postcontrast-enhanced MRI. Histology of the CNS lymphoma tissue included immunohistochemical staining with antibodies to CD34 for vascular endothelial cells and alpha smooth muscle actin (ASMA) for vascular smooth muscle cells, and histochemical staining included periodic acid-Schiff (PAS) and silver staining for reticulin fibers to evaluate microvessel density (MVD). RESULTS In primary DLBCL of the CNS, a positive correlation was found between the degree of necrosis and the size of the lymphoma (r=0.546, P=0.01). Delayed imaging enhancement was significantly correlated with the number of mature vessels, MVD, basement membrane, and reticulin fibers (r=0.593, 0.466, 0.446 and 0.497, respectively). Standardized ß regression coefficient analysis showed that the MVD, PAS-positive structures, the number of mature vessels, and reticulin fibers, were significantly associated with delayed enhancement on MRI (ß values, 0.425, 0.409, 0.295, and 0.188, respectively). CONCLUSIONS In primary DLBCL of the CNS, delayed imaging enhancement on MRI may be due to reduced neovascularization and vascular infiltration by lymphoma cells.

Blocking autophagy enhances the apoptosis effect of bufalin on human hepatocellular carcinoma cells through endoplasmic reticulum stress and JNK activation.

Bufalin extracts are a part of traditional Chinese medicine, Chansu. In the current study, we investigated the effect of bufalin on the proliferation of the human hepatocellular carcinoma (HCC) cell lines, Huh-7 and HepG-2, and explored the therapeutic potential of the drug. Our results demonstrated that bufalin markedly inhibited cell proliferation and promoted apoptosis in the Huh-7 and HepG-2 cells in vitro. The underlying mechanism of the bufalin-induced apoptosis was the induction of endoplasmic reticulum (ER) stress via the IRE1-JNK pathway. In addition, during the ER stress response, the autophagy pathway, characterized by the conversion of LC3-I to LC3-II, was activated, resulting in increased Beclin-1 protein levels, decreased p62 expression and stimulation of autophagic flux. Our data supported the pro-survival role of bufalin-induced autophagy when the autophagy pathway was blocked with specific chemical inhibitors; the involvement of the IRE1 pathway in the ER stress-induced autophagy was also demonstrated when the expression of IRE1 and CHOP was silenced using siRNA. These data indicate that combining bufalin with a specific autophagy inhibitor could be a promising therapeutic approach for the treatment of HCC.

Growth inhibition effect of HMME-mediated PDT on hepatocellular carcinoma HepG2 cells.

Photodynamic therapy (PDT) is considered a promising new strategy for liver cancer treatment. Three elements of PDT--optical output power, irradiation time, and photosensitizer concentration--play important roles in promoting cell death. This research aimed to characterize the effects of hematoporphyrin monomethyl ether (HMME)-based PDT on hepatocellular carcinoma cells HepG2 and thus elucidate the relationship between cell death and the three elements mentioned earlier. Furthermore, in this study, we present a parameter that represents the cumulative effects of these elements. The accumulation of HMME in HepG2 cells was observed by fluorescence microscopy. The absorption spectrum of HMME was detected using fluorescence spectral analysis. The viability of the treated cells was determined using the MTT assay, and cell apoptosis was evaluated using flow cytometry. We found that the fluorescence intensity was positively correlated with the incubation time for up to 2 h. The cell growth inhibition rate was significantly high and gradually increased with increasing concentrations of HMME or increasing light intensity, which was calculated as optical output power × irradiation time. Further analysis revealed an e-exponential decay of the cell survival rate to the product of the HMME concentration and the light intensity. We defined the product as parameter B (B = optical output power × irradiation time × HMME concentration). Similarly, the rate of cell apoptosis showed roughly e-exponential growth to parameter B. In conclusion, HMME-mediated PDT can significantly kill HepG2 cells, and the killing effect was related to the cumulative effects of the optical output power, the irradiation time, and the HMME concentration. Therefore, the newly defined parameter B, as a comprehensive physical quantity, may be of great significance for the regulation of light and photosensitizer according to patient-specific conditions in clinical practice.

Mapping the immunological battlefield in gastric cancer: prognostic implications of an immune gene expression signature.

BACKGROUND: Gastric cancer (GC) is a heterogeneous malignancy with variable clinical outcomes. The immune system has been implicated in GC development and progression, highlighting the importance of immune-related gene expression patterns and their prognostic significance. OBJECTIVE: This study aimed to identify differentially expressed immune-related genes (DEIRGs) and establish a prognostic index for GC patients using comprehensive bioinformatic analyses. METHODS: We integrated RNA sequencing data from multiple databases and identified DEIRGs by overlapping differentially expressed genes with immune-related genes. Functional enrichment analysis was performed to uncover the biological processes and signaling pathways associated with DEIRGs. We conducted a Weighted Gene Co-expression Network Analysis (WGCNA) to identify key gene modules related to with GC. Cox regression analysis was conducted to determine independent prognostic DEIRGs for overall survival prediction. Based on these findings, we developed an immune-related gene prognostic index (IRGPI) based on these findings. The prognostic value of the IRGPI was validated using survival analysis and an independent validation cohort. Functional enrichment analysis, gene mutation analysis, and immune cell profiling were performed to gain insights into the biological functions and immune characteristics associated with the IRGPI-based subgroups. RESULTS: We identified 493 DEIRGs significantly enriched in immune-related biological processes and signaling pathways associated with GC. WGCNA analysis revealed a significant module (turquoise module) associated with GC, revealing potential therapeutic targets. Cox regression analysis identified RNASE2, CGB5, CTLA4, and DUSP1 as independent prognostic DEIRGs. The IRGPI, incorporating the expression levels of these genes, demonstrated significant prognostic value in predicting overall survival. The IRGPI-based subgroups exhibited distinct biological functions, genetic alterations, and immune cell compositions. CONCLUSION: Our study identified DEIRGs and established a prognostic index (IRGPI) for GC patients. The IRGPI exhibited promising prognostic potential and provided insights into GC tumor biology and immune characteristics. These findings have implications for guiding therapeutic strategies.

Multivariate prognostic study on node-positive gastric cancer: is tumor size a prognostic indicator?

BACKGROUND/AIMS: We analyzed the clinicopathological factors of patients with node-positive gastric cancer, evaluated the prognostic factors associated with long-term survival and clarified the effect of tumor size on long-term survival. METHODOLOGY: The study included 591 patients who underwent curative resection for node-positive gastric cancer. Clinicopathological prognostic variables were evaluated as predictors of long-term survival by univariate and multivariate analyses. RESULTS: The 5-year survival rate was influenced by tumor size, tumor location, depth on invasion, level of lymph node metastasis, Borrmann classification, histological type, liver metastasis, peritoneal dissemination and disease stage. Of these, independent prognostic factors were depth on invasion and lymph node metastasis. Tumor size is an influence but not independent factor for the prediction of long-term survival in patients with node-positive gastric cancer. CONCLUSIONS: In patients with node-positive gastric cancer, two independent prognostic factors were depth on invasion and the status of lymph node metastasis.

A network biology approach to discover the molecular biomarker associated with hepatocellular carcinoma.

In recent years, high throughput technologies such as microarray platform have provided a new avenue for hepatocellular carcinoma (HCC) investigation. Traditionally, gene sets enrichment analysis of survival related genes is commonly used to reveal the underlying functional mechanisms. However, this approach usually produces too many candidate genes and cannot discover detailed signaling transduction cascades, which greatly limits their clinical application such as biomarker development. In this study, we have proposed a network biology approach to discover novel biomarkers from multidimensional omics data. This approach effectively combines clinical survival data with topological characteristics of human protein interaction networks and patients expression profiling data. It can produce novel network based biomarkers together with biological understanding of molecular mechanism. We have analyzed eighty HCC expression profiling arrays and identified that extracellular matrix and programmed cell death are the main themes related to HCC progression. Compared with traditional enrichment analysis, this approach can provide concrete and testable hypothesis on functional mechanism. Furthermore, the identified subnetworks can potentially be used as suitable targets for therapeutic intervention in HCC.

Impaired PI3K/Akt signal pathway and hepatocellular injury in high-fat fed rats.

AIM: to determine whether mitochondrial dysfunction resulting from high-fat diet is related to impairment of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt, also known as PKB) pathway. METHODS: rat models of nonalcoholic fatty liver were established by high-fat diet feeding. The expression of total and phosphorylated P13K and Akt proteins in hepatocytes was determined by Western blotting. Degree of fat accumulation in liver was measured by hepatic triglyceride. Mitochondrial number and size were determined using quantitative morphometric analysis under transmission electron microscope. The permeability of the outer mitochondrial membrane was assessed by determining the potential gradient across this membrane. RESULTS: after Wistar rats were fed with high-fat diet for 16 wk, their hepatocytes displayed an accumulation of fat (103.1 ± 12.6 vs 421.5 ± 19.7, P < 0.01), deformed mitochondria (9.0% ± 4.3% vs 83.0% ± 10.9%, P < 0.05), and a reduction in the mitochondrial membrane potential (389.385% ± 18.612% vs 249.121% ± 13.526%, P < 0.05). In addition, the expression of the phosphorylated P13K and Akt proteins in hepatocytes was reduced, as was the expression of the anti-apoptotic protein Bcl-2, while expression of the pro-apoptotic protein caspase-3 was increased. When animals were treated with pharmacological inhibitors of P13K or Akt, instead of high-fat diet, a similar pattern of hepatocellular fat accumulation, mitochondrial impairment, and change in the levels of PI3K, Akt, Bcl-2 was observed. CONCLUSION: high-fat diet appears to inhibit the PI3K/Akt signaling pathway, which may lead to hepatocellular injury through activation of the mitochondrial membrane pathway of apoptosis.