Genetic Polymorphisms in NLRP3 Inflammasome-Associated Genes in Patients with B-Cell Non-Hodgkin's Lymphoma.

PURPOSE: The role of NLRP3 inflammasome in the progression of many diseases has been increasingly recognized. However, the function of this molecular assembly in the development and progression of B-cell non-Hodgkin's lymphoma remains unclear. PATIENTS AND METHODS: In this study, we investigated the polymorphisms in the NLRP3 inflammasome associated genes in 281 patients with B-cell non-Hodgkin's lymphoma and 385 age- and gender-matched healthy controls. RESULTS: We found that IL-18 (rs1946518) and NFκB-94 ins/del (rs28362491) contributed to susceptibility to B-cell non-Hodgkin's lymphoma. Specifically, the allele "G" in IL-18 (rs1946518) and allele "ins" in NFκB-94 ins/del (rs28362491) were significantly associated with the risk of disease. The AA genotype of CARD8 (rs2043211) and the higher level of serum lactate dehydrogenase (LDH) led to statistically poorer B-cell non-Hodgkin's lymphoma survival. Less frequent genotype TT of CARD8 (rs2043211) was observed in patients with higher LDH level, clinical stages III-IV of disease, and IPI 3-5, although the relationship did not reach statistical significance. However, IPI is an independent prognostic factor for B-cell non-Hodgkin's lymphoma. CONCLUSION: IL-18 (rs1946518) and NFκB-94 ins/del (rs28362491) gene polymorphisms appear to be the factors influencing the risk of B-cell non-Hodgkin's lymphoma. CARD8 (rs2043211) polymorphisms are important factors for the survival of patients with this disease.

Ubenimex Reverses MDR in Gastric Cancer Cells by Activating Caspase-3-Mediated Apoptosis and Suppressing the Expression of Membrane Transport Proteins.

Gastric cancer (GC) is one of the most malignant tumors, accounting for 10% of deaths caused by all cancers. Chemotherapy is often necessary for treatment of GC; the FOLFOX regimen is extensively applied. However, multidrug resistance (MDR) of GC cells prevents wider application of this treatment. Ubenimex, an inhibitor of CD13, is used as an immune adjuvant to treat hematological malignancies. Here, we demonstrate that CD13 expression positively correlates with MDR development in GC cells. Moreover, Ubenimex reverses the MDR of SGC7901/X and MKN45/X cells and enhances their sensitivity to FOLFOX, in part by decreasing CD13 expression, which is accompanied by downregulation of Bcl-xl, Bcl-2, and survivin expression; increased expression of Bax; and activation of the caspase-3-mediated apoptotic cascade. In addition, Ubenimex downregulates expression of membrane transport proteins, such as P-gp and MRP1, by inhibiting phosphorylation in the PI3K/AKT/mTOR pathway to increase intracellular accumulations of 5-fluorouracil and oxaliplatin, a process for which downregulation of CD13 expression is essential. Therefore, the present results reveal a previously uncharacterized function of CD13 in promoting MDR development in GC cells and suggest that Ubenimex is a candidate for reversing the MDR of GC cells.

Ubenimex induces autophagy inhibition and EMT suppression to overcome cisplatin resistance in GC cells by perturbing the CD13/EMP3/PI3K/AKT/NF-κB axis.

Cisplatin (CDDP)-based chemotherapy is a standard treatment for gastric cancer (GC). However, chemoresistance is a major obstacle for CDDP application. Exploring underlying mechanisms of CDDP resistance development in GC and selecting an effective strategy to overcome CDDP resistance remain a challenge. Here, we demonstrate that a transmembrane ectoenzyme, CD13, endows GC patients with insensitivity to CDDP and predicts an undesirable prognosis in GC patients with CDDP treatment. Similarly, CD13 expression is positively related with CDDP resistance in GC cells. A CD13 inhibitor, Ubenimex, reverses CDDP resistance and renders GC cells sensitivity to CDDP, for which CD13 reduction is essential, and epithelial membrane protein 3 (EMP3) is a putative target downstream of CD13. Furthermore, Ubenimex decreases EMP3 expression by boosting its CpG island hypermethylation for which CD13 down-regulation is required. In addition, EMP3 is a presumptive modifier by which CD13 exerts functions in the phosphoinositol 3-kinase/protein kinase B (PI3K/AKT) pathway. Ubenimex inhibits the activation of the CD13/EMP3/PI3K/AKT/NF-κB pathway to overcome CDDP resistance in GC cells by suppressing autophagy and epithelial-mesenchymal transition (EMT). Therefore, CD13 is a potential indicator of CDDP resistance formation, and Ubenimex may serve as a potent candidate for reversing CDDP resistance in GC.

BRAF(V600E) mutation is not a positive predictor for distant metastasis in sporadic papillary thyroid carcinoma.

BACKGROUND: BRAF(V600E) mutation is correlated with local aggressive clinicopathological features in papillary thyroid carcinoma; yet the relationship between this genetic variation and distant papillary thyroid carcinoma metastasis was unclear. This study aimed to investigate whether BRAF(V600E) is predictive for distant metastasis in the Chinese population. METHODS: One hundred and seven patients with papillary thyroid carcinoma were enrolled in this study, including 43 patients with distant metastasis and 64 patients without. Quantitative real-time polymerase chain reaction was used to detect BRAF(V600E) mutation, while immunohistochemistry was performed to detect vascular endothelial growth factor (VEGF) expression. The associations between distant metastasis and BRAF(V600E) mutation, and VEGF expression as well as local clinicopathological factors were determined. RESULTS: A total of 28.6% of the patients in the distant metastasis group harbored BRAF(V600E) mutation, which was significantly lower than in the without distant metastasis group (68.8%, P < 0.001). BRAF(V600E) mutation was negatively correlated with positive VEGF expression (P = 0.001). Furthermore, 52.2% of the patients with distant metastasis exhibited VEGF expression, compared with 25.0% of those without. Higher levels of VEGF expression were also observed in the distant metastasis group. Tumor size, extra-thyroid invasion, and BRAF(V600E) mutation were independent predictors for distant metastasis according to multivariate analysis (odds ratios were 2.8, 12.4, and 0.3; 95% CI 1.483-5.334, and 2.950-52.407, 0.100-0.890; P = 0.002, 0.001, and 0.030, respectively). BRAF(V600E) mutation was negatively correlated with distant metastasis in adult subgroup analysis (P = 0.005) but was not an independent parameter. CONCLUSIONS: BRAF(V600E) mutation is predictive for distant metastasis in papillary thyroid carcinoma but not positively. VEGF may be involved in the pathogenesis of distant metastasis.

[Invasive capacity of differentiated thyroid carcinoma in pediatric and adolescent patients].

OBJECTIVE: To summarize the invasion features of differentiated thyroid carcinoma (DTC) in pediatric and adolescent patients. METHODS: The clinical data of 32 DTC cases (≤18 years old) were retrospectively analyzed for the invasive capacity of DTC in terms of age and gender. RESULTS: Bilateral (P=0.023), multifoci (P=0.037), and extrathyroid invasions (P=0.041) were more often in patients younger than 12 years old. CONCLUSION: DTC in pediatric and adolescent patients tend to have a more aggressive pattern, especially in patients younger than 12 years.