Radiation Therapy Changed the Second Malignancy Pattern in Rectal Cancer Survivors

Background and Objectives: Radiotherapy (RT) plays an important role in the treatment for locally advanced rectal cancer patients. It can bring radio exposure together with the survival benefit. Cancer survivors are generally at an increased risk for second malignancies, and survivors receiving RT may have higher risks than survivors not receiving RT. Whether the risk of an all-site second malignancy may increase after RT is still debated. This study aims to compare the second malignancy pattern in rectal cancer survivors after RT. Materials and Methods: The Surveillance, Epidemiology, and End Results (SEER) database was used for analysis. In total, 49,961 rectal cancer patients (20–84 years of age) were identified between 2000 and 2012 from 18 SEER registries. All patients underwent surgery. The occurrence of second malignancies diagnosed after rectal cancer diagnosis was compared in patients who received and did not receive RT. The standardized incidence ratios (SIRs) with 95% confidence intervals (CIs) were used. SEER*Stat was used to generate the 95% CIs for the SIR statistics using the exact method. Results: Of the total 49,961 patients, 5582 developed second malignancies. For all-site second primary malignancies, the age-adjusted SIRs were 1.14 (95% CI 1.1–1.18) and 1.00 (95% CI 0.96–1.04) in the no RT and RT groups, respectively. In 23,192 patients from the surgery-only group, 2604 had second malignancies, and in 26,769 patients who received RT, 2978 developed second malignancies. With respect to every site, the risk of secondary prostate cancer was significantly lower in the RT group (SIR = 0.39, 95% CI 0.33–0.46) than that in the surgery-only group (SIR = 1.04, 95% CI 0.96–1.12). Moreover, the risk of thyroid cancer was significantly higher in the RT group (SIR = 2.80, 95% CI 2.2–3.51) than that in the surgery-only group (SIR = 1.29, 95% CI 0.99–1.66). Conclusions: RT may change the second malignancy pattern in rectal cancer survivors; the risk of prostate cancer decreased, and the risk of thyroid cancer increased most significantly

The Exposure of Phosphatidylserine Influences Procoagulant Activity in Retinal Vein Occlusion by Microparticles, Blood Cells, and Endothelium

The pathogenesis of hypercoagulability in retinal vein occlusion (RVO) is largely unknown. Whether the exposure of phosphatidylserine (PS) and microparticle (MPs) release will affect procoagulant activity (PCA) in RVO needs to be investigated. Objectives. To evaluate PS expression, circulating MPs, and the corresponding PCA in RVO patients. Twenty-five RVO patients were compared with 25 controls. PS-positive cells were detected by flow cytometry. Cell-specific MPs were measured by lactadherin for PS and relevant CD antibody. We explored PCA with coagulation time, purified coagulation complex assays, and fibrin production assays. In RVO, MPs from platelets, erythrocytes, leukocyte, and endothelial cells were increased and the exposure of PS was elevated significantly when compared with controls. In addition, we showed that circulating MPs in RVO patients were mostly derived from platelets, representing about 60–70% of all MPs, followed by erythrocytes and leukocytes. Moreover, PS exposure, ECs, and MPs in RVO lead to shortened clotting time with upregulation of FXa and thrombin formation obviously. Importantly, ECs treated with RVO serum which bounded FVa and FXa explicitly suggested the damage of retinal vein endothelial cells. Furthermore, lactadherin can inhibit the combination between PS and coagulation factors by approximately 70% and then exert an anticoagulant effect. In summary, circulating MPs and exposed PS from different cells may contribute to the increased PCA in patients with RVO. Lactadherin can be used for PS detection and an anticoagulant agent

Research on Impermeability of Underwater Non-Dispersible Concrete in Saline Soil

The permeability of different strength grades of submerged non-dispersible concrete with different granulated slag admixtures in a saline soil environment simulated by different erosion solutions was investigated. The variation patterns of the chloride ion diffusion coefficient and pore characteristics were tested using NEL and MIP. The microscopic morphology of the specimens in different erosion environments and with slag doping was observed using SEM. The results showed that the impermeability of concrete in sulfate and complex salt environments was significantly reduced. The resistance of concrete to chloride ion penetration increased with the increase in strength grade, and the Cl− diffusion coefficient of C35 was 5–30% lower than those of C30 and C25 underwater non-dispersible concrete at 360 d. Meanwhile, the admixture of granulated blast-furnace slag optimized the pore size distribution and improved the matrix compactness and permeability

Dual Roles of Lactate in EGFR-TKI-Resistant Lung Cancer by Targeting GPR81 and MCT1

Lactate is critical in modeling tumor microenvironment causing chemotherapy resistance; however, the role of lactate in tyrosine kinase inhibitor (TKI) resistance has not been fully known. The aim of this study was to evaluate whether lactate could mediate TKI resistance through GPR81 and MCT1 in non-small-cell lung cancer (NSCLC). Here, we showed that lactate enhanced the cell viability and restrained erlotinib-induced apoptosis in PC9 and HCC827 cells. GPR81 and AKT expression were significantly increased with the addition of lactate, and siGPR81 reduced AKT expression resulting in a raised apoptosis rate with erlotinib treatment. Furthermore, we found that lactate also promoted MCT1 exposure, and inhibiting MCT1 with AZD3965 markedly impaired the glycolytic capacity. A significant increase of GPR81 and MCT1 expression was observed in insensitive tissues compared with sensitive ones by immunostaining in NSCLC patients. Our results indicate that lactate adopts dual strategies to promote TKI resistance in NSCLC, not only activating AKT signaling by GPR81, but also giving energy supply through MCT1-mediated input. Targeting GPR81 and MCT1 may provide new therapeutic modalities for TKI resistance in NSCLC

Procoagulant Activity of Blood and Endothelial Cells via Phosphatidylserine Exposure and Microparticle Delivery in Patients with Diabetic Retinopathy

Background/Aims: The mechanisms for thrombosis in diabetic retinopathy (DR) are complex and need to be further elucidated. The purpose of this study was to test phosphatidylserine (PS) exposure on microparticles (MPs) and MP-origin cells from the circulation and to analyze cell-/MP-associated procoagulant activity (PCA) in DR patients. Methods: PS-positive MPs and cells from healthy controls (n = 20) and diabetic patients (n = 60) were analyzed by flow cytometry and confocal microscopy. Clotting time and purified coagulation complex assays were used to measure PCA. Results: PS exposure on platelets and monocytes was higher in proliferative DR (PDR) patients than in non-PDR patients or controls. The highest levels of MPs (derived from platelets [30%], erythrocytes [13%], leukocytes [28%], and endothelial cells [10%]) were found in patients with PDR. In addition, PS exposure on blood cells and shed MPs in DR patients led to significantly increased FXa and FIIa generation, fibrin formation, and markedly shortened coagulation time. Moreover, lactadherin reduced 70% of PCA by blocking PS, while an anti-tissue factor antibody had a smaller effect. Conclusion: Our results confirmed that PCA in DR patients may be partly ascribed to PS exposure and MP release from blood and endothelial cells. Lactadherin may act as an efficient anticoagulant factor in this process

Prognostic implications and procoagulant activity of phosphatidylserine exposure of blood cells and microparticles in patients with atrial fibrillation treated with pulmonary vein isolation

The present study aimed to evaluate the procoagulant effects of phosphatidylserine (PS) exposure on blood cells and microparticles (MPs), and examine its role in predicting early recurrence atrial fibrillation (ERAF) in patients with atrial fibrillation (AF) treated with pulmonary vein isolation (PVI). Blood samples were obtained from 40 healthy controls and 56 patients with AF at baseline (prior to PVI), and 0, 1 h, 1 day, 3 days and 7 days following PVI. The exposure of PS (PS+) to blood cells (platelets, erythrocytes and leukocytes) and MPs was detected using flow cytometry. The procoagulant activity was evaluated by coagulation time, and the formation of factor Xa (FXa) and thrombin. In addition, independent factors associated with PS+ blood cells and MPs, and significant predictors of ERAF following PVI were investigated by statistical analyses. The numbers of PS+ blood cells and MPs were significantly increased by PVI (P355/µl were identified as independent predictors of ERAF (P<0.05). The increased numbers of PS+ platelets, erythrocytes, leukocytes and MPs contributed to the procoagulant state of AF, and hs-CRP and EMPs were able to predict ERAF following PVI

MiR-29a-deficiency causes thickening of the basilar membrane and age-related hearing loss by upregulating collagen IV and laminin

Age-related hearing loss (ARHL) is the most common sensory degenerative disease and can significantly impact the quality of life in elderly people. A previous study using GeneChip miRNA microarray assays showed that the expression of miR-29a changes with age, however, its role in hearing loss is still unclear. In this study, we characterized the cochlear phenotype of miR-29a knockout (miR-29a–/–) mice and found that miR-29a-deficient mice had a rapid progressive elevation of the hearing threshold from 2 to 5 months of age compared with littermate controls as measured by the auditory brainstem response. Stereocilia degeneration, hair cell loss and abnormal stria vascularis (SV) were observed in miR-29a–/– mice at 4 months of age. Transcriptome sequencing results showed elevated extracellular matrix (ECM) gene expression in miR-29a–/– mice. Both Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis revealed that the key differences were closely related to ECM. Further examination with a transmission electron microscope showed thickening of the basilar membrane in the cochlea of miR-29a–/– mice. Five Col4a genes (Col4a1-a5) and two laminin genes (Lamb2 and Lamc1) were validated as miR-29a direct targets by dual luciferase assays and miR-29a inhibition assays with a miR-29a inhibitor. Consistent with the target gene validation results, the expression of these genes was significantly increased in the cochlea of miR-29a–/– mice, as shown by RT-PCR and Western blot. These findings suggest that miR-29a plays an important role in maintaining cochlear structure and function by regulating the expression of collagen and laminin and that the disturbance of its expression could be a cause of progressive hearing loss

miR-181b/Notch2 overcome chemoresistance by regulating cancer stem cell-like properties in NSCLC

Abstract Background Lung cancer stem cells have the ability to self-renew and are resistant to conventional chemotherapy. MicroRNAs (miRNAs) regulate and control the expression and function of many target genes; therefore, miRNA disorders are involved in the pathogenesis of human diseases, such as cancer. However, the effects of miRNA dysregulation on tumour stemness and drug resistance have not been fully elucidated. miR-181b has been reported to be a tumour suppressor miRNA and is associated with drug-resistant non-small cell lung cancer. Methods Cancer stem cell (CSC)-like properties were tested by a cell proliferation assay and flow cytometry; miR-181b expression was measured by real-time PCR; and Notch2 and related proteins were detected by Western blotting and immunohistochemistry. A mouse xenograft model was also established. Results In this study, we found that ectopic miR-181b expression suppressed cancer stem cell properties and enhanced sensitivity to cisplatin (DDP) treatment by directly targeting Notch2. miR-181b could inactivate the Notch2/Hes1 signalling pathway. In addition, tumours from nude mice treated with miR-181b were significantly smaller than tumours from mice treated with control agomir. Decreased miR-181b expression and increased Notch2 expression were observed to have a significant relationship with overall survival (OS) and CSC-like properties in non-small cell lung cancer (NSCLC) patients. Conclusions This study elucidates an important role of miR-181b in the regulation of CSC-like properties, suggesting a potential therapeutic target for overcoming drug resistance in NSCLC