PURPOSE To compare the survival outcomes of neoadjuvant three-dimensional conformal radiotherapy (RT) followed by hepatectomy with hepatectomy alone in patients with hepatocellular carcinoma (HCC) and portal vein tumor thrombus (PVTT). PATIENTS AND METHODS A randomized, multicenter controlled study was conducted from January 2016 to December 2017 in patients with resectable HCC and PVTT. Patients were randomly assigned to receive neoadjuvant RT followed by hepatectomy (n = 82) or hepatectomy alone (n = 82). The modified Response Evaluation Criteria in Solid Tumors (mRECIST) guidelines were used to evaluate the therapeutic effects of RT. The primary end point was overall survival. The expression of interleukin-6 (IL-6) in patients’ serum before RT and in surgical specimens was correlated with response to RT. RESULTS In the neoadjuvant RT group, 17 patients (20.7%) had partial remission. The overall survival rates for the neoadjuvant RT group at 6, 12, 18, and 24 months were 89.0%, 75.2%, 43.9%, and 27.4%, respectively, compared with 81.7%, 43.1%, 16.7%, and 9.4% in the surgery-alone group ( P < .001). The corresponding disease-free survival rates were 56.9%, 33.0%, 20.3%, and 13.3% versus 42.1%, 14.9%, 5.0%, and 3.3% ( P < .001). On multivariable Cox regression analyses, neoadjuvant RT significantly reduced HCC-related mortality and HCC recurrence rates compared with surgery alone (hazard ratios, 0.35 [95% CI, 0.23 to 0.54; P < .001] and 0.45 [95% CI, 0.31 to 0.64; P < .001]). Increased expressions of IL-6 in pre-RT serum and tumor tissues were significantly associated with resistance to RT. CONCLUSION For patients with resectable HCC and PVTT, neoadjuvant RT provided significantly better postoperative survival outcomes than surgery alone. IL-6 may predict response to RT in these patients.
AS-IV prevents I/R-induced cardiac malfunction, maintains the integrity of myocardial structure through regulating energy metabolism. The beneficial effect of AS-IV on energy metabolism initiates during the phase of ischemia.
Background Diffuse intrinsic pontine gliomas (DIPGs) are highly lethal childhood brain tumors. Their unique genetic makeup, pathological heterogeneity, and brainstem location all present challenges to treatment. Developing mouse models that accurately reflect each of these distinct features will be critical to advance our understanding of DIPG development, progression, and therapeutic resistance. The aim of this study was to generate new mouse models of DIPG, and characterize the role of specific oncogenic combinations in DIPG pathogenesis. Methods We used in utero electroporation (IUE) to transfect neural stem cells in the developing brainstem with PiggyBac DNA transposon plasmids. Combinations of PDGFB, PdgfraD842V, or PdgfraWT, combined with dominant negative Trp53 (DNp53) and H3.3K27M expression induced fully penetrant brainstem gliomas. Results IUE enabled the targeted transfection of brainstem neural stem cells. PDGFB + DNp53 + H3.3K27M induced the rapid development of grade-IV gliomas. PdgfraD842V + DNp53 + H3.3K27M produced slower forming grade-III gliomas. PdgfraWT + DNp53 + H3.3K27M produced high and low-grade gliomas with extended latencies. PDGFB, PdgfraD842V, and PdgfraWT DIPG models display unique histopathological and molecular features found in human DIPGs. Conclusion Brainstem targeted in utero electroporation provides a rapid and flexible system to generate diverse DIPG mouse models. Using IUE to investigate mutation and pathohistological heterogeneity of DIPG will provide a valuable tool for future genetic and preclinical studies.
Increasing evidence has indicated a close association between immune infiltration in cancer and clinical outcomes. However, related research in thyroid cancer is still deficient. Our research comprehensively investigated the immune infiltration of thyroid cancer. Data derived from TCGA and GEO databases were analyzed by the CIBERSORT, ESTIMATE, and EPIC algorithms. The CIBERSORT algorithm calculates the proportions of 22 types of immune cells. ESTIMATE algorithm calculates a stromal score to represent all stromal cells in cancer. The EPIC algorithm calculates the proportions of cancer-associated fibroblasts (CAFs) and endothelial cells (ECs), which are the main components of stromal cells. We analyzed the correlation of immune infiltration with clinical characteristics and outcomes of patients. We determined that the infiltration of CD8+ T cells improved the survival of thyroid cancer patients. Overexpression of immune checkpoints was closely related to the development of thyroid cancer. In general, stromal cells were associated with the progression of thyroid cancer. Interestingly, CAFs and ECs had opposite roles in this process. In addition, the BRAFV600E mutation was related to the upregulation of immune checkpoints and CAFs and the downregulation of CD8+ T cells and ECs. Finally, we constructed an immune risk score model to predict the prognosis and development of thyroid cancer. Our research demonstrated a comprehensive panorama of immune infiltration in thyroid cancer, which may provide potential value for immunotherapy.
Although the pathogenesis of non-alcoholic fatty liver disease (NAFLD) is not completely understood, the increased influx of free fatty acids (FFAs) into the liver and the FFA-induced hepatic endoplasmic reticulum (ER) stress are two crucial pathogenic processes in the initiation and development of NAFLD. In this study we investigated the effects of astragaloside IV (AS-IV), a bioactive compound purified from Astragali Radix, on FFA-induced lipid accumulation in hepatocytes and elucidated the underlying mechanisms. Human HepG2 cells and primary murine hepatocytes were exposed to FFAs (1 mmol/L, oleate/palmitate, 2:1 ratio) with or without AS-IV for 24 h. Exposure to FFAs induced marked lipid accumulation in hepatocytes, whereas co-treatment with AS-IV (100 μg/mL) significantly attenuated this phenomenon. Notably, AS-IV (50-200 μg/mL) concentration-dependently enhanced the phosphorylation of AMPK, acetyl-CoA carboxylase (ACC) and SREBP-1c, inhibited the accumulation and nuclear translocation of mature SREBP-1 and subsequently decreased the mRNA levels of lipogenic genes including acc1, fas and scd1. AS-IV treatment also concentration-dependently attenuated FFA-induced hepatic ER stress evidenced by the reduction of the key markers, GRP78, CHOP and p-PERK. Pretreated the cells with the AMPK inhibitor compound C (20 μmol/L) greatly diminished these beneficial effects of AS-IV. Our results demonstrate that AS-IV attenuates FFA-induced ER stress and lipid accumulation in an AMPK-dependent manner in hepatocytes, which supports its use as promising therapeutics for hepatic steatosis.
Cardiotonic pills (CP) is a compound Chinese medicine widely used in China, as well as other countries, for the treatment of cardiovascular disease. However, limited data are available regarding the mechanism of action of CP on myocardial function during ischemia-reperfusion (I/R) injury. In this study, we examined the effect of CP on I/R-induced coronary microcirculatory disturbance and myocardial damage. Male Sprague-Dawley rats were subjected to left coronary anterior descending branch occlusion for 30 min followed by reperfusion with or without pretreatment with CP (0.1, 0.4, or 0.8 g/kg). Coronary blood flow, vascular diameter, velocity of red blood cells, and albumin leakage were evaluated in vivo after reperfusion. Neutrophil expression of CD18, malondialdehyde, inhibitor-kappaBalpha, myocardial infarction, endothelial expression of intercellular adhesion molecule 1, apoptosis-related proteins, and histological and ultrastructural evidence of myocardial damage were assessed after reperfusion. Pretreatment with CP (0.8 g/kg) significantly attenuated the I/R-induced myocardial microcirculatory disturbance, including decreased coronary blood flow and red blood cell velocity in arterioles, increased expression of CD18 on neutrophils and intercellular adhesion molecule 1 on endothelial cells, and albumin leakage from venules. In addition, the drug significantly ameliorated the I/R-induced myocardial damage and apoptosis indicated by increased malondialdehyde, infarct size, myocardial ultrastructural changes, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive myocardial cells, inhibitor-kappaBalpha degradation, and expression of Bcl-2, Bax, and caspase-3 in myocardial tissues. The results provide evidence for the potential role of CP in preventing microcirculatory disturbance and myocardial damage following I/R injury.
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