Efficacy and Safety of Hepatic Arterial Infusion Therapy with Cinobufacini in Advanced Hepatocellular Carcinoma with Macrovascular Invasion: A Retrospective Cohort Study.

Background: The presence of macrovascular invasion (MVI) is associated with poor prognosis in advanced hepatocellular carcinoma (HCC). This study aims to evaluate the efficacy and safety of Cinobufacini therapy via hepatic arterial infusion (HAI) in advanced HCC patients with MVI. Methods: The clinical records of 130 consecutive patients with unresectable advanced HCC and MVI who had received Cinobufacini or cisplatin plus 5-fluorouracil (CF) treatment via HAI were retrospectively analyzed. The therapeutic efficacy, overall survival (OS), progression-free survival (PFS), and adverse events were compared between the two treatment groups. Results: The Cinobufacini group demonstrated significant curative effects on treatment via HAI compared with the CF group, including the objective response rate (44.9% vs 27.9%, P=0.048), the median OS (14.8 months vs 11.1 months, P=0.010), and the median PFS (10.3 months vs 6.0 months, P=0.006). Result in subgroup analysis of portal vein invasion grade supported the efficacy in Cinobufacini treatment, especially in the median OS of Vp1-2 (18.3 months vs 14.3 months, P=0.043) and Vp3 (15.0 months vs 11.4 months, P=0.046), as well as the median PFS of Vp1-2 (14.8 months vs 10.2 months, P=0.028) and Vp3 (10.8 months vs 6.6 months, P=0.033) compared with CF treatment. Cox proportional hazards model and forest plot analysis of factors confirmed the survival benefit from HAI with Cinobufacini over CF (hazard ratio [HR], 0.61; 95% CI: 0.40-0.91; P=0.010). Multivariable analysis identified portal vein invasion grade (Vp4; HR, 1.78; 95% CI: 1.03-2.16; P=0.032) and AFP (>1000; HR, 1.61; 95% CI: 1.08-1.91; P=0.039) as the independent factors for prognosis. Moreover, the total incidence of adverse events in the Cinobufacini group was significantly lower than in the CF group (60.9% vs 82.0%, P=0.009). Conclusion: Cinobufacini therapy via HAI is a viable strategy for curing advanced HCC with MVI, due to prolonged survival and a superior safety profile.

Relationship between indices of circulating blood cells and bone homeostasis in osteoporosis.

Bone development have been shown to play an important role in regulating hematopoiesis as one major component of bone marrow microenvironment. Recent studies support the notion that there is an intricate relationship between hematopoiesis and bone homeostasis, however, little is known about the alterations in the hematopoietic lineages in pathologic conditions. Using various osteoporotic mouse models, we show here that bone microarchitecture abnormalities alter parameters of peripheral blood cells. The level of white blood cells is dynamics and negatively correlated with bone mineral density during the progression of osteoporosis. Furthermore, our clinical data confirm that osteoporosis is associated with abnormal circulating blood cell counts. These results demonstrated a causal link that osteoporosis is accompanied by the altered circulating blood cells, supporting the idea of a close interplay between hematopoiesis and bone homeostasis. Our study would propose that routine complete blood count might be applied as a potential diagnostic and putative marker for osteoporosis.

Irigenin alleviates angiotensin II-induced oxidative stress and apoptosis in HUVEC cells by activating Nrf2 pathway.

Endothelial dysfunction is closely related to various cardiovascular diseases. Oxidative stress and apoptosis are involved in the progress of endothelial dysfunction. Irigenin (IR) has antioxidative properties. We investigated IR as a novel therapy for angiotensin II (Ang II)-induced endothelial dysfunction and explored the potential mechanisms of IR. After human umbilical vein endothelial cell lines (HUVECs) were treated with Ang II (100, 200, 300 and 400 nmol/L) alone, IR (2.5, 5, 10, 20 and 40 µmol/L) alone or Ang II plus IR for 24 h, HUVECs viability, lactate dehydrogenase (LDH), apoptosis, oxidative stress, apoptosis-related protein and nuclear factor E2-related factor 2 (Nrf2) levels were detected by Cell Counting Kit (CCK)-8 assay, enzyme-linked immunosorbent assay, flow cytometry and western blot. Transfection rate of Nrf2 was detected by western blot. In the next rescue experiment, we used silent Nrf2 (siNrf2) to verify the previous experimental results. Different concentrations' Ang II repressed HUVECs viability and increased LDH release, and different concentrations' IR did not affect HUVECs viability or LDH release. Furthermore, IR elevated cell viability and Nrf2 level, inhibited LDH release, apoptosis, oxidative stress and apoptosis-related protein levels in Ang II-induced HUVECs. More important, siNrf2 suppressed the expression of Nrf2, and siNrf2 abrogated the protective effect of IR on Ang II-induced Nrf2 expression, cell viability, LDH activity, oxidative stress generation and apoptosis-related protein in HUVECs. IR protected HUVECs from Ang II-induced oxidative stress and apoptosis injury by activating Nrf2 pathway.

Hypoxia promotes the migration and invasion of human hepatocarcinoma cells through the HIF-1α-IL-8-Akt axis.

BACKGROUND: Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third most common cause of cancer-related death worldwide. The 5-year survival rate remains low despite considerable research into treatments of HCC, including surgery, radiotherapy and chemotherapy. Many mechanisms within HCC still require investigation, including the influence of hypoxia, which has a crucial role in many cancers and is associated with metastasis. Hypoxia inducible factor-1α (HIF-1α) is known to regulate the expression of many chemokines, including interleukin-8 (IL-8), which is associated with tumor metastasis. Although many studies have reported that HIF-1α is associated with HCC migration and invasion, the underlying mechanisms remain unknown. METHODS: The expression level of HIF-1α was determined in HCC cells. The correlation of IL-8 and HIF-1α expressions was assessed via knockdown of HIF-1α. HCC cells were also used to assess the influence of HIF-1α on HCC cell migration and invasion. LY294002, an inhibitor of the Akt pathway, was used to confirm the associated signaling pathways. RESULTS: We observed a significant attenuation of cell migration and invasion after silencing of HIF-1α. Exogenously expressing IL-8 restored migration and invasion. Akt was found to be involved in this process. CONCLUSION: Hypoxia promotes HCC cell migration and invasion through the HIF-1α-IL-8-Akt axis.

Metastasis-Associated Protein 1 Is Involved in Angiogenesis after Transarterial Chemoembolization Treatment.

BACKGROUND: Transarterial chemoembolization (TACE), a well-established treatment for unresectable hepatocellular carcinoma (HCC), blocks the arterial blood supply to the tumor, which can be short-lived as development of collateral neovessels, leading to the failure of treatment. Metastasis-associated protein 1 (MTA1) is involved in development of tumors and metastases. However, the role of MTA1 in angiogenesis is still obscure. METHODS: We detected the expression of MTA1 and hypoxia-inducible factor-1α (HIF-1α) and microvessel density (MVD) value in liver tumor tissues and tumor periphery before and after TACE treatment. Hepatocellular carcinoma cell line HepG2, tube formation assay, and chorioallantoic membrane (CAM) assay were applied to explore the mechanism of MTA1 in angiogenesis. RESULTS: We found that expression of MTA1 increased after TACE treatment, especially in tumor periphery, which was accompanied by markedly elevated MVD value, indicating a significant correlation between MTA1 and MVD value. Moreover, MTA1 contributed to neovascularization of residual tumors. Cellular experiments further revealed that MTA1 increased the stability and the expression of HIF-1α, and overexpression of MTA1 enhanced tube formation and neovessels of chick embryos. CONCLUSIONS: MTA1 is an active angiogenic regulator; our results shed light on better understanding in neovascularization, which are helpful to predict prognosis of TACE, and provide evidences for intervention to improve therapeutic effects on HCC.

Dialysis methods may affect carotid intima-media thickness in Chinese end-stage renal disease patients.

Atherosclerosis is the most common cause of cardiovascular morbidity in end-stage renal disease (ESRD) patients and carotid intima-media thickness (IMT) is an early independent predictor of atherosclerosis. The aim of this study is to compare the continuous ambulatory peritoneal dialysis (CAPD) and the maintenance hemodialysis (MHD) for carotid IMT in Chinese ESRD patients. A total of 72 CAPD patients, 92 MHD patients, and 50 age- and sex-matched healthy controls were included. Dialysis patients were divided into five subgroups according to dialysis duration: 3-6, 7-12, 13-59, 60-119, and 120-179 months. Carotid IMT and carotid plaques were detected for each patient. The carotid IMT and total plaque detection rate in the CAPD and MHD groups were considerably higher than in the healthy control group (p < 0.01). No significant difference was found in the carotid IMT and total plaque detection rate between the CAPD group and the MHD group (p > 0.05). However, after stratification by dialysis duration, the total carotid IMT in the CAPD subgroup was higher than in the MHD subgroup in dialysis duration of 60-119 and 120-179 months (p < 0.05), and there was no significant difference in the total plaque detection rate between the CAPD and MHD subgroups in the same dialysis duration (p > 0.05). Our study showed that both CAPD and MHD affect carotid IMT in Chinese ESRD patients, and the degree of atherosclerosis in CAPD patients might be higher than that in MHD patients after 5 years of dialysis.

IGF-I (CA) repeat polymorphisms and risk of cancer: a meta-analysis.

Insulin-like growth factor-I modulates cell growth and survival, and is thought to be important in tumor development. A (CA)19 repeat polymorphism in the promoter region of IGF-I gene that may affect transcription activity has been implicated as a risk factor for cancer, but individual studies have been inconclusive or controversial. Therefore, we performed a meta-analysis of 17 studies with IGF-I (CA)19 repeat genotyping on 8,799 patients and 13,901 controls. There were seven studies with prostate cancer (2,307 cases; 2,622 controls), seven studies with breast cancer (3,533 cases; 7,771 controls), and three studies with colorectal cancer (2,959 cases; 3,508 controls). Overall, the random effects odds ratio (OR) for the (CA)19 versus non-(CA)19 allele was 1.03 [95% confidence interval (CI), 0.95-1.11], with some between-study heterogeneity (P < 0.0001). There was no suggestion of an overall effect either in recessive or dominant modeling of (CA)19 allele effects, and the comparison of (CA)19 homozygosity versus non-(CA)19 homozygosity also showed no differential susceptibility to cancer (OR, 0.99; 95% CI, 0.84-1.16). No effect of (CA)19 was seen in subjects of breast cancer (seven comparisons, OR = 1.03; 95% CI, 0.90-1.17, P = 0.005 for heterogeneity), prostate cancer (seven comparisons, OR = 1.08; 95% CI, 0.88-1.27; P = 0.0002 for heterogeneity) and colorectal cancer (three comparisons, OR = 0.96; 95% CI, 0.89-1.03, P = 0.36, no significant between-study heterogeneity). There was also no evidence that the (CA)19 allele associated with the risk of cancer in Caucasians and Asians. The meta-analysis shows that this (CA)19 repeat polymorphism is unlikely to be a major determinant of susceptibility to cancer on a wide population basis. However, a larger single study is required to further evaluate the association IGF-I (CA)19 polymorphisms and the cancer risk in a specific population.