Anlotinib followed by transarterial chemoembolization and radiofrequency ablation is a safe and effective initial treatment for hepatocellular carcinoma patients with portal vein tumor thrombus: A retrospective case series study.

BACKGROUND: Portal vein tumor thrombus (PVTT) remains a poor prognostic factor occurring in about 10%-40% of patients with hepatocellular carcinoma (HCC) for the optimal treatment is controversial. Anlotinib is an novel small molecule inhibitor that has a broad spectrum of inhibitory activities on tumor angiogenesis and growth. However, so far, no studies have reported the use of anlotinib in the treatment of HCC patients with PVTT. Here, we evaluated the safety and efficacy of anlotinib, followed by transarterial chemoembolization (TACE) and radiofrequency ablation (RFA) for the treatment of patients with HCC and PVTT. MATERIALS AND METHODS: A total of 145 consecutive HCC patients who underwent TACE in combination with RFA were enrolled in the retrospective study. Twenty-eight patients were diagnosed with PVTT and received anlotinib as basic treatment. The adverse events (AEs) were graded according to the National Cancer Institute Common Terminology Criteria for AEs Version 4.0. Time to tumor progression (TTP) and overall survival (OS) were calculated using the Kaplan-Meier method. RESULTS: The most common toxicities related to anlotinib were pharyngalgia (53.6%), fatigue (42.9%), and hand-foot skin reaction (39.3%). The median OS was 13 months (range: 3-18 months) with 1-year OS rate of 64.3%. The median TTP was 7 months (range: 1-12 months) with 6-month rate of 46.4%. CONCLUSION: Anlotinib followed by TACE and RFA is a safe and effective initial treatment modality for HCC patients with PVTT. Anlotinib may be a promising therapeutic option for relieving and/or stabilizing HCC with PVTT.

Combined Effects of Elevated Temperature and Crude Oil Pollution on Oxidative Stress and Apoptosis in Sea Cucumber (Apostichopus japonicus, Selenka).

Currently, global climate change and oil pollution are two main environmental concerns for sea cucumber (Apostichopus japonicus) aquaculture. However, no study has been conducted on the combined effects of elevated temperature and oil pollution on sea cucumber. Therefore, in the present study, we treated sea cucumber with elevated temperature (26 °C) alone, water-accommodated fractions (WAF) of Oman crude oil at an optimal temperature of 16 °C, and Oman crude oil WAF at an elevated temperature of 26 °C for 24 h. Results showed that reactive oxygen species (ROS) level and total antioxidant capacity in WAF at 26 °C treatment were higher than that in WAF at 16 °C treatment, as evidenced by 6.03- and 1.31-fold-higher values, respectively. Oxidative damage assessments manifested that WAF at 26 °C treatment caused much severer oxidative damage of the biomacromolecules (including DNA, proteins, and lipids) than 26 °C or WAF at 16 °C treatments did. Moreover, compared to 26 °C or WAF at 16 °C treatments, WAF at 26 °C treatment induced a significant increase in cellular apoptosis by detecting the caspase-3 activity. Our results revealed that co-exposure to elevated temperature and crude oil could simulate higher ROS levels and subsequently cause much severer oxidative damage and cellular apoptosis than crude oil alone on sea cucumber.

Phenotypic and transcriptomic consequences in zebrafish early-life stages following exposure to crude oil and chemical dispersant at sublethal concentrations.

To further understand the underlying mechanisms involved in the developmental toxicity of crude oil and chemically dispersed crude oil on fish early-life stages (ELS), zebrafish (Danio rerio) embryos were exposed to GM-2 chemical dispersant (DISP), low-energy water-accommodated fractions (LEWAF), and chemically enhanced WAF (CEWAF) of Merey crude oil at sublethal concentrations for 120 h. We employed the General Morphology Score (GMS) and General Teratogenic Score (GTS) systems in conjunction with high-throughput RNA-Seq analysis to evaluate the phenotypic and transcriptomic responses in zebrafish ELS. Results showed that ΣPAHs concentrations in LEWAF and CEWAF solutions were 507.63 ± 80.95 ng·L-1 and 4039.51 ± 241.26 ng·L-1, respectively. The GMS and GTS values indicated that CEWAF exposure caused more severe developmental delay and higher frequencies of teratogenic effects than LEWAF exposure. Moreover, no significant change in heart rate was observed in LEWAF treatment, while CEWAF exposure caused a significant reduction in heart rate. LEWAF and CEWAF exposure exhibited an overt change in eye area, with a reduction of 4.0% and 25.3% (relative to the control), respectively. Additionally, no obvious impact on phenotypic development was observed in zebrafish embryo-larvae following DISP exposure. Significant changes in gene expression were detected in LEWAF and CEWAF treatments, with a total of 957 and 2062 differentially expressed genes (DEGs), respectively, while DISP exposure altered only 91 DEGs. Functional enrichment analysis revealed that LEWAF and CEWAF exposure caused significant perturbations in the pathways associated with phototransduction, retinol metabolism, metabolism of xenobiotics by cytochrome P450, and immune response-related pathways. Our results provide more valid evidence to corroborate the previous suggestion that ocular impairment is an equal or possibly more sensitive biomarker than cardiotoxicity in fish ELS exposed to oil-derived PAHs. All these findings could gain further mechanistic insights into the effects of crude oil and chemical dispersant on fish ELS.

Exposure to water-accommodated fractions of two different crude oils alters morphology, cardiac function and swim bladder development in early-life stages of zebrafish.

The present study investigated the developmental toxicity of water-accommodated fractions (WAFs) of Oman crude oil (OCO) and Merey crude oil (MCO) on zebrafish (Danio rerio) in early-life stages (ELS). Based on total petroleum hydrocarbons (TPH), LC50 values manifested that OCO WAF was 1.2-fold more lethal to zebrafish embryos than MCO WAF. As for hatching rate, EC50 value for OCO WAF was 5.7-fold lower than that for MCO WAF. To evaluate the sublethal morphological effects, semi-quantitative extended general morphological score (GMS) and general teratogenic score (GTS) systems were adopted. The GMS and GTS scores indicated that the WAFs caused remarkable developmental delay and high frequencies of malformation in a dose-dependent manner. Additionally, OCO and MCO WAFs exposure exhibited severe bradycardia (reduced heart rate) and overt reduction of stroke volume, with a concomitant decrease in the cardiac output. Meanwhile, the WAFs also induced dose-dependent down-regulated expressions of several key functional genes of excitation-contraction coupling in cardiomyocytes, including ryr2, atp2a2a, atp2a2b, ncx1h, and kcnh2. For key gene markers of swim bladder development, results showed that high dose of TPH induced significant down-regulation of hb9 and anxa5 with no obvious change of acta2, suggesting that the WAFs could affect the specification and development of epithelium and outer mesothelium of swim bladder in zebrafish ELS. A strong negative relationship between the failure of swim bladder inflation and cardiac dysfunction via cardiac output was found. All these findings provide novel insights into the complicated mechanisms of the developmental toxicity of crude oil on fish in ELS.

Toxicity of Water-Accommodated Fractions (WAF), Chemically Enhanced WAF (CEWAF) of Oman Crude Oil and Dispersant to Early-Life Stages of Zebrafish (Danio rerio).

This study focused on comparing the lethal and sublethal toxicity of water-accommodated fractions (WAF) and chemically enhanced WAF (CEWAF) of crude oil to zebrafish (Danio rerio) on early life stages (ELS). Results showed that the addition of GM-2 dispersant caused an increase in the levels of total petroleum hydrocarbons (TPHs) and total priority polycyclic aromatic hydrocarbons (ΣPAHs). Based on ΣPAHs, the LC20 estimates for WAF and CEWAF were 4.88 µg L-1 and 1.19 µg L-1, respectively, indicating that CEWAF was approximately four times more toxic. CEWAF exposure caused markedly lower hatching rates and higher malformation frequencies than WAF. Meanwhile, the general morphology score (GMS) values in CEWAF were about fourfold lower than that in WAF, indicating that CEWAF exposure induced more significant developmental delay. The results suggested that chemical dispersant enhanced the toxicity of crude oil to zebrafish on ELS and its application could increase the exposure of fishes to crude oil.