scholarly journals Assessment of the Effect of Sorafenib on Omega-6 and Omega-3 Epoxyeicosanoid Formation in Patients with Hepatocellular Carcinoma

2020 ◽  
Vol 21 (5) ◽  
pp. 1875 ◽  
Author(s):  
Can G. Leineweber ◽  
Anne Pietzner ◽  
Ingrid W. Zhang ◽  
Usha B. Blessin ◽  
Michael Rothe ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Experimental Studies ◽  
Small Sample ◽  
Omega 3 ◽  
Multikinase Inhibitor ◽  
Sorafenib Treatment ◽  
Promote Tumor Growth ◽  
Omega 6 ◽  
Tumor Growth And Metastasis ◽  
Anti Tumor Activity

Hepatocellular carcinoma (HCC) is a leading cause of cancer death. The multikinase inhibitor sorafenib is widely used for systemic therapy in advanced HCC. Sorafenib might affect epoxyeicosanoids, as it is also a potent inhibitor of the soluble epoxide hydrolase (sEH), which catalyzes the conversion of epoxides derived from long-chain polyunsaturated fatty acids (PUFAs), such as arachidonic acid (AA) and omega-3 docosahexaenoic acid (DHA), into their corresponding diols. Experimental studies with AA-derived epoxyeicosatrienoic acids (EETs) showed that they can promote tumor growth and metastasis, while DHA-derived 19,20-epoxydocosapentaenoic acid (19,20-EDP) was shown to have anti-tumor activity in mice. In this pilot study, we assessed the effect of sorafenib treatment on the presence of lipid mediators, such as EETs, in blood of the patients with HCC using the lipidomics technology. We found a significant increase in 11,12-EET and 14,15-EET levels in HCC patients treated with sorafenib. Furthermore, while not significant in this small sample set, the data presented indicate that sorafenib can also increase the level of omega-3 DHA-derived 19,20-EDP. While the effect on EETs might hamper the anti-tumor effect of sorafenib, we hypothesize that supplementation of DHA in sorafenib-treated HCC patients could increase the level of 19,20-EDP and thereby enhance its anti-tumor effect.

scholarly journals Donafenib Versus Sorafenib in First-Line Treatment of Unresectable or Metastatic Hepatocellular Carcinoma: A Randomized, Open-Label, Parallel-Controlled Phase II-III Trial

2021 ◽  
pp. JCO.21.00163
Author(s):  
Shukui Qin ◽  
Feng Bi ◽  
Shanzhi Gu ◽  
Yuxian Bai ◽  
Zhendong Chen ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Phase Ii ◽  
Objective Response ◽  
Chinese Patients ◽  
First Line ◽  
Open Label ◽  
Multikinase Inhibitor ◽  
Sorafenib Treatment ◽  
Advanced Hcc ◽  
Intention To Treat

PURPOSE Donafenib, a novel multikinase inhibitor and a deuterated sorafenib derivative, has shown efficacy in phase Ia and Ib hepatocellular carcinoma (HCC) studies. This study compared the efficacy and safety of donafenib versus sorafenib as first-line therapy for advanced HCC. PATIENTS AND METHODS This open-label, randomized, parallel-controlled, multicenter phase II-III trial enrolled patients with unresectable or metastatic HCC, a Child-Pugh score ≤ 7, and no prior systemic therapy from 37 sites across China. Patients were randomly assigned (1:1) to receive oral donafenib (0.2 g) or sorafenib (0.4 g) twice daily until intolerable toxicity or disease progression. The primary end point was overall survival (OS), tested for noninferiority and superiority. Efficacy was primarily assessed in the full analysis set (FAS), and safety was assessed in all treated patients. RESULTS Between March 21, 2016, and April 16, 2018, 668 patients (intention-to-treat) were randomly assigned to donafenib and sorafenib treatment arms; the FAS included 328 and 331 patients, respectively. Median OS was significantly longer with donafenib than sorafenib treatment (FAS; 12.1 v 10.3 months; hazard ratio, 0.831; 95% CI, 0.699 to 0.988; P = .0245); donafenib also exhibited superior OS outcomes versus sorafenib in the intention-to-treat population. The median progression-free survival was 3.7 v 3.6 months ( P = .0570). The objective response rate was 4.6% v 2.7% ( P = .2448), and the disease control rate was 30.8% v 28.7% (FAS; P = .5532). Drug-related grade ≥ 3 adverse events occurred in significantly fewer patients receiving donafenib than sorafenib (125 [38%] v 165 [50%]; P = .0018). CONCLUSION Donafenib showed superiority over sorafenib in improving OS and has favorable safety and tolerability in Chinese patients with advanced HCC, showing promise as a potential first-line monotherapy for these patients.

Radiofrequency ablation suppresses distant tumour growth in a novel rat model of multifocal hepatocellular carcinoma

2013 ◽  
Vol 126 (3) ◽  
pp. 243-252 ◽  
Author(s):  
Caroline Erös de Bethlenfalva-Hora ◽  
Joachim C. Mertens ◽  
Anne-Christine Piguet ◽  
Joachim Kettenbach ◽  
Johannes Schmitt ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Radiofrequency Ablation ◽  
Growth Factor ◽  
Rat Model ◽  
Tumour Growth ◽  
Sham Operation ◽  
Liver Tumours ◽  
Multikinase Inhibitor ◽  
Sorafenib Treatment ◽  
Treatment Groups

RFA (radiofrequency ablation) is an established therapy for HCC (hepatocellular carcinoma). The multikinase inhibitor sorafenib prolongs survival in advanced HCC. We examined the effects of RFA alone and in combination with sorafenib on a bystanding tumour in a two-tumour rat model of HCC. A total of 80 rats were implanted with two liver tumours and randomized to four treatment groups: vehicle and sham operation (control), sorafenib and sham operation (Sora/Sham), vehicle and RFA (Vh/RFA), and sorafenib and RFA (Sora/RFA) (n=10/group per time point). RFA or sham-operation was performed on the left lobe tumour on day 15. Animals were killed at day 18 and day 30. Non-RFA-targeted right lobe tumours were analysed for angiogenesis, growth factors [HGF (hepatocyte growth factor), EGF (epidermal growth factor) and VEGF (vascular endothelial growth factor)] and infiltrating immune cells (CD3 and CD68). At day 30, the non-RFA-targeted tumours were significantly smaller in all three treatment groups compared with control (Sora/Sham P≤0.0001, Vh/RFA P=0.005 and Sora/RFA P≤0.0001). The smallest tumours were observed in animals treated with a combination of sorafenib and RFA, whereas the size reduction seen in the RFA-only group indicated an RFA-mediated distant suppression of tumour growth. Growth factor measurement revealed transiently decreased EGF levels after RFA (P=0.008), whereas sorafenib treatment decreased HGF levels (P=0.001). MVD (microvessel density) was reduced by sorafenib (P=0.002) despite increased VEGF levels (P≤0.0001). The immune parameters revealed augmented T-cells and IL-10 (interleukin 10) levels in all three treatment groups; sorafenib additionally increased macrophage numbers (P≤0.0001). RFA and sorafenib alone resulted in significant volume reduction of the non-RFA-targeted tumour; this effect was enhanced when both modalities were combined.

scholarly journals Hypoxia induces sorafenib resistance mediated by autophagy via activating FOXO3a in hepatocellular carcinoma

2020 ◽  
Vol 11 (11) ◽  
Author(s):  
Chao Liang ◽  
Zhebin Dong ◽  
Xianlei Cai ◽  
Jie Shen ◽  
Yuan Xu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Term Therapy ◽  
Advanced Hepatocellular Carcinoma ◽  
Multikinase Inhibitor ◽  
Sorafenib Treatment ◽  
Clinical Prognosis ◽  
Nuclear Location ◽  
Long Term Therapy ◽  
Hcc Cells

AbstractSorafenib, a multikinase inhibitor, is considered as the only approved drug to cure the advanced hepatocellular carcinoma (HCC); however, the acquired chemoresistance caused by intratumoral hypoxia through sorafenib long term therapy induces sorafenib inefficacy. We demonstrated here that hypoxia significantly attenuated sensitivity of HCC cells to sorafenib treatment and reduced its proliferation. Autophagy was observed in sorafenib-treated HCC cells in hypoxia, and inhibition of autophagy by 3-MA eliminated hypoxia-induced sorafenib resistance. Further study revealed hypoxia-activated FOXO3a, an important cellular stress transcriptional factor, via inducing its dephosphorylation and nuclear location; and FOXO3a-dependent transcriptive activation of beclin-1 was responsible for hypoxia-induced autophagy in HCC cells. Knockout of FOXO3a inhibited the autophagy induced by sorafenib itself in normoxia and significantly enhanced the cytotoxicity of sorafenib in HCC cells; and it also inhibited the hypoxia-induced autophagy and achieved the same effect in sorafenib sensitivity-enhancement in HCC cells as it in normoxia. Finally, knockout of intratumoral FOXO3a significantly enhanced curative efficacy of sorafenib via inhibition of autophagy in xenograft tumors in nude mice. Collectively, our study suggests that FOXO3a plays a key role in regulating hypoxia-induced autophagy in sorafenib-treated HCC, and FOXO3-targeted therapy may serve as a promising approach to improve clinical prognosis of patients suffering from HCC.

scholarly journals A Novel Anti-Inflammatory Role of Omega-3 PUFAs in Prevention and Treatment of Atherosclerosis and Vascular Cognitive Impairment and Dementia

Nutrients ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 2279 ◽  
Author(s):  
Marialaura Simonetto ◽  
Marco Infante ◽  
Ralph L. Sacco ◽  
Tatjana Rundek ◽  
David Della-Morte
Keyword(s):  
Cognitive Impairment ◽  
Experimental Studies ◽  
Vascular Diseases ◽  
Vascular Cognitive Impairment ◽  
Inflammatory Factors ◽  
Omega 3 ◽  
Membrane Phospholipids ◽  
Pufa Supplementation ◽  
Omega 6 ◽  
Anti Inflammatory

Atherosclerosis is an inflammatory chronic disease affecting arterial vessels and leading to vascular diseases, such as stroke and myocardial infarction. The relationship between atherosclerosis and risk of neurodegeneration has been established, in particular with vascular cognitive impairment and dementia (VCID). Systemic atherosclerosis increases the risk of VCID by inducing cerebral infarction, or through systemic or local inflammatory factors that underlie both atherosclerosis and cognition. Omega-3 and omega-6 polyunsaturated fatty acids (PUFAs) are involved in inflammatory processes, but with opposite roles. Specifically, omega-3 PUFAs exert anti-inflammatory properties by competing with omega-6 PUFAs and displacing arachidonic acid in membrane phospholipids, decreasing the production of pro-inflammatory eicosanoids. Experimental studies and some clinical trials have demonstrated that omega-3 PUFA supplementation may reduce the risk of different phenotypes of atherosclerosis and cardiovascular disease. This review describes the link between atherosclerosis, VCID and inflammation, as well as how omega-3 PUFA supplementation may be useful to prevent and treat inflammatory-related diseases.

scholarly journals Ultrasound and Infrared Radiation in Pasta Production

2019 ◽  
Vol 48 (3) ◽  
pp. 96-104 ◽  
Author(s):  
Сергей Романчиков ◽  
Sergei Romanchikov
Keyword(s):  
Wheat Flour ◽  
Infrared Radiation ◽  
Experimental Studies ◽  
Food Product ◽  
Nutrient Content ◽  
Animal Protein ◽  
Omega 3 ◽  
Food Ration ◽  
High Nutrient ◽  
Omega 6

One of the current priorities of food supply for military personnel in the Far North and the Russian Arctic is to preserve its nutrition quality while maintaining the mass of food ration. To implement this task, the author proposes to produce soft wheat pasta with animal protein and high nutrient content (retinol, i.e. vitamin A, minerals, mineral nutrients, omega-3 and omega-6 fatty acids). Beef liver was added to the pasta as an enriching additive in the amount of 30% of the total dough. The composition of the ingredients, their quantity, and the effect on the amount of nutrients in the modified food product were calculated according to a specially designed program. Modernized equipment made it possible to use ultrasound and infrared radiation to intensify the technology of pasta production. A device for ultrasonic magnetostriction processing of flour reduced the contamination of wheat flour with pathogenic microorganisms and mold. An ultrasound press made it possible to use low gluten wheat flour. Modernization of the drying equipment by including sources of ultrasound and infrared radiation accelerated the process of drying. As a result, the pasta with a high content of animal protein did not lose in quality. The experimental studies revealed empirical dependency between the quality of the pasta and the ultrasound and infrared radiation. Intensification of the production of pasta with animal protein and a high nutrient content was 22–26%, while the strength of the finished product increased by 20–25%.

Teor e composição de lipídeos como ferramenta de gestão na nutrição de bovinos

2020 ◽  
Vol 9 (7) ◽  
pp. e334974037
Author(s):  
Graciele Araújo de Oliveira Caetano ◽  
Angela Aparecida da Fonseca ◽  
Cibelle Borges Figueiredo
Keyword(s):  
Omega 3 ◽  
Ácido Linoleico Conjugado ◽  
Omega 6 ◽  
3 Omega

Um fator diferencial na produção de bovinos é a compreensão da contribuição individual dos ácidos graxos e do papel dos lipídeos nos ruminantes, tanto na forma de análise (ácido graxo ou extrato etéreo), conceitos relacionados às características de ômega 3, ômega 6 e ácido linoleico conjugado na bio-hidrogenação, no metabolismo pós-absorção, bem como no conteúdo e composição dos ácidos graxos em relação à matéria seca dos alimentos. Sabe-se que diversos fatores podem afetar o teor, digestibilidade e degradabilidade das fibras presente na forragem, e o mesmo ocorre com os lipídeos. As diferenças entre os valores dos compostos presentes nos lipídeos podem ocorrer dependendo do ambiente, região do país ou fase de colheita e por isso, torna-se importante obter a análise da composição de ácidos graxos dos alimentos lipídicos, para que dessa maneira seja possível otimizar a utilização deste nutriente na dieta de animais ruminantes. Sendo assim, a proposta dessa revisão será trazer a discussão sobre o tema e abordar um entendimento sobre o conteúdo e composição de ácidos graxos dos ingredientes que compõem a dieta dos animais ruminantes, com ênfase na influência exercida no desempenho produtivo, imunonutrição, e no produto final (carne ou leite).

A randomized, double-blind, placebo-controlled study of polyunsaturated fatty acids efficacy in adolescents with anorexia nervosa

2020 ◽  
Vol 36 (2) ◽  
pp. 95-106
Author(s):  
Agnieszka M. Piróg-Balcerzak ◽  
Anna K. Bażyńska ◽  
Katarzyna Biernacka ◽  
Joanna Brągoszewska ◽  
Lidia Popek ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Anorexia Nervosa ◽  
Polyunsaturated Fatty Acids ◽  
Small Sample Size ◽  
Small Sample ◽  
Female Adolescent ◽  
Eating Attitude ◽  
Controlled Study ◽  
Omega 3 ◽  
Eat 26

Objective. Omega–3 polyunsaturated fatty acids (PUFAs) were tested in adolescent depression and in several neurodevelopmental disorders with partial success. Anorexia nervosa (AN) is characterised by deficiencies in fatty food intake and frequent comorbidity, including depressive and cognitive symptoms. Thus supplementation with PUFAs may be beneficial in this group of patients. The aim of the study was to assess whether PUFAs as an add-on treatment is associated with better improvement of body mass index (BMI) and psychopathological symptoms than placebo in patients with AN. Method. 61 female adolescent inpatients with AN were randomly allocated to omega–3 PUFAs supplementation or placebo for 10 weeks. Patients also participated in the behavioural programme and eclectic psychotherapy (treatment as usual, TAU). At baseline and follow-up visits, patients’ BMI and psychopathology were assessed with Clinical Global Impression Scale (CGI), Patient Global Impression Scale (PGI), and Eating Attitude Test (EAT-26). Results. After 10 weeks, both groups showed improvement in all parameters. Improvement in CGI scores was observed greater in placebo vs. PUFA-s group (p = 0.015) while other differences were not statistically significant. Omega–3 PUFAs supplementation appears not to be effective as an add-on treatment in inpatient adolescent girls with anorexia nervosa. Conclusions. The results should be analysed with caution due to small sample size and heterogeneity in TAU. As the TAU turned out to be highly effective, additional therapeutic effect of PUFA might not be visible. Nevertheless, that does not explain the tendency for better improvement in the placebo group.

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