Sorafenib enhances proteasome inhibitor-mediated cytotoxicity via inhibition of unfolded protein response and keratin phosphorylation

International Nuclear Information System (INIS)

Honma, Yuichi; Harada, Masaru

2013-01-01

Hepatocellular carcinoma (HCC) is highly resistant to conventional systemic therapies and prognosis for advanced HCC patients remains poor. Recent studies of the molecular mechanisms responsible for tumor initiation and progression have identified several potential molecular targets in HCC. Sorafenib is a multi-kinase inhibitor shown to have survival benefits in advanced HCC. It acts by inhibiting the serine/threonine kinases and the receptor type tyrosine kinases. In preclinical experiments sorafenib had anti-proliferative activity in hepatoma cells and it reduced tumor angiogenesis and increased apoptosis. Here, we demonstrate for the first time that the cytotoxic mechanisms of sorafenib include its inhibitory effects on protein ubiquitination, unfolded protein response (UPR) and keratin phosphorylation in response to endoplasmic reticulum (ER) stress. Moreover, we show that combined treatment with sorafenib and proteasome inhibitors (PIs) synergistically induced a marked increase in cell death in hepatoma- and hepatocyte-derived cells. These observations may open the way to potentially interesting treatment combinations that may augment the effect of sorafenib, possibly including drugs that promote ER stress. Because sorafenib blocked the cellular defense mechanisms against hepatotoxic injury not only in hepatoma cells but also in hepatocyte-derived cells, we must be careful to avoid severe liver injury. -- Graphical abstract: Display Omitted -- Highlights: •We examined the cytotoxic mechanisms of sorafenib in hepatoma cells. •Sorafenib induces cell death via apoptotic and necrotic fashion. •Sorafenib inhibits protein ubiquitination and unfolded protein response. •Autophagy induced by sorafenib may affect its cytotoxicity. •Sorafenib inhibits keratin phosphorylation and cytoplasmic inclusion formation

Sorafenib-induced defective autophagy promotes cell death by necroptosis.

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Kharaziha, Pedram; Chioureas, Dimitris; Baltatzis, George; Fonseca, Pedro; Rodriguez, Patricia; Gogvadze, Vladimir; Lennartsson, Lena; Björklund, Ann-Charlotte; Zhivotovsky, Boris; Grandér, Dan; Egevad, Lars; Nilsson, Sten; Panaretakis, Theocharis

2015-11-10

Autophagy is one of the main cytoprotective mechanisms that cancer cells deploy to withstand the cytotoxic stress and survive the lethal damage induced by anti-cancer drugs. However, under specific conditions, autophagy may, directly or indirectly, induce cell death. In our study, treatment of the Atg5-deficient DU145 prostate cancer cells, with the multi-tyrosine kinase inhibitor, sorafenib, induces mitochondrial damage, autophagy and cell death. Molecular inhibition of autophagy by silencing ULK1 and Beclin1 rescues DU145 cells from cell death indicating that, in this setting, autophagy promotes cell death. Re-expression of Atg5 restores the lipidation of LC3 and rescues DU145 and MEF atg5-/- cells from sorafenib-induced cell death. Despite the lack of Atg5 expression and LC3 lipidation, DU145 cells form autophagosomes as demonstrated by transmission and immuno-electron microscopy, and the formation of LC3 positive foci. However, the lack of cellular content in the autophagosomes, the accumulation of long-lived proteins, the presence of GFP-RFP-LC3 positive foci and the accumulated p62 protein levels indicate that these autophagosomes may not be fully functional. DU145 cells treated with sorafenib undergo a caspase-independent cell death that is inhibited by the RIPK1 inhibitor, necrostatin-1. Furthermore, treatment with sorafenib induces the interaction of RIPK1 with p62, as demonstrated by immunoprecipitation and a proximity ligation assay. Silencing of p62 decreases the RIPK1 protein levels and renders necrostatin-1 ineffective in blocking sorafenib-induced cell death. In summary, the formation of Atg5-deficient autophagosomes in response to sorafenib promotes the interaction of p62 with RIPK leading to cell death by necroptosis.

Sorafenib synergizes with metformin in NSCLC through AMPK pathway activation

NARCIS (Netherlands)

Groenendijk, Floris H; Mellema, Wouter W; van der Burg, Eline; Schut, Eva; Hauptmann, Michael; Horlings, Hugo M; Willems, Stefan M; van den Heuvel, Michel M; Jonkers, Jos; Smit, Egbert F; Bernards, René

2015-01-01

The multikinase inhibitor sorafenib is under clinical investigation for the treatment of many solid tumors, but in most cases, the molecular target responsible for the clinical effect is unknown. Furthermore, enhancing the effectiveness of sorafenib using combination strategies is a major clinical

Cerebrovascular Accidents Associated with Sorafenib in Hepatocellular Carcinoma

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Saif, Muhammad W.; Isufi, Iris; Peccerillo, Jennifer; Syrigos, Kostas N.

2011-01-01

Sorafenib is an oral angiogenetic multikinase inhibitor approved in the treatment of renal and hepatocellular carcinoma. Bleeding and venous thrombotic events have been described with angiogenetic agents but cerebrovascular accidents are rarely reported. We report two cases of patients with hepatocellular carcinoma who developed a cerebrovascular accident while on sorafenib. Neither patient had any risk factors for the cerebrovascular events apart from gender and age in the second patient. La...

Synergistic inhibitory effect of hyperbaric oxygen combined with sorafenib on hepatoma cells.

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Hai-Shan Peng

Full Text Available OBJECTIVES: Hypoxia is a common phenomenon in solid tumors, associated with chemotherapy and radiotherapy resistance, recurrence and metastasis. Hyperbaric oxygen (HBO therapy can increase tissue oxygen pressure and content to prevent the resistance, recurrence and metastasis of cancer. Presently, Sorafenib is a first-line drug, targeted for hepatocellular carcinoma (HCC but effective in only a small portion of patients and can induce hypoxia. The purpose of this study is to investigate the effect of HBO in combination with sorafenib on hepatoma cells. METHODS: Hepatoma cell lines (BEL-7402 and SK-Hep1 were treated with HBO at 2 atmosphere absolute pressure for 80 min per day or combined with sorafenib or cisplatin. At different time points, cells were tested for cell growth, colony formation, apoptosis, cell cycle and migration. Finally, miRNA from the hepatoma cells was detected by microRNA array and validated by qRT-PCR. RESULTS: Although HBO, sorafenib or cisplatin alone could inhibit growth of hepatoma cells, HBO combined with sorafenib or cisplatin resulted in much greater synergistic growth inhibition (cell proliferation and colony formation in hepatoma cells. Similarly, the synergistic effect of HBO and sorafenib on induction of apoptosis was also observed in hepatoma cells. HBO induced G1 arrest in SK-Hep1 not in BEL-7402 cells, but enhanced cell cycle arrest induced by sorafenib in BEL-7402 treated cells. However, HBO had no obvious effect on the migration of hepatoma cells, and microRNA array analysis showed that hepatoma cells with HBO treatment had significantly different microRNA expression profiles from those with blank control. CONCLUSIONS: We show for the first time that HBO combined with sorafenib results in synergistic growth inhibition and apoptosis in hepatoma cells, suggesting a potential application of HBO combined with sorafenib in HCC patients. Additionally, we also show that HBO significantly altered microRNA expression

Herb-Drug Interaction between the Traditional Hepatoprotective Formulation and Sorafenib on Hepatotoxicity, Histopathology and Pharmacokinetics in Rats

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Chin-Tsung Ting

2017-06-01

Full Text Available Sorafenib has been used as a standard therapy for advanced hepatocellular carcinoma (HCC. In Asia, patients with HCC are potentially treated with the combination of sorafenib and Chinese herbal medicines to improve the efficiency and reduce the side effects of sorafenib. However, limited information about the herb-drug interactions is available. We hypothesize that the Chinese herbal medicine may exert hepatoprotective effects on the sorafenib-treated group. The aim of this study is to investigate the pharmacokinetic mechanism of drug-drug interactions of sorafenib including interacting with hepatoprotective formulation, Long-Dan-Xie-Gan-Tang formulation (LDXGT and with two cytochrome P450 3A4 (CYP3A4 inhibitors, grapefruit juice and ketoconazole. Liver enzyme levels and histopathology of liver slices were used to evaluate sorafenib-induced hepatotoxicity and the potential hepatoprotective effects of the LDXGT formulation on subjects treated with the combination of sorafenib and the herbal medicine. In this study, a validated HPLC-photodiode array analytical system was developed for the pharmacokinetic study of sorafenib in rats. As the result of the pharmacokinetic data, pretreatment with the LDXGT formulation did not significantly interact with sorafenib compared with sorafenib oral administration alone. Furthermore, grapefruit juice and ketoconazole did not significantly affect sorafenib metabolism. Furthermore, pretreatment with variable, single or repeat doses of the LDXGT formulation did not suppress or exacerbate the sorafenib-induced hepatotoxicity and histopathological alterations. According to these results, the LDXGT formulation is safe, but has no beneficial effects on sorafenib-induced hepatotoxicity. A detailed clinical trial should be performed to further evaluate the efficacy or adverse effects of the LDXGT formulation in combination with sorafenib in humans.

A rare adverse reaction of sorafenib | Wang | Libyan Journal of ...

African Journals Online (AJOL)

2007-10-30

Sorafenib is a multikinase inhibitor thought to target vascular endothelial growth factor and its receptor. The European Medicines Agency (EAMA) and Food and Drug Administration (FDA) approved the use of sorafenib in late-stage hepatic cellular cancer (HCC) on October 30, 2007, and November 19, 2007, respectively.

Sorafenib modulates the radio sensitivity of hepatocellular carcinoma cells in vitro in a schedule-dependent manner

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Li Qiaoqiao

2012-10-01

Full Text Available Abstract Background Hepatocellular carcinoma (HCC has a high incidence and mortality. Radiotherapy and sorafenib have proven effective for HCC. Here, we investigated whether sorafenib modulated the response of HCC cells to irradiation in vitro, effect of timing of sorafenib, and the underlying mechanisms. Methods Cell viability of the HCC cell lines, SMMC-7721 and Bel-7402, was examined by the 3-(4,5-dimethylthiazol-2-yl-5(3-carboxymethoxyphenyl-2(4-sulfophenyl-2 H-terazolium (MTT assays. Clonogenic growth assays of SMMC-7721 and Bel-7402 were determined by colony formation assays. DNA damage was assessed by monitoring γ-HAX foci in irradiated cells with immunofluorescence microscopy, and cell cycle distribution changes were examined by flow cytometry. Effects of sorafenib (15 μM added 30 min prior to radiation (pre-irradiation sorafenib of SMMC-7721 and BEL-7402 or 24 h post-irradiation (post-irradiation sorafenib on irradiated SMMC-7721 and BEL-7402 cells were compared to those of radiation alone or no treatment. Results The effect of sorafenib was dependent on its time of addition in relationship to irradiation of cells. Pre-irradiation sorafenib did not significantly affect the viability of SMMC-7221 and BEL-7402 cells compared with irradiation treatment alone. In contrast, post-irradiation sorafenib increased the sensitivity of irradiated SMMC-7221 and BEL-7402 cells significantly in a time-dependent manner. Pre-irradiation sorafenib significantly increased the surviving fraction of SMMC-7221 and BEL-7402 cells in clonogenic assays whereas post-irradiation sorafenib significantly reduced the surviving fractions of SMMC-7221 and BEL-7402 cells. SMMC-7721 cells treated with sorafenib 30 min before irradiation had significantly fewer cells with γ-H2AX foci (23.8 ± 2.9% than SMMC-7721 cells receiving radiation alone (59.9 ± 2.4; P  Conclusions Sorafenib combined with irradiation exerted a schedule-dependent effect in

Localized palmar-plantar epidermal hyperplasia: a previously undefined dermatologic toxicity to sorafenib.

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Beldner, Matthew; Jacobson, Michael; Burges, Gene E; Dewaay, Deborah; Maize, John C; Chaudhary, Uzair B

2007-10-01

The development of multitargeted tyrosine kinase inhibitors has provided significant advances in the treatment of renal cell carcinoma. This case describes initial therapy for managing renal cell cancer with the administration of sorafenib, a multitargeted tyrosine kinase inhibitor. We report the development of localized palmar-plantar epidermal hyperplasia, a rare but significant cutaneous adverse event from sorafenib therapy. Mild-to-moderate dermatologic toxicity from sorafenib has been well described in the literature. We also review the current knowledge and the proposed hypothesis for the development of cutaneous events related to tyrosine kinase inhibitors. This particular case represents a unique form of dermatologic toxicity to sorafenib that has not previously been described in the literature.

Sorafenib modulates the radio sensitivity of hepatocellular carcinoma cells in vitro in a schedule-dependent manner

International Nuclear Information System (INIS)

Li, Qiaoqiao; Hu, Yonghong; Xi, Mian; He, Liru; Zhao, Lei; Liu, Mengzhong

2012-01-01

Hepatocellular carcinoma (HCC) has a high incidence and mortality. Radiotherapy and sorafenib have proven effective for HCC. Here, we investigated whether sorafenib modulated the response of HCC cells to irradiation in vitro, effect of timing of sorafenib, and the underlying mechanisms. Cell viability of the HCC cell lines, SMMC-7721 and Bel-7402, was examined by the 3-(4,5-dimethylthiazol-2-yl)-5(3-carboxymethoxyphenyl)-2(4-sulfophenyl)-2 H-terazolium (MTT) assays. Clonogenic growth assays of SMMC-7721 and Bel-7402 were determined by colony formation assays. DNA damage was assessed by monitoring γ-HAX foci in irradiated cells with immunofluorescence microscopy, and cell cycle distribution changes were examined by flow cytometry. Effects of sorafenib (15 μM) added 30 min prior to radiation (pre-irradiation sorafenib) of SMMC-7721 and BEL-7402 or 24 h post-irradiation (post-irradiation sorafenib) on irradiated SMMC-7721 and BEL-7402 cells were compared to those of radiation alone or no treatment. The effect of sorafenib was dependent on its time of addition in relationship to irradiation of cells. Pre-irradiation sorafenib did not significantly affect the viability of SMMC-7221 and BEL-7402 cells compared with irradiation treatment alone. In contrast, post-irradiation sorafenib increased the sensitivity of irradiated SMMC-7221 and BEL-7402 cells significantly in a time-dependent manner. Pre-irradiation sorafenib significantly increased the surviving fraction of SMMC-7221 and BEL-7402 cells in clonogenic assays whereas post-irradiation sorafenib significantly reduced the surviving fractions of SMMC-7221 and BEL-7402 cells. SMMC-7721 cells treated with sorafenib 30 min before irradiation had significantly fewer cells with γ-H2AX foci (23.8 ± 2.9%) than SMMC-7721 cells receiving radiation alone (59.9 ± 2.4; P < 0.001). Similarly, BEL-7402 cells receiving sorafenib prior to irradiation had significantly fewer cells with γ-H2AX foci (46.4 ± 3.8%) than those

Sorafenib ameliorates renal fibrosis through inhibition of TGF-β-induced epithelial-mesenchymal transition.

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Lining Jia

Full Text Available This study was to investigate whether sorafenib can inhibit the progression of renal fibrosis and to study the possible mechanisms of this effect.Eight-week-old rats were subjected to unilateral ureteral obstruction (UUO and were intragastrically administered sorafenib, while control and sham groups were administered vehicle for 14 or 21 days. NRK-52E cells were treated with TGF-β1 and sorafenib for 24 or 48 hours. HE and Masson staining were used to visualize fibrosis of the renal tissue in each group. The expression of α-SMA and E-cadherin in kidney tissue and NRK-52E cells were performed using immunohistochemistry and immunofluorescence. The apoptosis rate of NRK-52E cells was determined by flow cytometry analysis. The protein levels of Smad3 and p-Smad3 in kidney tissue and NRK-52E cells were detected by western blot analysis.HE staining demonstrated that kidney interstitial fibrosis, tubular atrophy, and inflammatory cell infiltration in the sorafenib-treated-UUO groups were significantly decreased compared with the vehicle-treated-UUO group (p<0.05. Masson staining showed that the area of fibrosis was significantly decreased in the sorafenib-treated-UUO groups compared with vehicle-treated-UUO group (p<0.01. The size of the kidney did not significantly increase; the cortex of the kidney was thicker and had a richer blood supply in the middle-dose sorafenib group compared with the vehicle-treated-UUO group (p<0.05. Compared with the vehicle-treated-UUO and TGF-β-stimulated NRK-52E groups, the expression of a-SMA and E-cadherin decreased and increased, respectively, in the UUO kidneys and NRK-52E cells of the sorafenib-treated groups (p<0.05. The apoptotic rate of NRK-52E cells treated with sorafenib decreased for 24 hours in a dose-dependent manner (p<0.05. Compared with the vehicle-treated UUO and TGF-β-stimulated NRK-52E groups, the ratio of p-Smad3 to Smad3 decreased in the sorafenib-treated groups (p<0.05.Our results suggest that

Prognostic significance of adverse events in patients with hepatocellular carcinoma treated with sorafenib.

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Granito, Alessandro; Marinelli, Sara; Negrini, Giulia; Menetti, Saverio; Benevento, Francesca; Bolondi, Luigi

2016-03-01

Sorafenib is the standard treatment for patients with hepatocellular carcinoma (HCC) with advanced stage disease. Although its effectiveness has been demonstrated by randomized clinical trials and confirmed by field practice studies, reliable markers predicting therapeutic response have not yet been identified. Like other tyrosine kinase inhibitors, treatment with sorafenib is burdened by the development of adverse effects, the most frequent being cutaneous toxicity, diarrhoea, arterial hypertension and fatigue. In recent years, several studies have analysed the correlation between off-target effects and sorafenib efficacy in patients with HCC. In this review, an overview of the studies assessing the prognostic significance of sorafenib-related adverse events is provided.

Sorafenib for Metastatic Thyroid Cancer

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A summary of results from an international phase III trial that compared sorafenib (Nexavar®) and a placebo for the treatment of locally advanced or metastatic differentiated thyroid cancer that is no longer responding to treatment with radioactive iodine

1082-39, an analogue of sorafenib, inhibited human cancer cell growth more potently than sorafenib.

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Chu, Jia-Hui; Zhao, Cui-Rong; Song, Zhi-Yu; Wang, Rui-Qi; Qin, Yi-Zhuo; Li, Wen-Bao; Qu, Xian-Jun

2014-04-01

1082-39, an analogue of sorafenib, is a derivative of indazole diarylurea. We evaluated the activity of 1082-39 against human cancer cell growth. Its effects and mechanisms of action were then compared with those of sorafenib. The experiments were performed in human melanoma M21 cells. Cell viability was estimated by using the colorimetric assay. Annexin V-FITC/PI staining assay was used to recognize the apoptotic cells. Further analysis of the mitochondria membrane potential (MMP) was performed by the JC-1 fluorescence probe staining. The levels of apoptotic proteins and kinases related to cancer proliferation were determined by western blotting assay. 1082-39 possessed the activity against cancer cell proliferation with time- and dose-dependent manner. 1082-39 induced M21 cell to apoptosis, showing the increase of annexin V-FITC/PI staining cells, the MMP collapse and releasing cytochrome c from mitochondria. Western blotting analysis showed the activation of the mitochondria-mediated intrinsic pathway, showing the increase of cleaved caspase-9, cleaved caspase-3 and cleaved PARP. Statistical analysis suggested that 1082-39 possessed greater activities than sorafenib in the inhibition of M21 proliferation and induction of apoptosis. These effects of 1082-39 might arise from its activity of regulation the PI3K/Akt and Wnt/β-catenin signaling pathways. 1082-39 is a promising candidate compound which could develop as a potent anticancer agent. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Synergistic growth inhibition by sorafenib and vitamin K2 in human hepatocellular carcinoma cells.

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Zhang, Yafei; Zhang, Bicheng; Zhang, Anran; Zhao, Yong; Zhao, Jie; Liu, Jian; Gao, Jianfei; Fang, Dianchun; Rao, Zhiguo

2012-09-01

Sorafenib is an oral multikinase inhibitor that has been proven effective as a single-agent therapy in hepatocellular carcinoma, and there is a strong rationale for investigating its use in combination with other agents. Vitamin K2 is nearly non-toxic to humans and has been shown to inhibit the growth of hepatocellular carcinoma. In this study, we evaluated the effects of a combination of sorafenib and vitamin K2 on the growth of hepatocellular carcinoma cells. Flow cytometry, 3-(4,5-dimethyl-2-thiazolyl-2,5-diphenyl-2H-tetrazolium bromide) and nude mouse xenograft assays were used to examine the effects of sorafenib and vitamin K2 on the growth of hepatocellular carcinoma cells. Western blotting was used to elucidate the possible mechanisms underlying these effects. Assays for 3-(4,5-dimethyl-2-thiazolyl-2,5-diphenyl-2H-tetrazolium bromide) revealed a strong synergistic growth-inhibitory effect between sorafenib and vitamin K2. Flow cytometry showed an increase in cell cycle arrest and apoptosis after treatment with a combination of these two drugs at low concentrations. Sorafenib-mediated inhibition of extracellular signal-regulated kinase phosphorylation was promoted by vitamin K2, and downregulation of Mcl-1, which is required for sorafenib-induced apoptosis, was observed after combined treatment. Vitamin K2 also attenuated the downregulation of p21 expression induced by sorafenib, which may represent the mechanism by which vitamin K2 promotes the inhibitory effects of sorafenib on cell proliferation. Moreover, the combination of sorafenib and vitamin K2 significantly inhibited the growth of hepatocellular carcinoma xenografts in nude mice. Our results determined that combined treatment with sorafenib and vitamin K2 can work synergistically to inhibit the growth of hepatocellular carcinoma cells. This finding raises the possibility that this combined treatment strategy might be promising as a new therapy against hepatocellular carcinoma, especially for patients

Cost-effectiveness of sorafenib versus SBRT for unresectable advanced hepatocellular carcinoma

International Nuclear Information System (INIS)

Leung, Henry W. C.; Liu, Chung-Feng; Chan, Agnes L. F.

2016-01-01

Stereotactic body radiotherapy (SBRT) has been shown to improve overall survival in patients with advanced hepatocellular carcinoma. This study aimed to assess the cost-effectiveness of SBRT compared to sorafenib which is the only drug for advanced hepatocellular carcinoma. A Markov decision-analytic model was performed to compare the cost-effectiveness of SBRT and sorafenib for unresectable advanced hepatocellular carcinoma. Patients transitioned between three health states: stable disease, progression disease and death. We calculated the data on cost from the perspective of our National Health Insurance Bureau. Sensitivity analyses were conducted to determine the impact of several variables. The incremental cost effectiveness ratio (ICER) for sorafenib compared to SBRT was NT$3,788,238 per quality-adjusted life year gained (cost/QALY), which was higher than the willingness to pay threshold of Taiwan according to WHO’s guideline. One-way sensitivity analysis revealed that the utility of progression disease for the sorafenib treatment, utility of progression free survival for SBRT, utility of progression free survival for sorafenib, utility of PFS to progression disease for SBRT and transition probability of progression disease to dead for SBRT were the most sensitive parameters in all cost scenarios. The Monte-Carlo simulation demonstrated that the probability of cost-effectiveness at a willingness to pay threshold of NT$ 2,213,145 per QALY was 100 % and 0 % chance for SBRT and sorafenib. This study indicated that SBRT for advanced hepatocellular carcinoma is cost-effective at a willingness to pay threshold as defined by WHO guideline in Taiwan

Radiation recall dermatitis induced by sorafenib. A case study and review of the literature

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Stieb, Sonja [University Hospital Zurich, Department of Radiation Oncology, Zurich (Switzerland); Paul Scherrer Institute, Villigen PSI, Center for Proton Therapy, Villigen (Switzerland); Riesterer, Oliver; Bruessow, Cornelia; Guckenberger, Matthias [University Hospital Zurich, Department of Radiation Oncology, Zurich (Switzerland); Pestalozzi, Bernhard [University Hospital Zurich, Department of Oncology, Zurich (Switzerland); Weiler, Stefan [University Hospital and University of Zurich, Department of Clinical Pharmacology and Toxicology, Zurich (Switzerland)

2016-05-15

Radiation recall dermatitis (RRD) is an acute inflammatory reaction confined to previously irradiated skin, mainly subsequent to the administration of certain chemotherapeutics. Here we present a rare case of RRD induced by the oral multikinase inhibitor sorafenib. A 77-year-old male with hepatocellular carcinoma was irradiated at ten different sites for bone metastases with 20-36 Gray in 5-12 fractions from January to March 2015. Sorafenib 400 mg was administered twice daily from mid-March. One week later the patient presented with fever and erythematous lesions on the right upper arm, mandible, and trunk. All skin symptoms were confined to previously irradiated areas. After RRD was diagnosed by exclusion of other causes and skin biopsy, sorafenib was paused. With the administration of topical corticosteroids and oral antihistamines, the skin reaction subsided within several days. Sorafenib was readministered after 3 weeks, which did not lead to recurrence of RRD but did cause fluctuating fever. Only four other such cases have been reported in the literature and WHO pharmacovigilance database on individual case safety reports. The current report is the first to show a potential relationship between the severity of sorafenib-induced RRD and radiation dose, histopathological features, and simultaneous acute radiation dermatitis and mucositis. RRD induced by sorafenib is a rare phenomenon, but should be considered in patients showing erythematous skin lesions 1-2 weeks after initiation of the drug, predominantly in areas where skin has been irradiated with an equivalent dose ≥ 30 Gy. Discontinuation of sorafenib with possible readministration should be evaluated with respect to the clinical situation and severity of reaction. (orig.) [German] Recall-Strahlendermatitis (RRD) ist eine akute Entzuendungsreaktion der Haut in zuvor bestrahlten Arealen, welche meist nach Einnahme bestimmter Chemotherapeutika auftritt. Nachfolgend praesentieren wir einen seltenen Fall von

Sunitinib versus sorafenib in advanced hepatocellular cancer: results of a randomized phase III trial.

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Cheng, Ann-Lii; Kang, Yoon-Koo; Lin, Deng-Yn; Park, Joong-Won; Kudo, Masatoshi; Qin, Shukui; Chung, Hyun-Cheol; Song, Xiangqun; Xu, Jianming; Poggi, Guido; Omata, Masao; Pitman Lowenthal, Susan; Lanzalone, Silvana; Yang, Liqiang; Lechuga, Maria Jose; Raymond, Eric

2013-11-10

Open-label, phase III trial evaluating whether sunitinib was superior or equivalent to sorafenib in hepatocellular cancer. Patients were stratified and randomly assigned to receive sunitinib 37.5 mg once per day or sorafenib 400 mg twice per day. Primary end point was overall survival (OS). Early trial termination occurred for futility and safety reasons. A total of 1,074 patients were randomly assigned to the study (sunitinib arm, n = 530; sorafenib arm, n = 544). For sunitinib and sorafenib, respectively, median OS was 7.9 versus 10.2 months (hazard ratio [HR], 1.30; one-sided P = .9990; two-sided P = .0014); median progression-free survival (PFS; 3.6 v 3.0 months; HR, 1.13; one-sided P = .8785; two-sided P = .2286) and time to progression (TTP; 4.1 v 3.8 months; HR, 1.13; one-sided P = .8312; two-sided P = .3082) were comparable. Median OS was similar among Asian (7.7 v 8.8 months; HR, 1.21; one-sided P = .9829) and hepatitis B-infected patients (7.6 v 8.0 months; HR, 1.10; one-sided P = .8286), but was shorter with sunitinib in hepatitis C-infected patients (9.2 v 17.6 months; HR, 1.52; one-sided P = .9835). Sunitinib was associated with more frequent and severe adverse events (AEs) than sorafenib. Common grade 3/4 AEs were thrombocytopenia (29.7%) and neutropenia (25.7%) for sunitinib; hand-foot syndrome (21.2%) for sorafenib. Discontinuations owing to AEs were similar (sunitinib, 13.3%; sorafenib, 12.7%). OS with sunitinib was not superior or equivalent but was significantly inferior to sorafenib. OS was comparable in Asian and hepatitis B-infected patients. OS was superior in hepatitis C-infected patients who received sorafenib. Sunitinib-treated patients reported more frequent and severe toxicity.

Triclosan treatment decreased the antitumor effect of sorafenib on hepatocellular carcinoma cells

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Wu M

2018-05-01

Full Text Available Man Wu,1,2 Guanren Zhao,2 Xiaomei Zhuang,1 Tianhong Zhang,1 Ce Zhang,2 Wenpeng Zhang,1 Zhenqing Zhang1 1State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, China; 2Department of Pharmacy, The 309th Hospital of PLA, Beijing, China Background: Triclosan is a widely applied antimicrobial agent which affects the endocrine system and homeostasis; it may also promote the cirrhosis and hepatocellular carcinoma (HCC growth in a mice model. The exact roles of triclosan in regulating human hepatocellular carcinoma development and treatment remain unknown. Methods: MHCC97-H, a highly aggressive HCC cell line, was treated with indicated concentration of triclosan or sorafenib. The expression of drug-resistance genes was examined by qPCR. The clearance or metabolism of sorafenib was determined by liquid chromatograph-mass spectrometer/mass spectrometer (LC-MS/MS. MTT assay was used to examine the MHCC97-H cell proliferation. Nude mice were used to exam the anti-tumor effect of sorafenib on subcutaneous and intrahepatic growth of MHCC97-H cells. Results: In the present study, triclosan could induce the expression of drug-resistance genes in MHCC97-H cells (a highly aggressive HCC cell line, accelerate the clearance of sorafenib, and attenuate the anti-proliferation effect of this molecular targeted agent in MHCC97-H cells. Triclosan decreased the antitumor effect of sorafenib on subcutaneous and intrahepatic growth of MHCC97-H in nude mice. Conclusion: By discovering the fact that triclosan treatment enhances sorafenib resistance in HCC cells, this work suggests exposure of triclosan is detrimental to HCC patients during chemotherapy. Keywords: HCC, triclosan, sorafenib resistance, drug clearance 

The observation and nursing for advanced hepatocellular carcinoma patients treated with Sorafenib

International Nuclear Information System (INIS)

Chen Yu; Xu Jing; Lin Fuqun

2011-01-01

Objective: To summarize the author's experience which was obtained in observing and nursing the adverse reactions of advanced hepatocellular carcinoma patients who were treated with Sorafenib. Methods: The adverse reactions and their severity observed in 34 patients with advanced hepatocellular carcinoma who were treated with Sorafenib were retrospectively analyzed. Results: Side effects or toxic reaction were observed in all the patients, which included neutropenia, foot-hand syndrome (FHS), fatigue, diarrhea, hypertention, rash, etc. Five patients had to cut down the dose of Sorafenib in order to relieve the symptom, among them one patient had grade 4 FHS, 3 patients had grade 3 FHS and one patient had grade 3 neutropenia. Conclusion: Being familiar with sorafenib's adverse reaction, closely observing the patients condition and affording appropriate nursing measures, all the above items can definitely improve the therapeutic results and patient's living quality. (authors)

GSK-3 inhibition in vitro and in vivo enhances antitumor effect of sorafenib in renal cell carcinoma (RCC)

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Kawazoe, Hisashi; Bilim, Vladimir N. [Laboratory of Molecular Oncology, Department of Urology, Yamagata University School of Medicine, Iida-nishi 2-2-2, Yamagata 990-9585 (Japan); Ugolkov, Andrey V., E-mail: ugolkov@northwestern.edu [Tumor Biology Core, Center for Developmental Therapeutics, Chemistry of Life Processes Institute, Silverman Hall B733, Northwestern University, Evanston, IL (United States); Yuuki, Kaori; Naito, Sei; Nagaoka, Akira; Kato, Tomoyuki [Laboratory of Molecular Oncology, Department of Urology, Yamagata University School of Medicine, Iida-nishi 2-2-2, Yamagata 990-9585 (Japan); Tomita, Yoshihiko, E-mail: ytomita@med.id.yamagata-u.ac.jp [Laboratory of Molecular Oncology, Department of Urology, Yamagata University School of Medicine, Iida-nishi 2-2-2, Yamagata 990-9585 (Japan)

2012-07-06

Highlights: Black-Right-Pointing-Pointer Sorafenib treatment upregulated GSK-3{beta} levels in RCC cells. Black-Right-Pointing-Pointer Pharmacologic inhibition of GSK-3 suppressed xenograft RCC tumor growth. Black-Right-Pointing-Pointer Inhibition of GSK-3 enhanced antitumor effect of sorafenib in vitro and in vivo. -- Abstract: Sorafenib is a multikinase inhibitor approved for the systemic treatment of renal cell carcinoma (RCC). However, sorafenib treatment has a limited effect due to acquired chemoresistance of RCC. Previously, we identified glycogen synthase kinase-3 (GSK-3) as a new therapeutic target in RCC. Here, we observed that sorafenib inhibits proliferation and survival of RCC cells. Significantly, we revealed that sorafenib enhances GSK-3 activity in RCC cells, which could be a potential mechanism of acquired chemoresistance. We found that pharmacological inhibition of GSK-3 potentiates sorafenib antitumor effect in vitro and in vivo. Our results suggest that combining GSK-3 inhibitor and sorafenib might be a potential new therapeutic approach for RCC treatment.

Distinct behaviour of sorafenib in experimental cachexia-inducing tumours: the role of STAT3.

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Míriam Toledo

Full Text Available The presence of a tumour is very often associated with wasting in the host, affecting both skeletal muscle and adipose tissue. In the present study we used sorafenib, a multi-kinase inhibitor with anti-tumour activity, in order to investigate the effects of chemotherapy on wasting. Three different experimental mouse tumour models were included: C26 colon carcinoma, B16 melanoma and Lewis lung carcinoma (LLC. The results obtained clearly show that sorafenib was effective in reducing tumour growth in LLC and B16 models, while it had no effect on C26. Interestingly, sorafenib treatment reduced the signs of muscle wasting and improved the physical activity in the LLC model and also in the C26, despite the absence of antineoplastic action in the latter. Our results discard a role for IL-6 in the action of sorafenib since the drug did not affect the levels of this cytokine. Conversely, sorafenib seems to act by influencing both STAT3 and ERK activity at muscle level, leading to reduced accumulation of Pax7 and atrogin-1. Sorafenib may interfere with muscle wasting by decreasing the activation of these signal transduction pathways.

Outcomes of sequential treatment with sorafenib followed by regorafenib for HCC: additional analyses from the phase 3 RESORCE trial.

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Finn, Richard S; Merle, Philippe; Granito, Alessandro; Huang, Yi-Hsiang; Bodoky, György; Pracht, Marc; Yokosuka, Osamu; Rosmorduc, Olivier; Gerolami, René; Caparello, Chiara; Cabrera, Roniel; Chang, Charissa; Sun, Weijing; LeBerre, Marie-Aude; Baumhauer, Annette; Meinhardt, Gerold; Bruix, Jordi

2018-04-25

The RESORCE trial showed that regorafenib improves overall survival (OS) in patients with hepatocellular carcinoma progressing during sorafenib treatment (hazard ratio [HR] 0.62, 95% confidence interval [CI] 0.50, 0.78; P<.0001). This exploratory analysis describes outcomes of sequential treatment with sorafenib followed by regorafenib. In RESORCE, 573 patients were randomized 2:1 to regorafenib 160mg/day or placebo for 3 weeks on/1 week off. Efficacy and safety were evaluated by last sorafenib dose. The time from the start of sorafenib to death was assessed. Time to progression (TTP) in RESORCE was analyzed by TTP during prior sorafenib treatment. HRs (regorafenib/placebo) for OS by last sorafenib dose were similar (0.67 for 800 mg/day; 0.68 for <800 mg/day). Rates of grade 3, 4, and 5 adverse events with regorafenib by last sorafenib dose (800 mg/day versus <800 mg/day) were 52%, 11%, and 15% versus 60%, 10%, and 12%, respectively. Median times (95% CI) from the start of sorafenib to death were 26.0 months (22.6, 28.1) for regorafenib and 19.2 months (16.3, 22.8) for placebo. Median time from the start of sorafenib to progression on sorafenib was 7.2 months for the regorafenib arm and 7.1 months for the placebo arm. An analysis of TTP in RESORCE in subgroups defined by TTP during prior sorafenib in quartiles (Q) showed HRs (regorafenib/placebo; 95% CI) of 0.66 (0.45, 0.96; Q1); 0.26 (0.17, 0.40; Q2); 0.40 (0.27, 0.60; Q3); and 0.54 (0.36, 0.81; Q4). These exploratory analyses show that regorafenib conferred a clinical benefit regardless of the last sorafenib dose or TTP on prior sorafenib. Rates of adverse events were generally similar regardless of the last sorafenib dose. This analysis examined characteristics and outcomes of patients with HCC who were treated with regorafenib after they had disease progression during sorafenib treatment. Regorafenib provided clinical benefit to patients regardless of the pace of their disease progression during prior sorafenib

Lipid nanocarriers containing sorafenib inhibit colonies formation in human hepatocarcinoma cells.

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Bondì, Maria Luisa; Botto, Chiara; Amore, Erika; Emma, Maria Rita; Augello, Giuseppa; Craparo, Emanuela Fabiola; Cervello, Melchiorre

2015-09-30

Here, the potential of two nanostructured lipid carriers (NLC) for controlled release of sorafenib was evaluated. The obtained systems showed characteristics suitable as drug delivery systems for the treatment of hepatocellular carcinoma (HCC) through parenteral administration. The use of a mixture between a solid lipid (tripalmitin) with a liquid lipid (Captex 355 EP/NF or Miglyol 812) to prepare NLC systems could give a higher drug loading capacity and a longer term stability during storage than that obtained by using only solid lipids. The obtained nanoparticles showed a nanometer size and high negative zeta potential values. Scansion electron microscopy (SEM) of the sorafenib loaded NLC revealed a spherical shape with a diameter <300 nm. In vitro biological studies demonstrated that sorafenib loaded into NLC had enhanced anti-tumor activity compared to that of free drug. This finding raises hope in terms of future drug delivery strategy of sorafenib loaded NLC, that can be useful for therapeutic application in HCC. Copyright © 2015 Elsevier B.V. All rights reserved.

Selective internal radiation therapy compared with sorafenib for hepatocellular carcinoma with portal vein thrombosis

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Edeline, Julien; Crouzet, Laurence; Pracht, Marc; Boucher, Eveline; Campillo-Gimenez, Boris; Rolland, Yan; Rohou, Tanguy; Guillygomarc'h, Anne; Boudjema, Karim; Lenoir, Laurence; Adhoute, Xavier; Clement, Bruno; Blanc, Jean-Frederic; Garin, Etienne

2016-01-01

Tumoural portal vein thrombosis (PVT) is a major prognostic factor in hepatocellular carcinoma (HCC). The efficacy of sorafenib, the only treatment approved at an advanced stage, is limited. Based on previous data, selective internal radiation therapy (SIRT), or 90 Y radioembolization, seems an interesting option. We aimed to compare both treatments in this population. We retrospectively compared patients treated in two centres for HCC with tumoural PVT. We compared overall survival (OS) between patients treated with SIRT and patients treated with sorafenib. Analyses were performed before and after 1:1 matching with a propensity score for controlling indication bias, using a Cox proportional hazards model. A total of 151 patients were analysed, 34 patients treated with SIRT and 117 patients treated with sorafenib only. In the whole population, SIRT was associated with a higher median OS as compared with sorafenib: 18.8 vs 6.5 months (log-rank p < 0.001). There was an imbalance of baseline characteristics between patients treated by SIRT and sorafenib, which justified patient matching with use of a propensity score: 24 patients treated with SIRT could be matched with 24 patients treated with sorafenib. OS was estimated with a median of 26.2 vs 8.7 months in patients treated with SIRT vs sorafenib, respectively (log-rank p = 0.054). Before and after patient matching, the adjusted hazard ratio related to treatment by SIRT was estimated at 0.62 [95 % confidence interval (CI) 0.39-0.97] (p = 0.037) and 0.40 (95 % CI 0.19-0.82) (p = 0.013), respectively. SIRT seems more effective than sorafenib in patients presenting with HCC and tumoural PVT. This hypothesis is being tested in prospective randomized trials. (orig.)

Selective internal radiation therapy compared with sorafenib for hepatocellular carcinoma with portal vein thrombosis

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Edeline, Julien [Centre Eugene Marquis, Medical Oncology Department, Rennes (France); Inserm UMR991, Rennes (France); Crouzet, Laurence; Pracht, Marc; Boucher, Eveline [Centre Eugene Marquis, Medical Oncology Department, Rennes (France); Campillo-Gimenez, Boris [Centre Eugene Marquis, Clinical Research Department, Rennes (France); Rolland, Yan; Rohou, Tanguy [Centre Eugene Marquis, Imaging Department, Rennes (France); Guillygomarc' h, Anne [CHU Pontchaillou, Hepatology Department, Rennes (France); Boudjema, Karim [CHU Pontchaillou, Hepatobiliary Surgery, Rennes (France); Lenoir, Laurence [Centre Eugene Marquis, Nuclear Medicine Department, Rennes (France); Adhoute, Xavier [Hopital Saint-Joseph, Hepato-Gastroenterology Department, Marseille (France); Clement, Bruno [Inserm UMR991, Rennes (France); Blanc, Jean-Frederic [Hopital Saint-Andre, Hepato-Gastroenterology Department, Bordeaux (France); Garin, Etienne [Inserm UMR991, Rennes (France); Centre Eugene Marquis, Nuclear Medicine Department, Rennes (France)

2016-04-15

Tumoural portal vein thrombosis (PVT) is a major prognostic factor in hepatocellular carcinoma (HCC). The efficacy of sorafenib, the only treatment approved at an advanced stage, is limited. Based on previous data, selective internal radiation therapy (SIRT), or {sup 90}Y radioembolization, seems an interesting option. We aimed to compare both treatments in this population. We retrospectively compared patients treated in two centres for HCC with tumoural PVT. We compared overall survival (OS) between patients treated with SIRT and patients treated with sorafenib. Analyses were performed before and after 1:1 matching with a propensity score for controlling indication bias, using a Cox proportional hazards model. A total of 151 patients were analysed, 34 patients treated with SIRT and 117 patients treated with sorafenib only. In the whole population, SIRT was associated with a higher median OS as compared with sorafenib: 18.8 vs 6.5 months (log-rank p < 0.001). There was an imbalance of baseline characteristics between patients treated by SIRT and sorafenib, which justified patient matching with use of a propensity score: 24 patients treated with SIRT could be matched with 24 patients treated with sorafenib. OS was estimated with a median of 26.2 vs 8.7 months in patients treated with SIRT vs sorafenib, respectively (log-rank p = 0.054). Before and after patient matching, the adjusted hazard ratio related to treatment by SIRT was estimated at 0.62 [95 % confidence interval (CI) 0.39-0.97] (p = 0.037) and 0.40 (95 % CI 0.19-0.82) (p = 0.013), respectively. SIRT seems more effective than sorafenib in patients presenting with HCC and tumoural PVT. This hypothesis is being tested in prospective randomized trials. (orig.)

OSU-2S/sorafenib synergistic antitumor combination against hepatocellular carcinoma: The role of PKCδ/p53

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Hany A Omar

2016-11-01

Full Text Available Background: Sorafenib (Nexavar® is an FDA-approved systemic therapy for advanced hepatocellular carcinoma (HCC. However, the low efficacy and adverse effects at high doses limit the clinical application of sorafenib and strongly recommend its combination with other agents aiming at ameliorating its drawbacks. OSU-2S, a PKCδ activator, was selected as a potential candidate anticancer agent to be combined with sorafenib to promote the anti-cancer activity through synergistic interaction. Methods: The antitumor effects of sorafenib, OSU-2S and their combination were assessed by MTT assay, caspase activation, Western blotting, migration/invasion assays in four different HCC cell lines. The synergistic interactions were determined by Calcusyn analysis. PKCδ knockdown was used to elucidate the role of PKCδ activation as a mechanism for the synergy. The knockdown/over-expression of p53 was used to explain the differential sensitivity of HCC cell lines to sorafenib and/or OSU-2S. Results: OSU-2S synergistically enhanced the anti-proliferative effects of sorafenib in the four used HCC cell lines with combination indices < 1. This effect was accompanied by parallel increases in caspase 3/7 activity, PARP cleavage, PKCδ activation and HCC cell migration/invasion. In addition, PKCδ knockdown abolished the synergy between sorafenib and OSU-2S. Furthermore, p53 restoration in Hep3B cells through the over-expression rendered them more sensitive to both agents while p53 knockdown from HepG2 cells increased their resistance to both agents. Conclusions: OSU-2S augments the anti-proliferative effect of sorafenib in HCC cell lines, in part, through the activation of PKCδ. The p53 status in HCC cells predicts their sensitivity towards both sorafenib and OSU-2S. The proposed combination represents a therapeutically relevant approach that can lead to a new HCC therapeutic protocol.

Sorafenib for Egyptian patients with advanced hepatocellular carcinoma; single center experience

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Abdel-Rahman, O.; Abdelwahab, M.; Shaker, M.; Abdelwahab, Sh.; Elbassiony, M.; Ellithy, M.

2014-01-01

Background: According to the results of a number of phase 3 randomized studies, sorafenib is the only approved systemic therapy for advanced HCC; however the issue of high eco- Sorafenib nomic cost remains challenging; thus we have conducted this retrospective analysis of our HCC patients treated with sorafenib. Methods: HCC Shams University Hospitals, in the period between 2010 and 2012 were reviewed. Eligible patients were those who had received sorafenib for advanced HCC not eligible for or progressed after surgery or locoregional therapy. We investigated the impact of baseline clinico pathological factors (age, gender, child status, performance score, BCLC tumor stage, cause of chronic liver disease, median baseline alpha fetoprotein level and previous treatment received for HCC) on overall survival (OS) in an adjusted Cox regression model. Results: 41 patients were included in the analysis fulfilling the inclusion criteria. At a median follow up period of 13 months, the median PFS for the whole group was 4 months; the median OS for the whole group is 6.25 months. Multivariate analysis identified three baseline characteristics that were prognostic indicators for overall survival: ECOG performance status (median OS for ECOG 1 = 7.01 months and for ECOG 2 = 3.03 months), Child-Pugh status (median OS for child A = 12.04 months and for child B = 5.23 months), and median baseline levels of alpha-fetoprotein. Conclusions: In limited resource countries like Egypt, we suggest that the use of sorafenib for the treatment of advanced HCC cases should be restricted to a highly selected subgroup of patients with good performance and child A.

Metronomic capecitabine in patients with hepatocellular carcinoma unresponsive to or ineligible for sorafenib treatment: report of two cases.

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Marinelli, Sara; Granito, Alessandro; Piscaglia, Fabio; Renzulli, Matteo; Stagni, Angela; Bolondi, Luigi

2013-01-01

Sorafenib, an oral multikinase inhibitor, is the only systemic agent proven to be effective in patients with hepatocellular carcinoma (HCC). There are no approved second line systemic therapies in patients who have had disease progression on or are not eligible to sorafenib. We describe two cases of unresectable HCC that were treated with low, "metronomic" doses of capecitabine. In the first patient, capecitabine was used after sorafenib failure. In the second case, treatment with capecitabine was attempted since the patient was considered not eligible for sorafenib due to spontaneous hepatic bleeding of a large HCC lesion. Treatment was effective and well tolerated in both patients with long-lasting objective responses. Lacking established second-line therapy, metronomic capecitabine may be a valid alternative in the treatment of HCC patients who are judged not eligible for sorafenib or those having progression disease on sorafenib.

Sorafenib metabolism is significantly altered in the liver tumor tissue of hepatocellular carcinoma patient.

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Ling Ye

Full Text Available BACKGROUND: Sorafenib, the drug used as first line treatment for hepatocellular carcinoma (HCC, is metabolized by cytochrome P450 (CYP 3A4-mediated oxidation and uridine diphosphate glucuronosyl transferase (UGT 1A9-mediated glucuronidation. Liver diseases are associated with reduced CYP and UGT activities, which can considerably affect drug metabolism, leading to drug toxicity. Thus, understanding the metabolism of therapeutic compounds in patients with liver diseases is necessary. However, the metabolism characteristic of sorafenib has not been systematically determined in HCC patients. METHODS: Sorafenib metabolism was tested in the pooled and individual tumor hepatic microsomes (THLMs and adjacent normal hepatic microsomes (NHLMs of HCC patients (n = 18. Commercial hepatic microsomes (CHLMs were used as a control. In addition, CYP3A4 and UGT1A9 protein expression in different tissues were measured by Western blotting. RESULTS: The mean rates of oxidation and glucuronidation of sorafenib were significantly decreased in the pooled THLMs compared with those in NHLMs and CHLMs. The maximal velocity (Vmax of sorafenib oxidation and glucuronidation were approximately 25-fold and 2-fold decreased in the pooled THLMs, respectively, with unchanged Km values. The oxidation of sorafenib in individual THLMs sample was significantly decreased (ranging from 7 to 67-fold than that in corresponding NHLMs sample. The reduction of glucuronidation in THLMs was observed in 15 out of 18 patients' samples. Additionally, the level of CYP3A4 and UGT1A9 expression were both notably decreased in the pooled THLMs. CONCLUSIONS: Sorafenib metabolism was remarkably decreased in THLMs. This result was associated with the down regulation of the protein expression of CYP3A4 and UGT1A9.

Sorafenib neoadjuvant therapy in the treatment of high risk renal cell carcinoma.

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Yushi Zhang

Full Text Available To evaluate the clinical efficacy of sorafenib as preoperative neoadjuvant therapy in patients with high risk renal cell carcinoma (RCC.Clinical data of 18 patients with high risk RCC who received surgery done successfully after preoperative neoadjuvant therapy with sorafenib in Peking Union Medical College Hospital (PUMCH from April 2007 to October 2013 have been reviewed and analyzed in this study.Among the 18 patients there were 13 male and 5 female, with a median age of 54.6 years. The objective response rate (ORR of the operation on the selected patients is very high (94.4%, including 4 cases (22.2% of partial response (PR and 13 cases (72.2% of stable disease (SD. After preoperative sorafenib treatment, the average tumor size of the 18 patients decreased from 7.8 cm (ranging from 3.6 to 19.2 cm to 6.2 cm (ranging from 2.4 to 16.8 cm, and the median value of average tumor CT value decreased from 61HU to 52 HU. Among the 5 patients who had IVC tumor thrombi, the grades of tumor thrombi in 2 patients who were grade II before sorafenib treatment became grade I and grade 0 respectively, 2 patients of grade III both became grade II.Preoperative neoadjuvant therapy with sorafenib for high risk RCC patients can significantly decrease primary tumor volume as well as tumor thrombus, which could help the nephron-sparing surgery (NSS or radical nephrectomy to be done successfully.

Sorafenib prevents liver fibrosis in a non-alcoholic steatohepatitis (NASH) rodent model

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Stefano, J.T.; Pereira, I.V.A.; Torres, M.M.; Bida, P.M. [Disciplina de Gastroenterologia Clínica (LIM-07), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Coelho, A.M.M. [Disciplina de Transplante de Órgãos do Aparelho Digestivo (LIM-37), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Xerfan, M.P. [Disciplina de Gastroenterologia Clínica (LIM-07), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Cogliati, B. [Departamento de Patologia, Faculdade de Medicina Veterinária e Zootecnia, Universidade de São Paulo, São Paulo, SP (Brazil); Barbeiro, D.F. [Disciplina de Emergências Clínicas (LIM-51), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Mazo, D.F.C. [Disciplina de Gastroenterologia Clínica (LIM-07), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Kubrusly, M.S.; D' Albuquerque, L.A.C. [Disciplina de Transplante de Órgãos do Aparelho Digestivo (LIM-37), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Souza, H.P. [Disciplina de Emergências Clínicas (LIM-51), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Carrilho, F.J.; Oliveira, C.P. [Disciplina de Gastroenterologia Clínica (LIM-07), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil)

2015-02-24

Liver fibrosis occurring as an outcome of non-alcoholic steatohepatitis (NASH) can precede the development of cirrhosis. We investigated the effects of sorafenib in preventing liver fibrosis in a rodent model of NASH. Adult Sprague-Dawley rats were fed a choline-deficient high-fat diet and exposed to diethylnitrosamine for 6 weeks. The NASH group (n=10) received vehicle and the sorafenib group (n=10) received 2.5 mg·kg{sup -1}·day{sup -1} by gavage. A control group (n=4) received only standard diet and vehicle. Following treatment, animals were sacrificed and liver tissue was collected for histologic examination, mRNA isolation, and analysis of mitochondrial function. Genes related to fibrosis (MMP9, TIMP1, TIMP2), oxidative stress (HSP60, HSP90, GST), and mitochondrial biogenesis (PGC1α) were evaluated by real-time quantitative polymerase chain reaction (RT-qPCR). Liver mitochondrial oxidation activity was measured by a polarographic method, and cytokines by enzyme-linked immunosorbent assay (ELISA). Sorafenib treatment restored mitochondrial function and reduced collagen deposition by nearly 63% compared to the NASH group. Sorafenib upregulated PGC1α and MMP9 and reduced TIMP1 and TIMP2 mRNA and IL-6 and IL-10 protein expression. There were no differences in HSP60, HSP90 and GST expression. Sorafenib modulated PGC1α expression, improved mitochondrial respiration and prevented collagen deposition. It may, therefore, be useful in the treatment of liver fibrosis in NASH.

Alpha-fetoprotein is a biomarker of unfolded protein response and altered proteostasis in hepatocellular carcinoma cells exposed to sorafenib.

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Houessinon, Aline; Gicquel, Albane; Bochereau, Flora; Louandre, Christophe; Nyga, Rémy; Godin, Corinne; Degonville, James; Fournier, Emma; Saidak, Zuzana; Drullion, Claire; Barbare, Jean-Claude; Chauffert, Bruno; François, Catherine; Pluquet, Olivier; Galmiche, Antoine

2016-01-28

Sorafenib is the treatment of reference for advanced hepatocellular carcinoma (HCC). A decrease in the serum levels of Alpha-fetoprotein (AFP) is reported to be the biological parameter that is best associated with disease control by sorafenib. In order to provide a biological rationale for the variations of AFP, we analyzed the various steps of AFP production in human HCC cell lines exposed to sorafenib. Sorafenib dramatically reduced the levels of AFP produced by HCC cells independently of its effect on cell viability. The mRNA levels of AFP decreased upon sorafenib treatment, while the AFP protein remained localized in the Golgi apparatus. Sorafenib activated the Regulated Inositol-Requiring Enzyme-1α (IRE-1α) and the PKR-like ER Kinase (PERK)-dependent arms of the Unfolded Protein Response (UPR). The inhibition of IRE-1α partially restored the mRNA levels of AFP upon treatment with sorafenib. The inhibition of both pathways partially prevented the drop in the production of AFP induced by sorafenib. The findings provide new insights on the regulation of AFP, and identify it as a biomarker suitable for the exploration of HCC cell proteostasis in the context of therapeutic targeting. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Plectin deficiency in liver cancer cells promotes cell migration and sensitivity to sorafenib treatment.

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Cheng, Chiung-Chi; Chao, Wei-Ting; Liao, Chen-Chun; Tseng, Yu-Hui; Lai, Yen-Chang Clark; Lai, Yih-Shyong; Hsu, Yung-Hsiang; Liu, Yi-Hsiang

2018-01-02

Plectin involved in activation of kinases in cell signaling pathway and plays important role in cell morphology and migration. Plectin knockdown promotes cell migration by activating focal adhesion kinase and Rac1-GTPase activity in liver cells. Sorafenib is a multi-targeting tyrosine kinase inhibitor that improves patient survival on hepatocellular carcinoma. The aim of this study is to investigate the correlation between the expression of plectin and cell migration as well as the sensitivity of hepatoma cell lines exposing to sorafenib. Hepatoma cell lines PLC/PRF/5 and HepG2 were used to examine the level of plectin expression and cell migration in comparison with Chang liver cell line. In addition, sensitivity of the 3 cell lines to sorafenib treatment was also measured. Expression of plectin was lower in PLC/PRF/5 and HepG2 hepatoma cells than that of Chang liver cells whereas HepG2 and PLC/PRF/5 cells exhibit higher rate of cell migration in trans-well migration assay. Immunohistofluorecent staining on E-cadherin revealed the highest rate of collective cell migration in HepG2 cells and the lowest was found in Chang liver cells. Likewise, HepG2 cell line was most sensitive to sorafenib treatment and Chang liver cells exhibited the least sensitivity. The drug sensitivity to sorafenib treatment showed inverse correlation with the expression of plectin. We suggest that plectin deficiency and increased E-cadherin in hepatoma cells were associated with higher rates of cell motility, collective cell migration as well as higher drug sensitivity to sorafenib treatment.

Sorafenib inhibits tumor growth and vascularization of rhabdomyosarcoma cells by blocking IGF-1R-mediated signaling

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Wessen Maruwge

2008-11-01

Full Text Available Wessen Maruwge1, Pádraig D’Arcy1, Annika Folin1,2, Slavica Brnjic1, Johan Wejde1, Anthony Davis1, Fredrik Erlandsson3, Jonas Bergh1,2, Bertha Brodin11Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden; 2Radiumhemmet, Karolinska University Hospital, Stockholm, Sweden; 3Bayer Pharmaceutical Corporation, SwedenAbstract: The growth of many soft tissue sarcomas is dependent on aberrant growth factor signaling, which promotes their proliferation and motility. With this in mind, we evaluated the effect of sorafenib, a receptor tyrosine kinase inhibitor, on cell growth and apoptosis in sarcoma cell lines of various histological subtypes. We found that sorafenib effectively inhibited cell proliferation in rhabdomyosarcoma, synovial sarcoma and Ewing’s sarcoma with IC50 values <5 µM. Sorafenib effectively induced growth arrest in rhabdomyosarcoma cells, which was concurrent with inhibition of Akt and Erk signaling. Studies of ligand-induced phosphorylation of Erk and Akt in rhabdomyosarcoma cells showed that insulin-like growth factor-1 is a potent activator, which can be blocked by treatment with sorafenib. In vivo sorafenib treatment of rhabdomyosarcoma xenografts had a significant inhibitory effect on tumor growth, which was associated with inhibited vascularization and enhanced necrosis in the adjacent tumor stroma. Our results demonstrate that in vitro and in vivo growth of rhabdomyosarcoma can be suppressed by treatment with sorafenib, and suggests the possibilities of using sorafenib as a potential adjuvant therapy for the treatment of rhabdomyosarcoma.Keywords: soft tissue sarcoma, kinase inhibitors, targeted therapy, vascularization

Combination of transcatheter arterial chemoembolization and interrupted dosing sorafenib improves patient survival in early–intermediate stage hepatocellular carcinoma

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Lee, Teng-Yu; Lin, Chen-Chun; Chen, Chiung-Yu; Wang, Tsang-En; Lo, Gin-Ho; Chang, Chi-Sen; Chao, Yee

2017-01-01

Abstract Background/Objective: The survival benefit of treatment for unresectable hepatocellular carcinoma (HCC) with transcatheter arterial chemoembolization (TACE) combined with sorafenib remains uncertain. We compared the survival of patients treated with TACE and sorafenib with that of patients treated with TACE alone. Methods: This was a post hoc analysis of the Study in Asia of the Combination of TACE with Sorafenib in Patients with HCC (START) trial. All patients who received TACE and interrupted dosing of sorafenib for early or intermediate-stage HCC in Taiwan from 2009 to 2010 were recruited into the TACE and sorafenib group. They were randomly matched 1:1 by age, sex, Child–Pugh score, tumor size, tumor number, and tumor stage with patients from Taichung Veterans General Hospital in Taiwan who received TACE alone and who fulfilled the selection criteria of the START trial during the same time period (control group). Patient survival [cumulative incidence and hazard ratio (HR)] of the 2 groups were analyzed and compared. Results: The baseline characteristics of the 36 patients in each group were similar. Tumor response rates were significantly better in the TACE and sorafenib group (P < .04). Overall survival of the TACE and sorafenib group was also significantly better than that of the control (TACE alone) group over the 2 years [78%, 95% confidence interval (95% CI) 64–91 vs 49, 95% CI 32–66; P = .012]. In the multivariate regression analysis, TACE and sorafenib was found to be independently associated with a decreased risk of mortality (HR 0.33, 95% CI 0.12–0.89; P = .015). Multivariate stratified analyses verified this association in each patient subgroup (all HR < 1.0). Conclusion: With a high patient tolerance to an interrupted sorafenib dosing schedule, the combination of TACE with sorafenib was associated with improved overall survival in early–intermediate stage HCC when compared with treatment with TACE alone. PMID

Targeting human liver cancer cells with lactobionic acid-G(4)-PAMAM-FITC sorafenib loaded dendrimers.

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Iacobazzi, Rosa Maria; Porcelli, Letizia; Lopedota, Angela Assunta; Laquintana, Valentino; Lopalco, Antonio; Cutrignelli, Annalisa; Altamura, Emiliano; Di Fonte, Roberta; Azzariti, Amalia; Franco, Massimo; Denora, Nunzio

2017-08-07

Reported here is the synthesis and biological evaluation of the asialoglycoprotein receptor (ASGP-R) targeted fourth generation poliamidoamine dendrimer (G(4)-PAMAM) loaded with sorafenib. The ASGP-R targeted dendrimer was obtained by conjugation of Lactobionic acid (La) to the G(4)-PAMAM dendrimer, followed by acetylation (Ac) of the free amino groups in order to reduce the non-specific interactions with the cell membrane. Moreover, by additionally grafting fluorescein (FITC), it was easy to characterize the internalization pathway and the intracellular fate of the targeted dendrimer Ac-La-G(4)-PAMAM-FITC. In vitro experiments performed on HepG-2 and HLE cell lines, allowed to study the ability of the dendrimers to affect the cell vitality. Confocal microscopy and cytofluorimetric analysis confirmed higher binding and uptake ability of the Ac-La-G(4)-PAMAM-FITC dendrimer in well differentiated and ASGP-R expressing human liver cancer cell line HepG-2 compared non-expressing HLE cells. Ac-La-G(4)-PAMAM-FITC dendrimer loaded with sorafenib was stable and showed sustained sorafenib release. As evidenced by the cytotoxicity studies, sorafenib included in the dendrimer maintained its effectiveness, and was able to produce a longer lasting effect over the time compared to molar equivalent doses of free sorafenib. This new targeted dendrimer appears to be a suitable carrier for the delivery of sorafenib to liver cancer cells expressing ASGP-R. Copyright © 2017 Elsevier B.V. All rights reserved.

Multicenter phase II study of sequential radioembolization-sorafenib therapy for inoperable hepatocellular carcinoma.

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Pierce K H Chow

Full Text Available The safety and tolerability of sequential radioembolization-sorafenib therapy is unknown. An open-label, single arm, investigator-initiated Phase II study (NCT0071279 was conducted at four Asia-Pacific centers to evaluate the safety and efficacy of sequential radioembolization-sorafenib in patients with hepatocellular carcinoma (HCC not amenable to curative therapies.Sorafenib (400 mg twice-daily was initiated 14 days post-radioembolization with yttrium-90 (90Y resin microspheres given as a single procedure. The primary endpoints were safety and tolerability and best overall response rate (ORR using RECIST v1.0.Secondary endpoints included: disease control rate (complete [CR] plus partial responses [PR] and stable disease [SD] and overall survival (OS.Twenty-nine patients with Barcelona Clinic Liver Cancer (BCLC stage B (38% or C (62% HCC received a median of 3.0 GBq (interquartile range, 1.0 90Y-microspheres followed by sorafenib (median dose/day, 600.0 mg; median duration, 4.1 months. Twenty eight patients experienced ≥1 toxicity; 15 (52% grade ≥3. Best ORR was 25%, including 2 (7% CR and 5 (18% PR, and 15 (54% SD. Disease control was 100% and 65% in BCLC stage B and C, respectively. Two patients (7% had sufficient response to enable radical therapy. Median survivals for BCLC stage B and C were 20.3 and 8.6 months, respectively.This study shows the potential efficacy and manageable toxicity of sequential radioembolization-sorafenib.ClinicalTrials.gov NCT00712790.

Magnetic resonance imaging following treatment of advanced hepatocellular carcinoma with sorafenib

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Joon-Il Choi

2014-06-01

Full Text Available Hepatocellular carcinomas are highly vascular tumors, showing progressive hypervascularity by the process of neoangiogenesis. Tumor angiogenesis is critical for tumor growth as well as metastatic spread therefore, imaging and quantification of tumor neo-angiogenesis is essential for monitoring response to targeted therapies and predicting disease progression. Sorafenib is a molecular targeting agent used for treating hypervascular tumors. This drug is now the standard of care in treatment of patients with advanced hepatocellular carcinoma. Due to its anti-angiogenic and anti-proliferative actions, imaging findings following treatment with Sorafenib are quite distinct when compared to conventional chemotherapeutic agents. Liver MRI is a widely adopted imaging modality for assessing treatment response in hepatocellular carcinoma and imaging features may reflect pathophysiological changes within the tumor. In this mini-review, we will discuss MRI findings after Sorafenib treatment in hepatocellular carcinoma and review the feasibility of MRI as an early biomarker in differentiating responders from non-responders after treatment with molecular targeting agents.

Cancer patients treated with sunitinib or sorafenib have sufficient antibody and cellular immune responses to warrant influenza vaccination.

Science.gov (United States)

Mulder, Sasja F; Jacobs, Joannes F M; Olde Nordkamp, Michel A M; Galama, Joep M D; Desar, Ingrid M E; Torensma, Ruurd; Teerenstra, Steven; Mulders, Peter F A; Vissers, Kris C P; Punt, Cornelis J A; de Vries, I Jolanda M; van Herpen, Carla M L

2011-07-01

The tyrosine kinase inhibitors sorafenib and sunitinib have efficacy in several types of cancer. Recent studies indicate that these agents affect the immune system. The way it affects the immune response to influenza vaccination is unknown. The aim of this study was to elucidate the specific immune response to seasonal flu vaccination in cancer patients treated with sunitinib or sorafenib. Sunitinib- or sorafenib-treated cancer patients were vaccinated against seasonal influenza with an inactivated vaccine. Healthy controls and patients with metastatic renal cell cancer (mRCC) without systemic treatment (nontreated mRCC controls) were included for comparison. Antibody responses were measured at baseline, day 8, and day 22 by a standard hemagglutination inhibition assay and cellular T-cell responses at baseline and day 8 by proliferation assay and secretion of cytokines. Forty subjects were enrolled: 16 patients treated with sunitinib, 6 patients with sorafenib, 7 nontreated mRCC controls, and 11 healthy controls. All patients treated with sunitinib and sorafenib developed seroprotection rates comparable with controls. Functional T-cell reactivity was observed in all groups, except for patients treated with sorafenib who showed a decreased proliferation rate and IFN-γ/IL-2 production and increased IL-10 compared with healthy controls. We conclude that influenza vaccination should be recommended to cancer patients treated with sunitinib or sorafenib.

Antagonism of Sorafenib and Regorafenib actions by platelet factors in hepatocellular carcinoma cell lines

International Nuclear Information System (INIS)

D’Alessandro, Rosalba; Refolo, Maria G; Lippolis, Catia; Giannuzzi, Grazia; Carella, Nicola; Messa, Caterina; Cavallini, Aldo; Carr, Brian I

2014-01-01

Platelets are frequently altered in hepatocellular carcinoma (HCC) patients. Platelet lysates (hPL) can enhance HCC cell growth and decrease apoptosis. The aims were to evaluate whether hPL can modulate the actions of Sorafenib or Regorafenib, two clinical HCC multikinase antagonists. Several human HCC cell lines were grown in the presence and absence of Sorafenib or Regorafenib, with or without hPL. Growth was measured by MTT assay, apoptosis was assessed by Annexin V and by western blot, and autophagy and MAPK growth signaling were also measured by western blot, and migration and invasion were measured by standard in vitro assays. Both Sorafenib and Regorafenib-mediated inhibition of cell growth, migration and invasion were all antagonized by hPL. Drug-mediated apoptosis and decrease in phospho-ERK levels were both blocked by hPL, which also increased anti-apoptotic phospho-STAT, Bax and Bcl-xL levels. Preliminary data, obtained with epidermal growth factor (EGF) and insulin-like growth factor-I (IGF-I), included in hPL, revealed that these factors were able to antagonized Sorafenib in a proliferation assay, in particular when used in combination. Platelet factors can antagonize Sorafenib or Regorafenib-mediated growth inhibition and apoptosis in HCC cells. The modulation of platelet activity or numbers has the potential to enhance multikinase drug actions

New Sorafenib Derivatives: Synthesis, Antiproliferative Activity Against Tumour Cell Lines and Antimetabolic Evaluation

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Branka Zorc

2012-01-01

Full Text Available Sorafenib is a relatively new cytostatic drug approved for the treatment of renal cell and hepatocellular carcinoma. In this report we describe the synthesis of sorafenib derivatives 4a–e which differ from sorafenib in their amide part. A 4-step synthetic pathway includes preparation of 4-chloropyridine-2-carbonyl chloride hydrochloride (1, 4-chloro-pyridine-2-carboxamides 2a–e, 4-(4-aminophenoxy-pyridine-2-carboxamides 3a–e and the target compounds 4-[4-[[4-chloro-3-(trifluoromethylphenyl]carbamoylamino]-phenoxy]-pyridine-2-carboxamides 4a–e. All compounds were fully chemically characterized and evaluated for their cytostatic activity against a panel of carcinoma, lymphoma and leukemia tumour cell lines. In addition, their antimetabolic potential was investigated as well. The most prominent antiproliferative activity was obtained for compounds 4a–e (IC50 = 1-4.3 μmol·L−1. Their potency was comparable to the potency of sorafenib, or even better. The compounds inhibited DNA, RNA and protein synthesis to a similar extent and did not discriminate between tumour cell lines and primary fibroblasts in terms of their anti-proliferative activity.

Hepatic Stellate Cell Coculture Enables Sorafenib Resistance in Huh7 Cells through HGF/c-Met/Akt and Jak2/Stat3 Pathways

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Weibo Chen

2014-01-01

Full Text Available Purpose. Tumor microenvironment confers drug resistance to kinase inhibitors by increasing RKT ligand levels that result in the activation of cell-survival signaling including PI3K and MAPK signals. We assessed whether HSC-LX2 coculture conferred sorafenib resistance in Huh7 and revealed the mechanism underlying the drug resistance. Experimental Design. The effect of LX2 on sorafenib resistance was determined by coculture system with Huh7 cells. The rescue function of LX2 supernatants was assessed by MTT assay and fluorescence microscopy. The underlying mechanism was tested by administration of pathway inhibitors and manifested by Western blotting. Results. LX2 coculture significantly induced sorafenib resistance in Huh7 by activating p-Akt that led to reactivation of p-ERK. LX2 secreted HGF into the culture medium that triggered drug resistance, and exogenous HGF could also induce sorafenib resistance. The inhibition of p-Akt blocked sorafenib resistance caused by LX2 coculture. Increased phosphorylation of Jak2 and Stat3 was also detected in LX2 cocultured Huh7 cells. The Jak inhibitor tofacitinib reversed sorafenib resistance by blocking Jak2 and Stat3 activation. The combined administration of sorafenib and p-Stat3 inhibitor S3I-201 augmented induced apoptosis even in the presence of sorafenib resistance. Conclusions. HSC-LX2 coculture induced sorafenib resistance in Huh7 through multiple pathways: HGF/c-Met/Akt pathway and Jak2/Stat3 pathway. A combined administration of sorafenib and S3I-201 was able to augment sorafenib-induced apoptosis even in the presence of LX2 coculture.

A phase I trial of sorafenib combined with cisplatin/etoposide or carboplatin/pemetrexed in refractory solid tumor patients.

Science.gov (United States)

Davies, Janine M; Dhruva, Nirav S; Walko, Christine M; Socinski, Mark A; Bernard, Stephen; Hayes, D Neil; Kim, William Y; Ivanova, Anastasia; Keller, Kimberly; Hilbun, Layla R; Chiu, Michael; Dees, E Claire; Stinchcombe, Thomas E

2011-02-01

Sorafenib has demonstrated single agent activity in non-small cell (NSCLC) and small cell lung cancer (SCLC). Carboplatin/pemetrexed (CbP) and cisplatin/etoposide (PE) are commonly used in the treatment of these diseases. A phase I trial escalating doses of sorafenib in combination with fixed doses of PE (Arm A) or CbP (Arm B) was performed using a 3-patient cohort design to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT); DLT were assessed in the first cycle. The trial was subsequently amended with closure of Arm B and to include Arm C with a reduced dose of carboplatin. Between 9/2007 and 9/2008, 20 pts were treated on the trial; median age 62 (range 42-73), male/female ratio 12/8, PS 0/1 ratio 6/14, and median number of prior therapies 2 (range 1-4). The most common tumor types were NSCLC and SCLC. On Arm A at dose level 0 (sorafenib 200 mg BID), 2 of 4 patients experienced DLT; 2 patients were enrolled at dose level -1 (sorafenib 200 mg QD) without DLT, but this arm was closed due to slow accrual. On Arm B, 2 of 3 patients experienced DLT at dose level 0 (sorafenib 200 mg BID). On Arm C at dose level 0 (sorafenib 200 mg BID), 1 of 6 patients experienced DLT, and at dose level +1 (sorafenib 400 mg BID) 2 of 5 patients experienced a DLT. The MTD of sorafenib was 200 mg BID continuously in combination with carboplatin (AUC of 5) and pemetrexed 500 mg/m² every 3 weeks. However, only 6 patients were treated at this dose level, and the results should be interpreted cautiously. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Fasting inhibits hepatic stellate cells activation and potentiates anti-cancer activity of Sorafenib in hepatocellular cancer cells.

Science.gov (United States)

Lo Re, Oriana; Panebianco, Concetta; Porto, Stefania; Cervi, Carlo; Rappa, Francesca; Di Biase, Stefano; Caraglia, Michele; Pazienza, Valerio; Vinciguerra, Manlio

2018-02-01

Hepatocellular carcinoma (HCC) has a poor outcome. Most HCCs develop in the context of liver fibrosis and cirrhosis caused by chronic inflammation. Short-term fasting approaches enhance the activity of chemotherapy in preclinical cancer models, other than HCC. Multi-tyrosine kinase inhibitor Sorafenib is the mainstay of treatment in HCC. However, its benefit is frequently short-lived. Whether fasting can alleviate liver fibrosis and whether combining fasting with Sorafenib is beneficial remains unknown. A 24 hr fasting (2% serum, 0.1% glucose)-induced changes on human hepatic stellate cells (HSC) LX-2 proliferation/viability/cell cycle were assessed by MTT and flow cytometry. Expression of lypolysaccharide (LPS)-induced activation markers (vimentin, αSMA) was evaluated by qPCR and immunoblotting. Liver fibrosis and inflammation were evaluated in a mouse model of steatohepatitis exposed to cycles of fasting, by histological and biochemical analyses. A 24 hr fasting-induced changes were also analyzed on the proliferation/viability/glucose uptake of human HCC cells exposed to Sorafenib. An expression panel of genes involved in survival, inflammation, and metabolism was examined by qPCR in HCC cells exposed to fasting and/or Sorafenib. Fasting decreased the proliferation and the activation of HSC. Repeated cycles of short term starvation were safe in mice but did not improve fibrosis. Fasting synergized with Sorafenib in hampering HCC cell growth and glucose uptake. Finally, fasting normalized the expression levels of genes which are commonly altered by Sorafenib in HCC cells. Fasting or fasting-mimicking diet diets should be evaluated in preclinical studies as a mean to potentiate the activity of Sorafenib in clinical use. © 2017 Wiley Periodicals, Inc.

Antitumor effects of regorafenib and sorafenib in preclinical models of hepatocellular carcinoma

OpenAIRE

Kissel, Maria; Berndt, Sandra; Fiebig, Lukas; Kling, Simon; Ji, Qunsheng; Gu, Qingyang; Lang, Tina; Hafner, Frank-Thorsten; Teufel, Michael; Zopf, Dieter

2017-01-01

The purpose of this study was to investigate the antitumor activity of regorafenib and sorafenib in preclinical models of HCC and to assess their mechanism of action by associated changes in protein expression in a HCC-PDX mouse model. Both drugs were administered orally once daily at 10 mg/kg (regorafenib) or 30 mg/kg (sorafenib), which recapitulate the human exposure at the maximally tolerated dose in mice. In a H129 hepatoma model, survival times differed significantly between regorafenib ...

Sorafenib promotes graft-versus-leukemia activity in mice and humans through IL-15 production in FLT3-ITD-mutant leukemia cells.

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Mathew, Nimitha R; Baumgartner, Francis; Braun, Lukas; O'Sullivan, David; Thomas, Simone; Waterhouse, Miguel; Müller, Tony A; Hanke, Kathrin; Taromi, Sanaz; Apostolova, Petya; Illert, Anna L; Melchinger, Wolfgang; Duquesne, Sandra; Schmitt-Graeff, Annette; Osswald, Lena; Yan, Kai-Li; Weber, Arnim; Tugues, Sonia; Spath, Sabine; Pfeifer, Dietmar; Follo, Marie; Claus, Rainer; Lübbert, Michael; Rummelt, Christoph; Bertz, Hartmut; Wäsch, Ralph; Haag, Johanna; Schmidts, Andrea; Schultheiss, Michael; Bettinger, Dominik; Thimme, Robert; Ullrich, Evelyn; Tanriver, Yakup; Vuong, Giang Lam; Arnold, Renate; Hemmati, Philipp; Wolf, Dominik; Ditschkowski, Markus; Jilg, Cordula; Wilhelm, Konrad; Leiber, Christian; Gerull, Sabine; Halter, Jörg; Lengerke, Claudia; Pabst, Thomas; Schroeder, Thomas; Kobbe, Guido; Rösler, Wolf; Doostkam, Soroush; Meckel, Stephan; Stabla, Kathleen; Metzelder, Stephan K; Halbach, Sebastian; Brummer, Tilman; Hu, Zehan; Dengjel, Joern; Hackanson, Björn; Schmid, Christoph; Holtick, Udo; Scheid, Christof; Spyridonidis, Alexandros; Stölzel, Friedrich; Ordemann, Rainer; Müller, Lutz P; Sicre-de-Fontbrune, Flore; Ihorst, Gabriele; Kuball, Jürgen; Ehlert, Jan E; Feger, Daniel; Wagner, Eva-Maria; Cahn, Jean-Yves; Schnell, Jacqueline; Kuchenbauer, Florian; Bunjes, Donald; Chakraverty, Ronjon; Richardson, Simon; Gill, Saar; Kröger, Nicolaus; Ayuk, Francis; Vago, Luca; Ciceri, Fabio; Müller, Antonia M; Kondo, Takeshi; Teshima, Takanori; Klaeger, Susan; Kuster, Bernhard; Kim, Dennis Dong Hwan; Weisdorf, Daniel; van der Velden, Walter; Dörfel, Daniela; Bethge, Wolfgang; Hilgendorf, Inken; Hochhaus, Andreas; Andrieux, Geoffroy; Börries, Melanie; Busch, Hauke; Magenau, John; Reddy, Pavan; Labopin, Myriam; Antin, Joseph H; Henden, Andrea S; Hill, Geoffrey R; Kennedy, Glen A; Bar, Merav; Sarma, Anita; McLornan, Donal; Mufti, Ghulam; Oran, Betul; Rezvani, Katayoun; Shah, Omid; Negrin, Robert S; Nagler, Arnon; Prinz, Marco; Burchert, Andreas; Neubauer, Andreas; Beelen, Dietrich; Mackensen, Andreas; von Bubnoff, Nikolas; Herr, Wolfgang; Becher, Burkhard; Socié, Gerard; Caligiuri, Michael A; Ruggiero, Eliana; Bonini, Chiara; Häcker, Georg; Duyster, Justus; Finke, Jürgen; Pearce, Erika; Blazar, Bruce R; Zeiser, Robert

2018-03-01

Individuals with acute myeloid leukemia (AML) harboring an internal tandem duplication (ITD) in the gene encoding Fms-related tyrosine kinase 3 (FLT3) who relapse after allogeneic hematopoietic cell transplantation (allo-HCT) have a 1-year survival rate below 20%. We observed that sorafenib, a multitargeted tyrosine kinase inhibitor, increased IL-15 production by FLT3-ITD + leukemia cells. This synergized with the allogeneic CD8 + T cell response, leading to long-term survival in six mouse models of FLT3-ITD + AML. Sorafenib-related IL-15 production caused an increase in CD8 + CD107a + IFN-γ + T cells with features of longevity (high levels of Bcl-2 and reduced PD-1 levels), which eradicated leukemia in secondary recipients. Mechanistically, sorafenib reduced expression of the transcription factor ATF4, thereby blocking negative regulation of interferon regulatory factor 7 (IRF7) activation, which enhanced IL-15 transcription. Both IRF7 knockdown and ATF4 overexpression in leukemia cells antagonized sorafenib-induced IL-15 production in vitro. Human FLT3-ITD + AML cells obtained from sorafenib responders following sorafenib therapy showed increased levels of IL-15, phosphorylated IRF7, and a transcriptionally active IRF7 chromatin state. The mitochondrial spare respiratory capacity and glycolytic capacity of CD8 + T cells increased upon sorafenib treatment in sorafenib responders but not in nonresponders. Our findings indicate that the synergism of T cells and sorafenib is mediated via reduced ATF4 expression, causing activation of the IRF7-IL-15 axis in leukemia cells and thereby leading to metabolic reprogramming of leukemia-reactive T cells in humans. Therefore, sorafenib treatment has the potential to contribute to an immune-mediated cure of FLT3-ITD-mutant AML relapse, an otherwise fatal complication after allo-HCT.

Successful treatment of paraganglioma with sorafenib: a case report and brief review of the literature

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Lin Y

2013-11-01

Full Text Available Yun Lin,1,* Qun Li,1,* Wei Huang,1 Xinyan Jia,1 Hong Jiang,1 Yong Gao,1 Qi Li1,21Department of Oncology, Shanghai East Hospital, 2Department of Oncology, Shanghai First People's Hospital, Shanghai, People's Republic of China*These authors contributed equally to this work, and are joint first authorsIntroduction: To date, no effective systemic therapies have been made available for paraganglioma. However, multiple mutations in susceptibility genes have been identified that are potential targets for sorafenib, an oral multitargeted tyrosine-kinase inhibitor.Case presentation: We report the case of a 69-year-old Chinese man with mediastinal paraganglioma that had metastasized to the bone. The paraganglioma responded to sorafenib, a novel multi-tyrosine kinase inhibitor that targets angiogenesis, the Raf-kinase pathway, the platelet-derived growth factor Ret, and c-Kit. The patient was diagnosed as having paraganglioma after biopsy of the mediastinal mass. We first treated the patient with radiotherapy. Then he tolerated an etoposide-and-cisplatin chemotherapy regimen. Subsequently, he received 6 months of maintenance treatment with sorafenib (400 mg twice daily. A dramatic reduction in tumor volume was observed. At present, the patient has achieved a partial response, and his clinical status remains unchanged.Conclusion: We suggest that sorafenib should be further investigated in the management of patients with paraganglioma.Keywords: sorafenib, paraganglioma, molecular-targeted drug

Synthesis of thermosensitive magnetic nanocarrier for controlled sorafenib delivery

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Heidarinasab, Amir [Department of Chemical Engineering, Science and Research Branch, Islamic Azad University, Tehran (Iran, Islamic Republic of); Ahmad Panahi, Homayon [Department of Chemistry, Central Tehran Branch, Islamic Azad University, Tehran (Iran, Islamic Republic of); Faramarzi, Mehdi, E-mail: faramarzi.iaug@gmail.com [Department of Chemical Engineering, Science and Research Branch, Islamic Azad University, Tehran (Iran, Islamic Republic of); Farjadian, Fatemeh [Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Shiraz University of Medical Sciences, Shiraz (Iran, Islamic Republic of)

2016-10-01

Allyl glycidyl ether/N-isopropylacrylamide-grafted magnetic nanoparticles were prepared using silica-coated magnetic nanoparticles as a substrate for radical copolymerization of allyl glycidyl ether and N-isopropylacrylamide. Chitosan was coupled with the prepared nanoparticles by opening the epoxy ring of the allyl glycidyl ether. The thermosensitive magnetic nanocarrier (TSMNC) obtained can be applied as a potent drug carrier. The TSMNC structure was characterized using Fourier transform infrared spectroscopy, X-ray diffraction, thermogravimetric analysis, differential scanning calorimetry, vibrating sample magnetometer, and elemental analysis. Its morphology and size were investigated using field emission scanning electron microscopy, transmission electron microscopy and dynamic light scattering. The feasibility of employing the TSMNC for adsorption and in vitro controlled release of the chemotherapeutic agent sorafenib was tested. The effect of the adsorption parameters of pH, temperature, and loading time of sorafenib onto TSMNC was evaluated. The adsorption data was fitted to the Langmuir and Freundlich isotherms and the relevant parameters derived. The drug release profile indicated that 88% of the adsorbed drug was released within 35 h at 45 °C and drug release was Fickian diffusion-controlled. The results confirmed that the TSMNC has a high adsorption capacity at low temperature and good controlled release in a slow rate at a high temperature and could be developed for further application as a drug nanocarrier. - Graphical abstract: Magnetic nanoparticles were functionalized with chitosan and N-isopropylacrylamide. It was evaluated for sorafenib (SFB) adsorption and tested as a controlled-release system in response to changes in temperature. The TSMNC showed superparamagnetic properties with a high adsorption capacity and desirable controlled release at below and above LCST. Display Omitted - Highlights: • A TSMNC was synthesized for controlled

Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer

DEFF Research Database (Denmark)

Brose, Marcia S; Nutting, Christopher M; Jarzab, Barbara

2014-01-01

cancer that had progressed within the past 14 months. Adult patients (≥18 years of age) with this type of cancer were enrolled from 77 centres in 18 countries. To be eligible for inclusion, participants had to have at least one measurable lesion by CT or MRI according to Response Evaluation Criteria...... cancer. Adverse events were consistent with the known safety profile of sorafenib. These results suggest that sorafenib is a new treatment option for patients with progressive radioactive iodine-refractory differentiated thyroid cancer. FUNDING: Bayer HealthCare Pharmaceuticals and Onyx Pharmaceuticals...

Research advances in sorafenib combined with orthotopic liver transplantation, radiofrequency ablation, and transarterial chemoembolization in treatment of hepatocellular carcinoma

Directory of Open Access Journals (Sweden)

ZHANG Mingjuan

2014-08-01

Full Text Available Hepatocellular carcinoma (HCC is one of the most common malignant tumors worldwide, and traditional surgery and chemotherapy provide limited benefit. Sorafenib, a multikinase inhibitor, was proved effective for advanced HCC in phase III clinical trial, which was a breakthrough in the treatment of HCC. In recent years, the studies on sorafenib combined with other therapies in the treatment of HCC have been conducted around the world, and inspiring results have been seen. The research advances in sorafenib combined with orthotopic liver transplantation, radiofrequency ablation, and transarterial chemoembolization in the treatment of HCC are summarized. It is thought that sorafenib combined with other anticancer therapies is expected to become a new approach of targeted therapy of HCC.

Sorafenib tosylate, Ribavirn and Sofosbuvir combination therapy for HCV virus infected patients with decompensated liver cancer.

Science.gov (United States)

Munir, Bushra; Ahmed, Bilal; Kiran, Shumaila; Jalal, Fatima; Zahoor, Muhammad Kashif; Shehzadi, Saba; Oranab, Sadaf; Kamran, Sayed Kashif; Ghaffar, Abdul

2017-11-01

Hepatitis C is the most common health problem worldwide and is major cause of death due to proliferation of hepatocellular carcinoma. The medicines available for HCV treatment overcome up-to 95% complications of HCV. However, liver cancer needs some additional care. Normally Sorafenib tosylate 200 mg is recommended for liver cancer. There is no such trial in which this drug could effectively be used in combination of direct acting antivirals for HCV. The study was conducted for HCV patients (n=30) with liver cancer having decompensated stage. Combination of Sorafenib tosylate, Ribavirn and Sofosbuvir were used for the pharmacokinetics of these medicines. Child pugh score less then 7 (CP A) in adults during treatment phase (received 12 weeks of Sorafenib tosylate 200 mg, Ribavirn and Sofosbuvir 400 mg once daily) have no side effect while child pugh score 7-9 (CP B) have evidence of hypertension. The main efficiency end point sustained virology response with overcoming liver cancer as well in 12 weeks after end treatment (SVR-LLC 12). Mean pharmacokinetic exposure to Sorafenib tosylate 200 mg, Ribavirn and Sofosbuvir at week 8th was 2.1, 1.5,1.2 times greater in CP B than in CP A. Adverse effects (AEs) were observed in 12 out of 30 patients but not severe as lethal for life. Treatment with Sorafenib tosylate, Ribavirn and Sofosbuvir for twelve weeks was harmless and well accepted, 100 % patients achieve (SVR LLC 12) with 10-fold cure rate more than previous ones. The combination therapy of Sorafenib tosylate, Ribavirn and Sofosbuvir was found helpful for the management of decompensated liver cancer.

A mesenchymal-like phenotype and expression of CD44 predict lack of apoptotic response to sorafenib in liver tumor cells.

Science.gov (United States)

Fernando, Joan; Malfettone, Andrea; Cepeda, Edgar B; Vilarrasa-Blasi, Roser; Bertran, Esther; Raimondi, Giulia; Fabra, Àngels; Alvarez-Barrientos, Alberto; Fernández-Salguero, Pedro; Fernández-Rodríguez, Conrado M; Giannelli, Gianluigi; Sancho, Patricia; Fabregat, Isabel

2015-02-15

The multikinase inhibitor sorafenib is the only effective drug in advanced cases of hepatocellular carcinoma (HCC). However, response differs among patients and effectiveness only implies a delay. We have recently described that sorafenib sensitizes HCC cells to apoptosis. In this work, we have explored the response to this drug of six different liver tumor cell lines to define a phenotypic signature that may predict lack of response in HCC patients. Results have indicated that liver tumor cells that show a mesenchymal-like phenotype, resistance to the suppressor effects of transforming growth factor beta (TGF-β) and high expression of the stem cell marker CD44 were refractory to sorafenib-induced cell death in in vitro studies, which correlated with lack of response to sorafenib in nude mice xenograft models of human HCC. In contrast, epithelial-like cells expressing the stem-related proteins EpCAM or CD133 were sensitive to sorafenib-induced apoptosis both in vitro and in vivo. A cross-talk between the TGF-β pathway and the acquisition of a mesenchymal-like phenotype with up-regulation of CD44 expression was found in the HCC cell lines. Targeted CD44 knock-down in the mesenchymal-like cells indicated that CD44 plays an active role in protecting HCC cells from sorafenib-induced apoptosis. However, CD44 effect requires a TGF-β-induced mesenchymal background, since the only overexpression of CD44 in epithelial-like HCC cells is not sufficient to impair sorafenib-induced cell death. In conclusion, a mesenchymal profile and expression of CD44, linked to activation of the TGF-β pathway, may predict lack of response to sorafenib in HCC patients. © 2014 UICC.

The multikinase inhibitor Sorafenib displays significant antiproliferative effects and induces apoptosis via caspase 3, 7 and PARP in B- and T-lymphoblastic cells

International Nuclear Information System (INIS)

Schult, Catrin; Boldt, Sonja; Wolkenhauer, Olaf; Neri, Luca Maria; Freund, Mathias; Junghanss, Christian; Dahlhaus, Meike; Ruck, Sabine; Sawitzky, Mandy; Amoroso, Francesca; Lange, Sandra; Etro, Daniela; Glass, Aenne; Fuellen, Georg

2010-01-01

Targeted therapy approaches have been successfully introduced into the treatment of several cancers. The multikinase inhibitor Sorafenib has antitumor activity in solid tumors and its effects on acute lymphoblastic leukemia (ALL) cells are still unclear. ALL cell lines (SEM, RS4;11 and Jurkat) were treated with Sorafenib alone or in combination with cytarabine, doxorubicin or RAD001. Cell count, apoptosis and necrosis rates, cell cycle distribution, protein phosphorylation and metabolic activity were determined. Sorafenib inhibited the proliferation of ALL cells by cell cycle arrest accompanied by down-regulation of CyclinD3 and CDK4. Furthermore, Sorafenib initiated apoptosis by cleavage of caspases 3, 7 and PARP. Apoptosis and necrosis rates increased significantly with most pronounced effects after 96 h. Antiproliferative effects of Sorafenib were associated with a decreased phosphorylation of Akt (Ser473 and Thr308), FoxO3A (Thr32) and 4EBP-1 (Ser65 and Thr70) as early as 0.5 h after treatment. Synergistic effects were seen when Sorafenib was combined with other cytotoxic drugs or a mTOR inhibitor emphasizing the Sorafenib effect. Sorafenib displays significant antileukemic activity in vitro by inducing cell cycle arrest and apoptosis. Furthermore, it influences PI3K/Akt/mTOR signaling in ALL cells

Radiosensitization effects of sorafenib on colon cancer cells

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Kim, Eun Ho; Kim, Mi-Sook; Jung, Won-Gyun; Jeong, Youn Kyoung [Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of)

2014-11-15

Radiotherapy is a standard therapy in the adjuvant treatment of resected colon and rectum cancers, and its combination with chemotherapy has been shown to reduce local failure and distant metastasis still further, thereby improving the outcome of treatment. One potential chemotherapeutic agent for this, sorafenib (Nexavar, BAY43-9006), is an oral multikinase inhibitor that blocks tumor cell proliferation and angiogenesis, and induces tumor cell apoptosis by inhibiting serine/threonine kinases (c-RAF and mutant and wild-type BRAF) as well as the receptor tyrosine kinases vascular endothelial growth factor receptor 2 and 3 (VEGFR2 and VEGFR3), platelet- derived growth factor receptor , FLT3, and c-KIT. Sorafenib is currently used in clinics to treat patients with advanced renal cell carcinoma, hepatocellular carcinoma, and thyroid cancer. These findings provide a molecular evidence base for the use of chemoradiation to treat colon cancer, and in vivo modeling should be used to further assess its suitability for clinical applications.

Hypothyroidism Side Effect in Patients Treated with Sunitinib or Sorafenib: Clinical and Structural Analyses

Science.gov (United States)

Shu, Mao; Zai, Xiaoli; Zhang, Beina; Wang, Rui; Lin, Zhihua

2016-01-01

Tyrosine kinase inhibitors (TKIs) provide more effective targeted treatments for cancer, but are subject to a variety of adverse effects, such as hypothyroidism. TKI-induced hypothyroidism is a highly complicated issue, because of not only the unrealized toxicological mechanisms, but also different incidences of individual TKI drugs. While sunitinib is suspected for causing thyroid dysfunction more often than other TKIs, sorafenib is believed to be less risky. Here we integrated clinical data and in silico drug-protein interactions to examine the pharmacological distinction between sunitinib and sorafenib. Statistical analysis on the FDA Adverse Event Reporting System (FAERS) confirmed that sunitinib is more concurrent with hypothyroidism than sorafenib, which was observed in both female and male patients. Then, we used docking method and identified 3 proteins specifically binding to sunitinib but not sorafenib, i.e., retinoid X receptor alpha, retinoic acid receptors beta and gamma. As potential off-targets of sunitinib, these proteins are well known to assemble with thyroid hormone receptors, which can explain the profound impact of sunitinib on thyroid function. Taken together, we established a strategy of integrated analysis on clinical records and drug off-targets, which can be applied to explore the molecular basis of various adverse drug reactions. PMID:26784451

The multi-targeted kinase inhibitor sorafenib inhibits enterovirus 71 replication by regulating IRES-dependent translation of viral proteins.

Science.gov (United States)

Gao, Meng; Duan, Hao; Liu, Jing; Zhang, Hao; Wang, Xin; Zhu, Meng; Guo, Jitao; Zhao, Zhenlong; Meng, Lirong; Peng, Yihong

2014-06-01

The activation of ERK and p38 signal cascade in host cells has been demonstrated to be essential for picornavirus enterovirus 71 (EV71) replication and up-regulation of virus-induced cyclooxygenase-2 (COX-2)/prostaglandins E2 (PGE2) expression. The aim of this study was to examine the effects of sorafenib, a clinically approved anti-cancer multi-targeted kinase inhibitor, on the propagation and pathogenesis of EV71, with a view to its possible mechanism and potential use in the design of therapy regimes for Hand foot and mouth disease (HFMD) patients with life threatening neurological complications. In this study, non-toxic concentrations of sorafenib were shown to inhibit the yield of infectious progeny EV71 (clinical BC08 strain) by about 90% in three different cell types. A similar inhibitory effect of sorafenib was observed on the synthesis of both viral genomic RNA and the VP1 protein. Interestingly, sorafenib exerted obvious inhibition of the EV71 internal ribosomal entry site (IRES)-mediated translation, the first step in picornavirus replication, by linking it to a firefly luciferase reporter gene. Sorafenib was also able to prevent both EV71-induced CPE and the activation of ERK and p38, which contributes to up-regulation COX-2/PGE2 expression induced by the virus. Overall, this study shows that sorafenib strongly inhibits EV71 replication at least in part by regulating viral IRES-dependent translation of viral proteins, indicating a novel potential strategy for the treatment of HFMD patients with severe neurological complications. To our knowledge, this is the first report that investigates the mechanism by which sorafenib inhibits EV71 replication. Copyright © 2014 Elsevier B.V. All rights reserved.

HATT: a phase IV, single-arm, open-label study of sorafenib in Taiwanese patients with advanced hepatocellular carcinoma.

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Lin, Shi-Ming; Lu, Sheng-Nan; Chen, Ping-Tsung; Jeng, Long-Bin; Chen, Shinn-Cherng; Hu, Chi-Tan; Yang, Sien-Sing; Le Berre, Marie-Aude; Liu, Xuan; Mitchell, David Y; Prins, Klaas; Grevel, Joachim; Peña, Carol A E; Meinhardt, Gerold

2017-03-01

Sorafenib significantly improves survival in patients with advanced hepatocellular carcinoma (HCC). This phase IV study assessed sorafenib efficacy/safety in Taiwanese patients with advanced HCC and Child-Pugh A status. All patients received 400 mg sorafenib BID. Safety, efficacy, sorafenib pharmacokinetics, and Child-Pugh progression were evaluated. A hand-foot skin reaction (HFSR) prevention substudy assessed HFSR incidence and grade/severity and time to HFSR in 29 and 34 patients randomized to corticosteroid and noncorticosteroid ointments, respectively, and in 88 nonrandomized patients. The 151 patients included 120 (80%) male patients and 81 (54%) with stage IV disease. Mean sorafenib dose was 626 mg/day, and median treatment duration was 4.2 months. Median overall survival (OS), progression-free survival, and time to progression (TTP) were 8.6, 2.7, and 3.8 months, respectively. Disease control and response rates (partial responses only) were 48 and 6.6%, respectively. Median TTP from Child-Pugh A to B/C was 88 days. Drug-related adverse events (AEs) occurred in 89.4% of patients; none were new or unexpected. The most frequent grade ≥3 drug-related, treatment-emergent AEs were HFSR (13.2%), diarrhea (11.9%), and hypertension (6.6%). Corticosteroid ointment tended to reduce the severity and incidence of all HFSR-associated parameters. Pharmacokinetic exposure was unaltered by Child-Pugh progression. The final pharmacokinetic model predicted 13.1 and 33.8% reductions in sorafenib exposure over 6 and 12 months, respectively. There was a trend of longer OS and TTP in Taiwanese patients with advanced HCC compared with patients with advanced HCC in the Asia-Pacific trial. Sorafenib exposure did not correlate with liver function. Reduced pharmacokinetic exposure over time was unrelated to reduced or interrupted dosing.

Yttrium-90 radioembolization vs sorafenib for intermediate-locally advanced hepatocellular carcinoma: a cohort study with propensity score analysis.

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Gramenzi, Annagiulia; Golfieri, Rita; Mosconi, Cristina; Cappelli, Alberta; Granito, Alessandro; Cucchetti, Alessandro; Marinelli, Sara; Pettinato, Cinzia; Erroi, Virginia; Fiumana, Silvia; Bolondi, Luigi; Bernardi, Mauro; Trevisani, Franco

2015-03-01

Sorafenib and transarterial (90) Y-radioembolization (TARE) are possible treatments for Barcelona Clinic Liver Cancer (BCLC) intermediate-advanced stage hepatocellular carcinoma (HCC). No study directly comparing sorafenib and TARE is currently available. This single-centre retrospective study compares the outcomes achieved with sorafenib and TARE in HCC patients potentially amenable to either therapy. Seventy-four sorafenib (71 ± 10 years, male 87%, BCLC B/C 53%/47%) and 63 TARE HCC patients (66 ± 9 years, male 79%, BCLC B/C 41%/59%) were included based on the following criteria: Child-Pugh class A/B, performance status ≤1, HCC unfit for other effective therapies, no metastases and no previous systemic chemotherapy. Median overall survivals of the two groups were comparable, being 14.4 months (95% CI: 4.3-24.5) in sorafenib and 13.2 months (95% CI: 6.1-20.2) in TARE patients, with 1-, 2- and 3-year survival rates of 52.1%, 29.3% and 14.7% vs 51.8%, 27.8% and 21.6% respectively. Two TARE patients underwent liver transplantation after successful down-staging. To minimize the impact of confounding factors on survival analysis, propensity model matched 32 patients of each group for median age, tumour gross pathology and the independent prognostic factors (portal vein thrombosis, performance status, Model for End Liver Disease). Even after matching, the median survival did not differ between sorafenib (13.1 months; 95% CI: 1.2-25.9) and TARE patients (11.2 months; 95% CI: 6.7-15.7), with comparable 1-, 2- and 3-year survival rates. In cirrhotic patients with intermediate-advanced or not-otherwise-treatable HCC, sorafenib and TARE provide similar survivals. Down-staging allowing liver transplantation only occurred after TARE. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Sorafenib-Regorafenib Sequential Therapy in Advanced Hepatocellular Carcinoma: A Single-Institute Experience.

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Ueshima, Kazuomi; Nishida, Naoshi; Kudo, Masatoshi

2017-01-01

Previously, no therapeutic agent has been known to improve the overall survival compared with placebo in patients with hepatocellular carcinoma (HCC), who have progressed after sorafenib. In this patient population, regorafenib was first demonstrated to confer a survival benefit in the RESORCE trial, and subsequently it was approved as a second-line treatment for patients with advanced HCC. An open-label expanded access program (EAP) of regorafenib was implemented for compassionate use. We investigated the efficacy and safety of regorafenib based on our experience of the RESORCE trial and the EAP. Data from 5 patients from the RESORCE trial and 6 from the EAP were analyzed retrospectively. All patients had tolerated prior sorafenib and were progressing during sorafenib treatment. The median progression-free survival was 9.2 months (95% CI 2.3-16.1). One patient achieved a partial response and 7 achieved stable disease. The objective response rate was 9.1%, and the disease control rate was 72.7%. No treatment-associated mortalities were observed. Grade 3 hypophosphatemia was observed in 2 patients, grade 2 anorexia was observed in 5 patients, and grade 3 neutropenia was observed in 2 patients. Grade 2 and grade 3 thrombocytopenia were observed in 2 and 3 patients, respectively. All treatment-related adverse events were improved by reduction or interruption of regorafenib. Five patients showed decreased serum albumin levels. Sorafenib and regorafenib sequential therapy presents a safe and effective treatment option for patients with advanced HCC. © 2017 S. Karger AG, Basel.

Epigastric Distress Caused by Esophageal Candidiasis in 2 Patients Who Received Sorafenib Plus Radiotherapy for Hepatocellular Carcinoma: Case Report.

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Chen, Kuo-Hsin; Weng, Meng-Tzu; Chou, Yueh-Hung; Lu, Yueh-Feng; Hsieh, Chen-Hsi

2016-03-01

Sorafenib followed by fractionated radiotherapy (RT) has been shown to decrease the phagocytic and candidacidal activities of antifungal agents due to radiosensitization. Moreover, sorafenib has been shown to suppress the immune system, thereby increasing the risk for candida colonization and infection. In this study, we present the 2 hepatocellular carcinoma (HCC) patients suffered from epigastric distress caused by esophageal candidiasis who received sorafenib plus RT. Two patients who had received sorafenib and RT for HCC with bone metastasis presented with hiccups, gastric ulcer, epigastric distress, anorexia, heart burn, and fatigue. Empiric antiemetic agents, antacids, and pain killers were ineffective at relieving symptoms. Panendoscopy revealed diffuse white lesions in the esophagus. Candida esophagitis was suspected. Results of periodic acid-Schiff staining were diagnostic of candidiasis. Oral fluconazole (150 mg) twice daily and proton-pump inhibitors were prescribed. At 2-weak follow-up, esophagitis had resolved and both patients were free of gastrointestinal symptoms. Physicians should be aware that sorafenib combined with RT may induce an immunosuppressive state in patients with HCC, thereby increasing their risk of developing esophagitis due to candida species.

Sorafenib targets the mitochondrial electron transport chain complexes and ATP synthase to activate the PINK1-Parkin pathway and modulate cellular drug response.

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Zhang, Conggang; Liu, Zeyu; Bunker, Eric; Ramirez, Adrian; Lee, Schuyler; Peng, Yinghua; Tan, Aik-Choon; Eckhardt, S Gail; Chapnick, Douglas A; Liu, Xuedong

2017-09-08

Sorafenib (Nexavar) is a broad-spectrum multikinase inhibitor that proves effective in treating advanced renal-cell carcinoma and liver cancer. Despite its well-characterized mechanism of action on several established cancer-related protein kinases, sorafenib causes variable responses among human tumors, although the cause for this variation is unknown. In an unbiased screening of an oncology drug library, we found that sorafenib activates recruitment of the ubiquitin E3 ligase Parkin to damaged mitochondria. We show that sorafenib inhibits the activity of both complex II/III of the electron transport chain and ATP synthase. Dual inhibition of these complexes, but not inhibition of each individual complex, stabilizes the serine-threonine protein kinase PINK1 on the mitochondrial outer membrane and activates Parkin. Unlike the protonophore carbonyl cyanide m -chlorophenylhydrazone, which activates the mitophagy response, sorafenib treatment triggers PINK1/Parkin-dependent cellular apoptosis, which is attenuated upon Bcl-2 overexpression. In summary, our results reveal a new mechanism of action for sorafenib as a mitocan and suggest that high Parkin activity levels could make tumor cells more sensitive to sorafenib's actions, providing one possible explanation why Parkin may be a tumor suppressor gene. These insights could be useful in developing new rationally designed combination therapies with sorafenib. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Correlation between LDH levels and response to sorafenib in HCC patients: an analysis of the ITA.LI.CA database.

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Sacco, Rodolfo; Mismas, Valeria; Granito, Alessandro; Musettini, Gianna; Masi, Gianluca; Caparello, Chiara; Vivaldi, Caterina; Felder, Martina; Bresci, Giampaolo; Fornaro, Lorenzo

2015-02-24

Lactate dehydrogenase (LDH) is a predictor of clinical outcome in hepatocellular carcinoma (HCC) patients. However, its predictive role in the clinical outcomes of sorafenib treatment has been poorly documented. The correlation between LDH levels and clinical outcomes in HCC patients treated with sorafenib and included in the nationwide Italian database ITA.LI.CA was investigated here. The ITA.LI.CA database contains data for 5,136 HCC patients. All patients treated with sorafenib treatment and with available LDH values were considered. Overall survival (OS) and time to progression (TTP) were compared in patients with LDH levels above and below a defined threshold, determined through an ROC analysis. An explorative analysis investigated the relationship between the variation of LDH levels during treatment and response to sorafenib. Baseline LDH levels were available for 97 patients. The most accurate cutoff value for LDH concentration was 297 U/L. Patients with LDH values above (n=45) and below (n=52) this threshold showed equal OS (12.0 months) and TTP (4.0 months) values. Data on LDH levels during sorafenib treatment were reported for 10 patients. LDH values decreased in 3 patients (mean difference = -219 U/L) who also reported a prolonged OS and TTP versus those with unmodified/increased LDH (OS: NE (not evaluated) vs. 8.0 months, p=0.0083; TTP: 19.0 vs. 3.0 months, p=0.008). The clinical benefits of sorafenib do not seem to be influenced by baseline LDH. According to the results of an explorative analysis, however, a decreased LDH concentration during sorafenib might be associated with improved clinical outcomes.

Sorafenib in Advanced Hepatocellular Carcinoma: A Nationwide Retrospective Study of Efficacy and Tolerability

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Anne Helene Køstner

2013-01-01

Full Text Available Background. Advanced HCC is a clinical challenge with limited treatment options. The multikinase inhibitor sorafenib is the first and only agent showing a survival benefit in these patients. In this study we evaluate the efficacy and tolerability of sorafenib in an unselected patient population. Furthermore we explore the role of alpha-fetoprotein (αFP as a potential biomarker for treatment efficacy and correlation to survival. Methods. Seventy-six patients with advanced HCC, not eligible for locoregional therapy, treated with sorafenib between 2007 and 2009 were included. Followup was until 2011. Results. Patients in PS 0-1 had a median overall survival (mOS of 6.2 months, compared to 1.8 months in patients with poorer PS (P=0.005. Child-Pugh A patients had a mOS of 6.6 months versus 3.6 months among patients in Child-Pugh B or C (P=0.0001. Serum αFP ≥ 200 at baseline was prognostic for a shorter survival. All patients with radiologically verified tumor response and baseline αFP ≥ 200 experienced a significant decline in αFP within the first four weeks of treatment. Conclusion. The survival of patients with advanced HCC treated with sorafenib is dependent on performance status and liver function. Treatment of patients with compromised liver function and poor performance status cannot be recommended. The correlation between αFP and objective tumor response warrants further investigation.

Simultaneous silencing of ACSL4 and induction of GADD45B in hepatocellular carcinoma cells amplifies the synergistic therapeutic effect of aspirin and sorafenib

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Xia, Hongping; Lee, Kee Wah; Chen, Jianxiang; Kong, Shik Nie; Sekar, Karthik; Deivasigamani, Amudha; Seshachalam, Veerabrahma Pratap; Goh, Brian Kim Poh; Ooi, London Lucien; Hui, Kam M

2017-01-01

Sorafenib is currently the only US Food and Drug Administration (FDA)-approved molecular inhibitor for the systemic therapy of advanced hepatocellular carcinoma (HCC). Aspirin has been studied extensively as an anti-inflammation, cancer preventive and therapeutic agent. However, the potential synergistic therapeutic effects of sorafenib and aspirin on advanced HCC treatment have not been well studied. Drug combination studies and their synergy quantification were performed using the combination index method of Chou-Talalay. The synergistic therapeutic effects of sorafenib and aspirin were evaluated using an orthotopic mouse model of HCC and comprehensive gene profiling analyses were conducted to identify key factors mediating the synergistic therapeutic effects of sorafenib and aspirin. Sorafenib was determined to act synergistically on HCC cells with aspirin in vitro. Using Hep3B and HuH7 HCC cells, it was demonstrated that sorafenib and aspirin acted synergistically to induce apoptosis. Mechanistic studies demonstrated that combining sorafenib and aspirin yielded significant synergistically anti-tumor effects by simultaneously silencing ACSL4 and the induction of GADD45B expression in HCC cells both in vitro and in the orthotopic HCC xenograft mouse model. Importantly, clinical evidence has independently corroborated that survival of HCC patients expressing ACSL4highGADD45Blow was significantly poorer compared to patients with ACSL4lowGADD45Bhigh, thus demonstrating the potential clinical value of combining aspirin and sorafenib for HCC patients expressing ACSL4highGADD45Blow. In conclusion, sorafenib and aspirin provide synergistic therapeutic effects on HCC cells that are achieved through simultaneous silencing of ACSL4 and induction of GADD45B expression. Targeting HCC with ACSL4highGADD45Blow expression with aspirin and sorafenib could provide potential synergistic therapeutic benefits. PMID:28900541

Sorafenib-Associated Heart Failure Complicated by Cardiogenic Shock after Treatment of Advanced Stage Hepatocellular Carcinoma: A Clinical Case Discussion

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Candace Wu

2017-01-01

Full Text Available Background. Sorafenib, an oral tyrosine kinase inhibitor (TKI, targets multiple tyrosine kinase receptors (TKRs involved in angiogenesis and tumor growth. Studies suggest that inhibition of TKR impacts cardiomyocyte survival. Inhibition of VEGF signaling interrupts angiogenesis and is associated with the development of hypertension and compensatory hypertrophy. Compensated hypertrophy ultimately leads to heart failure. Case Description. A 76-year-old man with a past medical history of systolic heart failure due to ischemic cardiomyopathy and stage IIIC hepatocellular carcinoma (HCC presented with symptoms of decompensated heart failure. Four months prior to admission, he was started on sorafenib. Results. Our patient was treated with intravenous furosemide and guideline directed therapy. Clinical status was complicated by the development of low cardiac output and shock requiring inotropic support. Careful titration of heart failure medication led to hemodynamic improvement and discontinuation of dobutamine. Conclusion. Greater awareness of sorafenib cardiotoxicity is essential. As TKI usage grows for treatment of cancers, heart failure-related complications will increase. In our patient, routine heart failure management and cessation of sorafenib led to clinical improvement. Future studies on the treatment of sorafenib cardiotoxicity should be explored further in this unique patient population.

Transferrin targeted core-shell nanomedicine for combinatorial delivery of doxorubicin and sorafenib against hepatocellular carcinoma.

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Malarvizhi, Giridharan Loghanathan; Retnakumari, Archana Payickattu; Nair, Shantikumar; Koyakutty, Manzoor

2014-11-01

Combinatorial drug delivery is an attractive, but challenging requirement of next generation cancer nanomedicines. Here, we report a transferrin-targeted core-shell nanomedicine formed by encapsulating two clinically used single-agent drugs, doxorubicin and sorafenib against liver cancer. Doxorubicin was loaded in poly(vinyl alcohol) nano-core and sorafenib in albumin nano-shell, both formed by a sequential freeze-thaw/coacervation method. While sorafenib from the nano-shell inhibited aberrant oncogenic signaling involved in cell proliferation, doxorubicin from the nano-core evoked DNA intercalation thereby killing >75% of cancer cells. Upon targeting using transferrin ligands, the nanoparticles showed enhanced cellular uptake and synergistic cytotoxicity in ~92% of cells, particularly in iron-deficient microenvironment. Studies using 3D spheroids of liver tumor indicated efficient penetration of targeted core-shell nanoparticles throughout the tissue causing uniform cell killing. Thus, we show that rationally designed core-shell nanoparticles can effectively combine clinically relevant single-agent drugs for exerting synergistic activity against liver cancer. Transferrin-targeted core-shell nanomedicine encapsulating doxorubicin and sorafenib was studied as a drug delivery system against hepatocellular carcinoma, resulting in enhanced and synergistic therapeutic effects, paving the way towards potential future clinical applications of similar techniques. Copyright © 2014 Elsevier Inc. All rights reserved.

Impact of neo-adjuvant Sorafenib treatment on liver transplantation in HCC patients - a prospective, randomized, double-blind, phase III trial

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Hoffmann, Katrin; Ganten, Tom; Gotthardtp, Daniel; Radeleff, Boris; Settmacher, Utz; Kollmar, Otto; Nadalin, Silvio; Karapanagiotou-Schenkel, Irini; Kalle, Christof von; Jäger, Dirk; Büchler, Markus W; Schemmer, Peter

2015-01-01

Liver Transplantation (LT) is treatment of choice for patients with hepatocellular carcinoma (HCC) within MILAN Criteria. Tumour progression and subsequent dropout from waiting list have significant impact on the survival. Transarterial chemoembolization (TACE) controls tumour growth in the treated HCC nodule, however, the risk of tumour development in the untreated liver is increased by simultaneous release of neo-angiogenic factors. Due to its anti-angiogenic effects, Sorafenib delays the progression of HCC. Aim of this study was to determine whether combination of TACE and Sorafenib improves tumour control in HCC patients on waiting list for LT. Fifty patients were randomly assigned on a 1:1 ratio in double-blinded fashion at four centers in Germany and treated with TACE plus either Sorafenib (n = 24) or placebo (n = 26). The end of treatment was development of progressive disease according to mRECIST criteria or LT. The primary endpoint of the trial was the Time-to-Progression (TTP). Other efficacy endpoints were Tumour Response, Progression-free Survival (PFS), and Time-to-LT (TTLT). The median time of treatment was 125 days with Sorafenib and 171 days with the placebo. Fourteen patients (seven from each group) developed tumour progression during the course of the study period. The Hazard Ratio of TTP was 1.106 (95% CI: 0.387, 3.162). The results of the Objective Response Rate, Disease Control Rate, PFS, and TTLT were comparable in both groups. The incidence of AEs was comparable in the placebo group (n = 23, 92%) and in the Sorafenib group (n = 23, 96%). Twelve patients (50%) on Sorafenib and four patients (16%) on placebo experienced severe treatment-related AEs. The TTP is similar after neo-adjuvant treatment with TACE and Sorafenib before LT compared to TACE and placebo. The Tumour Response, PFS, and TTLT were comparable. The safety profile of the Sorafenib group was similar to that of the placebo group

Drug-induced lung injury associated with sorafenib: analysis of all-patient post-marketing surveillance in Japan.

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Horiuchi-Yamamoto, Yuka; Gemma, Akihiko; Taniguchi, Hiroyuki; Inoue, Yoshikazu; Sakai, Fumikazu; Johkoh, Takeshi; Fujimoto, Kiminori; Kudoh, Shoji

2013-08-01

Sorafenib is a multi-kinase inhibitor currently approved in Japan for unresectable and/or metastatic renal cell carcinoma and unresectable hepatocellular carcinoma. Although drug-induced lung injury has recently been the focus of interest in Japanese patients treated with molecular targeting agents, the clinical features of patients receiving sorafenib remain to be completely investigated. All-patient post-marketing surveillance data was obtained within the frame of Special Drug Use Investigation; between April 2008 and March 2011, we summarized the clinical information of 62 cases with drug-induced lung injury among approximately 13,600 sorafenib-treated patients in Japan. In addition, we summarized the results of evaluation by a safety board of Japanese experts in 34 patients in whom pulmonary images were available. For the calculation of reporting frequency, interim results of Special Drug Use Investigation were used. In the sets of completed reports (2,407 in renal cell carcinoma and 647 in hepatocellular carcinoma), the reporting frequency was 0.33 % (8 patients; fatal, 4/8) and 0.62 % (4 patients; fatal, 2/4), respectively. Major clinical symptoms included dyspnea, cough, and fever. Evaluation of the images showed that 18 cases out of 34 patients had a pattern of diffuse alveolar damage. The patients with hepatocellular carcinoma showed a greater incidence and earlier onset of lung injury than those with renal cell carcinoma. Although the overall reporting frequency of sorafenib-induced lung injury is not considered high, the radiological diffuse alveolar damage pattern led to a fatal outcome. Therefore, early recognition of sorafenib-induced lung injury is crucial for physicians and patients.

Safety and efficacy of transarterial chemoembolization plus sorafenib for hepatocellular carcinoma with portal venous tumour thrombus

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Pan, T.; Li, X.-S.; Xie, Q.-K.; Wang, J.-P.; Li, W.; Wu, P.-H.; Zhao, M.

2014-01-01

Aim: To evaluate the safety and efficacy of combined therapy with transarterial chemoembolization (TACE) and sorafenib for hepatocellular carcinoma (HCC) with portal venous tumour thrombus (PVTT). Materials and methods: This study was approved by the institutional review board. From May 2009 to May 2012, 170 consecutive patients were newly diagnosed with advanced-stage HCC and treated with TACE plus sorafenib. Among them, 41 patients with PVTT were retrospectively enrolled in the study. The adverse events (AEs), overall survival (OS), time to progression (TTP), and prognostic factors were analysed. Statistical analysis was performed with the Kaplan–Meier method using the log-rank test and Cox regression models. Results: The most common AEs were hand–foot skin reaction related to sorafenib and fever related to TACE. Procedure-related mortality and grade 4 AEs were not observed. Grade 3 AEs were observed in five patients. During the median follow-up period of 13.5 months (range 1.4–45 months), the 6-month and 1-year survival rates were 87.7% and 53.6%, respectively. The median OS was 13 months (range 1.4–44.8 months), and the median TTP was 7 months (range 1–18.6 months). The Child–Pugh class (p = 0.022), extrahepatic metastasis (p = 0.009), and gross morphological type (nodular type versus diffuse type; p = 0.008) were prognostic factors related to OS in the multivariate analysis. Conclusion: TACE plus sorafenib in an interrupted therapeutic scheme was well tolerated and might improve OS for HCC patients with PVTT, especially in those with Child–Pugh class A, no extrahepatic metastasis, or nodular-type HCC. - Highlights: • We introduce the safety of TACE plus sorafenib for patients with advanced HCC and PVTT. • We suggest that the combined therapy might prolong the TTP and OS than sorafenib alone. • Clinic benefit determinations with the Child-Pugh class, extrahepatic metastasis or gross type

Sorafenib Increases Tumor Hypoxia in Cervical Cancer Patients Treated With Radiation Therapy: Results of a Phase 1 Clinical Study

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Milosevic, Michael F., E-mail: mike.milosevic@rmp.uhn.ca [Radiation Medicine Program, Princess Margaret Cancer Center, University Health Network, Toronto (Canada); Department of Radiation Oncology, University of Toronto, Toronto (Canada); Townsley, Carol A. [Department of Medical Oncology, Princess Margaret Cancer Center, University Health Network, Toronto (Canada); Chaudary, Naz [Department of Advanced Molecular Oncology, Princess Margaret Cancer Center, University Health Network, Toronto (Canada); Clarke, Blaise [Department of Pathology, Princess Margaret Cancer Center, University Health Network, Toronto (Canada); Department of Laboratory Medicine and Pathology, University of Toronto, Toronto (Canada); Pintilie, Melania [Department of Clinical Study Coordination and Biostatistics, Princess Margaret Cancer Center, University Health Network, Toronto (Canada); Fan, Stacy; Glicksman, Rachel [Radiation Medicine Program, Princess Margaret Cancer Center, University Health Network, Toronto (Canada); Haider, Masoom [Department of Medical Imaging, Sunnybrook Health Sciences Centre, Toronto (Canada); Department of Medical Imaging, University of Toronto, Toronto (Canada); Kim, Sunmo [Radiation Medicine Program, Princess Margaret Cancer Center, University Health Network, Toronto (Canada); MacKay, Helen [Department of Medical Oncology, Princess Margaret Cancer Center, University Health Network, Toronto (Canada); Department of Medicine, University of Toronto, Toronto (Canada); Yeung, Ivan [Radiation Medicine Program, Princess Margaret Cancer Center, University Health Network, Toronto (Canada); Department of Radiation Oncology, University of Toronto, Toronto (Canada); Hill, Richard P. [Department of Radiation Oncology, University of Toronto, Toronto (Canada); Department of Advanced Molecular Oncology, Princess Margaret Cancer Center, University Health Network, Toronto (Canada); Department of Medical Biophysics, University of Toronto, Toronto (Canada); and others

2016-01-01

Purpose: Preclinical studies have shown that angiogenesis inhibition can improve response to radiation therapy (RT). The purpose of this phase 1 study was to examine the angiogenesis inhibitor sorafenib in patients with cervical cancer receiving radical RT and concurrent cisplatin (RTCT). Methods and Materials: Thirteen patients with stage IB to IIIB cervical cancer participated. Sorafenib was administered daily for 7 days before the start of standard RTCT in patients with early-stage, low-risk disease and also during RTCT in patients with high-risk disease. Biomarkers of tumor vascularity, perfusion, and hypoxia were measured at baseline and again after 7 days of sorafenib alone before the start of RTCT. The median follow-up time was 4.5 years. Results: Initial complete response was seen in 12 patients. One patient died without achieving disease control, and 4 experienced recurrent disease. One patient with an extensive, infiltrative tumor experienced pelvic fistulas during treatment. The 4-year actuarial survival was 85%. Late grade 3 gastrointestinal toxicity developed in 4 patients. Sorafenib alone produced a reduction in tumor perfusion/permeability and an increase in hypoxia, which resulted in early closure of the study. Conclusions: Sorafenib increased tumor hypoxia, raising concern that it might impair rather than improve disease control when added to RTCT.

A Phase I Study of the Combination of Sorafenib With Temozolomide and Radiation Therapy for the Treatment of Primary and Recurrent High-Grade Gliomas

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Den, Robert B.; Kamrava, Mitchell; Sheng, Zhi; Werner-Wasik, Maria; Dougherty, Erin; Marinucchi, Michelle; Lawrence, Yaacov R.; Hegarty, Sarah; Hyslop, Terry; Andrews, David W.; Glass, Jon; Friedman, David P.; Green, Michael R.; Camphausen, Kevin; Dicker, Adam P.

2013-01-01

Purpose: Despite recent advances in the management of high-grade and recurrent gliomas, survival remains poor. Antiangiogenic therapy has been shown to be efficacious in the treatment of high-grade gliomas both in preclinical models and in clinical trials. We sought to determine the safety and maximum tolerated dose of sorafenib when combined with both radiation and temozolomide in the primary setting or radiation alone in the recurrent setting. Methods and Materials: This was a preclinical study and an open-label phase I dose escalation trial. Multiple glioma cell lines were analyzed for viability after treatment with radiation, temozolomide, or sorafenib or combinations of them. For patients with primary disease, sorafenib was given concurrently with temozolomide (75 mg/m 2 ) and 60 Gy radiation, for 30 days after completion of radiation. For patients with recurrent disease, sorafenib was combined with a hypofractionated course of radiation (35 Gy in 10 fractions). Results: Cell viability was significantly reduced with the combination of radiation, temozolomide, and sorafenib or radiation and sorafenib. Eighteen patients (11 in the primary cohort, 7 in the recurrent cohort) were enrolled onto this trial approved by the institutional review board. All patients completed the planned course of radiation therapy. The most common toxicities were hematologic, fatigue, and rash. There were 18 grade 3 or higher toxicities. The median overall survival was 18 months for the entire population. Conclusions: Sorafenib can be safely combined with radiation and temozolomide in patients with high-grade glioma and with radiation alone in patients with recurrent glioma. The recommended phase II dose of sorafenib is 200 mg twice daily when combined with temozolomide and radiation and 400 mg with radiation alone. To our knowledge, this is the first publication of concurrent sorafenib with radiation monotherapy or combined with radiation and temozolomide.

PKI-587 and sorafenib targeting PI3K/AKT/mTOR and Ras/Raf/MAPK pathways synergistically inhibit HCC cell proliferation.

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Gedaly, Roberto; Angulo, Paul; Hundley, Jonathan; Daily, Michael F; Chen, Changguo; Evers, B Mark

2012-08-01

Deregulated Ras/Raf/MAPK and PI3K/AKT/mTOR signaling pathways are found in hepatocellular carcinoma (HCC). This study aimed to test the inhibitory effects of PKI-587 and sorafenib as single agents or in combination on HCC (Huh7 cell line) proliferation. (3)H-thymidine incorporation and MTT assay were used to assess Huh7 cell proliferation. Phosphorylation of the key enzymes in the Ras/Raf/MAPK and PI3K/AKT/mTOR pathways was detected by Western blot. We found that PKI-587 is a more potent PI3K/mTOR inhibitor than PI-103. Combination of PKI-587 and sorafenib was a more effective inhibitor of Huh7 proliferation than the combination of PI-103 and sorafenib. Combination of PKI-587 and sorafenib synergistically inhibited epidermal growth factor (EGF)-stimulated Huh7 proliferation compared with monodrug therapy. EGF increased phosphorylation of Ras/Raf downstream signaling proteins MEK and ERK; EGF-stimulated activation was inhibited by sorafenib. However, sorafenib, as a single agent, increased AKT (Ser473) phosphorylation. EGF-stimulated AKT (ser473) activation was inhibited by PKI-587. PKI-587 is a potent inhibitor of AKT (Ser473), mTOR (Ser2448), and S6K (Thr389) phosphorylation; in contrast, rapamycin stimulated mTOR complex 2 substrate AKT(Ser473) phosphorylation although it inhibited mTOR complex 1 substrate S6K phosphorylation. PKI-587, as a single agent, stimulated MEK and ERK phosphorylation. However, when PKI-587 and sorafenib were used in combination, they inhibited all the tested kinases in the Ras/Raf /MAPK and PI3K/AKT/mTOR pathways. The combination of PKI-587 and sorafenib has the advantage over monodrug therapy on inhibition of HCC cell proliferation by blocking both PI3K/AKT/mTOR and Ras/Raf/MAPK signaling pathways. Copyright © 2012 Elsevier Inc. All rights reserved.

Initial Experience of Sorafenib Neoadjuvant Therapy Combined with Retroperitoneoscopy in Treating T2 Large Renal Carcinoma

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Chun-hua Lin

2015-01-01

Full Text Available Objectives. To investigate the safety and feasibility of sorafenib neoadjuvant therapy combined with retroperitoneoscopic radical nephrectomy (RRN in treating T2 large renal cell carcinoma (RCC. Methods. Retrospectively analyzed 5 cases (2 males and 3 females, aged 52–73 years of T2 stage large RCC who receive preoperative sorafenib targeted treatment (400 mg bid for 1–3 months and RRN between March, 2013, and July, 2014. Patient information, therapeutic regimen, drug adverse effect, tumor changes before and after surgery, and perioperative parameters were recorded. Results. During the sorafenib therapy adverse effects included 2 cases of hypertension (Grade I toxicity, 1 case of hand-foot syndrome (Grade I, and 1 case of diarrhea (Grade II, which were all tolerable for patients. CT scan and histopathological tests confirmed significant reduction in the longest dimension (LD and medium density (MD of the tumor after therapy as well as tumor hemorrhage, necrosis, and cystic degeneration. All 5 patients received RRN surgery successfully around 2 weeks after drug discontinuation with only 1 case of perioperative complication. Conclusions. Sorafenib neoadjuvant therapy could significantly reduce the size and aggressiveness of T2 large renal tumors, thus reducing the operative challenge and enabling patients who were previously disqualified for operation to receive surgical treatment.

Measurement of sorafenib plasma concentration by high-performance liquid chromatography in patients with advanced hepatocellular carcinoma: is it useful the application in clinical practice? A pilot study.

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Fucile, Carmen; Marenco, Simona; Bazzica, Marco; Zuccoli, Maria Laura; Lantieri, Francesca; Robbiano, Luigi; Marini, Valeria; Di Gion, Paola; Pieri, Giulia; Stura, Paola; Martelli, Antonietta; Savarino, Vincenzo; Mattioli, Francesca; Picciotto, Antonino

2015-01-01

Pharmacokinetics and dose-finding studies on sorafenib were conducted on heterogeneous groups of patients with solid tumors. Portal hypertension, gut motility impairment and altered bile enterohepatic circulation may explain different sorafenib toxicological profile in cirrhotic patients. This study evaluated sorafenib plasma concentration in a homogeneous group of cirrhotic patients with hepatocellular carcinoma (HCC). Sorafenib concentrations were determined by liquid chromatography in 12 consecutive patients. Data have been evaluated by the generalized estimating equations method (p value statistical level was set at α = 0.05). (1) There were not significant differences between sorafenib concentrations in patients who tolerate the full dose versus patients with reduced dose due to toxicity; (2) the average sorafenib concentrations measured 3 h after the morning dosing were lower than those measured 12 h after the evening dosing (p = 0.005); (3) sorafenib concentrations decrease overtime (p < 10(-4)); (4) it has been found an association between the development of severe adverse reactions and sorafenib concentrations (p < 10(-5)). The relationship between dose and concentration of sorafenib in HCC patients is poor and not clinically predictable, confirming the variability both in the maximum tolerated dose and in plasma concentrations. Several factors may influence the pharmacokinetics in patients with liver disease. This may explain the inter-patient variability of concentrations and the lack of differences in concentration at different dosages. It could be interesting to extend the series of HCC patients to enhance information on the kinetics of the drug; furthermore, to establish a threshold of plasma sorafenib concentrations to predict severe adverse reactions would be clinically useful.

Safety and efficacy results of the advanced renal cell carcinoma sorafenib expanded access program in North America.

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Stadler, Walter M; Figlin, Robert A; McDermott, David F; Dutcher, Janice P; Knox, Jennifer J; Miller, Wilson H; Hainsworth, John D; Henderson, Charles A; George, Jeffrey R; Hajdenberg, Julio; Kindwall-Keller, Tamila L; Ernstoff, Marc S; Drabkin, Harry A; Curti, Brendan D; Chu, Luis; Ryan, Christopher W; Hotte, Sebastien J; Xia, Chenghua; Cupit, Lisa; Bukowski, Ronald M

2010-03-01

The Advanced Renal Cell Carcinoma Sorafenib (ARCCS) program made sorafenib available to patients with advanced renal cell carcinoma (RCC) before regulatory approval. In this nonrandomized, open-label expanded access program, 2504 patients from the United States and Canada were treated with oral sorafenib 400 mg twice daily. Safety and efficacy were explored overall and in subgroups of patients including those with no prior therapy, nonclear cell (nonclear cell) RCC, brain metastases, prior bevacizumab treatment, and elderly patients. Sorafenib was approved for RCC 6 months after study initiation, at which time patients with no prior therapy or with nonclear cell RCC could enroll in an extension protocol for continued assessment for a period of 6 months. The most common grade > or =2 drug-related adverse events were hand-foot skin reaction (18%), rash (14%), hypertension (12%), and fatigue (11%). In the 1891 patients evaluable for response, complete response was observed in 1 patient, partial response in 67 patients (4%), and stable disease for at least 8 weeks in 1511 patients (80%). Median progression-free survival in the extension population was 36 weeks (95% confidence interval [CI], 33-45 weeks; censorship rate, 56%); median overall survival in the entire population was 50 weeks (95% CI, 46-52 weeks; censorship rate, 63%). The efficacy and safety results were similar across the subgroups. Sorafenib 400 mg twice daily demonstrated activity and a clinically acceptable toxicity profile in all patient subsets enrolled in the ARCCS expanded access program (clinicaltrials.gov identifier: NCT00111020).

Safety and toxicity of radioembolization plus Sorafenib in advanced hepatocellular carcinoma: analysis of the European multicentre trial SORAMIC.

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Ricke, Jens; Bulla, Karsten; Kolligs, Frank; Peck-Radosavljevic, Markus; Reimer, Peter; Sangro, Bruno; Schott, Eckart; Schütte, Kerstin; Verslype, Chris; Walecki, Jerzy; Malfertheiner, Peter

2015-02-01

The benefits of combined systemic and liver-directed treatments in inoperable intermediate- or advanced-stage hepatocellular carcinoma (HCC) have yet to be defined. This article presents the planned safety analyses for the first 40 patients randomized to radioembolization with yttrium-90 ((90) Y) resin microspheres followed by sorafenib (n = 20) or sorafenib only (n = 20) in the SORAMIC study. Patients identified for palliative treatment who were poor candidates for transarterial (chemo)embolization (including those failing TACE) with preserved liver function (Child-Pugh ≤B7) and ECOG performance status arm. Patients were followed up for a median of 8.3 months. Median total implanted activity of (90) Y was 1.87 (range: 0.54-2.35) GBq. Patients received a similar intensity and duration of sorafenib in the combination-treatment arm (median daily dose 614 mg over 8.5 months) and control arm (557 mg over 9.6 months). The incidence of total (196 vs. 222) and grade ≥3 (43 vs. 47) adverse events was similar in combination-treatment arm and control arm respectively (P > 0.05). No significant differences in the number of total or grade 3/4 toxicities were recorded for: total bilirubin, albumin, liver enzymes, ascites, Child-Pugh, fatigue, hand-foot skin reaction, blood pressure or diarrhoea. Radioembolization followed by sorafenib appears to be as well tolerated as sorafenib alone. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Sorafenib and locoregional deep electro-hyperthermia in advanced hepatocellular carcinoma: A phase II study

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GADALETA-CALDAROLA, GENNARO; INFUSINO, STEFANIA; GALISE, IDA; RANIERI, GIROLAMO; VINCIARELLI, GIANLUCA; FAZIO, VITO; DIVELLA, ROSA; DANIELE, ANTONELLA; FILIPPELLI, GIANFRANCO; GADALETA, COSMO DAMIANO

2014-01-01

The standard treatment for advanced hepatocellular carcinoma (HCC) is sorafenib, a multikinase inhibitor of tumor cell proliferation and angiogenesis. Hyperthermia inhibits angiogenesis and promotes apoptosis. Potential synergic antiangiogenic and proapoptotic effects represent the rationale for combining sorafenib with electro-hyperthermia (EHY) in HCC. A total of 21 patients (median age, 64 years; range, 55–73 years) with advanced HCC were enrolled in the current study between February 2009 and September 2010. EHY was achieved by arranging capacitive electrodes with a deep hypothermia radiofrequency field of 13.56 Mhz at 80 W for 60 min, three times per week for six weeks, followed by two weeks without treatment, in combination with sorafenib at a dose of 800 mg every other day. According to the modified Response Evaluation Criteria in Solid Tumors criteria, 50% achieved stable disease, 5% achieved partial response and 45% achieved progressive disease. No complete response was observed. The progression-free survival (PFS) rate at six months was 38%, while the median PFS and overall survival times were 5.2 [95% confidence interval (CI), 4.2–6.2) and 10.4 (95% CI, 10–11) months, respectively. The overall incidence of treatment-related adverse events was 80%, predominantly of grade 1 or 2. Grade 3 toxicity included fatigue, diarrhea, hand-foot skin reaction and hypertension. In the present study, the sorafenib plus EHY combination was feasible and well tolerated, and no major complications were observed. The initial findings indicated that this combination offers a promising option for advanced HCC. PMID:25202410

Prevention of pulmonary vascular and myocardial remodeling by the combined tyrosine and serine-/threonine kinase inhibitor, sorafenib, in pulmonary hypertension and right heart failure

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M. Klein

2008-06-01

Full Text Available Inhibition of tyrosine kinases can reverse pulmonary hypertension but little is known about the role of serine-/threonine kinases in vascular and myocardial remodeling. We investigated the effects of sorafenib, an inhibitor of the tyrosine kinases VEGFR, PDGFR and c-kit as well as the serine-/threonine kinase Raf-1, in pulmonary hypertension and right ventricular (RV pressure overload. In monocrotaline treated rats, sorafenib (10 mg·kg–1·d–1 p.o. reduced pulmonary arterial pressure, pulmonary artery muscularization and RV hypertrophy, and improved systemic hemodynamics (table 1. Sorafenib prevented phosphorylation of Raf-1 and suppressed activation of downstream signaling pathways (Erk 1/2. After pulmonary banding, sorafenib, but not the PDGFR/c-KIT/ABL-inhibitor imatinib reduced RV mass and RV filling pressure significantly. Congruent with these results, sorafenib only prevented ERK phosphorylation and vasopressin induced hypertrophy of the cardiomyocyte cell line H9c2 dose dependently (IC50 = 300 nM. Combined inhibition of tyrosine and serine-/threonine kinases by sorafenib prevents vascular and cardiac remodeling in pulmonary hypertension, which is partly mediated via inhibition of the Raf kinase pathway.

A pooled analysis of sequential therapies with sorafenib and sunitinib in metastatic renal cell carcinoma.

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Stenner, Frank; Chastonay, Rahel; Liewen, Heike; Haile, Sarah R; Cathomas, Richard; Rothermundt, Christian; Siciliano, Raffaele D; Stoll, Susanna; Knuth, Alexander; Buchler, Tomas; Porta, Camillo; Renner, Christoph; Samaras, Panagiotis

2012-01-01

To evaluate the optimal sequence for the receptor tyrosine kinase inhibitors (rTKIs) sorafenib and sunitinib in metastatic renal cell cancer. We performed a retrospective analysis of patients who had received sequential therapy with both rTKIs and integrated these results into a pooled analysis of available data from other publications. Differences in median progression-free survival (PFS) for first- (PFS1) and second-line treatment (PFS2), and for the combined PFS (PFS1 plus PFS2) were examined using weighted linear regression. In the pooled analysis encompassing 853 patients, the median combined PFS for first-line sunitinib and 2nd-line sorafenib (SuSo) was 12.1 months compared with 15.4 months for the reverse sequence (SoSu; 95% CI for difference 1.45-5.12, p = 0.0013). Regarding first-line treatment, no significant difference in PFS1 was noted regardless of which drug was initially used (0.62 months average increase on sorafenib, 95% CI for difference -1.01 to 2.26, p = 0.43). In second-line treatment, sunitinib showed a significantly longer PFS2 than sorafenib (average increase 2.66 months, 95% CI 1.02-4.3, p = 0.003). The SoSu sequence translates into a longer combined PFS compared to the SuSo sequence. Predominantly the superiority of sunitinib regarding PFS2 contributed to the longer combined PFS in sequential use. Copyright © 2012 S. Karger AG, Basel.

{sup 18}F-fluorodeoxyglucose uptake of hepatocellular carcinoma as a prognostic predictor in patients with sorafenib treatment

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Sung, Pil Soo; Yang, Keungmo; Hwang, Seawon; Song, Myeong Jun; Jang, Jeong Won; Choi, Jong Young; Yoon, Seung Kew; Bae, Si Hyun [The Catholic University of Korea, Division of Hepatology, Department of Internal Medicine, The Catholic University Liver Research Center, College of Medicine, Seoul (Korea, Republic of); Park, Hye Lim; Yoo, Ie Ryung [The Catholic University of Korea, Division of Nuclear Medicine, Department of Radiology, College of Medicine, Seoul (Korea, Republic of)

2018-03-15

Sorafenib, an oral multikinase inhibitor, is a recommended treatment option available for patients with Barcelona Clinic Liver Cancer (BCLC)-C stage hepatocellular carcinoma (HCC). This study aimed to evaluate the performance of {sup 18}F-fluorodeoxyglucose positron emission tomography ({sup 18}F-FDG PET) for predicting tumour progression during sorafenib treatment. We formed a retrospective cohort comprising patients treated with sorafenib for at least 30 days and undergoing {sup 18}F-FDG PET/CT within 1 month before treatment. For statistical analyses, the tumour-to-liver standardised uptake value (SUV) ratio (TLR) of the most hypermetabolic lesion was measured. Among a total of 35 patients, two obtained partial remission, and 11 showed stable disease after the first response evaluation. Patients with a TLR ≥ 2.9 (n = 17) had a median overall survival (OS) of 3.7 months after sorafenib treatment, whereas patients with a TLR < 2.9 (n = 18) had median OS of 12.2 months (P < 0.001), although the disease control rate was not significantly different between the two groups. Pretreatment TLR ≥ 2.9 (hazard ratio [HR] = 6.318, P = 0.002) and Child-Pugh class B (HR = 4.316, P = 0.044) were poor prognostic factors for OS, and a TLR ≥ 2.9 (HR = 2.911, P = 0.024) was the only poor prognostic factor for progression-free survival in a multivariate analysis. Pretreatment tumour metabolic activity assessed by {sup 18}F-FDG PET is an independent prognostic factor for survival in patients with BCLC-C stage HCC receiving sorafenib monotherapy, although it may not predict tumour response to the treatment. (orig.)

Inhibition of retinopathy of prematurity in rat by intravitreal injection of sorafenib

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Li-Li Tian

2014-04-01

Full Text Available AIM:To investigate the effect of intravitreal injection administered sorafenib, a multikinase inhibitor, in a rat model of oxygen-induced retinopathy (OIR.METHODS:Seven-day-old Sprague-Dawley rats (n=144 were randomly assigned to six groups. Group A received normal partial oxygen pressure and groups B, C, D, E and F were exposed to hyperoxia (75±2% from postnatal 7d (P7 to P12 to induce retinopathy of prematurity. The rats in groups C, D, E and F were received intravitreal injections of either vehicle (DMSO or sorafenib at P12 (5, 20 and 80 μg, respectively. Then they returned to normoxia after P12. The retinas were whole-mounted and imaged with a confocal microscopy. The vascular branching points were counted to quantify neovascularization at P17. Cross-sections of the retina were stained with hematoxylin and eosin (HE. The nuclei of new vessels breaking the internal limiting membrane were counted to quantify the proliferative neovascular response.RESULTS:The retinal vessel in groups B and C turned into tortuosity and a great deal of neovascularization were observed. Sorafenib-treated rats had significantly less neovascularization as compared with vehicle-treated and control rats in a dose dependent manner (P<0.05. The number of vascular branching points in A, B, C, D, E and F were 16.50±3.90, 37.44±6.47, 37.08±5.10, 30.80±6.85, 26.08±5.08 and 19.83±3.51, respectively. The number of the nuclei of retinal new vessel in A, B, C, D, E and F were 0.22±0.42, 35.66±4.70, 35.30±4.54, 27.30±4.28, 21.41±3.53, and 7.41±2.87, respectively. There were significant difference between each group (P＜0.05 except groups B and C.CONCLUSION: In the rat OIR model, sorafenib could inhibit retinal neovascularization in a dose dependent manner.

Early sorafenib-induced toxicity is associated with drug exposure and UGTIA9 genetic polymorphism in patients with solid tumors: a preliminary study.

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Pascaline Boudou-Rouquette

Full Text Available BACKGROUND: Identifying predictive biomarkers of drug response is of key importance to improve therapy management and drug selection in cancer therapy. To date, the influence of drug exposure and pharmacogenetic variants on sorafenib-induced toxicity remains poorly documented. The aim of this pharmacokinetic/pharmacodynamic (PK/PD study was to investigate the relationship between early toxicity and drug exposure or pharmacogenetic variants in unselected adult outpatients treated with single-agent sorafenib for advanced solid tumors. METHODS: Toxicity was recorded in 54 patients on days 15 and 30 after treatment initiation and sorafenib exposure was assessed in 51 patients. The influence of polymorphisms in CYP3A5, UGT1A9, ABCB1 and ABCG2 was examined in relation to sorafenib exposure and toxicity. Clinical characteristics, drug exposure and pharmacogenetic variants were tested univariately for association with toxicities. Candidate variables with p<0.1 were analyzed in a multivariate analysis. RESULTS: Gender was the sole parameter independently associated with sorafenib exposure (p = 0.0008. Multivariate analysis showed that increased cumulated sorafenib (AUC(cum was independently associated with any grade ≥ 3 toxicity (p = 0.037; UGT1A9 polymorphism (rs17868320 with grade ≥ 2 diarrhea (p = 0.015 and female gender with grade ≥ 2 hand-foot skin reaction (p = 0.018. Using ROC curve, the threshold AUC(cum value of 3,161 mg/L.h was associated with the highest risk to develop any grade ≥ 3 toxicity (p = 0.018. CONCLUSION: In this preliminary study, increased cumulated drug exposure and UGT1A9 polymorphism (rs17868320 identified patients at high risk for early sorafenib-induced severe toxicity. Further PK/PD studies on larger population are warranted to confirm these preliminary results.

Clinical experience and critical evaluation of the role of sorafenib in renal cell carcinoma

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Zustovich F

2011-05-01

Full Text Available Fable Zustovich1, Giuseppe Lombardi1, Davide Pastorelli1, Patrizia Farina1, Massimo Dal Bianco2, Luca De Zorzi2, Maurizia Dalla Palma1, Ornella Nicoletto1, Vittorina Zagonel11Oncologia Medica 1, Istituto Oncologico Veneto-IRCCS, Padova, Italy; 2UO Urologia, Ospedale Sant'Antonio, ULSS 16, Padova, ItalyAbstract: Renal cell carcinoma (RCC is a common malignancy worldwide with approximately 95,000 new cases per year and ranks as the sixth cause of cancer deaths. Until recently, the slightly active and very toxic cytokines were available for patients with advanced RCC. Advances have been made in understanding the molecular biology of renal cancer. The introduction of targeted agents has led to promising possibilities for treating these highly vascularized tumors. Angiogenesis inhibition is likely to represent the main potential therapeutic target. Sorafenib is an oral multikinase inhibitor with activity against tyrosine kinase receptors that are responsible for blood vessel development and has shown to be active in treating advanced RCC. In this review, we summarize the pharmacology, mode of action, pharmacokinetics, and safety of sorafenib use in therapy for advanced RCC.Keywords: sorafenib, pharmacokinetics, angiogenesis 

Hand-foot skin reaction is a beneficial indicator of sorafenib therapy for patients with hepatocellular carcinoma: a systemic review and meta-analysis.

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Wang, Ping; Tan, Gang; Zhu, Mingxin; Li, Weidong; Zhai, Bo; Sun, Xueying

2018-01-01

Sorafenib remains the only standard first-line drug for advanced hepatocellular carcinoma (HCC). Hand-foot skin reaction (HFSR) is a very common side-effect in patients treated with sorafenib, and also affects the treatment schedule and quality of life. However, the association of HFSR and response of HCC to sorafenib remain unclear. Databases including PubMed, EMBASE, Web of Science and Cochrane Central Register of Controlled Trials were searched up to May 7 th , 2017. Review Manager 5.3 software was adopted for performing meta-analyses, Newcastle-Ottawa Scale for assessing the bias of cohort studies, and GRADEprofler software for further assessing outcomes obtained from meta-analyses. 1478 articles were reviewed, and 12 cohort studies with 1017 participants were included in the analyses. The pooled hazard ratio (HR) of overall survival is 0.45 (95% confidence interval (CI) 0.36, 0.55; P The pooled HR of time to progression is 0.41 (95% CI 0.28, 0.60; P The results indicate that HFSR is a beneficial indicator for HCC patients receiving sorafenib therapy. However, molecular mechanisms accounting for sorafenib-induced HFSR in HCC patients remain.

Advanced inoperable type B3 thymoma: monitoring of a novel therapeutic approach with radio-chemotherapy and sorafenib by FDG-PET and CT

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Winder, T.; Gasser, K.; Schuster, A.; Becherer, A.; Vries, A. de; Gruber-Moesenbacher, U.; Muendlein, A.; Drexel, H.; Lang, A.

2010-01-01

This report highlights the benefit of radio-chemotherapy followed by sorafenib in a 55 years old woman, diagnosed with an inoperable type B3 thymoma and illustrates the potential usefulness of 18 F-FDG in monitoring treatment with sorafenib. (orig.)

Early α-fetoprotein response predicts survival in patients with advanced hepatocellular carcinoma treated with sorafenib

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Lee SH

2015-04-01

Full Text Available Sangheun Lee,1,* Beom Kyung Kim,2–5,* Seung Up Kim,2–5 Jun Yong Park,2–5 Do Young Kim,2–5 Sang Hoon Ahn,2–6 Kwang-Hyub Han2–6 1Department of Internal Medicine, International St Mary’s Hospital, Catholic Kwandong University, Incheon Metropolitan City, Republic of Korea; 2Department of Internal Medicine, 3Institute of Gastroenterology, 4Liver Cancer Special Clinic, Yonsei University College of Medicine, Seoul, Republic of Korea; 5Liver Cirrhosis Clinical Research Center, Seoul, Republic of Korea; 6Brain Korea 21 Project for Medical Science, Seoul, Republic of Korea.   *These authors contributed equally to this work Background: It is not clear whether tumor marker responses can predict survival during sorafenib treatment in hepatocellular carcinoma (HCC. We investigated whether the α-fetoprotein (AFP response is associated with survival in patients with advanced HCC treated with sorafenib. Methods: We retrospectively reviewed the records of 126 patients with advanced HCC treated with sorafenib between 2007 and 2012. An AFP response was defined as >20% decrease from baseline. At 6–8 weeks after commencing sorafenib, AFP and radiological responses were assessed by modified Response Evaluation Criteria in Solid Tumors. Results: The median overall survival (OS and progression-free survival (PFS were 6.2 and 3.5 months, respectively. Of the study population, a partial response (PR was identified in 5 patients (4.0%, stable disease (SD in 65 patients (51.6%, and progressive disease (PD in 57 patients (44.4%, respectively. AFP non-response was an independent prognostic factor for poor OS (median 10.9 months for AFP response vs 5.2 months for AFP non-response, together with Child-Pugh B, tumor diameter ≥10 cm, and portal vein invasion (all P<0.05, and PFS (median 5.3 months for AFP response vs 2.9 months for AFP non-response, together with tumor diameter ≥10 cm and portal vein invasion (all P<0.05. SD or PR was more frequently found

Metronomic capecitabine as second-line treatment in hepatocellular carcinoma after sorafenib failure.

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Granito, Alessandro; Marinelli, Sara; Terzi, Eleonora; Piscaglia, Fabio; Renzulli, Matteo; Venerandi, Laura; Benevento, Francesca; Bolondi, Luigi

2015-06-01

No standard second-line treatments are available for hepatocellular carcinoma patients who fail sorafenib therapy. We assessed the safety and efficacy of metronomic capecitabine after first-line sorafenib failure. Retrospective analysis of consecutive hepatocellular carcinoma patients receiving metronomic capecitabine between January 2012 and November 2014. The primary end-point was safety, secondary end-point was efficacy, including time-to-progression and overall survival. Twenty-six patients (80% Child-Pugh A, 80% Barcelona Clinic Liver Cancer stage C) received metronomic capecitabine (500 mg/bid). Median treatment duration was 3.2 months (range 0.6-31). Fourteen (53%) patients experienced at least one adverse event. The most frequent drug-related adverse events were bilirubin elevation (23%), fatigue (15%), anaemia (11%), lymphoedema (11%), and hand-foot syndrome (7.6%). Treatment was interrupted in 19 (73%) for disease progression, in 4 (15%) for liver deterioration, and in 1 (3.8%) for adverse event. Disease control was achieved in 6 (23%) patients. Median time-to-progression was 4 months (95% confidence interval 3.2-4.7). Median overall survival was 8 months (95% confidence interval 3.7-12.3). Metronomic capecitabine was well tolerated in hepatocellular carcinoma patients who had been treated with sorafenib. Preliminary data show potential anti-tumour activity with long-lasting disease control in a subgroup of patients that warrants further evaluation in a phase III study. Copyright © 2015 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Safety and tolerability of sorafenib in patients with radioiodine-refractory thyroid cancer

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Worden, F.; Fassnacht, M.; Shi, Y.; Hadjieva, T.; Bonichon, F.; Gao, M.; Fugazzola, L.; Ando, Y.; Hasegawa, Y.; do, J. Park; Shong, Y.K.; Smit, J.W.A.; Chung, J.; Kappeler, C.; Meinhardt, G.; Schlumberger, M.; Brose, M.S.

2015-01-01

Effective adverse event (AE) management is critical to maintaining patients on anticancer therapies. The DECISION trial was a multicenter, randomized, double-blind, placebo-controlled, Phase 3 trial which investigated sorafenib for treatment of progressive, advanced, or metastatic radioactive

Treatment of Recurrent Hepatocellular Carcinoma with Sorafenib in a HIV/HCV Co-Infected patient in HAART: A Case Report

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De Nardo Pasquale

2012-06-01

Full Text Available Abstract Background Liver disease is the second cause of death among HIV patients receiving highly active antiretroviral therapy (HAART in Europe. HIV patients have a high prevalence of chronic HBV (6–10% and HCV (33% co-infection, and accelerated progression of viral hepatitis. Furthermore, the long duration of both HIV and HCV diseases in the HAART era increases the risk of hepatocellular carcinoma. Findings We report the case of a 49 year -old HIV/HCV co-infected male patient who developed hepatocellular carcinoma. The patient underwent a partial hepatectomy, and a few months later was treated with transcatheter arterial chemoembolisation due to hepatocarcinoma recurrence. Two months later, advanced hepatocellular carcinoma was diagnosed and sorafenib therapy was initiated. The patient achieved partial response of the main lesions, complete regression of the smallest lesions and did not experience clinical progression during the 20-month follow-up period. During therapy with sorafenib, the patient was treated with HAART with good viral and immunological responses. We used the therapeutic drug monitoring to assess antiretroviral concentrations during co-administration of sorafenib. Fosamprenavir Ctrough was found under the minimum level recommended by international guidelines. No grade 3 or 4 toxicities were observed. At month 20 of treatment, new liver lesions with portal vein thrombosis were diagnosed. After 28 months of sorafenib therapy, the patient deceased for severe liver insufficiency. Conclusions Sorafenib monotherapy demonstrated a marked delay in HCC disease progression in an HIV/HCV co-infected patient. Fosamprenavir Ctrough was found under the minimum level recommended by international guidelines, suggesting a possible interaction.

PKI-587 and sorafenib alone and in combination on inhibition of liver cancer stem cell proliferation.

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Gedaly, Roberto; Galuppo, Roberto; Musgrave, Yolanda; Angulo, Paul; Hundley, Jonathan; Shah, Malay; Daily, Michael F; Chen, Changguo; Cohen, Donald A; Spear, Brett T; Evers, B Mark

2013-11-01

Deregulated Ras/Raf/mitogen-activated protein kinase and PI3 K/AKT/mTOR signaling pathways are significant in hepatocellular carcinoma proliferation (HCC). In this study we evaluated differences in the antiproliferative effect of dual PI3 K/Akt/mTOR and Ras/Raf/mitogen-activated protein kinase inhibition of non liver cancer stem cell lines (PLC and HuH7) and liver cancer stem cell (LCSC) lines (CD133, CD44, CD24, and aldehyde dehydrogenase 1-positive cells). Flow cytometry was performed on the resulting tumors to identify the LCSC markers CD133, CD44, CD24, and aldehyde dehydrogenase 1. Methylthiazol tetrazolium assay was used to assess cellular proliferation. Finally, a Western blot assay was used to evaluate for inhibition of specific enzymes in these two signaling pathways. Using flow cytometry, we found that LCSC contain 64.4% CD133 + cells, 83.2% CD44 + cells, and 96.4% CD24 + cells. PKI-587 and sorafenib caused inhibiton of LCSC and HCC cell proliferation. PLC cells were more sensitive to PKI-587 than LCSC or Huh7 (P PKI-587 and sorafenib caused significantly more inhibition than monotherapy in HuH7, PLC, and LCSC. Using the methylthiazol tetrazolium assay, we found that the LCSC proliferation was inhibited with sorafenib monotherapy 39% at 5 μM (P PKI-587 at 0.1 μM (P = 0.002, n = 12) compared with control. The combination of PKI-587 and sorafenib, however, synergistically inhibited LCSC proliferation by 86% (P = 0.002; n = 12). LCSC (CD133+, CD44+, CD24+) were able to develop very aggressive tumors with low cell concentrations at 4 to 6 wk. Cells CD133+, CD44+, CD24+, which demonstrated at least moderate resistance to therapy in vitro. The combination of PKI-587 and sorafenib was better than either drug alone at inhibiting of LCSC and on HCC cell proliferation. Copyright © 2013 Elsevier Inc. All rights reserved.

Efficacy and safety of sorafenib in combination with gemcitabine in patients with advanced hepatocellular carcinoma: a multicenter, open-label, single-arm phase II study.

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Srimuninnimit, Vichien; Sriuranpong, Virote; Suwanvecho, Suthida

2014-09-01

Currently, the only standard systemic treatment for advanced hepatocellular carcinoma is sorafenib monotherapy. The study was conducted to assess the efficacy and safety of the novel combination of sorafenib and gemcitabine in the treatment of advanced hepatocellular carcinoma. Between March 2008 and October 2010, patients with advanced pathologically proven hepatocellular carcinoma who had not received previous systemic therapy and had Child-Pugh liver function class A or B received sorafenib plus gemcitabine. Treatment included 4-week cycle of gemcitabine (1000 mg/m(2) days 1, 8, 15) to the maximum of six cycles together with sorafenib (400 mg twice daily). Patient continued sorafenib until disease progression or withdrawal from other reasons. The primary end point is progression-free survival. Forty-five patients were enrolled in this study. The median progression-free survival was 3.7 months (95% CI 3.5-3.8). The overall response rate was 4% with no complete responses and the disease control rate was 66%. The median overall survival (OS) was 11.6 months (95% CI 7.4-15.9). The median time to progression was 3.6 months (95% CI 3.4-3.7). The most frequently reported grade 3/4 treatment-related adverse events included thrombocytopenia 33%, neutropenia 16% and hand-foot skin reaction 13%. The study regimen was well tolerated. The combination of sorafenib and gemcitabine in advanced hepatocellular carcinoma is generally well tolerated and has modest clinical efficacy. The median OS is up to 1 year. However, well-designed randomized controlled trials with a sorafenib alone comparator arm are needed to confirm this finding. © 2014 Wiley Publishing Asia Pty Ltd.

Differential modulatory effects of GSK-3β and HDM2 on sorafenib-induced AIF nuclear translocation (programmed necrosis in melanoma

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Mier James W

2011-09-01

Full Text Available Abstract Background GSK-3β phosphorylates numerous substrates that govern cell survival. It phosphorylates p53, for example, and induces its nuclear export, HDM2-dependent ubiquitination, and proteasomal degradation. GSK-3β can either enhance or inhibit programmed cell death, depending on the nature of the pro-apoptotic stimulus. We previously showed that the multikinase inhibitor sorafenib activated GSK-3β and that this activation attenuated the cytotoxic effects of the drug in various BRAF-mutant melanoma cell lines. In this report, we describe the results of studies exploring the effects of GSK-3β on the cytotoxicity and antitumor activity of sorafenib combined with the HDM2 antagonist MI-319. Results MI-319 alone increased p53 levels and p53-dependent gene expression in melanoma cells but did not induce programmed cell death. Its cytotoxicity, however, was augmented in some melanoma cell lines by the addition of sorafenib. In responsive cell lines, the MI-319/sorafenib combination induced the disappearance of p53 from the nucleus, the down modulation of Bcl-2 and Bcl-xL, the translocation of p53 to the mitochondria and that of AIF to the nuclei. These events were all GSK-3β-dependent in that they were blocked with a GSK-3β shRNA and facilitated in otherwise unresponsive melanoma cell lines by the introduction of a constitutively active form of the kinase (GSK-3β-S9A. These modulatory effects of GSK-3β on the activities of the sorafenib/MI-319 combination were the exact reverse of its effects on the activities of sorafenib alone, which induced the down modulation of Bcl-2 and Bcl-xL and the nuclear translocation of AIF only in cells in which GSK-3β activity was either down modulated or constitutively low. In A375 xenografts, the antitumor effects of sorafenib and MI-319 were additive and associated with the down modulation of Bcl-2 and Bcl-xL, the nuclear translocation of AIF, and increased suppression of tumor angiogenesis

Effects of Sorafenib on C-Terminally Truncated Androgen Receptor Variants in Human Prostate Cancer Cells

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Mark Schrader

2012-09-01

Full Text Available Recent evidence suggests that the development of castration resistant prostate cancer (CRPCa is commonly associated with an aberrant, ligand-independent activation of the androgen receptor (AR. A putative mechanism allowing prostate cancer (PCa cells to grow under low levels of androgens, is the expression of constitutively active, C-terminally truncated AR lacking the AR-ligand binding domain (LBD. Due to the absence of a LBD, these receptors, termed ARΔLBD, are unable to respond to any form of anti-hormonal therapies. In this study we demonstrate that the multikinase inhibitor sorafenib inhibits AR as well as ARΔLBD-signalling in CRPCa cells. This inhibition was paralleled by proteasomal degradation of the AR- and ARΔLBD-molecules. In line with these observations, maximal antiproliferative effects of sorafenib were achieved in AR and ARΔLBD-positive PCa cells. The present findings warrant further investigations on sorafenib as an option for the treatment of advanced AR-positive PCa.

Paclitaxel/carboplatin with or without sorafenib in the first-line treatment of patients with stage III/IV epithelial ovarian cancer: a randomized phase II study of the Sarah Cannon Research Institute

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Hainsworth, John D; Thompson, Dana S; Bismayer, John A; Gian, Victor G; Merritt, William M; Whorf, Robert C; Finney, Lindsey H; Dudley, B Stephens

2015-01-01

This trial compared the efficacy and toxicity of standard first-line treatment with paclitaxel/carboplatin versus paclitaxel/carboplatin plus sorafenib in patients with advanced ovarian carcinoma. Patients with stage 3 or 4 epithelial ovarian cancer with residual measurable disease or elevated CA-125 levels after maximal surgical cytoreduction were randomized (1:1) to receive treatment with paclitaxel (175 mg/m 2 , 3 h infusion, day 1) and carboplatin (AUC 6.0, IV, day 1) with or without sorafenib 400 mg orally twice daily (PO BID). Patients were reevaluated for response after completing 6 weeks of treatment (two cycles); responding or stable patients received six cycles of paclitaxel/carboplatin. Patients receiving the sorafenib-containing regimen continued sorafenib (400 PO BID) for a total of 52 weeks. Eighty-five patients were randomized and received treatment.Efficacy was similar for patients receiving paclitaxel/carboplatin/sorafenib versus paclitaxel/carboplatin: overall response rates 69% versus 74%; median progression-free survival 15.4 versus 16.3 months; 2 year survival 76% versus 81%. The addition of sorafenib added substantially to the toxicity of the regimen; rash, hand–foot syndrome, mucositis, and hypertension were significantly more common in patients treated with sorafenib. The addition of sorafenib to standard paclitaxel/carboplatin did not improve efficacy and substantially increased toxicity in the first-line treatment of advanced epithelial ovarian cancer. Based on evidence from this study and other completed trials, sorafenib is unlikely to have a role in the treatment of ovarian cancer

Optimal therapy for patients with hepatocellular carcinoma and resistance or intolerance to sorafenib: challenges and solutions

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Ray EM

2017-11-01

Full Text Available Emily M Ray, Hanna K Sanoff Division of Hematology/Oncology, University of North Carolina, Chapel Hill, NC, USA Abstract: The only US Food and Drug Administration (FDA-approved first-line systemic therapy for hepatocellular carcinoma (HCC is sorafenib; however, resistance or intolerance to sorafenib is unfortunately common. In this review, we briefly describe systemic therapies that can be considered for patients with HCC who show resistance or intolerance to sorafenib. For all patients with HCC who need systemic therapy, we strongly advocate for participation in clinical trials. Cytotoxic chemotherapy plays a minor role in the treatment of advanced HCC, with some data supporting the use of FOLFOX (infusional fluorouracil, leucovorin, and oxaliplatin and GEMOX (gemcitabine-oxaliplatin. Multi-target kinase inhibitors such as lenvantinib and regorafenib have recently met their primary endpoints as first- and second-line therapy, respectively, with regorafenib now representing the only FDA-approved drug for second-line treatment of HCC. Other targeted therapies remain under investigation, but results so far have not significantly changed clinical practice. Immunotherapy is an interesting area of research in the treatment of HCC with preclinical and early clinical data demonstrating exciting results; thus numerous investigational studies are currently focusing on immunotherapy in the treatment of HCC. While systemic treatment options in HCC remain a challenge for providers, in this review, we summarize the current literature and highlight areas of progress with respect to the treatment of patients with HCC and resistance or intolerance to sorafenib. Keywords: liver cancer, chemotherapy, immunotherapy

Partial response to sorafenib treatment associated with transient grade 3 thrombocytopenia in a patient with locally advanced thyroid cancer

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Pitoia Fabian; Abelleira, Erika; Jerkovich, Fernando; Urciuoli, Carolina; Cross, Graciela, E-mail: fpitoia@intramed.net [Division de Endocrinologia, Hospital de Clinicas, Universidad de Buenos Aires Buenos Aires (Argentina)

2015-08-15

Advanced radioactive refractory and progressive or symptomatic differentiated thyroid carcinoma (DTC) is a rare condition. Sorafenib was recently approved for the treatment of these patients. We present the case of a 67 year old woman diagnosed with DTC who underwent a total thyroidectomy with central, lateral-compartment neck dissection and shaving of the trachea and esophagus due to tumor infiltration. A local recurrence was detected 14 months later requiring, additionally, two tracheal rings resection. The patient received a cumulative {sup 131}I dose of 650 mCi and developed dysphagia and dyspnea 63 months after initial surgery. A {sup 18}FGD-PET/CT showed progression of the local mass associated to hypermetabolic pulmonary nodules. Sorafenib 800 mg/day was then prescribed. A dose reduction to 400 mg/day was necessary due to grade 3 thrombocytopenia that appeared four months after drug prescription. Platelet count went to normal after this dose reduction. Five months after initiation of sorafenib, a partial response of the local mass with significant intra-tumoral necrosis was observed. We conclude that sorafenib is a valid option for locally advanced DTC and that the platelet count should be evaluated regularly because it seems that thrombocytopenia might be more frequently observed in DTC than in other types of tumors. (author)

Synthesis and conformational analysis of new arylated-diphenylurea derivatives related to sorafenib drug via Suzuki-Miyaura cross-coupling reaction

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Al-Masoudi, Najim A.; Essa, Ali Hashem; Alwaaly, Ahmed A. S.; Saeed, Bahjat A.; Langer, Peter

2017-10-01

Sorafenib, is a relatively new cytostatic drug approved for the treatment of renal cell and hepatocellular carcinoma. The development of new sorafenib analogues offers the possibility of generating structures of increased potency. To this end, a series of arylated-diphenylurea analogues 17-31 were synthesized via Suzuki-Miyaura coupling reaction, related to sorafenib by treatment of three diarylureas 2-4 having 3-bromo, 4-chloro and 2-iodo groups with various arylboronic acids. Conformational analysis of the new arylated urea analogues has been investigated using MOPAC 2016 of semi empirical PM7 Hamiltonian computational method. Our results showed that all compounds preferred the trans-trans conformations. Compound 17 has been selected to calculate the torsional energy profiles for rotation around the urea bonds and found to be existed predominantly in the trans-trans conformation with only very minimal fluctuation in conformation.

Randomize Trial of Cisplatin plus Gemcitabine with either Sorafenib or Placebo as First-line Therapy for Non-small Cell Lung Cancer

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Yan WANG

2011-03-01

Full Text Available Background and objective Platinum-based chemotherapy doublets reached an efficacy plateau in nonsmall-cell lung cancer (NSCLC. This randomized controlled study prospectively assessed the efficacy and safety of cisplatin plus gemcitabine with either Sorafenib or placebo as first-line therapy for NSCLC. Methods Thirty patients, which were confirmed advanced NSCLC histologically or cytologically, were randomly assigned to receive up to six cycles of cisplatin plus gemcitabine with sorafenib or placebo. The maintenance of sorafenib or placebo after chemotherapy will continued in patients with response or stable disease until disease progression or unacceptable adverse events. Results Overall demographics were balanced between experimental group (sorafenib+chemotherapy and controlled group (chemotherapy only. Overall response (OS rate was 55.6% and 41.7% in experimental arm and controlled arm, respectively (P=0.905. Median progressivefree survival (PFS and median overall survial were similar (5 months vs 4 months, P=0.75; 18 months vs 18 months, P=0.68. Adverse events were tolerable, though the risk of hypertension and diarrhea was increase in experimental arm. Since patients with ECOG PS 0, stage IIIb, no liver metastasis and tyrasine kinasis inhibitor treatment after study had longer survive, these factors seemed to be predictive factors favor of survival in Cox regression analyses. Conclusion No additional benefit of response rate, PFS or OS were observed from adding targeted agent-sorafenib to regular cisplatin plus gemcitabine chemotherapy. Selecting aproper patients is needed in further study.

[Randomize trial of cisplatin plus gemcitabine with either sorafenib or placebo as first-line therapy for non-small cell lung cancer].

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Wang, Yan; Wang, Lin; Liu, Yutao; Yu, Shufei; Zhang, Xiangru; Shi, Yuankai; Sun, Yan

2011-03-01

Platinum-based chemotherapy doublets reached an efficacy plateau in nonsmall-cell lung cancer (NSCLC). This randomized controlled study prospectively assessed the efficacy and safety of cisplatin plus gemcitabine with either Sorafenib or placebo as first-line therapy for NSCLC. Thirty patients, which were confirmed advanced NSCLC histologically or cytologically, were randomly assigned to receive up to six cycles of cisplatin plus gemcitabine with sorafenib or placebo. The maintenance of sorafenib or placebo after chemotherapy will continued in patients with response or stable disease until disease progression or unacceptable adverse events. Overall demographics were balanced between experimental group (sorafenib+chemotherapy) and controlled group (chemotherapy only). Overall response (OS) rate was 55.6% and 41.7% in experimental arm and controlled arm, respectively (P=0.905). Median progressive-free survival (PFS) and median overall survival were similar (5 months vs 4 months, P=0.75; 18 months vs 18 months, P=0.68). Adverse events were tolerable, though the risk of hypertension and diarrhea was increase in experimental arm. Since patients with ECOG PS 0, stage IIIb, no liver metastasis and tyrasine kinasis inhibitor treatment after study had longer survive, these factors seemed to be predictive factors favor of survival in Cox regression analyses. No additional benefit of response rate, PFS or OS were observed from adding targeted agent-sorafenib to regular cisplatin plus gemcitabine chemotherapy. Selecting aproper patients is needed in further study.

Sorafenib-induced defective autophagy promotes cell death by necroptosis

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Kharaziha, Pedram; Chioureas, Dimitris; Baltatzis, George; Fonseca, Pedro; Rodriguez, Patricia; Gogvadze, Vladimir; Lennartsson, Lena; Bj?rklund, Ann-Charlotte; Zhivotovsky, Boris; Grand?r, Dan; Egevad, Lars; Nilsson, Sten; Panaretakis, Theocharis

2015-01-01

Autophagy is one of the main cytoprotective mechanisms that cancer cells deploy to withstand the cytotoxic stress and survive the lethal damage induced by anti-cancer drugs. However, under specific conditions, autophagy may, directly or indirectly, induce cell death. In our study, treatment of the Atg5-deficient DU145 prostate cancer cells, with the multi-tyrosine kinase inhibitor, sorafenib, induces mitochondrial damage, autophagy and cell death. Molecular inhibition of autophagy by silencin...

Allosteric MEK1/2 Inhibitor Refametinib (BAY 86-9766 in Combination with Sorafenib Exhibits Antitumor Activity in Preclinical Murine and Rat Models of Hepatocellular Carcinoma

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Roberta Schmieder

2013-10-01

Full Text Available OBJECTIVE: The objectives of the study were to evaluate the allosteric mitogen-activated protein kinase kinase (MEK inhibitor BAY 86-9766 in monotherapy and in combination with sorafenib in orthotopic and subcutaneous hepatocellular carcinoma (HCC models with different underlying etiologies in two species. DESIGN: Antiproliferative potential of BAY 86-9766 and synergistic effects with sorafenib were studied in several HCC cell lines. Relevant pathway signaling was studied in MH3924a cells. For in vivo testing, the HCC cells were implanted subcutaneously or orthotopically. Survival and mode of action (MoA were analyzed. RESULTS: BAY 86-9766 exhibited potent antiproliferative activity in HCC cell lines with half-maximal inhibitory concentration values ranging from 33 to 762 nM. BAY 86-9766 was strongly synergistic with sorafenib in suppressing tumor cell proliferation and inhibiting phosphorylation of the extracellular signal-regulated kinase (ERK. BAY 86-9766 prolonged survival in Hep3B xenografts, murine Hepa129 allografts, and MH3924A rat allografts. Additionally, tumor growth, ascites formation, and serum alpha-fetoprotein levels were reduced. Synergistic effects in combination with sorafenib were shown in Huh-7, Hep3B xenografts, and MH3924A allografts. On the signaling pathway level, the combination of BAY 86-9766 and sorafenib led to inhibition of the upregulatory feedback loop toward MEK phosphorylation observed after BAY 86-9766 monotreatment. With regard to the underlying MoA, inhibition of ERK phosphorylation, tumor cell proliferation, and microvessel density was observed in vivo. CONCLUSION: BAY 86-9766 shows potent single-agent antitumor activity and acts synergistically in combination with sorafenib in preclinical HCC models. These results support the ongoing clinical development of BAY 86-9766 and sorafenib in advanced HCC.

Sorafenib for hepatocellular carcinoma patients beyond Milan criteria after orthotopic liver transplantation: a case control study

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Teng Chieh-Lin

2012-02-01

Full Text Available Abstract Background Orthotopic liver transplantation (OLT is one of the most effective treatments for patients with hepatocellular carcinoma (HCC within the Milan criteria. However, for patients beyond these criteria, the recurrence rate is higher and the prognosis is worse. Sorafenib is the only drug showing survival benefits in advanced HCC patients; however, its role in patients beyond the Milan criteria after OLT remains unclear and requires further investigation. Methods As a case-control study, we retrospectively analyzed 17 Chinese patients beyond Milan criteria undergoing OLT for HCC. These patients were stratified into adjuvant (n = 5, palliative (n = 6, and control groups (n = 6. Results Nine of 11 patients who received sorafenib after OLT needed dose reduction due to more than grade 2 side effects. The disease-free survival rates for patients with or without adjuvant sorafenib were 100% versus 37.5% (p = 0.034 at 6 months, 66.7% versus 9.4% (p = 0.026 at 12 months, and 66.7% versus 0.0% (p = 0.011 at 18 months, respectively. The overall survival rates for patients in palliative and control groups were 66.7% versus 40.0% (p = 0.248 at 6 months, 66.7% versus 40.0% (p = 0.248 at 12 months, and 50.0% versus 20.0% (p = 0.17 at 18 months, respectively. Patients in the adjuvant group had better overall survival rates than those in the palliative and control groups (p = 0.031 at 24-month follow-up. Conclusions Adjuvant sorafenib could possibly extend both disease-free and overall survival for HCC patients beyond Milan criteria after OLT.

Cost-effectiveness analysis of antiviral therapy in patients with advanced hepatitis B virus-related hepatocellular carcinoma treated with sorafenib.

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Zhang, Pengfei; Yang, Yu; Wen, Feng; Wheeler, John; Fu, Ping; Li, Qiu

2016-12-01

Antiviral therapy has been demonstrated to significantly improve the survival in patients with advanced hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). The aim of the study was to investigate the cost-effectiveness of antiviral therapy in patients with advanced HBV-related HCC treated with sorafenib. To conduct the analysis, a Markov model comprising three health states (progression-free survival, progressive disease, and death) was created. The efficacy data were derived from medical records. Cost data were collected based on the Chinese national drug prices. Utility data came from the previously published studies. One-way sensitivity analyses as well as probabilistic sensitivity analyses were performed to explore model uncertainties. In the base-case analysis, addition of antiviral therapy to sorafenib generated an effectiveness of 0.68 quality-adjusted life years (QALYs) at a cost of $25 026.04, while sorafenib monotherapy gained an effectiveness of 0.42 QALYs at a cost of $20 249.64. The incremental cost-effectiveness ratio (ICER) was $18 370.77/QALY for antiviral therapy group versus non-antiviral therapy group. On the other hand, the ICER between the two groups in patients with high or low HBV-DNA load, with or without cirrhosis, normal or elevated alanine aminotransferase/aspartate aminotransferase were $16 613.97/QALY, $19 774.16/QALY, $14 587.66/QALY, $19 873.84/QALY, $17 947.07/QALY, and $18 785.58/QALY, respectively. Based on the cost-effectiveness threshold ($20 301.00/QALY in China), addition of antiviral therapy to sorafenib is considered to be a cost-effective option compared with sorafenib monotherapy in patients with advanced HBV-related HCC in China from the patient's perspective. © 2016 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

A polymeric nanoparticle formulation of curcumin in combination with sorafenib synergistically inhibits tumor growth and metastasis in an orthotopic model of human hepatocellular carcinoma

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Hu, Bo [Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032 (China); Sun, Ding [Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032 (China); Department of Hepatobiliary Surgery, First Affiliated Hospital of Soochow University, Suzhou, 215004 (China); Sun, Chao; Sun, Yun-Fan; Sun, Hai-Xiang [Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032 (China); Zhu, Qing-Feng [The Johns Hopkins University School of Medicine, Division of Gastrointestinal and Liver Pathology, Baltimore, MD, 21205 (United States); Institute of Biomedical Sciences, Fudan University, Shanghai, 200032 (China); Yang, Xin-Rong [Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032 (China); Gao, Ya-Bo [Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai, 200032 (China); Tang, Wei-Guo [Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032 (China); Fan, Jia [Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032 (China); Institute of Biomedical Sciences, Fudan University, Shanghai, 200032 (China); Maitra, Anirban [The Sol Goldman Pancreatic Cancer Research Center, Departments of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205 (United States); and others

2015-12-25

Curcumin, a yellow polyphenol extracted from the rhizome of turmeric root (Curcuma longa) has potent anti-cancer properties in many types of tumors with ability to reverse multidrug resistance of cancer cells. However, widespread clinical application of this agent in cancer and other diseases has been limited due to its poor aqueous solubility. The recent findings of polymeric nanoparticle formulation of curcumin (NFC) have shown the potential for circumventing the problem of poor solubility, however evidences for NFC's anti-cancer and reverse multidrug resistance properties are lacking. Here we provide models of human hepatocellular carcinoma (HCC), the most common form of primary liver cancer, in vitro and in vivo to evaluate the efficacy of NFC alone and in combination with sorafenib, a kinase inhibitor approved for treatment of HCC. Results showed that NFC not only inhibited the proliferation and invasion of HCC cell lines in vitro, but also drastically suppressed primary tumor growth and lung metastases in vivo. Moreover, in combination with sorafenib, NFC induced HCC cell apoptosis and cell cycle arrest. Mechanistically, NFC and sorafenib synergistically down-regulated the expression of MMP9 via NF-κB/p65 signaling pathway. Furthermore, the combination therapy significantly decreased the population of CD133-positive HCC cells, which have been reported as cancer initiating cells in HCC. Taken together, NanoCurcumin provides an opportunity to expand the clinical repertoire of this agent. Additional studies utilizing a combination of NanoCurcumin and sorafenib in HCC are needed for further clinical development. - Highlights: • Polymeric nanoparticle formulation of curcumin not only inhibited the proliferation and invasion of HCC cell lines in vitro, but also drastically suppressed primary tumor growth and lung metastases in vivo. • In combination with sorafenib, NanoCurcumin induced HCC cell apoptosis and cell cycle arrest. • NanoCurcumin and

A polymeric nanoparticle formulation of curcumin in combination with sorafenib synergistically inhibits tumor growth and metastasis in an orthotopic model of human hepatocellular carcinoma

International Nuclear Information System (INIS)

Hu, Bo; Sun, Ding; Sun, Chao; Sun, Yun-Fan; Sun, Hai-Xiang; Zhu, Qing-Feng; Yang, Xin-Rong; Gao, Ya-Bo; Tang, Wei-Guo; Fan, Jia; Maitra, Anirban

2015-01-01

Curcumin, a yellow polyphenol extracted from the rhizome of turmeric root (Curcuma longa) has potent anti-cancer properties in many types of tumors with ability to reverse multidrug resistance of cancer cells. However, widespread clinical application of this agent in cancer and other diseases has been limited due to its poor aqueous solubility. The recent findings of polymeric nanoparticle formulation of curcumin (NFC) have shown the potential for circumventing the problem of poor solubility, however evidences for NFC's anti-cancer and reverse multidrug resistance properties are lacking. Here we provide models of human hepatocellular carcinoma (HCC), the most common form of primary liver cancer, in vitro and in vivo to evaluate the efficacy of NFC alone and in combination with sorafenib, a kinase inhibitor approved for treatment of HCC. Results showed that NFC not only inhibited the proliferation and invasion of HCC cell lines in vitro, but also drastically suppressed primary tumor growth and lung metastases in vivo. Moreover, in combination with sorafenib, NFC induced HCC cell apoptosis and cell cycle arrest. Mechanistically, NFC and sorafenib synergistically down-regulated the expression of MMP9 via NF-κB/p65 signaling pathway. Furthermore, the combination therapy significantly decreased the population of CD133-positive HCC cells, which have been reported as cancer initiating cells in HCC. Taken together, NanoCurcumin provides an opportunity to expand the clinical repertoire of this agent. Additional studies utilizing a combination of NanoCurcumin and sorafenib in HCC are needed for further clinical development. - Highlights: • Polymeric nanoparticle formulation of curcumin not only inhibited the proliferation and invasion of HCC cell lines in vitro, but also drastically suppressed primary tumor growth and lung metastases in vivo. • In combination with sorafenib, NanoCurcumin induced HCC cell apoptosis and cell cycle arrest. • NanoCurcumin and

Randomize Trial of Cisplatin plus Gemcitabine with either Sorafenib or Placebo as First-line Therapy for Non-small Cell Lung Cancer

OpenAIRE

Yan WANG; Lin WANG; Yutao LIU; Shufei YU; Xiangru ZHANG; Yuankai SHI; Yan SUN

2011-01-01

Background and objective Platinum-based chemotherapy doublets reached an efficacy plateau in nonsmall-cell lung cancer (NSCLC). This randomized controlled study prospectively assessed the efficacy and safety of cisplatin plus gemcitabine with either Sorafenib or placebo as first-line therapy for NSCLC. Methods Thirty patients, which were confirmed advanced NSCLC histologically or cytologically, were randomly assigned to receive up to six cycles of cisplatin plus gemcitabine with sorafenib or ...

Prospective randomized double-blind multicentre phase II study comparing gemcitabine and cisplatin plus sorafenib chemotherapy with gemcitabine and cisplatin plus placebo in locally advanced and/or metastasized urothelial cancer: SUSE (AUO-AB 31/05).

Science.gov (United States)

Krege, Susanne; Rexer, Heidrun; vom Dorp, Frank; de Geeter, Patrick; Klotz, Theodor; Retz, Margitte; Heidenreich, Axel; Kühn, Michael; Kamradt, Joern; Feyerabend, Susan; Wülfing, Christian; Zastrow, Stefan; Albers, Peter; Hakenberg, Oliver; Roigas, Jan; Fenner, Martin; Heinzer, Hans; Schrader, Mark

2014-03-01

To evaluate the efficacy and safety of gemcitabine and cisplatin in combination with sorafenib, a tyrosine-kinase inhibitor, compared with chemotherapy alone as first-line treatment in advanced urothelial cancer. The study was a randomized phase II trial. Its primary aim was to show an improvement in progression-free survival (PFS) of 4.5 months by adding sorafenib to conventional chemotherapy. Secondary objectives were objective response rate (ORR), overall survival (OS) and toxicity. The patients included in the trial had histologically confirmed locally advanced and/or metastatic urothelial cancer of the bladder or upper urinary tract. Chemotherapy with gemcitabine (1250 mg/qm on days 1 and 8) and cisplatin (70 mg/qm on day 1) repeated every 21 days, was administered to all patients in a double-blind randomization of additional sorafenib (400 mg twice daily) vs placebo (two tablets twice daily) on days 3-21. Treatment continued until progression or unacceptable toxicity, the maximum number of cycles was limited to eight. The response assessment was repeated after every two cycles. Between October 2006 and October 2010, 98 of 132 planned patients were recruited. Nine patients were ineligible. The final analysis included 40 patients in the sorafenib and 49 patients in the placebo arm. There were no significant differences between the two arms concerning ORR (sorafenib: complete response [CR] 12.5%, partial response [PR] 40%; placebo: CR 12%, PR 35%), median PFS (sorafenib: 6.3 months, placebo: 6.1 months) or OS (sorafenib: 11.3 months, placebo: 10.6 months). Toxicity was moderately higher in the sorafenib arm. Diarrrhoea occurred significantly more often in the sorafenib arm and hand-foot syndrome occurred only in the sorafenib arm. The study was closed prematurely because of slow recruitment. Although the addition of sorafenib to standard chemotherapy showed acceptable toxicity, the trial failed to show a 4.5 months improvement in PFS. © 2013 The Authors

Economic evaluation of everolimus versus sorafenib for the treatment of metastatic renal cell carcinoma after failure of first-line sunitinib.

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Casciano, Roman; Chulikavit, Maruit; Di Lorenzo, Giuseppe; Liu, Zhimei; Baladi, Jean-Francois; Wang, Xufang; Robertson, Justin; Garrison, Lou

2011-01-01

A recent indirect comparison study showed that sunitinib-refractory metastatic renal cell carcinoma (mRCC) patients treated with everolimus are expected to have improved overall survival outcomes compared to patients treated with sorafenib. This analysis examines the likely cost-effectiveness of everolimus versus sorafenib in this setting from a US payer perspective. A Markov model was developed to simulate a cohort of sunitinib-refractory mRCC patients and to estimate the cost per incremental life-years gained (LYG) and quality-adjusted life-years (QALYs) gained. Markov states included are stable disease without adverse events, stable disease with adverse events, disease progression, and death. Transition probabilities were estimated using a subset of the RECORD-1 patient population receiving everolimus after sunitinib, and a comparable population receiving sorafenib in a single-arm phase II study. Costs of antitumor therapies were based on wholesale acquisition cost. Health state costs accounted for physician visits, tests, adverse events, postprogression therapy, and end-of-life care. The model extrapolated beyond the trial time horizon for up to 6 years based on published trial data. Deterministic and probabilistic sensitivity analyses were conducted. The estimated gain over sorafenib treatment was 1.273 LYs (0.916 QALYs) at an incremental cost of $81,643. The deterministic analysis resulted in an incremental cost-effectiveness ratio (ICER) of $64,155/LYG ($89,160/QALY). The probabilistic sensitivity analysis demonstrated that results were highly consistent across simulations. As the ICER fell within the cost per QALY range for many other widely used oncology medicines, everolimus is projected to be a cost-effective treatment relative to sorafenib for sunitinib-refractory mRCC. Copyright © 2011 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

Phase 1 Pharmacogenetic and Pharmacodynamic Study of Sorafenib With Concurrent Radiation Therapy and Gemcitabine in Locally Advanced Unresectable Pancreatic Cancer

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Chiorean, E. Gabriela, E-mail: gchiorea@uw.edu [Department of Medicine, Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, Indiana (United States); Department of Medicine, University of Washington, Seattle, Washington (United States); Schneider, Bryan P. [Department of Medicine, Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, Indiana (United States); Akisik, Fatih M. [Department of Radiology, Indiana University School of Medicine, Indianapolis, Indiana (United States); Perkins, Susan M. [Department of Biostatistics, Indiana University School of Medicine, Indianapolis, Indiana (United States); Anderson, Stephen [Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana (United States); Johnson, Cynthia S. [Department of Biostatistics, Indiana University School of Medicine, Indianapolis, Indiana (United States); DeWitt, John [Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana (United States); Helft, Paul; Clark, Romnee; Johnston, Erica L.; Spittler, A. John [Department of Medicine, Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, Indiana (United States); Deluca, Jill [Department of Radiation Oncology, Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, Indiana (United States); Bu, Guixue [Department of Radiology, Indiana University School of Medicine, Indianapolis, Indiana (United States); Shahda, Safi; Loehrer, Patrick J. [Department of Medicine, Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, Indiana (United States); Sandrasegaran, Kumar [Department of Radiology, Indiana University School of Medicine, Indianapolis, Indiana (United States); Cardenes, Higinia R. [Department of Radiation Oncology, Indiana University School of Medicine, Indianapolis, Indiana (United States)

2014-06-01

Purpose: To define the safety, efficacy, and pharmacogenetic and pharmacodynamic effects of sorafenib with gemcitabine-based chemoradiotherapy (CRT) in locally advanced pancreatic cancer. Methods and Materials: Patients received gemcitabine 1000 mg/m{sup 2} intravenously weekly × 3 every 4 weeks per cycle for 1 cycle before CRT and continued for up to 4 cycles after CRT. Weekly gemcitabine 600 mg/m{sup 2} intravenously was given during concurrent intensity modulated radiation therapy of 50 Gy to gross tumor volume in 25 fractions. Sorafenib was dosed orally 400 mg twice daily until progression, except during CRT when it was escalated from 200 mg to 400 mg daily, and 400 mg twice daily. The maximum tolerated dose cohort was expanded to 15 patients. Correlative studies included dynamic contrast-enhanced MRI and angiogenesis genes polymorphisms (VEGF-A and VEGF-R2 single nucleotide polymorphisms). Results: Twenty-seven patients were enrolled. No dose-limiting toxicity occurred during induction gemcitabine/sorafenib followed by concurrent CRT. The most common grade 3/4 toxicities were fatigue, hematologic, and gastrointestinal. The maximum tolerated dose was sorafenib 400 mg twice daily. The median progression-free survival and overall survival for 25 evaluable patients were 10.6 and 12.6 months, respectively. The median overall survival for patients with VEGF-A -2578 AA, -1498 CC, and -1154 AA versus alternate genotypes was 21.6 versus 14.7 months. Dynamic contrast-enhanced MRI demonstrated higher baseline K{sup trans} in responding patients. Conclusions: Concurrent sorafenib with CRT had modest clinical activity with increased gastrointestinal toxicity in localized unresectable pancreatic cancer. Select VEGF-A/VEGF-R2 genotypes were associated with favorable survival.

Phase 1 Pharmacogenetic and Pharmacodynamic Study of Sorafenib With Concurrent Radiation Therapy and Gemcitabine in Locally Advanced Unresectable Pancreatic Cancer

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Chiorean, E. Gabriela; Schneider, Bryan P.; Akisik, Fatih M.; Perkins, Susan M.; Anderson, Stephen; Johnson, Cynthia S.; DeWitt, John; Helft, Paul; Clark, Romnee; Johnston, Erica L.; Spittler, A. John; Deluca, Jill; Bu, Guixue; Shahda, Safi; Loehrer, Patrick J.; Sandrasegaran, Kumar; Cardenes, Higinia R.

2014-01-01

Purpose: To define the safety, efficacy, and pharmacogenetic and pharmacodynamic effects of sorafenib with gemcitabine-based chemoradiotherapy (CRT) in locally advanced pancreatic cancer. Methods and Materials: Patients received gemcitabine 1000 mg/m 2 intravenously weekly × 3 every 4 weeks per cycle for 1 cycle before CRT and continued for up to 4 cycles after CRT. Weekly gemcitabine 600 mg/m 2 intravenously was given during concurrent intensity modulated radiation therapy of 50 Gy to gross tumor volume in 25 fractions. Sorafenib was dosed orally 400 mg twice daily until progression, except during CRT when it was escalated from 200 mg to 400 mg daily, and 400 mg twice daily. The maximum tolerated dose cohort was expanded to 15 patients. Correlative studies included dynamic contrast-enhanced MRI and angiogenesis genes polymorphisms (VEGF-A and VEGF-R2 single nucleotide polymorphisms). Results: Twenty-seven patients were enrolled. No dose-limiting toxicity occurred during induction gemcitabine/sorafenib followed by concurrent CRT. The most common grade 3/4 toxicities were fatigue, hematologic, and gastrointestinal. The maximum tolerated dose was sorafenib 400 mg twice daily. The median progression-free survival and overall survival for 25 evaluable patients were 10.6 and 12.6 months, respectively. The median overall survival for patients with VEGF-A -2578 AA, -1498 CC, and -1154 AA versus alternate genotypes was 21.6 versus 14.7 months. Dynamic contrast-enhanced MRI demonstrated higher baseline K trans in responding patients. Conclusions: Concurrent sorafenib with CRT had modest clinical activity with increased gastrointestinal toxicity in localized unresectable pancreatic cancer. Select VEGF-A/VEGF-R2 genotypes were associated with favorable survival

Inhibition of Cell Proliferation in an NRAS Mutant Melanoma Cell Line by Combining Sorafenib and α-Mangostin.

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Yun Xia

Full Text Available α-Mangostin is a natural product commonly used in Asia for cosmetic and medicinal applications including topical treatment of acne and skin cancer. Towards finding new pharmacological strategies that overcome NRAS mutant melanoma, we performed a cell proliferation-based combination screen using a collection of well-characterized small molecule kinase inhibitors and α-Mangostin. We found that α-Mangostin significantly enhances Sorafenib pharmacological efficacy against an NRAS mutant melanoma cell line. The synergistic effects of α-Mangostin and Sorafenib were associated with enhanced inhibition of activated AKT and ERK, induced ER stress, and reduced autophagy, eventually leading to apoptosis. The structure of α-Mangostin resembles several inhibitors of the Retinoid X receptor (RXR. MITF expression, which is regulated by RXR, was modulated by α-Mangostin. Molecular docking revealed that α-Mangostin can be accommodated by the ligand binding pocket of RXR and may thereby compete with RXR-mediated control of MITF expression. In summary, these data demonstrate an unanticipated synergy between α-Mangostin and sorafenib, with mechanistic actions that convert a known safe natural product to a candidate combinatorial therapeutic agent.

Phase 2 Study of Combined Sorafenib and Radiation Therapy in Patients With Advanced Hepatocellular Carcinoma

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Chen, Shang-Wen, E-mail: sjfchiou@gmail.com [Department of Radiation Oncology, China Medical University Hospital, Taichung, Taiwan (China); School of Medicine, Taipei Medical University, Taipei, Taiwan (China); School of Medicine, China Medical University, Taichung, Taiwan (China); Lin, Li-Ching [Department of Radiation Oncology, Chi-Mei Hospital, Tainan, Taiwan (China); School of Medicine, Taipei Medical University, Taipei, Taiwan (China); Kuo, Yu-Cheng [Department of Radiation Oncology, China Medical University Hospital, Taichung, Taiwan (China); Department of Biomedical Imaging and Radiological Science, China Medical University, Taichung, Taiwan (China); Liang, Ji-An [Department of Radiation Oncology, China Medical University Hospital, Taichung, Taiwan (China); School of Medicine, China Medical University, Taichung, Taiwan (China); Kuo, Chia-Chun [Department of Radiation Oncology, Taipei Medical University Hospital, Taipei, Taiwan (China); Chiou, Jeng-Fong [Department of Radiation Oncology, Taipei Medical University Hospital, Taipei, Taiwan (China); School of Medicine, Taipei Medical University, Taipei, Taiwan (China)

2014-04-01

Purpose: This phase 2 study evaluated the efficacy of radiation therapy (RT) with concurrent and sequential sorafenib therapy in patients with unresectable hepatocellular carcinoma (HCC). Methods and Materials: Forty patients with unresectable HCC unfit for transarterial chemoembolization were treated with RT with concurrent and sequential sorafenib. Sorafenib was administered from the commencement of RT at a dose of 400 mg twice daily and continued to clinical or radiologic progression, unacceptable adverse events, or death. All patients had underlying Child-Pugh A cirrhosis. The maximal tumor diameter ranged from 3.0 cm to 15.5 cm. Coexisting portal vein thrombosis was found in 24 patients and was irradiated simultaneously. The cumulative RT dose ranged from 40 Gy to 60 Gy (median, 50 Gy). Image studies were done 1 month after RT and then every 3 months thereafter. Results: Thirty-three (83%) completed the allocated RT. During RT, the incidence of hand-foot skin reactions ≥ grade 2 and diarrhea were 37.5% and 25%, respectively, and 35% of patients had hepatic toxicities grade ≥2. Twenty-two (55.0%) patients achieved complete or partial remission at the initial assessment, and 18 (45%) had stable or progressive disease. The 2-year overall survival and infield progression-free survival (IFPS) were 32% and 39%, respectively. A Cancer of the Liver Italian Program (CLIP) score ≥2 was associated with an inferior outcome in overall survival. Six patients (15%) developed treatment-related hepatic toxicity grade ≥3 during the sequential phase, and 3 of them were fatal. Conclusions: When RT and sorafenib therapy were combined in patients with unresectable HCC, the initial complete or partial response rate was 55% with a 2-year IFPS of 39%. A CLIP score ≥2 was associated with an inferior outcome in overall survival. Hepatic toxicities are a major determinant of the safety; the combination should be used with caution and needs further investigation.

Gateways to clinical trials.

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Bayés, M; Rabasseda, X; Prous, J R

2006-10-01

-globulin, ivabradine hydrochloride, ixabepilone; LA-419, lacosamide, landiolol, lanthanum carbonate, lidocaine/prilocaine, liposomal cisplatin, lutropin alfa; Matuzumab, MBP(82-98), mecasermin, MGCD-0103, MMR-V, morphine hydrochloride, mycophenolic acid sodium salt; Natalizumab, NCX-4016, neridronic acid, nesiritide, nilotinib, NSC-330507; O6-benzylguanine, olanzapine/fluoxetine hydrochloride, omalizumab; Panitumumab, parathyroid hormone (human recombinant), parecoxib sodium, PEG-filgrastim, peginterferon alfa-2a, peginterferon alfa-2b, pegvisomant, pemetrexed disodium, perospirone hydrochloride, pexelizumab, phorbol 12-myristate 13-acetate, pneumococcal 7-valent conjugate vaccine, posaconazole, pramiconazole, prasugrel, pregabalin, prilocaine; rAAV-GAD65, raclopride, rasagiline mesilate, retapamulin, rosuvastatin calcium, rotigotine, rufinamide; SarCNU, SB-743921, SHL-749, sirolimus-eluting stent, sitaxsentan sodium, sorafenib; TachoSil, tadalafil, talampanel, Taxus, tegaserod maleate, telithromycin, telmisartan/hydrochlorothiazide, temsirolimus, tenatoprazole, teriflunomide, tetrathiomolybdate, ticilimumab, timcodar dimesilate, tipifarnib, tirapazamine, TPI, tramiprosate, trifluridine/TPI, trimethoprim; Ularitide, Urocortin 2; Valdecoxib, valganciclovir hydrochloride, valproate magnesium, valspodar, vardenafil hydrochloride hydrate, vitespen, vofopitant hydrochloride, volociximab, vorinostat; Yttrium 90 (90Y) ibritumomab tiuxetan; Ziprasidone hydrochloride, zotarolimus, zotarolimus-eluting stent.

Targeted therapy for human hepatic carcinoma cells using folate-functionalized polymeric micelles loaded with superparamagnetic iron oxide and sorafenib in vitro

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Zhang L

2013-04-01

Full Text Available Lei Zhang,1 Faming Gong,2 Fang Zhang,3 Jing Ma,1 Peidong Zhang,1 Jun Shen3 1Department of Hepatobiliary and Pancreatic Surgery, 2PCFM Laboratory of Ministry of Education, School of Chemistry and Chemical Engineering, 3Department of Radiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China Background: The purpose of this study was to evaluate the inhibitory effect of targeted folate-functionalized micelles containing superparamagnetic iron oxide nanoparticles (SPIONs and sorafenib on human hepatic carcinoma (HepG2 cells in vitro, and to observe the feasibility of surveillance of this targeting therapeutic effect by magnetic resonance imaging. Methods: Sorafenib and SPIONs were loaded into polymeric micelles. The targeted nanocarrier was synthesized by functionalizing the micelles with folate. Folate-free micelles loaded with sorafenib and SPIONs were used as control (nontargeted micelles. Uptake of the nanocarrier by cells was assessed using Prussian blue staining after 1 hour of incubation with the polymeric micelles. The inhibitory effect of the targeted micelles on HepG2 cell proliferation at various concentrations of sorafenib was assessed in vitro using the methyl thiazolyl tetrazolium (MTT assay and apoptotic analysis using flow cytometry. Magnetic resonance imaging using a clinical 1.5 T scanner was performed to detect changes in the signal intensity of cells after incubation with the targeted micelles. Results: Prussian blue staining showed significantly more intracellular SPIONs in cells incubated with the targeted micelles than those incubated with nontargeted micelles. The MTT assay showed that the average inhibitory ratio in the targeted group was significantly higher than that in the nontargeted group (38.13% versus 22.54%, P = 0.028. The mean apoptotic rate in the targeted cells, nontargeted cells, and untreated cells was 17.01%, 11.04%, and 7.89%, respectively. The apoptotic rate in the

Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805): a double-blind, placebo-controlled, randomised, phase 3 trial

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Haas, Naomi B; Manola, Judith; Uzzo, Robert G; Flaherty, Keith T; Wood, Christopher G; Kane, Christopher; Jewett, Michael; Dutcher, Janice P; Atkins, Michael B; Pins, Michael; Wilding, George; Cella, David; Wagner, Lynne; Matin, Surena; Kuzel, Timothy M; Sexton, Wade J; Wong, Yu-Ning; Choueiri, Toni K; Pili, Roberto; Puzanov, Igor; Kohli, Manish; Stadler, Walter; Carducci, Michael; Coomes, Robert; DiPaola, Robert S

2016-01-01

Summary Background Renal-cell carcinoma is highly vascular, and proliferates primarily through dysregulation of the vascular endothelial growth factor (VEGF) pathway. We tested sunitinib and sorafenib, two oral anti-angiogenic agents that are effective in advanced renal-cell carcinoma, in patients with resected local disease at high risk for recurrence. Methods In this double-blind, placebo-controlled, randomised, phase 3 trial, we enrolled patients at 226 study centres in the USA and Canada. Eligible patients had pathological stage high-grade T1b or greater with completely resected non-metastatic renal-cell carcinoma and adequate cardiac, renal, and hepatic function. Patients were stratified by recurrence risk, histology, Eastern Cooperative Oncology Group (ECOG) performance status, and surgical approach, and computerised double-blind randomisation was done centrally with permuted blocks. Patients were randomly assigned (1:1:1) to receive 54 weeks of sunitinib 50 mg per day orally throughout the first 4 weeks of each 6 week cycle, sorafenib 400 mg twice per day orally throughout each cycle, or placebo. Placebo could be sunitinib placebo given continuously for 4 weeks of every 6 week cycle or sorafenib placebo given twice per day throughout the study. The primary objective was to compare disease-free survival between each experimental group and placebo in the intention-to-treat population. All treated patients with at least one follow-up assessment were included in the safety analysis. This trial is registered with ClinicalTrials.gov, number NCT00326898. Findings Between April 24, 2006, and Sept 1, 2010, 1943 patients from the National Clinical Trials Network were randomly assigned to sunitinib (n=647), sorafenib (n=649), or placebo (n=647). Following high rates of toxicity-related discontinuation after 1323 patients had enrolled (treatment discontinued by 193 [44%] of 438 patients on sunitinib, 199 [45%] of 441 patients on sorafenib), the starting dose of each

Phase I dose-finding study of sorafenib with FOLFOX4 as first-line treatment in patients with unresectable locally advanced or metastatic gastric cancer.

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Chi, Yihebali; Yang, Jianliang; Yang, Sheng; Sun, Yongkun; Jia, Bo; Shi, Yuankai

2015-06-01

To determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT) and efficacy of sorafenib in combination with FOLFOX4 (oxaliplatin/leucovorin (LV)/5-fluorouracil) as first-line treatment for advanced gastric cancer, we performed a phase I dose-finding study in nine evaluable patients with unresectable locally advanced or metastatic gastric cancer or gastroesophageal junction adenocarcinoma. According to modified Fibonacci method, the design of this study was to guide elevation of the sorafenib dosage to the next level (from 200 mg twice daily to 400 mg twice daily and then, if tolerated, 600 mg twice daily). If the patient achieved complete response (CR), partial response (PR) or stable disease (SD) after eight cycles of treatment, combination chemotherapy was scheduled to be discontinued and sorafenib monotherapy continued at the original dose until either disease progression or unacceptable toxicity. In sorafenib 200 mg twice daily group, DLT was observed in 1 of 6 patients, and in 400 mg twice daily group, it was observed in 2 of 3 patients. Seven of 9 (77.8%) evaluable patients achieved PR, with a median overall survival (OS) of 11.8 [95% confidence interval (CI): 8.9-14.7] months. Common adverse effects include hand-foot syndrome, leukopenia, neutropenia, anorexia, and nausea. Twice-daily dosing of sorafenib 200 mg in combination with FOLFOX4 was proven effective and safe for the treatment of advanced gastric cancer, and could be an appropriate dosage for subsequent phase II clinical studies.

Sorafenib suppresses TGF-β responses by inducing caveolae/lipid raft-mediated internalization/degradation of cell-surface type II TGF-β receptors: Implications in development of effective adjunctive therapy for hepatocellular carcinoma.

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Chung, Chih-Ling; Wang, Shih-Wei; Sun, Wei-Chih; Shu, Chih-Wen; Kao, Yu-Chen; Shiao, Meng-Shin; Chen, Chun-Lin

2018-04-18

Sorafenib is the only FDA approved drug for the treatment of advanced hepatocellular carcinoma (HCC) and other malignancies. Studies indicate that TGF-β signalling is associated with tumour progression in HCC. Autocrine and paracrine TGF-β promotes tumour growth and malignancy by inducing epithelial-mesenchymal transition (EMT). Sorafenib is believed to antagonize tumour progression by inhibiting TGF-β-induced EMT. It improves survival of patients but HCC later develops resistance and relapses. The underlying mechanism of resistance is unknown. Understanding of the molecular mechanism of sorafenib inhibition of TGF-β-induced signalling or responses in HCC may lead to development of adjunctive effective therapy for HCC. In this study, we demonstrate that sorafenib suppresses TGF-β responsiveness in hepatoma cells, hepatocytes, and animal liver, mainly by downregulating cell-surface type II TGF-β receptors (TβRII) localized in caveolae/lipid rafts and non-lipid raft microdomains via caveolae/lipid rafts-mediated internalization and degradation. Furthermore, sorafenib-induced downregulation and degradation of cell-surface TβRII is prevented by simultaneous treatment with a caveolae disruptor or lysosomal inhibitors. On the other hand, sorafenib only downregulates cell-surface TβRII localized in caveolae/lipid rafts but not localized in non-lipid raft microdomains in hepatic stellate cells. These results suggest that sorafenib inhibits TGF-β signalling mainly by inducing caveolae/lipid raft-mediated internalization and degradation of cell-surface TβR-II in target cells. They may also imply that treatment with agents which promote formation of caveolae/lipid rafts, TGF-β receptor kinase inhibitors (e.g., LY2157299) or TGF-β peptide antagonists (by liver-targeting delivery) may be considered as effective adjunct therapy with sorafenib for HCC. Copyright © 2018 Elsevier Inc. All rights reserved.

A comparative study of sorafenib and metronomic chemotherapy for Barcelona Clinic Liver Cancer-stage C hepatocellular carcinoma with poor liver function

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Hyun Yang

2017-06-01

Full Text Available Background/Aims Metronomic chemotherapy (MET is frequently administered in comparatively low doses as a continuous chemotherapeutic agent. The aim of this study was to evaluate the feasibility and overall survival (OS of MET compared to sorafenib for advanced hepatocellular carcinoma (HCC patients with portal vein tumor thrombosis (PVTT. Methods A total of 54 patients with advanced HCC and PVTT who had undergone MET were analyzed between 2005 and 2013. A total of 53 patients who had undergone sorafenib therapy were analyzed as the control group. The primary endpoint of this study was OS. Results The median number of MET cycles was two (1-15. The OS values for the MET group and sorafenib group were 158 days (132-184 and 117 days (92-142, respectively (P=0.029. The Cox proportional-hazard model showed that a higher risk of death was correlated with higher serum alpha fetoprotein level (≥400 mg/dL, hazard ratio [HR]=1.680, P=0.014 and Child-Pugh class B (HR=1.856, P=0.008. Conclusions MET was associated with more favorable outcomes in terms of overall survival than was sorafenib in patients with advanced HCC with PVTT, especially in patients with poor liver function. Therefore, MET can be considered as a treatment option in patients with advanced HCC with PVTT and poor liver function.

Efficacy and safety of sorafenib versus apatinib in the treatment of intermediate and advanced hepatocellular carcinoma: a comparative retrospective study

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Wang Y

2018-06-01

Full Text Available Yizhuo Wang,1,2 Qing Gou,1 Rongde Xu,1 Xiaoming Chen,1 Zejian Zhou1 1Department of Interventional Oncology, Guangdong Academy of Medical Sciences, Guangdong General Hospital, Guangzhou, Guangdong, People’s Republic of China; 2Medical College Shantou University, Shantou, Guangdong, People’s Republic of China Objective: To compare the efficacy and safety profiles of sorafenib and apatinib in patients with intermediate- and advanced-stage hepatocellular carcinoma (HCC. Methods: This was a single-center, retrospective study where we collected the clinical data of 72 patients, diagnosed with intermediate or advanced HCC from January 2014 to December 2016. Depending on the treatment received, 38 patients were categorized into group S (sorafenib group and 34 into group A (apatinib group. The patients in group A received the initial recommended dose of 750 mg once daily (QD, which was reduced to 250 mg QD in the case of any class 3 or 4 adverse event (AE. Sorafenib was administered orally 400 mg twice daily (BID, and dose was modified to 400 mg or 200 mg QD in the case of grade 3 or 4 AEs. The median overall survival (OS, progression-free survival (PFS, and AEs reported in the two groups were analyzed and compared. Results: Among the 38 patients treated with sorafenib, one patient had complete response (CR, 5 patients had partial response (PR, and 10 patients had stable disease (SD, and among the 34 patients treated with apatinib, 6 patients had PR and 7 patients had SD with no cases of CR. PFS in group S was significantly longer compared with that in group A (7.39 vs 4.79 months, respectively, P=0.031. Similar observations were made for median OS (10.4 months in group S vs 7.18 months in group A, P=0.011. However, there was no significant difference in the objective response rates (ORRs among the study population (15.7 vs 17.6%, P=0.829. Common AEs in group S included hand and foot syndrome (HFS and diarrhea, whereas common AEs in group A

Synthesis and Antitumor Activity of Triazole-Containing Sorafenib Analogs

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Wenjing Ye

2017-10-01

Full Text Available Using a highly effective binuclear Cu complex as the catalyst, the 1,3-dipolar cycloaddition reactions between 16 alkynes and two azides were successfully performed and resulted in the production of 25 new triazole-containing sorafenib analogs. Several compounds were evaluated as potent antitumor agents. Among them, 4-(4-(4-(3-fluorophenyl-1H-1,2,3-triazol-1-ylphenoxy-N-methylpicolinamide (8f potently suppressed the proliferation of HT-29 cancer cells by inducing apoptosis and almost completely inhibited colony formation at a low micromolar concentration.

The multikinase inhibitor Sorafenib enhances glycolysis and synergizes with glycolysis blockade for cancer cell killing

NARCIS (Netherlands)

Tesori, V.; Piscaglia, A.C.; Samengo, D.; Barba, M.; Bernardini, C.; Scatena, R.; Pontoglio, A.; Castellini, L.; Spelbrink, H.; Maulucci, G.; Puglisi, M.A.; Pani, G.; Gasbarrini, A.

2015-01-01

Although the only effective drug against primary hepatocarcinoma, the multikinase inhibitor Sorafenib (SFB) usually fails to eradicate liver cancer. Since SFB targets mitochondria, cell metabolic reprogramming may underlie intrinsic tumor resistance. To characterize cancer cell metabolic response to

Sorafenib blocks tumour growth, angiogenesis and metastatic potential in preclinical models of osteosarcoma through a mechanism potentially involving the inhibition of ERK1/2, MCL-1 and ezrin pathways

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Ferrari Stefano

2009-12-01

Full Text Available Abstract Background Osteosarcoma (OS is the most common primary bone tumour in children and young adults. Despite improved prognosis, metastatic or relapsed OS remains largely incurable and no significant improvement has been observed in the last 20 years. Therefore, the search for alternative agents in OS is mandatory. Results We investigated phospho-ERK 1/2, MCL-1, and phospho-Ezrin/Radixin/Moesin (P-ERM as potential therapeutic targets in OS. Activation of these pathways was shown by immunohistochemistry in about 70% of cases and in all OS cell lines analyzed. Mutational analysis revealed no activating mutations in KRAS whereas BRAF gene was found to be mutated in 4/30 OS samples from patients. Based on these results we tested the multi-kinase inhibitor sorafenib (BAY 43-9006 in preclinical models of OS. Sorafenib inhibited OS cell line proliferation, induced apoptosis and downregulated P-ERK1/2, MCL-1, and P-ERM in a dose-dependent manner. The dephosphorylation of ERM was not due to ERK inhibition. The downregulation of MCL-1 led to an increase in apoptosis in OS cell lines. In chick embryo chorioallantoic membranes, OS supernatants induced angiogenesis, which was blocked by sorafenib and it was also shown that sorafenib reduced VEGF and MMP2 production. In addition, sorafenib treatment dramatically reduced tumour volume of OS xenografts and lung metastasis in SCID mice. Conclusion In conclusion, ERK1/2, MCL-1 and ERM pathways are shown to be active in OS. Sorafenib is able to inhibit their signal transduction, both in vitro and in vivo, displaying anti-tumoural activity, anti-angiogenic effects, and reducing metastatic colony formation in lungs. These data support the testing of sorafenib as a potential therapeutic option in metastatic or relapsed OS patients unresponsive to standard treatments.

Therapeutic evaluation of sorafenib for hepatocellular carcinoma using contrast-enhanced ultrasonography: Preliminary result.

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Shiozawa, Kazue; Watanabe, Manabu; Ikehara, Takashi; Kogame, Michio; Kikuchi, Yoshinori; Igarashi, Yoshinori; Sumino, Yasukiyo

2016-07-01

The present study aimed to determine the usefulness of contrast-enhanced ultrasonography (CEUS) with Sonazoid in evaluating the therapeutic response to sorafenib for hepatocellular carcinoma (HCC). In total, 26 patients with advanced HCC who received sorafenib and were followed up by CEUS were enrolled in the present study. CEUS was performed prior to and within 2-4 weeks of treatment, and the images of the target lesion in the post-vascular phase with a re-injection method were analyzed. The presence (+) or absence (-) of intratumoral necrosis and the intratumoral vascular architecture on micro-flow imaging (MFI) were compared prior to and subsequent to treatment. Target lesions that exhibited non-enhancement after re-injection were considered to indicate intratumoral necrosis. The intratumoral vascular architecture was classified into three groups, as follows: Vd, the intratumoral vessels visually narrowed or decreased; Vnc, the vessels remained unchanged; and Vi, the vessels were thickened or increased. Survival curves were estimated using the Kaplan-Meier method and compared using the log rank test between the intratumoral necrosis (+) and (-) groups, and among the Vd, Vnc and Vi groups. PVnc group and 5 patients in the Vi group. The MSTs in the Vd, Vnc and Vi groups were 15.6 months (95% CI, 5.0-23.3), 11.0 months (95% CI, 3.5-17.6) and 3.6 months (95% CI: 1.2-6.0), respectively. The P-value for the differences between the Vd and Vnc groups, Vd and Vi groups, and Vnc and Vi groups were 0.78, 0.016 and 0.047, respectively, which indicated that the survival time decreased significantly in the Vi group. Evaluation of intratumoral vascular architecture using MFI demonstrates promise for assessing the therapeutic response to sorafenib in patients with HCC.

Fluoro-sorafenib (Regorafenib) effects on hepatoma cells: growth inhibition, quiescence and recovery

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Carr, Brian I.; Cavallini, Aldo; Lippolis, Catia; D’Alessandro, Rosalba; Messa, Caterina; Refolo, Maria Grazia; Tafaro, Angela

2015-01-01

To evaluate the growth-inhibitory properties of the potent multi-kinase antagonist Regorafenib (Fluoro-Sorafenib), which was synthesized as a more potent Sorafenib, a Raf inhibitor and to determine whether similar mechanisms were involved, human hepatoma cell lines were grown in the presence or absence of Regorafanib and examined for growth inhibition. Western blots were performed for Raf targets, for apoptosis and autophagy. Regorafenib inhibited growth of human Hep3B, PLC/PRF/5 and HepG2 cells in a concentration- and time-dependent manner. Multiple signaling pathways were altered, including MAP kinases phospho-ERK and phospho-JNK and its target phospho-c-Jun. There was evidence for apoptosis by FACS, cleavage of caspases and increased Bax levels; as well as induction of autophagy, as judged by increased Beclin-1 and LC3 (II) levels. Prolonged drug exposure resulted in cell quiescence. Full growth recovery occurred after drug removal, unlike with doxorubicin chemotherapy. Regorafenib is a potent inhibitor of cell growth. Cells surviving Regorafenib treatment remain viable, but quiescent and capable of regrowth following drug removal. The reversibility of tumor cell growth suppression after drug removal may have clinical implications. PMID:22777740

Synergistic effect of fisetin combined with sorafenib in human cervical cancer HeLa cells through activation of death receptor-5 mediated caspase-8/caspase-3 and the mitochondria-dependent apoptotic pathway.

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Lin, Ming-Te; Lin, Chia-Liang; Lin, Tzu-Yu; Cheng, Chun-Wen; Yang, Shun-Fa; Lin, Chu-Liang; Wu, Chih-Chien; Hsieh, Yi-Hsien; Tsai, Jen-Pi

2016-05-01

Combining antitumor agents with bioactive compounds is a potential strategy for improving the effect of chemotherapy on cancer cells. The goal of this study was to elucidate the antitumor effect of the flavonoid, fisetin, combined with the multikinase inhibitor, sorafenib, against human cervical cancer cells in vitro and in vivo. The combination of fisetin and sorafenib synergistically induced apoptosis in HeLa cells, which is accompanied by a marked increase in loss of mitochondrial membrane potential. Apoptosis induction was achieved by caspase-3 and caspase-8 activation which increased the ratio of Bax/Bcl-2 and caused the subsequent cleavage of PARP level while disrupting the mitochondrial membrane potential in HeLa cells. Decreased Bax/Bcl-2 ratio level and mitochondrial membrane potential were also observed in siDR5-treated HeLa cells. In addition, in vivo studies revealed that the combined fisetin and sorafenib treatment was clearly superior to sorafenib treatment alone using a HeLa xenograft model. Our study showed that the combination of fisetin and sorafenib exerted better synergistic effects in vitro and in vivo than either agent used alone against human cervical cancer, and this synergism was based on apoptotic potential through a mitochondrial- and DR5-dependent caspase-8/caspase-3 signaling pathway. This combined fisetin and sorafenib treatment represents a novel therapeutic strategy for further clinical developments in advanced cervical cancer.

A combination of sorafenib and nilotinib reduces the growth of castrate-resistant prostate cancer

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Archibald M

2016-01-01

Full Text Available Monica Archibald,1 Tara Pritchard,1 Hayley Nehoff,1 Rhonda J Rosengren,1 Khaled Greish,1,2 Sebastien Taurin1 1Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand; 2Aljawhara Centre for Molecular Medicine, Arabian Gulf University, Manama, Kingdom of Bahrain Abstract: Castrate-resistant prostate cancer (CRPC remains incurable due to the lack of effective therapies. Several tyrosine kinases have been implicated in the development and growth of CRPC, as such targeting these kinases may offer an alternative therapeutic strategy. We established the combination of two tyrosine kinase inhibitors (TKIs, sorafenib and nilotinib, as the most cytotoxic. In addtion, to improve their bioavailability and reduce their metabolism, we encapsulated sorafenib and nilotinib into styrene-co-maleic acid micelles. The micelles’ charge, size, and release rate were characterized. We assessed the effect of the combination on the cytotoxicity, cell cycle, apoptosis, protein expression, tumor spheroid integrity, migration, and invasion. The micelles exhibited a mean diameter of 100 nm, a neutral charge, and appeared highly stable. The micellar TKIs promoted greater cytotoxicity, decreased cell proliferation, and increased apoptosis relative to the free TKIs. In addition, the combination reduced the expression and activity of several tyrosine kinases and reduced tumor spheroid integrity and metastatic potential of CRPC cell lines more efficiently than the single treatments. The combination increased the therapeutic potential and demonstrated the relevance of a targeted combination therapy for the treatment of CRPC. In addition, the efficacy of the encapsulated drugs provides the basis for an in vivo preclinical testing. Keywords: sorafenib, nilotinib, castrate-resistant prostate cancer, tyrosine kinase inhibitors, nanomedicine

VEGF and VEGFR genotyping in the prediction of clinical outcome for HCC patients receiving sorafenib: the ALICE-1 study.

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Scartozzi, Mario; Faloppi, Luca; Svegliati Baroni, Gianluca; Loretelli, Cristian; Piscaglia, Fabio; Iavarone, Massimo; Toniutto, Pierluigi; Fava, Giammarco; De Minicis, Samuele; Mandolesi, Alessandra; Bianconi, Maristella; Giampieri, Riccardo; Granito, Alessandro; Facchetti, Floriana; Bitetto, Davide; Marinelli, Sara; Venerandi, Laura; Vavassori, Sara; Gemini, Stefano; D'Errico, Antonietta; Colombo, Massimo; Bolondi, Luigi; Bearzi, Italo; Benedetti, Antonio; Cascinu, Stefano

2014-09-01

Although new treatment modalities changed the global approach to hepatocellular carcinoma (HCC), this disease still represents a medical challenge. Currently, the therapeutic stronghold is sorafenib, a tyrosine kinase inhibitor (TKI) directed against the vascular endothelial growth factor (VEGF) family. Previous observations suggested that polymorphisms of VEGF and its receptor (VEGFR) genes may regulate angiogenesis and lymphangiogenesis and thus tumour growth control. The aim of our study was to evaluate the role of VEGF and VEGFR polymorphisms in determining the clinical outcome of HCC patients receiving sorafenib. From a multicentre experience 148 samples (tumour or blood samples) of HCC patients receiving sorafenib were tested for VEGF-A, VEGF-C and VEGFR-1,2,3 single nucleotide polymorphisms (SNPs). Patients' progression-free survival (PFS) and overall survival (OS) were analysed. At univariate analysis VEGF-A alleles C of rs25648, T of rs833061, C of rs699947, C of rs2010963, VEGF-C alleles T of rs4604006, G of rs664393, VEGFR-2 alleles C of rs2071559, C of rs2305948 were significant predictors of PFS and OS. At multivariate analysis rs2010963, rs4604006 and BCLC (Barcelona Clinic Liver Cancer) stage resulted to be independent factors influencing PFS and OS. Once prospectively validated, the analysis of VEGF and VEGFR SNPs may represent a clinical tool to better identify HCC patients more likely to benefit from sorafenib. On the other hand, the availability of more accurate predictive factors could help avoiding unnecessary toxicities to potentially resistant patients who may be optimal candidates for different treatments interfering with other tumour molecular pathways. © 2014 UICC.

Novel biomarker-based model for the prediction of sorafenib response and overall survival in advanced hepatocellular carcinoma: a prospective cohort study.

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Kim, Hwi Young; Lee, Dong Hyeon; Lee, Jeong-Hoon; Cho, Young Youn; Cho, Eun Ju; Yu, Su Jong; Kim, Yoon Jun; Yoon, Jung-Hwan

2018-03-20

Prediction of the outcome of sorafenib therapy using biomarkers is an unmet clinical need in patients with advanced hepatocellular carcinoma (HCC). The aim was to develop and validate a biomarker-based model for predicting sorafenib response and overall survival (OS). This prospective cohort study included 124 consecutive HCC patients (44 with disease control, 80 with progression) with Child-Pugh class A liver function, who received sorafenib. Potential serum biomarkers (namely, hepatocyte growth factor [HGF], fibroblast growth factor [FGF], vascular endothelial growth factor receptor-1, CD117, and angiopoietin-2) were tested. After identifying independent predictors of tumor response, a risk scoring system for predicting OS was developed and 3-fold internal validation was conducted. A risk scoring system was developed with six covariates: etiology, platelet count, Barcelona Clinic Liver Cancer stage, protein induced by vitamin K absence-II, HGF, and FGF. When patients were stratified into low-risk (score ≤ 5), intermediate-risk (score 6), and high-risk (score ≥ 7) groups, the model provided good discriminant functions on tumor response (concordance [c]-index, 0.884) and 12-month survival (area under the curve [AUC], 0.825). The median OS was 19.0, 11.2, and 6.1 months in the low-, intermediate-, and high-risk group, respectively (P functions on tumor response (c-index, 0.825) and 12-month survival (AUC, 0.803), and good calibration functions (all P > 0.05 between expected and observed values). This new model including serum FGF and HGF showed good performance in predicting the response to sorafenib and survival in patients with advanced HCC.

Pro-angiogenic TIE-2-expressing monocytes/TEMs as a biomarker of the effect of sorafenib in patients with advanced hepatocellular carcinoma.

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Shoji, Hirotaka; Yoshio, Sachiyo; Mano, Yohei; Doi, Hiroyoshi; Sugiyama, Masaya; Osawa, Yosuke; Kimura, Kiminori; Arai, Taeang; Itokawa, Norio; Atsukawa, Masanori; Aoki, Yoshihiko; Fukai, Moto; Taketomi, Akinobu; Mizokami, Masashi; Kanto, Tatsuya

2017-09-01

Sorafenib, a multi-kinase inhibitor, inhibits tumor angiogenesis and is the first-line systemic therapy for patients with advanced hepatocellular carcinoma (HCC). However, due to its limited effects and frequent occurrence of side effects, biomarkers are needed to predict the effects of sorafenib. We considered the possibility of using TIE-2-expressing monocytes (TEMs) to predict the response in sorafenib-treated patients with advanced HCC. TEMs serve as a diagnostic marker of HCC and are related to angiogenesis. We analyzed 25 advanced HCC patients and prospectively evaluated TEMs before (Pre TEMs) and at 1 month after initial therapy (T1m TEMs). The radiologic response was evaluated by modified Response Evaluation Criteria in Solid Tumors (mRECIST). Median survival time (MST) was significantly longer in the partial response/stable disease (PR/SD) group (21.8 months) than in the PD group (8.7 months). ΔTEMs (changes of T1m TEMs compared to Pre TEMs) were significantly lower in the PR/SD group than in the PD group. MST of the ΔTEMs low group (14.2 months) was significantly longer than that of the high group (8.7 months). Univariate and multivariate Cox regression analyses showed that ΔTEMs [hazard ratio (HR) = 8.53, 95% confidence interval (CI) = 1.51-48.16, p = 0.015] and Child-Pugh class (HR = 5.59, 95% CI = 1.06-29.63, p = 0.043) were independently associated with overall survival. Our results suggest that ΔTEMs could serve as a biomarker for predicting radiologic response and overall survival in sorafenib-treated patients with advanced HCC. © 2017 UICC.

Rationale and design of decision: a double-blind, randomized, placebo-controlled phase III trial evaluating the efficacy and safety of sorafenib in patients with locally advanced or metastatic radioactive iodine (RAI)-refractory, differentiated thyroid cancer

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Brose, Marcia S; Schlumberger, Martin; Nutting, Christopher M; Sherman, Steven I; Shong, Young Kee; Smit, Johannes WA; Reike, Gerhard; Chung, John; Kalmus, Joachim; Kappeler, Christian

2011-01-01

The incidence of thyroid cancer and the number of patients who die from this disease are increasing globally. Differentiated thyroid cancer (DTC) is the histologic subtype present in most patients and is primarily responsible for the increased overall incidence of thyroid cancer. Sorafenib is a multikinase inhibitor that targets several molecular signals believed to be involved in the pathogenesis of thyroid cancer, including those implicated in DTC. In phase II studies of patients with DTC, sorafenib treatment has yielded a median progression-free survival (PFS) of 58 to 84 weeks and disease control rates of 59% to 100%. The DECISION trial was designed to assess the ability of sorafenib to improve PFS in patients with locally advanced or metastatic, radioactive iodine (RAI)-refractory DTC. DECISION is a multicenter, double-blind, randomized, placebo-controlled phase III study in patients with locally advanced/metastatic RAI-refractory DTC. Study treatment will continue until radiographically documented disease progression, unacceptable toxicity, noncompliance, or withdrawal of consent. Efficacy will be evaluated every 56 days (2 cycles), whereas safety will be evaluated every 28 days (1 cycle) for the first 8 months and every 56 days thereafter. Following disease progression, patients may continue or start sorafenib, depending on whether they were randomized to receive sorafenib or placebo, at investigator discretion. Patients originally randomized to receive sorafenib will be followed up every 3 months for overall survival (OS); patients originally randomized to receive placebo will be followed up every month for 8 months after cross-over to sorafenib. The duration of the trial is expected to be 30 months from the time the first patient is randomized until the planned number of PFS events is attained. The primary endpoint is PFS; secondary endpoints include OS, time to disease progression, disease control rate, response rate, duration of response, safety, and

Predictive factors in patients with hepatocellular carcinoma receiving sorafenib therapy using time-dependent receiver operating characteristic analysis.

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Nishikawa, Hiroki; Nishijima, Norihiro; Enomoto, Hirayuki; Sakamoto, Azusa; Nasu, Akihiro; Komekado, Hideyuki; Nishimura, Takashi; Kita, Ryuichi; Kimura, Toru; Iijima, Hiroko; Nishiguchi, Shuhei; Osaki, Yukio

2017-01-01

To investigate variables before sorafenib therapy on the clinical outcomes in hepatocellular carcinoma (HCC) patients receiving sorafenib and to further assess and compare the predictive performance of continuous parameters using time-dependent receiver operating characteristics (ROC) analysis. A total of 225 HCC patients were analyzed. We retrospectively examined factors related to overall survival (OS) and progression free survival (PFS) using univariate and multivariate analyses. Subsequently, we performed time-dependent ROC analysis of continuous parameters which were significant in the multivariate analysis in terms of OS and PFS. Total sum of area under the ROC in all time points (defined as TAAT score) in each case was calculated. Our cohort included 175 male and 50 female patients (median age, 72 years) and included 158 Child-Pugh A and 67 Child-Pugh B patients. The median OS time was 0.68 years, while the median PFS time was 0.24 years. On multivariate analysis, gender, body mass index (BMI), Child-Pugh classification, extrahepatic metastases, tumor burden, aspartate aminotransferase (AST) and alpha-fetoprotein (AFP) were identified as significant predictors of OS and ECOG-performance status, Child-Pugh classification and extrahepatic metastases were identified as significant predictors of PFS. Among three continuous variables (i.e., BMI, AST and AFP), AFP had the highest TAAT score for the entire cohort. In subgroup analyses, AFP had the highest TAAT score except for Child-Pugh B and female among three continuous variables. In continuous variables, AFP could have higher predictive accuracy for survival in HCC patients undergoing sorafenib therapy.

Dynamic PET evaluation of elevated FLT level after sorafenib treatment in mice bearing human renal cell carcinoma xenograft.

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Ukon, Naoyuki; Zhao, Songji; Yu, Wenwen; Shimizu, Yoichi; Nishijima, Ken-Ichi; Kubo, Naoki; Kitagawa, Yoshimasa; Tamaki, Nagara; Higashikawa, Kei; Yasui, Hironobu; Kuge, Yuji

2016-12-01

Sorafenib, an oral multikinase inhibitor, has anti-proliferative and anti-angiogenic activities and is therapeutically effective against renal cell carcinoma (RCC). Recently, we have evaluated the tumor responses to sorafenib treatment in a RCC xenograft using [Methyl- 3 H(N)]-3'-fluoro-3'-deoxythythymidine ([ 3 H]FLT). Contrary to our expectation, the FLT level in the tumor significantly increased after the treatment. In this study, to clarify the reason for the elevated FLT level, dynamic 3'-[ 18 F]fluoro-3'-deoxythymidine ([ 18 F]FLT) positron emission tomography (PET) and kinetic studies were performed in mice bearing a RCC xenograft (A498). The A498 xenograft was established in nude mice, and the mice were assigned to the control (n = 5) and treatment (n = 5) groups. The mice in the treatment group were orally given sorafenib (20 mg/kg/day p.o.) once daily for 3 days. Twenty-four hours after the treatment, dynamic [ 18 F]FLT PET was performed by small-animal PET. Three-dimensional regions of interest (ROIs) were manually defined for the tumors. A three-compartment model fitting was carried out to estimate four rate constants using the time activity curve (TAC) in the tumor and the blood clearance rate of [ 18 F]FLT. The dynamic pattern of [ 18 F]FLT levels in the tumor significantly changed after the treatment. The rate constant of [ 18 F]FLT phosphorylation (k 3 ) was significantly higher in the treatment group (0.111 ± 0.027 [1/min]) than in the control group (0.082 ± 0.009 [1/min]). No significant changes were observed in the distribution volume, the ratio of [ 18 F]FLT forward transport (K 1 ) to reverse transport (k 2 ), between the two groups (0.556 ± 0.073 and 0.641 ± 0.052 [mL/g] in the control group). Our dynamic PET studies indicated that the increase in FLT level may be caused by the phosphorylation of FLT in the tumor after the sorafenib treatment in the mice bearing a RCC xenograft. Dynamic PET studies with kinetic

The combination of sorafenib and everolimus shows antitumor activity in preclinical models of malignant pleural mesothelioma

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Pignochino, Ymera; Dell’Aglio, Carmine; Inghilleri, Simona; Zorzetto, Michele; Basiricò, Marco; Capozzi, Federica; Canta, Marta; Piloni, Davide; Cemmi, Francesca; Sangiolo, Dario; Gammaitoni, Loretta; Soster, Marco; Marchiò, Serena; Pozzi, Ernesto; Morbini, Patrizia; Luisetti, Maurizio; Aglietta, Massimo; Grignani, Giovanni; Stella, Giulia M

2015-01-01

Malignant Pleural Mesothelioma (MPM) is an aggressive tumor arising from mesothelial cells lining the pleural cavities characterized by resistance to standard therapies. Most of the molecular steps responsible for pleural transformation remain unclear; however, several growth factor signaling cascades are known to be altered during MPM onset and progression. Transducers of these pathways, such as PIK3CA-mTOR-AKT, MAPK, and ezrin/radixin/moesin (ERM) could therefore be exploited as possible targets for pharmacological intervention. This study aimed to identify ‘druggable’ pathways in MPM and to formulate a targeted approach based on the use of commercially available molecules, such as the multikinase inhibitor sorafenib and the mTOR inhibitor everolimus. We planned a triple approach based on: i) analysis of immunophenotypes and mutational profiles in a cohort of thoracoscopic MPM samples, ii) in vitro pharmacological assays, ii) in vivo therapeutic approaches on MPM xenografts. No mutations were found in ‘hot spot’ regions of the mTOR upstream genes (e.g. EGFR, KRAS and PIK3CA). Phosphorylated mTOR and ERM were specifically overexpressed in the analyzed MPM samples. Sorafenib and everolimus combination was effective in mTOR and ERM blockade; exerted synergistic effects on the inhibition of MPM cell proliferation; triggered ROS production and consequent AMPK-p38 mediated-apoptosis. The antitumor activity was displayed when orally administered to MPM-bearing NOD/SCID mice. ERM and mTOR pathways are activated in MPM and ‘druggable’ by a combination of sorafenib and everolimus. Combination therapy is a promising therapeutic strategy against MPM. The online version of this article (doi:10.1186/s12885-015-1363-1) contains supplementary material, which is available to authorized users

Fisetin, a dietary flavonoid, augments the anti-invasive and anti-metastatic potential of sorafenib in melanoma.

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Pal, Harish C; Diamond, Ariana C; Strickland, Leah R; Kappes, John C; Katiyar, Santosh K; Elmets, Craig A; Athar, Mohammad; Afaq, Farrukh

2016-01-12

Melanoma is the most aggressive and deadly form of cutaneous neoplasm due to its propensity to metastasize. Oncogenic BRAF drives sustained activation of the BRAF/MEK/ERK (MAPK) pathway and cooperates with PI3K/AKT/mTOR (PI3K) signaling to induce epithelial to mesenchymal transition (EMT), leading to cell invasion and metastasis. Therefore, targeting these pathways is a promising preventive/therapeutic strategy. We have shown that fisetin, a flavonoid, reduces human melanoma cell invasion by inhibiting EMT. In addition, fisetin inhibited melanoma cell proliferation and tumor growth by downregulating the PI3K pathway. In this investigation, we aimed to determine whether fisetin can potentiate the anti-invasive and anti-metastatic effects of sorafenib in BRAF-mutated melanoma. We found that combination treatment (fisetin + sorafenib) more effectively reduced the migration and invasion of BRAF-mutated melanoma cells both in vitro and in raft cultures compared to individual agents. Combination treatment also effectively inhibited EMT as observed by a decrease in N-cadherin, vimentin and fibronectin and an increase in E-cadherin both in vitro and in xenograft tumors. Furthermore, combination therapy effectively inhibited Snail1, Twist1, Slug and ZEB1 protein expression compared to monotherapy. The expression of MMP-2 and MMP-9 in xenograft tumors was further reduced in combination treatment compared to individual agents. Bioluminescent imaging of athymic mice, intravenously injected with stably transfected CMV-luciferase-ires-puromycin.T2A.EGFP-tagged A375 melanoma cells, demonstrated fewer lung metastases following combination treatment versus monotherapy. Our findings demonstrate that fisetin potentiates the anti-invasive and anti-metastatic effects of sorafenib. Our data suggest that fisetin may be a worthy adjuvant chemotherapy for the management of melanoma.

Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial.

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Bruix, Jordi; Qin, Shukui; Merle, Philippe; Granito, Alessandro; Huang, Yi-Hsiang; Bodoky, György; Pracht, Marc; Yokosuka, Osamu; Rosmorduc, Olivier; Breder, Valeriy; Gerolami, René; Masi, Gianluca; Ross, Paul J; Song, Tianqiang; Bronowicki, Jean-Pierre; Ollivier-Hourmand, Isabelle; Kudo, Masatoshi; Cheng, Ann-Lii; Llovet, Josep M; Finn, Richard S; LeBerre, Marie-Aude; Baumhauer, Annette; Meinhardt, Gerold; Han, Guohong

2017-01-07

There are no systemic treatments for patients with hepatocellular carcinoma (HCC) whose disease progresses during sorafenib treatment. We aimed to assess the efficacy and safety of regorafenib in patients with HCC who have progressed during sorafenib treatment. In this randomised, double-blind, parallel-group, phase 3 trial done at 152 sites in 21 countries, adults with HCC who tolerated sorafenib (≥400 mg/day for ≥20 of last 28 days of treatment), progressed on sorafenib, and had Child-Pugh A liver function were enrolled. Participants were randomly assigned (2:1) by a computer-generated randomisation list and interactive voice response system and stratified by geographical region, Eastern Cooperative Oncology Group performance status, macrovascular invasion, extrahepatic disease, and α-fetoprotein level to best supportive care plus oral regorafenib 160 mg or placebo once daily during weeks 1-3 of each 4-week cycle. Investigators, patients, and the funder were masked to treatment assignment. The primary endpoint was overall survival (defined as time from randomisation to death due to any cause) and analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01774344. Between May 14, 2013, and Dec 31, 2015, 843 patients were screened, of whom 573 were enrolled and randomised (379 to regorafenib and 194 to placebo; population for efficacy analyses), and 567 initiated treatment (374 received regorafenib and 193 received placebo; population for safety analyses). Regorafenib improved overall survival with a hazard ratio of 0·63 (95% CI 0·50-0·79; one-sided p<0·0001); median survival was 10·6 months (95% CI 9·1-12·1) for regorafenib versus 7·8 months (6·3-8·8) for placebo. Adverse events were reported in all regorafenib recipients (374 [100%] of 374) and 179 (93%) of 193 placebo recipients. The most common clinically relevant grade 3 or 4 treatment-emergent events were hypertension (57 patients [15%] in the regorafenib group

Synergistic activity of vorinostat combined with gefitinib but not with sorafenib in mutant KRAS human non-small cell lung cancers and hepatocarcinoma.

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Jeannot, Victor; Busser, Benoit; Vanwonterghem, Laetitia; Michallet, Sophie; Ferroudj, Sana; Cokol, Murat; Coll, Jean-Luc; Ozturk, Mehmet; Hurbin, Amandine

2016-01-01

Development of drug resistance limits the efficacy of targeted therapies. Alternative approaches using different combinations of therapeutic agents to inhibit several pathways could be a more effective strategy for treating cancer. The effects of the approved epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (gefitinib) or a multi-targeted kinase inhibitor (sorafenib) in combination with a histone deacetylase inhibitor (vorinostat) on cell proliferation, cell cycle distribution, apoptosis, and signaling pathway activation in human lung adenocarcinoma and hepatocarcinoma cells with wild-type EGFR and mutant KRAS were investigated. The effects of the synergistic drug combinations were also studied in human lung adenocarcinoma and hepatocarcinoma cells in vivo. The combination of gefitinib and vorinostat synergistically reduced cell growth and strongly induced apoptosis through inhibition of the insulin-like growth factor-1 receptor/protein kinase B (IGF-1R/AKT)-dependent signaling pathway. Moreover, the gefitinib and vorinostat combination strongly inhibited tumor growth in mice with lung adenocarcinoma or hepatocarcinoma tumor xenografts. In contrast, the combination of sorafenib and vorinostat did not inhibit cell proliferation compared to a single treatment and induced G 2 /M cell cycle arrest without apoptosis. The sorafenib and vorinostat combination sustained the IGF-1R-, AKT-, and mitogen-activated protein kinase-dependent signaling pathways. These results showed that there was synergistic cytotoxicity when vorinostat was combined with gefitinib for both lung adenocarcinoma and hepatocarcinoma with mutant KRAS in vitro and in vivo but that the combination of vorinostat with sorafenib did not show any benefit. These findings highlight the important role of the IGF-1R/AKT pathway in the resistance to targeted therapies and support the use of histone deacetylase inhibitors in combination with EGFR-tyrosine kinase inhibitors, especially for

Efficacy and safety of selective internal radiotherapy with yttrium-90 resin microspheres compared with sorafenib in locally advanced and inoperable hepatocellular carcinoma (SARAH): an open-label randomised controlled phase 3 trial.

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Vilgrain, Valérie; Pereira, Helena; Assenat, Eric; Guiu, Boris; Ilonca, Alina Diana; Pageaux, Georges-Philippe; Sibert, Annie; Bouattour, Mohamed; Lebtahi, Rachida; Allaham, Wassim; Barraud, Hélène; Laurent, Valérie; Mathias, Elodie; Bronowicki, Jean-Pierre; Tasu, Jean-Pierre; Perdrisot, Rémy; Silvain, Christine; Gerolami, René; Mundler, Olivier; Seitz, Jean-Francois; Vidal, Vincent; Aubé, Christophe; Oberti, Frédéric; Couturier, Olivier; Brenot-Rossi, Isabelle; Raoul, Jean-Luc; Sarran, Anthony; Costentin, Charlotte; Itti, Emmanuel; Luciani, Alain; Adam, René; Lewin, Maïté; Samuel, Didier; Ronot, Maxime; Dinut, Aurelia; Castera, Laurent; Chatellier, Gilles

2017-12-01

Sorafenib is the recommended treatment for patients with advanced hepatocellular carcinoma. We aimed to compare the efficacy and safety of sorafenib to that of selective internal radiotherapy (SIRT) with yttrium-90 ( 90 Y) resin microspheres in patients with hepatocellular carcinoma. SARAH was a multicentre, open-label, randomised, controlled, investigator-initiated, phase 3 trial done at 25 centres specialising in liver diseases in France. Patients were eligible if they were aged at least 18 years with a life expectancy greater than 3 months, had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, Child-Pugh liver function class A or B score of 7 or lower, and locally advanced hepatocellular carcinoma (Barcelona Clinic Liver Cancer [BCLC] stage C), or new hepatocellular carcinoma not eligible for surgical resection, liver transplantation, or thermal ablation after a previously cured hepatocellular carcinoma (cured by surgery or thermoablative therapy), or hepatocellular carcinoma with two unsuccessful rounds of transarterial chemoembolisation. Patients were randomly assigned (1:1) by a permutated block method with block sizes two and four to receive continuous oral sorafenib (400 mg twice daily) or SIRT with 90 Y-loaded resin microspheres 2-5 weeks after randomisation. Patients were stratified according to randomising centre, ECOG performance status, previous transarterial chemoembolisation, and presence of macroscopic vascular invasion. The primary endpoint was overall survival. Analyses were done on the intention-to-treat population; safety was assessed in all patients who received at least one dose of sorafenib or underwent at least one of the SIRT work-up exams. This study has been completed and the final results are reported here. The trial is registered with ClinicalTrials.gov, number NCT01482442. Between Dec 5, 2011, and March 12, 2015, 467 patients were randomly assigned; after eight patients withdrew consent, 237 were assigned to

Extraordinary radiation super-sensitivity accompanying with sorafenib combination therapy: what lies beneath?

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Lee, Ja Young; Lee, Ju Hye; Yoon, Han Bin; Lee, Ho Jeong; Jeon, Ho Sang; Nam, Ji Ho [Dept. of Radiation Oncology, Pusan National University Yangsan Hospital, Yangsan (Korea, Republic of)

2017-06-15

Primary liver tumor, especially hepatocellular carcinoma (HCC), is a common cause of cancer death worldwide. The incidence is generally higher in Asian countries than in western countries. Carcinogenesis of HCC is often associated with hepatitis viral infections. Current standard treatment of HCC is surgical resection or transplantation in patients with early stage disease. However, the patient with advanced stage disease, surgical resection is often limited. Sorafenib or other treatment modalities are not so effective as well. We report a case of unusual radiation super-sensitivity in advanced stage HCC, and review the literature.

Cancer patients treated with sunitinib or sorafenib have sufficient antibody and cellular immune responses to warrant influenza vaccination

NARCIS (Netherlands)

Mulder, Sasja F.; Jacobs, Joannes F. M.; Olde Nordkamp, Michel A. M.; Galama, Joep M. D.; Desar, Ingrid M. E.; Torensma, Ruurd; Teerenstra, Steven; Mulders, Peter F. A.; Vissers, Kris C. P.; Punt, Cornelis J. A.; de Vries, I. Jolanda M.; van Herpen, Carla M. L.

2011-01-01

The tyrosine kinase inhibitors sorafenib and sunitinib have efficacy in several types of cancer. Recent studies indicate that these agents affect the immune system. The way it affects the immune response to influenza vaccination is unknown. The aim of this study was to elucidate the specific immune

Cancer patients treated with sunitinib or sorafenib have sufficient antibody and cellular immune responses to warrant influenza vaccination

NARCIS (Netherlands)

Mulder, S.F.; Jacobs, J.F.M.; Olde Nordkamp, M.A.M.; Galama, J.M.D.; Desar, I.M.E.; Torensma, R.; Teerenstra, S.; Mulders, P.F.; Vissers, K.C.P.; Punt, C.J.A.; Vries, I.J.M. de; Herpen, C.M.L. van

2011-01-01

PURPOSE: The tyrosine kinase inhibitors sorafenib and sunitinib have efficacy in several types of cancer. Recent studies indicate that these agents affect the immune system. The way it affects the immune response to influenza vaccination is unknown. The aim of this study was to elucidate the

Prognosis of patients with hepatocellular carcinoma treated with sorafenib: a comparison of five models in a large Canadian database.

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Samawi, Haider H; Sim, Hao-Wen; Chan, Kelvin K; Alghamdi, Mohammad A; Lee-Ying, Richard M; Knox, Jennifer J; Gill, Parneet; Romagnino, Adriana; Batuyong, Eugene; Ko, Yoo-Joung; Davies, Janine M; Lim, Howard J; Cheung, Winson Y; Tam, Vincent C

2018-05-15

Several systems (tumor-node-metastasis [TNM], Barcelona Clinic Liver Cancer [BCLC], Okuda, Cancer of the Liver Italian Program [CLIP], and albumin-bilirubin grade [ALBI]) were developed to estimate the prognosis of patients with hepatocellular carcinoma (HCC) mostly prior to the prevalent use of sorafenib. We aimed to compare the prognostic and discriminatory power of these models in predicting survival for HCC patients treated with sorafenib and to identify independent prognostic factors for survival in this population. Patients who received sorafenib for the treatment of HCC between 1 January 2008 and 30 June 2015 in the provinces of British Columbia and Alberta, and two large cancer centers in Toronto, Ontario, were included. Survival was assessed using the Kaplan-Meier method. Multivariate Cox regression was used to identify predictors of survival. The models were compared with respect to homogeneity, discriminatory ability, monotonicity of gradients, time-dependent area under the curve, and Akaike information criterion. A total of 681 patients were included. 80% were males, 86% had Child-Pugh class A, and 37% of patients were East Asians. The most common etiology for liver disease was hepatitis B (34%) and C (31%). In all model comparisons, CLIP performed better while BCLC and TNM7 performed less favorably but the differences were small. The utility of each system in allocating patients into different prognostic groups varied, for example, TNM poorly differentiated patients in advanced stages (8.7 months (m) (95% CI 6.5-11.5) versus 8.4 m (95% CI 7.0-9.6) for stages III and IV, respectively) while ALBI had excellent discrimination of early grades (15.6 m [95% CI 13.0-18.4] versus 8.3 m [95% CI 7.0-9.2] for grades 1 and 2, respectively). On multivariate analysis, hepatitis C, alcoholism, and prior hepatic resection were independently prognostic of better survival (P < 0.01). In conclusion, none of the prognostic systems was optimal in predicting survival

Phase II trial of sorafenib and erlotinib in advanced pancreatic cancer

International Nuclear Information System (INIS)

Cardin, Dana B; Goff, Laura; Li, Chung-I; Shyr, Yu; Winkler, Charles; DeVore, Russell; Schlabach, Larry; Holloway, Melanie; McClanahan, Pam; Meyer, Krista; Grigorieva, Julia; Berlin, Jordan; Chan, Emily

2014-01-01

This trial was designed to assess efficacy and safety of erlotinib with sorafenib in the treatment of patients with advanced pancreatic adenocarcinoma. An exploratory correlative study analyzing pretreatment serum samples using a multivariate protein mass spectrometry-based test (VeriStrat®), previously shown to correlate with outcomes in lung cancer patients treated with erlotinib, was performed. Patients received sorafenib 400 mg daily along with erlotinib 150 mg daily with a primary endpoint of 8-week progression free survival (PFS) rate. Pretreatment serum sample analysis by VeriStrat was done blinded to clinical and outcome data; the endpoints were PFS and overall survival (OS). Difference between groups (by VeriStrat classification) was assessed using log-rank P values; hazard ratios (HR) were obtained from Cox proportional hazards model. Thirty-six patients received study drug and were included in the survival analysis. Eight-week PFS rate of 46% (95% confidence interval (CI): 0.32–0.67) did not meet the primary endpoint of a rate ≥70%. Thirty-two patients were included in the correlative analysis, and VeriStrat “Good” patients had superior PFS (HR = 0.18, 95% CI: 0.06–0.57; P = 0.001) and OS (HR = 0.31 95% CI: 0.13–0.77, P = 0.008) compared to VeriStrat “Poor” patients. Grade 3 toxicities of this regimen included fever, anemia, diarrhea, dehydration, rash, and altered liver function. This study did not meet the primary endpoint, and this combination will not be further pursued. In this small retrospective analysis, the proteomic classification was significantly associated with clinical outcomes and is being further evaluated in ongoing studies

Sorafenib and everolimus for patients with unresectable high-grade osteosarcoma progressing after standard treatment: a non-randomised phase 2 clinical trial.

Science.gov (United States)

Grignani, Giovanni; Palmerini, Emanuela; Ferraresi, Virginia; D'Ambrosio, Lorenzo; Bertulli, Rossella; Asaftei, Sebastian Dorin; Tamburini, Angela; Pignochino, Ymera; Sangiolo, Dario; Marchesi, Emanuela; Capozzi, Federica; Biagini, Roberto; Gambarotti, Marco; Fagioli, Franca; Casali, Paolo Giovanni; Picci, Piero; Ferrari, Stefano; Aglietta, Massimo

2015-01-01

Results of previous study showed promising but short-lived activity of sorafenib in the treatment of patients with unresectable advanced and metastatic osteosarcoma. This treatment failure has been attributed to the mTOR pathway and might therefore be overcome with the addition of mTOR inhibitors. We aimed to investigate the activity of sorafenib in combination with everolimus in patients with inoperable high-grade osteosarcoma progressing after standard treatment. We did this non-randomised phase 2 trial in three Italian Sarcoma Group centres. We enrolled adults (≥18 years) with relapsed or unresectable osteosarcoma progressing after standard treatment (methotrexate, cisplatin, and doxorubicin, with or without ifosfamide). Patients received 800 mg sorafenib plus 5 mg everolimus once a day until disease progression or unacceptable toxic effects. The primary endpoint was 6 month progression-free survival (PFS). All analyses were intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT01804374. We enrolled 38 patients between June 16, 2011, and June 4, 2013. 17 (45%; 95% CI 28-61) of 38 patients were progression free at 6 months. Toxic effects led to dose reductions, or short interruptions, or both in 25 (66%) of 38 patients and permanent discontinuation for two (5%) patients. The most common grade 3-4 adverse events were lymphopenia and hypophosphataemia each in six (16%) patients, hand and foot syndrome in five (13%), thrombocytopenia in four (11%), and fatigue, oral mucositis, diarrhoea, and anaemia each in two (5%). One patient (3%) had a grade 3 pneumothorax that required trans-thoracic drainage, and that recurred at the time of disease progression. This was reported as a serious adverse event related to the study drugs in both instances. No other serious adverse events were reported during the trial. There were no treatment-related deaths. Although the combination of sorafenib and everolimus showed activity as a further-line treatment

Efficacy of sorafenib in BRAF-mutated non-small-cell lung cancer (NSCLC) and no response in synchronous BRAF wild type-hepatocellular carcinoma: a case report

International Nuclear Information System (INIS)

Casadei Gardini, Andrea; Chiadini, Elisa; Faloppi, Luca; Marisi, Giorgia; Delmonte, Angelo; Scartozzi, Mario; Loretelli, Cristian; Lucchesi, Alessandro; Oboldi, Devil; Dubini, Alessandra; Frassineti, Giovanni Luca; Ulivi, Paola

2016-01-01

Sorafenib is a multi-targeted kinase inhibitor with a demonstrated activity in renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC), and it is currently used for the treatment of these pathologies. Ongoing clinical trials are studying its activity in other malignancies, such as non-small-cell lung cancer (NSCLC). However, no biological marker is known to define either the sensitivity or resistance to the drug. Here we report a case of a patient with two synchronous tumors, HCC and NSCLC, with metastases in the contralateral lung and bone. The patient was treated with gemcitabine as first line, with a resulting progressive disease after two months, and then with sorafenib at standard dosage in the second line setting. After 6 months of treatment CT scan showed a partial response in the primary lesion of the lung, complete response of the metastasis in the contralateral lung, and stability of HCC. The patient had progression in the lung, liver and bone after 13 months of therapy. A molecular characterization of NSCLC and HCC lesions was performed, revealing a BRAF exon 11 mutation (G469V) only in NSCLC. We hypothesize that the response observed in NSCLC lesions could be due to the presence of BRAF mutation, and that this alteration could be responsible in determining sorafenib sensitivity. Results observed in this case encourage further research on the activity of sorafenib in both HCC and NSCLC, based on the presence of BRAF mutation. This could lead to a selection of HCC patients to be treated with this drug, and could help identify a novel treatment strategy for BRAF-mutated NSCLC patients

Orthotopic liver transplantation after the combined use of locoregional therapy and sorafenib for advanced hepatocellular carcinoma

Directory of Open Access Journals (Sweden)

Yoo EJ

2013-06-01

Full Text Available Eun Jin Yoo,1,* Hye Sun Shin,1,* Seung Up Kim,1,2,7 Dong Jin Joo,3,4 Jun Yong Park,1,2,7 Gi Hong Choi,3 Do Young Kim,1,2,7 Sang Hoon Ahn,1,2,7 Jinsil Seong,5 Myung Joo Koh,6 Kwang-Hyub Han,1,2,7 Chae Yoon Chon1,2,7 1Department of Internal Medicine, 2Institute of Gastroenterology, 3Department of Surgery, 4Research Institute for Transplantation, 5Department of Radiation Oncology, 6Department of Pathology, Yonsei University College of Medicine, Seoul, South Korea; 7Liver Cirrhosis Clinical Research Center, Seoul, South Korea *These authors contributed equally to this work Abstract: We herein report a patient with advanced hepatitis B virus-related hepatocellular carcinoma (HCC beyond the Milan criteria. He underwent orthotopic liver transplantation after successful HCC downstaging that satisfied the University of California, San Francisco criteria, using concurrent chemoradiation therapy with a combination of repeated hepatic arterial infusion chemotherapy (HAIC and sorafenib. A 52-year-old male was diagnosed with advanced hepatitis B virus-related HCC beyond the Milan criteria. He underwent concurrent chemoradiation therapy (50 Gy with 20 fractions over 5 weeks with HAIC using 5-fluorouracil at a dose of 500 mg/day, which was administered during the first and fifth weeks of radiation therapy as an initial treatment modality. This was followed by the combined use of HAIC using 5-fluorouracil (500 mg/m2 for 5 hours on days 1–3 and cisplatin (60 mg/m2 for 2 hours on day 2 every 4 weeks (twelve cycles and sorafenib (from the third to the twelfth cycle of HAIC to treat the remaining HCC. Because a remarkable decrease in the tumor burden that satisfied the University of California, San Francisco criteria was observed after these combination treatments, the patient underwent orthotopic liver transplantation with curative aim and survived for 11 months without evidence of HCC recurrence. Keywords: hepatocellular carcinoma, liver transplantation

Use of Ultrasmall Superparamagnetic Iron Oxide Enhanced Susceptibility Weighted Imaging and Mean Vessel Density Imaging to Monitor Antiangiogenic Effects of Sorafenib on Experimental Hepatocellular Carcinoma

Directory of Open Access Journals (Sweden)

Shuohui Yang

2017-01-01

Full Text Available We investigated effectiveness of ultrasmall superparamagnetic iron oxide enhanced susceptibility weighted imaging (USPIO-enhanced SWI and mean vessel density imaging (Q in monitoring antiangiogenic effects of Sorafenib on orthotopic hepatocellular carcinoma (HCC. Thirty-five HCC xenografts were established. USPIO-enhanced SWI and Q were performed on a 1.5 T MR scanner at baseline, 7, 14, and 21 days after Sorafenib treatment. Intratumoral susceptibility signal intensity (ITSS and Q were serially measured and compared between the treated (n = 15 and control groups (n = 15. Both ITSS and Q were significantly lower in the treated group at each time point (P < 0.05. Measurements in the treated group showed that ITSS persisted at 7 days (P = 0.669 and increased at 14 and 21 days (P < 0.05, while Q significantly declined at 7 days (P = 0.028 and gradually increased at 14 and 21 days. In the treated group, significant correlation was found between Q and histologic microvessel density (MVD (r = 0.753, P < 0.001, and ITSS correlated well with MVD (r = 0.742, P = 0.002 after excluding the data from baseline. This study demonstrated that USPIO-enhanced SWI and Q could provide novel biomarkers for evaluating antiangiogenic effects of Sorafenib on HCC.

Sorafenib promotes graft-versus-leukemia activity in mice and humans through IL-15 production in FLT3-ITD-mutant leukemia cells

NARCIS (Netherlands)

Mathew, N.R.; Baumgartner, F.; Braun, L.; O'Sullivan, D.; Thomas, S.; Waterhouse, M.; Muller, T.A.; Hanke, K.; Taromi, S.; Apostolova, P.; Illert, A.L.; Melchinger, W.; Duquesne, S.; Schmitt-Graeff, A.; Osswald, L.; Yan, K.L.; Weber, A; Tugues, S.; Spath, S.; Pfeifer, D.; Follo, M.; Claus, R.; Lubbert, M.; Rummelt, C.; Bertz, H.; Wasch, R.; Haag, J.; Schmidts, A.; Schultheiss, M.; Bettinger, D.; Thimme, R.; Ullrich, E.; Tanriver, Y.; Vuong, G.L.; Arnold, R.; Hemmati, P.; Wolf, D.; Ditschkowski, M.; Jilg, C.; Wilhelm, K.; Leiber, C.; Gerull, S.; Halter, J.; Lengerke, C.; Pabst, T.; Schroeder, T.; Kobbe, G.; Rosler, W.; Doostkam, S.; Meckel, S.; Stabla, K.; Metzelder, S.K.; Halbach, S.; Brummer, T.; Hu, Z; Dengjel, J.; Hackanson, B.; Schmid, C.; Holtick, U.; Scheid, C.; Spyridonidis, A.; Stolzel, F.; Ordemann, R.; Muller, L.P.; Sicre-de-Fontbrune, F.; Ihorst, G.; Kuball, J.; Ehlert, J.E.; Feger, D.; Wagner, E.M.; Cahn, J.Y.; Schnell, J.; Kuchenbauer, F.; Bunjes, D.; Chakraverty, R.; Richardson, S.; Gill, S.; Kroger, N.; Ayuk, F.; Vago, L.; Ciceri, F.; Muller, A.M.; Kondo, T.; Teshima, T.; Klaeger, S.; Kuster, B.; Kim, D.D.H.; Weisdorf, D.; Velden, W.J. van der; Dorfel, D.; Bethge, W.; Hilgendorf, I.; Hochhaus, A.; Andrieux, G.; Borries, M.; Busch, H.; Magenau, J.; Reddy, P.; Labopin, M.; Antin, J.H., et al.

2018-01-01

Individuals with acute myeloid leukemia (AML) harboring an internal tandem duplication (ITD) in the gene encoding Fms-related tyrosine kinase 3 (FLT3) who relapse after allogeneic hematopoietic cell transplantation (allo-HCT) have a 1-year survival rate below 20%. We observed that sorafenib, a

Transarterial chemoembolization combined with sorafenib for the treatment of hepatocellular carcinoma with hepatic vein tumor thrombus

Directory of Open Access Journals (Sweden)

Zhang YF

2016-07-01

Full Text Available Yong-Fa Zhang,1–3,* Wei Wei,1–3,* Jia-Hong Wang,1–3,* Li Xu,1–3 Pei-En Jian,1–3 Cheng-Zuo Xiao,4 Xiao-Ping Zhong,1–3 Ming Shi,1–3 Rong-Ping Guo1–3 1Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, 2State Key Laboratory of Oncology in South China, 3Collaborative Innovation Center for Cancer Medicine, Guangzhou, 4Department of General Surgery, Shenzhen Shajing Affiliated Hospital of Guangzhou Medical University, Shenzhen, People’s Republic of China *These authors contributed equally to this work Objective: To compare the treatment outcomes of sorafenib plus transarterial chemoembolization (TACE vs TACE alone in patients with hepatocellular carcinoma (HCC and hepatic vein tumor thrombus (HVTT.Methods: Twenty patients who were initially diagnosed with HCC and HVTT and received TACE combined with sorafenib during February 2009 to October 2013 were included in the study. To minimize selection bias, these patients were compared with 60 case-matched controls selected from a pool of 81 patients (in a 1:3 ratio who received TACE alone during the same period. The primary end point was overall survival (OS. The secondary end points were time to progression, disease control rate, and adverse events.Results: After a median follow-up period of 12.5 months (range, 1.03–44.23 months, the OS of the combined group was found to be significantly higher compared with the monotherapy group (14.9 vs 6.1 months, P=0.010. The time to progression was found to be significantly longer in the combined group (4.9 vs 2.4 months, P=0.016. Univariate and multivariate analyses revealed that the treatment allocation was an independent predictor of OS.Conclusion: Sorafenib plus TACE was well tolerated and was more effective in treating patients with advanced HCC and HVTT. Future trials with prospective larger samples are required to validate these results. Keywords: hepatocellular carcinoma, hepatic vein tumor thrombus, prognosis

Regulation of Multidrug Resistance Proteins by Genistein in a Hepatocarcinoma Cell Line: Impact on Sorafenib Cytotoxicity

OpenAIRE

Rigalli, Juan Pablo; Ciriaci, Nadia; Arias, Agostina; Ceballos, Mar?a Paula; Villanueva, Silvina Stella Maris; Luquita, Marcelo Gabriel; Mottino, Aldo Domingo; Ghanem, Carolina In?s; Catania, Viviana Alicia; Ruiz, Mar?a Laura

2015-01-01

Hepatocellular carcinoma (HCC) is the fifth most frequent cancer worldwide. Sorafenib is the only drug available that improves the overall survival of HCC patients. P-glycoprotein (P-gp), Multidrug resistance-associated proteins 2 and 3 (MRP2 and 3) and Breast cancer resistance protein (BCRP) are efflux pumps that play a key role in cancer chemoresistance. Their modulation by dietary compounds may affect the intracellular accumulation and therapeutic efficacy of drugs that are substrates of t...

Thyroid size change by CT monitoring after sorafenib or sunitinib treatment in patients with renal cell carcinoma: Comparison with thyroid function

International Nuclear Information System (INIS)

Kitajima, Kazuhiro; Takahashi, Satoru; Maeda, Tetsuo; Yoshikawa, Takeshi; Ohno, Yoshiharu; Fujii, Masahiko; Miyake, Hideaki; Fujisawa, Masato; Sugimura, Kazuro

2012-01-01

Objective: Hypothyroidism is a common complication in patients receiving tyrosine kinase inhibitors. We evaluated the relationship between thyroid size evident on CT and thyroid function in patients with advanced renal cell carcinoma (RCC) receiving tyrosine kinase inhibitors. Materials and methods: Forty-two patients with metastatic RCC receiving tyrosine kinase inhibitors (sorafenib n = 25; sunitinib n = 17) and, followed-up for ≥12 months were eligible. Patients who had ever shown an elevated thyroid-stimulating hormone (TSH) level of >10 mU/l were defined as having “hypothyroidism”. CT scans were performed before, and 3, 6, 9, and 12 months after the start of treatment. The area of the thyroid in the maximum section at each examination was measured and compared with that before treatment. Using repeated-measures ANOVA, differences in thyroid size were compared over time between patients with and without “hypothyroidism”, in relation to the type of drug employed. Results: Twenty-one patients (sorafenib 9, sunitinib 12) developed “hypothyroidism” 95 ± 88 days (range 12–315 days) after the start of treatment. In such patients, the thyroid was reduced in size to 89 ± 16% after 3 months, 81 ± 21% after 6 months, 71 ± 21% after 9 months and 68 ± 21% after 12 months, whereas the patients without “hypothyroidism” maintained a thyroid size of 90 ± 12% even after 12 months (p = 0.0030). Among the patients with “hypothyroidism”, those treated with sunitinib tended to show greater thyroid size reduction than those with sorafenib (59 ± 23% vs. 79 ± 13%, after 12 months). Conclusion: Tyrosine kinase inhibitors cause an apparent thyroid size reduction in patients with “hypothyroidism”

Thyroid size change by CT monitoring after sorafenib or sunitinib treatment in patients with renal cell carcinoma: Comparison with thyroid function

Energy Technology Data Exchange (ETDEWEB)

Kitajima, Kazuhiro, E-mail: kitajima@med.kobe-u.ac.jp [Department of Radiology, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe 650-0017 (Japan); Takahashi, Satoru; Maeda, Tetsuo; Yoshikawa, Takeshi; Ohno, Yoshiharu; Fujii, Masahiko [Department of Radiology, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe 650-0017 (Japan); Miyake, Hideaki; Fujisawa, Masato [Department of Urology, Kobe University Graduate School of Medicine, Kobe (Japan); Sugimura, Kazuro [Department of Radiology, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe 650-0017 (Japan)

2012-09-15

Objective: Hypothyroidism is a common complication in patients receiving tyrosine kinase inhibitors. We evaluated the relationship between thyroid size evident on CT and thyroid function in patients with advanced renal cell carcinoma (RCC) receiving tyrosine kinase inhibitors. Materials and methods: Forty-two patients with metastatic RCC receiving tyrosine kinase inhibitors (sorafenib n = 25; sunitinib n = 17) and, followed-up for ≥12 months were eligible. Patients who had ever shown an elevated thyroid-stimulating hormone (TSH) level of >10 mU/l were defined as having “hypothyroidism”. CT scans were performed before, and 3, 6, 9, and 12 months after the start of treatment. The area of the thyroid in the maximum section at each examination was measured and compared with that before treatment. Using repeated-measures ANOVA, differences in thyroid size were compared over time between patients with and without “hypothyroidism”, in relation to the type of drug employed. Results: Twenty-one patients (sorafenib 9, sunitinib 12) developed “hypothyroidism” 95 ± 88 days (range 12–315 days) after the start of treatment. In such patients, the thyroid was reduced in size to 89 ± 16% after 3 months, 81 ± 21% after 6 months, 71 ± 21% after 9 months and 68 ± 21% after 12 months, whereas the patients without “hypothyroidism” maintained a thyroid size of 90 ± 12% even after 12 months (p = 0.0030). Among the patients with “hypothyroidism”, those treated with sunitinib tended to show greater thyroid size reduction than those with sorafenib (59 ± 23% vs. 79 ± 13%, after 12 months). Conclusion: Tyrosine kinase inhibitors cause an apparent thyroid size reduction in patients with “hypothyroidism”.

Aspirin disrupts the mTOR-Raptor complex and potentiates the anti-cancer activities of sorafenib via mTORC1 inhibition.

Science.gov (United States)

Sun, Danni; Liu, Hongchun; Dai, Xiaoyang; Zheng, Xingling; Yan, Juan; Wei, Rongrui; Fu, Xuhong; Huang, Min; Shen, Aijun; Huang, Xun; Ding, Jian; Geng, Meiyu

2017-10-10

Aspirin is associated with a reduced risk of cancer and delayed progression of malignant disease. Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK)-mTOR signaling is believed to partially contribute to these anticancer effects, although the mechanism is unclear. In this study, we revealed the mechanism underlying the effects of aspirin on AMPK-mTOR signaling, and described a mechanism-based rationale for the use of aspirin in cancer therapy. We found that aspirin inhibited mTORC1 signaling through AMPK-dependent and -independent manners. Aspirin inhibited the AMPK-TSC pathway, thus resulting in the suppression of mTORC1 activity. In parallel, it directly disrupted the mTOR-raptor interaction. Additionally, the combination of aspirin and sorafenib showed synergetic effects via inhibiting mTORC1 signaling and the PI3K/AKT, MAPK/ERK pathways. Aspirin and sorafenib showed synergetic anticancer efficacy in the SMMC-7721 model. Our study provides mechanistic insights and a mechanism-based rationale for the roles of aspirin in cancer treatment. Copyright © 2017 Elsevier B.V. All rights reserved.

Clinical observation of transcatheter arterial chemoembolization combined with sorafenib on intermediate-advanced hepatocellular carcinoma

International Nuclear Information System (INIS)

Wei Zhaoguang; Lu Ligong; Shao Peijian; Hu Baoshan; Li Yong; Zhang Lei; He Xu; Yu Xianyi; Luo Xiaoning

2012-01-01

Objective: To evaluate the treatment effect and security of transcatheter arterial chemoembolization (TACE) combined with sorafenib for intermediate-advanced hepatocellular carcinoma. Methods: From July 2008 to November 2010,the treatment effects of two groups of patients with advanced hepatocellular carcinoma were retrospectively analyzed and compared, including 44 patients treated by sorafenib combined with TACE (test group) and the other 44 patients treated only with TACE (control group). To assess the treatment effect based on mRECIST, the time for patients' tumor progression (TTP), overall survival (OS) time and adverse events were recorded. Survival rate were analyzed using Kaplan-Meier method and Log-rank analysis in SPSS 18.0. Results: Till January 2011, 24 patients (54.5%) survived and 20 patients (include patients lost to visit) died (45.5%) among the test group, 13 patients survived (29.5 %) and 31 patients (include patients lost to visit) died (70.5 %) among the control group. No complete remission condition was observed in all patients. Among the test group, 1 patient got partial remission, 24 ones remain stable and 19 patients got progression. While among the control group, conditions remained stable in 21 patients and progressed in rest 23 ones. The disease control rate (DCR) in the test group and control group were 56.8% (25/44) and 47.7% (21/44) respectively, with no statistical significance (χ 2 =0.729, P=0.393). The median overall survival time (mOS) of test group and control group were 21.0 (95% CI: 14.9-27.1)months and 10.0 (95% CI: 6.4-13.6) months respectively, and the difference reached statistical significance (χ 2 =7.436, P=0.006). The median time to tumor progression (mTTP) of test group and control group was 11.0 (95% CI: 8.7-13.3) and 6.0 (95% CI: 3.9-8.1) months respectively, and the difference had statistical significance (χ 2 =10.437, P=0.001). The adverse events of test group mainly included hand-foot skin reaction, loss of

Effects of low concentrations of Regorafenib and Sorafenib on human HCC cell AFP, migration, invasion and growth in vitro

Science.gov (United States)

Carr, Brian Irving; D’Alessandro, Rosalba; Refolo, Maria Grazia; Iacovazzi, Palma Aurelia; Lippolis, Catia; Messa, Caterina; Cavallini, Aldo; Correale, Mario; Di Carlo, Antonio

2012-01-01

Sorafenib was shown in clinical trial to enhance survival in hepatocellular carcinoma (HCC) patients, but with minimal tumor shrinkage. To correlate several indices of HCC growth at various drug concentrations, HCC cells were grown in various low concentrations of two multi-kinase inhibitors, Regorafenib (Stivarga) and Sorafenib (Nexavar) and their effects were examined on alpha-fetoprotein (AFP), cell growth, migration and invasion. In two AFP positive human HCC cell lines, AFP was inhibited at 0.1–1µM drug concentrations. Cell migration and invasion were also inhibited at similar low drug concentrations. However, 10-fold higher drug concentrations were required to inhibit cell growth in both AFP positive and negative cells. To investigate this concentration discrepancy of effects, cells were then grown for prolonged times and sub-cultured in low drug concentrations and then their growth was re-tested. The growth in these drug-exposed cells was found to be slower than cells without prior drug exposure and they were also more sensitive to subsequent drug challenge. Evidence was also found for changes in cell signaling pathways in these slow-growth cells. Low multi-kinase inhibitor concentrations thus modulate several aspects of HCC cell biology. PMID:23169148

A pilot study to assess feasibility of value based pricing in Cyprus through pharmacoeconomic modelling and assessment of its operational framework: sorafenib for second line renal cell cancer.

Science.gov (United States)

Petrou, Panagiotis; Talias, Michael A

2014-01-01

The continuing increase of pharmaceutical expenditure calls for new approaches to pricing and reimbursement of pharmaceuticals. Value based pricing of pharmaceuticals is emerging as a useful tool and possess theoretical attributes to help health system cope with rising pharmaceutical expenditure. To assess the feasibility of introducing a value-based pricing scheme of pharmaceuticals in Cyprus and explore the integrative framework. A probabilistic Markov chain Monte Carlo model was created to simulate progression of advanced renal cell cancer for comparison of sorafenib to standard best supportive care. Literature review was performed and efficacy data were transferred from a published landmark trial, while official pricelists and clinical guidelines from Cyprus Ministry of Health were utilised for cost calculation. Based on proposed willingness to pay threshold the maximum price of sorafenib for the indication of second line renal cell cancer was assessed. Sorafenib value based price was found to be significantly lower compared to its current reference price. Feasibility of Value Based Pricing is documented and pharmacoeconomic modelling can lead to robust results. Integration of value and affordability in the price are its main advantages which have to be weighed against lack of documentation for several theoretical parameters that influence outcome. Smaller countries such as Cyprus may experience adversities in establishing and sustaining essential structures for this scheme.

Fisetin, a phytochemical, potentiates sorafenib-induced apoptosis and abrogates tumor growth in athymic nude mice implanted with BRAF-mutated melanoma cells.

Science.gov (United States)

Pal, Harish Chandra; Baxter, Ronald D; Hunt, Katherine M; Agarwal, Jyoti; Elmets, Craig A; Athar, Mohammad; Afaq, Farrukh

2015-09-29

Melanoma is the most deadly form of cutaneous malignancy, and its incidence rates are rising worldwide. In melanoma, constitutive activation of the BRAF/MEK/ERK (MAPK) and PI3K/AKT/mTOR (PI3K) signaling pathways plays a pivotal role in cell proliferation, survival and tumorigenesis. A combination of compounds that lead to an optimal blockade of these critical signaling pathways may provide an effective strategy for prevention and treatment of melanoma. The phytochemical fisetin is known to possess anti-proliferative and pro-apoptotic activities. We found that fisetin treatment inhibited PI3K signaling pathway in melanoma cells. Therefore, we investigated the effect of fisetin and sorafenib (an RAF inhibitor) alone and in combination on cell proliferation, apoptosis and tumor growth. Combination treatment (fisetin + sorafenib) more effectively reduced the growth of BRAF-mutated human melanoma cells at lower doses when compared to individual agents. In addition, combination treatment resulted in enhanced (i) apoptosis, (ii) cleavage of caspase-3 and PARP, (iii) expression of Bax and Bak, (iv) inhibition of Bcl2 and Mcl-1, and (v) inhibition of expression of PI3K, phosphorylation of MEK1/2, ERK1/2, AKT and mTOR. In athymic nude mice subcutaneously implanted with melanoma cells (A375 and SK-MEL-28), we found that combination therapy resulted in greater reduction of tumor growth when compared to individual agents. Furthermore, combination therapy was more effective than monotherapy in: (i) inhibition of proliferation and angiogenesis, (ii) induction of apoptosis, and (iii) inhibition of the MAPK and PI3K pathways in xenograft tumors. These data suggest that simultaneous inhibition of both these signaling pathways using combination of fisetin and sorafenib may serve as a therapeutic option for the management of melanoma.

Synergistic activity of vorinostat combined with gefitinib but not with sorafenib in mutant KRAS human non-small cell lung cancers and hepatocarcinoma

Directory of Open Access Journals (Sweden)

Jeannot V

2016-11-01

Full Text Available Victor Jeannot,1,2 Benoit Busser,1–3 Laetitia Vanwonterghem,1,2 Sophie Michallet,1,2 Sana Ferroudj,1,2 Murat Cokol,4 Jean-Luc Coll,1,2 Mehmet Ozturk,1,2,5 Amandine Hurbin1,2 1INSERM U1209, Department Cancer Targets and Experimental Therapeutics, Grenoble, France; 2University Grenoble Alpes, Institute for Advanced Biosciences, Grenoble, France; 3Department of Biochemistry, Toxicology and Pharmacology, Grenoble University Hospital, Grenoble, France; 4Faculty of Engineering and Natural Sciences, Sabanci University, Istanbul, Turkey; 5Faculty of Medicine, Dokuz Eyul University, Izmir Biomedicine and Genome Center, Izmir, Turkey Abstract: Development of drug resistance limits the efficacy of targeted therapies. Alternative approaches using different combinations of therapeutic agents to inhibit several pathways could be a more effective strategy for treating cancer. The effects of the approved epidermal growth factor receptor (EGFR-tyrosine kinase inhibitor (gefitinib or a multi-targeted kinase inhibitor (sorafenib in combination with a histone deacetylase inhibitor (vorinostat on cell proliferation, cell cycle distribution, apoptosis, and signaling pathway activation in human lung adenocarcinoma and hepatocarcinoma cells with wild-type EGFR and mutant KRAS were investigated. The effects of the synergistic drug combinations were also studied in human lung adenocarcinoma and hepatocarcinoma cells in vivo. The combination of gefitinib and vorinostat synergistically reduced cell growth and strongly induced apoptosis through inhibition of the insulin-like growth factor-1 receptor/protein kinase B (IGF-1R/AKT-dependent signaling pathway. Moreover, the gefitinib and vorinostat combination strongly inhibited tumor growth in mice with lung adenocarcinoma or hepatocarcinoma tumor xenografts. In contrast, the combination of sorafenib and vorinostat did not inhibit cell proliferation compared to a single treatment and induced G2/M cell cycle arrest without

Ilexgenin A exerts anti-inflammation and anti-angiogenesis effects through inhibition of STAT3 and PI3K pathways and exhibits synergistic effects with Sorafenib on hepatoma growth

Energy Technology Data Exchange (ETDEWEB)

Yang, Hao [Medical and Pharmaceutical Institute, Yangzhou University, Yangzhou 225001, Jiangsu (China); College of Medicine, Yangzhou University, Yangzhou 225001, Jiangsu (China); Institute of Pharmacology and Toxicology, Jiangsu Kanion Pharmaceutical Co., Ltd., Lianyungang 222000, Jiangsu (China); Wang, Juan [Medical and Pharmaceutical Institute, Yangzhou University, Yangzhou 225001, Jiangsu (China); College of Medicine, Yangzhou University, Yangzhou 225001, Jiangsu (China); Fan, Jin-hong; Zhang, Ya-qi; Zhao, Jun-xian [Medical and Pharmaceutical Institute, Yangzhou University, Yangzhou 225001, Jiangsu (China); Dai, Xiao-jun [Medical and Pharmaceutical Institute, Yangzhou University, Yangzhou 225001, Jiangsu (China); Chinese Medicine Hospital of Yangzhou City, Yangzhou 225009, Jiangsu (China); Liu, Qi; Shen, Yan-jun [Medical and Pharmaceutical Institute, Yangzhou University, Yangzhou 225001, Jiangsu (China); College of Medicine, Yangzhou University, Yangzhou 225001, Jiangsu (China); Liu, Chang [Medical and Pharmaceutical Institute, Yangzhou University, Yangzhou 225001, Jiangsu (China); Sun, Wei-dong, E-mail: zyykjc@sina.com [Medical and Pharmaceutical Institute, Yangzhou University, Yangzhou 225001, Jiangsu (China); Chinese Medicine Hospital of Yangzhou City, Yangzhou 225009, Jiangsu (China); Sun, Yun, E-mail: ysun@yzu.edu.cn [Medical and Pharmaceutical Institute, Yangzhou University, Yangzhou 225001, Jiangsu (China); College of Medicine, Yangzhou University, Yangzhou 225001, Jiangsu (China)

2017-01-15

Recently, we reported that Ilexgenin A exhibits anti-cancer activities and induces cell arrest. Here, we investigated the effect of Ilexgenin A on the inflammation, angiogenesis and tumor growth of hepatocellular carcinoma (HCC). Our current study revealed that Ilexgenin A significantly inhibited the inflammatory cytokines TNF-α and IL-6 levels and downregulated pro-angiogenic factor VEGF production and transcription in HepG2 cells. The underlying mechanism for Ilexgenin A effects appears to be through inhibiting STAT3 and PI3K pathways. Furthermore, we found that not only Ilexgenin A inhibited STAT3 and PI3K pathways in HepG2 cells but also blocked these signaling pathways in HUVECs. Most importantly, by employing two HCC xenografts models - HepG2 and H22, we showed that Ilexgenin A reduced tumor growth and exhibited synergy effect with Sorafenib. ELISA assay, histological analysis and immunohistochemistry examination revealed that the expression of VEGF and MVD was significantly decreased after the treatment with Ilexgenin A and the combination. Moreover, Ilexgenin A could enhance caspase-3/7 activity in vitro and transmission electron microscope indicated that the combination induced evident apoptosis of tumor cells and caused the structural changes of mitochondria in vivo. Although no apparent adverse effects occurred during the treatment period, Sorafenib monotherapy elicited hepatotoxicity for specific expression in the increased level of AST and the ratio of AST/ALT. However, the combination could remedy this adverse effect. In conclusion, the results described in the present study identifies Ilexgenin A as a promising therapeutic candidate that modulates inflammation, angiogenesis, and HCC growth. - Highlights: • Ilexgenin A exerts anti-inflammatory and anti-angiogenesis effects in hepatoma. • Ilexgenin A may exert these effects through inhibition of STAT3 and PI3K pathways. • Ilexgenin A exhibits synergistic effects with Sorafenib on hepatoma growth

Sorafenib paradoxically activates the RAS/RAF/ERK pathway in polyclonal human NK cells during expansion and thereby enhances effector functions in a dose- and time-dependent manner.

Science.gov (United States)

Lohmeyer, J; Nerreter, T; Dotterweich, J; Einsele, H; Seggewiss-Bernhardt, R

2018-03-24

Natural killer (NK) cells play a major role in host immunity against leukaemia and lymphoma. However, clinical trials applying NK cells have not been as efficient as hoped for. Patients treated with rapidly accelerated fibrosarcoma (RAF) inhibitors exhibit increased tumour infiltration by immune cells, suggesting that a combination of RAF inhibitors with immunotherapy might be beneficial. As mitogen-activated protein kinases (MAPKs) such as raf-1 proto-oncogene, serine/threonine kinase (CRAF) regulate NK cell functions, we performed an in-vitro investigation on the potential of clinically relevant short-acting tyrosine kinase inhibitors (TKIs) as potential adjuvants for NK cell therapy: NK cells from healthy human blood donors were thus treated with sorafenib, sunitinib or the pan-RAF inhibitor ZM336372 during ex-vivo expansion. Functional outcomes assessed after washout of the drugs included cytokine production, degranulation, cytotoxicity, apoptosis induction and signal transduction with/without target cell contact. Paradoxically, sorafenib enhanced NK cell effector functions in a time- and dose-dependent manner by raising the steady-state activation level. Of note, this did not lead to NK cell exhaustion, but enhanced activity against target cells such as K562 or Daudis mediated via the RAS/RAF/extracellular-regulated kinase (ERK) pathway, but not via protein kinase B (AKT). Our data will pave the path to develop a rationale for the considered use of RAF inhibitors such as sorafenib for pre-activation in NK cell-based adoptive immune therapy. © 2018 British Society for Immunology.

Design and discovery of thioether and nicotinamide containing sorafenib analogues as multikinase inhibitors targeting B-Raf, B-RafV600E and VEGFR-2.

Science.gov (United States)

Sun, Shaofeng; He, Zuopeng; Huang, Mindong; Wang, Ningning; He, Zongzhong; Kong, Xiangkai; Yao, Jianwen

2018-04-03

New sorafenib derivatives containing thioether and nicotinamide moiety were designed and synthesized as B-Raf, B-Raf V600E and VEGFR-2 multikinase inhibitors. Their in vitro enzymatic inhibitory activities against B-Raf, B-Raf V600E and VEGFR-2 and their antiproliferative activities against HCT-116 and B16BL6 cell lines were evaluated and described. Most of the compounds showed potent activities against both cell lines and specific kinases. Compounds a1, b1 and c4, which exhibited the most potent inhibitory activities against B-Raf with IC 50 of 21 nM, 27 nM and 17 nM, B-Raf V600E with IC 50 of 29 nM, 28 nM and 16 nM, VEGFR-2 with IC 50 of 84 nM, 46 nM and 63 nM, respectively, and good antiproliferative activities, also demonstrated competitive antiangiogenic activities to sorafenib in in vitro HUVEC tube formation assay. Copyright © 2018 Elsevier Ltd. All rights reserved.

Identification of a unique hepatocellular carcinoma line, Li-7, with CD13(+) cancer stem cells hierarchy and population change upon its differentiation during culture and effects of sorafenib.

Science.gov (United States)

Yamada, Takeshi; Abei, Masato; Danjoh, Inaho; Shirota, Ryoko; Yamashita, Taro; Hyodo, Ichinosuke; Nakamura, Yukio

2015-04-11

Cancer stem cell (CSC) research has highlighted the necessity of developing drugs targeting CSCs. We investigated a hepatocellular carcinoma (HCC) cell line that not only has CSC hierarchy but also shows phenotypic changes (population changes) upon differentiation of CSC during culture and can be used for screening drugs targeting CSC. Based on a hypothesis that the CSC proportion should decrease upon its differentiation into progenitors (population change), we tested HCC cell lines (HuH-7, Li-7, PLC/PRF/5, HLF, HLE) before and after 2 months culture for several markers (CD13, EpCAM, CD133, CD44, CD90, CD24, CD166). Tumorigenicity was tested using nude mice. To evaluate the CSC hierarchy, we investigated reconstructivity, proliferation, ALDH activity, spheroid formation, chemosensitivity and microarray analysis of the cell populations sorted by FACS. Only Li-7 cells showed a population change during culture: the proportion of CD13 positive cells decreased, while that of CD166 positive cells increased. The high tumorigenicity of the Li-7 was lost after the population change. CD13(+)/CD166(-) cells showed slow growth and reconstructed the bulk Li-7 populations composed of CD13(+)/CD166(-), CD13(-)/CD166(-) and CD13(-)/CD166(+) fractions, whereas CD13(-)/CD166(+) cells showed rapid growth but could not reproduce any other population. CD13(+)/CD166(-) cells showed high ALDH activity, spheroid forming ability and resistance to 5-fluorouracil. Microarray analysis demonstrated higher expression of stemness-related genes in CD166(-) than CD166(+) fraction. These results indicated a hierarchy in Li-7 cells, in which CD13(+)/CD166(-) and CD13(-)/CD166(+) cells serve as slow growing CSCs and rapid growing progenitors, respectively. Sorafenib selectively targeted the CD166(-) fraction, including CD13(+) CSCs, which exhibited higher mRNA expression for FGF3 and FGF4, candidate biomarkers for sorafenib. 5-fluorouracil followed by sorafenib inhibited the growth of bulk Li-7

Solubilities of sodium nitrate, sodium nitrite, and sodium aluminate in simulated nuclear waste

International Nuclear Information System (INIS)

Reynolds, D.A.; Herting, D.L.

1984-09-01

Solubilities were determined for sodium nitrate, sodium nitrite, and sodium aluminate in synthetic nuclear waste liquor. Solubilities were determined as a function of temperature and solution composition (concentrations of sodium hydroxide, sodium nitrate, sodium nitrite, and sodium aluminate). Temperature had the greatest effect on the solubilities of sodium nitrate and sodium nitrite and a somewhat lesser effect on sodium aluminate solubility. Hydroxide had a great effect on the solubilities of all three salts. Other solution components had minor effects. 2 references, 8 figures, 11 tables

Effective prevention of sorafenib-induced hand–foot syndrome by dried-bonito broth

Directory of Open Access Journals (Sweden)

Kamimura K

2018-04-01

Full Text Available Kenya Kamimura,1 Yoko Shinagawa-Kobayashi,1 Ryo Goto,1 Kohei Ogawa,1 Takeshi Yokoo,1 Akira Sakamaki,1 Satoshi Abe,1 Hiroteru Kamimura,1 Takeshi Suda,2 Hiroshi Baba,3 Takayuki Tanaka,4 Yoshizu Nozawa,5 Naoto Koyama,6 Masaaki Takamura,1 Hirokazu Kawai,1 Satoshi Yamagiwa,1 Yutaka Aoyagi,1 Shuji Terai1 1Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Niigata, Japan; 2Department of Gastroenterology and Hepatology, Uonuma Institute of Community Medicine, Niigata Medical and Dental Hospital, Minami-Uonuma, Niigata, Japan; 3Division of Anesthesiology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Niigata, Japan; 4Uonuma Eye Clinic, Uonuma, Niigata, Japan; 5Institute of Food Sciences and Technologies, Ajinomoto Co., Inc., Kawasaki, Kanagawa, Japan; 6Institute for Innovation, Ajinomoto Co., Inc., Kawasaki, Kanagawa, Japan Background: Sorafenib (SOR is a molecular medicine that prolongs the survival of patients with hepatocellular carcinoma (HCC. Therefore, the management of side effects is essential for the longer period of continuous medication. Among the various side effects, hand–foot syndrome (HFS is the most common, occurring in 30%–50% of patients, and often results in discontinuation of the SOR medication. However, its mechanism has not been clarified, and no effective prevention method has been reported for the symptoms. Therefore, this study aimed to analyze its mechanism and to develop an effective prevention regimen for the symptoms. Materials and methods: To assess the mechanism of SOR-induced HFS, the peripheral blood flow in the hand and foot was carefully monitored by Doppler ultrasound, thermography, and laser speckle flowgraphy in the cases treated with SOR and its contribution was assessed. Then, the effect of dried-bonito broth (DBB, which was reported to improve peripheral blood flow, on the prevention of the symptom was

Pre-clinical activity of PR-104 as monotherapy and in combination with sorafenib in hepatocellular carcinoma.

Science.gov (United States)

Abbattista, Maria R; Jamieson, Stephen M F; Gu, Yongchuan; Nickel, Jennifer E; Pullen, Susan M; Patterson, Adam V; Wilson, William R; Guise, Christopher P

2015-01-01

PR-104 is a clinical stage bioreductive prodrug that is converted in vivo to its cognate alcohol, PR-104A. This dinitrobenzamide mustard is reduced to activated DNA cross-linking metabolites (hydroxylamine PR-104H and amine PR-104M) under hypoxia by one-electron reductases and independently of hypoxia by the 2-electron reductase aldo-keto reductase 1C3 (AKR1C3). High expression of AKR1C3, along with extensive hypoxia, suggested the potential of PR-104 for treatment of hepatocellular carcinoma (HCC). However, a phase IB trial with sorafenib demonstrated significant toxicity that was ascribed in part to reduced PR-104A clearance, likely reflecting compromised glucuronidation in patients with advanced HCC. Here, we evaluate the activity of PR-104 in HCC xenografts (HepG2, PLC/PRF/5, SNU-398, Hep3B) in mice, which do not significantly glucuronidate PR-104A. Cell line differences in sensitivity to PR-104A in vitro under aerobic conditions could be accounted for by differences in both expression of AKR1C3 (high in HepG2 and PLC/PRF/5) and sensitivity to the major active metabolite PR-104H, to which PLC/PRF/5 was relatively resistant, while hypoxic selectivity of PR-104A cytotoxicity and reductive metabolism was greatest in the low-AKR1C3 SNU-398 and Hep3B lines. Expression of AKR1C3 in HepG2 and PLC/PRF/5 xenografts was in the range seen in 21 human HCC specimens. PR-104 monotherapy elicited significant reductions in growth of Hep3B and HepG2 xenografts, and the combination with sorafenib was significantly active in all 4 xenograft models. The results suggest that better-tolerated analogs of PR-104, without a glucuronidation liability, may have the potential to exploit AKR1C3 and/or hypoxia in HCC in humans.

Benefit-Risk Summary of Regorafenib for the Treatment of Patients with Advanced Hepatocellular Carcinoma That Has Progressed on Sorafenib.

Science.gov (United States)

Pelosof, Lorraine; Lemery, Steven; Casak, Sandra; Jiang, Xiaoping; Rodriguez, Lisa; Pierre, Vadryn; Bi, Youwei; Liu, Jiang; Zirkelbach, Jeanne Fourie; Patel, Anuja; Goldberg, Kirsten B; McKee, Amy E; Keegan, Patricia; Pazdur, Richard

2018-04-01

On April 27, 2017, the U.S. Food and Drug Administration approved regorafenib for the treatment of patients with advanced hepatocellular carcinoma (HCC) who had previously been treated with sorafenib. Approval was based on the results of a single, randomized, placebo-controlled trial (RESORCE) that demonstrated an improvement in overall survival (OS). Patients were randomly allocated to receive regorafenib160 mg orally once daily or matching placebo for the first 21 days of each 28-day cycle. The trial demonstrated a significant improvement in OS (hazard ratio [HR] = 0.63; 95% confidence interval [CI], 0.50-0.79, p  regorafenib arm and 7.8 months in the placebo arm. A statistically significant improvement in progression-free survival (PFS) based on modified RECIST for HCC [Semin Liver Dis 2010;30:52-60] (HR = 0.46; 95% CI, 0.37-0.56, p  regorafenib and placebo arms, respectively. The overall response rate, based on modified RECIST for HCC, was 11% in the regorafenib arm and 4% in the placebo arm. The toxicity profile was consistent with that observed in other indications; the most clinically significant adverse reactions were palmar-plantar erythrodysesthesia, diarrhea, and hypertension. Based on the improvement in survival and acceptable toxicity, a favorable benefit-to-risk evaluation led to approval for treatment of patients with advanced HCC. Regorafenib is the first drug approved by the U.S. Food and Drug Administration for the treatment of hepatocellular carcinoma that has progressed on sorafenib and is expected to become a standard of care for these patients. Published 2018. This article is a U.S. Government work and is in the public domain in the USA.

Dialysate sodium and sodium gradient in maintenance hemodialysis: a neglected sodium restriction approach?

OpenAIRE

Munoz Mendoza, Jair; Sun, Sumi; Chertow, Glenn M.; Moran, John; Doss, Sheila; Schiller, Brigitte

2011-01-01

Background. A higher sodium gradient (dialysate sodium minus pre-dialysis plasma sodium) during hemodialysis (HD) has been associated with sodium loading; however, its role is not well studied. We hypothesized that a sodium dialysate prescription resulting in a higher sodium gradient is associated with increases in interdialytic weight gain (IDWG), blood pressure (BP) and thirst.

Efficacy and Safety of Axitinib Versus Sorafenib in Metastatic Renal Cell Carcinoma: Subgroup Analysis of Japanese Patients from the Global Randomized Phase 3 AXIS Trial

OpenAIRE

Ueda, Takeshi; Uemura, Hirotsugu; Tomita, Yoshihiko; Tsukamoto, Taiji; Kanayama, Hiroomi; Shinohara, Nobuo; Tarazi, Jamal; Chen, Connie; Kim, Sinil; Ozono, Seiichiro; Naito, Seiji; Akaza, Hideyuki

2013-01-01

Objective Axitinib is a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors 1, 2 and 3. The efficacy and safety of axitinib in Japanese patients with metastatic renal cell carcinoma were evaluated. Methods A subgroup analysis was conducted in Japanese patients enrolled in the randomized Phase III trial of axitinib versus sorafenib after failure of one prior systemic therapy for metastatic renal cell carcinoma. Results Twenty-five (of 361) and 29 (o...

Effectiveness of Chlorinated Water, Sodium Hypochlorite, Sodium ...

African Journals Online (AJOL)

This study evaluated the efficacy of chlorinated water, sodium hypochlorite solution, sodium chloride solution and sterile distilled water in eliminating pathogenic bacteria on the surfaces of raw vegetables. Lettuce vegetables were dipped in different concentrations of chlorinated water, sodium hypochlorite solution, sodium ...

Sodium

Science.gov (United States)

Table salt is a combination of two minerals - sodium and chloride Your body needs some sodium to work properly. It helps with the function ... in your body. Your kidneys control how much sodium is in your body. If you have too ...

Methodology for Extraction of Remaining Sodium of Used Sodium Containers

International Nuclear Information System (INIS)

Jung, Minhwan; Kim, Jongman; Cho, Youngil; Jeong, Jiyoung

2014-01-01

Sodium used as a coolant in the SFR (Sodium-cooled Fast Reactor) reacts easily with most elements due to its high reactivity. If sodium at high temperature leaks outside of a system boundary and makes contact with oxygen, it starts to burn and toxic aerosols are produced. In addition, it generates flammable hydrogen gas through a reaction with water. Hydrogen gas can be explosive within the range of 4.75 vol%. Therefore, the sodium should be handled carefully in accordance with standard procedures even though there is a small amount of target sodium remainings inside the containers and drums used for experiment. After the experiment, all sodium experimental apparatuses should be dismantled carefully through a series of draining, residual sodium extraction, and cleaning if they are no longer reused. In this work, a system for the extraction of the remaining sodium of used sodium drums has been developed and an operation procedure for the system has been established. In this work, a methodology for the extraction of remaining sodium out of the used sodium container has been developed as one of the sodium facility maintenance works. The sodium extraction system for remaining sodium of the used drums was designed and tested successfully. This work will contribute to an establishment of sodium handling technology for PGSFR. (Prototype Gen-IV Sodium-cooled Fast Reactor)

Sodium fire tests for investigating the sodium leak in Monju

International Nuclear Information System (INIS)

Seino, Hiroshi; Miyahara, Shinya; Miyake, Osamu; Tanabe, Hiromi

1996-01-01

As a part of the work for investigating the sodium leak accident which occurred in Monju on December 8, 1995, three tests, (1) sodium leak test, (2) sodium fire test-I, and (3) sodium fire test-II, were carried out at OEC/PNC. Main objectives of these tests are to confirm leak and burning behavior of sodium from the damaged thermometer, and effects of the sodium fire on integrity of the surrounding structure, etc. The main conclusions obtained from the tests are shown as below. 1) Average sodium leak rate obtained from the sodium leak test was about 50 g/sec. This was equivalent to the value estimated from level change in the sodium overflow tank in the Monju accident. 2) Observation from video cameras in the sodium fire tests revealed that in early stages of sodium leak, sodium dropped down out of the flexible tube of thermometer in drips. This dripping and burning were expanded in range as sodium splashed on the duct. 3) Though, in the sodium fire test-I, there was a decrease of about 1 mm at a thickness of the burning pan in the vicinity in just under in the leak point, there were completely no crack and failure. In the meantime, in the sodium fire test-II the six open holes were found in the floor liner. By this liner failure, the reaction between sodium and concrete might take place. At present, while the detailed evaluation on the sodium fire test-II has been mainly carried out, the investigation for clarifying the cause of the liner failure has been also carried out. (author)

Sodium technology handbook

International Nuclear Information System (INIS)

2005-09-01

This document was published as a textbook for the education and training of personnel working for operations and maintenances of sodium facilities including FBR plants and those engaged in R and D activities related to sodium technology. This handbook covers the following technical areas. Properties of sodium. Compatibilities of sodium with materials. Thermalhydraulics and structural integrity. Sodium systems and components. Sodium instrumentations. Sodium handling technology. Sodium related accident evaluation and countermeasures for FBRs. Operation, maintenance and repair technology of sodium facilities. Safety measures related to sodium. Laws, regulations and internal rules related to sodium. The plannings and discussions of the handbook were made in the Sodium Technology Education Committee organized in O-arai Engineering Center consisting of the representatives of the related departments including Tsuruga headquarters. Experts in various departments participated in writing individual technical subjects. (author)

Inhibitin: a specific inhibitor of sodium/sodium exchange in erythrocytes.

OpenAIRE

Morgan, K; Brown, R C; Spurlock, G; Southgate, K; Mir, M A

1986-01-01

An inhibitor of ouabain-insensitive sodium/sodium exchange in erythrocytes has been isolated from leukemic promyelocytes. To explore the specific effects of this inhibitor, named inhibitin, sodium transport experiments were carried out in human erythrocytes. Inhibitin reduced ouabain-insensitive bidirectional sodium transport. It did not change net sodium fluxes, had no significant effect on rubidium influx, and did not inhibit sodium-potassium-ATPase activity. The inhibitory effect of inhibi...

Adiabatic flame temperature of sodium combustion and sodium-water reaction

International Nuclear Information System (INIS)

Okano, Y.; Yamaguchi, A.

2001-01-01

In this paper, background information of sodium fire and sodium-water reaction accidents of LMFBR (liquid metal fast breeder reactor) is mentioned at first. Next, numerical analysis method of GENESYS is described in detail. Next, adiabatic flame temperature and composition of sodium combustion are analyzed, and affect of reactant composition, such oxygen and moisture, is discussed. Finally, adiabatic reaction zone temperature and composition of sodium-water reaction are calculated, and affects of reactant composition, sodium vaporization, and pressure are stated. Chemical equilibrium calculation program for generic chemical system (GENESYS) is developed in this study for the research on adiabatic flame temperature of sodium combustion and adiabatic reaction zone temperature of sodium-water reaction. The maximum flame temperature of the sodium combustion is 1,950 K at the standard atmospheric condition, and is not affected by the existence of moisture. The main reaction product is Na 2 O (l) , and in combustion in moist air, with NaOH (g) . The maximum reaction zone temperature of the sodium-water reaction is 1,600 K, and increases with the system pressure. The main products are NaOH (g) , NaOH (l) and H2 (g) . Sodium evaporation should be considered in the cases of sodium-rich and high pressure above 10 bar

Sodium in diet

Science.gov (United States)

Diet - sodium (salt); Hyponatremia - sodium in diet; Hypernatremia - sodium in diet; Heart failure - sodium in diet ... Too much sodium in the diet may lead to: High blood pressure in some people A serious buildup of fluid in people with heart failure , cirrhosis of ...

In situ Microscopic Observation of Sodium Deposition/Dissolution on Sodium Electrode

OpenAIRE

Yuhki Yui; Masahiko Hayashi; Jiro Nakamura

2016-01-01

Electrochemical sodium deposition/dissolution behaviors in propylene carbonate-based electrolyte solution were observed by means of in situ light microscopy. First, granular sodium was deposited at pits in a sodium electrode in the cathodic process. Then, the sodium particles grew linearly from the electrode surface, becoming needle-like in shape. In the subsequent anodic process, the sodium dissolved near the base of the needles on the sodium electrode and the so-called ?dead sodium? broke a...

Quantitative therapy response assessment by volumetric iodine-uptake measurement: Initial experience in patients with advanced hepatocellular carcinoma treated with sorafenib

International Nuclear Information System (INIS)

Dai, Xu; Schlemmer, Heinz-Peter; Schmidt, Bernhard; Höh, Karolin; Xu, Ke; Ganten, Tom M.; Ganten, Maria-Katharina

2013-01-01

Objectives: To investigate the volumetric iodine-uptake (VIU) changes by dual-energy CT (DECT) in assessing the response to sorafenib treated hepatocellular carcinoma (HCC) patients, compared with AASLD (American Association for the Study of Liver Diseases) and Choi criteria. Materials and methods: Fifteen patients with HCC receiving sorafenib, monitored with contrast-enhanced DECT scans at baseline and a minimum of one follow-up (8–12 weeks) were retrospectively evaluated. 30 target lesions in total were analyzed for tumor response according to VIU and adapted Choi criteria and compared with the standard AASLD. Results: According to AASLD criteria, 67% target lesions showed disease control: partial response (PR) in 3% and stable disease (SD) in 63%. 33% lesions progressed (PD). Disease control rate presented by VIU (60%) was similar to AASLD (67%) and Choi (63%) (P > 0.05). For disease control group, change in mean VIU was from 149.5 ± 338.3 mg to 108.5 ± 284.1 mg (decreased 19.1 ± 42.9%); and for progressive disease group, change in mean VIU was from 163.7 ± 346.7 mg to 263.9 ± 537.2 mg (increased 230.5 ± 253.1%). Compared to AASLD (PR, 3%), VIU and Choi presented more PR (33% and 30%, respectively) in disease control group (P < 0.05). VIU has moderate consistency with both AASLD (kappa = 0.714; P < 0.005) and Choi (kappa = 0.648; P < 0.005), while VIU showed a better consistency and correlation with AASLD (kappa = 0.714; P < 0.005; r = 0.666, P < 0.005) than Choi with AASLD (kappa = 0.634, P < 0.005; r = 0.102, P = 0.296). Conclusion: VIU measurements by DECT can evaluate the disease control consistent with the current standard AASLD. Measurements are semi-automatic and therefore easy and robust to apply. As VIU reflects vital tumor burden in HCC, it is likely to be an optimal tumor response biomarker in HCC

The sodium coolant

International Nuclear Information System (INIS)

Rodriguez, G.

2004-01-01

The sodium is the best appropriate coolant for the fast neutrons reactors technology. Thus the fast neutrons reactors development is intimately bound to the sodium technology. This document presents the sodium as a coolant point of view: atomic structure and characteristics, sodium impacts on the fast neutron reactors technology, chemical properties of the sodium and the consequences, quality control in a nuclear reactor, sodium treatment. (A.L.B.)

Fluorescence imaging of bombesin and transferrin receptor expression is comparable to 18F-FDG PET in early detection of sorafenib-induced changes in tumor metabolism.

Directory of Open Access Journals (Sweden)

Jen-Chieh Tseng

Full Text Available Physical measurement of tumor volume reduction is the most commonly used approach to assess tumor progression and treatment efficacy in mouse tumor models. However, it is relatively insensitive, and often requires long treatment courses to achieve gross physical tumor destruction. As alternatives, several non-invasive imaging methods such as bioluminescence imaging (BLI, fluorescence imaging (FLI and positron emission tomography (PET have been developed for more accurate measurement. As tumors have elevated glucose metabolism, 18F-fludeoxyglucose (18F-FDG has become a sensitive PET imaging tracer for cancer detection, diagnosis, and efficacy assessment by measuring alterations in glucose metabolism. In particular, the ability of 18F-FDG imaging to detect drug-induced effects on tumor metabolism at a very early phase has dramatically improved the speed of decision-making regarding treatment efficacy. Here we demonstrated an approach with FLI that offers not only comparable performance to PET imaging, but also provides additional benefits, including ease of use, imaging throughput, probe stability, and the potential for multiplex imaging. In this report, we used sorafenib, a tyrosine kinase inhibitor clinically approved for cancer therapy, for treatment of a mouse tumor xenograft model. The drug is known to block several key signaling pathways involved in tumor metabolism. We first identified an appropriate sorafenib dose, 40 mg/kg (daily on days 0-4 and 7-10, that retained ultimate therapeutic efficacy yet provided a 2-3 day window post-treatment for imaging early, subtle metabolic changes prior to gross tumor regression. We then used 18F-FDG PET as the gold standard for assessing the effects of sorafenib treatment on tumor metabolism and compared this to results obtained by measurement of tumor size, tumor BLI, and tumor FLI changes. PET imaging showed ~55-60% inhibition of tumor uptake of 18F-FDG as early as days 2 and 3 post-treatment, without

Sodium pool fire analysis of sodium-cooled fast reactor by calculation

International Nuclear Information System (INIS)

Yu Hong; Xu Mi; Jin Degui

2002-01-01

Theoretical models were established according to the characteristic of sodium pool fire, and the SPOOL code was created independently. Some transient processes in sodium pool fire were modeled, including chemical reaction of sodium and oxygen; sodium combustion heat transfer modes in several kids of media; production, deposition and discharge of sodium aerosol; mass and energy exchange between different media in different ventilating conditions. The important characteristic parameters were calculated, such as pressure and temperature of gas, temperature of building materials, mass concentration of sodium aerosol, and so on. The SPOOL code, which provided available safety analysis tool for sodium pool fire accidents in sodium-cooled fast reactor, was well demonstrated with experimental data

Low sodium diet (image)

Science.gov (United States)

... for you. Look for these words on labels: low-sodium, sodium-free, no salt added, sodium-reduced, ... for you. Look for these words on labels: low-sodium, sodium-free, no salt added, sodium-reduced, ...

Scientific Opinion on the safety evaluation of the active substances, sodium carbonate peroxyhydrate coated with sodium carbonate and sodium silicate, bentonite, sodium chloride, sodium carbonate for use in active food contact materials

OpenAIRE

EFSA Panel on Food Contact Materials, Enzymes, Flavourings and Processing Aids (CEF)

2013-01-01

This scientific opinion of the Panel on Food Contact Materials, Enzymes, Flavourings and Processing Aids deals with the safety evaluation of the powder mixture of the active substances sodium carbonate peroxyhydrate coated with sodium carbonate and sodium silicate (FCM substance No 1009), bentonite (CAS No 1302-78-9, FCM No 393), sodium chloride (CAS No 7647-14-5, FCM No 985), sodium carbonate (CAS No 497-19-8, FCM No 1008) which are intended to be used as combined oxygen generator and carbon...

Development of sodium disposal technology. Experiment of sodium compound solidification process

International Nuclear Information System (INIS)

Matsumoto, Toshiyuki; Ohura, Masato; Yatoh, Yasuo

2007-07-01

A large amount of sodium containing radioactive waste will come up at the time of final shutdown/decommission of FBR plant. The radioactive waste is managed as solid state material in a closed can in Japan. As for the sodium, there is no established method to convert the radioactive sodium to solid waste. Further, the sodium is highly reactive. Thus, it is recommended to convert the sodium to a stable substance before the solidification process. One of the stabilizing methods is conversion of sodium into sodium hydroxide solution. These stabilization and solidification processes should be safe, economical, and efficient. In order to develop such sodium disposal technology, nonradioactive sodium was used and a basic experiment was performed. Waste-fluid Slag Solidification method was employed as the solidification process of sodium hydroxide solution. Experimental parameters were mixing ratio of the sodium hydroxide and the slag solidification material, temperature and concentration of the sodium hydroxide. The best parameters were obtained to achieve the maximum filling ratio of the sodium hydroxide under a condition of enough high compressive strength of the solidified waste. In a beaker level test, the solidified waste was kept in a long term and it was shown that there was no change of appearance, density, and also the compressive strength was kept at a target value. In a real scale test, homogeneous profiles of the density and the compressive strength were obtained. The compressive strength was higher than the target value. It was shown that the Waste-fluid Slag Solidification method can be applied to the solidification process of the sodium hydroxide solution, which was produced by the stabilization process. (author)

Inhibition of human UDP-glucuronosyltransferase enzymes by lapatinib, pazopanib, regorafenib and sorafenib: Implications for hyperbilirubinemia.

Science.gov (United States)

Miners, John O; Chau, Nuy; Rowland, Andrew; Burns, Kushari; McKinnon, Ross A; Mackenzie, Peter I; Tucker, Geoffrey T; Knights, Kathleen M; Kichenadasse, Ganessan

2017-04-01

Kinase inhibitors (KIs) are a rapidly expanding class of drugs used primarily for the treatment of cancer. Data relating to the inhibition of UDP-glucuronosyltransferase (UGT) enzymes by KIs is sparse. However, lapatinib (LAP), pazopanib (PAZ), regorafenib (REG) and sorafenib (SOR) have been implicated in the development of hyperbilirubinemia in patients. This study aimed to characterise the role of UGT1A1 inhibition in hyperbilirubinemia and assess the broader potential of these drugs to perpetrate drug-drug interactions arising from UGT enzyme inhibition. Twelve recombinant human UGTs from subfamilies 1A and 2B were screened for inhibition by LAP, PAZ, REG and SOR. IC 50 values for the inhibition of all UGT1A enzymes, except UGT1A3 and UGT1A4, by the four KIs were enzyme identified to date. In vitro-in vivo extrapolation indicates that inhibition of UGT1A1 contributes significantly to the hyperbilirubinemia observed in patients treated with REG and SOR, but not with LAP and PAZ. Inhibition of other UGT1A1 substrates in vivo is likely. Copyright © 2017 Elsevier Inc. All rights reserved.

C-Scan Performance Test of Under-Sodium ultrasonic Waveguide Sensor in Sodium

International Nuclear Information System (INIS)

Joo, Young Sang; Bae, Jin Ho; Kim, Jong Bum

2011-01-01

Reactor core and in-vessel structures of a sodium-cooled fast (SFR) are submerged in opaque liquid sodium in the reactor vessel. The ultrasonic inspection techniques should be applied for observing the in-vessel structures under hot liquid sodium. Ultrasonic sensors such as immersion sensors and rod-type waveguide sensors have developed in order to apply under-sodium viewing of the in-vessel structures of SFR. Recently the novel plate-type ultrasonic waveguide sensor has been developed for the versatile application of under-sodium viewing in SFR. In previous studies, the ultrasonic waveguide sensor module was designed and manufactured, and the feasibility study of the ultrasonic waveguide sensor was performed. To improve the performance of the ultrasonic waveguide sensor in the under-sodium application, a new concept of ultrasonic waveguide sensors with a Be coated SS304 plate is suggested for the effective generation of a leaky wave in liquid sodium and the non-dispersive propagation of A 0 -mode Lamb wave in an ultrasonic waveguide sensor. In this study, the C-scan performance of the under-sodium ultrasonic waveguide sensor in sodium has been investigated by the experimental test in sodium. The under-sodium ultrasonic waveguide sensor and the sodium test facility with a glove box system and a sodium tank are designed and manufactured to carry out the performance test of under-sodium ultrasonic waveguide sensor in sodium environment condition

Sodium safety manual

International Nuclear Information System (INIS)

Hayes, D.J.; Gardiner, R.L.

1980-09-01

The sodium safety manual is based upon more than a decade of experience with liquid sodium at Berkeley Nuclear Laboratories (BNL). It draws particularly from the expertise and experience developed in the course of research work into sodium fires and sodium water reactions. It draws also on information obtained from the UKAEA and other sodium users. Many of the broad principles will apply to other Establishments but much of the detail is specific to BNL and as a consequence its application at other sites may well be limited. Accidents with sodium are at best unpleasant and at worst lethal in an extremely painful way. The object of this manual is to help prevent sodium accidents. It is not intended to give detailed advice on specific precautions for particular situations, but rather to set out the overall strategy which will ensure that sodium activities will be pursued safely. More detail is generally conveyed to staff by the use of local instructions known as Sodium Working Procedures (SWP's) which are not reproduced in this manual although a list of current SWP's is included. Much attention is properly given to the safe design and operation of larger facilities; nevertheless evidence suggests that sodium accidents most frequently occur in small-scale work particularly in operations associated with sodium cleaning and special care is needed in all such cases. (U.K.)

Urinary Sodium and Potassium Excretion and Dietary Sources of Sodium in Maputo, Mozambique

Directory of Open Access Journals (Sweden)

Ana Queiroz

2017-08-01

Full Text Available This study aimed to evaluate the urinary excretion of sodium and potassium, and to estimate the main food sources of sodium in Maputo dwellers. A cross-sectional evaluation of a sample of 100 hospital workers was conducted between October 2012 and May 2013. Sodium and potassium urinary excretion was assessed in a 24-h urine sample; creatinine excretion was used to exclude unlikely urine values. Food intake in the same period of urine collection was assessed using a 24-h dietary recall. The Food Processor Plus® was used to estimate sodium intake corresponding to naturally occurring sodium and sodium added to processed foods (non-discretionary sodium. Salt added during culinary preparations (discretionary sodium was computed as the difference between urinary sodium excretion and non-discretionary sodium. The mean (standard deviation urinary sodium excretion was 4220 (1830 mg/day, and 92% of the participants were above the World Health Organization (WHO recommendations. Discretionary sodium contributed 60.1% of total dietary sodium intake, followed by sodium from processed foods (29.0% and naturally occurring sodium (10.9%. The mean (standard deviation urinary potassium excretion was 1909 (778 mg/day, and 96% of the participants were below the WHO potassium intake recommendation. The mean (standard deviation sodium to potassium molar ratio was 4.2 (2.4. Interventions to decrease sodium and increase potassium intake are needed in Mozambique.

Assessment of flow induced vibration in a sodium-sodium heat exchanger

Energy Technology Data Exchange (ETDEWEB)

Prakash, V. [Fast Reactor Technology Group, Indira Gandhi Centre for Atomic Research, Kalpakkam, Tamil Nadu (India)], E-mail: prakash@igcar.gov.in; Thirumalai, M.; Prabhakar, R.; Vaidyanathan, G. [Fast Reactor Technology Group, Indira Gandhi Centre for Atomic Research, Kalpakkam, Tamil Nadu (India)

2009-01-15

The 500 MWe Prototype Fast Breeder Reactor (PFBR) is under construction at Kalpakkam. It is a liquid metal sodium cooled pool type fast reactor with all primary components located inside a sodium pool. The heat produced due to fission in the core is transported by primary sodium to the secondary sodium in a sodium to sodium Intermediate Heat Exchanger (IHX), which in turn is transferred to water in the steam generator. PFBR IHX is a shell and tube type heat exchanger with primary sodium on shell side and secondary sodium in the tube side. Since IHX is one of the critical components placed inside the radioactive primary sodium, trouble-free operation of the IHX is very much essential for power plant availability. To validate the design and the adequacy of the support system provided for the IHX, flow induced vibration (FIV) experiments were carried out in a water test loop on a 60 deg. sector model. This paper discusses the flow induced vibration measurements carried out in 60 deg. sector model of IHX, the modeling criteria, the results and conclusion.

Sodium vapor deposition onto a horizontal flat plate above liquid sodium surface, (3)

International Nuclear Information System (INIS)

Kudo, Kazuhiko; Hirata, Masaru.

1978-01-01

Sodium vapour and sodium mist in the cover gas of a sodium system of a fast breeder reactor cause various problems. In this report, with the results of measurements of sodium mist concentration, the distribution of sodium mist diameter in cover gas was analytically obtained. The analysis was made by using the different nucleus model B. The measurement of the concentration of sodium mist was carried out with a sodium mist pot designed by the author. The experiment was done at the sodium temperature of 400 and 500 degree centigrade. The relations among sodium temperature, upper wall temperature, and the sodium mist concentration in cover gas were obtained. Evaluation of effective condensed nuclear radius in the cover gas was made by the comparison of analysis and experimental results. The results of this evaluation shows the following conclusions. It is impossible to express the distribution of sodium mist diameter by normal distribution or logarithmic normal distribution. Drop of sodium temperature results in the decrease of weight mean radius of generated sodium mist. Drop of upper wall temperature causes the decrease of weight mean radius, and increases sodium mist concentration. (Kato, T.)

An investigation of sodium iodide solubility in sodium-stainless steel systems

International Nuclear Information System (INIS)

Sagawa, Norihiko; Tashiro, Suguru

1996-01-01

Sodium iodide and major constituents of stainless steel in sodium are determined by using the steel capsules to obtain a better understanding on contribution of the constituents to the apparent iodide solubility in sodium. The capsule loaded with 20 g sodium and 0.1 - 0.3 g powder of sodium iodide is heated at its upper part in a furnace and cooled at its bottom on brass plates to establish a large temperature gradient along the capsule tube. After a given period of equilibration, the iodide and constituents are fixed in solidified sodium by quick quenching of the capsules. Sodium samples are taken from the sectioned capsule tube and submitted to sodium dissolution by vaporized water for determination of the iodine and to vacuum distillation for determination of the metal elements. Iron and nickel concentrations are observed to be lower in the samples at higher iodine concentrations. Chromium and manganese concentrations are seen to be insensitive to the iodine concentrations. The observations can be interpreted by a model that sodium oxide combines with metal iodide in sodium to form a complex compound and with consideration that the compound will fall and deposit onto the bottom of the capsule by thermal diffusion. (author)

49 CFR 173.189 - Batteries containing sodium or cells containing sodium.

Science.gov (United States)

2010-10-01

... 49 Transportation 2 2010-10-01 2010-10-01 false Batteries containing sodium or cells containing sodium. 173.189 Section 173.189 Transportation Other Regulations Relating to Transportation PIPELINE AND... Than Class 1 and Class 7 § 173.189 Batteries containing sodium or cells containing sodium. (a...

Cavitation erosion in sodium flow, sodium cavitation tunnel testing

International Nuclear Information System (INIS)

Courbiere, Pierre.

1981-04-01

The high-volume sodium flows present in fast neutron reactors are liable to induce cavitation phenomena in various portion of the sodium lines and pumps. The absence of sufficient data in this area led the C.E.A. to undertake an erosion research program in cavitating sodium flow. This paper discusses the considerations leading to the definition and execution of sodium cavitation erosion tests, and reviews the tests run with 400 0 C sodium on various steel grades: 316, 316 L, 316 Ti (Z8CNDT17-12), Poral (Z3CND18-12), 304 L and LN2 - clad 316 L (Ni coating-clad 316 L). Acoustic detection and signal processing methods were used with an instrument package designed and implemented at the Cadarache Nuclear Research Center

Removal of sodium from the component of the sodium purification loop

International Nuclear Information System (INIS)

Kim, Byung Ho; Jeong, Kyung Chai; Jeong, Ji Young; Kim, Jong Man; Choi, Byung Hae; Nam, Ho Yun

2005-01-01

The purpose of a cleaning process is to remove the residual sodium adhering to the component walls once it has been properly drained. It is necessary to clean and decontaminate a component, especially the large components of the primary coolant system; such as the intermediate heat exchangers and the primary pump. Improper and inadequate cleaning has in a number of cases resulted in problems in the storage, handling, and reuse of components. Several types of failures due to improper cleaning procedures have been defined in the past. Inadequate and incomplete removal of sodium results in residues which may contain metallic sodium and alkaline compounds such as sodium hydroxide, sodium oxide, sodium carbonate, and various types of alcoholates. Reinsertion of components containing these compounds into a high-temperature sodium system can result in either the intergranular penetration characteristic of a high-oxygen sodium or an accelerated corrosion due to oxygen. The methods used for cleaning sodium equipment depend on the condition and types of equipment to be cleaned and whether the equipment is to be reused. Cleaning methods are needed that will avoid a deleterious local overheating, material surface degradation or deposits, chemical, physical, or mechanical damage, and external effects. This paper discusses a steam-nitrogen gas cleaning method for the routine applications that permits the reuse of the cold trap in sodium

Apparatus for removing impurities in the sodium of sodium cooled reactors

Energy Technology Data Exchange (ETDEWEB)

Yamauchi, A

1970-11-11

An apparatus is provided for removing oxygen from liquid sodium flowing in a sodium cooled reactor. The removal of oxygen is complete with high efficiency. The liquid sodium to be purified is disposed outside a cylindrical wall and negatively charged, whereas sodium as a reducing material is disposed inside the same wall. The cylindrical wall is made of zirconia-calcia (ZrO/sub 2/)sub(0.87)(CaO)sub(0.13) solid electrolyte, the cylinder having a thickness of 2.5mm, a diameter of 3cm and a depth of 20cm under the sodium level. Electric resistance of the solid electrolyte is 2.3 ohm at 500/sup 0/C. A current of 1A by the application of 25 volts treats 0.3g of oxygen. Consequently, 1 liter or 1kg of liquid sodium containing 1,000ppm of oxygen can be purified for about 3 hours at an electrical consumption of 7.5 watt-hour. In one embodiment, a cylindrical electrolytic solid made of zirconia-calcia or zirconia-yttria was disposed in a container. Liquid sodium containing oxygen flowed outside of the cylinder. Liquid sodium as a reducing material was present inside the cylinder and the container and the cylinder were electrically insulated. An electrode was inserted at the center of the cylinder and a baffle plate at the upper portion of the electrode to shield heat and rising sodium vapor was provided. The space above the container was filled with an inert gas. The oxygen in the liquid sodium to be purified transferred through the wall of the cylinder into the interior of the cylinder so as to oxydize the reducing sodium material. The supersaturated sodium oxide inside the cylinder was deposited.

Effect of sodium lactate /sodium diacetate in combination with sodium nitrite on physiochemical, microbial properties and sensory evaluation of cow sausage

Directory of Open Access Journals (Sweden)

Habib Sedghi

2014-11-01

Full Text Available Sodium nitrite has been always considered as one of the common additives due to its antibacterial effects on Clostridium botulinum and meat products' color, however it produces cancer creating nitrosamine. Recently, organic acids and their salts such as lactates have been employed as antimicrobial compounds. Lactates also improve organileptic properties including color, texture and taste and antioxidant properties. Sodium lactate causes to more reduction of anaerobic spore former bacteria than nitrite, inhibits botulin produced by Clostridium botulinum. Sodium lactate produces a permanent reddish pink color through reduction of deoxymygloboline and producing deoxymyoglobuline. In this study, the decrease of sodium nitrite amount from 120ppm to 15ppm by adding sodium lactate / sodium diacetate led to achieve an acceptable product. The best results revealed through adding 3.0625% of sodium lactate / sodium diacetate in combination with 30ppm sodium nitrite. Results also exhibited more reduction of pathogens' growth than nitrite, enhanced flavor slightly, but unable to produce reddish pink color as produced by nitrite. Results also exhibited that sodium lactate / diacetate cause to retard in microbial growth, reducing chemical change, enhance sensory properties, partially improvement in taste and texture. Although inappropriate color demonstrated sodium lactate / diacetate's inability in red pink color production in 4th sample (contains 15 ppm nitrite, its synergy effect in combination with sodium nitrite on nitroso myoglobuline production has been proven, led to sodium nitrite reduction in sausages.

Electrolytic process to produce sodium hypochlorite using sodium ion conductive ceramic membranes

Science.gov (United States)

Balagopal, Shekar; Malhotra, Vinod; Pendleton, Justin; Reid, Kathy Jo

2012-09-18

An electrochemical process for the production of sodium hypochlorite is disclosed. The process may potentially be used to produce sodium hypochlorite from seawater or low purity un-softened or NaCl-based salt solutions. The process utilizes a sodium ion conductive ceramic membrane, such as membranes based on NASICON-type materials, in an electrolytic cell. In the process, water is reduced at a cathode to form hydroxyl ions and hydrogen gas. Chloride ions from a sodium chloride solution are oxidized in the anolyte compartment to produce chlorine gas which reacts with water to produce hypochlorous and hydrochloric acid. Sodium ions are transported from the anolyte compartment to the catholyte compartment across the sodium ion conductive ceramic membrane. Sodium hydroxide is transported from the catholyte compartment to the anolyte compartment to produce sodium hypochlorite within the anolyte compartment.

Report of sodium cavitation

International Nuclear Information System (INIS)

Murai, Hitoshi; Shima, Akira; Oba, Toshisaburo; Kobayashi, Ryoji; Hashimoto, Hiroyuki

1975-01-01

The damage of components for LMFBRs due to sodium cavitation is serious problem. This report summarizes the following items, (1) mechanism of the incipience of sodium cavitation, (2) damage due to sodium cavitation, (3) detection method for sodium cavitation, and (4) estimation method for sodium cavitation by the comparison with water cavitation. Materials were collected from the reports on liquid metal cavitation, sodium cavitation and water cavitation published from 1965 to now. The mechanism of the incipience of sodium cavitation cavitation parameters (mean location, distributed amount or occurrence aspect and stability), experiment of causing cavitation with Venturi tube, and growth of bubbles within superheated sodium. The sodium cavitation damage was caused by magnetostriction vibration method and with Venturi tube. The state of damage was investigated with the cavitation performance of a sodium pump, and the damage was examined in view of the safety of LMFBR plants. Sodium cavitation was detected with acoustic method, radiation method, and electric method. The effect of physical property of liquid on incipient cavitation was studied. These are thermodynamic effect based on quasistatic thermal equilibrium condition and the effect of the physical property of liquid based on bubble dynamics. (Iwase, T.)

Total-body sodium and sodium excess

International Nuclear Information System (INIS)

Aloia, J.F.; Cohn, S.H.; Abesamis, C.; Babu, T.; Zanzi, I.; Ellis, K.

1980-01-01

Total-body levels of sodium (TBNa), chlorine (TBCI), calcium (TBCa), and potassium (TBK) were measured by neutron activation and analysis of results by whole body counting in 66 postmenopausal women. The relationship between TBNa, and TBCl, TBK, and TBCa on the one hand, and height and weight on the other, were found to compare with those previously reported. The hypothesis that TBNa and TBCl are distributed normally could not be rejected. The sodium excess (Na/sub es/) is defined as the sodium that is present in excess of that associated with the extracellular fluid (chlorine) space; the Na/sub es/ approximates nonexchangeable bone sodium. In these 66 postmenopausal women, and in patients with different endocrinopathies previously described, the values on Na/sub es/ did not differ from the normal values except in the thyrotoxicosis patients, where they were decreased. A close relationship between Na/sub es/ and TBCa was maintained in the endocrinopathies studied. This relationship was found in conditions accompanied by either an increment or a loss of skeletal mass. It appears that the NA/sub es/ value is primarily dependent upon the calcium content of bone

Sodium fluxes in sweet pepper exposed to varying sodium concentrations

NARCIS (Netherlands)

Blom-Zandstra, M.; Vogelzang, S.A.; Veen, B.W.

1998-01-01

The sodium transport and distribution of sweet pepper (Capsicum annuum L.) under saline conditions were studied after transferring the plants to a sodium-free nutrient solution. Sodium stress up to 60 mM did not affect the growth of sweet pepper, as it appears able to counteract the unfavourable

Reaction velocity of sodium hydration in humid air and sodium carbonation in humid carbon dioxide atmosphere. Fundamental study on sodium carbonate process in FBR bulk sodium coolant disposal technology

International Nuclear Information System (INIS)

Tadokoro, Yutaka; Yoshida, Eiichi

1999-11-01

A sodium carbonate processing method, which changes sodium to sodium carbonate and/or sodium bicarbonate by humid carbon dioxide, has been examined and about to be applied to large test loops dismantling. However, that the basic data regarding the progress of the reaction is insufficient on the other hand, is a present condition. The present report therefore aims at presenting basic data regarding the reaction velocity of sodium hydration in humid air and sodium carbonation in humid carbon dioxide atmosphere, and observing the reaction progress, for the application to large test loops dismantling. The test result is summarized as follows. (1) Although the reaction velocity of sodium varied with sodium specimen sizes and velocity measurement methods, the reaction velocity of sodium hydration was in about 0.16 ∼ 0.34 mmh -1 (0.016 ∼ 0.033g cm -2 h -1 , 6.8x10 -4 ∼ 1.4x10 -3 mol cm -2 h -1 ) and that of sodium carbonation was in about 0.16 ∼ 0.27mmh -1 (0.016 ∼ 0.023g cm -2 h -1 , 6.8x10 -4 ∼ 1.1x10 -3 mol cm -2 h -1 ) (26 ∼ 31degC, RH 100%). (2) The reaction velocity of sodium in carbon dioxide atmosphere was greatly affected by vapor partial pressure (absolutely humidity). And the velocity was estimated in 0.08 ∼ 0.12mmh -1 (0.008 ∼ 0.012g cm -2 h -1 , 3.4x10 -4 ∼ 5.2x10 -4 mol cm -2 h -1 ) in the carbon dioxide atmosphere, whose temperature of 20degC and relative humidity of 80% are assumed real sodium carbonate process condition. (3) By the X-ray diffraction method, NaOH was found in humid air reaction product. Na 2 CO 3 , NaHCO 3 were found in carbon dioxide atmosphere reaction product. It was considered that Sodium changes to NaOH, and subsequently to NaHCO 3 through Na 2 CO 3 . (4) For the application to large test loops dismantling, it is considered possible to change sodium to a target amount of sodium carbonate (or sodium bicarbonate) by setting up gas supply quantity and also processing time appropriately according to the surface area

Sodium intake and dietary sources of sodium in undergraduate students from Novi Sad, Serbia

Directory of Open Access Journals (Sweden)

Jovičić-Bata Jelena

2016-01-01

Full Text Available Background/Aim. Data on sodium intake and sources of sodium in the diet in Serbia are limited. The aim of this study was to estimate the sodium intake and identify the sources of sodium in the diet of undergraduate students attending the University of Novi Sad. Methods. Students completed a questionnaire to gather data on their gender, age and university faculty attended, and then a 24 h dietary recall. The sodium intake of the students was calculated using the dietary recall data and data on the sodium content of foods. The contribution of different food groups as well as of specific foodstuffs to the total sodium intake was calculated. Results. The mean estimated sodium intake of the students was 3,938.5 ± 1,708.1 mg/day. The sodium intake of 89.1% of the surveyed students exceeded the guideline for sodium intake, the majority of the sodium coming from processed foods (78.9% of the total sodium intake. The food groups that contributed the most to the total sodium intake of the students were meat and meat products (21.7% and cereals and cereal-based products (18.6%. Bread and other bakery products were responsible for 13.1% of the total sodium intake. Conclusion. High sodium intake in students of the University of Novi Sad puts them at high risk of developing high blood pressure. The food industry should work towards reformulating products with high sodium content, especially bread and other bakery products. Efforts should be taken to reduce sodium intake among undergraduate students in Novi Sad.

Parametric Effect of Sodium Hydroxide and Sodium Carbonate on the Potency of a Degreaser

OpenAIRE

Babatope Abimbola Olufemi

2016-01-01

Experimental and statistical analysis was carried out on the comparative effect of sodium hydroxide and sodium carbonate on the potency of a laboratory produced degreaser in this work. The materials used include; octadecyl benzene sulphonic acid, sodium hydroxide, sodium carbonate, sodium metasilicate, carboxyl methyl cellulose (C.M.C), formadelhyde, perfume, colourant and distilled water. Different samples of degreaser were produced with varying composition of sodium hydroxide and sodium car...

Test Your Sodium Smarts

Science.gov (United States)

... You may be surprised to learn how much sodium is in many foods. Sodium, including sodium chloride ... foods with little or no salt. Test your sodium smarts by answering these 10 questions about which ...

Methods to Compose Sodium Fire Extinguishing Equipment on Sodium Test Facility

Energy Technology Data Exchange (ETDEWEB)

Kim, B H; Kim, J M; Jeong, J Y; Choi, B H

2008-06-15

Sodium fire is graded 'D' and it is difficult to extinguish sodium fire. In this report, the characteristics of sodium fire and the methods composing the suitable fire extinguishing systems to suppress fire effectively were described.

Methods to Compose Sodium Fire Extinguishing Equipment on Sodium Test Facility

International Nuclear Information System (INIS)

Kim, B. H.; Kim, J. M.; Jeong, J. Y.; Choi, B. H.

2008-06-01

Sodium fire is graded 'D' and it is difficult to extinguish sodium fire. In this report, the characteristics of sodium fire and the methods composing the suitable fire extinguishing systems to suppress fire effectively were described

Transformation of sodium from the Rapsodie fast breeder reactor into sodium hydroxide

International Nuclear Information System (INIS)

Roger, J.; Latge, C.; Rodriguez, G.

1994-01-01

One of the major problems raised by decommissioning a fast breeder reactor (FBR) concerns the disposal of the sodium coolant. The Desora operation was undertaken to eliminate the Rapsodie primary sodium as part of the partial decommissioning program, and to develop an operational sodium treatment unit for other needs. The process involves reacting small quantities of sodium in water inside a closed vessel, producing aqueous sodium hydroxide and hydrogen gas. It is described in this work. (O.L.). 4 figs

Sodium fire protection

International Nuclear Information System (INIS)

Raju, C.; Kale, R.D.

1979-01-01

Results of experiments carried out with sodium fires to develop extinguishment techniques are presented. Characteristics, ignition temperature, heat evolution and other aspects of sodium fires are described. Out of the powders tested for extinguishment of 10 Kg sodium fires, sodium bi-carbonate based dry chemical powder has been found to be the best extinguisher followed by large sized vermiculite and then calcium carbonate powders distributed by spray nozzles. Powders, however, do not extinguish large fires effectively due to sodium-concrete reaction. To control large scale fires in a LMFBR, collection trays with protective cover have been found to cause oxygen starvation better than flooding with inert gas. This system has an added advantage in that there is no damage to the sodium facilities as has been in the case of powders which often contain chlorine compounds and cause stress corrosion cracking. (M.G.B.)

A study of atomic interaction between suspended nanoparticles and sodium atoms in liquid sodium

International Nuclear Information System (INIS)

Saito, Jun-ichi; Ara, Kuniaki

2010-01-01

A feasibility study of suppression of the chemical reactivity of sodium itself using an atomic interaction between nanoparticles and sodium atoms has been carried out. We expected that the atomic interaction strengthens when the nanoparticle metal is the transition element which has a major difference in electronegativity from sodium. We also calculated the atomic interaction between nanoparticle and sodium atoms. It became clear that the atomic bond between the nanoparticle atom and the sodium atom is larger than that between sodium atoms, and the charge transfer takes place to the nanoparticle atom from the sodium atom. Using sodium with suspended nanoparticles, the fundamental physical properties related to the atomic interaction were investigated to verify the atomic bond. The surface tension of sodium with suspended nanoparticles increased, and the evaporation rate of sodium with suspended nanoparticles also decreased compared with that of sodium. Therefore the presence of the atomic interaction between nanoparticles and sodium was verified from these experiments. Because the fundamental physical property changes by the atomic interaction, we expected changes in the chemical reactivity characteristics. The chemical reaction properties of sodium with suspended nanoparticles with water were investigated experimentally. The released reaction heat and the reaction rate of sodium with suspended nanoparticles were reduced than those of sodium. The influence of the charge state of nanoparticle on the chemical process with water was theoretically investigated to speculate on the cause of reaction suppression. The potential energy in both primary and side reactions changed by the charge transfer, and the free energy of activation of the reaction with water increased. Accordingly, the reaction barrier also increased. This suggests there is a possibility of the reduction in the reaction of sodium by the suspension of nanoparticles. Consequently the possibility of the

Final report on the safety assessment of sodium sulfite, potassium sulfite, ammonium sulfite, sodium bisulfite, ammonium bisulfite, sodium metabisulfite and potassium metabisulfite.

Science.gov (United States)

Nair, Bindu; Elmore, Amy R

2003-01-01

Sodium Sulfite, Ammonium Sulfite, Sodium Bisulfite, Potassium Bisulfite, Ammonium Bisulfite, Sodium Metabisulfite, and Potassium Metabisulfite are inorganic salts that function as reducing agents in cosmetic formulations. All except Sodium Metabisulfite also function as hair-waving/straightening agents. In addition, Sodium Sulfite, Potassium Sulfite, Sodium Bisulfite, and Sodium Metabisulfite function as antioxidants. Although Ammonium Sulfite is not in current use, the others are widely used in hair care products. Sulfites that enter mammals via ingestion, inhalation, or injection are metabolized by sulfite oxidase to sulfate. In oral-dose animal toxicity studies, hyperplastic changes in the gastric mucosa were the most common findings at high doses. Ammonium Sulfite aerosol had an acute LC(50) of >400 mg/m(3) in guinea pigs. A single exposure to low concentrations of a Sodium Sulfite fine aerosol produced dose-related changes in the lung capacity parameters of guinea pigs. A 3-day exposure of rats to a Sodium Sulfite fine aerosol produced mild pulmonary edema and irritation of the tracheal epithelium. Severe epithelial changes were observed in dogs exposed for 290 days to 1 mg/m(3) of a Sodium Metabisulfite fine aerosol. These fine aerosols contained fine respirable particle sizes that are not found in cosmetic aerosols or pump sprays. None of the cosmetic product types, however, in which these ingredients are used are aerosolized. Sodium Bisulfite (tested at 38%) and Sodium Metabisulfite (undiluted) were not irritants to rabbits following occlusive exposures. Sodium Metabisulfite (tested at 50%) was irritating to guinea pigs following repeated exposure. In rats, Sodium Sulfite heptahydrate at large doses (up to 3.3 g/kg) produced fetal toxicity but not teratogenicity. Sodium Bisulfite, Sodium Metabisulfite, and Potassium Metabisulfite were not teratogenic for mice, rats, hamsters, or rabbits at doses up to 160 mg/kg. Generally, Sodium Sulfite, Sodium

Analytical study of sodium combustion phenomena under sodium leak accidents

International Nuclear Information System (INIS)

Kim, Byung Ho; Jeong, J. Y.; Jeong, K. C.; Kim, T. J.; Choi, J. H.

2001-12-01

The rise of temperature and pressure, the release of aerosol in the buildings as a result of sodium fire must be considered for the safety measures of LMR. Therefore for the safety of the LMR, it is necessary to understand the characteristics of sodium fire, resulting from the various type of leakage. ASSCOPS(Analysis of Simultaneous Sodium Combustion in Pool and Spray) is the computer code for the analysis of the thermal consequence of sodium leak and fire in LMR that has been developed by Japan Nuclear Cycle Development Institute(JNC) in Japan. In this study, a preliminary analysis of sodium leak and fire accidents in S/G building of KALIMER is made by using ASSCOPS code. Various phenomena of interest are spray and pool burning, peak pressure, temperature change, local structure temperature, aerosol behavior, drain system into smothering tank, ventilation characteristics at each cell with the safety venting system and nitrogen injection system. In this calculation, the dimension of the S/G building was chosen in accordance with the selected options of LMR name KALIMER(Korea). As a result of this study, it was shown that subsequent effect of sodium fire depended upon whether the sodium continued to leak from the pipe or not, whether the ventilation system was running, whether the inert gas injection system was provided, whether the sodium on floor was drained into the smothering tank or not, whether the building was sealed or not, etc. Specially the excessive rise of pressure into each cell was prevented by installing the pressure release plates on wall of the building

Electrolyte transport in distal colon of sodium-depleted rats: Effect of sodium repletion

International Nuclear Information System (INIS)

Turnamian, S.G.; Binder, H.J.

1988-01-01

Dietary sodium depletion increases plasma aldosterone level and, as a result, induces amiloride-sensitive electrogenic sodium absorption and electrogenic potassium secretion and stimulates Na + -K + -ATPase activity in rat distal colon, while inhibiting electroneutral sodium chloride absorption. To assess the events that occur as the aldosterone-stimulated colon reverts to normal, unidirectional 22 Na and 36 Cl fluxes were measured under voltage-clamp conditions across isolated distal colonic mucosa of rats that were initially dietary sodium depleted for 7 days and then sodium repleted for varying periods of time before the study. Within 8 h of dietary sodium repletion, plasma aldosterone level and Na + -K + -ATPase activity declined to normal, amiloride-sensitive electrogenic sodium absorption decreased by >90%, and active electrogenic potassium secretion also decreased markedly. In contrast, electroneutral sodium chloride absorption did not completely return to levels seen in normal animals until ∼64-68 h. These results demonstrate that maintenance of electrogenic sodium absorption and potassium secretion are directly dependent on elevated plasma aldosterone levels. The inhibition of electroneutral sodium absorption, although initiated by excess aldosterone, persists after normalization of the plasma aldosterone level, thereby implying that the inhibition is dependent on additional factor(s)

Sodium vapor deposition onto a horizontal flat plate above liquid sodium surface, 2

International Nuclear Information System (INIS)

Kudo, Kazuhiko; Hirata, Masaru.

1977-01-01

The sodium vapor deposition onto a horizontal flat plate above liquid sodium surface was studied. The analysis was performed by assuming that the sodium mist is emitted into the main flow without condensation and then grows up in the main flow and drops on the sodium surface. The effects of growth of sodium mist to the system were investigated. The model of the phenomena is the sodium deposition onto a horizontal flat plate which is placed above the sodium surface with the medium cover gas. One-dimensional analysis can be done. The rate of deposition is greatly reduced when the temperature of the flat plate is lowered. For the analysis of this phenomena, it is assumed that the sodium mist grows by condensation. One of results is that the real state may be the state between the state that the condensation of mist is made in the boundary layer and the state that the mist is condensed in the main flow. Others are that there is no effect of sodium mist condensation on the rate of deposition, and that the rate of the vaporization of sodium is given by the original and the modified model. (Kato, T.)

Operating experience with sodium valves in the TNO-sodium test facilities

International Nuclear Information System (INIS)

Gasselt, M.L.G. van

1974-01-01

The development of sodium components for the SNR-300 in Holland has reached the stage where full scale testing in sodium has almost been finished and construction is at its height. It is against this background that a review is given of the weaknesses in one area or the other of the commercially available types of sodium valves used in TNO's smaller test facilities at Apeldoorn and TNO's 50 MW sodium components test facility at Hengelo. (U.S.)

Astrocyte Sodium Signalling and Panglial Spread of Sodium Signals in Brain White Matter.

Science.gov (United States)

Moshrefi-Ravasdjani, Behrouz; Hammel, Evelyn L; Kafitz, Karl W; Rose, Christine R

2017-09-01

In brain grey matter, excitatory synaptic transmission activates glutamate uptake into astrocytes, inducing sodium signals which propagate into neighboring astrocytes through gap junctions. These sodium signals have been suggested to serve an important role in neuro-metabolic coupling. So far, it is unknown if astrocytes in white matter-that is in brain regions devoid of synapses-are also able to undergo such intra- and intercellular sodium signalling. In the present study, we have addressed this question by performing quantitative sodium imaging in acute tissue slices of mouse corpus callosum. Focal application of glutamate induced sodium transients in SR101-positive astrocytes. These were largely unaltered in the presence of ionotropic glutamate receptors blockers, but strongly dampened upon pharmacological inhibition of glutamate uptake. Sodium signals induced in individual astrocytes readily spread into neighboring SR101-positive cells with peak amplitudes decaying monoexponentially with distance from the stimulated cell. In addition, spread of sodium was largely unaltered during pharmacological inhibition of purinergic and glutamate receptors, indicating gap junction-mediated, passive diffusion of sodium between astrocytes. Using cell-type-specific, transgenic reporter mice, we found that sodium signals also propagated, albeit less effectively, from astrocytes to neighboring oligodendrocytes and NG2 cells. Again, panglial spread was unaltered with purinergic and glutamate receptors blocked. Taken together, our results demonstrate that activation of sodium-dependent glutamate transporters induces sodium signals in white matter astrocytes, which spread within the astrocyte syncytium. In addition, we found a panglial passage of sodium signals from astrocytes to NG2 cells and oligodendrocytes, indicating functional coupling between these macroglial cells in white matter.

Dynamic thermal baffle on lower head of FBR sodium-sodium intermediate heat exchanger

International Nuclear Information System (INIS)

Charbonnel, A.; Foussat, C.

1981-01-01

The cover head of the heat exchanger is bathed on the one side by the primary sodium of the 'cold' header of the vessel and on the other side by the secondary sodium which feeds the heat exchange tube bank through the lower tubesheet. In the case of transient or permanent operating conditions at partial ratings, there are large temperature differences between the inner sodium (inlet temperature conditions of secondary sodium) and the outer sodium (mean temperature conditions in the primary sodium outlet port), hence the necessity of designing a thermal baffle which protects the head and its connection to the tubesheet. A 'static' thermal baffle consisting of a thick steel plate enclosing static sodium around the head proves inadequate during transient operating conditions. This is why a 'dynamic' thermal baffle is used whose design is based on the fact that the primary sodium in the lower part of the outlet port is always at a temperature close to that of the secondary sodium in the inlet header and the head. The primary sodium is taken from the bottom of the outlet port by a ring deflector and circulates in an annulus created by a double housing and the head. It flows out through openings in the lower part of the housing. (orig./GL)

Small liquid sodium leaks

International Nuclear Information System (INIS)

Dufresne, J.; Rochedereux, Y.; Antonakas, D.; Casselman, C.; Malet, J.C.

1986-05-01

Usually, pessimistic considerations inassessing the safety of secondary sodium loops in LMFBR reactor lead to assume guillotine rupture releasing a large amount of sodium estimate the consequences of large sodium fires. In order to reduce these consequences, one has to detect the smallest leak as soon as possible and to evaluate the future of an initial small leak. Analysis of the relationship between crack size and sodium outflow rate; Analysis of a sodium pipe with a small open crack

Effects of topical flurbiprofen sodium, diclofenac sodium, ketorolac ...

African Journals Online (AJOL)

To evaluate corneal sensitivity by using the Cochet-Bonnet® esthesiometer in normal canine eyes at different time points following instillation of three different topical non-steroidal anti-inflammatory drugs (flurbiprofen sodium 0.03%, diclofenac sodium 0.1% and ketorolac tromethamine 0.5%) and benzalkonium chloride ...

Investigation of Plugging of Narrow Sodium Channels by Sodium and Carbon Dioxide Interaction

Energy Technology Data Exchange (ETDEWEB)

Park, Sun Hee; Wi, Myung-Hwan; Min, Jae Hong; Kim, Tae-joon [Korea Atomic Energy Research Institute, Daejeon (Korea, Republic of)

2014-10-15

The supercritical CO{sub 2} Brayton cycle system is known to be a promising power conversion system for improving the efficiency and preventing the sodium water reaction (SWR) of the current SFR concept using a Rankine steam cycle. PCHEs are known to have potential for reducing the volume occupied by the sodium-to-CO{sub 2} exchangers as well as the heat exchanger mass relative to traditional shell-and-tube heat exchangers. Here, we report a study on a plugging test by the interaction of sodium and CO{sub 2} to investigate design parameters of sodium channels in the realistic operating conditions. We investigated a plugging test by an interaction of sodium and CO{sub 2} with different cross sectional areas of the sodium channels. It was found that the flow rate of sodium decreased earlier and faster with a narrower cross sectional area compared to a wider one. Our experimental results are expected to be used for determining the sodium channel areas of PCHEs.

Liquid sodium pool fires

Energy Technology Data Exchange (ETDEWEB)

Casselman, C [DSN/SESTR, Centre de Cadarache, Saint-Paul-lez-Durance (France)

1979-03-01

Experimental sodium pool combustion results have led to a definition of the combustion kinetics, and have revealed the hazards of sodium-concrete contact reactions and the possible ignition of organic matter (paint) by hydration of sodium peroxide aerosols. Analysis of these test results shows that the controlling mechanism is sodium evaporation diffusion. (author)

Liquid sodium pool fires

International Nuclear Information System (INIS)

Casselman, C.

1979-01-01

Experimental sodium pool combustion results have led to a definition of the combustion kinetics, and have revealed the hazards of sodium-concrete contact reactions and the possible ignition of organic matter (paint) by hydration of sodium peroxide aerosols. Analysis of these test results shows that the controlling mechanism is sodium evaporation diffusion. (author)

Investigation for the sodium leak Monju. Sodium fire test-II

International Nuclear Information System (INIS)

Uchiyama, Naoki; Takai, Toshihide; Nishimura, Masahiro; Miyahara, Shinya; Miyake, Osamu; Tanabe, Hiromi

2000-08-01

As a part of the work for investigating the sodium leak accident which occurred in the Monju reactor (hereinafter referred to as Monju), sodium fire test-II was carried out using the SOLFA-1 (Sodium Leak, Fire and Aerosol) facility at OEC/PNC. In the test, the piping, ventilation duct, grating and floor liner were all full-sized and arranged in a rectangular concrete cell in the same manner as in Monju. The main objectives of the test were to confirm the leak and burning behavior of sodium from the damaged thermometer, and the effects of the sodium fire on the integrity of the surrounding structure. The main conclusions obtained from the test are shown below: (1) Burning Behavior of Leaked Sodium : Images taken with a cameras in the test reveal that in the early stages of the sodium leak, the sodium dropped down out of the flexible tube in drips. (2) Damage to the Ventilation Duct and Grating : The temperature of the ventilation duct's inner surface fluctuated between approximately 600degC and 700degC. The temperature of the grating began rising at the outset of the test, then fluctuated between roughly 600degC and 900degC. The maximum temperature was about 1000degC. After the test, damage to the ventilation duct and the grating was found. Damage to the duct was greater than that at Monju. (3) Effects on the Floor Liner : The temperature of the floor liner under the leak point exceed 1,000degC at 3 hours and 20 minutes into the test. A post test inspection of the liner revealed five holes in an area about 1m x 1m square under the leak point. There was also a decrease of the liner thickness on the north and west side of the leak point. (4) Effects on Concrete : The post test inspection revealed no surface damage on either the concrete side walls or the ceiling. However, the floor concrete was eroded to a maximum depth 8 cm due to a sodium-concrete reaction. The compressive strength of the concrete was not degraded in spite of the thermal effect. (5) Chemical

Control of sodium fires and sodium-water reactions in breeder reactors

International Nuclear Information System (INIS)

Foerster, K.; Ruloff, G.; Voss, J.

1985-01-01

The excellent neutronic and thermodynamic properties of sodium as a fast-reactor coolant are somewhat counterbalanced by its high oxygen affinity. Because incidents like sodium fires and sodium-water reactions cannot be absolutely excluded, their effects and preventive measures have to be investigated. Characteristics and counter-measures are discussed. (orig.) [de

Sodium aerosol recovering device

International Nuclear Information System (INIS)

Fujimori, Koji; Ueda, Mitsuo; Tanaka, Kazuhisa.

1997-01-01

A main body of a recovering device is disposed in a sodium cooled reactor or a sodium cooled test device. Air containing sodium aerosol is sucked into the main body of the recovering device by a recycling fan and introduced to a multi-staged metal mesh filter portion. The air about against each of the metal mesh filters, and the sodium aerosol in the air is collected. The air having a reduced sodium aerosol concentration circulates passing through a recycling fan and pipelines to form a circulation air streams. Sodium aerosol deposited on each of the metal mesh filters is scraped off periodically by a scraper driving device to prevent clogging of each of the metal filters. (I.N.)

Sodium characterization during the starting period of a sodium loop

International Nuclear Information System (INIS)

Lievens, F.; Parmentier, C.; Soenen, M.

1976-01-01

A sodium loop for analytical chemistry studies has been built by S.C.K./C.E.N. at Mol Belgium. Its first working period was used to test analytical methods, to characterize the sodium and to define the operating parameters of the loop. This report covers the working parameters of the loop, the characterization of the filling sodium and its purity evolution during the first working period of the loop

Final report on the safety assessment of potassium silicate, sodium metasilicate, and sodium silicate.

Science.gov (United States)

Elmore, Amy R

2005-01-01

Potassium Silicate, Sodium Metasilicate, and Sodium Silicate combine metal cations with silica to form inorganic salts used as corrosion inhibitors in cosmetics. Sodium Metasilicate also functions as a chelating agent and Sodium Silicate as a buffering and pH adjuster. Sodium Metasilicate is currently used in 168 formulations at concentrations ranging from 13% to 18%. Sodium Silicate is currently used in 24 formulations at concentrations ranging from 0.3% to 55%. Potassium Silicate and Sodium Silicate have been reported as being used in industrial cleaners and detergents. Sodium Metasilicate is a GRAS (generally regarded as safe) food ingredient. Aqueous solutions of Sodium Silicate species are a part of a chemical continuum of silicates based on an equilibrium of alkali, water, and silica. pH determines the solubility of silica and, together with concentration, determines the degree of polymerization. Sodium Silicate administered orally is readily absorbed from the alimentary canal and excreted in the urine. The toxicity of these silicates has been related to the molar ratio of SiO2/Na2O and the concentration being used. The Sodium Metasilicate acute oral LD50 ranged from 847 mg/kg in male rats to 1349.3 mg/kg in female rats and from 770 mg/kg in female mice to 820 mg/kg in male mice. Gross lesions of variable severity were found in the oral cavity, pharynx, esophagus, stomach, larynx, lungs, and kidneys of dogs receiving 0.25 g/kg or more of a commercial detergent containing Sodium Metasilicate; similar lesions were also seen in pigs administered the same detergent and dose. Male rats orally administered 464 mg/kg of a 20% solution containing either 2.0 or 2.4 to 1.0 ratio of sodium oxide showed no signs of toxicity, whereas doses of 1000 and 2150 mg/kg produced gasping, dypsnea, and acute depression. Dogs fed 2.4 g/kg/day of Sodium Silicate for 4 weeks had gross renal lesions but no impairment of renal function. Dermal irritation of Potassium Silicate, Sodium

Improving the Corrosion Inhibitive Strength of Sodium Sulphite in Hydrogen Cyanide Solution Using Sodium Benzoate

Directory of Open Access Journals (Sweden)

Muhammed Olawale Hakeem AMUDA

2008-12-01

Full Text Available The improvement in the inhibitive strength of sodium sulphite on corrosion of mild steel in hydrogen cyanide by adding sodium benzoate in regulated volume was investigated using the fundamental weight loss measurement.500 ppm concentration inhibitive mixtures of sodium benzoate and sodium sulphite in three different volume ratios (5/15, 10/10, 15/5 were formulated and studied for corrosion rate in 200ml hydrogen cyanide fluid. Result obtained indicates that the corrosion rate of mild steel in hydrogen cyanide in the presence of sodium benzoate/sodium sulphite inhibitive mixtures range 0.322mmpy to 1.1269mmpy across the three volumetric ratios considered. The 15ml5ml sodium benzoatesodium sulphite mixture had the best average corrosion rate of 0.5123mmpy.The corrosion rate followed reducing pattern after the first 200 hours of immersion. The average corrosion rate in the sodium benzoate / sodium sulphite mixture is less than the rate in sodium sulphite and the mixture is only effective after long time exposure.It is concluded that adding sodium benzoate to sodium sulphite in the volumetric ratio 155ml improves the inhibitive strength of sodium sulphite on the corrosion of mild steel in hydrogen cyanide environment.

Sub-classification of Advanced-Stage Hepatocellular Carcinoma: A Cohort Study Including 612 Patients Treated with Sorafenib.

Science.gov (United States)

Yoo, Jeong-Ju; Chung, Goh Eun; Lee, Jeong-Hoon; Nam, Joon Yeul; Chang, Young; Lee, Jeong Min; Lee, Dong Ho; Kim, Hwi Young; Cho, Eun Ju; Yu, Su Jong; Kim, Yoon Jun; Yoon, Jung-Hwan

2018-04-01

Advanced hepatocellular carcinoma (HCC) is associated with various clinical conditions including major vessel invasion, metastasis, and poor performance status. The aim of this study was to establish a prognostic scoring system and to propose a sub-classification of the Barcelona-Clinic Liver Cancer (BCLC) stage C. This retrospective study included consecutive patientswho received sorafenib for BCLC stage C HCC at a single tertiary hospital in Korea. A Cox proportional hazard model was used to develop a scoring system, and internal validationwas performed by a 5-fold cross-validation. The performance of the model in predicting risk was assessed by the area under the curve and the Hosmer-Lemeshow test. A total of 612 BCLC stage C HCC patients were sub- classified into strata depending on their performance status. Five independent prognostic factors (Child-Pugh score, α-fetoprotein, tumor type, extrahepatic metastasis, and portal vein invasion) were identified and used in the prognostic scoring system. This scoring system showed good discrimination (area under the receiver operating characteristic curve, 0.734 to 0.818) and calibration functions (both p advanced HCC. A prognostic scoring system with five independent factors is useful in predicting the survival of patients with BCLC stage C HCC.

Case report of severe Cushing's syndrome in medullary thyroid cancer complicated by functional diabetes insipidus, aortic dissection, jejunal intussusception, and paraneoplastic dysautonomia: remission with sorafenib without reduction in cortisol concentration.

Science.gov (United States)

Hammami, Muhammad M; Duaiji, Najla; Mutairi, Ghazi; Aklabi, Sabah; Qattan, Nasser; Abouzied, Mohei El-Din M; Sous, Mohamed W

2015-09-09

Normalization of cortisol concentration by multikinase inhibitors have been reported in three patients with medullary thyroid cancer-related Cushing's syndrome. Aortic dissection has been reported in three patients with Cushing's syndrome. Diabetes insipidus without intrasellar metastasis, intestinal intussusception, and paraneoplastic dysautonomia have not been reported in medullary thyroid cancer. An adult male with metastatic medullary thyroid cancer presented with hyperglycemia, hypernatremia, hypokalemia, hypertension, acne-like rash, and diabetes insipidus (urine volume >8 L/d, osmolality 190 mOsm/kg). Serum cortisol, adrenocorticoitropic hormone, dehydroepiandrostenedione sulfate, and urinary free cortisol were elevated 8, 20, 4.4, and 340 folds, respectively. Pituitary imaging was normal. Computed tomography scan revealed jejunal intussusception and incidental abdominal aortic dissection. Sorafenib treatment was associated with Cushing's syndrome remission, elevated progesterone (>10 fold), normalization of dehydroepiandrostenedione sulfate, but persistently elevated cortisol concentration. Newly-developed proximal lower limb weakness and decreased salivation were associated with elevated ganglionic neuronal acetylcholine receptor (alpha-3) and borderline P/Q type calcium channel antibodies. Extreme cortisol concentration may have contributed to aortic dissection and suppressed antidiuretic hormone secretion; which combined with hypokalemia due cortisol activation of mineralocorticoid receptors, manifested as diabetes insipidus. This is the first report of paraneoplastic dysautonomia and jejunal intussusception in medullary thyroid cancer, they may be related to medullary thyroid cancer's neuroendocrine origin and metastasis, respectively. Remission of Cushing's syndrome without measurable reduction in cortisol concentration suggests a novel cortisol-independent mechanism of action or assay cross-reactivity. Normalization of dehydroepiandrostenedione

Liquid sodium technology research

International Nuclear Information System (INIS)

Kim, W.C.; Lee, Y.W.; Nam, H.Y.; Chun, S.Y.; Kim, J.; Won, S.Y.

1982-01-01

This report describes the technology of impurity control and measurement of liquid sodium, problems associated with material degradation and change of heat transfer characteristics in liquid sodium, and the conceptual design of multipurpose sodium test loop. Discussion and the subsequent analysis are also made with regard to the test results for the sodium-H 2 0 reaction and its effects on the system. (author)

Development of a sodium ionization detector for sodium-to-gas leaks

International Nuclear Information System (INIS)

Swaminathan, K.; Elumalai, G.

1984-01-01

A sensitive sodium-to-gas leak detector has been indigenously developed for use in liquid metal cooled fast breeder reactor. The detector relies on the relative ease with which sodium vapour or its aerosols including its oxides and hydroxides can be thermally ionized compared with other possible constituents such as nitrogen, oxygen, water vapour etc. in a carrier gas and is therefore called sodium ionization detector (SID). The ionization current is a measure of sodium concentration in the carrier gas sampled through the detector. Different sensor designs using platinum and rhodium as filament materials in varying sizes were constructed and their responses to different sodium aerosol concentrations in the carrier gas were investigated. Nitrogen was used as the carrier gas. Both the background current and speed of response were found to depend on the diameter of the filament. There was also a particular collector voltage which yielded maximum sensitivity of the detector. The sensor was therefore optimised considering influence of above factors and a detector has been built which demonstrates a sensitivity better than 0.3 nanogram of sodium per cubic centimetre of carrier gas for a signal to background ratio of 1:1. Its usefulness in detecting sodium fires in experimental area was also demonstrated. Currently efforts are under way to improve the life time of the filament used in the above detector. (author)

A study on sodium-concrete reaction

Energy Technology Data Exchange (ETDEWEB)

Bae, Jae Heum; Min, Byong Hun [Suwon University, Suwon (Korea, Republic of)

1997-07-01

A small sodium-concrete reaction facility was designed, manufactured and installed. this facility has been operated under inert gas(N{sub 2}) with different experimental variables such as sodium injection temperature, injection amount of sodium, aging period of concrete, sodium reservoir temperature. As a result, it was found that sodium injection temperature and injected amount of sodium has little effect on sodium-concrete reaction. However, sodium reservoir temperature and aging period of concrete has relatively high impact on sodium-concrete reaction. Sodium-concrete reaction model has also been developed and compared with experimental results. (Author) 51 refs., 16 tabs., 64 figs.

Dietary sodium

DEFF Research Database (Denmark)

Graudal, Niels

2015-01-01

The 2013 Institute of Medicine (IOM) report "Sodium Intake in Populations: Assessment of Evidence" did not support the current recommendations of the IOM and the American Heart Association (AHA) to reduce daily dietary sodium intake to below 2,300 mg. The report concluded that the population...

Preliminary Plugging tests in Narrow Sodium Channels by Sodium and Carbon Dioxide reaction

Energy Technology Data Exchange (ETDEWEB)

Park, Sun Hee; Wi, Myung-Hwan; Min, Jae Hong [Korea Atomic Energy Research Institute, Daejeon (Korea, Republic of)

2015-05-15

This report is on the investigation of the physical/chemical phenomena that a slow loss of CO{sub 2} inventory into sodium after the sodium-CO{sub 2} boundary failure in PCHEs in realistic operating conditions. The first phenomenon is potential channel plugging inside the narrow PCHE channel. Unlike a conventional shell and- tube type HXs, failures in a PCHE are expected to be small cracks. If the faulted channel is blocked, it may have a positive function for plant safety because the pressure boundary would automatically recover due to this self-plugging. The other one is damage propagation on pressure boundary, which is referred to as potential wastage with combined corrosion/erosion effect. Physical/chemical phenomena that a slow loss of CO{sub 2} inventory into sodium after the sodium-CO{sub 2} boundary failure in printed circuit heat exchangers (PCHEs) were investigated. Our preliminary experimental results of plugging show that sodium flow immediately stopped as CO{sub 2} was injected through the nozzle at 300-400 .deg. C in 3 mm sodium channels, whereas sodium flow stopped about 60 min after CO{sub 2} injection in 5 mm sodium channels.

Corrosion behaviors of ceramics against liquid sodium. Sodium corrosion characteristics of sintering additives

International Nuclear Information System (INIS)

Tachi, Yoshiaki; Kano, Shigeki; Hirakawa, Yasushi; Yoshida, Eiichi

1998-01-01

It has been progressed as the Frontier Materials Research to research and develop ceramics to apply for several components of fast breeder reactor using liquid sodium as coolant instead of metallic materials. Grain boundary of ceramics has peculiar properties compared with matrix because most of ceramics are produced by hardening and firing their raw powders. Some previous researchers indicated that ceramics were mainly corroded at grain boundaries by liquid sodium, and ceramics could not be used under corrosive environment. Thus, it is the most important for the usage of ceramics in liquid sodium to improve corrosion resistance of grain boundaries. In order to develop the advanced ceramics having good sodium corrosion resistance among fine ceramics, which have recently been progressed in quality and characteristics remarkably, sodium corrosion behaviors of typical sintering additives such as MgO, Y 2 O 3 and AlN etc. have been examined and evaluated. As a result, the followings have been clarified and some useful knowledge about developing advanced ceramics having good corrosion resistance against liquid sodium has been obtained. (1) Sodium corrosion behavior of MgO depended on Si content. Samples containing large amount of Si were corroded severely by liquid sodium, whereas others with low Si contents showed good corrosion resistance. (2) Both Y 2 O 3 and AlN, which contained little Si, showed good sodium corrosion resistance. (3) MgO, Y 2 O 3 and AlN are thought to be corroded by liquid sodium, if they contain some SiO 2 . Therefore, in order to improve sodium corrosion resistance, it is very important for these ceramics to prevent the contamination of matrix with SiO 2 through purity control of their raw powders. (author)

Sodium waste technology: A summary report

International Nuclear Information System (INIS)

Abrams, C.S.; Witbeck, L.C.

1987-01-01

The Sodium Waste Technology (SWT) Program was established to resolve long-standing issues regarding disposal of sodium-bearing waste and equipment. Comprehensive SWT research programs investigated a variety of approaches for either removing sodium from sodium-bearing items, or disposal of items containing sodium residuals. The most successful of these programs was the design, test, and the production operation of the Sodium Process Demonstration Facility at ANL-W. The technology used was a series of melt-drain-evaporate operations to remove nonradioactive sodium from sodium-bearing items and then converting the sodium to storable compounds

Parametric study of sodium aerosols in the cover-gas space of sodium-cooled reactors

International Nuclear Information System (INIS)

Sheth, A.

1975-03-01

A mathematical model has been developed to describe the behavior of sodium aerosols in the cover-gas space of a sodium-cooled reactor. A review of the literature was first made to examine methods of aerosol generation, mathematical expressions representing aerosol behavior, and pertinent experimental investigations of sodium aerosols. In the development of the model, some terms were derived from basic principles and other terms were estimated from available correlations. The model was simulated on a computer, and important parameters were studied to determine their effects on the overall behavior of sodium aerosols. The parameters studied were sodium pool temperature, source and initial size of particles, film thickness at the sodium pool/cover gas interface, wall plating parameters, cover-gas flow rate, and type of cover gas (argon and helium). The model satisfactorily describes the behavior of sodium aerosol in argon, but not in helium. Possible reasons are given for the failure of the model with helium, and further experimental work is recommended. The mathematical model, with appropriate modifications to describe the behavior of sodium aerosols in helium, would be very useful in designing traps to remove aerosols from the cover gas of sodium-cooled reactors. (U.S.)

A Simple Quantitative Synthesis: Sodium Chloride from Sodium Carbonate.

Science.gov (United States)

Gold, Marvin

1988-01-01

Describes a simple laboratory procedure for changing sodium carbonate into sodium chloride by adding concentrated HCl to cause the reaction and then evaporating the water. Claims a good stoichiometric yield can be obtained in one three-hour lab period. Suggests using fume hood for the reaction. (ML)

Hidden Sodium

Centers for Disease Control (CDC) Podcasts

2013-03-04

In this podcast, learn about reducing sodium intake by knowing what to eat and the main sources of sodium in the diet. It's important for a healthy lifestyle.  Created: 3/4/2013 by National Center for Chronic Disease Prevention and Health Promotion (NCCDPHP).   Date Released: 3/4/2013.

[Sodium intake during pregnancy].

Science.gov (United States)

Delemarre, F M; Franx, A; Knuist, M; Steegers, E A

1999-10-23

International studies have yielded contradictory results on efficacy of a sodium-restricted diet during pregnancy in preventing and curing hypertension of pregnancy. In the Netherlands three studies have been performed to investigate the value of dietary sodium restriction in pregnancy; they concerned epidemiology, prevention and treatment. Midwives often prescribed this dietary intervention. Urinary sodium excretion was not related to blood pressure changes in pregnancy. Dietary sodium restriction from the third month of pregnancy onwards did not reduce the incidence of pregnancy-induced hypertension. Maternal side effects were a decreased intake of nutrients, decreased maternal weight gain, lowered plasma volume and stimulation of the renin-angiotensin-aldosterone system. A dietary sodium restriction in women with early symptoms of pregnancy-induced hypertension showed no therapeutic effect on blood pressure. There is no place for dietary sodium restriction in the prevention or treatment of hypertension in pregnancy.

Review of the sodium fire experiments including sodium-concrete-reactions and summary of the results

International Nuclear Information System (INIS)

Cherdron, W.

1996-01-01

In the technical and design concept of containment systems of sodium cooled breeder reactors it has to be considered, that leakages in sodium pipes lead to sodium fires. The temperature and pressure rise caused by sodium fires makes it indispensable to analyse these accidents to be able to assess the safety of the whole system. Generally sodium leakages may lead to three different types of fires with different consequences. The main influences are the geometry of the leakage, shape, size, location, and the sodium conditions, such as temperature, flow rate and velocity. It must be also considered the reaction of sodium with surfaces like concrete. The paper gives an overview over all the sodium fire experiments performed in the FAUNA-facility (220 m 3 ) of the Forschungszentrum Karlsruhe in the years 1979 to 1993. The experimental program started with the investigation of pool fires on burning areas between 2 and 12 m 2 with up to 500 kg of Sodium. The experiments had been continued with 3 combined fires and 40 experiments on spray fires. 7 experiments on sodium-concrete reactions completed the program. (author)

Sodium fires and its extinguishment

International Nuclear Information System (INIS)

Mikhedov, V.G.

1979-01-01

The fire safety problems of NPP with sodium coolants in USSR are presented. The design of sodium reactors is made with premises with sodium coolants being hermetic and filled with nitrogen. Some engineering solutions of fire safety including design, elaboration and choice of construction and protection materials are presented. Some theoretical aspects of sodium burning are presented as well as methods of sodium fire extinguishing methods including the use of powder

Toxicology of plutonium-sodium

International Nuclear Information System (INIS)

Hackett, P.L.

1982-01-01

Scenarios for liquid-metal fast breeder reactor (LMFBR) accidents predict the loss of sodium coolant, with subsequent core melt-down and release of mixed sodium-fuel aerosols [Na-(PuU)O 2 ] into the environment. Studies in other laboratories demonstrated that mixed aerosols of Na 2 O-PuO 2 were more readily transported from the lung than PuO 2 aerosols. We therefore devised a continuous aerosol-generating system for animal exposures in which laser-generated fuel aerosols were swept through sodium vapor to form sodium-fuel aerosols. These fuel and sodium-fuel aerosols were compared with regard to their physicochemical properties and their biological behavior following inhalation studies in rats and dogs

Sodium sieving in children

NARCIS (Netherlands)

Rusthoven, Esther; Krediet, Raymond T.; Willems, Hans L.; Monnens, Leo A.; Schröder, Cornelis H.

2005-01-01

Sodium sieving is a consequence of dissociation between the amount of water and sodium transported over the peritoneal membrane. This dissociation occurs in the presence of aquaporin-mediated water transport. Sieving of sodium can be used as a rough measure for aquaporin-mediated water transport.

Investigation for the sodium leak in Monju. Sodium leak and fire test-1

International Nuclear Information System (INIS)

Kawata, Koji; Ohno, Shuji; Miyahara, Shinya; Miyake, Osamu; Tanabe, Hiromi

2000-08-01

As a part of the work for investigating the sodium leak accident which occurred in the Monju reactor (hereinafter referred to as Monju) on December 8, 1995, three tests, (1) a sodium leak test, (2) a sodium leak and fire test-1, and (3) a sodium leak and fire test-II, were carried out at OEC/PEC. The main objectives of these tests were to confirm the leak and burning behavior of sodium from the damaged thermometer, and the effects of the sodium fire on the integrity of the surrounding structure. This report describes the results of the sodium fire test-I carried out as a preliminary test. The test was performed using the SOLFA-2 (Sodium Leak, Fire and Aerosol) facility on April 8, 1996. In this test, sodium heated to 480degC was leaked for approximately 1.5 hours from a leak simulating apparatus and caused to drop onto a ventilation duct and a grating with the same dimensions and layout as those in Monju. The main conclusions obtained from the test are shown below: 1) Observation from video cameras in the test revealed that in the early stages of the sodium leak, sodium dripped out of the flexible tube of the thermometer. This dripping and burning expanded in range as the sodium splashed on the duct. 2) No damage to the duct itself was detected. However, the aluminum louver frame of the ventilation duct's lower inlet was damaged. Its machine screws came off, leaving half of the grill (on the grating side) detached. 3) No large hole, like the one seen at Monju, was found when the grating was removed from the testing system for inspection, although the area centered on the point were the sodium dripped was damaged in a way indicating the first stages of grating failure. The 5mm square lattice was corroded through in some parts, and numerous blades (originally 3.2 mm thick) had become sharpened like the blade of a knife. 4) The burning pan underside thermocouple near the leak point measured 700degC in within approximately 10 minutes, and for the next hour remained

A Patient with MSUD: Acute Management with Sodium Phenylacetate/Sodium Benzoate and Sodium Phenylbutyrate

OpenAIRE

K?se, Melis; Canda, Ebru; Kagnici, Mehtap; U?ar, Sema Kalkan; ?oker, Mahmut

2017-01-01

In treatment of metabolic imbalances caused by maple syrup urine disease (MSUD), peritoneal dialysis, and hemofiltration, pharmacological treatments for elimination of toxic metabolites can be used in addition to basic dietary modifications. Therapy with sodium phenylacetate/benzoate or sodium phenylbutyrate (NaPB) in urea-cycle disorder cases has been associated with a reduction in branched-chain amino acid (BCAA) concentrations when the patients are on adequate dietary protein intake. Moreo...

Sodium-NaK engineering handbook. Volume III. Sodium systems, safety, handling, and instrumentation. [LMFBR

Energy Technology Data Exchange (ETDEWEB)

Foust, O J [ed.

1978-01-01

The handbook is intended for use by present and future designers in the Liquid Metals Fast Breeder Reactor (LMFBR) Program and by the engineering and scientific community performing other type investigation and exprimentation requiring high-temperature sodium and NaK technology. The arrangement of subject matter progresses from a technological discussion of sodium and sodium--potassium alloy (NaK) to discussions of varius categories and uses of hardware in sodium and NaK systems. Emphasis is placed on sodium and NaK as heat-transport media. Sufficient detail is included for basic understanding of sodium and NaK technology and of technical aspects of sodium and NaK components and instrument systems. Information presented is considered adequate for use in feasibility studies and conceptual design, sizing components and systems, developing preliminary component and system descriptions, identifying technological limitations and problem areas, and defining basic constraints and parameters.

Atmospheric dispersion of sodium aerosol due to a sodium leak in a fast breeder reactor complex

International Nuclear Information System (INIS)

Punitha, G.; Sudha, A. Jasmin; Kasinathan, N.; Rajan, M.

2008-01-01

Liquid sodium at high temperatures (470 K to 825 K) is used as the primary and secondary coolant in Liquid Metal cooled Fast Breeder Reactors (LMFBR). In the event of a postulated sodium leak in the Steam Generator Building (SGB) of a LMFBR, sodium readily combusts in the ambient air, especially at temperatures above 523 K. Intense sodium fire results and sodium oxide fumes are released as sodium aerosols. Sodium oxides are readily converted to sodium hydroxide in air due to the presence of moisture in it. Hence, sodium aerosols are invariably in the form of particulate sodium hydroxide. These aerosols damage not only the equipment and instruments due to their corrosive nature but also pose health hazard to humans. Hence, it is essential to estimate the concentration of sodium aerosols within the plant boundary for a sodium leak event. The Gaussian Plume Dispersion Model can obtain the atmospheric dispersion of sodium aerosols in an open terrain. However, this model dose not give accurate results for dispersion in spaces close to the point of release and with buildings in between. The velocity field due to the wind is altered to a large extent by the intervening buildings and structures. Therefore, a detailed 3-D estimation of the velocity field and concentration has to be obtained through rigorous computational fluid dynamics (CFD) approach. PHOENICS code has been employed to determine concentration of sodium aerosols at various distances from the point of release. The dispersion studies have been carried out for the release of sodium aerosols at different elevations from the ground and for different wind directions. (author)

Sodium intake and dietary sources of sodium in a sample of undergraduate students from Novi Sad, Serbia.

Science.gov (United States)

2017-07-01

Data on sodium intake and sources of sodium in the diet in Serbia are limited. The aim of this study was to estimate the sodium intake and identify the sources of sodium in the diet of undergraduate students attending the University of Novi Sad. Students completed a questionnaire to gather data on their gender, age and university faculty attended, and then a 24 h dietary recall. The sodium intake of the students was calculated using the dietary recall data and data on the sodium content of foods. The contribution of different food groups as well as of specific foodstuffs to the total sodium intake was calculated. The mean estimated sodium intake of the students was 3,938.5 ± 1,708.1 mg/day. The sodium intake of 89.1% of the surveyed students exceeded the guideline for sodium intake, the majority of the sodium coming from processed foods (78.9% of the total sodium intake). The food groups that contributed the most to the total sodium intake of the students were meat and meat products (21.7%) and cereals and cereal-based products (18.6%). Bread and other bakery products were responsible for 13.1% of the total sodium intake. High sodium intake in students of the University of Novi Sad puts them at high risk of developing high blood pressure. The food industry should work towards reformulating products with high sodium content, especially bread and other bakery products. Efforts should be taken to reduce sodium intake among undergraduate students in Novi Sad.

Technology for sodium purity control

Energy Technology Data Exchange (ETDEWEB)

Jeong, Ji Young; Kim, B. H.; Kim, T. J. [Korea Atomic Energy Research Institute, Taejon (Korea)

1999-10-01

When sodium is used as heat transfer fluid, the plugging in coolant flow, the corrosion of structure material and the transfer of radioactive material caused by the impurities in sodium are worth considerable. Accordingly, these impurities must be monitored and controlled continuously by sodium purification devices in the heat transfer system which sodium is used as coolant. Sodium purification loop was constructed for the purpose of accumulating the technology for purity control of the coolant, developing and verifying further efficient instruments for sodium purification. The plugging meter and the cold trap is used as the implement for measuring and controlling the oxygen and the hydrogen, the main impurities in sodium coolant. They are capable of excellent performance as the implements which could detect and monitor the impurities to the concentration limit required for nuclear reactor. Sodium purification loop could be used variably according to the experimental purpose. 18 refs., 34 figs., 8 tabs. (Author)

Naproxen sodium overdose

Science.gov (United States)

... page: //medlineplus.gov/ency/article/002507.htm Naproxen sodium overdose To use the sharing features on this page, please enable JavaScript. Naproxen sodium is a nonsteroidal anti-inflammatory drug (NSAID) used ...

Sodium fire suppression

International Nuclear Information System (INIS)

Malet, J.C.

1979-01-01

Ignition and combustion studies have provided valuable data and guidelines for sodium fire suppression research. The primary necessity is to isolate the oxidant from the fuel, rather than to attempt to cool the sodium below its ignition temperature. Work along these lines has led to the development of smothering tank systems and a dry extinguishing powder. Based on the results obtained, the implementation of these techniques is discussed with regard to sodium fire suppression in the Super-Phenix reactor. (author)

Sodium fire suppression

Energy Technology Data Exchange (ETDEWEB)

Malet, J C [DSN/SESTR, Centre de Cadarache, Saint-Paul-lez-Durance (France)

1979-03-01

Ignition and combustion studies have provided valuable data and guidelines for sodium fire suppression research. The primary necessity is to isolate the oxidant from the fuel, rather than to attempt to cool the sodium below its ignition temperature. Work along these lines has led to the development of smothering tank systems and a dry extinguishing powder. Based on the results obtained, the implementation of these techniques is discussed with regard to sodium fire suppression in the Super-Phenix reactor. (author)

Effect of histidine on sorafenib-induced vascular damage: Analysis using novel medaka fish model.

Science.gov (United States)

Shinagawa-Kobayashi, Yoko; Kamimura, Kenya; Goto, Ryo; Ogawa, Kohei; Inoue, Ryosuke; Yokoo, Takeshi; Sakai, Norihiro; Nagoya, Takuro; Sakamaki, Akira; Abe, Satoshi; Sugitani, Soichi; Yanagi, Masahiko; Fujisawa, Koichi; Nozawa, Yoshizu; Koyama, Naoto; Nishina, Hiroshi; Furutani-Seiki, Makoto; Sakaida, Isao; Terai, Shuji

2018-02-05

Sorafenib (SFN) is an anti-angiogenic chemotherapeutic that prolongs survival of patients with hepatocellular carcinoma (HCC); its side effects, including vascular damages such as hand-foot syndrome (HFS), are a major cause of therapy discontinuation. We previously reported that maintenance of peripheral blood flow by intake of dried bonito broth (DBB) significantly prevented HFS and prolonged the administration period. The amino acids contained in DBB probably contribute to its effects, but the mechanism has not been clarified. We hypothesized that histidine, the largest component among the amino acids contained in DBB, has effects on SFN-induced vascular damage, and evaluated this possibility using a novel medaka fish model. The fli::GFP transgenic medaka fish model has a fluorescently visible systemic vasculature. We fed the fish with SFN with and without histidine to compare blood flow and vascular structure among the differently fed models. The vascular cross-sectional area of each fish was measured to determine vascular diameter changes. Our results demonstrated that SFN-fed medaka developed a narrower vascular diameter. In addition, this narrowing was counteracted by addition of histidine to the medaka diet. We observed no positive effect of histidine on regeneration of cut vessels or on cell growth of endothelial cells and HCC cell lines. We proved the efficacy of the medaka model to assess vascular changes after administration of specific chemicals. And our results suggest that SFN causes vascular damage by narrowing peripheral vessel diameter, and that histidine effectively counteracts these changes to maintain blood flow. Copyright © 2018 Elsevier Inc. All rights reserved.

Sodium hydroxide poisoning

Science.gov (United States)

Sodium hydroxide is a very strong chemical. It is also known as lye and caustic soda. This ... poisoning from touching, breathing in (inhaling), or swallowing sodium hydroxide. This article is for information only. Do ...

Assessment of sodium status in large ruminants by measuring the sodium-to-potassium ratio in muzzle secretions.

Science.gov (United States)

Singh, S P; Rani, D

1999-09-01

To develop a simple diagnostic test to assess sodium status in large ruminants on the basis of the sodium-to-potassium ratio (Na:K) and to determine its relevance. 7 buffalo heifers and 21 lactating, pregnant, and nonpregnant dairy cows and heifers. Buffalo heifers were subjected in 2 experiments to variable dietary sodium intake or sodium depletion and changes in sodium and potassium concentrations; Na:K was simultaneously monitored in various body fluids to study its value for indicating sodium status. Validity of the muzzle secretion test was assessed. Muzzle secretion and urinary Na:K and sodium concentration, but not serum electrolyte concentrations, reflected the sodium status of buffalo heifers in response to the widely variable intake of sodium (0.03 to 0.16% of dry matter [DM]). Progressive sodium depletion during an 11-day period, using saliva deprivation caused reciprocal changes in sodium and potassium concentrations in saliva and muzzle secretion, but not in urine. Decreasing urine sodium concentration was associated with decreasing urine potassium concentration. Saliva, urine, and muzzle secretion Na:K closely reflected the degree of sodium deficit. Buffaloes or dairy cows maintained on optimal sodium intake had muzzle secretion and urine Na:K > 0.30. Muzzle secretion or urine Na:K muzzle secretion Na:K, and to a large extent urine Na:K, may be used as a convenient diagnostic tool to assess sodium status in large ruminants. It has accuracy similar to that of saliva Na:K.

Sodium fill of FFTF

International Nuclear Information System (INIS)

Waldo, J.B.; Greenwell, R.K.; Keasling, T.A.; Collins, J.R.; Klos, D.B.

1980-02-01

With construction of the Fast Flux Test Facility (FFTF) completed, the first major objective in the startup program was to fill the sodium systems. A sodium fill sequence was developed to match construction completion, and as systems became available, they were inerted, preheated, and filled with sodium. The secondary sodium systems were filled first while dry refueling system testing was in progress in the reactor vessel. The reactor vessel and the primary loops were filled last. This paper describes the methods used and some of the key results achieved for this major FFTF objective

Fires of sodium installations

International Nuclear Information System (INIS)

Hajek, L.; Tlalka, R.

1984-01-01

A survey is presented of the literature dealing with fires of sodium installations between 1974 and 1981. Also described are three experimental fires of ca 50 kg of sodium in an open area, monitored by UJV Rez. The experimental conditions of the experiments are described and a phenomenological description is presented of the course of the fires. The experiments showed a relationship between wind velocity in the area surrounding the fire and surface temperature of the sodium flame. Systems analysis methods were applied to sodium area, spray and tube fires. (author)

Enteric-coated mycophenolate sodium.

Science.gov (United States)

Gabardi, Steven; Tran, Jennifer L; Clarkson, Michael R

2003-11-01

To review the pharmacology, pharmacokinetics, efficacy, and safety of mycophenolate sodium. Primary literature was obtained via a MEDLINE search (1966-June 2003). Abstracts were obtained from the manufacturer and included in the analysis. All studies and abstracts evaluating mycophenolate sodium in solid organ transplantation were considered for inclusion. English-language studies and abstracts were selected for inclusion, but were limited to those consisting of human subjects. Mycophenolate sodium, a mycophenolic acid prodrug, is an inhibitor of T-lymphocyte proliferation. Mycophenolic acid reduces the incidence of acute rejection in renal transplantation. Mycophenolate sodium is enteric coated and has been suggested as a potential method to reduce the gastrointestinal adverse events seen with mycophenolate mofetil. Both mycophenolate mofetil and mycophenolate sodium have been shown to be therapeutically equivalent at decreasing the incidence of allograft rejection and loss. The frequency of adverse events is similar between both compounds, with the most common events being diarrhea and leukopenia. Mycophenolate sodium is effective in preventing acute rejection in renal transplant recipients. At doses of 720 mg twice daily, the efficacy and safety profiles are similar to those of mycophenolate mofetil 1000 mg twice daily. Mycophenolate sodium has been approved in Switzerland; approval in the US is pending.

The various sodium purification techniques

International Nuclear Information System (INIS)

Courouau, J.L.; Masse, F.; Rodriguez, G.; Latge, C.; Redon, B.

1997-01-01

In the framework of sodium waste treatment, the sodium purification phase plays an essential role in the chain of operations leading to the transformation of the active sodium, considered as waste, into a stable sodium salt. The objectives of the purification operations are: To keep a low impurity level, particularly a low concentration in oxygen and hydrogen, in order to allow its transfer to a processing plant, and in order to avoid risks of plugging and/or corrosion in sodium facilities; To reduce the sodium activity in order to limit the dose rate close to the facilities, and in order to reduce the activity of the liquid and gaseous effluents. After a recall of the different kind of impurities that can be present in sodium, and of the different purification methods that could be associated with, the following points are highlighted: (i) Oxygen and hydrogen purification needs, and presentation of some selection criteria for a purification unit adapted to a sodium processing plant, as well as 2 cold trap concepts that are in accordance with these criteria: PSICHOS and PIRAMIDE. (ii) Tritium reduction in a bulk of liquid sodium by swamping, isotopic exchange, or permeation throughout a membrane. (iii) Caesium trapping on carbonaceous matrix. The main matrices used at present are R.V.C. (Reticulated Vitreous Carbon) and Actitex/Pica products. Tests in the laboratory and on an experimental device have demonstrated the performances of these materials, which are able to reduce sodium activity in Cs 134 and Cs 137 to very low values. The sodium purification processes as regards to the hydrogen, oxygen and caesium, that are aimed at facilitating the subsequent treatment of sodium, are therefore mastered operations. Regarding the operations associated with the reduction of the tritium activity, the methods are in the process of being qualified, or to be qualified. (author)

Sodium carbonate poisoning

Science.gov (United States)

Sodium carbonate (known as washing soda or soda ash) is a chemical found in many household and industrial products. This article focuses on poisoning due to sodium carbonate. This article is for information only. Do NOT ...

Sodium removal disassembly and examination of the Fermi secondary sodium pump

International Nuclear Information System (INIS)

Maffei, H.P.; Funk, C.W.; Ballif, J.L.

1974-01-01

The Fermi secondary pump is a centrifugal single stage design. The pump had been operated more than 42,000 hours between 450 and 800 0 F. Sodium was drained from the pump in 1973 and the system was back filled with carbon dioxide. The pump was fabricated for 2.25 Cr-1 Mo Croloy steel. Prior to cleaning the pump was inerted and heated with 150 0 F nitrogen using the pump casing as the containment vessel. The water-vapor-nitrogen process was used in three increasing stages of water concentration. The hydrogen concentration in the discharge line was followed as an indicator of the sodium-water reaction rate. Upon completion of the hydrogen evolution, the pump was rinsed several times with hot water. Six pounds of sodium were removed from the pump during a process cycle of 79 hours including rinsing. The maximum pump temperature recorded was 175 0 F with no variation exceeding 10 0 F. The hydrogen concentration in the effluent provided a very satisfactory index for control of the reaction by adjustment of the water-vapor concentration feed to the system. Rinsing effectiveness was limited by a pool of water in the volute that was not drainable with the available system hook up. Sodium and its compounds were removed from all internal surfaces that could be observed by the first stage of disassembly. All such surfaces were coated with a black deposit. Areas above the sodium liquid level were coated with a vermillion colored oxide. Sodium was found on the (1) threads of the impeller nut lock screw, (2) impeller nut-tapered shaft interface, and (3) vapor deposited sodium was found in the oil seal

Sodium-concrete reaction model development

International Nuclear Information System (INIS)

Nguyen, D.H.; Muhlestein, L.D.; Postma, A.K.

1982-07-01

Major observations have been formulated after reviewing test results for over 100 sodium-concrete reaction tests. The observations form the basis for developing a mechanistic model to predict the transient behavior of sodium-concrete reactions. The major observations are listed. Mechanisms associated with sodium and water transport to the reaction zone are identified, and represented by appropriate mathematical expressions. The model attempts to explain large-scale, long-term (100 h) test results were sodium-concrete reactions terminated even in the presence of unreacted sodium and concrete

Sodium cleaning from sodium contaminated components and operation for experimental equipment

Energy Technology Data Exchange (ETDEWEB)

Kim, B. H.; Kim, J. M.; Kim, T. J.; Nam, H. Y.; Jeong, J. Y.; Choi, B. H.; Choi, J. H

2007-11-15

An objective of washing technology development for sodium contaminated equipment is to clean and reuse safely and effectively the used equipment through a washing and maintenance, and recovery of the sodium wastes generated during washing.

Specialists' meeting on sodium fires

International Nuclear Information System (INIS)

Kozlov, F.A.; Kuznetsova, R.I.

1989-01-01

The four sessions of the meeting covered the following topics: 1. general approach to fast reactor safety, standards of fire safety, maximum design basis accidents for sodium leaks and fires, status of sodium fires in different countries; 2. physical and chemical processes during combustion of sodium and its interaction with structural and technological materials and methods for structural protection; 3. methods of sodium fires extinguishing and measures for localizing aerosol combustion products, organization of fire fighting procedures, instruction and training of fire personnel; 4. elimination of the consequences of sodium fires

Specialists' meeting on sodium fires

Energy Technology Data Exchange (ETDEWEB)

Kozlov, F A; Kuznetsova, R I [eds.

1989-07-01

The four sessions of the meeting covered the following topics: 1. general approach to fast reactor safety, standards of fire safety, maximum design basis accidents for sodium leaks and fires, status of sodium fires in different countries; 2. physical and chemical processes during combustion of sodium and its interaction with structural and technological materials and methods for structural protection; 3. methods of sodium fires extinguishing and measures for localizing aerosol combustion products, organization of fire fighting procedures, instruction and training of fire personnel; 4. elimination of the consequences of sodium fires.

Tables of thermodynamic properties of sodium

International Nuclear Information System (INIS)

Fink, J.K.

1982-06-01

The thermodynamic properties of saturated sodium, superheated sodium, and subcooled sodium are tabulated as a function of temperature. The temperature ranges are 380 to 2508 K for saturated sodium, 500 to 2500 K for subcooled sodium, and 400 to 1600 K for superheated sodium. Tabulated thermodynamic properties are enthalpy, heat capacity, pressure, entropy, density, instantaneous thermal expansion coefficient, compressibility, and thermal pressure coefficient. Tables are given in SI units and cgs units

Intelligent type sodium instrumentations for LMFR

International Nuclear Information System (INIS)

Daolong Chen

1996-01-01

The constructions and their performances of a lot of newly developed intelligent type sodium instrumentations that consist of the intelligent type sodium flowmeter, the intelligent type immersed sodium flowmeter, the intelligent type sodium manometer and the intelligent type sodium level gauge are described. The graduation characteristic equations for corresponding transducer using the medium temperature as the parameter are given. Because the operating temperature limit of measured medium (sodium) is wide, so the on-line compensation of the temperature effect of their graduation characteristics much be considered. The tests show that these intelligent type sodium instrumentations possess of good linearity. The accurate sodium process parameter (flowrate, pressure and level) measurement data can be obtained by means of their on-line compensation function of the temperature effect. Moreover, these intelligent type sodium instrumentations possess of the self-inspection, the electric shutoff protection, the setting of full-scale, the setting of alarm limits (two upper limits and two lower limits alarms), the thermocouple breaking alarm, each other isolative the 0-10V direct-current analogue output and CENTRONICS standard digital output, and the alarm relay contact output. These intelligent type sodium instrumentations are suitable particularly for the instrument, control and protective systems of LMFR by means of these excellent functions based on microprocessor. The basic error of the intelligent type sodium flowmeter, immersed sodium flowmeter, sodium manometer and sodium level gauge is respectively ±2%, ±2.3%, ±0.3% and ±1.9% of measuring range. (author). 4 refs, 9 figs

Intravitreal flomoxef sodium in rabbits.

Science.gov (United States)

Mochizuki, K; Torisaki, M; Yamashita, Y; Komatsu, M; Tanahashi, T

1993-01-01

We studied the intraocular concentration of flomoxef sodium in nonvitrectomized and vitrectomized eyes of albino rabbits after intravenous administration of 100 mg/kg flomoxef sodium. The concentration of flomoxef sodium in the vitreous body was undetectable (flomoxef sodium was investigated with ophthalmoscopy, electroretinography (ERG) and light microscopy after intravitreal injection of 200, 500, 1,000 and 2,000 micrograms flomoxef sodium in albino and pigmented rabbits. No ERG changes were induced with 200 micrograms. Other higher doses caused transient ERG changes. After the 200-micrograms injection, the intravitreal concentration decreased exponentially, the half-life being 4.4 h. The antibacterial activity, broad coverage and low intravitreal toxicity of flomoxef sodium suggest that this compound may be used to treat bacterial endophthalmitis.

Sodium outleakage detection

International Nuclear Information System (INIS)

Casselman, C.

1979-01-01

Effective detection of outleakage from sodium facilities permits timely intervention capable of limiting the consequences of such leakage. Two types of detection systems are described: local and overall detection. The use of two independent systems in sodium facilities is recommended. (author)

Effects of low sodium diet versus high sodium diet on blood pressure, renin, aldosterone, catecholamines, cholesterol, and triglyceride

DEFF Research Database (Denmark)

Graudal, Niels Albert; Hubeck-Graudal, Thorbjorn; Jurgens, Gesche

2017-01-01

Background: In spite of more than 100 years of investigations the question of whether a reduced sodium intake improves health is still unsolved. Objectives: To estimate the effects of low sodium intake versus high sodium intake on systolic and diastolic blood pressure (SBP and DBP), plasma or serum...... results: A total of 185 studies were included. The average sodium intake was reduced from 201 mmol/day (corresponding to high usual level) to 66 mmol/day (corresponding to the recommended level). The effect of sodium reduction on blood pressure (BP) was as follows: white people with normotension: SBP.......0005) and triglyceride (P sodium intake as compared with high sodium intake. All effects were stable in 125 study populations with a sodium intake below 250 mmol/day and a sodium reduction intervention of at least one week. Authors' conclusions: Sodium reduction from an average high usual sodium...

Are Reductions in Population Sodium Intake Achievable?

Directory of Open Access Journals (Sweden)

Jessica L. Levings

2014-10-01

Full Text Available The vast majority of Americans consume too much sodium, primarily from packaged and restaurant foods. The evidence linking sodium intake with direct health outcomes indicates a positive relationship between higher levels of sodium intake and cardiovascular disease risk, consistent with the relationship between sodium intake and blood pressure. Despite communication and educational efforts focused on lowering sodium intake over the last three decades data suggest average US sodium intake has remained remarkably elevated, leading some to argue that current sodium guidelines are unattainable. The IOM in 2010 recommended gradual reductions in the sodium content of packaged and restaurant foods as a primary strategy to reduce US sodium intake, and research since that time suggests gradual, downward shifts in mean population sodium intake are achievable and can move the population toward current sodium intake guidelines. The current paper reviews recent evidence indicating: (1 significant reductions in mean population sodium intake can be achieved with gradual sodium reduction in the food supply, (2 gradual sodium reduction in certain cases can be achieved without a noticeable change in taste or consumption of specific products, and (3 lowering mean population sodium intake can move us toward meeting the current individual guidelines for sodium intake.

Gateways to clinical trials.

Science.gov (United States)

Bayés, M; Rabasseda, X; Prous, J R

2005-04-01

Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Trials Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity. prous.com. This issue focuses on the following selection of drugs: ABX-IL-8, Acclaim, adalimumab, AGI-1067, alagebrium chloride, alemtuzumab, Alequel, Androgel, anti-IL-12 MAb, AOD-9604, aripiprazole, atomoxetine hydrochloride; Biphasic insulin aspart, bosentan, botulinum toxin type B, bovine lactoferrin, brivudine; Cantuzumab mertansine, CB-1954, CDB-4124, CEA-TRICOM, choriogonadotropin alfa, cilansetron, CpG-10101, CpG-7909, CTL-102, CTL-102/CB-1954; DAC:GRF, darbepoetin alfa, davanat-1, decitabine, del-1 Genemedicine, dexanabinol, dextofisopam, dnaJP1, dronedarone hydrochloride, dutasteride; Ecogramostim, eletriptan, emtricitabine, EPI-hNE-4, eplerenone, eplivanserin fumarate, erlotinib hydrochloride, ertapenem sodium, escitalopram oxalate, esomeprazole magnesium, etoricoxib, ezetimibe; Falecalcitriol, fingolimod hydrochloride; Gepirone hydrochloride; HBV-ISS, HSV-2 theracine, human insulin; Imatinib mesylate, Indiplon, insulin glargine, ISAtx-247; L612 HuMAb, levodopa/carbidopa/entacapone, lidocaine/prilocaine, LL-2113AD, lucinactant, LY-156735; Meclinertant, metelimumab, morphine hydrochloride, morphine-6-glucuronide; Natalizumab, nimotuzumab, NX-1207, NYVAC-HIV C; Omalizumab, onercept, osanetant; PABA, palosuran sulfate, parathyroid hormone (human recombinant), parecoxib sodium, PBI-1402, PCK-3145, peginterferon alfa-2a, peginterferon alfa-2b, peginterferon alfa-2b/ribavirin, pemetrexed disodium, pimecrolimus, PINC, pregabalin; Ramelteon, rasagiline mesilate, rasburicase, rimonabant hydrochloride, RO-0098557, rofecoxib, rosiglitazone maleate/metformin hydrochloride; Safinamide mesilate, SHL-749, sitaxsentan sodium, sparfosic acid, SprayGel, squalamine, St. John's Wort

Sodium distiller II

International Nuclear Information System (INIS)

Goncalves, A.C.; Castro, P.M. e; Torres, A.R.; Correa, S.M.

1990-01-01

A sodium distiller allows the evaluation of the sodium purity, contained in plants and circuits of Fast Reactors. The sodium distillers of the IEN Reactor's Department was developed initially as a prototype, for the testing of the distillation process and in a second step, as a equipment dedicated to attendance the operation of these circuits. This last one was build in stainless steel, with external heat, rotating crucible of nickel for four samples, purge system for pipe cleaning and a sight glass that permits the observation of the distillation during all the operation. The major advantage of this equipment is the short time to do a distillation operation, which permits its routine utilization. As a consequence of the development of the distillers and its auxiliary systems an important amount of new information was gathered concerning components and systems behaviour under high temperature, vacuum and sodium. (author)

Sodium intake in US ethnic subgroups and potential impact of a new sodium reduction technology: NHANES Dietary Modeling.

Science.gov (United States)

Fulgoni, Victor L; Agarwal, Sanjiv; Spence, Lisa; Samuel, Priscilla

2014-12-18

Because excessive dietary sodium intake is a major contributor to hypertension, a reduction in dietary sodium has been recommended for the US population. Using the National Health and Nutrition Examination Survey (NHANES) 2007-2010 data, we estimated current sodium intake in US population ethnic subgroups and modeled the potential impact of a new sodium reduction technology on sodium intake. NHANES 2007-2010 data were analyzed using The National Cancer Institute method to estimate usual intake in population subgroups. Potential impact of SODA-LO® Salt Microspheres sodium reduction technology on sodium intake was modeled using suggested sodium reductions of 20-30% in 953 foods and assuming various market penetrations. SAS 9.2, SUDAAN 11, and NHANES survey weights were used in all calculations with assessment across age, gender and ethnic groups. Current sodium intake across all population subgroups exceeds the Dietary Guidelines 2010 recommendations and has not changed during the last decade. However, sodium intake measured as a function of food intake has decreased significantly during the last decade for all ethnicities. "Grain Products" and "Meat, Poultry, Fish, & Mixtures" contribute about 2/3rd of total sodium intake. Sodium reduction, using SODA-LO® Salt Microspheres sodium reduction technology (with 100% market penetration) was estimated to be 185-323 mg/day or 6.3-8.4% of intake depending upon age, gender and ethnic group. Current sodium intake in US ethnic subgroups exceeds the recommendations and sodium reduction technologies could potentially help reduce dietary sodium intake among those groups.

Effects of dietary sodium on metabolites: the Dietary Approaches to Stop Hypertension (DASH)-Sodium Feeding Study.

Science.gov (United States)

Derkach, Andriy; Sampson, Joshua; Joseph, Justin; Playdon, Mary C; Stolzenberg-Solomon, Rachael Z

2017-10-01

Background: High sodium intake is known to increase blood pressure and is difficult to measure in epidemiologic studies. Objective: We examined the effect of sodium intake on metabolites within the DASH (Dietary Approaches to Stop Hypertension Trial)-Sodium Trial to further our understanding of the biological effects of sodium intake beyond blood pressure. Design: The DASH-Sodium Trial randomly assigned individuals to either the DASH diet (low in fat and high in protein, low-fat dairy, and fruits and vegetables) or a control diet for 12 wk. Participants within each diet arm received, in random order, diets containing high (150 nmol or 3450 mg), medium (100 nmol or 2300 mg), and low (50 nmol or 1150 mg) amounts of sodium for 30 d (crossover design). Fasting blood samples were collected at the end of each sodium intervention. We measured 531 identified plasma metabolites in 73 participants at the end of their high- and low-sodium interventions and in 46 participants at the end of their high- and medium-sodium interventions ( N = 119). We used linear mixed-effects regression to model the relation between each log-transformed metabolite and sodium intake. We also combined the resulting P values with Fisher's method to estimate the association between sodium intake and 38 metabolic pathways or groups. Results: Six pathways were associated with sodium intake at a Bonferroni-corrected threshold of 0.0013 (e.g., fatty acid, food component or plant, benzoate, γ-glutamyl amino acid, methionine, and tryptophan). Although 82 metabolites were associated with sodium intake at a false discovery rate ≤0.10, only 4-ethylphenylsufate, a xenobiotic related to benzoate metabolism, was significant at a Bonferroni-corrected threshold ( P Sodium intake is associated with changes in circulating metabolites, including gut microbial, tryptophan, plant component, and γ-glutamyl amino acid-related metabolites. This trial was registered at clinicaltrials.gov as NCT00000608. © 2017

Sodium and cover gas chemistry in the high temperature sodium facility

International Nuclear Information System (INIS)

McCown, J.J.; Duncan, H.C.

1976-01-01

The equipment and procedures used in following sodium and cover gas chemistry changes in the High Temperature Sodium Facility are presented. The methods of analysis and results obtained are given. Impurity trends which have been measured during the facility operations are discussed

Method of processing waste sodium

International Nuclear Information System (INIS)

Shimoyashiki, Shigehiro; Takahashi, Kazuo.

1982-01-01

Purpose: To enable safety store of waste sodium in the form of intermetallic compounds. Method: Waste sodium used in a reactor is mixed with molten metal under an inert gas atmosphere and resulted intermetallic compounds are stored in a closely sealed container to enable quasi-permanent safety store as inert compound. Used waste sodium particularly, waste sodium in the primary system containing radioactive substances is charged in a waste sodium melting tank having a heater on the side, the tank is evacuated by a vacuum pump and then sealed with gaseous argon supplied from a gaseous argon tank, and waste sodium is melted under heating. The temperature and the amount of the liquid are measured by a thermometer and a level meter respectively. While on the other hand, molten metal such as Sn, Pb and Zn having melting point above 300 0 C are charged in a metal melting tank and heated by a heater. The molten sodium and the molten metals are charged into a mixing tank and agitated to mix by an induction type agitator. Sodium vapors in the tank are collected by traps. The air in the tank is replaced with gaseous argon. The molten mixture is closely sealed in a drum can and cooled to solidify for safety storage. (Seki, T.)

Some techniques for sodium removal in CIAE

International Nuclear Information System (INIS)

Yuan Waimai; Ding Dejun; Guo Huanfang; Hong Shuzhang; Zhou Shuxia; Shen Fenyang; Yang Zhongmin; Xu Yongxing

1997-01-01

In this paper the experiment and application on sodium removal and sodium disposal are presented. Steam-nitrogen process was used in CIAE for cleaning cold traps, sodium vapor traps, a sodium tank. Atomized water-nitrogen process was used for cleaning dummy fuel assembly for CEFR and a sintered stainless steel filter. Sprinkle process was used for cleaning some tubes. Bultylcellosolve was used for cleaning sintered stainless steel filter and sodium flow measurement device. Ethanol alcohol was used for cleaning electromagnetic pump. Paraffin, transformer-oil or their mixture was used for cleaning sodium valves, a sodium vapor trap and sodium-potassium alloy absorber. A small sintered stainless steel filter was distillated in vacuum. A simple sodium disposal device has been served for several years in CIA.E. It can dispose about 10 Kg sodium each time and the disposal process is no-aerosol. It operates in open air for non-radioactive sodium. In recent years a small sodium cleaning plant has been built. It can use atomized water, steam or organic alcohol to removal of sodium. The LAVEL cleaning plant and SLAPSO cleaning plant were introduced from Italy. And CEFR preliminary design on sodium cleaning for spent fuel assembly and on sodium removal-decontamination for large reactor components is introduced. Vapour-nitrogen process is planned to use in them. (author)

Impact Of Sodium Oxalate, Sodium Aluminosilicate, and Gibbsite/Boehmite on ARP Filter Performance

Energy Technology Data Exchange (ETDEWEB)

Poirier, M. [Savannah River Site (SRS), Aiken, SC (United States). Savannah River National Lab. (SRNL); Burket, P. [Savannah River Site (SRS), Aiken, SC (United States). Savannah River National Lab. (SRNL)

2015-11-01

The Savannah River Site (SRS) is currently treating radioactive liquid waste with the Actinide Removal Process (ARP) and the Modular Caustic Side Solvent Extraction Unit (MCU). Recently, the low filter flux through the ARP of approximately 5 gallons per minute has limited the rate at which radioactive liquid waste can be treated. Salt Batch 6 had a lower processing rate and required frequent filter cleaning. Savannah River Remediation (SRR) has a desire to understand the causes of the low filter flux and to increase ARP/MCU throughput. SRR requested SRNL to conduct bench-scale filter tests to evaluate whether sodium oxalate, sodium aluminosilicate, or aluminum solids (i.e., gibbsite and boehmite) could be the cause of excessive fouling of the crossflow or secondary filter at ARP. The authors conducted the tests by preparing slurries containing 6.6 M sodium Salt Batch 6 supernate, 2.5 g MST/L slurry, and varying concentrations of sodium oxalate, sodium aluminosilicate, and aluminum solids, processing the slurry through a bench-scale filter unit that contains a crossflow primary filter and a dead-end secondary filter, and measuring filter flux and transmembrane pressure as a function of time. Among the conclusions drwn from this work are the following: (1) All of the tests showed some evidence of fouling the secondary filter. This fouling could be from fine particles passing through the crossflow filter. (2) The sodium oxalate-containing feeds behaved differently from the sodium aluminosilicate- and gibbsite/boehmite-containing feeds.

Slicing sodium from bakery products

NARCIS (Netherlands)

Noort, M.

2012-01-01

The need for sodium reduction in our diet is clear to consumers, dieticians and food manufacturers. As sodium concentration has a strengthening effect on gluten, sodium reduction decreases dough mixing tolerance, dough resistance and induces dough stickiness. In particular, the latter may cause

Containment Sodium Chemistry Models in MELCOR.

Energy Technology Data Exchange (ETDEWEB)

Louie, David [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Humphries, Larry L. [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Denman, Matthew R [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States)

2017-04-01

To meet regulatory needs for sodium fast reactors’ future development, including licensing requirements, Sandia National Laboratories is modernizing MELCOR, a severe accident analysis computer code developed for the U.S. Nuclear Regulatory Commission (NRC). Specifically, Sandia is modernizing MELCOR to include the capability to model sodium reactors. However, Sandia’s modernization effort primarily focuses on the containment response aspects of the sodium reactor accidents. Sandia began modernizing MELCOR in 2013 to allow a sodium coolant, rather than water, for conventional light water reactors. In the past three years, Sandia has been implementing the sodium chemistry containment models in CONTAIN-LMR, a legacy NRC code, into MELCOR. These chemistry models include spray fire, pool fire and atmosphere chemistry models. Only the first two chemistry models have been implemented though it is intended to implement all these models into MELCOR. A new package called “NAC” has been created to manage the sodium chemistry model more efficiently. In 2017 Sandia began validating the implemented models in MELCOR by simulating available experiments. The CONTAIN-LMR sodium models include sodium atmosphere chemistry and sodium-concrete interaction models. This paper presents sodium property models, the implemented models, implementation issues, and a path towards validation against existing experimental data.

Evolutionary primacy of sodium bioenergetics

Directory of Open Access Journals (Sweden)

Wolf Yuri I

2008-04-01

Full Text Available Abstract Background The F- and V-type ATPases are rotary molecular machines that couple translocation of protons or sodium ions across the membrane to the synthesis or hydrolysis of ATP. Both the F-type (found in most bacteria and eukaryotic mitochondria and chloroplasts and V-type (found in archaea, some bacteria, and eukaryotic vacuoles ATPases can translocate either protons or sodium ions. The prevalent proton-dependent ATPases are generally viewed as the primary form of the enzyme whereas the sodium-translocating ATPases of some prokaryotes are usually construed as an exotic adaptation to survival in extreme environments. Results We combine structural and phylogenetic analyses to clarify the evolutionary relation between the proton- and sodium-translocating ATPases. A comparison of the structures of the membrane-embedded oligomeric proteolipid rings of sodium-dependent F- and V-ATPases reveals nearly identical sets of amino acids involved in sodium binding. We show that the sodium-dependent ATPases are scattered among proton-dependent ATPases in both the F- and the V-branches of the phylogenetic tree. Conclusion Barring convergent emergence of the same set of ligands in several lineages, these findings indicate that the use of sodium gradient for ATP synthesis is the ancestral modality of membrane bioenergetics. Thus, a primitive, sodium-impermeable but proton-permeable cell membrane that harboured a set of sodium-transporting enzymes appears to have been the evolutionary predecessor of the more structurally demanding proton-tight membranes. The use of proton as the coupling ion appears to be a later innovation that emerged on several independent occasions. Reviewers This article was reviewed by J. Peter Gogarten, Martijn A. Huynen, and Igor B. Zhulin. For the full reviews, please go to the Reviewers' comments section.

Sodium fire test at broad ranges of temperature and oxygen concentration. 4. Low temperature sodium spray fire tests

International Nuclear Information System (INIS)

Kawata, Koji; Miyahara, Shinya

2005-08-01

Sodium spray fire tests at the initial sodium temperature of 250degC were conducted under the atmospheric conditions of air and 3% oxygen containing nitrogen to determine the sodium burning rate and the aerosol release fraction and compare them with the test results at the initial sodium temperature of 500degC in air atmosphere. In the tests, sodium was supplied using a commercial spray nozzle into a stainless steel vessel of 100 m 3 volume (SOLFA-2). The sodium burning rate was calculated from two independent methods: the consumption rate of oxygen in the vessel and the enthalpy change of vessel components during the test. The aerosol release fraction was determined from the comparison between the measured aerosol concentrations and the calculated ones by the ABC-INTG code. The main conclusions were as follows, (1) In air atmosphere, a) sodium droplets ignited instantaneously and the spray fire was observed, and b) the sodium burning rate was about 440 g-Na/s and the fraction of supplied sodium was about 70%. (2) In 3% oxygen containing nitrogen, a) ignition of sodium droplets was not observed, and b) the sodium burning rate was about 44 g-Na/s and the fraction of supplied sodium was less than 10%. (author)

Hemodialysis for near-fatal sodium phosphate toxicity in a child receiving sodium phosphate enemas.

Science.gov (United States)

Becknell, Brian; Smoyer, William E; O'Brien, Nicole F

2014-11-01

This study aimed to demonstrate the importance of considering hemodialysis as a treatment option in the management of sodium phosphate toxicity. This is a case report of a 4-year-old who presented to the emergency department with shock, decreased mental status, seizures, and tetany due to sodium phosphate toxicity from sodium phosphate enemas. Traditional management of hyperphosphatemia with aggressive hydration and diuretics was insufficient to reverse the hemodynamic and neurological abnormalities in this child. This is the first report of the use of hemodialysis in a child without preexisting renal failure for the successful management of near-fatal sodium phosphate toxicity. Hemodialysis can safely be used as an adjunctive therapy in sodium phosphate toxicity to rapidly reduce serum phosphate levels and increase serum calcium levels in children not responding to conventional management.

Sodium sampling and impurities determination

International Nuclear Information System (INIS)

Docekal, J.; Kovar, C.; Stuchlik, S.

1980-01-01

Samples may be obtained from tubes in-built in the sodium facility and further processed or they are taken into crucibles, stored and processed later. Another sampling method is a method involving vacuum distillation of sodium, thus concentrating impurities. Oxygen is determined by malgamation, distillation or vanadium balance methods. Hydrogen is determined by the metal diaphragm extraction, direct extraction or amalgamation methods. Carbon is determined using dry techniques involving burning a sodium sample at 1100 degC or using wet techniques by dissolving the sample with an acid. Trace amounts of metal impurities are determined after dissolving sodium in ethanol. The trace metals are concentrated and sodium excess is removed. (M.S.)

ELTA: Citatrademark: Sodium measurement

International Nuclear Information System (INIS)

Mauvais, O.

2002-01-01

ELTA is pleased to present its last model of Sodium analyzers: CITA 2340: Automatically controlled sodium meter, integrating more automation and performances results respecting costs and wastes reduction. (authors)

Improving the Corrosion Inhibitive Strength of Sodium Sulphite in Hydrogen Cyanide Solution Using Sodium Benzoate

OpenAIRE

Muhammed Olawale Hakeem AMUDA; Olusegun Olusoji SOREMEKUN; Olakunle Wasiu SUBAIR; Atinuke OLADOYE

2008-01-01

The improvement in the inhibitive strength of sodium sulphite on corrosion of mild steel in hydrogen cyanide by adding sodium benzoate in regulated volume was investigated using the fundamental weight loss measurement.500 ppm concentration inhibitive mixtures of sodium benzoate and sodium sulphite in three different volume ratios (5/15, 10/10, 15/5) were formulated and studied for corrosion rate in 200ml hydrogen cyanide fluid. Result obtained indicates that the corrosion rate of mild steel i...

Summary of HEDL sodium fire tests

International Nuclear Information System (INIS)

Hillard, R.K.

1978-10-01

The sodium fire test program and related studies at the Hanford Engineering Development Laboratory (HEDL) are described. The program is analytical and experimental in scope, with computer code development and experimental verification. Tests have ranged in size from gram quantity laboratory tests to 1600-kg sodium spills. The experimental work is performed in two facilities: the Large Sodium Fire Facility (LSFF) and the Containment Systems Test Facility (CSTF). Sodium fire extinguishment tests which verified the Fast Flux Test Facility (FFTF) secondary sodium fire protection system are described and related informaion on sodium burning rates and smoke release rates are correlated. The burning rates are compared to theoretical predictions based on heat and mass transfer analogy, with good agreement. Comparisons with the SOFIRE-II code are also made. Sodium combustion aerosol properties are defined as to chemical and physical nature, settling in closed vessels and effect of added water vapor. The HAA-3B aerosol behavior computer code is compared to tests in the 850-m 3 CSTF containment vessel. Sodium spray tests in the CSTF are compared with the SPRAY computer code. An air cleaning program is described, which has the objective of removing high mass concentration sodium combustion aerosols from vented cells and containment buildings. The aerosol mass holding capacity of commercial filters was measured and an aqueous scrubber system is described. The effects of sodium spills on cell structures were investigated, including water release from heated concrete, the reaction of sodium with concrete, the formation and spontaneous recombination of hydrogen, and the ability of steel cell liners to withstand large spills of high temperature sodium without leaking

Intelligent type sodium instrumentations for LMFBR

International Nuclear Information System (INIS)

Chen Daolong

1996-07-01

The constructions and performances of lots of newly developed intelligent type sodium instrumentations are described. The graduation characteristic equations for corresponding transducer using the medium temperature as the parameter are given. These intelligent type sodium instrumentations are possessed of good linearity. The accurate measurement data of sodium process parameters (flowrate, pressure and level) can be obtained by means of their on-line compensation function of the temperature effect. Moreover, these intelligent type sodium instrumentations are possessed of the self-inspection, the electric shutoff protection, the setting of full-scale, the setting of alarm limits (two upper limits and two lower limits alarms), the thermocouple breaking alarm, mutual isolative the 0∼10 V direct-current analogue output and the CENTRONICS standard digital output, and the alarm relay contact output. Theses intelligent type sodium instrumentations are suitable particularly for the instrument, control and protective systems of LMFBR by means of these excellent functions based on microprocessor. The basic errors of the intelligent type sodium flowmeter, immersed sodium flowmeter, sodium manometer and sodium level gauge are +-2%, +-2.3%, +-0.3% and +-1.9% of measuring ranges respectively. (9 figs.)

Safety measuring for sodium handling

Energy Technology Data Exchange (ETDEWEB)

Jeong, Ji Young; Jeong, K C; Kim, T J; Kim, B H; Choi, J H

2001-09-01

This is the report for the safety measures of sodium handling. These contents are prerequisites for the development of sodium technology and thus the workers participate in sodium handling and experiments have to know them perfectly. As an appendix, the relating parts of the laws are presented.

Urinary Sodium Excretion and Dietary Sources of Sodium Intake in Chinese Postmenopausal Women with Prehypertension

Science.gov (United States)

Liu, Zhao-min; Ho, Suzanne C.; Tang, Nelson; Chan, Ruth; Chen, Yu-ming; Woo, Jean

2014-01-01

Background Reducing salt intake in communities is one of the most effective and affordable public health strategies to prevent hypertension, stroke and renal disease. The present study aimed to determine the sodium intake in Hong Kong Chinese postmenopausal women and identify the major food sources contributing to sodium intake and urine excretion. Methods This was a cross-sectional study among 655 Chinese postmenopausal women with prehypertension who were screened for a randomized controlled trial. Data collection included 24 h urine collection for the measurement of sodium, potassium and creatinine, 3-day dietary records, anthropometric measures and questionnaire survey on demographic data and dietary habits. Results The average salt intake estimated from urinary excretion was 7.8±3.2 g/d with 82.1% women above WHO recommendation of 5 g/day. Food groups as soup (21.6%), rice and noodles (13.5%), baked cereals (12.3%), salted/preserved foods (10.8%), Chinese dim sum (10.2%) and sea foods (10.1%) were the major contributors of non-discretionary salt. Discretionary salt use in cooking made a modest contribution to overall intake. Vegetable and fruit intake, age, sodium intake from salted foods, sea foods and soup were the independent determinants of urinary sodium excretion. Conclusions Our data revealed a significant room for reduction of the sodium intake. Efforts to reduce sodium from diets in Hong Kong Chinese postmenopausal women should focus on both processed foods and discretionary salt during cooking. Sodium reduction in soup and increase in fruit intake would be potentially effective strategy for reducing sodium. PMID:25083775

21 CFR 522.460 - Cloprostenol sodium.

Science.gov (United States)

2010-04-01

... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Cloprostenol sodium. 522.460 Section 522.460 Food... Cloprostenol sodium. (a)(1) Specifications. Each milliliter of the aqueous solution contains 263 micrograms of cloprostenol sodium (equivalent to 250 micrograms of cloprostenol) in a sodium citrate, anhydrous citric acid...

Effect of sodium ascorbate and sodium nitrite on protein and lipid oxidation in dry fermented sausages.

Science.gov (United States)

Berardo, A; De Maere, H; Stavropoulou, D A; Rysman, T; Leroy, F; De Smet, S

2016-11-01

The effects of sodium nitrite and ascorbate on lipid and protein oxidation were studied during the ripening process of dry fermented sausages. Samples were taken at day 0, 2, 8, 14, 21 and 28 of ripening to assess lipid (malondialdehyde) and protein (carbonyls and sulfhydryl groups) oxidation. Sodium ascorbate and nitrite were separately able to reduce the formation of malondialdehyde. Their combined addition resulted in higher amounts of carbonyl compounds compared to their separate addition or the treatment without any of both compounds. Moreover, sodium nitrite limited the formation of γ-glutamic semialdehyde whereas sodium ascorbate showed a pro-oxidant effect. A loss of thiol groups was observed during ripening, which was not affected by the use of sodium ascorbate nor sodium nitrite. In conclusion, sodium nitrite and ascorbate affected protein and lipid oxidation in different manners. The possible pro-oxidant effect of their combined addition on carbonyl formation might influence the technological and sensory properties of these products. Copyright © 2016 Elsevier Ltd. All rights reserved.

Compared With Usual Sodium Intake, Low- and Excessive-Sodium Diets Are Associated With Increased Mortality

DEFF Research Database (Denmark)

Graudal, Niels; Jürgens, Gesche; Baslund, Bo

2014-01-01

BACKGROUND: The effect of sodium intake on population health remains controversial. The objective was to investigate the incidence of all-cause mortality (ACM) and cardiovascular disease events (CVDEs) in populations exposed to dietary intakes of low sodium (<115 mmol), usual sodium (low usual so...

Sodium vapour aerosol formation and sodium deposition current work within the United Kingdom

Energy Technology Data Exchange (ETDEWEB)

Hawtin, P [Chemical Engineering Division, Atomic Energy Research Establishment, Harwell, Didcot, Oxon (United Kingdom); Seed, G [Nuclear Power Company (Risley) Ltd, Risley, Warrington, Cheshire (United Kingdom)

1977-01-01

The significance to reactor operation of sodium transport through the cover gas of a sodium-cooled fast reactor and its subsequent deposition on cooled reactor surfaces is fully appreciated in the UK. A programme of work is therefore underway designed to understand the mechanism of sodium transport under these conditions. This paper described the work which has so far been completed, discussed the work presently in progress, and outlines future plans. (author)

Development of the immersed sodium flowmeter

International Nuclear Information System (INIS)

Chen Daolong

1994-09-01

An immersed sodium flowmeter of the range 3 m 3 /h is developed. It is a flowmeter of entire-sealed construction, it can be operated in sodium. Its construction, the theoretical calculation of the calibration characteristic and the pressure loss, the test facility and the calibration test are presented in detail. It analytical expression of the calibration characteristic in the temperature limit 200∼600 degree C and the error analysis are given. The basic error of this immersed sodium flowmeter is below +-2.3% of the measuring range. The immersed sodium flowmeter can be used to resolve the sodium flowrate measuring problems of the in-reactor component of LMFBR, for example, the flowrate measuring of the in-reactor sodium purification loop, the flowrate measuring of the immersed sodium pump and the flowrate measuring of the in-reactor test component

Methodology for sodium fire vulnerability assessment of sodium cooled fast reactor based on the Monte-Carlo principle

Energy Technology Data Exchange (ETDEWEB)

Song, Wei [Nuclear and Radiation Safety Center, P. O. Box 8088, Beijing (China); Wu, Yuanyu [ITER Organization, Route de Vinon-sur-Verdon, 13115 Saint-Paul-lès-Durance (France); Hu, Wenjun [China Institute of Atomic Energy, P. O. Box 275(34), Beijing (China); Zuo, Jiaxu, E-mail: zuojiaxu@chinansc.cn [Nuclear and Radiation Safety Center, P. O. Box 8088, Beijing (China)

2015-11-15

Highlights: • Monte-Carlo principle coupling with fire dynamic code is adopted to perform sodium fire vulnerability assessment. • The method can be used to calculate the failure probability of sodium fire scenarios. • A calculation example and results are given to illustrate the feasibility of the methodology. • Some critical parameters and experience are shared. - Abstract: Sodium fire is a typical and distinctive hazard in sodium cooled fast reactors, which is significant for nuclear safety. In this paper, a method of sodium fire vulnerability assessment based on the Monte-Carlo principle was introduced, which could be used to calculate the probabilities of every failure mode in sodium fire scenarios. After that, the sodium fire scenario vulnerability assessment of primary cold trap room of China Experimental Fast Reactor was performed to illustrate the feasibility of the methodology. The calculation result of the example shows that the conditional failure probability of key cable is 23.6% in the sodium fire scenario which is caused by continuous sodium leakage because of the isolation device failure, but the wall temperature, the room pressure and the aerosol discharge mass are all lower than the safety limits.

Methodology for sodium fire vulnerability assessment of sodium cooled fast reactor based on the Monte-Carlo principle

International Nuclear Information System (INIS)

Song, Wei; Wu, Yuanyu; Hu, Wenjun; Zuo, Jiaxu

2015-01-01

Highlights: • Monte-Carlo principle coupling with fire dynamic code is adopted to perform sodium fire vulnerability assessment. • The method can be used to calculate the failure probability of sodium fire scenarios. • A calculation example and results are given to illustrate the feasibility of the methodology. • Some critical parameters and experience are shared. - Abstract: Sodium fire is a typical and distinctive hazard in sodium cooled fast reactors, which is significant for nuclear safety. In this paper, a method of sodium fire vulnerability assessment based on the Monte-Carlo principle was introduced, which could be used to calculate the probabilities of every failure mode in sodium fire scenarios. After that, the sodium fire scenario vulnerability assessment of primary cold trap room of China Experimental Fast Reactor was performed to illustrate the feasibility of the methodology. The calculation result of the example shows that the conditional failure probability of key cable is 23.6% in the sodium fire scenario which is caused by continuous sodium leakage because of the isolation device failure, but the wall temperature, the room pressure and the aerosol discharge mass are all lower than the safety limits.

Annular sodium flowsensor

International Nuclear Information System (INIS)

Kaiser, W.C.; Brewer, J.; Forster, G.A.

1983-01-01

This paper describes a unique eddy-current type liquid sodium flowsensor, designed as a joint effort between Argonne National Laboratory and Kaman Instrumentation Corp. Test results are included for operation of the flowsensor mounted on a sodium test loop whose configuration simulates the actual operating conditions, except for the magnetic field of the ALIP

Sodium pumping: pump problems

International Nuclear Information System (INIS)

Guer, M.; Guiton, P.

Information on sodium pumps for LMFBR type reactors is presented concerning ring pump design, pool reactor pump design, secondary pumps, sodium bearings, swivel joints of the oscillating annulus, and thermal shock loads

Summary of HEDL sodium fire tests

International Nuclear Information System (INIS)

Hilliard, R.K.

1979-01-01

The sodium fire test program and related studies at the Hanford Engineering Development Laboratory (HEDL), covering the period from 1972 to 1978, are described. The program is analytical and experimental in scope, with computer code development and experimental verification. Tests have ranged in size from gram quantity laboratory tests to 1600-kg sodium spills. The experimental work is performed in two facilities: the Large Sodium Fire Facility (LSFF) and the Containment Systems Test Facility (CSTF). The facilities are described and the experimental results summarized. Sodium fire extinguishment tests which verified the Fast Flux Test Facility (FFTF) secondary sodium fire protection system are described and related information on sodium burning rates and smoke release rates are correlated. The burning rates are compared to theoretical predictions based on heat and mass transfer analogy, with good agreement. Comparisons with the SOFIRE-II code are also made. Sodium combustion aerosol properties are defined as to chemical and physical nature, settling in closed vessels and effect of added water vapor. The HAA-38 aerosol behaviour computer code is compared to tests in the 850-m 3 CSTF containment vessel. Sodium spray tests in the CSTF are compared with the SPRAY computer code. An air cleaning program is described, which has the objective of removing high mass concentration sodium combustion aerosols from vented cells and containment buildings. The aerosol mass holding capacity of commercial filters was measured and an aqueous scrubber system is described. The effects of sodium spills on cell structures were investigated, including water release from heated concrete, the reaction of sodium with concrete, the formation and spontaneous recombination of hydrogen, and the ability of steel cell liners to withstand large spills of high temperature sodium without leaking. (author)

Summary of HEDL sodium fire tests

Energy Technology Data Exchange (ETDEWEB)

Hilliard, R K [Hanford Engineering Development Laboratory, Richland, WA (United States)

1979-03-01

The sodium fire test program and related studies at the Hanford Engineering Development Laboratory (HEDL), covering the period from 1972 to 1978, are described. The program is analytical and experimental in scope, with computer code development and experimental verification. Tests have ranged in size from gram quantity laboratory tests to 1600-kg sodium spills. The experimental work is performed in two facilities: the Large Sodium Fire Facility (LSFF) and the Containment Systems Test Facility (CSTF). The facilities are described and the experimental results summarized. Sodium fire extinguishment tests which verified the Fast Flux Test Facility (FFTF) secondary sodium fire protection system are described and related information on sodium burning rates and smoke release rates are correlated. The burning rates are compared to theoretical predictions based on heat and mass transfer analogy, with good agreement. Comparisons with the SOFIRE-II code are also made. Sodium combustion aerosol properties are defined as to chemical and physical nature, settling in closed vessels and effect of added water vapor. The HAA-38 aerosol behaviour computer code is compared to tests in the 850-m{sup 3} CSTF containment vessel. Sodium spray tests in the CSTF are compared with the SPRAY computer code. An air cleaning program is described, which has the objective of removing high mass concentration sodium combustion aerosols from vented cells and containment buildings. The aerosol mass holding capacity of commercial filters was measured and an aqueous scrubber system is described. The effects of sodium spills on cell structures were investigated, including water release from heated concrete, the reaction of sodium with concrete, the formation and spontaneous recombination of hydrogen, and the ability of steel cell liners to withstand large spills of high temperature sodium without leaking. (author)

Sodium Ferric Gluconate Injection

Science.gov (United States)

Sodium ferric gluconate injection is used to treat iron-deficiency anemia (a lower than normal number of ... are also receiving the medication epoetin (Epogen, Procrit). Sodium ferric gluconate injection is in a class of ...

Thermal analysis experiment for elucidating sodium-water chemical reaction mechanism in steam generator of sodium-cooled fast reactor

International Nuclear Information System (INIS)

Kikuchi, Shin; Kurihara, Akikazu; Ohshima, Hiroyuki

2012-01-01

For the purpose of elucidating the mechanism of the sodium-water surface reaction in a steam generator of sodium-cooled fast reactors, kinetic study of the sodium (Na)-sodium hydroxide (NaOH) reaction has been carried out by using Differential Thermal Analysis (DTA) technique. The parameters, including melting points of Na and NaOH, phase transition temperature of NaOH, Na-NaOH reaction temperature, and decomposition temperature of sodium hydride (NaH) have been identified from DTA curves. Based on the measured reaction temperature, rate constant of sodium monoxide (Na 2 O) generation was obtained. Thermal analysis results indicated that Na 2 O generation at the secondary overall reaction should be considered during the sodium-water reaction. (author)

Nutritional impact of sodium reduction strategies on sodium intake from processed foods

NARCIS (Netherlands)

Hendriksen, M.A.H.; Verkaik-Kloosterman, J.; Noort, M.W.; Raaij, J.M.A. van

2015-01-01

Background/objectives: Sodium intake in the Netherlands is substantially above the recommended intake of 2400 mg/day. This study aimed to estimate the effect of two sodium reduction strategies, that is, modification of the composition of industrially processed foods toward the technologically

Nutritional impact of sodium reduction strategies on sodium intake from processed foods

NARCIS (Netherlands)

Hendriksen, M.A.H.; Verkaik-Kloosterman, J.; Noort, M.W.J.; Raaij, van J.M.A.

2015-01-01

Background/objectives: Sodium intake in the Netherlands is substantially above the recommended intake of 2400¿mg/day. This study aimed to estimate the effect of two sodium reduction strategies, that is, modification of the composition of industrially processed foods toward the technologically

An effective method to screen sodium-based layered materials for sodium ion batteries

Science.gov (United States)

Zhang, Xu; Zhang, Zihe; Yao, Sai; Chen, An; Zhao, Xudong; Zhou, Zhen

2018-03-01

Due to the high cost and insufficient resource of lithium, sodium-ion batteries are widely investigated for large-scale applications. Typically, insertion-type materials possess better cyclic stability than alloy-type and conversion-type ones. Therefore, in this work, we proposed a facile and effective method to screen sodium-based layered materials based on Materials Project database as potential candidate insertion-type materials for sodium ion batteries. The obtained Na-based layered materials contains 38 kinds of space group, which reveals that the credibility of our screening approach would not be affected by the space group. Then, some important indexes of the representative materials, including the average voltage, volume change and sodium ion mobility, were further studied by means of density functional theory computations. Some materials with extremely low volume changes and Na diffusion barriers are promising candidates for sodium ion batteries. We believe that our classification algorithm could also be used to search for other alkali and multivalent ion-based layered materials, to accelerate the development of battery materials.

The dismantling of fast reactors: sodium processing

International Nuclear Information System (INIS)

Rodriguez, G.; Berte, M.; Serpante, J.P.

1999-01-01

Fast reactors require a coolant that does not slow down neutrons so water can not be used. Metallic sodium has been chosen because of its outstanding neutronic and thermal properties but sodium reacts easily with air and water and this implies that sodium-smeary components can not be considered as usual nuclear wastes. A stage of sodium neutralizing is necessary in the processing of wastes from fast reactors. Metallic sodium is turned into a chemically stable compound: soda, carbonates or sodium salts. This article presents several methods used by Framatome in an industrial way when dismantling sodium-cooled reactors. (A.C.)

Friction and wear in sodium

International Nuclear Information System (INIS)

Hoffman, N.J.; Droher, J.J.

1973-01-01

In the design of a safe and reliable sodium-cooled reactor one of the more important problem areas is that of friction and wear of components immersed in liquid sodium or exposed to sodium vapor. Sodium coolant at elevated temperatures may severely affect most oxide-bearing surface layers which provide corrosion resistance and, to some extent, lubrication and surface hardness. Consequently, accelerated deterioration may be experienced on engaged-motion contact surfaces, which could result in unexpected reactor shutdown from component malfunction or failure due to galling and seizure. An overall view of the friction and wear phenomena encountered during oscillatory rubbing of surfaces in high-temperature, liquid-sodium environments is presented. Specific data generated at the Liquid Metal Engineering Center (LMEC) on this subject is also presented. (U.S.)

Sodium ionization detector and sensor

International Nuclear Information System (INIS)

Hrizo, J.; Bauerle, J.E.

1979-01-01

Work conducted on a basic technology development effort with the Westinghouse Sodium Ionization Detector (SID) sensor is reported. Included are results obtained for three task areas: (1) On-line operational response testing - in-situ calibration techniques; (2) Performance-reliability characteristics of aged filaments; and (3) Evaluation of chemical interference effects. The results showed that a calibrator filament coated with a sodium compound, when activated, does supply the necessary sodium atoms to provide a valid operational in-situ test. The life time of new Cr 2 0 3 -protected SID sensor filaments can be extended by operating at a reduced temperature. However, there also is a reduction in the sensitivity. Non-sodium species, such as products from a smoldering fire and organic aerosols, produce an interference response from the sensor comparable to a typical sodium response

Stakeholder discussion to reduce population-wide sodium intake and decrease sodium in the food supply: a conference report from the American Heart Association Sodium Conference 2013 Planning Group.

Science.gov (United States)

Antman, Elliott M; Appel, Lawrence J; Balentine, Douglas; Johnson, Rachel K; Steffen, Lyn M; Miller, Emily Ann; Pappas, Antigoni; Stitzel, Kimberly F; Vafiadis, Dorothea K; Whitsel, Laurie

2014-06-24

A 2-day interactive forum was convened to discuss the current status and future implications of reducing sodium in the food supply and to identify opportunities for stakeholder collaboration. Participants included 128 stakeholders engaged in food research and development, food manufacturing and retail, restaurant and food service operations, regulatory and legislative activities, public health initiatives, healthcare, academia and scientific research, and data monitoring and surveillance. Presentation topics included scientific evidence for sodium reduction and public health policy recommendations; consumer sodium intakes, attitudes, and behaviors; food technologies and solutions for sodium reduction and sensory implications; experiences of the food and dining industries; and translation and implementation of sodium intake recommendations. Facilitated breakout sessions were conducted to allow for sharing of current practices, insights, and expertise. A well-established body of scientific research shows that there is a strong relationship between excess sodium intake and high blood pressure and other adverse health outcomes. With Americans getting >75% of their sodium from processed and restaurant food, this evidence creates mounting pressure for less sodium in the food supply. The reduction of sodium in the food supply is a complex issue that involves multiple stakeholders. The success of new technological approaches for reducing sodium will depend on product availability, health effects (both intended and unintended), research and development investments, quality and taste of reformulated foods, supply chain management, operational modifications, consumer acceptance, and cost. The conference facilitated an exchange of ideas and set the stage for potential collaboration opportunities among stakeholders with mutual interest in reducing sodium in the food supply and in Americans' diets. Population-wide sodium reduction remains a critically important component of

Methods in the treatment of sodium wastes

International Nuclear Information System (INIS)

Rodriguez, G.

1997-01-01

In the domain of sodium waste processing, we have followed a logical route that has enabled us to propose a global method with respect to sodium wastes. This approach has led to: The choice of only those sodium processes using water; The development of sodium purification methods; The development of methods for cutting metallic wastes soiled by or filled with sodium; The transformation of the resulting sodium hydroxide into ultimate solid wastes for surface storage. (author)

Sodium voiding analysis in Kalimer

International Nuclear Information System (INIS)

Chang, Won-Pyo; Jeong, Kwan-Seong; Hahn, Dohee

2001-01-01

A sodium boiling model has been developed for calculations of the void reactivity feedback as well as the fuel and cladding temperatures in the KALIMER core after onset of sodium boiling. The sodium boiling in liquid metal reactors using sodium as coolant should be modeled because of phenomenon difference observed from that in light water reactor systems. The developed model is a multiple -bubble slug ejection model. It allows a finite number of bubbles in a channel at any time. Voiding is assumed to result from formation of bubbles that fill the whole cross section of the coolant channel except for liquid film left on the cladding surface. The vapor pressure, currently, is assumed to be uniform within a bubble. The present study is focused on not only demonstration of the sodium voiding behavior predicted by the developed model, but also confirmation on qualitative acceptance for the model. In results, the model catches important phenomena for sodium boiling, while further effort should be made for the complete analysis. (author)

Sodium Fire Demonstration Facility Design and Operation

International Nuclear Information System (INIS)

Cho, Youngil; Kim, Jong-Man; Lee, Jewhan; Hong, Jonggan; Yeom, Sujin; Cho, Chungho; Jung, Min-Hwan; Gam, Da-Young; Jeong, Ji-Young

2014-01-01

Although sodium has good characteristics such as high heat transfer rate and stable nuclear property, it is difficult to manage because of high reactivity. Sodium is solid at the room temperature and it easily reacts with oxygen resulting in fire due to the reaction heat. Thus, sodium must be stored in a chemically stable place, i.e., an inert gas-sealed or oil filled vessel. When a sodium fire occurs, the Na 2 O of white fume is formed. It is mainly composed of Na 2 O 2 , NaOH, and Na 2 CO 3 , ranging from 0.1 to several tens of micrometers in size. It is known that the particle size increases by aggregation during floating in air. Thus, the protection method is important and should be considered in the design and operation of a sodium system. In this paper, sodium fire characteristics are described, and the demonstration utility of outbreak of sodium fire and its extinguishing is introduced. In this paper, sodium fire characteristics and a demonstration facility are described. The introduced sodium fire demonstration facility is the only training device used to observe a sodium fire and extinguish it domestically. Furthermore, the type of sodium fire will be diversified with the enhancement of the utility. It is expected that this utility will contribute to experience in the safe treatment of sodium by the handlers

Sodium-carbonate co-substituted hydroxyapatite ceramics

Directory of Open Access Journals (Sweden)

Zoltan Z. Zyman

2013-12-01

Full Text Available Powders of sodium-carbonate co-substituted hydroxyapatite, having sodium content in the range of 0.25–1.5 wt.% with a 0.25 wt.% step, were prepared by a precipitation-solid state reaction route. Compacts of the powders were sintered in a CO2 flow (4 mL/min at 1100 °C for 2 h. The sintered ceramics contained sodium and carbonate ions in the ranges of 0–1.5 wt.% and 1.3–6 wt.%, respectively, which are typical impurity concentrations in biological apatite. A relationship between sodium and carbonate contents and the type of carbonate substitution was found. The total carbonate content progressively increased with the sodium content. The obtained ceramics showed an AB-type carbonate substitution. However, the substitution became more B-type as the sodium content increased. As a result, the carbonation was almost B-type (94 % for the highest sodium content (1.5 wt.%.

Combustion suppressing device for leaked sodium

International Nuclear Information System (INIS)

Ooto, Akihiro.

1985-01-01

Purpose: To suppress the atmospheric temperature to secure the building safety and shorten the recovery time after the leakage in a chamber for containing sodium leaked from coolant circuit equipments or pipeways of LMFBR type rector by suppressing the combustion of sodium contained in the chamber. Constitution: To the inner wall of a chamber for containing sodium handling equipments, are vertically disposed a panel having a coolant supply port at the upper portion and a coolant discharge port at the lower portion thereof and defined with a coolant flowing channel and a panel for sucking the coolant discharged from the abovementioned panel and exhausting the same externally. Further, a corrugated combustion suppressing plate having apertures for draining the condensated leaked sodium is disposed near the sodium handling equipments. If ruptures are resulted to the sodium handling equipments or pipeway, leaked sodium is passed through the drain apertures in the suppressing plate and stored at the bottom of the containing chamber. (Horiuchi, T.)

21 CFR 172.822 - Sodium lauryl sulfate.

Science.gov (United States)

2010-04-01

... 21 Food and Drugs 3 2010-04-01 2009-04-01 true Sodium lauryl sulfate. 172.822 Section 172.822 Food... Multipurpose Additives § 172.822 Sodium lauryl sulfate. The food additive sodium lauryl sulfate may be safely... specifications: (1) It is a mixture of sodium alkyl sulfates consisting chiefly of sodium lauryl sulfate [CH2(CH2...

Sodium setpoint and gradient in bicarbonate hemodialysis.

Science.gov (United States)

Basile, Carlo; Libutti, Pasquale; Lisi, Piero; Vernaglione, Luigi; Casucci, Francesco; Losurdo, Nicola; Teutonico, Annalisa; Lomonte, Carlo

2013-01-01

The demonstration of an individual osmolar setpoint in hemodialysis (HD) is crucial to individualize dialysate sodium concentrations. Furthermore, the diffusive gradient between plasma and dialysate sodium is important in the "fine tuning" of the intradialytic sodium mass balance (MB). The design of this study included part A: a retrospective analysis of predialysis plasma sodium concentrations extracted from a 6-year database in our HD population (147 prevalent white anuric patients); and part B: study of intradialytic sodium kinetics in 48 patients undergoing one 4-hour bicarbonate HD session. Direct potentiometry with an ion-selective electrode was used for sodium measurements. Study part A: the mean number of plasma sodium measurements per patient was 16.06 ± 14.03 over a mean follow-up of 3.55 ± 1.76 years. The mean of the averaged plasma sodium concentrations was 136.7 ± 2.1 mmol/L, with a low mean intraindividual coefficient of variation (1.39 ± 0.4). Study part B: mean predialysis and postdialysis plasma sodium concentrations were 135.8 ± 0.9 and 138.0 ± 0.9 mmol/L (p<0.001). Mean inlet dialyzer sodium concentration was 138.7 ± 1.1 mmol/L; the hourly diffusion concentration gradients showed a statistically significant transfer from dialysate to plasma (Wilks ? <0.0001). A statistically significant relationship was found between sodium MB and diffusion gradient (p<0.02), and between sodium MB and ultrafiltration volume (p<0.01). A relatively "fixed" and individual osmolar setpoint in HD patients was shown for the first time in a long-term follow-up. A dialysate sodium concentration of 140 mmol/L determined a dialysate to plasma sodium gradient.

Docusate Sodium and Pregnancy

Science.gov (United States)

... a risk of miscarriage. Can use of docusate sodium during pregnancy cause birth defects? Few studies have been done to look at the possible risks of docusate sodium during pregnancy. However, the available studies show that when used ...

Thermal performance tests on a sodium-to-sodium heat exchanger

International Nuclear Information System (INIS)

Prahlad, B.; Kale, R.D.; Rajan, K.K.

1990-01-01

Thermal performance of a 3 MW sodium-to-sodium intermediate heat exchanger (IHX) was evaluated under temperature conditions typical of a Fast Breeder Reactor IHX. A regenerative figure of eight loop was used with the heat exchanger at the cross over point, and a 500 kW heat source and an air cooled sink to maintain the desired test conditions. The overall heat transfer coefficient was found to vary from 4.02 to 4.87 kW/m 2 ·K for Peclet numbers varying from 37 to 112.5 on the shell side and 44.4 to 133.5 on the tube side respectively. The Peclet numbers were representative of low turbulent regime in this case. While the overall heat transfer coefficient was found close to predictions using Lubarsky's correlation, it was somewhat lower than that predicted by later correlations of Spukunsky and Borishansky. The reasons for the lower overall heat transfer coefficient have been explained in terms of possible maldistribution of shell side flow in low turbulent regime reducing the effective heat transfer area and increased thermal contact resistance. Based on their findings the authors feel that heat transfer in a sodium-to-sodium heat exchanger at low Peclet numbers is expected to differ from that obtained with large Peclet numbers. (author)

Selective sodium intercalation into sodium nickel-manganese sulfate for dual Na-Li-ion batteries.

Science.gov (United States)

Marinova, Delyana M; Kukeva, Rosica R; Zhecheva, Ekaterina N; Stoyanova, Radostina K

2018-04-26

Double sodium transition metal sulfates combine in themselves unique intercalation properties with eco-compatible compositions - a specific feature that makes them attractive electrode materials for lithium and sodium ion batteries. Herein, we examine the intercalation properties of novel double sodium nickel-manganese sulfate, Na2Ni1/2Mn1/2(SO4)2, having a large monoclinic unit cell, through electrochemical and ex situ diffraction and spectroscopic methods. The sulfate salt Na2Ni1/2Mn1/2(SO4)2 is prepared by thermal dehydration of the corresponding hydrate salt Na2Ni1/2Mn1/2(SO4)2·4H2O having a blödite structure. The intercalation reactions on Na2Ni1-xMnx(SO4)2 are studied in two model cells: half-ion cell versus Li metal anode and full-ion cell versus Li4Ti5O12 anode by using lithium (LiPF6 dissolved in EC/DMC) and sodium electrolytes (NaPF6 dissolved in EC:DEC). Based on ex situ XRD and TEM analysis, it is found that sodium intercalation into Na2Ni1/2Mn1/2(SO4)2 takes place via phase separation into the Ni-rich monoclinic phase and Mn-rich alluaudite phase. The redox reactions involving participation of manganese and titanium ions are monitored by ex situ EPR spectroscopy. It has been demonstrated that manganese ions from the sulfate salt are participating in the electrochemical reaction, while the nickel ions remain intact. As a result, a reversible capacity of about 65 mA h g-1 is reached. The selective intercalation properties determine sodium nickel-manganese sulfate as a new electrode material for hybrid lithium-sodium ion batteries that is thought to combine the advantages of individual lithium and sodium batteries.

Evaluation of steam-to-sodium leak detectors in the sodium components test installation (SCTI)

Energy Technology Data Exchange (ETDEWEB)

McKee, J M; Simmons, W R

1975-07-01

Two nickel diffusion-membrane type hydrogen detectors were installed in the secondary sodium system of the Sodium Components Test Installation and evaluated during the 12-month performance test of the Modular Steam Generator (MSG). Hydrogen in the expansion tank cover gas was monitored with a gas chromatograph. During this period, numerous steam and hydrogen injections were made, simulating steam leaks into the sodium of an LMFBR steam generator. The response of the detectors was evaluated for leak sizes ranging from 10{sup -6} to 10{sup -4} 1b H{sub 2}O/sec, injection periods of 0.5 to 300 min, secondary sodium flow rates of 0.2 x 10{sup 6} to 1.5 x 10{sup 6} 1b/hr, and sodium temperatures of 400 to 950 deg. F. The response of the leak detection system was influenced significantly by two regimes of sodium temperature. Below 600 deg. F, the cover gas hydrogen detector gave the largest response; this is attributed to the long dissolution time of hydrogen bubbles relative to the transit time of hydrogen to the expansion tank. Above 600 deg. F, the hydrogen apparently dissolved rapidly and the detectors were much more effective in the sodium than in the cover gas. At least 75% of the hydrogen and 50% of the oxygen content of injected steam appeared as detectable activity if the reaction products were dispersed in the sodium stream and the sodium was above 600 deg. F. Hydrogen injections into semi-stagnant sodium at the MSG tube sheets were detected with better sensitivity than steam injections into the main sodium stream. It appeared that high local concentrations of hydrogen were quickly carried to the nearest detector by upward currents created by the injected gas. The alarm system functioned as expected, 2.1 ppb/min being the smallest rate-of-rise in hydrogen concentration to give an automatic alarm. With more sensitive rate-of-rise alarm settings, leaks as small as 2 x 10{sup -5} 1b H{sub 2}O/sec could be detected in a system such as the Clinch River Breeder

Evaluation of steam-to-sodium leak detectors in the sodium components test installation (SCTI)

International Nuclear Information System (INIS)

McKee, J.M.; Simmons, W.R.

1975-01-01

Two nickel diffusion-membrane type hydrogen detectors were installed in the secondary sodium system of the Sodium Components Test Installation and evaluated during the 12-month performance test of the Modular Steam Generator (MSG). Hydrogen in the expansion tank cover gas was monitored with a gas chromatograph. During this period, numerous steam and hydrogen injections were made, simulating steam leaks into the sodium of an LMFBR steam generator. The response of the detectors was evaluated for leak sizes ranging from 10 -6 to 10 -4 1b H 2 O/sec, injection periods of 0.5 to 300 min, secondary sodium flow rates of 0.2 x 10 6 to 1.5 x 10 6 1b/hr, and sodium temperatures of 400 to 950 deg. F. The response of the leak detection system was influenced significantly by two regimes of sodium temperature. Below 600 deg. F, the cover gas hydrogen detector gave the largest response; this is attributed to the long dissolution time of hydrogen bubbles relative to the transit time of hydrogen to the expansion tank. Above 600 deg. F, the hydrogen apparently dissolved rapidly and the detectors were much more effective in the sodium than in the cover gas. At least 75% of the hydrogen and 50% of the oxygen content of injected steam appeared as detectable activity if the reaction products were dispersed in the sodium stream and the sodium was above 600 deg. F. Hydrogen injections into semi-stagnant sodium at the MSG tube sheets were detected with better sensitivity than steam injections into the main sodium stream. It appeared that high local concentrations of hydrogen were quickly carried to the nearest detector by upward currents created by the injected gas. The alarm system functioned as expected, 2.1 ppb/min being the smallest rate-of-rise in hydrogen concentration to give an automatic alarm. With more sensitive rate-of-rise alarm settings, leaks as small as 2 x 10 -5 1b H 2 O/sec could be detected in a system such as the Clinch River Breeder Reactor Plant. A preliminary

Environmental, health, and safety issues of sodium-sulfur batteries for electric and hybrid vehicles. Volume 3, Transport of sodium-sulfur and sodium-metal-chloride batteries

Energy Technology Data Exchange (ETDEWEB)

Hammel, C J

1992-09-01

This report examines the shipping regulations that govern the shipment of dangerous goods. Since the elemental sodium contained in both sodium-sulfur and sodium-metal-chloride batteries is classified as a dangerous good, and is listed on both the national and international hazardous materials listings, both national and international regulatory processes are considered in this report The interrelationships as well as the differences between the two processes are highlighted. It is important to note that the transport regulatory processes examined in this report are reviewed within the context of assessing the necessary steps needed to provide for the domestic and international transport of sodium-beta batteries. The need for such an assessment was determined by the Shipping Sub-Working Group (SSWG) of the EV Battery Readiness Working Group (Working Group), created in 1990. The Working Group was created to examine the regulatory issues pertaining to in-vehicle safety, shipping, and recycling of sodium-sulfur batteries, each of which is addressed by a sub-working group. The mission of the SSWG is to establish basic provisions that will ensure the safe and efficient transport of sodium-beta batteries. To support that end, a proposal to the UN Committee of Experts was prepared by the SSWG, with the goal of obtaining a proper shipping name and UN number for sodium-beta batteries and to establish the basic transport requirements for such batteries (see the appendix for the proposal as submitted). It is emphasized that because batteries are large articles containing elemental sodium and, in some cases, sulfur, there is no existing UN entry under which they can be classified and for which modal transport requirements, such as the use of packaging appropriate for such large articles, are provided for. It is for this reason that a specific UN entry for sodium-beta batteries is considered essential.

Instrumentation for Sodium Circuits; Instrumentation des Circuits de Sodium

Energy Technology Data Exchange (ETDEWEB)

Cambillard, E. [CEA, Centre d' Etudes Nucleaires de Fontenay-aux-Roses (France); Lions, N. [CEA, Centre d' Etudes Nucleaires de Cadarache (France)

1967-06-15

Electromagnetic flow meters, level gauges and differential pressure gauges are among the main measurement instruments designed and tested at the Commissariat a l'Energie Atomique (CEA) for sodium reactors. The main characteristics of the flow meters used with RAPSODIE are indicated. The instruments used in this connection are of the permanent -magnet or electromagnet type (in the primary circuits). A description is given of the calibration methods employed - use is made of diaphragms or Venturi tubes as standard flow meters - and information is given on the results measured for maximum sodium flows of 400 m{sup 3}/h. Three types of continuous level gauge have been studied. Resistance gauge. Two varieties used for the 1 - and 10-MW test circuits of RAPSODIE are described. In one there is a compensation resistance along the whole height of the measuring element (the continuous gauges used with the RAPSODIE reactor are at present of this type). In the other type of gauge a device is incorporated to heat the measurement element and prevent the formation of conducting deposits (prototype sodium tests have been completed). Induction gauge. This type has two coupled coils and is fitted with a device to compensate for temperature effects. A description is given of a prototype which has been built and the results obtained in the course of sodium tests are described. Ultrasonic gauge. With this type, a transmitter is fitted on top of the outside of the sodium container; there is also a vertical wave guide, the bottom of which is immersed in the liquid metal and possesses a reflector system which returns the ultrasonic beam towards the surface. Fixed reference marks provide a permanent means of calibration and the whole apparatus is welded. This type of gauge is now being constructed. The differential pressure gauges that have been built, and used in particular with Venturi tube flow meters, are modified versions of the devices employed with the 1 - and 10-MW test circuits of

Targeting sodium channels in cardiac arrhythmia

NARCIS (Netherlands)

Remme, Carol Ann; Wilde, Arthur A. M.

2014-01-01

Cardiac voltage-gated sodium channels are responsible for proper electrical conduction in the heart. During acquired pathological conditions and inherited sodium channelopathies, altered sodium channel function causes conduction disturbances and ventricular arrhythmias. Although the clinical,

Simultaneous HPLC method for determination of sodium trimethoprim phenylpropanol disulphonate and sodium sulfaquinoxaline in veterinary drugs

Directory of Open Access Journals (Sweden)

Puangkaew Lakkanatinaporn

2004-11-01

Full Text Available A simple HPLC method has been developed for the separation and determination of sodium trimethoprim phenylpropanol disulphonate and sodium sulfaquinoxaline in veterinary preparations. Both drugs were separated well on a Kromasil C18 column (5 µm, 150 × 4.6 mm using a mixture of acetonitrile and 0.5% triethylamine in 1% acetic acid, pH 3 (18:82, v/v as the mobile phase at the flow rate of 1.5 ml/ min. The presence of both substances was monitored by UV absorption detection at 271 nm. The retention times of sodium trimethoprim phenylpropanol disulphonate and sodium sulfaquinoxaline were 3.2 and 16.0 min, respectively. The performance of the developed method was tested. Linear responses of both drugs were achieved between 48-145% of labeled amount over the concentration ranges of 35-101 µg/ml and 102-306 µg/ ml for sodium trimethoprim phenylpropanol disulphonate and sodium sulfaquinoxaline with correlation coefficients (R2 of 0.9980 and 0.9998, respectively. Accuracy expressed in term of recoveries were 101.4± 1.21% (n=6 for sodium trimethoprim phenylpropanol disulphonate and 99.7±0.92% (n=6 for sodium sulfaquinoxaline. Precision of the method in terms of the relative standard deviation is not more than 2% in all cases. These figures of merit indicated the validity of the developed method.

SNL/JAEA Collaborations on Sodium Fire Benchmarking.

Energy Technology Data Exchange (ETDEWEB)

Clark, Andrew Jordan [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Denman, Matthew R [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Takata, Takashi [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Ohshima, Hiroyuki [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States)

2017-11-01

Two sodium spray fire experiments performed by Sandia National Laboratories (SNL) were used for a code - to - code comparison between CONTAIN - LMR and SPHINCS. Both computer codes are used for modeling sodium accidents in sodium fast reactors. The comparison between the two codes provides insights into the ability of both codes to model sodium spray fires. The SNL T3 and T4 experiments are 20 kg sodium spray fires with sodium spray temperature s of 200 deg C and 500 deg C, respe ctively. Given the relatively low sodium temperature in the SNL T3 experiment, the sodium spray experienced a period of non - combustion. The vessel in the SNL T4 experiment experienced a rapid pressurization that caused of the instrumentation ports to fail during the sodium spray. Despite these unforeseen difficulties, both codes were shown in good agreement with the experiment s . The subsequent pool fire that develops from the unburned sodium spray is a significant characteristic of the T3 experiment. SPHIN CS showed better long - term agreement with the SNL T3 experiment than CONTAIN - LMR. The unexpected port failure during the SNL T4 experiment presented modelling challenges. The time at which the port failure occurred is unknown, but is believed to have occur red at about 11 seconds into the sodium spray fire. The sensitivity analysis for the SNL T4 experiment shows that with a port failure, the sodium spray fire can still maintain elevated pressures during the spray.

Wireless sensor network for sodium leak detection

International Nuclear Information System (INIS)

Satya Murty, S.A.V.; Raj, Baldev; Sivalingam, Krishna M.; Ebenezer, Jemimah; Chandran, T.; Shanmugavel, M.; Rajan, K.K.

2012-01-01

Highlights: ► Early detection of sodium leak is mandatory in any reactor handling liquid sodium. ► Wireless sensor networking technology has been introduced for detecting sodium leak. ► We designed and developed a wireless sensor node in-house. ► We deployed a pilot wireless sensor network for handling nine sodium leak signals. - Abstract: To study the mechanical properties of Prototype Fast Breeder Reactor component materials under the influence of sodium, the IN Sodium Test (INSOT) facility has been erected and commissioned at Indira Gandhi Centre for Atomic Research. Sodium reacts violently with air/moisture leading to fire. Hence early detection of sodium leak if any is mandatory for such plants and almost 140 sodium leak detectors are placed throughout the loop. All these detectors are wired to the control room for data collection and monitoring. To reduce the cost, space and maintenance that are involved in cabling, the wireless sensor networking technology has been introduced in the sodium leak detection system of INSOT. This paper describes about the deployment details of the pilot wireless sensor network and the measures taken for the successful deployment.

Synthesis and characterization of sodium alkoxides

Indian Academy of Sciences (India)

Unknown

technique and IR spectroscopy. The elemental ... for maintenance or disposal, need to be cleaned free of sodium for the ... scenario on sodium removal using different alcohols are ... ethoxide and sodium n-propoxide by KBr pellet method.

Reduced-Sodium Lunches Are Well-Accepted by Uninformed Consumers Over a 3-Week Period and Result in Decreased Daily Dietary Sodium Sodium Intakes: A Randomized Controlled Trial

NARCIS (Netherlands)

Janssen, A.M.; Kremer, S.; Stipriaan, van W.L.; Noort, M.W.J.; Vries, de J.H.M.; Temme, E.H.M.

2015-01-01

Background Processed foods are major contributors to excessive sodium intake in Western populations. We investigated the effect of food reformulation on daily dietary sodium intake. Objective To determine whether uninformed consumers accept reduced-sodium lunches and to determine the effect of

Salt craving: the psychobiology of pathogenic sodium intake.

Science.gov (United States)

Morris, Michael J; Na, Elisa S; Johnson, Alan Kim

2008-08-06

Ionic sodium, obtained from dietary sources usually in the form of sodium chloride (NaCl, common table salt) is essential to physiological function, and in humans salt is generally regarded as highly palatable. This marriage of pleasant taste and physiological utility might appear fortunate--an appealing taste helps to ensure that such a vital substance is ingested. However, the powerful mechanisms governing sodium retention and sodium balance are unfortunately best adapted for an environment in which few humans still exist. Our physiological and behavioral means for maintaining body sodium and fluid homeostasis evolved in hot climates where sources of dietary sodium were scarce. For many reasons, contemporary diets are high in salt and daily sodium intakes are excessive. High sodium consumption can have pathological consequences. Although there are a number of obstacles to limiting salt ingestion, high sodium intake, like smoking, is a modifiable behavioral risk factor for many cardiovascular diseases. This review discusses the psychobiological mechanisms that promote and maintain excessive dietary sodium intake. Of particular importance are experience-dependent processes including the sensitization of the neural systems underlying sodium appetite and the effects of sodium balance on hedonic state and mood. Accumulating evidence suggests that plasticity within the central nervous system as a result of experience with high salt intake, sodium depletion, or a chronic unresolved sodium appetite fosters enduring changes in sodium related appetitive and consummatory behaviors.

Too Much Sodium

Centers for Disease Control (CDC) Podcasts

This podcast is based on the February 2012 CDC Vital Signs report. Ninety percent of Americans age two and older eat too much sodium which can increase your risk for high blood pressure and often leads to heart disease and stroke, two leading causes of death in the US. Learn several small steps you can take to reduce the amount of sodium in your diet.

Sodium technology at EBR-II

International Nuclear Information System (INIS)

Holmes, J.T.; Smith, C.R.F.; Olson, W.H.

1976-01-01

Since the installation of purity monitoring systems in 1967, the control of the purity of the primary and secondary sodium and cover gas systems at the Experimental Breeder Reactor II (EBR-II) has been excellent. A rigorous monitoring program is being used to assure that operating limits for more than 25 chemical and radioactive impurities are not exceeded. The program involves the use of sophisticated sampling and analysis techniques and on-line monitors for both sodium and cover gas systems. Sodium purity control is accomplished by essentially continuous cold trapping of a small side stream of the total circulating sodium. The cold traps have been found to be very effective for the removal of the major chemical impurities (oxygen and hydrogen) and tritium but are almost ineffective for 131 I and 137 Cs that enter the sodium from fuel cladding breaks. Purging with pure argon maintains the cover gas purity

Leak detector of liquid sodium

International Nuclear Information System (INIS)

Himeno, Yoshiaki.

1975-01-01

Object: To arrange a cable core connected to a leakage current detector on the outer wall of piping for liquid sodium, devices or the like and apply a voltage to said core and outer wall to quickly and securely detect the leakage of liquid sodium. Structure: A cable, which is composed of metal coating formed of metal material (copper, steel, stainless, etc.) which is apt to be corroded by reaction products of liquid sodium with water and oxygen in air, and metal oxide (such as magnesium oxide, beryllium oxide, aluminum oxide) as an electric insulator is arranged on the outer wall of pipes or devices. In the event sodium is leaked from the pipes or devices, said metal coating and the insulator are corroded, and the leakage of sodium is sensed by a leakage current detector through the core in the cable. (Kamimura, M.)

A study on sodium-concrete reaction

Energy Technology Data Exchange (ETDEWEB)

Pae, Jae Huem; Min, Byung Hoon; Lee, Joon Sik; Lee, Choong Hui; Chung, Ki Hong; Keum, Choong Ki [Suwon University, Suwon (Korea, Republic of)

1994-07-15

Sodium is commonly used as a coolant in liquid metal reactor. A large amount of its leakage may be possible in hypothetical accidents, even though the possibility is very low. In case that the leaked hot sodium comes in direct contact with structural concrete of liquid metal reactor, the reactor`s integrity can be challenged by the rupture of structure materials, hydrogen generation and its explosion, and release of radioactive aerosols due to sodium-concrete reaction. The knowledge of sodium-concrete reaction is evaluated to be one of the important and indispensable technologies for the establishment of safety measure in liquid metal reactor. In this study, the experimental facility of sodium-concrete reaction is to be designed, constructed and operated. And the reaction phenomena of sodium-concrete reaction is also to be analyzed through the experimental results. The aim of this study is to establish the measure of safety and protection for sodium-related facilities and to secure one of the fundamental technologies of liquid metal reactor safety. 47 refs., 7 figs., 13 tab.

Dog rose (Rosa canina L.) as a functional ingredient in porcine frankfurters without added sodium ascorbate and sodium nitrite.

Science.gov (United States)

Vossen, Els; Utrera, Mariana; De Smet, Stefaan; Morcuende, David; Estévez, Mario

2012-12-01

The effect of dog rose (Rosa canina L.; RC), rich in polyphenols and ascorbic acid, on lipid and protein oxidation, colour stability and texture of frankfurters was investigated. Four treatments were prepared: with 5 or 30 g/kg RC extract and without sodium ascorbate and sodium nitrite (5RC and 30RC, respectively), a positive control (with sodium ascorbate and sodium nitrite; PC) and a negative control (without sodium ascorbate, sodium nitrite or RC extract; NC). Hexanal values were much higher throughout storage in NC compared to RC and PC frankfurters (Prose can act as a natural antioxidant in frankfurters, but not as full replacer for sodium nitrite. Copyright © 2012 Elsevier Ltd. All rights reserved.

Delaminated sodium nonatitanate and a method for producing delaminated sodium nonatitanate

Science.gov (United States)

Nyman, May D.

2016-02-02

A hydrothermal synthesis method of making a delaminated titanate is disclosed. The delaminated titanate has a unique structure or morphology. The delaminated titanate is first formed by forming at a low temperature a layered sodium nonatitanate (SNT), which may be referred to as layered sodium titanate. The layered SNT has a unique morphology. The layered SNT is then synthesized into a delaminated titanate having a unique morphology.

Effects of sodium fires on structures and materials. Practical experience with sodium leakage accidents

International Nuclear Information System (INIS)

Freudenstein, K.F.

1989-01-01

A few sodium leakage, incidents happened in SNR 300 nuclear power plant during pre-nuclear operation which were of minor importance with respect to sodium fires. The most important sodium fire accident in the past happened in the Almeria Solar platform in Spain during the attempt to repair a valve while leaving accidentally the circuit under 4 bar overpressure. Considerable damage to pipes, valves, its insulation and its support structures was observed in the influence zone of the fire. Post accident analysis gave a leaked mass of about 14 m 3 , at a sodium temperature of 225 deg. C, the leakage lasting approximately half an hour, and burning under convective heat exchange with the external air in a section of 40 m 2 up to a height of 6 m down to the catch pans. Some local temperatures were determined by metallurgical means, integral support temperatures estimated from mechanical deformation observed. From these temperatures it was concluded that a massive spray type fire must have happened. The results fall in the interpretation range of sodium-spray fire test results. (author)

Development of sodium technology

International Nuclear Information System (INIS)

Hwang, Sung Tai; Nam, H. Y.; Choi, Y. D.

2000-05-01

The objective of present study is to produce the experimental data for development and verification of computer codes for development of LMR and to develop the preliminary technologies for the future large scale verification experiments. A MHD experimental test loop has been constructed for the quantitative analysis of the effect of magnetic field on the sodium flow and experiments are carried out for three EM pumps. The previous pressure drop correlations are evaluated using the experimental data obtained from the pressure drop experiment in a 19-pin fuel assembly with wire spacer. An dimensionless variable is proposed to describe the amplitude and frequency of the fluctuation of free surface using the experimental data obtained from free surface experimental apparatus and an empirical correlation is developed using this dimensionless variable. An experimental test loop is constructed to measure the flow characteristics in IHX shell side and the local pressure drop in fuel assembly, and to test the vibration behaviour of fuel pins due to flow induced vibration. The sodium two-phase flow measuring technique using the electromagnetic flowmeter is developed and the sodium differential pressure drop measuring technique using the method of direct contact of sodium and oil is established. The work on the analysis of sodium fire characteristics and produce data for vlidation of computer code is performed. Perfect reopen time of self plugged leak path was observed to be about 130 minutes after water leak initiation. Reopen shape of a specimen appeared to be double layer of circular type, and reopen size of this specimen surface was about 2mm diameter on sodium side. In small water leakage experiments, the following correlation equation about the reopen time between sodium temperature and initial leak rate was obtained, τ c = δ·g -0.83 ·10 (3570/T Na -3.34) , in 400-500 deg C of liquid sodium atmosphere. The characteristics of pressure propagation and gas flow, and

Development of sodium technology

Energy Technology Data Exchange (ETDEWEB)

Hwang, Sung Tai; Nam, H Y; Choi, Y D [and others

2000-05-01

The objective of present study is to produce the experimental data for development and verification of computer codes for development of LMR and to develop the preliminary technologies for the future large scale verification experiments. A MHD experimental test loop has been constructed for the quantitative analysis of the effect of magnetic field on the sodium flow and experiments are carried out for three EM pumps. The previous pressure drop correlations are evaluated using the experimental data obtained from the pressure drop experiment in a 19-pin fuel assembly with wire spacer. An dimensionless variable is proposed to describe the amplitude and frequency of the fluctuation of free surface using the experimental data obtained from free surface experimental apparatus and an empirical correlation is developed using this dimensionless variable. An experimental test loop is constructed to measure the flow characteristics in IHX shell side and the local pressure drop in fuel assembly, and to test the vibration behaviour of fuel pins due to flow induced vibration. The sodium two-phase flow measuring technique using the electromagnetic flowmeter is developed and the sodium differential pressure drop measuring technique using the method of direct contact of sodium and oil is established. The work on the analysis of sodium fire characteristics and produce data for vlidation of computer code is performed. Perfect reopen time of self plugged leak path was observed to be about 130 minutes after water leak initiation. Reopen shape of a specimen appeared to be double layer of circular type, and reopen size of this specimen surface was about 2mm diameter on sodium side. In small water leakage experiments, the following correlation equation about the reopen time between sodium temperature and initial leak rate was obtained, {tau}{sub c} = {delta}{center_dot}g{sup -0.83}{center_dot}10{sup (3570/T{sub Na}-3.34)}, in 400-500 deg C of liquid sodium atmosphere. The characteristics

Characterization of ion distributions near the surface of sodium-containing and sodium-depleted calcium aluminosilicate glass melts

International Nuclear Information System (INIS)

Corrales, Louis R.; Du, Jincheng

2006-01-01

The distribution of cation and anion components of sodium containing calcium aluminosilicate glass was studied by classical molecular dynamics simulations in a high temperature melt in the bulk and at the vacuum-melt interface. A significant redistribution of the sodium and non-bridging oxygen ions was observed. Subsequently, a sodium depleted calcium aluminosilicate glass melt was simulated to determine the sensitivity of the redistribution of ions near the vacuum-melt interface to the presence of sodium ions. It is found that the thermodynamic equilibrium condition near a surface favors the enrichment of non-bridging oxygen ions that is closely associated with enrichment of the sodium ions

Under-Sodium-Viewing as one technique for periodic inspections in sodium-cooled fast reactors-- possibilities and limits

International Nuclear Information System (INIS)

Weiss, H.

1979-07-01

Periodic inspections are gaining increasingly technical importance for fast sodium cooled reactors. Among others the reactor tank and its internals have to be inspected, whereby licensing experts partly are requesting the standards of Light Water Reactors. This leads to difficulties in sodium cooled reactors because of the non-transparent coolant sodium and their compact structure. In order to avoid the complete dumping of the sodium, the under sodium viewing shall be applied besides other inspection methods. Since this is a new method, which is still in its development phase, this report presents and discusses the technical and physical basis and outlines possibilities and limits [de

Spot urine sodium measurements do not accurately estimate dietary sodium intake in chronic kidney disease12

Science.gov (United States)

Dougher, Carly E; Rifkin, Dena E; Anderson, Cheryl AM; Smits, Gerard; Persky, Martha S; Block, Geoffrey A; Ix, Joachim H

2016-01-01

Background: Sodium intake influences blood pressure and proteinuria, yet the impact on long-term outcomes is uncertain in chronic kidney disease (CKD). Accurate assessment is essential for clinical and public policy recommendations, but few large-scale studies use 24-h urine collections. Recent studies that used spot urine sodium and associated estimating equations suggest that they may provide a suitable alternative, but their accuracy in patients with CKD is unknown. Objective: We compared the accuracy of 4 equations [the Nerbass, INTERSALT (International Cooperative Study on Salt, Other Factors, and Blood Pressure), Tanaka, and Kawasaki equations] that use spot urine sodium to estimate 24-h sodium excretion in patients with moderate to advanced CKD. Design: We evaluated the accuracy of spot urine sodium to predict mean 24-h urine sodium excretion over 9 mo in 129 participants with stage 3–4 CKD. Spot morning urine sodium was used in 4 estimating equations. Bias, precision, and accuracy were assessed and compared across each equation. Results: The mean age of the participants was 67 y, 52% were female, and the mean estimated glomerular filtration rate was 31 ± 9 mL · min–1 · 1.73 m–2. The mean ± SD number of 24-h urine collections was 3.5 ± 0.8/participant, and the mean 24-h sodium excretion was 168.2 ± 67.5 mmol/d. Although the Tanaka equation demonstrated the least bias (mean: −8.2 mmol/d), all 4 equations had poor precision and accuracy. The INTERSALT equation demonstrated the highest accuracy but derived an estimate only within 30% of mean measured sodium excretion in only 57% of observations. Bland-Altman plots revealed systematic bias with the Nerbass, INTERSALT, and Tanaka equations, underestimating sodium excretion when intake was high. Conclusion: These findings do not support the use of spot urine specimens to estimate dietary sodium intake in patients with CKD and research studies enriched with patients with CKD. The parent data for this

Clinical impact of nonosmotic sodium storage

NARCIS (Netherlands)

Olde Engberink, R.H.G.

2017-01-01

High sodium intake is associated with hypertension and increased cardiovascular and renal risk. In this thesis we assessed whether these negative effects of sodium can be neutralised by glycosaminoglycans in the endothelial surface layer (i.e. nonosmotic sodium storage). Also, we investigate the

Designing solid-liquid interphases for sodium batteries

KAUST Repository

Choudhury, Snehashis

2017-10-06

Secondary batteries based on earth-abundant sodium metal anodes are desirable for both stationary and portable electrical energy storage. Room-temperature sodium metal batteries are impractical today because morphological instability during recharge drives rough, dendritic electrodeposition. Chemical instability of liquid electrolytes also leads to premature cell failure as a result of parasitic reactions with the anode. Here we use joint density-functional theoretical analysis to show that the surface diffusion barrier for sodium ion transport is a sensitive function of the chemistry of solid–electrolyte interphase. In particular, we find that a sodium bromide interphase presents an exceptionally low energy barrier to ion transport, comparable to that of metallic magnesium. We evaluate this prediction by means of electrochemical measurements and direct visualization studies. These experiments reveal an approximately three-fold reduction in activation energy for ion transport at a sodium bromide interphase. Direct visualization of sodium electrodeposition confirms large improvements in stability of sodium deposition at sodium bromide-rich interphases.

Sodium leak at Monju (II): Sodium leak, burning and aerosol behavior

International Nuclear Information System (INIS)

Funada, T.; Yamagishi, Y.

1996-01-01

The amount of leaked sodium was estimated as approximately 640 kg during the 220 minute leak. The ventilation duct and the walkway grating under the leak site were severely damaged by Na-Fe-O reaction, but the floor liner and the concrete wall were not. A total 100 kg of sodium aerosol was deposited in the reactor auxiliary building and 230 kg was released to the atmosphere. The sodium concentration at the site boundary was calculated as 0.05 mg/m 3 , NaOH equivalent, which was low in comparison with the permitted level of 2 mg/m 3 . The tritium quantity released was estimated as 4.4 x 10 7 Bq, which was about 0.03% of the average released value per month for a LWR. (author)

Mapping of sodium void worth and doppler effect for sodium-cooled fast reactor - 15458

International Nuclear Information System (INIS)

Krepel, J.; Pelloni, S.; Bortot, S.; Panadero, A.L.; Mikityuk, K.

2015-01-01

The sodium-cooled fast reactor (SFR) represents the reference and the most technologically mastered system among the Generation-IV reactors. Nevertheless, the sodium void worth in the fuel regions of SFR is usually positive. To overcome this safety drawback, low-void sodium-cooled fast spectrum core (CFV) was proposed by CEA. Such a CFV core is used in the frame of WP6 'Core safety' of the FP7 Euratom ESNII+ project as a reference SFR design. The overall sodium void effect is negative for the CFV core. Nevertheless, locally it is positive in the fuel region and negative in the sodium plenum. Similarly, also the Doppler effect is spatially dependent and it varies between the inner and outer fuel regions and between the middle and lower blankets. Accordingly, knowledge of the local distributions or actually mappings of the two safety-related parameters will be necessary, before safety assessment and transient analysis can be done. In this study these maps have been produced using the deterministic code ERANOS. The obtained mapping shows strong local dependency of both safety-related effects. A sensitivity of the void effect to the sodium plenum modeling was also demonstrated. The results may serve as an input for the transient analysis of the CFV core or as a cross-check for the Monte Carlo method based maps. (authors)

Carbon transport in sodium systems

International Nuclear Information System (INIS)

Martin Espigares, M.; Lapena, J.; La Torre, M. de

1983-01-01

Carbon activities in dynamic non isothermal sodium system are determined using an equilibratium method. Foils of Fe-18 w% Cr-8 W% Ni alloy with low carbon content (in the as received condition) are exposed to dynamic liquid sodium in the temperature range between 450 0 C and 700 0 C. The analysis was used to evaluate the carburization-decarburization behaviour of type 304 stainless steel exposed to sodium. (author)

Water Mock-up for the Sodium Waste Treatment Process

Energy Technology Data Exchange (ETDEWEB)

Nam, Ho Yun; Kim, Jong Man; Kim, Byung Ho; Lee, Yong Bum [Korea Atomic Energy Research Institute, Daejeon (Korea, Republic of)

2011-05-15

It is important to safely treat the waste sodium which was produced from the sodium cooled fast reactors and the sodium facilities. About 1.3 tons of sodium waste has accumulated at KAERI from the sodium experiments which have been carried out since 1990. Also, large scaled sodium experiments are scheduled to verify the design of the sodium cooled fast reactor. As a treatment method for the waste sodium produced at the sodium facility, an investigation of the reaction procedure of the waste sodium with the sodium hydroxide aqueous has been developed. The NOAH process was developed in France for the treatment of waste sodium produced from sodium facilities and reactors. In the NOAH process, a small amount of sodium waste is continuously injected into the upper space which is formed on the free surface of the aqueous and slowly reacted with sodium hydroxide aqueous. Since the density of the sodium is lower than that of the aqueous, the injected sodium waste sometimes accumulates above the free surface of the sodium hydroxide aqueous, and its reaction rate becomes slow or suddenly increases. In the improved process, the sodium was injected into a reaction vessel filled with a sodium hydroxide aqueous through an atomizing nozzle installed on a lower level than that of the aqueous to maintain the reaction uniformly. Fig.1 shows the sodium waste process which was proposed in KAERI. The aqueous is composed of 60% sodium hydroxide, and its temperature is about 60 .deg. C. The process is an exothermic reaction. The hydrogen gas is generated, and the concentration of the sodium hydroxide increases in this process. It needs several systems for the process, i.e. a waste sodium injection, a cooling of the aqueous, hydrogen ventilation, and neutralization with nitric acid. The atomizing nozzle was designed to inject the sodium with the nitrogen gas which supplies a heat to the sodium to prevent its solidification and to uniformly mix the sodium with the aqueous. There are

Ultrasonic imaging in liquid sodium

Energy Technology Data Exchange (ETDEWEB)

Lubeigt, E. [CEA Cadarache, DEN/DTN/STCP/LIET, 13108 Saint-Paul-Lez-Durance Cedex (France); Laboratoire de Mecanique et d' Acoustique, CNRS UPR 7051, 13402 Marseille Cedex 20 (France); Mensah, S.; Chaix, J.F.; Rakotonarivo, S. [Laboratoire de Mecanique et d' Acoustique, CNRS UPR 7051, 13402 Marseille Cedex 20 (France); Gobillot, G. [CEA Cadarache, DEN/DTN/STCP/LIET, 13108 Saint-Paul-Lez-Durance Cedex (France)

2015-07-01

The fourth generation of nuclear reactor can use liquid sodium as the core coolant. When the reactor is operating, sodium temperatures can reach up to 600 deg. C. During maintenance periods, when the reactor is shut down, the coolant temperature is reduced to 200 deg. C. Because molten sodium is optically opaque, ultrasonic imaging techniques are developed for maintenance activities. Under-sodium imaging aims at i) checking the health of immersed structures. It should also allow ii) to assess component degradation or damage as cracks and shape defects as well as iii) the detection of lost objects. The under-sodium imaging system has to sustain high temperature (up to 300 deg. C) and hostility of the sodium environment. Furthermore, specific constraints such as transducers characteristics or the limited sensor mobility in the reactor vessel have to be considered. This work focuses on developing a methodology for detecting damages such as crack defects with ultrasound devices. Surface-breaking cracks or deep cracks are sought in the weld area, as welds are more subject to defects. Traditional methods enabled us to detect emerging cracks of submillimeter size with sodium-compatible high-temperature transducer. The presented approach relies on making use of prior knowledge about the environment through the implementation of differential imaging and time-reversal techniques. Indeed, this approach allows to detect a change by comparison with a reference measurement and by focusing back to any change in the environment. It is a means of analysis and understanding of the physical phenomena making it possible to design more effective inspection strategies. Difference between the measured signals reveals the acoustic field scattered by a perturbation (a crack for instance), which may occur between periodical measurements. The imaging method relies on the adequate combination of two computed ultrasonic fields, one forward and one adjoint. The adjoint field, which carries the

Ultrasonic imaging in liquid sodium

International Nuclear Information System (INIS)

Lubeigt, E.; Mensah, S.; Chaix, J.F.; Rakotonarivo, S.; Gobillot, G.

2015-01-01

The fourth generation of nuclear reactor can use liquid sodium as the core coolant. When the reactor is operating, sodium temperatures can reach up to 600 deg. C. During maintenance periods, when the reactor is shut down, the coolant temperature is reduced to 200 deg. C. Because molten sodium is optically opaque, ultrasonic imaging techniques are developed for maintenance activities. Under-sodium imaging aims at i) checking the health of immersed structures. It should also allow ii) to assess component degradation or damage as cracks and shape defects as well as iii) the detection of lost objects. The under-sodium imaging system has to sustain high temperature (up to 300 deg. C) and hostility of the sodium environment. Furthermore, specific constraints such as transducers characteristics or the limited sensor mobility in the reactor vessel have to be considered. This work focuses on developing a methodology for detecting damages such as crack defects with ultrasound devices. Surface-breaking cracks or deep cracks are sought in the weld area, as welds are more subject to defects. Traditional methods enabled us to detect emerging cracks of submillimeter size with sodium-compatible high-temperature transducer. The presented approach relies on making use of prior knowledge about the environment through the implementation of differential imaging and time-reversal techniques. Indeed, this approach allows to detect a change by comparison with a reference measurement and by focusing back to any change in the environment. It is a means of analysis and understanding of the physical phenomena making it possible to design more effective inspection strategies. Difference between the measured signals reveals the acoustic field scattered by a perturbation (a crack for instance), which may occur between periodical measurements. The imaging method relies on the adequate combination of two computed ultrasonic fields, one forward and one adjoint. The adjoint field, which carries the

Distributed temperature sensor testing in liquid sodium

Energy Technology Data Exchange (ETDEWEB)

Gerardi, Craig, E-mail: cgerardi@anl.gov; Bremer, Nathan; Lisowski, Darius; Lomperski, Stephen

2017-02-15

Highlights: • Distributed temperature sensors measured high-resolution liquid-sodium temperatures. • DTSs worked well up to 400 °C. • A single DTS simultaneously detected sodium level and temperature. - Abstract: Rayleigh-backscatter-based distributed fiber optic sensors were immersed in sodium to obtain high-resolution liquid-sodium temperature measurements. Distributed temperature sensors (DTSs) functioned well up to 400 °C in a liquid sodium environment. The DTSs measured sodium column temperature and the temperature of a complex geometrical pattern that leveraged the flexibility of fiber optics. A single Ø 360 μm OD sensor registered dozens of temperatures along a length of over one meter at 100 Hz. We also demonstrated the capability to use a single DTS to simultaneously detect thermal interfaces (e.g. sodium level) and measure temperature.

Sodium-blood pressure interrelationship in pregnancy.

Science.gov (United States)

Franx, A; Steegers, E A; de Boo, T; Thien, T; Merkus, J M

1999-03-01

In non-pregnant individuals, a strong positive association of sodium intake with blood pressure has been established, but the relationship between sodium intake and blood pressure in human pregnancy remains obscure up to date. The aim of this prospective observational cohort study was to assess the relationship between urinary sodium excretion (as a measure for intake) and blood pressure from the early second trimester onwards throughout pregnancy. The study group consisted of 667 low-risk women with singleton pregnancies, of whom 350 were nulliparous and 317 parous. Blood pressure was measured in a standardised fashion at predetermined intervals from the first antenatal visit prior to 16 weeks gestation until delivery. Urinary sodium excretion was measured in 24-h urine collections on at least four occasions between 16 and 38 weeks gestation. Main outcome measures were the coefficients of correlation between changes in urinary sodium output and changes in blood pressure during six different gestational epochs. No significant correlations were found between changes in urinary sodium output and changes in blood pressure. Correlation coefficients were alike for nulliparous and parous women and for different gestational intervals. Prior to 32 weeks gestation, no differences were observed in sodium excretion between women who remained normotensive and those who developed gestational hypertension. These results suggest that changes in sodium intake are not associated with blood pressure changes in low-risk pregnant women. Blood pressure increases as observed in the second half of normotensive and hypertensive pregnancies are unlikely to be caused by changes in renal sodium handling.

Computational methodology of sodium-water reaction phenomenon in steam generator of sodium-cooled fast reactor

International Nuclear Information System (INIS)

Takata, Takashi; Yamaguchi, Akira; Uchibori, Akihiro; Ohshima, Hiroyuki

2009-01-01

A new computational methodology of sodium-water reaction (SWR), which occurs in a steam generator of a liquid-sodium-cooled fast reactor when a heat transfer tube in the steam generator fails, has been developed considering multidimensional and multiphysics thermal hydraulics. Two kinds of reaction models are proposed in accordance with a phase of sodium as a reactant. One is the surface reaction model in which water vapor reacts directly with liquid sodium at the interface between the liquid sodium and the water vapor. The reaction heat will lead to a vigorous evaporation of liquid sodium, resulting in a reaction of gas-phase sodium. This is designated as the gas-phase reaction model. These two models are coupled with a multidimensional, multicomponent gas, and multiphase thermal hydraulics simulation method with compressibility (named the 'SERAPHIM' code). Using the present methodology, a numerical investigation of the SWR under a pin-bundle configuration (a benchmark analysis of the SWAT-1R experiment) has been carried out. As a result, the maximum gas temperature of approximately 1,300degC is predicted stably, which lies within the range of previous experimental observations. It is also demonstrated that the maximum temperature of the mass weighted average in the analysis agrees reasonably well with the experimental result measured by thermocouples. The present methodology will be promising to establish a theoretical and mechanical modeling of secondary failure propagation of heat transfer tubes due to such as an overheating rupture and a wastage. (author)

Sodium concrete reaction - Structural considerations

International Nuclear Information System (INIS)

Ferskakis, G.N.

1984-01-01

An overview of the sodium concrete reaction phenomenon, with emphasis on structural considerations, is presented. Available test results for limestone, basalt, and magnetite concrete with various test article configurations are reviewed. Generally, tests indicate reaction is self limiting before all sodium is used. Uncertainties, however, concerning the mechanism for penetration of sodium into concrete have resulted in different theories about a reaction model. Structural behavior may be significant in the progression of the reaction due to thermal-structuralchemical interactions involving tensile cracking, compressive crushing, or general deterioration of concrete and the exposure of fresh concrete surfaces to react with sodium. Structural behavior of test articles and potential factors that could enhance the progression of the reaction are discussed

Tumorigenicity of sodium ascorbate in male rats.

Science.gov (United States)

Cohen, S M; Anderson, T A; de Oliveira, L M; Arnold, L L

1998-06-15

Sodium ascorbate, like other sodium salts such as saccharin, glutamate, and bicarbonate, produces urinary alterations when fed at high doses to rats, which results in mild superficial urothelial cytotoxicity and regeneration but not tumors in a standard 2-year bioassay. Sodium saccharin was shown to produce a low incidence of bladder tumors in rats if administered in a two-generation bioassay. In the present study, we evaluated sodium ascorbate in a two-generation bioassay that involved feeding to the male and female parental F344 rats for 4 weeks before mating, feeding the dams during gestation and lactation, and then feeding the weaned (at 28 days of age) male F1 generation rats for the remainder of their lifetime (up to 128 weeks of the experiment). Dietary levels of 1.0, 5.0, and 7.0% sodium ascorbate were tested. At 5.0 and 7.0% sodium ascorbate, there was an increase in urinary bladder urothelial papillary and nodular hyperplasia and the induction of a few papillomas and carcinomas. There was a dose-responsive increase in renal pelvic calcification and hyperplasia and inhibition of the aging nephropathy of rats even at the level of 1% sodium ascorbate. Because the short-term urothelial effects of sodium ascorbate in rats are inhibited by treatments producing urinary acidification to pH sodium ascorbate to evaluate the long-term effects. The combination of 7.0% sodium ascorbate plus 2.78% NH4Cl in the diet was toxic, and the group was terminated early during the course of the experiment. The group fed 5.0% sodium ascorbate plus 2.04% NH4Cl showed complete inhibition of the urothelial effects of sodium ascorbate and significant inhibition of its renal effects. We also demonstrated the presence of a calcium phosphate-containing urinary precipitate in rats fed sodium ascorbate at all doses, in a dose-responsive manner. The formation of the precipitate was inhibited by coadministration with NH4Cl. The proliferative effects of sodium ascorbate on the male rat

Improved modelling of sodium-spray fires and sodium-combustion aerosol chemical evolution - 15488

International Nuclear Information System (INIS)

Mathe, E.; Kissane, M.; Petitprez, D.

2015-01-01

In the context of the Generation IV Initiative, the consequences of a severe-accident in sodium-cooled fast reactor (SFR) must be studied. Being pyrophoric, sodium will burn upon contact with air in a containment creating toxic aerosols and we must take into account these fire aerosols when assessing the source term. We have developed a numerical simulation named NATRAC to calculate the mass of aerosols produced during a spray fire in a SFR severe accident. The results show that the mass of oxide aerosols can involve more than 60% of the ejected sodium. In a second part we have developed a numerical simulation named STARK based on the Cooper model that models the physico-chemical transformations of the aerosols. However, this model has never been validated and the literature does not permit to do so. In these conditions, we have designed and performed our own experiment ESSTIA to obtain the missing values of the parameters that govern Cooper model. The modified Cooper model we propose with the new parameters reproduces correctly the ESSTIA experimental data. The only parameter that has not yet been measured is the tortuosity of the sodium-fire aerosols surface layers. A dedicated experiment using real sodium-fire aerosols could eliminate any doubts about the uncertainty of the proposed Cooper model

Iodine release from sodium pool combustion

International Nuclear Information System (INIS)

Sagawa, N.; Fukushima, Y.; Yokota, N.; Akagane, K.; Mochizuki, K.

1979-01-01

Iodine release associated with sodium pool combustion was determined by heating 20 gr sodium containing sodium iodide, which was labelled with 131 I and dissolved in the sodium in concentration of 1∼1,000 ppm, to burn on a nickel crucible in conditioned atmosphere in a closed vessel of 0.4 m 3 . Oxygen concentration was changed in 5∼21% and humidity in 0∼89% by mixing nitrogen gas and air. Combustion products were trapped by a Maypack filter composed of particle filters, copper screens and activated charcoal beds and by a glass beads pack cooled by liquid argon. Iodine collected on these filter elements was determined by radio-gas chromatography. When the sodium sample burned in the atmosphere of air at room temperature, the release fractions observed were 6∼33% for sodium and 1∼20% for iodine added in the sodium. The release iodine was present in aerosol at a ratio of 98%, and the remainder in the gas form. The release fraction of iodine trended to decrease as oxygen concentration and humidity in the atmosphere increased. No organic iodide was detected in the combustion products. (author)

Evaluation tissue dissolution property of 2.5 % Sodium Hypochlorite Prepared by Hydrochloric Acid and Sodium Bicarbonate: An in vitro

Directory of Open Access Journals (Sweden)

Hamid Razavian

2016-08-01

Full Text Available Successful endodontic treatment requires chemical preparation in addition to mechanical preparation. The most common material for chemical preparations is sodium hypochlorite. One way to reduce the effects of pH adjustment is the use of sodium hypochlorite. The present paper was conducted to examine the effect of dilution with hydrochloric acid and sodium bicarbonate and reduce pH on ability of tissue solubility of sodium hypochlorite. The present study was conducted in vitro on bovine muscle tissue. Ability of tissue solubility was conducted in four groups respectively with active ingredient including 1 sodium hypochlorite diluted with distilled water 2 sodium hypochlorite diluted with sodium bicarbonate 3 sodium hypochlorite diluted with hydrochloric acid and finally 4 distilled water (control group. Each sample was firstly weighed and then placed in contact with 10 m/L solution for 60 minutes (five 12 -minute intervals. The sample was weighted every five minutes and solution was renewed. The results were analyzed using SPSS-21 Software based on variance analysis, Tukey and T-test (α=0.05. The findings showed that there was significant difference between first, second and third groups in terms of ability of tissue solubility. However, the tissue solubility in second and third groups was lower than first group and it was similar in second and third groups (P Value <0.001. Reduction of sodium bicarbonate PH using sodium hypochlorite and hydrochloric acid reduces ability of tissue solubility in sodium hypochlorite.

Enhanced electrochemical stability of carbon-coated antimony nanoparticles with sodium alginate binder for sodium-ion batteries

Directory of Open Access Journals (Sweden)

Jianmin Feng

2018-04-01

Full Text Available The poor cycling stability of antimony during a repeated sodium ion insertion and desertion process is the key issue, which leads to an unsatisfactory application as an anode material in a sodium-ion battery. Addressed at this, we report a facile two-step method to coat antimony nanoparticles with an ultrathin carbon layer of few nanometers (denoted Sb@C NPs for sodium-ion battery anode application. This carbon layer could buffer the volume change of antimony in the charge-discharge process and improve the battery cycle performance. Meanwhile, this carbon coating could also enhance the interfacial stability by firmly connecting the sodium alginate binders through its oxygen-rich surface. Benefitted from these advantages, an improved initial discharge capacity (788.5 mA h g−1 and cycling stability capacity (553 mA h g−1 after 50 times cycle have been obtained in a battery using Sb@C NPs as anode materials at 50 mA g−1. Keywords: Sodium-ion battery, Antimony, Sodium alginate, Liquid-phase reduction, Carbon coating

Restricting dietary sodium reduces plasma sodium response to exercise in the heat.

Science.gov (United States)

Koenders, E E; Franken, C P G; Cotter, J D; Thornton, S N; Rehrer, N J

2017-11-01

Exercise-associated hyponatremia can be life-threatening. Excessive hypotonic fluid ingestion is the primary etiological factor but does not explain all variability. Possible effects of chronic sodium intake are unknown. The aim of this study was to determine whether dietary sodium affects plasma sodium concentration [Na + ] during exercise in the heat, when water intake nearly matches mass loss. Endurance-trained men (n = 9) participated in this crossover experiment. Each followed a low-sodium (lowNa) or high-sodium (highNa) diet for 9 days with 24-h fluid intakes and urine outputs measured before experimental trials (day 10). The trials were ≥2 week apart. Trials comprised 3 h (or if not possible to complete, to exhaustion) cycling (55% VO 2max ; 34 °C, 65% RH) with water intake approximating mass loss. Plasma [Na + ], hematocrit, sweat and urine [Na + ], heart rate, core temperature, and subjective perceptions were monitored. Urine [Na + ] was lower on lowNa 24 h prior to (31 ± 24, 76 ± 30 mmol/L, P = 0.027) and during trials (10 ± 10, 52 ± 32 mmol/L, P = 0.004). Body mass was lower on lowNa (79.6 ± 8.5, 80.5 ± 8.9, P = 0.03). Plasma [Na + ] was lower on lowNa before (137 ± 2, 140 ± 3, P = 0.007) and throughout exercise (P = 0.001). Sweat [Na + ] was unaffected by diet (54.5 ± 40, 54.5 ± 23 mmol/L, P = 0.99). Heart rate and core temperature were higher on lowNa (P ≤ 0.001). Despite decreased urinary sodium losses, plasma sodium was lower on lowNa, with decreased mass indicating (extracellular) water may have been less, explaining greater heart rate and core temperature. General population health recommendations to lower salt intake may not be appropriate for endurance athletes, particularly those training in the heat. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Muzzle secretion electrolytes as a possible indicator of sodium status in buffalo (Bubalus bubalis) calves: effects of sodium depletion and aldosterone administration.

Science.gov (United States)

Kumar, S; Singh, S P

1981-01-01

In two separate experiments, the effects of sodium depletion and aldosterone administration on sodium and potassium concentrations in muzzle secretion, saliva and urine were studied in buffalo calves. Sodium deficiency in the animals was experimentally produced by unilateral parotid saliva deprivation for 18 days. During sodium depletion, the sodium levels in saliva and muzzle secretion gradually fell while the potassium level gradually rose. The concentrations of both of these cations in urine gradually fell during the course of sodium depletion. Aldosterone administration in normal (sodium-replete) animals simulated the effects of sodium depletion as far as cationic changes in saliva were concerned. However, aldosterone did not affect sodium and potassium concentration in the urine and in muzzle secretion in a manner similar to that caused by sodium depletion. Though the hormone decreased urinary sodium without affecting urinary potassium, it did not affect the muzzle sodium or potassium. Results suggest that aldosterone affects the composition of saliva and urine in buffaloes as it does in sheep and other ruminants. Similar changes in composition of muzzle secretion and saliva during sodium depletion indicate that the concentration of sodium in muzzle secretion could possibly be used to evaluate the sodium status of animals.

Cleaning of Sodium in the Cold Trap

International Nuclear Information System (INIS)

Kim, Byung Ho; Jeong, Ji Young; Kim, Jong Man; Choi, Byung Hae; Nam, Ho Yun

2005-01-01

The purpose of a cleaning process is to remove the residual sodium adhering to the component walls once it has been properly drained. It is necessary to clean and decontaminate a component, especially the large components of the primary coolant system; such as the intermediate heat exchangers and the primary pump. Improper and inadequate cleaning has in a number of cases resulted in problems in the storage, handling, and reuse of components. Several types of failures due to improper cleaning procedures have been defined in the past. Inadequate and incomplete removal of sodium results in residues which may contain metallic sodium and alkaline compounds such as sodium hydroxide, sodium oxide, sodium carbonate, and various types of alcoholates. Reinsertion of components containing these compounds into a high-temperature sodium system can result in either the intergranular penetration characteristic of a high- oxygen sodium or an accelerated corrosion due to oxygen. The methods used for cleaning sodium equipment depend on the condition and types of equipment to be cleaned and whether the equipment is to be reused. Cleaning methods are needed that will avoid a deleterious local overheating, material surface degradation or deposits, chemical, physical, or mechanical damage, and external effects. This paper discusses a steam-nitrogen gas cleaning method for the routine applications that permits the reuse of the cold trap in sodium

Visibility in sodium fume

International Nuclear Information System (INIS)

Hughes, G.W.; Anderson, N.R.

1971-01-01

The appearance of sodium fume of unknown concentration and the effects of short term exposure on unprotected workers is described. The molecular extinction coefficient of sodium fume is calculated from which light transmission data, and a rapid method for the estimation of the fume concentration is proposed. (author)

Modeling and Validation of Sodium Plugging for Heat Exchangers in Sodium-cooled Fast Reactor Systems

Energy Technology Data Exchange (ETDEWEB)

Ferroni, Paolo [Westinghouse Electric Company LLC, Cranberry Township, PA (United States). Global Technology Development; Tatli, Emre [Westinghouse Electric Company LLC, Cranberry Township, PA (United States); Czerniak, Luke [Westinghouse Electric Company LLC, Cranberry Township, PA (United States); Sienicki, James J. [Argonne National Lab. (ANL), Argonne, IL (United States); Chien, Hual-Te [Argonne National Lab. (ANL), Argonne, IL (United States); Yoichi, Momozaki [Argonne National Lab. (ANL), Argonne, IL (United States); Bakhtiari, Sasan [Argonne National Lab. (ANL), Argonne, IL (United States)

2016-06-29

The project “Modeling and Validation of Sodium Plugging for Heat Exchangers in Sodium-cooled Fast Reactor Systems” was conducted jointly by Westinghouse Electric Company (Westinghouse) and Argonne National Laboratory (ANL), over the period October 1, 2013- March 31, 2016. The project’s motivation was the need to provide designers of Sodium Fast Reactors (SFRs) with a validated, state-of-the-art computational tool for the prediction of sodium oxide (Na₂O) deposition in small-diameter sodium heat exchanger (HX) channels, such as those in the diffusion bonded HXs proposed for SFRs coupled with a supercritical CO₂ (sCO₂) Brayton cycle power conversion system. In SFRs, Na₂O deposition can potentially occur following accidental air ingress in the intermediate heat transport system (IHTS) sodium and simultaneous failure of the IHTS sodium cold trap. In this scenario, oxygen can travel through the IHTS loop and reach the coldest regions, represented by the cold end of the sodium channels of the HXs, where Na₂O precipitation may initiate and continue. In addition to deteriorating HX heat transfer and pressure drop performance, Na₂O deposition can lead to channel plugging especially when the size of the sodium channels is small, which is the case for diffusion bonded HXs whose sodium channel hydraulic diameter is generally below 5 mm. Sodium oxide melts at a high temperature well above the sodium melting temperature such that removal of a solid plug such as through dissolution by pure sodium could take a lengthy time. The Sodium Plugging Phenomena Loop (SPPL) was developed at ANL, prior to this project, for investigating Na₂O deposition phenomena within sodium channels that are prototypical of the diffusion bonded HX channels envisioned for SFR-sCO₂ systems. In this project, a Computational Fluid Dynamic (CFD) model capable of simulating the thermal-hydraulics of the SPPL test

Sodium Velocity Maps on Mercury

Science.gov (United States)

Potter, A. E.; Killen, R. M.

2011-01-01

The objective of the current work was to measure two-dimensional maps of sodium velocities on the Mercury surface and examine the maps for evidence of sources or sinks of sodium on the surface. The McMath-Pierce Solar Telescope and the Stellar Spectrograph were used to measure Mercury spectra that were sampled at 7 milliAngstrom intervals. Observations were made each day during the period October 5-9, 2010. The dawn terminator was in view during that time. The velocity shift of the centroid of the Mercury emission line was measured relative to the solar sodium Fraunhofer line corrected for radial velocity of the Earth. The difference between the observed and calculated velocity shift was taken to be the velocity vector of the sodium relative to Earth. For each position of the spectrograph slit, a line of velocities across the planet was measured. Then, the spectrograph slit was stepped over the surface of Mercury at 1 arc second intervals. The position of Mercury was stabilized by an adaptive optics system. The collection of lines were assembled into an images of surface reflection, sodium emission intensities, and Earthward velocities over the surface of Mercury. The velocity map shows patches of higher velocity in the southern hemisphere, suggesting the existence of sodium sources there. The peak earthward velocity occurs in the equatorial region, and extends to the terminator. Since this was a dawn terminator, this might be an indication of dawn evaporation of sodium. Leblanc et al. (2008) have published a velocity map that is similar.

Numerical Analysis of Flow Distribution in a Sodium Chamber of a Finned-tube Sodium-to-Air Heat Exchanger

Energy Technology Data Exchange (ETDEWEB)

Jo, Youngchul; Son, Seokkwon; Kim, Hyungmo; Eoh, Jaehyuk; Jeong, Jiyoung [Korea Atomic Energy Research Institute, Daejeon (Korea, Republic of)

2015-10-15

DHR systems consist of two diverse heat removal loops such as passive and active DHR systems, and the heat load imposed on the primary sodium pool is safely rejected into the environment through different kinds of sodium-to-air heat exchangers, e.g. M-shape and helical-coil type air-coolers. The former is called as an FHX(Forced-draft sodium-to-air Heat Exchanger) and the latter is simply called as an AHX(natural-draft sodium-to-Air Heat Exchanger). In a general sodium-to-air heat exchanger design, convection resistance in a shell-side air flow path becomes dominant factor affecting the mechanism of conjugate heat transfer from the sodium flow inside the tube to the air path across the sodium tube wall. Hence verification of the flow and heat transfer characteristics is one of the most important tasks to demonstrate decay heat removal performance. To confirm a kind of ultimate heat sink heat exchanger, a medium-scale Sodium thermal-hydraulic Experiment Loop for Finned-tube sodium-to-Air Heat exchanger (here after called the SELFA) has been designed and is recently being constructed at KAERI site. The introduction of the flow baffle inside the upper sodium chamber of the model FHX unit in the SELFA facility is briefly proposed and discussed as well. The present study aims at introducing a flow baffle design inside the upper sodium chamber to make more equalized flowrates flowing into each heat transfer tube of the model FHX unit. In the cases without the flow baffle geometry, it was observed lager discrepancies in flowrates at the heat transfer tubes. However it was also found that those kinds of discrepancies could be definitely decreased at around 1/10 by employing a flow baffle.

Dissolution of LMFBR fuel-sodium aerosols

International Nuclear Information System (INIS)

Allen, M.D.; Moss, O.R.

1979-01-01

Plutonium dioxide, normally insoluble in biological fluids, becomes much more soluble when mixed with sodium as the aerosol is formed. Sodium-fuel aerosols are approximately 20 times less soluble in simulated lung fluid than in distilled water. Solubility of sodium-fuel aerosols increases when Na 2 CO 3 are added to the distilled-water dissolution fluid. Mixed-oxide fuel aerosols without sodium present are relatively insoluble in distilled water, simulated lung fluid, and distilled water with Na 2 CO 3 and NaHCO 3 added

Sodium hypochlorite-induced acute kidney injury

Directory of Open Access Journals (Sweden)

Brandon W Peck

2014-01-01

Full Text Available Sodium hypochlorite (bleach is commonly used as an irrigant during dental proce-dures as well as a topical antiseptic agent. Although it is generally safe when applied topically, reports of accidental injection of sodium hypochlorite into tissue have been reported. Local necrosis, pain and nerve damage have been described as a result of exposure, but sodium hypo-chlorite has never been implicated as a cause of an acute kidney injury (AKI. In this report, we describe the first case of accidental sodium hypochlorite injection into the infraorbital tissue during a dental procedure that precipitated the AKI. We speculate that oxidative species induced by sodium hypochlorite caused AKI secondary to the renal tubular injury, causing mild acute tubular necrosis.

Corrosion performance of advanced structural materials in sodium.

Energy Technology Data Exchange (ETDEWEB)

Natesan, K.; Momozaki, Y.; Li, M.; Rink, D.L. (Nuclear Engineering Division)

2012-05-16

This report gives a description of the activities in design, fabrication, construction, and assembling of a pumped sodium loop for the sodium compatibility studies on advanced structural materials. The work is the Argonne National Laboratory (ANL) portion of the effort on the work project entitled, 'Sodium Compatibility of Advanced Fast Reactor Materials,' and is a part of Advanced Materials Development within the Reactor Campaign. The objective of this project is to develop information on sodium corrosion compatibility of advanced materials being considered for sodium reactor applications. This report gives the status of the sodium pumped loop at Argonne National Laboratory, the specimen details, and the technical approach to evaluate the sodium compatibility of advanced structural alloys. This report is a deliverable from ANL in FY2010 (M2GAN10SF050302) under the work package G-AN10SF0503 'Sodium Compatibility of Advanced Fast Reactor Materials.' Two reports were issued in 2009 (Natesan and Meimei Li 2009, Natesan et al. 2009) which examined the thermodynamic and kinetic factors involved in the purity of liquid sodium coolant for sodium reactor applications as well as the design specifications for the ANL pumped loop for testing advanced structural materials. Available information was presented on solubility of several metallic and nonmetallic elements along with a discussion of the possible mechanisms for the accumulation of impurities in sodium. That report concluded that the solubility of many metals in sodium is low (<1 part per million) in the temperature range of interest in sodium reactors and such trace amounts would not impact the mechanical integrity of structural materials and components. The earlier report also analyzed the solubility and transport mechanisms of nonmetallic elements such as oxygen, nitrogen, carbon, and hydrogen in laboratory sodium loops and in reactor systems such as Experimental Breeder Reactor-II, Fast Flux

Corrosion performance of advanced structural materials in sodium

International Nuclear Information System (INIS)

Natesan, K.; Momozaki, Y.; Li, M.; Rink, D.L.

2012-01-01

This report gives a description of the activities in design, fabrication, construction, and assembling of a pumped sodium loop for the sodium compatibility studies on advanced structural materials. The work is the Argonne National Laboratory (ANL) portion of the effort on the work project entitled, 'Sodium Compatibility of Advanced Fast Reactor Materials,' and is a part of Advanced Materials Development within the Reactor Campaign. The objective of this project is to develop information on sodium corrosion compatibility of advanced materials being considered for sodium reactor applications. This report gives the status of the sodium pumped loop at Argonne National Laboratory, the specimen details, and the technical approach to evaluate the sodium compatibility of advanced structural alloys. This report is a deliverable from ANL in FY2010 (M2GAN10SF050302) under the work package G-AN10SF0503 'Sodium Compatibility of Advanced Fast Reactor Materials.' Two reports were issued in 2009 (Natesan and Meimei Li 2009, Natesan et al. 2009) which examined the thermodynamic and kinetic factors involved in the purity of liquid sodium coolant for sodium reactor applications as well as the design specifications for the ANL pumped loop for testing advanced structural materials. Available information was presented on solubility of several metallic and nonmetallic elements along with a discussion of the possible mechanisms for the accumulation of impurities in sodium. That report concluded that the solubility of many metals in sodium is low (<1 part per million) in the temperature range of interest in sodium reactors and such trace amounts would not impact the mechanical integrity of structural materials and components. The earlier report also analyzed the solubility and transport mechanisms of nonmetallic elements such as oxygen, nitrogen, carbon, and hydrogen in laboratory sodium loops and in reactor systems such as Experimental Breeder Reactor-II, Fast Flux Test Facility, and

Amiloride-Sensitive Sodium Channels and Pulmonary Edema

Directory of Open Access Journals (Sweden)

Mike Althaus

2011-01-01

Full Text Available The development of pulmonary edema can be considered as a combination of alveolar flooding via increased fluid filtration, impaired alveolar-capillary barrier integrity, and disturbed resolution due to decreased alveolar fluid clearance. An important mechanism regulating alveolar fluid clearance is sodium transport across the alveolar epithelium. Transepithelial sodium transport is largely dependent on the activity of sodium channels in alveolar epithelial cells. This paper describes how sodium channels contribute to alveolar fluid clearance under physiological conditions and how deregulation of sodium channel activity might contribute to the pathogenesis of lung diseases associated with pulmonary edema. Furthermore, sodium channels as putative molecular targets for the treatment of pulmonary edema are discussed.

A method for the manufacture of nuclear-purity sodium

International Nuclear Information System (INIS)

Besson, Paul; Graff, Willy.

1973-01-01

Description is given of a method for the manufacture of sodium from the amalgam provided by sodium chloride aqueous electrolysis cells, comprising the steps of treating the sodium amalgam by a sodium polysulfide or a mixture of sodium polysulfide in anhydrous alcohol solution, then causing the thus obtained sodium monosulfide to react with a polysulfide or a mixture of polysulfides so as to obtain a mixture of sodium polysulfides with a higher sodium content, and finally separating sodium through the electrolysis of the sodium-rich polysulfides, the electrolysis being carried out in an electrolytic cell with β-alumina solid electrolyte operating at a temperature between 250 and 300 deg C, in which the polysulfide forms the anode compartment and sodium the cathode compartment [fr

21 CFR 582.1748 - Sodium caseinate.

Science.gov (United States)

2010-04-01

... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Sodium caseinate. 582.1748 Section 582.1748 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL... Additives § 582.1748 Sodium caseinate. (a) Product. Sodium caseinate. (b) Conditions of use. This substance...

21 CFR 182.1748 - Sodium caseinate.

Science.gov (United States)

2010-04-01

... 21 Food and Drugs 3 2010-04-01 2009-04-01 true Sodium caseinate. 182.1748 Section 182.1748 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) FOOD FOR... Substances § 182.1748 Sodium caseinate. (a) Product. Sodium caseinate. (b) Conditions of use. This substance...

21 CFR 582.1742 - Sodium carbonate.

Science.gov (United States)

2010-04-01

... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Sodium carbonate. 582.1742 Section 582.1742 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL... Additives § 582.1742 Sodium carbonate. (a) Product. Sodium carbonate. (b) Conditions of use. This substance...

The Sodium Tail of the Moon

Science.gov (United States)

Matta, M.; Smith, S.; Baumgardner, J.; Wilson, J.; Martinis, C.; Mendillo, M.

2009-01-01

During the few days centered about new Moon, the lunar surface is optically hidden from Earth-based observers. However, the Moon still offers an observable: an extended sodium tail. The lunar sodium tail is the escaping "hot" component of a coma-like exosphere of sodium generated by photon-stimulated desorption, solar wind sputtering and meteoroid impact. Neutral sodium atoms escaping lunar gravity experience solar radiation pressure that drives them into the anti-solar direction forming a comet-like tail. During new Moon time, the geometry of the Sun, Moon and Earth is such that the anti-sunward sodium flux is perturbed by the terrestrial gravitational field resulting in its focusing into a dense core that extends beyond the Earth. An all-sky camera situated at the El Leoncito Observatory (CASLEO) in Argentina has been successfully imaging this tail through a sodium filter at each lunation since April 2006. This paper reports on the results of the brightness of the lunar sodium tail spanning 31 lunations between April 2006 and September 2008. Brightness variability trends are compared with both sporadic and shower meteor activity, solar wind proton energy flux and solar near ultra violet (NUV) patterns for possible correlations. Results suggest minimal variability in the brightness of the observed lunar sodium tail, generally uncorrelated with any single source, yet consistent with a multi-year period of minimal solar activity and non-intense meteoric fluxes.

Liquid sodium oxygenmeter

International Nuclear Information System (INIS)

Jakes, D.; Fresl, M.; Svoboda, V.

1979-02-01

The results of test runs of two design varieties of liquid sodium oxygenmeter in sodium loops are described. The accuracy and sensitivity are discussed reached using this instrument within 1 and 10 p.p.m. of oxygen concentration. A change in the used reference system is proposed based on practical experiences and thermochemical calculations. Ceramic electrolyte corrosion is analysed and the possible interpretation of the corrosion effect on the galvanic cell electromotive force is suggested. (author)

Process for the production of sodium carbonate anhydrate

OpenAIRE

Oosterhof, H.; Van Rosmalen, G.M.; Witkamp, G.J.; De Graauw, J.

2000-01-01

The invention is directed to a process for the production of sodium carbonate-anhydrate having a bulk density of at least 800 kg/m, said process comprising: providing a suspension of solid sodium carbonate and/or solid sodium bicarbonate and/or solid double salts at least comprising one of sodium carbonate and sodium bicarbonate, in a mixture containing water and an organic, water miscible or partly water miscible solvent, which solvent influences the transition temperature below which sodium...

Determination of chloride and sulphur in sodium by ion chromatography and its application to PFBR sodium samples

International Nuclear Information System (INIS)

Vijayalakshmi, S.; Ushalakshmi, K.

2011-01-01

Analytical method using ion chromatography was developed for the determination of chloride and sulphur in sodium. In this method, sodium was dissolved in water and various sulphur species present in the sample was oxidized to sulphate using hydrogen peroxide. Carbon dioxide gas was passed through the solution to convert sodium hydroxide to carbonate solution. The resulting sample solution was analysed using suppressed Ion chromatography employing carbonate eluent. This method was applied to the analysis of sodium samples procured for prototype fast breeder reactor. (author)

21 CFR 556.620 - Sulfabromomethazine sodium.

Science.gov (United States)

2010-04-01

... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Sulfabromomethazine sodium. 556.620 Section 556... Tolerances for Residues of New Animal Drugs § 556.620 Sulfabromomethazine sodium. Tolerances for residues of sulfabromomethazine sodium in food are established as follows: (a) In the uncooked edible tissues of cattle at 0.1...

21 CFR 522.1145 - Hyaluronate sodium.

Science.gov (United States)

2010-04-01

... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Hyaluronate sodium. 522.1145 Section 522.1145 Food... Hyaluronate sodium. (a)(1) Specifications. Each milliliter of sterile aqueous solution contains 10 milligrams of hyaluronate sodium. (2) Sponsor. See 000009 in § 510.600(c). (3) Conditions of use—(i) Amount...

Characterization of Sodium Spray Aerosols

Energy Technology Data Exchange (ETDEWEB)

Nelson, C. T.; Koontz, R. L.; Silberberg, M. [Atomics International, North American Rockwell Corporation, Canoga Park, CA (United States)

1968-12-15

The consequences of pool and spray fires require evaluation in the safety analysis of liquid metal-cooled fast breeder reactors. Sodium spray fires are characterized by high temperature and pressure, produced during the rapid combustion of sodium in air. Following the initial energy release, some fraction of the reaction products are available as aerosols which follow the normal laws of agglomeration, growth, settling, and plating. An experimental study is underway at Atomics International to study the characteristics of high concentration sprays of liquid sodium in reduced oxygen atmospheres and in air. The experiments are conducted in a 31.5 ft{sup 3} (2 ft diam. by 10 ft high) vessel, certified for a pressure of 100 lb/in{sup 2} (gauge). The spray injection apparatus consists of a heated sodium supply pot and a spray nozzle through which liquid sodium is driven by nitrogen pressure. Spray rate and droplet size can be varied by the injection velocity (nozzle size, nitrogen pressure, and sodium temperature). Aerosols produced in 0, 4, and 10 vol. % oxygen environments have been studied. The concentration and particle size distribution of the material remaining in the air after the spray injection and reaction period are measured. Fallout rates are found to be proportional to the concentration of aerosol which remains airborne following the spray period. (author)

Sodium and potassium content and their ratio in meatballs in tomato sauce produced with lower amounts of sodium

Science.gov (United States)

Lilić, S.; Nikolić, D.; Pejkovski, Z.; Velebit, B.; Lakićević, B.; Korićanac, V.; Vranić, D.

2017-09-01

The goal of this study was to examine the possibility of partial replacement of sodium chloride with potassium chloride and ammonium chloride, with the target of achieving less sodium content in meatballs and tomato sauce as well as achieving a better Na:K ratio. The trial consisted of five groups. In the control group of meatballs and sauce, only sodium chloride was added. In group 1, half of the sodium chloride was replaced with potassium chloride related to control group while in group 2 one third of the sodium chloride was replaced with potassium chloride. In group 3, one third of the sodium chloride was replaced with ammonium chloride, and in group 4, sodium chloride was reduced to half the amount in the control group, and 1 g (0.25%) of ammonium chloride was also added. All products were acceptable according to sensory analyses. The largest reductions of sodium content were 44.64%, achieved in meatballs from group 1 and 50.62% in tomato sauce from group 4 in relation to meatballs and tomato sauce from control group. The highest Na:K ratio was calculated in meatballs and tomato sauce from control group, 2.88 and 4.39, respectively. The best Na:K ratio was in meatballs and tomato sauce from group 1, 0.60 and 0.92, respectively, in which half of sodium chloride was replaced with potassium chloride. However, in meatballs and tomato sauce from group 4, with only half the amount of sodium chloride related to control group, the Na:K ratio was worse because in these products, potassium chloride was not added.

Estimating 24-hour urinary sodium excretion from casual urinary sodium concentrations in Western populations

DEFF Research Database (Denmark)

Brown, Ian J; Dyer, Alan R; Chan, Queenie

2013-01-01

High intakes of dietary sodium are associated with elevated blood pressure levels and an increased risk of cardiovascular disease. National and international guidelines recommend reduced sodium intake in the general population, which necessitates population-wide surveillance. We assessed the util...

Sodium aerosol formation in an argon flow over hot sodium

International Nuclear Information System (INIS)

Clement, C.F.; Dolias, M.J.; UKAEA Atomic Energy Research Establishment, Harwell. Thermal Hydraulics Div.)

1987-01-01

Vapour evaporation, which partly forms aerosol, occurs when a cold gas flows over a hot liquid. A previous well-mixed model is extended to predict the final vapour plus aerosol content of such a flow in terms of its initial and final temperatures. The predictions are compared to results of the Copacabana II experiment in which argon passed over a sodium pool. Agreement is obtained for the final sodium density at moderate flow rates, and physical reasons are given as to why deviations occur at low and high flow rates. (author)

A high-capacity, low-cost layered sodium manganese oxide material as cathode for sodium-ion batteries.

Science.gov (United States)

Guo, Shaohua; Yu, Haijun; Jian, Zelang; Liu, Pan; Zhu, Yanbei; Guo, Xianwei; Chen, Mingwei; Ishida, Masayoshi; Zhou, Haoshen

2014-08-01

A layered sodium manganese oxide material (NaMn3 O5 ) is introduced as a novel cathode materials for sodium-ion batteries. Structural characterizations reveal a typical Birnessite structure with lamellar stacking of the synthetic nanosheets. Electrochemical tests reveal a particularly large discharge capacity of 219 mAh g(-1) in the voltage rang of 1.5-4.7 V vs. Na/Na(+) . With an average potential of 2.75 V versus sodium metal, layered NaMn3 O5 exhibits a high energy density of 602 Wh kg(-1) , and also presents good rate capability. Furthermore, the diffusion coefficient of sodium ions in the layered NaMn3 O5 electrode is investigated by using the galvanostatic intermittent titration technique. The results greatly contribute to the development of room-temperature sodium-ion batteries based on earth-abundant elements. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Physical properties of liquid sodium

International Nuclear Information System (INIS)

Alberdi Primicia, J.; Martinez Piquer, T.A.

1977-01-01

The molten sodium has been the more accepted coolant for the first generation of FBR, by this reason the knowledge of its technology is needed for the development of the next LMFBR. A series of necessary data for designing sodium liquid systems are given. Tables and graphics about the most important physical sodium properties between 1200-1400 degC are gathered. The results have been obtained from equations that relate the properties with temperature using a Fortran IV program. (author) [es

A Global Model of Meteoric Sodium

Science.gov (United States)

Marsh, Daniel R.; Janches, Diego; Feng, Wuhu; Plane, John M. C.

2013-01-01

A global model of sodium in the mesosphere and lower thermosphere has been developed within the framework of the National Center for Atmospheric Research's Whole Atmosphere Community Climate Model (WACCM). The standard fully interactive WACCM chemistry module has been augmented with a chemistry scheme that includes nine neutral and ionized sodium species. Meteoric ablation provides the source of sodium in the model and is represented as a combination of a meteoroid input function (MIF) and a parameterized ablation model. The MIF provides the seasonally and latitudinally varying meteoric flux which is modeled taking into consideration the astronomical origins of sporadic meteors and considers variations in particle entry angle, velocity, mass, and the differential ablation of the chemical constituents. WACCM simulations show large variations in the sodium constituents over time scales from days to months. Seasonality of sodium constituents is strongly affected by variations in the MIF and transport via the mean meridional wind. In particular, the summer to winter hemisphere flow leads to the highest sodium species concentrations and loss rates occurring over the winter pole. In the Northern Hemisphere, this winter maximum can be dramatically affected by stratospheric sudden warmings. Simulations of the January 2009 major warming event show that it caused a short-term decrease in the sodium column over the polar cap that was followed by a factor of 3 increase in the following weeks. Overall, the modeled distribution of atomic sodium in WACCM agrees well with both ground-based and satellite observations. Given the strong sensitivity of the sodium layer to dynamical motions, reproducing its variability provides a stringent test of global models and should help to constrain key atmospheric variables in this poorly sampled region of the atmosphere.

austenitic steel corrosion by oxygen-containing liquid sodium

International Nuclear Information System (INIS)

Rivollier, Matthieu

2017-01-01

France is planning to construct the 4. generation of nuclear reactors. They will use liquid sodium as heat transfer fluid and will be made of 316L(N) austenitic steel as structural materials. To guarantee optimal operation on the long term, the behavior of this steel must be verified. This is why corrosion phenomena of 316L(N) steel by liquid sodium have to be well-understood. Literature points out that several corrosion phenomena are possible. Dissolved oxygen in sodium definitely influences each of the corrosion phenomenon. Therefore, the austenitic steel corrosion in oxygen-containing sodium is proposed in this study. Thermodynamics data point out that sodium chromite formation on 316L(N) steel is possible in sodium containing roughly 10 μg.g -1 of oxygen for temperature lower than 650 C (reactor operating conditions).The experimental study shows that sodium chromite is formed at 650 C in the sodium containing 200 μg.g -1 of oxygen. At the same concentration and at 550 C, sodium chromite is clearly observed only for long immersion time (≥ 5000 h). Results at 450 C are more difficult to interpret. Furthermore, the steel is depleted in chromium in all cases.The results suggest the sodium chromite is dissolved in the sodium at the same time it is formed. Modelling of sodium chromite formation - approached by chromium diffusion in steel (in grain and grain boundaries -, and dissolution - assessed by transport in liquid metal - show that simultaneous formation and dissolution of sodium chromite is a possible mechanism able to explain our results. (author) [fr

PG BN 1600 sodium fire protection system

International Nuclear Information System (INIS)

Bar, J.; Urbancik, L.

1978-12-01

A design was developed of a fire protection system for steam generator of a 1600 MW sodium cooled fast reactor (BN-1600). Chemical reactions are described of liquid sodium with atmospheric components and solid materials coming into contact with sodium in its release from the steam generator, and in safeguarding protection against sodium fires. The requirements for the purity of nitrogen as an atmosphere inert to liquid sodium are given. Characteristics and basic parameters are shown of level and spray fires, elementary terms are explained concerning the properties of aerosols formed during fires, the methods and means of release signalling and fire alarm are described as are fire precautions using fire-fighting equipment, modifying the support tank and the cell bottom and building sewage pits. The design of the system comprises an alarm system for liquid sodium using point and line electric contact sensors and flame photometer based aerosol sensors as well as a fire-fighting system based on the system of channelling liquid sodium into emergency discharge tanks filled with an inert gas, a set of fire extinguishers and other fire fighting material, and measures for the elimination of sodium fire consequences. (J.B.)

Identification of impurities in sodium and its purification

International Nuclear Information System (INIS)

Subbotin, B.I.; Voltchkov, L.G.; Kozlov, F.A.; Zagorulko, Yu.I.; Kuznetsov, E.K.

1976-01-01

The paper presents some investigation results on sodium technology. In particular, a description is given of a calculation method for evaluation of sodium-cover gas-impurities equilibrium compositions as well as experimental results on development of methods for sodium sampling, equipment for non-metallic impurities (oxygen, hydrogen, carbon) constant control in sodium. The investigation results on sodium purification with cold traps are presented

Experience on sodium removal from various components

Energy Technology Data Exchange (ETDEWEB)

Kamei, M; Kanbe, M; Yagisawa, H; Sasaki, S; Kataoka, H; Fukada, T; Ishii, Y; Saito, R; Mimoto, Y [O-arai Engineering Centre, PNC, Ibaraki-ken, Tokio (Japan)

1978-08-01

Since 1970, OEC (O-arai Engineering Center) has been Investigating the following methods for removal of sodium from the components of sodium plants: steam cleaning for the 50 MW Steam Generator, secondary proto-type pump of 'JOYO' and Dummy fuel assembly of 'JOYO', alcohol cleaning for Sector Model of Intermediate Heat Exchanger (IHX) of 'JOYO', a sector model of Sodium-to-Air cooler of 'JOYO' and a proto-type isolation valve of 'JOYO' and cleaning by vacuumization at high temperature for Regenerative Heat Exchanger. This report describes the outline of the Sodium Disposal Facility and experience of sodium removal processing on the 50 MW Steam Generator, the crevices of the experimental sub-assemblies, the Fuel Handling Machine of 'MONJU' and the Regenerative Heat Exchanger of the Sodium Flow Test Facility. Through these experiences it was noted that, (1) Removal of sodium from crevices such as in bolted joints are very difficult. (2) Consideration is needed in the removal process where material damage might occur from the generation of hydro-oxides. (3) Some detection device to tell the completion of sodium removal as well as the end of reaction is required. (4) Requalification rules should be clarified. Efforts in this direction have been made in the case of a 'JOYO' prototype pump by reinstalling it after sodium removal five times. (author)

Experience on sodium removal from various components

International Nuclear Information System (INIS)

Kamei, M.; Kanbe, M.; Yagisawa, H.; Sasaki, S.; Kataoka, H.; Fukada, T.; Ishii, Y.; Saito, R.; Mimoto, Y.

1978-01-01

Since 1970, OEC (O-arai Engineering Center) has been Investigating the following methods for removal of sodium from the components of sodium plants: steam cleaning for the 50 MW Steam Generator, secondary proto-type pump of 'JOYO' and Dummy fuel assembly of 'JOYO', alcohol cleaning for Sector Model of Intermediate Heat Exchanger (IHX) of 'JOYO', a sector model of Sodium-to-Air cooler of 'JOYO' and a proto-type isolation valve of 'JOYO' and cleaning by vacuumization at high temperature for Regenerative Heat Exchanger. This report describes the outline of the Sodium Disposal Facility and experience of sodium removal processing on the 50 MW Steam Generator, the crevices of the experimental sub-assemblies, the Fuel Handling Machine of 'MONJU' and the Regenerative Heat Exchanger of the Sodium Flow Test Facility. Through these experiences it was noted that, (1) Removal of sodium from crevices such as in bolted joints are very difficult. (2) Consideration is needed in the removal process where material damage might occur from the generation of hydro-oxides. (3) Some detection device to tell the completion of sodium removal as well as the end of reaction is required. (4) Requalification rules should be clarified. Efforts in this direction have been made in the case of a 'JOYO' prototype pump by reinstalling it after sodium removal five times. (author)

Experience on sodium removal from various components

International Nuclear Information System (INIS)

Kamei, M.; Kanbe, M.; Yagisawa, H.; Sasaki, S.; Kataoka, H.

1978-02-01

Since 1970, OEC (O-arai Engineering Center) has been investigating the following methods for removal of sodium from the components of sodium plants: steam cleaning for the 50 MW Steam Generator, secondary proto-type pump of ''JOYO'' and Dummy fuel assembly of ''JOYO'', alcohol cleaning for Sector Model of Intermediate Heat Exchanger (IHX) of ''JOYO'', a sector model of Sodium-to-Air cooler of ''JOYO'' and a proto-type Isolation valve of ''JOYO'' and cleaning by vacuumization at high temperature for Regenerative Heat Exchanger. This report describes the outline of the Sodium Disposal Facility and experience of sodium removal processing on the 50 MW Steam Generator, the crevices of the experimental subassemblies, the Fuel Handling Machine of ''MONJU'' and the Regenerative Heat Exchanger of the Sodium Flow Test Facility. Through these experiences it was noted that, (1) Removal of Sodium from crevices such as in bolted joints are very difficult. (2) Consideration is needed in the removal process where material damage might occur from the generation of hydro-oxides. (3) Some detection device to tell the completion of sodium removal as well as the end of reaction is required. (4) Requalification rules should be clarified. Efforts in this direction have been made in the case of a ''JOYO'' prototype pump by reinstalling it after sodium removal five times. (author)

Sodium Carbonate is Saltier Than Sodium Chloride to Sodium-Depleted Rats.

Science.gov (United States)

St John, Steven J; McBrayer, Anya M; Krauskopf, Erin E

2017-10-01

In a series of behavioral experiments in the 1960s, G.R. Morrison identified several unique features of the taste of Na2CO3 to rats; namely, it is 1) considerably more intense than NaCl at isomolar concentrations, 2) avoided at 10 times lower concentrations than NaCl to thirsty rats, 3) preferred at 10 times lower concentrations than NaCl in sodium-depleted rats. He also demonstrated its qualitatively similarity to NaCl. In Experiment 1, we confirmed and extended many of Morrison's observations. Rats were injected with furosemide on 3 occasions to stimulate a sodium appetite. After each depletion, rats were given a brief-access taste test in a lickometer presenting, in random order, water and 7 concentrations of salt. One test used NaCl (0.028-0.89 M, quarter log steps), another used Na2CO3, and the third used Na2CO3, but at a tenfold lower concentration range (0.0028-0.089 M). Rats licked NaCl in an inverted-U shaped concentration-response function peaking at 0.158-0.281 M. As Morrison's results predicted, rats licked Na2CO3 in nearly identical fashion, but at a tenfold lower concentration range (peak at 0.0158-0.028 M). In a second experiment, furosemide-treated rats were repeatedly tested with the lower Na2CO3 range but mixed in the epithelial sodium channel blocker amiloride at various concentrations (3-300 μM, half log steps). Amiloride reduced licking for Na2CO3 and shifted the peak response rightward up to about half a log unit. Thus, this "super-saltiness" of Na2CO3 to rats is at least partly amiloride-dependent. © The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

21 CFR 558.60 - Arsanilate sodium.

Science.gov (United States)

2010-04-01

... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Arsanilate sodium. 558.60 Section 558.60 Food and... in Animal Feeds § 558.60 Arsanilate sodium. (a) Appprovals. Type A medicated articles: 20, 50, or 100...) Arsanilate sodium may be used in accordance with the provisions of this section in the combinations provided...

21 CFR 184.1742 - Sodium carbonate.

Science.gov (United States)

2010-04-01

... 21 Food and Drugs 3 2010-04-01 2009-04-01 true Sodium carbonate. 184.1742 Section 184.1742 Food... Specific Substances Affirmed as GRAS § 184.1742 Sodium carbonate. (a) Sodium carbonate (Na2CO3, CAS Reg. No... ore calcined to impure soda ash and then purified; or (3) synthesized from limestone by the Solvay...

The Sodium Process Facility at Argonne National Laboratory-West

International Nuclear Information System (INIS)

Michelbacher, J.A.; Henslee, S.P.; McDermott, M.D.; Price, J.R.; Rosenberg, K.E.; Wells, P.B.

1998-01-01

Argonne National Laboratory-West (ANL-W) has approximately 680,000 liters of raw sodium stored in facilities on site. As mandated by the State of Idaho and the US Department of Energy (DOE), this sodium must be transformed into a stable condition for land disposal. To comply with this mandate, ANL-W designed and built the Sodium Process Facility (SPF) for the processing of this sodium into a dry, sodium carbonate powder. The major portion of the sodium stored at ANL-W is radioactively contaminated. The sodium will be processed in three separate and distinct campaigns: the 290,000 liters of Fermi-1 primary sodium, the 50,000 liters of the Experimental Breeder Reactor-II (EBR-II) secondary sodium, and the 330,000 liters of the EBR-II primary sodium. The Fermi-1 and the EBR-II secondary sodium contain only low-level of radiation, while the EBR-II primary sodium has radiation levels up to 0.5 mSv (50 mrem) per hour at 1 meter. The EBR-II primary sodium will be processed last, allowing the operating experience to be gained with the less radioactive sodium prior to reacting the most radioactive sodium. The sodium carbonate will be disposed of in 270 liter barrels, four to a pallet. These barrels are square in cross-section, allowing for maximum utilization of the space on a pallet, minimizing the required landfill space required for disposal

The Sodium Process Facility at Argonne National Laboratory-West

Energy Technology Data Exchange (ETDEWEB)

Michelbacher, J.A.; Henslee, S.P. McDermott, M.D.; Price, J.R.; Rosenberg, K.E.; Wells, P.B.

1998-07-01

Argonne National Laboratory-West (ANL-W) has approximately 680,000 liters of raw sodium stored in facilities on site. As mandated by the State of Idaho and the US Department of Energy (DOE), this sodium must be transformed into a stable condition for land disposal. To comply with this mandate, ANL-W designed and built the Sodium Process Facility (SPF) for the processing of this sodium into a dry, sodium carbonate powder. The major portion of the sodium stored at ANL-W is radioactively contaminated. The sodium will be processed in three separate and distinct campaigns: the 290,000 liters of Fermi-1 primary sodium, the 50,000 liters of the Experimental Breeder Reactor-II (EBR-II) secondary sodium, and the 330,000 liters of the EBR-II primary sodium. The Fermi-1 and the EBR-II secondary sodium contain only low-level of radiation, while the EBR-II primary sodium has radiation levels up to 0.5 mSv (50 mrem) per hour at 1 meter. The EBR-II primary sodium will be processed last, allowing the operating experience to be gained with the less radioactive sodium prior to reacting the most radioactive sodium. The sodium carbonate will be disposed of in 270 liter barrels, four to a pallet. These barrels are square in cross-section, allowing for maximum utilization of the space on a pallet, minimizing the required landfill space required for disposal.

Modeling of under-expanded reactive CO2-into-sodium jets, in the frame of sodium fast reactors

International Nuclear Information System (INIS)

Vivaldi, D.

2013-01-01

This PhD work was motivated by the investigations in the frame of supercritical CO 2 Brayton cycles as possible energy conversion cycles for the Sodium-cooled Fast nuclear Reactors (SFRs). This technology represents an alternative to conventional steam Rankine cycles, with the main advantage represented by the elimination of the accidental sodium-water reaction scenario. Nevertheless, CO 2 chemically reacts with sodium, through an exothermic reaction leading to solid reaction products, mainly sodium carbonate. Following an accidental leakage inside the sodium-CO 2 heat exchanger of a SFR, the CO 2 , having an operating pressure of about 200 bars, would be injected into the low-operating pressure liquid sodium, creating an under-expanded reactive CO 2 -into-sodium jet. The under-expanded jet features a sonic gas injection velocity and an under-expansion in the first region downstream the leakage, where the CO 2 is accelerated to supersonic velocities. The exothermic reaction between the CO 2 and the sodium causes an increasing of the temperature inside the heat exchanger. An experimental facility was built at CEA Cadarache, for the realization of CO 2 -into-sodium jets: this facility has provided preliminary results in terms of temperature variations inside the jet due to the exothermic reaction. However, this type of experimental tests are complicated to realize and to analyse, due to the technical difficulties of realizing the contact between CO 2 and sodium, and to the incertitude of temperature measurement inside a two-phase high velocity jet. It follows that a numerical model of this kind of jets is required, in order to understand the CO 2 -sodium kinetics of reaction inside the jet and being able to transpose the phenomenon to relevant SFR sodium-CO 2 heat exchangers. This would allow to understand the consequences of a leakage inside a sodium-CO 2 heat exchanger, in terms of, for instance, temperature profiles inside the heat exchanger and on tube surfaces

Distributed temperature sensor testing in liquid sodium

Energy Technology Data Exchange (ETDEWEB)

Gerardi, Craig; Bremer, Nathan; Lisowski, Darius; Lomperski, Stephen

2017-02-01

Rayleigh-backscatter-based distributed fiber optic sensors were immersed in sodium to obtain high-resolution liquid-sodium temperature measurements. Distributed temperature sensors (DTSs) functioned well up to 400°C in a liquid sodium environment. The DTSs measured sodium column temperature and the temperature of a complex geometrical pattern that leveraged the flexibility of fiber optics. A single Ø 360 lm OD sensor registered dozens of temperatures along a length of over one meter at 100 Hz. We also demonstrated the capability to use a single DTS to simultaneously detect thermal interfaces (e.g. sodium level) and measure temperature.

A Patient with MSUD: Acute Management with Sodium Phenylacetate/Sodium Benzoate and Sodium Phenylbutyrate.

Science.gov (United States)

Köse, Melis; Canda, Ebru; Kagnici, Mehtap; Uçar, Sema Kalkan; Çoker, Mahmut

2017-01-01

In treatment of metabolic imbalances caused by maple syrup urine disease (MSUD), peritoneal dialysis, and hemofiltration, pharmacological treatments for elimination of toxic metabolites can be used in addition to basic dietary modifications. Therapy with sodium phenylacetate/benzoate or sodium phenylbutyrate (NaPB) in urea-cycle disorder cases has been associated with a reduction in branched-chain amino acid (BCAA) concentrations when the patients are on adequate dietary protein intake. Moreover, NaPB in treatment of MSUD patients is also associated with reduction of BCAA levels in a limited number of cases. However, there are not enough studies in the literature about application and efficacy of this treatment. Our case report sets an example of an alternative treatment's efficacy when extracorporeal procedures are not available due to technical difficulties during attack period of the disease.

Hydration status regulates sodium flux and inflammatory pathways through epithelial sodium channel (ENaC) in the skin.

Science.gov (United States)

Xu, Wei; Hong, Seok Jong; Zeitchek, Michael; Cooper, Garry; Jia, Shengxian; Xie, Ping; Qureshi, Hannan A; Zhong, Aimei; Porterfield, Marshall D; Galiano, Robert D; Surmeier, D James; Mustoe, Thomas A

2015-03-01

Although it is known that the inflammatory response that results from disruption of epithelial barrier function after injury results in excessive scarring, the upstream signals remain unknown. It has also been observed that epithelial disruption results in reduced hydration status and that the use of occlusive dressings that prevent water loss from wounds decreases scar formation. We hypothesized that hydration status changes sodium homeostasis and induces sodium flux in keratinocytes, which result in activation of pathways responsible for keratinocyte-fibroblast signaling and ultimately lead to activation of fibroblasts. Here, we demonstrate that perturbations in epithelial barrier function lead to increased sodium flux in keratinocytes. We identified that sodium flux in keratinocytes is mediated by epithelial sodium channels (ENaCs) and causes increased secretion of proinflammatory cytokines, which activate fibroblast via the cyclooxygenase 2 (COX-2)/prostaglandin E2 (PGE2) pathway. Similar changes in signal transduction and sodium flux occur by increased sodium concentration, which simulates reduced hydration, in the media in epithelial cultures or human ex vivo skin cultures. Blockade of ENaC, prostaglandin synthesis, or PGE2 receptors all reduce markers of fibroblast activation and collagen synthesis. In addition, employing a validated in vivo excessive scar model in the rabbit ear, we demonstrate that utilization of either an ENaC blocker or a COX-2 inhibitor results in a marked reduction in scarring. Other experiments demonstrate that the activation of COX-2 in response to increased sodium flux is mediated through the PIK3/Akt pathway. Our results indicate that ENaC responds to small changes in sodium concentration with inflammatory mediators and suggest that the ENaC pathway is a potential target for a strategy to prevent fibrosis.

Water simulation of sodium reactors

International Nuclear Information System (INIS)

Grewal, S.S.; Gluekler, E.L.

1981-01-01

The thermal hydraulic simulation of a large sodium reactor by a scaled water model is examined. The Richardson Number, friction coefficient and the Peclet Number can be closely matched with the water system at full power and the similarity is retained for buoyancy driven flows. The simulation of thermal-hydraulic conditions in a reactor vessel provided by a scaled water experiment is better than that by a scaled sodium test. Results from a correctly scaled water test can be tentatively extrapolated to a full size sodium system

Dietary sodium: where science and policy conflict: impact of the 2013 IOM Report on Sodium Intake in Populations.

Science.gov (United States)

Graudal, Niels

2015-02-01

The 2013 Institute of Medicine (IOM) report "Sodium Intake in Populations: Assessment of Evidence" did not support the current recommendations of the IOM and the American Heart Association (AHA) to reduce daily dietary sodium intake to below 2,300 mg. The report concluded that the population-based health outcome evidence was not sufficient to define a safe upper intake level for sodium. Recent studies have extended this conclusion to show that a sodium intake below 2,300 mg/day is associated with increased mortality. In spite of this increasing body of evidence, the AHA, Centers for Disease Control (CDC), other public health advisory bodies, and major medical journals have continued to support the current policy of reducing dietary sodium.

UK position paper on sodium fires

Energy Technology Data Exchange (ETDEWEB)

Vaughan, G J [National Nuclear Corporation Ltd., Risley, Warrington, Cheshire (United Kingdom); Glass, D [United Kingdom Atomic Energy Authority, Dounreay Nuclear Power Development Establishment, Thurso, Caithness (United Kingdom); Newman, R N [Central Electricity Generating Board, Berekely Nuclear Laboratory, Berkeley, Gloucestershire (United Kingdom); Ramsdale, S A [United Kingdom Atomic Energy Authority, Safety and Reliability Directorate, Culcheth, Cheshire (United Kingdom); Snelling, K W [United Kingdom Atomic Energy Authority, Atomic Energy Establishment, Winfrith, Dorchester, Dorset (United Kingdom)

1989-07-01

The UK has over several years developed a philosophy for the prevention, mitigation and extinguishment of sodium fires. The systems which were developed for PFR have been continuously revised and modified and from these considerations systems were proposed for CDFR. The latest phases of this development are described with reference to the CDFR plant. The current analytical and experimental work on fires, aerosols and sodium concrete reactions is also discussed. The UK are developing codes to analyse the effects of a sodium fire in a building and to model aerosol behaviour following a fire. Experimental work on small scale fires, aerosol behaviour, filtration devices and sodium concrete reaction is being carried out on a laboratory scale. Techniques for aerosol measurement and characterisation have also been developed and used both In the laboratory and large scale tests. Larger scale tests of sodium fire extinguishment techniques have also been performed. Currently a programme of tests (SOFA) of large scale fires in the open to investigate the chemical and physical changes in the aerosol and its dispersion in the atmosphere are just beginning. The UK studies are intended to both assist in the development of prevention and mitigation systems for design base and beyond design base accidents in any building which contains sodium (or sodium potassium alloy) and also to provide methods for assessing the risks from such accidents. (author)

UK position paper on sodium fires

International Nuclear Information System (INIS)

Vaughan, G.J.; Glass, D.; Newman, R.N.; Ramsdale, S.A.; Snelling, K.W.

1989-01-01

The UK has over several years developed a philosophy for the prevention, mitigation and extinguishment of sodium fires. The systems which were developed for PFR have been continuously revised and modified and from these considerations systems were proposed for CDFR. The latest phases of this development are described with reference to the CDFR plant. The current analytical and experimental work on fires, aerosols and sodium concrete reactions is also discussed. The UK are developing codes to analyse the effects of a sodium fire in a building and to model aerosol behaviour following a fire. Experimental work on small scale fires, aerosol behaviour, filtration devices and sodium concrete reaction is being carried out on a laboratory scale. Techniques for aerosol measurement and characterisation have also been developed and used both In the laboratory and large scale tests. Larger scale tests of sodium fire extinguishment techniques have also been performed. Currently a programme of tests (SOFA) of large scale fires in the open to investigate the chemical and physical changes in the aerosol and its dispersion in the atmosphere are just beginning. The UK studies are intended to both assist in the development of prevention and mitigation systems for design base and beyond design base accidents in any building which contains sodium (or sodium potassium alloy) and also to provide methods for assessing the risks from such accidents. (author)