75 FR 59606 - Airworthiness Directives; Pacific Aerospace Limited Models FU24-954 and FU24A-954 Airplanes

Federal Register 2010, 2011, 2012, 2013, 2014

2010-09-28

... Airworthiness Directives; Pacific Aerospace Limited Models FU24- 954 and FU24A-954 Airplanes AGENCY: Federal... Schletzbaum, Aerospace Engineer, FAA, Small Airplane Directorate, 901 Locust, Room 301, Kansas City, Missouri... Sec. 39.13 by adding the following new AD: 2010-20-18 Pacific Aerospace Limited: Amendment 39-16453...

Protoplanetary Formation and the FU Orionis Outburst

NASA Technical Reports Server (NTRS)

Bodenheimer, P. H.

1996-01-01

The following three publications which reference the above grant from the NASA Origins of Solar Systems program are attached and form the final technical report for this project. The research involved comparisons of the spectral energy distributions of FU Orionis objects with theoretical models and associated studies of the structure of the outbursting accretion disks, as well as related studies on the effects of magnetic fields in disks, which will lead in the future to models of FU Orionis outbursts which include the effects of magnetic fields. The project was renewed under a new grant NAGW-4456, entitled 'Effects of FU Orionis Outbursts on Protoplanetary Disks'. Work now being prepared for publication deals more specifically with the issue of the effects of the outbursts on protoplanetary formation. Models of the spectral energy distribution of FU Orionis stars. A simple model of a buoyant magnetic dynamo in accretion disks and a numerical study of magnetic buoyancy in an accretion disk have been submitted.

Effect of dietary arginine on growth, intestinal enzyme activities and gene expression in muscle, hepatopancreas and intestine of juvenile Jian carp (Cyprinus carpio var. Jian).

PubMed

Chen, Gangfu; Feng, Lin; Kuang, Shengyao; Liu, Yang; Jiang, Jun; Hu, Kai; Jiang, Weidan; Li, Shuhong; Tang, Ling; Zhou, Xiaoqiu

2012-07-01

The present study was conducted to test the hypothesis that dietary arginine promotes digestion and absorption capacity, and, thus, enhances fish growth. This improvement might be related to the target of rapamycin (TOR) and eIF4E-binding protein (4E-BP). A total of 1200 juvenile Jian carp, Cyprinus carpio var. Jian, with an average initial weight of 6.33 (SE 0.03) g, were fed with diets containing graded concentrations of arginine, namely, 9.8 (control), 12.7, 16.1, 18.5, 21.9 and 24.5 g arginine/kg diet for 9 weeks. An real-time quantitative PCR analysis was performed to determine the relative expression of TOR and 4E-BP in fish muscle, hepatopancreas and intestine. Dietary arginine increased (P < 0.05): (1) glutamate-oxaloacetate transaminase and glutamate-pyruvate transaminase activities in muscle and hepatopancreas; (2) intestine and hepatopancreas protein content, folds height, and trypsin, chymotrypsin, lipase, Na⁺/K⁺-ATPase, alkaline phosphatase, γ-glutamyl transpeptidase and creatine kinase activities in intestine; (3) Lactobacillus counts; (4) relative expression of TOR in the muscle, hepatopancreas and distal intestine (DI); (5) relative expression of 4E-BP in proximal intestine (PI) and mid-intestine (MI), as compared with the control group. In contrast, dietary arginine reduced (P < 0.05): (1) plasma ammonia content; (2) Aeromonas hydrophila and Escherichia coli counts; (3) relative expression of TOR in PI and MI; (4) relative expression of 4E-BP in the muscle, hepatopancreas and DI. The arginine requirement estimated by specific growth rate using quadratic regression analysis was found to be 18.0 g/kg diet. These results indicate that arginine improved fish growth, digestive and absorptive ability and regulated the expression of TOR and 4E-BP genes.

Variable X-ray Emission from FU Orionis

NASA Astrophysics Data System (ADS)

Skinner, Steve L.; Guedel, M.; Briggs, K. R.; Lamzin, S. A.; Sokal, K. R.

2009-05-01

FU Orionis is the prototype of a small but remarkable class of pre-main sequence stars ('FUors') that have undergone large optical outbursts thought to be linked to episodic accretion. FU Ori increased in optical brightness by about 6 mag in 1936-37 and is still in slow decline. Because of their high accretion rates, FUors are good candidates for exploring potential effects of accretion on X-ray emission. A recently completed survey of FUors with XMM-Newton detected X-rays from FU Ori and V1735 Cyg. We present new results from a sensitive 99 ksec (1.15 day) follow-up X-ray observation of FU Ori with Chandra. The Chandra ACIS-S CCD spectrum confirms the presence of a cool plasma component (kT < 1 keV) viewed under moderate absorption and a much hotter component (kT > 3 keV), viewed under high absorption, in accord with previous XMM results. The uninterrupted Chandra light curve shows that the hot component is slowly variable on a timescale of one day, but no variability is detected in the cool component. The slow variability and high plasma temperature point to a magnetic origin for the hot component, but other mechanisms (including accretion) may be responsible for the cool non-variable component. We will discuss these new results in the context of what is known about FU Ori from previous observations, including XMM (Skinner et al. 2006, ApJ, 643, 995) and HST (Kravtsova et al. 2007, Ast. Ltrs., 33, 755).

Cultivating a "Jian Zi": Exploring an Art Teacher's Responsive Pedagogy for the Development of Art Talent in Taiwan

ERIC Educational Resources Information Center

Chen, Wei-Ren

2017-01-01

This qualitative case study explored the operational curricula of an art teacher's responsive pedagogy that focused on the differentiation aspects for artistically talented students in an elementary school in Taiwan. Findings indicate that cultivating a "Jian Zi" is the heart of the value system embedded in the art teacher's responsive…

Learning from the past: Rare ε-Fe2O3 in the ancient black-glazed Jian (Tenmoku) wares

PubMed Central

Dejoie, Catherine; Sciau, Philippe; Li, Weidong; Noé, Laure; Mehta, Apurva; Chen, Kai; Luo, Hongjie; Kunz, Martin; Tamura, Nobumichi; Liu, Zhi

2014-01-01

Ancient Jian wares are famous for their lustrous black glaze that exhibits unique colored patterns. Some striking examples include the brownish colored “Hare's Fur” (HF) strips and the silvery “Oil Spot” (OS) patterns. Herein, we investigated the glaze surface of HF and OS samples using a variety of characterization methods. Contrary to the commonly accepted theory, we identified the presence of ε-Fe2O3, a rare metastable polymorph of Fe2O3 with unique magnetic properties, in both HF and OS samples. We found that surface crystals of OS samples are up to several micrometers in size and exclusively made of ε-Fe2O3. Interestingly, these ε-Fe2O3 crystals on the OS sample surface are organized in a periodic two dimensional fashion. These results shed new lights on the actual mechanisms and kinetics of polymorphous transitions of Fe2O3. Deciphering technologies behind the fabrication of ancient Jian wares can thus potentially help researchers improve the ε-Fe2O3 synthesis. PMID:24820819

γ-Tocotrienol prevents 5-FU-induced reactive oxygen species production in human oral keratinocytes through the stabilization of 5-FU-induced activation of Nrf2.

PubMed

Takano, Hideyuki; Momota, Yukihiro; Kani, Kouichi; Aota, Keiko; Yamamura, Yoshiko; Yamanoi, Tomoko; Azuma, Masayuki

2015-04-01

Chemotherapy-induced oral mucositis is a common adverse event in patients with oral squamous cell carcinoma, and is initiated through a variety of mechanisms, including the generation of reactive oxygen species (ROS). In this study, we examined the preventive effect of γ-tocotrienol on the 5-FU-induced ROS production in human oral keratinocytes (RT7). We treated RT7 cells with 5-FU and γ-tocotrienol at concentrations of 10 µg/ml and 10 nM, respectively. When cells were treated with 5-FU alone, significant growth inhibition was observed as compared to untreated cells. This inhibition was, in part, due to the ROS gene-rated by 5-FU treatment, because N-acetyl cysteine (NAC), a ROS scavenger, significantly ameliorated the growth of RT7 cells. γ-tocotrienol showed no cytotoxic effect on the growth of RT7 cells. Simultaneous treatment of cells with these agents resulted in the significant recovery of cell growth, owing to the suppression of ROS generation by γ-tocotrienol. Whereas 5-FU stimulated the expression of NF-E2-related factor 2 (Nrf2) protein in the nucleus up to 12 h after treatment of RT7 cells, γ-tocotrienol had no obvious effect on the expression of nuclear Nrf2 protein. Of note, the combined treatment with both agents stabilized the 5-FU-induced nuclear Nrf2 protein expression until 24 h after treatment. In addition, expression of Nrf2-dependent antioxidant genes, such as heme oxygenase-1 (HO-1) and quinone oxidoreductase-1 (NQO-1), was significantly augmented by treatment of cells with both agents. These findings suggest that γ-tocotrienol could prevent 5-FU-induced ROS generation by stabilizing Nrf2 activation, thereby leading to ROS detoxification and cell survival in human oral keratinocytes.

γ-tocotrienol prevents 5-FU-induced reactive oxygen species production in human oral keratinocytes through the stabilization of 5-FU-induced activation of Nrf2

PubMed Central

TAKANO, HIDEYUKI; MOMOTA, YUKIHIRO; KANI, KOUICHI; AOTA, KEIKO; YAMAMURA, YOSHIKO; YAMANOI, TOMOKO; AZUMA, MASAYUKI

2015-01-01

Chemotherapy-induced oral mucositis is a common adverse event in patients with oral squamous cell carcinoma, and is initiated through a variety of mechanisms, including the generation of reactive oxygen species (ROS). In this study, we examined the preventive effect of γ-tocotrienol on the 5-FU-induced ROS production in human oral keratinocytes (RT7). We treated RT7 cells with 5-FU and γ-tocotrienol at concentrations of 10 μg/ml and 10 nM, respectively. When cells were treated with 5-FU alone, significant growth inhibition was observed as compared to untreated cells. This inhibition was, in part, due to the ROS generated by 5-FU treatment, because N-acetyl cysteine (NAC), a ROS scavenger, significantly ameliorated the growth of RT7 cells. γ-tocotrienol showed no cytotoxic effect on the growth of RT7 cells. Simultaneous treatment of cells with these agents resulted in the significant recovery of cell growth, owing to the suppression of ROS generation by γ-tocotrienol. Whereas 5-FU stimulated the expression of NF-E2-related factor 2 (Nrf2) protein in the nucleus up to 12 h after treatment of RT7 cells, γ-tocotrienol had no obvious effect on the expression of nuclear Nrf2 protein. Of note, the combined treatment with both agents stabilized the 5-FU-induced nuclear Nrf2 protein expression until 24 h after treatment. In addition, expression of Nrf2-dependent antioxidant genes, such as heme oxygenase-1 (HO-1) and NAD(P)H:quinone oxidoreductase-1 (NQO-1), was significantly augmented by treatment of cells with both agents. These findings suggest that γ-tocotrienol could prevent 5-FU-induced ROS generation by stabilizing Nrf2 activation, thereby leading to ROS detoxification and cell survival in human oral keratinocytes. PMID:25625649

FU Orionis Outbursts and the Solar Nebula

NASA Technical Reports Server (NTRS)

Bell, Robbins; Young, Rich (Technical Monitor)

1998-01-01

Protostellar systems are variable on many timescales. The FU Orionis outburst is one of the most drastic forms of variability known to occur in low mass stellar systems. During a typical outburst lasting several decades, system luminosities may be a hundred times what is normal of the quiescent state. FU Orionis outburst events are believed to have significant impacts on the thermal structure of the protosolar nebula. Their existence has been utilized to explain features in the meteoritic record from thermally induced homogenization to chondrule formation. Recent numerical models have shown the viability of the hypothesis that the radiation observed during outburst is emitted by a luminous circumstellar disk transporting mass at a thousand times the quiescent rate. We will begin by describing what is known about the FU Orionis outburst phenomenon from recent observations and theory. We will discuss evidence that suggests that outburst radiation is emitted by a circumstellar disk rather than by the star and will briefly describe the thermal instability as a mechanism for outburst. Additional information is contained in the original extended abstract.

Effects of partial replacement of fish meal by yeast hydrolysate on complement system and stress resistance in juvenile Jian carp (Cyprinus carpio var. Jian).

PubMed

Yuan, Xiang-Yang; Liu, Wen-Bin; Liang, Chao; Sun, Cun-Xin; Xue, Yun-Fei; Wan, Zu-De; Jiang, Guang-Zhen

2017-08-01

A 10-week feeding trial was carried out to investigate the effects of dietary fish meal replacement by yeast hydrolysate (YH) on growth performance, complement system and stress resistance of juvenile Jian carp (Cyprinus carpio var. Jian) (initial average weight 19.44 ± 0.06 g). In the study, there were five groups: one control group was fed with a basal diet (YH0), and four treatment groups were fed with dietary fish meal replaced by 1% YH (YH1), 3% (YH3), 5% (YH5) and 7% (YH7), respectively. Each group had four replicates. At the end of feeding trial, twelve fish from each group (three fish per replicate) were randomly selected for assessing the growth and immunity. Meanwhile, 20 fish per replicate were injected by Aeromonas hydrophila. The results showed that (1) Replacement levels of YH significantly affected the growth of the fish with the highest values of weight gain (WG) occurred in fish fed YH3 diet. However, no significant difference in feed conversion ratios (FCR) was observed among all groups. (2) Pre-stressed plasma lysozyme activity, total protein and albumin contents and complement component 3 (C3) and complement component 4 (C4) levels of fish fed YH3 diet were significantly higher than those of fish fed YH0 diet. However, post-stressed immune parameters of fish in all groups were significantly lower. (3) There was a trend that the expression levels of the complement-related genes (c1r/s-A, c4-1, c3-H1, c5-1, fb/c2-A, mbl-2 and masp) initially increased and then decreased except mbl-2 and masp, with the maximum values observed in fish fed YH3 diet. Before stress, the expression levels of the inflammation-related genes (alp, il-1β and tnf-α) in the hepatopancreas and spleen of fish fed YH1 diet and YH7 diet were significant higher than that of fish fed YH0 diet. After stress, no significant difference in the expression levels of those genes was observed among all groups. These results indicated that FM replacement by YH could improve growth

A Photometric Study of the Contact Binary System FU Dra

NASA Astrophysics Data System (ADS)

Kaitchuck, R. H.; Hill, R. L.; Corn, A. P.; Gevirtz, J.; Levell, K. L.; Valenti, T. L.

2006-12-01

This paper reports new four-filter CCD observations of the contact binary FU Dra. The Wilson and Devinney model was used to simultaneously fit these light curves and published radial velocity data. The stellar masses, sizes, and densities were calculated. Five additional models involving dark spots, hot spots, and accretion heating were considered as explanations for the light curve asymmetry known as the "O'Connell effect" in FU Dra. No conclusive spot model choice could be made but the Liu and Yang model for accretion heating is an unlikely explanation for the O'Connell effect in FU Dra.

Inhibition effects of a negative electret 5-FU patch on the growth of a hypertrophic scar

NASA Astrophysics Data System (ADS)

Wang, YUAN; Lili, XU; Ping, HUANG; Xiaoqiang, AN; Lili, CUI; Jian, JIANG

2018-05-01

In this study, the hypertrophic scar (HS) model in rats was established. 5-fluorouracil (5-FU) patch, ‑1000 V and ‑2000 V polypropylene (PP) electret 5-FU patches were prepared and applied onto the wound. The in vitro permeation experiment was performed using the Franz diffusion cell system to determine the permeation cumulative amount and retention amount of 5-FU through/in scar skin. The inhibition effect of negative electret on growth of HS was studied by hematoxylin-eosin (HE) staining, Masson staining and the immunohistologicall methods. The permeation study indicated that a negative electret could enhance the permeation and retention of 5-FU through and in scar skin respectively. HE staining and Masson staining indicated a better effect for ‑1000 V and ‑2000 V electret 5-FU patches on HS inhibition after 28 d post-wounding compared with 5-FU patch. The immunohistological study showed much more reduced expressions of collegan type I, collegan type III, TGF-β1 and HSP47 in scar tissue after application of negative electret 5-FU patches than those of 5-FU patch. A negative electret 5-FU patch may be advantageous for HS treatment.

Overview of the Fusion Z-Pinch Experiment FuZE

NASA Astrophysics Data System (ADS)

Weber, T. R.; Shumlak, U.; Nelson, B. A.; Golingo, R. P.; Claveau, E. L.; McLean, H. S.; Tummel, K. K.; Higginson, D. P.; Schmidt, A. E.; UW/LLNL Team

2016-10-01

Previously, the ZaP device, at the University of Washington, demonstrated sheared flow stabilized (SFS) Z-pinch plasmas. Instabilities that have historically plagued Z-pinch plasma confinement were mitigated using sheared flows generated from a coaxial plasma gun of the Marshall type. Based on these results, a new SFS Z-pinch experiment, the Fusion Z-pinch Experiment (FuZE), has been constructed. FuZE is designed to investigate the scaling of SFS Z-pinch plasmas towards fusion conditions. The experiment will be supported by high fidelity physics modeling using kinetic and fluid simulations. Initial plans are in place for a pulsed fusion reactor following the results of FuZE. Notably, the design relies on proven commercial technologies, including a modest discharge current (1.5 MA) and voltage (40 kV), and liquid metal electrodes. Supported by DoE FES, NNSA, and ARPA-E ALPHA.

Anti-inflammatory and hepatoprotective effects of glycyrrhetinic acid on CCl4-induced damage in precision-cut liver slices from Jian carp (Cyprinus carpio var. jian) through inhibition of the nf-kƁ pathway.

PubMed

Cao, Liping; Ding, Weidong; Jia, Rui; Du, Jingliang; Wang, Tao; Zhang, Chunyun; Gu, Zhengyan; Yin, Guojun

2017-05-01

In order to evaluate the antioxidant and anti-inflammatory effects of glycyrrhetinic acid (GA) on carbon tetrachloride (CCl 4 )-induced damage in precision-cut liver slices (PCLS) from Jian carp (Cyprinus carpio. Jian), an acute liver damage model was established in this study. The viability of PCLS, levels of anti-oxidases in liver homogenates, expression of inflammation-related genes including nuclear factor-κB (nf-κB)/c-rel, inducible nitric oxide synthase (inos), interleukin-1β (il-1β), interleukin-6 (il-6) and interleukin-8 (il-8), and protein levels of (nf-κB)/c-rel in liver tissues were measured. The results showed that pretreatment of PCLS with GA at 5 and 10 μg/mL for 6 h significantly inhibited the cytotoxicity of CCl 4 . GA attenuated CCl 4 -induced oxidative stress in PCLS through promoting the recovery of superoxide dismutase (SOD) and glutathione (GSH) levels, and inhibiting malondialdehyde (MDA) synthesis. In inflammatory response, GA at both 5 and 10 μg/mL significantly inhibited the increase in mRNA levels of inflammatory cytokines including nf-kƁ/c-rel, inos, il-1β, il-6 and il-8, and the protein level of Nf-kƁ/C-rel induced by CCl 4 . Furthermore, treatment with pyrrolyl dithiocarbamate (PDTC, 4 μg/mL), an inhibitor of nuclear transcription factor nf-kB, significantly inhibited nf-kB levels, and transcription of downstream cytokines inos, il-1β, il-6 and il-8, also the viability of PCLS was significantly increased. These results indicated that GA suppressed inflammation and reduced cytotoxicity by inhibiting the nf-kƁ signaling pathway, and plays a role in liver protection. Copyright © 2017. Published by Elsevier Ltd.

Quality-adjusted survival with combination nal-IRI+5-FU/LV vs 5-FU/LV alone in metastatic pancreatic cancer patients previously treated with gemcitabine-based therapy: a Q-TWiST analysis.

PubMed

Pelzer, Uwe; Blanc, Jean-Frédéric; Melisi, Davide; Cubillo, Antonio; Von Hoff, Daniel D; Wang-Gillam, Andrea; Chen, Li-Tzong; Siveke, Jens T; Wan, Yin; Solem, Caitlyn T; Botteman, Marc F; Yang, Yoojung; de Jong, Floris A; Hubner, Richard A

2017-05-09

In the NAPOLI-1 Phase 3 trial, nal-IRI+5-fluorouracil and leucovorin (5-FU/LV) significantly improved median overall survival (6.1 vs 4.2 months, P=0.012) and progression-free survival (3.1 vs 1.5 months, P=0.0001) vs 5-FU/LV alone in metastatic pancreatic adenocarcinoma patients previously treated with gemcitabine-based therapy. This analysis evaluated between treatment differences in quality-adjusted time without symptoms of disease progression or toxicity (Q-TWiST). Overall survival was partitioned into time with grade ⩾3 toxicity (TOX), disease progression (REL), and time without disease progression symptoms or grade ⩾3 toxicity (TWiST). Mean Q-TWiST was calculated by weighting time spent by a utility of 1.0 for TWiST and 0.5 for TOX and REL. In threshold analyses, utility for TOX and REL were varied from 0.0 to 1.0. Patients in nal-IRI+5-FU/LV (n=117) vs 5-FU/LV (n=119) had significantly more mean time in TWiST (3.4 vs 2.4 months) and TOX (1.0 vs 0.3 months) but similar REL (2.5 vs 2.7 months). In the base case, nal-IRI+5-FU/LV patients had 1.3 months (95% CI, 0.4-2.1; 5.1 vs 3.9) greater Q-TWiST (threshold analyses range: 0.9-1.6 months). Within NAPOLI-1, nal-IRI+5-FU/LV resulted in statistically significant and clinically meaningful gains in quality-adjusted survival vs 5-FU/LV alone.

Genoprotective effect of the Chinese herbal decoction xiao jian zhong tang.

PubMed

Szeto, Yim-Tong; Cheng, Ngok-Fung; Pak, Sok-Cheon; Kalle, Wouter

2013-03-01

The Chinese herbal decoction formula Xiao Jian Zhong Tang (XJZT) is one of the classic formulas from the classic traditional Chinese medicine (TCM). Previous studies on XJZT found that it is effective for treating peptic ulcer, irritable bowel syndrome, functional gastroenteritis and similar psychosomatic disorders of the digestive organs. It has also been shown that all the herbs used in XJZT contain antioxidants. In this study, we investigated the in vitro DNA protection effect of the individual herb extracts and the whole formula. Water extract of the herbs and XJZT were used to pre-treat human lymphocytes. The lymphocytes were then exposed to hydrogen peroxide. The in vitro DNA protection effect of the herbs was investigated by comet assay. No DNA protective effect (P < 0.05) was found for individual herb extracts, but XJZT showed protection of human lymphocytic DNA upon oxidative stress (P < 0.05). The in vitro DNA protection effect of XJZT was conferred by the synergistic effect of the herbs, while the individual herbs had no such effect.

[Anti-tumor effect of 5-FU-PLLA-CNTs on human gastric carcinoma cell lines in vitro].

PubMed

Gu, Jun; Li, Maolan; Wu, Xiangsong; Wu, Wenguang; Zhang, Lin; Ding, Qichen; Yang, Jiahua; Weng, Hao; Ding, Qian; Bao, Runfa; Shu, Yijun; Liu, Yingbin

2014-04-01

To prepare cisPLLAtin-loaded polylactic acid/cnts, and to study the anti-tumor effect of 5-FU-PLLA-CNTs on human gastric carcinoma cell lines(MGC803 and MNK45). 5-FU-PLLA-CNTs were prepared with ultrasound emulsification. The morphology of 5-FU-PLLA-CNTs was determined by scanning electron microscope(SEM), and its drug loading and drug release curve in vitro were detected by UV-Vis-NIR spectrophotometer. Cells were divided into experiment, positive control and negative control groups. CCK8 method was used to test the cytotoxic effect of 5-FU-PLLA-CNTs in different concentrations on MGC803 and MNK45 cell proliferation. Flow cytometry was employed to measure the apoptotic rate of MGC803 and MNK45 cells before and after the intervention of 5-FU-PLLA-CNTs. Deep layer film of 5-FU-PLLA-CNTs was successfully established, whose drug-load rate was(4.54±0.43)%, entrapment rate was(21.56±2.36)%. In vitro release test showed release rate within 24 h of 5-FU-PLLA-CNTs was 23.9% in a as lowly increasing manner, and accumulating release rate was 85.3% at day 31. CCk8 experiment revealed, as compared to control group, 5-FU-PLLA-CNTs significantly inhibited the proliferation of two cell lines in dose-dependent and time-dependent manner. The best 5-FU-PLLA-CNTs concentration of inhibition for human gastric cancer cell lines was 1 mg/well. Flow cytometry indicated the apoptotic rate of MGC803 and MNK45 cells in experiment group treated by 1 mg/well 5-FU-PLLA-CNTs significantly increased as compared to negative control group (P<0.05), while the difference was not significant as compared to positive control group (P>0.05). The 5-FU-PLLA-CNTs has good drug sustained-release capacity, and can significantly kill and inhibit the proliferation of MGC803 and MNK45 cell lines.

Itch/β-arrestin2-dependent non-proteolytic ubiquitylation of SuFu controls Hedgehog signalling and medulloblastoma tumorigenesis.

PubMed

Infante, Paola; Faedda, Roberta; Bernardi, Flavia; Bufalieri, Francesca; Lospinoso Severini, Ludovica; Alfonsi, Romina; Mazzà, Daniela; Siler, Mariangela; Coni, Sonia; Po, Agnese; Petroni, Marialaura; Ferretti, Elisabetta; Mori, Mattia; De Smaele, Enrico; Canettieri, Gianluca; Capalbo, Carlo; Maroder, Marella; Screpanti, Isabella; Kool, Marcel; Pfister, Stefan M; Guardavaccaro, Daniele; Gulino, Alberto; Di Marcotullio, Lucia

2018-03-07

Suppressor of Fused (SuFu), a tumour suppressor mutated in medulloblastoma, is a central player of Hh signalling, a pathway crucial for development and deregulated in cancer. Although the control of Gli transcription factors by SuFu is critical in Hh signalling, our understanding of the mechanism regulating this key event remains limited. Here, we show that the Itch/β-arrestin2 complex binds SuFu and induces its Lys63-linked polyubiquitylation without affecting its stability. This process increases the association of SuFu with Gli3, promoting the conversion of Gli3 into a repressor, which keeps Hh signalling off. Activation of Hh signalling antagonises the Itch-dependent polyubiquitylation of SuFu. Notably, different SuFu mutations occurring in medulloblastoma patients are insensitive to Itch activity, thus leading to deregulated Hh signalling and enhancing medulloblastoma cell growth. Our findings uncover mechanisms controlling the tumour suppressive functions of SuFu and reveal that their alterations are implicated in medulloblastoma tumorigenesis.

Over-activation of AKT signaling leading to 5-Fluorouracil resistance in SNU-C5/5-FU cells

PubMed Central

Kim, Eun-Ji; Kang, Gyeoung-Jin; Kang, Jung-Il; Boo, Hye-Jin; Hyun, Jin Won; Koh, Young Sang; Chang, Weon-Young; Kim, Young Ree; Kwon, Jung-Mi; Maeng, Young Hee; Yoo, Eun-Sook; Lee, Chang Hoon; Kang, Hee-Kyoung

2018-01-01

Here, we investigated whether over-activation of AKT pathway is important in the resistance to 5-fluorouracil (5-FU) in SNU-C5/5-FU cells, 5-FU-resistant human colon cancer cells. When compared to wild type SNU-C5 cells (WT), SNU-C5/5-FU cells showed over-activation of PI3K/AKT pathway, like increased phosphorylation of AKT, mTOR, and GSK-3β, nuclear localization of β-catenin, and decreased E-cadherin. Moreover, E-cadherin level was down-regulated in recurrent colon cancer tissues compared to primary colon cancer tissues. Gene silencing of AKT1 or treatment of LY294002 (PI3 kinase inhibitor) increased E-cadherin, whereas decreased phospho-GSK-3β. LY294002 also reduced protein level of β-catenin with no influence on mRNA level. PTEN level was higher in SNU-C5/WT than SNU-C5/5-FU cells, whereas the loss of PETN in SNU-C5/WT cells induced characteristics of SNU-C5/5-FU cells. In SNU-C5/5-FU cells, NF-κB signaling was activated, along with the overexpression of COX-2 and stabilization of survivin. However, increased COX-2 contributed to the stabilization of survivin, which directly interacts with cytoplasmic procaspase-3, while the inhibition of AKT reduced this cascade. We finally confirmed that combination treatment with 5-FU and LY294002 or Vioxx could induce apoptosis in SNU-C5/5-FU cells. These data suggest that inhibition of AKT activation may overcome 5-FU-resistance in SNU-C5/5-FU cells. These findings provide evidence that over-activation of AKT is crucial for the acquisition of resistance to anticancer drugs and AKT pathway could be a therapeutic target for cancer treatment. PMID:29731993

Development of FuGO: An Ontology for Functional Genomics Investigations

PubMed Central

Whetzel, Patricia L.; Brinkman, Ryan R.; Causton, Helen C.; Fan, Liju; Field, Dawn; Fostel, Jennifer; Fragoso, Gilberto; Gray, Tanya; Heiskanen, Mervi; Hernandez-Boussard, Tina; Morrison, Norman; Parkinson, Helen; Rocca-Serra, Philippe; Sansone, Susanna-Assunta; Schober, Daniel; Smith, Barry; Stevens, Robert; Stoeckert, Christian J.; Taylor, Chris; White, Joe; Wood, Andrew

2009-01-01

The development of the Functional Genomics Investigation Ontology (FuGO) is a collaborative, international effort that will provide a resource for annotating functional genomics investigations, including the study design, protocols and instrumentation used, the data generated and the types of analysis performed on the data. FuGO will contain both terms that are universal to all functional genomics investigations and those that are domain specific. In this way, the ontology will serve as the “semantic glue” to provide a common understanding of data from across these disparate data sources. In addition, FuGO will reference out to existing mature ontologies to avoid the need to duplicate these resources, and will do so in such a way as to enable their ease of use in annotation. This project is in the early stages of development; the paper will describe efforts to initiate the project, the scope and organization of the project, the work accomplished to date, and the challenges encountered, as well as future plans. PMID:16901226

Everybody was Kung-Fu fighting-The beneficial effects of Tai Chi Qigong and self-defense Kung-Fu training on psychological and endocrine health in middle aged and older men.

PubMed

Walther, A; Lacker, T J; Ehlert, U

2018-02-01

Higher age is associated to a variety of physical and mental disorders. Age-related changes in steroid secretion have been suggested to be an underlying mechanism leading to frailty, depression, and sexual dysfunction. However, Tai chi qigong and similar forms of exercise have been shown to improve a great variety of health-related parameters in older individuals. We examined 56 self-reporting healthy men actively practicing Tai chi qigong and/or self-defense Kung-fu and 55 age-matched self-reporting healthy controls. Saliva samples were obtained in a standardized procedure for subsequent quantification of circulating testosterone and cortisol levels. In addition, depressive symptoms, life satisfaction, and sexual health were assessesd via self-report questionnaires. Age was negatively associated with testosterone, while no association emerged for cortisol. Tai chi qigong and/or self-defense Kung-fu training was neither associated with testosterone nor cortisol. More weekly Tai chi qigong and/or self-defense Kung-fu training (4 or more times per week) was instead associated with a lower CT-ratio, less depressive symptoms, and higher life satisfaction compared to individuals, who trained only one to three times per week. More years of Tai chi qigong and/or self-defense Kung-fu training were associated with less depressive symptoms and higher life satisfaction but not with the CT-ratio. No significant associations emerged for Tai chi qigong and/or self-defense Kung-fu training and sexual health. When compared to the age-matched controls, there is a significant effect of Tai chi, qigong and/or self-defense Kung-fu on the CT-ratio. Contrast analyses revealed a significantly lower CT-ratio for the high training load group in contrast to the low training load group. Further, in contrast to the control group, the low training load group exhibits a significantly higher CT-ratio. For depression, contrast analyses revealed a significantly lower level of depression in the

Mechanistic Study on Triptorelin Action in Protecting From 5-FU-Induced Ovarian Damage in Rats.

PubMed

Wang, Ying; Tian, Xiaoyu; Liang, Lingxia; Wang, Yan; Wang, Ruifang; Cheng, Xiaolin; Yan, Zhen; Chen, Yawei; Qi, Pengwei

2014-01-01

Triptorelin, a kind of GnRH agonist, is widely used in the treatment of hormone-responsive cancers in the clinic. This study aimed to discover the underlying mechanism of triptorelin in protection from 5-fluorouracil (5-FU)-induced ovarian damage in Sprague-Dawley rats. In the present study, after using 5-FU to induce ovarian damage in rats, body weight and wet ovaries were weighed, the levels of estradiol (E2), follicle-stimulating hormone (FSH), and anti-Müllerian hormone (AMH) in blood were detected, and the expression of Bcl-2, Bax, and NF-κB was determined. It suggested that, compared to the control, body weight gain, the ratio of ovarian wet weight to body weight, primary follicle numbers, and the levels of AMH were significantly decreased, while the concentration of E2 and FSH was heavily increased following 5-FU administration. In contrast, after coadministration of triptorelin with 5-FU, the ratio of ovarian wet weight to body weight and the levels of AMH were significantly increased, whereas the level of E2 and FSH was decreased significantly when compared with the 5-FU group. Furthermore, at indicated times, 5-FU led to the reduced Bcl-2 and NF-κB expression and increased Bax expression while triptorelin plus 5-FU increased Bcl-2 and NF-κB expression and decreased Bax expression. It was indicated that triptorelin could protect rats from 5-FU-induced ovarian damage by modulation of hormones, Bcl-2, Bax, and NF-κB. These results might highlight the mechanism of triptorelin as a protective agent in clinical chemotherapy for ovarian damage.

Galactosylated nanostructured lipid carriers for delivery of 5-FU to hepatocellular carcinoma.

PubMed

Varshosaz, Jaleh; Hassanzadeh, Farshid; Sadeghi, Hojjat; Khadem, Mostafa

2012-09-01

The aim of the present study was to design a targeted delivery system of 5-fluorouracil (5-FU) for hepatocellular carcinoma (HCC). Lactobionic acid (LB) was conjugated to stearyl amine (SA) by a chemical reaction. The nanostructured lipid carriers (NLCs), containing LB conjugate, lecithin, glyceryl monostearate, oil [oleic acid (OA) or Labrafac 5 or 10%], and 5-FU, were dissolved in alcohol/acetone, the oil phase was added to the aqueous phase containing Tween 80 or Solutol(®) HS15 (0.25 or 0.5%), and NLCs were prepared by an emulsification-solvent diffusion method. Physical properties and drug release were studied in NLCs. The thiazolyl blue tetrazolium bromide assay was used to study the cytotoxicity of NLCs on HepG(2) cells, and the cellular uptake of NLCs was determined by flow cytometry. Fourier transform infrared spectroscopy and (1)H-NMR spectra confirmed the successful conjugation of LB and SA. The optimized NLCs consisted of 0.5% Solutol HS15 and 10% OA oil. The particle size of these nanoparticles was 139.2 nm, with a zeta potential of -18 mV, loading efficiency of 34.2%, release efficiency after 2 hours of the release test was 72.6%, and crystallinity was 0.63%. The galactosylated NLCs of 5-FU were cytotoxic on the HepG(2) cell line in a half concentration of 5-FU and seems promising in reducing 5-FU dose in HCC.

Pre-operative combined 5-FU, low dose leucovorin, and sequential radiation therapy for unresectable rectal cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Minsky, B.D.; Cohen, A.M.; Kemeny, N.

1993-04-02

The authors performed a Phase 1 trial to determine the maximum tolerated dose of combined pre-operative radiation (5040 cGy) and 2 cycles (bolus daily [times] 5) of 5-FU and low dose LV (20 mg/m2), followed by surgery and 10 cycles of post-operative LV/5-FU in patients with unresectable primary or recurrent rectal cancer. Twelve patients were entered. The initial dose of 5-FU was 325 mg/m2. 5-FU was to be escalated while the LV remained constant at 20 mg/m2. Chemotherapy began on day 1 and radiation on day 8. The post-operative chemotherapy was not dose escalated; 5-FU: 425 mg/m2 and LV: 20more » mg/m2. The median follow-up was 14 months (7--16 months). Following pre-operative therapy, the resectability rate with negative margins was 91% and the pathologic complete response rate was 9%. For the combined modality segment (preoperative) the incidence of any grade 3+ toxicity was diarrhea: 17%, dysuria: 8%, mucositis: 8%, and erythema: 8%. The median nadir counts were WBC: 3.1, HGB: 8.8, and PLT: 153000. The maximum tolerated dose of 5-FU for pre-operative combined LV/5-FU/RT was 325 mg/m2 with no escalation possible. Therefore, the recommended dose was less than 325 mg/m2. Since adequate doses of 5-FU to treat systemic disease could not be delivered until at least 3 months (cycle 3) following the start of therapy, the authors do not recommend that this 5-FU, low dose LV, and sequential radiation therapy regimen be used as presently designed. However, given the 91% resectability rate they remain encouraged with this approach. 31 refs., 1 fig., 2 tabs.« less

Kung-fu versus swimming training and the effects on balance abilities in young adolescents.

PubMed

Baccouch, Rym; Rebai, Haithem; Sahli, Sonia

2015-11-01

Our purpose is to investigate the static balance control of young adolescents practicing kung-fu and swimming in order to find out which of these physical activities is the most effective in developing specific balance abilities in young adolescents. Comparative experimental study. University laboratory research. Three groups of 11-13-year-old boys (12 practicing Kung-Fu, 12 practicing swimming and 12 controls). Center of pressure (CoP) excursions were registered in upright bipedal and unipedal stances on a stabilometric force platform in eyes open (EO) and eyes closed (EC) conditions. Kung-fu practitioners control their balance (P < .05) better than controls and swimmers in the unipedal posture when visual inputs are available. Kung-fu training improved (P < .05) the bipedal balance control in the EO condition. However, swimming training developed (P < .05) bipedal balance control in both EO and EC conditions. The swimmers showed a lower reliance on vision (P < .05) compared to kung-fu practitioners. Both of these physical activities could be recommended for young adolescents as recreational or rehabilitation programs as they develop specific balance abilities that could be important for improving and maintaining optimal health. Copyright © 2015 Elsevier Ltd. All rights reserved.

[Professor Xu Fu-song's traditional Chinese medicine protocols for male diseases: A descriptive analysis].

PubMed

Liu, Cheng-yong; Xu, Fu-song

2015-04-01

To analyze the efficacy and medication principles of Professor Xu Fu-songs traditional Chinese medicine (TCM) protocols for male diseases. We reviewed and descriptively analyzed the unpublished complete medical records of 100 male cases treated by Professor Xu Fu-song with his TCM protocols from 1978 to 1992. The 100 cases involved 32 male diseases, most of which were difficult and complicated cases. The drug compliance was 95%. Each prescription was made up of 14 traditional Chinese drugs on average. The cure rate was 32% , and the effective rate was 85%. Professor Xu Fu-song advanced and proved some new theories and therapeutic methods. Professor Xu Fu-song's TCM protocols can be applied to a wide range of male diseases, mostly complicated, and are characterized by accurate differentiation of symptoms and signs, high drug compliance, and excellent therapeutic efficacy.

Synergetic Effect of SLN-Curcumin and LDH-5-Fu on SMMC-7721 Liver Cancer Cell Line

PubMed Central

Zhu, Rongrong; Wu, Xianzheng; Xiao, Yu; Gao, Bo; Xie, Qian

2013-01-01

Abstract Curcumin and 5-Fluorouracil (5-Fu) have been reported to have anticancer potentials and show certain synergetic effect on some cancer cell lines. However, the poor bioavailability and rapid metabolism limited their medical application. In this study, we encapsulated curcumin with solid lipid nanoparticles (SLN), 5-Fu with Layered double hydroxides (LDHs) separately and tested its properties and anticancer potentials. SLN-curcumin and LDH-5-Fu were determined to be 100 and 60 nm by Transmission Electron Microscopy detection, and the loading efficiency were 28%±2.5% and 16.7%±1.8%, individually. Furthermore, SLN-curcumin and LDH-5-Fu showed a significantly synergetic effect on SMMC-7721 cell stronger than plain drugs together, of which the Idrug loaded nano-carriers was only 0.315. FACS analysis revealed that the combination of SLN-curcumin and LDH-5-Fu induced 80.1% apoptosis in SMMC-7721 cells, which were 1.7-folds of the sum of the two plain drug loaded carriers. The results demonstrated the significant synergetic anticancer potentials of nano-encapsulated curcumin and 5-Fu, which could be further explored for the treatment of other carcinoma. PMID:23808828

[Study on garlic oil combined with 5-FU induced apoptosis of adenoid cystic carcinoma cell line ACC-M].

PubMed

Wu, Fayin; Zhou, Hefeng; Fan, Zhiying; Zhu, Yawen; Li, Yongye; Yao, Yukun; Ran, Dan

2014-02-01

To observe the effect of garlic oil combined with 5-FU induced apoptosis of adenoid cystic carcinoma cell line ACC-M. Human salivary in adenoid cystic carcinoma cell line AC-M was cultured, divided into the experimental group (5-FU group, garlic oil group, garlic oil + 5-FU group) and the control group, to observe the growth activity of tumor cells by MTT methods; to analyse the changes of cell cycle and apoptosis rate by flow cytometry. MTT experiments showed that 5-FU, garlic oil, garlic oil and 5-FU on ACC-M cells have inhibition in different concentration, with the increase of concentration and action time of the rise; Cell cycle analysis showed significant changes in flow cytometry. With the increase of concentration and the acting time, the G0/G1, phase of the cell ratio increased, S had no significant change, but G2/M phase cells decreased. Apoptosis rate display showed garlic oil combined with 5-FU induced apoptosis of ACC-M cells was significantly stronger than single group. Garlic oil can effectively induce the apoptosis of adenoid cystic carcinoma cell line ACC-M. The effect of garlic oil combined with 5-FU on ACC-M cells was stronger than the garlic oil, 5-FU used alone.

High-Resolution Near-Infrared Spectroscopy of FU Orionis Objects

NASA Astrophysics Data System (ADS)

Hartmann, Lee; Hinkle, Kenneth; Calvet, Nuria

2004-07-01

We present an analysis of recent near-infrared, high-resolution spectra of the variable FU Ori objects. During a phase of rapid fading in optical brightness during 1997, V1057 Cyg exhibited shell absorption in first-overtone (v''-v'=2-0) CO lines, blueshifted by about 50 km s-1 from the system velocity. This shell component had not been seen previously, nor was it present in 1999, although some blueshifted absorption asymmetry is seen at the latter epoch. The appearance of this CO absorption shell is connected with the roughly contemporaneous appearance of blueshifted, low-excitation optical absorption lines with comparable low velocities; we suggest that this shell was also responsible for some of the peculiar emission features seen in red-optical spectra of V1057 Cyg. FU Ori continues to exhibit broad CO lines, with some evidence for the double-peaked profiles characteristic of an accretion disk; the line profiles are consistent with previous observations. Both FU Ori and V1057 Cyg continue to exhibit lower rotational broadening at 2.3 μm than at optical wavelengths, in agreement with the prediction of differentially rotating disk models; we have a marginal detection of the same effect in V1515 Cyg. The relative population of the first-overtone CO rotational levels in the FU Ori objects suggests low excitation temperatures. We compare disk models to the observations and find agreement with overall line strengths and rotational broadening, but the observed line profiles are generally less double-peaked than predicted. We suggest that the discrepancy in line profiles is due to turbulent motions in FU Ori disks, an effect qualitatively predicted by recent simulations of the magnetorotational instability in vertically stratified accretion disks. Based on observations obtained at the Gemini Observatory, which is operated by the Association of Universities for Research in Astronomy (AURA), Inc., under a cooperative agreement with the NSF, on behalf of the Gemini

Teaching Tu Fu on the Night Shift.

ERIC Educational Resources Information Center

Brady, Philip

1995-01-01

Describes a teacher's unsuccessful attempt to introduce the poetry of Tu Fu, a wayward bureaucrat of the T'ang dynasty, to a class of part-time students. Uses his students' resistance to this poetry as an occasion to discuss the importance of personal responses to poetry, as opposed to "correct" academic responses. (TB)

Overcoming acquired drug resistance in colorectal cancer cells by targeted delivery of 5-FU with EGF grafted hollow mesoporous silica nanoparticles

NASA Astrophysics Data System (ADS)

Chen, Lijue; She, Xiaodong; Wang, Tao; He, Li; Shigdar, Sarah; Duan, Wei; Kong, Lingxue

2015-08-01

Acquired drug resistance (ADR) can be developed in colorectal cancer cells after 5-fluorouracil (5-FU) treatment and diminish the effectiveness of chemotherapy. In this work, acquired 5-FU resistance in the colorectal cancer cell line SW480 was obtained with the up-regulation of dihydropyrimidine dehydrogenase (DPYD) gene expression which can convert 5-FU to its inactive metabolite. To overcome ADR in colorectal cancer, hollow mesoporous silica nanoparticles (HMSNs) grafted with epidermal growth factor (EGF) were used as nanocarriers to deliver 5-FU to colorectal cancer cells with acquired drug resistance. The effect and mechanism of 5-FU loaded EGF grafted HMSNs (EGF-HMSNs-5-FU) in overcoming acquired drug resistance in SW480/ADR cells were studied. The EGF-HMSNs were demonstrated to be specifically internalized in EGFR overexpressed SW480/ADR cells via a receptor-mediated endocytosis and can escape from endo-lysosomes. The EGF-HMSNs-5-FU exhibited much higher cytotoxicity on SW480/ADR cells than HMSNs-5-FU and free 5-FU while the plain HMSNs did not show significant cytotoxicity. The mechanism of EGF-HMSNs-5-FU in overcoming drug resistance in SW480/ADR cells could be attributed to the specific internalization of EGF-HMSNs-5-FU in EGFR overexpressed cells which can lead to high intracellular drug accumulation and cause cell death through S phase arrest.Acquired drug resistance (ADR) can be developed in colorectal cancer cells after 5-fluorouracil (5-FU) treatment and diminish the effectiveness of chemotherapy. In this work, acquired 5-FU resistance in the colorectal cancer cell line SW480 was obtained with the up-regulation of dihydropyrimidine dehydrogenase (DPYD) gene expression which can convert 5-FU to its inactive metabolite. To overcome ADR in colorectal cancer, hollow mesoporous silica nanoparticles (HMSNs) grafted with epidermal growth factor (EGF) were used as nanocarriers to deliver 5-FU to colorectal cancer cells with acquired drug resistance. The

Oridonin enhances the cytotoxicity of 5-FU in renal carcinoma cells by inducting necroptotic death.

PubMed

Zheng, Wei; Zhou, Chun-Yan; Zhu, Xin-Qing; Wang, Xue-Jian; Li, Zi-Yao; Chen, Xiao-Chi; Chen, Feng; Che, Xiang-Yu; Xie, Xin

2018-06-26

5-fluorouracil (5-FU) is widely used for the treatment of renal carcinoma. However, drug resistance remains the reason for failure of chemotherapy. Oridonin, extracted from Chinese herb medicine, displays anti-tumor effect in several types of cancer. Whether oridonin could enhance the effect of 5-FU in renal carcinoma has not been studied. 786-O cells were used in the current study. Cell death was measured by MTT assay or live- and dead-cell staining assay. Glutathione (GSH) level was examined by ELISA. Necroptosis was identified by protein levels of receptors interaction protein-1 (RIP-1) and RIP-3, lactate dehydrogenase (LDH) and high mobility group box-1 protein (HMGB1) release, and poly [ADP-ribose] polymerase-1 (Parp-1) activity. Using a xenograft assay in nude mice, we tested the anti-tumor effects of the oridonin combined with 5-FU. 5-FU only induced apoptosis in 786-O cells. Oridonin activated both apoptosis and necroptosis in 786-O cells. Oridonin-induced necroptosis was reversed by addition of GSH or its precursorN-acetylcysteine (NAC). Oridonin-induced necroptosis was associated by activated JNK, p38, and ERK in 786-O cells, which were abolished by GSH or NAC treatment. However, JNK, p38, and ERK inhibitors showed no effect on oridonin induced-cell death. GSH or NAC treatment partly abolished the synergistic effects of oridonin and 5-FU on cell death. Oridonin enhanced the cytotoxicity of 5-FU both in vitro and in vivo. Oridonin enhances the cytotoxicity of 5-FU in renal cancer cells partially through inducing necroptosis, providing evidence of using necroptosis inducers in combination with chemotherapeutic agents for cancer treatment. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

THE MID-INFRARED EVOLUTION OF THE FU ORIONIS DISK

DOE Office of Scientific and Technical Information (OSTI.GOV)

Green, Joel D.; Jones, Olivia C.; Poteet, Charles A.

2016-11-20

We present new SOFIA-FORCAST observations obtained in 2016 February of the archetypal outbursting low-mass young stellar object FU Orionis, and we compare the continuum, solid-state, and gas properties with mid-infrared data obtained at the same wavelengths in 2004 with Spitzer -IRS. In this study, we conduct the first mid-infrared spectroscopic comparison of an FUor over a long time period. Over a 12-year period, UBVR monitoring indicates that FU Orionis has continued its steady decrease in overall brightness by ∼14%. We find that this decrease in luminosity occurs only at wavelengths ≲20 μ m. In particular, the continuum shortward of the silicate emission complex atmore » 10 μ m exhibits a ∼12% (∼3 σ ) drop in flux density but no apparent change in slope; both the Spitzer and SOFIA spectra are consistent with a 7200 K blackbody. Additionally, the detection of water absorption is consistent with the Spitzer spectrum. The silicate emission feature at 10 μ m continues to be consistent with unprocessed grains, unchanged over 12 years. We conclude that either the accretion rate in FU Orionis has decreased by ∼12–14% over this time baseline or the inner disk has cooled, but the accretion disk remains in a superheated state outside the innermost region.« less

FuGeF: A Resource Bound Secure Forwarding Protocol for Wireless Sensor Networks.

PubMed

Umar, Idris Abubakar; Mohd Hanapi, Zurina; Sali, A; Zulkarnain, Zuriati A

2016-06-22

Resource bound security solutions have facilitated the mitigation of spatio-temporal attacks by altering protocol semantics to provide minimal security while maintaining an acceptable level of performance. The Dynamic Window Secured Implicit Geographic Forwarding (DWSIGF) routing protocol for Wireless Sensor Network (WSN) has been proposed to achieve a minimal selection of malicious nodes by introducing a dynamic collection window period to the protocol's semantics. However, its selection scheme suffers substantial packet losses due to the utilization of a single distance based parameter for node selection. In this paper, we propose a Fuzzy-based Geographic Forwarding protocol (FuGeF) to minimize packet loss, while maintaining performance. The FuGeF utilizes a new form of dynamism and introduces three selection parameters: remaining energy, connectivity cost, and progressive distance, as well as a Fuzzy Logic System (FLS) for node selection. These introduced mechanisms ensure the appropriate selection of a non-malicious node. Extensive simulation experiments have been conducted to evaluate the performance of the proposed FuGeF protocol as compared to DWSIGF variants. The simulation results show that the proposed FuGeF outperforms the two DWSIGF variants (DWSIGF-P and DWSIGF-R) in terms of packet delivery.

Is HL Tauri and FU Orionis system in quiescence?

NASA Technical Reports Server (NTRS)

Lin, D. N. C.; Hayashi, M.; Bell, K. R.; Ohashi, N.

1994-01-01

A recent Nobeyama map of HL Tau reveals that gas is infalling in a flattened region approximately 1400 AU around the central star. The apparent motion of the gas provides the necessary condition for the formation of a Keplerian disk with a radius comparable to the size of the primordial solar nebula. The inferred mass infall rate onto the disk is approximately equal to 5 x 10(exp -6) solar mass/yr, which greatly exceeds the maximum estimate of the accretion rate onto the central star (approximately 7 x 10(exp -7) solar mass/yr). Consequently, mass must currently be accumulating in the disk. The estimated age and disk mass of HL Tau suggest that the accumulated matter has been flushed repeatedly on a timescale less than 10(exp 4) yr. Based on the similarites between their evolution patterns, we propose that HL Tau is an FU Orionis system in quiescence. In addition to HL Tau, 14 out of 86 pre-main-sequence stars in the Taurus-Auriga dark clouds have infrared luminosities much greater than their otherwise normal extinction-corrected stellar luminosities. These sources also tend to have flat spectra which may be due to the reprocessing of radiation by dusty, flattened, collapsing envelopes with infall rates a few 10(exp -6) solar mass/yr. Such rates are much larger than estimated central accretion rates for these systems, which suggests that mass must also be accumulating in these disks. If these sources are FU Orionis stars in quiescence, similar to HL Tau, their age and relative abundance imply that the FU Orionis phase occurs over a timescale of approixmately 10(exp 5) yr, and the quiescent phase between each outburst lasts approximately 10(exp 3) =10(exp 4) yr. These inferred properties are compatible with the scenario that FU Orionis outbursts are regulated by a thermal instability in the inner region of the disk.

Photometric variability in FU Ori and Z CMa as observed by MOST

NASA Astrophysics Data System (ADS)

Siwak, Michal; Rucinski, Slavek M.; Matthews, Jaymie M.; Kuschnig, Rainer; Guenther, David B.; Moffat, Anthony F. J.; Rowe, Jason F.; Sasselov, Dimitar; Weiss, Werner W.

2013-06-01

Photometric observations obtained by the MOST satellite were used to characterize optical small-scale variability of the young stars FU Ori and Z CMa. Wavelet analysis for FU Ori reveals the possible existence of several 2-9 d quasi-periodic features occurring nearly simultaneously; they may be interpreted as plasma parcels or other localized disc heterogeneities revolving at different Keplerian radii in the accretion disc. Their periods may shorten slowly which may be due to spiralling in of individual parcels towards the inner disc radius, estimated at 4.8 ± 0.2 R⊙. Analysis of additional multicolour data confirms the previously obtained relation between variations in the B - V colour index and the V magnitude. In contrast to the FU Ori results, the oscillation spectrum of Z CMa does not reveal any periodicities with the wavelet spectrum possibly dominated by outburst of the Herbig Be component.

The Impact of FU Orionis Outbursts and the Solar Nebula

NASA Technical Reports Server (NTRS)

Bell, Robbins; Young, Richard E. (Technical Monitor)

1998-01-01

Protostellar systems are variable on many timescales. One of the most dramatic forms of variability known to occur in low mass stellar systems is the FU Orionis outburst (Herbig 1977). Throughout a typical outburst lasting several decades, system luminosities may be a hundred times what is typical of the quiesent state. FU Orionis outburst events are thought to have significant impact on the thermal structure of the protosolar nebula; their existence has been used to explain features in the meteoritic record from thermally induced homogenization to the formation of chondrules. Until recently, the magnitude of the likely effect from such outbursts has been largely speculative due to the lack of a detailed understanding of the outburst mechanism. Recent numerical models (Bell\\& Lin 1994) have demonstrated the viability of the observational hypothesis (Hartmann\\& Kenyon 1985) that the radiation observed during outburst is emitted by a luminous circumstellar disk transporting mass at a thousand times the quiesent rate. Light curves and color and line width evolution observed in FU Orionis systems are naturally explained by time dependent outbursting model disks (Bell et al. 1995). The radial temperature structure and shape of the disk during outburst derived from these models may be used to calculate the outburst's expected impact on primitive material at various radii throughout the disk. In this review, we will begin by discussing what is known about the FU Orionis outburst phenomenon from recent observations and theory including statistically deduced outburst timescales and observed peak temperatures. Unless covered by another author, we will discuss the evidence which suggests that outburst radiation is emitted by a circumstellar disk rather than by the star and will briefly review the thermal instability as a mechanism for outburst. We will then report on recent work which investigates the likely heating of solar nebula material due to FU Orionis outbursts

First Results from the AKARI FU-HYU Mission Program

NASA Astrophysics Data System (ADS)

Pearson, C.; Serjeant, S.; Takagi, T.; Jeong, W.-S.; Negrello, M.; Matsuhara, H.; Wada, T.; Oyabu, S.; Lee, H. M.; Im, M.

2009-12-01

The AKARI FU-HYU mission program has carried out mid-infrared imaging of several well studied Spitzer fields. This imaging fills in the wavelength coverage lacking from the Spitzer surveys and gives an extremely high scientific return for minimal input for AKARI. We select fields already rich in multi-wavelength data from radio to X-ray wavelengths and present the results from our initial analysis in the GOODS-N field. We utilize the comprehansive multiwavelength coverage in the GOODS-N field to produce a multiwavelength catalogue from infrared to ultraviolet wavelengths including photometric redshifts. Using the FU-HYU catalogue we present colour-colour diagrams that map the passage of PAH features through our observation bands. These colour-colours diagrams are used as tools to extract anomalous colour populations, in particular a population of Silicate Break galaxies from the GOODS-N field.

The effects of Fu Zi on changes in the body heat of dogs.

PubMed

Chen, Tian-Tian; Qi, Chunhua; Guo, Huijun; Cheng, Ziqiang; Zhou, Dong; Liu, Haitao; Liu, Jianzhu

2009-03-01

The aim of the present study was to investigate the effects of Fu Zi on changes in the body heat of dogs. Twelve clinically healthy dogs were divided into two groups: the control group (six dogs) and the experimental group (six dogs). The control group was made to ingest normal saline mixed with canned meat, while the experimental group was made to ingest the Fu Zi solution mixed with canned meat. The infrared thermographic system was used to determine the level of body heat generated by these dogs. These areas include the dorsocranial (DCr), dorsocaudal (DCd), ventrocranial (VCr), and ventrocaudal (VCd) regions at pretreatment and were determined at 10, 20, 30, 50, 90, 120, 240, and 360 minutes after treatment for each of these areas. The results showed a tendency toward increased body heat until 30 minutes after ingestion of the Fu Zi powder mixed with canned meat. The significant differences in the changes of body heat were detected at 360 minutes in the DCd regions, 20 minutes in the VCr regions, and 30 minutes in the VCd regions between the experimental and control groups (p < 0.05). Based from our results, we find that Fu Zi can increase and maintain the dogs' body heat for at least 6 hours.

FuGeF: A Resource Bound Secure Forwarding Protocol for Wireless Sensor Networks

PubMed Central

Umar, Idris Abubakar; Mohd Hanapi, Zurina; Sali, A.; Zulkarnain, Zuriati A.

2016-01-01

Resource bound security solutions have facilitated the mitigation of spatio-temporal attacks by altering protocol semantics to provide minimal security while maintaining an acceptable level of performance. The Dynamic Window Secured Implicit Geographic Forwarding (DWSIGF) routing protocol for Wireless Sensor Network (WSN) has been proposed to achieve a minimal selection of malicious nodes by introducing a dynamic collection window period to the protocol’s semantics. However, its selection scheme suffers substantial packet losses due to the utilization of a single distance based parameter for node selection. In this paper, we propose a Fuzzy-based Geographic Forwarding protocol (FuGeF) to minimize packet loss, while maintaining performance. The FuGeF utilizes a new form of dynamism and introduces three selection parameters: remaining energy, connectivity cost, and progressive distance, as well as a Fuzzy Logic System (FLS) for node selection. These introduced mechanisms ensure the appropriate selection of a non-malicious node. Extensive simulation experiments have been conducted to evaluate the performance of the proposed FuGeF protocol as compared to DWSIGF variants. The simulation results show that the proposed FuGeF outperforms the two DWSIGF variants (DWSIGF-P and DWSIGF-R) in terms of packet delivery. PMID:27338411

Reply to communications by Fu et al. international journal of biometeorology

NASA Astrophysics Data System (ADS)

Wang, Huanjiong; Rutishauser, This; Tao, Zexing; Zhong, Shuying; Ge, Quansheng; Dai, Junhu

2016-12-01

Temperature sensitivity of plant phenology (ST) is a determining factor of as to what degree climate change impacts on plant species. Fu et al . (Int J Biometeorol 60:1611-1613, 2016) claimed that long long-term linear trends mask phenological shifts. However, the decreased and increased ST was both found in warming scenarios. The conceptual scheme telling the nonlinear relationship between spring temperature and leaf unfolding date proposed by Fu et al . (Int J Biometeorol 60:1611-1613, 2016) cannot be supported by observation data across Europe. Therefore, linking declined ST to climate warming is misleading, and future ST changes are more uncertain than they suggested.

GRP78 confers the resistance to 5-FU by activating the c-Src/LSF/TS axis in hepatocellular carcinoma.

PubMed

Gu, Yan-jiao; Li, Hong-dan; Zhao, Liang; Zhao, Song; He, Wu-bin; Rui, Li; Su, Chang; Zheng, Hua-chuan; Su, Rong-jian

2015-10-20

5-FU is a common first-line chemotherapeutic drug for the treatment of hepatocellular carcinoma. However the development of acquired resistance to 5-FU confines its clinical usages. Although this phenomenon has been the subject of intense investigation, the exact mechanism of acquired resistance to 5-FU remains elusive. Here, we report that over-expression of GRP78 contributes to acquired resistance to 5-FU in HCC by up-regulating the c-Src/LSF/TS axis. Moreover, we found that the resistance to 5-FU conferred by GRP78 is mediated by its ATPase domain. The ATPase domain differentially increased the expression of LSF, TS and promoted the phosphorylation of ERK and Akt. We further identified that GRP78 interacts physically with c-Src through its ATPase domain and promotes the phosphorylation of c-Src, which in turn increases the expression of LSF in the nucleus. Together, GRP78 confers the resistance to 5-FU by up-regulating the c-Src/LSF/TS axis via its ATPase domain.

Electrochemical degradation of 5-FU using a flow reactor with BDD electrode: Comparison of two electrochemical systems.

PubMed

Ochoa-Chavez, A S; Pieczyńska, A; Fiszka Borzyszkowska, A; Espinoza-Montero, P J; Siedlecka, E M

2018-06-01

In this study, the electrochemical degradation process of 5-fluorouracil (5-FU) in aqueous media was performed using a continuous flow reactor in an undivided cell (system I), and in a divided cell with a cationic membrane (Nafion ® 424) (system II). In system I, 75% of 5-FU degradation was achieved (50 mg L -1 ) with a applied current density j app  = 150 A m -2 , volumetric flow rate qv = 13 L h -1 , after 6 h of electrolysis (k app  = 0.004 min -1 ). The removal efficiency of 5-FU was higher (95%) when the concentration was 5 mg L -1 under the same conditions. Nitrates (22% of initial amount of N), fluorides (27%) and ammonium (10%) were quantified after 6 h of electrolysis. System II, 77% of 5-FU degradation was achieved (50 mg L -1 ) after 6 h of electrolysis (k app  = 0.004 min -1 ). The degradation rate of 5-FU was complete when the concentration was 5 mg L -1 under the same conditions. Nitrates (29% of initial amount of N), fluorides (25%) and ammonium (5%) were quantified after 6 h of electrolysis. In addition, the main organic byproducts identified by mass spectroscopy were aliphatic compound with carbonyl and carboxyl functionalities. Due to, the mineralization of 5-FU with acceptable efficiency of 88% found in system II (j app of 200 A m -2 ), this system seems to be more promising in the cytostatic drug removal. Moreover the efficiency of 5-FU removal in diluted solutions is better in system II than in system I. Copyright © 2018 Elsevier Ltd. All rights reserved.

Overview of the FuZE Fusion Z-Pinch Experiment

NASA Astrophysics Data System (ADS)

Shumlak, U.; Nelson, B. A.; Claveau, E. L.; Forbes, E. G.; Golingo, R. P.; Stepanov, A. D.; Weber, T. R.; Zhang, Y.; McLean, H. S.; Higginson, D. P.; Schmidt, A.; Tummel, K. K.

2017-10-01

Successful results of the sheared flow stabilized (SFS) Z-pinch from ZaP and ZaP-HD have motivated the new FuZE project to scale the plasma performance to fusion conditions. The SFS Z-pinch is immune to the instabilities that plague the conventional Z-pinch yet maintains the same favorable radial scaling. The plasma density and temperature increase rapidly with decreasing plasma radius, which naturally leads to a compact configuration at fusion conditions. The SFS Z-pinch is being investigated as a novel approach to a compact fusion device in a collaborative ARPA-E ALPHA project with the University of Washington and Lawrence Livermore National Laboratory. The project includes an experimental effort coupled with high-fidelity physics modeling using kinetic and fluid simulations. Along with scaling law analysis, computational and experimental results from the FuZE device are presented. This work is supported by an award from US ARPA-E.

NSC30049 inhibits Chk1 pathway in 5-FU-resistant CRC bulk and stem cell populations.

PubMed

Narayan, Satya; Jaiswal, Aruna S; Sharma, Ritika; Nawab, Akbar; Duckworth, Lizette Vila; Law, Brian K; Zajac-Kaye, Maria; George, Thomas J; Sharma, Jay; Sharma, Arun K; Hromas, Robert A

2017-08-22

The 5-fluorouracil (5-FU) treatment induces DNA damage and stalling of DNA replication forks. These stalled replication forks then collapse to form one sided double-strand breaks, leading to apoptosis. However, colorectal cancer (CRC) stem cells rapidly repair the stalled/collapsed replication forks and overcome treatment effects. Recent evidence suggests a critical role of checkpoint kinase 1 (Chk1) in preventing the replicative stress. Therefore, Chk1 kinase has been a target for developing mono or combination therapeutic agents. In the present study, we have identified a novel orphan molecule NSC30049 (NSC49L) that is effective alone, and in combination potentiates 5-FU-mediated growth inhibition of CRC heterogeneous bulk and FOLFOX-resistant cell lines in culture with minimal effect on normal colonic epithelial cells. It also inhibits the sphere forming activity of CRC stem cells, and decreases the expression levels of mRNAs of CRC stem cell marker genes. Results showed that NSC49L induces 5-FU-mediated S-phase cell cycle arrest due to increased load of DNA damage and increased γ-H2AX staining as a mechanism of cytotoxicity. The pharmacokinetic analysis showed a higher bioavailability of this compound, however, with a short plasma half-life. The drug is highly tolerated by animals with no pathological aberrations. Furthermore, NSC49L showed very potent activity in a HDTX model of CRC stem cell tumors either alone or in combination with 5-FU. Thus, NSC49L as a single agent or combined with 5-FU can be developed as a therapeutic agent by targeting the Chk1 pathway in 5-FU-resistant CRC heterogeneous bulk and CRC stem cell populations.

Quantitative LC-MS/MS analysis of seven ginsenosides and three aconitum alkaloids in Shen-Fu decoction

PubMed Central

2013-01-01

Background Shen-Fu decoction is a traditional Chinese medicine prescription with a 3:2 ratio of Radix Ginseng and Fuzi (Radix Aconiti lateralis praeparata). Ginsenosides and alkaloids are considered to be the main active components of Shen-Fu decoction. However, no analytical methods have been used to quantitatively analyse both components in Shen-Fu decoction simultaneously. Results We successfully developed a rapid resolution liquid chromatography coupled with tandem mass spectrometry (RRLC-MS/MS) method for the simultaneous analysis of seven ginsenosides and three aconitum alkaloids in Shen-Fu decoction, the decoction of Radix ginseng and Fuzi (Radix Aconiti lateralis praeparata). Chromatogrpahic separation by RPLC was achieved using a reversed-phase column and a water/acetonitrile mobile phase, containing 0.05% formic acid and using a gradient system. The method was optimized to allow for simultaneous analysis of all analytes in 11minutes without the need for baseline resolution of the components. Furthermore, the separation demonstrated good linearity (r > 0.9882), repeatability (RSD < 7.01%), intra- and inter-day precisions (RSD < 5.06%) and high yields of recovery (91.13-111.97%) for ten major constituents, namely ginsenoside-Re, Rg1, Rb1, Rc, Rb2, Rd, Rf, aconitine, hypacoitine and mesaconitine. Conclusions The developed method could be used as a rapid and reliable approach for assessment of the quantity of the major constituents in Shen-Fu decoction. PMID:24107599

Reply to ``Comment II on `Quantum secret sharing based on reusable Greenberger-Horne-Zeilinger states as secure carriers' ''

NASA Astrophysics Data System (ADS)

Karimipour, V.

2006-07-01

In the preceding Comment [Jian-Zhong Du, Su-Juan Qin, Qiao-Yan Wen, and Fu-Chen Zhu, Phys. Rev. A 74, 016301 (2006)], it has been shown that in a quantum secret sharing protocol proposed in [S. Bagherinezhad and V. Karimipour, Phys. Rev. A 67, 044302 (2003)], one of the receivers can cheat by splitting the entanglement of the carrier and intercepting the secret, without being detected. In this reply we show that a simple modification of the protocol prevents the receivers from this kind of cheating.

[Mining analysis on composition and medication of menstruation prescriptions in Fu Qingzhu's Obstetrics and Gynecology].

PubMed

Zhu, Jia-qing; Che, Yu-xia

2015-04-01

In this paper, menstruation prescriptions were selected from "Fu Qingzhu's Obstetrics and Gynecology" and analyzed by using GRI algorithm, correlation analysis, hierarchical clustering method through SPSS, Clementine and traditional Chinese medicine (TCM) inheritance auxiliary systems, in order to screen out 15 menopathy prescriptions, which involve 45 traditional Chinese medicine herbs. In the study, blood-tonifying and qi-tonifying herbs were found to be frequent in the prescriptions. The most frequent single herb was white paeony root, accounting for 9.6% in the total number of prescriptions; The most frequent herb pairs were white paeony root-radix rehmanniae preparata and paeony root-angelica sinensis. Among Fu Shan's menopathy prescriptions, 61 herbal pairs showed a correlation coefficient exceeding 0.05, which evolved into 16 pairs of core combinations. The analysis showed that menopathy prescriptions in volume 1 of "Fu Qingzhu's Obstetrics and Gynecology" focused on tonic traditional Chinese medicines involving liver, spleen and kidney and were adjusted according to changes in qi, blood, cold, hot and wet, which could provide a specific reference for further studies on Fu Shan's academic thoughts and traditional Chinese medicine clinical treatment of menopathy.

EVIDENCE FOR AN FU ORIONIS-LIKE OUTBURST FROM A CLASSICAL T TAURI STAR

DOE Office of Scientific and Technical Information (OSTI.GOV)

Miller, Adam A.; Poznanski, Dovi; Silverman, Jeffrey M.

2011-04-01

We present pre- and post-outburst observations of the new FU Orionis-like young stellar object PTF 10qpf (also known as LkH{alpha} 188-G4 and HBC 722). Prior to this outburst, LkH{alpha} 188-G4 was classified as a classical T Tauri star (CTTS) on the basis of its optical emission-line spectrum superposed on a K8-type photosphere and its photometric variability. The mid-infrared spectral index of LkH{alpha} 188-G4 indicates a Class II-type object. LkH{alpha} 188-G4 exhibited a steady rise by {approx}1 mag over {approx}11 months starting in August 2009, before a subsequent more abrupt rise of >3 mag on a timescale of {approx}2 months. Observationsmore » taken during the eruption exhibit the defining characteristics of FU Orionis variables: (1) an increase in brightness by {approx}>4 mag, (2) a bright optical/near-infrared reflection nebula appeared, (3) optical spectra are consistent with a G supergiant and dominated by absorption lines, the only exception being H{alpha} which is characterized by a P Cygni profile, (4) near-infrared spectra resemble those of late K-M giants/supergiants with enhanced absorption seen in the molecular bands of CO and H{sub 2}O, and (5) outflow signatures in H and He are seen in the form of blueshifted absorption profiles. LkH{alpha} 188-G4 is the first member of the FU Orionis-like class with a well-sampled optical to mid-infrared spectral energy distribution in the pre-outburst phase. The association of the PTF 10qpf outburst with the previously identified CTTS LkH{alpha} 188-G4 (HBC 722) provides strong evidence that FU Orionis-like eruptions represent periods of enhanced disk accretion and outflow, likely triggered by instabilities in the disk. The early identification of PTF 10qpf as an FU Orionis-like variable will enable detailed photometric and spectroscopic observations during its post-outburst evolution for comparison with other known outbursting objects.« less

Gravitational Instabilities, Chondrule Formation, and the FU Orionis Phenomenon

NASA Astrophysics Data System (ADS)

Boley, Aaron C.; Durisen, Richard H.

2008-10-01

Using analytic arguments and numerical simulations, we examine whether chondrule formation and the FU Orionis phenomenon can be caused by the burstlike onset of gravitational instabilities (GIs) in dead zones. At least two scenarios for bursting dead zones can work, in principle. If the disk is on the verge of fragmentation, GI activation near r ~ 4-5 AU can produce chondrule-forming shocks, at least under extreme conditions. Mass fluxes are also high enough during the onset of GIs to suggest that the outburst is related to an FU Orionis phenomenon. This situation is demonstrated by numerical simulations. In contrast, as supported by analytic arguments, if the burst takes place close to r ~ 1 AU, then even low pitch angle spiral waves can create chondrule-producing shocks and outbursts. We also study the stability of the massive disks in our simulations against fragmentation and find that although disk evolution is sensitive to changes in opacity, the disks we study do not fragment, even at high resolution and even for extreme assumptions.

[Study of the immunological mechanism of anti-tumor effects of 5-FU by establishing EL4 tumor-bearing mouse models].

PubMed

Li, Mo-Lin; Li, Chuan-Gang; Shu, Xiao-Hong; Li, Ming-Xia; Jia, Yu-Jie; Qin, Zhi-Hai

2007-11-01

To investigate the immunological mechanism of anti-tumor effect of 5-FU by establishing lymphoma EL4 tumor-bearing mouse models in wild type C57BL/6 mice and nude C57BL/6 mice, respectively. The mouse lymphoma EL4 cells were inoculated subcutaneously into wild type C57BL/6 mice (immune-competent mice). Twelve days later, 5-FU of different doses was administered intraperitoneally to treat these wild type C57BL/6 tumor-bearing mice. The size of tumors in the wild type C57BL/6 mice was observed and recorded to explore the minimal dose of 5-FU that could cure the tumor-bearing mice. Then the same amount of EL4 tumor cells was inoculated subcutaneously into wild type C57BL/6 mice and nude C57BL/6 mice (T cell-deficient mice) simultaneously, which had the same genetic background of C57BL/6. Twelve days later, 5-FU of the minimal dose was given intraperitoneally to treat both the wild type and nude C57BL/6 tumor-bearing mice. The size of tumors in the two different types of mice was observed and recorded. A single dose of 5-FU (75 mg/kg) cured both the EL4 tumor-bearing wild type C57BL/6 mice and the EL4 tumor-bearing nude C57BL/6 mice in the first week. Two weeks after 5-FU treatment, all of the nude mice died of tumor relapse while most of the wild type C57BL/6 mice were fully recovered. A single dose of 5-FU has marked anti-tumor effects on lymphoma EL4 tumor-bearing C57BL/6 mice with or without T lymphocytes. The relapse of tumors after 5-FU treatment might be related to the function of T lymphocytes.

The AKARI FU-HYU galaxy evolution program: first results from the GOODS-N field

NASA Astrophysics Data System (ADS)

Pearson, C. P.; Serjeant, S.; Negrello, M.; Takagi, T.; Jeong, W.-S.; Matsuhara, H.; Wada, T.; Oyabu, S.; Lee, H. M.; Im, M. S.

2010-05-01

The AKARI FU-HYU mission program carried out mid-infrared imaging of several well studied Spitzer fields preferentially selecting fields already rich in multi-wavelength data from radio to X-ray wavelengths filling in the wavelength desert between the Spitzer IRAC and MIPS bands. We present the initial results for the FU-HYU survey in the GOODS-N field. We utilize the supreme multiwavelength coverage in the GOODS-N field to produce a multiwavelength catalogue from infrared to ultraviolet wavelengths, containing more than 4393 sources, including photometric redshifts. Using the FU-HYU catalogue we present colour-colour diagrams that map the passage of PAH features through our observation bands. We find that the longer mid-infrared bands from AKARI (IRC-L18W 18 micron band) and Spitzer (MIPS24 24 micron band) provide an accurate measure of the total MIR emission of the sources and therefore their probable total mid-infrared luminosity. We also find that colours incorporating the AKARI IRC-S11 11 micron band produce a bimodal distribution where an excess at 11 microns preferentially selects moderate redshift star-forming galaxies. These powerful colour-colour diagnostics are further used as tools to extract anomalous colour populations, in particular a population of Silicate Break galaxies from the GOODS-N field showing that dusty starbursts can be selected of specific redshift ranges (z = 1.2-1.6) by mid-infrared drop-out techniques. The FU-HYU catalogue will be made publically available to the astronomical community.

Preoperative Capecitabine and Pelvic Radiation in Locally Advanced Rectal Cancer-Is it Equivalent to 5-FU Infusion Plus Leucovorin and Radiotherapy?

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chan, Alexander K., E-mail: alexc@cancerboard.ab.c; Wong, Alfred O.; Jenken, Daryl A.

2010-04-15

Purpose: The aim of this retrospective case-matching study was to compare the treatment outcomes and acute toxicity of preoperative radiotherapy (RT) with capecitabine vs. preoperative RT with intermittent 5-fluorouracil (5-FU) infusion, leucovorin, and mitomycin C in rectal cancer. Methods and Materials: We matched 34 patients who were treated with preoperative concurrent capecitabine and 50 Gy of RT by their clinical T stage (T3 or T4) and the tumor location (<=7 cm or >7 cm from the anal verge) with another 68 patients who were treated with preoperative intermittent 5-FU infusion, leucovorin, mitomycin C, and 50 Gy of RT for amore » comparison of the pathologic tumor response, local control, distant failure, and survival rates. Results: The pathologic complete response rate was 21% with capecitabine and 18% with 5-FU and leucovorin (p = 0.72). The rate of T downstaging after chemoradiation was 59% for both groups. The rate of sphincter-sparing resection was 38% after capecitabine plus RT and 43% after 5-FU plus RT (p = 0.67). At 3 years, there was no significant difference in the local control rate (93% for capecitabine and 92% for 5-FU and leucovorin), relapse-free rate (74% for capecitabine and 73% for 5-FU and leucovorin), or disease-specific survival rate (86% for capecitabine and 77% for 5-FU and leucovorin). The acute toxicity profile was comparable, with little Grade 3 and 4 toxicity. Conclusions: When administered with concurrent preoperative RT, both capecitabine and intermittent 5-FU infusion with leucovorin modulation provided comparable pathologic tumor response, local control, relapse-free survival, and disease-specific survival rates in rectal cancer.« less

Deltamethrin is metabolized by CYP6FU1, a cytochrome P450 associated with pyrethroid resistance, in Laodelphax striatellus.

PubMed

Elzaki, Mohammed Esmail Abdalla; Miah, Mohammad Asaduzzaman; Peng, Yingchuan; Zhang, Haomiao; Jiang, Ling; Wu, Min; Han, Zhaojun

2018-06-01

Cytochrome P450s (CYPs) are known to play a major role in metabolizing a wide range compounds. CYP6FU1 has been found to be over-expressed in a deltamethrin-resistant strain of Laodelphax striatellus. This study was conducted to express CYP6FU1 in Sf9 cells as a recombinant protein, to confirm its ability to degrade deltamethrin, chlorpyrifos, imidacloprid and traditional P450 probing substrates. Carbon monoxide difference spectrum analysis indicated that the intact CYP6FU1 protein was expressed in insect Sf9 cells. Catalytic activity tests with four traditional P450 probing substrates revealed that the expressed CYP6FU1 preferentially metabolized p-nitroanisole and ethoxyresorufin, but not ethoxycoumarin and luciferin-HEGE. The enzyme kinetic parameters were tested using p-nitroanisole. The michaelis constant (K m ) and catalytic constant (K cat ) values were 17.51 ± 4.29 µm and 0.218 ± 0.001 pmol min -1 mg -1 protein, respectively. Furthermore, CYP6FU1 activity for degradation of insecticides was tested by measuring substrate depletion and metabolite formation. The chromatogram analysis showed obvious nicotinamide-adenine dinucleotide phosphate (NADPH)-dependent depletion of deltamethrin, and formation of the unknown metabolite. Mass spectra and the molecular docking model showed that the metabolite was 4-hydroxy-deltamethrin. However, the recombinant CYP6FU1 could not metabolize imidacloprid and chlorpyrifos. These results confirmed that the over-expressed CYP6FU1 contributes to deltamethrin resistance in L. striatellus, and p-nitroanisole might be a potential diagnostic probe for deltamethrin metabolic resistance detection and monitoring. © 2017 Society of Chemical Industry. © 2017 Society of Chemical Industry.

X-RAY EMISSION FROM THE FU ORIONIS STAR V1735 CYGNI

DOE Office of Scientific and Technical Information (OSTI.GOV)

Skinner, Stephen L.; Sokal, Kimberly R.; Guedel, Manuel

2009-05-01

The variable star V1735 Cyg (=Elias 1-12) lies in the IC 5146 dark cloud and is a member of the class of FU Orionis objects whose dramatic optical brightenings are thought to be linked to episodic accretion. We report the first X-ray detections of V1735 Cyg and a deeply embedded class I protostar lying 24'' to its northeast. X-ray spectra obtained with EPIC on XMM-Newton reveal very high-temperature plasma (kT > 5 keV) in both objects, but no large flares. Such hard X-ray emission is not anticipated from accretion shocks and is a signature of magnetic processes. We place thesemore » new results into the context of what is presently known about the X-ray properties of FU Orionis stars and other accreting young stellar objects.« less

Colon cancer cells escape 5FU chemotherapy-induced cell death by entering stemness and quiescence associated with the c-Yes/YAP axis.

PubMed

Touil, Yasmine; Igoudjil, Wassila; Corvaisier, Matthieu; Dessein, Anne-Frédérique; Vandomme, Jérôme; Monté, Didier; Stechly, Laurence; Skrypek, Nicolas; Langlois, Carole; Grard, Georges; Millet, Guillaume; Leteurtre, Emmanuelle; Dumont, Patrick; Truant, Stéphanie; Pruvot, François-René; Hebbar, Mohamed; Fan, Fan; Ellis, Lee M; Formstecher, Pierre; Van Seuningen, Isabelle; Gespach, Christian; Polakowska, Renata; Huet, Guillemette

2014-02-15

Metastasis and drug resistance are the major limitations in the survival and management of patients with cancer. This study aimed to identify the mechanisms underlying HT29 colon cancer cell chemoresistance acquired after sequential exposure to 5-fluorouracil (5FU), a classical anticancer drug for treatment of epithelial solid tumors. We examined its clinical relevance in a cohort of patients with colon cancer with liver metastases after 5FU-based neoadjuvant chemotherapy and surgery. We show that a clonal 5F31 cell population, resistant to 1 μmol/L 5FU, express a typical cancer stem cell-like phenotype and enter into a reversible quiescent G0 state upon reexposure to higher 5FU concentrations. These quiescent cells overexpressed the tyrosine kinase c-Yes that became activated and membrane-associated upon 5FU exposure. This enhanced signaling pathway induced the dissociation of the Yes/YAP (Yes-associated protein) molecular complex and depleted nuclear YAP levels. Consistently, YES1 silencing decreased nuclear YAP accumulation and induced cellular quiescence in 5F31 cells cultured in 5FU-free medium. Importantly, YES1 and YAP transcript levels were higher in liver metastases of patients with colon cancer after 5FU-based neoadjuvant chemotherapy. Moreover, the YES1 and YAP transcript levels positively correlated with colon cancer relapse and shorter patient survival (P < 0.05 and P < 0.025, respectively). We identified c-Yes and YAP as potential molecular targets to eradicate quiescent cancer cells and dormant micrometastases during 5FU chemotherapy and resistance and as predictive survival markers for colon cancer. ©2013 AACR

Colon cancer cells escape 5FU chemotherapy-induced cell death by entering stemness and quiescence associated with the c-Yes/YAP axis

PubMed Central

Touil, Yasmine; Igoudjil, Wassila; Corvaisier, Matthieu; Dessein, Anne-Frédérique; Vandomme, Jérôme; Monté, Didier; Stechly, Laurence; Skrypek, Nicolas; Langlois, Carole; Grard, Georges; Millet, Guillaume; Leteurtre, Emmanuelle; Dumont, Patrick; Truant, Stéphanie; Pruvot, François-René; Hebbar, Mohamed; Fan, Fan; Ellis, Lee M.; Formstecher, Pierre; Van Seuningen, Isabelle; Gespach, Christian; Polakowska, Renata; Huet, Guillemette

2015-01-01

Purpose Metastasis and drug resistance are the major limitations in the survival and management of cancer patients. This study aimed to identify the mechanisms underlying HT29 colon cancer cell chemoresistance acquired after sequential exposure to 5-fluorouracil (5FU), a classical anticancer drug for treatment of epithelial solid tumors. We examined its clinical relevance in a cohort of colon cancer patients with liver metastases after 5FU-based neoadjuvant chemotherapy and surgery. Results We show that a clonal 5F31 cell population, resistant to 1μM 5FU, express a typical cancer stem cell-like phenotype and enter into a reversible quiescent G0-state upon re-exposure to higher 5FU concentrations. These quiescent cells overexpressed the tyrosine kinase c-Yes that became activated and membrane-associated upon 5FU exposure. This enhanced signaling pathway induced the dissociation of the Yes/YAP (Yes-associated protein) molecular complex and depleted nuclear YAP levels. Consistently, c-Yes silencing decreased nuclear YAP accumulation and induced cellular quiescence in 5F31 cells cultured in 5FU-free medium. Importantly, c-Yes and YAP transcript levels were higher in liver metastases of colon cancer patients after 5FU-based neoadjuvant chemotherapy. Moreover, the c-Yes and YAP levels positively correlated with colon cancer relapse and shorter patient survival (p<0.05 and p<0.025, respectively). Conclusions We identified c-Yes and YAP as potential molecular targets to eradicate quiescent cancer cells and dormant micrometastases during 5FU chemotherapy and resistance and as predictive survival markers for colon cancer. PMID:24323901

A concordant scenario to explain FU Orionis from deep centimeter and millimeter interferometric observations

NASA Astrophysics Data System (ADS)

Liu, Hauyu Baobab; Vorobyov, Eduard I.; Dong, Ruobing; Dunham, Michael M.; Takami, Michihiro; Galván-Madrid, Roberto; Hashimoto, Jun; Kóspál, Ágnes; Henning, Thomas; Tamura, Motohide; Rodríguez, Luis F.; Hirano, Naomi; Hasegawa, Yasuhiro; Fukagawa, Misato; Carrasco-Gonzalez, Carlos; Tazzari, Marco

2017-06-01

Aims: The aim of this work is to constrain properties of the disk around the archetype FU Orionis object, FU Ori, with as good as 25 au resolution. Methods: We resolved FU Ori at 29-37 GHz using the Karl G. Jansky Very Large Array (JVLA) in the A-array configuration, which provided the highest possible angular resolution to date at this frequency band ( 0.07 arcsec). We also performed complementary JVLA 8-10 GHz observations, Submillimeter Array (SMA) 224 GHz and 272 GHz observations, and compared these with archival Atacama Large Millimeter Array (ALMA) 346 GHz observations to obtain the spectral energy distributions (SEDs). Results: Our 8-10 GHz observations do not find evidence for the presence of thermal radio jets, and constrain the radio jet/wind flux to at least 90 times lower than the expected value from the previously reported bolometric luminosity-radio luminosity correlation. The emission at frequencies higher than 29 GHz may be dominated by the two spatially unresolved sources, which are located immediately around FU Ori and its companion FU Ori S, respectively. Their deconvolved radii at 33 GHz are only a few au, which is two orders of magnitude smaller in linear scale than the gaseous disk revealed by the previous Subaru-HiCIAO 1.6 μm coronagraphic polarization imaging observations. We are struck by the fact that these two spatially compact sources contribute to over 50% of the observed fluxes at 224 GHz, 272 GHz, and 346 GHz. The 8-346 GHz SEDs of FU Ori and FU Ori S cannot be fit by constant spectral indices (over frequency), although we cannot rule out that it is due to the time variability of their (sub)millimeter fluxes. Conclusions: The more sophisticated models for SEDs considering the details of the observed spectral indices in the millimeter bands suggest that the >29 GHz emission is contributed by a combination of free-free emission from ionized gas and thermal emission from optically thick and optically thin dust components. We hypothesize

Development of a novel probe sonication assisted enhanced loading of 5-FU in SPION encapsulated pectin nanocarriers for magnetic targeted drug delivery system.

PubMed

Dutta, Raj Kumar; Sahu, Saurabh

2012-09-01

A novel probe sonication method is developed to enhance loading of 5-fluorouracil (5-FU) in SPION encalsulated pectin nanocarriers of 100-150 nm size (referred here as MP-5FU nanocarriers). Probe sonication at 20 kHz for 60 min resulted in 5-FU loading efficiency of 33.2 ± 2.5%w/w and corresponding drug loading content of 18.2 ± 1.1 wt%. These are two folds higher than literature report of 5-FU loading in pectin. The enhanced loading is attributed to increase in the rate of dissolution of 5-FU in pectin due to transmission of kHz order sonic waves which increases temperature and pressure in the medium due to formation and collapsing of cavitation bubbles. The fabricated MP-5FU nanocarriers with saturation magnetization (43.13 emu/g) exhibited pH responsive, swelling controlled in vitro release of 5-FU in simulated gastric fluid at pH 1.2, in simulated intestinal fluid at pH 6.8, in simulated colonic fluid at pH 5.5, and in phosphate buffer solution at pH 7.4. The cytotoxicity of MP-5FU was measured by sulforhodamine B (SRB) assay and its GI(50) was more than 5mg/mL for cancer cells of HT-29 (colon) and Hep G2 (liver), while it was 3.7 mg/mL for cancer cells of MIA-PaCa-2 (Pancreas). Copyright © 2012 Elsevier B.V. All rights reserved.

[Effects of traditional Tibetan drug Liu Tea on proliferation and chemotherapeutic sensitivity of drug-resistant human gastric cancer cell BGC823/5-FU].

PubMed

Cheng, Yan; Hasiqi, Mei-Ge; Qin, Xiao-Zhen; Tang, Xiang-You; Chen, Jian-Nan; Wang, Hui-Yin; Gao, Ao

2016-02-01

To investigate the effects of Liu Tea extracts(LTE) on proliferation, apoptosis and drug sensitivity of drug-resistant gastric cancer cell BGC823/5-FU. MTT assay was used to analyze effect of LTE on cell growth and sensitivity chemotherapeutic drugs, and synergistic effect of the combination of LTE with 5-FU on BGC823/5-FU cells. Combination index (CI) was calculated by CompuSyn. Cell apoptosis was measured by flow cytometry (FCM). Protein expressions of P-gp, Bcl-2, Bax and Caspase-3 (17KD) were detected by Western blot at different concentrations of LTE in BGC823/5-FU cells (100, 200, 400 mg•L⁻¹). The results showed that LTE had an inhibitory effect on growth of BGC823/5-FU cell in a dose-time-dependent manner and significantly reduced IC₅₀ of 5-FU, CDDP, PTX and ADM to BGC823/5-FU cells(P<0.05), indicating it could reverse tolerance of drug resistant cells to chemotherapeutic drugs, with reversion multiples of 2.35, 1.68, 1.96, 0.52. The combination of LTE with 5-FU had positive synergistic effect on the BGC-823 cell line. FCM assay suggested that LTE could induce BGC823/5-FU apoptosis. The apoptosis rate was up to 46.2% when the cells were treated with 800 mg•L⁻¹ LTE after 24 h(P<0.01). According to the protein detection results, with the increase in concentration of LTE, the protein expression of Bcl-2 was gradually decreased(P<0.01), the expression of Bax and Caspase-3 were extremely increased(P<0.01), with statistical significance in difference(P<0.01) but no difference in the expression of P-gp between experiment group and control group. LTE can inhibit the growth of drug-resistant human gastric cancer cell BGC823/5-FU and reverse its chemotherapeutic tolerance to some extent. Inhibition of antiapoptotic proteins, activation of proapoptotic proteins and induction of apoptosis of resistant cells may be its main mechanisms. Copyright© by the Chinese Pharmaceutical Association.

Apigenin potentiates the antitumor activity of 5-FU on solid Ehrlich carcinoma: Crosstalk between apoptotic and JNK-mediated autophagic cell death platforms.

PubMed

Gaballah, Hanaa H; Gaber, Rasha A; Mohamed, Darin A

2017-02-01

Although 5- Fluorouracil (5-FU) has exhibited effectiveness against cancer, novel therapeutic strategies are needed to enhance its antitumor efficiency and modulate its cytotoxity. Apigenin, a flavonoid present in fruits and vegetables, is a potent dietary phytochemical effective in cancer chemoprevention. This study was undertaken to investigate the potential synergistic antitumor activity of apigenin and 5-FU on Solid Ehrlich carcinoma (SEC). Eighty Swiss albino male mice were divided into four equal groups: vehicle treated control SEC, SEC+5-FU, SEC+apigenin, SEC+ 5-FU+apigenin. Beclin-1 and caspases 3, 9 and JNK activities were estimated by ELISA; mRNA expression levels of the antiapoptotic gene Mcl-1 were estimated using quantitative real-time RT-PCR, while tissue malondialdehyde (MDA), glutathione peroxidase and total antioxidant capacity were evaluated spectrophotometrically. A part of the tumor was examined for histopathological and Ki-67 immunohistochemistry analysis. 5-FU and/or apigenin caused significant increase in tissue levels of Beclin-1, caspases 3, 9 and JNK activities, MDA with significant decrease in tumor volume, Mcl-1expression, tissue glutathione peroxidase and total antioxidant capacity and alleviated the histopathological changes with significant decrease of Ki-67 proliferation index compared to vehicle treated SEC control group. The combination of 5-FU and apigenin had a greater effect than each of 5-FU or apigenin alone against solid Ehrlich carcinoma in mice. Copyright © 2016 Elsevier Inc. All rights reserved.

Apigenin potentiates the antitumor activity of 5-FU on solid Ehrlich carcinoma: Crosstalk between apoptotic and JNK-mediated autophagic cell death platforms

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gaballah, Hanaa H., E-mail: hanaahibishy@hotmail.c

Background: Although 5- Fluorouracil (5-FU) has exhibited effectiveness against cancer, novel therapeutic strategies are needed to enhance its antitumor efficiency and modulate its cytotoxity. Apigenin, a flavonoid present in fruits and vegetables, is a potent dietary phytochemical effective in cancer chemoprevention. Aim: This study was undertaken to investigate the potential synergistic antitumor activity of apigenin and 5-FU on Solid Ehrlich carcinoma (SEC). Methods: Eighty Swiss albino male mice were divided into four equal groups: vehicle treated control SEC, SEC + 5-FU, SEC + apigenin, SEC + 5-FU + apigenin. Beclin-1 and caspases 3, 9 and JNK activities were estimated bymore » ELISA; mRNA expression levels of the antiapoptotic gene Mcl-1 were estimated using quantitative real-time RT-PCR, while tissue malondialdehyde (MDA), glutathione peroxidase and total antioxidant capacity were evaluated spectrophotometrically. A part of the tumor was examined for histopathological and Ki-67 immunohistochemistry analysis. Results: 5-FU and/or apigenin caused significant increase in tissue levels of Beclin-1, caspases 3, 9 and JNK activities, MDA with significant decrease in tumor volume, Mcl-1expression, tissue glutathione peroxidase and total antioxidant capacity and alleviated the histopathological changes with significant decrease of Ki-67 proliferation index compared to vehicle treated SEC control group. In conclusion: The combination of 5-FU and apigenin had a greater effect than each of 5-FU or apigenin alone against solid Ehrlich carcinoma in mice. - Highlights: • Apigenin potentiated 5-FU cytotoxicity in EAC solid tumor models in vivo. • It acted via autophagy stimulation, downregulating MCL-1 and Ki-67 expression. • It caused JNK activation and ROS accumulation; resulted in tumor growth inhibition. • Apigenin can be used as a co-adjuvant agent in cancer therapy.« less

Dietary choline deficiency and excess induced intestinal inflammation and alteration of intestinal tight junction protein transcription potentially by modulating NF-κB, STAT and p38 MAPK signaling molecules in juvenile Jian carp.

PubMed

Wu, Pei; Jiang, Wei-Dan; Jiang, Jun; Zhao, Juan; Liu, Yang; Zhang, Yong-An; Zhou, Xiao-Qiu; Feng, Lin

2016-11-01

This study investigated the effects of choline on intestinal mucosal immune and the possible mechanisms in fish by feeding juvenile Jian carp (Cyprinus carpio var. Jian) with graded levels of dietary choline (165-1820 mg/kg diet) for 65 days. The results firstly showed that choline deficiency induced inflammatory infiltration in the proximal intestine (PI), mid intestine (MI) and distal intestine (DI) of fish. Meanwhile, compared with the optimal choline group, choline deficiency decreased the activities of lysozyme and acid phosphatase, contents of complement 3 and IgM in the intestine, downregulated the mRNA levels of antimicrobial peptides (liver-expressed antimicrobial peptide (LEAP) 2A and defensin-3 in the PI and MI, LEAP-2B and hepcidin in the PI, MI and DI), anti-inflammatory cytokines (interleukin (IL) 10 and transforming growth factor β2 in the PI, MI and DI), and signaling molecule IκB in the PI, MI and DI; while upregulated the mRNA levels of pro-inflammatory cytokines (IL-6a and tumor necrosis factor α in the MI and DI, interferon γ2b in the PI and MI, IL-1β and IL-6b in the PI, MI and DI), and signaling molecules (Toll-like receptor 4 in the MI, myeloid differentiation primary response 88 in the PI and MI, Janus kinase 3 and tyrosine kinase 2 in the MI and DI, nuclear factor kappa B (NF-κB), signal transducers and activators of transcription (STAT) 4 and STAT5 in the PI, MI and DI) of juvenile Jian carp, further indicating that choline deficiency caused inflammation and immunity depression in the intestine of fish. But choline deficiency decreased the PI IL-6a mRNA level, and increased the DI LEAP-2A and defensin-3 mRNA levels with unknown reasons. Furthermore, dietary choline deficiency downregulated mRNA levels of tight junction (TJ) proteins (claudin 3c in the PI and MI, claudin 7, claudin 11 and occludin in the PI, MI and DI) and signaling molecule mitogen-activated protein kinases p38 in the PI, MI and DI of juvenile Jian carp, whereas

[Knockdown of DNA-PKcs inhibits cell cycle and its mechanism of drug-resistant Bel7402/5-Fu hepatocellular carcinoma cells].

PubMed

Li, Dayu; Liu, Yun; Yu, Chunbo; Liu, Xiping; Fan, Fang

2017-12-01

Objective To study the effect of the knock-down of the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) on the cell cycle of the multidrug-resistant (MDR) Bel7402/5-Fu hepatocellular carcinoma cells and its MDR mechanism. Methods After cationic liposome-mediated siDNA-PKcs oligonucleotide transfection, the drug sensitivity of Bel7402/5-Fu cells to 5-fluorouracil (5-Fu) and adriamycin (ADM) was determined by MTT assay; the cell cycle were detected by flow cytometry; meanwhile, the protein expressions of cell cycle-related proteins P21, cell cycle protein B1 (cyclin B1), cell cycle division protein 2 (CDC2) were tested by Western blotting; the expressions of ataxia telangiectasia mutated (ATM) and p53 at both mRNA and protein levels were detected by real-time PCR and Western blot analysis. Results The MTT results showed siDNA-PKcs increased the chemotherapeutic sensitivity of Bel7402/5-Fu cells to 5-Fu and ADM. The flow cytometric analysis showed siDNA-PKcs decreased the percentage of S-phase cells but increased the percentage of G2/M phase cells. Western blotting showed siDNA-PKcs increased the protein expression of P21 but decreased cyclinB1 and CDC2 proteins. In addition, siDNA-PKcs also increased the expressions of ATM and p53. Conclusion DNA-PKcs silencing increases P21 while decreases cyclin B1 and CDC2 expressions, and finally induces G2/M phase arrest in Bel7402/5-Fu cells, which may be related to ATM-p53 signaling pathway.

Assessment of surface concentrations in resorbable ocular implants: controlled drug delivery devices for 5-fluorouracil (5-FU)

NASA Astrophysics Data System (ADS)

Milne, Peter J.; Gautier, Sandrine; Parel, Jean-Marie A.; Jallet, Valerie

1997-05-01

The antineoplastic drug 5-fluorouracil (5-fluoro- 2,4,(1H,3H)-pyrimidinedione; 5-FU) has been used to control proliferation of penetrating fibroblasts and to prevent channel closure following glaucoma filtration surgery (trabeculectomy) or laser sclerectomy. Because of the toxicity of the drug, administration of low dosages slowly over time, at the site of the desired treatment, is indicated for optimum efficacy. Repeated injections of low dosages of the drug represent an undesirable intervention and may also result in unwanted toxicity to the corneal epithelium. A suitable biocompatible and resorbable polymer matrix composed of a poly (D,L-lactic-co-glycolic acid: PLGA) has been admixed with varying amounts of 5-FU and cast as shapes suitable for intracorneal implantation. Slow biodegradation of this polymer over a one to two week period has been shown to result in an acceptably slow drug release mechanism. An issue arising during the clinical evaluation of the efficacy of this drug delivery system was how best to quantify the concentration of 5-FU and its distribution spatially in the solid implant. FT-IR and FT-Raman spectroscopies distinguishes between the drug and the polymer matrix and were used to differentiate and quantitate the 5-FU concentration of the implants.

New insights on the AU-scale circumstellar structure of FU Orionis

NASA Astrophysics Data System (ADS)

Malbet, F.; Lachaume, R.; Berger, J.-P.; Colavita, M. M.; di Folco, E.; Eisner, J. A.; Lane, B. F.; Millan-Gabet, R.; Ségransan, D.; Traub, W. A.

2005-07-01

We report new near-infrared, long-baseline interferometric observations at the AU scale of the pre-main-sequence star FU Orionis with the PTI, IOTA and VLTI interferometers. This young stellar object has been observed on 42 nights over a period of 6 years from 1998 to 2003. We have obtained 287 independent measurements of the fringe visibility with 6 different baselines ranging from 20 to 110 m in length, in the H and K bands. Our data resolves FU Ori at the AU scale, and provides new constraints at shorter baselines and shorter wavelengths. Our extensive (u,v)-plane coverage, coupled with the published spectral energy distribution data, allows us to test the accretion disk scenario. We find that the most probable explanation for these observations is that FU Ori hosts an active accretion disk whose temperature law is consistent with standard models and with an accretion rate of dot M= (6.3 ± 0.6) × 10-5 (Mstar/M⊙)-1 M⊙ yr-1. We are able to constrain the geometry of the disk, including an inclination of 55-7+5 deg and a position angle of 47-11 0+7 deg. In addition, a 10 percent peak-to-peak oscillation is detected in the data (at the two-sigma level) from the longest baselines, which we interpret as a possible disk hot-spot or companion. The still somewhat limited (u, v) sampling and substantial measurement uncertainty prevent us from constraining the location of the spot with confidence, since many solutions yield a statistically acceptable fit. However, the oscillation in our best data set is best explained with an unresolved spot located at a projected distance of 10 ± 1 AU at the 130 ± 1 deg position angle and with a magnitude difference of Δ K ≈ 3.9 ± 0.2 and Δ H ≈ 3.6 ± 0.2 mag moving away from the center at a rate of 1.2 ± 0.6 AU yr-1. Although this bright spot on the surface of the disk could be tracing some thermal instabilities in the disk, we propose to interpret this spot as the signature of a companion of the central FU Ori system on

Producing High-Performance, Stable, Sheared-Flow Z-Pinches in the FuZE project

NASA Astrophysics Data System (ADS)

Golingo, R. P.; Shumlak, U.,; Nelson, B. A.; Claveau, E. L.; Forbes, E. G.; Stepanov, A. D.; Weber, T. R.; Zhang, Y.; McLean, H. S.; Tummel, K. K.; Higginson, D. P.; Schmidt, A. E.; University of Washington (UW) Collaboration; Lawrence Livermore National Laboratory (LLNL) Collaboration

2017-10-01

The Fusion Z-Pinch Experiment (FuZE) has made significant strides towards generating high-performance, stable Z-pinch plasmas with goals of ne = 1018 cm-3 and T =1 keV. The Z-pinch plasmas are stabilized with a sheared axial flow that is driven by a coaxial accelerator. The new FuZE device has been constructed and reproduces the major scientific achievements the ZaP project at the University of Washington; ne = 1016 cm-3,T = 100 eV, r<1 cm, and tstable >20 μs. These parameters are measured with an array of magnetic field probes, spectroscopy, and fast framing cameras. The plasma parameters are achieved using a small fraction of the maximum energy storage and gas injection capability of the FuZE device. Higher density, ne = 5×1017 cm-3, and temperature, T = 500 eV, Z-pinch plasmas are formed by increasing the pinch current. At the higher voltages and currents, the ionization rates in the accelerator increase. By modifying the neutral gas profile in the accelerator, the plasma flow from the accelerator is maintained, driving the flow shear. Formation and sustainment of the sheared-flow Z-pinch plasma will be discussed. Experimental data demonstrating high performance plasmas in a stable Z-pinches will be shown. This work is supported by an award from US ARPA-E.

Adjuvant 5FU plus levamisole in colonic or rectal cancer: improved survival in stage II and III

PubMed Central

Taal, B G; Van Tinteren, H; Zoetmulder, F A N

2001-01-01

Based on the first favourable results of adjuvant therapy of 5FU plus levamisole in Dukes C colonic cancer in 1990, we conducted a prospective trial. 1029 patients were randomised to receive one year 5FU plus levamisole or no further treatment following curative surgery for stage II or III colon (n = 730) or rectal cancer (n = 299). 45% were in stage II and 55% in stage III. With a median follow-up of 4 years and 9 months a significant reduction in odds of death (25%, SD 9%, P = 0.007) was observed for those with adjuvant treatment (65% at 5 year) compared to the observation group (55%). Improved relative survival was present in stage III (56% vs 44%), and in stage II patients (78% vs 70%). In rectal cancer a non-significant difference in disease-free or overall survival was observed. Distant metastases developed in 76%, while local recurrence alone occurred in 14%. An early start of adjuvant treatment (< 4 weeks) did not affect results. Compliance to 5FU plus levamisole was 69%. Severe toxicity did not occur. In conclusion, one year 5FU plus levamisole was of benefit in stage II and III colonic cancer; in rectal cancer a significant positive effect could not be demonstrated. © 2001 Cancer Research Campaign  http://www.bjcancer.com PMID:11720425

[Study on effect of jinshui liujun jian oral liquid on serum superoxide dismutase activity and malonyldialdehyde content in mice with chronic bronchitis].

PubMed

Zhao, C Y; Shen, Y S; Meng, H

2001-11-01

To study the effect of Jinshui Liujun Jian Oral Liquid (JLJOL) on serum superoxide dismutase (SOD) activity and malonyldialdehyde (MDA) content in mice with chronic bronchitis. JLJOL was given to the chronic bronchitis mice model (induced by smoking) through gastrogavage, and then SOD activity and MDA content were tested. SOD activity in model mice after JLJOL treatment was 0.67 +/- 0.15 NU/L, which was significantly higher than that in the untreated model (0.39 +/- 0.13 NU/L, P < 0.01). But the MDA content in treated mice was significantly lower than that in untreated one (9.26 +/- 2.90 nmol/L vs 16.07 +/- 5.62 nmol/L, P < 0.01). JLJOL could scavenge the injury of free radical on organism.

Intestinal immune responses of Jian carp against Aeromonas hydrophila depressed by choline deficiency: Varied change patterns of mRNA levels of cytokines, tight junction proteins and related signaling molecules among three intestinal segments.

PubMed

Wu, Pei; Liu, Yang; Jiang, Wei-Dan; Jiang, Jun; Zhang, Yong-An; Zhou, Xiao-Qiu; Feng, Lin

2017-06-01

This study aimed to investigate the effects of choline deficiency on intestinal inflammation of fish after Aeromonas hydrophila infection and the potential molecular mechanisms. Juvenile Jian carp (Cyprinus carpio var. Jian) were fed two diets containing choline at 165 (deficient group) and 607 mg/kg diet respectively for 65 days. Choline deficiency decreased intestinal lysozyme activity, C3 and IgM contents, increased acid phosphatase activity, downregulated mRNA levels of antimicrobial peptides [liver-expressed antimicrobial peptide (LEAP) 2A, LEAP-2B, hepcidin and defensin], cytokines [interleukin (IL) 6a, tumor necrosis factor α (TNF-α), interferon γ2b (IFN-γ2b), IL-6b and transforming growth factor β2 (TGF-β2) only in proximal intestine, IL-10 in mid and distal intestine], immune-related signaling molecules [Toll-like receptor 4 (TLR4), myeloid differentiation primary response 88 (MyD88), nuclear factor kappa B (NF-κB), inhibitor of NF-κB (IκB), Janus kinase 3 (JAK3), and signal transducers and activators of transcription 5 (STAT5)], tight junction proteins (claudin 3b, claudin 3c, claudin 11 and occludin), and mitogen-activated protein kinases p38 (p38 MAPK ) in proximal and distal intestine of juvenile Jian carp after A. hydrophila challenge. In contrast, choline deficiency upregulated mRNA levels of antimicrobial peptides (LEAP-2A, LEAP-2B, hepcidin and defensin), cytokines (IL-6b, IFN-γ2b and TGF-β2), immune-related signaling molecules (TLR4, MyD88, NF-κB, IκB, JAK3, STAT4 in three intestinal segments, and STAT6), claudin 11, and p38 MAPK in mid intestine of fish. This study provides new finding that choline deficiency-induced immune responses against A. hydrophila infection were varied among three intestinal segments in fish. Copyright © 2017 Elsevier Ltd. All rights reserved.

[Complete responses in patients with unresectable liver metastases from colorectal cancer with weekly high-dose 5-FU plus one-shot CDDP HAI].

PubMed

Udagawa, M; Okabe, S; Kuwabara, H; Ootsukasa, S; Arai, T; Maruyama, S; Murase, N; Yamashita, H; Iwai, T

1999-10-01

Thirty-two patients with unresectable liver metastases from colorectal cancer, treated by intermittent hepatic arterial infusion of high-dose 5-FU combined with CDDP, were assessed. As a result of this treatment, the overall response rate was 65.6%, and eight patients (25%) which contained three autopsy cases revealed a complete response. The mean doses of 5-FU and CDDP which was administered in the eight patients were 24.3 g and 65 mg, respectively. One of the eight patients showed complete disappearance of liver metastasis on the CT scan after arterial infusion of 4.5 g of 5-FU, and necrosis or disappearance of the tumor was present in more than 2/3 of the whole lesion. Autopsy showed focal or zonal necrosis, distorted reconstruction of architecture, and cholangiolitis of the liver which were administered more than 15 g of 5-FU. Intermittent hepatic arterial infusion of high-dose 5-FU combined with CDDP is proved to be a useful locoregional chemotherapy for liver metastasis from colorectal cancer. We should evolve new treatment modalities for extrahepatic metastases, as HAI combined with the systemic chemotherapeutic regimen.

Fluorescence and computational studies of thymidine phosphorylase affinity toward lipidated 5-FU derivatives

NASA Astrophysics Data System (ADS)

Lettieri, R.; D'Abramo, M.; Stella, L.; La Bella, A.; Leonelli, F.; Giansanti, L.; Venanzi, M.; Gatto, E.

2018-04-01

Thymidine phosphorylase (TP) is an enzyme that is up-regulated in a wide variety of solid tumors, including breast and colorectal cancers. It is involved in tumor growth and metastasis, for this reason it is one of the key enzyme to be inhibited, in an attempt to prevent tumor proliferation. However, it also plays an active role in cancer treatment, through its contribution in the conversion of the anti-cancer drug 5-fluorouracil (5-FU) to an irreversible inhibitor of thymidylate synthase (TS), responsible of the inhibition of the DNA synthesis. In this work, the intrinsic TP fluorescence has been investigated for the first time and exploited to study TP binding affinity for the unsubstituted 5-FU and for two 5-FU derivatives, designed to expose this molecule on liposomal membranes. These molecules were obtained by functionalizing the nitrogen atom with a chain consisting of six (1) or seven (2) units of glycol, linked to an alkyl moiety of 12 carbon atoms. Derivatives (1) and (2) exhibited an affinity for TP in the micromolar range, 10 times higher than the parent compound, irrespective of the length of the polyoxyethylenic spacer. This high affinity was maintained also when the compounds were anchored in liposomal membranes. Experimental results were supported by molecular dynamics simulations and docking calculations, supporting a feasible application of the designed supramolecular lipid structure in selective targeting of TP, to be potentially used as a drug delivery system or sensor device.

Down-regulation of BAX gene during carcinogenesis and acquisition of resistance to 5-FU in colorectal cancer.

PubMed

Manoochehri, Mehdi; Karbasi, Ashraf; Bandehpour, Mojgan; Kazemi, Bahram

2014-04-01

Carcinogenesis and resistance to chemotherapy could be as results of expression variations in apoptosis regulating genes. Changes in the expression of apoptosis interfering genes may contribute to colorectal carcinogenesis and resistance to 5-Flourouracil (5-FU) during treatment schedule period. The present study aimed to evaluate the expression of pro-apoptotic and anti-apoptotic genes in colorectal cancer tumor tissues, normal adjacent tissues, and tumor colorectal cancer cell line during acquiring resistance to 5-FU in HT-29 based on Bolus treatment protocol. The normal and tumor tissues were obtained from hospital after surgery and total RNA was extracted for expression analysis. The HT-29 colorectal cancer cell line was cultured and exposed with 5-FU in three stages based on Bolus protocol. The MTT assay and Real Time PCR were carried out to determine the sensitivity to the drug and expression of desired genes, respectively. The obtained data showed that Proapoptotic genes, BAX and BID, were down-regulated in resistant derivate cells compared to wild type HT-29 cells. On the other hand Antiapoptotic genes, CIAP1 and XIAP, showed upregulation in resistant cells compared to wild type ones. Furthermore, BAX and FAS genes showed down-regulation in tumor samples in comparison to normal adjacent tissues. In conclusion, the results of our study suggest that BAX down-regulation could contribute as an important factor during both colorectal carcinogenesis and cell resistance to 5-FU.

Dihydropyrimidine dehydrogenase gene (DPYD) polymorphism among Caucasian and non-Caucasian patients with 5-FU- and capecitabine-related toxicity using full sequencing of DPYD.

PubMed

Saif, Muhammad Wasif

2013-01-01

Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme of the degradation of pyrimidine base, and plays a pivotal role in the pharmacogenetic syndrome of 5-fluorouracil (5-FU). Deficiency of DPD activity leads to severe toxicities, even death, following administration of 5-FU. Several studies have demonstrated that molecular defects of the dihydropyrimidine dehydrogenase gene (DPYD) lead to the deficiency of DPD activity and cause this pharmacogenetic syndrome. We present the analysis of DPYD genotyping in untreated Caucasian patients (control group) and Caucasian patients with 5-FU/CAP-related grade 3/4 toxicities (toxicity group) who underwent a capecitabine TheraGuide 5-FU testing. Full sequencing of DPYD was performed in the Myriad Genetic Laboratories, Inc. as part of TheraGuide 5-FU test. Among 227 patients from the toxicity group, 27 (12%) had deleterious mutations in DPYD: twelve (5%) had IVS14 +1 G>A, eleven (5%) had D949V and four (2%) had other mutations. Only 7/192 (4%) patients from the control group had DPYD genotype abnormalities: two (1%) had IVS14 +1 G>A, four (2%) had D949V and one (1%) had other mutation. Genotype abnormalities were observed more frequently in the toxicity group (p=0.001). Among 65 patients with toxicities due to capecitabine, nine (14%) had mutated DPYD, which was more frequent than in the control group (p=0.006). Mutated DPYD is frequently observed in Caucasian patients who experience toxicities while receiving 5-FU/capecitabine. Screening of patients for DPYD mutations prior to administration of 5-FU/capecitabine using new pharmacogenetic testing methods, may help for identify those patients who are at greatest risk for adverse effects, allowing a more individualized approach to their chemotherapy management.

The expression of Msi-1 and its significance in small intestinal mucosa severely damaged by high-dose 5-FU.

PubMed

Yuqi, Luo; Chengtang, Wu; Ying, Wen; Shangtong, Lei; Kangxiong, Liao

2008-09-01

The purpose was to investigate the expression of musashi-1 (msi-1) and its significances in small intestinal mucosa that was severely damaged by high-dose 5-FU. A total of 40 adult C57BL/6J mice were divided into two groups: the control group (n = 8, group A) and experimental group (n = 32). The mice in the control group were treated with PBS by intraperitoneal injection, and the other mice were treated with high-dose 5-FU (150 mg/kg body weight for 5 consecutive days) by intraperitoneal injection. At the 1st (group B), 3rd (group C) and 5th (group D) day after treatment with high-dose 5-FU, the dying mice were killed, HE staining and immunohistochemical techniques were used to detect the expression of the putative marker of intestinal epithelial stem cells, msi-1, in samples of the middle intestine from these mice, and the percentage of the msi-1-positive cells from the intestinal mucosal cells of the mice in group B was detected by FACS. After treatment with high-dose 5-FU, the intestinal mucosa suffered severe damage: the villi and crypts disappeared, the number of msi-1-positive cells increased greatly, the intestinal epithelial cells could be divided into two fractions by FACS, and the percentage of msi-1-positive cells was up to 67.75% in the fraction in which the value of FSC was higher. After treatment with high-dose 5-FU, the percentage of intestinal stem cells had increased significantly, which was useful for the further isolation and enrichment of intestinal epithelial stem cells.

Fuels planning: science synthesis and integration; environmental consequences fact sheet 12: Water Erosion Prediction Project (WEPP) Fuel Management (FuMe) tool

Treesearch

William Elliot; David Hall

2005-01-01

The Water Erosion Prediction Project (WEPP) Fuel Management (FuMe) tool was developed to estimate sediment generated by fuel management activities. WEPP FuMe estimates sediment generated for 12 fuel-related conditions from a single input. This fact sheet identifies the intended users and uses, required inputs, what the model does, and tells the user how to obtain the...

A novel comprehensive set of fungal Real time PCR assays (fuPCR) for the detection of fungi in immunocompromised haematological patients-A pilot study.

PubMed

Rahn, Sebastian; Schuck, Anna; Kondakci, Mustafa; Haas, Rainer; Neuhausen, Nicole; Pfeffer, Klaus; Henrich, Birgit

2016-12-01

Fungal infections are recognized in an increasing number of patients with immunological deficits and are associated with high rates of mortality (Brown et al., 2012a). In this pilot-study, a rapid Real time PCR (fuPCR) was designed for the detection and differentiation of fungal pathogens in clinical specimens of haematological patients. The fuPCR, targeting the internal transcribed spacer region 2 (ITS2) of rDNA region, is comprised of seven multiplex reactions, which were shown to be specific and sensitive for a comprehensive spectrum of clinically relevant fungal species. This was validated by testing respective fungal DNAs in each fuPCR reaction and 28 respiratory samples of fungal pneumonia-proven patients. Clinical sample sets of throat swab, EDTA-blood and blood sera from 50 patients with severe haematological malignancies, including haematopoietic stem cell transfer (HSCT), and samples from 30 healthy individuals were then analysed. In a first step, 198 samples of immunosuppressed patients were solely examined by fuPCR; and 50.8% (33/65) respiratory swabs, 4.8% (3/63) EDTA blood samples and 1.4% (1/70) blood serum samples were tested positive. In a second step, 56 respiratory samples of immunosuppressed patients and 30 of healthy individuals were simultaneously analysed by fuPCR and standard cultivation techniques. By both methods 30.4% (17/56) swabs of the immunocompromised patients were tested positive, 37.5% (21/56) were tested negative and 32.1% (18/56) were tested fuPCR positive and culture negative. In analysing the blood samples of the immunocompromised patients 5.4% (3/56) EDTA blood samples and 16.1% (9/56) sera samples were tested fuPCR-positive, whereas all samples of 30 healthy individuals with no signs of immunological deficits were tested negative by fuPCR. 38.9% (14/36) of the fungi detected in respiratory samples of the immunosuppressed patients, belonged to Candida spp., 47.2% (17/36) to Saccharomyces spp., 5.6% (2/36) to Cladosporium spp

Design and Synthesis of a Biocompatible 1D Coordination Polymer as Anti-Breast Cancer Drug Carrier, 5-Fu: In Vitro and in Vivo Studies.

PubMed

Rezaei, Mahsa; Abbasi, Alireza; Dinarvand, Rassoul; Jeddi-Tehrani, Mahmood; Janczak, Jan

2018-05-17

Designable coordination polymers with suitable chemical diversities and biocompatible structures have been proposed as a promising class of vehicles for drug delivery systems. Here, we hydrothermally synthesized a novel one-dimensional (1D) coordination polymer, [Zn(H 2 O) 6 K 2 (H 2 BTC) 2 (H 2 O) 4 ](H 2 BTC) 2 ·2H 2 O, where H 3 BTC = benzene-1,3,5-tricarboxylic acid (trimesic acid), cp.1. As the hydrogen bonds stabilized 1D chains in three dimensions, the cp.1 could be a good candidate for delivering small-molecule chemotherapeutics such as 5-fluorouracil (5-Fu). The synthesized cp.1 showed a remarkable 5-Fu loading of 66% with encapsulation efficiency of 98% and almost complete release process. The 5-Fu-loaded cp.1 displayed a time-dependent cytotoxicity effect against breast cancer cell lines MCF-7 and 4T1. The cellular uptake of cp.1 particles was investigated via confocal laser scanning microscopy using fluorescein isothiocyanate and LysoTracker Red staining. Furthermore, the in vivo antitumor impact of 5-Fu-loaded cp.1 was studied on 4T1 breast cancer BALB/c mice model. The intratumor treatment of 5-Fu-loaded cp.1 demonstrated beneficial antitumor efficacy by postponing tumor growth. These results suggest that the 5-Fu-loaded cp.1 microparticles with a great locoregional delivery can be efficient anticancer drug carriers for further clinical treatments.

Interferometric view of the circumstellar envelopes of northern FU Orionis-type stars

NASA Astrophysics Data System (ADS)

Fehér, O.; Kóspál, Á.; Ábrahám, P.; Hogerheijde, M. R.; Brinch, C.

2017-11-01

Context. FU Orionis-type objects are pre-main sequence, low-mass stars with large outbursts in visible light that last for several years or decades. They are thought to represent an evolutionary phase during the life of every young star when accretion from the circumstellar disk is enhanced during recurring time periods. These outbursts are able to rapidly build up the star while affecting the physical conditions inside the circumstellar disk and thus the ongoing or future planet formation. In many models, infall from a circumstellar envelope seems to be necessary to trigger the outbursts. Aims: We characterise the morphology and the physical parameters of the circumstellar material around FU Orionis-type stars using the emission of millimetre-wavelength molecular tracers. The high-spatial-resolution study provides insight into the evolutionary state of the objects, the distribution of parameters in the envelopes and the physical processes forming the environment of these stars. Methods: We observed the J = 1-0 rotational transition of 13CO and C18O towards eight northern FU Orionis-type stars (V1057 Cyg, V1515 Cyg, V2492 Cyg, V2493 Cyg, V1735 Cyg, V733 Cep, RNO 1B and RNO 1C) and determine the spatial and velocity structure of the circumstellar gas on a scale of a few thousand AU. We derive temperatures and envelope masses and discuss the kinematics of the circumstellar material. Results: We detected extended CO emission associated with all our targets. Smaller-scale CO clumps were found to be associated with five objects with radii of 2000-5000 AU and masses of 0.02-0.5 M⊙; these are clearly heated by the central stars. Three of these envelopes are also strongly detected in the 2.7 mm continuum. No central CO clumps were detected around V733 Cep and V710 Cas which can be interpreted as envelopes but there are many other clumps in their environments. Traces of outflow activity were observed towards V1735 Cyg, V733 Cep and V710 Cas. Conclusions: The diversity of

A DPYD variant (Y186C) specific to individuals of African descent in a patient with life-threatening 5-FU toxic effects: potential for an individualized medicine approach.

PubMed

Saif, M Wasif; Lee, Adam M; Offer, Steven M; McConnell, Kathleen; Relias, Valerie; Diasio, Robert B

2014-01-01

5-Fluorouracil (5-FU) is commonly administered as a therapeutic agent for the treatment of various aggressive cancers. Severe toxic reactions to 5-FU have been associated with decreased levels of dihydropyrimidine dehydrogenase (DPD) enzyme activity. Manifestations of 5-FU toxicity typically include cytopenia, diarrhea, stomatitis, mucositis, neurotoxicity, and, in extreme cases, death. A variety of genetic variations in DPYD, the gene encoding DPD, are known to result in decreased DPD enzyme activity and to contribute to 5-FU toxic effects. Recently, it was reported that healthy African American individuals carrying the Y186C DPYD variant (rs115232898) had significantly reduced DPD enzyme activity compared with noncarriers of Y186C. Herein, we describe for the first time, to our knowledge, an African American patient with cancer with the Y186C variant who had severe toxic effects after administration of the standard dose of 5-FU chemotherapy. The patient lacked any additional toxic effect-associated variations in the DPYD gene or the thymidylate synthase (TYMS) promoter. This case suggests that Y186C may have contributed to 5-FU toxicity in this patient and supports the use of Y186C as a predictive marker for 5-FU toxic effects in individuals of African ancestry. Copyright © 2014 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.

Effect of “Jian-Pi-Zhi-Dong Decoction” on Gamma-Aminobutyric Acid in a Mouse Model of Tourette Syndrome

PubMed Central

Zhang, Wen; Yu, Wenjing; Wei, Li; Lee, Minkyoung; Wang, Sumei

2014-01-01

The purpose of this study was to explore the positive effects of Jian-Pi-Zhi-Dong Decoction (JPZDD) on Tourette syndrome (TS) by investigating the expression of gamma-aminobutyric acid (GABA) and its type A receptor (GABAAR) in the striatum of a TS mice model. The model was induced by 3,3′-iminodipropionitrile (IDPN) treatment; then mice were divided into 4 groups (n=22, each); control and IDPN groups were gavaged with saline and the remaining 2 groups were gavaged with tiapride and JPZDD. We recorded the stereotypic behaviors of TS mice and measured the content of GABA in striatum by HPLC and GABAAR expression by immunohistochemistry and real-time PCR. Our results showed that JPZDD inhibited the abnormal behaviors of TS model mice and decreased GABA levels and GABAAR protein and mRNA expression in the striatum of TS model mice. In brief, the mechanism by which JPZDD alleviates TS symptoms may be associated with GABAAR expression downregulation in striatum which may regulate GABA metabolism. PMID:24812567

Effects of nandrolone decanoate on the toxicity and anti-tumour action of CCNU and FU in murine tumours.

PubMed Central

Bibby, M. C.; Double, J. A.; Mughal, M. A.

1981-01-01

Pre-treatment with the anabolic steroid nandrolone decanoate (ND) increases the LD50 of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) and 5-Fluorouracil (FU) in NMRI mice. Administration of ND did not affect the anti-tumour action of CCNU against a transplantable mouse adenocarcinoma of the colon (MAC 13) or the anti-tumour action of FU against MAC 26. In both tumour lines ND had no significant effect on tumour growth. These data suggest that an increase in the anti-tumour selectivity of these agents may be produced by pre-treatment with ND. PMID:7295514

E2F1/TS Immunophenotype and Survival of Patients with Colorectal Cancer Treated with 5FU-Based Adjuvant Therapy.

PubMed

Sulzyc-Bielicka, Violetta; Domagala, Pawel; Bielicki, Dariusz; Safranow, Krzysztof; Rogowski, Wojciech; Domagala, Wenancjusz

2016-07-01

The predictive value of thymidylate synthase (TS) expression alone for 5FU-based treatment of colorectal cancer (CRC) has not been clinically confirmed. Little is known on the association of expression of E2F1, which controls the transcription of genes encoding proteins engaged in DNA synthesis including TS, and survival of patients with CRC. The purpose of this study is to assess the correlation between expression of both E2F1 and TS in CRCs and survival of patients administered adjuvant 5FU-based chemotherapy, in order to find a better predictor of treatment outcome than expression of TS or E2F1 alone. Nuclear TS and E2F1 were detected by immunohistochemistry in tissue microarrays from 190 CRCs (Astler-Coller stage B2 or C). Multivariate analysis identified significant association of the combined E2F1+TS+ immunophenotype with worse OS (HR = 3,78, P = 0,009) and DFS (HR = 2,30, P = 0,03) of patients with colon cancer. There were significant differences between E2F1+TS+ and E2F1-TS- Kaplan-Meier survival curves in relation to DFS (P = 0.008) and OS (P = 0.01). About 37 and 31 % difference in 3-year DFS and OS respectively were seen between patients with E2F1+TS+ vs. E2F1-TS- colon cancer immunophenotype. The E2F1+TS+ immunophenotype may be a marker of poor prognosis (the worst DFS and OS) of patients with colon cancer treated with 5FU-based adjuvant therapy. A subgroup of patients with this immunophenotype may require different and perhaps more aggressive treatment than 5FU-based chemotherapy. Thus, the combined E2F1/TS immunophenotype could be a potential indicator of colon cancer sensitivity to 5FU.

Laser sclerectomy and 5-FU controlled-drug-release biodegradable implant for glaucoma therapy

NASA Astrophysics Data System (ADS)

Villain, Franck L.; Parel, Jean-Marie A.; Kiss, Katalin; Parrish, Richard K.; Kuhne, Francois; Takesue, Yoshiko; Hostyn, Patrick

1993-06-01

Laser sclerectomy, a simple filtering procedure performed to alleviate high intraocular pressure in glaucoma patients, was taught to offer longer lasting effect and therefore improve the patient's outcome when compared with the standard trabeculectomy procedure. Recent clinical trials have shown that this was not the case and pharmacologic wound healing modulation is also required with this new procedure. Five-Fluorouracil (5-FU) is useful as an adjunct treatment for glaucoma filtering surgery. However, efficacy depends upon maintaining sustained drug levels, currently achieved by repeated daily injection of the drug for several weeks. To overcome this limitation, we designed a biodegradable implant for the sustained release of 5-FU. After laser sclerectomy, the implant is inserted through the same 1 mm wide conjunctival snip incision and positioned below the open channel. Implantation takes less than a minute. The implant releases the drug for over 15 days and totally biodegrades in less than 100 days. The combined laser surgery and implantation procedure show great potentials for the treatment of glaucoma.

Analytical estimation of annual runoff distribution in ungauged seasonally dry basins based on a first order Taylor expansion of the Fu's equation

NASA Astrophysics Data System (ADS)

Caracciolo, D.; Deidda, R.; Viola, F.

2017-11-01

The assessment of the mean annual runoff and its interannual variability in a basin is the first and fundamental task for several activities related to water resources management and water quality analysis. The scarcity of observed runoff data is a common problem worldwide so that the runoff estimation in ungauged basins is still an open question. In this context, the main aim of this work is to propose and test a simple tool able to estimate the probability distribution of the annual surface runoff in ungauged river basins in arid and semi-arid areas using a simplified Fu's parameterization of the Budyko's curve at regional scale. Starting from a method recently developed to derive the distribution of annual runoff, under the assumption of negligible inter-annual change in basin water storage, we here generalize the application to any catchment where the parameter of the Fu's curve is known. Specifically, we provide a closed-form expression of the annual runoff distribution as a function of the mean and standard deviation of annual rainfall and potential evapotranspiration, and the Fu's parameter. The proposed method is based on a first order Taylor expansion of the Fu's equation and allows calculating the probability density function of annual runoff in seasonally dry arid and semi-arid geographic context around the world by taking advantage of simple easy-to-find climatic data and the many studies with estimates of the Fu's parameter worldwide. The computational simplicity of the proposed tool makes it a valuable supporting tool in the field of water resources assessment for practitioners, regional agencies and authorities.

5-FU resistant EMT-like pancreatic cancer cells are hypersensitive to photochemical internalization of the novel endoglin-targeting immunotoxin CD105-saporin.

PubMed

Lund, Kaja; Olsen, Cathrine Elisabeth; Wong, Judith Jing Wen; Olsen, Petter Angell; Solberg, Nina Therese; Høgset, Anders; Krauss, Stefan; Selbo, Pål Kristian

2017-12-19

Development of resistance to 5-fluorouracil (5-FU) is a major problem in treatment of various cancers including pancreatic cancer. In this study, we reveal important resistance mechanisms and photochemical strategies to overcome 5-FU resistance in pancreatic adenocarcinoma. 5-FU resistant (5-FUR), epithelial-to-mesenchymal-like sub-clones of the wild type pancreatic cancer cell line Panc03.27 were previously generated in our lab. We investigated the cytotoxic effect of the endosomal/lysosomal-localizing photosensitizer TPCS 2a (fimaporfin) combined with light (photochemical treatment, PCT) using MTS viability assay, and used fluorescence microscopy to show localization of TPCS 2a and to investigate the effect of photodamage of lysosomes. Flow cytometric analysis was performed to investigate uptake of photosensitizer and to assess intracellular ROS levels. Expression and localization of LAMP1 was assessed using RT-qPCR, western blotting, and structured illumination microscopy. MTS viability assay was used to assess the effect of combinations of 5-FU, chloroquine (CQ), and photochemical treatment. Expression of CD105 was investigated using RT-qPCR, western blotting, flow cytometry, and fluorescence microscopy, and co-localization of TPCS 2a and anti-CD105-saporin was assessed using microscopy. Lastly, the MTS assay was used to investigate cytotoxic effects of photochemical internalization (PCI) of the anti-CD105-immunotoxin. The 5-FUR cell lines display hypersensitivity to PCT, which was linked to increased uptake of TPCS 2a , altered lysosomal distribution, lysosomal photodamage and increased expression of the lysosomal marker LAMP-1 in the 5-FUR cells. We show that inhibition of autophagy induced by either chloroquine or lysosomal photodamage increases the sensitivity to 5-FU in the resistant cells. The three 5-FUR sub-clones overexpress Endoglin (CD105). Treatment with the immunotoxin anti-CD105-saporin alone significantly reduced the viability of the CD105

Pharmacogenetic Analysis of INT 0144 Trial: Association of Polymorphisms with Survival and Toxicity in Rectal Cancer Patients Treated with 5-FU and Radiation

PubMed Central

Bohanes, Pierre; Rankin, Cathryn J.; Blanke, Charles D.; Winder, Thomas; Ulrich, Cornelia M.; Smalley, Stephen R.; Rich, Tyvin A.; Martensen, James A.; Benson, Al B.; Mayer, Robert J.; Cripps, Christine M.; Danenberg, Kathleen; Makar, Karen W.; Zhang, Wu; Benedetti, Jacqueline K.; Lenz, Heinz-Josef

2015-01-01

Purpose We tested whether 18 polymorphisms in 16 genes (GSTP1, COX2, IL-10, EGFR, EGF, FGFR4, CCDN1, VEGFR2, VEGF, CXCR2, IL-8, MMP3, ICAM1, ERCC1, RAD51 and XRCC3) would predict disease-free-survival (DFS), Overall survival (OS) and toxicity in the INT0144 trial, which was designed to investigate different postoperative regimen of 5-FU-based chemoradiation in locally advanced rectal cancers: Arm1 consisted of bolus 5-FU followed by 5-FU protracted venous infusion (PVI) with radiotherapy; Arm2 was induction and concomitant PVI 5-FU with radiotherapy Arm3 was induction and concomitant bolus 5-FU with radiotherapy. Patients and Methods DNA from 746 stage II/III rectal patients enrolled in the SWOG S9304 phase III trial was analyzed. Genomic DNA was extracted from FFPE tumor tissue. The polymorphisms were analyzed using direct DNA-sequencing or PCR-RFLP. Results GSTP1-Ile105Val (rs1695) was significantly associated with DFS and OS and its effect did not vary by treatment arm. The 5-year DFS and OS were 53% and 58%, respectively, for G/G, 66% and 72% for G/A and 57% and 66% for A/A patients. In Arm2, IL8-251A/A genotype (rs4073) was associated with a lower risk of toxicities (p=0.04). The VEGFR2 H472Q Q/Q genotype (rs1870377) was associated with a higher risk of grade 3–5 proximal upper gastrointestinal tract (PUGIT) mucositis (p=0.04) in Arm 2. However, in Arm 1 this genotype was associated with a lower risk of PUGIT mucositis (p=0.004). Conclusion rs1695 may be prognostic in patients with rectal cancer treated with adjuvant chemoradiation. rs4073 and rs1870377 may exhibit different associations with toxicity, according to the 5-FU schedule. PMID:25589620

Tai Chi and Kung-Fu practice maintains physical performance but not vascular health in young versus old participants.

PubMed

McAnulty, Steven; McAnulty, Lisa; Collier, Scott; Souza-Junior, Tacito P; McBride, Jeffrey

2016-01-01

Kung-Fu and Tai Chi along with other martial arts are gaining popularity but studies examining the benefits of martial arts on physical fitness, vascular health, nutrition, and psychological wellness are limited. Aging is associated with declines in these health components. The objectives of this study were to examine whether Tai Chi and Kung-Fu training would maintain physical fitness, vascular health, and psychological wellness components on older versus younger practitioners. Seventeen subjects were recruited and divided into Young (age <40 years, n=9) and Old (age 40 years and above, n=8). Participants reported twice for health screens, vascular and nutrition assessment, and fitness tests. Mean differences were compared between groups for all tests using Student's t-tests. Age, months of practice, systolic blood pressure, and cardiovascular augmentation index were significantly greater in Old versus Young (p=0.001, p=0.007, p=0.049, and p=0.011, respectively). Psychologically, old practitioners experienced greater sleep interference (p=0.035) and overall pain (p=0.036). No other differences existed for any variable. Our study indicates that the practice of Tai Chi and Kung-Fu maintains physical fitness in older compared to younger practitioners. However, age associated changes in cardiovascular stiffness, systolic blood pressure, and pain were not prevented.

Gee Fu: a sequence version and web-services database tool for genomic assembly, genome feature and NGS data.

PubMed

Ramirez-Gonzalez, Ricardo; Caccamo, Mario; MacLean, Daniel

2011-10-01

Scientists now use high-throughput sequencing technologies and short-read assembly methods to create draft genome assemblies in just days. Tools and pipelines like the assembler, and the workflow management environments make it easy for a non-specialist to implement complicated pipelines to produce genome assemblies and annotations very quickly. Such accessibility results in a proliferation of assemblies and associated files, often for many organisms. These assemblies get used as a working reference by lots of different workers, from a bioinformatician doing gene prediction or a bench scientist designing primers for PCR. Here we describe Gee Fu, a database tool for genomic assembly and feature data, including next-generation sequence alignments. Gee Fu is an instance of a Ruby-On-Rails web application on a feature database that provides web and console interfaces for input, visualization of feature data via AnnoJ, access to data through a web-service interface, an API for direct data access by Ruby scripts and access to feature data stored in BAM files. Gee Fu provides a platform for storing and sharing different versions of an assembly and associated features that can be accessed and updated by bench biologists and bioinformaticians in ways that are easy and useful for each. http://tinyurl.com/geefu dan.maclean@tsl.ac.uk.

RGO/AuNR/HA-5FU nanocomposite with multi-stage release behavior and efficient antitumor activity for synergistic therapy.

PubMed

Yang, Ying; Wang, Yunlong; Zhu, Manzhou; Chen, Yan; Xiao, Yazhong; Shen, Yuhua; Xie, Anjian

2017-05-02

A reduced graphene oxide (RGO)/gold nanorod (AuNR)/hydroxyapatite (HA) nanocomposite was designed and successfully synthesized for the first time. An anticancer drug, 5-fluorouracil (5FU), was chosen as a model drug to be loaded in RGO/AuNR/HA. The fabricated RGO/AuNR/HA-5FU showed robust, selective targeting and penetrating efficiency against HeLa cells due to the good compatibility and nontoxicity of HA, and showed excellent synergetic antitumor effects through combined chemotherapy (CT) by 5FU and photothermal therapy (PTT) by both RGO and AuNRs under near-infrared (NIR) laser irradiation. More importantly, this synergistic dual therapy based on RGO/AuNR/HA can also minimize side effects in normal cells and exhibits greater antitumor activity because of a multi-stage drug release ability triggered by the pH sensitivity of HA in the first stage and the combined photothermal conversion capabilities of RGO and AuNRs by means of the NIR laser irradiation in the second stage. This study suggests that the novel RGO/AuNR/HA multi-stage drug delivery system may represent a promising potential application of multifunctional composite materials in the biomedical field.

Study of the Outflow and Disk surrounding a Post-Outburst FU-Orionis Star

NASA Astrophysics Data System (ADS)

Mellon, Samuel N.; Perez, L. M.

2014-01-01

PP 13 is a fan-shaped cometary nebula located in the constellation of Perseus and embedded in the L1473 dark cloud. At optical wavelengths this region is obscured by the surrounding dark cloud, while at infrared and longer wavelengths two northern objects (PP13Na & PP13Nb) and one southern object (PP13S) are revealed. In the past, the young stellar object inside PP13S, called PP13S*, experienced an FU-Orionis type outburst due to a massive accretion episode and is currently returning to its quiescent state. Studying the FU-Orionis phase is crucial to our understanding of how low mass stars form; it is theorized that all low-mass stars go through this outburst phase while they are forming. I used CARMA 3mm interferometric observations of the PP13 region to study the continuum and molecular line emissions from PP13. With these observations, I determined the source of the previously detected outflow and learned new information about the double star system PP13Na and PP13Nb. Although I was not able to detect the accretion disk in the gas emissions, I plan to use computer modeling to help provide constraints on the properties of PP13S* and its outflow.

Effect of targeted magnetic nanoparticles containing 5-FU on expression of bcl-2, bax and caspase 3 in nude mice with transplanted human liver cancer

PubMed Central

Wang, Jian-Ming; Xiao, Bao-Lai; Zheng, Jian-Wei; Chen, Hai-Bing; Zou, Sheng-Quan

2007-01-01

AIM: To investigate the anti-tumor effect and mechanisms of magnetic nanoparticles targeting hepatocellular carcinoma. METHODS: Human hepatocellular carcinoma was induced in nude mice, and the mice were randomly divided into group A receiving normal saline, group B receiving magnetic nanoparticles containing 5-fluorouracil (5-FU), group C receiving 5-FU, and group D receiving magnetic nanoparticles containing 5-FU with a magnetic field built in tumor tissues. The tumor volume was measured on the day before treatment and 1, 4, 7, 10 and 13 d after treatment. Tumor tissues were isolated for examination of the expression of bcl-2, bax and caspase 3 by immunohistochemical method, reverse transcription polymerase chain reaction and Western blotting. RESULTS: The tumor volume was markedly lower in groups C and D than in groups A and B (group C or D vs group A or B, P < 0.01). The volume was markedly lower in group D than in group C (P < 0.05). The expression of protein and mRNA of bcl-2 was markedly lower in groups C and D than in groups A and B (group C or D vs group A or B, P < 0.01), and was markedly lower in group D than in group C (P < 0.01). The expression of bax and caspase 3 in groups C and D was significantly increased, compared with that in groups A and B (P < 0.01). CONCLUSION: The targeted magnetic nanoparticles containing 5-FU can improve the chemotherapeutic effect of 5-FU against hepatocellular carcinoma by decreasing the expression of bcl-2 gene, and increasing the expression of bax and caspase 3 genes. PMID:17589894

Dosimetric study of photobiomodulation therapy in 5-FU-induced oral mucositis in hamsters

NASA Astrophysics Data System (ADS)

Cotomacio, Claudia Carrara; Campos, Luana; Nesadal de Souza, Douglas; Arana-Chavez, Victor Elias; Simões, Alyne

2017-01-01

Oral mucositis (OM) is a debilitating consequence of cancer treatment that could be treated with photobiomodulation therapy (PBMT); however, there is no consensus about its dosimetric parameters for OM healing. The aim of this study was to compare different PBMT protocols on OM treatment, through clinical and histological analysis. Thirty hamsters were used, in an induced model of OM by 5-fluorouracil (5-FU) and superficial scratching, in seven days of follow-up. The animals were divided into five groups: control (C), which received only anesthesia and chemotherapeutic vehicle; chemotherapy (Ch), which received anesthesia, 5-FU, and scratches; laser 1 (L1), the same as Ch group, PBMT 6 J/cm2 and 0.24 J (one point); laser 2 (L2), the same as Ch group, PBMT 25 J/cm2 and 1 J (one point); and laser 3 (L3), the same as Ch group, PBMT 4 points of 0.24 J and 6 J/cm2 each. The laser used has λ=660 nm, 0.04 cm2 of spot area, and 40 mW. The best PBMT protocol to maintain lowest OM levels compared to Ch group was L1, followed by L2 and L3. Our results suggest that the application mode of PBMT and the energy delivered per area could interfere with the OM healing.

TS gene polymorphisms are not good markers of response to 5-FU therapy in stage III colon cancer patients.

PubMed

Fariña-Sarasqueta, A; Gosens, M J E M; Moerland, E; van Lijnschoten, I; Lemmens, V E P P; Slooter, G D; Rutten, H J T; van den Brule, Adriaan J C

2011-08-01

Although the predictive and prognostic value of thymidylate synthase (TS) expression and gene polymorphism in colon cancer has been widely studied, the results are inconclusive probably because of methodological differences. With this study, we aimed to elucidate the role of TS gene polymorphisms genotyping in therapy response in stage III colon carcinoma patients treated with 5-FU adjuvant chemotherapy. 251 patients diagnosed with stage III colon carcinoma treated with surgery followed by 5-FU based adjuvant therapy were selected. The variable number of tandem repeats (VNTR) and the single nucleotide polymorphism (SNP) in the 5'untranslated region of the TS gene were genotyped. There was a positive association between tumor T stage and the VNTR genotypes (p = 0.05). In both univariate and multivariate survival analysis no effects of the studied polymorphisms on survival were found. However, there was an association between both polymorphisms and age. Among patients younger than 60 years, the patients homozygous for 2R seemed to have a better overall survival, whereas among the patients older than 67 this longer survival was seen by the carriers of other genotypes. We conclude that the TS VNTR and SNP do not predict response to 5-FU therapy in patients with stage III colon carcinoma. However, age appears to modify the effects of TS polymorphisms on survival.

TS gene polymorphisms are not good markers of response to 5-FU therapy in stage III colon cancer patients.

PubMed

Fariña-Sarasqueta, A; Gosens, M J E M; Moerland, E; van Lijnschoten, I; Lemmens, V E P P; Slooter, G D; Rutten, H J T; van den Brule, A J C

2010-01-01

Although the predictive and prognostic value of thymidylate synthase (TS) expression and gene polymorphism in colon cancer has been widely studied, the results are inconclusive probably because of methodological differences. With this study, we aimed to elucidate the role of TS gene polymorphisms genotyping in therapy response in stage III colon carcinoma patients treated with 5-FU adjuvant chemotherapy. 251 patients diagnosed with stage III colon carcinoma treated with surgery followed by 5-FU based adjuvant therapy were selected. The variable number of tandem repeats (VNTR) and the single nucleotide polymorphism (SNP) in the 5'-untranslated region of the TS gene were genotyped. There was a positive association between tumor T stage and the VNTR genotypes (p=0.05).In both univariate and multivariate survival analysis no effects of the studied polymorphisms on survival were found. However, there was an association between both polymorphisms and age. Among patients younger than 60 years, the patients homozygous for 2R seemed to have a better overall survival, whereas among the patients older than 67 this longer survival was seen by the carriers of other genotypes. We conclude that the TS VNTR and SNP do not predict response to 5-FU therapy in patients with stage III colon carcinoma. However, age appears to modify the effects of TS polymorphisms on survival.

TS Gene Polymorphisms Are Not Good Markers of Response to 5-FU Therapy in Stage III Colon Cancer Patients

PubMed Central

Fariña-Sarasqueta, A.; Gosens, M. J. E. M.; Moerland, E.; van Lijnschoten, I.; Lemmens, V. E. P. P.; Slooter, G. D.; Rutten, H. J. T.; van den Brule, A. J. C.

2010-01-01

Aim: Although the predictive and prognostic value of thymidylate synthase (TS) expression and gene polymorphism in colon cancer has been widely studied, the results are inconclusive probably because of methodological differences. With this study, we aimed to elucidate the role of TS gene polymorphisms genotyping in therapy response in stage III colon carcinoma patients treated with 5-FU adjuvant chemotherapy. Patients and Methods: 251 patients diagnosed with stage III colon carcinoma treated with surgery followed by 5-FU based adjuvant therapy were selected. The variable number of tandem repeats (VNTR) and the single nucleotide polymorphism (SNP) in the 5′-untranslated region of the TS gene were genotyped. Results: There was a positive association between tumor T stage and the VNTR genotypes (p=0.05). In both univariate and multivariate survival analysis no effects of the studied polymorphisms on survival were found. However, there was an association between both polymorphisms and age. Among patients younger than 60 years, the patients homozygous for 2R seemed to have a better overall survival, whereas among the patients older than 67 this longer survival was seen by the carriers of other genotypes. Conclusion: We conclude that the TS VNTR and SNP do not predict response to 5-FU therapy in patients with stage III colon carcinoma. However, age appears to modify the effects of TS polymorphisms on survival. PMID:20966539

FU Orionis Outbursts in the Triangulum Galaxy (M33)

NASA Astrophysics Data System (ADS)

Zawadzki, Nicole; Moe, Maxwell

2018-01-01

FU Orionis systems (FUors) are young T-Tauri stars that brighten upwards of 6 magnitudes due to an instability in their disk. It is unclear whether all T-Tauri stars experience this period of disk instability to create FUor outbursts, or if a binary companion is required to trigger these instabilities. To date, there have been around 20 known FUors detected in the Milky Way. To better understand the occurrence rate of these instabilities more observations are needed. By using observations of M33 from the Canada-France-Hawaii telescope, SDSS, and an ongoing survey at the Bok 90” telescope, a 15+ year baseline can be established to identify FUor outbursts in M33. By measuring the occurrence rate of FUors in M33 from these observations, the question of whether a binary companion is required can be answered.

Irinotecan in second-line treatment of metastatic colorectal cancer: improved survival and cost-effect compared with infusional 5-FU.

PubMed

Iveson, T J; Hickish, T; Schmitt, C; Van Cutsem, E

1999-12-01

In a recent multicentre, randomised, controlled, open-label study (Rougier and colleagues, Lancet 1998, 352, 1407-1412), irinotecan significantly increased survival without any deterioration in quality of life compared with best-estimated infusional 5-fluorouracil (5-FU) therapy in the setting of second-line treatment for metastatic colorectal cancer. The aim of the cost-effectiveness analysis reported here was to compare the economic implications, from a U.K. perspective, of replacing 5-FU therapy [either as a single agent (Lokich regimen, B2) or in combination with folinic acid (de Gramont regimen, B1, or AIO regimen, B3)] with irinotecan as second-line therapy for metastatic colorectal cancer. Resource utilisation data collected prospectively during the study, supplemented by both a questionnaire to investigators and local expert clinical opinion, were used as a basis for estimating cumulative drug dosage, chemotherapy administration and treatment of complications. Drug acquisition costs were derived from the British National Formulary (March 1998), and unit costs for clinical consultation and services were derived from relevant 1996/1997 cost databases. Although cumulative drug acquisition costs per patient were higher with irinotecan than with infusional 5-FU therapy, these were at least partially offset by lower cumulative costs per patient associated with administration of therapy and treatment of complications in the irinotecan arm than in the 5-FU arm. Based on the incremental costs per life year gained (LYG), irinotecan was considered to be cost-effective by commonly accepted criteria compared with either the B1 or B2 regimens. Irinotecan was cost-saving compared with the B3 regimen (that is significant survival gain and a reduction in costs). Thus, not only is there strong evidence for the use of irinotecan as standard second-line therapy in metastatic colorectal cancer,but the results of this prospective economic evaluation have shown that irinotecan

Untargeted serum metabolomics reveals Fu-Zhu-Jiang-Tang tablet and its optimal combination improve an impaired glucose and lipid metabolism in type II diabetic rats.

PubMed

Tao, Yi; Chen, Xi; Cai, Hao; Li, Weidong; Cai, Baochang; Chai, Chuan; Di, Liuqing; Shi, Liyun; Hu, Lihong

2017-01-01

Fu-Zhu-Jiang-Tang tablet, a six-herb preparation, was proved to show beneficial effects on type II diabetes patients in clinical. This study aims to optimize the component proportion of the six-herb preparation and explore the serum metabolic signatures of type II diabetes rats after treatment with Fu-Zhu-Jiang-Tang tablet and its optimal combination. The component proportion of the preparation was optimized using uniform experimental design and machine learning techniques. Untargeted GC-MS metabolomic experiments were carried out with serum samples from model group and treatment groups. Data were normalized, multivariate and univariate statistical analysis performed and metabolites of interest putatively identified. 23 metabolites were significantly changed by Fu-Zhu-Jiang-Tang tablet treatment and the majority of these were decreased, including various carbohydrates (glucose, mannose, fructose, allose and gluconic acid), unsaturated fatty acids (palmitic acid, 9-octadecenoic acid, oleic acid, arachidonic acid), alanine, valine, propanoic acid, 3-hydroxybutyrate, along with pyrimidine and cholesterol. Increased concentrations of oxalic acid, leucine, glycine, serine, threonine, proline, lysine and citrate were observed. In the optimal combination-fed group, 21 metabolites were significantly affected and strikingly, the magnitudes of changes here were generally much greater than that of Fu-Zhu-Jiang-Tang tablet treated rats. 18 metabolites affected in both groups included various carbohydrates (mannose, glucose, allose, fructose and gluconic acid), unsaturated fatty acids (palmitic acid, 9-octadecenoic acid, oleic acid and arachidonic acid), short-chain fatty acids (oxalic acid, 3-hydroxybutyrate), and amino acids (alanine, valine, leucine, glycine, proline and lysine), as well as pyrimidine. Metabolites exclusively affected in optimal combination treated rat included succinic acid, cysteine and phenylalanine, whilst four metabolites (propanoic acid, citrate

Clinical Study on Lobaplatin Combined with 5-Fu and Concurrent Radiotherapy in Treating Patients with Inoperable Esophageal Cancer.

PubMed

Jia, Xiao-Jing; Huang, Jing-Zi

2015-01-01

To investigate short- and long-term treatment effects and side reactions of lobaplatin plus 5-Fu combined and concurrent radiotherapy in treating patients with inoperable middle-advanced stage esophageal cancer. Sixty patients with middle-advanced stage esophageal squamous cell cancer were retrospectively analyzed. All patients were administered lobaplatin (50 mg intravenously) for 2 h on day 1, and 5-Fu (500 mg/m2) injected intravenously from day 1 to 5 for 1 cycle, in an interval of 21 days for totally 4 cycles. At the same time, late-course accelerated hyperfractionated three-dimensional conformal radiotherapy was performed. Patients were firstly treated with conventional fractionated irradiation (1.8 Gy/d, 5 times/week, a total of 23 treatments, and DT41.4 Gy), and then treated with accelerated hyperfractionated irradiation (1.5 Gy, 2 times/d, a total of 27 Gy in 9 days, an entire course of 6-7 weeks, and DT 68.4 Gy). All patients completed treatment, including 10 complete response (CR), 41 partial response (PR), 7 stable disease (SD), and 2 progressive disease (PD). The total effective rate was 85.0% (51/60). Thirty-nine patients had an increased KPS score. One-, 2-, and 3-year survival rates were 85.3%, 57.5%, and 41.7%, respectively. The median survival time was 27 months. The adverse reactions included myelosuppression, which was mainly degreeI and II. The occurrence rate of radiation esophagitis was 17.5%. No significant hepatic or renal toxicity was observed. Lobaplatin plus 5-Fu combined with concurrent radiotherapy is safe and effective in treating patients with middle-advanced stage esophageal cancer. However, this result warrants further evaluation by randomized clinical studies.

Immunochemoradiotherapy for patients with oral squamous cell carcinoma: augmentation of OK-432-induced helper T cell 1 response by 5-FU and X-ray irradiation.

PubMed

Tano, Tomoyuki; Okamoto, Masato; Kan, Shin; Bando, Takashi; Goda, Hiroyuki; Nakashiro, Koh-ichi; Shimodaira, Shigetaka; Koido, Shigeo; Homma, Sadamu; Fujita, Tomonobu; Sato, Mitsunobu; Yamashita, Naomi; Hamakawa, Hiroyuki; Kawakami, Yutaka

2013-07-01

Eighty-one patients with oral squamous cell carcinoma (OSCC) received oral fluoropyrimidine UFT and radiotherapy (RT) with or without an immunotherapeutic agent OK-432. Both overall survival and progression-free survival of patients who received RT + UFT + OK-432 were significantly longer than those of patients who received RT + UFT (P = .0075 and P = .0175, respectively). Clinical response was also more favorable in RT + UFT + OK-432 group than in RT + UFT group (P = .0066). Next, in vitro experiments were conducted to examine the effect of 5-fluorouracil (5-FU) and X-ray irradiation in OK-432-induced immunity. Human peripheral blood mononuclear cells stimulated with OK-432 produced helper T cell 1 (Th1)-type cytokines as well as interleukin-10 (IL-10) and transforming growth factor-β (TGF-β), which are produced by Th2 and regulatory T cells (Tregs), respectively, and are inhibitory in antitumor immunity. OK-432-induced IL-10 and TGF-β but not Th1 cytokines were significantly inhibited by 5-FU and/or X-ray. 5-FU and X-ray also inhibited the expression of mRNAs for GATA-3 and Foxp3, which are transcription factors for Th2 and Tregs, respectively, but not for T-bet, a transcription factor for Th1. In addition, 5-FU and X-ray decreased the expression of mRNAs for suppressor of cytokine signaling 1 (SOCS1) and SOCS3. Antisense oligonucleotides for SOCS1 and SOCS3 markedly reduced OK-432-induced IL-10 and TGF-β. This is the first report clearly demonstrating that OK-432-based immunotherapy significantly enhanced the therapeutic effects of chemoradiotherapy in patients with OSCC as well as elucidating the mechanism of the synergistic effect of immunochemoradiotherapy in which 5-FU and radiation enhanced OK-432-induced Th1 response mediated by the inhibition of SOCS1 and SOCS3 gene expression.

Difference in effect of single immunosuppressive agents (cyclophosphamide, CCNU, 5-FU) on peripheral blood immune cell parameters and central nervous system immunoglobulin synthesis rate in patients with multiple sclerosis.

PubMed Central

Shih, W W; Baumhefner, R W; Tourtellotte, W W; Haskell, C M; Korn, E L; Fahey, J L

1983-01-01

Cyclophosphamide (CY), 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) and 5-fluorouracil (5-FU) were given in single course schedules to chronic progressive multiple sclerosis (MS) patients clinically stable for 6 months. The following peripheral immune cellular parameters were measured before, during and after each drug administration: white blood count (WBC), polymorphonuclear count (PMN), lymphocyte count, percentage of T cells, T cell response to phytohaemagglutinin (PHA), percentage of B cells, percentage of cells bearing receptors for the Fc portion of immunoglobulin (% FcR cells), killer (K) cell activity defined by antibody-dependent cellular cytotoxicity (ADCC), and natural killer (NK) cell activity. Central nervous system (CNS) immunoglobulin G (IgG) synthesis was also measured. The patients were followed carefully by both quantitative and qualitative methods for any change in their neurologic condition. Selective reduction in NK activity was observed with CY and 5-FU while no significant alteration was seen in %FcR cells and K activity. CY differed from 5-FU in reducing lymphocyte count and B cell percentage while 5-FU decreased the percentage of T cells. CCNU, but not the other drugs, reduced T cell proliferative response to PHA. In addition, CCNU, which is known to penetrate well into the nervous system, caused a modest reduction in CNS IgG synthesis, while 5-FU had an uncertain effect. Clinically the patients were unchanged or continued to progress in their disability. The results suggest an independence of the CNS immune from the systemic immune system in MS in response to many immunosuppressive drugs. PMID:6603303

Baseline [(18)F]FMISO μPET as a Predictive Biomarker for Response to HIF-1α Inhibition Combined with 5-FU Chemotherapy in a Human Colorectal Cancer Xenograft Model.

PubMed

De Bruycker, Sven; Vangestel, Christel; Van den Wyngaert, Tim; Wyffels, Leonie; Wouters, An; Pauwels, Patrick; Staelens, Steven; Stroobants, Sigrid

2016-08-01

The purpose of this study was to characterize imaging biomarkers for the potential benefit of hypoxia-inducible factor-1 (HIF-1)α inhibition (by PX-12) during 5-fluorouracil (5-FU) chemotherapy in the treatment of colorectal cancer (CRC). Therapy response to 5-FU ± PX-12 was assessed with baseline [(18)F]fluoromisonidazole ([(18)F]FMISO) and longitudinal 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]FDG) positron emission computed tomography (μPET/CT) in CRC xenograft model (n = 36) during breathing of a hypoxic (10 % O2) or normoxic (21 % O2) atmosphere. Ex vivo, immunohistochemistry was performed. Baseline [(18)F]FMISO uptake and relative tumor volume (RTV) 2 days after 5-FU or 5-FU + PX-12 administration correlated significantly (p ≤ 0.01). Under hypoxic breathing conditions, [(18)F]FDG uptake (-53.1 ± 8.4 %) and Ki67 expression (-16 %) decreased and RTV stagnated in the 5-FU + PX-12 treatment group, but not in 5-FU alone-treated tumors. Under normoxic breathing, [(18)F]FDG uptake (-23.5 ± 15.2 % and -72.8 ± 7.1 %) and Ki67 expression (-5 % and -19 %) decreased and RTV stagnated in both the 5-FU and the combination treatment group, respectively. Baseline [(18)F]FMISO μPET may predict the beneficial effect of HIF-1α inhibition during 5-FU chemotherapy in CRC.

Soil Organic Carbon Pool and Its Chemical Composition in Phyllostachy pubescens Forests at Two Altitudes in Jian-ou City, China.

PubMed

Ji, Haibao; Zhuang, Shunyao; Zhu, Zhaoliang; Zhong, Zheke

2015-01-01

Phyllostachys pubescens forests play an important role in soil organic carbon (SOC) sequestration in terrestrial ecosystems. However, the estimation and mechanism of SOC sequestration by P. pubescens forests remain unclear. In this study, the effect of P. pubescens forest distribution with elevation was investigated at two altitude sites in Jian-ou City, Southeast China. SOC storage was estimated and its chemical composition was obtained via 13C-nuclear magnetic resonance (NMR), chemical classification, and spectral analysis. Results showed that the SOC contents and stocks were significantly higher at the high-altitude site than at the low-altitude site in the entire soil profile (0-60 cm). The C contents of the three combined humus forms exhibited similar responses to the elevation change, and all of these forms were higher at the high-altitude site than at the low-altitude site regardless of soil layer. However, the proportions of the three combined humus C showed no significant differences between the two altitudes. The results of 13C-NMR showed that the SOC chemical composition did not significantly vary with elevation as well. This finding was consistent with the E465/E665 of the loosely combined humus. Overall, the results suggested that altitude should be considered during regional SOC estimation and that altitude affected the quantity rather than the quality of the SOC under the same P. pubescens vegetation.

Soil Organic Carbon Pool and Its Chemical Composition in Phyllostachy pubescens Forests at Two Altitudes in Jian-ou City, China

PubMed Central

Ji, Haibao; Zhuang, Shunyao; Zhu, Zhaoliang; Zhong, Zheke

2015-01-01

Phyllostachys pubescens forests play an important role in soil organic carbon (SOC) sequestration in terrestrial ecosystems. However, the estimation and mechanism of SOC sequestration by P. pubescens forests remain unclear. In this study, the effect of P. pubescens forest distribution with elevation was investigated at two altitude sites in Jian-ou City, Southeast China. SOC storage was estimated and its chemical composition was obtained via 13C-nuclear magnetic resonance (NMR), chemical classification, and spectral analysis. Results showed that the SOC contents and stocks were significantly higher at the high-altitude site than at the low-altitude site in the entire soil profile (0–60 cm). The C contents of the three combined humus forms exhibited similar responses to the elevation change, and all of these forms were higher at the high-altitude site than at the low-altitude site regardless of soil layer. However, the proportions of the three combined humus C showed no significant differences between the two altitudes. The results of 13C-NMR showed that the SOC chemical composition did not significantly vary with elevation as well. This finding was consistent with the E465/E665 of the loosely combined humus. Overall, the results suggested that altitude should be considered during regional SOC estimation and that altitude affected the quantity rather than the quality of the SOC under the same P. pubescens vegetation. PMID:26716688

Neoadjuvant 5-FU or Capecitabine Plus Radiation With or Without Oxaliplatin in Rectal Cancer Patients: A Phase III Randomized Clinical Trial

PubMed Central

Yothers, Greg; O’Connell, Michael J.; Beart, Robert W.; Wozniak, Timothy F.; Pitot, Henry C.; Shields, Anthony F.; Landry, Jerome C.; Ryan, David P.; Arora, Amit; Evans, Lisa S.; Bahary, Nathan; Soori, Gamini; Eakle, Janice F.; Robertson, John M.; Moore, Dennis F.; Mullane, Michael R.; Marchello, Benjamin T.; Ward, Patrick J.; Sharif, Saima; Roh, Mark S.; Wolmark, Norman

2015-01-01

Background: National Surgical Adjuvant Breast and Bowel Project R-04 was designed to determine whether the oral fluoropyrimidine capecitabine could be substituted for continuous infusion 5-FU in the curative setting of stage II/III rectal cancer during neoadjuvant radiation therapy and whether the addition of oxaliplatin could further enhance the activity of fluoropyrimidine-sensitized radiation. Methods: Patients with clinical stage II or III rectal cancer undergoing preoperative radiation were randomly assigned to one of four chemotherapy regimens in a 2x2 design: CVI 5-FU or oral capecitabine with or without oxaliplatin. The primary endpoint was local-regional tumor control. Time-to-event endpoint distributions were estimated using the Kaplan-Meier method. Hazard ratios were estimated from Cox proportional hazard models. All statistical tests were two-sided. Results: Among 1608 randomized patients there were no statistically significant differences between regimens using 5-FU vs capecitabine in three-year local-regional tumor event rates (11.2% vs 11.8%), 5-year DFS (66.4% vs 67.7%), or 5-year OS (79.9% vs 80.8%); or for oxaliplatin vs no oxaliplatin for the three endpoints of local-regional events, DFS, and OS (11.2% vs 12.1%, 69.2% vs 64.2%, and 81.3% vs 79.0%). The addition of oxaliplatin was associated with statistically significantly more overall and grade 3–4 diarrhea (P < .0001). Three-year rates of local-regional recurrence among patients who underwent R0 resection ranged from 3.1 to 5.1% depending on the study arm. Conclusions: Continuous infusion 5-FU produced outcomes for local-regional control, DFS, and OS similar to those obtained with oral capecitabine combined with radiation. This study establishes capecitabine as a standard of care in the pre-operative rectal setting. Oxaliplatin did not improve the local-regional failure rate, DFS, or OS for any patient risk group but did add considerable toxicity. PMID:26374429

Neoadjuvant 5-FU or Capecitabine Plus Radiation With or Without Oxaliplatin in Rectal Cancer Patients: A Phase III Randomized Clinical Trial.

PubMed

Allegra, Carmen J; Yothers, Greg; O'Connell, Michael J; Beart, Robert W; Wozniak, Timothy F; Pitot, Henry C; Shields, Anthony F; Landry, Jerome C; Ryan, David P; Arora, Amit; Evans, Lisa S; Bahary, Nathan; Soori, Gamini; Eakle, Janice F; Robertson, John M; Moore, Dennis F; Mullane, Michael R; Marchello, Benjamin T; Ward, Patrick J; Sharif, Saima; Roh, Mark S; Wolmark, Norman

2015-11-01

National Surgical Adjuvant Breast and Bowel Project R-04 was designed to determine whether the oral fluoropyrimidine capecitabine could be substituted for continuous infusion 5-FU in the curative setting of stage II/III rectal cancer during neoadjuvant radiation therapy and whether the addition of oxaliplatin could further enhance the activity of fluoropyrimidine-sensitized radiation. Patients with clinical stage II or III rectal cancer undergoing preoperative radiation were randomly assigned to one of four chemotherapy regimens in a 2x2 design: CVI 5-FU or oral capecitabine with or without oxaliplatin. The primary endpoint was local-regional tumor control. Time-to-event endpoint distributions were estimated using the Kaplan-Meier method. Hazard ratios were estimated from Cox proportional hazard models. All statistical tests were two-sided. Among 1608 randomized patients there were no statistically significant differences between regimens using 5-FU vs capecitabine in three-year local-regional tumor event rates (11.2% vs 11.8%), 5-year DFS (66.4% vs 67.7%), or 5-year OS (79.9% vs 80.8%); or for oxaliplatin vs no oxaliplatin for the three endpoints of local-regional events, DFS, and OS (11.2% vs 12.1%, 69.2% vs 64.2%, and 81.3% vs 79.0%). The addition of oxaliplatin was associated with statistically significantly more overall and grade 3-4 diarrhea (P < .0001). Three-year rates of local-regional recurrence among patients who underwent R0 resection ranged from 3.1 to 5.1% depending on the study arm. Continuous infusion 5-FU produced outcomes for local-regional control, DFS, and OS similar to those obtained with oral capecitabine combined with radiation. This study establishes capecitabine as a standard of care in the pre-operative rectal setting. Oxaliplatin did not improve the local-regional failure rate, DFS, or OS for any patient risk group but did add considerable toxicity. © The Author 2015. Published by Oxford University Press. All rights reserved. For

Observed Luminosity Spread in Young Clusters and FU Ori Stars: A Unified Picture

NASA Astrophysics Data System (ADS)

Baraffe, I.; Vorobyov, E.; Chabrier, G.

2012-09-01

The idea that non-steady accretion during the embedded phase of protostar evolution can produce the observed luminosity spread in the Herzsprung-Russell diagram (HRD) of young clusters has recently been called into question. Observations of FU Ori, for instance, suggest an expansion of the star during strong accretion events, whereas the luminosity spread implies a contraction of the accreting objects, decreasing their radiating surface. In this paper, we present a global scenario based on calculations coupling episodic accretion histories derived from numerical simulations of collapsing cloud prestellar cores of various masses and subsequent protostar evolution. Our calculations show that, assuming an initial protostar mass Mi ~ 1 M Jup, typical of the second Larson's core, both the luminosity spread in the HRD and the inferred properties of FU Ori events (mass, radius, accretion rate) can be explained by this scenario, providing two conditions. First, there must be some variation within the fraction of accretion energy absorbed by the protostar during the accretion process. Second, the range of this variation should increase with increasing accretion burst intensity and thus with the initial core mass and final star mass. The numerical hydrodynamics simulations of collapsing cloud prestellar cores indeed show that the intensity of the accretion bursts correlates with the mass and initial angular momentum of the prestellar core. Massive prestellar cores with high initial angular momentum are found to produce intense bursts characteristic of FU Ori-like events. Our results thus suggest a link between the burst intensities and the fraction of accretion energy absorbed by the protostar, with some threshold in the accretion rate, of the order of 10-5 M ⊙ yr-1, delimitating the transition from "cold" to "hot" accretion. Such a transition might reflect a change in the accretion geometry with increasing accretion rate, i.e., a transition from magnetospheric or thin

Investigation on biochemical compositional changes during the microbial fermentation process of Fu brick tea by LC-MS based metabolomics.

PubMed

Xu, Jie; Hu, Feng-Lin; Wang, Wei; Wan, Xiao-Chun; Bao, Guan-Hu

2015-11-01

Fu brick tea (FBT) is a unique post-fermented tea product which is fermented with fungi during the manufacturing process. In this study, we investigated the biochemical compositional changes occurring during the microbial fermentation process (MFP) of FBT based on non-targeted LC-MS, which was a comprehensive and unbiased methodology. Our data analysis took a two-phase approach: (1) comparison of FBT with other tea products using PCA analysis to exhibit the characteristic effect of MFP on the formation of Fu brick tea and (2) comparison of tea samples throughout the MFP of FBT to elucidate the possible key metabolic pathways produced by the fungi. Non-targeted LC-MS analysis clearly distinguished FBT with other tea samples and highlighted some interesting metabolic pathways during the MFP including B ring fission catechin. Our study demonstrated that those fungi had a significant influence on the biochemical profiles in the FBT and consequently contributed to its unique quality. Copyright © 2014 Elsevier Ltd. All rights reserved.

A pilot study of nimotuzumab combined with cisplatin and 5-FU in patients with advanced esophageal squamous cell carcinoma

PubMed Central

Ling, Yang; Chen, Jia; Tao, Min; Chu, Xiaoyuan; Zhang, Xizhi

2012-01-01

Objective To observe the short-term effect and adverse reaction of Nimotuzumab in combination with chemotherapy on advanced esophageal squamous cell carcinoma (ESCC). Method 19 patients were treated with the following protocol: Nimotuzumab 400mg/time/week in the 1st week, 200mg/time/week from the 2nd to 8th week, intravenous drip (IVD); Cisplatin 80 mg/m2, IVD, 4 weeks a cycle and repeated again; 5-FU 750 mg/m2, continuous 24-hours pump-in × 5 days, 4 weeks a cycle and repeated again. Result 16 of all 19 patients can be evaluated. After treatment, RP is 42.1% (95% CI, 19.9-64.3%) and DCR is 68.4%; the main side effects include arrest of bone marrow, gastrointestinal reactions, asthenia, etc. Conclusion Nimotuzumab in combination with cisplatin/5-FU regimens in patients with advanced ESCC is safe and effective, which deserves a further expanded sample research. PMID:22295168

Immunochemoradiotherapy for Patients with Oral Squamous Cell Carcinoma: Augmentation of OK-432-Induced Helper T Cell 1 Response by 5-FU and X-ray Irradiation1

PubMed Central

Tano, Tomoyuki; Okamoto, Masato; Kan, Shin; Bando, Takashi; Goda, Hiroyuki; Nakashiro, Koh-ichi; Shimodaira, Shigetaka; Koido, Shigeo; Homma, Sadamu; Fujita, Tomonobu; Sato, Mitsunobu; Yamashita, Naomi; Hamakawa, Hiroyuki; Kawakami, Yutaka

2013-01-01

Eighty-one patients with oral squamous cell carcinoma (OSCC) received oral fluoropyrimidine UFT and radiotherapy (RT) with or without an immunotherapeutic agent OK-432. Both overall survival and progression-free survival of patients who received RT + UFT + OK-432 were significantly longer than those of patients who received RT + UFT (P = .0075 and P = .0175, respectively). Clinical response was also more favorable in RT + UFT + OK-432 group than in RT + UFT group (P = .0066). Next, in vitro experiments were conducted to examine the effect of 5-fluorouracil (5-FU) and X-ray irradiation in OK-432-induced immunity. Human peripheral blood mononuclear cells stimulated with OK-432 produced helper T cell 1 (Th1)-type cytokines as well as interleukin-10 (IL-10) and transforming growth factor-β (TGF-β), which are produced by Th2 and regulatory T cells (Tregs), respectively, and are inhibitory in antitumor immunity. OK-432-induced IL-10 and TGF-β but not Th1 cytokines were significantly inhibited by 5-FU and/or X-ray. 5-FU and X-ray also inhibited the expression of mRNAs for GATA-3 and Foxp3, which are transcription factors for Th2 and Tregs, respectively, but not for T-bet, a transcription factor for Th1. In addition, 5-FU and X-ray decreased the expression of mRNAs for suppressor of cytokine signaling 1 (SOCS1) and SOCS3. Antisense oligonucleotides for SOCS1 and SOCS3 markedly reduced OK-432-induced IL-10 and TGF-β. This is the first report clearly demonstrating that OK-432-based immunotherapy significantly enhanced the therapeutic effects of chemoradiotherapy in patients with OSCC as well as elucidating the mechanism of the synergistic effect of immunochemoradiotherapy in which 5-FU and radiation enhanced OK-432-induced Th1 response mediated by the inhibition of SOCS1 and SOCS3 gene expression. PMID:23814492

Evaluation of RRTMG and Fu-Liou RTM Performance against LBLRTM-DISORT Simulations and CERES Data in terms of Ice Clouds Radiative Effects

NASA Astrophysics Data System (ADS)

Gu, B.; Yang, P.; Kuo, C. P.; Mlawer, E. J.

2017-12-01

Evaluation of RRTMG and Fu-Liou RTM Performance against LBLRTM-DISORT Simulations and CERES Data in terms of Ice Clouds Radiative Effects Boyan Gu1, Ping Yang1, Chia-Pang Kuo1, Eli J. Mlawer2 Department of Atmospheric Sciences, Texas A&M University, College Station, TX 77843, USA Atmospheric and Environmental Research (AER), Lexington, MA 02421, USA Ice clouds play an important role in climate system, especially in the Earth's radiation balance and hydrological cycle. However, the representation of ice cloud radiative effects (CRE) remains significant uncertainty, because scattering properties of ice clouds are not well considered in general circulation models (GCM). We analyze the strengths and weakness of the Rapid Radiative Transfer Model for GCM Applications (RRTMG) and Fu-Liou Radiative Transfer Model (RTM) against rigorous LBLRTM-DISORT (a combination of Line-By-Line Radiative Transfer Model and Discrete Ordinate Radiative Transfer Model) calculations and CERES (Clouds and the Earth's Radiant Energy System) flux observations. In total, 6 US standard atmospheric profiles and 42 atmospheric profiles from Atmospheric and Environmental Research (AER) Company are used to evaluate the RRTMG and Fu-Liou RTM by LBLRTM-DISORT calculations from 0 to 3250 cm-1. Ice cloud radiative effect simulations with RRTMG and Fu-Liou RTM are initialized using the ice cloud properties from MODIS collection-6 products. Simulations of single layer ice cloud CRE by RRTMG and LBLRTM-DISORT show that RRTMG, neglecting scattering, overestimates the TOA flux by about 0-15 W/m2 depending on the cloud particle size and optical depth, and the most significant overestimation occurs when the particle effective radius is small (around 10 μm) and the cloud optical depth is intermediate (about 1-10). The overestimation reduces significantly when the similarity rule is applied to RRTMG. We combine ice cloud properties from MODIS Collection-6 and atmospheric profiles from the Modern

Potential emerging treatment in vitiligo using Er:YAG in combination with 5FU and clobetasol.

PubMed

Mokhtari, Fatemeh; Bostakian, Anis; Shahmoradi, Zabihollah; Jafari-Koshki, Tohid; Iraji, Fariba; Faghihi, Gita; Hosseini, Sayed Mohsen; Bafandeh, Behzad

2018-04-01

Vitiligo is a pigmentary disorder of skin affecting at least 1% of the world population of all races in both sexes. Its importance is mainly due to subsequent social and psychological problems rather than clinical complications. Various treatment choices are available for vitiligo; however, laser-based courses have shown to give more acceptable results. The aim of this trial was to evaluate the efficacy of Er:YAG laser as a supplementary medicine to topical 5FU and clobetasol in vitiligo patients. Two comparable vitiligo patches from 38 eligible patients were randomized to receive topical 5FU and clobetasol in control group and additional Er:YAG laser in intervention group. Major outcomes of interest were the size of patch and pigmentation score at randomization and 2 and 4 months after therapy. Final sample included 18 (47%) male patients and age of 35.66±8.04. The performance Er:YAG group was superior in all sites. Reduction in the size of patches was greater in Er:YAG group (p-value=.004). Also, this group showed a higher pigmentation scores in the trial period than control group (p-value<.001). Greater reduction in the size and increase in pigmentation score was seen in Er:YAG group especially for short periods after therapy and repeating laser sessions may help improving final outcomes. Er:AYG could help in reducing complications of long-term topical treatments, achieving faster response, and improving patient adherence. © 2017 Wiley Periodicals, Inc.

Tumor 5-FU-related mRNA Expression and Efficacy of Oral Fluoropyrimidines in Adjuvant Chemotherapy of Colorectal Cancer.

PubMed

Koda, Keiji; Miyauchi, Hideaki; Kosugi, Chihiro; Kaiho, Takashi; Takiguchi, Nobuhiro; Kobayashi, Susumu; Maruyama, Takashi; Matsubara, Hisahiro

2016-10-01

It has not been elucidated whether the clinical efficacy of oral fluoropyrimidines for adjuvant chemotherapy of colorectal cancer varies with tumor biological characteristics. A multicenter randomized trial was performed comparing oral tegafur/gimeracil/oteracil (S-1) and uracil-tegafur/ leucovorin (UFT/LV) as adjuvant therapy for stage III colorectal cancer. Postoperative survival was compared based on the 5-FU-related mRNA levels in cancer tissues. Among patients with tumor expressing dihydropyrimidine dehydrogenase (DPD) mRNA within the 66.7th percentile (lower 2/3) of all cases, overall survival (OS) was significantly better in the S-1 than in the UFT/LV group. In the S-1 group, patients with low DPD-expressing tumors had significantly better OS than those with highly expressing tumors. Patients with low thymidine synthase (TS)-expressing tumors had significantly better OS than those with highly expressing tumors. The efficacy of oral fluoropyrimidines as adjuvant chemotherapy for colorectal cancer may be influenced by the level of 5-FU-related mRNA in cancer tissues. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Diversity of lactic acid bacteria in suan-tsai and fu-tsai, traditional fermented mustard products of Taiwan.

PubMed

Chao, Shiou-Huei; Wu, Ruei-Jie; Watanabe, Koichi; Tsai, Ying-Chieh

2009-11-15

Fu-tsai and suan-tsai are spontaneously fermented mustard products traditionally prepared by the Hakka tribe of Taiwan. We chose 5 different processing stages of these products for analysis of the microbial community of lactic acid bacteria (LAB) by 16S rRNA gene sequencing. From 500 LAB isolates we identified 119 representative strains belonging to 5 genera and 18 species, including Enterococcus (1 species), Lactobacillus (11 species), Leuconostoc (3 species), Pediococcus (1 species), and Weissella (2 species). The LAB composition of mustard fermented for 3 days, known as the Mu sample, was the most diverse, with 11 different LAB species being isolated. We used sequence analysis of the 16S rRNA gene to identify the LAB strains and analysis of the dnaA, pheS, and rpoA genes to identify 13 LAB strains for which identification by 16S rRNA gene sequences was not possible. These 13 strains were found to belong to 5 validated known species: Lactobacillus farciminis, Leuconostoc mesenteroides, Leuconostoc pseudomesenteroides, Weissella cibaria, and Weissella paramesenteroides, and 5 possibly novel Lactobacillus species. These results revealed that there is a high level of diversity in LAB at the different stages of fermentation in the production of suan-tsai and fu-tsai.

The LANDFIRE Total Fuel Change Tool (ToFuΔ) user’s guide

USGS Publications Warehouse

Smail, Tobin; Martin, Charley; Napoli, Jim

2011-01-01

LANDFIRE fuel data were originally developed from coarse-scale existing vegetation type, existing vegetation cover, existing vegetation height, and biophysical setting layers. Fire and fuel specialists from across the country provided input to the original LANDFIRE National (LF_1.0.0) fuel layers to help calibrate fuel characteristics on a more localized scale. The LANDFIRE Total Fuel Change Tool (ToFu∆) was developed from this calibration process. Vegetation is subject to constant change – and fuels are therefore also dynamic, necessitating a systematic method for reflecting changes spatially so that fire behavior can be accurately accessed. ToFuΔ allows local experts to quickly produce maps that spatially display any proposed fuel characteristics changes. ToFu∆ works through a Microsoft Access database to produce spatial results in ArcMap based on rule sets devised by the user that take into account the existing vegetation type (EVT), existing vegetation cover (EVC), existing vegetation height (EVH), and biophysical setting (BpS) from the LANDFIRE grid data. There are also options within ToFu∆ to add discrete variables in grid format through use of the wildcard option and for subdividing specific areas for different fuel characteristic assignments through the BpS grid. The ToFu∆ user determines the size of the area for assessment by defining a Management Unit, or “MU.” User-defined rule sets made up of EVT, EVC, EVH, and BpS layers, as well as any wildcard selections, are used to change or refine fuel characteristics within the MU. Once these changes have been made to the fuel characteristics, new grids are created for fire behavior analysis or planning. These grids represent the most common ToFu∆ output. ToFuΔ is currently under development and will continue to be updated in the future. The current beta version (0.12), released in March 2011, is compatible with Windows 7 and will be the last release until the fall of 2011.

Attachment of an anti-MUC1 monoclonal antibody to 5-FU loaded BSA nanoparticles for active targeting of breast cancer cells.

PubMed

Kouchakzadeh, Hasan; Shojaosadati, Seyed Abbas; Mohammadnejad, Javad; Paknejad, Malihe; Rasaee, Mohammad Javad

2012-01-01

With PR81 as a murine monoclonal antibody (mAb) that was prepared against the human breast cancer, the MUC1 receptor specific targeting is possible. In this study, PR81-conjugated bovine serum albumin (BSA) nanoparticles loaded with anticancer drug 5-fluorouracil (5-FU) were developed. Enzyme linked immunosorbant assay (ELISA) results showed high immunoreactivity of PR81 mAb conjugated to nanoparticles towards MUC1 related peptide or native cancerous MUC1 and almost no cross-reaction to non-specific proteins. In vitro experiments were performed to determine the ability of this new drug delivery system on overcoming MCF-7 breast cancer cells in comparison with four other systems. The results revealed that these cell-type specific drug loaded nanoparticles could achieve more cell death as compared to when the 5-FU was used with no carriers. Stability studies of produced drug delivery system proved high immunoreactivity of conjugated PR81 even after 11 days of storage in room temperature.

A new case of the enigmatic Candidatus Neoehrlichia sp. (FU98) in a fox from the Czech Republic.

PubMed

Hodžić, Adnan; Mitkovà, Barbora; Modrý, David; Juránková, Jana; Frgelecová, Lucia; Forejtek, Pavel; Steinbauer, Vladimír; Duscher, Georg Gerhard

2017-02-01

This study reports a new case of Candidatus Neoehrlichia sp. (FU98) infection in a fox from the Czech Republic, and provides confirmatory evidence on the occurrence of this newly identified sequence type. However, further studies are needed to investigate the distribution, host range and possible vector(s) for this bacterium, as well as its impact on animals and humans. Copyright © 2016 Elsevier Ltd. All rights reserved.

[A case of advanced gastric cancer with carcinomatosa peritonitis effectively treated by 5-FU and low-dose CDDP therapy].

PubMed

Saito, E; Kunii, Y; Wada, G; Tsuchiya, S; Yamasaki, T; Sakakibara, N

1997-07-01

A 66-year-old woman was admitted to our clinic for appetite loss and abdominal distension in August 1995. Endoscopic study revealed an advanced gastric cancer in the upper body of her stomach. Abdominal CT study revealed massive ascites and para-aortic lymph nodal involvement. Cytological study of the ascites revealed class V. She was diagnosed to be in the terminal stage of gastric cancer with carcinomatosa peritonitis. Combination chemotherapy with 5-fluorouracil (5-FU) and low-dose cisplatin (CDDP) was given by continuous intravenous injection of 5-FU 500 mg/day, and intermittent intravenous injection of CDDP 30 mg/week was performed for reduction of the ascites and her complaint. Endoscopic study 6 weeks after starting chemotherapy could not find crater of the gastric cancer but only a shallow ulcerative lesion. The biopsy specimen of that lesion was group III. No ascites and over 50% reduction of the para-aortic lymph node were found by the abdominal CT study. This state persisted over 4 weeks. No myelo-suppression, renal dysfunction or any severe side effect were observed during chemotherapy. Her performance status improved from 3 to 1.

[Post-stroke constipation treated with acupuncture therapy of regulating qi circulation of fu-organ].

PubMed

Ren, Zhen; Wu, Qing-Ming; Li, Dan-Dan; Liu, Wei-Ai; Li, Xiang-Rong; Lin, Xu-Ming

2013-10-01

To compare the difference in the efficacy on post-stroke constipation between acupuncture therapy of regulating qi circulation of fe-organ and Shengxue Tongbian Capsules. Seventy-five patients of post-stroke constipation were randomized into an acupuncture group (39 cases) and a Chinese medicine group (36 cases). The unit mode comprehensive therapy of stroke was adopted as basic treatment in the two groups. In the acupuncture group, acupuncture therapy of regulating qi circulation of fu-organ was added at Tianshu (ST 25), Zhigou (TE 6), Qihai (CV 6) and Zusanli (ST 36), once every day. In the Chinese medicine group, Shengrue Tongbian Capsules were supplemented for oral administration, once every day, 10 g each time. The clinical symptom score of constipation was observed before treatment, after 1 and 2 weeks treatment in the two groups, respectively. The efficacy in 1 week and 2 weeks of treatment and the adverse reaction were observed. In 1 and 2 weeks of treatment, the clinical symptom score of constipation was reduced significantly as compared with that before treatment in the two groups (all P < 0.05). The improvements in the acupuncture group were significant than those in the Chinese medicine group in 2 weeks of treatment (8.03 +/- 2.38 vs 9.20 +/- 2.45, P < 0.05). Concerning to the occurrence of adverse reaction, there was 1 case of local bruises in needling local site in the acupuncture group; and there were 1 case of abdominal pain, 3 cases of diarrhea and 2 cases of nausea and vomiting in the Chinese medicine group. Both the acupuncture therapy of regulating qi circulation of fu-organ and Shengxue Tongbian Capsules achieve the significant efficacy on post-stroke constipation. The efficacy of the acupuncture therapy of regulating qi circulation of fe-organ is better and the adverse reaction is less after long-term persistent treatment.

Basic research supported developments of chemotherapy in nonresectable isolated colorectal liver metastases to a protocol of hepatic artery infusion using mitoxantrone, 5-FU + folinic acid and mitomycin C.

PubMed

Link, K H; Kornmann, M; Leder, G; Pillasch, A F; Sunelaitis, E; Schatz, M; Pressmar, J; Beger, H G

1999-02-01

Since the developments in systemic chemotherapy of metastasized colorectal cancer have not resulted in substantial gains in survival times, we wished to improve the course of isolated nonresectable colorectal liver metastases (CPLM) by hepatic arterial infusion treatment. Patients (pts) with CRLM have a worse fate than those pts whose liver metastases could be resected. Systemic (i.v.) chemotherapy for CRLM/colorectal metastases does not improve survival to a relevant level (median survival time (med. surv.) after 5-Fluorouracil + Folinic Acid (5-FU + FA) i.v.: 6.4-14.3 months (m)). Hepatic artery infusion (HAI) with 5-Fluorode-oxyuridine (5-FUDR) has been demonstrated in a metaanalysis of randomized trials to be superior to i.v. treatment/palliative care (med. surv.: 15 vs. 10 m). The benefit of HAI with 5-FUDR, although recommended as treatment for CRLM, is severely compromised by the 5-FUDR induced hepatotoxicity, leading eventually to sclerosing cholangitis (SC)/liver scirrhosis. We have stepwise developed a protocol for HAI of CRLM, which is superior to HAI with 5-FUDR, and, most evidently, to systemic chemotherapy. Between 1982-1997, 222 CR (L) M patients were treated within subsequent protocols (Table). In protocol A, 68 CRLM pts received HAI with 5-FUDR (A1: nonrandomized pts; A2: randomized pts). In protocol B (randomized pts.), 46 pts received 5-FUDR i.a. (via HAI) + i.v. In protocol C, systemic chemotherapy with 5-FU + FA was conducted in 34 pts with metastasized colorectal cancers, including CRLM. In protocol D 5-FU + FA was delivered via HAI in 25 pts with CRLM. In protocol E, based on in vitro phase II studies and the results of protocol D, Mitoxantrone and Mitomycin C were added to 5-FU + FA (MFFM). Fifty (50) CRLM pts received HAI with MFFM. The response rates, med. surv. times, systemic toxicity and SC rates are shown in the table. HAI with MFFM produced objective responses in 66%, the med. surv. was 27.4 m, and no SC occurred. The ports surgically

Anticancer effect of bromelain with and without cisplatin or 5-FU on malignant peritoneal mesothelioma cells.

PubMed

Pillai, Krishna; Ehteda, Anahid; Akhter, Javid; Chua, Terence C; Morris, David L

2014-02-01

Malignant peritoneal mesothelioma (MPM) is a rare neoplasm of the peritoneum, causally related to asbestos exposure. Nonspecific symptoms with a late diagnosis results in poor survival (<1 year). Treatment with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy has improved survival in some patients (median 3-5 years). Hence, new therapies are urgently needed. MUC1 is a glycosylation-dependent protein that confers tumours with invasiveness, metastasis and chemoresistance. Bromelain (cysteine proteinase) hydrolyses glycosidic bonds. Therefore, we investigated the antitumour effect of bromelain on MUC1-expressing MPM cell lines. MUC1 expressions in cells were assessed using immunofluorescent probes with cells grown on cover slips and western blot analysis on cell lysates. The cell lines were treated with various concentrations of bromelain and after 4 and 72 h, their viability was assessed using standard sulforhodamine assays. The cells were also treated with combinations of bromelain and cytotoxic drugs (cisplatin or 5-FU) and their viability was assessed at 72 h. Finally, with western blotting, the effects of bromelain on cellular survival proteins were investigated. PET cells expressed more MUC1 compared with YOU cells. The cell viability of both PET and YOU cells was adversely affected by bromelain, with PET cells being slightly resistant. The addition of bromelain increased the cytotoxicity of cisplatin significantly in both cell lines. However, 5-FU with bromelain did not show any significant increase in cytotoxicity. Bromelain-induced cell death is by apoptosis and autophagy. Bromelain has the potential of being developed as a therapeutic agent in MPM.

MACC1 mediates chemotherapy sensitivity of 5-FU and cisplatin via regulating MCT1 expression in gastric cancer.

PubMed

Wang, Chunlin; Wen, Zhaowei; Xie, Jianming; Zhao, Yang; Zhao, Liang; Zhang, Shuyi; Liu, Yajing; Xue, Yan; Shi, Min

2017-04-08

Chemotherapeutic insensitivity is a main obstacle for effective treatment of gastric cancer (GC), the underlying mechanism remains to be investigated. Metastasis-associated in colon cancer-1 (MACC1), a transcription factor highly expressed in GC, is found to be related to chemotherapy sensitivity. Monocarboxylate transporter 1 (MCT1), a plasma membrane protein co-transporting lactate and H + , mediates drug sensitivity by regulating lactate metabolism. Targeting MCT1 has recently been regarded as a promising way to treat cancers and MCT1 inhibitor has entered the clinical trial for GC treatment. However, the correlation of these two genes and their combined effects on chemotherapy sensitivity has not been clarified. In this study, we found that MACC1 and MCT1 were both highly expressed in GC and exhibited a positive correlation in clinical samples. Further, we demonstrated that MACC1 could mediate sensitivity of 5-FU and cisplatin in GC cells, and MACC1 mediated MCT1 regulation was closely related to this sensitivity. A MCT1 inhibitor AZD3965 recovered the sensitivity of 5-FU and cisplatin in GC cells which overexpressed MACC1. These results suggested that MACC1 could influence the chemotherapy sensitivity by regulating MCT1 expression, providing new ideas and strategy for GC treatment. Copyright © 2017 Elsevier Inc. All rights reserved.

Estimation of Asian Dust Aerosol Effect on Cloud Radiation Forcing Using Fu-Liou Radiative Model and CERES Measurements

NASA Technical Reports Server (NTRS)

Su, Jing; Huang, Jianping; Fu, Qiang; Minnis, Patrick; Ge, Jinming; Bi, Jianrong

2008-01-01

The impact of Asian dust on cloud radiative forcing during 2003-2006 is studied by using the Earth's Radiant Energy Budget Scanner (CERES) data and the Fu-Liou radiative transfer model. Analysis of satellite data shows that the dust aerosol significantly reduced the cloud cooling effect at TOA. In dust contaminated cloudy regions, the 4-year mean values of the instantaneous shortwave, longwave and net cloud radiative forcing are -138.9, 69.1, and -69.7 Wm(sup -2), which are 57.0, 74.2, and 46.3%, respectively, of the corresponding values in more pristine cloudy regions. The satellite-retrieved cloud properties are significantly different in the dusty regions and can influence the radiative forcing indirectly. The contributions to the cloud radiation forcing by the dust direct, indirect and semi-direct effects are estimated using combined satellite observations and Fu-Liou model simulation. The 4-year mean value of combination of indirect and semi-direct shortwave radiative forcing (SWRF) is 82.2 Wm(sup -2), which is 78.4% of the total dust effect. The direct effect is only 22.7 Wm(sup -2), which is 21.6% of the total effect. Because both first and second indirect effects enhance cloud cooling, the aerosol-induced cloud warming is mainly the result of the semi-direct effect of dust.

Cold CO Gas in the Envelopes of FU Orionis-type Young Eruptive Stars

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kóspál, Á.; Ábrahám, P.; Moór, A.

FU Orionis-type objects (FUors) are young stellar objects experiencing large optical outbursts due to highly enhanced accretion from the circumstellar disk onto the star. FUors are often surrounded by massive envelopes, which play a significant role in the outburst mechanism. Conversely, the subsequent eruptions might gradually clear up the obscuring envelope material and drive the protostar on its way to become a disk-only T Tauri star. Here we present an APEX {sup 12}CO and {sup 13}CO survey of eight southern and equatorial FUors. We measure the mass of the gaseous material surrounding our targets, locate the source of the COmore » emission, and derive physical parameters for the envelopes and outflows, where detected. Our results support the evolutionary scenario where FUors represent a transition phase from envelope-surrounded protostars to classical T Tauri stars.« less

Study on the Correlation between Gene Expression and Enzyme Activity of Seven Key Enzymes and Ginsenoside Content in Ginseng in Over Time in Ji'an, China.

PubMed

Yin, Juxin; Zhang, Daihui; Zhuang, Jianjian; Huang, Yi; Mu, Ying; Lv, Shaowu

2017-12-11

Panax ginseng is a traditional medicine. Fresh ginseng is one of the most important industries related to ginseng development, and fresh ginseng of varying ages has different medicinal properties. Previous research has not systematically reported the correlation between changes in key enzyme activity with changes in ginsenoside content in fresh ginseng over time. In this study, for the first time, we use ginseng samples of varying ages in Ji'an and systematically reported the changes in the activity of seven key enzymes (HMGR, FPS, SS, SE, DS, CYP450, and GT). We investigated the content of ginsenoside and gene expression of these key enzymes. Ginsenoside content was measured using HPLC. HPLC, GC-MS, and LC-MS were combined to measure the enzyme activity of the key enzymes. Quantitative PCR was used in the investigation of gene expression. By analyzing the correlation between the enzyme activity and the transcription level of the key enzymes with ginsenoside content, we found that DS and GT enzyme activities are significantly correlated with the ginsenoside content in different ages of ginseng. Our findings might provide a new strategy to discriminate between ginseng of different years. Meanwhile, this research provides important information for the in-depth study of ginsenoside biosynthesis.

Mass loss from pre-main-sequence accretion disks. I - The accelerating wind of FU Orionis

NASA Technical Reports Server (NTRS)

Calvet, Nuria; Hartmann, Lee; Kenyon, Scott J.

1993-01-01

We present evidence that the wind of the pre-main-sequence object FU Orionis arises from the surface of the luminous accretion disk. A disk wind model calculated assuming radiative equilibrium explains the differential behavior of the observed asymmetric absorption-line profiles. The model predicts that strong lines should be asymmetric and blueshifted, while weak lines should be symmetric and double-peaked due to disk rotation, in agreement with observations. We propose that many blueshifted 'shell' absorption features are not produced in a true shell of material, but rather form in a differentially expanding wind that is rapidly rotating. The inference of rapid rotation supports the proposal that pre-main-sequence disk winds are rotationally driven.

Urine metabolic profile changes of CCl4-liver fibrosis in rats and intervention effects of Yi Guan Jian Decoction using metabonomic approach

PubMed Central

2013-01-01

Background Yi Guan Jian Decoction (YGJD), a famous Chinese prescription, has long been employed clinically to treat liver fibrosis. However, as of date, there is no report on the effects of YGJD from a metabonomic approach. In this study, a urine metabonomic method based on gas chromatography coupled with mass spectrometry (GC/MS) was employed to study the protective efficacy and metabolic profile changes caused by YGJD in carbon tetrachloride (CCl4)-induced liver fibrosis. Methods Urine samples from Wistar rats of three randomly divided groups (control, model, and YGJD treated) were collected at various time-points, and the metabolic profile changes were analyzed by GC/MS with principal component analysis (PCA) and partial least squares-discriminate analysis (PLS-DA). Furthermore, histopathology and biochemical examination were also carried out to ensure the success of CCl4-induced liver fibrosis model. Results Urine metabolic profile studies suggested distinct clustering of the three groups, and YGJD group was much closer to the control group by showing a tendency of recovering towards the control group. Fourteen significantly changed metabolites were found, and YGJD treatment could reverse the levels of these metabolites to normal levels or close to normal levels. Conclusions The current study indicates that the YGJD has significant anti-fibrotic effects on CCl4-induced liver fibrosis in rats, which might be by regulating the dysfunction of energy metabolism, amino acid metabolism, tryptophan metabolism, cytochrome P450 metabolism, and gut microflora metabolism. The metabonomic approach can be recommended to study the pharmacological effect and mechanism of complex Chinese medicines. PMID:23725349

Cytotoxicity of nitric oxide in Fu5 rat hepatoma cells: evidence for co-operative action with hydrogen peroxide.

PubMed Central

Ioannidis, I; de Groot, H

1993-01-01

The NO-releasing compounds 3-morpholinosydnonimine-N-ethylcarbamide (SIN-1), sodium nitroprusside (SNP) and S-nitroso-N-acetyl-DL-penicillamine (SNAP) mediated a rapid loss of viability of Fu5 rat hepatoma cells. SIN-1 in addition to NO also released the superoxide anion radical (O2-.). Its cytotoxicity, however, was not affected by superoxide dismutase. In contrast, the H2O2-converting enzyme catalase significantly, but not completely, diminished cell damage, indicating participation of H2O2 in the tumoricidal activity of SIN-1. Glucose oxidase (5 m-units/ml), producing similar amounts of H2O2 to 5 mM SIN-1, had no effect on cell viability. When 5 m-units/ml glucose oxidase was added to incubations with 5 mM SNP, which alone initiated cell injury of about 40%, cell damage was significantly increased up to 95%. Similar results were observed with 1 mM SNAP and 20 m-units/ml xanthine oxidase, which mediated cytotoxicity of about 90% when both compounds were added together, compared with 35% and 55% cell injury, respectively, induced by the single compounds. The results indicate that a co-operative action with H2O2 enhances the tumoricidal activity of NO in Fu5 cells. No evidence for an interplay of NO with O2-. in cytotoxicity, e.g. via the peroxynitrite anion (ONOO-), was found. PMID:8257422

Anti-mitotic potential of 7-diethylamino-3(2 Prime -benzoxazolyl)-coumarin in 5-fluorouracil-resistant human gastric cancer cell line SNU620/5-FU

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kim, Nam Hyun; Kim, Su-Nam; Oh, Joa Sub

2012-02-24

Highlights: Black-Right-Pointing-Pointer DBC exerts antiproliferative potential against 5FU-resistant human gastric cancer cells. Black-Right-Pointing-Pointer This effect is mediated by destabilization of microtubules and subsequent mitotic arrest. Black-Right-Pointing-Pointer DBC enhances apoptosis via caspase activation and downregulation of antiapoptotic genes. -- Abstract: In this study, we investigate an anti-mitotic potential of the novel synthetic coumarin-based compound, 7-diethylamino-3(2 Prime -benzoxazolyl)-coumarin, in 5-fluorouracil-resistant human gastric cancer cell line SNU-620-5FU and its parental cell SNU-620. It exerts the anti-proliferative effects with similar potencies against both cancer cells, which is mediated by destabilization of microtubules and subsequent mitotic arrest. Furthermore, this compound enhances caspase-dependent apoptotic cell deathmore » via decreased expression of anti-apoptotic genes. Taken together, our data strongly support anti-mitotic potential of 7-diethylamino-3(2 Prime -benzoxazolyl)-coumarin against drug-resistant cancer cells which will prompt us to further develop as a novel microtubule inhibitor for drug-resistant cancer chemotherapy.« less

Neoadjuvant Treatment With Single-Agent Cetuximab Followed by 5-FU, Cetuximab, and Pelvic Radiotherapy: A Phase II Study in Locally Advanced Rectal Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bertolini, Federica; Chiara, Silvana; Bengala, Carmelo

2009-02-01

Purpose: Preoperative chemoradiotherapy followed by surgery represents the standard of care for locally advanced rectal cancer (LARC). Cetuximab has proved activity in advanced colorectal cancer, and its incorporation in preoperative treatment may increase tumor downstaging. Methods and Materials: After biopsy and staging, uT3/uT4 N0/+ LARC received single-agent cetuximab in three doses, followed by weekly cetuximab plus 5-fluorouracil (5-FU), concomitantly with RT. Sample size was calculated according to Bryant and Day test, a two-stage design with at least 10 pathologic complete remissions observed in 60 patients (pts) able to complete the treatment plan. Results: Forty pts with LARC were entered: male/femalemore » = 34/6; median age: 61 (range, 28-77); 12 uT3N0 Ed(30%); 25 uT3N1 (62%); 3 uT4N1 (8%); all Eastern Cooperative Oncology Group = 0. Thirty-five pts completed neoadjuvant treatment; 5 (12%) withdrew therapy after one cetuximab administration: three for hypersensitivity reactions, one for rapid progression, and one for purulent arthritis. They continued 5-FU in continuous infusion in association with RT. Thirty-one pts (77%) presented with acnelike rash; dose reduction/interruption of treatment was necessary in six pts (15%): two for Grade 3 acnelike rash, two for Grade 3 gastrointestinal toxicity, and two for refusal. Thirty-eight pts were evaluable for pathological response (one patient refused surgery, and one was progressed during neoadjuvant treatment). Pathological staging was: pT0N0 three pts (8%), pT1N0 1 pt (3%); pT2N0 13 pts (34%), and pT3 19 pts (50%) (N0:9, N1:5; N2:5); pT4 2 pts (5%). Conclusions: Preoperative treatment with 5-FU, cetuximab, and pelvic RT is feasible with acceptable toxicities; however, the rate of pathologic responses is disappointingly low.« less

Validation of the 12-gene colon cancer recurrence score in NSABP C-07 as a predictor of recurrence in patients with stage II and III colon cancer treated with fluorouracil and leucovorin (FU/LV) and FU/LV plus oxaliplatin.

PubMed

Yothers, Greg; O'Connell, Michael J; Lee, Mark; Lopatin, Margarita; Clark-Langone, Kim M; Millward, Carl; Paik, Soonmyung; Sharif, Saima; Shak, Steven; Wolmark, Norman

2013-12-20

Accurate assessments of recurrence risk and absolute treatment benefit are needed to inform colon cancer adjuvant therapy. The 12-gene Recurrence Score assay has been validated in patients with stage II colon cancer from the Cancer and Leukemia Group B 9581 and Quick and Simple and Reliable (QUASAR) trials. We conducted an independent, prospectively designed clinical validation study of Recurrence Score, with prespecified end points and analysis plan, in archival specimens from patients with stage II and III colon cancer randomly assigned to fluorouracil (FU) or FU plus oxaliplatin in National Surgical Adjuvant Breast and Bowel Project C-07. Recurrence Score was assessed in 892 fixed, paraffin-embedded tumor specimens (randomly selected 50% of patients with tissue). Data were analyzed by Cox regression adjusting for stage and treatment. Continuous Recurrence Score predicted recurrence (hazard ratio for a 25-unit increase in score, 1.96; 95% CI, 1.50 to 2.55; P < .001), as well as disease-free and overall survival (both P < .001). Recurrence Score predicted recurrence risk (P = .001) after adjustment for stage, mismatch repair, nodes examined, grade, and treatment. Recurrence Score did not have significant interaction with stage (P = .90) or age (P = .76). Relative benefit of oxaliplatin was similar across the range of Recurrence Score (interaction P = .48); accordingly, absolute benefit of oxaliplatin increased with higher scores, most notably in patients with stage II and IIIA/B disease. The 12-gene Recurrence Score predicts recurrence risk in stage II and stage III colon cancer and provides additional information beyond conventional clinical and pathologic factors. Incorporating Recurrence Score into the clinical context may better inform adjuvant therapy decisions in stage III as well as stage II colon cancer.

Validation of the 12-Gene Colon Cancer Recurrence Score in NSABP C-07 As a Predictor of Recurrence in Patients With Stage II and III Colon Cancer Treated With Fluorouracil and Leucovorin (FU/LV) and FU/LV Plus Oxaliplatin

PubMed Central

Yothers, Greg; O'Connell, Michael J.; Lee, Mark; Lopatin, Margarita; Clark-Langone, Kim M.; Millward, Carl; Paik, Soonmyung; Sharif, Saima; Shak, Steven; Wolmark, Norman

2013-01-01

Purpose Accurate assessments of recurrence risk and absolute treatment benefit are needed to inform colon cancer adjuvant therapy. The 12-gene Recurrence Score assay has been validated in patients with stage II colon cancer from the Cancer and Leukemia Group B 9581 and Quick and Simple and Reliable (QUASAR) trials. We conducted an independent, prospectively designed clinical validation study of Recurrence Score, with prespecified end points and analysis plan, in archival specimens from patients with stage II and III colon cancer randomly assigned to fluorouracil (FU) or FU plus oxaliplatin in National Surgical Adjuvant Breast and Bowel Project C-07. Methods Recurrence Score was assessed in 892 fixed, paraffin-embedded tumor specimens (randomly selected 50% of patients with tissue). Data were analyzed by Cox regression adjusting for stage and treatment. Results Continuous Recurrence Score predicted recurrence (hazard ratio for a 25-unit increase in score, 1.96; 95% CI, 1.50 to 2.55; P < .001), as well as disease-free and overall survival (both P < .001). Recurrence Score predicted recurrence risk (P = .001) after adjustment for stage, mismatch repair, nodes examined, grade, and treatment. Recurrence Score did not have significant interaction with stage (P = .90) or age (P = .76). Relative benefit of oxaliplatin was similar across the range of Recurrence Score (interaction P = .48); accordingly, absolute benefit of oxaliplatin increased with higher scores, most notably in patients with stage II and IIIA/B disease. Conclusion The 12-gene Recurrence Score predicts recurrence risk in stage II and stage III colon cancer and provides additional information beyond conventional clinical and pathologic factors. Incorporating Recurrence Score into the clinical context may better inform adjuvant therapy decisions in stage III as well as stage II colon cancer. PMID:24220557

Low levels of Caspase-3 predict favourable response to 5FU-based chemotherapy in advanced colorectal cancer: Caspase-3 inhibition as a therapeutic approach.

PubMed

Flanagan, L; Meyer, M; Fay, J; Curry, S; Bacon, O; Duessmann, H; John, K; Boland, K C; McNamara, D A; Kay, E W; Bantel, H; Schulze-Bergkamen, H; Prehn, J H M

2016-02-04

Colorectal cancer (CRC) is one of the most common cancers in the Western world. 5-Fluorouracil (5FU)-based chemotherapy (CT) remains the mainstay treatment of CRC in the advanced setting, and activates executioner caspases in target cells. Executioner caspases are key proteins involved in cell disassembly during apoptosis. Activation of executioner caspases also has a role in tissue regeneration and repopulation by stimulating signal transduction and cell proliferation in neighbouring, non-apoptotic cells as reported recently. Tissue microarrays (TMAs) consisting of tumour tissue from 93 stage II and III colon cancer patients were analysed by immunohistochemistry. Surprisingly, patients with low levels of active Caspase-3 had an increased disease-free survival time. This was particularly pronounced in patients who received 5FU-based adjuvant CT. In line with this observation, lower serum levels of active Caspase-3 were found in patients with metastasised CRC who revealed stable disease or tumour regression compared with those with disease progression. The role of Caspase-3 in treatment responses was explored further in primary human tumour explant cultures from fresh patient tumour tissue. Exposure of explant cultures to 5FU-based CT increased the percentage of cells positive for active Caspase-3 and Terminal Deoxynucleotidyl Transferase dUTP Nick end Labelling (TUNEL), but also the expression of regeneration and proliferation markers β-Catenin and Ki-67, as well as cyclooxygenase-2 (COX-2). Of note, selective inhibition of Caspase-3 with Ac-DNLD-CHO, a selective, reversible inhibitor of Caspase-3, significantly reduced the expression of proliferation markers as well as COX-2. Inhibition of COX-2 with aspirin or celecoxib did not affect Caspase-3 levels but also reduced Ki-67 and β-Catenin levels, suggesting that Caspase-3 acted via COX-2 to stimulate cell proliferation and tissue regeneration. This indicates that low levels of active Caspase-3 may represent a

USP22 knockdown enhanced chemosensitivity of hepatocellular carcinoma cells to 5-Fu by up-regulation of Smad4 and suppression of Akt

PubMed Central

Li, Jiazhi; Yang, Xiaozhou; Yin, Huimin; Xiao, Congshu; Sheng, Jie; Li, Yang; Tang, Bo; Li, Rongkuan

2017-01-01

USP22, a member of the deubiquitinases (DUBs) family, is known to be a key subunit of the human Spt-Ada-Gcn5 acetyltransferase (hSAGA) transcriptional cofactor complex. Within hSAGA, USP22 removes ubiquitin from histone proteins, thus regulating the transcription and expression of downstream genes. USP22 plays important roles in many cancers; however, its effect and the mechanism underlying HCC chemoresistance remain unclear. In the present study, we found that USP22 was highly expressed in chemoresistant HCC tissues and cells and was correlated with the prognosis of HCC patients who received chemotherapy. Silencing USP22 in chemoresistant HCC Bel/Fu cells dramatically inhibited proliferation, migration, invasion and epithelial-mesenchymal transition in vitro; suppressed tumorigenic and metastatic capacities in vivo; and inhibited drug resistance-related proteins (MDR1, LRP, MRP1). Mechanistically, we found that USP22 knockdown exerts its function through down-regulating PI3K and activating Smad4, which inhibited phosphorylation of Akt. Silencing Smad4 blocked USP22 knockdown-induced Akt inhibition in Bel/Fu cells. Our results, for the first time, provide evidence that USP22 plays a critical role in the development of chemoresistant HCC cells and that high USP22 expression serves as a molecular marker for the prognosis of HCC patients who undergo chemotherapy. PMID:28445968

USP22 knockdown enhanced chemosensitivity of hepatocellular carcinoma cells to 5-Fu by up-regulation of Smad4 and suppression of Akt.

PubMed

Zhang, Jing; Luo, Nan; Tian, Yu; Li, Jiazhi; Yang, Xiaozhou; Yin, Huimin; Xiao, Congshu; Sheng, Jie; Li, Yang; Tang, Bo; Li, Rongkuan

2017-04-11

USP22, a member of the deubiquitinases (DUBs) family, is known to be a key subunit of the human Spt-Ada-Gcn5 acetyltransferase (hSAGA) transcriptional cofactor complex. Within hSAGA, USP22 removes ubiquitin from histone proteins, thus regulating the transcription and expression of downstream genes. USP22 plays important roles in many cancers; however, its effect and the mechanism underlying HCC chemoresistance remain unclear. In the present study, we found that USP22 was highly expressed in chemoresistant HCC tissues and cells and was correlated with the prognosis of HCC patients who received chemotherapy. Silencing USP22 in chemoresistant HCC Bel/Fu cells dramatically inhibited proliferation, migration, invasion and epithelial-mesenchymal transition in vitro; suppressed tumorigenic and metastatic capacities in vivo; and inhibited drug resistance-related proteins (MDR1, LRP, MRP1). Mechanistically, we found that USP22 knockdown exerts its function through down-regulating PI3K and activating Smad4, which inhibited phosphorylation of Akt. Silencing Smad4 blocked USP22 knockdown-induced Akt inhibition in Bel/Fu cells. Our results, for the first time, provide evidence that USP22 plays a critical role in the development of chemoresistant HCC cells and that high USP22 expression serves as a molecular marker for the prognosis of HCC patients who undergo chemotherapy.

Calculating clear-sky radiative heating rates using the Fu-Liou RTM with inputs from observed and reanalyzed profiles

NASA Astrophysics Data System (ADS)

Dolinar, E. K.; Dong, X.; Xi, B.

2015-12-01

One-dimensional radiative transfer models (RTM) are a common tool used for calculating atmospheric heating rates and radiative fluxes. In the forward sense, RTMs use known (or observed) quantities of the atmospheric state and surface characteristics to determine the appropriate surface and top-of-atmosphere (TOA) radiative fluxes. The NASA CERES science team uses the modified Fu-Liou RTM to calculate atmospheric heating rates and surface and TOA fluxes using the CERES observed TOA shortwave (SW) and longwave (LW) fluxes as constraints to derive global surface and TOA radiation budgets using a reanalyzed atmospheric state (e.g. temperature and various greenhouse gases) from the newly developed MERRA-2. However, closure studies have shown that using the reanalyzed state as input to the RTM introduces some disparity between the RTM calculated fluxes and surface observed ones. The purpose of this study is to generate a database of observed atmospheric state profiles, from satellite and ground-based sources, at several permanent Atmospheric Radiation Measurement (ARM) Program sites, including the Southern Great Plains (SGP), Northern Slope of Alaska (NSA) and Tropical Western Pacific Nauru (TWP-C2), and Eastern North Atlantic (ENA) permanent facilities. Since clouds are a major modulator of radiative transfer within the Earth's atmosphere, we will focus on the clear-sky conditions in this study, which will set up the baseline for our cloudy studies in the future. Clear-sky flux profiles are calculated using the Edition 4 NASA LaRC modified Fu-Liou RTM. The aforementioned atmospheric profiles generated in-house are used as input into the RTM, as well as from reanalyses. The calculated surface and TOA fluxes are compared with ARM surface measured and CERES satellite observed SW and LW fluxes, respectively. Clear-sky cases are identified by the ARM radar-lidar observations, as well as satellite observations, at the select ARM sites.

The GOFURTGO Study: AGITG Phase II Study of fixed dose rate gemcitabine–oxaliplatin integrated with concomitant 5FU and 3-D conformal radiotherapy for the treatment of localised pancreatic cancer

PubMed Central

Goldstein, D; Spry, N; Cummins, M M; Brown, C; van Hazel, G A; Carroll, S; Selva-Nayagam, S; Borg, M; Ackland, S P; Wratten, C; Shapiro, J; Porter, I W T; Hruby, G; Horvath, L; Bydder, S; Underhill, C; Harvey, J; Gebski, V J

2012-01-01

Background: Locally advanced inoperable pancreatic cancer (LAPC) has a poor prognosis. By increasing intensity of systemic therapy combined with an established safe chemoradiation technique, our intention was to enhance the outcomes of LAPC. In preparation for phase III evaluation, the feasibility and efficacy of our candidate regimen gemcitabine–oxaliplatin chemotherapy with sandwich 5-fluorouracil (5FU) and three-dimensional conformal radiotherapy (3DCRT) needs to be established. Methods: A total of 48 patients with inoperable LAPC without metastases were given gemcitabine (1000 mg m−2 d1 + d15 q28) and oxaliplatin (100 mg m−2 d2 + d16 q28) in induction (one cycle) and consolidation (three cycles), and 5FU 200 mg m−2 per day over 6 weeks during 3DCRT 54 Gy. Results: Median duration of sustained local control (LC) was 15.8 months, progression-free survival (PFS) was 11.0 months, and overall survival was 15.7 months. Survival rates for 1, 2, and 3 years were 70.2%, 21.3%, and 12.8%, respectively. Global quality of life did not significantly decline from baseline during treatment, which was associated with modest treatment-related toxicity. Conclusion: Fixed-dose gemcitabine and oxaliplatin, combined with an effective and safe regimen of 5FU and 3DCRT radiotherapy, was feasible and reasonably tolerated. The observed improved duration of LC and PFS with more intensive therapy over previous trials may be due to patient selection, but suggest that further evaluation in phase III trials is warranted. PMID:22134511

[Clinical evaluation of combination chemotherapy of aclacinomycin A (ACM) and 5-fluorouracil (5-FU) for advanced carcinoma of gastrointestinal tract].

PubMed

Kikuchi, K

1982-04-01

Clinical evaluation of the combination chemotherapy of ACM and 5-FU(AF therapy) for patients with far-advanced, recurrent and inoperable gastric and colorectal carcinomas was made by the study group composed of 13 major hospitals in Tohoku area. Fifty-nine patients were treated with this regimen and 41 (gastric carcinoma 32 cases, colorectal carcinoma 8 cases and bile duct carcinoma 1 case) were evaluable. The schedule of treatment was as follows: 40mg of ACM was given twice a week (the 1st and 4th days) by intravenous one-shot injection along with 250mg of 5-FU everyday by intravenous drip infusion. No patients received anti-cancer drugs and radiation therapy for one month before AF therapy. As to the clinical efficacy, 32 patients with gastric carcinoma showed a relatively good response rate of 3% on CR and 22% on PR by Koyama and Saito's criteria. The rate that showed more than I-A by Karnofsky's criteria was 38%. The clinical effects on patients with colorectal carcinoma or bile duct carcinoma were negligible. As to the histological types, 16 cases with poorly-differentiated gastric carcinoma showed a response rate of 6% on PR, but 16 patients with well a differentiated gastric carcinoma showed that of 38% of PR and 6% of CR. The effective cases were more frequently observed in well-differentiated carcinoma than poorly-differentiated carcinoma. The major side effects of AF therapy were bone marrow suppression and gastrointestinal toxicity. The former was observed in 45% of all patients and the latter in 27% of them. Hepatic toxicity, abnormal change of ECG and hemorrhagic diathesis were not observed.

A randomised placebo-exercise controlled trial of Kung Fu training for improvements in body composition in overweight/obese adolescents: the “Martial Fitness” study

PubMed Central

Tsang, Tracey W.; Kohn, Michael; Chow, Chin Moi; Singh, M Fiatarone

2009-01-01

The purpose of the study was to investigate if Chinese martial arts (Kung Fu, KF) might be effective for improving body composition, as well as being an appealing form of physical activity for inexperienced, sedentary, overweight/obese adolescents. Twenty subjects (age: 13.3 ± 1.8 y; BMI percentile: 98.6(86.5 - 99.8); 60% girls) were randomly-assigned to the supervised KF or placebo (Tai Chi, TC) control group 3 d.wk-1 for 6 months. We assessed body composition, including total and regional fat and lean mass, total and regional bone mineral density (BMD), percent lean and fat mass, body mass index and waist circumference, at baseline and after 6 months of training using anthropometry and dual-energy X-ray absorptiometry (DXA). Habitual physical activity and dietary intake were recorded as covariates via self-report at each time-point. As expected due to natural growth, significant increases in height, weight, total and lumbar BMD, and lean mass were seen in the cohort over time, with a trend for increased whole body fat mass, with no difference between groups. By contrast, percent fat and android fat mass via DXA did not increase in either group over time. The absence of a similar expected increase in central adiposity over 6 months could indicate a positive effect of participation in both programs on the metabolically critical abdominal adiposity in this cohort. Further research in this area is warranted to determine ways to increase uptake and compliance, and to see if longer-term martial arts training not only maintains, but improves abdominal fat mass and related metabolic health indices in overweight/ obese adolescents. Key points Participation in our martial arts trial attenuated the increases in body fat mass expected due to growth in our overweight/obese adolescent group. All subjects allocated to the Kung Fu intervention were satisfied with their Kung Fu training, in contrast to our placebo-exercise (Tai Chi) subjects, suggesting that this form of

Two Δ6-desaturase-like genes in common carp (Cyprinus carpio var. Jian): structure characterization, mRNA expression, temperature and nutritional regulation.

PubMed

Ren, Hong-tao; Zhang, Guang-qin; Li, Jian-lin; Tang, Yong-kai; Li, Hong-xia; Yu, Ju-hua; Xu, Pao

2013-08-01

Δ6-Desaturase is the rate-limiting enzyme involved in highly unsaturated fatty acid (HUFA) biosynthesis. There is very little information on the evolution and functional characterization of Δ6Fad-a and Δ6Fad-b in common carp (Cyprinus carpio var. Jian). In the present study, the genomic sequences and structures of two putative Δ6-desaturase-like genes in common carp genome were obtained. We investigated the mRNA expression patterns of Δ6Fad-a and Δ6Fad-b in tissue, hatching carp embryos, larvae by temperature shock and juveniles under nutritional regulation. Our results showed that the two Δ6Fad genes had identical coding exon structures, being comprised of 12 coding exons, and with introns of distinct size and sequence composition. They were not allelic variants of a single gene. Both Δ6Fad genes were highly expressed in liver, intestine (pyloric caeca) and brain. The Δ6Fad-a and Δ6Fad-b mRNAs showed an increase in expression from newly hatched to 25 days after hatching. The expression levels of Δ6Fad-a were obviously regulated by temperature, whereas Δ6Fad-b was not affected by temperature. The regulation of Δ6Fad-a and Δ6Fad-b in response to dietary fatty acid composition was determined in liver, brain and intestine (pyloric caeca) of common carp fed with diets: diet1with fish oil (FO) rich in n-3 HUFA, diet2 with corn oil (CO, 18:2n-6) and diet3 with linseed oil (LO, 18:3n-3). The differential expression of Δ6Fad-a and Δ6Fad-b genes in liver, brain and intestine in common carps was fed with different oil sources, respectively. Further work is in progress to determine the mechanism of differential expression of the Δ6Fad-a and Δ6Fad-b genes in different tissues and the roles of transcription factors in regulating HUFA synthesis. Copyright © 2013 Elsevier B.V. All rights reserved.

Characteristics of GHG flux from water-air interface along a reclaimed water intake area of the Chaobai River in Shunyi, Beijing

NASA Astrophysics Data System (ADS)

He, Baonan; He, Jiangtao; Wang, Jian; Li, Jie; Wang, Fei

2018-01-01

To understand greenhouse gas (GHG) flux in reclaimed water intake area impact on urban climate, 'static chamber' method was used to investigate the spatio-diurnal variations and the influence factors of GHG fluxes at water-air interface from Jian River to Chaobai River. Results showed that the average fluxes of CO2 from the Jian River and the Chaobai River were 73.46 mg(m2·h)-1 and -64.75 mg(m2·h)-1, respectively. CO2 was emitted the most in the Jian River, but it was absorbed from the atmosphere in the Chaobai River. Unary linear regression analyses demonstrated that Chlorophyll a (Chl a) and pH variation controlled the carbon source and sink from the Jian River to the Chaobai River. The diurnal variation of CO2 fluxes was higher at night than in the daytime in the Jian River, and it was the inverse in the Chaobai River, which highly correlated with dissociative CO2 and HCO3- transformation to CO32-. The average fluxes of CH4 from the Jian River and Chaobai River were 0.973 mg(m2·h)-1 and 5.556 mg(m2·h)-1, respectively, which increased along the water flow direction. Unary and multiple linear regression analyses demonstrated that Chl a and total organic carbon (TOC) controlled the increase of CH4 along the flow direction. The diurnal variation of CH4 fluxes was slightly higher in the daytime than at night due to the effect of water temperature.

Jin Fu Kang Oral Liquid Inhibits Lymphatic Endothelial Cells Formation and Migration

PubMed Central

Wang, Dan; Tang, Jie

2016-01-01

Lung cancer is the leading cause of cancer-related deaths worldwide. Jin Fu Kang (JFK), an oral liquid prescription of Chinese herbal drugs, has been clinically available for the treatment of non-small cell lung cancer (NSCLC). Lymphangiogenesis is a primary event in the process of cancer development and metastasis, and the formation and migration of lymphatic endothelial cells (LECs) play a key role in the lymphangiogenesis. To assess the activity of stromal cell-derived factor-1 (SDF-1) and the coeffect of SDF-1 and vascular endothelial growth factor-C (VEGF-C) on the formation and migration of LECs and clarify the inhibitory effects of JFK on the LECs, the LECs were differentiated from CD34+/VEGFR-3+ endothelial progenitor cells (EPCs), and JFK-containing serums were prepared from rats. SDF-1 and VEGF-C both induced the differentiation of CD34+/VEGFR-3+ EPCs towards LECs and enhanced the LECs migration. Couse of SDF-1 and VEGF-C displayed an additive effect on the LECs formation but not on their migration. JFK inhibited the formation and migration of LECs, and the inhibitory effects were most probably via regulation of the SDF-1/CXCR4 and VEGF-C/VEGFR-3 axes. The current finding suggested that JFK might inhibit NSCLC through antilymphangiogenesis and also provided a potential to discover antilymphangiogenesis agents from natural resources. PMID:27698675

Jin Fu Kang Oral Liquid Inhibits Lymphatic Endothelial Cells Formation and Migration.

PubMed

He, Hai-Lang; Wang, Dan; Tang, Jie; Zhou, Xian-Mei; Li, Jian-Xin; Xu, Ling

2016-01-01

Lung cancer is the leading cause of cancer-related deaths worldwide. Jin Fu Kang (JFK), an oral liquid prescription of Chinese herbal drugs, has been clinically available for the treatment of non-small cell lung cancer (NSCLC). Lymphangiogenesis is a primary event in the process of cancer development and metastasis, and the formation and migration of lymphatic endothelial cells (LECs) play a key role in the lymphangiogenesis. To assess the activity of stromal cell-derived factor-1 (SDF-1) and the coeffect of SDF-1 and vascular endothelial growth factor-C (VEGF-C) on the formation and migration of LECs and clarify the inhibitory effects of JFK on the LECs, the LECs were differentiated from CD34 + /VEGFR-3 + endothelial progenitor cells (EPCs), and JFK-containing serums were prepared from rats. SDF-1 and VEGF-C both induced the differentiation of CD34 + /VEGFR-3 + EPCs towards LECs and enhanced the LECs migration. Couse of SDF-1 and VEGF-C displayed an additive effect on the LECs formation but not on their migration. JFK inhibited the formation and migration of LECs, and the inhibitory effects were most probably via regulation of the SDF-1/CXCR4 and VEGF-C/VEGFR-3 axes. The current finding suggested that JFK might inhibit NSCLC through antilymphangiogenesis and also provided a potential to discover antilymphangiogenesis agents from natural resources.

A Reactor Development Scenario for the FuZE Sheared-Flow Stabilized Z-pinch

NASA Astrophysics Data System (ADS)

McLean, Harry S.; Higginson, D. P.; Schmidt, A.; Tummel, K. K.; Shumlak, U.; Nelson, B. A.; Claveau, E. L.; Forbes, E. G.; Golingo, R. P.; Stepanov, A. D.; Weber, T. R.; Zhang, Y.

2017-10-01

We present a conceptual design, scaling calculations, and development path for a pulsed fusion reactor based on a flow-stabilized Z-pinch. Experiments performed on the ZaP and ZaP-HD devices have largely demonstrated the basic physics of sheared-flow stabilization at pinch currents up to 100 kA. Initial experiments on the FuZE device, a high-power upgrade of ZaP, have achieved 20 usec of stability at pinch current 100-200 kA and pinch diameter few mm for a pinch length of 50 cm. Scaling calculations based on a quasi-steady-state power balance show that extending stable duration to 100 usec at a pinch current of 1.5 MA and pinch length of 50 cm, results in a reactor plant Q 5. Future performance milestones are proposed for pinch currents of: 300 kA, where Te and Ti are calculated to exceed 1-2 keV; 700 kA, where DT fusion power would be expected to exceed pinch input power; and 1 MA, where fusion energy per pulse exceeds input energy per pulse. This work funded by USDOE ARPA-E and performed under the auspices of Lawrence Livermore National Laboratory under Contract DE-AC52-07NA27344. LLNL-ABS-734770.

How can we reduce phosphorus export from lowland polders? Implications from a sensitivity analysis of a coupled model.

PubMed

Huang, Jiacong; Gao, Junfeng; Yan, Renhua

2016-08-15

Phosphorus (P) export from lowland polders has caused severe water pollution. Numerical models are an important resource that help water managers control P export. This study coupled three models, i.e., Phosphorus Dynamic model for Polders (PDP), Integrated Catchments model of Phosphorus dynamics (INCA-P) and Universal Soil Loss Equation (USLE), to describe the P dynamics in polders. Based on the coupled models and a dataset collected from Polder Jian in China, sensitivity analysis were carried out to analyze the cause-effect relationships between environmental factors and P export from Polder Jian. The sensitivity analysis results showed that P export from Polder Jian were strongly affected by air temperature, precipitation and fertilization. Proper fertilization management should be a strategic priority for reducing P export from Polder Jian. This study demonstrated the success of model coupling, and its application in investigating potential strategies to support pollution control in polder systems. Copyright © 2016. Published by Elsevier B.V.

Degradation of 5-FU by means of advanced (photo)oxidation processes: UV/H2O2, UV/Fe2+/H2O2 and UV/TiO2--Comparison of transformation products, ready biodegradability and toxicity.

PubMed

Lutterbeck, Carlos Alexandre; Wilde, Marcelo Luís; Baginska, Ewelina; Leder, Christoph; Machado, Ênio Leandro; Kümmerer, Klaus

2015-09-15

The present study investigates the degradation of the antimetabolite 5-fluorouracil (5-FU) by three different advanced photo oxidation processes: UV/H2O2, UV/Fe(2+)/H2O2 and UV/TiO2. Prescreening experiments varying the H2O2 and TiO2 concentrations were performed in order to set the best catalyst concentrations in the UV/H2O2 and UV/TiO2 experiments, whereas the UV/Fe(2+)/H2O2 process was optimized varying the pH, Fe(2+) and H2O2 concentrations by means of the Box-Behnken design (BBD). 5-FU was quickly removed in all the irradiation experiments. The UV/Fe(2+)/H2O2 and UV/TiO2 processes achieved the highest degree of mineralization, whereas the lowest one resulted from the UV/H2O2 treatment. Six transformation products were formed during the advanced (photo)oxidation processes and identified using low and high resolution mass spectrometry. Most of them were formed and further eliminated during the reactions. The parent compound of 5-FU was not biodegraded, whereas the photolytic mixture formed in the UV/H2O2 treatment after 256 min showed a noticeable improvement of the biodegradability in the closed bottle test (CBT) and was nontoxic towards Vibrio fischeri. In silico predictions showed positive alerts for mutagenic and genotoxic effects of 5-FU. In contrast, several of the transformation products (TPs) generated along the processes did not provide indications for mutagenic or genotoxic activity. One exception was TP with m/z 146 with positive alerts in several models of bacterial mutagenicity which could demand further experimental testing. Results demonstrate that advanced treatment can eliminate parent compounds and its toxicity. However, transformation products formed can still be toxic. Therefore toxicity screening after advanced treatment is recommendable. Copyright © 2015 Elsevier B.V. All rights reserved.

Recurrence and 5-FU sensitivity of stage I/II node-negative breast, lung, or gastric cancer with occult neoplastic cells in lymph node sinuses.

PubMed

Mukai, Masaya; Sato, Shinkichi; Tajima, Takayuki; Ninomiya, Hiromi; Wakui, Kanako; Komatsu, Nobukazu; Tsuchiya, Kazutoshi; Nakasaki, Hisao; Makuuchi, Hiroyasu

2006-04-01

This study was designed to examine the relationship between the presence of occult neoplastic cells (ONCs) in lymph nodes (LNs) and survival in 238 patients with stage I/II LN-negative cancer of the breast, lung, or stomach. In addition, immunohistochemistry for TS and DPD was used to compare the 5-FU sensitivity of the primary tumor in ONC (+) patients. The 5-year relapse-free survival (RFS) rate of 215 ONC (-) patients and 23 ONC (+) patients was 95.2 and 82.6%, respectively (p=0.0107). The 5-year overall survival (OS) rate of the ONC (-) and (+) patients was 97.4 and 77.4%, respectively (p=0.0000). The 6 ONC (+) patients with recurrence showed high and low TS expression in 33.3% (2/6) and 66.7% (4/6), respectively, while high and low DPD expression was observed in 16.7% (1/6) and 83.3% (5/6), respectively. In the 17 ONC (+) patients without recurrence, the corresponding values were 64.7% (11/17), 35.3% (6/17), 29.4% (5/17), and 70.6% (12/17). Patients with a combination of high TS and low DPD expression accounted for 33.3% (2/6) of the ONC (+) patients with recurrence and 52.9% (9/17) of those without recurrence, showing no significant difference between the two groups. These results suggest that ONCs are associated with a lower survival rate and that ONC (+) patients are unlikely to respond to 5-FU+LV therapy.

FU Orionis outbursts, preferential recondensation of water ice, and the formation of giant planets

NASA Astrophysics Data System (ADS)

Hubbard, Alexander

2017-02-01

Ices, including water ice, prefer to recondense on to preexisting nuclei rather than spontaneously forming grains from a cloud of vapour. Interestingly, different potential recondensation nuclei have very different propensities to actually nucleate water ice at the temperatures associated with freeze-out in protoplanetary discs. Therefore, if a region in a disc is warmed and then recooled, water vapour should not be expected to refreeze evenly on to all available grains. Instead, it will preferentially recondense on to the most favorable grains. When the recooling is slow enough, only the most favorable grains will nucleate ice, allowing them to recondense thick ice mantles. We quantify the conditions for preferential recondensation to rapidly create pebble-sized grains in protoplanetary discs and show that FU Orionis type outbursts have the appropriate cooling rates to drive pebble creation in a band about 5 au wide outside of the quiescent frost line from approximately Jupiter's orbit to Saturn's (about -10 au). Those pebbles could be of the appropriate size to proceed to planetesimal formation via the Streaming Instability, or to contribute to the growth of planetesimals through pebble accretion. We suggest that this phenomenon contributed to the formation of the gas giants in our own Solar system.

Gauge-theoretic invariants for topological insulators: a bridge between Berry, Wess-Zumino, and Fu-Kane-Mele

NASA Astrophysics Data System (ADS)

Monaco, Domenico; Tauber, Clément

2017-07-01

We establish a connection between two recently proposed approaches to the understanding of the geometric origin of the Fu-Kane-Mele invariant FKM\\in Z_2, arising in the context of two-dimensional time-reversal symmetric topological insulators. On the one hand, the Z_2 invariant can be formulated in terms of the Berry connection and the Berry curvature of the Bloch bundle of occupied states over the Brillouin torus. On the other, using techniques from the theory of bundle gerbes, it is possible to provide an expression for FKM containing the square root of the Wess-Zumino amplitude for a certain U( N)-valued field over the Brillouin torus. We link the two formulas by showing directly the equality between the above-mentioned Wess-Zumino amplitude and the Berry phase, as well as between their square roots. An essential tool of independent interest is an equivariant version of the adjoint Polyakov-Wiegmann formula for fields T^2 → U(N), of which we provide a proof employing only basic homotopy theory and circumventing the language of bundle gerbes.

Neuroprotective effects of dietary supplement Kang-fu-ling against high-power microwave through antioxidant action.

PubMed

Hu, Shaohua; Peng, Ruiyun; Wang, Changzhen; Wang, Shuiming; Gao, Yabing; Dong, Ji; Zhou, Hongmei; Su, Zhentao; Qiao, Shanyi; Zhang, Shouguo; Wang, Lin; Wen, Xiaoxue

2014-09-01

Kang-fu-ling (KFL) is a polybotanical dietary supplement with antioxidant properties. This study aimed to evaluate the potential protective effects of KFL on cognitive deficit induced by high-power microwave (HPM) and the underlying mechanism for this neuroprotection. The electron spin resonance technique was employed to evaluate the free radical scavenging activity of KFL in vitro and KFL exhibited scavenging hydroxyl radical activity. KFL at doses of 0.75, 1.5 and 3 g kg(-1) and vehicle were administered orally once daily for 14 days to male Wistar rats after being exposed to 30 mW cm(-2) HPM for 15 minutes. KFL reversed HPM-induced memory loss and the histopathological changes in hippocampus of rats. In addition, KFL displayed a protective effect against HPM-induced oxidative stress and activated the nuclear factor-E2-related factor 2 (Nrf2) and its target genes in the hippocampus of rats. The Nrf2-antioxidant response element (ARE) signaling pathway may be involved in the neuroprotective effects of KFL against HPM-induced oxidative stress. In summary, the dietary supplement KFL is a promising natural complex, which ameliorates oxidative stress, with neuroprotective effects against HPM.

Optimization of LDL targeted nanostructured lipid carriers of 5-FU by a full factorial design.

PubMed

Andalib, Sare; Varshosaz, Jaleh; Hassanzadeh, Farshid; Sadeghi, Hojjat

2012-01-01

Nanostructured lipid carriers (NLC) are a mixture of solid and liquid lipids or oils as colloidal carrier systems that lead to an imperfect matrix structure with high ability for loading water soluble drugs. The aim of this study was to find the best proportion of liquid and solid lipids of different types for optimization of the production of LDL targeted NLCs used in carrying 5-Fu by the emulsification-solvent evaporation method. The influence of the lipid type, cholesterol or cholesteryl stearate for targeting LDL receptors, oil type (oleic acid or octanol), lipid and oil% on particle size, surface charge, drug loading efficiency, and drug released percent from the NLCs were studied by a full factorial design. The NLCs prepared by 54.5% cholesterol and 25% of oleic acid, showed optimum results with particle size of 105.8 nm, relatively high zeta potential of -25 mV, drug loading efficiency of 38% and release efficiency of about 40%. Scanning electron microscopy of nanoparticles confirmed the results of dynamic light scattering method used in measuring the particle size of NLCs. The optimization method by a full factorial statistical design is a useful optimization method for production of nanostructured lipid carriers.

A feasibility study of [sup 252]Cf neutron brachytherapy, cisplatin + 5-FU chemo-adjuvant and accelerated hyperfractionated radiotherapy for advanced cervical cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Murayama, Y.; Wierzbicki, J.; Bowen, M.G.

The purpose was to evaluate the feasibility and toxicity of [sup 252]Cf neutron brachytherapy combined with hyperaccelerated chemoradiotherapy for Stage III and IV cervical cancers. Eleven patients with advanced Stage IIIB-IVA cervical cancers were treated with [sup 252]Cf neutron brachytherapy in an up-front schedule followed by cisplatin (CDDP; 50 mg/m[sup 2]) chemotherapy and hyperfractionated accelerated (1.2 Gy bid) radiotherapy given concurrently with intravenous infusion of 5-Fluorouracil (5-FU) (1000 mg/m[sup 2]/day [times] 4 days) in weeks 1 and 4 with conventional radiation (weeks 2, 3, 5, and 6). Total dose at a paracervical point A isodose surface was 80-85 Gy-eq bymore » external and intracavitary therapy and 60 Gy at the pelvic sidewalls. Patients tolerated the protocol well. There was 91% compliance with the chemotherapy and full compliance with the [sup 252]Cf brachytherapy and the external beam radiotherapy. There were no problems with acute chemo or radiation toxicity. One patient developed a rectovaginal fistula (Grade 3-4 RTOG criteria) but no other patients developed significant late cystitis, proctitis or enteritis. There was complete response (CR) observed in all cases. With mean follow-up to 26 months, local control has been achieved with 90% actuarial 3-year survival with no evidence of disease (NED). [sup 252]Cf neutrons can be combined with cisplatin and 5-FU infusion chemotherapy plus hyperaccelerated chemoradiotherapy without unusual side effects or toxicity and with a high local response and tumor control rate. Further study of [sup 252]Cf neutron-chemoradiotherapy for advanced and bulky cervical cancer are indicated. The authors found chemotherapy was more effective with the improved local tumor control. 18 refs., 2 tabs.« less

Effect of Jian-Pi-Zhi-Dong Decoction on striatal glutamate and γ-aminobutyric acid levels detected using microdialysis in a rat model of Tourette syndrome

PubMed Central

Zhang, Wen; Wei, Li; Yu, Wenjing; Cui, Xia; Liu, Xiaofang; Wang, Qian; Wang, Sumei

2016-01-01

Background Jian-Pi-Zhi-Dong Decoction (JPZDD) is a dedicated treatment of Tourette syndrome (TS). The balance of neurotransmitters in the cortico-striato-pallido-thalamo-cortical network is crucial to the occurrence of TS and related to its severity. This study evaluated the effect of JPZDD on glutamate (Glu) and γ-aminobutyric acid (GABA) and their receptors in a TS rat model. Materials and methods Rats were divided into four groups (n=12 each). TS was induced in three of the groups by injecting them with 3,3′-iminodipropionitrile for 7 consecutive days. Two model groups were treated with tiapride (Tia) or JPZDD, while the control and the remaining model group were gavaged with saline. Behavior was assessed by stereotypic score and autonomic activity. Striatal Glu and GABA contents were detected using microdialysis. Expressions of N-methyl-D-aspartate receptor 1 and GABAA receptor (GABAAR) were observed using Western blot and real-time polymerase chain reaction. Results Tia and JPZDD groups had decreased stereotypy compared with model rats; however, the JPZDD group showed a larger decrease in stereotypy than the Tia group at a 4-week time point. In a spontaneous activity test, the total distance of the JPZDD and Tia groups was significantly decreased compared with the model group. The Glu levels of the model group were higher than the control group and decreased with Tia or JPZDD treatment. The GABA level was higher in the model group than the control group. Expressions of GABAAR protein in the model group were higher than in the control group. Treatment with Tia or JPZDD reduced the expression of GABAAR protein. In the case of the mRNA expression, only Tia reduced the expression of N-methyl-D-aspartate receptor 1, compared with the model group. Conclusion JPZDD could alleviate impairments in behavior and dysfunctional signaling by downregulating GABAAR in the striatum. We suggest that this acts to maintain the balance of Glu and GABA. PMID:27279743

Technical note: Fu-Liou-Gu and Corti-Peter model performance evaluation for radiative retrievals from cirrus clouds

NASA Astrophysics Data System (ADS)

Lolli, Simone; Campbell, James R.; Lewis, Jasper R.; Gu, Yu; Welton, Ellsworth J.

2017-06-01

We compare, for the first time, the performance of a simplified atmospheric radiative transfer algorithm package, the Corti-Peter (CP) model, versus the more complex Fu-Liou-Gu (FLG) model, for resolving top-of-the-atmosphere radiative forcing characteristics from single-layer cirrus clouds obtained from the NASA Micro-Pulse Lidar Network database in 2010 and 2011 at Singapore and in Greenbelt, Maryland, USA, in 2012. Specifically, CP simplifies calculation of both clear-sky longwave and shortwave radiation through regression analysis applied to radiative calculations, which contributes significantly to differences between the two. The results of the intercomparison show that differences in annual net top-of-the-atmosphere (TOA) cloud radiative forcing can reach 65 %. This is particularly true when land surface temperatures are warmer than 288 K, where the CP regression analysis becomes less accurate. CP proves useful for first-order estimates of TOA cirrus cloud forcing, but may not be suitable for quantitative accuracy, including the absolute sign of cirrus cloud daytime TOA forcing that can readily oscillate around zero globally.

A randomized phase II study of weekly nab-paclitaxel plus gemcitabine or simplified LV5FU2 as first-line therapy in patients with metastatic pancreatic cancer: the AFUGEM GERCOR trial.

PubMed

Bachet, Jean-Baptiste; Chibaudel, Benoist; Bonnetain, Franck; Validire, Pierre; Hammel, Pascal; André, Thierry; Louvet, Christophe

2015-10-06

Metastatic pancreatic adenocarcinoma (PAC) prognosis remains dismal and gemcitabine monotherapy has been the standard treatment over the last decade. Currently, two first-line regimens are used in this setting: FOLFIRINOX and nab-paclitaxel plus gemcitabine. Increasing translational data on the predictive value of hENT1 for determining gemcitabine efficacy suggest that a non-gemcitabine-based regimen is favored in about 60 % of patients with PAC due to high resistance of PAC to this cytotoxic drug. This study aims to evaluate the efficacy of weekly nab-paclitaxel combined with gemcitabine or a simplified (s) LV5FU2 regimen in patients with previously untreated metastatic PAC. AFUGEM is a two-stage, open-label, randomized, multicenter, phase II trial. Patients with PAC who meet the inclusion criteria and provide written informed consent will be randomized in a 1:2 ratio to either nab-paclitaxel (125 mg/m(2)) plus gemcitabine (1000 mg/m(2)) given on days 1, 8, and 15 every 28 days or nab-paclitaxel (125 mg/m(2)) plus sLV5FU2 (leucovorin 400 mg/m(2) followed by bolus 400 mg/m(2) 5-fluorouracil and by 5-fluorouracil 2400 mg/m(2) as an 46-h intravenous infusion) given on days 1 and 15 every 28 days. A total of 114 patients will be randomized to one of the treatment arms. The primary endpoint is progression-free survival at 4 months. Secondary outcomes are rate and duration of response, disease control, overall survival, safety, and quality of life. Potential biomarkers of gemcitabine (hENT1, dCK) and 5-fluorouracil (TS) efficacy will be assessed. The AFUGEM trial is designed to provide valuable information regarding efficacy and tolerability of nab-paclitaxel plus gemcitabine and nab-paclitaxel plus sLV5FU2 regimens. Identification of potential predictive biomarkers of gemcitabine and 5-fluorouracil is likely to drive therapeutic decisions in patients with metastatic PAC. AFUGEM is registered at Clinicaltrials.gov: NCT01964534 , October 15, 2013.

[Comparison of Curative Effect between Fu Fang Huang Dai Pian and Arsenic Trioxide in Treatment of 45 Patients with Acute Promyelocytic Leukaemia].

PubMed

Wang, Jian; Huang, Jun-Bin; Liu, Zu-Lin; Zhang, Bi-Hong; Xu, Hong-Gui; Xue, Hong-Man; Chen, Chun

2017-12-01

To investigate the clinical efficacy of Fu Fan Huang Dai Pian(RIF) and arsenic trioxide (ATO) regimens for treatment of children with acute promyelocytic leukemia (APL) and to explore the risk factors affecting the prognosis of patients. The clinical data of 45 newly diagnosed APL children admitted in our hospital from January 2004 to May 2017 were analyzed retrospectively. Among 45 APL children, 25 children were treated by chemotherapetic regimen including RIF (RIF group), another 20 children were treated by chemotherapeutic regimen including ATO (ATO group). The follow-up was performed in all APL children. The prognosis and incidence of side reactions from drugs in 2 groups were compared, and the high risk factors affecting the prognosis of patients were analyzed. The median follow-up time was 49.8% months. In RIF group, no early death occured in 25 APL children; 5 cases did not achieve complete remission (CR) after induction therapy, CR rate was 88%. Out of 25 cases 2 caes relapsed, 3 cases died, 20 cases maintained contined CR (CCR), 2 cases failed to be followed-up. In ATO group, 2 cases suffered from early death, 5 cases did not achieve CR after induction therapy, CR rate was 90%, 2 caese relapsed and died, 15 cases maintained CCR, the follow-up failed in 1 caes. The 5 year- OS and EFS rate in all the patients were predicted as (82.2±6.2)% and (76.4±6.6)% respectively. The OS and EFS rate in RIF group were (86.1±7.4)% and (78.4±8.6)% respectively, which were significantly different from OS and EFS rate (76.4%±10.6%) and (74.0%±10.1%) respectively in ATO group (all P>0.05). As for the side reaction from drug, except for the cardiac damage (P<0.05), incidence of other side reactions was not significantly different between 2 groups (P>0.05). In addition, the 5 year-OS and EFS rates in APL children with CNSL were significantly lower than those in APL children without CNSL (all P<0.05), the 5 year OS and EFS rate in APL children did not reache M1 and with

New Ceratocystis species from Eucalyptus and Cunninghamia in South China.

PubMed

Liu, FeiFei; Mbenoun, Michael; Barnes, Irene; Roux, Jolanda; Wingfield, Michael J; Li, GuoQing; Li, JieQiong; Chen, ShuaiFei

2015-06-01

During routine surveys for possible fungal pathogens in the rapidly expanding plantations of Eucalyptus and Cunninghamia lanceolata in China, numerous isolates of unknown species in the genus Ceratocystis (Microascales) were obtained from tree wounds. In this study we identified the Ceratocystis isolates from Eucalyptus and Cunninghamia in the GuangDong, GuangXi, FuJian and HaiNan Provinces of South China based on morphology and through comparisons of DNA sequence data for the ITS, partial β-tubulin and TEF-1α gene regions. Morphological and DNA sequence comparisons revealed two previously unknown species residing in the Indo-Pacific Clade. These are described here as Ceratocystis cercfabiensis sp. nov. and Ceratocystis collisensis sp. nov. Isolates of Ceratocystis cercfabiensis showed intragenomic variation in their ITS sequences and four strains were selected for cloning of the ITS gene region. Twelve ITS haplotypes were obtained from 17 clones selected for sequencing, differing in up to seven base positions and representing two separate phylogenetic groups. This is the first evidence of multiple ITS types in isolates of Ceratocystis residing in the Indo-Pacific Clade. Caution should thus be exercised when using the ITS gene region as a barcoding marker for Ceratocystis species in this clade. This study also represents the first record of a species of Ceratocystis from Cunninghamia.

Association between ERCC1 and TS mRNA levels and disease free survival in colorectal cancer patients receiving oxaliplatin and fluorouracil (5-FU) adjuvant chemotherapy.

PubMed

Li, Sheng; Zhu, Liangjun; Yao, Li; Xia, Lei; Pan, Liangxi

2014-08-29

Aim was to explore the association of ERCC1 and TS mRNA levels with the disease free survival (DFS) in Chinese colorectal cancer (CRC) patients receiving oxaliplatin and 5-FU based adjuvant chemotherapy. Total 112 Chinese stage II-III CRC patients were respectively treated by four different chemotherapy regimens after curative operation. The TS and ERCC1 mRNA levels in primary tumor were measured by real-time RT-PCR. Kaplan-Meier curves and log-rank tests were used for DFS analysis. The Cox proportional hazards model was used for prognostic analysis. In univariate analysis, the hazard ratio (HR) for the mRNA expression levels of TS and ERCC1 (logTS: HR = 0.820, 95% CI = 0.600 - 1.117, P = 0.210; logERCC1: HR = 1.054, 95% CI = 0.852 - 1.304, P = 0.638) indicated no significant association of DFS with the TS and ERCC1 mRNA levels. In multivariate analyses, tumor stage (IIIc: reference, P = 0.083; IIb: HR = 0.240, 95% CI = 0.080 - 0.724, P = 0.011; IIc: HR < 0.0001, P = 0.977; IIIa: HR = 0.179, 95% CI = 0.012 - 2.593, P = 0.207) was confirmed to be the independent prognostic factor for DFS. Moreover, the Kaplan-Meier DFS curves showed that TS and ERCC1 mRNA levels were not significantly associated with the DFS (TS: P = 0.264; ERCC1: P = 0.484). The mRNA expression of ERCC1 and TS were not applicable to predict the DFS of Chinese stage II-III CRC patients receiving 5-FU and oxaliplatin based adjuvant chemotherapy.

Transcatheter Embolization of Peripheral Renal Artery for Hemorrhagic Urological Emergencies using FuAiLe Medical Glue

PubMed Central

An, Tianzhi; Zhang, Shasha; Xu, Min; Zhou, Shi; Wang, Weiping

2015-01-01

Our objective was to review the technical success and clinical outcomes of transcatheter embolization of peripheral renal artery with FuAiLe medical glue (FAL). All patients who underwent FAL embolization for peripheral renal artery bleeding were retrospectively analyzed for underlying pathologies, technical success and outcome of embolization procedure. 14 consecutive patients underwent FAL embolization between November 2009 and February 2013. The causes of bleeding were post biopsy (n = 5), blunt trauma (n = 5), percutaneous lithotripsy of kidney stones (n = 3), and complication of cardiac catheterization (n = 1). Bleeding was effectively controlled with a single injection of FAL. Mean volume of FAL mixture (FAL:Lipiodol, 1:1) was 0.5 mL (range, 0.2–0.8 mL). No reflux of the embolic agent was noted. Average cost of FAL for each procedure was $74. Postembolization clinical follow-up showed no evidence of recurrent hematuria, progression of hematoma, hypertension, or elevation of serum creatinine. Doppler ultrasound examinations in 13 patients demonstrated no abscess, renal parenchyma infarction, or renal artery abnormalities. Superselective FAL embolization may be used for the treatment of active bleeding from peripheral renal arteries. It has a high success rate and is quicker and less expensive than embolization with other agents. PMID:25765607

Transcatheter embolization of peripheral renal artery for hemorrhagic urological emergencies using FuAiLe medical glue.

PubMed

An, Tianzhi; Zhang, Shasha; Xu, Min; Zhou, Shi; Wang, Weiping

2015-03-13

Our objective was to review the technical success and clinical outcomes of transcatheter embolization of peripheral renal artery with FuAiLe medical glue (FAL). All patients who underwent FAL embolization for peripheral renal artery bleeding were retrospectively analyzed for underlying pathologies, technical success and outcome of embolization procedure. 14 consecutive patients underwent FAL embolization between November 2009 and February 2013. The causes of bleeding were post biopsy (n = 5), blunt trauma (n = 5), percutaneous lithotripsy of kidney stones (n = 3), and complication of cardiac catheterization (n = 1). Bleeding was effectively controlled with a single injection of FAL. Mean volume of FAL mixture (FAL:Lipiodol, 1:1) was 0.5 mL (range, 0.2-0.8 mL). No reflux of the embolic agent was noted. Average cost of FAL for each procedure was $74. Postembolization clinical follow-up showed no evidence of recurrent hematuria, progression of hematoma, hypertension, or elevation of serum creatinine. Doppler ultrasound examinations in 13 patients demonstrated no abscess, renal parenchyma infarction, or renal artery abnormalities. Superselective FAL embolization may be used for the treatment of active bleeding from peripheral renal arteries. It has a high success rate and is quicker and less expensive than embolization with other agents.

Kinematical Comparison Analysis on the Discus Athletes Throwing Techniques Based on Data Project

NASA Astrophysics Data System (ADS)

Junming, Li; Jihe, Zhou; Ting, Long

2017-09-01

In the discus final site of throwing event series game of China’s track and field sport in April, 2015, three dimensional camera analytical method which is an application of kinematical data project was used on female discus athletes’ discus throwing technology. And analysis was made for the top four discus throwers’ last exertion action, related kinematics parameter was thus obtained. Analysis results show that: first, Lu Xiaoxin behaves better in body twist tight effect when it is left foot on the ground and in capacity of beyond devices, followed by Su Xinyue and Tan Jian, with Feng Bin relatively weaker; second, our athletes’ discus shots speed is to be upgraded compared with world excellent female discus athletes; third, discus is left slightly earlier, with Tan Jian throwing in a reasonable angle, Feng Bin, Lu Xiaoxin in a larger angle, and Sue Xinyue in a smaller angle. Feng bin has a higher height of release, followed by Lu Xiaoxin and Tan jian.

Further Characterization of 394-GHz Gyrotron FU CW GII with Additional PID Control System for 600-MHz DNP-SSNMR Spectroscopy

NASA Astrophysics Data System (ADS)

Ueda, Keisuke; Matsuki, Yoh; Fujiwara, Toshimichi; Tatematsu, Yoshinori; Ogawa, Isamu; Idehara, Toshitaka

2016-09-01

A 394-GHz gyrotron, FU CW GII, has been designed at the University of Fukui, Japan, for dynamic nuclear polarization (DNP)-enhanced solid-state nuclear magnetic resonance (SSNMR) experiments at 600-MHz 1H resonant frequency. After installation at the Institute for Protein Research (IPR), Osaka University, Japan, a PID feedback control system was equipped to regulate the electron gun heater current for stabilization of the electron beam current, which ultimately achieved stabilization of output power when operating in continuous wave (CW) mode. During exploration to further optimize operating conditions, a continuous tuning bandwidth of approximately 1 GHz was observed by varying the operating voltage at a fixed magnetic field. In the frequency range required for positive DNP enhancement, the output power was improved by increasing the magnetic field and the operating voltage from their initial operational settings. In addition, fine tuning of output frequency by varying the cavity cooling water temperature was demonstrated. These operating conditions and ancillary enhancements are expected to contribute to further enhancement of SSNMR signal.

mFOLFOX6 Plus Panitumumab Versus 5-FU/LV Plus Panitumumab After Six Cycles of Frontline mFOLFOX6 Plus Panitumumab: A Randomized Phase II Study of Patients With Unresectable or Advanced/Recurrent, RAS Wild-type Colorectal Carcinoma (SAPPHIRE)-Study Design and Rationale.

PubMed

Nagata, Naoki; Mishima, Hideyuki; Kurosawa, Shuichi; Oba, Koji; Sakamoto, Junichi

2017-06-01

In Japan, oxaliplatin (OXA)/5-fluorouracil (5-FU)/leucovorin (LV)-the mFOLFOX6 regimen-is the most frequently used first-line chemotherapy backbone for metastatic colorectal cancer. However, peripheral nerve disorders caused by OXA during mFOLFOX6 therapy can decrease patients' quality of life. OXA can be safely discontinued from a FOLFOX regimen after 6 cycles during first-line therapy. Also, for patients who discontinue OXA without having experienced peripheral nerve disorders, reintroducing OXA in the later stages of treatment could remain an option. The study is a phase II, multicenter, open-label, parallel-group, randomized, controlled exploratory study comparing the efficacy and safety of mFOLFOX6 plus panitumumab and 5-FU/LV plus panitumumab in patients with chemotherapy-naïve, unresectable, advanced or recurrent colorectal carcinoma of RAS wild-type (SAPPHIRE; ClinicalTrials.gov identifier, NCT02337946). Eligible patients will receive 6 cycles of mFOLFOX6 plus panitumumab combination therapy, followed by 1:1 randomization to either further treatment with mFOLFOX6 plus panitumumab or discontinuation of OXA and treatment with 5-FU/LV plus panitumumab. Up to 100 randomized patients will receive treatment for approximately 12 months or until any of the criteria for treatment discontinuation have been met. The primary endpoint is progression-free survival rate at 9 months after the day of randomization. The secondary endpoints are progression-free survival, overall survival, response rate, and interval to treatment failure. Safety will be evaluated according to the incidence and severity of adverse events, including the incidence of peripheral nerve and skin disorders. Additional endpoints will include maintenance of performance status, continuation of OXA in the mFOLFOX6 plus panitumumab group, and continuation of panitumumab in both groups. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

IDH1 R132H Mutation Enhances Cell Migration by Activating AKT-mTOR Signaling Pathway, but Sensitizes Cells to 5-FU Treatment as NADPH and GSH Are Reduced.

PubMed

Zhu, Huixia; Zhang, Ye; Chen, Jianfeng; Qiu, Jiangdong; Huang, Keting; Wu, Mindan; Xia, Chunlin

2017-01-01

Mutations of isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) gene were recently discovered in vast majority of World Health Organization (WHO) grade II/III gliomas. This study is to understand the effects of IDH1 R132H mutation in gliomagenesis and to develop new strategies to treat glioma with IDH1 R132H mutation. Over expression of IDH1 R132H in U87MG cells was done by transfecting cells with IDH1 R132H plasmid. MTT assay, scratch repair assay and western blot were performed to study effects of IDH1 R132H mutation on cell proliferation, migration, regulating AKT-mTOR signaling pathway and cell death respectively. NADP+/NADPH and GSH quantification assays were performed to evaluate effects of IDH1 R132H mutation on the production of antioxidant NADPH and GSH. We found that over expression of IDH1 R132H mutation decreased cell proliferation consistent with previous reports; however, it increased cell migration and enhanced AKT-mTOR signaling pathway activation. Mutations in isocitrate dehydrogenase (IDH) 1 also change the function of the enzymes and cause them to produce 2-hydroxyglutarate and not produce NADPH. We tested the level of NADPH and GSH and demonstrated that IDH1 R132H mutant stable cells had significantly low NADPH and GSH level compared to control or IDH1 wild type stable cells. The reduced antioxidants (NADPH and GSH) sensitized U87MG cells with IDH R132H mutant to 5-FU treatment. Our study highlights the important role of IHD1 R132H mutant in up- regulating AKT-mTOR signaling pathway and enhancing cell migration. Furthermore, we demonstrate that IDH1 R132H mutation affects cellular redox status and sensitizes gliomas cells with IDH1 R132H mutation to 5FU treatment.

[Isolation and characterization of petroleum catabolic broad-host-range plasmids from Shen-Fu wastewater irrigation zone].

PubMed

Wang, Ya-Fei; Wang, Ya-Fei; Li, Hui; Li, Xiao-Bin

2013-11-01

Based on triparental mating, we isolated a total of eight broad host range (BHR) petroleum hydrocarbon catabolic plasmids from the soils, sediments, and wastewater samples in the Shen-Fu irrigation zone. The antibiotic resistance of the plasmids was tested, and then, the plasmids were transferred to Escherichia coli EC100. The plasmids carrying no antibiotic resistance were tagged by miniTn5 transposon consisting of antibiotic resistant genes. The PCR-based incompatibility test revealed that the pS3-2C and pS4-6G belonged to Inc P group, the pS3-2G, pW22-3G, and pA15-7G belonged to Inc N group, the pS7-2G was identified as Inc W plasmid, and the pA23-1G and pA10-1C were placed into Inc Q group. By adopting the reported PCR amplification methods of petroleum hydrocarbon-degrading catabolic genes, the petroleum-degrading capability of these BHR plasmids were preliminarily analyzed. The plasmids pS3-2G, pS7-2G, pA23-1G, pW22-3G, and pA10-1C carried aromatic ring- hydroxylating dioxygenase gene phdA and toluene monooxygenase gene touA; the plasmid pA15-7G carried touA and toluene dioxygenase gene tod; the plasmid pS3-2C carried ben, phdA, and tod; whereas the pS4-6G only carried ben. The host range test showed that all the isolated plasmids except pS3-2C could be transferred and maintained stably in the representative strains Agrobacterium tumefaciens C58, Cupriavidus necator JMP228, and E. coli EC100 of the alpha-, beta-, and gamma-Proteobacteria, respectively.

Metabolomic analysis of anti-hypoxia and anti-anxiety effects of Fu Fang Jin Jing Oral Liquid.

PubMed

Liu, Xia; Zhu, Wei; Guan, Shuhong; Feng, Ruihong; Zhang, Hui; Liu, Qiuhong; Sun, Peng; Lin, Donghai; Zhang, Naixia; Shen, Jun

2013-01-01

Herba Rhodiolae is a traditional Chinese medicine used by the Tibetan people for treating hypoxia related diseases such as anxiety. Based on the previous work, we developed and patented an anti-anxiety herbal formula Fu Fang Jin Jing Oral Liquid (FJJOL) with Herba Rhodiolae as a chief ingredient. In this study, the anti-hypoxia and anti-anxiety effects of FJJOL in a high altitude forced-swimming mouse model with anxiety symptoms will be elucidated by NMR-based metabolomics. In our experiments, the mice were divided randomly into four groups as flatland group, high altitude saline-treated group, high altitude FJJOL-treated group, and high altitude diazepam-treated group. To cause anxiety effects and hypoxic defects, a combination use of oxygen level decreasing (hypobaric cabin) and oxygen consumption increasing (exhaustive swimming) were applied to mice. After a three-day experimental handling, aqueous metabolites of mouse brain tissues were extracted and then subjected to NMR analysis. The therapeutic effects of FJJOL on the hypobaric hypoxia mice with anxiety symptoms were verified. Upon hypoxic exposure, both energy metabolism defects and disorders of functional metabolites in brain tissues of mice were observed. PCA, PLS-DA and OPLS-DA scatter plots revealed a clear group clustering for metabolic profiles in the hypoxia versus normoxia samples. After a three-day treatment with FJJOL, significant rescue effects on energy metabolism were detected, and levels of ATP, fumarate, malate and lactate in brain tissues of hypoxic mice recovered. Meanwhile, FJJOL also up-regulated the neurotransmitter GABA, and the improvement of anxiety symptoms was highly related to this effect. FJJOL ameliorated hypobaric hypoxia effects by regulating energy metabolism, choline metabolism, and improving the symptoms of anxiety. The anti-anxiety therapeutic effects of FJJOL were comparable to the conventional anti-anxiety drug diazepam on the hypobaric hypoxia mice. FJJOL might serve as

IDH1 R132H Mutation Enhances Cell Migration by Activating AKT-mTOR Signaling Pathway, but Sensitizes Cells to 5-FU Treatment as NADPH and GSH Are Reduced

PubMed Central

Qiu, Jiangdong; Huang, Keting; Wu, Mindan; Xia, Chunlin

2017-01-01

Aim of study Mutations of isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) gene were recently discovered in vast majority of World Health Organization (WHO) grade II/III gliomas. This study is to understand the effects of IDH1 R132H mutation in gliomagenesis and to develop new strategies to treat glioma with IDH1 R132H mutation. Materials and methods Over expression of IDH1 R132H in U87MG cells was done by transfecting cells with IDH1 R132H plasmid. MTT assay, scratch repair assay and western blot were performed to study effects of IDH1 R132H mutation on cell proliferation, migration, regulating AKT-mTOR signaling pathway and cell death respectively. NADP+/NADPH and GSH quantification assays were performed to evaluate effects of IDH1 R132H mutation on the production of antioxidant NADPH and GSH. Results We found that over expression of IDH1 R132H mutation decreased cell proliferation consistent with previous reports; however, it increased cell migration and enhanced AKT-mTOR signaling pathway activation. Mutations in isocitrate dehydrogenase (IDH) 1 also change the function of the enzymes and cause them to produce 2-hydroxyglutarate and not produce NADPH. We tested the level of NADPH and GSH and demonstrated that IDH1 R132H mutant stable cells had significantly low NADPH and GSH level compared to control or IDH1 wild type stable cells. The reduced antioxidants (NADPH and GSH) sensitized U87MG cells with IDH R132H mutant to 5-FU treatment. Conclusion Our study highlights the important role of IHD1 R132H mutant in up- regulating AKT-mTOR signaling pathway and enhancing cell migration. Furthermore, we demonstrate that IDH1 R132H mutation affects cellular redox status and sensitizes gliomas cells with IDH1 R132H mutation to 5FU treatment. PMID:28052098

Emissions of particle-phase polycyclic aromatic hydrocarbons (PAHs) in the Fu Gui-shan Tunnel of Nanjing, China

NASA Astrophysics Data System (ADS)

Chen, Fei; Hu, Wei; Zhong, Qin

2013-04-01

Real-world vehicle emission factors for PM10 (particulate matter with aerodynamic diameter smaller than 10 μm) and particle-phase polycyclic aromatic hydrocarbons (PAHs) from mixed vehicles were quantified in the Fu Gui-shan Tunnel of Nanjing during summer and winter of 2010. Concentrations of PM10 and sixteen particle phase polycyclic aromatic hydrocarbons (PAHs) in the entrance and exit of the tunnel were studied. The results showed that the four most abundant particular phase polycyclic aromatic hydrocarbons (PAHs) of motor vehicle were benzo[ghi]perylene, benzo[k]fluoranthene, benz[a]anthracene and benzo[a]pyrene. The emission factors for PM10 and particle-phase PAHs were 687 mg veh- 1 km- 1 and 18.853 mg veh- 1 km- 1 in summer, 714 mg veh- 1 km- 1 and 20.374 mg veh- 1 km- 1 in winter. Higher particle-phase PAH emission factors were found to be associated with a high proportion of diesel-fueled vehicles (DV). The estimated PM10 emission factor of gasoline-fueled vehicles (GV) was 513 mg veh- 1 km- 1 and the value for DV was 914 mg veh- 1 km- 1, while EFDV of particulate PAH (31.290 mg veh- 1 km- 1) was nearly 4 times higher than EFGV (9.310 mg veh- 1 km- 1). The five highest emission factors of diesel-fueled vehicles (DV) were benzo[ghi]perylene, benzo[k]fluoranthene, Indeno[1,2,3-cd]pyrene, benz[a]anthracene and benzo[a]pyrene, which was similarly found in the gasoline-fueled vehicles (GV). The sum of these five emission factors accounted for ~ 69% of the total particle-phase PAH of DV and ~ 67% of GV.

Synergistic anti-tumor activity through combinational intratumoral injection of an in-situ injectable drug depot.

PubMed

Kim, Da Yeon; Kwon, Doo Yeon; Kwon, Jin Seon; Park, Ji Hoon; Park, Seung Hun; Oh, Hyun Ju; Kim, Jae Ho; Min, Byoung Hyun; Park, Kinam; Kim, Moon Suk

2016-04-01

Here, we describe combinational chemotherapy via intratumoral injection of doxorubicin (Dox) and 5-fluorouracil (Fu) to enhance the efficacy and reduce the toxicity of systemically administered Fu and Dox in cancer patients. As the key concept in this work, mixture formulations of Dox-loaded microcapsules (Dox-M) and Fu-loaded Pluronic(®) hydrogels (Fu-HP) or Fu-loaded diblock copolymer hydrogels (Fu-HC) have been employed as drug depots. The in vitro and in vivo drug depot was designed as a formulation of Dox-M dispersed inside an outer shell of Fu-HP or Fu-HC after injection. The Dox-M/Fu-HP and Dox-M/Fu-HC formulations are free flowing at room temperature, indicating injectability, and formed a structural gelatinous depot in vitro and in vivo at body temperature. The Fu-HP, Fu-HC, Dox-M/Fu-HP, Dox-M/Fu-HC, and Dox-M formulations were easily injected into tumor centers in mice using a needle. Dox-M/Fu-HC produced more significant inhibitory effects against tumor growth than that by Dox-M/Fu-HP, while Fu-HP, Fu-HC and Dox-M had the weakest inhibitory effects of the tested treatments. The in vivo study of Dox and Fu biodistribution showed that high Dox and Fu concentrations were maintained in the target tumor only, while distribution to normal tissues was not observed, indicating that Dox and Fu concentrations below their toxic plasma concentrations should not cause significant systemic toxicity. The Dox-M/Fu-HP and Dox-M/Fu-HC drug depots described in this work showed excellent performance as chemotherapeutic delivery systems. The results reported here indicate that intratumoral injection using combination chemotherapy with Dox-M/Fu-HP or Dox-M/Fu-HC could be of translational research by enhancing the synergistic inhibitory effects of Dox and Fu on tumor growth, while reducing their systemic toxicity in cancer patients. Copyright © 2016 Elsevier Ltd. All rights reserved.

YiQiFuMai Powder Injection Attenuates Ischemia/Reperfusion-Induced Myocardial Apoptosis Through AMPK Activation.

PubMed

Li, Fang; Zheng, Xianjie; Fan, Xiaoxue; Zhai, Kefeng; Tan, Yisha; Kou, Junping; Yu, Boyang

2016-12-01

The YiQiFuMai powder injection (YQFM), a traditional Chinese medicine (TCM) prescription re-developed based on the well-known TCM formula Sheng-maisan, showed a wide range of pharmacological activities in cardiovascular diseases in clinics. However, its role in protection against myocardial ischemia/reperfusion (MI/R) injury has not been elucidated. The present study not only evaluated the cardioprotective effect of YQFM from MI/R injury but also investigated the potential molecular mechanisms both in vivo and in vitro. The myocardium infarct size, production of lactate dehydrogenase (LDH), creatine kinase (CK), cardiac function, TUNEL staining, and caspase-3 activity were measured. Cell viability was determined, and cell apoptosis was measured by Hoechst 33342 staining and flow cytometry. Mitochondrial membrane potential (ΔΨm) was measured, and ATP content was quantified by bioluminescent assay. Expression of apoptosis-related proteins, including Caspase-3, Bcl-2, Bax, AMPKα, and phospho-AMPKα, was analyzed by western blotting. AMPKα siRNA transfection was also applied to the mechanism elucidation. YQFM at a concentration of 1.06 g/kg significantly reduced myocardium infarct size and the production of LDH, CK in serum, improved the cardiac function, and also produced a significant decrease of apoptotic index. Further, combined treatment with compound C partly attenuated the anti-apoptotic effect of YQFM. In addition, pretreatment with YQFM ranging from 25 to 400 μg/mL markedly improved cell viability and decreased LDH release. Moreover, YQFM inhibited H9c2 apoptosis, blocked the expression of caspase-3, and modulated Bcl-2 and Bax proteins, leading to an increased mitochondrial membrane potential and cellular ATP content. Mechanistically, YQFM activated AMP-activated protein kinase (AMPK) signaling pathways whereas pretreatment with AMPK inhibitor Compound C and application of transfection with AMPKα siRNA attenuated the anti-apoptotic effect of YQFM

The compound Chinese medicine "Kang Fu Ling" protects against high power microwave-induced myocardial injury.

PubMed

Zhang, Xueyan; Gao, Yabing; Dong, Ji; Wang, Shuiming; Yao, Binwei; Zhang, Jing; Hu, Shaohua; Xu, Xinping; Zuo, Hongyan; Wang, Lifeng; Zhou, Hongmei; Zhao, Li; Peng, Ruiyun

2014-01-01

The prevention and treatment of Microwave-caused cardiovascular injury remains elusive. This study investigated the cardiovascular protective effects of compound Chinese medicine "Kang Fu Ling" (KFL) against high power microwave (HPM)-induced myocardial injury and the role of the mitochondrial permeability transition pore (mPTP) opening in KFL protection. Male Wistar rats (100) were divided into 5 equal groups: no treatment, radiation only, or radiation followed by treatment with KFL at 0.75, 1.5, or 3 g/kg/day. Electrocardiography was used to Electrophysiological examination. Histological and ultrastructural changes in heart tissue and isolated mitochondria were observed by light microscope and electron microscopy. mPTP opening and mitochondrial membrane potential were detected by confocal laser scanning microscopy and fluorescence analysis. Connexin-43 (Cx-43) and endothelial nitric oxide synthase (eNOS) were detected by immunohistochemistry. The expression of voltage-dependent anion channel (VDAC) was detected by western blotting. At 7 days after radiation, rats without KFL treatment showed a significantly lower heart rate (P<0.01) than untreated controls and a J point shift. Myocyte swelling and rearrangement were evident. Mitochondria exhibited rupture, and decreased fluorescence intensity, suggesting opening of mPTP and a consequent reduction in mitochondrial membrane potential. After treatment with 1.5 g/kg/day KFL for 7 d, the heart rate increased significantly (P<0.01), and the J point shift was reduced flavorfully (P<0.05) compared to untreated, irradiated rats; myocytes and mitochondria were of normal morphology. The fluorescence intensities of dye-treated mitochondria were also increased, suggesting inhibition of mPTP opening and preservation of the mitochondrial membrane potential. The microwave-induced decrease of Cx-43 and VDAC protein expression was significantly reversed. Microwave radiation can cause electrophysiological, histological and

Pilot study of postoperative adjuvant chemoradiation for advanced gastric cancer: Adjuvant 5-FU/cisplatin and chemoradiation with capecitabine

PubMed Central

Lee, Hyung-Sik; Choi, Youngmin; Hur, Won-Joo; Kim, Hyo-Jin; Kwon, Hyuk-Chan; Kim, Sung-Hyun; Kim, Jae-Seok; Lee, Jong-Hoon; Jung, Ghap-Joong; Kim, Min-Chan

2006-01-01

AIM: To evaluate the efficacy and toxicity of postoperative chemoradiation using FP chemotherapy and oral capecitabine during radiation for advanced gastric cancer following curative resection. METHODS: Thirty-one patients who had underwent a potentially curative resection for Stage III and IV (M0) gastric cancer were enrolled. Therapy consists of one cycle of FP (continuous infusion of 5-FU 1000 mg/m2 on d 1 to 5 and cisplatin 60 mg/m2 on d 1) followed by 4500 cGy (180 cGy/d) with capecitabine (1650 mg/m2 daily throughout radiotherapy). Four wk after completion of the radiotherapy, patients received three additional cycles of FP every three wk. The median follow-up duration was 22.2 mo. RESULTS: The 3-year disease free and overall survival in this study were 82.7% and 83.4%, respectively. Four patients (12.9%) showed relapse during follow-up. Eight patients did not complete all planned adjuvant therapy. Grade 3/4 toxicities included neutropenia in 50.2%, anemia in 12.9%, thrombocytopenia in 3.2% and nausea/vomiting in 3.2%. Neither grade 3/4 hand foot syndrome nor treatment related febrile neutropenia or death were observed. CONCLUSION: These preliminary results suggest that this postoperative adjuvant chemoradiation regimen of FP before and after capecitabine and concurrent radiotherapy appears well tolerated and offers a comparable toxicity profile to the chemoradiation regimen utilized in INT-0116. This treatment modality allowed successful loco-regional control rate and 3-year overall survival. PMID:16489675

Wheat germ agglutinin-conjugated chitosan-Ca-alginate microparticles for local colon delivery of 5-FU: development and in vitro characterization.

PubMed

Glavas Dodov, M; Calis, S; Crcarevska, M S; Geskovski, N; Petrovska, V; Goracinova, K

2009-11-03

The aim of this work was to prepare lectin-conjugated chitosan-Ca-alginate microparticles (MPs) loaded with acid-resistant particles of 5-fluorouracil (5-FU) for efficient local treatment of colon cancer. MPs were prepared by a novel one-step spray-drying technique and after wheat germ agglutinin (WGA) conjugation, they were characterized for size, swelling behavior, surface charge, entrapment efficiency and in vitro drug release. Prepared particles were spherical, with 6.73 microg/mg of WGA conjugated onto their surface. The size and zeta potential increased after conjugation, from 6.6 to 14.7 microm and from 9.6 to 15.3 mV, while drug encapsulation was 75.6 and 72.8%, respectively after conjugation. The swelling behavior of beads was mainly determined by properties of the cross-linked chitosan-alginate network. In vitro drug release studies carried out in simulated in vivo conditions with respect to pH, confirmed the potential of the particles to release the drug in a controlled manner. Also, the drug release was not significantly affected by WGA conjugation. The retention of biorecognitive activity of WGA after covalent coupling to MPs was confirmed by haemagglutination test. Functionalized MPs showed excessive mucoadhesiveness in vitro, due to the positive surface charge, pH-dependent swelling of the matrix and lectin-sugar recognition.

A novel methodology for AV and VV delay optimization in CRT: results from a randomized pilot clinical trial.

PubMed

Di Molfetta, Arianna; Forleo, Giovanni B; Santini, Luca; Fresiello, Libera; Papavasileiou, Lida P; Magliano, Giulia; Sergi, Domenico; Capria, Ambrogio; Romeo, Francesco; Ferrari, Gianfranco

2013-09-01

The aim of this work was to determine whether the use of a newly developed methodology (Alg1) for AV and VV optimization improves cardiac resynchronization therapy (CRT) clinical and echocardiographic (ECHO) outcomes. In this single-center pilot clinical trial, 80 consecutive patients (79 % male; 70.1 ± 11.2 years) receiving CRT were randomly assigned to AV and VV optimization using Alg1 (group A) or standard commercial procedures (group B). Clinical status and ECHOs were analyzed at baseline (_0) , 3 (fu1), and 6 months (fu2) of follow-up evaluating left ventricular end systolic (LVESV) and end diastolic (LVEDV) volumes, ejection fraction (EF), Minnesota test, and 6-min walk test (6MWT). Alg1 is based on a cardiovascular model fed with patient data. Baseline characteristics did not differ significantly between groups. Group A had a better clinical outcome and reverse remodeling. Remodeling was calculated as the difference (Δ) between fu1 and _0 and between fu2 and fu1, respectively: [LVESV (ml): ΔA_fu1 = -55.3, ΔB_fu1 = -13.5, p_fu1 = 0.002; ΔA_fu2 = -22.8, ΔB_fu2 = 3.0, p_fu2 = 0.04], [LVEDV (ml): ΔA_fu1 = -61.9, ΔB_fu1 = -16.1, p_fu1 = 0.01; ΔA_fu2 = -30.4, ΔB_fu2 = 11.3, p_fu2 = 0.02]; Minnesota test: total (p_fu1 = 0.01; p_fu2 = 0.04), physical (p_fu1 = 0.01; p_fu2 = 0.03) and emotional scores (p_fu1 = 0.04; p_fu2 = 0.03) and in 6MWT (m) (p_fu2 = 0.008). No statistically significant difference was observed in QRS width. Compared with current standard of care, CRT optimization using Alg1 is associated with better outcomes, showing the power of a tailored CRT.

Development of theranostic pH-sensitive liposomal nanoparticle for early detection and treatment of colon cancer

NASA Astrophysics Data System (ADS)

Udofot, Ofonime Cosmas

Purpose: 5-Fluorouracil (5-FU) is a main drug used in the treatment of cancer alone or in combination with other anticancer drugs. 5-FU is associated with poor permeability and short membrane half-life (5-20 min), due to its rapid metabolism in the body. Therefore it has become necessary for the continuous administration of high doses of 5-FU to maintain the minimum therapeutic serum concentration, which gives rise to associated severe side effect, and ultimately lead to severe toxic effect. The aim of this study is to formulate 5-FU-loaded pH-sensitive liposomal nanoparticles (pHLNps-5-FU) and evaluate the 5-FU release characteristics and anticancer effect of pHLNps-5-FU both in vitro and in vivo. Methods: Particle size and zeta potential were determined using particle size analyzer. Release pattern of pHLNps-5-FU formulations was evaluated at 37oC at pH 3, 5, 6.5 and 7.4 while drug release kinetics of 5-FU from pHLNp3--5-FU formulation was determined at pH 3 and 7.4 at different time points (37oC). Cell viability and clonogenic studies were conducted to evaluate the effectiveness of pHLNps-5-FU on HCT-116 and HT-29 cell lines while cellular uptake of rhodamine labeled pHLNps-5-FU was determined by flow cytometry and confocal imaging. The biodistribution and pharmacokinetics parameters of the administered 5-FU and pHLNps-5-FU were compared in nude mice while the efficacy of 5-FU and pHLNps-5-FU were determined in subcutaneous models of HT-29 and HCT-116 mice. Results: The average size of the pHLNps-5-FU liposome was 200 +/- 9.8, 181.9 +/- 9.1 and 164.3 +/- 8.4 nm. In-vitro drug release of 5-FU from pHLNps-5-FU was highest at pH of 3.8 from the different pHLNps-5-FU was observed. Both cells treated with pHLNps-5-FU reduced their viability to 2--3 fold lower compared to that of 5-FU. Flow cytometry and confocal imaging confirmed higher uptake of rhodamine labeled pHLNps-5-FU on both cell lines. Drug release profile of the chosen pHLNp-5-FU was best in pH of 3 and

In situ delivery of thermosensitive gel-mediated 5-fluorouracil microemulsion for the treatment of colorectal cancer

PubMed Central

Wang, Lu-Lu; Huang, Shuai; Guo, Hui-Hui; Han, Yan-Xing; Zheng, Wen-Sheng; Jiang, Jian-Dong

2016-01-01

In situ administration of 5-fluorouracil (5FU) “thermosensitive” gel effectively reduced systemic side effects in treating colon rectal cancer; however, the penetration efficacy of the formulation was considerably low due to the poor lipid solubility of 5FU. The aim of this study was to develop thermosensitive gel-mediated 5FU water-in-oil microemulsion (TG-5FU-ME) for improving the infiltration of 5FU. An in vitro release test showed that TG-5FU-ME sustained the drug’s release up to 10 hours. TG-5FU-ME exhibited good stability, and the microemulsion entrapped did not show any change in morphology and 5FU content during the 4-month storage. Transportation test in the Caco-2 cell monolayer showed that TG-5FU-ME had a permeability 6.3 times higher than that of 5FU thermosensitive gel, and the intracellular uptake of 5FU increased by 5.4-fold compared to that of 5FU thermosensitive gel. In vivo tissue distribution analysis exhibited that the TG-5FU-ME group had drug levels in rectal tissue and mesenteric lymph nodes, which were significantly higher than those of 5FU thermosensitive gel group, with very low blood levels of 5FU in both groups. Furthermore, TG-5FU-ME was not associated with detectable morphological damage to the rectal tissue. Conclusively, TG-5FU-ME might be an efficient rectal delivery system to treat colorectal cancer. PMID:27660416

Inhibition of PI3K suppresses propagation of drug-tolerant cancer cell subpopulations enriched by 5-fluorouracil.

PubMed

Ishida, Kaoru; Ito, Chie; Ohmori, Yukimi; Kume, Kohei; Sato, Kei A; Koizumi, Yuka; Konta, Akari; Iwaya, Takeshi; Nukatsuka, Mamoru; Kobunai, Takashi; Takechi, Teiji; Nishizuka, Satoshi S

2017-05-23

Drug-tolerant cancer cell subpopulations are responsible for relapse after chemotherapy. By continuously exposing the gastric cancer cell line MKN45 to 5-FU for >100 passages, we established a 5-fluorouracil (5-FU)-tolerant line, MKN45/5FU. Orthotopic xenografts of MKN45/5FU cells in the stomach of nude mice revealed that these cells had a high potential to metastasize to sites such as the liver. Levels of phosphorylated phosphatidylinositide 3-kinase (PI3K) increased both in 5-FU-tolerant subpopulations according to the 5-FU dose, and in gastric submucosal orthotopic xenografts of MKN45/5FU cells. Sequential administration of 5-FU and a PI3K inhibitor, GDC-0941, targeted the downstream ribosomal S6 kinase phosphorylation to significantly suppress 5-FU-tolerant subpopulations and tumor propagation of orthotopic MKN45/5FU xenografts. These results suggest that administration of 5-FU followed by GDC-0941 may suppress disease relapse after 5-FU-based gastric cancer chemotherapy.

On-line monitoring the extract process of Fu-fang Shuanghua oral solution using near infrared spectroscopy and different PLS algorithms

NASA Astrophysics Data System (ADS)

Kang, Qian; Ru, Qingguo; Liu, Yan; Xu, Lingyan; Liu, Jia; Wang, Yifei; Zhang, Yewen; Li, Hui; Zhang, Qing; Wu, Qing

2016-01-01

An on-line near infrared (NIR) spectroscopy monitoring method with an appropriate multivariate calibration method was developed for the extraction process of Fu-fang Shuanghua oral solution (FSOS). On-line NIR spectra were collected through two fiber optic probes, which were designed to transmit NIR radiation by a 2 mm flange. Partial least squares (PLS), interval PLS (iPLS) and synergy interval PLS (siPLS) algorithms were used comparatively for building the calibration regression models. During the extraction process, the feasibility of NIR spectroscopy was employed to determine the concentrations of chlorogenic acid (CA) content, total phenolic acids contents (TPC), total flavonoids contents (TFC) and soluble solid contents (SSC). High performance liquid chromatography (HPLC), ultraviolet spectrophotometric method (UV) and loss on drying methods were employed as reference methods. Experiment results showed that the performance of siPLS model is the best compared with PLS and iPLS. The calibration models for AC, TPC, TFC and SSC had high values of determination coefficients of (R2) (0.9948, 0.9992, 0.9950 and 0.9832) and low root mean square error of cross validation (RMSECV) (0.0113, 0.0341, 0.1787 and 1.2158), which indicate a good correlation between reference values and NIR predicted values. The overall results show that the on line detection method could be feasible in real application and would be of great value for monitoring the mixed decoction process of FSOS and other Chinese patent medicines.

Metabolomic Analysis of Anti-Hypoxia and Anti-anxiety Effects of Fu Fang Jin Jing Oral Liquid

PubMed Central

Guan, Shuhong; Feng, Ruihong; Zhang, Hui; Liu, Qiuhong; Sun, Peng; Lin, Donghai; Zhang, Naixia; Shen, Jun

2013-01-01

Background Herba Rhodiolae is a traditional Chinese medicine used by the Tibetan people for treating hypoxia related diseases such as anxiety. Based on the previous work, we developed and patented an anti-anxiety herbal formula Fu Fang Jin Jing Oral Liquid (FJJOL) with Herba Rhodiolae as a chief ingredient. In this study, the anti-hypoxia and anti-anxiety effects of FJJOL in a high altitude forced-swimming mouse model with anxiety symptoms will be elucidated by NMR-based metabolomics. Methods In our experiments, the mice were divided randomly into four groups as flatland group, high altitude saline-treated group, high altitude FJJOL-treated group, and high altitude diazepam-treated group. To cause anxiety effects and hypoxic defects, a combination use of oxygen level decreasing (hypobaric cabin) and oxygen consumption increasing (exhaustive swimming) were applied to mice. After a three-day experimental handling, aqueous metabolites of mouse brain tissues were extracted and then subjected to NMR analysis. The therapeutic effects of FJJOL on the hypobaric hypoxia mice with anxiety symptoms were verified. Results Upon hypoxic exposure, both energy metabolism defects and disorders of functional metabolites in brain tissues of mice were observed. PCA, PLS-DA and OPLS-DA scatter plots revealed a clear group clustering for metabolic profiles in the hypoxia versus normoxia samples. After a three-day treatment with FJJOL, significant rescue effects on energy metabolism were detected, and levels of ATP, fumarate, malate and lactate in brain tissues of hypoxic mice recovered. Meanwhile, FJJOL also up-regulated the neurotransmitter GABA, and the improvement of anxiety symptoms was highly related to this effect. Conclusions FJJOL ameliorated hypobaric hypoxia effects by regulating energy metabolism, choline metabolism, and improving the symptoms of anxiety. The anti-anxiety therapeutic effects of FJJOL were comparable to the conventional anti-anxiety drug diazepam on the

The Compound Chinese Medicine “Kang Fu Ling” Protects against High Power Microwave-Induced Myocardial Injury

PubMed Central

Zhang, Xueyan; Gao, Yabing; Dong, Ji; Wang, Shuiming; Yao, Binwei; Zhang, Jing; Hu, Shaohua; Xu, Xinping; Zuo, Hongyan; Wang, Lifeng; Zhou, Hongmei; Zhao, Li; Peng, Ruiyun

2014-01-01

Background The prevention and treatment of Microwave-caused cardiovascular injury remains elusive. This study investigated the cardiovascular protective effects of compound Chinese medicine “Kang Fu Ling” (KFL) against high power microwave (HPM)-induced myocardial injury and the role of the mitochondrial permeability transition pore (mPTP) opening in KFL protection. Methods Male Wistar rats (100) were divided into 5 equal groups: no treatment, radiation only, or radiation followed by treatment with KFL at 0.75, 1.5, or 3 g/kg/day. Electrocardiography was used to Electrophysiological examination. Histological and ultrastructural changes in heart tissue and isolated mitochondria were observed by light microscope and electron microscopy. mPTP opening and mitochondrial membrane potential were detected by confocal laser scanning microscopy and fluorescence analysis. Connexin-43 (Cx-43) and endothelial nitric oxide synthase (eNOS) were detected by immunohistochemistry. The expression of voltage-dependent anion channel (VDAC) was detected by western blotting. Results At 7 days after radiation, rats without KFL treatment showed a significantly lower heart rate (P<0.01) than untreated controls and a J point shift. Myocyte swelling and rearrangement were evident. Mitochondria exhibited rupture, and decreased fluorescence intensity, suggesting opening of mPTP and a consequent reduction in mitochondrial membrane potential. After treatment with 1.5 g/kg/day KFL for 7 d, the heart rate increased significantly (P<0.01), and the J point shift was reduced flavorfully (P<0.05) compared to untreated, irradiated rats; myocytes and mitochondria were of normal morphology. The fluorescence intensities of dye-treated mitochondria were also increased, suggesting inhibition of mPTP opening and preservation of the mitochondrial membrane potential. The microwave-induced decrease of Cx-43 and VDAC protein expression was significantly reversed. Conclusion Microwave radiation can cause

Organochlorines and metals induce changes in the mitochondria-rich cells of fish gills: an integrative field study involving chemical, biochemical and morphological analyses.

PubMed

Fernandes, M N; Paulino, M G; Sakuragui, M M; Ramos, C A; Pereira, C D S; Sadauskas-Henrique, H

2013-01-15

Through integrating chemical, biochemical and morphological analyses, this study investigated the effects of multiple pollutants on the gill mitochondria-rich cells (MRCs) in two fish species, Astyanax fasciatus and Pimelodus maculatus, collected from five sites (FU10, FU20, FU30, FU40 and FU50) in the Furnas Hydroelectric Power Station reservoir. Water analyses revealed aluminum, iron and zinc as well as organochlorine (aldrin/dieldrin, endosulfan, heptachlor/heptachlor epoxide and metolachlor) contamination at all of the sites, with the exception of FU10. Copper, chrome, iron and zinc were detected in the gills of both species, and aldrin/dieldrin, endosulfan and heptachlor/heptachlor epoxide were detected in the gills of fish from all of the sites, with the exception of FU10. Fish collected at FU20, FU30 and FU50 exhibited numerous alterations in the surface architecture of their pavement cells and MRCs. The surface MRC density and MRC fractional area were lower in fish from FU20, FU30, FU40 and FU50 than in those from the reference site (FU10) in the winter, and some variability between the sites was observed in the summer. The organochlorine contamination at FU20 and FU50 was associated with variable changes in the MRCs and inhibition of Na(+)/K(+)-ATPase (NKA) activity, especially in P. maculatus. At FU30, the alterations in the MRCs were associated with the contaminants present, especially metals. A multivariate analysis demonstrated a positive association between the biological responses of both species and environmental contamination, indicating that under realistic conditions, a mixture of organochlorines and metals affected the MRCs by inhibiting NKA activity and inducing morphological changes, which may cause an ionic imbalance. Copyright © 2012 Elsevier B.V. All rights reserved.

[Textual research on Chen Ye and his Jia cang jing yan fang (Family-preserved Empirical Recipes) of the Song Dynasty].

PubMed

Zhang, Xuedan; Zhang, Ruqing; Chen, Dexing

2014-01-01

Chen Ye, an official of the Southern Song Dynasty, also known as Chen Rihua as his styled name, was born in Changle, Fuzhou in the reign of Shaoxing, and died during the reign of Duanping. He had been consecutively in the positions of Jiang shi lang (Court Gentleman for Ceremonial Service), Zhi zhou (Prefect) of Lingding, the Ti xing (Judicial Commissioner) of Guangdong, the Zong ling (Overseer-general) of Sichuan, Shan ding (Reviser), Shu lin and other positions in Tongzhou, Yuanzhou. His works included 1 volume of Gu ling xian sheng nian pu (Mr. Guling's Chronological Biography), 1 volume of Tan xie (On Humor), 1 volume of Shi hua (Poetry), 8 volumes of Jin yuan li shu (Jin Yuan's Smart Technique), 3 volumes of Yi jian zhi lei bian (Classified Compilation of Yijian's Annals), (Zeng guang) Suo sui lu (Augmented Records of Trivial Matters), 5 volumes of Jia cang jing yan fang (Family-preserved Empirical Recipes). He also compiled the 8-volume Yin jiang zhi (Yinjiang's Annals), published the 2-volume Jia cang ji yao fang (Collected Essential Recipes from Family Preservation), and other proses and poetry. Jia cang jing yan fang was a formulary compiled by Chen Ye, which was lost. Altogether 74 of its recipes were cited in Fu ren da quan liang fang (Complete Effective Prescriptions for Women's Diseases), Shou qin yang lao shu (A Book for Pursuing Seniors' Longevity and Healthcare), Pu ji fang (Prescriptions for Universal Relief) and Yong le da dian (Yongle Encyclopedia).

Novel 5-fluorouracil-resistant human esophageal squamous cell carcinoma cells with dihydropyrimidine dehydrogenase overexpression

PubMed Central

Kikuchi, Osamu; Ohashi, Shinya; Nakai, Yukie; Nakagawa, Shunsaku; Matsuoka, Kazuaki; Kobunai, Takashi; Takechi, Teiji; Amanuma, Yusuke; Yoshioka, Masahiro; Ida, Tomomi; Yamamoto, Yoshihiro; Okuno, Yasushi; Miyamoto, Shin’ichi; Nakagawa, Hiroshi; Matsubara, Kazuo; Chiba, Tsutomu; Muto, Manabu

2015-01-01

5-Fluorouracil (5-FU) is a key drug for the treatment of esophageal squamous cell carcinoma (ESCC); however, resistance to it remains a critical limitation to its clinical use. To clarify the mechanisms of 5-FU resistance of ESCC, we originally established 5-FU-resistant ESCC cells, TE-5R, by step-wise treatment with continuously increasing concentrations of 5-FU. The half maximal inhibitory concentration of 5-FU showed that TE-5R cells were 15.6-fold more resistant to 5-FU in comparison with parental TE-5 cells. TE-5R cells showed regional copy number amplification of chromosome 1p including the DPYD gene, as well as high mRNA and protein expressions of dihydropyrimidine dehydrogenase (DPD), an enzyme involved in 5-FU degradation. 5-FU treatment resulted in a significant decrease of the intracellular 5-FU concentration and increase of the concentration of α-fluoro-ureidopropionic acid (FUPA), a metabolite of 5-FU, in TE-5R compared with TE-5 cells in vitro. Conversely, gimeracil, a DPD inhibitor, markedly increased the intracellular 5-FU concentration, decreased the intracellular FUPA concentration, and attenuated 5-FU resistance of TE-5R cells. These results indicate that 5-FU resistance of TE-5R cells is due to the rapid degradation of 5-FU by DPD overexpression. The investigation of 5-FU-resistant ESCC with DPYD gene copy number amplification and consequent DPD overexpression may generate novel biological evidence to explore strategies against ESCC with 5-FU resistance. PMID:26396918

Impact of Martial Arts (Judo, Karate, and Kung Fu) on Bone Mineral Density Gains in Adolescents of Both Genders: 9-Month Follow-Up.

PubMed

Ito, Igor H; Kemper, Han C G; Agostinete, Ricardo R; Lynch, Kyle R; Christofaro, Diego G D; Ronque, Enio R; Fernandes, Rômulo A

2017-11-01

To compare bone mineral density (BMD) gains in adolescents of both genders stratified according to different martial art styles in a 9-month follow-up study. The longitudinal study consisted of 29 adolescents of both genders and age between 11 and 17 years stratified into a control group (not engaged in any sport) and 50 fighters (kung fu/karate, n = 29; judo, n = 21). All 79 subjects underwent anthropometric measures (weight, height, leg length, and height set) and dual-energy X-ray absorptiometry (BMD, in g/cm 2 ) at 2 moments, baseline and 9 months later. Maturity offset (age at peak height velocity), lean soft tissue, chronological age, and resistance training were treated as covariates. Male judoists presented higher gains in BMD-spine [0.098 g/cm 2 (95% confidence interval, 0.068-0.128)] than control group [0.040 g/cm 2 (95% confidence interval, 0.011-0.069)] (post hoc test with P = .030). There was no effect of martial art on BMD gains among girls. Independently of gender, in all multivariate models, lean soft tissue constituted the most relevant covariate. Judo practice in adolescents affected the bone accrual significantly after 9-month follow-up compared with controls, mainly in boys.

[Synthesis, characterization and antitumor activity of 5-fluorouracil-nicotinamide cocrystal].

PubMed

Min, W U; Xingang, Liu; Yu, Xue; Qi, Chen; Xiurong, H U; Jun, Zhou; Guping, Tang

2017-03-25

Objective: To synthesize 5-fluorouracil-nicotinamide (5-FU-NCT) cocrystal and to investigate its physicochemical and biological properties. Methods: The cocrystal of 5-Fu-NCT was prepared through the cooling technology. PXRD, NMR, FTIR and DSC were used to characterize the structure of 5-FU-NCT cocrystal. Solubility was measured by HPLC method. Drug resistant human liver cancer BEL-7402/5-FU cells were treated with 5-FU-NCT cocrystal, the inhibition effect was tested by MTT and HE staining, and cancer cell migration was determined by scratch test. Results: According to PXRD, NMR, FTIR and DSC results, the cocrystal of 5-Fu-NCT had been synthesized successfully. The characteristic diffraction peaks (2θ/°) of the cocrystal were 16.4, 20.4, 22.3, 27.9 and 30.1. The solubility of 5-FU-NCT was 13.5 g/L as measured by HPLC. The antitumor activity tests showed that 5-FU-NCT cocrystal enhanced anticancer effect of 5-FU, and the IC50 of 5-FU and 5-FU-NCT was 129.6 μg/mL and 42.6 μg/mL, respectively. Conclusion: 5-Fu-NCT cocrystal have been synthesized successfully through the cooling technology and it shows an enhanced anticancer effect in comparison to 5-FU on BEL-7402/5-FU cells.

Nitrate reductase-mediated early nitric oxide burst alleviates oxidative damage induced by aluminum through enhancement of antioxidant defenses in roots of wheat (Triticum aestivum).

PubMed

Sun, Chengliang; Lu, Lingli; Liu, Lijuan; Liu, Wenjing; Yu, Yan; Liu, Xiaoxia; Hu, Yan; Jin, Chongwei; Lin, Xianyong

2014-03-01

• Nitric oxide (NO) is an important signaling molecule involved in the physiological processes of plants. The role of NO release in the tolerance strategies of roots of wheat (Triticum aestivum) under aluminum (Al) stress was investigated using two genotypes with different Al resistances. • An early NO burst at 3 h was observed in the root tips of the Al-tolerant genotype Jian-864, whereas the Al-sensitive genotype Yang-5 showed no NO accumulation at 3 h but an extremely high NO concentration after 12 h. Stimulating NO production at 3 h in the root tips of Yang-5 with the NO donor relieved Al-induced root inhibition and callose production, as well as oxidative damage and ROS accumulation, while elimination of the early NO burst by NO scavenger aggravated root inhibition in Jian-864. • Synthesis of early NO in roots of Jian-864 was mediated through nitrate reductase (NR) but not through NO synthase. Elevated antioxidant enzyme activities were induced by Al stress in both wheat genotypes and significantly enhanced by NO donor, but suppressed by NO scavenger or NR inhibitor. • These results suggest that an NR-mediated early NO burst plays an important role in Al resistance of wheat through modulating enhanced antioxidant defense to adapt to Al stress. © 2013 The Authors. New Phytologist © 2013 New Phytologist Trust.

1D Nanostructures: Controlled Fabrication and Energy Applications

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hu, Michael Z.

2013-01-01

Jian Wei, Xuchun Song, Chunli Yang, and Michael Z. Hu, 1D Nanostructures: Controlled Fabrication and Energy Applications, Journal of Nanomaterials, published special issue (http://www.hindawi.com/journals/jnm/si/197254/) (2013).

5-fluorouracil Toxicity Mechanism Determination in Human Keratinocytes: in vitro Study on HaCaT Cell Line.

PubMed

Hartinger, Jan; Veselý, Pavel; Šíma, Martin; Netíková, Irena; Matoušková, Eva; Petruželka, Luboš

5-fluorouracil (5-FU) and capecitabine therapy is often accompanied by palmar-plantar erythrodysesthesia (PPE) which is manifestation of 5-FU toxicity in keratinocytes. The main mechanisms of 5-FU action are thymidylate synthase (TS) inhibition which can be abrogated by thymidine and strengthened by calciumfolinate (CF) and incorporation of fluorouridinetriphosphate into RNA which can be abrogated by uridine. For proper PPE treatment 5-FU mechanism of action in keratinocytes needs to be elucidated. We used the 5-FU toxicity modulators uridine, thymidine and CF to discover the mechanism of 5-FU action in human keratinocyte cell line HaCaT. To measure the cellular viability, we used MTT test and RTCA test. CF did not augment 5-FU toxicity and 5-FU toxicity was weakened by uridine. Therefore, the primary mechanism of 5-FU toxicity in keratinocytes is 5-FU incorporation into RNA. The uridine protective effect cannot fully develop in the presence of CF. Thymidine addition to 5-FU and uridine treated cells not only prevents the toxicity-augmenting CF effect but it also prolongs the 5-FU treated cells survival in comparison to uridine only. Therefore, it can be assumed that in the presence of uridine the 5-FU toxicity mechanism is switched from RNA incorporation to TS inhibition. Although particular 5-FU toxicity mechanisms were previously described in various cell types, this is the first time when various combinations of pyrimidine nucleosides and CF were used for 5-FU toxicity mechanism elucidation in human keratinocytes. We suggest that for PPE treatment ointment containing uridine and thymidine should be further clinically tested.

Mature Results of a Prospective Randomized Trial Comparing 5-Flourouracil with Leucovorin to 5-Flourouracil with Levamisole as Adjuvant Therapy of Stage II and III Colorectal Cancer- The Israel Cooperative Oncology Group (ICOG) Study

PubMed Central

Figer, Arie; Nissan, Aviram; Shani, Adi; Borovick, Riva; Stiener, Mariana; Baras, Mario; Freund, Herbert R.; Sulkes, Aaron; Stojadinovic, Alexander; Peretz, Tamar

2011-01-01

Objective: Survival benefit with adjuvant therapy was shown in patients with Stage III colorectal cancer (CRC). This study evaluates long-term (10-year) outcome in patients with CRC randomly assigned to adjuvant 5-Fluorouracil/Leucovorin (5FU+LV) or 5-FU/Levamisole (5FU+LEV). Methods: Between 1990 and 1995, 398 patients with curatively resected Stage II-III CRC were randomly assigned to adjuvant 5FU+LV or 5FU+LEV for 12 months. Results: No difference was evident in 10-year relapse-free or overall survival between study groups. Grade III toxicity was similar between groups; however, neurotoxicity was significantly greater with 5FU+LEV (p=0.02) and gastrointestinal toxicity with 5FU+LV (p=0.03). Female patients treated with 5FU+LEV had improved overall survival. Conclusions: Adjuvant treatment of CRC is still based on leucovorin modulated fluorouracil. The long-term follow-up results of this trial indicate that the adjuvant treatment of Stage II-III CRC with 5FU+LV or 5FU+LEV is equally effective. The finding of improved survival in female subjects treated with 5FU+LEV warrants further study to determine if Levamisole is a better modulator of 5-FU than Leucovorin in this patient subset. PMID:21475636

Dai-Huang-Fu-Zi-Tang Alleviates Intestinal Injury Associated with Severe Acute Pancreatitis by Regulating Mitochondrial Permeability Transition Pore of Intestinal Mucosa Epithelial Cells

PubMed Central

Kang, Xin; Liang, Zhengkai; Zhan, Libin; Song, Jianbo; Wang, Yi; Yang, Yilun; Fan, Zhiwei; Bai, Lizhi

2017-01-01

Objective The aim of the present study was to examine whether Dai-Huang-Fu-Zi-Tang (DHFZT) could regulate mitochondrial permeability transition pore (MPTP) of intestinal mucosa epithelial cells for alleviating intestinal injury associated with severe acute pancreatitis (SAP). Methods A total of 72 Sprague-Dawley rats were randomly divided into 3 groups (sham group, SAP group, and DHFZT group, n = 24 per group). The rats in each group were divided into 4 subgroups (n = 6 per subgroup) accordingly at 1, 3, 6, and 12 h after the operation. The contents of serum amylase, D-lactic acid, diamine oxidase activity, and degree of MPTP were measured by dry chemical method and enzyme-linked immunosorbent assay. The change of mitochondria of intestinal epithelial cells was observed by transmission electron microscopy. Results The present study showed that DHFZT inhibited the openness of MPTP at 3, 6, and 12 h after the operation. Meanwhile, it reduced the contents of serum D-lactic acid and activity of diamine oxidase activity and also drastically relieved histopathological manifestations and epithelial cells injury of intestine. Conclusion DHFZT alleviates intestinal injury associated SAP via reducing the openness of MPTP. In addition, DHFZT could also decrease the content of serum diamine oxidase activity and D-lactic acid after SAP. PMID:29403537

Bcl-XL small interfering RNA suppresses the proliferation of 5-fluorouracil-resistant human colon cancer cells.

PubMed

Zhu, Hongbo; Guo, Wei; Zhang, Lidong; Davis, John J; Teraishi, Fuminori; Wu, Shuhong; Cao, Xiaobo; Daniel, Jonathan; Smythe, W Roy; Fang, Bingliang

2005-03-01

5-Fluorouracil (5-FU) is commonly used to treat human colon cancers but resistance to this compound is frequently observed in clinics. To characterize mechanisms of resistance to 5-FU and to develop new strategies for overcoming it, we established two cell lines that were resistant to 5-FU but not other chemotherapeutic agents from parental 5-FU-sensitive cell lines. Western blot analysis revealed that these resistant cells overexpressed the proteins Bcl-XL, Bcl-Xs, and Bik, and further data showed that the cells were resistant to 5-FU-induced DNA damage and cell cycle disorder. However, in parental cells, enforced expression of Bcl-XL protein provided only limited protection from 5-FU-induced apoptosis and overexpression of Bcl-XL protein did not affect 5-FU-induced DNA damage or cell cycle changes; these findings suggested that overexpression of Bcl-XL protein was not the major contributor to 5-FU resistance in any of our cells lines. Even so, knockdown of Bcl-XL protein expression by Bcl-XL-specific small interfering RNA could inhibit proliferation more effectively in 5-FU-resistant cells than in 5-FU-sensitive cells, and the combination of Bcl-XL-specific small interfering RNA and 5-FU had additive effect on the inhibition of 5-FU-resistant cells. These results suggest that down-regulation of Bcl-XL protein expression might provide a new treatment strategy for human 5-FU-resistant colon cancer therapy.

Preliminary pharmacology of galactosylated chitosan/5-fluorouracil nanoparticles and its inhibition of hepatocellular carcinoma in mice

PubMed Central

Cheng, Mingrong; Liu, Zheng; Wan, Tao; He, Bing; Zha, Bingbing; Han, Jiang; Chen, Houxiang; Yang, Fengxiao; Li, Qing; Wang, Wei; Xu, Hongzhi; Ye, Tao

2012-01-01

Biodegradable polymer nanoparticle drug delivery systems are characterized by targeted drug delivery, improved pharmacokinetic and biodistribution, enhanced drug stability and lowered side effects; these drug delivery systems are widely used for delivery of cytotoxic agents. The galactosylated chitosan (GC)/5-fluorouracil (5-FU) nanoparticle is a nanomaterial made by coupling GC, a polymer known to have the advantages described above, and 5-FU. The GC/5-FU nanoparticle is a sustained release system, it was showed that the peak time, half-life time, mean residence time (MRT) and area of under curve (AUC) of GC/5-FU were longer or more than those of the 5-FU group, but the maximum concentration (Cmax) was lower. The distribution of GC/5-FU in vivo revealed the greatest accumulation in the hepatic cancer tissues, and the hepatic cell was the target of the nanoparticles. Toxicology research showed that the toxicity of GC-5-FU was lower than that of 5-FU in mice. In vivo experiments showed that GC/5-FU can significantly inhibit tumor growth in an orthotropic liver cancer mouse model. GC/5-FU treatment can significantly lower the tumor weight and increase the survival time of mice when compared with 5-FU treatment alone. Flow cytometry and the TUNEL assay revealed that compared with 5-FU, GC/5-FU caused higher rates of G0-G1 arrest and apoptosis in hepatic cancer cells. PMID:22954702

Polysaccharides from Tricholoma matsutake and Lentinus edodes enhance 5-fluorouracil-mediated H22 cell growth inhibition.

PubMed

Ren, Ming; Ye, Lingyan; Hao, Xiaoshi; Ren, Zhixing; Ren, Shuping; Xu, Kun; Li, Juan

2014-06-01

Few studies have investigated the effects produced by combinations of polysaccharides and chemotherapeutic drugs in cancer treatment. We hypothesized that a combination of polysaccharides (COP) from Lentinus edodes and Tricholoma matsutake would improve the efficacy of 5-fluorouracil (5-FU)-mediated inhibition of H22 cell growth. Mice were injected H22 cells and then treated with either 5-FU, polysaccharides from Tricholoma matsutake (PTM), polysaccharides from Lentinus edodes (PL), PTM+PL, 5-FU+PTM, 5-FU+ PL, or 5-FU + COP. The tumor weight and volume, and splenic CD4 + and CD8 + T cell frequencies, were determined. Additionally, splenic natural killer (NK) cell and cytotoxic T lymphocyte (CTL) activities were assessed and the serum levels of tumor necrosis factor-alpha (TNF-alpha), Interleukin-2 (IL-2), and Interferon-gamma (IFN-gamma) were measured. Compared with mice from the control, 5-FU, PL, PTM, PTM + PL, 5-FU + PL, and 5-FU + PTM groups, mice treated with 5-FU + COP showed: (a) significantly reduced tumor weight and volume (P < 0.05); (b) significantly higher serum levels of TNF-alpha, IL-2, and IFN-gamma (P < 0.05); (c) significantly increased CD4+ and CD8+ T cell frequencies in the spleen (P < 0.05); and (d) significantly increased splenic NK cell and CTL activities (P < 0.05). The tumor weight and volume in mice treated with 5-FU+PL or 5-FU+PTM were significantly reduced compared with mice treated with 5-FU alone (P < 0.05). Serum levels of TNF-alpha, IL-2, and IFN-gamma, frequencies of CD4 + and CD8+ T cells in the spleen, and splenic NK and CTL activities were also significantly increased in mice treated with 5-FU+PL or 5-FU+PTM compared with mice treated with 5-FU alone (P < 0.05). Polysaccharides from Lentinus edodes and Tricholoma matsutake could enhance the efficacy of 5-FU-mediated H22 cell growth inhibition.

Involvement of RhoGDI2 in the resistance of colon cancer cells to 5-fluorouracil.

PubMed

Zheng, Zhong; Li, Jianfang; He, Xiangyi; Chen, Xuehua; Yu, Beiqin; Ji, Jun; Zhang, Jianian; Wang, Tingfeng; Gu, Qinlong; Zhu, Zhenggang; Liu, Bingya

2010-01-01

The acquisition of resistance to 5-FU is one of the most prominent obstacles to successful chemotherapy, and the mechanisms underlying the resistance are not fully understood. The aim of this study is to identify novel mediators of 5-FU resistance in colon cancer cells. LoVo colon cancer cells were induced to 5-FU resistance in vitro. The global protein profiles between LoVo and its 5-FU resistant derivative cell line LoVo/5-FU were analyzed by two dimensional gel electrophoresis-based comparative proteomics. The identified proteins expression was confirmed by Western blot analysis. The cytotoxicity of 5-FU was measured in LoVo/5-FU after knockdown of RhoGDI2 (one of the identified protien). Three differentially expressed proteins were identified. RhoGDI2 and CapG were upregulated, whereas proapoptotic protein Maspin was down-regulated in LoVo/5-FU and validated by Western blotting. Furthermore, knockdown of RhoGDI2 expression by transfection with the RhoGDI2-specific siRNA significantly reduced the resistance to 5-FU in LoVo/5-FU (p < 0.05). These novel data suggest that these differentially expressed proteins may contribute to the development of 5-FU resistance in colon cancer cells.

An Inhalable Powder Formulation Based on Micro- and Nanoparticles Containing 5-Fluorouracil for the Treatment of Metastatic Melanoma

PubMed Central

Reolon, Luciano Antonio; Amaral-Machado, Lucas; Gremião, Maria Palmira Daflon; Guterres, Silvia S.

2018-01-01

Melanoma is the most aggressive and lethal type of skin cancer, with a poor prognosis because of the potential for metastatic spread. The aim was to develop innovative powder formulations for the treatment of metastatic melanoma based on micro- and nanocarriers containing 5-fluorouracil (5FU) for pulmonary administration, aiming at local and systemic action. Therefore, two innovative inhalable powder formulations were produced by spray-drying using chondroitin sulfate as a structuring polymer: (a) 5FU nanoparticles obtained by piezoelectric atomization (5FU-NS) and (b) 5FU microparticles of the mucoadhesive agent Methocel™ F4M for sustained release produced by conventional spray drying (5FU-MS). The physicochemical and aerodynamic were evaluated in vitro for both systems, proving to be attractive for pulmonary delivery. The theoretical aerodynamic diameters obtained were 0.322 ± 0.07 µm (5FU-NS) and 1.138 ± 0.54 µm (5FU-MS). The fraction of respirable particles (FR%) were 76.84 ± 0.07% (5FU-NS) and 55.01 ± 2.91% (5FU-MS). The in vitro mucoadhesive properties exhibited significant adhesion efficiency in the presence of Methocel™ F4M. 5FU-MS and 5FU-NS were tested for their cytotoxic action on melanoma cancer cells (A2058 and A375) and both showed a cytotoxic effect similar to 5FU pure at concentrations of 4.3 and 1.7-fold lower, respectively. PMID:29385692

Argonne HEP Lunch Seminars

Science.gov Websites

reactor neutrino experiment July 29, 2008 August 5, 2008 Adam Clark (Rockhurst University) and Teng Jian August 12, 2008 Peter de Maagt THz Technology August 19, 2008 Razmick Mirzoyan Recent Developments on Low

Pegylated Liposomal Irinotecan Hydrochloride Trihydrate for Treating Pancreatic Cancer After Gemcitabine: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

PubMed

Fleeman, Nigel; Abdulla, Ahmed; Bagust, Adrian; Beale, Sophie; Richardson, Marty; Stainthorpe, Angela; Boland, Angela; Kotas, Eleanor; McEntee, Joanne; Palmer, Daniel

2018-03-01

The National Institute for Health and Care Excellence (NICE) invited the manufacturer (Shire Pharmaceuticals) of pegylated liposomal irinotecan hydrochloride trihydrate (liposomal irinotecan) to submit clinical and cost-effectiveness evidence for its use in combination with 5-fluorouracil (5-FU) and folic acid/leucovorin (LV) for treating patients with pancreatic cancer following prior treatment with gemcitabine as part of the institute's Single Technology Appraisal process. The Liverpool Reviews and Implementation Group at the University of Liverpool was commissioned to act as the Evidence Review Group (ERG). This article presents a summary of the company's evidence, the ERG review and the resulting NICE guidance (TA440), issued on 26 April 2017. Clinical evidence for liposomal irinotecan + 5-FU/LV versus 5-FU/LV was derived from 236 patients with metastatic pancreatic cancer in the multinational, open-label, randomised controlled NAPOLI-1 trial. Results from analyses of progression-free survival and overall survival showed statistically significant improvements for patients treated with liposomal irinotecan + 5-FU/LV compared with those treated with 5-FU/LV. However, 5-FU/LV alone is rarely used in National Health Service clinical practice for patients with metastatic pancreatic cancer previously treated with gemcitabine. The company, ERG and Appraisal Committee (AC) all agreed that oxaliplatin + 5-FU/LV is the most commonly used treatment. Oxaliplatin + 5-FU/LV was compared with 5-FU/LV in two trials identified by the company. However, the company and the ERG both considered attempts to compare the efficacy of liposomal irinotecan + 5-FU/LV with oxaliplatin + 5-FU/LV to be methodologically flawed; not only was there heterogeneity between trials and their populations but also the proportional hazards assumption required to conduct a robust indirect treatment comparison (ITC) was violated. Nonetheless, data derived from an ITC were used to inform the

75 FR 17743 - Ocean Transportation Intermediary License Applicants

Federal Register 2010, 2011, 2012, 2013, 2014

2010-04-07

..., Managing Member. Integres Global Logistics, Inc., 10995 Gold Center Drive, Suite 120, Rancho Cordova, CA..., DC 20573. Non-Vessel-Operating Common Carrier--Ocean Transportation Intermediary: HPK Logistics (USA... (Qualifying Individual) Jian Sun, President. Cargo Logistics International, LLC, 8761 Dorchester Road, Suite...

Herb-drug pharmacokinetic interaction of a traditional chinese medicine jia-wei-xiao-yao-san with 5-Fluorouracil in the blood and brain of rat using microdialysis.

PubMed

Chiang, Meng-Hsuan; Chang, Li-Wen; Wang, Ju-Wen; Lin, Lie-Chwen; Tsai, Tung-Hu

2015-01-01

According to a survey from the National Health Insurance Research Database (NHIRD), Jia-Wei-Xiao-Yao-San (JWXYS) is the most popular Chinese medicine for cancer patients in Taiwan. 5-Fluorouracil (5-FU) is a general anticancer drug for the chemotherapy. To investigate the herb-drug interaction of JWXYS on pharmacokinetics of 5-FU, a microdialysis technique coupled with a high-performance liquid chromatography system was used to monitor 5-FU in rat blood and brain. Rats were divided into four parallel groups, one of which was treated with 5-FU (100 mg/kg, i.v.) alone and the remaining three groups were pretreated with a different dose of JWXYS (600, 1200, or 2400 mg/kg/day for 5 consecutive days) followed by a combination with 5-FU. This study demonstrates that 5-FU with JWXYS (600 mg/kg/day or 1200 mg/kg/day) has no significant effect on the pharmacokinetics of 5-FU in the blood and brain. However, JWXYS (2400 mg/kg/day) coadministered with 5-FU extends the elimination half-life and increases the volume of distribution of 5-FU in the blood. The elimination half-life of 5-FU in the brain for the pretreatment group with 2400 mg/kg/day of JWXYS is significantly longer than that for the group treated with 5-FU alone and also reduces the clearance. This study provides practical dosage information for clinical practice and proves the safety of 5-FU coadministered with JWXYS.

Herb-Drug Pharmacokinetic Interaction of a Traditional Chinese Medicine Jia-Wei-Xiao-Yao-San with 5-Fluorouracil in the Blood and Brain of Rat Using Microdialysis

PubMed Central

Chiang, Meng-Hsuan; Chang, Li-Wen; Wang, Ju-Wen; Lin, Lie-Chwen; Tsai, Tung-Hu

2015-01-01

According to a survey from the National Health Insurance Research Database (NHIRD), Jia-Wei-Xiao-Yao-San (JWXYS) is the most popular Chinese medicine for cancer patients in Taiwan. 5-Fluorouracil (5-FU) is a general anticancer drug for the chemotherapy. To investigate the herb-drug interaction of JWXYS on pharmacokinetics of 5-FU, a microdialysis technique coupled with a high-performance liquid chromatography system was used to monitor 5-FU in rat blood and brain. Rats were divided into four parallel groups, one of which was treated with 5-FU (100 mg/kg, i.v.) alone and the remaining three groups were pretreated with a different dose of JWXYS (600, 1200, or 2400 mg/kg/day for 5 consecutive days) followed by a combination with 5-FU. This study demonstrates that 5-FU with JWXYS (600 mg/kg/day or 1200 mg/kg/day) has no significant effect on the pharmacokinetics of 5-FU in the blood and brain. However, JWXYS (2400 mg/kg/day) coadministered with 5-FU extends the elimination half-life and increases the volume of distribution of 5-FU in the blood. The elimination half-life of 5-FU in the brain for the pretreatment group with 2400 mg/kg/day of JWXYS is significantly longer than that for the group treated with 5-FU alone and also reduces the clearance. This study provides practical dosage information for clinical practice and proves the safety of 5-FU coadministered with JWXYS. PMID:25861367

Quantum kung fu

NASA Astrophysics Data System (ADS)

Flicker, Felix

2014-07-01

If someone puts you in an armlock, what should you do? If you happen to be a martial artist well-practised in the art of joint manipulation, or chin na, you will know the answer already: there is one simple move that will allow you to turn the tables on your aggressor, leaving them on the wrong end of a throw.

Dietary Quercetin Reduces Chemotherapy-Induced Fatigue in Mice

PubMed Central

Mahoney, Sara E.; Davis, J. Mark; Murphy, E. Angela; McClellan, Jamie L.; Pena, Marjory M.

2014-01-01

Purpose While fatigue is the most commonly reported symptom of chemotherapy, there are currently no effective treatments for chemotherapy-induced fatigue (CIF). We used a mouse model to examine the benefits of quercetin on CIF as measured by voluntary wheel running activity and sought to determine whether quercetin may be associated with a decrease in inflammation and/or anemia. Methods Mice were assigned to 1 of 4 groups: placebo-vehicle (Plac-PBS), placebo-5-fluorouracil (Plac-5FU), quercetin-vehicle (Quer-PBS), or quercetin-5-fluorouracil (Quer-5FU). All mice were given a daily injection of either 60 mg/kg of 5-FU or phosphate buffered saline (PBS) for 5 days. Quercetin (0.02%) treatment was administered in the food 3 days prior to 5-FU administration and for the duration of the experiment (ie, days −2 to 14). A second group of mice was sacrificed at 5 and 14 days post initial injection for assessment of monocyte chemoattractant protein-1 (MCP-1) and anemia. Results Voluntary wheel running was reduced in both the Plac-5FU and Quer-5FU groups following 5-FU injection (P < .05). However, the Quer-5FU group recovered to baseline levels by approximately day 7, whereas the Plac-5FU group remained suppressed. MCP-1 was significantly elevated at 14 days in Plac-5FU (P < .001), but no changes were seen with Quer-5FU. Treatment with 5-FU resulted in anemia at both 5 days and 14 days; however, quercetin blocked this effect at 14 days (P < .001). Conclusion These results demonstrate the beneficial effect of quercetin on improving recovery of voluntary physical activity following 5-FU treatment, which may be linked to a decrease in inflammation and anemia. PMID:24626097

PLGA nanoparticles for the oral delivery of 5-Fluorouracil using high pressure homogenization-emulsification as the preparation method and in vitro/in vivo studies.

PubMed

Li, XueMing; Xu, YuanLong; Chen, GuoGuang; Wei, Ping; Ping, QiNeng

2008-01-01

The objective of the present study was to incorporate the hydrophilic anti-cancer drug 5-Fluorouracil(5-FU) into poly(lactide-co-glycolide) (PLGA) nanoparticles(NP) to improve the oral bioavailability. Owing to the high solubility of 5-FU in basic water, the water-in-oil-in-water (w/o/w) emulsification process has been chosen as one of the most appropriate method for the encapsulation of 5-FU, and the ammonia solution was used as the inner aqueous phase solvent to increase the solubility of 5-FU. In order to reach submicron size as well as increasing the grade of monodispersity compared to previous preparation techniques, we prepared 5-FU loaded PLGA-NP by a high-pressure emulsification-solvent evaporation process. The PLGA-NPs were characterized with respect to their morphology, particle size, size distribution, 5-FU encapsulation efficiency, in vitro and in vivo studies in rats. In vitro release of 5-FU from nanoparticles appeared to have two components with an initial rapid release due to the surface associated drug and followed by a slower exponential release of 5-FU, which was dissolved in the core. The in vivo research was studied in male Sprague-Dawley rats after an oral 5-FU dose of 45 mg/kg. Single oral administration of 5-FU loaded PLGA-NP to rats produced bioavailability, which was statistically higher than 5-FU solution as negative control. And the MRT (mean residence time) of 5-FU loaded PLGA-NP was significantly (P < 0.05) modified. Thus, it is possible to design a controlled drug delivery system for oral 5-FU delivery, improving therapy efficiency by possible reduction of time intervals between peroral administrations and reduction of local gastrointestinal side effects.

Perceived family and peer invalidation as predictors of adolescent suicidal behaviors and self-mutilation.

PubMed

Yen, Shirley; Kuehn, Kevin; Tezanos, Katherine; Weinstock, Lauren M; Solomon, Joel; Spirito, Anthony

2015-03-01

The present study investigates the longitudinal relationship between perceived family and peer invalidation and adolescent suicidal events (SE) and self-mutilation (SM) in a 6 month follow-up (f/u) study of adolescents admitted to an inpatient psychiatric unit for suicide risk. Adolescents (n=119) and their parent(s) were administered interviews and self-report assessments at baseline and at a 6 month f/u, with 99 (83%) completing both assessments. The Adolescent Longitudinal Interval Follow-Up Evaluation (A-LIFE) was modified to provide weekly ratings (baseline and each week of f/u) for perceived family and peer invalidation. Regression analyses examined whether: 1) Prospectively rated perceived family and peer invalidation at baseline predicted SE and SM during f/u; and 2) chronicity of perceived invalidation operationalized as proportion of weeks at moderate to high invalidation during f/u was associated with SE and SM during f/u. Multiple regression analyses, controlling for previously identified covariates, revealed that perceived family invalidation predicted SE over f/u for boys only and perceived peer invalidation predicted SM over f/u in the overall sample. This was the case for both baseline and f/u ratings of perceived invalidation. Our results demonstrate the adverse impact of perceived family and peer invalidation. Specifically, boys who experienced high perceived family invalidation were more likely to have an SE over f/u. Both boys and girls who experienced high perceived peer invalidation were more likely to engage in SM over f/u.

[Evaluation of intraarterial infusion chemotherapy for liver metastasis from gastric cancer FEM: combination therapy of 5-FU, epirubicin and MMC].

PubMed

Takada, Joji; Katsuki, Yoshio; Hamada, Hiromi; Tsuji, Yasushige

2003-10-01

We evaluated the effectiveness of FEM (5-FU, epirubicin, MMC) therapy. Data for 111 patients with liver metastasis from gastric cancer were collected from January 1977, until June 2003 (synchronous: 74 cases, asynchronous: 37 cases). Thirty patients were H1, 20 were H2 and 61 were classified as H3. The patients were divided into the following groups: Group A: Resection of the primary lesion and hepatic resection (n = 10), Group A1: Hepatic resection only (5 cases), Group A2: Hepatic resection and intraarterial infusion (5 cases). Group B: Resection of the primary lesion (n = 67), Group B1: Resection of the primary lesion only (46 cases), Group B2: Intraarterial infusion (21 cases). In Groups A2 and B2, FEM therapy was applied to A2a (4 cases) and B2a (8 cases). Non-FEM therapy was applied to A2b (1 case) and B2b (13 cases). Group C consisted of 34 cases in which resection of the primary lesion was not undertaken. Survival rates were then compared. 1-year survival rates and 50% survival period for each group were as follows: Group A: 33%, 5.9 months; Group B: 22%. 4.8 months; and Group C: 6%, 3.9 months, respectively. One case from Group A2a and 2 cases from Group B2a have survived for 3 years or longer. 1) We treated 3 patients with liver metastasis from gastric cancer who survived for 3 years or longer. 2) Resection of the primary lesion along with hepatic intraarterial infusion therapy (in addition to hepatic resection), especially in combination with FEM therapy, provided an extended length of survival.

The protective effects of naringin against 5-fluorouracil-induced hepatotoxicity and nephrotoxicity in rats.

PubMed

Gelen, Volkan; Şengül, Emin; Yıldırım, Serkan; Atila, Gözde

2018-04-01

5-fluorouracil-induced (5-FU), an anticarcinogenic agent, is reported to have side-effects that include hepatotoxicity and nephrotoxicity. The study objective was to investigate the protective effects of naringin on 5-FU-induced hepatotoxicity and nephrotoxicity. Thirty rodents were assigned to three groups. The control group received 1 ml of intragastric distilled water for 14 days. The 5-FU group received 1 ml of distilled water for 14 days as a placebo. On day 9, this same group received a 20 mg/kg dose of 5-FU administered intraperitoneally(IP) for a further five days. The naringin+5-FU group received a 100 mg/kg dose of naringin (IP) for 14 days. On day 9, 20 mg/kg of 5-FU was administered (IP) to this group for a further five days. On day 15, the rats were decapitated, and blood and renal and hepatic tissues were taken. It was determined that serum creatinine, BUN, AST, ALT, ALP, and LDH levels, as well as cytokine levels in the liver and kidney tissues were significantly elevated in the 5-FU group, compared to the control group. The comparative values were similar in the control and naringin+5-FU groups. When the liver tissue was examined histopathologically, in the control group it was found to be normal in structure. However, necrosis was observed in the hepatocytes of the pericentric region in the 5-FU group. 8-OHdG cell density was significantly elevated in the 5-FU group, compared to the control and naringin+5-FU groups. Naringin was observed to have a protective effect on 5-FU-induced liver and kidney damage.

Estimation of the effect of food on the disposition of oral 5-fluorouracil in combination with eniluracil.

PubMed

Shepard, Dale R; Mani, Sridhar; Kastrissios, Helen; Learned-Coughlin, Susan; Smith, Deborah; Ertel, Phillip; Magnum, Steve; Janisch, Linda; Fleming, Gini F; Schilsky, Richard L; Ratain, Mark J

2002-05-01

To determine the effect of food on the pharmacokinetics of 5-fluoruracil (5-FU) taken orally with eniluracil and to compare the performance of different pharmacokinetic analysis methods in the detection a potential food-drug interaction. In a randomized, open-label, two-way crossover study, 12 patients received eniluracil (50 mg, orally) on days 1 and 2 and 5-FU (20 mg/m(2), orally) on day 2 following either a 2-h fast or 20 min after a standard meal. Treatments were separated by 7 days. Timed blood samples were collected during the first two treatment periods and 5-FU concentrations determined by GC/MS. Data were analyzed and pharmacokinetic parameter estimates were obtained using a noncompartmental, two-stage and population analysis methods. In fasted individuals, the clearance/bioavailability of 5-FU was estimated to be 5.6 l/h. The mean absorption lag-time was 0.24 h and was followed by rapid absorption of 5-FU. Administration of 5-FU and eniluracil with food resulted in a decrease in the 5-FU absorption rate constant by 90%. As a result, the peak plasma concentration (C(max)) of 5-FU was decreased by 21% and the time to C(max) was increased 2.9-fold. Clearance of 5-FU, relative bioavailability, and area under the plasma concentration vs time curve (AUC) remained unchanged with coadministration of food. Similar results were obtained using all three data analysis methods. Administration of food with oral 5-FU and eniluracil slowed absorption of 5-FU and decreased 5-FU C(max), but did not effect AUC. Further investigation of the incorporation of population pharmacokinetic approaches in food effect studies is warranted.

[Evaluation of intra-arterial infusion chemotherapy for liver metastasis from gastric cancer FEM--combination therapy of 5 FU, Epirubicin and MMC].

PubMed

Takada, Joji; Katsuki, Yoshio; Hamada, Hiromi; Tsuji, Yasushige

2002-11-01

We evaluated the effectiveness of FEM (5-FU, Epirubicin, MMC) therapy. One hundred ten cases of liver metastasis from gastric cancer were collected from January, 1977 until June, 2001 (synchronous: 74 cases, asynchronous: 36 cases). Twenty-nine cases were H1, 20 cases were H2 and 61 cases were H3. The patients were divided into the following groups: Group A: Resection of the primary lesion and hepatic resection (n = 9); Group A1: Hepatic resection only (5 cases), Group A2: Hepatic resection and intra-arterial infusion (4 cases). Group B: Resection of the primary lesion (n = 67); Group B1: Resection of the primary lesion only (46 cases), Group B2: Intra-arterial infusion (21 cases). In Groups A2 and B2, FEM therapy was applied to A2a (3 cases) and B2a (8 cases). Non-FEM therapy was applied to A2b (1 case) and B2b (13 cases). Group C consisted of 34 cases in which resection of the primary lesion was not undertaken. Survival rates were then compared. One-year survival rates and 50% survival period for each group were as follows: Group A: 33%, 5.9 months; Group B: 22%, 4.8 months; and Group C: 6%, 3.9 months, respectively. Five patients from Groups A2a and B2a survived for one year or longer. 1. The prognosis with liver metastasis from gastric cancer, even with a number of therapies, is not promising. 2. Resection of the primary lesion along with hepatic intra-arterial infusion therapy (in addition to hepatic resection), especially in combination with FEM therapy, provided an extended survival.

Effect of Chinese traditional compound, Gan-fu-kang, on CCl(4)-induced liver fibrosis in rats and its probable molecular mechanisms.

PubMed

Xu, Ting-Ting; Jiang, Miao-Na; Li, Cong; Che, Ying; Jia, Yu-Jie

2007-03-01

To explore the antifibrotic effect of traditional Chinese medicine compound Gan-fu-kang (GFK) on CCl(4)-induced liver fibrosis in rats and its probable mechanisms. The effects of GFK on CCl(4)-induced liver fibrosis were tested in rats. The liver histopathology was examined by light microscope, polaring microscope and electron microscope. The activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were assayed and the content of albumin (ALB) and hydroxyproline in the liver was measured. The expression of transforming growth factor-beta(1) (TGF-beta(1)) and laminin (LN) was determined by immunohistochemistry. Semi-quantitive computation of collagen types I and III and laminin was done. The expression of MMP-2 and TIMP-1 was assayed by reverse transcription polymerase chain reaction (RT-PCR). Upon pathological examination, GFK treatment had significantly reversed liver fibrosis. Hepatic extracellular matrix (ECM) deposition was significantly reduced, as evidenced by the reduction of the content of hydroxyproline, collagen types I and III, and laminin. Hepatic function was improved by GFK treatment, as evidenced by the increase of plasma ALB and A/G, and by the decrease of serum ALT and AST. TGF-beta(1) in liver was significantly reduced. A significant expression of MMP-2 and TIMP-1 mRNA in liver were downregulated after GFK treatment. The traditional Chinese medicine compound recipe GFK has an antifibrotic effect on CCl(4)-induced liver fibrosis in rats, which improves hepatic function and lessens the deposition of collagen in the liver. The probable antifibrotic mechanisms were: inhibiting the expression of TGF-beta(1) and decreasing expressions of MMP-2 and TIMP-1.

Evidence that tRNA modifying enzymes are important in vivo targets for 5-fluorouracil in yeast

PubMed Central

Gustavsson, Marie; Ronne, Hans

2008-01-01

We have screened a collection of haploid yeast knockout strains for increased sensitivity to 5-fluorouracil (5-FU). A total of 138 5-FU sensitive strains were found. Mutants affecting rRNA and tRNA maturation were particularly sensitive to 5-FU, with the tRNA methylation mutant trm10 being the most sensitive mutant. This is intriguing since trm10, like many other tRNA modification mutants, lacks a phenotype under normal conditions. However, double mutants for nonessential tRNA modification enzymes are frequently temperature sensitive, due to destabilization of hypomodified tRNAs. We therefore tested if the sensitivity of our mutants to 5-FU is affected by the temperature. We found that the cytotoxic effect of 5-FU is strongly enhanced at 38°C for tRNA modification mutants. Furthermore, tRNA modification mutants show similar synthetic interactions for temperature sensitivity and sensitivity to 5-FU. A model is proposed for how 5-FU kills these mutants by reducing the number of tRNA modifications, thus destabilizing tRNA. Finally, we found that also wild-type cells are temperature sensitive at higher concentrations of 5-FU. This suggests that tRNA destabilization contributes to 5-FU cytotoxicity in wild-type cells and provides a possible explanation why hyperthermia can enhance the effect of 5-FU in cancer therapy. PMID:18314501

Development of sulfadiazine-decorated PLGA nanoparticles loaded with 5-fluorouracil and cell viability.

PubMed

Guimarães, Pedro Pires Goulart; Oliveira, Sheila Rodrigues; de Castro Rodrigues, Gabrielle; Gontijo, Savio Morato Lacerda; Lula, Ivana Silva; Cortés, Maria Esperanza; Denadai, Ângelo Márcio Leite; Sinisterra, Rubén Dario

2015-01-08

The aim of this work was to synthesize sulfadiazine-poly(lactide-co-glycolide) (SUL-PLGA) nanoparticles (NPs) for the efficient delivery of 5-fluorouracil to cancer cells. The SUL-PLGA conjugation was assessed using FTIR, 1H-NMR, 13C-NMR, elemental analysis and TG and DTA analysis. The SUL-PLGA NPs were characterized using transmission and scanning electron microscopy and dynamic light scattering. Additionally, the zeta potential, drug content, and in vitro 5-FU release were evaluated. We found that for the SUL-PLGA NPs, Dh = 114.0 nm, ZP = -32.1 mV and the encapsulation efficiency was 49%. The 5-FU was released for up to 7 days from the NPs. Cytotoxicity evaluations of 5-FU-loaded NPs (5-FU-SUL-PLGA and 5-FU-PLGA) on two cancer cell lines (Caco-2, A431) and two normal cell lines (fibroblast, osteoblast) were compared. Higher cytotoxicity of 5-FU-SUL-PLGA NPs were found to both cancer cell lines when compared to normal cell lines, demonstrating that the presence of SUL could significantly enhance the cytotoxicity of the 5-FU-SUL-PLGA NPs when compared with 5-FU-PLGA NPs. Thus, the development of 5-FU-SUL-PLGA NPs to cancer cells is a promising strategy for the 5-FU antitumor formulation in the future.

Effect of Conjugated Linoleic Acid-enriched Butter After 24 hours of Intestinal Mucositis Induction.

PubMed

Barros, Patrícia Aparecida Vieira de; Generoso, Simone de Vasconcelos; Andrade, Maria Emília Rabelo; da Gama, Marco Antonio Sundfeld; Lopes, Fernando Cesar Ferraz; de Sales E Souza, Éricka Lorenna; Martins, Flaviano Dos Santos; Miranda, Sued Eustáquio Mendes; Fernandes, Simone Odília Antunes; Cardoso, Valbert Nascimento

2017-01-01

Mucositis is the most common side effect due to chemotherapy or radiotherapy. It refers to the inflammation of intestinal mucous membranes, and it is associated with complications such as diarrhea, weight loss, and increased intestinal permeability (IP). This study was designed to evaluate the effect of diet containing conjugated linoleic acid (CLA)-enriched butter on intestinal damage and inflammatory response after 24 h of 5-fluorouracil (5-FU)-induced mucositis. Mice were divided into four groups: CTL; CLA; 5-FU, and CLA 5-FU, and they were fed for 31 days. On the 30th experimental day, mucositis was induced by unique injection of 300 mg/kg of 5-FU. After 24 h (31st experimental day), IP was evaluated; ileum and fecal material were collected to determine cytokine level and myeloperoxidase (MPO) activity and secretory immunoglobulin A (sIgA). The 5-FU group showed an increase in IP and MPO activity (CTL vs. 5-FU: P < 0.05). Additionally, increased levels of IP and MPO were observed in CLA 5-FU group compared to those in the test groups (P < 0.05). Animals in the CLA 5-FU group showed reduced concentrations of sIgA (CTL vs. CLA 5-FU: P < 0.05). CLA-enriched butter exacerbating the 5-FU-induced intestinal damage. Safety concerns regarding the use of CLA require further investigation.

5-fluorouracil attenuates dextran sodium sulfate-induced acute colitis in mice.

PubMed

Xiao, Junhua; Lu, Zhanjun; Sheng, Jiaqing; Song, Yunna; Jiang, Weiliang; Liu, Fei; Zheng, Ping

2016-03-01

5‑Fluorouracil (5‑FU) has been predominantly used in the clinic for cancer chemotherapy. Previous studies have demonstrated that 5‑FU has an anti‑inflammatory function. In the current study, the potential therapeutic role of 5‑FU in dextran sodium sulfate (DSS)‑induced acute mouse colitis was investigated. Effects on the severity of colitis were studied via histochemical and immunohistochemical staining, cytokine levels were determined by reverse transcriptoin‑quantitative polymerase chain reaction and the effect of 5‑FU on NF‑κB was examined by western blotting. Administration of 5‑FU ameliorated the severity of acute DSS‑induced colitis. The disease activity score was significantly lower in the 5‑FU + DSS‑treated mice compared with the DSS‑treated group (P<0.01). Tumor necrosis factor‑α, interleukin‑1β and interferon γ mRNA expression levels were significantly downregulated in the colon tissue of DSS mice treated with 5‑FU compared with the untreated DSS mice (P<0.05). In addition, the number of CD4+ T cells in the colonic lamina propria and myeloperoxidase activity were significantly decreased in the 5‑FU + DSS‑treated mice (P<0.05). Furthermore, 5‑FU treatment significantly reduced p‑NF‑κB‑p56 protein expression levels in the colon tissue of DSS‑treated mice (P<0.05). The present results demonstrated that 5‑FU minimizes the abnormal immune cytokine response and relieves the pathophysiological disorders associated with experimental acute colitis. Thus, the modulating inflammatory response role of 5‑FU may be partially associated with inhibiting NF‑κB activation and 5‑FU may be a novel therapeutic strategy for the treatment of inflammatory bowel disease.

Development and evaluation of nanostructured lipid carrier-based hydrogel for topical delivery of 5-fluorouracil

PubMed Central

Rajinikanth, Paruvathanahalli Siddalingam; Chellian, Jestin

2016-01-01

The aim of this study was to develop a nanostructured lipid carrier (NLC)-based hydrogel and study its potential for the topical delivery of 5-fluorouracil (5-FU). Precirol® ATO 5 (glyceryl palmitostearate) and Labrasol® were selected as the solid and liquid lipid phases, respectively. Poloxamer 188 and Solutol® HS15 (polyoxyl-15-hydroxystearate) were selected as surfactants. The developed lipid formulations were dispersed in 1% Carbopol® 934 (poly[acrylic acid]) gel medium in order to maintain the topical application consistency. The average size, zeta potential, and polydispersity index for the 5-FU-NLC were found to be 208.32±8.21 nm, −21.82±0.40 mV, and 0.352±0.060, respectively. Transmission electron microscopy study revealed that 5-FU-NLC was <200 nm in size, with a spherical shape. In vitro drug permeation studies showed a release pattern with initial burst followed by sustained release, and the rate of 5-FU permeation was significantly improved for 5-FU-NLC gel (10.27±1.82 μg/cm2/h) as compared with plain 5-FU gel (2.85±1.12 μg/cm2/h). Further, skin retention studies showed a significant retention of 5-FU from the NLC gel (91.256±4.56 μg/cm2) as compared with that from the 5-FU plain gel (12.23±3.86 μg/cm2) in the rat skin. Skin irritation was also significantly reduced with 5-FU-NLC gel as compared with 5-FU plain gel. These results show that the prepared 5-FU-loaded NLC has high potential to improve the penetration of 5-FU through the stratum corneum, with enormous retention and with minimal skin irritation, which is the prerequisite for topically applied formulations. PMID:27785014

The protective effects of naringin against 5-fluorouracil-induced hepatotoxicity and nephrotoxicity in rats

PubMed Central

Gelen, Volkan; Şengül, Emin; Yıldırım, Serkan; Atila, Gözde

2018-01-01

Objective(s): 5-fluorouracil-induced (5-FU), an anticarcinogenic agent, is reported to have side-effects that include hepatotoxicity and nephrotoxicity. The study objective was to investigate the protective effects of naringin on 5-FU-induced hepatotoxicity and nephrotoxicity. Materials and Methods: Thirty rodents were assigned to three groups. The control group received 1 ml of intragastric distilled water for 14 days. The 5-FU group received 1 ml of distilled water for 14 days as a placebo. On day 9, this same group received a 20 mg/kg dose of 5-FU administered intraperitoneally(IP) for a further five days. The naringin+5-FU group received a 100 mg/kg dose of naringin (IP) for 14 days. On day 9, 20 mg/kg of 5-FU was administered (IP) to this group for a further five days. On day 15, the rats were decapitated, and blood and renal and hepatic tissues were taken. Results: It was determined that serum creatinine, BUN, AST, ALT, ALP, and LDH levels, as well as cytokine levels in the liver and kidney tissues were significantly elevated in the 5-FU group, compared to the control group. The comparative values were similar in the control and naringin+5-FU groups. When the liver tissue was examined histopathologically, in the control group it was found to be normal in structure. However, necrosis was observed in the hepatocytes of the pericentric region in the 5-FU group. 8-OHdG cell density was significantly elevated in the 5-FU group, compared to the control and naringin+5-FU groups. Conclusion: Naringin was observed to have a protective effect on 5-FU-induced liver and kidney damage. PMID:29796225

Active Ingredients of Hange-shashin-to, Baicalelin and 6-Gingerol, Inhibit 5-Fluorouracil-Induced Upregulation of CXCL1 in the Colon to Attenuate Diarrhea Development.

PubMed

Sakai, Hiroyasu; Tabata, Shoko; Kimura, Minami; Yabe, Saori; Isa, Yosuke; Kai, Yuki; Sato, Fumiaki; Yumoto, Tetsuro; Miyano, Kanako; Narita, Minoru; Uezono, Yasuhito

2017-01-01

5-Fluorouracil (5-FU) is widely used as an anti cancer drug and is known to cause severe diarrhea. Recently we suggested that levels of chemokine (C-X-C motif) ligand 1 (CXCL1) and neutrophil recruitment in the colonic mucosa were drastically increased by the 5-FU administration in mice. Hange-shashin-to (HST) is prescribed in Japan for treat gastritis, stomatitis, and inflammatory diarrhea. We therefore examined the effects of HST and its active ingredients on 5-FU-induced CXCL1 upregulation in cultured colon tissue, and also examined the effects of HST on 5-FU-induced diarrhea development in the mouse. The distal colon isolated from the mouse was incubated with 5-FU and HST. Mice were given 5-FU (50 mg/kg, intraperitoneally (i.p.)) daily for four days. HST (300 mg/kg, per os (p.o.)) was administered 30 min before mice received 5-FU. mRNA levels of CXCL1 in the colon were examined using quantitative RT-PCR. 5-FU enhanced CXCL1 mRNA in the colon but the effect by 5-FU was markedly suppressed by application of HST and its active ingredients, baicalein and 6-gingerol. Nuclear factor kappa B (NF-κB) was activated by 5-FU treatment in cultured colon tissue, which was also suppressed by HST and the combination of baicalein and 6-gingerol. Furthermore, HST reduced 5-FU-induced diarrhea development. Under such experimental condition, CXCL1 gene, protein levels of neutrophil elastase and myeloperoxidase upregulation induced by 5-FU in the colon was attenuated by HST. These findings suggest that HST, especially baicalein and 6-gingerol, prevent the development of neutrophil recruitment and diarrhea by the inhibition of NF-κB activity.

The novel HDAC inhibitor OBP-801/YM753 enhances the effects of 5-fluorouracil with radiation on esophageal squamous carcinoma cells.

PubMed

Furutani, Akinobu; Sowa, Yoshihiro; Fujiwara, Hitoshi; Otsuji, Eigo; Sakai, Toshiyuki

2014-01-01

Histone deacetylase (HDAC) inhibitors have been shown to enhance the effects of 5-fluorouracil (5-FU) against various cancer cells; however, no report has shown that an HDAC inhibitor may enhance the effects of 5-FU with radiation. Therefore, we investigated whether the novel HDAC inhibitor OBP-801/YM753 could enhance the effects of 5-FU with radiation on esophageal squamous carcinoma KYSE170 cells. The inhibition of the cell growth was significantly stronger with the combination of OBP-801/YM753 with 5-FU than with the 5-FU treatment only. Furthermore, inhibition of the colony formation was the most effective with the combined treatment of OBP-801/YM753, 5-FU, and radiation. Western blot analysis showed that OBP-801/YM753 suppressed the expression of thymidylate synthase induced by 5-FU. Therefore, this three-combined therapy is promising for patients with esophageal squamous carcinoma.

Piper betle leaf extract enhances the cytotoxicity effect of 5-fluorouracil in inhibiting the growth of HT29 and HCT116 colon cancer cells.

PubMed

Ng, Pek Leng; Rajab, Nor Fadilah; Then, Sue Mian; Mohd Yusof, Yasmin Anum; Wan Ngah, Wan Zurinah; Pin, Kar Yong; Looi, Mee Lee

2014-08-01

The combination effect of Piper betle (PB) and 5-fluorouracil (5-FU) in enhancing the cytotoxic potential of 5-FU in inhibiting the growth of colon cancer cells was investigated. HT29 and HCT116 cells were subjected to 5-FU or PB treatment. 5-FU and PB were then combined and their effects on both cell lines were observed after 24 h of treatment. PB-5-FU interaction was elucidated by isobologram analysis. Apoptosis features of the treated cells were revealed by annexin V/PI stain. High-performance liquid chromatography (HPLC) was performed to exclude any possible chemical interaction between the compounds. In the presence of PB extract, the cytotoxicity of 5-FU was observed at a lower dose (IC50 12.5 µmol/L) and a shorter time (24 h) in both cell lines. Both cell lines treated with 5-FU or PB alone induced a greater apoptosis effect compared with the combination treatment. Isobologram analysis indicated that PB and 5-FU interacted synergistically and antagonistically in inhibiting the growth of HT29 and HCT116 cells, respectively. In the presence of PB, a lower dosage of 5-FU is required to achieve the maximum drug effect in inhibiting the growth of HT29 cells. However, PB did not significantly reduce 5-FU dosage in HCT116 cells. Our result showed that this interaction may not solely contribute to the apoptosis pathway.

Piper betle leaf extract enhances the cytotoxicity effect of 5-fluorouracil in inhibiting the growth of HT29 and HCT116 colon cancer cells*

PubMed Central

Ng, Pek Leng; Rajab, Nor Fadilah; Then, Sue Mian; Mohd Yusof, Yasmin Anum; Wan Ngah, Wan Zurinah; Pin, Kar Yong; Looi, Mee Lee

2014-01-01

Objective: The combination effect of Piper betle (PB) and 5-fluorouracil (5-FU) in enhancing the cytotoxic potential of 5-FU in inhibiting the growth of colon cancer cells was investigated. Methods: HT29 and HCT116 cells were subjected to 5-FU or PB treatment. 5-FU and PB were then combined and their effects on both cell lines were observed after 24 h of treatment. PB-5-FU interaction was elucidated by isobologram analysis. Apoptosis features of the treated cells were revealed by annexin V/PI stain. High-performance liquid chromatography (HPLC) was performed to exclude any possible chemical interaction between the compounds. Results: In the presence of PB extract, the cytotoxicity of 5-FU was observed at a lower dose (IC50 12.5 μmol/L) and a shorter time (24 h) in both cell lines. Both cell lines treated with 5-FU or PB alone induced a greater apoptosis effect compared with the combination treatment. Isobologram analysis indicated that PB and 5-FU interacted synergistically and antagonistically in inhibiting the growth of HT29 and HCT116 cells, respectively. Conclusions: In the presence of PB, a lower dosage of 5-FU is required to achieve the maximum drug effect in inhibiting the growth of HT29 cells. However, PB did not significantly reduce 5-FU dosage in HCT116 cells. Our result showed that this interaction may not solely contribute to the apoptosis pathway. PMID:25091987

Chemotherapeutic strategies in metastatic colorectal cancer: an overview of current clinical trials.

PubMed

Köhne-Wömpner, C H; Schmoll, H J; Harstrick, A; Rustum, Y M

1992-04-01

5-Fluorouracil (5-FU) is still the mainstay of chemotherapy in patients with metastatic colorectal cancer. A prolonged infusion of 5-FU is more active than any other schedule of 5-FU used to date. Cisplatin does not improve treatment results compared with 5-FU alone and is not recommended outside clinical trials. Biomodulation of 5-FU is a major step forward in the treatment of colorectal cancer patients and as the standard chemotherapy for advanced colorectal cancer. Two schedules of folinic acid daily for 5-day (low and high doses) and weekly high dose in combination with daily or weekly 5-FU are the most widely used schedules. Although the response rates to either schedule are comparable, the profile of toxicity is different, being stomatitis for the daily schedule and diarrhea for the weekly schedule as the dose-limiting toxicity. Modulation of 5-FU by methotrexate is time dependent. An interval of 24 hours between methotrexate and 5-FU is necessary for effective modulation. Other modulators, like interferon and N-phosphonoactyl-L-aspartate (PALA), are promising treatment options currently under investigation in randomized trials. The data from phase II and III trials using modulation of 5-FU by folinic acid, PALA, or methotrexate, or using continuous infusion 5-FU indicate that all of these strategies are active. Randomized trials are currently underway to further investigate these therapeutic approaches and whether a specific modulation offers more therapeutic advantages.

FLAIR vascular hyperintensities predict early ischemic recurrence in TIA.

PubMed

Nam, Ki-Woong; Kim, Chi Kyung; Kim, Tae Jung; Oh, Kyungmi; Han, Moon-Ku; Ko, Sang-Bae; Yoon, Byung-Woo

2018-02-27

To evaluate the relationship between fluid-attenuated inversion recovery (FLAIR) vascular hyperintensity (FVH) and early ischemic lesion recurrence (follow-up diffusion-weighted imaging [FU-DWI] [+]) in patients with lesion-negative TIA. We recruited consecutive patients with lesion-negative TIA within 24 hours of symptom onset, who underwent follow-up MRI during the acute period. FVH was defined as a focal or serpentine high signal intensity on FLAIR images. Other potential confounders were adjusted to evaluate the relationship between FVH and FU-DWI (+). Furthermore, to compare clinical outcomes between the FU-DWI (+) and FU-DWI (-) groups, we assessed 1-year recurrent ischemic stroke or TIA. Among 392 patients with lesion-negative TIA, 82 patients had FU-DWI (+) on the follow-up MRI. In the multivariate analysis, FVH remained an independent predictor of FU-DWI (+) (adjusted odds ratio [aOR] = 4.77, 95% confidence interval [CI] 2.45-9.29, p < 0.001). The time to initial MRI (aOR = 0.49, 95% CI = 0.33-0.70, p < 0.001) and intracranial atherosclerosis (aOR = 2.07, 95% CI = 1.10-3.92, p = 0.025) were also associated with FU-DWI (+), independent of FVH. In clinical outcomes, the FU-DWI (+) group showed more frequent 1-year recurrent ischemic stroke events than the FU-DWI (-) group (10.7% vs 3.1%, respectively, p = 0.007). FVH is associated with FU-DWI (+) in patients with lesion-negative TIA. As FU-DWI (+) frequently occurs during the acute period and has a subsequent worse outcome after discharge, additional radiologic or clinical markers for it are necessary. © 2018 American Academy of Neurology.

Estimating the terrestrial N processes in subtropical mountainous forestry catchment through INCA-N: A case study in FuShan catchment, Taiwan

NASA Astrophysics Data System (ADS)

Lu, Meng-Chang; Huang, -Chuan, Jr.; Chang, Chung-Te; Shih, Yu-Ting; Lin, Teng-Chiu

2016-04-01

The riverine DIN is a crucial indicator for eutrophication in river network. The riverine DIN export in Taiwan is featured by the extremely high yield, ~3800 kg-N km-2yr-1, nearly 20-fold than the global average, showing the interesting terrestrial N process yet rarely documented. In this study we collected the DIN samples in rainwater, soil water, and stream water in a mountainous forest watershed, FuShan experimental forest watershed 1 (WS1) which is a natural broadleaf forest without human activities. Based on the intensive observations, we applied the INCA-N to simulate the riverine DIN response and thus estimate the terrestrial N processes in a global synthesis. The result showed that both discharge and DIN yield were simulated well with the average Nash-Sutcliffe efficiency coefficient of 0.83 and 0.76 , respectively. Among all N processes, N uptake, mineralization, nitrification, denitrfication, and immobilization are significantly positive correlated with soil moisture (R2>0.99), which indicates that soil moisture greatly influences N cycle processes. The average rate of mineralization and nitrification in wet years are consistent with documented values, whereas the rates in dry years are lower than the observations. Despite the high nitrification rate, the secondary forest may uptake abundant N indicating the plant uptake, which responds for removing considerable nitrate, is a controlling factor in forest ecosystem. Our simulated denitrification rate falls between the documented rates of temperate forest and agricultural area, and that may be affected by the high N-deposition in Taiwan. Simulated in-stream denitrification rate is less than 10% of the rate in soil, and is a little lower than that in temperate forest. This preliminary simulation provides an insightful guide to establish the monitoring programme and improve the understanding of N cycle in subtropical.

2004 Army Research Office in Review

DTIC Science & Technology

2004-01-01

23 Uncool Tunable LWIR Microbolometer...but also for speech in multimedia applications. ELECTRONICS Uncooled Tunable LWIR Microbolometer – Multi- or hyper- spectral images contain...Analysis of NURBS Curves and Surfaces Jian-Ao Lian, Prairie View A&M University The multiresolution structure of NURBS ( nonuniform rational B

Making the Most of MASINT and Advanced Geospatial Intelligence

DTIC Science & Technology

2012-04-10

mining contracts and new job creation that ultimately supports economic development. This 22 type of forensic level analysis can make MASINT an...and Technology, ed. John D. Bossler (London: Taylor and Francis, 2002), 305 17 Jian Guo Liu and Philippa J. Mason, Essential Image Processing and

Relaxations of fluorouracil tautomers by decorations of fullerene-like SiCs: DFT studies

NASA Astrophysics Data System (ADS)

Kouchaki, Alireza; Gülseren, Oğuz; Hadipour, Nasser; Mirzaei, Mahmoud

2016-06-01

Decorations of silicon carbide (SiC) fullerene-like nanoparticles by fluorouracil (FU) and its tautomers are investigated through density functional theory (DFT) calculations. Two models of fullerene-like particles including Si12C8 and Si8C12 are constructed to be counterparts of decorated hybrid structures, FU@Si12C8 and FU@Si8C12, respectively. The initial models including original FU and tautomeric structures and SiC nanoparticles are individually optimized and then combined for further optimizations in the hybrid forms. Covalent bonds are observed for FU@Si12C8 hybrids, whereas non-covalent interactions are seen for FU@Si8C12 ones. The obtained properties indicated that Si12C8 model could be considered as a better counterpart for interactions with FU structures than Si8C12 model. The results also showed significant effects of interactions on the properties of atoms close to the interacting regions in nanoparticles. Finally, the tautomeric structures show different behaviors in interactions with SiC nanoparticles, in which the SiC nanoparticles could be employed to detect the situations of tautomeric processes for FU structures.

miR-338-3p confers 5-fluorouracil resistance in p53 mutant colon cancer cells by targeting the mammalian target of rapamycin.

PubMed

Han, Jia; Li, Jie; Tang, Kaijie; Zhang, Huahua; Guo, Bo; Hou, Ni; Huang, Chen

2017-11-15

Evidence demonstrate that p53 mutations and microRNAs (miRs) are important components of 5-FU resistance in colorectal cancer (CRC). miR-338-3p has been reported associated with cancer prognosis. However whether or not it influences chemotherapy sensitivity and the underlying mechanisms have not been elucidated. Here, three types of human colon cancer cell lines, HT29 (mutant p53), HCT116 (wild-type p53), and HCT116 p53 -/- (deficient p53), were treated with 5-FU. We showed that expression of miR-338-3p was correlated with apoptosis and 5-FU resistance in colon cancer cells. Ectopic expression of miR-338-3p conferred resistance to 5-FU in HCT116 cells. Further experiments indicated that miR-338-3p mediated 5-FU resistance through down-regulation of mTOR expression. Moreover, inhibition of miR-338-3p in HT29 and HCT116 p53 -/- cells increased their sensitivity to 5-FU treatment. Furthermore, we detected autophagy changes in our experiment because mTOR was known prominently regulating autophagy and the competition between autophagy and apoptosis in response to 5-FU was a mechanism influencing 5-FU sensitivity. Our results reveal a critical and novel role of miR-338-3p in the correlation of 5-FU resistance with p53 status. Moreover, the miR-338-3p inhibitor has the potential to overcome 5-FU resistance in p53 mutant colon cancer cells. Copyright © 2017 Elsevier Inc. All rights reserved.

Effects of 5-Fluorouracil on Morphology, Cell Cycle, Proliferation, Apoptosis, Autophagy and ROS Production in Endothelial Cells and Cardiomyocytes

PubMed Central

Focaccetti, Chiara; Bruno, Antonino; Magnani, Elena; Bartolini, Desirée; Principi, Elisa; Dallaglio, Katiuscia; Bucci, Eraldo O.; Finzi, Giovanna; Sessa, Fausto; Noonan, Douglas M.; Albini, Adriana

2015-01-01

Antimetabolites are a class of effective anticancer drugs interfering in essential biochemical processes. 5-Fluorouracil (5-FU) and its prodrug Capecitabine are widely used in the treatment of several solid tumors (gastro-intestinal, gynecological, head and neck, breast carcinomas). Therapy with fluoropyrimidines is associated with a wide range of adverse effects, including diarrhea, dehydration, abdominal pain, nausea, stomatitis, and hand-foot syndrome. Among the 5-FU side effects, increasing attention is given to cardiovascular toxicities induced at different levels and intensities. Since the mechanisms related to 5-FU-induced cardiotoxicity are still unclear, we examined the effects of 5-FU on primary cell cultures of human cardiomyocytes and endothelial cells, which represent two key components of the cardiovascular system. We analyzed at the cellular and molecular level 5-FU effects on cell proliferation, cell cycle, survival and induction of apoptosis, in an experimental cardioncology approach. We observed autophagic features at the ultrastructural and molecular levels, in particular in 5-FU exposed cardiomyocytes. Reactive oxygen species (ROS) elevation characterized the endothelial response. These responses were prevented by a ROS scavenger. We found induction of a senescent phenotype on both cell types treated with 5-FU. In vivo, in a xenograft model of colon cancer, we showed that 5-FU treatment induced ultrastructural changes in the endothelium of various organs. Taken together, our data suggest that 5-FU can affect, both at the cellular and molecular levels, two key cell types of the cardiovascular system, potentially explaining some manifestations of 5-FU-induced cardiovascular toxicity. PMID:25671635

Bimonthly 24 h infusion of high-dose 5-fluorouracil vs EAP regimen in patients with advanced gastric cancer. A randomized phase II study.

PubMed

Popov, I P; Jelić, S B; Krivokapić, Z V; Jezdić, S D; Pesko, P M; Micev, M T; Babić, D R

2008-01-01

To investigate the activity and toxicity of high dose (HD) infusional 5-FU in comparison to EAP regimen as first-line chemotherapy in patients with advanced gastric cancer. Histologically confirmed measurable advanced gastric cancer, age < 72 yr, ECOG performance status 0-2, no prior chemo- and radiotherapy, adequate organ functions. EAP arm: doxorubicin (40 mg/m(2)), etoposide (360 mg/m(2)), and cisplatin (80 mg/m(2)) every 28 d; HD 5-FU arm: 5-FU 2.6 g/m(2) 24 h infusion, biweekly. Sixty patients were randomized. Patient characteristics (arms EAP/HD 5-FU): Median age 57/55 yr, median PS 1/1, LAD (patients) 3/8, M1 (patients) 27/22. Median number of cycles (range): EAP arm 4 (2-8), HD 5-FU arm 2 (1-8). Worst toxicity per cycle (grade 3 and 4 in%): Neutropenia 20/3, thrombocytopenia 9/0, anemia 9/13, diarrhea 3/10, nausea 17/7, vomiting 10/0 for EAP and HD 5-FU arms, respectively. All patients were eligible for response in both arms. Confirmed response rate (95%CI): EAP arm 34% [16-50%]/HD 5-FU arm 10% (0-21%), no change: 46/40%, progression of disease: 20/50, respectively. Overall survival (range): EAP arm A 7 mo [3-27], HD 5-FU arm 6 mo (4-25). Infusional HD 5-FU showed a low incidence of severe toxicity. But given the low efficacy of 5-FU in the dosage we applied in the study, it cannot be recommended as a single treatment for further studies. Assessment of higher dose intensity and/or dose density of 5-FU, with introduction of other active drugs in combination, could be an option for further studies.

Peri-tumor administration of 5-fluorouracil sol-gel using a hollow microneedle for treatment of gastric cancer.

PubMed

Jung, Yoon Suk; Koo, Dong-Hoe; Yang, Jeong-Yoon; Lee, Hee-Young; Park, Jung-Hwan; Park, Jung Ho

2018-11-01

The aim of this study was to investigate the effectiveness of treating gastric cancer by injecting a pluronic F-127 sol-gel formulation of 5-fluorouracil (5-FU) into normal tissue surrounding the tumor using a hollow microneedle. The MTS tetrazolium assay was performed to assess the cytotoxicity of 5-FU after application to gastric cancer cells at different concentrations for 1, 5 and 10 h. Gastric cancer cells were inoculated subcutaneously into 30 male nude mice (CrjBALB/c-nu/nu mice, male); the inoculated mouse were divided into three groups. One group received no treatment, whereas the two other groups received free 5-FU gel (40 mg/kg) and 5-FU gel (40 mg/kg) for 4 days, respectively. Mean tumor volume, apoptotic index (TUNEL) and proliferative index (Ki 67) were evaluated in all groups. Cell viability was 77.3% when 1.22 g of free 5-FU was administered, whereas cell viability was 37.4% and 43.5% when 0.122 g of free 5-FU was administered per hour for 10 h and 0.244 g of free 5-FU was administered for 5 h (p < .01). The 5-FU sol-gel induced apoptosis and significantly inhibited cell proliferation compared to the free 5-FU (p < .01). In addition, xenografted tumor growth was significantly suppressed by administration of the 5-FU sol-gel formulation to inoculated mice (p < .01), and 71% (5/7) of xenografted tumors disappeared after 4 weeks. In conclusion, peri-tumor injection of a 5-FU sol-gel formulation into normal tissue surrounding the tumor mass using a hollow microneedle is an effective method for treating gastric cancer.

Effects of 5-fluorouracil in nuclear and cellular morphology, proliferation, cell cycle, apoptosis, cytoskeletal and caveolar distribution in primary cultures of smooth muscle cells.

PubMed

Filgueiras, Marcelo de Carvalho; Morrot, Alexandre; Soares, Pedro Marcos Gomes; Costa, Manoel Luis; Mermelstein, Cláudia

2013-01-01

Colon cancer is one of the most prevalent types of cancer in the world and is one of the leading causes of cancer death. The anti-metabolite 5- fluorouracil (5-FU) is widely used in the treatment of patients with colon cancer and other cancer types. 5-FU-based chemotherapy has been shown to be very efficient in the improvement of overall survival of the patients and for the eradication of the disease. Unfortunately, common side effects of 5-FU include severe alterations in the motility of the gastrointestinal tissues. Nevertheless, the molecular and cellular effects of 5-FU in smooth muscle cells are poorly understood. Primary smooth muscle cell cultures are an important tool for studies of the biological consequences of 5-FU at the cellular level. The avian gizzard is one of the most robust organs of smooth muscle cells. Here we studied the molecular and cellular effects of the chemotherapic drug 5-FU in a primary culture of chick gizzard smooth muscle cells. We found that treatment of smooth muscle cells with 5-FU inhibits cell proliferation by the arrest of cells in the G1 phase of cell cycle and induce apoptosis. 5-FU induced a decrease in the percentage of histone H3-positive cells. Treatment of cells with 5-FU induced changes in cellular and nuclear morphology, a decrease in the number of stress fibers and a major decrease in the number of caveolin-3 positive cells. Our results suggest that the disorganization of the actin cytoskeleton and the reduction of caveolin-3 expression could explain the alterations in contractility observed in patients treated with 5-FU. These findings might have an impact in the understanding of the cellular effects of 5-FU in smooth muscle tissues and might help the improvement of new therapeutic protocols for the treatment of colon cancer.

Effects of 5-Fluorouracil in Nuclear and Cellular Morphology, Proliferation, Cell Cycle, Apoptosis, Cytoskeletal and Caveolar Distribution in Primary Cultures of Smooth Muscle Cells

PubMed Central

Filgueiras, Marcelo de Carvalho; Morrot, Alexandre; Soares, Pedro Marcos Gomes; Costa, Manoel Luis; Mermelstein, Cláudia

2013-01-01

Colon cancer is one of the most prevalent types of cancer in the world and is one of the leading causes of cancer death. The anti-metabolite 5- fluorouracil (5-FU) is widely used in the treatment of patients with colon cancer and other cancer types. 5-FU-based chemotherapy has been shown to be very efficient in the improvement of overall survival of the patients and for the eradication of the disease. Unfortunately, common side effects of 5-FU include severe alterations in the motility of the gastrointestinal tissues. Nevertheless, the molecular and cellular effects of 5-FU in smooth muscle cells are poorly understood. Primary smooth muscle cell cultures are an important tool for studies of the biological consequences of 5-FU at the cellular level. The avian gizzard is one of the most robust organs of smooth muscle cells. Here we studied the molecular and cellular effects of the chemotherapic drug 5-FU in a primary culture of chick gizzard smooth muscle cells. We found that treatment of smooth muscle cells with 5-FU inhibits cell proliferation by the arrest of cells in the G1 phase of cell cycle and induce apoptosis. 5-FU induced a decrease in the percentage of histone H3-positive cells. Treatment of cells with 5-FU induced changes in cellular and nuclear morphology, a decrease in the number of stress fibers and a major decrease in the number of caveolin-3 positive cells. Our results suggest that the disorganization of the actin cytoskeleton and the reduction of caveolin-3 expression could explain the alterations in contractility observed in patients treated with 5-FU. These findings might have an impact in the understanding of the cellular effects of 5-FU in smooth muscle tissues and might help the improvement of new therapeutic protocols for the treatment of colon cancer. PMID:23646193

In-vitro and in-vivo assessment of dextran-appended cellulose acetate phthalate nanoparticles for transdermal delivery of 5-fluorouracil.

PubMed

Garg, Ashish; Rai, Gopal; Lodhi, Santram; Jain, Alok P; Yadav, Awesh K

2016-06-01

The aim of this research was transdermal delivery of 5-fluorouracil (5-FU) using dextran-coated cellulose acetate phthalate (CAP) nanoparticulate formulation. CAP nanoparticles were prepared using drug-polymer ratio (1:1 to 1:3) and surfactant ratio (2.5, 5 and 10%). Dextran coating was made using aminodextran. The results showed that the optimized CAP nanoparticles (CNs) and dextran-coated CAP nanoparticles represented core-corona nanoparticles with the mean diameter of 75 ± 3 and 79 ± 2 nm, respectively, and entrapment efficiency was 82.5 ± 0.06 and 78.2 ± 0.12, respectively. Dextran-coated nanoparticles (FDCNs) and CAP nanoparticles (FCNs) showed in vitro 5-FU release upto 31 h and 8 h, respectively. Moreover, the cumulative amount of 5-FU penetrated through excised skin from FDCNs was 2.94 folds than that of the FU cream. Concentration of 5-FU in epidermis and dermis were also studied. In dermis, concentration of 5-FU was found higher in case of FDCN formulation than plain FU cream. FDCNs were found more hemocompatible in comparison to FCNs. The hematological data recommended that FDCNs formulation was less immunogenic compared to FU creams formulation. In blood level study, FDCNs exhibited 153, 12, 16.66 and 16.24-fold higher values for area under the curve, Tmax, Cmax and mean residence time (MRT) compared with those of FU cream, respectively. The in-vitro cytotoxicity was assessed using the MCF-7 by the MTT test and was compared to the plain 5-FU solution. All the detailed evidence showed that FDCNs could provide a promising tuning as a transdermal delivery system of 5-FU.

Acriflavine enhances the antitumor activity of the chemotherapeutic drug 5-fluorouracil in colorectal cancer cells.

PubMed

Zargar, Parisa; Ghani, Esmaeel; Mashayekhi, Farideh Jalali; Ramezani, Amin; Eftekhar, Ebrahim

2018-06-01

5-Fluorouracil (5-FU)-based chemotherapy improves the overall survival rates of patients with colorectal cancer (CRC). However, only a small proportion of patients respond to 5-FU when used as a single agent. The aim of the present study was to investigate whether the anticancer property of 5-FU is potentiated by combination treatment with acriflavine (ACF) in CRC cells. Additionally, the potential underlying molecular mechanisms of the cytotoxic effect of ACF were determined. The cytotoxic effects of ACF, 5-FU and irinotecan on different CRC cell lines with different p53 status were investigated using an MTT assay. SW480 cells that express a mutated form of p53 and two other CRC cell lines were used, HCT116 and LS174T, with wild-type p53. To determine the effect of ACF on the sensitivity of cells to 5-FU, cells were co-treated with the 30% maximal inhibitory concentration (IC 30 ) of ACF and various concentrations of 5-FU, or pretreated with the IC 30 of ACF and various concentrations of 5-FU. To assess the mechanism of action of ACF, cells were treated with IC 30 values of the compound and then the reverse transcription-quantitative polymerase chain reaction was used to evaluate mRNA levels of hypoxia-inducible factor-1α (HIF-1α) and topoisomerase 2. Results indicate that pretreatment with ACF markedly sensitized CRC cells to the cytotoxic effects of 5-FU, whereas simultaneous treatment with ACF and 5-FU were not able to alter the resistance of CRC cells to 5-FU. In comparison with irinotecan, ACF was a more potent agent for enhancing the antitumor activity of 5-FU. ACF did not alter the mRNA levels of either HIF-1α or topoisomerase 2. The results of the present study reveal for the first time that pretreatment of CRC cells with ACF markedly increases the cytotoxic effects of 5-FU, regardless of the p53 status of cells.

Treatment with Saccharomyces boulardii reduces the inflammation and dysfunction of the gastrointestinal tract in 5-fluorouracil-induced intestinal mucositis in mice.

PubMed

Justino, Priscilla F C; Melo, Luis F M; Nogueira, Andre F; Costa, Jose V G; Silva, Luara M N; Santos, Cecila M; Mendes, Walber O; Costa, Marina R; Franco, Alvaro X; Lima, Aldo A; Ribeiro, Ronaldo A; Souza, Marcellus H L P; Soares, Pedro M G

2014-05-01

Intestinal mucositis is an important toxic side effect of 5-fluorouracil (5-FU) treatment. Saccharomyces boulardii is known to protect from intestinal injury via an effect on the gastrointestinal microbiota. The objective of the present study was to evaluate the effect of S. boulardii on intestinal mucositis induced by 5-FU in a murine model. Mice were divided into saline, saline (control)+5-FU or 5-FU+S. boulardii (16 × 10⁹ colony-forming units/kg) treatment groups, and the jejunum and ileum were removed after killing of mice for the evaluation of histopathology, myeloperoxidase (MPO) activity, and non-protein sulfhydryl group (mainly reduced glutathione; GSH), nitrite and cytokine concentrations. To determine gastric emptying, phenol red was administered orally, mice were killed 20 min after administration, and the absorbance of samples collected from the mice was measured by spectrophotometry. Intestinal permeability was measured by the urinary excretion rate of lactulose and mannitol following oral administration. S. boulardii significantly reversed the histopathological changes in intestinal mucositis induced by 5-FU and reduced the inflammatory parameters: neutrophil infiltration (control 1·73 (SEM 0·37) ultrastructural MPO (UMPO)/mg, 5-FU 7·37 (SEM 1·77) UMPO/mg and 5-FU+S. boulardii 4·15 (SEM 0·73) UMPO/mg); nitrite concentration (control 37·00 (SEM 2·39) μm, 5-FU 59·04 (SEM 11·41) μm and 5-FU+S. boulardii 37·90 (SEM 5·78) μm); GSH concentration (control 477·60 (SEM 25·25) μg/mg, 5-FU 270·90 (SEM 38·50) μg/mg and 5-FU+S. boulardii 514·00 (SEM 38·64) μg/mg). Treatment with S. Boulardii significantly reduced the concentrations of TNF-α and IL-1β by 48·92 and 32·21 % in the jejunum and 38·92 and 61·79 % in the ileum. In addition, S. boulardii decreased the concentrations of chemokine (C-X-C motif) ligand 1 by 5-fold in the jejunum and 3-fold in the ileum. Interestingly, S. boulardii reduced the delay in gastric emptying

[Different responses of growth and root development of Schima superba provenance to the adjacent plant competition in different nutrient conditions].

PubMed

Yao, Jia Bao; Chu, Xiu Li; Zhou, Zhi Chun; Tong, Jian She; Wang, Hui; Yu, Jia Zhong

2017-04-18

Growth and root development of three Schima superba seedling provenances were influenced by adjacent plant competition in the homogeneous and heterogeneous nutrient environment, which revealed the reasons of S. superba competition differences in the different genotypes. The results indicated that, compared with homogeneous nutrient environment, all three S. superba provenances showed higher seedling height, more dry matter accumulation, and significant root proliferation in heterogeneous nutrient environment. Under heterogeneous nutrient environment, the seedlings of S. superba from Jian'ou of Fujian exhibited higher competitive advantage in growth than that of S. superba from Longquan of Zhejiang and Xinfeng of Jiangxi, especially standing out under mixed cultivation with seedlings of Cunninghamia lanceolata. Under mixed cultivation, the root growth parameters of S. superba such as root length, root surface area and volume increased by 20.4%-69.0% compared with the single plant, which enhanced the foraging ability and growth advantage. To some extent, however, the root development in Longquan of Zhejiang and Xinfeng of Jiangxi was suppressed when subjected to the pattern of mixed cultivation. Besides, the root growth and development of all three S. superba provenances were suppressed, which might be due to their root self-recognition in the pattern of mono cultivation. Therefore, the seedling growth in Jian'ou of Fujian decreased significantly, but seedling growth in Longquan of Zhejiang and Xinfeng of Jiangxi was not suppressed, even increased evidently, as their root physiological plasticity might play the crucial role in seedling growth. Hence the S. superba from Jian'ou of Fujian with high foraging efficiency and competition ability was suggested with the method of mixed forestation to improve the S. superba forest plantation productivity.

Curcumin Inhibits 5-Fluorouracil-induced Up-regulation of CXCL1 and CXCL2 of the Colon Associated with Attenuation of Diarrhoea Development.

PubMed

Sakai, Hiroyasu; Kai, Yuki; Oguchi, Aya; Kimura, Minami; Tabata, Shoko; Yaegashi, Miyabi; Saito, Taiki; Sato, Ken; Sato, Fumiaki; Yumoto, Tetsuro; Narita, Minoru

2016-12-01

The compound 5-fluorouracil (5-FU) is used in cancer chemotherapy and is known to cause diarrhoea. We recently reported that chemokine (C-X-C motif) ligand 1 (CXCL1) and neutrophils in the colonic mucosa were markedly increased by the administration of 5-FU in mice. Curcumin has anti-inflammatory, antitumour and antioxidant properties. Therefore, we examined the effect of curcumin on 5-FU-induced diarrhoea development and CXCL1 and CXCL2 up-regulation in the colon. Mice were given 5-FU (50 mg/kg, i.p.) daily for 4 days. Curcumin (100 or 300 mg/kg, p.o.) was administered on the day before the first administration of 5-FU and administered 30 min. before the administration of 5-FU. Gene expression levels of CXCL1 and CXCL2 in the colon were examined by real-time RT-PCR. Curcumin reduced the 5-FU-induced diarrhoea development. Under this condition, the CXCL1 and CXCL2 gene up-regulated by 5-FU administration was inhibited by curcumin. The gene expression of CXCL1 and CXCL2 was also enhanced by 5-FU application in vitro. The 5-FU-induced up-regulated CXCL1 and CXCL2 gene expressions were inhibited by curcumin, Bay-117082 and bortezomib, nuclear factor kappa B (NF-κB) inhibitors, C646, a p300/cyclic adenosine monophosphate response element-binding protein-histone acetyltransferase (HAT) inhibitor. In conclusion, these findings suggested that curcumin prevented the development of diarrhoea by inhibiting NF-κB and HAT activation. © 2016 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

Dietary emu oil supplementation suppresses 5-fluorouracil chemotherapy-induced inflammation, osteoclast formation, and bone loss.

PubMed

Raghu Nadhanan, Rethi; Abimosleh, Suzanne M; Su, Yu-Wen; Scherer, Michaela A; Howarth, Gordon S; Xian, Cory J

2012-06-01

Cancer chemotherapy can cause osteopenia or osteoporosis, and yet the underlying mechanisms remain unclear, and currently, no preventative treatments are available. This study investigated damaging effects of 5-fluorouracil (5-FU) on histological, cellular, and molecular changes in the tibial metaphysis and potential protective benefits of emu oil (EO), which is known to possess a potent anti-inflammatory property. Female dark agouti rats were gavaged orally with EO or water (1 ml·day(-1)·rat(-1)) for 1 wk before a single ip injection of 5-FU (150 mg/kg) or saline (Sal) was given. The treatment groups were H(2)O + Sal, H(2)O + 5-FU, EO + 5-FU, and EO + Sal. Oral gavage was given throughout the whole period up to 1 day before euthanasia (days 3, 4, and 5 post-5-FU). Histological analysis showed that H(2)O + 5-FU significantly reduced heights of primary spongiosa on days 3 and 5 and trabecular bone volume of secondary spongiosa on days 3 and 4. It reduced density of osteoblasts slightly and caused an increase in the density of osteoclasts on trabecular bone surface on day 4. EO supplementation prevented reduction of osteoblasts and induction of osteoclasts and bone loss caused by 5-FU. Gene expression studies confirmed an inhibitory effect of EO on osteoclasts since it suppressed 5-FU-induced expression of proinflammatory and osteoclastogenic cytokine TNFα, osteoclast marker receptor activator of nuclear factor-κB, and osteoclast-associated receptor. Therefore, this study demonstrated that EO can counter 5-FU chemotherapy-induced inflammation in bone, preserve osteoblasts, suppress osteoclast formation, and potentially be useful in preventing 5-FU chemotherapy-induced bone loss.

Population Pharmacokinetic-Pharmacodynamic Modeling of 5-Fluorouracil for Toxicities in Rats.

PubMed

Kobuchi, Shinji; Ito, Yukako; Sakaeda, Toshiyuki

2017-08-01

Myelosuppression is a dose-limiting toxicity of 5-fluorouracil (5-FU). Predicting the inter- and intra-patient variability in pharmacokinetics and toxicities of 5-FU may contribute to the individualized medicine. This study aimed to establish a population pharmacokinetic-pharmacodynamic model that could evaluate the inter- and intra-individual variability in the plasma 5-FU concentration, 5-FU-induced body weight loss and myelosuppression in rats. Plasma 5-FU concentrations, body weight loss, and blood cell counts in rats following the intravenous administration of various doses of 5-FU for 4 days were used to develop the population pharmacokinetic-pharmacodynamic model. The population pharmacokinetic model consisting of a two-compartment model with Michaelis-Menten elimination kinetics successfully characterized the individual and population predictions of the plasma concentration of 5-FU and provided credible parameter estimates. The estimates of inter-individual variability in maximal rate of saturable metabolism and residual variability were 8.1 and 22.0%, respectively. The population pharmacokinetic-pharmacodynamic model adequately described the individual complete time-course of alterations in body weight loss, erythrocyte, leukocyte, and lymphocyte counts in rats treated with various doses of 5-FU. The inter-individual variability of the drug effects in the pharmacodynamic model for body weight loss was 82.6%, which was relatively high. The results of the present study suggest that not only individual fluctuations in the 5-FU concentration but also the cell sensitivity would affect the onset and degree of 5-FU-induced toxicity. This population pharmacokinetic-pharmacodynamic model could evaluate the inter- and intra-individual variability in drug-induced toxicity and guide the assessments of novel anticancer agents in drug development.

The Herb-Drug Pharmacokinetic Interaction of 5-Fluorouracil and Its Metabolite 5-Fluoro-5,6-Dihydrouracil with a Traditional Chinese Medicine in Rats.

PubMed

Liu, Ju-Han; Cheng, Yung-Yi; Hsieh, Chen-Hsi; Tsai, Tung-Hu

2017-12-23

Xiang-Sha-Liu-Jun-Zi-Tang (XSLJZT) is the most common traditional formula given to colorectal and breast cancer patients in Taiwan, according to a statistical study of the National Health Insurance Research Database. 5-Fluorouracil (5-FU) is widely used as the first line of treatment for colorectal cancer. Thus, the aim of study is to investigate the pharmacokinetic interaction of XSLJZT and 5-FU. To investigate the herb-drug interaction of XSLJZT with 5-FU as well as its metabolite 5-fluoro-5,6-dihydrouracil (5-FDHU) using pharmacokinetics, a high-performance liquid chromatography (HPLC) system coupled with a photodiode array detector was developed to monitor 5-FU and 5-FDHU levels in rat blood. Rats were divided into three cohorts, one of which was administered 5-FU (100 mg/kg, iv-intravenous) alone, while the other two groups were pretreated with low and high doses of XSLJZT (600 mg/kg/day or 2400 mg/kg/day for 5 consecutive days) in combination with 5-FU. The results demonstrated that 5-FU level was not significantly different between the group treated with only 5-FU and the group pretreated with a normal dose of XSLJZT (600 mg/kg/day). However, pharmacokinetic analysis revealed that pretreatment with a high dose of XSLJZT (2400 mg/kg/day) extended the residence time and increased the volume of distribution of 5-FU. No significant distinctions were found in 5-FDHU pharmacokinetic parameters at three doses of XSLJZT. Overall, the pharmacokinetic results confirm the safety of coadministering 5-FU with XSLJZT, and provide practical dosage information for clinical practice.

UFT and leucovorin: a review of its clinical development and therapeutic potential in the oral treatment of cancer.

PubMed

Hoff, P M; Pazdur, R; Benner, S E; Canetta, R

1998-07-01

UFT is an oral antineoplastic drug combining uracil and tegafur in a 4:1 molar ratio. Tegafur acts as a prodrug of 5-fluorouracil (5-FU), being slowly metabolized by cytochrome P450 to 5-FU. Uracil competitively inhibits the metabolism of 5-FU, resulting in increased plasma and tumor 5-FU concentrations. At equimolar doses, higher peak plasma 5-FU concentrations are achieved with UFT plus oral leucovorin with similar systemic 5-FU exposure compared with low-dose continuous 5-FU infusions. The elimination half-life of 5-FU following UFT administration is approximately 7 h compared with 0.2 h with i.v. 5-FU. In phase II studies of UFT plus oral leucovorin for the treatment of advanced colorectal cancer, response rates ranged from 25 to 42%. UFT plus oral leucovorin is well tolerated, with manageable diarrhea being the only dose-limiting toxicity; the regimen is not associated with significant myelosuppression, mucositis, hand-foot syndrome or alopecia. UFT, with or without leucovorin, has also been evaluated alone or in combination with other cytotoxic agents for the treatment of advanced lung, breast and gastric cancers. UFT has also been evaluated as adjuvant therapy for colorectal, breast, gastric, head and neck, and superficial bladder cancers. UFT plus leucovorin offers patients an entirely oral cancer treatment, and appears to provide potential advantages over bolus 5-FU regimens with regard to toxicity and convenience of administration. These benefits should be advantageous in the adjuvant setting, as well as in advanced disease settings in which palliation is an important consideration. Ongoing clinical trials will further define the role of this promising oral treatment regimen.

Influence of an elemental diet on 5-fluorouracil-induced morphological changes in the mouse salivary gland and colon.

PubMed

Kawashima, Rei; Fujimaki, Mio; Ikenoue, Yuka; Danjo, Keiko; Koizumi, Wasaburo; Ichikawa, Takafumi

2016-04-01

The elemental diet (ED) Elental® reportedly reduces adverse reactions to chemotherapy in digestive system cancer patients; however, the mechanism is unclear. Therefore, we verified the protective effect of ED against gastrointestinal disorders induced by the antineoplastic drug 5-fluorouracil (5-FU). After 5 days of tail vein injections of 40 mg/kg/day 5-FU in female BALB/c mice, the mice were given oral ED (ED group) or dextrin with the same number of calories (control group). We measured the weight of salivary glands and the PAS-positive area of colonic mucosa and verified the antitumor effect in tumor-bearing mice given 5-FU and ED. Although body weight decreased after 5-FU treatment, ED group mice weighed more than control group mice. Additionally, although control mice developed diarrhea after 5-FU treatment, the ED group showed only loose stools. The control group saliva volume was approximately one sixth of the vehicle group volume after 5-FU treatment; this was improved to approximately half in the ED group. The area ratio of PAS-positive cells in the colonic mucosa was reduced by 5-FU treatment, with the ratio being higher in the ED group than that in the control group. Similar tumor growth suppression was observed in the 5-FU and ED groups. ED alleviated adverse reactions to 5-FU without affecting antitumor activity. Protection against 5-FU-induced weight loss was potentially due to both improved nutritional support with combined ingredients and prevention of diarrhea that is associated with reduced colonic goblet cells and decreased saliva production from reduced salivary gland contraction.

Conversion of 5-fluorocytosine to 5-fluorouracil by human intestinal microflora

DOE Office of Scientific and Technical Information (OSTI.GOV)

Harris, B.; Manning, B.; Federle, T.

1986-03-01

5-Fluorocytosine (FC) is used to treat systemic fungal infections in man. Its clinical effectiveness has been limited by hematologic toxicity which may be secondary to the formation of 5-fluorouracil (FU). It is unclear how FU is formed since human cells lack cytosine deaminase. The present study examined if intestinal microflora (IMF) could convert FC to FU in man. An in vitro semicontinuous culture system was inoculated with human feces and maintained with sterile nutrient suspension. The microbial community was assessed for cell count and anaerobes as well as formation of volatile fatty acids and CH/sub 4/. The system approximated thatmore » believed to occur in vivo. The study was initiated with addition of purified (6-/sup 14/C)-FC. Unlabelled FC was then added to the system daily for 2 weeks following which (6-/sup 14/C)-FC was again added. Following each addition of (6-/sup 14/C)-FC, samples were removed at 2,4,8,24,48,72, and 96 hr. Utilizing HPLC, FC and FU could be separated with quantitation of radioactivity in each peak. Following the initial dose, no detectable FU was observed during the first 8 hr, but after 24 hr increasing levels were detected (9.42 ..mu..g FU/ml after 4 days). Following chronic administration of FC, increased levles of FU were noted without an 8 hr lag time in the production of FU (31.86 ..mu..g FU/ml after 4 days). In summary, these studies demonstrate that IMF can convert FC to FU possibly accounting for toxicity observed following administration of FC.« less

Lipid metabolism of commercial layers fed diets containing aflatoxin, fumonisin, and a binder.

PubMed

Siloto, E V; Oliveira, E F A; Sartori, J R; Fascina, V B; Martins, B A B; Ledoux, D R; Rottinghaus, G E; Sartori, D R S

2013-08-01

Aflatoxins (AF) and fumonisins (FU) are a major problem faced by poultry farmers, leading to huge economic losses. This experiment was conducted to determine the effects of AF (1 mg/kg of feed) and FU (25 mg/kg of feed), singly or in combination, on the lipid metabolism in commercial layers and investigate the efficacy of a commercial binder (2 kg/t of feed) on reducing the toxic effects of these mycotoxins. A total of 168 Hisex Brown layer hens, 37 wk of age, were randomized into a 3 × 2 + 1 factorial arrangement (3 diets with no binder containing AF, FU, and AF+FU; 3 diets with binder containing AF, FU, and AF+FU; and a control diet with no mycotoxins and binders), totaling 7 treatments. The hens contaminated with AF showed the characteristic effects of aflatoxicosis, such as a yellow liver, resulting from the accumulation of liver fat, lower values of plasma very low-density lipoprotein and triglycerides, and higher relative weight of the kidneys and liver. Hepatotoxic and nephrotoxic effects of FU were not observed in this study. On the other hand, the FU caused a reduction in small intestine length and an increase in abdominal fat deposition. The glucan-based binder prevented some of the deleterious effects of these mycotoxins, particularly the effects of AF on hepatic lipid metabolism, kidney relative weight, and FU in the small intestine.

Application of artificial neural network to investigate the effects of 5-fluorouracil on ribonucleotides and deoxyribonucleotides in HepG2 cells

PubMed Central

Guo, Jianru; Chen, QianQian; Lam, Christopher Wai Kei; Wang, Caiyun; Wong, Vincent Kam Wai; Xu, Fengguo; Jiang, ZhiHong; Zhang, Wei

2015-01-01

Endogenous ribonucleotides and deoxyribonucleotides are essential metabolites that play important roles in a broad range of key cellular functions. Their intracellular levels could also reflect the action of nucleoside analogues. We investigated the effects of 5-fluorouracil (5-FU) on ribonucleotide and deoxyribonucleotide pool sizes in cells upon exposure to 5-FU for different durations. Unsupervised and supervised artificial neural networks were compared for comprehensive analysis of global responses to 5-FU. As expected, deoxyuridine monophosphate (dUMP) increased after 5-FU incubation due to the inhibition of thymine monophosphate (TMP) synthesis. Interestingly, the accumulation of dUMP could not lead to increased levels of deoxyuridine triphosphate (dUTP) and deoxyuridine diphosphate (dUDP). After the initial fall in intracellular deoxythymidine triphosphate (TTP) concentration, its level recovered and increased from 48 h exposure to 5-FU, although deoxythymidine diphosphate (TDP) and TMP continued to decrease compared with the control group. These findings suggest 5-FU treatment caused unexpected changes in intracellular purine polls, such as increases in deoxyadenosine triphosphate (dATP), adenosine-triphosphate (ATP), guanosine triphosphate (GTP) pools. Further elucidation of the mechanism of action of 5-FU in causing these changes should enhance development of strategies that will increase the anticancer activity of 5-FU while decreasing its resistance. PMID:26578061

Construction of METHFR shRNA/5-fluorouracil co-loaded folate-targeted chitosan polymeric nanoparticles and its anti-carcinoma effect on gastric cells growth

NASA Astrophysics Data System (ADS)

Xin, Lin; Fan, Ji-Chang; Le, Yi-Guan; Zeng, Fei; Cheng, Hua; Hu, Xiao-yun; Cao, Jia-Qing

2016-05-01

PEGylated and folate-targeted chitosan polymeric nanoparticles (FPNs) for the treatment of gastric carcinoma were prepared successfully. OQC-anchored folate conjugates were synthesized and used in assembling FPNs nano-system for enhancing intracellular uptake against folate receptor overexpressing cancer cells. The results indicated that folate-targeted chitosan polymeric nanoparticles (CPNs) can reverse drug-resistant SGC-7901 cells of 5-fluorouracil (5-FU) compared with non-targeted CPNs. Increased therapeutic efficiency of 5-FU/METHFR shRNA co-loaded PNs were also tested in SGC-7901 cells and compaed with 5-FU or METHFR shRNA in solution, which was associated with increased cell inhibition function for single drug group and synergistic effects of 5-FU and METHFR shRNA at 2.0 µg/mL FPNs concentration. In addition, the cell accumulation levels of 5-FU in SGC-7901 cells was time dependent for these nanoparticles. FPNs (effective diameter: 83.2 ± 1.1 nm; polydispersity index: 0.193) could significantly boost cellular accumulation of 5-FU and overcome the drug efflux mechanism of MDR than 5-FU-loaded NPNs and 5-FU in solution. In conclusion, ligand-targeted PNs can be used as a potentially effective drug delivery system.

Anti-influenza A virus characteristics of a fucoidan from sporophyll of Undaria pinnatifida in mice with normal and compromised immunity.

PubMed

Hayashi, Kyoko; Lee, Jung-Bum; Nakano, Takahisa; Hayashi, Toshimitsu

2013-04-01

Undaria pinnatifida, an edible brown alga, contains fucoidan (FuC), a sulfated polysaccharide, that inhibited the in vitro replication of influenza A virus, and stimulated both innate and adaptive immune defense functions in virus-infected mice. In the present study, the effects of oral administration of FuC were evaluated on influenza virus infection in immunocompetent and immunocompromised mice, where the efficacy of FuC was demonstrated in reducing viral replication, decreasing weight loss and mortality, and prolonging survival. Oral FuC resulted in increased neutralizing antibody production in the mucosa and blood. In contrast, while suppressing virus yields in mice more markedly than FuC, oseltamivir significantly reduced the neutralizing antibody titers in both the mucosa and blood. In immunocompromised mice, drug-resistant viruses frequently recovered after oseltamivir treatment; no resistant viruses were isolated from FuC-treated mice. FuC could be a candidate for the development of new therapeutic options including its combination with neuraminidase inhibitors such as oseltamivir. Copyright © 2013 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.

A Prospective Randomized Controlled Trial of the Efficacy of External Physical Vibration Lithecbole after Extracorporeal Shock Wave Lithotripsy for a Lower Pole Renal Stone Less Than 2 cm.

PubMed

Long, Qilai; Zhang, Jian; Xu, Zhibing; Zhu, Yanjun; Liu, Li; Wang, Hang; Guo, Jianming; Wang, Guomin

2016-04-01

We evaluate the efficacy and safety of external physical vibration lithecbole in improving the clearance rates of lower pole renal stones after shock wave lithotripsy. A total of 71 patients with lower pole renal stones (6 to 20 mm) were prospectively randomized into 2 groups. In the treatment group 34 patients were treated with external physical vibration lithecbole after shock wave lithotripsy. In the control group 37 patients underwent shock wave lithotripsy only. External physical vibration lithecbole was performed without anesthesia by the same team using the Friend-I External Physical Vibration Lithecbole (Fu Jian Da Medical Instrument Co., Ltd, Zhengzhou, China). The stone-free rate, stone expulsion rate, stone expulsion time and incidence of complications were monitored. External physical vibration lithecbole was successful in assisting the discharge of stone fragments. The stone-free status was 76.5% in the treatment group and 48.6% in the control group (p=0.008). Stone expulsion rates at day 1, week 1 and week 3 were 76.5% (26), 94.1% (32) and 94.1% (32) in the treatment group vs 43.2% (16), 73.0% (27) and 89.2% (33) in the control group, respectively. Mean stone fragment expulsion time was 11.2 minutes in the treatment group and 9.17 hours in the control group (p=0.016). There was no significant difference in complications between the 2 groups (p >0.05). External physical vibration lithecbole was efficacious in assisting the discharge of lower pole renal stone fragments and can be used as an adjunctive method of minimally invasive stone treatment. However, additional investigations are needed to confirm the efficacy. Copyright © 2016 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Ontology Matching Across Domains

DTIC Science & Technology

2010-05-01

matching include GMO [1], Anchor-Prompt [2], and Similarity Flooding [3]. GMO is an iterative structural matcher, which uses RDF bipartite graphs to...AFRL under contract# FA8750-09-C-0058. References [1] Hu, W., Jian, N., Qu, Y., Wang, Y., “ GMO : a graph matching for ontologies”, in: Proceedings of

Curcumin Enhances the Anticancer Effect Of 5-fluorouracil against Gastric Cancer through Down-Regulation of COX-2 and NF- κB Signaling Pathways.

PubMed

Yang, Hongru; Huang, Shaoqiu; Wei, Yumeng; Cao, Shousong; Pi, Chao; Feng, Ting; Liang, Jing; Zhao, Ling; Ren, Guosheng

2017-01-01

Background: 5-fluorouracil (5-FU) is one of the most commonly used first-line anticancer drugs to treat gastric cancer in clinical practice. However, severe adverse events such as gastrointestinal toxicity and bone marrow suppression limit its clinical application. Combination chemotherapy to combine two or more anticancer drugs with different mechanistic action is an effective anticancer strategy against gastric cancer. Therefore, we studied the anticancer effect of the combination of 5-FU with curcumin against gastric cancer MKN45 and AGS cells (normal gastric mucosal GES-1 cells as control) and associated molecular mechanisms. Methods: Cytotoxicity of 5-FU and curcumin alone or in combination was evaluated in MKN45, AGS and GES cells by MTT assay. The protein expressions of COX-2 and NF-κB were evaluated in MKN45 cells by Western blotting analysis. In addition, antitumor activity of 5-FU and curcumin alone or in combination was evaluated in nude mice bearing MKN45 tumor xenografts in vivo . Results: The combination of 5-FU and curcumin (2:1, mol/mol) showed 2.2-, 3.5-fold and 2.3-, 3.9-fold enhanced cytotoxic effect compared to 5-FU or curcumin alone and generated synergistic effect at the concentration of 5-FU (>4.09 and >5.71 μmol/l) and curcumin (>2.05 and > 2.86 μmol/l) in MKN45 cells for 48 h and 72 h exposures, respectively. The combination of 5-FU and curcumin also potentiated cytotoxicity in AGS cells compared to 5-FU or curcumin alone but the effect was moderate. However, the cytotoxicity of 5-FU and curcumin alone or in combination was much less in GES-1 cells. Furthermore, the protein expressions of COX-2 and NF-κB in MKN45 cells were decreased by 44.79% and 37.67%, 47.17% and 48.21%, 60.21% and 62.44%, respectively, after treatment of curcumin (25 μmol/l) and 5-FU (50 μmol/l) alone or in combination for 48 h. Curcumin also enhanced the anticancer activity of 5-FU without increasing toxicity in nude mice bearing MKN45 tumor xenografts in vivo

Relative emissions intensity of dairy production systems: employing different functional units in life-cycle assessment.

PubMed

Ross, S A; Topp, C F E; Ennos, R A; Chagunda, M G G

2017-08-01

This study aimed to assess the merit and suitability of individual functional units (FU) in expressing greenhouse gas emissions intensity in different dairy production systems. An FU provides a clearly defined and measurable reference to which input and output data are normalised. This enables the results from life-cycle assessment (LCA) of different systems to be treated as functionally equivalent. Although the methodological framework of LCA has been standardised, selection of an appropriate FU remains ultimately at the discretion of the individual study. The aim of the present analysis was to examine the effect of different FU on the emissions intensities of different dairy production systems. Analysis was based on 7 years of data (2004 to 2010) from four Holstein-Friesian dairy systems at Scotland's Rural College's long-term genetic and management systems project, the Langhill herd. Implementation of LCA accounted for the environmental impacts of the whole-farm systems and their production of milk from 'cradle to farm gate'. Emissions intensity was determined as kilograms of carbon dioxide equivalents referenced to six FU: UK livestock units, energy-corrected milk yield, total combined milk solids yield, on-farm land used for production, total combined on- and off-farm land used for production, and the proposed new FU-energy-corrected milk yield per hectare of total land used. Energy-corrected milk was the FU most effective for reflecting differences between the systems. Functional unit that incorporated a land-related aspect did not find difference between systems which were managed under the same forage regime, despite their comprising different genetic lines. Employing on-farm land as the FU favoured grazing systems. The proposed dual FU combining both productivity and land use did not differentiate between emissions intensity of systems as effectively as the productivity-based units. However, this dual unit displayed potential to quantify in a simple way

Bcl-2/Bax protein ratio predicts 5-fluorouracil sensitivity independently of p53 status

PubMed Central

Mirjolet, J-F; Barberi-Heyob, M; Didelot, C; Peyrat, J-P; Abecassis, J; Millon, R; Merlin, J-L

2000-01-01

p53 tumour-suppressor gene is involved in cell growth control, arrest and apoptosis. Nevertheless cell cycle arrest and apoptosis induction can be observed in p53-defective cells after exposure to DNA-damaging agents such as 5-fluorouracil (5-FU) suggesting the importance of alternative pathways via p53-independent mechanisms. In order to establish relationship between p53 status, cell cycle arrest, Bcl-2/Bax regulation and 5-FU sensitivity, we examined p53 mRNA and protein expression and p53 protein functionality in wild-type (wt) and mutant (mt) p53 cell lines. p53 mRNA and p53 protein expression were determined before and after exposure to equitoxic 5-FU concentration in six human carcinoma cell lines differing in p53 status and displaying marked differences in 5-FU sensitivity, with IC 50 values ranging from 0.2–22.6 mM. 5-FU induced a rise in p53 mRNA expression in mt p53 cell lines and in human papilloma virus positive wt p53 cell line, whereas significant decrease in p53 mRNA expression was found in wt p53 cell line. Whatever p53 status, 5-FU altered p53 transcriptional and translational regulation leading to up-regulation of p53 protein. In relation with p53 functionality, but independently of p53 mutational status, after exposure to 5-FU equitoxic concentration, all cell lines were able to arrest in G1. No relationship was evidenced between G1 accumulation ability and 5-FU sensitivity. Moreover, after 5-FU exposure, Bax and Bcl-2 proteins regulation was under p53 protein control and a statistically significant relationship (r= 0.880,P= 0.0097) was observed between Bcl-2/Bax ratio and 5-FU sensitivity. In conclusion, whatever p53 status, Bcl-2 or Bax induction and Bcl-2/Bax protein ratio were correlated to 5-FU sensitivity. © 2000 Cancer Research Campaign PMID:11044365

Panaxadiol, a purified ginseng component, enhances the anti-cancer effects of 5-fluorouracil in human colorectal cancer cells.

PubMed

Li, Xiao-Li; Wang, Chong-Zhi; Mehendale, Sangeeta R; Sun, Shi; Wang, Qi; Yuan, Chun-Su

2009-11-01

Colorectal cancer is a major cause of morbidity and mortality for cancer worldwide. Although 5-fluorouracil (5-FU) is one of the most widely used chemotherapeutic agents in first-line therapy for colorectal cancer, serious side effects limit its clinical usefulness. Panaxadiol (PD) is the purified sapogenin of ginseng saponins, which exhibit anti-tumor activity. In this study, we investigated the possible synergistic anti-cancer effects of PD and 5-FU on a human colorectal cancer cell line, HCT-116. Cell viability was evaluated by an MTS cell proliferation assay. Morphological observation was performed by crystal violet cell viability staining assay. Cell cycle distribution and apoptotic effects were analyzed by flow cytometry after staining with PI/RNase or Annexin V/PI. Cell growth was markedly suppressed in HCT-116 cells treated by 5-FU (20-100 microM) for 24 or 48 h with time-dependent effects. The significant suppression on HCT-116 cell proliferation was observed after treatment with PD (25 microM) for 24 and 48 h. Panaxadiol (25 microM) markedly (P < 0.05) enhanced the anti-proliferative effects of 5-FU (5, 10, 20 microM) on HCT-116 cells compared to single treatment of 5-FU for 24 and 48 h. Flow cytometric analysis on DNA indicated that PD and 5-FU selectively arrested cell cycle progression in the G1 phase and S phase (P < 0.01), respectively, compared to the control condition. Combination use of 5-FU with PD significantly (P < 0.001) increased cell cycle arrest in the S phase compared to that treated by 5-FU alone. The combination of 5-FU and PD significantly enhanced the percentage of apoptotic cells when compared with the corresponding cell groups treated by 5-FU alone (P < 0.001). Panaxadiol enhanced the anti-cancer effects of 5-FU on human colorectal cancer cells through the regulation of cell cycle transition and the induction of apoptotic cells.

Orotate phosphoribosyl transferase mRNA expression and the response of cholangiocarcinoma to 5-fluorouracil

PubMed Central

Hahnvajanawong, Chariya; Chaiyagool, Jariya; Seubwai, Wunchana; Bhudhisawasdi, Vajarabhongsa; Namwat, Nisana; Khuntikeo, Narong; Sripa, Banchob; Pugkhem, Ake; Tassaneeyakul, Wichittra

2012-01-01

AIM: To determine whether expression of certain enzymes related to 5-fluorouracil (5-FU) metabolism predicts 5-FU chemosensitivity in cholangiocarcinoma (CCA). METHODS: The histoculture drug response assay (HDRA) was performed using surgically resected CCA tissues. Tumor cell viability was determined morphologically with hematoxylin and eosin- and terminal deoxynucleotide transferase-mediated dUTP nick-end labeling-stained tissues. The mRNA expression of thymidine phosphorylase (TP), orotate phosphoribosyl transferase (OPRT), thymidylate synthase (TS), and dihydropyrimidine dehydrogenase (DPD) was determined with real-time reverse transcriptase-polymerase chain reaction. The levels of gene expression and the sensitivity to 5-FU were evaluated. RESULTS: Twenty-three CCA tissues were obtained from patients who had been diagnosed with intrahepatic CCA and who underwent surgical resection at Srinagarind Hospital, Khon Kaen University from 2007 to 2009. HDRA was used to determine the response of these CCA tissues to 5-FU. Based on the dose-response curve, 200 μg/mL 5-FU was selected as the test concentration. The percentage of inhibition index at the median point was selected as the cut-off point to differentiate the responding and non-responding tumors to 5-FU. When the relationship between TP, OPRT, TS and DPD mRNA expression levels and the sensitivity of CCA tissues to 5-FU was examined, only OPRT mRNA expression was significantly correlated with the response to 5-FU. The mean expression level of OPRT was significantly higher in the responder group compared to the non-responder group (0.41 ± 0.25 vs 0.22 ± 0.12, P < 0.05). CONCLUSION: OPRT mRNA expression may be a useful predictor of 5-FU chemosensitivity of CCA. Whether OPRT mRNA could be used to predict the success of 5-FU chemotherapy in CCA patients requires confirmation in patients. PMID:22912546

A novel antimicrobial therapy for the control of Aeromonas hydrophila infection in aquaculture using marine polysaccharide coated gold nanoparticle.

PubMed

Vijayakumar, Sekar; Vaseeharan, Baskaralingam; Malaikozhundan, Balasubramanian; Gobi, Narayanan; Ravichandran, Samuthirapandian; Karthi, Sellamuthu; Ashokkumar, Balasubramaniem; Sivakumar, Natesan

2017-09-01

In the present study, we prepared fucoidan coated Au-NPs (Fu-AuNPs), and examined its antimicrobial activity against Aeromonas hydrophila. The green synthesized Fu-AuNPs were bio-physically characterized by Ultraviolet-visible (UV-Vis) spectroscopy, X-ray Diffraction (XRD), Fourier Transform Infrared spectroscopy (FTIR), Higher Transmission Electron Microscopy (HR-TEM), Zeta potential analysis and Energy Dispersive X-ray spectroscopy (EDX). Fu-AuNPs were crystalline in nature, spherical to triangular in shape, with particle size ranging within 10-100 nm. The synthesized Fu-AuNPs at 100 μg mL -1 showed inhibition zone against A. hydrophila (23.2 mm) which is much higher than that of commercial antibiotic chloramphenicol (17.3 mm). The biofilm inhibitory activity of Fu-AuNPs against Gram negative (Aeromonas hydrophila) was higher. Light and confocal laser scanning microscopic observations showed that the Fu-AuNPs at 100 μg mL -1 inhibited the biofilm of A. hydrophila. The cytotoxicity study indicated that Fu-AuNPs were effective in inhibiting the viability of human cervical cancer cells (HeLa) at 100 μg mL -1 . In another experiment, the antibacterial effect of Fu-AuNPs on tilapia, Oreochromis mossambicus were evaluated in vivo. The mortality rate of O. mossambicus infected by A. hydrophila was much higher (90%), whereas, the mortality of O. mossambicus that received Fu-AuNPs followed by challenge with A. hydrophia was reduced to 30%. This study concludes that Fu-AUNPs are effective in the control of A. hydrophila infections in O. mossambicus. Copyright © 2017 Elsevier Ltd. All rights reserved.

Differential activation of cell death and autophagy results in an increased cytotoxic potential for trifluorothymidine compared to 5-fluorouracil in colon cancer cells.

PubMed

Bijnsdorp, Irene V; Peters, Godefridus J; Temmink, Olaf H; Fukushima, Masakazu; Kruyt, Frank A

2010-05-15

Trifluorothymidine (TFT) is part of the oral drug formulation TAS-102. Both 5-fluorouracil (5-FU) and TFT can inhibit thymidylate synthase and be incorporated into DNA. TFT shows only moderate cross-resistance to 5-FU. Therefore, we examined whether mechanistic differences in cell death could underlie their different modes of action in colorectal cancer cell lines (WiDR, Lovo92 and Colo320). Drug cytotoxicity was determined by SRB- and clonogenic assays, cell death by flow cytometry (PI and annexin V), caspase cleavage by Western blotting and activity assays and in vivo activity in the hollow fiber assay. The IC(50) values of TFT were 1-6 fold lower than for 5-FU, and clonogenic survival was less than 0.9% at 3 muM TFT, while 2-20% of the cells still survived after 20 muM 5-FU. In general, TFT was a more potent inducer of apoptosis than 5-FU, although the contribution of caspases varied between the used cell lines and necrosis-like cell death was detected. Accordingly, both drugs induced caspase (Z-VAD) independent cell death and lysosomal cathepsin B was involved. Activation of autophagy recovery mechanisms was only triggered by 5-FU, but not by TFT as determined by LC3B expression and cleavage. Inhibition of autophagy by 3-MA in 5-FU exposed cells reduced cell survival. Also, in vivo TFT (as TAS-102) caused more cell death than a 5-FU formulation. We conclude that TFT and 5-FU induce cell death via both caspase-dependent and independent mechanisms. The TFT was more potent than 5-FU, because it induces higher levels of cell death and does not elicit an autophagic survival response in the cancer cell lines. This provides a strong molecular basis for further application of TFT in cancer therapy.

What evidence do we have to replace in-hospital implantable cardioverter defibrillator follow-up?

PubMed

Brugada, P

2006-01-01

Due to the increasing number of patients with an implantable cardioverter defibrillator (ICD), new options for ICD patient follow-up management are required. Patients with ICD indication according to the guidelines received an ICD with Home Monitoring technology. The devices enabled the transmission of the relevant episode, therapy, and system integrity data. Patients were followed for 12 months with routine controls every 3 months. The physician analyzed the Home Monitoring data before the routine follow-up visit (FU) and gave a forecast on the necessity of the pending FU, which was compared with the evaluation after the FU. Based on the derived forecast reliability, a patient management scheme was developed and its impact on patient safety was assessed retrospectively. A total of 271 patients were enrolled (40 f, mean age 62+/-12 years, mean LVEF 39+/-15%, 65% ischemic heart disease, 20% cardiomyopathy) and followed for 339+/-109 days. Of 908 pairs of Home Monitoring data and FU data evaluation, 129 there were false negative results for 92 patients. Safety concerns from false negative forecasts can be minimized with a patient management scheme containing the following elements: 1) never skip the first routine FU; 2) never skip a routine FU for a patient having already shown pacing threshold problems; 3) perform FU following hospitalizations; 4) perform FU following episode detection by the ICD; and 5) perform a routine FU if the patient reports symptoms. The retrospective analysis showed, that if the patients had been managed using this scheme, 503 of 1079 routine FU could have been skipped with only one safety concern, a three month delay in the detection of silent paroxysmal atrial fibrillation in one patient. Home Monitoring in ICD therapy over 12 months is feasible. The data transmitted relevantly contribute to a remarkable reduction of follow-up burden and enable the individualization of routine follow-up.

May cannabinoids prevent the development of chemotherapy-induced diarrhea and intestinal mucositis? Experimental study in the rat.

PubMed

Abalo, R; Uranga, J A; Pérez-García, I; de Andrés, R; Girón, R; Vera, G; López-Pérez, A E; Martín-Fontelles, M I

2017-03-01

The antineoplastic drug 5-fluoruracil (5-FU) is a pirimidine analog, which frequently induces potentially fatal diarrhea and mucositis. Cannabinoids reduce gastrointestinal motility and secretion and might prevent 5-FU-induced gut adverse effects. Here, we asked whether cannabinoids may prevent diarrhea and mucositis induced by 5-FU in the rat. Male Wistar rats received vehicle or the non-selective cannabinoid agonist WIN 55,212-2 (WIN; 0.5 mg kg -1 injection -1 , 1 injection day -1 , 4 consecutive days) by intraperitoneal (ip) route; on the first 2 days, animals received also saline or 5-FU (150 mg kg -1 injection -1 , cumulative dose of 300 mg kg -1 ). Gastrointestinal motor function was radiographically studied after barium contrast intragastric administration on experimental days 1 and 4. Structural alterations of the stomach, small intestine and colon were histologically studied on day 4. PAS staining and immunohistochemistry for Ki67, chromogranin A and CD163 were used to detect secretory, proliferating, and endocrine cells, and activated macrophages respectively. As shown radiographically, 5-FU induced significant gastric emptying delay (on days 1 and 4) and diarrhea (on day 4). WIN did not significantly alter the motility curves obtained for either control or 5-FU-treated animals but tended to reduce the severity of 5-FU-induced diarrhea and increased permanence of barium from day 1 to the beginning of day 4 in 5-FU-treated animals. 5-FU-induced mucositis was severe and not counteracted by WIN. 5-FU-induced diarrhea, but not mucositis, was partly prevented by WIN at a low dose. Cannabinoids might be useful to prevent chemotherapy-induced diarrhea. © 2016 John Wiley & Sons Ltd.

Development and characterization of hyaluronic acid decorated PLGA nanoparticles for delivery of 5-fluorouracil.

PubMed

Yadav, Awesh K; Agarwal, Abhinav; Rai, Gopal; Mishra, Pradeep; Jain, Sanyog; Mishra, Anil K; Agrawal, Himanshu; Agrawal, Govind P

2010-11-01

The present investigation was aimed to develop and explore the prospective of engineered PLGA nanoparticles as vehicles for targeted delivery of 5-fluorouracil (5-FU). Nanoparticles of 5-FU-loaded hyaluronic acid-poly(ethylene glycol)-poly(lactide-co-glycolide) (HA-PEG-PLGA-FU) copolymer were prepared and characterized by FTIR, NMR, transmission electron microscopy, particle size analysis, DSC, and X-ray diffractometer measurement studies. The nanoparticulate formulation was evaluated for in vitro release, hemolytic toxicity, and hematological toxicity. Cytotoxicity studies were performed on Ehrlich ascites tumor (EAT) cell lines using MTT cell proliferation assay. Biodistribution studies of 99m Tc labeled formulation were conducted on EAT-bearing mice. The in vivo tumor inhibition study was also performed after i.v. administration of HA-PEG-PLGA-FU nanoparticles. The HA conjugated formulation was found to be less hemolytic but more cytotoxic as compared to free drug. The hematological data suggested that HA-PEG-PLGA-FU formulation was less immunogenic compared to plain drug. The tissue distribution studies displayed that HA-PEG-PLGA-FU were able to deliver a higher concentration of 5-FU in the tumor mass. In addition, the HA-PEG-PLGA-FU nanoparticles reduced tumor volume significantly in comparison with 5-FU. Thus, it was concluded that the conjugation of HA imparts targetability to the formulation, and enhanced permeation and retention effect ruled out its access to the non-tumor tissues, at the same time favored selective entry in tumors, thereby reducing the side-effects both in vitro and in vivo.

Cadmium modifies the cell cycle and apoptotic profiles of human breast cancer cells treated with 5-fluorouracil.

PubMed

Asara, Yolande; Marchal, Juan A; Carrasco, Esther; Boulaiz, Houria; Solinas, Giuliana; Bandiera, Pasquale; Garcia, Maria A; Farace, Cristiano; Montella, Andrea; Madeddu, Roberto

2013-08-12

Industrialisation, the proximity of factories to cities, and human work activities have led to a disproportionate use of substances containing heavy metals, such as cadmium (Cd), which may have deleterious effects on human health. Carcinogenic effects of Cd and its relationship with breast cancer, among other tumours, have been reported. 5-Fluorouracil (5-FU) is a fluoropyrimidine anticancer drug used to treat solid tumours of the colon, breast, stomach, liver, and pancreas. The purpose of this work was to study the effects of Cd on cell cycle, apoptosis, and gene and protein expression in MCF-7 breast cancer cells treated with 5-FU. Cd altered the cell cycle profile, and its effects were greater when used either alone or in combination with 5-FU compared with 5-FU alone. Cd significantly suppressed apoptosis of MCF-7 cells pre-treated with 5-FU. Regarding gene and protein expression, bcl2 expression was mainly upregulated by all treatments involving Cd. The expression of caspase 8 and caspase 9 was decreased by most of the treatments and at all times evaluated. C-myc expression was increased by all treatments involving Cd, especially 5-FU plus Cd at the half time of treatment. Cd plus 5-FU decreased cyclin D1 and increased cyclin A1 expression. In conclusion, our results indicate that exposure to Cd blocks the anticancer effects of 5-FU in MCF-7 cells. These results could have important clinical implications in patients treated with 5-FU-based therapies and who are exposed to high levels of Cd.

5-Fluorouracil as an enhancer of aminolevulinate-based photodynamic therapy for skin cancer: New use for a venerable agent?

NASA Astrophysics Data System (ADS)

Maytin, Edward V.; Anand, Sanjay; Wilson, Clara; Iyer, Karthik

2011-02-01

5-Fluorouracil (5-FU) was developed in the 1950s as an anticancer drug and is now widely used to treat many cancers, including colon and breast carcinoma. 5-FU causes fluoronucleotide misincorporation into RNA and DNA, inhibits thymidylate synthase, and leads to growth arrest and apoptosis. For skin precancers (actinic keratoses; AK), 5-FU is prescribed as a topical agent and was essentially the only option for treating widespread AK of the skin prior to FDA approval of photodynamic therapy (PDT) in 1999. PDT is now gradually replacing 5-FU as a preferred treatment for AK, but neither PDT nor 5-FU are effective for true skin cancers (basal or squamous cell), particularly for tumors >1 mm in depth. In our ongoing work to improve the efficacy of PDT for skin cancer, we previously showed that PDT efficacy can be significantly enhanced by preconditioning tumors with methotrexate (MTX), which leads to increased production of protoporphyrin IX (PpIX) in target cells. However, because MTX must be given orally or intravenously, it is considered unacceptable for widespread human use due to potential toxicity. MTX and 5-FU exert similar effects on the thymidylate synthesis pathway, so we reasoned that topical 5-FU could be a potential alternative to MTX. In this paper, exploratory studies that test 5-FU as a preconditioning agent for PDT are presented. In a cutaneous model of squamous cell carcinoma (chemically-induced papillomatous tumors in mice), 5-FU significantly enhances PpIX accumulation and therefore emerges as a new candidate agent for combination therapy with PDT.

Cadmium Modifies the Cell Cycle and Apoptotic Profiles of Human Breast Cancer Cells Treated with 5-Fluorouracil

PubMed Central

Asara, Yolande; Marchal, Juan A.; Carrasco, Esther; Boulaiz, Houria; Solinas, Giuliana; Bandiera, Pasquale; Garcia, Maria A.; Farace, Cristiano; Montella, Andrea; Madeddu, Roberto

2013-01-01

Industrialisation, the proximity of factories to cities, and human work activities have led to a disproportionate use of substances containing heavy metals, such as cadmium (Cd), which may have deleterious effects on human health. Carcinogenic effects of Cd and its relationship with breast cancer, among other tumours, have been reported. 5-Fluorouracil (5-FU) is a fluoropyrimidine anticancer drug used to treat solid tumours of the colon, breast, stomach, liver, and pancreas. The purpose of this work was to study the effects of Cd on cell cycle, apoptosis, and gene and protein expression in MCF-7 breast cancer cells treated with 5-FU. Cd altered the cell cycle profile, and its effects were greater when used either alone or in combination with 5-FU compared with 5-FU alone. Cd significantly suppressed apoptosis of MCF-7 cells pre-treated with 5-FU. Regarding gene and protein expression, bcl2 expression was mainly upregulated by all treatments involving Cd. The expression of caspase 8 and caspase 9 was decreased by most of the treatments and at all times evaluated. C-myc expression was increased by all treatments involving Cd, especially 5-FU plus Cd at the half time of treatment. Cd plus 5-FU decreased cyclin D1 and increased cyclin A1 expression. In conclusion, our results indicate that exposure to Cd blocks the anticancer effects of 5-FU in MCF-7 cells. These results could have important clinical implications in patients treated with 5-FU-based therapies and who are exposed to high levels of Cd. PMID:23941782

Effect of histone deacetylase inhibitor in combination with 5-fluorouracil on pancreas cancer and cholangiocarcinoma cell lines.

PubMed

Iwahashi, Shuichi; Ishibashi, Hiroki; Utsunomiya, Tohru; Morine, Yuji; Ochir, Tovuu Lkhaguva; Hanaoka, Jun; Mori, Hiroki; Ikemoto, Tetsuya; Imura, Satoru; Shimada, Mitsuo

2011-02-01

Histone deacetylase (HDAC) is well known to be associated with tumorigenesis through epigenetic regulation, and its inhibitors (HDACIs) induce differentiation and apoptosis of tumor cells. We examined the therapeutic effects of valproic acid (VPA, a HDACI) with a combination of 5-fluorouracil (5-FU) in vitro. A human pancreas cancer cell line (SUIT-2) and a cholangiocarcinoma cell line (HuCCT1) were used. Cell viabilities were evaluated by a cell proliferation assay. We determined the anticancer effects of VPA combined with 5-FU in these cell lines. Pancreas cancer (SUIT-2): No effect of 5-FU (1.0 µM) was observed, but 17% and 30% of proliferation-inhibitory effects were recognized in a dose of 2.5 or 5.0 µM, respectively. Cell viability was only weakly reduced by VPA (0.5 mM). However, in combination of 5-FU (1.0 µM) with VPA (0.5 mM), 19% of inhibitory effect was observed. Cholangiocarcinoma (HuCCT1): 5-FU (1.0 µM) did not suppress the cell viability, but 5-FU (2.5 µM) suppressed by 23%. VPA (0.5 mM) did not suppress the cell viability, while VPA (1.0 mM) weakly decreased it by 11%. Combination of 5-FU (1.0 µM) and VPA (0.5 mM) markedly reduced the cell viability by 30%. VPA augmented the anti-tumor effects of 5-FU in cancer cell lines. Therefore, a combination therapy of 5-FU plus VPA may be a promising therapeutic option for patients with pancreas cancer and cholangiocarcinoma.

Novel mRNA isoforms and mutations of uridine monophosphate synthetase and 5-fluorouracil resistance in colorectal cancer.

PubMed

Griffith, M; Mwenifumbo, J C; Cheung, P Y; Paul, J E; Pugh, T J; Tang, M J; Chittaranjan, S; Morin, R D; Asano, J K; Ally, A A; Miao, L; Lee, A; Chan, S Y; Taylor, G; Severson, T; Hou, Y-C; Griffith, O L; Cheng, G S W; Novik, K; Moore, R; Luk, M; Owen, D; Brown, C J; Morin, G B; Gill, S; Tai, I T; Marra, M A

2013-04-01

The drug fluorouracil (5-FU) is a widely used antimetabolite chemotherapy in the treatment of colorectal cancer. The gene uridine monophosphate synthetase (UMPS) is thought to be primarily responsible for conversion of 5-FU to active anticancer metabolites in tumor cells. Mutation or aberrant expression of UMPS may contribute to 5-FU resistance during treatment. We undertook a characterization of UMPS mRNA isoform expression and sequence variation in 5-FU-resistant cell lines and drug-naive or -exposed primary and metastatic tumors. We observed reciprocal differential expression of two UMPS isoforms in a colorectal cancer cell line with acquired 5-FU resistance relative to the 5-FU-sensitive cell line from which it was derived. A novel isoform arising as a consequence of exon skipping was increased in abundance in resistant cells. The underlying mechanism responsible for this shift in isoform expression was determined to be a heterozygous splice site mutation acquired in the resistant cell line. We developed sequencing and expression assays to specifically detect alternative UMPS isoforms and used these to determine that UMPS was recurrently disrupted by mutations and aberrant splicing in additional 5-FU-resistant colorectal cancer cell lines and colorectal tumors. The observed mutations, aberrant splicing and downregulation of UMPS represent novel mechanisms for acquired 5-FU resistance in colorectal cancer.

Poloxamer 188 and propylene glycol-based rectal suppository enhances anticancer effect of 5-fluorouracil in mice.

PubMed

Paek, Seung-Hwan; Xuan, Jing-Ji; Choi, Han-Gon; Park, Byung Chul; Lee, Yoon-Seok; Jeong, Tae-Cheon; Jin, Chun Hua; Oh, Yu-Kyoung; Kim, Jung-Ae

2006-05-01

The tumoricidal and apoptosis-inducing activities of 5-fluorouracil (5-FU) have been demonstrated in experimental and clinical investigations. Clinically, the 5-FU suppository form has been widely adopted for its advantages of less systemic toxicity, higher local tissue concentrations, and reduced first-pass effect. In this study, we investigated the feasibility of rectal administration of 5-FU suppository based on poloxamer 188 (P188) and propylene glycol (PG) and its anticancer effect on the murine experimental cancer models. The rectal suppository was made with 70% P188 and 30% PG, which was a solid phase at room temperature and instantly melted at physiological temperature. The treatment with the 5-FU suppository was more effective than the oral route in decreasing the volume of rectal cancer in mice. In addition, the survival rate of the mice with rectal cancer was higher in the group treated with the 5-FU suppository than in the group treated with 5-FU orally. Furthermore, in mice skin cancers induced by inoculation of murine CT-26 colon carcinoma cells, the anticancer effect of 5-FU was significantly enhanced by the rectal administration of the suppository than by oral treatment. Taken together, the results suggest that a poloxamer gel system with 5-FU/P188/PG is an effective rectal dosage form for the treatment of both rectal and non-rectal cancers.

Preparation Matters

ERIC Educational Resources Information Center

Dougherty, Chrys; Mellor, Lynn

2009-01-01

In "Orange Juice or Orange Drink?," the authors provided evidence that many students are receiving credit for courses with little indication that they have learned the content implied by the course titles (Dougherty, Mellor, & Jian, 2006). Yet in pursuit of the goal of preparing all students for college and careers, many policymakers…

How Much Do You Trust Me? Learning a Case-Based Model of Inverse Trust

DTIC Science & Technology

2014-10-01

155–156 5. Jian, J.Y., Bisantz, A.M., Drury , C.G.: Foundations for an empirically determined scale of trust in automated systems. International...517–527 8. Carlson, M.S., Desai, M., Drury , J.L., Kwak, H., Yanco, H.A.: Identifying factors that influence trust in automated cars and medical

High glucose-induced resistance to 5-fluorouracil in pancreatic cancer cells alleviated by 2-deoxy-D-glucose.

PubMed

Cheng, Yao; Diao, Dongmei; Zhang, Hao; Guo, Qi; Wu, Xuandi; Song, Yongchun; Dang, Chengxue

2014-03-01

Abnormal glucose metabolism from hyperglycemia or diabetes aggravates the progression of pancreatic cancer. It is unknown whether high glucose has an impact on the antitumor effect of 5-fluorouracil (5-Fu) and whether targeting aberrant glucose metabolism using 2-deoxy-D-glucose (2-DG) may reverse this effect in high-glucose microenvironments. The cell viability of AsPC-1 and Panc-1 was analyzed by MTT assay following 5-Fu treatment at different glucose concentrations. Altered sensitivity to 5-Fu by 2-DG was also analyzed. LY294002 was used to inhibit PI3K-Akt signaling to determine the mechanism involved. In response to glucose, 5-Fu-induced cell growth inhibition was attenuated in a dose-dependent manner, accompanied with activated p-Akt, while 2-DG enhanced 5-Fu-induced cell growth inhibition. Moreover, blocking the PI3K/Akt pathway by LY294002 effectively eliminated 2-DG-induced apoptosis. In conclusion, high glucose weakens the antitumor effect of 5-Fu via PI3K / Akt signaling. Using 2-DG in combination with 5-Fu significantly increased their therapeutic effectiveness in high-glucose microenvironments.

Transfection of Murine and Human Hematopoietic Progenitors with Rearranged Immunoglobulin Genes

DTIC Science & Technology

1991-01-01

fluorouracil (SFU) to eliminate most cycling progenitors. Previous studies have shown that 5FU -treatment enriches for one early progenitor with high...Table I shows a time course of SCA-I positive cell expression various times post- 5FU treatment. Table 1 clearly shows that 5FU treatment can increase...the percentage of SCA-l-positive cells to 6-7% by day 7 post- 5FU treatment. The level of SCA-I expression falls to approximately 1% of total nucleated

Cost-effectiveness analysis of 5-fluorouracil 0.5%/salicylic acid 10% in the treatment of actinic keratosis in Spain.

PubMed

Nieves, Diana; Puig-Peiró, Ruth; Ferrándiz, Carlos; Plazas, Maria Josep; Brosa, Max

2015-06-01

The aim of this study is to conduct a cost-effectiveness analysis of 5-fluorouracil 0.5%/salicylic acid 10% (5-FU/SA) in the treatment of isolated hyperkeratotic actinic keratosis lesions in Spain. An analytical decision-making model was constructed to compare whether 5-FU/SA was a cost-effective option compared with cryotherapy from the perspective of the Spanish National Health System with a time horizon of 6 months. Costs were expressed in 2014 euros. The cost of patients with hyperkeratotic actinic keratosis treated with 5-FU/SA or cryotherapy was €266 and €285, respectively. 5-FU/SA was associated with higher rates of treatment success and, consequently, more quality-adjusted life years, than cryotherapy. Therefore, 5-FU/SA was the dominant treatment, as it was associated with a lower treatment cost and greater effectiveness than cryotherapy. Economically, 5-FU/SA was a dominant option compared with cryotherapy in the treatment of isolated hyperkeratotic actinic keratosis lesions in Spain.

Simultaneous, But Not Consecutive, Combination With Folinate Salts Potentiates 5-Fluorouracil Antitumor Activity In Vitro and In Vivo.

PubMed

Di Paolo, Antonello; Orlandi, Paola; Di Desidero, Teresa; Danesi, Romano; Bocci, Guido

2017-08-07

The combination of folinate salts to 5-fluoruracil (5-FU)-based schedules is an established clinical routine in the landscape of colorectal cancer treatment. The aim of this study was to investigate the pharmacological differences between the sequential administration of folinate salts (1 h before, as in clinical routine) followed by 5-FU and the simultaneous administration of both drugs. Proliferation and apoptotic assays were performed on human colon cancer cells exposed to 5-FU, calcium (CaLV), or disodium (NaLV) levofolinate or their simultaneous and sequential combination for 24 and 72 h. TYMS and SLC19A1 gene expression was performed with real-time PCR. In vivo experiments were performed in xenografted nude mice, which were treated with 5-FU escalating doses and CaLV or NaLV alone or in simultaneous and sequential combination. The simultaneous combination of folinate salts and 5-FU was synergistic (NaLV) or additive (CaLV) in a 24-h treatment in both cell lines. In contrast, the sequential combination of both folinate salts and 5-FU was antagonistic at 24 and 72 h. The simultaneous combination of 5-FU and NaLV or CaLV inhibited TYMS gene expression at 24 h, whereas the sequential combination reduced SLC19A1 gene expression. In vivo experiments confirmed the enhanced antitumor activity of the 5-FU + NaLV simultaneous combination with a good toxicity profile, whereas the sequential combination with CaLV failed to potentiate 5-FU activity. In conclusion, only the simultaneous, but not the consecutive, in vitro and in vivo combination of 5-FU and both folinate salt formulations potentiated the antiproliferative effects of the drugs.

MEK5/ERK5 signaling inhibition increases colon cancer cell sensitivity to 5-fluorouracil through a p53-dependent mechanism

PubMed Central

Pereira, Diane M.; Simões, André E. S.; Gomes, Sofia E.; Castro, Rui E.; Carvalho, Tânia; Rodrigues, Cecília M. P.; Borralho, Pedro M.

2016-01-01

The MEK5/ERK5 signaling pathway is emerging as an important contributor to colon cancer onset, progression and metastasis; however, its relevance to chemotherapy resistance remains unknown. Here, we evaluated the impact of the MEK5/ERK5 cascade in colon cancer cell sensitivity to 5-fluorouracil (5-FU). Increased ERK5 expression was correlated with poor overall survival in colon cancer patients. In colon cancer cells, 5-FU exposure impaired endogenous KRAS/MEK5/ERK5 expression and/or activation. In turn, MEK5 constitutive activation reduced 5-FU-induced cytotoxicity. Using genetic and pharmacological approaches, we showed that ERK5 inhibition increased caspase-3/7 activity and apoptosis following 5-FU exposure. Mechanistically, this was further associated with increased p53 transcriptional activation of p21 and PUMA. In addition, ERK5 inhibition increased the response of HCT116 p53+/+ cells to 5-FU, but failed to sensitize HCT116 p53−/− cells to the cytotoxic effects of this chemotherapeutic agent, suggesting a p53-dependent axis mediating 5-FU sensitization. Finally, ERK5 inhibition using XMD8-92 was shown to increase the antitumor effects of 5-FU in a murine subcutaneous xenograft model, enhancing apoptosis while markedly reducing tumor growth. Collectively, our results suggest that ERK5-targeted in hibition provides a promising therapeutic approach to overcome resistance to 5-FU-based chemotherapy and improve colon cancer treatment. PMID:27144434

Experimental cystic echinococcosis therapy: In vitro and in vivo combined 5-fluorouracil/albendazole treatment.

PubMed

Pensel, Patricia E; Elissondo, Natalia; Gambino, Guillermo; Gamboa, Gabriela Ullio; Benoit, J P; Elissondo, María C

2017-10-15

Human cystic echinococcosis is a zoonosis caused by the larval stage of the tapeworm Echinococcus granulosus sensu lato (s. l.). Although benzimidazole compounds such as albendazole (ABZ) and mebendazole have been the cornerstone of chemotherapy for the disease, there is often no complete recovery after treatment. Hence, new strategies are required to improve treatment of human cystic echinococcosis. The goals of the current study were as follows: (i) to evaluate the in vitro efficacy of the 5-fluorouracil (5-FU) and ABZ combination against E. granulosus s. l. protoscoleces and cysts, (ii) to compare the clinical efficacy of 5-FU alone or in combination with ABZ in infected mice. The combination of 5-FU+ABZ had a stronger in vitro effect against larval stage than that did both drugs alone. Even at the lowest concentration of 5-FU+ABZ combination (1μg/ml), the reduction of the viability of protoscoleces and cysts was greater than that observed with drugs alone at 10μg/ml. The results were confirmed at the ultrastructural level by scanning electron microscopy. These data helped to justify the in vivo investigations assessing the therapeutic potential of the combination of 5-FU and ABZ suspension in CF-1 mice infected with E. granulosus sensu stricto (s. s.) metacestodes. Treatment with 5-FU (10mg/kg) or 5-FU (10mg/kg) + ABZ suspension (5mg/kg) reduced the weight of cysts recovered from mice compared with control groups. Interestingly, the effect of 5-FU given weekly for 5 consecutive weeks was comparable to that observed with ABZ suspension under a daily schedule during 30days. Co-administration of 5-FU with ABZ did not enhance the in vivo efficacy of drugs alone calculated in relation to cysts weights. However, the combination provoked greater ultrastructural alterations compared to the monotherapy. In conclusion, we demonstrated the efficacy of 5-FU either alone or co-administrated with ABZ against murine experimental cystic echinococcosis. Since 5-FU treatments

Nano-formulation for topical treatment of precancerous lesions: skin penetration, in vitro, and in vivo toxicological evaluation.

PubMed

Calienni, Maria Natalia; Temprana, Carlos Facundo; Prieto, Maria Jimena; Paolino, Donatella; Fresta, Massimo; Tekinay, Ayse Begum; Alonso, Silvia Del Valle; Montanari, Jorge

2018-06-01

With the aim of improving the topical delivery of the antineoplastic drug 5-fluorouracil (5FU), it was loaded into ultradeformable liposomes composed of soy phosphatidylcholine and sodium cholate (UDL-5FU). The liposome populations had a mean size of 70 nm without significant changes in 56 days, and the ultradeformable formulations were up to 324-fold more elastic than conventional liposomes. The interaction between 5FU and the liposomal membrane was studied by three methods, and also release profile was obtained. UDL-5FU did penetrate the stratum corneum of human skin. At in vitro experiments, the formulation was more toxic on a human melanoma-derived than on a human keratinocyte-derived cell line. Cells captured liposomes by metabolically active processes. In vivo toxicity experiments were carried out in zebrafish (Danio rerio) larvae by studying the swimming activity, morphological changes, and alterations in the heart rate after incubation. UDL-5FU was more toxic than free 5FU. Therefore, this nano-formulation could be useful for topical application in deep skin precancerous lesions with advantages over current treatments. This is the first work that assessed the induction of apoptosis, skin penetration in a Saarbrücken penetration model, and the toxicological effects in vivo of an ultradeformable 5FU-loaded formulation.

Synthesis and colon-specific drug delivery of a poly(acrylic acid-co-acrylamide)/MBA nanosized hydrogel.

PubMed

Ray, Debajyoti; Mohapatra, Dillip K; Mohapatra, Ranjit K; Mohanta, Guru P; Sahoo, Prafulla K

2008-01-01

Intravenous administration of 5-fluorouracil (5-FU) for colon cancer therapy produces severe systemic side-effects due to its cytotoxic effect on normal cells. The main objective of the present study was to develop novel oral site-specific delivery of 5-FU to the colon with less drug being released in the stomach or small intestine using biodegradable hydrogel, hydrogel nanoparticles and comparing the targeting efficiency of 5-FU to colon from both. Poly(acrylic acid-co-acrylamide) (P(AA-co-Am)) normal hydrogel and hydrogel nanoparticles (HN) were synthesized by free radical polymerization using N,N-methylene-bis-acrylamide (MBA) as cross-linker, potassium persulfate as reaction initiator and 5-FU was loaded. HN were found to be degradable in physiological medium and showed comparatively higher swelling in rat caecal medium (RCM). 5-FU entrapment was increased by increasing Am (wt%) monomer feed. In vitro release of 5-FU from normal hydrogel and HN in pH progressive medium, it was found that a AA/Am ratio of 25:75 showed higher release in RCM. The Higuchi model yielded good adjustment of in vitro release kinetics. A higher amount of 5-FU reached the colon in HN (61 +/- 2.1%) than normal hydrogel (40 +/- 3.6%) by organ biodistribution studies in albino rats.

Chitosan produced from Mucorales fungi using agroindustrial by-products and its efficacy to inhibit Colletotrichum species.

PubMed

Ramos Berger, Lúcia Raquel; Montenegro Stamford, Thayza Christina; de Oliveira, Kataryne Árabe Rimá; de Miranda Pereira Pessoa, Adjane; de Lima, Marcos Antonio Barbosa; Estevez Pintado, Maria Manuela; Saraiva Câmara, Marcos Paz; de Oliveira Franco, Luciana; Magnani, Marciane; de Souza, Evandro Leite

2018-03-01

This study evaluated corn steep liquor (CSL) and papaya peel juice (PPJ) in mixture as substrates for the cultivation (96h, 28°C, pH 5.6, 150rpm) of Mucorales fungi for chitosan production, and determined the growth-inhibitory effect of the fungal chitosan (FuCS) obtained under optimized conditions against phytopathogenic Colletotrichum species. All Mucorales fungi tested were capable of growing in CSL-PPJ medium, showing FuCS production in the range of 5.02 (Fennelomyces heterothalicus SIS 28) - 15.63mg/g (Cunninghamella elegans SIS 41). Highest FuCS production (37.25mg/g) was achieved when C. elegans was cultivated in medium containing 9.43% CSL and 42.5% PPJ. FuCS obtained under these conditions showed a deacetylation degree of 86%, viscosity of 120cP and molecular weight of 4.08×10 4 g/mol. FuCS at 5000, 7500 and 10,000ppm inhibited the growth of all Colletotrichum species tested. FuCS also induced alterations in the morphology of C. fructicola hyphae. CSL-PPJ mixtures are suitable substrates for the cultivation of Mucorales fungi for FuCS production. Chitosan from C. elegans cultivated in CSL-PPJ medium is effective in inhibiting phytopathogenic Colletotrichum species. Copyright © 2017 Elsevier B.V. All rights reserved.

Glycyrrhetinic acid-modified chitosan nanoparticles enhanced the effect of 5-fluorouracil in murine liver cancer model via regulatory T-cells

PubMed Central

Cheng, Mingrong; Xu, Hongzhi; Wang, Yong; Chen, Houxiang; He, Bing; Gao, Xiaoyan; Li, Yingchun; Han, Jiang; Zhang, Zhiping

2013-01-01

Modified chitosan nanoparticles are a promising platform for drug, such as 5-fluorouracil (5-FU), gene, and vaccine delivery. Here, we used chitosan and hepatoma cell-specific binding molecule glycyrrhetinic acid (GA) to synthesize glycyrrhetinic acid-modified chitosan (GA-CTS). The synthetic product was confirmed by infrared spectroscopy and hydrogen nuclear magnetic resonance. By combining GA-CTS and 5-FU, we obtained a GA-CTS/5-FU nanoparticle, with a particle size of 193.7 nm, drug loading of 1.56%, and a polydispersity index of 0.003. The GA-CTS/5-FU nanoparticle provided a sustained-release system comprising three distinct phases of quick, steady, and slow release. In vitro data indicated that it had a dose- and time-dependent anticancer effect. The effective drug exposure time against hepatic cancer cells was increased in comparison with that observed with 5-FU. In vivo studies on an orthotropic liver cancer mouse model demonstrated that GA-CTS/5-FU significantly inhibited cancer cell proliferation, resulting in increased survival time. The antitumor mechanisms for GA-CTS/5-FU nanoparticle were possibly associated with an increased expression of regulatory T-cells, decreased expression of cytotoxic T-cell and natural killer cells, and reduced levels of interleukin-2 and interferon gamma. PMID:24187487

New Insights into the RNA-Based Mechanism of Action of the Anticancer Drug 5′-Fluorouracil in Eukaryotic Cells

PubMed Central

Mojardín, Laura; Botet, Javier; Quintales, Luis; Moreno, Sergio; Salas, Margarita

2013-01-01

5-Fluorouracil (5FU) is a chemotherapeutic drug widely used in treating a range of advanced, solid tumours and, in particular, colorectal cancer. Here, we used high-density tiling DNA microarray technology to obtain the specific transcriptome-wide response induced by 5FU in the eukaryotic model Schizosaccharomyces pombe. This approach combined with real-time quantitative PCR analysis allowed us to detect splicing defects of a significant number of intron-containing mRNA, in addition to identify some rRNA and tRNA processing defects after 5FU treatment. Interestingly, our studies also revealed that 5FU specifically induced the expression of certain genes implicated in the processing of mRNA, tRNA and rRNA precursors, and in the post-transcriptional modification of uracil residues in RNA. The transcription of several tRNA genes was also significantly induced after drug exposure. These transcriptional changes might represent a cellular response mechanism to counteract 5FU damage since deletion strains for some of these up-regulated genes were hypersensitive to 5FU. Moreover, most of these RNA processing genes have human orthologs that participate in conserved pathways, suggesting that they could be novel targets to improve the efficacy of 5FU-based treatments. PMID:24223771

Comparative proteomic analysis of the ribosomes in 5-fluorouracil resistance of a human colon cancer cell line using the radical-free and highly reducing method of two-dimensional polyacrylamide gel electrophoresis.

PubMed

Kimura, Kosei; Wada, Akira; Ueta, Masami; Ogata, Akihiko; Tanaka, Satoru; Sakai, Akiko; Yoshida, Hideji; Fushitani, Hideo; Miyamoto, Akiko; Fukushima, Masakazu; Uchiumi, Toshio; Tanigawa, Nobuhiko

2010-11-01

Many auxiliary functions of ribosomal proteins (r-proteins) have received considerable attention in recent years. However, human r-proteins have hardly been examined by proteomic analysis. In this study, we isolated ribosomal particles and subsequently compared the proteome of r-proteins between the DLD-1 human colon cancer cell line and its 5-fluorouracil (5-FU)-resistant sub-line, DLD-1/5-FU, using the radical-free and highly reducing method of two-dimensional polyacrylamide gel electrophoresis, which has a superior ability to separate basic proteins, and we discuss the role of r-proteins in 5-FU resistance. Densitometric analysis was performed to quantify modulated proteins, and protein spots showing significant changes were identified by employing matrix-assisted laser desorption/ionization time-of-flight/time-of-flight mass spectrometry. Three basic proteins (L15, L37 and prohibitin) which were significantly modulated between DLD-1 and DLD-1/5-FU were identified. Two proteins, L15 and L37, showed down-regulated expression in DLD-1/5-FU in comparison to DLD-1. Prohibitin, which is not an r-protein and is known to be localized in the mitochondria, showed up-regulated expression in DLD-1/5-FU. These 3 proteins may be related to 5-FU resistance.

Rapid ultrasonic stimulation of inflamed tissue with diagnostic intent

PubMed Central

McClintic, Abbi M.; Dickey, Trevor C.; Gofeld, Michael; Ray Illian, P.; Kliot, Michel; Kucewicz, John C.; Loeser, John D.; Richebe, Philippe G.; Mourad, Pierre D.

2013-01-01

Previous studies have observed that individual pulses of intense focused ultrasound (iFU) applied to inflamed and normal tissue can generate sensations, where inflamed tissue responds at a lower intensity than normal tissue. It was hypothesized that successively applied iFU pulses will generate sensation in inflamed tissue at a lower intensity and dose than application of a single iFU pulse. This hypothesis was tested using an animal model of chronic inflammatory pain, created by injecting an irritant into the rat hind paw. Ultrasound pulses were applied in rapid succession or individually to rats' rear paws beginning at low peak intensities and progressing to higher peak intensities, until the rats withdrew their paws immediately after iFU application. Focused ultrasound protocols consisting of successively and rapidly applied pulses elicited inflamed paw withdrawal at lower intensity and estimated tissue displacement values than single pulse protocols. However, both successively applied pulses and single pulses produced comparable threshold acoustic dose values and estimates of temperature increases. This raises the possibility that temperature increase contributed to paw withdrawal after rapid iFU stimulation. While iFU-induction of temporal summation may also play a role, electrophysiological studies are necessary to tease out these potential contributors to iFU stimulation. PMID:23927192

Combination photodynamic therapy using 5-fluorouracil and aminolevulinate enhances tumor-selective production of protoporphyrin IX and improves treatment efficacy of squamous skin cancers and precancers

NASA Astrophysics Data System (ADS)

Maytin, Edward V.; Anand, Sanjay

2016-03-01

In combination photodynamic therapy (cPDT), a small-molecule drug is used to modulate the physiological state of tumor cells prior to giving aminolevulinate (ALA; a precursor for protoporphyrin IX, PpIX). In our laboratory we have identified three agents (methotrexate, 5-fluorouracil, and vitamin D) that can enhance therapeutic effectiveness of ALAbased photodynamic therapy for cutaneous squamous cell carcinoma (SCC). However, only one (5-fluorouracil; 5-FU) is FDA-approved for skin cancer management. Here, we describe animal and human studies on 5-FU mechanisms of action, in terms of how 5-FU pretreatment leads to enhanced PpIX accumulation and improves selectivity of ALA-PDT treatment. In A431 subcutaneous tumors in mice, 5-FU changed expression of heme enzyme (upregulating coproporphyrinogen oxidase, and down-regulating ferrochelatase), inhibited tumor cell proliferation (Ki-67), enhanced differentiation (E-cadherin), and led to strong, tumor-selective increases in apoptosis. Interestingly, enhancement of apoptosis by 5-FU correlated strongly with an increased accumulation of p53 in tumor cells that persisted for 24 h post- PDT. In a clinical trial using a split-body, bilaterally controlled study design, human subjects with actinic keratoses (AK; preneoplastic precursors of SCC) were pretreated on one side of the face, scalp, or forearms with 5-FU cream for 6 days, while the control side received no 5-FU. On the seventh day, the levels of PpIX in 4 test lesions were measured by noninvasive fluorescence dosimetry, and then all lesions were treated with PDT using methyl-aminolevulinate (MAL) and red light (635 nm). Relative amounts of PpIX were found to be increased ~2-fold in 5-FU pretreated lesions relative to controls. At 3 months after PDT, the overall clinical response to PDT (reduction in lesion counts) was 2- to 3-fold better for the 5-FU pretreated lesions, a clinically important result. In summary, 5-FU is a useful adjuvant to aminolevulinate-based PDT

International Symposium on Solubility Phenomena (3rd) Held in Guildford, Surrey England on 23 - 26 August 1988

DTIC Science & Technology

1988-08-26

metallic iron in these cases, though the ferrate Na FeO is4 3 not existent at such low oxygen potentials. 𔃾 U Wednesday morning 24 August 1988 SESSION 3...acknowledged. 44 ’I 44 P9 Measurement and Calculation of Transfer Enthalpies of Potassium Chloride from Water to Water - Dioxane Mixture W Jian Ji, L

Rebamipide attenuates 5-Fluorouracil-induced small intestinal mucositis in a mouse model.

PubMed

Kim, Hyun Jin; Kim, Jin Hyun; Moon, Won; Park, Jongha; Park, Seun Ja; Song, Geun Am; Han, Seung Hee; Lee, Jong Hun

2015-01-01

5-Fluorouracil (5-FU)-induced intestinal mucositis is one of the most common morbidities in chemotherapy and involves the reactive oxygen species (ROS) system, apoptosis, and inflammatory cytokines. Rebamipide exerts a mucosal-protective effect, mediated through several mechanisms. The aim of this study was to evaluate the effects of rebamipide in 5-FU-induced mouse small-intestinal mucositis. BALB/c mice were assigned randomly to four groups; (1) control group (n=10; receiving saline orally for 6 d), (2) rebamipide group (n=10; 150 mg/kg rebamipide for 6 d orally), (3) 5-FU group (n=10; 30 mg/kg 5-FU for 5 d, intraperitoneally (i.p.)), and (4) rebamipide +5-FU group (n=10; 150 mg/kg rebamipide for 6 d orally and 30 mg/kg 5-FU for 5 d, i.p.). Body weights and diarrhea scales were assessed. At day 5, the mice were sacrificed. Small intestinal tissue was used for: (1) hematoxylin and eosin (HE) staining for determination of small intestinal villi height, (2) terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) assay, (3) immunohistochemistry for inducible nitric oxide synthase (iNOS), F4/80, and transforming growth factor (TGF)-β1, (4) measurement of serum and tissue GSH levels, and (5) measurement of serum tumor necrosis factor (TNF)-α levels. Rebamipide attenuated the severity of mucosal injury reflected by body weight changes, degrees of diarrhea, and heights of villi. Rebamipide reduced the expression of iNOS and TGF-β1, apoptosis, macrophage accumulation, serum TNF-α levels, and prevented reductions in serum and tissue glutathione (GSH) levels by 5-FU administration. These results suggest that rebamipide promotes several mechanisms of mucosal protection and attenuated the 5-FU-induced mucosal injury. In conclusion, administration of rebamipide may have significant protective effects against 5-FU-induced intestinal mucositis.

Curcumin Chemosensitizes 5-Fluorouracil Resistant MMR-Deficient Human Colon Cancer Cells in High Density Cultures

PubMed Central

Shakibaei, Mehdi; Buhrmann, Constanze; Kraehe, Patricia; Shayan, Parviz; Lueders, Cora; Goel, Ajay

2014-01-01

Objective Treatment of colorectal cancer (CRC) remains a clinical challenge, as more than 15% of patients are resistant to 5-Fluorouracil (5-FU)-based chemotherapeutic regimens, and tumor recurrence rates can be as high as 50–60%. Cancer stem cells (CSC) are capable of surviving conventional chemotherapies that permits regeneration of original tumors. Therefore, we investigated the effectiveness of 5-FU and plant polyphenol (curcumin) in context of DNA mismatch repair (MMR) status and CSC activity in 3D cultures of CRC cells. Methods High density 3D cultures of CRC cell lines HCT116, HCT116+ch3 (complemented with chromosome 3) and their corresponding isogenic 5-FU-chemo-resistant derivative clones (HCT116R, HCT116+ch3R) were treated with 5-FU either without or with curcumin in time- and dose-dependent assays. Results Pre-treatment with curcumin significantly enhanced the effect of 5-FU on HCT116R and HCR116+ch3R cells, in contrast to 5-FU alone as evidenced by increased disintegration of colonospheres, enhanced apoptosis and by inhibiting their growth. Curcumin and/or 5-FU strongly affected MMR-deficient CRC cells in high density cultures, however MMR-proficient CRC cells were more sensitive. These effects of curcumin in enhancing chemosensitivity to 5-FU were further supported by its ability to effectively suppress CSC pools as evidenced by decreased number of CSC marker positive cells, highlighting the suitability of this 3D culture model for evaluating CSC marker expression in a close to vivo setting. Conclusion Our results illustrate novel and previously unrecognized effects of curcumin in enhancing chemosensitization to 5-FU-based chemotherapy on DNA MMR-deficient and their chemo-resistant counterparts by targeting the CSC sub-population. (246 words in abstract). PMID:24404205

Curcumin chemosensitizes 5-fluorouracil resistant MMR-deficient human colon cancer cells in high density cultures.

PubMed

Shakibaei, Mehdi; Buhrmann, Constanze; Kraehe, Patricia; Shayan, Parviz; Lueders, Cora; Goel, Ajay

2014-01-01

Treatment of colorectal cancer (CRC) remains a clinical challenge, as more than 15% of patients are resistant to 5-Fluorouracil (5-FU)-based chemotherapeutic regimens, and tumor recurrence rates can be as high as 50-60%. Cancer stem cells (CSC) are capable of surviving conventional chemotherapies that permits regeneration of original tumors. Therefore, we investigated the effectiveness of 5-FU and plant polyphenol (curcumin) in context of DNA mismatch repair (MMR) status and CSC activity in 3D cultures of CRC cells. High density 3D cultures of CRC cell lines HCT116, HCT116+ch3 (complemented with chromosome 3) and their corresponding isogenic 5-FU-chemo-resistant derivative clones (HCT116R, HCT116+ch3R) were treated with 5-FU either without or with curcumin in time- and dose-dependent assays. Pre-treatment with curcumin significantly enhanced the effect of 5-FU on HCT116R and HCR116+ch3R cells, in contrast to 5-FU alone as evidenced by increased disintegration of colonospheres, enhanced apoptosis and by inhibiting their growth. Curcumin and/or 5-FU strongly affected MMR-deficient CRC cells in high density cultures, however MMR-proficient CRC cells were more sensitive. These effects of curcumin in enhancing chemosensitivity to 5-FU were further supported by its ability to effectively suppress CSC pools as evidenced by decreased number of CSC marker positive cells, highlighting the suitability of this 3D culture model for evaluating CSC marker expression in a close to vivo setting. Our results illustrate novel and previously unrecognized effects of curcumin in enhancing chemosensitization to 5-FU-based chemotherapy on DNA MMR-deficient and their chemo-resistant counterparts by targeting the CSC sub-population. (246 words in abstract).

Regulatory role of Lactobacillus acidophilus on inflammation and gastric dysmotility in intestinal mucositis induced by 5-fluorouracil in mice.

PubMed

Justino, Priscilla F C; Melo, Luis F M; Nogueira, Andre F; Morais, Cecila M; Mendes, Walber O; Franco, Alvaro X; Souza, Emmanuel P; Ribeiro, Ronaldo A; Souza, Marcellus H L P; Soares, Pedro Marcos Gomes

2015-03-01

Lactobacillus acidophilus is widely used for gastrointestinal disorders, but its role in inflammatory conditions like in chemotherapy-induced mucositis is unclear. Here, we report the effect of L. acidophilus on 5-fluorouracil-induced (5-FU) intestinal mucositis in mice. Mice weighing 25-30 g (n = 8) were separated into three groups, saline, 5-FU, and 5-FU + L. acidophilus (5-FU-La) (16 × 10(9) CFU/kg). In the 5-FU-La group, L. acidophilus was administered concomitantly with 5-FU on the first day and alone for two additional days. Three days after the last administration of L. acidophilus, the animals were euthanized and the jejunum and ileum were removed for histopathological assessment and for evaluation of levels of myeloperoxidase activity, sulfhydryl groups, nitrite, and cytokines (TNF-α, IL-1β, CXCL-1, and IL-10). In addition, we investigated gastric emptying using spectrophotometry after feeding a 1.5-ml test meal by gavage and euthanasia. Data were submitted to ANOVA and Bonferroni's test, with the level of significance at p < 0.05. Intestinal mucositis induced by 5-FU significantly (p < 0.05) reduced the villus height-crypt depth ratio and GSH concentration and increased myeloperoxidase activity and the nitrite concentrations compared with the control group. Furthermore, 5-FU significantly (p < 0.05) increased cytokine (TNF-α, IL-1β, and CXCL-1) concentrations and decreased IL-10 concentrations compared with the control group. 5-FU also significantly (p < 0.05) delayed gastric emptying and gastrointestinal transit compared with the control group. All of these changes were significantly (p < 0.05) reversed by treatment with L. acidophilus. Lactobacillus acidophilus improves the inflammatory and functional aspects of intestinal mucositis induced by 5-FU.

Analysis of molecular mechanisms of 5-fluorouracil-induced steatosis and inflammation in vitro and in mice

PubMed Central

Freese, Kim; Schiergens, Tobias S.; Kuecuekoktay, Fulya Suzan; Teufel, Andreas; Thasler, Wolfgang E.; Müller, Martina; Bosserhoff, Anja K.; Hellerbrand, Claus

2017-01-01

Chemotherapy-associated steatohepatitis is attracting increasing attention because it heralds an increased risk of morbidity and mortality in patients undergoing surgery because of liver metastases. The aim of this study was to develop in vitro and in vivo models to analyze the pathogenesis of 5-fluorouracil (5-FU)-induced steatohepatitis. Therefore, primary human hepatocytes and HepG2 hepatoma cells were incubated with 5-FU at non-toxic concentrations up to 24 h. Furthermore, hepatic tissue of C57BL/6N mice was analyzed 24 h after application of a single 5-FU dose (200 mg/kg body weight). In vitro, incubation with 5-FU induced a significant increase of hepatocellular triglyceride levels. This was paralleled by an impairment of mitochondrial function and a dose- and time-dependently increased expression of fatty acid acyl-CoA oxidase 1 (ACOX1), which catalyzes the initial step for peroxisomal β-oxidation. The latter is known to generate reactive oxygen species, and consequently, expression of the antioxidant enzyme heme oxygenase 1 (HMOX1) was significantly upregulated in 5-FU-treated cells, indicative for oxidative stress. Furthermore, 5-FU significantly induced c-Jun N-terminal kinase (JNK) activation and the expression of pro-inflammatory genes IL-8 and ICAM-1. Also in vivo, 5-FU significantly induced hepatic ACOX1 and HMOX1 expression as well as JNK-activation, pro-inflammatory gene expression and immune cell infiltration. In summary, we identified molecular mechanisms by which 5-FU induces hepatocellular lipid accumulation and inflammation. Our newly developed models can be used to gain further insight into the pathogenesis of 5-FU-induced steatohepatitis and to develop therapeutic strategies to inhibit its development and progression. PMID:28055957

Polydopamine-coated liposomes as pH-sensitive anticancer drug carriers.

PubMed

Zong, Wei; Hu, Ying; Su, Yingchun; Luo, Nan; Zhang, Xunan; Li, Qingchuan; Han, Xiaojun

2016-05-01

Stimuli-responsive drug carriers are considered to play important roles in chemotherapy. We fabricated pH-sensitive polydopamine-protected liposomes (liposome@PDA) drug delivery systems, which were characterised with microscope, scanning electron microscope (SEM), UV-vis spectrometer and Fourier transform infrared (FTIR) technieques. The typical chemotherapeutic agent, 5-fluorouracil (5-FU), was loaded into liposome@PDA capsules. The maximum release percentages of 5-FU are 3.2%, 29.5%, 52.7%, 76.7% in the solution with pH 7.42, 6.87, 4.11 and 3.16, respectively. The in vitro cell cytotoxity experiments were carried out using 5-FU-loaded capsules at pH 6.87 solution, which simulate the true pH around cancerous cells. At 1.5 μM concentration, the free 5-FU, 5-FU-loaded liposome capsules and 5-FU-loaded capsules showed the cell viability of 50.56%, 22.66% and 21.63%, respectively. It confirms that drug-loaded capsules performed better than free drug. The results demonstrate the great potential of liposome@PDA capsules as carriers in biomedical applications.

Fabrication of functional hollow microspheres constructed from MOF shells: Promising drug delivery systems with high loading capacity and targeted transport

PubMed Central

Gao, Xuechuan; Hai, Xiao; Baigude, Huricha; Guan, Weihua; Liu, Zhiliang

2016-01-01

An advanced multifunctional, hollow metal-organic framework (MOF) drug delivery system with a high drug loading level and targeted delivery was designed and fabricated for the first time and applied to inhibit tumour cell growth. This hollow MOF targeting drug delivery system was prepared via a simple post-synthetic surface modification procedure, starting from hollow ZIF-8 successfully obtained for the first time via a mild phase transformation under solvothermal conditions. As a result, the hollow ZIF-8 exhibits a higher loading capacity for the model anticancer drug 5-fluorouracil (5-FU). Subsequently, 5-FU-loaded ZIF-8 was encapsulated into polymer layers (FA-CHI-5-FAM) with three components: a chitosan (CHI) backbone, the imaging agent 5-carboxyfluorescein (5-FAM), and the targeting reagent folic acid (FA). Thus, an advanced drug delivery system, ZIF-8/5-FU@FA-CHI-5-FAM, was fabricated. A cell imaging assay demonstrated that ZIF-8/5-FU@FA-CHI-5-FAM could target and be taken up by MGC-803 cells. Furthermore, the as-prepared ZIF-8/5-FU@FA-CHI-5-FAM exhibited stronger cell growth inhibitory effects on MGC-803 cells because of the release of 5-FU, as confirmed by a cell viability assay. In addition, a drug release experiment in vitro indicated that ZIF-8/5-FU@FA-CHI-5-FAM exhibited high loading capacity (51%) and a sustained drug release behaviour. Therefore, ZIF-8/5-FU@FA-CHI-5-FAM could provide targeted drug transportation, imaging tracking and localized sustained release. PMID:27876876

Targeting miR-21 enhances the sensitivity of human colon cancer HT-29 cells to chemoradiotherapy in vitro

DOE Office of Scientific and Technical Information (OSTI.GOV)

Deng, Jun; Lei, Wan; Fu, Jian-Chun

2014-01-17

Highlight: •MiR-21 plays a significant role in 5-FU resistance. •This role might be attributed to targeting of hMSH2 as well as TP and DPD via miR-21 targeted hMSH2. •Indirectly targeted TP and DPD to influence 5-FU chemotherapy sensitivity. -- Abstract: 5-Fluorouracil (5-FU) is a classic chemotherapeutic drug that has been widely used for colorectal cancer treatment, but colorectal cancer cells are often resistant to primary or acquired 5-FU therapy. Several studies have shown that miR-21 is significantly elevated in colorectal cancer. This suggests that this miRNA might play a role in this resistance. In this study, we investigated this possibilitymore » and the possible mechanism underlying this role. We showed that forced expression of miR-21 significantly inhibited apoptosis, enhanced cell proliferation, invasion, and colony formation ability, promoted G1/S cell cycle transition and increased the resistance of tumor cells to 5-FU and X radiation in HT-29 colon cancer cells. Furthermore, knockdown of miR-21 reversed these effects on HT-29 cells and increased the sensitivity of HT-29/5-FU to 5-FU chemotherapy. Finally, we showed that miR-21 targeted the human mutS homolog2 (hMSH2), and indirectly regulated the expression of thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD). These results demonstrate that miR-21 may play an important role in the 5-FU resistance of colon cancer cells.« less

The influence of cimetidine on the pharmacokinetics of 5-fluorouracil.

PubMed Central

Harvey, V J; Slevin, M L; Dilloway, M R; Clark, P I; Johnston, A; Lant, A F

1984-01-01

The influence of cimetidine pretreatment on the pharmacokinetics of 5-fluorouracil (5FU) has been studied in 15 ambulant patients with carcinoma. Neither pretreatment with a single dose of cimetidine (400 mg) nor with daily treatment at 1000 mg for 1 week altered 5FU pharmacokinetics. Pretreatment with cimetidine for 4 weeks (1000 mg daily) led to increased peak plasma concentrations of 5FU and also area under the plasma concentration-time curve (AUC). The peak plasma concentration after oral 5FU was increased by 74% from 18.7 +/- 4.5 micrograms/ml (mean +/- s.e. mean) to 32.6 +/- 4.4 micrograms/ml (P less than 0.05) and AUC was increased by 72% from 528 +/- 133 micrograms/ml-1 min (mean +/- s.e. mean) to 911 +/- 152 micrograms ml-1 min (P less than 0.05). After intravenous 5FU, AUC was increased by 27% from 977 +/- 96 micrograms ml-1 min (mean +/- s.e. mean) to 1353 +/- 124 micrograms ml-1 min (P less than 0.01). Total body clearance for 5FU following intravenous administration was decreased by 28% from 987 +/- 116 ml/min (mean +/- s.e. mean) to 711 +/- 87 ml/min (P less than 0.01). The elimination half-life of 5FU was not altered by cimetidine. The basis of the interaction between 5FU and cimetidine is uncertain but probably a combination of inhibited drug metabolism and reduced liver blood flow. The therapeutic implications are considerable and additional care should be taken in patients receiving the two drugs concomitantly. PMID:6487480

Value of percutaneous radiofrequency ablation with or without percutaneous vertebroplasty for pain relief and functional recovery in painful bone metastases.

PubMed

Clarençon, Frédéric; Jean, Betty; Pham, Hang-Phuong; Cormier, Evelyne; Bensimon, Gilbert; Rose, Michèle; Maksud, Philippe; Chiras, Jacques

2013-01-01

To evaluate the effectiveness of percutaneous radiofrequency (RF) ablation with or without percutaneous vertebroplasty (PV) on pain relief, functional recovery and local recurrence at 6 months' follow-up (FU), in patients with painful osseous metastases. Thirty RF ablations were performed in 24 patients (mean age: 61 years) with bone metastases. Half of the patients had an additional PV. The primary end point was pain relief evaluated by a visual analogue scale (VAS) before treatment, and at 1 and 6 months' FU. Functional outcome was assessed according to the evolution of their ability to walk at 6 months' FU. Imaging FU was available in 20 out of 24 patients with a mean delay of 4.7 months. Reduction of pain was obtained at 6 months FU in 81% of cases (15 out of 18). Mean pretreatment VAS was 6.4 (±2.7). Mean VAS was 1.9 (±2.4) at 1 month FU, and 2.3 (±2.9) at 6 months' FU. Pain was significantly reduced at 6 months FU (mean VAS reduction = 4.1; P < 0.00001). Functional improvement was obtained in 74% of the cases. Major complications rate was 12.5 % (3 out of 24) with 2 skin burns, and 1 case of myelopathy. Local tumour recurrence or progression was recorded in 5 cases. Radiofrequency ablation is an effective technique in terms of pain relief and functional recovery for the treatment of bone metastases, which provides a relatively low rate of local recurrence.

The conditions required for the induction of petite yeast mutants by fluorinated pyrimidines.

PubMed

Oliver, S G; Williamson, D H

1976-08-02

Cytoplasmic petite mutagenesis by 5-fluorouracil (5FU) was prevented by temperature sensitive mutations which blcoked either nuclear transcription or cytoplasmic translation. However, 5FU was also ineffective in resting cells and in cells exposed to alpha-mating factor, showing that cell division or nuclear DNA synthesis is required for the mutagenic event to take place. In addition, the mutagenic effect of 5FU was completely prevented by daunomycin, and since this agent preferentially inhibits respiratory growth and was shown to selectively block RNA synthesis in the mitochondria, it was concluded that petite mutagensis resulted from incorporation of 5FU into mitochondrial RNA. Since inhibition of mitochondrial protein synthesis by erythromycin had little immediate effect on the mutagenicity of 5FU, it was deduced that the RNA in question is not directly involved in mitochondrial translation, and may have a regulatory function.

In vitro combinatorial anticancer effects of 5-fluorouracil and curcumin loaded N,O-carboxymethyl chitosan nanoparticles toward colon cancer and in vivo pharmacokinetic studies.

PubMed

Anitha, A; Sreeranganathan, Maya; Chennazhi, Krishna Prasad; Lakshmanan, Vinoth-Kumar; Jayakumar, R

2014-09-01

Colon cancer is the third most leading causes of death due to cancer worldwide and the chemo drug 5-fluorouracil's (5-FU) applicability is limited due to its non-specificity, low bioavailability and overdose. The efficacy of 5-FU in colon cancer chemo treatment could be improved by nanoencapsulation and combinatorial approach. In the present study curcumin (CUR), a known anticancer phytochemical, was used in combination with 5-FU and the work focuses on the development of a combinatorial nanomedicine based on 5-FU and CUR in N,O-carboxymethyl chitosan nanoparticles (N,O-CMC NPs). The developed 5-FU-N,O-CMC NPs and CUR-N,O-CMC NPs were found to be blood compatible. The in vitro drug release profile in pH 4.5 and 7.4 showed a sustained release profile over a period of 4 days. The combined exposure of the nanoformulations in colon cancer cells (HT 29) proved the enhanced anticancer effects. In addition, the in vivo pharmacokinetic data in mouse model revealed the improved plasma concentrations of 5-FU and CUR which prolonged up to 72 h unlike the bare drugs. In conclusion, the 5-FU and CUR released from the N,O-CMC NPs produced enhanced anticancer effects in vitro and improved plasma concentrations under in vivo conditions. Copyright © 2014 Elsevier B.V. All rights reserved.

In vitro anticancer evaluation of 5-fluorouracil lipid nanoparticles using B16F10 melanoma cell lines

NASA Astrophysics Data System (ADS)

Shenoy, Vikram S.; Gude, Rajiv P.; Murthy, Rayasa S. Ramachandra

2013-05-01

The present study is aimed to investigate the formulation and in vitro anticancer activities of solid lipid nanoparticles (SLNs) of 5-fluorouracil (5-FU) prepared using glyceryl monostearate (GMS) and cetyl palmitate (CP) by hot homogenization method. The lipids were selected based on the partition coefficient of 5-FU in lipids. The lipid nanoparticles were optimized for process and formulation parameters. The optimized nanoparticles were characterized for their zeta potential, morphology, release kinetics, and anticancer activity. Higher entrapments were achieved using a combination of emulsifiers. The zeta potential of the optimized CP and GMS SLN formulation were -8.26 and -9.35 mV, respectively. Both the optimized formulations were spherical. The in vitro release studies of SLNs of both the lipid carriers followed Peppas-Korsenmeyer equation when carried out at pH 3.5 and 7.4. The chemosensitivity assay carried out in B16F10 cell lines revealed that CP SLNs had better cytotoxicity than 5-FU solution and GMS SLNs at 48 h of incubation. Subtoxic concentration of 5-FU-loaded CP SLNs (0.12 μg/mL) possessed comparable antimigrational activity, colony inhibition activity, and cytopathic as that of 5-FU solution effects. The results indicated that encapsulating 5-FU in CP would be a promising delivery system for delivering 5-FU.

Comparison of Intralesional Triamcinolone Acetonide, 5-Fluorouracil, and Their Combination for the Treatment of Keloids

PubMed Central

Srivastava, Sunil; Patil, Aditya Nanasaheb; Prakash, Chaitra; Kumari, Hiranmayi

2017-01-01

Objective: Despite the myriad options available, there is no universally accepted treatment for keloids. Our objective was to compare three regimens and establish superiority in terms of objective and subjective outcomes. Approach: In this randomized parallel group study, 60 patients were enrolled and randomly allocated to three groups. Patients received intralesional injections of triamcinolone acetonide (TAC) in Group TAC, 5-fluorouracil (5FU) in Group 5FU, and a combination in Group T + F every 3 weeks till 24 weeks or till the keloid resolved. Results: There was a reduction in all parameters at every successive assessment in all three groups. Improvement in terms of height, vascularity, and pliability was fastest with 5FU, TAC, and T + F group, respectively, which was statistically significant. Decrease in pigmentation was significantly faster with T+F. Reduction in pruritus, however, was significantly faster with 5FU than the other groups, but the difference in reduction of pain among the three groups was not significant. Telangiectasias and skin atrophy were seen most commonly in TAC group, while skin ulceration was a common problem in 5FU group. Conclusion: TAC, 5FU, and their combination are all effective in keloid scars. A combination of TAC +5FU seems to offer the balanced benefit of faster and more efficacious response with lesser adverse effects when compared to individual drugs. PMID:29098115

Foliar uptake, carbon fluxes and water status are affected by the timing of daily fog in saplings from a threatened cloud forest.

PubMed

Berry, Z Carter; White, Joseph C; Smith, William K

2014-05-01

In cloud forests, foliar uptake (FU) of water has been reported for numerous species, possibly acting to relieve daily water and carbon stress. While the prevalence of FU seems common, how daily variation in fog timing may affect this process has not been studied. We examined the quantity of FU, water potentials, gas exchange and abiotic variation at the beginning and end of a 9-day exposure to fog in a glasshouse setting. Saplings of Abies fraseri (Pursh) Poir. and Picea rubens Sarg. were exposed to morning (MF), afternoon (AF) or evening fog (EF) regimes to assess the ability to utilize fog water at different times of day and after sustained exposure to simulated fog. The greatest amount of FU occurred during MF (up to 50%), followed by AF (up to 23%) and then EF, which surprisingly had no FU. There was also a positive relationship between leaf conductance and FU, suggesting a role of stomata in FU. Moreover, MF and AF lead to the greatest improvements in daily water balance and carbon gain, respectively. Foliar uptake was important for improving plant ecophysiology but was influenced by diurnal variation in fog. With climate change scenarios predicting changes to cloud patterns and frequency that will likely alter diurnal patterns, cloud forests that rely on this water subsidy could be affected. © The Author 2014. Published by Oxford University Press. All rights reserved.

Understanding attrition from international Internet health interventions: a step towards global eHealth.

PubMed

Geraghty, Adam W A; Torres, Leandro D; Leykin, Yan; Pérez-Stable, Eliseo J; Muñoz, Ricardo F

2013-09-01

Worldwide automated Internet health interventions have the potential to greatly reduce health disparities. High attrition from automated Internet interventions is ubiquitous, and presents a challenge in the evaluation of their effectiveness. Our objective was to evaluate variables hypothesized to be related to attrition, by modeling predictors of attrition in a secondary data analysis of two cohorts of an international, dual language (English and Spanish) Internet smoking cessation intervention. The two cohorts were identical except for the approach to follow-up (FU): one cohort employed only fully automated FU (n = 16 430), while the other cohort also used 'live' contact conditional upon initial non-response (n = 1000). Attrition rates were 48.1 and 10.8% for the automated FU and live FU cohorts, respectively. Significant attrition predictors in the automated FU cohort included higher levels of nicotine dependency, lower education, lower quitting confidence and receiving more contact emails. Participants' younger age was the sole predictor of attrition in the live FU cohort. While research on large-scale deployment of Internet interventions is at an early stage, this study demonstrates that differences in attrition from trials on this scale are (i) systematic and predictable and (ii) can largely be eliminated by live FU efforts. In fully automated trials, targeting the predictors we identify may reduce attrition, a necessary precursor to effective behavioral Internet interventions that can be accessed globally.

Capecitabine treatment patterns in patients with gastroesophageal cancer in the United States

PubMed Central

Saif, Muhammad Wasif; Shi, Nianwen; Zelt, Susan

2009-01-01

AIM: To assess the use of capecitabine-based therapy and associated complication rates in patients with gastroesophageal cancer (GEC) in a real-world treatment setting. METHODS: Patients with claims between 2004 and 2005 were identified from the Thomson Reuters MarketScan® databases. Capecitabine regimens were compared with 5-fluorouracil (5-FU) and other chemotherapy regimens, and were stratified by treatment setting. RESULTS: We identified 1013 patients with GEC: approximately half had treatment initiated with a 5-FU regimen, whereas 11% had therapy initiated with a capecitabine regimen. The mean capecitabine dose overall was 2382 ± 1118 mg/d, and capecitabine was used as monotherapy more often than in combination. Overall, 5-FU regimens were the most common treatment option in neoadjuvant and adjuvant settings, while other non-capecitabine regimens were used more widely in first- and second-line settings. The overall unadjusted complication rate for capecitabine regimens was about half of that seen with 5-FU regimens. In multivariate analyses, capecitabine recipients had a 51% (95% CI: 26%-81%) lower risk of developing any complication than 5-FU recipients did. The risk of developing bone marrow, constitutional, gastrointestinal tract, infectious, or skin complications was lower with capecitabine therapy than with 5-FU. CONCLUSION: Capecitabine appeared to have a favorable side effect profile compared with 5-FU, which indicates that it may be a treatment option for GEC. PMID:19764093

Attrition in longitudinal randomized controlled trials: home visits make a difference.

PubMed

Peterson, Janey C; Pirraglia, Paul A; Wells, Martin T; Charlson, Mary E

2012-11-23

Participant attrition in longitudinal studies can introduce systematic bias, favoring participants who return for follow-up, and increase the likelihood that those with complications will be underestimated. Our aim was to examine the effectiveness of home follow-up (Home F/U) to complete the final study evaluation on potentially "lost" participants by: 1) evaluating the impact of including and excluding potentially "lost" participants (e.g., those who required Home F/U to complete the final evaluation) on the rates of study complications; 2) examining the relationship between timing and number of complications on the requirement for subsequent Home F/U; and 3) determining predictors of those who required Home F/U. We used data from a randomized controlled trial (RCT) conducted from 1991-1994 among coronary artery bypass graft surgery patients that investigated the effect of High mean arterial pressure (MAP) (intervention) vs. Low MAP (control) during cardiopulmonary bypass on 5 complications: cardiac morbidity/mortality, neurologic morbidity/mortality, all-cause mortality, neurocognitive dysfunction and functional decline. We enhanced completion of the final 6-month evaluation using Home F/U. Among 248 participants, 61 (25%) required Home F/U and the remaining 187 (75%) received Routine F/U. By employing Home F/U, we detected 11 additional complications at 6 months: 1 major neurologic complication, 6 cases of neurocognitive dysfunction and 4 cases of functional decline. Follow-up of 61 additional Home F/U participants enabled us to reach statistical significance on our main trial outcome. Specifically, the High MAP group had a significantly lower rate of the Combined Trial Outcome compared to the Low MAP group, 16.1% vs. 27.4% (p=0.032). In multivariate analysis, participants who were ≥ 75 years (OR=3.23, 95% CI 1.52-6.88, p=0.002) or on baseline diuretic therapy (OR=2.44, 95% CI 1.14-5.21, p=0.02) were more likely to require Home F/U. In addition, those in the

Fluoropyrimidine-associated cardiotoxicity: revisited.

PubMed

Saif, M Wasif; Shah, Manasi M; Shah, Anuj R

2009-03-01

The syndrome of 5-fluorouracil (5-FU)-associated cardiotoxicity remains poorly defined. We performed a literature review (1969 - 2007) and compiled data derived from 377 evaluable cases out of 448 reported cases. Patient age ranged from 14 to 86 years. Of the patients 65% were 55 years old and the male:female ratio was 1.5:1. The most commonly treated tumors were gastrointestinal (60%), head and neck (22%) and breast (4%). Of the patients 14% had a history of heart disease whereas cardiac risk factors were found in 37%. Mode of administration included: continuous infusion (72%); bolus (22.5%); intermediate infusion (3%); oral (2%); and intraperitoneal (1 patient). The dosages of 5-FU used were < 750 mg/m(2)/day (36%), 751 - 999 (16%), 1,000 (26%), 1,001 - 1,499 (4%) and 1,500 (16%). Of the patients 54% received 5-FU in combination with other chemotherapeutic agents (cisplatin 44%) whereas 51% received 5-FU alone or with leucovorin. Only 4% patients had undergone previous or concomitant radiation therapy to the mediastinum. Of cardiac incidents that happened 69% were seen during or within 72 h of the first cycle of 5-FU. Angina occurred in 45% of patients whereas myocardial infarction was seen in 22%, arrhythmias in 23, acute pulmonary edema in 5, cardiac arrest and pericarditis in 1.4 and heart failure in 2. Electro-cardiographic evidence of ischemia or ST-T changes were recorded in 69% of patients, but abnormal cardiac enzymes were found in only 12%. The cardiac symptoms were reproducible in 47%, including in one patient subsequently treated with 5-FU p.o. Symptoms were also elicited when the same patients were treated with lower doses or different schedules. Of the patients 68% responded to conservative anti-anginal therapy, although prophylactic coronary vasodilators had limited efficacy. Overall, 8% of patients showing cardiotoxicity on 5-FU administration died. Furthermore, 13% reexposed to 5-FU died. Our review suggests that 5-FU cardiotoxicity is an

Limits to TYMS and TP53 genes as predictive determinants for fluoropyrimidine sensitivity and further evidence for an RNA-based toxicity as a major influence

PubMed Central

Brody, Jonathan R.; Hucl, Tomas; Costantino, Christina L.; Eshleman, James; Gallmeier, Eike; Zhu, Heng; Heijden, Michael S. van der; Winter, Jordan M; Wikiewicz, Agnieszka K.; Yeo, Charles J.; Kern, Scott E.

2010-01-01

The major determinants of 5-flurouracil response would appear, based on accumulated literature, to be thymidylate synthase (TYMS, TS) expression levels, TS gene modifications, and TP53 status. We tested 5-fluorouracil sensitivity in yeast and human cancer cell models in which TS or TP53 alleles and expression were varied. Polymorphic TS tandem repeat status, TS expression levels reported, TS intragenic mutations, and TP53 status in outbred and experimental cancer cell lines did not predict 5-FU sensitivity or resistance. Novel observations included a dose-resistant persistence of unbound TS protein in many cancers and, upon 5-FU treatment of the colon cancer cell line, HCT116, evidence of allelic switching favoring transcripts of the mutant TS allele. The reported alleles having an intragenic mutation could not be causally associated with major degrees of 5-FU sensitivity. In yeast, TS protein was altered upon treatment with fluoro-deoxyuridine monophosphate, but 5-FU toxicity appeared largely to be RNA-based, being rescued by uridine rather than by thymidine. Cancer cell lines were also rescued from 5-FU toxicity with uridine rather than thymidine. Additionally, a TS (CDC21) knockout yeast strain, obviating any potential role for TS protein as a target, was hypersensitive to 5-FU. When denatured proteins from cancer cells treated with radio-labeled 5-FU were, labeled species with alternative molecular weights other than TS were visualized, providing further evidence for alternative 5-FU protein targets. These data emphasize that TS and TP53 status do not consistently explain the variance in responses of fluoropyrimidine-treated cancer cells, in part due to RNA-based toxicity. PMID:19155291

Aptamer and 5-fluorouracil dual-loading Ag2S quantum dots used as a sensitive label-free probe for near-infrared photoluminescence turn-on detection of CA125 antigen.

PubMed

Jin, Hui; Gui, Rijun; Gong, Jun; Huang, Wenxue

2017-06-15

In this article, Ag 2 S quantum dots (QDs) were prepared by a facile aqueous synthesis method, using thiourea as a new sulfur precursor. Based on electrostatic interactions, 5-fluorouracil (5-Fu) was combined with the aptamer of CA125 antigen to fabricate aptamer/5-Fu complex. The surface of as-prepared Ag 2 S QDs was modified with polyethylenimine, followed by combination with the aptamer/5-Fu complex to form Ag 2 S QDs/aptamer/5-Fu hybrids. During the combination of Ag 2 S QDs with aptamer/5-Fu complex, near-infrared (NIR) photoluminescence (PL) of QDs (peaked at 850nm) was markedly reduced under excitation at 625nm, attributed to photo-induced electron transfer from QDs to 5-Fu. However, the addition of CA125 induced obvious NIR PL recovery, which was ascribed to the strong binding affinity of CA125 with its aptamer, and the separation of aptamer/5-Fu complex from the surface of QDs. Hence, the Ag 2 S QDs/aptamer/5-Fu hybrids were developed as a novel NIR PL turn-on probe of CA125. In the concentration range of [CA125] from 0.1 to 10 6 ngmL -1 , there were a good linear relationship between NIR PL intensities of Ag 2 S QDs and Log[CA125], and a low limit of detection of 0.07ngmL -1 . Experimental results revealed the highly selective and sensitive NIR PL responses of this probe to CA125, over other potential interferences. In real human body fluids, this probe also exhibited superior analytical performance, together with high detection recoveries. Copyright © 2016 Elsevier B.V. All rights reserved.

Optimized synthesis of glycyrrhetinic acid-modified chitosan 5-fluorouracil nanoparticles and their characteristics

PubMed Central

Cheng, Mingrong; Chen, Houxiang; Wang, Yong; Xu, Hongzhi; He, Bing; Han, Jiang; Zhang, Zhiping

2014-01-01

The nanoparticle drug delivery system, which uses natural or synthetic polymeric material as a carrier to deliver drugs to targeted tissues, has a broad prospect for clinical application for its targeting, slow-release, and biodegradable properties. Here, we used chitosan (CTS) and hepatoma cell-specific binding molecule glycyrrhetinic acid to synthesize glycyrrhetinic acid-modified chitosan (GA-CTS). The synthetic product was confirmed by infrared (IR) spectra and hydrogen-1 nuclear magnetic resonance. The GA-CTS/5-fluorouracil (5-FU) nanoparticles were synthesized by combining GA-CTS and 5-FU and conjugating 5-FU onto the GA-CTS nanomaterial. The central composite design was performed to optimize the preparation process as CTS:tripolyphosphate sodium (TPP) weight ratio =5:1, 5-FU:CTS weight ratio =1:1, TPP concentration =0.05% (w/v), and cross-link time =50 minutes. GA-CTS/5-FU nanoparticles had a mean particle size of 193.7 nm, a polydispersity index of 0.003, a zeta potential of +27.4 mV, and a drug loading of 1.56%. The GA-CTS/5-FU nanoparticle had a protective effect on the drug against plasma degrading enzyme, and provided a sustained release system comprising three distinct phases of quick, steady, and slow release. Our study showed that the peak time, half-life time, mean residence time and area under the curve of GA-CTS/5-FU were longer or more than those of the 5-FU group, but the maximum concentration (Cmax) was lower. We demonstrated that the nanoparticles accumulated in the liver and have significantly inhibited tumor growth in an orthotropic liver cancer mouse model. PMID:24493926

Cytocompatible chitosan-graft-mPEG-based 5-fluorouracil-loaded polymeric nanoparticles for tumor-targeted drug delivery.

PubMed

Antoniraj, M Gover; Ayyavu, Mahesh; Henry, Linda Jeeva Kumari; Nageshwar Rao, Goutham; Natesan, Subramanian; Sundar, D Sathish; Kandasamy, Ruckmani

2018-03-01

Biodegradable materials like chitosan (CH) and methoxy polyethylene glycol (mPEG) are widely being used as drug delivery carriers for various therapeutic applications. In this study, copolymer (CH-g-mPEG) of CH and carboxylic acid terminated mPEG was synthesized by carbodiimide-mediated acid amine reaction. The resultant hydrophilic copolymer was characterized by Fourier transform infrared spectroscopy and 1 H NMR studies, revealing its relevant functional bands and proton peaks, respectively. Blank polymeric nanoparticles (B-PNPs) and 5-fluorouracil loaded polymeric nanoparticles (5-FU-PNPs) were formulated by ionic gelation method. Furthermore, folic acid functionalized FA-PNPs and FA-5-FU-PNPs were prepared for folate receptor-targeted drug delivery. FA-5-FU-PNPs were characterized by particle size, zeta potential, and in vitro drug release studies, resulting in 197.7 nm, +29.9 mv, and sustained drug release of 88% in 24 h, respectively. Cytotoxicity studies were performed for FA-PNPs and FA-5-FU-PNPs in MCF-7 cell line, which exhibited a cell viability of 80 and 41%, respectively. In vitro internalization studies were carried out for 5-FU-PNPs and FA-5-FU-PNPs which demonstrated increased cellular uptake of FA-5-FU-PNPs by receptor-mediated transport. Significant (p < .01) reduction (1.5-fold) of reactive oxygen species (ROS) accumulation was observed in lipopolysaccharides-stimulated RAW264.7 macrophages, revealing its potent antioxidant property. From the obtained results, it is concluded that folic acid functionalization of 5-FU-PNPs is an ideal approach for sustained and targeted drug delivery, thereby influencing better therapeutic effect.

Journal of Aeronautics.

DTIC Science & Technology

1982-07-21

aerodynamic tool for design of elastic aircraft. Several numerical examples are given and some dynamical problems of elastic aircraft are also discussed...Qiangang, Wu Changlin, Jian Zheng Northwestern Polytechnical University Abstract: A numerical metbod,6* ted for predicting the aerodynamic characte- ristics... Numerical value calculation method is one important means of the present research on elastic aircraft pneumatic characteristics. Be- cause this

RNA Chimeras as a Gene Signature of Breast Cancer

DTIC Science & Technology

2014-06-01

respectively, migrated as expected from their formula molecular weight (FMW), when a 10% divergence, i.e 36-44 kD or 23-29 kD, is considered as the wild...yang2, Hai-hong Shen3, Gung-wei Chirn4, Jian-hua Zhou5, Emily Weiss2, Emily Pauline Holman2, D. Joshua Liao2* 1 Guangxi Veterinary Research Institute

Prevention of oral mucositis due to 5-fluorouracil treatment with oral cryotherapy.

PubMed

Baydar, Mustafa; Dikilitas, Mustafa; Sevinc, Alper; Aydogdu, Ismet

2005-08-01

One of the most common and important side effects of 5-fluorouracil (5-FU) is mucositis with ulcerations in the oral cavity. We investigated the effects of local cryotherapy on mucositis incidence administrated durng 5-FU treatment. In a total of 99 courses, 5-FU and folinic acid combination chemotherapy was given to 40 patients. In our study, we considered every course as a single case, and cryotherapy was given to the same patient in one course but not given in the next. While mucositis developed in 6.7% of the courses given with cryotherapy, this ratio was 38.9% in courses given without cryotherapy. In the logistic regression analysis, development of mucositis had been found to correlate only with cryotherapy. Odds ratio (OR) = 11.5; in the 95% confidence interval (CI) = 3.2 - 41.9; (p = 0.001). Results of initial studies evaluating the effects of cryotherapy in preventing mucositis due to 5-FU based chemotherapy regimens were promising. We concluded that oral cooling prevents 5-FU induced mucositis. This effective prophylactic treatment should be used in patients who are at increased risk for developing 5-FU induced mucositis.

Prevention of oral mucositis due to 5-fluorouracil treatment with oral cryotherapy.

PubMed Central

Baydar, Mustafa; Dikilitas, Mustafa; Sevinc, Alper; Aydogdu, Ismet

2005-01-01

INTRODUCTION: One of the most common and important side effects of 5-fluorouracil (5-FU) is mucositis with ulcerations in the oral cavity. We investigated the effects of local cryotherapy on mucositis incidence administrated durng 5-FU treatment. METHODS: In a total of 99 courses, 5-FU and folinic acid combination chemotherapy was given to 40 patients. In our study, we considered every course as a single case, and cryotherapy was given to the same patient in one course but not given in the next. RESULTS: While mucositis developed in 6.7% of the courses given with cryotherapy, this ratio was 38.9% in courses given without cryotherapy. In the logistic regression analysis, development of mucositis had been found to correlate only with cryotherapy. Odds ratio (OR) = 11.5; in the 95% confidence interval (CI) = 3.2 - 41.9; (p = 0.001). DISCUSSION: Results of initial studies evaluating the effects of cryotherapy in preventing mucositis due to 5-FU based chemotherapy regimens were promising. We concluded that oral cooling prevents 5-FU induced mucositis. This effective prophylactic treatment should be used in patients who are at increased risk for developing 5-FU induced mucositis. PMID:16173332

Loss to Follow-Up and Social Background in an Inception Cohort of Patients With Severe Traumatic Brain Injury: Results From the PariS-TBI Study.

PubMed

Jourdan, Claire; Bayen, Eleonore; Bahrami, Stephane; Ghout, Idir; Darnoux, Emmanuelle; Azerad, Sylvie; Ruet, Alexis; Vallat-Azouvi, Claire; Weiss, Jean-Jacques; Aegerter, Philippe; Mateo, Joaquim; Vigue, Bernard; Tazarourte, Karim; Pradat-Diehl, Pascale; Azouvi, Philippe

2016-01-01

To assess determinants of loss to follow-up (FU) at 2 time points of an inception traumatic brain injury (TBI) cohort. The PariS-TBI study consecutively included 504 adults with severe TBI on the accident scene (76% male, mean age 42 years, mean Glasgow Coma Scale 5). No exclusion criteria were used. Loss to FU at 1 and 4 years was defined among survivors as having no outcome data other than survival status. Among 257 1-year survivors, 118 (47%) were lost to FU at 1 year and 98 (40%) at 4 years. Main reasons for loss to FU were impossibility to achieve contact (109 at 1 year, 52 at 4 years) and refusal to participate (respectively 5 and 24). At 1 year, individuals not working preinjury or with nonaccidental traumas were more often lost to FU in univariate and multivariable analyses. At 4 years, loss to FU was significantly associated with preinjury alcohol abuse and unemployment. Relationship with injury severity was not significant. Socially disadvantaged persons are underrepresented in TBI outcome research. It could result in overestimation of outcome and biased estimates of sociodemographic characteristics' effects. These persons, particularly unemployed individuals, require special attention in clinical practice.

Accidental and experimentally induced 5-fluorouracil toxicity in dogs.

PubMed

Sayre, Rebecca S; Barr, James W; Bailey, E Murl

2012-10-01

To summarize the literature involving 5-fluorouracil (5-FU) toxicosis in dogs. 5-Fluorouracil's mechanism of action revolves around the metabolism of 5-FU into fluorouridine triphosphate which then interferes with RNA synthesis and function as well as the inhibition of thymidylate synthase which ultimately impairs DNA stability. Toxicity of 5-FU is the most pronounced on rapidly dividing cells. Toxicity manifests itself mainly in the neurologic, gastrointestinal, respiratory, or hematopoietic systems. History of accidental exposure to 5-FU-containing products. Therapy for 5-FU toxicosis involves typical decontamination procedures and symptomatic therapy for the subsequent toxicity. Seizure control and treatment of the severe gastrointestinal signs that follow are the primary goals in the acute setting. As the disease progresses, management of the sequelae to bone marrow suppression and pulmonary complications are essential. The prognosis for dogs with ingestion of 5-FU is dependent on the amount consumed, with severe intoxication carrying a poor prognosis. Toxic doses can be as little as 5 mg/kg, and doses ≥40 mg/kg are reported to be uniformly fatal. © Veterinary Emergency and Critical Care Society 2012.

Unravelling the potential of a new uracil phosphoribosyltransferase (UPRT) from Arabidopsis thaliana in sensitizing HeLa cells towards 5-fluorouracil.

PubMed

Narayanan, Sharmila; Sanpui, Pallab; Sahoo, Lingaraj; Ghosh, Siddhartha Sankar

2016-10-01

In silico studies with uracil phosphoribosyltransferase from Arabidopsis thaliana (AtUPRT) revealed its lower binding energies for uracil and 5-fluorouracil (5-FU) as compared to those of bacterial UPRT indicating the prospective of AtUPRT in gene therapy implications. Hence, AtUPRT was cloned and stably expressed in cervical cancer cells (HeLa) to investigate the effect of prodrug 5-FU on these transfected cancer cells. The treatment of AtUPRT-expressing HeLa (HeLa-UPP) cells with 5-FU for 72h resulted in significant decrease in cell viability. Moreover, 5-FU was observed to induce apoptosis and perturb mitochondrial membrane potential in HeLa-UPP cells. While cell cycle analysis revealed significant S-phase arrest as a result of 5-FU treatment in HeLa-UPP cells, quantitative gene expression analysis demonstrated simultaneous upregulation of important cell cycle related genes, cyclin D1 and p21. The survival fractions of non-transfected, vector-transfected and AtUPRT-transfected HeLa cells, following 5-FU treatment, were calculated to be 0.425, 0.366 and 0.227, respectively. Copyright © 2016 Elsevier B.V. All rights reserved.

Differences in the Onset and Severity of Symptoms of Malignant Hyperthermia With Different Inhalational Anesthetics

DTIC Science & Technology

1999-10-01

also received succinylcholine (Fu, Scharf, Mangar & Miller, 1996;Michalek- Sauberer , Fricker, Gradwohl, & Gilly, 1997). The case reported by Fu and...the case reported by Michaelek- Sauberer and colleagues (1997), a pediatric patient received desflurane. After 90 minutes of surgery, the patient s...Malignant Hyperthermia 61 biopsy (Fu et al., 1996; Michalek- Sauberer et al., 1997). In both case reports, there was a wide variability of

Emergency use of uridine triacetate for the prevention and treatment of life‐threatening 5‐fluorouracil and capecitabine toxicity

PubMed Central

Saif, Muhammad Wasif; El‐Rayes, Bassel F.; Fakih, Marwan G.; Cartwright, Thomas H.; Posey, James A.; King, Thomas R.; von Borstel, Reid W.; Bamat, Michael K.

2016-01-01

BACKGROUND Increased susceptibility to 5‐fluorouracil (5‐FU)/capecitabine can lead to rapidly occurring toxicity caused by impaired clearance, dihydropyrimidine dehydrogenase deficiency, and other genetic variations in the enzymes that metabolize 5‐FU. Life‐threatening 5‐FU overdoses occur because of infusion pump errors, dosage miscalculations, and accidental or suicidal ingestion of capecitabine. Uridine triacetate (Vistogard) was approved in 2015 for adult and pediatric patients who exhibit early‐onset severe or life‐threatening 5‐FU/capecitabine toxicities or present with an overdose. Uridine triacetate delivers high concentrations of uridine, which competes with toxic 5‐FU metabolites. METHODS In 2 open‐label clinical studies, patients who presented with a 5‐FU/capecitabine overdose or an early onset of severe toxicities were treated. Patients received uridine triacetate as soon as possible (most within the first 96 hours after 5‐FU/capecitabine). Outcomes included survival, resumption of chemotherapy, and safety. Their survival was compared with the survival of a historical cohort of overdose patients who received only supportive care. RESULTS A total of 137 of 142 overdose patients (96%) treated with uridine triacetate survived and had a rapid reversal of severe acute cardiotoxicity and neurotoxicity; in addition, mucositis and leukopenia were prevented, or the patients recovered from them. In the historical cohort, 21 of 25 patients (84%) died. Among the 141 uridine triacetate–treated overdose patients with a diagnosis of cancer (the noncancer patients included 6 intentional or accidental pediatric overdoses), 53 resumed chemotherapy in < 30 days (median time after 5‐FU, 19.6 days), and this indicated a rapid recovery from toxicity. Adverse reactions in patients receiving uridine triacetate included vomiting (8.1%), nausea (4.6%), and diarrhea (3.5%). CONCLUSIONS In these studies, uridine triacetate was a safe and effective

Predictive markers for the response to 5-fluorouracil therapy in cancer cells: Constant-field gel electrophoresis as a tool for prediction of response to 5-fluorouracil-based chemotherapy

PubMed Central

SALEH, E. M.; EL-AWADY, R. A.; ANIS, N.

2013-01-01

The prediction of response or severe toxicity and therapy individualisation are extremely important in cancer chemotherapy. There are few tools to predict chemoresponse or toxicity in cancer patients. We investigated the correlation between the induction and repair of DNA double-strand breaks (DSBs) using constant-field gel electrophoresis (CFGE) and evaluating cell cycle progression and the sensitivity of four cancer cell lines to 5-fluorouracil (5FU). Using a sulphorhodamine-B assay, colon carcinoma cells (HCT116) were found to be the most sensitive to 5FU, followed by liver carcinoma cells (HepG2) and breast carcinoma cells (MCF-7). Cervical carcinoma cells (HeLa) were the most resistant. As measured by CFGE, DSB induction, but not residual DSBs, exhibited a significant correlation with the sensitivity of the cell lines to 5FU. Flow cytometric cell cycle analysis revealed that 14% of HCT116 or HepG2 cells and 2% of MCF-7 cells shifted to sub-G1 phase after a 96-h incubation with 5FU. Another 5FU-induced cell cycle change in HCT116, HepG2 and MCF-7 cells was the mild arrest of cells in G1 and/or G2/M phases of the cell cycle. In addition, 5FU treatment resulted in the accumulation of HeLa cells in the S and G2/M phases. Determination of Fas ligand (Fas-L) and caspase 9 as representative markers for the extrinsic and intrinsic pathways of apoptosis, respectively, revealed that 5FU-induced apoptosis in HCT116 and HepG2 results from the expression of Fas-L (extrinsic pathway). Therefore, the induction of DNA DSBs by 5FU, detected using CFGE, and the induction of apoptosis are candidate predictive markers that may distinguish cancer cells which are likely to benefit from 5FU treatment and the measurement of DSBs using CFGE may aid the prediction of clinical outcome. PMID:23255942

Oxaliplatin and protracted venous infusion of 5-fluorouracil in patients with advanced or relapsed 5-fluorouracil pretreated colorectal cancer

PubMed Central

Chau, I; Webb, A; Cunningham, D; Hill, M; Waters, J S; Norman, A; Massey, A

2001-01-01

The purpose of this study was to evaluate the activity and safety of oxaliplatin and protracted venous infusion of 5-fluorouracil (PVI 5-FU) in patients with advanced or relapsed 5-FU pretreated colorectal cancer. 38 patients with advanced or metastatic colorectal carcinoma with documented progression on or within 6 months following 5-FU or thymidylate synthase inhibitor containing chemotherapy were recruited between June 1997 and September 2000. Oxaliplatin (100 mg m−2) was given every 2 weeks and PVI 5-FU (300 mg m−2day−1) was administered. Median age of patients was 61 years. 17 patients had >2 sites of disease involvement. 10 had received 5-FU based adjuvant chemotherapy. 16 received oxaliplatin and PVI 5-FU as second-line chemotherapy for advanced disease and 22 as third or subsequent lines. Median follow up was 6.1 months. The best achieved objective tumour response rate was 29% (11 partial responses 95% confidence interval [CI] = 15–46%). 20 patients (52.6%) had stable disease. The median duration of response was 3.9 months. Even for patients who had previously received both 5-FU and irinotecan (n= 22), 27.3% had partial response with oxaliplatin and PVI 5-FU. 37 patients had symptoms on entry into the study. 25 patients had pain, 10 had anorexia and 28 had lethargy. 64%, 70% and 17.9% had symptomatic improvement after treatment respectively. Grade 3–4 toxicities were anaemia 10.6%, neutropenia 2.6%, thrombocytopenia 5.2%, diarrhoea 18.9%, nausea and vomiting 2.7%, infection 5.4% and lethargy 37.8%. The median survival was 9.1 months. Probability of overall survival at 6 months was 58.4% (95% CI = 38.7–73.7%). The median failure-free survival was 4 months. Oxaliplatin and PVI 5FU is an active and well tolerated regimen in patients with heavily pre-treated advanced colorectal cancer. © 2001 Cancer Research Campaign PMID:11720458

Supramolecular hydrogen-bonding patterns in 1:1 cocrystals of 5-fluorouracil with 4-methylbenzoic acid and 3-nitrobenzoic acid.

PubMed

Mohana, Marimuthu; Muthiah, Packianathan Thomas; McMillen, Colin D

2017-03-01

The design of a pharmaceutical cocrystal is based on the identification of specific hydrogen-bond donor and acceptor groups in active pharmaceutical ingredients (APIs) in order to choose a `complementary interacting' molecule that can act as an efficient coformer. 5-Fluorouracil (5FU) is a pyrimidine derivative with two N-H donors and C=O acceptors and shows a diversity of hydrogen-bonding motifs. Two 1:1 cocrystals of 5-fluorouracil (5FU), namely 5-fluorouracil-4-methylbenzoic acid (5FU-MBA), C 4 H 3 FN 2 O 2 ·C 8 H 8 O 2 , (I), and 5-fluorouracil-3-nitrobenzoic acid (5FU-NBA), C 4 H 3 FN 2 O 2 ·C 7 H 5 NO 4 , (II), have been prepared and characterized by single-crystal X-ray diffraction. In (I), the MBA molecules form carboxylic acid dimers [R 2 2 (8) homosynthon]. Similarly, the 5FU molecules form two types of base pair via a pair of N-H...O hydrogen bonds [R 2 2 (8) homosynthon]. In (II), 5FU interacts with the carboxylic acid group of NBA via N-H...O and O-H...O hydrogen bonds, generating an R 2 2 (8) ring motif (heterosynthon). Furthermore, the 5FU molecules form base pairs [R 2 2 (8) homosynthon] via N-H...O hydrogen bonds. Both of the crystal structures are stabilized by C-H...F interactions.

Synthesis of Glycyrrhetinic Acid-Modified Chitosan 5-Fluorouracil Nanoparticles and Its Inhibition of Liver Cancer Characteristics in Vitro and in Vivo

PubMed Central

Cheng, Mingrong; Gao, Xiaoyan; Wang, Yong; Chen, Houxiang; He, Bing; Xu, Hongzhi; Li, Yingchun; Han, Jiang; Zhang, Zhiping

2013-01-01

Nanoparticle drug delivery (NDDS) is a novel system in which the drugs are delivered to the site of action by small particles in the nanometer range. Natural or synthetic polymers are used as vectors in NDDS, as they provide targeted, sustained release and biodegradability. Here, we used the chitosan and hepatoma cell-specific binding molecule, glycyrrhetinic acid (GA), to synthesize glycyrrhetinic acid-modified chitosan (GA-CTS). The synthetic product was confirmed by Fourier transformed infrared spectroscopy (FT-IR) and 1H-nuclear magnetic resonance (1H-NMR). By combining GA-CTS and 5-FU (5-fluorouracil), we obtained a GA-CTS/5-FU nanoparticle, with a particle size of 217.2 nm, a drug loading of 1.56% and a polydispersity index of 0.003. The GA-CTS/5-FU nanoparticle provided a sustained release system comprising three distinct phases of quick, steady and slow release. We demonstrated that the nanoparticle accumulated in the liver. In vitro data indicated that it had a dose- and time-dependent anti-cancer effect. The effective drug exposure time against hepatic cancer cells was increased in comparison with that observed with 5-FU. Additionally, GA-CTS/5-FU significantly inhibited the growth of drug-resistant hepatoma, which may compensate for the drug-resistance of 5-FU. In vivo studies on an orthotropic liver cancer mouse model demonstrated that GA-CTS/5-FU significantly inhibited tumor growth, resulting in increased survival time. PMID:24048270

Evaluation of the Cytotoxic Effects of Hyperthermia and 5-Fluorouracil Loaded Magnetic Nanoparticles on Human Colon Cancer Cell Line HT-29.

PubMed

Eynali, Samira; Khoei, Samideh; Khoei, Sepideh; Esmaelbeygi, Elaheh

2016-10-04

The purpose of this study was to evaluate the combined effects of heat and poly lactic-co-glycolic acid (PLGA) nanoparticles, as 5-fluorouracil carriers with/without iron oxide core, on the viability and proliferation capacity of human colon cancer cell line HT-29 in the spheroid model. HT-29 spheroid cells were treated with different concentrations of 5-FU or 5-FU loaded into both nanoparticles for 74 h. Hyperthermia was then performed at 43°C for 60 min. Finally, the effects of the mentioned treatments on cell viability and proliferation capacity were evaluated using the trypan blue dye exclusion test and colony formation assay, respectively. Our results showed that hyperthermia, in combination with 5-FU or PLGA nanoparticles as 5-FU carriers, significantly enhanced the cytotoxic effects as compared to the control group. Considering that nanoparticles could increase the intracellular concentration of drugs in cancer cells, the extent of cytotoxic effects following treatment with 5-FU loaded into both nanoparticles was significantly higher than that with free 5-FU. In addition, the presence of iron oxide cores in nanoparticles during hyperthermia enhanced the cytotoxic effects of hyperthermia compared with nanoparticles without iron oxide core. Based on this study, hyperthermia in combination with 5-FU-loaded PLGA nanoparticles with iron oxide core drastically reduced the proliferation capacity of HT-29 cells; therefore, it may be considered a new direction in the treatment of colon cancer.

"Organic brain syndrome" secondary to 5-fluorouracil toxicity.

PubMed

Lynch, H T; Droszcz, C P; Albano, W A; Lynch, J F

1981-01-01

A 68-year-old woman, who was treated with 5-fluorouracil (5-FU) intravenous therapy weekly for variable periods following hemicolectomy for adenocarcinoma of the cecum, had at least two well-described episodes of mental confusion, disorientation, and deterioration, in the absence of cerebellar tract signs. The sensorium cleared after cessation of 5-FU, only to deteriorate following readministration of the drug. She was thought to have organic brain syndrome during her most recent mental relapse. Her mental status has now been intact for more than one year since her last exposure to 5-FU. This is believed to be the third patient who has shown mental changes which could be attributable to 5-FU toxicity. Since 5-FU is the most frequently used chemotherapy for the treatment of colonic cancer, it is important that this form of toxicity be recognized lest subject patients be judged to have irreversible organic brain syndrome or metastatic carcinoma.

[Spatial and temporal patterns of the ecological compensation criterion in Jiangxi Province, China based on carbon footprint.

PubMed

Hu, Xiao Fei; Zou, Yan; Fu, Chun

2017-02-01

Carbon footprint is a new method to measure carbon emissions, and the ecological compensation criterion can be determined according to the regional carbon footprint and carbon carrying capacity. The spatial and temporal patterns of ecological compensation criterion were studied among 11 cities in Jiangxi Province using carbon footprint, carbon capacity and carbon surplus/deficit models. Our results found that carbon footprint in Jiangxi Province showed a rapid growth trend from 2000 to 2013, with an average annual growth rate of 8.7%. The carbon carrying capacity always remained surplus, but the net carbon surplus amount decreased from 2000 to 2013. Among the 11 cities, Nanchang and Jiujiang made the biggest contribution to total carbon emission, and Ganzhou, Ji'an and Shangrao had provided the largest contribution to carbon total absorption. In 2013, the total carbon surplus amount was 2.273 billion yuan in Jiangxi Province. Ganzhou, Ji'an, Fuzhou and Shangrao should be given priority to ecological compensation money. These results could provide a scientific basis for the establishment of ecological compensation mechanism in Jiangxi Province and the transfer of CO 2 emission rights.

In vitro additive antitumor effects of dimethoxycurcumin and 5-fluorouracil in colon cancer cells.

PubMed

Zhao, Huiying; Liu, Qingchun; Wang, Saisai; Dai, Fang; Cheng, Xiaofei; Cheng, Xiaobin; Chen, Wenbin; Zhang, Min; Chen, Dong

2017-07-01

Dimethoxycurcumin (DMC) is a lipophilic analog of curcumin, an effective treatment for colon cancer, which has greater chemical and metabolic stability. Chemotherapy treatments, such as 5-fluorouracil (5-Fu), play a key role in the current management of colon cancer. In this study, we investigated the antitumor efficacy of DMC in combination with 5-Fu in SW480 and SW620 colon cancer cells. CCK-8 assay was used to evaluate the inhibitory effect of DMC and 5-Fu on cancer cells proliferation, and the combination index was calculated. The influence of DMC and 5-Fu on cell cycle, apoptosis, reactive oxygen species (ROS) production, and mitochondrial membrane potential in SW480 and SW620 cells was determined using flow cytometry, and the related signaling pathways were detected by western blot. Transmission electron microscopy was used to observe endoplasmic reticulum expansion. DMC- and/or 5-Fu-induced apoptosis, stimulated G0/G1 phase arrest, increased ROS levels, decreased mitochondrial membrane potential, and enhanced endoplasmic reticulum expansion. The induction of apoptosis is involved in the increasing of Bax and cytochrome c and decreasing of Bcl2 expressions. Increased production of ROS was accompanied by upregulation of CHOP and Noxa. Combination therapy of DMC and 5-Fu had increased efficacy on the above pathways compared with either drug alone. Based on the calculated IC 50 , combination treatment with DMC and 5-Fu had an additive antitumor effect in both cell lines. Combined treatment with DMC and 5-Fu led to an additive antitumor effect in colon cancer cells that was related to apoptosis induction, G0/G1 phase arrest, increased ROS production, decreased mitochondrial membrane potential, and enhanced endoplasmic reticulum expansion. © 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Translocator protein ligand-PLGA conjugated nanoparticles for 5-fluorouracil delivery to glioma cancer cells.

PubMed

Laquintana, Valentino; Denora, Nunzio; Lopalco, Antonio; Lopedota, Angela; Cutrignelli, Annalisa; Lasorsa, Francesco Massimo; Agostino, Giulia; Franco, Massimo

2014-03-03

Translocator protein 18 kDa (TSPO) is a promising target for molecular imaging and for targeted drug delivery to tumors overexpressing TSPO. In our previous work, new macromolecular conjugates with a high affinity and selectivity for TSPO were prepared by conjugating the biodegradable poly(d,l-lactic-co-glycolic acid) (PLGA) polymer with two potent and selective TSPO ligands, namely, compounds 1 and 2. Based on this, nanoparticle delivery systems (NPs), employing TSPO ligand-PLGA conjugated (PLGA-TSPO) polymers, were prepared. Furthermore, to evaluate the ability of the new NPs to be used as a drug delivery systems for anticancer therapy, PLGA-TSPO NPs were loaded with 5-fluorouracil (5-FU), chosen as a model hydrophilic anticancer drug. The main goal of this work was to investigate the synergistic potential of using NP conjugates PLGA-TSPO, TSPO ligands being pro-apoptotic agents, to simultaneously deliver a cytotoxic anticancer drug. To better highlight the occurrence of synergistic effects, dual drug loaded PLGA NPs (PLGA NPs/5-FU/1) and dual drug loaded PLGA-TSPO NPs (PLGA-TSPO NPs/5-FU/1), with 5-FU and TSPO ligand 1 physically incorporated together, were also prepared and characterized. The particle size and size distribution, surface morphology, and drug encapsulation efficiency, as well as the drug release kinetics, were investigated. In vitro cytotoxicity studies were carried out on C6 glioma cells overexpressing TSPO, and to evaluate the potential uptake of these nanoparticulate systems, the internalization of fluorescent labeled PLGA-TSPO NPs (FITC-PLGA-TSPO NPs) was also investigated by fluorescence microscopy. Results demonstrated that PLGA-TSPO NPs/5-FU and dual drug loaded PLGA NPs/5-FU/1 and PLGA-TSPO NPs/5-FU/1 could significantly enhance toxicity against human cancer cells due to the synergistic effect of the TSPO ligand 1 with the anticancer drug 5-FU.

[Preparation and evaluation of taste masked orally disintegrating tablets with granules made by the wet granulation method].

PubMed

Kawano, Yayoi; Ito, Akihiko; Sasatsu, Masanaho; Machida, Yoshiharu; Onishi, Hiraku

2010-12-01

Using furosemide (FU) as a model drug, we examined the wet granulation method as a way to improve the taste masking and physical characteristics of orally disintegrating tablets (ODTs). In the wet granulation method, yogurt powder (YO) was used as a corrective and maltitol (MA) was used as a binding agent. The taste masked FU tablets were prepared using the direct compression method. Microcrystalline cellulose (Avicel® PH-302) and mannitol were added as excipients at a mixing ratio of 1/1 by weight. Based on the results of sensory test on taste, the prepared granules markedly improved the taste of FU, and a sufficient masking effect was obtained at the YO/FU ratio of 1 or more. Furthermore, it was found that the masking effect achieved by YO granules made with the wet granulation method was similar to or better than that produced by the granules made with dry granulation method. All types of tablets displayed sufficient hardness (over 3.5×10(-2) kN), and rapidly disintegrating tablets were obtained with YO granules produced at a mixing ratio of FU/YO=1/1, which disintegrated within 20 s. Disintegration time lengthened as the mixing ratio of YO to FU increased. In the mixing ratio of FU/YO=1/1, the hardness of tablets with granules made by the wet granulation method exceeded that of tablets with granules made by the dry granulation method, with minimal differences in disintegration time. The hardness and disintegration time of the tablets with granules made by the wet granulation method could be controlled by varying the compression force. In conclusion, YO was found to be a useful additive for masking unpleasant tastes. FU ODTs with improved taste, rapid disintegration and greater hardness could be prepared with YO-containing granules made by the wet granulation method using MA as a binding agent.

Combinatorial anticancer effects of curcumin and 5-fluorouracil loaded thiolated chitosan nanoparticles towards colon cancer treatment.

PubMed

Anitha, A; Deepa, N; Chennazhi, K P; Lakshmanan, Vinoth-Kumar; Jayakumar, R

2014-09-01

Evaluation of the combinatorial anticancer effects of curcumin/5-fluorouracil loaded thiolated chitosan nanoparticles (CRC-TCS-NPs/5-FU-TCS-NPs) on colon cancer cells and the analysis of pharmacokinetics and biodistribution of CRC-TCS-NPs/5-FU-TCS-NPs in a mouse model. CRC-TCS-NPs/5-FU-TCS-NPs were developed by ionic cross-linking. The in vitro combinatorial anticancer effect of the nanomedicine was proven by different assays. Further the pharmacokinetics and biodistribution analyses were performed in Swiss Albino mouse using HPLC. The 5-FU-TCS-NPs (size: 150±40nm, zeta potential: +48.2±5mV) and CRC-TCS-NPs (size: 150±20nm, zeta potential: +35.7±3mV) were proven to be compatible with blood. The in vitro drug release studies at pH4.5 and 7.4 showed a sustained release profile over a period of 4 days, where both the systems exhibited a higher release in acidic pH. The in vitro combinatorial anticancer effects in colon cancer (HT29) cells using MTT, live/dead, mitochondrial membrane potential and cell cycle analysis measurements confirmed the enhanced anticancer effects (2.5 to 3 fold). The pharmacokinetic studies confirmed the improved plasma concentrations of 5-FU and CRC up to 72h, unlike bare CRC and 5-FU. To conclude, the combination of 5-FU-TCS-NPs and CRC-TCS-NPs showed enhanced anticancer effects on colon cancer cells in vitro and improved the bioavailability of the drugs in vivo. The enhanced anticancer effects of combinatorial nanomedicine are advantageous in terms of reduction in the dosage of 5-FU, thereby improving the chemotherapeutic efficacy and patient compliance of colorectal cancer cases. Copyright © 2014 Elsevier B.V. All rights reserved.

Atomistic computer simulations on multi-loaded PAMAM dendrimers: a comparison of amine- and hydroxyl-terminated dendrimers

NASA Astrophysics Data System (ADS)

Badalkhani-Khamseh, Farideh; Ebrahim-Habibi, Azadeh; Hadipour, Nasser L.

2017-12-01

Poly(amidoamine) (PAMAM) dendrimers have been extensively studied as delivery vectors in biomedical applications. A limited number of molecular dynamics (MD) simulation studies have investigated the effect of surface chemistry on therapeutic molecules loading, with the aim of providing insights for biocompatibility improvement and increase in drug loading capacity of PAMAM dendrimers. In this work, fully atomistic MD simulations were employed to study the association of 5-Fluorouracil (5-FU) with amine (NH2)- and hydroxyl (OH)-terminated PAMAM dendrimers of generations 3 and 4 (G3 and G4). MD results show a 1:12, 1:1, 1:27, and 1:4 stoichiometry, respectively, for G3NH2-FU, G3OH-FU, G4NH2-FU, and G4OH-FU complexes, which is in good agreement with the isothermal titration calorimetry results. The results obtained showed that NH2-terminated dendrimers assume segmented open structures with large cavities and more drug molecules can encapsulate inside the dendritic cavities of amine terminated dendrimers. However, OH-terminated have a densely packed structure and therefore, 5-FU drug molecules are more stable to locate close to the surface of the dendrimers. Intermolecular hydrogen bonding analysis showed that 5-FU drug molecules have more tendency to form hydrogen bonds with terminal monomers of OH-terminated dendrimers, while in NH2-terminated these occur both in the inner region and the surface. Furthermore, MM-PBSA analysis revealed that van der Waals and electrostatic energies are both important to stabilize the complexes. We found that drug molecules are distributed uniformly inside the amine and hydroxyl terminated dendrimers and therefore, both dendrimers are promising candidates as drug delivery systems for 5-FU drug molecules.

The impact of organochlorines and metals on wild fish living in a tropical hydroelectric reservoir: bioaccumulation and histopathological biomarkers.

PubMed

Paulino, Marcelo Gustavo; Benze, Tayrine Paschoaletti; Sadauskas-Henrique, Helen; Sakuragui, Marise Margareth; Fernandes, João Batista; Fernandes, Marisa Narciso

2014-11-01

This study evaluates the contaminants in water and their bioaccumulation in the gills and liver of two ecologically distinct fish species, Astyanax fasciatus and Pimelodus maculatus, living in the reservoir of the Furnas hydroelectric power station located in Minas Gerais in the southeastern Brazil. The histological alterations in these organs are also examined. Water and fish were collected in June and December from five sites (site 1: FU10, site 2: FU20, site 3: FU30, site 4: FU40 and site 5: FU50) in the reservoir, and agrochemicals and metals selected based on their use in the field crops surrounding the reservoir were analyzed in the water and in the fish gills and livers. The concentrations of the organochlorines aldrin/dieldrin, endosulfan and heptachlor/heptachlor epoxide as well as the metals copper, chromium, iron and zinc in the gills and livers of both fish species were higher in June than in December; the liver accumulated higher concentrations of contaminants than the gills. The organochlorine metolachlor was detected only in the liver. The histological pattern of changes was similar in both species with regard to contaminant accumulation in the gills and liver. Fish from FU10, the least contaminated site, exhibited normal gill structure and moderate to heavy liver damage. Fish collected at FU20 to FU50, which were contaminated with organochlorines and metals, showed slight to moderate gill damage in June and irreparable liver damage in the livers in June and December. The histological changes in the gills and liver were suitable to distinguishing contaminated field sites and are therefore useful biomarkers for environmental contamination representing a biological end-point of exposure. Copyright © 2014 Elsevier B.V. All rights reserved.

Adjuvant Chemotherapy With FOLFOX for Primary Colorectal Cancer Is Associated With Increased Somatic Gene Mutations and Inferior Survival in Patients Undergoing Hepatectomy for Metachronous Liver Metastases

PubMed Central

Andreou, Andreas; Kopetz, Scott; Maru, Dipen M.; Chen, Su S.; Zimmitti, Giuseppe; Brouquet, Antoine; Shindoh, Junichi; Curley, Steven A.; Garrett, Christopher; Overman, Michael J.; Aloia, Thomas A.; Vauthey, Jean-Nicolas

2013-01-01

Objective We hypothesized that metachronous colorectal liver metastases (CLM) have different biology after failure of oxaliplatin (FOLFOX) compared to 5-fluorouracil (5-FU) or no chemotherapy for adjuvant treatment of colorectal cancer (CRC). Background It is unclear whether patients treated with liver resection for metachronous CLM after adjuvant FOLFOX for CRC have worse outcomes than those who received 5-FU or no chemotherapy. Methods We identified 341 patients who underwent hepatectomy for metachronous CLM (disease-free interval ≥12 months, 1993–2010). Mass-spectroscopy genotyping for somatic gene mutations in CLM was performed in a subset of 129 patients. Results Adjuvant treatment for primary CRC was FOLFOX in 77 patients, 5-FU in 169 patients, and no chemotherapy in 95 patients. Node-positive primary was comparable between FOLFOX and 5-FU but lower in the no-chemotherapy group (P < 0.0001). Median metastasis size was smaller in the FOLFOX group (2.5 cm) than in the 5-FU (3.0 cm) or no-chemotherapy (3.5 cm) groups, (P = 0.008) although prehepatectomy chemotherapy utilization, metastases number, and carcinoembryonic antigen levels were similar. Disease-free survival (DFS) and overall survival (OS) rates after hepatectomy were worse in patients treated with adjuvant FOLFOX [DFS at 3 years: 14% vs 38% (5-FU) vs 45% (no-chemo), OS at 3 years: 58% vs 70% (5-FU) vs 84% (no-chemo)]. On multivariate analysis, adjuvant FOLFOX was associated with worse DFS (P < 0.0001) and OS (P < 0.0001). Mutation analysis revealed ≥1 mutations in 57% of patients (27/47) after FOLFOX, 29% (12/41) after 5-FU, and 32% (13/41) after no chemotherapy (P = 0.011). Conclusions Adjuvant FOLFOX for primary CRC is associated with a high rate of somatic mutations in liver metastases and inferior outcomes after hepatectomy for metachronous CLM. PMID:22968062

Adjuvant chemotherapy with FOLFOX for primary colorectal cancer is associated with increased somatic gene mutations and inferior survival in patients undergoing hepatectomy for metachronous liver metastases.

PubMed

Andreou, Andreas; Kopetz, Scott; Maru, Dipen M; Chen, Su S; Zimmitti, Giuseppe; Brouquet, Antoine; Shindoh, Junichi; Curley, Steven A; Garrett, Christopher; Overman, Michael J; Aloia, Thomas A; Vauthey, Jean-Nicolas

2012-10-01

We hypothesized that metachronous colorectal liver metastases (CLM) have different biology after failure of oxaliplatin (FOLFOX) compared to 5-fluorouracil (5-FU) or no chemotherapy for adjuvant treatment of colorectal cancer (CRC). It is unclear whether patients treated with liver resection for metachronous CLM after adjuvant FOLFOX for CRC have worse outcomes than those who received 5-FU or no chemotherapy. We identified 341 patients who underwent hepatectomy for metachronous CLM (disease-free interval ≥12 months, 1993-2010). Mass-spectroscopy genotyping for somatic gene mutations in CLM was performed in a subset of 129 patients. Adjuvant treatment for primary CRC was FOLFOX in 77 patients, 5-FU in 169 patients, and no chemotherapy in 95 patients. Node-positive primary was comparable between FOLFOX and 5-FU but lower in the no-chemotherapy group (P < 0.0001). Median metastasis size was smaller in the FOLFOX group (2.5 cm) than in the 5-FU (3.0 cm) or no-chemotherapy (3.5 cm) groups, (P = 0.008) although prehepatectomy chemotherapy utilization, metastases number, and carcinoembryonic antigen levels were similar. Disease-free survival (DFS) and overall survival (OS) rates after hepatectomy were worse in patients treated with adjuvant FOLFOX [DFS at 3 years: 14% vs 38% (5-FU) vs 45% (no-chemo), OS at 3 years: 58% vs 70% (5-FU) vs 84% (no-chemo)]. On multivariate analysis, adjuvant FOLFOX was associated with worse DFS (P < 0.0001) and OS (P < 0.0001). Mutation analysis revealed ≥1 mutations in 57% of patients (27/47) after FOLFOX, 29% (12/41) after 5-FU, and 32% (13/41) after no chemotherapy (P = 0.011). Adjuvant FOLFOX for primary CRC is associated with a high rate of somatic mutations in liver metastases and inferior outcomes after hepatectomy for metachronous CLM.

Longitudinal Change Detected by Spectral Domain Optical Coherence Tomography in the Optic Nerve Head and Peripapillary Retina in Experimental Glaucoma

PubMed Central

Strouthidis, Nicholas G.; Fortune, Brad; Yang, Hongli; Sigal, Ian A.

2011-01-01

Purpose. To investigate whether longitudinal changes deep within the optic nerve head (ONH) are detectable by spectral domain optical coherence tomography (SDOCT) in experimental glaucoma (EG) and whether these changes are detectable at the onset of Heidelberg Retina Tomography (HRT; Heidelberg Engineering, Heidelberg, Germany)–defined surface topography depression. Methods. Longitudinal SDOCT imaging (Spectralis; Heidelberg Engineering) was performed in both eyes of nine rhesus macaques every 1 to 3 weeks. One eye of each underwent trabecular laser-induced IOP elevation. Four masked operators delineated internal limiting membrane (ILM), retinal nerve fiber layer (RNFL), Bruch's membrane/retinal pigment epithelium (BM/RPE), neural canal opening (NCO), and anterior lamina cribrosa surface (ALCS) by using custom software. Longitudinal changes were assessed and compared between the EG and control (nonlasered) eyes at the onset of HRT-detected surface depression (follow-up 1; [FU1]) and at the most recent image (follow-up 2; [FU2]). Results. Mean IOP in EG eyes was 7.1 to 24.6 mm Hg at FU1 and 13.5 to 31.9 mm Hg at FU2. In control eyes, the mean IOP was 7.2 to 12.6 mm Hg (FU1) and 8.9 to 16.0 mm Hg (FU2). At FU1, neuroretinal rim decreased and ALCS depth increased significantly (paired t-test, P < 0.01); no change in RNFL thickness was detected. At FU2, however, significant prelaminar tissue thinning, posterior displacement of NCO, and RNFL thinning were observed. Conclusions. Longitudinal SDOCT imaging can detect deep ONH changes in EG eyes, the earliest of which are present at the onset of HRT-detected ONH surface height depression. These parameters represent realistic targets for SDOCT detection of glaucomatous progression in human subjects. PMID:21217108

Analytical detection and biological assay of antileukemic drug 5-fluorouracil using gold nanoparticles as probe.

PubMed

Selvaraj, Vaithilingam; Alagar, Muthukaruppan

2007-06-07

Gold nanoparticles are reported and evaluated as probes for the detection of anticancer drug 5-fluorouracil (5FU). The nature of binding between 5FU and gold nanoparticles via complexation is investigated using ultraviolet visible spectrophotometry, cyclic voltammetry, transmission electron microscopy, fluorescence and Fourier transform infrared (FTIR) spectroscopy. The bound antileukemic drug is fluorescent and the quenching property of gold nanoparticles could be exploited for biological investigations. The 5FU-colloidal gold complex (Au@5FU) is observed to have appreciable antibacterial and antifungal activity against Micrococcus luteus, Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, Aspergillus fumigatus, and Aspergillus niger. The experimental studies suggest that gold nanoparticles have the potential to be used as effective carriers for anticancer drugs.

Synergistic antitumor effect of 3-bromopyruvate and 5-fluorouracil against human colorectal cancer through cell cycle arrest and induction of apoptosis.

PubMed

Chong, Dianlong; Ma, Linyan; Liu, Fang; Zhang, Zhirui; Zhao, Surong; Huo, Qiang; Zhang, Pei; Zheng, Hailun; Liu, Hao

2017-09-01

3-Bromopyruvic acid (3-BP) is a well-known inhibitor of energy metabolism. It has been proposed as an anticancer agent as well as a chemosensitizer for use in combination with anticancer drugs. 5-Fluorouracil (5-FU) is the first-line chemotherapeutic agent for colorectal cancer; however, most patients develop resistance to 5-FU through various mechanisms. The aim of this study was to investigate whether 3-BP has a synergistic antitumor effect with 5-FU on human colorectal cancer cells. In our study, combined 3-BP and 5-FU treatment upregulated p53 and p21, whereas cyclin-dependent kinase CDK4 and CDK2 were downregulated, which led to G0/G1 phase arrest. Furthermore, there was an increase in reactive oxygen species levels and a decrease in adenosine triphosphate levels. It was also observed that Bax expression increased, whereas Bcl-2 expression reduced, which were indicative of mitochondria-dependent apoptosis. In addition, the combination of 3-BP and 5-FU significantly suppressed tumor growth in the BALB/c mice in vivo. Therefore, 3-BP inhibits tumor proliferation and induces S and G2/M phase arrest. It also exerts a synergistic antitumor effect with 5-FU on SW480 cells.

Anti-EGFR Antibody Conjugation of Fucoidan-Coated Gold Nanorods as Novel Photothermal Ablation Agents for Cancer Therapy.

PubMed

Manivasagan, Panchanathan; Bharathiraja, Subramaniyan; Santha Moorthy, Madhappan; Oh, Yun-Ok; Song, Kyeongeun; Seo, Hansu; Oh, Junghwan

2017-05-03

The development of novel photothermal ablation agents as cancer nanotheranostics has received a great deal of attention in recent decades. Biocompatible fucoidan (Fu) is used as the coating material for gold nanorods (AuNRs) and subsequently conjugated with monoclonal antibodies against epidermal growth factor receptor (anti-EGFR) as novel photothermal ablation agents for cancer nanotheranostics because of their excellent biocompatibility, biodegradability, nontoxicity, water solubility, photostability, ease of surface modification, strongly enhanced absorption in near-infrared (NIR) regions, target specificity, minimal invasiveness, fast recovery, and prevention of damage to normal tissues. Anti-EGFR Fu-AuNRs have an average particle size of 96.37 ± 3.73 nm. Under 808 nm NIR laser at 2 W/cm 2 for 5 min, the temperature of the solution containing anti-EGFR Fu-AuNRs (30 μg/mL) increased by 52.1 °C. The anti-EGFR Fu-AuNRs exhibited high efficiency for the ablation of MDA-MB-231 cells in vitro. In vivo photothermal ablation exhibited that tumor tissues fully recovered without recurrence and finally were reconstructed with normal tissues by the 808 nm NIR laser irradiation after injection of anti-EGFR Fu-AuNRs. These results suggest that the anti-EGFR Fu-AuNRs would be novel photoablation agents for future cancer nanotheranostics.

A Computerized Wear Particle Atlas for Ferrogram and Filtergram Analyses

DTIC Science & Technology

1998-01-01

A Computerised Wear Particle Atlas for Ferrogram and Filtergram Analyses Jian G. Ding Lubrosoft P/L P 0 Box 2368, Rowville Melbourne VIC 3178...Australia (61-3) 9759-9083 Abstract: A new computerised wear particle atlas has been developed for identification of solid particles and...differentiation of wear severity of lubricated equipment. This atlas contains 892 images of representative solid particles selected from thousands of filtergram

Supermultiplicative Speedups of Probabilistic Model-Building Genetic Algorithms

DTIC Science & Technology

2009-02-01

physicists as well as practitioners in evolutionary computation. The project was later extended to the one-dimensional SK spin glass with power -law... Brasil ) 10. Yuji Sato (Hosei University, Japan) 11. Shunsukc Saruwatari (Tokyo University, Japan) 12. Jian-Hung Chen (Feng Chia University, Taiwan...scalability. In A. Tiwari, J. Knowlcs, E. Avincri, K. Dahal, and R. Roy (Eds.) Applications of Soft Computing: Recent Trends. Berlin: Springer (2006

Electro-Optical and Optical Components for Processor to Processor Interconnects

DTIC Science & Technology

2013-04-01

Kwiat and others were instrumental in explicitly co-entangling other properties such as momentum (path) [4]. Others such as Barnett and Zeilinger ...19 4. References: 1. D. Bouwmeester, J.W. Pan, K. Mattle, M. Eibl, H. Weinfurter and A. Zeilinger , “Experimental quantum teleportation...Nature, Vol. 390, 11 December 1997, pp. 575- 579. 2. Jian-Wei Pan, Dik Bouwmeester, Harald Weinfurter, and Anton Zeilinger , “Experimental Entanglement

Proceedings of the Conference on Environmental Toxicology (14th) Held at Dayton, OH on 15-17 November 1983

DTIC Science & Technology

1984-08-01

be a safe level. Men exposed to dibromo- chloropropane for less than 3 months have normal sperm density in ejaculates. Those men exposed between 1 ...FERTILIZATION FURTHER EVALUATION I ~ II SPERMATOGENIC EVALUATION SEMEN BIOCHEMISTRY* MEASURE UNSCHEDULED I DNA SYNTHESIS 1 ) SPERM COUNT 2) SPERM... 1 JiAN 73 IOWBSSOLETE. SECURITY CLASSIFICATION OF THIS PAGE SECURITY CLASSIFICATION OF THIS PAGE 18. Subject Terms Occupational Health

A Case of Neurotoxicity Following 5-Fluorouracil-based Chemotherapy

PubMed Central

Ki, Seung Seog; Jeong, Jin Mo; Kim, Seong Ho; Jeong, Sook Hyang; Lee, Jin Hyuk; Han, Chul Ju; Kim, You Cheol; Lee, Jhin Oh; Hong, Young Joon

2002-01-01

5-Fluorouracil (5-FU) is a commonly used chemotherapeutic agent. However, its neurotoxicity is rare and not well recognized. We report a case of 5-FU neurotoxicity with organic brain syndrome and progression to multifocal leukoencephalopathy in a 44-year-old male patient having malignant gastrointestinal stromal tumor. 5-FU-induced neurotoxicity should, therefore, be considered as an important differential diagnosis in cancer patients with neurological abnormality and history of chemotherapy. PMID:12014219

The Integration of Chuji Calendars in the Late Western Zhou Dynasty

NASA Astrophysics Data System (ADS)

Li, Y.

2017-03-01

In this paper, we investigate 23 four-element-materials contained Chuji (characters usually on bronze vessels, perhaps represent the moon phase) in the late Western Zhou Dynasty. It is assumed that all 5 elder-year data (kings' year>25 yr) should belong to the periods of king Li or king Xuan. At the same time, in order to guarantee the completeness, compatibility, and objectivity of these kinds of calendars, in the paper we build up them respectively according to the 24 characters of Chinese ancient calendar. We use the transformation platform for Chinese ancient dates to finish the calendars, consider the five different first years when both kings took their powers, set the moon age of Chuji cover any day in a lunar month, and as far as possible give every result for each material as in different kings' period. As a result, we totally derive 13 calendars according to different combinations of the characters of ancient calendars. When subdivided by the different combinations of the kings' periods, 33 solutions are obtained, but the moon phases of Chuji are usually in the second half month. The best result, with Jian Mao and the leap month in the end of the year, is related with the BC878 (BC827) as the first year of king Li (king Xuan). The coincidence rate of 23 data is 100%, and average moon phases are 19.84 days. The suboptimum choices have four solutions; the coincidence rate is 95.7%, respectively with Jian Chen and the leap month in the middle of the year; together with Jian Wu and the leap month in the middle or end of the year. We point out that these results may constitute and link respectively with other materials (even with other moon phases) as long as have the same calendar features. After adopting more materials and higher qualification, the scope of the solutions can be further limited and narrow. In addition, the different researchers can easily obtain or intercept their needed results respectively from this paper.

5-Fluorouracil sensitivity varies among oral micro-organisms.

PubMed

Vanlancker, Eline; Vanhoecke, Barbara; Smet, Rozel; Props, Ruben; Van de Wiele, Tom

2016-08-01

5-Fluorouracil (5-FU), a commonly used chemotherapeutic agent, often causes oral mucositis, an inflammation and ulceration of the oral mucosa. Micro-organisms in the oral cavity are thought to play an important role in the aggravation and severity of mucositis, but the mechanisms behind this remain unclear. Although 5-FU has been shown to elicit antibacterial effects at high concentrations (>100 µM), its antibacterial effect at physiologically relevant concentrations in the oral cavity is unknown. This study reports the effect of different concentrations of 5-FU (range 0.1-50 µM) on the growth and viability of bacterial monocultures that are present in the oral cavity and the possible role in the activity of dihydropyrimidine dehydrogenase (DPD), an enzyme involved in 5-FU resistance. Our data showed a differential sensitivity among the tested oral species towards physiological concentrations of 5-FU. Klebsiellaoxytoca, Streptococcus salivarius, Streptococcus mitis, Streptococcus oralis, Pseudomonas aeruginosa and Lactobacillus salivarius appeared to be highly resistant to all tested concentrations. In contrast, Lactobacillusoris, Lactobacillus plantarum, Streptococcus pyogenes, Fusobacterium nucleatum and Neisseria mucosa showed a significant reduction in growth and viability starting from very low concentrations (0.2-3.1 µM). We can also provide evidence that DPD is not involved in the 5-FU resistance of the selected species. The observed variability in response to physiological 5-FU concentrations may explain why certain microbiota lead to a community dysbiosis and/or an overgrowth of certain resistant micro-organisms in the oral cavity following cancer treatment.

Selenium Nanoparticles Induce the Chemo-Sensitivity of Fluorouracil Nanoparticles in Breast and Colon Cancer Cells.

PubMed

Abd-Rabou, Ahmed A; Shalby, Aziza B; Ahmed, Hanaa H

2018-05-11

Drug resistance is a major challenge of breast and colon cancer therapies leading to treatment failure. The main objective of the current study is to investigate whether selenium nanoparticles (nano-Se) can induce the chemo-sensitivity of 5-fluorouracil (FU)-encapsulated poly (D, L-lactide-co-glycolide) nanoparticles (nano-FU) in breast and colon cancer cell lines. Nano-Se and nano-FU were synthesized and characterized, then applied individually or in combination upon MCF7, MDA-MB-231, HCT 116, and Caco-2 cancerous cell lines. Cytotoxicity, cellular glucose uptake, and apoptosis, as well as malondialdehyde (MDA), nitric oxide (NO), and zinc (Zn) levels, were investigated upon the different treatments. We have resulted that nano-FU induced cell death in MCF7 and Caco-2 more effectively than MDA-MB-231 and HCT 116 cell lines. Moreover, nano-FU plus nano-Se potentiate MCF7 and Caco-2 chemo-sensitivity were higher than MDA-MB-231 and HCT 116 cancerous cell lines. It is relevant to note that Se and FU nano-formulations inhibited cancer cell bioenergetics via glucose uptake slight blockage. Furthermore, nano-FU increased the levels of NO and MDA in media over cancer cells, while their combinations with nano-Se rebalance the redox status with Zn increment. We noticed that MCF7 cell line is sensitive, while MDA-MB-231 cell line is resistant to Se and nano-Se. This novel approach could be of great potential to enhance the chemo-sensitivity in breast and colon cancer cells.

Coarse and fine sediment transportation patterns and causes downstream of the Three Gorges Dam

NASA Astrophysics Data System (ADS)

Li, Songzhe; Yang, Yunping; Zhang, Mingjin; Sun, Zhaohua; Zhu, Lingling; You, Xingying; Li, Kanyu

2017-11-01

Reservoir construction within a basin affects the process of water and sediment transport downstream of the dam. The Three Gorges Reservoir (TGR) affects the sediment transport downstream of the dam. The impoundment of the TGR reduced total downstream sediment. The sediment group d≤0.125 mm (fine particle) increased along the path, but the average was still below what existed before the reservoir impoundment. The sediments group d>0.125 mm (coarse particle) was recharged in the Yichang to Jianli reach, but showed a deposition trend downstream of Jianli. The coarse sediment in the Yichang to Jianli section in 2003 to 2007 was above the value before the TGR impoundment. However, the increase of both coarse and fine sediments in 2008 to 2014 was less than that in 2003 to 2007. The sediment retained in the dam is the major reason for the sediment reduction downstream. However, the retention in different river reaches is affected by riverbed coarsening, discharge, flow process, and conditions of lake functioning and recharging from the tributaries. The main conclusions derived from our study are as follows: 1) The riverbed in the Yichang to Shashi section was relatively coarse, thereby limiting the supply of fine and coarse sediments. The fine sediment supply was mainly controlled by TGR discharge, whereas the coarse sediment supply was controlled by the duration of high flow and its magnitude. 2) The supply of both coarse and fine sediments in the Shashi to Jianli section was controlled by the amount of total discharge. The sediment supply from the riverbed was higher in flood years than that in the dry years. The coarse sediment tended to deposit, and the deposition in the dry years was larger than that in the flood years. 3) The feeding of the fine sediment in the Luoshan to Hankou section was mainly from the riverbed. The supply in 2008 to 2014 was more than that in 2003 to 2007. Around 2010, the coarse sediments transited from depositing to scouring that was

Fluoropyrimidine and platinum toxicity pharmacogenetics: an umbrella review of systematic reviews and meta-analyses.

PubMed

Campbell, Jared M; Bateman, Emma; Peters, Micah Dj; Bowen, Joanne M; Keefe, Dorothy M; Stephenson, Matthew D

2016-03-01

Fluoropyrimidine (FU) and platinum-based chemotherapies are greatly complicated by their associated toxicities. This umbrella systematic review synthesized all systematic reviews that investigated associations between germline variations and toxicity, with the aim of informing personalized medicine. Systematic reviews are important in pharmacogenetics where false positives are common. Four systematic reviews were identified for FU-induced toxicity and three for platinum. Polymorphisms of DPYD and TYMS, but not MTHFR, were statistically significantly associated with FU-induced toxicity (although only DPYD had clinical significance). For platinum, GSTP1 was found to not be associated with toxicity. This umbrella systematic review has synthesized the best available evidence on the pharmacogenetics of FU and platinum toxicity. It provides a useful reference for clinicians and identifies important research gaps.

Capecitabine Plus Oxaliplatin Compared With Fluorouracil/Folinic Acid As Adjuvant Therapy for Stage III Colon Cancer: Final Results of the NO16968 Randomized Controlled Phase III Trial.

PubMed

Schmoll, Hans-Joachim; Tabernero, Josep; Maroun, Jean; de Braud, Filippo; Price, Timothy; Van Cutsem, Eric; Hill, Mark; Hoersch, Silke; Rittweger, Karen; Haller, Daniel G

2015-11-10

To report the final efficacy findings and biomarker analysis from the NO16968 trial comparing bolus fluorouracil/folinic acid (FU/FA) with capecitabine plus oxaliplatin (XELOX) in resected stage III colon cancer. After curative resection, patients were randomly assigned to receive XELOX, as oxaliplatin 130 mg/m(2) on day 1 and capecitabine 1,000 mg/m(2) twice daily on days 1 to 14 every 3 weeks, or bolus FU/FA, as the Mayo Clinic or Roswell Park regimens, for 6 months. The primary end point was disease-free survival (DFS). Secondary end points included overall survival (OS). The intention-to-treat population comprised 1,886 patients (XELOX, n = 944; FU/FA, n = 942). Seven-year DFS rates were 63% and 56% in the XELOX and FU/FA groups, respectively (hazard ratio [HR], 0.80; 95% CI, 0.69 to 0.93; P = .004). Seven-year OS rates were 73% and 67% in the XELOX and FU/FA groups, respectively (HR, 0.83; 95% CI, 0.70 to 0.99; P = .04). A total of 68% and 77% of patients who experienced relapse or a new colorectal cancer in the XELOX and FU/FA groups, respectively, received drug treatment for metastatic disease. Four hundred ninety-eight patients consented to the biomarker analysis: 242 in the XELOX group and 256 in the FU/FA group. Low tumor expression of dihydropyrimidine dehydrogenase may be predictive for XELOX efficacy; in the XELOX group, for high versus low dihydropyrimidine dehydrogenase expression levels, DFS HR was 2.45 (95% CI, 1.55 to 3.86; P < .001), and OS HR was 2.75 (95% CI, 1.65 to 4.59; P < .001). In the FU/FA group, no statistically significant associations were observed between any tumor biomarker and outcomes. XELOX improved OS compared with bolus FU/FA in patients with resected stage III colon cancer after a median follow-up of almost 7 years. XELOX should be considered a standard adjuvant treatment option in patients with stage III disease. Tumoral dihydropyrimidine dehydrogenase expression is a promising predictive, and potentially, highly clinically

[Donor supply of scalp and specificities of hair transplantation in Asians].

PubMed

Tsilosani, A Z; Mshvenieradze, E G

2008-01-01

In 2005--2007 in a hair transplantation clinic 'Talizi' the flow of international patients increased dramatically, including those from Central and Eastern Asia. During this period 211 ethnic Asian patients underwent operations, including 146 patients from South Korea, 2--from China, 62-- from Kazakhstan and 1--from Philippines. Black and straight hair give impact of low density due to considerable contrast with characteristic for Asians light color scalp; therefore, from the very beginning we tried to transplant as many grafts (follicular units - FU) as possible. For the operation we chose strip version (FUSS) that enables to receive large number of grafts. The scale of transplantation varied in a range of 1200-3800 FU, on average--2500-3000 FU. Though, even from the very first cases we faced specificities of ethnic Asian scalp that significantly complicated our work: low density and low hair/graft ratio in donor zone in contrast to information from special literature, and low laxity (flexibility) of the scalp. We set an objective to specify indicators of donor density (number of FU on a sq.cm and hair/FU ratio), to study bio-mechanical specificities of ethnic Asian scalp and develop optimal surgical tactics for these patients after the evaluation of transplantation results. Observation group was composed of 211 patients from abovementioned countries and a sub-group--50 Korean patients for medium-scale hair transplantation (2000-3000 FU) by strip version. Study of donor characteristics of these patients revealed low density--74 FU/cm2; on 1 cm2 grow only 121 hairs, whereas hair/FU ration was 1,63. Strength required to close would edges (scalp tension power) varied from 1,4 kg-f to 2,6 kg-f depending on scalp flexibility and number of transplanted grafts (strip width), and amounted on average to 2,16 +/- 0,02 kg-f, p < 0,001%. This indicator is about 1,5 times exceeding the one of ethnic Caucasian patient group (1,47 +/- 0,02 kg-f, p < 0,001%). Low donor density of

[Recent advance in chemotherapy for advanced colorectal cancer].

PubMed

Aiba, K

1996-04-01

Chemotherapy for advanced colorectal cancer is reviewed stressing the historical development of combination chemotherapy and the application of a new idea called biochemical modulation based upon a preclinical biochemical and molecular pharmacological rationale. While 5-fluorouracil (5-FU) is a key drug for more than three decades, many a combination chemotherapy with 5-FU and other drugs such as methyl-CCNU, vincristine, streptozocin, mitomycin C and so on has been studied extensively only to show no significant improvement compared with monotherapy with 5-FU. Recently, the mechanisms of 5-FU action have been recognized more in detail biochemically, and it enabled us to try the drug in a more optimal way. For example, bolus i.v. infusion of 5-FU can produce a response rate of around 10% to 15% at most for advanced colorectal cancer. On the other hand, a more continuous mode of i.v. infusion, typically known as protracted i.v. infusion lasting up to 6 weeks or more, can produce the response rate of up to 40%. The difference underlying the mechanisms of action in these typical two administrative methods is that the main target can be RNA-directed cytotoxicity in the bolus type infusion and it can be shifted toward DNA-directed cytotoxicity in the continuous type infusion through the inhibition of thymidylate synthase (TS) enzyme activity which is relevant to DNA de novo synthesis. More importantly, investigations using clinical materials imply that DNA-directed cytotoxicity may be more relevant in a clinical setting, showing consistent findings between bench-top experiments and the clinical outcome. Given a precise knowledge about the mechanisms of 5-FU action, we could have developed a new type combination chemotherapy called biochemical modulation which manipulates non-cytotoxic agents or cytotoxic agents in non-cytotoxic level as modulators enhancing cytotoxicity of 5-FU biochemically. Among modulators, leucovorin (LV) has been shown to have a pivotal role in

Determination of furfural and hydroxymethylfurfural from baby formula using headspace solid phase microextraction based on nanostructured polypyrrole fiber coupled with ion mobility spectrometry.

PubMed

Kamalabadi, Mahdie; Ghaemi, Elham; Mohammadi, Abdorreza; Alizadeh, Naader

2015-08-15

Furfural (Fu) and hydroxymethylfurfural (HMFu) are extracted using a dodecylbenzenesulfonate-doped polypyrrole coating as a fiber for headspace solid phase microextraction (HS-SPME) method in baby formula samples and detected using ion mobility spectrometry (IMS). Sample pH, salt effect, extraction time and temperature were investigated and optimized as effective parameters in HS-SPME. The calibration curves were linear in the range of 20-300 ng g(-1) (R(2)>0.99). Limits of detection for Fu and HMFu were 6 ng g(-1) and 5 ng g(-1), respectively. The RSD% of Fu and HMFu for five analyses was 4.4 and 4.9, respectively. The proposed method was successfully applied to determine of Fu and HMFu in the different baby formula samples with satisfactory result. The results were in agreement with those obtained using HPLC analysis. The HS-SPME-IMS is precise, selective and sensitive analytical method for determination of Fu and HMFu in baby formula samples, without any derivatization process. Copyright © 2015 Elsevier Ltd. All rights reserved.

Phase I study of the thrombospondin-1-mimetic angiogenesis inhibitor ABT-510 with 5-fluorouracil and leucovorin: a safe combination.

PubMed

Hoekstra, R; de Vos, F Y F L; Eskens, F A L M; de Vries, E G E; Uges, D R A; Knight, R; Carr, R A; Humerickhouse, R; Verweij, J; Gietema, J A

2006-03-01

We performed a phase I study with the thrombospondin-1-mimetic angiogenesis inhibitor ABT-510 combined with 5-fluorouracil and leucovorin (5-FU/LV) to determine safety profile and assess pharmacokinetic interactions. Patients with advanced solid malignancies received LV 20 mg/m(2) followed by 5-FU 425 mg/m(2) both administered intravenously in 15 min daily for 5 days every 4 weeks. ABT-510 was administered subcutaneously twice daily continuously from day 2 onwards. Blood and urine samples for pharmacokinetic analyses were collected at days 1, 5 and 22. Twelve patients received a total of 45 cycles of 5-FU/LV combined with ABT-510. ABT-510 dose levels studied were 50 and 100 mg. The combination was well tolerated, with a toxicity profile comparable to that of 5-FU/LV alone. At the dose levels studied no significant pharmacokinetic interactions were observed. These data indicate that ABT-510 administered twice daily subcutaneously can be safely combined with 5-FU/LV administered daily for 5 days, every 4 weeks.

New Topical Treatment Options for Actinic Keratosis: A Systematic Review.

PubMed

Stockfleth, Eggert; Sibbring, Gillian C; Alarcon, Ivette

2016-01-01

This systematic review compared the relative efficacy of 5-fluorouracil 0.5% in salicylic acid 10% (5-FU/SA), ingenol mebutate (IMB) and imiquimod 2.5%/3.75% (IMI) for actinic keratosis on the face, forehead or scalp. Only 11 publications, relating to 7 randomised controlled trials, met inclusion criteria and it was only possible to compare the effect of all 3 treatments on complete clinical clearance, and the effect of 5-FU/SA and IMB on actinic keratosis recurrence rate. Despite a higher vehicle response rate for 5-FU/SA, complete clinical clearance was higher than IMB and IMI (55.4, 42.2, and 25.0-30.6/34.0-35.6%, [corrected] respectively). 5-FU/SA was also associated with lower actinic keratosis recurrence rate than IMB at 12 months post-treatment (32.7 vs. 53.9%). Although qualitative assessment suggested a numerical advantage of 5-FU/SA over IMB and IMI in terms of complete clinical clearance and sustained clearance, clinical data from longer term trials, with comparable outcome measures, are required to corroborate these findings.

Dual drug encapsulated thermo-sensitive fibrinogen-graft-poly (N-isopropyl acrylamide) nanogels for breast cancer therapy.

PubMed

Rejinold, N Sanoj; Baby, Thejus; Chennazhi, K P; Jayakumar, R

2014-02-01

5-FU/Megestrol acetate loaded fibrinogen-graft-PNIPAAm Nanogels (5-FU/Meg-fib-graft-PNIPAAm NGs) were prepared for thermo responsive drug delivery toward α5β1-integrins expressing breast cancer cells in vitro (MCF-7 cells). The 60-100 nm sized fib-graft-PNIPAAm nanogels (LCST=35 °C) were prepared by CaCl2 cross-linker. 5-FU/Meg-fib-graft-PNIPAAm NGs showed particle size of 165-195 nm size. The drug loading efficiency with 5-FU was 60% and 70% for Meg. "Drug release was greater above the lower critical solution temperature (LCST). Above LCST, drug release system triggers apopotosis and enhance toxicity to MCF-7 cells when compared to the equivalent dose of the free drug. This effect was due to the greater uptake of the drug by MCF-7 cells". 5-FU/Meg-fib-graft-PNIPAAm NGs is portrayed here as a new combinatorial thermo-responsive drug delivery agent for breast cancer therapy. Copyright © 2013 Elsevier B.V. All rights reserved.

Investigation on the spectrum-effect relationships of Da-Huang-Fu-Zi-Tang in rats by UHPLC-ESI-Q-TOF-MS method.

PubMed

Liu, Xiao; Wang, Xiao-li; Wu, Li; Li, Huan; Qin, Kun-ming; Cai, Hao; Pei, Ke; Liu, Ting; Cai, Bao-chang

2014-07-03

Da-Huang-Fu-Zi-Tang (DHFZT) is a crucial TCM formula commonly used for the treatment of acute pancreatitis in Chinese clinical application. Our previous work found that DHFZT could act against pancreatic injury in rats with severe acute pancreatitis (SAP). The goal of this paper was to study the underlying correlations between the chemical spectra and the protective effect of DHFZT on pancreatic acinar cell to reveal the real bioactive compounds in DHFZT. The fingerprint chromatograms of rat serum after oral administration of DHFZT were established by UHPLC-ESI-Q-TOF-MS technique. At the same time, the model of anti-acute pancreatitis on cells was established by adding 10(-7) mol/L cerulein to AR42J cell line, and the protective effects of the serum on pancreatic acinar cell from injury was evaluated by detecting the efficacy of amylase. Then, the spectrum-effect relationships between UHPLC fingerprints and anti-acute pancreatitis activities were evaluated using canonical correlation analysis (CCA) statistical method. The chromatogram separation was performed on a C18 reversed phase UHPLC column (2.1 mm × 100 mm, 3.5 μm, Agilent), the column temperature was set at 35°C. The mobile phase consisted of 0.1% formic acid and acetonitrile with gradient elution. The serum samples were analyzed both in negative and positive ion mode. The mother and productive ions were scanned within the mass range of m/z 100-1200 and 50-1200, respectively. A thorough analysis of a great deal of information of the constituents in the rat serum was undertaken. The structure identification of the detected compounds was achieved by using high resolution MS values as well as the MS/MS fragments. Eighteen peaks in rat serum after oral administration of DHFZT were detected within only 30 min recorded chromatograms. The structure of the 18 compounds were then given out, of which 10 were the original form of compounds absorbed from DHFZT, 8 were the metabolites of the compounds existed in rat

EuroEco (European Health Economic Trial on Home Monitoring in ICD Patients): a provider perspective in five European countries on costs and net financial impact of follow-up with or without remote monitoring

PubMed Central

Heidbuchel, Hein; Hindricks, Gerd; Broadhurst, Paul; Van Erven, Lieselot; Fernandez-Lozano, Ignacio; Rivero-Ayerza, Maximo; Malinowski, Klaus; Marek, Andrea; Garrido, Rafael F. Romero; Löscher, Steffen; Beeton, Ian; Garcia, Enrique; Cross, Stephen; Vijgen, Johan; Koivisto, Ulla-Maija; Peinado, Rafael; Smala, Antje; Annemans, Lieven

2015-01-01

Aim Remote follow-up (FU) of implantable cardiac defibrillators (ICDs) allows for fewer in-office visits in combination with earlier detection of relevant findings. Its implementation requires investment and reorganization of care. Providers (physicians or hospitals) are unsure about the financial impact. The primary end-point of this randomized prospective multicentre health economic trial was the total FU-related cost for providers, comparing Home Monitoring facilitated FU (HM ON) to regular in-office FU (HM OFF) during the first 2 years after ICD implantation. Also the net financial impact on providers (taking national reimbursement into account) and costs from a healthcare payer perspective were evaluated. Methods and results A total of 312 patients with VVI- or DDD-ICD implants from 17 centres in six EU countries were randomised to HM ON or OFF, of which 303 were eligible for data analysis. For all contacts (in-office, calendar- or alert-triggered web-based review, discussions, calls) time-expenditure was tracked. Country-specific cost parameters were used to convert resource use into monetary values. Remote FU equipment itself was not included in the cost calculations. Given only two patients from Finland (one in each group) a monetary valuation analysis was not performed for Finland. Average age was 62.4 ± 13.1 years, 81% were male, 39% received a DDD system, and 51% had a prophylactic ICD. Resource use with HM ON was clearly different: less FU visits (3.79 ± 1.67 vs. 5.53 ± 2.32; P < 0.001) despite a small increase of unscheduled visits (0.95 ± 1.50 vs. 0.62 ± 1.25; P < 0.005), more non-office-based contacts (1.95 ± 3.29 vs. 1.01 ± 2.64; P < 0.001), more Internet sessions (11.02 ± 15.28 vs. 0.06 ± 0.31; P < 0.001) and more in-clinic discussions (1.84 ± 4.20 vs. 1.28 ± 2.92; P < 0.03), but with numerically fewer hospitalizations (0.67 ± 1.18 vs. 0.85 ± 1.43, P = 0.23) and shorter length-of-stay (6.31 ± 15.5 vs. 8.26 ± 18.6; P = 0.27), although

EuroEco (European Health Economic Trial on Home Monitoring in ICD Patients): a provider perspective in five European countries on costs and net financial impact of follow-up with or without remote monitoring.

PubMed

Heidbuchel, Hein; Hindricks, Gerd; Broadhurst, Paul; Van Erven, Lieselot; Fernandez-Lozano, Ignacio; Rivero-Ayerza, Maximo; Malinowski, Klaus; Marek, Andrea; Romero Garrido, Rafael F; Löscher, Steffen; Beeton, Ian; Garcia, Enrique; Cross, Stephen; Vijgen, Johan; Koivisto, Ulla-Maija; Peinado, Rafael; Smala, Antje; Annemans, Lieven

2015-01-14

Remote follow-up (FU) of implantable cardiac defibrillators (ICDs) allows for fewer in-office visits in combination with earlier detection of relevant findings. Its implementation requires investment and reorganization of care. Providers (physicians or hospitals) are unsure about the financial impact. The primary end-point of this randomized prospective multicentre health economic trial was the total FU-related cost for providers, comparing Home Monitoring facilitated FU (HM ON) to regular in-office FU (HM OFF) during the first 2 years after ICD implantation. Also the net financial impact on providers (taking national reimbursement into account) and costs from a healthcare payer perspective were evaluated. A total of 312 patients with VVI- or DDD-ICD implants from 17 centres in six EU countries were randomised to HM ON or OFF, of which 303 were eligible for data analysis. For all contacts (in-office, calendar- or alert-triggered web-based review, discussions, calls) time-expenditure was tracked. Country-specific cost parameters were used to convert resource use into monetary values. Remote FU equipment itself was not included in the cost calculations. Given only two patients from Finland (one in each group) a monetary valuation analysis was not performed for Finland. Average age was 62.4 ± 13.1 years, 81% were male, 39% received a DDD system, and 51% had a prophylactic ICD. Resource use with HM ON was clearly different: less FU visits (3.79 ± 1.67 vs. 5.53 ± 2.32; P < 0.001) despite a small increase of unscheduled visits (0.95 ± 1.50 vs. 0.62 ± 1.25; P < 0.005), more non-office-based contacts (1.95 ± 3.29 vs. 1.01 ± 2.64; P < 0.001), more Internet sessions (11.02 ± 15.28 vs. 0.06 ± 0.31; P < 0.001) and more in-clinic discussions (1.84 ± 4.20 vs. 1.28 ± 2.92; P < 0.03), but with numerically fewer hospitalizations (0.67 ± 1.18 vs. 0.85 ± 1.43, P = 0.23) and shorter length-of-stay (6.31 ± 15.5 vs. 8.26 ± 18.6; P = 0.27), although not significant. For

Radiation induction of drug resistance in RIF-1 tumors and tumor cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hopwood, L.E.; Moulder, J.E.

1989-11-01

The RIF-1 tumor cell line contains a small number of cells (1-20 per 10(6) cells) that are resistant to various single antineoplastic drugs, including 5-fluorouracil (5FU), methotrexate (MTX), and adriamycin (ADR). For 5FU the frequency of drug resistance is lower for tumor-derived cells than for cells from cell culture; for MTX the reverse is true, and for ADR there is no difference. In vitro irradiation at 5 Gy significantly increased the frequency of drug-resistant cells for 5FU, MTX, and ADR. In vivo irradiation at 3 Gy significantly increased the frequency of drug-resistant cells for 5FU and MTX, but not formore » ADR. The absolute risk for in vitro induction of MTX, 5FU, and ADR resistance, and for in vivo induction of 5FU resistance, was 1-3 per 10(6) cells per Gy; but the absolute risk for in vivo induction of MTX resistance was 54 per 10(6) cells per Gy. The frequency of drug-resistant cells among individual untreated tumors was highly variable; among individual irradiated tumors the frequency of drug-resistant cells was significantly less variable. These studies provide supporting data for models of the development of tumor drug resistance, and imply that some of the drug resistance seen when chemotherapy follows radiotherapy may be due to radiation-induced drug resistance.« less

Comparative label-free LC-MS/MS analysis of colorectal adenocarcinoma and metastatic cells treated with 5-fluorouracil.

PubMed

Bauer, Kerry M; Lambert, Paul A; Hummon, Amanda B

2012-06-01

A label-free mass spectrometric strategy was used to examine the effect of 5-fluorouracil (5-FU) on the primary and metastatic colon carcinoma cell lines, SW480 and SW620, with and without treatment. 5-FU is the most common chemotherapeutic treatment for colon cancer. Pooled biological replicates were analyzed by nanoLC-MS/MS and protein quantification was determined via spectral counting. Phenotypic and proteomic changes were evident and often similar in both cell lines. The SW620 cells were more resistant to 5-FU treatment, with an IC(50) 2.7-fold higher than that for SW480. In addition, both cell lines showed pronounced abundance changes in pathways relating to antioxidative stress response and cell adhesion remodeling due to 5-FU treatment. For example, the detoxification enzyme NQO1 was increased with treatment in both cell lines, while disparate members of the peroxiredoxin family, PRDX2 or PRDX5 and PRDX6, were elevated with 5-FU exposure in either SW480 or SW620, respectively. Cell adhesion-associated proteins CTNNB1 and RhoA showed decreased expression with 5-FU treatment in both cell lines. The differential quantitative response in the proteomes of these patient-matched cell lines to drug treatment underscores the subtle molecular differences separating primary and metastatic cancer cells. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Spontaneous ultra fast synthesis of gold nanoparticles using Punica granatum for cancer targeted drug delivery.

PubMed

Ganeshkumar, Moorthy; Sathishkumar, Muniram; Ponrasu, Thangavel; Dinesh, Murugan Girija; Suguna, Lonchin

2013-06-01

Rapid synthesis of mono-dispersed gold nanoparticles through economically feasible green chemistry approach is highly desirable. In this study, we have developed a method to synthesize mono-dispersed gold nanoparticles (PAuNPs) by mixing gold solution with fruit peel extract of Punica granutum without using any surfactant or external energy. In this method, physiologically stable, biocompatible PAuNPs were formed within 60s. Casein, being a biocompatible polymer, is used to couple the prepared PAuNPs for functionalization of folic acid, which is highly expressed in cancer cells. These functionalized PAuNPs could be used for targeted drug delivery for cancer with enhanced therapeutic efficacy and minimal side effects. PAuNPs were characterized by UV, IR, TEM, Particle size analyzer and zeta potential measurement. In vitro stability of the PAuNPs was also analyzed. Hemocompatibility of PAuNPs was evaluated in human blood samples and found that the particles were hemocompatible. The toxicity of the PAuNPs, 5-Fu and 5Fu@PAuNPs was analyzed in zebrafish embryos. The in vitro cytotoxicity of free 5-Fu, 5Fu@PAuNPs-Fa was investigated against MCF-7 cells (breast cancer) and observed that the amount of 5-Fu required to achieve 50% of growth of inhibition (Ic50) was much lower when compared to free 5-Fu. Copyright © 2013 Elsevier B.V. All rights reserved.

Chrysin Attenuates Cell Viability of Human Colorectal Cancer Cells through Autophagy Induction Unlike 5-Fluorouracil/Oxaliplatin.

PubMed

Lin, Yueh-Ming; Chen, Chih-I; Hsiang, Yi-Ping; Hsu, Yung-Chia; Cheng, Kung-Chuan; Chien, Pei-Hsuan; Pan, Hsiao-Lin; Lu, Chien-Chang; Chen, Yun-Ju

2018-06-14

Chemotherapeutic 5-fluorouracil (5-FU) combined with oxaliplatin is often used as the standard treatment for colorectal cancer (CRC). The disturbing side effects and drug resistance commonly observed in chemotherapy motivate us to develop alternative optimal therapeutic options for CRC treatment. Chrysin, a natural and biologically active flavonoid abundant in propolis, is reported to have antitumor effects on a few CRCs. However, whether and how chrysin achieves similar effectiveness to the 5-FU combination is not clear. In this study, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), western blotting, fluorescence microscopy, and reactive oxygen species (ROS) production were assayed. We found that chrysin exhibited similar inhibition of cell viability as the 5-FU combination in a panel of human CRC cells. Furthermore, the results showed that chrysin significantly increased the levels of LC3-II, an autophagy-related marker, in CRC cells, which was not observed with the 5-FU combination. More importantly, blockage of autophagy induction restored chrysin-attenuated CRC cell viability. Further mechanistic analysis revealed that chrysin, not the 5-FU combination, induced ROS generation, and in turn, inhibited the phosphorylation of protein kinase B (Akt) and mammalian target of rapamycin (mTOR). Collectively, these results imply that chrysin may be a potential replacement for the 5-FU and oxaliplatin combination to achieve antitumor activity through autophagy for CRC treatment in the future.

Protective effect of Bu-zhong-yi-qi decoction, the water extract of Chinese traditional herbal medicine, on 5-fluorouracil-induced renal injury in mice.

PubMed

Xiong, Ying; Shang, Bingzhen; Xu, Siying; Zhao, Ran; Gou, He; Wang, Chun

2016-09-01

Drug-induced renal injury is a serious toxic side effect of 5-fluorouracil (5-FU) treatment. Bu-zhong-yi-qi decoction (BZYQD), a water extract of Chinese traditional herbal medicine, is widely used in Asia as an alternative treatment to reduce the side effects of chemotherapy and also improve cancer survival. However, the mechanism is unknown. This study is designed to investigate the protective effect of BZYQD on 5-FU-induced renal injury in mice. Mice were divided into four groups: the control, 5-FU, 5-FU + low, and high BZYQD group. Mice in the three latter groups were administered 5-FU (100 mg/kg/day, intraperitoneally) for six days, and in the 5-FU + low and high BZYQD groups were given BZYQD (1 or 2 g raw herb/kg/day, intragastrically) beginning four days before 5-FU and continuing until the termination of the experiment. The right kidney fixed in formalin for histological examination and the left was homogenized to measure the levels of apoptosis-related proteins and activities of oxidative stress-related biomarkers. Blood samples were collected for measuring renal function-related biochemical indices. Renal morphology injury, increased urea nitrogen and creatinine concentration, and decreased SOD, CAT, and GSH-Px were all observed in 5-FU-administrated mice. However, BZYQD almost reversed the morphological injury as well as renal function-related indices and antioxidant enzyme activity. These results suggest that BZYQD inhibits 5-FU-induced renal injury, possibly through the reduction of apoptosis and necrosis in renal tubular epithelial cells via the antioxidant mechanism. Henceforth, BZYQD may be a potential antioxidant against drug-induced oxidative stress.

Activation of p38-MAPK by CXCL4/CXCR3 axis contributes to p53-dependent intestinal apoptosis initiated by 5-fluorouracil.

PubMed

Gao, Jing; Gao, Jin; Qian, Lan; Wang, Xia; Wu, Mingyuan; Zhang, Yang; Ye, Hao; Zhu, Shunying; Yu, Yan; Han, Wei

2014-08-01

Chemotherapy-induced mucositis (CIM) is a major does limiting side-effect of chemoagents such as 5-fluorouracil (5-FU). Molecules involved in this disease process are still not fully understood. We proposed that the homeostatically regulated genes during CIM may participate in the disease. A cluster of such genes were previously identified by expression gene-array from the mouse jejunum in 5-FU-induced mucositis model. Here, we report that CXCL4 is such a homeostatically regulated gene and serves as a new target for the antibody treatment of CIM. CXCL4 and its receptor CXCR3 were confirmed at both the gene and protein levels to be homeostatically regulated during 5-FU-induced mucositis. Using of CXCL4 neutralizing monoclonal antibody (CXCL4mab) decreased the incidence, severity, and duration of the chemotherapy-induced diarrhea, the major symptom of CIM, in a 5-FU mouse CIM model. Mechanistically, CXCL4mab reduced the apoptosis of the crypt epithelia by suppression of the 5-FU-induced expression of p53 and Bax through its receptor CXCR3. The downstream signaling pathway of CXCL4 in activation of the epithelial apoptosis was identified in an intestinal epithelial cell line (IEC-6). CXCL4 activated the phosphorylation of p38 MAPK, which mediated the stimulated expression of p53 and Bax, and resulted in the ultimate activation of Caspase-8, -9, and -3. Taken together, activation of CXCL4 expression by 5-FU in mice participates in 5-FU-induced intestinal mucositis through upregulation of p53 via activation of p38-MAPK, and CXCL4mab is potentially beneficial in preventing CIM in the intestinal tract.

Activation of p38-MAPK by CXCL4/CXCR3 axis contributes to p53-dependent intestinal apoptosis initiated by 5-fluorouracil

PubMed Central

Gao, Jing; Gao, Jin; Qian, Lan; Wang, Xia; Wu, Mingyuan; Zhang, Yang; Ye, Hao; Zhu, Shunying; Yu, Yan; Han, Wei

2014-01-01

Chemotherapy-induced mucositis (CIM) is a major does limiting side-effect of chemoagents such as 5-fluorouracil (5-FU). Molecules involved in this disease process are still not fully understood. We proposed that the homeostatically regulated genes during CIM may participate in the disease. A cluster of such genes were previously identified by expression gene-array from the mouse jejunum in 5-FU-induced mucositis model. Here, we report that CXCL4 is such a homeostatically regulated gene and serves as a new target for the antibody treatment of CIM. CXCL4 and its receptor CXCR3 were confirmed at both the gene and protein levels to be homeostatically regulated during 5-FU-induced mucositis. Using of CXCL4 neutralizing monoclonal antibody (CXCL4mab) decreased the incidence, severity, and duration of the chemotherapy-induced diarrhea, the major symptom of CIM, in a 5-FU mouse CIM model. Mechanistically, CXCL4mab reduced the apoptosis of the crypt epithelia by suppression of the 5-FU-induced expression of p53 and Bax through its receptor CXCR3. The downstream signaling pathway of CXCL4 in activation of the epithelial apoptosis was identified in an intestinal epithelial cell line (IEC-6). CXCL4 activated the phosphorylation of p38 MAPK, which mediated the stimulated expression of p53 and Bax, and resulted in the ultimate activation of Caspase-8, -9, and -3. Taken together, activation of CXCL4 expression by 5-FU in mice participates in 5-FU-induced intestinal mucositis through upregulation of p53 via activation of p38-MAPK, and CXCL4mab is potentially beneficial in preventing CIM in the intestinal tract. PMID:24800927

Target Organ Damage and Target Systolic Blood Pressure in Clinical Practice: The Campania Salute Network.

PubMed

D'Amato, Andrea; Mancusi, Costantino; Losi, Maria Angela; Izzo, Raffaele; Arnone, Maria Immacolata; Canciello, Grazia; Senese, Salvatore; De Luca, Nicola; de Simone, Giovanni; Trimarco, Bruno

2018-05-07

Lowering systolic blood pressure (SBP) below the conventional threshold (140 mm Hg) reduces left ventricular (LV) hypertrophy and incident cardiovascular (CV) events. We assessed whether different thresholds of SBP as the average value during follow-up (FU) have different impact on changes in target organ damage (TOD). From the Campania Salute Network registry, we selected 4,148 hypertensive patients with average SBP-FU <140 mm Hg, and without history of prevalent CV or chronic kidney disease (i.e., FU <130 mm Hg) or "Usual" (SBP-FU ≥130) BP control. At baseline and at the last available control visit, we assessed LV mass index (LVMi, g/m2.7), carotid intimal-medial thickness (IMT, mm), and glomerular filtration rate by CKD-EPI equation (GFR, ml/min/1.73 m2) as markers of TOD. Time trend of TOD for tight and usual subgroups were compared, adjusting for significant confounders. During a median of 74 months (interquartile range: 35-108 months), 1,824 patients (44%) were classified as tight control. They were younger, with less prevalent obesity, diabetes, lower initial LVMi, and IMT, and were taking less Ca++-channel blockers during FU than the usual control subgroup (all P < 0.05). In both subgroups, there were no changes over time in LVMi and GFR, whereas the IMT increased during the FU (P < 0.004), with no significant effect of degree of SBP control. In a registry of treated hypertensive patients from a tertiary care center, progression of TODs is not related to average SBP during FU.

Skin tumor development after UV irradiation and photodynamic therapy is unaffected by short-term pretreatment with 5-fluorouracil, imiquimod and calcipotriol. An experimental hairless mouse study.

PubMed

Bay, Christiane; Togsverd-Bo, Katrine; Lerche, Catharina M; Haedersdal, Merete

2016-01-01

Photodynamic therapy (PDT) delays ultraviolet (UV) radiation-induced squamous cell carcinomas (SCCs) in hairless mice. Efficacy may be enhanced by combining PDT with antineoplastic or pro-differentiating agents. We investigated if pretreatment with 5-fluorouracil (5FU), imiquimod (IMIQ) or calcipotriol (CAL) before PDT further delays tumor onset. Hairless mice (n=224) were exposed 3 times weekly to 3 standard erythema doses (SED) of UV radiation. Methyl-aminolevulinate (MAL)-PDT sessions were given on days 45 and 90 before SCC development. Three applications of topical 5FU, IMIQ or CAL were given before each PDT session. Fluorescence photography quantified protoporphyrin IX (PpIX) formation. PDT delayed UV-induced SCC development by 59 days (212 days UV-MAL-PDT vs. 153 days UV-control, P<0.001). Pretreatment with 5FU, IMIQ or CAL before PDT did not further delay SCC onset compared to PDT alone (207 days UV-5FU-MAL-PDT, 215 days UV-IMIQ-MAL-PDT, 206 days UV-CAL-MAL-PDT vs. 212 days UV-MAL-PDT, P=ns). PpIX fluorescence intensified by 5FU-pretreatment (median 21,392 au UV-5FU-MAL-PDT, P=0.011), decreased after IMIQ-pretreatment (12,452 au UV-IMIQ-MAL-PDT, P<0.001), and was unaffected by CAL-pretreatment (19,567 au UV-CAL-MAL-PDT, P=ns) compared to MAL alone (18,083 au UV-MAL-PDT). Short-term three-day pretreatment with 5FU, IMIQ and CAL before PDT does not further delay tumor onset in UV-exposed hairless mice. Copyright © 2015 Elsevier B.V. All rights reserved.

A phase I, pharmacokinetic, and pharmacodynamic study of two schedules of vorinostat in combination with 5-fluorouracil and leucovorin in patients with refractory solid tumors.

PubMed

Fakih, Marwan G; Fetterly, Gerald; Egorin, Merrill J; Muindi, Josephia R; Espinoza-Delgado, Igor; Zwiebel, James A; Litwin, Alan; Holleran, Julianne L; Wang, Kangsheng; Diasio, Robert B

2010-07-15

We conducted a phase I clinical trial to determine the maximum tolerated dose (MTD) of daily or twice daily vorinostat x 3 days when combined with fixed doses of 5-fluorouracil (FU) and leucovorin every 2 weeks. Vorinostat doses were escalated in a standard 3 x 3 phase I design. FU/leucovorin was started on day 2 of vorinostat and consisted of leucovorin 400 mg/m(2) i.v. over 2 hours followed by FU 400 mg/m(2) i.v. bolus and 2,400 mg/m(2) over 46 hours (sLV5FU2). Forty-three patients were enrolled. Grade 3 fatigue, and hand and foot syndrome were the dose-limiting toxicities (DLT) at the 2,000 mg vorinostat once-daily dose level. Grade 3 fatigue and mucositis were DLTs at the 800 mg vorinostat twice-daily dose level. None of six patients at the 1,700 mg once daily or six patients at the 600 mg twice daily dose levels had a DLT; those dose levels represent the MTD. Twenty-one of 38 patients with FU-refractory colorectal cancer had stable disease, and one had a partial response. Vorinostat maximum serum concentrations at the MTD exceeded concentrations associated with thymidylate synthase downregulation in vitro. No pharmacokinetic interactions were noted between vorinostat and FU. The MTD of vorinostat in combination with sLV5FU2 is 1,700 mg orally once daily x 3 or 600 mg orally twice daily x 3 days every 2 weeks. Clinical activity in refractory colorectal cancer supports further clinical development of this combination. Copyrighth 2010 AACR.

A Phase I, Pharmacokinetic, and Pharmacodynamic Study of Two Schedules of Vorinostat in Combination with 5-Fluorouracil and Leucovorin in Patients with Refractory Solid Tumors

PubMed Central

Fakih, Marwan G.; Fetterly, Gerald; Egorin, Merrill J.; Muindi, Josephia R.; Espinoza-Delgado, Igor; Zwiebel, James A.; Litwin, Alan; Holleran, Julianne L.; Wang, Kangsheng; Diasio, Robert B.

2010-01-01

Purpose We conducted a phase I clinical trial to determine the maximum tolerated dose (MTD) of daily or twice daily vorinostat × 3 days when combined with fixed doses of 5-fluorouracil (FU) and leucovorin every 2 weeks. Experimental Design Vorinostat doses were escalated in a standard 3 × 3 phase I design. FU/leucovorin was started on day 2 of vorinostat and consisted of leucovorin 400 mg/m2 i.v. over 2 hours followed by FU 400 mg/m2 i.v. bolus and 2,400 mg/m2 over 46 hours (sLV5FU2). Results Forty-three patients were enrolled. Grade 3 fatigue, and hand and foot syndrome were the dose-limiting toxicities (DLT) at the 2,000 mg vorinostat once-daily dose level. Grade 3 fatigue and mucositis were DLTs at the 800 mg vorinostat twice-daily dose level. None of six patients at the 1,700 mg once daily or six patients at the 600 mg twice daily dose levels had a DLT; those dose levels represent the MTD. Twenty-one of 38 patients with FU-refractory colorectal cancer had stable disease, and one had a partial response. Vorinostat maximum serum concentrations at the MTD exceeded concentrations associated with thymidylate synthase downregulation in vitro. No pharmacokinetic interactions were noted between vorinostat and FU. Conclusions The MTD of vorinostat in combination with sLV5FU2 is 1,700 mg orally once daily × 3 or 600 mg orally twice daily × 3 days every 2 weeks. Clinical activity in refractory colorectal cancer supports further clinical development of this combination. PMID:20463088

Theoretical studies of chromospheres and winds in cool stars

NASA Technical Reports Server (NTRS)

Hartmann, L.

1986-01-01

Propagation of pulsational waves through the atmosphere of the M supergiant alpha Ori was explored using a time dependent hydrodynamic code. Wind properties for three FU Orionis objects were determined using radiative transfer models based on optical line profiles. The effects of varying wind temperature while keeping the velocity steady were considered. Using the premise that FU Orionis eruptions result from massive accretions from a disk into a T Tauri star explains a variety of observational peculiarities of FU Orionis objects.

Diet soda intake is associated with long-term increases in waist circumference in a bi-ethnic cohort of older adults: The San Antonio Longitudinal Study of Aging

PubMed Central

Fowler, Sharon PG; Williams, Ken; Hazuda, Helen P

2015-01-01

BACKGROUND/OBJECTIVES Diet soda (DS) intake (DSI) has been associated with increased cardiometabolic risk, but its specific impact in older adults has not been addressed. Because central obesity increases cardiovascular risk, we examined the relationship between DSI and long-term waist circumference (WC) change (ΔWC) in the bi-ethnic San Antonio Longitudinal Study of Aging (SALSA). DESIGN Prospective cohort study. SETTING San Antonio, Texas, neighborhoods PARTICIPANTS SALSA examined 749 Mexican-American and European-American individuals ≥ 65 years old at baseline (BL: 1992-1996); 79.1% of survivors completed follow-up 1 (FU1) (2000-2001, n=474); 73.4%, FU2 (2001-2003, n=413); and 71.0%, FU3 (2003-2004, n=375). Participants completed a mean of 2.64 follow-up intervals, for 9.41 total follow-up years. MEASUREMENTS DSI, WC, height and weight were measured at outset and conclusion of each interval: BL-FU1, FU1-FU2, and FU2-FU3. RESULTS Adjusted for initial WC, demographics, physical activity, diabetes, and smoking, mean interval ΔWC (95% confidence interval) for all DS users was almost triple that among non-users: 2.11 (1.45-2.76) vs. 0.77 (0.29-1.23) cm, respectively (p < 0.001). For non-, occasional, and daily DS users, adjusted interval ΔWCs were 0.77 (0.29-1.23), 1.76 (0.96-2.57), and 3.04 (1.82-4.26) cm, respectively (p=0.002 for trend). This translates to ΔWCs of 0.80, 1.83, and 3.16 inches, respectively, for these groups, over the total SALSA follow-up. In sub-analyses stratified separately by key covariates, ΔWC point estimates were consistently higher among DS users. CONCLUSION In a striking dose-response relationship, increasing diet soda intake was associated with escalating abdominal obesity, a potential pathway for heightened cardiometabolic risk in this aging population. PMID:25780952

Biological evaluation of 5-fluorouracil nanoparticles for cancer chemotherapy and its dependence on the carrier, PLGA

PubMed Central

Nair K, Lekha; Jagadeeshan, Sankar; Nair, S Asha; Kumar, GS Vinod

2011-01-01

Nanoscaled devices have great potential for drug delivery applications due to their small size. In the present study, we report for the first time the preparation and evaluation of antitumor efficacy of 5-fluorouracil (5-FU)-entrapped poly (D, L-lactic-co-glycolic acid) (PLGA) nanoparticles with dependence on the lactide/glycolide combination of PLGA. 5-FU-loaded PLGA nanoparticles with two different monomer combinations, 50-50 and 90-10 were synthesized using a modified double emulsion method, and their biological evaluation was done in glioma (U87MG) and breast adenocarcinoma (MCF7) cell lines. 5-FU-entrapped PLGA 50-50 nanoparticles showed smaller size with a high encapsulation efficiency of 66%, which was equivalent to that of PLGA 90-10 nanoparticles. Physicochemical characterization of nanoparticles using differential scanning calorimetry and X-ray diffraction suggested the presence of 5-FU in molecular dispersion form. In vitro release studies showed the prolonged and sustained release of 5-FU from nanoparticles with both the PLGA combinations, where PLGA 50-50 nanoparticles showed faster release. Nanoparticles with PLGA 50-50 combination exhibited better cytotoxicity than free drug in a dose- and time-dependent manner against both the tumor cell lines. The enhanced efficiency of PLGA 50-50 nanoparticles to induce apoptosis was indicated by acridine orange/ethidium bromide staining. Cell cycle perturbations studied using flow cytometer showed better S-phase arrest by nanoparticles in comparison with free 5-FU. All the results indicate that PLGA 50-50 nanoparticles possess better antitumor efficacy than PLGA 90-10 nanoparticles and free 5-FU. Since, studies have shown that long-term exposure of ailing tissues to moderate drug concentrations is more favorable than regular administration of higher concentration of the drug; our results clearly indicate the potential of 5-FU-loaded PLGA nanoparticles with dependence on carrier combination as controlled release

Preparation of orally disintegrating tablets with taste-masking function: masking effect in granules prepared with correctives using the dry granulation method and evaluation of tablets prepared using the taste-masked granules.

PubMed

Kawano, Yayoi; Ito, Akihiko; Sasatsu, Masanaho; Machida, Yoshiharu

2010-01-01

We investigated several methods of taste masking in the preparation of orally disintegrating tablets (ODTs), using furosemide (FU) as a model drug. Four types of FU preparations were prepared: granules with maltitol (MA), granules with yogurt powder (YO), a physical mixture of FU and MA, and a physical mixture of FU and YO. All taste-masking granules were prepared using the dry granulation method. The taste of each type of preparation was evaluated. All four preparations markedly improved the taste of the FU tablets, but the mixing ratios of the correctives did not affect the masking effect. No difference in masking effect was found between MA and YO in the physical mixtures, but the masking effect in the granules with YO was superior to that of the granules with MA. Taste-masked FU tablets were prepared using the direct compression method; crystalline cellulose (Avicel PH-302) and mannitol were added as excipients at the mixing ratio of 1/1. All four types of tablets displayed sufficient hardness, but MA-containing tablets were harder than YO-containing tablets. The hardness of the tablets prepared from YO granules increased as the YO content increased. The most rapidly disintegrating tablets were those of YO granules prepared at a mixing ratio of FU/YO=1/1, which disintegrated within 20 s, followed by the tablets of MA granules prepared at a mixing ratio of FU/MA=1/1. The disintegration times of the tablets made from physical mixtures, in contrast, were longer than 200 s. Disintegration time lengthened as the mixing ratio of YO or MA increased. The hardness and disintegration time of these tablets could be controlled by varying the compression pressure. We found that YO is more useful than MA in masking unpleasant tastes and confirmed that orally disintegrating tablets with taste-masking function can be prepared using granules of YO prepared using the dry granulation method as a new corrective.

Sustained effects of neurofeedback in ADHD: a systematic review and meta-analysis.

PubMed

Van Doren, Jessica; Arns, Martijn; Heinrich, Hartmut; Vollebregt, Madelon A; Strehl, Ute; K Loo, Sandra

2018-02-14

Neurofeedback (NF) has gained increasing interest in the treatment of attention-deficit/hyperactivity disorder (ADHD). Given learning principles underlie NF, lasting clinical treatment effects may be expected. This systematic review and meta-analysis addresses the sustainability of neurofeedback and control treatment effects by considering randomized controlled studies that conducted follow-up (FU; 2-12 months) assessments among children with ADHD. PubMed and Scopus databases were searched through November 2017. Within-group and between-group standardized mean differences (SMD) of parent behavior ratings were calculated and analyzed. Ten studies met inclusion criteria (NF: ten studies, N = 256; control: nine studies, N = 250). Within-group NF effects on inattention were of medium effect size (ES) (SMD = 0.64) at post-treatment and increased to a large ES (SMD = 0.80) at FU. Regarding hyperactivity/impulsivity, NF ES were medium at post-treatment (SMD = 0.50) and FU (SMD = 0.61). Non-active control conditions yielded a small significant ES on inattention at post-treatment (SMD = 0.28) but no significant ES at FU. Active treatments (mainly methylphenidate), had large ES for inattention (post: SMD = 1.08; FU: SMD = 1.06) and medium ES for hyperactivity/impulsivity (post: SMD = 0.74; FU: SMD = 0.67). Between-group analyses also revealed an advantage of NF over non-active controls [inattention (post: SMD = 0.38; FU: SMD = 0.57); hyperactivity-impulsivity (post: SMD = 0.25; FU: SMD = 0.39)], and favored active controls for inattention only at pre-post (SMD = - 0.44). Compared to non-active control treatments, NF appears to have more durable treatment effects, for at least 6 months following treatment. More studies are needed for a properly powered comparison of follow-up effects between NF and active treatments and to further control for non-specific effects.

Development of In Situ Gelling and Bio Adhesive 5-Fluorouracil Enema

PubMed Central

Wang, Lu-Lu; Zheng, Wen-Sheng; Chen, Shao-Hua; Fang, Xia-Qin

2013-01-01

In this study, a novel 5-Fluorouracil (5-FU) enema with good bio adhesion and temperature sensitivity was developed using in situ gelling technology. The preparation was formulated as a free-flowing liquid before use, while a layer of gel film was quickly formed when administered in the rectum, with a large contact surface area. It also demonstrated good biocompatibility, appropriate gel strength and bio adhesive force with excellent adhesion to rectal mucosa and prolonged action time, allowing more effective drug absorption and diffusion to surrounding tissues. Poloxamer 407 and poloxamer 188 were applied to adjust the gelling temperature. With the addition of carbopol and polycarbophil (bio adhesive substances), the solubility of 5-FU and gel strength increased, the temperature of gelation and the surface area of drug contact on mucous epithelium decreased. Decreased adhesive force between the preparation and the mucous membrane of the rectum was demonstrated with improving carbopol and polycarbophil’s concentration. In vitro release demonstrated that 5-FU in situ gelling enema with different bases had a rapid and almost complete drug release. We used an optimized formulation of P407/P188/polycarbophil/5-FU (17/2.5/0.2/1.0) for animal experiments. The result showed that the drug evenly covered the surface of the rectum and there was no leakage in 6 hours. The in situ gelling enema showed significantly higher rectal tissue levels of 5-FU compared with suppository and intravenous administration, indicating that 5-FU could be well absorbed due to the enlarged releasing area, longer retention time and larger amount of dissolved active ingredients. Systemically, 5-FU levels in the enema group were similar to those in the suppository group and significantly lower than the intravenous group. The enema was not associated with morphological damage to rectal tissue. These results suggest that the bio adhesive and in situ gelling enema could be a more effective rectal

Development of in situ gelling and bio adhesive 5-Fluorouracil enema.

PubMed

Wang, Lu-Lu; Zheng, Wen-Sheng; Chen, Shao-Hua; Fang, Xia-Qin

2013-01-01

In this study, a novel 5-Fluorouracil (5-FU) enema with good bio adhesion and temperature sensitivity was developed using in situ gelling technology. The preparation was formulated as a free-flowing liquid before use, while a layer of gel film was quickly formed when administered in the rectum, with a large contact surface area. It also demonstrated good biocompatibility, appropriate gel strength and bio adhesive force with excellent adhesion to rectal mucosa and prolonged action time, allowing more effective drug absorption and diffusion to surrounding tissues. Poloxamer 407 and poloxamer 188 were applied to adjust the gelling temperature. With the addition of carbopol and polycarbophil (bio adhesive substances), the solubility of 5-FU and gel strength increased, the temperature of gelation and the surface area of drug contact on mucous epithelium decreased. Decreased adhesive force between the preparation and the mucous membrane of the rectum was demonstrated with improving carbopol and polycarbophil's concentration. In vitro release demonstrated that 5-FU in situ gelling enema with different bases had a rapid and almost complete drug release. We used an optimized formulation of P407/P188/polycarbophil/5-FU (17/2.5/0.2/1.0) for animal experiments. The result showed that the drug evenly covered the surface of the rectum and there was no leakage in 6 hours. The in situ gelling enema showed significantly higher rectal tissue levels of 5-FU compared with suppository and intravenous administration, indicating that 5-FU could be well absorbed due to the enlarged releasing area, longer retention time and larger amount of dissolved active ingredients. Systemically, 5-FU levels in the enema group were similar to those in the suppository group and significantly lower than the intravenous group. The enema was not associated with morphological damage to rectal tissue. These results suggest that the bio adhesive and in situ gelling enema could be a more effective rectal

Intensive virtual reality-based training for upper limb motor function in chronic stroke: a feasibility study using a single case experimental design and fMRI.

PubMed

Schuster-Amft, Corina; Henneke, Andrea; Hartog-Keisker, Birgit; Holper, Lisa; Siekierka, Ewa; Chevrier, Edith; Pyk, Pawel; Kollias, Spyros; Kiper, Daniel; Eng, Kynan

2015-01-01

To evaluate feasibility and neurophysiological changes after virtual reality (VR)-based training of upper limb (UL) movements. Single-case A-B-A-design with two male stroke patients (P1:67 y and 50 y, 3.5 and 3 y after onset) with UL motor impairments, 45-min therapy sessions 5×/week over 4 weeks. Patients facing screen, used bimanual data gloves to control virtual arms. Three applications trained bimanual reaching, grasping, hand opening. Assessments during 2-week baseline, weekly during intervention, at 3-month follow-up (FU): Goal Attainment Scale (GAS), Chedoke Arm and Hand Activity Inventory (CAHAI), Chedoke-McMaster Stroke Assessment (CMSA), Extended Barthel Index (EBI), Motor Activity Log (MAL). Functional magnetic resonance imaging scans (FMRI) before, immediately after treatment and at FU. P1 executed 5478 grasps (paretic arm). Improvements in CAHAI (+4) were maintained at FU. GAS changed to +1 post-test and +2 at FU. P2 executed 9835 grasps (paretic arm). CAHAI improvements (+13) were maintained at FU. GAS scores changed to -1 post-test and +1 at FU. MAL scores changed from 3.7 at pre-test to 5.5 post-test and 3.3 at FU. The VR-based intervention was feasible, safe, and intense. Adjustable application settings maintained training challenge and patient motivation. ADL-relevant UL functional improvements persisted at FU and were related to changed cortical activation patterns. Implications for Rehabilitation YouGrabber trains uni- and bimanual upper motor function. Its application is feasible, safe, and intense. The control of the virtual arms can be done in three main ways: (a) normal (b) virtual mirror therapy, or (c) virtual following. The mirroring feature provides an illusion of affected limb movements during the period when the affected upper limb (UL) is resting. The YouGrabber training led to ADL-relevant UL functional improvements that were still assessable 12 weeks after intervention finalization and were related to changed cortical

Use of subconjunctival injections of 5-fluorouracil to rescue and prolong intraocular pressure reduction for a failing Ahmed glaucoma implant.

PubMed

Kaplowitz, Kevin; Khodadadeh, Sarah; Wang, Samantha; Lee, Daniel; Tsai, James C

2017-06-01

5-Fluorouracil (5-FU) has been well described for a failing trabeculectomy bleb, but not for aqueous shunts. We sought to determine whether subconjunctival 5-FU prolongs the intraocular pressure (IOP) efficacy of Ahmed shunts. We included all patients with Ahmed FP-7 implantation by one surgeon at Yale University. Patients with <3 months follow-up were excluded. Injections were done on a case-by-case basis, usually for IOP > 21 on >2 medications. Five-milligram (0.1 cc) injections were made over the plate. The control group consisted of Ahmed FP-7 patients without injections. The main outcome measure was IOP. Secondary outcome was success (IOP <21 mmHg, 20% decrease from preoperative IOP, and no reoperation). The average age of controls was 72.5 ± 16.6 years, and 63.7 ± 18.8 with 5-FU (p = 0.02). Forty-four patients received 5-FU and 45 did not. Mean preoperative IOP in controls was 31.5 ± 11 mmHg on 3.1 ± 1 medications, and 31.9 ± 9.0 mmHg (p = 0.86) on 3.3 ± 0.9 medications with 5-FU (p = 0.18). At a mean 137 days after surgery, mean pre-injection IOP was 25.3 ± 7.7 mmHg on 2.0 ± 1.3 medications. Five years following implantation, control IOPs averaged 12.9 ± 7.1 mmHg (53% decrease from preoperative IOP, p < 0.001) on 1.4 ± 1.1 medications versus 17.2 ± 4.9 mmHg (46% decrease from preoperative, 32% decrease from pre-5FU IOP, p < 0.001) on 2.7 ± 0.8 medications with 5-FU. The IOP at 5 years was statistically similar in both groups (p = 0.23). Five-year success rates trended higher with 5-FU (77 vs. 67%, p = 0.38). Subconjunctival injection of 5-FU sustained a significant long-term decline in intraocular pressures in eyes with failing Ahmed shunts. Outcomes between eyes receiving injections and controls were statistically similar.

A comparative study of the safety and efficacy effect of 5-fluorouracil or mitomycin C mounted biological delivery membranes in a rabbit model of glaucoma filtration surgery.

PubMed

Wu, Zhihong; Li, Shuning; Wang, Ningli; Liu, Wanshun; Liu, Wen

2013-01-01

To investigate the potential usage of biological delivery membranes containing mitomycin C (MMC) or 5-fluorouracil (5-FU) in the construction of glaucoma-filtering blebs, and to evaluate their safety and efficacy. Chitosan was selected as the biological membrane carrier to prepare sustained-released membranes. Twelve micrograms of 5-FU or MMC was covalently conjugated onto the membranes by solvent volatilization. Rabbits underwent glaucoma filtration surgery and were randomly allocated into one of the four treatment regimens: glaucoma filtration operation with no implantation of chitosan membrane group (as control), drug-free chitosan membrane implantation group (blank/placebo group), membrane containing 5-FU treatment group (5-FU group), and membrane containing MMC treatment group (MMC group). Each group consisted of 12 rabbits. Intraocular pressure (IOP) was measured and evaluated over a 28-day period follow-up preoperatively, then after surgery on days 1, 3, 5, 7, 14, 21, and 28 by Tono-Pen. The aqueous humor was analyzed in each experimental and control groups at days 4, 6, 8, 10, 12, 14, 16, and 20 after operation. Bleb survival and anterior segment were examined with a slit lamp microscope and photographed simultaneously. Two rabbits from each group were killed on day 28 and eight eye samples obtained for histopathological study. Corneas and lenses were examined by transmission and scanning electron microscopy. Both 5-FU and MMC significantly prolonged bleb survival compared with control groups. The filtering bleb's survival period was significantly more prolonged in the MMC and 5-FU groups (maintained 14 days) than the other two groups (maintained 7 days). Significantly lower IOP was observed within the control, blank, and 5-FU groups after surgery on day 14 compared with that before operation, with F-values of 6.567, 11.426, and 13.467, respectively (P < 0.01). The most significant lower IOP was recorded in the MMC group on day 28 postoperation (F-value 26

A comparative study of the safety and efficacy effect of 5-fluorouracil or mitomycin C mounted biological delivery membranes in a rabbit model of glaucoma filtration surgery

PubMed Central

Wu, Zhihong; Li, Shuning; Wang, Ningli; Liu, Wanshun; Liu, Wen

2013-01-01

Purpose To investigate the potential usage of biological delivery membranes containing mitomycin C (MMC) or 5-fluorouracil (5-FU) in the construction of glaucoma-filtering blebs, and to evaluate their safety and efficacy. Methods Chitosan was selected as the biological membrane carrier to prepare sustained-released membranes. Twelve micrograms of 5-FU or MMC was covalently conjugated onto the membranes by solvent volatilization. Rabbits underwent glaucoma filtration surgery and were randomly allocated into one of the four treatment regimens: glaucoma filtration operation with no implantation of chitosan membrane group (as control), drug-free chitosan membrane implantation group (blank/placebo group), membrane containing 5-FU treatment group (5-FU group), and membrane containing MMC treatment group (MMC group). Each group consisted of 12 rabbits. Intraocular pressure (IOP) was measured and evaluated over a 28-day period follow-up preoperatively, then after surgery on days 1, 3, 5, 7, 14, 21, and 28 by Tono-Pen. The aqueous humor was analyzed in each experimental and control groups at days 4, 6, 8, 10, 12, 14, 16, and 20 after operation. Bleb survival and anterior segment were examined with a slit lamp microscope and photographed simultaneously. Two rabbits from each group were killed on day 28 and eight eye samples obtained for histopathological study. Corneas and lenses were examined by transmission and scanning electron microscopy. Results Both 5-FU and MMC significantly prolonged bleb survival compared with control groups. The filtering bleb’s survival period was significantly more prolonged in the MMC and 5-FU groups (maintained 14 days) than the other two groups (maintained 7 days). Significantly lower IOP was observed within the control, blank, and 5-FU groups after surgery on day 14 compared with that before operation, with F-values of 6.567, 11.426, and 13.467, respectively (P < 0.01). The most significant lower IOP was recorded in the MMC group on day 28

Microprocessor-controlled iontophoretic drug delivery of 5-fluorouracil: pharmacodynamic and pharmacokinetic study.

PubMed

Chandrashekar, N S; Shobha Rani, R H

2007-01-01

The purpose of this study was to fabricate monolithic 5-fluorouracil (5-FU) transdermal patch with microprocessor- controlled iontophoretic delivery, to evaluate the pharmacodynamic effects on Dalton's lymphoma ascites (DLA) induced in Balb/c mice, and to study pharmacokinetics in rabbits. The transdermal patches were prepared by solvent casting method; a reprogrammable microprocessor was developed and connected to the patches. DLA cells were injected to the hind limb of Balb/c mice (10 animals/group). In the first group of mice 5-FU was administered i.v. (12 mg/kg). In the second group of mice, transdermal patches (20 mg/patch/animal) were installed and kept for 10 consecutive days, while the third (control) group was kept without any treatment. The tumor diameter was measured every 5th day for 30 days, and the animal survival time and death pattern were studied. The electric current density protocol of 0.5 mA/cm(2) for 30 min was used in the pharmacokinetic study in rabbits. There was a significant reduction in tumor volume in the animals treated with monolithic matrix 5-FU transdermal patch compared to untreated controls and i.v. therapy. Tumor volume of the control animals was 5.8 cm(3) on the 30th day, while in 5-FU with transdermal patch delivery animals it was only 0.23 cm(3) (p <0.05). DLA cells tumor-bearing mice treated with 5-FU with transdermal patch had significantly increased lifespan (ILS). Control animals survived only 21+/-1 days after the tumor inoculation, while i.v. 5-FU and 5-FU patches animals survived 24+/-2.7 days and 39.5+/-1.87 days with ILS of 25.58% and 88.09%, respectively (p <0.01). There was significant sustained release of 5-FU through microprocessor-controlled patches and half-life was significantly higher (p <0.05) compared to the i.v. route. Cytotoxic concentration of 5-FU can be achieved through the transdermal drug delivery and effective therapeutic drug concentration can be maintained up to 24 h, with less toxicity. A new

Degradation of the cytostatic 5-Fluorouracil in water by Fenton and photo-assisted oxidation processes.

PubMed

Governo, Mariana; Santos, Mónica S F; Alves, Arminda; Madeira, Luís M

2017-01-01

Cytostatics are part of the forefront research topics due to their high prescription, high toxicity, and the lack of effective solutions to stop their entrance and spread in the environment. Among them, 5-Fluorouracil (5-Fu) has received particular attention because is one of the most prescribed active substances in chemotherapy worldwide. The degradation of 5-Fu by advanced oxidation processes (AOPs) is a poorly addressed topic, and this work brings valuable inputs concerning this matter. Herein, the efficacy of Fenton's process in the degradation of 5-Fu is explored for the first time; the study of the main variables and its successful application to the treatment of real wastewaters is demonstrated. Moreover, hydrogen peroxide-based and photo-assisted techniques (direct photolysis, photodegradation with H 2 O 2 and photo-Fenton) are also investigated for purposes of comparison. Under the best operation conditions obtained (T = 30 °C, [Fe 2+ ] 0  = 0.5 mM; [H 2 O 2 ] 0  = 240 mM and pH = 3 for [5-Fu] 0  = 0.38 mM), 5-Fu was completely eliminated after 2 h of Fenton's reaction and about 50 % of mineralization was reached after 8 h. The best performance was obtained by the photo-Fenton process, with 5-Fu mineralization level as high as 67 %, using an iron dose within the legal limits required for direct water discharge. Toxicity (towards Vibrio fischeri) of the effluents that resulted from the application of the above-mentioned AOPs was also evaluated; it was found that the degradation products generated from the photo-assisted processes are less toxic than the parent compound, putting into evidence the relevance of such technologies for degradation of cytostatics like 5-Fu.

Grape seed extract protects IEC-6 cells from chemotherapy-induced cytotoxicity and improves parameters of small intestinal mucositis in rats with experimentally-induced mucositis.

PubMed

Cheah, Ker Y; Howarth, Gordon S; Yazbeck, Roger; Wright, Tessa H; Whitford, Eleanor J; Payne, Caroline; Butler, Ross N; Bastian, Susan E P

2009-02-01

Mucositis is a common side-effect of high-dose chemotherapy regimens. Grape seed extract (GSE) represents a rich source of proanthocyanidins with the potential to decrease oxidative damage and inflammation within the gastrointestinal tract. We evaluated GSE for its capacity to decrease the severity of chemotherapy-induced mucositis in vitro and in vivo. In vitro: GSE was administered to IEC-6 intestinal epithelial cells prior to damage induced by 5-Fluorouracil (5-FU). Cell viability was determined by neutral red assay. In vivo: Female Dark Agouti rats (130-180 g) were gavaged with 1 ml GSE (400 mg/kg) daily (day 3-11) and received 5-FU (150 mg/kg) by intraperitoneal (i.p.) injection on day nine to induce mucositis. Rats were sacrificed at day 12 and intestinal tissues collected for myeloperoxidase and sucrase activity assays and histological analyses. Statistical analysis was performed by one-way ANOVA. GSE prevented the decrease in IEC-6 cell viability induced by 5-FU (p < 0.01). Compared with 5-FU controls, GSE significantly reduced myeloperoxidase activity by 86% and 27% in the proximal jejunum (p < 0.001) and distal ileum (p < 0.05) respectively; decreased qualitative histological scores of damage (p < 0.05) in the proximal jejunum; increased villus height in the proximal jejunum (17%; p < 0.05) and distal ileum (50%; p < 0.01), and attenuated the 5-FU-induced reduction of mucosal thickness by 16% in the jejunum (p < 0.05) and 45% in the ileum (p < 0.01). GSE partially protected IEC-6 cells from 5-FU-induced cytotoxicity and ameliorated intestinal damage induced by 5-FU in rats. GSE may represent a promising prophylactic adjunct to conventional chemotherapy for preventing intestinal mucositis.

ON THE DISTANCE OF THE MAGELLANIC CLOUDS USING CEPHEID NIR AND OPTICAL-NIR PERIOD-WESENHEIT RELATIONS

DOE Office of Scientific and Technical Information (OSTI.GOV)

Inno, L.; Bono, G.; Buonanno, R.

2013-02-10

We present the largest near-infrared (NIR) data sets, JHKs, ever collected for classical Cepheids in the Magellanic Clouds (MCs). We selected fundamental (FU) and first overtone (FO) pulsators, and found 4150 (2571 FU, 1579 FO) Cepheids for Small Magellanic Cloud (SMC) and 3042 (1840 FU, 1202 FO) for Large Magellanic Cloud (LMC). Current sample is 2-3 times larger than any sample used in previous investigations with NIR photometry. We also discuss optical VI photometry from OGLE-III. NIR and optical-NIR Period-Wesenheit (PW) relations are linear over the entire period range (0.0 < log P {sub FU} {<=} 1.65) and their slopesmore » are, within the intrinsic dispersions, common between the MCs. These are consistent with recent results from pulsation models and observations suggesting that the PW relations are minimally affected by the metal content. The new FU and FO PW relations were calibrated using a sample of Galactic Cepheids with distances based on trigonometric parallaxes and Cepheid pulsation models. By using FU Cepheids we found a true distance moduli of 18.45 {+-} 0.02(random) {+-} 0.10(systematic) mag (LMC) and 18.93 {+-} 0.02(random) {+-} 0.10(systematic) mag (SMC). These estimates are the weighted mean over 10 PW relations and the systematic errors account for uncertainties in the zero point and in the reddening law. We found similar distances using FO Cepheids (18.60 {+-} 0.03(random) {+-} 0.10(systematic) mag (LMC) and 19.12 {+-} 0.03(random) {+-} 0.10(systematic) mag (SMC)). These new MC distances lead to the relative distance, {Delta}{mu} = 0.48 {+-} 0.03 mag (FU, log P = 1) and {Delta}{mu} = 0.52 {+-} 0.03 mag (FO, log P = 0.5), which agrees quite well with previous estimates based on robust distance indicators.« less

Relationship Between Tumor Gene Expression and Recurrence in Four Independent Studies of Patients With Stage II/III Colon Cancer Treated With Surgery Alone or Surgery Plus Adjuvant Fluorouracil Plus Leucovorin

PubMed Central

O'Connell, Michael J.; Lavery, Ian; Yothers, Greg; Paik, Soonmyung; Clark-Langone, Kim M.; Lopatin, Margarita; Watson, Drew; Baehner, Frederick L.; Shak, Steven; Baker, Joffre; Cowens, J. Wayne; Wolmark, Norman

2010-01-01

Purpose These studies were conducted to determine the relationship between quantitative tumor gene expression and risk of cancer recurrence in patients with stage II or III colon cancer treated with surgery alone or surgery plus fluorouracil (FU) and leucovorin (LV) to develop multigene algorithms to quantify the risk of recurrence as well as the likelihood of differential treatment benefit of FU/LV adjuvant chemotherapy for individual patients. Patients and Methods We performed quantitative reverse transcription polymerase chain reaction (RT-qPCR) on RNA extracted from fixed, paraffin-embedded (FPE) tumor blocks from patients with stage II or III colon cancer who were treated with surgery alone (n = 270 from National Surgical Adjuvant Breast and Bowel Project [NSABP] C-01/C-02 and n = 765 from Cleveland Clinic [CC]) or surgery plus FU/LV (n = 308 from NSABP C-04 and n = 508 from NSABP C-06). Overall, 761 candidate genes were studied in C-01/C-02 and C-04, and a subset of 375 genes was studied in CC/C-06. Results A combined analysis of the four studies identified 48 genes significantly associated with risk of recurrence and 66 genes significantly associated with FU/LV benefit (with four genes in common). Seven recurrence-risk genes, six FU/LV-benefit genes, and five reference genes were selected, and algorithms were developed to identify groups of patients with low, intermediate, and high likelihood of recurrence and benefit from FU/LV. Conclusion RT-qPCR of FPE colon cancer tissue applied to four large independent populations has been used to develop multigene algorithms for estimating recurrence risk and benefit from FU/LV. These algorithms are being independently validated, and their clinical utility is being evaluated in the Quick and Simple and Reliable (QUASAR) study. PMID:20679606

Relationship between tumor gene expression and recurrence in four independent studies of patients with stage II/III colon cancer treated with surgery alone or surgery plus adjuvant fluorouracil plus leucovorin.

PubMed

O'Connell, Michael J; Lavery, Ian; Yothers, Greg; Paik, Soonmyung; Clark-Langone, Kim M; Lopatin, Margarita; Watson, Drew; Baehner, Frederick L; Shak, Steven; Baker, Joffre; Cowens, J Wayne; Wolmark, Norman

2010-09-01

These studies were conducted to determine the relationship between quantitative tumor gene expression and risk of cancer recurrence in patients with stage II or III colon cancer treated with surgery alone or surgery plus fluorouracil (FU) and leucovorin (LV) to develop multigene algorithms to quantify the risk of recurrence as well as the likelihood of differential treatment benefit of FU/LV adjuvant chemotherapy for individual patients. We performed quantitative reverse transcription polymerase chain reaction (RT-qPCR) on RNA extracted from fixed, paraffin-embedded (FPE) tumor blocks from patients with stage II or III colon cancer who were treated with surgery alone (n = 270 from National Surgical Adjuvant Breast and Bowel Project [NSABP] C-01/C-02 and n = 765 from Cleveland Clinic [CC]) or surgery plus FU/LV (n = 308 from NSABP C-04 and n = 508 from NSABP C-06). Overall, 761 candidate genes were studied in C-01/C-02 and C-04, and a subset of 375 genes was studied in CC/C-06. A combined analysis of the four studies identified 48 genes significantly associated with risk of recurrence and 66 genes significantly associated with FU/LV benefit (with four genes in common). Seven recurrence-risk genes, six FU/LV-benefit genes, and five reference genes were selected, and algorithms were developed to identify groups of patients with low, intermediate, and high likelihood of recurrence and benefit from FU/LV. RT-qPCR of FPE colon cancer tissue applied to four large independent populations has been used to develop multigene algorithms for estimating recurrence risk and benefit from FU/LV. These algorithms are being independently validated, and their clinical utility is being evaluated in the Quick and Simple and Reliable (QUASAR) study.

Ellagitannins from pomegranate ameliorates 5-fluorouracil-induced intestinal mucositis in rats while enhancing its chemotoxicity against HT-29 colorectal cancer cells through intrinsic apoptosis induction.

PubMed

Chen, Xiao-Xin; Lam, Kar Ho; Feng, Yibin; Xu, Kai; Sze, Stephen C W; Tang, Chi Wai; Leung, George P H; Lee, Calvin Kai-Fai; Shi, Jun; Yang, Zhijun; Li, Sheng-Tao; Zhang, Zhang-Jin; Zhang, Yanbo

2018-06-19

Worldwide, colorectal cancer (CRC) is a deleterious disease causing millions of death annually. 5-Fluorouracil (5-FU) is a first-line chemotherapy for CRC, but chemoresistance and gastrointestinal mucositis limit its efficacy. Polyphenol-rich foods are increasingly popular due to their potential beneficial role in cancer. Ellagitannins is a group of phenolic compounds commonly found in pomegranate, strawberries, raspberries, etc. The objective of this study was to explore whether ellagitannins from pomegranate (PETs) could ameliorate 5-FU-induced intestinal mucositis and enhance its efficacy against CRC. The results showed that PETs (100 mg/kg) counteracted 5-FU-induced intestinal mucositis in rats. The number of apoptotic cells per crypt was reduced from 1.50±0.21 to 0.85±0.18 (P<0.05). Moreover, PETs induced HT-29 CRC cell death through intrinsic apoptosis as demonstrated by dissipation of mitochondrial membrane potential, increased Bax to Bcl-2 ratio, and cleavage of caspase 9 and caspase 3. PETs and 5-FU combination treatments exhibited synergistic cytotoxicity against HT-29 cells with a weighted combination index of 0.3494. PETs (80 µg/mL) and 5-FU (40 µg/mL) treatments for 48 h induced 14.03±0.76% and 16.42±1.15% of HT-29 cells to undergo apoptosis while the combination treatment further increased apoptosis cells to 34.00±1.54% (P<0.05). Combination treatment of the cells also enhanced S phase cell cycle arrest as compared with PETs or 5-FU monotherapy (P<0.05). These results suggest that dietary ellagitannins from pomegranate could alleviate intestinal mucositis in rats induced by 5-FU while enhancing its toxicity against HT-29 cells through potentiation of apoptosis and cell cycle arrest.

Hematopoietic stem cells found in lineage-positive subsets in the bone marrow of 5-fluorouracil-treated mice.

PubMed

Nishi, N; Osawa, M; Ishikawa, R; Nishikawa, M; Tsumura, H; Inoue, H; Sudo, T

1995-09-01

It is known that treatment of mice with 5-fluorouracil (5-FU, 150 mg/kg) confers radioprotection. To investigate this effect, we performed bone marrow transplantation (BMT) using C57BL/6-Ly5 congenic mice treated with 5-FU five days prior to experiments. The mononuclear cells (MNC) in 5-FU-treated bone marrow (BM) were 10 times more radioprotective than those in untreated BM. Moreover, the number of BM MNC expressing c-kit on their surface from 5-FU-treated mice was markedly decreased relative to those from untreated controls. These results showed that the surface characteristics of cells that contributed to this radio-protective effect differ from those of stem cells as reported recently. BM MNC of mice treated with 5-FU were separated on the basis of expression of the lineage-specific antigens (Lin), c-kit, and Ly6A/E. When injected into lethally irradiated mice, 1,000 Lin+ and Lin-c-kit+Ly6A/E+ cells showed radioprotective effects such that 100% and 60% survived, respectively. Flow cytometric analysis 165 days after BMT showed that 88.8% and 65.1% of peripheral blood (PB) in mice transplanted with Lin+ and Lin-c-kit+Ly6A/E+ was derived from donor mice, respectively. After six months, donor-derived Lin-c-kit+Ly6A/E+ cells which showed radioprotective effects on a secondary irradiated host were detected from mice transplanted with Lin+ cells from 5-FU-treated mice. Taken together, these findings demonstrated that stem cells expressing Lin+ present in the BM of mice treated with 5-FU other than Lin-c-kit+Ly6A/E+ cells and these Lin+ cells play an important role in the recovery of myeloablative mice.

Smad4 sensitizes colorectal cancer to 5-fluorouracil through cell cycle arrest by inhibiting the PI3K/Akt/CDC2/survivin cascade.

PubMed

Zhang, Binhao; Leng, Chao; Wu, Chao; Zhang, Zhanguo; Dou, Lei; Luo, Xin; Zhang, Bixiang; Chen, Xiaoping

2016-03-01

5-Fluorouracil (5-FU), a cell cycle-specific antimetabolite, is one of the most commonly used chemotherapeutic agents for colorectal cancer (CRC). Yet, resistance to 5-FU-based chemotherapy is still an obstacle to the treatment of this malignancy. Mutation or loss of Smad4 in CRC is pivotal for chemoresistance. However, the mechanism by which Smad4 regulates the chemosensitivity of CRC remains unclear. In the present study, we investigated the role of Smad4 in the chemosensitivity of CRC to 5-FU, and whether Smad4-regulated cell cycle arrest is involved in 5-FU chemoresistance. We used Smad4-expressing CT26 and Smad4-null SW620 cell lines as experimental models, by knockdown or transgenic overexpression. Cells or tumors were treated with 5-FU to determine chemosensitivity by cell growth, tumorigenicity assay and a mouse model. Cell cycle distribution was examined with flow cytometric analysis, and cell cycle-related proteins were examined by western blotting. Smad4 deficiency in CT26 and SW620 cells induced chemoresistance to 5-FU both in vitro and in vivo. Smad4 deficiency attenuated G1 or G2 cell cycle arrest by activating the PI3K/Akt/CDC2/survivin pathway. The PI3K inhibitor, LY294002, reversed the activation of the Akt/CDC2/survivin cascade in the Smad4-deficient cells, while it had little effect on cells with high Smad4 expression. In conclusion, we discovered a novel mechanism mediated by Smad4 to trigger 5-FU chemosensitivity through cell cycle arrest by inhibiting the PI3K/Akt/CDC2/survivin cascade. The present study also implies that LY294002 has potential therapeutic value to reverse the chemosensitivity of CRC with low Smad4 expression.

Anatomic ligament consolidation of the superior acromioclavicular ligament and the coracoclavicular ligament complex after acute arthroscopically assisted double coracoclavicular bundle stabilization.

PubMed

Jobmann, S; Buckup, J; Colcuc, C; Roessler, P P; Zimmermann, E; Schüttler, K F; Hoffmann, R; Welsch, F; Stein, T

2017-09-18

The consolidation of the acromioclavicular (AC) and coracoclavicular (CC) ligament complex after arthroscopically assisted stabilization of acute acromioclavicular joint (ACJ) separation is still under consideration. Fifty-five consecutive patients after arthroscopically assisted double-CC-bundle stabilization within 14 days after acute high-grade ACJ separation were studied prospectively. All patients were clinically analysed preoperatively (FU0) and post-operatively (FU1 = 6 months; FU2 = 12 months). The structural MRI assessments were performed at FU0 (injured ACJ) and at FU2 bilateral (radiologic control group) and assessed separately the ligament thickness and length at defined regions for the conoid, trapezoid and the superior AC ligament. Thirty-seven patients were assessed after 6.5 months and after 16.0 months. The 16-month MRI analysis revealed for all patients continuous ligament healing for the CC-complex and the superior AC ligament with in the average hypertrophic consolidation compared to the control side. Separate conoid and trapezoid strands (double-strand configuration) were detected in 27 of 37 (73%) patients, and a single-strand configuration was detected in 10 of 37 (27%) patients; both configurations showed similar CCD data. The ligament healing was not influenced by the point of surgery, age at surgery and heterotopic ossification. The clinical outcome was increased (FU0-FU2): Rowe, 47.7-97.0 pts.; TAFT, 3.9-10.6 pts.; NAS pain , 8.9-1.4 pts. (all P < 0.05). The arthroscopically assisted double-CC-bundle stabilization within 14 days after acute high-grade ACJ separation showed 16 months after surgery sufficient consolidations of the AC and double-CC ligament complex in 73%. III, Case series.

Carboxymethyl pachyman (CMP) reduces intestinal mucositis and regulates the intestinal microflora in 5-fluorouracil-treated CT26 tumour-bearing mice.

PubMed

Wang, Canhong; Yang, Shuxian; Gao, Li; Wang, Lili; Cao, Li

2018-05-23

The compound 5-fluorouracil (5-FU) is the first choice chemotherapeutic agent for the treatment of colorectal cancer (CRC), but intestinal mucositis is a primary limiting factor in anticancer therapy. There is currently no broadly effective targeted treatment to cure this side effect. Carboxymethylated pachyman (CMP) is a polysaccharide that is modified from the structure of pachyman isolated from Poria cocos (Chinese name: Fu Ling). Meanwhile, recent studies have shown that CMP exhibits immune regulatory, anti-inflammatory and antioxidant activities. Therefore, the purpose of this study was to evaluate the intestinal protective effect of CMP in 5-FU-treated CT26 tumour-bearing mice and to further explore its underlying mechanism(s) of action. Initially, a CT26 colon carcinoma xenograft mice model was established. The colon length, colon tissue injury, intestinal flora, short-chain fatty acids (SCFAs) and indicators linked to inflammation, antioxidation and apoptosis were then measured. Our results showed that CMP in combination with 5-FU reversed intestinal shortening (p < 0.01) and alleviated 5-FU-induced colon injury (p < 0.001) via suppression of ROS production; increasing the levels of CAT, GSH-Px and GSH; decreasing expression of NF-κB, p-p38 and Bax; and elevating the levels of Nrf2 and Bcl-2. More importantly, CMP had a significant impact and counteracted the intestinal microflora disorders produced by 5-FU by increasing the proportion of Bacteroidetes, lactobacilli, and butyric acid-producing and acetic acid-producing bacteria and restoring the intestinal flora diversity. Overall, this work suggested that CMP could regulate the ecological balance of the intestinal flora and reduce colon injuries induced by 5-FU in CT26 tumour-bearing mice, and the mechanism involved may be associated with the regulation of the NF-κB, Nrf2-ARE and MAPK/P38 pathways.

Knockdown of long non‑coding RNA PVT1 reverses multidrug resistance in colorectal cancer cells.

PubMed

Fan, Heng; Zhu, Jian-Hua; Yao, Xue-Qing

2018-06-01

Multidrug resistance (MDR) is one of the primary causes of chemotherapy failure in colorectal cancer (CRC), and extensive biological studies into MDR are required. The non‑coding RNA plasmacytoma variant translocation 1 (PVT1) has been demonstrated to be associated with low survival rates in patients with CRC. However, whether PVT1 serves a critical function in the MDR of CRC remains to be determined. To determine the association between PVT1 expression and 5‑fluorouracil (5‑FU) resistance in CRC, the expression levels of PVT1 mRNA in 5‑FU‑resistant CRC tissues and cell lines (HCT‑8/5‑FU and HCT‑116/5‑FU) were assessed by a reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR). Cytotoxicity was evaluated using a Cell Counting Kit‑8 assay and apoptosis rates were assessed via flow cytometry. In the present study, PVT1 mRNA was highly expressed in 5‑FU‑resistant CRC tissues and cell lines. HCT‑8/5‑FU and HCT‑116/5‑FU cells transfected with small interfering RNA PVT1 and treated with 5‑FU exhibited higher apoptotic rates and lower survival rates. By contrast, overexpression of PVT1 in HCT‑8 and HCT‑116 cells transfected with lentiviral vector‑PVT1‑green fluorescent protein and treated with 5‑FU exhibited lower apoptosis rates and higher survival rates. RT‑qPCR and western blotting demonstrated that the overexpression of PVT1 increased the mRNA and protein expression levels of multidrug resistance‑associated protein 1, P‑glycoprotein, serine/threonine‑protein kinase mTOR and apoptosis regulator Bcl2. The present study indicates that PVT1 overexpression may promote MDR in CRC cells, and suggested that inhibition of PVT1 expression may be an effective therapeutic strategy for reversing MDR in CRC.

Long-term stability of 5-fluorouracil stored in PVC bags and in ambulatory pump reservoirs.

PubMed

Martel, P; Petit, I; Pinguet, F; Poujol, S; Astre, C; Fabbro, M

1996-02-01

Prolonged infusions of 5-fluorouracil (5FU) have been used since the early 1960s, but recently there has been a major resurgence of interest, partly because of the advent of electronically controlled portable infusion pumps. Admixtures of new formulation 5FU were subjected to stability studies to establish the feasability of continuous infusions. In the first study, the stability of 5FU, 1 or 10 mg ml(-1), was determined in poly(vinyl chloride) (PVC) bags (0.9% sodium chloride injection or 5% dextrose injection) at 4 and 21 degrees C after storage for 0, 1, 2, 3, 4, 7 and 14 days. In the second study, the stability of undiluted 5FU was tested at different temperatures (4 or 33 degrees C) in ethylene-vinyl acetate (EVA) or PVC ambulatory pump reservoirs after storage for 0, 3, 5, 7 and 14 days. For each condition, samples from each admixture were tested for drug concentration by stability-indicating high-performance liquid chromatography. The admixtures were also monitored for precipitation, colour change and pH. Evaporative water loss from the containers was measured. The stability of 5FU in PVC bags was unaffected by 14 days of storage at either 4 or 21 degrees C. When stored in EVA reservoirs, 5FU was stable for at least 2 weeks at 33 degrees C and for 3 days at 4 degrees C (a precipitate was observed after 3 days). In PVC reservoirs, 5FU was stable for over 14 days at 33 degrees C, but at 4 degrees C a precipitate appeared after 5 days. Loss of water through the reservoirs was substantial only at 33 degrees C for 14 days, and gave falsely high readings.

Patient satisfaction and suggestions for improvement of remote ICD monitoring.

PubMed

Petersen, Helen Høgh; Larsen, Mie Christa Jensen; Nielsen, Olav Wendelboe; Kensing, Finn; Svendsen, Jesper Hastrup

2012-09-01

The study aim was to evaluate patient acceptance and content with remote follow-up (FU) of their implantable cardioverter defibrillator (ICD) and to estimate patients' wish for changes in remote follow-up routines. Four hundred seventy-four ICD patients at the device follow-up clinic at Rigshospitalet using CareLink® (Medtronic) remote follow-up, who had made ≥2 transmissions, received a questionnaire. Three hundred eighty-five patients (81.2%) answered. Mean time with ICD was 56 ± 45 months and mean age was 62 ± 13 years; 80% was male. Diagnosis related to ICD implant was: ischemic heart disease in 56% and dilated cardiomyopathy in 21%. Twenty-six percent had primary prophylactic indication. Mean time on remote FU was 16.4 ± 6.9 months. Mean time spent on in-clinic FU (two-way transport and FU) was 4 h and 36 min ± 7 h and 50 min, excluding 12 patients from Greenland and Faroe Islands. Ninety-five percent of the patients was very content or content with remote FU compared to in-clinic FU; 3% was less content and 2% was not content. For scheduled transmissions, 21% of the patients wished for a faster reply (sms or e-mail) compared to current practice with a letter. Eighty-four percent preferred more detailed information concerning ICD leads, battery status, and ICD therapies. A total of 96 patients (25%) had performed extra unscheduled remote transmissions: 20 due to shock, 20 due to alarm, 35 due to palpitations, and 18 for other or combined reasons. Ninety-five percent of the patients were content with the remote FU. Only 25% had unscheduled transmissions and most unscheduled transmissions were for appropriate reasons. Eighty-four percent of the patients wished for a more detailed response and 21% wished for a faster reply after routine transmissions.

Preoperative chemoradiotherapy with capecitabine versus protracted infusion 5-fluorouracil for rectal cancer: A matched-pair analysis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Das, Prajnan; Lin, Edward H.; Bhatia, Sumita

2006-12-01

Purpose: To retrospectively compare the acute toxicity, pathologic response, relapse rates, and survival in rectal cancer patients treated with preoperative radiotherapy (RT) and either concurrent capecitabine or concurrent protracted infusion 5-fluorouracil (5-FU). Methods: Between June 2001 and February 2004, 89 patients with nonmetastatic rectal adenocarcinoma were treated with preoperative RT and concurrent capecitabine, followed by mesorectal excision. These patients were individually matched by clinical T and N stage (as determined by endoscopic ultrasound and CT scans) with 89 control patients treated with preoperative RT and concurrent protracted infusion 5-FU between September 1997 and August 2002. Results: In each group, 5more » patients (6%) had Grade 3-4 toxicity during chemoradiotherapy. The pathologic complete response rate was 21% with capecitabine and 12% with protracted infusion 5-FU (p = 0.19). Of the 89 patients in the capecitabine group and 89 in the 5-FU group, 46 (52%) and 55 (62%), respectively, had downstaging of the T stage after chemoradiotherapy (p = 0.20). The estimated 3-year local control (p = 0.15), distant control (p = 0.86), and overall survival (p = 0.12) rate was 94.4%, 86.3%, and 89.8% for patients treated with capecitabine and 98.6%, 86.6%, and 96.4% for patients treated with protracted infusion 5-FU, respectively. Conclusion: Preoperative concurrent capecitabine and concurrent protracted infusion 5-FU were both well tolerated, with similar, low rates of Grade 3-4 acute toxicity. No significant differences were seen in the pathologic response, local and distant recurrence, or overall survival among patients treated with preoperative RT and concurrent capecitabine compared with those treated with RT and concurrent protracted infusion 5-FU.« less

Studies on activated cytostatic fluorouracil as photosensitizer: to use in eye tumor treatment

NASA Astrophysics Data System (ADS)

Pascu, Mihail-Lucian; Carstocea, Benone D.; Brezeanu, Mihail; Voicu, Letitia; Staicu, Angela; Gazdaru, Doina M.; Pascu, Ruxandra A.

2004-09-01

Hydroxypyrimidine 5-fluorouracil (5-FU) belongs to the cytostatics group known as antimetabolites. The effect of UV irradiation on 5-FU was investigated by absorption and fluorescence spectroscopy. The study of the photosensitizer properties of 5-FU was made since their effects could be enhanced by exposure to UV radiation at different doses. Solutions 2.5x10-4M in natural saline water (0.8% NaCl), irradiated with optical beams emitted by N2 laser and UV Hg classic lamp, were used. The 5-FU was chosen due to its strong absorption along a large spectral range which makes possible the fluorescence excitation in UV. The absorption spectra exhibit bands between 250 - 450 nm. The emission fluorescence was measured in the 400-550 nm spectral range, with λex=320 and 350 nm for samples irradiated with Hg lamp and with λex=360 nm for samples irradiated with N2 laser. The excitation fluorescence was measured in the spectral range 200-400 nm, with λem=440 nm for samples irradiated with N2 laser. The spectra reveal a fluorescence enhancement with the exposure time, with a maximum at 3 min due to the transformation of 5-FU molecule into a fluorescent tautomeric form. The destruction more rapid than usual of the neovascularisation was observed for conjunctive of rabbit eyes, when they are impregnated with 5-FU solution and exposed to incoherent UV and visible light.

Polymeric nano-encapsulation of 5-fluorouracil enhances anti-cancer activity and ameliorates side effects in solid Ehrlich Carcinoma-bearing mice.

PubMed

Haggag, Yusuf A; Osman, Mohamed A; El-Gizawy, Sanaa A; Goda, Ahmed E; Shamloula, Maha M; Faheem, Ahmed M; McCarron, Paul A

2018-05-29

Biodegradable PLGA nanoparticles, loaded with 5-fluorouracil (5FU), were prepared using a double emulsion method and characterised in terms of mean diameter, zeta potential, entrapment efficiency and in vitro release. Poly (vinyl alcohol) was used to modify both internal and external aqueous phases and shown have a significant effect on nanoparticulate size, encapsulation efficiency and the initial burst release. Addition of poly (ethylene glycol) to the particle matrix, as part of the polymeric backbone, improved significantly the encapsulation efficiency. 5FU-loaded NPs were spherical in shape and negatively charged with a size range of 185-350 nm. Biological evaluation was performed in vivo using a solid Ehrlich carcinoma (SEC) murine model. An optimised 5FU-loaded formulation containing PEG as part of a block copolymer induced a pronounced reduction in tumour volume and tumour weight, together with an improved percentage tumour growth inhibition. Drug-loaded nanoparticles showed no significant toxicity or associated changes on liver and kidney function in tested animals, whereas increased alanine aminotransferase, aspartate aminotransferase and serum creatinine were observed in animals treated with free 5FU. Histopathological examination demonstrated enhanced cytotoxic action of 5FU-loaded nanoparticles when compared to the free drug. Based on these findings, it was concluded that nano-encapsulation of 5FU using PEGylated PLGA improved encapsulation and sustained in vitro release. This leads to increased anti-tumour efficacy against SEC, with a reduction in adverse effects. Published by Elsevier Masson SAS.

A new name and seventeen new combinations in the Magnolia (Magnoliaceae) of China and Vietnam.

PubMed

Callaghan, Chris; Png, Siak-Khoon Sk

2013-12-01

A new name is proposed and seventeen new combinations are made as a result of the previous reduction of the remaining genera of subfamily Magnolioideae (Magnoliaceae) into the genus Magnolia. The replacement name Magnolia fansipanensis is proposed for Manglietia crassifolia Q. N. Vu et al., since its transfer to Magnolia would create an illegitimate later homonym of the fossil name M. crassifolia Göpp. A further 17 new combinations are made to transfer the following taxa to Magnolia: Manglietia guangzhouensis A. Q. Dong et al., M. kaifui Q. W. Zeng & X. M. Hu, M. lawii N. H. Xia & W. F. Liao, plus Michelia concinna H. Jiang & E. D. Liu, M. jianfenglingensis G. A. Fu & K. Pan, M. viridipetala Y. W. Law et al., M. wuzhishangensis G. A. Fu & K. Pan, M. xianianhei Q. N. Vu and Yulania carnosa D. L. Fu & D. L. Zhang, Y. cuneatofolia T. B. Chao (probably Zhao) et al., Y. dabieshanensis T. B. Zhao et al., Y. dimorpha T. B. Zhao & Z. X. Chen, Y. fragarigynandria T. B. Zhao et al., Y. shirenshanensis D. L. Fu & T. B. Zhao, Y. shizhenii D. L. Fu & F. W. Li, Y. verrucata D. L. Fu et al. and Y. xinyangensis T. B. Zhao et al. The transfer of the above taxa to Magnolia is necessary following the present almost universal recognition of Magnolioideae as one of two monogeneric subfamilies within Magnoliaceae.

Zebularine suppresses the apoptotic potential of 5-fluorouracil via cAMP/PKA/CREB pathway against human oral squamous cell carcinoma cells.

PubMed

Suzuki, Maiko; Shinohara, Fumiaki; Endo, Manabu; Sugazaki, Masaki; Echigo, Seishi; Rikiishi, Hidemi

2009-07-01

During tumorigenesis, tumor suppressor and tumor-related genes are commonly silenced by aberrant DNA methylation in their promoter regions, which is one of the important determinants of susceptibility to 5-fluorouracil (5-FU) in oral squamous cell carcinoma (OSCC) cells. Here, we examine the chemotherapeutic efficacy of epigenetic agents on 5-FU cytotoxicity. We investigated the effect of a DNA methyltransferase (DNMT) inhibitor, zebularine (Zeb), on the chemosensitivity of 5-FU and cisplatin (CDDP) by MTT and TUNEL methods, and compared the molecular mechanism of action with those of a GSK3beta inhibitor, LiCl, and an Hsp90 inhibitor, 17-AAG. A significant apoptotic effect by a combination of Zeb or 17-AAG was found in CDDP treatment; however, considerable suppression of 5-FU-induced apoptosis was observed after incubation with Zeb, 17-AAG, or LiCl. Zeb's suppressive effects were associated with activation of the cAMP/PKA/CREB pathway, differing from mechanisms of 17-AAG and LiCl. Suppression of 5-FU-induced apoptosis by Zeb was not associated with increased Bcl-2 and Bcl-xL expressions dependent on transcription factor CREB, and with the expression level of thymidylate synthase. In the present study, we identified a more detailed mechanism of action by which Zeb suppresses 5-FU-induced apoptosis. These results indicate that combination therapies have to be carefully investigated due to potential harmful effects in the clinical application of DNMT inhibitors.

siRNA targeting decoy receptor 3 enhances the sensitivity of gastric carcinoma cells to 5-fluorouracil.

PubMed

Xu, Xiao-Tao; Tao, Ze-Zhang; Song, Qi-Bin; Yao, Yi; Ruan, Peng

2012-09-01

In order to investigate the effects of RNA interference of decoy receptor 3 (DcR3) on the sensitivity of gastric cancer cells to 5-fluorouracil (5-FU) and the relevant mechanisms, siRNA against DcR3 was transfected into the gastric cancer cell line AGS. AGS cells were treated with different doses of 5-FU or for different time periods. The sensitivity of AGS cells to 5-FU was determined. The cell survival rate was detected by MTT assay. The apoptotic rate was determined by DAPI staining, and the expression of related proteins were detected by western blot analysis. The results showed that the cell survival rate was significanlty decreased in the knockdown group compared to the control group at different doses of 5-FU (P<0.01). After different time periods of treatment with 5-FU, the cell survival rate in the knockdown group was significantly decreased compared to the control group, respectively (P<0.01). The apoptotic rate of AGS cells in the knockdown group was increased along with the increasing dose of siRNA. The siRNA against DcR3 enhanced the expression of Fas, FasL, caspase-3 and caspase-8. In conclusion, knockdown of DcR3 by RNA interference enhances apoptosis and inhibits the growth of gastric cancer cells. Downregulation of DcR3 enhances the sensitivity of gastric cancer cells to 5-FU and increased the expression of Fas, FasL and caspase-3/8.

Quantification of the fluorine containing drug 5-fluorouracil in cancer cells by GaF molecular absorption via high-resolution continuum source molecular absorption spectrometry

NASA Astrophysics Data System (ADS)

Krüger, Magnus; Huang, Mao-Dong; Becker-Roß, Helmut; Florek, Stefan; Ott, Ingo; Gust, Ronald

The development of high-resolution continuum source molecular absorption spectrometry made the quantification of fluorine feasible by measuring the molecular absorption as gallium monofluoride (GaF). Using this new technique, we developed on the example of 5-fluorouracil (5-FU) a graphite furnace method to quantify fluorine in organic molecules. The effect of 5-FU on the generation of the diatomic GaF molecule was investigated. The experimental conditions such as gallium nitrate amount, temperature program, interfering anions (represented as corresponding acids) and calibration for the determination of 5-FU in standard solution and in cellular matrix samples were investigated and optimized. The sample matrix showed no effect on the sensitivity of GaF molecular absorption. A simple calibration curve using an inorganic sodium fluoride solution can conveniently be used for the calibration. The described method is sensitive and the achievable limit of detection is 0.23 ng of 5-FU. In order to establish the concept of "fluorine as a probe in medicinal chemistry" an exemplary application was selected, in which the developed method was successfully demonstrated by performing cellular uptake studies of the 5-FU in human colon carcinoma cells.

DPYD*2A and MTHFR C677T predict toxicity and efficacy, respectively, in patients on chemotherapy with 5-fluorouracil for colorectal cancer.

PubMed

Nahid, Noor Ahmed; Apu, Mohd Nazmul Hasan; Islam, Md Reazul; Shabnaz, Samia; Chowdhury, Surid Mohammad; Ahmed, Maizbha Uddin; Nahar, Zabun; Islam, Md Siddiqul; Islam, Mohammad Safiqul; Hasnat, Abul

2018-01-01

Significant inter-individual variation in the sensitivity to 5-fluorouracil (5-FU) represents a major therapeutic hindrance either by impairing drug response or inducing adverse drug reactions (ADRs). This study aimed at exploring the cause behind this inter-individual alterations in consequences of 5-fluorouracil-based chemotherapy by investigating the effects of DPYD*2A and MTHFR C677T polymorphisms on toxicity and response of 5-FU in Bangladeshi colorectal cancer patients. Colorectal cancer patients (n = 161) receiving 5-FU-based chemotherapy were prospectively enrolled. DPYD and MTHFR polymorphisms were assessed in peripheral leukocytes. Multivariate analyses were applied to evaluate which variables could predict chemotherapy-induced toxicity and efficacy. Multivariate analyses showed that DPYD*2A polymorphism was a predictive factor (P = 0.023) for grade 3 and grade 4 5-fluorouracil-related toxicities. Although MTHFR C677T polymorphism might act as forecasters for grade 3 or grade 4 neutropenia, diarrhea, and mucositis, this polymorphism was found to increase significantly (P = 0.006) the response of 5-FU. DPYD*2A and MTHFR C677T polymorphisms could explain 5-FU toxicity or clinical outcome in Bangladeshi colorectal patients.

[Synergistic effect of cell kinetics-directed chemo-endocrine therapy on experimental mammary tumors].

PubMed

Ueki, H

1987-11-01

We tried to demonstrate that the cell kinetics-directed chemoendocrine therapy is more effective on hormone dependent breast cancer than empirical combination of the endocrine therapy and chemotherapy. Cell kinetics of each tumor was measured by flow cytometric analysis. Estrogen dependent human breast cancer cell line MCF-7 was used in vitro. In vivo, androgen dependent SC-115 carcinoma was transplanted to DDS mice. In vitro, tamoxifen was administered as the endocrine therapy. In vivo, we carried out testectomy on DDS mice. Effect of the endocrine therapy on the cell kinetics of the tumor was thought to be G1-S depression. High density 5FU was administered as the chemotherapeutic agents, whose content was 1 microgram/ml in vitro and 40 mg/kg in vivo. 5FU brought temporary decrease of cells in S phase. Only anteceding 5FU administration had synergistic effect in combination of 5FU and the endocrine therapy. 5FU was convinced to act more effectively on cells in S phase, so it was shown that cell kinetics-directed schedule was superior to the empirical treatment schedule in chemoendocrine therapy.

Fabrication and Cytotoxicity of Fucoidan-Cisplatin Nanoparticles for Macrophage and Tumor Cells.

PubMed

Hwang, Pai-An; Lin, Xiao-Zhen; Kuo, Ko-Liang; Hsu, Fu-Yin

2017-03-14

Fucoidan, an anionic, sulfated polysaccharide from brown seaweed, is known to exhibit antitumor and immunomodulatory functions. To develop an immune protection and chemotherapeutic agent, fucoidan-cisplatin nanoparticles (FCNPs) were designed. FCNPs were prepared by mixing cisplatin with fucoidan solution or fucoidan with cisplatin solution, followed by dialysis to remove trace elements. The nanoparticles, comprising 10 mg of fucoidan and 2 mg of cisplatin, which exhibited the highest cisplatin content and loading efficiency during the production process, were named as Fu100Cis20. The cisplatin content, cisplatin loading efficiency, nanoparticle size, and zeta potential of Fu100Cis20 were 18.9% ± 2.7%, 93.3% ± 7.8%, 181.2 ± 21.0 nm, and -67.4 ± 2.3 mV, respectively. Immune protection assay revealed that Fu100Cis20-treated RAW264.7 cells were protected from the cytotoxicity of cisplatin. Furthermore, antitumor assay indicated that Fu100Cis20-treated HCT-8 cells showed stronger cytotoxicity than those treated with cisplatin alone. These results suggested that fucoidan-based nanoparticles exhibited suitable particle size and high drug encapsulation, and that Fu100Cis20 has potential application in both immunotherapy and chemotherapy.

Improved phase-ellipse method for in-situ geophone calibration.

USGS Publications Warehouse

Liu, Huaibao P.; Peselnick, L.

1986-01-01

For amplitude and phase response calibration of moving-coil electromagnetic geophones 2 parameters are needed, namely the geophone natural frequency, fo, and the geophone upper resonance frequency fu. The phase-ellipse method is commonly used for the in situ determination of these parameters. For a given signal-to-noise ratio, the precision of the measurement of fo and fu depends on the phase sensitivity, f(delta PHI/delta PHIf). For some commercial geophones (f(delta PHI/delta PHI) at fu can be an order of magnitude less than the sensitivity at fo. Presents an improved phase-ellipse method with increased precision. Compared to measurements made with the existing phase-ellipse methods, the method shows a 6- and 3-fold improvement in the precision, respectively, on measurements of fo and fu on a commercial geophone.-from Authors

Chemotheraphy, Neurotoxicity, and Cognitive Decline: Developing a Mouse Model and Potential Interventions

DTIC Science & Technology

2011-09-01

dUTP nick-end labeling (TUNEL) as a function of pre & co-treatment with 1) N-acetyl cysteine (NAC) 2) Melatonin & 3) Fluoxetine . Saline Group...4 time points for a total of 20 C57BL/6J mice) 5-FU + Melatonin Group: (n=5 x 4 time points for a total of 20 C57BL/6J mice) 5-FU + Fluoxetine ...56 days, and 6 months after 5-FU treatment using Ki-67 as a function of pre & co-treatment with 1) NAC 2) Melatonin & 3) Fluoxetine . 1c

Photonic Devices Based on Surface and Composition-Engineered Infrared Colloidal Nanocrystals

DTIC Science & Technology

2012-01-27

NQD/P3HT solar cells , the need for submicron-phase-separated polymer-NQD blends is therefore expressed by the limiting exciton diffusion length ...P3HT:PbSe are very critical in designing the PM-HJ solar cells : The thickness of P3HT should approximate to the thickness of exciton diffuse length in... cells , luminescent solar concentrators, light emitting diodes, lasers, photonic crystals, CdSe, PbSe, Germanium Jian Xu Pennsylvania State University

Thermal Investigations of Nanoaluminum/Perfluoropolyether Core-Shell Impregnated Composites for Structural Energetics

DTIC Science & Technology

2014-07-19

that undergo an oxidation reduction thermite reaction releasing energy. Advances in the field have generated diverse material platforms ranging from bulk...This is a pre ignition reaction (PIR) similar to the one observed by Pantoya and Dean in n Al/Teflon thermite based reactions [14]. PIR exotherms were...2010) 2560–2569. [5] S. Yan, G. Jian, M.R. Zachariah, Electrospun nanofiber-based thermite textiles and their reactive properties, ACS Appl. Mater

The Effects of Level of Autonomy on Human-Agent Teaming for Multi-Robot Control and Local Security Maintenance

DTIC Science & Technology

2013-11-01

different types of tasks, the associated costs of task switching also increase (Squire et al., 2006). Task switching costs may be increased with higher...switching costs as well, particularly when managing robot teams of increasing size (Squire et al., 2006). 1.3 Individual Differences The effects of...Research: Ready to Deliver the Promises. Mind 2003, 2 (3), 4. Jian, J.; Bisantz, A. M.; Drury , C. G. Foundations for an Empirically Determined Scale

Case-Based Behavior Adaptation Using an Inverse Trust Metric

DTIC Science & Technology

2014-06-01

Jian, Bisantz, and Drury 2000; Muir 1987), about how trust- worthy the robot was behaving. However, this might not be practical in situations that are...5). Carlson, M. S.; Desai, M.; Drury , J. L.; Kwak, H.; and Yanco, H. A. 2014. Identifying factors that influence trust in automated cars and medical...and Drury , C. G. 2000. Foundations for an empirically determined scale of trust in automated systems. International Journal of Cogni- tive Ergonomics

Curcumin synergizes with 5-fluorouracil by impairing AMPK/ULK1-dependent autophagy, AKT activity and enhancing apoptosis in colon cancer cells with tumor growth inhibition in xenograft mice.

PubMed

Zhang, Pan; Lai, Ze-Lin; Chen, Hui-Fen; Zhang, Min; Wang, An; Jia, Tao; Sun, Wen-Qin; Zhu, Xi-Min; Chen, Xiao-Feng; Zhao, Zheng; Zhang, Jun

2017-12-22

Chemoresistance is a major obstacle that limits the benefits of 5-Fluorouracil (5-Fu)-based chemotherapy for colon cancer patients. Autophagy is an important cellular mechanism underlying chemoresistance. Recent research advances have given new insights into the use of natural bioactive compounds to overcome chemoresistance in colon cancer chemotherapy. As one of the multitargeted and safer phytomedicines, curcumin has been reported to work as cancer-specific chemosensitizer, presumably via induction of autophagic signaling pathways. The precise therapeutic effect of curcumin on autophagy in determining tumorous cells' fate, however, remains unclear. This study was conducted to investigate the differential modulations of the treatments either with 5-Fu alone or 5-Fu combined with curcumin on cellular autophagic responses and viabilities in the human colon cancer cells HCT116 and HT29, and explore molecular signaling transductions underlying the curcumin-mediated autophagic changes and potentiation of 5-Fu's cytotoxicity in vitro and in vivo. Cell proliferation assay and morphology observation were used to identify the cytotoxicity of different combinations of curcumin and 5-Fu in HCT116 and HT29 cells. Cell immunofluorescence assay, Flow cytometry and Western blot were employed to detect changes of autophagy and the autophagy-related signaling pathways in the colon cancer cells and/or xenograft mice. Curcumin could significantly augment the cytotoxicity of 5-Fu to the tumorous cells, and the pre-treatment with curcumin followed by 5-Fu (pre-Cur) proved to be the most effective one compared to other two combinations. The chemosensitizing role of curcumin might attribute to the autophagy turnover from being activated in 5-Fu mono-treatment to being inhibited in the pre-Cur treatment as indicated by the changes in expression of beclin-1, p62 and LC3II/LC3I and the intensity of Cyto-ID Green staining. The autophagic alterations appeared to be contributed by down

Retraction: Nucleophagy in Human Disease: Beyond the Physiological Role. [Tohoku J. Exp. Med., 2018, 244 (1), 75-81. doi: 10.1620/tjem.244.75. Review.].

PubMed

2018-02-01

Retracted Review article: Nucleophagy in Human Disease: Beyond the Physiological Role. [Tohoku J. Exp. Med., 2018, 244 (1), 75-81. doi: 10.1620/tjem.244.75.] The above Review article was published online on January 27, 2018. Soon after its publication (on February 1, 2018), Dr. Nian Fu and Prof. Linxi Chen informed the Editor-in-Chief, The Tohoku Journal of Experimental Medicine (TJEM), about serious violation of publication ethics. Indeed, Dr. Nian Fu and Prof. Linxi Chen were astonished to find their names as coauthors of this Review article, because they were not involved in the submission process of this Review article and they do not know any of other coauthors. In addition, the Review article is similar to their unpublished manuscript. After a thorough investigation in accordance with the recommendations of the Committee on Publication Ethics (COPE), the Editor-in-Chief of TJEM decided to retract this Review article. The reasons for Retraction are summarized below: forged authors and an unexpected case of plagiarism. Forged authors: Dr. Nian Fu and Prof. Linxi Chen were added as co-authors of the Review article without their knowledge. In fact, the signature provided by Prof. Linxi Chen is apparently different from the signature of a coauthor, named Linxi Chen, on the AUTHORS’ RESPONSIBILITY FORM, provided by the corresponding author of the Review article. More critically, the signature provided by Dr. Nian Fu is completely different from the signature of Nian Fu, because the Chinese characters are different between the two signatures. In addition, the replies from three authors (Ming Zhou, Hongwen Ji and Yong Xia) clearly indicate that they misunderstand the identity of Dr. Nina Fu. We also attempted to contact two authors, named Nian Fu and Linxi Chen, via e-mail. As expected, the forged authors did not respond to our inquiries, despite that their e-mail addresses appear to be active. An unexpected case of plagiarism: This Review article is similar to the

Plasma concentrations of 5-fluorouracil and its metabolites in colon cancer patients.

PubMed

Casale, Federico; Canaparo, Roberto; Serpe, Loredana; Muntoni, Elisabetta; Pepa, Carlo Della; Costa, Mario; Mairone, Lorenza; Zara, Gian Paolo; Fornari, Gianni; Eandi, Mario

2004-08-01

5-Fluorouracil (5-FU) is a common anticancer agent used in the treatment of solid tumours, with a reported variability in the pharmacokinetic profile and inter-patient differences in efficacy and toxicity. Since 5-FU is intracellularly metabolised to active cytotoxic fluoronucleotides, some authors suggested it would be useful to determine the plasma levels of its main metabolites 5-fluoro-5,6-dihydrouracil (5-FUH2), 5-fluorouridine (5-FUrd) and 5-fluoro-2'-deoxyuridine (5-FdUrd), in order to better characterise population pharmacokinetics-pharmacodynamics (PK-PD) of this drug. We developed and validated an HPLC method to simultaneously determine plasma concentrations of 5-FU and the three main metabolites, and we analysed the plasma concentration-time curves of the first dose of 18 colon cancer patients treated with folinic acid and 5-FU 400 mg m(-2) by intra-venous bolus injection as adjuvant chemotherapy. Non-compartmental PK analysis has been applied to 5-FU and 5-FUH2 concentrations, estimating the following parameters (median values): Cmax 55.44 and 6.23 microg ml(-1), respectively, AUC(0-2 h) 11.59 and 5.94 hx microg ml(-1), CLTB 30.64 and 51.81 lh(-1) m(-2), 5-FUH2/5-FU AUC ratio 0.47 (range 0.29-1.12). We verified the patient covariables which could influence the inter-patient variability in the area under the time-concentration curves, and we observed that age, sex, weight, body surface area, cycle of therapy, toxicity development and 5-FUrd or 5-FdUrd detectability did not have statistical influence on 5-FUH2/5-FU AUC ratio. In eight subjects, we compared the PK data of the first and the fifth day of dose administration, and we found stable 5-FU values, but the 5-FUH2 disposition decreased with lower AUC(0-2 h) (7.90 hx microg ml(-1) versus 5.99 hx microg ml(-1)) and, particularly, Cmax (8.38 microg ml(-1) versus 5.50 microg ml(-1)) at day 5. This fact, evident in almost every patient, could suggest a possible reduction in the catabolic pathway of 5-FU

Novel strategy for prevention of esophageal stricture after endoscopic surgery.

PubMed

Mizutani, Taro; Tadauchi, Akimitsu; Arinobe, Manabu; Narita, Yuji; Kato, Ryuji; Niwa, Yasumasa; Ohmiya, Naoki; Itoh, Akihiro; Hirooka, Yoshiki; Honda, Hiroyuki; Ueda, Minoru; Goto, Hidemi

2010-01-01

Recently, novel endoscopic surgery, including endoscopic submucosal dissection (ESD), was developed to resect a large superficial gastrointestinal cancer. However, circumferential endoscopic surgery in the esophagus can lead to esophageal stricture that affects the patient's quality of life. This major complication is caused by scar formation, and develops during the two weeks after endoscopic surgery. We hypothesized that local administration of a controlled release anti-scarring agent can prevent esophageal stricture after endoscopic surgery. The aims of this study were to develop an endoscopically injectable anti-scarring drug delivery system, and to verify the efficacy of our strategy to prevent esophageal stricture. We focused on 5-Fluorouracil (5-FU) as an anti-scarring agent, which has already been shown to be effective not only for treatment of cancers, but also for treatment of hypertrophic skin scars. 5-FU was encapsulated by liposome, and then mixed with injectable 2% atelocollagen (5FLC: 5FU-liposome-collagen) to achieve sustained release. An in vitro 5-FU releasing test from 5FLC was performed using high-performance liquid chromatography (HPLC). Inhibition of cell proliferation was investigated using normal human dermal fibroblast cells (NHDF) with 5FLC. In addition, a canine esophageal mucosal resection was carried out, and 5FLC was endoscopically injected into the ulcer immediately after the operation, and compared with a similar specimen injected with saline as a control. 5-FU was gradually released from 5FLC for more than 2 weeks in vitro. The solution of 5-FU released from 5FLC inhibited NHDF proliferation more effectively than 5-FU alone. In the canine model, no findings of stricture were observed in the 5FLC-treated dog at 4 weeks after the operation and no vomiting occurred. In contrast, marked esophageal strictures were observed with repeated vomiting in the control group. Submucosal fibrosis was markedly reduced histologically in the 5FLC

Curcumin Enhances the Effect of Chemotherapy against Colorectal Cancer Cells by Inhibition of NF-κB and Src Protein Kinase Signaling Pathways

PubMed Central

Shakibaei, Mehdi; Mobasheri, Ali; Lueders, Cora; Busch, Franziska; Shayan, Paviz; Goel, Ajay

2013-01-01

Objective Development of treatment resistance and adverse toxicity associated with classical chemotherapeutic agents highlights the need for safer and effective therapeutic approaches. Herein, we examined the effectiveness of a combination treatment regimen of 5-fluorouracil (5-FU) and curcumin in colorectal cancer (CRC) cells. Methods Wild type HCT116 cells and HCT116+ch3 cells (complemented with chromosome 3) were treated with curcumin and 5-FU in a time- and dose-dependent manner and evaluated by cell proliferation assays, DAPI staining, transmission electron microscopy, cell cycle analysis and immunoblotting for key signaling proteins. Results The individual IC50 of curcumin and 5-FU were approximately 20 µM and 5 µM in HCT116 cells and 5 µM and 1 µM in HCT116+ch3 cells, respectively (p<0.05). Pretreatment with curcumin significantly reduced survival in both cells; HCT116+ch3 cells were considerably more sensitive to treatment with curcumin and/or 5-FU than wild-type HCT116 cells. The IC50 values for combination treatment were approximately 5 µM and 1 µM in HCT116 and 5 µM and 0.1 µM in HCT116+ch3, respectively (p<0.05). Curcumin induced apoptosis in both cells by inducing mitochondrial degeneration and cytochrome c release. Cell cycle analysis revealed that the anti-proliferative effect of curcumin and/or 5-FU was preceded by accumulation of CRC cells in the S cell cycle phase and induction of apoptosis. Curcumin potentiated 5-FU-induced expression or cleavage of pro-apoptotic proteins (caspase-8, -9, -3, PARP and Bax), and down-regulated anti-apoptotic (Bcl-xL) and proliferative (cyclin D1) proteins. Although 5-FU activated NF-κB/PI-3K/Src pathway in CRC cells, this was down-regulated by curcumin treatment through inhibition of IκBα kinase activation and IκBα phosphorylation. Conclusions Combining curcumin with conventional chemotherapeutic agents such as 5-FU could provide more effective treatment strategies against chemoresistant colon cancer

Dual sphingosine kinase inhibitor SKI-II enhances sensitivity to 5-fluorouracil in hepatocellular carcinoma cells via suppression of osteopontin and FAK/IGF-1R signalling

DOE Office of Scientific and Technical Information (OSTI.GOV)

Grbčić, Petra; Tomljanović, Ivana; Klobučar, Marko

Hepatocellular carcinoma (HCC) represents the third leading cause of cancer-related deaths globally. Although 5-Fluorouracil (5-FU) is used as the first choice treatment for advanced HCC, it exerts poor efficacy and is associated with acquired and intrinsic resistance. Sphingosine kinases (Sphk) 1 and 2 play tumour-promoting roles in different cancer types including HCC and thus represent promising pharmacological targets. In the present study, we have investigated for the first time the anticancer efficacy and underlying molecular mechanisms of combined administration of 5-FU and dual Sphk1/Sphk2 inhibitor SKI-II (4-[[4-(4-chlorophenyl)-1,3-thiazol-2-yl]amino]phenol) in HepG2 hepatocellular carcinoma cells. Here, we report that co-administration of 5-FU andmore » SKI-II at low sub-toxic concentrations of 20 μM and 5 μM, respectively, synergistically inhibit cell proliferation, markedly reduce cell migration and the clonogenic survival, and increase apoptosis induction in HepG2 cells. Additional Western blot analyses have shown that possible mechanisms underlying enhanced sensitivity to 5-FU induced by dual Sphk 1/2 inhibition could include abrogation of FAK-regulated IGF-1R activity and down-regulation of osteopontin expression culminating in the inhibition of NF-κB activity and its downstream signalling mediated by sirtuin 1 and p38 MAPK. Our results clearly show that pharmacological blockade of both Sphk isoforms represents a promising strategy to boost the anti-tumour efficacy of 5-FU and provide a rationale for further in vivo studies into the possible use of SKI-II inhibitor as an adjunct to 5-FU treatment in HCC. - Highlights: • Pharmacological inhibition of sphingosine kinase 1/2 augments cytotoxic effects of 5-FU in HepG2 cells. • Co-administration of 5-FU and SKI-II synergistically inhibits cell proliferation, reduces cell migration and clonogenic survival and increases apoptosis induction in HepG2 cells. • The mechanism underlying

E-ELT M5 field stabilisation unit scale 1 demonstrator design and performances evaluation

NASA Astrophysics Data System (ADS)

Casalta, J. M.; Barriga, J.; Ariño, J.; Mercader, J.; San Andrés, M.; Serra, J.; Kjelberg, I.; Hubin, N.; Jochum, L.; Vernet, E.; Dimmler, M.; Müller, M.

2010-07-01

The M5 Field stabilization Unit (M5FU) for European Extremely Large Telescope (E-ELT) is a fast correcting optical system that shall provide tip-tilt corrections for the telescope dynamic pointing errors and the effect of atmospheric tiptilt and wind disturbances. A M5FU scale 1 demonstrator (M5FU1D) is being built to assess the feasibility of the key elements (actuators, sensors, mirror, mirror interfaces) and the real-time control algorithm. The strict constraints (e.g. tip-tilt control frequency range 100Hz, 3m ellipse mirror size, mirror first Eigen frequency 300Hz, maximum tip/tilt range +/- 30 arcsec, maximum tiptilt error < 40 marcsec) have been a big challenge for developing the M5FU Conceptual Design and its scale 1 demonstrator. The paper summarises the proposed design for the final unit and demonstrator and the measured performances compared to the applicable specifications.

Xue-fu-Zhu-Yu decoction protects rats against retinal ischemia by downregulation of HIF-1α and VEGF via inhibition of RBP2 and PKM2.

PubMed

Tan, Shu-Qiu; Geng, Xue; Liu, Jorn-Hon; Pan, Wynn Hwai-Tzong; Wang, Li-Xiang; Liu, Hui-Kang; Hu, Lei; Chao, Hsiao-Ming

2017-07-14

Retinal ischemia-related eye diseases result in visual dysfunction. This study investigates the protective effects and mechanisms of Xue-Fu-Zhu-Yu decoction (XFZYD) with respect to retinal ischemia. Retinal ischemia (I) was induced in Wistar rats by a high intraocular pressure (HIOP) of 120 mmHg for 1 h, which was followed by reperfusion of the ischemic eye; the fellow untreated eye acted as a control. Electroretinogram (ERG), biochemistry and histopathology investigations were performed. Significant ischemic changes occurred after ischemia including decreased ERG b-wave ratios, less numerous retinal ganglion cells (RGCs), reduced inner retinal thickness, fewer choline acetyltransferase (ChAT) labeled amacrine cell bodies, increased glial fibrillary acidic protein (GFAP) immunoreactivity and increased vimentin Müller immunolabeling. These were accompanied by significant increases in the mRNA/protein concentrations of vascular endothelium growth factor, hypoxia-inducible factor-1α, pyruvate kinase M2 and retinoblastoma-binding protein 2. The ischemic changes were concentration-dependently and significantly altered when XFZYD was given for seven consecutive days before or after retina ischemia, compared to vehicle. These alterations included enhanced ERG b-wave amplitudes, more numerous RGCs, enhanced inner retinal thickness, a greater number of ChAT immunolabeled amacrine cell bodies and decreased GFAP/vimentin immunoreactivity. Furthermore, decreased mRNA levels of VEGF, HIF-1α, PKM2, and RBP2 were also found. Reduced protein concentrations of VEGF, HIF-1α, PKM2, and RBP2 were also demonstrated. Furthermore, there was an inhibition of the ischemia-associated increased ratios (target protein/β-actin) in the protein levels of VEGF, HIF-1α, PKM2, and RBP2, which were induced by Shikonin, JIB-04 or Avastin. XFZYD would seem to protect against well-known retinal ischemic changes via a synergistic inhibition of RBP2 and PKM2, as well as down-regulation of HIF-1�

Understanding and Preventing Loss to Follow-up: Experiences From the Spinal Cord Injury Model Systems.

PubMed

Kim, Hwasoon; Cutter, Gary R; George, Brandon; Chen, Yuying

2018-01-01

Background: One of the most critical threats to the validity of any longitudinal research is the bias caused by study attrition. Prevention efforts should be focused on those individuals at high risk of non-participation to improve the generalizability of study findings. Objective: To identify demographic and clinical factors associated with loss to follow-up (FU) at post-injury years 1 to 35 among 25,871 people with spinal cord injury (SCI) enrolled in the National Spinal Cord Injury Database. Methods: Loss to FU was defined as no research information obtained from participants who were eligible for the planned data collection. Generalized linear mixed models were used for analysis of factors at each post-injury year. Results: The loss to FU rates were 23.1% and 32.9% for post-injury years 1 and 5, respectively, and remained >40% between post-injury years 20 and 35. The FU rate varied by study sites and was improved in recent injury cohorts. People who were more seriously injured and those who attained higher levels of education were more likely to return for FU than their counterparts. People who were at risk of being marginalized in society (non-whites, those with less education, the unemployed, victims of violence, and those with no health insurance) had the highest odds of being lost to FU across all post-injury years. Conclusion: These findings can be used to identify individuals who are less likely to participate in follow-up, which may allow targeted attention to improve their response rate.

Overcoming multidrug resistance in 2D and 3D culture models by controlled drug chitosan-graft poly(caprolactone)-based nanoparticles.

PubMed

Shi, Wei-Bin; Le, Van-Minh; Gu, Chun-Hua; Zheng, Yuan-Hong; Lang, Mei-Dong; Lu, Yan-Hua; Liu, Jian-Wen

2014-04-01

The principal limitations of chemotherapy are dose-limiting systemic toxicity and the development of multidrug-resistant phenotypes. The aim of this study was to investigate the efficiency of a new sustained drug delivery system based on chitosan and ε-caprolactone to overcome multidrug resistance in monolayer and drug resistance associated with the three-dimensional (3D) tumor microenvironment in our established 3D models. The 5-fluorouracil (5-FU)-loaded nanoparticles (NPs) were characterized by transmission electron microscope and dynamic light scattering, and its released property was determined at different pH values. 5-FU/NPs exhibited well-sustained release properties and markedly enhanced the cytotoxicity of 5-FU against HCT116/L-OHP or HCT8/VCR MDR cells in two-dimensional (2D) and its parental cells in 3D collagen gel culture with twofold to threefold decrease in the IC50 values, as demonstrated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, Hoechst/propidium iodide staining and flow cytometry analysis. Furthermore, the possible mechanism was explored by high-performance liquid chromatography and rhodamine 123 accumulation experiment. Overall, the results demonstrated that 5-FU/NPs increase intracellular concentration of 5-FU and enhance its anticancer efficiency by inducing apoptosis. It was suggested that this novel NPs are a promising carrier to decrease toxic of 5-FU and has the potential to reverse the forms of both intrinsic and acquired drug resistance in 2D and 3D cultures. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

Isoconversional approach for non-isothermal decomposition of un-irradiated and photon-irradiated 5-fluorouracil.

PubMed

Mohamed, Hala Sh; Dahy, AbdelRahman A; Mahfouz, Refaat M

2017-10-25

Kinetic analysis for the non-isothermal decomposition of un-irradiated and photon-beam-irradiated 5-fluorouracil (5-FU) as anti-cancer drug, was carried out in static air. Thermal decomposition of 5-FU proceeds in two steps. One minor step in the temperature range of (270-283°C) followed by the major step in the temperature range of (285-360°C). The non-isothermal data for un-irradiated and photon-irradiated 5-FU were analyzed using linear (Tang) and non-linear (Vyazovkin) isoconversional methods. The results of the application of these free models on the present kinetic data showed quite a dependence of the activation energy on the extent of conversion. For un-irradiated 5-FU, the non-isothermal data analysis indicates that the decomposition is generally described by A3 and A4 modeles for the minor and major decomposition steps, respectively. For a photon-irradiated sample of 5-FU with total absorbed dose of 10Gy, the decomposition is controlled by A2 model throughout the coversion range. The activation energies calculated in case of photon-irradiated 5-FU were found to be lower compared to the values obtained from the thermal decomposition of the un-irradiated sample probably due to the formation of additional nucleation sites created by a photon-irradiation. The decomposition path was investigated by intrinsic reaction coordinate (IRC) at the B3LYP/6-311++G(d,p) level of DFT. Two transition states were involved in the process by homolytic rupture of NH bond and ring secession, respectively. Published by Elsevier B.V.

Recurrence rates and patient assessed outcomes of 0.5% 5-fluorouracil in combination with salicylic acid treating actinic keratoses.

PubMed

Stockfleth, Eggert; Zwingers, Thomas; Willers, Christoph

2012-01-01

Actinic keratoses (AK) have been classified as early in situ squamous cell carcinomas and should be treated. To evaluate the clinical benefit of 5-fluorouracil 0.5%/salicylic acid 10.0% (5-FU/SA) versus 3% diclofenac/hyaluronic acid (HA) for the treatment of AK and report patients' assessments of efficacy, tolerability and practicability. Randomised, placebo-controlled, double-blind, parallel-group, multicentre trial. Patients received topical 0.5% 5-FU/SA once daily, its vehicle or diclofenac/HA twice daily for maximum of 12 weeks. Lesion recurrence rates were evaluated at 6 and 12 months after end of treatment (EOT). Patients' assessments were evaluated at 6 weeks, EOT, post-treatment (PT) visit, 6 and 12 months. At 12 months 85.8% of lesions did not recur in the 5-FU/SA group compared to 79.8% (p=0.04419) in the vehicle and 81.0% (p=0.02476) in the diclofenac/HA groups. At PT visit 93.2% patients (n=163/175) in the 5-FU/SA group rated clinical improvement as "very good" or "good" compared to vehicle (66.7%, n=62/93, p<0.0001) and diclofenac/HA (81.6%, n=142/174, p<0.0001). Local side effects (inflammation and burning) were more common with 0.5% FU/SA but in general did not lead to discontinuation of therapy. Overall, patients were satisfied with the therapy. At 12 months, there were no differences in practicability and handling between treatments. Topical 0.5% 5-FU/SA demonstrated superior sustained clinical efficacy versus diclofenac/HA with acceptable tolerability. Patient satisfaction was high.

Modified 5-fluorouracil: Uridine phosphorylase inhibitor

NASA Astrophysics Data System (ADS)

Lashkov, A. A.; Shchekotikhin, A. A.; Shtil, A. A.; Sotnichenko, S. E.; Mikhailov, A. M.

2016-09-01

5-Fluorouracil (5-FU) is a medication widely used in chemotherapy to treat various types of cancer. Being a substrate for the reverse reaction catalyzed by uridine phosphorylase (UPase), 5-FU serves as a promising prototype molecule (molecular scaffold) for the design of a selective UPase inhibitor that enhances the antitumor activity of 5-FU and exhibits intrinsic cytostatic effects on cancer cells. The chemical formula of the new compound, which binds to the uracil-binding site and, in the presence of a phosphate anion, to the phosphate-binding site of UPase, is proposed and investigated by molecular simulation methods.

SIDE-EFFECTS OF COMBINED RADIATION AND CHEMOTHERAPY IN THE TREATMENT OF MALIGNANT TUMORS

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ottoman, R.E.; Langdon, E.A.; Rochlin, D.B.

1963-12-01

A study was made of the effects of 5-fluorouracil (FU) and x irradiation, separately and in combination, upon multiple metastatic tumors within individual patients. Fourteen cases satisfied the criteria for a controlled study. In 4, the effects of irradiation alone were greater than the combination, in 4 the effects were equal, and in 6 the effects of irradiation were less than those of combination therapy. This study failed to demonstrate a significant alteration in the tumor response by the addition of FU to x irradiation. Four instances of unusual reactions in previously irradiated skin were noted following FU administration. (auth)

Enhanced anticancer efficacy and tumor targeting through folate-PEG modified nanoliposome loaded with 5-fluorouracil

NASA Astrophysics Data System (ADS)

Le, Van Minh; Tran Nho, Trung Duc; Trieu Ly, Hai; Vo, Thanh Sang; Dung Nguyen, Hoang; Thu Huong Phung, Thi; Zou, Aihua; Liu, Jianwen

2017-03-01

Cancer targeted therapies have attracted considerable attention over the past year. Recently, 5-fluouracil (5-FU), which has high toxicity to normal cells and short half-life associated with rapid metabolism, is one of the most commonly used therapies in the treatment of cancer. In this study the folic acid-conjugated pegylated nanoliposomes were synthesized and then loaded into them with 5-FU to improve the anti-tumor efficacy. The average size of liposomes (LPs) was about 52.7 nm which was identified by TEM. In the liposome uptake studies, the level uptake of folate-conjugated liposomes has increased compared to non-conjugated LPs according to LPs concentration, incubation time and presence of concentration of free folic acid (FA). The MTT assay and apoptotic test were carried out in HCT116 and MCF-7 cells for 24 or 48 h. The results revealed that the folate-PEG modified 5-Fu loaded nanoliposomes had strong cytotoxicity to cancer cell compared to pure 5-FU or PEG modified 5-FU loaded liposomes in a concentration- and time-dependent manner, and mainly enhanced the cancer cell death through folate-mediated endocytosis. Hence, the folate-PEG modified nanoliposome is a potential targeted drug-delivery system for the treatment of FR-positive cancers.

[Efficacy and side-effects of docetaxel combined with cisplatin on the treatment of local advanced esophageal cancer with concomitant radiation therapy].

PubMed

Zhang, Ting-rong; Zhao, Tao; Xu, Xin; Gu, Xiao-wei; Pan, Yu-kai

2010-10-01

To investigate the therapeutical effect and side-effect of docetaxel combined with cisplatin (DDP) on the treatment of local advanced esophageal cancer with concomitant radiation therapy. Ninety patients with LOCAL advanced esophageal squamous cell carcinoma were divided into two groups: (DDP + 5-Fu) group and (docetaxel + DDP) group. Chemotherapy was carried out every 4 weeks for a total of 4 courses. The radiation dose was 50.4 Gy/28FX. The median survival time of patients in the (DDP + 5-Fu) group was 16 months and that in (docetaxel + DDP) group was 21 months (P = 0.0278). The 3-year survival rate in the (docetaxel + DDP) group was obviously higher than that in the (DDP + 5-Fu) group (23.9% vs. 12.1%). The ORR in (docetaxel + DDP) group (84.5%) was significantly higher than that in the (DDP + 5-Fu) group (71.1%) (P = 0.025). No significant differences were observed in the incidence of side-effects in the two groups. The conventional dose chemotherapy of docetaxel + DDP with concomitant radiation therapy showed a better partial remission rate and long-term survival rate for the treatment of local advanced esophageal cancer than the traditional chemotherapy (DDP + 5-Fu) with concomitant radiation therapy and the side-effects are not increased.

5-Fluorouracil-resistant strain of Methanobacterium thermoautotrophicum.

PubMed

Nagle, D P; Teal, R; Eisenbraun, A

1987-09-01

Growth of Methanobacterium thermoautotrophicum Marburg is inhibited by the pyrimidine, 5-fluorouracil (FU). It was shown previously that methanogenesis is not inhibited to the same extent as growth. A spontaneously occurring FU-resistant strain (RTAE-1) was isolated from a culture of strain Marburg. The growth of both strains was inhibited by 5-fluorodeoxyuridine but not 5-fluorocytosine, and the wild type was more susceptible to inhibition by 5-azauracil and 6-azauracil than was strain RTAE-1. The cellular targets for the pyrimidine analogs are not known. When the accumulation of 14C-labeled uracil or FU by the two strains was compared, the wild type took up 15-fold more radiolabel per cell than did the FU-resistant strain. In the wild type, radiolabel from uracil was incorporated into the soluble pool, RNA, and DNA. The metabolism of uracil appeared to involve a uracil phosphoribosyltransferase activity. Strain Marburg extracts contained this enzyme, whereas FU-resistant strain RTAE-1 extracts had less than 1/10 as much activity. Although it is possible that a change in permeability to the compounds plays a role in the stable resistance of strain RTAE-1, the fact that it lacks the ability to metabolize pyrimidines to nucleotides is sufficient to account for its phenotype.

5-Fluorouracil-resistant strain of Methanobacterium thermoautotrophicum.

PubMed Central

Nagle, D P; Teal, R; Eisenbraun, A

1987-01-01

Growth of Methanobacterium thermoautotrophicum Marburg is inhibited by the pyrimidine, 5-fluorouracil (FU). It was shown previously that methanogenesis is not inhibited to the same extent as growth. A spontaneously occurring FU-resistant strain (RTAE-1) was isolated from a culture of strain Marburg. The growth of both strains was inhibited by 5-fluorodeoxyuridine but not 5-fluorocytosine, and the wild type was more susceptible to inhibition by 5-azauracil and 6-azauracil than was strain RTAE-1. The cellular targets for the pyrimidine analogs are not known. When the accumulation of 14C-labeled uracil or FU by the two strains was compared, the wild type took up 15-fold more radiolabel per cell than did the FU-resistant strain. In the wild type, radiolabel from uracil was incorporated into the soluble pool, RNA, and DNA. The metabolism of uracil appeared to involve a uracil phosphoribosyltransferase activity. Strain Marburg extracts contained this enzyme, whereas FU-resistant strain RTAE-1 extracts had less than 1/10 as much activity. Although it is possible that a change in permeability to the compounds plays a role in the stable resistance of strain RTAE-1, the fact that it lacks the ability to metabolize pyrimidines to nucleotides is sufficient to account for its phenotype. PMID:3624203

Nogo-B receptor promotes the chemoresistance of human hepatocellular carcinoma via the ubiquitination of p53 protein

PubMed Central

Long, Fei; Liu, Ying; Liu, Zhenzhen; Li, Song; Yang, Xuejun; Sun, Deguang; Wang, Haibo; Liu, Qinlong; Liang, Rui; Li, Yan; Gao, Zhenming; Shao, Shujuan; Miao, Qing Robert; Wang, Liming

2016-01-01

Nogo-B receptor (NgBR), a type I single transmembrane domain receptor is the specific receptor for Nogo-B. Our previous work demonstrated that NgBR is highly expressed in breast cancer cells, where it promotes epithelial mesenchymal transition (EMT), an important step in metastasis. Here, we show that both in vitro and in vivo increased expression of NgBR contributes to the increased chemoresistance of Bel7402/5FU cells, a stable 5-FU (5-Fluorouracil) resistant cell line related Bel7402 cells. NgBR knockdown abrogates S-phase arrest in Bel7402/5FU cells, which correlates with a reduction in G1/S phase checkpoint proteins p53 and p21. In addition, NgBR suppresses p53 protein levels through activation of the PI3K/Akt/MDM2 pathway, which promotes p53 degradation via the ubiquitin proteasome pathway and thus increases the resistance of human hepatocellular cancer cells to 5-FU. Furthermore, we found that NgBR expression is associated with a poor prognosis of human hepatocellular carcinoma (HCC) patients. These results suggest that targeting NgBR in combination with chemotherapeutic drugs, such as 5-FU, could improve the efficacy of current anticancer treatments. PMID:26840457

Strategic Studies Quarterly. Volume 8, Number 1, Spring 2014

DTIC Science & Technology

2014-01-01

Charles E. Costanzo, PhD Christopher M. Hemmer, PhD Kimberly A. Hudson, PhD Nori Katagiri, PhD Zachary J . Zwald, PhD Strategic Studies Quarterly (SSQ...first successful carrier-based takeoff and landing with the Jian-15 ( J -15) in November 2012, certified its first group of aircraft carrier pilots and...September 2013.3 The Liaoning will continue to conduct short deployments and shipboard aviation training until 2015 to 2016, when China’s first J -15

[On academic thought and clinical application of LI Yan-Fang's middle-warmer energy method].

PubMed

Li, Li-Jun

2010-10-01

The present paper introduces LI Yan-Fang's middle-warmer energy method from acupoint selection, needling methods, treatment principle and his clinical experiences in treatment of stroke and insomnia etc. The acupuncture prescription of this method consist of Shangwan (CV 13), Zhongwan (CV 12), Jianli (CV 11), Xiawan (CV 10), Shuifen (CV 9), Huangshu (KI 16) and Qihai (CV 6) etc as the main acupoints combined with strict manipulation and depth of needling to treat clinical diseases.

MIMO Radar - Diversity Means Superiority

DTIC Science & Technology

2007-10-01

Jian 5e. TASK NUMBER 5f. WORK UNIT NUMBER 7. PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ESI 8. PERFORMING ORGANIZATION Department of Electrical and...several estimators for the proposed MIMO radar system. The remainder of this report is organized as follows. Chapter 2 pres ,lt> t hc MIMO radar...A 17) with 0 denoting the Kronecker product. Substituting Equations (A 9) - (A 7) into (A ()). and after soic ( I I hIx II, nipulations, we get CRB(O

76 FR 55614 - Airworthiness Directives; Pacific Aerospace Limited Airplanes

Federal Register 2010, 2011, 2012, 2013, 2014

2011-09-08

...-0971; Directorate Identifier 2011-CE-030-AD] RIN 2120-AA64 Airworthiness Directives; Pacific Aerospace... (AD) for Pacific Aerospace Limited Models FU24-954 and FU24A-954 airplanes modified with an unapproved... INFORMATION CONTACT: Karl Schletzbaum, Aerospace Engineer, FAA, Small Airplane Directorate, 901 Locust, Room...

Adjuvant treatment or primary topical monotherapy for ocular surface squamous neoplasia: a systematic review.

PubMed

Viani, Gustavo Arruda; Fendi, Ligia Issa de

2017-01-01

In this systematic review, we evaluated studies involving adjuvant and primary topical treatment for ocular surface squamous neoplasia (OSSN). The findings were: (i) adjuvant 5-fluorouracil (5-FU) reduces the risk of relapse after surgical excision with mild side effects [level Ib, grade of recommendation (GR) A]. (ii) Primary topical mitomycin (MMC) produces a high rate of complete response, low recurrence rate, and mild side effects (level Ib, GR A). (iii) Primary chemotherapy versus adjuvant chemotherapy produce similar rates of recurrence, with no significant difference (level IIb, GR B). (iv) Adjuvant 5-FU versus MMC showed no significant differences, with mild side effects in both groups and a better toxicity profile for MMC (level III, GR C). (v) Primary topical 5-FU versus MMC versus interferon (IFN) showed similar rates of tumor recurrence, mild side effects for all drugs, and more severe side effects in the 5-FU arm, followed successively by MMC and IFN (level III, GR C).

Gene Amplification and Point Mutations in Pyrimidine Metabolic Genes in 5-Fluorouracil Resistant Leishmania infantum

PubMed Central

Ritt, Jean-François; Raymond, Frédéric; Leprohon, Philippe; Légaré, Danielle; Corbeil, Jacques; Ouellette, Marc

2013-01-01

Background The human protozoan parasites Leishmania are prototrophic for pyrimidines with the ability of both de novo biosynthesis and uptake of pyrimidines. Methodology/Principal Findings Five independent L. infantum mutants were selected for resistance to the pyrimidine analogue 5-fluorouracil (5-FU) in the hope to better understand the metabolism of pyrimidine in Leishmania. Analysis of the 5-FU mutants by comparative genomic hybridization and whole genome sequencing revealed in selected mutants the amplification of DHFR-TS and a deletion of part of chromosome 10. Point mutations in uracil phosphorybosyl transferase (UPRT), thymidine kinase (TK) and uridine phosphorylase (UP) were also observed in three individual resistant mutants. Transfection experiments confirmed that these point mutations were responsible for 5-FU resistance. Transport studies revealed that one resistant mutant was defective for uracil and 5-FU import. Conclusion/Significance This study provided further insights in pyrimidine metabolism in Leishmania and confirmed that multiple mutations can co-exist and lead to resistance in Leishmania. PMID:24278495

Formation and characterization of β-cyclodextrin (β-CD) - polyethyleneglycol (PEG) - polyethyleneimine (PEI) coated Fe3O4 nanoparticles for loading and releasing 5-Fluorouracil drug.

PubMed

Prabha, G; Raj, V

2016-05-01

In this work, β-cyclodextrin (β-CD) - polyethyleneglycol (PEG) - polyethyleneimine (PEI) coated iron oxide nanoparticles (Fe3O4-β-CD-PEG-PEI) were developed as drug carriers for drug delivery applications. The 5- Fluorouracil (5-FU) was chosen as model drug molecule. The developed nanoparticles (Fe3O4-β-CD-PEG-PEI) were characterized by various techniques such as Fourier transform infrared (FTIR) spectroscopy, X-ray diffraction (XRD), Scanning electron microscopy (SEM), transmission electron microscopy (TEM) and vibrating sample magnetometry (VSM). The average particles size range of 5-FU loaded Fe3O4-β-CD, Fe3O4-β-CD-PEG and Fe3O4-β-CD-PEG-PEI nanoparticles were from 151 to 300nm and zeta potential value of nanoparticles were from -43mV to -20mV as measured using Malvern Zetasizer. Finally, encapsulation efficiency (EE), loading capacity (LC) and in-vitro drug release performance of 5-FU drug loaded Fe3O4-β-CD, Fe3O4-β-CD-PEG and Fe3O4-β-CD-PEG-PEI nanoparticles was evaluated by UV-vis spectroscopy. In-vitro cytotoxicity tests investigated by MTT assay indicate that 5-FU loaded Fe3O4-β-CD-PEG-PEI nanoparticles were toxic to cancer cells and non-toxic to normal cells. The in-vitro release behavior of 5-FU from drug (5-FU) loaded Fe3O4-β-CD-PEG-PEI composite at different pH values and temperature was studied. It was found that 5-FU was released faster in pH 6.8 than in the acidic mediums (pH 1.2), and the released quantity was higher. Therefore, the newly prepared Fe3O4-β-CD-PEG-PEI carrier exhibits a promising potential capability for anticancer drug delivery in tumor therapy. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

A 5-fluorouracil-loaded floating gastroretentive hollow microsphere: development, pharmacokinetic in rabbits, and biodistribution in tumor-bearing mice

PubMed Central

Huang, Yu; Wei, Yumeng; Yang, Hongru; Pi, Chao; Liu, Hao; Ye, Yun; Zhao, Ling

2016-01-01

5-Fluorouracil (5-FU) was loaded in hollow microspheres to improve its oral bioavailability. 5-FU hollow microspheres were developed by a solvent diffusion–evaporation method. The effect of Span 80 concentration, ether/ethanol volume ratio, and polyvinyl pyrrolidone/ethyl cellulose weight ratio on physicochemical characteristics, floating, and in vitro release behaviors of 5-FU hollow microspheres was investigated and optimized. The formulation and technology composed of Span 80 (1.5%, w/v), ether/ethanol (1.0:10.0, v/v), and polyvinyl pyrrolidone/ethyl cellulose (1.0:10.0, w/w) were employed to develop three batch samples, which showed an excellent reproducibility. The microspheres were spherical with a hollow structure with high drug loading amount (28.4%±0.5%) and production yield (74.2%±0.6%); they exhibited excellent floating and sustained release characteristics in simulated gastric and intestinal fluid. Pharmacokinetic studies demonstrated that 5-FU hollow microspheres significantly enhanced oral bioavailability (area under curve, [AUC](0−t): 12.53±1.65 mg/L*h vs 7.80±0.83 and 5.82±0.83 mg/L*h) with longer elimination half-life (t1/2) (15.43±2.12 hours vs 2.25±0.22 and 1.43±0.18 hours) and mean residence time (7.65±0.97 hours vs 3.61±0.41 and 2.34±0.35 hours), in comparison with its solid microspheres and powder. In vivo distribution results from tumor-bearing nude mice demonstrated that the animals administered with 5-FU hollow microspheres had much higher drug content in tumor, plasma, and stomach at 1 and 8 hours except for 0.5 hours sample collection time point in comparison with those administered with 5-FU solid microspheres and its powder. These results suggested that the hollow microspheres would be a promising controlled drug delivery system for an oral chemotherapy agent like 5-FU. PMID:27042001

A 5-fluorouracil-loaded floating gastroretentive hollow microsphere: development, pharmacokinetic in rabbits, and biodistribution in tumor-bearing mice.

PubMed

Huang, Yu; Wei, Yumeng; Yang, Hongru; Pi, Chao; Liu, Hao; Ye, Yun; Zhao, Ling

2016-01-01

5-Fluorouracil (5-FU) was loaded in hollow microspheres to improve its oral bioavailability. 5-FU hollow microspheres were developed by a solvent diffusion-evaporation method. The effect of Span 80 concentration, ether/ethanol volume ratio, and polyvinyl pyrrolidone/ethyl cellulose weight ratio on physicochemical characteristics, floating, and in vitro release behaviors of 5-FU hollow microspheres was investigated and optimized. The formulation and technology composed of Span 80 (1.5%, w/v), ether/ethanol (1.0:10.0, v/v), and polyvinyl pyrrolidone/ethyl cellulose (1.0:10.0, w/w) were employed to develop three batch samples, which showed an excellent reproducibility. The microspheres were spherical with a hollow structure with high drug loading amount (28.4%±0.5%) and production yield (74.2%±0.6%); they exhibited excellent floating and sustained release characteristics in simulated gastric and intestinal fluid. Pharmacokinetic studies demonstrated that 5-FU hollow microspheres significantly enhanced oral bioavailability (area under curve, [AUC](0-t): 12.53±1.65 mg/L(*)h vs 7.80±0.83 and 5.82±0.83 mg/L(*)h) with longer elimination half-life (t1/2) (15.43±2.12 hours vs 2.25±0.22 and 1.43±0.18 hours) and mean residence time (7.65±0.97 hours vs 3.61±0.41 and 2.34±0.35 hours), in comparison with its solid microspheres and powder. In vivo distribution results from tumor-bearing nude mice demonstrated that the animals administered with 5-FU hollow microspheres had much higher drug content in tumor, plasma, and stomach at 1 and 8 hours except for 0.5 hours sample collection time point in comparison with those administered with 5-FU solid microspheres and its powder. These results suggested that the hollow microspheres would be a promising controlled drug delivery system for an oral chemotherapy agent like 5-FU.

Randomized trial of calcipotriol combined with 5-fluorouracil for skin cancer precursor immunotherapy

PubMed Central

Cunningham, Trevor J.; Tabacchi, Mary; Eliane, Jean-Pierre; Tuchayi, Sara Moradi; Manivasagam, Sindhu; Mirzaalian, Hengameh; Turkoz, Ahu; Kopan, Raphael; Schaffer, Andras; Saavedra, Arturo P.; Wallendorf, Michael; Cornelius, Lynn A.; Demehri, Shadmehr

2016-01-01

BACKGROUND. Actinic keratosis is a precursor to cutaneous squamous cell carcinoma. Long treatment durations and severe side effects have limited the efficacy of current actinic keratosis treatments. Thymic stromal lymphopoietin (TSLP) is an epithelium-derived cytokine that induces a robust antitumor immunity in barrier-defective skin. Here, we investigated the efficacy of calcipotriol, a topical TSLP inducer, in combination with 5-fluorouracil (5-FU) as an immunotherapy for actinic keratosis. METHODS. The mechanism of calcipotriol action against skin carcinogenesis was examined in genetically engineered mouse models. The efficacy and safety of 0.005% calcipotriol ointment combined with 5% 5-FU cream were compared with Vaseline plus 5-FU for the field treatment of actinic keratosis in a randomized, double-blind clinical trial involving 131 participants. The assigned treatment was self-applied to the entirety of the qualified anatomical sites (face, scalp, and upper extremities) twice daily for 4 consecutive days. The percentage of reduction in the number of actinic keratoses (primary outcome), local skin reactions, and immune activation parameters were assessed. RESULTS. Calcipotriol suppressed skin cancer development in mice in a TSLP-dependent manner. Four-day application of calcipotriol plus 5-FU versus Vaseline plus 5-FU led to an 87.8% versus 26.3% mean reduction in the number of actinic keratoses in participants (P < 0.0001). Importantly, calcipotriol plus 5-FU treatment induced TSLP, HLA class II, and natural killer cell group 2D (NKG2D) ligand expression in the lesional keratinocytes associated with a marked CD4+ T cell infiltration, which peaked on days 10–11 after treatment, without pain, crusting, or ulceration. CONCLUSION. Our findings demonstrate the synergistic effects of calcipotriol and 5-FU treatment in optimally activating a CD4+ T cell–mediated immunity against actinic keratoses and, potentially, cancers of the skin and other organs. TRIAL

Pre-exposure to 50 Hz-electromagnetic fields enhanced the antiproliferative efficacy of 5-fluorouracil in breast cancer MCF-7 cells

PubMed Central

Chen, Sha; Sun, Xiongshan; Guan, Xiao; Yang, Yao; Peng, Bingjie; Pan, Xiaodong; Li, Jinfang; Yi, Weijing; Li, Peng; Zhang, Hongwei; Feng, Dongfang; Chen, An; Li, Xiaohui; Yin, Zuoming

2018-01-01

Resistance to 5-fluorouracil (5-FU) and its induced immune suppression have prevented its extensive application in the clinical treatment of breast cancer. In this study, the combined effect of 50 Hz-EMFs and 5-FU in the treatment of breast cancer was explored. MCF-7 and MCF10A cells were pre-exposed to 50 Hz-EMFs for 0, 2, 4, 8 and 12 h and then treated with different concentrations of 5-FU for 24 h; cell viability was analyzed by MTT assay and flow cytometry. After pre-exposure to 50 Hz-EMFs for 12 h, apoptosis and cell cycle distribution in MCF-7 and MCF10A cells were detected via flow cytometry and DNA synthesis was measured by EdU incorporation assay. Apoptosis-related and cell cycle-related gene and protein expression levels were monitored by qPCR and western blotting. Pre-exposure to 50 Hz-EMFs for 12 h enhanced the antiproliferative effect of 5-FU in breast cancer cell line MCF-7 in a dose-dependent manner but not in normal human breast epithelial cell line MCF10A. Exposure to 50 Hz-EMFs had no effect on apoptosis and P53 expression of MCF-7 and MCF10A cells, whereas it promoted DNA synthesis, induced entry of MCF-7 cells into the S phase of cell cycle, and upregulated the expression levels of cell cycle-related proteins Cyclin D1 and Cyclin E. Considering the pharmacological mechanisms of 5-FU in specifically disrupting DNA synthesis, this enhanced inhibitory effect might have resulted from the specific sensitivity of MCF7 cells in active S phase to 5-FU. Our findings demonstrate the enhanced cytotoxic activity of 5-FU on MCF7 cells through promoting entry into the S phase of the cell cycle via exposure to 50 Hz-EMFs, which provides a novel method of cancer treatment based on the combinatorial use of 50 Hz-EMFs and chemotherapy. PMID:29617363

5-Fluorouracil Adjuvant Chemotherapy Does Not Increase Survival in Patients with CpG Island Methylator Phenotype Colorectal Cancer

PubMed Central

Jover, Rodrigo; Nguyen, Thuy-Phuong; Pérez-Carbonell, Lucía; Zapater, Pedro; Payá, Artemio; Alenda, Cristina; Rojas, Estefanía; Cubiella, Joaquín; Balaguer, Francesc; Morillas, Juan D.; Clofent, Juan; Bujanda, Luis; Reñé, Josep M; Bessa, Xavier; Xicola, Rosa M.; Nicolás-Pérez, David; Castells, Antoni; Andreu, Montserrat; Llor, Xavier; Boland, C. Richard; Goel, Ajay

2011-01-01

Background & Aims 5-FU-based adjuvant chemotherapy does not increase survival times of patients with colorectal tumors with microsatellite instability. We determined the response of patients with colorectal tumors with the CpG island methylator phenotype (CIMP) to 5-FU-based therapy. Methods We analyzed a population-based cohort of 302 patients with colorectal cancer (CRC) for a median follow-up time of 50.7 months. CIMP status was determined by analysis of the CACNAG1, SOCS1, RUNX3, NEUROG1, and MLH1 promoters; tumors were considered to be CIMP-positive (CIMP+) if at least 3 promoters were methylated. Results Tumors from 29.5% (89/302) of patients were CIMP+; this did not influence disease-free survival (log rank=.26). Of tumors of TNM stages II–III (n=196), 32.7% were CIMP+. Among patients with CRC stages II–III who did not receive adjuvant 5-FU chemotherapy, those with CIMP+ tumors had longest times of disease-free survival (log rank=.04); patients with CIMP+ tumors who received chemotherapy had shorter times of disease-free survival (log rank=0.02). In patients with CIMP-negative tumors, adjuvant 5-FU chemotherapy significantly increased time of disease-free survival (log-rank=.00001). However, in patients with CIMP+ tumors, adjuvant 5-FU chemotherapy did not affect time of disease-free survival (log rank=.7). Multivariate analysis showed a significant, independent interaction between 5-FU treatment and CIMP status (hazard ratio [HR]=0.6; 95% confidence interval [CI], .5–.8). Among patients with CIMP+ tumors, adjuvant chemotherapy was not an independent predictor of outcome (HR=0.8; 95% CI, 0.3–2.0). In patients who did not receive adjuvant 5-FU chemotherapy, CIMP status was the only independent predictor of survival (HR=2.0; 95% CI, 1.1–3.8) Conclusion Patients with CIMP+ colorectal tumors do not benefit from 5-FU–based adjuvant chemotherapy. PMID:21185836

Assessment of toxicity and genotoxicity of low doses of 5-fluorouracil in zebrafish (Danio rerio) two-generation study.

PubMed

Kovács, Róbert; Csenki, Zsolt; Bakos, Katalin; Urbányi, Béla; Horváth, Ákos; Garaj-Vrhovac, Vera; Gajski, Goran; Gerić, Marko; Negreira, Noelia; López de Alda, Miren; Barceló, Damià; Heath, Ester; Kosjek, Tina; Žegura, Bojana; Novak, Matjaž; Zajc, Irena; Baebler, Špela; Rotter, Ana; Ramšak, Živa; Filipič, Metka

2015-06-15

Residues of anti-neoplastic drugs represent new and emerging pollutants in aquatic environments. Many of these drugs are genotoxic, and it has been postulated that they can cause adverse effects in aquatic ecosystems. 5-Fluorouracil (5-FU) is one of the most extensively used anti-neoplastic drugs in cancer therapy, and this article describes the results of the first investigation using a two-generation toxicity study design with zebrafish (Danio rerio). Exposure of zebrafish to 5-FU (0.01, 1.0 and 100 μg/L) was initiated with adult zebrafish (F0 generation) and continued through the hatchings and adults of the F1 generation, and the hatchings of the F2 generation, to day 33 post-fertilisation. The exposure did not affect survival, growth and reproduction of the zebrafish; however, histopathological changes were observed in the liver and kidney, along with genotoxic effects, at all 5-FU concentrations. Increases in DNA damage determined using the comet assay were significant in the liver and blood cells, but not in the gills and gonads. In erythrocytes, a significant, dose-dependent increase in frequency of micronuclei was observed at all 5-FU concentrations. Whole genome transcriptomic analysis of liver samples of F1 generation zebrafish exposed to 0.01 μg/L and 1 μg/L 5-FU revealed dose-dependent increases in the number of differentially expressed genes, including up-regulation of several DNA-damage-responsive genes and oncogenes (i.e., jun, myca). Although this chronic exposure to environmentally relevant concentrations of 5-FU did not affect the reproduction of the exposed zebrafish, it cannot be excluded that 5-FU can lead to degenerative changes, including cancers, which over long-term exposure of several generations might affect fish populations. The data from this study contribute to a better understanding of the potential consequences of chronic exposure of fish to low concentrations of anti-neoplastic drugs, and they demonstrate that further studies

Roles of p38 and JNK protein kinase pathways activated by compound cantharidin capsules containing serum on proliferation inhibition and apoptosis of human gastric cancer cell line

PubMed Central

Sun, Yonghao; Zhang, Dejuan; Mao, Mao; Lu, Yangping; Jiao, Ning

2017-01-01

The aim of the present study was to investigate the inhibitory effect of compound cantharides capsules (CCCs) on the viability and apoptosis of human gastric cancer cell lines, BGC-823 and SGC-7901, and to detect its regulation of gene expression levels, as well as its inhibition mechanisms. Each cell line was grouped into a control group, CCC serum group, 5-fluorouracil (5-FU) group, combination therapy group (CCC serum + 5-FU) and serum control group. Growth curves were measured and flow cytometry was used to detect cell apoptosis and cell viability. The mRNA expression level of proliferation-related C-MYC and p53 genes were assayed by reverse transcription-quantitative polymerase chain reaction. Protein phosphorylation levels of proliferating cell nuclear antigen, p38 mitogen-activated protein kinase, extracellular signal-related kinase 1/2, c-Jun N-terminal kinase (JNK) and IκB were assayed by western blotting. The combined CCC serum and 5-FU group exhibited a higher inhibition rate in both cell lines and CCC serum therapy demonstrated a similar effect to 5-FU treatment, as demonstrated in the MTT and cell growth assay. Combined therapy significantly decreased the C-MYC mRNA expression levels and increased p53 mRNA expression levels (P<0.05). Combined therapy of 5-FU and CCC was more significant compared with CCC serum or 5-FU only (P<0.05). P38 and JNK-related protein phosphorylation are involved in apoptosis initiated by CCC combined 5-FU therapy. Combined therapy was able to significantly inhibit human gastric cancer cell growth (P<0.05), and advance cell apoptosis compared with CCC serum only. CCC serum resulted in downregulation of the c-Myc gene and upregulation of the p53 gene. p38 and JNK-related protein phosphorylation is involved in the inhibition of cell viability and apoptosis of human gastric cancer cell lines. PMID:28810654

Roles of p38 and JNK protein kinase pathways activated by compound cantharidin capsules containing serum on proliferation inhibition and apoptosis of human gastric cancer cell line.

PubMed

Sun, Yonghao; Zhang, Dejuan; Mao, Mao; Lu, Yangping; Jiao, Ning

2017-08-01

The aim of the present study was to investigate the inhibitory effect of compound cantharides capsules (CCCs) on the viability and apoptosis of human gastric cancer cell lines, BGC-823 and SGC-7901, and to detect its regulation of gene expression levels, as well as its inhibition mechanisms. Each cell line was grouped into a control group, CCC serum group, 5-fluorouracil (5-FU) group, combination therapy group (CCC serum + 5-FU) and serum control group. Growth curves were measured and flow cytometry was used to detect cell apoptosis and cell viability. The mRNA expression level of proliferation-related C-MYC and p53 genes were assayed by reverse transcription-quantitative polymerase chain reaction. Protein phosphorylation levels of proliferating cell nuclear antigen, p38 mitogen-activated protein kinase, extracellular signal-related kinase 1/2, c-Jun N-terminal kinase (JNK) and IκB were assayed by western blotting. The combined CCC serum and 5-FU group exhibited a higher inhibition rate in both cell lines and CCC serum therapy demonstrated a similar effect to 5-FU treatment, as demonstrated in the MTT and cell growth assay. Combined therapy significantly decreased the C-MYC mRNA expression levels and increased p53 mRNA expression levels (P<0.05). Combined therapy of 5-FU and CCC was more significant compared with CCC serum or 5-FU only (P<0.05). P38 and JNK-related protein phosphorylation are involved in apoptosis initiated by CCC combined 5-FU therapy. Combined therapy was able to significantly inhibit human gastric cancer cell growth (P<0.05), and advance cell apoptosis compared with CCC serum only. CCC serum resulted in downregulation of the c-Myc gene and upregulation of the p53 gene. p38 and JNK-related protein phosphorylation is involved in the inhibition of cell viability and apoptosis of human gastric cancer cell lines.

Systematic review and economic evaluation of bevacizumab and cetuximab for the treatment of metastatic colorectal cancer.

PubMed

Tappenden, P; Jones, R; Paisley, S; Carroll, C

2007-03-01

To assess the clinical effectiveness and cost-effectiveness of bevacizumab and cetuximab in the treatment of individuals with metastatic colorectal cancer (CRC). Searches of main electronic databases were conducted in April and May 2005. For the assessment of bevacizumab, trials were included if they recruited participants with untreated metastatic CRC for first-line treatment. Only trials comparing bevacizumab in combination with irinotecan and/or established fluorouracil (5-FU)-containing or releasing regimens given as first-line therapy were included. For the assessment of cetuximab, trials were included if they recruited participants with epidermal growth-factor receptor-expressing metastatic CRC who had previously failed irinotecan-including therapy. Independent cost-effectiveness models of bevacizumab and cetuximab were developed using survival modelling methods. Adding bevacizumab to irinotecan in combination with 5-FU/folic acid (FA) plus irinotecan resulted in a statistically significant increase in median overall survival (OS) of 4.7 months. Adding bevacizumab to 5-FU/FA resulted in a non-significant increase in median OS of 3.7 months within one study and 7.7 months in another. Adding bevacizumab to irinotecan, fluorouracil and leucovorin (IFL) resulted in a statistically significant increase in median progression-free survival (PFS) of 4.4 months. Adding bevacizumab to 5-FU/FA resulted in a statistically significant increase in median PFS of 3.7 months, and a statistically significant increase in time to disease progression of 3.8 months compared to FU/FA alone. An overall tumour response rate of 44.8% was reported for bevacizumab plus IFL compared to 34.8% for IFL plus placebo. This addition was statistically significant. The addition of bevacizumab to 5-FU/FA resulted in a significant difference in tumour response rate within one study, but not another. Bevacizumab in combination with IFL or 5-FU/FA was observed to result in an increase of grade 3

Hardness evaluation of cured urea-formaldehyde resins with different formaldehyde/urea mole ratios using nanoindentation method

Treesearch

Byung-Dae Park; Charles R. Frihart; Yan Yu; Adya P. Singh

2013-01-01

To understand the influence of formaldehyde/urea (F/U) mole ratio on the properties of urea–formaldehyde (UF) resins, this study investigated hardness of cured UF resins with different F/U mole ratios using a nanoindentation method. The traditional Brinell hardness (HB) method was also used...

Clinical pharmacokinetics of unbound docetaxel: role of polysorbate 80 and serum proteins.

PubMed

Loos, Walter J; Baker, Sharyn D; Verweij, Jaap; Boonstra, Joke G; Sparreboom, Alex

2003-10-01

Our objectives were to study the extent of docetaxel binding to plasma in the presence and absence of its excipient, polysorbate 80 (Tween 80; Imperial Chemical Industries PLC, London, United Kingdom), in vitro and to evaluate the pharmacokinetics of unbound docetaxel in vivo. Equilibrium dialysis was used for determination of the fraction unbound (f(u)) docetaxel and was applied to study the pharmacokinetic behavior of unbound docetaxel in 23 patients with cancer receiving an intravenous infusion of the drug formulated in polysorbate 80 (Taxotere; Aventis Pharma SA, Vitry-sur-Seine Cedex, France). Polysorbate 80, added at clinically relevant concentrations (up to 1.0 microL/mL), increased f(u) in vitro by 13% (7.84% +/- 0.0752% versus 6.95% +/- 0.0678%, P <.00001). Similarly, f(u) calculated on the basis of the observed area under the plasma concentration-time curve (AUC) values [f(u)(AUC)] in vivo was 12% higher than f(u) in pretreatment samples [f(u)(pre)] (6.00% +/- 1.03% versus 5.49% +/- 1.01%, P =.038). Of various serum proteins evaluated, only alpha(1)-acid glycoprotein was significantly related to f(u) (P <.0018), with higher f(u) in the presence of lower protein levels. Total docetaxel clearance was related to alpha(1)-acid glycoprotein (R(2) = 0.13, P =.058), f(u)(pre) (R(2) = 0.15, P =.039), and f(u)(AUC) (R(2) = 0.29, P =.0048). This study demonstrates that the plasma binding of docetaxel is influenced by both alpha(1)-acid glycoprotein and its formulation vehicle. Further investigation is required to resolve the potential clinical significance of these observations.

Involvement of FFA1 and FFA4 in the regulation of cellular functions during tumor progression in colon cancer cells.

PubMed

Takahashi, Kaede; Fukushima, Kaori; Onishi, Yuka; Minami, Kanako; Otagaki, Shiho; Ishimoto, Kaichi; Fukushima, Nobuyuki; Honoki, Kanya; Tsujiuchi, Toshifumi

2018-08-01

Free fatty acid receptor 1 (FFA1) and FFA4 mediate a variety of biological responses through binding of medium- and long-chain free fatty acids. The aim of this study was to investigate an involvement of FFA1 and FFA4 in the regulation of cellular functions during tumor progression in colon cancer cells. The long-term fluorouracil (5-FU) and cisplatin (CDDP) treated cells were generated from DLD1 cells (DLD-5FU and DLD-CDDP cells, respectively). FFAR1 expressions were lower in DLD-5FU and DLD-CDDP cells than in DLD1 cells. In contrast, DLD-5FU and DLD-CDDP cells showed the high FFAR4 expressions, compared with DLD1 cells. The cell motile activities of DLD-5FU and DLD-CDDP cells were reduced by GW9508 which is an agonist of FFA1 and FFA4. Moreover, GW1100, an antagonist of FFA1, inhibited the cell motile activities of DLD-5FU and DLD-CDDP cells. To evaluate whether FFA1 and FFA4 regulate the enhancement of cell motility, invasion and colony formation, highly migratory (hmDLD1) cells were established from DLD1 cells. FFAR1 expression was significantly higher in hmDLD1 cells than in DLD1 cells, but no change of FFAR4 expression was observed. The elevated cell motile and invasive activities and colony formation of hmDLD1 cells were suppressed by FFA1 inhibition. These results suggest that FFA1 and FFA4 are involved in the regulation of cellular functions during tumor progression in colon cancer DLD1 cells. Copyright © 2018 Elsevier Inc. All rights reserved.

Oral and intestinal microflora in 5-fluorouracil treated rats, translocation to cervical and mesenteric lymph nodes and effects of probiotic bacteria.

PubMed

Von Bültzingslöwen, I; Adlerberth, I; Wold, A E; Dahlén, G; Jontell, M

2003-10-01

Serious systemic infections may occur during cancer chemotherapy due to disturbances in the oropharyngeal and gastrointestinal microflora, impaired mucosal barrier functions and immunosuppression. Bacteria may spread from the gastrointestinal tract to the regional lymph nodes. The routes for bacterial spread from the oral cavity are less well known. In the present study we investigated changes in the oral and intestinal microfloras in rats given 50 mg/kg 5-fluorouracil (5-FU) i.v. for 6 days. Bacterial dissemination to the lymph nodes draining the oral cavity and the lymph nodes draining the gastrointestinal tract was examined. Effects of adding the probiotic strain Lactobacillus plantarum 299v in the drinking water to the rats were measured. 5-FU treatment caused an increase in the number of facultative and strictly anaerobic bacteria in biopsies from the oral cavity and an increase in the number of facultative anaerobes in the large intestine. The proportion of facultative gram-negative rods increased in both the oral cavity and intestine. Bacteria translocated to both the cervical and mesenteric lymph nodes in untreated animals and increased in numbers after 5-FU treatment due to an increase in the number of facultative gram-negative rods. Treatment with L. plantarum 299v improved food intake and body weight in 5-FU-treated rats. It also reduced the 5-FU-induced raise in the total numbers of facultative anaerobes in the intestine, but did not reduce translocation and did not prevent diarrhea. This study reinforces the oral cavity, along with the gastrointestinal tract, as a source for bacterial dissemination. The use of probiotic bacteria may reduce some side effects of 5-FU treatment.

Indomethacin-5-fluorouracil-methyl ester dry emulsion: a potential oral delivery system for 5-fluorouracil.

PubMed

Wang, Jing; Hu, Yanchen; Li, Ling; Jiang, Tongying; Wang, Siling; Mo, Fengkui

2010-06-01

To produce a combined effect of indomethacin (IDM) and 5-fluorouracil (5FU) for cancer therapy, the side effects of IDM on the gastrointestinal (GI) tract were reduced and the oral adsorption of 5FU was improved. Indomethacin-5-fluorouracil-methyl ester (IFM) dry emulsion was prepared and evaluated as a potential oral delivery system for 5FU. IFM was synthesized by formation of an ester between IDM and 5FU intermediate and then characterized by structure, melting point, solubility, apparent partition coefficient, and incubation with GI tract contents and plasma. Gum acacia and sodium carboxymethyl cellulose (CMC-Na) were applied as the adsorbent and solid carrier to prepare IFM dry emulsion. IFM dry emulsion was then characterized by reconstitution in water and in situ intestinal perfusion experiment. Physicochemical properties of the new synthesized compound confirmed the formation of IFM. Incubation of IFM in the contents of the GI tract and plasma revealed that IFM was not relatively stable in GI contents during the time period of transit through the GI tract, whereas it was very unstable in plasma and released 5FU rapidly. The IFM dry emulsion could be easily reconstituted in water, and the mean particle size was 2.416 microm. The absorption rate constant (K) for IFM with concentration of 2, 5, and 10 microg/mL in the in situ perfusion experiment were 0.473, 0.423, and 0.433/h, respectively, demonstrating passive diffusion of IFM across the biological membranes. This study indicates that the IFM dry emulsion may represent a potentially useful oral delivery system for 5FU.

Interventional Exclusion of Iliac Artery Aneurysms Using the Flow-Diverting Multilayer Stent

DOE Office of Scientific and Technical Information (OSTI.GOV)