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991.
Di Giacomo AM Danielli R Calabrò L Bertocci E Nannicini C Giannarelli D Balestrazzi A Vigni F Riversi V Miracco C Biagioli M Altomonte M Maio M 《Cancer immunology, immunotherapy : CII》2011,60(4):467-477
Aim of study
To evaluate the feasibility of ipilimumab treatment for metastatic melanoma outside the boundaries of clinical trials, in a setting similar to that of daily practice.Methods
Ipilimumab was available upon physician request in the Expanded Access Programme for patients with life-threatening, unresectable stage III/IV melanoma who failed or did not tolerate previous treatments and for whom no therapeutic option was available. Induction treatment with ipilimumab 10?mg/kg was administered intravenously every 3?weeks, for a total of 4 doses, with maintenance doses every 12?weeks based on physicians?? discretion and clinical judgment. Tumors were assessed at baseline, Week 12, and every 12?weeks thereafter per mWHO response criteria, and clinical response was scored as complete response (CR), partial response (PR), stable disease (SD), or progressive disease. Durable disease control (DC) was defined as SD at least 24?weeks from the first dose, CR, or PR.Results
Disease control rate at 24 and 60?weeks was 29.6% and 15%, respectively. Median overall survival at a median follow-up of 8.5?months was 9?months. The 1- and 2-year survival rates were 34.8% and 23.5%, respectively. Changes in lymphocyte count slope and absolute number during ipilimumab treatment appear to correlate with clinical response and survival, respectively. Adverse events were predominantly immune related, manageable, and generally reversible. One patient died from pancytopenia, considered possibly treatment related.Conclusion
Ipilimumab was a feasible treatment for malignant melanoma in heavily pretreated, progressing patients. A sizeable proportion of patients experienced durable DC, including benefits to long-term survival. 相似文献992.
993.
Parise EM Lilly N Kay K Dossat AM Seth R Overton JM Williams DL 《American journal of physiology. Regulatory, integrative and comparative physiology》2011,301(6):R1692-R1699
Hypothalamic orexin neurons project to the hindbrain, and 4th-ventricle intracerebroventricular (4th-icv) injection of orexin-A treatment increases food intake. We assessed the effects of hindbrain orexin-A and the orexin-1-receptor antagonist SB334867 on meal pattern in rats consuming standard chow. When injected 4th-icv shortly before dark onset, lower doses of orexin-A increased food intake over a 2-h period by increasing the size of the first meal relative to vehicle, whereas the highest dose increased food intake by causing the second meal to be taken sooner. Conversely, hindbrain SB334867 reduced food intake by decreasing the size of the first meal of the dark phase. We also examined the effects of 4th-icv orexin-A and SB334867 on locomotor activity. Only the highest dose of orexin-A increased activity, and SB334867 had no effect. In addition, hindbrain SB334867 induced c-Fos in the nucleus of the solitary tract. These data support the suggestion that endogenous hindbrain orexin-A acts to limit satiation. Both orexin-A and the pancreatic satiation hormone amylin require an intact area postrema to affect food intake, so we asked whether 4th-icv orexin-A impairs the satiating effect of peripheral amylin treatment. Amylin reduced the size of the first meal of the dark cycle when rats were pretreated with 4th-icv saline, yet amylin was ineffective after 4th-icv orexin-A pretreatment. Using double-label immunohistochemistry, we determined that some orexin-A fibers in the area postrema are located in proximity to amylin-responsive neurons. Therefore, hindbrain orexin-A may increase food intake, in part, by reducing the ability of rats to respond to amylin during a meal. 相似文献
994.
Soriano D Orozco-Segovia A Márquez-Guzmán J Kitajima K Gamboa-de Buen A Huante P 《Annals of botany》2011,107(6):939-951
Background and Aims
The size and composition of seed reserves may reflect the ecological strategy and evolutionary history of a species and also temporal variation in resource availability. The seed mass and composition of seed reserves of 19 co-existing tree species were studied, and we examined how they varied among species in relation to germination and seedling growth rates, as well as between two years with contrasting precipitation (652 and 384 mm).Methods
Seeds were collected from a tropical deciduous forest in the northwest of Mexico (Chamela Biological Station). The seed dry mass, with and without the seed coat, and the concentrations of lipids, nitrogen and non-structural carbohydrates for the seed minus seed coat were determined. The anatomical localization of these reserves was examined using histochemical analysis. The germination capacity, rate and lag time were determined. The correlations among these variables, and their relationship to previously reported seedling relative growth rates, were evaluated with and without phylogenetic consideration.Key Results
There were interannual differences in seed mass and reserve composition. Seed was significantly heavier after the drier year in five species. Nitrogen concentration was positively correlated with seed coat fraction, and was significantly higher after the drier year in 12 species. The rate and lag time of germination were negatively correlated with each other. These trait correlations were also supported for phylogenetic independent contrasts. Principal component analysis supported these correlations, and indicated a negative association of seedling relative growth rate with seed size, and a positive association of germination rate with nitrogen and lipid concentrations.Conclusions
Nitrogen concentration tended to be higher after the drier year and, while interannual variations in seed size and reserve composition were not sufficient to affect interspecific correlations among seed and seedling traits, some of the reserves were related to germination variables and seedling relative growth rate. 相似文献995.
One way to restore physiological blood flow to occluded arteries involves the deformation of plaque using an intravascular balloon and preventing elastic recoil using a stent. Angioplasty and stent implantation cause unphysiological loading of the arterial tissue, which may lead to tissue in-growth and reblockage; termed "restenosis." In this paper, a computational methodology for predicting the time-course of restenosis is presented. Stress-induced damage, computed using a remaining life approach, stimulates inflammation (production of matrix degrading factors and growth stimuli). This, in turn, induces a change in smooth muscle cell phenotype from contractile (as exists in the quiescent tissue) to synthetic (as exists in the growing tissue). In this paper, smooth muscle cell activity (migration, proliferation, and differentiation) is simulated in a lattice using a stochastic approach to model individual cell activity. The inflammation equations are examined under simplified loading cases. The mechanobiological parameters of the model were estimated by calibrating the model response to the results of a balloon angioplasty study in humans. The simulation method was then used to simulate restenosis in a two dimensional model of a stented artery. Cell activity predictions were similar to those observed during neointimal hyperplasia, culminating in the growth of restenosis. Similar to experiment, the amount of neointima produced increased with the degree of expansion of the stent, and this relationship was found to be highly dependant on the prescribed inflammatory response. It was found that the duration of inflammation affected the amount of restenosis produced, and that this effect was most pronounced with large stent expansions. In conclusion, the paper shows that the arterial tissue response to mechanical stimulation can be predicted using a stochastic cell modeling approach, and that the simulation captures features of restenosis development observed with real stents. The modeling approach is proposed for application in three dimensional models of cardiovascular stenting procedures. 相似文献
996.
Tomza-Marciniak A Pilarczyk B Bąkowska M Pilarczyk R Wójcik J Marciniak A Hendzel D 《Biological trace element research》2011,144(1-3):517-524
The present study was undertaken to evaluate the concentration of selenium and selected heavy metals and their possible relationship in serum of 25 healthy lactating cows (Montbéliarde) reared in a non-polluted area, in the western part of Poland. Cadmium, lead, copper, and zinc concentrations were determined by inductively coupled plasma-atomic emission spectrometry and Se concentration was determined fluorimetrically. The content of Se, Zn, and Cu was 0.083?±?0.026, 0.629?±?0.413, and 0.152?±?0.042?μg/mL, respectively. The presence of the Cd and Pb was found in all serum samples. The mean concentration of these metals was 0.0009?±?0.0008 and 0.018?±?0.016?μg/mL, respectively. Analysis of correlations between Se and toxic metals showed a negative and significant (P?0.05) relationship between selenium concentration and lead and cadmium concentration in the serum of the animals studied, with correlation coefficients of r?=?-0.595 and r?=?-0.618, respectively. For copper and zinc, this relationship was also negative but not significant (r?=?-0.255 and r?=?-0.203). Our study demonstrated that the level of toxic metals decreased as serum selenium concentration increased. It seems necessary to conduct further research on the interactions between these elements in blood, serum, and target organs concomitantly with the determination of their intake. 相似文献
997.
Leal E Fernández-Durán B Guillot R Ríos D Cerdá-Reverter JM 《Journal of comparative physiology. B, Biochemical, systemic, and environmental physiology》2011,181(8):1035-1044
Repetitive aquaculture-related protocols may act as cyclic stressors that induce chronic stress in cultured fish. The sea
bass is particularly sensitive to stressful conditions and the mere presence of humans will disturb feeding behavior. In this
paper, we study whether chronic stress induced by repetition of acute stress protocols affects long-term feeding behavior
and growth performance in sea bass and whether exogenous cortisol may induce stress-like changes in these parameters. We demonstrate
that both chronic stress and dietary cortisol decrease food intake and have a negative effect on feed conversion efficiency,
severely impairing sea bass performance. Both experimental approaches induced changes in the daily feeding activity by lengthening
the active feeding periods. Fish subjected to a cyclic stressor modify their daily feeding pattern in an attempt to avoid
interference with the time of the stressor. The delay in feeding when fish are acutely and repeatedly stressed could be of
substantial adaptive importance. 相似文献
998.
Diana C. Tan Gavin R. Flematti Emilio L. Ghisalberti Krishnapillai Sivasithamparam Sukumar Chakraborty Friday Obanor Martin John Barbetti 《Mycotoxin Research》2011,27(2):123-135
Sheep grazing in Western Australia can partially or completely refuse to consume annual Medicago pods contaminated with a number of different Fusarium species. Many Fusarium species are known to produce trichothecenes as part of their array of toxigenic secondary metabolites, which are known to
cause feed refusal in animals. This study reports the identity of Fusarium species using species-specific PCR primers and a characterization of the toxigenic secondary metabolites produced by 24 Fusarium isolates associated with annual legume-based pastures and particularly those associated with sheep feed refusal disorders
in Western Australia. Purification of the fungal extracts was facilitated by a bioassay-guided fractionation using brine shrimp.
A number of trichothecenes (3-acetyldeoxynivalenol, deoxynivalenol, fusarenon-X, monoacetoxyscirpenols, diacetoxyscirpenol,
scirpentriol, HT-2 toxin and T-2 toxin), enniatins (A, A1, B, and B1), chlamydosporol and zearalenone were identified using
GC/MS and/or NMR spectroscopy. Some of the crude extracts and fractions showed significant activity against brine shrimp at
concentrations as low as 5 μg ml-1, and are likely to be involved in the sheep feed refusal disorders. This is the first report of chlamydosporol production
by confirmed Fusarium spp.; of the incidence of F. brachygibbosum and F. venenatum in Australia and of F. tricinctum in Western Australia; and of mycotoxin production by Fusarium species from Western Australia. 相似文献
999.
Lim DM Wang ML 《American journal of physiology. Gastrointestinal and liver physiology》2011,301(1):G91-G99
The mechanisms by which gastroesophageal reflux disease esophagitis develops are controversial. Although many support the notion that caustic injury leads to reflux esophagitis, others have proposed that reflux esophagitis is caused by esophageal epithelial cytokine-mediated inflammation. We previously demonstrated that Toll-like receptor 3 (TLR3) is highly expressed and functional in the nontransformed human esophageal epithelial cell line EPC2-hTERT. In addition to activation by viral double-stranded RNA, TLR3 can be activated by endogenous mRNA released by necrotic cells. In the present study, we investigated the role of esophageal epithelial TLR3 to sense danger signals released by necrotic esophageal epithelial cells in vitro. Following induction of freeze-thaw necrosis, necrotic EPC2-hTERT cell supernatants (NCS) were used to stimulate EPC2-hTERT monolayers, leading to NF-κB-dependent induction of IL-8 mRNA expression. Responses to self-derived NCS were not observed in transformed gastrointestinal epithelial cell lines, including TE-1 and Caco-2 cells, suggesting that the ability to sense endogenous danger signals is unique to nontransformed esophageal epithelial cells. To determine the immunostimulatory role of epithelial RNA, EPC2-hTERT cells were stimulated with self-derived mRNA, which significantly induced IL-8 mRNA expression. Finally, suppression of TLR3 signaling in a DN-TLR3 cell line, hTERT-ΔTIR-TLR3, led to reduced NCS-induced IL-8 induction by both NCS and mRNA stimulation. Our results demonstrate that human esophageal epithelial cells can sense endogenous danger signals, in part through TLR3 signaling. This supports the concept that epithelial injury plays an inciting role in the pathogenesis of reflux-induced esophagitis, providing important insights into the mechanisms by which epithelial injury leads to inflammation. 相似文献
1000.
Expression, localization, and functional role for synaptotagmins in pancreatic acinar cells 总被引:1,自引:0,他引:1
Falkowski MA Thomas DD Messenger SW Martin TF Groblewski GE 《American journal of physiology. Gastrointestinal and liver physiology》2011,301(2):G306-G316
Secretagogue-induced changes in intracellular Ca(2+) play a pivotal role in secretion in pancreatic acini yet the molecules that respond to Ca(2+) are uncertain. Zymogen granule (ZG) exocytosis is regulated by soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complexes. In nerve and endocrine cells, Ca(2+)-stimulated exocytosis is regulated by the SNARE-associated family of proteins termed synaptotagmins. This study examined a potential role for synaptotagmins in acinar secretion. RT-PCR revealed that synaptotagmin isoforms 1, 3, 6, and 7 are present in isolated acini. Immunoblotting and immunofluorescence using three different antibodies demonstrated synaptotagmin 1 immunoreactivity in apical cytoplasm and ZG fractions of acini, where it colocalized with vesicle-associated membrane protein 2. Synaptotagmin 3 immunoreactivity was detected in membrane fractions and colocalized with an endolysosomal marker. A potential functional role for synaptotagmin 1 in secretion was indicated by results that introduction of synaptotagmin 1 C2AB domain into permeabilized acini inhibited Ca(2+)-dependent exocytosis by 35%. In contrast, constructs of synaptotagmin 3 had no effect. Confirmation of these findings was achieved by incubating intact acini with an antibody specific to the intraluminal domain of synaptotagmin 1, which is externalized following exocytosis. Externalized synaptotagmin 1 was detected exclusively along the apical membrane. Treatment with CCK-8 (100 pM, 5 min) enhanced immunoreactivity by fourfold, demonstrating that synaptotagmin is inserted into the apical membrane during ZG fusion. Collectively, these data indicate that acini express synaptotagmin 1 and support that it plays a functional role in secretion whereas synaptotagmin 3 has an alternative role in endolysosomal membrane trafficking. 相似文献