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排序方式: 共有117条查询结果,搜索用时 15 毫秒
71.
Roman Eisner Cynthia Stretch Thomas Eastman Jianguo Xia David Hau Sambasivarao Damaraju Russell Greiner David S. Wishart Vickie E. Baracos 《Metabolomics : Official journal of the Metabolomic Society》2011,7(1):25-34
Cancer-associated muscle wasting is associated with reduction in functional status, in response to treatment and in life expectancy.
Methods currently used to assess muscle loss involve diagnostic imaging techniques such as computed tomography (CT), which
are costly, inconvenient, invasive, time consuming and have limited ability to detect early or slowly evolving wasting. We
present a novel approach using single time-point urinary metabolite profiles to determine whether a patient is experiencing
muscle wasting. We analyzed 93 random urine samples from patients with cancer using 1H-NMR. Using two successive CT images we assessed their lumbar skeletal muscle area (cm2) to estimate the rate of muscle change (% loss or gain over time) for each patient. The average muscle change over time was
−4.71%/100 days in the muscle-losing group and +3.91%/100 days in the comparator group. Bivariate statistics identified metabolites
related with muscle loss, including constituents and metabolites of muscle (creatine, creatinine, 3-OH-isovalerate), amino
acids (Leu, Ile, Val, Ala, Thr, Tyr, Gln, Ser) and intermediary metabolites. We also applied machine-learning techniques to
identify patterns of urinary metabolites that identify which patients are likely to lose muscle mass. We evaluated the predictive
performance of 8 machine-learning approaches using fivefold cross validation and permutation testing, and found that SVM provided
the best generalization accuracy (82.2%). These results suggest that 1H-NMR analysis of a single random urine sample may be a fast, cheap, safe and inexpensive tool to screen and monitor muscle
loss, and that useful classifiers for predicting related metabolic conditions are possible with the methodology presented. 相似文献
72.
XB Lin LA Dieleman A Ketabi I Bibova MB Sawyer H Xue CJ Field VE Baracos MG Gänzle 《PloS one》2012,7(7):e39764
Intestinal microbiota mediate toxicity of irinotecan (CPT-11) cancer therapies and cause systemic infection after CPT-11-induced loss of barrier function. The intestinal microbiota and their functions are thus potential targets for treatment to mitigate CPT-11 toxicity. However, microbiota changes during CPT-11 therapy remain poorly described. This study analysed changes in intestinal microbiota induced by CPT-11 chemotherapy. Qualitative and quantitative taxonomic analyses, and functional analyses were combined to characterize intestinal microbiota during CPT-11-based chemotherapy, and in presence or absence of oral glutamine, a treatment known to reduce CPT-11 toxicity. In the first set of experiments tumour-bearing rats received a dose-intensive CPT-11 regimen (125 mg kg(-1)×3 days), with or without oral glutamine bolus (0.75 g kg(-1)). In a subsequent more clinically-oriented chemotherapy regimen, rats received two cycles of CPT-11 (50 mg kg(-1)) followed by 5-flurouracil (50 mg kg(-1)). The analysis of fecal samples over time demonstrated that tumours changed the composition of intestinal microbiota, increasing the abundance of clostrridial clusters I, XI, and Enterobacteriaceae. CPT-11 chemotherapy increased cecal Clostridium cluster XI and Enterobacteriaceae, particularly after the dose-intensive therapy. Glutamine treatment prevented the reduced abundance of major bacterial groups after CPT-11 administration; i.e. total bacteria, Clostridium cluster VI, and the Bacteroides-group. Virulence factor/toxin genes of pathogenic Escherichia coli and Clostridium difficile were not detected in the cecal microbiota. In conclusion, both colon cancer implantation and CPT-11-based chemotherapies disrupted the intestinal microbiota. Oral glutamine partially mitigated CPT-11 toxicity and induced temporary changes of the intestinal microbiota. 相似文献
73.
74.
Leslie W. Tari Xiaoming Li Michael Trzoss Daniel C. Bensen Zhiyong Chen Thanh Lam Junhu Zhang Suk Joong Lee Grayson Hough Doug Phillipson Suzanne Akers-Rodriguez Mark L. Cunningham Bryan P. Kwan Kirk J. Nelson Amanda Castellano Jeff B. Locke Vickie Brown-Driver Timothy M. Murphy Voon S. Ong Chris M. Pillar Dean L. Shinabarger Jay Nix Felice C. Lightstone Sergio E. Wong Toan B. Nguyen Karen J. Shaw John Finn 《PloS one》2013,8(12)
Increasing resistance to every major class of antibiotics and a dearth of novel classes of antibacterial agents in development pipelines has created a dwindling reservoir of treatment options for serious bacterial infections. The bacterial type IIA topoisomerases, DNA gyrase and topoisomerase IV, are validated antibacterial drug targets with multiple prospective drug binding sites, including the catalytic site targeted by the fluoroquinolone antibiotics. However, growing resistance to fluoroquinolones, frequently mediated by mutations in the drug-binding site, is increasingly limiting the utility of this antibiotic class, prompting the search for other inhibitor classes that target different sites on the topoisomerase complexes. The highly conserved ATP-binding subunits of DNA gyrase (GyrB) and topoisomerase IV (ParE) have long been recognized as excellent candidates for the development of dual-targeting antibacterial agents with broad-spectrum potential. However, to date, no natural product or small molecule inhibitors targeting these sites have succeeded in the clinic, and no inhibitors of these enzymes have yet been reported with broad-spectrum antibacterial activity encompassing the majority of Gram-negative pathogens. Using structure-based drug design (SBDD), we have created a novel dual-targeting pyrimidoindole inhibitor series with exquisite potency against GyrB and ParE enzymes from a broad range of clinically important pathogens. Inhibitors from this series demonstrate potent, broad-spectrum antibacterial activity against Gram-positive and Gram-negative pathogens of clinical importance, including fluoroquinolone resistant and multidrug resistant strains. Lead compounds have been discovered with clinical potential; they are well tolerated in animals, and efficacious in Gram-negative infection models. 相似文献
75.
76.
Dirk W. Luchtman Melissa J. S. Chee Barbora Doslikova Daniel L. Marks Vickie E. Baracos William F. Colmers 《PloS one》2015,10(10)
Some animals and humans fed a high-energy diet (HED) are diet-resistant (DR), remaining as lean as individuals who were naïve to HED. Other individuals become obese during HED exposure and subsequently defend the obese weight (Diet-Induced Obesity- Defenders, DIO-D) even when subsequently maintained on a low-energy diet. We hypothesized that the body weight setpoint of the DIO-D phenotype resides in the hypothalamic paraventricular nucleus (PVN), where anorexigenic melanocortins, including melanotan II (MTII), increase presynaptic GABA release, and the orexigenic neuropeptide Y (NPY) inhibits it. After prolonged return to low-energy diet, GABA inputs to PVN neurons from DIO-D rats exhibited highly attenuated responses to MTII compared with those from DR and HED-naïve rats. In DIO-D rats, melanocortin-4 receptor expression was significantly reduced in dorsomedial hypothalamus, a major source of GABA input to PVN. Unlike melanocortin responses, NPY actions in PVN of DIO-D rats were unchanged, but were reduced in neurons of the ventromedial hypothalamic nucleus; in PVN of DR rats, NPY responses were paradoxically increased. MTII-sensitivity was restored in DIO-D rats by several weeks’ refeeding with HED. The loss of melanocortin sensitivity restricted to PVN of DIO-D animals, and its restoration upon prolonged refeeding with HED suggest that their melanocortin systems retain the ability to up- and downregulate around their elevated body weight setpoint in response to longer-term changes in dietary energy density. These properties are consistent with a mechanism of body weight setpoint. 相似文献
77.
Vickie B. Shim Mark Battley Iain A. Anderson 《Computer methods in biomechanics and biomedical engineering》2013,16(14):1495-1499
Bone in the pelvis is a composite material with a complex anatomical structure that is difficult to model computationally. Rather than assigning material properties to increasingly smaller elements to capture detail in three-dimensional finite element (FE) models, properties can be assigned to Gauss points within larger elements. As part of a validation process, we compared experimental and analytical results from a composite beam under four-point load to FE models with material properties assigned to refined elements and Gauss points within larger elements. Both FE models accurately predicted deformation and the analytical predictions of internal shear stress. 相似文献
78.
Boesten LS Zadelaar SM De Clercq S Francoz S van Nieuwkoop A Biessen EA Hofmann F Feil S Feil R Jochemsen AG Zurcher C Havekes LM van Vlijmen BJ Marine JC 《Cell death and differentiation》2006,13(12):2089-2098
p53 is a potent inhibitor of cell growth and an inducer of apoptosis. During embryonic development, Mdm2 and Mdm4 inhibit the growth suppressive activities of p53. However, whether tight surveillance of p53 activity is required in quiescent cells is unknown. To test this, conditional inactivation of mdm2 and mdm4 was carried out in smooth muscle cells (SMCs). Upon SMC-specific inactivation of mdm2, and not of mdm4, mice rapidly became ill and died. Necropsy showed small intestinal dilation, and histological analyses indicated a severe reduction in the number of intestinal SMCs. Increased p53 levels and activity were detected in the remaining SMCs, and the phenotype was completely rescued on a p53-null background. Interestingly, intestinal SMCs are caspase-3-negative and therefore did not undergo caspase-3-dependent apoptotic cell death. Together, Mdm2, but not Mdm4, prevents accumulation of active p53 in quiescent SMCs and thereby the induction of p53-mediated caspase-3-independent cell death. 相似文献
79.
Frederick Cohen Michael F.T. Koehler Philippe Bergeron Linda O. Elliott John A. Flygare Matthew C. Franklin Lewis Gazzard Stephen F. Keteltas Kevin Lau Cuong Q. Ly Vickie Tsui Wayne J. Fairbrother 《Bioorganic & medicinal chemistry letters》2010,20(7):2229-2233
A series of IAP antagonists based on thiazole or benzothiazole amide isosteres was designed and synthesized. These compounds were tested for binding to the XIAP-BIR3 and ML-IAP BIR using a fluorescence polarization assay. The most potent of these compounds, 19a and 33b, were found to have Ki’s of 20–30 nM against ML-IAP and 50–60 nM against XIAP-BIR3. 相似文献
80.
Coyle B McCann M Kavanagh K Devereux M McKee V Kayal N Egan D Deegan C Finn GJ 《Journal of inorganic biochemistry》2004,98(8):1361-1366
[Ag(2)(NH(3))(2)(salH)(2)] (salH(2)=salicylic acid) was synthesised from salicylic acid and Ag(2)O in concentrated aqueous NH(3) and the dimeric Ag(I) complex was characterised using X-ray crystallography. The complex is centrosymmetric with each metal coordinated to a salicylate carboxylate oxygen and to an ammonia nitrogen atom in an almost linear fashion. The two [Ag(NH(3))(salH)] units in the complex are linked by an Ag-Ag bond. Whilst metal-free salH(2) did not prevent the growth of the fungal pathogen Candida albicans [Ag(2)(NH(3))(2)(salH)(2)], [Ag(2)(salH)(2)] and some simple Ag(I) salts greatly inhibited cell reproduction. SalH(2), [Ag(2)(NH(3))(2)(salH)(2)] [Ag(2)(salH)(2)] and AgClO(4) produced a dose-dependent cytotoxic response against the three human derived cancer cell lines, Cal-27, Hep-G2 and A-498, with the Ag(I)-containing reagents being the most effective. 相似文献