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排序方式: 共有409条查询结果,搜索用时 218 毫秒
51.
Martínez González S Hernández AI Varela C Rodríguez-Arístegui S Lorenzo M Rodríguez A Rivero V Martín JI Saluste CG Ramos-Lima F Cendón E Cebrián D Aguirre E Gomez-Casero E Albarrán M Alfonso P García-Serelde B Oyarzabal J Rabal O Mulero F Gonzalez-Granda T Link W Fominaya J Barbacid M Bischoff JR Pizcueta P Pastor J 《Bioorganic & medicinal chemistry letters》2012,22(10):3460-3466
Phosphoinositide-3-kinase (PI3K) is an important target for cancer therapeutics due to the deregulation of this signaling pathway in a wide variety of human cancers. Herein, we describe the optimization of imidazo [1,2-a] pyrazines, which allow us to identify compound 14 (ETP-46321), with potent biochemical and cellular activity and good pharmacokinetic properties (PK) after oral dosing. ETP-46321 PK/PD studies showed time dependent downregulation of AKT(Ser473) phosphorylation, which correlates with compound levels in tumor tissue and demonstrating to be efficacious in a GEMM mouse tumor model driven by a K-Ras(G12V) oncogenic mutation. Treatment with ETP-46321 resulted in significant tumor growth inhibition. 相似文献
52.
S Martínez González AI Hernández C Varela M Lorenzo F Ramos-Lima E Cendón D Cebrián E Aguirre E Gomez-Casero MI Albarrán P Alfonso B García-Serelde G Mateos J Oyarzabal O Rabal F Mulero T Gonzalez-Granda W Link J Fominaya M Barbacid JR Bischoff P Pizcueta C Blanco-Aparicio J Pastor 《Bioorganic & medicinal chemistry letters》2012,22(16):5208-5214
Phosphoinositide-3-kinases (PI3K) are a family of lipid kinases mediating numerous cell processes such as proliferation, migration and differentiation. PI3K is an important target for cancer therapeutics due to the deregulation of this signaling pathway in a wide variety of human cancers. Herein, we describe the rapid identification of ETP-46992, within 2-aminocarbonyl imidazo [1,2-a] pyrazine series, with suitable pharmacokinetic (PK) properties that allows the establishment of mechanism of action and efficacy in vivo studies. ETP-46992 showed tumor growth inhibition in a GEMM mouse tumor model driven by a K-Ras(G12V) oncogenic mutation and in tumor xenograft models with PI3K pathway deregulated (BT474). 相似文献
53.
Milena Sant Pamela Minicozzi Claudia Allemani Claudia Cirilli Massimo Federico Riccardo Capocaccia Mario Budroni Pina Candela Emanuele Crocetti Fabio Falcini Stefano Ferretti Mario Fusco Adriano Giacomin Francesco La Rosa Lucia Mangone Maurilio Natali Maurizio Ponz De Leon Adele Traina Rosario Tumino Paola Zambon 《Cancer epidemiology》2012,36(6):541-547
BackgroundPopulation-based cancer registry studies of care patterns can help elucidate reasons for the marked geographic variation in cancer survival across Italy. The article provides a snapshot of the care delivered to cancer patients in Italy.MethodsRandom samples of adult patients with skin melanoma, breast, colon and non-small cell lung cancers diagnosed in 2003–2005 were selected from 14 Italian cancer registries. Logistic models estimated odds of receiving standard care (conservative surgery plus radiotherapy for early breast cancer; surgery plus chemotherapy for Dukes C colon cancer; surgery for lung cancer; sentinel node biopsy for >1 mm melanoma, vs. other treatment) in each registry compared to the entire sample (reference).ResultsStage at diagnosis for breast, colon and melanoma was earlier in north/central than southern registries. Odds of receiving standard care were lower than reference in Sassari (0.68, 95%CI 0.51–0.90) and Napoli (0.48, 95%CI 0.35–0.67) for breast cancer; did not differ across registries for Dukes C colon cancer; were higher in Romagna (3.77, 95%CI 1.67–8.50) and lower in Biella (0.38, 95%CI 0.18–0.82) for lung cancer; and were higher in Reggio Emilia (2.37, 95%CI 1.12–5.02) and lower in Ragusa (0.27, 95%CI 0.14–0.54) for melanoma.ConclusionsNotwithstanding limitations due to variations in the availability of clinical information and differences in stage distribution between north/central and southern registries, our study shows that important disparities in cancer care persist across Italy. Thus the public health priority of reducing cancer survival disparities will not be achieved in the immediate future. 相似文献
54.
Agnieszka Bielach Kate?ina Podle?áková Peter Marhavy Jér?me Duclercq Candela Cuesta Bruno Müller Wim Grunewald Petr Tarkowski Eva Benková 《The Plant cell》2012,24(10):3967-3981
The architecture of a plant’s root system, established postembryonically, results from both coordinated root growth and lateral root branching. The plant hormones auxin and cytokinin are central endogenous signaling molecules that regulate lateral root organogenesis positively and negatively, respectively. Tight control and mutual balance of their antagonistic activities are particularly important during the early phases of lateral root organogenesis to ensure continuous lateral root initiation (LRI) and proper development of lateral root primordia (LRP). Here, we show that the early phases of lateral root organogenesis, including priming and initiation, take place in root zones with a repressed cytokinin response. Accordingly, ectopic overproduction of cytokinin in the root basal meristem most efficiently inhibits LRI. Enhanced cytokinin responses in pericycle cells between existing LRP might restrict LRI near existing LRP and, when compromised, ectopic LRI occurs. Furthermore, our results demonstrate that young LRP are more sensitive to perturbations in the cytokinin activity than are developmentally more advanced primordia. We hypothesize that the effect of cytokinin on the development of primordia possibly depends on the robustness and stability of the auxin gradient. 相似文献
55.
56.
Traditionally regarded as stable through the entire lifespan, the intestinal microbiota has now emerged as an extremely plastic entity, capable of being reconfigured in response to different environmental factors. In a mutualistic context, these microbiome fluctuations allow the host to rapidly adjust its metabolic and immunologic performances in response to environmental changes. Several circumstances can disturb this homeostatic equilibrium, inducing the intestinal microbiota to shift from a mutualistic configuration to a disease-associated profile. A mechanistic comprehension of the dynamics involved in this process is needed to deal more rationally with the role of the human intestinal microbiota in health and disease. 相似文献
57.
Milagros Demarchi Marina Chiappero Jürgen Laudien Ricardo Sahade 《Journal of experimental marine biology and ecology》2008,364(1):29-34
The actual Arctic biota shows a strong affinity with that of the Boreal Atlantic and Pacific ones, as a result of an active recolonization process after the Quaternary glaciations. The geographic distribution of sessile species is usually linked to larvae dispersive capabilities which can be directly related with time spent in the plankton. Ascidians larvae are lecitothorphic and short-lived, which suggest that ascidians could be not efficient dispersers. However, the solitary ascidian Styela rustica (Linnaeus, 1767) (Tunicata, Ascidiacea) shows a wide distribution pattern from the North Atlantic to the Arctic that, together with the relatively recent colonization of the Arctic system could indicate that this species efficiently disperses and colonizes new habitats. In this study we used ISSR-PCR markers to study the genetic structure of five populations of the ascidian Styela rustica at Kongsfjorden, west Spitsbergen (Svalbard archipelago). We analyzed whether this species presents a low genetic structure, as can be expected due to the historical process of recent post glaciations colonization, or if there is genetic differentiation at a local scale, caused by short-lived larvae and limited dispersal potential. The genetic diversity in each population assessed using the marker diversity index (M) ranged from 0.288 to 0.324. Population HN, situated close to a fast retreating glacier, showed the lowest diversity. Processes associated with deglatiation (icebergs calving from the glacier that scour the benthos and the increment of inorganic particulate matter on the water column) would drive to reduced population sizes and explain the reduced genetic variability observed in the HN population with respect to the others in the fjord. This suggests a possible linkage with the global warming process. Although the weak genetic structure found among the studied populations could indicate a founder effect, the genetic landscape shape analysis together with a positive relationship between genetic and geographic distances also suggest possible current gene flow among populations in the fjord. 相似文献
58.
Because of its growing prevalence in Western countries, the metabolic syndrome, a common metabolic disorder that clusters a constellation of abnormalities, including central obesity, hypertension, dyslipidemia and insulin resistance, is emerging as one of the most important public health problems in the world, taking into account that it is a major risk factor mainly for type 2 diabetes and cardiovascular diseases, and also for many types of cancer. Although the pathogenesis of this syndrome is complex and not fully understood, obesity and insulin resistance, accompanied by an altered profile of number of hormones and cytokines produced by the adipose tissue, seem to be the main causative agents. A prime therapeutic approach to the prevention and treatment of this syndrome involves lifestyle changes. Among dietary modifications, dietary fiber intake could play an interesting role in the management of metabolic syndrome through different mechanisms related to its dietary sources, specific chemical structure and physical properties, or fermentability in the gut. According to all of these variables, the different types of dietary fibers have been reported to take part in the control of body weight, glucose and lipid homeostasis, insulin sensitivity and in the regulation of many inflammation markers involved in the pathogenesis of metabolic syndrome, and which are also considered to be among its features. 相似文献
59.
60.
E. Schiantarelli A. De la Peña M. Candela 《TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik》2001,102(2-3):335-341
The Landsberg erecta× Columbia recombinant inbred lines (RILs) of Arabidopsis have been used in order to identify and localize chromosome regions involved in the genetic control of the in vitro regeneration
ability. Callus morphology (CM) and shoot regeneration (SR) traits have been considered for both leaf and root explants. The
MAPMAKER analysis of leaf culture data has revealed at least one chromosome region involved with CM and several with SR, the
29–30 region of chromosome 1 being common for the two traits. Root explants did not segregate for CM but several QTLs have
been detected for SR. The chromosome regions involved with leaf culture regeneration seem to be different from those of root
cultures, although the regeneration of abnormal shoots in leaf explants share two chromosome regions with the regeneration
of normal shoots in root cultures.
Received: 19 April 2000 / Accepted: 12 May 2000 相似文献