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11.
12.
Anti-PlGF inhibits growth of VEGF(R)-inhibitor-resistant tumors without affecting healthy vessels 总被引:13,自引:0,他引:13
Fischer C Jonckx B Mazzone M Zacchigna S Loges S Pattarini L Chorianopoulos E Liesenborghs L Koch M De Mol M Autiero M Wyns S Plaisance S Moons L van Rooijen N Giacca M Stassen JM Dewerchin M Collen D Carmeliet P 《Cell》2007,131(3):463-475
Novel antiangiogenic strategies with complementary mechanisms are needed to maximize efficacy and minimize resistance to current angiogenesis inhibitors. We explored the therapeutic potential and mechanisms of alphaPlGF, an antibody against placental growth factor (PlGF), a VEGF homolog, which regulates the angiogenic switch in disease, but not in health. alphaPlGF inhibited growth and metastasis of various tumors, including those resistant to VEGF(R) inhibitors (VEGF(R)Is), and enhanced the efficacy of chemotherapy and VEGF(R)Is. alphaPlGF inhibited angiogenesis, lymphangiogenesis, and tumor cell motility. Distinct from VEGF(R)Is, alphaPlGF prevented infiltration of angiogenic macrophages and severe tumor hypoxia, and thus, did not switch on the angiogenic rescue program responsible for resistance to VEGF(R)Is. Moreover, it did not cause or enhance VEGF(R)I-related side effects. The efficacy and safety of alphaPlGF, its pleiotropic and complementary mechanism to VEGF(R)Is, and the negligible induction of an angiogenic rescue program suggest that alphaPlGF may constitute a novel approach for cancer treatment. 相似文献
13.
Influence of morphology and rheology on the production characteristics of the basidiomycete Cyathus striatus 总被引:3,自引:0,他引:3
The influence of the pellet morphology of the basidiomycete Cyathus striatus on the production of the antibiotics striatals A, B, and C was investigated. The main operating parameters in fermenters of different sizes were the tip speed and the volumetric power input. Different methods were developed for quantification of morphological characteristics. The apparent viscosity of the suspension was measured with a cylinder rheometer. Sediment density was measured with a sedimentation apparatus. Particle size distributions were recorded with an image analysis system. By means of the presented measuring methods, morphological characteristics could be determined and enabled an early assessment of the fermentation course and the antibiotics production. During the exponential growth phase of the fungus the relative sediment height correlated with the biomass concentration. The pellet morphology at this stage influenced the later production of striatals. The yield of the striatals was markedly influenced by pellet size and sediment density. Since these morphological characteristics determine the rheological properties of the culture the measurement of the apparent viscosity of the culture in the production phase allowed predictions of the production yield. 相似文献
14.
Lesage B Beullens M Nuytten M Van Eynde A Keppens S Himpens B Bollen M 《The Journal of biological chemistry》2004,279(53):55978-55984
Protein Ser/Thr phosphatase-1 (PP1) is a ubiquitous eukaryotic enzyme that controls numerous cellular processes by the dephosphorylation of key regulatory proteins. PP1 is expressed in various cellular compartments but is most abundant in the nucleus. We have examined the determinants for the nuclear localization of enhanced green fluorescent protein-tagged PP1 in COS1 cells. Our studies show that PP1gamma(1) does not contain a functional nuclear localization signal and that its nuclear accumulation does not require Sds22, which has previously been implicated in the nuclear accumulation of PP1 in yeast (Peggie, M. W., MacKelvie, S. H., Bloecher, A., Knatko, E. V., Tatchell, K., and Stark, M. J. R. (2002) J. Cell Sci. 115, 195-206). However, the nuclear targeting of PP1 isoforms was alleviated by the mutation of their binding sites for proteins that interact via an RVXF motif. Moreover, one of the mutants with a cytoplasmic accumulation and decreased affinity for RVXF motifs (PP1gamma(1)-F257A) could be re-targeted to the nucleus by the overexpression of nuclear interactors (NIPP1 (nuclear inhibitor of PP1) and PNUTS (PP1 nuclear targeting subunit)) with a functional RVXF motif. Also, the addition of a synthetic RVXF-containing peptide to permeabilized cells resulted in the loss of nuclear enhanced green fluorescent protein-PP1gamma(1). Finally, NIPP1(-/-) mouse embryos showed a nuclear hyperphosphorylation on threonine, consistent with a role for NIPP1 in the nuclear targeting and/or retention of PP1. Our data suggest that both the nuclear translocation and the nuclear retention of PP1 depend on its binding to interactors with an RVXF motif. 相似文献
15.
Pedro Casado Maria P Alcolea Francesco Iorio Juan-Carlos Rodríguez-Prados Bart Vanhaesebroeck Julio Saez-Rodriguez Simon Joel Pedro R Cutillas 《Genome biology》2013,14(4):R37
Background
Tumor classification based on their predicted responses to kinase inhibitors is a major goal for advancing targeted personalized therapies. Here, we used a phosphoproteomic approach to investigate biological heterogeneity across hematological cancer cell lines including acute myeloid leukemia, lymphoma, and multiple myeloma.Results
Mass spectrometry was used to quantify 2,000 phosphorylation sites across three acute myeloid leukemia, three lymphoma, and three multiple myeloma cell lines in six biological replicates. The intensities of the phosphorylation sites grouped these cancer cell lines according to their tumor type. In addition, a phosphoproteomic analysis of seven acute myeloid leukemia cell lines revealed a battery of phosphorylation sites whose combined intensities correlated with the growth-inhibitory responses to three kinase inhibitors with remarkable correlation coefficients and fold changes (> 100 between the most resistant and sensitive cells). Modeling based on regression analysis indicated that a subset of phosphorylation sites could be used to predict response to the tested drugs. Quantitative analysis of phosphorylation motifs indicated that resistant and sensitive cells differed in their patterns of kinase activities, but, interestingly, phosphorylations correlating with responses were not on members of the pathway being targeted; instead, these mainly were on parallel kinase pathways.Conclusion
This study reveals that the information on kinase activation encoded in phosphoproteomics data correlates remarkably well with the phenotypic responses of cancer cells to compounds that target kinase signaling and could be useful for the identification of novel markers of resistance or sensitivity to drugs that target the signaling network. 相似文献16.
Pacchiarotta T Hensbergen PJ Wuhrer M van Nieuwkoop C Nevedomskaya E Derks RJ Schoenmaker B Koeleman CA van Dissel J Deelder AM Mayboroda OA 《Journal of Proteomics》2012,75(3):1067-1073
Urinary tract infection (UTI) is the most common bacterial infection leading to substantial morbidity and considerable health care expenditures across all ages. Here we present an exploratory UPLC-MS study of human urine in the context of febrile, complicated urinary tract infection aimed to reveal and identify possible markers of a host response on infection. A UPLC-MS based workflow, taking advantage of Ultra High Resolution (UHR) Qq-ToF-MS, and multivariate data handling were applied to a carefully selected group of 39 subjects with culture-confirmed febrile Escherichia coli UTI. Using a combination of unsupervised and supervised multivariate modeling we have pinpointed a number of peptides specific for UTI. An unequivocal structural identification of these peptides, as O-glycosylated fragments of the human fibrinogen alpha 1 chain, required MS2 and MS3 experiments on two different MS platforms: ESI-UHR-Qq-ToF and ESI-ion trap, a blast search and, finally, confirmation was achieved by matching experimental tandem mass spectra with those of custom synthesized candidate-peptides.In conclusion, exploiting non-targeted UPLC-MS based approach for the investigation of UTI related changes in urine, we have identified and structurally characterized unique O-glycopeptides, which are, to our knowledge, the first demonstration of O-glycosylation of human fibrinogen alpha 1-chain. 相似文献
17.
Hui Tian Gabriel L Fiorin Anja Kombrink Jeroen R Mesters Bart P H J Thomma 《Plant physiology》2022,190(3):2033
Chitin is a homopolymer of β-(1,4)-linked N-acetyl-D-glucosamine (GlcNAc) and a major structural component of fungal cell walls. In plants, chitin acts as a microbe-associated molecular pattern (MAMP) that is recognized by lysin motif (LysM)-containing plant cell surface-localized pattern recognition receptors (PRRs) that activate a plethora of downstream immune responses. To deregulate chitin-induced plant immunity and successfully establish infection, many fungal pathogens secrete LysM domain-containing effector proteins during host colonization. The LysM effector Ecp6 from the tomato (Solanum lycopersicum) leaf mold fungus Cladosporium fulvum can outcompete plant PRRs for chitin binding because two of its three LysM domains cooperate to form a composite groove with ultra-high (pM) chitin-binding affinity. However, most functionally characterized LysM effectors contain only two LysMs, including Magnaporthe oryzae MoSlp1, Verticillium dahliae Vd2LysM, and Colletotrichum higginsianum ChElp1 and ChElp2. Here, we performed modeling, structural, and functional analyses to investigate whether such dual-domain LysM effectors can also form ultra-high chitin-binding affinity grooves through intramolecular LysM dimerization. However, our study suggests that intramolecular LysM dimerization does not occur. Rather, our data support the occurrence of intermolecular LysM dimerization for these effectors, associated with a substantially lower chitin binding affinity than monitored for Ecp6. Interestingly, the intermolecular LysM dimerization allows for the formation of polymeric complexes in the presence of chitin. Possibly, such polymers may precipitate at infection sites to eliminate chitin oligomers, and thus suppress the activation of chitin-induced plant immunity.Fungal LysM effectors composed of two LysM domains bind chitin via intermolecular LysM dimerization, leading to polymers that may precipitate to eliminate chitin from infection sites to prevent the activation of host immune receptors. 相似文献
18.
Mihai G. Netea Leo A. B. Joosten Monique Keuter Frank Wagener Anton F. H. Stalenhoef Jos W. M. van der Meer Bart Jan Kullberg 《PloS one》2009,4(1)
Background
Circulating lipoproteins improve the outcome of severe Gram-negative infections through neutralizing lipopolysaccharides (LPS), thus inhibiting the release of proinflammatory cytokines.Methods/Principal Findings
Low density lipoprotein receptor deficient (LDLR−/−) mice, with a 7-fold increase in LDL, are resistant against infection with Salmonella typhimurium (survival 100% vs 5%, p<0.001), and 100 to 1000-fold lower bacterial burden in the organs, compared with LDLR+/+ mice. Protection was not due to differences in cytokine production, phagocytosis, and killing of Salmonella organisms. The differences were caused by the excess of lipoproteins, as hyperlipoproteinemic ApoE−/− mice were also highly resistant to Salmonella infection. Lipoproteins protect against infection by interfering with the binding of Salmonella to host cells, and preventing organ invasion. This leads to an altered biodistribution of the microorganisms during the first hours of infection: after intravenous injection of Salmonella into LDLR+/+ mice, the bacteria invaded the liver and spleen within 30 minutes of infection. In contrast, in LDLR−/− mice, Salmonella remained constrained to the circulation from where they were efficiently cleared, with decreased organ invasion.Conclusions
plasma lipoproteins are a potent host defense mechanism against invasive Salmonella infection, by blocking adhesion of Salmonella to the host cells and subsequent tissue invasion. 相似文献19.
Cohn RD van Erp C Habashi JP Soleimani AA Klein EC Lisi MT Gamradt M ap Rhys CM Holm TM Loeys BL Ramirez F Judge DP Ward CW Dietz HC 《Nature medicine》2007,13(2):204-210
Skeletal muscle has the ability to achieve rapid repair in response to injury or disease. Many individuals with Marfan syndrome (MFS), caused by a deficiency of extracellular fibrillin-1, exhibit myopathy and often are unable to increase muscle mass despite physical exercise. Evidence suggests that selected manifestations of MFS reflect excessive signaling by transforming growth factor (TGF)-beta (refs. 2,3). TGF-beta is a known inhibitor of terminal differentiation of cultured myoblasts; however, the functional contribution of TGF-beta signaling to disease pathogenesis in various inherited myopathic states in vivo remains unknown. Here we show that increased TGF-beta activity leads to failed muscle regeneration in fibrillin-1-deficient mice. Systemic antagonism of TGF-beta through administration of TGF-beta-neutralizing antibody or the angiotensin II type 1 receptor blocker losartan normalizes muscle architecture, repair and function in vivo. Moreover, we show TGF-beta-induced failure of muscle regeneration and a similar therapeutic response in a dystrophin-deficient mouse model of Duchenne muscular dystrophy. 相似文献
20.
Three-dimensional pore space quantification of apple tissue using X-ray computed microtomography 总被引:1,自引:0,他引:1
The microstructure and the connectivity of the pore space are important variables for better understanding of the complex
gas transport phenomena that occur in plant tissues. In this study, we present an experimental procedure for image acquisition
and image processing to quantitatively characterize in 3D the pore space of apple tissues (Malus domestica Borkh.) for two cultivars (Jonagold and Braeburn) taken from the fleshy part of the cortex using X-ray computer microtomography.
Preliminary sensitivity analyses were performed to determine the effect of the resolution and the volume size (REV, representative
elementary volume analysis) on the computed porosity of apple samples. For comparison among cultivars, geometrical properties
such as porosity, specific surface area, number of disconnected pore volumes and their distribution parameters were extracted
and analyzed in triplicate based on the 3D skeletonization of the pore space (medial axis analysis). The results showed that
microtomography provides a resolution at the micrometer level to quantitatively analyze and characterize the 3D topology of
the pore space in apple tissue. The computed porosity was confirmed to be highly dependent of the resolution used, and the
minimum REV of the cortical flesh of apple fruit was estimated to be 1.3 mm3. Comparisons among the two cultivars using a resolution of 8.5 μm with a minimum REV cube showed that in spite of the complexity
and variability of the pore space network observed in Jonagold and Braeburn apples, the extracted parameters from the medial
axis were significantly different (P-value < 0.05). Medial axis parameters showed potential to differentiate the microstructure between the two evaluated apple
cultivars. 相似文献