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41.
Diabetic retinopathy is associated with a switch in splicing from anti- to pro-angiogenic isoforms of vascular endothelial growth factor 总被引:10,自引:0,他引:10
Aims/hypothesis Proliferative diabetic retinopathy results from excess blood vessel growth into the vitreous fluid of the eye. Retinal angiogenesis is regulated by expression of vascular endothelial growth factor (VEGF), and many studies have shown that VEGF is critically involved in proliferative diabetic retinopathy. VEGF is alternatively spliced to form the angiogenic (VEGFxxx) and potentially anti-angiogenic (VEGFxxxb) family of isoforms. The VEGFxxxb family is found in normal tissues, but down-regulated in renal and prostate cancer. Previous studies on endogenous expression of VEGF in the eye have not distinguished between the two families of isoforms.Methods We measured VEGFxxxb isoform expression in normal human eye tissue (lens, sclera, retina and iris) and vitreous fluid using enzyme-linked immunosorbent assay and Western blotting with a VEGFxxxb-specific antibody.Results VEGFxxxb protein was expressed in lens, sclera, retina, iris and vitreous fluid. Multiple isoforms were seen, including VEGF165b, VEGF121b, VEGF145b, VEGF183b and VEGF189b. In non-diabetic patients, 64±7% of the VEGF in the vitreous was VEGFxxxb (n=18), whereas in diabetic patients only 12.5±3.6% of total VEGF was VEGFxxxb.Conclusions/interpretation Since VEGFxxxb inhibits VEGFxxx-induced angiogenesis in a one-to-one stoichiometric manner, these results show that in the eye of diabetic patients VEGF splicing was switched from an anti-angiogenic to a pro-angiogenic environment. This occurred through changes to the ratio of VEGFxxx : VEGFxxxb. Alterations to splicing, and through that to the balance of VEGF isoforms, could therefore be a potential therapeutic strategy for diabetic retinopathy.Konopatskaya and Perrin are joint first authors. 相似文献
42.
Nicholas Beazley-Long Jing Hua Thomas Jehle Richard P. Hulse Rick Dersch Christina Lehrling Heather Bevan Yan Qiu Wolf A. Lagrèze David Wynick Amanda J. Churchill Patrick Kehoe Steven J. Harper David O. Bates Lucy F. Donaldson 《The American journal of pathology》2013,183(3):918-929
Vascular endothelial growth factor (VEGF) A is generated as two isoform families by alternative RNA splicing, represented by VEGF-A165a and VEGF-A165b. These isoforms have opposing actions on vascular permeability, angiogenesis, and vasodilatation. The proangiogenic VEGF-A165a isoform is neuroprotective in hippocampal, dorsal root ganglia, and retinal neurons, but its propermeability, vasodilatatory, and angiogenic properties limit its therapeutic usefulness. In contrast, a neuroprotective effect of endogenous VEGF-A165b on neurons would be advantageous for neurodegenerative pathologies. Endogenous expression of human and rat VEGF-A165b was detected in hippocampal and cortical neurons. VEGF-A165b formed a significant proportion of total VEGF-A in rat brain. Recombinant human VEGF-A165b exerted neuroprotective effects in response to multiple insults, including glutamatergic excitotoxicity in hippocampal neurons, chemotherapy-induced cytotoxicity of dorsal root ganglion neurons, and retinal ganglion cells (RGCs) in rat retinal ischemia-reperfusion injury in vivo. Neuroprotection was dependent on VEGFR2 and MEK1/2 activation but not on p38 or phosphatidylinositol 3–kinase activation. Recombinant human VEGF-A165b is a neuroprotective agent that effectively protects both peripheral and central neurons in vivo and in vitro through VEGFR2, MEK1/2, and inhibition of caspase-3 induction. VEGF-A165b may be therapeutically useful for pathologies that involve neuronal damage, including hippocampal neurodegeneration, glaucoma diabetic retinopathy, and peripheral neuropathy. The endogenous nature of VEGF-A165b expression suggests that non–isoform-specific inhibition of VEGF-A (for antiangiogenic reasons) may be damaging to retinal and sensory neurons.Vascular endothelial growth factor (VEGF) A, originally described as a potent vascular permeability and growth factor for endothelial cells, is up-regulated in the brain during stroke and ischemic episodes1 and has been linked with many neuronal diseases. The most widely studied isoform of VEGF-A, VEGF-A165a, is up-regulated in hypoxia, induces increased vascular permeability in neuronal vasculature, and can stimulate angiogenesis after ischemic episodes. The resulting edema and hyperemia can be damaging, but VEGF-A165a has also been found to have direct anticytotoxic effects on neurons, raising the possibility that it may act as an endogenous neuroprotective agent in neurodegenerative pathologies. VEGF-A exerts neurotrophic (survival) and neurotropic (neurogenesis and axon outgrowth) actions, which, although initially thought to be a function of increased angiogenesis and perfusion after neuronal injury,2 are now appreciated as direct effects of VEGF-A on neurons.The vegfa gene encodes numerous products by differential splicing, but not all isoforms exert the same effects.3 Alternative splicing of exon 8 leads to two functionally distinct families: the proangiogenic VEGF-Axxxa family and the counteracting VEGF-Axxxb family.4,5 VEGF-A165b prevents the VEGF-A165a effects on increased vascular permeability, blood vessel growth, and vasodilatation.4–7The therapeutic potential of VEGF-A and anti–VEGF-A treatments are now widely recognized, and effective anti–VEGF-A treatments are available in ophthalmology8 and oncology.9 The finding that VEGF-A is implicated in neuronal disorders (eg, Alzheimer disease, Parkinson disease, Huntington disease, diabetic neuropathy, and amyotrophic lateral sclerosis10) provides a rationale for the use of VEGF-A as a therapeutic agent in neurodegenerative conditions. Although this rationale is supported by preclinical evidence,11 the identification of the VEGF-Axxxb family requires reexamination of VEGF-A isoforms in these contexts to allow for the clear evidence that VEGF-A splicing variants are not functionally equivalent3 and to determine whether augmentation of the proangiogenic isoform family (VEGF-Axxxa) alone may have deleterious effects (eg, in occult malignancy and carcinoma in situ).The neuroprotective profile of the exon 8 alternatively spliced isoforms VEGF-Axxxb remains unexplored. Interestingly, VEGF-Axxxb isoforms do not exhibit the vascular effects seen with VEGF-Axxxa isoforms, such as a sustained increase in capillary permeability or hypotension.5,12 The lack of these potential adverse effects may make VEGF-Axxxb isoforms more amenable as therapeutic agents in neurodegenerative diseases.We therefore tested the hypothesis that VEGF-A165b is neuroprotective for central and peripheral neurons. We found that VEGF-A165b is expressed in central neurons and is neuroprotective in vitro and in vivo. This finding indicates that VEGF-A165b may prove to be a suitable therapeutic agent in neurodegenerative disorders, exhibiting fewer adverse effects than VEGF-A165a. 相似文献
43.
Hywyn Churchill Harris Naina Richard Boriack Dinesh Rakheja Weina Chen 《International journal of clinical and experimental pathology》2015,8(9):11753-11759
Objectives: Angioimmunoblastic T-cell lymphoma (AITL) is an aggressive peripheral T-cell lymphoma with mutations in genes encoding isocitrate dehydrogenase1 and 2 (IDH1 and IDH2). Mutant IDH generates the oncometabolite D-2-hydroxyglutarate (D-2HG). We report the first case of discordant intracellular and plasma D-2HG levels in a patient with IDH2 R172S mutated AITL. Methods: An 87-year-old woman was diagnosed with AITL in the groin lymph node by morphologic and immunophenotypic analyses, and molecular studies by DNA sequencing. D-2HG was measured in both tumoral tissue and in pre-treatment plasma by liquid chromatography-tandem mass spectrometry. Results: While D-2HG was markedly elevated in the tissue sample, its level in plasma was normal. We discuss this discordant D-2HG result within the context of previously reported discordant 2HG results in other IDH mutated tumors, and its implication for using circulating D-2HG as a biomarker of IDH mutation. In addition, this case also harbored mutations in RHOA, TET2, and TP53. The molecular pathogenesis is briefly discussed. Conclusion: While our case suggests that circulating D-2HG is not a reliable marker of IDH mutation in AITL, more cases need to be studied to arrive at a definite conclusion. 相似文献
44.
45.
Shervin S. Churchill Michael C. Leo Eileen M. Brennan Claudia Sellmaier Judy Kendall Gail M. Houck 《Maternal and child health journal》2018,22(8):1172-1182
Objective Evaluate the efficacy of a 12 month nursing case-management intervention over a period of 18 months, 6 months after the end of intervention, for families of children attention deficit hyperactivity disorder (ADHD). Methods Mother and child dyads were enrolled to participate in a randomized controlled clinical trial. Children were 4–18 years old. Data were collected at baseline, 6, 12, and 18 months or 6 months after the termination of direct intervention. Longitudinal analyses, using generalized estimating equations, were conducted to assess change in study outcomes relating to family function, maternal stress, and child behavior over the 18 month period. Results Compared to control families, some family function outcomes were moderately improved in the intervention group. In particular, intervention families demonstrated substantial improvement in implementing family behavior controls (p value?=?0.038) and improvement in family satisfaction (not statistically significant p?=?0.062). Although there was improvement in the overall family function measure there was not a statistically significant difference between groups. Maternal stress and child behavior outcomes were not significantly different between control and intervention groups by the end of the intervention. Conclusions for Practice Addressing ADHD is complex and requires the assessment of comorbidities that might exacerbate negative behavior. Our findings support the latest American Academy of Pediatrics guidelines to use behavioral therapy as the first line of treatment in young children. Nursing case-management interventions that provide direct family education and improve family function, especially with respect to providing structure and behavior control, may complement and facilitate behavioral therapy for treatment of ADHD and improving child behavior. 相似文献
46.
Donna C. Jessop Ph.D Paul Sparks Ph.D Nicola Buckland BSc Peter R. Harris Ph.D Sue Churchill Ph.D 《Annals of behavioral medicine》2014,47(2):137-147
Background
There is limited evidence that self-affirmation manipulations can promote health behavior change.Purpose
The purpose of this study was to explore whether the efficacy of a self-affirmation manipulation at promoting exercise could be enhanced by an implementation intention intervention.Methods
Participants (Study 1?N?=?120, Study 2?N?=?116) were allocated to one of four conditions resulting from the two (self-affirmation manipulation: no affirmation, affirmation) by two (implementation intention manipulation: no implementation intention, implementation intention) experimental design. Exercise behavior was assessed 1 week post-intervention.Results
Contrary to prediction, those participants receiving both manipulations were significantly less likely to increase the amount they exercised compared to those receiving only the self-affirmation manipulation.Conclusion
Incorporating an implementation intention manipulation alongside a self-affirmation manipulation had a detrimental effect on exercise behavior; participants receiving both manipulations exercised significantly less in the week following the intervention. 相似文献47.
48.
Cassandra D. M. Churchill Mariusz Klobukowski Jack A. Tuszynski 《Chemical biology & drug design》2015,86(2):190-199
Laulimalide, a cancer chemotherapeutic in preclinical development, has a unique binding site located on two adjacent β‐tubulin units between tubulin protofilaments of a microtubule. Our extended protein model more accurately mimics the microtubule environment, and together with a 135 ns molecular dynamics simulation, identifies a new binding mode for laulimalide, which differs from the modes presented in work using smaller protein models. The new laulimalide–residue interactions that are computationally revealed explain the contacts observed via independent mass shift perturbation experiments. The inclusion of explicit solvent shows that many laulimalide–tubulin interactions are water mediated. The new contacts between the drug and the microtubule structure not only improve our understanding of laulimalide binding but also will be essential for efficient derivatization and optimization of this prospective cancer chemotherapy agent. Observed changes in secondary protein structure implicate the S7–H9 loop (M–loop) and H1′–S2 loop in the mechanism by which laulimalide stabilizes microtubules to exert its cytotoxic effects. 相似文献
49.
A study was conducted on the phosphorylation of proteins in the neutrophil cytosol in response to phorbol myristate acetate (PMA) and N- formyl-methionyl-leucyl-phenylalanine (fMLP). Autoradiography of gel electrophoretograms prepared from neutrophils incubated with 32Pi in the presence and absence of the activators showed nine proteins whose state of phosphorylation was affected by neutrophil activation. 32P was gained by eight of these proteins and was lost by the ninth. For all but one of these proteins, the change in the extent of labeling appeared to reach completion by one to two minutes. It was possible to quantitate the changes in 32P content of three of the nine proteins. One of these was the 20-kD protein that lost label when the neutrophils were activated. Quantitation showed that over half the 32P present in this protein in the resting state was gone within 0.2 minutes after activation. The other two were proteins weighing 11 and 69 kD. The phosphorylation characteristics of these two proteins differed, depending on whether activation had been carried out with PMA or fMLP. These differences in protein phosphorylation support other evidence suggesting that PMA and fMLP do not activate neutrophils by identical biochemical pathways. Differences in phosphorylation between resting and activated cells were not affected by dibutyryl cyclic guanosine monophosphate (cGMP), dibutyryl cyclic adenosine monophosphate (cAMP), theophylline, aspirin, hydrocortisone, or colchicine. The differences were abolished, however, by 30 mumol/L trifluoperazine. This finding is consistent with the hypothesis that the calcium/calmodulin system plays a biochemical role in the activation of neutrophils. 相似文献
50.
Comparing within‐subject classification and regularization methods in fMRI for large and small sample sizes 下载免费PDF全文
In recent years, a variety of multivariate classifier models have been applied to fMRI, with different modeling assumptions. When classifying high‐dimensional fMRI data, we must also regularize to improve model stability, and the interactions between classifier and regularization techniques are still being investigated. Classifiers are usually compared on large, multisubject fMRI datasets. However, it is unclear how classifier/regularizer models perform for within‐subject analyses, as a function of signal strength and sample size. We compare four standard classifiers: Linear and Quadratic Discriminants, Logistic Regression and Support Vector Machines. Classification was performed on data in the linear kernel (covariance) feature space, and classifiers are tuned with four commonly‐used regularizers: Principal Component and Independent Component Analysis, and penalization of kernel features using L1 and L2 norms. We evaluated prediction accuracy (P) and spatial reproducibility (R) of all classifier/regularizer combinations on single‐subject analyses, over a range of three different block task contrasts and sample sizes for a BOLD fMRI experiment. We show that the classifier model has a small impact on signal detection, compared to the choice of regularizer. PCA maximizes reproducibility and global SNR, whereas Lp‐norms tend to maximize prediction. ICA produces low reproducibility, and prediction accuracy is classifier‐dependent. However, trade‐offs in (P,R) depend partly on the optimization criterion, and PCA‐based models are able to explore the widest range of (P,R) values. These trends are consistent across task contrasts and data sizes (training samples range from 6 to 96 scans). In addition, the trends in classifier performance are consistent for ROI‐based classifier analyses. Hum Brain Mapp 35:4499–4517, 2014. © 2014 Wiley Periodicals, Inc . 相似文献