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排序方式: 共有125条查询结果,搜索用时 0 毫秒
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Ashton A. Connor Robert E. Denroche Gun Ho Jang Mathieu Lemire Amy Zhang Michelle Chan-Seng-Yue Gavin Wilson Robert C. Grant Daniele Merico Ilinca Lungu John M.S. Bartlett Dianne Chadwick Sheng-Ben Liang Jenna Eagles Faridah Mbabaali Jessica K. Miller Paul Krzyzanowski Heather Armstrong Steven Gallinger 《Cancer cell》2019,35(2):267-282.e7
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Fluid shear stress generated by blood flowing over the endothelium is a major determinant of arterial tone, vascular remodeling, and atherogenesis. Nitric oxide (NO) produced by endothelial NO synthase (eNOS) plays an essential role in regulation of vascular function and structure by blood flow, but the molecular mechanisms that transduce mechanical force to eNOS activation are not well understood. In this study, we found that laminar flow (shear stress=12 dyne/cm2) rapidly activates vascular endothelial growth factor receptor 2 (VEGFR2) in a ligand-independent manner and leads to eNOS activation in cultured endothelial cells. Flow-stimulated VEGFR2 recruits phosphoinositide 3-kinase and mediates activation of Akt and eNOS. Inhibiting VEGFR2 kinase with selective inhibitors blocks flow-induced activation of Akt and eNOS and production of NO. Decreasing VEGFR2 expression with antisense VEGFR2 oligonucleotides significantly attenuates activation of Akt and eNOS. Furthermore, Src kinases are involved in flow-stimulated VEGFR2 because inhibiting Src kinases by PP2, a selective inhibitor for Src kinases, abolishes flow-induced VEGFR2 tyrosine phosphorylation and downstream signaling. Finally, we show that inhibiting VEGFR2 kinase significantly reduces flow-mediated NO-dependent arteriolar dilation in vivo. These data identify VEGFR2 as a key mechanotransducer that activates eNOS in response to blood flow. 相似文献
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Pressure ulcer prevention is an important long‐term care (LTC) quality indicator. While the Braden Scale is a recommended risk assessment tool, there is a paucity of information specifically pertaining to its validity within the LTC setting. We, therefore, undertook a systematic review and meta‐analysis comparing Braden Scale predictive and concurrent validity within this context. We searched the Medline, EMBASE, PsychINFO and PubMed databases from 1985–2014 for studies containing the requisite information to analyze tool validity. Our initial search yielded 3,773 articles. Eleven datasets emanating from nine published studies describing 40,361 residents met all meta‐analysis inclusion criteria and were analyzed using random effects models. Pooled sensitivity, specificity, positive predictive value (PPV), and negative predictive values were 86%, 38%, 28%, and 93%, respectively. Specificity was poorer in concurrent samples as compared with predictive samples (38% vs. 72%), while PPV was low in both sample types (25 and 37%). Though random effects model results showed that the Scale had good overall predictive ability [RR, 4.33; 95% CI, 3.28–5.72], none of the concurrent samples were found to have “optimal” sensitivity and specificity. In conclusion, the appropriateness of the Braden Scale in LTC is questionable given its low specificity and PPV, in particular in concurrent validity studies. Future studies should further explore the extent to which the apparent low validity of the Scale in LTC is due to the choice of cutoff point and/or preventive strategies implemented by LTC staff as a matter of course. 相似文献
6.
MMP2 role in breast cancer brain metastasis development and its regulation by TIMP2 and ERK1/2 总被引:2,自引:0,他引:2
Matrix metalloproteinase 2 (MMP2) is important in breast cancer (BC) invasion and metastasis. We previously reported that
BC brain metastases, in a rat syngeneic model developed in our laboratory, have high expression and activity of MMP2. The
MMP2 mechanism of action in the brain is still under intense scrutiny. To study the role of MMP2 in the development of BC
brain metastasis we transfected ENU1564 rat mammary adenocarcinoma cells with tissue inhibitor of MMP2 (TIMP2). Animals inoculated
with ENU1564-TIMP2 cells had decreased orthotopic tumor growth, decreased orthotopic metastastic behavior and did not develop
brain metastases. These results were associated with decreased MMP2 activity, demonstrated by gel zymography. Mitogen activated
protein kinase (MAPK) pathway components, such as ERK1/2, have been correlated to MMP expression and/or astrocyte activity.
We found that BC brain metastases have peripheral astrocyte reactivity and higher expression of glial fibrillary acidic protein
(GFAP) and phosphorylated-ERK1/2 (p-ERK1/2). Additionally, rat astrocyte-conditioned media increased in vitro invasion of
ENU1564 cancer cells and increased expression of MMP2 and p-ERK1/2. Blockage of ERK1/2 phosphorylation by treatment with MEK
inhibitor (PD98059) decreased the expression of MMP2 in cancer cells grown in rat astrocyte-conditioned media. Our results
are highly suggestive that MMP2 plays a role in the development of BC metastases, in particular to the brain. Furthermore,
our results suggest that astrocyte factors and the ERK1/2 signaling pathway may be associated with BC brain metastasis development;
and that ERK1/2 may regulate MMP2 in a way that is modifiable by astrocyte factors. 相似文献
7.
Bares M Lungu O Liu T Waechter T Gomez CM Ashe J 《Experimental brain research. Experimentelle Hirnforschung. Expérimentation cérébrale》2007,180(2):355-365
The ability to precisely time events is essential for both perception and action. There is evidence that the cerebellum is
important for the neural representation of time in a variety of behaviors including time perception, the tapping of specific
time intervals, and eye-blink conditioning. It has been difficult to assess the contribution of the cerebellum to timing during
more dynamic motor behavior because the component movements themselves may be abnormal or any motor deficit may be due to
an inability to combine the component movements into a complete action rather than timing per se. Here we investigated the
performance of subjects with cerebellar disease in predictive motor timing using a task that involved mediated interception
of a moving target, and we tested the effect of movement type (acceleration, deceleration, constant), speed (slow, medium,
fast), and angle (0°, 15° and 30°) on performance. The subjects with cerebellar damage were significantly worse at interception
than healthy controls even when we controlled for basic motor impairments such as response time. Our data suggest that subjects
with damage to the cerebellum have a fundamental problem with predictive motor timing and indicate that the cerebellum plays
an essential role in integrating incoming visual information with motor output when making predictions about upcoming actions.
The findings demonstrate that the cerebellum may have properties that would facilitate the processing or storage of internal
models of motor behavior. 相似文献
8.
Liu T Lungu OV Waechter T Willingham DT Ashe J 《Experimental brain research. Experimentelle Hirnforschung. Expérimentation cérébrale》2007,180(2):273-280
There is a significant overlap between the processes and neural substrates of spatial cognition and those subserving memory
and learning. However, for procedural learning, which often is spatial in nature, we do not know how different forms of spatial
knowledge, such as egocentric and allocentric frames of reference, are utilized nor whether these frames are differentially
engaged during implicit and explicit processes. To address this issue, we trained human subjects on a movement sequence presented
on a bi-dimensional (2D) geometric frame. We then systematically manipulated the geometric frame (allocentric) or the sequence
of movements (egocentric) or both, and retested the subjects on their ability to transfer the sequence knowledge they had
acquired in training and also determined whether the subjects had learned the sequence implicitly or explicitly. None of the
subjects (implicit or explicit) showed evidence of transfer when both frames of reference were changed which suggests that
spatial information is essential. Both implicit and explicit subjects transferred when the egocentric frame was maintained
indicating that this representation is common to both processes. Finally, explicit subjects were also able to benefit from
the allocentric frame in transfer, which suggests that explicit procedural knowledge may have two tiers comprising egocentric
and allocentric representations. 相似文献
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