| 501. |
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| 502. |
- Wang, Gang, et al.
(author)
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Spirometric phenotypes from early childhood to young adulthood : a Chronic Airway Disease Early Stratification study
- 2021
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In: ERJ Open Research. - : ERS Publications. - 2312-0541. ; 7:4
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Journal article (peer-reviewed)abstract
- Background: The prevalences of obstructive and restrictive spirometric phenotypes, and their relation to early-life risk factors from childhood to young adulthood remain poorly understood. The aim was to explore these phenotypes and associations with well-known respiratory risk factors across ages and populations in European cohorts.Methods: We studied 49334 participants from 14 population-based cohorts in different age groups (⩽10, >10–15, >15–20, >20–25 years, and overall, 5–25 years). The obstructive phenotype was defined as forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) z-score less than the lower limit of normal (LLN), whereas the restrictive phenotype was defined as FEV1/FVC z-score ⩾LLN, and FVC z-score Results: The prevalence of obstructive and restrictive phenotypes varied from 3.2–10.9% and 1.8–7.7%, respectively, without clear age trends. A diagnosis of asthma (adjusted odds ratio (aOR=2.55, 95% CI 2.14–3.04), preterm birth (aOR=1.84, 1.27–2.66), maternal smoking during pregnancy (aOR=1.16, 95% CI 1.01–1.35) and family history of asthma (aOR=1.44, 95% CI 1.25–1.66) were associated with a higher prevalence of obstructive, but not restrictive, phenotype across ages (5–25 years). A higher current body mass index (BMI was more often observed in those with the obstructive phenotype but less in those with the restrictive phenotype (aOR=1.05, 95% CI 1.03–1.06 and aOR=0.81, 95% CI 0.78–0.85, per kg·m−2 increase in BMI, respectively). Current smoking was associated with the obstructive phenotype in participants older than 10 years (aOR=1.24, 95% CI 1.05–1.46).Conclusion: Obstructive and restrictive phenotypes were found to be relatively prevalent during childhood, which supports the early origins concept. Several well-known respiratory risk factors were associated with the obstructive phenotype, whereas only low BMI was associated with the restrictive phenotype, suggesting different underlying pathobiology of these two phenotypes.
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| 503. |
- Wang, Tianyan, et al.
(author)
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PIP5K1α is Required for Promoting Tumor Progression in Castration-Resistant Prostate Cancer
- 2022
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In: Frontiers in Cell and Developmental Biology. - : Frontiers Media S.A.. - 2296-634X. ; 10
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Journal article (peer-reviewed)abstract
- PIP5K1α has emerged as a promising drug target for the treatment of castration-resistant prostate cancer (CRPC), as it acts upstream of the PI3K/AKT signaling pathway to promote prostate cancer (PCa) growth, survival and invasion. However, little is known of the molecular actions of PIP5K1α in this process. Here, we show that siRNA-mediated knockdown of PIP5K1α and blockade of PIP5K1α action using its small molecule inhibitor ISA-2011B suppress growth and invasion of CRPC cells. We demonstrate that targeted deletion of the N-terminal domain of PIP5K1α in CRPC cells results in reduced growth and migratory ability of cancer cells. Further, the xenograft tumors lacking the N-terminal domain of PIP5K1α exhibited reduced tumor growth and aggressiveness in xenograft mice as compared to that of controls. The N-terminal domain of PIP5K1α is required for regulation of mRNA expression and protein stability of PIP5K1α. This suggests that the expression and oncogenic activity of PIP5K1α are in part dependent on its N-terminal domain. We further show that PIP5K1α acts as an upstream regulator of the androgen receptor (AR) and AR target genes including CDK1 and MMP9 that are key factors promoting growth, survival and invasion of PCa cells. ISA-2011B exhibited a significant inhibitory effect on AR target genes including CDK1 and MMP9 in CRPC cells with wild-type PIP5K1α and in CRPC cells lacking the N-terminal domain of PIP5K1α. These results indicate that the growth of PIP5K1α-dependent tumors is in part dependent on the integrity of the N-terminal sequence of this kinase. Our study identifies a novel functional mechanism involving PIP5K1α, confirming that PIP5K1α is an intriguing target for cancer treatment, especially for treatment of CRPC.
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| 504. |
- Wilkinson, M., et al.
(author)
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Partitioned postseismic deformation associated with the 2009 Mw 6.3 L'Aquila earthquake surface rupture measured using a terrestrial laser scanner
- 2010
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In: Geophysical Research Letters. - 0094-8276 .- 1944-8007. ; 37, s. L10309-
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Journal article (peer-reviewed)abstract
- Using 3D terrestrial laser scan (TLS) technology, we have recorded postseismic deformation on and adjacent to the surface rupture formed during the 6th April 2009 L'Aquila normal faulting earthquake (Mw 6.3). Using surface modeling techniques and repeated surveys 8-124 days after the earthquake, we have produced a 4D dataset of postseismic deformation across a 3 x 65 m area at high horizontal spatial resolution. We detected millimetre-scale movements partitioned between discrete surface rupture slip and development of a hangingwall syncline over 10's of meters. We interpret the results as the signal of shallow afterslip in the fault zone. We find 52% of the total postseismic hangingwall vertical motion occurs as deformation within 30 m of the surface rupture. The total postseismic vertical motions are approximately 50% that of the coseismic. We highlight the importance of quantifying partitioned postseismic contributions when applying empirical slip-magnitude datasets to infer palaeoearthquake magnitudes. Citation: Wilkinson, M., et al. (2010), Partitioned postseismic deformation associated with the 2009 Mw 6.3 L'Aquila earthquake surface rupture measured using a terrestrial laser scanner.
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| 505. |
- Wismans, Jac, 1948, et al.
(author)
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Development and Evaluation of the ES-2 Dummy
- 2001
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Reports (other academic/artistic)abstract
- Over the last year, the European Enhanced Vehicle-safety Committee Working Group 12 has assessed and reviewed the performance of the enhanced anthropomorphic test device for lateral impacts, EUROSID-2 (ES-2). The objectives for this work have been the following: - To verify whether the proposed design is addressing the shortcomings of the regulatory test device EUROSID-1 as identified previously by EEVC and NHTSA- To make sure that the original EUROSID-1 biofidelity and performance in normal test conditions is preserved. - To reach a well-balanced conclusion, the working group has undertaken a test program to assess the most important requirements for the ES-2 dummy, biofidelity, sensitivity, repeatability, handling, durability, certification and full-scale performance in comparison with EUROSID-1.In addition, but no less important, the working group has reviewed and explored the findings of full-scale tests conducted at several member organisations within ACEA. ACEA has reported the most important findings in September 2000. Subsequently, WG 12 has further investigated the issues raised in this report. On the basis of this work, the working group has concluded the following with regards to the ES-2 specifications and performance:The ES-2 prototype as tested is superior to current test device EUROSID-1 and, hence, a more appropriate test device for regulatory testing. The important shortcomings of the EUROSID-1 have been satisfactorily addressed with ES-2, whilst biofidelity is maintained, in some areas even somewhat improved. It should be noted, however, that the assessment of thorax biofidelity was based on deflection and force-time data only, and does not incorporate an assessment of V*C. It is recommended to adopt the hardware design without further modification and to use the new proposed certification procedures, with the exception of the high velocity pelvis test.Overall test results in full-scale tests have shown that some critical dummy measurement values for ES-2 have increased compared to EUROSID-1, in particular rib deflection, 17%, and V*C, 23%1 on average. Other values on the other hand have brought down such as the pubic force (10%) due to improved leg interaction. Contrary to the full-scale results, the ES-2 gave equal or lower values for all critical measurements in the biofidelity tests.For the large majority of vehicles tested, the different results would not affect pass or fail with respect to current regulatory limits. It should be noted, however, that, maintaining the rating levels in consumer testing, ES-2 results would lead motoring consumers to believe the protection offered in side impact has decreased while in fact the safety performance of these vehicles has not changed.A force transducer has been developed to measure the force applied to the back plate. It is recommended to use the force transducer in full vehicle assessment.Finally, the working group believes the ES-2 dummy forms a solid basis for interim harmonisation and will further support activities to help realise this objective.
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| 506. |
- Wolfraim, Lawrence A, et al.
(author)
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Loss of Smad3 in acute T-cell lymphoblastic leukemia
- 2004
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In: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 351:6, s. 552-559
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Journal article (peer-reviewed)abstract
- BACKGROUND: The receptors for transforming growth factor β (TGF-β) and their signaling intermediates make up an important tumor-suppressor pathway. The role of one of these intermediates - Smad3 - in the pathogenesis of lymphoid neoplasia is unknown. METHODS: We measured Smad3 messenger RNA (mRNA) and protein in leukemia cells obtained at diagnosis from 19 children with acute leukemia, including 10 with T-cell acute lymphoblastic leukemia (ALL), 7 with pre-B-cell ALL, and 2 with acute nonlymphoblastic leukemia (ANLL). All nine exons of the SMAD3 gene (MADH3) were sequenced. Mice in which one or both alleles of Smad3 were inactivated were used to evaluate the role of Smad3 in the response of normal T cells to TGF-β and in the susceptibility to spontaneous leukemogenesis in mice in which both alleles of the tumor suppressor p27Kip1 were deleted. RESULTS: Smad3 protein was absent in T-cell ALL but present in pre-B-cell ALL and ANLL. No mutations were found in the MADH3 gene in T-cell ALL, and Smad3 mRNA was present in T-cell ALL and normal T cells at similar levels. In mice, the loss of one allele for Smad3 impairs the inhibitory effect of TGF-β on the proliferation of normal T cells and works in tandem with the homozygous inactivation of p27Kip1 to promote T-cell leukemogenesis. CONCLUSIONS: Loss of Smad3 protein is a specific feature of pediatric T-cell ALL. A reduction in Smad3 expression and the loss of p27Kip1 work synergistically to promote T-cell leukemogenesis in mice.
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| 507. |
- Woodward, A, et al.
(author)
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Scaling up task-sharing psychological interventions for refugees in Jordan: a qualitative study on the potential barriers and facilitators
- 2023
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In: Health policy and planning. - : Oxford University Press (OUP). - 1460-2237. ; 38:3, s. 310-320
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Journal article (peer-reviewed)abstract
- Training nonspecialists in providing evidence-based psychological interventions (i.e. task-sharing) can effectively increase community access to psychological support. However, task-sharing interventions for this purpose are rarely used at scale. The aim of this study was to examine the factors influencing the potential for scaling up (i.e. scalability) of a task-sharing psychological intervention called Problem Management Plus (PM+) for Syrian refugees in Jordan. Semi-structured individual (n = 17) and group interviews (n = 20) were conducted with stakeholders knowledgeable about PM+ and the mental health system for Syrian refugees in Jordan. Using ‘system innovation perspective’, this study conceptualized the context as landscape developments, and systemic considerations were divided into culture (shared ways of thinking) and structure (ways of organizing). Political momentum was identified as a landscape trend likely facilitating scaling up, while predicted reductions in financial aid was regarded as a constraint. In terms of culture, the medicalized approach to mental health, stigma and gender were reported barriers for scaling up PM+. Using non-stigmatizing language and offering different modalities, childcare options and sessions outside of working hours were suggestions to reduce stigma, accommodate individual preferences and increase the demand for PM+. In relation to structure, the feasibility of scaling up PM+ largely depends on the ability to overcome legal barriers, limitations in human and financial resources and organizational challenges. We recommend sustainable funding to be made available for staff, training, supervision, infrastructure, coordination, expansion and evaluation of ‘actual’ scaling up of PM+. Future research may examine the local feasibility of various funding, training and supervision models. Lessons learned from actual scaling up of PM+ and similar task-sharing approaches need to be widely shared.
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| 508. |
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| 509. |
- Yusuf, S., et al.
(author)
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Telmisartan to prevent recurrent stroke and cardiovascular events
- 2008
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In: New England Journal of Medicine. - : Massachusetts medical society. - 1533-4406 .- 0028-4793. ; 359:12, s. 1225-37
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Journal article (peer-reviewed)abstract
- BACKGROUND: Prolonged lowering of blood pressure after a stroke reduces the risk of recurrent stroke. In addition, inhibition of the renin-angiotensin system in high-risk patients reduces the rate of subsequent cardiovascular events, including stroke. However, the effect of lowering of blood pressure with a renin-angiotensin system inhibitor soon after a stroke has not been clearly established. We evaluated the effects of therapy with an angiotensin-receptor blocker, telmisartan, initiated early after a stroke. METHODS: In a multicenter trial involving 20,332 patients who recently had an ischemic stroke, we randomly assigned 10,146 to receive telmisartan (80 mg daily) and 10,186 to receive placebo. The primary outcome was recurrent stroke. Secondary outcomes were major cardiovascular events (death from cardiovascular causes, recurrent stroke, myocardial infarction, or new or worsening heart failure) and new-onset diabetes. RESULTS: The median interval from stroke to randomization was 15 days. During a mean follow-up of 2.5 years, the mean blood pressure was 3.8/2.0 mm Hg lower in the telmisartan group than in the placebo group. A total of 880 patients (8.7%) in the telmisartan group and 934 patients (9.2%) in the placebo group had a subsequent stroke (hazard ratio in the telmisartan group, 0.95; 95% confidence interval [CI], 0.86 to 1.04; P=0.23). Major cardiovascular events occurred in 1367 patients (13.5%) in the telmisartan group and 1463 patients (14.4%) in the placebo group (hazard ratio, 0.94; 95% CI, 0.87 to 1.01; P=0.11). New-onset diabetes occurred in 1.7% of the telmisartan group and 2.1% of the placebo group (hazard ratio, 0.82; 95% CI, 0.65 to 1.04; P=0.10). CONCLUSIONS: Therapy with telmisartan initiated soon after an ischemic stroke and continued for 2.5 years did not significantly lower the rate of recurrent stroke, major cardiovascular events, or diabetes. (ClinicalTrials.gov number, NCT00153062.)
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| 510. |
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