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101.
ABSTRACT: Longitudinal cohort studies are ideal for investigating how epigenetic patterns change over time and relate to changing exposure patterns and the development of disease. We highlight the challenges and opportunities in this approach. 相似文献
102.
Sean?HJ?Kim Andre?J?Jackson Rim?Hur C?Anthony?HuntEmail author 《Theoretical biology & medical modelling》2012,9(1):39
Objective
Develop and validate particular, concrete, and abstract yet plausible in silico mechanistic explanations for large intra- and interindividual variability observed for eleven bioequivalence study participants. Do so in the face of considerable uncertainty about mechanisms.Methods
We constructed an object-oriented, discrete event model called subject (we use small caps to distinguish computational objects from their biological counterparts). It maps abstractly to a dissolution test system and study subject to whom product was administered orally. A subject comprises four interconnected grid spaces and event mechanisms that map to different physiological features and processes. Drugs move within and between spaces. We followed an established, Iterative Refinement Protocol. Individualized mechanisms were made sufficiently complicated to achieve prespecified Similarity Criteria, but no more so. Within subjects, the dissolution space is linked to both a product-subject Interaction Space and the GI tract. The GI tract and Interaction Space connect to plasma, from which drug is eliminated.Results
We discovered parameterizations that enabled the eleven subject simulation results to achieve the most stringent Similarity Criteria. Simulated profiles closely resembled those with normal, odd, and double peaks. We observed important subject-by-formulation interactions within subjects.Conclusion
We hypothesize that there were interactions within bioequivalence study participants corresponding to the subject-by-formulation interactions within subjects. Further progress requires methods to transition currently abstract subject mechanisms iteratively and parsimoniously to be more physiologically realistic. As that objective is achieved, the approach presented is expected to become beneficial to drug development (e.g., controlled release) and to a reduction in the number of subjects needed per study plus faster regulatory review.103.
Thirty-three dairy farms in the Norwegian counties of ?stfold and Akershus in which cubicle sheds had been in use for at least
one year and with a herd size of less than 60 cows, were contacted and asked to participate in a study. The study focused
on heifers' use of cubicles and concentrate dispenser just after being transferred from rearing accommodation to the milking
herd. For each heifer, the farmer recorded cubicle use once nightly between 9 and 11 pm. The daily amount of concentrate released
in the dispenser and the allotted daily ration were also recorded. The recording period was 15 consecutive days for cubicle
use and 7 days for concentrate dispenser use. Cubicle refusal behaviour, i.e. lying outside the cubicles, was analysed by
logistic regression using rearing accommodation of heifers, herd size, heifer age, and housing layout as independent variables,
and herd as a clustering variable. On Day 2 after transfer, 34% of the heifers were showing cubicle refusal behaviour (N =
340). By Day 15 this percentage had dropped to 23. Cubicle refusal was lower throughout the whole period among heifers which
used the cubicles on the 3 first days after transfer compared to those which did not. This tendency could also be detected
several months later. The analysis showed cubicle refusal to be significantly associated with rearing accommodation (OR =
6.1, c.i.95%OR = 1.5–24.3, P = 0.01) and cubicle layout in the shed (OR = 0.2, c.i.95%OR = 0.0–0.7, P = 0.01). None of the tested variables were found to be significant for failure to use the concentrate dispenser,
a behaviour which was less frequent than cubicle refusal. However, 8 percent of the heifers did not visit the dispenser at
all throughout the 7 days of observation. 相似文献
104.
This study aims to obtain osmosis-induced swelling strains of normal and proteoglycan (PG) depleted articular cartilage using an ultrasound system and to investigate the changes in its mechanical properties due to the PG depletion using a layered triphasic model. The swelling strains of 20 cylindrical cartilage-bone samples collected from different bovine patellae were induced by decreasing the concentration of bath saline and monitored by the ultrasound system. The samples were subsequently digested by a trypsin solution for approximately 20 min to deplete proteoglycans, and the swelling behaviors of the digested samples were measured again. The bi-layered triphasic model proposed in our previous study (Wang et al., J Biomech Eng-Trans ASME 2007; 129: 413-422) was used to predict the layered aggregate modulus Hafrom the data of depth-dependent swelling strain, fixed charge density and water content. It was found that the region near the bone, for the normal specimens, had a significantly higher aggregate modulus (Ha1= 20.6±18.2 MPa) in comparison with the middle zone and the surface layer (Ha2= 7.8±14.5 MPa and Ha3= 3.6±3.2 MPa, respectively) (p < 0.001). The normalized thickness of the deep layer h1 was 0.68±0.20. After the trypsin digestion, the parametric values decreased to Ha1 = 13.6±9.6 MPa, Ha2 = 6.7±11.5 MPa, Ha3 = 2.7±3.2 MPa, and h1 = 0.57±0.28. Other models were also used to analyze data and the results were compared. This study showed that high-frequency ultrasound measurement combined with the triphasic modeling was capable of nondestructively quantifying the alterations in the layered mechanical properties of the proteoglycan-depleted articular cartilage. 相似文献
105.
Uwe Reusch Johannes Duell Kristina Ellwanger Carmen Herbrecht Stefan HJ Knackmuss Ivica Fucek Markus Eser Fionnuala McAleese Vera Molkenthin Fabrice Le Gall Max Topp Melvyn Little Eugene A Zhukovsky 《MABS-AUSTIN》2015,7(3):584-604
To harness the potent tumor-killing capacity of T cells for the treatment of CD19+ malignancies, we constructed AFM11, a humanized tetravalent bispecific CD19/CD3 tandem diabody (TandAb) consisting solely of Fv domains. The molecule exhibits good manufacturability and stability properties. AFM11 has 2 binding sites for CD3 and 2 for CD19, an antigen that is expressed from early B cell development through differentiation into plasma cells, and is an attractive alternative to CD20 as a target for the development of therapeutic antibodies to treat B cell malignancies. Comparison of the binding and cytotoxicity of AFM11 with those of a tandem scFv bispecific T cell engager (BiTE) molecule targeting the same antigens revealed that AFM11 elicited more potent in vitro B cell lysis. Though possessing high affinity to CD3, the TandAb mediates serial-killing of CD19+ cells with little dependence of potency or efficacy upon effector:target ratio, unlike the BiTE. The advantage of the TandAb over the BiTE was most pronounced at lower effector:target ratios. AFM11 mediated strictly target-dependent T cell activation evidenced by CD25 and CD69 induction, proliferation, and cytokine release, notwithstanding bivalent CD3 engagement. In a NOD/scid xenograft model, AFM11 induced dose-dependent growth inhibition of Raji tumors in vivo, and radiolabeled TandAb exhibited excellent localization to tumor but not to normal tissue. After intravenous administration in mice, half-life ranged from 18.4 to 22.9 h. In a human ex vivo B-cell chronic lymphocytic leukemia study, AFM11 exhibited substantial cytotoxic activity in an autologous setting. Thus, AFM11 may represent a promising therapeutic for treatment of CD19+ malignancies with an advantageous safety risk profile and anticipated dosing regimen. 相似文献
106.
Anna E van der Windt Esther Haak Ruud HJ Das Nicole Kops Tim JM Welting Marjolein MJ Caron Niek P van Til Jan AN Verhaar Harrie Weinans Holger Jahr 《Arthritis research & therapy》2010,12(3):R100
Introduction
Chondrocytes experience a hypertonic environment compared with plasma (280 mOsm) due to the high fixed negative charge density of cartilage. Standard isolation of chondrocytes removes their hypertonic matrix, exposing them to nonphysiological conditions. During in vitro expansion, chondrocytes quickly lose their specialized phenotype, making them inappropriate for cell-based regenerative strategies. We aimed to elucidate the effects of tonicity during isolation and in vitro expansion on chondrocyte phenotype. 相似文献107.
Michael P. Gardner Carmen Martin-Ruiz Rachel Cooper Rebecca Hardy Avan Aihie Sayer Cyrus Cooper Ian J. Deary John Gallacher Sarah E. Harris Paul G. Shiels John M. Starr Diana Kuh Thomas von Zglinicki Yoav Ben-Shlomo the Halcyon study team 《PloS one》2013,8(7)
Background
Telomeres are involved in cellular ageing and shorten with increasing age. If telomere length is a valuable biomarker of ageing, then telomere shortening should be associated with worse physical performance, an ageing trait, but evidence for such an association is lacking. The purpose of this study was to examine whether change in telomere length is associated with physical performance.Methods
Using data from four UK adult cohorts (ages 53–80 years at baseline), we undertook cross-sectional and longitudinal analyses. We analysed each study separately and then used meta-analytic methods to pool the results. Physical performance was measured using walking and chair rise speed, standing balance time and grip strength. Telomere length was measured by quantitative real-time polymerase chain reaction (PCR) in whole blood at baseline and follow-up (time 1, time 2).Results
Total sample sizes in meta-analyses ranged from 1,217 to 3,707. There was little evidence that telomere length was associated with walking speed, balance or grip strength, though weak associations were seen with chair rise speed and grip strength at baseline (p = 0.02 and 0.01 respectively). Faster chair rise speed at follow-up, was associated with a smaller decline in telomere length between time 1 and time 2 (standardised coefficient per SD increase 0.061, 95% CI 0.006, 0.115, p = 0.03) but this was consistent with chance (p = 0.08) after further adjustment.Conclusions
Whereas shortening of leukocyte telomeres might be an important measure of cellular ageing, there is little evidence that it is a strong biomarker for physical performance. 相似文献108.
As an alternative to pharmacological treatment to diseases, lifestyle interventions, such as dietary changes and physical activities, can help maintain healthy metabolic conditions. Recently, the emerging analyses of volatile organic compounds (VOCs) from breath and short-chain fatty acids (SCFAs) from plasma/feces have been considered as useful tools for the diagnosis and mechanistic understanding of metabolic diseases. Furthermore, diet-induced changes of SCFAs in individuals with diagnosed metabolic abnormalities have been correlated with the composition changes of the gut microbiome. More interestingly, the analysis of exhaled breath (breathomics) has gained attention as a useful technique to measure the human VOC profile altered as a result of dietary interventions. In this mini-review, we examined recent clinical trials that performed promising dietary interventions, SCFAs analysis in plasma/feces, and VOC profile analysis in exhaling breath to understand the relationship between dietary intervention and metabolic health. 相似文献
109.
Background
Water Rails (Rallus aquaticus) inhabit fragmented freshwater wetlands across their Palearctic distribution. Disjunct populations are now thought to be morphologically similar over their vast geographic range, though four subspecies had been recognized previously. The fossil record suggests that Water Rails (R. aquaticus) were already spread across the Palearctic by the Pleistocene ~2 million years ago, and the oldest fossil remains thought to be closely related to the common ancestor of water rails date from the Pliocene. 相似文献110.
Richard M. Dodds Holly E. Syddall Rachel Cooper Michaela Benzeval Ian J. Deary Elaine M. Dennison Geoff Der Catharine R. Gale Hazel M. Inskip Carol Jagger Thomas B. Kirkwood Debbie A. Lawlor Sian M. Robinson John M. Starr Andrew Steptoe Kate Tilling Diana Kuh Cyrus Cooper Avan Aihie Sayer 《PloS one》2014,9(12)