18 research outputs found
A longitudinal study of muscle rehabilitation in the lower leg after cast removal using Magnetic Resonance Imaging and strength assessment
Acknowledgements We thank the A&E nurses and plaster technicians for identifying suitable patients, the MRI radiographers for performing the scanning, Dr Scott Semple for invaluable help in some of the pilot studies and Mr E. C. Stevenson for constructing the footrest used in the scanner. We are very grateful to the dedicated patients themselves who gave considerable amounts of time to come in for scanning, exercise and assessment during the course of this study.Peer reviewedPublisher PD
Circulating Proteomic Signatures of Chronological Age
To elucidate the proteomic features of aging in plasma, the subproteome targeted by the SOMAscan assay was profiled in blood samples from 202 females from the TwinsUK cohort. Findings were replicated in 677 independent individuals from the AddNeuroMed, Alzheimer's Research UK, and Dementia Case Registry cohorts. Results were further validated using RNAseq data from whole blood in TwinsUK and the most significant proteins were tested for association with aging-related phenotypes after adjustment for age. Eleven proteins were associated with chronological age and were replicated at protein level in an independent population. These were further investigated at gene expression level in 384 females from the TwinsUK cohort. The two most strongly associated proteins were chordin-like protein 1 (meta-analysis β [SE] = 0.013 [0.001], p = 3.66 × 10−46) and pleiotrophin (0.012 [0.005], p = 3.88 × 10−41). Chordin-like protein 1 was also significantly correlated with birthweight (0.06 [0.02], p = 0.005) and with the individual Framingham 10-years cardiovascular risk scores in TwinsUK (0.71 [0.18], p = 9.9 × 10−5). Pleiotrophin is a secreted growth factor with a plethora of functions in multiple tissues and known to be a marker for cardiovascular risk and osteoporosis. Our study highlights the importance of proteomics to identify some molecular mechanisms involved in human health and agin
Circulating Proteomic Signatures of Chronological Age.
To elucidate the proteomic features of aging in plasma, the subproteome targeted by the SOMAscan assay was profiled in blood samples from 202 females from the TwinsUK cohort. Findings were replicated in 677 independent individuals from the AddNeuroMed, Alzheimer's Research UK, and Dementia Case Registry cohorts. Results were further validated using RNAseq data from whole blood in TwinsUK and the most significant proteins were tested for association with aging-related phenotypes after adjustment for age. Eleven proteins were associated with chronological age and were replicated at protein level in an independent population. These were further investigated at gene expression level in 384 females from the TwinsUK cohort. The two most strongly associated proteins were chordin-like protein 1 (meta-analysis β [SE] = 0.013 [0.001], p = 3.66 × 10(-46)) and pleiotrophin (0.012 [0.005], p = 3.88 × 10(-41)). Chordin-like protein 1 was also significantly correlated with birthweight (0.06 [0.02], p = 0.005) and with the individual Framingham 10-years cardiovascular risk scores in TwinsUK (0.71 [0.18], p = 9.9 × 10(-5)). Pleiotrophin is a secreted growth factor with a plethora of functions in multiple tissues and known to be a marker for cardiovascular risk and osteoporosis. Our study highlights the importance of proteomics to identify some molecular mechanisms involved in human health and aging
Metabolomic markers reveal novel pathways of ageing and early development in human populations
BACKGROUND
Human ageing is a complex, multifactorial process and early developmental factors affect health outcomes in old age.
METHODS
Metabolomic profiling on fasting blood was carried out in 6055 individuals from the UK. Stepwise regression was performed to identify a panel of independent metabolites which could be used as a surrogate for age. We also investigated the association with birthweight overall and within identical discordant twins and with genome-wide methylation levels.
RESULTS
We identified a panel of 22 metabolites which combined are strongly correlated with age (R(2) = 59%) and with age-related clinical traits independently of age. One particular metabolite, C-glycosyl tryptophan (C-glyTrp), correlated strongly with age (beta = 0.03, SE = 0.001, P = 7.0 × 10(-157)) and lung function (FEV1 beta = -0.04, SE = 0.008, P = 1.8 × 10(-8) adjusted for age and confounders) and was replicated in an independent population (n = 887). C-glyTrp was also associated with bone mineral density (beta = -0.01, SE = 0.002, P = 1.9 × 10(-6)) and birthweight (beta = -0.06, SE = 0.01, P = 2.5 × 10(-9)). The difference in C-glyTrp levels explained 9.4% of the variance in the difference in birthweight between monozygotic twins. An epigenome-wide association study in 172 individuals identified three CpG-sites, associated with levels of C-glyTrp (P < 2 × 10(-6)). We replicated one CpG site in the promoter of the WDR85 gene in an independent sample of 350 individuals (beta = -0.20, SE = 0.04, P = 2.9 × 10(-8)). WDR85 is a regulator of translation elongation factor 2, essential for protein synthesis in eukaryotes.
CONCLUSIONS
Our data illustrate how metabolomic profiling linked with epigenetic studies can identify some key molecular mechanisms potentially determined in early development that produce long-term physiological changes influencing human health and ageing
Stromal Cell-Derived Factor-1 and Hepatocyte Growth Factor Guide Axon Projections to the Extraocular Muscles
Empowering the Potential of CAR-T Cell Immunotherapies by Epigenetic Reprogramming
T-cell-based, personalized immunotherapy can nowadays be considered the mainstream treatment for certain blood cancers, with a high potential for expanding indications. Chimeric antigen receptor T cells (CAR-Ts), an ex vivo genetically modified T-cell therapy product redirected to target an antigen of interest, have achieved unforeseen successes in patients with B-cell hematologic malignancies. Frequently, however, CAR-T cell therapies fail to provide durable responses while they have met with only limited success in treating solid cancers because unique, unaddressed challenges, including poor persistence, impaired trafficking to the tumor, and site penetration through a hostile microenvironment, impede their efficacy. Increasing evidence suggests that CAR-Ts’ in vivo performance is associated with T-cell intrinsic features that may be epigenetically altered or dysregulated. In this review, we focus on the impact of epigenetic regulation on T-cell differentiation, exhaustion, and tumor infiltration and discuss how epigenetic reprogramming may enhance CAR-Ts’ memory phenotype, trafficking, and fitness, contributing to the development of a new generation of potent CAR-T immunotherapies
Bravo 48-hour Wireless pH Monitoring in Patients With Non-cardiac Chest Pain. Objective Gastroesophageal Reflux Disease Parameters Predict the Responses to Proton Pump Inhibitors
Background/Aims
In patients with non-cardiac chest pain (NCCP), gastroesophageal reflux
disease (GERD) is the commonest cause and ambulatory pH is of great
value in identifying these patients. However, parameters in the context
of predicting therapeutic response are still unknown. By extending the
monitoring period, we could better evaluate the best evidence for GERD
association. Our aims were (1) to compare the outcomes of 48-hour pH
monitoring to 24-hour and (2) to determine whether objective parameters
could predict the treatment success in patients with NCCP using Bravo pH
system.
Methods
Pathological esophageal acid reflux (PEAR) and positive symptom index
(SI) were calculated after 24-hour and compared to the 48-hour study.
Evidence suggestive of GERD diagnosis was considered if PEAR and/or SI
(+) were present on each different day. After pH study, all patients
received proton pump inhibitor twice a day for 4 weeks. Treatment
success was determined at the end of therapy.
Results
Thirty-two patients with NCCP participated. GERD was identified in 20
(62.5%) patients; 17 (53.1%) had PEAR, 3 (9.4%) SI (+) and 7 (22%)
both. Twelve (41%) patients exhibited PEAR values on day 1, while 17
after 2 days; a 12.1 % gain. SI (+) was found in 6 patients (18.8%) on
day 1 and in 4 more on day 2, a gain of 12.5%. Significantly higher
proportion of patients with GERD indicators showed improvement compared
to those without (90% vs 16.7%, P < 0.005).
Conclusions
In patients with NCCP, 48-hour pH measurement identified GERD as the
cause of NCCP with an increased yield by almost 12% compared to 12
hours. Objective GERD parameters could predict response to antireflux
therapy
Success Stories and Challenges Ahead in Hematopoietic Stem Cell Gene Therapy: Hemoglobinopathies as Disease Models
Gene therapy is a relatively novel field that amounts to around four
decades of continuous growth with its good and bad moments. Currently,
the field has entered the clinical arena with the ambition to fulfil its
promises for a permanent fix of incurable genetic disorders.
Hemoglobinopathies as target diseases and hematopoietic stem cells
(HSCs) as target cells of genetic interventions had a major share in the
research effort toward efficiently implementing gene therapy. Dissection
of HSC biology and improvements in gene transfer and gene expression
technologies evolved in an almost synchronous manner to a point where
the two fields seem to be functionally intercalated. In this review, we
focus specifically on the development of gene therapy for hemoglobin
disorders and look at both gene addition and gene correction strategies
that may dominate the field of HSC-directed gene therapy in the near
future and transform the therapeutic landscape for genetic diseases.</p>