21 research outputs found
Estimates of Black Hole Spin Properties of 55 Sources
Studies of black hole spin and other parameters as a function of redshift
provide information about the physical state and merger and accretion histories
of the systems. One way that black hole spin may be estimated is through
observations of extended radio sources. These sources, powered by outflows from
an AGN, allow the beam power and total outflow energy to be studied. In a broad
class of models, the beam power of the outflow is related to the spin of the
black hole. This relationship is used to estimate black hole spins for 55 radio
sources. The samples studied include 7 FRII quasars and 19 FRII radio galaxies
with redshifts between 0.056 and 1.79, and 29 radio sources associated with CD
galaxies with redshifts between 0.0035 and 0.291. The FRII sources studied have
estimated spin values of between about 0.2 and 1; there is a range of values at
a given redshift, and the values tend to increase with increasing redshift.
Results obtained for FRII quasars are very similar to those obtained for FRII
galaxies. A broader range of spin values are obtained for the sample of radio
sources associated with CD galaxies studied. The fraction of the spin energy
extracted per outflow event is estimated and ranges from about 0.03 to 0.5 for
FRII sources and 0.002 to about 1 for radio sources associated with CD
galaxies; the data are consistent with this fraction being independent of
redshift though the uncertainties are large. The results obtained are
consistent with those predicted by numerical simulations that track the merger
and accretion history of AGN, supporting the idea that, for AGN with powerful
large-scale outflows, beam power is directly related to black hole spin.Comment: 13 pages; to appear in MNRA
Brief research report: in-depth immunophenotyping reveals stability of CD19 CAR T-cells over time
Variability or stability might have an impact on treatment success and toxicity of CD19 CAR T-cells. We conducted a prospective observational study of 12 patients treated with Tisagenlecleucel for CD19+ B-cell malignancies. Using a 31-color spectral flow cytometry panel, we analyzed differentiation stages and exhaustion markers of CAR T-cell subsets prior to CAR T-cell infusion and longitudinally during 6 months of follow-up. The majority of activation markers on CAR T-cells showed stable expression patterns over time and were not associated with response to therapy or toxicity. Unsupervised cluster analysis revealed an immune signature of CAR T-cell products associated with the development of immune cell-associated neurotoxicity syndrome. Warranting validation in an independent patient cohort, in-depth phenotyping of CAR T-cell products as well as longitudinal monitoring post cell transfer might become a valuable tool to increase efficacy and safety of CAR T-cell therapy
Placenta-specific methylation of the vitamin D 24-hydroxylase gene: implications for feedback autoregulation of active vitamin D levels at the fetomaternal interface
Plasma concentrations of biologically active vitamin D (1,25-
(OH)2D) are tightly controlled via feedback regulation of renal
1-hydroxylase (CYP27B1; positive) and 24-hydroxylase
(CYP24A1; catabolic) enzymes. In pregnancy, this regulation is
uncoupled, and 1,25-(OH)2D levels are significantly elevated,
suggesting a role in pregnancy progression. Epigenetic regulation
of CYP27B1 and CYP24A1 has previously been described in
cell and animal models, and despite emerging evidence for a
critical role of epigenetics in placentation generally, little is
known about the regulation of enzymes modulating vitamin D
homeostasis at the fetomaternal interface. In this study, we
investigated the methylation status of genes regulating vitamin
D bioavailability and activity in the placenta. No methylation of
the VDR (vitamin D receptor) and CYP27B1 genes was found in
any placental tissues. In contrast, the CYP24A1 gene is methylated
in human placenta, purified cytotrophoblasts, and primary
and cultured chorionic villus sampling tissue. No methylation
was detected in any somatic human tissue tested. Methylation
was also evident in marmoset and mouse placental tissue. All
three genes were hypermethylated in choriocarcinoma cell
lines, highlighting the role of vitaminDderegulation in this cancer.
Gene expression analysis confirmed a reduced capacity for
CYP24A1 induction with promoter methylation in primary cells
and in vitro reporter analysis demonstrated that promoter
methylation directly down-regulates basal promoter activity
and abolishes vitamin D-mediated feedback activation. This
study strongly suggests that epigenetic decoupling of vitamin D
feedback catabolism plays an important role in maximizing
active vitamin D bioavailability at the fetomaternal interface
Six weeks of home enteral nutrition versus standard care after esophagectomy or total gastrectomy for cancer: study protocol for a randomized controlled trial
Background: Each year approximately 3000 patients in the United Kingdom undergo surgery for esophagogastric
cancer. Jejunostomy feeding tubes, placed at the time of surgery for early postoperative nutrition, have been
shown to have a positive impact on clinical outcomes in the short term. Whether feeding out of hospital is of
benefit is unknown. Local experience has identified that between 15 and 20% of patients required ‘rescue’
jejunostomy feeding for nutritional problems and weight loss while at home. This weight loss and poor nutrition
may contribute to the detrimental effect on the overall quality of life (QoL) reported in these patients.
Methods/Design: This randomized pilot and feasibility study will provide preliminary information on the routine
use of jejunostomy feeding after hospital discharge in terms of clinical benefits and QoL. Sixty participants
undergoing esophagectomy or total gastrectomy will be randomized to receive either a planned program of six
weeks of home jejunostomy feeding after discharge from hospital (intervention) or treatment-as-usual (control). The
intention of this study is to inform a multi-centre randomized controlled trial. The primary outcome measures will
be recruitment and retention rates at six weeks and six months. Secondary outcome measures will include disease
specific and general QoL measures, nutritional parameters, total and oral nutritional intake, hospital readmission
rates, and estimates of healthcare costs. Up to 20 participants will also be enrolled in a qualitative sub-study that will
explore participants’ and carers’ experiences of home tube feeding.
The results will be disseminated by presentation at surgical, gastroenterological and dietetic meetings and
publication in appropriate peer review journals. A patient-friendly lay summary will be made available on the
University of Leicester and the University Hospitals of Leicester NHS Trust websites. The study has full ethical and
institutional approval and started recruitment in July 2012.
Trial registration: UKClinical Research Network ID #12447 (Main study); UKCRN ID#13361 (Qualitative sub study);
ClinicalTrials.gov #NCT01870817 (First registered 28 May 2013
Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans
Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have
fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in
25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16
regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of
correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP,
while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in
Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium
(LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region.
Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant
enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the
refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa,
an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of
PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent
signals within the same regio
Neonatal Systemic AAV Induces Tolerance to CNS Gene Therapy in MPS I Dogs and Nonhuman Primates
The potential host immune response to a nonself protein poses a fundamental challenge for gene therapies targeting recessive diseases. We demonstrate in both dogs and nonhuman primates that liver-directed gene transfer using an adeno-associated virus (AAV) vector in neonates induces a persistent state of immunological tolerance to the transgene product, substantially improving the efficacy of subsequent vector administration targeting the central nervous system (CNS). We applied this approach to a canine model of mucopolysaccharidosis type I (MPS I), a progressive neuropathic lysosomal storage disease caused by deficient activity of the enzyme α-l-iduronidase (IDUA). MPS I dogs treated systemically in the first week of life with a vector expressing canine IDUA did not develop antibodies against the enzyme and exhibited robust expression in the CNS upon intrathecal AAV delivery at 1 month of age, resulting in complete correction of brain storage lesions. Newborn rhesus monkeys treated systemically with AAV vector expressing human IDUA developed tolerance to the transgene, resulting in high cerebrospinal fluid (CSF) IDUA expression and no antibody induction after subsequent CNS gene therapy. These findings suggest that inducing tolerance to the transgene product during a critical period in immunological development can improve the efficacy and safety of gene therapy
Emerging and Enduring Inequalities
The Australian Sociological Association Annual Conference 2012 will be a joint event including both TASA and the Sociological Association of Aotearoa New Zealand (SAANZ), including a special trans-Tasman plenary session