1,793 research outputs found
Premenopausal endogenous oestrogen levels and breast cancer risk: a meta-analysis.
BACKGROUND: Many of the established risk factors for breast cancer implicate circulating hormone levels in the aetiology of the disease. Increased levels of postmenopausal endogenous oestradiol (E2) have been found to increase the risk of breast cancer, but no such association has been confirmed in premenopausal women. We carried out a meta-analysis to summarise the available evidence in women before the menopause. METHODS: We identified seven prospective studies of premenopausal endogenous E2 and breast cancer risk, including 693 breast cancer cases. From each study we extracted odds ratios of breast cancer between quantiles of endogenous E2, or for unit or s.d. increases in (log transformed) E2, or (where odds ratios were unavailable) summary statistics for the distributions of E2 in breast cancer cases and unaffected controls. Estimates for a doubling of endogenous E2 were obtained from these extracted estimates, and random-effect meta-analysis was used to obtain a pooled estimate across the studies. RESULTS: Overall, we found weak evidence of a positive association between circulating E2 levels and the risk of breast cancer, with a doubling of E2 associated with an odds ratio of 1.10 (95% CI: 0.96, 1.27). CONCLUSION: Our findings are consistent with the hypothesis of a positive association between premenopausal endogenous E2 and breast cancer risk
New Experimental Limits on Macroscopic Forces Below 100 Microns
Results of an experimental search for new macroscopic forces with Yukawa
range between 5 and 500 microns are presented. The experiment uses 1 kHz
mechanical oscillators as test masses with a stiff conducting shield between
them to suppress backgrounds. No signal is observed above the instrumental
thermal noise after 22 hours of integration time. These results provide the
strongest limits to date between 10 and 100 microns, improve on previous limits
by as much as three orders of magnitude, and rule out half of the remaining
parameter space for predictions of string-inspired models with low-energy
supersymmetry breaking. New forces of four times gravitational strength or
greater are excluded at the 95% confidence level for interaction ranges between
200 and 500 microns.Comment: 25 Pages, 7 Figures: Minor Correction
Therapeutic potential of TLR8 agonist GS-9688 (selgantolimod) in chronic hepatitis B: re-modelling of antiviral and regulatory mediators
Background & Aims:
GSβ9688 (selgantolimod) is a tollβlike receptor 8 (TLR8) agonist in clinical development for the treatment of chronic hepatitis B (CHB). Antiviral activity of GSβ9688 has previously been evaluated in vitro in hepatitis B virus (HBV)βinfected hepatocytes and in vivo in the woodchuck model of CHB. Here we evaluated the potential of GSβ9688 to boost responses contributing to viral control and to modulate regulatory mediators.
Approach & Results:
We characterised the effect of GSβ9688 on immune cell subsets in vitro in PBMC of healthy controls and CHB patients. GSβ9688 activated dendritic cells and mononuclear phagocytes to produce ILβ12 and other immunomodulatory mediators, inducing a comparable cytokine profile in healthy controls and CHB patients. GSβ9688 increased the frequency of activated natural killer (NK) cells, mucosalβassociated invariant Tβcells (MAITs), CD4+ follicular helper Tβcells (TFH) and, in ~50% of patients, HBVβspecific CD8+Tβcells expressing interferonβΞ³ (IFNΞ³). Moreover, in vitro stimulation with GSβ9688 induced NK cell expression of IFNΞ³ and TNFΞ± and promoted hepatocyte lysis. We also assessed whether GSβ9688 inhibited immunosuppressive cell subsets that might enhance antiviral efficacy. Stimulation with GSβ9688 reduced the frequency of CD4+ regulatory Tβcells and monocytic myeloidβderived suppressor cells (MDSC). Residual MDSC expressed higher levels of negative immune regulators, galectinβ9 and PDβL1. Conversely, GSβ9688 induced an expansion of immunoregulatory TNFβrelated apoptosisβinducing ligand+ (TRAIL) regulatory NK cells and degranulation of arginaseβI+ polymorphonuclearβMDSC (PMNβMDSC).
Conclusions:
GSβ9688 induces cytokines in human PBMC that are able to activate antiviral effector function by multiple immune mediators (HBVβspecific CD8+Tβcells, TFH, NK cells and MAITs). Whilst reducing the frequency of some immunoregulatory subsets, it enhances the immunosuppressive potential of others, highlighting potential biomarkers and immunotherapeutic targets to optimise the antiviral efficacy of GSβ9688
Mammary cancer and epithelial stem cells: a problem or a solution?
The existing paradigms for stem cells in adult tissues include the integument, the alimentary canal, the lung, the liver, skeletal muscle and bone marrow. The mammary gland, by contrast, is the 'new kid on the block'. What little is known about stem cells in the mammary gland indicates that they possess a prodigious capacity for self-renewal. More importantly, in rodents, they persist with undiminished reproductive vigor throughout the organism's lifetime without regard to age or reproductive history. Do these stem cells represent primary targets for mammary neoplasia? If so, what are the implications for prevention/therapy
Mycobacterium tuberculosis monoarthritis in a child
A child with isolated Mycobacterium tuberculosis monoarthritis, with features initially suggesting oligoarthritis subtype of juvenile idiopathic arthritis, is presented. This patient illustrates the need to consider the possibility of tuberculosis as the cause of oligoarthritis in high-risk pediatric populations even in the absence of a tuberculosis contact history and without evidence of overt pulmonary disease
Multiethnic Genetic Association Studies Improve Power for Locus Discovery
To date, genome-wide association studies have focused almost exclusively on populations of European ancestry. These studies continue with the advent of next-generation sequencing, designed to systematically catalog and test low-frequency variation for a role in disease. A complementary approach would be to focus further efforts on cohorts of multiple ethnicities. This leverages the idea that population genetic drift may have elevated some variants to higher allele frequency in different populations, boosting statistical power to detect an association. Based on empirical allele frequency distributions from eleven populations represented in HapMap Phase 3 and the 1000 Genomes Project, we simulate a range of genetic models to quantify the power of association studies in multiple ethnicities relative to studies that exclusively focus on samples of European ancestry. In each of these simulations, a first phase of GWAS in exclusively European samples is followed by a second GWAS phase in any of the other populations (including a multiethnic design). We find that nontrivial power gains can be achieved by conducting future whole-genome studies in worldwide populations, where, in particular, African populations contribute the largest relative power gains for low-frequency alleles (<5%) of moderate effect that suffer from low power in samples of European descent. Our results emphasize the importance of broadening genetic studies to worldwide populations to ensure efficient discovery of genetic loci contributing to phenotypic trait variability, especially for those traits for which large numbers of samples of European ancestry have already been collected and tested
Transduction of SIV-Specific TCR Genes into Rhesus Macaque CD8+ T Cells Conveys the Ability to Suppress SIV Replication
The SIV/rhesus macaque model for HIV/AIDS is a powerful system for examining the contribution of T cells in the control of AIDS viruses. To better our understanding of CD8(+) T-cell control of SIV replication in CD4(+) T cells, we asked whether TCRs isolated from rhesus macaque CD8(+) T-cell clones that exhibited varying abilities to suppress SIV replication could convey their suppressive properties to CD8(+) T cells obtained from an uninfected/unvaccinated animal.We transferred SIV-specific TCR genes isolated from rhesus macaque CD8(+) T-cell clones with varying abilities to suppress SIV replication in vitro into CD8(+) T cells obtained from an uninfected animal by retroviral transduction. After sorting and expansion, transduced CD8(+) T-cell lines were obtained that specifically bound their cognate SIV tetramer. These cell lines displayed appropriate effector function and specificity, expressing intracellular IFNΞ³ upon peptide stimulation. Importantly, the SIV suppression properties of the transduced cell lines mirrored those of the original TCR donor clones: cell lines expressing TCRs transferred from highly suppressive clones effectively reduced wild-type SIV replication, while expression of a non-suppressing TCR failed to reduce the spread of virus. However, all TCRs were able to suppress the replication of an SIV mutant that did not downregulate MHC-I, recapitulating the properties of their donor clones.Our results show that antigen-specific SIV suppression can be transferred between allogenic T cells simply by TCR gene transfer. This advance provides a platform for examining the contributions of TCRs versus the intrinsic effector characteristics of T-cell clones in virus suppression. Additionally, this approach can be applied to develop non-human primate models to evaluate adoptive T-cell transfer therapy for AIDS and other diseases
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