72 research outputs found
The Depsipeptide Romidepsin Reverses HIV-1 Latency In Vivo.
UNLABELLED: Pharmacologically-induced activation of replication competent proviruses from latency in the presence of antiretroviral treatment (ART) has been proposed as a step towards curing HIV-1 infection. However, until now, approaches to reverse HIV-1 latency in humans have yielded mixed results. Here, we report a proof-of-concept phase Ib/IIa trial where 6 aviremic HIV-1 infected adults received intravenous 5 mg/m2 romidepsin (Celgene) once weekly for 3 weeks while maintaining ART. Lymphocyte histone H3 acetylation, a cellular measure of the pharmacodynamic response to romidepsin, increased rapidly (maximum fold range: 3.7-7.7 relative to baseline) within the first hours following each romidepsin administration. Concurrently, HIV-1 transcription quantified as copies of cell-associated un-spliced HIV-1 RNA increased significantly from baseline during treatment (range of fold-increase: 2.4-5.0; p = 0.03). Plasma HIV-1 RNA increased from <20 copies/mL at baseline to readily quantifiable levels at multiple post-infusion time-points in 5 of 6 patients (range 46-103 copies/mL following the second infusion, p = 0.04). Importantly, romidepsin did not decrease the number of HIV-specific T cells or inhibit T cell cytokine production. Adverse events (all grade 1-2) were consistent with the known side effects of romidepsin. In conclusion, romidepsin safely induced HIV-1 transcription resulting in plasma HIV-1 RNA that was readily detected with standard commercial assays demonstrating that significant reversal of HIV-1 latency in vivo is possible without blunting T cell-mediated immune responses. These finding have major implications for future trials aiming to eradicate the HIV-1 reservoir.
TRIAL REGISTRATION: clinicaltrials.gov NTC02092116
Social inequality in cancer survivorship:Educational differences in healthârelated quality of life among 27,857 cancer survivors in Denmark
BackgroundWith a growing population of cancer survivors in Denmark, the evaluation of health-related quality of life (HRQoL) has become increasingly important. We describe variations in HRQoL between educational groups in a national population of cancer survivors.MethodsWe conducted a cross-sectional questionnaire study among breast, prostate, lung, and colon cancer survivors diagnosed in 2010â2019 in Denmark. We used the EORTC QLQ-C30 to assess HRQoL including physical, role, emotional, cognitive, social functioning, and symptoms (fatigue, nausea and vomiting, pain, dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Information on educational level and clinical data were extracted from national registers and clinical databases. Levels of impaired functioning and severe symptoms were identified using newly established thresholds for clinical importance. Multivariate logistic regression was used to examine associations between education and HRQoL. All statistical tests were 2-sided.ResultsIn total, 27,857 (42%) participated in the study. Up to 72% and 75% of cancer survivors with short education (â€9âyears) reported impaired functioning and severe symptoms, respectively. Cancer survivors with short compared to long education (>12âyears) were more likely to report impaired functioning and severe symptoms, with for example significantly higher odds ratios (ORs) for impaired physical function (breast ORâ=â2.41, 99% CIâ=â2.01â2.89; prostate ORâ=â1.81, 99% CIâ=â1.48â2.21; lung ORâ=â2.97, 99% CIâ=â1.95â4.57; and colon cancer ORâ=â1.69, 99% CIâ=â1.28â2.24).ConclusionsCancer survivors with short education are at greater risk of impaired HRQoL than survivors with long education 2â12âyears after diagnosis. This underscores the need for systematic screening and symptom management in cancer aftercare, in order to reach all cancer survivors, also cancer survivors with short education
Quels facteurs influencent le plus la distribution du bois de cĆur et la croissance radiale dans les plantations de teck?
Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus
A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 Ă 10-20), ER-negative BC (P=1.1 Ă 10-13), BRCA1-associated BC (P=7.7 Ă 10-16) and triple negative BC (P-diff=2 Ă 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 Ă 10-3) and ABHD8 (P<2 Ă 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3âČ-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk
Do pregnant women still smoke? A study of smoking patterns among 261,029 primiparous women in Denmark 1997-2005
Risk of thyroid cancer after exposure to fertility drugs: results from a large Danish cohort study
ANP and BNP in atrial fibrillation before and after cardioversion - and their relationship to cardiac volume and function
Acquisition and persistence of human papillomavirus infection in younger men: a prospective follow-up study among Danish soldiers
Accuracy of self-reported family history of cancer in a large case-control study of ovarian cancer
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