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Staphylococcus aureus colonizes patients with atopic dermatitis (AD) and exacerbates disease by promoting inflammation. The present study investigated the safety and mechanisms of action of Staphylococcus hominis A9 ( Sh A9), a bacterium isolated from healthy human skin, as a topical therapy for AD. Sh A9 killed S. aureus on the skin of mice and inhibited expression of a toxin from S. aureus ( psm α) that promotes inflammation. A first-in-human, phase 1, double-blinded, randomized 1-week trial of topical Sh A9 or vehicle on the forearm skin of 54 adults with S. aureus -positive AD (NCT03151148) met its primary endpoint of safety, and participants receiving Sh A9 had fewer adverse events associated with AD. Eczema severity was not significantly different when evaluated in all participants treated with Sh A9 but a significant decrease in S. aureus and increased Sh A9 DNA were seen and met secondary endpoints. Some S. aureus strains on participants were not directly killed by Sh A9, but expression of mRNA for psm α was inhibited in all strains. Improvement in local eczema severity was suggested by post-hoc analysis of participants with S. aureus directly killed by Sh A9. These observations demonstrate the safety and potential benefits of bacteriotherapy for AD. First-in-human test of topical application of a commensal bacterium on skin of individuals with atopic dermatitis reduces colonization by proinflammatory Staphylococcus aureus .

Antiretroviral therapy (ART) cannot cure HIV infection because of a persistent reservoir of latently infected cells. Approaches that force HIV transcription from these cells, making them susceptible to killing—termed kick and kill regimens—have been explored as a strategy towards an HIV cure. RIVER is the first randomised trial to determine the effect of ART-only versus ART plus kick and kill on markers of the HIV reservoir. This phase 2, open-label, multicentre, randomised, controlled trial was undertaken at six clinical sites in the UK. Patients aged 18–60 years who were confirmed as HIV-positive within a maximum of the past 6 months and started ART within 1 month from confirmed diagnosis were randomly assigned by a computer generated randomisation list to receive ART-only (control) or ART plus the histone deacetylase inhibitor vorinostat (the kick) and replication-deficient viral vector T-cell inducing vaccines encoding conserved HIV sequences ChAdV63. HIVconsv-prime and MVA.HIVconsv-boost (the kill; ART + V + V; intervention). The primary endpoint was total HIV DNA isolated from peripheral blood CD4+ T-cells at weeks 16 and 18 after randomisation. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, NCT02336074. Between June 14, 2015 and Jul 11, 2017, 60 men with HIV were randomly assigned to receive either an ART-only (n=30) or an ART + V + V (n=30) regimen; all 60 participants completed the study, with no loss-to-follow-up. Mean total HIV DNA at weeks 16 and 18 after randomisation was 3·02 log10 copies HIV DNA per 106 CD4+ T-cells in the ART-only group versus 3·06 log10 copies HIV DNA per 106 CD4+ T-cells in ART + V + V group, with no statistically significant difference between the two groups (mean difference of 0·04 log10 copies HIV DNA per 106 CD4+ T-cells [95% CI −0·03 to 0·11; p=0·26]). There were no intervention-related serious adverse events. This kick and kill approach conferred no significant benefit compared with ART alone on measures of the HIV reservoir. Although this does not disprove the efficacy kick and kill strategy, for future trials enhancement of both kick and kill agents will be required. Medical Research Council (MR/L00528X/1).

The arbuscular mycorrhizal (AM) symbiosis is a beneficial association established between land plants and the members of a subphylum of fungi, the Glomeromycotina. How the two symbiotic partners regulate their association is still enigmatic. Secreted fungal peptides are candidates for regulating this interaction. We searched for fungal peptides with similarities with known plant signalling peptides. We identified CLAVATA (CLV)/EMBRYO SURROUNDING REGION (ESR)-RELATED PROTEIN (CLE) genes in phylogenetically distant AM fungi: four Rhizophagus species and one Gigaspora species. These CLE genes encode a signal peptide for secretion and the conserved CLE C-terminal motif. They seem to be absent in the other fungal clades. Rhizophagus irregularis and Gigaspora rosea CLE genes (RiCLE1 and GrCLE1) are transcriptionally induced in symbiotic vs asymbiotic conditions. Exogenous application of synthetic RiCLE1 peptide on Medicago truncatula affects root architecture, by slowing the apical growth of primary roots and stimulating the formation of lateral roots. In addition, pretreatment of seedlings with RiCLE1 peptide stimulates mycorrhization. Our findings demonstrate for the first time that in addition to plants and nematodes,AMfungi also possess CLE genes. These results pave the way for deciphering new mechanisms by which AM fungi modulate plant cellular responses during the establishment of AM symbiosis.

Patterns of gene expression of human pregnancy are poorly understood. In a trial of vitamin D supplementation in pregnant women, peripheral blood transcriptomes were measured longitudinally on 30 women and used to characterize gene co-expression networks. Studies suggest that increased maternal Vitamin D levels may reduce the risk of asthma in early life, yet the underlying mechanisms have not been examined. In this study, we used a network-based approach to examine changes in gene expression profiles during the course of normal pregnancy and evaluated their association with maternal Vitamin D levels. The VDAART study is a randomized clinical trial of vitamin D supplementation in pregnancy for reduction of pediatric asthma risk. The trial enrolled 881 women at 10-18 weeks of gestation. Longitudinal gene expression measures were obtained on thirty pregnant women, using RNA isolated from peripheral blood samples obtained in the first and third trimesters. Differentially expressed genes were identified using significance of analysis of microarrays (SAM), and clustered using a weighted gene co-expression network analysis (WGCNA). Gene-set enrichment was performed to identify major biological pathways. Comparison of transcriptional profiles between first and third trimesters of pregnancy identified 5839 significantly differentially expressed genes (FDR<0.05). Weighted gene co-expression network analysis clustered these transcripts into 14 co-expression modules of which two showed significant correlation with maternal vitamin D levels. Pathway analysis of these two modules revealed genes enriched in immune defense pathways and extracellular matrix reorganization as well as genes enriched in notch signaling and transcription factor networks. Our data show that gene expression profiles of healthy pregnant women change during the course of pregnancy and suggest that maternal Vitamin D levels influence transcriptional profiles. These alterations of the maternal transcriptome may contribute to fetal immune imprinting and reduce allergic sensitization in early life. clinicaltrials.gov NCT00920621.

ZBTB7A is frequently mutated in acute myeloid leukemia (AML) with t(8;21) translocation. However, the oncogenic collaboration between mutated ZBTB7A and the RUNX1–RUNX1T1 fusion gene in AML t(8;21) remains unclear. Here, we investigate the role of ZBTB7A and its mutations in the context of normal and malignant hematopoiesis. We demonstrate that clinically relevant ZBTB7A mutations in AML t(8;21) lead to loss of function and result in perturbed myeloid differentiation with block of the granulocytic lineage in favor of monocytic commitment. In addition, loss of ZBTB7A increases glycolysis and hence sensitizes leukemic blasts to metabolic inhibition with 2-deoxy-d-glucose. We observed that ectopic expression of wild-type ZBTB7A prevents RUNX1-RUNX1T1-mediated clonal expansion of human CD34+ cells, whereas the outgrowth of progenitors is enabled by ZBTB7A mutation. Finally, ZBTB7A expression in t(8;21) cells lead to a cell cycle arrest that could be mimicked by inhibition of glycolysis. Our findings suggest that loss of ZBTB7A may facilitate the onset of AML t(8;21), and that RUNX1-RUNX1T1-rearranged leukemia might be treated with glycolytic inhibitors.

Leptin is an adipocyte-derived hormone that controls food intake and reproductive and immune functions in rodents. In uncontrolled human studies, low leptin levels are associated with impaired immune responses and reduced T-cell counts; however, the effects of leptin replacement on the adaptive immune system have not yet been reported in the context of randomized, controlled studies and/or in conditions of chronic acquired leptin deficiency. To address these questions, we performed a randomized, double-blinded, placebo-controlled trial of recombinant methionyl-human leptin (metreleptin) administration in replacement doses in women experiencing the female triad (hypothalamic amenorrhea) with acquired chronic hypoleptinemia induced by negative energy balance. Metreleptin restored both CD4 ⁺ T-cell counts and their in vitro proliferative responses in these women. These changes were accompanied by a transcriptional signature in which genes relevant to cell survival and hormonal response were up-regulated, and apoptosis genes were down-regulated in circulating immune cells. We also observed that signaling pathways involved in cell growth/survival/proliferation, such as the STAT3, AMPK, mTOR, ERK1/2, and Akt pathways, were activated directly by acute in vivo metreleptin administration in peripheral blood mononuclear cells and CD4 ⁺ T-cells both from subjects with chronic hypoleptinemia and from normoleptinemic, lean female subjects. Our data show that metreleptin administration, in doses that normalize circulating leptin levels, induces transcriptional changes, activates intracellular signaling pathways, and restores CD4 ⁺ T-cell counts. Thus, metreleptin may prove to be a safe and effective therapy for selective CD4 ⁺ T-cell immune reconstitution in hypoleptinemic states such as tuberculosis and HIV infection in which CD4 ⁺ T cells are reduced.

In a recent intervention study, the daily supplementation with 200 mg monomeric and oligomeric flavanols (MOF) from grape seeds for 8 weeks revealed a vascular health benefit in male smokers. The objective of the present study was to determine the impact of MOF consumption on the gene expression profile of leukocytes and to assess changes in DNA methylation. Gene expression profiles were determined using whole genome microarrays (Agilent) and DNA methylation was assessed using HumanMethylation450 BeadChips (Illumina). MOF significantly modulated the expression of 864 genes. The majority of the affected genes are involved in chemotaxis, cell adhesion, cell infiltration or cytoskeleton organisation, suggesting lower immune cell adhesion to endothelial cells. This was corroborated by in vitro experiments showing that MOF exposure of monocytes attenuates their adhesion to TNF-a -stimulated endothelial cells. Nuclear factor kappa B (NF-k B) reporter gene assays confirmed that MOF decrease the activity of NF-B. Strong inter-individual variability in the leukocytes’ DNA methylation was observed. As a consequence, on group level, changes due to MOF supplementation could not be found. Our study revealed that an 8 week daily supplementation with 200 mg MOF modulates the expression of genes associated with cardiovascular disease pathways without major changes of their DNA methylation state. However, strong inter-individual variation in leukocyte DNA methylation may obscure the subtle epigenetic response to dietary flavanols. Despite the lack of significant changes in DNA methylation, the modulation of gene expression appears to contribute to the observed vascular health effect of MOF in humans

Background Adenosine deaminase (ADA) and osteopontin (OPN) may play opposing roles in the pathogenesis of COPD. Deficiency of ADA results in enhanced adenosine signaling which up-regulates OPN expression. Although statins suppress OPN in cancer cells, little is known about their effects on ADA and OPN in COPD patients. Methods We extended a previous randomized double-blind placebo crossover study to investigate the effects of simvastatin (20 mg/day) on sputum ADA and OPN expression and explored the underlying signaling pathways involved by conducting in vitro experiments with cigarette smoke extract (CSE)-treated monocyte-derived macrophages (MDM) from COPD patients and healthy subjects. Results Simvastatin decreased sputum IL-13, OPN and CD73, while increasing ADA expression, irrespective of inhaled corticosteroid treatment and smoking status in parallel to increased inosine levels. The degree of simvastatin-restored ADA activity was significantly correlated with the magnitude of changes in pre-bronchodilator FEV 1 . Mechanistic exploration showed that CSE enhanced the expression of IL-13, which induced an increase in OPN and inhibited ADA mRNA accumulation in MDM from COPD patients but not healthy subjects through a STAT6-dependent mechanism. Simvastatin treatment inhibited IL-13 transcription in a dose-dependent manner, and therefore diminished the IL-13-induced increase in OPN and restored IL-13-suppressed ADA. There was no effect of simvastatin on adenosine receptors in CSE-stimulated MDM, indicating that its effects were on the adenosine pathway. Conclusion Simvastatin reversed IL-13-suppressed ADA activity that leads to the down-regulation of adenosine signaling and therefore inhibits OPN expression through the direct inhibition of IL-13-activated STAT6 pathway. Inhibition of IL-13 may reverse the imbalance between ADA and OPN in COPD and therefore may prevent COPD progression.

Measurement of the transcripts of BCR-ABL, the key molecular abnormality in chronic myeloid leukemia (CML), provides an estimate of the burden of leukemic cells in a given patient. A profound reduction in blood levels of BCR-ABL transcripts was much more frequent among patients treated with imatinib than among those treated with interferon alfa plus cytarabine. Responses superior to those with interferon plus cytarabine. Chronic myeloid leukemia (CML) is a clonal disease of the hematopoietic stem cell in which a reciprocal translocation, t(9;22)(q34;q11), forms the Philadelphia chromosome (Ph) and creates a novel fusion gene, BCR-ABL . 1 This gene expresses an activated tyrosine kinase that is central to the pathogenesis of CML. 2 , 3 The median survival among patients with CML is three to six years, with most deaths resulting from progression of the disease into a blastic phase. Survival among patients treated with interferon alfa is superior to that among patients treated with hydroxyurea. 4 The addition of cytarabine to interferon alfa may further improve median . . .

Through drug exposure, a rare, transient transcriptional program characterized by high levels of expression of known resistance drivers can get ‘burned in’, leading to the selection of cells endowed with a transcriptional drug resistance and thus more chemoresistant cancers. Therapies that target signalling molecules that are mutated in cancers can often have substantial short-term effects, but the emergence of resistant cancer cells is a major barrier to full cures 1 , 2 . Resistance can result from secondary mutations 3 , 4 , but in other cases there is no clear genetic cause, raising the possibility of non-genetic rare cell variability 5 , 6 , 7 , 8 , 9 , 10 , 11 . Here we show that human melanoma cells can display profound transcriptional variability at the single-cell level that predicts which cells will ultimately resist drug treatment. This variability involves infrequent, semi-coordinated transcription of a number of resistance markers at high levels in a very small percentage of cells. The addition of drug then induces epigenetic reprogramming in these cells, converting the transient transcriptional state to a stably resistant state. This reprogramming begins with a loss of SOX10-mediated differentiation followed by activation of new signalling pathways, partially mediated by the activity of the transcription factors JUN and/or AP-1 and TEAD. Our work reveals the multistage nature of the acquisition of drug resistance and provides a framework for understanding resistance dynamics in single cells. We find that other cell types also exhibit sporadic expression of many of these same marker genes, suggesting the existence of a general program in which expression is displayed in rare subpopulations of cells.