This book investigates the troubled relationship between medieval
studies and medievalism. Acknowledging that the medieval and
medievalism are mutually constitutive, and that their texts can be
read ...using similar strategies, it argues that medieval writers
offer powerful models for the ways in which contemporary desire
determines the constitution of the past. This desire can not only
connect us with the past but can reconnect readers in the present
with the lost history of what may be called the 'medievalism of the
medievals'. In other words, to come to terms with the history of
the medieval is to understand that it alread y offers us a
model of how to relate to the past.
Pre-clinical models have shown that targeting pancreatic stellate cells with all-trans-retinoic-acid (ATRA) reprograms pancreatic stroma to suppress pancreatic ductal adenocarcinoma (PDAC) growth. ...Here, in a phase Ib, dose escalation and expansion, trial for patients with advanced, unresectable PDAC (n = 27), ATRA is re-purposed as a stromal-targeting agent in combination with gemcitabine-nab-paclitaxel chemotherapy using a two-step adaptive continual re-assessment method trial design. The maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D, primary outcome) is the FDA/EMEA approved dose of gemcitabine-nab-paclitaxel along-with ATRA (45 mg/m
orally, days 1-15/cycle). Dose limiting toxicity (DLT) is grade 4 thrombocytopenia (n = 2). Secondary outcomes show no detriment to ATRA pharmacokinetics.. Median overall survival for RP2D treated evaluable population, is 11.7 months (95%CI 8.6-15.7 m, n = 15, locally advanced (2) and metastatic (13)). Exploratory pharmacodynamics studies including changes in diffusion-weighted (DW)-MRI measured apparent diffusion coefficient after one cycle, and, modulation of cycle-specific serum pentraxin 3 levels over various cycles indicate stromal modulation. Baseline stromal-specific retinoid transport protein (FABP5, CRABP2) expression may be predicitve of response. Re-purposing ATRA as a stromal-targeting agent with gemcitabine-nab-paclitaxel is safe and tolerable. This combination will be evaluated in a phase II randomized controlled trial for locally advanced PDAC. Clinical trial numbers: EudraCT: 2015-002662-23; NCT03307148. Trial acronym: STARPAC.
Earliest known human burial in Africa Martinón-Torres, María; d'Errico, Francesco; Santos, Elena ...
Nature (London),
05/2021, Letnik:
593, Številka:
7857
Journal Article
Recenzirano
Odprti dostop
The origin and evolution of hominin mortuary practices are topics of intense interest and debate
. Human burials dated to the Middle Stone Age (MSA) are exceedingly rare in Africa and unknown in East ...Africa
. Here we describe the partial skeleton of a roughly 2.5- to 3.0-year-old child dating to 78.3 ± 4.1 thousand years ago, which was recovered in the MSA layers of Panga ya Saidi (PYS), a cave site in the tropical upland coast of Kenya
. Recent excavations have revealed a pit feature containing a child in a flexed position. Geochemical, granulometric and micromorphological analyses of the burial pit content and encasing archaeological layers indicate that the pit was deliberately excavated. Taphonomical evidence, such as the strict articulation or good anatomical association of the skeletal elements and histological evidence of putrefaction, support the in-place decomposition of the fresh body. The presence of little or no displacement of the unstable joints during decomposition points to an interment in a filled space (grave earth), making the PYS finding the oldest known human burial in Africa. The morphological assessment of the partial skeleton is consistent with its assignment to Homo sapiens, although the preservation of some primitive features in the dentition supports increasing evidence for non-gradual assembly of modern traits during the emergence of our species. The PYS burial sheds light on how MSA populations interacted with the dead.
Topical application of phorbol myristate acetate (PMA) elicits intense local inflammation that facilitates outgrowth of premalignant lesions in skin after carcinogen exposure. The inflammatory ...response to PMA treatment activates immune stimulatory mechanisms. However, we show here that PMA exposure also induces plasmacytoid dendritic cells (pDCs) in local draining lymph nodes (dLNs) to express indoleamine 2,3 dioxygenase (IDO), which confers T cell suppressor activity on pDCs. The induced IDO-mediated inhibitory activity in this subset of pDCs was potent, dominantly suppressing the T cell stimulatory activity of other DCs that comprise the major fraction of dLN DCs. IDO induction in pDCs depended on inflammatory signaling by means of IFN type I and II receptors, the TLR/IL-1 signaling adaptor MyD88, and on cellular stress responses to amino acid withdrawal by means of the integrated stress response kinase GCN2. Consistent with the hypothesis that T cell suppressive, IDO⁺ pDCs elicited by PMA exposure create local immune privilege that favors tumor development, IDO-deficient mice exhibited a robust tumor-resistant phenotype in the standard DMBA/PMA 2-stage carcinogenesis model of skin papilloma formation. Thus, IDO is a key immunosuppressive factor that facilitates tumor progression in this setting of chronic inflammation driven by repeated topical PMA exposure.
Background:
Germline variation in the 71 Crohn's disease (CD) loci implicated by genome‐wide association studies (GWAS) only accounts for approximately 25% of estimated heritability. The contribution ...of epigenetic alterations to disease pathogenesis is emerging as a research priority.
Materials and Methods:
The methylation status of 27,578 CpG sites across the genome was analyzed using the Illumina Human Methylation27 assay in DNA extracted from whole blood samples from 40 adult females (21 ileal CD, 19 healthy controls) and 16 girls with childhood‐onset CD, all nonsmokers. Our primary analysis compared methylation profiles in adult cases and controls.
Results:
Our data define a global methylation profile characteristic of ileal CD. In all, 1117 sites were differentially methylated (corrected P < 0.01); 50 showed significantly altered methylation in cases compared with controls (uncorrected P < 10−6, corrected P < 0.0006), including genes altering immune activation: MAPK13, FASLG, PRF1, S100A13, RIPK3, and IL‐21R. Gene ontology analyses implicated immunity‐related pathways as targets of epigenetic modification (immune system processes P = 1.3 × 10−22, immune response P = 8.1 × 10−16, defense responses to bacteria P = 1.8 × 10−15). Ingenuity canonical pathway analyses implicated dendritic cell activity (P = 2.4 × 10−8) and differential regulation of cytokines by interleukin (IL)‐17A and IL‐17F (P = 5.8 × 10−7). We identified a significant enrichment of methylation changes within 50 kb of CD GWAS loci (8.6‐fold P = 0.021 in adults; 2.4‐fold P = 0.009 in adults and children combined), including IL‐27, IL‐19, TNF, MST1, and NOD2. Methylation status was predictive of disease status (sensitivity 0.71, specificity 0.83). Disease activity, drug therapy, NOD2 and DNMT3A genotypes were not associated with methylation changes.
Conclusions:
These data provide an important insight into the impact of epigenetic mechanisms in the pathogenesis of CD. (Inflamm Bowel Dis 2011;)
It has recently been proposed that experimental autoimmune encephalomyelitis, once considered the classical Th1 disease, is predominantly Th17 driven. In this study we show that myelin-reactive Th1 ...preparations devoid of contaminating IL-17(+) cells are highly pathogenic. In contrast, Th17 preparations lacking IFN-gamma(+) cells do not cause disease. Our key observation is that only Th1 cells can access the noninflamed CNS. Once Th1 cells establish the experimental autoimmune encephalomyelitis lesion, Th17 cells appear in the CNS. These data shed important new light on the ability of Th1 vs Th17 cells to access inflamed vs normal tissue. Because the IL-17-triggered release of chemokines by stromal cells could attract many other immune cells, allowing Th17 cells to access the tissues only under conditions of inflammation may be a key process limiting (auto)immune pathology. This has major implications for the design of therapeutic interventions, many of which are now aiming at Th17 rather than Th1 cells.
A nonheme iron(III) terminal methoxide complex, FeIII(N3PyO2Ph)(OCH3)ClO4, was synthesized. Reaction of this complex with the triphenylmethyl radical (Ph3C•) leads to formation of Ph3COCH3 and the ...one-electron-reduced iron(II) center, as seen by UV–vis, EPR, 1H NMR, and Mössbauer spectroscopy. These results indicate that homolytic Fe–O bond cleavage occurs together with C–O bond formation, providing a direct observation of the “radical rebound” process proposed for both biological and synthetic nonheme iron centers.
Abstract
Testing the effect of rare variants on phenotypic variation is difficult due to the need for extremely large cohorts to identify associated variants given expected effect sizes. An ...alternative approach is to investigate the effect of rare genetic variants on DNA methylation (DNAm) as effect sizes are expected to be larger for molecular traits compared with complex traits. Here, we investigate DNAm in healthy ageing populations—the Lothian Birth Cohorts of 1921 and 1936—and identify both transient and stable outlying DNAm levels across the genome. We find an enrichment of rare genetic single nucleotide polymorphisms (SNPs) within 1 kb of DNAm sites in individuals with stable outlying DNAm, implying genetic control of this extreme variation. Using a family-based cohort, the Brisbane Systems Genetics Study, we observed increased sharing of DNAm outliers among more closely related individuals, consistent with these outliers being driven by rare genetic variation. We demonstrated that outlying DNAm levels have a functional consequence on gene expression levels, with extreme levels of DNAm being associated with gene expression levels toward the tails of the population distribution. This study demonstrates the role of rare SNPs in the phenotypic variation of DNAm and the effect of extreme levels of DNAm on gene expression.
The skin provides an important first line of defence and immunological barrier to invasive pathogens, but immune responses must also be regulated to maintain barrier function and ensure tolerance of ...skin surface commensal organisms. In schistosomiasis-endemic regions, populations can experience repeated percutaneous exposure to schistosome larvae, however little is known about how repeated exposure to pathogens affects immune regulation in the skin. Here, using a murine model of repeated infection with Schistosoma mansoni larvae, we show that the skin infection site becomes rich in regulatory IL-10, whilst in its absence, inflammation, neutrophil recruitment, and local lymphocyte proliferation is increased. Whilst CD4+ T cells are the primary cellular source of regulatory IL-10, they expressed none of the markers conventionally associated with T regulatory (Treg) cells (i.e. FoxP3, Helios, Nrp1, CD223, or CD49b). Nevertheless, these IL-10+ CD4+ T cells in the skin from repeatedly infected mice are functionally suppressive as they reduced proliferation of responsive CD4+ T cells from the skin draining lymph node. Moreover, the skin of infected Rag-/- mice had impaired IL-10 production and increased neutrophil recruitment. Finally, we show that the mechanism behind IL-10 production by CD4+ T cells in the skin is due to a combination of an initial (day 1) response specific to skin commensal bacteria, and then over the following days schistosome-specific CD4+ T cell responses, which together contribute towards limiting inflammation and tissue damage following schistosome infection. We propose CD4+ T cells in the skin that do not express markers of conventional T regulatory cell populations have a significant role in immune regulation after repeated pathogen exposure and speculate that these cells may also help to maintain skin barrier function in the context of repeated percutaneous insult by other skin pathogens.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
ObjectivesTo describe the characteristics of clinical study report (CSR) documents published by the European Medicines Agency (EMA), and for included pivotal trials, to quantify the timeliness of ...access to trial results from CSRs compared with conventional published sources.DesignCross-sectional analysis of CSR documents published by the EMA from 2016 to 2018.MethodsCSR files and medication summary information were downloaded from the EMA. Individual trials in each submission were identified using document filenames. Number and length of documents and trials were determined. For pivotal trials, trial phase, dates of EMA document publication and matched journal and registry publications were obtained.ResultsThe EMA published documents on 142 medications that were submitted for regulatory drug approval. Submissions were for initial marketing authorisations in 64.1%. There was a median of 15 (IQR 5–46) documents, 5 (IQR 2–14) trials and 9629 (IQR 2711–26,673) pages per submission, and a median of 1 (IQR 1–4) document and 336 (IQR 21–1192) pages per trial. Of all identified pivotal trials, 60.9% were phase 3 and 18.5% were phase 1. Of 119 unique submissions to the EMA, 46.2% were supported by a single pivotal trial, with 13.4% based on a single pivotal phase 1 trial. No trial registry results were identified for 26.1% trials, no journal publications for 16.7% and 13.5% of trials had neither. EMA publication was the earliest information source for 5.8% of pivotal trials, available a median 523 days (IQR 363–882 days) before the earliest publication.ConclusionsThe EMA Clinical Data website contains lengthy clinical trial documents. Almost half of submissions to the EMA were based on single pivotal trials, many of which were phase 1 trials. CSRs were the only source and a timelier source of information for many trials. Access to unpublished trial information should be open and timely to support decision-making for patients.
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