Differential Interleukin-2 Transcription Kinetics Render Mouse but Not Human T Cells Vulnerable to Splicing Inhibition Early after Activation

T cells are nodal players in the adaptive immune response against pathogens and malignant cells. Alternative splicing plays a crucial role in T cell activation, which is analyzed mainly at later time points upon stimulation. Here we have discovered a 2-h time window early after stimulation where optimal splicing efficiency or, more generally, gene expression efficiency is crucial for successful T cell activation. Reducing the splicing efficiency at 4 to 6 h poststimulation significantly impaired murine T cell activation, which was dependent on the expression dynamics of the Egr1-Nab2-interleukin-2 (IL-2) pathway. This time window overlaps the time of peak IL-2 de novo transcription, which, we suggest, represents a permissive time window in which decreased splicing (or transcription) efficiency reduces mature IL-2 production, thereby hampering murine T cell activation. Notably, the distinct expression kinetics of the Egr1-Nab2-IL-2 pathway between mouse and human render human T cells refractory to this vulnerability. We propose that the rational temporal modulation of splicing or transcription during peak de novo expression of key effectors can be used to fine-tune stimulation-dependent biological outcomes. Our data also show that critical consideration is required when extrapolating mouse data to the human system in basic and translational research

Genomics and epigenomics: new promises of personalized medicine for cancer patients

Recent years have brought about a marked extension of our understanding of the somatic basis of cancer. Parallel to the large-scale investigation of diverse tumor genomes the knowledge arose that cancer pathologies are most often not restricted to single genomic events. In contrast, a large number of different alterations in the genomes and epigenomes come together and promote the malignant transformation. The combination of mutations, structural variations and epigenetic alterations differs between each tumor, making individual diagnosis and treatment strategies necessary. This view is summarized in the new discipline of personalized medicine. To satisfy the ideas of this approach each tumor needs to be fully characterized and individual diagnostic and therapeutic strategies designed. Here, we will discuss the power of high-throughput sequencing technologies for genomic and epigenomic analyses. We will provide insight into the current status and how these technologies can be transferred to routine clinical usage

P01.55. Turmeric inhibits parathyroid hormone-related protein (PTHrP) secretion from human rheumatoid synoviocytes

Excessive production of parathyroid hormone-related protein (PTHrP) by tumor-like synoviocytes contributes to joint destruction in rheumatoid arthritis (RA). Having previously demonstrated that curcuminoid-only and essential oil-only fractions of turmeric prevent joint destruction in an animal model of RA, we hypothesized that synoviocyte PTHrP production could be one signaling pathway targeted by turmeric (Curcuma longa L.) in RA

Correction to: The hidden therapist: evidence for a central role of music in psychedelic therapy.

The article The hidden therapist: evidence for a central role of music in psychedelic therapy, written by Mendel Kaelen, Bruna Giribaldi, Jordan Raine, Lisa Evans, Christopher Timmerman, Natalie Rodriguez, Leor Roseman, Amanda Feilding, David Nutt, Robin Carhart-Harris, was originally published electronically on the publisher's internet portal

Turmeric inhibits parathyroid hormone-related protein (PTHrP) secretion from human rheumatoid synoviocytes

Excessive production of parathyroid hormone-related protein (PTHrP) by tumor-like synoviocytes contributes to joint destruction in rheumatoid arthritis (RA). Having previously demonstrated that curcuminoid-only and essential oil-only fractions of turmeric prevent joint destruction in an animal model of RA, we hypothesized that synoviocyte PTHrP production could be one signaling pathway targeted by turmeric (Curcuma longa L.) in RA

Evaluation of propofol for repeated prolonged deep sedation in children undergoing proton radiation therapy

Background The aim of this study is to evaluate the safety and sufficiency of a fixed dose rate propofol infusion for repeated prolonged deep sedation in children for proton radiation therapy (PRT). Methods With ERB approval, we recorded anaesthesia monitoring data in children undergoing repeated prolonged propofol sedation for PRT. Sedation was introduced with a single bolus of i.v. midazolam 0.1 mg kg−1 followed by repeated small boluses of propofol until sufficient depth of sedation was obtained. Sedation was maintained with fixed dose rate propofol infusion of 10 mg kg−1 h−1 in all patients up to the end of the radiation procedure. Patient characteristics, number and duration of sedation, propofol induction dose, necessity to alter propofol infusion rate, and heart rate, mean arterial pressure, respiratory rate were noted at the end of the radiation procedure before cessation of the propofol infusion. Data are mean (sd) or range (median) as appropriate. Results Eighteen children aged from 1.4 to 4.2 yr (2.6 yr) had 27.6 (sd 2.0) (497 in total) radiation procedures within 44.1 (4.0) days lasting 55.7 (8.8) min. Propofol bolus dose for induction, monitoring, and positioning was 3.7 (1.0) mg kg−1. Propofol bolus requirements were quite stable over the successive weeks of treatment and variability was larger between individuals than over time. In none of the children did propofol infusion rate need to be changed from the pre-set 10 mg kg−1 h−1 flow rate because of haemodynamic state, respiratory conditions or inadequate anaesthesia. Conclusions Repeated prolonged deep sedation over several weeks in very young children using a fixed rate propofol infusion was safe and adequate for all patient

Isolation of modulators of Organic Anion Transporting Polypeptides (OATPs) from Rollinia emarginata Schlecht (Annonaceae)

Comparative Medicine - OneHealth and Comparative Medicine Poster SessionOrganic Anion Transporting Polypeptides (OATPs) comprise a superfamily of sodium-independent membrane transporters which are involved in transporting numerous endogenous and exogenous substances. OATPs are expressed in different tissues such as intestine, liver, kidney and brain, and are responsible for the uptake of important drugs including cholesterol-lowering agents (statins), endothelin receptor antagonists (sartans), the anticancer drugs methotrexate, SN-38, paclitaxel and docetaxel, as well as the antibiotic rifampicin. Through a strategic collaboration, we search for novel small molecules from the organic extract of Rollinia emarginata Schlecht. (Annonaceae) that interact with the liver specific OATP1B1 and OATP1B3 applying a bioassay guided isolation approach. The organic extract was fractionated using different chromatographic techniques, and each fraction was tested for its effect on OATP1B1- and OATP1B3-mediated transport of 1µM estrone-3-sulfate and 0.1µM estradiol-17||-glucuronide. Several inhibitors, including both substrate-specific and non-specific, were isolated and chemically identified. For instance, the compound Quercetin 3-O-||-L-arabinopyranosyl (1 ->2)||-L-rhamnopyranoside was shown to inhibit both OATP1B1- and OATP1B3-mediated transport of estradiol-17||-glucuronide by more than 90%, relative to control (DMSO). However, with respect to transport of 1µM estrone-3-sulfate it inhibits OATP1B1 by only 45% while, interestingly, stimulating transport mediated by OATP1B3 (2 fold over control). Thanks to our collaborative efforts, we were able to show that plants can be suitable source of small molecules that modulate OATPs using bioassay guided isolation approach

Appropriating Risk Factors: The Reception of an American Approach to Chronic Disease in the two German States, c. 1950–1990

Risk factors have become a dominant approach to the aetiology of chronic disease worldwide. The concept emerged in the new field of chronic disease epidemiology in the United States in the 1950s, around near-iconic projects such as the Framingham Heart Study. In this article I examine how chronic disease epidemiology and the risk factor concept were adopted and adapted in the two German states. I draw on case studies that illuminate the characteristics of the different contexts and different take on traditions in social hygiene, social medicine and epidemiology. I also look at critics of the risk factor approach in East and West Germany, who viewed risk factors as intellectually dishonest and a new surveillance tool

Protection of Trabecular Bone in Ovariectomized Rats by Turmeric (Curcuma longa L.) is Dependent on Extract Composition

This document is the Accepted Manuscript version of a Published Work that appeared in final form in the Journal of Agricultural and Food Chemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://doi.org/10.1021/jf101873fExtracts prepared from turmeric (Curcuma longa L., [Zingiberaceae]) containing bioactive phenolic curcuminoids were evaluated for bone-protective effects in a hypogonadal rat model of postmenopausal osteoporosis. Three-month female Sprague Dawley rats were ovariectomized (OVX) and treated with a chemically complex turmeric fraction (41% curcuminoids by weight) or a curcuminoid-enriched turmeric fraction (94% curcuminoids by weight), both dosed at 60mg/kg 3x per week, or vehicle alone. Effects of two months of treatment on OVX-induced bone loss were followed prospectively by serial assessment of bone mineral density (BMD) of the distal femur using dual-energy x-ray absorptiometry (DXA), while treatment effects on trabecular bone microarchitecture were assessed at two months by micro-computerized tomography (μCT). Chemically complex turmeric did not prevent bone loss, however, the curcuminoid-enriched turmeric prevented up to 50% of OVX-induced loss of trabecular bone and also preserved the number and connectedness of the strut-like trabeculae. These results suggest that turmeric may have bone-protective effects but that extract composition is a critical factor

Climate of the Past Open Access Using palaeo-climate comparisons to constrain future projections

www.clim-past.net/10/221/2014/ doi:10.5194/cp-10-221-2014 © Author(s) 2014. CC Attribution 3.0 License