► Neutrinos leave a distinct imprint on the large scale structure of the Universe. ► Large surveys are sensitive to the sum of the neutrino masses. ► We collect and explain current and future ...constraints from different probes of the structure of the Universe.
Cosmological and astrophysical measurements provide powerful constraints on neutrino masses complementary to those from accelerators and reactors. Here we provide a guide to these different probes, for each explaining its physical basis, underlying assumptions, current and future reach.
Whether hormetic responses result from a direct or an overcompensation type of stimulatory response has been an unresolved and contentious issue in both radiation and chemical toxicology. The goal of ...the present article is to identify numerous examples of overcompensation stimulation in the biological biomedical literature and to evaluate their descriptive and quantitative features. The findings provide support for the hypothesis that hormetic dose-response relationships from a broad array of biological models can occur after an initial disruption in homeostasis. The finding also demonstrates the significant role of temporal factors in the assessment of dose response relationships.
Dysregulated cell cycling is a universal hallmark of cancer and is often mediated by abnormal activation of cyclin-dependent kinases (CDKs) and their cyclin partners. Over-expression of individual ...complexes are reported in multiple myeloma (MM), making them attractive therapeutic targets. In this study, we investigate the preclinical activity of a novel small-molecule multi-CDK inhibitor, AT7519, in MM. We show the anti-MM activity of AT7519 displaying potent cytotoxicity and apoptosis; associated with in vivo tumor growth inhibition and prolonged survival. At the molecular level, AT7519 inhibited RNA polymerase II (RNA pol II) phosphorylation, a CDK9, 7 substrate, associated with decreased RNA synthesis confirmed by ³H Uridine incorporation. In addition, AT7519 inhibited glycogen synthase kinase 3β (GSK-3β) phosphorylation; conversely pretreatment with a selective GSK-3 inhibitor and shRNA GSK-3β knockdown restored MM survival, suggesting the involvement of GSK-3β in AT7519-induced apoptosis. GSK-3β activation was independent of RNA pol II dephosphorylation confirmed by α-amanitin, a specific RNA pol II inihibitor, showing potent inhibition of RNA pol II phosphorylation without corresponding effects on GSK-3β phosphorylation. These results offer new insights into the crucial, yet controversial role of GSK-3β in MM and show significant anti-MM activity of AT7519, providing the rationale for its clinical evaluation in MM. Oncogene (2010) 29, 2325-2336; doi: 10.1038/onc.2009.510; published online 25 January 2010 Keywords: myeloma; cyclin-dependent kinase; GSK-3β; RNA pol II
Summary
Background
Infliximab and adalimumab are highly effective in Crohn's Disease (CD). This is supported by clinical trials and open‐label studies using either infliximab or adalimumab, thus not ...allowing a proper comparison between these anti‐TNFs in CD.
Aim
To evaluate the efficacy and safety of infliximab and adalimumab in active CD.
Methods
In a longitudinal study, CD patients with indication for anti‐TNFs were treated with infliximab or adalimumab.
Results
Ninety‐three patients were treated with infliximab (n = 44) or adalimumab (n = 49). In the infliximab group, the induction was completed by 77.3% of patients, due to no response (n = 2), delayed hypersensitivity reactions (DHR) or infusion reactions (n = 8). Maintenance with infliximab was completed by 60% of patients, due to clinical worsening or loss of efficacy (n = 5), DHR or infusion reactions (n = 5). In the adalimumab group, all patients completed the induction, while maintenance was completed by 67% of patients, due to clinical worsening or loss of efficacy (n = 8), DHR (n = 1), other causes (n = 7). In both groups, the CDAI significantly reduced at baseline vs. each visit (P < 0.04). The Kaplan–Meier survival analysis performed to evaluate the risk of steroid‐free remission in patients treated with infliximab vs. adalimumab detected no differences (log‐rank test P = 0.4). Cox proportional‐hazards regression identified two predictors of steroid‐free remission using anti‐TNFs: no smokers HR = 2.94 (1.52–5.70), P = 0.001 and non stricturing non penetrating behaviour HR = 3.116 (1.06–9.13), P = 0.03826.
Conclusions
Infliximab and adalimumab showed a similar efficacy. No smoking and non‐stricturing non‐penetrating behaviour were predictors of steroid‐free remission.
In Crohn's disease (CD), knockdown of Smad7, an inhibitor of Transforming Growth Factor (TGF)-β1 activity, with a specific antisense oligonucleotide (GED0301) seems to be safe and tolerable and ...associates with TGF-β1-mediated suppression of inflammatory pathways.
Since TGF-β1 has pro-fibrogenic effects in many organs, we evaluated whether GED0301 treatment associates with the formation of small bowel strictures.
Fifteen patients with active, inflammatory CD, receiving oral GED0301 once daily for 7 days, were monitored for the formation of small bowel strictures by Small Intestine Contrast Ultrasonography (SICUS). Serum basic fibroblast growth factor (bFGF) and human chitinase 3-like 1 (also known as YKL-40), two markers of CD-related intestinal strictures, and matrix metalloproteinases (MMP) and tissue inhibitor 1 of MMPs (TIMP1) were analysed at day 0 and day 180 by ELISA. Crohn's disease activity index (CDAI) changes were also monitored.
Fourteen patients completed the 6-month study; the remaining underwent intestinal resection for a severe relapse not responsive to medical treatment. No patient developed small bowel stricture and none experienced obstructive symptoms during the study period. GED0301 treatment induced no significant change in the circulating levels of bFGF, YKL-40, MMPs and TIMP1. Seven of 12 patients who reached clinical remission following GED0301 treatment maintained a CDAI < 150 at day 180.
Short-term treatment of patients with Crohn's disease using GED0301 is not associated with the development of small bowel stricture, thus reinforcing the concept that this drug is safe at least at early time points.
Despite the long history of hormesis-related experimental research no systematic effort to describe its early history has been undertaken. The present paper attempts to reconstruct and assess the ...early history of such research and to evaluate how advances in related scientific fields affected the course of hormesis-related research. The purpose of this paper is not only to satisfy this gap in current knowledge, but also to provide a foundation for the assessment of how the concept of hormetic dose-response relationships may have affected the nature of the bioassay especially with respect to hazard assessment practices within a modern risk assessment Eramework.
Earlier studies have shown that ascorbic acid (vitamin C) inhibits bortezomib-induced cytotoxicity against cancer cells in vitro. However, the clinical significance of vitamin C on bortezomib ...treatment is unclear. In this study, we examined whether daily oral intake of vitamin C inhibits antimultiple myeloma (MM) activities of bortezomib. Vitamin C, at orally achievable concentrations, inhibited in vitro MM cell cytotoxicity of bortezomib and blocked its inhibitory effect on 20S proteasome activity. Specifically, plasma collected from healthy volunteers taking 1 g/day vitamin C reduced bortezomib-induced MM cell death in vitro. This antagonistic effect of vitamin C against proteasome inhibitors is limited to the boronate class of inhibitors (bortezomib and MG262). In vivo activity of this combination treatment was then evaluated using our xenograft model of human MM in SCID (severe combined immune-deficient) mice. Bortezomib (0.1 mg/kg twice a week for 4 weeks) significantly inhibits in vivo MM cell growth, which was blocked by oral vitamin C (40 mg/kg/day). Therefore, our results for the first time show that vitamin C can significantly reduce the activity of bortezomib treatment in vivo; and importantly, suggest that patients receiving treatment with bortezomib should avoid taking vitamin C dietary supplements.
Purpose
The advantages offered by structured reporting have already been highlighted in the literature. However, there is still no evidence on the validity of this reporting method for the study of ...abdominal wall defects. This study aims to show the experience of the Trentino Hernia Team (THT) multidisciplinary group in the development and use of a structured CT scan report for the study of abdominal wall defects.
Methods
A regional multidisciplinary team (THT group) used a Delphi method to identify and select the most important CT scan parameters needed to describe and stage abdominal wall defects for correct preoperative planning. Based on the selected parameters, a CT scan structured report was worked out and collectively accepted. The first 20 structured reports obtained were individually tested for compilation speed and homogeneity of the data reported by five distinct radiologists. The reports were then evaluated by five different surgeons to test the simplicity of interpretation.
Results
We produced a model of a structured report for the study of the abdominal wall defects and tested it in our hospital network on the first 20 reports. The average completion time was 18 min (range 12–25). There was no heterogeneity among the reported data. The reports were analysed by five distinct surgeons to evaluate completeness and simplicity of interpretation. Each surgeon used a Likert scale from 0 to 5 to evaluate each report, producing average scores of 4.8 and 4.1 for completeness and comprehensibility respectively, with a mean combined total score of 8.9 out of 10.
Conclusions
Our structured report represents a fundamental tool capable of providing the surgeon with all the measurements of the parameters necessary for correct preoperative planning. At the same time, it is of crucial help for the radiologists representing an easy and fast way to report all the needed parameters using the same standards.
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