Development and performance of the Clinical Trials ESSDAI (ClinTrialsESSDAI), consisting of frequently active clinical domains, in two randomised controlled trials in primary Sjogren's syndrome

Objective. To develop and evaluate the Clinical Trials EULAR Sjogren's Syndrome Disease Activity Index (ClinTrialsESSDAI), consisting of frequently active clinical domains of the ESSDAI, using two randomised controlled trials in primary Sjogren's syndrome (pSS). Methods. The ASAP-III trial in abatacept (80 pSS patients) and TRACTISS trial in rituximab (133 pSS patients) were analysed. The most frequently active clinical domains were selected, and ClinTrialsESSDAI total score was calculated using existing weightings of the ClinESSDAI (which also excludes the biological domain). Performance of the ClinTrialsESSDAI was compared to ClinESSDAI and ESSDAI. Responsiveness was assessed using standardised response mean (SRM), and discrimination was assessed using adjusted mean difference. Results. Besides the biological domain, the most frequently active domains were glandular, articular, haematological, constitutional, lymphadenopathy and cutaneous. These domains were selected for the ClinTrialsESSDAI. At primary endpoint visits, SRM values of ClinTrialsESSDAI, ClinESSDAI and ESSDAI were respectively -0.65/-0.59, -0.63/-0.59 and - 0.64/-0.61 for abatacept/placebo and -0.33/-0.13, -0.34/0.12 and -0.41/-0.16 for rituximab/placebo. Adjusted mean differences between active treatment and placebo groups were respectively -1.7, -1.4 and -1.1 for ASAP-III and -1.1, -1.1 and -1.2 for TRACTISS. Conclusion. The ClinTrialsESSDAI, consisting of six frequently active clinical domains of the ESSDAI, shows closely similar responsiveness and discrimination between treatment groups compared to the ClinESSDAI and ESSDAI. Therefore, this ClinTrialsESSDAI is not preferable to ClinESSDAI and ESSDAI for use as primary endpoint. A composite endpoint combining response at multiple clinically relevant items seems more suitable as primary study endpoint in pSS

The Gerasimov-Drell-Hearn Sum Rule and the Spin Structure of the Nucleon

The Gerasimov-Drell-Hearn sum rule is one of several dispersive sum rules that connect the Compton scattering amplitudes to the inclusive photoproduction cross sections of the target under investigation. Being based on such universal principles as causality, unitarity, and gauge invariance, these sum rules provide a unique testing ground to study the internal degrees of freedom that hold the system together. The present article reviews these sum rules for the spin-dependent cross sections of the nucleon by presenting an overview of recent experiments and theoretical approaches. The generalization from real to virtual photons provides a microscope of variable resolution: At small virtuality of the photon, the data sample information about the long range phenomena, which are described by effective degrees of freedom (Goldstone bosons and collective resonances), whereas the primary degrees of freedom (quarks and gluons) become visible at the larger virtualities. Through a rich body of new data and several theoretical developments, a unified picture of virtual Compton scattering emerges, which ranges from coherent to incoherent processes, and from the generalized spin polarizabilities on the low-energy side to higher twist effects in deep inelastic lepton scattering.Comment: 32 pages, 19 figures, review articl

FANCD2 expression affects platinum response and further characteristics of high grade serous ovarian cancer in cells with different genetic backgrounds

High-grade serous ovarian cancer (HGSOC) is the most prevalent subtype of ovarian cancer and demonstrates 5-year survival of just 40%. One of the major causes of mortality is the development of tumour resistance to platinum-based chemotherapy, which can be modulated by dysregulation of DNA damage repair pathways. We therefore investigated the contribution of the DNA interstrand crosslink repair protein FANCD2 to chemosensitivity in HGSOC. Increased FANCD2 protein expression was observed in some cell line models of platinum resistant HGSOC compared with paired platinum sensitive models. Knockdown of FANCD2 in some cell lines, including the platinum resistant PEO4, led to increased carboplatin sensitivity. Investigation into mechanisms of FANCD2 regulation showed that increased FANCD2 expression in platinum resistant cells coincides with increased expression of mTOR. Treatment with mTOR inhibitors resulted in FANCD2 depletion, suggesting that mTOR can mediate platinum sensitivity via regulation of FANCD2. Tumours from a cohort of HGSOC patients showed varied nuclear and cytoplasmic FANCD2 expression, however this was not significantly associated with clinical characteristics. Knockout of FANCD2 was associated with increased cell migration, which may represent a non-canonical function of cytoplasmic FANCD2. We conclude that upregulation of FANCD2, possibly mediated by mTOR, is a potential mechanism of chemoresistance in HGSOC and modulation of FANCD2 expression can influence platinum sensitivity and other tumour cell characteristics

RFWD3 modulates response to platinum chemotherapy and promotes cancer associated phenotypes in high grade serous ovarian cancer

Background: DNA damage repair is frequently dysregulated in high grade serous ovarian cancer (HGSOC), which can lead to changes in chemosensitivity and other phenotypic differences in tumours. RFWD3, a key component of multiple DNA repair and maintenance pathways, was investigated to characterise its impact in HGSOC.Methods: RFWD3 expression and association with clinical features was assessed using in silico analysis in the TCGA HGSOC dataset, and in a further cohort of HGSOC tumours stained for RFWD3 using immunohistochemistry. RFWD3 expression was modulated in cell lines using siRNA and CRISPR/cas9 gene editing, and cells were characterised using cytotoxicity and proliferation assays, flow cytometry, and live cell microscopy. Results: Expression of RFWD3 RNA and protein varied in HGSOCs. In cell lines, reduction of RFWD3 expression led to increased sensitivity to interstrand crosslinking (ICL) inducing agents mitomycin C and carboplatin. RFWD3 also demonstrated further functionality outside its role in DNA damage repair, with RFWD3 deficient cells displaying cell cycle dysregulation, reduced cellular proliferation and reduced migration. In tumours, low RFWD3 expression was associated with increased tumour mutational burden, and complete response to platinum chemotherapy. Conclusions: RFWD3 expression varies in HGSOCs, which can lead to functional effects at both the cellular and tumour levels.<br/

Compton Scattering by the Proton using a Large-Acceptance Arrangement

Compton scattering by the proton has been measured using the tagged-photon facility at MAMI (Mainz) and the large-acceptance arrangement LARA. The new data are interpreted in terms of dispersion theory based on the SAID-SM99K parameterization of photo-meson amplitudes. It is found that two-pion exchange in the t-channel is needed for a description of the data in the second resonance region. The data are well represented if this channel is modeled by a single pole with mass parameter m(sigma)=600 MeV. The asymptotic part of the spin dependent amplitude is found to be well represented by pi-0-exchange in the t-channel. A backward spin-polarizability of gamma(pi)=(-37.1+-0.6(stat+syst)+-3.0(model))x10^{-4}fm^4 has been determined from data of the first resonance region below 455 MeV. This value is in a good agreement with predictions of dispersion relations and chiral pertubation theory. From a subset of data between 280 and 360 MeV the resonance pion-photoproduction amplitudes were evaluated leading to a E2/M1 multipole ratio of the p-to-Delta radiative transition of EMR(340 MeV)=(-1.7+-0.4(stat+syst)+-0.2(model))%. It was found that this number is dependent on the parameterization of photo-meson amplitudes. With the MAID2K parameterization an E2/M1 multipole ratio of EMR(340 MeV)=(-2.0+-0.4(stat+syst)+-0.2(model))% is obtained

Origin Of The Far Off-Axis GRB171205A

We show that observed properties of the low luminosity GRB171205A and its afterglow, like those of most other low-luminosity (LL) gamma ray bursts (GRBs) associate with a supernova (SN), indicate that it is an ordinary SN-GRB, which was produced by inverse Compton scattering of glory light by a highly relativistic narrowly collimated jet ejected in a supernova explosion and viewed from a far off-axis angle. As such, VLA/VLBI follow-up radio observations of a superluminal displacement of its bright radio afterglow from its parent supernova, will be able to test clearly whether it is an ordinary SN-GRB viewed from far off-axis or it belongs to a distinct class of GRBs, which are different from ordinary GRBs, and cannot be explained by standard fireball models of GRBs as ordinary GRBsComment: 5 pages, 6 figures, updated data in Fig. 3, Corrected GRB angular distance used in Fig.