Field-angle Dependence of the Zero-Energy Density of States in the Unconventional Heavy-Fermion Superconductor CeCoIn5

Field-angle dependent specific heat measurement has been done on the heavy-fermion superconductor CeCoIn5 down to ~ 0.29 K, in a magnetic field rotating in the tetragonal c-plane. A clear fourfold angular oscillation is observed in the specific heat with the minima (maxima) occurring along the [100] ([110]) directions. Oscillation persists down to low fields H << Hc2, thus directly proving the existence of gap nodes. The results indicate that the superconducting gap symmetry is most probably of dxy type.Comment: 8 pages, 3 figures, to be published in J. Phys. Condens. Matte

Orbital-based Scenario for Magnetic Structure of Neptunium Compounds

In order to understand a crucial role of orbital degree of freedom in the magnetic structure of recently synthesized neptunium compounds NpTGa_5 (T=Fe, Co, and Ni), we propose to discuss the magnetic phase of an effective two-orbital model, which has been constructed based on a j-j coupling scheme to explain the magnetic structure of uranium compounds UTGa_5. By analyzing the model with the use of numerical technique such as exact diagonalization, we obtain the phase diagram including several kinds of magnetic states. An orbital-based scenario is discussed to understand the change in the magnetic structure among C-, A-, and G-type antiferromagnetic phases, experimentally observed in NpFeGa_5, NpCoGa_5, and NpNiGa_5.Comment: 18 pages, 8 figures, to appear in New Journal of Physic

Harmonising data collection from osteoarthritis studies to enable stratification: recommendations on core data collection from an Arthritis Research UK clinical studies group

Objective. Treatment of OA by stratifying for commonly used and novel therapies will likely improve the range of effective therapy options and their rational deployment in this undertreated, chronic disease. In order to develop appropriate datasets for conducting post hoc analyses to inform approaches to stratification for OA, our aim was to develop recommendations on the minimum data that should be recorded at baseline in all future OA interventional and observational studies.Methods. An Arthritis Research UK study group comprised of 32 experts used a Delphi-style approach supported by a literature review of systematic reviews to come to a consensus on core data collection for OA studies.Results. Thirty-five systematic reviews were used as the basis for the consensus group discussion. For studies with a primary structural endpoint, core domains for collection were defined as BMI, age, gender, racial origin, comorbidities, baseline OA pain, pain in other joints and occupation. In addition to the items generalizable to all anatomical sites, joint-specific domains included radiographic measures, surgical history and anatomical factors, including alignment. To demonstrate clinical relevance for symptom studies, the collection of mental health score, self-efficacy and depression scales were advised in addition to the above.Conclusions. Currently it is not possible to stratify patients with OA into therapeutic groups. A list of core and optional data to be collected in all OA interventional and observational studies was developed, providing a basis for future analyses to identify predictors of progression or response to treatment

The ADMR Receptor Mediates the Effects of Adrenomedullin on Pancreatic Cancer Cells and on Cells of the Tumor Microenvironment

Adrenomedullin (AM) is highly expressed in pancreatic cancer and stimulates pancreatic cancer cells leading to increased tumor growth and metastasis. The current study examines the role of specific AM receptors on tumor and cells resembling the tumor microenvironment (human pancreatic stellate--HPSC, human umbilical vein-- HUVEC and mouse lung endothelial cells--MLEC).AM receptors ADMR and CRLR were present in HPSC, HUVEC and MLECs while PDAC cells possessed only ADMR receptors as assessed by RT-PCR and western blotting. All cell lines expressed and secreted AM as indicated by ELISA. The growth of each of the cell lines was stimulated by exogenous AM and inhibited by the antagonist AMA. AM also stimulated in vitro angiogenesis assessed by polygon formation of endothelial cell lines. SiRNA-mediated silencing of ADMR, but not CRLR, reduced basal growth of all cells examined and reduced polygon formation of endothelial cells in vitro. Orthotopic tumors developed with shADMR bearing cancer cells had dramatically reduced primary tumor volume (>90%) and lung and liver metastasis compared to shControl bearing cells. To validate ADMR as a potential therapeutic target, in vivo studies were conducted using neutral nanoliposomes to systemically deliver human siRNA to ADMR to silence human cancer cells and mouse siRNA to ADMR to silence mouse tumor stromal cells. Systemic silencing of both human and mouse ADMR had no obvious adverse effects but strongly reduced tumor development.ADMR mediates the stimulatory effects of AM on cancer cells and on endothelial and stellate cells within the tumor microenvironment. These data support the further development of ADMR as a useful target treatment of pancreatic cancer

Development of EULAR recommendations for the reporting of clinical trial extension studies in rheumatology

Objectives: Our initiative aimed to produce recommendations on post-randomised controlled trial (RCT) trial extension studies (TES) reporting using European League Against Rheumatism (EULAR) standard operating procedures in order to achieve more meaningful output and standardisation of reports. Methods: We formed a task force of 22 participants comprising RCT experts, clinical epidemiologists and patient representatives. A two-stage Delphi survey was conducted to discuss the domains of evaluation of a TES and definitions. A ‘0–10’ agreement scale assessed each domain and definition. The resulting set of recommendations was further refined and a final vote taken for task force acceptance. Results: Seven key domains and individual components were evaluated and led to agreed recommendations including definition of a TES (100% agreement), minimal data necessary (100% agreement), method of data analysis (agreement mean (SD) scores ranging between 7.9 (0.84) and 9.0 (2.16)) and reporting of results as well as ethical issues. Key recommendations included reporting of absolute numbers at each stage from the RCT to TES with reasons given for drop-out at each stage, and inclusion of a flowchart detailing change in numbers at each stage and focus (mean (SD) agreement 9.9 (0.36)). A final vote accepted the set of recommendations. Conclusions: This EULAR task force provides recommendations for implementation in future TES to ensure a standardised approach to reporting. Use of this document should provide the rheumatology community with a more accurate and meaningful output from future TES, enabling better understanding and more confident application in clinical practice towards improving patient outcomes

Clinically relevant mutations in the ABCG2 transporter uncovered by genetic analysis linked to erythrocyte membrane protein expression

The ABCG2 membrane protein is a key xeno- and endobiotic transporter, modulating the absorption and metabolism of pharmacological agents and causing multidrug resistance in cancer. ABCG2 is also involved in uric acid elimination and its impaired function is causative in gout. Analysis of ABCG2 expression in the erythrocyte membranes of healthy volunteers and gout patients showed an enrichment of lower expression levels in the patients. By genetic screening based on protein expression, we found a relatively frequent, novel ABCG2 mutation (ABCG2-M71V), which, according to cellular expression studies, causes reduced protein expression, although with preserved transporter capability. Molecular dynamics simulations indicated a stumbled dynamics of the mutant protein, while ABCG2-M71V expression in vitro could be corrected by therapeutically relevant small molecules. These results suggest that personalized medicine should consider this newly discovered ABCG2 mutation, and genetic analysis linked to protein expression provides a new tool to uncover clinically important mutations in membrane proteins. © 2018 The Author(s)

Pro-apoptotic Bid is required for the resolution of the effector phase of inflammatory arthritis

Rheumatoid arthritis is an autoimmune disease characterized by hyperplasia of the synovial lining and destruction of cartilage and bone. Recent studies have suggested that a lack of apoptosis contributes to the hyperplasia of the synovial lining and to the failure in eliminating autoreactive cells. Mice lacking Fas or Bim, two pro-apoptotic proteins that mediate the extrinsic and intrinsic death cascades, respectively, develop enhanced K/BxN serum transfer-induced arthritis. Since the pro-apoptotic protein Bid functions as an intermediate between the extrinsic and intrinsic apoptotic pathways, we examined the role that it plays in inflammatory arthritis. Mice deficient in Bid (Bid-/-) show a delay in the resolution of K/BxN serum transfer-induced arthritis. Bid-/- mice display increased inflammation, bone destruction, and pannus formation compared to wild-type mice. Furthermore, Bid-/- mice have elevated levels of CXC chemokine and IL-1β in serum, which are associated with more inflammatory cells throughout the arthritic joint. In addition, there are fewer apoptotic cells in the synovium of Bid-/- compared to Wt mice. These data suggest that extrinsic and intrinsic apoptotic pathways cooperate through Bid to limit development of inflammatory arthritis

Evidence for Regulated Interleukin-4 Expression in Chondrocyte-Scaffolds under In Vitro Inflammatory Conditions

OBJECTIVE: To elucidate the anti-inflammatory and anabolic effects of regulated expression of IL-4 in chondrocyte-scaffolds under in vitro inflammatory conditions. METHODS: Mature articular chondrocytes from dogs (n = 3) were conditioned through transient transfection using pcDNA3.1.cIL-4 (constitutive) or pCOX-2.cIL-4 (cytokine-responsive) plasmids. Conditioned cells were seeded in alginate microspheres and rat-tail collagen type I matrix (CaReS®) to generate two types of tissue-engineered 3-dimensional scaffolds. Inflammatory arthritis was simulated in the packed chondrocytes through exogenous addition of recombinant canine (rc) IL-1β (100 ng/ml) plus rcTNFα (50 ng/ml) in culture media for 96 hours. Harvested cells and culture media were analyzed by various assays to monitor the anti-inflammatory and regenerative (anabolic) properties of cIL-4. RESULTS: cIL-4 was expressed from COX-2 promoter exclusively on the addition of rcIL-1β and rcTNFα while its expression from CMV promoter was constitutive. The expressed cIL-4 downregulated the mRNA expression of IL-1β, TNFα, IL-6, iNOS and COX-2 in the cells and inhibited the production of NO and PGE(2) in culture media. At the same time, it up-regulated the expression of IGF-1, IL-1ra, COL2a1 and aggrecan in conditioned chondrocytes in both scaffolds along with a diminished release of total collagen and sGAG into the culture media. An increased amount of cIL-4 protein was detected both in chondrocyte cell lysate and in concentrated culture media. Neutralizing anti-cIL-4 antibody assay confirmed that the anti-inflammatory and regenerative effects seen are exclusively driven by cIL-4. There was a restricted expression of IL-4 under COX-2 promoter possibly due to negative feedback loop while it was over-expressed under CMV promoter (undesirable). Furthermore, the anti-inflammatory /anabolic outcomes from both scaffolds were reproducible and the therapeutic effects of cIL-4 were both scaffold- and promoter-independent. CONCLUSIONS: Regulated expression of therapeutic candidate gene(s) coupled with suitable scaffold(s) could potentially serve as a useful tissue-engineering tool to devise future treatment strategies for osteoarthritis