Long-term safety study of infliximab in moderate-to-severe chronic obstructive pulmonary disease

SummaryRationaleThere was an increased number of malignancies in infliximab-treated (5.7%) over placebo-treated (1.3%) patients in a 44-week, phase 2 clinical study of 234 patients with moderate-to-severe chronic obstructive pulmonary disease (COPD).ObjectivesTo collect malignancy and mortality data from completed clinical studies of infliximab in COPD treatment.MethodsThe multicenter, observational Remicade Safety Under Long-Term Study in COPD (RESULTS COPD) collected malignancy and mortality data every six months for five years from patients who received ≥1 study-agent dose in a phase 2 study. Co-primary endpoints were the number of patients with malignancy and the number of deaths. Secondary endpoints included the number of patients with a malignancy according to malignancy type.ResultsThere was a gap period between the end of the phase 2 study and the initiation of RESULTS COPD, during which six malignancies and 14 deaths were reported spontaneously for the 107 (45.7%) of 234 patients with long-term safety information. Twenty-eight patients (overall 12.0%; placebo 10.4%, infliximab 12.7%) reported malignancies, including 12 patients during RESULTS COPD. Twenty-six patients (overall 11.1%; placebo 9.1%, infliximab 12.1%) died, including nine during RESULTS COPD. Lung cancer was the most common malignancy type (placebo n = 2; infliximab n = 10).ConclusionsThe greater proportion of malignancies observed with infliximab versus placebo in a phase 2 study diminished over the long-term follow-up. Due to the observational nature, limited patient participation, potential reporting bias from the interim spontaneous reporting period, and unblinding of all patients, more definitive conclusions cannot be drawn.Trial Registration Number: NCT00056264

A universal method for depositing patterned materials in-situ

Current techniques of patterned material deposition require separate steps for patterning and material deposition. The complexity and harsh working conditions post serious limitations for fabrication. Here, we introduce a novel single-step and easy-to-adapt method that can deposit materials in-situ. Its unique methodology is based on the semiconductor nanoparticle assisted photon-induced chemical reduction and optical trapping. This universal mechanism can be used for depositing a large selection of materials including metals, insulators and magnets, with quality on par with current technologies. Patterning with several materials together with optical-diffraction-limited resolution accuracy can be achieved from macroscopic to microscopic scale. Furthermore, the setup is naturally compatible with optical microscopy based measurements, thus sample characterisation and material deposition can be realised in-situ. Various devices fabricated with this method in 2D or 3D show it is ready for deployment in practical applications. This revolutionary method will provide a distinct tool in material technology

Effect of Intravenous Golimumab on Fatigue and the Relationship with Clinical Response in Adults with Active Ankylosing Spondylitis in the Phase 3 GO-ALIVE Study

INTRODUCTION: We studied the effect of intravenous (IV)-golimumab on fatigue and the association of fatigue improvement with clinical response post hoc in adults with active ankylosing spondylitis (AS) in the GO-ALIVE trial. METHODS: Patients were randomized to IV-golimumab 2 mg/kg (N = 105) at week (W) 0, W4, then every 8 W (Q8W) or placebo (N = 103) at W0, W4, W12, crossover to IV-golimumab 2 mg/kg at W16, W20, then Q8W through W52. Fatigue measures included Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) Question #1 (fatigue; 0 [none], 10 [worst]; decrease indicates improvement) and 36-Item Short Form Health Survey (SF-36) vitality subscale (0 [worst], 100 [best]; increase indicates improvement). Minimum clinically important difference is ≥ 1 for BASDAI-fatigue and ≥ 5 for SF-36 vitality. GO-ALIVE primary endpoint was Assessment of SpondyloArthritis international Society ≥ 20% improvement criteria (ASAS20). Other clinical outcomes assessed included other ASAS responses, Ankylosing Spondylitis Disease Activity Score, and Bath Ankylosing Spondylitis Functional Index score. The distribution-based minimally important differences (MIDs) were determined for BASDAI-fatigue and SF-36 vitality. The relationship between improvement in fatigue and clinical outcomes was assessed via multivariable logistic regression. RESULTS: Mean changes in BASDAI-fatigue/SF-36 vitality scores were greater with IV-golimumab versus placebo at W16 (- 2.74/8.46 versus - 0.73/2.08, both nominal p ≤ 0.003); by W52 (after crossover), differences between groups narrowed (- 3.18/9.39 versus - 3.07/9.17). BASDAI-fatigue/SF-36 vitality MIDs were achieved by greater proportions of IV-golimumab-treated versus placebo-treated patients at W16 (75.2%/71.4% versus 42.7%/35.0%). A one-point/five-point improvement in BASDAI-fatigue/SF-36 vitality scores at W16 increased likelihood of achieving ASAS20 (odds ratios [95% confidence intervals]: 3.15 [2.21, 4.50] and 2.10 [1.62, 2.71], respectively) and ASAS40 (3.04 [2.15, 4.28] and 2.24 [1.68, 3.00], respectively) responses at W16; concurrent improvements and clinical response at W52 were consistent. A one-point/five-point improvement in BASDAI-fatigue/SF-36 vitality scores at W16 predicted increased likelihood of achieving ASAS20 (1.62 [1.35, 1.95] and 1.52 [1.25, 1.86], respectively) and ASAS40 (1.62 [1.37, 1.92] and 1.44 [1.20, 1.73], respectively) responses at W52. CONCLUSIONS: IV-golimumab provided important and sustained fatigue improvement in patients with AS that positively associated with achieving clinical response. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02186873

Personal non-commercial use only

ABSTRACT. Objective. To evaluate the effects of intravenous (IV) golimumab 2 mg/kg + methotrexate (MTX) on patient-reported measures of health-related quality of life (HRQOL) in patients with active rheumatoid arthritis (RA) despite prior MTX therapy. Methods. In this randomized, multicenter, double-blind, placebo-controlled, phase III trial, adults with RA were randomly assigned to receive IV placebo (n = 197) or golimumab 2 mg/kg (n = 395) infusions at Week 0, Week 4, and every 8 weeks thereafter. Results. Mean HAQ-DI improvements from baseline were significantly greater with golimumab + MTX than placebo + MTX at Week 14 and Week 24 (p < 0.001). Significantly greater improvements in all 8 individual SF-36 subscores and both the SF-36 PCS and MCS scores (p < 0.001) also accompanied golimumab + MTX therapy. Improved EQ-5D and EQ-5D VAS (p < 0.001) and FACIT-Fatigue (p < 0.001) scores were also observed for golimumab + MTX-treated patients at Week 12, Week 16, and Week 24, and greater proportions of golimumab + MTX-treated patients had clinically meaningful improvements in these measures. Greater reductions in disease effect on productivity were observed with golimumab + MTX versus placebo + MTX at Week 24 (p < 0.001)

Mountain building in Taiwan: A thermokinematic model

The Taiwan mountain belt is classically viewed as a case example of a critical wedge growing essentially by frontal accretion and therefore submitted to distributed shortening. However, a number of observations call for a significant contribution of underplating to the growth of the orogenic wedge. We propose here a new thermokinematic model of the Taiwan mountain belt reconciling existing kinematic, thermometric and thermochronological constraints. In this model, shortening across the orogen is absorbed by slip on the most frontal faults of the foothills. Crustal thickening and exhumation are sustained by underplating beneath the easternmost portion of the wedge (Tananao Complex, TC), where the uplift rate is estimated to ~6.3 mm a^(−1), and beneath the westernmost internal region of the orogen (Hsueshan Range units, HR), where the uplift rate is estimated to ~4.2 mm a^(−1). Our model suggests that the TC units experienced a synchronous evolution along strike despite the southward propagation of the collision. It also indicates that they have reached a steady state in terms of cooling ages but not in terms of peak metamorphic temperatures. Exhumation of the HR units increases northward but has not yet reached an exhumational steady state. Presently, frontal accretion accounts for less than ~10% of the incoming flux of material into the orogen, although there is indication that it was contributing substantially more (~80%) before 4 Ma. The incoming flux of material accreted beneath the TC significantly increased 1.5 Ma ago. Our results also suggest that the flux of material accreted to the orogen corresponds to the top ~7 km of the upper crust of the underthrust Chinese margin. This indicates that a significant amount (~76%) of the underthrust material has been subducted into the mantle, probably because of the increase in density associated with metamorphism. We also show that the density distribution resulting from metamorphism within the orogenic wedge explains well the topography and the gravity field. By combining available geological data on the thermal and kinematic evolution of the wedge, our study sheds new light onto mountain building processes in Taiwan and allows for reappraising the initial structural architecture of the passive margin

On the direct insulator-quantum Hall transition in two-dimensional electron systems in the vicinity of nanoscaled scatterers.

A direct insulator-quantum Hall (I-QH) transition corresponds to a crossover/transition from the insulating regime to a high Landau level filling factor ν > 2 QH state. Such a transition has been attracting a great deal of both experimental and theoretical interests. In this study, we present three different two-dimensional electron systems (2DESs) which are in the vicinity of nanoscaled scatterers. All these three devices exhibit a direct I-QH transition, and the transport properties under different nanaoscaled scatterers are discussed.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

The histone H3K36 demethylase Rph1/KDM4 regulates the expression of the photoreactivation gene PHR1

The dynamics of histone methylation have emerged as an important issue since the identification of histone demethylases. We studied the regulatory function of Rph1/KDM4 (lysine demethylase), a histone H3K36 demethylase, on transcription in Saccharomyces cerevisiae. Overexpression of Rph1 reduced the expression of PHR1 and increased UV sensitivity. The catalytically deficient mutant (H235A) of Rph1 diminished the repressive transcriptional effect on PHR1 expression, which indicates that histone demethylase activity contributes to transcriptional repression. Chromatin immunoprecipitation analysis demonstrated that Rph1 was associated at the upstream repression sequence of PHR1 through zinc-finger domains and was dissociated after UV irradiation. Notably, overexpression of Rph1 and H3K36A mutant reduced histone acetylation at the URS, which implies a crosstalk between histone demethylation and acetylation at the PHR1 promoter. In addition, the crucial checkpoint protein Rad53 acted as an upstream regulator of Rph1 and dominated the phosphorylation of Rph1 that was required for efficient PHR1 expression and the dissociation of Rph1. The release of Rph1 from chromatin also required the phosphorylation at S652. Our study demonstrates that the histone demethylase Rph1 is associated with a specific chromatin locus and modulates histone modifications to repress a DNA damage responsive gene under control of damage checkpoint signaling

Marine Biocatalysts: Enzymatic Features and Applications

In several recent reports related to biocatalysis the enormous pool of biodiversity found in marine ecosystems is considered a profitable natural reservoir for acquiring an inventory of useful biocatalysts. These enzymes are characterized by well-known habitat-related features such as salt tolerance, hyperthermostability, barophilicity and cold adaptivity. In addition, their novel chemical and stereochemical characteristics increase the interest of biocatalysis practitioners both in academia and research industry. In this review, starting from the analysis of these featuring habitat-related properties, important examples of marine enzymes in biocatalysis will be reported. Completion of this report is devoted to the analysis of novel chemical and stereochemical biodiversity offered by marine biocatalysts with particular emphasis on current or potential applications of these enzymes in chemical and pharmaceutical fields. The analysis of literature cited here and the many published patent applications concerning the use of marine enzymes supports the view that these biocatalysts are just waiting to be discovered, reflecting the importance of the marine environment. The potential of this habitat should be thoroughly explored and possibly the way to access useful biocatalysts should avoid destructive large-scale collections of marine biomass for enzyme production. These two aspects are day by day increasing in interest and a future increase in the use of marine enzymes in biocatalysis should be expected

Significance of Metastatic Lymph Node Ratio on Stimulated Thyroglobulin Levels in Papillary Thyroid Carcinoma after Prophylactic Unilateral Central Neck Dissection

Background: Prognostic significance of metastatic central lymph node ratio (CLNR) in papillary thyroid carcinoma (PTC) remains unknown. Because postsurgical detectable stimulated thyroglobulin (DsTg) after radioiodine ablation may imply persistent or recurrent disease, we evaluated the association between CLNR and rate of DsTg in patients with PTC who underwent unilateral prophylactic central neck dissection. Methods: To be eligible for analysis, the prophylactic central neck dissection specimen had to contain ≥3 central lymph nodes (CLNs) with ≥1 harboring metastasis. Of 129 specimens, 51 (39.5%) were eligible. CLNR was calculated as follows: (number of metastatic CLNs/number of CLNs retrieved) × 100. They were categorized into group 1 (CLNR 66.67%) (n = 22). Postablation sTg level was measured 6 months after radioiodine ablation. A multivariate analysis was conducted to identify factors for postablation DsTg. Results: Young age, palpable neck swelling, large tumor size, advanced tumor, node, metastasis system (TNM) stage, and large number of metastatic CLNs were significantly associated with high CLNR (Ppublished_or_final_versionSpringer Open Choice, 21 Feb 201

Innovative solutions to sticky situations: Antiadhesive strategies for treating bacterial infections

ABSTRACT Bacterial adherence to host tissue is an essential process in pathogenesis, necessary for invasion and colonization and often required for the efficient delivery of toxins and other bacterial effectors. As existing treatment options for common bacterial infections dwindle, we find ourselves rapidly approaching a tipping point in our confrontation with antibiotic-resistant strains and in desperate need of new treatment options. Bacterial strains defective in adherence are typically avirulent and unable to cause infection in animal models. The importance of this initial binding event in the pathogenic cascade highlights its potential as a novel therapeutic target. This article seeks to highlight a variety of strategies being employed to treat and prevent infection by targeting the mechanisms of bacterial adhesion. Advancements in this area include the development of novel antivirulence therapies using small molecules, vaccines, and peptides to target a variety of bacterial infections. These therapies target bacterial adhesion through a number of mechanisms, including inhibition of pathogen receptor biogenesis, competition-based strategies with receptor and adhesin analogs, and the inhibition of binding through neutralizing antibodies. While this article is not an exhaustive description of every advancement in the field, we hope it will highlight several promising examples of the therapeutic potential of antiadhesive strategies.</jats:p