bluuebunny/crossref_metadata_2025_split huggingface dataset:
The novel S59P mutation in the TNFRSF1A gene identified in an adult onset TNF receptor associated periodic syndrome (TRAPS) constitutively activates NF-κB pathway
Authors: Greco Eliana , Aita Ada , Galozzi Paola , Gava Alessandra , Sfriso Paolo , Negm Ola H , Tighe Patrick , Caso Francesco , Navaglia Filippo , Dazzo Emanuela , De Bortoli Marzia , Rampazzo Alessandra , Obici Laura , Donadei Simona , Merlini Giampaolo , Plebani Mario , Todd Ian , Basso Daniela , Punzi Leonardo 
Published: April 2015

Abstract
Introduction
Mutations in the TNFRSF1A gene, encoding tumor necrosis factor receptor 1 (TNF-R1), are associated with the autosomal dominant autoinflammatory disorder, called TNF receptor associated periodic syndrome (TRAPS). TRAPS is clinically characterized by recurrent episodes of long-lasting fever and systemic inflammation. A novel mutation (c.262 T > C; S59P) in the TNFRSF1A gene at residue 88 of the mature protein was recently identified in our laboratory in an adult TRAPS patient. The aim of this study was to functionally characterize this novel TNFRSF1A mutation evaluating its effects on the TNF-R1-associated signaling pathways, firstly NF-κB, under particular conditions and comparing the results with suitable control mutations.

Methods
HEK-293 cell line was transfected with pCMV6-AC construct expressing wild-type (WT) or c.262 T > C (S59P), c.362G > A (R92Q), c.236C > T (T50M) TNFRSF1A mutants. Peripheral blood mononuclear cells (PBMCs) were instead isolated from two TRAPS patients carrying S59P and R92Q mutations and from five healthy subjects. Both transfected HEK-293 and PBMCs were stimulated with tumor necrosis factor (TNF) or interleukin 1β (IL-1β) to evaluate the expression of TNF-R1, the activation of TNF-R1-associated downstream pathways and the pro-inflammatory cytokines by means of immunofluorescent assay, array-based technique, immunoblotting and immunometric assay, respectively.

Results
TNF induced cytoplasmic accumulation of TNF-R1 in all mutant cells. Furthermore, all mutants presented a particular set of active TNF-R1 downstream pathways. S59P constitutively activated IL-1β, MAPK and SRC/JAK/STAT3 pathways and inhibited apoptosis. Also, NF-κB pathway involvement was demonstrated in vitro by the enhancement of p-IκB-α and p65 nuclear subunit of NF-κB expression in all mutants in the presence of TNF or IL-1β stimulation. These in vitro results correlated with patients’ data from PBMCs. Concerning the pro-inflammatory cytokines secretion, mainly IL-1β induced a significant and persistent enhancement of IL-6 and IL-8 in PBMCs carrying the S59P mutation.

Conclusions
The novel S59P mutation leads to defective cellular trafficking and to constitutive activation of TNF-R1. This mutation also determines constitutive activation of the IL-1R pathway, inhibition of apoptosis and enhanced and persistent NF-κB activation and cytokine secretion in response to IL-1β stimulation.
Evaluation of the effect of tofacitinib on measured glomerular filtration rate in patients with active rheumatoid arthritis: results from a randomised controlled trial
Authors: Kremer Joel M , Kivitz Alan J , Simon-Campos Jesus A , Nasonov Evgeny L , Tony Hans-Peter , Lee Soo-Kon , Vlahos Bonnie , Hammond Constance , Bukowski Jack , Li Huihua , Schulman Seth L , Raber Susan , Zuckerman Andrea , Isaacs John D 
Published: April 2015

Abstract
Introduction
Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). During the clinical development programme, increases in mean serum creatinine (SCr) of approximately 0.07 mg/dL and 0.08 mg/dL were observed which plateaued early. This study assessed changes in measured glomerular filtration rate (mGFR) with tofacitinib relative to placebo in patients with active RA.

Methods
This was a randomised, placebo-controlled, Phase 1 study (NCT01484561). Patients were aged ≥18 years with active RA. Patients were randomised 2:1 to oral tofacitinib 10 mg twice daily (BID) in Period 1 then placebo BID in Period 2 (tofacitinib → placebo); or oral placebo BID in both Periods (placebo → placebo). Change in mGFR was evaluated by iohexol serum clearance at four time points (run-in, pre-dose in Period 1, Period 1 end, and Period 2 end). The primary endpoint was the change in mGFR from baseline to Period 1 end. Secondary endpoints included: change in mGFR at other time points; change in estimated GFR (eGFR; Cockcroft–Gault equation) and SCr; efficacy; and safety.

Results
148 patients were randomised to tofacitinib → placebo (N = 97) or placebo → placebo (N = 51). Baseline characteristics were similar between groups. A reduction of 8% (90% confidence interval [CI]: 2%, 14%) from baseline in adjusted geometric mean mGFR was observed during tofacitinib treatment in Period 1 vs placebo. During Period 2, mean mGFR returned towards baseline during placebo treatment, and there was no difference between the two treatment groups at the end of the study – ratio (tofacitinib → placebo/placebo → placebo) of adjusted geometric mean fold change of mGFR was 1.04 (90% CI: 0.97, 1.11). Post-hoc analyses, focussed on mGFR variability in placebo → placebo patients, were consistent with this conclusion. At study end, similar results were observed for eGFR and SCr. Clinical efficacy and safety were consistent with prior studies.

Conclusion
Increases in mean SCr and decreases in eGFR in tofacitinib-treated patients with RA may occur in parallel with decreases in mean mGFR; mGFR returned towards baseline after tofacitinib discontinuation, with no significant difference vs placebo, even after post-hoc analyses. Safety monitoring will continue in ongoing and future clinical studies and routine pharmacovigilance.

Trial registration
Clinicaltrials.gov NCT01484561. Registered 30 November 2011.
Comparing recruitment, retention, and safety reporting among geographic regions in multinational Alzheimer’s disease clinical trials
Authors: Grill Joshua D , Raman Rema , Ernstrom Karin , Aisen Paul , Dowsett Sherie A , Chen Yun-Fei , Liu-Seifert Hong , Hake Ann Marie , Miller David S , Doody Rachelle S , Henley David B , Cummings Jeffrey L 
Published: April 2015

Abstract
Introduction
Most Alzheimer’s disease (AD) clinical trials enroll participants multinationally. Yet, few data exist to guide investigators and sponsors regarding the types of patients enrolled in these studies and whether participant characteristics vary by region.

Methods
We used data derived from four multinational phase III trials in mild to moderate AD to examine whether regional differences exist with regard to participant demographics, safety reporting, and baseline scores on the Mini Mental State Examination (MMSE), the 11-item Alzheimer’s Disease Assessment Scale–Cognitive subscale (ADAS-cog11), the Clinical Dementia Rating scale Sum of Boxes (CDR-SB), the Alzheimer’s Disease Cooperative Study–Activities of Daily Living Inventory (ADCS-ADL), and the Neuropsychiatric Inventory (NPI). We assigned 31 participating nations to 7 geographic regions: North America, South America/Mexico, Western Europe/Israel, Eastern Europe/Russia, Australia/South Africa, Asia, and Japan.

Results
North America, Western Europe/Israel, and Australia/South Africa enrolled similar proportions of men, apolipoprotein E ε4 carriers, and participants with spouse study partners, whereas Asia, Eastern Europe/Russia, and South America/Mexico had lower proportions for these variables. North America and South America/Mexico enrolled older subjects, whereas Asia and South America/Mexico enrolled less-educated participants than the remaining regions. Approved AD therapy use differed among regions (range: 73% to 92%) and was highest in North America, Western Europe/Israel, and Japan. Dual therapy was most frequent in North America (48%). On the MMSE, North America, Western Europe/Israel, Japan, and Australia/South Africa had higher (better) scores, and Asia, South America/Mexico, and Eastern Europe/Russia had lower scores. Eastern Europe/Russia had more impaired ADAS-cog11 scores than all other regions. Eastern Europe/Russia and South America/Mexico had more impaired scores for the ADCS-ADL and the CDR-SB. Mean scores for the CDR-SB in Asia were milder than all regions except Japan. NPI scores were lower in Asia and Japan than in all other regions. Participants in North America and Western Europe/Israel reported more adverse events than those in Eastern Europe/Russia and Japan.

Conclusions
These findings suggest that trial populations differ across geographic regions on most baseline characteristics and that multinational enrollment is associated with sample heterogeneity. The data provide initial guidance with regard to the regional differences that contribute to this heterogeneity and are important to consider when planning global trials.
Prospective adherence to specific immunotherapy in Europe (PASTE) survey protocol
Authors: Makatsori Melina , Senna Gianenrico , Pitsios Constantinos , Lleonart Ramon , Klimek Ludger , Nunes Carlos , Rukhadze Maia , Rogala Barbara , Gawlik Radoslaw , Panzner Petr , Pfaar Oliver , Calderon Moises 
Published: April 2015

AbstractBackgroundAdherence to allergen immunotherapy is important for its effectiveness. There is currently limited data available on allergen immunotherapy adherence outside of clinical trials i.e. in real‐life clinical practice. As part of a European Academy of Allergy and Clinical Immunology Immunotherapy Interest group initiative, we endeavoured to design a survey in order to prospectively evaluate adherence to subcutaneous and sublingual immunotherapy across different European countries.Method/DesignThe inclusion criteria for this prospective, multi‐country survey were set as: adults, starting clinically indicated allergen immunotherapy for respiratory allergic disorders or Hymenoptera venom allergy. An online survey was designed in order to enrol participants and assess adherence to immunotherapy.Eight countries (Czech Republic, Georgia, Germany, Greece, Italy, Poland, Portugal, Spain) were selected to reflect different parts of Europe and differences in allergens and routes of immunotherapy administration. Each country has an allocated National co‐ordinator that has identified local Allergy departments willing to enrol participants in this survey.Each participant will be followed up for a total of three years. In order to assess adherence, a 4‐monthly follow‐up form detailing any missed doses and reasons will be completed online. In case of a participant discontinuing treatment, reasons for this will be recorded.DiscussionThe use of online survey software has enabled us to make this survey a reality and reach clinicians in different countries. Forty‐five centres have enrolled a total of over 1,350 participants. It is hoped that this prospective real life survey will enable us to gain a better understanding of reasons that affect adherence to subcutaneous and sublingual immunotherapy and assist in developing ways to improve this.
An innovative technique for contrast enhancement of computed tomography images using normalized gamma-corrected contrast-limited adaptive histogram equalization
Authors: Al-Ameen Zohair , Sulong Ghazali , Rehman Amjad , Al-Dhelaan Abdullah , Saba Tanzila , Al-Rodhaan Mznah 
Published: April 2015

Abstract
Image contrast is an essential visual feature that determines whether an image is of good quality. In computed tomography (CT), captured images tend to be low contrast, which is a prevalent artifact that reduces the image quality and hampers the process of extracting its useful information. A common tactic to process such artifact is by using histogram-based techniques. However, although these techniques may improve the contrast for different grayscale imaging applications, the results are mostly unacceptable for CT images due to the presentation of various faults, noise amplification, excess brightness, and imperfect contrast. Therefore, an ameliorated version of the contrast-limited adaptive histogram equalization (CLAHE) is introduced in this article to provide a good brightness with decent contrast for CT images. The novel modification to the aforesaid technique is done by adding an initial phase of a normalized gamma correction function that helps in adjusting the gamma of the processed image to avoid the common errors of the basic CLAHE of the excess brightness and imperfect contrast it produces. The newly developed technique is tested with synthetic and real-degraded low-contrast CT images, in which it highly contributed in producing better quality results. Moreover, a low intricacy technique for contrast enhancement is proposed, and its performance is also exhibited against various versions of histogram-based enhancement technique using three advanced image quality assessment metrics of Universal Image Quality Index (UIQI), Structural Similarity Index (SSIM), and Feature Similarity Index (FSIM). Finally, the proposed technique provided acceptable results with no visible artifacts and outperformed all the comparable techniques.
The contraction principle for mappings on a modular metric space with a graph
Authors: Alfuraidan Monther Rashed 
Published: April 2015

AbstractWe give a generalization of the Banach contraction principle on a modular metric space endowed with a graph. The notion of a modular metric on an arbitrary set and the corresponding modular spaces, generalizing classical modulars over linear spaces like Orlicz spaces, were recently introduced. This paper can be seen as the modular metric version of Jachymski’s fixed point result for mappings on a metric space with a graph.
Prolonged exposure to neutrophil extracellular traps can induce mitochondrial damage in macrophages and dendritic cells
Authors: Donis-Maturano Luis , Sánchez-Torres Luvia E , Cerbulo-Vázquez Arturo , Chacón-Salinas Rommel , García-Romo Gina S , Orozco-Uribe Mariana C , Yam-Puc Juan C , González-Jiménez Marco A , Paredes-Vivas Yuriria L , Calderón-Amador Juana , Estrada-Parra Sergio , Estrada-García Iris , Flores-Romo Leopoldo 
Published: April 2015

Abstract
Neutrophils are one the earliest, crucial innate defenses against innumerable pathogens. Their main microbicidal activities include phagocytosis and degranulation, with many pharmacologically active molecules contributing to inflammation. Recently, a novel antimicrobial mechanism was discovered; the Neutrophil Extracelullar Traps (NETs) formed by extrusion of DNA and associated molecules (histones, elastase, antimicrobial peptides, among others) which trap and kill microorganisms. Since NETs were recently described, research has focused on their induction and microbicidal properties, and recently on disease involvement. However, the functional consequences of NETs interacting with other immune cells, either resident or recruited during early inflammation, have not been assessed.
We therefore investigated the consequences of exposing two major APCs, macrophages (Mfs) and conventional Dendritic Cells (cDCs) to NETs. Our data revealed that at early times (30 min), both Antigen Presenting Cells (APCs) showed induction of important costimulatory molecules (CD80, CD86). Unexpectedly, however, at later times (6 and 24 hours) NETs apparently triggered a cell death process in these APCs by a caspase- and Apoptosis induced factor (AIF)-dependent pathway, suggesting mitochondrial damage. By rhodamine-123 labelling we found that in both APCs, relatively prolonged exposure to NETs or their components importantly decreased the mitochondrial membrane potential. Ultrastructural analysis confirmed mitochondrial alterations in both APCs.
Our results would suggest that early in inflammation, NETs can activate the two main APCs (Mfs and cDCs), but as the process continues, NETs can then initiate apoptosis of these cells through mitochondrial harm. Conceivable, this “late” induction of cell death in these two APCs might start limiting an ongoing inflammatory process to control it.
Using quality mapping to predict spatial variation in local properties and component performance in Mg alloy thin-walled high-pressure die castings: an ICME approach and case study
Authors: Forsmark Joy H , Zindel Jacob W , Godlewski Larry , Zheng Jiang , Allison John E , Li Mei 
Published: April 2015

AbstractThis paper explores the use of quality mapping for the prediction of the spatial variation in local properties in thin-walled high-pressure die castings (HPDC) of the magnesium alloy AM60. The work investigates the role of casting parameters on local ductility and yield strength and presents a model for predicting local ductility and yield strength in a cast component. A design of experiment (DOE) was created to examine the role of various casting parameters on local properties such as ductility and yield strength. Over 1,200 tensile samples were excised from cast parts and tested. Casting simulations were also conducted for each experimental condition. Local properties were predicted, and the local property (quality map) model was compared with a prototype production component. The results of this model were used as input to a performance simulation software code to simulate the component-level behavior under two different loading conditions. In this study, the authors bypassed the traditional Integrated Computational Materials Engineering (ICME; process-microstructure-properties) approach in favor of a semi-empirical quality mapping approach to provide estimates of manufacturing sensitive local properties for use in process and component design.
Who will benefit from antidepressants in the acute treatment of bipolar depression? A reanalysis of the STEP-BD study by Sachs et al. 2007, using Q-learning
Authors: Wu Fan , Laber Eric B , Lipkovich Ilya A , Severus Emanuel 
Published: April 2015

Abstract

Background
There is substantial uncertainty regarding the efficacy of antidepressants in the treatment of bipolar disorders.

Methods
Traditional randomized controlled trials and statistical methods are not designed to discover if, when, and to whom an intervention should be applied; thus, other methodological approaches are needed that allow for the practice of personalized, evidence-based medicine with patients with bipolar depression.

Results
Dynamic treatment regimes operationalize clinical decision-making as a sequence of decision rules, one per stage of clinical intervention, that map patient information to a recommended treatment. Using data from the acute depression randomized care (RAD) pathway of the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study, we estimate an optimal dynamic treatment regime via Q-learning.

Conclusions
The estimated optimal treatment regime presents some evidence that patients in the RAD pathway of STEP-BD who experienced a (hypo)manic episode before the depressive episode may do better to forgo adding an antidepressant to a mandatory mood stabilizer.
Postoperative abnormal response of C-reactive protein as an indicator for infectious complications after oral oncologic surgery with primary reconstruction
Authors: Akashi Masaya , Furudoi Shungo , Hashikawa Kazunobu , Sakakibara Akiko , Hasegawa Takumi , Shigeta Takashi , Minamikawa Tsutomu , Komori Takahide 
Published: April 2015

Background C-reactive protein (CRP) screening has been reported to be reliable for detection of infectious complications. Postoperative abnormal response of CRP can predict wound infection in colorectal surgery. This study aimed to determine the efficacy of CRP monitoring to detect infectious complications in oral oncologic surgery. Methods One hundred patients who underwent oral cancer resection with primary reconstruction were enrolled. Postoperative kinetics of CRP were classified into a normal or abnormal response. Results A normal CRP response after surgery was observed in 61 patients and an abnormal response was observed in 39. There were postoperative infectious complications in 21 patients, with surgical site infections in 13 patients (early onset in six and late onset in seven). Non-wound infections were found in nine patients. Sensitivity, specificity, the positive predictive value, and the negative predictive value for abnormal CRP response as a predictor for early infectious complications were 100%, 70.1%, 35.9%, and 100%, respectively. Conclusion Postoperative serial CRP screening is a useful test as an indicator of infectious complications in oral oncologic surgery. Normal CRP responses can rule out almost all early infectious complications.
Acoustic-gravity waves in the atmosphere generated by infragravity waves in the ocean
Authors: Godin Oleg A , Zabotin Nikolay A , Bullett Terence W 
Published: April 2015

Abstract
Infragravity waves are surface gravity waves in the ocean with periods longer than approximately 30 s. Infragravity waves propagate transoceanic distances and, because of their long wavelengths, provide a mechanism for coupling wave processes in the ocean, atmosphere, and the solid Earth. Here, we present a strict physical justification for the hypothesis that background ocean waves may generate waves in the upper atmosphere. We show that, at frequencies below a certain transition frequency of about 3 mHz, infragravity waves continuously radiate their energy into the upper atmosphere in the form of acoustic-gravity waves. Based on ionospheric observations and estimates of the fluxes of the mechanical energy and momentum from the deep ocean, we conclude that acoustic-gravity waves of oceanic origin may have an observable impact on the upper atmosphere. We anticipate our work to be a starting point for a detailed analysis of global manifestations of the ocean-generated background acoustic-gravity waves.
Assembly of cellulases with synthetic protein scaffolds in vitro
Authors: Yu Ting , Gao Xin , Ren Yuhong , Wei Dongzhi 
Published: April 2015

Abstract

Background
Enzymatic cascades in metabolic pathways are spatially organized in such a way as to facilitate the flow of substrates. The construction of artificial cellulase complexes that mimic natural multienzyme assemblies can potentially enhance the capacity for cellulose hydrolysis. In this study, an artificial cellulase complex was constructed by tethering three cellulases to a synthetic protein scaffold.

Results
Three pairs of interacting proteins were selected and characterized. The artificial protein scaffolds were constructed by fusing three interacting proteins. Cellulases were tethered to these synthetic scaffolds in different orders. The optimal assembly resulted in a 1.5-fold higher hydrolysis of cellulose than that achieved by unassembled cellulases.

Conclusions
A novel artificial protein scaffold was constructed and used to assemble three cellulases. The resultant increase in enzymatic activity suggests that this can be used as a strategy for enhancing the biocatalytic capacity of enzyme cascades.