bluuebunny/crossref_metadata_2025_split huggingface dataset:
TIMP-1 resistant matrix metalloproteinase-9 is the predominant serum active isoform associated with MRI activity in patients with multiple sclerosis
Authors: Trentini Alessandro , Manfrinato Maria C , Castellazzi Massimiliano , Tamborino Carmine , Roversi Gloria , Volta Carlo A , Baldi Eleonora , Tola Maria R , Granieri Enrico , Dallocchio Franco , Bellini Tiziana , Fainardi Enrico ,   the Emilia-Romagna network for Multiple Sclerosis (ERMES) study group, Granieri E , Castellazzi M , Casetta I , Tola MR , Fainardi E , Dallocchio F , Bellini T , Rizzo R , Rotola A , Di Luca D , Seraceni S , Contini C , Sabbioni S , Negrini M , Tognon M , Antonelli T , Groppo E , Gentile M , Baldi E , Caniatti ML , Ceruti S , Manfrinato MR , Trentini A , Bortolotti D , Miotto E , Ferracin M , Mazzoni E , Pietrobon S , Masini I , Rotondo JC , Martini F , Baruzzi A , D’Alessandro R , Michelucci R , Salvi F , Stecchi S , Scandellari C , Terzano G , Granella F , Nichelli P , Sola P , Ferraro D , Vitetta F , Simone AM , Bedin R , Marcello N , Motti L , Montepietra S , Guidetti D , Immovilli P , Montanari E , Pesci I , Guareschi A , Greco G , Santangelo M , Mauro AM , Malagù S , Rasi F , Spadoni M , Galeotti M , Fiorani L , Neri W , Ravasio A , Pasquinelli M , Gutman S , Monaldini C 
Published: February 2015

Background: The activity of matrix metalloproteinase-9 (MMP-9) depends on two isoforms, an 82 kDa active MMP-9 modulated by its specific tissue inhibitor (TIMP-1), and a 65 kDa TIMP-1 resistant active MMP-9. The relevance of these two enzymatic isoforms in multiple sclerosis (MS) is still unknown. Objective: To investigate the contribution of the TIMP-1 modulated and resistant active MMP-9 isoforms to MS pathogenesis. Methods: We measured the serum levels of the 82 kDa and TIMP-1 resistant active MMP-9 isoforms by activity assay systems in 86 relapsing–remitting MS (RRMS) patients, categorized according to clinical and magnetic resonance imaging (MRI) evidence of disease activity, and in 70 inflammatory (OIND) and 69 non-inflammatory (NIND) controls. Results: Serum levels of TIMP-1 resistant MMP-9 were more elevated in MS patients than in OIND and NIND ( p < 0.05, p < 0.02, respectively). Conversely, 82 kDa active MMP-9 was higher in NIND than in the OIND and MS patients ( p < 0.01 and p < 0.00001, respectively). MRI-active patients had higher levels of TIMP-1 resistant MMP-9 and 82 kDa active MMP-9, than did those with MRI inactive MS ( p < 0.01 and p < 0.05, respectively). Conclusion: Our findings suggested that the TIMP-1 resistant MMP-9 seem to be the predominantly active isoform contributing to MS disease activity.
Anti-MOG antibodies plead against MS diagnosis in an Acquired Demyelinating Syndromes cohort
Authors: Ketelslegers Immy A , Van Pelt Daniëlle E , Bryde Susanne , Neuteboom Rinze F , Catsman-Berrevoets Coriene E , Hamann Dörte , Hintzen Rogier Q 
Published: February 2015

Background: Acquired demyelinating syndromes (ADS) in children are a group of distinct first immune-mediated demyelinating events of the central nervous system (CNS). Predictive biomarkers for future diagnosis are lacking. A putative target antigen is myelin oligodendrocyte glycoprotein (MOG). We analyzed the presence of MOG antibodies in a cohort of ADS patients in The Netherlands. Methods: Using a cell-based assay, we analyzed 117 children with ADS from a nationwide cohort, whom were divided into five groups: optic neuritis (ON; n = 20), transverse myelitis (TM; n = 7), other monofocal ADS ( n = 22), polyfocal ADS without encephalopathy ( n = 44) and polyfocal ADS with encephalopathy ( n = 24). Additionally, we tested children with other neurological diseases (OND; n = 13), healthy children ( n = 31) and adult polyfocal ADS plus encephalopathy (ADEM) patients ( n = 29). Results: We found that 21 of the 117 children with ADS tested anti-MOG seropositive (18%). The group of patients with ADEM had the highest prevalence of anti-MOG seropositivity (42% versus 18% in the non-encephalopathic polyfocal ADS patients). Although 47 ADS children had a final diagnosis of multiple sclerosis (MS), in only one of them were MOG antibodies detected (2%), with only borderline positivity. Only 1 out of the 29 adult ADEM patients tested anti-MOG seropositive. Conclusions: MOG antibodies are strongly skewed towards ADS children that present with an ADEM-like disease onset. The presence of such antibodies pleads against a future diagnosis of MS.
Regulation of Treg-associated CD39 in multiple sclerosis and effects of corticotherapy during relapse
Authors: Muls Nathalie GV , Dang Hong Anh , Sindic Christian JM , van Pesch Vincent 
Published: February 2015

Background: Accumulating data highlight proinflammatory processes leading to MS relapses. Whether anti-inflammatory mechanisms are concomitantly activated is unclear. The ectonucleotidase CD39 has been described as a novel T regulatory cell (Treg) marker. The purpose of this study was to explore whether regulatory mechanisms are activated during MS relapses and reinforced by intravenous methylprednisolone (ivMP). Methods: Blood samples were collected from stable and relapsing MS patients and healthy controls. We used FOXP3 methylation-specific qPCR and CD4+CD25highFOXP3+ analysis to quantify Tregs. Cytokine mRNA expression levels were measured in peripheral blood mononuclear cells (PBMCs) and in CD4+ T cells. CD39 expression was determined by flow cytometry in monocytes, NK, T and B cells. CD39 enzymatic activity was assessed by ATP luminometry. Results: The proportion of Tregs was similar in relapsing MS patients and healthy controls. CD39 mRNA level was higher in PBMCs of relapsing MS patients than in controls. The proportion of CD39-expressing Tregs was higher in MS patients. IvMP decreased the overall proportion of Tregs while it increased CD39 mRNA levels, the proportions of CD39-expressing Tregs and monocytes as well as CD39 ectonucleotidase activity. Conclusions: Our data suggest that immunoregulatory mechanisms are ongoing in MS patients, particularly during relapses, and strengthened by ivMP.
Unilateral and bilateral upper limb dysfunction at body functions, activity and participation levels in people with multiple sclerosis
Authors: Bertoni Rita , Lamers Ilse , Chen Christine C , Feys Peter , Cattaneo Davide 
Published: February 2015

Background: There has been limited research on upper limb dysfunction in people with multiple sclerosis (PwMS). Objective: The objective of this paper is to study unilateral and bilateral upper limb dysfunction at different International Classification of Functioning (ICF) levels according to overall disability in PwMS. Methods: A total of 105 PwMS (16 with EDSS<4 (mild); 17 with EDSS 4–5.5 (moderate); 37 with EDSS 6–6.5 (severe); 35 with EDSS>6.5 (severe non-ambulant)) were recruited from two rehabilitation centers and assessed in a cross-sectional study. Results: The whole sample showed a diminished sensory function (median (first/third interquartile)) score of 3 (2/3) on the Monofilament Test and a reduced strength 91 (76/100) points on the Motricity Index (Body-Function level). Sensory dysfunction did not increase with higher EDSS while strength decreased from 100 (86/100) in the mild subgroups to 91 (80/100) points in the severe subgroup. All showed diminished dexterity, scoring 0.28 peg/s (0.17/0.35) on the Nine-Hole Peg Test (NHPT) (activity level). Score was better for the mild (0.38 (0.35/0.46)) peg/s compared to the severe subgroup (0.28 (0.17/0.35)). Sixty-eight percent, 44% and 75% of PwMS showed bilateral disorders in sensation, strength and dexterity, respectively. The Community Integration Questionnaire (participation level) showed a 35% reduction in home activities, even among PwMS with EDSS<4. Conclusion: This study showed uni-/bilateral upper limb abnormalities at all ICF levels increasing with the overall disability.
The influence of cognitive dysfunction on benefit from learning and memory rehabilitation in MS: A sub-analysis of the MEMREHAB trial
Authors: Chiaravalloti Nancy D. , DeLuca John 
Published: February 2015

Background: This study examined the influence of processing speed (PS) on benefit from treatment with the modified Story Memory Technique© (mSMT), a behavioral intervention shown to improve new learning and memory in multiple sclerosis (MS). Methods: This double-blind, placebo-controlled, randomized clinical trial included 85 participants with clinically definite MS, 45 assigned to the treatment group and 40 to the placebo-control group. Participants completed baseline and follow-up neuropsychological assessment. The present study represents a post-hoc analysis to examine the role of PS on treatment efficacy. Findings: The treatment group showed a significantly improved CVLT learning slope relative to the placebo group post-treatment, after co-varying PS performance. SDMT performance was a significant predictor of benefit from mSMT treatment, beyond group assignment. Post-hoc analysis indicated a significant correlation between the SDMT and overall cognition, indicating that the SDMT may be serving as a proxy for overall cognitive impairment. Interpretation: Performance on measures of cognitive dysfunction aside from learning and memory impact the benefit of mSMT treatment. While the current study focused on PS as a critical factor, PS may be serving as a marker for generalized cognitive dysfunction. Implications for cognitive rehabilitation in MS are discussed.© Kessler Foundation Inc. All rights reserved.
Fingolimod effect on brain volume loss independently contributes to its effect on disability
Authors: Sormani MP , De Stefano N , Francis G , Sprenger T , Chin P , Radue EW , Kappos L 
Published: February 2015

Background: Brain volume loss occurs in patients with relapsing–remitting MS. Fingolimod reduced brain volume loss in three phase 3 studies. Objective: To evaluate whether the effect of fingolimod on disability progression was mediated by its effects on MRI lesions, relapses or brain volume loss, and the extent of this effect. Methods: Patients (992/1272; 78%) from the FTY720 Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis (FREEDOMS) study were analyzed. Month-24 percentage brain volume change, month-12 MRI-active lesions and relapse were assessed. The Prentice criteria were used to test surrogate marker validity. The proportion of treatment effect on disability progression explained by each marker was calculated. Results: Two-year disability progression was associated with active T2 lesions (OR = 1.24; p = 0.001) and more relapses during year 1 (OR = 2.90; p < 0.001) and lower percentage brain volume change over two years (OR = 0.78; p < 0.001). Treatment effect on active T2 lesions, relapses and percentage brain volume change explained 46%, 60% and 23% of the fingolimod effect on disability. Multivariate analysis showed the number of relapses during year 1 (OR = 2.62; p < 0.001) and yearly percentage brain volume change over two years (OR = 0.85; p = 0.009) were independent predictors of disability progression, together explaining 73% of fingolimod effect on disability. Conclusions: The treatment effect on relapses and, to a lesser extent, brain volume loss were both predictors of treatment effect on disability; combining these predictors better explained the effect on disability than either factor alone.
Comparison of Injury Severity Between Moped and Motorcycle Crashes: A Finnish Two-Year Prospective Hospital-Based Study
Authors: Airaksinen N. , Nurmi-Lüthje I. , Lüthje P. 
Published: February 2015

Background and Aims: The coverage of the official statistics is poor in motorcycle and moped accidents. The aim of this study was to analyze the severity of motorcycle and moped crashes, and to define the degree of under-reporting in official statistics. Material and Methods: All first attendances due to an acute motorcyclist or moped driver injury registered in the emergency department between June 2004 and May 2006 were analyzed. The severity of the injuries was classified using the Abbreviated Injury Scale score and the New Injury Severity Score. The hospital injury data were compared to the traffic accident statistics reported by the police and compiled and maintained by Statistics Finland. Results: A total of 49 motorcyclists and 61 moped drivers were involved in crashes, leading to a total of 94 and 109 injuries, respectively. There were slightly more vertebral and midfoot fractures among motorcyclists than among moped drivers (p = 0.038 and 0.016, respectively). No significant differences were found between the severity (maximum Abbreviated Injury Scale and median New Injury Severity Scores) of the motorcycle and moped crashes. There was no in-hospital mortality. The degree of agreement (overlap) between the hospital dataset and the official statistics was 32%. The rate of under-reporting was 68%. Conclusions: According to the maximum Abbreviated Injury Scale and New Injury Severity Scores, the injury severity was equal for motorcycle and moped crashes. The degree of agreement between the hospital dataset and the official statistics was 32%.
Amputation-Free Survival after Crural Percutaneous Transluminal Angioplasty for Critical Limb Ischemia
Authors: Strøm M. , Konge L. , Lönn L. , Schroeder T. V. , Rørdam P. 
Published: February 2015

Background and Aim: To evaluate the amputation-free survival after below the knee percutaneous transluminal angioplasty in a consecutive group of patients with critical ischemia of the lower extremity. Materials and Methods: A total of 70 consecutive patients with critical ischemia were treated with below the knee percutaneous transluminal angioplasty at the vascular center at Rigshospitalet with the purpose of limb salvage. All patients were deemed unfit for major surgery due to anatomical limitations or severe co-morbidity, and no prior attempts of revascularization were performed. Follow-up clinical examinations were performed within 6 weeks and after 1 year. All medical records were crosschecked with the national vascular registry ensuring a valid 1-year status in 97% of the patients. Results: A total of 15 major amputations were performed during follow-up, with 11 amputations performed within the first year. Complications after percutaneous transluminal angioplasty were rare. Cumulative mortality after 1 and 2 years was 22% and 34%, respectively. Amputation-free survival at 1 and 2 years of follow-up was 68% and 58%, respectively. There were no association between known risk factors such as diabetes, ischemic ulcers, cardiac disease, history of smoking, major amputation, or overall amputation. Conclusion: Below the knee percutaneous transluminal angioplasty in patients with end-stage peripheral arterial disease and critical limb ischemia is a safe procedure in relieving critical ischemia, reducing the short-term rate of a major amputation as opposed to best medical treatment alone.
T1ρ Dispersion in Articular Cartilage
Authors: Keenan Kathryn E. , Besier Thor F. , Pauly John M. , Smith R. Lane , Delp Scott L. , Beaupre Gary S. , Gold Garry E. 
Published: February 2015

Objective This study assessed T1ρ relaxation dispersion, measured by magnetic resonance imaging (MRI), as a tool to noninvasively evaluate cartilage material and biochemical properties. The specific objective was to answer two questions: (1) does cartilage initial elastic modulus ( E0) correlate with T1ρ dispersion effects and (2) does collagen or proteoglycan content correlate with T1ρ dispersion effects? Design Cadaveric patellae with and without visible cartilage damage on conventional MR were included. T2 and T1ρ relaxation times at 500 and 1000 Hz spin-lock field amplitudes were measured. We estimated T1ρ dispersion effects by measuring T1ρ relaxation time at 500 and 1000 Hz and T2 relaxation time and using a new tool, the ratio T1ρ/T2. Cartilage initial elastic modulus, E0, was measured from initial response of mechanical indentation creep tests. Collagen and proteoglycan contents were measured at the indentation test sites; proteoglycan content was measured by their covalently linked sulfated glycosaminoglycans (sGAG). Pearson correlation coefficients were determined, taking into account the clustering of multiple samples within a single patella specimen. Results Cartilage initial elastic modulus, E0, increased with decreasing values of T1ρ/T2 measurements at both 500 Hz ( P = 0.034) and 1000 Hz ( P = 0.022). 1/T1ρ relaxation time (500 Hz) increased with increasing sGAG content ( P = 0.041). Conclusions T1ρ/T2 ratio, a new tool, and cartilage initial elastic modulus are both measures of water–protein interactions, are dependent on the cartilage structure, and were correlated in this study.
A novel inflammatory pathway mediating rapid hepcidin-independent hypoferremia
Authors: Guida Claudia , Altamura Sandro , Klein Felix A. , Galy Bruno , Boutros Michael , Ulmer Artur J. , Hentze Matthias W. , Muckenthaler Martina U. 
Published: February 2015

Key PointsStimulation of Toll-like receptors 2 and 6 reduces ferroportin expression in mouse macrophages by hepcidin-independent mechanism(s). Reduced expression of ferroportin in macrophages that recycle iron from red cells is sufficient to rapidly induce hypoferremia in mice.
Controllable size-selective method to prepare graphene quantum dots from graphene oxide
Authors: Fan Tianju , Zeng Wenjin , Tang Wei , Yuan Chunqiu , Tong Songzhao , Cai Kaiyu , Liu Yidong , Huang Wei , Min Yong , Epstein Arthur J 
Published: February 2015

Abstract
We demonstrated one-step method to fabricate two different sizes of graphene quantum dots (GQDs) through chemical cutting from graphene oxide (GO), which had many advantages in terms of simple process, low cost, and large scale in manufacturing with higher production yield comparing to the reported methods. Several analytical methods were employed to characterize the composition and morphology of the resultants. Bright blue luminescent GQDs were obtained with a produced yield as high as 34.8%. Moreover, how the different sizes affect fluorescence wavelength mechanism was investigated in details.
Lobular breast cancer: molecular basis, mouse and cellular models
Authors: Christgen Matthias , Derksen Patrick WB 
Published: February 2015

AbstractInfiltrating lobular breast cancer (ILC) is the most common special breast cancer subtype. With mutational or epigenetic inactivation of the cell adhesion molecule E-cadherin (CDH1) being confined almost exclusively to ILC, this tumor entity stands out from all other types of breast cancers. The molecular basis of ILC is linked to loss of E-cadherin, as evidenced by human CDH1 germline mutations and conditional knockout mouse models. A better understanding of ILC beyond the level of descriptive studies depends on physiologically relevant and functional tools. This review provides a detailed overview on ILC models, including well-characterized cell lines, xenograft tumors and genetically engineered mouse models. We consider advantages and limitations of these models and evaluate their representativeness for human ILC. The still incompletely defined mechanisms by which loss of E-cadherin drives malignant transformation are discussed based on recent findings in these models. Moreover, candidate genes and signaling pathways potentially involved in ILC development and progression as well as anticancer drug and endocrine resistance are highlighted.
CD4+ T cell STAT3 phosphorylation precedes acute GVHD, and subsequent Th17 tissue invasion correlates with GVHD severity and therapeutic response
Authors: Betts Brian C , Sagatys Elizabeth M , Veerapathran Anandharaman , Lloyd Mark C , Beato Francisca , Lawrence Harshani R , Yue Binglin , Kim Jongphil , Sebti Said M , Anasetti Claudio , Pidala Joseph 
Published: February 2015

Abstract
Th17 cells contribute to severe GVHD in murine bone marrow transplantation. Targeted deletion of the RORγt transcription factor or blockade of the JAK2-STAT3 axis suppresses IL-17 production and alloreactivity by Th17 cells. Here, we show that pSTAT3 Y705 is increased significantly in CD4+ T cells among human recipients of allogeneic HCT before the onset of Grade II–IV acute GVHD. Examination of target-organ tissues at the time of GVHD diagnosis indicates that the amount of RORγt + Th17 cells is significantly higher in severe GVHD. Greater accumulation of tissue-resident Th17 cells also correlates with the use of MTX- compared with Rapa-based GVHD prophylaxis, as well as a poor therapeutic response to glucocorticoids. RORγt is optimally suppressed by concurrent neutralization of TORC1 with Rapa and inhibition of STAT3 activation with S3I-201, supporting that mTOR- and STAT3-dependent pathways converge upon RORγt gene expression. Rapa-resistant T cell proliferation can be totally inhibited by STAT3 blockade during initial allosensitization. We conclude that STAT3 signaling and resultant Th17 tissue accumulation are closely associated with acute GVHD onset, severity, and treatment outcome. Future studies are needed to validate the association of STAT3 activity in acute GVHD. Novel GVHD prevention strategies that incorporate dual STAT3 and mTOR inhibition merit investigation.
Soma influences GSC progeny differentiation via the cell adhesion-mediated steroid-let-7-Wingless signaling cascade that regulates chromatin dynamics
Authors: König Annekatrin , Shcherbata Halyna R. 
Published: February 2015

ABSTRACT
It is known that signaling from the germline stem cell niche is required to maintain germline stem cell identity in Drosophila. However, it is not clear whether the germline stem-cell daughters differentiate by default (because they are physically distant from the niche) or whether additional signaling is necessary to initiate the differentiation program. Previously, we showed that ecdysteroid signaling cell non-autonomously regulates early germline differentiation via its soma-specific co-activator and co-repressor, Taiman and Abrupt. Now, we demonstrate that this regulation is modulated by the miRNA let-7, which acts in a positive feedback loop to confer ecdysone signaling robustness via targeting its repressor, the transcription factor Abrupt. This feedback loop adjusts ecdysteroid signaling in response to some stressful alterations in the external and internal conditions, which include temperature stress and aging, but not nutritional deprivation. Upon let-7 deficit, escort cells fail to properly differentiate: their shape, division, and cell adhesive characteristics are perturbed. These cells have confused cellular identity and form columnar-like rather than squamous epithelium and fail to send protrusions in between differentiating germline cysts, affecting soma-germline communication. Particularly, levels of the homophilic cell adhesion protein Cadherin, which recruits Wg signaling transducer β-catenin, are increased in mutant escort cells and, correspondingly, in the adjacent germline cells. Readjustment of heterotypic (soma-germline) cell adhesion modulates Wg signaling intensity in the germline, which in turn regulates histone modifications that promote expression of the genes necessary to trigger early germline differentiation. Thus, our data first show the intrinsic role for Wg signaling in the germline and support a model where the soma influences the tempo of germline differentiation in response to external conditions.