bluuebunny/crossref_metadata_2025_split huggingface dataset:
Upregulated miR-146a expression in peripheral blood mononuclear cells from rheumatoid arthritis patients
Authors: Pauley Kaleb M , Satoh Minoru , Chan Annie L , Bubb Michael R , Reeves Westley H , Chan Edward KL 
Published: May 2012

Abstract
Introduction
MicroRNAs are small noncoding RNA molecules that negatively regulate gene expression via degradation or translational repression of their targeted mRNAs. It is known that aberrant microRNA expression can play important roles in cancer, but the role of microRNAs in autoimmune diseases is only beginning to emerge. In this study, the expression of selected microRNAs is examined in rheumatoid arthritis.

Methods
Total RNA was isolated from peripheral blood mononuclear cells obtained from patients with rheumatoid arthritis, and healthy and disease control individuals, and the expression of miR-146a, miR-155, miR-132, miR-16, and microRNA let-7a was analyzed using quantitative real-time PCR.

Results
Rheumatoid arthritis peripheral blood mononuclear cells exhibited between 1.8-fold and 2.6-fold increases in miR-146a, miR-155, miR-132, and miR-16 expression, whereas let-7a expression was not significantly different compared with healthy control individuals. In addition, two targets of miR-146a, namely tumor necrosis factor receptor-associated factor 6 (TRAF6) and IL-1 receptor-associated kinase 1 (IRAK-1), were similarly expressed between rheumatoid arthritis patients and control individuals, despite increased expression of miR-146a in patients with rheumatoid arthritis. Repression of TRAF6 and/or IRAK-1 in THP-1 cells resulted in up to an 86% reduction in tumor necrosis factor-α production, implicating that normal miR-146a function is critical for the regulation of tumor necrosis factor-α production.

Conclusions
Recent studies have shown that synovial tissue and synovial fibroblasts from patients with rheumatoid arthritis exhibit increased expression of certain microRNAs. Our data thus demonstrate that microRNA expression in rheumatoid arthritis peripheral blood mononuclear cells mimics that of synovial tissue/fibroblasts. The increased microRNA expression in rheumatoid arthritis patients is potentially useful as a marker for disease diagnosis, progression, or treatment efficacy, but this will require confirmation using a large and well defined cohort. Our data also suggest a possible mechanism contributing to rheumatoid arthritis pathogenesis, whereby miR-146a expression is increased but unable to properly function, leading to prolonged tumor necrosis factor-α production in patients with rheumatoid arthritis.
Elevated expression of caspase-3 inhibitors, survivin and xIAP correlates with low levels of apoptosis in active rheumatoid synovium
Authors: Dharmapatni Anak ASSK , Smith Malcolm D , Findlay David M , Holding Christopher A , Evdokiou Andreas , Ahern Michael J , Weedon Helen , Chen Paul , Screaton Gavin , Xu Xiao N , Haynes David R 
Published: May 2012

Abstract
Introduction
Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is a tumour necrosis factor (TNF) family member capable of inducing apoptosis in many cell types.

Methods
Using immunohistochemistry, terminal deoxynucleotidyl transferase biotin-dUTP nick end labelling (TUNEL) and real-time PCR we investigated the expression of TRAIL, TRAIL receptors and several key molecules of the intracellular apoptotic pathway in human synovial tissues from various types of arthritis and normal controls. Synovial tissues from patients with active rheumatoid arthritis (RA), inactive RA, osteoarthritis (OA) or spondyloarthritis (SpA) and normal individuals were studied.

Results
Significantly higher levels of TRAIL, TRAIL R1, TRAIL R2 and TRAIL R4 were observed in synovial tissues from patients with active RA compared with normal controls (p < 0.05). TRAIL, TRAIL R1 and TRAIL R4 were expressed by many of the cells expressing CD68 (macrophages). Lower levels of TUNEL but higher levels of cleaved caspase-3 staining were detected in tissue from active RA compared with inactive RA patients (p < 0.05). Higher levels of survivin and x-linked inhibitor of apoptosis protein (xIAP) were expressed in active RA synovial tissues compared with inactive RA observed at both the protein and mRNA levels.

Conclusions
This study indicates that the induction of apoptosis in active RA synovial tissues is inhibited despite stimulation of the intracellular pathway(s) that lead to apoptosis. This inhibition of apoptosis was observed downstream of caspase-3 and may involve the caspase-3 inhibitors, survivin and xIAP.
Physiological tonicity improves human chondrogenic marker expression through nuclear factor of activated T-cells 5 in vitro
Authors: van der Windt Anna E , Haak Esther , Das Ruud HJ , Kops Nicole , Welting Tim JM , Caron Marjolein MJ , van Til Niek P , Verhaar Jan AN , Weinans Harrie , Jahr Holger 
Published: May 2012

Abstract
Introduction
Chondrocytes experience a hypertonic environment compared with plasma (280 mOsm) due to the high fixed negative charge density of cartilage. Standard isolation of chondrocytes removes their hypertonic matrix, exposing them to nonphysiological conditions. During in vitro expansion, chondrocytes quickly lose their specialized phenotype, making them inappropriate for cell-based regenerative strategies. We aimed to elucidate the effects of tonicity during isolation and in vitro expansion on chondrocyte phenotype.

Methods
Human articular chondrocytes were isolated and subsequently expanded at control tonicity (280 mOsm) or at moderately elevated, physiological tonicity (380 mOsm). The effects of physiological tonicity on chondrocyte proliferation and chondrogenic marker expression were evaluated. The role of Tonicity-responsive Enhancer Binding Protein in response to physiological tonicity was investigated using nuclear factor of activated T-cells 5 (NFAT5) RNA interference.

Results
Moderately elevated, physiological tonicity (380 mOsm) did not affect chondrocyte proliferation, while higher tonicities inhibited proliferation and diminished cell viability. Physiological tonicity improved expression of chondrogenic markers and NFAT5 and its target genes, while suppressing dedifferentiation marker collagen type I and improving type II/type I expression ratios >100-fold. Effects of physiological tonicity were similar in osteoarthritic and normal (nonosteoarthritic) chondrocytes, indicating a disease-independent mechanism. NFAT5 RNA interference abolished tonicity-mediated effects and revealed that NFAT5 positively regulates collagen type II expression, while suppressing type I.

Conclusions
Physiological tonicity provides a simple, yet effective, means to improve phenotypical characteristics during cytokine-free isolation and in vitro expansion of human articular chondrocytes. Our findings will lead to the development of improved cell-based repair strategies for chondral lesions and provides important insights into mechanisms underlying osteoarthritic progression.
Resistin in idiopathic inflammatory myopathies
Authors: Filková Mária , Hulejová Hana , Kuncová Klára , Pleštilová Lenka , Cerezo Lucie Andrés , Mann Heřman , Klein Martin , Zámečník Josef , Gay Steffen , Vencovský Jiří , Šenolt Ladislav 
Published: May 2012

Abstract
Introduction
The purpose of this study was to evaluate and compare the serum levels and local expression of resistin in patients with idiopathic inflammatory myopathies to controls, and to determine the relationship between resistin levels, inflammation and disease activity.

Methods
Serum resistin levels were determined in 42 patients with inflammatory myopathies and 27 healthy controls. The association among resistin levels, inflammation, global disease activity and muscle strength was examined. The expression of resistin in muscle tissues from patients with inflammatory myopathies and healthy controls was evaluated. Gene expression and protein release from resistin-stimulated muscle and mononuclear cells were assessed.

Results
In patients with inflammatory myopathies, the serum levels of resistin were significantly higher than those observed in controls (8.53 ± 6.84 vs. 4.54 ± 1.08 ng/ml, P < 0.0001) and correlated with C-reactive protein (CRP) levels (r = 0.328, P = 0.044) and myositis disease activity assessment visual analogue scales (MYOACT) (r = 0.382, P = 0.026). Stronger association was observed between the levels of serum resistin and CRP levels (r = 0.717, P = 0.037) as well as MYOACT (r = 0.798, P = 0.007), and there was a trend towards correlation between serum resistin and myoglobin levels (r = 0.650, P = 0.067) in anti-Jo-1 positive patients. Furthermore, in patients with dermatomyositis, serum resistin levels significantly correlated with MYOACT (r = 0.667, P = 0.001), creatine kinase (r = 0.739, P = 0.001) and myoglobin levels (r = 0.791, P = 0.0003) and showed a trend towards correlation with CRP levels (r = 0.447, P = 0.067). Resistin expression in muscle tissue was significantly higher in patients with inflammatory myopathies compared to controls, and resistin induced the expression of interleukins (IL)-1β and IL-6 and monocyte chemoattractant protein (MCP)-1 in mononuclear cells but not in myocytes.

Conclusions
The results of this study indicate that higher levels of serum resistin are associated with inflammation, higher global disease activity index and muscle injury in patients with myositis-specific anti-Jo-1 antibody and patients with dermatomyositis. Furthermore, up-regulation of resistin in muscle tissue and resistin-induced synthesis of pro-inflammatory cytokines in mononuclear cells suggest a potential role for resistin in the pathogenesis of inflammatory myopathies.
Surface-enhanced laser desorption/ionization time-of-flight proteomic profiling of breast carcinomas identifies clinicopathologically relevant groups of patients similar to previously defined clusters from cDNA expression
Authors: Brozkova Kristyna , Budinska Eva , Bouchal Pavel , Hernychova Lenka , Knoflickova Dana , Valik Dalibor , Vyzula Rostislav , Vojtesek Borivoj , Nenutil Rudolf 
Published: May 2012

Abstract
Introduction
Microarray-based gene expression profiling represents a major breakthrough for understanding the molecular complexity of breast cancer. cDNA expression profiles cannot detect changes in activities that arise from post-translational modifications, however, and therefore do not provide a complete picture of all biologically important changes that occur in tumors. Additional opportunities to identify and/or validate molecular signatures of breast carcinomas are provided by proteomic approaches. Surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) offers high-throughput protein profiling, leading to extraction of protein array data, calling for effective and appropriate use of bioinformatics and statistical tools.

Methods
Whole tissue lysates of 105 breast carcinomas were analyzed on IMAC 30 ProteinChip Arrays (Bio-Rad, Hercules, CA, USA) using the ProteinChip Reader Model PBS IIc (Bio-Rad) and Ciphergen ProteinChip software (Bio-Rad, Hercules, CA, USA). Cluster analysis of protein spectra was performed to identify protein patterns potentially related to established clinicopathological variables and/or tumor markers.

Results
Unsupervised hierarchical clustering of 130 peaks detected in spectra from breast cancer tissue lysates provided six clusters of peaks and five groups of patients differing significantly in tumor type, nuclear grade, presence of hormonal receptors, mucin 1 and cytokeratin 5/6 or cytokeratin 14. These tumor groups resembled closely luminal types A and B, basal and HER2-like carcinomas.

Conclusion
Our results show similar clustering of tumors to those provided by cDNA expression profiles of breast carcinomas. This fact testifies the validity of the SELDI-TOF MS proteomic approach in such a type of study. As SELDI-TOF MS provides different information from cDNA expression profiles, the results suggest the technique's potential to supplement and expand our knowledge of breast cancer, to identify novel biomarkers and to produce clinically useful classifications of breast carcinomas.
Familial relative risks for breast cancer by pathological subtype: a population-based cohort study
Authors: Mavaddat Nasim , Pharoah Paul D , Blows Fiona , Driver Kristy E , Provenzano Elena , Thompson Deborah , MacInnis Robert J , Shah Mitul ,   The SEARCH Team, Easton Douglas F , Antoniou Antonis C 
Published: May 2012

Abstract
Introduction
The risk of breast cancer to first degree relatives of breast cancer patients is approximately twice that of the general population. Breast cancer, however, is a heterogeneous disease and it is plausible that the familial relative risk (FRR) for breast cancer may differ by the pathological subtype of the tumour. The contribution of genetic variants associated with breast cancer susceptibility to the subtype-specific FRR is still unclear.

Methods
We computed breast cancer FRR for subtypes of breast cancer by comparing breast cancer incidence in relatives of breast cancer cases from a population-based series with known estrogen receptor (ER), progesterone receptor (PR) or human epidermal growth factor receptor 2 (HER2) status with that expected from the general population. We estimated the contribution to the FRR of genetic variants associated with breast cancer susceptibility using subtype-specific genotypic relative risks and allele frequencies for each variant.

Results
At least one marker was measured for 4,590 breast cancer cases, who reported 9,014 affected and unaffected first-degree female relatives. There was no difference between the breast cancer FRR for relatives of patients with ER-negative (FRR = 1.78, 95% confidence intervals (CI): 1.44 to 2.11) and ER-positive disease (1.82, 95% CI: 1.67 to 1.98), P = 0.99. There was some suggestion that the breast cancer FRR for relatives of patients with ER-negative disease was higher than that for ER-positive disease for ages of the relative less than 50 years old (FRR = 2.96, 95% CI: 2.04 to 3.87; and 2.05, 95% CI: 1.70 to 2.40 respectively; P = 0.07), and that the breast cancer FRR for relatives of patients with ER-positive disease was higher than for ER-negative disease when the age of the relative was greater than 50 years (FRR = 1.76, 95% CI: 1.59 to 1.93; and 1.41, 95% CI: 1.08 to 1.74 respectively, P = 0.06). We estimated that mutations in BRCA1 and BRCA2 explain 32% of breast cancer FRR for relatives of patients with ER-negative and 9.4% of the breast cancer FRR for relatives of patients with ER-positive disease. Twelve recently identified common breast cancer susceptibility variants were estimated to explain 1.9% and 9.6% of the FRR to relatives of patients with ER-negative and ER-positive disease respectively.

Conclusions
FRR for breast cancer was significantly increased for both ER-negative and ER-positive disease. Including receptor status in conjunction with genetic status may aid risk prediction in women with a family history.
Promotion of variant human mammary epithelial cell outgrowth by ionizing radiation: an agent-based model supported by in vitro studies
Authors: Mukhopadhyay Rituparna , Costes Sylvain V , Bazarov Alexey V , Hines William C , Barcellos-Hoff Mary Helen , Yaswen Paul 
Published: May 2012

Abstract
Introduction
Most human mammary epithelial cells (HMEC) cultured from histologically normal breast tissues enter a senescent state termed stasis after 5 to 20 population doublings. These senescent cells display increased size, contain senescence associated β-galactosidase activity, and express cyclin-dependent kinase inhibitor, p16INK4A (CDKN2A; p16). However, HMEC grown in a serum-free medium, spontaneously yield, at low frequency, variant (v) HMEC that are capable of long-term growth and are susceptible to genomic instability. We investigated whether ionizing radiation, which increases breast cancer risk in women, affects the rate of vHMEC outgrowth.

Methods
Pre-stasis HMEC cultures were exposed to 5 to 200 cGy of sparsely (X- or γ-rays) or densely (1 GeV/amu 56Fe) ionizing radiation. Proliferation (bromodeoxyuridine incorporation), senescence (senescence-associated β-galactosidase activity), and p16 expression were assayed in subcultured irradiated or unirradiated populations four to six weeks following radiation exposure, when patches of vHMEC became apparent. Long-term growth potential and p16 promoter methylation in subsequent passages were also monitored. Agent-based modeling, incorporating a simple set of rules and underlying assumptions, was used to simulate vHMEC outgrowth and evaluate mechanistic hypotheses.

Results
Cultures derived from irradiated cells contained significantly more vHMEC, lacking senescence associated β-galactosidase or p16 expression, than cultures derived from unirradiated cells. As expected, post-stasis vHMEC cultures derived from both unirradiated and irradiated cells exhibited more extensive methylation of the p16 gene than pre-stasis HMEC cultures. However, the extent of methylation of individual CpG sites in vHMEC samples did not correlate with passage number or treatment. Exposure to sparsely or densely ionizing radiation elicited similar increases in the numbers of vHMEC compared to unirradiated controls. Agent-based modeling indicated that radiation-induced premature senescence of normal HMEC most likely accelerated vHMEC outgrowth through alleviation of spatial constraints. Subsequent experiments using defined co-cultures of vHMEC and senescent cells supported this mechanism.

Conclusions
Our studies indicate that ionizing radiation can promote the outgrowth of epigenetically altered cells with pre-malignant potential.
Potential for the embryonic morphogen Nodal as a prognostic and predictive biomarker in breast cancer
Authors: Strizzi Luigi , Hardy Katharine M , Margaryan Naira V , Hillman David W , Seftor Elisabeth A , Chen Beiyun , Geiger Xochiquetzal J , Thompson E Aubrey , Lingle Wilma L , Andorfer Cathy A , Perez Edith A , Hendrix Mary JC 
Published: May 2012

Abstract
Introduction
The re-emergence of the tumour growth factor-beta (TGF-beta)-related embryonic morphogen Nodal has recently been reported in several different human cancers. In this study, we examined the expression of Nodal in a series of benign and malignant human breast tissues to determine the clinical significance of this expression and whether Nodal could represent a potential therapeutic target in breast cancer.

Methods
Tissue sections from 431 therapeutically naive patients diagnosed with benign or malignant breast disease were stained for Nodal by immunohistochemistry and analysed in a blinded manner. The degree of Nodal staining was subsequently correlated with available clinical data, such as diagnoses and disease stage. These tissue findings were further explored in breast cancer cell lines MDA-MB-231 and MDA-MB-468 treated with a Nodal blocking antibody to determine biological effects for target validation.

Results
A variable degree of Nodal staining was detected in all samples. The intensity of Nodal staining was significantly greater in undifferentiated, advanced stage, invasive breast cancer compared with benign breast disease or early stage breast cancer. Treatment of human breast cancer cells in vitro with Nodal blocking antibody significantly reduced proliferation and colony-forming ability in soft agar, concomitant with increased apoptosis.

Conclusions
These data suggest a potential role for Nodal as a biomarker for disease progression and a promising target for anti-Nodal therapy in breast cancer.
miRNA-125b regulates TNF-α production in CD14+ neonatal monocytes via post-transcriptional regulation
Authors: Huang Hsin-Chun , Yu Hong-Ren , Huang Li-Tung , Huang Hui-Chen , Chen Ron-Fu , Lin I-Chun , Ou Chia-Yo , Hsu Te-Yao , Yang Kuender D 
Published: May 2012

Abstract
Neonatal monocytes express lower miR-125b, a negative regulator of TNF-α expression, resulting in higher TNF-α responses after LPS stimulation.
Neonates, although deficient in cell immunity, frequently reveal sepsis with augmented proinflammatory reactions. Here, we found that neonatal monocytes produced significantly higher TNF-α mRNA and protein than adult monocytes. Assessment of the transcriptional factor found no significant difference of NF-κB p65 level between neonatal and adult monocytes. Addition of Act D to access the half-life of TNF-α mRNA revealed no significant difference of the LPS-induced TNF-α mRNA half-life between them, whereas CHX increased neonatal TNF-α mRNA significantly. This suggests that a post-transcriptional mechanism involves the augmentation of TNF-α production by neonatal monocytes. To examine whether miRNA was involved in the post-transcriptional regulation, differential displays of miRNA array between neonatal and adult MNCs were performed, along with the discovery of hsa-miR-103, hsa-miR-125b, hsa-miR-130a, hsa-miR-454-3p, and hsa-miR-542-3p, which were greater than a twofold decrease or increase after LPS treatment for 4 h. The functional validation identified that miR-125b decreased significantly in association with higher TNF-α expression by neonatal monocytes after LPS stimulation. Transfection of the miR-125b precursor into neonatal monocytes significantly repressed the TNF-α mRNA and protein expression, suggesting that miR-125b negatively regulates TNF-α expression in neonatal monocytes. Modulation of miRNA expression may be used to regulate TNF-α production in newborns with altered proinflammatory reactions.
White matter abnormalities and illness severity in major depressive disorder
Authors: Cole James , Chaddock Christopher A. , Farmer Anne E. , Aitchison Katherine J. , Simmons Andrew , McGuffin Peter , Fu Cynthia H. Y. 
Published: May 2012

BackgroundWhite matter abnormalities have been implicated in the aetiology of major depressive disorder; however, the relationship between the severity of symptoms and white matter integrity is currently unclear.AimsTo investigate white matter integrity in people with major depression and healthy controls, and to assess its relationship with depressive symptom severity.MethodDiffusion tensor imaging data were acquired from 66 patients with recurrent major depression and a control group of 66 healthy individuals matched for age, gender and IQ score, and analysed with tract-based spatial statistics. The relationship between white matter integrity and severity of depression as measured by the Beck Depression Inventory was examined.ResultsDepressive illness was associated with widespread regions of decreased white matter integrity, including regions in the corpus callosum, superior longitudinal fasciculus and anterior corona radiata, compared with the control group. Increasing symptom severity was negatively correlated with white matter integrity, predominantly in the corpus callosum.ConclusionsWidespread alterations in white matter integrity are evident in major depressive disorder. These abnormalities are heightened with increasing severity of depressive symptoms.