bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluation of B lymphocyte stimulator and a proliferation inducing ligand as candidate biomarkers in lupus nephritis based on clinical and histopathological outcome following induction therapy
Authors: Parodis Ioannis , Zickert Agneta , Sundelin Birgitta , Axelsson Magnus , Gerhardsson Jakob , Svenungsson Elisabet , Malmström Vivianne , Gunnarsson Iva 
Published: January 2015

ObjectivesLupus nephritis (LN) is a major cause of morbidity in patients with systemic lupus erythematosus (SLE). B cells have a central role in the pathogenesis of SLE. B lymphocyte stimulator (BLyS) and a proliferation inducing ligand (APRIL) are pivotal in B cell homeostasis. We aimed to investigate a potential role of serum BLyS and APRIL as biomarkers in LN, especially as predictors of treatment response.MethodsSixty-four patients with active LN (52 proliferative lupus nephritis (PLN); 12 membranous LN) were included. Renal biopsies were performed at baseline and after immunosuppressive treatment. Serum levels of BLyS, APRIL and autoantibodies were measured on both biopsy occasions and in 64 individually matched controls. Renal biopsies were evaluated using the International Society of Nephrology/Renal Pathology Society classification, and scored for Activity Index and Chronicity Index. Clinical responders (CR) were required to have ≥50% reduction in proteinuria, normal or improved renal function, and inactive urinary sediment. Histopathological responders (HR) were required to have ≥50% improvement in Activity Index.ResultsBaseline BLyS levels were significantly higher in LN patients compared with controls (p<0.001) and remained unchanged following induction treatment. APRIL levels were significantly higher in patients compared with controls at baseline (p=0.005) and decreased following treatment (p<0.001). Among PLN patients, APRIL levels decreased significantly only in responders (CR: p=0.009; HR: p=0.01). Baseline BLyS levels <1.5 ng/mL predicted treatment response, attaining a positive predictive value of 92% for CR with PLN at baseline.ConclusionsBLyS and APRIL were affected differently by immunosuppression; BLyS levels remained unchanged following therapy while APRIL levels decreased. Despite unchanged BLyS levels following therapy, low baseline levels predicted both clinical and histopathological improvement. Our data support APRIL as a candidate biomarker of renal disease activity in lupus patients with proliferative glomerulonephritis and point to low baseline BLyS levels predicting treatment response in LN, especially in PLN.
Efficacy of high-resolution cone-beam CT in the evaluation of carotid atheromatous plaque
Authors: Tanabe Jun , Tanaka Michihiro , Kadooka Keisuke , Hadeishi Hiromu 
Published: January 2015

IntroductionA major disadvantage of carotid artery stenting (CAS) is the high incidence of perioperative cerebral embolism. Cerebral embolism after CAS is associated with soft plaque. Currently, higher spatial resolution imaging can be obtained with cone-beam CT (CB-CT). The correlation between the degree of contrast enhancement of the vasa vasorum (VV) on CB-CT and the vulnerability of plaque in terms of risk factors for CAS was evaluated.Methods18 patients who underwent CAS had high-resolution CB-CT to evaluate enhancement of the VV covering carotid plaque performed intraoperatively. The appearance of the surface of the carotid plaque was classified as either enhancing (VV-positive) or non-enhancing (VV-negative). Carotid plaque vulnerability on black-blood MRI (BB-MRI) and postoperative ipsilateral ischemic lesions on diffusion-weighted imaging (DWI) were analyzed in the two groups.ResultsOf the 18 patients, 9 were VV-positive and 9 were VV-negative. The proportion of ipsilateral new ischemic lesions on DWI was significantly higher in the VV-positive group than in the VV-negative group (8/9 patients (88.9%) vs 3/9 patients (33.3%), p=0.026). BB-MRI was performed preoperatively in 15 of 18 patients. The proportion of unstable plaque on BB-MRI was significantly higher in the VV-positive group than in the VV-negative group (9/9 patients (100%) vs 1/6 patients (16.7%), p=0.002).ConclusionsEnhancement of the VV covering carotid plaque on high-resolution CB-CT was significantly associated with unstable plaque on BB-MRI and postoperative ipsilateral new ischemic lesions.
Patenting in the University and Public Research Centers Considering Their Knowledge Profiles
Authors: Corona Leonel 
Published: January 2015

One important agent in the process of converting scientific knowledge into technology are University Research Centers (RCs), which are engaged in scientific research (Sc), technology development (Tech), technical services (S), and teaching activities (t). The products of these activities are the publication of "papers", graduation of students, mainly Masters and Ph.Ds., services and patents which are part of technology development and technology transfer (TT) to industry. The mix of these functional activities and products defines the RC's profile. This paper focuses on how patents contribute to the Mexico National University (UNAM [note: UNAM is the Spanish acronym of the National Autonomous University of Mexico.]) RCs' profiles. The statistical analysis shows no direct effect of technology intensity on patenting. There is no sustained increase in UNAM patenting for the period 1975–2007, although two maximum peaks of patent granted appeared in 1993 and in 2005 which were triggered by a variety of internal and external events. One explanation of this pattern is the role played by the UNAM's Technology Transfer Offices (TTO) which have moved forward and backwards changing from being a centralized agency to a more flexible and diverse organization within RCs, showing a lack of a proactive university policy on patenting and TT. An overlapping policy of the disciplinary UNAM's RC structure with entrepreneurial attitudes could provide better dynamics for applied science and technology, and would have a positive impact on TT.
Breast Cancer Risk Associated with Estrogen Exposure and Truncating Mutation Location inBRCA1/2Carriers
Authors: Lecarpentier Julie , Noguès Catherine , Mouret-Fourme Emmanuelle , Buecher Bruno , Gauthier-Villars Marion , Stoppa-Lyonnet Dominique , Bonadona Valérie , Fricker Jean-Pierre , Berthet Pascaline , Caron Olivier , Coupier Isabelle , Pujol Pascal , Faivre Laurence , Gesta Paul , Eisinger François , Mari Véronique , Gladieff Laurence , Lortholary Alain , Luporsi Elisabeth , Leroux Dominique , Venat-Bouvet Laurence , Maugard Christine M. , Colas Chrystelle , Tinat Julie , Lasset Christine , Andrieu Nadine 
Published: January 2015

AbstractBackground: Mutations in BRCA1/2 confer a high risk of breast cancer, but literature values of this risk vary. A genotype–phenotype correlation has been found in both genes, and the effect of reproductive factors differs according to mutation location. Therefore, we hypothesize that such a variation may exist for other factors related to estrogen exposure.Methods: We used a weighted Cox regression model to assess variation in breast cancer risk with these factors using location of mutation in homogeneous breast cancer risk region of BRCA1/2 in the GENEPSO study.Results: We found that late age at menarche reduced breast cancer risk by 31% and that among BRCA1 carriers, a long or a short menstrual cycle increased risk (by 65% and 73%, respectively). Among premenopausal women, overweight was associated with a 45% decrease in risk whereas underweight was associated with an increased risk (HR, 2.40). A natural menopause, mainly after age 50, was associated with a high breast cancer risk (HR, 2.46), and a significant interaction between menopause status and the location of mutations was found leading up to 10% variation in absolute risk according to the age at menopause.Conclusions: As observed in the general population, a late menarche, a long or a short menstrual cycle, over- or underweight, and being postmenopausal were associated with breast cancer risk in BRCA1/2 carriers. The association with the menopause was observed only when the mutation was located in the “high-risk” zones.Impact: Taking into account modifier factors, location of mutation might be important for the clinical management of BRCA1/2 mutation carriers. Cancer Epidemiol Biomarkers Prev; 24(4); 698–707. ©2015 AACR.
Sequence Variation in Mature MicroRNA-499 Confers Unfavorable Prognosis of Lung Cancer Patients Treated with Platinum-Based Chemotherapy
Authors: Qiu Fuman , Yang Lei , Ling Xiaoxuan , Yang Rongrong , Yang Xiaorong , Zhang Lisha , Fang Wenxiang , Xie Chenli , Huang Dongsheng , Zhou Yifeng , Lu Jiachun 
Published: January 2015

AbstractPurpose: This study was implemented to investigate the associations between SNP in mature microRNA (miRNA) sequence and lung cancer prognosis and to verify the function of those SNP.Experimental Design: Eight SNPs (rs3746444T&gt;C in hsa-mir-499, rs4919510C&gt;G in hsa-mir-608, rs13299349G&gt;A in hsa-mir-3152, rs12220909G&gt;C in hsa-mir-4293, rs2168518G&gt;A in hsa-mir-4513, rs8078913T&gt;C in hsa-mir-4520a, rs11237828T&gt;C in hsa-mir-5579, and rs9295535T&gt;C in hsa-mir-5689) were analyzed in a southern Chinese population with 576 patients with lung cancer, and the significant results were validated in two additional cohorts of 346 and 368 patients, respectively. A series of experiments were performed to evaluate the relevancies of those potentially functional SNPs.Results: We found that the microRNA-499 rs3746444T&gt;C polymorphism exhibited a consistently poor prognosis for patients with lung cancer in the discovery set [HR, 1.24; 95% confidence interval (CI), 1.02–1.49; P = 0.028], in the validation set I (HR, 1.31; 95% CI, 1.01–1.71; P = 0.048) and in the validation set II (HR, 1.45; 95% CI, 1.12–1.86; P = 0.004). The adverse effect of CT/CC variants was more remarkable in patients receiving platinum-based chemotherapy. Further functional assays demonstrated that the rs3746444C variant allele influences the expression of several cancer-related genes and affects lung cancer cells' proliferation and tumor growth in vivo and in vitro via the cisplatinum resistance.Conclusion: Our findings suggested that the rs3746444T&gt;C polymorphism in mature miR-499 sequence could contribute to poor prognosis by modulating cancer-related genes' expression and thus involve tumorigenesis and anti-chemotherapy, which may be a useful biomarker to predict lung cancer patients' prognosis. Clin Cancer Res; 21(7); 1602–13. ©2015 AACR.
Global Promoter Methylation Analysis Reveals Novel Candidate Tumor Suppressor Genes in Natural Killer Cell Lymphoma
Authors: Küçük Can , Hu Xiaozhou , Jiang Bei , Klinkebiel David , Geng Huimin , Gong Qiang , Bouska Alyssa , Iqbal Javeed , Gaulard Philippe , McKeithan Timothy W. , Chan Wing C. 
Published: January 2015

Abstract
Purpose: To identify tumor suppressor genes epigenetically silenced by promoter hypermethylation in extranodal natural killer cell lymphoma (NKCL).
Experimental Design: Promoter methylation was analyzed with global and locus-specific methylation assays in NKCL cases and NK cell lines. Gene expression profiles were used to identify genes for which aberrant promoter methylation was associated with transcriptional silencing. Selected DNA methylations were validated by RRBS, pyrosequencing, or q-MSP. Decitabine treatment was performed to evaluate reactivation of methylated genes. The tumor suppressor effect of silenced genes was evaluated functionally by reintroducing them into NK cell lines.
Results: We observed significant promoter hypermethylation in most NKCL samples compared with normal NK cells. Correlation of global promoter methylation with gene expression profiles identified 95 genes with strong evidence for being silenced because of promoter methylation, including BCL2L11 (BIM), DAPK1, PTPN6 (SHP1), TET2, SOCS6, and ASNS. Known tumor suppressor genes were significantly overrepresented in this set of genes. Decitabine treatment of NK cell lines was associated with reexpression of all 10 selected methylated and silenced genes. Ectopic expression of frequently silenced BIM in two BIM-nonexpressing NK cell lines led to increased apoptosis and eventual elimination of BIM-transduced cells. It also sensitized these cell lines to chemotherapy-induced apoptosis. Similarly, reintroduction of SOCS6 significantly inhibited growth in SOCS6-nonexpressing NK cell lines. NK cell lines lacking ASNS expression showed increased sensitivity to treatment with l-asparaginase. Reintroduction of ASNS reduced drug sensitivity.
Conclusion: Promoter region hypermethylation is frequent in NKCL, and aberrantly methylated genes are pathologically and clinically significant. Clin Cancer Res; 21(7); 1699–711. ©2015 AACR.
Bevacizumab in Patients with Nonsquamous Non–Small Cell Lung Cancer and Asymptomatic, Untreated Brain Metastases (BRAIN): A Nonrandomized, Phase II Study
Authors: Besse Benjamin , Le Moulec Sylvestre , Mazières Julien , Senellart Hélène , Barlesi Fabrice , Chouaid Christos , Dansin Eric , Bérard Henri , Falchero Lionel , Gervais Radj , Robinet Gilles , Ruppert Anne-Marie , Schott Roland , Léna Hervé , Clément-Duchêne Christelle , Quantin Xavier , Souquet Pierre Jean , Trédaniel Jean , Moro-Sibilot Denis , Pérol Maurice , Madroszyk Anne-Catherine , Soria Jean-Charles 
Published: January 2015

Abstract
Purpose: The phase II prospective, noncomparative BRAIN study (NCT00800202) investigated efficacy and safety of bevacizumab in chemotherapy-naïve or pretreated patients with non–small cell lung cancer (NSCLC) and asymptomatic untreated brain metastases to provide data in this previously unexplored subgroup.
Experimental Design: Patients with stage IV nonsquamous NSCLC, Eastern Cooperative Oncology Group performance status 0–1, and untreated, asymptomatic brain metastases received first-line bevacizumab (15 mg/kg) plus carboplatin (area under the curve ×6) and paclitaxel (200 mg/m2) every 3 weeks (B + CP), or second-line bevacizumab plus erlotinib (150 mg/d; B + E). Six-month progression-free survival (PFS) was the primary endpoint. The trial could be stopped if there were more than three (B + CP) or more than two (B + E) intracranial hemorrhages.
Results: In first-line B + CP cohort (n = 67), 6-month PFS rate was 56.5% with a median PFS of 6.7 months [95% confidence interval (CI), 5.7–7.1] and median overall survival (OS) of 16.0 months. Investigator-assessed overall response rate (ORR) was 62.7%: 61.2% in intracranial lesions and 64.2% in extracranial lesions. Because of low enrolment (n = 24), efficacy results for the second-line B + E cohort were exploratory only; 6-month PFS rate was 57.2%, median PFS was 6.3 months (95% CI, 3.0–8.4), median OS was 12.0 months, and ORR was 12.5%. Adverse events were comparable with previous trials of bevacizumab. One grade 1 intracranial hemorrhage occurred and resolved without sequelae.
Conclusions: The BRAIN study demonstrates encouraging efficacy and acceptable safety of bevacizumab with first-line paclitaxel and carboplatin in patients with NSCLC and asymptomatic, untreated brain metastases. Clin Cancer Res; 21(8); 1896–903. ©2015 AACR.
HOTAIR Long Noncoding RNA Promotes Gastric Cancer Metastasis through Suppression of Poly r(C)-Binding Protein (PCBP) 1
Authors: Zhang Zi-Zhen , Shen Zhi-Yong , Shen Yan-Ying , Zhao En-Hao , Wang Ming , Wang Chao-Jie , Cao Hui , Xu Jia 
Published: January 2015

Abstract
The objective of this study was to evaluate the role of HOTAIR long noncoding RNA in gastric cancer metastasis. We analyzed HOTAIR expression levels by real-time reverse transcription PCR and Northern blot analysis in 100 gastric tissues (50 gastric cancer tissues and 50 adjacent normal mucosa), and in four gastric cancer cell lines. Transient RNAi-mediated knockdown and pcDNA-mediated overexpression of HOTAIR were performed. Stable shRNA-mediated knockdown and lentiviral-mediated overexpression of HOTAIR were to study the role of HOTAIR on in vivo tumorigenicity and metastatic burden in the context of xenograft assays. Proteomic profiling was performed to decipher differential protein expression in cells with different HOTAIR expression levels. One of the differentially regulated proteins, Poly r(C)-binding protein (PCBP) 1, was subsequently validated and its function evaluated through xenograft assays. Expression of HOTAIR was significantly higher in cancerous tissues than in adjacent normal mucosa. HOTAIR expression levels dictated in vitro and in vivo tumorigenicity and metastatic potential in these cells. PCBP1 and HOTAIR have an inverse relationship, both at expression level and in function. A direct interaction between the two was confirmed through RNA immunoprecipitation coupled with quantitative real-time PCR. PCBP1 was confirmed to be an inhibitor of gastric cancer pathogenesis and as functionally opposite to HOTAIR long noncoding RNA. In conclusion, HOTAIR expression may serve as a potentially important disease biomarker for the identification of high-risk gastric cancer patients. Moreover, our findings provide mechanistic evidence for HOTAIR overexpression and PCBP1 downregulation and the ensuing malignant phenotype in both cultured and xenograft gastric cancer cells. Mol Cancer Ther; 14(5); 1162–70. ©2015 AACR.
Mipomersen, an Antisense Oligonucleotide to Apolipoprotein B-100, Reduces Lipoprotein(a) in Various Populations With Hypercholesterolemia
Authors: Santos Raul D. , Raal Frederick J. , Catapano Alberico L. , Witztum Joseph L. , Steinhagen-Thiessen Elisabeth , Tsimikas Sotirios 
Published: January 2015

Objective—
Lp(a) is an independent, causal, genetic risk factor for cardiovascular disease and aortic stenosis. Current pharmacological lipid-lowering therapies do not optimally lower Lp(a), particularly in patients with familial hypercholesterolemia (FH).

Approach and Results—

In 4 phase III trials, 382 patients on maximally tolerated lipid-lowering therapy were randomized 2:1 to weekly subcutaneous mipomersen 200 mg (n=256) or placebo (n=126) for 26 weeks. Populations included homozygous FH, heterozygous FH with concomitant coronary artery disease (CAD), severe hypercholesterolemia, and hypercholesterolemia at high risk for CAD. Lp(a) was measured 8× between baseline and week 28 inclusive. Of the 382 patients, 57% and 44% had baseline Lp(a) levels >30 and >50 mg/dL, respectively. In the pooled analysis, the mean percent decrease (median, interquartile range in Lp(a) at 28 weeks was significantly greater in the mipomersen group compared with placebo (−26.4 [−42.8, −5.4] versus −0.0 [−10.7, 15.3];
P
<0.001). In the mipomersen group in patients with Lp(a) levels >30 or >50 mg/dL, attainment of Lp(a) values ≤30 or ≤50 mg/dL was most frequent in homozygous FH and severe hypercholesterolemia patients. In the combined groups, modest correlations were present between percent change in apolipoprotein B-100 and Lp(a) (
r
=0.43;
P
<0.001) and low-density lipoprotein cholesterol and Lp(a) (
r
=0.36;
P
<0.001) plasma levels.

Conclusions—
Mipomersen consistently and effectively reduced Lp(a) levels in patients with a variety of lipid abnormalities and cardiovascular risk. Modest correlations were present between apolipoprotein B-100 and Lp(a) lowering but the mechanistic relevance mediating Lp(a) reduction is currently unknown.
Gestational Diabetes Mellitus Impairs Fetal Endothelial Cell Functions Through a Mechanism Involving MicroRNA-101 and Histone Methyltransferase Enhancer of Zester Homolog-2
Authors: Floris Ilaria , Descamps Betty , Vardeu Antonella , Mitić Tijana , Posadino Anna Maria , Shantikumar Saran , Sala-Newby Graciela , Capobianco Gianpiero , Mangialardi Giuseppe , Howard Lynsey , Dessole Salvatore , Urrutia Raul , Pintus Gianfranco , Emanueli Costanza 
Published: January 2015

Objective—
Gestational diabetes mellitus (GDM) produces fetal hyperglycemia with increased lifelong risks for the exposed offspring of cardiovascular and other diseases. Epigenetic mechanisms induce long-term gene expression changes in response to in utero environmental perturbations. Moreover, microRNAs (miRs) control the function of endothelial cells (ECs) under physiological and pathological conditions and can target the epigenetic machinery. We investigated the functional and expressional effect of GDM on human fetal ECs of the umbilical cord vein (HUVECs). We focused on miR-101 and 1 of its targets, enhancer of zester homolog-2 (EZH2), which trimethylates the lysine 27 of histone 3, thus repressing gene transcription. EZH2 exists as isoforms α and β.

Approach and Results—

HUVECs were prepared from GDM or healthy pregnancies and tested in apoptosis, migration, and Matrigel assays. GDM-HUVECs demonstrated decreased functional capacities, increased miR-101 expression, and reduced EZH2- β and trimethylation of histone H3 on lysine 27 levels. MiR-101 inhibition increased EZH2 expression and improved GDM-HUVEC function. Healthy HUVECs were exposed to high or normal
d
-glucose concentration for 48 hours and then tested for miR-101 and EZH2 expression. Similar to GDM, high glucose increased miR-101 expression. Chromatin immunoprecipitation using an antibody for EZH2 followed by polymerase chain reaction analyses for miR-101 gene promoter regions showed that both GDM and high glucose concentration reduced EZH2 binding to the miR-101 locus in HUVECs. Moreover, EZH2-β overexpression inhibited miR-101 promoter activity in HUVECs.

Conclusions—
GDM impairs HUVEC function via miR-101 upregulation. EZH2 is both a transcriptional inhibitor and a target gene of miR-101 in HUVECs, and it contributes to some of the miR-101-induced defects of GDM-HUVECs.
Impaired Integrin β3 Delays Endothelial Cell Regeneration and Contributes to Arteriovenous Graft Failure in Mice
Authors: Liang Ming , Wang Yun , Liang Anlin , Dong Jin-Fei , Du Jie , Cheng Jizhong 
Published: January 2015

Objective—
Neointima formation is associated with stenosis and subsequent thrombosis in arteriovenous grafts (AVGs). A role of integrin β3 in the neointima formation of AVGs remains poorly understood.

Approach and Results—

In integrin β3
−/−
mice, we found significantly accelerated occlusion of AVGs compared with the wild-type mice. This is caused by the development of neointima and lack of endothelial regeneration. The latter is a direct consequence of impaired functions of circulating angiogenic cells (CACs) and platelets in integrin β3
−/−
mice. Evidence suggests the involvement of platelet regulating CAC homing to and differentiation at graft sites via transforming growth factor-β1 and Notch signaling pathway. First, CACs deficient of integrin β3 impaired adhesion activity toward exposed subendothelium. Second, platelets from integrin β3
−/−
mice failed to sufficiently stimulate CACs to differentiate into mature endothelial cells. Finally, we found that transforming growth factor-β1 level was increased in platelets from integrin β3
−/−
mice and resulted in enhanced Notch1 activation in CACs in AVGs. These results demonstrate that integrin β3 is critical for endothelial cell homing and differentiation. The increased transforming growth factor-β1 and Notch1 signaling mediates integrin β3
−/−
-induced AVG occlusion. This accelerated occlusion of AVGs was reversed in integrin β3
−/−
mice transplanted with the bone marrow from wild-type mice.

Conclusions—
Our results suggest that boosting integrin β3 function in the endothelial cells and platelets could prevent neointima and thrombosis in AVGs.