bluuebunny/crossref_metadata_2025_split huggingface dataset:
Folate Deficiency Induces Dysfunctional Long and Short Telomeres; Both States Are Associated with Hypomethylation and DNA Damage in Human WIL2-NS Cells
Authors: Bull Caroline F. , Mayrhofer Graham , O'Callaghan Nathan J. , Au Amy Y. , Pickett Hilda A. , Low Grace Kah Mun , Zeegers Dimphy , Hande M. Prakash , Fenech Michael F. 
Published: November 2013

Abstract
The essential role of dietary micronutrients for genome stability is well documented, yet the effect of folate deficiency or excess on telomeres is not known. Accordingly, human WIL2-NS cells were maintained in medium containing 30, 300, or 3,000 nmol/L folic acid (FA) for 42 days to test the hypothesis that chronic folate deficiency would cause telomere shortening and dysfunction. After 14 days, telomere length (TL) in FA-deficient (30 nmol/L) cultures was 26% longer than that of 3,000 nmol/L FA cultures; however, this was followed by rapid telomere attrition over the subsequent 28 days (P trend, P &lt; 0.0001); both long and short telomere status was positively correlated with biomarkers of chromosome instability (P ≤ 0.003) and mitotic dysfunction (P = 0.01), measured by the cytokinesis-block micronucleus cytome (CBMN-cyt) assay. The early increase in TL was associated with FA-deficiency–induced global DNA hypomethylation (P = 0.05), with an effect size similar to that induced by the DNA methyltransferase inhibitor, 5-aza-2′-deoxycytidine. Quantitative PCR analysis indicated a negative association between FA concentration and uracil incorporation into telomeric DNA (r = −0.47, P = 0.1), suggesting a possible plausible mechanism for uracil as a cause of folate deficiency–induced telomere dysfunction or deletion. Peptide nucleic acid-FISH (PNA-FISH) analysis showed that FA deficiency resulted in 60% of micronuclei containing acentric terminal fragments, an observation consistent with the 3-fold increase in terminal deletions (P = 0.0001). Together, these results demonstrate the impact of folate deficiency on biomarkers of telomere maintenance and integrity, and provide evidence that dysfunctional long telomeres may be as important as critically short telomeres as a cause of chromosomal instability. Cancer Prev Res; 7(1); 128–38. ©2013 AACR.
CD4 T Cells Require ICOS-Mediated PI3K Signaling to Increase T-Bet Expression in the Setting of Anti-CTLA-4 Therapy
Authors: Chen Hong , Fu Tihui , Suh Woong-Kyung , Tsavachidou Dimitra , Wen Sijin , Gao Jianjun , Ng Tang Derek , He Qiuming , Sun Jingjing , Sharma Padmanee 
Published: November 2013

Abstract
The transcription factor T-bet controls the Th1 genetic program in T cells for effective antitumor responses. Anti-CTLA-4 immunotherapy elicits dramatic antitumor responses in mice and in human patients; however, factors that regulate T-bet expression during an antitumor response mediated by anti-CTLA-4 remain to be elucidated. We were the first to report that treatment with anti-CTLA-4 led to an increase in the frequency of T cells expressing inducible costimulator (ICOS). In both treated patients and mice, our data revealed that CD4+ICOShi T cells can act as effector T cells, which produce the Th1 cytokine IFN-γ. We also showed in a small retrospective analysis that an increased frequency of CD4+ICOShi T cells correlated with better clinical outcome and the absence of ICOS or its ligand (ICOSL) in mouse models led to impaired tumor rejection. Here, we show that CD4+ICOShi T cells from anti-CTLA-4–treated patients had an increase in signaling via the phospoinositide-3-kinase (PI3K) pathway and an increase in expression of T-bet. An ICOS-specific siRNA transfected into human T cells led to diminished PI3K signaling and T-bet expression. Therefore, we hypothesized that ICOS, and specifically ICOS-mediated PI3K signaling, was required for T-bet expression. We conducted studies in ICOS-deficient and ICOS-YF mice, which have a single amino acid change that abrogates PI3K signaling by ICOS. We found that ICOS-mediated PI3K signaling is required for T-bet expression during an antitumor response elicited by anti-CTLA-4 therapy. Our data provide new insight into the regulation of T-bet expression and suggest that ICOS can be targeted to improve Th1 antitumor responses. Cancer Immunol Res; 2(2); 167–76. ©2013 AACR.
Validation of the J-Chronic Total Occlusion Score for Chronic Total Occlusion Percutaneous Coronary Intervention in an Independent Contemporary Cohort
Authors: Nombela-Franco Luis , Urena Marina , Jerez-Valero Miguel , Nguyen Can Manh , Ribeiro Henrique Barbosa , Bataille Yoann , Rodés-Cabau Josep , Rinfret Stéphane 
Published: November 2013

Background—
Chronic total occlusion (CTO) recanalization is a complex and technically challenging procedure. The J-CTO score has been proposed to stratify case complexity and procedural success rates. However, the score has never been tested outside the setting of the original study. Moreover, its predictive value when using a hybrid antegrade or retrograde approach is unknown. We investigated the performance of the J-CTO score for predicting procedure complexity and success in an independent contemporary cohort.

Methods and Results—

A total of 209 consecutive patients who underwent CTO recanalization by a high-volume operator were included. Clinical and angiographic data were prospectively collected. The J-CTO score was applied for each patient, and discrimination and calibration were evaluated in the whole cohort, and according to the approach (antegrade 47% and retrograde 53%). Clinical and angiographic differences were noted between the original and studied cohort. The mean J-CTO score was 2.18±1.26, and successful guidewire crossing within 30 minutes and final angiographic success were 44.5% and 90.4%, respectively. The J-CTO score demonstrated good discrimination (
c
statistic, >0.70) and calibration (Hosmer–Lemeshow
P
>0.1) in the whole cohort and for antegrade and retrograde approaches. However, the final success rate was not associated with the J-CTO score.

Conclusions—
In this independent cohort, the J-CTO score showed good discriminatory and calibration capacity for guidewire CTO crossing within 30 minutes but it does not for final success rate. The J-CTO score helps to predict complexity of CTO recanalization, and the simplicity of the score supports the widespread use as a clinical tool.
Serial Observation of Drug-Eluting Absorbable Metal Scaffold
Authors: Waksman Ron , Prati Francesco , Bruining Nico , Haude Michael , Böse Dirk , Kitabata Hironori , Erne Paul , Verheye Stefan , Degen Hubertus , Vermeersch Paul , Di Vito Luca , Koolen Jacques , Erbel Raimund 
Published: November 2013

Background—
The drug-eluting absorbable metal scaffold has demonstrated feasibility, safety, and promising clinical and angiographic outcomes at 12 months in human coronary arteries. This study aimed to evaluate the degradation rate and long-term vascular responses to drug-eluting absorbable metal scaffold.

Methods and Results—

BIOSOLVE-I was a multicenter, single-arm, first-in-man trial assessing the safety and performance of drug-eluting absorbable metal scaffold in 46 patients with coronary artery disease. Patients who underwent serial invasive imaging, such as quantitative coronary angiography, intravascular ultrasound, and optical coherence tomography, at 6 and 12 months were included in this study. From postimplantation to follow-up, arterial curvature and angulation were significantly increased by the degradation process. The greatest increase was seen from postimplantation to 6 months. The systolic–diastolic changes of the curvature and angulation gradually improved throughout the follow-up period. At the site of implantation, vasoconstriction (−10% mean reduction) was observed during the acetylcholine test at 6 months. The average percent hyperechogenicity of the scaffolded segments showed a continuous decrease over time, with the most pronounced changes within the first 6 months (from 22.1±7.0% to 15.8±3.7%;
P
<0.001). Struts discernible on optical coherence tomography at 6 and 12 months showed full neointimal coverage, with stabilization of the mean scaffold area from 6 to 12 months. Furthermore, the mean neointimal area (1.55±0.51 versus 1.58±0.34 mm
2
;
P
=0.794) remained unchanged from 6 to 12 months.

Conclusions—
This serial analysis of drug-eluting absorbable metal scaffold confirmed the safety and efficacy of this new device, with vasomotion restoration and continued degradation over time demonstrated by multi-invasive imaging modalities.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01168830.
Longitudinal Effects of a Decade of Aging on Carotid Artery Stiffness
Authors: Gepner Adam D. , Korcarz Claudia E. , Colangelo Laura A. , Hom Elizabeth K. , Tattersall Matthew C. , Astor Brad C. , Kaufman Joel D. , Liu Kiang , Stein James H. 
Published: November 2013

Background and Purpose—
Arterial stiffening is associated with hypertension, stroke, and cognitive decline; however, the effects of aging and cardiovascular disease risk factors on carotid artery stiffening have not been assessed prospectively in a large multiethnic longitudinal study.

Methods—
Distensibility coefficient and the Young’s elastic modulus (YEM) of the right common carotid artery were calculated at baseline and after a mean of 9.4 (standard deviation [SD], 0.5) years in 2650 participants. Effects of age and cardiovascular disease risk factors were evaluated by multivariable mixed regression and ANCOVA models.

Results—

At baseline, participants were 59.9 (SD, 9.4) years old (53% women; 25% black, 22% Hispanic, 14% Chinese). YEM increased from 1581 (SD, 927) to 1749 (SD, 1306) mm Hg (
P
<0.0001), and distensibility coefficient decreased from 3.1 (SD, 1.3) to 2.7 (SD, 1.1)×10
–3
mm Hg
−1
(
P
<0.001), indicating progressive arterial stiffening. YEM increased more among participants who were aged >75 years old at baseline (
P
<0.0001). In multivariable analyses, older age and less education independently predicted worsening YEM and distensibility coefficient. Stopping antihypertensive medication during the study period predicted more severe worsening of YEM (β=360.2 mm Hg;
P
=0.008). Starting antihypertensive medication after examination 1 was predictive of improvements in distensibility coefficient (β=1.1×10
–4
mm Hg
–1
;
P
=0.024).

Conclusions—
Arterial stiffening accelerates with advanced age. Older individuals experience greater increases in YEM than do younger adults, even after considering the effects of traditional risk factors. Treating hypertension may slow the progressive decline in carotid artery distensibility observed with aging and improve cerebrovascular health.
Nontraumatic Subarachnoid Hemorrhage in Maintenance Dialysis Hospitalizations
Authors: Sakhuja Ankit , Schold Jesse D. , Kumar Gagan , Katzan Irene , Navaneethan Sankar D. 
Published: November 2013

Background and Purpose—
Subarachnoid hemorrhage (SAH) is associated with high mortality, and patients on maintenance dialysis have been shown to be at higher risk for stroke including SAH. However, the outcomes of patients on maintenance dialysis with SAH are not well known. This study was designed to look at incidence and outcomes of SAH in those on maintenance dialysis.

Methods—
Using the Nationwide Inpatient Sample Database, hospitalizations with nontraumatic SAH were identified. Age-adjusted incidence rates were calculated by direct standardization to the 2000 US standard population. Logistic regression was used to assess the risk factors for mortality.

Results—

Of an estimated 149 091 hospitalizations with SAH, 1631 patients (10.9%) were on maintenance dialysis. Unadjusted incidence of SAH hospitalizations was higher in maintenance dialysis than in the general population (73.5 versus 11.2 per 100 000 population), and similar results were seen on age-adjusted analysis. The unadjusted all-cause inpatient mortality rate for SAH admissions was higher in maintenance dialysis versus the general population (38.4% versus 21.9%;
P
<0.001). Maintenance dialysis was an independent predictor of mortality (odds ratio, 2.48; 95% confidence interval, 1.85–3.34), although other significant predictors of mortality were similar in both subgroups. Incidence of SAH hospitalizations has been relatively stable during the study period, but mortality seems to be decreasing.

Conclusions—
SAH hospitalizations are more common and associated with higher mortality in patients on maintenance dialysis than in the general population. Although being on maintenance dialysis is an independent predictor for mortality in patients with SAH, other predictors of mortality evaluated in this study are not necessarily different between the 2 groups.
Soluble Urokinase Plasminogen Activator Receptor
Authors: Persson Margaretha , Östling Gerd , Smith Gustav , Hamrefors Viktor , Melander Olle , Hedblad Bo , Engström Gunnar 
Published: November 2013

Background and Purpose—
Recent studies indicate that the urokinase system could have an important role in atherogenesis and plaque rupture. The relationships among the soluble urokinase plasminogen activator receptor (suPAR), carotid plaque, and incidence of ischemic stroke and coronary artery disease (CAD) events were studied in a prospective cohort.

Methods—
Occurrence of carotid plaque and plasma levels of suPAR were assessed in 5166 men and women, aged 45 to 68 years, participating in the Malmö Diet and Cancer study. Incidences of ischemic stroke and CAD were monitored during a mean follow-up of 15 years.

Results—
Subjects with carotid plaque had significantly higher levels of suPAR compared with those without carotid plaque. suPAR was associated with increased incidence of ischemic stroke (hazard ratio [HR] for third versus first tertile, 1.50; 95% confidence interval [CI], 1.06–2.11) and CAD (HR, 1.55; 95% CI, 1.13–2.13) after adjustment for risk factors. The risk factor–adjusted HR for ischemic stroke was 2.21 (95% CI, 1.52–3.22) in subjects with carotid plaque and high suPAR (ie, third tertile) and 1.51 (95% CI, 1.05–2.17) in subjects with carotid plaque and low suPAR compared with those without carotid plaque and low suPAR (reference). High levels of suPAR significantly increased the risk of ischemic stroke and CAD in subjects with carotid plaque.

Conclusions—
suPAR is associated with increased occurrence of carotid plaque and increased incidence of ischemic stroke and CAD. Presence of both elevated levels of suPAR and carotid plaque increases the risk of ischemic stroke in an additive way.
Survival Differences between Organ Preservation Surgery and Definitive Radiotherapy in Early Supraglottic Squamous Cell Carcinoma
Authors: Arshad Hassan , Jayaprakash Vijayvel , Gupta Vishal , Cohan David M. , Ambujakshan Dildeep , Rigual Nestor R. , Singh Anurag K. , Hicks Wesley L. 
Published: November 2013

ObjectiveSingle‐modality treatment, either with organ preservation surgery (OPS) or definitive radiation (RT), is the treatment of choice for patients with early supraglottic squamous cell carcinoma (SGC). However, studies comparing the effectiveness of these 2 techniques are lacking. This study compares the survival outcomes in early SGC patients treated with OPS versus RT.Study DesignSecondary data analysis.SettingSurveillance, Epidemiology and End Results database.Subjects and MethodsThis study included adult patients with early‐stage (T1N0, T2N0) SGC undergoing single‐modality treatment with either OPS (with or without neck dissection [ND]) or RT between 1988 and 2008. Survival analysis was used to compare the overall survival (OS) and disease‐specific survival (DSS) between patients treated with OPS+ND, OPS alone, and RT.ResultsA total of 2631 T1/T2 N0 SGC patients were identified, of whom 167 (6%) were treated with OPS+ND, 186 (7%) with OPS only, and 2278 patients (87%) with definitive RT only. In stage I (T1N0) SGC patients, a significantly better 5‐year DSS was noted for both OPS+ND (81% vs 68%, hazard ratio [HR] = 0.61, P =. 03) and OPS only (82% vs 68%, HR = 0.70, P =. 05) when compared with definitive RT. For stage II (T2N0) patients, only OPS+ND resulted in a significantly better 5‐year DSS (86% vs 60%, HR = 0.31, P <. 001) when compared with patients treated with RT.ConclusionsPatients with early SGC who underwent OPS+ND had better OS and DSS than patients undergoing RT alone. OPS+ND may be considered a viable and preferred treatment option in these patients.
PML4 facilitates erythroid differentiation by enhancing the transcriptional activity of GATA-1
Authors: Wu Jie , Zhou Li-Quan , Yu Wei , Zhao Zhi-Guo , Xie Xue-Min , Wang Wen-Tian , Xiong Jian , Li Man , Xue Zheng , Wang Xing , Zhang Peng , Mao Bei-Bei , Hao De-Long , Lv Xiang , Liu De-Pei 
Published: November 2013

Key Points
PML4 promotes erythroid differentiation in K562, primary erythroid cells, and GATA-1–rescued G1E-ER4 cells, but not in GATA-1–deficient G1E cells. PML4 interacts with GATA-1 and enhances its transcriptional activity by stimulating GATA-1/P300 cooperation and GATA-1 acetylation.
Polyphosphate amplifies proinflammatory responses of nuclear proteins through interaction with receptor for advanced glycation end products and P2Y1 purinergic receptor
Authors: Dinarvand Peyman , Hassanian Seyed Mahdi , Qureshi Shabir H. , Manithody Chandrashekhara , Eissenberg Joel C. , Yang Likui , Rezaie Alireza R. 
Published: November 2013

Key Points
Extracellular nuclear proteins H4 and HMGB1 are highly proinflammatory cytokines. Inorganic polyP dramatically amplifies proinflammatory responses of H4 and HMGB1 through the RAGE and P2Y1 receptors.
Growth rate-coordinated transcriptome reorganization in bacteria
Authors: Matsumoto Yuki , Murakami Yoshie , Tsuru Saburo , Ying Bei-Wen , Yomo Tetsuya 
Published: November 2013

AbstractBackgroundCell growth rate reflects an organism’s physiological state and largely relies on the ability of gene expression to respond to the environment. The relationship between cellular growth rate and gene expression remains unknown.ResultsGrowth rate-coordinated changes in gene expression were discovered by analyzing exponentially growingEscherichia colicells cultured under multiple defined environments, in which osmotic pressure, temperature and starvation status were varied. Gene expression analyses showed that all 3,740 genes in the genome could be simply divided into three clusters (C1, C2 and C3), which were accompanied by a generic trend in the growth rate that was coordinated with transcriptional changes. The direction of transcriptional change in C1 indicated environmental specificity, whereas those in C2 and C3 were correlated negatively and positively with growth rates, respectively. The three clusters exhibited differentiated gene functions and gene regulation task division.ConclusionsWe identified three gene clusters, exhibiting differential gene functions and distinct directions in their correlations with growth rates. Reverses in the direction of the growth rate correlated transcriptional changes and the distinguished duties of the three clusters indicated how transcriptome homeostasis is maintained to balance the total expression cost for sustaining life in new habitats.
Molecular diagnosis of distal renal tubular acidosis in Tunisian patients: proposed algorithm for Northern Africa populations for the ATP6V1B1, ATP6V0A4 and SCL4A1genes
Authors: Elhayek Donia , Perez de Nanclares Gustavo , Chouchane Slaheddine , Hamami Saber , Mlika Adnène , Troudi Monia , Leban Nadia , Ben Romdane Wafa , Gueddiche Mohamed Neji , El Amri Féthi , Mrabet Samir , Ben Chibani Jemni , Castaño Luis , Haj Khelil Amel , Ariceta Gema 
Published: November 2013

Abstract

Background
Primary distal renal tubular acidosis (dRTA) caused by mutations in the genes that codify for the H + −ATPase pump subunits is a heterogeneous disease with a poor phenotype-genotype correlation. Up to now, large cohorts of dRTA Tunisian patients have not been analyzed, and molecular defects may differ from those described in other ethnicities. We aim to identify molecular defects present in the ATP6V1B1, ATP6V0A4 and SLC4A1 genes in a Tunisian cohort, according to the following algorithm: first, ATP6V1B1 gene analysis in dRTA patients with sensorineural hearing loss (SNHL) or unknown hearing status. Afterwards, ATP6V0A4 gene study in dRTA patients with normal hearing, and in those without any structural mutation in the ATP6V1B1 gene despite presenting SNHL. Finally, analysis of the SLC4A1 gene in those patients with a negative result for the previous studies.

Methods
25 children (19 boys) with dRTA from 20 families of Tunisian origin were studied. DNAs were extracted by the standard phenol/chloroform method. Molecular analysis was performed by PCR amplification and direct sequencing.

Results
In the index cases, ATP6V1B1 gene screening resulted in a mutation detection rate of 81.25%, which increased up to 95% after ATP6V0A4 gene analysis. Three ATP6V1B1 mutations were observed: one frameshift mutation (c.1155dupC; p.Ile386fs), in exon 12; a G to C single nucleotide substitution, on the acceptor splicing site (c.175-1G > C; p.?) in intron 2, and one novel missense mutation (c.1102G > A; p.Glu368Lys), in exon 11. We also report four mutations in the ATP6V0A4 gene: one single nucleotide deletion in exon 13 (c.1221delG; p.Met408Cysfs*10); the nonsense c.16C > T; p.Arg6*, in exon 3; and the missense changes c.1739 T > C; p.Met580Thr, in exon 17 and c.2035G > T; p.Asp679Tyr, in exon 19.

Conclusion
Molecular diagnosis of ATP6V1B1 and ATP6V0A4 genes was performed in a large Tunisian cohort with dRTA. We identified three different ATP6V1B1 and four different ATP6V0A4 mutations in 25 Tunisian children. One of them, c.1102G > A; p.Glu368Lys in the ATP6V1B1 gene, had not previously been described. Among deaf since childhood patients, 75% had the ATP6V1B1 gene c.1155dupC mutation in homozygosis. Based on the results, we propose a new diagnostic strategy to facilitate the genetic testing in North Africans with dRTA and SNHL.
Structure of the S100A4/myosin-IIA complex
Authors: Ramagopal Udupi A , Dulyaninova Natalya G , Varney Kristen M , Wilder Paul T , Nallamsetty Sridevi , Brenowitz Michael , Weber David J , Almo Steven C , Bresnick Anne R 
Published: November 2013

Abstract

Background
S100A4, a member of the S100 family of Ca2+-binding proteins, modulates the motility of both non-transformed and cancer cells by regulating the localization and stability of cellular protrusions. Biochemical studies have demonstrated that S100A4 binds to the C-terminal end of the myosin-IIA heavy chain coiled-coil and disassembles myosin-IIA filaments; however, the mechanism by which S100A4 mediates myosin-IIA depolymerization is not well understood.

Results
We determined the X-ray crystal structure of the S100A4Δ8C/MIIA1908-1923 peptide complex, which showed an asymmetric binding mode for the myosin-IIA peptide across the S100A4 dimer interface. This asymmetric binding mode was confirmed in NMR studies using a spin-labeled myosin-IIA peptide. In addition, our NMR data indicate that S100A4Δ8C binds the MIIA1908-1923 peptide in an orientation very similar to that observed for wild-type S100A4. Studies of complex formation using a longer, dimeric myosin-IIA construct demonstrated that S100A4 binding dissociates the two myosin-IIA polypeptide chains to form a complex composed of one S100A4 dimer and a single myosin-IIA polypeptide chain. This interaction is mediated, in part, by the instability of the region of the myosin-IIA coiled-coil encompassing the S100A4 binding site.

Conclusion
The structure of the S100A4/MIIA1908-1923 peptide complex has revealed the overall architecture of this assembly and the detailed atomic interactions that mediate S100A4 binding to the myosin-IIA heavy chain. These structural studies support the idea that residues 1908–1923 of the myosin-IIA heavy chain represent a core sequence for the S100A4/myosin-IIA complex. In addition, biophysical studies suggest that structural fluctuations within the myosin-IIA coiled-coil may facilitate S100A4 docking onto a single myosin-IIA polypeptide chain.