bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Incorporation of 5-Fluorouracil into RNA Affects the Ribonucleolytic Activity of the Exosome Subunit Rrp6
Authors: Silverstein Rebecca A. , González de Valdivia Ernesto , Visa Neus 
Published: February 2011

Abstract
5-Fluorouracil (5FU) is a fluoropyrimidine used for the treatment of solid tumors. 5FU is a precursor of dTTP and UTP during biogenesis, and it interferes with both DNA and RNA metabolism. The RNA exosome, a multisubunit complex with ribonucleolytic activity, has been identified as one of the targets of 5FU in yeast. Studies in human cells have shown that the catalytic subunit of the nuclear exosome, Rrp6, is specifically targeted. Here, we have investigated the direct effect of 5FU on the activity of Rrp6 in Drosophila S2 cells, and we have identified two aspects of Rrp6 function that are altered by 5FU. First, gel filtration analysis revealed that the repertoire of multimolecular complexes that contain Rrp6 is modified by exposure to 5FU, which is consistent with the proposal that incorporation of 5FU into RNA leads to the sequestration of Rrp6 in ribonucleoprotein complexes. Second, the incorporation of 5FU into RNA renders the RNA less susceptible to degradation by Rrp6, as shown by Rrp6 activity assays in vitro. Our results imply that aberrant transcripts synthesized in 5FU-treated cells cannot be turned over efficiently by the surveillance machinery. Together with previous results on the mechanisms of action of 5FU, our findings suggest that the cytotoxicity of 5FU at the RNA level is the result of at least three different effects: the increased levels of retroviral transcripts with mutagenic potential, the reduced synthesis of ribosomes, and the inhibition of the nuclear RNA surveillance pathways. Drugs that reinforce any of these effects may boost the cytotoxicity of 5FU. Mol Cancer Res; 9(3); 332–40. ©2011 AACR.
Characterization of the Methylation Patterns in Human Papillomavirus Type 16 Viral DNA in Head and Neck Cancers
Authors: Park Il-Seok , Chang Xiaofei , Loyo Myriam , Wu Gaosong , Chuang Alice , Kim Myoung Sook , Chae Young Kwang , Lyford-Pike Sofia , Westra William H. , Saunders John R. , Sidransky David , Pai Sara Isabel 
Published: February 2011

Abstract
Human papillomavirus (HPV) type 16 can integrate into the host genome, thereby rendering the viral coding genes susceptible to epigenetic modification. Using bisulfite genomic sequencing, we determined the methylation status of all 110 CpG sites within the viral epigenome in advanced stage III/IV HPV-16–associated head and neck cancers. We found that the viral genome was hypomethylated in the majority of head and neck cancers, in particular within the viral regulatory region, long control region (LCR), which controls transcription of the E6 and E7 oncogenes. The hypomethylation status of LCR correlated with detectable levels of E6 and E7 expression, which suggests that the tumors may still be dependent on these viral oncogenes to maintain the malignant phenotype. In addition to the methylation status of LCR, we report other potential factors which may influence intratumoral E6 and E7 expression including viral copy number and integration site. We were able to detect the viral epigenetic alterations in sampled body fluids, such as serum and saliva, which correlated with the changes observed in the primary tumors. Because viral epigenetic changes occur in the setting of viral integration into the human genome, the detection of methylated HPV genes in the serum and/or saliva may have diagnostic potential for early detection strategies of viral integration and assessment of risk for cancer development in high-risk individuals. Our findings also support continued targeting of the E6 and/or E7 antigens through various vaccine strategies against HPV-associated cancers. Cancer Prev Res; 4(2); 207–17. ©2011 AACR.
Cortical Mechanisms of Cognitive Control for Shifting Attention in Vision and Working Memory
Authors: Tamber-Rosenau Benjamin J. , Esterman Michael , Chiu Yu-Chin , Yantis Steven 
Published: February 2011

Abstract
Organisms operate within both a perceptual domain of objects and events, and a mnemonic domain of past experiences and future goals. Each domain requires a deliberate selection of task-relevant information, through deployments of external (perceptual) and internal (mnemonic) attention, respectively. Little is known about the control of attention shifts in working memory, or whether voluntary control of attention in these two domains is subserved by a common or by distinct functional networks. We used human fMRI to examine the neural basis of cognitive control while participants shifted attention in vision and in working memory. We found that these acts of control recruit in common a subset of the dorsal fronto-parietal attentional control network, including the medial superior parietal lobule, intraparietal sulcus, and superior frontal sulcus/gyrus. Event-related multivoxel pattern classification reveals, however, that these regions exhibit distinct spatio-temporal patterns of neural activity during internal and external shifts of attention, respectively. These findings constrain theoretical accounts of selection in working memory and perception by showing that populations of neurons in dorsal fronto-parietal network regions exhibit selective tuning for acts of cognitive control in different cognitive domains.
Rural/Urban Variations in Diabetes Self-Care and Quality of Care in a National Sample of US Adults With Diabetes
Authors: Strom Joni L. , Lynch Cheryl P. , Egede Leonard E. 
Published: February 2011

Purpose The purpose of this study was to examine differences in diabetes self-care and provider-based quality-of-care indicators between rural and urban dwellers in a nationally representative sample of adults with diabetes. Methods Data were analyzed on 52 817 individuals with type 2 diabetes from the 2007 Behavioral Risk Factor Surveillance Survey. Rural and urban residence was based on metropolitan statistical area. Self-care behaviors (nutrition, physical activity, self-monitoring) and quality-of-care indicators (clinical visits, glycemic control, preventive measures) were self-reported. Logistic regression analyses were done using STATA 10 to assess the independent effect of rural/urban residence on self-care and each quality measure and to account for the complex survey design. Results Rural residents comprised 21% of the sample and were less likely to receive diabetes education (57% vs 51%, P < .001). The final adjusted model showed that foot self-checks (odds ratio, 1.42; 95% confidence interval, 1.27-1.59) and blood glucose testing at least once daily (odds ratio, 1.14; 95% confidence interval, 1.02-1.26) were significantly higher among rural individuals. Provider-based quality of care was not significantly different by rural/urban residence. Conclusion Contrary to what has been reported, there were no significant differences in diabetes quality of care between rural and urban dwellers. In addition, rural dwellers appeared to have better self-care behaviors than urban dwellers. Further research is needed to clarify the reasons for these findings.
Role of Depression in Outcomes of Endoscopic Sinus Surgery
Authors: Litvack Jamie R. , Mace Jess , Smith Timothy L. 
Published: February 2011

ObjectiveTo prospectively measure the prevalence and effect of symptomatic depression on chronic rhinosinusitis (CRS) patients’ quality of life (QOL), disease severity, and outcomes of endoscopic sinus surgery (ESS).Study DesignProspective cohort study.SettingAcademic, tertiary care center.Subjects and MethodsSeventy‐six patients with CRS were enrolled prior to ESS and followed postoperatively for a mean (SD) of 13.3 (5.4) months. Lund‐Mackay computed tomography score, Lund‐Kennedy endoscopy score, Patient Health Questionnaire–9 (PHQ‐9), 2 disease‐specific QOL instruments (Rhinosinusitis Disability Index [RSDI] and Chronic Sinusitis Survey [CSS]), and 1 general QOL instrument (Medical Outcomes Study Short Form–36 [SF‐36]) were measured. Differences in outcome scores were analyzed using univariate and multivariate analyses.ResultsOnly 7 (9.2%) patients reported a history of depression, but 19 (25.0%) patients scored in the range of moderate or severe depression on the PHQ‐9. Mean (SD) preoperative scores were significantly worse in depressed patients on the RSDI (62.7 [18.2] vs 45.3 [16.3]; P <. 001) and 7 of 8 SF‐36 domains (all P ≤. 011). Patients with depression significantly improved on both disease‐specific QOL instruments (mean [SD] change; RSDI: 33.5 [24.7], P =. 017; CSS: 25.0 [20.9], P =. 012) and 3 SF‐36 domains (all P ≤. 050). Postoperative change scores were not significantly different from patients without depression on the RSDI, CSS, or SF‐36. Severity of depression significantly improved postoperatively in depressed patients (preoperative PHQ‐9 scores: 13.4 [2.0] vs 6.1 [4.5], P =. 017).ConclusionCRS patients with depression had worse baseline QOL than other CRS patients but experienced comparable postoperative improvement in QOL after ESS. Interestingly, depression severity significantly improved after ESS.
31P-MRS demonstrates a reduction in high-energy phosphates in the occipital lobe of migraine without aura patients
Authors: Reyngoudt Harmen , Paemeleire Koen , Descamps Benedicte , De Deene Yves , Achten Eric 
Published: February 2011

Background: Differences in brain energy metabolism have been found between migraine patients and controls in previous phosphorus magnetic resonance spectroscopy (31P-MRS) studies, most of them emphasizing migraine with aura (MwA). The aim of this study was to verify potential changes in resting-state brain energy metabolism in patients with migraine without aura (MwoA) compared to control subjects by 31P-MRS at 3 tesla. Methods: Quantification was performed using the phantom replacement technique. MRS measurements were performed interictally and in the medial occipital lobe of 19 MwoA patients and 26 age-matched controls. Results: A significantly decreased phosphocreatine concentration ([PCr]) was found as in previous studies. While adenosine triphosphate concentration ([ATP]) was considered to be constant in previously published work, this study found a significant decrease in the measured [ATP] in MwoA patients. The inorganic phosphate ([Pi]) and magnesium ([Mg2+]) concentrations were not significantly different between MwoA patients and controls. Conclusions: The altered metabolic concentrations indicate that the energy metabolism in MwoA patients is impaired, certainly in a subgroup of patients. The actual decrease in [ATP] adds further strength to the theory of the presence of a mitochondrial component in the pathophysiology of migraine.
Long-Term Assessment of Posterolateral Ligament Femoral-Fibular Reconstruction in Chronic Multiligament Unstable Knees
Authors: Noyes Frank R. , Barber-Westin Sue D. 
Published: February 2011

Background: The authors previously reported the initial results of a femoral-fibular posterolateral reconstruction in which an Achilles tendon allograft was passed through a fibular tunnel adjacent to the anatomical fibular attachment site of the fibular collateral ligament and a femoral tunnel anterior and posterior to its femoral attachment site. Purpose: To compare the short-term results (mean, 3.5 years) to the long-term results (mean, 14 years) of posterolateral femoral-fibular knee ligament reconstructions in regard to restoration of posterolateral knee stability. Study Design: Case series; Level of evidence, 4. Methods: The authors report on 21 patients who underwent a posterolateral femoral-fibular reconstruction after sustaining multiligament ruptures with chronic instability. The results were determined by a comprehensive knee examination, stress radiographs, standing posteroanterior radiographs, knee arthrometer testing, the Cincinnati Knee Rating System, and the International Knee Documentation Committee rating system. Results: In the short-term analysis, the posterolateral reconstruction restored normal or nearly normal lateral joint opening and external tibial rotation according to International Knee Documentation Committee criteria in 16 of 21 patients (76%), whereas the other 5 were deemed early failures. Fourteen of these patients were followed 10.0 to 19.4 years postoperatively. Retention of normal or nearly normal lateral joint opening and external tibial rotation was found, and there were no significant differences between evaluations for symptoms, sports and daily activity functions, overall knee ratings, and knee ligament function. At the long-term follow-up evaluation, 71% had no symptoms with low-impact sports. However, concurrent arthritis affected 14% who had symptoms with sports (but no symptoms with daily activities) and 14% who had symptoms with daily activities. Conclusion: The long-term success rate of the femoral-fibular procedure in restoring posterolateral stability warrants consideration of this procedure, particularly in acute cases or when operative time is prolonged and a more simplified procedure is indicated.
Increased HIV-specific CD8+ T-cell cytotoxic potential in HIV elite controllers is associated with T-bet expression
Authors: Hersperger Adam R. , Martin Jeffrey N. , Shin Lucy Y. , Sheth Prameet M. , Kovacs Colin M. , Cosma Gabriela L. , Makedonas George , Pereyra Florencia , Walker Bruce D. , Kaul Rupert , Deeks Steven G. , Betts Michael R. 
Published: February 2011

Abstract
Recent data suggest that CD8+ T-cell effector activity is an important component in the control of HIV replication in elite controllers (ECs). One critical element of CD8+ T-cell effector function and differentiation is the T-box transcription factor T-bet. In the present study, we assessed T-bet expression, together with the effector proteins perforin, granzyme A (Grz A), granzyme B (Grz B), and granulysin, in HIV-specific CD8+ T cells from ECs (n = 20), chronically infected progressors (CPs; n = 18), and highly active antiretroviral therapy (HAART)–suppressed individuals (n = 19). Compared with the other cohort groups, HIV-specific CD8+ T cells among ECs demonstrated a superior ability to express perforin and Grz B, but with no detectable difference in the levels of Grz A or granulysin. We also observed higher levels of T-bet in HIV-specific CD8+ T cells from ECs, with an ensuing positive correlation between T-bet and levels of both perforin and Grz B. Moreover, HIV-specific CD8+ T cells in ECs up-regulated T-bet to a greater extent than CPs after in vitro expansion, with concomitant up-regulation of perforin and Grz B. These results suggest that T-bet may play an important role in driving effector function, and its modulation may lead to enhanced effector activity against HIV.
Enhancer of Zeste Homolog 2 Overexpression Has a Role in the Development of Anaplastic Thyroid Carcinomas
Authors: Borbone Eleonora , Troncone Giancarlo , Ferraro Angelo , Jasencakova Zuzana , Stojic Lovorka , Esposito Francesco , Hornig Nadine , Fusco Alfredo , Orlando Valerio 
Published: February 2011

Abstract

Context:
Enhancer of zeste homolog 2 (EZH2) is a histone lysine methyltransferase belonging to the polycomb group protein family. Overexpression of EZH2 has been found in several human malignancies including hematological and solid tumors.

Objectives:
In this study we investigated the expression levels of EZH2 and its polycomb group protein partners in thyroid carcinoma tissues with different degrees of malignancy to identify potential new therapeutic targets for anaplastic thyroid carcinoma (ATC).

Results:
We show that high EZH2 expression levels are characteristic of undifferentiated ATC, whereas no significant changes were observed in well-differentiated papillary and follicular thyroid carcinomas as compared with normal thyroid. Knockdown of EZH2 in ATC cell lines results in cell growth inhibition, loss of anchorage-independent growth, migration, and invasion properties. Moreover, we demonstrate that EZH2 directly controls differentiation of ATC cells by silencing the thyroid specific transcription factor paired-box gene 8 (PAX8).

Conclusions:
EZH2 is specifically overexpressed in ATC, and it directly contributes to transcriptional silencing of PAX8 gene and ATC differentiation.
Inhibition of the Ras/Raf/MEK/ERK and RET Kinase Pathways with the Combination of the Multikinase Inhibitor Sorafenib and the Farnesyltransferase Inhibitor Tipifarnib in Medullary and Differentiated Thyroid Malignancies
Authors: Hong David S. , Cabanillas Maria E. , Wheler Jennifer , Naing Aung , Tsimberidou Apostolia M. , Ye Lei , Waguespack Steven G. , Hernandez Mike , El Naggar Alder K. , Bidyasar Savita , Wright John , Sherman Steven I. , Kurzrock Razelle 
Published: February 2011

Abstract

Purpose:
Ras/Raf/MAPK kinase/ERK and rearranged in transformation (RET) kinase pathways are important in thyroid cancer. We tested sorafenib, a B-Raf, RET, and vascular endothelial growth factor receptor kinase inhibitor, combined with tipifarnib, a farnesyltransferase inhibitor that inactivates Ras and other farnesylated proteins.

Patients and Methods:
We treated 35 patients with differentiated thyroid cancer (DTC) and medullary thyroid cancer (MTC) in a phase I trial. Sorafenib and tipifarnib were given for 21 d with 7 d rest in each 28-d cycle.

Results:
We enrolled 22 patients with metastatic DTC (16 papillary, five follicular, and one poorly differentiated) and 13 patients with MTC, of whom 15 with DTC and 10 with MTC reached first restaging. When tissue was available, eight of 15 DTC patients (53%) had B-Raf mutations; eight of 13 MTC (61.5%) patients had RET mutations. MTC partial response rate was 38% (five of 13) (duration = 9+, 12, 13, 16+, and 34+ months), stable disease of at least 6 months was 31% (four of 13). The DTC partial response rate was 4.5% (one of 22), and stable disease of at least 6 months was 36% (eight of 22). Median progression-free survival for all 35 patients was 18 months (95% confidence interval, 14.6 to not reached months). Median overall survival has not been reached, with a median follow-up of 24 months with 80% overall survival. Grade 1–2 toxicities were mainly rash, fatigue, and diarrhea. The most common grade 3–4 toxicities were rash, rise in amylase/lipase, and fatigue.

Conclusions:
Inhibiting the Ras/Raf/MAPK kinase/ERK and RET kinase pathways with sorafenib and tipifarnib is well tolerated and active against thyroid cancer.
1,25-Dihydroxyvitamin D3 Reduces TGF-β3-Induced Fibrosis-Related Gene Expression in Human Uterine Leiomyoma Cells
Authors: Halder Sunil K. , Goodwin J. Shawn , Al-Hendy Ayman 
Published: February 2011

Abstract

Background:
Uterine leiomyomas (fibroids) are the most common benign estrogen-dependent tumors of premenopausal women. TGF-β3 up-regulates the synthesis of many of extracellular matrix proteins that are associated with tissue fibrosis.

Objective:
To examine the effect of 1,25-dihydroxyvitamin D3 (vitamin D3) on TGF-β3-induced fibrosis-related protein expression in immortalized human uterine leiomyoma (HuLM) cells.

Methods:
HuLM cells were treated with TGF-β3 with or without vitamin D3. Western blot analyses were employed to test the effect of vitamin D3 on TGF-β3-induced protein expression of collagen type 1, fibronectin, and plasminogen activator inhibitor-1 proteins. Western blots as well as immunofluorescence analyses were used to verify the effect of vitamin D3 on TGF-β3-induced Smad activation involved in extracellular matrix protein synthesis and deposition, which ultimately lead to tissue fibrosis.

Results:
We observed that TGF-β3 induced fibronectin and collagen type 1 protein expression in HuLM cells, and that effect was suppressed by vitamin D3. TGF-β3 also induced protein expression of plasminogen activator inhibitor-1, an important TGF-β target, in HuLM cells, which was also inhibited by vitamin D3. Additionally, TGF-β3 induced phosphorylation of Smad2 as well as nuclear translocation of Smad2 and Smad3 in HuLM cells, whereas vitamin D significantly reduced all these TGF-β3-mediated effects. Therefore, our results suggest that vitamin D3 has consistently reduced TGF-β3 effects that are involved in the process of fibrosis in human leiomyoma cells.

Conclusion:
Vitamin D3 is an antifibrotic factor that might be potentially useful as a novel therapeutic for nonsurgical treatment of benign uterine fibroids.
Limited Value of Ovarian Function Markers following Orthotopic Transplantation of Ovarian Tissue after Gonadotoxic Treatment
Authors: Janse Femi , Donnez Jacques , Anckaert Ellen , de Jong Frank H. , Fauser Bart C. J. M. , Dolmans Marie-Madeleine 
Published: February 2011

Abstract

Context:
In young women, some treatments for cancer or other conditions (such as sickle cell anemia) may give rise to primary ovarian insufficiency. Ovarian transplantation is one of the available options for fertility preservation, with highly variable pregnancy rates.

Objective:
The objective of the study was to investigate markers of ovarian reserve and ovarian function in women up to 7 yr after orthotopic ovarian transplantation. Secondary objectives were to assess the relationship between markers of ovarian reserve and pregnancy rate along with the duration of ovarian function.

Design:
This was a prospective cohort study in 10 women, with a mean follow-up of 2.5 yr.

Setting:
The study was conducted at a university hospital in Brussels, Belgium.

Patients:
Patients included 10 women who were about to receive or had previously received gonadotoxic treatment. In seven women cryopreservation of ovarian tissue was performed before starting treatment. Subsequently autografts were orthotopically transplanted in these women. Three women, who had already developed primary ovarian insufficiency due to treatment, underwent orthotopic transplantation of ovarian allograft tissue originating from their human leukocyte antigen-compatible sisters.

Main Outcome Measures:
Serum concentrations of FSH, LH, estradiol, inhibin B, and anti-Müllerian hormone (AMH) were measured.

Results:
On average, first menses took place after 4.7 months. Duration of graft functioning varied from 2 to more than 60 months. FSH concentrations remained elevated, whereas estradiol levels normalized and AMH was low to undetectable. Inhibin B varied among women and was not associated with the duration of ovarian function (hazard ratio 0.966, 95% confidence interval 0.881–1.059). Two spontaneous pregnancies occurred. Endocrine characteristics were not significantly different in these women.

Conclusions:
Low AMH and inhibin B concentrations may suggest decreased ovarian reserve in women after ovarian transplantation. AMH and inhibin B levels may not be associated with the duration of ovarian graft function or probability to achieve a pregnancy.