bluuebunny/crossref_metadata_2025_split huggingface dataset:
hTERT Inhibition Triggers Epstein–Barr Virus Lytic Cycle and Apoptosis in Immortalized and Transformed B Cells: A Basis for New Therapies
Authors: Giunco Silvia , Dolcetti Riccardo , Keppel Sonia , Celeghin Andrea , Indraccolo Stefano , Dal Col Jessica , Mastorci Katy , De Rossi Anita 
Published: February 2013

Abstract
Purpose: Induction of viral lytic cycle, which induces death of host cells, may constitute a useful adjunct to current therapeutic regimens for Epstein–Barr virus (EBV)-driven malignancies. Human telomerase reverse transcriptase (hTERT), essential for the oncogenic process, may modulate the switch from latent to lytic infection. The possible therapeutic role of hTERT inhibition combined with antiviral drugs was investigated.
Experimental Design: EBV-negative BL41 and convertant EBV-positive BL41/B95.8 Burkitt's lymphoma cell lines and lymphoblastoid cell lines (LCL) were infected with retroviral vector encoding short hairpin RNA (shRNA) anti-hTERT and cultured with or without the prodrug ganciclovir. The effects on EBV lytic replication, cell proliferation, and apoptosis were characterized.
Results: hTERT silencing by shRNA induced the expression of BZLF1, EA-D, and gp350 EBV lytic proteins and triggered a complete lytic cycle. This effect was associated with downregulation of BATF, a negative regulator of BZLF1 transcription. hTERT silencing also resulted in antiproliferative and proapoptotic effects. In particular, hTERT inhibition induced an accumulation of cells in the S-phase, an effect likely due to the dephosphorylation of 4E-BP1, an AKT1-dependent substrate, which results in a decreased availability of proteins needed for cell-cycle progression. Besides inducing cell death through activation of complete EBV lytic replication, hTERT inhibition triggered AKT1/FOXO3/NOXA–dependent apoptosis in EBV-positive and -negative Burkitt's lymphoma cells. Finally, ganciclovir enhanced the apoptotic effect induced by hTERT inhibition in EBV-positive Burkitt's lymphomas and LCLs.
Conclusions: These results suggest that combination of antiviral drugs with strategies able to inhibit hTERT expression may result in therapeutically relevant effects in patients with EBV-related malignancies. Clin Cancer Res; 19(8); 2036–47. ©2013 AACR.
Efficacy and Safety of Retreatment with Ipilimumab in Patients with Pretreated Advanced Melanoma Who Progressed after Initially Achieving Disease Control
Authors: Robert Caroline , Schadendorf Dirk , Messina Marianne , Hodi F. Stephen , O'Day Steven 
Published: February 2013

Abstract
Purpose: Ipilimumab is a fully human monoclonal antibody against cytotoxic T-lymphocyte–associated antigen-4 (CTLA-4) that has been shown to improve survival in patients with pretreated, advanced melanoma in a phase III trial. Some patients in this study who initially responded to ipilimumab treatment but later progressed were eligible for retreatment with their original randomized regimen. Here, outcomes for these patients concerning baseline characteristics, best overall response, and disease control rate are assessed and considered with respect to the overall study population.
Experimental Design: In the phase III study, 676 pretreated patients were randomly allocated to treatment with ipilimumab 3 mg/kg plus gp100 vaccine, ipilimumab 3 mg/kg plus placebo, or gp100 vaccine alone. Of these patients, 32 had a partial or complete objective response or stable disease after treatment and met the eligibility criteria for retreatment, although a total of 40 patients were retreated.
Results: Best overall response rates (complete responses plus partial responses) for 31 retreatment-eligible patients in the ipilimumab plus gp100 and ipilimumab plus placebo groups were 3 of 23 (13.0%) and 3 of 8 (37.5%), respectively, and disease control rates were 65.2% and 75.0%. No new types of toxicities occurred during retreatment and most events were mild-to-moderate.
Conclusion: Ipilimumab provided durable objective responses and/or stable disease in qualifying patients who received retreatment upon disease progression with a similar toxicity profile to that seen during their original treatment regimen. Clin Cancer Res; 19(8); 2232–9. ©2013 AACR.
Clinical Significance of CD33 Nonsynonymous Single-Nucleotide Polymorphisms in Pediatric Patients with Acute Myeloid Leukemia Treated with Gemtuzumab-Ozogamicin–Containing Chemotherapy
Authors: Mortland Leslie , Alonzo Todd A. , Walter Roland B. , Gerbing Robert B. , Mitra Amit K. , Pollard Jessica A. , Loken Michael R. , Hirsch Betsy , Raimondi Susana , Franklin Janet , Pounds Stanley , Cao Xueyuan , Rubnitz Jeffrey E. , Ribeiro Raul C. , Gamis Alan , Meshinchi Soheil , Lamba Jatinder K. 
Published: February 2013

Abstract
Purpose: The purpose of this study was to evaluate clinical implications of CD33 single-nucleotide polymorphisms (SNP) in pediatric patients with acute myeloid leukemia (AML) treated with gemtuzumab-ozogamicin (GO)–based therapy.
Experimental Design: We genotyped four CD33 SNPs: rs35112940 (G&gt;A; Arg304Gly), rs12459419 (C&gt;T; Ala14Val), rs2455069 (A&gt;G; Arg69Gly), and rs1803254 (G&gt;C; 3′UTR) in pediatric patients undergoing induction chemotherapy containing GO (COG-AAML03P1 trial; n = 242) or not containing GO (St. Jude AML02 trial; n = 172).
Results: CD33 SNPs were correlated significantly with clinical characteristics and treatment outcome. The coding SNPs, rs35112940 and rs12459419, were significantly associated with clinical endpoints in COG-AAML03P1 but not in the St. Jude AML02 trial. Specifically, among white patients in COG-AAML03P1, the 3-year overall survival (OS) rate from remission was 84% ± 8% for those homozygous (GG) for rs35112940 versus 68% ± 15% for the other genotypes (P = 0.018); these patients also had a lower relapse risk and superior disease-free survival. Likewise, patients homozygous for variant allele (TT) for rs12459419 were more likely to have favorable risk disease than CC and CT genotypes (52% vs. 31%, P = 0.034) and significantly lower diagnostic blast CD33 expression than other genotypes (P &lt; 0.001).
Conclusion: Our data suggest that genetic variations in CD33 could impact clinical outcome of GO-based therapy in pediatric AMLs. Clin Cancer Res; 19(6); 1620–7. ©2013 AACR.
Sorafenib or Placebo with Either Gemcitabine or Capecitabine in Patients with HER-2–Negative Advanced Breast Cancer That Progressed during or after Bevacizumab
Authors: Schwartzberg Lee S. , Tauer Kurt W. , Hermann Robert C. , Makari-Judson Grace , Isaacs Claudine , Beck J. Thaddeus , Kaklamani Virginia , Stepanski Edward J. , Rugo Hope S. , Wang Wei , Bell-McGuinn Katherine , Kirshner Jeffrey J. , Eisenberg Peter , Emanuelson Richard , Keaton Mark , Levine Ellis , Medgyesy Diana C. , Qamar Rubina , Starr Alexander , Ro Sunhee Kwon , Lokker Nathalie A. , Hudis Clifford A. 
Published: February 2013

Abstract
Purpose: We assessed adding the multikinase inhibitor sorafenib to gemcitabine or capecitabine in patients with advanced breast cancer whose disease progressed during/after bevacizumab.
Experimental Design: This double-blind, randomized, placebo-controlled phase IIb study (ClinicalTrials.gov NCT00493636) enrolled patients with locally advanced or metastatic human epidermal growth factor receptor 2 (HER2)–negative breast cancer and prior bevacizumab treatment. Patients were randomized to chemotherapy with sorafenib (400 mg, twice daily) or matching placebo. Initially, chemotherapy was gemcitabine (1,000 mg/m2 i.v., days 1, 8/21), but later, capecitabine (1,000 mg/m2 orally twice daily, days 1–14/21) was allowed as an alternative. The primary endpoint was progression-free survival (PFS).
Results: One hundred and sixty patients were randomized. More patients received gemcitabine (82.5%) than capecitabine (17.5%). Sorafenib plus gemcitabine/capecitabine was associated with a statistically significant prolongation in PFS versus placebo plus gemcitabine/capecitabine [3.4 vs. 2.7 months; HR = 0.65; 95% confidence interval (CI): 0.45–0.95; P = 0.02], time to progression was increased (median, 3.6 vs. 2.7 months; HR = 0.64; 95% CI: 0.44–0.93; P = 0.02), and overall response rate was 19.8% versus 12.7% (P = 0.23). Median survival was 13.4 versus 11.4 months for sorafenib versus placebo (HR = 1.01; 95% CI: 0.71−1.44; P = 0.95). Addition of sorafenib versus placebo increased grade 3/4 hand–foot skin reaction (39% vs. 5%), stomatitis (10% vs. 0%), fatigue (18% vs. 9%), and dose reductions that were more frequent (51.9% vs. 7.8%).
Conclusion: The addition of sorafenib to gemcitabine/capecitabine provided a clinically small but statistically significant PFS benefit in HER2-negative advanced breast cancer patients whose disease progressed during/after bevacizumab. Combination treatment was associated with manageable toxicities but frequently required dose reductions. Clin Cancer Res; 19(10); 2745–54. ©2013 AACR.
Copy Number Aberrations of Genes Regulating Normal Thymus Development in Thymic Epithelial Tumors
Authors: Petrini Iacopo , Wang Yisong , Zucali Paolo A. , Lee Hye Seung , Pham Trung , Voeller Donna , Meltzer Paul S. , Giaccone Giuseppe 
Published: February 2013

Abstract
Purposes: To determine whether the deregulation of genes relevant for normal thymus development can contribute to the biology of thymic epithelial tumors (TET).
Experimental Design: Using array comparative genomic hybridization, we evaluated the copy number aberrations of genes regulating thymus development. The expression of genes most commonly involved in copy number aberrations was evaluated by immunohistochemistry and correlated with patients' outcome. Correlation between FOXC1 copy number loss and gene expression was determined in a confirmation cohort. Cell lines were used to test the role of FOXC1 in tumors.
Results: Among 31 thymus development-related genes, PBX1 copy number gain and FOXC1 copy number loss were presented in 43.0% and 39.5% of the tumors, respectively. Immunohistochemistry on a series of 132 TETs, including those evaluated by comparative genomic hybridization, revealed a correlation between protein expression and copy number status only for FOXC1 but not for PBX1. Patients with FOXC1-negative tumors had a shorter time to progression and a trend for a shorter disease-related survival. The correlation between FOXC1 copy number loss and mRNA expression was confirmed in a separate cohort of 27 TETs. Ectopic FOXC1 expression attenuated anchorage-independent cell growth and cell migration in vitro.
Conclusion: Our data support a tumor suppressor role of FOXC1 in TETs. Clin Cancer Res; 19(8); 1960–71. ©2013 AACR.
Noninvasive Localization of Maximal Frequency Sites of Atrial Fibrillation by Body Surface Potential Mapping
Authors: Guillem Maria S. , Climent Andreu M. , Millet Jose , Arenal Ángel , Fernández-Avilés Francisco , Jalife José , Atienza Felipe , Berenfeld Omer 
Published: February 2013

Background—
Ablation of high-frequency sources in patients with atrial fibrillation (AF) is an effective therapy to restore sinus rhythm. However, this strategy may be ineffective in patients without a significant dominant frequency (DF) gradient. The aim of this study was to investigate whether sites with high-frequency activity in human AF can be identified noninvasively, which should help intervention planning and therapy.

Methods and Results—
In 14 patients with a history of AF, 67-lead body surface recordings were simultaneously registered with 15 endocardial electrograms from both atria including the highest DF site, which was predetermined by atrial-wide real-time frequency electroanatomical mapping. Power spectra of surface leads and the body surface location of the highest DF site were compared with intracardiac information. Highest DFs found on specific sites of the torso showed a significant correlation with DFs found in the nearest atrium (ρ=0.96 for right atrium and ρ=0.92 for left atrium) and the DF gradient between them (ρ=0.93). The spatial distribution of power on the surface showed an inverse relationship between the frequencies versus the power spread area, consistent with localized fast sources as the AF mechanism with fibrillatory conduction elsewhere.

Conclusions—
Spectral analysis of body surface recordings during AF allows a noninvasive characterization of the global distribution of the atrial DFs and the identification of the atrium with the highest frequency, opening the possibility for improved noninvasive personalized diagnosis and treatment.
Association of Hypertension With Stroke Recurrence Depends on Ischemic Stroke Subtype
Authors: Wang Yilong , Xu Jie , Zhao Xingquan , Wang David , Wang Chunxue , Liu Liping , Wang Anxin , Meng Xia , Li Hao , Wang Yongjun 
Published: February 2013

Background and Purpose—
The association between hypertension (HTN) and stroke recurrence is unclear, but may be influenced by different subtypes of stroke. This study aims to explore whether HTN contributes to the recurrence of certain subtypes of ischemic stroke (IS).

Methods—
Data from the China National Stroke Registry was examined and 1-year follow-up data for stroke recurrence was analyzed. Trial of Org 10172 in Acute Stroke Treatment criteria was used to classify the subtypes of all IS. HTN was defined when resting blood pressure was ≥140/90 mm Hg on repeated measurements during hospitalization or a patient had been on antihypertensive medication. Recurrent stroke was defined as a new neurological deficit compatible to IS or intracerebral hemorrhage. The association between HTN and stroke recurrence in patients with different IS subtypes was analyzed by using univariable and multivariable logistic regression models.

Results—

Of 11 560 patients with IS, 8409 (72.7%) had HTN and 2050 (17.7%) experienced a recurrent stroke within 1 year. Patients with HTN had an insignificantly higher stroke recurrence rate than those without (18.0% versus 17.0%;
P
=0.21). After stratification by Trial of Org 10172 in Acute Stroke Treatment subtypes, multivariable analysis revealed a significant association between HTN and stroke recurrence in small-artery occlusion subtype (odds ratio, 1.52; 95% confidence interval, 1.03–2.31), but not in the other subtypes (large-artery atherosclerosis: odds ratio, 0.99; 95% confidence interval, 0.81–1.21; cardioembolic: odds ratio, 1.14; 95% confidence interval, 0.75–1.73; other: odds ratio, 0.88; 95% confidence interval, 0.71–1.09).

Conclusions—
Our results showed that HTN is specifically related to the recurrent strokes in patients with small-vessel diseases, not other subtypes of IS.
Spot Sign Number Is the Most Important Spot Sign Characteristic for Predicting Hematoma Expansion Using First-Pass Computed Tomography Angiography
Authors: Huynh Thien J. , Demchuk Andrew M. , Dowlatshahi Dar , Gladstone David J. , Krischek Özlem , Kiss Alex , Hill Michael D. , Molina Carlos A. , Rodriguez-Luna David , Dzialowski Imanuel , Silva Yolanda , Czlonkowska Anna , Lum Cheemun , Boulanger Jean-Martin , Gubitz Gord , Bhatia Rohit , Padma Vasantha , Roy Jayanta , Kase Carlos S. , Aviv Richard I. 
Published: February 2013

Background and Purpose—
The spot sign score (SSS) provides risk stratification for hematoma expansion in acute intracerebral hemorrhage; however, external validation is needed. We sought to validate the SSS and assess prognostic performance of individual spot characteristics associated with hematoma expansion from a prospective multicenter intracerebral hemorrhage study.

Methods—
Two hundred twenty-eight intracerebral hemorrhage patients within 6 hours after ictus were enrolled in the Predicting Hematoma Growth and Outcome in Intracerebral Hemorrhage Using Contrast Bolus CT (PREDICT) study, a multicenter prospective intracerebral hemorrhage cohort study. Patients were evaluated with baseline noncontrast computerized tomography, computerized tomography angiography, and 24-hour follow-up computerized tomography. Primary outcome was significant hematoma expansion (>6 mL or >33%) and secondary outcome was absolute and relative expansion. Blinded computerized tomography angiography spot sign characterization and SSS calculation were independently performed by 2 neuroradiologists and a radiology resident. Diagnostic performance of the SSS and individual spot characteristics were examined with multivariable regression, receiver operating characteristic analysis, and tests for trend.

Results—

SSS and spot number independently predicted significant, absolute, and relative hematoma expansion (
P
<0.05 each) and demonstrated near perfect interobserver agreement (κ=0.82 and κ=0.85, respectively). Incremental risk of hematoma expansion among spot-positive patients was not identified for SSS (
P
trend=0.720) but was demonstrated for spot number (
P
trend=0.050). Spot number and SSS demonstrated similar area under the curve (0.69 versus 0.68;
P
=0.306) for hematoma expansion.

Conclusions—
Multicenter external validation of the SSS demonstrates that the spot number alone provides similar prediction but improved risk stratification of hematoma expansion compared with the SSS.
Cognitive Decline After Stroke
Authors: Kliper Efrat , Bashat Dafna Ben , Bornstein Natan M. , Shenhar-Tsarfaty Shani , Hallevi Hen , Auriel Eitan , Shopin Ludmila , Bloch Sivan , Berliner Shlomo , Giladi Nir , Goldbourt Uri , Shapira Itzhak , Korczyn Amos D. , Assayag Einor Ben 
Published: February 2013

Background and Purpose—
Inflammation may contribute to cognitive impairment after stroke. Inflammatory markers are associated with hippocampal atrophy. We tested whether markers of inflammation, erythrocyte sedimentation rate (ESR), and serum levels of C-reactive protein are associated with reduced hippocampal volume and poor cognitive performance among stroke survivors.

Methods—
We analyzed 368 consecutive cases from our prospective study of first-ever mild–moderate stroke patients. MRI, cognitive tests, and inflammatory markers were determined. Patients were reevaluated 6 and 12 months after the event.

Results—

ESR remained unchanged in follow-up examinations, suggesting a chronic inflammation background in some patients. Higher levels of C-reactive protein and ESR were associated with worse performance in cognitive tests, particularly memory scores. This association was maintained for ESR (but not C-reactive protein) after adjustment for confounders (
P
=0.002). Patients with smaller hippocampi had inferior cognitive results. Moreover, in a multivariate regression model, higher ESR values (but not C-reactive protein) were related to reduced hippocampal volume (
P
=0.049).

Conclusions—
This report shows a strong relationship between ESR and hippocampal volume, as well as with cognitive performance among poststroke patients. This could plausibly relate to incipient cognitive decline via hippocampal pathways.
Culture Re-introduced: Contestation of Human Rights in Contemporary Russia
Authors: Preclik Petr 
Published: February 2013

AbstractThis article explores the current human-rights discourse in the Russian Federation through its relationship with the Council of Europe, the strongest human-rights regime that Russia has signed up for. Against the background of current international-relations theories, the article argues that human-rights scholarship should re-introduce the concept of culture into its research designs in order to be able to explain the interaction between cultural groupings and globally dominant discourses, such as human rights. The article further argues that human rights ought to be conceptualized as symbolic technologies and studied as discursive variables that enter the cycle of national-identity formation. To that end, I use the contestation thesis proposed by Andrei Tsygankov. The article concludes that Russia is currently actively securing itself against the dominant and universal human-rights discourse, which is perceived as hindering independent societal development in Russia. This state of securization is illustrated in the current debates within PACE on topics connected with human rights and Russia.
Tilting at Windmills? The European Response to Violations of Media Freedom in Russia
Authors: Schönfeld Dorothea 
Published: February 2013

AbstractThis article is a study about the measures that European organizations take in response to violations of media freedom in Russia. Despite vigorous efforts, the media situation has not improved considerably. What are the reasons for the apparent inefficiency of the European enforcement mechanism? To overcome the tangle of sometimes contradictory historical, sociological, philosophical, and mere pragmatic explanations, one has to distinguish obstacles at the conceptual level from obstacles at the level of implementation. I will argue that insistence on a specific Russian mentality and another idea of freedom of expression in the Russian context is a mere rhetorical trick of the ruling political forces to hide the lack of democratic commitment in Russia and to avoid criticism from the West. Whereas these 'ideological' reasons—or, at least, their historical necessity—can be rejected, 'practical' reasons for the small impact of European measures cannot be denied. When exclusively addressing those responsible in the Russian government, European organizations underestimate not only reluctance by the Russian authorities but also the complexity of the whole situation. Without a change of journalistic behavior and some institutions closely connected with the work of journalists—and, most notably, a comprehensive alteration of public opinion—it is improbable that the situation of the media will change in the future.
Orthodox Pluralism: Contours of Freedom of Religion in the Russian Federation and Strasbourg Jurisprudence
Authors: Hallinan Dara 
Published: February 2013

AbstractThis article takes as its principal question whether the Russian protection of freedom of religion in law and practice is compatible with the model created by Strasbourg jurisprudence. Considering freedom of religion as a keystone of the Strasbourg model of democracy and in light of increasing concern and uncertainty at democratic progress in the Russian Federation, the article attempts to isolate the realities of the situation in relation to this unique right. It considers both systems in law and their operation in a broader social context and finally considers issues of compatibility between them. In its conclusion, the author argues that, although the Russian Federation's legal framework establishes a similar model of protection to that of Strasbourg, this framework has been manipulated and diminished in importance by, and because of, extralegal relationships (particularly between the state and the Russian Orthodox Church) to the point where it is impossible to say that the systems are compatible. Further, the author suggests that the fact that these extralegal relationships can play such a role shows deep fissures in the rule of law in this area. This is indicative of wider problems relating to domestic rule of law generally and is therefore indicative of problems relating to foundational democratic principles.
Islamic Law in a Plural Context:The Struggle over Inheritance Law in Colonial West Sumatra
Authors: von Benda-Beckmann Franz , von Benda-Beckmann Keebet 
Published: February 2013

Abstract
The paper deals with the historical dynamics of the struggle over inheritance law in West Sumatra under the colonial rule of the Dutch Indies. The Minangkabau in West Sumatra are an interesting example of legal pluralism in Muslim societies. Their adat (indigenous law and social organisation) of matrilineal heritage regulated kinship, group affiliation, inheritance of property, and succession to office. Since the sixteenth century they have been devout Muslims. Their history is characterised by dynamic transformations of the relationship between adat and Islam, and—since their incorporation into the colony of the Dutch East Indies in the early nineteenth century—with the state. The paper shows how these conflicts and negotiations produced different results in different arenas. The agreements reached in the political arena were usually different from the use of law in the decision-making processes of village and state courts, as were the actual practices of villagers in everyday property and inheritance affairs.