bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chromatin Remodeling Underlies the Senescence-Associated Secretory Phenotype of Tumor Stromal Fibroblasts That Supports Cancer Progression
Authors: Pazolli Ermira , Alspach Elise , Milczarek Agnieszka , Prior Julie , Piwnica-Worms David , Stewart Sheila A. 
Published: March 2012

Abstract
Age is a major risk factor for the development of cancer. Senescent fibroblasts, which accumulate with age, secrete protumorigenic factors collectively referred to as the senescence-associated secretory phenotype (SASP). Here, we examined the molecular mechanisms that control SASP activation, focusing on the known SASP factor osteopontin (OPN). We found that expression of the canonical SASP members interleukin (IL)-6 and IL-8, but not OPN, were dependent upon a persistent DNA damage response (DDR) as evidenced by ATM and NF-κB activation. Treatment with several histone deacetylase (HDAC) inhibitors robustly activated SASP in the absence of DNA breaks, suggesting that DDR-dependent SASP activation occurs in response to chromatin remodeling rather than physical breaks in DNA. In the setting of HDAC inhibition, IL-6 and IL-8 expression remained dependent upon ATM and NF-κB, while OPN expression remained independent of these factors. Further analysis revealed that HDAC1 inhibition was sufficient to induce OPN expression, which is interesting given that loss of HDAC1 expression correlates with increased OPN expression within the stromal compartment of invasive breast cancers. Importantly, fibroblasts treated with HDAC inhibitors promoted tumor growth in vivo. Our findings therefore indicate that HDAC modulation plays an important role in stromal cell activation, with important implications for the use of HDAC inhibitors in the treatment of cancer. Cancer Res; 72(9); 2251–61. ©2012 AACR.
Reconsidering the Paradigm of Cancer Immunotherapy by Computationally Aided Real-time Personalization
Authors: Kogan Yuri , Halevi–Tobias Karin , Elishmereni Moran , Vuk-Pavlović Stanimir , Agur Zvia 
Published: March 2012

Abstract
Although therapeutic vaccination often induces markers of tumor-specific immunity, therapeutic responses remain rare. An improved understanding of patient-specific dynamic interactions of immunity and tumor progression, combined with personalized application of immune therapeutics would increase the efficacy of immunotherapy. Here, we developed a method to predict and enhance the individual response to immunotherapy by using personalized mathematical models, constructed in the early phase of treatment. Our approach includes an iterative real-time in-treatment evaluation of patient-specific parameters from the accruing clinical data, construction of personalized models and their validation, model-based simulation of subsequent response to ongoing therapy, and suggestion of potentially more effective patient-specific modified treatment. Using a mathematical model of prostate cancer immunotherapy, we applied our model to data obtained in a clinical investigation of an allogeneic whole-cell therapeutic prostate cancer vaccine. Personalized models for the patients who responded to treatment were derived and validated by data collected before treatment and during its early phase. Simulations, based on personalized models, suggested that an increase in vaccine dose and administration frequency would stabilize the disease in most patients. Together, our findings suggest that application of our method could facilitate development of a new paradigm for studies of in-treatment personalization of the immune agent administration regimens (P-trials), with treatment modifications restricted to an approved range, resulting in more efficacious immunotherapies. Cancer Res; 72(9); 2218–27. ©2012 AACR.
Detection of Tumor PIK3CA Status in Metastatic Breast Cancer Using Peripheral Blood
Authors: Higgins Michaela J. , Jelovac Danijela , Barnathan Evan , Blair Brian , Slater Shannon , Powers Penny , Zorzi Jane , Jeter Stacie C. , Oliver George R. , Fetting John , Emens Leisha , Riley Carol , Stearns Vered , Diehl Frank , Angenendt Philipp , Huang Peng , Cope Leslie , Argani Pedram , Murphy Kathleen M. , Bachman Kurtis E. , Greshock Joel , Wolff Antonio C. , Park Ben H. 
Published: March 2012

Abstract
Purpose: We sought to evaluate the feasibility of detecting PIK3CA mutations in circulating tumor DNA (ctDNA) from plasma of patients with metastatic breast cancer using a novel technique called BEAMing.
Experimental Design: In a retrospective analysis, 49 tumor and temporally matched plasma samples from patients with breast cancer were screened for PIK3CA mutations by BEAMing. We then prospectively screened the ctDNA of 60 patients with metastatic breast cancer for PIK3CA mutations by BEAMing and compared the findings with results obtained by screening corresponding archival tumor tissue DNA using both sequencing and BEAMing.
Results: The overall frequency of PIK3CA mutations by BEAMing was similar in both patient cohorts (29% and 28.3%, respectively). In the retrospective cohort, the concordance of PIK3CA mutation status by BEAMing between formalin-fixed, paraffin-embedded (FFPE) samples and ctDNA from temporally matched plasma was 100% (34 of 34). In the prospective cohort, the concordance rate among 51 evaluable cases was 72.5% between BEAMing of ctDNA and sequencing of archival tumor tissue DNA. When the same archival tissue DNA was screened by both sequencing and BEAMing for PIK3CA mutations (n = 41 tissue samples), there was 100% concordance in the obtained results.
Conclusions: Analysis of plasma-derived ctDNA for the detection of PIK3CA mutations in patients with metastatic breast cancer is feasible. Our results suggest that PIK3CA mutational status can change upon disease recurrence, emphasizing the importance of reassessing PIK3CA status on contemporary (not archival) biospecimens. These results have implications for the development of predictive biomarkers of response to targeted therapies. Clin Cancer Res; 18(12); 3462–9. ©2012 AACR.
Twenty-Two–Year Trends in Incidence of Myocardial Infarction, Coronary Heart Disease Mortality, and Case Fatality in 4 US Communities, 1987–2008
Authors: Rosamond Wayne D. , Chambless Lloyd E. , Heiss Gerardo , Mosley Thomas H. , Coresh Josef , Whitsel Eric , Wagenknecht Lynne , Ni Hanyu , Folsom Aaron R. 
Published: March 2012

Background—
Knowledge of trends in the incidence of and survival after myocardial infarction (MI) in a community setting is important to understanding trends in coronary heart disease (CHD) mortality rates.

Methods and Results—
We estimated race- and gender-specific trends in the incidence of hospitalized MI, case fatality, and CHD mortality from community-wide surveillance and validation of hospital discharges and of in- and out-of-hospital deaths among 35- to 74-year-old residents of 4 communities in the Atherosclerosis Risk in Communities (ARIC) Study. Biomarker adjustment accounted for change from reliance on cardiac enzymes to widespread use of troponin measurements over time. During 1987–2008, a total of 30 985 fatal or nonfatal hospitalized acute MI events occurred. Rates of CHD death among persons without a history of MI fell an average 4.7%/y among men and 4.3%/y among women. Rates of both in- and out-of-hospital CHD death declined significantly throughout the period. Age- and biomarker-adjusted average annual rate of incident MI decreased 4.3% among white men, 3.8% among white women, 3.4% among black women, and 1.5% among black men. Declines in CHD mortality and MI incidence were greater in the second decade (1997–2008). Failure to account for biomarker shift would have masked declines in incidence, particularly among blacks. Age-adjusted 28-day case fatality after hospitalized MI declined 3.5%/y among white men, 3.6%/y among black men, 3.0%/y among white women, and 2.6%/y among black women.

Conclusions—
Although these findings from 4 communities may not be directly generalizable to blacks and whites in the entire United States, we observed significant declines in MI incidence, primarily as a result of downward trends in rates between 1997 and 2008.
Infarct Volume Is a Pivotal Biomarker After Intra-Arterial Stroke Therapy
Authors: Yoo Albert J. , Chaudhry Zeshan A. , Nogueira Raul G. , Lev Michael H. , Schaefer Pamela W. , Schwamm Lee H. , Hirsch Joshua A. , González R. Gilberto 
Published: March 2012

Background and Purpose—
Pretreatment infarct volume appears to predict clinical outcome after intra-arterial therapy. To confirm the importance of infarct size in patients undergoing intra-arterial therapy, we sought to characterize the relationship between final infarct volume (FIV) and long-term functional outcome in a prospective cohort of endovascularly treated patients.

Methods—
From our prospective intra-arterial therapy database, we identified 107 patients with acute ischemic stroke with anterior circulation proximal artery occlusions who underwent final infarct imaging and had 3-month modified Rankin Scale scores. Clinical, imaging, treatment, and outcome data were analyzed.

Results—

Mean age was 66.6 years. Median admission National Institutes of Health Stroke Scale score was 17. Reperfusion (Thrombolysis In Cerebral Infarction 2A–3) was achieved in 78 (72.9%) patients. Twenty-seven (25.2%) patients achieved a 3-month good outcome (modified Rankin Scale 0–2), and 30 (28.0%) died. Median FIV was 71.4 cm
3
. FIV independently correlated with functional outcome across the entire modified Rankin Scale. In receiver operating characteristic analysis, it was the best discriminator of both good outcome (area under the curve=0.857) and mortality (area under the curve=0.772). A FIV of approximately 50 cm
3
demonstrated the greatest accuracy for distinguishing good versus poor outcome, and a FIV of approximately 90 cm
3
was highly specific for a poor outcome. The interaction term between FIV and age was the only independent predictor of good outcome (
P
<0.0001). The impact of FIV was accentuated in patients <80 years.

Conclusions—
Among patients with anterior circulation acute ischemic stroke who undergo intra-arterial therapy, final infarct volume is a critical determinant of 3-month functional outcome and appears suitable as a surrogate biomarker in proof-of-concept intra-arterial therapy trials.
Contemporary Outcome Measures in Acute Stroke Research
Authors: Lees Kennedy R. , Bath Philip M.W. , Schellinger Peter D. , Kerr Daniel M. , Fulton Rachael , Hacke Werner , Matchar David , Sehra Ruchir , Toni Danilo 
Published: March 2012

Background and Purpose—
The diversity of available outcome measures for acute stroke trials is challenging and implies that the scales may be imperfect. To assist researchers planning trials and to aid interpretation, this article reviews and makes recommendations on the available choices of scales. The aim is to identify an approach that will be universally accepted and that should be included in most acute trials, without seeking to restrict options for special circumstances.

Methods—
The article considers outcome measures that have been widely used or are currently advised. It examines desirable properties for outcome measures such as validity, relevance, responsiveness, statistical properties, availability of training, cultural and language issues, resistance to comorbidity, as well as potential weaknesses. Tracking and agreement among outcomes are covered.

Results—
Typical ranges of scores for the common scales are described, along with their statistical properties, which in turn influence optimal analytic techniques. The timing of recovery on scores and usual practice in trial design are considered.

Conclusions—
The preferred outcome measure for acute trials is the modified Rankin Scale, assessed at 3 months after stroke onset or later. The interview should be conducted by a certified rater and should involve both the patient and any relevant caregiver. Incremental benefits at any level of the modified Rankin Scale may be acceptable. The modified Rankin Scale is imperfect but should be retained in its present form for comparability with existing treatment comparisons. No second measure should be required, but correlations with supporting scales may be used to confirm consistency in direction of effects on other measures.
Factors Influencing In-Hospital Delay in Treatment With Intravenous Thrombolysis
Authors: Mikulík Robert , Kadlecová Pavla , Czlonkowska Anna , Kobayashi Adam , Brozman Miroslav , Švigelj Viktor , Csiba Laszlo , Fekete Klara , Kõrv Janika , Demarin Vida , Vilionskis Aleksandras , Jatuzis Dalius , Krespi Yakup , Ahmed Niaz 
Published: March 2012

Background and Purpose—
Shortening door-to-needle time (DNT) for the thrombolytic treatment of stroke can improve treatment efficacy by reducing onset-to-treatment time. The goal of our study was to explore the association between DNT and outcome and to identify factors influencing DNT to better understand why some patients are treated late.

Methods—
Prospectively collected data from the Safe Implementation of Treatments in Stroke-East registry (SITS-EAST: 9 central and eastern European countries) on all patients treated with thrombolysis between February 2003 and February 2010 were analyzed. Multiple logistic regression analysis was used to identify predictors of DNT ≤60 minutes.

Results—

Altogether, 5563 patients were treated with thrombolysis within 4.5 hours of symptom onset. Of these, 2097 (38%) had DNT ≤60 minutes. In different centers, the proportion of patients treated with DNT ≤60 minutes ranged from 18% to 84% (
P
<0.0001). Patients with longer DNT (in 60-minute increments) had less chance of achieving a modified Rankin Scale score of 0 to 1 at 3 months (adjusted OR, 0.86; 95% CI, 0.77–0.97). DNT ≤60 minutes was independently predicted by younger age (in 10-year increments; OR, 0.92; 95% CI, 0.87–0.97), National Institutes of Health Stroke Scale score 7 to 24 (OR, 1.44; 95% CI, 1.2–1.7), onset-to-door time (in 10-minute increments; OR, 1.19; 95% CI, 1.17–1.22), treatment center (
P
<0.001), and country (
P
<0.001).

Conclusions—
Thrombolysis of patients with older age and mild or severe neurological deficit is delayed. The perception that there is sufficient time before the end of the thrombolytic window also delays treatment. It is necessary to improve adherence to guidelines and to treat patients sooner after arrival to hospital.
Does Body Mass Index Impact on the Relationship Between Systolic Blood Pressure and Cardiovascular Disease?
Authors: Tsukinoki Rumi , Murakami Yoshitaka , Huxley Rachel , Ohkubo Takayoshi , Fang Xianghua , Suh Il , Ueshima Hirotsugu , Lam Tai-Hing , Woodward Mark 
Published: March 2012

Background and Purpose—
Elevated blood pressure and excess body mass index (BMI) are established risk factors for cardiovascular disease (CVD) but controversy exists as to whether, and how, they interact.

Methods—
The interactions between systolic blood pressure and BMI on coronary heart disease, ischemic and hemorrhagic stroke and CVD were examined using data from 419 448 participants (≥30 years) in the Asia-Pacific region. BMI was categorized into 5 groups, using standard criteria, and systolic blood pressure was analyzed both as a categorical and continuous variable. Cox proportional hazard models, stratified by sex and study, were used to estimate hazard ratios, adjusting for age and smoking and the interaction was assessed by likelihood ratio tests.

Results—
During 2.6 million person-years of follow-up, there were 10 877 CVD events. Risks of CVD and subtypes increased monotonically with increasing systolic blood pressure in all BMI subgroups. There was some evidence of a decreasing hazard ratio, per additional 10 mm Hg systolic blood pressure, with increasing BMI, but the differences, although significant, are unlikely to be of clinical relevance. The hazard ratio for CVD was 1.34 (95% CI, 1.32–1.36) overall with individual hazard ratios ranging between 1.28 and 1.36 across all BMI groups. For coronary heart disease, ischemic stroke, and hemorrhagic stroke, the overall hazard ratios per 10 mm Hg systolic blood pressure were 1.24, 1.46, and 1.65, respectively.

Conclusions—
Increased blood pressure is an important determinant of CVD risk irrespective of BMI. Although its effect tends to be weaker in people with relatively high BMI, the difference is not sufficiently great to warrant alterations to existing guidelines.
Clinical Risk Factors for Adverse Events in Allopurinol Users
Authors: Ryu Hee Jung , Song Ran , Kim Hye Won , Kim Jin Hyun , Lee Eun Young , Lee Yun Jong , Song Yeong Wook , Lee Eun Bong 
Published: March 2012

AbstractAllopurinol, one of the most commonly used uric acid–lowering agents, can cause serious adverse events. To investigate the risk factors for allopurinol‐induced adverse events, the authors enrolled 94 patients who developed allopurinol‐induced adverse events and 378 controls who were randomly chosen from 1934 patients who used allopurinol but did not develop any adverse events in this retrospective case control study. Univariate analysis showed that patients who developed allopurinol‐induced adverse events had more chronic kidney disease (46% vs 30%, P = .005), more hypertension (42% vs 30%, P = .036), less tumor lysis syndrome (P = .030), higher cholesterol (P = .013), and lower aspartate aminotransferase (P = .002) and alanine aminotransferase levels (P = .033) and more commonly used angiotensin receptor blockers (27% vs 15%, P = .007), colchicines (16% vs 5%, P = .010), or statins (19% vs 8%, P = .002) than those who did not. In multiple logistic regression analysis, the use of colchicines (odds ratio, 3.11; 95% confidence interval, 1.28‐7.58; P = .012) and statins (2.10; 1.03‐4.25; P = .041) was an independent risk factor predicting adverse events in allopurinol users. In conclusion, patients who use colchicine or statins are at significant risk for developing allopurinol‐induced adverse events.
Identification of Acetabular Labral Pathological Changes in Asymptomatic Volunteers Using Optimized, Noncontrast 1.5-T Magnetic Resonance Imaging
Authors: Schmitz Matthew R. , Campbell Scot E. , Fajardo Ryan S. , Kadrmas Warren R. 
Published: March 2012

Background: Acetabular labral tears as a source of potential hip pain have received a great deal of attention in recent literature. The gold standard for identifying acetabular labral tears is hip arthroscopy, but recent advances in optimized, noncontrast magnetic resonance imaging (MRI) have proven effectiveness in identifying intra-articular hip pathological changes without the invasive nature of hip arthroscopy or gadolinium-enhanced arthrography. There are little data in the literature on imaging results in an asymptomatic population. Purpose: The objective of this study was to use an optimized, noncontrast 1.5-T MRI protocol to identify hip abnormalities, including paralabral cysts, in asymptomatic volunteers. Study Design: Case series (prevalence); Level of evidence, 4. Methods: In this study, 42 hips in asymptomatic patients with an average age of 34 years (range, 27-43 years) were prospectively imaged with optimized, noncontrast 1.5-T MRI scans. Two fellowship-trained musculoskeletal radiologists interpreted the scans at 2 different points in time and commented on the presence of labral abnormalities including paralabral cysts. The results were analyzed for both interobserver and intraobserver reliability. Results: Acetabular paralabral cysts were identified in 11 of 42 (26.2%) and 9 of 42 (21.4%) hips by the 2 respective radiologists, with an interobserver reliability of 90.5% (κ = .74) and intraobserver reliability of 95.2% (κ = .87). In addition, acetabular labral tears were identified in 36 of 42 (85.7%) and 34 of 42 (80.9%) hips, with an interobserver reliability of 90.5% (κ = .70) and intraobserver reliability of 95.2% (κ = .83). Conclusion: Utilizing an optimized, noncontrast 1.5-T MRI protocol, we report the previously undescribed prevalence of acetabular labral pathological abnormalities and paralabral cysts in a young, asymptomatic population. This emphasizes the importance of correlating patient symptoms with history and physical examination when evaluating patients with hip pain and radiographic abnormalities as defined by MRI criteria. These data demonstrate that labral tears can occur without symptoms.
The genotoxic, hepatotoxic, nephrotoxic, haematotoxic and histopathological effects in rats after aluminium chronic intoxication
Authors: Geyikoglu Fatime , Türkez Hasan , Bakir Tülay Ozhan , Cicek Mustafa 
Published: March 2012

Aluminium (Al) is used in water purification and is also present in several manufactured foods and medicines. Al is known to induce a broad range of physiological, biochemical and behavioural dysfunctions in laboratory animals and humans. This investigation was carried out to investigate the effects of subchronic exposure to Al (as AlCl3) in rats. Sprague-Dawley rats were randomly separated into two groups. Group 1 rats treated with sodium chloride served as the control, group 2 rats were treated with Al (as AlCl3, 5 mg/kg body weight) intraperitonally for 10 weeks. Animals were killed and blood samples were analyzed for blood serum alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) enzyme activities and creatinine, urea (U) and uric acid (UA) levels for evaluating hepatotoxicity and nephrotoxicity. Blood parameters including red blood cells (RBCs), haemoglobin (Hb) concentration, haematocrit (Ht), platelets (PLTs) and white blood cells (WBCs) were compared between control and experimental group to assess haematoxicity. In order to determine the genotoxicity, the number of micronucleated hepatocytes (MNHEPs) was counted in isolated hepatocytes. In addition, histological alterations in liver and kidney samples were investigated. After exposure with Al, the enzymatic activities of ALP, AST, ALT and LDH, and the levels of U and UA significantly increased. RBC, WBC, PLT, Hb and Ht revealed significant decreases in experimental group compared to the control. AlCl3 caused a significant increase in MNHEPs. Furthermore, severe pathological damages were established in both liver and kidney samples. Subchronic exposure to low doses of Al can produce serious dysfunctions in rat blood, liver and kidney, and exposure to this metal can result in greater damages.
Effect of a Fall Prevention Program on Balance Maintenance Using a Quasi-experimental Design in Real-World Settings
Authors: Robitaille Yvonne , Fournier Michel , Laforest Sophie , Gauvin Lise , Filiatrault Johanne , Corriveau Hélène 
Published: March 2012

Objectives: To examine the effect of a fall prevention program offered under real-world conditions on balance maintenance several months after the program. To explore the program’s impact on falls. Method: A quasi-experimental study was conducted among community-dwelling seniors, with pre- and postintervention measures of balance performance and self-reported falls. Ten community-based organizations offered the intervention (98 participants) and 7 recruited participants to the study’s control arm (102 participants). An earlier study examined balance immediately after the 12-week program. The present study focuses on the 12-month effect. Linear regression (balance) and negative binomial regression (falls) procedures were performed.falls. Results: During the 12-month study period, experimental participants improved and maintained their balance as reflected by their scores on three performance tests. There was no evidence of an effect on falls.falls. Discussion: Structured group exercise programs offered in community-based settings can maintain selected components of balance for several months after the program’s end.