bluuebunny/crossref_metadata_2025_split huggingface dataset:
PARP-1 Inhibition as a Targeted Strategy to Treat Ewing's Sarcoma
Authors: Brenner J. Chad , Feng Felix Y. , Han Sumin , Patel Sonam , Goyal Siddharth V. , Bou-Maroun Laura M. , Liu Meilan , Lonigro Robert , Prensner John R. , Tomlins Scott A. , Chinnaiyan Arul M. 
Published: January 2012

Abstract
Ewing's sarcoma family of tumors (ESFT) refers to aggressive malignancies which frequently harbor characteristic EWS-FLI1 or EWS-ERG genomic fusions. Here, we report that these fusion products interact with the DNA damage response protein and transcriptional coregulator PARP-1. ESFT cells, primary tumor xenografts, and tumor metastases were all highly sensitive to PARP1 inhibition. Addition of a PARP1 inhibitor to the second-line chemotherapeutic agent temozolamide resulted in complete responses of all treated tumors in an EWS-FLI1–driven mouse xenograft model of ESFT. Mechanistic investigations revealed that DNA damage induced by expression of EWS-FLI1 or EWS-ERG fusion genes was potentiated by PARP1 inhibition in ESFT cell lines. Notably, EWS-FLI1 fusion genes acted in a positive feedback loop to maintain the expression of PARP1, which was required for EWS-FLI–mediated transcription, thereby enforcing oncogene-dependent sensitivity to PARP-1 inhibition. Together, our findings offer a strong preclinical rationale to target the EWS-FLI1:PARP1 intersection as a therapeutic strategy to improve the treatment of ESFTs. Cancer Res; 72(7); 1608–13. ©2012 AACR.
IGFBP Ratio Confers Resistance to IGF Targeting and Correlates with Increased Invasion and Poor Outcome in Breast Tumors
Authors: Becker Marc A. , Hou Xiaonan , Harrington Sean C. , Weroha S. John , Gonzalez Sergio E. , Jacob Kristina A. , Carboni Joan M. , Gottardis Marco M. , Haluska Paul 
Published: January 2012

Abstract
Purpose: To improve the significance of insulin-like growth factor–binding protein 5 (IGFBP-5) as a prognostic and potentially predictive marker in patients with breast cancer.
Experimental Design: Increased IGFBP-5 expression was identified in MCF-7 cells resistant (MCF-7R4) to the IGF-1R/insulin receptor (InsR) inhibitor BMS-536924 and its role examined by targeted knockdown and overexpression in multiple experimental models. Protein expression of IGFBP-5 was measured by immunohistochemistry in a cohort of 76 patients with breast cancer to examine correlative associations with invasive tumor fraction and outcome. The use of a combined IGFBP-5/IGFBP-4 (BPR) expression ratio was applied to predict anti-IGF-1R/InsR response in a panel of breast cancer lines and outcome in multiple breast tumor cohorts.
Results: IGFBP-5 knockdown decreased BMS-536924 resistance in MCF-7R4 cells, whereas IGFBP-5 overexpression in MCF-7 cells conferred resistance. When compared with pathologically normal reduction mammoplasty tissue, IGFBP-5 expression levels were upregulated in both invasive and histologically normal adjacent breast cancer tissue. In both univariate and multivariate modeling, metastasis-free survival, recurrence free survival (RFS), and overall survival (OS) were significantly associated with high IGFBP-5 expression. Prognostic power of IGFBP-5 was further increased with the addition of IGFBP-4 where tumors were ranked based upon IGFBP-5/IGFBP-4 expression ratio (BPR). Multiple breast cancer cohorts confirm that BPR (high vs. low) was a strong predictor of RFS and OS.
Conclusion: IGFBP-5 expression is a marker of poor outcome in patients with breast cancer. An IGFBP-5/IGFBP-4 expression ratio may serve as a surrogate biomarker of IGF pathway activation and predict sensitivity to anti-IGF-1R targeting. Clin Cancer Res; 18(6); 1808–17. ©2012 AACR.
Increased Levels of COX-2 and Prostaglandin E2 Contribute to Elevated Aromatase Expression in Inflamed Breast Tissue of Obese Women
Authors: Subbaramaiah Kotha , Morris Patrick G. , Zhou Xi Kathy , Morrow Monica , Du Baoheng , Giri Dilip , Kopelovich Levy , Hudis Clifford A. , Dannenberg Andrew J. 
Published: January 2012

Abstract
Obesity is a risk factor for hormone receptor-positive breast cancer in postmenopausal women. Estrogen synthesis is catalyzed by aromatase, which is encoded by CYP19. We previously showed that aromatase expression and activity are increased in the breast tissue of overweight and obese women in the presence of characteristic inflammatory foci [crown-like structures of the breast (CLS-B)]. In preclinical studies, proinflammatory prostaglandin E2 (PGE2) is a determinant of aromatase expression. We provide evidence that cyclooxygenase (COX)-2–derived PGE2 stimulates the cyclic AMP (cAMP)→PKA signal transduction pathway that activates CYP19 transcription, resulting in increased aromatase expression and elevated progesterone receptor levels in breast tissues from overweight and obese women. We further demonstrate that a measure of in-breast inflammation (CLS-B index) is a better correlate of these biologic end points than body mass index. The obesity→inflammation→aromatase axis is likely to contribute to the increased risk of hormone receptor-positive breast cancer and the worse prognosis of obese patients with breast cancer.
Significance: We show that obesity-associated inflammatory foci in the human breast are associated with elevated COX-2 levels and activation of the PGE2→cAMP→PKA signal transduction pathway resulting in increased aromatase expression. These findings help to explain the link among obesity, low-grade chronic inflammation, and breast cancer with important clinical implications. Cancer Discov; 2(4); 356–65. ©2012 AACR.
Read the Commentary on this article by Wang and DuBois, p. 308
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Trends in Use of Implantable Cardioverter-Defibrillator Therapy Among Patients Hospitalized for Heart Failure
Authors: Al-Khatib Sana M. , Hellkamp Anne S. , Hernandez Adrian F. , Fonarow Gregg C. , Thomas Kevin L. , Al-Khalidi Hussein R. , Heidenreich Paul A. , Hammill Stephen , Yancy Clyde , Peterson Eric D. ,   for the Get With the Guidelines Steering Committee and Hospitals
Published: January 2012

Background—
Prior studies have demonstrated low use of implantable cardioverter defibrillators (ICDs) as primary prevention, particularly among women and blacks. The degree to which the overall use of ICD therapy and disparities in use have changed is unclear.

Methods and Results—

We examined 11 880 unique patients with a history of heart failure and left ventricular ejection fraction ≤35% who were ≥65 years old and enrolled in the Get With the Guidelines–Heart Failure (GWTG-HF) program from January 2005 through December 2009. We determined the rate of ICD use by year for the overall population and for sex and race groups. From 2005 to 2007, overall ICD use increased from 30.2% to 42.4% and then remained unchanged in 2008 to 2009. After adjustment for potential confounders, ICD use increased significantly in the overall study population during 2005 to 2007 (odds ratio, 1.28; 95% confidence interval, 1.11–1.48 per year;
P
=0.0008) and in black women (odds ratio, 1.82; 95% confidence interval, 1.28–2.58 per year;
P
=0.0008), white women (odds ratio, 1.30; 95% confidence interval, 1.06–1.59 per year;
P
=0.010), black men (odds ratio, 1.54; 95% confidence interval, 1.19–1.99 per year;
P
=0.0009), and white men (odds ratio, 1.25; 95% confidence interval, 1.06–1.48 per year;
P
=0.0072). The increase in ICD use was greatest among blacks.

Conclusions—
In the GWTG-HF quality improvement program, a significant increase in ICD therapy use was observed over time in all sex and race groups. The previously described racial disparities in ICD use were no longer present by the end of the study period; however, sex differences persisted.
Population Pharmacokinetic/Pharmacodynamic Modeling to Assist Dosing Schedule Selection for Dovitinib
Authors: Wang Xiaofeng , Kay Andrea , Anak Oezlem , Angevin Eric , Escudier Bernard , Zhou Wei , Feng Yilin , Dugan Margaret , Schran Horst 
Published: January 2012

AbstractDovitinib is an oral multitargeted kinase inhibitor with potent activity against receptors for vascular endothelial growth factor, platelet‐derived growth factor, and basic fibroblast growth factor. Initial phase 1 to 2 studies of dovitinib using a continuous daily dosing schedule has shown that dovitinib exhibits a prolonged and overproportional increase in dose and exposure relationship above 400 mg/d. To address this, intermittent dosing schedules were explored using a model‐based approach. A semi‐mechanistic population pharmcokinetic/pharmacodynamic (PD) model was developed from 4 dovitinib phase 1 studies with daily dosing schedules. Autoinduction of cytochrome P450 1A (CYP1A) responsible for dovitinib metabolism was described using an indirect response model. Simulation of dovitinib plasma concentration profiles following 4 intermittent dosing schedules suggested that intermittent dosing could prevent prolonged drug accumulation. Based on the simulated plasma profiles, PD response, and patient compliance, a 5‐days‐on/2‐days‐off intermittent dosing schedule was selected for a phase 1 to 2 clinical study. The observed dovitinib plasma concentrations in this study confirmed the model predictions. Furthermore, dovitinib was well tolerated, and antitumor activity was observed as well in this new study. The 5‐days‐on/2‐days‐off dosing schedule is currently used in a dovitinib registration trial and other clinical trials.
Pharmacokinetics of Pentoxifylline and Its Main Metabolites in Patients With Different Degrees of Heart Failure Following a Single Dose of a Modified‐Release Formulation
Authors: Nisi Alessandra , Panfili Marco , De Rosa Giovanni , Boffa Giovanni , Groppa Francesca , Gusella Milena , Padrini Roberto 
Published: January 2012

AbstractPentoxifylline (PTX) is extensively metabolized in the body, and all its 3 plasma metabolites (M1, M4, M5) are pharmacologically active. The authors evaluated the pharmacokinetics of PTX and its metabolites in 20 patients with chronic heart failure (CHF). Eleven had moderate and 9 severe CHF. The time courses of PTX, M1, M4, and M5 plasma levels were determined after oral administration of a sustained‐release 600‐mg tablet of PTX, and for each compound, AUC, maximal plasma concentration (Cmax), and time to Cmax (Tpeak) were calculated. Compared with patients with moderate CHF, those with severe CHF showed a significant delay in Tpeak of PTX (3.9 vs 1.6 hours) and M5 (5.6 vs 3.6 hours), a 59% significant increase in M5 AUC, and a 56% nonsignificant increase in PTX AUC. In the whole population, the AUCs of PTX, M4, and M5 were inversely correlated with markers of liver function, whereas the AUCs of M4 and M5 were inversely correlated with the creatinine clearance. In view of the kinetic features of slow‐release formulations (flip‐flop phenomenon), the delay in Tpeak of PTX in patients with severe CHF compared with moderate CHF should be ascribed to a reduced elimination rate.
Prevalence of Laryngopharyngeal Reflux Symptoms
Authors: Sone Michihiko , Katayama Naomi , Kato Toshinari , Izawa Kazuhiro , Wada Masaki , Hamajima Nobuyuki , Nakashima Tsutomu 
Published: January 2012

ObjectiveTo investigate the prevalence of laryngopharyngeal reflux (LPR) symptoms in health checkup examinees and in patients with otitis media with effusion (OME) of undetermined etiology and the significance of age, body mass index (BMI), and pepsinogen (PG) concentration in middle ear effusions (MEEs).Study DesignCross‐sectional study.SettingHealth checkup and private clinics.Subjects and MethodsA total of 410 subjects who had undergone a health checkup were asked to respond to the reflux symptom index (RSI) to identify the distribution of the RSI score, and the results were compared with 62 patients with OME by BMI and PG concentration in the MEEs.ResultsThe RSI‐positive (score >13) rate was 7.1% in the health checkup examinees. The highest rate was observed in men in their 40s, who had the highest average BMI. None of the men in their 80s were RSI positive. The RSI‐positive rate in patients with OME was 21.0%. None of the male patients ≥70 years of age were RSI positive, whereas the average PG concentration was significantly higher in this group.ConclusionThe prevalence of LPR symptoms evaluated by the RSI was significantly higher in OME patients than in the health checkup examinees; however, a similar pattern in which LPR symptoms were prominent in middle‐aged men with a high BMI and much less in elderly men was observed. Middle‐aged men with a high BMI might be diagnosed as having LPR disease based on the relevant symptoms. LPR findings would be more sensitive than symptoms in elderly men.
Patient Self‐assessment of Nasal Fractures and Self‐referral to an Ear, Nose, and Throat Department
Authors: Baring David E. C. , Bowyer Duncan J. , Adamson Richard 
Published: January 2012

ObjectiveTo assess if patients can safely self‐assess their need for ear, nose, and throat (ENT) review following initial emergency department attendance for nasal trauma.Study DesignThis prospective study was divided into 2 parts. The initial part evaluated an information sheet for patients to lead them through a self‐assessment to establish if they require ENT review following nasal injury. The second part of the study investigated outcomes following the introduction of the self‐assessment.SettingThis work was conducted at a District General Hospital in Scotland.Subjects and MethodsForty‐nine consecutive patients underwent self‐assessment plus blinded otolaryngology assessment, after which self‐assessment was introduced as routine. This was evaluated comparing outcomes of 49 new consecutive nasal injuries against the original group using subjective patient scores of nasal cosmesis and nasal airway following injury and any subsequent treatment.ResultsThere was no significant difference in outcome between the 2 study periods. After the introduction of self‐assessment, there was a large reduction in the nonattendance rate for nasal injuries and in the attendances of patients with nasal injuries not requiring manipulation.ConclusionIn our institution, patients can be relied on to safely self‐assess their nasal injuries to decide if they need ENT review when provided with appropriate information. This reduces the outpatient burden on the ENT department with no deterioration in subjective patient outcomes.
The Impact of Explicit Values Clarification Exercises in a Patient Decision Aid Emerges After the Decision Is Actually Made
Authors: Feldman-Stewart Deb , Tong Christine , Siemens Rob , Alibhai Shabbir , Pickles Tom , Robinson John , Brundage Michael D. 
Published: January 2012

Purpose To determine if particular values clarification exercises included in a patient decision aid had discernible impact on postdecisional regret in patients with early-stage prostate cancer. Methods A multicenter randomized controlled trial compared 2 versions of a computerized patient decision aid: only structured information compared to the structured information plus values clarification exercises. Assessments were conducted during the decision aid visit; telephone follow-up interviews were conducted when patients made their decisions with their physician, 3 months after completing treatment, and >1 year later (per a mailing). Outcome measures included the Decisional Conflict Scale, the Preparation for Decision Making Scale, and the Decision Regret Scale. Results A total of 156 patients participated, 75 provided information only and 81 provided information plus values clarification exercises. The groups did not differ significantly on any outcome evaluated at the decision aid visit; in both groups, decisional conflict decreased immediately after using the decision aid. Between-group differences emerged after the decision was actually made. The values clarification exercises group reported higher Preparation for Decision Making Scale scores at the decision follow-up and at the >1-year follow-up. Regret did not differ significantly between groups at the 3-month follow-up but was lower for the values clarification exercises group than for the information group at the >1-year follow-up. Conclusion The results suggest that the values clarification exercises led to better preparation for decision making and to less regret. The impact, however, only emerged after the decision was made.
The PACE study: Past-year prevalence of migraine in Parma’s adult general population
Authors: Ferrante Tullia , Castellini Paola , Abrignani Giorgia , Latte Lilia , Russo Marco , Camarda Cecilia , Veronesi Licia , Pasquarella Cesira , Manzoni Gian Camillo , Torelli Paola 
Published: January 2012

Background: In the literature there are few data about the prevalence of primary headaches, including migraine, in the Italian general population. The PACE study (PArma CEfalea, or ‘Headache in Parma’) is an observational study aimed at detecting the prevalence and clinical features of primary headaches in the city of Parma’s adult general population. Materials and methods: A total of 904 subjects representative of Parma’s adult general population were interviewed face-to-face by a physician from the Parma Headache Centre. They were given a specially designed and validated questionnaire for the diagnosis of primary headaches according to the ICHD-II criteria. Results: Past-year adjusted prevalence of definite migraine, including migraine with and without aura and chronic migraine, was 24.7% (95% CI 21.9 to 27.5); 13% (95% CI 9.7 to 16.4) were men and 32.9% (95% CI 28.8 to 37.0) were women. Past-year prevalence of probable migraine was 5.1% (95% CI 3.6 to 6.5): 5.2% (95% CI 3.0 to 7.4) in men and 5% (95% CI 3.1 to 6.9) in women. Conclusions: The high prevalence of definite migraine is the major difference between our results and the literature data. Such a difference in results may be due to the use of a different investigational approach compared with the other epidemiological studies. However, an actual higher frequency of migraine in the Italian general population cannot be excluded given the lack of studies on this topic.
Is Early Passive Motion Exercise Necessary After Arthroscopic Rotator Cuff Repair?
Authors: Kim Yang-Soo , Chung Seok Won , Kim Joon Yub , Ok Ji-Hoon , Park In , Oh Joo Han 
Published: January 2012

Background: Early passive motion exercise has been the standard rehabilitation protocol after rotator cuff repair for preventing postoperative stiffness. However, recent approaches show that longer immobilization may enhance tendon healing and quality. Purpose: To elucidate whether early passive motion exercise affects functional outcome and tendon healing after arthroscopic rotator cuff repair. Study Design: Randomized controlled trial; Level of evidence, 1. Methods: One hundred five consecutive patients who underwent arthroscopic repair for small to medium-sized full-thickness rotator cuff tears were included. Patients with large to massive tears and concomitant stiffness or labral lesions were excluded. Patients were instructed to wear an abduction brace for 4 to 5 weeks after surgery and to start active-assisted shoulder exercise after brace weaning. Fifty-six patients were randomly allocated into group 1: early passive motion exercises were conducted 3 to 4 times per day during the abduction brace-wearing period. Forty-nine patients were allocated into group 2: no passive motion was allowed during the same period. Range of motion (ROM) and visual analog scale (VAS) for pain were measured preoperatively and 3, 6, and 12 months postoperatively. Functional evaluations, including Constant score, Simple Shoulder Test (SST), and American Shoulder and Elbow Surgeons (ASES) score, were also evaluated at 6 and 12 months postoperatively. Ultrasonography, magnetic resonance imaging, or computed tomography arthrography was utilized to evaluate postoperative cuff healing. Results: There were no statistical differences between the 2 groups in ROM or VAS for pain at each time point. Functional evaluations were not statistically different between the 2 groups either. The final functional scores assessed at 12 months for groups 1 and 2 were as follows: Constant score, 69.81 ± 3.43 versus 69.83 ± 6.24 ( P = .854); SST, 9.00 ± 2.12 versus 9.00 ± 2.59 ( P = .631); and ASES score, 73.29 ± 18.48 versus 82.90 ± 12.35 ( P = .216). Detachment of the repaired cuff was identified in 12% of group 1 and 18% of group 2 ( P = .429). Conclusion: Early passive motion exercise after arthroscopic cuff repair did not guarantee early gain of ROM or pain relief but also did not negatively affect cuff healing. We suggest that early passive motion exercise is not mandatory after arthroscopic repair of small to medium-sized full-thickness rotator cuff tears, and postoperative rehabilitation can be modified to ensure patient compliance.
Treatment of Traumatic Anterior Shoulder Dislocation in Patients Older Than 60 Years
Authors: Shin Sang-Jin , Yun Yeo-Hon , Kim Dong Jun , Yoo Jae Doo 
Published: January 2012

Background: The prevalence of traumatic anterior shoulder dislocation in the elderly population has increased; however, no consensus has been reached regarding the management of shoulder dislocations in elderly patients. Purpose: This study investigated the clinical manifestations of traumatic anterior shoulder dislocation in patients older than 60 years and evaluated the functional outcomes of different treatment modalities based on associated abnormalities and the number of dislocations. Study Design: Case series; Level of evidence, 4. Methods: Sixty-seven patients older than 60 at the time of primary shoulder dislocation were included. Magnetic resonance imaging or ultrasonography was performed on all patients to confirm associated injuries. Fifty-two patients were treated for primary shoulder dislocation and 15 for recurrent dislocation. Results: Postinjury examinations revealed no associated injuries in 31 patients with primary shoulder dislocation; these patients recovered shoulder function after rehabilitation (American Shoulder and Elbow Surgeons [ASES] score: 93 ± 6; Constant score: 89 ± 8). For the other 36 patients, 33 were found to have rotator cuff tears (isolated cuff tears in 16), and 3 were found to have an isolated Bankart lesion. The average ASES score of the 17 patients with primary shoulder dislocation who were treated operatively was 83 ± 10, and the average Constant score was 78 ± 13 at final follow-up. The average ASES score of patients with recurrent shoulder dislocation was 89 ± 9, and the average Constant score was 84 ± 13. No statistically significant differences in functional shoulder outcomes between patients with primary and recurrent dislocation were evident ( P > .05). However, patients who were treated nonoperatively showed significantly better recovery of shoulder function than patients who were treated operatively regardless of the number of dislocations ( P < .001). No recurrent shoulder dislocation was observed in any patient during an average follow-up period of 55 months. Conclusion: The accurate diagnosis of associated injuries after traumatic anterior shoulder dislocation in patients older than 60 is critical for the recovery of shoulder function because more than half of patients had rotator cuff tears or anterior capsulolabral lesions, which may lead to recurrent shoulder dislocation. Satisfactory clinical outcomes without recurrence were obtained after early detection of abnormalities and different treatment modalities based on associated injuries and the number of dislocations experienced.