bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antihelminth Compound Niclosamide Downregulates Wnt Signaling and Elicits Antitumor Responses in Tumors with Activating APC Mutations
Authors: Osada Takuya , Chen Minyong , Yang Xiao Yi , Spasojevic Ivan , Vandeusen Jeffrey B. , Hsu David , Clary Bryan M. , Clay Timothy M. , Chen Wei , Morse Michael A. , Lyerly H. Kim 
Published: April 2011

Abstract
Wnt/β-catenin pathway activation caused by adenomatous polyposis coli (APC) mutations occurs in approximately 80% of sporadic colorectal cancers (CRC). The antihelminth compound niclosamide downregulates components of the Wnt pathway, specifically Dishevelled-2 (Dvl2) expression, resulting in diminished downstream β-catenin signaling. In this study, we determined whether niclosamide could inhibit the Wnt/β-catenin pathway in human CRCs and whether its inhibition might elicit antitumor effects in the presence of APC mutations. We found that niclosamide inhibited Wnt/β-catenin pathway activation, downregulated Dvl2, decreased downstream β-catenin signaling, and exerted antiproliferative effects in human colon cancer cell lines and CRC cells isolated by surgical resection of metastatic disease, regardless of mutations in APC. In contrast, inhibition of NF-κB or mTOR did not exert similar antiproliferative effects in these CRC model systems. In mice implanted with human CRC xenografts, orally administered niclosamide was well tolerated, achieved plasma and tumor levels associated with biologic activity, and led to tumor control. Our findings support clinical explorations to reposition niclosamide for the treatment of CRC. Cancer Res; 71(12); 4172–82. ©2011 AACR.
KLF4-Mediated Negative Regulation of IFITM3 Expression Plays a Critical Role in Colon Cancer Pathogenesis
Authors: Li Dawei , Peng Zhihai , Tang Huamei , Wei Ping , Kong Xiangyu , Yan Dongwang , Huang Fei , Li Qiang , Le Xiangdong , Li Qi , Xie Keping 
Published: April 2011

Abstract
Purpose: IFITM3, an IFN-inducible gene, is overexpressed in human colorectal cancer. In this study, we sought to determine the clinical significance and underlying mechanisms of its dysregulated expression in human colon tumor specimens and murine models of this disease.
Experimental Design: IFITM3 expression in a tissue microarray of tumor and matched normal colon tissue specimens and lymph node metastasis specimens obtained from 203 patients with colon cancer was measured immunohistochemically.
Results: IFITM3 was expressed at higher levels in colon tumors and, particularly, nodal metastases than in normal colon tissue. A Cox proportional hazards model showed that IFITM3 expression was an independent prognostic factor for disease-free survival in patients with colon cancer. Knockdown of IFITM3 expression by a specific siRNA significantly suppressed the proliferation, colony formation, migration, and invasion of colon cancer cells in vitro and tumor growth and metastasis in a xenograft model. Restored expression of KLF4, a putative tumor suppressor, downregulated IFITM3 expression in colon cancer cells in vitro. Two KLF4-binding sites in the IFITM3 promoter bound specifically to KLF4 protein in a chromatin immunoprecipitation assay and promoter mutagenesis analyses. Specific deletion of KLF4 led to IFITM3 overexpression in colon mucosa in Villin-Cre+;Klf4fl/fl mice. An inverse correlation between loss of KLF4 expression and IFITM3 overexpression was evident in human colon tumors.
Conclusion: These clinical and mechanistic findings indicate that IFITM3 is a direct transcriptional target of KLF4 and that dysregulated KLF4 expression leads to aberrant IFITM3 expression, thus contributing to colon cancer progression and metastasis. Clin Cancer Res; 17(11); 3558–68. ©2011 AACR.
Biological Function and Prognostic Significance of Peroxisome Proliferator-Activated Receptor δ in Rectal Cancer
Authors: Yang Lie , Zhang Hong , Zhou Zong-Guang , Yan Hui , Adell G , Sun Xiao-Feng 
Published: April 2011

Abstract
Purpose: To investigate the expression significance of PPAR β/δ in relation to radiotherapy (RT), clinicopathologic, and prognostic variables of rectal cancer patients.
Experimental Design: We included 141 primary rectal cancer patients who participated in a Swedish clinical trial of preoperative RT. Tissue microarray samples from the excised rectal cancers and the adjacent or distant normal mucosa and lymph node metastases were stained with PPAR δ antibody. Survival probability was computed by the Kaplan–Meier method and Cox regression model. The proliferation of colon cancer cell lines KM12C, KM12SM, and KM12L4a was assayed after PPAR δ knockdown.
Results: PPAR δ was increased from adjacent or distant normal mucosa to primary cancers, whereas it decreased from primary cancers to lymph node metastases. After RT, PPAR δ was increased in normal mucosa, whereas it decreased in primary cancers and lymph node metastases. In primary cancers, the high expression of PPAR δ was related to higher frequency of stage I cases, lower lymph node metastasis rate, and low expression of Ki-67 in the unirradiated cases, and related to favorable survival in the cases either with or without RT. The proliferation of the KM12C, KM12SM, or KM12L4a cells was significantly accelerated after PPAR δ knockdown.
Conclusions: RT decreases the PPAR δ expression in primary rectal cancers and lymph node metastases. PPAR δ is related to the early development of rectal cancer and inhibits the proliferation of colorectal cancer cells. Increase of PPAR δ predicts favorable survival in the rectal cancer patients either with or without preoperative RT. Clin Cancer Res; 17(11); 3760–70. ©2011 AACR.
Diastolic Blood Pressure as a Biomarker of Axitinib Efficacy in Solid Tumors
Authors: Rini Brian I. , Schiller Joan H. , Fruehauf John P. , Cohen Ezra E.W. , Tarazi Jamal C. , Rosbrook Brad , Bair Angel H. , Ricart Alejandro D. , Olszanski Anthony J. , Letrent Kristen J. , Kim Sinil , Rixe Olivier 
Published: April 2011

Abstract
Purpose: To evaluate if diastolic blood pressure (dBP) ≥90 mm Hg during axitinib treatment is a marker of efficacy.
Experimental Design: The relationship between dBP ≥90 mm Hg and efficacy was retrospectively explored across 5 phase II studies of single-agent axitinib for the treatment of 4 different tumor types. All patients had baseline BP ≤140/90 mm Hg and were stratified into 2 groups based on in-clinic BP measurements after initiating therapy: those with dBP &lt;90 mm Hg throughout therapy and those with at least 1 dBP ≥90 mm Hg. Median overall survival (mOS), median progression-free survival (mPFS), objective response rate (ORR), and adverse events were evaluated by dBP group in individual and pooled analyses.
Results: Two-hundred thirty patients were evaluated. Patients with dBP ≥90 mm Hg had a significantly lower relative risk of death than those with dBP &lt;90 mm Hg [adjusted HR (95% CI) = 0.55 (0.39, 0.77); P &lt; 0.001]. The relative risk of progression was also lower in patients with dBP ≥90 mm Hg [HR (95% CI) = 0.76 (0.54, 1.06), P = 0.107], and ORR was significantly higher (43.9% vs. 12.0%; P &lt; 0.001). In an 8-week landmark analysis, mOS (25.8 vs. 14.9 months) and mPFS (10.2 vs. 7.1 months) were greater for patients in the ≥90 mm Hg group. Adverse events were similar between groups.
Conclusions: Axitinib efficacy correlated with dBP ≥90 mm Hg. Further investigation of dBP as a predictive biomarker of efficacy in patients receiving axitinib is warranted. Clin Cancer Res; 17(11); 3841–9. ©2011 AACR.
The Addition of Bevacizumab to Standard Radiation Therapy and Temozolomide Followed by Bevacizumab, Temozolomide, and Irinotecan for Newly Diagnosed Glioblastoma
Authors: Vredenburgh James J. , Desjardins Annick , Reardon David A. , Peters Katherine B. , Herndon James E. , Marcello Jennifer , Kirkpatrick John P. , Sampson John H. , Bailey Leighann , Threatt Stevie , Friedman Allan H. , Bigner Darell D. , Friedman Henry S. 
Published: April 2011

Abstract
Purpose: To determine if the addition of bevacizumab to radiation therapy and temozolomide, followed by bevacizumab, temozolomide, and irinotecan, for newly diagnosed glioblastoma patients is safe and effective.
Experimental Design: A total of 75 patients with newly diagnosed glioblastoma were enrolled in the phase II trial that investigated the addition of bevacizumab to standard radiation therapy and daily temozolomide followed by the addition of bevacizumab and irinotecan to adjuvant temozolomide. The bevacizumab was given at 10 mg/kg every 14 days beginning a minimum of 4 weeks postcraniotomy. Two weeks after radiation therapy, the patients began 6 to 12 cycles of 5-day temozolomide with bevacizumab and irinotecan every 14 days. The primary endpoint was the proportion of patients alive 16 months after informed consent.
Results: The therapy had moderate toxicity. Three patients, one of whom had a grade 2 central nervous system hemorrhage, came off study during radiation therapy. Seventy patients started the postradiation therapy, and 16 (23%) terminated this adjuvant therapy early because of toxicity. The median overall survival was 21.2 months (95% CI: 17.2–25.4), and 65% of the patients were alive at 16 months (95% CI: 53.4–74.9). The median progression-free survival was 14.2 months (95% CI: 12–16).
Conclusion: The addition of bevacizumab to standard radiation therapy and temozolomide, followed by bevacizumab, irinotecan, and temozolomide, for the treatment of newly diagnosed glioblastoma has moderate toxicity and may improve efficacy compared with historical controls. The results from phase III trials are required before the role of bevacizumab for newly diagnosed glioblastoma is established. Clin Cancer Res; 17(12); 4119–24. ©2011 AACR.
X-Ray Magnetic Resonance Fusion to Internal Markers and Utility in Congenital Heart Disease Catheterization
Authors: Dori Yoav , Sarmiento Marily , Glatz Andrew C. , Gillespie Matthew J. , Jones Virginia M. , Harris Matthew A. , Whitehead Kevin K. , Fogel Mark A. , Rome Jonathan J. 
Published: May 2011

Background—
X-ray magnetic resonance fusion (XMRF) allows for use of 3D data during cardiac catheterization. However, to date, technical requirements have limited the use of this modality in clinical practice. We report on a new internal-marker XMRF method that we have developed and describe how we used XMRF during cardiac catheterization in congenital heart disease.

Methods and Results—
XMRF was performed in a phantom and in 23 patients presenting for cardiac catheterization who also needed cardiac MRI for clinical reasons. The registration process was performed in <5 minutes per patient, with minimal radiation (0.004 to 0.024 mSv) and without contrast. Registration error was calculated in a phantom and in 8 patients using the maximum distance between angiographic and 3D model boundaries. In the phantom, the measured error in the anteroposterior projection had a mean of 1.15 mm (standard deviation, 0.73). The measured error in patients had a median of 2.15 mm (interquartile range, 1.65 to 2.56 mm). Internal markers included bones, airway, image artifact, calcifications, and the heart and vessel borders. The MRI data were used for road mapping in 17 of 23 (74%) cases and camera angle selection in 11 of 23 (48%) cases.

Conclusions—
Internal marker–based registration can be performed quickly, with minimal radiation, without the need for contrast, and with clinically acceptable accuracy using commercially available software. We have also demonstrated several potential uses for XMRF in routine clinical practice. This modality has the potential to reduce radiation exposure and improve catheterization outcomes.
Plasma B-Type Natriuretic Peptide Levels and Recurrent Arrhythmia After Successful Ablation of Lone Atrial Fibrillation
Authors: Hussein Ayman A. , Saliba Walid I. , Martin David O. , Shadman Mazyar , Kanj Mohamed , Bhargava Mandeep , Dresing Thomas , Chung Mina , Callahan Thomas , Baranowski Bryan , Tchou Patrick , Lindsay Bruce D. , Natale Andrea , Wazni Oussama M. 
Published: May 2011

Background—
Plasma B-type natriuretic peptide (BNP) is abnormally elevated in patients with lone atrial fibrillation (AF). The exact significance and prognostic implications of this elevation have yet to be determined. Little is known about BNP in lone AF patients undergoing arrhythmia ablation. We sought to determine the relationship between BNP levels and the risk of recurrent arrhythmia after ablation of lone AF.

Methods and Results—

We followed up 726 patients with lone AF undergoing first-time arrhythmia ablation. All had BNP levels measured on the day of ablation with of the point-of-care Triage Meter assay (Biosite Diagnostics, San Diego, CA). At baseline, factors associated with elevated BNP levels in multivariable linear regression analysis (with log BNP being the dependent variable) were older age (β regression coefficient for +1-year change, 0.025;
P
<0.0001), longer duration of AF (β for +1-year change, 0.031;
P
=0.01), nonparoxysmal AF (versus paroxysmal; β, 0.52;
P
<0.0001), and larger left atrial size (β for +1-cm
2
change, 0.040;
P
<0.0001). The BNP levels were strongly associated with arrhythmia recurrence in univariate- (hazard ratio for +1-log-BNP change, 2.32; 95% confidence interval, 2.11 to 2.74;
P
<0.001) and covariate- (hazard ratio for +1-log-BNP change, 2.13; 95% confidence interval, 2.06 to 2.38;
P
<0.001) adjusted Cox proportional hazards analysis. The covariate-adjusted hazard ratios for recurrent arrhythmia were 1.6, 2.7, 4.3, and 5.7 for the second, third, fourth, and fifth quintiles, respectively, compared with patients in the lowest quintile (
P
for trend across quintiles <0.001).

Conclusions—
B-type natriuretic peptide levels correlate with AF burden (chronicity, altered hemodynamics, and anatomic remodeling) in patients with lone AF and are strong predictors of recurrent arrhythmia after ablation. Elevated BNP levels may reflect increased cardiac chamber wall stress and/or intrinsic atrial disease, thus increasing the risk of arrhythmia recurrence.
Atrial Fibrillation and Death After Myocardial Infarction
Authors: Jabre Patricia , Jouven Xavier , Adnet Frédéric , Thabut Gabriel , Bielinski Suzette J. , Weston Susan A. , Roger Véronique L. 
Published: May 2011

Background—
Atrial fibrillation (AF) often coexists with myocardial infarction (MI), yet its prognostic influence is disputed. Prior reports studied the relationship of AF during early hospitalization for acute MI to the risk of death and could not address the timing of AF in relation to the MI (ie, before, during, after). Furthermore, as data come mostly from clinical trials, their applicability to the community is uncertain. The aims of our study were to assess the occurrence of AF among MI patients, determine whether it has changed over time, and quantify its impact and the impact of its timing on mortality after MI.

Methods and Results—
This was a community-based cohort of 3220 patients hospitalized with incident (first-ever) MI from 1983 to 2007 in Olmsted County, MN. Atrial fibrillation was identified by diagnostic codes and ECG. Outcomes were all-cause and cardiovascular death. Atrial fibrillation before MI was identified in 304 patients, and 729 developed AF after MI (218 [30%] within 2 days, 119 [16%] between 3 and 30 days, and 392 [54%] >30 days post-MI). The cumulative incidence of AF after MI at 5 years was 19% and did not change over the calendar year of MI (the incidence of AF was the same regardless of when the MI occurred). During a mean follow-up of 6.6 years, 1638 deaths occurred. AF was associated with an increased risk of death (hazard ratio [95% confidence interval] 3.77 [3.37 to 4.21]), independently of clinical characteristics at the time of MI and heart failure. This risk differed markedly according to the timing of AF, and was the greatest for AF occurring >30 days post MI (hazard ratio [95% confidence interval] 1.63 [1.37 to 1.93] for AF within 2 days, 1.81 [0.45 to 2.27] for AF between 3 and 30 days, and 2.58 [2.21 to 3.00] for AF >30 days post MI).

Conclusions—
In the community, AF is frequent in the setting of MI. Atrial fibrillation carries an excess risk of death, which is the highest for AF developing >30 days after MI.
The Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF): International Prospective Validation and Reliability Trial in 402 patients
Authors: Scherber Robyn , Dueck Amylou C. , Johansson Peter , Barbui Tiziano , Barosi Giovanni , Vannucchi Alessandro M. , Passamonti Francesco , Andreasson Bjorn , Ferarri Maria L. , Rambaldi Alessandro , Samuelsson Jan , Birgegard Gunnar , Tefferi Ayalew , Harrison Claire N. , Radia Deepti , Mesa Ruben A. 
Published: May 2011

Abstract
Symptomatic burden in myeloproliferative neoplasms is present in most patients and compromises quality of life. We sought to validate a broadly applicable 18-item instrument (Myeloproliferative Neoplasm Symptom Assessment Form [MPN-SAF], coadministered with the Brief Fatigue Inventory) to assess symptoms of myelofibrosis, essential thrombocythemia, and polycythemia vera among prospective cohorts in the United States, Sweden, and Italy. A total of 402 MPN-SAF surveys were administered (English [25%], Italian [46%], and Swedish [28%]) in 161 patients with essential thrombocythemia, 145 patients with polycythemia vera, and 96 patients with myelofibrosis. Responses among the 3 administered languages showed great consistency after controlling for MPN subtype. Strong correlations existed between individual items and key symptomatic elements represented on both the MPN-SAF and the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30. Enrolling physicians' blinded opinion of patient symptoms (6 symptoms assessed) were highly correlated with corresponding patients' responses. Serial administration of the English MPN-SAF among 53 patients showed that most MPN-SAF items are well correlated (r > 0.5, P < .001) and highly reproducible (intraclass correlation coefficient > 0.7). The MPN-SAF is a comprehensive and reliable instrument that is available in multiple languages to evaluate symptoms associated with all types of MPNs in clinical trials globally.
Involvement of mast cells in monocrotaline-induced pulmonary hypertension in rats
Authors: Dahal Bhola K , Kosanovic Djuro , Kaulen Christina , Cornitescu Teodora , Savai Rajkumar , Hoffmann Julia , Reiss Irwin , Ghofrani Hossein A , Weissmann Norbert , Kuebler Wolfgang M , Seeger Werner , Grimminger Friedrich , Schermuly Ralph T 
Published: May 2011

Abstract

Background
Mast cells (MCs) are implicated in inflammation and tissue remodeling. Accumulation of lung MCs is described in pulmonary hypertension (PH); however, whether MC degranulation and c-kit, a tyrosine kinase receptor critically involved in MC biology, contribute to the pathogenesis and progression of PH has not been fully explored.

Methods
Pulmonary MCs of idiopathic pulmonary arterial hypertension (IPAH) patients and monocrotaline-injected rats (MCT-rats) were examined by histochemistry and morphometry. Effects of the specific c-kit inhibitor PLX and MC stabilizer cromolyn sodium salt (CSS) were investigated in MCT-rats both by the preventive and therapeutic approaches. Hemodynamic and right ventricular hypertrophy measurements, pulmonary vascular morphometry and analysis of pulmonary MC localization/counts/activation were performed in animal model studies.

Results
There was a prevalence of pulmonary MCs in IPAH patients and MCT-rats as compared to the donors and healthy rats, respectively. Notably, the perivascular MCs were increased and a majority of them were degranulated in lungs of IPAH patients and MCT-rats (p < 0.05 versus donor and control, respectively). In MCT-rats, the pharmacological inhibitions of MC degranulation and c-kit with CSS and PLX, respectively by a preventive approach (treatment from day 1 to 21 of MCT-injection) significantly attenuated right ventricular systolic pressure (RVSP) and right ventricular hypertrophy (RVH). Moreover, vascular remodeling, as evident from the significantly decreased muscularization and medial wall thickness of distal pulmonary vessels, was improved. However, treatments with CSS and PLX by a therapeutic approach (from day 21 to 35 of MCT-injection) neither improved hemodynamics and RVH nor vascular remodeling.

Conclusions
The accumulation and activation of perivascular MCs in the lungs are the histopathological features present in clinical (IPAH patients) and experimental (MCT-rats) PH. Moreover, the accumulation and activation of MCs in the lungs contribute to the development of PH in MCT-rats. Our findings reveal an important pathophysiological insight into the role of MCs in the pathogenesis of PH in MCT- rats.
SNPPicker: High quality tag SNP selection across multiple populations
Authors: Sicotte Hugues , Rider David N , Poland Gregory A , Dhiman Neelam , Kocher Jean-Pierre A 
Published: May 2011

Abstract

Background
Linkage Disequilibrium (LD) bin-tagging algorithms identify a reduced set of tag SNPs that can capture the genetic variation in a population without genotyping every single SNP. However, existing tag SNP selection algorithms for designing custom genotyping panels do not take into account all platform dependent factors affecting the likelihood of a tag SNP to be successfully genotyped and many of the constraints that can be imposed by the user.

Results
SNPPicker optimizes the selection of tag SNPs from common bin-tagging programs to design custom genotyping panels. The application uses a multi-step search strategy in combination with a statistical model to maximize the genotyping success of the selected tag SNPs. User preference toward functional SNPs can also be taken into account as secondary criteria. SNPPicker can also optimize tag SNP selection for a panel tagging multiple populations. SNPPicker can optimize custom genotyping panels including all the assay-specific constraints of Illumina's GoldenGate and Infinium assays.

Conclusions
A new application has been developed to maximize the success of custom multi-population genotyping panels. SNPPicker also takes into account user constraints including options for controlling runtime. Perl Scripts, Java source code and executables are available under an open source license for download at http://mayoresearch.mayo.edu/mayo/research/biostat/software.cfm