bluuebunny/crossref_metadata_2025_split huggingface dataset:
Having Pancreatic Cancer with Tumoral Loss of ATM and Normal TP53 Protein Expression Is Associated with a Poorer Prognosis
Authors: Kim Haeryoung , Saka Burcu , Knight Spencer , Borges Michael , Childs Erica , Klein Alison , Wolfgang Christopher , Herman Joseph , Adsay Volkan N. , Hruban Ralph H. , Goggins Michael 
Published: February 2014

Abstract
Purpose: To determine how often loss of ataxia-telangiectasia–mutated (ATM) protein expression occurs in primary pancreatic ductal adenocarcinomas and to determine its prognostic significance.
Experimental Design: The expression of ATM and TP53 was determined by immunohistochemistry in 397 surgically resected pancreatic ductal adenocarcinomas (Hopkins; Johns Hopkins Medical Institutions, Baltimore, MD), a second set of 159 cases (Emory; Emory University Hospital, Atlanta, GA), and 21 cancers after neoadjuvant chemoradiotherapy. Expression was correlated with the clinicopathologic parameters, including survival.
Results: Tumoral ATM loss was observed in one cancer known to have biallelic inactivation of ATM and 50 of the first 396 (12.8%) cases, significantly more often in patients with a family history of pancreatic cancer (12/49; 24.5%) than in those without (38/347; 11.0%; P = 0.019). In the Hopkins series, ATM loss was associated with a significantly decreased overall survival in patients whose cancers had normal TP53 expression (P = 0.019) and was a significant independent predictor of decreased overall survival (P = 0.014). Seventeen (10.7%) of 159 Emory cases had tumoral ATM loss and tumoral ATM loss/normal TP53 was associated with poorer overall survival (P = 0.1). Multivariate analysis of the combined Hopkins/Emory cases found that tumoral ATM loss/normal TP53 was an independent predictor of decreased overall survival [HR = 2.61; confidence interval (CI), 1.27–5.37; P = 0.009]. Of 21 cancers examined after neoadjuvant chemoradiotherapy, one had tumoral loss of ATM; it had no histologic evidence of tumor response.
Conclusions: Tumoral loss of ATM protein was detected more often in patients with a family history of pancreatic cancer than in those without. Patients whose pancreatic cancers had loss of ATM but normal TP53 had worse overall survival after pancreatic resection. Clin Cancer Res; 20(7); 1865–72. ©2014 AACR.
Preclinical Activity of the Oral Proteasome Inhibitor MLN9708 in Myeloma Bone Disease
Authors: Garcia-Gomez Antonio , Quwaider Dalia , Canavese Miriam , Ocio Enrique M. , Tian Ze , Blanco Juan F. , Berger Allison J. , Ortiz-de-Solorzano Carlos , Hernández-Iglesias Teresa , Martens Anton C.M. , Groen Richard W.J. , Mateo-Urdiales Joaquín , Fraile Susana , Galarraga Miguel , Chauhan Dharminder , San Miguel Jesús F. , Raje Noopur , Garayoa Mercedes 
Published: February 2014

Abstract
Purpose: MLN9708 (ixazomib citrate), which hydrolyzes to pharmacologically active MLN2238 (ixazomib), is a next-generation proteasome inhibitor with demonstrated preclinical and clinical antimyeloma activity, but yet with an unknown effect on myeloma bone disease. Here, we investigated its bone anabolic and antiresorptive effects in the myeloma setting and in comparison with bortezomib in preclinical models.
Experimental Design: The in vitro effect of MLN2238 was tested on osteoclasts and osteoclast precursors from healthy donors and patients with myeloma, and on osteoprogenitors derived from bone marrow mesenchymal stem cells also from both origins. We used an in vivo model of bone marrow–disseminated human myeloma to evaluate MLN2238 antimyeloma and bone activities.
Results: Clinically achievable concentrations of MLN2238 markedly inhibited in vitro osteoclastogenesis and osteoclast resorption; these effects involved blockade of RANKL (receptor activator of NF-κB ligand)-induced NF-κB activation, F-actin ring disruption, and diminished expression of αVβ3 integrin. A similar range of MLN2238 concentrations promoted in vitro osteoblastogenesis and osteoblast activity (even in osteoprogenitors from patients with myeloma), partly mediated by activation of TCF/β-catenin signaling and upregulation of the IRE1 component of the unfolded protein response. In a mouse model of bone marrow–disseminated human multiple myeloma, orally administered MLN2238 was equally effective as bortezomib to control tumor burden and also provided a marked benefit in associated bone disease (sustained by both bone anabolic and anticatabolic activities).
Conclusion: Given favorable data on pharmacologic properties and emerging clinical safety profile of MLN9708, it is conceivable that this proteasome inhibitor may achieve bone beneficial effects in addition to its antimyeloma activity in patients with myeloma. Clin Cancer Res; 20(6); 1542–54. ©2014 AACR.
Downregulation of FOXO3a Promotes Tumor Metastasis and Is Associated with Metastasis-Free Survival of Patients with Clear Cell Renal Cell Carcinoma
Authors: Ni Dong , Ma Xin , Li Hong-Zhao , Gao Yu , Li Xin-Tao , Zhang Yu , Ai Qing , Zhang Peng , Song Er-Lin , Huang Qing-Bo , Fan Yang , Zhang Xu 
Published: February 2014

Abstract
Purpose: To explore the mechanisms underlying clear-cell renal cell carcinoma (ccRCC) metastasis using transcriptional profiling and bioinformatics analysis of ccRCC samples, and to elucidate the role of FOXO3a in ccRCC metastasis.
Experimental Design: Gene expression profiling was performed using four primary metastatic and five primary nonmetastatic ccRCC samples. The mRNA and protein levels of FOXO3a in ccRCC samples were investigated by real-time reverse transcription PCR and immunohistochemistry, respectively. The association between metastasis-free survival of patients with ccRCC and FOXO3a mRNA levels was analyzed. Biologic functions of FOXO3a in renal cancer cell lines were investigated. The influence of FOXO3a on tumor metastasis was also studied in vivo orthotopic xenograft tumor model. Finally, the mechanism by which FOXO3a attenuation could increase invasion and migration of tumor cells was explored.
Results: Bioinformatics analysis of the profiling data identified FOXO3a as a key factor in ccRCC metastasis. FOXO3a expression was decreased in primary metastatic ccRCC samples. Patients with low FOXO3a mRNA levels had poor metastasis-free survival (P = 0.003). Knocking down FOXO3a induced tumor cell invasion and migration in the nonmetastatic ccRCC cells. Induced FOXO3a overexpression in SN12-PM6 cells could inhibit tumor metastasis in vivo. Downregulation of FOXO3a increased SNAIL1 expression, thereby activating the epithelial–mesenchymal transition (EMT) of RCC cell lines.
Conclusions: The loss of FOXO3a induced EMT of tumor cells by upregulating SNAIL1, which promoted tumor cells metastasis in vitro and in vivo. Thus, FOXO3a could be considered as an independent prognostic factor in ccRCC metastasis and could be a marker of occult metastases. Clin Cancer Res; 20(7); 1779–90. ©2014 AACR.
Functional Identification of Cancer-Specific Methylation of CDO1, HOXA9, and TAC1 for the Diagnosis of Lung Cancer
Authors: Wrangle John , Machida Emi Ota , Danilova Ludmila , Hulbert Alicia , Franco Noreli , Zhang Wei , Glöckner Sabine C. , Tessema Mathewos , Van Neste Leander , Easwaran Hariharan , Schuebel Kornel E. , Licchesi Julien , Hooker Craig M. , Ahuja Nita , Amano Jun , Belinsky Steven A. , Baylin Stephen B. , Herman James G. , Brock Malcolm V. 
Published: February 2014

Abstract
Purpose: Non–small cell lung cancer (NSCLC) is the leading cause of cancer mortality in the world. Novel diagnostic biomarkers may augment both existing NSCLC screening methods as well as molecular diagnostic tests of surgical specimens to more accurately stratify and stage candidates for adjuvant chemotherapy. Hypermethylation of CpG islands is a common and important alteration in the transition from normal tissue to cancer.
Experimental Design: Following previously validated methods for the discovery of cancer-specific hypermethylation changes, we treated eight NSCLC cell lines with the hypomethylating agent deoxyazacitidine or trichostatin A. We validated the findings using a large publicly available database and two independent cohorts of primary samples.
Results: We identified &gt;300 candidate genes. Using The Cancer Genome Atlas (TCGA) and extensive filtering to refine our candidate genes for the greatest ability to distinguish tumor from normal, we define a three-gene panel, CDO1, HOXA9, and TAC1, which we subsequently validate in two independent cohorts of primary NSCLC samples. This three-gene panel is 100% specific, showing no methylation in 75 TCGA normal and seven primary normal samples and is 83% to 99% sensitive for NSCLC depending on the cohort.
Conclusion: This degree of sensitivity and specificity may be of high value to diagnose the earliest stages of NSCLC. Addition of this three-gene panel to other previously validated methylation biomarkers holds great promise in both early diagnosis and molecular staging of NSCLC. Clin Cancer Res; 20(7); 1856–64. ©2014 AACR.
Radiation-Enhanced Lung Cancer Progression in a Transgenic Mouse Model of Lung Cancer Is Predictive of Outcomes in Human Lung and Breast Cancer
Authors: Delgado Oliver , Batten Kimberly G. , Richardson James A. , Xie Xian-Jin , Gazdar Adi F. , Kaisani Aadil A. , Girard Luc , Behrens Carmen , Suraokar Milind , Fasciani Gail , Wright Woodring E. , Story Michael D. , Wistuba Ignacio I. , Minna John D. , Shay Jerry W. 
Published: February 2014

Abstract
Purpose: Carcinogenesis is an adaptive process between nascent tumor cells and their microenvironment, including the modification of inflammatory responses from antitumorigenic to protumorigenic. Radiation exposure can stimulate inflammatory responses that inhibit or promote carcinogenesis. The purpose of this study is to determine the impact of radiation exposure on lung cancer progression in vivo and assess the relevance of this knowledge to human carcinogenesis.
Experimental Design: K-rasLA1 mice were irradiated with various doses and dose regimens and then monitored until death. Microarray analyses were performed using Illumina BeadChips on whole lung tissue 70 days after irradiation with a fractionated or acute dose of radiation and compared with age-matched unirradiated controls. Unique group classifiers were derived by comparative genomic analysis of three experimental cohorts. Survival analyses were performed using principal component analysis and k-means clustering on three lung adenocarcinoma, three breast adenocarcinoma, and two lung squamous carcinoma annotated microarray datasets.
Results: Radiation exposure accelerates lung cancer progression in the K-rasLA1 lung cancer mouse model with dose fractionation being more permissive for cancer progression. A nonrandom inflammatory signature associated with this progression was elicited from whole lung tissue containing only benign lesions and predicts human lung and breast cancer patient survival across multiple datasets. Immunohistochemical analyses suggest that tumor cells drive predictive signature.
Conclusions: These results demonstrate that radiation exposure can cooperate with benign lesions in a transgenic model of cancer by affecting inflammatory pathways, and that clinically relevant similarities exist between human lung and breast carcinogenesis. Clin Cancer Res; 20(6); 1610–22. ©2014 AACR.
Topical Application of a Mucoadhesive Freeze-Dried Black Raspberry Gel Induces Clinical and Histologic Regression and Reduces Loss of Heterozygosity Events in Premalignant Oral Intraepithelial Lesions: Results from a Multicentered, Placebo-Controlled Clinical Trial
Authors: Mallery Susan R. , Tong Meng , Shumway Brian S. , Curran Alice E. , Larsen Peter E. , Ness Gregory M. , Kennedy Kelly S. , Blakey George H. , Kushner George M. , Vickers Aaron M. , Han Brian , Pei Ping , Stoner Gary D. 
Published: February 2014

Abstract
Purpose: Approximately 30% higher grade premalignant oral intraepithelial neoplasia (OIN) lesions will progress to oral cancer. Although surgery is the OIN treatment mainstay, many OIN lesions recur, which is highly problematic for both surgeons and patients. This clinical trial assessed the chemopreventive efficacy of a natural product-based bioadhesive gel on OIN lesions.
Experimental Design: This placebo-controlled multicenter study investigated the effects of topical application of bioadhesive gels that contained either 10% w/w freeze-dried black raspberries (BRB) or an identical formulation devoid of BRB placebo to biopsy-confirmed OIN lesions (0.5 g × q.i.d., 12 weeks). Baseline evaluative parameters (size, histologic grade, LOH events) were comparable in the randomly assigned BRB (n = 22) and placebo (n = 18) gel cohorts. Evaluative parameters were: histologic grade, clinical size, and LOH.
Results: Topical application of the BRB gel to OIN lesions resulted in statistically significant reductions in lesional sizes, histologic grades, and LOH events. In contrast, placebo gel lesions demonstrated a significant increase in lesional size and no significant effects on histologic grade or LOH events. Collectively, these data strongly support BRB's chemopreventive impact. A cohort of very BRB-responsive patients, as demonstrated by high therapeutic efficacy, was identified. Corresponding protein profiling studies, which demonstrated higher pretreatment levels of BRB metabolic and keratinocyte differentiation enzymes in BRB-responsive lesions, reinforce the importance of local metabolism and differentiation competency.
Conclusions: Results from this trial substantiate the LOH reductions identified in the pilot BRB gel study and extend therapeutic effects to significant improvements in histologic grade and lesional size. Clin Cancer Res; 20(7); 1910–24. ©2014 AACR.
Electrophysiologic Profile and Results of Invasive Risk Stratification in Asymptomatic Children and Adolescents With the Wolff–Parkinson–White Electrocardiographic Pattern
Authors: Kubuš Peter , Vít Pavel , Gebauer Roman A. , Materna Ondřej , Janoušek Jan 
Published: February 2014

Background—
Data on the results and clinical effect of an invasive risk stratification strategy in asymptomatic young patients with the Wolff–Parkinson–White electrocardiographic pattern are scarce.

Methods and Results—
Eighty-five consecutive patients aged <18 years with a Wolff–Parkinson–White pattern and persistent preexcitation at maximum exercise undergoing invasive risk stratification were retrospectively studied. Adverse accessory pathway (AP) properties were defined according to currently consented criteria as any of the following: shortest preexcited RR interval during atrial fibrillation/rapid atrial pacing ≤250 ms (or antegrade effective refractory period ≤250 ms if shortest preexcited RR interval was not available) or inducible atrioventricular re-entrant tachycardia. Age at evaluation was median 14.9 years. Eighty-two patients had a structurally normal heart and 3 had hypertrophic cardiomyopathy. A single manifest AP was present in 80, 1 manifest and 1 concealed AP in 4, and 2 manifest APs in 1 patient. Adverse AP properties were present in 32 of 85 patients (37.6%) at baseline and in additional 16 of 44 (36.4%) after isoproterenol. Ablation was performed in 41 of these 48 patients. Ablation was deferred in the remaining 7 for pathway proximity to the atrioventricular node. In addition, 18 of the low-risk patients were ablated based on patient/parental decision.

Conclusions—
Adverse AP properties at baseline were exhibited by 37.6% of the evaluated patients with an asymptomatic Wolff–Parkinson–White preexcitation persisting at peak exercise. Isoproterenol challenge yielded additional 36.4% of those tested at higher risk. Ablation was performed in a total of 69.4% of patients subjected to invasive risk stratification.
Hospital Variation in Intravenous Inotrope Use for Patients Hospitalized With Heart Failure
Authors: Allen Larry A. , Fonarow Gregg C. , Grau-Sepulveda Maria V. , Hernandez Adrian F. , Peterson Pamela N. , Partovian Chohreh , Li Shu-Xia , Heidenreich Paul A. , Bhatt Deepak L. , Peterson Eric D. , Krumholz Harlan M. 
Published: February 2014

Background—
Prior claims analyses suggest that the use of intravenous inotropic therapy for patients hospitalized with heart failure varies substantially by hospital. Whether differences in the clinical characteristics of the patients explain observed differences in the use of inotropic therapy is not known.

Methods and Results—

We sought to characterize institutional variation in inotrope use among patients hospitalized with heart failure before and after accounting for clinical factors of patients. Hierarchical generalized linear regression models estimated risk-standardized hospital-level rates of inotrope use within 209 hospitals participating in Get With The Guidelines-Heart Failure (GWTG-HF) registry between 2005 and 2011. The association between risk-standardized rates of inotrope use and clinical outcomes was determined. Overall, an inotropic agent was administered in 7691 of 126 564 (6.1%) heart failure hospitalizations: dobutamine 43%, dopamine 24%, milrinone 17%, or a combination 16%. Patterns of inotrope use were stable during the 7-year study period. Use of inotropes varied significantly between hospitals even after accounting for patient and hospital characteristics (median risk-standardized hospital rate, 5.9%; interquartile range, 3.7%–8.6%; range, 1.3%–32.9%). After adjusting for case-mix and hospital structural differences, model intraclass correlation indicated that 21% of the observed variation in inotrope use was potentially attributable to random hospital effects (ie, institutional preferences). Hospitals with higher risk-standardized inotrope use had modestly longer risk-standardized length of stay (
P
=0.005) but had no difference in risk-standardized inpatient mortality (
P
=0.12)

Conclusions—
Use of intravenous inotropic agents during hospitalization for heart failure varies significantly among US hospitals even after accounting for patient and hospital factors.
Quantitative Doppler-Echocardiographic Imaging and Clinical Outcomes With Left Ventricular Systolic Dysfunction
Authors: Miller Wayne L. , Mahoney Douglas W. , Enriquez-Sarano Maurice 
Published: February 2014

Background—
Doppler-echocardiography provides quantitative imaging of systolic and diastolic left ventricular (LV) function, functional mitral regurgitation (FMR), and pulmonary hypertension (PH) in patients with LV systolic dysfunction. Whether PH is linked to survival independently of LV features and FMR in symptomatic and asymptomatic patients is unknown.

Methods and Results—

Patients with LV ejection fraction ≤40% and quantitative Doppler-echocardiography assessment of FMR and PH were studied. Patients were frequency matched for those with Doppler-echocardiography estimated pulmonary systolic pressure ≥45 mm Hg (n=692) and those without PH (n=692; pulmonary systolic pressure, <45 mm Hg) for age, sex, LV ejection fraction, and quantified FMR severity and analyzed for long-term survival after diagnosis. During follow-up (median, 8.9 years), 885 deaths (63.5%) occurred, with PH being associated with higher 5-year mortality: 51±2% versus 37±2%,
P
<0.001. In multivariate analysis, PH demonstrated increased mortality risk independent of age, sex, severity of diastolic and systolic LV dysfunction, FMR, comorbidities, and symptom (hazard ratio, 1.34; 95% confidence limit, 1.17–1.53;
P
<0.001). Subgroup analysis, stratified by symptoms, degree of FMR, and severity of LV dysfunction, demonstrated that PH was associated with excess mortality in all subgroups.

Conclusions—
In this large cohort of patients with LV systolic dysfunction, in whom FMR and LV characteristics were quantified and matched between those with and without PH, the presence of PH was an independent factor for excess mortality and not a surrogate for the severity of LV systolic dysfunction or FMR. In asymptomatic or symptomatic patients with or without FMR, PH is a critical marker for poor outcomes.
Innate Response Activator B Cells Aggravate Atherosclerosis by Stimulating T Helper-1 Adaptive Immunity
Authors: Hilgendorf Ingo , Theurl Igor , Gerhardt Louisa M.S. , Robbins Clinton S. , Weber Georg F. , Gonen Ayelet , Iwamoto Yoshiko , Degousee Norbert , Holderried Tobias A.W. , Winter Carla , Zirlik Andreas , Lin Herbert Y. , Sukhova Galina K. , Butany Jagdish , Rubin Barry B. , Witztum Joseph L. , Libby Peter , Nahrendorf Matthias , Weissleder Ralph , Swirski Filip K. 
Published: February 2014

Background—
Atherosclerotic lesions grow via the accumulation of leukocytes and oxidized lipoproteins in the vessel wall. Leukocytes can attenuate or augment atherosclerosis through the release of cytokines, chemokines, and other mediators. Deciphering how leukocytes develop, oppose, and complement each other’s function and shape the course of disease can illuminate our understanding of atherosclerosis. Innate response activator (IRA) B cells are a recently described population of granulocyte macrophage colony-stimulating factor–secreting cells of hitherto unknown function in atherosclerosis.

Methods and Results—
Here, we show that IRA B cells arise during atherosclerosis in mice and humans. In response to a high-cholesterol diet, IRA B cell numbers increase preferentially in secondary lymphoid organs via Myd88-dependent signaling. Mixed chimeric mice lacking B cell–derived granulocyte macrophage colony-stimulating factor develop smaller lesions with fewer macrophages and effector T cells. Mechanistically, IRA B cells promote the expansion of classic dendritic cells, which then generate interferon γ–producing T helper-1 cells. This IRA B cell–dependent T helper-1 skewing manifests in an IgG1-to-IgG2c isotype switch in the immunoglobulin response against oxidized lipoproteins.

Conclusions—
Granulocyte macrophage colony-stimulating factor–producing IRA B cells alter adaptive immune processes and shift the leukocyte response toward a T helper-1–associated milieu that aggravates atherosclerosis.
Trans‐Oral Brush Biopsies and Quantitative PCR for EBV DNA Detection and Screening of Nasopharyngeal Carcinoma
Authors: Ng Raymond H. W. , Ngan Roger , Wei William Ignace , Gullane Patrick J. , Phillips John 
Published: February 2014

ObjectivesTo evaluate a newly developed noninvasive ambulatory, quantitative polymerase chain reaction (Q‐PCR) Epstein‐Barr virus (EBV) DNA detection and screening system (NP Screen™) for nasopharyngeal carcinoma (NPC).Study DesignCorrelation of the nasopharyngeal epithelial EBV‐DNA levels and clinical findings by nasopharyngoscopy and final pathologic diagnosis of NPC with biopsy.SettingMulticenter ENT/Oncology clinics in Hong Kong (Radiation Oncology Clinic at the Queen Elizabeth Hospital and Radiation Oncology Clinic and Head and Neck Clinic, Queen Mary Hospital, University of Hong Kong) and in Toronto, Canada (the Otolaryngology‐Head and Neck Clinic at the Rouge Valley Health System and 2 large ENT practices in Toronto).MethodsA single‐use trans‐oral brush was used for rapid, nontraumatic nasopharyngeal (NP) epithelial cells DNA harvest in 600 Chinese patients, combined with a preservation and shipping kit for remote, real‐time Q‐PCR EBV DNA determinations.ResultsAll 600 patients had NP brushings using NP Screen in an ambulatory environment, and no adverse events or complications were recorded. A final 578 patients were included with sufficient amount of DNA for completion of the Q‐PCR assay. Of these 578 patients, 94 were confirmed positive for NPC histologically. The study yielded a sensitivity of 98.9%, specificity of 99.3%, positive predictive value (PPV) of 96.9%, and negative predictive value (NPP) of 99.7% for NP Screen in detecting NPC. Endoscopy had a sensitivity of 94%, specificity 97.1%, PPV 85%, and NPP 98.9%.ConclusionsThe trans‐oral brushing system fulfills the characteristics of a noninvasive, sensitive, specific detection method suitable for routine, large‐scale ambulatory NPC risk assessment for high‐risk NPC populations.