bluuebunny/crossref_metadata_2025_split huggingface dataset:
TIE-2 and VEGFR Kinase Activities Drive Immunosuppressive Function of TIE-2–Expressing Monocytes in Human Breast Tumors
Authors: Ibberson Mark , Bron Sylvian , Guex Nicolas , Faes-van't Hull Eveline , Ifticene-Treboux Assia , Henry Luc , Lehr Hans-Anton , Delaloye Jean-François , Coukos George , Xenarios Ioannis , Doucey Marie-Agnès 
Published: May 2013

Abstract
Purpose: Tumor-associated TIE-2–expressing monocytes (TEM) are highly proangiogenic cells critical for tumor vascularization. We previously showed that, in human breast cancer, TIE-2 and VEGFR pathways control proangiogenic activity of TEMs. Here, we examine the contribution of these pathways to immunosuppressive activity of TEMs.
Experimental Design: We investigated the changes in immunosuppressive activity of TEMs and gene expression in response to specific kinase inhibitors of TIE-2 and VEGFR. The ability of tumor TEMs to suppress tumor-specific T-cell response mediated by tumor dendritic cells (DC) was measured in vitro. Characterization of TEM and DC phenotype in addition to their interaction with T cells was done using confocal microscopic images analysis of breast carcinomas.
Results: TEMs from breast tumors are able to suppress tumor-specific immune responses. Importantly, proangiogenic and suppressive functions of TEMs are similarly driven by TIE-2 and VEGFR kinase activity. Furthermore, we show that tumor TEMs can function as antigen-presenting cells and elicit a weak proliferation of T cells. Blocking TIE-2 and VEGFR kinase activity induced TEMs to change their phenotype into cells with features of myeloid dendritic cells. We show that immunosuppressive activity of TEMs is associated with high CD86 surface expression and extensive engagement of T regulatory cells in breast tumors. TIE-2 and VEGFR kinase activity was also necessary to maintain high CD86 surface expression levels and to convert T cells into regulatory cells.
Conclusions: These results suggest that TEMs are plastic cells that can be reverted from suppressive, proangiogenic cells into cells that are able to mediate an antitumoral immune response. Clin Cancer Res; 19(13); 3439–49. ©2013 AACR.
Platinum-Based Chemotherapy for Variant Castrate-Resistant Prostate Cancer
Authors: Aparicio Ana M. , Harzstark Andrea L. , Corn Paul G. , Wen Sijin , Araujo John C. , Tu Shi-Ming , Pagliaro Lance C. , Kim Jeri , Millikan Randall E. , Ryan Charles , Tannir Nizar M. , Zurita Amado J. , Mathew Paul , Arap Wadih , Troncoso Patricia , Thall Peter F. , Logothetis Christopher J. 
Published: May 2013

Abstract
Purpose: Clinical features characteristic of small-cell prostate carcinoma (SCPC), “anaplastic,” often emerge during the progression of prostate cancer. We sought to determine the efficacy of platinum-based chemotherapy in patients meeting at least one of seven prospectively defined “anaplastic” clinical criteria, including exclusive visceral or predominantly lytic bone metastases, bulky tumor masses, low prostate-specific antigen levels relative to tumor burden, or short response to androgen deprivation therapy.
Experimental Design: A 120-patient phase II trial of first-line carboplatin and docetaxel (CD) and second-line etoposide and cisplatin (EP) was designed to provide reliable clinical response estimates under a Bayesian probability model with early stopping rules in place for futility and toxicity.
Results: Seventy-four of 113 (65.4%) and 24 of 71 (33.8%) were progression free after four cycles of CD and EP, respectively. Median overall survival (OS) was 16 months [95% confidence interval (CI), 13.6–19.0 months]. Of the seven “anaplastic” criteria, bulky tumor mass was significantly associated with poor outcome. Lactic acid dehydrogenase strongly predicted for OS and rapid progression. Serum carcinoembryonic antigen (CEA) concentration strongly predicted OS but not rapid progression. Neuroendocrine markers did not predict outcome or response to therapy.
Conclusion: Our findings support the hypothesis that patients with “anaplastic” prostate cancer are a recognizable subset characterized by a high response rate of short duration to platinum-containing chemotherapies, similar to SCPC. Our results suggest that CEA is useful for selecting therapy in men with castration-resistant prostate cancer and consolidative therapies to bulky high-grade tumor masses should be considered in this patient population. Clin Cancer Res; 19(13); 3621–30. ©2013 AACR.
Autophagy Opposes p53-Mediated Tumor Barrier to Facilitate Tumorigenesis in a Model of PALB2-Associated Hereditary Breast Cancer
Authors: Huo Yanying , Cai Hong , Teplova Irina , Bowman-Colin Christian , Chen Guanghua , Price Sandy , Barnard Nicola , Ganesan Shridar , Karantza Vassiliki , White Eileen , Xia Bing 
Published: May 2013

Abstract
Hereditary breast cancers stem from germline mutations in susceptibility genes such as BRCA1, BRCA2, and PALB2, whose products function in the DNA damage response and redox regulation. Autophagy is an intracellular waste disposal and stress mitigation mechanism important for alleviating oxidative stress and DNA damage response activation; it can either suppress or promote cancer, but its role in breast cancer is unknown. Here, we show that similar to Brca1 and Brca2, ablation of Palb2 in the mouse mammary gland resulted in tumor development with long latency, and the tumors harbored mutations in Trp53. Interestingly, impaired autophagy, due to monoallelic loss of the essential autophagy gene Becn1, reduced Palb2-associated mammary tumorigenesis in a Trp53–wild-type but not conditionally null background. These results indicate that, in the face of DNA damage and oxidative stress elicited by PALB2 loss, p53 is a barrier to cancer development, whereas autophagy facilitates cell survival and tumorigenesis.
Significance: Our findings directly show a tumor-promoting role of autophagy in a new model of hereditary breast cancer. Given the close functional relationship and the genetic similarity between PALB2 and BRCA1/2, our results further suggest that inhibition of autophagy may represent a new avenue to the prevention or treatment of a significant portion of hereditary breast cancers, namely those associated with DNA damage and oxidative stress. Cancer Discov; 3(8); 894–907. ©2013 AACR.
This article is highlighted in the In This Issue feature, p. 826
Classification of Acute Decompensated Heart Failure
Authors: Loehr Laura R. , Agarwal Sunil K. , Baggett Chris , Wruck Lisa M. , Chang Patricia P. , Solomon Scott D. , Shahar Eyal , Ni Hanyu , Rosamond Wayne D. , Heiss Gerardo 
Published: May 2013

Background—
An algorithm to classify heart failure (HF) end points inclusive of contemporary measures of biomarkers and echocardiography was recently proposed by an international expert panel. Our objective was to assess agreement of HF classification by this contemporaneous algorithm with that by a standardized physician reviewer panel, when applied to data abstracted from community-based hospital records.

Methods and Results—

During 2005–2007, all hospitalizations were identified from 4 US communities under surveillance as part of the Atherosclerosis Risk in Communities (ARIC) study. Potential HF hospitalizations were sampled by
International Classification of Diseases
discharge codes and demographics from men and women aged ≥55 years. The HF classification algorithm was automated and applied to 2729 (n=13 854 weighted hospitalizations) hospitalizations in which either brain natriuretic peptide measures or ejection fraction were documented (mean age, 75 years). There were 1403 (54%; n=7534 weighted) events classified as acute decompensated HF by the automated algorithm, and 1748 (68%; n=9276 weighted) such events by the ARIC reviewer panel. The chance-corrected agreement between acute decompensated HF by physician reviewer panel and the automated algorithm was moderate (κ=0.39). Sensitivity and specificity of the automated algorithm with ARIC reviewer panel as the referent standard were 0.68 (95% confidence interval, 0.67–0.69) and 0.75 (95% confidence interval, 0.74–0.76), respectively.

Conclusions—
Although the automated classification improved efficiency and decreased costs, its accuracy in classifying HF hospitalizations was modest compared with a standardized physician reviewer panel.
The Future of Diabetes Education
Authors: Martin Annette Lenzi , Lipman Ruth D. 
Published: May 2013

Purpose The purpose of the article is to explore challenges and opportunities associated with the state of practice for diabetes education and diabetes educators. Methods Observations, assumptions, predictions, and recommendations based on a literature review and the 2011 workforce study and workforce summit held by the American Association of Diabetes Educators (AADE) are presented. Results Demand for diabetes educators is projected to increase. The employer base will broaden beyond traditional outpatient venues and extend into industry, retail pharmacy clinics, and community-based organizations. Increasing roles in management, quality assurance, and technology interface design are possible for diabetes educators. Challenges limiting diabetes education such as poor understanding of what diabetes educators do and underutilization of diabetes education continue to need redress. Conclusions Increasing utilization of diabetes education and insight about health care trends can allow diabetes educators to thrive in the workplace of the future. Diabetes educators are urged to promote the evidence concerning the benefits of diabetes education, to work to increase physician referrals, and to acquire needed competencies for the workplace of the future.
Initial Validity and Reliability of the Banff Patella Instability Instrument
Authors: Hiemstra Laurie A. , Kerslake Sarah , Lafave Mark R. , Heard S. Mark , Buchko Gregory M.L. , Mohtadi Nicholas G.H. 
Published: May 2013

Background: Patellofemoral instability is a well-recognized problem, but there are currently no published patient-reported quality of life outcome measures that are disease specific for the treatment of this population. Purpose: To establish the content validity, initial construct validity, and initial reliability of the Banff Patella Instability Instrument (BPII). Study Design: Cohort study (diagnosis); Level of evidence, 2. Methods: The content of the BPII was validated using a modified 3-stage Ebel procedure and analysis of floor and ceiling effects. As a measure of internal consistency, the Cronbach α was utilized to assess how reliably the 32 items of the questionnaire measured a similar construct. Test-retest reliability of the BPII was calculated using an intraclass correlation coefficient (ICC). Construct validity was evaluated on 150 questionnaires completed by patients with a confirmed diagnosis of patellofemoral instability. A one-way between-group analysis of variance was employed to determine if the BPII was able to differentiate between patients presenting at the initial orthopaedic consultation relative to patients presenting at 6 months and 12 months postoperatively. Results: Content validity was clearly established as each item in the BPII achieved a minimum of 83.3% agreement (range, 83.3%-100%) for relevance among the expert panelists. The average agreement was 96.9%; 24 items achieved 100% agreement. There was no evidence of floor or ceiling effects. Reliability (internal consistency) of the BPII was established at the initial orthopaedic consultation (α = .91), 6 months postoperatively (α = .97), and 12 months postoperatively (α = .97). Test-retest analysis resulted in an ICC of 0.98 between tests. Construct validity was established as there was a statistically significant difference in BPII scores at the initial orthopaedic consultation and 6-month and 12-month postoperative appointments (F2,146 = 75.62; P < .001). Conclusion: The BPII demonstrates content validity, strong initial reliability, and a statistically significant level of construct validity in patients with patellofemoral instability. This population includes patients with recurrent patellofemoral instability as well as surgically stabilized patients.
Tibiotalocalcaneal Arthrodesis With Bulk Femoral Head Allograft for Salvage of Large Defects in the Ankle
Authors: Jeng Clifford L. , Campbell John T. , Tang Edward Y. , Cerrato Rebecca A. , Myerson Mark S. 
Published: May 2013

Background: Tibiotalocalcaneal arthrodesis in patients with large segmental bony defects presents a substantial challenge to successful reconstruction. These defects typically occur following failed total ankle replacement, avascular necrosis of the talus, trauma, osteomyelitis, Charcot, or failed reconstructive surgery. This study examined the outcomes of tibiotalocalcaneal (TTC) arthrodesis using bulk femoral head allograft to fill this defect. Methods: Thirty-two patients underwent TTC arthrodesis with bulk femoral head allograft. Patients who demonstrated radiographic union were contacted for SF-12 clinical scoring and repeat radiographs. Patients with asymptomatic nonunions were also contacted for SF-12 scoring alone. Preoperative, intraoperative, and postoperative factors were analyzed to determine positive predictors for successful fusion. Results: Sixteen patients healed their fusion (50% fusion rate). Diabetes mellitus was found to be the only predictive factor of outcome; all 9 patients with diabetes developed a nonunion. In this series, 19% of the patients went on to require a below-knee amputation. Conclusions: Although the radiographic fusion rate was low, when the 7 patients who had an asymptomatic nonunion were combined with the radiographic union group, the overall rate of functional limb salvage rose to 71%. TTC arthrodesis using femoral head allograft should be considered a salvage procedure that is technically difficult and carries a high risk for complications. Patients with diabetes mellitus are at an especially high risk for nonunion. Level of Evidence: Level IV, retrospective case series.
Leukemia surfaceome analysis reveals new disease-associated features
Authors: Mirkowska Paulina , Hofmann Andreas , Sedek Lukasz , Slamova Lucie , Mejstrikova Ester , Szczepanski Tomasz , Schmitz Maike , Cario Gunnar , Stanulla Martin , Schrappe Martin , van der Velden Vincent H. J. , Bornhauser Beat C. , Wollscheid Bernd , Bourquin Jean-Pierre 
Published: May 2013

Key PointsProteomic analysis of the leukemia cell surface reveals new leukemia-associated features with a potential to improve diagnostics. The ALL surfaceome is a resource for systematic functional exploration.
Characterization of a novel NKG2D and NKp46 double-mutant mouse reveals subtle variations in the NK cell repertoire
Authors: Sheppard Sam , Triulzi Chiara , Ardolino Michele , Serna Daniel , Zhang Lily , Raulet David H. , Guerra Nadia 
Published: May 2013

Key Points
NKG2D, but not NKp46, has a modest, NK cell intrinsic influence on shaping the NK cell receptor repertoire. NKG2D deficiency does not alter the NK cell response to MCMV infection.
The lupus anticoagulant: results from 2257 patients attending a high-risk pregnancy clinic
Authors: Clark Christine A. , Davidovits Judith , Spitzer Karen A. , Laskin Carl A. 
Published: May 2013

Key Points
Only 62 (2.7%) of 2257 high-risk patients tested positive for LAC over 6 years; only 5 (0.02%) with early recurrent miscarriage tested positive. The 2 assays recommended by ISTH guidelines were less effective than our 4-assay panel at capturing and describing LAC-positive patients.
Clinical features, anger management and anxiety: a possible correlation in migraine children
Authors: Tarantino Samuela , De Ranieri Cristiana , Dionisi Cecilia , Citti Monica , Capuano Alessandro , Galli Federica , Guidetti Vincenzo , Vigevano Federico , Gentile Simonetta , Presaghi Fabio , Valeriani Massimiliano 
Published: May 2013

AbstractBackgroundPsychological factors can increase severity and intensity of headaches. While great attention has been placed on the presence of anxiety and/or depression as a correlate to a high frequency of migraine attacks, very few studies have analyzed the management of frustration in children with headache. Aim of this study was to analyze the possible correlation between pediatric migraine severity (frequency and intensity of attacks) and the psychological profile, with particular attention to the anger management style.MethodsWe studied 62 migraineurs (mean age 11.2 ± 2.1 years; 29 M and 33 F). Patients were divided into four groups according to the attack frequency (low, intermediate, high frequency, and chronic migraine). Pain intensity was rated on a 3-levels graduate scale (mild, moderate and severe pain). Psychological profile was assessed by Picture Frustration Study test for anger management and SAFA-A scale for anxiety.ResultsWe found a relationship between IA/OD index (tendency to inhibit anger expression) and both attack frequency (r = 0.328, p = 0.041) and intensity (r = 0.413, p = 0.010). When we analyzed the relationship between anxiety and the headache features, a negative and significant correlation emerged between separation anxiety (SAFA-A Se) and the frequency of attacks (r = −0.409, p = 0.006). In our patients, the tendency to express and emphasize the presence of the frustrating obstacle (EA/OD index) showed a positive correlation with anxiety level (“Total anxiety” scale: r = 0.345; p = 0.033).ConclusionsOur results suggest that children suffering from severe migraine tend to inhibit their angry feelings. On the contrary, children with low migraine attack frequency express their anger and suffer from separation anxiety.
Odontogenic ameloblast-associated protein (ODAM) inhibits growth and migration of human melanoma cells and elicits PTEN elevation and inactivation of PI3K/AKT signaling
Authors: Foster James S , Fish Lindsay M , Phipps Jonathan E , Bruker Charles T , Lewis James M , Bell John L , Solomon Alan , Kestler Daniel P 
Published: May 2013

Abstract

Background
The Odontogenic Ameloblast-associated Protein (ODAM) is expressed in a wide range of normal epithelial, and neoplastic tissues, and we have posited that ODAM serves as a novel prognostic biomarker for breast cancer and melanoma. Transfection of ODAM into breast cancer cells yields suppression of cellular growth, motility, and in vivo tumorigenicity. Herein we have extended these studies to the effects of ODAM on cultured melanoma cell lines.

Methods
The A375 and C8161 melanoma cell lines were stably transfected with ODAM and assayed for properties associated with tumorigenicity including cell growth, motility, and extracellular matrix adhesion. In addition, ODAM–transfected cells were assayed for signal transduction via AKT which promotes cell proliferation and survival in many neoplasms.

Results
ODAM expression in A375 and C8161 cells strongly inhibited cell growth and motility in vitro, increased cell adhesion to extracellular matrix, and yielded significant cytoskeletal/morphologic rearrangement. Furthermore, AKT activity was downregulated by ODAM expression while an increase was noted in expression of the PTEN (phosphatase and tensin homolog on chromosome 10) tumor suppressor gene, an antagonist of AKT activation. Increased PTEN in ODAM-expressing cells was associated with increases in PTEN mRNA levels and de novo protein synthesis. Silencing of PTEN expression yielded recovery of AKT activity in ODAM-expressing melanoma cells. Similar PTEN elevation and inhibition of AKT by ODAM was observed in MDA-MB-231 breast cancer cells while ODAM expression had no effect in PTEN-deficient BT-549 breast cancer cells.

Conclusions
The apparent anti-neoplastic effects of ODAM in cultured melanoma and breast cancer cells are associated with increased PTEN expression, and suppression of AKT activity. This association should serve to clarify the clinical import of ODAM expression and any role it may serve as an indicator of tumor behavior.
Chronic inhibition of tumor cell-derived VEGF enhances the malignant phenotype of colorectal cancer cells
Authors: Yamagishi Naoko , Teshima-Kondo Shigetada , Masuda Kiyoshi , Nishida Kensei , Kuwano Yuki , Dang Duyen T , Dang Long H , Nikawa Takeshi , Rokutan Kazuhito 
Published: May 2013

Abstract

Background
Vascular endothelial growth factor-a (VEGF)-targeted therapies have become an important treatment for a number of human malignancies. The VEGF inhibitors are actually effective in several types of cancers, however, the benefits are transiently, and the vast majority of patients who initially respond to the therapies will develop resistance. One of possible mechanisms for the acquired resistance may be the direct effect(s) of VEGF inhibitors on tumor cells expressing VEGF receptors (VEGFR). Thus, we investigated here the direct effect of chronic VEGF inhibition on phenotype changes in human colorectal cancer (CRC) cells.

Methods
To chronically inhibit cancer cell-derived VEGF, human CRC cell lines (HCT116 and RKO) were chronically exposed (2 months) to an anti-VEGF monoclonal antibody (mAb) or were disrupted the Vegf gene (VEGF-KO). Effects of VEGF family members were blocked by treatment with a VEGF receptor tyrosine kinase inhibitor (VEGFR-TKI). Hypoxia-induced apoptosis under VEGF inhibited conditions was measured by TUNEL assay. Spheroid formation ability was assessed using a 3-D spheroid cell culture system.

Results
Chronic inhibition of secreted/extracellular VEGF by an anti-VEGF mAb redundantly increased VEGF family member (PlGF, VEGFR1 and VEGFR2), induced a resistance to hypoxia-induced apoptosis, and increased spheroid formation ability. This apoptotic resistance was partially abrogated by a VEGFR-TKI, which blocked the compensate pathway consisted of VEGF family members, or by knockdown of Vegf mRNA, which inhibited intracellular function(s) of all Vegf gene products. Interestingly, chronic and complete depletion of all Vegf gene products by Vegf gene knockout further augmented these phenotypes in the compensate pathway-independent manner. These accelerated phenotypes were significantly suppressed by knockdown of hypoxia-inducible factor-1α that was up-regulated in the VEGF-KO cell lines.

Conclusions
Our findings suggest that chronic inhibition of tumor cell-derived VEGF accelerates tumor cell malignant phenotypes.
Standard or hypofractionated radiotherapy in the postoperative treatment of breast cancer: a retrospective analysis of acute skin toxicity and dose inhomogeneities
Authors: Tortorelli Grazia , Di Murro Luana , Barbarino Rosaria , Cicchetti Sara , di Cristino Daniela , Falco Maria Daniela , Fedele Dahlia , Ingrosso Gianluca , Janniello Dania , Morelli Pasquale , Murgia Alessandra , Ponti Elisabetta , Terenzi Sara , Tolu Barbara , Santoni Riccardo 
Published: May 2013

Abstract

Background
To identify predictive factors of radiation-induced skin toxicity in breast cancer patients by the analysis of dosimetric and clinical factors.

Methods
339 patients treated between January 2007 and December 2010 are included in the present analysis. Whole breast irradiation was delivered with Conventional Fractionation (CF) (50Gy, 2.0/day, 25 fractions) and moderate Hypofractionated Schedule (HS) (44Gy, 2.75Gy/day, 16 fractions) followed by tumour bed boost. The impact of patient clinical features, systemic treatments and, in particular, dose inhomogeneities on the occurrence of different levels of skin reaction has been retrospectively evaluated.

Results
G2 and G3 acute skin toxicity were 42% and 13% in CF patients and 30% and 7.5% in HS patients respectively. The retrieval and revaluation of 200 treatment plans showed a strong correlation between areas close to the skin surface, with inhomogeneities >107% of the prescribed dose, and the desquamation areas as described in the clinical records.

Conclusions
In our experience dose inhomogeneity underneath G2 – G3 skin reactions seems to be the most important predictor for acute skin damage and in these patients more complex treatment techniques should be considered to avoid skin damage. Genetic polymorphisms too have to be investigated as possible promising candidates for predicting acute skin reactions.