bluuebunny/crossref_metadata_2025_split huggingface dataset:
miRNA-7 Attenuation in Schwannoma Tumors Stimulates Growth by Upregulating Three Oncogenic Signaling Pathways
Authors: Saydam Okay , Senol Ozlem , Würdinger Thomas , Mizrak Arda , Ozdener Gokhan Baris , Stemmer-Rachamimov Anat O. , Yi Ming , Stephens Robert M. , Krichevsky Anna M. , Saydam Nurten , Brenner Gary J. , Breakefield Xandra O. 
Published: December 2010

Abstract
Micro RNAs (miRNA) negatively regulate protein-coding genes at the posttranscriptional level and are critical in tumorigenesis. Schwannomas develop from proliferation of dedifferentiated Schwann cells, which normally wrap nerve fibers to help support and insulate nerves. In this study, we carried out high-throughput miRNA expression profiling of human vestibular schwannomas by using an array representing 407 known miRNAs to explore the role of miRNAs in tumor growth. Twelve miRNAs were found to be significantly deregulated in tumor samples as compared with control nerve tissue, defining a schwannoma-typical signature. Among these miRNAs, we focused on miR-7, which was one of the most downregulated in these tumors and has several known oncogene targets, including mRNAs for epidermal growth factor receptor (EGFR) and p21-activated kinase 1 (Pak1). We found that overexpression of miR-7 inhibited schwannoma cell growth both in culture and in xenograft tumor models in vivo, which correlated with downregulation of these signaling pathways. Furthermore, we identified a novel direct target of miR-7, the mRNA for associated cdc42 kinase 1 (Ack1), with the expression levels of miR-7 and Ack1 being inversely correlated in human schwannoma samples. These results represent the first miRNA profiling of schwannomas and the first report of a tumor suppressor function for miR-7 in these tumors that is mediated by targeting the EGFR, Pak1, and Ack1 oncogenes. Our findings suggest miR-7 as a potential therapeutic molecule for schwannoma treatment, and they prompt clinical evaluation of drugs that can inhibit the EGFR, Pak1, and Ack1 signaling pathways to treat this tumor type. Cancer Res; 71(3); 852–61. ©2010 AACR.
Bulky DNA Adducts in White Blood Cells: A Pooled Analysis of 3,600 Subjects
Authors: Ricceri Fulvio , Godschalk Roger W. , Peluso Marco , Phillips David H. , Agudo Antonio , Georgiadis Panagiotis , Loft Steffen , Tjonneland Anne , Raaschou-Nielsen Ole , Palli Domenico , Perera Frederica , Vermeulen Roel , Taioli Emanuela , Sram Radim J. , Munnia Armelle , Rosa Fabio , Allione Alessandra , Matullo Giuseppe , Vineis Paolo 
Published: December 2010

Abstract
Background: Bulky DNA adducts are markers of exposure to genotoxic aromatic compounds, which reflect the ability of an individual to metabolically activate carcinogens and to repair DNA damage. Polycyclic aromatic hydrocarbons (PAHs) represent a major class of carcinogens that are capable of forming such adducts. Factors that have been reported to be related to DNA adduct levels include smoking, diet, body mass index (BMI), genetic polymorphisms, the season of collection of biologic material, and air pollutants.
Methods: We pooled 11 studies (3,600 subjects) in which bulky DNA adducts were measured in human white blood cells with similar 32P-postlabeling techniques and for which a similar set of variables was available, including individual data on age, gender, ethnicity, batch, smoking habits, BMI, and season of blood collection, and a limited set of gene variants.
Results: Lowest DNA adduct levels (P = 0.006) were observed in the spring (median = 0.50 adducts per 108 nucleotides), followed by summer (0.64), autumn (0.70), and winter (0.85). The same pattern emerged in multivariate analysis but only among never smokers (P = 0.02). Adduct levels were significantly lower (P = 0.001) in northern Europe (the Netherlands and Denmark; mean = 0.60, median = 0.40) than in southern Europe (Italy, Spain, France, and Greece; mean = 0.79, median = 0.60).
Conclusions: In this large pooled analysis, we have found only weak associations between bulky DNA adducts and exposure variables. Seasonality (with higher adducts levels in winter) and air pollution may partly explain some of the interarea differences (north vs. south Europe), but most inter-area and interindividual variations in adduct levels still remain unexplained.
Impact: Our study describes the largest pooled analysis of bulky DNA adducts so far, showing that interindividual variation is still largely unexplained, though seasonality seems to play a role. Cancer Epidemiol Biomarkers Prev; 19(12); 3174–81. ©2010 AACR.
The Road from Discovery to Clinical Diagnostics: Lessons Learned from the First FDA-ClearedIn VitroDiagnostic Multivariate Index Assay of Proteomic Biomarkers
Authors: Zhang Zhen , Chan Daniel W. 
Published: December 2010

AbstractBackground: After more than a decade of biomarker discovery research using advanced genomic and proteomic technologies, very few biomarkers have been translated into clinical diagnostics for patient care. This has become an urgent issue to be addressed because the continuing funding from both the public and private sources are called into question.Methods: We use as an example, OVA1, the first in vitro diagnostic multivariate index assay (IVDMIA) of proteomic biomarkers recently cleared by the US FDA (Food and Drug Administration) to describe our experience through the long road from biomarker discovery, to validation, and finally to multi-institutional trial for regulatory approval by the FDA.Results: We discuss 3 issues that are key bridges in the path of biomarker development to actual clinical diagnostics: 1) to generate sufficient and “portable” evidence in preliminary validation studies to support investment for large-scale validation trials; 2) to carefully and clearly define clinical utility that balances desire for broad applicability and feasibility for completing clinical trials for regulatory approval; and 3) to select/develop assays with analytical performance suitable for clinical deployment.Conclusions: We learned that the road from biomarker discovery, validation, to clinical diagnostics could be long and winding, and often frustrating. However, we also know that, with the right approaches, at the end of the road, there is a rainbow waiting for us.Impact: Provide insights and recommendations for the translation of proteomic biomarkers into clinical diagnostics. Cancer Epidemiol Biomarkers Prev; 19(12); 2995–9. ©2010 AACR.
Volumetric Breast Density from Full-Field Digital Mammograms and Its Association with Breast Cancer Risk Factors: A Comparison with a Threshold Method
Authors: Lokate Mariëtte , Kallenberg Michiel G.J. , Karssemeijer Nico , Van den Bosch Maurice A.A.J. , Peeters Petra H.M. , Van Gils Carla H. 
Published: December 2010

Abstract
Introduction: Breast density, a strong breast cancer risk factor, is usually measured on the projected breast area from film screen mammograms. This is far from ideal, as breast thickness and technical characteristics are not taken into account. We investigated whether volumetric density measurements on full-field digital mammography (FFDM) are more strongly related to breast cancer risk factors than measurements with a computer-assisted threshold method.
Methods: Breast density was measured on FFDMs from 370 breast cancer screening participants, using a computer-assisted threshold method and a volumetric method. The distribution of breast cancer risk factors among quintiles of density was compared between both methods. We adjusted for age and body mass index (BMI) with linear regression analysis.
Results: High percent density was strongly related to younger age, lower BMI, nulliparity, late age at first delivery and pre/perimenopausal status, to the same extent with both methods (all P &lt; 0.05). Similarly strong relationships were seen for the absolute dense area but to a lesser extent for absolute dense volume. A larger dense volume was only significantly associated with late age at menopause, use of menopausal hormone therapy, and, in contrast to the other methods, high BMI.
Conclusion: Both methods related equally well to known breast cancer risk factors.
Impact: Despite its alleged higher precision, the volumetric method was not more strongly related to breast cancer risk factors. This is in agreement with other studies. The definitive relationship with breast cancer risk still needs to be investigated. Cancer Epidemiol Biomarkers Prev; 19(12); 3096–105. ©2010 AACR.
Dietary Benzo[a]pyrene Intake from Meat and the Risk of Colorectal Cancer
Authors: Tabatabaei Seyed Mehdi , Heyworth Jane S. , Knuiman Matthew W. , Fritschi Lin 
Published: December 2010

Abstract
Introduction: One possible mechanism for the postulated link between high consumption of meat and colorectal cancer (CRC) is the content of benzo[a]pyrene (BaP) in meat.
Methods: We investigated this association in a population-based case-control study in Western Australia (567 cases and 713 controls). Participants' self-report of meat consumption and lifestyle was used in conjunction with the CHARRED carcinogen database to estimate their BaP intake.
Results: Dietary exposure to BaP from meat consumption was not associated with the risk of CRC.
Conclusions: Our findings do not support the hypothesis that BaP exposure from meat consumption is a risk factor for CRC.
Impact statement: This large-scale case-control study used a detailed meat questionnaire in conjunction with the CHARRED database in a large population with high meat intake but was unable to find any association between intake of BaP and colorectal cancer. Cancer Epidemiol Biomarkers Prev; 19(12); 3182–4. ©2010 AACR.
New Strategies in Acute Lymphoblastic Leukemia: Translating Advances in Genomics into Clinical Practice
Authors: Mullighan Charles G. 
Published: December 2010

Abstract
B-precursor acute lymphoblastic leukemia (B-ALL) is the most common childhood malignancy and remains a leading cause of death in children and young adults. Current therapeutic approaches involve intensive combination chemotherapy, which fails in up to one quarter of patients. New treatment approaches directed against rational therapeutic targets are required. Recent genomic profiling of ALL has identified several genetic alterations associated with a high risk of treatment failure. Deletion or sequence mutation of the lymphoid transcription factor gene IKZF1 (IKAROS) is associated with a high rate of leukemic relapse, and testing for IKZF1 alterations at diagnosis may aid risk stratification. A subset of B-ALL patients with IKZF1 alterations have a transcriptional profile similar to BCR-ABL1–positive ALL, and these patients commonly have novel rearrangements and mutations resulting in aberrant cytokine receptor signaling and activation of kinase signaling cascades, including rearrangement of CRLF2 and activating mutations of Janus kinases (JAK1 and JAK2). JAK inhibitor therapy is under investigation in children with relapsed and refractory malignancies, including leukemia. Clin Cancer Res; 17(3); 396–400. ©2010 AACR.
Atlantic Hurricane Season of 2009
Authors: Berg Robert J. , Avila Lixion A. 
Published: December 2010

The 2009 Atlantic season was marked by below-average tropical cyclone activity with the formation of nine tropical storms, the fewest since the 1997 Atlantic hurricane season. Of these, three became hurricanes and two strengthened into major hurricanes (category 3 or higher on the Saffir–Simpson Hurricane Wind Scale). In addition, there were two tropical depressions that did not reach storm strength. The numbers of tropical storms and hurricanes were below the long-term averages of 11 named storms and 6 hurricanes, although the number of major hurricanes equaled the long-term average of 2. Many of the cyclones remained relatively weak. Only one tropical cyclone, Tropical Storm Claudette, made landfall in the United States, although Ida affected the northern Gulf Coast as a tropical storm before moving inland as an extratropical cyclone. Hurricane Bill and Tropical Storm Danny indirectly affected the East Coast by producing high surf, rip currents, and beach erosion; Bill also produced tropical storm conditions over Bermuda and parts of Atlantic Canada. Hurricane Ida made landfall in Nicaragua and also affected parts of Honduras, the Yucatan Peninsula of Mexico, and western Cuba. Tropical Storm Erika had minor effects on the northern Leeward Islands, mainly in the form of light rain, and Tropical Storm Grace moved through the Azores with little impact. The death toll from the 2009 Atlantic tropical cyclones was six. A verification of National Hurricane Center official forecasts during 2009 is also presented. Official track errors and forecast skill set records for accuracy at lead times between 24 and 72 h. Official intensity forecast errors were mostly larger than the previous 5-yr means, although intensity forecast skill was at or above historical highs since the intensity skill baseline [i.e., Decay-Statistical Hurricane Intensity Forecast model version 5 (Decay-SHIFOR5)] errors were well above average.
Repeat Concussions in the National Football League
Authors: Casson Ira R. , Viano David C. , Powell John W. , Pellman Elliot J. 
Published: December 2010

Background: Repeat concussion is an important issue in the National Football League (NFL). An initial description of repeat injuries was published for 6 years (1996-2001). Hypothesis: The characteristics and frequency of repeat concussion in the NFL have not changed in the subsequent 6 years (2002-2007). Study Design: Case control. Methods: From 1996 to 2007, concussions were reported using a standardized form documenting signs and symptoms, loss of consciousness and medical action taken. Data on repeat concussions were analyzed for the 12 years and compared between the 2 periods. Results: In 2002-2007, 152 players had repeat concussions (vs 160 in 1996-2001); 44 had 3+ head injuries (vs 52). The positions most often associated with repeat concussion in 2002-2007 were the defensive secondary, kick unit, running back, and linebacker. The odds for repeat concussion were elevated for wide receivers, tight ends, and linebackers but lower than in the earlier period. During 2002-2007, over half of players with repeat concussion were removed from play, and fewer immediately returned (vs 1996-2001). The average duration between concussions was 1.25 years for 2002-2007 and 1.65 years for the 12-year period. Over 12 years, 7.6% of all repeat concussions occurred within 2 weeks of the prior concussion. Conclusions: The defensive secondary, kick unit, running back, and linebacker have the highest incidence of repeat concussion. During 2002-2007, more than half of players with repeat concussion were removed from play, and only a fraction immediately returned. Although concussion was managed more conservatively by team physicians in the recent 6 years, repeat concussions occurred at similar rates during both periods.
Mutated RAS and constitutively activated Akt delineate distinct oncogenic pathways, which independently contribute to multiple myeloma cell survival
Authors: Steinbrunn Torsten , Stühmer Thorsten , Gattenlöhner Stefan , Rosenwald Andreas , Mottok Anja , Unzicker Christian , Einsele Hermann , Chatterjee Manik , Bargou Ralf C. 
Published: December 2010

AbstractWe have recently shown that approximately half of primary multiple myeloma (MM) samples display constitutive Akt activity, which disposes them for sensitivity to Akt inhibition. The Akt pathway counts among the signaling conduits for oncogenic RAS and activating mutations of K- and N-RAS frequently occur in MM. We therefore analyzed the relation between RAS mutation and Akt dependency in biopsies and CD138-purified cells from MM patients (n = 65) and the function of oncogenic RAS for MM cell survival in a range of MM cell lines with differing RAS status. Whereas RAS mutations do not predict Akt dependency, oncogenic RAS retains an important role for MM cell survival. Knockdown of either K- or N-RAS strongly decreased the viability of MM cells that harbored the respective oncogenic isoform, whereas ablation of wild-type RAS isoforms had little or no effect. Silencing of oncogenic RAS did not affect the Akt pathway, again indicating lack of a direct link. Combined inhibition of RAS and Akt strongly enhanced MM cell death. These data suggest that oncogenic RAS and Akt may independently contribute to MM cell survival. Targeting of both pathways could provide an attractive therapeutic strategy for patients with oncogenic RAS and dysregulated Akt signaling.
HIV-1 Vif promotes the G1- to S-phase cell-cycle transition
Authors: Wang Jiangfang , Reuschel Emma L. , Shackelford Jason M. , Jeang Lauren , Shivers Debra K. , Diehl J. Alan , Yu Xiao-Fang , Finkel Terri H. 
Published: December 2010

AbstractHIV-1 depends on host-cell resources for replication, access to which may be limited to a particular phase of the cell cycle. The HIV-encoded proteins Vpr (viral protein R) and Vif (viral infectivity factor) arrest cells in the G2 phase; however, alteration of other cell-cycle phases has not been reported. We show that Vif drives cells out of G1 and into the S phase. The effect of Vif on the G1-to-S transition is distinct from its effect on G2, because G2 arrest is Cullin5-dependent, whereas the G1-to-S progression is Cullin5-independent. Using mass spectrometry, we identified 2 novel cellular partners of Vif, Brd4 and Cdk9, both of which are known to regulate cell-cycle progression. We confirmed the interaction of Vif and Cdk9 by immunoprecipitation and Western blot, and showed that small interfering RNAs (siRNAs) specific for Cdk9 inhibit the Vif-mediated G1-to-S transition. These data suggest that Vif regulates early cell-cycle progression, with implications for infection and latency.
Decrease in Depression Symptoms Is Associated With Longer Survival in Patients With Metastatic Breast Cancer: A Secondary Analysis
Authors: Giese-Davis Janine , Collie Kate , Rancourt Kate M.S. , Neri Eric , Kraemer Helena C. , Spiegel David 
Published: December 2010

Purpose Numerous studies have examined the comorbidity of depression with cancer, and some have indicated that depression may be associated with cancer progression or survival. However, few studies have assessed whether changes in depression symptoms are associated with survival. Methods In a secondary analysis of a randomized trial of supportive-expressive group therapy, 125 women with metastatic breast cancer (MBC) completed a depression symptom measure (Center for Epidemiologic Studies–Depression Scale [CES-D]) at baseline and were randomly assigned to a treatment group or to a control group that received educational materials. At baseline and three follow-up points, 101 of 125 women completed a depression symptom measure. We used these data in a Cox proportional hazards analysis to examine whether decreasing depression symptoms over the first year of the study (the length of the intervention) would be associated with longer survival. Results Median survival time was 53.6 months for women with decreasing CES-D scores over 1 year and 25.1 months for women with increasing CES-D scores. There was a significant effect of change in CES-D over the first year on survival out to 14 years (P = .007) but no significant interaction between treatment condition and CES-D change on survival. Neither demographic nor medical variables explained this association. Conclusion Decreasing depression symptoms over the first year were associated with longer subsequent survival for women with MBC in this sample. Further research is necessary to confirm this hypothesis in other samples, and causation cannot be assumed based on this analysis.
Phase I Trial of a Personalized Peptide Vaccine for Patients Positive for Human Leukocyte Antigen–A24 With Recurrent or Progressive Glioblastoma Multiforme
Authors: Terasaki Mizuhiko , Shibui Soichiro , Narita Yoshitaka , Fujimaki Takamitsu , Aoki Tomokazu , Kajiwara Koji , Sawamura Yutaka , Kurisu Kaoru , Mineta Toshihiro , Yamada Akira , Itoh Kyogo 
Published: December 2010

Purpose Personalized selection of suitable peptides for patients could offer a novel approach to developing cancer vaccines that boost anticancer immunity. We present the results of a phase I trial of 14 kinds of vaccine candidates (ITK-1) in patients with recurrent or progressive glioblastoma multiforme (GBM). Patients and Methods From January 2006 to January 2008, 12 patients from eight Japanese hospitals who were positive for human leukocyte antigen–A24, including 10 patients refractory to temozolomide (TMZ), were enrolled. The dose escalation trial included three dose groups (1, 3, and 5 mg) to determine the safety and tolerability of ITK-1 peptides. Immunologic response was monitored by measuring levels of cytotoxic T-lymphocyte precursors and peptide-specific immunoglobulin G. In another ITK-1 phase I trial for advanced prostate cancer, the vaccination schedule was skipped or discontinued in all three patients receiving the highest dose (5 mg/peptide) because of injection site reactions. This trial was therefore ended without enrollment for the highest dose, and data were analyzed by intention to treat. Results No serious adverse drug reactions were encountered, and treatment was well tolerated. The vaccine induced dose-dependent immune boosting. The recommended dose of ITK-1 peptides is 3 mg/peptide. Conclusion Personalized vaccination with ITK-1 peptides could be recommended in further stages of clinical trials. The safety and increased frequency of immune boosting offers potential clinical benefits in cases of recurrent or progressive GBM, even in TMZ-refractory settings.
Safety, Pharmacokinetics, and Immunomodulatory Effects of Lenalidomide in Children and Adolescents With Relapsed/Refractory Solid Tumors or Myelodysplastic Syndrome: A Children's Oncology Group Phase I Consortium Report
Authors: Berg Stacey L. , Cairo Mitchell S. , Russell Heidi , Ayello Janet , Ingle Ashish Mark , Lau Henry , Chen Nianhang , Adamson Peter C. , Blaney Susan M. 
Published: December 2010

PurposeTo determine the maximum-tolerated or recommended phase II dose, dose-limiting toxicities (DLTs), pharmacokinetics (PK), and immunomodulatory effects of lenalidomide in children with recurrent or refractory solid tumors or myelodysplastic syndrome (MDS).Patients and MethodsCohorts of children with solid tumors received lenalidomide once daily for 21 days, every 28 days at dose levels of 15 to 70 mg/m2/dose. Children with MDS received a fixed dose of 5 mg/m2/dose. Specimens for PK and immune modulation were obtained in the first cycle.ResultsForty-nine patients (46 solid tumor, three MDS), median age 16 years (range, 1 to 21 years), were enrolled, and 42 were fully assessable for toxicity. One patient had a cerebrovascular ischemic event of uncertain relationship to lenalidomide. DLTs included hypercalcemia at 15 mg/m2; hypophosphatemia/hypokalemia, neutropenia, and somnolence at 40 mg/m2; and urticaria at 55 mg/m2. At the highest dose level evaluated (70 mg/m2), zero of six patients had DLT. A maximum-tolerated dose was not reached. No objective responses were observed. PK studies (n = 29) showed that clearance is faster in children younger than 12 years of age. Immunomodulatory studies (n = 26) showed a significant increase in serum interleukin (IL) -2, IL-15, granulocyte-macrophage colony-stimulating factor, natural killer (NK) cells, NK cytotoxicity, and lymphokine activated killer (LAK) cytoxicity, and a significant decrease in CD4+/CD25+regulatory T cells.ConclusionLenalidomide is well-tolerated at doses up to 70 mg/m2/d for 21 days in children with solid tumors. Drug clearance in children younger than 12 years is faster than in adolescents and young adults. Lenalidomide significantly upregulates cellular immunity, including NK and LAK activity.