bluuebunny/crossref_metadata_2025_split huggingface dataset:
Study of a Biparametric Family of Iterative Methods
Authors: Campos B. , Cordero A. , Magreñán Á. A. , Torregrosa J. R. , Vindel P. 
Published: December 2014

The dynamics of a biparametric family for solving nonlinear equations is studied on quadratic polynomials. This biparametric family includes thec-iterative methods and the well-known Chebyshev-Halley family. We find the analytical expressions for the fixed and critical points by solving 6-degree polynomials. We use the free critical points to get the parameter planes and, by observing them, we specify some values of(α, c)with clear stable and unstable behaviors.
Intraindividual Variation and Short-term Temporal Trend in DNA Methylation of Human Blood
Authors: Shvetsov Yurii B. , Song Min-Ae , Cai Qiuyin , Tiirikainen Maarit , Xiang Yong-Bing , Shu Xiao-Ou , Yu Herbert 
Published: December 2014

Abstract
Background: Between- and within-person variation in DNA methylation levels are important parameters to be considered in epigenome-wide association studies. Temporal change is one source of within-person variation in DNA methylation that has been linked to aging and disease.
Methods: We analyzed CpG-site–specific intraindividual variation and short-term temporal trend in leukocyte DNA methylation among 24 healthy Chinese women, with blood samples drawn at study entry and after 9 months. Illumina HumanMethylation450 BeadChip was used to measure methylation. Intraclass correlation coefficients (ICC) and trend estimates were summarized by genomic location and probe type.
Results: The median ICC was 0.36 across nonsex chromosomes and 0.80 on the X chromosome. There was little difference in ICC profiles by genomic region and probe type. Among CpG loci with high variability between participants, more than 99% had ICC &gt; 0.8. Statistically significant trend was observed in 10.9% CpG loci before adjustment for cell-type composition and in 3.4% loci after adjustment.
Conclusions: For CpG loci differentially methylated across subjects, methylation levels can be reliably assessed with one blood sample. More samples per subject are needed for low-variability and unmethylated loci. Temporal changes are largely driven by changes in cell-type composition of blood samples, but temporal trend unrelated to cell types is detected in a small percentage of CpG sites.
Impact: This study shows that one measurement can reliably assess methylation of differentially methylated CpG loci. Cancer Epidemiol Biomarkers Prev; 24(3); 490–7. ©2014 AACR.
A Pooled Analysis of Cigarette Smoking and Risk of Multiple Myeloma from the International Multiple Myeloma Consortium
Authors: Andreotti Gabriella , Birmann Brenda M. , Cozen Wendy , De Roos Anneclaire J. , Chiu Brian C.H. , Costas Laura , de Sanjosé Silvia , Moysich Kirsten , Camp Nicola J. , Spinelli John J. , Pahwa Punam , Dosman James A. , McLaughlin John R. , Boffetta Paolo , Staines Anthony , Weisenburger Dennis , Benhaim-Luzon Véronique , Brennan Paul , Costantini Adele Seniori , Miligi Lucia , Campagna Marcello , Nieters Alexandra , Becker Nikolaus , Maynadié Marc , Foretová Lenka , Zheng Tongzhang , Tricot Guido , Milliken Kevin , Krzystan Joseph , Steplowski Emily , Baris Dalsu , Purdue Mark P. 
Published: December 2014

Abstract
Background: Past investigations of cigarette smoking and multiple myeloma have been underpowered to detect moderate associations, particularly within subgroups. To clarify this association, we conducted a pooled analysis of nine case–control studies in the International Multiple Myeloma Consortium, with individual-level questionnaire data on cigarette smoking history and other covariates.
Methods: Using a pooled population of 2,670 cases and 11,913 controls, we computed odds ratios (OR) and 95% confidence intervals (CI) relating smoking to multiple myeloma risk using unconditional logistic regression adjusting for gender, age group, race, education, body mass index, alcohol consumption, and study center.
Results: Neither ever smokers (OR, 0.95; 95% CI, 0.87–1.05), current smokers (OR, 0.82; 95% CI, 0.73–0.93), nor former smokers (OR, 1.03; 95% CI, 0.92–1.14) had increased risks of multiple myeloma compared with never smokers. Analyses of smoking frequency, pack-years, and duration did not reveal significant or consistent patterns, and there was no significant effect modification by subgroups.
Conclusion: Findings from this large pooled analysis do not support the hypothesis of cigarette smoking as a causal factor for multiple myeloma.
Impact: Cigarette smoking is one of the most important risk factors for cancer, but the association with multiple myeloma was inconclusive. This study had excellent power to detect modest associations, and had individual-level data to evaluate confounding and effect modification by potentially important factors that were not evaluated in previous studies. Our findings confirm that smoking is not a risk factor for multiple myeloma. Cancer Epidemiol Biomarkers Prev; 24(3); 631–4. ©2014 AACR.
Epigenetics Markers of Metastasis and HPV-Induced Tumorigenesis in Penile Cancer
Authors: Feber Andrew , Arya Manit , de Winter Patricia , Saqib Muhammad , Nigam Raj , Malone Peter R. , Tan Wei Shen , Rodney Simon , Lechner Matthias , Freeman Alex , Jameson Charles , Muneer Asif , Beck Stephan , Kelly John D. 
Published: December 2014

Abstract
Purpose: Penile cancer is a rare malignancy in the developed world with just more than 1,600 new cases diagnosed in the United States per year; however, the incidence is much higher in developing countries. Although HPV is known to contribute to tumorigenesis, little is known about the genetic or epigenetic alterations defining penile cancer.
Experimental Design: Using high-density genome-wide methylation arrays, we have identified epigenetic alterations associated with penile cancer. Q-MSP was used to validate lymph node metastasis markers in 50 cases. A total of 446 head and neck squamous cell carcinoma (HNSCC) and cervical squamous cell carcinoma (CESCC) samples were used to validate HPV-associated epigenetic alterations.
Results: We defined 6,933 methylation variable positions (MVP) between normal and tumor tissue, which includes 997 hypermethylated differentially methylated regions associated with tumor supressor genes, including CDO1, AR1, and WT1. Analysis of penile cancer tumors identified a 4 gene epi-signature which accurately predicted lymph node metastasis in an independent cohort (AUC of 89%). Finally, we explored the epigenetic alterations associated with penile cancer HPV infection and defined a 30 loci lineage-independent HPV specific epi-signature which predicts HPV status and survival in independent HNSCC, CESC cohorts. Epi-signature–negative patients have a significantly worse overall survival [HNSCC P = 0.00073; 95% confidence interval (CI), 0.021–0.78; CESC P = 0.0094; HR = 3.91, 95% CI = 0.13–0.78], HPV epi-signature is a better predictor of survival than HPV status alone.
Conclusions: These data demonstrate for the first time genome-wide epigenetic events involved in an aggressive penile cancer phenotype and define the epigenetic alterations common across multiple HPV-driven malignancies. Clin Cancer Res; 21(5); 1196–206. ©2014 AACR.
Pathological Response and Circulating Tumor Cell Count Identifies Treated HER2+ Inflammatory Breast Cancer Patients with Excellent Prognosis: BEVERLY-2 Survival Data
Authors: Pierga Jean-Yves , Petit Thierry , Lévy Christelle , Ferrero Jean-Marc , Campone Mario , Gligorov Joseph , Lerebours Florence , Roché Henri , Bachelot Thomas , Charafe-Jauffret Emmanuelle , Bonneterre Jacques , Hernandez Juana , Bidard François-Clément , Viens Patrice 
Published: December 2014

Abstract
Purpose: The BEVERLY-2 single-arm phase II trial assessed the efficacy and safety of combining neoadjuvant chemotherapy with bevacizumab and trastuzumab for the treatment of HER2-positive inflammatory breast cancer (IBC). Here, we report the results of a preplanned survival analysis at 3 years of follow-up, along with the association between outcome and circulating biomarkers and pathologic complete response (pCR).
Experimental Design: Patients received fluorouracil, epirubicin, cyclophosphamide, and bevacizumab (cycles 1–4) and docetaxel, trastuzumab, and bevacizumab (cycles 5–8) before surgery, followed by trastuzumab and bevacizumab for 30 weeks after surgery. Circulating tumor cell (CTC) and endothelial cell (CEC) counts were assessed at baseline, cycle 5, preoperative, postoperative, and at 1 year.
Results: Fifty-two patients were included. The 3-year disease-free survival (DFS) rate was 68% and overall survival (OS) rate was 90%. pCR (centrally reviewed) was strongly associated with 3-year DFS [80% and 53% in patients with/without pCR, respectively (P = 0.03)]. CTC detection also independently predicted 3-year DFS [81% vs. 43% for patients with &lt;1 vs. ≥1 CTC/7.5 mL at baseline (P = 0.01)]. Patients with no CTCs detected at baseline and with pCR had a high 3-year DFS (95%). CEC changes during treatment had no prognostic value.
Conclusions: Our study suggests that the prognosis of IBC relies on more than the achievement of pCR and highlights the role of early hematogenous tumor dissemination as assessed by CTCs. Combining these two prognostic factors isolates a subgroup of IBC with excellent survival when treated with bevacizumab- and trastuzumab-containing regimens. Clin Cancer Res; 21(6); 1298–304. ©2014 AACR.
Angiogenic Cytokines Are Antibody Targets During Graft-versus-Leukemia Reactions
Authors: Piesche Matthias , Ho Vincent T. , Kim Haesook , Nakazaki Yukoh , Nehil Michael , Yaghi Nasser K. , Kolodin Dmitriy , Weiser Jeremy , Altevogt Peter , Kiefel Helena , Alyea Edwin P. , Antin Joseph H. , Cutler Corey , Koreth John , Canning Christine , Ritz Jerome , Soiffer Robert J. , Dranoff Glenn 
Published: December 2014

Abstract
Purpose: The graft-versus-leukemia (GVL) reaction is an important example of immune-mediated tumor destruction. A coordinated humoral and cellular response accomplishes leukemia cell killing, but the specific targets remain largely uncharacterized. To learn more about the antigens that elicit antibodies during GVL reactions, we analyzed patients with advanced myelodysplasia (MDS) and acute myelogenous leukemia (AML) who received an autologous, granulocyte-macrophage colony-stimulating factor (GM-CSF)–secreting tumor cell vaccine early after allogeneic hematopoietic stem cell transplantation (HSCT).
Experimental Design: A combination of tumor-derived cDNA expression library screening, protein microarrays, and antigen-specific ELISAs were used to characterize sera obtained longitudinally from 15 patients with AML/MDS who were vaccinated early after allogeneic HSCT.
Results: A broad, therapy-induced antibody response was uncovered, which primarily targeted intracellular proteins that function in growth, transcription/translation, metabolism, and homeostasis. Unexpectedly, antibodies were also elicited against eight secreted angiogenic cytokines that play critical roles in leukemogenesis. Antibodies to the angiogenic cytokines were evident early after therapy, and in some patients manifested a diversification in reactivity over time. Patients that developed antibodies to multiple angiogenic cytokines showed prolonged remission and survival.
Conclusions: These results reveal a potent humoral response during GVL reactions induced with vaccination early after allogeneic HSCT and raise the possibility that antibodies, in conjunction with natural killer cells and T lymphocytes, may contribute to immune-mediated control of myeloid leukemias. Clin Cancer Res; 21(5); 1010–8. ©2014 AACR.
Correlation of PD-L1 Tumor Expression and Treatment Outcomes in Patients with Renal Cell Carcinoma Receiving Sunitinib or Pazopanib: Results from COMPARZ, a Randomized Controlled Trial
Authors: Choueiri Toni K. , Figueroa David J. , Fay André P. , Signoretti Sabina , Liu Yuan , Gagnon Robert , Deen Keith , Carpenter Christopher , Benson Peter , Ho Thai H. , Pandite Lini , de Souza Paul , Powles Thomas , Motzer Robert J. 
Published: December 2014

Abstract
Purpose: The interaction of programmed death-1 ligand (PD-L1) with its receptor (PD-1) on T cells inactivates antitumor immune responses. PD-L1 expression has been associated with poor outcomes in renal cell carcinoma (RCC) but has not been investigated in advanced RCC patients receiving VEGF-targeted therapy.
Experimental Design: Formalin-fixed paraffin-embedded specimens were collected at baseline from patients in the COMPARZ trial. Tumor cell PD-L1 expression by IHC was evaluated using H-score (HS). Dual PD-L1/CD68 staining was used to differentiate PD-L1 tumor expression from tumor-associated macrophages. Intratumor CD8-positive T cells were quantified morphometrically. Associations between biomarkers and survival were investigated using the log-rank test.
Results: HS data were available from 453 of 1,110 patients. Sixty-four percent of patients had negative PD-L1 expression (HS = 0). Patients with HS &gt; 55 (n = 59, 13%) had significantly shorter overall survival (OS) than those with HS ≤ 55 in both pazopanib and sunitinib arms (median 15.1 vs. 35.6 and 15.3 vs. 27.8 months, respectively, P = 0.03). In both arms, median OS was shortest in patients with HS &gt; 55 and intratumor CD8-positive T-cell counts &gt; 300 (9.6 and 11.9 months with pazopanib and sunitinib, respectively). Median OS in patients with HS ≤ 55 and CD8-positive T-cell counts ≤ 300 was 36.8 and 28.0 months with pazopanib and sunitinib, respectively. Progression-free survival results were similar to OS results.
Conclusions: Increased tumor cell PD-L1, or PD-L1 plus tumor CD8-positive T-cell counts, were associated with shorter survival in patients with metastatic RCC receiving VEGF-targeted agents. These findings may have implications for future design of randomized clinical trials in advanced RCC. Clin Cancer Res; 21(5); 1071–7. ©2014 AACR.
Impaired Self-Renewal and Increased Colitis and Dysplastic Lesions in Colonic Mucosa of AKR1B8-Deficient Mice
Authors: Shen Yi , Ma Jun , Yan Ruilan , Ling Hongyan , Li Xiaoning , Yang Wancai , Gao John , Huang Chenfei , Bu Yiwen , Cao Yu , He Yingchun , Wan Laxiang , Zu Xuyu , Liu Jianghua , Huang Mei Chris , Stenson William F. , Liao Duan-Fang , Cao Deliang 
Published: December 2014

Abstract
Purpose: Ulcerative colitis and colitis-associated colorectal cancer (CAC) is a serious health issue, but etiopathological factors remain unclear. Aldo-keto reductase 1B10 (AKR1B10) is specifically expressed in the colonic epithelium, but downregulated in colorectal cancer. This study was aimed to investigate the etiopathogenic role of AKR1B10 in ulcerative colitis and CAC.
Experimental Design: Ulcerative colitis and CAC biopsies (paraffin-embedded sections) and frozen tissues were collected to examine AKR1B10 expression. Aldo-keto reductase 1B8 (the ortholog of human AKR1B10) knockout (AKR1B8−/−) mice were produced to estimate its role in the susceptibility and severity of chronic colitis and associated dysplastic lesions, induced by dextran sulfate sodium (DSS) at a low dose (2%). Genome-wide exome sequencing was used to profile DNA damage in DSS-induced colitis and tumors.
Results: AKR1B10 expression was markedly diminished in over 90% of ulcerative colitis and CAC tissues. AKR1B8 deficiency led to reduced lipid synthesis from butyrate and diminished proliferation of colonic epithelial cells. The DSS-treated AKR1B8−/− mice demonstrated impaired injury repair of colonic epithelium and more severe bleeding, inflammation, and ulceration. These AKR1B8−/− mice had more severe oxidative stress and DNA damage, and dysplasias were more frequent and at a higher grade in the AKR1B8−/− mice than in wild-type mice. Palpable masses were seen in the AKR1B8−/− mice only, not in wild-type.
Conclusions: AKR1B8 is a critical protein in the proliferation and injury repair of the colonic epithelium and in the pathogenesis of ulcerative colitis and CAC, being a new etiopathogenic factor of these diseases. Clin Cancer Res; 21(6); 1466–76. ©2014 AACR.
Systemic High-Dose Corticosteroid Treatment Does Not Improve the Outcome of Ipilimumab-Related Hypophysitis: A Retrospective Cohort Study
Authors: Min Le , Hodi Frank Stephen , Giobbie-Hurder Anita , Ott Patrick A. , Luke Jason J. , Donahue Hilary , Davis Meredith , Carroll Rona S. , Kaiser Ursula B. 
Published: December 2014

Abstract
Purpose: To examine the onset and outcome of ipilimumab-related hypophysitis and the response to treatment with systemic high-dose corticosteroids (HDS).
Experimental Design: Twenty-five patients who developed ipilimumab-related hypophysitis were analyzed for the incidence, time to onset, time to resolution, frequency of resolution, and the effect of systemic HDS on clinical outcome. To calculate the incidence, the total number (187) of patients with metastatic melanoma treated with ipilimumab at Dana-Farber Cancer Institute (DFCI; Boston, MA) was retrieved from the DFCI oncology database. Comparisons between corticosteroid treatment groups were performed using the Fisher exact test. The distributions of overall survival were based on the method of Kaplan–Meier.
Results: The overall incidence of ipilimumab-related hypophysitis was 13%, with a higher rate in males (16.1%) than females (8.7%). The median time to onset of hypophysitis after initiation of ipilimumab treatment was 9 weeks (range, 5–36 weeks). Resolution of pituitary enlargement, secondary adrenal insufficiency, secondary hypothyroidism, male secondary hypogonadism, and hyponatremia occurred in 73%, 0%, 64%, 45%, and 92% of patients, respectively. Systemic HDS treatment did not improve the outcome of hypophysitis as measured by resolution frequency and time to resolution. One-year overall survival in the cohort of patients was 83%, and while it was slightly higher in patients who did not receive HDS, there was no statistically significant difference between treatment arms.
Conclusion: Systemic HDS therapy in patients with ipilimumab-related hypophysitis may not be indicated. Instead, supportive treatment of hypophysitis-related hormone deficiencies with the corresponding hormone replacement should be given. Clin Cancer Res; 21(4); 749–55. ©2014 AACR.
Dynamic Epigenetic Regulation by Menin During Pancreatic Islet Tumor Formation
Authors: Lin Wenchu , Watanabe Hideo , Peng Shouyong , Francis Joshua M. , Kaplan Nathan , Pedamallu Chandra Sekhar , Ramachandran Aruna , Agoston Agoston , Bass Adam J. , Meyerson Matthew 
Published: December 2014

Abstract
The tumor suppressor gene MEN1 is frequently mutated in sporadic pancreatic neuroendocrine tumors (PanNET) and is responsible for the familial multiple endocrine neoplasia type 1 (MEN-1) cancer syndrome. Menin, the protein product of MEN1, associates with the histone methyltransferases (HMT) MLL1 (KMT2A) and MLL4 (KMT2B) to form menin–HMT complexes in both human and mouse model systems. To elucidate the role of methylation of histone H3 at lysine 4 (H3K4) mediated by menin–HMT complexes during PanNET formation, genome-wide histone H3 lysine 4 trimethylation (H3K4me3) signals were mapped in pancreatic islets using unbiased chromatin immunoprecipitation coupled with next-generation sequencing (ChIP-seq). Integrative analysis of gene expression profiles and histone H3K4me3 levels identified a number of transcripts and target genes dependent on menin. In the absence of Men1, histone H3K27me3 levels are enriched, with a concomitant decrease in H3K4me3 within the promoters of these target genes. In particular, expression of the insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2) gene is subject to dynamic epigenetic regulation by Men1-dependent histone modification in a time-dependent manner. Decreased expression of IGF2BP2 in Men1-deficient hyperplastic pancreatic islets is partially reversed by ablation of RBP2 (KDM5A), a histone H3K4-specific demethylase of the jumonji, AT-rich interactive domain 1 (JARID1) family. Taken together, these data demonstrate that loss of Men1 in pancreatic islet cells alters the epigenetic landscape of its target genes.
Implications: Epigenetic profiling and gene expression analysis in Men1-deficient pancreatic islet cells reveals vital insight into the molecular events that occur during the progression of pancreatic islet tumorigenesis. Mol Cancer Res; 13(4); 689–98. ©2014 AACR.
Progress in Late Results Among Pediatric Cardiac Surgery Patients
Authors: Raissadati Alireza , Nieminen Heta , Jokinen Eero , Sairanen Heikki 
Published: December 2014

Background—
Surgical treatment of congenital cardiac defects in Finland started >60 years ago. We analyzed the survival of all the pediatric cardiac surgery patients operated on before 2010.

Methods and Results—

Data were obtained retrospectively from a pediatric cardiac surgery database. Patient status was received from the Finnish Population Registry. Survival was determined with the Kaplan–Meier method, and the survival rate was compared with a sex- and age-matched general population. Between 1953 and 2009, 13 876 cardiac operations were performed on 10 964 pediatric patients in Finland. Follow-up coverage was 98%. The 60-year survival for the entire study was 70% versus 86% for the general population. The number and proportion of severe cardiac defects increased in the 2000s. The long-term survival of patients with severe defects improved significantly across decades. For instance, the 22-year survival rate of patients with transposition of the great arteries operated on in 1953 to 1989 and in 1990 to 2009 improved from 71% to 93% (hazard ratio for death, 0.29; 95% confidence interval, 0.17–0.49;
P
<0.0001), respectively. The mean patient age at operation decreased from 8.9 to 2.2 years (95% confidence interval, 6.2–7.1;
P
<0.0001). The early mortality of patients decreased from a maximum of 7% in the 1970s to 3% in the 2000s (95% confidence interval, 0.05–0.08;
P
<0.0001).

Conclusions—
Patients are diagnosed and treated at an increasingly younger age. Advanced diagnostics, surgical methods, and postoperative intensive care have led to substantial improvements in both early and late results among pediatric cardiac surgery patients.
Achievements in Congenital Heart Defect Surgery
Authors: Erikssen Gunnar , Liestøl Knut , Seem Egil , Birkeland Sigurd , Saatvedt Kjell Johan , Hoel Tom Nilsen , Døhlen Gaute , Skulstad Helge , Svennevig Jan Ludvig , Thaulow Erik , Lindberg Harald Lauritz 
Published: December 2014

Background—
This article presents an update of the results achieved by modern surgery in congenital heart defects (CHDs) over the past 40 years regarding survival and the need for reoperations, especially focusing on the results from the past 2 decades.

Methods and Results—

From 1971 to 2011, all 7038 patients <16 years of age undergoing surgical treatment for CHD at Rikshospitalet (Oslo, Norway) were enrolled prospectively. CHD diagnosis, date, and type of all operations were recorded, as was all-cause mortality until December 31, 2012. CHDs were classified as simple (3751/7038=53.2%), complex (2918/7038=41.5%), or miscellaneous (369/7037=5.2%). Parallel to a marked, sequential increase in operations for complex defects, median age at first operation decreased from 1.6 years in 1971 to 1979 to 0.19 years in 2000 to 2011. In total, 1033 died before January 1, 2013. Cumulative survival until 16 years of age in complex CHD operated on in 1971 to 1989 versus 1990 to 2011 was 62.4% versus 86.9% (
P
<0.0001). In the comparison of patients operated on in 2000 to 2004 versus 2005 to 2011, 1-year survival was 90.7% versus 96.5% (
P
=0.003), and 5-year cumulative survival was 88.8% versus 95.0% (
P
=0.0003). In simple versus complex defects, 434 (11.6%) versus 985 (33.8%) patients needed at least 1 reoperation before 16 years of age. In complex defects, 5-year cumulative freedom of reoperation among patients operated on in 1990 to 1999 versus 2000 to 2011 was 66% versus 73% (
P
=0.0001).

Conclusions—
Highly significant, sequential improvements in survival and reductions in reoperations after CHD surgery were seen. A future challenge is to find methods to reduce the need for reoperations and further reduce long-term mortality.