bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic polymorphisms in PTPN22, PADI-4, and CTLA-4 and risk for rheumatoid arthritis in two longitudinal cohort studies: evidence of gene-environment interactions with heavy cigarette smoking
Authors: Costenbader Karen H , Chang Shun-Chiao , De Vivo Immaculata , Plenge Robert , Karlson Elizabeth W 
Published: May 2008

Abstract
Introduction
PTPN22, PADI-4, and CTLA-4 have been associated with risk for rheumatoid arthritis (RA). We investigated whether polymorphisms in these genes were associated with RA in Caucasian women included in two large prospective cohorts, adjusting for confounding factors and testing for interactions with smoking.

Methods
We studied RA risk associated with PTPN22 (rs2476601), PADI-4 (rs2240340), and CTLA-4 (rs3087243) in the Nurses' Health Study (NHS) and NHSII. Participants in NHS were aged 30 to 55 years at entry in 1976; those in NHSII were aged 25 to 42 years at entry in 1989. We confirmed incident RA cases through to 2002 in NHS and to 2003 in NHSII by questionnaire and medical record review. We excluded reports not confirmed as RA. In a nested case-control design involving participants for whom there were samples for genetic analyses (45% of NHS and 25% of NHSII), each incident RA case was matched to a participant without RA by year of birth, menopausal status, and postmenopausal hormone use. Genotyping was performed using Taqman single nucleotide polymorphism allelic discrimination on the ABI 7900 HT (Applied Biosystems, 850 Lincoln Centre Drive, Foster City, CA 94404 USA) with published primers. Human leukocyte antigen shared epitope (HLA-SE) genotyping was performed at high resolution. We employed conditional logistic regression analyses, adjusting for smoking and reproductive factors. We tested for additive and multiplicative interactions between each genotype and smoking.

Results
A total of 437 incident RA cases were matched to healthy female control individuals. Mean (± standard deviation) age at RA diagnosis was 55 (± 10), 57% of RA cases were rheumatoid factor (RF) positive, and 31% had radiographic erosions at diagnosis. PTPN22 was associated with increased RA risk (pooled odds ratio in multivariable dominant model = 1.46, 95% confidence interval [CI] = 1.02 to 2.08). The risk was stronger for RF-positive than for RF-negative RA. A significant multiplicative interaction between PTPN22 and smoking for more than 10 pack-years was observed (P = 0.04). CTLA-4 and PADI-4 genotypes were not associated with RA risk in the pooled results (pooled odds ratios in multivariable dominant models: 1.27 [95% CI = 0.88 to 1.84] for CTLA-4 and 1.04 [95% CI = 0.77 to 1.40] for PADI-4). No gene-gene interaction was observed between PTPN22 and HLA-SE.

Conclusion
After adjusting for smoking and reproductive factors, PTPN22 was associated with RA risk among Caucasian women in these cohorts. We found both additive and multiplicative interactions between PTPN22 and heavy cigarette smoking.
Autoantibodies as potential biomarkers for breast cancer
Authors: Zhong Li , Ge Kun , Zu Jin-chi , Zhao Long-hua , Shen Wei-ke , Wang Jian-fei , Zhang Xiao-gang , Gao Xu , Hu Wanping , Yen Yun , Kernstine Kemp H 
Published: May 2008

Abstract
Introduction
Only a limited number of tumor markers for breast cancer are currently available. Antibodies to tumor-associated proteins may expand the number of available tumor markers for breast cancer and may be used together in a serum profile to enhance sensitivity and specificity.

Methods
In the present study, we interrogated a breast cancer cDNA T7 phage library for tumor-associated proteins using biopan enrichment techniques with sera from normal individuals and from breast cancer patients. The enrichment of tumor-associated proteins after biopanning was tested using a plaque-lift assay and immunochemical detection. The putative tumor-associated phage clones were collected for PCR and sequencing analysis. Unique and open reading frame phage-expressed proteins were then used to develop phage protein ELISAs to measure corresponding autoantibodies using 87 breast cancer patients and 87 normal serum samples. A logistic regression model and leave-one-out validation were used to evaluate predictive accuracies with a single marker as well as with combined markers. Identities of those selected proteins were revealed through the sequence BLAST program.

Results
We harvested 100 putative tumor-associated phage clones after biopan enrichment. Sequencing analysis revealed that six phage proteins were inframe and unique. Antibodies to these six phage-expressed proteins were measured by ELISAs, and the results showed that three of the phage clones had statistical significance in discriminating patients from normal individuals. BLAST results of the three proteins showed great matches to ASB-9, SERAC1, and RELT. Measurements of the three predictive phage proteins were combined in a logistic regression model that achieved 80% sensitivity and 100% specificity in prediction of sample status, whereas leave-one-out validation achieved 77.0% sensitivity and 82.8% specificity among 87 patient samples and 87 control samples. Receiver operating characteristic curve analysis and the leave-one-out method both showed that combined measurements of the three antibodies were more predictive of disease than any of the single antibodies studied, underscoring the importance of identifying multiple potential markers.

Conclusion
Serum autoantibody profiling is a promising approach for early detection and diagnosis of breast cancer. Rather than one autoantibody, a panel of autoantibodies appears preferable to achieve superior accuracy. Further refinements will need to be made to further improve the accuracy. Once refined, the assay must be applied to a prospective patient population to demonstrate applicability.
Adrenal insufficiency in prolonged critical illness
Authors: Wu Jenn-Yu , Hsu Szu-Chun , Ku Shih-Chi , Ho Chao-Chi , Yu Chong-Jen , Yang Pan-Chyr 
Published: May 2008

Abstract
Introduction
Adrenal insufficiency is common in critically ill patients and affects their prognosis, but little is known about how adrenal function changes during prolonged critical illness. This study was conducted to investigate dynamic changes in cortisol levels in patients with critical illness who do not improve after treatment.

Methods
This observational cohort study was performed in the intensive care units of a university hospital. We studied acutely ill patients with initial cortisol level above 34 μg/dl, but who did not improve after treatment and in whom follow-up cortisol levels were determined during critical illness. All clinical information and outcomes were recorded.

Results
Fifty-seven patients were included. Ten patients had follow-up cortisol levels above 34 μg/dl, 32 patients had levels between 34 and 15 μg/dl, and 15 patients had levels under 15 μg/dl. Outcomes did not differ significantly among the three groups with different follow-up cortisol levels. In Cox regression analysis, those patients who survived to hospital discharge with second cortisol levels under 15 μg/dl had a longer hospital length of stay (odds ratio = 14.8, 95% confidence interval = 2.4 to 90.0; P = 0.004).

Conclusion
The majority of acutely ill patients who remained in a critical condition had decreased serum cortisol levels. Depressed cortisol levels at follow up may lead to worse clinical outcomes. We propose that repeated adrenal function testing be conducted in patients with prolonged critical illness.
MDM2 SNP309 Is Associated With Poor Outcome in B-Cell Chronic Lymphocytic Leukemia
Authors: Gryshchenko Irina , Hofbauer Sebastian , Stoecher Markus , Daniel Peter T. , Steurer Michael , Gaiger Alexander , Eigenberger Karin , Greil Richard , Tinhofer Inge 
Published: May 2008

Purpose A single nucleotide polymorphism (SNP) at position 309 in the promoter region of MDM2 leading to increased expression of MDM2 and attenuated function of p53 has been negatively associated with onset and outcome of disease in solid tumors. Because inactivation of p53 by deletion and/or mutations also impacts on the clinical course of B-cell chronic lymphocytic leukemia (B-CLL), we assessed the role of the SNP309 genotype in B-CLL. Patients and Methods The frequency of SNP309 T/T, T/G, or G/G genotypes and the p53 status (wild type, mutated, or deleted) were assessed and correlated with clinical outcome in 140 B-CLL patients and a second independent cohort. In addition, the correlation of the MDM2 SNP309 genotype with the MDM2 protein expression level in B-CLL cells was evaluated by immunoblotting. Results A significant negative association of the SNP309 T/G and G/G genotypes with overall survival was seen (T/G genotype, relative risk = 3.7; 95% CI, 1.2 to 11.5; P = .02; G/G genotype, relative risk = 9.1; 95% CI, 2.4 to 35.1; P = .001), but no correlation with incidence or onset of B-CLL was observed. The influence of the heterozygous SNP309 T/G genotype on treatment-free survival depended on the p53 status but not on the CD38, Zap-70, or IgVH mutational status or Rai stage of B-CLL patients. The unfavorable SNP309 T/G and G/G genotypes were associated with a gene-dosage–dependent increase of MDM2 expression. Conclusion The MDM2 SNP309 genotype influencing MDM2 expression levels was identified as an additional independent risk factor in B-CLL. Targeting MDM2-p53 interactions might emerge as a successful treatment strategy for B-CLL.
Utilization and Outcomes of Minimally Invasive Radical Prostatectomy
Authors: Hu Jim C. , Wang Qin , Pashos Chris L. , Lipsitz Stuart R. , Keating Nancy L. 
Published: May 2008

Purpose Demand for minimally invasive radical prostatectomy (MIRP) to treat prostate cancer is increasing; however, outcomes remain unclear. We assessed utilization, complications, lengths of stay, and salvage therapy rates for MIRP versus open radical prostatectomy assessed whether MIRP surgeon volume is associated with better outcomes. Methods We identified 2,702 men undergoing MIRP and open radical prostatectomy during 2003 to 2005 from a national 5% sample of Medicare beneficiaries. We assessed the association between surgical approach and outcomes, adjusting for surgeon volume, age, race, comorbidity, and geographic region. Results MIRP utilization increased from 12.2% in 2003 to 31.4% in 2005. Men undergoing MIRP versus open radical prostatectomy had fewer perioperative complications (29.8% v 36.4%; P = .002) and shorter lengths of stay (1.4 v 4.4 days; P < .001); however, they were more likely to receive salvage therapy (27.8% v 9.1%, P < .001). In adjusted analyses, MIRP versus open radical prostatectomy was associated with fewer perioperative complications (odds ratio [OR], 0.73; 95% CI, 0.60 to 0.90), shorter lengths of stay (parameter estimate, −2.99; 95% CI, −3.45 to −2.53) but more anastomotic strictures (OR, 1.40; 95% CI, 1.04 to 1.87) and higher rates of salvage therapy (OR, 3.67; 95% CI, 2.81 to 4.81). Patients of high-volume MIRP experienced fewer anastomotic strictures (OR, 0.93; 95% CI, 0.87 to 0.99) and less salvage therapy (OR, 0.92; 95% CI, 0.88 to 0.98). Conclusion Men undergoing MIRP versus open radical prostatectomy have lower risk for perioperative complications and shorter lengths of stay, but are at higher risk for salvage therapy and anastomotic strictures. However, risk for these unfavorable outcomes decreases with increasing MIRP surgical volume.
Safety and Efficacy of Darbepoetin Alfa in Previously Untreated Extensive-Stage Small-Cell Lung Cancer Treated With Platinum Plus Etoposide
Authors: Pirker Robert , Ramlau Rodryg A. , Schuette Wolfgang , Zatloukal Petr , Ferreira Irene , Lillie Tom , Vansteenkiste Johan F. 
Published: May 2008

Purpose A placebo-controlled, double-blind, randomized, phase III study was conducted in patients with extensive-stage small-cell lung cancer receiving first-line platinum-containing chemotherapy to determine if increasing or maintaining hemoglobin concentration with darbepoetin alfa could increase patient survival. Patients and Methods Darbepoetin alfa (300 μg) or placebo was administered once per week for 4 weeks then every 3 weeks for up to six cycles of chemotherapy (carboplatin plus etoposide or cisplatin plus etoposide) plus 3 weeks after the last dose of chemotherapy. Patients with disease progression were observed until death or until all patients completed their end-of-study visit and 496 deaths had occurred. The two coprimary end points were change in hemoglobin concentration from baseline to the end of the chemotherapy period and overall survival; statistical testing of survival was done if change in hemoglobin was significant at P < .05. Results The study enrolled 600 patients. Patients' hemoglobin levels dropped due to the myelosuppressive chemotherapy; however, treatment with darbepoetin alfa maintained hemoglobin levels significantly higher than placebo (P < .001). There was no statistically significant difference in overall survival between the treatment groups (hazard ratio [HR], 0.93; 95% CI, 0.78 to 1.11; P = .431). As expected, darbepoetin alfa was associated with a higher incidence of thromboembolic events (darbepoetin alfa, 9%; placebo, 5%). The transfusion risk was lower in the darbepoetin versus placebo group (HR, 0.40; 95% CI, 0.29 to 0.55). Conclusion The results of this study did not demonstrate improved survival after treatment with darbepoetin alfa; however, they reinforce the benefit of erythropoiesis-stimulating agents in reducing transfusions and their neutral impact on survival in patients with chemotherapy-induced anemia.
Erlotinib for Advanced Non–Small-Cell Lung Cancer in the Elderly: An Analysis of the National Cancer Institute of Canada Clinical Trials Group Study BR.21
Authors: Wheatley-Price Paul , Ding Keyue , Seymour Lesley , Clark Gary M. , Shepherd Frances A. 
Published: May 2008

Purpose National Cancer Institute of Canada Clinical Trials Group Study BR.21 established erlotinib as a standard of care in patients with non–small-cell lung cancer (NSCLC) after failure of first- or second-line chemotherapy. The current study analyzes the influence of age on outcomes in BR.21. Patients and Methods BR.21 was a double-blind phase III trial that randomly assigned 731 patients to erlotinib 150 mg daily or placebo. End points included progression-free survival and overall survival (OS), response, quality of life (QOL), drug exposure, and toxicity, which are analyzed in this retrospective study by the following two age groups: ≥ 70 years (elderly) or less than 70 years (young). Results There were 163 elderly patients (112 on erlotinib, 51 on placebo) and 568 young patients (376 on erlotinib, 192 on placebo). There was no significant difference between age groups randomly assigned to erlotinib or placebo in progression-free survival (elderly: 3.0 v 2.1 months; hazard ratio [HR] = 0.63; 95% CI, 0.44 to 0.90; P = .009; young: 2.1 v 1.8 months; HR = 0.64; 95% CI, 0.53 to 0.76; P < .0001; interaction, P = .77) or OS (elderly: 7.6 v 5.0 months; HR = 0.92; 95% CI, 0.64 to 1.34; P = .67; young: 6.4 v 4.7 months; HR = 0.73; 95% CI, 0.61 to 0.89; P = .0014; interaction, P = .31). Response rates were similar between age groups. Elderly patients, compared with young patients, had significantly more overall and severe (grade 3 and 4) toxicity (35% v 18%; P < .001), were more likely to discontinue treatment as a result of treatment-related toxicity (12% v 3%; P < .0001), and had lower relative dose-intensity (64% v 82% received > 90% planned dose; P < .001). Conclusion Elderly patients treated with erlotinib gain similar survival and QOL benefits as younger patients but experience greater toxicity.
Hyperghrelinemia Precedes Obesity in Prader-Willi Syndrome
Authors: Feigerlová Eva , Diene Gwenaëlle , Conte-Auriol Françoise , Molinas Catherine , Gennero Isabelle , Salles Jean-Pierre , Arnaud Catherine , Tauber Maïthé 
Published: May 2008

AbstractBackground: High plasma ghrelin levels have been reported in Prader-Willi syndrome (PWS). However, little is known about plasma ghrelin in these children during the first years of life characterized by a failure to thrive.Objective: The objective of the study was to investigate total plasma ghrelin levels in children with PWS and controls from 2 months to 17 years.Subjects and Methods: Forty children with PWS [24 boys, 16 girls, median age 3.6 yr, median body mass index (BMI) Z-score 0.3] were compared with 84 controls (57 boys, 27 girls, median age 4.2 yr median BMI Z-score 0.1). Children were then divided into two groups according to age and GH treatment.Results: Median plasma ghrelin levels were significantly higher in children with PWS, compared with controls at any age (568 vs. 173, P &lt; 0.0001) and decreased with age in both groups (P &lt; 0.0001). In the whole group of PWS, we found an inverse relationship between ghrelin and BMI Z-score, insulin, homeostasis model assessment insulin resistance index, leptin, and lean mass. Plasma ghrelin levels were higher in children with PWS than controls, both in the youngest children below 3 yr who were not receiving GH (771 vs. 233, P &lt; 0.0001) and in the children older than 3 yr, all of whom were treated with GH (428 vs. 159, P &lt; 0.0001).Conclusions: Plasma ghrelin levels in children with PWS are elevated at any age, including during the first years of life, thus preceding the development of obesity.
Absence of an Acute Insulin Response Predicts Onset of Type 2 Diabetes in a Caucasian Population with Impaired Glucose Tolerance
Authors: Nijpels G. , Boorsma W. , Dekker J. M. , Hoeksema F. , Kostense P. J. , Bouter L. M. , Heine R. J. 
Published: May 2008

AbstractContext: In persons with impaired glucose tolerance (IGT), both impaired insulin secretion and insulin resistance contribute to the conversion to type 2 diabetes mellitus (T2DM). However, few studies have used criterion standard measures to asses the predictive value of impaired insulin secretion and insulin resistance for the conversion to T2DM in a Caucasian IGT population.Objectives: The objective of the study was to determine the predictive value of measures of insulin secretion and insulin resistance derived from a hyperglycemic clamp, including the disposition index, for the development of T2DM in a Caucasian IGT population.Design, Setting, and Participants: The population-based Hoorn IGT study consisted of 101 Dutch IGT subjects (aged &lt; 75 yr), with mean 2-h plasma glucose values, of two separate oral glucose tolerance tests, between 8.6 and 11.1 mmol/liter. A hyperglycemic clamp at baseline was performed to assess first-phase and second-phase insulin secretion and insulin sensitivity. During follow-up, conversion to T2DM was assessed by means of 6-monthly fasting glucose levels and yearly oral glucose tolerance tests.Results: The cumulative incidence of T2DM was 34.7%. Hazard ratio for T2DM development adjusted for age, sex, and body mass index was 5.74 [95% confidence interval (CI) 2.60–12.67] for absence of first insulin peak, 1.58 (95% CI 0.60–4.17) for lowest vs. highest tertile of insulin sensitivity, and 1.78 (95% CI 0.65–4.88) for lowest vs. highest tertile of the disposition index.Conclusions: In these Caucasian persons with IGT, the absence of the first insulin peak was the strongest predictor of T2DM.
Urinary Prolactin as a Reliable Marker for Preeclampsia, Its Severity, and the Occurrence of Adverse Pregnancy Outcomes
Authors: Leaños-Miranda Alfredo , Márquez-Acosta Janeth , Cárdenas-Mondragón Guadalupe María , Chinolla-Arellano Zarela Lizbeth , Rivera-Leaños Roxana , Bermejo-Huerta Sara , Romero-Arauz Juan Fernando , Alvarez-Jiménez Guadalupe , Ramos-León Julio César , Ulloa-Aguirre Alfredo 
Published: May 2008

Abstract
Context: It has been proposed that preeclampsia may result from of an imbalance in angiogenic factors. Although prolactin (PRL) is mainly related to lactation, it is also involved in other biological functions, including angiogenesis.
Objective: Our objective was to determine the relationship among preeclampsia, serum and urinary PRL (uPRL) levels, and excretion of antiangiogenic PRL fragments in urine.
Study design: Using a cross-sectional design, uPRL and serum PRL levels, and the presence of PRL isoforms were determined in 546 pregnant women: 207 healthy pregnant, 124 with gestational hypertension, 48 with mild preeclampsia, and 167 with severe preeclampsia (sPE).
Results: uPRL concentrations were significantly (P &lt; 0.001) higher in preeclampsia (11.99 ng/mg creatinine) than in healthy pregnancy (0.20 ng/mg creatinine) and gestational hypertension (0.19 ng/mg creatinine), and were even higher in sPE compared with mild preeclampsia (21.20 vs. 2.77 ng/mg creatinine, respectively; P &lt; 0.001). Antiangiogenic PRL fragments (14–16 kDa) were detected in 21.6% of urine samples from women with sPE but in none from other groups. Patients with hemolysis, elevated liver enzymes, low platelet count syndrome, and/or eclampsia, placental abruption, acute renal failure, and pulmonary edema exhibited highest uPRL concentrations (P ≤ 0.028) and frequency of antiangiogenic PRL fragments in urine (P ≤ 0.036). High-serum PRL levels were associated with sPE independently of gestational age, proteinuria, and prolactinuria (P = 0.032).
Conclusions: Preeclampsia is characterized by increased uPRL excretion. uPRL concentrations and their isoforms appear to be suitable markers to assess the severity of preeclampsia and occurrence of adverse outcomes. PRL and and/or its isoforms might be involved in the pathophysiology of preeclampsia.
Gender Specificity of Body Adiposity and Circulating Adiponectin, Visfatin, Insulin, and Insulin Growth Factor-I at Term Birth: Relation to Prenatal Growth
Authors: Ibáñez Lourdes , Sebastiani Giorgia , Lopez-Bermejo Abel , Díaz Marta , Gómez-Roig Maria Dolores , de Zegher Francis 
Published: May 2008

Abstract
Context: Fetal development is thought to be gender specific for adiposity and circulating insulin and IGF-I but not adipokinemia, as judged by serum visfatin and adiponectin at term birth. We studied the potential relationship between these gender specificities and fetal growth.
Setting: The study was conducted at a university hospital.
Study Population: Subjects included 96 strictly matched neonates born appropriate for gestational age (AGA; 24 girls, 24 boys) or small for gestational age (SGA; 24 girls, 24 boys).
Main Outcomes: Outcomes included serum insulin, IGF-I, visfatin, total and high-molecular-weight (HMW) adiponectin, osteocalcin at term birth, and neonatal body composition by absorptiometry.
Results: Cord insulin and IGF-I levels were higher in girls than boys (P ≤ 0.01), in both the AGA and SGA subpopulation. In AGA newborns, fat and lean mass were each gender specific (P &lt; 0.0001), whereas visfatin and total and HMW adiponectin were not. Conversely, in SGA newborns, visfatin and HMW adiponectin were gender specific (higher levels in girls), whereas body adiposity was not. In SGA fetuses, the distribution of adiponectin isoforms was in both genders shifted toward HMW (P &lt; 0.005 vs. AGA). Cord osteocalcin did not differ by either gender or birth weight.
Conclusion: At term birth, the gender specificity of adiposity and circulating visfatin and HMW adiponectin appeared to depend on prenatal growth, whereas the gender specificity of insulin and IGF-I levels did not. The fetal shift in adiponectin isoforms may contribute to explain why SGA newborns tend to be hypersensitive to insulin.
Synthesis and Chiral Recognition of Novel Regioselectively Substituted Amylose Derivatives
Authors: Kondo Shunsuke , Yamamoto Chiyo , Kamigaito Masami , Okamoto Yoshio 
Published: May 2008

Abstract
Two novel amylose derivatives 1a and 1b bearing different substituents at 2-, 3-, and 6-positions of a glucose ring have been successfully synthesized, and their abilities of enantiomer resolution in high-performance liquid chromatography (HPLC) have been evaluated. These derivatives exhibited the ability comparable or better to the commercial amylose-based column, Chiralpak AD.