bluuebunny/crossref_metadata_2025_split huggingface dataset:
In silico regulatory analysis for exploring human disease progression
Authors: Holloway Dustin T , Kon Mark , DeLisi Charles 
Published: June 2008

Abstract

Background
An important goal in bioinformatics is to unravel the network of transcription factors (TFs) and their targets. This is important in the human genome, where many TFs are involved in disease progression. Here, classification methods are applied to identify new targets for 152 transcriptional regulators using publicly-available targets as training examples. Three types of sequence information are used: composition, conservation, and overrepresentation.

Results
Starting with 8817 TF-target interactions we predict an additional 9333 targets for 152 TFs. Randomized classifiers make few predictions (~2/18660) indicating that our predictions for many TFs are significantly enriched for true targets. An enrichment score is calculated and used to filter new predictions.
Two case-studies for the TFs OCT4 and WT1 illustrate the usefulness of our predictions:
• Many predicted OCT4 targets fall into the Wnt-pathway. This is consistent with known biology as OCT4 is developmentally related and Wnt pathway plays a role in early development.
• Beginning with 15 known targets, 354 predictions are made for WT1. WT1 has a role in formation of Wilms' tumor. Chromosomal regions previously implicated in Wilms' tumor by cytological evidence are statistically enriched in predicted WT1 targets. These findings may shed light on Wilms' tumor progression, suggesting that the tumor progresses either by loss of WT1 or by loss of regions harbouring its targets.
• Targets of WT1 are statistically enriched for cancer related functions including metastasis and apoptosis. Among new targets are BAX and PDE4B, which may help mediate the established anti-apoptotic effects of WT1.
• Of the thirteen TFs found which co-regulate genes with WT1 (p ≤ 0.02), 8 have been previously implicated in cancer. The regulatory-network for WT1 targets in genomic regions relevant to Wilms' tumor is provided.

Conclusion
We have assembled a set of features for the targets of human TFs and used them to develop classifiers for the determination of new regulatory targets. Many predicted targets are consistent with the known biology of their regulators, and new targets for the Wilms' tumor regulator, WT1, are proposed. We speculate that Wilms' tumor development is mediated by chromosomal rearrangements in the location of WT1 targets.

Reviewers
This article was reviewed by Trey Ideker, Vladimir A. Kuznetsov(nominated by Frank Eisenhaber), and Tzachi Pilpel.
Neutrophil-dependent tumor rejection and priming of tumoricidal CD8+ T cell response induced by dendritic cells overexpressing CD95L
Authors: Buonocore Sofia , Haddou Najate Ouled , Moore Fabrice , Florquin Sandrine , Paulart Frédéric , Heirman Carlo , Thielemans Kris , Goldman Michel , Flamand Véronique 
Published: June 2008

AbstractOverexpression of CD95 (Fas/Apo-1) ligand (CD95L) has been shown to induce T cell tolerance but also, neutrophilic inflammation and rejection of allogeneic tissue. We explored the capacity of dendritic cells (DCs) genetically engineered to overexpress CD95L to induce an antitumor response. We first found that DCs overexpressing CD95L, in addition to MHC class I-restricted OVA peptides (CD95L-OVA-DCs), induced increased antigen-specific CD8+ T cell responses as compared with DCs overexpressing OVA peptides alone. The enhanced T cell responses were associated with improved regression of a tumor expressing OVA, allowing survival of all animals. When DCs overexpressing CD95L (CD95L-DCs) were injected with the tumor expressing OVA, in vivo tumor proliferation was strikingly inhibited. A strong cellular apoptosis and a massive neutrophilic infiltrate developed in this setting. Neutrophil depletion prevented tumor regression as well as enhanced IFN-γ production induced by CD95L-OVA-DCs. Furthermore, the CD8+ T cell response induced by the coadministration of tumor cells and CD95L-DCs led to rejection of a tumor implanted at a distance from the DC injection site. In summary, DCs expressing CD95L promote tumor rejection involving neutrophil-mediated innate immunity and CD8+ T cell-dependent adaptative immune responses.
Phase I/II Study of Biweekly Paclitaxel and Radiation in Androgen-Ablated Locally Advanced Prostate Cancer
Authors: Sanfilippo Nicholas J. , Taneja Samir S. , Chachoua Abraham , Lepor Herbert , Formenti Silvia C. 
Published: June 2008

Purpose To determine the maximum-tolerated dose (MTD) of concurrent paclitaxel and radiation therapy (RT) in patients with locally advanced prostate cancer. Materials and Methods Eligible patients had T2-4 tumors with Gleason scores greater than 7 and/or PSA levels greater than 10 ng/mL and/or had tumors with pathologic stage TxN1. Hormonal ablation was initiated 3 months before RT and was given for 9 months. RT was delivered daily (1.8 Gy) with concurrent twice-weekly paclitaxel (30 mg/m2). The whole pelvis was irradiated to 39.6 Gy. The radiation dose was escalated as follows: 63 Gy, 66.6 Gy, 70.2 Gy, and 73.8 Gy. The last RT dose level was fixed at 73.8 Gy. Results Between January 2000 and October 2006, 22 patients were enrolled. The median age was 59 years (range, 48 to 72 years); the median PSA level was 22.4 ng/mL (range, 2.8 to 113 ng/mL). The number of patients per stage was as follows: three with T1, eight with T2, 11 with T3, and five with pN1 = 5. No grade 3 toxicities occurred at 63 Gy. Grade 3 diarrhea occurred in three patients at 66.6 Gy. The protocol then was amended to treat the prostate volume first followed by the whole pelvis. No grade 3 toxicities were observed at 70.2 Gy. One patient experienced grade 3 diarrhea at 73.8 Gy. Five additional patients were treated to 73.8 Gy without grade 3 toxicity, which established the MTD for combined paclitaxel and RT at 73.8 Gy. At 38 months median follow-up (range, 9 to 87 months), 21 (95%) of 22 patients are alive. Six (27%) of 22 experienced recurrence. Conclusion Concurrent biweekly paclitaxel with RT is feasible, with an MTD of 73.8 Gy. Recovery of gonadal function occurs in the majority of patients. These results encourage testing in a phase III setting.
CRHR1 Polymorphisms Predict Bone Density in Survivors of Acute Lymphoblastic Leukemia
Authors: Jones Terreia S. , Kaste Sue C. , Liu Wei , Cheng Cheng , Yang Wenjian , Tantisira Kelan G. , Pui Ching-Hon , Relling Mary V. 
Published: June 2008

Purpose Corticosteroids are a critical component of therapy for acute lymphoblastic leukemia (ALL) but are associated with late effects, such as osteoporosis. Risk factors remain poorly defined. Because CRHR1 polymorphisms have been associated with other corticosteroid effects, our goal was to define whether CRHR1 polymorphisms predict which patients with ALL are likely to develop bone mineral deficits. Patients and Methods The mean bone mineral density z scores of 309 long-term survivors of ALL were determined by quantitative computed tomography of the trabecular lumbar spine. We analyzed whether CRHR1 genotypes, adjusted for sex, ALL treatment regimen, and weight, could predict bone density. Results We found that three single nucleotide polymorphisms (SNPs), all in linkage disequilibrium, were associated with bone density in a sex-specific manner. Bone density was lower in males (P = .001), in nonblack patients (P < .08), in those who were not overweight (P < .001), and in those who received intensive antimetabolites and glucocorticoids (P < .001). After adjustment for these features, the G allele at the rs1876828 SNP was associated with lower z scores (P = .02) in males but tended to have the opposite association in females (P = .09). Conclusion CRHR1 polymorphisms may impact the risk of bone density deficits in patients treated with corticosteroids and antimetabolites in a sex-specific manner.
Phase I and Pharmacokinetic Study of Lapatinib and Docetaxel in Patients With Advanced Cancer
Authors: LoRusso Patricia M. , Jones Suzanne F. , Koch Kevin M. , Arya Nikita , Fleming Ronald A. , Loftiss Jill , Pandite Lini , Gadgeel Shirish , Weber Barbara L. , Burris Howard A. 
Published: June 2008

Purpose This phase I study assessed the safety, optimally tolerated regimen (OTR), pharmacokinetics, pharmacodynamics, and preliminary clinical activity of lapatinib and docetaxel in patients with advanced solid tumors. Patients and Methods Doses of lapatinib (oral once daily, continuous) and docetaxel (intravenous, every 3 weeks) were escalated in cohorts of at least three patients based on dose-limiting toxicities in the first treatment cycle until the OTR was reached. The protocol was amended to include pegfilgrastim because of dose-limiting toxicity (neutropenia), and a second dose-escalation phase was conducted to determine the OTR for the combination of docetaxel, lapatinib, and pegfilgrastim. After the determination of the OTR, the pharmacokinetics of lapatinib and docetaxel were determined to estimate the potential for an interaction between docetaxel and lapatinib at the OTR dose level. Results Fifty-two patients with advanced solid tumors were enrolled. The OTR dose level for lapatinib and docetaxel with pegfilgrastim was 1,250 mg (once daily) and 75 mg/m2 (once every 3 weeks), respectively. Overall, adverse events (AEs) were mild to moderate in severity. The drug-related AEs reported by most patients (≥ 25%) were diarrhea (56%), rash (52%), fatigue (27%), and nausea (25%). Of 43 patients assessable for clinical response, two patients had confirmed partial responses. The pharmacokinetics of lapatinib (area under the curve, maximum serum concentration) and docetaxel (area under the curve, clearance) in combination were not significantly different than when the drugs are administered separately. Conclusion The combination of docetaxel and lapatinib with pegfilgrastim was well tolerated. No pharmacokinetic interaction was observed. Clinical activity was seen in this phase I drug combination trial.
Longitudinal Changes in Insulin Sensitivity and Body Composition of Small-For-Gestational-Age Adolescents after Cessation of Growth Hormone Treatment
Authors: Willemsen Ruben H. , Willemsen Sten P. , Hokken-Koelega Anita C. S. 
Published: June 2008

Context: GH treatment reduces insulin sensitivity (Si). For small-for-gestational-age (SGA) subjects, who might have an increased risk to develop cardiovascular disease and type 2 diabetes, it is still uncertain how Si, β-cell function, and body composition change over time after stopping GH treatment.Objective: Our objective was to investigate longitudinal changes in Si, β-cell function, and body composition after cessation of long-term GH treatment.Design and Patients: We conducted a longitudinal study that included 48 SGA adolescents studied at adult height, while still on GH, and 6 months after GH stop and compared them with 38 appropriate-for-gestational-age (AGA) controls at both time points.Outcome Measure: We took paired measurements of Si and β-cell function, assessed by frequently sampled iv glucose tolerance tests with tolbutamide, and body composition, measured by dual-energy x-ray absorptiometry.Results: After stopping GH, Si (P = 0.006), glucose effectiveness (Sg; P = 0.009) and β-cell function (disposition index; P = 0.024) increased, whereas insulin secretion (acute insulin response; not significant) decreased. Fat percentage increased (P &lt; 0.0005), and lean body mass decreased (P &lt; 0.0005), but fat distribution remained unaltered, and body composition remained within the normal range. Compared with AGA controls, Si was lower during GH and became similar after GH stop, acute insulin response was higher at both time points, and glucose effectiveness and disposition index became higher.Conclusions: The GH-induced lower Si in SGA adolescents increases after stopping long-term GH treatment and becomes similar to that of AGA controls. Discontinuation of GH treatment is, however, also associated with an increase in percent body fat and with a decrease in lean body mass, without changes in fat distribution.
A 2-Approximation Algorithm for Stochastic Inventory Control Models with Lost Sales
Authors: Levi Retsef , Janakiraman Ganesh , Nagarajan Mahesh 
Published: June 2008

In this paper, we describe the first computationally efficient policies for stochastic inventory models with lost sales and replenishment lead times that admit worst-case performance guarantees. In particular, we introduce dual-balancing policies for lost-sales models that are conceptually similar to dual-balancing policies recently introduced for a broad class of inventory models in which demand is backlogged rather than lost. That is, in each period, we balance two opposing costs: the expected marginal holding costs against the expected marginal lost-sales cost. Specifically, we show that the dual-balancing policies for the lost-sales models provide a worst-case performance guarantee of two under relatively general demand structures. In particular, the guarantee holds for independent (not necessarily identically distributed) demands and for models with correlated demands such as the AR(1) model and the multiplicative autoregressive demand model. The policies and the worst-case guarantee extend to models with capacity constraints on the size of the order and stochastic lead times. Our analysis has several novel elements beyond the balancing ideas for backorder models.
Cholinergic Regulation of Ghrelin and Peptide YY Release May Be Impaired in Obesity
Authors: Maier Christina , Riedl Michaela , Vila Greisa , Nowotny Peter , Wolzt Michael , Clodi Martin , Ludvik Bernhard , Luger Anton 
Published: June 2008

OBJECTIVE—Ghrelin and peptide YY (PYY) are both hormones derived from the gastrointestinal tract involved in appetite regulation. The cholinergic part of the vagal nerve is involved in the regulation of glucose and insulin. The aim of this study was to examine the effects of the cholinergic antagonist atropine on ghrelin, PYY, glucose, and insulin under basal conditions and after meal ingestion in lean and obese subjects.
REASEARCH DESIGN AND METHODS—Eight lean and eight obese subjects were included in a randomized, double-blind, placebo-controlled crossover study with 4 study days in randomized order (atropine/placebo ± breakfast). Plasma ghrelin, PYY, insulin, and glucose were measured. Hunger and satiety feelings were rated on a 10-cm visual analog scale.
RESULTS—In lean individuals, atropine led to a decrease in ghrelin concentrations comparable and nonadditive with breakfast ingestion and a significant decrease in both basal and meal-induced PYY concentrations. In obese subjects, atropine did not significantly change ghrelin or PYY concentrations, whereas it induced a comparable increase in heart rate and meal-induced glucose concentrations in the two study groups. Only lean, not obese, subjects experienced sustained feelings of satiety after breakfast.
CONCLUSIONS—The impaired cholinergic regulation of the postprandial drop in ghrelin concentrations and rise in PYY concentrations might be part of the deregulated food intake in obese subjects.
Association Testing of Novel Type 2 Diabetes Risk Alleles in the JAZF1, CDC123/CAMK1D, TSPAN8, THADA, ADAMTS9, and NOTCH2 Loci With Insulin Release, Insulin Sensitivity, and Obesity in a Population-Based Sample of 4,516 Glucose-Tolerant Middle-Aged Danes
Authors: Grarup Niels , Andersen Gitte , Krarup Nikolaj T. , Albrechtsen Anders , Schmitz Ole , Jørgensen Torben , Borch-Johnsen Knut , Hansen Torben , Pedersen Oluf 
Published: June 2008

OBJECTIVE— We evaluated the impact on diabetes-related intermediary traits of common novel type 2 diabetes–associated variants in the JAZF1 (rs864745), CDC123/CAMK1D (rs12779790), TSPAN8 (rs7961581), THADA (rs7578597), ADAMTS9 (rs4607103), and NOTCH2 (rs10923931) loci, which were recently identified by meta-analysis of genome-wide association data.
RESEARCH DESIGN AND METHODS— We genotyped the six variants in 4,516 middle-aged glucose-tolerant individuals of the population-based Inter99 cohort who were all characterized by an oral glucose tolerance test (OGTT).
RESULTS— Homozygous carriers of the minor diabetes risk G-allele of the CDC123/CAMK1D rs12779790 showed an 18% decrease in insulinogenic index (95% CI 10–27%; P = 4 × 10−5), an 18% decrease in corrected insulin response (CIR) (8.1–29%; P = 4 × 10−4), and a 13% decrease in the ratio of area under the serum-insulin and plasma-glucose curves during an OGTT (AUC-insulin/AUC-glucose) (5.8–20%; P = 4 × 10−4). Carriers of the diabetes-associated T-allele of JAZF1 rs864745 had an allele-dependent 3% decrease in BIGTT-AIR (0.9–4.3%; P = 0.003). Furthermore, the diabetes-associated C-allele of TSPAN8 rs7961581 associated with decreased levels of CIR (4.5% [0.5–8.4]; P = 0.03), of AUC-insulin/AUC-glucose ratio (3.9% [1.2–6.7]; P = 0.005), and of the insulinogenic index (5.2% [1.9–8.6]; P = 0.002). No association with traits of insulin release or insulin action was observed for the THADA, ADAMTS9, or NOTCH2 variants.
CONCLUSIONS— If replicated, our data suggest that type 2 diabetes at-risk alleles in the JAZF1, CDC123/CAMK1D, and TSPAN8 loci associate with various OGTT-based surrogate measures of insulin release, emphasizing the contribution of abnormal pancreatic β-cell function in the pathogenesis of type 2 diabetes.
Increase in Endoplasmic Reticulum Stress–Related Proteins and Genes in Adipose Tissue of Obese, Insulin-Resistant Individuals
Authors: Boden Guenther , Duan Xunbao , Homko Carol , Molina Ezequiel J. , Song WeiWei , Perez Oscar , Cheung Peter , Merali Salim 
Published: June 2008

OBJECTIVE—To examine fat biopsy samples from lean insulin-sensitive and obese insulin-resistant nondiabetic individuals for evidence of endoplasmic reticulum (ER) stress.
RESEARCH DESIGN AND METHODS—Subcutaneous fat biopsies were obtained from the upper thighs of six lean and six obese nondiabetic subjects. Fat homogenates were used for proteomic (two-dimensional gel and MALDI-TOF/TOF), Western blot, and RT-PCR analysis.
RESULTS—Proteomic analysis revealed 19 differentially upregulated proteins in fat of obese subjects. Three of these proteins were the ER stress–related unfolded protein response (UPR) proteins calreticulin, protein disulfide-isomerase A3, and glutathione-S-transferase P. Western blotting revealed upregulation of several other UPR stress–related proteins, including calnexin, a membrane-bound chaperone, and phospho c-jun NH2-terminal kinase (JNK)-1, a downstream effector protein of ER stress. RT-PCR analysis revealed upregulation of the spliced form of X-box binding protein-1s, a potent transcription factor and part of the proximal ER stress sensor inositol-requiring enzyme-1 pathway.
CONCLUSIONS—These findings represent the first demonstration of UPR activation in subcutaneous adipose tissue of obese human subjects. As JNK can inhibit insulin action and activate proinflammatory pathways, ER stress activation of JNK may be a link between obesity, insulin resistance, and inflammation.
Sustained Weight Loss Following 12-Month Pramlintide Treatment as an Adjunct to Lifestyle Intervention in Obesity
Authors: Smith Steve R. , Aronne Louis J. , Burns Colleen M. , Kesty Nicole C. , Halseth Amy E. , Weyer Christian 
Published: June 2008

OBJECTIVE—To assess long-term weight loss efficacy and safety of pramlintide used at different dosing regimens and in conjunction with lifestyle intervention (LSI).
RESEARCH DESIGN AND METHODS—In a 4-month, double-blind, placebo-controlled, dose-ranging study, 411 obese subjects were randomized to receive pramlintide (six arms: 120, 240, and 360 μg b.i.d. and t.i.d.) or placebo in conjunction with a structured LSI program geared toward weight loss. Of the 4-month evaluable subjects (n = 270), 77% opted to continue preexisting treatment during an 8-month single-blind extension (LSI geared toward weight maintenance).
RESULTS—At month 4, mean weight loss from baseline in the pramlintide arms ranged from 3.8 ± 0.7 to 6.1 ± 0.8 kg (2.8 ± 0.8 kg with placebo). By month 12, initial 4-month weight loss was regained in the placebo group but was maintained in all but the 120-μg b.i.d. group. Placebo-corrected weight loss with 120 μg t.i.d. and 360 μg b.i.d. averaged 3.2 ± 1.2 kg (3.1 ± 1.1% body wt) and 3.3 ± 1.1 kg (3.1 ± 1.0% body wt), respectively, at month 4 (both P &lt; 0.01; 4-month evaluable n = 270) and 6.1 ± 2.1 kg (5.6 ± 2.1% body wt) and 7.2 ± 2.3 kg (6.8 ± 2.3% body wt), respectively, at month 12 (both P &lt; 0.01; 12-month evaluable n = 146). At month 12, 40 and 43% of subjects treated with 120 μg t.i.d. and 360 μg b.i.d., respectively, achieved ≥10% weight loss (vs. 12% for placebo). Nausea, the most common adverse event with pramlintide in the 4-month study (9–29% pramlintide vs. 2% placebo), was generally mild to moderate and occurred in &lt;10% of subjects during the extension.
CONCLUSIONS—When used over 12 months as an adjunct to LSI, pramlintide treatment, with low-dose three-times-daily or higher-dose two-times-daily regimens, helped obese subjects achieve greater initial weight loss and enhanced long-term maintenance of weight loss.
Weight Change in Diabetes and Glycemic and Blood Pressure Control
Authors: Feldstein Adrianne C. , Nichols Gregory A. , Smith David H. , Stevens Victor J. , Bachman Keith , Rosales A. Gabriela , Perrin Nancy 
Published: June 2008

OBJECTIVE—Weight loss in type 2 diabetes is undisputedly important, and data from community settings are limited. We evaluated weight change and resulting glycemic and blood pressure control in type 2 diabetic patients at an HMO.
RESEARCH DESIGN AND METHODS—Using electronic medical records, this retrospective cohort study identified 2,574 patients aged 21–75 years who received a new diagnosis of type 2 diabetes between 1997 and 2002. We estimated 3-year weight trajectories using growth curve analyses, grouped similar trajectories into four categories using cluster analysis, compared category characteristics, and predicted year-4 above-goal A1C and blood pressure by group.
RESULTS—The weight-trajectory groups were defined as higher stable weight (n = 418; 16.2%), lower stable weight (n = 1,542; 59.9%), weight gain (n = 300; 11.7%), and weight loss (n = 314; 12.2%). The latter had a mean weight loss of 10.7 kg (−9.8%; P &lt; 0.001) by 18 months, with near-complete regain by 36 months. After adjusting for age, sex, baseline control, and related medication use, those with higher stable weight, lower stable weight, or weight-gain patterns were more likely than those who lost weight to have above-goal A1C (odds ratio [OR] 1.66 [95% CI 1.12–2.47], 1.52 [1.08–2.14], and 1.77 [1.15–2.72], respectively). Those with higher stable weight or weight-gain patterns were more likely than those who lost weight to have above-goal blood pressure (1.83 [1.31–2.57] and 1.47 [1.03–2.10], respectively).
CONCLUSIONS—A weight-loss pattern after new diagnosis of type 2 diabetes predicted improved glycemic and blood pressure control despite weight regain. The initial period postdiagnosis may be a critical time to apply weight-loss treatments to improve risk factor control.
Isospora cagasebi sp. nov. (Apicomplexa, Eimeriidae) from the bananaquit, Coereba flaveola of Brazil
Authors: Berto Bruno , Flausino Walter , Luz Hermes , Ferreira Ildemar , Lopes Carlos 
Published: June 2008

AbstractIsospora cagasebi sp. nov. (Apicomplexa, Eimeriidae) is reported from a bananaquit, Coereba flaveola from Brazil. Oocysts are sub-spherical, 24.9 × 24.5 (23.0–26.1 × 22.6–25.4), with a smooth, bilayered wall ∼1.4 and mean L:W ratio 1.0; micropyle, oocyst residuum and polar granule are absent. Sporocysts are elongate ovoidal, 18.7 × 11.5 (17.6–19.4 × 10.4–12.3), with both Stieda and substieda bodies and mean L:W ratio 1.6; sporocyst residuum present and sporozoites each with 2 refractiles bodies.