bluuebunny/crossref_metadata_2025_split huggingface dataset:
The histone 3 lysine 4 methyltransferase, Mll2, is only required briefly in development and spermatogenesis
Authors: Glaser Stefan , Lubitz Sandra , Loveland Kate L , Ohbo Kazu , Robb Lorraine , Schwenk Frieder , Seibler Jost , Roellig Daniela , Kranz Andrea , Anastassiadis Konstantinos , Stewart A Francis 
Published: April 2009

AbstractBackgroundHistone methylation is thought to be central to the epigenetic mechanisms that maintain and confine cellular identity in multi-cellular organisms. To examine epigenetic roles in cellular homeostasis, we conditionally mutated the histone 3 lysine 4 methyltransferase, Mll2, in embryonic stem (ES) cells, during development and in adult mice using tamoxifen-induced Cre recombination.ResultsIn ES cells, expression profiling unexpectedly revealed that only one gene,Magoh2, is dependent upon Mll2 and few other genes were affected. Loss of Mll2 caused loss of H3K4me3 at theMagoh2promoter and concomitant gain of H3K27me3 and DNA methylation. Hence Mll2, which is orthologous toDrosophilaTrithorax, is required to prevent Polycomb-Group repression of theMagoh2promoter, and repression is further accompanied by DNA methylation. Early loss of Mll2in uterorecapitulated the embryonic lethality found inMll2-/- embryos. However, loss of Mll2 after E11.5 produced mice without notable pathologies. Hence Mll2 is not required for late development, stem cells or homeostasis in somatic cell types. However it is required in the germ cell lineage. Spermatogenesis was lost upon removal of Mll2, although spermatogonia A persisted.ConclusionThese data suggest a bimodal recruit and maintain model whereby Mll2 is required to establish certain epigenetic decisions during differentiation, which are then maintained by redundant mechanisms. We also suggest that these mechanisms relate to the epigenetic maintenance of CpG island promoters.
Inflammation predicts accelerated brachial arterial wall changes in patients with recent-onset rheumatoid arthritis
Authors: Hannawi Suad , Marwick Thomas H , Thomas Ranjeny 
Published: April 2009

Abstract
Introduction
Patients with recent-onset rheumatoid arthritis (RA) have impaired brachial artery endothelial function compared with controls matched for age, sex and cardiovascular risk factors. The present study examined endothelium-dependent (flow-mediated dilatation (FMD)) and independent (glyceryl trinitrate (GTN)-mediated dilatation (GMD)) structural responses in early RA patients, and determined progress over one year.

Methods
Brachial artery FMD and GMD and carotid intima media thickness (cIMT) were studied using ultrasound in 20 patients diagnosed with early RA in whom symptoms had been present for less than 12 months, and in 20 control subjects matched for age, sex and established cardiovascular risk factors. FMD and GMD were re-assessed after 12 months in RA patients and the change in each parameter was calculated. Data were analysed by univariate regression.

Results
Mean FMD and GMD were significantly lower in early RA patients at baseline than in controls, but each parameter significantly improved in one year. FMD and GMD responses were positively associated with each other. Patients' age, C-reactive protein (CRP) level and cIMT at baseline and CRP level at one year, were negatively associated with change in brachial responses in one year.

Conclusions
Patients with recent-onset RA have altered brachial artery responses signifying both functional and structural abnormalities. However, early control of inflammation may reduce arterial dysfunction and thus the tendency for atherosclerotic progression.
Identification and functional characterization of cis-regulatory elements in the apicomplexan parasite Toxoplasma gondii
Authors: Mullapudi Nandita , Joseph Sandeep J , Kissinger Jessica C 
Published: April 2009

Abstract
Background
Toxoplasma gondii is a member of the phylum Apicomplexa, which consists entirely of parasitic organisms that cause several diseases of veterinary and human importance. Fundamental mechanisms of gene regulation in this group of protistan parasites remain largely uncharacterized. Owing to their medical and veterinary importance, genome sequences are available for several apicomplexan parasites. Their genome sequences reveal an apparent paucity of known transcription factors and the absence of canonical cis-regulatory elements. We have approached the question of gene regulation from a sequence perspective by mining the genomic sequence data to identify putative cis-regulatory elements using a de novo approach.

Results
We have identified putative cis-regulatory elements present upstream of functionally related groups of genes and subsequently characterized the function of some of these conserved elements using reporter assays in the parasite. We show a sequence-specific role in gene-expression for seven out of eight identified elements.

Conclusions
This work demonstrates the power of pure sequence analysis in the absence of expression data or a priori knowledge of regulatory elements in eukaryotic organisms with compact genomes.
Phase II Study of Eribulin Mesylate, a Halichondrin B Analog, in Patients With Metastatic Breast Cancer Previously Treated With an Anthracycline and a Taxane
Authors: Vahdat Linda T. , Pruitt Brian , Fabian Carol J. , Rivera Ragene R. , Smith David A. , Tan-Chiu Elizabeth , Wright Jonathan , Tan Antoinette R. , DaCosta Noshir A. , Chuang Ellen , Smith John , O'Shaughnessy Joyce , Shuster Dale E. , Meneses Nicole L. , Chandrawansa Kumari , Fang Fang , Cole Patricia E. , Ashworth Simon , Blum Joanne L. 
Published: April 2009

Purpose Eribulin mesylate (E7389), a nontaxane microtubule dynamics inhibitor, is a structurally simplified, synthetic analog of the marine natural product halichondrin B. This open-label, single-arm, phase II study evaluated efficacy and tolerability of eribulin in heavily pretreated patients with metastatic breast cancer (MBC). Methods MBC patients who were previously treated with an anthracycline and a taxane received eribulin mesylate (1.4 mg/m2) as a 2- to 5-minute intravenous (IV) infusion on days 1, 8, and 15 of a 28-day cycle. Because of neutropenia (at day 15), an alternative regimen of eribulin on days 1 and 8 of a 21-day cycle was administered. The primary end point was overall response rate. Results Of the 103 patients treated, the median number of prior chemotherapy regimens was four (range, one to 11 regimens). In the per-protocol population (n = 87), eribulin achieved an independently reviewed objective response rate (all partial responses [PRs]) of 11.5% (95% CI, 5.7 to 20.1) and a clinical benefit rate (PR plus stable disease ≥ 6 months) of 17.2% (95% CI, 10.0 to 26.8). The median duration of response was 171 days (5.6 months; range, 44 to 363 days), the median progression-free survival was 79 days (2.6 months; range, 1 to 453 days), and the median overall survival was 275 days (9.0 months; range, 15 to 826 days). The most common drug-related grades 3 to 4 toxicities were as follows: neutropenia, 64%; leukopenia, 18%; fatigue, 5%; peripheral neuropathy, 5%; and febrile neutropenia, 4%. Conclusion Eribulin demonstrated activity with manageable tolerability (including infrequent grade 3 and no grade 4 neuropathy) in heavily pretreated patients with MBC when dosed as a short IV infusion on days 1 and 8 of a 21-day cycle.
Dose-Intensified Compared With Standard Chemotherapy for Nonmetastatic Ewing Sarcoma Family of Tumors: A Children's Oncology Group Study
Authors: Granowetter Linda , Womer Richard , Devidas Meenakshi , Krailo Mark , Wang Chenguang , Bernstein Mark , Marina Neyssa , Leavey Patrick , Gebhardt Mark , Healey John , Shamberger Robert Cooper , Goorin Allen , Miser James , Meyer James , Arndt Carola A.S. , Sailer Scott , Marcus Karen , Perlman Elizabeth , Dickman Paul , Grier Holcombe E. 
Published: April 2009

Purpose The Ewing sarcoma family of tumors (ESFT) is a group of malignant tumors of soft tissue and bone sharing a chromosomal translocation affecting the EWS locus. The Intergroup INT-0091 demonstrated the superiority of a regimen of vincristine, cyclophosphamide, doxorubicin (VDC), and dactinomycin alternating with ifosfamide and etoposide (IE) over VDC for patients with nonmetastatic ESFT of bone. The goal of this study was to determine whether a dose-intensified regimen of VDC alternating with IE would further improve the outcome for patients with nonmetastatic ESFT of bone or soft tissue. Methods Patients with previously untreated, nonmetastatic ESFT of bone or soft tissue were eligible. They were randomly assigned to receive standard doses of VDC/IE over 48 weeks or a dose-intensified regimen of VDC/IE over 30 weeks. Results Four hundred seventy-eight patients met eligibility requirements: 231 patients received the standard regimen; 247 patients received the intensified regimen. The 5-year event-free survival (EFS) and overall survival rates for all eligible patients were 71.1% (95% CI, 67.7% to 75.0%) and 78.6% (95% CI, 74.6% to 82.1%), respectively. There was no significant difference (P = .57) in EFS between patients treated with the standard (5-year EFS, 72.1%; 95% CI, 65.8% to 77.5%) or intensified regimen (5-year EFS, 70.1%; 63.9% to 75%). Patients with soft tissue tumors accounted for 20% of the study population; there was no difference in outcome between patients with soft tissue and bone primary sites. Conclusion Dose escalation of alkylating agents as tested in this trial did not improve the outcome for patients with nonmetastatic ESFT of bone or soft tissue.
High Prevalence of Vitamin D Deficiency Despite Supplementation in Premenopausal Women With Breast Cancer Undergoing Adjuvant Chemotherapy
Authors: Crew Katherine D. , Shane Elizabeth , Cremers Serge , McMahon Donald J. , Irani Dinaz , Hershman Dawn L. 
Published: April 2009

Purpose Vitamin D deficiency is associated with increased breast cancer risk and decreased breast cancer survival. The purpose of this study was to determine the prevalence of vitamin D deficiency, as measured by serum 25-hydroxyvitamin D (25-OHD), in premenopausal women at initiation of adjuvant chemotherapy for breast cancer and after 1 year of vitamin D supplementation. Patients and Methods The study included 103 premenopausal women from the northeastern United States with stages I to III breast cancer who received adjuvant chemotherapy and participated in a 1-year zoledronate intervention trial. All patients were prescribed vitamin D3 (cholecalciferol) 400 IU and calcium carbonate 1,000 mg daily. At baseline and at 6 and 12 months, bone mineral density (BMD) measurements were obtained and blood was collected and analyzed in batches for serum 25-OHD. Vitamin D deficiency was defined as serum 25-OHD less than 20 ng/mL, insufficiency as 20 to 29 ng/mL, and sufficiency as 30 ng/mL or greater. Results At baseline, 74% of women were vitamin D deficient (median, 17 ng/mL). Vitamin D deficiency was slightly less common in white women (66%) compared with black (80%) and Hispanic (84%) women. After vitamin D supplementation for 1 year, less than 15% of white and Hispanic women, and no black women, achieved sufficient 25-OHD levels. Vitamin D levels did not correlate with baseline BMD and were not altered by chemotherapy or bisphosphonate use. Conclusion Vitamin D deficiency is highly prevalent in women with breast cancer. The current recommended dietary allowance of vitamin D is too low to increase serum 25-OHD greater than 30 ng/mL. Optimal dosing for bone health and, possibly, improved survival has yet to be determined.
Comparison of Models to Predict Nonsentinel Lymph Node Status in Breast Cancer Patients With Metastatic Sentinel Lymph Nodes: A Prospective Multicenter Study
Authors: Coutant Charles , Olivier Camille , Lambaudie Eric , Fondrinier Eric , Marchal Fréderic , Guillemin François , Seince Nathalie , Thomas Véronique , Levêque Jean , Barranger Emmanuel , Darai Emile , Uzan Serge , Houvenaeghel Gilles , Rouzier Roman 
Published: April 2009

PurposeSeveral models have been developed to predict nonsentinel lymph node (non-SN) status in patients with breast cancer with sentinel lymph node (SN) metastasis. The purpose of our investigation was to compare available models in a prospective, multicenter study.Patients and MethodsIn a cohort of 561 positive-SN patients who underwent axillary lymph node dissection, we evaluated the areas under the receiver operating characteristic curves (AUCs), calibration, rates of false negatives (FN), and number of patients in the group at low risk for non-SN calculated from nine models. We also evaluated these parameters in the subgroup of patients with micrometastasis or isolated tumor cells (ITC) in the SN.ResultsAt least one non-SN was metastatic in 147 patients (26.2%). Only two of nine models had an AUC greater than 0.75. Three models were well calibrated. Two models yielded an FN rate less than 5%. Three models were able to assign more than a third of patients in the low-risk group. Overall, the Memorial Sloan-Kettering Cancer Center nomogram and Tenon score outperform other methods for all patients, including the subgroup of patients with only SN micrometastases or ITC.ConclusionOur study suggests that all models do not perform equally, especially for the subgroup of patients with only micrometastasis or ITC in the SN. We point out available evaluation methods to assess their performance and provide guidance for clinical practice.
Prognosis After Ipsilateral Breast Tumor Recurrence and Locoregional Recurrences in Patients Treated by Breast-Conserving Therapy in Five National Surgical Adjuvant Breast and Bowel Project Protocols of Node-Negative Breast Cancer
Authors: Anderson Stewart J. , Wapnir Irene , Dignam James J. , Fisher Bernard , Mamounas Eleftherios P. , Jeong Jong-Hyeon , Geyer Charles E. , Wickerham D. Lawrence , Costantino Joseph P. , Wolmark Norman 
Published: April 2009

Purpose Locoregional failure (LRF) after breast-conserving therapy (BCT) is associated with increased risk of distant disease and death. The magnitude of this risk has not been adequately characterized in patients with lymph node-negative disease. Patients and Methods Our study population included 3,799 women randomly assigned to five National Surgical Adjuvant Breast and Bowel Project protocols of node-negative disease (ie, B-13, B-14, B-19, B-20, and B-23) who underwent lumpectomy and whole breast irradiation with or without adjuvant systemic therapy. Cumulative incidences of ipsilateral breast tumor recurrence (IBTR) and other locoregional recurrence (oLRR) were calculated, along with distant-disease–free interval (DDFI) and overall survival (OS) after these events. Cox models were employed to model mortality by using clinical and pathologic factors jointly with these events. Results Four hundred nineteen patients (11.0%) experienced LRF: 342 (9.0%) experienced IBTR, and 77 (2.0%) experienced oLRR. The 12-year cumulative incidences of IBTR and oLRR in patients treated with adjuvant systemic therapy were 6.6% and 1.8%, respectively. Overall, 37.1% of IBTRs and 72.7% of oLRRs occurred within 5 years of diagnosis. Older age, black race, higher body mass index (BMI), larger tumors, and occurrence of IBTR or oLRR were significantly associated with increased mortality. The 5-year OS after IBTR and oLRR were 76.6% and 34.9%, respectively. Adjusted hazard ratios for mortality associated with IBTR and oLRR were significantly higher in estrogen receptor (ER)–negative patients than in ER-positive patients (P = .002 and P < .0001, respectively). Patients with early LRF had worse OS and DDFI than those with later-occurring LRF. Conclusion Although LRF is uncommon in patients with node-negative breast cancer who are treated with lumpectomy, radiation, and adjuvant systemic therapy, those who do develop LRF have substantially worse OS and DDFI.
Effects of Chemotherapy in AIDS-Associated Non-Hodgkin's Lymphoma on Kaposi's Sarcoma Herpesvirus DNA in Blood
Authors: Lin Lan , Lee Jeannette Y. , Kaplan Lawrence D. , Dezube Bruce J. , Noy Ariela , Krown Susan E. , Levine Alexandra M. , Yu Yanxing , Hayward Gary S. , Ambinder Richard F. 
Published: April 2009

Purpose To determine the relative frequency with which Kaposi's sarcoma–associated herpesvirus/HHV-8 (KSHV) DNA is detected in peripheral-blood mononuclear cells (PBMCs) and in plasma of patients with AIDS-KS and AIDS-associated non-Hodgkin's lymphoma (NHL; AIDS-NHL); to determine whether the presence of viral DNA in plasma reflects lysis of tumor cells or reflects the presence of viremia (ie, virion-encapsidated DNA); and to determine the effect of lymphoma therapy on KSHV DNA. Patients and Methods Samples were obtained from patients enrolled in AIDS Malignancy Consortium clinical trials and from healthy donors. Real time PCR was used to quantify KSHV DNA in peripheral blood mononuclear cells (PBMC) and plasma. DNase digestion and fragment size determination studies were used to characterize the DNA detected. Results In patients with AIDS-KS, KSHV DNA was detected in PBMC (54%) and in plasma (62%). In patients with AIDS-NHL, KSHV DNA was detected in PBMC (19%) and in plasma (22%). Median copy numbers also differed. KSHV DNA in plasma appeared to be encapsidated. In six patients with AIDS-NHL who were treated with chemotherapy (with or without rituximab), KSHV copy number declined in PBMC and in plasma. Conclusion KSHV DNA is sometimes detected in PBMC or in plasma of patients with AIDS-NHL without KS. Among patients with KSHV DNA detected in PBMC or in plasma, copy number does not distinguish between patients with AIDS-NHL and AIDS-KS. KSHV DNA in plasma likely reflects viremia and not simply lysis of tumor or other KSHV-infected cells. KSHV DNA copy number in PBMC and in plasma declined with lymphoma-directed cytotoxic chemotherapy in each of the six patients studied.
Comprehensive Pharmacogenetic Analysis of Irinotecan Neutropenia and Pharmacokinetics
Authors: Innocenti Federico , Kroetz Deanna L. , Schuetz Erin , Dolan M. Eileen , Ramírez Jacqueline , Relling Mary , Chen Peixian , Das Soma , Rosner Gary L. , Ratain Mark J. 
Published: April 2009

Purpose We aim to identify genetic variation, in addition to the UGT1A1*28 polymorphism, that can explain the variability in irinotecan (CPT-11) pharmacokinetics and neutropenia in cancer patients. Patients and Methods Pharmacokinetic, genetic, and clinical data were obtained from 85 advanced cancer patients treated with single-agent CPT-11 every 3 weeks at doses of 300 mg/m2 (n = 20) and 350 mg/m2 (n = 65). Forty-two common variants were genotyped in 12 candidate genes of the CPT-11 pathway using several methodologies. Univariate and multivariate models of absolute neutrophil count (ANC) nadir and pharmacokinetic parameters were evaluated. Results Almost 50% of the variation in ANC nadir is explained by UGT1A1*93, ABCC1 IVS11 –48C>T, SLCO1B1*1b, ANC baseline levels, sex, and race (P < .0001). More than 40% of the variation in CPT-11 area under the curve (AUC) is explained by ABCC2 –24C>T, SLCO1B1*5, HNF1A 79A>C, age, and CPT-11 dose (P < .0001). Almost 30% of the variability in SN-38 (the active metabolite of CPT-11) AUC is explained by ABCC1 1684T>C, ABCB1 IVS9 –44A>G, and UGT1A1*93 (P = .004). Other models explained 17%, 23%, and 27% of the variation in APC (a metabolite of CPT-11), SN-38 glucuronide (SN-38G), and SN-38G/SN-38 AUCs, respectively. When tested in univariate models, pretreatment total bilirubin was able to modify the existing associations between genotypes and phenotypes. Conclusion On the basis of this exploratory analysis, common polymorphisms in genes encoding for ABC and SLC transporters may have a significant impact on the pharmacokinetics and pharmacodynamics of CPT-11. Confirmatory studies are required.
Inactivation of Drosophila Huntingtin affects long-term adult functioning and the pathogenesis of a Huntington’s disease model
Authors: Zhang Sheng , Feany Mel B. , Saraswati Sudipta , Littleton J. Troy , Perrimon Norbert 
Published: April 2009

SUMMARYA polyglutamine expansion in the huntingtin (HTT) gene causes neurodegeneration in Huntington’s disease (HD), but the in vivo function of the native protein (Htt) is largely unknown. Numerous biochemical and in vitro studies have suggested a role for Htt in neuronal development, synaptic function and axonal trafficking. To test these models, we generated a null mutant in the putative Drosophila HTT homolog (htt, hereafter referred to asdhtt) and, surprisingly, found that dhtt mutant animals are viable with no obvious developmental defects. Instead, dhtt is required for maintaining the mobility and long-term survival of adult animals, and for modulating axonal terminal complexity in the adult brain. Furthermore, removing endogenous dhtt significantly accelerates the neurodegenerative phenotype associated with a Drosophila model of polyglutamine Htt toxicity (HD-Q93), providing in vivo evidence that disrupting the normal function of Htt might contribute to HD pathogenesis.
Ethanol induces embryonic malformations by competing for retinaldehyde dehydrogenase activity during vertebrate gastrulation
Authors: Kot-Leibovich Hadas , Fainsod Abraham 
Published: April 2009

SUMMARYHuman embryos exposed to alcohol (ethanol) develop a complex developmental phenotype known as fetal alcohol spectrum disorder (FASD). In Xenopus embryos, ethanol reduces the levels of retinoic acid (RA) signaling during gastrulation. RA, a metabolite of vitamin A (retinol), is required for vertebrate embryogenesis, and deviation from its normal levels results in developmental malformations. Retinaldehyde dehydrogenase 2 (RALDH2) is required to activate RA signaling at the onset of gastrulation. We studied the effect of alcohol on embryogenesis by manipulating retinaldehyde dehydrogenase activity in ethanol-treated embryos. In alcohol-treated embryos, we analyzed RA signaling levels, phenotypes induced and changes in gene expression. Developmental defects that were characteristic of high ethanol concentrations were phenocopied by a low ethanol concentration combined with partial RALDH inhibition, whereas Raldh2 overexpression rescued the developmental malformations induced by high ethanol. RALDH2 knockdown resulted in similar RA signaling levels when carried out alone or in combination with ethanol treatment, suggesting that RALDH2 is the main target of ethanol. The biochemical evidence that we present shows that, at the onset of RA signaling during early gastrulation, the ethanol effect centers on the competition for the available retinaldehyde dehydrogenase activity. In light of the multiple regulatory roles of RA, continued embryogenesis in the presence of abnormally low RA levels provides an etiological explanation for the malformations observed in individuals with FASD.