bluuebunny/crossref_metadata_2025_split huggingface dataset:
Human genes with CpG island promoters have a distinct transcription-associated chromatin organization
Authors: Vavouri Tanya , Lehner Ben 
Published: November 2012

Abstract
Background
More than 50% of human genes initiate transcription from CpG dinucleotide-rich regions referred to as CpG islands. These genes show differences in their patterns of transcription initiation, and have been reported to have higher levels of some activation-associated chromatin modifications.

Results
Here we report that genes with CpG island promoters have a characteristic transcription-associated chromatin organization. This signature includes high levels of the transcription elongation-associated histone modifications H4K20me1, H2BK5me1 and H3K79me1/2/3 in the 5' end of the gene, depletion of the activation marks H2AK5ac, H3K14ac and H3K23ac immediately downstream of the transcription start site (TSS), and characteristic epigenetic asymmetries around the TSS. The chromosome organization factor CTCF may be bound upstream of RNA polymerase in most active CpG island promoters, and an unstable nucleosome at the TSS may be specifically marked by H4K20me3, the first example of such a modification. H3K36 monomethylation is only detected as enriched in the bodies of active genes that have CpG island promoters. Finally, as expression levels increase, peak modification levels of the histone methylations H3K9me1, H3K4me1, H3K4me2 and H3K27me1 shift further away from the TSS into the gene body.

Conclusions
These results suggest that active genes with CpG island promoters have a distinct step-like series of modified nucleosomes after the TSS. The identity, positioning, shape and relative ordering of transcription-associated histone modifications differ between genes with and without CpG island promoters. This supports a model where chromatin organization reflects not only transcription activity but also the type of promoter in which transcription initiates.
Gene Expression–Based Model Using Formalin-Fixed Paraffin-Embedded Biopsies Predicts Overall Survival in Advanced-Stage Classical Hodgkin Lymphoma
Authors: Scott David W. , Chan Fong Chun , Hong Fangxin , Rogic Sanja , Tan King L. , Meissner Barbara , Ben-Neriah Susana , Boyle Merrill , Kridel Robert , Telenius Adele , Woolcock Bruce W. , Farinha Pedro , Fisher Richard I. , Rimsza Lisa M. , Bartlett Nancy L. , Cheson Bruce D. , Shepherd Lois E. , Advani Ranjana H. , Connors Joseph M. , Kahl Brad S. , Gordon Leo I. , Horning Sandra J. , Steidl Christian , Gascoyne Randy D. 
Published: November 2012

PurposeOur aim was to reliably identify patients with advanced-stage classical Hodgkin lymphoma (cHL) at increased risk of death by developing a robust predictor of overall survival (OS) using gene expression measured in routinely available formalin-fixed paraffin-embedded tissue (FFPET).MethodsExpression levels of 259 genes, including those previously reported to be associated with outcome in cHL, were determined by digital expression profiling of pretreatment FFPET biopsies from 290 patients enrolled onto the E2496 Intergroup trial comparing doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) and Stanford V regimens in locally extensive and advanced-stage cHL. A model for OS separating patients into low- and high-risk groups was produced using penalized Cox regression. The model was tested in an independent cohort of 78 patients enriched for treatment failure but otherwise similar to patients in a population-based registry of patients treated with ABVD. Weighted analysis methods generated unbiased estimates of predictor performance in the population-based registry.ResultsA 23-gene outcome predictor was generated. The model identified a population at increased risk of death in the validation cohort. There was a 29% absolute difference in 5-year OS between the high- and low-risk groups (63% v 92%, respectively; log-rank P < .001; hazard ratio, 6.7; 95% CI, 2.6 to 17.4). The predictor was superior to the International Prognostic Score and CD68 immunohistochemistry in multivariate analyses.ConclusionA gene expression–based predictor, developed in and applicable to routinely available FFPET biopsies, identifies patients with advanced-stage cHL at increased risk of death when treated with standard-intensity up-front regimens.
Randomized Phase III Trial of ABVD Versus Stanford V With or Without Radiation Therapy in Locally Extensive and Advanced-Stage Hodgkin Lymphoma: An Intergroup Study Coordinated by the Eastern Cooperative Oncology Group (E2496)
Authors: Gordon Leo I. , Hong Fangxin , Fisher Richard I. , Bartlett Nancy L. , Connors Joseph M. , Gascoyne Randy D. , Wagner Henry , Stiff Patrick J. , Cheson Bruce D. , Gospodarowicz Mary , Advani Ranjana , Kahl Brad S. , Friedberg Jonathan W. , Blum Kristie A. , Habermann Thomas M. , Tuscano Joseph M. , Hoppe Richard T. , Horning Sandra J. 
Published: November 2012

PurposeAlthough ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) has been established as the standard of care in patients with advanced Hodgkin lymphoma, newer regimens have been investigated, which have appeared superior in early phase II studies. Our aim was to determine if failure-free survival was superior in patients treated with the Stanford V regimen compared with ABVD.Patients and MethodsThe Eastern Cooperative Oncology Group, along with the Cancer and Leukemia Group B, the Southwest Oncology Group, and the Canadian NCIC Clinical Trials Group, conducted this randomized phase III trial in patients with advanced Hodgkin lymphoma. Stratification factors included extent of disease (localized v extensive) and International Prognostic Factors Project Score (0 to 2 v 3 to 7). The primary end point was failure-free survival (FFS), defined as the time from random assignment to progression, relapse, or death, whichever occurred first. Overall survival, a secondary end point, was measured from random assignment to death as a result of any cause. This design provided 87% power to detect a 33% reduction in FFS hazard rate, or a difference in 5-year FFS of 64% versus 74% at two-sided .05 significance level.ResultsThere was no significant difference in the overall response rate between the two arms, with complete remission and clinical complete remission rates of 73% for ABVD and 69% for Stanford V. At a median follow-up of 6.4 years, there was no difference in FFS: 74% for ABVD and 71% for Stanford V at 5 years (P = .32).ConclusionABVD remains the standard of care for patients with advanced Hodgkin lymphoma.
Long-Term Results of RTOG 91-11: A Comparison of Three Nonsurgical Treatment Strategies to Preserve the Larynx in Patients With Locally Advanced Larynx Cancer
Authors: Forastiere Arlene A. , Zhang Qiang , Weber Randal S. , Maor Moshe H. , Goepfert Helmuth , Pajak Thomas F. , Morrison William , Glisson Bonnie , Trotti Andy , Ridge John A. , Thorstad Wade , Wagner Henry , Ensley John F. , Cooper Jay S. 
Published: November 2012

PurposeTo report the long-term results of the Intergroup Radiation Therapy Oncology Group 91-11 study evaluating the contribution of chemotherapy added to radiation therapy (RT) for larynx preservation.Patients and MethodsPatients with stage III or IV glottic or supraglottic squamous cell cancer were randomly assigned to induction cisplatin/fluorouracil (PF) followed by RT (control arm), concomitant cisplatin/RT, or RT alone. The composite end point of laryngectomy-free survival (LFS) was the primary end point.ResultsFive hundred twenty patients were analyzed. Median follow-up for surviving patients is 10.8 years. Both chemotherapy regimens significantly improved LFS compared with RT alone (induction chemotherapy v RT alone: hazard ratio [HR], 0.75; 95% CI, 0.59 to 0.95; P = .02; concomitant chemotherapy v RT alone: HR, 0.78; 95% CI, 0.78 to 0.98; P = .03). Overall survival did not differ significantly, although there was a possibility of worse outcome with concomitant relative to induction chemotherapy (HR, 1.25; 95% CI, 0.98 to 1.61; P = .08). Concomitant cisplatin/RT significantly improved the larynx preservation rate over induction PF followed by RT (HR, 0.58; 95% CI, 0.37 to 0.89; P = .0050) and over RT alone (P < .001), whereas induction PF followed by RT was not better than treatment with RT alone (HR, 1.26; 95% CI, 0.88 to 1.82; P = .35). No difference in late effects was detected, but deaths not attributed to larynx cancer or treatment were higher with concomitant chemotherapy (30.8% v 20.8% with induction chemotherapy and 16.9% with RT alone).ConclusionThese 10-year results show that induction PF followed by RT and concomitant cisplatin/RT show similar efficacy for the composite end point of LFS. Locoregional control and larynx preservation were significantly improved with concomitant cisplatin/RT compared with the induction arm or RT alone. New strategies that improve organ preservation and function with less morbidity are needed.
Fibroblast Growth Factor Receptor 1 Gene Amplification Is Associated With Poor Survival and Cigarette Smoking Dosage in Patients With Resected Squamous Cell Lung Cancer
Authors: Kim Hye Ryun , Kim Dae Joon , Kang Dae Ryong , Lee Jin Gu , Lim Sun Min , Lee Chang Young , Rha Sun Young , Bae Mi Kyung , Lee Young Joo , Kim Se Hoon , Ha Sang-Jun , Soo Ross Andrew , Chung Kyung Young , Kim Joo Hang , Lee Ji Hyun , Shim Hyo Sup , Cho Byoung Chul 
Published: November 2012

Purpose To investigate the frequency and the prognostic role of fibroblast growth factor receptor 1 (FGFR1) amplification in patients with surgically resected squamous cell carcinoma of the lung (SCCL) and the association between smoking and FGFR1 amplification. Patients and Methods Gene copy number of FGFR1 was investigated in microarrayed tumors from 262 patients with SCCL who had tumor tissue as well as smoking and survival data available. Gene copy number was evaluated by fluorescent in situ hybridization, and an FGFR1-amplified tumor (FGFR1 amp+) was prespecified as a tumor with nine or more copies of FGFR1. Results Among 262 patients, the frequency of FGFR1 amp+ was 13.0%. Patients with FGFR1 amp+ had significantly shorter disease-free survival (DFS; 26.9 v 94.6 months; P < .001) as well as shorter overall survival (OS; 51.2 v 115.0 months; P = .002) than those without FGFR1 amp+. Multivariate modeling confirmed that patients with FGFR1 amp+ had a significantly greater risk of recurrence and death than those without FGFR1 amp+ after adjusting for sex, smoking status, pathologic stage, and adjuvant chemotherapy (DFS: adjusted hazard ratio [AHR], 2.24; 95% CI, 1.45 to 3.45; P < .001; OS: AHR, 1.83; 95% CI, 1.15 to 2.89; P = .01). The frequency of FGFR1 amp+ was significantly higher in current smokers than in former smokers and never-smokers (28.9% v 2.5% v 0%; Ptrend < .001). As the smoking dosage increased, so did the incidence of FGFR1 amp+ (Ptrend = .002). Conclusion FGFR1 amplification is an independent negative prognostic factor in surgically resected SCCL and is associated with cigarette smoking in a dose-dependent manner. FGFR1 amplification is a relevant therapeutic target in Asian patients with SCCL.
The chromatin remodeling factor Chd1l is required in the preimplantation embryo
Authors: Snider Alyssa C. , Leong Denise , Wang Q. Tian , Wysocka Joanna , Yao Mylene W. M. , Scott Matthew P. 
Published: November 2012

Summary
During preimplantation development, the embryo must establish totipotency and enact the earliest differentiation choices, processes that involve extensive chromatin modification. To identify novel developmental regulators, we screened for genes that are preferentially transcribed in the pluripotent inner cell mass (ICM) of the mouse blastocyst. Genes that encode chromatin remodeling factors were prominently represented in the ICM, including Chd1l, a member of the Snf2 gene family. Chd1l is developmentally regulated and expressed in embryonic stem (ES) cells, but its role in development has not been investigated. Here we show that inhibiting Chd1l protein production by microinjection of antisense morpholinos causes arrest prior to the blastocyst stage. Despite this important function in vivo, Chd1l is non-essential for cultured ES cell survival, pluripotency, or differentiation, suggesting that Chd1l is vital for events in embryos that are distinct from events in ES cells. Our data reveal a novel role for the chromatin remodeling factor Chd1l in the earliest cell divisions of mammalian development.
Duplication and maintenance of the Myb genes of vertebrate animals
Authors: Davidson Colin J. , Guthrie Erin E. , Lipsick Joseph S. 
Published: November 2012

Summary
Gene duplication is an important means of generating new genes. The major mechanisms by which duplicated genes are preserved in the face of purifying selection are thought to be neofunctionalization, subfunctionalization, and increased gene dosage. However, very few duplicated gene families in vertebrate species have been analyzed by functional tests in vivo. We have therefore examined the three vertebrate Myb genes (c-Myb, A-Myb, and B-Myb) by cytogenetic map analysis, by sequence analysis, and by ectopic expression in Drosophila. We provide evidence that the vertebrate Myb genes arose by two rounds of regional genomic duplication. We found that ubiquitous expression of c-Myb and A-Myb, but not of B-Myb or Drosophila Myb, was lethal in Drosophila. Expression of any of these genes during early larval eye development was well tolerated. However, expression of c-Myb and A-Myb, but not of B-Myb or Drosophila Myb, during late larval eye development caused drastic alterations in adult eye morphology. Mosaic analysis implied that this eye phenotype was cell-autonomous. Interestingly, some of the eye phenotypes caused by the retroviral v-Myb oncogene and the normal c-Myb proto-oncogene from which v-Myb arose were quite distinct. Finally, we found that post-translational modifications of c-Myb by the GSK-3 protein kinase and by the Ubc9 SUMO-conjugating enzyme that normally occur in vertebrate cells can modify the eye phenotype caused by c-Myb in Drosophila. These results support a model in which the three Myb genes of vertebrates arose by two sequential duplications. The first duplication was followed by a subfunctionalization of gene expression, then neofunctionalization of protein function to yield a c/A-Myb progenitor. The duplication of this progenitor was followed by subfunctionalization of gene expression to give rise to tissue-specific c-Myb and A-Myb genes.
Gastrointestinal defects of the Gas1 mutant involve dysregulated Hedgehog and Ret signaling
Authors: Biau Sandrine , Jin Shiying , Fan Chen-Ming 
Published: November 2012

Summary
The gastrointestinal (GI) tract defines the digestive system and is composed of the stomach, intestine and colon. Among the major cell types lining radially along the GI tract are the epithelium, mucosa, smooth muscles and enteric neurons. The Hedgehog (Hh) pathway has been implicated in directing various aspects of the developing GI tract, notably the mucosa and smooth muscle growth, and enteric neuron patterning, while the Ret signaling pathway is selectively required for enteric neuron migration, proliferation, and differentiation. The growth arrest specific gene 1 (Gas1) encodes a GPI-anchored membrane protein known to bind to Sonic Hh (Shh), Indian Hh (Ihh), and Ret. However, its role in the GI tract has not been examined. Here we show that the Gas1 mutant GI tract, compared to the control, is shorter, has thinner smooth muscles, and contains more enteric progenitors that are abnormally distributed. These phenotypes are similar to those of the Shh mutant, supporting that Gas1 mediates most of the Shh activity in the GI tract. Because Gas1 has been shown to inhibit Ret signaling elicited by Glial cell line-derived neurotrophic factor (Gdnf), we explored whether Gas1 mutant enteric neurons displayed any alteration of Ret signaling levels. Indeed, isolated mutant enteric progenitors not only showed increased levels of phospho-Ret and its downstream effectors, phospho-Akt and phospho-Erk, but also displayed altered responses to Gdnf and Shh. We therefore conclude that phenotypes observed in the Gas1 mutant are due to a combination of reduced Hh signaling and increased Ret signaling.
Radiation dose reduction for chest CT with non-linear adaptive filters
Authors: Singh Sarabjeet , Digumarthy Subba R , Back Anni , Shepard Jo-Anne O , Kalra Mannudeep K 
Published: November 2012

Background CT radiation dose reduction results in increased noise or graininess of images which affects the diagnostic information. One of the approaches to lower radiation exposure to patients is to reduce image noise with the use of image processing software in low radiation dose images. Purpose To assess image quality and accuracy of non-linear adaptive filters (NLAF) at low dose chest CT. Material and Methods In an IRB approved prospective study, 24 patients (mean age, 63±7.3 years; M:F ratio, 11:13) gave informed consent for acquisition of four additional chest CT image series at 150, 110, 75, and 40 mAs (baseline image series) on a 64-slice MDCT over an identical 10-cm length. NLAF was used to process three low dose (110, 75, and 40 mAs) image series (postprocessed image series). Two radiologists reviewed baseline and postprocessed images in a blinded manner for image quality. Objective noise, CT attenuation values, patient weight, transverse diameters, CTDIvol, and DLP were recorded. Statistical analysis was performed using parametric and non-parametric tests for comparing postprocessed and baseline images. Results No lesions were missed on baseline or postprocessed CT images ( n = 80 lesions, 73 lesions <1 cm). At 40 mAs, subjective noise in mediastinal window settings were graded as unacceptable in baseline images and acceptable in postprocessed images. Visibility of smaller structures improved from suboptimal visibility in baseline images at 40 mAs to excellent in postprocessed images at 40 mAs. No major artifacts were seen due to NLAF postprocessing, except for minor beam hardening artifacts not affecting diagnostic decision-making (14/22) in both baseline and postprocessed image series. Diagnostic confidence for chest CT was improved to fully confident in postprocessed images at 40 mAs. Compared to baseline images, postprocessing reduced objective noise by 26% (14.2±4.7/19.2±6.4), 31.5% (15.2±4.7/22.2±5.7), and 41.5% (16.9±6/28.9±10.2) at 110 mAs, 75 mAs, and 40 mAs tube current-time product levels. Conclusion Applications of NLAF can help reduce tube current down to 40 mAs for chest CT while maintaining lesion conspicuity and image quality.
Cemented polyethylene and cementless porous-coated acetabular components have similar outcomes at a mean of seven years after total hip replacement
Authors: Angadi D. S. , Brown S. , Crawfurd E. J. P. 
Published: November 2012

The aim of this prospective randomised study was to compare the clinical and radiological results of a cemented all-polyethylene Ultima acetabular component with those of a cementless porous-coated acetabular component (PFC) following total hip replacement (THR). A total of 287 patients received either a polyethylene acetabular component (group A) or a cobalt–chromium porous-coated component (group B) with an identical cemented femoral component and 28 mm cobalt-chromium head, thus making it the largest study of its type. Patients were evaluated radiologically and clinically using the Harris hip score (HHS). Group A comprised 183 patients (73 male, 110 female) with a mean age of 71.3 years (55 to 89). Group B comprised 104 patients (48 male, 56 female) with a mean age of 69.8 years (56 to 89). A total of 16 patients (13 in Group A, three in Group B) did not have post-operative data for analysis. The mean follow-up in group A was 7.52 years (0.4 to 15.0) and in Group B 7.87 years (0.5 to 14.0).At final follow-up the mean HHS was similar between groups A and B (74.5 (25 to 100) and 78.0 (37 to 100), respectively; p = 0.068). The total number of revisions for any cause was 28, 17 of which were in group A and 11 in group B. The ten-year survivorship was 86.8% (95% confidence interval (CI) 78.4 to 92.1) and 89.2% (95% CI 78.3 to 94.8) for groups A and B, respectively (log-rank p-value = 0.938). A total of 20 cemented and two cementless acetabular components had evidence of acetabular radiolucencies or acetabular component migration at last follow-up (p = 0.001).These results indicate that patients with a cemented all-polyethylene and cementless porous-coated polyethylene lined acetabular component have similar long-term clinical outcomes.
The results of uncemented total hip replacement in children with juvenile idiopathic arthritis at ten years
Authors: Daurka J. S. , Malik A. K. , Robin D. A. , Witt J. D. 
Published: November 2012

The inherent challenges of total hip replacement (THR) in children include the choice of implant for the often atypical anatomical morphology, its fixation to an immature growing skeleton and the bearing surface employed to achieve a successful long-term result. We report the medium-term results of 52 consecutive uncemented THRs undertaken in 35 paediatric patients with juvenile idiopathic arthritis. The mean age at the time of surgery was 14.4 years (10 to 16). The median follow-up was 10.5 years (6 to 15). During the study period 13 THRs underwent revision surgery. With revision as an endpoint, subgroup analysis revealed 100% survival of the 23 ceramic-on-ceramic THRs and 55% (16 of 29) of the metal- or ceramic-on-polyethylene. This resulted in 94% (95% CI 77.8 to 98.4) survivorship of the femoral component and 62% (95% CI 41.0 to 78.0) of the acetabular component. Revision of the acetabular component for wear and osteolysis were the most common reasons for failure accounting for 11 of the 13 revisions.The success seen in patients with a ceramic-on-ceramic articulation seems to indicate that this implant strategy has the potential to make a major difference to the long-term outcome in this difficult group of patients.
The safety of peri-articular local anaesthetic injection for patients undergoing total knee replacement with autologous blood transfusion
Authors: Wallace D. F. , Emmett S. R. , Kang K. K. , Chahal G. S. , Hiskens R. , Balasubramanian S. , McGuinness K. , Parsons H. , Achten J. , Costa M. L. 
Published: November 2012

Intra-operative, peri-articular injection of local anaesthesia is an increasingly popular way of controlling pain following total knee replacement. At the same time, the problems associated with allogenic blood transfusion have led to interest in alternative methods for managing blood loss after total knee replacement, including the use of auto-transfusion of fluid from the patient’s surgical drain. It is safe to combine peri-articular infiltration with auto-transfusion from the drain. We performed a randomised clinical trial to compare the concentration of local anaesthetic in the blood and in the fluid collected in the knee drain in patients having either a peri-articular injection or a femoral nerve block. Clinically relevant concentrations of local anaesthetic were found in the fluid from the drains of patients having peri-articular injections (4.92 μg/ml (sd 3.151)). However, none of the patients having femoral nerve blockade had detectable levels. None of the patients in either group had clinically relevant concentrations of local anaesthetic in their blood after re-transfusion.The evidence from this study suggests that it is safe to use peri-articular injection in combination with auto-transfusion of blood from peri-articular drains during knee replacement surgery.