bluuebunny/crossref_metadata_2025_split huggingface dataset:
RIZ1 is potential CML tumor suppressor that is down-regulated during disease progression
Authors: Lakshmikuttyamma Ashakumary , Takahashi Naoto , Pastural Elodie , Torlakovic Emina , Amin Hesham M , Garcia-Manero Guillermo , Voralia Michael , Czader Magdalena , DeCoteau John F , Geyer C Ronald 
Published: July 2009

Abstract

Background
RIZ1 expression and activity are reduced in many cancers. In AML cell lines and patient material, RIZ1 expression is reduced relative to normal bone marrow. In chronic myelogenous leukemia (CML), blastic transformation is associated with loss of heterozygosity in the region where RIZ1 is located. RIZ1 is a PR domain methyltransferase that methylates histone H3 lysine 9, a modification important for transcriptional repression. In CML blast crisis cell lines RIZ1 represses insulin-like growth factor-1 expression and autocrine signaling. Together these observations suggest that RIZ1 may have a role in the chronic phase to blast crisis transition in CML.

Results
In CML patient material, we observed that RIZ1 expression was decreased during progression from chronic phase to blast crisis. RIZ1 was expressed in mature myeloid and CD34+ cells demonstrating that decreased RIZ1 expression in blast crisis is not due to an increased immature cell population. Expression of RIZ1 CML blast crisis cell lines decreased proliferation, increased apoptosis, and enhanced differentiation.

Conclusion
RIZ1 is a candidate tumor suppressor gene whose expression is decreased in blast crisis. Loss of RIZ1 activity results in decreased apoptosis and differentiation and enhanced proliferation. Together these results suggest that loss of RIZ1 expression will lead to an increase in myeloid blast cell population resulting in CML progression.
Head & neck optical diagnostics: vision of the future of surgery
Authors: Upile Tahwinder , Jerjes Waseem , Sterenborg Henricus JCM , El-Naggar Adel K , Sandison Ann , Witjes Max JH , Biel Merrill A , Bigio Irving , Wong Brian JF , Gillenwater Ann , MacRobert Alexander J , Robinson Dominic J , Betz Christian S , Stepp Herbert , Bolotine Lina , McKenzie Gordon , Mosse Charles Alexander , Barr Hugh , Chen Zhongping , Berg Kristian , D'Cruz Anil K , Stone Nicholas , Kendall Catherine , Fisher Sheila , Leunig Andreas , Olivo Malini , Richards-Kortum Rebecca , Soo Khee Chee , Bagnato Vanderlei , Choo-Smith Lin-Ping , Svanberg Katarina , Tan I Bing , Wilson Brian C , Wolfsen Herbert , Yodh Arjun G , Hopper Colin 
Published: July 2009

Abstract
Review paper and Proceedings of the Inaugural Meeting of the Head and Neck Optical Diagnostics Society (HNODS) on March 14th 2009 at University College London.
The aim of our research must be to provide breakthrough translational research which can be applied clinically in the immediate rather than the near future. We are fortunate that this is indeed a possibility and may fundamentally change current clinical and surgical practice to improve our patients' lives.
Flow cytometry analysis of glucocorticoid receptor expression and binding in steroid-sensitive and steroid-resistant patients with systemic lupus erythematosus
Authors: Du Juan , Li Min , Zhang Denghai , Zhu Xiaoyan , Zhang Weiwei , Gu Wei , Feng Yinglu , Zhai Xiaofeng , Ling Changquan 
Published: July 2009

Abstract
Introduction
Glucocorticoid (GC) therapy is the main treatment for systemic lupus erythematosus (SLE). However, some patients are resistant to these agents. Abnormalities of glucocorticoid receptor (GR) seem to be related to steroid resistance. This study evaluated GRs in T lymphocytes and monocytes of SLE patients by flow cytometry (FCM) using a monoclonal antibody (mAb) and FITC-Dex probes.

Methods
Thirty-five patients with SLE before treatment and 27 age- and sex-matched normal controls were studied. Disease activity scores were determined before and after treatment and used to divide the patients into steroid-resistant (SR) and steroid-sensitive (SS) groups. GRs in T lymphocytes (CD3+) and monocytes (CD14+) were examined by FCM with GR-mAb and FITC-Dex probes before treatment. Peripheral blood mononuclear cells (PBMCs) were isolated for in vitro GCs sensitivity assays. The validity of FCM analysis of intracellular staining for GR with GR-mAb and FITC-Dex probes was evaluated through comparison with western blot and radioligand binding assay (RLBA) in U937 and K562 cells in vitro. One-way ANOVA, student's t test, linear regression and spearman correlation were performed.

Results
A significant decrease in GR binding and the expression in K562 and U937 cells with 10-6 M dexamethasone (Dex) was found compared with those without Dex. In addition, a positive correlation was found between FCM and RLBA as well as FCM and Western blot. The expression and binding of both CD3/GR and CD14/GR in SR patients with SLE, detected by FCM, were all lower than those in SS patients with SLE, whereas there was no significant difference in SS patients and controls. In vitro corticosteroid sensitivity assay indicated that PHA-stimulated tumour necrosis factor-α (TNF-α), IL-12 and interferon-γ (IFN-γ) secretion was significantly inhibited by 10-6 M Dexamethasone in all controls and SS patients, compared with that in SR group, which confirms patient classification as SR and SS by disease activity index (SLEDAI) score.

Conclusions
Abnormalities of expression and binding of the GR may be involved in tissue resistance to steroids in SLE patients. Determination of GR expression and binding by FCM may be useful in predicting the response to steroid treatment of SLE patients.

Trial registration
Clinical trial registration number NCT00600652.
Randomized Double-Blind 2 × 2 Trial of Low-Dose Tamoxifen and Fenretinide for Breast Cancer Prevention in High-Risk Premenopausal Women
Authors: Decensi Andrea , Robertson Chris , Guerrieri-Gonzaga Aliana , Serrano Davide , Cazzaniga Massimiliano , Mora Serena , Gulisano Marcella , Johansson Harriet , Galimberti Viviana , Cassano Enrico , Moroni Simona M. , Formelli Franca , Lien Ernst A. , Pelosi Giuseppe , Johnson Karen A. , Bonanni Bernardo 
Published: July 2009

Purpose Tamoxifen and fenretinide are active in reducing premenopausal breast cancer risk and work synergistically in preclinical models. The authors assessed their combination in a two-by-two biomarker trial. Patients and Methods A total of 235 premenopausal women with pT1mic/pT1a breast cancer (n = 21), or intraepithelial neoplasia (IEN, n = 160), or 5-year Gail risk ≥ 1.3% (n = 54) were randomly allocated to either tamoxifen 5 mg/d, fenretinide 200 mg/d, their combination, or placebo. We report data for plasma insulin-like growth factor I (IGF-I), mammographic density, uterine effects, and breast neoplastic events after 5.5 years. Results During the 2-year intervention, tamoxifen significantly lowered IGF-I and mammographic density by 12% and 20%, respectively, fenretinide by 4% and 10% (not significantly), their combination by 20% and 22%, with no evidence for a synergistic interaction. Tamoxifen increased endometrial thickness principally in women becoming postmenopausal, whereas fenretinide decreased endometrial thickness significantly. The annual rate of breast neoplasms (n = 48) was 3.5% ± 1.0%, 2.1% ± 0.8%, 4.7% ± 1.3%, and 5.2% ± 1.3% in the tamoxifen, fenretinide, combination, and placebo arms, respectively, with hazard ratios (HRs) of 0.70 (95% CI, 0.32 to 1.52), 0.38 (95% CI, 0.15 to 0.90), and 0.96 (95% CI, 0.46 to 1.99) relative to placebo (tamoxifen × fenretinide adverse interaction P = .03). There was no clear association with tumor receptor type. Baseline IGF-I and mammographic density did not predict breast neoplastic events, nor did change in mammographic density. Conclusion Despite favorable effects on plasma IGF-I levels and mammographic density, the combination of low-dose tamoxifen plus fenretinide did not reduce breast neoplastic events compared to placebo, whereas both single agents, particularly fenretinide, showed numerical reduction in annual odds of breast neoplasms. Further follow-up is indicated.
Index to Predict Invasive Mold Infection in High-Risk Neutropenic Patients Based on the Area Over the Neutrophil Curve
Authors: Portugal Rodrigo D. , Garnica Marcia , Nucci Marcio 
Published: July 2009

Purpose Patients with prolonged and profound neutropenia are at high risk to develop invasive mold infections (IMIs). We developed an index (D-index) that combines duration and severity of neutropenia. The aim of this study was to test the D-index as a predictor of IMI. Patients and Methods The D-index was based on a graph plotting the absolute neutrophil counts during neutropenia and was the area over the neutrophil curve. We tested the D-index in 11 patients with acute myeloid leukemia (AML) who developed IMI during neutropenia and 33 AML patients without IMI (controls). We also calculated a cumulative D-index (c-D-index), defined as the cumulative D-index from the start of neutropenia until the date of the first clinical manifestation of IMI in patient cases. We compared the D-index and c-D-index with duration of neutropenia and defined a cutoff for IMI using the receiver operating characteristic (ROC) curve. Results The median duration of neutropenia and profound neutropenia of patient cases were significantly higher compared with controls (P = .002 and P = .001, respectively), as were the D-index (P < .001) and c-D-index (P = .02). The D-index and c-D-index performed better than duration of neutropenia in ROC curve analysis. For a cutoff point of 5,800 of the c-D-index, the sensitivity and specificity were 91% and 58%, respectively, and for a prevalence of IMI of 5%, 10%, and 15%, the negative predictive values were 99%, 98%, and 97%, respectively. Conclusion The high negative predictive value of the c-D-index may be of help in defining different risks for IMI in febrile neutropenic patients.
Clinical Trial Designs for Predictive Biomarker Validation: Theoretical Considerations and Practical Challenges
Authors: Mandrekar Sumithra J. , Sargent Daniel J. 
Published: July 2009

Purpose Biomarkers can add substantial value to current medical practice by providing an integrated approach to prediction using the genetic makeup of the tumor and the genotype of the patient to guide patient-specific treatment selection. We discuss and evaluate various clinical trial designs for the validation of biomarker-guided therapy. Methods Designs for predictive marker validation are broadly classified as retrospective (ie, using data from previously well-conducted randomized controlled trials [RCTs]) versus prospective (enrichment, unselected, hybrid, or adaptive analysis). We discuss the salient features of each design in the context of real trials. Results Well-designed retrospective analysis from well-conducted prospective RCTs can bring forward effective treatments to marker-defined subgroups of patients in a timely manner (eg, KRAS and colorectal cancer). Enrichment designs are appropriate when preliminary evidence suggest that patients with or without that marker profile do not benefit from the treatments in question; however, this may sometimes leave questions unanswered (eg, trastuzumab and breast cancer). An unselected design is optimal where preliminary evidence regarding treatment benefit and assay reproducibility is uncertain (eg, epidermal growth factor receptor and lung cancer). Hybrid designs are appropriate when preliminary evidence demonstrate the efficacy of certain treatments for a marker-defined subgroup, making it unethical to randomly assign patients with that marker status to other treatments (eg, multigene assay and breast cancer). Adaptive analysis designs allow for prespecified marker-defined subgroup analyses of data from an RCT. Conclusion The implementation of these design strategies will lead to a more rapid clinical validation of biomarker-guided therapy.
Merkel Cell Carcinoma: Recent Progress and Current Priorities on Etiology, Pathogenesis, and Clinical Management
Authors:   The Rockville Merkel Cell Carcinoma Group
Published: July 2009

Purpose To expedite improved understanding, diagnosis, treatment, and prevention of Merkel cell carcinoma (MCC), a rare malignancy of cutaneous neuroendocrine cells that has a 28% 2-year mortality rate. Methods This article summarizes a workshop that discussed the state-of-the-art research and priorities for research on MCC and on a new human polyomavirus (ie, MCPyV) recently discovered in 80% of MCC tumors. Results Normal Merkel cells are widely distributed in the epidermis near the end of nerve axons and may function as mechanoreceptors or chemoreceptors. Malignant MCC cells typically stain for cytokeratin 20 as well as for other epithelial and neuroendocrine markers. MCC subtypes, which are based on histology, on cell line growth properties, and on gene expression profiles, have been reported but have not been linked to prognosis. Clinical management has been empiric. MCPyV is clonally integrated at various sites in the human genome of MCC tumors, with truncating mutations in the viral, large T antigen gene that interrupt viral replication. MCPyV seroprevalence may be high, as with previously known human polyomaviruses. MCC risk is increased 11-fold with AIDS and with other cell-mediated immune deficiencies, B-cell neoplasms, and ultraviolet radiation exposure. Conclusion Development and validation of a range quantitative polymerase chain reaction and serologic assays for detection of MCPyV, as well as an infectious clone of the virus, would clarify the fundamental biology, natural history, and epidemiology of the virus, of MCC, and of other diseases. Contingent on standardized histologic diagnosis and staging of MCC, consortia are needed to clarify the risks and benefits of sentinel lymph node biopsy, adjuvant radiation therapy, and salvage therapies; consortia are needed also for epidemiologic studies of MCC etiology.
Effects of eccentric compression by a crossed-tape technique after endovenous laser ablation of the great saphenous vein: a randomized study
Authors: Lugli M , Cogo A , Guerzoni S , Petti A , Maleti O 
Published: July 2009

Objectives To evaluate the effect of eccentric compression applied by a new crossed-tape technique on procedure-related pain occurrence after endovenous laser ablation (ELA) of the great saphenous vein (GSV). Methods From April 2005 to June 2006, 200 consecutive ELA procedures were randomized to receive (group A: 100) or not (group B: 100) an eccentric compression applied in the medial aspect of the thigh. Patients were scheduled for a seven-day examination to assess the level of pain experienced. Pain intensity was measured using a visual analogue scale giving a numerical grade from 0 (no pain) to 10 (worst pain ever). Results The intensity of postoperative pain was significantly reduced ( P < 0.001) in the eccentric compression group as compared with the non-compression one. Conclusions This technique of eccentric compression greatly reduces the intensity of postoperative pain after ELA of the GSV.
Sclerotherapy of varicose veins in patients with documented thrombophilia: a prospective controlled randomized study of 105 cases
Authors: Hamel-Desnos C M , Gillet J-L , Desnos P R , Allaert F A 
Published: July 2009

Objectives The aim of this study was to assess thrombotic complications following sclerotherapy in thrombophilic patients in combination with thromboprophylaxis, in two randomized arms using low molecular weight heparin (LMWH) or warfarin. Patients and methods This study received approval from the Ethics Committee. A total of 105 patients (81 females, 24 males) ranging in age from 20 to 82 years (mean 50) were selected: 75 with Factor V Leiden mutation, 18 with prothrombin 20210A mutation, 7 with high level of Factor VIII, 5 combinations of these. After randomization, 51 and 54 patients received warfarin and LMWH, respectively. A total of 199 sclerotherapy sessions were performed. Foam was used in 160 treatments. Results No episodes of symptomatic deep vein thrombosis (DVT) or pulmonary embolism (PE) occurred; no instances of DVT were revealed by ultrasound-monitoring. Conclusions This study suggests that in the three most common forms of thrombophilia, sclerotherapy, in combination with thromboprophylaxis, can be performed safely. Prophylaxis with LMWH is easier to use than warfarin.
Candidate gene analysis of femoral neck trabecular and cortical volumetric bone mineral density in older men
Authors: Yerges Laura M , Klei Lambertus , Cauley Jane A , Roeder Kathryn , Kammerer Candace M , Ensrud Kristine E , Nestlerode Cara S , Lewis Cora , Lang Thomas F , Barrett-Connor Elizabeth , Moffett Susan P , Hoffman Andrew R , Ferrell Robert E , Orwoll Eric S , Zmuda Joseph M 
Published: July 2009

Abstract
In contrast to conventional dual-energy X-ray absorptiometry, quantitative computed tomography separately measures trabecular and cortical volumetric bone mineral density (vBMD). Little is known about the genetic variants associated with trabecular and cortical vBMD in humans, although both may be important for determining bone strength and osteoporotic risk. In the current analysis, we tested the hypothesis that there are genetic variants associated with trabecular and cortical vBMD at the femoral neck by genotyping 4608 tagging and potentially functional single-nucleotide polymorphisms (SNPs) in 383 bone metabolism candidate genes in 822 Caucasian men aged 65 years or older from the Osteoporotic Fractures in Men Study (MrOS). Promising SNP associations then were tested for replication in an additional 1155 men from the same study. We identified SNPs in five genes (IFNAR2, NFATC1, SMAD1, HOXA, and KLF10) that were robustly associated with cortical vBMD and SNPs in nine genes (APC, ATF2, BMP3, BMP7, FGF18, FLT1, TGFB3, THRB, and RUNX1) that were robustly associated with trabecular vBMD. There was no overlap between genes associated with cortical vBMD and trabecular vBMD. These findings identify novel genetic variants for cortical and trabecular vBMD and raise the possibility that some genetic loci may be unique for each bone compartment. © 2010 American Society for Bone and Mineral Research
Peano differentiable extensions in o-minimal structures
Authors: Fischer Andreas 
Published: July 2009

AbstractPeano differentiability generalizes ordinary differentiability to higher order. There are two ways to define Peano differentiability for functions defined on non-open sets. For both concepts, we investigate the question under which conditions a function defined on a closed set can be extended to a Peano differentiable function on the ambient space if the sets and functions are definable in an o-minimal structure expanding a real closed field.
Anti-Terrorismus-Politik. Ein deutsch-italienischer Vergleich 1969–1982
Authors: Hürter Johannes 
Published: July 2009

Vorspann
Zwei Staaten, ein Problem. Nirgendwo im Europa der 1970er Jahre verübten linksextreme Terroristen so viele Anschläge und Morde wie in Italien und der Bundesrepublik. Beide Demokratien waren gezwungen, auf diese Herausforderung zu reagieren. Die Interaktion von Terrorismus, Staat und Gesellschaft prägte ein ganzes Jahrzehnt. Dabei fiel dem politisch-administrativen Handeln eine Schlüsselrolle zu. Für welche Gegenmaßnahmen entschieden sich Regierung und Parlament? Erwies sich der demokratische Rechtsstaat als stark und gefestigt und zugleich als flexibel und integrativ genug, um die terroristische Gefahr zu bewältigen, ohne selbst Schaden zu nehmen? Ein Ländervergleich verspricht neue Erkenntnisse für beide nationalen Beispiele.
Epistatic Effects of the Protease/Chaperone HflB on Some Damaged Forms of the Escherichia coli Ammonium Channel AmtB
Authors: Inwood William B , Hall Jason A , Kim Kwang-Seo , Demirkhanyan Lusine , Wemmer David , Zgurskaya Helen , Kustu Sydney 
Published: July 2009

Abstract
The Escherichia coli ammonium channel AmtB is a trimer in which each monomer carries a pore for substrate conduction and a cytoplasmic C-terminal extension of ∼25 residues. Deletion of the entire extension leaves the protein with intermediate activity, but some smaller lesions in this region completely inactivate AmtB, as do some lesions in its cytoplasmic loops. We here provide genetic evidence that inactivation depends on the essential protease HflB, which appears to cause inactivation not as a protease but as a chaperone. Selection for restored function of AmtB is a positive selection for loss of the ATPase/chaperone activity of HflB and reveals that the conditional lethal phenotype for hflB is cold sensitivity. Deletion of only a few residues from the C terminus of damaged AmtB proteins seems to prevent HflB from acting on them. Either yields the intermediate activity of a complete C-terminal deletion. HflB apparently “tacks” damaged AmtB tails to the adjacent monomers. Knowing that HflB has intervened is prerequisite to determining the functional basis for AmtB inactivation.
Conservation of Domain Structure in a Fast-Evolving Heterochromatic SUUR Protein in Drosophilids
Authors: Yurlova Anna A , Makunin Igor V , Kolesnikova Tatyana D , Posukh Olga V , Belyaeva Elena S , Zhimulev Igor F 
Published: July 2009

Abstract
Different genomic regions replicate at a distinct time during S-phase. The SuUR mutation alters replication timing and the polytenization level of intercalary and pericentric heterochromatin in Drosophila melanogaster salivary gland polytene chromosomes. We analyzed SuUR in different insects, identified conserved regions in the protein, substituted conserved amino acid residues, and studied effects of the mutations on SUUR function. SuUR orthologs were identified in all sequenced drosophilids, and a highly divergent ortholog was found in the mosquito genome. We demonstrated that SUUR evolves at very high rate comparable with that of Transformer. Remarkably, upstream ORF within 5′ UTR of the gene is more conserved than SUUR in drosophilids, but it is absent in the mosquito. The domain structure and charge of SUUR are maintained in drosophilids despite the high divergence of the proteins. The N-terminal part of SUUR with similarity to the SNF2/SWI2 proteins displays the highest level of conservation. Mutation of two conserved amino acid residues in this region impairs binding of SUUR to polytene chromosomes and reduces the ability of the protein to cause DNA underreplication. The least conserved middle part of SUUR interacting with HP1 retains positively and negatively charged clusters and nuclear localization signals. The C terminus contains interlacing conserved and variable motifs. Our results suggest that SUUR domains evolve with different rates and patterns but maintain their features.
Transcription Independent Insulation at TFIIIC-Dependent Insulators
Authors: Valenzuela Lourdes , Dhillon Namrita , Kamakaka Rohinton T 
Published: July 2009

Abstract
Chromatin insulators separate active from repressed chromatin domains. In yeast the RNA pol III transcription machinery bound to tRNA genes function with histone acetylases and chromatin remodelers to restrict the spread of heterochromatin. Our results collectively demonstrate that binding of TFIIIC is necessary for insulation but binding of TFIIIB along with TFIIIC likely improves the probability of complex formation at an insulator. Insulation by this transcription factor occurs in the absence of RNA polymerase III or polymerase II but requires specific histone acetylases and chromatin remodelers. This analysis identifies a minimal set of factors required for insulation.