bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Combination of Rifampin plus Moxifloxacin Is Synergistic for Suppression of Resistance but Antagonistic for Cell Kill ofMycobacterium tuberculosisas Determined in a Hollow-Fiber Infection Model
Authors: Drusano G. L. , Sgambati Nicole , Eichas Adam , Brown David L. , Kulawy Robert , Louie Arnold 
Published: August 2010

ABSTRACTMoxifloxacin is under development for expanded use againstMycobacterium tuberculosis. Rifampin is a mainstay of therapy. We examined the interaction of moxifloxacin plus rifampin for log-phase and nonreplicating persister (NRP) organisms. For this evaluation, we employed our hollow-fiber infection model, in which organisms are exposed to clinically relevant drug concentration-time profiles and the impact on bacterial cell kill and resistant subpopulation amplification is determined. In log phase, resistance emergence was observed in all monotherapy regimens and in no combination therapy regimen. No difference was seen in time to a 3-log reduction in the bacterial burden; there was a significant difference in time to resistance emergence (P= 0.0006). In the NRP experiment, no resistance emergence was seen. There was a significant difference between the monotherapy and combination therapy regimens in time to a 3-log reduction in the bacterial burden (P= 0.042). The combination is efficacious for suppressing resistant organisms but is antagonistic for cell kill.IMPORTANCEM. tuberculosisinfects one-third of the world’s population. Multiresistant organisms have become more frequent, threatening our ability to provide adequate chemotherapy. Moxifloxacin has been seen as an important new agent with the potential to supplant isoniazid or add to the rifampin/isoniazid combination.M. tuberculosisalso exists in different physiological states, including the NRP phenotype. We examined the moxifloxacin/rifampin combination in a newin vitrosystem to allow judgment of how moxifloxacin would interact with rifampin and allow its performance in clinical trials to be placed into perspective. Importantly, the combination suppressed resistance emergence, but at the price of slightly slowing bacterial cell kill. This new combination is a welcome addition to the physician’s armamentarium.
Programmed cell death 4 (PDCD4) expression during multistep Barrett's carcinogenesis
Authors: Fassan Matteo , Pizzi Marco , Battaglia Giorgio , Giacomelli Luciano , Parente Paola , Bocus Paolo , Ancona Ermanno , Rugge Massimo 
Published: August 2010

AimTo test the contribution of programmed cell death 4 (PDCD4) tumour suppressor gene in Barrett's carcinogenesis.MethodsPDCD4 immunohistochemical expression was assessed in 88 biopsy samples obtained from histologically proven long-segment Barrett's mucosa (BM; 25 non-intestinal columnar metaplasia, 25 intestinal metaplasia (IM), 16 low-grade intraepithelial neoplasia (LG-IEN), 12 high-grade IEN (HG-IEN) and 10 Barrett's adenocarcinoma (BAc)). As controls, 25 additional samples of native oesophageal mucosa (N) were obtained from patients with dyspepsia. To further support the data, the expression levels of miR-21, an importantPDCD4expression regulator, in 14 N, 5 HG-IEN and 11 BAc samples were determined by quantitative real-time PCR analysis.ResultsPDCD4 immunostaining decreased progressively and significantly with the progression of the phenotypic changes occurring during Barrett's carcinogenesis (p<0.001). Normal basal squamous epithelial layers featured strong PDCD4 nuclear immunoreaction (mostly coexisting with weak–moderate cytoplasmic staining). Non-intestinal columnar metaplasia and intestinal metaplasia preserved a strong nuclear immunostaining; conversely, a significant decrease in PDCD4 nuclear expression was seen in dysplastic (LG-IEN and HG-IEN) and neoplastic lesions. Weak–moderate cytoplasmic immunostaining was evident in cases of LG-IEN, while HG-IEN and BAc samples showed weak cytoplasmic or no protein expression. As expected, miR-21 expression was significantly upregulated in HG-IEN and BAc samples, consistently withPDCD4dysregulation.ConclusionsThese data support a significant role forPDCD4downregulation in the progression of BM to BAc, and confirm miR-21 as a negative regulator ofPDCD4in vivo. Further efforts are needed to validatePDCD4as a potential prognostic marker in patients with Barrett's oesophagus.
Renal Cancer Resistance to Antiangiogenic Therapy Is Delayed by Restoration of Angiostatic Signaling
Authors: Bhatt Rupal S. , Wang Xiaoen , Zhang Liang , Collins Michael P. , Signoretti Sabina , Alsop David C. , Goldberg S. Nahum , Atkins Michael B. , Mier James W. 
Published: August 2010

Abstract
Treatment of metastatic renal cell cancer (RCC) with antiangiogenic agents that block vascular endothelial growth factor (VEGF) receptor 2 signaling produces tumor regression in a substantial fraction of patients; however, resistance typically develops within 6 to 12 months. The purpose of this study was to identify molecular pathways involved in resistance. Treatment of mice bearing either 786-0 or A498 human RCC xenografts with sorafenib or sunitinib produced tumor growth stabilization followed by regrowth despite continued drug administration analogous to the clinical experience. Tumors and plasma were harvested at day 3 of therapy and at the time of resistance to assess pathways that may be involved in resistance. Serial perfusion imaging, and plasma and tumor collections were obtained in mice treated with either placebo or sunitinib alone or in combination with intratumoral injections of the angiostatic chemokine CXCL9. Sunitinib administration led to an early downmodulation of IFNγ levels as well as reduction of IFNγ receptor and downstream angiostatic chemokines CXCL9 to 11 within the tumor. Intratumoral injection of CXCL9, although producing minimal effects by itself, when combined with sunitinib resulted in delayed resistance in vivo accompanied by a prolonged reduction of microvascular density and tumor perfusion as measured by perfusion imaging relative to sunitinib alone. These results provide evidence that resistance to VEGF receptor therapy is due at least in part to resumption of angiogenesis in association with reduction of IFNγ-related angiostatic chemokines, and that this resistance can be delayed by concomitant administration of CXCL9. Mol Cancer Ther; 9(10); 2793–802. ©2010 AACR.
The Problem of Delimitation of Bangladesh’s Maritime Boundaries with India and Myanmar: Prospects for a Solution
Authors: Shah Alam M. , Al Faruque Abdullah 
Published: August 2010

AbstractThe sea areas of Bangladesh are reportedly rich in straddling fish stocks and mineral resources, including hydrocarbons. But a long-standing dispute over maritime boundary delimitation with India and Myanmar remains a major stumbling block in exploration of these resources. The overlapping claims of these three countries over the maritime zones in the Bay of Bengal need to be settled for peaceful exploration of natural resources. While India and Myanmar want to delimit the maritime boundary on the basis of the equidistance principle, Bangladesh demands that delimitation should be based on the equitable method. The special geographical circumstances of the coastal zones of these countries warrant that any delimitation, whether agreed or determined by a third party, must result in an equitable solution. The decisions of the international courts and tribunals, state practice, and the Law of the Sea Convention clearly demonstrate that there has been a shift from the equidistance principle to the equitable principle of delimitation and strongly indicate that the equitable principle is the preferred method of delimitation.
Whose European Citizenship in the Stockholm Programme? The Enactment of Citizenship by Third Country Nationals in the EU
Authors: Wiesbrock Anja , Carrera Sergio 
Published: August 2010

AbstractThe Stockholm Programme and the European Commission’s Action Plan implementing it have positioned the freedom, security and justice of ‘European citizens’ at the heart of the EU’s political agenda for the next five years. Yet, who are the ‘citizens’ about whom the Council and the European Commission are so interested? At first sight it would appear as if only those individuals holding the nationality of a Member State would fall within this category. This paper challenges this assumption, however, and argues that as a consequence of litigation by individuals before EU courts and of the growing importance given to the act of mobility in citizenship and immigration law, the personal scope of the freedoms accorded to European citizenship already covers certain categories of third-country nationals (TCNs). Through an examination of selected landmark rulings of the Court of Justice in Luxembourg, the paper demonstrates how the requirement of being a national of an EU Member State is progressively becoming less important when defining the boundaries of the European citizenry. TCNs already enjoy and benefit from a number of European citizenship-related and citizenship-like freedoms, rights, benefits and general principles, which are subject to protection and scrutiny at the EU level. This development, we argue, is not only an indication of a continuing loss of discretionary power by the nation-state with respect to European citizenship, but may also constitute a clear signal that a new European citizenship of TCNs is in the making in the Union. This citizenship places the freedom to move and non-discrimination on the basis of nationality at the core of its identity.
Phylogenetic analysis of the druid flies (Diptera: Schizophora: Clusiidae) based on morphological and molecular data
Authors: Fu Jinzhong , Lonsdale Owen , Wiegmann Brian , Marshall Stephen 
Published: August 2010

AbstractIn this paper, the Clusiidae (Diptera: Schizophora) is analyzed phylogenetically using morphological and molecular data sets, and then redefined on the basis of derived morphological characters. The biology and distribution of the Clusiidae are also reviewed, a key is provided to the World genera, the status of the genus Craspedochaeta Czerny is reevaluated and the type of Heterochroa pictipennis Wulp is discussed. Molecular data sets include genomic DNA sequences from the mitochondrial genes COI (cytochrome oxidase subunit I) and COII (cytochrome oxidase subunit II), the large ribosomal nuclear subunit 28S, and the nuclear protein-coding carbomoylphosphate synthase (CPS) domain of CAD (or “rudimentary”). Genes were analyzed separately, in combination with each other, and in combination with a morphological data set. Although individual molecular data sets often provided conflicting phylogenetic signals, the topologies of the cladograms produced from each data set alone or in combination were largely similar. Most genus-level relationships and several basal divergences were unresolved, but Apiochaeta was very strongly and consistently supported as Sobarocephalinae, not Clusiinae. The Clusiinae and Sobarocephalinae are subsequently redefined using an adjusted morphological tree — retaining Apiochaeta in the Sobarocephalinae — that is only slightly longer (8.4%, or seven steps) than the most parsimonious tree. Our results illustrate the benefits of multiple independent data sets for phylogenetic reconstruction in order to verify and refine existing classifications.
T1 cortical hypointensities and their association with cognitive disability in multiple sclerosis
Authors: Bagnato Francesca , Salman Zeena , Kane Robert , Auh Sungyoung , Cantor Fredric K , Ehrmantraut Mary , Gallo Antonio , Ikonomidou Vasiliki N , Ohayon Joan , Pellicano Clelia , Stern Susan K , McFarland Henry F 
Published: August 2010

Background: Neocortical lesions (NLs) largely contribute to the pathology of multiple sclerosis (MS), although their relevance in patients’ disability remains unknown. Objective: To assess the incidence of T1 hypointense NLs by 3.0-Tesla magnetic resonance imaging (MRI) in patients with MS and examine neocortical lesion association with cognitive impairment. Methods: In this case-control study, 21 MS patients and 21 age-, sex- and years of education-matched healthy volunteers underwent: (i) a neuropsychological examination rating cognitive impairment (Minimal Assessment of Cognitive Function in MS); (ii) a 3.0-Tesla MRI inclusive of an isotropic 1.0 mm3 three-dimensional inversion prepared spoiled gradient-recalled-echo (3D-IRSPGR) image and T1- and T2-weighted images. Hypointensities on 3D-IRSPGR lying in the cortex, either entirely or partially were counted and association between NLs and cognitive impairment investigated. Results: A total of 95 NLs were observed in 14 (66.7%) patients. NL+ patients performed poorer (p = 0.020) than NLpatients only on the delayed recall component of the California Verbal Learning Test. This difference lost statistical significance when a correction for white matter lesion volume was employed. Conclusions: Although T 1 hypointense NLs may be present in a relatively high proportion of multiple sclerosis patients, the impact that they have in cognitive impairment is not independent from white matter disease.
Identification of novel cluster groups in pediatric high-risk B-precursor acute lymphoblastic leukemia with gene expression profiling: correlation with genome-wide DNA copy number alterations, clinical characteristics, and outcome
Authors: Harvey Richard C. , Mullighan Charles G. , Wang Xuefei , Dobbin Kevin K. , Davidson George S. , Bedrick Edward J. , Chen I-Ming , Atlas Susan R. , Kang Huining , Ar Kerem , Wilson Carla S. , Wharton Walker , Murphy Maurice , Devidas Meenakshi , Carroll Andrew J. , Borowitz Michael J. , Bowman W. Paul , Downing James R. , Relling Mary , Yang Jun , Bhojwani Deepa , Carroll William L. , Camitta Bruce , Reaman Gregory H. , Smith Malcolm , Hunger Stephen P. , Willman Cheryl L. 
Published: August 2010

Abstract
To resolve the genetic heterogeneity within pediatric high-risk B-precursor acute lymphoblastic leukemia (ALL), a clinically defined poor-risk group with few known recurring cytogenetic abnormalities, we performed gene expression profiling in a cohort of 207 uniformly treated children with high-risk ALL. Expression profiles were correlated with genome-wide DNA copy number abnormalities and clinical and outcome features. Unsupervised clustering of gene expression profiling data revealed 8 unique cluster groups within these high-risk ALL patients, 2 of which were associated with known chromosomal translocations (t(1;19)(TCF3-PBX1) or MLL), and 6 of which lacked any previously known cytogenetic lesion. One unique cluster was characterized by high expression of distinct outlier genes AGAP1, CCNJ, CHST2/7, CLEC12A/B, and PTPRM; ERG DNA deletions; and 4-year relapse-free survival of 94.7% ± 5.1%, compared with 63.5% ± 3.7% for the cohort (P = .01). A second cluster, characterized by high expression of BMPR1B, CRLF2, GPR110, and MUC4; frequent deletion of EBF1, IKZF1, RAG1-2, and IL3RA-CSF2RA; JAK mutations and CRLF2 rearrangements (P < .0001); and Hispanic ethnicity (P < .001) had a very poor 4-year relapse-free survival (21.0% ± 9.5%; P < .001). These studies reveal striking clinical and genetic heterogeneity in high-risk ALL and point to novel genes that may serve as new targets for diagnosis, risk classification, and therapy.
Vascular remodeling of the vitelline artery initiates extravascular emergence of hematopoietic clusters
Authors: Zovein Ann C. , Turlo Kirsten A. , Ponec Ryan M. , Lynch Maureen R. , Chen Kevin C. , Hofmann Jennifer J. , Cox Timothy C. , Gasson Judith C. , Iruela-Arispe M. Luisa 
Published: August 2010

AbstractThe vitelline artery is a temporary structure that undergoes extensive remodeling during midgestation to eventually become the superior mesenteric artery (also called the cranial mesenteric artery, in the mouse). Here we show that, during this remodeling process, large clusters of hematopoietic progenitors emerge via extravascular budding and form structures that resemble previously described mesenteric blood islands. We demonstrate through fate mapping of vascular endothelium that these mesenteric blood islands are derived from the endothelium of the vitelline artery. We further show that the vitelline arterial endothelium and subsequent blood island structures originate from a lateral plate mesodermal population. Lineage tracing of the lateral plate mesoderm demonstrates contribution to all hemogenic vascular beds in the embryo, and eventually, all hematopoietic cells in the adult. The intraembryonic hematopoietic cell clusters contain viable, proliferative cells that exhibit hematopoietic stem cell markers and are able to further differentiate into myeloid and erythroid lineages. Vitelline artery–derived hematopoietic progenitor clusters appear between embryonic day 10 and embryonic day 10.75 in the caudal half of the midgut mesentery, but by embryonic day 11.0 are sporadically found on the cranial side of the midgut, thus suggesting possible extravascular migration aided by midgut rotation.
Characterisation of the role of Vrp1 in cell fusion during the development of visceral muscle of Drosophila melanogaster
Authors: Eriksson Therese , Varshney Gaurav , Aspenström Pontus , Palmer Ruth H 
Published: August 2010

AbstractBackgroundInDrosophilamuscle cell fusion takes place both during the formation of the somatic mesoderm and the visceral mesoderm, giving rise to the skeletal muscles and the gut musculature respectively. The core process of myoblast fusion is believed to be similar for both organs. The actin cytoskeleton regulator Verprolin acts by binding to WASP, which in turn binds to the Arp2/3 complex and thus activates actin polymerization. While Verprolin has been shown to be important for somatic muscle cell fusion, the function of this protein in visceral muscle fusion has not been determined.ResultsVerprolin is specifically expressed in the fusion competent myoblasts of the visceral mesoderm, suggesting a role in visceral mesoderm fusion. We here describe a novel Verprolin mutant allele which displays subtle visceral mesoderm fusion defects in the form of mislocalization of the immunoglobulin superfamily molecule Duf/Kirre, which is required on the myoblast cell surface to facilitate attachment between cells that are about to fuse, indicating a function for Verprolin in visceral mesoderm fusion. We further show that Verprolin mutant cells are capable of both migrating and fusing and that the WASP-binding domain of Verprolin is required for rescue of the Verprolin mutant phenotype.ConclusionsVerprolin is expressed in the visceral mesoderm and plays a role in visceral muscle fusion as shown by mislocalization of Duf/Kirre in theVerprolinmutant, however it is not absolutely required for myoblast fusion in either the visceral or the somatic mesoderm.
Evaluation of HIV protease and nucleoside reverse transcriptase inhibitors on proliferation, necrosis, apoptosis in intestinal epithelial cells and electrolyte and water transport and epithelial barrier function in mice
Authors: Braga Neto Manuel B , Aguiar Carolina V , Maciel Jamilly G , Oliveira Bruna MC , Sevilleja Jesus E , Oriá Reinaldo B , Brito Gerly AC , Warren Cirle A , Guerrant Richard L , Lima Aldo AM 
Published: August 2010

AbstractBackgroundProtease inhibitors (PI's) and reverse transcriptase drugs are important components of highly active antiretroviral therapy (HAART) for treating human acquired immunodeficiency syndrome (AIDS). Long-term clinical therapeutic efficacy and treatment compliance of these agents have been limited by undesirable side-effects, such as diarrhea. This study aims to investigate the effects of selected antiretroviral agents on intestinal histopathology and functionin vivoand on cell proliferation and deathin vitro.MethodsSelected antiretroviral drugs were given orally over 7 days, to Swiss mice, as follows: 100 mg/kg of nelfinavir (NFV), indinavir (IDV), didanosine (DDI) or 50 mg/kg of zidovudine (AZT). Intestinal permeability measured by lactulose and mannitol assays; net water and electrolyte transport, in perfused intestinal segments; and small intestinal morphology and cell apoptosis were assessed in treated and control mice.In vitrocell proliferation was evaluated using the WST-1 reagent and apoptosis and necrosis by flow cytometry analysis.ResultsNFV, IDV, AZT and DDI caused significant reductions in duodenal and in jejunal villus length (p < 0.05). IDV and AZT increased crypt depth in the duodenum and AZT increased crypt depth in the jejunum. NFV, AZT and DDI significantly decreased ileal crypt depth. All selected antiretroviral drugs significantly increased net water secretion and electrolyte secretion, except for DDI, which did not alter water or chloride secretion. Additionally, only NFV significantly increased mannitol and lactulose absorption. NFV and IDV caused a significant reduction in cell proliferationin vitroat both 24 h and 48 h. DDI and AZT did not alter cell proliferation. There was a significant increase in apoptosis rates in IEC-6 cells after 24 h with 70 ug/mL of NFV (control: 4.7% vs NFV: 22%) while IDV, AZT and DDI did not show any significant changes in apoptosis compared to the control group. In jejunal sections, IDV and NFV significantly increased the number of TUNEL positive cells.ConclusionThe PI's, NFV and IDV, increased cell apoptosisin vivo, water and electrolyte secretion and intestinal permeability and decreased villus length and cell proliferation. NFV was the only drug tested that increased cell apoptosisin vitro. The nucleoside reverse transcriptase inhibitors, AZT and DDI, did not affect cell apoptosis or proliferation. These findings may partly explain the intestinal side-effects associated with PI's.
Genome wide screen identifies microsatellite markers associated with acute adverse effects following radiotherapy in cancer patients
Authors: Michikawa Yuichi , Suga Tomo , Ishikawa Atsuko , Hayashi Hideki , Oka Akira , Inoko Hidetoshi , Iwakawa Mayumi , Imai Takashi 
Published: August 2010

AbstractBackgroundThe response of normal tissues in cancer patients undergoing radiotherapy varies, possibly due to genetic differences underlying variation in radiosensitivity.MethodsCancer patients (n = 360) were selected retrospectively from the RadGenomics project. Adverse effects within 3 months of radiotherapy completion were graded using the National Cancer Institute Common Toxicity Criteria; high grade group were grade 3 or more (n = 180), low grade group were grade 1 or less (n = 180). Pooled genomic DNA (gDNA) (n = 90 from each group) was screened using 23,244 microsatellites. Markers with different inter-group frequencies (Fisher exact testP< 0.05) were analyzed using the remaining pooled gDNA. Silencing RNA treatment was performed in cultured normal human skin fibroblasts.ResultsForty-seven markers had positive association values; including one in theSEMA3Apromoter region (P = 1.24 × 10-5).SEMA3Aknockdown enhanced radiation resistance.ConclusionsThis study identified 47 putative radiosensitivity markers, and suggested a role forSEMA3Ain radiosensitivity.