bluuebunny/crossref_metadata_2025_split huggingface dataset:
Human embryonic stem cells differentiate into a homogeneous population of natural killer cells with potent in vivo antitumor activity
Authors: Woll Petter S. , Grzywacz Bartosz , Tian Xinghui , Marcus Rebecca K. , Knorr David A. , Verneris Michael R. , Kaufman Dan S. 
Published: April 2009

Abstract
Natural killer (NK) cells serve as important effectors for antitumor immunity, and CD56+CD45+ NK cells can be routinely derived from human embryonic stem cells (hESCs). However, little is know about the ability of hESC-derived NK cells to mediate an effective in vivo antitumor response. Using bioluminescent imaging, we now demonstrate that H9 line hESC-derived NK cells mediate effective clearance of human tumor cells in vivo. In addition to increased in vitro killing of diverse tumor targets, the in vivo tumor clearance by H9 hESC-derived NK cells was more effective compared with NK cells derived from umbilical cord blood (UCB). Phenotypic analysis demonstrates the hESC-derived NK cells are uniformly CD94+CD117low/−, an NK-cell population characterized by potent cytolytic activity and thus more competent to mediate tumor clearance. These studies demonstrate that hESCs provide an important model to study human lymphocyte development and may serve as a novel source for antitumor immunotherapy.
Amelioration of murine β-thalassemia through drug selection of hematopoietic stem cells transduced with a lentiviral vector encoding both γ-globin and the MGMT drug-resistance gene
Authors: Zhao Huifen , Pestina Tamara I. , Nasimuzzaman Md , Mehta Perdeep , Hargrove Phillip W. , Persons Derek A. 
Published: April 2009

Abstract
Correction of murine models of β-thalassemia has been achieved through high-level globin lentiviral vector gene transfer into mouse hematopoietic stem cells (HSCs). However, transduction of human HSCs is less robust and may be inadequate to achieve therapeutic levels of genetically modified erythroid cells. We therefore developed a double gene lentiviral vector encoding both human γ-globin under the transcriptional control of erythroid regulatory elements and methylguanine methyltransferase (MGMT), driven by a constitutive cellular promoter. MGMT expression provides cellular resistance to alkylator drugs, which can be administered to kill residual untransduced, diseased HSCs, whereas transduced cells are protected. Mice transplanted with β-thalassemic HSCs transduced with a γ-globin/MGMT vector initially had subtherapeutic levels of red cells expressing γ-globin. To enrich γ-globin–expressing cells, transplanted mice were treated with the alkylator agent 1,3-bis-chloroethyl-1-nitrosourea. This resulted in significant increases in the number of γ-globin–expressing red cells and the amount of fetal hemoglobin, leading to resolution of anemia. Selection of transduced HSCs was also obtained when cells were drug-treated before transplantation. Mice that received these cells demonstrated reconstitution with therapeutic levels of γ-globin–expressing cells. These data suggest that MGMT-based drug selection holds promise as a modality to improve gene therapy for β-thalassemia.
IL-10 is up-regulated in multiple cell types during viremic HIV infection and reversibly inhibits virus-specific T cells
Authors: Brockman Mark A. , Kwon Douglas S. , Tighe Daniel P. , Pavlik David F. , Rosato Pamela C. , Sela Jennifer , Porichis Filippos , Le Gall Sylvie , Waring Michael T. , Moss Kristin , Jessen Heiko , Pereyra Florencia , Kavanagh Daniel G. , Walker Bruce D. , Kaufmann Daniel E. 
Published: April 2009

AbstractMurine models indicate that interleukin-10 (IL-10) can suppress viral clearance, and interventional blockade of IL-10 activity has been proposed to enhance immunity in chronic viral infections. Increased IL-10 levels have been observed during HIV infection and IL-10 blockade has been shown to enhance T-cell function in some HIV-infected subjects. However, the categories of individuals in whom the IL-10 pathway is up-regulated are poorly defined, and the cellular sources of IL-10 in these subjects remain to be determined. Here we report that blockade of the IL-10 pathway augmented in vitro proliferative capacity of HIV-specific CD4 and CD8 T cells in individuals with ongoing viral replication. IL-10 blockade also increased cytokine secretion by HIV-specific CD4 T cells. Spontaneous IL-10 expression, measured as either plasma IL-10 protein or IL-10 mRNA in peripheral blood mononuclear cells (PBMCs), correlated positively with viral load and diminished after successful antiretroviral therapy. IL-10 mRNA levels were up-regulated in multiple PBMC subsets in HIV-infected subjects compared with HIV-negative controls, particularly in T, B, and natural killer (NK) cells, whereas monocytes were a major source of IL-10 mRNA in HIV-infected and -uninfected individuals. These data indicate that multiple cell types contribute to IL-10–mediated immune suppression in the presence of uncontrolled HIV viremia.
Venom factor V from the common brown snake escapes hemostatic regulation through procoagulant adaptations
Authors: Bos Mettine H. A. , Boltz Michael , St. Pierre Liam , Masci Paul P. , de Jersey John , Lavin Martin F. , Camire Rodney M. 
Published: April 2009

AbstractVenomous snakes produce an array of toxic compounds, including procoagulants to defend themselves and incapacitate prey. The Australian snake Pseudonaja textilis has a venom-derived prothrombin activator homologous to coagulation factors V (FV) and Xa (FXa). Here we show that the FV component (pt-FV) has unique biologic properties that subvert the normal regulatory restraints intended to restrict an unregulated procoagulant response. Unlike human FV, recombinant pt-FV is constitutively active and does not require proteolytic processing to function. Sequence comparisons show that it has shed a large portion of the central B-domain, including residues that stabilize the inactive procofactor state. Remarkably, pt-FV functions in the absence of anionic membranes as it binds snake-FXa with high affinity in solution. Furthermore, despite cleavage in the heavy chain, pt-FV is functionally resistant to activated protein C, an anticoagulant. We speculate this stability is the result of noncovalent interactions and/or a unique disulfide bond in pt-FV linking the heavy and light chains. Taken together, these findings provide a biochemical rationale for the strong procoagulant nature of venom prothrombinase. Furthermore, they illustrate how regulatory mechanisms designed to limit the hemostatic response can be uncoupled to provide a sustained, disseminated procoagulant stimulus for use as a biologic toxin.
Gene expression profiling to characterize sediment toxicity – a pilot study using Caenorhabditis elegans whole genome microarrays
Authors: Menzel Ralph , Swain Suresh C , Hoess Sebastian , Claus Evelyn , Menzel Stefanie , Steinberg Christian EW , Reifferscheid Georg , Stürzenbaum Stephen R 
Published: April 2009

AbstractBackgroundTraditionally, toxicity of river sediments is assessed using whole sediment tests with benthic organisms. The challenge, however, is the differentiation between multiple effects caused by complex contaminant mixtures and the unspecific toxicity endpoints such as survival, growth or reproduction. The use of gene expression profiling facilitates the identification of transcriptional changes at the molecular level that are specific to the bio-available fraction of pollutants.ResultsIn this pilot study, we exposed the nematodeCaenorhabditis elegansto three sediments of German rivers with varying (low, medium and high) levels of heavy metal and organic contamination. Beside chemical analysis, three standard bioassays were performed: reproduction ofC. elegans, genotoxicity (Comet assay) and endocrine disruption (YES test). Gene expression was profiled using a whole genome DNA-microarray approach to identify overrepresented functional gene categories and derived cellular processes. Disaccharide and glycogen metabolism were found to be affected, whereas further functional pathways, such as oxidative phosphorylation, ribosome biogenesis, metabolism of xenobiotics, aging and several developmental processes were found to be differentially regulated only in response to the most contaminated sediment.ConclusionThis study demonstrates how ecotoxicogenomics can identify transcriptional responses in complex mixture scenarios to distinguish different samples of river sediments.
Rapid assessment of the effect of ciprofloxacin on chromosomal DNA from Escherichia coli using an in situ DNA fragmentation assay
Authors: Tamayo María , Santiso Rebeca , Gosalvez Jaime , Bou Germán , Fernández José Luis 
Published: April 2009

Abstract

Background
Fluoroquinolones are extensively used antibiotics that induce DNA double-strand breaks (DSBs) by trapping DNA gyrase and topoisomerase IV on DNA. This effect is usually evaluated using biochemical or molecular procedures, but these are not effective at the single-cell level. We assessed ciprofloxacin (CIP)-induced chromosomal DNA breakage in single-cell Escherichia coli by direct visualization of the DNA fragments that diffused from the nucleoid obtained after bacterial lysis in an agarose microgel on a slide.

Results
Exposing the E. coli strain TG1 to CIP starting at a minimum inhibitory concentration (MIC) of 0.012 μg/ml and at increasing doses for 40 min increased the DNA fragmentation progressively. DNA damage started to be detectable at the MIC dose. At a dose of 1 μg/ml of CIP, DNA damage was visualized clearly immediately after processing, and the DNA fragmentation increased progressively with the antibiotic incubation time. The level of DNA damage was much higher when the bacteria were taken from liquid LB broth than from solid LB agar. CIP treatment produced a progressively slower rate of DNA damage in bacteria in the stationary phase than in the exponentially growing phase. Removing the antibiotic after the 40 min incubation resulted in progressive DSB repair activity with time. The magnitude of DNA repair was inversely related to CIP dose and was noticeable after incubation with CIP at 0.1 μg/ml but scarce after 10 μg/ml. The repair activity was not strictly related to viability. Four E. coli strains with identified mechanisms of reduced sensitivity to CIP were assessed using this procedure and produced DNA fragmentation levels that were inversely related to MIC dose, except those with very high MIC dose.

Conclusion
This procedure for determining DNA fragmentation is a simple and rapid test for studying and evaluating the effect of quinolones.
Clinical outcomes of spontaneous bacterial peritonitis due to extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiellaspecies: A retrospective matched case-control study
Authors: Song Kyoung-Ho , Jeon Jae Hyun , Park Wan Beom , Park Sang-Won , Kim Hong Bin , Oh Myoung-don , Lee Hyo-Suk , Kim Nam Joong , Choe Kang Won 
Published: April 2009

Abstract

Background
Clinical outcomes of spontaneous bacterial peritonitis (SBP) due to extended-spectrum β-lactamase-producing Escherichia coli and Klebsiella species (ESBL-EK) have not been adequately investigated.

Methods
We conducted a retrospective matched case-control study to evaluate the outcomes of SBP due to ESBL-EK compared with those due to non-ESBL-EK. Cases were defined as patients with liver cirrhosis and SBP due to ESBL-EK isolated from ascites. Control patients with liver cirrhosis and SBP due to non-ESBL-EK were matched in a 3:1 ratio to cases according to the following five variables: age (± 5 years); gender; species of infecting organism; Child-Pugh score (± 2); Acute Physiological and Chronic Health Evaluation II score (± 2). 'Effective initial therapy' was defined as less than 72 hours elapsing between the time of obtaining a sample for culture and the start of treatment with an antimicrobial agent to which the EK was susceptible. Cephalosporin use for ESBL-EK was considered 'ineffective', irrespective of the minimum inhibitory concentration. ESBL production was determined according to the Clinical and Laboratory Standards Institute guidelines on stored isolates.

Results
Of 1026 episodes of SBP in 958 patients from Jan 2000 through Dec 2006, 368 (35.9%) episodes in 346 patients were caused by SBP due to EK, isolated from ascites. Of these 346 patients, twenty-six (7.5%) patients with SBP due to ESBL-EK were compared with 78 matched controls. Treatment failure, evaluated at 72 hours after initial antimicrobial therapy, was greater among the cases (15/26, 58% vs. 10/78, 13%, P = .006); 30-day mortality rate was also higher than in the controls (12/26, 46% vs. 11/78, 15%, P = .001). When the case were classified according to the effectiveness of the initial therapy, 'ineffective initial therapy' was associated with higher 30-day mortality rate (11/18, 61% vs. 1/8, 13%, P = .036).

Conclusion
SBP due to ESBL-EK had poorer outcomes than SBP due to non-ESBL-EK. Ineffective initial therapy seems to be responsible for the higher rate of treatment failure and mortality in SBP due to ESBL-EK.
Cetuximab in combination with irinotecan/5-fluorouracil/folinic acid (FOLFIRI) in the initial treatment of metastatic colorectal cancer: a multicentre two-part phase I/II study
Authors: Raoul Jean-Luc , Van Laethem Jean-Luc , Peeters Marc , Brezault Catherine , Husseini Fares , Cals Laurent , Nippgen Johannes , Loos Anja-Helena , Rougier Philippe 
Published: April 2009

Abstract

Background
This study was designed to investigate the efficacy and safety of the epidermal growth factor receptor (EGFR) inhibitor cetuximab combined with irinotecan, folinic acid (FA) and two different doses of infusional 5-fluorouracil (5-FU) in the first-line treatment of EGFR-detectable metastatic colorectal cancer.

Methods
The 5-FU dose was selected on the basis of dose-limiting toxicities (DLTs) during part I of the study. Patients received cetuximab (400 mg/m2 initial dose and 250 mg/m2/week thereafter) and every 2 weeks irinotecan (180 mg/m2), FA (400 mg/m2) and 5-FU (either low dose [LD], 300 mg/m2 bolus plus 2,000 mg/m2 46-hour infusion, n = 7; or, high-dose [HD], 400 mg/m2 bolus plus 2,400 mg/m2; n = 45).

Results
Only two DLTs occurred in the HD group, and HD 5-FU was selected for use in part II. Apart from rash, commonly observed grade 3/4 adverse events such as leucopenia, diarrhoea, vomiting and asthenia occurred within the expected range for FOLFIRI. Among 52 patients, the overall response rate was 48%. Median progression-free survival (PFS) was 8.6 months (counting all reported progressions) and the median overall survival was 22.4 months. Treatment facilitated the resection of initially unresectable metastases in fourteen patients (27%): of these, 10 patients (71%) had no residual tumour after surgery, and these resections hindered the estimation of PFS.

Conclusion
The combination of cetuximab and FOLFIRI was active and well tolerated in this setting. Initially unresectable metastases became resectable in one-quarter of patients, with a high number of complete resections, and these promising results formed the basis for the investigation of FOLFIRI with and without cetuximab in the phase III CRYSTAL trial.
Foot and ankle injuries during the Athens 2004 Olympic Games
Authors: Badekas Thanos , Papadakis Stamatios A , Vergados Nikolaos , Galanakos Spyros P , Siapkara Angeliki , Forgrave Mike , Romansky Nick , Mirones Steven , Trnka Hans‐Jeorg , Delmi Marino 
Published: April 2009

AbstractBackgroundMajor, rare and complex incidents can occur at any mass‐gathering sporting event and team medical staff should be appropriately prepared for these. One such event, the Athens Olympic Games in 2004, presented a significant sporting and medical challenge. This study concerns an epidemiological analysis of foot and ankle injuries during the Games.MethodsAn observational, epidemiological survey was used to analyse injuries in all sport tournaments (men's and women's) over the period of the Games.ResultsA total of 624 injuries (525 soft tissue injuries and 99 bony injuries) were reported. The most frequent diagnoses were contusions, sprains, fractures, dislocations and lacerations. Significantly more injuries in male (58%) versus female athletes (42%) were recorded. The incidence, diagnosis and cause of injuries differed substantially between the team sports.ConclusionOur experience from the Athens Olympic Games will inform the development of public health surveillance systems for future Olympic Games, as well as other similar mass events.
Phase II Trial of Consolidation Docetaxel and Samarium-153 in Patients With Bone Metastases From Castration-Resistant Prostate Cancer
Authors: Fizazi Karim , Beuzeboc Philippe , Lumbroso Jean , Haddad Vincent , Massard Christophe , Gross-Goupil Marine , Di Palma Mario , Escudier Bernard , Theodore Christine , Loriot Yohann , Tournay Elodie , Bouzy Jeannine , Laplanche Agnes 
Published: April 2009

PurposeTo assess docetaxel combined with samarium-153–ethylene diamine tetramethylene phosphonic acid (EDTMP), a radiopharmaceutical with a high affinity for bone, in patients with castration-resistant prostate cancer (CRPC).Patients and MethodsPatients with bone metastases from CRPC who achieved a response or stabilization after four cycles of docetaxel and estramustine were given consolidation docetaxel 20 mg/m2/wk for 6 weeks and samarium-153-EDTMP (37 MBq/kg) during week 1. Prostate-specific antigen (PSA) response was assessed by using consensus criteria, and pain was assessed by using a visual analog scale (VAS). This study used a Simon two-step design with PSA–progression-free survival (PFS) as the primary end point.ResultsForty-three patients were included in the trial. A PSA response was obtained in 77% (95% CI, 61% to 82%). The pain response rate was 69% (95% CI, 49% to 85%). At least five of the six planned weekly injections of docetaxel were administered to 34 patients (81%). The consolidation docetaxel–samarium-153–EDTMP regimen was well tolerated; there was no febrile neutropenia, and only two episodes (5%) of rapidly reversible grade 3 thrombocytopenia occurred. Although a serum PSA relapse eventually occurred in all patient cases, this regimen resulted in pain control in the long-term. The median PSA-PFS was 6.4 months (95% CI, 6 to 7 months). The median survival was 29 months (95% CI, 22 to 31); the 1-year survival rate was 77% (62% to 87%); and the 2-year survival rate was 56% (41% to 70%).ConclusionCombining docetaxel and samarium-153–EDTMP in patients with bone metastases from CRPC is well tolerated, and it yields major pain relief that persists long after treatment. Overall survival compares favorably with that expected in this population of patients, most of whom exhibit symptoms.
Serum Vascular Endothelial Growth Factor and Fibronectin Predict Clinical Response to High-Dose Interleukin-2 Therapy
Authors: Sabatino Marianna , Kim-Schulze Seunghee , Panelli Monica C. , Stroncek David , Wang Ena , Taback Bret , Kim Dae Won , DeRaffele Gail , Pos Zoltan , Marincola Francesco M. , Kaufman Howard L. 
Published: April 2009

Purpose High-dose interleukin-2 (IL-2) induces durable therapeutic responses in a small subset of patients with metastatic melanoma and renal cell carcinoma, but simple pretreatment predictors of response have not been identified. Patients and Methods To identify predictive biomarkers of clinical response, sera from patients treated with high-dose IL-2 were collected for analysis using a customized, multiplex antibody-targeted protein array platform that surveyed expression of soluble factors associated with tumor immunobiology. Soluble factors associated with clinical responses were analyzed using a multivariate permutation test, and survival outcomes were determined using Kaplan-Meier and log-rank tests. Results A training set from 10 patients identified 68 potentially relevant soluble factors that were then tested in an independent validation set of 49 patients. Class comparison revealed a cluster of 11 biomarkers that were associated with therapeutic outcome. Vascular endothelial growth factor (VEGF) and fibronectin were identified as independent predictors of response. In particular, high levels of these proteins were correlated with lack of clinical response and decreased overall survival. Conclusion Serum VEGF and fibronectin are easily measured pretreatment biomarkers that could serve to exclude patients unlikely to respond to IL-2 therapy.
Comparison of Sentinel Lymph Node Biopsy Alone and Completion Axillary Lymph Node Dissection for Node-Positive Breast Cancer
Authors: Bilimoria Karl Y. , Bentrem David J. , Hansen Nora M. , Bethke Kevin P. , Rademaker Alfred W. , Ko Clifford Y. , Winchester David P. , Winchester David J. 
Published: April 2009

Purpose For women with breast cancer, the role of completion axillary lymph node dissection (ALND) after identification of nodal metastases by sentinel lymph node biopsy (SLNB) has been questioned. Our objectives were to assess national nodal evaluation practice patterns and to examine differences in recurrence and survival for SLNB alone versus SLNB with completion ALND. Patients and Methods From the National Cancer Data Base (1998 to 2005), women with clinically node-negative breast cancer who underwent SLNB and who had nodal metastases were identified. Practice patterns and outcomes were examined for patients who underwent SLNB alone versus SLNB with completion ALND (median follow-up, 63 months). Results Of 97,314 patients, 20.8% underwent SLNB alone, and 79.2% underwent SLNB with completion ALND. In 2004 to 2005, patients were significantly more likely to undergo SLNB alone if they were older, had smaller tumors, or were treated at non–National Cancer Institute–designated cancer centers. In patients with macroscopic nodal metastases (n = 20,075 during 1998 to 2000), there was a nonsignificant trend toward better outcomes for completion ALND (v SLNB alone) after analysis was adjusted for differences between the two groups: axillary recurrence (hazard ratio [HR], 0.58; 95% CI, 0.32 to 1.06) and overall survival (HR, 0.89; 95% CI, 0.76 to 1.04). In patients with microscopic nodal metastases (n = 2,203 during 1998 to 2000), there were no significant differences in axillary recurrence or survival for patients who underwent SLNB alone versus completion ALND. Conclusion Compared with SLNB alone, completion ALND does not appear to improve outcomes for breast cancer patients with microscopic nodal metastases; however, there was a nonsignificant trend toward better outcomes with completion ALND for those with macroscopic disease.