bluuebunny/crossref_metadata_2025_split huggingface dataset:
A multicenter phase 2 study of the farnesyltransferase inhibitor tipifarnib in intermediate- to high-risk myelodysplastic syndrome
Authors: Fenaux Pierre , Raza Azra , Mufti Ghulam J. , Aul Carlo , Germing Ulrich , Kantarjian Hagop , Cripe Larry , Kerstens René , De Porre Peter , Kurzrock Razelle 
Published: February 2007

Abstract
This multicenter phase 2 study evaluated the use of tipifarnib (R115777) in patients with poor-risk myelodysplastic syndrome (MDS; French-American-British classification). Patients (n = 82) received tipifarnib 300 mg orally twice daily for the first 21 days of each 28-day cycle. Twenty-six patients (32%) responded to tipifarnib: 12 (15%) complete responses (CRs) and 14 (17%) hematologic improvements; 37 patients (45%) had stable disease (modified International Working Group criteria, 2006). Among the 12 CRs, the median response duration was 11.5 months (range, 2.0-21.9 months), the median time to progression was 12.4 months (range, 3.9-23.8 months), and 7 were still alive at time of analysis (all > 3 years). Median overall survival was 11.7 months (95% CI, 9.4-15.0). Grade 3-4 neutropenia (18%) and thrombocytopenia (32%) were the most common treatment-related adverse events; severe nonhematologic adverse events were rarely reported. In this study, durable responses and acceptable side effects were observed. Tipifarnib is an active agent for the treatment of patients with intermediate- to high-risk MDS.
Physiologic systemic iron metabolism in mice deficient for duodenal Hfe
Authors: Spasic Maja Vujic , Kiss Judit , Herrmann Thomas , Kessler Regina , Stolte Jens , Galy Bruno , Rathkolb Birgit , Wolf Eckhard , Stremmel Wolfgang , Hentze Matthias W. , Muckenthaler Martina U. 
Published: February 2007

AbstractMutations in the Hfe gene result in hereditary hemochromatosis (HH), a disorder characterized by increased duodenal iron absorption and tissue iron overload. Identification of a direct interaction between Hfe and transferrin receptor 1 in duodenal cells led to the hypothesis that the lack of functional Hfe in the duodenum affects TfR1-mediated serosal uptake of iron and misprogramming of the iron absorptive cells. Contrasting this view, Hfe deficiency causes inappropriately low expression of the hepatic iron hormone hepcidin, which causes increased duodenal iron absorption. We specifically ablated Hfe expression in mouse enterocytes using Cre/LoxP technology. Mice with efficient deletion of Hfe in crypt- and villi-enterocytes maintain physiologic iron metabolism with wild-type unsaturated iron binding capacity, hepatic iron levels, and hepcidin mRNA expression. Furthermore, the expression of genes encoding the major intestinal iron transporters is unchanged in duodenal Hfe-deficient mice. Our data demonstrate that intestinal Hfe is dispensable for the physiologic control of systemic iron homeostasis under steady state conditions. These findings exclude a primary role for duodenal Hfe in the pathogenesis of HH and support the model according to which Hfe is required for appropriate expression of the “iron hormone” hepcidin which then controls intestinal iron absorption.
Functional characterization of natural killer cells in type I leukocyte adhesion deficiency
Authors: Castriconi Roberta , Dondero Alessandra , Cantoni Claudia , Della Chiesa Mariella , Prato Carola , Nanni Marina , Fiorini Maurilia , Notarangelo Lucia , Parolini Silvia , Moretta Lorenzo , Notarangelo Luigi , Moretta Alessandro , Bottino Cristina 
Published: February 2007

Abstract
In this study, we analyzed IL-2–activated polyclonal natural killer (NK) cells derived from 2 patients affected by leukocyte adhesion deficiency type I (LAD1), an immunodeficiency characterized by mutations of the gene coding for CD18, the β subunit shared by major leukocyte integrins. We show that LAD1 NK cells express normal levels of various triggering NK receptors (and coreceptors) and that mAb-mediated engagement of these receptors results in the enhancement of both NK cytolytic activity and cytokine production. Moreover, these activating NK receptors were capable of recognizing their specific ligands on target cells. Thus, LAD1 NK cells, similarly to normal NK cells, were capable of killing most human tumor cells analyzed and produced high amounts of IFN-γ when cocultured in presence of target cells. Murine target cells represented a common exception, as they were poorly susceptible to LAD1 NK cells. Finally, LAD1 NK cells could efficiently kill or induce maturation of monocyte-derived immature dendritic cells (DCs). Altogether our present study indicates that in LAD1 patients, 3 important functions of NK cells (eg, cytotoxicity, IFN-γ production, and DC editing) are only marginally affected and provides new insight on the cooperation between activating receptors and LFA-1 in the induction of NK cell activation and function.
Distinctive NK-cell receptor repertoires sustain high-level constitutive NK-cell activation in HIV-exposed uninfected individuals
Authors: Ravet Sophie , Scott-Algara Daniel , Bonnet Elodie , Tran Hung Khiem , Tran Ton , Nguyen Ngai , Truong Lien Xuan , Theodorou Ioannis , Barré-Sinoussi Françoise , Pancino Gianfranco , Paul Pascale 
Published: February 2007

AbstractWe have previously associated high natural killer (NK)–cell activity and protection against HIV-1 infection in Vietnamese exposed uninfected intravascular drug users (EUs). Considering that activating and inhibitory signals sensed by NK-cell receptors regulate NK-cell activation, we performed phenotypic and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) transcript analyses of the NK-cell receptor (NKR) repertoire in 25 EUs, 19 HIV+ intravenous drug users, and 26 uninfected blood donors. Although NK-cell activation was not linked to a unique NKR repertoire in EUs, various patterns consistent with NK-cell activation were detected in EUs: high KIR3DS1/KIR3DL1 ratio associated with down-regulated KIR3DL1 transcript levels, KIR2DL3+ low-affinity receptor expansion associated to group HLA-C1 ligand in 2DS2−/2DL2− EUs, enhanced NKG2C/NKG2A ratio, and increased CD69 expression. Remarkably, EUs exhibited high constitutive degranulation activity in the absence of exogenous stimulation, as shown by the CD107a assay. Furthermore, CD161 expression was increased within the CD107a+ NK-cell compartment. Our results suggest that in response to viral exposition, particular genetic or regulated features of the NKR repertoire of EUs contribute to their high constitutive NK-cell potential. This might allow NK cells to generate a more rapid and effective immune response to HIV-1, thereby contributing to prevention toward infection.
Ancestry and pharmacogenetics of antileukemic drug toxicity
Authors: Kishi Shinji , Cheng Cheng , French Deborah , Pei Deqing , Das Soma , Cook Edwin H. , Hijiya Nobuko , Rizzari Carmelo , Rosner Gary L. , Frudakis Tony , Pui Ching-Hon , Evans William E. , Relling Mary V. 
Published: February 2007

AbstractTreatment-related toxicity in acute lymphoblastic leukemia (ALL) can not only be life threatening but may also affect relapse risk. In 240 patients, we determined whether toxicities were related to 16 polymorphisms in genes linked to the pharmacodynamics of ALL chemotherapy, adjusting for age, race (self-reported or via ancestry-informative markers), sex, and disease risk group (lower- vs higher-risk therapy). Toxicities (gastrointestinal, infectious, hepatic, and neurologic) were assessed in each treatment phase. During the induction phase, when drugs subject to the steroid/cytochrome P4503A pathway predominated, genotypes in that pathway were important: vitamin D receptor (odds ratio [OR], 6.85 [95% confidence interval [CI], 1.73-27.0]) and cytochrome P4503A5 (OR, 4.61 [95% CI, 1.11-19.2]) polymorphisms were related to gastrointestinal toxicity and infection, respectively. During the consolidation phase, when antifolates predominated, the reduced folate carrier polymorphism predicted gastrointestinal toxicity (OR, 10.4 [95% CI, 1.35-80.4]) as it also did during continuation (OR, 2.01 [95% CI, 1.06-4.11]). In all 3 treatment phases, a glucuronosyltransferase polymorphism predicted hyperbilirubinemia (P = .017, P < .001, and P < .001) and methotrexate clearance (P = .028), which was also independently associated with hyperbilirubinemia (P = .026). The genotype-phenotype associations were similar whether analyses were adjusted by self-reported race or ancestry-informative genetic markers. Germ-line polymorphisms are significant determinants of toxicity of antileukemic therapy.
Road tunnel air pollution induces bronchoalveolar inflammation in healthy subjects
Authors: Larsson B-M. , Sehlstedt M. , Grunewald J. , Sköld C. M. , Lundin A. , Blomberg A. , Sandström T. , Eklund A. , Svartengren M. 
Published: January 2007

Traffic-related air pollution is associated with adverse respiratory effects. The aim of the present study was to investigate whether exposure to air pollution in a road tunnel causes airway inflammatory and blood coagulation responses.A total of 16 healthy subjects underwent bronchoscopy with bronchial mucosal biopsies and bronchoalveolar lavage (BAL) on two occasions, in random order: once at 14 h after a 2-h exposure to air pollution in a busy road tunnel, and once after a control day with subjects exposed to urban air during normal activities. Peripheral blood was sampled prior to bronchoscopy.The road tunnel exposures included particulate matter with a 50% cut-off aerodynamic diameter of 2.5 μm, particulate matter with a 50% cut-off aerodynamic diameter of 10 μm and nitrogen dioxide which had median concentrations of 64, 176 and 230 µg·m−3, respectively. Significantly higher numbers of BAL fluid total cell number, lymphocytes and alveolar macrophages were present after road tunnel exposureversuscontrol. Significantly higher nuclear expression of the transcription factor component c-Jun was found in the bronchial epithelium after exposure. No upregulation of adhesion molecules or cellular infiltration was present and blood coagulation factors were unaffected.In conclusion, exposure of healthy subjects to traffic-related air pollution resulted in a lower airway inflammatory response with cell migration, together with signs of an initiated signal transduction in the bronchial epithelium.
Resistance of quiescent and proliferating airway epithelial cells to H2O2challenge
Authors: Smit-de Vries M. P. , van der Toorn M. , Bischoff R. , Kauffman H. F. 
Published: January 2007

Alveolar epithelial cell injury and recovery are important in the pathogenesis of oxidant-induced lung damage. The alveolar cell line A549 was used to study responses of proliferating and quiescent cells in culture to time- and dose-dependent hydrogen peroxide (H2O2) challenges.Recovery was monitored after 24 h of incubation in fresh medium with 10% serum. The adherent cells were counted and the resistance and recovery of the attached cells was assessed by appearance, by measuring the number of viable, apoptotic and necrotic cells using fluorescent-activated cell sorting, and by determining the intracellular free thiol content.A549 cells recovered from a 1-h challenge with up to 1 mM H2O2but could not sustain a more prolonged challenge (6 or 24 h) with 0.5 mM or 1.0 mM H2O2. These more severe conditions resulted in: loss of cells by detachment from the plate surface; reduced numbers of viable cells primarily due to necrosis; and a strong reduction of the intracellular free thiol content.Quiescent cells proved to be more sensitive to oxidative stress than proliferating cells. Intracellular free thiol levels apparently play a decisive role in cell survival, preferentially protecting proliferating cells.
Motif kernel generated by genetic programming improves remote homology and fold detection
Authors: Håndstad Tony , Hestnes Arne JH , Sætrom Pål 
Published: January 2007

Abstract

Background
Protein remote homology detection is a central problem in computational biology. Most recent methods train support vector machines to discriminate between related and unrelated sequences and these studies have introduced several types of kernels. One successful approach is to base a kernel on shared occurrences of discrete sequence motifs. Still, many protein sequences fail to be classified correctly for a lack of a suitable set of motifs for these sequences.

Results
We introduce the GPkernel, which is a motif kernel based on discrete sequence motifs where the motifs are evolved using genetic programming. All proteins can be grouped according to evolutionary relations and structure, and the method uses this inherent structure to create groups of motifs that discriminate between different families of evolutionary origin. When tested on two SCOP benchmarks, the superfamily and fold recognition problems, the GPkernel gives significantly better results compared to related methods of remote homology detection.

Conclusion
The GPkernel gives particularly good results on the more difficult fold recognition problem compared to the other methods. This is mainly because the method creates motif sets that describe similarities among subgroups of both the related and unrelated proteins. This rich set of motifs give a better description of the similarities and differences between different folds than do previous motif-based methods.
The rheumatoid arthritis shared epitope increases cellular susceptibility to oxidative stress by antagonizing an adenosine-mediated anti-oxidative pathway
Authors: Ling Song , Li Zhanguo , Borschukova Olga , Xiao Liqun , Pumpens Paul , Holoshitz Joseph 
Published: January 2007

Abstract
We have recently demonstrated that the rheumatoid arthritis (RA) shared epitope (SE) acts as a ligand that triggers nitric oxide (NO) signaling in opposite cells. Given the known pro-oxidative effect of NO and the proposed role of oxidative stress in the pathogenesis of RA, this study explores whether SE-triggered signaling can increase cellular oxidative stress. cAMP levels, adenylyl cyclase activity, and protein kinase A activity were measured using commercial kits. Generation of reactive oxygen species (ROS) was quantified using the fluorochrome dichlorofluorescein diacetate. Oxidative DNA damage was quantified using the single-cell electrophoresis technique. Here, we report that cells exposed to cell surface SE-positive HLA-DR (human leukocyte antigen-DR) molecules, to cell-free recombinant proteins genetically engineered to express the SE motif, or to SE-positive synthetic peptide showed diminished cAMP-dependent signaling, increased ROS levels, and higher vulnerability to oxidative DNA damage. Introduction of single amino acid substitutions into SE-positive peptides revealed a consensus five-amino acid sequence motif of Q/R-K/R-X-X-A that is necessary and sufficient for SE-triggered signaling. The pro-oxidative effect of the SE could be reversed by inhibiting NO production. We conclude that the SE acts as a signaling ligand that activates an NO-mediated pro-oxidative pathway. The potential contribution of this signaling aberration to RA pathogenesis is discussed.
Simplified electrophysiological evaluation of peripheral nerves in critically ill patients: the Italian multi-centre CRIMYNE study
Authors: Latronico Nicola , Bertolini Guido , Guarneri Bruno , Botteri Marco , Peli Elena , Andreoletti Serena , Bera Paola , Luciani Davide , Nardella Anna , Vittorielli Elena , Simini Bruno , Candiani Andrea 
Published: January 2007

Abstract
Introduction
Critical illness myopathy and/or neuropathy (CRIMYNE) is frequent in intensive care unit (ICU) patients. Although complete electrophysiological tests of peripheral nerves and muscles are essential to diagnose it, they are time-consuming, precluding extensive use in daily ICU practice. We evaluated whether a simplified electrophysiological investigation of only two nerves could be used as an alternative to complete electrophysiological tests.

Methods
In this prospective, multi-centre study, 92 ICU patients were subjected to unilateral daily measurements of the action potential amplitude of the sural and peroneal nerves (compound muscle action potential [CMAP]). After the first ten days, complete electrophysiological investigations were carried out weekly until ICU discharge or death. At hospital discharge, complete neurological and electrophysiological investigations were performed.

Results
Electrophysiological signs of CRIMYNE occurred in 28 patients (30.4%, 95% confidence interval [CI] 21.9% to 40.4%). A unilateral peroneal CMAP reduction of more than two standard deviations of normal value showed the best combination of sensitivity (100%) and specificity (67%) in diagnosing CRIMYNE. All patients developed the electrophysiological signs of CRIMYNE within 13 days of ICU admission. Median time from ICU admission to CRIMYNE was six days (95% CI five to nine days). In 10 patients, the amplitude of the nerve action potential dropped progressively over a median of 3.0 days, and in 18 patients it dropped abruptly within 24 hours. Multi-organ failure occurred in 21 patients (22.8%, 95% CI 15.4% to 32.4%) and was strongly associated with CRIMYNE (odds ratio 4.58, 95% CI 1.64 to 12.81). Six patients with CRIMYNE died: three in the ICU and three after ICU discharge. Hospital mortality was similar in patients with and without CRIMYNE (21.4% and 17.2%; p = 0.771). At ICU discharge, electrophysiological signs of CRIMYNE persisted in 18 (64.3%) of 28 patients. At hospital discharge, diagnoses in the 15 survivors were critical illness myopathy (CIM) in six cases, critical illness polyneuropathy (CIP) in four, combined CIP and CIM in three, and undetermined in two.

Conclusion
A peroneal CMAP reduction below two standard deviations of normal value accurately identifies patients with CRIMYNE. These should have full neurological and neurophysiological evaluations before discharge from the acute hospital.
Preorganization in biological systems: Are conformational constraints worth the energy?
Authors: Martin Stephen F. 
Published: February 2007

Abstract
It is generally assumed that preorganizing a flexible ligand in the three-dimensional shape it adopts when bound to a macromolecular receptor will provide a derivative having an increased binding affinity, primarily because the rigidified molecule is expected to benefit from a lesser entropic penalty during complexation. We now provide the first experimental evidence that demonstrates this common belief is not universally true. Indeed, we find that ligand preorganization may be accompanied by an unfavorable entropy of binding, even when the constrained ligand exhibits a higher binding affinity than its flexible control. Thus, the effects that ligand preorganization have upon energetics and structure in protein-ligand interactions must be reevaluated.
Modified mesoporous materials as Pd scavengers and catalyst supports
Authors: Crudden Cathleen M. , McEleney Kevin , MacQuarrie Stephanie L. , Blanc Alexandre , Sateesh Mutyala , Webb Jonathan D. 
Published: February 2007

Abstract
The use of mesoporous molecular sieves (MMSs) modified by mercaptopropyl trimethoxysilane (MPTMS) to scavenge Pd is described. The ordered mesoporous material displays excellent ability to remove Pd from organic and aqueous solutions. After only one treatment, a 500-ppm solution of PdCl2 in water can be reduced to 1 ppb. In addition, the resulting material is an effective, leach-proof catalyst for the Suzuki-Miyaura and Mizoroki-Heck reactions. Thus, the Suzuki-Miyaura reaction can be conducted in water at 80 °C with as little as 3 ppb Pd leaching. Hot filtrations and three-phase tests confirm that the catalyst acts without leaching Pd from the surface.
Widening the usefulness of epoxides and aziridines in synthesis
Authors: Hodgson David M. , Humphreys Philip G. , Hughes Steven P. 
Published: February 2007

Abstract
Deprotonation of terminal epoxides and aziridines with organolithium/diamine combinations or lithium amides allows the regio- and stereoselective formation of α-lithiated species. Judicious choice of reaction conditions allows these species to operate as nucleophiles, enolate equivalents, vinyl cation equivalents, or carbenes.
Physician Attitudes Regarding Breakthrough Varicella Disease and a Potential Second Dose of Varicella Vaccine
Authors: Davis Matthew M. , Marin Mona , Cowan Anne E. , Guris Dalya , Clark Sarah J. 
Published: February 2007

OBJECTIVE. We assessed physicians’ attitudes about the 1-dose varicella vaccination program and whether physicians think a 2-dose recommendation is needed to reduce the risk of breakthrough disease.
METHODS. We conducted a national mail survey of a random sample of 550 pediatricians and 550 family physicians from April to June 2005. Physicians who provide outpatient primary care to children ≤6 years of age were eligible for analysis.
RESULTS. Surveys were returned by 727 respondents, for a response rate of 69%; 610 physicians were eligible. Most respondents (94%) recommend routine 1-dose varicella vaccination, and 79% have seen breakthrough disease in the past 5 years (95% of pediatricians and 58% of family physicians). The majority (68%) agreed or strongly agreed that the current burden of breakthrough disease is acceptable. Only 38% (46% of pediatricians and 28% of family physicians) agreed or strongly agreed that a second dose of varicella vaccine is needed to address the burden of breakthrough disease, whereas 40% were neutral. However, if the Advisory Committee on Immunization Practices were to recommend a second dose of varicella vaccine, then 65% of pediatricians and 39% of family physicians would likely follow the recommendation. Most respondents (78%) would be more willing to recommend a second dose if a combination measles-mumps-rubella-varicella vaccine was available.
CONCLUSIONS. Pediatricians and family physicians support the 1-dose varicella vaccination program. A new Advisory Committee on Immunization Practices recommendation for a second dose of varicella vaccine for children was issued after the survey (in June 2006). Two of 3 pediatricians and 2 of 5 family physicians stated that they would adopt a 2-dose recommendation in practice; rates of adoption may be bolstered with current availability of measles-mumps-rubella-varicella vaccine and harmonization of the varicella vaccination schedule with that of measles-mumps-rubella vaccine.