bluuebunny/crossref_metadata_2025_split huggingface dataset:
Frequent CBL mutations associated with 11q acquired uniparental disomy in myeloproliferative neoplasms
Authors: Grand Francis H. , Hidalgo-Curtis Claire E. , Ernst Thomas , Zoi Katerina , Zoi Christine , McGuire Carolann , Kreil Sebastian , Jones Amy , Score Joannah , Metzgeroth Georgia , Oscier David , Hall Andrew , Brandts Christian , Serve Hubert , Reiter Andreas , Chase Andrew J. , Cross Nicholas C. P. 
Published: April 2009

Abstract
Recent evidence has demonstrated that acquired uniparental disomy (aUPD) is a novel mechanism by which pathogenetic mutations in cancer may be reduced to homozygosity. To help identify novel mutations in myeloproliferative neoplasms (MPNs), we performed a genome-wide single nucleotide polymorphism (SNP) screen to identify aUPD in 58 patients with atypical chronic myeloid leukemia (aCML; n = 30), JAK2 mutation–negative myelofibrosis (MF; n = 18), or JAK2 mutation–negative polycythemia vera (PV; n = 10). Stretches of homozygous, copy neutral SNP calls greater than 20Mb were seen in 10 (33%) aCML and 1 (6%) MF, but were absent in PV. In total, 7 different chromosomes were involved with 7q and 11q each affected in 10% of aCML cases. CBL mutations were identified in all 3 cases with 11q aUPD and analysis of 574 additional MPNs revealed a total of 27 CBL variants in 26 patients with aCML, myelofibrosis or chronic myelomonocytic leukemia. Most variants were missense substitutions in the RING or linker domains that abrogated CBL ubiquitin ligase activity and conferred a proliferative advantage to 32D cells overexpressing FLT3. We conclude that acquired, transforming CBL mutations are a novel and widespread pathogenetic abnormality in morphologically related, clinically aggressive MPNs.
Two distinct pathways regulate platelet phosphatidylserine exposure and procoagulant function
Authors: Schoenwaelder Simone M. , Yuan Yuping , Josefsson Emma C. , White Michael J. , Yao Yu , Mason Kylie D. , O'Reilly Lorraine A. , Henley Katya J. , Ono Akiko , Hsiao Sarah , Willcox Abbey , Roberts Andrew W. , Huang David C. S. , Salem Hatem H. , Kile Benjamin T. , Jackson Shaun P. 
Published: April 2009

AbstractProcoagulant platelets exhibit hallmark features of apoptotic cells, including membrane blebbing, microvesiculation, and phosphatidylserine (PS) exposure. Although platelets possess many well-known apoptotic regulators, their role in regulating the procoagulant function of platelets is unclear. To clarify this, we investigated the consequence of removing the essential mediators of apoptosis, Bak and Bax, or directly inducing apoptosis with the BH3 mimetic compound ABT-737. Treatment of platelets with ABT-737 triggered PS exposure and a marked increase in thrombin generation in vitro. This increase in procoagulant function was Bak/Bax- and caspase-dependent, but it was unaffected by inhibitors of platelet activation or by chelating extracellular calcium. In contrast, agonist-induced platelet procoagulant function was unchanged in Bak−/−Bax−/− or caspase inhibitor–treated platelets, but it was completely eliminated by extracellular calcium chelators or inhibitors of platelet activation. These studies show the existence of 2 distinct pathways regulating the procoagulant function of platelets.
Pesticide exposure and risk of monoclonal gammopathy of undetermined significance in the Agricultural Health Study
Authors: Landgren Ola , Kyle Robert A. , Hoppin Jane A. , Beane Freeman Laura E. , Cerhan James R. , Katzmann Jerry A. , Rajkumar S. Vincent , Alavanja Michael C. 
Published: April 2009

Abstract
Pesticides are associated with excess risk of multiple myeloma, albeit inconclusively. We included 678 men (30-94 years) from a well-characterized prospective cohort of restricted-use pesticide applicators to assess the risk of monoclonal gammopathy of undetermined significance (MGUS). Serum samples from all subjects were analyzed by electrophoresis performed on agarose gel; samples with a discrete or localized band were subjected to immunofixation. Age-adjusted prevalence estimates of MGUS were compared with MGUS prevalence in 9469 men from Minnesota. Associations between pesticide exposures and MGUS prevalence were assessed by logistic regression models adjusted for age and education level. Among study participants older than 50 years (n = 555), 38 were found to have MGUS, yielding a prevalence of 6.8% (95% CI, 5.0%-9.3%). Compared with men from Minnesota, the age-adjusted prevalence of MGUS was 1.9-fold (95% CI, 1.3- to 2.7-fold) higher among male pesticide applicators. Among applicators, a 5.6-fold (95% CI, 1.9- to 16.6-fold), 3.9-fold (95% CI, 1.5- to 10.0-fold), and 2.4-fold (95% CI, 1.1- to 5.3-fold) increased risk of MGUS prevalence was observed among users of the chlorinated insecticide dieldrin, the fumigant mixture carbon-tetrachloride/carbon disulfide, and the fungicide chlorothalonil, respectively. In summary, the prevalence of MGUS among pesticide applicators was twice that in a population-based sample of men from Minnesota, adding support to the hypothesis that specific pesticides are causatively linked to myelomagenesis.
Rescue of coagulation factor VII function by the U1+5A snRNA
Authors: Pinotti Mirko , Balestra Dario , Rizzotto Lara , Maestri Iva , Pagani Franco , Bernardi Francesco 
Published: April 2009

Abstract
Our previous studies with genomic minigenes have demonstrated that an engineered small nuclear RNA-U1 (U1+5a) partially rescued coagulation factor VII (FVII) mRNA processing impaired by the 9726+5G>A mutation. Here, to evaluate the U1+5a effects on FVII function, we devised a full-length FVII splicing-competent construct (pSCFVII-wt). This construct drove in COS-1 cells the synthesis of properly processed FVII transcripts and of secreted functional FVII (23 ± 4 ng/mL), which were virtually undetectable upon introduction of the 9726+5G>A mutation (pSCFVII-9726+5a). Cotransfection of pSCFVII-9726+5a with pU1+5a resulted in a partial rescue of FVII splicing and protein biosynthesis. The level increase in medium was dose dependent and, with a molar excess (1.5×) of pU1+5a, reached 9.5% plus or minus 3.2% (5.0 ± 2.8 ng/mL) of FVII-wt coagulant activity. These data provide the first insights into the U1-snRNA–mediated rescue of donor splice sites at protein level, thus further highlighting its therapeutic implications in bleeding disorders, which would benefit even from tiny increase of functional levels.
Pralatrexate-induced tumor cell apoptosis in the epidermis of a patient with HTLV-1 adult T-cell lymphoma/leukemia causing skin erosions
Authors: Marneros Alexander G. , Grossman Marc E. , Silvers David N. , Husain Sameera , Nuovo Gerard J. , MacGregor-Cortelli Barbara , Neylon Ellen , Patterson Molly , O'Connor Owen A. , Zain Jasmine M. 
Published: April 2009

Abstract
Pralatrexate is a novel antifolate, which shows increased antitumor activity in human tumor xenograft studies in mice compared with methotrexate. We investigated the effects of pralatrexate in a patient with adult T-cell lymphoma/leukemia with significant skin involvement. Atypical lymphocytes in epidermal Pautrier microabscesses were positive for HTLV-1. After the patient presented with leukemic conversion and with worsening of an erythematous generalized papular rash, he received one dose of pralatrexate. Within one week, his skin developed innumerable small erosions limited to the areas of the papular rash, sparing unaffected skin. Here we present in vivo evidence that pralatrexate-induced erosions in skin affected by adult T-cell lymphoma/leukemia are a manifestation of apoptosis of tumor cells infiltrating the epidermis and are not the result of cytotoxicity by pralatrexate on keratinocytes. This distinction is critical and may profoundly influence the clinical decision to continue pralatrexate treatment. Pralatrexate-induced skin erosions may indicate response to treatment.
Pseudomonas aeruginosain patients hospitalised for COPD exacerbation: a prospective study
Authors: Garcia-Vidal C. , Almagro P. , Romaní V. , Rodríguez-Carballeira M. , Cuchi E. , Canales L. , Blasco D. , Heredia J. L. , Garau J. 
Published: April 2009

Risk factors forPseudomonas aeruginosa(PA) isolation in patients hospitalised for chronic obstructive pulmonary disease (COPD) exacerbation remain controversial. The aim of our study was to determine the incidence and risk factors for PA isolation in sputum at hospital admission in a prospective cohort of patients with acute exacerbation of COPD.We prospectively studied all patients with COPD exacerbation admitted to our hospital between June 2003 and September 2004. Suspected predictors of PA isolation were studied. Spirometry tests and 6-min walking tests were performed 1 month after the patients were discharged. High-resolution computed tomography (HRCT) was performed in a randomised manner in one out of every two patients to quantify the presence and extent of bronchiectasis. Patients were followed up during the following year for hospital re-admissions.A total of 188 patients were included, of whom 31 (16.5%) had PA in sputum at initial admission. The BODE (body mass index, airflow obstruction, dyspnoea, exercise capacity) index (OR 2.18, CI 95% 1.26–3.78; p = 0.005), admissions in the previous year (OR 1.65, CI 95% 1.13–2.43; p = 0.005), systemic steroid treatment (OR 14.7, CI 95% 2.28–94.8; p = 0.01), and previous isolation of PA (OR 23.1, CI 95% 5.7–94.3; p<0.001) were associated with PA isolation. No relationship was seen between bronchiectasis in HRCT and antibiotic use in the previous 3 months.PA in sputum at hospital admission is more frequent in patients with poorer scoring on the BODE index, previous hospital admissions, oral corticosteroids and prior isolation of PA.
Utility of quantitative T-cell responsesversusunstimulated interferon-γ for the diagnosis of pleural tuberculosis
Authors: Dheda K. , van Zyl-Smit R. N. , Sechi L. A. , Badri M. , Meldau R. , Meldau S. , Symons G. , Semple P. L. , Maredza A. , Dawson R. , Wainwright H. , Whitelaw A. , Vallie Y. , Raubenheimer P. , Bateman E. D. , Zumla A. 
Published: April 2009

The clinical utility of antigen-specific interferon (IFN)-γ release assays (IGRAs) using pleural mononuclear cells, for the diagnosis of tuberculosis (TB), requires clarification.We compared the diagnostic utility of unstimulated pleural IFN-γ levels with several pleural antigen-specific T-cell IGRAs (early secretory antigenic target-6 and culture filtrate protein-10 (T-SPOT.®TB, QuantiFERON®-TB Gold In-tube), purified protein derivative (PPD) and heparin-binding haemagglutinin (HBHA)) in 78 South African TB suspects. Test results were compared against a clinical score and a reference standard.Out of 74 evaluable subjects 48, seven and 19 had definite, probable and no TB, respectively. 11 (15%) out of 74 pleural samples (nine (19%) out of 48 of the definite TB cases) had total cell counts that were inadequate for T-cell processing. In the remaining 63 samples, the sensitivity, specificity, positive predictive value and negative predictive value of different diagnostic methods were as follows. Maximal bioclinical score: 54, 89, 92 and 43%, respectively; T-SPOT.®TB: 86, 60, 84 and 64%, respectively; QuantiFERON®-TB Gold In-tube: 57, 80, 87 and 44%, respectively; HBHA-specific IGRA: 59, 31, 64 and 27%, respectively; PPD-specific IGRA: 81, 40, 76 and 46%, respectively; and pleural fluid unstimulated IFN-γ: 97, 100, 100 and 94%, respectively.Unstimulated IFN-γ was the most accurate test for distinguishing TB from non-TB effusions in a high-burden setting. The antigen-specific T-cell IGRAs were limited by suboptimal accuracy and the inability to isolate sufficient mononuclear cells to perform the assay.
Impaired detection ofMycobacterium tuberculosisimmunity in patients using high levels of immunosuppressive drugs
Authors: Sester U. , Wilkens H. , van Bentum K. , Singh M. , Sybrecht G. W. , Schäfers H-J. , Sester M. 
Published: April 2009

We have previously shown, in renal transplant recipients on maintenance immunosuppression, that a whole-blood assay was superior in detecting immunity towards purified protein derivative (PPD) compared with skin testing. As blood tests may have limitations during high-dose immunosuppression therapy, the present study was aimed at characterising the effect of high immunosuppressive drug levels on PPD-specific T-cell immunity.PPD-reactive CD4 T-cells from 13 renal transplant recipients were longitudinally quantified by the induction of cytokines using flow cytometry. To further address the effect of high and low maintenance immunosuppression, drug effects were studiedin vitroand in 49 age-matched lung transplant recipients and 49 renal transplant recipients.Maintenance immunosuppression after renal transplantation did not affect PPD-specific T-cell detection (median T-cell frequencies 0.55% before and 0.46% >12 months after transplantation), whereas specific T-cell frequencies were significantly lower 3 months after transplantation (0.15%; p = 0.0002). Likewise, high-level maintenance immunosuppression after lung transplantation was associated with a significantly lower prevalence in PPD-specific T-cell reactivity compared with renal transplant recipients (16.7%versus52.1%; p = 0.0005). In line with the observations madein vivo, calcineurin inhibitors analysedin vitroled to a dose-dependent decrease in antigen-specific T-cell reactivity.The flow cytometric assay is not adversely affected by low drug doses. In contrast, decreased levels of PPD-specific T-cells early after transplantation and low prevalence of PPD-reactivity in lung transplant recipients suggest a reduced sensitivity ofin vitrotesting during high-level immunosuppression.
Seasonality of tuberculosis in an Eastern-Asian country with an extreme continental climate
Authors: Naranbat N. , Nymadawa P. , Schopfer K. , Rieder H. L. 
Published: April 2009

Aggregate monthly notifications of incident sputum smear-positive tuberculosis (TB) in Mongolia, stratified by sex and age groups, were analysed separately for Ulaanbaatar, Mongolia, and the rest of the country for the 9-yr period from 1998 to 2006. TB notifications were compared with ambient surface temperature.More than twice as many TB cases were notified in the peak month (April) compared with the trough months (October–December), paralleling the temperature curve. The fluctuations recurred consistently over the entire observation period, were identical in the capital compared with the rest of the country, and were independent of age and sex.TB notifications parallel the temperature amplitudes and have a magnitude not reported elsewhere. We hypothesise that the influence of temperature on life either indoors or outdoors is consistent with the transmission probability ofMycobacterium tuberculosisand the subsequent delay to disease recognition and notification with the incubation period, possibly co-determined by other factors, rather than accessibility to services.
Clinical relevance ofMycobacterium malmoenseisolation in the Netherlands
Authors: Hoefsloot W. , van Ingen J. , de Lange W. C. M. , Dekhuijzen P. N. R. , Boeree M. J. , van Soolingen D. 
Published: April 2009

Uncertainty exists about the clinical relevance ofMycobacterium malmoenseisolation, especially in pulmonary samples. We therefore determined clinical relevance, treatment and outcome ofM. malmoenseisolation in the Netherlands.A retrospective medical file study was conducted for all patients in the Netherlands from whomMycobacterium malmoensehad been isolated between January 2002 and January 2006. Diagnostic criteria for nontuberculous mycobacterial (NTM) disease published by the American Thoracic Society (ATS) were used to determine clinical relevance. Treatment was compared with guidelines published by the British Thoracic Society.In total, 51 patients were found from whomM. malmoensewas isolated. Of these, 40 (78%) patients had pulmonary isolates and 32 (80%) of them met the ATS diagnostic criteria. Cavitary disease was most common (n = 28; 88%). Patients with pulmonary disease were mostly males, with an average age of 56 yrs and pre-existing chronic obstructive pulmonary disease. Cervical lymphadenitis was the most common extrapulmonary disease type. Adherence to treatment guidelines was poor. A good clinical response to treatment was observed in 70% and 73% of patients treated for pulmonary and extrapulmonary disease, respectively.In conclusion,M. malmoenseis a clinically highly relevant NTM in the Netherlands causing serious pulmonary morbidity. Adherence to treatment guidelines is not satisfactory.
Azithromycin has an antiproliferative and autophagic effect on airway smooth muscle cells
Authors: Stamatiou R. , Paraskeva E. , Boukas K. , Gourgoulianis K. I. , Molyvdas P-A. , Hatziefthimiou A. A. 
Published: April 2009

Azithromycin is used in long-term, low-dose treatment of airway diseases where airway wall remodelling is present. Since it improves total score symptom and respiratory function of such patients, we hypothesise that azithromycin's additional clinical benefits are due to an inhibition of airway smooth muscle cell (SMC) proliferation.Rabbit tracheal SMCs were treated with azithromycin (10−5to 10−6 M) in the presence or absence of 10% fetal bovine serum (FBS). The proliferation was estimated using the Cell Titer 96® AQueousOne Solution Assay (Promega, Madison, WI, USA). Cell viability was assessed with Trypan blue staining and flow cytometry after 7-aminoactinomycin D (7-AAD) staining. Induction of autophagy was studied by indirect immmunofluorescence and/or Western blotting with antibodies against human smooth muscle α-actin, beclin 1, light chain 3 and caspase 3. The involvement of the phosphoinositide 3-kinase pathway was investigated with the inhibitors LY294002 and wortmannin.Incubation with azithromycin for 72 h in the presence of FBS reduced SMC proliferation and viability in a dose-dependent manner. Azithromycin treatment was accompanied by the formation of cytoplasmic vacuoles, characteristic of autophagy. All these effects were reversible after azithromycin removal and prevented by the autophagy inhibitor, 3-methyladenine, or LY294002, but not by wortmannin.In conclusion, azithromycin reduces proliferation and causes autophagy of airway SMCs.
Propofolversuscombined sedation in flexible bronchoscopy: a randomised non-inferiority trial
Authors: Stolz D. , Kurer G. , Meyer A. , Chhajed P. N. , Pflimlin E. , Strobel W. , Tamm M. 
Published: April 2009

Combined sedation with a benzodiazepine and an opiate has been proposed as standard sedation for bronchoscopy. Propofol is a sedative–hypnotic with a rapid onset of action and fast recovery time, but carries the potential risk of respiratory failure.Consecutive patients (n = 200) were randomly allocated to receive either the combination midazolam and hydrocodone or intravenous propofol. The primary end-points were the mean lowest arterial oxygen saturation during bronchoscopy and the readiness-for-discharge score 1 h after the procedure.The mean lowest arterial oxygen saturation during bronchoscopy did not differ across treatment groups (p = 0.422), and the number of patients recording an arterial oxygen saturation of ≤90% on at least one occasion was similar in both groups (p = 0.273). The median (interquartile range) readiness-for-discharge score 1 h after the procedure was significantly higher in the propofol group than in the combined sedation group (8 (6–9)versus7 (5–9); p = 0.035). Patients assigned propofol exhibited less tachycardia during bronchoscopy and for ≥1 h after the examination. Minor procedural complications were noted in 71 (35.5%) patients and exhibited a similar incidence in both treatment arms (p = 0.460).Propofol is as effective and safe as combined sedation in patients undergoing flexible bronchoscopy, thus representing an appealing option if timely discharge is a priority.
Efficacy of moxifloxacin in the treatment of bronchial colonisation in COPD
Authors: Miravitlles M. , Marín A. , Monsó E. , Vilà S. , de la Roza C. , Hervás R. , Esquinas C. , García M. , Millares L. , Morera J. , Torres A. 
Published: April 2009

This study was designed to investigate the efficacy of moxifloxacin for the eradication of bacterial colonisation of the airways in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD).Out of 119 stable patients with COPD screened, 40 (mean age 69 yrs, mean forced expiratory volume in 1 s 50% predicted) were colonised with potentially pathogenic microorganisms (PPMs) and were included in a randomised, double-blind, placebo-controlled trial with moxifloxacin 400 mg daily for 5 days.Eradication rates were 75% with moxifloxacin and 30% with placebo at 2 weeks (p = 0.01). Bacterial persistence at 8 weeks was still higher (not significantly) in the placebo arm (five (25%) out of 20versusone (5%) out of 20; p = 0.18). The frequencies of acquisition of a new PPM were high and similar in both treatment groups; consequently, the prevalence of colonisation at 8 weeks was also similar between treatment arms. No difference was found in the number of patients with exacerbations during the 5-month follow-up. Only the acquisition of a new PPM during follow-up showed a statistically significant relationship with occurrence of an exacerbation.Moxifloxacin was effective in eradicating PPMs in patients with positive sputum cultures. However, most patients were recolonised after 8 weeks of follow-up. Acquisition of a new strain of bacteria was associated with an increased risk of developing an exacerbation.
Both Ca2+ and Zn2+ are essential for S100A12 protein oligomerization and function
Authors: Moroz Olga V , Burkitt Will , Wittkowski Helmut , He Wei , Ianoul Anatoli , Novitskaya Vera , Xie Jingjing , Polyakova Oxana , Lednev Igor K , Shekhtman Alexander , Derrick Peter J , Bjoerk Per , Foell Dirk , Bronstein Igor B 
Published: April 2009

Abstract

Background
Human S100A12 is a member of the S100 family of EF-hand calcium-modulated proteins that are associated with many diseases including cancer, chronic inflammation and neurological disorders. S100A12 is an important factor in host/parasite defenses and in the inflammatory response. Like several other S100 proteins, it binds zinc and copper in addition to calcium. Mechanisms of zinc regulation have been proposed for a number of S100 proteins e.g. S100B, S100A2, S100A7, S100A8/9. The interaction of S100 proteins with their targets is strongly dependent on cellular microenvironment.

Results
The aim of the study was to explore the factors that influence S100A12 oligomerization and target interaction. A comprehensive series of biochemical and biophysical experiments indicated that changes in the concentration of calcium and zinc led to changes in the oligomeric state of S100A12. Surface plasmon resonance confirmed that the presence of both calcium and zinc is essential for the interaction of S100A12 with one of its extracellular targets, RAGE – the Receptor for Advanced Glycation End products. By using a single-molecule approach we have shown that the presence of zinc in tissue culture medium favors both the oligomerization of exogenous S100A12 protein and its interaction with targets on the cell surface.

Conclusion
We have shown that oligomerization and target recognition by S100A12 is regulated by both zinc and calcium. Our present work highlighted the potential role of calcium-binding S100 proteins in zinc metabolism and, in particular, the role of S100A12 in the cross talk between zinc and calcium in cell signaling.