bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cooperative integrin/ITAM signaling in platelets enhances thrombus formation in vitro and in vivo
Authors: Zhi Huiying , Rauova Lubica , Hayes Vincent , Gao Cunji , Boylan Brian , Newman Debra K. , McKenzie Steven E. , Cooley Brian C. , Poncz Mortimer , Newman Peter J. 
Published: December 2012

Key PointsThese data establish FcγRIIa as a physiologically important functional conduit for αIIbβ3-mediated outside-in signaling.
Distinct gene-expression profiles associated with the susceptibility of pathogen-specific CD4 T cells to HIV-1 infection
Authors: Hu Haitao , Nau Martin , Ehrenberg Phil , Chenine Agnes-Laurence , Macedo Camila , Zhou Yu , Daye Z. John , Wei Zhi , Vahey Maryanne , Michael Nelson L. , Kim Jerome H. , Marovich Mary , Ratto-Kim Silvia 
Published: December 2012

Key PointsDifferent pathogen-specific CD4 T cells manifest remarkable difference in susceptibility to HIV infection. Distinct gene-expression profiles of pathogen-specific CD4 T cells are associated with their susceptibilities to HIV infection.
Characteristics and outcome of early-onset, severe forms of Wiskott-Aldrich syndrome
Authors: Mahlaoui Nizar , Pellier Isabelle , Mignot Cécile , Jais Jean-Philippe , Bilhou-Nabéra Chrystèle , Moshous Despina , Neven Bénédicte , Picard Capucine , de Saint-Basile Geneviève , Cavazzana-Calvo Marina , Blanche Stéphane , Fischer Alain 
Published: December 2012

Key PointsThis study identified a distinct subgroup of WAS patients with an early onset (before the age of 2 years) of severe, life-threatening manifestations. HSCT is a curative strategy in this subgroup of patients and should be performed as early in life as possible, even when a fully matched donor is lacking.
Coming full circle: 70 years of chronic lymphocytic leukemia cell redistribution, from glucocorticoids to inhibitors of B-cell receptor signaling
Authors: Burger Jan A. , Montserrat Emili 
Published: December 2012

AbstractChronic lymphocytic leukemia (CLL) cells proliferate in pseudofollicles within the lymphatic tissues, where signals from the microenvironment and BCR signaling drive the expansion of the CLL clone. Mobilization of tissue-resident cells into the blood removes CLL cells from this nurturing milieu and sensitizes them to cytotoxic drugs. This concept recently gained momentum after the clinical activity of kinase inhibitors that target BCR signaling (spleen tyrosine kinase, Bruton tyrosine kinase, PI3Kδ inhibitors) was established. Besides antiproliferative activity, these drugs cause CLL cell redistribution with rapid lymph node shrinkage, along with a transient surge in lymphocytosis, before inducing objective remissions. Inactivation of critical CLL homing mechanism (chemokine receptors, adhesion molecules), thwarting tissue retention and recirculation into the tissues, appears to be the basis for this striking clinical activity. This effect of BCR-signaling inhibitors resembles redistribution of CLL cells after glucocorticoids, described as early as in the 1940s. As such, we are witnessing a renaissance of the concept of leukemia cell redistribution in modern CLL therapy. Here, we review the molecular basis of CLL cell trafficking, homing, and redistribution and similarities between old and new drugs affecting these processes. In addition, we outline how these discoveries are changing our understanding of CLL biology and therapy.
Local and systemic cytokine profiles in nonsevere and severe community-acquired pneumonia
Authors: Paats Marthe S. , Bergen Ingrid M. , Hanselaar Wessel E.J.J. , Groeninx van Zoelen E. Christine , Hoogsteden Henk C. , Hendriks Rudi W. , van der Eerden Menno M. 
Published: December 2012

Local inflammatory responses in community-acquired pneumonia (CAP) remain insufficiently elucidated, especially in patients with nonsevere CAP. In this study we determined local and systemic cytokine responses in CAP patients and correlated these with disease severity and other clinical parameters.Levels of interleukin (IL)-6, IL-8, IL-10, IL-1β, tumour necrosis factor-α, interferon (IFN)-γ, IL-22, IL-17A and IL-4 were determined in bronchoalveolar lavage fluid and serum of 20 CAP patients upon admission and 10 healthy individuals. Systemic cytokine levels were also measured on days 7 and 30.In bronchoalveolar lavage fluid of CAP patients, levels of IL-6, IL-8 and IFN-γ were significantly increased compared with healthy individuals, but no correlations with disease severity were found. Systemic levels of IL-6, IL-10 and IFN-γ were significantly higher in severe CAP patients than in nonsevere CAP patients and healthy individuals. Moreover, these cytokines showed a significant correlation with the pneumonia severity index. In the total group of CAP patients, systemic IL-8 and IL-22 levels were also increased compared with healthy individuals.We therefore conclude that IL-6, IL-10 and IFN-γ are important cytokines in CAP, although differences in disease severity upon admission are only reflected by systemic levels of these cytokines.
High prevalence of occult left heart disease in scleroderma-pulmonary hypertension
Authors: Fox Benjamin D. , Shimony Avi , Langleben David , Hirsch Andrew , Rudski Lawrence , Schlesinger Robert , Eisenberg Mark J. , Joyal Dominique , Hudson Marie , Boutet Kim , Serban Alexandrina , Masetto Ariel , Baron Murray 
Published: December 2012

Our study aimed to determine the prevalence of occult left-heart disease in patients with scleroderma and pulmonary hypertension. In patients with pulmonary hypertension (mean pulmonary artery pressure (mean PAP) ≥25 mmHg), differentiation between pre- and post-capillary pulmonary hypertension has been made according to pulmonary artery wedge pressure (PAWP) less than or more than 15 mmHg, respectively.We performed a retrospective chart review of 107 scleroderma patients. All patients with suspected pulmonary hypertension had routine right or left heart catheterisation with left ventricular end-diastolic pressure (LVEDP) measurement pre-/post-fluid challenge. We extracted demographic, haemodynamic and echocardiographic data. Patients were classified into one of four groups: haemodynamically normal (mean PAP<25 mmHg); pulmonary venous hypertension (PVH) (mean PAP≥25 mmHg, PAWP>15 mmHg); occult PVH (mean PAP≥25 mmHg, PAWP≤15 mmHg, LVEDP>15 mmHg before or after fluid challenge); and pulmonary arterial hypertension (PAH) (mean PAP≥25 mmHg, PAWP≤15 mmHg and LVEDP≤15 mmHg before or after fluid challenge).53 out of 107 patients had pulmonary hypertension. Based on the PAWP-based definition, 29 out of 53 had PAH and 24 out of 53 had PVH. After considering the resting and post-fluid-challenge LVEDP, 11 PAH patients were reclassified as occult PVH. The occult PVH group was haemodynamically, echocardiographically and demographically closer to the PVH group than the PAH group.PVH had high prevalence in our scleroderma-pulmonary hypertension population. Distinguishing PAH from PVH with only PAWP may result in some PVH patients being misclassified as having PAH.
Physical activity in COPD patients: patterns and bouts
Authors: Donaire-Gonzalez David , Gimeno-Santos Elena , Balcells Eva , Rodríguez Diego A. , Farrero Eva , de Batlle Jordi , Benet Marta , Ferrer Antoni , Barberà Joan A. , Gea Joaquim , Rodriguez-Roisin Robert , Antó Josep M. , Garcia-Aymerich Judith 
Published: December 2012

The present study aims to describe the pattern of physical activity and the frequency, duration and intensity of physical activity bouts in patients with chronic obstructive pulmonary disease (COPD), to assess how these patterns differ according to COPD severity, and to explore whether these patients meet the general guidelines for physical activity for older adults.177 patients (94% male, mean±sdage 71±8 years and forced expiratory volume in 1 s 52±16% predicted) wore the SenseWear Pro2Armband accelerometer for eight consecutive days. Physical activity bouts were defined as periods of ≥10 min above 1.5 metabolic equivalent tasks and classified according to their median intensity.Patients engaged in activity a median of 153 min·day−1and 57% of that time was spent in bouts. Median frequencies of bouts per day were four and three for all and moderate-to-vigorous intensities, respectively. With increasing COPD severity, time in physical activity, proportion of time in bouts and frequency of bouts decreased. 61% of patients fulfilled the recommended physical activity guidelines.In conclusion, COPD patients of all spirometric severity stages engage in physical activity bouts of moderate-to-vigorous intensities. Patients with severe and very severe COPD perform their daily activities in fewer and shorter bouts than those in mild and moderate stages.
Risk of deep vein thrombosis and pulmonary embolism in asthma
Authors: Majoor Christof J. , Kamphuisen Pieter W. , Zwinderman Aeilko H. , ten Brinke Anneke , Amelink Marijke , Rijssenbeek-Nouwens Lucia , Sterk Peter J. , Büller Harry R. , Bel Elisabeth H. 
Published: December 2012

Increasing evidence suggests that patients with asthma have activated coagulation within the airways. Whether this leads to an increase in venous thromboembolic events is unknown. We therefore assessed the incidence of venous thromboembolic events in patients with mild-to-moderate and severe asthma as compared with an age- and sex-matched reference population.648 patients with asthma (283 with severe and 365 patients with mild-to-moderate asthma) visiting three Dutch outpatient asthma clinics were studied. All patients completed a questionnaire about a diagnosis of deep vein thrombosis and pulmonary embolism in the past, their risk factors, history of asthma and medication use. All venous thromboembolic events were objectively verified.In total, 35 venous thromboembolic events (16 deep vein thrombosis and 19 pulmonary embolism) occurred at a median age of 39 (range 20–63) years. The incidence of pulmonary embolism in patients with severe asthma was 0.93 (95% CI 0.42–1.44) per 1000 person-years, 0.33 (95% CI 0.07–0.60) in mild-to-moderate asthma and 0.18 (95% CI 0.03–0.33) in the general population, respectively. Severe asthma and oral corticosteroid use were independent risk factors of pulmonary embolism (hazard ratios 3.33 (1.16–9.93) and 2.82 (1.09–7.30), respectively). Asthma was not associated with deep vein thrombosis.Severe asthma greatly enhances the risk of pulmonary embolism, particularly if chronic corticosteroids are used.
Welding, longitudinal lung function decline and chronic respiratory symptoms: a systematic review of cohort studies
Authors: Szram Joanna , Schofield Susie J. , Cosgrove Martin P. , Cullinan Paul 
Published: December 2012

While the acute respiratory risks of welding are well characterised, more chronic effects, including those on lung function, are less clear. We carried out a systematic review of published longitudinal studies of lung function decline in welders.Original cohort studies documenting two or more sequential measurements of lung function were reviewed. Meta-analysis was carried out on studies with suitable data on forced expiratory volume in 1 s (FEV1).Seven studies were included; their quality (measured on the Newcastle–Ottawa scale) was good, although exposure assessment was limited and the studies showed significant heterogeneity. Five had data suitable for meta-analysis; the pooled estimate of the difference in FEV1decline between welders and nonwelders was -9.0 mL·year−1(95% CI -22.5–4.5; p=0.193). The pooled estimates of difference in annual FEV1decline between welders and referents who smoked was -13.7 mL·year−1(95% CI -33.6–6.3; p=0.179). For welders and referents who did not smoke the estimated difference was -3.8 mL·year−1(95% CI -20.2–12.6; p=0.650). Symptom prevalence data were mainly narrative; smoking appeared to have the greatest effect on symptom evolution.Collectively, available longitudinal data on decline of lung function in welders and respiratory symptoms suggest a greater effect in those who smoke, supporting a focus on smoking cessation as well as control of fume exposure in this trade. Further prospective studies are required to confirm these findings.
Protein interface classification by evolutionary analysis
Authors: Duarte Jose M , Srebniak Adam , Schärer Martin A , Capitani Guido 
Published: December 2012

Abstract

Background
Distinguishing biologically relevant interfaces from lattice contacts in protein crystals is a fundamental problem in structural biology. Despite efforts towards the computational prediction of interface character, many issues are still unresolved.

Results
We present here a protein-protein interface classifier that relies on evolutionary data to detect the biological character of interfaces. The classifier uses a simple geometric measure, number of core residues, and two evolutionary indicators based on the sequence entropy of homolog sequences. Both aim at detecting differential selection pressure between interface core and rim or rest of surface. The core residues, defined as fully buried residues (>95% burial), appear to be fundamental determinants of biological interfaces: their number is in itself a powerful discriminator of interface character and together with the evolutionary measures it is able to clearly distinguish evolved biological contacts from crystal ones. We demonstrate that this definition of core residues leads to distinctively better results than earlier definitions from the literature. The stringent selection and quality filtering of structural and sequence data was key to the success of the method. Most importantly we demonstrate that a more conservative selection of homolog sequences - with relatively high sequence identities to the query - is able to produce a clearer signal than previous attempts.

Conclusions
An evolutionary approach like the one presented here is key to the advancement of the field, which so far was missing an effective method exploiting the evolutionary character of protein interfaces. Its coverage and performance will only improve over time thanks to the incessant growth of sequence databases. Currently our method reaches an accuracy of 89% in classifying interfaces of the Ponstingl 2003 datasets and it lends itself to a variety of useful applications in structural biology and bioinformatics. We made the corresponding software implementation available to the community as an easy-to-use graphical web interface at http://www.eppic-web.org.
Evolutionary relationships between miRNA genes and their activity
Authors: Zhu Yan , Skogerbø Geir , Ning Qianqian , Wang Zhen , Li Biqing , Yang Shuang , Sun Hong , Li Yixue 
Published: December 2012

Abstract

Background
The emergence of vertebrates is characterized by a strong increase in miRNA families. MicroRNAs interact broadly with many transcripts, and the evolution of such a system is intriguing. However, evolutionary questions concerning the origin of miRNA genes and their subsequent evolution remain unexplained.

Results
In order to systematically understand the evolutionary relationship between miRNAs gene and their function, we classified human known miRNAs into eight groups based on their evolutionary ages estimated by maximum parsimony method. New miRNA genes with new functional sequences accumulated more dynamically in vertebrates than that observed in Drosophila. Different levels of evolutionary selection were observed over miRNA gene sequences with different time of origin. Most genic miRNAs differ from their host genes in time of origin, there is no particular relationship between the age of a miRNA and the age of its host genes, genic miRNAs are mostly younger than the corresponding host genes. MicroRNAs originated over different time-scales are often predicted/verified to target the same or overlapping sets of genes, opening the possibility of substantial functional redundancy among miRNAs of different ages. Higher degree of tissue specificity and lower expression level was found in young miRNAs.

Conclusions
Our data showed that compared with protein coding genes, miRNA genes are more dynamic in terms of emergence and decay. Evolution patterns are quite different between miRNAs of different ages. MicroRNAs activity is under tight control with well-regulated expression increased and targeting decreased over time. Our work calls attention to the study of miRNA activity with a consideration of their origin time.
Structural analysis of the genome of breast cancer cell line ZR-75-30 identifies twelve expressed fusion genes
Authors: Schulte Ina , Batty Elizabeth M , Pole Jessica CM , Blood Katherine A , Mo Steven , Cooke Susanna L , Ng Charlotte , Howe Kevin L , Chin Suet-Feung , Brenton James D , Caldas Carlos , Howarth Karen D , Edwards Paul AW 
Published: December 2012

Abstract

Background
It has recently emerged that common epithelial cancers such as breast cancers have fusion genes like those in leukaemias. In a representative breast cancer cell line, ZR-75-30, we searched for fusion genes, by analysing genome rearrangements.

Results
We first analysed rearrangements of the ZR-75-30 genome, to around 10kb resolution, by molecular cytogenetic approaches, combining array painting and array CGH. We then compared this map with genomic junctions determined by paired-end sequencing. Most of the breakpoints found by array painting and array CGH were identified in the paired end sequencing—55% of the unamplified breakpoints and 97% of the amplified breakpoints (as these are represented by more sequence reads). From this analysis we identified 9 expressed fusion genes: APPBP2-PHF20L1, BCAS3-HOXB9, COL14A1-SKAP1, TAOK1-PCGF2, TIAM1-NRIP1, TIMM23-ARHGAP32, TRPS1-LASP1, USP32-CCDC49 and ZMYM4-OPRD1. We also determined the genomic junctions of a further three expressed fusion genes that had been described by others, BCAS3-ERBB2, DDX5-DEPDC6/DEPTOR and PLEC1-ENPP2. Of this total of 12 expressed fusion genes, 9 were in the coamplification. Due to the sensitivity of the technologies used, we estimate these 12 fusion genes to be around two-thirds of the true total. Many of the fusions seem likely to be driver mutations. For example, PHF20L1, BCAS3, TAOK1, PCGF2, and TRPS1 are fused in other breast cancers. HOXB9 and PHF20L1 are members of gene families that are fused in other neoplasms. Several of the other genes are relevant to cancer—in addition to ERBB2, SKAP1 is an adaptor for Src, DEPTOR regulates the mTOR pathway and NRIP1 is an estrogen-receptor coregulator.

Conclusions
This is the first structural analysis of a breast cancer genome that combines classical molecular cytogenetic approaches with sequencing. Paired-end sequencing was able to detect almost all breakpoints, where there was adequate read depth. It supports the view that gene breakage and gene fusion are important classes of mutation in breast cancer, with a typical breast cancer expressing many fusion genes.
Membranoproliferative glomerulonephritis complicating Waldenström’s macroglobulinemia
Authors: Kratochvil David , Amann Kerstin , Bruck Heike , Büttner Maike 
Published: December 2012

Abstract

Background
Lymphoproliferative disorders causing paraproteinemia can be associated with various kidney injuries including the deposition of monoclonal immunoglobulins (Ig). A known glomerular manifestation of Waldenström’s macroglobulinemia is characterized by prominent intracapillary hyaline thrombi and lack of conspicuous glomerular proliferation. The present case was special in 2 aspects: 1. the diagnosis of glomerulonephritis was unexpected before renal biopsy, 2. the prominent glomerular proliferation paired with large intracapillary hyaline thrombi is uncommon in Waldenström’s macroglobulinemia-associated glomerulonephritis.

Case presentation
A 73-year-old Caucasian woman with a long-standing history of rheumatoid arthritis and Waldenström’s macroglobulinemia was admitted for acute renal failure (ARF), which initially was presumed to be the consequence of extrarenal causes. Proteinuria and hematuria were only mild. In renal core biopsy, a membranoproliferative glomerulonephritis (MPGN) and prominent intracapillary hyaline monoclonal IgM thrombi were found in addition to acute tubular necrosis. Of note, the patient’s history was positive for purpuric skin changes, suspicious for cryoglobulinemia. However, serological tests for cryoglobulins were repeatedly negative. The ARF resolved before the start of immunomodulatory therapy for Waldenström’s macroglobulinemia.

Conclusion
The presence of MPGN with prominent hyaline thrombi in the context of Waldenström’s macroglobulinemia is uncommon and can be oligosymptomatic. We discuss this case in the context of previous literature and classifications suggested for monoclonal Ig-related renal pathologies.
Disseminated tumor cells as selection marker and monitoring tool for secondary adjuvant treatment in early breast cancer. Descriptive results from an intervention study
Authors: Synnestvedt Marit , Borgen Elin , Wist Erik , Wiedswang Gro , Weyde Kjetil , Risberg Terje , Kersten Christian , Mjaaland Ingvil , Vindi Lise , Schirmer Cecilie , Nesland Jahn Martin , Naume Bjørn 
Published: December 2012

Abstract

Background
Presence of disseminated tumor cells (DTCs) in bone marrow (BM) after completion of systemic adjuvant treatment predicts reduced survival in breast cancer. The present study explores the use of DTCs to identify adjuvant insufficiently treated patients to be offered secondary adjuvant treatment intervention, and as a surrogate marker for therapy response.

Methods
A total of 1121 patients with pN1-3 or pT1c/T2G2-3pN0-status were enrolled. All had completed primary surgery and received 6 cycles of anthracycline-containing chemotherapy. BM-aspiration was performed 8-12 weeks after chemotherapy (BM1), followed by a second BM-aspiration 6 months later (BM2). DTC-status was determined by morphological evaluation of immunocytochemically detected cytokeratin-positive cells. If DTCs were present at BM2, docetaxel (100 mg/m2, 3qw, 6 courses) was administered, followed by DTC-analysis 1 month (BM3) and 13 months (BM4) after the last docetaxel infusion.

Results
Clinical follow-up (FU) is still ongoing. Here, the descriptive data from the study are presented. Of 1085 patients with a reported DTC result at both BM1 and BM2, 94 patients (8.7%) were BM1 positive and 83 (7.6%) were BM2 positive. The concordance between BM1 and BM2 was 86.5%. Both at BM1 and BM2 DTC-status was significantly associated with lobular carcinomas (p = 0.02 and p = 0.03, respectively; chi-square). In addition, DTC-status at BM2 was also associated with pN-status (p = 0.009) and pT-status (p = 0.03). At BM1 28.8% and 12.8% of the DTC-positive patients had ≥2 DTCs and ≥3 DTCs, respectively. At BM2, the corresponding frequencies were 47.0% and 25.3%. Of 72 docetaxel-treated patients analyzed at BM3 and/or BM4, only 15 (20.8%) had persistent DTCs. Of 17 patients with ≥3 DTCs before docetaxel treatment, 12 patients turned negative after treatment (70.6%). The change to DTC-negativity was associated with the presence of ductal carcinoma (p = 0.009).

Conclusions
After docetaxel treatment, the majority of patients experienced disappearance of DTCs. As this is not a randomized trial, the results can be due to effects of adjuvant (docetaxel/endocrine/trastuzumab) treatment and/or limitations of the methodology. The clinical significance of these results awaits mature FU data, but indicates a possibility for clinical use of DTC-status as a residual disease-monitoring tool and as a surrogate marker of treatment response.

Trial registration
Clin Trials Gov NCT00248703