Clinicogenetic risk models predict early progression of follicular lymphoma after first-line immunochemotherapy.

Follicular lymphoma (FL) is a clinically and molecularly heterogeneous disease. Posttreatment surrogate end points, such as progression of disease within 24 months (POD24) are promising predictors for overall survival (OS) but are of limited clinical value, primarily because they cannot guide up-front treatment decisions. We used the clinical and molecular data from 2 independent cohorts of symptomatic patients in need of first-line immunochemotherapy (151 patients from a German Low-Grade Lymphoma Study Group [GLSG] trial and 107 patients from a population-based registry of the British Columbia Cancer Agency [BCCA]) to validate the predictive utility of POD24, and to evaluate the ability of pretreatment risk models to predict early treatment failure.

Eradication of methicillin resistant Staphylococcus aureus detected for the first time in cystic fibrosis: A single center observational study.

Objective: To retrospectively identify CF patients with methicillin resistant Staphylococcus aureus (MRSA) and to assess the long-term success of an eradication scheme introduced in 2002 for all newly colonized patients.

Patients: All microbiological results from all 505 CF patients followed between 2002 and 2012 were analyzed focusing on the detection of MRSA.

Methods: Retrospective patient record analysis of MRSA positive CF patients regarding eradication and clinical outcome.

Influences on immunization rates: Vaccination coverage of mumps, measles, rubella and varicella before and after the STIKO intervention 2011 - A retrospective study.

Background: In September 2011, the German Standing Committee on Vaccinations (STIKO) changed their recommendation regarding the mumps-measles-rubella-varicella vaccination (MMRV). We compared the immunization rates against MMRV in Germany before and after the STIKO intervention.

Methods: We recorded the immunization status of children born between 09/2008 and 08/2012 in 35 selected doctor's surgeries in Germany.

Clonal evolution in relapsed and refractory diffuse large B-cell lymphoma is characterized by high dynamics of subclones.

Little information is available about the role of certain mutations for clonal evolution and the clinical outcome during relapse in diffuse large B-cell lymphoma (DLBCL). Therefore, we analyzed formalin-fixed-paraffin-embedded tumor samples from first diagnosis, relapsed or refractory disease from 28 patients using next-generation sequencing of the exons of 104 coding genes. Non-synonymous mutations were present in 74 of the 104 genes tested.

Acetylation of C/EBPα inhibits its granulopoietic function.

CCAAT/enhancer-binding protein alpha (C/EBPα) is an essential transcription factor for myeloid lineage commitment. Here we demonstrate that acetylation of C/EBPα at lysine residues K298 and K302, mediated at least in part by general control non-derepressible 5 (GCN5), impairs C/EBPα DNA-binding ability and modulates C/EBPα transcriptional activity. Acetylated C/EBPα is enriched in human myeloid leukaemia cell lines and acute myeloid leukaemia (AML) samples, and downregulated upon granulocyte-colony stimulating factor (G-CSF)- mediated granulocytic differentiation of 32Dcl3 cells.

A novel role of MMP-13 for murine DC function: its inhibition dampens T-cell activation.

Dendritic cells (DCs) have been shown to express matrix metalloproteinase 13 (MMP-13), but little is known about its specific function in DCs and its role in inflammatory conditions. In the present study, we describe a novel role of MMP-13 in regulating the immunostimulatory function of murine DCs through moderating MHC-I surface presentation, endocytosis and cytokine/chemokine secretion. MMP-13 expression was confirmed in bone marrow-derived DCs at both the mRNA and the protein level and, furthermore, at the activity level.

Surface proteome analysis identifies platelet derived growth factor receptor-alpha as a critical mediator of transforming growth factor-beta-induced collagen secretion.

Fibroblasts are extracellular matrix-producing cells in the lung. Fibroblast activation by transforming growth factor-beta leads to myofibroblast-differentiation and increased extracellular matrix deposition, a hallmark of pulmonary fibrosis. While fibroblast function with respect to migration, invasion, and extracellular matrix deposition has been well-explored, little is known about the surface proteome of lung fibroblasts in general and its specific response to fibrogenic growth factors, in particular transforming growth factor-beta.

Exercise Reduces Lung Fibrosis Involving Serotonin/Akt Signaling.

Purpose: Idiopathic pulmonary fibrosis (IPF) is a chronic fibrosing interstitial pneumonia, which involves aberrant serotonin (5-hydroxytryptamine [5-HT]) and Akt signaling. As protective effects of chronic aerobic training (AT) have been demonstrated in the context of lung injury, this study investigated whether AT attenuates bleomycin-induced lung fibrosis partly via a reduction of 5-HT and AKT signaling.

Methods: Seventy-two C57BL/6 male mice were distributed in Control (Co), Exercise (Ex), Fibrosis (Fi), and Fibrosis + Exercise (Fi + Ex) groups.

Integration of gene mutations in risk prognostication for patients receiving first-line immunochemotherapy for follicular lymphoma: a retrospective analysis of a prospective clinical trial and validation in a population-based registry.

Background: Follicular lymphoma is a clinically and genetically heterogeneous disease, but the prognostic value of somatic mutations has not been systematically assessed. We aimed to improve risk stratification of patients receiving first-line immunochemotherapy by integrating gene mutations into a prognostic model.

Methods: We did DNA deep sequencing to retrospectively analyse the mutation status of 74 genes in 151 follicular lymphoma biopsy specimens that were obtained from patients within 1 year before beginning immunochemotherapy consisting of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP).

Validated prediction of pro-invasive growth factors using a transcriptome-wide invasion signature derived from a complex 3D invasion assay.

The invasion of activated fibroblasts represents a key pathomechanism in fibrotic diseases, carcinogenesis and metastasis. Invading fibroblasts contribute to fibrotic extracellular matrix (ECM) formation and the initiation, progression, or resistance of cancer. To construct transcriptome-wide signatures of fibroblast invasion, we used a multiplex phenotypic 3D invasion assay using lung fibroblasts.

Time- and compartment-resolved proteome profiling of the extracellular niche in lung injury and repair.

The extracellular matrix (ECM) is a key regulator of tissue morphogenesis and repair. However, its composition and architecture are not well characterized. Here, we monitor remodeling of the extracellular niche in tissue repair in the bleomycin-induced lung injury mouse model.

Multidimensional immunolabeling and 4D time-lapse imaging of vital ex vivo lung tissue.

During the last decades, the study of cell behavior was largely accomplished in uncoated or extracellular matrix (ECM)-coated plastic dishes. To date, considerable cell biological efforts have tried to model in vitro the natural microenvironment found in vivo. For the lung, explants cultured ex vivo as lung tissue cultures (LTCs) provide a three-dimensional (3D) tissue model containing all cells in their natural microenvironment.

Platelet-derived growth factor signaling in the lung. From lung development and disease to clinical studies.

Platelet-derived growth factors (PDGFs) and their receptors (PDGFRs) represent one of the most intensively studied families of growth factors in the last four decades. PDGF signaling plays an essential role in cell proliferation, differentiation, migration, and survival. In vivo studies have documented an important role of PDGF signaling in the normal development of several organs, such as the kidney, eye, or lung.

Tissue remodelling in chronic bronchial diseases: from the epithelial to mesenchymal phenotype.

Airway remodelling is a critical feature of chronic bronchial diseases, characterised by aberrant repair of the epithelium and accumulation of fibroblasts, which contribute to extracellular matrix (ECM) deposition resulting in fixed bronchial obstruction. Recently, epithelial-mesenchymal transition (EMT) has been identified as a new source of fibroblasts that could contribute to the remodelling of the airways. This phenomenon consists of the loss of the epithelial phenotype by bronchial epithelial cells and the acquisition of a mesenchymal phenotype.

Multiplex profiling of cellular invasion in 3D cell culture models.

To-date, most invasion or migration assays use a modified Boyden chamber-like design to assess migration as single-cell or scratch assays on coated or uncoated planar plastic surfaces. Here, we describe a 96-well microplate-based, high-content, three-dimensional cell culture assay capable of assessing invasion dynamics and molecular signatures thereof. On applying our invasion assay, we were able to demonstrate significant effects on the invasion capacity of fibroblast cell lines, as well as primary lung fibroblasts.

Gli1 mediates lung cancer cell proliferation and Sonic Hedgehog-dependent mesenchymal cell activation.

Non-Small-Cell-Lung-Cancer (NSCLC) represents approximately 85% of all lung cancers and remains poorly understood. While signaling pathways operative during organ development, including Sonic Hedgehog (Shh) and associated Gli transcription factors (Gli1-3), have recently been found to be reactivated in NSCLC, their functional role remains unclear. Here, we hypothesized that Shh/Gli1-3 could mediate NSCLC autonomous proliferation and epithelial/stromal signaling in the tumoral tissue.

Next-generation personalized drug discovery: the tripeptide GHK hits center stage in chronic obstructive pulmonary disease.

Chronic lung diseases (CLDs), including chronic obstructive pulmonary disease (COPD), are the second leading cause of death worldwide. The first report of database-driven drug discovery in carefully phenotyped COPD specimens has now been published in Genome Medicine, combining gene expression data in defined emphysematous areas with connectivity-map-based compound discovery. This joint effort may lead the way to novel and potentially more efficient concepts of personalized drug discovery for COPD in particular, and CLD in general.

New cellular and molecular mechanisms of lung injury and fibrosis in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis is a serious and progressive chronic lung disease that is characterised by altered cellular composition and homoeostasis in the peripheral lung, leading to excessive accumulation of extracellular matrix and, ultimately, loss of lung function. It is the interstitial pneumonia with the worst prognosis--mortality 3-5 years after diagnosis is 50%. During the past decade, researchers have described several novel cellular and molecular mechanisms and signalling pathways implicated in the pathogenesis of idiopathic pulmonary fibrosis, resulting in the identification of new therapeutic targets.

Quantification of ETS exposure in hospitality workers who have never smoked.

Background: Environmental Tobacco Smoke (ETS) was classified as human carcinogen (K1) by the German Research Council in 1998. According to epidemiological studies, the relative risk especially for lung cancer might be twice as high in persons who have never smoked but who are in the highest exposure category, for example hospitality workers. In order to implement these results in the German regulations on occupational illnesses, a valid method is needed to retrospectively assess the cumulative ETS exposure in the hospitality environment.

Meconium ileus-it is time to act now!

Meconium ileus is a life-threatening presentation of neonates with cystic fibrosis (CF). Notwithstanding, today the long-term prognosis of such patients is comparable to that of CF patients not diagnosed in screening programs and not suffering from this insult,1-3 as confirmed by the article of Johnson et al. in this issue of Pediatric Pulmonology.