Lymphocyte predominant cells detect Moraxella catarrhalis-derived antigens in nodular lymphocyte-predominant Hodgkin lymphoma.

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare lymphoma of B-cell origin with frequent expression of functional B-cell receptors (BCRs). Here we report that expression cloning followed by antigen screening identifies DNA-directed RNA polymerase beta' (RpoC) from Moraxella catarrhalis as frequent antigen of BCRs of IgD <sup>+</sup> LP cells. Patients show predominance of HLA-DRB1*04/07 and the IgVH genes encode extraordinarily long CDR3s. High-titer, light-chain-restricted anti-RpoC IgG1/κ-type serum-antibodies are additionally found in these patients. RpoC and MID/hag, a superantigen co-expressed by Moraxella catarrhalis that is known to activate IgD <sup>+</sup> B cells by binding to the Fc domain of IgD, have additive activation effects on the BCR, the NF-κB pathway and the proliferation of IgD <sup>+</sup> DEV cells expressing RpoC-specific BCRs. This suggests an additive antigenic and superantigenic stimulation of B cells with RpoC-specific IgD <sup>+</sup> BCRs under conditions of a permissive MHC-II haplotype as a model of NLPHL lymphomagenesis, implying future treatment strategies

PET-based delineation of tumour volumes in lung cancer: Comparison with pathological findings

Purpose The objective of the study was to validate an adaptive, contrast-oriented thresholding algorithm (COA) for tumour delineation in 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) for non-small cell lung cancer (NSCLC) in comparison with pathological findings. The impact of tumour localization, tumour size and uptake heterogeneity on PET delineation results was also investigated. Methods PET tumour delineation by COA was compared with both CT delineation and pathological findings in 15 patients to investigate its validity. Correlations between anatomical volume, metabolic volume and the pathology reference as well as between the corresponding maximal diameters were determined. Differences between PET delineations and pathological results were investigated with respect to tumour localization and uptake heterogeneity. Results The delineated volumes and maximal diameters measured on PET and CT images significantly correlated with the pathology reference (both r > 0.95, p  < 0.0001). Both PET and CT contours resulted in overestimation of the pathological volume (PET 32.5 ± 26.5 %, CT 46.6 ± 27.4 %). CT volumes were larger than those delineated on PET images (CT 60.6 ± 86.3 ml, PET 48.3 ± 61.7 ml). Maximal tumour diameters were similar for PET and CT (51.4 ± 19.8 mm for CT versus 53.4 ± 19.1 mm for PET), slightly overestimating the pathological reference (mean difference CT 4.3 ± 3.2 mm, PET 6.2 ± 5.1 mm). PET volumes of lung tumours located in the lower lobe were significantly different from those determined from pathology (p = 0.037), whereas no significant differences were observed for tumours located in the upper lobe (p = 0.066). Only minor correlation was found between pathological tumour size and PET heterogeneity (r = −0.24). Conclusion PET tumour delineation by COA showed a good correlation with pathological findings. Tumour localization had an influence on PET delineation results. The impact of tracer uptake heterogeneity on PET delineation should be considered carefully and individually in each patient. Altogether, PET tumour delineation by COA for NSCLC patients is feasible and reliable with the potential for routine clinical application

Fhl-1, a new key protein in pulmonary hypertension

BACKGROUND: Pulmonary hypertension (PH) is a severe disease with a poor prognosis. Different forms of PH are characterized by pronounced vascular remodeling, resulting in increased vascular resistance and subsequent right heart failure. The molecular pathways triggering the remodeling process are poorly understood. We hypothesized that underlying key factors can be identified at the onset of the disease. Thus, we screened for alterations to protein expression in lung tissue at the onset of PH in a mouse model of hypoxia-induced PH. METHODS AND RESULTS: Using 2-dimensional polyacrylamide gel electrophoresis in combination with matrix-assisted laser desorption/ionization time-of-flight analysis, we identified 36 proteins that exhibited significantly altered expression after short-term hypoxic exposure. Among these, Fhl-1, which is known to be involved in muscle development, was one of the most prominently upregulated proteins. Further analysis by immunohistochemistry, Western blot, and laser-assisted microdissection followed by quantitative polymerase chain reaction confirmed the upregulation of Fhl-1, particularly in the pulmonary vasculature. Comparable upregulation was confirmed (1) after full establishment of hypoxia-induced PH, (2) in 2 rat models of PH (monocrotaline-treated and hypoxic rats treated with the vascular endothelial growth factor receptor antagonist SU5416), and (3) in lungs from patients with idiopathic pulmonary arterial hypertension. Furthermore, we demonstrated that regulation of Fhl-1 was hypoxia-inducible transcription factor dependent. Abrogation of Fhl-1 expression in primary human pulmonary artery smooth muscle cells by small-interfering RNA suppressed, whereas Fhl-1 overexpression increased, migration and proliferation. Coimmunoprecipitation experiments identified Talin1 as a new interacting partner of Fhl-1. CONCLUSIONS: Protein screening identified Fhl-1 as a novel protein regulated in various forms of PH, including idiopathic pulmonary arterial hypertension