Biology and Signal Transduction pathways of the Lymphotoxin-αβ/LTβR system

This review focuses on the biological functions and signalling pathways activated by Lymphotoxin α (LTα)/Lymphotoxin β (LTβ) and their receptor LTβR. Genetic mouse models shed light on crucial roles for LT/LTβR to build and to maintain the architecture of lymphoid organs and to ensure an adapted immune response against invading pathogens. However, chronic inflammation, autoimmunity, cell death or cancer development are disorders that occur when the LT/LTβR system is twisted. Biological inhibitors, such as antagonist antibodies or decoy receptors, have been developed and used in clinical trials for diseases associated to the LT/LTβR system. Recent progress in the understanding of cellular trafficking and NF-κB signaling pathways downstream of LTα/LTβ may bring new opportunities to develop therapeutics that target the pathological functions of these cytokines

Optimisation methods for advanced design of aircraft panels: a comparison

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NF-κB inducing kinase (NIK) inhibitors: Identification of new scaffolds using virtual screening

As a wide variety of pro-inflammatory cytokines are involved in the development of rheumatoid arthritis (RA), there is an urgent need for the discovery of novel therapeutic strategies. Among these, the inhibition of the NF-κB inducing kinase (NIK), a key enzyme of the NF-κB alternative pathway activation, represents a potential interesting approach. In fact, NIK is involved downstream of many tumor necrosis factor receptors (TNFR) like CD40, RANK or LTβR, implicated in the pathogenesis of RA. But, up to now, the number of reported putative NIK inhibitors is extremely limited. In this work, we report a virtual screening (VS) study combining various filters including high-throughput docking using a 3D-homology model and ranking by using different scoring functions. This work led to the identification of two molecular fragments, 4H-isoquinoline-1,3-dione (5) and 2,7-naphthydrine-1,3,6,8-tetrone (6) which inhibit NIK with an IC50 value of 51 and 90 μM, respectively. This study opens new perspectives in the field of the NF-κB alternative pathway inhibition. © 2010 Elsevier Ltd. All rights reserved

Vessel based delineation guidelines for the elective lymph node regions in breast cancer radiation therapy - PROCAB guidelines

Objective A national project to improve the quality of breast radiation therapy was started, named PROCAB (PROject on CAncer of the Breast). One of the objectives was to reach a national consensus guideline for the delineation of the regional lymph node areas in breast radiation therapy. Methods The realization of the new guidelines was a step by step process that started with multiple expert meetings where the existing guidelines were analyzed and the delineations of the lymph node regions were performed together with a surgeon, specialized in the anatomy of the drainage of the breast. Results The delineation guidelines are vessel-based. Since the occurrence of pathological lymph nodes is typically around the veins, the cranial and caudal borders of all different nodal regions are based on a 5 mm margin around the veins, except for the parasternal lymph node area. Compared to the existing guidelines there are some major changes. Conclusion With this project a national as well as a European (ESTRO) consensus guideline for the delineation of the regional lymph node areas in breast RT is reached. The new delineation atlas is vessel-based and no longer field-based

Role of IKK and ERK pathways in intrinsic inflammation of cystic fibrosis airways

in cystic fibrosis (CF) patients, pulmonary inflammation is a major cause of morbidity and mortality and may precede bacterial colonization. The aim of the present study was to investigate the molecular mechanisms underlying intrinsic inflammation in cystic fibrosis air-ways. Using different cystic fibrosis cell models, we first demonstrated that, beside a high constitutive nuclear factor of kappaB (NF-kappa B) activity, CF cells showed a higher activator protein-1 (AP-1) activity as compared to their respective control cells. Gene expression profiles, confirmed by RT-PCR and ELISA, showed over-expression of numerous NF-KB and AP-1-dependent pro-inflammatory genes in CF cells in comparison with control cells. Activation of NF-KB was correlated with higher inhibitor of kappa B kinase (IKK) activity. In addition, Bio-plex phosphoprotein assays revealed higher extracellular signal-regulated kinase (ERK) phosphorylation in CFT-2 cells. Inhibition of this kinase strongly decreased expression of pro-inflammatory genes coding for growth-regulated proteins (Gro-alpha, Gro-beta and Gro-gamma) and interleukins (IL-1 beta, IL-6 and IL-8). Moreover, inhibition of secreted interleukin-1 beta (IL-1 beta) and basic fibroblast growth factor (bFGF) with neutralizing antibodies reduced pro-inflammatory gene expression. Our data thus demonstrated for the first time that the absence of functional cystic fibrosis transmembrane conductance regulator (CFTR) at the plasma membrane leads to an intrinsic AP-1, in addition to NF-kappa B, activity and consequently to a pro-inflammatory state sustained through autocrine factors such as IL-1 beta and bFGF. (c) 2007 Elsevier Inc. All rights reserved

Noncanonical NF-kappaB Signaling Is Limited by Classical NF-kappaB Activity.

peer reviewedPrecise regulation of nuclear factor kappaB (NF-kappaB) signaling is crucial for normal immune responses, and defective NF-kappaB activity underlies a range of immunodeficiencies. NF-kappaB is activated through two signaling cascades: the classical and noncanonical pathways. The classical pathway requires inhibitor of kappaB kinase beta (IKKbeta) and NF-kappaB essential modulator (NEMO), and hypomorphic mutations in the gene encoding NEMO (ikbkg) lead to inherited immunodeficiencies, collectively termed NEMO-ID. Noncanonical NF-kappaB activation requires NF-kappaB-inducing kinase (NIK) and IKKalpha, but not NEMO. We found that noncanonical NF-kappaB was basally active in peripheral blood mononuclear cells from NEMO-ID patients and that noncanonical NF-kappaB signaling was similarly enhanced in cell lines lacking functional NEMO. NIK, which normally undergoes constitutive degradation, was aberrantly present in resting NEMO-deficient cells, and regulation of its abundance was rescued by reconstitution with full-length NEMO, but not a mutant NEMO protein unable to physically associate with IKKalpha or IKKbeta. Binding of NEMO to IKKalpha was not required for ligand-dependent stabilization of NIK or noncanonical NF-kappaB signaling. Rather, an intact and functional IKK complex was essential to suppress basal NIK activity in unstimulated cells. Despite interacting with IKKalpha and IKKbeta to form an IKK complex, NEMO mutants associated with immunodeficiency failed to rescue classical NF-kappaB signaling or reverse the accumulation of NIK. Together, these findings identify a crucial role for classical NF-kappaB activity in the suppression of basal noncanonical NF-kappaB signaling

Pyrazolo[4,3-c]isoquinolines as potential inhibitors of NF-κB activation

In this work, we aimed to build a 3D-model of NIK and to study the binding of pyrazolo[4,3-c]isoquinolines with a view to highlight the structural elements responsible for their inhibitory potency. However, in the course of this work, we unexpectedly found that the pyrazolo[4,3-c]isoquinolines initially reported as NIK inhibitors were neither inhibitors of this enzyme nor of the alternative NF-κB pathway, but were in fact inhibitors of another kinase, the TGF-β activated kinase 1 (TAK1) which is involved in the classical NF-κB pathway. © 2010 Elsevier Inc. All rights reserved

Treatment and Prognosis of Patients with Lung Cancer and Combined Interstitial Lung Disease.

Interstitial lung disease (ILD) is associated with a higher lung cancer (LC) risk and may impact cancer's clinical characteristics, treatment strategies, and outcomes. This impact's extent is unclear, particularly in Caucasians. In this retrospective observational study, we reviewed the files of all LC patients diagnosed in a 38-month period. Expert radiologists reviewed the computed tomography scans performed at diagnosis. Patients with LC and ILD ( = 29, 7%) were compared to those without ILD ( = 363, 93%) for population and cancer characteristics, treatments, and clinical outcomes. Patients with LC and ILD were older (73 ± 8 vs. 65 ± 11 years; < 0.001). There was no significant difference in LC histology, localization, stage, or treatment modalities. The respiratory complication rate after cancer treatment was significantly higher in the ILD group (39% vs. 6%; < 0.01). Overall survival rates were similar at 12 (52% vs. 59%; = 0.48) and 24 months (41% vs. 45%; = 0.64) but poorer in the ILD group at 36 months, although not statistically significant (9% vs. 39%; = 0.06). The ILD group had a higher probability of death (hazard ratio (HR) = 1.49 [0.96;2.27]), but this was not statistically significant ( = 0.06). In a Cox regression model, patients with ILD treated surgically had a significantly higher mortality risk (HR = 2.37 [1.1;5.09]; = 0.03). Patients with combined LC and ILD have worse clinical outcomes even when similar treatment modalities are offered

TNFL–Induced p100 processing (TIPP) relies on the internalization of the cognate TNFR

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