Decreased survival in patients treated by chemotherapy after targeted therapy compared to immunotherapy in metastatic melanoma.

Background: Cytotoxic chemotherapy (CC) is currently used in metastatic melanoma after patients have developed resistance to immune checkpoint inhibitors (ICI) and/or Mitogen-Activated Protein Kinase inhibitors (MAPKi). We sought to evaluate if a previous treatment by ICI or MAPKi influences clinical outcomes in patients treated by CC in metastatic melanoma.

Methods: Eighty-eight patients with a metastatic melanoma, treated by CC after a previous treatment by ICI or MAPKi between January 2009 and October 2019, were retrospectively analyzed.

The E3 ubiquitin ligases HOIP and cIAP1 are recruited to the TNFR2 signaling complex and mediate TNFR2-induced canonical NF-κB signaling.

Tumor Necrosis Factor (TNF) is a proinflammatory cytokine that elicits its action by binding to two cell surface TNF receptors (TNFR), TNFR1 and TNFR2, which are expressed by many different cell types. Stimulation of TNFR1 activates canonical NF-κB signaling, leading to the NF-κB dependent expression of a large number of genes. Canonical NF-κB signaling requires the assembly of a TNFR1 signaling complex at the cell membrane, whose formation is regulated by different protein ubiquitination events.

[Intelligent videosurveillance and falls detection: Perceptions of professionals and managers].

Description: Gerontechnologies can be used to detect accidental falls. However, existing systems do not entirely meet users' expectations. Our team developed an intelligent video-monitoring systems to fill these gaps.

MALT1 cleaves the E3 ubiquitin ligase HOIL-1 in activated T cells, generating a dominant negative inhibitor of LUBAC-induced NF-κB signaling.

Human paracaspase 1 (PCASP1), better known as mucosa associated lymphoid tissue lymphoma translocation 1 (MALT1), plays a key role in immunity and inflammation by regulating gene expression in lymphocytes and other immune cell types. Deregulated MALT1 activity has been implicated in autoimmunity, immunodeficiency and certain types of lymphoma. As a scaffold MALT1 assembles downstream signaling proteins for nuclear factor-κB (NF-κB) activation, while its proteolytic activity further enhances NF-κB activation by cleaving NF-κB inhibitory proteins.

XEDAR activates the non-canonical NF-κB pathway.

Members of the tumor necrosis factor receptor (TNFR) superfamily are involved in a number of physiological and pathological responses by activating a wide variety of intracellular signaling pathways. The X-linked ectodermal dysplasia receptor (XEDAR; also known as EDA2R or TNFRSF27) is a member of the TNFR superfamily that is highly expressed in ectodermal derivatives during embryonic development and binds to ectodysplasin-A2 (EDA-A2), a member of the TNF family that is encoded by the anhidrotic ectodermal dysplasia (EDA) gene. Although XEDAR was first described in the year 2000, its function and molecular mechanism of action is still largely unclear.

The multifaceted role of the E3 ubiquitin ligase HOIL-1: beyond linear ubiquitination.

Ubiquitination controls and fine-tunes many signaling processes driving immunity, inflammation, and cancer. The E3 ubiquitin ligase HOIL-1 (heme-oxidized IRP2 ubiquitin ligase-1) is increasingly implicated in different signaling pathways and plays a vital role in immune regulation. HOIL-1 co operates with the E3 ubiquitin ligase HOIP (HOIL-1 interacting protein) to modify specific nuclear factor-κB (NF-κB) signaling proteins with linear M1-linked polyubiquitin chains.

MALT1--a universal soldier: multiple strategies to ensure NF-κB activation and target gene expression.

The paracaspase MALT1 (mucosa associated lymphoid tissue lymphoma translocation gene 1) is an intracellular signaling protein that plays a key role in innate and adaptive immunity. It is essential for nuclear factor κB (NF-κB) activation and proinflammatory gene expression downstream of several cell surface receptors. MALT1 has been most studied in the context of T-cell receptor-induced NF-κB signaling, supporting T-cell activation and proliferation.

The biology of A20-binding inhibitors of NF-kappaB activation (ABINs).

The family of A20-Binding Inhibitors of NF-kappaB (ABINs) consists of three proteins, ABIN-1, ABIN-2 and ABIN-3, which were originally identified as A20-binding proteins and inhibitors of cytokines and Lipopolysaccharide (LPS) induced NF-kappaB activation. ABIN family members have limited sequence homology in a number of short regions that mediate A20-binding, ubiquitin-binding, and NF-kappaB inhibition. The functional role of A20 binding to ABINs remains unclear, although an adaptor function has been suggested.

The use of transdermal buprenorphine to relieve radiotherapy-related pain in head and neck cancer patients.

Many head and neck cancer (HNC) patients experience painful therapy-related mucositis and dermatitis. This prospective observational study evaluated transdermal buprenorphine use in HNC patients to relieve treatment-related pain. During treatment with paracetamol or tramadol, visual analogue scale (VAS)-pain scores >30/100 occurred in 26/45 patients 4 weeks after starting cancer therapy, persisting for ≥2 weeks after treatment.

IκB kinase ε (IKKε): a therapeutic target in inflammation and cancer.

The innate immune system forms our first line of defense against invading pathogens and relies for a major part on the activation of two transcription factors, NF-κB and IRF3. Signaling pathways that activate these transcription factors are intertwined at the level of the canonical IκB kinases (IKKα, IKKβ) and non-canonical IKK-related kinases (IKKε, TBK1). Recently, significant progress has been made in understanding the function and mechanism of action of IKKε in immune signaling.

Structure and function of the Type III secretion system of Pseudomonas aeruginosa.

Pseudomonas aeruginosa is a dangerous pathogen particularly because it harbors multiple virulence factors. It causes several types of infection, including dermatitis, endocarditis, and infections of the urinary tract, eye, ear, bone, joints and, of particular interest, the respiratory tract. Patients with cystic fibrosis, who are extremely susceptible to Pseudomonas infections, have a bad prognosis and high mortality.

A20 inhibits LUBAC-mediated NF-κB activation by binding linear polyubiquitin chains via its zinc finger 7.

Linear polyubiquitination of proteins has recently been implicated in NF-κB signalling and is mediated by the linear ubiquitin chain assembly complex (LUBAC), consisting of HOIL-1, HOIP and Sharpin. However, the mechanisms that regulate linear ubiquitination are still unknown. Here, we show that A20 is rapidly recruited to NEMO and LUBAC upon TNF stimulation and that A20 inhibits LUBAC-induced NF-κB activation via its C-terminal zinc-finger 7 (ZF7) domain.

A20 (Tnfaip3) deficiency in myeloid cells protects against influenza A virus infection.

The innate immune response provides the first line of defense against viruses and other pathogens by responding to specific microbial molecules. Influenza A virus (IAV) produces double-stranded RNA as an intermediate during the replication life cycle, which activates the intracellular pathogen recognition receptor RIG-I and induces the production of proinflammatory cytokines and antiviral interferon. Understanding the mechanisms that regulate innate immune responses to IAV and other viruses is of key importance to develop novel therapeutic strategies.

Regulation of TNF-induced NF-κB activation by different cytoplasmic ubiquitination events.

TNF is a multifunctional cytokine that plays a key role in innate immunity by inducing the expression of a variety of genes that are involved in an inflammatory response. TNF-induced NF-κB activation is one of the best studied signaling pathways in mammalian cells and has recently led to a revival of research in the biology of ubiquitin. Many NF-κB signaling proteins are modified by specific ubiquitin ligases with different types of ubiquitin chains that are recognized by other proteins and which determine the outcome of ubiquitination.

Linear ubiquitination in NF-κB signaling and inflammation: What we do understand and what we do not.

Despite its small size, ubiquitin is one of the most versatile signaling molecules in the cell and affects distinct cellular processes. It forms the building block of a repertoire of posttranslational modifications of cellular proteins, ranging from the attachment of a single ubiquitin to ubiquitin chains of different linkage. Proteins that contain ubiquitin chain-specific ubiquitin-binding domains recognize different types of ubiquitination and determine the mode of signaling of modified proteins.

TAX1BP1, a ubiquitin-binding adaptor protein in innate immunity and beyond.

The innate immune system senses and protects against invading microorganisms and endogenous danger signals by triggering inflammatory and antimicrobial responses. However, dysregulation of these pathways, which involve the transcription factors nuclear factor-κB (NF-κB) and interferon regulatory factor (IRF) 3, can lead to severe inflammatory diseases. Tax1-binding protein 1 (TAX1BP1) plays a key role in the negative regulation of NF-κB and IRF3 signaling by acting in concert with the ubiquitin-editing enzyme A20.

Expression, biological activities and mechanisms of action of A20 (TNFAIP3).

A20 (also known as TNFAIP3) is a cytoplasmic protein that plays a key role in the negative regulation of inflammation and immunity. Polymorphisms in the A20 gene locus have been identified as risk alleles for multiple human autoimmune diseases, and A20 has also been proposed to function as a tumor suppressor in several human B-cell lymphomas. A20 expression is strongly induced by multiple stimuli, including the proinflammatory cytokines TNF and IL-1, and microbial products that trigger pathogen recognition receptors, such as Toll-like receptors.

ABINs: A20 binding inhibitors of NF-kappa B and apoptosis signaling.

ABINs have been described as three different proteins (ABIN-1, ABIN-2, ABIN-3) that bind the ubiquitin-editing nuclear factor-kappaB (NF-kappaB) inhibitor protein A20 and which show limited sequence homology. Overexpression of ABINs inhibits NF-kappaB activation by tumor necrosis factor (TNF) and several other stimuli. Similar to A20, ABIN-1 and ABIN-3 expression is NF-kappaB dependent, implicating a potential role for the A20/ABIN complex in the negative feedback regulation of NF-kappaB activation.

Cellular expression of A20 and ABIN-3 in response to Toll-like receptor-4 stimulation.

Although Toll-like receptor (TLR)-induced expression of several proinflammatory genes is required to provoke an efficient immune response, excessive or prolonged activation of TLR signaling can contribute to the development of septic shock and several inflammatory diseases. Given this inherent danger of unrestrained TLR signaling to the organism, it is not surprising that many negative feedback mechanisms have evolved to hold TLR signaling in check. In this context, TLR stimulation induces several negative regulators of TLR-induced signaling to nuclear factor (NF)-kappaB dependent gene expression.

A20: central gatekeeper in inflammation and immunity.

Inappropriate functioning of the immune system is linked to immune deficiency, autoimmune disease, and cancer. It is therefore not surprising that intracellular immune signaling pathways are tightly controlled. One of the best studied transcription factors in immune signaling is NF-kappaB, which is activated by multiple receptors and regulates the expression of a wide variety of proteins that control innate and adaptive immunity.

Smurf2 is a TRAF2 binding protein that triggers TNF-R2 ubiquitination and TNF-R2-induced JNK activation.

TRAF2 plays a central role in TNF-induced signalling to NF-kappaB and JNK/p38 MAPK. To better understand the molecular mechanisms that mediate this dual function of TRAF2, we performed a yeast two-hybrid screening for TRAF2 interacting proteins using the Sos recruitment system. This resulted in the identification of the E3 ubiquitin ligase Smurf2 as a TRAF2 binding protein.

Expression of the NF-kappaB inhibitor ABIN-3 in response to TNF and toll-like receptor 4 stimulation is itself regulated by NF-kappaB.

Although the nuclear factor-kappaB (NF-kappaB)-dependent gene expression is critical to the induction of an efficient immune response to infection or tissue injury, excessive or prolonged NF-kappaB signalling can contribute to the development of several inflammatory diseases. Therefore, the NF-kappaB signal transduction pathway is tightly regulated by several intracellular proteins. We have previously identified A20-binding inhibitor of NF-kappaB activation (ABIN)-3 as an lipopolysaccharide (LPS)-inducible protein in monocytes that negatively regulates NF-B activation in response to tumour necrosis factor (TNF) and LPS.

LIND/ABIN-3 is a novel lipopolysaccharide-inducible inhibitor of NF-kappaB activation.

Recognition of lipopolysaccharide (LPS) by Toll-like receptor (TLR)4 initiates an intracellular signaling pathway leading to the activation of nuclear factor-kappaB (NF-kappaB). Although LPS-induced activation of NF-kappaB is critical to the induction of an efficient immune response, excessive or prolonged signaling from TLR4 can be harmful to the host. Therefore, the NF-kappaB signal transduction pathway demands tight regulation.