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Adult Ocular and Orbital (Ocular Adnexa) Tumors
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
P.N. Plowman, Rachel Lewis, J.L. Hungerford
It has long been recognized that cytogenetics can be prognostic in uveal melanoma, and loss of chromosome 3 (monosomy 3) is associated with poor prognosis. More recently, it has been realized that the biology of uveal melanoma differs from that of cutaneous melanoma. The vast majority (85–95%) of uveal melanoma is characterized by activating mutations in genes encoding the G-protein-alpha subunits GNAQ or GNA11, which lead to stimulation of the MAPK and phosphatidylinositol 3-kinase (PI3K)/Akt pathways,13–15 as well as the transcriptional co-activator Yes-associated protein 1 (YAP1) through the Trio-Rho/Rac signaling circuit. Additional mutations mutually exclusive to those in GNAQ/11 have been identified in phospholipase C β4 (PLCB4) and the G-protein coupled receptor cysteinyl leukotriene receptor 2 (CYSLTR2), affirming the importance of the G-alpha signaling pathway in uveal melanoma.
Profiling plasma extracellular vesicle by pluronic block-copolymer based enrichment method unveils features associated with breast cancer aggression, metastasis and invasion
Published in Journal of Extracellular Vesicles, 2018
Zhenyu Zhong, Matthew Rosenow, Nick Xiao, David Spetzler
Almost half of the proteins that are highly enriched by F68 method (122 out of 263) were not able to match the categories described in Figure 3(C), further studies might be necessary to illustrate whether these proteins are cargos that are packaged by either specific or non-specific means into EVs other than through the EV biogenesis pathway. Interestingly, most of these proteins belong to three sub-categories, including integral components of membrane, cytoplasm (cytosol) and nucleus proteins. The integral components of membrane include those proteins that might involve in interaction with the membrane bound receptor signalling cascades, such as C-C chemokine receptor type 8 (CCR8), cysteinyl leukotriene receptor 2 (CYSLTR2), probable G-protein coupled receptor 151 (GPR151), ATP-binding cassette sub-family G member 5 (ABCG5); a lot of proteins were identified as cytoplasm/cytosol and nucleus proteins with RNA/DNA binding capability, including YTH domain-containing family protein 1 (YTHDF1), cysteine/serine-rich nuclear protein 1 (CSRNP1), PHD finger protein 21A (PHF21A), RNA-binding protein 42 (RBM42), zinc finger protein (ZFAT), transducin-like enhancer protein 1 (TLE1), homeobox-containing protein 1 (HMBOX1), single-stranded DNA cytosine deaminase (AICDA), Krueppel-like factor 17 (KLF17), which are involved in various functions from potential translation regulation, tumour suppressor to transcription factor activity. The finding is consistent with the study that reveals that transcriptional regulator proteins were highly abundant in EVs [39], the potential biological implication of such factors being highly enriched in the plasma EVs that might deserve more investigation.
Unpacking the genetic etiology of uveal melanoma
Published in Expert Review of Ophthalmology, 2020
Sophie Thornton, Helen Kalirai, Karen Aughton, Sarah E. Coupland
Mutations in cysteinyl leukotriene receptor 2 (CYSLTR2) were first described by Moore et al. in 2016, who identified a recurrent hotspot mutation encoding a p.Leu129Gln substitution in four UM lacking mutations in either GNAQ, GNA11, or PLCB4 [53]. Further analyses by the TCGA-UM study confirmed the presence of these mutations in 4% of UM [39]. Similar to GNAQ/11 mutations, CYSLTR2 mutations have also been observed in the same location in blue nevi. Leu129 is situated in a functional hub of the receptor, transmembrane helix 3, and mutations at this site lead to constitutively active Gαq, leaving the cell unresponsive to leukotriene stimulation.
Cysteinyl leukotriene induces eosinophil extracellular trap formation via cysteinyl leukotriene 1 receptor in a murine model of asthma
Published in Experimental Lung Research, 2021
Aline Andrea da Cunha, Josiane Silva Silveira, Géssica Luana Antunes, Keila Abreu da Silveira, Rodrigo Benedetti Gassen, Ricardo Vaz Breda, Paulo Márcio Pitrez
Therapeutic strategies to reduce eosinophilic inflammation in the lung have been related to a decrease in asthma symptoms.4 Eosinophils are able to release inflammatory cytokines, reactive oxygen species (ROS), cytotoxic granule, eosinophil extracellular trap (EET), and lipid mediators such as leukotrienes.5–8 Leukotrienes are synthesized from arachidonic acid through the 5-lipoxygenase pathway and play multiple roles in inflammatory disorders, such as asthma.9,10 There are two classes of leukotrienes, leukotriene B4 (LTB4) and cysteinyl leukotriene (cysLT). The LTB4 is involved in neutrophilic inflammation11,12; and cysLT induce eosinophilic inflammation.13 The stimulation of leukocytes by allergens induces the liberation of arachidonic acid from the phospholipids membrane by phospholipase A2. The 5-lipoxygenase, with the aid of the 5-lipoxygenase-activating protein (FLAP), catalyzes the conversion of arachidonic acid to 5-hydroperoxyeicosatetraenoic acid (5-HPETE) followed by the generation of leukotriene A4 (LTA4). The LTA4 can be metabolized by LTA4 hydrolase into LTB4 or it can be conjugated to glutathione by leukotriene C4 synthase (LTC4S) to LTC4, which may then be sequentially metabolized into leukotriene D4 (LTD4) and, finally, in leukotriene E4 (LTE4).9 The LTC4, LTD4, and LTE4 are cysLTs due to the presence of cysteine in their structure.14 The major cellular sources of cysLT production are eosinophils.13 In eosinophils, synthesis of cysLT occurs in perinuclear membranes and lipid bodies in the cytoplasm. There are three types of cysLT receptors: cysteinyl leukotriene receptor 1 (cysLT1), cysteinyl leukotriene receptor 2 (cysLT2), and cysteinyl leukotriene receptor 3 (cysLT3).15 The CysLT1 receptor is expressed on airway smooth muscle cells, eosinophils, B cells, mast cells, monocytes, and macrophages.16 Activation of cysLT1 receptor induces bronchoconstriction, mucus secretion, and airway edema in asthma.17 Moreover, there are two main therapeutic strategies to antagonize cysLT in patients with asthma. The first strategy is decreasing cysLT production by inhibiting 5-lipoxygenase or FLAP.18 The second strategy is the inhibition of cysLT1 receptor with antagonists leading to the reduction of cysLT binding on target cells.18 Thus, cysLT plays an important role in asthma pathophysiology. However, cysLT participation in the mechanism of eosinophil extracellular trap (EET) formation in asthma is not completely understood.