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Leukemias
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
BCR-ABL1-negative MPNs are a group of clonal hematological malignancies characterized by excessive accumulation of one or more myeloid cell lineages and an inherent ability to transform to AML. An important landmark in the study of MPNs was the discovery, in 2005, of the deregulated JAK2 signaling and a recurrent somatic mutation involving JAK2V617F as a pivotal phenotypic driver, and the hyperactive JAK-STAT pathway might be considered a unifying target for therapy of all classic MPNs.89–92 The next was the discovery of three further driver mutations, the thrombopoietin receptor (MPL) gene at exon 10, JAK2 exon 12, and the calreticulin (CALR) gene at exon 9, between 2006 and 2013.93–96 A third was the demonstration of safety and efficacy of INCB018424 (later named ruxolitinib), a JAK1 and JAK2 inhibitor, in myelofibrosis (MF).97
Modulating Cytolytic Responses to Infectious Pathogens
Published in Thomas F. Kresina, Immune Modulating Agents, 2020
Rebecca Pogue Caley, Jeffrey A. Frelinger
The MHC class I heavy chain (HC) and β2-microglobulin (β2M) are cotranslationally transported into the lumen of the ER. In humans, the class I heavy chain interacts with a number of chaperone proteins, including BiP and calnexin. In humans, but not mice, calnexin appears to bind free heavy chain and not the HC/β2M heterodimer [33]. In humans, this heterodimer associates with calreticulin (Figure 1). The role of calreticulin in the assembly of mouse class I is unknown. The calreticulin/ HC/βM complex binds to TAP-associated glycoprotein (Tapasin, also known as gp48K) [34,35]. Both the calreticulin and tapasin interactions in human require β2M to be bound to the heavy chain; therefore, Tapasin and calreticulin may bind to the HC/β2M heterodimer through a different site. It is unclear whether Tapasin binds alone to the calreticulin/HC/β2M complex and then binds to the TAP dimer or whether the calreticulin/HC/β2M complex binds a Tapasin/TAP complex. Either pathway causes the HC/β2M heterodimer to be located beside the point of entry of peptide into the ER lumen [34,35].
Structure, Biochemical Properties, and Biological Functions of Integrin Cytoplasmic Domains
Published in Yoshikazu Takada, Integrins: The Biological Problems, 2017
Martin E. Hemler, Jonathan B. Weitzman, Renata Pasqualini, Satoshi Kawaguchi, Paul D. Kassner, Feodor B. Berdichevsky
Immobilized KLGFFKR-peptide has been used in an affinity chromatography experiment to isolate a 60-kDa protein from a Triton-soluble cell extract prepared from human osteosarcoma cells. This 60-kDa protein, which appears to be the human equivalent of rabbit calreticulin,81 bound to purified α3 subunit, but not β1, consistent with the presence of a KXGFFKR sequence at the transmembrane/cytoplasm interface of α3 (as in most other α subunits). However, the significance of this observation remains to be determined, since in vivo p60/calreticulin is predominantly localized in the endoplasmic reticulum (ER). Further experiments will be required to verify the hypothesis that interaction of p60 with integrin α subunits might be important for the assembly of heterodimers in the ER.81
Trial watch: chemotherapy-induced immunogenic cell death in oncology
Published in OncoImmunology, 2023
Jenny Sprooten, Raquel S. Laureano, Isaure Vanmeerbeek, Jannes Govaerts, Stefan Naulaerts, Daniel M. Borras, Lisa Kinget, Jitka Fucíková, Radek Špíšek, Lenka Palová Jelínková, Oliver Kepp, Guido Kroemer, Dmitri V. Krysko, An Coosemans, Rianne D.W. Vaes, Dirk De Ruysscher, Steven De Vleeschouwer, Els Wauters, Evelien Smits, Sabine Tejpar, Benoit Beuselinck, Sigrid Hatse, Hans Wildiers, Paul M. Clement, Peter Vandenabeele, Laurence Zitvogel, Abhishek D. Garg
Finally, optimizing the detection of ICD in response to chemotherapy has also been investigated further since the last Trial Watch publication235. Zhang et al. (Chonnam National University Medical School, Hwasun, Korea) engineered calreticulin-targeting monobodies to detect ICD more accurately236. Via this method, they were able to detect surface expression in multiple cancer cell lines and in mice treated with ICD inducers. Similar to this, Kim et al. (Gyeongsang National University, Jinju, Korea) created a synthetic 18F-labeled peptide that specifically binds calreticulin237. Via this method, they were able to detect calreticulin surface exposure in mouse colon cancer tumors via a small-animal positron emission tomography (PET) scan. This staining was visible in tumors treated with multiple ICD inducers including doxorubicin, oxaliplatin, and radiation.
Targeting stearoyl-coa desaturase enhances radiation induced ferroptosis and immunogenic cell death in esophageal squamous cell carcinoma
Published in OncoImmunology, 2022
Hui Luo, Xiaohui Wang, Shuai Song, Yunhan Wang, Qinfu Dan, Hong Ge
As shown in Figure 4a, extracellular ATP release was observed in KYSE70 cells exposed to different concentrations of MF-438; after treatment with 0.25 μM, the RLU fold increased significantly compared with untreated control group. Meanwhile, radiation-induced ATP release was detected, and correlated directly with RT dose. The combined strategies resulted in an RLU increase compared with RT alone (Figure 4b). Similar results were obtained from KYSE410 cells (Figure 4c,d). These outcomes indicated radiation-induced ATP release was enhanced by MF-438. Next, we analyzed the amount of calreticulin on the surface of cancer cells. Although MF-438 failed to induce cell-surface expression of calreticulin, RT-mediated calreticulin translocation was noticed and this effect appears to occur in a dose dependent manner (Figure 4e–h). Interestingly, there was no synergistic effect between MF-438 and RT in inducing the translocation of calreticulin to cell membrane. Finally, extracellular HMGB1 was measured among the treatment groups. Similar to the results of ATP extracellular release, both MF-438 and RT contributed to the secretion of HMGB1 from tumor cells to extracellular space. The combination of RT and MF-438 resulted in enhanced HMGB1 extracellular release (Figure 4i–l).
Membrane protective role of autophagic machinery during infection of epithelial cells by Candida albicans
Published in Gut Microbes, 2022
Pierre Lapaquette, Amandine Ducreux, Louise Basmaciyan, Tracy Paradis, Fabienne Bon, Amandine Bataille, Pascale Winckler, Bernhard Hube, Christophe d’Enfert, Audrey Esclatine, Elisabeth Dubus, Marie-Agnès Bringer, Etienne Morel, Frédéric Dalle
For immunoblotting, we used the following primary antibodies: rabbit polyclonal anti-LC3B (7543) and rabbit polyclonal anti-Actin (A2066), purchased from Sigma, and the secondary antibody anti-rabbit IRDye 680RD Goat anti-Rabbit IgG (926–68071) purchased from Li-Cor. For immunofluorescence experiments, we used the primary antibodies described below. Rabbit monoclonal anti-ATG16L1 (D6D5) and rabbit monoclonal anti-Alix-1 (92880S) were purchased from Cell Signaling Technology. Rabbit polyclonal anti-LC3B (7543) was purchased from Sigma. Rabbit polyclonal anti-Candida albicans (BP-1006) was purchased from Origene. Rabbit polyclonal anti-Calreticulin (10292–1) was purchased from Proteintech. Rabbit polyclonal anti-LAMP2A (ab18528) and rabbit monoclonal anti-phospho-ATG16L1 (Ser278) (EPR19016) were purchased from Abcam. Mouse monoclonal anti-LAMP1 (H4A3) was purchased from DSHB Iowa. Mouse monoclonal anti-WIPI 2 (2A2) was purchased from Millipore. Mouse monoclonal anti-TOM20 (F-10) was purchased from Santa Cruz Biotechnology. Mouse monoclonal anti-Galectin-3 (MAB11541) was purchased from R&D systems. Mouse monoclonal anti-anti β-D-glucans (400–2) was purchased from Biosupplies. Fluorescent secondary antibodies: Alexa Fluor-conjugated anti-rabbit IgG −350, −488, and −568 and Alexa Fluor-conjugated anti-mouse IgG −350, −488, −568 were purchased from Invitrogen (A11046, A11034, A11036, A31552, A11001, A11004, and 1/500), and FITC-conjugated anti-GST antibody was purchased from Rockland.