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Alternative Tumor-Targeting Strategies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
To illustrate this therapeutic approach, two examples are provided here. The first involves the use of MMP enzymes to trigger the release of a cytotoxic agent from a liposome. In this study, researchers at Fudan University (China) utilized a short 8-mer peptide, GPVGLIGK, known to be sensitive to cleavage by MMP-2 and 9, as the basis for their drug-release trigger. They inserted this peptidic sequence as part of the chemical structure of a multi-block copolymer from which they constructed liposomes filled with the cytotoxic agent paclitaxel, a potent tubulin inhibitor (Figure 10.22). Construction of the liposomes was achieved by preparing an inverse emulsion based on poly(ethylene glycol) diacrylate (PEGDA)-based precursors and D-α-tocopheryl polyethylene glycol succinate. Polymerization was activated with N-hydroxysuccinimide leading to incorporation of GPVGLIGK as a spacer between the α-tocopherol succinate and methoxide-polyethylene glycol units to produce the MMP-sensitive block-copolymer mPEG2K-(GPVGLIGK)-α-TOS.
The Large Bowel and the Anal Canal
Published in E. George Elias, CRC Handbook of Surgical Oncology, 2020
The use of immune stimulators such as BCG with or without 5-FU was claimed to improve the survival of patients with Dukes C disease when compared with matched histological controls who were treated by surgery only.97 However, subsequent controlled studies failed to confirm these findings.98,99 In one of these studies,99 the use of methanol extraction residue (MER) of BCG with chemotherapy even decreased the survival. This is not surprising as the use of strong antigens such as BCG or MER may deviate the immune response by sensitizing the patient to the BCG rather than the weak tumor antigens. Similar negative results were seen with the use of Corynebacterium parvum.100
Neurosurgery: Functional neurosurgery
Published in Hemanshu Prabhakar, Charu Mahajan, Indu Kapoor, Essentials of Geriatric Neuroanesthesia, 2019
Suparna Bharadwaj, Christine Dy-Valdez, Jason Chui
Dexmedetomidine has emerged as an attractive alternative for DBS procedures. It has the desirable properties of having a minimal suppressive effect on MER at low doses and a minimal risk of respiratory depression. A low-dose dexmedetomidine infusion at 0.3–0.6 μg/kg/h has been successfully used during DBS in parkinsonian patients with minimal interference with MER and macrostimulation (29,30). A retrospective study of 19 patients found that dexmedetomidine provided better patient satisfaction and reduced the use of intraoperative antihypertensives compared to the absence of anesthetics during DBS (monitored anesthetic care) (29), while another retrospective study showed that the addition of dexmedetomidine to propofol did not reduce the use of antihypertensives (32). Dexmedetomidine has become the sedative agent of choice in many institutes because of its perceived benefits over other agents (31), although the evidence is limited and the number of patients in the studies are small.
MerTK-mediated efferocytosis promotes immune tolerance and tumor progression in osteosarcoma through enhancing M2 polarization and PD-L1 expression
Published in OncoImmunology, 2022
Jinti Lin, Ankai Xu, Jiakang Jin, Man Zhang, Jianan Lou, Chao Qian, Jian Zhu, Yitian Wang, Zhengming Yang, Xiumao Li, Wei Yu, Bing Liu, Huimin Tao
Mechanistically, efferocytosis includes three processes: recruitment, recognition, and phagocytosis.23,36 In the second process, several receptors on phagocytes recognize the signaling of apoptotic cells and then activate efferocytosis, which include MerTK, CD300 family, T cell immunoglobulin, and mucin domain containing 4 (TIM4), brain-specific angiogenesis inhibitor 1 (BAI1), and so on.23 The efferocytosis in osteosarcoma has rarely been studied. We identify that macrophages recognize apoptotic osteosarcoma cells by MerTK in osteosarcoma. MerTK belongs to the receptor tyrosine kinase family (Tryo3, Axl, and MerTK), which is mainly distributed on the cell surface.26 Previous papers reported that MerTK was abnormally expressed in various cancers.24,37 Our data are further strengthened by analyses of several osteosarcoma patient data sets. We find that MerTK is highly expressed in osteosarcoma, and the abnormal expression of MerTK can activate pathways of phagosome, lysosome, and endocytosis, all of which are involved in the downstream of efferocytosis. MerTK has been reported as a key target of efferocytosis and immune tolerance in multiple tumors.25,29,38 Compared to Tryo3 and Axl, MerTK is considered as the main receptor of efferocytosis.23,39 In efferocytosis, TIM4 helps to secure apoptotic cells on phagocytes, but it cannot transduce signals by itself.40
Scavenger Receptor A1 Signaling Pathways Affecting Macrophage Functions in Innate and Adaptive Immunity
Published in Immunological Investigations, 2022
Elizabeth Linares-Alcántara, Fela Mendlovic
SR-A1 has been shown to play a role in phagocytosis of different apoptotic cells, also known as efferocytosis. SR-A1 is responsible for 50% of thymocyte clearance (Platt et al. 1996). The role of SR-A1 in tolerance regulation has emerged. Systemic lupus erythematosus patients have anti-SR-A1 autoantibodies that interfere with apoptotic cell clearance in vitro (Chen et al. 2011; Wermeling et al. 2007). Mer tyrosine kinase (Mertk) is a transmembrane receptor tyrosine kinase. It is highly expressed in macrophages and DCs (Strick and Vollrath 2010) and acts as a receptor for apoptotic cells (Seitz et al. 2007). The SR-A1 and Mertk associations have been linked to macrophage's capability to phagocytize apoptotic cells, this allows inflammation to come to a resolution. Both Mertk and phospholipase C-gamma 2 (PLCγ2) were involved in phagocytic activity in J774A.1 macrophages. After exposure to apoptotic cells, SR-A1 associates with Mertk, an essential step in the phosphorylation of Mertk, and subsequently of PLCγ2 and optimal signaling for apoptotic cell phagocytosis. Thus, SR-A1 seems to be involved in the regulation of proinflammatory signals together with Mertk. Nevertheless, the absence of SR-A1 in vivo does not result in apoptotic cell clearance defects, probably due to compensatory mechanisms by other receptors (Todt et al. 2008) (Figure 3B).
MERTK retinopathy: biomarkers assessing vision loss
Published in Ophthalmic Genetics, 2021
Dhimas H. Sakti, Elisa E. Cornish, Nina Mustafic, Afsah Zaheer, Stephanie Retsas, Sulekha Rajagopalan, Clara WT Chung, Lisa Ewans, Peter McCluskey, Benjamin M. Nash, Robyn V. Jamieson, John R. Grigg
The genetic analysis in our patient cohort included one novel MERTK variant c.[648_652del] p.(Thr217Serfs*7) that was not present in ClinVar or the published literature (Table 1). The change is predicted to disrupt normal translation of MERTK. Recently, the role of MERTK has been linked to acute anterior uveitis (AAU) in a genome-wide association study (GWAS) that characterized the genetic associations of AAU, providing further evidence for a MERTK role in ocular inflammation (21,89). In our cohort, one patient presented with marked optic disc swelling and, despite extensive investigations, no cause was identified. The disc swelling preceded the symptoms and signs of retinal degeneration. This has not been reported previously in MERTK-RP patients. In view of the subsequent identification of a MERTK gene defect, the disc swelling may reflect an inflammatory contribution from defects in MERTK immune function (11,22–24,90–92). Alternatively, there may have been sub-clinical inflammation as reported for other RP patients with swollen optic discs (93–95). Disruption of photoreceptor OS and other cell death mechanisms may contribute to these inflammatory conditions (96,97). In cases of unexplained optic disc swelling, consideration should be given to investigations for an underlying uveitis or retinopathy.