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Molecular Drivers in Lung Adenocarcinoma: Therapeutic Implications
Published in Surinder K. Batra, Moorthy P. Ponnusamy, Gene Regulation and Therapeutics for Cancer, 2021
Imayavaramban Lakshmanan, Apar Kishor Ganti
A variety of targeted agents against RET pathways has been studied in other malignancies. These include vandetanib, cabozantinib, sunitinib, sorafenib, fostamatinib and ponatinib with good response, especially in RET mutated tumors [73]. However, studies with RET inhibitors in NSCLC are lacking. Vandetanib has been shown to have some in vitro activity against cancer cells with RET rearrangements [74]. Gautschi et al. described a case of lung adenocarcinoma, positive for RET-KIF5B, where vandetanib was used at disease progression following chemotherapy, surgery and radiation, with the development of disease remission after four weeks of vandetanib treatment [78]. A prospective phase II trial studying the role of cabozantinib, a multi-tyrosine kinase inhibitor and a potent inhibitor of RET, in NSCLC patients with RET rearrangements also showed partial responses in two out of three cases and prolonged stable disease after eight months in the third case, with no progression of the disease reported in any of the three [77]. There are ongoing phase II trials to evaluate the efficacy of lenvatinib, vandetanib, and sunitinib in NSCLC with RET rearrangements [79].
Modern Rehabilitation Techniques for COVID-19
Published in Wenguang Xia, Xiaolin Huang, Rehabilitation from COVID-19, 2021
Ellis classified unreasonable beliefs into three kinds, namely, people’s irrational beliefs about themselves, about others, and about their surroundings and events. These unreasonable beliefs have three characteristics. First, those beliefs are too absolute. For example, “My illness must be cured, otherwise my life would become worthless!” Second, those beliefs contain over-generalization. For example, if a treatment does not work as it should, the patient would think that there is no possibility of being cured. When a person does something that does not meet their own standard of satisfaction, they think it will lead to terrible or disastrous consequences. For example, if a patient needs a tracheotomy, they may think, “Once the tracheotomy is done, my life will soon be over”. To correct patients’ irrational beliefs, the therapist can act as an active instructor to persuade and guide patients to rethink their assumptions, reasoning, and views of life that they concluded due to psychological imbalance. Ellis noted that successful therapy involves changing not only the way people deal with problem but also their behavior. For that reason, the therapist can give the patients homework, asking them to do something that contributes to developing a reasonable outlook on life. RET can help patients deal with anxiety, depression, fear, and interpersonal problems from both cognitive and behavioral perspectives.
Endocrine and Neuroendocrine Tumors
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Natasha Shrikrishnapalasuriyar, P.N. Plowman, Márta Korbonits, Ashley B. Grossman
RET is a transmembrane receptor protein-tyrosine kinase that is required for the development of the nervous system/neural crest and several other tissues. The mechanism of activation of RET by its glial-cell derived neurotrophic factor (GDNF) ligands requires additional GDNF family receptor-α (GFRα) co-receptors (GFRα1/2/3/4). RET point mutations have been reported in multiple endocrine neoplasia (MEN2A, MEN2B) and medullary thyroid carcinoma. RET fusion proteins have been reported in papillary thyroid and non-small cell lung adenocarcinomas. There has been much recent interest and clinical benefit from the use of the RET inhibitors in the therapy of metastatic medullary thyroid cancer. Vandetanib and cabozantinib have been licensed and are of proven efficacy; recently, a more potent agent, Blue-667, has become available and looks more promising still. This last drug has activity in the brain (of more importance in the RET-driven lung cancers than medullary carcinoma of thyroid). Side-effects such as hypertension, ECG changes, and blood test abnormalities are usually minor but close monitoring is required—as for all cancer patients on tyrosine kinase inhibitors.
An updated patent review of rearranged during transfection (RET) kinase inhibitors (2016–present)
Published in Expert Opinion on Therapeutic Patents, 2022
Rearranged during transfection (RET) is a transmembrane receptor tyrosine kinase encoded by the RET proto-oncogene located on chromosome 10. RET is integral for the development of kidneys and the enteric nervous system during embryogenesis.1 RET is expressed in neural cells and is required for proliferation, differentiation, and survival of these cells[1]. In addition, RET signaling is known to contribute to the regulation and function of hematopoietic cells and spermatogenesis [2,3]. The structure of RET (Figure 1) is similar to other receptor tyrosine kinases, and consists of an intracellular tyrosine kinase domain, a transmembrane domain, and an extracellular domain with four cadherin-like domains and a conserved cysteine region (C609, C611, C618, C620, C630, and C640)[4]. This cysteine region plays a key role in protein conformation and ligand binding [5,6]. RET activating ligands belong to the glial-cell derived neurotrophic factor (GDNF) family of ligands (GFLs) and include GDNF, neurturin, artemin, and persephin[7]. Ligands binds to the GDNF family receptor-α (GFR-α), which then causes dimerization of RET (Figure 1) and subsequent activation through autophosphorylation of the intracellular tyrosine kinase domain (Y687, Y752, Y806, Y809, Y826, Y900, Y905, Y928, Y981, Y1015, Y1062, and Y1062). Following autophosphorylation, multiple signaling pathways (such as PI3K, MAPK, JAK/STAT, and PKC pathways) are activated that regulate survival, differentiation, and proliferation[7].
Discovery, preclinical development, and clinical application of pralsetinib in the treatment of thyroid cancer
Published in Expert Opinion on Drug Discovery, 2022
Pietro Locantore, Roberto Novizio, Andrea Corsello, Rosa Maria Paragliola, Alfredo Pontecorvi, Salvatore Maria Corsello
Focusing on thyroid cancers, DTC (including papillary, follicular, Hürthle and poorly differentiated thyroid cancer), anaplastic thyroid cancer, and MTC [14] constitute the three main histotypes. The Cancer Genome Atlas (TCGA) shows that mutations associated with thyroid cancer mostly affect two signaling pathways: mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3 kinase (PI3K) pathways. When a somatic or a germline mutation affects these pathways at any step, it constitutively activates the downstream signaling, causing uncontrolled cell replication, loss of differentiation, and inhibition of apoptosis. In thyroid cancers, altered RET proto-oncogene codes for a constitutively activate TK-R [15,16] with subsequent activation of MAPK and PI3K pathways, therefore assuming an important driver role in the genesis and progression of the tumor [16–18]. 10–20% of PTC are characterized by rearrangements of RET gene, while for MTC two forms can be distinguished: sporadic (~80%) with 40%–50% of cases associated to somatic RET point mutations and hereditary (~20%), with ~95% of cases associated to RET germline point mutations. Ret germline mutation can also account for multiple endocrine neoplasia (MEN) type 2.
Reticulocyte Hemoglobin Equivalent (Ret-He) Combined with Red Blood Cell Distribution Width Has a Differentially Diagnostic Value for Thalassemias
Published in Hemoglobin, 2019
Yu Lian, Jun Shi, Neng Nie, Zhendong Huang, Yingqi Shao, Jing Zhang, Jinbo Huang, Xingxin Li, Meili Ge, Peng Jin, Min Wang, Yizhou Zheng
Reticulocyte Hb equivalent (Ret-He), a new hematological parameter in routine blood assays, can play a critical role in the differential diagnosis of microcytic hypochromic anemia. Due to the shorter lifespan of reticulocytes, Ret-He seems to be a good assessment of erythropoiesis activity and iron availability [4]. Moreover, the detection of Ret-He data requires only several microliters of peripheral blood, which is easily available and convenient to operate. A few studies have assessed the value of Ret-He in the auxiliary diagnosis of thalassemia trait, iron deficiency anemia and chronic diseases in both adults and children [5–9]. However, little is known about the utilization of Ret-He in the discrimination between thalassemia trait, CSA and typical microcytic anemia, iron deficiency anemia. In this study, we aimed to evaluate the efficacy of Ret-He combined with red blood cell (RBC) distribution width (RDW) between thalassemia trait, CSA and iron deficiency anemia, all of which present with microcytic hypochromic anemia, and further explore the best cutoff value in the discrimination of these conditions.