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Academic literature on the topic 'RET Inhibitors'

Author: Grafiati

Published: 9 March 2023

Last updated: 10 March 2023

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Journal articles on the topic "RET Inhibitors"

Bhujbal, Swapnil P., Seketoulie Keretsu, and Seung Joo Cho. "Molecular Modelling Studies on Pyrazole Derivatives for the Design of Potent Rearranged during Transfection Kinase Inhibitors." Molecules 26, no. 3 (January 28, 2021): 691. http://dx.doi.org/10.3390/molecules26030691.

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RET (rearranged during transfection) kinase, one of the receptor tyrosine kinases, plays a crucial role in the development of the human nervous system. It is also involved in various cell signaling networks responsible for the normal cell division, growth, migration, and survival. Previously reported clinical studies revealed that deregulation or aberrant activation of RET signaling can cause several types of human cancer. For example, medullary thyroid carcinoma (MTC) and multiple endocrine neoplasia (MEN2A, MEN2B) occur due to sporadic mutation or germline RET mutation. A number of RET kinase inhibitors have been approved by the FDA for the treatment of cancer, such as cabozantinib, vandetanib, lenvatinib, and sorafenib. However, each of these drugs is a multikinase inhibitor. Hence, RET is an important therapeutic target for cancer drug design. In this work, we have performed various molecular modelling studies, such as molecular docking and dynamics simulation for the most active compound of the pyrazole series as RET kinase inhibitors. Furthermore, molecular mechanics Poisson–Boltzmann surface area (MM/PBSA) free energy calculation and 3-dimensional quantitative structure–activity relationship (3D-QSAR) were performed using g_mmpbsa and SYBYL-X 2.1 package. The results of this study revealed the crucial binding site residues at the active site of RET kinase and contour map analysis showed important structural characteristics for the design of new highly active inhibitors. Therefore, we have designed ten RET kinase inhibitors, which showed higher inhibitory activity than the most active compound of the series. The results of our study provide insights to design more potent and selective RET kinase inhibitors.

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Kim, Dong Wook, Young Suk Jo, Hye Sook Jung, Hyo Kyun Chung, Jung Hun Song, Ki Cheol Park, Su Hyeon Park, et al. "An Orally Administered Multitarget Tyrosine Kinase Inhibitor, SU11248, Is a Novel Potent Inhibitor of Thyroid Oncogenic RET/Papillary Thyroid Cancer Kinases." Journal of Clinical Endocrinology & Metabolism 91, no. 10 (October 1, 2006): 4070–76. http://dx.doi.org/10.1210/jc.2005-2845.

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Abstract Context: The oncogenic RET/PTC tyrosine kinase causes papillary thyroid cancer (PTC). The use of inhibitors specific for RET/PTC may be useful for targeted therapy of PTC. Objective: The objective of the study was to evaluate the efficacies of the recently developed kinase inhibitors SU11248, SU5416, and SU6668 in inhibition of RET/PTC. Design: SU11248, SU5416, and SU6668 were synthesized, and their inhibitory potencies were evaluated using an in vitro RET/PTC kinase assay. The inhibitory effects of the compounds on RET/PTC were evaluated by quantifying the autophosphorylation of RET/PTC, signal transducer and activator of transcription (STAT)-3 activation, and the morphological reversal of RET/PTC-transformed cells. Results: An in vitro kinase assay revealed that SU5416, SU6668, and SU11248 inhibited phosphorylation of the synthetic tyrosine kinase substrate peptide E4Y by RET/PTC3 in a dose-dependent manner with IC50 of approximately 944 nm for SU5416, 562 nm for SU6668, and 224 nm for SU11248. Thus, SU11248 effectively inhibits the kinase activity of RET/PTC3. RET/PTC-mediated Y705 phosphorylation of STAT3 was inhibited by addition of SU11248, and the inhibitory effects of SU11248 on the tyrosine phosphorylation and transcriptional activation of STAT3 were very closely correlated with decreased autophosphorylation of RET/PTC. SU11248 caused a complete morphological reversion of transformed NIH-RET/PTC3 cells and inhibited the growth of TPC-1 cells that have an endogenous RET/PTC1. Conclusion: SU11248 is a highly effective tyrosine kinase inhibitor of the RET/PTC oncogenic kinase.

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Subbiah, Vivek, Dong Yang, Vamsidhar Velcheti, Alexander Drilon, and Funda Meric-Bernstam. "State-of-the-Art Strategies for Targeting RET-Dependent Cancers." Journal of Clinical Oncology 38, no. 11 (April 10, 2020): 1209–21. http://dx.doi.org/10.1200/jco.19.02551.

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Activating receptor tyrosine kinase RET (rarranged during transfection) gene alterations have been identified as oncogenic in multiple malignancies. RET gene rearrangements retaining the kinase domain are oncogenic drivers in papillary thyroid cancer, non–small-cell lung cancer, and multiple other cancers. Activating RET mutations are associated with different phenotypes of multiple endocrine neoplasia type 2 as well as sporadic medullary thyroid cancer. RET is thus an attractive therapeutic target in patients with oncogenic RET alterations. Multikinase inhibitors with RET inhibitor activity, such as cabozantinib and vandetanib, have been explored in the clinic for tumors with activating RET gene alterations with modest clinical efficacy. As a result of the nonselective nature of these multikinase inhibitors, patients had off-target adverse effects, such as hypertension, rash, and diarrhea. This resulted in a narrow therapeutic index of these drugs, limiting ability to dose for clinically effective RET inhibition. In contrast, the recent discovery and clinical validation of highly potent selective RET inhibitors (pralsetinib, selpercatinib) demonstrating improved efficacy and a more favorable toxicity profile are poised to alter the landscape of RET-dependent cancers. These drugs appear to have broad activity across tumors with activating RET alterations. The mechanisms of resistance to these next-generation highly selective RET inhibitors is an area of active research. This review summarizes the current understanding of RET alterations and the state-of-the-art treatment strategies in RET-dependent cancers.

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Ramesh, Priyanka, and Shanthi Veerappapillai. "Designing Novel Compounds for the Treatment and Management of RET-Positive Non-Small Cell Lung Cancer—Fragment Based Drug Design Strategy." Molecules 27, no. 5 (February 28, 2022): 1590. http://dx.doi.org/10.3390/molecules27051590.

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Rearranged during transfection (RET) is an oncogenic driver receptor that is overexpressed in several cancer types, including non-small cell lung cancer. To date, only multiple kinase inhibitors are widely used to treat RET-positive cancer patients. These inhibitors exhibit high toxicity, less efficacy, and specificity against RET. The development of drug-resistant mutations in RET protein further deteriorates this situation. Hence, in the present study, we aimed to design novel drug-like compounds using a fragment-based drug designing strategy to overcome these issues. About 18 known inhibitors from diverse chemical classes were fragmented and bred to form novel compounds against RET proteins. The inhibitory activity of the resultant 115 hybrid molecules was evaluated using molecular docking and RF-Score analysis. The binding free energy and chemical reactivity of the compounds were computed using MM-GBSA and density functional theory analysis, respectively. The results from our study revealed that the developed hybrid molecules except for LF21 and LF27 showed higher reactivity and stability than Pralsetinib. Ultimately, the process resulted in three hybrid molecules namely LF1, LF2, and LF88 having potent inhibitory activity against RET proteins. The scrutinized molecules were then subjected to molecular dynamics simulation for 200 ns and MM-PBSA analysis to eliminate a false positive design. The results from our analysis hypothesized that the designed compounds exhibited significant inhibitory activity against multiple RET variants. Thus, these could be considered as potential leads for further experimental studies.

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Marcello, Krista, Marcia S. Brose, Taofeek K. Owonikoko, Karen L. Reckamp, Laura J. Tafe, Rachael Andrie, and Kevin Obholz. "Clinical application of precision medicine among oncologists: A case study in RET-targeted therapy." Journal of Clinical Oncology 40, no. 16_suppl (June 1, 2022): e18705-e18705. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.e18705.

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e18705 Background: Precision medicine has revolutionized cancer care across multiple tumor types and new actionable biomarkers and targeted therapies are emerging at an unprecedented pace, creating myriad opportunities to optimize care and mitigate the often-dire sequelae of traditional cancer therapy. Many oncology healthcare professionals (HCPs) in practice are not employing optimal testing methodologies to detect biomarkers in patients who could benefit from novel targeted therapies. In this study, we analyze HCP awareness and application of RET alteration testing and integration of recently approved, new-generation selective RET inhibitors into practice for appropriate patients with NSCLC and thyroid cancer. Methods: In August 2020 HCPs were surveyed on RET alteration testing and use of RET-targeted therapeutics in their current practice. Study eligibility criteria included active HCPs in an oncology, pulmonology, or pathology practice. A curriculum of live and online educational activities was then developed for any interested oncologists and pathologists on RET alteration testing and/or targeted therapy for RET-altered lung and thyroid cancers. These activities included case studies, polling, and evaluations that provided additional insight on self-identified practice trends. In June 2021, at the completion of the educational program, eligible HCPs were surveyed again on RET alteration testing and selection of RET inhibitor therapy for appropriate patients. Results: In August 2020, 123 practicing HCPs completed the initial survey and 33% were testing patients for RET gene alterations and 18% were aware of the most sensitive testing assay for detection of RET fusions. 25% and 7%, respectively, were aware of the current indications for RET inhibitors in RET fusion–positive NSCLC and RET-altered thyroid cancer. Self-identified practice trends identified among the unselected cohort of 12,537 individual HPCs participating in the educational activities also demonstrated similar lack of appropriate testing for RET alterations and use of RET inhibitors. In June 2021, 60 practicing HCPs completed the follow-up survey and 40% were testing patients for RET gene alterations and 25% were aware of the most sensitive testing assay for detection of RET fusions. 52% and 22%, respectively, were aware of the current indications for RET inhibitors in RET fusion–positive NSCLC and RET-altered thyroid cancer. Conclusions: The rate of broad testing for RET alterations across patients with NSCLC and thyroid cancer remains low and many HCPs lack understanding of when to consider treating with a RET inhibitor. These results underscore the lag in adoption of optimal precision medicine approaches in oncology and the need for expert guidance and educational activities to optimize individualized, biomarker-driven treatment approaches for patients with cancer.

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Gild, Matti L., Iñigo Landa, Mabel Ryder, Ronald A. Ghossein, Jeffrey A. Knauf, and James A. Fagin. "Targeting mTOR in RET mutant medullary and differentiated thyroid cancer cells." Endocrine-Related Cancer 20, no. 5 (July 4, 2013): 659–67. http://dx.doi.org/10.1530/erc-13-0085.

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Inhibitors of RET, a tyrosine kinase receptor encoded by a gene that is frequently mutated in medullary thyroid cancer, have emerged as promising novel therapies for the disease. Rapalogs and other mammalian target of rapamycin (mTOR) inhibitors are effective agents in patients with gastroenteropancreatic neuroendocrine tumors, which share lineage properties with medullary thyroid carcinomas. The objective of this study was to investigate the contribution of mTOR activity to RET-induced signaling and cell growth and to establish whether growth suppression is enhanced by co-targeting RET and mTOR kinase activities. Treatment of the RET mutant cell lines TT, TPC-1, and MZ-CRC-1 with AST487, a RET kinase inhibitor, suppressed growth and showed profound and sustained inhibition of mTOR signaling, which was recapitulated by siRNA-mediated RET knockdown. Inhibition of mTOR with INK128, a dual mTORC1 and mTORC2 kinase inhibitor, also resulted in marked growth suppression to levels similar to those seen with RET blockade. Moreover, combined treatment with AST487 and INK128 at low concentrations suppressed growth and induced apoptosis. These data establish mTOR as a key mediator of RET-mediated cell growth in thyroid cancer cells and provide a rationale for combinatorial treatments in thyroid cancers with oncogenic RET mutations.

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Drilon, Alexander, Jun Zhong, Ying Lu, Yongbo Liu, Hao Wang, Minchun Chen, Xiaohu Chen, John Zhu, Shun Lu, and Vivek Subbiah. "Abstract 5363: The preclinical selectivity and activity of APS03118, a highly selective and potent next-generation RET inhibitor." Cancer Research 82, no. 12_Supplement (June 15, 2022): 5363. http://dx.doi.org/10.1158/1538-7445.am2022-5363.

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Abstract Backgroud: Oncogenic RET is an actionable target across a variety of cancers. Selective RET inhibitors selpercatinib and pralsetinib were recently approved by the FDA and EMA for patients with RET-dependent NSCLC and thyroid cancers. The solvent front mutations (SFMs) RET G810C/S/R have been identified as mechanisms of acquired resistance to both drugs. The gatekeeper RET V804 mutation cannot be inhibited by selected next-generation RET inhibitors in development. APS03118 is a novel next-generation RET inhibitor which is potent against a range of RET fusions and mutations including both SFMs and gatekeeper mutations. Methods: The selectivity, anti-RET activity, and intracranial efficacy of APS03118 were confirmed in vitro and in vivo in a variety of RET-dependent tumor models. Results: APS03118 was highly selective against a panel of 468 kinases and demonstrated 130-fold selectivity over VEGFR-2. In enzymatic assays, APS03118 showed low nanomolar potency against wild type RET and 25 RET mutations/fusions, including the inhibition of RET G810R/C/S (IC50 0.04-5 nM) and RET V804M/L/E (IC50 0.04-1 nM). APS03118 inhibited RET phosphorylation (IC50 <15 nM) in Ba/F3 engineered RET cells (WT, G810R, V804M, M918T). In cell proliferation assays, APS03118 potently inhibited KIF5B-RET Ba/F3 (WT, V804M, V804L, M918T), CCDC6-RET Ba/F3 (WT, V804M, S904F), LC2/ad (CCDC6-RET), TT (RET C634W) (IC50 < 10nM); Ba/F3 RET G810R and G810S IC50 (8-65 nM). APS03118 demonstrated marked anti-tumor efficacy in vivo in RET-driven cell-derived (Ba/F3 KIF5B-RET, V804M, TT (C634W)) and patient-derived (KIF5B-RET, CCDC6-RET, CCDC6-RET V804M) xenograft tumor models. At 10 mg/kg BID, tumor regression was observed in these xenograft models (TGI 87-108%). Tumors completely subsided in CCDC6-RET orthotopic brain model with a 100% survival rate. In the Ba/F3 KIF5B-RET G810R xenograft model, APS03118 30 mg/kg BID showed 90% TGI and was well tolerated, and RET G810 mutations often drive clinical progression on current RET inhibitors. Conclusions: APS03118 is a novel highly selective next-generation RET inhibitor that possesses potent in vitro and in vivo activity against a diverse range of RET alterations, including SFMs-mediated resistance. A first-in-human phase 1 trial for patients with RET-driven solid tumors with activating RET alterations is planned for 2022. Citation Format: Alexander Drilon, Jun Zhong, Ying Lu, Yongbo Liu, Hao Wang, Minchun Chen, Xiaohu Chen, John Zhu, Shun Lu, Vivek Subbiah. The preclinical selectivity and activity of APS03118, a highly selective and potent next-generation RET inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5363.

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Nosaki, Kaname, Shingo Matsumoto, Kiyotaka Yoh, Takaya Ikeda, Yuichiro Ohe, Masahiro Kodani, Noriko Yanagitani, et al. "Genetic profiling and the response to RET inhibitors in RET fusion positive non-small cell lung cancer (NSCLC) identified by international genomic screening project (LC-SCRUM-Asia)." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): 9557. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.9557.

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9557 Background: RET fusions are targetable oncogenic drivers in 1 – 2 % of NSCLC, yet no RET inhibitors are approved. Selective RET inhibitors, such as LOXO-292 and BLU-667, are currently in development. The impact of co-occurring mutation on outcome in RET-TKI therapy remains largely unknown. Methods: In an international genome screening project in Asia (LC-SCRUM-Asia), 161 cancer-related genes have been analyzed by a next-generation sequencing (NGS) system, Oncomine™ Comprehensive Assay. The therapeutic efficacy and survival of RET fusion+ NSCLC were evaluated using a large-scale clinicogenomic database in the LC-SCRUM-Japan. Results: From Feb 2013 to Dec 2019, a total of 7177 patients with non-squamous NSCLC were enrolled. RET fusion were detected in 167 patients (2.3 %). Median age was 61 years (range: 29 - 85), 60 % were female, 61 % were never-smokers, 99 % had adenocarcinoma, and 78 % had stage IIIB/IV disease. Based on our database, the median overall survival was 37 months. 62 patients received RET inhibitor therapy. RET fusions was identified by NGS assay (KIF5B-RET: 75, CCDC6-RET: 30, Others: 2) in 107 patients. Co-occurring genomic alterations were detected in 62 (58 %) patients, the median number of co-mutations was 1 (range 0 - 4). The most common co-occurring mutations in tumor involved TP53 (31; 29 %), STK11 (6; 6 %), CDKN2A (5; 5 %) and TSC2 (5; 5 %). In 23 patients treated with RET inhibitor (unapproved drugs), there was a strong association between co-occurring mutation and time to treatment discontinuation (TTD) in RET inhibitor therapy; HR 2.75 (95%CI 1.71 - 15.6, P = 0.0096). Conclusions: RET rearrangements continue to represent a rare but high unmet need disease. Co-occurring mutation was significantly associated with shorter TTD. Our data is the largest cohort of advanced-stage RET fusion+ NSCLC profiled by NGS to date. Co-occurring mutation should be evaluated in the development of novel targeted therapies for RET fusion+ NSCLC.

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Cascetta, Priscilla, Vincenzo Sforza, Anna Manzo, Guido Carillio, Giuliano Palumbo, Giovanna Esposito, Agnese Montanino, et al. "RET Inhibitors in Non-Small-Cell Lung Cancer." Cancers 13, no. 17 (September 1, 2021): 4415. http://dx.doi.org/10.3390/cancers13174415.

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RET rearrangements are observed in 1–2% of non-small-cell lung cancer (NSCLC) patients and result in the constitutive activation of downstream pathways normally implied in cell proliferation, growth, differentiation and survival. In NSCLC patients, RET rearrangements have been associated with a history of non-smoking, a higher rate of brain metastasis at initial diagnosis and a low immune infiltrate. Traditionally, RET fusions are considered mutually exclusive with other oncogenic drivers, even though a co-occurrence with EGFR mutations and MET amplifications has been observed. Cabozantinib, vandetanib and lenvatinib are the first multi-kinase inhibitors tested in RET-rearranged NSCLC patients with contrasting results. More recently, two selective RET inhibitors, selpercatinib and pralsetinib, demonstrated higher efficacy rates and good tolerability and they were approved for the treatment of patients with metastatic RET fusion-positive NSCLC on the bases of the results of phase II studies. Two ongoing phase III clinical trials are currently comparing selpercatinib or pralsetinib to standard first line treatments and will definitively establish their efficacy in RET-positive NSCLC patients.

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Dissertations / Theses on the topic "RET Inhibitors"

Frett, Brendan. "Discovery and Development of Novel Ret Inhibitors for the Treatment of Pervasive Malignancies." Diss., The University of Arizona, 2014. http://hdl.handle.net/10150/325495.

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Targeted cancer therapeutics represent the advent of a new therapeutic age, brought forth by the small molecule tyrosine kinase inhibitor (TKI) imatinib (Gleevec®). Imatinib is able to cause complete and sustained remissions in patients with chronic myelogenous leukemia (CML) driven by the Abelson (ABL) kinase, which caused a massive paradigm shift in how cancer is treated. The following research has been completed to extend the principles of imatinib therapy to the rearranged during transfection (RET) kinase. The RET kinase is involved in driving the pathology of medullary thyroid cancer (MTC), papillary thyroid carcinoma (PTC), certain non-small cell lung cancers (NSCLC), chronic myelomonocytic leukemia (CMML), tamoxifen resistant breast cancer, and Spitz melanoma. A heavily diverse population of solid and liquid carcinomas are driven by the RET oncogene, and patients presenting with these cancers could significantly benefit from a RET inhibitor. Previous drug discovery campaigns identified RET activity after therapeutic development for an unrelated kinase, as the case with vandetanib (Calpresa®) and cabozantinib (Cometriq®). Both agents fail to achieve dominant activity on RET and are more active on the vascular endothelial growth factor receptor 2 (VEGFR2), yet still achieve efficacy in RET driven tumors. This likely results from interrupting the oncogene cooperation between RET and VEGFR2; VEGFR2 provides the nutrients through angiogenesis that RET requires to promote proliferation and survival. We hypothesized that an equipotent RET/VEGFR2 dual inhibitor could maximize inhibiting the cooperation between RET and VEGFR2 in RET driven cancers. The inhibitor should be developed to maintain activity on all known RET mutations for treatment durability. In that case, the RET oncogene, despite mutating, will always be inhibited. Through research efforts, Pz-1 was identified as a sub-nanomolar, equipotent inhibitor of both RET (IC₅₀<0.001 µM) and VEGFR2 (IC₅₀<0.001 µM). Pz-1 was found active on every known, clinically relevant RET mutant tested at an IC₅₀≤0.001 µM. Through RET-driven xenograft models, Pz-1 was found active at an oral dose as low as 0.3 mg/kg/day.

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Myers, Samuel Harry. "Development of novel receptor tyrosine kinase inhibitors by a chemocentric approach." Thesis, University of Edinburgh, 2017. http://hdl.handle.net/1842/28769.

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In recent years, there has been a major movement in the pharmaceutical industry towards the development of molecules that selectivity inhibit a previously-validated specific target. This is referred to as target-based drug discovery. It was hoped that adopting this approach would usher in a new golden age of drug discovery. However, this has not been the case, with issues arising such as the target’s mechanism of action being poorly understood, with it not playing the expected role in the disease progression, or feedback resistance mechanisms causing the target to lose its role in the disease. In contrast to this, in the past 20 years it has been argued that developing drugs in a target-agnostic way and screening them against an expressed phenotype i.e. phenotypic drug discovery, has been more successful, despite fewer programs being run in the manner. The AXL kinase is a receptor tyrosine kinase (RTK) and a member of the TAM family, along with MER and TYRO3. AXL has long been associated with numerous types of cancer. Having been first discovered in 1991 in acute myeloid leukaemia (AML), it has gone on to be more associated with advanced solid tumours such as brain, breast, and lung, with the trend being that increased AXL correlates with a poorer prognosis for the patient. Upon the activation of AXL by the vitamin K ligand GAS6, a series of downstream pathways are activated that go on to encourage cell survival, proliferation, and migration. In addition to this, AXL has been shown to be involved in crosstalk with other kinase pathways, resulting in AXL expression being associated with chemoresistance and survival mechanisms. Despite the promising outlook for AXL inhibitors, to date only one selective AXL inhibitor, BGB324 (formally R428) has entered clinical trials, with selective AXL inhibitors being difficult to develop due to a lack of a crystal structure or a reliable homology model. To address the aforementioned issues that target-based approaches can suffer from, and due to AXL lacking a crystal structure, the work in this thesis utilised a pragmatic drug design method that started from ligands/existing scaffolds known to inhibit the target from the literature (publications, clinical trials and patents). A series of small libraries were prepared and then tested against a selected phenotype e.g. cell viability, in at least two cell types: one that expressed the target (e.g. AXL) and one that did not. Hits were optimised for potency against the desired phenotype. The compounds then went through target deconvolution (kinase screening) to confirm the target of the inhibitors. Employing this approach, we initially synthesised two small libraries of potential AXL inhibitors. The potency of these compounds was tested using cell-based phenotypic assays, by evaluating cell viability in both native and chemo-resistant breast cancer cells. These libraries were optimised through focused combinatorial synthesis and phenotypic screening, to yield a small collection of antiproliferative hits. These hits were then profiled against a panel of twelve select kinases. The first library, while giving some important structural information, did not inhibit the kinases screened in a meaningful manner. However, the second library gave several potent compounds, inhibiting AXL, FLT3, and RET, with one compound being selective for AXL. The leads from this series were optimised further, through SAR studies, gaining important structural information in order to improve potency and selectivity of the compounds. The flexibility of the phenotypic cell-based approach allowed the pursuit of FLT3 inhibitors, resulting in the synthesis of one of the most potent FLT3 inhibitors synthesised to date.

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Vargas, Carla Vaz Ferreira. "O papel dos marcadores de angiogênese no feocromocitoma." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2013. http://hdl.handle.net/10183/143794.

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Medullary thyroid carcinoma (MTC) is a rare malignant tumor originating from thyroid parafollicular C cells. This tumor accounts for 3-4% of thyroid gland neoplasias. MTC may occur sporadically or inherited. The hereditary MTC is part of syndromes of multiple endocrine neoplasia (MEN) 2A and 2B, familial medullary thyroid carcinoma (FMTC). Germline mutations of the RET (REarranged during Transfection) protooncogene cause hereditary form of cancer, whereas somatic mutations can be present in sporadic form of the disease. The RET gene encodes a receptor tyrosine kinase involved in the activation of intracellular signaling pathways leading to proliferation, growth, differentiation, migration and survival. Nowadays, the only possibility of cure for MTC patients consists of total thyroidectomy associated with lymph node dissection. Based on the knowledge of the pathogenic mechanisms of MTC, new drugs have been developed in attempt to control metastatic disease. Of these, the small-molecule tyrosine kinase inhibitors (TKIs) represent one of the most promising agents for MTC treatment and clinical trials have shown encouraging results. Hopefully, the cumulative knowledge about the targets of action of these drugs as well as TKI-associated side effects will help on choosing the best therapeutic approach in order to enhance its benefits.

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SARONNI, DAVIDE. "TYROSINE KINASE INHIBITORS IN NEUROENDOCRINE TUMORS: FROM IN VITRO TO ZEBRAFISH MODEL." Doctoral thesis, Università degli Studi di Milano, 2022. http://hdl.handle.net/2434/917967.

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(1) Background: Neuroendocrine neoplasms (NENs) are a group of tumors that arise from neuroendocrine cells throughout the body, with the lungs and gastrointestinal tract being the most common sites of origin. In patients with NENs and distant metastases, surgery is generally not curative. Although well-differentiated and low-grade NENs, classified as neuroendocrine tumors (NETs), are usually less aggressive than poorly-differentiated NENs, they can develop distant metastases in about 15% of cases. These patients require chronic medical management. However, the clinical efficacy of these treatments is limited by the low objective response rate, due to the occurrence of tumor resistance and the high biological heterogeneity of these neoplasms. (2) Research problem: We addressed this study on two rare NETs: lung neuroendocrine tumors (LNETs) and medullary thyroid carcinoma (MTC). LNETs represent about 2% of lung tumors, while MTCs are rare thyroid tumors caused by mutations in the RET proto-oncogene. Both NETs are well-differentiated neoplasms and are known to be highly vascularized. Therefore, they represent a potential target for tyrosine kinase inhibitors (TKIs) selective for receptors involved in angiogenesis. The aim of this project was to evaluate the antitumor activity of several new TKIs both in vitro, using LNETs (NCI-H727, UMC-11 and NCI-H835) and MTC (TT and MZ-CRC-1) cell lines, and in vivo, adopting a novel zebrafish xenograft model to study angiogenesis. In LNETs we tested: sulfatinib, a small molecule that inhibits the Vascular Endothelial Growth Factor Receptor (VEGFR) 1, 2, and 3, and the Fibroblast Growth Factor Receptor type 1 (FGFR1); cabozantinib, a multi-target inhibitor selective for VEGFR2, c-Met, Kit, Axl and Flt3; and axitinib, a multi-target TKI of VEGFR1, 2, 3 and Platelet-Derived Growth Factor Receptor-beta (PDGFRβ). In MTC we tested: sulfatinib; SPP86, a RET-specific inhibitor; and SU5402, an inhibitor of the FGFR1 and VEGFR2. (3) Methodology: In LNETs and MTC cells the effects of selected TKIs have been evaluated in vitro through: MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) assays, for assessing cell viability; flow-cytometer analysis, for the evaluation of cell cycle and apoptosis; and wound-healing assay, to study cell migration. In vivo we took advantage of the transgenic zebrafish line of Tg(fli1a:EGFP)y1. Through the xenotransplantation of NET cells in the subperidermal space near the subintestinal vein, we assessed the effects of TKIs on tumor-induced angiogenesis and cancer dissemination. (4) Key Results: In LNET cell lines we observed a dose-dependent decrease in cell viability after incubation with all TKIs. This effect seems to be related to the perturbation of the cell cycle and induction in apoptosis. In NCI-H727 wound healing assay showed a significant reduction in cell migration only after incubation with cabozantinib. In the zebrafish model, we found a significant reduction of the tumor-induced angiogenesis in implanted LNET cell lines after treatment with all TKIs. Cabozantinib and axitinib were more potent than sulfatinib in inhibition of angiogenesis, while cabozantinib was the most efficient in reducing cell migration from the transplantation site to the tail. In MTC cell lines, sulfatinib, SU5402 and SPP86 showed a decrease in cell viability, confirmed by the significant reduction in S phase cell population. Moreover, sulfatinib and SPP86 showed for both cell lines a significant induction of apoptosis. Sulfatinib and SPP86 inhibited the migration of TT and MZCRC-1 cells, evaluated through the wound healing assay, while SU5402 was able to inhibit migration only in TT cells. In vivo we observed a significant reduction of TT cells-induced angiogenesis in zebrafish embryos after treatment with sulfatinib and SPP86. (5) Conclusions: Despite sulfatinib resulted the most potent compound in terms of inhibition of LNET cell proliferation, cabozantinib showed in vivo the most effective impact in reducing tumor-induced angiogenesis. Cabozantinib was the only TKI able to inhibit in vivo the dissemination of implanted LNET cells. According to these data, cabozantinib could represent a potential candidate in the therapy of patients with highly vascularized LNET. In MTC cell lines, SPP86 and sulfatinib displayed a similar antitumor activity both in vitro and in vivo, suggesting a good efficacy of specific RET inhibitors (SPP86) with potentially less adverse effects than multitarget TKIs (sulfatinib). In addition, this study showed that the zebrafish model for NETs represents an innovative tool for drug screening with several advantages compared with rodent models: rapidity of procedure, animal immune suppression is not required, lower number of tumor cells for implant and the optical transparency provides a real-time monitoring of cell-stromal interactions and cancer progression in living animals.

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Lakshmanan, Aparna. "Modulation of Sodium Iodide Symporter-mediated Thyroidal Radioiodide Uptake by Small Molecule Inhibitors, Natural Plant-based Products and microRNAs." The Ohio State University, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=osu1429407914.

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Lee, David. "Age-Related Differences in In-vitro Sensitivity to Inhibition of Human Red Blood Cell Acetylcholinesterase and Plasma Butyrylcholinesterase by the Cholinesterase Inhibitors Physostigmine (PHYS), Pyridostigmine (PYR), Donepezil (DON) and Galantamine (GAL)." VCU Scholars Compass, 2009. http://scholarscompass.vcu.edu/etd/1937.

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Alzheimer’s disease (AD) is a chronic, progressive neurodegenerative disorder, characterized clinically by a progressive loss of memory, cognitive function, ability to care for oneself and psychiatric symptoms. First-line agents for the treatment of AD are ChE inhibitors (DON, GAL), whose modest clinical efficacy and the high incidence of dose-limiting toxicities limit their clinical utility. In addition to AD, ChE inhibitors (PYR) are used for other medical conditions, such as myasthenia gravis (MG). Furthermore, ChE inhibitors (PYR) are used by military personnel prophylactically if impending exposure to chemical warfare agents, e.g., soman, is suspected. The purpose of this research project was to understand the effect of age on the in-vitro sensitivity of ChE inhibitors in human RBCs and plasma. Understanding possible covariates, such as age and gender, may assist in optimizing dosing regimens of ChE inhibitors and/or developing newer ChE inhibitors with better adverse effect profiles. Plasma PHYS concentrations were measured by a validated HPLC-FD method. RBC AChE activity and plasma BuChE activity were measured by a modified Ellman’s colorimetric method using the model substrates, acetylthiocholine and butyrylthiocholine, respectively. The kinetics of RBC and plasma ChE activity followed Michaelis-Menten kinetics. Acetylthiocholine was found to be a nonselective substrate (RBC AChE Km = 73 μM; plasma BuChE Km = 117 μM); while butyrylthiocholine was a selective substrate for plasma BuChE (RBC AChE Km = 130,000 μM; plasma BuChE Km = 72 μM). For the following studies, RBC AChE activity was measured using acetylthiocholine as the substrate and plasma BuChE activity was measured using butyrylthiocholine as the substrate. This research project was performed in two parts: First, mechanistic studies of PHYS, PYR, DON and GAL, explored and determined the mechanism of in-vitro inhibition of RBC AChE and plasma BuChE inhibition, as well as the in-vitro degradation of PHYS in human whole blood, plasma and RBC. PHYS was rapidly degraded in human whole blood, RBC and plasma and followed Michaelis-Menten kinetics but its degradation clearance - scaled to whole blood clearance - was only predicted to account for 4-6% (i.e., 195-261 ml/min) of the reported total body clearance for PHYS (4500 ml/min). RBCs were responsible for 60% of the whole blood clearance while plasma accounted for 40% of the whole blood clearance. Inhibition results indicated that both PHYS and PYR were nonselective and rapid suicide ChE inactivators. PYR inactivated RBC AChE more rapidly at low concentrations and inactivated plasma BuChE more rapidly at high concentrations, but inactivated both more rapidly than PHYS. PHYS was a more potent inactivator than PYR with a Ki for RBC AChE of 0.011 μM and 0.063 μM, respectively, and 0.023 μM and 0.036 μM, respectively for plasma BuChE. DON was found to be a noncompetitive inhibitor for RBC AChE (Ki,noncomp = 114 μM), but a competitive inhibitor for plasma BuChE (Ki,comp = 213 μM). GAL was found to be a competitive inhibitor for both RBC AChE (Ki,comp = 66 μM) and plasma BuChE (Ki,comp = 358 μM). The second part involved a clinical study with ten young and nine elderly healthy subjects, balanced for gender, who donated blood for an in-vitro study in order to assess any age- and gender-related differences in in-vitro sensitivity to RBC AChE and plasma BuChE inhibition to all four ChE inhibitors. Elderly adults were found to be 2-3-fold less sensitive compared to the young adults for PHYS (BuChE Ki,pss; 0.010 and 0.015 μM, young and elderly, respectively) and PYR (AChE Ki,pss; 0.12 and 0.25 μM, young and elderly, respectively) only, while neither DON nor GAL showed any age-related differences in sensitivity. The observed differences for PHYS and PYR may be due to kinetic differences in ChE inactivation between young and aged adults, rather then a difference in binding affinities/potencies. These carbamate ChE inhibitors, presumably, have a slower decarbamoylation rate in younger adults than elderly adults, which leads to the observed difference in in-vitro sensitivity. The above in-vitro results were consistent with results of a meta-analysis: In a study by Knapp et al. (1991), young males (n=6), receiving 18 mg, 24 mg and 30 mg PHYS tablets, showed similar ex-vivo plasma BuChE sensitivity to (28 %/(ng/ml)) as the in-vitro sensitivity for young males in the current study (33 %/(ng/ml)). On the other hand, in the study by Men (2004), elderly males (n=8) and females (n=8), receiving 6.7 μg/kg PHYS as 30-minute infusion, showed similar ex-vivo RBC AChE sensitivity (12 %/(ng/ml)) as the in-vitro sensitivity for elderly subjects in the current study (9.7 %/(ng/ml)). This suggests that in-vitro measurement of ChE sensitivity is predictive of ex-vivo sensitivity in clinical studies. The study results suggest that elderly adults may require a 2-3-fold higher blood concentration than young adults to achieve the same ChE inhibition. This may explain why for epistigmine, an investigational carbamate ChE inhibitor for the treatment of AD, the maximum tolerated dose observed in young adults (40 mg single dose) was lower than for older adults (90 mg/day). Higher sensitivity in young adults prevented further dose escalation, while all elderly subjects tolerated higher doses. This research may have implications for other diseases and conditions, most notably MG and as a prophylaxis of nerve gases poisoning. As patients with MG age, they may become less sensitive to PYR, the most common symptomatic treatment for MG, and an increase in dose may be required. Further, older military personnel assigned to receive PYR, may require increased doses to achieve the targeted 10% RBC AChE inhibition, necessary to protect against nerve gas poisoning.

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Murata, Toru. "Inhibitory effect of Y-27632,a ROCK inhibitor,on progression of rat liver fibrosis in association with inactivation of hepatic stellate cells." Kyoto University, 2002. http://hdl.handle.net/2433/149343.

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Gemmill, R. J. "The passivation of aluminium in inhibited red fuming nitric acid." Thesis, University of Nottingham, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.376493.

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Nelson, Kathryn Jane. "Conditioned inhibition in the rat from incomplete reductions in reinforcement." Thesis, University of Cambridge, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.329276.

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Otto, Anne. "The protection of rosuvastatin and ramipril against the development of nitrate tolerance in the rat and mouse aorta." Doctoral thesis, Universite Libre de Bruxelles, 2006. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/210861.

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Organic nitrates, such as nitroglycerine (NTG), are widely used for their potent vasodilator capacity in the management of coronary artery disease and heart failure. Unfortunately, their beneficial effect is rapidly lost due to the development of nitrate tolerance, which is translated by an impaired vasorelaxation to NTG and an increased oxidative stress production. Although the mechanisms of the development of nitrate tolerance are still not fully elucidated, much interest has been focused in treating nitrate-receiving patients together with other drugs in order to overcome the development of nitrate tolerance. The Nitric Oxide generating enzyme, eNOS, and the superoxide anion generating enzyme, NAD(P)H oxidase, have been suggested to play a role in the development of nitrate tolerance. The aim of this study was to analyse the underlying mechanism by which ramipril, an ACE inhibitor and rosuvastatin, a new molecule of the statin class, are able to protect against the development of nitrate tolerance in the aortas isolated from rats, wild-type (wt) and eNOS-/- mice.

These results show that ramipril as well as rosuvastatin are able to protect against the development of nitrate tolerance in the wt and eNOS-/- mice aortas suggesting that eNOS is not necessary for their protective effect. The aortas from nitrate tolerant rats and mice showed a significant increase in the NAD(P)H oxidase activation compared to the aortas from the control and from the co-treated ramipril+NTG or rosuvastatin+NTG animals. In line with these findings were the results obtained by RT-PCR analysis: the mRNA expression of the different subunits of the NAD(P)H oxidase, such as gp91phox, p22phox, were significantly decreased after rosuvastatin or ramipril treatment in wt and eNOS-/- mice aortas. Apocynin, the NAD(P)H oxidase inhibitor was also able to inhibit the development of nitrate tolerance in the rat and mouse aortas.

In conclusion, these results suggest that rosuvastatin and ramipril are able to protect against the development of nitrate tolerance by counteracting the nitrate-induced oxidative stress. The mechanism of protection involves a direct interaction with the NAD(P)H oxidase pathway and seems to be completely independent of the eNOS pathway.

Doctorat en sciences pharmaceutiques
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Books on the topic "RET Inhibitors"

Patel, Sunit Mohanlal. The effects of the inhibitory amino acid gamma-aminobutyric acid (GABA) on food intake in the rat. Portsmouth: University of Portsmouth, 2003.

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Hughes, Sarah Jane. Investigation into the mechanism by which relaxin inhibits tension development in the uterus of the non-pregnant rat. Manchester: University of Manchester, 1994.

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Cheung, Hermia. Effect of dopamine depletion on D1 receptor binding in rat brain; and metabolism studies of D1 agonist R-[11C]SKF 82957 and phosphodiesterase-4 inhibitor R-[11C}rolipram. Ottawa: National Library of Canada, 2003.

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Michaud, Dominique. Recombinant Protease Inhibitors in Plants (Biotechnology Intelligence Unit). R. G. Landes, 2000.

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Allaerts, W. Involvement of Folliculo-Stellate Cells in Inhibitory Interactions in Rat Anterior Pituitary. Leuven University Press, 1989.

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Smith, Kevin Robert. Characterization of a disulfonic stilbene inhibitor binding to human red cell membranes. 1986.

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Longman, Susan Dawn. Cardiovascular studies with angiotensin converting enzyme inhibitors in the rat: Effects of arterial blood pressure and plasma and tissue angiotensin converting enzyme (ACE) activity of acute and chronic administration of ACE inhibitors in sodium deficient normotensive (NT) rats. Bradford, 1986.

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The effect of bestatin, an aminopeptidase inhibitor, in reducing ethanol consumption in the rat: Mechanism of action and clinical significance. Ottawa: National Library of Canada, 1994.

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Gitz, Dennis Corbin. The effects of the PAL inhibitor AIP on phenolic expression, growth and development, and UV-B tolerance in red cabbage and in duckweed. 1996.

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Valgimigli, Marco, and Marco Angelillis. Treatment of non-ST elevation acute coronary syndromes. Edited by Stefan James. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780198784906.003.0311.

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Treatment of patients presenting with a non-ST elevation acute coronary syndrome (NSTE-ACS) aims at immediate relief of ischaemia and the prevention of serious adverse events, including death, myocardial (re)infarction, and life-threatening arrhythmias. In NSTE-ACS, patient management is guided by risk stratification (troponin, electrocardiogram, risk scores, etc.). Treatment options include anti-ischaemic and antithrombotic drugs and coronary revascularization including percutaneous coronary interventions, or coronary artery bypass grafting. While long-term secondary prevention with aspirin monotherapy is currently the gold standard approach for all NSTE-ACS patients who tolerate the drug, additional medications on top of aspirin such as oral P2Y12 inhibitors or oral anticoagulation have been investigated across clinical trials and their long-term use should be guided by the ischaemic versus bleeding risk status of each single individual patient.

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Book chapters on the topic "RET Inhibitors"

Dahlmann, B., L. Kuehn, and H. Reinauer. "Identification of two alkaline cysteine proteinases from rat skeletal muscle." In Cysteine Proteinases and their Inhibitors, edited by Vito Turk, 133–46. Berlin, Boston: De Gruyter, 1986. http://dx.doi.org/10.1515/9783110846836-018.

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Wood, L., J. W. C. Bird, G. Yorke, and F. J. Roisen. "Chicken and rat muscle cystatins and their localization in cultured myoblasts." In Cysteine Proteinases and their Inhibitors, edited by Vito Turk, 667–84. Berlin, Boston: De Gruyter, 1986. http://dx.doi.org/10.1515/9783110846836-063.

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Samejima, T., H. Kaji, and A. Takeda. "The interaction of papain molecule with thiol proteinase inhibitors from newborn rat epidermis." In Cysteine Proteinases and their Inhibitors, edited by Vito Turk, 561–68. Berlin, Boston: De Gruyter, 1986. http://dx.doi.org/10.1515/9783110846836-052.

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Yamamoto, K., and Y. Kato. "Comparison of characteristics and drug-induced modifications of rat spleen cathepsins B and H." In Cysteine Proteinases and their Inhibitors, edited by Vito Turk, 79–88. Berlin, Boston: De Gruyter, 1986. http://dx.doi.org/10.1515/9783110846836-013.

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Fukuyama, K., S. Toku, S. Nakano, and W. L. Epstein. "Distribution and solubilization of a high molecular weight cysteine proteinase inhibitor from rat epidermis." In Cysteine Proteinases and their Inhibitors, edited by Vito Turk, 685–92. Berlin, Boston: De Gruyter, 1986. http://dx.doi.org/10.1515/9783110846836-064.

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Grüllich, Carsten. "Cabozantinib: A MET, RET, and VEGFR2 Tyrosine Kinase Inhibitor." In Recent Results in Cancer Research, 207–14. Berlin, Heidelberg: Springer Berlin Heidelberg, 2014. http://dx.doi.org/10.1007/978-3-642-54490-3_12.

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Sueiras-Diaz, Javier, D. Michael Jones, D. Michael Evans, Michael Szelke, Brenda J. Leckie, Sheila R. Beattie, Elisabeth C. H. Wallace, and James J. Morton. "Potent in vivo inhibitors of rat renin." In Peptides, 510–11. Dordrecht: Springer Netherlands, 1988. http://dx.doi.org/10.1007/978-94-010-9595-2_153.

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Gauthier, F., T. Moreau, N. Gutman, A. El Moujahed, and F. Esnard. "Inhibition of cathepsins B, H and L by rat thiostatin, the circulating α1 cysteine proteinase inhibitor, and by an active fragment." In Cysteine Proteinases and their Inhibitors, edited by Vito Turk, 719–28. Berlin, Boston: De Gruyter, 1986. http://dx.doi.org/10.1515/9783110846836-067.

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Grüllich, Carsten. "Cabozantinib: Multi-kinase Inhibitor of MET, AXL, RET, and VEGFR2." In Recent Results in Cancer Research, 67–75. Cham: Springer International Publishing, 2018. http://dx.doi.org/10.1007/978-3-319-91442-8_5.

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Nieto-Sampedro, M., F. F. Santos-Benito, and A. Ramón-Cueto. "Rat Brain Astrocyte Mitogen Inhibitors and Glial Reaction." In Brain Repair, 155–66. London: Macmillan Education UK, 1990. http://dx.doi.org/10.1007/978-1-349-11358-3_12.

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Conference papers on the topic "RET Inhibitors"

Schubert, Laura, Anh T. Le, Andrea E. Doak, and Robert C. Doebele. "Abstract 1842: Novel KIF5B-RET+ NSCLC cell lines demonstrate differential responses to RET inhibitors." In Proceedings: AACR Annual Meeting 2018; April 14-18, 2018; Chicago, IL. American Association for Cancer Research, 2018. http://dx.doi.org/10.1158/1538-7445.am2018-1842.

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Raman, Renuka, Jacques Villefranc, Timothy Ullmann, Jessica Thiesmeyer, Viviana Anelli, Chantal Pauli, Rohan Bareja, et al. "Abstract 1434: Uncovering the mechanism of adaptive resistance to RET inhibitors in RET rearranged thyroid cancer." In Proceedings: AACR Annual Meeting 2021; April 10-15, 2021 and May 17-21, 2021; Philadelphia, PA. American Association for Cancer Research, 2021. http://dx.doi.org/10.1158/1538-7445.am2021-1434.

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Rahal, Rami, Erica K. Evans, Wei Hu, Michelle Maynard, Paul Fleming, Lucian DiPietro, Joseph L. Kim, et al. "Abstract 2641: The development of potent, selective RET inhibitors that target both wild-type RET and prospectively identified resistance mutations to multi-kinase inhibitors." In Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LA. American Association for Cancer Research, 2016. http://dx.doi.org/10.1158/1538-7445.am2016-2641.

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Hegde, Aparna, Le Huang, Shuang Liu, Kenneth Hess, Maria Cabanillas, Mimi Hu, Naifa Busaidy, et al. "Abstract 4997: Responsiveness to immune checkpoint inhibitors in RET dependent cancers." In Proceedings: AACR Annual Meeting 2019; March 29-April 3, 2019; Atlanta, GA. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1538-7445.sabcs18-4997.

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Huang, Jui-wen, Ching-Huai Ko, Ting-Shou Chen, On Lee, Hsiang-Wen Tseng, Yuan-Jang Tsai, Chih-Peng Liu, Yen-Chun Chen, Ling-Mei Wang, and Chrong-Shiong Hwang. "Abstract 728: Development of pharmacophore-based RET inhibitors for thyroid cancer therapy." In Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC. American Association for Cancer Research, 2010. http://dx.doi.org/10.1158/1538-7445.am10-728.

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Brandhuber, Barbara J., Nisha Nanda, Julia Haas, Karyn Bouhana, Lance Williams, Shannon Winski, Michael Burkard, et al. "Abstract B192: Identification and characterization of highly potent and selective RET kinase inhibitors for the treatment of RET-driven cancers." In Abstracts: AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; November 5-9, 2015; Boston, MA. American Association for Cancer Research, 2015. http://dx.doi.org/10.1158/1535-7163.targ-15-b192.

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Kolakowski, Gabrielle R., Erin D. Anderson, Joshua A. Ballard, Barbara J. Brandhuber, Kevin R. Condroski, Eliana B. Gomez, Thomas C. Irvin, et al. "Abstract 1464: Pre-clinical characterization of potent and selective next-generation RET inhibitors." In Proceedings: AACR Annual Meeting 2021; April 10-15, 2021 and May 17-21, 2021; Philadelphia, PA. American Association for Cancer Research, 2021. http://dx.doi.org/10.1158/1538-7445.am2021-1464.

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Liu, Xuan, Tao Shen, Qingling Huang, Teng Peng, Frank Hilberg, Jianfeng Cai, Blaine H. Mooers, and Jie Wu. "Abstract 2117: Different sensitivities of four protein tyrosine kinase inhibitors towards drug-resistant RET mutations." In Proceedings: AACR Annual Meeting 2019; March 29-April 3, 2019; Atlanta, GA. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1538-7445.sabcs18-2117.

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Reports on the topic "RET Inhibitors"

Kang, Jing, Jun Zhang, Zongsheng Tian, Ye Xu, Jiangbi Li, and Mingxina Li. The efficacy and safety of immune-checkpoint inhibitor plus chemotherapy versus chemotherapy for non-small cell lung cancer: an updated systematic review and meta-analysis. INPLASY - International Platform of Registered Systematic Review and Meta-analysis Protocols, May 2022. http://dx.doi.org/10.37766/inplasy2022.5.0156.

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Review question / Objective: Population: histologically confirmed advanced NSCLC patients; Intervention: received immune-checkpoint inhibitor plus chemotherapy; Comparison:received chemotherapy; Outcome: reported OS, PFS, ORR and TRAEs; Study design: RCT. Condition being studied: Lung cancer is the primary cause of cancer-related deaths, with an estimated 2.20 million new cases and 1.79 million deaths every year, and 85% of all primary lung cancers are non-small cell lung cancer. Eligibility criteria: Studies were considered eligible if they met the following criteria: (1) being an randomized controlled trial published in English, (2) histologically confirmed advanced NSCLC patients, (3) reported OS, PFS, ORR and TRAEs, (4) the intervention group received immune-checkpoint inhibitor plus chemotherapy, while the control group received chemotherapy, (5) When numerous papers reporting the same trial were found, the most current or most complete publications were chosen. The following were the exclusion criteria: (1) duplicate articles, (2) reviews, meta-analyses, case reports, editorials and letters, (3) molecular biology or animal research, (4) retrospective or prospective observational cohort studies.

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Song, Yaowen, Shuiyu Lin, Jun Chen, Silu Ding, and Jun Dang. First-line treatment with TKI plus brain radiotherapy vs TKI alone in EGFR-mutated non-small-cell lung cancer with brain metastases: a systematic review and meta-analysis. INPLASY - International Platform of Registered Systematic Review and Meta-analysis Protocols, January 2023. http://dx.doi.org/10.37766/inplasy2023.1.0013.

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Review question / Objective: It remains uncertain whether first-line treatment with upfront brain radiotherapy (RT) in combination with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) is superior to EGFR-TKIs alone in EGFR-mutated non-small-cell lung cancer with newly diagnosed brain metastases (BMs). We performed a meta-analysis to address this issue. Condition being studied: Brain radiotherapy (RT) has been shown to damage the blood-brain barrier (BBB) and improve the concentration of EGFR-TKIs in the CSF. Additionally, RT can result in a reduction of EGFR-TKIs resistance. Therefore, EGFR-TKIs in combination with brain RT should be more effective than EGFR-TKIs alone theoretically. However, results from retrospective studies are inconsistent. There is the possibility that patients characteristics or brain RT technique affect the efficacy of treatments. To date, there is still no randomized controlled trials (RCTs) comparing the two treatment strategies.

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Wu, Xiaoqi, Jisen Zhao, Maoxia Fan, and Dongo Guo. Quality of Evidence Supporting the Effects of Xinmailong injection in Heart Failure: An Overview of Systematic Reviews and Meta-Analyses. INPLASY - International Platform of Registered Systematic Review and Meta-analysis Protocols, October 2022. http://dx.doi.org/10.37766/inplasy2022.10.0023.

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Review question / Objective: 2.1.1 type of research SRs/MAs of RCT (randomized controlled trial) of Xinmailong injection for the treatment of heart failure. 2.1.2 Subject investigated All included patients met internationally recognized diagnostic criteria for heart failure.There are no limitations on age, gender, ethnicity, time of onset, source of cases and language of publication. 2.1.3 Type of Intervention The control group was treated with conventional basic Western medicine recommended by the guidelines related to heart failure[1, 11], including antiplatelet drugs, anticoagulants, vasodilators, beta-blockers,ACEI (angiotensin-converting enzyme inhibitors), lipid-lowering drugs, and diuretic agents. and other drug treatment. The intervention group was given Xinmailong injection on the basis of the control group.

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Liu, Miao, Hongan Wang, Jing Lu, Zhiyue Zhu, Chaoqun Song, Ye Tian, Xinzhi Chen, et al. Vitamin D supplementation in the treatment of Myasthenia Gravis A protocol for a systematic review and meta-analysis. INPLASY - International Platform of Registered Systematic Review and Meta-analysis Protocols, September 2022. http://dx.doi.org/10.37766/inplasy2022.9.0129.

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Review question / Objective: The patients should meet the internationally recognized diagnostic criteria for myasthenia gravis and be definitely diagnosed as myasthenia gravis, excluding MG patients caused by congenital, drug and other factors, as well as patients with serious primary diseases, autoimmune diseases or mental diseases. Patients are not restricted by race, region, gender, age, background, course of disease and other factors. We will focus on trials using vitamin D as an intervention at any dose and in any regimen (eg daily/weekly/monthly intake). The control group was routinely given western medicine, including cholinesterase inhibitors, glucocorticoids, immunosuppressants, alone or in combination, or placebo. The intervention group was treated with vitamin D on the basis of western medicine treatment in the control group. The specific dosage form and dose were not limited, and the shortest course of treatment should be 4 weeks. Main outcome measures: (1) Quantitative score of myasthenia gravis (QMG); (2) Recurrence rate; (3) Effective. Secondary outcome measures: (1) The level of serum acetylcholine receptor antibody (AchRab); (2) The levels of inflammatory factors such as IL-6 and IL-10; (3) Clinical absolute score; (4) TCM syndrome score scale; (5) Quality of life score (QOL); (6) Incidence rate of adverse events. All randomized controlled trials (RCT) literatures from the establishment to September 2022 were retrieved and classified.

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Friedlander, Michael, Clinton Dawes, and Y. (Joel) Kashman. The Interaction between Epiphytes and Seaweeds. United States Department of Agriculture, June 1995. http://dx.doi.org/10.32747/1995.7571355.bard.

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Two Israeli laboratories (IOLR and TAU) cooperated with one American laboratory (USF) in the research of the interaction between epiphytes (Ulva sp.) and the cultivated seaweed (Gracilaria sp.) The main objectives included the following aspects: Structural aspects, effects of different irradiances on growth, sensitivity studies, allelopathic excretions, selective chemicals and integration of studies of epiphytization. The studies were operated in outdoor tanks, indoor growth chambers and in the lab. The main conclusions and their relevance for mariculture are as following: 1. The green algal epiphyte, does penetrate its red algal host. 2. Gracilaria spp. in monoculture released more halogenated hydrocarbons than in biculture with U lactuca, whereas other metabolic parameters did not show a discriminating effect in biculture. 3. Hydrogen peroxide and halogenated hydrocarbons could be a part of the effective excretion compounds in biculture. 4. The presence of mature Gracilaria inhibited the growth of U. lactuca sporelings. 5. G. conferta is most sensitive to epiphytes among Gracilaria species tested. 6. The use of green light can enhance growth in basiphytes but inhibit epiphytes. 7. Effective selectivity has been defined by the use of hydrogen hypochlorite. 8. It may be more profitable in seaweed mariculture to select for epiphyte resistant strains than to search for inhibitors of epiphytization. 9 It is important as well to examine how the basiphyte may be able to prevent penetration. 10. Definition of the effective excretions in biculture has still to be done.

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Bostock, Richard M., Dov Prusky, and Martin Dickman. Redox Climate in Quiescence and Pathogenicity of Postharvest Fungal Pathogens. United States Department of Agriculture, May 2003. http://dx.doi.org/10.32747/2003.7586466.bard.

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Monilinia fructicola causes brown rot blossom blight and fruit rot in stone fruits. Immature fruit are highly resistant to brown rot but can become infected. These infections typically remain superficial and quiescent until they become active upon maturation of the fruit. High levels of chlorogenic acid (CGA) and related compounds occur in the peel of immature fruit but these levels decline during ripening. CGA inhibits cutinase expression, a putative virulence factor, with little or no effect on spore germination or hyphal growth. To better understand the regulation of cutinase expression by fruit phenolics, we examined the effect of CGA, caffeic acid (CA) and related compounds on the redox potential of the growth medium and intracellular glutathione (GSH) levels. The presence of CA in the medium initially lowered the electrochemical redox potential of the medium, increased GSH levels and inhibited cutinase expression. Conidia germinated in the presence of CA, CGA, or GSH produced fewer appressoria and had elongated germ tubes compared to the controls. These results suggest that host redox compounds can regulate fungal infectivity. In order to genetically manipulate this fungus, a transformation system using Agrobacterium was developed. The binary transformation vector, pPTGFPH, was constructed from the plasmid pCT74, carrying green fluorescent protein (GFP) driven by the ToxA promoter of Pyrenophora tritici-repentis and hygromycin B phosphotransferase (hph) under control of the trpC promoter of from Aspergillus nidulans, and the binary vector pCB403.2, carrying neomycin phosphotransferase (nptII) between the T-DNA borders. Macroconidia of M. fructicola were coincubated with A. tumefaciens strain LBA 4404(pPTGFPH) on media containing acetosyringone for two days. Hygromycin- and G418-resistant M. fructicola transformants were selected while inhibiting A. tumefaciens with cefotaxime. Transformants expressing GFP fluoresced brightly, and were formed with high efficiency and frequency of T-DNA integration frequency. The use of these transformants for in situ studies on stone fruit tissues is discussed.

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Moran, Nava, Richard Crain, and Wolf-Dieter Reiter. Regulation by Light of Plant Potassium Uptake through K Channels: Biochemical, Physiological and Biophysical Study. United States Department of Agriculture, September 1995. http://dx.doi.org/10.32747/1995.7571356.bard.

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The swelling of plant motor cells is regulated by various signals with almost unknown mediators. One of the obligatory steps in the signaling cascade is the activation of K+-influx channels -K+ channels activated by hyperpolarization (KH channels). We thus explored the regulation of these channels in our model system, motor cell protoplasts from Samanea saman, using patch-clamp in the "whole cell" configuration. (a) The most novel finding was that the activity of KH channels in situ varied with the time of the day, in positive correlation with cell swelling: in Extensor cells KH channels were active in the earlier part of the day, while in Flexor cells only during the later part of the day; (b) High internal pH promoted the activity of these channels in Extensor cells, opposite to the behavior of the equivalent channels in guard cells, but in conformity with the predicted behavior of the putative KH channel, cloned from S. saman recently; (c) HIgh external K+ concentration increased (KH channel currents in Flexor cells. BL depolarized the Flexor cells, as detected in cell-attached patch-clamp recording, using KD channels (the K+-efflux channels) as "voltage-sensing devices". Subsequent Red-Light (RL) pulse followed by Darkness, hyperpolarized the cell. We attribute these changes to the inhibition of the H+-pump by BL and its reactivation by RL, as they were abolished by an H+-pump inhibitor. BL increased also the activity KD channels, in a voltage-independent manner - in all probability by an independent signaling pathway. Blue-Light (BL), which stimulates shrinking of Flexor cells, evoked the IP3 signaling cascade (detected directly by IP3 binding assay), known to mobilize cytosolic Ca2+. Nevertheless, cytosolic Ca2+ . did not activate the KD channel in excised, inside-out patches. In this study we established a close functional similarity of the KD channels between Flexor and Extensior cells. Thus the differences in their responses must stem from different links to signaling in both cell types.

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Elroy-Stein, Orna, and Dmitry Belostotsky. Mechanism of Internal Initiation of Translation in Plants. United States Department of Agriculture, December 2010. http://dx.doi.org/10.32747/2010.7696518.bard.

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Original objectives Elucidation of PABP's role in crTMV148 IRES function in-vitro using wheat germ extract and krebs-2 cells extract. Fully achieved. Elucidation of PABP's role in crTMV148 IRES function in-vivo in Arabidopsis. Characterization of the physical interactions of PABP and other potential ITAFs with crTMV148 IRES. Partly achieved. To conduct search for additional ITAFs using different approaches and evaluate the candidates. Partly achieved. Background of the topic The power of internal translation via the activity of internal ribosomal entry site (IRES) elements allow coordinated synthesis of multiple gene products from a single transcription unit, and thereby enables to bypass the need for sequential transformation with multiple independent transgenes. The key goal of this project was to identify and analyze the IRES-trans-acting factors (ITAFs) that mediate the activity of a crucifer-infecting tobamovirus (crTMV148) IRES. The remarkable conservation of the IRES activity across the phylogenetic spectrum (yeast, plants and animals) strongly suggests that key ITAFs that mediate its activity are themselves highly conserved. Thus, crTMV148 IRES offers opportunity for elucidation of the fundamental mechanisms underlying internal translation in higher plants in order to enable its rational manipulation for the purpose of agricultural biotechnology. Major conclusions and achievements. - CrTMV IRES requires PABP for maximal activity. This conclusion was achieved by PABP depletion and reconstitution of wheat germ- and Krebs2-derived in-vitro translation assays using Arabidopsis-derived PABP2, 3, 5, 8 and yeast Pab1p. - Mutations in the internal polypurine tract of the IRES decrease the high-affinity binding of all phylogenetically divergent PABPs derived from Arabidopsis and yeast in electro mobility gel shift assays. - Mutations in the internal polypurine tract decrease IRES activity in-vivo. - The 3'-poly(A) tail enhances crTMV148 IRES activity more efficiently in the absence of 5'-methylated cap. - In-vivo assembled RNPs containing proteins specifically associated with the IRES were purified from HEK293 cells using the RNA Affinity in Tandem (RAT) approach followed by their identification by mass spectroscopy. - This study yielded a list of potential protein candidates that may serve as ITAFs of crTMV148 IRES activity, among them are a/b tubulin, a/g actin, GAPDH, enolase 1, ribonuclease/angiogenin inhibitor 1, 26S proteasome subunit p45, rpSA, eEF1Bδ, and proteasome b5 subunit. Implications, both scientific and agriculture. The fact that the 3'-poly(A) tail enhances crTMV148 IRES activity more efficiently in the absence of 5'-methylated cap suggests a potential joint interaction between PABP, the IRES sequence and the 3'-poly(A). This has an important scientific implication related to IRES function in general.

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Reisch, Bruce, Avichai Perl, Julie Kikkert, Ruth Ben-Arie, and Rachel Gollop. Use of Anti-Fungal Gene Synergisms for Improved Foliar and Fruit Disease Tolerance in Transgenic Grapes. United States Department of Agriculture, August 2002. http://dx.doi.org/10.32747/2002.7575292.bard.

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Original objectives . 1. Test anti-fungal gene products for activity against Uncinula necator, Aspergillus niger, Rhizopus stolonifer and Botrytis cinerea. 2. For Agrobacterium transformation, design appropriate vectors with gene combinations. 3. Use biolistic bombardment and Agrobacterium for transformation of important cultivars. 4. Characterize gene expression in transformants, as well as level of powdery mildew and Botrytis resistance in foliage of transformed plants. Background The production of new grape cultivars by conventional breeding is a complex and time-consuming process. Transferring individual traits via single genes into elite cultivars was proposed as a viable strategy, especially for vegetatively propagated crops such as grapevines. The availability of effective genetic transformation procedures, the existence of genes able to reduce pathogen stress, and improved in vitro culture methods for grapes, were combined to serve the objective of this proposal. Effective deployment of resistance genes would reduce production costs and increase crop quality, and several such genes and combinations were used in this project. Progress The efficacy of two-way combinations of Trichoderma endochitinase (CHIT42), synthetic peptide ESF12 and resveratrol upon the control of growth of Botrytis cinerea and Penicillium digitatum were evaluated in vitro. All pairwise interactions were additive but not synergistic. Per objective 2, suitable vectors with important gene combinations for Agrobacterium transformation were designed. In addition, multiple gene co-transformation by particle bombardment was also tested successfully. In New York, transformation work focused on cultivars Chardonnay and Merlot, while the technology in Israel was extended to 41B, R. 110, Prime, Italia, Gamay, Chardonnay and Velika. Transgenic plant production is summarized in the appendix. Among plants developed in Israel, endochitinase expression was assayed via the MuchT assay using material just 1-5 days after co-cultivation. Plants of cv. Sugraone carrying the gene coding for ESF12, a short anti-fungal lytic peptide under the control of the double 358 promoter, were produced. Leaf extracts of two plants showed inhibition zones that developed within 48 h indicating the inhibitory effect of the leaf extracts on the six species of bacteria. X fastidiosa, the causal organism of Pierce's disease, was very sensitive to leaf extracts from ESF12 transformed plants. Further work is needed to verify the agricultural utility of ESF12 transformants. In New York, some transformants were resistant to powdery mildew and Botrytis fruit rot. Major conclusions, solutions, achievements and implications The following scientific achievements resulted from this cooperative BARD project: 1. Development and improvement of embryogenesis and tissue culture manipulation in grape, while extending these procedures to several agriculturally important cultivars both in Israel and USA. 2. Development and improvement of novel transformation procedures while developing transformation techniques for grape and other recalcitrant species. 3. Production of transgenic grapevines, characterization of transformed vines while studying the expression patterns of a marker gene under the control of different promoter as the 35S CaMV in different part of the plants including flowers and fruits. 4. Expression of anti-fungal genes in grape: establishment of transgenic plants and evaluation of gene expression. Development of techniques to insert multiple genes. 5. Isolation of novel grape specific promoter to control the expression of future antimicrobial genes. It is of great importance to report that significant progress was made in not only the development of transgenic grapevines, but also in the evaluation of their potential for increased resistance to disease as compared with the non engineered cultivar. In several cases, increased disease resistance was observed. More research and development is still needed before a product can be commercialized, yet our project lays a framework for further investigations.

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Dolja, Valerian V., Amit Gal-On, and Victor Gaba. Suppression of Potyvirus Infection by a Closterovirus Protein. United States Department of Agriculture, March 2002. http://dx.doi.org/10.32747/2002.7580682.bard.

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The plant virus family Polyviridae is the largest and most destructive of all plant viruses. Despite the continuous effort to develop resistant plant varieties, there is a desperate need for novel approaches conferring wide-range potyvirus resistance. Based on experiments with the tobacco etch potyvirus (TEV)-derived gene expression vector, we suggested approach for screening of the candidate resistance genes. This approach relies on insertion of the genes into a virus vector and evaluation of the phenotypes of the resulting recombinant viruses. The genes which suppress infection by the recombinant virus are selected as candidates for engineering transgenic resistance. Our analysis of the TEV variants expressing proteins of the beet yellows closterovirus (BYV) revealed that one of those, the leader proteinase (L-Pro), strongly and specifically interfered with the hybrid TEV infection. Since closterovirus L-Pro is evolutionary related to potyviral helper component-proteinase (HC-Pro), we suggested that the L-Pro interfered with HC-Pro function via a trans-dominant inhibitory effect. Based on these findings, we proposed to test two major hypotheses. First, we suggested that L-Pro-mediated suppression of potyvirus infection is a general phenomenon effective against a range of potyviruses. The second hypothesis stated that the suppression effect can be reproduced in transgenic plants expressing L-Pro, and can be utilized for generation of resistance to potyviruses. In accord with these hypotheses, we developed two original objectives of our proposal: A) to determine the range of the closterovirus-derived suppression of potyviral infection, and B) to try and utilize the L-Pro-mediated suppression for the development of transgenic resistance to potyviruses. In the first phase of the project, we have developed all major tools and technologies required for successful completion of the proposed research. These included TEV and ZYMV vectors engineered to express several closteroviral L-Pro variants, and generation of the large collection of transgenic plants. To our satisfaction, characterization of the infection phenotypes exhibited by chimeric TEV and ZYMV variants confirmed our first hypothesis. For instance, similar to TEV-L- Pro(BYV) chimera, ZYMV-L-Pro(LIYV) chimera was debilitated in its systemic spread. In contrast, ZYMV-GUS chimera (positive control) was competent in establishing vigorous systemic infection. These and other results with chimeric viruses indicated that several closteroviral proteinases inhibit long-distance movement of the potyviruses upon co-expression in infected plants. In order to complete the second objective, we have generated ~90 tobacco lines transformed with closteroviral L-Pro variants, as well as ~100 lines transformed with BYV Hsp70-homolog (Hsp70h; a negative control). The presence and expression of the trans gene in each line was initially confirmed using RT-PCR and RNA preparations isolated from plants. However, since detection of the trans gene-specific RNA can not guarantee production of the corresponding protein, we have also generated L-Pro- and Hsp70h-specific antisera using corresponding synthetic peptides. These antisera allowed us to confirm that the transgenic plant lines produced detectable, although highly variable levels of the closterovirus antigens. In a final phase of the project, we tested susceptibility of the transgenic lines to TEV infection. To this end, we determined that the minimal dilution of the TEV inoculum that is still capable of infecting 100% of nontransgenic plants was 1:20, and used 10 plants per line (in total, ~2,000 plants). Unfortunately, none of the lines exhibited statistically significant reduction in susceptibility. Although discouraging, this outcome prompted us to expand our experimental plan and conduct additional experiments. Our aim was to test if closteroviral proteinases are capable of functioning in trans. We have developed agroinfection protocol for BYV, and tested if co- expression of the L-Pro is capable of rescuing corresponding null-mutant. The clear-cut, negative results of these experiments demonstrated that L-Pro acts only in cis, thus explaining the lack of resistance in our transgenic plants. We have also characterized a collection of the L-Pro alanine- scanning mutants and found direct genetic evidence of the requirement for L-Pro in virus systemic spread. To conclude, our research supported by BARD confirmed one but not another of our original hypotheses. Moreover, it provided an important insight into functional specialization of the viral proteinases and generated set of tools and data with which we will be able to address the molecular mechanisms by which these proteins provide a variety of critical functions during virus life cycle.

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