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1
Drilon, Alexander E., Dayong Zhai, Evan Rogers, Wei Deng, Xin Zhang, Jane Ung, Dong Lee et al. „The next-generation RET inhibitor TPX-0046 is active in drug-resistant and naïve RET-driven cancer models.“ Journal of Clinical Oncology 38, Nr. 15_suppl (20.05.2020): 3616. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.3616.
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3616 Background: RET fusions/mutations drive oncogenesis in lung and thyroid cancers, and several other malignancies. Selective RET inhibitors (selpercatinib/pralsetinib) are active in patients with these cancers; unfortunately, resistance often occurs. On-target resistance includes the acquisition of solvent front mutations (SFMs i.e. RET G810 substitutions). TPX-0046 is a structurally differentiated RET inhibitor that is potent against a range of RET fusions and mutations including SFMs. Methods: The rationally-designed, compact, macrocyclic RET/SRC inhibitor TPX-0046 was characterized in RET-driven in vitro and in vivo tumor models. Results: In enzymatic assays, TPX-0046 showed low nanomolar potency against wild-type RET and 18 RET mutations/fusions. It was potent against SRC and spared VEGFR2/KDR. TPX-0046 inhibited RET phosphorylation (IC50 < 10 nM) in tumor cell lines (LC2/ad, CCDC6-RET; TT, RET C634W) and Ba/F3 engineered RET models (WT, G810R). In cell proliferation assays, TPX-0046 inhibited KIF5B-RET Ba/F3, LC2/ad, and TT cells with IC50 values ~1 nM. Ba/F3 RET engineered cells with SFMs (e.g. G810C/R/S) were potently inhibited by TPX-0046 (mean proliferation IC50 1–17 nM). TPX-0046 demonstrated marked in vivo anti-tumor efficacy in RET-driven cell-derived and patient-derived xenograft tumor models. In a Ba/F3 KIF5B-RET xenograft model, a single dose of 5 mg/kg TPX-0046 inhibited > 80% of RET phosphorylation (corresponding mean free plasma concentration: 51 nM). At 5 mg/kg BID, tumor regression was observed in RET-dependent xenograft models, including those that harbor RET SFMs: TT, CTG-0838 PDX (NSCLC, KIF5B-RET), CR1520 PDX (CRC, NCOA4-RET), Ba/F3 KIF5B-RET, and Ba/F3 KIF5B-RET G810R. Conclusions: TPX-0046 is a unique next-generation RET inhibitor that possesses potent in vitro and in vivo activity against a diverse range of RET alterations, including SFM-mediated resistance. A phase 1/2 trial for RET inhibitor-resistant and naïve RET-driven cancers is on-going (NCT04161391).
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Ammer, Stefanie, Christian Lambertz und Matthias Gauly. „Comparison of different measuring methods for body temperature in lactating cows under different climatic conditions“. Journal of Dairy Research 83, Nr. 2 (Mai 2016): 165–72. http://dx.doi.org/10.1017/s0022029916000182.
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The aim of the research described here was to compare different methods of body temperature (BT) measurements in dairy cows. It was hypothesised that reticular temperature (RET) values reflect the physiological status of the animals in an equivalent way to rectal (RT) and vaginal (VT) measurements. RT, VT and RET temperatures of twelve lactating Holstein–Friesian cows were measured over five consecutive days in June and October 2013. While RT and VT were manually measured three times a day, RET was automatically recorded at 10 min intervals using a bolus in the reticulum. For comparison with RT and VT, different RET values were used: single values at the respective recording times (RET-SIN), and mean (RET-MEAN) and median (RET-MED) values of 2 h prior to RT and VT measurements. Overall, body temperatures averaged 38·1 ± 0·6, 38·2 ± 0·4, 38·7 ± 0·9, 38·5 ± 0·7 and 38·7 ± 0·5 °C for RT, VT, RET-SIN, RET-MEAN and RET-MED, respectively. RT and VT were lower than all RET measurements, while RET-SIN and RET-MED were higher than RET-MEAN (P < 0·001). RET-MEAN and RET-MED values were higher in the morning, whereas RT and VT were greatest in the evening (P < 0·001). Overall, records of RT and VT were strongly correlated (r = 0·75; P < 0·001). In contrast to RET-SIN and RET-MEAN, RET-MED was higher correlated to RT and VT. In June, coefficients were higher between all methods than in October. Relation of barn T to RT and VT was stronger when compared to RET measurements. RET-SIN was higher correlated to barn T than RET-MEAN or RET-MED. Correlation between VT and barn T was strongest (r = 0·48; P < 0·001). In summary, RET-MED showed highest correlation with VT and RT. However, single RET measurements (influenced by water or feed intake) can lead to extreme variations and differences to single VT and RT values.
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Hennige, Anita M., Reiner Lammers, Wolfgang Höppner, Dorit Arlt, Volker Strack, Reinhard Teichmann, Fausto Machicao, Axel Ullrich, Hans-Ulrich Häring und Monika Kellerer. „Inhibition of Ret Oncogene Activity by the Protein Tyrosine Phosphatase SHP1“. Endocrinology 142, Nr. 10 (01.10.2001): 4441–47. http://dx.doi.org/10.1210/endo.142.10.8453.
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Abstract Germline mutations in the Ret protooncogene give rise to the inherited endocrine cancer syndromes MEN types 2A and 2B and familiar medullary thyroid carcinoma. Although it is well accepted that the constitutive active tyrosine kinase of Ret oncogenes ultimately leads to malignant transformation, it is not clear whether a decrease in the autophosphorylation of oncogenic Ret forms can affect the mitogenic and transforming activities of Ret. Potential modulators of the tyrosine kinase activity of Ret could be tyrosine phosphatases that are expressed in human thyroid tissue. Therefore, we investigated the impact of the tyrosine phosphatases SHP1 and SHP2 on the intrinsic tyrosine kinase activity and oncogenic potency of Ret with a 9-bp duplication in the cysteine-rich domain (codons 634–636), which was described in a patient with MEN type 2A recently. SHP1 and SHP2 were stably overexpressed in NIH3T3 fibroblasts together with Ret-9bp. Coexpression of SHP1 with Ret-9bp reduced the autophosphorylation of Ret-9bp by 19 ± 7% (P = 0.01, n = 4), whereas no effect was seen with SHP2. Furthermore, Ret-9bp could be coimmunoprecipitated with SHP1 but not with SHP2 antibodies. Suppression of the Ret-9bp tyrosine kinase activity by SHP1 caused a decrease in activation of Erk2 (extracellular signal-regulated kinase) and abolished PKB/Akt (protein kinase B) phosphorylation. In addition, diminished Ret-9bp autophosphorylation led to reduced phosphorylation of the transcription factor jun-D. Finally, the inhibitory effect on Ret-9bp signaling resulted in a 40–60% reduction of[ 3H]thymidine incorporation and in reduced ability of NIH3T3 cells to form colonies in soft agar. In conclusion, the data suggest that SHP1 caused a moderate reduction of Ret autophosphorylation, which led to a strong suppression of the Ret oncogene activity.
4
Durick, Kyle, Gordon N. Gill und Susan S. Taylor. „Shc and Enigma Are Both Required for Mitogenic Signaling by Ret/ptc2“. Molecular and Cellular Biology 18, Nr. 4 (01.04.1998): 2298–308. http://dx.doi.org/10.1128/mcb.18.4.2298.
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ABSTRACT Ret/ptc2 is a constitutively active, oncogenic form of the c-Ret receptor tyrosine kinase. Like the other papillary thyroid carcinoma forms of Ret, Ret/ptc2 is activated through fusion of the Ret tyrosine kinase domain to the dimerization domain of another protein. Investigation of requirements for Ret/ptc2 mitogenic activity, using coexpression with dominant negative forms of Ras and Raf, indicated that these proteins are required for mitogenic signaling by Ret/ptc2. Because activation of Ras requires recruitment of Grb2 and SOS to the plasma membrane, the subcellular distribution of Ret/ptc2 was investigated, and it was found to localize to the cell periphery. This localization was mediated by association with Enigma via the Ret/ptc2 sequence containing tyrosine 586. Because Shc interacts with MEN2 forms of Ret, and because phosphorylation of Shc results in Grb2 recruitment and subsequent signaling through Ras and Raf, the potential interaction between Ret/ptc2 and Shc was investigated. The PTB domain of Shc also interacted with Ret/ptc2 at tyrosine 586, and this association resulted in tyrosine phosphorylation of Shc. Coexpression of chimeric proteins demonstrated that mitogenic signaling from Ret/ptc2 required both recruitment of Shc and subcellular localization by Enigma. Because Shc and Enigma interact with the same site on a Ret/ptc2 monomer, dimerization of Ret/ptc2 allows assembly of molecular complexes that are properly localized via Enigma and transmit mitogenic signals via Shc.
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Corsini, Raymond J. „Putting the “B” in ret: It had to be“. Journal of Rational-Emotive and Cognitive-Behavior Therapy 13, Nr. 1 (März 1995): 5–7. http://dx.doi.org/10.1007/bf02354554.
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Ahn, Beung-chul, Viola W. Zhu und Sun Min Lim. „The Next Target for NSCLC: Let It Be “RET”“. Journal of Thoracic Oncology 15, Nr. 12 (Dezember 2020): 1803–5. http://dx.doi.org/10.1016/j.jtho.2020.09.008.
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Carlomagno, Francesca, Teresa Guida, Suresh Anaganti, Livia Provitera, Svend Kjaer, Neil Q. McDonald, Anderson J. Ryan und Massimo Santoro. „Identification of tyrosine 806 as a molecular determinant of RET kinase sensitivity to ZD6474“. Endocrine-Related Cancer 16, Nr. 1 (März 2009): 233–41. http://dx.doi.org/10.1677/erc-08-0213.
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ZD6474 (vandetanib, Zactima, Astra Zeneca) is an anilinoquinazoline used to target the receptor tyrosine kinase RET in familial and sporadic thyroid carcinoma (IC50: 100 nM). The aim of this study was to identify molecular determinants of RET sensitivity to ZD6474. Here, we show that mutation of RET tyrosine 806 to cysteine (Y806C) induced RET kinase resistance to ZD6474 (IC50: 933 nM). Y806 maps close to the gate-keeper position at the RET kinase nucleotide-binding pocket. Although tyrosine 806 is a RET auto-phosphorylation site, its substitution to phenylalanine (Y806F) did not markedly affect RET susceptibility to ZD6474 (IC50: 87 nM), suggesting that phosphorylation of Y806 is not required for compound binding. Accordingly, the introduction of a phosphomimetic residue (Y806E) also caused resistance to ZD6474, albeit of a lesser degree (IC50: 512 nM) than the cysteine mutation. Y806C/E RET mutants were also resistant to ZD6474 with respect to intracellular signalling and activation of an AP1-responsive promoter. We conclude that Y806 is a molecular determinant of RET sensitivity to ZD6474. Y806C is a natural RET mutation identified in a patient affected by multiple endocrine neoplasia type 2B. Based on its rare occurrence, it is unlikely that Y806C will be a frequent cause of refractoriness to ZD6474; however, it may be envisaged that mutations at this site can mediate secondary resistance formation in patients treated with the compound.
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Jones, Stanton L. „Rational-Emotive Therapy in Christian Perspective“. Journal of Psychology and Theology 17, Nr. 2 (Juni 1989): 110–20. http://dx.doi.org/10.1177/009164718901700203.
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Rational-emotive therapy (RET), a common cognitive-behavioral approach to psychotherapy, is critiqued from a Christian perspective. Positively, RET is openly value-oriented, prizing of rationality, and balanced in its attempt to deal with the thoughts, behaviors, and feelings of the client from a rational perspective. Such an approach can be a helpful tool for the Christian therapist to use. Difficulties with RET thought from a Christian perspective include incompatibilities with values endorsed by RET, an overemphasis on rationality, problems with the understanding of rationality and emotion, and an overly atomistic view of the self. These tensions make it quite impossible for a truly Christian approach to therapy to be overly identified with RET. Two systems of “Christian counseling” which are quite akin to RET are briefly examined in light of the RET critique.
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Dawasaz, A. A., Ibrahim Alshahrani, Syed M. Yassin, Sadatullah Syed, Mohammad Shahul Hameed, Fawaz Baig, Rafi Ahmad Togoo und Luqman Master. „Detection of Dental Caries’ and Dermatoglyphics’ Association with Relative Enamel Thickness Using CBCT Images in Saudi Subpopulation: A Novel Approach“. BioMed Research International 2021 (26.07.2021): 1–7. http://dx.doi.org/10.1155/2021/5550916.
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Background. Dental caries is the localized destruction of dental hard tissues (enamel and dentine). Decayed, Missing, and Filled Teeth (DMFT) index is the most commonly used dental caries index. Thickness of the outermost part of the tooth called the enamel is determined by the rate of deposition of enamel proteins. Relative enamel thickness (RET) gives a measure of enamel thickness with respect to dentine. Dental caries is influenced by a genetically determined factor called dermatoglyphics (DG). As the genes responsible for RET and DG lie on the same chromosome and develop during the same time of intrauterine life, it is biologically plausible to correlate RET and DG. Aims. This study consists of two primary aims: (1) to assess RET using cone beam computed tomography images and correlate it with caries and (2) to correlate RET with DG. Materials and Methods. 148 dental subjects were assessed for DMFT caries score and were categorized as Group 1 with DMFT = 0 and Group 2 with DMFT ≥ 1 . Following this, their DG pattern was recorded digitally. The CBCT images of these subjects were assessed for RET, and the data were analyzed statistically. Results. Mean RET in our sample population is 18.45 (SD 3.79) while mean DMFT is 5.34 (SD 5.13). Mean RET in Group 1 subjects was 19.82 (SD 4.05) while that in the Group 2 was 17.68 (SD 3.43). RET and DMFT showed a statistically significant negative correlation ( p = 0.007 ). The “Single Loop” DG characteristic showed a statistically significant difference between males and females ( p = 0.031 ). The “Simple Arch” type of DG was positively correlated with RET. Conclusion. This is the first in vivo study to assess RET using CBCT images and correlate with DMFT and DG. RET is inversely related to DMFT while directly proportional to the “Simple arch” DG pattern. Males and females differed in their “Single Loop” DG characteristic.
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Wang, Lei, Yu Zhang, Yu Gao, Yang Fan, Luyao Chen, Kan Liu, Qingyu Meng, Chaofei Zhao und Xin Ma. „Prognostic and Predictive Values of Subcellular Localisation of RET in Renal Clear-Cell Carcinoma“. Disease Markers 2016 (2016): 1–8. http://dx.doi.org/10.1155/2016/6870470.
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Metastatic renal cell carcinoma (RCC) presents a poor prognosis and an unpredictable course. To date, no validated biomarkers can predict the outcome of RCC. Ongoing efforts are conducted to identify the molecular markers of RCC progression, as well as the targets for novel therapeutic approaches. RET is a tyrosine kinase receptor which has been investigated as a possible target in other cancers because it is involved in oncogenic activation. To evaluate the predictive and prognostic functions of RET in ccRCC, a tissue microarray study was conducted on 273 ccRCC patients. Results showed that both RET cytoplasmic and nuclear expression were independently associated with PFS and OS, and the combined RET cytoplasmic and nuclear statuses demonstrated that the ratio of high nuclear RET and cytoplasmic RET was the strongest predictor of both PFS and OS. The high cytoplasmic RET expression retained its independent poor prognostic value in targeted drug treated patients. The RET nuclear expression was associated with distant metastasis. Moreover, the RET nuclear expression was an independent predictor of ccRCC postoperative metastasis. In conclusion, RET may be useful in prognostication and can be used at initial diagnosis to identify patients with high potential to develop metastasis.
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Zhang, Kai, Huajun Chen, Ye Wang, Lin Yang, Chengzhi Zhou, Weiqiang Yin, Guangsuo Wang et al. „Clinical Characteristics and Molecular Patterns of RET-Rearranged Lung Cancer in Chinese Patients“. Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics 27, Nr. 5 (07.05.2019): 575–82. http://dx.doi.org/10.3727/096504018x15344979253618.
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RET rearrangement has been proven as an oncogenic driver in patients with lung cancer. However, the prevalence, clinical characteristics, molecular features, and therapeutic options in RET-rearranged patients remain unclear, especially in Chinese lung cancer patients. We retrospectively collected 6,125 Chinese lung cancer patients who have been profiled using next-generation sequencing (NGS). The clinical demographics and molecular features of RET rearrangement-positive patients were analyzed. RET rearrangements were identified in 84 patients with a proportion of 1.4% in our cohort. The median age at diagnosis was 58 years, and it mainly occurred in females with adenocarcinoma histology. KIF5B-RET was the most frequent fusion type and accounted for 53.8% (57/106) of all RET fusions identified, with K15-R12 as the most frequent variant (71.9%). Among 47 RET+ patients profiled with larger panels, 72.3% (34/47) harbored concurrent alterations. TP53 ranked as the most common concurrent alteration, and concomitant EGFR oncogenic alterations were identified in seven patients. Moreover, an adenocarcinoma patient harboring concurrent RET fusion and EGFR L858R responded to combinatorial treatment of cabozantinib and osimertinib, with a progression-free survival of 5 months. Our study improved knowledge of clinical characteristics and molecular features of RET-rearranged lung cancers in China. It might be helpful to guide clinicians for more effective personalized diagnostic and therapeutic approaches.
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Sapio, Maria Rosaria, Anna Guerra, Vincenzo Marotta, Elisabetta Campanile, Raffaele Formisano, Maurilio Deandrea, Manuela Motta et al. „High Growth Rate of Benign Thyroid Nodules Bearing RET/PTC Rearrangements“. Journal of Clinical Endocrinology & Metabolism 96, Nr. 6 (01.06.2011): E916—E919. http://dx.doi.org/10.1210/jc.2010-1599.
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Context: Benign thyroid nodules display a broad range of behaviors from a stationary size to a progressive growth. The RET/PTC oncogene has been documented in a fraction of benign thyroid nodules, besides papillary thyroid carcinomas, and it might therefore influence their growth. Objective: The aim of the present work was to evaluate whether RET/PTC in benign thyroid nodules associates with a different nodular growth rate. Study Design: In this prospective multicentric study, 125 subjects with benign nodules were included. RET rearrangements were analyzed in cytology samples; clinical and ultrasonographic nodule characteristics were assessed at the start and at the end of the study. Results: RET/PTC was present in 19 nodules. The difference between the mean baseline nodular volume of the RET/PTC− and RET/PTC+ nodules was not significant. After 36 months of follow-up, the RET/PTC+ group (n = 16) reached a volume higher than the RET/PTC− group (n = 90) (5.04 ± 2.67 vs. 3.04 ± 2.26 ml; P = 0.0028). We calculated the monthly change of nodule volumes as a percentage of baseline. After a mean follow-up of 36.6 months, the monthly volume increase of nodules bearing a RET rearrangement was 4.3-fold that of nodules with wild-type RET (1.83 ± 1.2 vs. 0.43 ± 1.0% of baseline volume; P < 0.0001). Conclusions: Benign thyroid nodules bearing RET rearrangements grow more rapidly than those with wild-type RET. Searching for RET rearrangements in benign thyroid nodules might be useful to the clinician in choosing the more appropriate and timely therapeutic option.
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Fusco, Alfredo, und Massimo Santoro. „20 years of RET/PTC in thyroid cancer: clinico-pathological correlations“. Arquivos Brasileiros de Endocrinologia & Metabologia 51, Nr. 5 (Juli 2007): 731–35. http://dx.doi.org/10.1590/s0004-27302007000500010.
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The RET/PTC oncogene has been isolated almost twenty years ago. During these years, the research has given a final answer to several questions. In fact, it has been demonstrated that: a) RET/PTC is an early event in the process of thyroid carcinogenesis and has a critical role in the generation of the papillary carcinoma; b) RET/PTC activation is essentially restricted to the papillary histotype and to the Hürthle thyroid tumors; c) its incidence increases after exposure to radiations. However, some questions have not found a final answer yet: a) which is the real frequency of RET/PTC activation? Likely it is around 20%, but this point is still questionable; b) which other gene modifications are required to lead a thyroid cell carrying a RET/PTC oncogene to the malignant phenotype?, and c) is there any correlation between RET/PTC activation and clinical parameters? We hope that these questions will have a clear answer in the near future.
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Pelicci, Giuliana, Flavia Troglio, Alessandra Bodini, Rosa Marina Melillo, Valentina Pettirossi, Laura Coda, Antonio De Giuseppe, Massimo Santoro und Pier Giuseppe Pelicci. „The Neuron-Specific Rai (ShcC) Adaptor Protein Inhibits Apoptosis by Coupling Ret to the Phosphatidylinositol 3-Kinase/Akt Signaling Pathway“. Molecular and Cellular Biology 22, Nr. 20 (15.10.2002): 7351–63. http://dx.doi.org/10.1128/mcb.22.20.7351-7363.2002.
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ABSTRACT Rai is a recently identified member of the family of Shc-like proteins, which are cytoplasmic signal transducers characterized by the unique PTB-CH1-SH2 modular organization. Rai expression is restricted to neuronal cells and regulates in vivo the number of postmitotic sympathetic neurons. We report here that Rai is not a common substrate of receptor tyrosine kinases under physiological conditions and that among the analyzed receptors (Ret, epidermal growth factor receptor, and TrkA) it is activated specifically by Ret. Overexpression of Rai in neuronal cell lines promoted survival by reducing apoptosis both under conditions of limited availability of the Ret ligand glial cell line-derived neurotrophic factor (GDNF) and in the absence of Ret activation. Overexpressed Rai resulted in the potentiation of the Ret-dependent activation of phosphatidylinositol 3-kinase (PI3K) and Akt. Notably, increased Akt phosphorylation and PI3K activity were also found under basal conditions, e.g., in serum-starved neuronal cells. Phosphorylated and hypophosphorylated Rai proteins form a constitutive complex with the p85 subunit of PI3K: upon Ret triggering, the Rai-PI3K complex is recruited to the tyrosine-phosphorylated Ret receptor through the binding of the Rai PTB domain to tyrosine 1062 of Ret. In neurons treated with low concentrations of GDNF, the prosurvival effect of Rai depends on Rai phosphorylation and Ret activation. In the absence of Ret activation, the prosurvival effect of Rai is, instead, phosphorylation independent. Finally, we showed that overexpression of Rai, at variance with Shc, had no effects on the early peak of mitogen-activated protein kinase (MAPK) activation, whereas it increased its activation at later time points. Phosphorylated Rai, however, was not found in complexes with Grb2. We propose that Rai potentiates the MAPK and PI3K signaling pathways and regulates Ret-dependent and -independent survival signals.
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Santoro, M., W. T. Wong, P. Aroca, E. Santos, B. Matoskova, M. Grieco, A. Fusco und P. P. di Fiore. „An epidermal growth factor receptor/ret chimera generates mitogenic and transforming signals: evidence for a ret-specific signaling pathway“. Molecular and Cellular Biology 14, Nr. 1 (Januar 1994): 663–75. http://dx.doi.org/10.1128/mcb.14.1.663-675.1994.
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A chimeric expression vector which encoded for a molecule encompassing the extracellular domain of the epidermal growth factor (EGF) receptor (EGFR) and the intracellular domain of the ret kinase (EGFR/ret chimera) was generated. Upon ectopic expression in mammalian cells, the EGFR/ret chimera was correctly synthesized and transported to the cell surface, where it was shown capable of binding EGF and transducing an EGF-dependent signal intracellularly. Thus, the EGFR/ret chimera allows us to study the biological effects and biochemical activities of the ret kinase under controlled conditions of activation. Comparative analysis of the growth-promoting activity of the EGFR/ret chimera expressed in fibroblastic or hematopoietic cells revealed a biological phenotype clearly distinguishable from that of the EGFR, indicating that the two kinases couple with mitogenic pathways which are different to some extent. Analysis of biochemical pathways implicated in the transduction of mitogenic signals also evidenced significant differences between the ret kinase and other receptor tyrosine kinases. Thus, the sum of our results indicates the existence of a ret-specific pathway of mitogenic signaling.
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Santoro, M., W. T. Wong, P. Aroca, E. Santos, B. Matoskova, M. Grieco, A. Fusco und P. P. di Fiore. „An epidermal growth factor receptor/ret chimera generates mitogenic and transforming signals: evidence for a ret-specific signaling pathway.“ Molecular and Cellular Biology 14, Nr. 1 (Januar 1994): 663–75. http://dx.doi.org/10.1128/mcb.14.1.663.
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A chimeric expression vector which encoded for a molecule encompassing the extracellular domain of the epidermal growth factor (EGF) receptor (EGFR) and the intracellular domain of the ret kinase (EGFR/ret chimera) was generated. Upon ectopic expression in mammalian cells, the EGFR/ret chimera was correctly synthesized and transported to the cell surface, where it was shown capable of binding EGF and transducing an EGF-dependent signal intracellularly. Thus, the EGFR/ret chimera allows us to study the biological effects and biochemical activities of the ret kinase under controlled conditions of activation. Comparative analysis of the growth-promoting activity of the EGFR/ret chimera expressed in fibroblastic or hematopoietic cells revealed a biological phenotype clearly distinguishable from that of the EGFR, indicating that the two kinases couple with mitogenic pathways which are different to some extent. Analysis of biochemical pathways implicated in the transduction of mitogenic signals also evidenced significant differences between the ret kinase and other receptor tyrosine kinases. Thus, the sum of our results indicates the existence of a ret-specific pathway of mitogenic signaling.
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Wu, Jie, und Vivek Subbiah. „RETooling the RET Inhibitor Pralsetinib for ESR1 Fusion–Positive Breast Cancer and Beyond“. Cancer Research 83, Nr. 19 (02.10.2023): 3159–61. http://dx.doi.org/10.1158/0008-5472.can-23-1021.
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Abstract Transcriptionally active fusions of ESR1 (ESR1-TAF) and somatic mutations in the estrogen receptor alpha (ERα) ligand-binding domain (LBD) cause endocrine therapy resistance in breast cancer. In searching for therapeutic target kinase(s) in these breast cancers, Gou and colleagues identified FLT4, RET, JAK1, and IGF1R as the top upregulated kinases induced by ESR1-TAFs and ERα LBD mutants in breast cancer cells. Among them, inhibition of RET by pralsetinib suppressed ESR1-TAF–driven and ERα LBD mutant–driven cell proliferation and patient-derived xenograft growth. Pralsetinib is an inhibitor of the RET protein tyrosine kinase that is approved for treating oncogenic RET mutation–positive and RET fusion–positive thyroid cancers and non–small cell lung cancer. The work by Gou and colleagues reinforces the knowledge of RET as an ESR1 target gene and highlights that RET interacts with ERα to promote breast cancer tumorigenesis and antiestrogen resistance. It also raises the prospect of repositioning pralsetinib to target wildtype RET in ER-positive breast cancer. See related article by Gou et al., p. 3237
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Vargiolu, Manuela, Daniela Fusco, Ivana Kurelac, Dietmar Dirnberger, Ralf Baumeister, Isabella Morra, Antonio Melcarne, Roberto Rimondini, Giovanni Romeo und Elena Bonora. „The Tyrosine Kinase Receptor RET Interacts in Vivo with Aryl Hydrocarbon Receptor-Interacting Protein to Alter Survivin Availability“. Journal of Clinical Endocrinology & Metabolism 94, Nr. 7 (01.07.2009): 2571–78. http://dx.doi.org/10.1210/jc.2008-1980.
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Context: RET is a tyrosine kinase transmembrane receptor expressed in two main alternative isoforms: RET9 and RET51. RET transduces a positive signal leading to survival, differentiation, or migration in the presence of its ligand glial cell line-derived neurotrophic factor, whereas in its absence a proapoptotic fragment that initiates a negative signaling for apoptosis is generated. The signal transduction mechanisms leading to apoptosis are still unclear. Objective: To shed light on the mechanisms of RET-induced apoptosis, we searched for novel interactors of RET51. Design: The “split ubiquitin yeast two-hybrid system” was used with RET51 as bait against a human brain expression library. Results: We identified aryl hydrocarbon receptor-interacting protein (AIP), a cochaperone recently found mutated in pituitary adenoma patients, as a novel interactor of RET. We showed that RET interacts specifically with AIP both in mammalian cell lines and in vivo in the pituitary gland, regardless of the presence of pituitary adenoma-specific mutations. AIP and RET genes were sequenced in 28 pituitary adenoma, but no relevant mutations were found. In addition, we identified the proapoptotic domain of RET as responsible for the interaction with AIP. Finally, we demonstrated that the AIP-RET interaction does not require RET kinase activity or kinase-dependent signal transduction and that it prevents the formation of the AIP-survivin complex. Conclusions: The identification of the AIP-RET complex represents a starting point to study key cellular processes involved in RET-induced apoptosis.
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Chatterjee, Sumantra, Lauren E. Fries, Or Yaacov, Nan Hu, Hanna E. Berk-Rauch und Aravinda Chakravarti. „RET enhancer haplotype-dependent remodeling of the human fetal gut development program“. PLOS Genetics 19, Nr. 11 (10.11.2023): e1011030. http://dx.doi.org/10.1371/journal.pgen.1011030.
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Hirschsprung disease (HSCR) is associated with deficiency of the receptor tyrosine kinase RET, resulting in loss of cells of the enteric nervous system (ENS) during fetal gut development. The major contribution to HSCR risk is from common sequence variants in RET enhancers with additional risk from rare coding variants in many genes. Here, we demonstrate that these RET enhancer variants specifically alter the human fetal gut development program through significant decreases in gene expression of RET, members of the RET-EDNRB gene regulatory network (GRN), other HSCR genes, with an altered transcriptome of 2,382 differentially expressed genes across diverse neuronal and mesenchymal functions. A parsimonious hypothesis for these results is that beyond RET’s direct effect on its GRN, it also has a major role in enteric neural crest-derived cell (ENCDC) precursor proliferation, its deficiency reducing ENCDCs with relative expansion of non-ENCDC cells. Thus, genes reducing RET proliferative activity can potentially cause HSCR. One such class is the 23 RET-dependent transcription factors enriched in early gut development. We show that their knockdown in human neuroblastoma SK-N-SH cells reduces RET and/or EDNRB gene expression, expanding the RET-EDNRB GRN. The human embryos we studied had major remodeling of the gut transcriptome but were unlikely to have had HSCR: thus, genetic or epigenetic changes in addition to those in RET are required for aganglionosis.
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Ahmed, Attique, und Muhammad Naeem. „A Novel Framework for Selecting Elicitation Technique based on Attribute Mapping“. International Journal of Engineering and Applied Computer Science 04, Nr. 02 (30.03.2022): 19–24. http://dx.doi.org/10.24032/ijeacs/0402/001.
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The software development process is completely based on the requirements of stakeholders. If the requirements of stakeholders are being integrated into the proposed system, then it can be assumed that the end product is going to be optimal and successful. To achieve a successful product, different Requirement Elicitation Techniques (RET) are being practiced. The selection of a suitable RET is based on the nature of the product being developed. So, a single RET doesn’t fit all products. In this paper, we differentiate all RETs from each other which makes it easier for an analyst to choose suitable RET from the available ones. We further designed a novel mapping framework that extracts the best suited RET to any software based on its attributes. We have further implemented the proposed framework by using an online vehicle booking system as a running example.
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Luesma, M. J., I. Cantarero, J. M. Álvarez-Dotu, S. Santander und C. Junquera. „New Insights into c-Ret Signalling Pathway in the Enteric Nervous System and Its Relationship with ALS“. BioMed Research International 2014 (2014): 1–7. http://dx.doi.org/10.1155/2014/328348.
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The receptor tyrosine kinase Ret (c-Ret) transduces the glial cell line-derived neurotrophic factor (GDNF) signal, one of the neurotrophic factors related to the degeneration process or the regeneration activity of motor neurons in amyotrophic lateral sclerosis (ALS). The phosphorylation of several tyrosine residues of c-Ret seems to be altered in ALS. c-Ret is expressed in motor neurons and in the enteric nervous system (ENS) during the embryonic period. The characteristics of the ENS allow using it as model for central nervous system (CNS) study and being potentially useful for the research of human neurological diseases such as ALS. The aim of the present study was to investigate the cellular localization and quantitative evaluation of marker c-Ret in the adult human gut. To assess the nature of c-Ret positive cells, we performed colocalization with specific markers of cells that typically are located in the enteric ganglia. The colocalization of PGP9.5 and c-Ret was preferentially intense in enteric neurons with oval morphology and mostly peripherally localized in the ganglion, so we concluded that the c-Ret receptor is expressed by a specific subtype of enteric neurons in the mature human ENS of the gut. The functional significance of these c-Ret positive neurons is discussed.
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Rocco, Danilo, Luigi Sapio, Luigi Della Gravara, Silvio Naviglio und Cesare Gridelli. „Treatment of Advanced Non-Small Cell Lung Cancer with RET Fusions: Reality and Hopes“. International Journal of Molecular Sciences 24, Nr. 3 (26.01.2023): 2433. http://dx.doi.org/10.3390/ijms24032433.
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RET-selective tyrosine kinase inhibitors (TKIs) selpercatinib and pralsetinib have revolutionized the landscape of RET-positive (RET+) advanced non-small cell lung cancer (NSCLC) treatment thanks to their efficacy and safety profiles. This class of medications currently represents the standard of care for both naïve and patients that have not received selective RET-TKIs in the first-line setting. However, we presently lack a satisfactory understanding of resistance mechanism developing after selective RET-TKIs usage, as well as a specific treatment for patients progressing on selpercatinib or pralsetinib. Chemotherapy ± immunotherapy is considered as a recommended subsequent second-line regimen in these patients. Therefore, it is of paramount importance to better define and understand the resistance mechanisms triggered by RET-TKIs. With this in mind, the present review article has been conceived to provide a comprehensive overview about RET+ advanced NSCLC, both from a therapeutic and molecular point of view. Besides comparing the clinical outcome achieved in RET+ advanced NSCLC patients after multikinase inhibitors (MKIs) and/or RET-selective TKIs’ administration, we focused on the molecular mechanisms accountable for their long-term resistance. Finally, a critical perspective on many of today’s most debated issues and concerns is provided, with the purpose of shaping the possible pharmacological approaches for tomorrow’s therapies.
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Rungngu, Susanti Lisupindan Palimbong, Audrey Wahani und Max F. J. Mantik. „Reticulocyte hemoglobin equivalent for diagnosing iron deficiency anemia in children“. Paediatrica Indonesiana 56, Nr. 2 (19.07.2016): 90. http://dx.doi.org/10.14238/pi56.2.2016.90-4.
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Background The prevalence of iron deficiency anemia (IDA) remains high in Indonesian children. When anemia is detected in a patient, the physician’s task is to identify the cause, address it, provide iron therapy, and prevent recurrence. However, prevention is best done by early detection. The reticulocyte hemoglobin equivalent (Ret-He) is a direct measurement of iron level in reticulocytes recently produced in the bone marrow. The Ret-He measurement may be an early indicator of iron deficiency, as it is sensitive at the initial stage of the condition.Objective To assess for a relationship between Ret-He and IDA as well as to evaluate the usefulness of Ret-He for diagnosing IDA in children.Methods This analytic, observational study with cross-sectional approach included 50 children aged 6-12 years and was performed from November 2013 to March 2014. The subjects were divided into IDA or non-IDA groups, based on ferritin levels. A correlation analysis using logistic regression was performed and the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and odds ratio (OR) were calculated. Results were considered to be statistically significant for P values <0.05.Results A low Ret-He level was significantly associated with IDA in children (P=0.005). The Ret-He cut-off point of 27.8 pg/L had sensitivity of 43.8%, specificity 85.3%, PPV 58.3%, and NPV 76.3%, with OR 4.5 (95%CI 1.1 to 17.7).Conclusion We find a significant positive relationship between Haemoglobin (Hb) and Ret-He in children, A low level of Ret-He is associated with greater risk of IDA in children. The Ret-He has a high specificity. As such, Ret-He may be useful as a screening tool for early detection of IDA in children.
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Robb, Harold B. „Using RET to Reduce Psychological Dysfunction Associated with Supernatural Belief Systems“. Journal of Cognitive Psychotherapy 7, Nr. 4 (Januar 1993): 281–89. http://dx.doi.org/10.1891/0889-8391.7.4.281.
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This paper provides a general approach to using Rational-Emotive Therapy with any person experiencing psychological dysfunction in relation to their supernatural belief system. It shows how the principles of RET are used when supernaturalism is: (1) used metaphorically, (2) conceptualized as origin, (3) in concert with RET and (4) in conflict with RET.
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Tang, Ming-Jer, Dane Worley, Michele Sanicola und Gregory R. Dressler. „The RET–Glial Cell-derived Neurotrophic Factor (GDNF) Pathway Stimulates Migration and Chemoattraction of Epithelial Cells“. Journal of Cell Biology 142, Nr. 5 (07.09.1998): 1337–45. http://dx.doi.org/10.1083/jcb.142.5.1337.
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Embryonic development requires cell migration in response to positional cues. Yet, how groups of cells recognize and translate positional information into morphogenetic movement remains poorly understood. In the developing kidney, the ureteric bud epithelium grows from the nephric duct towards a group of posterior intermediate mesodermal cells, the metanephric mesenchyme, and induces the formation of the adult kidney. The secreted protein GDNF and its receptor RET are required for ureteric bud outgrowth and subsequent branching. However, it is unclear whether the GDNF–RET pathway regulates cell migration, proliferation, survival, or chemotaxis. In this report, we have used the MDCK renal epithelial cell line to show that activation of the RET pathway results in increased cell motility, dissociation of cell adhesion, and the migration towards a localized source of GDNF. Cellular responses to RET activation include the formation of lamellipodia, filopodia, and reorganization of the actin cytoskeleton. These data demonstrate that GDNF is a chemoattractant for RET-expressing epithelial cells and thus account for the developmental defects observed in RET and GDNF mutant mice. Furthermore, the RET-transfected MDCK cells described in this report are a promising model for delineating RET signaling pathways in the renal epithelial cell lineage.
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Yusof, Nurasyikin. „The Paediatric Iron Deficiency Assessment with Reticulocyte Haemoglobin Equivalent (Ret-He) in Comparison with Biochemical Markers of Serum Ferritin and Transferrin Saturation“. Medicine & Health 16, Nr. 2 (29.12.2021): 138–47. http://dx.doi.org/10.17576/mh.2021.1602.10.
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Diagnosis of iron deficiency anaemia (IDA) is a challenge as the conventional methods often diagnose the disease at the later stage. Haemoglobin content of reticulocytes is useful to identify IDA at earlier stage. The objective of this study was to evaluate reticulocyte-haemoglobin equivalent (Ret-He) in diagnosing IDA in children and to compare it with other conventional methods. This prospective study was conducted on 120 paediatric patients aged 12 years and below, who attended Hospital Sultanah Aminah Johor Bahru, Malaysia with haemoglobin <12 g/dL. Ret-He and serum iron, ferritin and transferrin saturation were measured. Using a cut-off point of 20% for transferrin saturation, 81 out of 120 subjects (67.5%) were found as iron deficient. Based on the diagnosis of IDA, cut-off value for Ret-He using the Receiver Operating Characteristics (ROC) curve analysis was found as 22.65 pg. Ret-He showed a good sensitivity and specificity of 77.8% and 66.7%, respectively. As compared with Ret-He, serum ferritin showed a sensitivity of only 18.9%. However, a good specificity of 100% suggest it is useful for ruling in the disease but not suitable for screening. Transferrin saturation showed a good sensitivity and specificity, but it is biologically variable and not cost effective as a screening tool. Correlation study showed serum iron and transferrin saturation have significant positive correlation with Ret-He (r=0.415 to 0.518). However, there was no correlation between Ret-He and serum ferritin (r=0.051, p=0.578). This study shows that Ret-He at a cut-off point of 22.65 pg has a better sensitivity and potentially be useful as a screening tool in the paediatric population.
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Song, Xingju, Xu Yang, Taotao Zhang, Jing Liu und Qun Liu. „A Novel Rhoptry Protein as Candidate Vaccine against Eimeria tenella Infection“. Vaccines 8, Nr. 3 (12.08.2020): 452. http://dx.doi.org/10.3390/vaccines8030452.
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Eimeria tenella (E. tenella) is a highly pathogenic and prevalent species of Eimeria that infects chickens, and it causes a considerable disease burden worldwide. The secreted proteins and surface antigens of E. tenella at the sporozoite stage play an essential role in the host–parasite interaction, which involves attachment and invasion, and these interactions are considered vaccine candidates based on the strategy of cutting off the invasion pathway to interrupt infection. We selected two highly expressed surface antigens (SAGs; Et-SAG13 and Et-SAG) and two highly expressed secreted antigens (rhoptry kinases Eten5-A, Et-ROPK-Eten5-A and dense granule 12, Et-GRA12) at the sporozoite stage. Et-ROPK-Eten5-A and Et-GRA12 were two unexplored proteins. Et-ROPK-Eten5-A was an E. tenella-specific rhoptry (ROP) protein and distributed in the apical pole of sporozoites and merozoites. Et-GRA12 was scattered in granular form at the sporozoite stage. To evaluate the potential of rEt-ROPK-Eten5-A, rEt-GRA12, rEt-SAG13 and rEt-SAG proteins as a coccidiosis vaccine, the protective efficacy was examined based on survival rate, lesion score, body weight gain, relative body weight gain and oocyst output. The survival rate was significantly improved in rEt-ROPK-Eten5-A (100%) and rEt-GRA12 (100%) immune chickens compared to the challenged control group (40%). The average body weight gains of rEt-ROPK-Eten5-A, rEt-GRA12, rEt-SAG13 and rEt-SAG immunized chickens were significantly higher than those of unimmunized chickens. The mean lesion score and oocyst output of the rEt-ROPK-Eten5-A immunized chickens were significantly reduced compared to unimmunized challenged chickens. These results suggest that the rEt-ROPK-Eten5-A protein effectively triggered protection against E. tenella in chickens and provides a useful foundation for future work developing anticoccidial vaccines.
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Alqahtani, Tariq, Vishnu Kumarasamy, Sahar Saleh Alghamdi, Rasha Saad Suliman, Khalid Bin Saleh, Mohammed A. Alrashed, Mohammed Aldhaeefi und Daekyu Sun. „Adefovir Dipivoxil as a Therapeutic Candidate for Medullary Thyroid Carcinoma: Targeting RET and STAT3 Proto-Oncogenes“. Cancers 15, Nr. 7 (05.04.2023): 2163. http://dx.doi.org/10.3390/cancers15072163.
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Aberrant gene expression is often linked to the progression of various cancers, making the targeting of oncogene transcriptional activation a potential strategy to control tumor growth and development. The RET proto-oncogene’s gain-of-function mutation is a major cause of medullary thyroid carcinoma (MTC), which is part of multiple endocrine neoplasia type 2 (MEN2) syndrome. In this study, we used a cell-based bioluminescence reporter system driven by the RET promoter to screen for small molecules that potentially suppress the RET gene transcription. We identified adefovir dipivoxil as a transcriptional inhibitor of the RET gene, which suppressed endogenous RET protein expression in MTC TT cells. Adefovir dipivoxil also interfered with STAT3 phosphorylation and showed high affinity to bind to STAT3. Additionally, it inhibited RET-dependent TT cell proliferation and increased apoptosis. These results demonstrate the potential of cell-based screening assays in identifying transcriptional inhibitors for other oncogenes.
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Livia, Resvi, Fajar Wasilah und Leni Lismayanti. „Comparison of Reticulocyte Hemoglobin Equivalent Levels between Low and Normal Birth Weight Newborns“. INDONESIAN JOURNAL OF CLINICAL PATHOLOGY AND MEDICAL LABORATORY 29, Nr. 1 (19.01.2023): 64–68. http://dx.doi.org/10.24293/ijcpml.v29i1.1943.
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Low Birth Weight (LBW) newborns face a risk of iron deficiency. Iron deficiency hinders growth, and motoric, and cognitive development. Newborns with LBW sometimes suffer from inflammation, which affects the commonly used iron measurements. Reticulocyte hemoglobin equivalent (Ret-He) is considered a potential tool to measure iron profile because it measures functional iron, and it is not affected by inflammation. This study compared the Ret-He in LBW and normal birth weight newborns. This cross-sectional study was done retrospectively by observing and comparing the hematology data of newborns from November to December 2019. The difference in Ret-He level was assessed using a non-parametric test. Out of 70 newborns, 26 were normal and 44 were LBW. The proportion of LBW newborns with anemia was higher than the proportion of normal ones (29.6% vs 7.7%, p=0.03). The median value of Ret-He in LBW was lower compared to normal birth weight (32.6 vs 33.3 pg, p=0.09), however, the values were still within the normal limits. Five from 70 of these newborns' Ret-He levels were under the reference range (7.14%). There was found that CRP levels were higher in LBW newborns than normal ones (5.6% vs 5%, p=0.98). There was a positive correlation between Ret-He and the birth weight of the newborns (r= 0.34, p =<0.01). There was no significant difference in Ret-He levels of LBW compared to normal babies. Further research is needed with a larger sample size to better assess the association of Ret-He and iron profiles in newborns.
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Zhu, Yongqiang, Jia Wang und Minghong Shang. „Abstract LB330: FHND5071: a selective RET inhibitor with unique pharmacokinetic profile“. Cancer Research 83, Nr. 8_Supplement (14.04.2023): LB330. http://dx.doi.org/10.1158/1538-7445.am2023-lb330.
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Abstract Background: Gene rearrangements (fusions) and mutations in RET have the potential to be oncogenic drivers and have been observed in a variety of tumors types. Selective RET inhibitors selpercatinib and pralsetinib have been approved for patients with RET-altered cancers. FHND5071 is a novel kinase inhibitor which specifically targets RET activated forms and has unique pharmacokinetic profile. Methods: The pharmacological profile of FHND5071 have been confirmed in in vitro and in vivo evaluations, including enzyme and cell-based assays, PK/PD study, and RET-dependent tumor models. Results: In enzymatic assays, FHND5071 potently inhibited RET wild type, RET fusions and mutations with the IC50 of 4.47~19.26 nM and demonstrated 89-fold selectivity over KDR (VEGFR-2). FHND5071-M2, the active metabolite identified in pre-clinical pharmacokinetics, had the same potency as FHND5071. In cellular settings, FHND5071 inhibited the proliferation of Ba/F3 engineered cells (RET WT, RET V804M, RET M918T) and inhibited RET phosphorylation in HEK-293 engineered cells (WT, V804M, RET M918T, KIF5B-RET, CCDC6-RET) with the similar potency compared with selpercatinib. In PK/PD study (Ba/F3 KIF5B-RET allograft model), compared with selpercatinib, FHND5071 had longer Tmax and MRT in plasma and tumor tissue. FHND5071 preferred to be distributed into tissues. The exposure of FHND5071 in tumor tissue (AUC0-t) was ~28 times that of selpercatinib and the concentration of FHND5071 in brain tissue was ~33 times that of selpercatinib at 4 h after dosing. Meanwhile, after FHND5071 administration, RET phosphorylation and the downstream signaling protein (pAKT, pErk1/2) were significantly inhibited in tumor tissue and the inhibition was maintained for 24 h at least. But the duration of inhibition with selpercatinib was shorter than that of FHND5071. In tumor models, FHND5071 exhibited significant anti-tumor efficacy in Ba/F3 KIF5B-RET model at oral dose levels ≥3 mg/kg once daily (QD) without inducing significant toxicity. FHND5071 QD exhibited similar anti-tumor activity as selpercatinib administrated twice a day (BID) at 30 mg/kg. 30 mg/kg FHND5071 (QD) demonstrated significant anti-tumor efficacy with 100% TGI in patient-derived xenograft models (colorectal cancer with CCDC6-RET and ovarian cancer with NCOA4-RET). In CCDC6-RET intracranial xenograft model, 30 mg/kg FHND5071 (QD) significant prolonged life time of model mice. The median survival time was 56 days and the increase in life-span was 51% (p<0.005 compared with the vehicle group). Conclusions: FHND5071 demonstrated excellent selectivity and anti-tumor efficacy. The unique pharmacokinetic profile of FHND5071 supported the frequency of once-a-day dosing and better efficacy in target organ and brain tumor in clinical. FHND5071 has received IND approval from NMPA and FDA. It is currently in the dose-escalation segment of a first-in-human phase 1 trial for patients with RET-driven solid tumors. Citation Format: Yongqiang Zhu, Jia Wang, Minghong Shang. FHND5071: a selective RET inhibitor with unique pharmacokinetic profile [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB330.
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Gou, Qitao, Xiaochuan Gan, Longhao Li, Qiheng Gou und Tao Zhang. „Precious Gene: The Application of RET-Altered Inhibitors“. Molecules 27, Nr. 24 (13.12.2022): 8839. http://dx.doi.org/10.3390/molecules27248839.
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The well-known proto-oncogene rearrangement during transfection (RET), also known as ret proto-oncogene Homo sapiens (human), is a rare gene that is involved in the physiological development of some organ systems and can activate various cancers, such as non-small cell lung cancer, thyroid cancer, and papillary thyroid cancer. In the past few years, cancers with RET alterations have been treated with multikinase inhibitors (MKIs). However, because of off-target effects, these MKIs have developed drug resistance and some unacceptable adverse effects. Therefore, these MKIs are limited in their clinical application. Thus, the novel highly potent and RET-specific inhibitors selpercatinib and pralsetinib have been accelerated for approval by the Food and Drug Administration (FDA), and clinical trials of TPX-0046 and zetletinib are underway. It is well tolerated and a potential therapeutic for RET-altered cancers. Thus, we will focus on current state-of-the-art therapeutics with these novel RET inhibitors and show their efficacy and safety in therapy.
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Bunker, Lisa D., Christina Nessler und Julie L. Wambaugh. „Effect Size Benchmarks for Response Elaboration Training: A Meta-Analysis“. American Journal of Speech-Language Pathology 28, Nr. 1S (11.03.2019): 247–58. http://dx.doi.org/10.1044/2018_ajslp-17-0152.
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Purpose With a number of single-case experimental design studies reporting the effects of treatment for response (and modified response) elaboration training (RET/M-RET), it is important to consolidate data over multiple participants to allow comparison within/between individuals and across similar treatments. The purpose of this study was to conduct a meta-analysis of single-case experimental design studies of RET/M-RET and to determine effect size (ES) benchmarks to allow comparison to “group” data. Method Database and bibliographical searches identified 20 investigations of RET/M-RET. Nine studies had sufficient experimental quality, compliance with the essential components of the RET protocol, and consistency in the dependent variable (i.e., accurate content production in response to picture stimuli) to be retained for the meta-analysis. Probe data for a total of 26 persons with aphasia (PWA) were extracted from published graphs (if raw data were not available) to calculate weighted ESs at the end of treatment and at follow-up for both treated and untreated stimuli. The first, second, and third quartiles of the distributions were used to serve at benchmarks for small, medium, and large effects. Results Nearly all participants demonstrated positive effects as a result of RET/M-RET, indicating an association with positive changes in content production for PWA. Small, medium, and large benchmarks are reported for treated items after treatment and at follow-up, as well as for untreated items after treatment and at follow-up. Conclusions With a larger sample of 26 participants, this analysis indicates that RET/M-RET are associated with positive changes in content production for PWA. ES benchmarks allow clinicians/researchers to compare an individual's performance across multiple applications of treatment to performance of other PWA and to other treatments with similar outcomes.
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Khatri, Ujjwol, Neetu Dayal, Xueqing Hu, Elizabeth Larocque, Nimishetti Naganna, Tao Shen, Xuan Liu et al. „Abstract 3851: Targeting RET solvent-front mutants with an alkynyl nicotinamide-based inhibitor“. Cancer Research 83, Nr. 7_Supplement (04.04.2023): 3851. http://dx.doi.org/10.1158/1538-7445.am2023-3851.
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Abstract Selpercatinib (LOXO-292, LY3527723) and pralsetinib (BLU-667) are first-in-class RET-targeted cancer therapy drugs. However, secondary RET mutations that confer selpercatinib/pralsetinib resistance have been identified, necessitating development of next-generation RET Tyrosine kinase inhibitors (TKIs). While the G810C/R/S/V mutations located at the RET kinase solvent-front site were detected in selpercatinib-treated patients, it was unclear whether all of these and other potential G810 mutants are resistant to selpercatinib and pralsetinib. We profiled selpercatinib and pralsetinib on all six possible G810 mutants derived from single nucleotide substitution. Surprisingly, the G810V mutant found in a clinical study was not resistant to selpercatinib or pralsetinib. Besides G810C/R/S, G810D also conferred selpercatinib/pralsetinib resistance. We found that alkynyl nicotinamide compounds such as HSN608 have better drug-like properties than alkynyl benzamides. HSN608 inhibited RET and RET V804M gatekeeper mutant, and all six G810 mutants with low nanomolar IC50s in the BaF3/KIF5B-RET mutant cell model. In cell derived xenograft (CDX) tumors driven by KIF5B-RET(G810C), HSN608 caused regression of the selpercatinib-resistant tumors. This study clarifies the sensitivities of different RET solvent-front mutants to selpercatinib and pralsetinib, and identifies an alkylnyl nicotinamide-based RET TKI for inhibiting selpercatinib/pralsetinib-resistant G810 mutants. Citation Format: Ujjwol Khatri, Neetu Dayal, Xueqing Hu, Elizabeth Larocque, Nimishetti Naganna, Tao Shen, Xuan Liu, Frederick W. Holtsberg, M. Javad Aman, Herman O. Sintim, Jie Wu. Targeting RET solvent-front mutants with an alkynyl nicotinamide-based inhibitor. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3851.
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Sahakian, Nicolas, Frédéric Castinetti und Pauline Romanet. „Molecular Basis and Natural History of Medullary Thyroid Cancer: It is (Almost) All in the RET“. Cancers 15, Nr. 19 (05.10.2023): 4865. http://dx.doi.org/10.3390/cancers15194865.
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Medullary thyroid cancer (MTC) is a rare disease, which can be either sporadic (roughly 75% of cases) or genetically determined (multiple endocrine neoplasia type 2, due to REarranged during Transfection RET germline mutations, 25% of cases). Interestingly, RET pathogenic variants (mainly M918T) have also been reported in aggressive forms of sporadic MTC, suggesting the importance of RET signalling pathways in the pathogenesis of MTC. The initial theory of RET codon-related MTC aggressiveness has been recently questioned by studies suggesting that this would only define the age at disease onset rather than the aggressiveness of MTC. Other factors might however impact the natural history of the disease, such as RET polymorphisms, epigenetic factors, environmental factors, MET (mesenchymal–epithelial transition) alterations, or even other genetic alterations such as RAS family (HRAS, KRAS, NRAS) genetic alterations. This review will detail the molecular bases of MTC, focusing on RET pathways, and the potential mechanisms that explain the phenotypic intra- and interfamilial heterogeneity.
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Sijmons, R. H., R. M. W. Hofstra, F. A. Wijburg, T. P. Links, R. P. Zwierstra, A. Vermey, D. C. Aronson et al. „Oncological implications of RET gene mutations in Hirschsprung’s disease“. Gut 43, Nr. 4 (01.10.1998): 542–47. http://dx.doi.org/10.1136/gut.43.4.542.
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Background—Germline mutations of the RET proto-oncogene identical to those found in the tumour predisposition syndrome multiple endocrine neoplasia type 2A (MEN2A), were detected in 2.5–5% of sporadic and familial cases of Hirschsprung’s disease. Some patients with Hirschsprung’s disease may therefore be exposed to a highly increased risk of tumours.Aims—To define clinical use of RET gene testing in Hirschsprung’s disease and related patient management from an oncological point of view.Methods—Sixty patients with Hirschsprung’s disease were screened for RET mutations. In three, MEN2A type RET mutations were detected. Case reports for these three patients are presented.Results and conclusions—Only 22 families or sporadic patients with Hirschsprung’s disease and MEN2A type RET mutations have been reported. Therefore, it is difficult to predict tumour risk for patients with familial or sporadic Hirschsprung’s disease, and their relatives, who carry these mutations. For these mutation carriers, periodic screening for tumours as in MEN2A is advised, but prophylactic thyroidectomy is offered hesitantly. RET gene testing in familial or sporadic Hirschsprung’s disease is not recommended at present outside a complete clinical research setting. In combined MEN2A/Hirschsprung’s disease families RET gene testing, tumour screening, and prophylactic thyroidectomy are indicated as in MEN2A.
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Di Cristofaro, J., V. Vasko, V. Savchenko, S. Cherenko, A. Larin, M. D. Ringel, M. Saji et al. „ret/PTC1 and ret/PTC3 in thyroid tumors from Chernobyl liquidators: comparison with sporadic tumors from Ukrainian and French patients“. Endocrine-Related Cancer 12, Nr. 1 (März 2005): 173–83. http://dx.doi.org/10.1677/erc.1.00884.
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Like children exposed to Chernobyl fallout, the workers who cleaned up after the accident, also known as liquidators, have exhibited an increased incidence of thyroid cancer. A high prevalence of ret/PTC3 rearrangement has been found in pediatric post-Chernobyl thyroid tumors, but this feature has not been investigated in liquidator thyroid tumors. In this study we analyzed the prevalence of ret/PTC1 and ret/PTC3 in thyroid tumors from 21 liquidators, 31 nonirradiated adult Ukrainian patients, and 34 nonirradiated adult French patients. ret rearrangements in carcinomas were found in 83.3% of liquidators, 64.7% of Ukrainian patients, and 42.9% of French patients. The prevalence of ret/PTC1 was statistically similar in the three groups. The prevalence of ret/PTC3 was significantly higher in liquidators than in French patients (P = 0.03) but it was also high in nonirradiated Ukrainian patients who exhibited values intermediate between liquidators and French patients. In adenomas the prevalence of rearrangement was significantly higher in all Ukrainians than in French patients (P = 0.004). Like children exposed to Chernobyl fallout, liquidators showed a high prevalence of ret/PTC3. This finding suggests that irradiation had the same effect regardless of age. However, given the high rate of ret/PTC3 in nonirradiated adult Ukrainians, the possibility of genetic susceptibility or low-level exposure to radiation in that group cannot be excluded.
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Peng, Hai Xin, und Rui Kang. „Stimulate and Eliminate Electronic Product Design Defects By Reliability Enhancement Testing“. Advanced Materials Research 663 (Februar 2013): 621–25. http://dx.doi.org/10.4028/www.scientific.net/amr.663.621.
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This paper first introduces the test profile of Reliability Enhancement Testing(RET) then completed in the past three years, a large number of the implementation results of the RET test were statistically analyzed, given the distribution of the design defect, the last two design defects excitation and elimination process were be detailed explanation, and demonstrated it is exceptionally effective that the RET test inspire and eliminate electronic product design defects.
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Bhujbal, Swapnil P., Seketoulie Keretsu und Seung Joo Cho. „Molecular Modelling Studies on Pyrazole Derivatives for the Design of Potent Rearranged during Transfection Kinase Inhibitors“. Molecules 26, Nr. 3 (28.01.2021): 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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Sung, Bongsuk, und Woo-Yong Song. „Are Political Factors More Relevant Than Economic Factors in Firm-Level Renewable Energy Technology Export? Evidence from Path Analysis“. Sustainability 13, Nr. 16 (06.08.2021): 8788. http://dx.doi.org/10.3390/su13168788.
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Renewable energy technology (RET) firms are key economic entities in the export of RET-related products and components, in which RET firms’ exports are affected largely by policy and market. Nonetheless, the effects of policy and market factors on RET firm-level export have never received attention from researchers. This study aims to fill the gap by taking a political economy approach to establish a structural equation model to analyze the path of political-economic factor-firms’ market orientation-based export. This study reveals that RET firms’ market-orientation-based export enhancement depends entirely on political forces. Particularly, two government intervention instruments, environmental policy and export promotion policy, were highlighted. However, the effects of renewable energy policies on the exports of RET firms through market orientation are negative and statistically significant. This study proves that the effects of inter-firm competition and market attractiveness on RET firms’ exports through their market orientation are negative and statistically significant and insignificant, respectively. Further, this study demonstrates that RET firms’ market orientation has a significant positive effect on their export performance. We conclude that in order to improve RET-related policy effectiveness and efficiency, it will be useful to consider firms’ heterogeneity in response to external factors. Additionally, a full mediation model in the academic investigation of the effects of various external factors, including public policies and market factors, on firm-level export, and the implementation of firm-level export-induced policy, taking into account firms’ managerial interpretations to external factors, should be considered.
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Lin, Hao, Yujie Liu, Ruitao Zhou, Yutao Feng, Huiya Cao, Peisu Suo, JIA Guo und Shifu Chen. „Noncanonical RET fusions in Chinese patients with non-small cell lung cancer from DNA-based next-generation sequencing.“ Journal of Clinical Oncology 42, Nr. 16_suppl (01.06.2024): e20000-e20000. http://dx.doi.org/10.1200/jco.2024.42.16_suppl.e20000.
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e20000 Background: The FDA has approved selpercatinib and pralsetinib for the treatment of metastatic RET fusion-positive non-small cell lung cancer in adult patients. Although the overall response rate is high and the response is durable, the outcomes may vary due to different fusion types of the same driver gene. Methods: We retrospectively collected and analyzed 14062 samples (tumour tissue or plasma) from Chinese lung cancer patients who underwent tissue-based or ctDNA-based next-generation sequencing (NGS) assays at HaploX Genomic Sequencing Center from May 18, 2020, to January 11, 2024. All samples with a RET gene fusion were included and classified based on the fusion partner gene and breakpoint position. Results: A total of 157 (1.1%) samples with DNA-based NGS harbored a RET gene fusion. Among the samples with a RET gene fusion, the most common RET fusion partners at the DNA level were KIF5B (73.2%) and CCDC6 (21.0%). We categorized RET fusions into canonical fusions and noncanonical fusions based on fusion partner and breakpoint position, and the proportions of canonical fusions and noncanonical fusions were 88.5% (139/157) and 11.5% (18/157) respectively. Among the samples with a noncanonical RET fusion, 5 samples harbored a RET fusion with an uncommon fusion partner, it remains unclear whether these fusions lead to RET activation. Conclusions: In this retrospective study, we identify different types of RET fusions in Chinese lung cancer patients. The majority are canonical fusions, which can benefit from tyrosine kinase inhibitors in clinical, the rest are noncanonical fusions, and their role in precision therapy needs further verification by RNA-based NGS or other assays. All in all, our research helps guide precision therapy in clinical settings. [Table: see text]
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Imtiaz, Isma, Ayesha Younas, Ayisha Imran, Abuzar Siddique, Nauman Aslam Malik und Akhtar Sohail Chughtai. „SIGNIFICANCE OF MEASURING RETICULOCYTE HEMOGLOBIN (RET-HE) IN CHRONIC KIDNEY DISEASE PATIENTS“. Pakistan Journal of Pathology 34, Nr. 2 (27.06.2023): 37–41. http://dx.doi.org/10.55629/pakjpathol.v34i2.748.
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Objective: To determine the significance of measuring reticulocyte hemoglobin (Ret-He) in chronic kidney disease patients. Material and Methods: It was a cross sectional study conducted at Chughtai Healthcare from March 2021 to March 2022. Approval was obtained from the ethical and research committee of the institute. 102 patients, both males and females, between the ages of 10-75 years, diagnosed cases of CKD were included in the study. Informed consent was taken from all the patients. Blood specimens were collected in EDTA vials and serum separating vials and tested for serum iron, serum ferritin, total iron binding capacity (TIBC), transferrin saturation and complete blood count’(CBC). Ret-He was obtained by flowcytometry method using Sysmex XN 1000. Patients with acute infections/ inflammation, liver diseases, pregnant females, any coexisting bleeding disorder and malignancy were excluded from the study. Results: There is a significant positive correlation between Iron and Ret-He, a positive correlation between Ret-He and Transferrin saturation and no correlation between Ret-He and ferritin along with TIBC. Conclusion: Ret-He’ is a reliable and economical test that can be used for detecting iron deficiency, especially in patients with chronic inflammatory conditions such as CKD. Key Words: Chronic kidney disease (CKD), Reticulated hemoglobin (Ret-He), Iron deficiency anemia
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Kotani, Takaya, Junya Takegaki, Ryo Takagi, Koichi Nakazato und Naokata Ishii. „Consecutive bouts of electrical stimulation-induced contractions alter ribosome biogenesis in rat skeletal muscle“. Journal of Applied Physiology 126, Nr. 6 (01.06.2019): 1673–80. http://dx.doi.org/10.1152/japplphysiol.00665.2018.
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Ribosome biogenesis has been implicated in resistance exercise training (RET)-induced skeletal muscle hypertrophy. However, it is unclear how increasing bouts of RET affects ribosome content and biogenesis. This was investigated in the present study using simulated RET where rat skeletal muscle is subjected to increasing bouts of electrical stimulation. Sprague-Dawley rats were randomly assigned to the following seven groups: sedentary for 5 days (SED) or 6 wk (SED_6w), resistance-exercise trained with 1 bout (1B), 2 bouts (2B), 3 bouts (3B), 6 bouts (6B), and 18 bouts (18B). RET was simulated on the right gastrocnemius muscle by transcutaneous electric stimulation under isoflurane anesthesia, and a RET bout was given 3 times a week. Rats in 1B, 2B, and 3B groups showed increased 45S precursor (pre-) rRNA and 18S+28S rRNA content per muscle weight and elevated mRNA levels of c- myc and upstream binding factor (UBF). Increases in phosphorylated UBF and total cyclin D1 protein level were observed 48 h after RET; the former increased as a function of RET duration. In 3B, 6B, and 18B groups, the 18S+28S rRNA content per muscle weight was kept unchanged, and 45S pre-rRNA, cyclin D1, and phosphorylated UBF levels in 18B were lower than those in 3B. These results suggest that RET activates ribosome biogenesis and increases ribosome content through modulation of UBF and cyclin D1 activity at its early phase. Additional bouts of RET may not lead to a further increase in ribosome content per muscle weight through possibly the attenuation of transcription process. NEW & NOTEWORTHY Ribosome biogenesis has been implicated in resistance exercise training-induced skeletal muscle hypertrophy. However, it remains unclear how this is influenced by the volume of repeated bouts of resistance exercise training. Using resistance exercise training model with rat skeletal muscle, we provide evidence that ribosome biogenesis is stimulated by the initial few bouts of resistance exercise training with no additional effect of further increase in the exercise bout.
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Borrello, Maria Grazia, Antonella Aiello, Bernard Peissel, Maria Grazia Rizzetti, Piera Mondellini, Debora Degl'Innocenti, Veronica Catalano et al. „Functional characterization of the MTC-associated germline RET-K666E mutation: evidence of oncogenic potential enhanced by the G691S polymorphism“. Endocrine-Related Cancer 18, Nr. 4 (20.06.2011): 519–27. http://dx.doi.org/10.1530/erc-10-0306.
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Activating mutations of RET, a gene encoding two isoforms of a tyrosine kinase receptor physiologically expressed in several neural crest-derived cell lineages, are associated with the inherited forms of medullary thyroid carcinoma (MTC). The identification and characterization of novel RET mutations involved in MTC is valuable, as RET gene testing plays a crucial role in the management of these patients. In an MTC patient, we have identified a germline c.1996A>G transition in heterozygosis leading to K666E substitution. In addition, the conservative S904S (c.2712C>G) and the non-conservative functional G691S (c.2071G>A) polymorphisms have been identified. Through functional studies, we demonstrate for the first time that K666E is a gain-of-function mutation with oncogenic potential, based on its ability to transform NIH3T3 cells. It was not possible to define whether K666E is a de novo or inherited RET variant in the patient, as the family history was negative for MTC, and the carrier status of family members could not be tested. Our results, together with a recent report of co-segregation of the mutation in three MTC families, suggest that K666E is a causative MTC mutation. As we have shown that the same patient allele carries both K666E and G691S variants, the latter known to increase downstream RET signaling, a possible role for the G691S polymorphism has also been investigated. We have demonstrated that, although RET-G691S is not oncogenic per se, it enhances the transforming activity of the RET-K666E mutant, thus suggesting a modifier role for this functional polymorphism.
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Garcia-Rendueles, Angela R., Miguel Chenlo, Fernando Oroz-Gonjar, Antonia Solomou, Anisha Mistry, Sayka Barry, Carles Gaston-Massuet et al. „RET signalling provides tumorigenic mechanism and tissue specificity for AIP-related somatotrophinomas“. Oncogene 40, Nr. 45 (29.09.2021): 6354–68. http://dx.doi.org/10.1038/s41388-021-02009-8.
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AbstractIt is unclear how loss-of-function germline mutations in the widely-expressed co-chaperone AIP, result in young-onset growth hormone secreting pituitary tumours. The RET receptor, uniquely co-expressed in somatotrophs with PIT1, induces apoptosis when unliganded, while RET supports cell survival when it is bound to its ligand. We demonstrate that at the plasma membrane, AIP is required to form a complex with monomeric-intracellular-RET, caspase-3 and PKCδ resulting in PIT1/CDKN2A-ARF/p53-apoptosis pathway activation. AIP-deficiency blocks RET/caspase-3/PKCδ activation preventing PIT1 accumulation and apoptosis. The presence or lack of the inhibitory effect on RET-induced apoptosis separated pathogenic AIP variants from non-pathogenic ones. We used virogenomics in neonatal rats to demonstrate the effect of mutant AIP protein on the RET apoptotic pathway in vivo. In adult male rats altered AIP induces elevated IGF-1 and gigantism, with pituitary hyperplasia through blocking the RET-apoptotic pathway. In females, pituitary hyperplasia is induced but IGF-1 rise and gigantism are blunted by puberty. Somatotroph adenomas from pituitary-specific Aip-knockout mice overexpress the RET-ligand GDNF, therefore, upregulating the survival pathway. Somatotroph adenomas from patients with or without AIP mutation abundantly express GDNF, but AIP-mutated tissues have less CDKN2A-ARF expression. Our findings explain the tissue-specific mechanism of AIP-induced somatotrophinomas and provide a previously unknown tumorigenic mechanism, opening treatment avenues for AIP-related tumours.
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Loura, Luís M. S., Rodrigo F. M. de Almeida und Manuel Prieto. „Methodologies and formalisms of resonance energy transfer in biophysics. Application to membrane model systems“. International Journal of Photoenergy 5, Nr. 4 (2003): 223–31. http://dx.doi.org/10.1155/s1110662x03000369.
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The formalisms of resonance energy transfer (RET) to a distribution of acceptors are reviewed for several geometries relevant to membranes (planar, bilayer, multilayer) and random probe distribution. Models for nonrandom probe distribution (mean concentration model, phase separation model) are presented. Selected examples of quantitative applications of RET to these systems are described. It is illustrated how information about domain size, partition coefficients, phase composition, phase separation kinetics and bilayer aggregation can be obtained from time-resolved RET data.
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Muhibullah, Nouman Shafique, Navneet Kaur, Jawad Ahmed, Sarmad Zain, Syed Mujtaba Ali Naqvi, Shammas Bajwa et al. „Efficacy and safety of selpercatinib in advanced RET-altered thyroid cancers: A meta-analysis and systematic review.“ Journal of Clinical Oncology 42, Nr. 16_suppl (01.06.2024): e18073-e18073. http://dx.doi.org/10.1200/jco.2024.42.16_suppl.e18073.
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e18073 Background: Selpercatinib is a highly selective RET inhibitor that is used for the treatment of RET-mutant medullary thyroid cancers, but its efficacy and safety is not fully understood. Our objective is to summarize available literature on the safety and efficacy profile of Selpercatinib. Methods: A search was conducted on PubMed, Embase and Cochrane from foundation to 31st January 2024. Patients aged above 18 with Advanced RET-Altered Medullary Thyroid Cancers who received Selpercatinib were identified. Data abstraction was done based on objective response rate, complete response rate, any grade adverse effect (AE) and grade ≥3 AE. Analysis was done using R (v.4.3) and reported as proportions with respective 95% confidence intervals (CI) on forest plots. Results: Four studies were identified that reported the use of Selpercatinib in Advanced RET-Altered Medullary Thyroid Cancers. Our analysis showed that the pooled proportion of objective response rate and complete response rate was 74.8% (95% CI: 70.1% – 79%) and 4.9% (95% CI: 3.1% – 7.7%) respectively. Pooled proportion of patients experiencing any grade AE and grade ≥3 AE was 93.4% (95% CI: 90.4% – 95.6%) and 46.2% (95% CI: 41.1% – 51.3%) respectively. Conclusions: Selpercatinib is a novel RET inhibitor which has potential use against RET-Altered Thyroid Cancers. It has an overall acceptable safety and efficacy profile. However it requires further studies to establish its adverse effects and clinical application. [Table: see text]
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Prazeres, Hugo, Joana Torres, Fernando Rodrigues, Joana P. Couto, João Vinagre, Manuel Sobrinho-Simões und Paula Soares. „How to Treat a Signal? Current Basis for RET-Genotype-Oriented Choice of Kinase Inhibitors for the Treatment of Medullary Thyroid Cancer“. Journal of Thyroid Research 2011 (2011): 1–10. http://dx.doi.org/10.4061/2011/678357.
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The significance ofRETin thyroid cancer comes from solid evidence that, when inherited, anRETactivating mutation primes C-cells to transform into medullary carcinomas. Moreover, environmental exposure to radiation also induces rearranged transforming RET “isoforms” that are found in papillary thyroid cancer. TheRETgene codes for a tyrosine kinase receptor that targets a diverse set of intracellular signaling pathways. The nature ofRETpoint mutations predicts differences in the mechanisms by which the receptor becomes activated and correlates with different forms of clinical presentation, age of onset, and biological aggressiveness. A number of RET-targeting Tyrosine Kinase Inhibitors (TKIs) are currently undergoing clinical trials to evaluate their effectiveness in the treatment of thyroid cancer, and it is conceivable that the RET genotype may also influence response to these compounds. The question that now emerges is whether, in the future, the rational for treatment of refractory thyroid cancer will be based on the management of an abnormal RET signal. In this paper we address the RET-targeting TKIs and review studies about the signaling properties of distinct RET mutants as a means to predict response and design combinatorial therapies for the soon to be available TKIs.
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Cetta, Francesco, Gennaro Chiappetta, Rosa Marina Melillo, Margherita Petracci, Giulia Montalto, Massimo Santoro und Alfredo Fusco. „The ret/ptc1 Oncogene Is Activated in Familial Adenomatous Polyposis-Associated Thyroid Papillary Carcinomas1“. Journal of Clinical Endocrinology & Metabolism 83, Nr. 3 (01.03.1998): 1003–6. http://dx.doi.org/10.1210/jcem.83.3.4614.
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Familial adenomatous polyposis (FAP) is caused by germ-line mutations of the apc gene, and it is associated with an increased risk of developing papillary thyroid carcinomas. We have previously reported that a significant fraction of sporadic human papillary thyroid carcinomas is characterized by gene rearrangements affecting the ret protooncogene. These rearrangements generate chimeric transforming oncogenes designated ret/ptc. By a combined immunohistochemical and RT-PCR approach, we analyzed, for ret/ptc oncogene activation, papillary thyroid carcinomas occurred in two FAP kindreds, both showing typical apc gene mutations. Kindred 1 had seven members affected by FAP, and among these, three patients showed papillary thyroid carcinomas. Kindred 2 had two patients, mother and daughter, affected by colonic polyposis; the 20-yr-old daughter showed also a papillary carcinoma. Here we report that ret/ptc1 oncogene was activated in two of the three papillary carcinomas of FAP kindred 1 and in the papillary carcinoma of FAP kindred 2. These findings document that loss of function of apc coexists with gain of function of ret in some papillary thyroid carcinomas, suggesting that ret/ptc1 oncogene activation could be a progression step in the development of FAP-associated thyroid tumors.
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Ibáñez, Carlos F., Gustavo Paratcha und Fernanda Ledda. „RET-independent signaling by GDNF ligands and GFRα receptors“. Cell and Tissue Research 382, Nr. 1 (31.07.2020): 71–82. http://dx.doi.org/10.1007/s00441-020-03261-2.
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Abstract The discovery in the late 1990s of the partnership between the RET receptor tyrosine kinase and the GFRα family of GPI-anchored co-receptors as mediators of the effects of GDNF family ligands galvanized the field of neurotrophic factors, firmly establishing a new molecular framework besides the ubiquitous neurotrophins. Soon after, however, it was realized that many neurons and brain areas expressed GFRα receptors without expressing RET. These observations led to the formulation of two new concepts in GDNF family signaling, namely, the non-cell-autonomous functions of GFRα molecules, so-called trans signaling, as well as cell-autonomous functions mediated by signaling receptors distinct from RET, which became known as RET-independent signaling. To date, the best studied RET-independent signaling pathway for GDNF family ligands involves the neural cell adhesion molecule NCAM and its association with GFRα co-receptors. Among the many functions attributed to this signaling system are neuronal migration, neurite outgrowth, dendrite branching, spine formation, and synaptogenesis. This review summarizes our current understanding of this and other mechanisms of RET-independent signaling by GDNF family ligands and GFRα receptors, as well as their physiological importance.
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Hasibuan, Husni Gunawan, Syafrizal Nasution und Radar Radius Tarigan. „Correlation of Reticulocyte Hemoglobin Equivalent (Ret-He) Levels and Iron Deficiency Anemia in CKD Patients Treating Regular Hemodialysis“. International Journal of Research and Review 8, Nr. 11 (11.11.2021): 10–16. http://dx.doi.org/10.52403/ijrr.20211102.
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Background: Anemia appears in the early stages of CKD and its prevalence increases as kidney function declines. Ret-HE can be used to diagnose iron-deficiency anemia. Indonesia does not yet have appropriate research data on RET-He levels in CKD patients undergoing hemodialysis as a parameter to assess iron. Therefore, this study aims to examine the ability of RET-He as an alternative parameter to assess iron deficiency in hemodialysis patients. Method: This research is a correlation analytic study with a cross-sectional design, carried out in February-May 2021 at the Hemodialysis Installation of H. Adam Malik Hospital. Blood sample collection and examination are carried out at the Clinical Pathology Laboratory. Primary and secondary data were collected from interviews, questionnaires, or patient medical records. The data will be analyzed by Pearson correlation test using SPSS software. Results: A total of 41 samples consisted of 31 anemic patients and 10 anemic patients with normal RET-He levels. Demographic characteristics based on age group with an average of 47±13.28 years. The correlation of Ret-HE and TSAT levels in CKD patients undergoing hemodialysis shows a significance value of 0.000, so it can be concluded that there is a correlation between RET-HE and TSAT levels with a significance value of <0.05. According to the Pearson correlation number of 0.618 which is in the range of 0.61 to 0.80. Conclusion: There is a positive correlation between Ret-HE levels and iron deficiency anemia in CKD patients undergoing regular hemodialysis. Keywords: CKD, RET-HE, Hemodialysis.