المؤلفون: Raad, Angie¹ (AUTHOR), Rizzo, Maria² (AUTHOR), Appiah, Katherine³ (AUTHOR), Kearns, Isabella⁴ (AUTHOR), Hernandez, Luis⁵ (AUTHOR) luis.hernandez3@takeda.com

المصدر: PharmacoEconomics. May2024, Vol. 42 Issue 5, p527-568. 42p.

مصطلحات موضوعية: *COST effectiveness, *ECONOMIC databases, EPIDERMAL growth factor receptors, NON-small-cell lung carcinoma, PROTEIN-tyrosine kinase inhibitors

الشركة/الكيان: GREAT Britain. National Health Service

مستخلص: Background: Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, with up to 32% of patients with NSCLC harboring an epidermal growth factor receptor (EGFR) mutation. NSCLC harboring an EGFR mutation has a dedicated treatment pathway, with EGFR tyrosine kinase inhibitors and platinum-based chemotherapy often being the therapy of choice. Objective: The aim of this study was to systemically review and summarize economic models of first-line treatments used for locally advanced or metastatic NSCLC harboring EGFR mutations, as well as to identify areas for improvement for future models. Methods: Literature searches were conducted via Ovid in PubMed, MEDLINE, MEDLINE In-Process, Embase, Evidence-Based Medicine Reviews: Health Technology Assessment, Evidence-Based Medicine Reviews: National Health Service Economic Evaluation Database, and EconLit. An initial search was conducted on 19 December 2022 and updated on 11 April 2023. Studies were selected according to predefined criteria using the Population, Intervention, Comparator, Outcome and Study design (PICOS) framework. Results: Sixty-seven articles were included in the review, representing 59 unique studies. The majority of included models were cost-utility analyses (n = 52), with the remaining studies being cost-effectiveness analyses (n = 4) and a cost-minimization analysis (n = 1). Two studies incorporated both a cost-utility and cost-minimization analysis. Although the model structure across studies was consistently reported, justification for this choice was often lacking. Conclusions: Although the reporting of economic models in NSCLC harboring EGFR mutations is generally good, many of these studies lacked sufficient reporting of justification for structural choices, performing extensive sensitivity analyses and validation in economic evaluations. In resolving such gaps, the validity of future models can be increased to guide healthcare decision making in rare indications. [ABSTRACT FROM AUTHOR]

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المؤلفون: Shi, Yulong^1,2 (AUTHOR), Li, Chongwu³ (AUTHOR), Zhang, Xinben¹ (AUTHOR), Peng, Cheng^1,2 (AUTHOR), Sun, Peng⁴ (AUTHOR), Zhang, Qian⁵ (AUTHOR), Wu, Leilei³ (AUTHOR), Ding, Ying⁶ (AUTHOR) dingying@njmu.edu.cn, Xie, Dong³ (AUTHOR) dingying@njmu.edu.cn, Xu, Zhijian^1,2 (AUTHOR) dingying@njmu.edu.cn, Zhu, Weiliang^1,2 (AUTHOR) dingying@njmu.edu.cn

المصدر: Briefings in Bioinformatics. May2024, Vol. 25 Issue 3, p1-10. 10p.

مصطلحات موضوعية: *INFORMATION retrieval, DEEP learning, EPIDERMAL growth factor receptors, LUNG cancer, NON-small-cell lung carcinoma

مستخلص: As key oncogenic drivers in non-small-cell lung cancer (NSCLC), various mutations in the epidermal growth factor receptor (EGFR) with variable drug sensitivities have been a major obstacle for precision medicine. To achieve clinical-level drug recommendations, a platform for clinical patient case retrieval and reliable drug sensitivity prediction is highly expected. Therefore, we built a database, D3EGFRdb, with the clinicopathologic characteristics and drug responses of 1339 patients with EGFR mutations via literature mining. On the basis of D3EGFRdb, we developed a deep learning-based prediction model, D3EGFRAI, for drug sensitivity prediction of new EGFR mutation-driven NSCLC. Model validations of D3EGFRAI showed a prediction accuracy of 0.81 and 0.85 for patients from D3EGFRdb and our hospitals, respectively. Furthermore, mutation scanning of the crucial residues inside drug-binding pockets, which may occur in the future, was performed to explore their drug sensitivity changes. D3EGFR is the first platform to achieve clinical-level drug response prediction of all approved small molecule drugs for EGFR mutation-driven lung cancer and is freely accessible at https://www.d3pharma.com/D3EGFR/index.phpTest. [ABSTRACT FROM AUTHOR]

: Copyright of Briefings in Bioinformatics is the property of Oxford University Press / USA and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

المؤلفون: Polonio Alcalá, Emma

المساهمون: University/Department: Universitat de Girona. Departament de Ciències Mèdiques, University/Department: Universitat de Girona. Departament d'Enginyeria Mecànica i de la Construcció Industrial

مرشدي الرسالة: Ciurana, Quim de, Puig i Miquel, Teresa

المصدر: TDX (Tesis Doctorals en Xarxa)

مصطلحات موضوعية: Càncer de mama triple negatiu, Cáncer de mama triple negativo, Triple negative breast cancer, TNBC, Càncer de pulmó de cèl·lules no petites, Cáncer de pulmón de células no pequeñas, Non-small cell lung cancer, NSCLC, Receptor del factor de creixement epidèrmic mutat, Receptor del factor de crecimiento epidérmico mutado, Epidermal growth factor receptor mutated, EGFRm, Sintasa d'àcids grassos, Sintasa de ácidos grasos, Cultiu cel·lular 3D, Cultivo celular 3D, 3D cell culture, Àcid polilàctic, Ácido poliláctico, Polylactic acid, Policaprolactona, Polycaprolactone, Fabricació additiva, Fabricación aditiva, Additive manufacturing

الوصف: Although there are therapies for triple negative breast cancer (TNBC) and epidermal growth factor-mutated non-small cell lung cancer (EGFRm NSCLC), these two subtypes of cancer are very aggressive, and most patients develop resistance to treatment. Cancer stem cells (CSCs) are a small population that is part of the tumor and are responsible for its initiation, recurrence, progression, and metastasis because they can resist anti-cancer therapies. Hence, the removal of CSCs could be an effective treatment for TNBC and EGFRm NSCLC. Unfortunately, there are no available therapies for this malignant population. Furthermore, the study of CSCs in the laboratory is limited because of their low representation within tumors and the impossibility of studying them with traditional cell culture in two dimensions (2D). Consequently, several three-dimensional (3D) cell culture systems have been developed to allow the research of this subpopulation, such as polymeric structures manufactured by fused filament fabrication (FFF) and electrospinning (ES). Therefore, the first objective of this thesis was to evaluate polylactic acid (PLA) as a material for scaffold fabrication. The 3D supports manufactured by FFF and ES were tested as 3D cell culture systems for expanding breast CSCs (BCSCs) using a TNBC cell model. Although the 3D-cultured cells adhered and grew satisfactorily, especially in the PLA-ES scaffolds, none of the 3D PLA structures showed significant BCSC enrichment

الوصف (مترجم): Tot i que existeixen teràpies contra el càncer de mama triple negatiu (TNBC) i el càncer de pulmó de cèl·lula no petita amb el factor de creixement epidèrmic mutat (EGFRm NSCLC), aquests dos subtipus de càncer són molt agressius i la majoria de pacients desenvolupen resistència al tractament. Les cèl·lules mare del càncer (CSC) són una petita població que forma part del tumor i són responsables del seu inici, reaparició, progressió i metàstasis, ja que poden resistir a les teràpies anticàncer. Per tant, l’eliminació de les CSCs podria ser un tractament efectiu contra el TNBC i EGFRm NSCLC. Desafortunadament, no existeix una teràpia disponible contra aquesta població maligna. A més, l'estudi en el laboratori de les CSCs es troba limitat a causa de la seva baixa representació dintre dels tumors i de la impossibilitat d’estudiar-les amb el cultiu cel·lular tradicional, en dues dimensions (2D). Consegüentment, s'han desenvolupat diferents sistemes de cultiu cel·lular en tres dimensions (3D), per així permetre la investigació d'aquesta subpoblació, com per exemple les estructures polimèriques obtingudes per la fabricació per filament fos (FFF) i l'electrofilat (ES). Per tant, el primer objectiu d'aquesta tesi va ser avaluar l'àcid polilàctic (PLA) com a material per a la fabricació de scaffolds. Els suports 3D obtinguts mitjançant FFF i ES van ser testats com a sistema de cultiu cel·lular 3D per a l'expansió de les CSCs de mama (BCSC) utilitzant un model cel·lular de TNBC. Encara que les cèl·lules sembrades en 3D van adherir-se i van créixer adequadament, especialment en els scaffolds de PLA-ES, cap de les estructures 3D de PLA mostrava un enriquiment significatiu de les BCSCs
Programa de Doctorat en Biologia Molecular, Biomedicina i Salut

وصف الملف: application/pdf

الوصول الحر: http://hdl.handle.net/10803/688874Test

المؤلفون: Polak, David, Falcoff, Diego, Chackartchi, Tali, Asher, Ran, Assad, Rawi

المصدر: International Journal of Oral & Maxillofacial Implants; May/Jun2024, Vol. 39 Issue 3, p473-478, 6p

مصطلحات موضوعية: PLATELET-rich fibrin, PLATELET-derived growth factor, DENTAL materials, DYNAMICS, ENZYME-linked immunosorbent assay, TREATMENT effectiveness, HOMOGRAFTS, FLUORESCENT antibody technique, DESCRIPTIVE statistics, BONE morphogenetic proteins, BONE grafting, VOLUNTEERS, BONE substitutes, IMMUNOASSAY, ORAL health, BLOOD donors, PSYCHOSOCIAL factors

مستخلص: Background: Platelet-rich fibrin (PRF) is used to prepare "sticky bone" by combining it with bone graft material. The present study investigated the ability of different bone grafts to absorb growth factors from the PRF and release them over time. Materials and Methods: Human blood was collected from 10 healthy volunteers for liquid PRF preparation. Bovine bone, allograft (mineralized and demineralized), and synthetic bone were each mixed with the PRF to prepare a sticky bone. All sticky bone samples were incubated for up to 4 days. The absorption and release pattern kinetics of two selective growth factors within the PRF--platelet-derived growth factor (PDGF) and bone morphogenetic protein-2 (BMP-2)--were quantified with immunofluorescence staining and enzyme-linked immunoassay (ELISA) testing. Results: All bone graft materials adsorbed the examined growth factors from the PRF. ß-TCP showed the highest adsorption levels, followed by the xenograft, and the allografts showed the lowest adsorption levels. Furthermore, PDGF showed a fast-release pattern from the grafts, whereas BMP-2 was released at a later stage. Similar to the adsorption pattern, the ß-TCP and xenograft were better able to sustain the release of the PRF growth factors from the graft than the allografts. Conclusions: The adsorption of PDGF and BMP-2 differ between graft materials, with superior results for ß-TCP, followed by xenograft, then allograft materials. [ABSTRACT FROM AUTHOR]

: Copyright of International Journal of Oral & Maxillofacial Implants is the property of Quintessence Publishing Company Inc. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

المؤلفون: Miró Domènech, Laura

المساهمون: University/Department: Universitat de Girona. Departament de Biologia

مرشدي الرسالة: Peracaula Miró, Rosa, Massaguer i Vall-llovera, Anna

المصدر: TDX (Tesis Doctorals en Xarxa)

مصطلحات موضوعية: Càncer de pàncrees, Cáncer de páncreas, Pancreatic cancer, Àcid siàlic, Ácido siálico, Sialic acid, EGFR, Receptor del factor de creixement epidèrmic, Receptor del factor de crecimiento epidérmico, Epidermal growth factor receptor, Sialyl-Lewis X, Inhibidor de sialiltransferases, Inhibidor de sialiltransferasas, Sialyltransferase inhibitor, Fenotip tumoral, Fenotipo tumoral, Tumour phenotype, Ratolins singènics, Ratones singénicos, Syngeneic mice

الوصف: Pancreatic ductal adenocarcinoma (PDA) presents a dismal prognosis mainly due to its delayed diagnosis, its aggressiveness, and resistance to existing therapies. Aberrant glycosylation and, in particular, the overexpression of several sialylated determinants such as sialyl-Lewisx/a (sLex/a), have been associated to cancer progression and metastatic spread, in addition to the modulation of the immune cell component of the tumour microenvironment. Previous studies from our group demonstrated that the α2,3-sialyltransferases (ST) ST3GAL3 and ST3GAL4, two enzymes that transfer sialic acid (SA) to generate α2,3-sialylated determinants, promote the invasive and metastatic phenotype of PDA cell lines. In addition, these enzymes were shown to sialylate cell adhesion molecules involved in tumour progression, such as α2β1 integrin and E-cadherin, regulating their function and signalling pathways. These findings, together with the fact that expression levels of STs and SA levels are generally increased in the serum of cancer patients, being indicative of poor prognosis, highlight the importance of reducing hypersialylation in PDA. Blocking sialylation by modifying ST mRNA expression or by sialidase treatment has been used to study the role of tumour SA, but the application of these approaches to the clinical setting is complex. Nonetheless, the recent discovery and development of ST inhibitors have represented a new strategy to pharmacologically inhibit SA expression in tumours and have opened a path to therapeutically target STs. The Epidermal Growth Factor Receptor (EGFR), an important membrane receptor involved in cell proliferation, contributes to several processes favouring cancer onset, progression, and metastatic spread in nearly all neoplasms, including PDA. EGFR is a glycoprotein membrane receptor that can be sialylated by STs that, in turn, can modulate its function. In this regard, the study of EGFR glycosylation in different cancer types has recently increased, although the role of EGFR sialylation in PDA progression is still unclear, and would be of high interest for scientists developing EGFR-targeted therapies. Under these premises, in this study we principally aimed to gain insight into the role of the STs and their generated tumour sialoglycans on the phenotype of PDA cells; as well as to study their effect on the function and signalling of EGFR

الوصف (مترجم): L'adenocarcinoma ductal pancreàtic (PDA) presenta un pronòstic nefast degut principalment al seu diagnòstic tardà, la seva agressivitat i la resistència a les teràpies existents. La glicosilació aberrant i, en particular, la sobreexpressió de diversos determinants sialilats com el sialil-Lewisx/a (sLex/a), s'han associat amb la progressió del càncer i la formació de metàstasi, a part de la modulació del component immunitari cel·lular del microambient tumoral. En estudis previs del grup s’ha demostrat que les α2,3-sialiltransferases (ST) ST3GAL3 i ST3GAL4, dos enzims que transfereixen àcid siàlic (SA) per generar determinants α2,3-sialilats, promouen el fenotip invasiu i metastàtic de les línies cel·lulars de PDA. A més, s’ha demostrat que aquests enzims sialilen molècules d'adhesió cel·lular implicades en la progressió del tumor, com la integrina α2β1 i la E-cadherina, regulant la seva funció i les vies de senyalització. Aquests resultats, juntament amb el fet que els nivells d'expressió de les STs i els nivells totals de SA s'incrementen generalment en el sèrum dels pacients amb càncer sent indicadors de mal pronòstic, posen de manifest la importància de reduir la hipersialilació en PDA. La disminució de la sialilació modificant l'expressió de l'ARNm de les ST o mitjançant el tractament amb sialidasa s’ha utilitzat per estudiar el paper de l’SA al tumor, però l'aplicació d'aquestes estratègies a l’àmbit clínic és complexa. No obstant això, el recent descobriment i desenvolupament d'inhibidors de les ST han representat una nova estratègia per inhibir farmacològicament l'expressió d’SA en tumors i han portat a considerar les STs com a possibles dianes terapèutiques. El receptor del factor de creixement epidèrmic (EGFR), un receptor de membrana implicat en la proliferació cel·lular, contribueix en diversos processos que afavoreixen l'aparició, la progressió i la propagació del càncer en gairebé totes les neoplàsies, inclòs el PDA. L’EGFR és un receptor de membrana glicoproteic que pot ser sialilat per les STs que, alhora, poden modular la seva funció. En aquest sentit, l'estudi de la glicosilació de l’EGFR en diferents tipus de tumors ha augmentat recentment però el rol de la sialilació de l’EGFR en la progressió del PDA encara no està clar, i el seu estudi seria de gran interès per als científics que desenvolupen teràpies dirigides contra EGFR. Sota aquestes premisses, en aquest estudi es planteja com a objectiu principal conèixer el rol de les STs, i els corresponents sialoglicans tumorals generats, en el fenotip de les cèl·lules de PDA; així com estudiar el seu efecte sobre la funció i la senyalització de l'EGFR
Programa de Doctorat en Biologia Molecular, Biomedicina i Salut

وصف الملف: application/pdf

الوصول الحر: http://hdl.handle.net/10803/688165Test

المؤلفون: Geisler, Hannah C.¹ (AUTHOR), Ghalsasi, Aditi A.¹ (AUTHOR), Safford, Hannah C.¹ (AUTHOR), Swingle, Kelsey L.¹ (AUTHOR), Thatte, Ajay S.¹ (AUTHOR), Mukalel, Alvin J.¹ (AUTHOR), Gong, Ningqiang¹ (AUTHOR), Hamilton, Alex G.¹ (AUTHOR), Han, Emily L.¹ (AUTHOR), Nachod, Benjamin E.¹ (AUTHOR), Padilla, Marshall S.¹ (AUTHOR), Mitchell, Michael J.^1,2,3,4,5,6 (AUTHOR) mjmitch@seas.upenn.edu

المصدر: Journal of Controlled Release. Jul2024, Vol. 371, p455-469. 15p.

مصطلحات موضوعية: *TROPHOBLAST, *EPIDERMAL growth factor receptors, *PLACENTA, *LIPIDS, *MESSENGER RNA, *PLACENTAL growth factor, *NUCLEIC acids

مستخلص: The full potential of ionizable lipid nanoparticles (LNPs) as an in vivo nucleic acid delivery platform has not yet been realized given that LNPs primarily accumulate in the liver following systemic administration, limiting their success to liver-centric conditions. The engineering of LNPs with antibody targeting moieties can enable extrahepatic tropism by facilitating site-specific LNP tethering and driving preferential LNP uptake into receptor-expressing cell types via receptor-mediated endocytosis. Obstetric conditions stemming from placental dysfunction, such as preeclampsia, are characterized by overexpression of cellular receptors, including the epidermal growth factor receptor (EGFR), making targeted LNP platforms an exciting potential treatment strategy for placental dysfunction during pregnancy. Herein, an EGFR antibody-conjugated LNP (aEGFR-LNP) platform was developed by engineering LNPs with increasing densities of antibody functionalization. aEGFR-LNPs were screened in vitro in immortalized placental trophoblasts and in vivo in non-pregnant and pregnant mice and compared to non-targeted formulations for extrahepatic, antibody-targeted mRNA LNP delivery to the placenta. Our top performing LNP with an intermediate density of antibody functionalization (1:5 aEGFR-LNP) mediated a ∼twofold increase in mRNA delivery in murine placentas and a ∼twofold increase in LNP uptake in EGFR-expressing trophoblasts compared to non-targeted counterparts. These results demonstrate the potential of antibody-conjugated LNPs for achieving extrahepatic tropism, and the ability of aEGFR-LNPs in promoting mRNA delivery to EGFR-expressing cell types in the placenta. [Display omitted] • Strain-promoted azide-DBCO cycloaddition produces stable antibody-conjugated LNPs • Pregnancy alters EGFR antibody-conjugated LNP biodistribution in vivo • Intermediate EGFR antibody density enhances mRNA LNP delivery to the placenta • EGFR antibody-conjugated LNPs enhance uptake in EGFR-expressing trophoblasts [ABSTRACT FROM AUTHOR]

المؤلفون: Kong, Ben L.¹ (AUTHOR) kong@ohsu.edu, Stommel, Jayne M.¹ (AUTHOR), Keck, Jamie M.¹ (AUTHOR), Kilburn, David^1,2 (AUTHOR), Streblow, Aaron³ (AUTHOR), Egger, Julian¹ (AUTHOR), Creason, Allison L.¹ (AUTHOR), Suciu, Christopher G.^1,4 (AUTHOR), Guimaraes, Alexander R.^1,2,5 (AUTHOR), Corless, Christopher L.^1,4 (AUTHOR), Mills, Gordon B.^1,2 (AUTHOR), Pejovic, Tanja B.¹ (AUTHOR)

المصدر: JCO Precision Oncology. 6/21/2024, Vol. 8, p1-7. 7p.

مصطلحات موضوعية: *EPIDERMAL growth factor receptors, *EPIDERMAL growth factor, *TRASTUZUMAB

مستخلص: Case report of a HER2-expressed ovarian clear cell carcinoma with exceptional response to trastuzumab deruxtecan. [ABSTRACT FROM AUTHOR]

المؤلفون: Bakri, Sophie J.¹ (AUTHOR) bakri.sophie@mayo.edu, Lynch, Jeff² (AUTHOR), Howard-Sparks, Michelle² (AUTHOR), Saint-Juste, Stephan³ (AUTHOR), Saim, Said² (AUTHOR)

المصدر: PLoS ONE. 6/4/2024, Vol. 19 Issue 6, p1-22. 22p.

مصطلحات موضوعية: *VASCULAR endothelial growth factor receptors, *VASCULAR endothelial growth factor antagonists, *SUNITINIB, *BEVACIZUMAB, *MACULAR degeneration

مستخلص: Purpose: Pathological angiogenesis and vascular instability are observed in diabetic retinopathy (DR), diabetic macular edema (DME), and wet age-related macular degeneration (wAMD). Many receptor tyrosine kinases (RTKs) including vascular endothelial growth factor receptors (VEGFRs) contribute to angiogenesis, whereas the RTK TIE2 is important for vascular stability. Pan-VEGFR tyrosine kinase inhibitors (TKIs) such as vorolanib, sunitinib, and axitinib are of therapeutic interest over current antibody treatments that target only one or two ligands. This study compared the anti-angiogenic potential of these TKIs. Methods: A kinase HotSpot™ assay was conducted to identify TKIs inhibiting RTKs associated with angiogenesis and vascular stability. Half-maximal inhibitory concentration (IC50) for VEGFRs and TIE2 was determined for each TKI. In vitro angiogenesis inhibition was investigated using a human umbilical vein endothelial cell sprouting assay, and in vivo angiogenesis was studied using the chorioallantoic membrane assay. Melanin binding was assessed using a melanin-binding assay. Computer modeling was conducted to understand the TIE2-axitinib complex as well as interactions between vorolanib and VEGFRs. Results: Vorolanib, sunitinib, and axitinib inhibited RTKs of interest in angiogenesis and exhibited pan-VEGFR inhibition. HotSpot™ assay and TIE2 IC50 values showed that only axitinib potently inhibited TIE2 (up to 89%). All three TKIs effectively inhibited angiogenesis in vitro. In vivo, TKIs were more effective at inhibiting VEGF-induced angiogenesis than the anti-VEGF antibody bevacizumab. Of the three TKIs, only sunitinib bound melanin. TKIs differ in their classification and binding to VEGFRs, which is important because type II inhibitors have greater selectivity than type I TKIs. Conclusions: Vorolanib, sunitinib, and axitinib exhibited pan-VEGFR inhibition and inhibited RTKs associated with pathological angiogenesis. Of the three TKIs, only axitinib potently inhibited TIE2 which is an undesired trait as TIE2 is essential for vascular stability. The findings support the use of vorolanib for therapeutic inhibition of angiogenesis observed in DR, DME, and wAMD. [ABSTRACT FROM AUTHOR]

المؤلفون: Kim, Jin-Soo¹ (AUTHOR) gistmd74@snu.ac.kr, Kim, Mi Young¹ (AUTHOR), Hong, Sungyoul² (AUTHOR) sungyoul@snu.ac.kr

المصدر: International Journal of Molecular Sciences. Jun2024, Vol. 25 Issue 11, p5975. 13p.

مصطلحات موضوعية: *HEPATOCYTE growth factor, *CELL lines, *PROTEIN kinase B, *EPIDERMAL growth factor, *CANCER cells, *AGAR, *STOMACH cancer

مستخلص: Capmatinib and savolitinib, selective MET inhibitors, are widely used to treat various MET-positive cancers. In this study, we aimed to determine the effects of these inhibitors on MET-amplified gastric cancer (GC) cells. Methods: After screening 37 GC cell lines, the following cell lines were found to be MET-positive with copy number variation >10: SNU-620, ESO51, MKN-45, SNU-5, and OE33 cell lines. Next, we assessed the cytotoxic response of these cell lines to capmatinib or savolitinib alone using cell counting kit-8 and clonogenic cell survival assays. Western blotting was performed to assess the effects of capmatinib and savolitinib on the MET signaling pathway. Xenograft studies were performed to evaluate the in vivo therapeutic efficacy of savolitinib in MKN-45 cells. Savolitinib and capmatinib exerted anti-proliferative effects on MET-amplified GC cell lines in a dose-dependent manner. Savolitinib inhibited the phosphorylation of MET and downstream signaling pathways, such as the protein kinase B (AKT) and extracellular signal-regulated kinase (ERK) pathways, in MET-amplified GC cells. Additionally, savolitinib significantly decreased the number of colonies formed on the soft agar and exerted dose-dependent anti-tumor effects in an MKN-45 GC cell xenograft model. Furthermore, a combination of trastuzumab and capmatinib exhibited enhanced inhibition of AKT and ERK activation in human epidermal growth factor receptor-2 (HER2)- and MET-positive OE33 cells. Targeting MET with savolitinib and capmatinib efficiently suppressed the growth of MET-amplified GC cells. Moreover, these MET inhibitors exerted synergistic effects with trastuzumab on HER2- and MET-amplified GC cells. [ABSTRACT FROM AUTHOR]

المؤلفون: Halvatsiotis, Panagiotis¹ (AUTHOR) pahalv@gmail.com, Tsokaki, Theodora¹ (AUTHOR), Tsitsis, Vasileios² (AUTHOR), Palaiodimou, Lina³ (AUTHOR), Tsivgoulis, Georgios³ (AUTHOR), Tsangaris, Iraklis⁴ (AUTHOR), Panagiotou, Maria Ourania¹ (AUTHOR), Houhoula, Dimitra⁵ (AUTHOR)

المصدر: Diagnostics (2075-4418). Jun2024, Vol. 14 Issue 11, p1206. 11p.

مصطلحات موضوعية: *GESTATIONAL diabetes, *VASCULAR endothelial growth factor receptors, *PREGNANT women, *GENETIC polymorphisms, *VASCULAR endothelial growth factors, *EPIDERMAL growth factor receptors

مستخلص: The increased prevalence of obesity worldwide has been implicated in the alarming rise of the incidence of gestational diabetes and preeclampsia, which are both considered threatening conditions for both mother and fetus. We studied gene polymorphisms of the proinflammatory cytokine Interleukin 6 (IL-6) and the gene expression levels of VEGF (vascular endothelial growth factor) and VEGF-R (endothelial growth factor receptor), all known to be involved in pregnancy complications, aiming to identify possible predisposing risk factors in pregnancies with obesity. The G allele of IL-6 was found to correspond with an increased risk for gestational diabetes and preeclampsia occurrence. Furthermore, in obese pregnant mothers with either gestational diabetes or pre-existing type 2 diabetes and those who developed preeclampsia, it was confirmed that gene expression levels of VEGF were reduced while they were increased for VEGF receptors. We conclude that the genetic profile of an obese pregnant woman shares a common background with that of a patient with pre-existing type 2 diabetes mellitus, and therefore predisposes them to complications in pregnancy. [ABSTRACT FROM AUTHOR]