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排序方式: 共有53条查询结果,搜索用时 15 毫秒
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Morana Vojnic Daisuke Kubota Christopher Kurzatkowski Michael Offin Ken Suzawa Ryma Benayed Adam J. Schoenfeld Andrew J. Plodkowski John T. Poirier Charles M. Rudin Mark G. Kris Neal X. Rosen Helena A. Yu Gregory J. Riely Maria E. Arcila Romel Somwar Marc Ladanyi 《Journal of thoracic oncology》2019,14(5):802-815
44.
Hannah O’Farrell Bryant Harbourne Zimple Kurlawala Yusuke Inoue Amy L. Nagelberg Victor D. Martinez Daniel Lu Min Hee Oh Bradley P. Coe Kelsie L. Thu Romel Somwar Stephen Lam Wan L. Lam Arun M. Unni Levi Beverly William W. Lockwood 《Journal of thoracic oncology》2019,14(4):656-671
Introduction
Targeted therapies for lung adenocarcinoma (LUAD) have improved patient outcomes; however, drug resistance remains a major problem. One strategy to achieve durable response is to develop combination-based therapies that target both mutated oncogenes and key modifiers of oncogene-driven tumorigenesis. This is based on the premise that mutated oncogenes, although necessary, are not sufficient for malignant transformation. We aimed to uncover genetic alterations that cooperate with mutant EGFR during LUAD development.Methods
We performed integrative genomic analyses, combining copy number, gene expression and mutational information for over 500 LUAD tumors. Co-immunoprecipitation and Western blot analysis were performed in LUAD cell lines to confirm candidate interactions while RNA interference and gene overexpression were used for in vitro and in vivo functional assessment.Results
We identified frequent amplifications/deletions of chromosomal regions affecting the activity of genes specifically in the context of EGFR mutation, including amplification of the mutant EGFR allele and deletion of dual specificity phosphatase 4 (DUSP4), which have both previously been reported. In addition, we identified the novel amplification of a segment of chromosome arm 16p in mutant-EGFR tumors corresponding to increased expression of Golgi Associated, Gamma Adaptin Ear Containing, ARF Binding Protein 2 (GGA2), which functions in protein trafficking and sorting. We found that GGA2 interacts with EGFR, increases EGFR protein levels and modifies EGFR degradation after ligand stimulation. Furthermore, we show that overexpression of GGA2 enhances EGFR mediated transformation while GGA2 knockdown reduces the colony and tumor forming ability of EGFR mutant LUAD.Conclusions
These data suggest that overexpression of GGA2 in LUAD tumors results in the accumulation of EGFR protein and increased EGFR signaling, which helps drive tumor progression. Thus, GGA2 plays a cooperative role with EGFR during LUAD development and is a potential therapeutic target for combination-based strategies in LUAD. 相似文献45.
Hiroki Sato Michael Offin Daisuke Kubota Helena A. Yu Clare Wilhelm Shinichi Toyooka Romel Somwar Mark G. Kris Marc Ladanyi 《Journal of thoracic oncology》2021,16(1):113-126
IntroductionUnlike common EGFR mutations, many less common EGFR mutations remain poorly characterized in terms of oncogenic function and drug sensitivity. Here, we characterize the subset of lung adenocarcinoma harboring EGFR L861Q through both preclinical and clinical investigations.MethodsWe reviewed clinical and genomic data from patients with EGFR-mutant lung cancer. We established cells expressing EGFR mutations and performed functional analysis of L861Q in comparison with common EGFR mutations.ResultsAmong the patients with lung cancer, 3.4% (47 of 1367) possess an EGFR L861Q mutation. Of the patients with L861Q, 23.4% (11 of 47) had a concurrent exon 18 mutation (typically involving G719). In vitro studies revealed that the oncogenic activity of L861Q is dependent on asymmetric dimerization. Cells expressing L861Q were less sensitive to EGFR-specific inhibitors compared with cells expressing L858R but were similarly sensitive to pan-ERBB inhibitors. In cells expressing L861Q, ERBB2 phosphorylation was markedly higher compared with cells expressing L858R, and an enhanced interaction between EGFR and ERBB2 was observed in coimmunoprecipitation studies. In addition, treatment with osimertinib enhanced expression of the antiapoptotic protein MCL1, and knockdown of ERBB2 suppressed the expression of MCL1 in L861Q, raising the possibility of differential allele-specific cross-phosphorylation of ERBB2. Moreover, compared with EGFR-specific inhibitors, pan-ERBB inhibitors exerted superior growth inhibitory effects on cells expressing compound L861Q/G719X mutations.ConclusionsOur results suggest that ERBB2 plays a previously unrecognized role in EGFR L861Q-driven tumorigenesis, and pan-ERBB inhibitors are likely to be more effective than selective EGFR tyrosine kinase inhibitors in this setting. 相似文献
46.
Brandon L. Guthrie Robert Y. Choi Rose Bosire James N. Kiarie Romel D. Mackelprang Anne Gatuguta Grace C. John-Stewart Carey Farquhar 《AIDS and behavior》2010,14(5):1066-1071
This study examines the incidence and predictors of pregnancy in HIV-1-discordant couples from Nairobi, Kenya. Women from
454 discordant couples were followed for up to 2 years. One-year cumulative incidence of pregnancy was 9.7%. Pregnancy rates
did not differ significantly between HIV-1-infected and uninfected women (HR = 1.46). The majority of pregnancies occurred
among women < 30 years old reporting a desire for future children (1-year incidence 22.2%). Pregnancy rates may be high among
discordant couples, indicating desire for children may override concerns of HIV-1 transmission and increase unprotected sex,
and highlighting the need to make conception safer. 相似文献
47.
Sowjanya Bapani Narendranath Epperla Yusuf Kasirye Richard Mercier Romel Garcia-Montilla 《Clinical Medicine & Research》2013,11(2):86-90
Thrombotic thrombocytopenic purpura (TTP) is a hematological disease characterized by microangiopathic hemolytic anemia and thrombocytopenia. Although the link between ADAMTS13 deficiency and idiopathic TTP has been well-established, the role of trimethoprim-sulfamethoxazole (TMP-SMX) in the pathogenesis of TTP is not yet well elucidated. To the best of our knowledge, there have been only two previous reports linking this medication with the development of TTP. We present the case of a healthy woman, age 26 years, who developed TTP during TMP-SMX therapy for urinary tract infection. She was found to have ADAMTS13 deficiency with anti-ADAMTS13 antibodies. Her condition responded to discontinuation of the TMP-SMX, plasmapheresis, and rituximab therapy. We speculate that the acquired ADAMTS13 deficiency might have been triggered by the TMP-SMX therapy. 相似文献
48.
Marissa N Balak Yixuan Gong Gregory J Riely Romel Somwar Allan R Li Maureen F Zakowski Anne Chiang Guangli Yang Ouathek Ouerfelli Mark G Kris Marc Ladanyi Vincent A Miller William Pao 《Clinical cancer research》2006,12(21):6494-6501
PURPOSE: In patients whose lung adenocarcinomas harbor epidermal growth factor receptor (EGFR) tyrosine kinase domain mutations, acquired resistance to the tyrosine kinase inhibitors (TKI) gefitinib (Iressa) and erlotinib (Tarceva) has been associated with a second-site EGFR mutation, which leads to substitution of methionine for threonine at position 790 (T790M). We aimed to elucidate the frequency and nature of secondary EGFR mutations in patients with acquired resistance to TKI monotherapy. EXPERIMENTAL DESIGN: Tumor cells from patients with acquired resistance were examined for secondary EGFR kinase domain mutations by molecular analyses. RESULTS: Eight of 16 patients (50% observed rate; 95% confidence interval, 25-75%) had tumor cells with second-site EGFR mutations. Seven mutations were T790M and one was a novel D761Y mutation found in a brain metastasis. When combined with a drug-sensitive L858R mutation, the D761Y mutation modestly reduced the sensitivity of mutant EGFR to TKIs in both surrogate kinase and cell viability assays. In an autopsy case, the T790M mutation was found in multiple visceral metastases but not in a brain lesion. CONCLUSIONS: The T790M mutation is common in patients with acquired resistance. The limited spectrum of TKI-resistant mutations in EGFR, which binds to erlotinib in the active conformation, contrasts with a wider range of second-site mutations seen with acquired resistance to imatinib, which binds to ABL and KIT, respectively, in closed conformations. Collectively, our data suggest that the type and nature of kinase inhibitor resistance mutations may be influenced by both anatomic site and mode of binding to the kinase target. 相似文献
49.
Sustained exposure of L6 myotubes to high glucose and insulin decreases insulin-stimulated GLUT4 translocation but upregulates GLUT4 activity 总被引:13,自引:0,他引:13
Hyperglycemia and hyperinsulinemia are cardinal features of acquired insulin resistance. In adipose cell cultures, high glucose and insulin cause insulin resistance of glucose uptake, but because of altered GLUT4 expression and contribution of GLUT1 to glucose uptake, the basis of insulin resistance could not be ascertained. Here we show that GLUT4 determines glucose uptake in L6 myotubes stably overexpressing myc-tagged GLUT4. Preincubation for 24 h with high glucose and insulin (high Glc/Ins) reduced insulin-stimulated GLUT4 translocation by 50%, without affecting GLUT4 expression. Insulin receptor and insulin receptor substrate-1 tyrosine phosphorylation, phosphatidylinositol 3-kinase activation, and Akt phosphorylation also diminished, as did insulin-mediated glucose uptake. However, basal glucose uptake rose by 40% without any gain in surface GLUT4. High Glc/Ins elevated basal p38 mitogen-activated protein kinase (MAPK) phosphorylation and activity, and a short inhibition of p38 MAPK with SB202190 corrected the rise in basal glucose uptake, suggesting that p38 MAPK activity contributes to this rise. We propose that in a cellular model of skeletal muscle, chronic exposure to high Glc/Ins reduced the acute, insulin-elicited GLUT4 translocation. In addition, basal state GLUT4 activity was augmented to partially compensate for the translocation defect, resulting in a more robust glucose uptake than what would be predicted from the amount of cell surface GLUT4 alone. 相似文献
50.
Yewon Kim Byeol Han Yu-Jin Kim Jeeyoon Shin Seongyoon Kim Romel Hidayat Jae-Min Park Wonyong Koh Won-Jun Lee 《RSC advances》2019,9(30):17291
We studied the atomic layer deposition (ALD) and the tellurization of Ge–Sb films to prepare conformal crystalline Ge–Sb–Te (GST) films and to achieve void-free gap filling for emerging phase-change memory applications. ALD Ge–Sb film was prepared by alternating exposures to GeCl2-dioxane and Sb(SiEt3)3 precursors at 100 °C. The growth rate was 0.021 nm per cycle, and the composition ratio of Ge to Sb was approximately 2.2. We annealed the ALD Ge–Sb films with a pulsed feeding of di(tert-butyl)tellurium. The ALD Ge–Sb films turned into GST films by the tellurization annealing. When the tellurization temperature was raised to 190 °C or higher temperatures, the Raman peaks corresponding to Ge–Sb bond and amorphous Ge–Ge bond disappeared. The Raman peaks corresponding to Ge–Te and Sb–Te bonds were evolved at 200 °C or higher temperatures, resulting in the phase transition temperature of 123 °C. At 230 °C or higher temperatures, the entire film was fully tellurized to form a GST film having a relatively uniform composition of Ge3Sb2Te6, and the carbon impurities in the as-deposited ALD Ge–Sb film were eliminated. As the tellurization temperature increases, the volume of the ALD film is expanded owing to the incorporation of tellurium, resulting in complete filling of a trench pattern by GST film after the tellurization at 230 °C.We studied the atomic layer deposition (ALD) and the tellurization of Ge–Sb films to prepare conformal crystalline Ge–Sb–Te (GST) films and to achieve void-free gap filling for emerging phase-change memory applications. 相似文献