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61.
JeongYun Choi Haeseung Lee EunJi Kwon HyeonJoon Kong OkSeon Kwon HyukJin Cha 《Molecular oncology》2021,15(2):679
The acquisition of chemoresistance remains a major cause of cancer mortality due to the limited accessibility of targeted or immune therapies. However, given that severe alterations of molecular features during epithelial‐to‐mesenchymal transition (EMT) lead to acquired chemoresistance, emerging studies have focused on identifying targetable drivers associated with acquired chemoresistance. Particularly, AXL, a key receptor tyrosine kinase that confers resistance against targets and chemotherapeutics, is highly expressed in mesenchymal cancer cells. However, the underlying mechanism of AXL induction in mesenchymal cancer cells is poorly understood. Our study revealed that the YAP signature, which was highly enriched in mesenchymal‐type lung cancer, was closely correlated to AXL expression in 181 lung cancer cell lines. Moreover, using isogenic lung cancer cell pairs, we also found that doxorubicin treatment induced YAP nuclear translocation in mesenchymal‐type lung cancer cells to induce AXL expression. Additionally, the concurrent activation of TGFβ signaling coordinated YAP‐dependent AXL expression through SMAD4. These data suggest that crosstalk between YAP and the TGFβ/SMAD axis upon treatment with chemotherapeutics might be a promising target to improve chemosensitivity in mesenchymal‐type lung cancer.
Abbreviations
- AUC
- area under the curve
- AXL
- AXL receptor tyrosine kinase
- BCL2
- B‐cell lymphoma 2
- CTD2
- cancer target discovery and development
- CTGF
- connective tissue growth factor
- DEG
- differentially expressed genes
- DOXO
- doxorubicin
- EMT
- epithelial–mesenchymal transition
- Eto
- etoposide
- FDA
- Food and Drug Administration
- ITGB3
- integrin beta‐3
- MAPK
- mitogen‐activated protein kinase
- MMP2
- matrix metalloproteinase‐2
- MMP9
- matrix metalloproteinase‐9
- mRNA
- messenger RNA
- NF‐κB
- nuclear factor kappa‐light‐chain‐enhancer of activated B cells
- SBE
- SMAD binding element
- SERPINE1
- serpin family E member 1
- siRNA
- small interfering RNA
- ssGSEA
- single‐sample gene set enrichment analysis
- TCGA
- The Cancer Genome Atlas
- TGFβ
- transforming growth factor beta
- YAP
- Yes‐associated protein
- YAP8SA
- mutants of inhibitory phosphorylation site at eight serine to Alanine of YAP
- ZEB1
- zinc finger E‐box binding homeobox 1
- ZEB2
- zinc finger E‐box‐binding homeobox 2
62.
63.
Rafiye Ciftciler Haluk Demiroglu Yahya Buyukasık Elifcan Aladag Salih Aksu Ibrahim C. Haznedaroglu Nilgun Sayınalp Osman Ozcebe Umit Yavuz Malkan Hakan Goker 《Clinical Lymphoma, Myeloma & Leukemia》2019,19(3):177-182
Background
Refractory acute myeloid leukemia (AML) includes AML includes failure of disease to respond to standard induction chemotherapy, relapse within 6 months after first CR, and 2 or more relapses. The outcome of these patients is usually very poor; only a small proportion can be rescued by allogenic hematopoietic stem-cell transplantation (allo-HSCT). The aim of this study was to evaluate the efficacy and feasibility of allo-HSCT in patients with refractory AML.Patients and Methods
We retrospectively analyzed the clinical outcome of 91 patients who were diagnosed with treatment-refractory AML at Hacettepe University Hospital between January 2002 and June 2018. Patients' disease status included refractory AML, defined as failure to respond to standard induction chemotherapy and relapse within 6 months after first complete remission.Results
The median follow-up was 12 months (range, 0.5-184 months) for the entire group. Kaplan-Meier estimates of the 3-year overall survival for patients who underwent allo-HSCT and patients who received only salvage chemotherapy were 67% and 12%, respectively. Additionally, the Kaplan-Meier estimates of 5-year overall survival for patients who underwent allo-HSCT and patients who received only salvage chemotherapy were 44% and 4%, respectively (P < .001). Complete remission was obtained in 25 patients (83.3%) who underwent allo-HSCT; however, the disease of only 3 patients (3.8%) exhibited complete response after salvage chemotherapy.Conclusion
Allo-HSCT is still the best-known treatment option with curative potential in patients with treatment-refractory AML. Therefore, all efforts should be made in an attempt to find a suitable matched donor in order to perform allo-HSCT. 相似文献64.
背景 呼吸道合胞病毒(RSV)毛细支气管炎易出现反复喘息,且下呼吸道分泌物中半胱氨酸白三烯(CysLTs)水平升高。而孟鲁司特是一种白三烯受体拮抗剂,关于其治疗RSV毛细支气管炎症状的研究相对较少。目的 探讨孟鲁司特改善婴幼儿RSV毛细支气管炎后症状及减轻反复喘息发作的有效性和安全性。方法 2015年6月-2017年6月连续纳入在潍坊市妇幼保健院出院的RSV毛细支气管炎患儿,随机分为治疗组、对照组。Ⅰ期,治疗组:口服孟鲁司特颗粒(4 mg)12周,1次/d;对照组:口服安慰剂12周,1次/d。对两组无症状天数、个人日记评分进行评估。随访9个月(Ⅱ期),观察Ⅰ+Ⅱ期反复喘息人数和医疗资源应用情况等。依据意向性分析(ITT)原则,应用全分析集(FAS)分析数据。结果 共纳入研究对象186例,治疗组92例,对照组94例。治疗组完成Ⅰ期研究的患儿为89例,对照组为90例;治疗组完成Ⅰ+Ⅱ期的患儿为84例,对照组为86例。治疗组平均依从性为97.8%(7 560/7 728),对照组平均依从性为97.4%(7 690/7 896),两组患儿平均依从性比较,差异无统计学意义(χ2=3.16,P=0.07)。在Ⅰ期研究期间,两组无症状天数、日间无症状天数、夜间无症状天数、个人日记评分比较,差异均无统计学意义(P>0.05)。在整个研究过程中(Ⅰ+Ⅱ期),治疗组RSV毛细支气管炎喘息复发人数少于对照组(P<0.05),治疗组喘息患儿出现2次及以上喘息比例低于对照组(χ2=5.14,P=0.02)。Ⅰ+Ⅱ期研究期间治疗组医疗资源应用人数、β-受体激动剂应用人数、糖皮质激素应用人数、住院人数低于对照组(P<0.05)。在事后亚组分析中,治疗组有湿疹史与父母哮喘史的患儿中无症状天数〔(49.7±20.2)、(51.3±20.9)d〕多于对照组〔(36.3±20.4)、(37.8±19.3)d〕(t=2.19,P=0.03;t=2.24,P=0.03)。整个研究过程中没有患儿因不良反应退出研究,两组间胃肠道紊乱、皮疹、转氨酶升高发生率比较,差异均无统计学意义(χ2=0.23,P=0.63;χ2=0.03,P=0.86;χ2=0.15,P=0.69)。结论 口服孟鲁司特(4 mg)12周不能改善RSV毛细支气管炎患儿呼吸道症状,但能降低患儿反复喘息发作次数。口服孟鲁司特(4 mg)有一定效果且安全。 相似文献
65.
Cis-diamminedichloridoplatinum(II)(CDDP)-based combination chemotherapy is frequently used in gastrointestinal cancer. The synergistic mechanism of all-trans retinoic acid (ATRA), cisplatin (CDDP) and 5-fluorouracil (5-FU) in combination remains unclear. Despite their potent antitumor properties, resistance to CDDP and 5-FU develops frequently in tumors. To clarify this mechanism, we determined the sensitivity to each drug and their combination in two gastrointestinal cancer stem cells (CSCs) subpopulation.Here, we report the identification and separation of CD44+ cells from human gastric carcinoma (AGS) and human esophageal squamous cell carcinoma (KYSE-30) cancer cell lines by magnetic activated cell sorting (MACS). We allowed the CD44± cells to grow 6 days at a subtoxic concentration of ATRA and then treated with different concentration of CDDP and 5-FU for 24 h. The cytotoxicity was examined by cell proliferation MTT assay. Additionally, AO/EB staining was used for detection of apoptotic cells. In order to determine whether the growth inhibition was also associated with changes in cell cycle distribution, cell cycle analysis was performed using flow cytometry.Low concentration of ATRA (1 μM, 6days) followed by 5-FU and CDDP was found to be more effective than either drugs alone, thus resulting in synergistic cytotoxicity in Kyse-30 and AGSCD44± cells. Furthermore, there was an indication that the combination of ATRA with 5FU and CDDP caused an increase in cell cycle arrest in G2/M and G0/G1.We conclude that low concentration of ATRA enhances the cytotoxicity of CDDP and 5FU by facilitating apoptosis and cell cycle arrest in gastrointestinal CSCs and provide a rational basis for the design of novel, well-tolerated CDDP- and 5FU-based chemotherapy in human gastrointestinal carcinoma. 相似文献
66.
Harit Kapoor Kush Raj Lohani Tommy H. Lee Devendra K. Agrawal Sumeet K. Mittal 《CTS Clinical and Translational Science》2015,8(6):841-847
Esophageal adenocarcinoma is the fastest rising cancer in the United States. It develops from long‐standing gastroesophageal reflux disease which affects >20% of the general population. It carries a very poor prognosis with 5‐year survival <20%. The disease is known to sequentially progress from reflux esophagitis to a metaplastic precursor, Barrett''s esophagus and then onto dysplasia and esophageal adenocarcinoma. However, only few patients with reflux develop Barrett''s esophagus and only a minority of these turn malignant. The reason for this heterogeneity in clinical progression is unknown. To improve patient management, molecular changes which facilitate disease progression must be identified. Animal models can provide a comprehensive functional and anatomic platform for such a study. Rats and mice have been the most widely studied but disease homology with humans has been questioned. No animal model naturally simulates the inflammation to adenocarcinoma progression as in humans, with all models requiring surgical bypass or destruction of existing antireflux mechanisms. Valuable properties of individual models could be utilized to holistically evaluate disease progression. In this review paper, we critically examined the current animal models of Barrett''s esophagus, their differences and homologies with human disease and how they have shaped our current understanding of Barrett''s carcinogenesis. 相似文献
67.
背景与目的以免疫检查点抑制剂(immune checkpoint inhibitors, ICIs)为代表的免疫治疗越来越广泛地应用于肺癌治疗。然而,对于程序性死亡受体配体1(programmed cell death-ligand 1, PD-L1)高表达,即肿瘤比例评分(tumor proportion score, TPS)≥50%的晚期非小细胞肺癌(non-small cell lung cancer, NSCLC)患者,采用单纯免疫治疗还是免疫联合化疗在临床上仍存争议。本研究旨在评估PD-L1高表达的晚期NSCLC患者接受单纯免疫治疗与免疫联合化疗的疗效。方法本研究回顾性分析了49例PD-L1高表达晚期NSCLC患者的临床资料。PD-L1表达采用22C3抗体行免疫组化染色,按TPS判读PD-L1表达水平。比较不同临床特征分组患者的客观缓解率(objective response rate,ORR)和无进展生存时间(progression free survival, PFS)。结果免疫单药与免疫联合化疗组的ORR分别为47.1%(8/17)和43.8%(14/32),差异无统计学意义(P=0.825)。免疫单药与免疫联合化疗组的中位PFS分别为8.0个月和6.8个月,差异无统计学意义(P=0.502)。并对本组PD-L1高表达患者免疫治疗的预测因素进行了分析,结果显示,一线免疫治疗ORR(12/19, 63.2%)显著优于二线及以上免疫治疗(10/30, 33.3%),差异有统计学意义(P=0.041),二者间PFS无差异。年龄、性别、吸烟史、功能状态评分(performance status, PS)、病理类型、肿瘤大小、肿瘤淋巴结转移(tumor node metastasis, TNM)分期与ORR和PFS不相关。结论PD-L1高表达的晚期NSCLC患者接受免疫单药和免疫联合化疗的疗效相近。PD-L1高表达患者一线免疫治疗的ORR更佳。对此类人群的最佳治疗方案有待于前瞻性临床研究进一步探索。 相似文献
68.
《Clinical neurophysiology》2021,132(12):3104-3115
ObjectiveWe aimed to establish an objective neurophysiological test protocol that can be used to assess the somatosensory nervous system.MethodsIn order to assess most fiber subtypes of the somatosensory nervous system, repetitive stimuli of seven different modalities (touch, vibration, pinprick, cold, contact heat, laser, and warmth) were synchronized with the electroencephalogram (EEG) and applied on the cheek and dorsum of the hand and dorsum of the foot in 21 healthy subjects and three polyneuropathy (PNP) patients. Latencies and amplitudes of the modalities were assessed and compared. Patients received quantitative sensory testing (QST) as reference.ResultsWe found reproducible evoked potentials recordings for touch, vibration, pinprick, contact-heat, and laser stimuli. The recording of warm-evoked potentials was challenging in young healthy subjects and not applicable in patients. Latencies were shortest within Aβ-fiber-mediated signals and longest within C-fibers. The test protocol detected function loss within the Aβ-fiber and Aδ-fiber-range in PNP patients. This function loss corresponded with QST findings.ConclusionIn this pilot study, we developed a neurophysiological test protocol that can specifically assess most of the somatosensory modalities. Despite technical challenges, initial patient data appear promising regarding a possible future clinical application.SignificanceEstablished and custom-made stimulators were combined to assess different fiber subtypes of the somatosensory nervous system using modality-specific evoked potentials. 相似文献
69.
《Clinical neurophysiology》2019,130(12):2231-2237
ObjectiveThe clinical and neurophysiological characteristics of myoclonus in Angelman syndrome (AS) have been evaluated in single case or small cohorts, with contrasting results. We evaluated the features of myoclonus in a wide cohort of AS patients.MethodsWe performed polygraphic EEG-EMG recording in 24 patients with genetically confirmed AS and myoclonus. Neurophysiological investigations included jerk-locked back-averaging (JLBA), cortico-muscular coherence (CMC) and generalised partial directed coherence (GPDC). CMC and GPDC analyses were compared to those obtained from 10 healthy controls (HC).ResultsTwenty-four patients (aged 3–35 years, median 20) were evaluated. Sequences of quasi-continuous rhythmic jerks mostly occurred at alpha frequency or just below (mean 8.4 ± 1.4 Hz), without EEG correlate. JLBA did not show any clear transient preceding the jerks. CMC showed bilateral over-threshold CMC in alpha band that was prominent on the contralateral hemisphere in the patient group as compared to HC group. GPDC showed a significantly higher alpha outflow from both hemispheres toward activated muscles in the patient group, and a significantly higher beta outflow from contralateral hemisphere in the HC group.ConclusionsThese neurophysiological findings suggest a subcortical generator of myoclonus in AS.SignificanceMyoclonus in AS has not a cortical origin as previously hypothesised. 相似文献
70.
目的 探讨PDCA 循环在消化道肿瘤伴糖尿病患者营养全程管理中的效果观察。方法 运用PDCA循环对80例不同程度营养不良的消化道肿瘤伴糖尿病患者实施营养全程管理,比较干预前后患者的体重、BMI指数、糖化血红蛋白、血红蛋白、总蛋白、白蛋白及球蛋白水平。结果 患者血红蛋白、总蛋白、白蛋白及球蛋白水平均有提高,比较差异均有统计学意义(P<0.05)。结论 PDCA循环管理在消化道肿瘤伴糖尿病患者营养全程管理中有较大的优势, 值得推广。 相似文献