Mounting evidence has shown that miRNA-150 expression is upregulated in gastric cancer (GC) and is associated with gastric carcinogenesis, but the underlying oncogenic mechanism remains elusive. ...Here, we discovered that miRNA-150 targets the tumor suppressor SUFU to promote cell proliferation, migration, and the epithelial-mesenchymal transition (EMT) via the dual activation of Hedgehog (Hh) and Wnt signaling. MiRNA-150 was highly expressed in GC tissues and cell lines, and the level of this miRNA was negatively related to that of SUFU. In addition, both the miRNA-150 and SUFU levels were associated with tumor differentiation. Furthermore, miRNA-150 activated GC cell proliferation and migration
. We found that miRNA-150 inhibitors repressed not only Wnt signaling by promoting cytoplasmic β-catenin localization, but also repressed Hh signaling and EMT. MiRNA-150 inhibition also resulted in significant tumor volume reductions
, suggesting the potential application of miRNA-150 inhibitors in GC therapy. The expression of genes downstream of Hh and Wnt signaling was also reduced in tumors treated with miRNA-150 inhibitors. Notably, anti-SUFU siRNAs rescued the inhibitory effects of miRNA-150 inhibitors on Wnt signaling, Hh activation, EMT, cell proliferation, cell migration, and colony formation. Taken together, these findings indicate that miRNA-150 is oncogenic and promotes GC cell proliferation, migration, and EMT by activating Wnt and Hh signaling via the suppression of SUFU expression.
The shaking table is a good reproduction of the structure response test method in the laboratory. This paper explores the shaking or vibration table from the aspects of construction, control ...technology, test method and application. The construction time of a typical shaking table in China and around the world is given, and the indicators such as table size and performance parameters are hereto summarised. This paper expounds the significance of the construction of the shaking table, analyses its development and the advantages and disadvantages of its control technology, and discusses its existing mainstream test methods and application process. The application of the shaking table technology in related research fields is introduced in detail. This provides a reference for the further selection, upgrade, development and utilisation of seismic research simulation of shaking table.
Highlights • Co-culture with bone marrow stroma can induce Bortezomib resistance in U266 cells. • Activated NF-κB signaling pathway plays a vital role in Bortezomib resistance. • HHT enhances ...anti-myeloma effects of Bortezomib both in vitro and in vivo.
Abstract
Background: GQ1001 is a novel HER2-targeted antibody-drug conjugate (ADC) that was developed using innovative conjugation technologies coined intelligent Ligase-Dependent Conjugation (iLDC), ...that can significantly improves homogeneity and biostability of ADC. In preclinical studies, GQ1001 showed a robust anti-tumor response in multiple HER2+ models alone or in combination with HER2 TKIs and chemotherapeutics, and excellent pharmacokinetics and safety profiles in rats and monkeys due to low level of payload release. Herein we report the initial results of the ongoing phase Ia study, which aims to investigate the safety, tolerability, pharmacokinetics and antitumor activity of GQ1001 in subjects with HER2+ advanced solid tumors.
Methods: In phase Ia dose escalation, a modified 3+3 model was adopted to assess the safety, dose-limiting toxicity (DLT) and maximal tolerable dose (MTD) or dose recommended for dose expansion (DRDE) of GQ1001. GQ1001 was administered intravenously as a monotherapy on Day 1 of 21-day cycles. The starting dose was 1.2 mg/kg, followed by 2.4, 3.6, 4.8, 6.0, 7.2 and 8.4 mg/kg.
Results: As of Dec. 28th, 2022, 32 subjects with HER2-positive advanced solid tumors, predominantly in breast (9), gastric or gastro-esophageal junction (9) and salivary gland (4), were enrolled and received GQ1001 treatment. Patients had a median 3 (range, 0-11) prior lines of therapies, and 37.5% of those previously received ≥2 lines of anti-HER2 therapies. Median exposure time of GQ1001 was 18.5 weeks. The longest treatment duration exceeded 370 days. No DLT was observed in all doses, MTD was not reached up to 8.4 mg/kg, the highest dose tested. Treatment-related adverse events (TRAEs) occurred in 24 subjects (75%). The most common TRAEs (>10.0%) were aspartate aminotransferase (AST) increased (37.5%), thrombocytopenia (28.1%), alanine aminotransferase (ALT) increased (25.0%), pyrexia (21.9%), anemia (18.8%), alkaline phosphatase increased (12.5%), vomiting (12.5%) and nausea (12.5%). Grade ≥3 TRAEs occurred in 9 subjects (28.1%), including 5 myelosuppression, 2 abnormal liver function, 1 hypertension and 1 vomiting. There were no drug-related deaths. The pharmacokinetics analysis showed the concentration of GQ1001 and TAb generally peaked rapidly and declined in a roughly biphasic manner. Among 15 evaluable subjects who received ≥ 7.2 mg/kg, 6 cases achieved confirmed partial response, and 3 had stable disease, the median progression-free survival was 4.8 months
Conclusions: GQ1001 demonstrates an excellent tolerability and promising antitumor activity in heavily pretreated HER2-positive advanced solid tumors, supporting further evaluation of the safety and efficacy of GQ1001 at DRDE of 8.4 mg/kg in the following phase Ib trial. (NCT04450732; sponsored by GeneQuantum Healthcare (Suzhou) Co., Ltd.)
Citation Format: Charlotte Lemech, Chenfei Zhou, Xianbao Zhan, Yan Shi, Jieqiong Liu, Sarina A Piha-Paul, Gary Richardson, Gang Qin, Paul H. Song, Lili Shi, Yajun Sun, Yi Xia. GQ1001: A next generation HER2-targeting ADC that exhibits promising early clinical efficacy with excellent tolerance in a multi-center, Phase Ia study 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 CT178.
Flexure hinges based micro-displacement structure has been widely used for micro-precision machinery, and the natural frequency characteristics analysis is one of the most important elements in the ...structure design. In this paper, natural frequency characteristics analysis of a micro-displacement structure with parallel flexible hinges is presented. The effects of each structure parameter to the natural frequency of the micro-displacement structure are simulation by dynamics modeling. The parameters can be divided into three categories, namely, parallel flexure hinges parameter, micro-displacement structure parameter and material parameter. Two micro-displacement structures using common materials are machined for frequency test. The test results of two micro-displacement structure verified the modeling analysis, and the natural frequency characteristics analysis in this paper can be referenced in micro-displacement structure design.
Firstly, the superior performance and industrial application prospects of non-rotationally symmetric (NRS) optical surfaces are detailed. Secondly, those high precision machining processes to ...generate NRS optical surfaces are overviewed, it’s been stressed that fast tool servo (FTS) based diamond turning has been the most promising, cost-effective, and high precision machining process to generate NRS surfaces. Finally, the recent research progress in FTS based diamond turning of NRS optical surfaces is remarked, both the tool trajectory generation and the FTS actuation techniques are discussed, the limitations of the existing researches are disclosed, and then the academic and technological researches to be urgently carried out are suggested.
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