We investigated the protective effects of a selective α1A-adrenoceptor antagonist, silodosin (Silod) on urinary bladder function in cyclophosphamide (CYP)-induced cystitis rats, with and without desensitization of the capsaicin (CAP)-sensitive afferent nerve pathway. Male Wistar rats (310-400 g) were pretreated with Silod (0, 100, or 300 μg/kg/day, p.o.) for 1 week before cystometry, and were administered either CYP (150 mg/kg, i.p.) or saline 2 days before the experiment. In another experiment, the rats were treated with CAP (125 mg/kg, s.c.) 4 days before the cystometry. The rat bladders were harvested, weighed, and evaluated histologically. The cystometric evaluation showed significant reductions in the intercontraction interval (ICI), single voided volume (SVV), and bladder compliance in CYP-treated rats compared to those in the vehicle-treated rats. High-dose Silod or CAP treatment significantly increased the ICI and SVV in the CYP rats. However, high-dose Silod treatment did not increase the ICI and SVV in CAP-treated CYP rats. Treatment with Silod did not improve the bladder weight, edema, and leukocyte infiltration resulting from the CYP-induced bladder inflammation. These data suggest that blockade of α1-adrenoceptors by Silod inhibited the CAP-sensitive afferent pathway in rats with cystitis.
Structural health monitoring technologies have provided extensive methods to sense the stress of steel structures. However, monitored stress is a relative value rather than an absolute value in the structure’s current state. Among all the stress measurement methods, ultrasonic methods have shown great promise. The shear-wave amplitude spectrum and phase spectrum contain stress information along the propagation path. In this study, the influence of uniaxial stress on the amplitude and phase spectra of a shear wave propagating in steel members was investigated. Furthermore, the shear-wave amplitude spectrum and phase spectrum were compared in terms of characteristic frequency (CF) collection, parametric calibration, and absolute stress measurement principles. Specifically, the theoretical expressions of the shear-wave amplitude and phase spectra were derived. Three steel members were used to investigate the effect of the uniaxial stress on the shear-wave amplitude and phase spectra. CFs were extracted and used to calibrate the parameters in the stress measurement formula. A linear relationship was established between the inverse of the CF and its corresponding stress value. The test results show that both the shear-wave amplitude and phase spectra can be used to evaluate uniaxial stress in structural steel members.
Background: Previous studies have demonstrated that engineered 3D stem cells could greatly increase the safety and stability as multifunctional biologics for in vivo inoculation. We designed a kind of novel 3D-pluripotent stem cell biologics which achieved promising results in animal experiments of mice and rhesus monkeys. To evaluate the safety and efficacy of this therapy in clinic, we conducted this phase I study in patients with advanced non-small-cell lung cancer (NSCLC) after standard treatment failure. Methods: Using a dose-escalation strategy, 5*106, 1*107 or 2.5*107 of 3D-pluripotent stem cells are injected subcutaneously every 7 days in a 28-day cycle for a total of 3 cycles until PD or unacceptable toxicity. Assessments includes safety and preliminary anti-tumor effects. Result: With 3 subjects in each dose-escalation, nine patients were available for clinical evaluation. All patients had experienced at least 2 lines of previous treatment (range 2-6 lines, median 3 lines). All treatment-related adverse events (AEs) were Grade 1. No dose-limiting toxicities (DLTs) were observed. The most frequent treatment-related AEs were local injection reactions and itchy skin. Six patients exhibited stable disease (disease control rate 66.7%) and 3 patients had tumor shrinkage. Two of the 9 patients obtained over-long progression-free survival (PFS) of 16.0 months and exceeded 28.3 months, respectively. Three patients are still surviving so far. Their OS time had exceeded 18.4 months (C-02), 28.3 months (A-02) and 29.4 months (A-01), respectively. For the overall, The median PFS was 16.6 weeks (95% confidence interval (95% CI), 7.0-26.2 weeks) and the median overall survival (OS) was 31.6 weeks (95% CI, 26.9-36.3 weeks). Exploratory single-cell RNA-seq analysis revealed the existence of functional NKT cells in these three patients with long-term survival. Functional NKT cells have been demonstrated by CD57/CD8 double-positive co-expression dynamics using cyclical FACS assay, with a co-expression index over 12~13% for A-02 patient lasting to the latest of 28 months after the end of treatment and over 13.8% for C-02 patient for a duration about 12 months and declined shortly before disease progression. Conclusion: Our study proves the clinic safety and preliminary efficacy of 3D-pluripotent stem cell biologics in the clinic. The final dose of 2.5*107 3D stem cells injected every 7 days in a 28-d cycle was well tolerated. This protocol has a promising prospect with the characteristics of low toxicity and exceptional efficacy to convert the utility to long-term survival. Functional NKT cells may play a key role in this therapy by MHC unrestricted immunocompetence. Citation Format: Meijuan Huang, Xiancheng Chen, Yi Qin, Yaling Long, Qian Li, Yanna Zhang, Min Yu, Panyan Hou, Nanxi Liu, Yanying Li, Yang Yu, Xiaojuan Zhou, Youling Gong, Ke Wang, Jiang Zhu, Feng Peng, Yongsheng Wang, You Lu, Yuquan Wei. A phase I clinical trial of 3D-pluripotent stem cell biologics in heavily treated advanced NSCLC patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT510.
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