Chemotherapy plays a crucial role in triple-negative breast cancer (TNBC) treatment as it not only directly kills cancer cells but also induces immunogenic cell death. However, the chemotherapeutic efficacy was strong...Chemotherapy plays a crucial role in triple-negative breast cancer (TNBC) treatment as it not only directly kills cancer cells but also induces immunogenic cell death. However, the chemotherapeutic efficacy was strongly restricted by the acidic and hypoxic tumor environment. Herein, we have successfully formulated PLGA-based nanoparticles concurrently loaded with doxorubicin (DOX), hemoglobin (Hb) and CaCO3 by a CaCO3-assisted emulsion method, aiming at the effective treatment of TNBC. We found that the obtained nanomedicine (DHCaNPs) exhibited effective drug encapsulation and pH-responsive drug release behavior. Moreover, DHCaNPs demonstrated robust capabilities in neutralizing protons and oxygen transport. Consequently, DHCaNPs could not only serve as oxygen nanoshuttles to attenuate tumor hypoxia but also neutralize the acidic tumor microenvironment (TME) by depleting lactic acid, thereby effectively overcoming the resistance to chemotherapy. Furthermore, DHCaNPs demonstrated a notable ability to enhance antitumor immune responses by increasing the frequency of tumor-infiltrating effector lymphocytes and reducing the frequency of various immune-suppressive cells, therefore exhibiting a superior efficacy in suppressing tumor growth and metastasis when combined with anti-PD-L1 (αPD-L1) immunotherapy. In summary, this study highlights that DHCaNPs could effectively attenuate the acidic and hypoxic TME, offering a promising strategy to figure out an enhanced chemo-immunotherapy to benefit TNBC patients.展开更多
目的:研究G蛋白耦联受体激酶相互作用分子1(G-protein-coupled receptor kinase interacting protein 1,GIT1),细胞外信号调节激酶1/2(Extracellular signal-regulated kinases1 and 2,ERK1/2)在脊髓缺血再灌注损伤过程中的作用。方法:...目的:研究G蛋白耦联受体激酶相互作用分子1(G-protein-coupled receptor kinase interacting protein 1,GIT1),细胞外信号调节激酶1/2(Extracellular signal-regulated kinases1 and 2,ERK1/2)在脊髓缺血再灌注损伤过程中的作用。方法:电镜观察缺血30min再灌注不同时间段[A组(对照组)再灌注0min、B组再灌注30min、C组再灌注2h、D组再灌注8h]脊髓组织标本的形态学改变,Westernblot检测各组脊髓标本中ERK1/2和GIT1的表达及其磷酸化,免疫共沉淀分析GIT1同活化的ERK1/2(phospho-ERK1/2,pERK1/2)相互作用的变化,免疫组织化学分析pERK1/2在神经细胞内的定位表达。结果:电镜结果显示D组脊髓神经细胞出现早期凋亡的征象;Western blot结果显示pERK1/2的表达、GIT1的磷酸化在C、D二组较对照组明显增加且均随再灌注时间延长呈明显增加的趋势;免疫共沉淀结果显示GIT1-pERK1/2结合力在C、D两组较对照组明显增加;免疫组织化学结果显示pERK1/2明显滞留于C、D两组的脊髓神经细胞胞浆区内。结论:缺血再灌注损伤过程中ERK1/2的活化以及在胞核外区域的滞留可能导致了脊髓神经细胞的凋亡,而GIT1作为细胞浆内局部黏附蛋白同pERK1/2的结合可能导致了其在胞浆区的滞留。展开更多
A modified GIT model for describing the variational trend of mean clutter reflectivity as a function of wind speed is proposed. It uses two slope adjustment factors and two critical wind-speed factors to define and ad...A modified GIT model for describing the variational trend of mean clutter reflectivity as a function of wind speed is proposed. It uses two slope adjustment factors and two critical wind-speed factors to define and adjust the increasing slope of reflectivity with respect to wind speed. In addition, it uses a constant factor to compensate the overall amplitude of clutter reflectivity. The performance of the modified GIT model has been verified on the basis of the L-band low-grazing-angle radar sea clutter data. The results are in good agreement with the experimental data, indicating that the model is more effective in predicting the wind-speed behavior of clutter reflectivity than the conventional GIT model, especially for lower and higher wind speeds. We believe that the proposed model can provide deeper insights into the relationship between radar sea clutter reflectivity and sea state conditions.展开更多
This study sought to investigate the clinical efficacy and safety of combined oral therapy with sildenafil and doxazosin GITS compared to sildenafil monotherapy in treating Chinese patients with erectile dysfunction ...This study sought to investigate the clinical efficacy and safety of combined oral therapy with sildenafil and doxazosin GITS compared to sildenafil monotherapy in treating Chinese patients with erectile dysfunction （ED） and lower urinary tract symptoms secondary to benign prostatic hyperplasia （BPH/LUTS）. The trial was conducted in hospitals in Beijing, Shanghai, Changsha, Wuhan and Guangzhou, five major cities in China. A total of 250 patients diagnosed with ED and BPH/LUTS aged 50-75 years, and who had International Index of Erection Function-5 （IIEF-5） scores ≤ 21 and International Prostate Symptom Score （IPSS） ≥ 10 points, were enrolled and randomly divided into Group A （168 cases; doxazosin GITS 4 mg once daily plus sildenafi125-100 mg on demand） and Group B （82 cases; sildenafi125-100 mg on demand）. Efficacies were evaluated by IIEF-5 and IPSS scores and a quality of life （QoL） questionnaire, and adverse effects were evaluated during the treatment period. There were no statistically significant differences in mean age, and IIEF-5, IPSS and QoL scores pre-treatment between the two groups. After treatment, IIEF-5, IPSS and QoL scores were significantly improved in Group A, while only IIEF-5 scores were significantly improved in Group B compared with pre-treatment. There were no significant differences in side effects between the two groups. The results indicated that combined therapy with sildenafil and doxazosin GITS for the treatment of ED and BPH/LUTS is safe and effective compared to sildenafil monotherapy.展开更多
基金supported by the Key R&D Program of Lishui City(2021ZDYF12,2022ZDYF07,2023zdyf14)Natural Science Foundation of China(82072026,82072025 and 82272090)+1 种基金Zhejiang Provincial Natural Science Foundation(LY23H180003,LQ22H180010)Provincial and Ministerial Joint Construction of Key Projects(WKJ-ZJ-2317).
文摘Chemotherapy plays a crucial role in triple-negative breast cancer (TNBC) treatment as it not only directly kills cancer cells but also induces immunogenic cell death. However, the chemotherapeutic efficacy was strongly restricted by the acidic and hypoxic tumor environment. Herein, we have successfully formulated PLGA-based nanoparticles concurrently loaded with doxorubicin (DOX), hemoglobin (Hb) and CaCO3 by a CaCO3-assisted emulsion method, aiming at the effective treatment of TNBC. We found that the obtained nanomedicine (DHCaNPs) exhibited effective drug encapsulation and pH-responsive drug release behavior. Moreover, DHCaNPs demonstrated robust capabilities in neutralizing protons and oxygen transport. Consequently, DHCaNPs could not only serve as oxygen nanoshuttles to attenuate tumor hypoxia but also neutralize the acidic tumor microenvironment (TME) by depleting lactic acid, thereby effectively overcoming the resistance to chemotherapy. Furthermore, DHCaNPs demonstrated a notable ability to enhance antitumor immune responses by increasing the frequency of tumor-infiltrating effector lymphocytes and reducing the frequency of various immune-suppressive cells, therefore exhibiting a superior efficacy in suppressing tumor growth and metastasis when combined with anti-PD-L1 (αPD-L1) immunotherapy. In summary, this study highlights that DHCaNPs could effectively attenuate the acidic and hypoxic TME, offering a promising strategy to figure out an enhanced chemo-immunotherapy to benefit TNBC patients.
基金Project supported by the National Natural Science Foundation of China(Grant No.61172031)
文摘A modified GIT model for describing the variational trend of mean clutter reflectivity as a function of wind speed is proposed. It uses two slope adjustment factors and two critical wind-speed factors to define and adjust the increasing slope of reflectivity with respect to wind speed. In addition, it uses a constant factor to compensate the overall amplitude of clutter reflectivity. The performance of the modified GIT model has been verified on the basis of the L-band low-grazing-angle radar sea clutter data. The results are in good agreement with the experimental data, indicating that the model is more effective in predicting the wind-speed behavior of clutter reflectivity than the conventional GIT model, especially for lower and higher wind speeds. We believe that the proposed model can provide deeper insights into the relationship between radar sea clutter reflectivity and sea state conditions.
文摘This study sought to investigate the clinical efficacy and safety of combined oral therapy with sildenafil and doxazosin GITS compared to sildenafil monotherapy in treating Chinese patients with erectile dysfunction （ED） and lower urinary tract symptoms secondary to benign prostatic hyperplasia （BPH/LUTS）. The trial was conducted in hospitals in Beijing, Shanghai, Changsha, Wuhan and Guangzhou, five major cities in China. A total of 250 patients diagnosed with ED and BPH/LUTS aged 50-75 years, and who had International Index of Erection Function-5 （IIEF-5） scores ≤ 21 and International Prostate Symptom Score （IPSS） ≥ 10 points, were enrolled and randomly divided into Group A （168 cases; doxazosin GITS 4 mg once daily plus sildenafi125-100 mg on demand） and Group B （82 cases; sildenafi125-100 mg on demand）. Efficacies were evaluated by IIEF-5 and IPSS scores and a quality of life （QoL） questionnaire, and adverse effects were evaluated during the treatment period. There were no statistically significant differences in mean age, and IIEF-5, IPSS and QoL scores pre-treatment between the two groups. After treatment, IIEF-5, IPSS and QoL scores were significantly improved in Group A, while only IIEF-5 scores were significantly improved in Group B compared with pre-treatment. There were no significant differences in side effects between the two groups. The results indicated that combined therapy with sildenafil and doxazosin GITS for the treatment of ED and BPH/LUTS is safe and effective compared to sildenafil monotherapy.
