Rapalogs induce non-apoptotic,autophagy-dependent cell death in HPV-negative TP53 mutant head and neck squamous cell carcinoma

TP53 is the most frequently mutated gene in head and neck squamous cell carcinoma (HNSCC). Patients with HPV-negative TP53 mutant HNSCC have the worst prognosis, necessitating additional agents for treatment. Since mutant p53 causes sustained activation of the PI3K/AKT/mTOR signaling pathway, we investigated the effect of rapalogs RAD001 and CCI-779 on HPV-negative mutTP53 HNSCC cell lines and xenografts. Rapalogs significantly reduced cell viability and colony formation. Interestingly, rapalogs-induced autophagy with no effect on apoptosis. Pretreatment with autophagy inhibitors, 3-methyladenine (3-MA) and ULK-101 rescued the cell viability by inhibiting rapalog-induced autophagy, suggesting that both RAD001 and CCI-779 induce non-apoptotic autophagy-dependent cell death (ADCD). Moreover, rapalogs upregulated the levels of ULK1 and pULK1 S555 with concomitant downregulation of the mTORC1 pathway. However, pretreatment of cells with rapalogs prevented the ULK-101-mediated inhibition of ULK1 to sustained autophagy, suggesting that rapalogs induce ADCD through the activation of ULK1. To further translate our in vitro studies, we investigated the effect of RAD001 in HPV-negative mutTP53 (HN31 and FaDu) tumor cell xenograft model in nude mice. Mice treated with RAD001 exhibited a significant tumor volume reduction without induction of apoptosis, and with a concomitant increase in autophagy. Further, treatment with RAD001 was associated with a considerable increase in pULK1 S555 and ULK1 levels through the inhibition of mTORC1. 3-MA reversed the effect of RAD001 on FaDu tumor growth suggesting that RAD001 promotes ACDC in HPV-negative mutTP53 xenograft. This is the first report demonstrating that rapalogs promote non-apoptotic ADCD in HPV-negative mutTP53 HNSCC via the ULK1 pathway. Further studies are required to establish the promising role of rapalogs in preventing the regrowth of HPV-negative mutTP53 HNSCC.     

中医药对淋巴管新生与回流功能的作用研究进展＊

淋巴管作为循环系统的重要组成部分之一，具有调节机体体液稳态，协助免疫监视和肠道脂质吸收等重要作用。淋巴管新生是机体生理和病理过程中维持脉管系统结构和功能正常的重要手段，淋巴管新生调控对于防治肿瘤、心血管等诸多疾病有着潜在的临床转化意义；淋巴回流功能则与关节炎症等疾病发病机制关系密切。在循环系统中，相较于中医药调控血管相关疾病的发病机制已取得很大进展，近年来对于淋巴管的研究则明显相对滞后。本文从中医药作用于淋巴管新生及回流功能角度对这一领域的研究进展作一综述，以期为临床上中医药治疗相关疾病提供新的思路与方法。     

Seltene Superinfektion bei einem COVID-19-Patienten – Eine Chronologie

Die Anaesthesiologie - Bei einem 55-jährigen Mann, der sich zur elektiven Ablation bei Vorhofflimmern in der Klinik befand, wurde nach einer Reanimationssituation auf der peripheren Station...