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Jing-Min Zheng,1,* Han-Xi Zhou,1,* Hong-Yuan Yu,1,* Yu-Hui Xia,2 Qing-Xin Yu,2 Hang-Shuai Qu,1 Jia-Qian Bao1 1Department of Urology, Taizhou Hospital, Wenzhou Medical University, Linhai, Zhejiang, People’s Republic of China; 2Department of Pathology, Taizhou Hospital, Wenzhou Medical University, Linhai, Zhejiang, People’s Republic of China*These authors contributed equally to this work.Correspondence: Jing-Min ZhengDepartment of Urology, Taizhou Hospital, Wenzhou Medical University, 150 Ximen Road, Linhai, Zhejiang, 317000, People’s Republic of ChinaTel +86-576-85133065Fax +86-576-85199800Email zhengjingmin@enzemed.comBackground: Contradictive results about the direct role of C5a/C5aR1 axis in different cancer cells have been reported. The direct effect of C5a on human renal cell carcinoma (RCC) cells and the underlying mechanism are not clear. The aim of this study is to investigate the role of C5a/C5aR1 axis in RCC cells and its working mechanism.Methods: RCC cells were infected with lentivirus Lenti-C5a, which was designed to over-express secretory C5a in the cells, or directly treated with recombinant C5a, the influence of these treatments in the cells and the underlying mechanism were explored.Results: Transfection of RCC cells with Lenti-C5a markedly increased the production of C5a and significantly increased the proliferation, migration, and invasion of RCC cells, but direct addition of C5a to the cell culture medium had no such effects though it indeed induced a transient intracellular calcium rise. RCC cells were found to express carboxypeptidase D and M, which reportedly to inactivate C5a. Also, the RCC cells stably transfected with Lenti-C5a produced larger transgrafted tumors in nude mice compared with the non-transfected or control virus transfected cells. In addition, over-expression of C5a significantly increased the expression and phosphorylation of STAT3 as well as the phosphorylated JNK level. Furthermore, the effect of C5a over-expression on RCC cells’ proliferation, migration, and invasion could be blocked by Stattic, a STAT3-specific inhibitor.Conclusion: Chronic over-activation of C5a/C5aR1 axis could directly increase RCC cells’ proliferation, migration, and invasion and thus contribute directly to the progression of the disease. Over-activation of STAT3 pathway is among the underlying mechanism.Keywords: C5a, C5aR1, renal cell carcinoma, STAT3

Hume's epistemological legacy is often perceived as a predominantly negative sceptical one. His infamous problem of induction continues to perplex philosophers to this day, and many of his sceptical worries maintain their interest in contemporary eyes (e.g. with regard to reason, the senses, substance, causation). Yet Hume's positive epistemological contributions also hold significance for philosophy in this day and age. In this paper, I aim to situate Hume's epistemology in a more contemporary context, particularly with regard to the theme of reliabilism that runs throughout this epistemology. This will take the shape of examining correspondences and contrasts between Hume's epistemologies in the Treatise and Enquiry and reliabilism, as well as an examination of how Hume's framework might handle some major challenges for reliabilist epistemologies. In particular, I argue that that while Hume is tempted to an epistemology that is intimately tied to truth in the Treatise, he backs away when confronted with the excesses of scepticism in the conclusion of Book 1, and winds up with an epistemology most similar to the contemporary epistemological frameworks of dogmatism and phenomenal conservatism. Yet, largely because of his reliance on the passions (a respect in which he diverges from these two contemporary frameworks), the epistemology of the Treatise remains crucially dissociated from truth. Meanwhile, in the first Enquiry, he proceeds to develop a two-tiered epistemological framework that first accords all our justification with default authority, and then founds all-things-considered epistemic justification on our evidence for the reliability of our faculties. The first tier most resembles the contemporary epistemological framework of conservatism, while the second tier most closely resembles approved-list reliabilism. In this, a clear reliabilist thread runs through the epistemology of the Enquiry. I will also argue that although Hume did not appear to fully appreciate one of the most significant challenges for reliabilism-that is, the generality problem-his philosophical framework nevertheless contains the beginnings of a response to it.

Objective: To explore the treatment methods and experience of open fracture of lower limb in high altitude area., Methods: From January 2016 to January 2021, 62 patients with open fractures of lower limbs were treated by staged surgery with the concept of injury control orthopedics, emphasizing wound treatment and combining various fracture fixation methods. There were 51 males and 11 females, ranging in age from 14 to 59 years old, with a mean of (37.2±12.3) years old; and the course of disease ranged from 7 to 59 days, with a mean of (23.7±15.5) days. According to Gustilo Anderson classification, there were 14 cases of typeⅠ, 24 cases of typeⅡ, 14 cases of typeⅢA, 8 cases of typeⅢB and 2 cases of typeⅢC. The fracture repair and wound healing were observed, and the clinical efficacy was evaluated by Johner-Wruhs evaluation standard., Results: Fifty-five patients were followed up, and the duration ranged from 4 to 36 months, with a mean of (14.7±8.5) months, and 7 cases were lost to follow-up. According to Johner-Wruhs evaluation criteria, 33 cases got an excellent result, 16 good, 4 poor and 2 bad. The wound healing was poor in 2 cases, partial necrosis of Achilles tendon in 1 case, nonunion of fracture in 1 case and delayed healing of fracture in 2 cases., Conclusion: It is an effective method to treat the open fracture of lower extremity in high altitude area to pay attention to the management of soft tissue injury, the management of wound moisturizing, staged operation of fracture and full protection of blood supply at the fracture end. Paying attention to the treatment of soft tissue injury and the management of wound moisturizing, staged operation of fracture and full protection of blood supply at the fracture end are effective methods for the treatment of open fracture of lower limbs in high altitude areas.