The deregulation of annexin A1 (ANXA1), a regulator of inflammation and immunity, leads to cancer growth and metastasis. However, whether ANXA1 is involved in cancer immunosuppression is still unclear. Here, we report that ANXA1 knockdown (i) dramatically downregulates programmed cell death-ligand 1 (PD-L1) expression in breast cancer, lung cancer, and melanoma cells; (ii) promotes T cell-mediated killing of cancer cells in vitro; and (iii) inhibits cancer immune escape in immune-competent mice via downregulating PD-L1 expression and increasing the number and killing activity of CD8+ T cells. Mechanistically, ANXA1 functioned as a sponge molecule for interaction of PARP1 and Stat3. Specifically, binding of ANXA1 to PARP1 decreased PARP1’s binding to Stat3, which reduced poly(ADP-ribosyl)ation and dephosphorylation of Stat3 and thus, increased Stat3’s transcriptional activity, leading to transcriptionally upregulated expression of PD-L1 in multiple cancer cells. In clinical samples, expression of ANXA1 and PD-L1 was significantly higher in breast cancer, non-small cell lung cancer, and skin cutaneous melanoma compared to corresponding normal tissues and positively correlated in cancer tissues. Moreover, using both ANXA1 and PD-L1 proteins for predicting efficacy of anti-PD-1 immunotherapy and patient prognosis were superior to using individual proteins. Our data suggest that ANXA1 promotes cancer immune escape via binding PARP1 and upregulating Stat3-induced expression of PD-L1, that ANXA1 is a potential new target for cancer immunotherapy, and combination of ANXA1 and PD-L1 expression is a potential marker for predicting efficacy of anti-PD-1 immunotherapy in multiple cancers.

In a computational program there can be two kinds of errors: (i) critical errors and (ii) non-critical errors. A critical error stops the program in a global way, which means the error cannot be fixed in the subsequent computation process. A non-critical error partially stops the computation program, and the error can be fixed in the subsequent computation process. We argue that two kinds of errors correspond to two kinds of suspension and can be modeled using Paraconsistent Weak Kleene ($ {\textsf{PWK}}$) belief revision theory, with the help of a new interpretation of the third value of $ {\textsf{PWK}}$, that is, off-topic. According to this new interpretation, if a proposition obtains the third value $\textbf{u}$, it means it is off-topic. Within our framework of $ {\textsf{PWK}}$ belief revision theory, we will show that a non-critical error corresponds to a non-critical suspension and that a critical error corresponds to a critical suspension.

No abstract

No abstract

Casing damage is a common problem in oil and gas fields due to the complicated stress state of casing. Especially in the horizontal well section, the casing is difficult to be centered, and the eccentric casing is prone to failure under non-uniform in-situ stress. In order to study the influence of non-uniform in-situ stress and non-uniform cement sheath on the stress state of casing, a numerical model of the coupling of casing, cement sheath and formation is established. The stress distribution characteristics of casing under four conditions of uniform in-situ stress uniform cement sheath, uniform in-situ stress non-uniform cement sheath, non-uniform in-situ stress uniform cement sheath and non-uniform in-situ stress non-uniform cement sheath are compared. The results show that the non-uniform cement sheath will cause the stress distribution of casing to be uneven, and the maximum stress on the casing is proportional to the amount of eccentricity. The non-uniform in-situ stress will cause the casing stress to be uneven and affect the extreme value of the stress on the casing inner wall. The results will provide the theoretical basis for the casing damage prediction effectively.