<p>Supplementary Figure S1. High expression of UBA1 is associated with low levels of intratumoral CD8+ T cells and predictive of ICB resistance and poor survival in ICB cohorts.</p>
Abstract PARP inhibitors sensitize pancreatic ductal adenocarcinoma (PDAC) to radiation by inducing DNA damage and replication stress. These mechanisms also have the potential to enhance radiation-induced type I interferon (T1IFN)–mediated antitumoral immune responses. We hypothesized that the PARP inhibitor olaparib would also potentiate radiation-induced T1IFN to promote antitumor immune responses and sensitization of otherwise resistant PDAC to immunotherapy. To test this hypothesis, we assessed the effects of olaparib and radiation on T1IFN production and sensitivity to αPD-L1 immunotherapy, as well as on the tumor microenvironment by single-cell RNA sequencing. We found that olaparib enhanced T1IFN production after radiation and had superior therapeutic efficacy in immunocompetent models. Olaparib and radiation treatment sensitized PDAC tumors to αPD-L1, resulting in decreased tumor burden and a 33% complete response rate. Combination treatment provided durable immune responses as shown by tumor rejection upon tumor rechallenge of previously cured mice. Furthermore, single-cell RNA sequencing analysis revealed that combination treatment induced an immunogenic tumor microenvironment characterized by interferon (IFN) responses in both PDAC and myeloid cell populations, macrophage polarization, and increased CD8+ terminal effector T-cell frequency and activity, findings which were confirmed by IHC and flow cytometry. Furthermore, CD8+ T cells and T1IFN signaling were required for therapeutic efficacy as host depletion of CD8+ T cells or the T1IFN receptor diminished treatment responses. Overall, our results indicate that olaparib enhances radiation-induced T1IFN-mediated immune signaling and subsequently an adaptive immune response, thus sensitizing pancreatic cancer to αPD-L1 therapy, supporting an ongoing clinical trial of this therapy in patients with PDAC.
The tracks left by charged particles in a gaseous time projection chamber~(TPC) incorporate important information about the interaction process and drift of electrons in gas. The electron diffusion information carried by the tracks is an effective signature to reconstruct $z_0$, the vertex position in drift direction at which the event takes place. In this paper, we propose to reconstruct $z_0$ with convolution neural network~(CNN) in the PandaX-III experiment. A CNN model VGGZ0net is built and validated with Monte Carlo simulation data. It gives $z_0$ with a 11~cm precision for the events above 2~MeV uniformly distributed along a drift distance of 120~cm, and then the electron lifetime can be deduced. The energy resolution of detector is significantly improved after the electron lifetime correction, i.e., from 10.1\% to 4.0\% FWHM at the Q-value of double beta decay of $^{136}$Xe for the scenario with an electron lifetime of 6.5~ms. The CNN model is also successfully applied to the experimental data of the PandaX-III prototype detector for $z_0$ reconstruction.
Online shopping is becoming increasingly important as more and more manufacturers sell products on the Internet, and many users are using the Internet to express and share their opinions. However, it is impossible for consumers to read all product reviews. Therefore, it is necessary to design effective systems to summarize the pros and cons of product characteristics, so that consumers can quickly find their favorable products. In this paper, we present a product ranking system using opinion mining techniques. Users can specify product features to get back the ranking results of all matched products. In this system, we consider three issues while calculating product scores: 1) product reviews, 2) product popularity, and 3) product release month. Finally, the experimental results show that the system is practical and the ranking results are interesting.
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