High time resolution and accuracy are of critical importance in the studies of timing analysis and time delay localization of Gamma-Ray Bursts (GRBs), Soft Gamma-ray Repeaters (SGRs) and pulsars. The Gravitational wave high-energy Electromagnetic Counterpart All-sky Monitor (GECAM) consisting of two micro-satellites, GECAM-A and GECAM-B, launched on Dec. 10, 2020, is aimed at monitoring and locating X-ray and gamma-ray bursts all over the sky. To achieve its scientific goals, GECAM is designed to have the highest time resolution (0.1 $\mu {\rm s}$) among all GRB detectors ever flown. Here, we make a comprehensive time calibration campaign including both on-ground and on-orbit tests to derive not only the relative time accuracy of GECAM satellites and detectors, but also the absolute time accuracy of GECAM-B. Using the on-ground calibration with a $\rm ^{22}Na$ radioactive source, we find that the relative time accuracy between GECAM-A and GECAM-B is about 0.15 $\mu {\rm s}$ (1σ). To measure the relative time accuracy between all detectors of a single GECAM satellite, cosmic ray events detected on orbit are utilized since they could produce many secondary particles simultaneously record by multiple detectors. We find that the relative time accuracy among all detectors onboard GECAM-B is about 0.12 $\mu {\rm s}$ (1σ). Finally, we use the novel Li-CCF method to perform the absolute time calibration with Crab pulsar and SGR J1935+2154, both of which were jointly observed by GECAM-B and Fermi/GBM, and obtain that the time difference between GECAM-B and Fermi/GBM is 3.06 ± 6.04 $\mu {\rm s}$ (1σ).
BackgroundThe expansion of intratumoral stem-like CD8+ T (Tstem) cells provides a potential approach to improving the therapeutic efficacy of immune checkpoint blockade (ICB). Thus, here we demonstrate a strategy to facilitate Tstem cell expansion by combining an alarmin high-mobility group nucleosome binding domain 1 (HMGN1) peptide with programmed death-ligand 1 (PD-L1) blockade.MethodsThe antitumor effects of HMGN1, anti-PD-L1 antibody, and their combined treatment were monitored in the B16F10, LLC, Colon26, or the EO771 tumor-bearing mice. The comprehensive immunologic analyses, such as high-dimensional flow cytometry, transcriptome analysis, and single-cell RNA sequencing, were used to investigate the cellular and molecular mechanisms of antitumor immune responses after treatments.ResultsThe HMGN1 peptide synergizes with PD-L1 blockade in augmenting the number of mature DCs enriched in immunoregulatory molecules (mregDCs) in tumors, and enhancing their MHC class I antigen-presenting program, which is correlated with the expansion of intratumoral Tstem cells, specifically promoting the Tstem cells but restricting terminally exhausted CD8+ T (Tex) cells, owing to the regulatory molecules expressed on mregDCs.ConclusionOur results indicate that HMGN1 peptide serves as an immunoadjuvant to promote effective anti-PD-L1 immunotherapy and implicate that mregDCs play a role beyond facilitating Tstem cell expansion.
A comprehensive analysis of magnetoimpedance (MI) phenomena in Fe-based nanocrystalline ribbons is presented in this paper. Giant MI responses have been observed in nanocrystalline samples annealed over the temperature range 490 and 600 • C. More than 400% increases of the MI ratio were obtained both in Fe 73.5 CuNb 3 Si 13.5 B 9 and in Fe 88 Zr 7 B 4 Cu ribbons. The sensitivity can reach a value larger than 60% Oe −1 in the field range 3-7.2 Oe at 800 kHz for Fe 73.5 CuNb 3 Si 13.5 B 9 ribbons. No MI effect was observed in an as-quenched amorphous Fe 88 Zr 7 B 4 Cu sample, because of its very low permeability. A mostly resistive feature was found in an as-quenched amorphous Fe 73.5 CuNb 3 Si 13.5 B 9 sample. The field dependences of the effective permeability show a typical transverse anisotropy property, and the development of the transverse anisotropy in naturally annealed Fe-based ribbons was analysed.
23Colorectal cancer (CRC) is a malignant cancer with high incidence and mortality in the 24 world, as the result of the traditional treatments. Immunotherapy targeting neoantigens 25 can induce durable tumor regression in cancer patients, but is almost limited to 26 individual treatment, resulting from the unique neoantigens. Many shared oncogenic 27 mutations are detected, but whether the common neoantigens can be identified in CRC 28 is unknown. Using the somatic mutations data from 321 CRC patients combined with 29 a filter standard and 7 predicted algorithms, we screened and obtained 25 HLA-30 A*11:01 restricted common neoantigens with high binding affinity (IC50<50 nM) and 31 presentation score (EPIC>0.9). Except the positive epitope KRAS_G12V8-16, 11 out of 32 25 common neoantigens were proved to be naturally processed and presented on 33 constructed K562 cell surface by mass spectroscopy (MS), and 11 out of 25 common 34 neoantigens specifically induced in vitro pre-stimulated cytotoxic lymphocyte (CTL) 35 to secrete IFN-. However, only 2 out of 25 common neoantigens were simultaneously 36 presented and immunogenic. Moreover, using cell-sorting technology combined with 37 single-cell RNA sequencing, the immune repertoire profiles of C1orf170_S418G413-421 38 and KRAS_G12V8-16-specific CTL were clarified. Therefore, common neoantigens 39 with presentation and immunogenicity could be found in CRC, which would be 40 developed as the universal targets for CRC immunotherapy. 41 42 43 44 45 46 Colorectal cancer (CRC) is the third commonest diagnosed malignant cancer and 47 the second leading cause of cancer death in the world [1]. In 2018, more than 1.8 48 million new cases of CRC and almost 881 thousand cases of CRC-interrelated death 49 occurred in the world [1], and the global burden of CRC is estimated to reach over 2.2 50 million new cases and 1.1 million cancer deaths by 2030 [2]. Traditionally surgical 51 resection can cure the early stage of CRC, but about 50% of patients ultimately die of 52 distant metastases. While chemotherapy, radiation therapy and targeted therapy can 53 extend overall survival, less than 15% of patients with metastatic CRC survive 54 beyond 5 years [3]. Therefore, the novel and more effective therapeutic approaches 55 for CRC are necessary to develop. 56 In the recent years, based on a better knowledge of the complex interactions 57 between the immune system and the tumor microenvironment, immunotherapy has 58 become a novel effective and promising therapeutic strategy for cancer, and its 59 efficacy was widely tested by CRC model. The vast majority of CRC patients with 60 deficient mismatch repair (dMMR) or highly microsatellite instable (MSI-H) benefit 61 from immune checkpoint inhibitors, which is not effective in other CRC patients with 62 proficient MMR (pMMR) or microsatellite stable (MSS) [4]. Patients with CRC do 63 not respond to autologous tumour lysate DC (ADC) and peptide vaccines [4]. T cells, 64 which are engineered to express an affinity-enhanced T-cell rece...
Background Colorectal cancer (CRC) is the second leading cause of cancer-related deaths globally. It is essential to identify new CRC-associated therapeutic targets and diagnostic biomarkers. Previous studies have demonstrated that a series of circular RNAs (circRNAs) play a crucial role in CRC pathogenesis. This study assessed the potential of hsa_circ_0064559 in tumor cell growth and progression of CRC. Methods Six pairs of matched CRC and normal colorectal tissue samples were sequenced using the Affymetrix Clariom D array. Using RNA interference, the expression of thirteen circRNAs was knocked down in CRC cells. The proliferation of CRC cell lines (RKO and SW620 cells) was detected using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay. Apoptosis and cell cycle were determined by flow-cytometric analysis. An in vivo study uses nude mice to establish a CRC mouse model. The differentially expressed genes were analyzed using Affymetrix primeview human GeneChip array and verified by polymerase chain reaction. Results Affymetrix Clariom D array analysis revealed that thirteen circRNAs were upregulated in CRC. The proliferation of CRC cell lines was decreased, while the proportion of apoptotic and G1 phase cells was higher after hsa_circ_0064559 knockdown. In vivo xenograft nude mice model revealed that the volume and weight of the tumor were reduced by hsa_circ_0064559 knockdown. In Affymetrix primeview human GeneChip array, we found six upregulated genes (STAT1, ATF2, TNFRSF10B, TGFBR2, BAX, and SQSTM1) and two downregulated genes (SLC4A7 and CD274) related to apoptosis and proliferation of colorectal cancer cells after hsa_circ_0064559 knockdown. Conclusions The hsa_circ_0064559 knockdown could inhibit the proliferation, promote apoptosis in CRC cell lines in vitro, and inhibit the development of CRC tumors in vivo. The mechanism may be related to activating a wide range of signaling pathways. The hsa_circ_0064559 may be a potential biomarker for early diagnosis or prognosis of CRC and a novel drug target for CRC therapy.
ObjectivesTo evaluate the safety and efficiency of percutaneous transhepatic flexible ureteroscope-guided frequency-doubled dual pulse ND:YAG laser lithotripsy (PTFU-FREDDY) for refractory choledocholithiasis.MethodsFrom December 2017 to October 2018, 24 refractory choledocholithiasis patients with large common bile duct stones, anatomic variations, multiple stones or stones at difficult locations (impacted, above a biliary stricture) were admitted to two centers. Four patients were considered intolerant to surgery or endoscopic retrograde cholangiopancreatography (ERCP), and 2 had ERCP failure, the others refused. All patients underwent PTFU-FREDDY. Clinical success rate, recurrence of calculus, laser safety, and related complications, such as fever, haematoma, and local thermal damage were recorded. ResultsPatients’ mean age was 66.0±12.1 (43-89) years. Sex ratio was 1:1.2 (male: female). The mean diameter of stones was 21.8±2.4 mm. All stones were successfully broken and pushed into the duodenum. The mean lithotripsy frequency and procedure time of Bilirubin stones was higher than cholesterol stones, and the mixed were in middle,P<0.01. One patient(4.2%)had haemobilia, requiring immediate transarterial embolisation with 100mg 300-500um gelatin sponge particles. No pancreatitis, sepsis, or serious local thermal damage, such as bile duct perforation, was observed. The rates of Grade A/B of fever, abdominal pain, nausea, and vomiting were 12.5%, 12.5%, 8.3%, and 4.2% during follow-up, respectively. The recurrence was none at the endpoint of 12 months.Conclusion PTFU-FREDDY is a safe and effective alternative treatment for refractory choledocholithiasis, especially when traditional treatments fail or are difficult to perform.
Magneto-impedance effects have been studied in amorphous and nanocrystalline ribbons. Large magneto-impedance responses have been obtained in nanocrystalline samples by applying a longitudinal DC field, but not in amorphous samples. It was found that the transverse field dependences of the resistance and the reactance of nanocrystalline samples show very broad peaks at relatively high fields (above 35 Oe), while the longitudinal magnetic responses show very sharp peaks at the field of 2 - 7 Oe, sharing some common features with those reported for Co-based amorphous wire and ribbon samples, and can be understood from the same mechanism. It was also found experimentally that the properties of the longitudinal and transverse field dependences of the effective permeability of nanocrystalline samples correlates with those of the impedance, showing a sharp decrease for the longitudinal applied field and a slow decrease for the transverse applied field at a corresponding field value and, the higher the effective permeability, the larger is the magneto-impedance effect at a fixed frequency. and a sensitivity of 20% at a low field (2 Oe) are obtained in this paper.
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