Abstract The China Spallation Neutron Source (CSNS), operational since 2018, is upgrading to CSNS-II, increasing the proton beam power to 500 kW and requiring advancements in detector technology and readout electronics. This paper summarizes the current state of readout electronics at CSNS and outlines the challenges posed by the CSNS-II upgrade, including higher neutron flux, vacuum operation requirements, and demands for higher spatial resolution. We present the development of low-power electronics suitable for vacuum environments, such as customized ASIC preamplifiers and digitization modules for 3 He position-sensitive detectors. Additionally, we discuss the implementation of high-resolution Timepix4-based neutron cameras and high-density readout systems for 3 He-GEM detectors. Preliminary results from demonstrator tests indicate that these solutions meet the stringent requirements of CSNS-II. These advancements will play a crucial role in the success of upcoming neutron instruments and significantly contribute to materials science research.
Abstract Clinical hyperthermic intraperitoneal chemotherapy (HIPEC) is regarded as a potential treatment that can prolong survival of patients with peritoneal metastases after cytoreductive surgery. However, treated tumor cells are prone to becoming heat resistant to HIPEC therapy through high expression of heat shock proteins (HSPs). Here, a carrier-free bifunctional nanoinhibitor was developed for HIPEC therapy in the management of peritoneal metastases. Self-assembly of the nanoinhibitor was formed by mixing Mn ion and epigallocatechin gallate (EGCG) in a controllable manner. Such nanoinhibitor directly inhibited HSP90 and impaired the HSP90 chaperone cycle by reduced intracellular ATP level. Additionally, heat and Mn ion synergistically induced oxidative stress and expression of caspase 1, which activated GSDMD by proteolysis and caused pyroptosis in tumor cells, triggering immunogenic inflammatory cell death and induced maturation of dendritic cells through the release of tumor antigens. This strategy to inhibit heat resistance in HIPEC presented an unprecedented paradigm for converting “cold” tumors into “hot” ones, thus significantly eradicating disseminated tumors located deep in the abdominal cavity and stimulating immune response in peritoneal metastases of a mouse model. Collectively, the nanoinhibitor effectively induced pyroptosis of colon tumor cells under heat conditions by inhibiting heat stress resistance and increasing oxidative stress, which may provide a new strategy for treatment of colorectal peritoneal metastases.
RNA-binding proteins (RBPs) play essential roles in tumorigenesis and progression, but their functions in gastric cancer (GC) remain largely elusive. Here, it is reported that Pumilio 1 (PUM1), an RBP, induces metabolic reprogramming through post-transcriptional regulation of DEP domain-containing mammalian target of rapamycin (mTOR)-interacting protein (DEPTOR) in GC. In clinical samples, elevated expression of PUM1 is associated with recurrence, metastasis, and poor survival. In vitro and in vivo experiments demonstrate that knockdown of PUM1 inhibits the proliferation and metastasis of GC cells. In addition, RNA-sequencing and bioinformatics analyses show that PUM1 is enriched in the glycolysis gene signature. Metabolomics studies confirm that PUM1 deficiency suppresses glycolytic metabolism. Mechanistically, PUM1 binds directly to DEPTOR mRNA pumilio response element to maintain the stability of the transcript and prevent DEPTOR degradation through post-transcriptional pathway. PUM1-mediated DEPTOR upregulation inhibits mTORC1 and alleviates the inhibitory feedback signal transmitted from mTORC1 to PI3K under normal conditions, thus activating the PI3K-Akt signal and glycolysis continuously. Collectively, these results reveal the critical epigenetic role of PUM1 in modulating DEPTOR-dependent GC progression. These conclusions support further clinical investigation of PUM1 inhibitors as a metabolic-targeting treatment strategy for GC.
Background: Management of patients with prostate cancer and bone metastatic disease remains a major clinical challenge. Loss or mutation of p53 has been identified to be involved in the tumor progression and metastasis. Nevertheless, direct evidence of a specific role for wild-type p53 (wt-p53) in bone metastasis and the mechanism by which this function is mediated in prostate cancer remain obscure. Methods: The expression and protein levels of wt-53, AIP4, and CXCR4 in prostate cancer cells and clinical specimens were assessed by real-time PCR, immunohistochemistry and western blot analysis. The role of wt-p53 in suppressing aggressive and metastatic tumor phenotypes was assessed using in vitro transwell chemotaxis, wound healing, and competitive colocalization assays. Furthermore, whether p53 deletion facilitates prostate cancer bone-metastatic capacity was explored using an in vivo bone-metastatic model. The mechanistic model of wt-p53 in regulating gene expression was further explored by a luciferase reporter assay and chromatin immunoprecipitation (ChIP) assay. Results: Our findings revealed that wt-p53 suppressed the prostate cancer cell migration rate, chemotaxis and attachment toward the osteoblasts in vitro. The bone-metastatic model showed that deletion of wt-p53 remarkably increased prostate cancer bone-metastatic capacity in vivo. Mechanistically, wt-p53 could induce the ligand-induced degradation of the chemokine receptor CXCR4 by transcriptionally upregulating the expression of ubiquitin ligase AIP4. Treatment with the CXCR4 inhibitor AMD3100 or transduction of the AIP4 plasmid abrogated the pro-bone metastasis effects of TP53 deletion. Conclusion: Wt-p53 suppresses the metastasis of prostate cancer cells to bones by regulating the CXCR4/CXCL12 activity in the tumor cells/bone marrow microenvironment interactions. Our findings suggest that targeting the wt-p53/AIP4/CXCR4 axis might be a promising therapeutic strategy to manage prostate cancer bone metastasis.
In recent years, tyrosine kinase inhibitors (TKIs) have been shown capable of inhibiting the ATP-binding cassette (ABC) transporter-mediated multidrug resistance (MDR). In this study, we determine whether osimertinib, a novel selective, irreversible EGFR (epidermal growth factor receptor) TKI, could reverse ABC transporter-mediated MDR. The results showed that, at non-toxic concentrations, osimertinib significantly sensitized both ABCB1-transfected and drug-selected cell lines to substrate anticancer drugs colchicine, paclitaxel, and vincristine. Osimertinib significantly increased the accumulation of [3H]-paclitaxel in ABCB1 overexpressing cells by blocking the efflux function of ABCB1 transporter. In contrast, no significant alteration in the expression levels and localization pattern of ABCB1 was observed when ABCB1 overexpressing cells were exposed to 0.3 µM osimertinib for 72 h. In addition, ATPase assay showed osimertinib stimulated ABCB1 ATPase activity. Molecular docking and molecular dynamic simulations showed osimertinib has strong and stable interactions at the transmembrane domain of human homology ABCB1. Taken together, our findings suggest that osimertinib, a clinically-approved third-generation EGFR TKI, can reverse ABCB1-mediated MDR, which supports the combination therapy with osimertinib and ABCB1 substrates may potentially be a novel therapeutic stategy in ABCB1-positive drug resistant cancers.
Alkaline phosphatase (ALP) is distributed widely in living organisms and is an important biomarker closely related to many physiological and pathological processes. However, in vivo real-time detection of ALP remains a significant challenge. Herein, we developed a turn-on molecular probe (denoted as LET-3) to visualize ALP activity in tumor tissues through near-infrared fluorescence (NIRF) and photoacoustic (PA) dual-modal imaging. LET-3, composed of NIR hemicyanine dye (LET-CyOH) and a phosphate moiety, showed a 23-fold NIRF enhancement at 730 nm and 27-fold PA enhancement at 710 nm upon activation by ALP. More importantly, both in vitro and in vivo diagnostic experiments indicated that LET-3 has a high sensitivity and good selectivity for ALP. These findings provide a promising strategy for in vivo ALP detection using NIRF and PA dual-channel turn-on probes.
Photodynamic therapy is a medical technique, which is gaining increasing attention to treat various types of cancer. Among the investigated classes of photosensitizers (PSs), the use of Ru(II) polypyridine complexes is gaining momentum. However, the currently investigated compounds generally show poor cancer cell selectivity. As a consequence, high drug doses are needed, which can cause side effects. To overcome this limitation, there is a need for the development of a suitable drug delivery system to increase the amount of PS delivered to the tumor. Herein, we report the encapsulation of a promising Ru(II) polypyridyl complex into polymeric nanoparticles with terminal biotin groups. Thanks to this design, the particles showed much higher selectivity for cancer cells in comparison to noncancerous cells in a 2D monolayer and 3D multicellular tumor spheroid model. As a highlight, upon intravenous injection of an identical amount of the Ru(II) polypyridine complex of the nanoparticle formulation, an improved accumulation inside an adenocarcinomic human alveolar basal epithelial tumor of a mouse up to a factor of 8.7 compared to the Ru complex itself was determined. The nanoparticles were found to have a high phototoxic effect upon one-photon (500 nm) or two-photon (800 nm) excitation with eradication of adenocarcinomic human alveolar basal epithelial tumor inside a mouse model. Overall, this work describes, to the best of our knowledge, the first in vivo study demonstrating the cancer cell selectivity of a very promising Ru(II)-based PDT photosensitizer encapsulated into polymeric nanoparticles with terminal biotin groups.
Abstract Photoacoustic (PA) imaging (PAI) is a noninvasive and nonionizing biomedical imaging modality that combines the advantages of optical imaging and ultrasound imaging. Based on PAI, photoacoustic detection (PAD) is an emerging approach that is involved with the interaction between PA probes and analytes resulting in the changes of photoacoustic signals for molecular detection with rich contrast, high resolution, and deep tissue penetration. This Review focuses on the recent development of PA probes in PAD. The following contents will be discussed in detail: 1) the construction of PA probes; 2) the applications and mechanisms of PAD to different types of analytes, including microenvironments, small biomolecules, or metal ions; 3) the challenges and perspectives of PA probes in PAD.
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