We integrate the genomics, proteomics, and phosphoproteomics of 480 clinical tissues from 146 patients in a Chinese colorectal cancer (CRC) cohort, among which 70 had metastatic CRC (mCRC). Proteomic ...profiling differentiates three CRC subtypes characterized by distinct clinical prognosis and molecular signatures. Proteomic and phosphoproteomic profiling of primary tumors alone successfully distinguishes cases with metastasis. Metastatic tissues exhibit high similarities with primary tumors at the genetic but not the proteomic level, and kinase network analysis reveals significant heterogeneity between primary colorectal tumors and their liver metastases. In vivo xenograft-based drug tests using 31 primary and metastatic tumors show personalized responses, which could also be predicted by kinase-substrate network analysis no matter whether tumors carry mutations in the drug-targeted genes. Our study provides a valuable resource for better understanding of mCRC and has potential for clinical application.
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•A large-scale proteogenomics study of metastatic colorectal cancers•Phosphoproteomic pattern distinguishes metastasis and predicts drug response•A workflow from generation of large omics datasets to in vivo drug testing models•Improves the selection of treatment strategies for patients without druggable mutation
Li et al. provide a global proteogenomic landscape for metastatic colorectal cancer in a Chinese cohort. Proteomic and phosphoproteomic profiling of primary tumors successfully distinguishes cases with metastasis and, together with network analysis, accurately reflects the drug responses of primary and metastatic tumors.
A deep memory bare-bones particle swarm optimization algorithm (DMBBPSO) for single-objective optimization problems is proposed in this paper. The DMBBPSO is able to perform high-precision local ...search while maintaining a large global search, thus providing a reliable solution to high-dimensional complex optimization problems. Normally, maintaining high accuracy while conducting global searches is an important challenge for single-objective optimizers. Traditional particle swarms optimizers can rapidly lose the diversity during iterations and are unable to perform global searches efficiently, and thus are more likely to be trapped by local optima. To address this problem, the DMBBPSO combines multiple memory storage mechanism (MMSM) and a layer-by-layer activation strategy (LAS). The MMSM catalyzes a set of deep memories to increase the diversity of the particle swarm. For every single particle, both of the personal best position and deep memories will be used in the evaluation process. The LAS enables the particle swarm to avoid premature convergence while enhancing local search capabilities. The collaboration between MMSM and LAS enhances the diversity of the particle swarm, which in turn enhances the robustness of the DMBBPSO. To investigate the optimization ability of the DMBBPSO for single-objective optimization problems, The CEC2017 benchmark functions are used in experiments. Five state-of-the-art evolutionary algorithms are used in the control group. Finally, experimental results demonstrate that the DMBBPSO can provide high precision results for single-objective optimization problems.
Intrahepatic cholangiocarcinoma (ICC) ranks as the second most malignant type of primary liver cancer with a high degree of incidence and a very poor prognosis. Fat mass and obesity-associated ...protein (FTO) functions as an eraser of the RNA m
A modification, but its roles in ICC tumorigenesis and development remain unknown. We showed here that the protein level of FTO was downregulated in clinical ICC samples and cell lines and that FTO expression was inversely correlated with the expression of CA19-9 and micro-vessel density (MVD). A Kaplan-Meier survival analysis showed that a low expression of
predicted poor prognosis in ICC.
, decreased endogenous expression of
obviously reduced apoptosis of ICC cells. Moreover,
suppressed the anchorage-independent growth and mobility of ICC cells. Through mining the database, FTO was found to regulate the integrin signaling pathway, inflammation signaling pathway, epidermal growth factor receptor (EGFR) signaling pathway, angiogenesis, and the pyrimidine metabolism pathway. RNA decay assay showed that oncogene
mRNA stability was impaired by FTO. In addition, the overexpression of FTO suppressed tumor growth
. In conclusion, our study demonstrated the critical roles of FTO in ICC.
Abstract
The Low-Energy X-ray Polarization Detector (LPD) is one of the payloads in the POLAR-2 experiment, designed as an external payload for the China Space Station deployment in early 2026. LPD ...is specifically designed to observe the polarization of gamma-ray burst (GRB) prompt emission in the energy range of 2–10 keV, with a wide field of view (FoV) of 90° in preliminary design. This observation is achieved using an array of X-ray photoelectric polarimeters based on gas pixel detectors. Due to the wide FoV configuration, the in-orbit background count rate in the soft X-ray range is high, while GRBs themselves also exhibit high flux in this energy band. In order to assess the contribution of various background components to the total count rate, we conducted detailed simulations using the GEANT4 C++ package. Our simulations encompassed the main interactions within the instrument materials and provided insights into various background components within the wide-FoV scheme. The simulation results reveal that among the background components, the primary contributors are the cosmic X-ray background (CXB) and bright X-ray sources. The total background count rate of LPD, after applying the charged particle background rejection algorithm, is approximately 0.55 counts cm
–2
s
–1
on average, and it varies with the detector’s orbit and pointing direction. Furthermore, we performed comprehensive simulations and comparative analyses of the CXB and X-ray bright sources under different FoVs and detector pointings. These analyses provide valuable insights into the background characteristics for soft X-ray polarimeter with wide FoV.
Intratumoral immune status influences tumor therapeutic response, but it remains largely unclear how the status determines therapies for patients with intrahepatic cholangiocarcinoma. Here, we ...examine the single-cell transcriptional and TCR profiles of 18 tumor tissues pre- and post- therapy of gemcitabine plus oxaliplatin, in combination with lenvatinib and anti-PD1 antibody for intrahepatic cholangiocarcinoma. We find that high CD8 GZMB
and CD8 proliferating proportions and a low Macro CD5L
proportion predict good response to the therapy. In patients with a poor response, the CD8 GZMB
and CD8 proliferating proportions are increased, but the CD8 GZMK
proportion is decreased after the therapy. Transition of CD8 proliferating and CD8 GZMB
to CD8 GZMK
facilitates good response to the therapy, while Macro CD5L
-CD8 GZMB
crosstalk impairs the response by increasing CTLA4 in CD8 GZMB
. Anti-CTLA4 antibody reverses resistance of the therapy in intrahepatic cholangiocarcinoma. Our data provide a resource for predicting response of the combination therapy and highlight the importance of CD8
T-cell status conversion and exhaustion induced by Macro CD5L
in influencing the response, suggesting future avenues for cancer treatment optimization.
Autophagy can protect stressed cancer cell by degradation of damaged proteins and organelles. However, the regulatory mechanisms behind this cellular process remain incompletely understood. Here, we ...demonstrate that RSK2 (p90 ribosomal S6 kinase 2) plays a critical role in ER stress-induced autophagy in breast cancer cells. We demonstrated that the promotive effect of RSK2 on autophagy resulted from directly binding of AMPKα2 in nucleus and phosphorylating it at Thr172 residue. IRE1α, an ER membrane-associated protein mediating unfolded protein response (UPR), is required for transducing the signal for activation of ERK1/2-RSK2 under ER stress. Suppression of autophagy by knockdown of RSK2 enhanced the sensitivity of breast cancer cells to ER stress both in vitro and in vivo. Furthermore, we demonstrated that inhibition of RSK2-mediated autophagy rendered breast cancer cells more sensitive to paclitaxel, a chemotherapeutic agent that induces ER stress-mediated cell death. This study identifies RSK2 as a novel controller of autophagy in tumor cells and suggests that targeting RSK2 can be exploited as an approach to reinforce the efficacy of ER stress-inducing agents against cancer.
The present study was conducted to evaluate the protective effects of astaxanthin against lipopolysaccharide (LPS)-induced inflammatory responses in Channa argus in vivo and ex vivo. Primary ...hepatocytes were exposed to different concentrations of LPS for 24 h to induce an inflammatory response, and the protective effects of astaxanthin against LPS-induced inflammation were studied ex vivo and in vivo. Hepatocytes exposed to LPS (5–20 μg mL−1) alone for 24 h resulted in a significant increase in lactate dehydrogenase release (LDH), Nitric oxide (NO) production and Malondialdehyde (MDA) content, 10 μg mL−1 LPS could induced inflammatory response in hepatocytes. Gene expression of TLR4, NFkBp65, MAPKp38, TNF-α, IL-6 and IL-1β mRNA expression were also enhanced ex vivo (p < 0.05). In vivo test demonstrated that pretreatment with astaxanthin prevented the LPS-induced upregulation of pro-inflammatory cytokines TNF-α, IL-6 and IL-1β. Besides, astaxanthin blocked the expression of Toll-like receptor 4 (TLR4) and then suppressed the phosphorylation of nuclear transcription factor-kappa B (NF-κB) p65 and degradation inhibitor of NF-κBα (IκBα). Further study showed that astaxanthin could suppress the phosphorylation of p38, extracellular signal-regulated kinase (ERK) and c-jun NH2-terminal kinase (JNK) in mitogen-activated protein kinase (MAPK) signal pathway. In conclusion, our results suggest that astaxanthin played an anti-inflammatory role by regulating TLR4 and the NF-κB and MAPK signaling pathways in C. argus.
•We established LPS induced inflammatory response model in Channa argus hepatocytes in vitro.•Astaxanthin prevented LPS-induced upregulation of pro-inflammatory cytokines and related gene expression.•Astaxanthin attenuates inflammatory responses by suppressing NF-κB and MAPK signaling pathways in Channa argus.
Small guide RNA (sgRNA) is an important component of the CRISPR/Cas9 system. The gene editing efficiency of the CRISPR/Cas9 system could be enhanced by using highly active U6 promoters to drive the ...expression of sgRNA. Therefore, we constructed various expression vectors based on the 11 GmU6 promoters predicted and cloned in the whole soybean genome. The expression of truncated GUS driven by 11 GmU6 promoters was tested in hairy roots and by Arabidopsis thaliana transformation. The results indicated that higher transcriptional levels were driven by 5 GmU6 promoters (GmU6-4, GmU6-7, GmU6-8, GmU6-10 and GmU6-11) in both soybean hairy roots and Arabidopsis thaliana. In addition, three genes, Glyma03g36470, Glyma14g04180 and Glyma06g136900, were selected as targets to detect the transcriptional levels of multiple GmU6 promoters. Mutations in these three genes were detected in soybean hairy roots after Agrobacterium rhizogenes infection, indicating efficient target gene editing, including nucleotide insertion, deletion, and substitution. Mutation efficiencies differed among the 11 GmU6 promoters, ranging from 2.8% to 20.6%, and markedly higher efficiencies were obtained with all three genes using the GmU6-8 (20.3%) and GmU6-10 (20.6%) promoters. These two GmU6 promoters also showed higher ability to drive truncated GUS transcription in both soybean hairy roots and transformed Arabidopsis thaliana. These results will help to construct an efficient CRISPR-Cas9 gene editing system and promote the application of the CRISPR-Cas9 genome editing system in soybean molecular breeding.
•Eleven GmU6 promoters predicted in the whole soybean genome.•The transcriptional levels of multiple GmU6 promoters were tested in soybean hair roots and transferred Arabidopsis.•The CRISPR -Cas9 system with GmU6-8 and GmU6-10 showed higher ability.
Porcine reproductive and respiratory syndrome virus (PRRSV) is a pathogen that causes severe abortions in sows and high piglet mortality, resulting in huge economic losses to the pig industry ...worldwide. The emerging and novel PRRSV isolates are clinically and biologically important, as there are likely recombination and pathogenic differences among PRRSV genomes. Furthermore, the NADC34-like strain has become a major epidemic strain in some parts of China, but the characterization and pathogenicity of the latest strain in Inner Mongolia have not been reported in detail. In this study, an NADC34-like strain (CHNMGKL1-2304) from Tongliao City, Inner Mongolia was successfully isolated and characterized, and confirmed the pathogenicity in pigs. The phylogenetic tree showed that this strain belonged to sublineage 1.5 and had high homology with the strain JS2021NADC34. There is no recombination between CHNMGKL1-2304 and any other domestic strains. Animal experiments show that the CHNMGKL1-2304 strain is moderately virulent to piglets, which show persistent fever, weight loss and high morbidity but no mortality. The presence of PRRSV nucleic acids was detected in both blood, tissues, nasal and fecal swabs. In addition, obvious pathological changes and positive signals were observed in lung, lymph node, liver and spleen tissues when subjected to hematoxylin-eosin (HE) staining and immunohistochemistry (IHC). This report can provide a basis for epidemiological investigations and subsequent studies of PRRSV.
: To determine the role of UCH-L1 in regulating ERα expression, and to evaluate whether therapeutic targeting of UCH-L1 can enhance the efficacy of anti-estrogen therapy against breast cancer with ...loss or reduction of ERα.
: Expressions of UCH-L1 and ERα were examined in breast cancer cells and patient specimens. The associations between UCH-L1 and ERα, therapeutic response and prognosis in breast cancer patients were analyzed using multiple databases. The molecular pathways by which UCH-L1 regulates ERα were analyzed using immunoblotting, qRT-PCR, immunoprecipitation, ubiquitination, luciferase and ChIP assays. The effects of UCH-L1 inhibition on the efficacy of tamoxifen in ERα (-) breast cancer cells were tested both
and
.
: UCH-L1 expression was conversely correlated with ERα status in breast cancer, and the negative regulatory effect of UCH-L1 on ERα was mediated by the deubiquitinase-mediated stability of EGFR, which suppresses ERα transcription. High expression of UCH-L1 was associated with poor therapeutic response and prognosis in patients with breast cancer. Up-regulation of ERα caused by UCH-L1 inhibition could significantly enhance the efficacy of tamoxifen and fulvestrant in ERα (-) breast cancer both
and
.
: Our results reveal an important role of UCH-L1 in modulating ERα status and demonstrate the involvement of UCH-L1-EGFR signaling pathway, suggesting that UCH-L1 may serve as a novel adjuvant target for treatment of hormone therapy-insensitive breast cancers. Targeting UCH-L1 to sensitize ER negative breast cancer to anti-estrogen therapy might represent a new therapeutic strategy that warrants further exploration.
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