50 research outputs found

    Gene mutation analysis using next‐generation sequencing and its clinical significance in patients with myeloid neoplasm: A multi‐center study from China

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    Abstract Background Myeloid neoplasms (MN) tend to relapse and deteriorate. Exploring the genomic mutation landscape of MN using next‐generation sequencing (NGS) is a great measure to clarify the mechanism of oncogenesis and progression of MN. Methods This multicenter retrospective study investigated 303 patients with MN using NGS from 2019 to 2021. The characteristics of the mutation landscape in the MN subgroups and the clinical value of gene variants were analyzed. Results At least one mutation was detected in 88.11% of the patients (267/303). TET2 was the most common mutation in the cohort, followed by GATA2, ASXL1, FLT3, DNMT3A, and TP53. Among patients with myeloid leukemia (ML), multivariate analysis showed that patients aged ≄60 years had lower overall survival (OS, p = 0.004). Further analysis showed TET2, NPM1, SRSF2, and IDH1 gene mutations, and epigenetic genes (p < 0.050) presented significantly higher frequency in older patients. In patients with myelodysplastic syndrome (MDS) and myelodysplastic neoplasms (MPN), univariate analysis showed that BCORL1 had a significant impact on OS (p = 0.040); however, in multivariate analysis, there were no factors significantly associated with OS. Differential analysis of genetic mutations showed FLT3, TP53, MUC16, SRSF2, and KDM5A mutated more frequently (p < 0.050) in secondary acute myeloid leukemia (s‐AML) than in MDS and MPN. TP53, U2AF1, SRSF2, and KDM5A were mutated more frequently (p < 0.050) in s‐AML than in primary AML. KDM5A was observed to be restricted to patients with s‐AML in this study, and only co‐occurred with MUC16 and TP53 (2/2, 100%). Another mutation was MUC16, and its co‐occurrence pattern differed between s‐AML and AML. MUC16 mutations co‐occurred with KDM5A and TP53 in 66.7% (2/3) of patients with s‐AML and co‐occurred with CEBPA in 100% (4/4) of patients with AML. Conclusions Our results demonstrate different genomic mutation patterns in the MN subgroups and highlight the clinical value of genetic variants

    Nanobody-based trispecific T cell engager (Nb-TriTE) enhances therapeutic efficacy by overcoming tumor-mediated immunosuppression

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    Abstract Background T cell engagers (TCEs) have been established as an emerging modality for hematologic malignancies, but solid tumors remain refractory. However, the upregulation of programmed cell death 1 (PD-1) is correlated with T cell dysfunction that confer tumor-mediated immunosuppression. Developing a novel nanobody-based trispecific T cell engager (Nb-TriTE) would be a potential strategy to improve therapeutic efficacy. Methods Given the therapeutic potential of nanobodies (Nbs), we first screened Nb targeting fibroblast activation protein (FAP) and successfully generated a Nb-based bispecific T cell engager (Nb-BiTE) targeting FAP. Then, we developed a Nb-TriTE by fusing an anti-PD-1 Nb to the Nb-BiTE. The biological activity and antitumor efficacy of the Nb-TriTE were evaluated in vitro and in both cell line-derived and patient-derived xenograft mouse models. Results We had for the first time successfully selected a FAP Nb for the generation of novel Nb-BiTE and Nb-TriTE, which showed good binding ability to their targets. Nb-TriTE not only induced robust tumor antigen-specific killing, potent T cell activation and enhanced T cell function in vitro, but also suppressed tumor growth, improved survival and mediated more T cell infiltration than Nb-BiTE in mouse models of different solid tumors without toxicity. Conclusions This novel Nb-TriTE provides a promising and universal platform to overcome tumor-mediated immunosuppression and improve patient outcomes in the future

    Autophagy‐Activated Self‐reporting Photosensitizer Promoting Cell Mortality in Cancer Starvation Therapy

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    Abstract Cancer starvation therapy have received continuous attention as an efficient method to fight against wide‐spectrum cancer. However, during cancer starvation therapy, the protective autophagy promotes cancer cells survival, compromising the therapeutic effect. Herein, a novel strategy by combination of autophagy‐activated fluorescent photosensitizers (PSs) and cancer starvation therapy to realize the controllable and efficient ablation of tumor is conceived. Two dual‐emissive self‐reporting aggregation‐induced emission luminogens (AIEgens), TPAQ and TPAP, with autophagy‐activated reactive oxygen species (ROS) generation are prepared to fight against the protective autophagy in cancer starvation therapy. When protective autophagy occurs, a portion of TPAQ and TPAP will translocate from lipid droplets to acidic lysosomes with significant redshift in fluorescence emission and enhanced ROS generation ability. The accumulation of ROS induced by TPAQ‐H and TPAP‐H causes lysosomal membrane permeabilization (LMP), which further results in cell apoptosis and promotes cell death. In addition, TPAQ and TPAP can enable the real‐time self‐reporting to cell autophagy and cell death process by observing the change of red‐emissive fluorescence signals. Particularly, the efficient ablation of tumor via the combination of cancer starvation therapy and photodynamic therapy (PDT) induced by TPAQ has been successfully confirmed in 3D tumor spheroid chip, suggesting the validation of this strategy

    Regulation of IFN-Îł-mediated PD-L1 expression by MYC in colorectal cancer with wild-type KRAS and TP53 and its clinical implications

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    Introduction: In the tumor microenvironment, interferon gamma (IFN-Îł) secreted by tumor infiltrating lymphocytes can upregulate programmed cell death 1 ligand 1 (PD-L1) expression in many cancers. The present study evaluated the expression of PD-L1 in selected colorectal cancer cell lines with IFN-Îł treatment and explored the correlation between programmed cell death 1 ligand 1 expression and KRAS/TP53 mutation status.Methods: The selected colorectal cancer cell lines had known KRAS mutations or TP53 mutations. TCGA data analysis were used to investigate the correlation between overall survival of patient with anti-PD-1/PD-L1 immunotherapy and KRAS/TP53 mutation status. Besides, the correlation between PD-L1 expression and KRAS/TP53 mutation status were also investigated by using TCGA data analysis. In vitro experiments were used to explore the mechanism underlying KRAS- and TP53-related PD-L1 expression.Results: Firstly, TCGA data analysis for gene expression and overall survival and an in vitro study revealed that the wild-type KRAS/TP53 cell lines exhibited hyperresponsiveness to interferon gamma exposure and correlated with better survival in patients receiving anti-PD-1/PD-L1 treatment. Secondly, experimental data revealed that interferon gamma induced the upregulation of programmed cell death 1 ligand 1 mainly through regulating MYC in wild-type KRAS and TP53 colorectal cancers.Discussion: Our findings revealed that the response to anti-PD-1/PD-L1 cancer immunotherapy frequently happened in wild-type KRAS and TP53 colorectal cancers, which were also found to show higher programmed cell death 1 ligand 1 expression. Our results indicate that the wild-type KRAS/TP53 colorectal cancer cell lines may respond better to interferon gamma treatment, which causes increased programmed cell death 1 ligand 1 expression and may be a mechanism underlying the better responses to anti-PD-1/PD-L1 therapies in wild-type KRAS and wild-type TP53 colorectal cancer. Furthermore, the experimental results suggest that interferon gamma regulated programmed cell death 1 ligand 1 expression through the regulation of MYC, which may further affect the response to PD-1/PD-L1 cancer immunotherapy. These results suggest a novel potential treatment strategy for enhancing the efficacy of PD-1/PD-L1 blockade immunotherapy in most colorectal cancer patients

    Table_3_The association between outdoor air pollution and lung cancer risk in seven eastern metropolises of China: Trends in 2006-2014 and sex differences.docx

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    There is a positive association between air pollution and lung cancer burden. This study aims to identify and examine lung cancer risks and mortality burdens associated with air pollutants, including PM10, NO2 and SO2, in seven eastern metropolises of China. The study population comprised a population from seven eastern metropolises of China. The yearly average values (YAV, ÎŒg/m3) of the PM10, NO2 and SO2 levels were extracted from China Statistical Yearbook (CSYB) for each selected city from 2006 to 2014. Data collected in the China Cancer Registry Annual Report (CCRAR) provide lung cancer incidence and mortality information. A two-level normal random intercept regression model was adopted to analyze the association between the lung cancer rates and individual air pollutant concentration within a five-year moving window of past exposure. The yearly average values of PM10, SO2 and NO2 significantly decreased from 2006 to 2014. Consistently, the male age-adjusted incidence rate (MAIR) and male age-adjusted mortality rate (MAMR) decreased significantly from 2006 to 2014.Air pollutants have a lag effect on lung cancer incidence and mortality for 2-3 years. NO2 has the significant association with MAIR (RR=1.57, 95% CI: 1.19-2.05, p=0.002), MAMR (RR=1.70, 95% CI: 1.32-2.18, p=0.0002) and female age-adjusted mortality rate (FAMR) (RR=1.27, 95% CI: 1.08-1.49, p=0.003). Our findings suggested that air pollutants may be related to the occurrence and mortality of lung cancer. NO2 was significantly associated with the risk of lung cancer, followed by SO2. Air pollutants have the strongest lag effect on the incidence and mortality of lung cancer within 2-3 years.</p

    Paclitaxel Induces the Apoptosis of Prostate Cancer Cells via ROS-Mediated HIF-1&alpha; Expression

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    Prostate cancer (PCa) is the most common malignancy to endanger the health of male genitourinary system. Clinically, paclitaxel (PTX) (C47H51NO14), a diterpene alkaloid, is commonly used as an effective natural antineoplastic drug during the treatment of PCa. However, the mechanism and pathway involved in the function of PTX are poorly understood. In the current study, we employed the CCK-8 assay, revealing that PTX can inhibit the survival and induce the apoptosis of PC3M cells (a human prostate cancer cell line) in a concentration-dependent manner. Reactive oxygen species (ROS), as a metabolic intermediate produced by the mitochondrial respiratory chain, are highly accumulated under the PTX treatment, which results in a sharp decrease of the mitochondrial membrane potential in PC3M cells. Additionally, the migration and invasion of PC3M cells are weakened due to PTX treatment. Further analysis reveals that N-acetylcysteine (NAC), which functions as an antioxidant, not only rescues the decreased mitochondrial membrane potential induced by the abnormal ROS level, but also restores the migration and invasion of PC3M cells. In a subsequent exploration of the detailed mechanism, we found that hypoxia-inducible factor (HIF)-1&alpha; works as a downstream gene that can respond to the increased ROS in PC3M cells. Under PTX treatment, the expression levels of HIF-1&alpha; mRNA and protein are significantly increased, which stimulate the activation of JNK/caspase-3 signaling and promote the apoptosis of PC3M cells. In summary, we demonstrate that PTX regulates the expression of HIF-1&alpha; through increased ROS accumulation, thereby promoting the activation of JNK/caspase-3 pathway to induce the apoptosis of PCa cells. This study provides new insights into the mechanism of antineoplastic action of taxanes and unveils the clinical benefit of the ROS-HIF-1&alpha; signaling pathway, which may offer a potential therapeutic target to prevent the development of PCa

    Crosstalk between the Circadian Clock and Histone Methylation

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    The circadian clock and histone modifications could form a feedback loop in Arabidopsis; whether a similar regulatory mechanism exists in rice is still unknown. Previously, we reported that SDG724 and OsLHY are two rice heading date regulators in rice. SDG724 encodes a histone H3K36 methyltransferase, and OsLHY is a vital circadian rhythm transcription factor. Both could be involved in transcription regulatory mechanisms and could affect gene expression in various pathways. To explore the crosstalk between the circadian clock and histone methylation in rice, we studied the relationship between OsLHY and SDG724 via the transcriptome analysis of their single and double mutants, oslhy, sdg724, and oslhysdg724. Screening of overlapped DEGs and KEGG pathways between OsLHY and SDG724 revealed that they could control many overlapped pathways indirectly. Furthermore, we identified three candidate targets (OsGI, OsCCT38, and OsPRR95) of OsLHY and one candidate target (OsCRY1a) of SDG724 in the clock pathway. Our results showed a regulatory relationship between OsLHY and SDG724, which paved the way for revealing the interaction between the circadian clock and histone H3K36 methylation

    Table_1_The association between outdoor air pollution and lung cancer risk in seven eastern metropolises of China: Trends in 2006-2014 and sex differences.docx

    No full text
    There is a positive association between air pollution and lung cancer burden. This study aims to identify and examine lung cancer risks and mortality burdens associated with air pollutants, including PM10, NO2 and SO2, in seven eastern metropolises of China. The study population comprised a population from seven eastern metropolises of China. The yearly average values (YAV, ÎŒg/m3) of the PM10, NO2 and SO2 levels were extracted from China Statistical Yearbook (CSYB) for each selected city from 2006 to 2014. Data collected in the China Cancer Registry Annual Report (CCRAR) provide lung cancer incidence and mortality information. A two-level normal random intercept regression model was adopted to analyze the association between the lung cancer rates and individual air pollutant concentration within a five-year moving window of past exposure. The yearly average values of PM10, SO2 and NO2 significantly decreased from 2006 to 2014. Consistently, the male age-adjusted incidence rate (MAIR) and male age-adjusted mortality rate (MAMR) decreased significantly from 2006 to 2014.Air pollutants have a lag effect on lung cancer incidence and mortality for 2-3 years. NO2 has the significant association with MAIR (RR=1.57, 95% CI: 1.19-2.05, p=0.002), MAMR (RR=1.70, 95% CI: 1.32-2.18, p=0.0002) and female age-adjusted mortality rate (FAMR) (RR=1.27, 95% CI: 1.08-1.49, p=0.003). Our findings suggested that air pollutants may be related to the occurrence and mortality of lung cancer. NO2 was significantly associated with the risk of lung cancer, followed by SO2. Air pollutants have the strongest lag effect on the incidence and mortality of lung cancer within 2-3 years.</p

    Table_2_The association between outdoor air pollution and lung cancer risk in seven eastern metropolises of China: Trends in 2006-2014 and sex differences.docx

    No full text
    There is a positive association between air pollution and lung cancer burden. This study aims to identify and examine lung cancer risks and mortality burdens associated with air pollutants, including PM10, NO2 and SO2, in seven eastern metropolises of China. The study population comprised a population from seven eastern metropolises of China. The yearly average values (YAV, ÎŒg/m3) of the PM10, NO2 and SO2 levels were extracted from China Statistical Yearbook (CSYB) for each selected city from 2006 to 2014. Data collected in the China Cancer Registry Annual Report (CCRAR) provide lung cancer incidence and mortality information. A two-level normal random intercept regression model was adopted to analyze the association between the lung cancer rates and individual air pollutant concentration within a five-year moving window of past exposure. The yearly average values of PM10, SO2 and NO2 significantly decreased from 2006 to 2014. Consistently, the male age-adjusted incidence rate (MAIR) and male age-adjusted mortality rate (MAMR) decreased significantly from 2006 to 2014.Air pollutants have a lag effect on lung cancer incidence and mortality for 2-3 years. NO2 has the significant association with MAIR (RR=1.57, 95% CI: 1.19-2.05, p=0.002), MAMR (RR=1.70, 95% CI: 1.32-2.18, p=0.0002) and female age-adjusted mortality rate (FAMR) (RR=1.27, 95% CI: 1.08-1.49, p=0.003). Our findings suggested that air pollutants may be related to the occurrence and mortality of lung cancer. NO2 was significantly associated with the risk of lung cancer, followed by SO2. Air pollutants have the strongest lag effect on the incidence and mortality of lung cancer within 2-3 years.</p
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