E74 Like ETS Transcription Factor 3 (ELF3) functions as a transcriptional factor to regulate non-small cell lung cancer (NSCLC) differentiation and progression. Poly(ADP-ribose) polymerase (PARP) inhibitors demonstrate anti-tumor effect in NSCLC. This study aimed to investigate whether ELF3 confers synthetic lethal with PARP inhibitor in NSCLC.The sensitivity of PARP inhibitor, Olaparib, to different NSCLC cell lines was determined by half maximal inhibitory concentration (IC50). Expression of ELF3 in NSCLC cell lines was evaluated by western blot. The effects of ELF3 on cytotoxicity of Olaparib to NSCLC were investigated by MTT (3-(4,5- di methyl thiazol -2-yl)-2,5-di phenyl tetrazolium bromide) and colony formation assays. The underlying mechanism involved in synthetic lethality with ELF3 and PARP inhibitors in NSCLC were detected by immunofluorescence and Western blot.ELF3 was up-regulated in NSCLC cell lines exhibiting resistance to PARP inhibitor, Olaparib. Knock down of ELF3 decreased the sensitivity and enhanced cytotoxicity of Olaparib to NSCLC cells. Moreover, knock down of ELF3 increased S139 phosphorylated histone H2AX (γH2AX), and inhibited homologous recombination activity via down-regulation of DNA repair protein RAD51 homolog 1 (RAD51), thus showing deficiency in DNA damage repair. Over-expression of ELF3 could up-regulate phosphorylation of AKT (Protein kinase B), while knock down of ELF3 regulated homologous recombination-mediated DNA repair via down-regulation of phosphorylation of AKT.Knock down of ELF3 revealed homologous recombination deficiency via AKT signaling pathway, and synthetic lethality with ELF3 inhibition and PARP inhibitor indicated the clinical significance of PARP inhibitor in ELF3-deficient NSCLC.
Background: Radiotherapy is one of standard therapeutic regimens for medulloblastoma (MB). Tumor cells utilize DNA damage repair (DDR) mechanisms to survive and develop resistance during radiotherapy. It has been found that targeting DDR sensitizes tumor cells to radiotherapy in several types of cancer, but whether and how DDR pathways are involved in MB radiotherpy response remains to be delineated.Methods: Single-cell RNA sequencing (scRNA-seq) was performed on four medulloblastoma tissues followed by enrichment assay. FANCD2 expression was evaluated in MB samples and public MB databases. The function of FANCD2 in MB cells was examined via assays of CCK-8, clone formation, lactate dehydrogenase (LDH) activity determination, and mouse orthotopic models. FANCD2-related signaling pathway was investigated using assays of peroxidation, malondialdehyde assay (MDA), reduced glutathione assay (GSH), and FerroOrange.Results: Here, we reported that Fanconi anemia group D2 protein (FANCD2) highly expressed in malignant MB cell population. FANCD2 played oncogenic role and predicted worse prognosis of MB patients. Moreover, FANCD2 knockdown markedly suppressed viability, mobility, and growth of MB cells and sensitized MB cells to irradiation. Mechanistically, FANCD2 deficiency leaded to accumulation of Fe2+ through DMT1 upregulation, which further activated ferroptosis and reduced proliferation of MB cells. Using orthotopical mouse model, we observed that radiotherapy combined with silencing FANCD2 significantly inhibiting the growth of MB cell-derived xenograft tumors.Conclusion: Altogether, FANCD2 plays an important role in DDR of MB radiotherapy. Silencing FANCD2 could repress MB growth by upregulating DMT1 to activate ferroptosis, therefore it could be considered as a therapeutic target to sensitize MB cells to radiotherapy.
Interbody fusion is recognized as the golden standard of surgical intervention for degenerative disc disease (DDD). Interbody fusion cage made of polyetheretherketone (PEEK) is commonly used in lumbar interbody fusion surgery in the treatment of DDD worldwide. However, there are some limitations of PEEK including their bio-inert nature and impediment to host bone integration. This study aimed to evaluate the degradation profile and osteoinductive potential of biodegradable Mg-Zn-Nd-Zr cages with/without micro-arc oxidation (MAO) coatings. The Mg-Zn-Nd-Zr alloy cages, whether coated with MAO or not, demonstrated commendable biocompatibility and biomechanical properties. Immersion and electrochemical tests show better corrosion resistance of MAO coatings in vitro. mRNA sequencing, RT-qPCR and Western blotting revealed that Mg-Zn-Nd-Zr and Mg-Zn-Nd-Zr/MAO had a better effectiveness on osteoinductivity. In vivo evaluations in ovine models over 12 weeks and 24 weeks post-implantation revealed radiological and histological evidence of enhanced bone formation adjacent to the Mg-Zn-Nd-Zr alloy cages compared to PEEK counterparts. Moreover, the MAO-coated cages exhibited a reduced propensity for gas formation. The Mg-Zn-Nd-Zr alloy is as a superior osteoinductive material compared with PEEK, with the MAO coating offering an advantage in mitigating gas production. Nonetheless, further research is warranted to refine the alloy's composition or surface treatments, particularly to address the challenges associated with rapid gas evolution during the early post-implantation period.
Our objective was to evaluate the association of rs12255372 in theTCF7L2 gene with type 2 diabetes mellitus (T2DM) in the world population. We carried out a survey of the literature about the effect of rs12255372 on genetic susceptibility to T2DM by consulting PubMed, the Cochrane Library, and Embase from 2006 to 2012, and then performed a meta-analysis of all the studies in order to evaluate the association between rs12255372 and T2DM. A total of 33 articles including 42 studies (with 34,076 cases and 36,192 controls) were confirmed to be eligible and were included in the final meta-analysis: 6 studies conducted on Europeans, 14 on Caucasians, 17 on Asians, 2 on Africans, and 3 on Americans. Overall, the effect size was as follows: for the variant allele T (OR = 1.387, 95%CI = 1.351-1.424), for the TT genotype (OR = 1.933, 95%CI = 1.815-2.057), for the GT genotype (OR = 1.363, 95%CI = 1.315-1.413), for the dominant model (OR = 1.425, 95%CI = 1.344-1.510), and for the recessive model (OR = 1.659, 95%CI = 1.563-1.761). In summary, by pooling all available qualified data from genetic studies on rs12255372 and T2DM, we have confirmed that rs12255372 is significantly associated with susceptibility to T2DM in the global population.
We aimed to investigate the radiosensitizing efficacy of the poly-ADP-ribose polymerase (PARP) inhibitor, olaparib, and the Bloom syndrome protein (BLM) helicase inhibitor, ML216, in non-small cell lung cancer (NSCLC) cells.Radiosensitization of NSCLC cells was assessed by colony formation and tumor growth assays. Mechanistically, the effects of ML216, olaparib, and radiation on cell and tumor proliferation, DNA damage, cell cycle, apoptosis, homologous recombination (HR) repair, and non-homologous end joining (NHEJ) repair activity were determined.Both olaparib and ML216 enhanced the radiosensitivities of olaparib-sensitive H460 and H1299 cells, which was seen as decreased surviving fractions and Rad51 foci, increased total DNA damage, and γH2AX and 53BP1 foci (P < 0.05). The expressions of HR repair proteins were remarkably decreased in olaparib-treated H460 and H1299 cells after irradiation (P < 0.05), while olaparib combined with ML216 exerted a synergistic radiosensitization effect on olaparib-resistant A549 cells. In addition to increases of double strand break (DSB) damage and decreases of Rad51 foci, olaparib combined with ML216 also increased pDNA-PKcs (S2056) foci, abrogated G2 cell cycle arrest, and induced apoptosis in A549 lung cancer after irradiation in vitro and in vivo (P < 0.05). Moreover, Western blot showed that olaparib combined with ML216 and irradiation inhibited HR repair, promoted NHEJ repair, and inactivated cell cycle checkpoint signals both in vitro and in vivo (P < 0.05).Taken together, these results showed the efficacy of PARP and BLM helicase inhibitors for radiosensitizing NSCLC cells, and supported the model that BLM inhibition sensitizes cells to PARP inhibitor-mediated radiosensitization, as well as providing the basis for the potential clinical development of this combination for tumors intrinsically resistant to PARP inhibitors and radiotherapy.
Background Anlotinib is a multi-targeted tyrosine kinase inhibitor mainly targeting angiogenesis signaling. The predictive marker of anlotinib’s efficacy remains elusive. This study was designed to explore the predictive marker of anlotinib in non-small cell lung cancer (NSCLC). Methods We prospectively enrolled 52 advanced NSCLC patients who underwent at least one line of targeted therapy or chemotherapy between August 2018 and March 2020. Patients were divided into durable responders (DR) and non-durable responders (NDR) based on the median progression-free survival (PFS, 176 days). The Olink Immuno-Oncology panel (92 proteins) was used to explore the predictive protein biomarkers in plasma samples before treatment (baseline) and on the first treatment evaluation (paired). Results At baseline, the response to anlotinib was not significantly associated with age, gender, smoke history, histology, oligo-metastases, EGFR mutations, and other clinical characteristics. The results of PFS-related protein biomarkers at baseline were all not satisfying. Then we assessed the changes of 92 proteins levels in plasma on the first treatment evaluation. We obtained a Linear discriminant analysis (LDA) model based on 7 proteins, with an accuracy of 100% in the original data and an accuracy of 89.2% in cross validation. The 7 proteins were CD70, MIC-A/B, LAG3, CAIX, PDCD1, MMP12, and PD-L2. Multivariate Cox analysis further showed that the changes of CD70 (HR 25.48; 95% CI, 4.90–132.41, P=0.000) and MIC-A/B (HR 15.04; 95% CI, 3.81–59.36, P=0.000) in plasma were the most significant prognostic factors for PFS. Conclusion We reported herein a LDA model based on the changes of 7 proteins levels in plasma before and after treatment, which could predict anlotinib responders among advanced NSCLC patients with an accuracy of 100%. Further studies are warranted to verify the prediction performance of the LDA model.
Concanavalin A (Con A) exhibited multiple roles in cancer cells. However, the role of Con A in endothelial cells was not reported.Our present study investigated the potential angiogenic role of Con A in endothelial cells and ischaemic hind-limb mice.Human umbilical vein endothelial cells and Ea.hy926 cells were employed to determine the effect of Con A (0.3, 1, and 3 μg/mL) or vehicle on angiogenesis and cell proliferation with tube formation, ELISA, flow cytometry, EdU, and western blot. Hind-limb ischaemic mice were conducted to determine the pro-angiogenic effect of Con A (10 mg/kg) for 7 days.Con A promoted tube formation to about three-fold higher than the control group and increased the secretion of VEGFa, PDGFaa, and bFGF in the medium. The cell viability was promoted to 1.3-fold by Con A 3 μg/mL, and cell cycle progression of G0G1 phase was decreased from 77% in the vehicle group to 70% in Con A 3 μg/mL, G2M was promoted from 15 to 19%, and S-phase was from 7 to 10%. Con A significantly stimulated phosphorylation of Akt and ERK1/2 and expression of cyclin D1 and decreased the expression of p27. These effects of Con A were antagonised by the PI3K inhibitor LY294002 (10 μM) and MEK pathway antagonist PD98059 (10 μM). Moreover, Con A (10 mg/kg) exhibited a repair effect in ischaemic hind-limb mice.This study will provide a new option for treating ischaemic disease by local injection with Con A.
The present study investigates cytogenetic damage in lymphocytes, derived from three victims who were unfortunately exposed to cobalt-60 (60Co) radiation (the 1999 accident occurred in a village in China's Henan province). Case A of the three victims was exposed to a higher dose of 60Co radiation than Cases B and C. The chromosomal aberrations, cytokinesis-block micronucleus (CBMN, the CBMN assay), and DNA double-strand breaks (DSBs, the comet assay) examined in this study are biomarkers for cytogenetic abnormalities. After the lymphocytes collected from the victims were cultured, the frequencies of dicentric chromosomes and rings (dic + r) and CBMN in the first mitotic division detected in the lymphocytes of Case A were found to be substantially higher than in Cases B and C. Similarly, the DNA-DSB level found in the peripheral blood collected from Case A was much higher than those of Cases B and C. These results suggest that an acutely enhanced induction of the 60Co-induced cytogenetic abnormality frequency in humans depends on the dose of 60Co radiation. This finding is supported by the data obtained using practical techniques to evaluate early lymphoid-tissue abnormalities induced after exposure to acute radiation.
Abstract In this data article, 146 villagers (exposed group) were randomly selected from the workers who involved in the e-wastes recycling directly as a daily job in Tianjin. Control group, including 121 villagers, came from another town without e-waste disposal sites. Chromosomal aberrations (CA) and cytokinesis blocking micronucleus (CBMN) were performed to detect the cytogenetic effect for each subject. DNA damage was detected using comet assay; the DNA percentage in the comet tail (TDNA%), tail moment (TM), and Olive tail moment (OTM) were recorded to describe DNA damage to lymphocytes and spermatozoa. Routine semen analysis, spermatozoa motility and morphology were analyzed. The RT 2 Profiler PCR array was used to measure levels of expression of 84 genes related to quality of DNA. It showed significant relationships between CA, CBMN, DNA damage and exposure time in exposure subjects. The alteration of sperm motility rate, abnormality rate and total sperm counts had association with exposure time and age.
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