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Aim: The prognosis of high-risk, locally advanced cervical cancer (LACC) remains poor following concurrent chemoradiotherapy (CCRT). We investigated whether the effect of CCRT can be enhanced by programmed cell death protein 1 (PD-1) inhibitor. Methods: A retrospective cohort study was conducted to compare the efficacy and safety of CCRT group (n = 82) and PD-1 inhibitor plus CCRT group (n = 70). Results: Compared with the CCRT group, the PD-1 inhibitor plus CCRT group had significantly higher objective response rate, median progression-free survival, leukopenia and fatigue. The addition of PD-1 inhibitor to CCRT showed a favorable trend in overall survival without statistical significance. Conclusion: PD-1 inhibitor plus CCRT presented a significant survival benefit and a manageable safety profile in high-risk LACC. Article highlights The prognosis of high-risk locally advanced cervical cancer (LACC) (FIGO 2014 stage IB2–IIB with positive para-aortic lymph nodes and stage IIIA–IVA) remains poor after concurrent chemoradiotherapy (CCRT). Programmed death ligand-1 (PD-1) inhibitors have shown efficacy in patients with cervical cancer, and whether the effect of CCRT can be enhanced by PD-1 inhibitor is a hot topic in high-risk LACC research. This retrospective cohort study was conducted to compare the efficacy and safety of CCRT alone (n = 82 patients) and PD-1 inhibitor plus CCRT (n = 70 patients). Compared with the CCRT-alone group, the PD-1 inhibitor plus CCRT group had a significantly higher objective response rate and median progression-free survival (PFS) but also higher incidence of leukopenia and fatigue. The addition of PD-1 inhibitor to CCRT showed a favorable trend in overall survival (OS) without statistical significance. Compared with the PD-L1-negative subgroup, PFS (p = 0.002) and OS (p = 0.032) in the PD-L1-positive subgroup were significantly improved. Multivariate analysis showed that total radiotherapy duration >56 days (hazard ratio [HR]: 4.799), FIGO 2009 stage IVA (HR: 6.464), and combined PD-1 inhibitor (HR: 0.324) were independent determinants of disease progression. PD-1 inhibitor plus CCRT presented a significant survival benefit and a manageable safety profile in high-risk LACC. It can be considered as a new alternative treatment for this patient population. The effects of different timing of PD-1 inhibitor combination with radiotherapy and different duration of PD-1 inhibitor maintenance therapy on survival outcomes need to be further explored in future studies. This is an exploratory study that adds to the literature on high-risk LACC and PD-1 inhibitor, prospective studies are needed to determine the value of PD-1 inhibitor plus CCRT for high-risk LACC. [ABSTRACT FROM AUTHOR]

Background: Mental stress-induced neurotransmitters can affect the immune system in various ways. Therefore, a better understanding of the role of neurotransmitters in the tumour immune microenvironment is expected to promote the development of novel anti-tumour therapies. Methods: In this study, we analysed the plasma levels of neurotransmitters in anti-programmed cell death protein 1 (PD-1) monoclonal antibody (mAb)-resistance patients and sensitive patients, to identify significantly different neurotransmitters. Subsequently, animal experiments and experiments in vitro were used to reveal the specific mechanism of norepinephrine's (NE) effect on immunotherapy. Results: The plasma NE levels were higher in anti-PD-1 mAb-resistance patients, which may be the main cause of anti-PD-1 mAb resistance. Then, from the perspective of the immunosuppressive microenvironment to explore the specific mechanism of NE-induced anti-PD-1 mAb resistance, we found that NE can affect the secretion of C-X-C Motif Chemokine Ligand 9 (CXCL9) and adenosine (ADO) in tumour cells, thereby inhibiting chemotaxis and function of CD8+ T cells. Notably, the WNT7A/β-catenin signalling pathway plays a crucial role in this progression. Conclusion: NE can affect the secretion of CXCL9 and ADO in tumour cells, thereby inhibiting chemotaxis and the function of CD8+ T cells and inducing anti-PD-1 mAb resistance in lung adenocarcinoma (LUAD). [ABSTRACT FROM AUTHOR]

N,N-dimethylformamide (DMF) is an organic solvent with stable chemical properties and high boiling point. Based on its good solubility, DMF is widely used in synthetic textile, leather, electronics, pharmaceutical and pesticide industries. However, the DMF pollutes the environment and does harm to human liver function, kidney function, and nerve function. Herein, an efficient DMF-degrading strain, DM175A1-1, was isolated and identified as Paracoccus sulfuroxidans . This strain can use DMF as the sole source of carbon and nitrogen. Whole-genome sequencing of strain DM175A1-1 revealed that it has a 3.99-Mbp chromosome a 120-kbp plasmid1 and a 40-kbp plasmid2. The chromosome specifically harbors the dmfA1 and dmfA2 essential for the initial steps of DMF degradation. And it also carries the some part of genes facilitating subsequent methylotrophic metabolism and glutathione-dependent pathway. Through further DMF tolerance degradation experiments, DM175A1-1 can tolerate DMF concentrations up to 10,000 mg/L, whereas the majority of Paracoccus strains could only show degradation activity below 1,000 mg/L. And the efficiency of organic nitrogen conversion to NH 3 -N in DMF can reach 99.0% when the hydraulic retention time (HRT) is controlled at 5 days. Meanwhile, it showed a significant degradation effect at a pharmaceutical enterprise in Zhejiang Province with high concentration of DMF wastewater. This study provides a new strain Paracoccus sulfuroxidans DM175A1-1 which shows a significant influence on DMF degradation, and reveals the characterization on its DMF degradation. It lays the foundation for the application of biological method in the efficient degradation of DMF in industrial wastewater., Competing Interests: YS and WZ were employed by Trend Biotech Co., Ltd. XL and LS were employed by Zhoushan Sewerage Treatment Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zheng, Su, Zhang, Liu, Shao, Shen, Zhang, Wang and Miao.)

The nuclear receptor-binding SET domain (NSD) protein family encoding histone lysine methyltransferases is involved in cancer progression. However, the role of NSDs in esophageal squamous cell carcinoma (ESCC) remains unclear. Here we examined the expression of NSDs in cisplatin-resistant and parental ESCC cells and revealed the upregulation of NSD2 in cisplatin-resistant cells. Ectopic expression of NSD2 increased cisplatin resistance and attenuated cisplatin-induced apoptosis. Colony formation assay indicated that NSD2 overexpression enhanced long-term survival of ESCC cells after treatment with cisplatin. In contrast, knockdown of NSD2 inhibited ESCC cell proliferation and sensitized ESCC cells to cisplatin. Depletion of NSD2 augmented the cytotoxic effect of cisplatin on EC109 xenograft tumors. NSD2 stimulated long non-coding RNA MACC1-AS1 in ESCC cells. Knockdown of MACC1-AS1 impaired NSD2-induced cisplatin resistance. Moreover, MACC1-AS1 overexpression promoted ESCC cell proliferation and cisplatin resistance. Clinically, MACC1-AS1 was upregulated in ESCC relative to adjacent noncancerous tissues. High MACC1-AS1 levels were significantly associated with reduced overall survival of ESCC patients. There was a positive correlation between MACC1-AS1 and NSD2 expression in ESCC specimens. Taken together, MACC1-AS1 induced by NSD2 mediates resistance to cisplatin in ESCC and may represent a novel target to improve cisplatin-based chemotherapy., Competing Interests: The authors declare no competing interests., (© 2020 The Authors.)

Therapeutic targeting of advanced or metastatic non-small-cell lung cancer (NSCLC) represents a major goal of clinical treatment. Polo-like kinase 1 (PLK1) is an essential mitotic kinase in cell cycle progression and is associated with oncogenesis in a large spectrum of cancer types, including NSCLC. Volasertib (BI 6727) is a potent, selective, PLK1 inhibitor that is currently under phase 2 clinical trials with modest antitumor activity against solid tumors. As the combination of volasertib with pemetrexed does not improve efficacy for NSCLC treatment, it is crucial to identify compounds that could enhance efficacy with volasertib. Immunomodulatory drugs (IMiDs) bind to E3 ligase CRBN and repurposes it to ubiquitinate other proteins as neo-substrates, representing an effective treatment for hematologic malignancies. In this study, by screening IMiDs, we found that a novel CRBN modulator, CC-885, can synergistically inhibit NSCLC with volasertib both in vitro and in vivo . This synergistic effect overcomes volasertib resistance caused by PLK1 mutations and is compromised in CRBN-or p97-depleted cells. Mechanistically, CC-885 selectively promotes CRBN- and p97-dependent PLK1 ubiquitination and degradation, thereby enhancing the sensitivity of NSCLC to volasertib. In conclusion, our findings reveal that PLK1 is a neo-substrate of CUL4-CRBN induced by CC-885 and represent a combinational approach for treating NSCLC., (© 2020 The Authors.)