STING agonism overcomes STAT3-mediated immunosuppression and adaptive resistance to PARP inhibition in ovarian cancer

BackgroundPoly (ADP-ribose) polymerase (PARP) inhibition (PARPi) has demonstrated potent therapeutic efficacy in patients with BRCA-mutant ovarian cancer. However, acquired resistance to PARPi remains a major challenge in the clinic.MethodsPARPi-resistant ovarian cancer mouse models were generated by long-term treatment of olaparib in syngeneic Brca1-deficient ovarian tumors. Signal transducer and activator of transcription 3 (STAT3)-mediated immunosuppression was investigated in vitro by co-culture experiments and in vivo by analysis of immune cells in the tumor microenvironment (TME) of human and mouse PARPi-resistant tumors. Whole genome transcriptome analysis was performed to assess the antitumor immunomodulatory effect of STING (stimulator of interferon genes) agonists on myeloid cells in the TME of PARPi-resistant ovarian tumors. A STING agonist was used to overcome STAT3-mediated immunosuppression and acquired PARPi resistance in syngeneic and patient-derived xenografts models of ovarian cancer.ResultsIn this study, we uncover an adaptive resistance mechanism to PARP inhibition mediated by tumor-associated macrophages (TAMs) in the TME. Markedly increased populations of protumor macrophages are found in BRCA-deficient ovarian tumors that rendered resistance to PARPi in both murine models and patients. Mechanistically, PARP inhibition elevates the STAT3 signaling pathway in tumor cells, which in turn promotes protumor polarization of TAMs. STAT3 ablation in tumor cells mitigates polarization of protumor macrophages and increases tumor-infiltrating T cells on PARP inhibition. These findings are corroborated in patient-derived, PARPi-resistant BRCA1-mutant ovarian tumors. Importantly, STING agonists reshape the immunosuppressive TME by reprogramming myeloid cells and overcome the TME-dependent adaptive resistance to PARPi in ovarian cancer. This effect is further enhanced by addition of the programmed cell death protein-1 blockade.ConclusionsWe elucidate an adaptive immunosuppression mechanism rendering resistance to PARPi in BRCA1-mutant ovarian tumors. This is mediated by enrichment of protumor TAMs propelled by PARPi-induced STAT3 activation in tumor cells. We also provide a new strategy to reshape the immunosuppressive TME with STING agonists and overcome PARPi resistance in ovarian cancer.Peer reviewe

A Review on Structural Failure of Composite Pressure Hulls in Deep Sea

With the increasing application and study of lightweight and high strength fiber reinforced polymer composites in ocean industry, the structural failure problem of composite pressure hulls has attracted great attention from many researchers in China and globally. Analysis of the structural failure mechanisms is foundational to the design of deep-sea composite pressure hulls, since nowadays the design rules of pressurized vessels is mostly formulated according to their failure modes. Hence, this paper aims to review the research on the structural failure of composite pressure hulls in deep sea settings. First of all, the applied research status on composite material in marine equipment is analyzed, including inspection modalities for composite pressure hulls. The review then focuses on the three main failure modes, namely overall buckling, material failure and snap buckling of the deep-sea composite pressure hulls. The study identifies further problems of composite pressure hulls to be solved through the application of the deep sea equipment research, aiming to provide a reference for the study of mechanical behavior, ultimate strength computation, and design of thick composite pressure hulls for deep sea equipment

Latent profile analysis of nurses’ perceived professional benefits in China: a cross-sectional study

Objective To identify profiles of nurses’ perceived professional benefits as well as their predictors.Design Cross-sectional study.Setting The study was carried out online in China.Methods From 6 July to 27 July 2022, a total of 1309 registered nurses participated in the survey by convenient sampling. We collected the Nurses’ Perceived Professional Benefits Questionnaire and demographic data. Using latent profile analysis (LPA), subgroups of nurses’ perceived professional benefits were identified. Moreover, univariate and multinomial logistic regression analyses were conducted to find the factors that were linked with the profiles.Results The survey was validly completed by 1309 nurses, with a 92.9% effective return rate. The findings of the LPA demonstrated three unique profiles: low-perceived professional benefits (11.8%), moderate-perceived professional benefits (57.1%) and high-perceived professional benefits (31.1%). There was a correlation between marital status, the number of night shifts per month and leadership role.Conclusions According to our research, registered nurses have three unique professional benefit profiles. In order to sustain the nursing workforce, despite the fact that nurses get a high level of professional benefits, interventions are necessary to increase nurses’ perception of their professional value

Sophocarpine Attenuates LPS-Induced Liver Injury and Improves Survival of Mice through Suppressing Oxidative Stress, Inflammation, and Apoptosis

Septic liver injury/failure that is mainly characterized by oxidative stress, inflammation, and apoptosis led to a great part of terminal liver pathology with limited effective intervention. Here, we used a lipopolysaccharide (LPS) stimulation model to simulate the septic liver injury and investigated the effect of sophocarpine on LPS-stimulated mice with endotoxemia. We found that sophocarpine increases the survival rate of mice and attenuates the LPS-induced liver injury, which is indicated by pathology and serum liver enzymes. Further research found that sophocarpine ameliorated hepatic oxidative stress indicators (H2O2, O2∙−, and NO) and enhanced the expression of antioxidant molecules such as superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH). In addition, sophocarpine also attenuated regional and systematic inflammation and further reduced apoptosis of hepatocytes. Mechanistic evidence was also investigated in the present study as sophocarpine inhibited hepatic expression of the CYP2E/Nrf2 pathway during oxidative stress, inactivated p38/JNK cascade and NF-κB pathway, and, meanwhile, suppressed PI3K/AKT signaling that reduced apoptosis. Conclusively, the present study unveiled the protective role of sophocarpine in LPS-stimulated oxidative reaction, inflammation, and apoptosis by suppressing the CYP2E/Nrf2/ROS as well as PI3K/AKT pathways, suggesting its promising role in attenuating inflammation and liver injury of septic endotoxemia

Tumor vasculature-targeted recombinant mutated human TNF-α enhanced the antitumor activity of doxorubicin by increasing tumor vessel permeability in mouse xenograft models.

OBJECTIVE: Increasing evidence suggests that, when used in combination, tumor necrosis factor-α (TNF-α) synergizes with traditional chemotherapeutic drugs to exert a heightened antitumor effect. The present study investigated the antitumor efficacy of recombinant mutated human TNF-α specifically targeted to the tumor vasculature (RGD-rmhTNF-α) combined with the chemotherapeutic agent doxorubicin in 2 murine allografted tumor models. METHODS: Mice bearing hepatoma or sarcoma allografted tumors were treated with various doses of RGD-rmhTNF-α alone or in combination with doxorubicin (2 mg/kg). We then evaluated tumor growth and tumor vessel permeability as well as intratumoral levels of RGD-rmhTNF-α and doxorubicin. RESULTS: RGD-rmhTNF-α treatment enhanced the permeability of the tumor vessels and increased intratumoral doxorubicin levels. In addition, intratumoral RGD-rmhTNF-α levels were significantly higher than that of rmhTNF-α. In both of the tested tumor models, administering RGD-rmhTNF-α in combination with doxorubicin resulted in an enhanced antitumor response compared to either treatment alone. Double-agent combination treatment of doxorubicin with 50,000 IU/kg RGD-rmhTNF-α induced stronger antitumor effects on H22 allografted tumor-bearing mice than the single doxorubicin agent alone. Moreover, doxorubicin with 10,000 IU/kg RGD-rmhTNF-α synergized to inhibit tumor growth in S180 allografted tumor-bearing mice. CONCLUSIONS: These results suggest that targeted delivery of low doses of RGD-rmhTNF-α into the tumor vasculature increases the antitumor efficacy of chemotherapeutic drugs

Polyphenolic extract from Artemisia selengensis Turcz ameliorates experimental oral mucositis

Oral mucositis is a common and frequentoccurring disease and there is no effective treatment. In this study, we investigated the efficacy of polyphenolic extract from Artemisia selengensis Turcz (PPAST) in the prevention and treatment of oral mucositis. Cultured human gingival fibroblast cell HGF-1 was used as an in vitro experimental model to confirm the effect of PPAST inhibition of lipopolysaccharide(LPS) on cytotoxicity and its effect on the production of inflammatory cytokines. A rat model of oral ulcer was induced by acetic acid cauterization, and the curative effect of PPAST on oral ulcer was investigated from ulcer area and ulcer duration. PPAST significantly inhibited the toxic effect of LPS on HGF1 cells, improved the survival rate of HGF1 cells, and showed a concentration-dependent inhibition of TNF-α in HGF-1 cell. Treatment with PPAST reduced mucositis scores, promoted oral ulcer healing, and reduced plasma TNF-α levels in rats. Experimental data show that PPAST is safe and effective in the prevention and treatment of oral inflammatory diseases