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  • BMJ  (6)
  • 1
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    Height-based dosing algorithm of bupivacaine in spinal anaesthesia for decreasing maternal hypotension in caesarean section without prophylactic fluid preloading and vasopressors: study protocol for a randomised controlled non-inferiority trial
    BMJ ; 2019
    In:  BMJ Open Vol. 9, No. 5 ( 2019-05-16), p. e024912-
    Details
    In: BMJ Open, BMJ, Vol. 9, No. 5 ( 2019-05-16), p. e024912-
    Abstract: Effectively preventing or treating spinal-induced maternal hypotension is considered to be the Holy Grail of obstetric anaesthesia. Prophylactic fluid preloading and vasopressors decrease hypotension but may aggravate heart load, induce fetal acidosis or maternal bradycardia. Using low-dose local anaesthetic decreases hypotension but may cause insufficient anaesthesia. Whether there is a height-based dosing algorithm of local anaesthetic in spinal anaesthesia for caesarean section that can provide sufficient anaesthesia with less hypotension without prophylactic fluid preloading and vasopressors is unclear. This study was designed to investigate a height-based dosing algorithm of bupivacaine in spinal anaesthesia for caesarean section. Methods and analysis This single-centre, double-blinded, prospective, non-inferiority, randomised controlled trial will include 264 parturients (between 18 and 45 years of age) who are scheduled for caesarean section. All participants will not receive prophylactic fluid preloading. The participants will be randomly divided into two groups: the test group or conventional group. For parturients in the test group, 0.5% isobaric bupivacaine (1.15–1.70 mL) will be injected into the subarachnoid space without prophylactic vasopressors. The bupivacaine dose depends on the height of subjects. For parturients in the conventional group, 0.5% bupivacaine (1.8 mL) will be injected into the subarachnoid space along with prophylactic vasopressors. The primary outcome is the incidence of maternal hypotension. The secondary outcomes include the failure rate of spinal anaesthesia, level of sensory block, degree of motor block, other complications in parturients, time of operation, neonatal outcome and quality of anaesthesia. Ethics and dissemination This study was approved by the Ethics Committee of Shenzhen People’s Hospital of Jinan University (Permit No. SZY-00251, chairperson Xiaofang Yu) on 8 February 2018The study results will be disseminated through peer-reviewed journals, professional societies and meetings. Trial registration number NCT03497364 ; Pre-results.
    Type of Medium: Online Resource
    ISSN: 2044-6055 , 2044-6055
    URL: Article
    URL: Article
    DOI: 10.1136/bmjopen-2018-024912
    DOI: 10.1136/bmjopen-2018-024912.supp1
    Language: English
    Publisher: BMJ
    Publication Date: 2019
    detail.hit.zdb_id: 2599832-8
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  • 2
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    Macrophage GSK3β-deficiency inhibits the progression of hepatocellular carcinoma and enhances the sensitivity of anti-PD1 immunotherapy
    BMJ ; 2022
    In:  Journal for ImmunoTherapy of Cancer Vol. 10, No. 12 ( 2022-12), p. e005655-
    Details
    In: Journal for ImmunoTherapy of Cancer, BMJ, Vol. 10, No. 12 ( 2022-12), p. e005655-
    Abstract: Glycogen synthase kinase 3β (GSK3β) was originally discovered to regulate glycogen synthesis and show a relationship to tumors. However, the biological functions of GSK3β in tumor-associated macrophages (TAMs) in cancers including hepatocellular carcinoma (HCC) remain unclear. Methods The enrichment of GSK3β in tumor tissues was assessed by Gene Expression Omnibus (GEO) database. The in vitro and in vivo assays assisted in evaluating how GSK3β in TAMs affected HCC in terms of proliferation, invasion and migration. Immunofluorescence was used to assess GSK3β expression in TAMs in the anti-PD1 therapy non-responsive HCC group and the responsive group. Western blot and coimmunoprecipitation were performed to demonstrate the interaction between GSK3β and PD-L1. We carried out in vivo experiments in a C57BL/6 mouse model of HCC established through subcutaneous injection. Results GEO single-cell RNA sequencing data suggested that GSK3β was highly enriched in TAMs of HCC. According to in vitro and in vivo experiments, reducing GSK3β in TAMs inhibits the cancer cell proliferation, invasion, and migration. The immunofluorescence and immunohistochemistry results confirmed that the GSK3β is significantly upregulated in TAMs of the anti-PD1 therapy non-responsive group in comparison with the responsive group. In vitro and in vivo experiments confirmed that reduced GSK3β in TAMs are capable of enhancing the sensitivity of anti-PD1 immunotherapy for HCC by decreasing PD-L1 ubiquitination. Mass spectrometry results suggested that high expression of CD14 + GSK3β + in the peripheral blood mononuclear cell (PBMC) can predict non-responsive to anti-PD1 treatment. Moreover, escitalopram is confirmed to act as GSK3β inhibitor that can increase the sensitivity of anti-PD1 immunotherapy for HCC. Conclusions This study revealed that macrophage GSK3β deficiency can inhibit the development of HCC by inhibiting the M2 phenotype and enhance the sensitivity of anti-PD1 immunotherapy for HCC by decreasing PD-L1 ubiquitination. The expression of CD14 + GSK3β + in PBMC can noninvasively predict anti-PD1 sensitivity in HCC patients, which provides novel strategies to predict anti-PD1 sensitivity, increase anti-PD1 therapeutic effect, and bring new hope for HCC patients.
    Type of Medium: Online Resource
    ISSN: 2051-1426
    URL: Article
    DOI: 10.1136/jitc-2022-005655
    Language: English
    Publisher: BMJ
    Publication Date: 2022
    detail.hit.zdb_id: 2719863-7
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  • 3
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    Assessing health-related quality of life and health utilities in patients with chronic hepatitis B-related diseases in China: a cross-sectional study
    BMJ ; 2021
    In:  BMJ Open Vol. 11, No. 9 ( 2021-09), p. e047475-
    Details
    In: BMJ Open, BMJ, Vol. 11, No. 9 ( 2021-09), p. e047475-
    Abstract: The health-related quality of life (HRQoL) and utilities of patients with chronic hepatitis B (CHB) virus infection, including compensated cirrhosis (CC), decompensated cirrhosis (DC) and different stages of hepatocellular carcinoma (HCC), have not been well described in China. This study aimed to evaluate HRQoL and utilities and provide parameters for the economic evaluation of CHB-related diseases. Methods We conducted a multicentre cross-sectional and study to measure the HRQoL of patients with CHB, CC, DC and HCC using the Chinese short form (SF) 36 health survey V.2. The utilities were extracted based on the SF-six dimension scoring model. Multivariable regression analyses identified the effects on HRQoL. Results A total of 1071 patients (639 with CHB, 125 with CC, 85 with DC and 222 with HCC) were invited to complete the questionnaire. Physical HRQoL was not impaired in the CHB stage, while mental HRQoL was significantly impaired. Physical composite summary scores have a more significant decrease than mental composite summary scores at the advanced stages (CC, DC and HCC). The utility scores of CHB only, CC, DC and HCC were 0.773, 0.750, 0.683 and 0.640, respectively. The utility scores in the early, middle and terminal stages of HCC were 0.656, 0.635 and 0.615, respectively. Conclusion Slowing the progress of CHB-related diseases and providing psychological support early are the key points to improving the quality of life with the diseases. The utility values estimated in this study can provide a vital instrument for cost-effectiveness studies on CHB-related diseases.
    Type of Medium: Online Resource
    ISSN: 2044-6055 , 2044-6055
    URL: Article
    DOI: 10.1136/bmjopen-2020-047475
    Language: English
    Publisher: BMJ
    Publication Date: 2021
    detail.hit.zdb_id: 2599832-8
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  • 4
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    Distinct single-cell immune ecosystems distinguish true and de novo HBV-related hepatocellular carcinoma recurrences
    BMJ ; 2023
    In:  Gut Vol. 72, No. 6 ( 2023-06), p. 1196-1210
    Details
    In: Gut, BMJ, Vol. 72, No. 6 ( 2023-06), p. 1196-1210
    Abstract: Revealing the single-cell immune ecosystems in true versus de novo hepatocellular carcinoma (HCC) recurrences could help the optimal development of immunotherapies. Design We performed 5’and VDJ single-cell RNA-sequencing on 34 samples from 20 recurrent HCC patients. Bulk RNA-sequencing, flow cytometry, multiplexed immunofluorescence, and in vitro functional analyses were performed on samples from two validation cohorts. Results Analyses of mutational profiles and evolutionary trajectories in paired primary and recurrent HCC samples using whole-exome sequencing identified de novo versus true recurrences, some of which occurred before clinical diagnosis. The tumour immune microenvironment (TIME) of truly recurrent HCCs was characterised by an increased abundance in KLRB1 + CD8 + T cells with memory phenotype and low cytotoxicity. In contrast, we found an enrichment in cytotoxic and exhausted CD8 + T cells in the TIME of de novo recurrent HCCs. Transcriptomic and interaction analyses showed elevated GDF15 expression on HCC cells in proximity to dendritic cells, which may have dampened antigen presentation and inhibited antitumour immunity in truly recurrent lesions. In contrast, myeloid cells’ cross talk with T cells-mediated T cell exhaustion and immunosuppression in the TIME of de novo recurrent HCCs. Consistent with these findings, a phase 2 trial of neoadjuvant anti-PD-1 immunotherapy showed more responses in de novo recurrent HCC patients. Conclusion True and de novo HCC recurrences occur early, have distinct TIME and may require different immunotherapy strategies. Our study provides a source for genomic diagnosis and immune profiling for guiding immunotherapy based on the type of HCC recurrence and the specific TIME.
    Type of Medium: Online Resource
    ISSN: 0017-5749 , 1468-3288
    URL: Article
    DOI: 10.1136/gutjnl-2022-328428
    RVK:
    XA 10000
    Language: English
    Publisher: BMJ
    Publication Date: 2023
    detail.hit.zdb_id: 1492637-4
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  • 5
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    Targeting tumour-intrinsic N 7 -methylguanosine tRNA modification inhibits MDSC recruitment and improves anti-PD-1 efficacy
    BMJ ; 2023
    In:  Gut Vol. 72, No. 8 ( 2023-08), p. 1555-1567
    Details
    In: Gut, BMJ, Vol. 72, No. 8 ( 2023-08), p. 1555-1567
    Abstract: Intrahepatic cholangiocarcinoma (ICC) exhibits very low response rate to immune checkpoint inhibitors (ICIs) and the underlying mechanism is largely unknown. We investigate the tumour immune microenvironment (TIME) of ICCs and the underlying regulatory mechanisms with the aim of developing new target to inhibit tumour growth and improve anti-programmed cell death protein-1 (PD-1) efficacy. Design Tumour tissues from patients with ICC together with hydrodynamic ICC mouse models were employed to identify the key cell population in TIME of ICCs. Functional analysis and mechanism studies were performed using cell culture, conditional knockout mouse model and hydrodynamic transfection ICC model. The efficacy of single or combined therapy with anti-PD-1 antibody, gene knockout and chemical inhibitor were evaluated in vivo. Results Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) are enriched in advanced ICCs and significantly correlated with N 7 -methylguanosine tRNA methyltransferase METTL1. Using diverse in vivo cancer models, we demonstrate the crucial immunomodulator function of METTL1 in regulation of PMN-MDSC accumulation in TIME and ICC progression. Mechanistically, CXCL8 in human and Cxcl5 in mouse are key translational targets of METTL1 that facilitate its function in promoting PMN-MDSC accumulation in TIME and ICC progression in vivo. Co-blockade of METTL1 and its downstream chemokine pathway enhances the anti-PD-1 efficacy in ICC preclinical mouse models. Conclusions Our data uncover novel mechanisms underlying chemokine regulation and TIME shaping at the layer of messenger RNA translation level and provide new insights for development of efficient cancer immunotherapeutic strategies.
    Type of Medium: Online Resource
    ISSN: 0017-5749 , 1468-3288
    URL: Article
    DOI: 10.1136/gutjnl-2022-327230
    RVK:
    XA 10000
    Language: English
    Publisher: BMJ
    Publication Date: 2023
    detail.hit.zdb_id: 1492637-4
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  • 6
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    Prognostic nomograms to predict overall survival and cause specific death in vulvar squamous cell carcinoma
    BMJ ; 2022
    In:  International Journal of Gynecologic Cancer Vol. 32, No. 6 ( 2022-06), p. 706-715
    Details
    In: International Journal of Gynecologic Cancer, BMJ, Vol. 32, No. 6 ( 2022-06), p. 706-715
    Abstract: The incidence of vulvar squamous cell carcinoma has been rising in recent decades. The prognosis of patients with vulvar squamous cell carcinoma was explored, and nomograms were constructed to predict survival rates. Methods Vulvar squamous cell carcinoma patient data were downloaded from the Surveillance, Epidemiology, and End Results (SEER) database and randomly divided into a training dataset and testing dataset. Univariable and multivariable Cox regression were used to identify risk factors affecting vulvar squamous cell carcinoma overall survival in the training dataset. Cumulative incidence function and Fine–Gray regression were used to analyze cancer specific death in the training dataset. Overall survival and cancer specific death nomograms were constructed and validated in the testing and whole datasets. Receiver operating characteristic and calibration were used to verify the predictive value and clinical applicability of the models. Results Age ≥60 years, grade 3, American Joint Committee on Cancer stages III and IV, TNM (tumor, nodes, metastasis) stages T2, T3, N1, and M1 had a negative effect on overall survival in vulvar cancer patients. Surgery (hazard ratio (HR)=0.416, 95% confidence interval (CI) 0.349 to 0.496, p 〈 0.001) and chemotherapy (HR=0.637, 95% CI 0.544 to 0.746, p 〈 0.001) may improve overall survival. Age, tumor grade, American Joint Committee on Cancer stage, T stage, N stage, M stage, surgery, and chemotherapy significantly affected vulvar cancer specific death. For area under the receiver operating characteristic curve, the predictive ability of the nomograms for overall survival and cancer specific death for 1 year (area under the curve (AUC)=0.862), 3 years (AUC=0.832), and 5 years (AUC=0.808) were all 〉 0.800. Conclusion The nomograms established in our study had an excellent predictive ability for overall survival and cancer specific death in vulvar cancer patients.
    Type of Medium: Online Resource
    ISSN: 1048-891X , 1525-1438
    URL: Article
    URL: Article
    DOI: 10.1136/ijgc-2021-003211
    DOI: 10.1136/ijgc-2021-003211.supp1
    Language: English
    Publisher: BMJ
    Publication Date: 2022
    detail.hit.zdb_id: 2009072-9
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