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OBJECTIVE To evaluate the efficacy and safety of PD-1/PD-L1 inhibitors for neoadjuvant treatment of bladder cancer， and to provide evidence-based reference for clinical treatment. METHODS Retrieved from PubMed， Cochrane Library， Embase， American Society of Clinical Oncology Meeting Library， CNKI， VIP and Wanfang database， etc.， the randomized controlled trials （RCTs）， non-RCT， case-control studies， cohort studies， etc. about PD-1/PD-L1 inhibitors for neoadjuvant treatment of bladder cancer were collected from the inception to Jan 31st， 2023. After literature screening， data extraction and quality evaluation， RevMan 5.3 software was used to perform meta-analysis of single-group rates； sensitivity analysis and publication bias analysis were conducted using Stata12 software. RESULTS A total of 25 studies were included in this discussion， involving 940 patients. The results of meta-analysis showed that the pathologic complete response （pCR） rate was 32% [OR＝0.32， 95%CI （0.22， 0.45）， P＝0.006]， downstaging rate was 52% [OR＝0.52， 95%CI （0.45， 0.60）， P＝0.55]， and the incidence of ≥grade 3 immune-related adverse events （irAEs） was 16% [OR＝0.16， 95%CI （0.11， 0.22）， P＜0.000 01]. Subgroup analysis showed that the patients receiving PD-1/PD-L1 inhibitors alone had a pCR rate of 25% and a incidence of Grade≥3 irAEs of 9%； the patients receiving combined immunotherapy had a pCR rate of 29% and a incidence of Grade≥3 irAEs of 28%； the patients receiving PD-1/PD-L1 inhibitors combined with chemotherapy had a pCR rate of 43% and a incidence of Grade≥3 irAEs of 12%； PD-L1 positive patients had a pCR rate of 44%， and PD-L1 negative patients had a pCR rate of 25%. The results of the sensitivity analysis showed that the study was robust. The results of the publication bias analysis showed that there was no significant publication bias. CONCLUSIONS PD-1/PD-L1 inhibitors are effective and safe for adjuvant treatment of bladder cancer.
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Using chemoproteomic techniques, we first identified EIF2AK2, eEF1A1, PRDX3 and VPS4B as direct targets of berberine (BBR) for its synergistically anti-inflammatory effects. Of them, BBR has the strongest affinity with EIF2AK2 via two ionic bonds, and regulates several key inflammatory pathways through EIF2AK2, indicating the dominant role of EIF2AK2. Also, BBR could subtly inhibit the dimerization of EIF2AK2, rather than its enzyme activity, to selectively modulate its downstream pathways including JNK, NF-κB, AKT and NLRP3, with an advantage of good safety profile. In EIF2AK2 gene knockdown mice, the inhibitory IL-1β, IL-6, IL-18 and TNF-α secretion of BBR was obviously attenuated, confirming an EIF2AK2-dependent anti-inflammatory efficacy. The results highlight the BBR's network mechanism on anti-inflammatory effects in which EIF2AK2 is a key target, and inhibition of EIF2AK2 dimerization has a potential to be a therapeutic strategy against inflammation-related disorders.
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Programmed cell death ligand 1 (PD-L1)/programmed cell death protein 1 (PD-1) cascade is an effective therapeutic target for immune checkpoint blockade (ICB) therapy. Targeting PD-L1/PD-1 axis by small-molecule drug is an attractive approach to enhance antitumor immunity. Using flow cytometry-based assay, we identify tubeimoside-1 (TBM-1) as a promising antitumor immune modulator that negatively regulates PD-L1 level. TBM-1 disrupts PD-1/PD-L1 interaction and enhances the cytotoxicity of T cells toward cancer cells through decreasing the abundance of PD-L1. Furthermore, TBM-1 exerts its antitumor effect in mice bearing Lewis lung carcinoma (LLC) and B16 melanoma tumor xenograft
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Programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) blocking therapy has become a major pillar of cancer immunotherapy. Compared with antibodies targeting, small-molecule checkpoint inhibitors which have favorable pharmacokinetics are urgently needed. Here we identified berberine (BBR), a proven anti-inflammation drug, as a negative regulator of PD-L1 from a set of traditional Chinese medicine (TCM) chemical monomers. BBR enhanced the sensitivity of tumour cells to co-cultured T-cells by decreasing the level of PD-L1 in cancer cells. In addition, BBR exerted its antitumor effect in Lewis tumor xenograft mice through enhancing tumor-infiltrating T-cell immunity and attenuating the activation of immunosuppressive myeloid-derived suppressor cells (MDSCs) and regulatory T-cells (Tregs). BBR triggered PD-L1 degradation through ubiquitin (Ub)/proteasome-dependent pathway. Remarkably, BBR selectively bound to the glutamic acid 76 of constitutive photomorphogenic-9 signalosome 5 (CSN5) and inhibited PD-1/PD-L1 axis through its deubiquitination activity, resulting in ubiquitination and degradation of PD-L1. Our data reveals a previously unrecognized antitumor mechanism of BBR, suggesting BBR is small-molecule immune checkpoint inhibitor for cancer treatment.
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Twenty-six novel tricyclic sophoridinic and matrinic derivatives containing a common chlorinated benzene fragment were designed, synthesized and evaluated for their anti-ebolavirus (EBOV) activities. Structure-activity relationship analysis indicated: (i) 12-dichlorobenzyl motif was beneficial for the activity; (ii) the chiral configuration at C5 atom might not affect the activity much. Among the target compounds, compound exhibited the most potent potency against EBOV with an IC value of 5.29 μmol/L and an SI value of over 37.8. Further anti-EBOV assay of identified its high effectiveness, and anti-MARV assay of suggested its inspiring broad-spectrum anti-filovirus activity. The results provided powerful information on further strategic optimization and development of this kind of compounds against filoviruses.
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Objective To investigate dose escalation by metabolic sub-volume based on standard uptake values ( SUV) gradient of pre-treatment positron emission tomography/computed tomography ( PET/CT) for locally advanced non-small cell lung cancer ( NSCLC) radiotherapy. Methods The pre-treatment 18 F-FDG PET/CT images of 29 patients with locally advanced NSCLC were analyzed retrospectively. Gross tumor volume ( GTV) was delineated on the PET/CT fusion images. Tumor metabolic sub-volume was segmented according to the threshold of 50% and 75% maximum standard uptake values ( SUVmax ) . The region that under 50% SUVmax was defined as GTV1. From 50% to 75% SUVmax was defined as GTV2,and over 75% SUVmax was defined as GTV3. PTV (planning target volume), PTV1, PTV2 and PTV3 were extended from GTV, GTV1, GTV2 and GTV3, and different plans were designed subsequently. Plan 1 was designed for PTV with prescription dose 60 Gy, and Plan 2 was designed for PTV1, PTV2 and PTV3 with prescription dose 60-66 Gy, 66-72 Gy and≥72 Gy, respectively. The dosimetric parameters between tumor target and organs at risk (OARs) were compared. Results Compared to Plan 1, the absorbed dose in Plan 2 that covers 2% volume of the PTV ( D2 ) was increased from 66. 5 Gy to 78. 5 Gy and the dose was escalated by about 23. 2%. The average dose of PTV1, PTV2 and PTV3 increased by 2. 8% (62. 7-64. 4 Gy), 10. 3% (63. 5 -70. 0 Gy), 18. 7% (63. 8 -75. 8 Gy), and the average dose of PTV increased by 8. 9% (63. 2-68. 8 Gy). The sub-regional dose had been effectively improved. There was no significant difference in target coverage between Plan 1 and Plan 2 ( P >0. 05 ) . Homogeneity index (HI) was decreased with the escalation of maximum dose for Plan 2(t=23. 3, P<0. 05). There was no statistically significant difference in radiation dose of OARs between two plans ( P>0. 05 ) . Conclusions Dose escalation based on metabolic sub-volume from 18 F-FDG PET/CT was feasible, and radiation dose escalation of sub-volume with high metabolic activity can be achieved without increasing the OARs dose.
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Objective To investigate dose escalation by metabolic sub-volume based on standard uptake values ( SUV) gradient of pre-treatment positron emission tomography/computed tomography ( PET/CT) for locally advanced non-small cell lung cancer ( NSCLC) radiotherapy. Methods The pre-treatment 18 F-FDG PET/CT images of 29 patients with locally advanced NSCLC were analyzed retrospectively. Gross tumor volume ( GTV) was delineated on the PET/CT fusion images. Tumor metabolic sub-volume was segmented according to the threshold of 50% and 75% maximum standard uptake values ( SUVmax ) . The region that under 50% SUVmax was defined as GTV1. From 50% to 75% SUVmax was defined as GTV2,and over 75% SUVmax was defined as GTV3. PTV (planning target volume), PTV1, PTV2 and PTV3 were extended from GTV, GTV1, GTV2 and GTV3, and different plans were designed subsequently. Plan 1 was designed for PTV with prescription dose 60 Gy, and Plan 2 was designed for PTV1, PTV2 and PTV3 with prescription dose 60-66 Gy, 66-72 Gy and≥72 Gy, respectively. The dosimetric parameters between tumor target and organs at risk (OARs) were compared. Results Compared to Plan 1, the absorbed dose in Plan 2 that covers 2% volume of the PTV ( D2 ) was increased from 66. 5 Gy to 78. 5 Gy and the dose was escalated by about 23. 2%. The average dose of PTV1, PTV2 and PTV3 increased by 2. 8% (62. 7-64. 4 Gy), 10. 3% (63. 5 -70. 0 Gy), 18. 7% (63. 8 -75. 8 Gy), and the average dose of PTV increased by 8. 9% (63. 2-68. 8 Gy). The sub-regional dose had been effectively improved. There was no significant difference in target coverage between Plan 1 and Plan 2 ( P >0. 05 ) . Homogeneity index (HI) was decreased with the escalation of maximum dose for Plan 2(t=23. 3, P<0. 05). There was no statistically significant difference in radiation dose of OARs between two plans ( P>0. 05 ) . Conclusions Dose escalation based on metabolic sub-volume from 18 F-FDG PET/CT was feasible, and radiation dose escalation of sub-volume with high metabolic activity can be achieved without increasing the OARs dose.
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Objective To explore the effect of inhibiting Akt phosphorylation on tumor necrosis factor related apoptosis inducing ligand (TRAIL)-induced apoptosis of human non-small cell lung cancer (NSCLC) H1299 cells with wild type EGFR and KRAS.Methods The TRAIL-induced apoptosis was examined by the Annexin V-FITC/PI.The expressions of TRAIL-activated Akt phosphorylation and p-Akt were measured by Western blot.After cells were treated with LY294002, an inhibitor of PI3K-Akt pathway, Annexin V-FITC/PI and Western blot were used to analyze the alteration of TRAIL-induced apoptosis and Akt phosphorylation, respectively.Results H1299 cells were not sensitive to TRAIL-induced apoptosis.When TRAIL concentration was 100 ng/ml, the apoptosis rate of the test group was significantly higher than that of the control group [(15.06±1.29) ％ vs (3.56±0.50) ％, t =66.953, P =0.000].When TRAIL concentration was 500 ng/ml, the difference was not statistically significant compared with apoptosis rate of 100 ng/ml TRAIL group [(18.65±2.09) ％ vs (15.06±1.29) ％, t =2.423, P =0.136].The expression level of Akt phosphorylation in H1299 cells was increased by TRAIL in a time-dependent way.When cells were pretreated with LY294002, TRAIL-induced Akt phosphorylation was suppressed to baseline level.At the same time, the apoptosis rate in LY294002-treated group was significantly higher than that in TRAIL group [(41.65±4.62) ％ vs (15.82±0.61) ％, t =39.028, P =0.001].Conclusions TRAIL-induced Akt phosphorylation can antagonize TRAIL-induced apoptosis.Inhibition of Akt phosphorylation can significantly enhance the sensitivity of NSCLC H1299 cells with wild type EGFR and KRAS to TRAIL-induced apoptosis.
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Objective:To investigate the expression level of pyruvate kinase M2 (PKM2) in tissues of non-small cell lung cancer (NSCLC) patients and the correlation between PKM2 expression level and radiation sensitivity. Methods:A total of 45 NSCLC pa-tients were chosen and treated with radiotherapy for two months after surgery. The patients were classified into four groups based on the curative effect. The mRNA expression levels of PKM2 in tumor and the homologous paraneoplastic tissues of NSCLC patients were de-tected prior to radiotherapy using real time-polymerase chain reaction (RT-PCR), and the protein expressions of PKM2 in the tumor and paraneoplastic tissues of NSCLC patients were detected with Western blot analysis and immunohistochemical method. The mRNA and protein expression levels of PKM2 in the tumor tissues of different groups were detected with RT-PCR and Western blot assays. Re-sults:The effective rate of radiotherapy for 2 months is 44.8%in NSCLC patients. The expression level of PKM2 is significantly high-er in tumor tissues than in homologous paraneoplastic tissues of NSCLC patients and is negatively correlated with the curative effect of radiotherapy. Conclusion:The expression level of PKM2 is significantly higher in tumor tissues than in the paraneoplastic tissues of NSCLC patients. Patients with lower PKM2 expression level are more sensitive to radiotherapy.
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LPS stimulation of macrophages production of IFN-beta plays a key role in innate immunity defending the microbial invasion. In this study, the effect of S632A3 promoting LPS-induced IFN-beta production and the underlying mechanism were investigated, mRNA level was measured by real-time PCR, cytokine production was determined by ELISA, GSK-3beta activity was investigated by kinase assay, protein phosphorylation and expression were evaluated by Western blotting. The results revealed that S632A3 significantly augmented IFN-beta production by LPS-stimulated macrophages. S632A3 inhibition of the activation of GSK-3beta, reduced the threonine 239 phosphorylation of transcription factor c-Jun but increased the total level of c-Jun in LPS-stimulated macrophages. Moreover, small interfering RNA-mediated knockdown of c-Jun level abrogated the ability of S632A3 to augment IFN-beta. The study thus demonstrates S632A3 being a new anti-inflammation lead compound and provides a molecular mechanism by which S632A3 promoted LPS-induced IFN-beta production in macrophages through inhibiting the activation of GSK-3beta.
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Objective Increased morbidity of auto-immune disease in senescent individual might be related with the defects of apoptosis after stimulation or induction. Changes of apoptotic features in splenic T lymphocytes were studied in senescent mice. Methods Flow cytometry was used to study the rates of apoptosis by analysing sub-G 1 peak. DNA ladder was observed by agarose gel electrophoresis. Free calcium levels in both cells were detected by Fluo-3 loading. Bcl-2 protein levels were detected by Western blot. Results After co-stimulation with IL-2/ConA, flow cytometry showed that average apoptotic percentage of old T cells was 38.3% ?10.3%,significantly lower than that of young ones (58.6% ? 4.0%, P
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0.05).Conclusion:p53 and bcl-2 have relationship with oncogenesis and progression of NSCLC.p53 and bcl-2 have no significant correlation,which suggests that bcl-2 has control mechanism for apoptosis different from p53.