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Recent clinical studies have shown that mutation of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) gene in cancer cells may be associated with immunosuppressive tumor microenvironment (TME) and poor response to immune checkpoint blockade (ICB) therapy. Therefore, efficiently restoring PTEN gene expression in cancer cells is critical to improving the responding rate to ICB therapy. Here, we screened an adeno-associated virus (AAV) capsid for efficient PTEN gene delivery into B16F10 tumor cells. We demonstrated that intratumorally injected AAV6-PTEN successfully restored the tumor cell PTEN gene expression and effectively inhibited tumor progression by inducing tumor cell immunogenic cell death (ICD) and increasing immune cell infiltration. Moreover, we developed an anti-PD-1 loaded phospholipid-based phase separation gel (PPSG), which formed an in situ depot and sustainably release anti-PD-1 drugs within 42 days in vivo. In order to effectively inhibit the recurrence of melanoma, we further applied a triple therapy based on AAV6-PTEN, PPSG@anti-PD-1 and CpG, and showed that this triple therapy strategy enhanced the synergistic antitumor immune effect and also induced robust immune memory, which completely rejected tumor recurrence. We anticipate that this triple therapy could be used as a new tumor combination therapy with stronger immune activation capacity and tumor inhibition efficacy.
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Due to the insufficient long-term protection and significant efficacy reduction to new variants of current COVID-19 vaccines, the epidemic prevention and control are still challenging. Here, we employ a capsid and antigen structure engineering (CASE) strategy to manufacture an adeno-associated viral serotype 6-based vaccine (S663V-RBD), which expresses trimeric receptor binding domain (RBD) of spike protein fused with a biological adjuvant RS09. Impressively, the engineered S663V-RBD could rapidly induce a satisfactory RBD-specific IgG titer within 2 weeks and maintain the titer for more than 4 months. Compared to the licensed BBIBP-CorV (Sinopharm, China), a single-dose S663V-RBD induced more endurable and robust immune responses in mice and elicited superior neutralizing antibodies against three typical SARS-CoV-2 pseudoviruses including wild type, C.37 (Lambda) and B.1.617.2 (Delta). More interestingly, the intramuscular injection of S663V-RBD could overcome pre-existing immunity against the capsid. Given its effectiveness, the CASE-based S663V-RBD may provide a new solution for the current and next pandemic.
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Photothermal therapy has been intensively investigated for treating cancer in recent years. However, the long-term therapeutic outcome remains unsatisfying due to the frequently occurred metastasis and recurrence. To address this challenge, immunotherapy has been combined with photothermal therapy to activate anti-tumor immunity and relieve the immunosuppressive microenvironment within tumor sites. Here, we engineered silica-based core‒shell nanoparticles (JQ-1@PSNs-R), in which silica cores were coated with the photothermal agent polydopamine, and a bromodomain-containing protein 4 (BRD4) inhibitor JQ-1 was loaded in the polydopamine layer to combine photothermal and immune therapy for tumor elimination. Importantly, to improve the therapeutic effect, we increased the surface roughness of the nanoparticles by hydrofluoric acid (HF) etching during the fabrication process, and found that the internalization of JQ-1@PSNs-R was significantly improved, leading to a strengthened photothermal killing effect as well as the increased intracellular delivery of JQ-1. In the animal studies, the multifunctional nanoparticles with rough surfaces effectively eradicated melanoma via photothermal therapy, successfully activated tumor-specific immune responses against residual tumor cells, and further prevented tumor metastasis and recurrence. Our results indicated that JQ-1@PSNs-R could serve as an innovative and effective strategy for combined cancer therapy.
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AIM: To investigate the role of sorafenib in promoting ferroptosis in HCC, and whether cell death can be induced by activating mitochondrial oxidative stress and consequent mitochondrial dysfunction. METHODS: Hepatocellular carcinoma cell lines Huh7 and HCC-LM3 were treated with different concentrations of sorafenib, the cell viability was determined by CCK-8 assay; mitochondrial membrane potential (MMP) was measured by Tetramethylrhodamine (TMRM) staining; The mitochondrial oxygen consumption rate was monitored by the Seahorse XF24 Analyzer; mitochondrial superoxide indicator (Mitosox) was used to determine the level of reactive oxygen species (ROS) in mitochondria; the formation of total ROS was determined by dichlorofluorescein diacetate (DCF-DA) staning. Finally, The recovery of oxidative damage and cell death induced by sorafenib was observed after pretreated by glutathione (GSH). RESULTS: With the increasing concentration of sorafenib, the survival of the Huh7 and HCC-LM3 was significantly decreased. Sorafenib also inhibited the oxygen consumption rate and decreased oxidative phosphorylation, which results in the depolarization of MMP, ROS accumulation and eventually ferroptosis of HCC cells. However, the occurrence of oxidative stress induced by sorafenib in HCC cells can be effectively reversed by the pretreatment of GSH. CONCLUSION: The ferroptosis can be induced by sorafenib through inducing mitochondrial dysfunction and ROS accumulation in HCC cells. However, the GSH can restore oxidative damage. Therefore, induction of the GSH deficiency in HCC may be a potential therapeutic option to enhance the efficacy of sorafenib.
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An essential step for cancer vaccination is to break the immunosuppression and elicit a tumor-specific immunity. A major hurdle against cancer therapeutic vaccination is the insufficient immune stimulation of the cancer vaccines and lack of a safe and efficient adjuvant for human use. We discovered a novel cancer immunostimulant, trichosanthin (TCS), that is a clinically used protein drug in China, and developed a well-adaptable protein-engineering method for making recombinant protein vaccines by fusion of an antigenic peptide, TCS, and a cell-penetrating peptide (CPP), termed an "all-in-one" vaccine, for transcutaneous cancer immunization. The TCS adjuvant effect on antigen presentation was investigated and the antitumor immunity of the vaccines was investigated using the different tumor models. The vaccines were prepared
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Objective@#To investigate the clinical value of preoperative selective arterial embolization for spinal tumors.@*Methods@#The clinical data of 42 consecutive patients who underwent spinal tumor resection in department of orthopedics Shengjing Hospital of China Medical University from January 2017 to December 2018 were retrospectively analyzed. Patients were divided into embolization group (20 cases) and non-embolization group (22 cases) according to whether they underwent arterial embolization before tumor resection. Two surgical treatments including vertebral resection and laminectomy were performed. The embolization group included 12 cases of vertebral resection and 8 cases of laminectomy; while the non-embolization group included 13 cases of vertebral resection and 9 cases of laminectomy. The difference of intraoperative estimated blood loss, total number of transfused packed red blood cell, calibrated estimated blood loss, operation time and hospitalization time were compared using independent sample t test.@*Results@#Twenty patients in the embolization group underwent successful interventional embolization without serious complications. There were no significant differences between the embolization group and the non-embolization group in terms of intraoperative estimated blood loss, total number of transfused packed red blood cell, calibrated estimated blood loss, operation time, and hospitalization time (P>0.05). Among the patients who underwent vertebral resection, intraoperative estimated blood loss, total number of transfused packed red blood cell and calibrated estimated blood loss were (1 966.7±898.8) ml, (7.42±3.27) U and (91.3±39.2) g/L in the embolization group, and (2 838.5±1 143.5) ml, (11.04±4.08) U and (133.0±46.4) g/L in the non-embolization group, respectively, with statistically significant differences (t=-2.107, -2.436, -2.419, P<0.05). However, there was no significant difference in the operation time and hospitalization time between the two subgroups (t=-0.780, -0.549, P>0.05). Among the patients who underwent laminectomy, there were no significant differences in the above-mentioned indicators between the embolization group and the non-embolization group (P>0.05).@*Conclusion@#Selective arterial embolization for spinal tumors is a relatively safe interventional procedure. Preoperative embolization does not significantly reduce the amount of blood loss during surgical procedures. After the surgical procedures were differentiated, preoperative embolization significantly reduces the amount of blood loss in patients underwent vertebral resection, while patients who underwent laminectomy do not benefit significantly.
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Objective:To investigate the clinical value of preoperative selective arterial embolization for spinal tumors.Methods:The clinical data of 42 consecutive patients who underwent spinal tumor resection in department of orthopedics Shengjing Hospital of China Medical University from January 2017 to December 2018 were retrospectively analyzed. Patients were divided into embolization group (20 cases) and non-embolization group (22 cases) according to whether they underwent arterial embolization before tumor resection. Two surgical treatments including vertebral resection and laminectomy were performed. The embolization group included 12 cases of vertebral resection and 8 cases of laminectomy; while the non-embolization group included 13 cases of vertebral resection and 9 cases of laminectomy. The difference of intraoperative estimated blood loss, total number of transfused packed red blood cell, calibrated estimated blood loss, operation time and hospitalization time were compared using independent sample t test. Results:Twenty patients in the embolization group underwent successful interventional embolization without serious complications. There were no significant differences between the embolization group and the non-embolization group in terms of intraoperative estimated blood loss, total number of transfused packed red blood cell, calibrated estimated blood loss, operation time, and hospitalization time ( P>0.05). Among the patients who underwent vertebral resection, intraoperative estimated blood loss, total number of transfused packed red blood cell and calibrated estimated blood loss were (1 966.7±898.8) ml, (7.42±3.27) U and (91.3±39.2) g/L in the embolization group, and (2 838.5±1 143.5) ml, (11.04±4.08) U and (133.0±46.4) g/L in the non-embolization group, respectively, with statistically significant differences ( t=-2.107, -2.436, -2.419, P<0.05). However, there was no significant difference in the operation time and hospitalization time between the two subgroups ( t=-0.780, -0.549, P>0.05). Among the patients who underwent laminectomy, there were no significant differences in the above-mentioned indicators between the embolization group and the non-embolization group ( P>0.05). Conclusion:Selective arterial embolization for spinal tumors is a relatively safe interventional procedure. Preoperative embolization does not significantly reduce the amount of blood loss during surgical procedures. After the surgical procedures were differentiated, preoperative embolization significantly reduces the amount of blood loss in patients underwent vertebral resection, while patients who underwent laminectomy do not benefit significantly.
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Objective To explore the potential clinical value of mean platelet volume (MPV) in predicting the curative effect of TACE for hepatocellular carcinoma (HCC). Methods The clinical data of 263 HCC patients, who were treated with TACE at authors' hospital during the period from January 2012 to June 2016, were collected. The MPV data before initial TACE, before and after each repeated TACE were recorded. The time of tumor progression (TTP; referring to mRECIST standard), was documented. Based on the MPV determined before initial TACE, the patients were divided into low - MPV group and high - MPV group, and the TTP between the two groups was compared. Results A total of 263 patients were enrolled in this study. In HCC patients, the MPV determined before initial TACE was (9. 45±1. 24) fL, while the MPV determined after initial TACE was (9. 01±1. 11) fL, the difference between the two was statistically significant (t=4. 344, P＜0. 05). The MPV determined at the time when HCC lesion first developed progression was (9. 38±1. 16) fL, which was significantly different with the MPV of (9. 01±1. 11) fL that was obtained after initial TACE (t=3. 498, P＜0. 05). Taking the median value of MPV determined before initial TACE (9. 3 fL) as the cutoff value, the patients were divided into the low - MPV group and the high - MPV group according to patient' s MPV determined before initial TACE. Statistically significant difference in the time when HCC lesion first developed progression existed between the low - MPV group and the high - MPV group (P＜0. 05). COX regression analysis showed that BCLC stage B and C, MPV value before initial TACE were the independent risk predictors of tumor progression. Conclusion The pre-TACE and post-TACE MPV values in HCC patients treated with TACE has certain clinical significance in evaluating the curative effect of TACE. Moreover, MPV value before initial TACE has some value in predicting the time of HCC progression after TACE. (J Intervent Radiol, 2018, 27:257-262)
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Objective To study the expression of p16/mcm2 immunocytochemical dual staining in cervical lesions and its association with high-risk HPV infection,and discuss its clinical value in cervical cancer screening.Methods From May to December 2015,a total of 1 127 women receiving cervical cancer screening,high-risk HPV (HR-HPV) test and liquid-based cytology test were included in the study.p16/mcm2 immunocytochemical dual staining was performed on residual cytology specimens and the results were compared with histopathology results.Results p16/mcm2 had a higher expression risk in HPV16/18 group and other HR-HPV group compared with HPV negative group,with OR of 15.95 (95％CI:9.59-26.51) and 10.53 (95％CI:7.41-14.98),respectively.The positive rate of p16/mcm2 increased with cervical intraepithelial neoplasia (CIN) severity,and was higher in both CIN2 group and CIN3 group than in benign lesion group (P＜0.05).The overall sensitivity of p16/mcm2 to detect CIN2 + and CIN3 + lesions were 86.1％ and 92.0％,respectively,and the overall specificity were 46.1％ and 44.4％,respectively.In group with cytologic diagnoses of atypical squamous cells (ASC) and low-grade squamous intraepithelial lesion (LSIL),the sensitivity to detect CIN2 + and CIN3 + lesions were 85.7％ and 87.5％,respectively,and the specificity were 45.5％ and 44.1％,respectively.Conclusions p16/mcm2 dual staining has higher sensitivity than cytology test and better specificity than HPV test.It can identify high-grade cervical lesions and guide the classification of CIN.p16/mcm2 might be used as an innovative biomarker for cervical cancer screening.
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Objective To study the expression of p16/mcm2 immunocytochemical dual staining in cervical lesions and its association with high-risk HPV infection,and discuss its clinical value in cervical cancer screening.Methods From May to December 2015,a total of 1 127 women receiving cervical cancer screening,high-risk HPV (HR-HPV) test and liquid-based cytology test were included in the study.p16/mcm2 immunocytochemical dual staining was performed on residual cytology specimens and the results were compared with histopathology results.Results p16/mcm2 had a higher expression risk in HPV16/18 group and other HR-HPV group compared with HPV negative group,with OR of 15.95 (95％CI:9.59-26.51) and 10.53 (95％CI:7.41-14.98),respectively.The positive rate of p16/mcm2 increased with cervical intraepithelial neoplasia (CIN) severity,and was higher in both CIN2 group and CIN3 group than in benign lesion group (P＜0.05).The overall sensitivity of p16/mcm2 to detect CIN2 + and CIN3 + lesions were 86.1％ and 92.0％,respectively,and the overall specificity were 46.1％ and 44.4％,respectively.In group with cytologic diagnoses of atypical squamous cells (ASC) and low-grade squamous intraepithelial lesion (LSIL),the sensitivity to detect CIN2 + and CIN3 + lesions were 85.7％ and 87.5％,respectively,and the specificity were 45.5％ and 44.1％,respectively.Conclusions p16/mcm2 dual staining has higher sensitivity than cytology test and better specificity than HPV test.It can identify high-grade cervical lesions and guide the classification of CIN.p16/mcm2 might be used as an innovative biomarker for cervical cancer screening.
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Objective@#to investigate the clinical value of p16/Ki-67 immunocytochemical dual staining (abbreviated as p16/Ki-67 dual staining) in cervical intraepithelial neoplasia (CIN) and cervical cancer screening.@*Methods@#From July to November 2015, a total of 980 women attending cervical cancer screening and receiving high-risk human papillomavirus (HR-HPV) test and thinprep cytologic test (TCT) were included in the study. p16/Ki-67 immunocytochemical dual staining was performed on residual cytologic specimens and compared with histopathology results.@*Results@#The expression risks of p16/Ki-67 in HPV16/18 group and another HR-HPV group were higher than HPV negative group, with an odds ratio of 10.64 (95%CI: 5.66~20.02) and 5.40 (95%CI: 3.62~8.04), respectively. The positive rate of p16/Ki-67 increased with the grade of TCT and histologic diagnosis, and was higher in both CIN2 and CIN3 groups than normal group (P<0.05). The sensitivity of p16/Ki-67 to detect CIN2+ and CIN3+ lesions was 89.3% and 94.1%, respectively, and the specificity was 69.3% and 66.8%, respectively. The sensitivity of TCT to detect CIN2+ and CIN3+ lesions was 60.7% and 64.7%, respectively, and the specificity was 49.3% and 49.1%, respectively.@*Conclusions@#Compared with TCT, p16/Ki-67 dual staining has higher sensitivity and specificity. It can identify high-grade cervical lesions and guide the classification of CIN. p16/Ki-67 dual staining in conjunction with HPV test may be considered as an efficient method for cervical cancer screening.
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Objective To evaluate effects of artesunate on rosacea-like inflammation in mouse models.Methods Twenty-five male BALB/c mice aged 7 weeks were injected subcutaneously with 40 μ1 antibacterial peptide LL-37 into the back once every 12 hours for 4 sessions to establish mouse models with rosacea-like inflammation.These 25 mice were randomly and equally divided into 5 groups:after each injection of LL-37,model group were gavaged with sodium chloride physiological solution,treatment groups gavaged with 25,50 and 100 mg/kg artesunate solution separately,and positive control group gavaged with 30 mg/kg doxycycline hydrochloride solution.Another 5 healthy mice injected subcutaneously with pure water into the back for 4 sessions served as blank control group.Forty-eight hours after the initial injection of LL-37,changes in skin lesions and the intensity of erythema were assessed.Skin tissues at the dorsal injection site were resected and subjected to HE staining,the tissue structure was observed and the number of inflammatory cells was counted.Enzyme-linked immunosorbent assay (ELISA) was performed to estimate the activity of myeloperoxidase (MPO) in skin lesions.Results The model group showed obvious inflammatory reactions,and significantly increased erythema score (3.20 ± 0.84),inflammatory cell count (517.27 ± 99.43) and MPO activity (0.57 ± 0.08) compared with the blank control group (all P ＜ 0.01).The positive control group showed significantly decreased erythema score (1.60 ± 0.89),inflammatory cell count (270.93 ± 124.63) and MPO activity (0.40 ± 0.05) compared with the model group (P ＜ 0.05,0.01,0.01,respectively).Moreover,the erythema score,inflammatory cell counts and MPO activity were all significantly lower in 50-(1.80 ± 0.84,286.00 ± 33.72,0.43 ± 0.05,respectively) and 100-mg/kg artesunate groups (1.40 ± 0.55,258.00 ± 36.44,0.40 ± 0.06,respectively) than in the model group (P ＜ 0.05 or 0.01).However,there were no significant differences in the erythema score,inflammatory cell count and MPO activity between 50-or 100-mg/kg artesunate group and the positive control group (P ＞ 0.05).Conclusion Artesunate can inhibit rosacea-like inflammatory reactions in mouse models,especially the middle-and high-dose artesunate.
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This study was aimed to analyze the composition principles of prescriptions for sequela of apoplexy collected in the CNKI by the Traditional Chinese Medicine Inheritance Platform (TCMIP), in order to provide a reference for clinical selection of medication. Prescriptions for the sequela of apoplexy treatment in CNKI were collected. Based on the TCMIP, the medication rules of prescription were analyzed by data mining method after data entry. A total of 190 prescriptions involving 204 herbs for sequela of apoplexy treatment were screened and studied. The herbs for blood-activating andqi-tonifying were used with higher frequency. There were 36 commonly used herbal pairs. The herb pair of Dang-Gui(Radix Angelicae Sinensis) andHuang-Qi (Radix Astragali) was with the highest frequency. The herbal combination with three types of herbs wasDi-Long (Pheretima),Dang-Gui andHuang-Qi. The herbal combination with four types of herbs wasChuan-Xiong (Rhizoma Chuanxiong),Di-Long,Dang-Gui andHuang-Qi. The analysis on association rule showed thatChuan-Xiong,Dang-Gui,Tao-Ren (Semen Persicae),Hong-Hua(Flos carthami) andHuang-Qiwere often combined with each other. A total of 48 core combinations and 11 new prescriptions were mined. It was concluded that the prescriptions for sequela of apoplexy were mainly composed with herbs for blood-activating,qi-tonifying and collateral-dredging. According to the flavor and meridian tropism theory of Chinese medicine, the herbal medication selection in the prescription was mostly warm and hot in nature, sweet and pungent flavor, and the meridian tropism of the liver and spleen meridian.