Nanopharmaceuticals containing quantum dot nanoparticles (Q-Dot NPs) for treating serious cancers such as breast cancer have made fantastic proposals. In this study, ZnO quantum dot NPs are formulated via ZnO@PVP nano...Nanopharmaceuticals containing quantum dot nanoparticles (Q-Dot NPs) for treating serious cancers such as breast cancer have made fantastic proposals. In this study, ZnO quantum dot NPs are formulated via ZnO@PVP nanopolymer as co-assistants coordinating with efficacious suitable wetting agents, PEG-binding compound, and W/O emulsifier for producing eco-friendly water-based nanodrug. Several characterization techniques containing SEM, TEM, FTIR, photoluminescence, zeta potential, and UV-Vis absorption were employed for ZnO Q-Dot NPs in nanodrug. This work aims to investigate the anti-tumor effects of such nanomedicine on the 4T1 breast cancer cell line in BALB/c mice, being elaborated through intraperitoneal, injection (IVP) and oral therapy. The impressive findings showed that ZnO nanodrug caused changes in blood factors, having the most effectiveness at 40 μg/ml concentration after two weeks of oral treatments. The significant increase in white blood cells (WBC) neutrophils and meaningful decreases in lymphocytes and especially cholesterol were powerful simultaneous impacts, successfully treating malignant breast cancer masses. In this significant animal model research for breast cancer, the sick mice recovered entirely and even had a safe space to mate. Histopathological results showed no evidence of breast tumor formation or metastasis in the group treated with nanodrug and their children. This nanomedicine has a therapeutic effect, and is ready to be applied for treating volunteer breast cancer patients. However, its prevention (inhibitory) effect can also be analyzed and added to current data in future studies.展开更多
目的探讨核基质结合区结合蛋白,富含A-T序列特异性结合蛋白1(special A-T rich sequencebinding protein 1,SATB1)对乳腺癌干细胞表型CD44+/CD24-的影响及机制。方法用SATB1相关小干扰RNA(SATB1related small interfering RNA,SATB1-siR...目的探讨核基质结合区结合蛋白,富含A-T序列特异性结合蛋白1(special A-T rich sequencebinding protein 1,SATB1)对乳腺癌干细胞表型CD44+/CD24-的影响及机制。方法用SATB1相关小干扰RNA(SATB1related small interfering RNA,SATB1-siRNA)双链寡核糖核酸干扰MDA-MB-231细胞;pEGFP-N1-SATB1-GFP真核表达质粒瞬时转染MCF7细胞后,流式细胞术检测SATB1对乳腺癌干细胞表型CD44+/CD24-表达的影响。结果 MCF7细胞转染SATB1后,表达CD44+/CD24-的细胞比例明显升高;MDA-MB-231细胞在SATB1-siRNA干扰后,表达CD44+/CD24-的细胞比例明显降低(P<0.05)。结论 SATB1可能在形成并维持乳腺癌肿瘤干细胞特性中起重要作用。展开更多
目的:预测并鉴定乳腺癌相关抗原受体酪氨酸激酶样孤儿受体1(receptor tyrosine kinase like orphan receptor 1,ROR1)H-2Kd限制性细胞毒性T淋巴细胞(cytotoxic T lymphocyte,CTL)表位,为研究以ROR1为靶点的乳腺癌免疫治疗奠定基础。方法...目的:预测并鉴定乳腺癌相关抗原受体酪氨酸激酶样孤儿受体1(receptor tyrosine kinase like orphan receptor 1,ROR1)H-2Kd限制性细胞毒性T淋巴细胞(cytotoxic T lymphocyte,CTL)表位,为研究以ROR1为靶点的乳腺癌免疫治疗奠定基础。方法:采用生物信息学方法预测乳腺癌相关抗原ROR1 H-2Kd限制性CTL表位,选取预测软件中评分较高的抗原表位肽进行人工合成及纯化。肽结合试验检测抗原表位肽与H-2Kd分子的亲和力。选用亲和力较高的抗原表位肽体外刺激脾淋巴细胞,ELISA法检测细胞因子γ-干扰素(interferon-γ,IFN-γ)和白介素-12(interleukin-12,IL-12)的分泌。结果:预测的4条候选ROR1 CTL表位肽均具有较高的亲和力,其荧光指数(fluorescence index,FI)在30μg/ml时均大于1.5。ELISA结果显示表位肽ROR1(NYMFPSQGI)可在体外有效诱导IFN-γ和IL-12细胞因子的产生。结论:ROR1(NYMFPSQGI)为乳腺癌相关抗原ROR1H-2Kd限制性CTL表位,为研究以ROR1为靶点的乳腺癌免疫治疗奠定了基础。展开更多
Tumor immunotherapy is a rapidly emerging form of cancer treatment. In the current study, a nanoparticle-based vaccine was constructed and the efficacy was assessed through analysis of immune cell populations, tumor g...Tumor immunotherapy is a rapidly emerging form of cancer treatment. In the current study, a nanoparticle-based vaccine was constructed and the efficacy was assessed through analysis of immune cell populations, tumor growth rates, and metastasis. The vaccine was fabricated through encapsulation of plasmid DNA encoding the tumor-associated antigen Mage-b, and the TLR9 agonist CpG oligodeoxynucleotides by a biodegradable polymer, poly(L,D-lactic-coglycolic acid) (PLGA). The size and shape of the nanoparticles suggested that they were an appropriate size for uptake by professional antigen presenting cells;dendritic cells. Furthermore, effects of the immunopotentiating drug cyclo-phosphamide was included to decrease systemic populations of regulatory T cells (Treg);immune system sentinels that down-regulate immune responses. The vaccine was assessed using the 4T1 murine mammary carcinoma model which is a model for stage IV breast cancer. The combined cyclophosphamide/nanoparticle vaccine was shown to significantly reduce 4T1 tumor growth rates and lung metastasis in female BALB/c mice.展开更多
Background Immune checkpoint inhibitors(ICIs)shed new light on triple-negative breast cancer(TNBC),but only a minority of patients demonstrate response.Therefore,adaptive immune resistance(AIR)needs to be further defi...Background Immune checkpoint inhibitors(ICIs)shed new light on triple-negative breast cancer(TNBC),but only a minority of patients demonstrate response.Therefore,adaptive immune resistance(AIR)needs to be further defined to guide the development of ICI regimens.Methods Databases,including The Cancer Genome Atlas,Gene Ontology Resource,University of California Santa Cruz Genome Browser,and Pubmed,were used to screen epigenetic modulators,regulators for CD8+T cells,and transcriptional regulators of programmed cell death-ligand 1(PD-L1).Human peripheral blood mononuclear cell(Hu-PBMC)reconstruction mice were adopted for xenograft transplantation.Tumor specimens from a TNBC cohort and the clinical trial CTR20191353 were retrospectively analyzed.RNA-sequencing,Western blotting,qPCR and immunohistochemistry were used to assess gene expression.Coculture assays were performed to evaluate the regulation of TNBC cells on T cells.Chromatin immunoprecipitation and transposase-accessible chromatin sequencing were used to determine chromatin-binding and accessibility.Results The epigenetic modulator AT-rich interaction domain 1A(ARID1A)gene demonstrated the highest expression association with AIR relative to other epigenetic modulators in TNBC patients.Low ARID1A expression in TNBC,causing an immunosuppressive microenvironment,promoted AIR and inhibited CD8+T cell infiltration and activity through upregulating PD-L1.However,ARID1A did not directly regulate PD-L1 expression.We found that ARID1A directly bound the promoter of nucleophosmin 1(NPM1)and that low ARID1A expression increased NPM1 chromatin accessibility as well as gene expression,further activating PD-L1 transcription.In Hu-PBMC mice,atezolizumab demonstrated the potential to reverse ARID1A deficiency-induced AIR in TNBC by reducing tumor malignancy and activating anti-tumor immunity.In CTR20191353,ARID1A-low patients derived more benefit from pucotenlimab compared to ARID1A-high patients.Conclusions In AIR epigenetics,low ARID1A expression in TNBC contributed to AIR via the ARID1A/NPM1/PD-L1 axis,leading to poor outcome but sensitivity to ICI treatment.展开更多
文摘Nanopharmaceuticals containing quantum dot nanoparticles (Q-Dot NPs) for treating serious cancers such as breast cancer have made fantastic proposals. In this study, ZnO quantum dot NPs are formulated via ZnO@PVP nanopolymer as co-assistants coordinating with efficacious suitable wetting agents, PEG-binding compound, and W/O emulsifier for producing eco-friendly water-based nanodrug. Several characterization techniques containing SEM, TEM, FTIR, photoluminescence, zeta potential, and UV-Vis absorption were employed for ZnO Q-Dot NPs in nanodrug. This work aims to investigate the anti-tumor effects of such nanomedicine on the 4T1 breast cancer cell line in BALB/c mice, being elaborated through intraperitoneal, injection (IVP) and oral therapy. The impressive findings showed that ZnO nanodrug caused changes in blood factors, having the most effectiveness at 40 μg/ml concentration after two weeks of oral treatments. The significant increase in white blood cells (WBC) neutrophils and meaningful decreases in lymphocytes and especially cholesterol were powerful simultaneous impacts, successfully treating malignant breast cancer masses. In this significant animal model research for breast cancer, the sick mice recovered entirely and even had a safe space to mate. Histopathological results showed no evidence of breast tumor formation or metastasis in the group treated with nanodrug and their children. This nanomedicine has a therapeutic effect, and is ready to be applied for treating volunteer breast cancer patients. However, its prevention (inhibitory) effect can also be analyzed and added to current data in future studies.
文摘目的 研究T细胞免疫球蛋白黏蛋白3(TIM-3)及乳腺癌易感基因相关蛋白1(BAP1)、泛素特异性蛋白酶39(USP39)与早期胃癌免疫浸润的关系。方法 选取2019年4月至2021年12月于我院行内镜下黏膜剥离术(ESD)治疗的87例早期胃癌患者,收集其术后病理组织及其癌旁组织;采用免疫组织化学法检测组织TIM-3、BAP1、USP39及CD3^(+)、CD4^(+)、CD8^(+)、CD68^(+)阳性表达,实时荧光定量PCR法检测其mRNA表达;采用Spearman法分析相关性;并比较TIM-3、BAP1、USP39阳性表达的病理参数,随访统计阴阳性表达者生存时间,COX回归分析影响预后的危险因素。结果 TIM-3、BAP1、USP39在胃癌组织中阳性表达率高于癌旁组织(P<0.05)。胃癌组织TIM-3 m RNA、BAP1 m RNA、USP39 mRNA表达量高于癌旁组织(P<0.05)。胃癌组织中CD3^(+)、CD4^(+)阳性率高于癌旁组织,CD8^(+)、CD68^(+)阳性表达率低于癌旁组织(P<0.05)。TIM-3、BAP1、USP39阳性表达在年龄、性别方面,无统计学意义(P>0.05);在分化程度、淋巴结转移方面,具有统计学意义(P<0.05)。经Spearman分析显示,TIM-3、BAP1、USP39表达与CD3^(+)、CD4^(+)浸润量呈正相关(P<0.05),与CD8^(+)、CD68^(+)浸润量呈负相关(P<0.05)。术后随访1年,TIM-3、BAP1、USP39阳性表达者生存率分别为75.68%(56/74)、73.33%(44/60)、71.43%(40/56),阴性表达者分别为100.00%(13/13)、92.59%(25/27)、93.55%(29/31);阴阳性表达患者生存率差异有统计学意义(P<0.05)。经COX多因素分析显示,分化程度对胃癌预后无显著影响(P>0.05),淋巴结转移、TIM-3、BAP1、USP39阳性表达为影响预后的危险因素(P<0.05)。结论 TIM-3、BAP1、USP39在胃癌组织中阳性表达率高,其表达与组织免疫浸润有关,且TIM-3、BAP1、USP39阳性表达者预后差。
文摘Tumor immunotherapy is a rapidly emerging form of cancer treatment. In the current study, a nanoparticle-based vaccine was constructed and the efficacy was assessed through analysis of immune cell populations, tumor growth rates, and metastasis. The vaccine was fabricated through encapsulation of plasmid DNA encoding the tumor-associated antigen Mage-b, and the TLR9 agonist CpG oligodeoxynucleotides by a biodegradable polymer, poly(L,D-lactic-coglycolic acid) (PLGA). The size and shape of the nanoparticles suggested that they were an appropriate size for uptake by professional antigen presenting cells;dendritic cells. Furthermore, effects of the immunopotentiating drug cyclo-phosphamide was included to decrease systemic populations of regulatory T cells (Treg);immune system sentinels that down-regulate immune responses. The vaccine was assessed using the 4T1 murine mammary carcinoma model which is a model for stage IV breast cancer. The combined cyclophosphamide/nanoparticle vaccine was shown to significantly reduce 4T1 tumor growth rates and lung metastasis in female BALB/c mice.
基金National Science and Technology Major Project.Grant Number:2020ZX09201-013。
文摘Background Immune checkpoint inhibitors(ICIs)shed new light on triple-negative breast cancer(TNBC),but only a minority of patients demonstrate response.Therefore,adaptive immune resistance(AIR)needs to be further defined to guide the development of ICI regimens.Methods Databases,including The Cancer Genome Atlas,Gene Ontology Resource,University of California Santa Cruz Genome Browser,and Pubmed,were used to screen epigenetic modulators,regulators for CD8+T cells,and transcriptional regulators of programmed cell death-ligand 1(PD-L1).Human peripheral blood mononuclear cell(Hu-PBMC)reconstruction mice were adopted for xenograft transplantation.Tumor specimens from a TNBC cohort and the clinical trial CTR20191353 were retrospectively analyzed.RNA-sequencing,Western blotting,qPCR and immunohistochemistry were used to assess gene expression.Coculture assays were performed to evaluate the regulation of TNBC cells on T cells.Chromatin immunoprecipitation and transposase-accessible chromatin sequencing were used to determine chromatin-binding and accessibility.Results The epigenetic modulator AT-rich interaction domain 1A(ARID1A)gene demonstrated the highest expression association with AIR relative to other epigenetic modulators in TNBC patients.Low ARID1A expression in TNBC,causing an immunosuppressive microenvironment,promoted AIR and inhibited CD8+T cell infiltration and activity through upregulating PD-L1.However,ARID1A did not directly regulate PD-L1 expression.We found that ARID1A directly bound the promoter of nucleophosmin 1(NPM1)and that low ARID1A expression increased NPM1 chromatin accessibility as well as gene expression,further activating PD-L1 transcription.In Hu-PBMC mice,atezolizumab demonstrated the potential to reverse ARID1A deficiency-induced AIR in TNBC by reducing tumor malignancy and activating anti-tumor immunity.In CTR20191353,ARID1A-low patients derived more benefit from pucotenlimab compared to ARID1A-high patients.Conclusions In AIR epigenetics,low ARID1A expression in TNBC contributed to AIR via the ARID1A/NPM1/PD-L1 axis,leading to poor outcome but sensitivity to ICI treatment.
