Esophageal cancer usually has a poor prognosis.Given the significant breakthrough with tumor immunotherapy,an increasing number of clinical studies have demonstrated that the combination of radiotherapy and immune che...Esophageal cancer usually has a poor prognosis.Given the significant breakthrough with tumor immunotherapy,an increasing number of clinical studies have demonstrated that the combination of radiotherapy and immune checkpoint inhibitors(ICIs)may have a synergistic effect and good outcome in esophageal cancer.Clinical studies of immunoradiotherapy(iRT)for esophageal cancer have proliferated enormously from 2021 to the present.However,a summary of the efficacy and toxicity of combined therapy to guide esophageal cancer treatment in clinical practice is lacking.For this review,we integrate the latest data to analyze and assess the efficacy and safety of iRT for esophageal cancer.In addition,we discuss better predictive biomarkers,therapeutic options for specific populations,and other challenges to identify directions for future research design.展开更多
AIM: To evaluate the association between of the interleukin-10 (IL-10) promoter polymorphisms and survival of advanced gastric cancer (GC) patients. METHODS: The IL-10 (-1082, rs1800896; -819, rs1800871; and-592, rs18...AIM: To evaluate the association between of the interleukin-10 (IL-10) promoter polymorphisms and survival of advanced gastric cancer (GC) patients. METHODS: The IL-10 (-1082, rs1800896; -819, rs1800871; and-592, rs1800896) genotypes in 234 patients with advanced gastric cancer and in 243 healthy controls were determined by polymerase chain reaction-restriction fragment length polymorphism assay. Odds ratios (OR) and 95% confidence intervals (CI) were calculated by unconditional logistic regression for the associations between IL-10 genotypes and the risk of GC. The Kaplan-Meier method with log-rank testing was used to evaluate the association between genotype and survival of the patients.RESULTS: The IL-10 -1082 G allele and GCC (-1082, -819 and -592) haplotype were associated with increased gastric cancer risks (OR 1.2, 95% CI 0.6-3.2, P = 0.007, for -1082 G allele, OR = 2.3, 95% CI, 1.2-4.1, P = 0.005, for GCC haplotype, respectively). However, none of the three IL-10 gene polymorphisms (-1082, -819 and -592) was correlated with gastric cancer survival (P > 0.05), and none of the genotypes of the three IL-10 sites was found as independent prognostic risk factors in the multivariate test. CONCLUSION: IL-10 gene promoter polymorphisms may not be associated with the prognosis of advanced gastric cancer.展开更多
In steady state, the intestinal epithelium forms an important part of the gut barrier to defend against luminal bacterial attack. However, the intestinal epithelium is compromised by ionizing irradiation due to its in...In steady state, the intestinal epithelium forms an important part of the gut barrier to defend against luminal bacterial attack. However, the intestinal epithelium is compromised by ionizing irradiation due to its inherent selfrenewing capacity. In this process, small intestinal bacterial overgrowth is a critical event that reciprocally alters the immune milieu. In other words, intestinal bacterial dysbiosis induces inflammation in response to intestinal injuries, thus influencing the repair process of irradiated lesions. In fact, it is accepted that commensal bacteria can generally enhance the host radiation sensitivity. To address the determination of radiation sensitivity, we hypothesize that Paneth cells press a critical "button" because these cells are central to intestinal health and disease by using their peptides, which are responsible for controlling stem cell development in the small intestine and luminal bacterial diversity. Herein,the most important question is whether Paneth cells alter their secretion profiles in the situation of ionizing irradiation. On this basis, the tolerance of Paneth cells to ionizing radiation and related mechanisms by which radiation affects Paneth cell survival and death will be discussed in this review. We hope that the relevant results will be helpful in developing new approaches against radiation enteropathy.展开更多
Novel advances in the field of brain imaging have enabled the unprecedented clinical application of various imaging modalities to facilitate disease diagnosis and treatment. Electrical impedance tomography(EIT) is a f...Novel advances in the field of brain imaging have enabled the unprecedented clinical application of various imaging modalities to facilitate disease diagnosis and treatment. Electrical impedance tomography(EIT) is a functional imaging technique that measures the transfer impedances between electrodes on the body surface to estimate the spatial distribution of electrical properties of tissues. EIT offers many advantages over other neuroimaging technologies,which has led to its potential clinical use. This qualitative review provides an overview of the basic principles,algorithms, and system composition of EIT. Recent advances in the field of EIT are discussed in the context of epilepsy,stroke, brain injuries and edema, and other brain diseases. Further, we summarize factors limiting the development of brain EIT and highlight prospects for the field. In epilepsy imaging, there have been advances in EIT imaging depth,from cortical to subcortical regions. In stroke research, a bedside EIT stroke monitoring system has been developed for clinical practice, and data support the role of EIT in multi-modal imaging for diagnosing stroke. Additionally, EIT has been applied to monitor the changes in brain water content associated with cerebral edema, enabling the early identification of brain edema and the evaluation of mannitol dehydration. However, anatomically realistic geometry,inhomogeneity, cranium completeness, anisotropy and skull type, etc., must be considered to improve the accuracy of EIT modeling. Thus, the further establishment of EIT as a mature and routine diagnostic technique will necessitate the accumulation of more supporting evidence.展开更多
Background:Currently,due to synergy enhancement of anti-tumor effects and potent stimulation of abscopal effects,combination therapy with irradiation and programmed cell death protein 1/programmed death-ligand 1(PD-1/...Background:Currently,due to synergy enhancement of anti-tumor effects and potent stimulation of abscopal effects,combination therapy with irradiation and programmed cell death protein 1/programmed death-ligand 1(PD-1/PD-L1)immune checkpoint inhibition(immuno-radiotherapy,iRT)has revolutionized the therapeutic guidelines.It has been demonstrated that tumor-draining lymph nodes(TDLN)are essential for effective antitumor immunity induced by radiotherapy,immunotherapy,or iRT.Given that the function of TDLN in iRT remains unclear,this study aimed to investigate the function and mechanism of TDLN in iRT-induced abscopal effects.Methods:The function of TDLN was evaluated using unilateral or bilateral MC38 and B16F10 subcutaneous tumor models with or without indicated TDLN.The flow cytometry,multiple immunofluorescence analysis,and NanoString analysis were utilized to detect the composition and function of the immune cells in the primary and abscopal tumor microenvironment.Additionally,we tempted to interrogate the possible mechanisms via RNA-sequencing of tumor-infiltrating lymphocytes and TDLN.Results:TDLN deficiency impaired the control of tumor growth by monotherapy.Bilateral TDLN removal rather than unilateral TDLN removal substantially curtailed iRT-stimulated anti-tumor and abscopal effects.Furthermore,in the absence of TDLN,the infiltration of CD45+and CD8+T cells was substantially reduced in both primary and abscopal tumors,and the anti-tumor function of CD8+T cells was attenuated as well.Additionally,the polarization of tumor-associated macrophages in primary and abscopal tumors were found to be dependent on intact bilateral TDLN.RNA-sequencing data indicated that impaired infiltration and anti-tumor effects of immune cells partially attributed to the altered secretion of components from the tumor microenvironment.Conclusions:TDLN play a critical role in iRT by promoting the infiltration of CD8+T cells and maintaining the M1/M2 macrophage ratio.展开更多
Radiochemotherapy(RCT)is a powerful treatment for cervical cancer,which affects not only malignant cells but also the immune and stromal compartments of the tumor.Understanding the remodeling of the local ecosystem in...Radiochemotherapy(RCT)is a powerful treatment for cervical cancer,which affects not only malignant cells but also the immune and stromal compartments of the tumor.Understanding the remodeling of the local ecosystem induced by RCT would provide valuable insights into improving treatment strategies for cervical cancer.In this study,we applied single-cell RNA-sequencing to paired pre-and post-RCT tumor biopsies from patients with cervical cancer and adjacent normal cervical tissues.We found that the residual population of epithelial cells post-RCT showed upregulated expression of MHC class II genes.Moreover,RCT led to the accumulation of monocytic myeloid-derived suppressor cells with increased pro-inflammatory features and CD16+NK cells with a higher cytotoxic gene expression signature.However,subclusters of T cells showed no significant increase in the expression of cytotoxic features post-RCT.These results reveal the complex responses of the tumor ecosystem to RCT,providing evidence of activation of innate immunity and MHC-II upregulation in cervical cancer.展开更多
Epidermal growth factor receptor(EGFR)-tyrosine kinase inhibitors(TKIs)are effective targeted therapy drugs for advanced nonsmall cell lung cancer(NSCLC)patients carrying sensitized EGFR mutations.The rapid developmen...Epidermal growth factor receptor(EGFR)-tyrosine kinase inhibitors(TKIs)are effective targeted therapy drugs for advanced nonsmall cell lung cancer(NSCLC)patients carrying sensitized EGFR mutations.The rapid development of EGFR-TKIs resistance represents a major clinical challenge for managing NSCLC.The chromosome 4q12 is the first genome-wide association study(GWAS)-reported locus associated with progression-free survival(PFS)of NSCLC patients treated with EGFR-TKIs.However,the biological significance of the noncoding transcripts at 4q12 in NSCLC remains elusive.In the present study,we identified two 4q12 long noncoding RNAs(lncRNAs)LCETRL3 and LCETRL4 which could significantly dimmish EGFR-TKIs efficiency.In line with their oncogenic role,evidently higher LCETRL3 and LCETRL4 levels were observed in NSCLC tissues as compared with normal specimens.Importantly,lncRNA LCETRL3 can interact with oncoprotein TDP43 and inhibit ubiquitination and degradation of TDP43.Similarly,lncRNA LCETRL4 can bind and stabilize oncoprotein EIF2S1 through reducing ubiquitin-proteasome degradation of EIF2S1.In particular,elevated levels of LCETRL3 or LCETRL4 in NSCLC cells resulted in stabilization of TDP43 or EIF2S1,increased levels of NOTCH1 or phosphorylated PDK1,activated AKT signaling and,thus,EGFR-TKIs resistance.Taken together,our data revealed a novel model that integrates two lncRNAs transcribed from the 4q12 locus into the regulation of EGFR-TKIs resistance in NSCLC.These findings shed new light on the importance of functionally annotating lncRNAs in the GWAS loci and provided insights to declare novel druggable targets,i.e.,lncRNAs,which may unlock the therapeutic potential of EGFR-TKIs resistant NSCLC in the clinic.展开更多
Dear Editor,Increasing numbers of studies have revealed the immunomodulating effects of radiotherapy when combined with immune checkpoint inhibitors,as radioimmunotherapy has proven to be a promising treatment[1].Radi...Dear Editor,Increasing numbers of studies have revealed the immunomodulating effects of radiotherapy when combined with immune checkpoint inhibitors,as radioimmunotherapy has proven to be a promising treatment[1].Radioimmunotherapy has shown significantly improved tumor responses than radiotherapy or immunotherapy alone in various malignant tumors[2–4].It has also been applied to cervical cancer in multiple ongoing clinical trials(NCT03612791[5]and NCT02635360[6]).However,tumor recurrence andmetastasis are often unavoidable.As such,investigations into radioimmunotherapy-induced tumor ecosystem evolution are essential for guiding improvements in treatment strategies that achieve better long-term disease control.To date,several studies have investigated radiochemotherapy-induced tumor ecosystem evolution using bulk RNA-sequencing and immune staining[7,8].However,these findings were limited owing to the cellular heterogeneity in cancers.Single-cell RNA-sequencing(scRNA-seq)enables the characterization of cell compositions and transcriptomic states in the tumor at single-cell resolution.展开更多
基金supported by National Natural Science Foundation of China(No.82172865)Clinical Research Special Fund of Wu Jieping Medical Foundation(No.320.6750.2021-02-51 and 320.6750.2021-17-13).
文摘Esophageal cancer usually has a poor prognosis.Given the significant breakthrough with tumor immunotherapy,an increasing number of clinical studies have demonstrated that the combination of radiotherapy and immune checkpoint inhibitors(ICIs)may have a synergistic effect and good outcome in esophageal cancer.Clinical studies of immunoradiotherapy(iRT)for esophageal cancer have proliferated enormously from 2021 to the present.However,a summary of the efficacy and toxicity of combined therapy to guide esophageal cancer treatment in clinical practice is lacking.For this review,we integrate the latest data to analyze and assess the efficacy and safety of iRT for esophageal cancer.In addition,we discuss better predictive biomarkers,therapeutic options for specific populations,and other challenges to identify directions for future research design.
基金Supported by Natural Science Foundation of Shandong Province China, No. ZR2009CM138
文摘AIM: To evaluate the association between of the interleukin-10 (IL-10) promoter polymorphisms and survival of advanced gastric cancer (GC) patients. METHODS: The IL-10 (-1082, rs1800896; -819, rs1800871; and-592, rs1800896) genotypes in 234 patients with advanced gastric cancer and in 243 healthy controls were determined by polymerase chain reaction-restriction fragment length polymorphism assay. Odds ratios (OR) and 95% confidence intervals (CI) were calculated by unconditional logistic regression for the associations between IL-10 genotypes and the risk of GC. The Kaplan-Meier method with log-rank testing was used to evaluate the association between genotype and survival of the patients.RESULTS: The IL-10 -1082 G allele and GCC (-1082, -819 and -592) haplotype were associated with increased gastric cancer risks (OR 1.2, 95% CI 0.6-3.2, P = 0.007, for -1082 G allele, OR = 2.3, 95% CI, 1.2-4.1, P = 0.005, for GCC haplotype, respectively). However, none of the three IL-10 gene polymorphisms (-1082, -819 and -592) was correlated with gastric cancer survival (P > 0.05), and none of the genotypes of the three IL-10 sites was found as independent prognostic risk factors in the multivariate test. CONCLUSION: IL-10 gene promoter polymorphisms may not be associated with the prognosis of advanced gastric cancer.
基金National Natural Science Foundation of China,No.81874254 and No.81773353。
文摘In steady state, the intestinal epithelium forms an important part of the gut barrier to defend against luminal bacterial attack. However, the intestinal epithelium is compromised by ionizing irradiation due to its inherent selfrenewing capacity. In this process, small intestinal bacterial overgrowth is a critical event that reciprocally alters the immune milieu. In other words, intestinal bacterial dysbiosis induces inflammation in response to intestinal injuries, thus influencing the repair process of irradiated lesions. In fact, it is accepted that commensal bacteria can generally enhance the host radiation sensitivity. To address the determination of radiation sensitivity, we hypothesize that Paneth cells press a critical "button" because these cells are central to intestinal health and disease by using their peptides, which are responsible for controlling stem cell development in the small intestine and luminal bacterial diversity. Herein,the most important question is whether Paneth cells alter their secretion profiles in the situation of ionizing irradiation. On this basis, the tolerance of Paneth cells to ionizing radiation and related mechanisms by which radiation affects Paneth cell survival and death will be discussed in this review. We hope that the relevant results will be helpful in developing new approaches against radiation enteropathy.
基金supported by the National Natural Science Foundation of China (81773353)Jilin Scientific and Technological Development Program (20200404148YY, 20200601005JC, 20210101317JC)+2 种基金Jilin Province Special Projec t of Medical and Health Talents (JLSCZD2019-032)the Research Funding Program of Norman Bethune Biomedical Engineering Center (BQEGCZX2019025)National College Students Innovation and Entrepreneurship Training Program (CN)(202010183691)。
文摘Novel advances in the field of brain imaging have enabled the unprecedented clinical application of various imaging modalities to facilitate disease diagnosis and treatment. Electrical impedance tomography(EIT) is a functional imaging technique that measures the transfer impedances between electrodes on the body surface to estimate the spatial distribution of electrical properties of tissues. EIT offers many advantages over other neuroimaging technologies,which has led to its potential clinical use. This qualitative review provides an overview of the basic principles,algorithms, and system composition of EIT. Recent advances in the field of EIT are discussed in the context of epilepsy,stroke, brain injuries and edema, and other brain diseases. Further, we summarize factors limiting the development of brain EIT and highlight prospects for the field. In epilepsy imaging, there have been advances in EIT imaging depth,from cortical to subcortical regions. In stroke research, a bedside EIT stroke monitoring system has been developed for clinical practice, and data support the role of EIT in multi-modal imaging for diagnosing stroke. Additionally, EIT has been applied to monitor the changes in brain water content associated with cerebral edema, enabling the early identification of brain edema and the evaluation of mannitol dehydration. However, anatomically realistic geometry,inhomogeneity, cranium completeness, anisotropy and skull type, etc., must be considered to improve the accuracy of EIT modeling. Thus, the further establishment of EIT as a mature and routine diagnostic technique will necessitate the accumulation of more supporting evidence.
基金the Academic Promotion Program of Shandong First Medical Univer-sity(2019ZL002)Research Unit of Radiation Oncology,Chinese Academy of Medical Sciences(2019RU071)+2 种基金the foundation of National Natural Science Foundation of China(81627901,81972863,82030082 and 31900649)the foundation of Natural Science Foundation of Shandong(ZR201911040452 and ZR2019LZL018)the Cancer Pre-vention and Treatment Joint Fund of Natural Science Foundation of Shandong Province(ZR2020LZL014).
文摘Background:Currently,due to synergy enhancement of anti-tumor effects and potent stimulation of abscopal effects,combination therapy with irradiation and programmed cell death protein 1/programmed death-ligand 1(PD-1/PD-L1)immune checkpoint inhibition(immuno-radiotherapy,iRT)has revolutionized the therapeutic guidelines.It has been demonstrated that tumor-draining lymph nodes(TDLN)are essential for effective antitumor immunity induced by radiotherapy,immunotherapy,or iRT.Given that the function of TDLN in iRT remains unclear,this study aimed to investigate the function and mechanism of TDLN in iRT-induced abscopal effects.Methods:The function of TDLN was evaluated using unilateral or bilateral MC38 and B16F10 subcutaneous tumor models with or without indicated TDLN.The flow cytometry,multiple immunofluorescence analysis,and NanoString analysis were utilized to detect the composition and function of the immune cells in the primary and abscopal tumor microenvironment.Additionally,we tempted to interrogate the possible mechanisms via RNA-sequencing of tumor-infiltrating lymphocytes and TDLN.Results:TDLN deficiency impaired the control of tumor growth by monotherapy.Bilateral TDLN removal rather than unilateral TDLN removal substantially curtailed iRT-stimulated anti-tumor and abscopal effects.Furthermore,in the absence of TDLN,the infiltration of CD45+and CD8+T cells was substantially reduced in both primary and abscopal tumors,and the anti-tumor function of CD8+T cells was attenuated as well.Additionally,the polarization of tumor-associated macrophages in primary and abscopal tumors were found to be dependent on intact bilateral TDLN.RNA-sequencing data indicated that impaired infiltration and anti-tumor effects of immune cells partially attributed to the altered secretion of components from the tumor microenvironment.Conclusions:TDLN play a critical role in iRT by promoting the infiltration of CD8+T cells and maintaining the M1/M2 macrophage ratio.
基金This study was supported by funds from the National Natural Science Foundation of China(82030082 and 81871895)the Academic Promotion Program of Shandong First Medical University(2019ZL002)+4 种基金Key Research and Development Project of Shandong Province of China(2021CXGC011102)the Radiation Oncology Innovate Unit,Chinese Academy of Medical Sciences(2019RU071)Young Taishan Scholars and Academic Promotion Program of Shandong First Medical University(2019RC003)Shandong Provincial Natural Science Foundation(ZR2021QH006)Beijing Bethune Charitable Foundation(flzh202118).
文摘Radiochemotherapy(RCT)is a powerful treatment for cervical cancer,which affects not only malignant cells but also the immune and stromal compartments of the tumor.Understanding the remodeling of the local ecosystem induced by RCT would provide valuable insights into improving treatment strategies for cervical cancer.In this study,we applied single-cell RNA-sequencing to paired pre-and post-RCT tumor biopsies from patients with cervical cancer and adjacent normal cervical tissues.We found that the residual population of epithelial cells post-RCT showed upregulated expression of MHC class II genes.Moreover,RCT led to the accumulation of monocytic myeloid-derived suppressor cells with increased pro-inflammatory features and CD16+NK cells with a higher cytotoxic gene expression signature.However,subclusters of T cells showed no significant increase in the expression of cytotoxic features post-RCT.These results reveal the complex responses of the tumor ecosystem to RCT,providing evidence of activation of innate immunity and MHC-II upregulation in cervical cancer.
基金This work was supported by Taishan Scholars Program of Shandong Province(tsqn20161060)(to M.Y.)National Natural Science Foundation of China(82173070 and 31871306)(to M.Y.)+1 种基金Natural Science Foundation of Shandong Province(ZR2021LZL004)(to M.Y.)Program of Science and Technology for the youth innovation team in universities of Shandong Province(2020KJL001)(to M.Y.).
文摘Epidermal growth factor receptor(EGFR)-tyrosine kinase inhibitors(TKIs)are effective targeted therapy drugs for advanced nonsmall cell lung cancer(NSCLC)patients carrying sensitized EGFR mutations.The rapid development of EGFR-TKIs resistance represents a major clinical challenge for managing NSCLC.The chromosome 4q12 is the first genome-wide association study(GWAS)-reported locus associated with progression-free survival(PFS)of NSCLC patients treated with EGFR-TKIs.However,the biological significance of the noncoding transcripts at 4q12 in NSCLC remains elusive.In the present study,we identified two 4q12 long noncoding RNAs(lncRNAs)LCETRL3 and LCETRL4 which could significantly dimmish EGFR-TKIs efficiency.In line with their oncogenic role,evidently higher LCETRL3 and LCETRL4 levels were observed in NSCLC tissues as compared with normal specimens.Importantly,lncRNA LCETRL3 can interact with oncoprotein TDP43 and inhibit ubiquitination and degradation of TDP43.Similarly,lncRNA LCETRL4 can bind and stabilize oncoprotein EIF2S1 through reducing ubiquitin-proteasome degradation of EIF2S1.In particular,elevated levels of LCETRL3 or LCETRL4 in NSCLC cells resulted in stabilization of TDP43 or EIF2S1,increased levels of NOTCH1 or phosphorylated PDK1,activated AKT signaling and,thus,EGFR-TKIs resistance.Taken together,our data revealed a novel model that integrates two lncRNAs transcribed from the 4q12 locus into the regulation of EGFR-TKIs resistance in NSCLC.These findings shed new light on the importance of functionally annotating lncRNAs in the GWAS loci and provided insights to declare novel druggable targets,i.e.,lncRNAs,which may unlock the therapeutic potential of EGFR-TKIs resistant NSCLC in the clinic.
基金supported by funds fromtheNationalNatural Science Foundation of China(82030082)the Academic Promotion Program of Shandong First Medical University(2019ZL002)+3 种基金the Radiation Oncology Innovate Unit,Chinese Academy of Medical Sciences(2019RU071)Key Research and Development Project of Shandong Province of China(2021CXGC011102)Shandong Provincial Natural Science Foundation(ZR2021QH006)Beijing Bethune Charitable Foundation(flzh202118).
文摘Dear Editor,Increasing numbers of studies have revealed the immunomodulating effects of radiotherapy when combined with immune checkpoint inhibitors,as radioimmunotherapy has proven to be a promising treatment[1].Radioimmunotherapy has shown significantly improved tumor responses than radiotherapy or immunotherapy alone in various malignant tumors[2–4].It has also been applied to cervical cancer in multiple ongoing clinical trials(NCT03612791[5]and NCT02635360[6]).However,tumor recurrence andmetastasis are often unavoidable.As such,investigations into radioimmunotherapy-induced tumor ecosystem evolution are essential for guiding improvements in treatment strategies that achieve better long-term disease control.To date,several studies have investigated radiochemotherapy-induced tumor ecosystem evolution using bulk RNA-sequencing and immune staining[7,8].However,these findings were limited owing to the cellular heterogeneity in cancers.Single-cell RNA-sequencing(scRNA-seq)enables the characterization of cell compositions and transcriptomic states in the tumor at single-cell resolution.
