INTRODUCTION AND OBJECTIVE: Regulatory T cells (Tregs) play a major role in the development of an immunosuppressive tumor microenvironment. CCR8 has recently been identified as an important chemokine receptor on intratumoral Tregs and is known to be critical for CCR8+Treg-mediated immunosuppression. This study aimed to investigate the clinical significance and inherent molecular mechanisms of intratumoral CCR8+ Tregs in Muscle-invasive bladder cancer (MIBC). METHODS: 259 MIBC patients from two independent clinic centers were included in the study. 83 fresh MIBC tumor tissues were used to evaluate the proportion and function of immune cells via flow cytometry and ex vivo intervention experiments. 396 MIBC patients of TCGA were applied for bioinformatics analysis. RESULTS: We found that the CCR8 expression by intratumoral Tregs maintained the stability and potentiated their suppressive function by upregulating the expression of transcript factors Foxo1 and c-Maf. High level of CCR8+ Tregs is associated with immune tolerance and predicts poor survival and inferior therapeutic responsiveness to chemotherapy. Moreover, we revealed that CCR8 blockade using neutralizing antibody destabilized intratumoral Tregs into a fragile phenotype, reactivated the antitumor immunity and augmented the therapeutic benefits of the anti-PD-1 antibody in MIBC. CONCLUSIONS: Our study presents the mechanism of CCR8 in maintaining the stability of intratumoral Tregs in MIBC and indicates that therapeutic targeting of CCR8 could provide a more specific modulation of Tregs and augment immunotherapy in patients with MIBC.Source of Funding: This study was funded by grants from National Natural Science Foundation of China (81570607, 81671628, 31770851, 81702496, 81702497, 81702805, 81772696, 81871306, 81872082, 81902556, 81902563, 81902898, 81974393), Three-year action plan for promoting clinical skills and clinical innovation in municipal hospitals of Shanghai Shenkang (16CR2003A), National Natural Science Foundation for Young Scholars of China (81902566), Shanghai Jiaotong University Medical-Engineering Cross Research Fund (YG2019QNA53), National Key R&D Program of China (2017YFC0114303), Shanghai Municipal Natural Science Foundation (16ZR1406500, 17ZR1405100, 19ZR1431800), Guide Project of Science and Technology Commission of Shanghai Municipality (17411963100), Shanghai Sailing Program (18YF1404500, 19YF1407900, 19YF1427200), Shanghai Municipal Commission of Health and Family Planning Program (20174Y0042, 201840168, 20184Y0151), Fudan University Shanghai Cancer Center for Outstanding Youth Scholars Foundation (YJYQ201802) and Shanghai Cancer Research Charity Center. All these study sponsors have no roles in the study design, in the collection, analysis and interpretation of data.
Thrombocytopenia caused by long-term radiotherapy and chemotherapy exists in cancer treatment. Previous research demonstrates that 5-Hydroxtrayptamine (5-HT) and its receptors induces the formation of megakaryocytes (MKs) and platelets. However, the relationships between 5-HT1A receptor (5-HTR1A) and MKs is unclear so far. We screened and investigated the mechanism of vilazodone as a 5-HTR1A partial agonist in promoting MK differentiation and evaluated its therapeutic effect in thrombocytopenia. We employed a drug screening model based on machine learning (ML) to screen the megakaryocytopoiesis activity of VLZ. The effects of Vilazodone (VLZ) on megakaryocytopoiesis were verified in HEL and Meg-01 cells. Tg (itga2b: eGFP) zebrafish was performed to analyze the alterations in thrombopoiesis. Moreover, we established a thrombocytopenia mice model to investigate VLZ administration accelerates platelet recovery and function. We carried out network pharmacology, Western blotting and immunofluorescence to demonstrate the potential targets and pathway of VLZ. VLZ has been predicted to have a potential biological action. Meanwhile, VLZ administration promotes MK differentiation and thrombopoiesis in cells and zebrafish models. Progressive experiments showed that VLZ has a potential therapeutic effect on radiation-induced thrombocytopenia in vivo. The network pharmacology and associated mechanism study indicated that SRC and MAPK signaling are both involved in the processes of megakaryopoiesis facilitated by VLZ. Furthermore, the expression of 5-HTR1A during megakaryocyte differentiation is closely related to the activation of SRC and MAPK. Our findings demonstrated that the expression of 5-HTR1A on MK, VLZ could bind to the 5-HTR1A receptor and further regulate the SRC/MAPK signaling pathway to facilitate megakaryocyte differentiation and platelet production, which provides new insights into the alternative therapeutic options for thrombocytopenia.
Thrombocytopenia caused by long-term radiotherapy and chemotherapy exists in cancer treatment. Previous research demonstrates that 5-Hydroxtrayptamine (5-HT) and its receptors induces the formation of megakaryocytes (MKs) and platelets. However, the relationships between 5-HT1A receptor (5-HTR1A) and MKs is unclear so far. We screened and investigated the mechanism of vilazodone as a 5-HTR1A partial agonist in promoting MK differentiation and evaluated its therapeutic effect in thrombocytopenia. We employed a drug screening model based on machine learning (ML) to screen the megakaryocytopoiesis activity of VLZ. The effects of Vilazodone (VLZ) on megakaryocytopoiesis were verified in HEL and Meg-01 cells. Tg (itga2b: eGFP) zebrafish was performed to analyze the alterations in thrombopoiesis. Moreover, we established a thrombocytopenia mice model to investigate VLZ administration accelerates platelet recovery and function. We carried out network pharmacology, Western blotting and immunofluorescence to demonstrate the potential targets and pathway of VLZ. VLZ has been predicted to have a potential biological action. Meanwhile, VLZ administration promotes MK differentiation and thrombopoiesis in cells and zebrafish models. Progressive experiments showed that VLZ has a potential therapeutic effect on radiation-induced thrombocytopenia in vivo. The network pharmacology and associated mechanism study indicated that SRC and MAPK signaling are both involved in the processes of megakaryopoiesis facilitated by VLZ. Furthermore, the expression of 5-HTR1A during megakaryocyte differentiation is closely related to the activation of SRC and MAPK. Our findings demonstrated that the expression of 5-HTR1A on MK, VLZ could bind to the 5-HTR1A receptor and further regulate the SRC/MAPK signaling pathway to facilitate megakaryocyte differentiation and platelet production, which provides new insights into the alternative therapeutic options for thrombocytopenia.
Abstract Patients with small-cell lung cancer (SCLC), a highly metastatic type of lung cancer, show a dismal 5-year survival of only 5%. Effective therapies are urgently needed. Notably, about fifteen-percent of SCLC-patients harbor anti-Hu autoantibodies, which are associated with improved survival. This suggests that the anti-Hu response might be harnessed for immunotherapy. A conditional SCLC mouse model with floxed Rb1 and p53 alleles, in which the cancer is induced by instilling Cre-recombinase into the lungs via intratracheal intubation, offers a unique opportunity to study the immune response in detail. We have previously shown that, just like human SCLC patients, a fraction of these SCLC-carrying mice show an anti-Hu autoantibody response. Here we examine the presence of anti-Hu reactive T-cells using a prospective cohort (n=45) of SCLC-induced mice. All mice develop SCLC, showing systemic disease in 4-7 months following inactivation of floxed Rb1 and p53 alleles. Monthly autoantibody analysis by western blotting revealed an antibody response in a subset of mice, sometimes as early as 1 month after induction. Reactivity usually peaked approximately 3-4 months after induction and declined as disease progressed. This suggests an immune escape mechanism and/or antibody adsorption by the rapidly proliferating tumors. T-cells were isolated at euthanasia from the spleens of moribund mice. Proliferating anti-HuD CD4-positive T-cells were detected in fifty-one-percent of mice (eighteen out of thirty-five) by flow cytometry. Anti-HuD T-cell proliferation from spleen cells was validated in a subsequent prospective cohort (n=45) of SCLC-induced mice using thymidine incorporation. Stratifying for antibody positive and negative mice using an stringent cutoff, there was no significant difference in T cell response between the two groups (p=0.11), however four mice in the antibody positive group showed the most elevated anti-HuD T-cell response. Our observations warrant a much larger study, in which in-depth characterization of the humoral and cellular the anti-HuD immune response is carried out at multiple time points and correlated with a detailed analysis of the stage of tumor development and mestastasis. Preliminary data hints at a negative correlation between the anti-HuD antibody and T-cell response on one hand and tumor size and metastasis on the other. The observation that the Hu antigen in mice with SCLC is a target for both humoral and cellular immune responses underscores the utility of this mouse model in the preclinical evaluation the anti-Hu immune response for therapy and clinical translation. Citation Format: Mario A. Pulido, Vincent Lombardi, Diane Lee, Yiwei Wang, Eric Chung, Lina Wang, W. Martin Kast, Omid Akbari, Ite A. Laird-Offringa. Fluctuating antibody response and CD4-positive T-cells in a small-cell lung cancer mouse model. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3623. doi:10.1158/1538-7445.AM2014-3623
Lower respiratory tract infection (LRTI) is a clinical multi-infectious disease caused by viral, bacterial, and other microbial infections.The present study aims to explore the therapeutic effects of high-flow nasal cannula (HFNC) oxygen therapy and its influence on the serum levels of inflammatory factors in senior patients with LRTI.In this randomized controlled trial, 84 senior patients with LRTI were enrolled between March 2017 and December 2019 and divided into the observation group and the control group according to the random number table method, with 42 cases in each group. Conventional nasal cannula (CNC) oxygen therapy was conducted in the control group and HFNC was conducted in the observation group. After 3 days of treatment, sputum properties, sputum volume, sputum viscosity, and sputum crust formation were recorded to determine the clinical efficacy. ELISA was performed to detect the serum levels of tumor necrosis factor alpha (TNF-α) and interlukein (IL)-8 before and after treatment.The total efficacy in the observation group was 92.86%, which was higher than in the control group (73.81%) (P< 0.05). Three days after treatment, the percentage of grade I sputum in the observation group (73.81%) was higher than in the control group (40.48%). Moreover, the percentage of grade II sputum (23.81%), the percentage of grade III sputum (2.38%), together with the sputum crust formation rate in the observation group (4.76%) were all lower than in the control group (45.24, 14.28, and 26.19%, respectively) (P< 0.05). Three days after treatment, the levels of IL-8 (0.21 ± 0.03 pg/L) and TNF-α (1.27 ± 0.14 ng/L) in the observation group were lower than in the control group (0.30 ± 0.04 pg/L, and 1.49 ± 0.18 ng/L) (t= 6.525, 11.665, 6.252, respectively; P< 0.05).The application of HFNC in senior patients with LRTI could improve respiratory humidification, reduce the number of sputum aspirations, and improve anti-inflammatory effects. It is worthy of application in elderly patients with LRTI.
Atopic dermatitis (AD) has been shown to be closely related to gut dysbiosis mediated through the gut−skin axis, and thus the gut microbiome has recently been explored as a potential therapeutic target for the treatment of AD. Contrasting and varying efficacy have been reported since then. In order to investigate the determining factor of probiotics responsiveness in individuals with AD, we initiated the analysis of 41 AD patients with varying disease severity in Hong Kong, whereas the severity was assessed by Eczema Area and Severity Index (EASI) by board certified dermatologist. 16S rRNA sequencing on the fecal samples from AD patients were performed to obtain the metagenomics profile at baseline and after 8 weeks of oral administration of a novel E3 probiotics formula (including prebiotics, probiotics and postbiotics). While EASI of the participants were significantly lower after the probiotics treatment (p < 0.001, paired Wilcoxon signed rank), subjects with mild AD were found to be more likely to respond to the probiotics treatment. Species richness among responders regardless of disease severity were significantly increased (p < 0.001, paired Wilcoxon signed rank). Responders exhibited (1) elevated relative abundance of Clostridium, Fecalibacterium, Lactobacillus, Romboutsia, and Streptococcus, (2) reduced relative abundance of Collinsella, Bifidobacterium, Fusicatenibacter, and Escherichia-Shigella amid orally-intake probiotics identified using the machine learning algorithm and (3) gut microbiome composition and structure resembling healthy subjects after probiotics treatment. Here, we presented the gut microbiome dynamics in AD patients after the administration of the E3 probiotics formula and delineated the unique gut microbiome signatures in individuals with AD who were responding to the probiotics. These findings could guide the future development of probiotics use for AD management.
Background: Alpha-fetoprotein (AFP) is an important marker for hepatocellular carcinoma, and the detection of serum AFP is currently the principle method for the diagnosis of hepatocellular carcinoma. The prevalence of gastric cancer (GC) with high level of serum AFP is extremely rare, but has unique clinical features. Case summary: We herein present a rare case with GC and high level of serum AFP. A 64-year-old Chinese female underwent gastrectomy was diagnosed as gastric adenocarcinoma and the pathological stage was T1bN0M0, IA. With the progression of disease, the tumor widely metastasized and the serum AFP level increased progressively with the highest level of 3396 ng/mL. She successively entered into 3 lines palliative systematic chemotherapy and fourth-line targeted therapy of apatinib, a small molecule tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor-2. Although previous studies suggested that the prognosis of this special type of GC was poor, this patient lived for 22 months after tumor transfer. Apatinib kept her progression-free survival for 5 months, and the overall survival was 4.5 years. Conclusion: So, we speculate that maybe we can focus apatinib on serum AFP elevated GC patients.
Background Pancreatic cancer is renowned for its elevated incidence and mortality rates on a global scale. The disease burden of pancreatic cancer is anticipated to increase, particularly in Asia, due to its vast and rapidly aging population. Methods Data from the Global Burden of Disease 2019 were analyzed for pancreatic cancer burden across 52 countries in Asia, including the incidence, mortality, and disability-adjusted life years (DALY) for pancreatic cancer, with a focus on risk factors such as high body mass index (BMI), elevated fasting plasma glucose, and smoking. We applied the Estimated Annual Percentage Change, the Age–Period–Cohort model, and decomposition analysis to evaluate incidence trends and effects. Results From 1990 to 2019, both incidence and mortality rates of pancreatic cancer in Asia significantly increased, with an average annual standardized incidence rate change of 1.73%. Males consistently exhibited higher rates than females, with smoking as a key risk factor. Central Asia reported the highest rates, and South Asia the lowest. The incidence rose with age, peaking in those aged 70~74. The disease burden increased in all age groups, particularly in populations aged 55 and above, representing 84.41% of total cases in 2019, up from 79.01% in 1990. Pancreatic cancer ranked the fifth in incidence among six major gastrointestinal tumors but presented a significant growth rate of mortality and DALY. Conclusion With the growing, aging population in Asia, the pancreatic cancer burden is projected to escalate, bringing a significant public health challenge. Hence, comprehensive public health strategies emphasizing early detection, risk modification, and optimized treatment of pancreatic cancer are imperative.
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