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Background Clinical observation suggests the atheroprotective effect of chloroquine and its derivatives, while its mechanism remains unclear. This study aimed to observe the protective effect of chloroquine against atherosclerosis and explore the underlying mechanism. Methods Ataxia telangiectasia mutated (ATM) wild-type or haploinsufficient apolipoprotein-E-knockout (ATM+/+ ApoE−/− or ATM+/− ApoE−/−) mice were treated with different dosages of chloroquine. Anti-CD25 antibody was used to deplete natural Tregs in ATM+/+ ApoE−/− mice. The atherosclerotic burden in different groups of mice was comprehensively evaluated by H&E staining and Masson staining. The effect of chloroquine on the regulatory T cells (Tregs) was assessed in vivo and in vitro by flow cytometry and immunohistochemical staining. The expression of related proteins was detected by real-time polymerase chain reaction and western blotting. Results In ATM+/+ ApoE−/− mice, chloroquine alleviated atherosclerotic lesions, stabilized the plaque, and increased Treg counts in the atherosclerotic lesions and spleens. However, in ATM haploinsufficient mice (ATM+/− ApoE−/−), chloroquine no longer prevented atherosclerosis or impacted Treg counts. Abolishing Treg cells using an anti-CD25 antibody in vivo abrogated the atheroprotective effect of chloroquine. In vitro, chloroquine promoted the differentiation of Tregs from naïve T cells, which was accompanied by enhanced ATM/AMP-activated protein kinase (AMPK) activity and reduced downstream mammalian target of rapamycin (mTOR) activity. Discussion These findings suggest that chloroquine ameliorates atherosclerosis and stabilizes plaque by modulating Tregs differentiation through the regulation of the ATM/AMPK/mTOR pathway. [ABSTRACT FROM AUTHOR]

In the previous study, we had showed the expression of CD133+ CD54+ CD44+ cellular subpopulation of circulating tumor cells ( CTCs) was significantly associated with liver metastasis of colorectal cancer ( CRC). This study aimed to explore whether this subpopulation of CTCs have a prognostic value in CRC patients. Flow cytometry was used to detect the expression of cellular subpopulations of CTCs with CD133, CD54, and CD44 in 152 CRC patients, between December 2013 and October 2014. The impact of clinicopathological factors and the expression of cellular subpopulations of CTCs on overall survival were then analyzed. CRC patients with liver metastases who underwent resection of the primary tumor accompanied by surgical treatment for metastasis had a better survival than other patients ( P < 0.001). The liver metastatic CRC patients with high expression of CD133+ CD54+ ( P < 0.001), CD133− CD54+ ( P = 0.004), and CD133+ CD44+ CD54+ ( P = 0.003) cellular subpopulations of CTCs had a worse survival than those patients with low expression. Multivariable survival analyses identified carcinoembryonic antigen levels (hazard ratio [ HR] = 3.056; 95% confidence interval [ CI] = 1.354-6.897; P = 0.007), treatment strategy ( HR = 0.212; 95% CI = 0.056-0.808; P = 0.023), and CD133+ CD44+ CD54+ cellular subpopulation of CTCs ( HR = 6.459; 95% CI = 1.461-28.558; P = 0.014) as independent prognostic factors for CRC patients with liver metastasis. CD133+ CD44+ CD54+ cellular subpopulation of CTCs has a prognostic value in CRC patients with liver metastasis, especially in the survival of CRC patients with liver metastasis who did not undergo surgical treatment for metastasis. [ABSTRACT FROM AUTHOR]

Background: Clinical observation suggests the atheroprotective effect of chloroquine and its derivatives, while its mechanism remains unclear. This study aimed to observe the protective effect of chloroquine against atherosclerosis and explore the underlying mechanism., Methods: Ataxia telangiectasia mutated (ATM) wild-type or haploinsufficient apolipoprotein-E-knockout (ATM +/+ ApoE -/- or ATM +/- ApoE -/- ) mice were treated with different dosages of chloroquine. Anti-CD25 antibody was used to deplete natural Tregs in ATM +/+ ApoE -/- mice. The atherosclerotic burden in different groups of mice was comprehensively evaluated by H&E staining and Masson staining. The effect of chloroquine on the regulatory T cells (Tregs) was assessed in vivo and in vitro by flow cytometry and immunohistochemical staining. The expression of related proteins was detected by real-time polymerase chain reaction and western blotting., Results: In ATM +/+ ApoE -/- mice, chloroquine alleviated atherosclerotic lesions, stabilized the plaque, and increased Treg counts in the atherosclerotic lesions and spleens. However, in ATM haploinsufficient mice (ATM +/- ApoE -/- ), chloroquine no longer prevented atherosclerosis or impacted Treg counts. Abolishing Treg cells using an anti-CD25 antibody in vivo abrogated the atheroprotective effect of chloroquine. In vitro, chloroquine promoted the differentiation of Tregs from naïve T cells, which was accompanied by enhanced ATM/AMP-activated protein kinase (AMPK) activity and reduced downstream mammalian target of rapamycin (mTOR) activity., Discussion: These findings suggest that chloroquine ameliorates atherosclerosis and stabilizes plaque by modulating Tregs differentiation through the regulation of the ATM/AMPK/mTOR pathway., Competing Interests: The authors declare no conflicts of interest in this work., (Thieme. All rights reserved.)

Aim: To investigate the count of circulating tissue factor-positive (TF + ) procoagulant microparticles (MPs) in patients with type 1 diabetes mellitus (T1DM)., Methods: This case-control study included patients with T1DM and age and sex-matched healthy volunteers. The counts of phosphatidylserine-positive (PS + ) MPs and TF + PS + MPs and the subgroups derived from different cell types were measured in the peripheral blood sample of the two groups using multicolor flow cytometric assay. We compared the counts of each MP between groups as well as the ratio of the TF + PS + MPs and PS + MPs (TF + PS + MPs/PS + MPs)., Results: We recruited 36 patients with T1DM and 36 matched healthy controls. Compared with healthy volunteers, PS + MPs, TF + PS + MPs and TF + PS + MPs/PS + MPs were elevated in patients with T1DM (PS + MPs: 1078.5 ± 158.08 vs 686.84 ± 122.04/μL, P <0.001; TF + PS + MPs: 202.10 ± 47.47 vs 108.33 ± 29.42/μL, P <0.001; and TF + PS + MPs/PS + MPs: 0.16 ± 0.04 vs 0.19 ± 0.05, P = 0.004), mostly derived from platelet, lymphocytes and endothelial cells. In the subgroup analysis, the counts of total and platelet TF + PS + MPs were increased in patients with diabetic retinopathy (DR) and with higher HbA1c, respectively., Conclusion: Circulating TF + PS + MPs and those derived from platelet, lymphocytes and endothelial cells were elevated in patients with T1DM., Competing Interests: Professor Ruth LM Cordiner reports Rising Star Educational Award from International Diabetes Center, Co-Sponsored by Sanofi. The authors report no other conflicts of interest in this work., (© 2019 Zhang et al.)

In the previous study, we had showed the expression of CD133 + CD54 + CD44 + cellular subpopulation of circulating tumor cells (CTCs) was significantly associated with liver metastasis of colorectal cancer (CRC). This study aimed to explore whether this subpopulation of CTCs have a prognostic value in CRC patients. Flow cytometry was used to detect the expression of cellular subpopulations of CTCs with CD133, CD54, and CD44 in 152 CRC patients, between December 2013 and October 2014. The impact of clinicopathological factors and the expression of cellular subpopulations of CTCs on overall survival were then analyzed. CRC patients with liver metastases who underwent resection of the primary tumor accompanied by surgical treatment for metastasis had a better survival than other patients (P < 0.001). The liver metastatic CRC patients with high expression of CD133 + CD54 + (P < 0.001), CD133 - CD54 + (P = 0.004), and CD133 + CD44 + CD54 + (P = 0.003) cellular subpopulations of CTCs had a worse survival than those patients with low expression. Multivariable survival analyses identified carcinoembryonic antigen levels (hazard ratio [HR] = 3.056; 95% confidence interval [CI] = 1.354-6.897; P = 0.007), treatment strategy (HR = 0.212; 95% CI = 0.056-0.808; P = 0.023), and CD133 + CD44 + CD54 + cellular subpopulation of CTCs (HR = 6.459; 95% CI = 1.461-28.558; P = 0.014) as independent prognostic factors for CRC patients with liver metastasis. CD133 + CD44 + CD54 + cellular subpopulation of CTCs has a prognostic value in CRC patients with liver metastasis, especially in the survival of CRC patients with liver metastasis who did not undergo surgical treatment for metastasis., (© 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)