Comparative Study on Iron Content Detection by Energy Spectral CT and MRI in MDS Patients.

Objective: The purpose of this study was to identify the difference between dual energy spectral computed tomography (DECT) and magnetic resonance imaging (MRI) used to detect liver/cardiac iron content in Myelodysplastic syndrome (MDS) patients with differently adjusted serum ferritin (ASF) levels. Method: Liver and cardiac iron content were detected by DECT and MRI. Patients were divided into different subgroups according to the level of ASF. The receiver operating characteristic curve (ROC) analysis was applied in each subgroup. The correlation between iron content detected by DECT/MRI and ASF was analyzed in each subgroup. Result: ROC curves showed that liver virtual iron content (LVIC) Az was significantly less than liver iron concentration (LIC) Az in the subgroup with ASF < 1,000 ng/ml. There was no significant difference between LVIC Az and LIC Az in the subgroup with 1,000 ≤ ASF < 2,500 ng/ml and 2,500 ≤ ASF < 5,000 ng/ml. LVIC Az was significantly higher than LIC Az in the subgroup with ASF <5,000 and 5,000 ≤ ASF ng/ml. In patients undergoing DECT and MRI examination on the same day, ASF was significantly correlated with LVIC, whereas no significant correlation was observed between ASF and LIC. After removing the data of ASF > 5,000 mg/L in LIC, LIC became correlated with ASF. There was no significant difference between the subgroup with 2,500 ≤ ASF < 5,000 ng/ml and 5,000 ng/ml ≤ ASF in LIC expression. Furthermore, both LIC and liver VIC had significant correlations with ASF in patients with ASF < 2,500 ng/ml, while LVIC was still correlated with ASF, LIC was not correlated with ASF in patients with 2,500 ng/ml ≤ ASF. Moreover, neither cardiac VIC nor myocardial iron content (MIC) were correlated with ASF in these subgroups. Conclusion: MRI and DECT were complementary to each other in liver iron detection. In MDS patients with high iron content, such as ASF ≥ 5,000 ng/ml, DECT was more reliable than the MRI in the assessment of iron content. But in patients with low iron content, such as ASF < 1,000 ng/ml, MRI is more reliable than DECT. Therefore, for the sake of more accurately evaluating the iron content, the appropriate detection method can be selected according to ASF.

Analysis of the influencing factors related to liver and cardiac iron overload in MDS patients detected by MRI in the real world.

OBJECTIVES: We aim to explore and analyze the related influencing factors of liver and cardiac iron overload in MDS patients detected by magnetic resonance imaging (MRI). METHODS: We have detected cardiac T2* and liver T2* by MRI in 105 MDS patients. Among them, 20 patients accepted MRI examination before and after iron chelation therapy (ICT). Results: We found that adjusted ferritin (ASF) was significantly correlated with liver T2* and cardiac T2*. RBC transfusion volume, brain natriuretic peptide (BNP) and age were the related factors of cardiac T2*, while RBC transfusion volume and erythropoietin (EPO) were related factors of liver T2*. After ICT, the changes of ASF and liver T2* were earlier than cardiac T2*. Chronic hepatitis but virus copy normal's has no significant effect on liver iron deposition. CONCLUSION: These results showed special attention should be paid to these related influencing factors of liver and cardiac T2* expression when we evaluated iron overload and detected the efficacy of ICT in MDS patients.

Cellular senescence induced by S100A9 in mesenchymal stromal cells through NLRP3 inflammasome activation.

Bone marrow stromal cells from patients with myelodysplastic syndrome (MDS) display a senescence phenotype, but the underlying mechanism has not been elucidated. Pro-inflammatory signaling within the malignant clone and the bone marrow microenvironment has been identified as a key pathogenetic driver of MDS. Our study revealed that S100A9 is highly-expressed in lower-risk MDS. Moreover, normal primary mesenchymal stromal cells (MSCs) and the human stromal cell line HS-27a co-cultured with lower-risk MDS bone marrow mononuclear cells acquired a senescence phenotype. Exogenous supplemented S100A9 also induced cellular senescence in MSCs and HS-27a cells. Importantly, Toll-like receptor 4 (TLR4) inhibition or knockdown attenuated the cellular senescence induced by S100A9. Furthermore, we showed that S100A9 induces NLRP3 inflammasome formation, and IL-1ß secretion; findings in samples from MDS patients further confirmed these thoughts. Moreover, ROS and IL-1ß inhibition suppressed the cellular senescence induced by S100A9, whereas NLRP3 overexpression and exogenous IL-1ß supplementation induces cellular senescence. Our study demonstrated that S100A9 promotes cellular senescence of bone marrow stromal cells via TLR4, NLRP3 inflammasome formation, and IL-1ß secretion for its effects. Our findings deepen the understanding of the molecular mechanisms involved in MDS reprogramming of MSCs and indicated the essential role of S100A9 in tumor-environment interactions in bone marrow.

[Effects of Abnormal Iron Metabolism on EPO-STAT5 Signaling Pathway in Anemia Patients].

OBJECTIVE: To study the effects of iron metabolism abnormality on EPO-STAT5 signaling pathway in anemia patients. METHODS: According to diseases, the patients were divided into 3 groups: lower risk myelodysplastic syndrome (MDS) group (30 cases) including 14 cases of non-iron over load and 16 cases of iron over load, 12 cases of them were treated by iron chelation therapy; anemia of chronic disease (ACD) group (12 cases) and iron deficiency anemia (IDA) group (12 cases). In addition, the healthy control group was selected. The iron metaloslism index (SF, SI, TIBC), serum level of EPO, plasma level of P-STAT5 and STAT-5 mRNA expression in peripheral blood cells were detected and compared in different groups. Moreover, the effects of iron metabolism abnormality on the expression of EPO and STAT5 in anemia patients were analyzed. RESULTS: compared with non-iron over load group, the EPO level in iron over load group significantly increased (P<0.05), the expression of STAT5 mRNA and P-STAT5 significantly decreased (P<0.05). After iron chelation therapy, the EPO level in serum significantly decreased (P<0.05), the expression of STAT5 mRNA and P-STAT5 was up-regulated significantly (P<0.05). Compared with healthy control group, the expression of EPO in ACD group was down-regulated significantly, while the expression of STAT5 mRNA was not different, but the P-STAT5 expression was down-regulated significantly (P<0.05). Compared with the healtly control group, the EPO expression in IDA group was enhanced significantly (P<0.05), the expression of STAT5 mRNA and P-STAT5 were also significantly enhanced (P<0.05). CONCLUSION: The excessive iron load or chronic inflammation may inhibit the activation of EPO-STAT5 signaling pathway and aggravate the anemia.

[Underlying Mechanisms of Iron Overloading in Myelodysplastic Syndrome -Review].

Myelodysplastic Syndromes(MDS) comprise a heterogenous group of hematopoietic stem cell malignancies characterized by peripheral cytopenias and have a substantial risk of progression to acute myeloid leukemia(AML). MDS, without effective cure methods, is one of the common hematologic malignant tumors with great threaten to people's health. The phenomenon of iron overloading is common in MDS, which has a poor effect on overall survival and leukemic progression to MDS but get good prognosis by iron chelation therapy. Therefore, increasing researchers are interested in iron overloading of MDS. So far, many researchers have reported that blood transfusion, ineffective hematopoiesis, genetic changes, mitochondrial apoptosis and ROS were found to be important in the incidence of iron overloading. There is greatly valuable to guide iron chelation therapy to study the relationship between those elements with iron overloading. In this paper, we reviewed the great important and specific influence of blood transfusion, ineffective hematopoiesis, genetic changes, mitochondrial apoptosis and ROS in the mechanism of iron overloading, which there is a great significance on iron overloading- associated MDS.

[Iron chelation therapy and its influence on the alleviation of EPO resistance in MDS patients].

This study was aimed to investigate the changes of erythropoietin (EPO), hemoglobin(Hb) and recombinant EPO (rEPO) levels in MDS patients receiving iron chelation therapy, and to explore the relationship between EPO and serum ferritin(SF). A total of 172 MDS patients and 30 healthy controls were studied. The levels of SF, EPO, serum iron (SI), total iron binding capacity (TIBC), C-reaction protein (CRP) and Hb were measured respectively, the level of SF was adjusted according to the changes of CRP. Among them, there were 34 cases of low-risk (SF>1 000 mg/L) receiving deferoxamine therapy, whose changes of SF, EPO, SI, TIBC, Hb levels were detected and compared before and after treatment. Besides, the difference in the incidence of EPO resistance in iron overload group and non-iron overload group was assessed before and after therapy, and 58 cases of low-risk and EPO<1 000 U/L MDS patients were given rEPO therapy. The results showed that the level of EPO in non-iron overload group was higher than that in the normal control group (997.44 ± 473.48 vs 467.27 ± 238.49, P < 0.05). Obviously, the level of EPO in iron overload group was higher than that in non-iron overload group and control group (3257.59 ± 697.19 vs 997.44 ± 473.48, P = 0.012, 3257.59 ± 697.19 vs 467.27 ± 238.49, P = 0.002). Otherwise, the incidence of EPO resistance in iron overload group was higher than that in non-iron overload group (18/35 vs 2/23, P = 0.001), and the level of EPO and SF was positively related to each other in iron overload group (r = 0.310,P = 0.036). After receiving iron chelation therapy, the levels of SF, SI, TIBC and EPO in iron overload group were significantly lower than that before therapy (3942.38 ± 641.82 vs 2266.35 ± 367.31, P = 0.028;48.61 ± 10.65 vs 28.52 ± 12.61, P = 0.034;59.84 ± 12.62 vs 33.76 ± 15.43, P = 0.045;3808.01 ± 750.22 vs 1954.78 ± 473.18, P = 0.042). Moreover, the level of Hb increased (35 ± 18 vs 57 ± 21, P = 0.046) and the EPO resistance in some patients was decreased. It is concluded that iron chelation therapy can improve the efficacy of EPO to alleviate EPO resistance in patients wtih anemic MDS, decrease the pathological level of EPO, enhance Hb levels and reduce the dependency on blood transfusion.

[Effect of GDF15 on iron overloading and erythropoiesis].

Ineffective erythropoiesis is recognized as the principal reason of non-transfusional iron overload. In the process of expanded erythropoiesis, the apoptosis of erythroblasts induces the up-regulation of GDF15. GDF15 suppresses hepcidin production by the hepatocytes. Subsequently, low hepcidin levels increase iron absorption from the intestine resulting in iron overload. Physiological dose of GDF15 can promote the growth and differentiation of erythroid progenitors, but the high dose of GDF15 can suppress the secretion of hepcidin. The regulation of GDF15 may also be related to iron levels, epigenetic regulation and hypoxia. In this article the GDF15 and its expression and distribution, roles of GDF15 in erythropoiesis and iron overload, as well as the regulation factors of GDF15 are reviewed.