Publications by authors named "Shihui Ma"

30 Publications

  • Page 1 of 1

Prognostic Prediction of Cytogenetically Normal Acute Myeloid Leukemia Based on a Gene Expression Model.

Front Oncol 2021 27;11:659201. Epub 2021 May 27.

State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.

Acute myeloid leukemia (AML) refers to a heterogeneous group of hematopoietic malignancies. The well-known European Leukemia Network (ELN) stratifies AML patients into three risk groups, based primarily on the detection of cytogenetic abnormalities. However, the prognosis of cytogenetically normal AML (CN-AML), which is the largest AML subset, can be hard to define. Moreover, the clinical outcomes associated with this subgroup are diverse. In this study, using transcriptome profiles collected from CN-AML patients in the BeatAML cohort, we constructed a robust prognostic Cox model named NEST (Nine-gEne SignaTure). The validity of NEST was confirmed in four external independent cohorts. Moreover, the risk score predicted by the NEST model remained an independent prognostic factor in multivariate analyses. Further analysis revealed that the NEST model was suitable for bone marrow mononuclear cell (BMMC) samples but not peripheral blood mononuclear cell (PBMC) samples, which indirectly indicated subtle differences between BMMCs and PBMCs. Our data demonstrated the robustness and accuracy of the NEST model and implied the importance of the immune dysfunction in the leukemogenesis that occurs in CN-AML, which shed new light on the further exploration of molecular mechanisms and treatment guidance for CN-AML.
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http://dx.doi.org/10.3389/fonc.2021.659201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8190396PMC
May 2021

Radiation-induced bystander effects impair transplanted human hematopoietic stem cells via oxidative DNA damage.

Blood 2021 Jun;137(24):3339-3350

State Key Laboratory of Experimental Hematology, National Research Center for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Center for Stem Cell Medicine and Department of Stem Cell & Regenerative Medicine, Chinese Academy of Medical Sciences-Peking Union Medical College, Tianjin, China.

Total body irradiation (TBI) is commonly used in host conditioning regimens for human hematopoietic stem cell (HSC) transplantation to treat various hematological disorders. Exposure to TBI not only induces acute myelosuppression and immunosuppression, but also injures the various components of the HSC niche in recipients. Our previous study demonstrated that radiation-induced bystander effects (RIBE) of irradiated recipients decreased the long-term repopulating ability of transplanted mouse HSCs. However, RIBE on transplanted human HSCs have not been studied. Here, we report that RIBE impaired the long-term hematopoietic reconstitution of human HSCs as well as the colony-forming ability of human hematopoietic progenitor cells (HPCs). Our further analyses revealed that the RIBE-affected human hematopoietic cells showed enhanced DNA damage responses, cell-cycle arrest, and p53-dependent apoptosis, mainly because of oxidative stress. Moreover, multiple antioxidants could mitigate these bystander effects, though at different efficacies in vitro and in vivo. Taken together, these findings suggest that RIBE impair human HSCs and HPCs by oxidative DNA damage. This study provides definitive evidence for RIBE on transplanted human HSCs and further justifies the necessity of conducting clinical trials to evaluate different antioxidants to improve the efficacy of HSC transplantation for the patients with hematological or nonhematological disorders.
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http://dx.doi.org/10.1182/blood.2020007362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8233686PMC
June 2021

Preoperative evaluation and influencing factors of sentinel lymph node detection for early breast cancer with contrast-enhanced ultrasonography: What matters.

Medicine (Baltimore) 2021 Apr;100(13):e25183

Breast Center.

Abstract: Sentinel lymph node (SLN) is important in the early diagnosis of breast cancer. We aimed to evaluate the role of contrast-enhanced ultrasonography (CEUS) in the preoperative evaluation for SLN and potentially influencing factors, to provide evidence to the management of breast cancer.Patients with breast cancer who treated in our hospital from May 2018 to May 2020 were selected. All patients underwent CEUS examination to find SLN and judged whether the lymph node had cancer metastasis. We evaluated the sensitivity, specificity, and accuracy of CEUS in predicting SLN, and its differences in pathological diagnosis results and related influencing factors were also analyzed.A total of 108 patients with breast cancer were included. And a total of 248 SLNs were detected. The sensitivity of CEUS to the preoperative evaluation of SLN was 84.67%, the specificity was 81.14%, the positive predictive value was 76.08%, and the negative predictive value was 89.27%, the positive likelihood ratio was 4.06, and the negative likelihood ratio was 0.14. The area under the curve of the preoperative evaluation of SLN in CEUS examination was 0.813 (95% confidence interval: 0.765-0.911), and there was significant difference in the size of SLNs between SLN-negative and SLN-positive groups (P = .043).Preoperative CEUS has good predictive value for the SLN detection in patients with breast cancer, and it is worthy of clinical application.
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http://dx.doi.org/10.1097/MD.0000000000025183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8021290PMC
April 2021

Hematopoietic Stem Cell Heterogeneity Is Linked to the Initiation and Therapeutic Response of Myeloproliferative Neoplasms.

Cell Stem Cell 2021 03 22;28(3):502-513.e6. Epub 2021 Feb 22.

State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China; Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Tianjin, China; Department of Stem Cell & Regenerative Medicine, Peking Union Medical College, Tianjin, China. Electronic address:

The implications of stem cell heterogeneity for disease pathogenesis and therapy are poorly defined. JAK2V617F myeloproliferative neoplasms (MPNs), harboring the same mutation in hematopoietic stem cells (HSCs), display diverse phenotypes, including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). These chronic malignant disorders are ideal models to analyze the pathological consequences of stem cell heterogeneity. Single-cell gene expression profiling with parallel mutation detection demonstrated that the megakaryocyte (Mk)-primed HSC subpopulation expanded significantly with enhanced potential in untreated individuals with JAK2V617F ET, driven primarily by the JAK2 mutation and elevated interferon signaling. During treatment, mutant HSCs were targeted preferentially in the Mk-primed HSC subpopulation. Interestingly, homozygous mutant HSCs were forced to re-enter quiescence, whereas their heterozygous counterparts underwent apoptosis. This study provides important evidence for the association of stem cell heterogeneity with the pathogenesis and therapeutic response of a malignant disease.
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http://dx.doi.org/10.1016/j.stem.2021.01.018DOI Listing
March 2021

ANGPTL2-containing small extracellular vesicles from vascular endothelial cells accelerate leukemia progression.

J Clin Invest 2021 Jan;131(1)

State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.

Small extracellular vesicles (SEVs) are functional messengers of certain cellular niches that permit noncontact cell communications. Whether niche-specific SEVs fulfill this role in cancer is unclear. Here, we used 7 cell type-specific mouse Cre lines to conditionally knock out Vps33b in Cdh5+ or Tie2+ endothelial cells (ECs), Lepr+ BM perivascular cells, Osx+ osteoprogenitor cells, Pf4+ megakaryocytes, and Tcf21+ spleen stromal cells. We then examined the effects of reduced SEV secretion on progression of MLL-AF9-induced acute myeloid leukemia (AML), as well as normal hematopoiesis. Blocking SEV secretion from ECs, but not perivascular cells, megakaryocytes, or spleen stromal cells, markedly delayed the leukemia progression. Notably, reducing SEV production from ECs had no effect on normal hematopoiesis. Protein analysis showed that EC-derived SEVs contained a high level of ANGPTL2, which accelerated leukemia progression via binding to the LILRB2 receptor. Moreover, ANGPTL2-SEVs released from ECs were governed by VPS33B. Importantly, ANGPTL2-SEVs were also required for primary human AML cell maintenance. These findings demonstrate a role of niche-specific SEVs in cancer development and suggest targeting of ANGPTL2-SEVs from ECs as a potential strategy to interfere with certain types of AML.
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http://dx.doi.org/10.1172/JCI138986DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773400PMC
January 2021

Mesenchymal stem cells suppress leukemia via macrophage-mediated functional restoration of bone marrow microenvironment.

Leukemia 2020 09 24;34(9):2375-2383. Epub 2020 Feb 24.

State Key Laboratory of Experimental Hematology, CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China.

Bone marrow (BM) mesenchymal stem cells (MSCs) are critical components of the BM microenvironment and play an essential role in supporting hematopoiesis. Dysfunction of MSCs is associated with the impaired BM microenvironment that promotes leukemia development. However, whether and how restoration of the impaired BM microenvironment can inhibit leukemia development remain unknown. Using an established leukemia model and the RNA-Seq analysis, we discovered functional degeneration of MSCs during leukemia progression. Importantly, intra-BM instead of systemic transfusion of donor healthy MSCs restored the BM microenvironment, demonstrated by functional recovery of host MSCs, improvement of thrombopoiesis, and rebalance of myelopoiesis. Consequently, intra-BM MSC treatment reduced tumor burden and prolonged survival of the leukemia-bearing mice. Mechanistically, donor MSC treatment restored the function of host MSCs and reprogrammed host macrophages into arginase 1 positive phenotype with tissue-repair features. Transfusion of MSC-reprogrammed macrophages largely recapitulated the therapeutic effects of MSCs. Taken together, our study reveals that donor MSCs reprogram host macrophages to restore the BM microenvironment and inhibit leukemia development.
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http://dx.doi.org/10.1038/s41375-020-0775-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987218PMC
September 2020

Correction: PDGFB-expressing mesenchymal stem cells improve human hematopoietic stem cell engraftment in immunodeficient mice.

Bone Marrow Transplant 2020 Jun;55(6):1211-1212

State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41409-020-0781-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608374PMC
June 2020

Targeting of apoptosis gene loci by reprogramming factors leads to selective eradication of leukemia cells.

Nat Commun 2019 12 6;10(1):5594. Epub 2019 Dec 6.

State Key Laboratory of Experimental Hematology, Beijing, China.

Applying somatic cell reprogramming strategies in cancer cell biology is a powerful approach to analyze mechanisms of malignancy and develop new therapeutics. Here, we test whether leukemia cells can be reprogrammed in vivo using the canonical reprogramming transcription factors-Oct4, Sox2, Klf4, and c-Myc (termed as OSKM). Unexpectedly, we discover that OSKM can eradicate leukemia cells and dramatically improve survival of leukemia-bearing mice. By contrast, OSKM minimally impact normal hematopoietic cells. Using ATAC-seq, we find OSKM induce chromatin accessibility near genes encoding apoptotic regulators in leukemia cells. Moreover, this selective effect also involves downregulation of H3K9me3 as an early event. Dissection of the functional effects of OSKM shows that Klf4 and Sox2 play dominant roles compared to c-Myc and Oct4 in elimination of leukemia cells. These results reveal an intriguing paradigm by which OSKM-initiated reprogramming induction can be leveraged and diverged to develop novel anti-cancer strategies.
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http://dx.doi.org/10.1038/s41467-019-13411-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6898631PMC
December 2019

PDGFB-expressing mesenchymal stem cells improve human hematopoietic stem cell engraftment in immunodeficient mice.

Bone Marrow Transplant 2020 06 5;55(6):1029-1040. Epub 2019 Dec 5.

State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China.

The bone marrow (BM) niche regulates multiple hematopoietic stem cell (HSC) processes. Clinical treatment for hematological malignancies by HSC transplantation often requires preconditioning via total body irradiation, which severely and irreversibly impairs the BM niche and HSC regeneration. Novel strategies are needed to enhance HSC regeneration in irradiated BM. We compared the effects of EGF, FGF2, and PDGFB on HSC regeneration using human mesenchymal stem cells (MSCs) that were transduced with these factors via lentiviral vectors. Among the above niche factors tested, MSCs transduced with PDGFB (PDGFB-MSCs) most significantly improved human HSC engraftment in immunodeficient mice. PDGFB-MSC-treated BM enhanced transplanted human HSC self-renewal in secondary transplantations more efficiently than GFP-transduced MSCs (GFP-MSCs). Gene set enrichment analysis showed increased antiapoptotic signaling in PDGFB-MSCs compared with GFP-MSCs. PDGFB-MSCs exhibited enhanced survival and expansion after transplantation, resulting in an enlarged humanized niche cell pool that provide a better humanized microenvironment to facilitate superior engraftment and proliferation of human hematopoietic cells. Our studies demonstrate the efficacy of PDGFB-MSCs in supporting human HSC engraftment.
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http://dx.doi.org/10.1038/s41409-019-0766-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269905PMC
June 2020

Effects of telomere length on leukemogenesis.

Sci China Life Sci 2020 Feb 8;63(2):308-311. Epub 2019 Jul 8.

State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China.

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http://dx.doi.org/10.1007/s11427-019-9588-7DOI Listing
February 2020

A Retrospective Propensity Score Matched Study of the Preoperative C-Reactive Protein to Albumin Ratio and Prognosis in Patients with Resectable Non-Metastatic Breast Cancer.

Med Sci Monit 2019 Jun 11;25:4342-4352. Epub 2019 Jun 11.

Department of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, Guandong, China (mainland).

BACKGROUND A retrospective study aimed to investigate the association between the CRP to albumin ratio and prognosis in patients with resectable non-metastatic breast cancer in terms of disease-free survival (DFS) and overall survival (OS) using propensity score matching. MATERIAL AND METHODS Patients with newly diagnosed resectable non-metastatic breast cancer (n=200) who underwent modified radical mastectomy between January 2008 to June 2013 included a group with an increased CRP to albumin ratio ≥0.029 (n=80) and a group with reduced CRP to albumin ratio <0.029 (n=120). Propensity score matching was used to estimate the prognostic role of the CRP to albumin ratio, and a 1: 1 matching using four covariates was performed to overcome selection bias. The prognostic significance of the CRP to albumin ratio was analyzed using receiver operating characteristic (ROC) curves. Kaplan-Meier survival analysis and a Cox proportional hazards model were conducted to identify the impact on DFS and OS. RESULTS An increased CRP to albumin ratio was associated with increased age, post-menopausal status, and a high risk of recurrence or death in patients with breast cancer. An increased preoperative CRP to albumin ratio was significantly associated with reduced disease-free survival (DFS) and overall survival (OS) (all P<0.05). Multivariate analysis showed that an increased CRP to albumin ratio was an independent risk factor for long-term outcome and predicted reduced DFS (HR, 2.225; P=0.024) and OS (HR, 9.189; P=0.003). CONCLUSIONS Preoperative evaluation of the CRP to albumin ratio was an independent prognostic indicator in patients with resectable breast cancer.
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http://dx.doi.org/10.12659/MSM.913684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6582690PMC
June 2019

Bifunctional Template-Induced [email protected] Dual-Shelled Hollow Nanosphere-Based Coatings for Smart Windows.

ACS Appl Mater Interfaces 2019 May 16;11(17):15960-15968. Epub 2019 Apr 16.

School of Chemical and Environmental Engineering China University of Mining and Technology (Beijing) , Beijing 100083 , China.

Thermochromic vanadium dioxide (VO) as one of the most promising candidates for smart windows has attracted widespread attention in recent years. Excellent optical performances (luminous transmittance, T, and solar modulation efficiency, Δ T) of VO-based coatings are usually pursued as crucial issues. In the current work, we report an ingenious approach for the synthesis of [email protected] dual-shell hollow nanospheres (DSHNs) and the preparation of DSHNs thermochromic coatings. A sequential bifunctional template-induced mechanism for the formation of DSHNs was proposed. Because of the unique hollow-core and dual-shell structure, the as-prepared [email protected] DSHNs coatings exhibited appealing optical performances with enhanced luminous transmittance of 61.8% and solar modulation efficiency of 12.6%, compared with continuous and dense VO coatings. It has been proved that the improvement of visible transmittance could be ascribed to the effective reduction of refractive index (from 2.6 to 1.6 at 630 nm). In addition, its excellent thermochromic performance has been confirmed by the model cubes measurements, expressing a great potential as energy-efficient smart windows in high-rise buildings. The bifunctional template-induced synthetic strategy may inspire more facile, efficient and inexpensive processes for development of well-defined multishelled hollow nanostructures for varied applications.
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http://dx.doi.org/10.1021/acsami.8b22113DOI Listing
May 2019

Bone marrow endothelial cell-derived interleukin-4 contributes to thrombocytopenia in acute myeloid leukemia.

Haematologica 2019 10 21;104(10):1950-1961. Epub 2019 Feb 21.

State Key Laboratory of Experimental Hematology

Normal hematopoiesis can be disrupted by the leukemic bone marrow microenvironment, which leads to cytopenia-associated symptoms including anemia, hemorrhage and infection. Thrombocytopenia is a major and sometimes fatal complication in patients with acute leukemia. However, the mechanisms underlying defective thrombopoiesis in leukemia have not been fully elucidated. In the steady state, platelets are continuously produced by megakaryocytes. Using an -induced acute myeloid leukemia mouse model, we demonstrated a preserved number and proportion of megakaryocyte-primed hematopoietic stem cell subsets, but weakened megakaryocytic differentiation via both canonical and non-canonical routes. This primarily accounted for the dramatic reduction of megakaryocytic progenitors observed in acute myeloid leukemia bone marrow and a severe disruption of the maturation of megakaryocytes. Additionally, we discovered overproduction of interleukin-4 from bone marrow endothelial cells in acute myeloid leukemia and observed inhibitory effects of interleukin-4 throughout the process of megakaryopoiesis Furthermore, we observed that inhibition of interleukin-4 in combination with induction chemotherapy not only promoted recovery of platelet counts, but also prolonged the duration of remission in our acute myeloid leukemia mouse model. Our study elucidates a new link between interleukin-4 signaling and defective megakaryopoiesis in acute myeloid leukemia bone marrow, thereby offering a potential therapeutic target in acute myeloid leukemia.
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http://dx.doi.org/10.3324/haematol.2018.214593DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6886411PMC
October 2019

TGF-β1 Negatively Regulates the Number and Function of Hematopoietic Stem Cells.

Stem Cell Reports 2018 07 21;11(1):274-287. Epub 2018 Jun 21.

State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing Road 288, Tianjin 300020, China. Electronic address:

Transforming growth factor β1 (TGF-β1) plays a role in the maintenance of quiescent hematopoietic stem cells (HSCs) in vivo. We asked whether TGF-β1 controls the cell cycle status of HSCs in vitro to enhance the reconstitution activity. To examine the effect of TGF-β1 on the HSC function, we used an in vitro culture system in which single HSCs divide with the retention of their short- and long-term reconstitution ability. Extensive single-cell analyses showed that, regardless of its concentration, TGF-β1 slowed down the cell cycle progression of HSCs but consequently suppressed their self-renewal potential. Cycling HSCs were not able to go back to quiescence with TGF-β1. This study revealed a negative role of TGF-β1 in the regulation of the HSC number and reconstitution activity.
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http://dx.doi.org/10.1016/j.stemcr.2018.05.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6067088PMC
July 2018

High repetition rates optically active langasite electro-optically Q-switched laser at 1.34 μm.

Opt Express 2017 Oct;25(20):24007-24014

An electro-optically Q-switched pulsed laser at 1.34 μm with a repetition rate of 100 kHz applying optically active langasite (LaGaSiO) crystal has been reported. With Nd:YVO as laser crystal, the electro-optically Q-switched pulsed lasers were obtained with the maximum repetition rate of 100 kHz, maximum average output power of 2.42 W, and a minimum pulse width of 2.4 ns. Based on the theory of rate equations, the optimal pulse energy of the electro-optical Q-switching could be calculated. The experimental results have been found to be matched well with the theoretical calculations. To the best of our knowledge, this work presents the highest repetition rate and shortest pulse width which are achieved by an electric-optic LGS Q-switching at the wavelength of 1.34 μm, and it enriches the material categories for generating the high repetition rate pulsed laser.
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http://dx.doi.org/10.1364/OE.25.024007DOI Listing
October 2017

Predictive Value of Circulating Tumor Cells for Evaluating Short- and Long-Term Efficacy of Chemotherapy for Breast Cancer.

Med Sci Monit 2017 Oct 7;23:4808-4816. Epub 2017 Oct 7.

Department of General Surgery, Zhujiang Hospital, Southern Medical University, Zhongshan, Guangdong, China (mainland).

BACKGROUND The present study investigated the role of circulating tumor cells (CTCs) counts in predicting the short- and long-term efficacy of chemotherapy for breast cancer (BC). MATERIAL AND METHODS Peripheral venous blood was extracted from 187 BC patients. CTCs were measured by flow cytometry. Spearman's correlation analysis was performed to examine the correlation between the efficacy of chemotherapy and CTC counts. A receiver operating characteristic (ROC) curve was plotted to estimate the predictive value of CTC counts. The Kaplan-Meier method was employed to calculate disease-free survival (DFS) and overall survival (OS). Cox regression analysis was used to determine risk factors for prognosis of BC. RESULTS Complete response (CR) + partial response (PR) was achieved by 65.8% of BC patients. After chemotherapy, CTC counts were decreased in both the CR + PR and SD + PD groups. Spearman's correlation analysis indicated that CTC counts before chemotherapy were positively correlated with clinical response to chemotherapy (r=0.45, P<0.05). For predicting clinical response to chemotherapy, CTC counts yielded an area under the curve (AUC) of 0.958, with sensitivity reaching 96.9% and specificity reaching 85.4%. The Kaplan-Meier method and Cox regression analysis indicated that tumor node metastasis (TNM) staging, lymph node metastasis (LNM), ki-67, endocrine therapy, and CTC counts were risk factors for prognosis of BC. CONCLUSIONS These findings indicate that BC patients with CTCs ³8 exhibited poor response to chemotherapy and poor OS. CTC counts can serve as an indicator in predicting short- and long-term efficacy of chemotherapy for BC.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5642643PMC
http://dx.doi.org/10.12659/msm.903736DOI Listing
October 2017

Intron 1 GATA site enhances ALAS2 expression indispensably during erythroid differentiation.

Nucleic Acids Res 2017 01 7;45(2):657-671. Epub 2016 Oct 7.

State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China

The first intronic mutations in the intron 1 GATA site (int-1-GATA) of 5-aminolevulinate synthase 2 (ALAS2) have been identified in X-linked sideroblastic anemia (XLSA) pedigrees, strongly suggesting it could be causal mutations of XLSA. However, the function of this int-1-GATA site during in vivo development remains largely unknown. Here, we generated mice lacking a 13 bp fragment, including this int-1-GATA site (T AGATAA: AGCCCC) and found that hemizygous deletion led to an embryonic lethal phenotype due to severe anemia resulting from a lack of ALAS2 expression, indicating that this non-coding sequence is indispensable for ALAS2 expression in vivo Further analyses revealed that this int-1-GATA site anchored the GATA site in intron 8 (int-8-GATA) and the proximal promoter, forming a long-range loop to enhance ALAS2 expression by an enhancer complex including GATA1, TAL1, LMO2, LDB1 and Pol II at least, in erythroid cells. However, compared with the int-8-GATA site, the int-1-GATA site is more essential for regulating ALAS2 expression through CRISPR/Cas9-mediated site-specific deletion. Therefore, the int-1-GATA site could serve as a valuable site for diagnosing XLSA in cases with unknown mutations.
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http://dx.doi.org/10.1093/nar/gkw901DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5314798PMC
January 2017

Efficient high repetition rate electro-optic Q-switched laser with an optically active langasite crystal.

Sci Rep 2016 07 27;6:30517. Epub 2016 Jul 27.

State Key Laboratory of Crystal Materials and Institute of Crystal Materials, Shandong University, Jinan 250100, China.

With an optically active langasite (LGS) crystal as the electro-optic Q-switch, we demonstrate an efficient Q-switched laser with a repetition rate of 200 kHz. Based on the theoretical analysis of the interaction between optical activity and electro-optic property, the optical activity of the crystal has no influence on the birefringence during Q-switching if the quarter wave plate used was rotated to align with the polarization direction. With a Nd:LuVO4 crystal possessing a large emission cross-section and a short fluorescence lifetime as the gain medium, a stable LGS Q-switched laser was designed with average output power of 4.39 W, corresponding to a slope efficiency of 29.4% and with a minimum pulse width of 5.1 ns. This work represents the highest repetition rate achieved so far in a LGS Q-switched laser and it can provide a practical Q-switched laser with a tunable high repetition rates for many applications, such as materials processing, laser ranging, medicine, military applications, biomacromolecule materials, remote sensing, etc.
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http://dx.doi.org/10.1038/srep30517DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4962309PMC
July 2016

A novel lymphoid progenitor cell population (LSK(low)) is restricted by p18(INK4c).

Exp Hematol 2016 09 8;44(9):874-885.e5. Epub 2016 Jun 8.

State Key Laboratory of Experimental Hematology, Tianjin, China; Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China; Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Tianjin, China; Department of Stem Cell & Regenerative Medicine, Peking Union Medical College, Tianjin, China; Collaborative Innovation Center for Cancer Medicine, Tianjin, China. Electronic address:

The cyclin-dependent kinase inhibitor CDKN2C (p18(INK4c)) restrains self-renewal in hematopoietic stem cells (HSCs) and participates in the development and maturation of lymphoid cells. Deficiency in p18 predisposes mice and humans to hematopoietic lymphoid malignancies such as T-cell leukemia and multiple myeloma. However, the mechanism by which p18 regulates differentiation from HSCs to lymphoid cells is poorly understood. In this study, we found that a progenitor population characterized by its expression of surface markers, Lin(-) Sca-1(+) c-Kit(low) (LSK(low)), was markedly expanded in the bone marrow of p18 knock-out (p18(-/-)) mice. This novel population possessed lymphoid differentiation potential, but not myeloid differentiation potential, both in vitro and in vivo. Whereas LSK(low) cells and common lymphoid progenitors (CLPs) overlapped functionally in generating lymphoid cells, they were distinct cell populations, because they had different gene expression profiles. Unlike CLPs, LSK(low) cells did not express the interleukin-7 receptor. LSK(low) cells were derived from HSCs and were independent of the p18-deleted microenvironment. This cell population may represent a previously unappreciated transitional stage from HSCs to lymphoid progenitors that is strictly restricted by p18 under physiological conditions. Likewise, LSK(low) might serve as a new cellular target of lymphoid malignances in the absence of p18.
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http://dx.doi.org/10.1016/j.exphem.2016.05.015DOI Listing
September 2016

Diverse in vivo effects of soluble and membrane-bound M-CSF on tumor-associated macrophages in lymphoma xenograft model.

Oncotarget 2016 Jan;7(2):1354-66

State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.

Macrophage colony-stimulating factor (M-CSF) is an important cytokine for monocyte/macrophage lineage. Secretory M-CSF (sM-CSF) and membrane-bound M-CSF (mM-CSF) are two major alternative splicing isoforms. The functional diversity of these isoforms in the activation of tumor-associated macrophages (TAMs), especially in lymphoma microenvironment, has not been documented. Here, we studied the effects of M-CSF isoforms on TAMs in xenograft mouse model. More infiltrating TAMs were detected in microenvironment with mM-CSF and sM-CSF. TAMs could be divided into three subpopulations based on their expression of CD206 and Ly6C. While sM-CSF had greater potential to recruit and induce differentiation of TAMs and TAM subpopulations, mM-CSF had greater potential to induce proliferation of TAMs and TAM subpopulations. Though both isoforms educated TAMs and TAM subpopulations to M2-like macrophages, mM-CSF and sM-CSF induced different spectrums of phenotype-associated genes in TAMs and TAM subpopulations. These results suggested the diverse effects of M-CSF isoforms on the activation of TAMs and TAM subpopulations in lymphoma microenvironments.
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http://dx.doi.org/10.18632/oncotarget.6362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4811465PMC
January 2016

NK cells play a significant role in immunosurveillance at the early stage of MLL-AF9 acute myeloid leukemia via CD226/CD155 interactions.

Sci China Life Sci 2015 Dec 20;58(12):1288-98. Epub 2015 Nov 20.

State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Collaborative Innovation Center for Cancer Medicine, Tianjin, 300020, China.

Acute myeloid leukemia (AML) is an aggressive hematological malignancy, and the mechanism underlying immune system involvement in leukemia development is unclear. In the present study, we utilized a myeloid/lymphoid or mixed-lineage leukemia; translocated to, 3 (MLLT3/MLL-AF9)-induced AML mouse model with or without exposure to irradiation. We found that the leukemia cells could survive and expand in hosts with intact immune systems, whereas leukemia progression was accelerated in mice with impaired immune systems. Moreover, the leukemia cells escaped from host immunosurveillance via editing their immunogenicity, including the up-regulation of an inhibitory antigen (i.e., CD47) and the down-regulation of active antigens (i.e., CD86, CD54, retinoic acid early transcript (RAE), histocompatibility 2, D region locus b (H2-Db) and H2-Dd). Natural killer (NK) cells were activated in the early phase of AML progression, whereas T cells were stimulated in the late phase. Furthermore, NK cell depletion showed that NK cells were necessary for the elimination of leukemia cells in our AML mouse model. Notably, CD155/CD226 primarily mediated the interaction between NK cells and leukemia cells and contributed to the antitumor effects of NK cells during the early phase of AML. Clinical data from patients with diverse hematological malignancies showed that CD155 expression was decreased in hematological malignancies. Taken together, our results demonstrate that NK cells play a pivotal role in immunosurveillance against leukemia cells during the early stage of AML primarily through the CD226/CD155 interaction; however, NK cells are not sufficient to eliminate leukemia cells.
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http://dx.doi.org/10.1007/s11427-015-4968-3DOI Listing
December 2015

ATF4 plays a pivotal role in the development of functional hematopoietic stem cells in mouse fetal liver.

Blood 2015 Nov 17;126(21):2383-91. Epub 2015 Sep 17.

State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Disease Hospital, Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China; Collaborative Innovation Center for Cancer Medicine, Tianjin, China.

The fetal liver (FL) serves as a predominant site for expansion of functional hematopoietic stem cells (HSCs) during mouse embryogenesis. However, the mechanisms for HSC development in FL remain poorly understood. In this study, we demonstrate that deletion of activating transcription factor 4 (ATF4) significantly impaired hematopoietic development and reduced HSC self-renewal in FL. In contrast, generation of the first HSC population in the aorta-gonad-mesonephros region was not affected. The migration activity of ATF4(-/-) HSCs was moderately reduced. Interestingly, the HSC-supporting ability of both endothelial and stromal cells in FL was significantly compromised in the absence of ATF4. Gene profiling using RNA-seq revealed downregulated expression of a panel of cytokines in ATF4(-/-) stromal cells, including angiopoietin-like protein 3 (Angptl3) and vascular endothelial growth factor A (VEGFA). Addition of Angptl3, but not VEGFA, partially rescued the repopulating defect of ATF4(-/-) HSCs in the culture. Furthermore, chromatin immunoprecipitation assay in conjunction with silencing RNA-mediated silencing and complementary DNA overexpression showed transcriptional control of Angptl3 by ATF4. To summarize, ATF4 plays a pivotal role in functional expansion and repopulating efficiency of HSCs in developing FL, and it acts through upregulating transcription of cytokines such as Angptl3 in the microenvironment.
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http://dx.doi.org/10.1182/blood-2015-03-633354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4653766PMC
November 2015

Leukemic marrow infiltration reveals a novel role for Egr3 as a potent inhibitor of normal hematopoietic stem cell proliferation.

Blood 2015 Sep 17;126(11):1302-13. Epub 2015 Jul 17.

State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Collaborative Innovation Center for Cancer Medicine, Tianjin, China; Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Tianjin, China; Department of Stem Cell and Regenerative Medicine, Peking Union Medical College, Tianjin, China.

Cytopenias resulting from the impaired generation of normal blood cells from hematopoietic precursors are important contributors to morbidity and mortality in patients with leukemia. However, the process by which normal hematopoietic cells are overtaken by emerging leukemia cells and how different subsets of hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) are distinctly influenced during leukemic cell infiltration is poorly understood. To investigate these important questions, we used a robust nonirradiated mouse model of human MLL-AF9 leukemia to examine the suppression of HSCs and HPCs during leukemia cell expansion in vivo. Among all the hematopoietic subsets, long-term repopulating HSCs were the least reduced, whereas megakaryocytic-erythroid progenitors were the most significantly suppressed. Notably, nearly all of the HSCs were forced into a noncycling state in leukemic marrow at late stages, but their reconstitution potential appeared to be intact upon transplantation into nonleukemic hosts. Gene expression profiling and further functional validation revealed that Egr3 was a strong limiting factor for the proliferative potential of HSCs. Therefore, this study provides not only a molecular basis for the more tightened quiescence of HSCs in leukemia, but also a novel approach for defining functional regulators of HSCs in disease.
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http://dx.doi.org/10.1182/blood-2015-01-623645DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4574014PMC
September 2015

Small-molecule inhibitors targeting INK4 protein p18(INK4C) enhance ex vivo expansion of haematopoietic stem cells.

Nat Commun 2015 Feb 18;6:6328. Epub 2015 Feb 18.

1] Department of Pharmaceutical Sciences, Computational Chemical Genomics Screening Center, School of Pharmacy, NIH National Center of Excellence for Drug Abuse Research, Drug Discovery Institute, Pittsburgh, Pennsylvania 15260, USA [2] Department of Computational and System Biology, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA.

Among cyclin-dependent kinase inhibitors that control the G1 phase in cell cycle, only p18 and p27 can negatively regulate haematopoietic stem cell (HSC) self-renewal. In this manuscript, we demonstrate that p18 protein is a more potent inhibitor of HSC self-renewal than p27 in mouse models and its deficiency promoted HSC expansion in long-term culture. Single-cell analysis indicated that deleting p18 gene favoured self-renewing division of HSC in vitro. Based on the structure of p18 protein and in-silico screening, we further identified novel smallmolecule inhibitors that can specifically block the activity of p18 protein. Our selected lead compounds were able to expand functional HSCs in a short-term culture. Thus, these putative small-molecule inhibitors for p18 protein are valuable for further dissecting the signalling pathways of stem cell self-renewal and may help develop more effective chemical agents for therapeutic expansion of HSC.
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http://dx.doi.org/10.1038/ncomms7328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4508125PMC
February 2015

Notch1-induced T cell leukemia can be potentiated by microenvironmental cues in the spleen.

J Hematol Oncol 2014 Nov 4;7:71. Epub 2014 Nov 4.

State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, 300020, China.

Background: Leukemia is a systemic malignancy originated from hematopoietic cells. The extracellular environment has great impacts on the survival, proliferation and dissemination of leukemia cells. The spleen is an important organ for extramedullary hematopoiesis and a common infiltration site in lymphoid malignancies. Splenomegaly, frequently observed in T cell acute lymphoblastic leukemia (T-ALL), is associated with poor prognosis. However, how the spleen microenvironment distinctly affects T-ALL cells as opposed to bone marrow (BM) microenvironment has not been addressed.

Methods: A Notch1-induced mouse T-ALL model was applied in this study. Flow cytometry and two-photon fluorescence microscopy were used to analyze early distribution of T-ALL cells. MILLIPLEX® MAP Multiplex Immunoassay was performed to measure cytokine/chemokine levels in different microenvironments. Transwell and co-culture experiments were used to test the effects of splenic microenvironment in vitro. Splenectomy was performed to assess the organ specific impact on the survival of T-ALL-bearing mice.

Results: More leukemia cells were detected in the spleen than in the BM after injection of T-ALL cells by flow cytometry and two-photon fluorescence microscopy analysis. By screening a panel of cytokines/chemokines, a higher level of MIP-3β was found in the splenic microenvironment than BM microenvironment. In vitro transwell experiment further confirmed that MIP-3β recruits T-ALL cells which express a high level of MIP-3β receptor, CCR7. Furthermore, the splenic microenvironment stimulates T-ALL cells to express a higher level of MIP-3β, which further recruits T-ALL cells to the spleen. Co-culture experiment found that the splenic microenvironment more potently stimulated the proliferation and migration of T-ALL cells than BM. Moreover, the mice transplanted with T-ALL cells from the spleen had a shorter life span than those transplanted from BM, suggesting increased potency of the T-ALL cells induced by the splenic microenvironment. In addition, splenectomy prolonged the survival of leukemic mice.

Conclusions: Our study demonstrates an organ specific effect on leukemia development. Specifically, T-ALL cells can be potentiated by splenic microenvironment and thus spleen may serve as a target organ for the treatment of some types of leukemia.
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http://dx.doi.org/10.1186/s13045-014-0071-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4229605PMC
November 2014

Influence of autoantibodies against AT1 receptor and AGTR1 polymorphisms on candesartan-based antihypertensive regimen: results from the study of optimal treatment in hypertensive patients with anti-AT1-receptor autoantibodies trial.

J Am Soc Hypertens 2014 Jan 13;8(1):21-7. Epub 2013 Oct 13.

Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan 430022, People's Republic of China. Electronic address:

The autoantibodies against angiotensin AT1 receptors (AT1-AAs) in patients with essential hypertension exhibited an agonistic action like angiotensin II and maintained high blood pressure (BP). Angiotensin II receptor gene (AGTR1) polymorphisms were associated with BP response to RAS inhibition in the hypertensive population. Furthermore, the BP response to AT1 receptor blockers varied significantly among individuals with hypertension. We hypothesized that the polymorphisms of the AGTR1 and AT1-AAs might affect antihypertensive response to AT1 receptor blockers based in patients with primary hypertension. Patients who received a candesartan-based regimen came from the SOT-AT1 study (Study of Optimal Treatment in Hypertensive Patients with Anti-AT1-Receptor Autoantibodies). The established enzyme-labeled immunosorbent assay was used to detect AT1-AAs in the sera of the patients. Genotype 3 single nucleotide polymorphisms in AGTR1 gene was used by DNA sequencing. The correlations among AT1-AAs, AGTR1 gene polymorphisms or haplotypes, and the antihypertensive effect candesartan-based were analyzed using SPSS. The percentage of systolic BP reduction that was candesartan-based was greater in AT1-AA positive groups than in AT1-AA negative ones (21 ± 8 vs. 18 ± 9; P = .001). Meanwhile, systolic BP reduction that was candesartan-based was more significant in the group of rs5186 AC genotypes than AA homozygotes after adjusting for other confounding factors (37.55 ± 13.7 vs. 32.47 ± 17.27 mm Hg; adjusted P = .028). Furthermore, haplotypes (GCC) and (AAC) had impacts on the antihypertensive effect of candesartan therapy. The AT1-AAs, AGTR1 gene polymorphisms and haplotypes solely or jointly have influences on candesartan-based antihypertensive response in patients with primary hypertension.
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http://dx.doi.org/10.1016/j.jash.2013.08.002DOI Listing
January 2014

Hematopoietic stem cell regeneration enhanced by ectopic expression of ROS-detoxifying enzymes in transplant mice.

Mol Ther 2013 Feb 8;21(2):423-32. Epub 2013 Jan 8.

State Key Laboratory for Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.

High levels of reactive oxygen species (ROS) can exhaust hematopoietic stem cells (HSCs). Thus, maintaining a low state of redox in HSCs by modulating ROS-detoxifying enzymes may augment the regeneration potential of HSCs. Our results show that basal expression of manganese superoxide dismutase (MnSOD) and catalase were at low levels in long-term and short-term repopulating HSCs, and administration of a MnSOD plasmid and lipofectin complex (MnSOD-PL) conferred radiation protection on irradiated recipient mice. To assess the intrinsic role of elevated MnSOD or catalase in HSCs and hematopoietic progenitor cells, the MnSOD or catalase gene was overexpressed in mouse hematopoietic cells via retroviral transduction. The impact of MnSOD and catalase on hematopoietic progenitor cells was mild, as measured by colony-forming units (CFUs). However, overexpressed catalase had a significant beneficial effect on long-term engraftment of transplanted HSCs, and this effect was further enhanced after an insult of low-dose γ-irradiation in the transplant mice. In contrast, overexpressed MnSOD exhibited an insignificant effect on long-term engraftment of transplanted HSCs, but had a significant beneficial effect after an insult of sublethal irradiation. Taken together, these results demonstrate that HSC function can be enhanced by ectopic expression of ROS-detoxifying enzymes, especially after radiation exposure in vivo.
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http://dx.doi.org/10.1038/mt.2012.232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3594016PMC
February 2013

Correlation between HLA-DRB1, HLA-DQB1 polymorphism and autoantibodies against angiotensin AT(1) receptors in Chinese patients with essential hypertension.

Clin Cardiol 2011 May;34(5):302-8

Department of Cardilogy, Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China.

Background: The autoantibodies (AAs) against angiotensin AT(1) receptors (AT(1) -AAs) have been discovered in patients with preeclampsia, malignant hypertension, and essential hypertension (EH); however, the mechanism of AA production remains to be investigated.

Hypothesis: Polymorphisms of HLA-DRB1 or HLA-DQB1 are related to production of AAs in autoimmune diseases. We hypothesis that the polymorphisms of the HLA molecules are also associated with production of AT(1) -AAs in patients with EH.

Methods: We enrolled 394 patients with EH and 224 normotensive subjects in this study. Autoantibodies in sera of donors were detected by enzyme-linked immunosorbent assay. The subjects' clinical data were collected, including gender, age, body mass index, blood pressure, smoking status, and diabetes. The patients and the normotensive subjects were classified respectively into AA-positive and AA-negative groups. Typing of DNA for HLA-DRB1 and HLA-DQB1 alleles was done by polymerase chain reaction amplification with sequence-specific primers.

Results: Thirteen HLA-DRB1 and 7 HLA-DQB1 alleles were found in this population. The frequencies of AT(1) -AAs were related to blood pressure level. The frequency of AT(1) -AAs in the EH group was higher than that in the normotensive group (P = 0.0001). The levels of AAs in different groups of EH show a significant difference (P = 0.027). In addition, HLA-DRB1(*) 04 and HLA-DRB1(*) 14 (odds ratio [OR]: 3.06, 95% confidence interval [CI]: 1.56-5.97, P = 0.001; and OR: 2.53, 95% CI: 1.080-5.91, P = 0.033, respectively) were related to AT(1) -AA production in normotensive subjects after adjusting for covariants. The HLA-DRB1(*) 04 allele might be related to AT(1) -AA production in hypertensive subjects, and the P value was of baseline statistical significance after adjusting for blood pressure and other covariants (OR: 1.63, 95% CI: 0.95-2.78, P = 0.070).

Conclusions: These results suggest a difference in the immunogenetic background between the positive and negative AAs with hypertension or normotension. The HLA-DRB1(*) 04 allele increases the risk for AT(1) -AA production.
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http://dx.doi.org/10.1002/clc.20852DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6652716PMC
May 2011

Association analysis about HLA-DRB1, -DQB1 polymorphism and auto-antibodies against α(1)-adrenergic receptors in Chinese patients with essential hypertension.

Clin Exp Hypertens 2010 ;32(8):532-9

Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China.

The auto-antibodies against α(1)-adrenergic receptors (α(1)-AAs) with agonist activity likes norepinephrine have been discovered in patients with essential hypertension but the mechanism of α(1)-AA production remains unclear. We supposed the α(1)-AAs be correlated to the HLA-DQB1 and DRB1 alleles. Three hundred ninety-six patients with essential hypertension (EH) and 224 normotensives were enrolled, and DNA typing was detected by protein coupled receptor (PCR) amplification with sequence-specific primers. Analysis was performed by α(2) and logistic regression. There were the significant associations of the haplotype HLA-DQB1*0301-DRB1*04 with the prevalence of α(1)-AAs in hypertensive patients and it obviously added to the risk for the α(1)-AA production (adjusted P = 0.019, OR 4.037, 95% CI 1.259-12.947). In normotensives, the haplotype HLA-DQB1*05-DRB1*04 provided a strong predisposition in α (1)-AAs production (adjusted P = 0.024, OR 3.922, 95% CI 1.200-12.817). These results suggest the HLA-DRB1*04 might be the primary risk alleles associated with α(1)-AA production on the haplotypes HLA-DQB1*0301-DRB1*04 and HLA-DQB1*05-DRB1*04 and increased the risk for α (1)-AA production.
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http://dx.doi.org/10.3109/10641963.2010.496520DOI Listing
March 2011
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