Recombinant human thrombopoietin promotes platelet recovery in DCAG-treated patients with intermediate-high-risk MDS/hypoproliferative AML.

BACKGROUND: This study aimed to explore the effects of recombinant human thrombopoietin (rhTPO) on platelet recovery in decitabine, cytarabine, aclarubicin, and G-CSF (DCAG)-treated patients with intermediate-high-risk myelodysplastic syndrome/hypo proliferative acute myeloid leukemia. METHODS: Recruited patients were at a ratio of 1:1 into 2 groups: the rhTPO group (DCAG + rhTPO) and control group (DCAG). The primary endpoint was the time for platelets to recover to ≥ 20 × 109/L. The secondary endpoints were the time for platelets to recover to ≥ 30 × 109/L and ≥ 50 × 109/L, overall survival (OS), and progression-free survival (PFS). RESULTS: The time required for platelet recovery to ≥ 20 × 109/L, ≥30 × 109/L, and ≥ 50 × 109/L in the rhTPO group was significantly shorter (6.5 ±â€…2.2 vs 8.4 ±â€…3.1 days, 9.0 ±â€…2.7 vs 12.2 ±â€…3.9 days, 12.4 ±â€…4.7 vs 15.5 ±â€…9.3 days, respectively; all P < .05 vs controls). The amount of platelet transfusion in the rhTPO group was smaller (4.4 ±â€…3.1 vs 6.1 ±â€…4.0 U, P = .047 vs controls). The bleeding score was lower (P = .045 vs controls). The OS and PFS were significantly different (P = .009 and P = .004). The multivariable analysis showed that age, karyotype, and time for PLT recovery to ≥ 20 × 109/L were independently associated with OS. Adverse events were similar. CONCLUSIONS: This study suggests that rhTPO leads to a faster platelet recovery after DCAG treatment, reduces the risk of bleeding, reduces the number of platelet transfusions, and prolongs the OS and PFS.

Changes in PM2.5-related health burden in China's poverty and non-poverty areas during 2000-2020: A health inequality perspective.

China suffers from severe PM2.5 pollution that has resulted in a huge health burden. Such PM2.5-related health burden has long been suspected to differ between China's poverty-stricken areas (PAs) and non-poverty-stricken areas (NPAs). Yet, evidence-based examination of this long-held belief, which is critical as a barrier of environmental injustice to advancing China's sustainability, is still missing. Here our study shows that the PM2.5 pollution is more serious in China's NPAs than PAs-with their annual averages being respectively 54.83 µg/m3 and 43.63 µg/m3-causing higher premature mortality in the NPAs. Compared to economic inequality, China's total PM2.5-related premature mortality was relatively evenly distributed during 2000-2015 across regions of varying levels of gross domestic product (GDP) per capita but increased slightly in 2015-2020 owing to the dramatic change in age structure. The elderly population increased by 31 %. PM2.5-related premature deaths were more severe for populations of low socioeconomic status, and such environmental health inequalities could be amplified by population aging. Additionally, population migration from China's PAs to developed cities contributed to 638, 779, 303, 954, and 896 premature deaths in 2000, 2005, 2010, 2015, and 2020, respectively. Changes in the age structure (53 %) and PM2.5 concentration (28 %) had the greatest impact on premature deaths, followed by changes in population (12 %) and baseline mortality (8 %). The contribution rate of changes in the age structure and PM2.5 concentration was higher in PAs than in NPAs. Our findings provide insight into PM2.5-related premature death and environmental inequality, and may inform more equitable clean air policies to achieve China's sustainable development goals.

Understanding the Regional Integration Process from the Perspective of Agglomeration and Urban Networks: Case Study in Central China.

Previously, urban planning approaches have tended to convert local agglomeration into network connections to advance urban development. However, is this successful experience learned from developed counties appropriate for developing countries? Scholars hold different opinions on this debate. To answer this question, we need to examine the effects of urban agglomeration in developing countries with a quantitative method. In this paper, we introduced a method of examining network connections from a geospatial perspective to explore the practice and spatial consequences of regional integration using a new concept of "coupling distance" based on metal valence bond theory. Then we applied this method to conduct an empirical case study of the urban agglomeration in the middle reaches of the Yangtze River region in China. We found that: (1) the real integration scale of the investigated urban areas was less than one-fourth the planned area, as most of interactions between cities are local, although we see the positive facilitation of urban networks on cross-provincial integration. (2) In terms of spatial consequences, the study area demonstrated phenomena of "agglomeration shadows", "enclaves" and "inverse integration". Specifically, these "agglomeration shadows" were all in their province's geometric centers, which seemed to have suffered a "central position curse". (3) Both "enclaves" and "inverse integration" call for a readjustment of government-led regional integration planning. Differently, the former has a positive attitude towards integration while the latter holds the opposite attitude. This study hopes to provide operationalizing methods and guidelines for planners and decision makers in the field of regional integration planning.

IDO, TDO, and AHR overexpression is associated with poor outcome in diffuse large B-cell lymphoma patients in the rituximab era.

Although Indoleamine 2,3-dioxygenase (IDO), tryptophan-2,3-dioxygenase (TDO), and aryl hydrocarbon receptor (AHR) are involved in cancer immune escape, their prognostic impact on diffuse large B-cell lymphoma (DLBCL) is unknown.To examine the prognostic impact of IDO, TDO, and AHR on patients with DLBCL.This was a retrospective study on treatment-naïve patients with newly diagnosed DLBCL at the Henan Province People's Hospital between 01/2012 and 06/2015. Patients with inflammatory reactive lymph nodes were included as controls. All cases were reviewed by 2 pathologists. IDO, TDO, and AHR positivity was determined through immunochemistry. Survival was examined using the Kaplan-Meier method and multivariable Cox analyses.The positive expression of TDO (50.0% vs 16.7%, P = .005) and AHR (60.0% vs 8.3%, P < .001) were higher in DLBCL than in inflammatory control. The overall survival of IDO, TDO, and AHR positive expression in DLBCL patients was 34.6, 26.7, and 32.2 months, respectively, which is significantly shorter than that of the corresponding negative patients (49.0 months, P = .04; 58.2 months, P < .001; 58.0 months, P < .001; respectively). The multivariable analysis showed that TDO expression and Ann-Arbor stage were independently associated with PFS (TDO: HR = 8.347, 95%CI: 2.992-23.289, P < .001; stage: HR = 2.729, 95%CI: 1.571-4.739, P < .001) and OS (TDO: HR = 9.953, 95%CI: 3.228-30.686, P < .001; stage: HR = 2.681, 95%CI: 1.524-4.719, P = .001) in DLBCL patients.Overexpression of IDO, TDO, and AHR is associated with poor survival of patients with DLBCL and could be involved in the immune escape of cancer cells. Further studies are necessary to determine whether these proteins can be targeted by treatment regimens.

Improved Outcomes of All-trans-retinoic Acid and Arsenic Trioxide Plus Idarubicin as a Frontline Treatment in Adult Patients With Acute Promyelocytic Leukemia.

INTRODUCTION: The purpose of this study was to explore the outcomes of all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) plus idarubicin (IDA) as a frontline treatment in adult patients with acute promyelocytic leukemia (APL). PATIENTS AND METHODS: We analyzed the outcomes of ATRA and intravenous ATO plus IDA as a frontline induction therapy in 118 patients with APL with high-risk (HR) and standard-risk (SR) disease from January 2008 to December 2017. The medical records of 118 patients with APL (HR, n = 45; SR, n = 73) who received the frontline triple combination regimen at Henan Provincial People's Hospital and Tongji Hospital were retrospectively reviewed. Consolidation therapy comprised 6 cycles of ATO and ATRA plus IDA, and IDA was administered in 1 to 4 cycles of consolidation therapy based on the comparable clinical efficacy compared with 6 cycles and fewer side effects to myocardium without subsequent maintenance therapy. RESULTS: Of 118 patients, there were 3 (2.5%) early deaths and 115 (97.5%) hematologic complete remissions; 102 (88.7%) of 115 patients achieved molecular complete remission following induction therapy, and all patients were polymerase chain reaction-negative for promyelocytic leukemia-retinoic acid receptor alpha after the first cycle of consolidation therapy. The 5-year overall survival (OS) and event-free survival (EFS) were 93.0% ± 2.9% and 92.4% ± 3.0%, respectively. Early death, hematologic complete remissions, molecular complete remissions, and toxicities were comparable between the HR and SR groups. The cumulative incidence of relapse in the HR group was 4.7% (n = 2), and the cumulative incidence of relapse in the SR group was 0. The OS and EFS of the SR and HR groups were comparable (92.3% ± 4.5% vs. 92.8% ± 4.0%; X2 = 0.263; P = .608; 92.3% ± 4.5% vs. 91.1% ± 4.2%, X2 = 0.917; P = .338). The total dosage of IDA was approximately 181 to 258 mg, and no patient experienced cardiotoxicity. OS and EFS were not influenced by fms-related tyrosine kinase 3 internal tandem duplication mutation status (P = .405 and P = .528, respectively). CONCLUSION: The triple combination of ATRA and ATO plus IDA as both an induction and consolidation therapy for the HR and SR groups attained excellent outcomes, and this regimen was effective, safe, and easy, without maintenance therapy. The triple combination treatment might be a preferred frontline therapy for patients with APL, especially for those with HR or the APL fms-related tyrosine kinase 3 internal tandem duplication mutation.

iTRAQ-based quantitative protein expression profiling of biomarkers in childhood B-cell and T-cell acute lymphoblastic leukemia.

PURPOSE: This study screened serum proteins to identify potential biomarkers for childhood B-cell and T-cell acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: Serum collected from 20 newly diagnosed B-cell ALL, 20 T-cell ALL and 20 healthy children. The peptides from these samples were subjected to iTRAQ. Differentially expressed proteins (DEPs) were further validated by ELISA in 24 B-ALL, 24 T-ALL, and 24 healthy children. RESULTS: Bioinformatics analysis revealed several pathways, including atherosclerosis signaling, interleukin signaling and production in macrophages and clathrin-mediated endocytosis signaling, that were closely related to childhood T-cell ALL. Furthermore, four selected proteins, namely LRG1, S100A8, SPARC and sL-selectin, were verified by ELISA. These results were consistent with the results of the proteomics analysis. CONCLUSION: Serum S100A8 may serve as new diagnostic biomarkers in childhood B-cell ALL and T-cell ALL.

[Expression and Clinical Significance of C/EBPα Gene in Elderly Multiple Myeloma].

OBJECTIVE: To investigate the expression of C/EBPα gene in elderly patients with multiple myeloma （MM） and its prognostic significance. METHODS: Sixty-nine olderly patients with multiple myeloma (MM) treated in our hospital from February 2015 to October 2017 were selected and enrolled in the MM group, 38 healthy persons received physical examination were selected and enrolled in the control group. The bone marrow of 2 groups was collected and the mononuclear cells were isolated.The mRNA expression level of C/EBPα gene in mononuclear cells was determined by RT-PCR, the Western blot was used to detect the protin expression level of PBMNC C/EBPα, and the protein level of C/EBPα in bone marrow was detected by immunohistochemistry. The correlations of C/EBPα gene expression with the clinical characteristics and survival time in MM patients were analyzed. RESULTS: The expression level of mRNA and protein of C/EBPα in MM patients was significantly lower than that in the control group (P<0.05). The expression level of C/EBPα gene significantly correlated with the ISS stage, CRP, Calcium, ß2-MG, LDH and the percentage of myeloma cells in MM patients (P<0.05). The expression of C/EBPα gene was not correlate with sex, age, immunoglobulin typing, Hb in MM patients (P>0.05).Immunohistochemical staining showed that the bone marrow samples of the control group were stained more deeply, and the staining intensity in bone marrow samples of MM patients with CR, PR and relapse was successively descended. The protein level of C/EBPα in CR patients with MM was significantly higher than that in PR and relapsed patients by Western blot (P<0.05). Kaplan-Meier survival analysis showed that OS and DFS in the patients with high expression of C/EBPα gene were higher than those in low expression group (P<0.05). Multivariate Cox regression analysis showed that CRP,ratio of myeloma cells and C/EBPα gene were independent factors affecting OS and PFS (P<0.05). CONCLUSION: The expression level of C/EBPα gene in MM patients is low that may stimulate the genesis of MM, and the expression of C/EBPα gene closely relates with the development of MM disease.

Comparison of Outcomes of Frontline Immunosuppressive Therapy and Frontline Haploidentical Hematopoietic Stem Cell Transplantation for Children with Severe Aplastic Anemia Who Lack an HLA-Matched Sibling Donor.

We compared the outcomes of immunosuppressive therapy (IST) with those of T cell-replete haploidentical donor hematopoietic stem cell transplantation (haplo-HSCT) in children and adolescents with severe aplastic anemia (SAA). The medical records of 49 patients with SAA who received frontline IST (n = 29) or frontline haplo-HSCT (n = 20) between 2012 and 2016 were analyzed retrospectively. Fourteen patients responded after the first IST, and 1 patient responded after the second IST in the frontline IST group; 12 patients underwent salvage HSCT after IST failure. Sixteen of the 20 patients who underwent frontline haplo-HSCT survived without treatment failure. The 3-year overall survival of the frontline IST group was comparable to that of the frontline haplo-HSCT group (79.3 ± 7.5% versus 85.0 ± 8.0%; χ2 = 0.110; P = .740). The 3-year failure-free survival was lower in the frontline IST group compared with the frontline haplo-HSCT group (35.9 ± 10.9% versus 80.0 ± 8.9%; χ2 = 4.089; P = .043). Five patients of the IST group who underwent salvage HSCT achieved long survival without event. The event-free survival was lower in the salvage HSCT group compared with the haplo-HSCT group (41.7 ± 14.2% versus 80.0 ± 8.9%; χ2 = 3.992; P = .046), and the incidences of acute GVHD, grade II-IV acute GVHD, chronic GVHD, and severe infection were comparable between the 2 groups. Our results suggest that frontline haplo-HSCT may be a better treatment than IST for children and adolescents with SAA who lack an HLA age-matched familial donor.

MicroRNA-9 suppresses cancer proliferation and cell cycle progression in acute lymphoblastic leukemia with inverse association of neuropilin-1.

Acute lymphoblastic leukemia (ALL) is one of the most common and most malign childhood cancers. In this work, we investigated the expression and function of human mature microRNA-9 (miR-9) in ALL. In ALL in vitro cell lines and in situ clinical specimens, gene expression of miR-9 was tested by qRT-PCR. MiR-9 was overexpressed in CEM/C1 and Molt-3 cells to investigate its possible anti-cancer effects on ALL in vitro proliferation, cell-cycle progression, and in vivo explant growth. The possible downstream target of miR-9, neuropilin-1 (NRP1), was examined by dual-luciferase activity assay, qRT-PCR, and Western blot. NRP1was upregulated in miR-9-overexpressed CEM/C1 and Molt-3 cells to investigate the functional involvement of NRP1 in miR-9-mediated regulation on ALL in vitro proliferation and cell-cycle progression. MiR-9 was downregulated in ALL cell lines and leukemic T-cells of ALL patients. Lentivirus-mediated miR-9 overexpression inhibited ALL in vitro proliferation, cell-cycle progression, and in vivo explant growth. NRP1 was confirmed be the downstream target of miR-9, and inversely modulated by miR-9 in ALL. NRP1 upregulation reversed the anti-cancer regulations of miR-9 on ALL in vitro proliferation and cell-cycle progression. MiR-9 is downregulated in ALL. Overexpressing miR-9 may inhibit ALL development, possible through its downstream target of NRP1.

Effects of Decitabine on the proliferation of K562 cells and the expression of DR4 gene.

OBJECTIVE: To investigate the role of DR4 gene in the occurrence, development and prognosis of acute myeloid leukemia (AML), find a new regulatory gene of Decitabine for the treatment of AML, namely DR4 gene, and explore the molecular mechanism of AML in the treatment of AML. METHODS: The methylation level and the mRNA expression level of DR4 gene promoters of bone marrow mononuclear cells in 122 patients with newly diagnosed AML and 24 patients with iron deficiency anemia (IDA) were detected using Methylation specific PCR (MS-PCR) and Q-RT-PCR, respectively, and a correlation analysis of them was conducted. The effects of Decitabine on the proliferation of K562 cells were detected using CCK-8 assay. Then, the effects of Decitabine on the methylation level and the mRNA expression level of DR4 genes of K562 cells treated with Decitabine were detected using MS-PCR and Q-RT-PCR, respectively. The effects of Decitabine on the cell cycle and apoptosis of K562 cells were detected using flow cytometry. RESULTS: Compared with the control group, the methylation level (P = .002) of DR4 genes of bone marrow mononuclear cells in patients with newly diagnosed AML was high. The methylation level (P = .01) of DR4 genes of bone marrow mononuclear cells in patients of the positive group of enlargement of liver, spleen and lymph node was lower than that of the negative group, and the methylation level (P = .006) of DR4 genes in patients of the high risk group of clinical stage was lower than that of the low risk group, and the methylation level (P = .03) of DR4 genes in patients of the group where patients did not achieve complete remission (CR1) after a course of induction chemotherapy was lower than that of the group where patients achieved complete remission (CR1) after a course of induction chemotherapy. There was a significant negative correlation (P < .01) between the methylation level and the mRNA expression level of DR4 genes of bone marrow mononuclear cells in 122 patients with newly diagnosed AML. After the K562 cells were treated with Decitabine for 48 h, the methylation level of DR4 gene promoters gradually decreased, while the mRNA expression level of DR4 genes gradually increased, both of which showed a concentration-dependent relationship. After the K562 cells were treated with 5 µmol/L Decitabine for 48 h, the K562 cells in G0/G1 phase and G2/M phase increased significantly, and the K562 cells in S phase decreased significantly. CONCLUSION: DR4 gene played an important role in the occurrence and development of AML. Decitabine can effectively inhibit the proliferation of K562 cells, which probably partly because it can terminate the methylation effect of DR4 gene promoters and restore the mRNA expression of DR4 genes.

[Preliminary study of HCT-CI score system for prognosis prediction in elderly patients with acute myeloid leukemia after chemotherapy].

OBJECTIVE: To investigate the value of the HCT-CI score in chemotherapy risk assessment and prognosis of elderly patients with acute myeloid leukemia (AML). METHODS: The clinical data of 116 AML patients older than 60 years in the department of Hematology, Henan Provincial People's Hospital from January 2000 to December 2010 were analyzed retrospectively. All patients received cytarabine-based regimens, including protocol DA, MA, IA, AA or CAG, followed by cytarabine-based postremission treatment. (1) Comorbidities were evaluated by using HCT-CI score, the early death rates and median survival time were compared among these different groups. (2) These prognostic factors were analyzed by univariate and multivariate analyses. RESULTS: (1) All 116 cases were followed-up. The patient cohort was divided into those with HCT-CI scores of 0, 1 or 2, or ≥ 3. Early death rates were 3.7%, 12.1% and 23.21% in above three groups, respectively (P < 0.01). Overall survival were 345, 225 and 113 days, respectively (P < 0.01). (2) HCT-CI score ≥ 3 (P < 0.01), antecedent MDS history (P = 0.035), high-risk karyotype (P = 0.018), white blood cells at diagnosis ≥ 100×10(9)/L (P = 0.041) were independent adverse prognostic factors with multivariate analysis. CONCLUSION: (1) The HCT-CI score can objectively assess elderly AML patients with comorbidities and predict chemotherapy risk in older patients receiving AML induction therapy. (2) Antecedent MDS history, high-risk karyotype, high white blood cell, and HCT-CI score ≥ 3 are independent adverse prognostic factors of elderly AML patients.

[Study on the diagnostic value of lung biopsy in hematologic patients with lung infection].

OBJECTIVE: To evaluate the diagnostic value and safety of percutaneous lung biopsy in hematologic patients with lung infection. METHODS: 28 cases hematologic patients received CT-guided percutaneous lung biopsy when they developed a fever associated with pulmonary nodules or lumps in CT scan whose clinical diagnosis were unclear during or after chemotherapy. Sample of each lesion were drawn twice. The lung tissue was re-scanned after lung biopsy to check up in order to discover bleeding and pneumothorax. Biopsy tissue was examined by bacteria culture, acid-fast staining and pathology. Pathological examination contained HE staining, acid-fast stain, PAS stain, TB-DNA, methenamine silver and others. RESULTS: 28 cases contain 24 males and 4 females. Median age was 40 15 - 77 years old. Blood tests were as follows: 3 cases with HGB > 110 g/L, 9 with HGB 90 - 110 g/L, 12 with HGB 60 - 89 g/L, 4 with HGB < 60 g/L. 8 with WBC > 10×10(9)/L, 6 with WBC (4 - 10)×10(9)/L, 13 with WBC < 4×10(9)/L, 1 with WBC < 2×10(9)/L; 14 with PLT > 100×10(9)/L, 5 with PLT (50 - 100)×10(9)/L, 5 with PLT < 50×10(9)/L, 4 with PLT < 30×10(9)/L. 4 cases had mild extended PT, 3 mild extended APTT, 3 FIB lower than normal. Lung CT scans were as follows: 4 cases with simply lesion in right lung, 4 with simply lesion in left lung, 20 with lesions in bilateral lung. 8 cases were diagnosed as fungal infection, 3 as tuberculosis infection, 1 as lung cancer, 1 as pulmonary infiltration of lymphoma, 1 as pulmonary infiltration of leukemia, and 14 as inflammatory changes with no specific diagnosis. 4 cases came with pneumothorax during lung biopsy, mild to moderate in 3 cases and severe in 1 case. Severe patient turned better after CT-guided suction. 3 cases with mild hemoptysis turned better after treatment. CONCLUSION: When hematopathy patients are with pulmonary nodules or lumps in CT scan whose clinical diagnosis is unclear, CT-guided percutaneous lung biopsy is safe and conducive to early diagnosis and conducive to early rehabilitation of patients if the coagulation function is basically normal and platelet count is not too low.

[Effect of ginsenoside on apoptosis of human leukemia-60 cells].

OBJECTIVE: To study the effect of ginsenoside on apoptosis of human leukemia-60 (HL-60) cells and its mechanism. METHODS: MTT cytotoxicity assay was used to determine the growth inhibition activity of ginsenoside (100, 50, 25, 12.5, 6.25, 3.125 and 1.5625 µmol/L) on HL-60 cells. The apoptosis of HL-60 cells after treatment with ginsenoside (0,5,10 and 20 µmol/L) was determined by Annexin V-FITC/PI staining and flow cytometry. The cleavage of total proteins by caspase-8, caspase-9 and caspase-3 was evaluated by Western blot. The cleavage of caspase-3 protein was detected by Western blot after treatment with 10 µmol/L ginsenoside and caspase-8 and 9 inhibitors. RESULTS: Ginsenoside had potent cytotoxicity on HL-60 cells, with an IC50 value of 7.3±1.2 µmol/L. After treatment with ginsenoside (0, 5, 10 and 20 µmol/L) for 48 hours, the apoptotic rate displayed a dose dependency, as shown by flow cytometry, with significant differences between the groups (F=12.67, P<0.01). Western blot showed that there were caspase-9 and caspase-3 cleavage bands, but without caspase-8 cleavage band. The specific inhibitor of caspase-9 Z-LEHD-FMK could block the caspase-3 cleavage induced by 10 µmol/L ginsenoside, but the specific inhibitor of caspase-8 Z-IETD-FMK did not have this effect. CONCLUSIONS: Ginsenoside can induce apoptosis of HL-60 cells, which may be related to a mitochondria-dependent pathway.