bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mechanism Research of Reversal in Multidrug Resistance by Magnetic Nanoparticle Fe3O4 Syndesis with 5-Bromotetrandrine and Daunomycin
Authors: Chen Bao-An , Wu Wei-wei , Cheng Jian , Gao Feng , Xu Wen-lin , Shen Hui-lin , Ding Jia-hua , Gao Chong , Sun Yun-Yu , Wang Jun , Zhao Gang , Song Huihui , Bao Wen , Sun Xin-chen , Cheng Hong-yan , Deng Yu-xia , Li Guo-hong , Liu Li-jie , Chen Wen-ji , Wang Jue-qiong , Yuan Peng , Pei Xiao-ping , Chen Ning-na , Wang Xue-mei 
Published: April 2020

Abstract
Objective To evaluate the MDR reversal activity of magnetic nanoparticle Fe3O4 (Nano-Fe3O4) and 5-bromotetrandrine (BrTet) on multidrug resistance cell line K562/A02 solitarily or symphysially, and to investigate the reversal mechanism of this coopration.
Methods The proliferation of K562 and K562/A02 cells which were cultured with daunomycin (DNR) alone or in combination with Nano-Fe3O4, BrTet or both for 48h were evaluated by MTT assay. DNR accumulation and P-gp of K562 and K562/A02 were analyzed by fluorospectrophotometry.
Results The IC50 of DNR for K562 and K562/A02 cells were 2.74±0.19μM and 32.33±8.40μM, respectively; but the sensitivity of K562/A02 cells to DNR was partially restored after culturing with Nano-Fe3O4, BrTet solitarily and symphysially (the IC50 were 7.04±0.85μM, 4.25±2.16μM, 1.80±0.30μM; the FR were 4.32, 7.61, 17.96, respectively), but had no effects on K562 cell lines. The differences had statistical significance. Flow cytometry assay showed that Nano-Fe3O4 and BrTet increased the DNR accumulation in K562/A02 cells, especially in the group of synergia of these two agents. The mean fluorescence intensity of endocellular DNR increased from 2614 pretreated with DNR only to 4783 incubated with these two reversal reagents, while the values were 3364, 4077 for incubating with Nano-Fe3O4 and BrTet respectively. P-gp were down regulated through pretreating with Nano-Fe3O4, BrTet alone and symphysially in K562/A02 cells by fluorospectrophotometry assay.
Conclusion Nano-Fe3O4 and BrTet synergisticly showed significant MDR reversal activity in vitro. The reversal activity may be related to the inhibition of P-gp overexpression and the increasing of the anticancer drug accumulation intracelluarly.
Pediatric Therapy-Related Myelodysplastic Syndrome/Acute Myeloid Leukemia: The M. D. Anderson Cancer Center Experience
Authors: Aguilera Dolly G , Vaklavas Christos , Tsimberidou Apostolia-Maria , Wen Sijin , Medeiros L. Jeffrey , Corey Seth J. 
Published: April 2020

Abstract
Background: Therapy-related myelodysplastic syndrome/acute myeloid leukemia (t-MDS/AML) is a long-term complication of pediatric cancer and it carries a poor prognosis.
Patients and Methods: We retrospectively studied pediatric t-MDS/AML patients treated at M. D. Anderson from 1975 to 2007. We also compared these patients to pediatric patients with de novo MDS/AML during this time interval.
Results: Among 2589 children with cancer treated at M. D. Anderson, we identified 22 (0.85%) patients with t-MDS/AML and 141 (5.4%) patients with de novo MDS/AML. Patients with t-MDS/AML had a median age of 14 years (range, 3–20). There was a male and Hispanic predominance. The most common primary malignancies were osteosarcoma and Hodgkin lymphoma. The median latency period was 4.1 years. Fourteen patients received AML-type chemotherapy, 5 underwent allogeneic stem cell transplantation (SCT) as induction therapy, and 3 received supportive care. Fourteen patients underwent SCT as induction (n=5), post-remission (n=5), or salvage therapy (n=4). Their respective 2-year survival rates were 20%, 40%, and 25% (p= 0.85). Patients with de novo AML were younger (p=0.001), and had higher rates of CR (p=0.03), and survival (p&lt;0.0001). Independent factors predicting shorter survival were poor/intermediate-risk cytogenetics (p=0.01), lower hemoglobin level (p=0.0001), and t-MDS/AML (vs. de novo) (p=0.003).
Conclusion: Childhood t-MDS/AML has a poor prognosis. Although patients benefited from AML-type induction chemotherapy followed by SCT as post-remission therapy, effective therapies are needed.
Incidence of HFE Gene Mutations in Chinese Patients with Myelodysplastic Syndrome and Aplastic Anemia
Authors: Nie Ling , Yang Lin , Li Qinghua , Wang Jianxiang , Xiao Zhijian 
Published: April 2020

Abstract
The C282Y and H63D mutations of HFE gene responsible for hereditary hemochromatosis lead to absorption of excess dietary iron, tissue iron deposition and occurrence of clinical complications such as congestive heart failure, arrhythmia, hepatocellular cirrhosis, insulin resistance and diabetes. Iron overload is one important clinical feature in patients with myelodysplastic syndrome (MDS) and aplastic anemia(AA). However, the conflict has been existing about influence of HFE gene mutations on iron overload in MDS patients. In the present study, we analyzed the incidence of the C282Y and H63D mutations of HFE gene in 271 MDS patients, 402 AA patients and 1615 healthy controls by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). No C282Y mutations and compound heterozygote were observed in the entire cohort. The genotype distribution of H63D heterozygous and homozygous did not differ significantly in AA cases from those in controls(9.7%vs. 10.2%, 0.25%vs. 0.24% respectively, Pearson Chi-square p both &gt;0.05). While the frequency of the H63D heterozygous in MDS patients was significantly lower than controls (4.1%vs. 10.7%, Pearson Chi-square p=0.002). H63D homozygous was not found in MDS patients. The incidence of C282Y and H63D mutations of HFE gene in Chinese MDS cases is lower than those reported in the literature. Comparing the pretransfusion serum ferritin(SF), serum iron concentration(SI) and transferrin saturation values(TS) between HFE-mutation and HFE-wild MDS groups, we did not find a significant difference (all P&gt;0.05); However, Only SI values were significantly higher in the HFE-mutation AA cases than those in HFE-wild ones[42.6(24.6–60.4)umol/Lvs. 32.0(8.4–63.3)umol/L, P=0.011]. We further estimated the function of important organs in MDS and AA patients. There is no significantly difference in Alanine amino transferase (ALT), Aspartate amino transferase (AST), fasting blood sugar, and electrocardiogram(ECG) between HFE-mutation and HFE-wild MDS and AA groups irrespective of the red blood cell transfusion history. The results suggest that the distribution of C282Y and H63D mutations has ethnic and genetic differences, and is very rare in Chinese population. The mutations of HFE gene are not main factors of iron overload in Chinese patients with myelodysplastic syndrome and aplastic anemia.
Impact of Baseline Renal Function on Transfusion-Independence Response, Survival, and Transformation to Acute Myeloid Leukemia in Patients with Deletion 5q: A Sub-Analysis of the MDS-003 Study
Authors: Battiwalla Minoo , Fu Tommy , Knight Robert D. , List Alan F. 
Published: April 2020

Abstract
Introduction: Lenalidomide reduced transfusion requirements and reversed cytologic and cytogenetic abnormalities in patients who have myelodysplastic syndrome (MDS) with the chromosome 5q31 deletion del(5q)] (List et al., NEJM 2006). Dose-adjusted lenalidomide is safe and effective in MDS patients with del(5q) and severe renal impairment (Knop et al., Leuk Lymph 2008), but the impact of baseline renal function on outcomes has not been specifically studied. This MDS-003 clinical trial sub-analysis investigates the impact of baseline renal function on the transfusion-independence (TI) response, overall survival, and transformation to acute myeloid leukemia (AML).
Methods: Transfusion-dependent, Low/Int-1-risk patients with primary MDS and del(5q) with/without additional cytogenetic abnormalities were treated with lenalidomide 10 mg daily for 21 days every 28 days. Patients were treated until disease progression, treatment failure, or treatment-limiting adverse events. This sub-analysis included patients with normal renal function (creatinine clearance [CrCl] &gt;80 mL/min) and patients with mild (CrCl 50–80 mL/min), moderate (30–50 mL/min), or severe renal impairment (CrCl &lt;30 mL/min). CrCl was calculated according to the Cockcroft-Gault formula. Red blood cell (RBC) transfusion-dependent anemia was defined as having received ≥2 units of RBCs within 8 weeks of the first day of study treatment. Neutropenia was defined as a baseline absolute neutrophil count of &lt;1,000/μL. Thrombocytopenia was defined as a baseline platelet count of &lt; 100,000/μL. TI response, overall survival, and transformation to AML were assessed.
Results: Of 148 patients enrolled in the study, 70 patients had normal renal function and 70 patients had renal impairment (47 mild, 19 moderate and 4 severe impairment; with renal data missing for 8 patients). The TI response was 44/70 (63%) for patients with normal renal function and 48/70 (69%) for patients with impaired renal function (P=0.47). In the subcategories, the TI responses were 79%, 53% and 25% for mild, moderate and severe impairment, respectively (P=0.07, P=0.42 and P=0.13 vs. normal function). Renal impairment resulted in shorter median overall survival compared with no renal impairment (hazard ratio of 2.88, 95% confidence interval, 2.24–3.45). The transformation to AML rate was 19% for normal patients and 20% for patients with renal impairment.
Conclusion: In this analysis, baseline renal function does not have a significant impact on achieving transfusion independence or transformation to AML. Patients with moderate to severe renal impairment had a shorter survival than patients with normal renal function.
Clinical Efficacy of Decitabine in Patients with Myelodysplastic Syndrome (MDS)
Authors: Golenkov Anatoli , Dudina Galina , Buravtsova Iolanta , Voronova Olga , Chukavina Marina 
Published: April 2020

Abstract
Decitabine (DACOGEN, Janssen Pharmaceutica N.V. and Eisai Inc.) is an efficient hypomethylating agent approved for the treatment of MDS in the United States and other countries. Previous studies from North America reported the efficacy and safety of decitabine 15 mg/m2 every 8 hours for 3 days every 6 weeks (3-d schedule; Kantarjian, Cancer2006;106:1794) and 20 mg/m2 once daily for 5 days every 4 weeks (5-d schedule; Kantarjian Blood2007;109:52 and Steensma, ASH2007;110:1450) in MDS patients. The aim of the study reported here was to assess the clinical efficacy and safety of the 3-d schedule of decitabine in MDS patients in Russia. A total of 15 patients with MDS were enrolled: 9 male and 6 female; average age 62 years. Diagnoses included refractory anemia with ringed sideroblasts (RARS) in 3 patients, refractory anemia with excess blasts (RAEB) in 9 patients, refractory anemia with excess blasts in transformation (RAEB-T) in 2 patients, and chronic myelomonocytic leukemia (CMML) in 1 patient. Cytogenetic abnormalities included: -Y in 2 patients, del(5q) in 2 patients, and del(5q)+t(11;17) in 1 patient. At the time of this analysis, decitabine treatment had been administered for 1–2 cycles in 7 patients and for 3 cycles in 8 patients. The most frequent grade ≥3 adverse events were neutropenia (n=8, including 5 with neutropenic fever) and thrombocytopenia (n=4). Two patients with RAEB-T had severe neutropenia with infection: a necrotic lesion of hemorrhoids (n=1) and lower limb cellulitis (n=1). No other grade ≥3 adverse events were observed. Among the 8 patients who had received 3 cycles of decitabine, transfusion dependence was 100% before treatment and 38% (3/8) after decitabine treatment, with prolongation of transfusion independence periods in all 8 patients. Average hemoglobin level was 6.8 g/dL before treatment and 8.4 g/dL after 3 cycles of decitabine treatment. Overall response rate was 50% after 3 cycles of decitabine, including complete response (CR) in 1 (13%) patient and partial response (PR) in 3 (38%) patients. The other 4 patients who had received 3 cycles of decitabine had stable disease. The median time to first treatment response was 2 cycles. In this study of MDS patients in Russia, toxicity was consistent with previous studies and patients responded well to decitabine treatment on a 3-day dosing schedule.
Antitumor Activity of Cda-2, An Extract from Unine, in a High-Risk Myelodysplastic Syndrome Cells in Vitro
Authors: Qiu Lin , Wang Xiao-dan , Han Bing-hong , Zhan Zhao-min , Bo-long Zhang , Ma Jun 
Published: April 2020

Abstract
DNA methyltransferase inhibitors (DNMTI), including 5-azacytidine and 5-aza-2′- deoxycytidine, are a new class of epigenetic drug, which exhibit higher response rates in myelodysplastic syndrome (MDS) patients. Cell differentiation agent (CDA-2) is a kind of urine extracts, which contains several DNMTIs. A phase IV clinical trials for MDS showed total response rate is 69.22%. In the present study, we investigated the mechanism of CDA-2 on MDS using high-risk MDS cell line namely MuTz-1. MTT assay results showed that CDA-2 significantly inhibit the cell growth at a dose and time-dependent manner. Flow cytometer anlyasis showed that this growth inhibition was remarkblely associated with cycle arrest in G1-phase, but not associated with apoptosis. In addition, CDA-2 increased the expression of CD11b/CD14, a pair markers representing cell differentiation. we found the spectrum of hypermethylated tumor suppressor genes (TIMP3, CDKN2B, CHFR, CD44, RASSF1, TP73, IGSF4, CDH13 and DAPK) in MuTz-1 cells by Methylation-Specific Multiplex ligation-dependent Probe amplification (MS-MLPA), but the hypermethylation of these genes were remarkable decreased, as well as the expressions of DNA methyltransferase genes DNMT1 and DNMT3B at mRNA and protein level were downregulated in the treatment for 3 days with CDA-2. Also, we used CDA-2 for treatment of three MDS patients, whose several tumor suppressor genes are hypermethylated. After tour weeks of treatment, all the hypermethylation genes were undetected, part of this result was verified by methylation specific PCR (MSP) and bisulphite sequencing. In conclusion, our results demonstrated that CDA-2 may be an effective agent targeting hepermethylated tumor suppressor genes on MDS.
Incidence and Clinical Significance of Scoring System in Myelodysplastic Syndromes Including Hematological and Cytogenetic Profiles from a Single Institution
Authors: Kim Myungshin , Lim Jihyang , Kim Yonggoo , Han Kyungja , Kim Yoo-Jin , Cho Seok-Goo , Min Woo-Sung 
Published: April 2020

Abstract
Background: Mydelodysplastic syndromes (MDS) are clonal stem cell disorders characterized by hypercellular marrow with ineffective hematopoiesis determining peripheral cytopenia. Recently, the WHO developed a new classification that identifies the following subtypes: RA, RARS, 5q- syndrome (MDS 5q-), RCMD, RCMD with ringed sideroblasts (RCMDS), RAEB-1, RAEB-2 and MDS unclassifiable (MDS-U). The goals of our study were to establish the incidence of chromosome abnormalities in MDS patients, to correlate chromosomal defects with WHO subtype and peculiar clinical-biological findings.
Patients and Methods: We studied 242 consecutive MDS patients who were admitted in the hematology department of St. Mary’s hospital from 2000 to 2007. The diagnosis was made according to the World Health Organization classification system. The chromosome analysis of the BM cells at diagnosis was performed by the G-staining method with trypsin and karyotyped according to the ISCN 2005.
Results: The median age of patients was 50 (2–84). WHO classification was as follows: RA (n=21, 8.7%), RARS (n=7, 2.9%), RCMD (n=62, 25.6%), RCMDS (n=6, 2.5%), RAEB-1 (n=63, 26.0%), RAEB-2 (n=74, 30.6%), MDSU (n=7, 2.9%), MDS 5q- (n=2, 0.8%). Chromosomal abnormalities were found in 51.2% of patients. The cases with good, intermediate and poor cytogenetic risk features were observed in 55.0%, 29.3%, and 15.7%. Trisomy 8 was most common abnormality in all cases. 1q+, 5q-, 20q- were followed. By International Prognostic Scoring System (IPSS) 13 (5.4%) patients were classified in low group; 141 (58.3%) intermediate-1, 60 (24.8%) intermediate-2, and 28 (11.6%) high were classified. By WHO classification-based prognostic scoring system (WPSS), 14 (5.8%) patients were classified in very low group; 25 (10.3%) low, 57 (23.6%) intermediate, 110 (45.5%) high, and 36 (14.9%) very high were classified. Thirty-six patients (14.9%) progressed into AML. Both IPSS and WPSS was shown to predict survival and leukemia progression, even in a short-term prospective study (P&lt;0.001).
Conclusions: It is important to diagnose MDS accurately on the base of cytopenia, bone marrow morphology and clonal chromosomal abnormalities. IPSS and WPSS provide good prediction of survival and risk of leukemic evolution in MDS patients. The evaluation of clinical, hematological and cytogenetic analysis in more cases for long time follow-up will be helpful to standardize diagnosis of MDS.
Intrinsic Drug Resistance in Multiple Myeloma to Doxorubicin Is Mediated by Soluble Factors
Authors: Sullivan Daniel , Dawson Jana L. , Ciaravino Elizabeth J. , Turner Joel G. 
Published: April 2020

Abstract
Drug resistance continues to be a major obstacle in the treatment of multiple myeloma. Data have shown that the bone marrow microenvironment plays an important role in drug resistance. Whether it is mediated through the physical interaction of stromal and tumor cells or by soluble factors, this communication is essential for survival by both normal and tumor cells. In the current study we use a transwell system to allow passage of soluble factors from high density (drug resistant) to low density (drug sensitive) human myeloma 8226 cells. In our model, 8226 cells translocate topoisomerase IIa (topo IIa) from the nucleus to the cytoplasm when at high density (3 × 106 cells/ml) for 16 hours, rendering the cells 38-fold resistant to doxorubicin (DOX), a topo II poison, relative to low density cells (see column 1 in graph A & B below). When low density (2 × 105 cells/ml) cells are separated from the high density cells by a 3.0 micron porous membrane for 16 hrs, we observed a 14-fold increase in resistance in the sensitive cells after a 1 hr exposure to DOX as compared to cells exposed to low density cells (see column 1 in graph C & D). Moreover, this increased resistance was less pronounced (2.5 fold) with topotecan (TPT), a topo I inhibitor, and no effect was seen when cis-platinum (CIS PLAT), a non-topo drug, was used in this system (see columns 2 & 3 in graph C & D), suggesting that topo IIa may be the specific target. This mechanism also appears to be time-driven, as the resistance increases over time in the sensitive cells during the course of the 16 hr exposure. In addition, drug resistance to DOX was observed when the sensitive cells were exposed to only “conditioned” media, but no effect was seen when exposed to high density cells in fresh media, suggesting that soluble factors are released from drug resistant cells into the microenvironment causing drug sensitive cells to acquire an increased ability to evade programmed cell death.
Figure Figure
Molecular Profiling of Extramedullary and Medullary Plasmacytomas
Authors: Motyckova Gabriela , Rahemtullah Aliyah , Vaghela Nileshwari , Vallet Sonia , Ackerman Adam , Mukherjee Siddhartha , Pozzi Samantha , Santo Loredana , Cirstea Diana , Toomey Christiana , Hochberg Ephraim P. , Cin Paola Dal , Rodig Scott , Hideshima Teru , Anderson Kenneth C , Munshi Nikhil , Raje Noopur 
Published: April 2020

Abstract
Plasmacytomas are rare plasma cells disorders and are potentially cured with local approaches such as radiation treatment. Extramedullary plasmacytomas usually progress slowly, can recur locally, and develop into multiple myeloma (MM) less frequently (8–36%) compared to solitary medullary plasmacytomas (60%). Biologically these cells are independent of bone marrow microenvironment for their growth and survival and the understanding of the differences in their underlying molecular characteristic can provide crucial insights into the pathogenesis of progression to MM. To investigate the differences between extramedullary and medullary plasmacytomas, we sought to molecularly profile these tumors by tissue microarrays, gene expression, microRNA, and FISH. We identified 78 patients from our data base with a pathological diagnosis of plasmacytoma. Of the 78 patients, 11 patients presented with extramedullary plasmacytomas, and 50 had medullary plasmacytomas. Seventeen patients who had been previously identified as having plasmacytomas were later confirmed to have MM. Among the patients with extramedullary plasmacytomas (n=11), 1 patient presented with multiple lesions. Three of 11 (27%) patients progressed to develop MM at a median of 12 months. Fifty patients presented with medullary plasmacytomas, of which 23 had solitary lesions and 27 (54%) progressed to MM at a median of 20.5 months. There was a male preponderance (76% vs 34%) and the median age at diagnosis was 59.6 years (range 30.4–84.3). Tissue microarrays were performed on 52 patients (7: extramedullary, 29: medullary, 16: MM) in whom paraffin-embedded tissue was available. Samples were stained for CD138, CD27, CD56, cyclin D1, Bcl-2, Ki-67 and light chain restriction by immunohistochemistry and/or in situ hybridization. Both paraffin and fresh frozen tissue was available for 12 medullary, 3 extramedullary, and 2 MM samples at diagnosis for comparison. FISH for del 13q, t(4;14), t(11;14), and t(14;16) was performed on these samples. Gene and microRNA profiling was also performed. The differential profile of gene and microRNA expression between the two subtypes of plasmacytomas and MM will be presented. Differential expression patterns of factors involved in proliferation, survival, adhesion, and stroma-cancer cell interactions may help explain plasmacytoma biology and identify factors responsible for progression to multiple myeloma. These insights may help identify new therapeutic approaches and targets in the treatment of plasma cell disorders.