bluuebunny/crossref_metadata_2025_split huggingface dataset:
Disease-Related Mortality in Patients with Lower-Risk Myelodysplastic Syndrome (MDS)
Authors: Dayyani Farshid , Conley Anthony P , Pierce Sherry , Strom Sara , Stevenson William , Borthakur Gautam , Kantarjian Hagop , Garcia-Manero Guillermo 
Published: April 2020

Abstract
We have recently developed a risk model specific for patients with lower risk MDS that allows the identification of poor prognosis patients (Leukemia. 2008; 22:538-3). We showed that the majority of patients classified by IPSS as low risk actually have poor outcomes with respect to overall survival. The cause of death (COD) of these patients is not well understood. In order to guide early therapeutic intervention, it is important to identify whether the mortality in this group is attributable to causes related to MDS or whether death occurs due to age-related comorbidities. The aim of the present study was to examine the rate of disease-related deaths in a cohort of 269 deceased patients with low or intermediate-1 disease by IPSS at presentation to a tertiary care center from 1980 to 2006. Autopsy, final progress note, physician letter, or death certificate were used to determine COD. For each patient, we categorized the COD as disease-related vs. non-related. MDS-related death was defined as infection, bleeding, transformation to acute myeloid leukemia (AML), or disease progression. Non-related causes included accidents, coronary events, heart failure, respiratory and renal failure, non-hemorrhagic stroke, and chronic hepatitis. Median age at presentation and at time of death was 66 years (range 19–88) and 67 years (range 21–90), respectively. Overall median survival was 59 weeks (range = 1–831). By FAB classification, all subgroups were identified (RA = 41.3%, RARS = 5.8%, RAEB = 28.6%, RAEB-t = 12.3%, CMML = 12.0%). By IPSS score, most patients were Intermediate-1 (Int-1 = 79% and Low = 21%). Most patients had diploid cytogenetics (58.3%), and the most common cytogenetic abnormality was deletion of chromosome 5 (9.1%). Almost all patients received supportive care only. The COD was identified as MDS-related in 229 of 269 patients (85%). The most common disease-related COD was infection (39% of all deaths) followed by hemorrhage (34%) and transformation to AML (23%). The most frequent non-disease-related COD were cardiovascular events (19 of 40 patients). 8 of 269 patients died of a secondary neoplasm. Our data demonstrates that the majority of patients with low- or intermediate risk MDS will succumb to causes related to their underlying disease. Although these results need to be validated prospectively, early therapeutic intervention could be considered in the management of these patients to improve survival.
Utility of Oligonucleotide Array Comparative Genomic Hybridization to Identify Cryptic Copy Number Alterations in Myelodysplastic Syndromes
Authors: Chung Wendy K , Weisberger James , Sun Yi , Brenholz Pauline , Warren Stephanie , Brown-Kipphut Brigette A , Aradhya Swaroop , LeDuc Charles A , Grodman Marc , Burack Richard , Iqbal M. Anwar , Bennett John M. 
Published: April 2020

Abstract
Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematological neoplasms characterized by peripheral cytopenias due to ineffective hematopoiesis and significant cytologic atypia in one or more of the myeloid lineages. There is a variable risk of progression to acute myeloid leukemia, which is dependent on the blast count and certain recurrent cytogenetic abnormalities. Cytogenetic characterization is important in both diagnosis and prognosis, but can be of limited value in lower-risk MDS subtypes because of the low frequency of karyotypic abnormalities detected by chromosome analysis. Recently, array comparative genomic hybridization (aCGH) has been shown to be an important technique in detecting gross and cryptic copy number changes in leukemias. However, there is little data on aCGH application in MDS. We used a custom design 105,000 probe oligonucleotide aCGH platform to analyze 44 bone marrows, in which a diagnosis of MDS was made to determine the clinical utility of oligonucleotide aCGH. All bone marrows were analyzed by morphology, flow cytometry, cytogenetics, and fluorescent in situ hybridization (FISH). Gender matched normal controls were used to assess copy number alterations in MDS samples. We classified significant gains and losses
as a minimum of 10% deviation from the baseline of at least 10 contiguous oligonucleotide probes spanning at least 1 Mb and as not within a previously defined region of copy number polymorphism in the Database of Genomic Variants.
Array CGH was able to detect all cytogenetically identified imbalances present in more than 1 cell, but as expected did not detect any of the balanced translocations or inversions. Of the 24 cases that were cytogenetically normal, 9 (38%) had anomalies detected by aCGH. In 5 (25%) of the 20 cases with at least one cytogenetic abnormality detected previously by chromosome analysis, additional imbalances were identified by aCGH. Recurrent copy number losses detected by aCGH were observed in 13/44 (29.5%) of cases and included 5q21 in 5 cases, chromosome 7 in 2 cases, 12p13 in 3 cases, 13q21-31 in 3 cases, and 20q12-13 in 2 cases. Oligonucleotide aCGH was able to provide extremely high resolution of the boundaries of the gains and losses due to the high oligonucleotide probe density. In 14/44 cases (31.8%), oligonucleotide aCGH provided novel information not provided by conventional cytogenetics and FISH and can be used to precisely define recurrent gains and losses. Our data demonstrates the clinical applicability of oligonucleotide aCGH in the diagnosis of MDS in addition to conventional cytogenetics to detect new cryptic abnormalities which may provide novel targets for therapy.
Serum Proteome Profiling Detects Myelodysplastic Syndromes and Different Expression of Fibrinogen Between RAEB and RCMD
Authors: Zhong Liye , Liu TianHao , Geng SuXia , Lu Zesheng , Weng Jianyu , Du Xin 
Published: April 2020

Abstract
BACKGROUND&OBJECTIVE FMyelodysplastic syndromes (MDS) are among the most frequent hematologic malignancies. The diagnosis of MDS can be difficult, and there is a paucity of molecular markers. The pathophysiology is still largely unknown. Therefore, we investigated whether serum proteome profiling may serve as a noninvasive platform to discover novel molecular markers for MDS and establish the predictive models that may be of help to serologic diagnosis and classification of MDS.
METHODS FSerum samples were collected from 14 MDS patients including to 8 Refractory anemia with excess blasts in transformation (RAEB) and 6 Refractory cytopenia with multilineage dysplasia (RCMD) and 18 non-MDS hematologic malignancies and 8 age- and sex-matched healthy subjects. Serum peptides were separated and purified with a purification kit of magnetic beads, using magnetic beads-based weak cation exchange chromatography (MB-WCX) and MB-IMAC Cu, bases on immobilized metal ion affinity chromatography on the surface of superparamagnetic microparticles. We generated serum proteome profiles by matrix-assisted laser desorption/ionization time of-flight mass spectrometry (MALDI-TOF- MS) and identified a profile that distinguishes MDS from non-MDS hematologic malignancies and healthy subjects.
RESULTS FA totaI of 146 effective protein peaks were detected at the molecular range of 1.02 tO 10.25 ku, Among which 7 protein peaks were different significantly among MDS patients, non-MDS hematologic malignancies and healthy subjects (P&lt;0.05). There was also different for Peptide mass fingerprinting in MDS patients, and the samples were divided into two groups, which was identical with clinical classification about RAEB and RCMD, using 3-cross validation approach. There was significantly different expression protein between RCMD and RAEB patients, which was identified as a piece of fibrinogen peptide. The expressions of fibrinogen in RAEB subtype patients were higher than RCMD subtype patients.
CONCLUSION F Using the MALDI-TOF-MS technique may help to identify serum proteomic biomarkers related to MDS. The predictive models can discriminate MDS patients from other hematologic malignancies and healthy people effectively and help to identify MDS clinical classification. The different expression of Fibrinogen between RAEB and RCMD may suggested heterogeneity of etiopathogenisis in different subtypeof MDS.
Depleting Autologous Activated CD4+ t Lymphocytes Increased Generation of Colony-Forming-Cells(CFC) in Patients with Myelodysplastic Syndromes
Authors: Zhang Zheng , Li Xiao , Zhang Qianqiao , Tao Ying , He Qi 
Published: April 2020

Abstract
Objective To investigate how autoimmune mechanism playing a role in generation of colony-forming-cells(CFC), bone mononuclear cells(BMNC) from MDS were removed of autologous activated CD4+ T cells in vitro and cultured to find out effect of T cells on MDS hemopietic progenitor.
Methods BMNC from 25 patients with low-grade MDS and 5 normal donors were depleted of CD4+CCR5+ T lymphocytes using magnetic sorting. Depleted and plused CD4+CCR5+ T BMNC were seeded onto methycellulose and the correlation of colony-forming-cell (CFC) number and the polarization of T cells were analyzed, the generation of CFC, the immunophenotype and the clonal cells(which had cytogenetic markers detected by FISH), was compared respectively.
Results ¢Å The capacity of BMNC from 5 healthy donors to generate CFC remained unchanged in the CD4+CCR5+ T lymphocyte-depleted and lymphocyte-plused BMNC. In contrast, cultures initiated with CD4+CCR5+ T lymphocyte-depleted BMNC from patients with low-grade MDS exhibited significantly increased generation of CFC compared with the corresponding lymphocyte-plused cultures, but the lymphocyte-plused cultures had no generation of CFC. ¢Æ The number of CFU-E from the CD4+CCR5+ T lymphocyte-depleted BMNC from patients with low-grade MDS showed significantly correlation with the percentage of Th1 (r=0.52, p≤¼ 0.05), but had no correlation with the percentage of Tc1 and the rate of Th1/Th2 and Tc1/Tc2 (p &gt;0.05); The number of CFC, CFU-G and CFU-GE had no correlation with the polarization of T lymphocyte (P &gt;0.05). ¢Ç The percentage of CD34 in bone nucleated cells of low-grade MDS was higher than that in healthy donors(1.8% vs. 1.0%, P &gt;0.05), that of CD33 in nucleated cells of low-grade MDS was significantly higher than that in healthy donors[(20.3±5.8)% vs.(13.8±1.8)%(P≤¼0.05)], and that of CD13 in nucleated cells of low-grade MDS was significantly higher than that in healthy donors[(21.1±6.4)% vs. (11.6±1.8)%(p&lt;0.05)]. After cultivation, the percentage of CD34 in low-grade MDS nucleated cells decreased to 1.4%(P &gt;0.05), that of CD33 decreased to (12.1±3.7)%(p&lt;0.05), and that of CD13 decreased to (17.1±5.4)%(p&lt;0.05), but the percentage of CD34, CD33 and CD13 had no significantly changed in healthy donors between pre-culture and post-culture. ¢È FISH analysis in 6 patients revealed that +8 clone was increased(from 51% to 61%), but 20q- and -7 clone cell had no significantly changed.
Conclusion In certain subtypes of MDS, selectedly removement of autologous activated CD4T cells can increase the generation of colony-forming-cells(CFC) in vitro, and improve the differentiation of MDS medullary system, but the increased CFC consisting of residual normal hemopoiesis or conal hemopoiesis were still unconcluded.
Site-Specific PEGylation of Factor VIII (PEG-FVIII) Preserves Full Clotting Activity and Extends Therapeutic Efficacy in HemophiliaA Dogs
Authors: Liu Tongyao , Lillicrap David , Zhang Xin , Labelle Andrea , Powell Sandra , Mei Baisong , Murphy John E. , Pierce Glenn F. , Jiang Haiyan 
Published: April 2020

Abstract
To improve the effectiveness of Factor VIII replacement therapy for Hemophilia A, we sought to develop a PEGylated Factor VIII that would effectively treat bleeding episodes, while reducing the frequency of intravenous injections required for prophylaxis. Previously, we found that the site-specific PEGylation of Factor VIII (PEG-FVIII) preserves full clotting activity, prolongs circulating half-life and extends therapeutic efficacy in a number of bleeding models in hemophilic mice. To further characterize its activity, four naïve Hemophilia A dogs were treated with either PEG-FVIII or unmodified BDD-FVIII in a cross-over study design. All treated dogs showed normalized Whole Blood Clotting Time (WBCT), whole blood Thromboelastograph (TEG) profile, and Cuticle Bleeding Time within 30 min from dosing. Pharmacokinetic analysis of the decay of plasma FVIII activity and antigen levels showed that PEG-FVIII achieved 2-fold longer half-life and reduced clearance and volume of distribution relative to BDD-FVIII. Consistently, PEG-FVIII also demonstrated significantly prolonged efficacy relative to BDD-FVIII by measurement of WBCT and TEG. Both BDD-FVIII and PEG-FVIII were well tolerated in naïve HemA dogs, normal hematology and serum chemistry values were observed following administration. However, two naive dogs that received BDD-FVIII and one naive dog that received PEG-FVIII developed detectable neutralizing antibodies to human FVIII as early as on day 9 post-treatment. In summary, consistent with our previously reported findings in hemophilic mice, in comparison to BDD-FVIII, PEG-FVIII demonstrated superior half-life, full activity in stopping acute bleeding and prolonged efficacy in hemophilia A dogs. Taken together, the results support the use of site-specific PEGylation to create a homogeneous therapeutic for both prophylactic and on-demand treatment of patients with Hemophilia A.
Polymorphisms in CD31/PECAM-1 and CD38 Genes Are Associated with Susceptibility to Multiple Myeloma
Authors: Jamroziak Krzysztof , Szemraj Zofia , Szemraj Janusz , Grzybowska-Izydorczyk Olga , Oszajca Katarzyna , Janiszewska Grazyna , Balcerczak Ewa , Mirowski Marek , Urbanska-Rys Halina , Robak Tadeusz 
Published: April 2020

Abstract
Interactions with bone marrow microenvironment play a major role in the control of multiple myeloma (MM) growth and survival. MM clonal plasma cells co-express high levels of a signaling receptor CD38 and its ligand, the platelet endothelial adhesion molecule-1, CD31//PECAM-1. Homotypic and heterotypic interactions through these adhesion molecules (CD31/CD31, CD38/CD31 and CD38/hyaluronate interactions) may be involved in the pathogenesis of MM. The objective of this study was to investigate whether inherited variants in CD31/PECAM-1 and CD38 genes influence on susceptibility to MM. A total of 189 Caucasian patients with MM and 209 healthy controls were genotyped with the use of PCR-based methods. Genotyping was performed to assess allelic frequencies of three non-synonymous single nucleotide polymorphisms (SNPs) in CD31/PECAM1 gene including 373C&gt;G (Leu 125Val), 1688G&gt;A (Ser563Asn) and 2008A&gt;G (Arg670Gly) as well as two SNPs in CD38 gene including 184C&gt;G in intron 1 and non-synonymous 418C&gt;T (Arg140Trp) in exon 3. Analyzing the prevalence of investigated genetic variants, we found that allelic frequencies of two SNPs in CD31/PECAM-1 gene and intron 1 184C&gt;G SNP in CD38 gene differed significantly between MM patients and controls. Concerning CD31/PECAM-1 SNPs, the carriership of 373G allele was associated with the relative risk of MM of 4.5 (p=8×10−10), while in carriers of 1688A allele the relative risk of MM reached 3.0 (p=2×10−6). Regarding CD38 gene, compared to wild-type 184C-allele carriers, the carriers of variant 184G-allele had 3.4-fold increased risk of MM (p=1×1−9). In conclusion, the results of this study suggest that inherited variants in ligand-receptor CD31/PECAM1 - CD38 system contribute to the genetic susceptibility to MM in Caucasians.
Personalized Genetic Monitoring of myeloma using analytic multivariate analysis of total Fully-Sequenced Circulating DNA
Authors: Durie Brian GM , Beck Julia , Jagannath Sundar , Urnovitz Howard B. , Schutz Ekkehard 
Published: April 2020

Abstract
There is no single sequence or breakpoint region linked to all patients with myeloma. It was thus elected to extract, amplify and fully sequence all (total) DNA present in circulating blood (CNA) using pyrosequencing with the Roche/454 sequencer (GSFLX). The origin of circulating DNA was investigated by local alignment analyses using BLAST and compared with the circulating DNA of 47 healthy individuals, aged 18 to 64 years. Thirty-one samples were subjected to total CNA sequencing during the course of the disease for a patient with lambda Bence Jones myeloma sequentially monitored from relapse, through complete response for 38 months and then with development of subsequent relapse. Conventional monitoring included both serum free light chain analyses and whole body CT-PET imaging. For comparative purposes the CNA was categorized by origin, functionality, chromosomal localization and genes, based on public databases (human reference genome build 36.2 and corresponding annotation file seq_gene.md as downloaded from NCBI (ftp.ncbi.nih.gov). The average length of sequenced nucleotides was 185.7 nucleotides and the total number of nucleotides sequenced per sample was 1.2 – 2.6 million. CNA sequences occurring with a frequency significantly greater or less than those observed for healthy controls were evaluated in detail. The next steps were to examine correlations with initial active myeloma, response to treatment, the complete remission state off all therapy, and subsequent relapse. The presence of 10 DNA sequences was highly correlated with the disease course: ZMYM2; TSPAN5; TLL1; PRKD1; ANTXR1; SYT14; PRKCH; MBNL1; EGFR and EDG7. Of these ZYMYM2 was highly correlated with disease reactivation and relapse off therapy. TSPAN5 showed a clear pattern with reduction to background levels during remission, but increase at the very earliest sign of relapse evident on CT-PET. Conversely, other sequences (GRID1; KIF16B) increased substantially during the peak impact of successful therapy. Multivariate analyses were used to identify the best combinations of gene sequences predictive of disease course and outcome. The combination of four genes (GRID1; PRKD1; ANTXR1; GAB1) was sufficient to define the early active disease data points vs the normal controls (odds-ratio OR: 135 [10.6 to 172]; p&lt;.0001). When the resulting model was kept and used as a search engine for the whole 2 years course, the time course followed the treatment success (OR: 54; p=.0017) and failure as well as the final relapse(OR: 13.3; p=.004)
In conclusion: Total sequencing of DNA has proved promising in providing personalized molecular monitoring for myeloma. The details of associated DNA sequences provide insights to the underlying molecular pathophysiology linked to myeloma disease progression, response to successful therapy as well as subsequent relapse. Further testing is ongoing.
Molecular Mechanism of CD56 Expression in Human Myeloma Cells
Authors: Iqbal Mohd S. , Otsuyama Ken-ichiro , Shamsasenjan Karim , Kawano Michio M. 
Published: April 2020

Abstract
CD56 (NCAM1), one of the non-B cell lineage markers, is frequently detected on primary myeloma cells from more than 80% patients with overt myeloma. Microarray analysis of the CD56(+) myeloma cell lines showed markedly increased expressions of transcription factors involved in the neuronal cell lineage compared to the CD56(−) myeloma cell lines. There are three important binding sites of transcription factors such as HOX, SOX and PAX, present in the CD56 promoter region. Furthermore, ChIP analysis showed the specific bindings of HOXB9 and SOX1 in the CD56 promoter region of both the CD56(+) and CD56(−) myeloma cell line, while there was no significant difference observed in the PAX8 expression between the CD56(+) and CD56(−) myeloma cell lines. RT-PCR and western blot analysis confirmed that HOXB3 and HOXB9 as well as some of their potential cofactors were up-regulated in the CD56(+) myeloma cell lines with the concomitant down-regulation of the SOX1 and OCT3/4. First, we focused on the role of down-regulation of SOX1 in the CD56(−) myeloma cell line by the shRNA transfection. However, shRNA against SOX1 failed to induce CD56 expression in CD56(−) myeloma cell line. Therefore, these results indicate that the down-regulation of SOX1 alone may not be enough for the CD56 induction which might also require the overexpression of either HOXB9 or HOXB3, and the further study in the molecular mechanism of CD56 expression might contribute to the understanding of complex network of the interaction of transcription factors in human myeloma cells.
Biological Significance of Constitutive NF-κB Activity Levels in Human Myeloma Cell Lines
Authors: Otsuyama Ken-ichiro , Amin Jakia , Shamsasenjan Karim , Iqbal Mohd S. 
Published: April 2020

Abstract
To elucidate the mechanism of constitutive NF-κB activity in human myeloma cell lines, constitutive expression of all the NF-κB family, RelA (p65), c-Rel, RelB, NF-κB1 (p105/p50) and NF-κB2 (p100/p52), genes in different human myeloma cell lines, such as IL-6-independent (AMO1, NOP2), IL-6-dependent (ILKM2, ILKM8) and IL-6-responsive cell line (U266), were first checked by RT-PCR and western blot analysis. In the electrophoretic mobility shift assay (EMSA) for κB main consensus, total DNA binding activity levels for NF-κB were higher in IL-6-dependent, IL-6-responsive and IL-6-independent human myeloma cell lines respectively. Supershift analysis with anti-NF-κB family antibodies and immunoprecipitation followed by western blotting, confirmed that p50/p50, p50/RelB and p50/p52 as the principal player responsible for constitutive activation of NF-κB in IL-6-independent cell lines. However, beside these major dimers, p50/p65 dimer was also involved in the constitutive NF-κB activation in IL-6-dependent and IL-6-responsive cell lines. Moreover, on the basis of microarray data in human myeloma cell lines, we confirmed that the expression levels of NF-κB target genes, such as NFKB2, RELB, NFKBIA, MALT1 and CD54, showed correlation with the level of DNA binding activity for NF-κB. Therefore, these data suggest that the difference of total DNA-binding activities for NF-κB partly depended on the different p50/p65 activity among the IL-6-independent, IL-6-dependent and IL-6-responsive human myeloma cell lines, and further studies in the different NF-κB-dimers activity levels might contribute to the clarification of the regulation of NF-κB target genes expression in human myeloma cell lines.
Identification of An Atypical Paraprotein with Inconsistent M-Spike Quantitation in Four Patients with Waldenstrom’s Macroglobulinemia
Authors: Brunker Patricia A. R. , Glidden Elizabeth , Ghobrial Irene M. , Lindeman Neal I. 
Published: April 2020

Abstract
The densitometric quantitation of the M-spike in patients with a monoclonal gammopathy is a standard method used to monitor diseases such as multiple myeloma and Waldenstrom’s macroglobulinemia. Typically, M-spike quantitation shows synchronous parallel trends with other measures of disease status, such as nephelometric immunoglobulin heavy chain measurements, and with clinical condition. However, we report a series of four patients with Waldenstrom’s macroglobulinemia and IgM paraproteins with atypical appearing M-spikes that were significantly discordant with the total IgM measurements and clinical condition (Figure 1). Each of these patients had paraprotein bands that were extremely narrow and intense with slight migration from the sample application site (Figure 2). Although similar band morphology may be seen with cryoglobulins, all of these patients had repeatedly negative cryoglobulin tests. Pre-treatment of these samples with beta-mercaptoethanol (BME) to reduce disulfide bonds led to normal-appearing and migrating M-spikes that, when quantitated, gave precise results that were consistent with the total IgM measurements. This technique has permitted continued use of the M-spike to monitor disease progression in these patients, and demonstrates the importance of careful visual inspection of the SPEP gels prior to performing M-spike quantitation in the clinical laboratory.
Figure 1: Figure 1:. Figure 2: Figure 2:.