bluuebunny/crossref_metadata_2025_split huggingface dataset:
No Effect of Aging on the Donor Hematopoietic Stem Cell Compartment in Allogeneic Stem Cell Transplant.
Authors: Arora Amit , Sharp John G. , Lynch J. C. , Kessinger A. 
Published: October 2019

Abstract
Background: Literature regarding the association of aging and stem cell numbers is conflicting. No compelling evidence exists that hematopoietic stem cell numbers decline with age. Early progenitor cells represent only a fraction of total CD34 cells. The ratio of CFU-GM/CD34 provides a relative estimate of the proportion of primitive hematopoietic stem cells in the stem cell compartment. The hypothesis is that primitive stem cell numbers decrease with age.
Methods: This study describes the relationship between the CFU-GM/CD34+ ratio (categorized as quartiles) and donor characteristics in 108 normal donors of cytokine mobilized hematopoietic stem cells for allogeneic transplant between 6/1995 and 11/2003. The relationship between the CFU-GM/CD 34+ and cell collection characteristics were also studied. Donor characteristics included: age, gender, race/ethnicity, ABO blood group, weight, height, body surface area (BSA); collection characteristics included: total number of mononuclear cells/kg (MNC), CFU-GM/kg (Colony Forming Unit- Granulocyte Monocyte), CD34+ cells/kg and the ratio of CFU-GM/CD34 collected.
Results: The median age of the donors was 42.5 years with range from 10.9 years to 71.4 years. The median CFU-GM/CD34 ratio was 0.060 with range from 0.009 to 0.248. The multivariate analysis demonstrated that higher MNC numbers were associated with a significantly higher CFU-CM/CD34 ratio (p<0.01). No significant decrease in the CFU-GM/CD34 ratio was found with increasing age indicating no general compromise in the stem cell compartment of donors with aging. A non-significant association of the CFU-GM/CD34 ratio to donor gender (p=0.071) and BSA (p=0.072) was also observed.
CONCLUSION: No significant decline in donor hematopoietic stem cell compartment was seen with aging.
Relationship of CFU-GM/CD34+ Ratio Quartiles to Donor and Collection characteristics
CFU-GM/CD34+ Ratio Quartiles First (0.009–0.034) Second (0.035–0.059) Third (0.06–0.076) Fourth (0.077–0.248) All (n=108) Abbreviation: CFU GM: Colony Forming Unit- Granulocyte Macrophage; MNC: Mononuclear cell Donor Sex (n) Male 19 19 11 18 67 Female 8 8 16 9 41 BSA sq m Median 2.04 2.02 1.81 1.96 1.99 Range (1.65–2.57) (1.59–2.35) (1.46–2.38) (1.30–2.45) (1.30–2.57) Total MNC Collected Median (10E8/kg) 5.86 5.77 6.83 8.49 6.22 Range (10E8/kg) (3.07–11.24) (2.37–13.10) (2.96–15.77) (3.31–15.48) (2.37–15.77)
Rituximab-Mediated Inhibition of the Transcription Repressor Yin-Yang 1 (YY1) in NHL B Cell Lines: Upregulation of Fas Expression and Sensitization to Fas-Induced Apoptosis.
Authors: Vega Mario I. , Huerta-Yepez Sara , Jazirehi Ali R. , Garban Hermes , Bonavida Benjamin 
Published: October 2019

Abstract
We have reported that rituximab triggers and inhibits anti-apoptotic gene products in NHL B-cell lines resulting in sensitization to drug-induced apoptosis (Alas et al., Clin. Cancer Res.8:836, 2001; Jazirehi et al., Mol. Cancer Therapy2:1183, 2003; Vega et al., Oncogene23:3530, 2004 ). This study investigated whether rituximab also modifies intracellular signaling pathways resulting in the sensitization of NHL cells to Fas-induced apoptosis. Treatment of the NHL cell lines (2F7, Ramos, and Raji) with rituximab (20 μg/ml) sensitized the cells to CH-11 (FasL agonist mAb) -induced apoptosis and synergy was achieved. Fas expression was up-regulated by rituximab as early as 6 h post treatment as determined by flow cytometry, RT-PCR, and Western. Rituximab inhibited both the expression and activity of the transcription repressor Yin-Yang 1 (YY1) that negatively regulates Fas transcription. Inhibition of YY1 resulted in upregulation of Fas expression and sensitization of the tumor cells to CH-11-induced apoptosis. Downregulation of YY1 expression was the result of rituximab-induced inhibition of both the p38MAPK signaling pathway and constitutive NF- κB activity. The dual roles of NF-κB and YY1 in the regulation of Fas expression were corroborated by the use of a dominant-active inhibitor of NF- κB (Ramos IκB-ER mutant) and YY1 siRNA, respectively. The role of rituximab-mediated inhibition of the p38MAPK/NF- κB/YY1 pathways, which result in both Fas upregulation and sensitization to CH11-induced apoptosis, was corroborated by the use of specific chemical inhibitors directed at various targets of these pathways. Rituximab-mediated sensitization to CH-11-induced apoptosis was executed through the Type II mitochondrial apoptotic pathway. Altogether, these findings provide a novel mechanism of rituximab-mediated signaling by inhibiting the p38MAPK/NF- κB/YY1 pathways and resulting in the sensitization of B NHL to Fas-induced apoptosis. These findings may have significant clinical implications and suggest an additional mechanism of rituximab-mediated effect in vivo in addition to CDC and ADCC.
Effects of SB559457, a Novel Small Molecule Thrombopoietin Receptor (TpoR) Agonist, on Human Hematopoietic Cell Growth and Differentiation.
Authors: Kalota Anna , Brennan Kistin , Erickson-Miller Connie L. , Danet Gwenn , Carroll Martin , Gewirtz Alan M. 
Published: October 2019

Abstract
Treatment of thrombocytopenia resulting from chemotherapy, radiation, or stem cell transplantation remains problematic. Hopes that TPO, the major regulator of megakaryocyte maturation, might prove clinically useful for this purpose have not been fulfilled, in part because of untoward reactions to the molecule. To avoid undesirable side effects, small molecule TpoR agonists are being developed. We have evaluated the biological effects of one such molecule, SB559457, a hydrazone compound, on hematopoietic cells. We first examined SB559457’s ability to stimulate proliferation of the recombinant human TPO (rhTPO) dependent cell line UT-7/TPO. We found a dose dependent augmentation of cell proliferation at doses between 1 and 10 μM, with maximal effects, compared to 100ng/ml of rhTPO at 10μM. We then evaluated SB559457’s growth promoting effects on normal human CD34+ cells. We again found growth stimulation to be dose dependent between 1 and 10 μM and also noted enhancement when SB559457 was combined with IL-3 and SCF. Specifically, incubation of CD34 cells in 10 μM SB559457 for 7 days lead to a 2 fold increase in cell number; incubation of cells with IL3 and SCF in addition to SB559457 lead to a 12 fold increase in cell number after 7 days. Both results were comparable to those seen with 100 ng/ml of rhTPO. Curiously, the addition of IL-6 to cultures containing IL-3 and SCF compromised the ability of SB559457, but not Tpo, to stimulate CD34+ cell growth. To determine if SB559457 stimulates megakaryocyte differentiation directly, CD34+ cells were incubated in cytokines with rhTPO or SB559457 for periods of 7–10 days, after which time cells in culture were examined for degree of polyploidization, and expression of megakaryocyte lineage markers CD41 and CD61. 14% of cells grown in SB559457 showed greater than 4N DNA content compared to 8% in rhTPO. These same cells expressed the megakaryocyte markers CD41 and CD61on 35% of cells, comparable to the results with rhTPO. Preliminary results demonstrate that incubation of CD34 cells in SB559457 maintained stem cells numbers, as assayed by NOD/SCID engraftment, for at least 4 days at a level comparable to the levels maintained by rhTPO. These results demonstrate that SB559457 is a bona fide Tpo R agonist that likely acts through activation of c-mpl, the receptor for TPO. These experiments provide a rationale for the evaluation of SB559457, or SB559457 congeners, in patients with thrombocytopenia.
Genetic Pathways in t-MDS and t-AML, a Revised Model.
Authors: Pedersen-Bjergaard Jens , Christiansen Debes H. , Andersen Mette K. 
Published: October 2019

Abstract
Jens Pedersen-Bjergaard, Debes H. Christiansen, Mette K. Andersen. Dept. Clinical Genetics, University Hospital Rigshospitalet, Copenhagen, Denmark. 140 unselected patients with t-MDS (n=90) or overt t-AML (n=50) were studied for chromosome aberrations, for mutations of 6 different genes and 69 patients were examined for methylation of the p15 promotor. Cytogenetically, 5q−/ −5: n=34; 7q−/ −7 but normal chromosomes 5: n=39; balanced translocations: n=23; normal karyotype: n=24; other abnormalities: n=20. Mutations of p53: n=34; AML1: n=22; FLT3: n=11; c-KIT: n=2; K- or N-RAS: n=14; BRAF: n=2; methylation of the p15 promotor: 55/69 cases.
Abnormalities of chromosomes 5 and 7 were significantly associated with t-MDS (p=0.001), whereas balanced translocations and a normal karyotype were significantly associated with overt t-AML, (p=0.0001 and p=0.006 respectively).
Mutations of p53 were significantly associated with 5q−/ −5 (p=0.001), with 17p−/−17 (p=0.0004), with a complex karyotype (p=0.001), and with MLL and AML1 amplifications. Mutations of AML1 were significantly associated with 7q−/−7 )(p=0.001) and with t-MDS progressing to t-AML (p=0.0001). Mutations of FLT3 were significantly associated with presentation as overt t-AML (p=0.0002), with a normal karyotype (p=0.004) and with previously radiotherapy only (p=0.03). RAS mutations were significantly associated with t-MDS progressing to overt t-AML (p=0.008) and borderline with a normal karyotype (p=0.07). Methylation of p15 was significantly associated with 7q−/−7 (p=0.0006).
Mutations of FLT3, RAS and c-KIT were mutually exclusive, and a synergism between AML1 and RAS mutations (22/5/14, p=0.046) and between p53 and AML1 mutations in patients with 7q−/−7 is suggested.
Based on these findings a revised model of the genetic pathways of t-MDS and t-AML (Blood2002;99: 1909–1912) is discussed.
Characteristics and Prognosis of Patients (pts) with Acute Megakaryocytic Leukemia (AMegL) Treated at M.D. Anderson Cancer Center Since 1987.
Authors: Oki Yasuhiro , Estey Elihu , Kantarjian Hagop , Cortes Jorge , Faderl Stefan , O’Brien Susan , Koller Charles , Beran Miloslav , Keating Michael J. , Pierce Sherry , Garcia-Manero Guillermo 
Published: October 2019

Abstract
AMegL is a rare form of acute myeloid leukemia (AML) associated with poor prognostic features. Here, we report the experience at M.D. Anderson Cancer Center from 1987 to 2003. Among 1861 pts with newly diagnosed AML (excluding APL), 38 pts (2%) had AMegL. The diagnosis of AMegL was based on (i) morphological features defined by FAB classification and (ii) immunophenotypypical positivity for CD42 and CD61 whenever available. All 38 pts received induction chemotherapy containing cytarabine and anthracyclines. Sixteen (42%) were males; median age was 54 years (range 21–78); 11 (29%) had antecedent hematologic disorder (AHD) and/or MDS, and 4 (11%) had previously received chemotherapy for other malignancies. Median white blood cell count at diagnosis was 3.5x109/L (0.5–49.9), hemoglobin 7.8 g/dl (3.2–10.9), platelet count 34.5x109/L (5–2292), and the median bone marrow blast percentage was 30% (0–80). For pts with <30% bone marrow blasts, diagnosis of AMegL was supported by peripheral blood blasts ≥30%. Significant bone marrow fibrosis was found in 24 pts (63%). Cytogenetic analysis was available in 30 pts (79%) due to insufficient material or insufficient metaphases. Twenty-seven pts (71%) showed abnormalities: deletion 7 in 15 pts (39%), deletion 5 in 14 (37%), chromosome 3 abnormality in 6 (16%) and trisomy 8 in 4 (11%). Philadelphia chromosome was detected in 2 pts (5%). Sixteen pts (42%) achieved a complete remission (CR). None of 22 pts with primary refractory disease achieved a complete remission from subsequent chemotherapies. Median overall survival of all AMegL pts (n=38) was 24 compared to 38 weeks for the control group (non AmegL AML pts, excluding APL,N=1823) (p<0.01). Median disease free survival of pts with AMegL (n=16) and other AML (n=1031) was 23 and 52 weeks, respectively (p<0.001). Two pts with primary refractory disease and three who developed relapsed disease eventually underwent allogeneic stem cell transplantation. Median survival after stem cell transplantation was 21 weeks. In summary, AMegL is a rare form of AML, which is observed in pts with AHD and/or MDS or as secondary leukemia. AMegL is highly associated with poor cytogenetic abnormalities, translating into a low CR rate and dismal outcome.
Heterogeneity of New Hodgkin’s Disease Patients in Terms of Their Quality of Life.
Authors: Novik Andri A. , Ionova Tatiana I. , Kishtovich Anton V. , Uspenskaya Olga S. , Osipova Nina E. , Fedorenko Denis A. 
Published: October 2019

Abstract
Background: It is quite obvious that population of new Hodgkin’s disease (HD) patients is heterogeneous in terms of clinical characteristics. Therefore stratification of patients is necessary to select appropriate treatment regimen. It was shown that new lymphoma patient population is heterogeneous in terms of base-line QoL (Novik A et al, 2003).
The aim of the study was to identify if new HD patients are heterogeneous in terms of QoL and to stratify patients using QoL parameters.
Patients and methods: 114 new HD patients (stage IIB-IV, mean age 30.2 (SD 13.5), males/females - 55/59) were enrolled in the study. Patients filled in EORTC QLQ-C30 at baseline. The method of integral profiles (MIP) was used to calculate integral QoL index (IQL), the coefficient of QoL deformation (CQLD) and the index of symptom severity (ISS). The above indexes were used for stratification by the cluster analysis (Ward method, percent of cases correctly classified - 98.25%). Discriminant analysis was performed for stratification testing.
Results: Three groups of HD patients were identified after stratification. IQL, CQLD and ISS were as follows: subgroup 1 (n=5, mean age 40.8 (22.9), male/female 1/4) − 0.04, 1.7, 0.17; subgroup 2 (n=47, mean age 34.3 (14.5), male/female 23/24) − 0.35, 0.62, 0.09; subgroup 3 (n=62; mean age 26.0 (9.7); male/female 31/31) − 0.74, 0.24, 0.01. Group 1 has the worst QoL and is characterized by low IQL, pronounced symptoms and high deformation of QoL profile. Group 3 has the best QoL with high IQL, weak symptoms and low deformation of QoL profile. Group 2 has intermediate values of above parameters. Differences between groups were significant (p<0.05) by ANOVA.
Conclusion: The method of integral profiles to obtain the integral QoL index and the coefficient of QoL deformation in HD patients is proposed. Stratification of new HD patients by cluster analysis resulted in three patient subgroups according to their QoL data. Identification of subgroups of HD patients on the basis of their QoL has a good potential for better stratification of new HD patients and in doing so might be used for improvement of the intervention strategies.
Overexpression of Mitochondrial Ferritin Causes Cytosolic Iron Starvation and Changes Cellular Iron Homeostatis.
Authors: Nie Guangjun , Sheftel Alex D. , Kim Sangwon F. , Ponka Prem 
Published: October 2019

Abstract
Cytosolic ferritin is well known to sequester and store iron and, consequently, protect cells against iron-mediated free radical damage. However, the function of the newly discovered mitochondrial ferritin (MtFt) is unknown. To examine the role of MtFt in cellular iron metabolism, we established a cell line that stably overexpresses the mouse MtFt under the control of tetracycline. The overexpression of MtFt caused a dose-dependent iron deficiency in the cytosol that was revealed by increased RNA-biding activity of iron regulatory proteins (IRPs) with a concomitant increase in transferrin receptor levels and a decrease in cytosolic ferritin. Consequently, the induction of MtFt resulted in a dramatic increase (2-fold) in cellular iron uptake from transferrin, most of which ended up in MtFt within mitochondria. Similarly, the induction of MtFt caused a shift of iron from cytosolic ferritin to MtFt. Moreover, the cell permeable iron chelator salicylaldehyde isonicotinoyl hydrazone (SIH) mobilized approximately twice as much iron from wild-type cells as compared to those overexpressing MtFt suggesting that iron in this protein is less accessible to SIH. Furthermore, the expression of MtFt was associated with a decrease in the activity of both mitochondrial and cytosolic aconitase activity, the latter being in agreement with the increase of IRP binding activity. In conclusion, our results indicate that the overexpression of MtFt causes a dramatic change in intracellular iron homeostasis and that the shunt of iron to mitochondrial storage protein likely limits its availability for functional iron proteins.
DHPLC Scan of Iron Genes in Consecutive Patients with Suspected Iron Overload.
Authors: Girelli Domenico , Biasiotto Giorgio , Foglieni Barbara , Bozzini Claudia , Polotti Anna , Ferrari Francesca , Tenuti Ilaria , Gerardi Gian Mario , Cremonesi Laura , Corrocher Roberto , Arosio Paolo 
Published: October 2019

Abstract
Background: Hereditary Hemochromatosis, once considered a monogenic disorder, is now seen as a polygenic disease, with clinical phenotype also influenced by several environmental factors. Besides the classic HFE gene, other genes involved in modulation of iron homeostasis and clinical phenotype include those coding for hemojuvelin and hepcidin (both responsible for Juvenile Hemochromatosis), ferroportin, and, possibly, H-ferritin.
Methods: we used DHPLC to scan mutations in the above mentioned genes in 55 consecutive patients recently referred to our tertiary care unit for iron overload disorders. Many of them had at least biochemical signs of iron overload not explained, or not completely explained, by classic or rare HFE mutations.
Main results: the −72 C→T variation in the promoter of hepcidin gene, near the putative TATA box, was found in a H63D heterozygous male with unexplained biochemical signs (serum ferritin 660 μg/L, TS 45%), who, rather, should have been protected by several previous blood donations. We recently found this new hepcidin mutation in a family from another cohort (Biasiotto et al., in press): genotype/phenotype correlation data were also consisting with a functional role of this mutation. Two other hepcidin variations were found in this series, the 108 G→A (new), and the 212 G→A. While the first appeared silent, familial study suggests that the second may be functional in association with C282Y. No new or functional variations were found in hemojuvelin or H-ferritin genes. Several polymorphisms were detected in the ferroportin gene, including two new sequence variations (−116 T→C in the promoter; 691+20C C→T in intron 4), that occurred in two unrelated subjects with wild-type HFE genotype. Their functional role is currently under investigation by extensive family studies and/or quantitative evaluation of hepatic iron by MRI/liver biopsy.
Conclusions: DHPLC scan of iron genes appears as a helpful tool for integrating clinical data in selected patients referring for suspected iron overload, as well as for rapid identification of new mutations.
DMT1: Tissue Specific Expression and Alternative Splicing.
Authors: Mims Martha P. , Guan Yongli , Prchal Josef T. 
Published: October 2019

Abstract
Divalent metal ion transporter 1 (DMT1) functions in iron absorption at the apical surface of the duodenal enterocyte and in iron transport out of the endosomal compartment of the erythroblast, however, DMT1 is also expressed in cells which have no apparent role in iron metabolism. At least 4 isoforms of DMT1 mRNA have been identified that contain alternative 5′ (1A, 1B) and 3′ (IRE+, IRE-) exons. Recently we reported the first human mutation of the DMT1 gene in a patient with severe hypochromic/microcytic anemia. This patient was homozygous for a mutation in the ultimate nucleotide of exon 12 which resulted in preferential skipping of exon 12 during processing of pre-mRNA. Amplification of DMT1 mRNA from peripheral blood cells of this patient revealed multiple products; hematopoietic cells from normal controls had a similar, but not identical, pattern. No such additional PCR products were seen when DMT1 mRNA from other tissues or cultured cells was evaluated. To further investigate this observation, we amplified full length (1700–1800 bp) DMT1 transcripts (1A/IRE+, 1A/IRE-, 1B/IRE+ and 1B/IRE-) from a variety of tissues types, cell lines, and from hematopoietic cells. Expression of the 4 isoforms differed between the different cell types. EBV lymphocytes expressed primarily 1B/IRE+ and 1B/IRE- isoforms. Notably, EBV lymphocytes derived from the mutant patient expressed DMT1 mRNA which was 120 bp smaller than DMT1 PCR products from controls, corresponding to skipping of exon 12. Platelets, granulocytes and reticulocytes expressed primarily the 1B/IRE+ isoform, however, unlike the other cell types examined, more than one mRNA species was present (see figure). Full length high molecular weight PCR products derived from these cells were isolated and subcloned. Plasmid DNA was isolated, subjected to digestion with EcoR1, and the DMT1 inserts were sequenced. All inserts began with exon 1B and ended with exon 16 (IRE+); however, none contained “normal” full length DMT1 sequence. The majority contained either truncated portions of exon 3 or inserted portions of intron 3. Utilization of cryptic splice sites within exon 3 or within intron 3 resulted in early stop codons. We propose that alternative splicing of DMT1 mRNA either via skipping of entire exons or via the use of cryptic splice sites may provide a manner for regulating DMT1 activity in hematopoietic cells. Further studies are underway to elucidate this possibility and to evaluate the signals for alternative splicing.
Figure Figure