bluuebunny/crossref_metadata_2025_split huggingface dataset:
GATA-1 Protein Levels Are Not Altered and Are Correlated to the Jak-2 Mutation Status in Patients with Idiopathic Myelofibrosis (IMF).
Authors: Wang Jen-Chin , Xiao Ying-Li , Chang Tsong H , Hunis Brian , Astrow Alan 
Published: April 2020

Abstract
GATA-1 is important in megakaryocytopoiesis, and the fact that GATA-1low mice eventually develop myelofibrosis indicates that GATA-1 is important in the pathogenesis of idiopathic myelofibrosis (IMF). Previous study has shown that GATA-1 levels were lower in protein content in CD61+ cells of patients with IMF (Vannucci et al., Am J Pathol 167:849 2005). But the study was done with pooled protein from only three patients. We used ELISA assay (GATA-1 ELISA kit, Panomics, CA) to assay the protein content from nuclear extracts of blood hematopoietic progenitor cells (CD34+cells) and megakaryocytes (CD61+ cells) from patients with IMF and compared the results with those of patients with other myeloproliferative disorders and with controls. CD 61+ cells were obtained from 10-day cultures of blood CD34+ cells in serum-free culture medium with thrombopoietin and stem cell growth factor as described. The results are shown in Table 1. No statistical difference was found in the GATA-1 content in the nuclear extracts in CD34+ or CD61+ cells. We further analyze the GATA-1 levels in relation to the JAK2 status and significant correlation between the levels of GATA-1 levels and positive JAK2 nutation were found in blood CD34+ cells (p=0.01) and subsignificant in CD61+cells (p=0.08) (Table2) .These preliminary results suggest that GATA-1 protein contents are not altered and higher GATA-1 levels are seen in JAK-2 mutation positive patients with IMF.
Table 1. GATA-1 Levels in Patients with IMF and others IMF MPD Controls GATA-1 Levels: mean± SE of ng/2μg protein; n: numbers of patients CD34+ cells 27.58±3.2 (n=9) 30.57±5.4 (n=4) 28.06±2.9 (n=7) CD61+ cells 58.99±11.53 (n=8) 38.64±18.2(n=4) 41.03±11.3 (n=6) Table 2. Correlation between GATA-1 Levels and JAK2 Status in Patients with IMF JAK2 mutation Positive JAK2 mutation Negative P Value GATA-1 Levels: mean±SE(ng/2μg protein): n: numbers of patients CD34 + cells 35.6±3.4 (n=4) 21.1±2.7(n=5) 0.01 CD61+ cells 73.7±13.0(n=4) 43.8±13.7(n=5) 0.08
JAK2 V617F Mutation in Essential Thrombocythemia.
Authors: Ahn Jeong Yeal , Park Pil Whan , Seo Yiel Hea , Shin Dong-Bok , Lee Jae-Hoon , Yoo Soo-Jin , Bang Soo-Mee 
Published: April 2020

Abstract
Background: Essential thrombocythemia (ET) is thought to reflect transformation of a multipotent hematopoietic stem cell, but its molecular pathogenesis has remained obscure. But tyrosine kinase, especially Janus kinase 2 (JAK2) has been implicated in myeloproliferative disorders other than chronic myeloid leukemia. We investigated the incidence and its correlation with other clinicopathologic variables of JAK2 mutation in patients with ET and reactive thrombocytosis (RT).
Method: JAK2 mutation analysis, using allele-specific polymerase chain reaction, was undertaken on genomic DNA from bone marrow aspirates of 24 patients with ET and peripheral blood in 36 patients with RT.
Results: JAK2 mutation was detected in 11 patients (46%) among the 24 patients with ET and was not found in 36 patients with RT. In patients with ET, older age and leukocytosis were related with JAK2 mutation without statistical significance (p=0.172 and 0.094, respectively). But this mutation was not correlated with sex, hemoglobin, platelet count, splenomegaly, increased cellularity of bone marrow, bone marrow fibrosis and vascular complications.
Conclusions: The current observation strengthens the specific association between JAK2 mutation and ET. At the diagnosis of ET, identification of JAK2 mutation should be incorporated in foundation for new approaches.
Mcl-1 Promoter Insertions as an Independent Prognostic Factor for Treatment Free Survival in Chronic Lymphocytic Leukaemia.
Authors: Hooper Laura , Delgado Julio , Starczynski Jane , Evans Jason , Pepper Chris , Greenwell Pamela , Fegan Chris , Pratt Guy 
Published: April 2020

Abstract
Mcl-1 (Myeloid cell leukaemia 1) is an anti-apoptotic member of the Bcl-2 family of proteins and is known to be important in the biology of Chronic Lymphocytic Leukaemia (CLL). A study by Moshynska et al demonstrated that a 6 or 18 nucleotide promoter insertion within the Mcl-1 promoter region influenced clinical outcome in CLL. In this study the presence of the insertion was also associated with high Mcl-1 mRNA and Mcl-1 protein levels. Subsequently there have been a number of published reports showing that these insertions have no impact at all on survival or any role in the pathogenesis of CLL. Using PCR and WAVE analysis, we analysed both the 6–18bp Mcl-1 promoter insertions in a cohort of a 100 CLL patients and 100 normal controls. Mcl-1 promoter insertions occurred at a similar frequency in the control and CLL groups. Mcl-1 promoter insertions did not correlate with any of the established prognostic factors in CLL (CD38 expression, VH mutation status, LDT, Zap 70 and stage), did not correlate with Mcl-1 protein levels and did not influence overall survival (P values &gt;0.05). However Mcl-1 promoter insertions significantly affected treatment free survival (P= 0.002). This result needs confirming in a larger number of patients as it suggests that promoter insertions identify patients that are more likely to require therapy and again raises the question of its role, if any, in CLL pathology.
Chronic Lymphocytic Leukemia (CLL) in Parents and Children.
Authors: Mauro Francesca R. , Ghia Emanuela M. , De Propris Maria S. , Giammartini Elena , Starza Irene Della , Giannarelli Diana , Giudice Ilaria Del , Santangelo Simona , Brugnoletti Fulvia , Gentile Massimo , Guarini Anna , Foa Robert 
Published: April 2020

Abstract
Chronic lymphocytic leukemia (CLL) is the most frequent form of leukemia in which familial aggregation has been observed. The affected relative is usually a sibling and less frequently a child. In the present study we evaluated whether CLL affecting parents and their children was associated with different clinical features, survival, immunoglobulin (Ig) VH genes repertoire and mutation status. The family history of 2% of the CLL patients diagnosed at our institution was characterized by the presence of a parent or a child affected by CLL. Other lymphoproliferative diseases, such as non-Hodgkin lymphoma, Hodgkin disease and acute lymphoid leukemia, affecting parents or children were also recorded in 3% of cases. Among the 17 identified parent/child CLL pairs there was a higher, though not significant, rate of gender concordant pairs than expected. Children were significantly younger at diagnosis than their parents. No significant differences in stage distribution, clinical course, survival and proportion of unmutated cases emerged between the two generations. In no case the parent and the respective child shared an identical IgVH repertoire. However, a significantly higher than expected usage of VH3-23 (p&lt;0.005), VH3-21 (p&lt;0.005), VH5-51 (p=0.001), VH1-18 (p= .90E-04), VH3-30.3 (p&lt;0.005) genes was recorded. Of interest, a VH5-51 gene usage has been also described by other authors in multiaffected families. By flow cytometry and PCR analysis, no clonal lymphocytes were found in the peripheral blood of 38 young healthy (median age: 37 years) relatives included in the third generation of these multiply affected families. This could be explained not only by the relatively small sample of subjects analyzed but also by their relatively younger age compared to that of the healthy individuals analyzed in other series. In conclusion, the coexistence of CLL in parents and offspring is a relatively uncommon event. The differences in the IgVH gene repertoire could reflect a different ontogeny of these cases. Affected children show a significantly earlier, but not a more aggressive clinical course. These data can be used to offer counselling to CLL patients.
Co-Expression of CD38 with Zap-70 Is Predictive of Treatment Intervention in Patients (pts) with Early Stage Chronic Lymphocytic Leukemia (CLL).
Authors: Coignet Jean-Gabriel , Padmanabhan Swaminathan , Manochakian Rami , Miller Kena C. , Wallace Paul , Block AnneMarie , Chanan-Khan Asher Alban 
Published: April 2020

Abstract
Introduction: CLL is a heterogeneous disease where advanced stage pts have compromised survival despite treatment, while early stage pts may not require any intervention. Based on current NCI-WG guidelines, most early stage (Rai stage 0 and 1) CLL pts do not require treatment until the development of progressive or symptomatic disease, though eventually over 70% of CLL pts will receive therapy. Currently, there are no markers to predict this subset of pts. Several markers of adverse prognosis, including ZAP-70+, CD38+, un-mutated IgVH gene and cytogenetic aberrations (17p-, 11q-, +12) have been identified. These markers are primarily studied in context of aggressive clinical course and survival outcome. The value of these markers to predict the necessity of treatment intervention in early stage CLL pts has not yet been completely evaluated. We investigated the expression pattern of Zap-70 and CD38 to examine their predictive value in identifying early stage CLL pts who will require therapeutic intervention.
Methods & Results: 93 CLL pts were evaluated since 2002 at our institution. Flow cytometry was used to determine Zap-70 and CD38 expression on CD19+ CLL cells obtained from peripheral blood. Pts were considered to be positive for Zap-70 and CD38 expression if ≥ 20% and ≥ 30% of the cell stained for these proteins, respectively. For the Zap-70 analysis we used similar methodology as described by Crespo et al.1 Thirty-six (19M, 17F) pts had limited stage CLL, based on Rai staging criterion. Median age was 65 years (range 43–86) with stage 0 or 1 observed in 14 and 22 pts, respectively. Median time from diagnosis is 2 years (range &lt;1–17). Increased expression of either Zap-70 or CD38 was seen in 22 and 7 pts, respectively. Five (14%) pts were positive for both. All (100%) pts with concurrent increased expression of Zap-70 and CD38 required treatment (p=0.003), as compared to 30% of patients requiring treatment that were negative for both proteins or positive for only protein. Among the pts that required treatment 4 had 13q- and one had trisomy 12 on cytogenetic analysis.
Conclusion: Our study, demonstrates for the first time, the clinical utility of CD38 and Zap-70 co-expression in determining the probability of treatment intervention in early stage CLL pts. Although the number of pts studied is small, our findings highlight a potentially important use of these markers in the management of early-stage CLL pts. These observations warrant validation in a larger cohort of pts early stage CLL pts as well as correlation with other prognostic markers such as cytogenetic and IgVH gene mutational status.
Variations in Proteasome Enzymatic Activities in Plasma of Patients with Chronic Lymphocytic Leukemia and Their Value in Predicting Clinical Behavior.
Authors: Ma Wanlong , O’Brien Susan , Jilani Iman , Zhang Xi , Kantarjian Hagop , Estov Zeev , Ferrajoli Alessandra , Keating Michael , Giles Francis , Albitar Maher 
Published: April 2020

Abstract
The ubiquitin-proteasome pathway plays a major role in degrading proteins that regulate important cellular processes including cell cycle regulation, apoptosis, DNA repair, and stress response. Proteasomes have 2 active sites each for 3 different peptidase activities: chymotrypsin-like (Ch-L), trypsin-like (Tr-L), and caspase-like (Cas-L) (postglutamyl peptide hydrolytic-like). Different proteasome inhibitors affect each of the activities differently and at different concentrations. For example, NPI-0052 inhibits Ch-L and Tr-L activities at lower concentrations than does bortezomib, while bortezomib inhibits Cas-L at lower concentrations than does NPI-0052. These enzymatic activities are usually measured in normal or tumor cells to monitor therapy with proteasome inhibitors. We developed fluorogenic kinetic assays using peptide-AMC (7-amino 4-methylcoumoran) substrates to measure Ch-L, Tr-L, and Cas-L activities in peripheral blood plasma rather than cells. This approach allowed us to standardize measurements and express enzymatic activity as pmol AMC/sec/mL plasma. We tested Ch-L, Tr-L, and Cas-L activities in the plasma of 226 patients with chronic lymphocytic leukemia (CLL) and assessed their correlations with clinical behavior. Ch-L, Tr-L, and Cas-L activities were significantly (P &lt;0.001) higher in the plasma of patients with CLL (medians: 1.47, 2.44, and 1.38 pmol AMC/sec/mL, respectively) than in healthy volunteers (n = 42) (medians: 0.80, 0.74, and 0.81 pmol AMC/sec/mL, respectively). Although Ch-L and Cas-L activities did not differ significantly between men and women with CLL, Tr-L activity was significantly higher in women (P = 0.01). Rai stage correlated with Ch-L (P &lt;0.001) but not Cas-L or Tr-L activity. Only Ch-L activity correlated with WBC count (P &lt;0.001). β2-microglobulin levels correlated strongly with Ch-L activity (R=0.40, P &lt;0.001) and weakly with Cas-L activity (R=0.25, P = 0.001) but not with Tr-L activity. Ch-L and Cas-L activities were both strong and independent predictor of survival when examined as continuous variables (P=0.02 for both), as well as when the median was used as a cut-off point (P =0.02 and P=0.03, respectively). Both Ch-L and Cas-L activities were independent of β2-microglobulin in predicting survival, but both correlated with each other and were not independent of each other in predicting survival. There was no correlation between Tr-L activity and survival. These data suggest not only that proteasome activity as measured in the plasma of patients with CLL has important prognostic value, but also that CLL patients may benefit from proteasome inhibition therapy that specifically targets Ch-L or Cas-L activities.
Comparison of a Quantitative PCR Method with FISH for the Assessment of the Four Aneuploïdies Commonly Evaluated in CLL Patients.
Authors: Bastard Christian , Fruchart Christophe , Raux Gregory , Parmentier Francoise , Vaur Dominique , Tilly Herve 
Published: April 2020

Abstract
Four chromosomal defects associated with prognosis have been identified in CLL patients, namely deletions of the 13q13-q14, 11q22 and 17p13 regions and trisomy 12. Due to the low proliferation index of these tumors and to the fact that some defects can be cryptic, the detection of these abnormalities by conventional cytogenetics is difficult. Therefore, the resulting aneuploidies are usually evaluated by fluorescent in situ hybridisation (FISH). As probes are expensive and FISH time consuming, we aimed to compare a quantitative PCR method - quantitative PCR of short fluorescent fragments (QMPSF) - with FISH for the detection of these acquired aneuploidies in a series of 110 patients with Binet stage A CLL. Genes located in the deleted or gained regions were selected as target genes - DLEU2 at 13q14, ATM at 11q22, p53 at 17p13, POU6F1 and MDM2 at 12q13 and 12q15 respectively - and amplified using a method based on the simultaneous amplification of short fluorescent genomic fragments under quantitative conditions. A chromosomal imbalance involving one or several of the four loci was detected in 76 patients (69%) either by FISH or QMPSF or both. A deletion of chromosome 13 was found in 61 patients (55%). A 11q22 deletion was present in 9 patients (8%), a trisomy 12 in 9 (8%) and a 17p deletion in one. The rather low frequency of the three latter defects reflects the fact that only patients with stage A CLL at diagnosis were studied, and neither stage B or C CLL. The 13q deletion was isolated in 53 patients and associated with a second defect in 8: these were six of the 11q22 deletions, one trisomy 12 and the 17p deletion. When the 13q deletion was associated with either a 11q deletion or a trisomy 12 both abnormalities were present in the same proportion of cells. This was not the case for the 17p deletion which appeared to be a secondary event, since, as evaluated by FISH, it was present in 24% of cells whereas the 13q deletion was present in 85% of interphase nuclei. FISH and QMPSF results were identical for 103 of 110 patients. The secondary 17p deletion was not detected whereas all other discrepancies could be explained. This study demonstrates that a single multiplex PCR can replace FISH in CLL patients. However, whereas QMPSF is perfectly adapted to the detection of primary defects, care should be taken when searching for minor clonal evolutions present in a small proportion of tumor cells.
CD200 Is a New Prognostic Factor in Multiple Myeloma.
Authors: Moreaux Jerome , Hose Dirk , Reme Thierry X. , Jourdan Eric , Hundemer Michael , Eric Legouffe , Moine Philippe , Bourin Philippe , Moos Marion , Corre Jill , Mölher Thomas , DeVos John , Rossi Jean-Francois , Goldschmidt Hartmut , Klein Bernard 
Published: April 2020

Abstract
Using Affymetrix microarrays, we identified the expression of the CD200 gene in multiple myeloma cells (MMC) of 112 patients with newly-diagnosed multiple myeloma (MM). The CD200 gene was either absent or present (Affymetrix call) in 22% and 78% of MMC, respectively. CD200 was not expressed by CD14 monocytes, CD15 polynuclear cells and CD3 T cells that were purified from the bone marrow of 5 newly-diagnosed patients. It is also not expressed in 7 osteoclast samples. BM stromal cells from 5 patients with MM expressed CD200, but at a 3.9 fold lower median signal compared to that in CD200present MMC (P = .04). CD200 is a membrane glycoprotein that imparts an immunoregulatory signal through CD200R, leading to the suppression of T-cell-mediated immune responses. Patients with CD200absent MMC have an increased event free survival (24 months) compared to patients with CD200present MMC (14 months), after high-dose therapy and stem cell transplantation. In a Cox-proportional-hazard model, the absence or presence of CD200 expression in MMC is predictive for EFS for patients independently of ISS stage or B2M serum levels. Thus, CD200 is an independent prognosis factor for patients with MM that could represent a new therapeutic target in MM.
The Small-Molecule VEGF-Receptor Inhibitor Pazopanib (GW786034B) Targets Both Tumor and Endothelial Cells in Multiple Myeloma.
Authors: Podar Klaus , Tonon Giovanni , Sattler Martin , Tai Yu-Tzu , LeGouill Steven , Yasui Hiroshi , Ishitsuka Kenji , Kumar Rakesh , Pandite Lini N. , Hideshima Teru , Chauhan Dharminder , Anderson Kenneth C. 
Published: April 2020

Abstract
A critical role for vascular endothelial factor (VEGF) has been demonstrated in multiple myeloma (MM) pathogenesis. Here we characterized the effect of the novel and potent small-molecule VEGF-receptor inhibitor pazopanib on MM cells in the bone marrow milieu. Pazopanib inhibits VEGF-triggered signaling pathways in both tumor and endothelial cells, thereby blocking in vitro MM cell growth, survival, and migration; and inhibits VEGF-induced upregulation of adhesion molecules on both endothelial and tumor cells, thereby abrogating endothelial cell-MM cell binding and associated cell proliferation. We show that pazopanib is the first-in-class VEGF-receptor inhibitor to inhibit in vivo tumor cell growth associated with increased MM cell apoptosis, decreased angiogenesis, and prolonged survival in a mouse xenograft model of human MM. Low-dose pazopanib demonstrates synergistic cytotoxicity with conventional (melphalan) and novel (bortezomib, immunomodulatory drugs) therapies. Finally, gene expression and signaling network analysis show transcriptional changes of several cancer-related genes, in particular cMyc. Using siRNA, we confirm the role of cMyc in VEGF-production and -secretion, as well as angiogenesis. These preclinical studies provide the rationale for clinical evaluation of pazopanib, alone and in combination with conventional and novel therapies, to increase efficacy, overcome drug resistance, reduce toxicity, and improve patient outcome in MM.
Predictive Factors of Early Mortality in Patients with Multiple Myeloma (MM). Multicentric Study in Chile (1998–2002).
Authors: Conte Guillermo F. , Figueroa Gaston L. , Lois Vivianne I. , Cabrera Maria E. , Leon Alvaro R. , Garcia Hernan L. , Rojas Hernan H. 
Published: April 2020

Abstract
There is no data about the prognosis of patients with MM in Chile, except mortality rate records. The objective of this study is to know the clinical features, survival rates and factors related to early mortality of cases with MM treated in six large medical centers in Chile.
Method: Retrospective demographic data, clinical features and survival rate records of patients with MM were collected between 1998 and 2002. Survival curves were generated and a multivariate analysis of factors associated to early mortality was carried out.
Results: Data of 245 patients was collected. A 51.8% of them corresponded to IgG myeloma, 25.3% to IgA and a 6.1% to light chains. Distribution according Durie and Salmon was: Stage I: 8.1%; Stage II: 12.7%; Stage III: 60.7% and 18.4% without information. It is pointed out that, among clinical features, a 50% of the cases presented anemia (Hb &lt;10gr/dL), a 30% renal failure (creatininemia &gt;2 mg/dL) and a 28% hypercalcemia (&gt;10.5 mg/dL). The median survival was 33 months. A 20% of patients died within the six first months after diagnosis. The multivariate analysis identified three factors associated to early mortality (survival &lt;6 months): males (p=0.016), beta2-microglobulin &gt;3.5 mg/L (p=0.021) and albuminemia &lt; 3.5 gr/dL (p=0.016).
Conclusions: It was observed that, in Chilean population, patients with MM presented a short survival time, and a significative proportion of patients (20%) died within the first six months after the first diagnosis. More than a half of cases were diagnosed at an advanced stage. (Durie and Salmon: Stage III). Three factors associated to early mortality, two of which (beta2-microglobulin and albuminemia) are the foundations of the new international staging system, might be identified.