bluuebunny/crossref_metadata_2025_split huggingface dataset:
RH Gene Polymorphisms Are Risk Factor for Alloimmunization in Patients with Sickle Cell Disease.
Authors: Westhoff Connie M. , Vege Sunitha 
Published: November 2019

Abstract
Transfusion therapy for treatment of sickle cell disease (SCD) is predicted to increase, following the significant benefit of chronic red cell transfusion demonstrated by the stroke prevention trial (STOP). Despite progress in mitigating negative effects of transfusion therapy with the use of iron chelating agents, alloimmunization remains a significant problem. Patients with SCD have a higher incidence of antibody production compared to other patient groups undergoing chronic transfusion. To limit alloimmunization, many programs transfuse SCD patients with RBCs that are phenotype-matched for the most immunogenic blood groups, Rh and K, and some programs also supply RBCs from African-American (AA) donors. Although this approach reduces the incidence of alloantibody production, it is resource- and cost-prohibitive for many programs, and, importantly, some patients (∼5%) still become alloimmunized. The development of high-throughput genotyping for blood group antigens will make antigen-matching cost effective; therefore, it is important to determine why some patients become alloimmunized despite antigen-matching. We investigated the antibody specificity and sequenced the RH genes in 46 SCD patients who were alloimmunized, despite having received Rh and K matched units. The antibodies identified included anti-D, or -C, or -e, and/or antibodies to high-prevalence antigens. None had anti-E. RH gene sequencing revealed that 20 patients had a RHD-CE(3–7)-D hybrid gene in which RHD exons 3 through 7 are replaced with reciprocal exons from RHCE. The resulting Rh protein encodes an altered C antigen. This D-CE-D gene was also linked to an RHce allele encoding altered e antigen. These patients had anti-C and/or anti-e in their serum (i.e.-hrB). We screened healthy AA donors and found that the prevalence of the hybrid RHD-CE(3–7)-D gene in this population is 5–8%. The remaining 26 patients were homozygous for mutations in RHce and had produced anti-e, and some also had mutations in RHD and had produced anti-D. These results suggest that inheritance of a RHD-CE-D gene or altered RHce, with or without altered RHD, underlies Rh alloimmunization in SCD. The altered Rh proteins are not distinguished with current serologic typing reagents. Therefore, these patients are not truly Rh antigen matched. The development of RH genotyping platforms offers a potential solution to prevent alloimmunization by identifying SCD patients who are homozygous for variant alleles and at risk for production of alloantibodies to Rh antigens. The 5–8% of donor units with the same RH genotype could be directed to these high risk patients.
Analysis of JAK2 V167F Mutation in Myelodysplastic Syndromes.
Authors: Fermo Elisa , Zaninoni Anna , Imperiali Francesca G. , Bianchi Paola , Colombi Mariangela , Barcellini Wilma , Zanella Alberto 
Published: November 2019

Abstract
The somatic mutation JAK2 V617F has been identified as a pathogenic factor in typical chronic myeloproliferative diseases (MPD) such as polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis with myeloid metaplasia (MMF). In typical forms of myelodysplastic syndromes (MDS), JAK2 V617F mutation is rarely present (2–5%); on the contrary, it has been found with higher prevalence in patients with RARS-T (i.e. MDS/MPD-U with platelet count >600×109/L and ringed sideroblasts more than 15%) and in a subgroup of MDS patients with isolated 5q deletion and a proliferative bone marrow. In this study we analysed the JAK2 V617F mutational status in 53 MDS patients (26 males, 27 females; median age at the time of the study 76 years, range 45–91). Patients were classified as follows: 4 cases 5q- syndrome, 3 RCMD, 5 MDS/MPD, 1 MDS-U, 23 RA, 12 RARS, 5 RAEB. DNA was extracted from purified granulocytes; all samples were analyzed by allele-specific polymerase chain reaction (PCR), according to Baxter el al (2005). DNA samples were further subjected to direct sequencing for confirmatory testing. The JAK2 V617F mutation was present in 3 cases, with an overall frequency of 5%. With respect to MDS subtype, 1 patient had RA and 2 RARS. Among the 12 RARS patients, the two V617F postive displayed thrombocytosis (680×109/L and 649×109/L), whereas none of the 10 RARS V617F negative patients showed high platelet counts (median Plt 157×109/L, range 5–422×109/L). In one JAK2 mutant case, thrombocytosis required treatment with hydroxyurea. Moreover, the two V617F positive RARS patients displayed higher WBC count (6.2×109/L and 8.5×109/L) than the V617F negatives (median WBC 4.05×109/L); no difference was observed in Hb levels. The JAK2 positive RA patient had 10% of sideroblasts in bone marrow, normal platelet and WBC count and no proliferative characteristics; since the occurrence of the mutation may be an early event and preceed the classical manifestations of MDS/MPD, a longer follow-up is necessary to determine its possible prognostic significance. Considering the V617F negative MDS cases, only one patient, diagnosed as MDS/MPD, showed a platelet count >600×109/L. In conclusion, we confirmed recent reports showing that JAK2 V617F is present with low prevalence (about 5%) in MDS; in particular, the JAK2 mutation identifies a subset of MDS patients with and “overlap” syndrome, characterised by proliferative bone marrow morphology and frequent thrombocytosis and leucocytosis, who may benefit from JAK2 specifically targeted therapies.
Copper and Iron Status in Myelodysplastic Syndromes.
Authors: Saouli Zoi , Kontoninas Zisis , Girtovitis Fotios , Kaiafa Georgia , Ntaios George , Andreadis Charalambos , Tsoukali Helen , Haztitolios Apostolos , Papadopoulos Athanasios 
Published: November 2019

Abstract
Introduction: Copper is an essential mineral found in many tissues. It is involved in iron incorporation into hemoglobin, hemolytic syndromes, while copper deficiency provokes iron overload and induces dysplastic changes to erythrocytes. On the other hand, there are references that iron overload can result in mild copper deficiency. There seems to be equivocal relationship between these two elements.
Aim: The aim of this study is to determine copper and iron status in myelodysplastic patients and to investigate if copper deficiency correlates with the type of myelodysplastic syndrome.
Materials and methods: We studied 52 patients with myelodysplastic syndrome, 29 men and 23 women(mean age 67,05± years). No other simultaneous disease was confirmed which could contribute to copper disorders. Patients were categorized in two groups. Group A, composed of 21 patients frequently transfused(approximately once monthly), suffering from RAEB, RAEB-t AND CMML. Group B included 31 patients, who either didn’t often need transfusion, or responded to erythropoietin, suffering from RA and RARS. Copper, iron and ferritin levels measurments were performed. Copper was measured by flame atomic absorption spectrometry (normal range: 0,8–1,3mg/l).
Results:
Nine patients of group A revealed copper deficiency(mean value 0,66±0,06mg/L). Mean copper value was 0,8±0,11mg/L for that group. All of them had elevated iron levels (average:602,23±160,46μg/dl) and high ferritin levels(average:1769±693,85ng/ml) All group B patients were found to have normal copper levels(Mean value was 1,15±0,09), indicating a statistically significant difference compared to group A patients(p<0,0001). Iron and ferritin levels were within normal range(average105,22±28,63 and 82,9±28,42 respectively)
Conclusions: Copper levels, in multitransfused patients with poor prognosis myelodysplastic syndrome and iron overload, are significantly lower than in oligotransfused ones with good prognosis who consequently present normal iron burden.
Circulating Dendritic Cells of the Patients with Myelodysplastic Syndromes.
Authors: Shao Zonghong , Wang Huaquan , Xing Limin , Fu Rong , Tu Fengmei 
Published: November 2019

Abstract
Objective To investigate the quantity, subsets of dendritic cells(DC) and costimulatory molecule expression in peripheral blood(PB) of the patients with myelodysplastic syndromes(MDS).
Methods Total DC(Lin1+HLA-DR+), myeloid DC(mDC) (Lin1+HLA-DR+ CD11c+) and plasma DC(Lin1+HLA-DR+CD123+) in fresh whole PB samples of 38 MDS patients and 19 normal controls were assayed with flow cytometer and the monoclonal antibodies. The expression of CD80, CD86 and CD40, the costimulatory molecules on these DC were also assayed in the same way.
Results. Total DC in PB of MDS patients was more than that of normal controls significantly [(41.4±10.9)×106/L vs (12.1±1.4)×106/L](P<0.05). mDC in PB of MDS patients was more than that of normal controls too [(20.8±7.2)×106/L vs (5.5±0.9)×106/L](P<0.05). pDC in PB of MDS patients was not significantly more than that of normal controls [(9.5±2.8)×106/L vs (6.6±0.7)×106/L] (P>0.05). The percentage of total DC in PB mononuclear cells(PBMNC) of MDS patients was higher than that of normal controls[(2.78±0.59)% vs (0.68±0.08)%](P<0.05). The percentage of mDC in PBMNC of MDS cases was also higher than that of normal controls[(1.15±0.33)% vs (0.32±0.05)%](P<0.05). The percentage of pDC in PBMNC of MDS cases was not significantly higher than that of normal controls[(0.64±0.19)% vs (0.37±0.04)%](P>0.05).
Conclusion DC, mainly mDC, increased significantly in MDS, but pDC did not. The costimulatory molecules(CD80 and CD86) except CD40 expressed more on the DC of MDS patients. It was suggested that the APC relating the inflammatory injury increased in MDS, but the APC relating to antitumour immunity did not. What we found here might be involved into the pathogenesis of MDS.
Activation of Nuclear Factor KappaB in ETV6/FLT3-Transformed Ba/F3 Cells Depends on the FLT3 Tyrosine 591.
Authors: Vu Hoang Anh , Xinh Phan Thi , Kano Yasuhiko , Ishida Takaomi , Watanabe Toshiki , Tokunaga Katsushi , Sato Yuko 
Published: November 2019

Abstract
The FLT3 gene is one of the most frequently mutated genes in hematologic malignancies. Mutated FLT3 has been found to lead to strong constitutive activation of several signaling proteins such as STAT5, CBL, VAV, SHP2, NF-kB, and AKT. Recently, we have reported that FLT3 contributed to leukemogenesis through generating a ETV6/FLT3 fusion gene in a patient with myeloproliferative disorder and a t(12;13)(p13;q12) translocation, which is the first report to show that FLT3 fusion gene can be involved in leukemogenesis. The ETV6/FLT3 which contained the helix-loop-helix oligomerization domain of ETV6 fused to the juxtamembrane (JM) domain plus tyrosine kinase (TK) domains of FLT3, conferred interleukin-3-independent growth on Ba/F3 cells (Vu HA, et al. LEUKEMIA20:1414–21, 2006). To assess a role of the JM domain of FLT3 in the ETV6/FLT3 protein, we generated a series of ETV6/FLT3 mutants (tyrosine to phenylalanine substitution and deletion of the JM domain or N-terminal region of the TK1 domain). Each mutant was introduced into Ba/F3 cells and downstream signaling as well as cell proliferation was investigated. We found that the wild-type ETV6/FLT3 in Ba/F3 cells was a constitutively activated tyrosine kinase that led to activation of STAT5, AKT, MAPK, and NF-kB pathways as well as up-regulation of PIM-1. Deletion of the JM domain retained compatible level of autophosphorylation of the fusion protein as well as activation of STAT5, AKT and MAPK, suggesting that the JM domain is dispensable for STAT5, MAPK and AKT activations. In contrast, deletion of the JM domain did abrogate interleukin-3-independent growth of Ba/F3 cells, PIM-1 up-regulation, and activation of NF-kB. Importantly, while substitutions of other 3 tyrosines (589, 597, and 599) had no affect on NF-kB activation, the substitution of tyrosine 591 to phenylalanine abrogated this activation. Our results suggest that the tyrosine 591 in JM domain of FLT3 in ETV6/FLT3 is critical for NF-kB activation to support cell survival and PIM-1 up-regulation.
p53 in B Cell Chronic Lymphocytic Leukemia (CLL) and Lymphoma with Peripheral Blood Expression along Treatment with Fludarabine and Other Treatment Regimens.
Authors: Barragan Carlos Sergio , Hansson Silvia B. , Cicchini Silvina A. , Tamashiro Monica , Dinardi Pablo G. 
Published: November 2019

Abstract
Objective: To determine the expression of mutated p53 at diagnosis, along the treatment and after relapse and correlation itself with rapid disease progression. Mutated p53 was established as marker of disease progression and poor prognosis. Fludarabine is one of the standard treatments for both diseases despite the fact that it promotes p53 gene subset activating apoptosis system.
Patients Materials and method: Forty four patients were enrolled throughout two years. They were studied before, along and after treatment with immunocytochemistry for establishing the frequency of mutated p53 protein. The treatment regimens given were CHOP, one patients with Anaplastic B large cell Lymphoma; CHOP-R (Rituximab tm), one Mantle cell Lymphoma and one B Diffuse Large cell Lymphoma and Cyclophosfamide + Fludarabine oral 20 CLL patient. One patient had a follicular Lymphoma and undergo Autologous Bone Marrow transplantation (ABMT). Other prognosis markers were analyzed, such as p38 and zap 70.
Results: We detected twelve positive cases, two of them CLL both were first negative and then became positive; one spontaneously and the other after second line treatment with fludarabine and relapse. Seven patients with CLL were positive at diagnosis. Three positive p53 patients with Lymphoma, one of them HIV-AIDS the other after ABMT had a rapid progression and promptly died. All the patients with CLL are still alive two of them, the younger patients have a fast duplication of cellular counts and tumor burden.
Conclusion: It is necesary more cases to assert that p53 alone at diagnosis predict bad evolution at least in older patients with CLL who in our experience had a good development, otherwise all the Lymphoma patients and CLL after treatment p53 + had a worts outcome.
Malignant B Cells from Hairy Cell Leukemia Express an Innate Phenotype and Undergo IgD Class Switching in Response to Innate Environmental Factors, Including BAFF and APRIL.
Authors: Chiu April , Chen Kang , He Bing , Dillon Stacey , Chadburn Amy , Knowles Daniel M. , Xu Weifeng , Cerutti Andrea 
Published: November 2019

Abstract
Hairy cell leukemia (HCL) is a rare chronic lymphoproliferative disorder characterized by massive infiltration of the spleen by malignant B cells displaying a distinctive “hairy” morphology. These hairy cells (HCs) often contain hypermutated Ig genes, suggesting an ontogenetic relationship with post-germinal center memory B cells. However, unlike memory B cells, HCs usually express CD11c and CD103, two molecules typically associated with mucosal innate immune cells. The goal of this study was to elucidate the ontogeny and growth mechanisms of HCs. We found that HCs interacted with splenic endothelial cells expressing B cell-activating factor of the TNF family (BAFF) and a proliferation-inducing ligand (APRIL), two innate B cell-stimulating factors involved in T cell-independent antibody responses, including Ig class switching. In agreement with prior studies indicating that BAFF and APRIL play an important role in B cell tumors, HCs expressed transmembrane activator and calcium modulator and cyclophylin ligand interactor (TACI), B cell maturation antigen (BCMA), and BAFF receptor (BAFF-R), three receptors that bind BAFF and APRIL. In addition, HCs expressed microbial carbohydrate and endocytic receptors usually expressed by innate immune cells, including DEC-205 (CD205), mannose receptor (CD206), langerin (CD207) and dendritic cell-specific ICAM-3-grabbing non-integrin (CD209). This phenotype was different from that of naïve, germinal center, memory and plasmacytoid B cells, but similar to that of a subset of splenic marginal zone and mucosal B cells. Like these innate B cells, HCs contained activation-induced cytidine deaminase, a DNA-editing enzyme required for class switching, and showed signs of ongoing IgM-to-IgD class switching, a mucosal Ig diversifying process typically triggered by BAFF and APRIL. Our findings suggest that HCL may emerge as a result of chronic stimulation of an innate B cell precursor through a T-cell independent pathway involving microbial carbohydrates, BAFF and APRIL.
A Retrospective Analysis of Response to High Dose Rituximab Monotherapy in CLL/NHL Patients Who Received Prior Standard Dose Rituximab Therapy.
Authors: Moffa Casey A. , Thatikonda Chandana , Pathe Neeta , Rossetti James M. , Shadduck Richard K. , Lister John 
Published: November 2019

Abstract
Background: Rituximab at standard dose (375 mg/m2) in combination with chemotherapy has been used to treat CLL and NHL. We retrospectively evaluated the response and toxicity of high dose rituximab (HDR) (500 mg/m2 thrice weekly for 2 weeks, total dose 3 gm/m2) in patients with CLL or NHL, who had received prior treatment with standard rituximab as either monotherapy or in combination chemotherapy, to determine if there was a dose response relationship.
Methods: Eight patients with either CLL or NHL who had received HDR therapy were evaluated. Patients received HDR because they refused conventional treatment or failed to respond to prior combination chemotherapy. Seven of the patients had prior combination therapy, whereas 1 had received standard dose rituximab alone. Response to HDR was evaluated based upon absolute lymphocyte count approximately 21 days after the final treatment in CLL patients and PET/CT scan after the final treatment for NHL.
Results: Mean age at treatment: 70 yrs (range = 57–83), males (n=7) and female (n=1), CLL (n=5) and NHL (n=3). One patient with CLL had Richter’s transformation. Patients received prior treatments with rituxan alone (n=1), combination therapy for CLL with FCR, FR or PCR (n=5) or combination therapy for NHL with hyperCVAD-R, CHOP-R or RICE (n=2). Of the 5 patients with CLL treated with HDR, 3 achieved partial remission (PR) while the remaining 2 patients developed progressive disease. Complete remission, however, could not be assessed secondary to lack of a post treatment bone marrow biopsy. All 3 patients with NHL developed progressive disease. One patient developed rigors during the infusion of HDR requiring IV steroids. No infusion was stopped secondary to toxicity.
Conclusions: Based upon our findings, HDR was active in patients with relapsed CLL but not in relapsed NHL. Further exploration of this dose-response relationship is warranted in patients with CLL.
Epidemiology of Plasma Cell Disorders in a General Hospital: A Retrospective Study of 102 Patients.
Authors: Ricca Irene , Tamponi Giacomo , Arnò Celeste , Bosio Angelo , Cerrato Flavio , Coggiola Marisa , Epifani Giuseppe , Giacometto Fiorella , Monaco Gabriele , Pallisco Ottavio , Scalabrino Elisa , Varvello Loris , Raucci Carlo A. , Salomone Attilio , Pascale Claudio 
Published: November 2019

Abstract
INTRODUCTION Plasma cell disorders are a group of diseases characterized by the proliferation of a plasma cell clone which produces a monoclonal protein (M protein). The most common type is Monoclonal Gammopathies of Undetermined Significance (MGUS), followed by multiple myeloma (MM) and Waldenstrom’s Macroglobulinemia (WM). In particular, the frequency of MGUS increases with age and its rate of progression is approximately 1% per year. Because of the high prevalence and the different fields of clinical practice in which these patients are followed, it could be of great interest to know the epidemiology of these diseases out of the Hematology Units.
AIM OF THE STUDY to describe the frequency and the progression risk of plasma cell disorders in a General Hospital during more than a twenty-year period.
METHODS We retrospectively reviewed the medical records of patients with diagnosis of MGUS, MM or WM seen at our center from 1984 through 2006. Statistical analysis were performed using GraphPad Prism 4 (GraphPad Software, Inc.).
RESULTS The study included 102 patients: 78 affected by MGUS (76%), 14 by MM (14%) and 10 by WM (10%). Patients’ clinical features are summarized in the Table. Median follow-up was 48 months (range:12–280). Among the 89 patients with a first diagnosis of MGUS, malignant transformation occurred in 11 patients (7 MM and 4 WM). The median time from diagnosis of MGUS to diagnosis of a lymphoplasma cell proliferative disorder was 60 months (range 12–196). Median time to progression (TTP) was 167 months, as shown in Figure. The cumulative probability of progression was 13.5% at 5 years and 29.2% at 10 years. The amount of serum M protein at diagnosis was a significant predictor of progression.
CONCLUSIONS MGUS are very common in clinical practice, accounting in our study for more than 75% of plasma cell disorders. The premalignant nature of this condition is comfirmed by the rate of transformation in lymphoplasma cell proliferative disorders (50% of MM and 40% of WM, in this study). Even if our results may be biased by the short follow-up period, the only significant predictor of progression was the size of serum M protein at presentation.
Table: Patients’ characteristics Characteristics MGUS MM WM Gender male/female 41/37 4/10 7/3 Age at diagnosis median (range) 69 yrs (30–91) 72 yrs (51–90) 75 yrs (67–85) Serum M protein median (range) 1.26 g/dl (0.17–2.92) 3.85 g/dl (0.62–8.10) 3.20 g/dl (2.22–4.9) Isotype IgG 46 8 - IgA 14 6 - IgM 15 - 10 biclonal 3 - - Immunoparesis yes/no 20/58 14/0 10/0 BJ proteinuria pos/neg 11/67 11/3 1/9 Figure Figure
New Zealand (NZ) Pacific Peoples and Maori Have a Higher Risk of Developing Multiple Myeloma Than Other New Zealanders.
Authors: Phillips Julia K. , Purdie Gordon L. 
Published: November 2019

Abstract
The incidence of multiple myeloma shows ethnic variation, myeloma age-standardized incidence being higher in African Americans at 11.3 per 100,000 than White Americans in whom the incidence is 5.1 per 100,000 (standardized to US 2000 census population)[Ries et al (2007) http://seer.cancer.gov/csr/1975_2004/]. NZ has a number of ethnic minorities, which includes Maori and Pacific peoples. New diagnoses of multiple myeloma in NZ are reported to a national cancer registry. Since 1994 this has been a legal requirement. We examined data from the cancer registry for 1996 to 2004 to establish the relative incidence of multiple myeloma in NZ ethnic groups. During this period ICD-9 (multiple myeloma and immunoproliferative neoplasms) was used for coding until 2000 when it was replaced by ICD-10 (multiple myeloma and malignant plasma cell neoplasms). Between 1996 and 2004 there were 2101 myeloma registrations. Median age was between 70 and 75yrs. M:F ratio was 1.3. Maori accounted for 160 patients (7.6%), Pacific peoples 81 (3.8%). Mean age-standardized annual incidence rates per 100,000 and 95% confidence intervals (WHO world standard population (WSP)) for the 9 year period were as follows:-
All Male Female Maori 6.4 (5.4–7.6) 7.9 (6.3–9.8) 4.9 (3.8–6.3) Pacific Peoples 8.4 (6.6–10.8) 10.9 (7.8–15.2) 6.0 (4.3–8.4) Non-Maori, non-Pacific 4.4 (4.2–4.6) 5.4 (5.1–5.7) 3.4 (3.1–3.6) All ethnicities 4.6 (4.4–4.8) 5.7 (5.4–6.0) 3.6 (3.3–3.8)
The population adjusted incidence of multiple myeloma was significantly higher in Pacific peoples (ratio 1.93 (95% CI 1.50–2.48)) and Maori (ratio 1.46 (95% CI 1.23–1.74)) than in the non Maori, non Pacific population.
Conclusion: The overall incidence of myeloma in NZ (4.6 per 100,000, 95%CI 4.4–4.8 WSP) is higher than that reported for a UK population (3.3 per 100,000 WSP) [Phekoo et al (2004) Brit J Haem 127:299]. The incidence of myeloma in NZ Pacific peoples is especially high at 8.4 per 100,000. The incidence of myeloma in NZ Maori at 6.4 per 100,000 is intermediate between that of the NZ non Maori, non Pacific population and that of Pacific peoples.