bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prospective Evaluation of the Prevalence of Elevated Tricuspid Regurgitant Jet Velocity and Associated Clinical and Echocardiographic Factors in Children and Adolescents with Sickle Cell Disease.
Authors: Campbell Andrew D. , Minniti Caterina , Sable Craig , Ensing Greg , Dham Niti , Rana Sohail , Darbari D. , Onyekwere Onyinye , Kato Greg J. , Gladwin Mark T. , Castro Oswaldo , Gordeuk Victor 
Published: October 2019

Abstract
Background: Echocardiography (ECHO)-determined tricuspid regurgitation jet velocity (TRV) ≥2.5 m/s occurs in about 30% of adults with sickle cell disease(SCD)and is associated with increased mortality. The frequency and significance of high TRV in children is not known. We determined the prevalence and risk factors of elevated estimated systolic pulmonary artery pressures in 228 patients with SCD and 39 controls.
Methods: Patients with SCD (Hb SS, SC, SB thalassemia or other major sickling phenotypes) aged 3 to 20 years were evaluated clinically and with ECHO and six minute walk tests at their steady state. Healthy, non-SCD controls, matched for ethnicity, sex and age, were also evaluated.
Results: A comparison of patients and controls is summarized in Table 1. 184 patients (81%) had hemoglobin SS phenotype and 28 (12%) had hemoglobin SC. TRV was measurable in 214 (94%) of the patients and 34 (87%) of the controls. In a multivariate logistic regression model, each 10 mm Hg increase in systolic blood pressure was associated with an estimated 2.0-fold increase in the odds of TRV≥2.5 m/sec (P = 0.002) and a 10-fold increase in LDH with a 25-fold increase in the odds (P = 0.015).
Conclusion: This study of children with SCD who have limited iron overload and limited renal dysfunction compared with the aging SCD population provides a unique window into the early pathogenesis of PH in SCD. TRV and LVMI are significantly higher in children and adolescents with SCD at steady state than age-matched control participants. Among children with SCD, TRV elevation is independently associated with systolic BP and LDH concentration. In this analysis we find a strong association with hemolysis and systemic hypertension and surprisingly no associations with vaso-occlusive events or biomarkers (VOC, ACS, HU use, WBC and platelet counts).
Table I. Comparison of SCD and control subjects. Results in mean (SD) unless otherwise stated. SCD(n=228) Control (n=39) p Age in years 12 (5) 12 (5) 0.7 Female (%) 48% 46% 0.8 Systolic BP (mm Hg) 112 (11) 116 (15) 0.1 Diastolic BP (mm Hg) 64 (9) 68 (10) 0.040 Six minute walk in meters 454 (76) 498 (84) 0.006 TRV in m/sec 2.3 (0.3) 2.1 (0.3) 0.003 TRV 2.5 m/sec (%) 21% 3% 0.012 LV intern. diastolic diam Z-score 1.2(1.4) −0.3(1.2) <0.001 LV mass index 88 (25) 59 (13) <0.001 Table II. Comparison of SCD patients according to TRV category. Results in mean (SD) unless otherwise stated. Variables TRV <2.5 (n= 169) TRV ≥2.5 (n=45) p History of acute chest syndrome (%) 20% 40% 0.034 Hydroxyurea therapy 42% 44% 0.8 Hemoglobin in g/dl 9.3 (1.8) 8.9 (1.7) 0.071 LDH in U/L 393 (163) 474 (170) 0.009 Total Bilirubin in mg/dL 2.7 (1.9) 3.8 (2.2) 0.004
Variation in the Small Guanosine Triphosphate (GTP)-Binding Protein, Secretion-Associated and RAS-Related (SAR1A) Gene and Response to Hydroxyurea Treatment in Sickle Cell Disease.
Authors: Kumkhaek Chutima , Zhu Jianqiong , Taylor James G. , Hoppe Carolyn , Kato Gregory J. , Rodgers Griffin P. 
Published: October 2019

Abstract
Hydroxyurea (HU) is a well-known chemotherapeutic agent and a potent ribonuclease reductase inhibitor that induces Hb F synthesis in sickle cell disease and some thalassemia syndromes. Our group has shown that the HU-inducible small guanosine triphosphate (GTP)-binding protein, secretion-associated and RAS-related (SAR) protein plays a role in g-globin gene induction and erythroid cell maturation by causing cell apoptosis and G1/S-phase arrest through the reduction of PI3 kinase and ERK phosphorylation and increased p21 and GATA2 expression. Our preliminary analysis indicates that HU inducibility is mediated at the transcriptional level, and is localized to elements in the SAR1A promoter. The aim of this study was to assess whether polymorphisms in the SAR1A gene promoter are associated with Hb F levels or HU therapeutic responses. We studied 386 sickle cell disease patients consisting of 269 adults treated with or without HU and 117 newborns with sickle cell disease identified from a newborn screening program. Twenty point mutations, including one nonsynonymous variant, were identified in SAR1A, including nine previously reported in SNP databases. A difference in genotype frequencies was observed between adults and newborns for rs2310991 in the 5′UTR (odd ratio [OR] = 1.9, 95% confidence interval [CI] = 1.1–3.2, P=0.009) and +31 T>C in 5′UTR (odd ratio [OR] 9.8 [ 1.3–73.9]; confidence interval [CI] 95%; P<0.001). Three previously unknown SNPs in the upstream 5′UTR (−809 C>T, −502 G>T and −385 C>A) were significantly associated with the HbF response in Hb SS patients treated with HU (P<0.05). Our data suggest that the SAR1A polymorphism might contribute to the regulation of HbF expression and modulate patient responses to HU in sickle cell disease.
Efficacy of High-Dose Sequential Chemotherapy and Autograft for Transformed Non Hodgkin’s B Cell Lymphoma: Results of a Retrospective Analysis from GITIL (Gruppo Italiano Terapie Innovative nei Linfomi).
Authors: Di Nicola Massimo , Devizzi Liliana , Rambaldi Alessandro , Zanni Manuela , Benedetti Fabio , Patti Caterina , Barbui Tiziano , Tarella Corrado , Gianni Alessandro M. 
Published: October 2019

Abstract
Background - Follicular lymphoma (FL) transforms in a more aggressive lymphoma in 25–60% of patients representing the outgrowth of a more malignant subclone. Transformation is usually associated to a rapidly progressive clinical course, refractoriness to treatment, and short survival. To define the impact of high dose sequential (HDS) therapy and peripheral blood stem cell (PBSC) autograft on outcome of transformed FL (TFL), we analyzed a consecutive series of 66 pts with a confirmed diagnosis of TFL registered at the GITIL centers from March 1988 to September 2004 and treated with the HDS regimen.
Methods - Biopsy-proven histological transformation (HT) in diffuse large B cell lymphoma (DLBCL) was observed at diagnosis (n=24; 36%) or at relapse after a treatment for FL (n= 42; 64%). Main patient characteristics were as follows: male/female 36/30; median age 51 yrs (range 33–66), stage I-II/III-IV 8/58, IPI score 0–1/≥2 28/38. HDS regimen included: i. 3 APO or 3 DHAP courses (for patients relapsed after anthracycline-containing regimens); ii. sequential administration of hd-CTX (7g/mq), hd-Ara-C, (2g/mq q12h for 6 days) hd-Etoposide (2.4 g/mq), with PBSC harvests following hd-CY and hd-Ara-C; iii. myeloablative regimen with hd-Mitoxantrone/L-Pam (n=28) or BEAM (n=28 pts who could not receive additional anthracycline), or TBI-PAM (n=3); iv. PBSC autograft; v. consolidation radiotherapy on bulky disease. From January 1999, hd-CTX and hd-Ara-C has been supplemented with Rituximab (RHDS; n=34) with in-vivo purging intent.
Results - Overall 59 patients achieved a complete remission (CR; 89%), 1 patient responded partially and underwent allogeniec bone marrow transplantation, 6 patients died for progressive disease while on therapy (PD; 9%). With a median follow-up of 67 months (range 23–170), 42 patients are alive (63.6%), 24 patients relapsed and died for progressive disease (n= 23) or toxicity (n= 1). Five-year event free survival (EFS) and overall survival (OS) are 53.0% and 63.6%, respectively. No significant differences in OS and EFS were observed between patients with HT at diagnosis or at relapse, with IPI O-1 vs IPI >2. Of note, pts treated with R-HDS showed an improved clinical outcome (OS: 76% vs. 50%; EFS: 67.6 vs. 37.5 respectively), with a large difference that did not reach statistical significance because of the limited number of patients.
Conclusion - Our data strongly suggest that HDS regimen, in particular when supplemented with rituximab (R-HDS), is a very effective regimen in transformed B cell lymphoma.
Effects of Steroid Treatment on Childhood ALL Stem Cells.
Authors: Cox Charlotte V. , Diamanti Paraskevi , Kearns Pamela R. , Blair Allison 
Published: October 2019

Abstract
Several lines of evidence indicate a central role for stem cells in the pathogenesis of human leukaemias and exemplify the need to develop strategies that target this sub-population of cells. It is proposed that these cells may exhibit different chemo-sensitivity and consequently may be resistant to drug regimens designed to kill the bulk leukaemia population. Inherently resistant leukaemia stem cells may contribute to subsequent disease relapse. Clearly, there is a need to assess the relative efficacy of therapeutic agents on the sub-populations of cells in addition to the bulk leukaemia. We have previously demonstrated that the sub-population of childhood acute lymphoblastic leukaemia (ALL) cells, capable of serially engrafting NOD/SCID mice, have a CD34+/CD19− or CD34+/CD7− phenotype in B cell precursor (BCP) ALL and T-ALL, respectively. In this investigation we have compared the efficacy of a current glucocorticoid therapeutic agent on these putative ALL stem cells with their effects on the bulk leukaemia population. The effect of dexamethasone (dex), a key component of the treatment of childhood ALL, on primary ALL cells from 13 paediatric cases was examined. Unsorted ALL cells were co-cultured with and without dex for 48 hours. Subsequently, cell viability and apoptosis were evaluated by flow cytometry using propidium iodide and annexin V staining, with Flow-Count fluorospheres to directly determine absolute cell counts. Primary cells from 11 patients with BCP ALL were sorted for expression of CD34/CD19 and cells from 2 T-ALL cases were sorted for expression of CD34/CD7. The unsorted cells and the sorted sub-fractions were co-cultured with increasing concentrations of dex (0.05 to 500 μM) to compare the relative chemosensitivity of the bulk and putative leukaemia stem cell populations. The unsorted leukaemia populations were completely refractory to dex with no significant difference in the levels of apoptosis observed or the absolute number of viable cells in the treated samples and in the untreated controls. Interestingly, when the sorted populations were assessed, an increase in the absolute numbers of viable CD34+/CD19− (1.2–9.7 fold, P<0.02) and CD34+/CD7− (2.6–5 fold, P<0.04) leukaemia cells were observed even at the highest steroid dose, compared to the respective untreated sub-fractions. The other leukaemic sub-fractions did not show a significant increase in the number of viable cells following dex exposure. These data show that 10 out of 11 drug treated primary leukaemia cells were resistant to dex. The putative CD34+/CD19− BCP ALL cells and CD34+/CD7− T-ALL cells showed a significantly enhanced proliferative potential when exposed to the drug, suggesting that it is these cells that may be responsible for disease relapse.
Effect of FMS-Like Tyrosine Kinase-3 Mutations on Prognosis in Acute Myeloid Leukemia: A Single Institution Experience between 2000 and 2007.
Authors: Ghanem Hady A. , Jones Dan , Kantarjian Hagop M. , Faderl Stefan , Estey Elihu H. , Pierce Sherry , O’Brien Susan , Cortes Jorge , Ravandi Farhad 
Published: October 2019

Abstract
Mutations of the FMS-like tyrosine kinase-3 gene (FLT3), including internal tandem duplication (ITD) of the juxtamembrane domain or activating point mutations of the second tyrosine kinase domain involving codon 835 or 836 are among the most common molecular abnormalities in acute myeloid leukemia (AML). A clear negative impact of FLT3 mutation on survival has been demonstrated in AML patients younger than 60 years; however, this negative effect on prognosis or survival has not been confirmed in older patients. We evaluated 661 patients with AML treated at MD Anderson Cancer center between 2000 and 2007 for FLT3 mutations including 281 patients ≤ 60 years and 380 patients > 60 years. Median age for the entire group was 65 years (range, 17 to 86). A FLT3 mutation was present in 124 patients (18.7%). Patients with FLT3 mutations had a significantly higher WBC (median, 16.5 vs. 4.2, p<0.001) and a higher percentage of bone marrow blasts (median, 62% V/S 40%, p<0.001) at initial presentation. These differences were equally seen in both sexes. Patients with FLT3 mutations were younger than those without mutations (median age 58 vs. 64, p=0.005). Patients with FLT3 mutations were less likely to have an antecedent hematological disease compared to those without mutations (p<0.001). FLT3 mutations were less frequent in patients with core binding factor leukemia [t(8;21), inv(16)]. FLT3 mutations were more common in patients with acute promyelocytic leukemia (APL) than other FAB subgroups (p<0.001). Induction death and complete remission rates were not affected by FLT3 status. When favorable prognosis subgroups [APL, t(8;21), inv(16)] were excluded, patients with FLT3 mutations had a significantly shorter overall survival; this difference was seen in patients younger than 60 (p=0.019), as well as in patients over 60 (p=0.015). We have further confirmed a clear negative impact of FLT3 mutations on survival in patients ≤ 60 years and have demonstrated a negative impact on survival even in patients older than 60 years. FLT3 inhibitors should be considered as a component of therapy in older patients with non-favorable AML and FLT3 mutation.
A JAK2-V617F Activating Mutation in Addition to C-KIT and FLT3 Mutations Is Associated with Clinical Outcome in Patients with t(8;21)(q22;q22;) Acute Myeloid Leukemia.
Authors: Nanri Tomoko , Iwanaga Eisaku , Matsuno Naofumi , Kawakita Toshiro , Suzushima Hitoshi , Kawano Fumio , Mitsuya Hiroaki , Asou Norio 
Published: October 2019

Abstract
AML1-MTG8 generated by t(8;21)(q22:q22) contributes to leukemic transformation but additional events are required for full leukemogenesis. Mutations in the receptor tyrosine kinase (RTK) including C-KIT and FLT3 genes appear to be the genetic events that cause acute myeloid leukemia (AML) harboring t(8;21) and are associated with unfavorable prognosis (Nanri et al. Leukemia19:1361;2005). On the other hand, the activating V617F mutation in the JAK2 cytoplasmic tyrosine kinase has been detected in a significant proportion of patients with myeloproliferative disorders. Although the same mutation has been identified in a small number of AML patients, it is likely that a relatively high incidence of JAK2-V617F mutation has been seen in t(8;21) AML patients. However, whether they are associated with other biological parameters and whether they influence clinical prognosis in patients with t(8;21) AML have not been determined. To clarify the biological and prognostic impact of the JAK2 mutation, we examined the clinical and prognostic relevance of the mutation. Of 45 patients with t(8;21) AML, mutations in the C-KIT and internal tandem duplications (ITD) in the FLT3 were observed in 18 (40%) and 3 (6.7%), respectively. We detected the JAK2-V617F mutation in 3 patients with t(8;21) AML (6.7%), which was consistent with previous studies. Although the occurrence of C-KIT and FLT3 mutations was mutually exclusive, one patient harboring JAK2 mutation also had a C-KIT second tyrosine kinase mutation and another one patient had a K-RAS mutation. Collectively, a total of 23 (51%) patients showed mutations in the RTK pathway. One patient carrying both C-KIT and JAK2 mutations did not respond to multiple induction chemotherapies. Another patient with the JAK2 and K-RAS mutations achieved a complete remission (CR) but later relapsed. Remaining one patient received allogeneic stem cell transplantation during first CR and continued CR. As we were limited to study a small number of mutated cases for a comparison of clinical and genetic features, we examined the clinical significance of C-KIT, FLT3 and JAK2 mutations as a collective group. A cumulative incidence of relapse (CIR) in 21 patients with RTK mutations was 77%, whereas CIR in 19 patients lacking mutations was 26% (P=0.0083). The 6-year relapse-free survival in patients with mutations was 20% compared to 54% in those without mutations (P=0.0595). These results suggest that the mutations in the JAK2, C-KIT and FLT3 could be an additional genetic events leading to the development of AML and are associated with the clinical outcome in patients with t(8;21) AML.
Reguatory T-Cell Subsets Demonstrate Quantitative Differences but Not Functional Abnormalities in Patients with Multiple Myeloma (MM) Compared with Healthy Controls.
Authors: Feyler Sylvia , von Lilienfeld-Toal Marie , Marles Lee , Rawstron Andy , Owen Roger G. , Ashcroft John , Cook Gordon 
Published: October 2019

Abstract
The immunologically hostile microenvironment of MM contributes to the limited success of immunotherapy strategies. In addition to direct tumour-induced immunosuppression, tumour cells may generate suppressor cells such as Treg cells which can profoundly suppress immune responses and induce tolerance. This study aimed to determine if Treg subsets are increased in the peripheral blood (PB) and bone marrow (BM) of patients with MGUS/MM and how this correlates with increasing disease burden. PB samples from 166 patients with MGUS/MM (Newly diagnosed (ND), n=34; Plateau/low disease burden (LD), n=63; Relapsed/refractory (R/R), n=27 and MGUS, n=42) with a median age of 69 years (range 39–89 yrs) were analysed by FACS and compared to PB from 32 age/sex matched controls. Using a sequential gating strategy, naturally occurring Treg cells (nTregs) were identified as CD4+/CD25+/FoxP3+ T-cells and expressed as a percentage of the CD4+ T-cells. Double negative T cells (DN Tregs) were identified as CD3+/CD4−/CD8−/alphabeta-TCR+/gammadelta−TCR− and expressed as a percentage of the CD3+ cells. Sera were analysed by ELISA for IL10 and TGF-beta. nTReg cells were significantly increased in patients with MGUS/MM compared with controls (Controls 1.6% ± 0.2, MGUS 2.3% ± 0.3, ND 2.4% ± 0.2, LD 4.2% ± 0.7 & R/R 3.8% ± 0.5; p=0.003). There was a positive correlation of nTRegs number with paraprotein level (R=0.3, p=0.005). Patients on Thalidomide at the time of sample collection had significantly higher numbers of nTRegs of 6% in comparison to patients who never received Thalidomide (3%) and patients who previously received the drug (3.5%, p=0.005). Analysis of BM (n=12) demonstrated a significantly reduced number of nTRegs in comparison to PB (1.6% vs 3.0%, p=0.025), which is higher than the number of nTRegs in the BM of controls (0.7%). Functionally, nTRegs from patients demonstrated suppressive activity of both autologous and allogeneic T-cells similar to nTRegs cells from control PB (p=NS). In contrast, DN TRegs were significantly reduced in patients with myeloma (ND 1.0% ± 0.2, LD 1.1% ± 0.1, R/R 1.3% ± 0.2) compared with MGUS and controls (2.1% ± 0.9 & 3.3% ± 0.7, respectively; p=0.02). Serum IL10 levels were significantly lower in ND (17 ± 38 pg/ml) and LD (29 ± 36 pg/ml) than in Controls (55 ± 89 pg/ml), MGUS (72 ± 151 pg/ml) and R/R (90 ±182 pg/ml, p=0.02). TGF-b levels differed significantly between groups (Controls 3765 ± 1593 pg/ml, MGUS 3506 ± 1504 pg/ml, ND 4774 ± 9879 pg/ml, LD 1915 ± 1324 pg/ml, R/R 2802 ± 2011 pg/ml, p=0.025). These results provide further evidence of immune dysregulation in MM. The association with advanced disease stage suggests a causal association.
Induction of UBC9 and the Sumoylation Pathway in Multiple Myeloma Promotes Plasma Cell Growth and Correlates with Decreased Patient Survival.
Authors: Driscoll James J. , Lefkimmiatis Konstantinos , Fulciniti Mariateresa , Prabhala Rao , Pelluru Dheeraj , Greipp Philip R. , Munshi Nikhil C. 
Published: October 2019

Abstract
The pursuit of rationale, targeted therapies relies on a detailed understanding of the mechanisms that subvert normal growth control and lead to development of Multiple Myeloma (MM). To further define the mechanistic steps that contribute to MM pathogenesis, we examined mRNA expression profiles of CD138+ plasma cells obtained from normal, Monoclonal Gammopathy of Unknown Significance (MGUS), and MM patient samples. Using genomic results in combination with molecular and cellular-based assays, we demonstrate a critical role for UBC9 and the sumoylation pathway in myeloma cell growth and survival. Notably, Reverse Transcriptase Polymerase Chain Reaction (RT-PCR) demonstrated a ten-fold induction in UBC9; a gene that encodes the sole Sumo-conjugating enzyme in human cells. We demonstrated an elevation of UBC9 in both MM primary patient cells and in a number of patient-derived MM cell lines. In addition, a number of other sumoylation pathway components were induced in primary MM cells at the gene and protein level relative to normal plasma cells. We believe that induction of UBC9 is an early genetic event in the pathogenesis of MM since the induction was observed at the gene and protein level in plasma cells from patients with MGUS. Importantly, UBC9 induction was functionally significant since a different pattern of sumoylation was observed in total cell lysate from MM patient plasma cells relative to that of normal plasma cells. Furthermore, overexpresion of a mutant form of UBC9 deficient in Sumo-conjugating activity increased the sensitivity of plasma cells to apoptosis by chemotherapeutic agents and these cells were impaired in other essential functions that included cellular proliferation, DNA synthesis, resistance to apoptosis and adhesion to bone marrow stroma. Immunoblotting of MM patient cell lysates also demonstrated a similar induction of the UBC9 gene product (Ubc9) as well as induction of the Sumo ligases Nse2 and PIAS1. These studies identify UBC9 as a target upregulated early in the pathogenesis of MM and indicate a critical role for sumoylation in disrupting the controls that govern normal plasma cell growth. To further develop prognostically relevant molecular signatures and classifications of MM subtypes, we analyzed the survival outcome of patients that expressed induced levels of UBC9, as well as other sumoylation components, and demonstrate significantly reduced survival of such patients following current treatment modalities. The results provide evidence for critical role of UBC9 and sumoylation in MM pathogenesis. Furthermore, sumoylation pattern may serve as a therapeutic target in MM, help stratify clinical management and provide a framework for the identification of sumoylation pathway targets that govern MM cell growth and progression.