bluuebunny/crossref_metadata_2025_split huggingface dataset:
Growth Hormone Deficiency after Chemotherapy for Acute Lymphoblastic Leukemia in Children Who Have Not Received Cranial Radiation.
Authors: Haddy Theresa B. , Nunez Susan B. , Mosher Revonda B. , Reaman Gregory H. 
Published: April 2020

Abstract
Chemotherapy-related growth failure is a significant problem in children with acute lymphoblastic leukemia (ALL). Growth impairment after cranial radiation (CR) is likely to result in diminished adult height, but growth impairment following chemotherapy without CR is usually followed by catch-up growth and normal final height. We report two ALL survivors treated with chemotherapy without CR who required growth hormone (GH) replacement due to absence of catch-up growth. A 15 year old boy and a 12 year old girl, off therapy for 9 and 6 years, respectively, developed growth failure. Peak GH responses to stimulation using arginine and clonidine were inadequate, 3.4 ng/ml and 0.1–3.0 ng/ml, respectively (normal &gt;10 ng/ml). Additional studies included bone age, magnetic resonance imaging of the hypothalamic-pituitary area, insulin-like growth factor (IGF-1), insulin-like growth factor-binding protein (IGF-BP3), and thyroid function tests. Other causes of growth failure were ruled out; the children had received neither CR nor radiation of the long bones, were not subjected to transplantation, and showed no evidence of premature puberty or hypothyroidism. Chemotherapy included methotrexate, 6 mercaptopurine, vincristine, adriamycin, cyclophosphamide, l-asparaginase, dexamethasone, cytarabine, 6 thioguanine, and intrathecal methotrexate. Both children responded to GH replacement therapy. Of 235 ALL survivors treated at our single institution since 1997 with chemotherapy without CR, the 2 we report here were diagnosed with GH deficiency resulting in growth deceleration, generally thought to be primarily a complication of CR. Children treated for ALL should be carefully monitored for growth failure.
CD133+ Hematopoietic Cells Successfully Reconstitute Hematopoiesis Following Autologous Peripheral Blood Stem Cell Transplantation.
Authors: Hale Gregory A. , Horwitz Edwin , Leung Wing , Woodard Paul , Eldridge Paul , Yusuf Usman , Benaim Ely , Kasow Kimberly , Srivastava Kumar , Handgretinger Rupert 
Published: April 2020

Abstract
CD133 is a unique antigen found on hematopoietic precursor cells, with a limited expression on non-hematopoietic cells. These features make it an attractive marker for obtaining tumor-free hematopoietic grafts. We conducted a prospective clinical trial for patients with solid tumors and lymphomas who required autologous HSCT. 11 children (6 male, 5 female) had CD133+ peripheral blood stem cells (PBSC) collected for subsequent autologous HSCT. The median age was 12.4 yrs (range, 2.2–26). Diagnosis included Hodgkin lymphoma (1 stable disease, 2 PR), neuroblastoma (2 PR), NHL (2PR), Ewing sarcoma (1 stable disease), CNS PNET (1 PR), and desmoplastic small round cell tumor (1 PR). All had received priming chemotherapy with growth factor support. PBSC were collected in 1 or 2 procedures when the absolute CD34+ count was ≥ 40/ul. A stem cell product was cryopreserved as a backup. The PBSC product was processed on the CliniMACS device with positive selection methodology using the CD133 antigen. Prior to CD133 selection, the graft contained 0.3–4.9% CD34+ cells and 0.3–4.4% CD133+ cells. Following CD133 selection, the graft contained 45.1–98.4% CD34+ cells and 45.9–98.8% CD133+ cells. The stem cell products contained a median of 5.4 x 106 CD34+/kg (range, 2.61–7.89) and 5.3 x 106 CD133+/kg (range, 2.54–8.04). One patient who had PBSC collected has not yet proceeded to HSCT. All were conditioned with busulfan 37.5 mg/m2/dose for 16 doses and melphalan 70 mg/m2 for 2 doses. A cell dose from 2 x 106 CD133+/kg to a maximum of 8 X 106 CD133+/kg was infused. G-CSF 5 mcg/kg/day was initiated on day +5 and continued until ANC ≥ 3,000/mm3 for 2 consecutive days. All 10 patients engrafted and no patient required infusion of the back-up stem cell product. No infusion reactions were observed during infusion of the stem cell product. The median time to ANC ≥ 500/mm3 was day + 11 (range, 10–13) for all 10 patients. Of the 8 evaluable patients (1 had hemorrhagic cystitis, 1 severe epistaxis), all achieved an unsupported platelet count of greater than 20,000/mm3 at a median of day + 17 (range, 12–20). This trial demonstrates that infusion of CD133+ hematopoietic cells can reconstitute hematopoiesis following myeloablative HSCT. Further studies are needed to describe the ability of CD133 selection to obtain tumor free hematopoietic grafts.
ZAP-70 Expression in Human B cells: Analysis of Normal Cells and Acute Lymphoblastic Leukemia (ALL) Cells with Pro/Pre B Phenotype.
Authors: Crespo Marta , Villamor Neus , Gine Eva , Colomer Dolors , Marafioti Teresa , Campo Elies , Montserrat Emili , Bosch Francesc 
Published: April 2020

Abstract
ZAP-70 is a protein tyrosine kinase of the Syk/ZAP-70 family that plays a critical role in the signal transduction from the T-cell receptor. In human lymphocytes, ZAP-70 gene has been reported to be expressed in T and NK derived cells, and in IgVH unmutated B-chronic lymphocytic leukemia cells. More recently, ZAP-70 expression has been shown to be required for the development of pro-B cells to pre-B cells in mice. To ascertain the expression of ZAP-70 gene in human immature B-cell stages, we analyzed ZAP-70 protein and/or mRNA in normal human B cells at different stages of B cell maturation, including pro/pre-B cells and tumoral cells from 20 B-ALL. ZAP-70 expression was assessed by flow cytometry (FC), immunofluorescence (IF), and/or by quantitative real time RT-PCR (QRT-PCR). In normal bone marrow, ZAP-70 expression was found only in T and in immature B cells (CD19+/CD10+/CD20 −). Moreover, T cells -but no mature B cells- from normal tonsil expressed ZAP-70, as assessed by QRT-PCR and IF. In B-ALLs, a high ZAP-70 expression by FC was observed in 9/13 cases (mean, 82.6%, range 60–99%), whereas in 4 cases ZAP-70 was barely detectable (mean, 13%). By QRT-PCR, 10/16 B-ALLs showed levels of expression similar to ZAP-70 non-expressing cell lines and normal B-cells, whereas in the remaining cases ZAP-70 expression was 3–4 times higher than in normal mature B-cells. Taken together, a high expression of ZAP-70 was found in 11/21 (52%) B-ALLs. No relationship was observed between the level of ZAP-70 expression and the B-ALL maturation status. In conclusion, among normal B cell subsets ZAP-70 expression is restricted to B-cells with pro/pre phenotype. In addition, ZAP-70 is expressed in 52% of B-ALLs, probably as a reflection of their B-cell origin.
Higher Expression of Cytochrome-c and Caspase-3 in the Primary Acute Lymphoblastic Leukemic Cells with Negative Expression of VEGF and Its Receptors Than with Positive Expressed Cells under VP16 Induction.
Authors: Liang Aibin , Gu Long-Jun 
Published: April 2020

Abstract
Flow cytometry and immunofluorescent staining were employed to examine the apoptosis signals, cytochrome-c and Caspase-3, in the primary leukemia cells with or without expression of VEGF and its receptors and normal healthy donor’s lymphocytes. We found that primary leukemic cells and normal lymphocytes didn’t secrete Cyt-c from mitochondria and no caspase-3 activation without the treatment of VP16. Instead, after incubation with VP16 (30mg/L) for 8 hours, normal lymphocytes and most of de novo leukemia cells secreted Cyt-c into cytosol from mitochondria and had the activation of caspase-3 in the cellular plasma. However, primary leukemia blasts with higher expression of VEGF and its receptors revealed lower secretion of Cyt-C and down-regulated activation of Caspase-3. Results showed that Cyt-c secretion and Caspase-3 activation were prone to occur in the VEGF negatively expressed blasts than positively expressed cells. This indicates that lower secretion of Cyt-c from mitochondria and inactivation of Caspase-3 are two of the pivotal mechanisms of anti-apoptosis for refractory leukemia clone with highly expressed VEGF and its receptors.
A Risk Model for Early Intracranial Hemorrhage in Acute Leukemia.
Authors: Kim Hawk , Choi Seong-Jun , Lee Je-Hwan , Lee Jung-Shin , Lee Kyoo Hyung 
Published: April 2020

Abstract
Early intracranial hemorrhage (EICH), which is defined by noticeable ICH within 10 days of diagnosis, is a life-threatening hemorrhagic complication in patients with acute leukemia. To ascertain risk factors associated with EICH, we retrospectively analyzed 792 newly-diagnosed acute leukemia patients treated between July 1988 and March 2003. Thirty-one patients (3.9 %) had analyzable EICH. Multivariate analysis showed that female gender (OR = 3.064, P &lt; 0.001), acute promyelocytic leukemia (OR = 8.797, P = 0.003), leukocytosis (OR = 6.056, P = 0.004), and prolonged prothrombin time (OR = 10.026, P = 0.016) were factors significantly associated with occurrence of EICH. Risk scores (RS) were calculated by a product of odds ratio and each risk factor (RF) and taking their sum, generating an RS ranging 0 to 27.943. The cutoff of RS 9 was of statistical significance to predict probability of EICH. Receiver-operating characteristics curve shows the sensitivity and 1 - specificity relative to risk score (AUC = 0.917; S.E. = 0.021; 95% CI, 0.876–0.958; Figure 1). In this regards, RF for EICH was classified as major (prolonged prothrombin time) and minor (female gender, acute promyelocytic leukemia, leukocytosis). Risk model demonstrated that EICH was low probable when no major RF and less than two minor RFs were present. Risk model for ICH in acute leukemia classified acute leukemia patients into two risk groups; low probable EICH group (LPG) and probable EICH group (PG). When applied to our patients, PG was positively correlated with more incidence of FICH than LPG (n = 27/173 vs. 4/619, P &lt; 0.001). Induction chemotherapy could be undertook more frequently in LPG than in PG (p = 0.002, Table 1). Kaplan-Meier curves show the probability of EICH-free survival relative to probability of EICH. ICH-free survival was significantly longer in LPG than in PG (p &lt; 0.0001, Figure 2). Our findings suggest that our risk model may predict the occurrence of EICH in patients with acute leukemia.
Table 1. The relationship of risk model and frequency of early intracranial hemorrhage (EICH) or performance of induction chemotherapy.
Figure Figure Figure Figure Low probable EICH group, n (%) Probable EICH group, n (%) P EICH (−) 615 (77.7 %) 146 (18.4 %) &lt; 0.001 EICH (+) 4 (0.5 %) 27 (3.4 %) Induction chemotherapy (+) 563 (71.1 %) 143 (18.1 %) 0.002 Induction chemotherapy (−) 56 (7.1 %) 30 (3.8 %)
Characterization and Functional Analysis of a Murine Model for Chronic Myeloid Leukemia Stem Cells.
Authors: Sozer Selcuk , Echlin Debbie R. , Rossi Randall M. , Grimes Barry A. , Jordan Craig T. 
Published: April 2020

Abstract
The purpose of this study was to characterize the phenotype and analyze the functional characteristics of CML stem cells (CML-SCs) in a mouse model system. A retrovirus transduction model was employed using a vector expressing p210/BCR/ABL and the green fluorescent protein (GFP). Transplantation studies of BCR/ABL infected cells in recipient mice demonstrated an aggressive myeloproliferative disease within approximately 3 weeks, as has previously been observed with this approach. Phenotypic analysis of bone marrow from BCR/ABL mice showed contribution by the transduced cells to multiple lineages, suggesting a primitive stem/progenitor cell gives rise to the disease. Subsequent analysis of primary cells that arise in vivo showed the leukemia-initiating activity resides in cells that are Sca-1+/c-kit+/Lin-. Cell cycle analyses (as detected by BrdU incorporation) of the Lin−/c-kit+/Sca-1+ compartment of BCR/ABL mice demonstrated an enhanced cycle rate (approximately 2-fold) in the leukemic population, signifying a possible increase in the self-renewal or proliferative properties of this primitive compartment that could lead to development/progression of the disease. Further, comparison of the BCR/ABL mice and GFP control mice revealed preferential over-expression of CD24 (heat-stable antigen) in the primitive leukemic cells (90% vs. 52% in normal counterparts) demonstrating a possible BCR/ABL induced activation of the antigen. Sorting and serial transplantation studies of CD24+ vs CD24− cells from BCR/ABL mice showed that the leukemia-initiating activity resides in the CD24+/Lin− population. Collectively, these data indicate that BCR/ABL expression increases proliferation of primitive CML cells and up-regulates the CD24 antigen. We suggest that the CD24 antigen represents a potential marker to distinguish normal from CML stem cells and that it may confer specific functional properties on the CML population.
Comparison of Platelet-Rich Plasma Serotonin Level and Quantitative Neutrophil PRV-1 Assay in Chronic Myeloproliferative Disorders.
Authors: Koch Cody A. , Lasho Terra L. , Tefferi Ayalew 
Published: April 2020

Abstract
In a prospective study of 100 subjects, an ELISA assay was used to measure platelet-rich plasma (PRP) serotonin levels in patients with polycythemia vera (PV; n=26), essential thrombocythemia (ET; n=14), myelofibrosis with myeloid metaplasia (MMM; n=26), secondary or spurious polycythemia (SP; n=20) and controls (n=14). Neutrophil PRV-1 expression was concurrently assayed by real-time PCR in 69 patients (23 PV, 17 SP, 12 ET, 7 MMM, 10 controls). Table 1 outlines the median and range of measured values across the different study groups.
Table 1
Controls SP PV ET MMM Age in years N/A 49 (18–77) 64 (32–83) 52 (18–81) 60 (22–80) Plt count x 109/L N/A 249 (157–371) 509 (191–940) 613 (284–1100) 259 (64–955) PRP serotonin; ng/109 plts 567 (360–1071) 609 (369–1780) 205 (0–496) 385 (137–1026) 90 (0–278) PRV-1/GAPDH ratio 1.28 (1.20–1.43) 1.23 (1.13–1.38) 1.03 (0.84–1.28) 1.24 (0.99–1.44) 1.25 (1.11–1.40)
A highly significant difference (p &lt; 0.0001), in PRP serotonin levels, was seen among the different disease categories and control group (table 1). The lowest levels were registered for MMM and PV with a statistically significant difference between the two groups (p = 0.015) but a large degree of overlap. The results in both were significantly as well as markedly lower than those of controls as well as SP with only slight overlap in the PV group and no overlap in the MMM group (p &lt; 0.0001; table 1). The PRP serotonin levels in patients with ET were significantly reduced compared to both controls (p = 0.019) and SP (p = 0.002) and significantly increased compared to both PV (p = 0.0008) and MMM (p &lt; 0.0001). However, there was a substantial degree of overlap in values between ET and other disease categories and controls. Neither aspirin nor cytoreductive therapy correlated with PRP serotonin levels (p = 0.116 and p = 0.148, respectively). Similarly, within a specific disease category, PRP serotonin level did not significantly correlate with platelet count, hemoglobin level, leukocyte count, spleen size, disease duration, or gender. However, an inverse correlation with age was noted only in MMM. In general, there was not a significant correlation between PRP serotonin level and neutrophil PRV-1 expression in each of the three myeloproliferative disease variants. Tests of sensitivity, specificity, and accuracy in distinguishing PV from SP were 92, 95, and 93% for the PRP serotonin assay and 78, 95, 86% for neutrophil PRV-1 assay, respectively. The current study suggests that PRP serotonin concentration might be considered as one of several biological markers that complement each other for the diagnosis of PV.
Abnormal Expression of the Plasma Cell Differentiation Factor X-Box Protein 1 (Xbp-1) in Waldenstrom’s Macroglobulinemia.
Authors: Xu Lian , Leleu Xavier , Hunter Zachary R. , Santos Daniel D. , Ho Allen W. , Hatjiharissi Evdoxia , O’Connor Kelly , Manning Robert J. , Chemaly Mariana , Branagan Andrew R. , Patterson Christopher J. , Verselis Sigitas , Fox Edward , Anderson Kenneth C. , Treon Steven 
Published: April 2020

Abstract
INTRODUCTION: Xbp-1 is a ubiquitously expressed basic leucine zipper protein which serves as key transcription factor for plasma cell differentiation and immunoglobulin production. XBP-1 mRNA undergoes splicing at an IRE-1a specific cleavage site to produce a spliced form (Xbp-1s) which due to a frame shift results in a more stable and potent transcription factor than the unspliced form (Xbp-1us). Previous observations demonstrated that Xbp-1 was highly expressed in multiple myeloma (MM), though its expression in other B-cell disorders including Waldenstrom’s macroglobulinemia (WM) remains to be clarified.
METHODOLOGY: In this study, we investigated the different forms of Xbp-1 in CD19+ selected bone marrow (BM) cells from 61 patients with the consensus panel definition of WM using semi-quantitative PCR analysis. CD19+ selected BM cells from 6 healthy donors, and CD138+ selected BM cells from 4 MM patients were used as controls. All RT-PCR results were normalized to b-actin levels. Sequencing of Xbp-1 in CD19+ selected LPC was also performed for 20 WM patients.
RESULTS: In 9/61 (15%) WM patients, Xbp-1 transcripts were undetectable. Among WM patients expressing Xbp-1, as well as all MM patients evaluated, higher levels of XBP-1us were observed in comparison to normal healthy donors (p=0.001). Decreased XBP-1s transcript levels were also observed among WM and MM patients versus healthy donors, but did not reach statistical significance. Sequence analysis of Xbp1 in CD19+ selected BM LPC demonstrated variants 10/20 WM patients in exon 1 that are currently under investigation.
CONCLUSIONS: Abnormal expression of Xbp-1 is common in patients with WM, and includes loss of expression, and aberrations in splice patterns. The genetic basis for these findings is under investigation.
Identification of Surrogate Prognostic Markers and Genes Implicated in Immunoglobulin Gene (IgVH) Somatic Hypermutation in Small B-Cell Lymphomas.
Authors: Tracey Lorraine , Aggarwal Mohit , Algara Patrocinio , Garcia Juan F. , Garcia-Cosio Monica , Rodriguez Antonia , Martinez Nerea , Camacho Francisca I. , Roncador Giovanna , Sanchez-Aguilera Abel , Ruiz-Ballesteros Elena , Mollejo Manuela , Garcia-Marco Jose A. , Piris Miguel A. 
Published: April 2020

Abstract
Immunoglobulin (Ig) gene somatic hypermutation (SHM) is a prognostic factor in small B-cell lymphomas, as demonstrated by studies reporting that hypermutated chronic lymphocytic leukemia (CLL) and splenic marginal zone lymphoma (SMZL) cases show a better prognosis, while hypermutated mantle cell lymphoma (MCL) cases display specific clinicopathological features (leukemic course, increased survival).
However both the mechanisms and markers of SHM are poorly characterized, with the partial exception of the role of the genes ZAP70 and AID. With the purpose of identifying SHM surrogate markers in small B-cell lymphomas, we analyzed IgVH mutational status and expression profiles of 93 small B-cell lymphoma patient samples including SMZL (24 cases), MCL (33 cases) and CLL (36 cases). Patients were classified into two groups: high SHM (&gt;5% mutations) and low SHM (&lt;5% mutations). T-test analysis with 100,000 permutations was performed and 39 genes were identified whose expression is significantly different (p&lt;0.005, FDR&lt;0.05) between cases with high and low SHM burdens.
To dissect the molecular mechanisms of Ig somatic hypermutation and validate the observed findings, SHM was induced in a model system and compared to results in patient samples. The BL2 cell line was used, and SHM was induced by treating the cells with IL4 and CD40. After 24 hours, active SHM was confirmed by western blot using an anti-AID monoclonal antibody on treated and untreated cells. These same cells were analyzed using microarrays, to identify the genes that were induced or downregulated during the SHM activation. A total of 29 genes (18 upregulated and 11 downregulated) were identified which are significantly differentially expressed in the cell line model during induction of SHM (expression change &gt;0.4 Log2 scale) and are also differentially expressed between cases with high and low SHM (p&lt;0.001, FDR&lt;0.1). In both analyses, the upregulated genes are implicated in transcription, DNA repair and replication and chromosome maintenance, correlating well with previous hypotheses indicating that active transcription is necessary for SHM. Based on these observations, a group of 10 key genes, implicated in DNA repair, replication and transcription, were selected and protein expression was analyzed in a set of tissue microrrays containing 150 paraffin embedded small B-cell lymphoma cases, for which clinical data is available and SHM status is known. These proteins may provide a surrogate marker for prognosis and/or analysis of IgVH SHM in patient samples using paraffin-embedded tissue samples.
A Novel Mutation in the von Willebrand Factor Propeptide Causes Defective Regulated Storage in Platelets and Weibel-Palade Bodies.
Authors: Haberichter Sandra L. , Budde Ulrich , Drewke Elke , Obser Tobias , Wermes Cornelia , Schneppenheim Reinhard 
Published: April 2020

Abstract
Two children from a Turkish consanguineous family suffering from significant mucocutaneous bleeding episodes were diagnosed with von Willebrand disease type 2A. The relative reduction of large plasma von Willebrand factor (VWF) multimers together with the absent triplet structure was consistent with type 2A (phenotype IIC) VWD. Surprisingly, platelet VWF was completely deficient of multimers beyond the VWF protomer, suggesting defective α-granular storage of larger multimers. The two patients were nearly unresponsive to DDAVP, consistent with a lack of regulated VWF release from endothelial cell Weibel-Palade bodies, suggesting defective storage in endothelial cells as well as in platelets. We identified the homozygous mutation in these patients, N528S, in the D2 domain of the VWF propeptide (VWFpp). To examine the effect of the N528S mutation on VWF regulated storage, a VWF expression vector containing the mutation was constructed and expressed in AtT-20 cells that contain an intact regulated storage pathway. Transfected cells were immunofluorescently labeled and the intracellular localization of VWFpp and VWF were examined by confocal microscopy. In cells expressing N528S-VWF, VWF was not stored in granules but was localized to the endoplasmic reticulum (ER). Our previous studies have shown that VWF granular storage is initiated by VWFpp: VWF is trafficked to storage granules through its non-covalent association with VWFpp. To determine if the loss of granular storage of N528S-VWF was due to defective VWFpp trafficking, an N528S-VWFpp expression vector was constructed and expressed in AtT-20 cells. The N528S-VWFpp was found to be colocalized with endogenous ACTH-containing storage granules, demonstrating normal granular trafficking of the variant VWFpp. The N528S-VWFpp was co-expressed with propeptide-deleted, mature VWF (Δpro) to examine regulated storage when the two proteins are expressed in trans. In the majority of transfected AtT-20 cells, N528S-VWFpp was trafficked to granules while the coexpressed Δpro appeared to be ER-localized, consistent with a loss of non-covalent association between VWFpp and VWF. In a subset of cells neither VWFpp nor VWF were stored in granules. In contrast, when N528S-VWF was expressed as a full-length construct (in cis), VWFpp granular storage was observed only in a subset of cells and the majority of transfected cells demonstrated ER-localization of both proteins, suggesting the loss of regulated storage of N528S-VWF is not due to defective VWFpp sorting, but rather an aberrant interaction of VWFpp with the mature VWF protein. Together these data indicate that the phenotype observed in patients with N528S variant VWF is result of defective multimerization, storage, and secretion due to an aberrant VWFpp/VWF interaction.