bluuebunny/crossref_metadata_2025_split huggingface dataset:
Radioimmunotherapy for Myeloablation Before SCT in Paediatric Patients with Malignant and Non-Malignant Diseases.
Authors: Schulz Ansgar S. , Gatz Susanne , Schuetz Catharina , Blumstein Norbert , Glatting Gerhard , Kull Thomas , Reske Sven , Debatin Klaus-Michael , Friedrich Wilhelm 
Published: October 2019

Abstract
Radioimmunotherapy (RIT) using radio-labelled monoclonal antibodies can be used for targeted radiation of the bone marrow in the context of SCT. We explored this treatment in 32 pediatric patients with malignant and non-malignant bone marrow disorders with very high risk patterns from disease or comorbidity. For RIT the Yttrium-90 labelled anti-CD66 (n=30) or anti-CD45 (n=2) monoclonal antibodies were used. Dosimetry was performed about 3 weeks before SCT and showed favourable organ distribution. RIT was administered on an outpatient basis 12 to 15 days before SCT. The mean BM dose was 27 Gy (range 11–46) in malignant diseases and 17 Gy (range 16–20) in non-malignant diseases. Patient characteristics were as follows:
malignant diseases (n=16): 7 ALL, 8 AML, 1 Neuroblastoma °IV; disease status pre-BMT: 7 CR2, 2 CR>2, 7 PR/NR; non-malignant diseases (n=16): 12 immunologic disorders (SCID, CID, Hyper-IgM-Syndrome, Hyper-IgE-Syndrome, CGD-Syndrome, Griscelli-Syndrome, IFN-γ-Receptor-Deficiency.), 4 hematologic disorders (Thalassemia major, congenital haemolytic anaemia).
Additional risk factors were active aspergillosis (n=4), acute pneumonia (n=5), liver fibrosis (n=4) and previous transplant (n=7). RIT was followed by high dose conditioning (based on TBI or high dose Busulfan) in 9 malignant cases or by reduced intensity conditioning (based on Fludarabin ± Melphalan) in 7 malignant and all non-malignant cases. Donors were HLA-genoidentical (n=10), matched unrelated (n=15), mismatched related (n=1), mismatched unrelated (n=2) or HLA-haploidentical relatives (n=4). RIT was well tolerated in all patients and no sign of significant additional or unexpected toxicity was observed. Myeloablation was achieved in all patients. All but 2 patients, who rejected their HLA-haploidentical grafts, showed a primary engraftment within the normal time frame after SCT. Six patients died, 3 from TRM and 3 from relapse. Eleven out of 16 patients with malignant diseases survive 3–53 months (median 26 months), 15 out of 16 patients with non-malignant diseases survive 3–30 months (median 11 months). Interestingly, all but one of the 23 patients treated by RIT and reduced intensity chemo-conditioning survive (1 y estimated survival 0.9, 95% CI 0.51–0.99). Taken together, targeted immunotherapy is a promising approach for myeloablation in pediatric patients with high comorbidity and/or high relapse risk.
Syk Tyrosine Kinase Is Overexpressed in the Majority of Peripheral T- and NK-Cell Lymphomas, and Represents a Potential Therapeutic Target.
Authors: Feldman Andrew L. , Sun David X. , Law Mark E. , Novak Anne J. , Attygalle Ayoma D. , Thorland Erik C. , Fink Stephanie R. , Vrana Julie A. , Caron B. Lynn , Morice William G. , Remstein Ellen D. , Grogg Karen L. , Kurtin Paul J. , Macon William R. , Dogan Ahmet 
Published: October 2019

Abstract
Peripheral T- and NK-cell lymphomas (PTCLs) are fatal in the majority of patients, and conventional chemotherapy is minimally effective. Targeted inhibition of tyrosine kinases (TKs) might be a useful treatment strategy, but TK overexpression by PTCLs has not been well characterized (except ALK). Recently a novel translocation t(5;9) fusing the ITK and SYK genes was reported in a subset of unspecified-type PTCLs, associated with high SYK gene expression and Syk protein positivity. Syk is a non-receptor TK important in immunoreceptor signal transduction, providing proliferation and survival signals in a variety of hematopoietic cells. Syk is absent or expressed at very low levels in most normal post-thymic T cells, where this signal transduction role is fulfilled by ZAP70. Since Syk TK inhibitors are now in clinical trials for other diseases, we sought to determine the incidence of t(5;9) and Syk overexpression in PTCL. Tissue microarrays were constructed using triplicate cores from paraffin-embedded tissue blocks. Cases were studied using fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC). Additional studies were performed using flow cytometry and Western blot. There were 141 PTCLs, including 35 angioimmunoblastic, 66 unspecified, 21 anaplastic large cell, 2 enteropathy-associated, 5 hepatosplenic, 5 extranodal NK/T, and 7 other. No evidence of t(5;9) was identified by FISH in 86 informative cases. Normal T-cell subsets from peripheral blood, spleen, and lymph node were negative for Syk by IHC, flow cytometry, and Western blot. Syk was positive by immunohistochemistry in 133 of 141 (94%) PTCLs. All 8 Syk negative cases were extranodal, cytotoxic PTCLs. Western blot on frozen tissue correlated with IHC results in paraffin. All 4 Syk-positive cases tested showed phosphorylation of tyrosine residues 525/526, known to be required for Syk activation. We conclude that Syk is overexpressed in most PTCLs, including the vast majority of nodal cases. Syk may substitute for ZAP70 in these tumors and provide ongoing proliferation and survival signaling. The overexpression of Syk and phosphorylation of its Y525/526 residues suggest Syk may be a suitable target for pharmacologic TK inhibition as a treatment option for patients with PTCL.
Gain-of-Function Mutations and Copy Number Increases of Notch2 in Diffuse Large B-Cell Lymphoma.
Authors: Lee Suk Young , Kumano Keiki , Nakazaki Kumi , Sanada Masashi , Yamamoto Go , Nannya Yasuhito , Suzuki Ritsuro , Ota Satoshi , Ota Yasunori , Izutsu Koji , Sakata-Yanagimoto Mamiko , Hangaishi Akira , Yagita Hideo , Fukayama Masashi , Seto Masao , Kurokawa Mineo , Ogawa Seishi , Chiba Shigeru 
Published: October 2019

Abstract
[Background] Signaling through the Notch receptors, triggered by the binding of ligands expressed on neighboring cells, has a key role in determining cell fate in a variety of cell lineages, including lymphocytes. The physiologic roles of two of the four mammalian Notch genes, Notch1 and Notch2, have been clarified in mouse models. Notch1 is preferentially expressed in immature T cells and is essential for specification of early hematopoietic progenitors toward the T-cell fate and for early T-cell development in the thymus. In contrast, Notch2 is preferentially expressed in mature B cells and is required for the generation of a mature B-cell subset, known as splenic marginal zone B (MZB) cells. Deregulation of Notch1 function results in the development of T-cell acute lymphoblastic leukemia (T-ALL) in a number of mouse experimental models, and more importantly, more than 50% of childhood and 30% to 40% of adult human T-ALL cases carry Notch1 mutations that lead to deregulated activation of Notch signaling, indicating that accelerated Notch signaling contributes to the development of human neoplasms.
[Results and Discussion] We screened Notch2 gene mutations at the heterodimerization and PEST domains in 109 B-cell lymphoma samples, and found mutations in 5 samples, all of which were diffuse large B-cell lymphomas (DLBCL; in DLBCL, 5 of 63 samples, ∼8%). These mutations lead to partial or complete deletion of the PEST domain, or a single amino acid substitution at the C-terminus of Notch2 protein. All five DLBCL cases with Notch2 mutations were uniformly immunohistochemically negative for CD10 and positive for BCL6 and MUM-1, whereas only 10 out of 24 Notch2 mutation-negative subjects showed this staining pattern. This observation might imply a link between Notch2 mutations and a fraction of non-germinal center B-cell-like DLBCL (non-GCB-DLBCL), according to the immunohistchemistry-based DLBCL subclassification. Interestingly, high-density oligonucleotide microarray analysis revealed that two of the five Notch2 mutation-carrying samples had an increased copy number of the mutated Notch2 allele, and in another sample of the five the total copy number of the Notch2 allele was increased. Furthermore, in the Notch activation-sensitive luciferase reporter assay in vitro, mutant Notch2 receptors showed increased activity compared with wild-type Notch2. These findings implicate Notch2 gain-of-function mutations in the pathogenesis of a subset of B-cell lymphomas, and suggest broader roles for Notch gene mutations in human cancers.
A Multi-Site, Prospective Cross-Over Study of Intranasal Desmopressin and Oral Tranexamic Acid in Women with Menorrhagia and Abnormal Laboratory Hemostasis.
Authors: Kouides Peter A. , Heit John A. , Philipp Claire S. , Stein Sid F. , Lukes Andrea S. , Byams Vanessa R. , Dowling Nicole F. , Evatt Bruce L. , Miller Connie R. , Owens Sally , Skerette Nyasha , Kulkarni Roshni 
Published: October 2019

Introduction: Menorrhagia is a common health problem affecting ∼5-10% of women. The optimal management of menorrhagia among women with abnormal laboratory hemostasis is uncertain. The goal of this study was to determine the effect of intranasal desmopressin (IN-DDAVP) vs. oral tranexamic acid (TA) on menstrual blood loss (MBL) and quality of life (QOL).
Methods: In a cross-over study design, 117 consenting women 18–50 years of age with menorrhagia (defined as subjective report of heavy bleeding and a pictorial blood assessment chart [PBAC] score > 100) with a negative gynecological evaluation and abnormal laboratory hemostasis (62% platelet dysfunction, 15% von Willebrand disease, 23% other coagulation defect or combined) were randomly assigned to initial IN-DDAVP or TA therapy each for two menstrual cycles, followed by cross-over to the second study drug for an additional two cycles. MBL by PBAC was measured at baseline and after each menstrual cycle while QOL was assessed by four validated instruments: Health Related Quality of Life (HRQOL), SF-36®, Center for Epidemiologic Studies Depression Scale (CES-D) and the Ruta menorrhagia questionnaire.
Results: There was a statistically significant decrease in the PBAC for both treatments. On average, the estimated decrease in the PBAC from baseline for IN-DDAVP was −66.0 (CI = (−89.5, −42.6)) and for TA, −107.8 (CI = (−131.5, −84.1)). The decrease in the PBAC score was larger for TA with a difference of 41.8 (p-value = 0.0002, CI = (20.4, 63.2)) between the two treatments. In the multivariable analysis, the test for treatment-cycle number interaction was not significant, suggesting no carry-over effect. The test for a treatment type effect was significant (p<0.0001) suggesting a greater reduction in PBAC score with TA compared to IN-DDAVP. Both IN-DDAVP and TA generally improved QOL as assessed by each of the four instruments. Over-all, the Ruta Menorrhagia Questionnaire and the Center for Epidemiologic Studies Depression Scale measurements showed the most statistically significant improvements.
Conclusion: Both TA and IN-DDDAVP reduce MBL and improve QOL in females with menorrhagia and abnormal laboratory hemostasis.The significance of these findings are underscored by the fact that prior studies of menorrhagia treatment in these patients have not included validated QOL instruments. The marked improvement in MBL and QOL noted with TA and IN-DDAVP appears to justify hemostasis screening in women presenting with menorrhagia for whom no gynecological cause can be found.
Children with t(12;21)/TEL-AML1-Positive Acute Lymphoblastic Leukemia Exhibit a Distinct Germline Genomic Signature.
Authors: Trevino Lisa R. , Yang Wenjian , Hunger Stephen , Carroll William L. , Devidas Meenakshi , Willman Cheryl L. , Downing James , Evans William E. , Pui Ching-Hon , Relling Mary V. 
Published: October 2019

Abstract
High-throughput genome-wide studies have identified significant associations between inherited genetic variations and complex diseases. To delineate the heterogeneous nature of pediatric acute lymphoblastic leukemia (ALL), we performed a genome-wide interrogation of approximately 600K single nucleotide polymorphisms (SNPs) in 470 Caucasian children (using > 99% European ancestry genetic markers to define race) with newly diagnosed ALL to identify the contribution of germline SNP genotypes to ALL subtype. Our patient population included children enrolled on St Jude Children’s Research Hospital Total XIIIB and Total XV ALL protocols and the COG9906 ALL protocol. The study cohort included 47 cases with the t(12;21)/TEL-AML1 (aka ETV6/RUNX1) translocation, 116 with hyperdiploidy > 50 chromosomes, 46 with T-lineage ALL, and 139 with non-hyperdiploid B-lineage ALL (without known translocations). Using genotype data from the Affymetrix 100K and 500K Mapping Array sets and logistic regression analyses, we found that only patients with TEL-AML1-positive ALL demonstrated a distinct germline SNP signature (p = 0.043, 1000 permutations) compared to patients with other ALL subtypes. We identified 1,046 germline SNPs whose allele frequencies discriminated TEL-AML1 ALL from non-TEL-AML1 ALL (p < 0.005). For example, the odds ratio associated with the risk of TEL-AML1 vs. other ALL subtypes for the T vs. C allele at the ITPR2 SNP (rs12814812) was 3.5 (p=0.000019), and that for the G vs. A allele at the IL26 SNP (rs11570906) was 3.1 (p = 0.000111). These 1,046 SNPs represent 224 unique genes. Among these 1,046 SNPs, 28 cis SNPs were significantly associated with the mRNA expression of 19 genes in diagnostic leukemic lymphoblasts. Of these 19 genes, the gene expression of the growth factor, ANGPT2;, coagulation factor, F13A1; and the enzyme, AGA, differed significantly between TEL-AML1-positive and negative cases. We also identified one intronic SNP in each of the translocation target genes (RUNX1 and ETV6) whose genotype frequencies differed between TEL-AML1-positive and negative cases (p = 0.01 and 0.03 respectively). Conversely, SNPs in high linkage disequilibrium with previously hypothesized risk alleles in MTHFR and NQO1 did not differ in allele frequencies between the two subgroups (p > 0.05). It is well recognized that TEL-AML1-positive ALL represents a fourth of childhood cases but is exceedingly rare in adults, and hence, it is not surprising that the TEL-AML1-positive ALL subtype may be more likely to be affected by inherited genomic variability compared to other subtypes. We conclude that inherited genetic variation may contribute to risk of or pathogenesis of the TEL-AML1 subtype of childhood ALL.
Missplicing of Glycogen Synthase Kinase 3β: A Potential Mechanism of Blast Crisis Chronic Myeloid Leukemia Stem Cell Generation.
Authors: Abrahamsson Annelie , Geron Ifat , Gotlib Jason , Dao Kim-Hien , Giles Francis , Newton Isabel , Kavalerchik Edward , Durocher Jeffrey , Creusot Remi , Karimi Mobin , Jones Carol , Zehnder James , Keating Armand , Negrin Robert , Weissman Irving L. , Jamieson Catriona H.M. 
Published: October 2019

Abstract
Recent evidence suggests that a rare population of self-renewing cancer stem cells (CSC) is responsible for cancer progression and therapeutic resistance. Chronic myeloid leukemia (CML) represents an important paradigm for understanding the genetic and epigenetic events involved in CSC production. CML progresses from a chronic phase in hematopoietic stem cells (HSC) that harbor the BCR-ABL translocation, to blast crisis, characterized by aberrant activation of β-catenin within granulocyte-macrophage progenitors (GMP). Here we show that blast crisis CML myeloid progenitors can serially transplant leukemia in immunocompromised mice, and thus are enriched for leukemia stem cells (LSC). Genomic DNA and cDNA sequencing analysis of Wnt/β-catenin pathway regulatory genes including APC, GSK3β, axin 1, β-catenin, LEF-1, cyclin D1 and c-myc in 49 normal and 51 CML HSC, GMP and lineage-positive populations revealed that in 57% of blast crisis samples a novel in-frame splice deletion of the GSK3β kinase domain occurred in blast crisis CML GMP, but not blasts found in blast crisis or normal progenitors. CML progenitors with misspliced GSK3β have enhanced β-catenin expression as well as serial engraftment potential. We propose that chronic phase CML is initiated by BCR-ABL expression in an HSC clone but that progression to blast crisis may include missplicing of GSK3β in GMP LSC, enabling unphosphorylated β-catenin to participate in LSC self-renewal. Missplicing of GSK3β represents an unique mechanism for the emergence of blast crisis CML LSC, is a potential diagnostic indicator of disease progression and represents a novel therapeutic target in blast crisis CML. As the first description of GSK3β dysregulation in cancer, this research provides a focal point for investigating whether GSK3β missplicing also triggers β-catenin activation in other CSC.
Reduced Oxidative Stress and Enhanced Nitric Oxide (NO) Bioavailability in Transgenic-Knockout Sickle Mice Expressing Fetal Hemoglobin (HbF) Is Mediated by Decreased Sickling and Hemolysis.
Authors: Dasgupta Trisha , Fabry Mary E. , Kaul Dhananjay K. 
Published: October 2019

Abstract
The primary event in the vaso-occlusive pathophysiology of sickle cell disease (SCD) is polymerization of hemoglobin S under deoxygenated conditions. In SCD, sub-clinical transient vaso-occlusive events caused by red cell sickling are likely to be more frequent resulting in “reperfusion injury” that generates reactive oxygen species and results in chronic oxidative stress that will contribute to multiple organ damage. In fact, previous studies have suggested that sickling is etiologic to repefusion injury and oxidative stress (Kaul and Hebbel, JCI, 2000), although the effect of antisickling therapy on oxidative stress has not been evaluated. Increasing the levels of antisickling fetal hemoglobin (HbF) by hydroxyurea therapy markedly reduces polymer formation. HbF exerts an ameliorating effect in sickle cell disease patients both on red cells and in the prevention of multiple organ damage. Here, we hypothesize that induction of HbF by genetic manipulation (in the absence of pharmacological manipulation) will reduce organ oxidative stress by reducing sickling and hemolysis, and thereby increase NO bioavailability. To test our hypothesis, we measured activity of selected antioxidants and lipid peroxidation (LPO) in BERK mice expressing exclusively human α- and βS-globins and varying levels of HbF, i.e., BERK (<1% HbF), BERKγM (20% HbF) and BERKγH (40% HbF). Percent sickled cells in venous samples (drawn in 2.5% glutaraldehyde solution in 0.1M cacodylate buffer) showed a distinct decrease with increased %HbF (P<0.05, multiple comparisons). Consistent with maximal sickling, BERK mice showed 5.4–6.9-fold increase in LPO in various tissues (muscle, kidney and liver) compared with C57BL controls (P<0.001). In contrast, BERKγM and BERKγH mice showed a marked decrease (73% and 80%, respectively) in LPO compared with BERK mice (P<0.001). Also, activity/levels of antioxidants (superoxide dismutase [SOD], catalase, glutathione peroxidase [GPx] and reduced glutathione [GSH]) showed significant decreases in BERK mice (P<0.001–0.00001). On the other hand, BERKγM and BERKγH mice showed significant increases in antioxidant activity (P<0.05–0.0001). Induction of HbF was associated with increased levels of NO metabolites (NOx) and reduced hemolysis; the latter is in agreement with our previous observations in BERKγM mice (Kaul et al. JCI, 2004). These results strongly suggest that reduced sickling and hemolysis in the presence of HbF cause increased NO bioavailability. NO is well known to exert antioxidative effects. Thus, we show for the first time that the induction of antisickling HbF leads to an increase in NO bioavailability and a decrease in oxidative stress, and that these protective effects are mediated primarily by reduced intravascular sickling.
Sulindac Sulfide Reverts the Activation of the WNT-Signaling and Aberrant Self Renewal Induced by the AML-Associated Fusion Proteins PML/RARα and PLZF/RARα.
Authors: Steinert Gunnar , Seshire Anita , Hoelzer Dieter , Ruthardt Martin , Puccetti Elena 
Published: October 2019

Abstract
Leukemia-specific translocations - t(15;17), t(11;17), or t(8;21) - lead to the expression of leukemia associated fusion proteins (LAFP) such as PML/RAR, PLZF/RAR and AML-1/ETO. LAFP induce and maintain a leukemic phenotype by blocking terminal differentiation of hematopoietic progenitors and by increasing the self renewal potential of the leukemic stem cells (LSC). The key mechanims by which LAFP increase LSC self renewal is the activation of the Wnt-signaling pathway by up-regulating of γ-catenin and β-catenin at a transcriptional level. The aberrant activation of Wnt-signaling by the LAFP decisively contributes to the pathogenesis of AML. To disclose whether a “leukemic stem cell therapy” is effective we targeted the Wnt-signaling by Sulindac Sulfid (SuSu) in PML/RAR- or PLZF/RAR- (X-RAR) positive stem cell models. SuSu represents the active metabolite of Sulindac, a nonsteroidal anti-inflammatory drug (NSAID), known to inactivate the Wnt-signaling. SuSu was used at a clinically achievable concentration of 50–100 μM. As leukemia models we used U937 cells stably expressing the X-RAR and NB4 cells. As stem cell models we used i.) the aldehyde dehydrogenase positive/CD34+/CD38- fraction of the KG-1 cells stably expressing the X-RAR; ii.) Sca-1+/lin- murine HSC retrovirally transduced with the X-RAR in semi solid medium. The amount of total γ-catenin and β-catenin and activated β-catenin was determined by immunoblotting. We report that SuSu i.) down-regulated not only β-catenin but also γ-catenin in X-RAR expressing U937 and KG-1 cells; ii.) reduced the active form of β-catenin in the presence of X-RAR; iii.) induced a high apoptosis rate in PML/RAR-positive NB4 cells; iv.) reduced the “stem cell fraction” of KG-1 cells expressing X-RAR but not of mock transfected controls; iv.) reduced the self renewal potential of X-RAR-positive HSC as revealed by a significantly reduced replating efficiency. Here we provide evidence that the exposure to therapeutically achievable dosages of a NSAID revert the aberrant activation of the Wnt-signaling by LAFP. The significant reduction of the aberrant self renewal potential of HSC in the presence of X-RAR further support that the inhibition of the aberrantly activated Wnt signaling in AML might be a valid molecular therapy approach which has to further validated in in vivo leukemia models and in a more clinical setting.