bluuebunny/crossref_metadata_2025_split huggingface dataset:
Presence of clone-specific antigen receptor gene rearrangements at birth indicates an in utero origin of diverse types of early childhood acute lymphoblastic leukemia
Authors: Fasching Karin , Panzer Simon , Haas Oskar A. , Marschalek Rolf , Gadner Helmut , Panzer-Grümayer E. Renate 
Published: October 2019

Abstract
There is strong evidence that infant leukemias with a t(4;11) translocation originate in utero. To test whether other subtypes of childhood leukemias are also initiated during fetal life, we used clone-specific genetic markers for the analysis of neonatal blood spots from 5 children aged 6 months to 4 years 8 months at diagnosis of pro-B, common acute lymphoblastic leukemia (ALL), and T-ALL. In all children, the clonotypic antigen receptor gene rearrangements were already present at birth. The estimated amount of clonotypic cells was in the range of 10 to 100 cells per blood spot. In 2 infants with a t(4;11) positive ALL, we detected similar amounts of the fusion gene sequences compared with the clonal antigen receptor gene rearrangements, suggesting the presence of both markers in the same cells. Our data indicate that the first leukemogenic event of diverse types of childhood ALL may already occur in utero.
Expression and coreceptor activity of STRL33/Bonzo on primary peripheral blood lymphocytes
Authors: Sharron Matthew , Pöhlmann Stefan , Price Ken , Lolis Elias , Tsang Monica , Kirchhoff Frank , Doms Robert W. , Lee Benhur 
Published: October 2019

Abstract
CCR5 and CXCR4 are the major coreceptors that mediate human immunodeficiency virus 1 (HIV-1) infection, while most simian immunodeficiency virus (SIV) isolates use CCR5. A number of alternative coreceptors can also mediate infection of some virus strains in vitro, although little is known about their in vivo relevance. Therefore, we characterized the expression pattern and coreceptor activity of one of these alternative coreceptors, STRL33/Bonzo, using a newly developed monoclonal antibody. In addition to being highly expressed (approximately 1000-7000 STRL33 ABS [antibody binding sites]) on specific subsets of natural killer cells (CD3−/CD16−/low/CD56+ and CD3−/CD16low/CD56−) and CD19+ B lymphocytes (approximately 300-5000 STRL33 ABS), STRL33 was expressed at levels sufficient to support virus infection on freshly isolated, truly naive CD4+/CD45RA+/CD62L+cells (6000-11 000 ABS). STRL33 expression on peripheral blood mononuclear cells (PBMCs) was increased by mitogenic stimulation (OKT3/IL-2 [interleukin-2] had a greater effect than phytohemaglutinin (PHA)/IL-2), but it was dramatically decreased upon Ficoll purification. Infection of CCR5− human peripheral blood lymphocytes (PBLs) showed that 2 different SIV envelope (Env) proteins mediated entry into STRL33+cells. More importantly, the preferential infection of STRL33+ cells in CCR5− PBLs by an R5/X4/STRL33 HIV-1 maternal isolate in the presence of a potent CXCR4 antagonist (AMD3100) suggests that STRL33 can be used as a coreceptor by HIV-1 on primary cells. Rhesus macaque (rh) STRL33 was used less efficiently than human STRL33 by the majority of SIV Env proteins tested despite similar levels of expression, thereby making it less likely that STRL33 is a relevant coreceptor in the rhesus macaque system. In summary, the expression pattern and coreceptor activity of STRL33 suggest its involvement in trafficking of tumor-infiltrating lymphocytes and indicate that STRL33 may be a relevant coreceptor in vivo.
An in vivo competitive repopulation assay for various sources of human hematopoietic stem cells
Authors: Rosler Elen S. , Brandt John E. , Chute John , Hoffman Ronald 
Published: October 2019

Abstract
The marrow repopulating potential (MRP) of different sources of human hematopoietic stem cells (HSCs) was directly compared using an in vivo assay in which severe combined immunodeficient disease (SCID) mice were implanted with human fetal bones. HSCs from 2 human lymphocyte antigen (HLA)-mismatched donors were injected individually or simultaneously into the fetal bones of a 3rd distinct HLA type and donor and recipient myeloid and lymphoid cells were identified after 8 to 10 weeks. The study compared the MRP of umbilical cord blood (CB) and adult bone marrow (ABM) CD34+ cells as well as grafts of each type expanded ex vivo. Equal numbers of CB and ABM CD34+ cells injected individually demonstrated similar abilities to establish multilineage hematopoiesis. However, when CB and ABM cells were transplanted simultaneously, the engraftment of CB cells was markedly superior to ABM. CB and ABM CD34+ cells were expanded ex vivo using either a porcine microvascular endothelial cell (PMVEC)-based coculture system or a stroma-free expansion system. Primary CB CD34+ cells or CD34+ cells expanded in either culture system demonstrated a similar ability to engraft. However, the MRP of expanded grafts simultaneously injected with primary CB cells was uniformly inferior to primary CB cells. CD34+ cell grafts expanded in the stroma-free system, furthermore, outcompeted CD34+ cells expanded using the PMVEC coculture system. The triple HLA-mismatched SCID-hu model represents a novel in vivo stem cell assay system that permits the direct demonstration of the functional consequences of ex vivo HSC expansion and ontogeny-related differences in HSCs.
VCAM-1 has a tissue-specific role in mediating interleukin-4–induced eosinophil accumulation in rat models: evidence for a dissociation between endothelial-cell VCAM-1 expression and a functional role in eosinophil migration
Authors: Larbi Karen Y. , Allen Andrew R. , Tam Frederick W. K. , Haskard Dorian O. , Lobb Roy R. , Silva Patricia M. R. , Nourshargh Sussan 
Published: October 2019

AbstractEosinophil accumulation has been associated with the pathogenesis of numerous allergic inflammatory disorders. Despite the great interest in this response, many aspects of eosinophil accumulation remain unknown. This is particularly true with respect to tissue-specific mechanisms that may regulate the accumulation of eosinophils in different organs. This study addressed this issue by investigating and comparing the roles of α4-integrins and vascular cell adhesion molecule 1 (VCAM-1) adhesion pathways in interleukin 4 (IL-4)–induced eosinophil accumulation in 2 different rat models of inflammation, namely pleural and cutaneous inflammation. Similar to our previous findings in studies in rat skin, locally administered IL-4 induced a time- and dose-dependent accumulation of eosinophils in rat pleural cavities, a response that was associated with generation of the chemokine eotaxin. The IL-4–induced eosinophil accumulation in skin and pleural cavities was totally inhibited by an antirat α4-integrins monoclonal antibody (mAb) (TA-2). In contrast, whereas an antirat VCAM-1 mAb (5F10) totally blocked the response in skin, IL-4–induced eosinophil accumulation in rat pleural cavities was not affected by VCAM-1 blockade. A radiolabeled mAb technique demonstrated that endothelial-cell VCAM-1 expression was induced in response to IL-4 in both skin and pleural membrane. The results indicate that although endothelial-cell VCAM-1 is present in skin and pleura, a functional role for it in IL-4–induced eosinophil accumulation was evident only in skin. These findings suggest the existence of tissue-specific adhesive mechanisms in regulating leukocyte migration in vivo and demonstrate a dissociation between VCAM-1 expression and eosinophil accumulation.
Lymphoproliferative disease of granular T lymphocytes presenting as aplastic anemia
Authors: Go Ronald S. , Tefferi Ayalew , Li Chin-Yang , Lust John A. , Phyliky Robert L. 
Published: October 2019

AbstractLymphoproliferative disease of granular T lymphocyte (T-LDGL), also known as T-cell large granular lymphocyte leukemia, is a clonal disorder of cytotoxic T lymphocytes that is clinically manifested as chronic neutropenia and anemia. Association with autoimmune disorders is common. In 9 patients, T-LDGL is reported as presenting as aplastic anemia. The clinical characteristics were similar to acquired aplastic anemia. Morphologic evidence of increased granular lymphocytes in the peripheral blood and an excess of CD3+/CD8+/CD57+ cells in the bone marrow were found in most cases. Cyclophosphamide was ineffective, but noncytotoxic immunosuppressive agents generally produced a good response. After a median follow-up of 49 months, 5 patients had died from the disease or related complications. Median survival was 40 months. Aplastic anemia can be a presenting manifestation of T-LDGL, and T-LDGL should be considered in the differential diagnosis of acquired aplastic anemia.
Spontaneous remission of granulocyte colony-stimulating factor–associated leukemia in a child with severe congenital neutropenia
Authors: Jeha Sima , Chan Ka Wah , Aprikyan Andrew G. , Hoots W. Keith , Culbert Steven , Zietz Hallie , Dale David C. , Albitar Maher 
Published: October 2019

Abstract
Leukemia is observed with increased frequency in patients with severe congenital neutropenia (SCN). In the past decade, recombinant human granulocyte colony-stimulating factor (rh G-CSF) has prolonged the survival of patients with SCN increasingly reported to have leukemias. In this communication acute myelogenous leukemia (AML) associated with a mutation of the G-CSF receptor (G-CSF-R) developed in a patient with SCN maintained on long-term G-CSF therapy. The blast count in the blood and bone marrow fell to undetectable levels twice on withholding G-CSF and without chemotherapy administration, but the mutant G-CSF-R was detectable during this period. The patient subsequently underwent successful allogeneic bone marrow transplantation. After transplantation, the patient's neutrophil elastase (ELA-2) mutation and G-CSF-R mutation became undetectable by polymerase chain reaction. This report provides novel insights on leukemia developing in congenital neutropenia.
Level of minimal residual disease after consolidation therapy predicts outcome in acute myeloid leukemia
Authors: Venditti Adriano , Buccisano Francesco , Del Poeta Giovanni , Maurillo Luca , Tamburini Anna , Cox Christina , Battaglia Alessandra , Catalano Gianfranco , Del Moro Beatrice , Cudillo Laura , Postorino Massimiliano , Masi Mario , Amadori Sergio 
Published: October 2019

Abstract
We used flow cytometry to quantify minimal residual disease (MRD) in 56 patients with acute myeloid leukemia (AML) expressing a leukemia-associated phenotype. Thirty-four patients aged 18 to 60 years were entered into the AML-10 protocol (induction, consolidation, and autologous stem-cell transplantation [ASCT]), whereas 22 patients older than 60 years received the AML-13 protocol (induction, consolidation, and consolidation II). After induction, the level of MRD that was best associated with treatment outcome was 4.5 × 10−4 residual leukemic cells. However, the outcome in patients with at least 4.5 × 10−4 cells (n = 26) was not significantly different from that in patients with fewer leukemic cells (n = 30); there were 15 (58%) relapses in the first group and 12 (40%) relapses in the second. After consolidation, the most predictive MRD cutoff value was 3.5 × 10−4cells: 22 patients had an MRD level of 3.5 × 10−4 cells or higher and 17 (77%) of these patients had relapse, compared with 5 of 29 patients (17%) with lower MRD levels (P &lt; .001). An MRD level of 3.5 × 10−4 cells or higher after consolidation was significantly correlated with poor or intermediate-risk cytogenetic findings, a multidrug resistance 1 (MDR1) phenotype, short duration of overall survival, and short duration of relapse-free survival (P = .014, .031, .00022, and .00014, respectively). In multivariate analysis, this MRD status was significantly associated with a high frequency of relapse (P &lt; .001) and a short duration of overall (P = .025) and relapse-free survival (P = .007). ASCT did not alter the prognostic effect of high MRD levels after consolidation: the relapse rate after transplantation was 70%. Thus, we found that an MRD level of 3.5 × 10−4 cells or higher at the end of consolidation strongly predicts relapse and is significantly associated with an MDR1 phenotype and intermediate or unfavorable cytogenetic findings.
Successful stem cell transplantation following orthotopic liver transplantation from the same haploidentical family donor in a girl with hemophagocytic lymphohistiocytosis
Authors: Matthes-Martin Susanne , Peters Christina , Königsrainer Alfred , Fritsch Gerhard , Lion Thomas , Heitger Andreas , Kapelari Klaus , Kronberger Martina , Offner Felix , Wrba Fritz , Margreiter Raimund , Gadner Helmut 
Published: October 2019

Abstract
The case of a 4-month-old girl with familial hemophagocytic lymphohistiocytosis is described. The patient underwent stem cell transplantation from her haploidentical mother 2 months after receiving a living-related liver transplant from the same donor for acute hepatic failure. Conditioning regimen consisted of 16 mg/kg busulfan, 200 mg/kg cyclophosphamide, 10 mg/kg thiothepa, and antithymocyte globulin. Myeloid engraftment occurred on day +10, but CD3+ cells of recipient origin remained. To convert the T-cell chimerism, the patient received donor lymphocyte infusion on day +43, and subsequently the allelic pattern changed to complete donor genotype on day +57. Four months after stem cell transplantation the patient is disease free, with complete donor chimerism in bone marrow and stable hepatic graft function without any immunosuppressive therapy.
Stable in vivo expression of glucose-6-phosphate dehydrogenase (G6PD) and rescue of G6PD deficiency in stem cells by gene transfer
Authors: Rovira Ana , De Angioletti Maria , Camacho-Vanegas Olga , Liu Delong , Rosti Vittorio , Gallardo Humilidad F. , Notaro Rosario , Sadelain Michel , Luzzatto Lucio 
Published: October 2019

AbstractMany mutations of the housekeeping gene encoding glucose-6-phosphate dehydrogenase (G6PD) cause G6PD deficiency in humans. Some underlie severe forms of chronic nonspherocytic hemolytic anemia (CNSHA) for which there is no definitive treatment. By using retroviral vectors pseudotyped with the vesicular stomatitis virus G glycoprotein that harbor the human G6PD (hG6PD) complementary DNA, stable and lifelong expression of hG6PD was obtained in all the hematopoietic tissues of 16 primary bone marrow transplant (BMT) recipient mice and 14 secondary BMT recipients. These findings demonstrate the integration of a functional gene in totipotent stem cells. The average total G6PD in peripheral blood cells of these transplanted mice, measured as enzyme activity, was twice that of untransplanted control mice. This allowed the inference that the amount of G6PD produced by the transduced gene must be therapeutically effective. With the same vectors both the cloning efficiency and the ability to form embryoid bodies were restored in embryonic stem cells, in which the G6PD gene had been inactivated by targeted homologous recombination, thus effectively rescuing their defective phenotype. Finally, expression of normal human G6PD in hG6PD-deficient primary hematopoietic cells and in human hematopoietic cells engrafted in nonobese diabetic/severe combined immunodeficient mice was obtained. This approach could cure severe CNSHA caused by G6PD deficiency.
Spontaneous thrombosis in mice carrying the factor V Leiden mutation
Authors: Cui Jisong , Eitzman Daniel T. , Westrick Randal J. , Christie Patricia D. , Xu Zuojun J. , Yang Angela Y. , Purkayastha Anjali A. , Yang Tony L. , Metz Alan L. , Gallagher Kim P. , Tyson Julia A. , Rosenberg Robert D. , Ginsburg David 
Published: October 2019

AbstractA polymorphism in coagulation factor V, factor V Leiden (FVL), is the major known genetic risk factor for thrombosis in humans. Approximately 10% of mutation carriers experience clinically significant thrombosis in their lifetime. In a small subset of patients, thrombosis is associated with coinheritance of other prothrombotic gene mutations. However, the potential contribution of additional genetic risk factors in the majority of patients remains unknown. To gain insight into the molecular basis for the variable expressivity of FVL, mice were generated carrying the homologous mutation (R504Q [single-letter amino acid codes]) inserted into the endogenous murine Fv gene. Adult heterozygous (FvQ/+) and homozygous (FvQ/Q) mice are viable and fertile and exhibit normal survival. Compared with wild-type mice, adult FvQ/Q mice demonstrate a marked increase in spontaneous tissue fibrin deposition. No differences in fetal development or survival are observed among FvQ/Q,FvQ/+ or control littermates on the C57BL/6J genetic background. In contrast, on a mixed 129Sv-C57BL/6J genetic background,FvQ/Q mice develop disseminated intravascular thrombosis in the perinatal period, resulting in significant mortality shortly after birth. These results may explain the high degree of conservation of the R504/R506 activated protein C cleavage site within FV among mammalian species and suggest an important contribution of other genetic factors to the thrombosis associated with FVL in humans.
Ligation of E-cadherin on in vitro–generated immature Langerhans-type dendritic cells inhibits their maturation
Authors: Riedl Elisabeth , Stöckl Johannes , Majdic Otto , Scheinecker Clemens , Knapp Walter , Strobl Herbert 
Published: October 2019

AbstractEpithelial tissues of various organs contain immature Langerhans cell (LC)-type dendritic cells, which play key roles in immunity. LCs reside for long time periods at an immature stage in epithelia before migrating to T-cell–rich areas of regional lymph nodes to become mature interdigitating dendritic cells (DCs). LCs express the epithelial adhesion molecule E-cadherin and undergo homophilic E-cadherin adhesion with surrounding epithelial cells. Using a defined serum-free differentiation model of human CD34+hematopoietic progenitor cells, it was demonstrated that LCs generated in vitro in the presence of transforming growth factor β1 (TGF-β1) express high levels of E-cadherin and form large homotypic cell clusters. Homotypic LC clustering can be inhibited by the addition of anti–E- cadherin monoclonal antibodies (mAbs). Loss of E-cadherin adhesion of LCs by mechanical cluster disaggregation correlates with the rapid up-regulation of CD86, neo-expression of CD83, and diminished CD1a cell surface expression by LCs—specific phenotypic features of mature DCs. Antibody ligation of E-cadherin on the surfaces of immature LCs after mechanical cluster disruption strongly reduces the percentages of mature DCs. The addition of mAbs to the adhesion molecules LFA-1 or CD31 to parallel cultures similarly inhibits homotypic LC cluster formation, but, in contrast to anti–E-cadherin, these mAbs fail to inhibit DC maturation. Thus, E-cadherin engagement on immature LCs specifically inhibits the acquisition of mature DC features. E-cadherin–mediated LC maturation suppression may represent a constitutive active epithelial mechanism that prevents the uncontrolled maturation of immature LCs.
Molecular analysis of 9 new families with chronic granulomatous disease caused by mutations in CYBA, the gene encoding p22phox
Authors: Rae Julie , Noack Deborah , Heyworth Paul G. , Ellis Beverly A. , Curnutte John T. , Cross Andrew R. 
Published: October 2019

AbstractChronic granulomatous disease is a rare inherited disorder caused by nonexistent or severely decreased phagocyte superoxide production that results in a severe defect in host defense and consequent predisposition to microbial infection. The enzyme responsible for generating the superoxide, NADPH oxidase, involves at least 5 protein components. The absence of, or a defect in, any 1 of 4 of these proteins (p22phox, p47phox, p67phox, or gp91phox) gives rise to the known types of chronic granulomatous disease. One of the rarest forms of the disease is due to defects in the CYBA gene encoding p22phox, which together with gp91phox forms flavocytochromeb558, the catalytic core of NADPH oxidase. To date, only 9 kindreds with p22phoxdeficiency have been described in the literature comprising 10 mutant alleles. Four polymorphisms in the CYBA gene have also been reported. Here we describe 9 new, unrelated kindreds containing 12 mutations, 9 of which are novel. In addition, we report 3 new polymorphisms. The novel mutations are (a) deletion of exons 2 and 3, (b) a missense mutation in exon 3 (T155→C), (c) a splice site mutation at the 5′ end of intron 3, (d) a missense mutation in exon 2 (G74→T), (e) a nonsense mutation in exon 1 (G26→A), (f) a missense mutation in exon 4 (C268→T), (g) a frameshift in exon 3 due to the insertion of C at C162, (h) a nonsense mutation in exon 2 (G107→A), and (i) a missense mutation in exon 2 (G70→A).
Pathologic interaction between megakaryocytes and polymorphonuclear leukocytes in myelofibrosis
Authors: Schmitt Alain , Jouault Hélène , Guichard Josette , Wendling Françoise , Drouin Arnaud , Cramer Elisabeth M. 
Published: October 2019

Abstract
Idiopathic myelofibrosis (MF) is a myeloproliferative syndrome characterized by an increase in bone marrow collagen. Megakaryocytes (Mks), which store growth factors in their α granules, are known to be involved in the pathogenesis of MF. Previously, mice given bone marrow grafts infected with a retrovirus carrying murine thrombopoietin (TPO) complementary DNA developed a disease resembling human idiopathic MF. In this study, we used this murine model (TPO mice) to determine whether release of α granules is responsible for fibroblast activation and development of fibrosis. The intracellular trafficking of several α-granule proteins (von Willebrand factor, fibrinogen, and transforming growth factor β (TGFβ), which are stored in the granule matrix; and αIIbβ3 integrin and P-selectin (CD62p), which are located in the α-granule membrane) was studied with immune electron microscopy in bone marrow Mks from TPO mice. P-selectin immunolabeling increased consistently and was occasionally found lining the demarcation membrane system. Evidence of extensive emperipolesis was also found in TPO mouse Mks, involving almost exclusively neutrophil and eosinophil polymorphonuclear (PMN) cells with altered morphologic features. In parallel, the host Mks had myeloperoxidase-positive granules scattered in their cytoplasm, associated with marked ultrastructural cytoplasmic alterations and ruptured α-granule membranes. Similar observations were made in bone marrow biopsy specimens from 12 patients with idiopathic MF; indeed, there was an increased rate of emperipolesis involving mostly PMN cells, abnormal P-selectin expression, and mutual subcellular PMN and Mk alterations. This study indicates that in idiopathic MF, abnormal P-selectin distribution in Mks induces selective sequestration of PMN cells. This results in a release of α-granular proteins and growth factors, which in turn induces fibroblast activation and fibrosis deposition.