bluuebunny/crossref_metadata_2025_split huggingface dataset:
IRC011, a New Synthetic Chelator With Selective Interaction With Catabolic Red Blood Cell Iron: Evaluation in Hypertransfused Rats With Hepatocellular and Reticuloendothelial Radioiron Probes and in Iron-Loaded Rat Heart Cells in Culture
Authors: Rivkin Gurion , Link Gabriela , Simhon Elliot , Cyjon Rosa L. , Klein Joseph Y. , Hershko Chaim 
Published: October 2019

Abstract
A major consideration in the selection of new and improved iron chelators for clinical use is preferential interaction with the most toxic iron compartment. We describe the biologic properties of a new synthetic hexadentate iron chelator (IRC011) that is a substituted polyaza compound. Unlike deferoxamine (DF ), the polyaza structure of IRC011 does not contain any readily hydrolyzable covalent bonds and is anticipated to resist in vivo biotransformation. In the present studies, the ability of IRC011 to remove radioiron from iron-loaded heart cells in vitro was similar to DF, with a decrease to 20.0 ± 0.4% and 19.7 ± 0.5% of initial values after 24 hours of incubation with 0.3 mmol/L of DF or IRC011, respectively. The in vivo interaction of IRC011 with specific iron stores was studied in hypertransfused rats using selective labeling of reticuloendothelial (RE) iron stores with 59Fe-heat-denatured red blood cells (DRBCs) and of hepatocellular stores with 59Fe-ferritin. The pattern of radioiron excretion with IRC011 was quite different from that with DF. Although with both compounds, hepatocellular iron excretion was through the bile, whereas RE iron excretion was mainly in the urine, the magnitude of these effects was quite different. After the administration of a single parenteral dose of 200 mg/kg representing a 53% higher iron-binding capacity for IRC011 compared with DF, 48-hour urinary excretion of RE iron with IRC011 was 22.8% ± 1.1% (% of total body 59Fe), but only 6.0% ± 3.6% with DF. By contrast, the corresponding biliary excretion of hepatocellular radioiron was 14.2% ± 3.2% with DF, but only 0.7% ± 0.3% with IRC011. Thus, the new iron chelator IRC011 is distinguished from DF by the following features: (1) a higher affinity to Fe(III), (2) anticipated resistance to in vivo catabolism, (3) preferential interaction with RE iron derived from RBC breakdown, and (4) selective renal excretion. Because RBC breakdown is the most likely source of the toxic nontranferrin plasma iron, IRC011 may be a useful iron chelator for protecting vital organs from peroxidative damage.
Exclusion of Three Candidate Genes as Determinants of Congenital Dyserythropoietic Anemia Type II (CDA-II)
Authors: Iolascon Achille , Miraglia del Giudice Emanuele , Perrotta Silverio , Granatiero Matteo , Zelante Leopoldo , Gasparini Paolo 
Published: October 2019

AbstractCongenital dyserythropoietic anemia type II (CDA-II) is the most common form of inherited dyserythropoiesis. Previous studies have shown that the anion transporter (band 3) is narrower and it migrates faster on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE); this aspect was related to insufficient glycosylation. Biochemical data support the hypothesis that this disease is due to a deficiency of N-acetylglucosaminyltransferase II (GnT II) or α-Mannosidase II (α-Man II), which represent the key to glycosylation. In addition, a third candidate gene is α-Man IIx, which shows a strong homology with α-Man II. The knowledge of the chromosomal localization of these putative genes allowed us to perform a linkage study using three sets of microsatellite markers flanking the candidate genes. Six families with two or more affected children were enrolled in this study. The data obtained exclude linkage to all three candidate genes. In consideration of the biochemical data (reduction of enzymatic activity) of the same enzymes, our results suggest the hypothesis that a defect in an unknown transcriptional factor is involved in CDA-II.
Phenotypic and Functional Analysis of Fas (CD95) Expression in Primary Central Nervous System Lymphoma of Patients With Acquired Immunodeficiency Syndrome
Authors: Baiocchi Robert A. , Khatri Vijay P. , Lindemann Matthew J. , Ross Mary E. , Papoff Giuliana , Caprio Anthony J. , Caprio Thomas V. , Fenstermaker Robert , Ruberti Giovina , Bernstein Zale P. , Caligiuri Michael A. 
Published: October 2019

AbstractThe poor prognosis associated with patients afflicted with the acquired immunodeficiency syndrome and primary central nervous system lymphoma (AIDS-PCNSL) is due in part to the intrinsic resistance of this Epstein-Barr virus (EBV)-associated tumor to conventional antineoplastic therapy. Fas (CD95) is a transmembrane protein receptor that transmits an intracellular signal leading to rapid programmed cell death following ligation with its natural ligand or anti-Fas antibodies. Fas expression and function were assessed in AIDS-PCNSL biopsy samples and in EBV+ human B-cell tumors that spontaneously developed in severe combined immune deficient (SCID) mice engrafted with human lymphocytes (hu-PBL-SCID mice). All tumors samples showed high-density surface expression of Fas by flow cytometry or immunohistochemical staining. Cells from two AIDS-PCNSL biopsy samples that did not express pan B-cell markers did not express Fas antigen. All tumors examined were susceptible to Fas-mediated apoptosis, as measured by standard assays for endonucleolytic cleavage of DNA. The response to Fas-mediated apoptosis was dependent on log-fold increases in the concentration of immobilized anti-Fas antibody, but could also be induced with a mobilized anti-Fas antibody. No evidence for intrinsic resistance to Fas-mediated apoptosis (ie, secreted or truncated forms of Fas) could be shown. Radiation-induced apoptosis of neoplastic EBV+ B cells was enhanced by activation of Fas, and prolonged exposure to interleukin-2 increased both Fas expression and Fas-induced apoptosis. As the normal brain parenchyma appears to have either low-density or absent expression of Fas, and antineoplastic therapy can be selectively delivered to the CNS with little systemic toxicity, local delivery of Fas-activating molecules could prove to be a useful component in the multimodal treatment of AIDS-PCNSL.
Infection of Human Marrow Stroma by Human Immunodeficiency Virus-1 (HIV-1) Is Both Required and Sufficient for HIV-1–Induced Hematopoietic Suppression In Vitro: Demonstration by Gene Modification of Primary Human Stroma
Authors: Bahner Ingrid , Kearns Karen , Coutinho Sunita , Leonard Earl H. , Kohn Donald B. 
Published: October 2019

AbstractPatients with human immunodeficiency virus-1 (HIV-1) infection often present with bone marrow (BM) failure that may affect all hematopoietic lineages. It is presently unclear whether this failure reflects a direct viral impairment of the CD34+ hematopoietic progenitor cells or whether the virus affects the BM microenvironment. To study the effects of HIV-1 on the BM microenvironment, we examined the stromal cell monolayers in long-term BM culture (LTBMC), which are the in vitro equivalent of the hematopoietic microenvironment. We assessed the hematopoietic support function (HSF ) of human stromal layers by determining the cellular proliferation and colony-forming ability of hematopoietic progenitors from BM cells grown on the stromal layers. We show that the HSF is reduced by in vitro infection of the human stromal cell layer by a monocytotropic isolate of HIV-1 (JR-FL). There is no loss of HSF when the stromal cell layer is resistant to HIV-1 replication, either using murine stromal cell layers that are innately resistant to HIV-1 infection or using human stromal cells genetically modified to express a gene that inhibits HIV-1 replication (an RRE decoy). Decreased HSF was seen using either human or murine hematopoietic cells, if the stromal cells were human cells that were susceptible to HIV-1 infection. These in vitro studies implicate HIV-1 replication in the stroma as the essential component causing decreased hematopoietic cell production in HIV-1 infection.
Loss of Tolerance to Exogenous and Endogenous Factor VIII in a Mild Hemophilia A Patient With an Arg593 to Cys Mutation
Authors: Thompson Arthur R. , Murphy Michael E.P. , Liu MiaoLiang , Saenko Evgueni L. , Healey John F. , Lollar Pete , Scandella Dorothea 
Published: October 2019

AbstractA 42-year-old patient with mild hemophilia A developed spontaneous muscle hematomas 1 month after intense therapy with factor VIII concentrates. Factor VIII clotting activity was less than 1% and his factor VIII inhibitor was 10 Bethesda units (BU)/mL. The titer peaked at 128 BU despite daily infusions of factor VIII; 1 year later, the titer was 13 BU with no spontaneous bleeding for 4 months. The plasma inhibitor was 95% neutralized by factor VIII A2 domain but less than 15% neutralized by light-chain or C2 domain. His inhibitor did not cross-react with porcine factor VIII and was at least 10-fold less reactive to a series of hybrid factor VIII proteins in which human residues 484-508 are replaced by the homologous porcine sequence (Healey et al, J Biol Chem 270:14505, 1995). The inhibitor patient's DNA encoding his A2 domain and flanking sequences showed a C-T transition predicting Arg593 to Cys. Thirteen patients from 5 unrelated families with Cys593 have not developed inhibitors. Factor VIII clotting activity from one of them was inhibited similarly to diluted normal plasma by inhibitor patient plasma. In an homologous structure, ceruloplasmin (Zaitseva et al, J Biol Inorgan Chem 1:15,1996), the residue equivalent to Arg593, is in a loop distinct from residues 484-508. On solution phase immunoprecipitation with labeled factor VIII fragments, A2, light chain, and C2 domains bound. In contrast to typical immune responses to factor VIII in patients with severe hemophilia A, this patient's inhibitor was almost entirely reactive with common epitopes within the A2 domain whereas by more sensitive immunoprecipitation testing antibodies to light chain epitopes were also present. Accordingly, immune responsiveness to exogenous factor VIII (antigen burden) appears to be more critical than his endogenous, hemophilic factor VIII to his developing high-titer anti–factor VIII antibodies and loss of tolerance to both native and hemophilic factor VIII proteins.
Altered Tumor Growth and Metastasis of a T-Cell Lymphoma in Timp-1 Transgenic Mice
Authors: Krüger Achim , Fata Jimmie E. , Khokha Rama 
Published: October 2019

Abstract
The concept of tumor suppression by tissue inhibitor of metalloproteinases (TIMPs) has evolved primarily from studies of genetically modulated tumor cells. The next step is to focus on the host and assess the protective potential of host TIMP-1 on primary tumor growth and metastasis. We generated two transgenic mouse lines with altered Timp-1 expression in skin and liver: one overexpressed Timp-1 (Timp-1high), and the other had antisense RNA–mediated Timp-1 reduction (Timp-1low). ESbL-lacZ T-lymphoma cells provided the tumor challenge, as they form primary tumors upon intradermal injection with spontaneous metastasis to liver. Metastases were examined in X-Gal–stained whole-organ mounts. Timp-1 overexpression inhibited intradermal tumor growth and spontaneous metastasis, leading to prolonged survival of the mice. The opposite effects occurred in Timp-1low mice, leading to shorter host survival. Experimental metastasis assays showed that Timp-1–compromised livers in Timp-1low mice showed at least a doubling of metastatic foci and numerous additional micrometastases, indicative of increased host susceptibility. However, Timp-1high mouse livers showed an unaltered metastatic load in the experimental metastasis assay. In conclusion, these data demonstrate that Timp-1 levels within a tissue predetermine the development and progression of T-cell lymphoma.
Growth of Human T-Cell Lineage Acute Leukemia in Severe Combined Immunodeficiency (SCID) Mice and Non-obese Diabetic SCID Mice
Authors: Steele Jeremy P.C. , Clutterbuck Robyn D. , Powles Ray L. , Mitchell Paul L.R. , Horton Clive , Morilla Ricardo , Catovsky Daniel , Millar John L. 
Published: October 2019

AbstractPrimary leukemic cells from patients with acute lymphoblastic leukemia (ALL) can be injected intravenously into mice with severe combined immunodeficiency (SCID) to create a model of human leukemia. Leukemic cells disseminate to murine tissues in a clinicopathologic pattern similar to that seen in humans. Thus far, reports of engraftment of lymphoid leukemia in SCID mice have mainly been from patients with B-cell lineage ALL, for which engraftment occurs more frequently with cells from high-risk patients. There are few data on the engraftment of T-cell lineage ALL in SCID mice. Leukemic cells from 19 patients (16 adult and three pediatric) with T-cell lineage ALL were injected into SCID mice, with overt engraftment of 12 cases (63%). Engraftment of leukemia in SCID mice was associated with earlier death due to leukemia of the patient donors (P < .01, log-rank test). The recently developed non-obese diabetic (NOD)/SCID mouse may expand the uses of the SCID model. Cells from the seven patients with T-cell lineage ALL that failed to cause leukemia in SCID mice were injected into NOD/SCID mice. Overt leukemia engraftment was observed in all seven cases. Thus, growth of human T-cell lineage ALL cells in SCID mice was associated with a high-risk patient group. However, this association was not observed when NOD/SCID mice were used, suggesting that this model would no longer predict patients likely to die early of leukemia, but may provide a more realistic system for studying the biology and treatment of the disease.
Two New EPO Receptor Mutations: Truncated EPO Receptors Are Most Frequently Associated With Primary Familial and Congenital Polycythemias
Authors: Kralovics Robert , Indrak Karel , Stopka Tomas , Berman Brian W. , Prchal Jaroslav F. , Prchal Josef T. 
Published: October 2019

Abstract
Primary polycythemias are caused by an acquired or inborn mutation affecting hematopoietic/erythroid progenitors that results in an abnormal response to hematopoietic cytokines. Primary familial and congenital polycythemia (PFCP; also known as familial erythrocytosis) is characterized by elevated red blood cell mass, low serum erythropoietin (EPO) level, normal oxygen affinity of hemoglobin, and typically autosomal dominant inheritance. In this study we screened for mutations in the cytoplasmic domain of the EPO receptor (EPOR; exons 7 and 8 of the EPOR gene) in 27 unrelated subjects with primary or unidentified polycythemia. Two new EPOR mutations were found, which lead to truncation of the EPOR similarly to previously described mutations in PFCP subjects. The first is a 7-bp deletion (del59855991) found in a Caucasian family from Ohio. The second mutation (5967insT) was found in a Caucasian family from the Czech Republic. In both cases the EPO dose responses of the erythroid progenitors of the affected subjects were examined to confirm the diagnosis of PFCP. In one of these families, the in vitro behavior of erythroid progenitors in serum-containing cultures without the addition of EPO mimicked the behavior of polycythemia vera progenitors; however, we show that antibodies against either EPO or the EPOR distinguish the in vitro growth abnormality of polycythemia vera erythroid progenitors from that seen in this particular PFCP family. We conclude that PFCP is a disorder that appears to be associated in some families with EPOR mutations. So far, most of the described EPOR mutations (6 out of 8) associated with PFCP result in an absence of the C-terminal negative regulatory domain of the receptor.
Hereditary Hyperferritinemia-Cataract Syndrome Caused by a 29-Base Pair Deletion in the Iron Responsive Element of Ferritin L-Subunit Gene
Authors: Girelli Domenico , Corrocher Roberto , Bisceglia Luigi , Olivieri Oliviero , Zelante Leopoldo , Panozzo Giacomo , Gasparini Paolo 
Published: October 2019

AbstractIron availability regulates ferritin synthesis posttranscriptionally by the interaction between iron-regulatory proteins (IRPs) and an iron responsive element (IRE), a stem-loop sequence located on the 5′ untranslated region of ferritin mRNA. IRPs recognize IREs as a sequence/structure motif, blocking ferritin translation. Recently, we and others independently described families with a combination of hyperferritinemia (serum L-ferritin ≥ 1,000 μg/L, without iron overload) and congenital bilateral cataract, transmitted as an autosomal-dominant trait. The molecular basis were two distinct point mutations in the highly conserved CAGUG(X) hexaloop of L-ferritin IRE on chromosome 19. A new three-generation family with a similar phenotype and a unique genotype is here reported. DNA amplification by polymerase chain reaction and sequence analysis showed a 29-base pair deletion in the L-ferritin IRE, involving the whole 5′ sequence essential to the base pairing of the IRE stem. This deletion is predicted to cause the disruption of IRE stem-loop secondary structure and the nearly complete abolition of the negative control of ferritin synthesis by IRE/IRP binding. Hereditary Hyperferritinemia-Cataract Syndrome (HHCS) appears as a new genetic disorder with a unique phenotype associated with at least four different mutations in the L-ferritin IRE. Hematologists should take into account HHCS in the differential diagnosis of unexplained hyperferritinemia.
Autologous Versus Unrelated Donor Allogeneic Marrow Transplantation for Acute Lymphoblastic Leukemia
Authors: Weisdorf Daniel J. , Billett Amy L. , Hannan Peter , Ritz Jerome , Sallan Stephen E. , Steinbuch Michael , Ramsay Norma K.C. 
Published: October 2019

AbstractBone marrow transplantation (BMT) can cure patients with high-risk or recurrent acute lymphoblastic leukemia (ALL). Those lacking a related donor can receive either autologous or histocompatible unrelated donor (URD) marrow. Autotransplantation may result in higher risk of relapse, whereas URD allografts, although associated with serious posttransplant toxicities, may reduce relapse risk. Six years (1987 to 1993) of consecutive autologous BMT (University of Minnesota, Dana Farber Cancer Institute; n = 214) were compared with URD transplants (National Marrow Donor Program; n = 337). Most transplants (70% autologous, 48% URD) were in early remission (first or second complete remission [CR1 or CR2]); 376 patients (75% autologous, 64% URD) were less than 18 years old. Autologous BMT led to significantly lower transplant-related mortality (TRM; relative risk [RR] 0.35; P = .001). URD transplantation offered greater protection against relapse (autologous RR 3.1; P = .001). Patients greater than 18 years old, women, and BMT recipients beyond CR2 had higher TRM, whereas adults, BMT recipients in CR2+, or BMT recipients during 1991 through 1993 had significantly more relapse. After 25 months median follow-up, 100 URD and 56 autologous recipients survive leukemia free. URD BMT in CR2 resulted in superior disease-free survival (DFS), especially for adult patients. Multivariate analysis showed superior DFS for children, men, and BMT during CR1 or 2. Autologous and URD BMT can extend survival for a minority of patients unlikely to be cured by chemotherapy, and the results with either technique are comparable. Greater toxicity and TRM after URD BMT are counterbalanced by better protection against relapse. Prospective studies addressing additional clinical variables are needed to guide clinical decision making about transplant choices for patients with ALL.
Antitumor Effects of Nonconjugated Murine Lym-2 and Human-Mouse Chimeric CLL-1 Monoclonal Antibodies Against Various Human Lymphoma Cell Lines In Vitro and In Vivo
Authors: Funakoshi Satoshi , Hirano Akio , Beckwith Margaret , Asai Osamu , Jorgensen Gitte , Tian Zhi-gang , Hornick Jason L. , Hu Peisheng , Khawli Leslie A. , Epstein Alan L. , Longo Dan L. , Murphy William J. 
Published: October 2019

AbstractLym-2 is a murine monoclonal antibody (MoAb) directed towards a human class II molecule variant reactive with both normal and neoplastic human B lymphocytes. Previous studies have shown that signals transmitted by class II molecules that stimulate normal lymphocytes can be inhibitory for B-cell lymphoma growth by signaling activation-induced cell death. Therefore, we sought to evaluate the effects of nonconjugated murine Lym-2 and a human-mouse chimeric Lym-2 (chCLL-1; with murine variable regions and human constant regions) MoAb on the growth of various human lymphomas by using both in vitro and in vivo assays. Cell lines derived from Burkitt's lymphomas, diffuse large cell B-cell lymphomas, anaplastic large-cell lymphomas, and Epstein-Barr virus–induced B-cell lymphomas were incubated with Lym-2 or chCLL-1 in vitro, and effects on proliferation were determined by [3H]-thymidine incorporation. The effects of Lym-2 in vitro were also compared with those of Lym-1, which is a similar MoAb that has been evaluated clinically. After immobilization, which enhances crosslinking of the MoAbs, both Lym-2 and chCLL-1 were capable of directly inhibiting the growth of various lymphoma lines in vitro. These human lymphomas were then transferred into mice with severe combined immunodeficiency to evaluate the efficacy of these MoAbs in vivo. Treatment with either murine Lym-2 or the chimeric chCLL-1 were significantly effective in improving the survival of tumor-bearing mice. These results indicate that stimulation by nonconjugated chCLL-1 may offer a biological approach to the treatment of various human lymphomas.
Immunotherapy of Multiple Myeloma With a Monoclonal Antibody Directed Against a Plasma Cell-Specific Antigen, HM1.24
Authors: Ozaki Shuji , Kosaka Masaaki , Wakatsuki Shingo , Abe Masahiro , Koishihara Yasuo , Matsumoto Toshio 
Published: October 2019

AbstractMultiple myeloma remains an incurable malignancy because of marked resistance of tumor cells to conventional chemotherapeutic agents. Alternative strategies are needed to solve these problems. To develop a new strategy, we have generated a monoclonal antibody (MoAb), which detects a human plasma cell-specific antigen, HM1.24. In this report, we evaluated the in vivo antitumor effect of unconjugated anti-HM1.24 MoAb on human myeloma xenografts implanted into severe combined immunodeficiency (SCID) mice. Two models of disseminated or localized tumors were established in SCID mice by either intravenous or subcutaneous injection of human myeloma cell lines, ARH-77 and RPMI 8226. When mice were treated with a single intraperitoneal injection of anti-HM1.24 MoAb 1 day after tumor inoculation, the development of disseminated myeloma was completely inhibited. In mice bearing advanced tumors, multiple injections of anti-HM1.24 MoAb reduced the tumor size and significantly prolonged survival, including tumor cure, in a dose-dependent manner. The proliferation of cultured human myeloma cells was inhibited in vitro by anti-HM1.24 IgG-mediated complement-dependent cytotoxicity, but not by the antibody alone. Moreover, spleen cells from SCID mice mediated antibody-dependent cell cytotoxicity against RPMI 8226 cells. These results indicate that anti-HM1.24 MoAb can be used for immunotherapy of multiple myeloma and related plasma cell dyscrasias.