bluuebunny/crossref_metadata_2025_split huggingface dataset:
Twice-Daily Deferasirox Improves Cardiac Iron Chelation in the Gerbil Model of Iron Cardiomyopathy.
Authors: Otto-Duessel Maya , Aguilar Michelle I. , Nick Hanspeter , Moats Rex , Wood John C. 
Published: October 2019

Abstract
Introduction: Iron cardiomyopathy remains the leading cause of death in thalassemia major patients because effective chelation of cardiac iron is difficult. Cardiac iron stores respond more slowly to chelation therapy and appear to require a sustained gradient of labile iron species between myocytes and serum. We have previously demonstrated the efficacy of once-daily deferasirox in removing stored cardiac iron in the gerbil but changes in cardiac iron were relatively modest compared with hepatic iron. We postulated that twice daily dosing (BID), by sustaining a longer labile iron gradient from myocytes to serum, would produce better cardiac iron chelation than a comparable once daily dose (QD).
Methods: Twenty four eight-to-ten week old female Mongolian gerbils underwent iron dextran loading for 10 weeks, followed by a 1 week iron equilibration period. Animals were divided into 3 treatment groups of 8 animals apiece and treated with deferasirox 100 mg/kg/day as a single dose (n=8), deferasirox 100 mg/kg/day divided BID (n=8), or sham chelation (n=8) for a total of 12 weeks. Following euthanasia, organs were harvested for quantitative iron determination and tissue histology.
Results: All of the animals tolerated the 10-week loading and 12-week chelation with no adverse events. After the 22-week period, hepatic iron content was 17.7 ± 4.8 mg and 21.1 ± 5.3 mg in the QD and BID groups, compared with 43.1 ± 5.3 mg in the sham-chelated animals (p < 0.0001 sham versus treatment, p=0.2 between groups). Corresponding cardiac iron content was 0.19 ± 0.04 mg, 0.16 ± 0.04 mg and 0.23 ± 0.04 mg respectively. These changes were significant in the BID group (p< 0.006 versus sham). While BID versus QD cardiac iron contents were not statistically different, treatment groups were clearly distinct when viewed as a scattergram of heart and liver iron content (Figure 1). The BID treated animals exhibited lower cardiac iron for any given hepatic iron content. This is best observed by comparing the ratio of cardiac to hepatic iron content (Figure 2, which was 0.78% in the BID group versus 1.11% in the QD treated animals (p=0.0007).
Discussion: In Mongolian gerbils, deferasirox effectively removed liver and cardiac iron with either BID or QD dosing. BID dosing changed the relative cardiac and liver iron chelation profile compared with QD dosing, trading improvements in cardiac iron elimination for a modest decrease in hepatic chelation. Caution should be exercised in extrapolating these results to humans, however clinical studies of BID administration should be considered for patients requiring high chelator dosing or who have high cardiac iron burden.
Figure 1 Figure 1. Figure 2 Figure 2.
A C-Terminal Exosite of von Willebrand Factor Domain A2 Interacts with ADAMTS13 Spacer Domain To Accelerate Substrate Cleavage.
Authors: Gao Weiqiang , Anderson Patricia J. , Majerus Elaine M. , Tuley Elodee A. , Sadler J. Evan 
Published: October 2019

Abstract
ADAMTS13 is a plasma metalloproteinase that limits platelet-rich thrombi by cleaving von Willebrand factor (VWF) at the Tyr1605-Met1606 bond in the A2 domain. A minimal substrate that consists of GST linked to VWF residues Asp1596-Arg1668 with a C-terminal 6×His tag (GST-VWF73) is cleaved rapidly by plasma ADAMTS13. Further removal of Glu1660-Arg1668, which comprises a predicted C-terminal α-helix (GST-VWF64) markedly reduced the rate of cleavage, suggesting this helix comprises an exosite for substrate recognition. By amino acid sequencing, ADAMTS13 was shown to cleave the Tyr1605-Met1606 bond of GST-VWF64. Truncation of ADAMTS13 after certain structural domains had different effects on substrate cleavage. After removal of the GST moiety by proteolysis, the kinetic constants for cleavage of VWF73 and VWF64 were determined for several recombinant ADAMTS13 variants using a quantitative MALDI-MS assay (Table). Comparison of the specificity constants (kcat/Km) shows that ADAMTS13 truncated after the spacer domain (construct MDTCS) cleaved VWF73 ~20-fold faster than did a similar enzyme without the spacer domain (construct MDTC). In contrast, both MDTCS and MDTC cleaved VWF64 slowly at a rate similar to the cleavage of VWF73 by MDTC. Most of the variation in cleavage rates was explained by differences in Km, suggesting that the spacer domain recognizes an exosite at the C-terminus of VWF73 that is missing from VWF64. Cleavage of VWF73 yields a C-terminal product (cVWF63). Purified cVWF63 (7.5 μM) inhibited MDTCS activity toward VWF73 or VWF64 (1.5 μM) by »90%, but did not inhibit MDTC, suggesting that the exosite of VWF73 or cVWF63 interacts directly with the spacer domain. Moreover, cVWF63 inhibited the cleavage of multimeric VWF by full-length ADAMTS13 and MDTCS up to 80%, but did not inhibit MDTC. The selective effects of deleting the ADAMTS13 spacer domain and Glu1660-Arg1668 of the VWF domain A2 suggest that the C-terminal exosite of the VWF A2 domain accelerates substrate cleavage by binding specifically to the ADAMTS13 spacer domain.
Table Kinetics studies of VWF73 and VWF64 cleavage by ADAMTS13 and its truncations VWF73 VWF64 Enzyme K m (μM) k cat (s−1) k cat /K m (×105 M−1 s−1) K m (μM) k cat (s−1) k cat /K m (×105 M−1 s−1) FL-ADAMTS13 1.7±0.4 1.3±0.1 7.5±2.0 37.7±12.8 1.9±0.4 0.5±0.3 MDTCS 0.8±0.2 1.7±0.1 20.5±6.6 5.5±1.4 0.6±0.1 1.0±0.3 MDTC 16.0±4.5 1.8±0.3 1.1±0.5 17.9±6.3 1.6±0.3 0.9±0.5
The Role of Survivin in Angiogenesis during Zebrafish Embryonic Development.
Authors: Leung Anskar Y.H. , Ma Alvin C.H. , Meng Anming , Verfaillie Catherine M. , Liang Raymond 
Published: October 2019

Abstract
We investigated the role of survivin in angiogenesis during zebrafish development. Morpholinos (MOs) targeting the 5′ untranslated region (UTR) (SurUTR) and sequences flanking the initiation codon (SurATG) of zebrafish survivin-1 gene were injected into embryos at 1–4 cell stage. Vasculature was examined by microangiography and GFP expression in Tg(fli1:GFP) embryos. In embryos co-injected with SurUTR and SurATG-MOs, vasculogenesis was intact but angiogenesis was markedly perturbed, especially in the inter-segmental vessels (ISV) of the trunk, the inner optic circle and optic veins of developing eyes and the sub-intestinal vessels. Apoptosis was increased, as shown by TUNEL staining and increase in caspase-3 activity. Efficacy of SurUTR and SurATG-MOs was demonstrated by translation inhibition of co-injected 5′UTR survivin:GFP plasmids. The phenotypes could be recapitulated by splice-site MO targeting the exon2-intron junction of survivin gene and rescued by survivin mRNA. Injection of human vascular endothelial growth factor (VEGF) protein induced ectopic angiogenesis and increased survivin expression, whereas treatment with a VEGF receptor inhibitor markedly reduced angiogenesis and suppressed survivin expression. Hematopoietic cell development at 18 hpf, before the onset of circulation, was unaffected in the survivin MO injected embryos. In conclusion, survivin is involved in angiogenesis during zebrafish development and is under VEGF regulation.
NOTCH1-Induced T-Cell Leukemia in Transgenic Zebrafish.
Authors: Chen Jihua , Jette Cicely , Kanki John P. , Aster Jon , Thomas Look A. , Griffin James D. 
Published: October 2019

Abstract
Activating mutations in the NOTCH1 gene have been found in about 60% of patients with T-cell acute lymphoblastic leukemia (T-ALL). In order to study the molecular mechanisms by which altered Notch signaling induces leukemia, a zebrafish model of NOTCH1-induced T-cell leukemia was generated using TAN-1, the NOTCH1 oncogene generated by the t(7;9)(q34;q34.3) chromosome translocation associated with human T-ALL. Seven of sixteen mosaic fish developed a T cell lymphoproliferative disease at about 5 months. These neoplastic cells extensively invaded tissues throughout the fish and caused an aggressive and lethal leukemia when transplanted into irradiated recipient fish. A stable transgenic fish line was then generated, which also develops leukemia, but with a longer latency for leukemia onset. This longer latency allowed crosses to be done to evaluate potential genetic interactions between NOTCH1 and other T-ALL oncogenes. Interestingly, LMO2 did not cooperate with NOTCH1 to induce T-ALL, while bcl2 had dramatic effects on latency and progression of T-ALL in this zebrafish model. These results suggest that the transforming functions of NOTCH1 and LMO2 may be redundant, while the functions of NOTCH1 and bcl2 are highly complementary. The ability of this model to detect a strong interaction between NOTCH1 and bcl2 suggests that genetic modifier screens have a high likelihood of revealing other genes that can cooperate with NOTCH1 to induce T-ALL.
Relationship between mTOR-Mediated Upregulation of Glycolysis and Chemosensitivity of ALL Blasts.
Authors: Frolova Olga , Buglio Daniela , Samudio Ismael , McQueen Teresa , Kantarjian Hagop , Weiser Mary A. , Andreeff Michael , Konopleva Marina 
Published: October 2019

Abstract
Cancer cells exhibit a high rate of glycolysis, which leads to a stringent dependence on extracellular glucose for maintaining intracellular ATP levels. Leukemic cells infiltrating bone marrow have been shown to be markedly hypoxic compared to normal bone marrow cells, and stimulation of glycolysis is thought to be an adaptive mechanism to hypoxia. The serine/threonine kinase AKT promotes continued cell growth and metabolism by increasing glucose uptake, stimulating glycolysis and ATP production, at least in part via mTOR-dependent stabilization of HIF1-α. The purpose of this study was to investigate the role of mTOR signaling in the regulation of glycolytic activity of leukemic cells growing under high glucose or hypoxic conditions. Culture of Jurkat cells or primary ALL lymphoblasts in hypoxia (1% O2) resulted in robust induction of HIF-1α protein level which was significantly higher in high glucose conditions. This induction was blocked by inhibition of mTOR signaling, in association with decreased HK-2 mRNA and Glut-1 mRNA/protein expression. Likewise, hypoxia induced lactic acid production, a surrogate marker of glycolysis, and this induction was prevented by RAD001 (p=0.01). This data suggest that PI3K/AKT/mTOR pathway critically controls HIF-1α-dependent upregulation of glucose transport and glycolysis under in leukemic cells growing under pro-glycolytic conditions. We next examined the relationship between enhanced glycolytic activity and chemosensitivity to Doxorubicin. Doxorubicin (25ng/ml) efficiently inhibited growth of Jurkat cells under normoxic conditions supplemented with 4 mM glucose (equivalent of 72mg/dl). In contrast, Doxorubicin was approximately 50% less effective when cells were cultured either in high (14mM, equivalent of 252mg/dl) glucose or under hypoxia with low- or high-glucose supplementation. Inhibition of mTOR signaling strikingly enhanced effects of Doxorubicin resulting in complete inhibition of growth, and this effect was apparent only under high glucose conditions. We next examined effects of RAD001 in samples from 11 patients’ samples from newly diagnosed B-ALL patients growing under high/low glucose in hypoxic or normoxic conditions. RAD001 alone did not induce apoptosis in ALL cells (p>0.05). In contrast, inhibition of mTOR signaling significantly enhanced Doxorubicin-induced apoptosis in 8 samples, with highest sensitization observed in high glucose environment (specific apoptosis, Doxorubicin alone, 5.6%, RAD001 7.7%, RAD001+Doxorubicin 22.4%, p<0.02). In conclusion, blockade of mTOR-dependent HIF-1α and its downstream target Glut-1 efficiently promotes chemosensitivity of ALL cells under pro-glycolytic conditions. Hence, mTOR inhibition or blockade of HIF-1α-mediated glycolysis may play an important role in chemosensitization and improved outcomes in ALL.
A Phase II Study of Nilotinib, a Novel Tyrosine Kinase Inhibitor Administered to Imatinib Resistant or Intolerant Patients with Chronic Myelogenous Leukemia (CML) in Blast Crisis (BC) or Relapsed/Refractory Ph+ Acute Lymphoblastic Leukemia (ALL).
Authors: Ottmann Oliver , Kantarjian Hagop , Larson Richard , le Courte Philipp , Baccarani Michele , Rafferty Teresa , Weitzman Aaron , Giles Francis 
Published: October 2019

Abstract
Nilotinib is a highly selective, aminopyrimidine which is 30-fold more potent in vitro than imatinib and active against 32/33 imatinib resistant Bcr-Abl mutations. This open-label study was designed to evaluate the safety and efficacy of Nilotinib administered at a dose of 400 mg bid by hematologic/cytogenetic response (HR/CyR) rates in imatinib resistant or intolerant BC patients or patients with relapsed/refractory Ph+ALL. Preliminary data are presented for 96 BC and 34 Ph+ALL patients. The median age for the Ph+ALL patients was 47 years (range 26 to 75) and for the BC patients 54 years (range 19 to 78). There were 16 males and 18 females with Ph+ALL and 60 males and 36 females with BC. Chromosomal abnormalities other than Ph+ were noted in 12 (35%) and 48 (50%) of BC patients. Extramedullary involvement was present in 3 (9%) Ph+ALL patients and 35 (37%) of BC patients. Treatment is ongoing for 8 (24%) of Ph+ALL patients and 31 (32%) of BC patients. The majority of discontinuations were due to disease progression and occurred in 18 (53%) BC patients and 41 (43%) Ph+ALL. CHR was reported in 12 (13%) BC patients, marrow responses in 6 (6%), return to chronic phase and stable disease in 17 (18%) patients each. Complete responses were reported in 2 (6%) Ph+ALL 1 relapsed/refractory and 1 patient with minimal residual disease). The most frequent Grade 3 or 4 adverse events occurring in patients with Ph+ALL were thrombocytopenia in 3 (9%) patients, and 2 (6%) patients each had neutropenia, blood bilirubin increased, ALT elevation and bone pain. The most frequent Grade 3 or 4 adverse events occurring in patients with BC were thrombocytopenia 23 (24%), neutropenia 17 (18%), and anemia in 9 (9%) of patients. Nilotinib has clinical activity and an acceptable safety and tolerability profile in pts with imatinib resistant or intolerant BC and relapsed/refractory Ph+ ALL patients.
In Vivo Control of Acute Lymphoblastic Leukemia by Immunostimulatory CpG Oligonucleotides.
Authors: Reid Gregor S.D. , Fujii Hisaki , Trudeau Jacqueline , Hall Junior , Fish Jonathan D. , Teachey David T. , Brown Valerie I. , Schultz Kirk R. , Grupp Stephan A. 
Published: October 2019

Abstract
Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. While current therapy is effective for the majority of children, relapsed ALL remains the fifth most common pediatric malignancy and responds very poorly to treatment. In addition, about 50% of ALL cases occur in adults, and while remission is achieved in many patients the majority of these will succumb to relapsed disease. In most cases relapse is treated with more intensive chemotherapy or hematopoietic cell transplantation, therapies that are associated with significant toxicity. In both patient populations, therefore, there is an urgent need for novel approaches to inhibit disease progression. Immunostimulatory DNA oligonucleotides containing CpG motifs (CpG ODN) have been shown to induce strong anti-tumor immune activity in a variety of model systems and are currently being evaluated in clinical trials. We have previously reported that CpG ODN stimulation of ALL cells alters their antigen presentation ability and enhances Th1 responses by allogeneic T cells. In this study, using NOD-SCID mice bearing xenografts of primary human ALL or human ALL cell lines, we demonstrate that CpG ODN stimulate significant immune activity against ALL cells in vivo. A single intravenous injection of 300micrograms Class B CpG ODN induced a significant reduction in percentage of human ALL cells in peripheral blood (P<0.0001), spleen (P=0.0036) and liver (P=0.0004), but not bone marrow (P=0.254), compared to PBS treatment of mice. The reduced leukemia burden in the spleens of CpG ODN treated mice correlated with a significantly higher percentage of Annexin-V positive ALL cells (P=0.008 for PBS vs CpG; P=0.016 for CpG vs control ODN), indicating the induction of leukemia cell death in these mice. In addition, repeated administration of CpG ODN mediated continued disease control, and significantly improved survival of mice with established primary sample or cell line derived human ALL (P=0.002). The death of leukemia cells in vivo was independent of the ability of ALL cells to respond directly to CpG ODN, and correlated with the production of significant amounts of interferon-alpha, interferon-gamma and IL-12 in treated mice. Cell depletion studies implicate natural killer cells in the CpG ODN induced killing of human ALL. Preliminary results obtained using the Emu-ret transgenic mouse model of B cell leukemia indicate that CpG ODN treatment also induces killing of syngeneic leukemia cells, and work is ongoing to identify the immune mechanisms mediating this activity. Based on these results, we hypothesize that CpG ODN will have considerable potential as a novel agent for the prevention of ALL progression.
Benefit of Targeted Intensification for NCI High Risk Childhood Lymphoblastic Leukaemia: Results of the United Kingdom Medical Research Council Trial ALL97 and ALL97/99.
Authors: Vora Ajay , Ward Rachel , Payne Jeanette , Mitchell Chris , Eden Tim , Kinsey Sally , Lilleyman John , Richards Sue 
Published: October 2019

Abstract
In November1999, the UK childhood ALL trial, ALL 97, adopted CCG risk stratification and treatment regimens in favour of the UKALL approach due to concerns over lower event-free survival (EFS) in the UK compared to the US. A key new feature in the amended trial, ALL97/99, was NCI risk group and early marrow response targeted intensification. Of 1935 patients registered in the trial between January 1997 and June 2002, 997 were treated on ALL97 and 938 on ALL97/99. EFS was better in ALL97/99 compared with ALL 97 (5 year EFS: ALL 97 = 74.1%, 95% CI 71.4%–76.8% vs ALL 97/99 = 78.9%, 76.0%–81.8%, p=0.002). To investigate whether particular sub-groups benefited more or less with the CCG approach, we compared outcomes for different risk groups within the two parts of the trial in regard to EFS, overall survival (OS) and CNS relapse risk. All p values quoted are two-sided. EFS and OS were significantly better in ALL97/99 compared with ALL97 for NCI high risk (HR) patients (5 year EFS: ALL 97 = 61.8%, 95% CI: 56.9–66.7%, ALL 97/99 = 71.8% 95% CI: 66.7–76.9%, p = 0.0006. 5 year OS: ALL97 = 71.3%, 95% CI: 66.8–75.8%, ALL97/99 = 80.3% 95% CI: 76.0–84.6%, p = 0.005), but did not differ significantly for NCI standard risk (SR) patients (5 year EFS: ALL 97 = 81.7% 95% CI: 78.6–84.8%, ALL 97/99 = 83.3% 95% CI: 79.8–86.8%, p = 0.3. 5 year OS: ALL97 = 91.2% 95% CI: 89.0–93.4%, ALL97/99 = 92.6% 95% CI: 90.4–94.8%, p = 0.5). The incidence of isolated CNS relapse was also significantly lower in ALL97/99 for NCI HR (ALL97 = 8% vs ALL97/99 = 3.5%, p = 0.01) but not NCI SR patients (ALL97 = 3.5% vs ALL97/99 = 2.7%, p = 0.6). Despite restricting the use of cranial radiotherapy to patients with overt CNS disease (CNS 3, <5% of all patients), the incidence of isolated CNS relapse in ALL97/99 was reassuringly low, even for sub-groups at high risk of CNS relapse such as those with WCC > 100 × 10 9/l (4.8%) or T cell phenotype (3.8%). Isolated CNS relapse risk in ALL97/99 patients randomised to dexamethasone (which was compared with prednisolone in the trial) was 1.8%, similar to that reported with use of cranial radiotherapy for a higher proportion of patients. A targeted intensification approach improves EFS for NCI HR patients and, especially when combined with systemic dexamethasone, results in a low incidence of isolated CNS relapse for high risk sub-groups without use of cranial radiotherapy.
Outcomes in Children and Adolescents with a Markedly Elevated White Blood Cell Count (>200,000) at Diagnosis of High Risk Acute Lymphoblastic Leukemia (ALL): A Report from the Children’s Oncology Group.
Authors: Hastings Caroline , Sather Harland N. , Seibel Nita L. , Nachman James , Steinherz Peter G. , Bertolone Kathy , DeLaat Cynthia , Ettinger Lawrence J. , Franklin Janet , Robert Freyer David , Mattano Leonard A. , Mitchell Torrey L. , Rubin Charles M. , Pyesmany Allan F. , Heerema Nyla A. , Edens Cheryl , Gaynon Paul S. 
Published: October 2019

Abstract
In prior studies, children and adolescents with markedly elevated (ME) WBC≥200,000 had a poor outcome. We examined the outcome of these patients enrolled on CCG l961 (n=250) and compared them to other patients with WBC<200,000 (n=1800). Criteria for CCG-1961 enrollment included age 1–9 years and WBC ≥ 50,000; or age ≥ 10 years with any WBC. Two-thirds of ME WBC patients were male; one third were ≥ 10 years of age, and 7% had CNS disease at diagnosis. Among patients with evaluable immunophenotypes (n=223), 46% had B precursor and 55% had T cell ALL. Event free survival (EFS) at 5 years for ME vs lower WBC patients was 60% and 73%, respectively (p<.0001). Survival (S) at 5 years was 73% vs 82% for ME and lower WBC patients, respectively (p=.0015). EFS for ME B precursor patients was 45% compared to 72% for lower WBC B precursor patients (p<.0001). EFS for ME and lower WBC T cell patients was 71% and 74%. On CCG 1961, rapid early response (RER) patients were randomized to receive stronger or standard intensity therapy and standard or longer intensification. Slow early response (SER) patients received increased intensity therapy and were randomized to receive sequential idarubicin/cyclophosphamide or weekly doxorubicin in intensification. All SER patients received 2 delayed intensifications. EFS for RER ME WBC patients (n=143) was 73% for stronger intensification and 60% for standard intensification. EFS for RER ME WBC was 72% for standard duration and 59% for longer duration intensification. EFS was 61% for SER patients (n=83) with no difference among regimens. Eleven of 103 B lineage ME WBC patients had Ph+ ALL of those there were 8 subsequent events. Patients with CNS 2 had significantly worse outcome (4 year EFS 52%) compared to patients with CNS 3 (4 year EFS 59%) or CNS 1(4 year EFS 68%) status at diagnosis, (p=.04). In conclusion, a ME WBC appears to have no prognostic significance for T cell patients while a ME WBC is highly prognostic for B precursor patients. Stronger intensification improves EFS for RER ME WBC patients as compared to standard intensification. Although the numbers are small, the magnitude of this difference is similar to the outcome of the entire study.