bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeted Disruption of the Mouse Mitoferrin (Slc25A37) Mitochondrial Solute Carrier Results in Defective Primitive and Definitive Erythropoiesis.
Authors: Paw Barry H. , Gwynn Babette , Langer Nathaniel B. , Shaw George C. , Lambert Amy J. , Boyer Leah A. , Li Liangtao , Stolte Jens , Robledo Raymond F. , Sahr Kenneth E. , Schlaeger Thorsten M. , Hentze Matthias W. , Muckenthaler Martina U. , Kaplan Jerry , Peters Luanne L. 
Published: October 2019

Abstract
We previously described a zebrafish mutant, frascati (frs), which exhibits profound hypochromic anemia and erythroid maturation arrest due to defects in mitochondrial iron uptake. Through positional cloning, we showed that the frs gene encodes a novel member of the vertebrate mitochondrial solute carrier family (SLC25), mitoferrin (mfrn, slc25a37). Mfrn, which is highly expressed in fetal and adult hematopoietic tissues of zebrafish and mouse, functions as the major mitochondrial iron importer essential for heme biosynthesis in vertebrate erythroblasts (Shaw GC, et al. 2006 Nature 440:96–100). To study the function of Mfrn in mammalian organisms, we identified an embryonic stem (ES) cell clone that harbors a gene trap b-geo cassette in intron 1 that inactivates the Mfrn locus. Homozygous disruption of the Mfrn locus results in embryonic lethality at E11.5 from profound anemia due to a failure of primitive erythropoiesis, confirming the requirement of Mfrn in mammalian development . Circumventing the embryonic lethality, we generated Mfrn−/− ES cells to study the role of Mfrn in definitive erythropoiesis by in vitro differentiation of embryoid bodies and mixed chimera assays. Mfrn−/− ES cells were defective in promoting the growth, differentiation, and hemoglobinization of both primitive and definitive erythroblasts by in vitro differentiation of embryoid bodies. In mixed chimera studies, Mfrn−/− ES cells failed to contribute to the erythroid compartment of adult mosaic mice, whereas measurable contribution of Mfrn−/− donor cells could be assayed in the non-erythroid, leukocyte compartment. Transcriptome microarray analysis, using the mouse Affymetrix GeneChip and the custom IronChip, revealed unexpected down-regulation of transcripts for heme-biosynthetic enzymes in Mfrn−/− erythroblasts. The block in protoprophyrin synthesis, as well as mitochondrial heme synthesis, could be partially rescued by the addition of aminolevulinic acid (ALA) to Mfrn−/− erythroblasts in vitro. Our data demonstrate that mitochondrial iron homeostasis, working through the Mfrn iron importer, coordinately regulates the synthetic pathways for porphyrin and heme in developing mammalian erythroblasts.
Hematologic Improvement, Transfusion Independence, and Safety Assessed Using Three Alternative Dosing Schedules of Azacitidine in Patients with Myelodysplastic Syndromes.
Authors: Lyons Roger M. , Cosgriff Thomas , Modi Sanjiv , McIntyre Heidi , Beach C.L. , Backstrom Jay T. 
Published: October 2019

Abstract
Efficacy and safety of azacitidine (Vidaza®), at the FDA-approved dosing schedule of 75 mg/m2/day x 7 days every 28 days, was demonstrated in a phase III CALGB study by Silverman et al (JCO2002; 20:2429) for the treatment of myelodysplastic syndromes (MDS). The objective of this phase II, multicenter, randomized, open-label study in all FAB subtypes of MDS was to study the treatment response and safety of 3 alternative subcutaneous azacitidine dosing schedules, eliminating the need for weekend azacitidine injections. Patients were randomized to either AZA 5-2-2 (75 mg/m2 day x 5 days, followed by 2 days no treatment, followed by 75 mg/m2/day x 2 days), AZA 5-2-5 (50 mg/m2/day x 5 days, followed by 2 days no treatment, followed by 50 mg/m2/day x 5 days) or AZA 5 (75 mg/m2/day x 5 days). After 6 cycles of azacitidine, patients meeting International Working Group MDS response/improvement criteria (Blood2000; 96:3671), defined as complete remission, partial remission, stable disease, or hematologic improvement, were eligible to receive an additional 12 cycles. As of July 1st, a total of 106 patients have been randomized in the AZA 5-2-2 (n=33), AZA 5-2-5 (n=35), and AZA 5 (n=38) treatment arms. Based on FAB classification, most patients have RA (42%, 45/106) or RAEB (30%, 32/106). Of 80 patients who have received ≥2 cycles of treatment, hematologic improvement (major or minor in at least 1 cell line) occurred in 58% (46/80) of the patients (Table). Median time to improvement in the 3 arms ranged between 1 and 3 cycles (AZA 5-2-2: 1.1, AZA 5-2-5: 3.0, AZA 5: 2.6). Of 38 patients who were RBC transfusion dependent at baseline, 27 (71%) became independent (AZA 5-2-2: 59%, 10/17, AZA 5-2-5: 89%, 8/9; AZA 5: 75%, 9/12). The most common grade 3 or 4 events included neutropenia 29%, 28/98 (AZA 5-2-2: 44%, 14/32; AZA 5-2-5: 20%, 6/30, and AZA 5: 22%, 8/36), thrombocytopenia 15%, 15/98 (AZA 5-2-2: 28%, 9/32; AZA 5-2-5: 10%, 3/30, and AZA 5: 8%, 3/36) and anemia 12%, 12/98 (AZA 5-2-2: 16%, 5/32; AZA 5-2-5: 17%, 5/30, and AZA 5: 6%, 2/36). The frequency of patients with a grade 3 or 4 infection was 15%, 15/98 (AZA 5-2-2: 19%, 6/32; AZA 5-2-5: 23%, 7/30; AZA 5: 6%, 2/36) or hemorrhage was 4%, 4/98 (AZA 5-2-2: 6%, 2/32; AZA 5-2-5: 7%, 2/30; AZA 5: 0/36). Updated data will be available at the time of the meeting. Based on preliminary results, these data indicate that the 3 alternative dosing schedules provide clinical benefit (i.e., transfusion independence and hematologic improvement) and are consistent with the FDA-approved 75 mg/m2/day x 7 days dosing results from previous CALGB studies.
Table: Hematologic Improvement Response Rates
Treatment of Myelodysplastic Syndromes with del 5q before the Lenalidomide Era: The GFM Experience.
Authors: Kelaidi Charikleia , Park Sophie , Brechignac Sabine , Mannone Lionel , Vey Norbert , Dombret Herve , Aljassem Lina , Stamatoullas Aspasia , Adès Lionel , Giraudier Stéphane , de Botton Stéphane , Mahé Béatrice , Lepelley Pascale , Picard Françoise , Leroux Geneviève , Daniel Marie-Thérèse , Bouscary Didier , Dreyfus François , Fenaux Pierre 
Published: October 2019

Abstract
Background: MDS with del 5q are characterized by profound anemia, which until the recent introduction of lenalidomide (N Engl J Med2005; 352: 549–57, J Clin Oncol2005;16S:5), was considered generally unresponsive to available treatments. In order to reevaluate the outcome of those patients in the pre-lenalidomide era, we analyzed response of anemia in MDS with del 5q treated with EPO ± G-CSF and thalidomide in previous GFM trials.
Patients: MDS with del 5q included in 419 MDS treated with EPO or Darbepoetin (DAR) ± G-CSF by GFM centers (including 3 successive GFM trials: Blood2004; 104: 321–7; Blood2005;106 suppl 1: 712a; Br J Haematol2006;133: 513–9 and submitted to ASH 2006), and in 134 MDS treated with thalidomide in two successive GFM trials (Br J Haematol2005; 131: 609–18, and submitted to ASH 2006). Patients received at least 30,000 U/w of EPO or 300 mg/w of DAR and doses ranging from 50 to 800 mg/d of Thalidomide during at least 12 weeks.
Results: 48 MDS with del 5q received EPO (or DAR) ± G-CSF, including 30 pts with del 5q alone, 9 with one and 9 with >1 additional cytogenetic abn; 21/48 had marrow blasts ≥5% (7 had >10%). 17 had the “5q- syndrome” according to WHO. Median pre-treatment EPO level was 287 UI/L (range 12–5,665), i.e. significantly more than in non del 5q cases (median 68, p<0.001). 22/48 pts (46%) had erythroid response, including 15 major and 7 minor (11 responses after EPO or DAR alone and 11 after EPO or DAR + G-CSF) vs. 64% in pts without del 5q (p=0.01) (p= 0.066 after adjustment for marrow blasts). The response rate was 52%, 55%, 22% and 33%, respectively in del 5q pts with the 5q- syndrome, one additional cytogenetic abn, >1 additional cytogenetic abn, and marrow blasts ≥5%. Response duration was significantly shorter in MDS with del 5q than in other MDS (mean 12 vs. 24 months, p=0.019) and in pts with 5q- syndrome vs. other MDS with marrow blasts <5% (mean 11vs. 24months, p=0.025). 20 pts with del 5q were treated with thalidomide. 6/20 had an erythroid response (30 %, including 3 major and 3 minor responses) vs. 29% of other MDS (p=NS)
Conclusion: MDS with del 5q with ≤1 additional cytogenetic abn and no excess of marrow blasts may have erythroid response to EPO ± G-CSF but responses are generally very short, while response rates to thalidomide are low. Those results are clearly inferior to results obtained with lenalidomide in MDS with del 5q.
Correlation of Clinical Features with Mutational Status in Children with Juvenile Myelomonocytic Leukemia.
Authors: Yoshida Nao , Yagasaki Hiroshi , Xu Yinyan , Tanaka Makito , Nishio Nobuhiro , Hidaka Hirokazu , Hama Asahito , Takahashi Yoshiyuki , Manabe Atsushi , Kojima Seiji 
Published: October 2019

Abstract
Juvenile myelomonocytic leukemia (JMML) is a rare clonal myeloproliferative disorder that affects young children. It is characterized by specific hypersensitivity to granulocyte-macrophage colony-stimulating factor (GM-CSF) in vitro. Mutations in RAS, NF1, or PTPN11 positioned in the GM-CSF signal transduction pathway, which contribute to myeloid proliferation, have been recognized in the pathogenesis of JMML. Recently a multi-step model for leukemogenesis has been proposed. In this model, the pathogenesis of leukemia requires at least two classes of mutations:primary mutations of genes implicated in cell differentiation such as AML1 and PU.1 andadditional mutations of genes contributing to myeloid proliferation such as FLT3, RAS, and PTPN11.
We hypothesized that in patients with JMML, in addition to known mutations of genes in the GM-CSF pathway involved in myeloid proliferation, potential causative mutations of other classes might be acquired. AML1 encodes a transcription factor that is essential for definitive hematopoiesis, and its mutations have recently been found in adults with acute myeloid leukemia and myelodysplastic syndrome. However, no information is available on the profiles of mutations in these genes and the relationship between these mutations and clinical features of JMML in children. We analyzed mutations of N-RAS, K-RAS, and PTPN11 in 50, and of AML1 in 30 Japanese children with JMML by direct sequencing. Correlation between the mutational status and clinical and laboratory findings, including age at diagnosis, sex, fetal hemoglobin (HbF), platelets count, cytogenetic abnormalities, and hepatomegaly, all which are suggested prognostic factors for JMML, were also assessed. Of the 50 patients with JMML, cytogenetic abnormalities were detected in 14, including 8 with monosomy 7. PTPN11 and N-/K-RAS mutations were found in 24 (48%) and 7 (14%) patients, respectively, and a novel mutation in AML1 was identified in one patient. No simultaneous mutations in these genes were found. Age at diagnosis was older (median 36 vs 11 months, p=0.0005) and HbF level was higher (31.0% vs 5.1%, p=0.033) in patients with the PTPN11 mutation than those with the RAS mutation. No difference was observed between patients with PTPN11 and RAS mutations in sex ratio, white blood cell count, platelets count, and the incidence of cytogenetic abnormalities and hepatomegaly. Our results suggest that the clinical outcome of patients with PTPN11 might differ from those with RAS mutations because a higher level of HbF and older age have been reported to be poor prognostic factors. In one patient with JMML, we identified a novel mutation in the AML1 gene that belongs to the class of genes contributing to cell differentiation instead of the class of genes in the GM-CSF pathway involved in myeloid proliferation.
FIP1L1-PDGFRalpha Positive Hypereosinophilic Syndrome (HES). The Response to Imatinib (IM) Is Durable. A Report of 21 Patients with a Follow-Up of 12 to 67 Months.
Authors: Rondoni Michela , Ottaviani Emanuela , Piccaluga Pier Paolo , Paolini Stefania , Merante Serena , Cilloni Daniela , Malagola Michele , Palmisano Michela , Grafone Tiziana , Messa Francesca , Buccisano Francesco , Tiribelli Mario , Pane Fabrizio , Saglio Giuseppe , Martinelli Giovanni , Baccarani Michele 
Published: October 2019

Abstract
An interstitial deletion in the long arm of chromosome 4 leads to the formation of a novel fusion gene (FIP1L1-PDGFRalpha) coding for a constitutively activated form of PDGFRalpha. The fusion gene has been identified only in patients with the hypereosinophilic syndrome and has become a marker of clonal HES. The PDGFRalpha transcript can be neutralized by several protein tyrosine kinase inhibitors (PTKI). Recently, imatinib mesylate (IM) has been shown to induce remissions (Cools J, N Engl J Med. 2003; 348:1199–200, Pardanani A, Blood2003;102:3093–6, Cortes J, Blood2003; 102:4714–6) but remission duration is still undefined. The aim of this study was to evaluate the duration of IM in FIP1L1-PDGFRalpha positive HES patients. Hypereosinophilic syndrome was defined according to Chusid criteria (Blood, 1994; 83: 2759–2779). The FIP1L1-PDGFRalpha transcript was identified and monitored every six months on bone marrow cells using a nested retrospective reverse transcriptase polymerase chain reaction (RT-PCR), as reported by Cools J (N Engl J Med.2003; 348:1199–200). Twenty-one FIP1L1-PDGFRalpha positive HES patients have been enrolled in a prospective national study of treatment with IM at a daily dose of 400 mg. All patients were male. Median age was 48 years ( range 25–72). All 21 patients achieved a complete hematologic response (CHR) in less than one month. Currently, the median follow-up of all 21 patients is 28 months ( range 13– 67), with 13 patients with a follow-up longer than 2 years. The longest follow-up are 42, 46 and 67 months. All these patients remained in complete hematologic remission and all became PCR negative and have remained PCR negative as of today. All patients are continuing on imatinib, but in several cases the dose has been reduced to 300, 200 or 100 mg daily. No patients developed heart failure.
We conclude that in FIP1L1-PDGFRalpha positive HES patients the therapeutic effect of IM at doses ranging from 400 to 100 mg daily is sustained over time, up to five years, without detectable adverse effects.
Risk of Recurrent Venous Thromboembolism Reduced by High Density Lipoproteins.
Authors: Eichinger Sabine , Pecheniuk Natalie M. , Hron Gregor , Deguchi Hiroshi , Kyrle Paul A. , Griffin John H. 
Published: October 2019

Abstract
Venous thrombosis is clinically distinct from arterial thrombosis, with notable differences in thrombus appearance, pathogenic mechanisms, and therapeutic approaches. High-density lipoprotein (HDL) protects against arterial atherothrombosis, but it is not known if HDL protects against recurrent venous thromboembolism. We hypothesized that HDL protects against recurrent venous thrombosis because of its multiple antithrombotic and anti-inflammatory actions. These protective activities include down-regulation of thrombin generation by acting as an anticoagulant cofactor for activated protein C/protein S, enhancement of protective endothelial nitric oxide synthase activity, reduction of leukocyte adhesion to endothelium, and anti-apoptotic effects on endothelium. To test our hypothesis, we prospectively studied 772 patients who had a first episode of spontaneous venous thromboembolism. During an average follow-up observation period of 48 months we recorded the end point of objectively documented, symptomatic recurrent venous thromboembolism. Patients with a genetic deficiency of a plasma coagulation inhibitor deficiency, with a lupus anticoagulant, or with cancer as well as those who required long-term antithrombotic treatment or were on statin therapy were excluded. The relationship between plasma lipoprotein parameters and recurrence of venous thrombosis was evaluated. Plasma apolipoproteins AI and B were measured by immunoassays for all subjects. Using NMR, we determined the levels of ten major lipoprotein subclasses in plasma for 99 patients with venous thrombosis recurrence and for 297 matched patients without recurrence. Recurrent venous thromboembolism developed in 100 of the 772 patients (12.8%). Patients with recurrence compared to those without recurrence had lower mean (±SD) plasma levels of apolipoprotein AI (1.12±0.22 vs. 1.23±0.27 mg/ml, P<0.001) but similar apolipoprotein B levels. The relative risk of recurrence was 0.87 (95% CI, 0.80 to 0.94) for each increase of 0.1 mg/ml in plasma apolipoprotein AI. For patients with apolipoprotein AI above the 67th percentile of the study population values compared with those with lower levels, the relative risk of recurrence was 0.51 (95% CI 0.32–0.83). Comparisons of plasma lipoprotein particle levels from subjects with recurrence versus those without recurrence gave similar results showing that HDL particle concentrations were lower in subjects with recurrence. Patients with high levels of apolipoprotein AI, HDL-cholesterol, and large HDL particles had decreased risk of recurrent venous thromboembolism. In summary, these novel findings that HDL appears to protect against recurrent venous thrombosis may have implications for testing HDL parameters to predict risk and may imply that lipid-altering drugs that increase HDL might reduce the risk for first or recurrent venous thrombotic events.
LBH589, a Novel Deacetylase Inhibitor (DACi), Treatment of Patients with Cutaneous T-Cell Lymphoma (CTCL). Skin Gene Expression Profiles in the First 24 Hours Related to Clinical Response Following Therapy.
Authors: Prince Miles , George D.J. , Johnstone R. , McCormack C. , Ellis L. , Williams-Truax R. , Atadja P. , Zhao C. , Dugan M. , Culver K. 
Published: October 2019

Abstract
Background: LBH589 is a novel DACi in Phase I trials. Pre-clinical studies have demonstrated that DACi alter gene expression and other DACi have induced disease regression in CTCL. Indeed, CTCL is an ideal disease to assess variation in tumor gene expression over time following drug administration. In this study we evaluated the safety and activity of LBH589 in CTCL and examined changes in tumor gene expression in the first 24 hours following oral LBH589.
Methods: Pts with advanced-stage CTCL, who had progressed following prior systemic therapy were entered into the oral DLT dose level 30 mg M,W,F cohort (n=1), the subsequent MTD dose level 20 mg M,W, F weekly (n=9). LBH589 was continued until disease progression or unacceptable toxicity. Intensive cardiac monitoring was performed. Six pts had 3 mm punch biopsies from CTCL-involved skin lesions at 0, 4, 8 and 24 h after administration, which were subjected to gene expression profiling using Affymetrix U133 plus 2.0 GeneChips with 47,000 probesets. Alteration in gene expression patterns was confirmed by QRT-PCR of selected genes. Individual gene expression analysis is underway, utilizing set enrichment analysis to elucidate the functional categories which correlate with degree of patient response.
Results: 10 pts are currently evaluable for response. 2 of the pts attained a complete response (CR), 4 attained a partial response (PR), 1 achieved stable disease (SD) with ongoing improvement, and 2 progressed on treatment (PD). (RR = 6/10; 60%). Microarray data on 5 pts demonstrated distinct gene expression response profiles between pts. Individual gene expression within patient tumors varied over the timepoints in the first 24 hours following treatment. To demonstrate effects of LBH589 as an epigenetic modulator, global changes in gene expression patterns in responding versus progressing patients have been delineated. In addition, functional categories of genes which correlate with degree of patient response have been identified.
Conclusions: LBH589 induces CR’s in CTCL pts. Preliminary microarray analysis of tumor samples have identified distinct gene expression profiles.
Zanolimumab, a Fully Human Monoclonal Antibody: Early Results of an Ongoing Clinical Trial in Patients with CD4+ Mycosis Fungoides (MF) Type CTCL (Stage IB-IVB) Who Are Refractory or Intolerant to Targretin and One Other Standard Therapy.
Authors: Duvic Madeleine , Kim Youn , Korman Neil J. , Boh Erin , Lerner Adam , Heffernan Michael P. , Hymes Kenneth B. , Pacheco Theresa , Elmets Craig A. , Lisby Steen , Baadsgaard Ole 
Published: October 2019

Abstract
Zanolimumab (previously referred to as HuMax-CD4) is a fully human monoclonal IgG1k antibody, targeting the CD4 molecule on T-cells. It exhibits cytotoxic and anti-proliferative effects and has previously shown efficacy in cutaneous T-cell lymphoma. We report the early safety and peripheral CD4+ cell depletion results from the open-label, dose escalation part of a US phase III efficacy study. So far, 21 patients have been recruited and the results from the 4 mg/kg dose group (9 patients) and 8 mg/kg dose group (6 patients) are available. Zanolimumab was administered iv, once weekly for 12 weeks. In total, 2 Serious Adverse Events have been reported. Of these, 1 case of large cell transformation in a patient with large cells present prior to inclusion was judged possibly related to treatment by investigator. No increase in toxicity was seen upon dose escalation. Marked depletion of CD4+ T-cells was observed after just 1 infusion of zanolimumab at both dose levels. One week following the last dose, the median (range) peripheral blood CD4+ T-cell count compared to baseline values was decreased from 831 per μL (167–1928) to 24 per μL (4–141) in 4 mg/kg dose-group and from 638 per μL (182–1024) to 9 per μL (4–19) in the 8 mg/kg dose-group. These initial data indicate that zanolimumab has an acceptable tolerability profile at the doses tested and results in a rapid and pronounced decrease in peripheral CD4+ counts in MF CTCL patients.
Novel Treatment of Burkitt Lymphoma with Dose-Adjusted EPOCH-Rituximab: Preliminary Results Showing Excellent Outcome.
Authors: Dunleavy Kieron , Pittaluga Stefania , Janik John , Grant Nicole , Shovlin Margaret , Little Richard , Yarchoan Robert , Steinberg Seth , Jaffe Elaine S. , Wilson Wyndham H. 
Published: October 2019

Abstract
Burkitt Lymphoma (BL) is a highly proliferative lymphoma with a propensity to present in extranodal sites. Standard treatment for BL involves intensive, multi-agent chemotherapy that is highly effective but associated with considerable toxicity and treatment-related mortality, particularly in older patients. Based on the observation that DA-EPOCH overcomes the adverse effect of high proliferation in diffuse large B-cell lymphomas, we hypothesized it may be effective in BL. We have undertaken a study of DA-EPOCH-Rituximab in untreated BL in an attempt to maintain a high cure rate with low treatment related toxicity. Eligible patients had untreated BL and could be HIV positive or negative. HIV negative patients (n=13) received 6 cycles of DA-EPOCH-R as previously described (Blood99: 2685, 2002). Patients with HIV-associated BL (n=4) received 3–6 cycles of DA-EPOCH-R for 1 cycle beyond CR for a minimum of 3 cycles. All patients received intrathecal methotrexate prophylaxis and therapy was administered in the outpatient clinic where possible. Characteristics of 17 patients include median age (range) 27 (18–66) and ECOG PS 1 (1–3); stage III/IV 9 (53%); LDH > N 9 (53%); male sex 13 (76%) and; extranodal sites 11 (65%). All 11 (65%) patients with extranodal disease had abdominal or pelvic involvement at diagnosis. No patients had central nervous system disease on presentation. Response is CR/CRu in 100% of patients. One patient received consolidative radiotherapy to a single site of residual disease. At a median potential follow-up of 28 months, OS and PFS are both 100% and EFS is 92.3%. Significant toxicities include fever/neutropenia in 16%, grade 4 neutropenia in 47% and grade 3/4 thrombocytopenia in 22% of cycles. There were no treatment related deaths and no tumor lysis syndrome. In conclusion, DA-EPOCH-R appears to be highly effective with relatively low toxicity compared to standard intensive high-dose regimens for BL. Infusional chemotherapy may reduce or eliminate the risk of tumor lysis syndrome. Accrual continues.
Figure Figure