bluuebunny/crossref_metadata_2025_split huggingface dataset:
Development of a Measure of Health-Related Quality of Life for Non-Hodgkin’s Lymphoma Clinical Research: The Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym).
Authors: Cella David , Webster Kimberly , Cashy John , Kutikova Lucie , Burgess Michael F. , Lin Boris K. , Bowman Lee , Liepa Astra M. , Gauthier Janine E. , Gregory Stephanie A. , Johnson Stephen A. , Cheson Bruce D. ,   on Behalf of the FACT-Lym Development Group
Published: April 2020

Abstract
Background: The FACT-Lym was developed to address the disease-specific quality-of-life (QOL) issues for patients with non-Hodgkin’s lymphoma (NHL).
Methods: Items for inclusion in the lymphoma subscale for the FACT instrument were generated from interviews with health care providers and published literature on NHL. Items were selected based on symptom relevance, disease-specificity and clinical relevance. Validation testing was conducted with NHL patients. Patients completed the FACT-Lym and other measures at three timepoints: baseline (T1), 3–7 days (T2), and 8–12 weeks (T3). These patients were also interviewed about item content.
Results: From a pool of 69 items, 22 items were selected for testing based on relevance ratings of 17 experts. Items included B symptoms, sleep disturbance, anorexia, pruritus, pain, swelling, dyspnea, fatigue, emotional lability, worries, and uncertainty about the future. 75 NHL patients participated in validation testing (55% female, 59% with indolent disease, and 84% currently receiving treatment). Patient interviews confirmed item relevance and comprehensiveness. Item correlations, expert relevancy ratings, and patient input further reduced the subscale to 15 items. Internal consistency coefficients (alpha) for the 15–item subscale (.80, .86, .83) and test-retest stability (.85) suggest very good reliability. Correlations between the subscale and the SF-36 physical (r=.62) and mental (r=.47) summary scores reflect concurrent validity. Responsiveness to ECOG performance status rating and treatment status (on vs. off) equaled or exceeded that of the more established FACT subscale scores. From T1 to T3, subscale scores declined (−6.8, effect size= −0.86) in 14 patients who reported themselves as worsened, increased (3.9, effect size= 0.49) in 28 patients who reported themselves as improved, and did not change (−0.2, effect size= −0.02) in 18 patients who reported themselves as unchanged.
Conclusions: The FACT-Lym addresses QOL concerns that are relevant to NHL patients and is reliable and valid for use in clinical research.
Prognostic Gene-Expression Signatures in Adult Acute Myeloid Leukemia with Normal Karyotype.
Authors: Bullinger Lars , Bair Eric , Kranz Raphael , Dohner Konstanze , Frohling Stefan , Schlenk Richard F. , Tibshirani Robert , Dohner Hartmut , Pollack Jonathan R. 
Published: April 2020

Abstract
Acute myeloid leukemia (AML) encompasses a large number of morphologically similar but molecularly distinct variants. Recurrent cytogenetic aberrations have been shown to constitute markers of diagnostic and prognostic value. However, despite recent successes in detecting novel molecular markers like FLT3 (fms-related tyrosine kinase 3) mutation, treatment stratification is still difficult, especially for the 40–45% of patients with intermediate-risk, normal karyotype disease. To better characterize AML at the molecular level, and to address the need for improved risk stratification, we recently profiled gene expression in a large series of adult AML patients (Bullinger et al., N Engl J Med350:1605, 2004). By unsupervised analysis we identified new prognostically-relevant AML subgroups, and using a supervised learning algorithm we constructed a gene-expression based outcome predictor, which accurately predicted overall survival across all patients, including for the subset of AML cases normal karyotype. Having demonstrated the presence at diagnosis of normal karyotype signatures correlating with clinical outcome, we have now sought to refine a prognostic signature specific for normal karyotype disease. Towards this goal, we have now profiled 119 samples of adult AML patients with normal karyotype using 42k cDNA microarrays from the Stanford Functional Genomics Facility. By semi-supervised analysis using the supervised principal component method (Bair et al., PLoS Biology2:511, 2004), we built a cross-validated gene-expression based outcome predictor in a randomly partitioned training set (n=60 samples). This outcome signature, comprising only 16 genes, significantly predicted outcome class for normal karyotype samples in the independent test set (n=59 samples; P=0.001). In multivariate analysis, the 16-gene signature was a strong [odds ratio=0.35 (0.13 to 0.91); P=0.01] factor in predicting overall survival, independent of known prognostic factors including FLT3 mutations and preceeding malignancy. Our findings support the utility of expression profiling for improved risk stratification and clinical management of the clinically important subclass of AML patients with normal karyotype disease.
Disclosure of Copy Number Alterations in AML with Normal Karyotype Using Matrix-Based Comparative Genomic Hybridization.
Authors: Rucker Frank G. , Bullinger Lars , Kestler Hans A. , Lichter Peter , Dohner Konstanze , Dohner Hartmut 
Published: April 2020

Abstract
Clonal chromosome abnormalities represent one of the most important prognostic factors in adult acute myeloid leukemia (AML), and cytogenetic data are used for risk-adapted treatment strategies. By conventional cytogenetic analysis, approximately 50% of patients lack clonal chromosome aberrations, and normal cytogenetics are associated with an intermediate clinical outcome. This clinically heterogeneous group seems to be in part characterized by molecular markers, such as MLL, FLT3, CEBPA, and NPM1 mutations.
In order to identify novel candidate regions of genomic imbalances, we applied comparative genomic hybridization to microarrays (matrix-CGH). Using this high-resolution genome-wide screening approach we analyzed 49 normal karyotype AML cases characterized for the most common clinically relevant molecular markers (MLL-PTD n=13, FLT3-ITD n=7, FLT3-ITD/NPM1+ n=4, MLL-PTD/FLT3-ITD n=3, CEBPA+ n=12, CEBPA+/FLT3-ITD n=1; CEBPA+/NPM1+ n=1; no molecular markers n=8) with a microarray platform consisting of 2799 different BAC or PAC clones. A set of 1500 of these clones covers the whole human genome with a physical distance of approximately 2 Mb. The remaining 1299 clones either contiguously span genomic regions known to be frequently involved in hematologic malignancies (e.g., 1p, 2p, 3q, 7q, 9p, 11q, 12q, 13q, 17p, 18q) (n=600) or contain oncogenes or tumor suppressor genes (n=699).
In addition to known copy number polymorphisms in 5q11, 7q22, 7q35, 14q32, and 15q11, the CLuster Along Chromosomes method (CLAC; http://www-stat.stanford.edu/~wp57/CGH-Miner) disclosed copy number alterations (CNAs) in terms of gains in 1p, 11q, 12q, and 17p. CNAs in terms of losses were identified in 9p, 11q, 12p, 12q, and 13q. Two-class supervised analyses using the significance analysis of microarrays (SAM) method identified for the MLL-PTD cases a gain of a single clone harboring the MLL gene.
While the significance of these findings, which are currently validated using fluorescence in-situ hybridization (FISH), still remains to be determined, our preliminary results already demonstrate the power and reliablity of this microarray-based technique allowing genome-wide screens of genomic imbalances as the MLL aberration was detected in all cases known to have a MLL-PTD. Furthermore, ongoing correlation of high-resolution genomic profiling with global gene expression studies will help to disclose pathways underlying normal karyotype AML, thereby leading to new insights of leukemogenesis.
Extended Follow-Up and Analysis with Central Radiological Review of Patients Receiving FavId® (Id/KLH) Vaccine Following Rituximab.
Authors: Koc Omer , Redfern Charles , Wiernik Peter , Rosenfelt Fred , Winter Jane , Guthrie Troy , Kaplan Lawrence , Holman Peter , Densmore John , Hainsworth John , Lin Thomas , Castillo Rene , Janakiraman Nalini , Gold Dan , Gutheil John , Bender John 
Published: April 2020

Abstract
Background: Idiotype vaccination (Id/KLH) is a promising approach to the treatment of patients (pts) with B-cell malignancies. Our experience suggests that Id/KLH may function best in pts with lower tumor burden who are less heavily pretreated. We have conducted a phase II trial of Id/KLH following cytoreduction with rituximab in patients with treatment naive (TN) or relapsed/refractory (R/R) follicular NHL (FL).
Treatment: Pts received rituximab, 375mg/m2, IV, weekly x 4, wk 1–4. Pts with without progression received Id/KLH, 1 mg, SQ, monthly x 6, starting on wk 12, with GM-CSF, 250 mcg, SQ, on days 1–4. Pts could receive booster Id/KLH on a reduced schedule until disease progression.
Results: One hundred three pts were enrolled and received rituximab; 89 pts received Id/KLH. The last patient was registered in Dec 2003. Among these 89 evaluable pts, 55 were R/R to prior therapy, and 34 were TN. The overall response rate (ORR) following rituximab (assessed at month 3 based on a centralized read of CT scans) was 49% (44/89). Following Id/KLH, the ORR improved to 64% (57/89). The median time for improved response following initiation of Id/KLH treatment was 6.6 months (range 5.8 – 23.4 months) which was consistent with the time required to demonstrate an immune response in those pts tested. Prognostic factors for time to tumor progression (TTP) were evaluated and demonstrated a significant negative relationship for liver involvement (hazard ratio; HR = 9.3, p=0.0017) and 3 or more prior regimens (HR=4.7, p=0.0035). Median TTP has not been reached in the TN group (N=34) and in pts who relapsed after prior chemotherapy (N=26), with an actuarial 18 month progression free survival rate of 69% and 70%, respectively. The group of pts who would be eligible for the ongoing phase 3 randomized registration study (N=71) of rituximab followed by Id/KLH have also not reached median TTP. T-cell responses to both Id and KLH were observed in 80% and 86% of pts respectively (N=15) and were seen after a median of 2 doses of Id/KLH. Likewise, antibody responses to Id and KLH were seen in 13% and 69% respectively (N=23) and developed after a median of 5 to 6 doses of Id/KLH.
Conclusion: Id/KLH, administered following rituximab to pts with FL, appears to result in an increase in the response rate and TTP compared to that reported for rituximab alone. We also observed a high rate of cellular immunity against idiotype following Id/KLH. These data support the design of an ongoing PIII clinical study of Id/KLH following rituximab which excluded pts with poor prognostic indicators.
Expression of Tropomodulin1 (Tmod1) in the Heart Rescues Embryonic Lethality of Tmod1 Null Mice and Results in a Mild Hemolytic Anemia Due to Absence of Tmod1 in Red Blood Cells.
Authors: Fowler Velia M. , Moyer Jeannette , Nowak Roberta , Fritz-Six Kimberly , Ferreira-Mota Carmela , Sussman Mark A. 
Published: April 2020

Abstract
Tropomodulin1 (Tmod1) caps the pointed ends of actin filaments in the red blood cell (RBC) membrane skeleton and is proposed to regulate actin filament lengths and organization in the membrane skeleton. Tmod1 is first expressed at E7.5 of mouse embryogenesis in blood islands of the yolk sac and in the cardiac myocytes of the developing heart tube. Targeted deletion of the Tmod1 gene in mice leads to abnormal cardiac development and defective vasculogenesis and hematopoesis in the yolk sac, followed by embryonic lethality between E9.5–10. To investigate the function of Tmod1 in RBCs we rescued the embryonic lethality of the Tmod1 null mouse by crossing with a TOT mouse that expresses a Tmod1 transgene in the heart under the control of the α-myosin heavy chain promoter. Genotyping of litters from crosses of Tmod1-/+;TOT+ mice with Tmod1+/− mice demonstrates that embryos with no endogenous Tmod1 but expressing the Tmod1 transgene (Tmod1−/−;TOT+) develop to term with no apparent defects in vasculogenesis or hematopoeisis. Western blotting and immunofluorescence staining demonstrates that Tmod1 protein is present in the heart but absent from RBCs in Tmod1−/−;TOT+ rescued embryos or adult mice. Instead, the Tmod3 isoform that is normally present in embryonic RBCs, but not detected in adult RBCs of wild-type mice, is increased on the membranes of Tmod1-deficient adult RBCs. Hematological analyses reveal that these Tmod1-deficient mice exhibit a compensated mild hemolytic anemia, with decreased mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH), increased red cell distribution width (RDW), and reticulocytosis. Quantitative western blotting demonstrates that major RBC membrane proteins are not altered in the absence of Tmod1, but that there is about a two-fold increase in levels of actin and tropomyosin on the membrane, suggesting that actin filaments may be longer than in normal RBCs. We conclude that 1) Tmod1 in RBCs is not required for embryonic development or viability, 2) yolk sac and hematopoetic defects in Tmod1 null mice are secondary to cardiac defects, 3) Tmod’s function in embryonic RBCs may be performed by the Tmod3 isoform that is normally expressed in these RBCs, and 4) the absence of Tmod1 in adult RBCs is incompletely compensated by up-regulation of Tmod3, leading to altered actin filaments, decreased membrane stability and a mild hemolytic anemia.
Four ABVD and Involved-Field Radiotherapy in Unfavorable Supradiaphragmatic Clinical Stages (CS) I-II Hodgkin’s Lymphoma (HL): Preliminary Results of the EORTC-GELA H9-U Trial.
Authors: Ferme Christophe , Diviné Marine , Vranovsky Andrej , Morschhauser Frank , Bouabdallah Réda , Gabarre Jean , Bastard-Stamatoullas Aspasia , Delarue Richard , Zagonel Vittorina , Jaubert Jérôme , Hagenbeek Anton , Kramer Mark Henri H. , Rieux Chantal , Thomas José , Henry-Amar Michel 
Published: April 2020

Abstract
The aim of the trial was to compare three modalities of chemotherapy and involved-field radiotherapy (IF-RT) in adult patients with supradiaphragmatic CS I-II HL with risk factors. Patients were randomized if they presented with age ≥ 50, or CS II4–5, or A + ESR ≥ 50, or B + ESR ≥ 30, or MT ratio ≥ 0.35. The trial compared ABVD x 6 cycles and IF-RT (36–40 Gy) vs ABVD x 4 cycles and IF-RT vs BEACOPP baseline x 4 cycles and IF-RT. From October 1998 to September 2002, 808 patients were enrolled in 111 institutions from 10 European countries. The proportions of grade 3–4 chemotherapy-related hematological toxicity (mainly WBC) were 74%, 70% and 63%, respectively; That of grade 1–3 RT-related hematological toxicity were 10%, 12% and 17%, respectively. Ten (2+3+5, 1%) patients stopped chemotherapy because of toxicity and 8 (2+2+4, 1%) refused the treatment; Six (2+2+2, 1%) patients stopped radiotherapy because of toxicity and 9 (3+1+5, 1%) refused the treatment. The proportions of patients in CR/CRu were 74%, 71% and 59% after 6, 4 ABVD and 4 BEACOPP, respectively. After a median follow-up of 57 months (range 33–81), 78 events (26 progressions, 37 relapses, 15 deaths) were observed. At July 2005, the 4-year event-free survival (EFS) and overall survival (OS) rates are as follows:
Treatment No. Pts CR-CRu /PR /NC-PD 4-yr EFS 4-yr OS 6 ABVD + IF-RT 276 87% /8% /5% 91% 95% 4 ABVD + IF-RT 277 86% /11% /3% 87% 94% 4 BEACOPP + IF-RT 255 84% /12% /4% 90% 93% P value 0.607 0.380 0.978
Overall, 42 patients have died of progressive disease (5, 7 and 7 patients), treatment-related complication (7, 5 and 2), intercurrent disease (1, 0 and 2), second malignancy (1 NHL, 0 and 1 AML) or cause unspecified (0, 3 and 1). These preliminary results indicate that a combination of 4 cycles of ABVD and IF-RT is sufficient to cure a large majority of HL patients with unfavorable early stage disease and that BEACOPP baseline has no advantage over ABVD in these patients.
Silencing Reversed: Coordinated Expression of Embryonic and Fetal Globin Genes in Adult Human Erythroblasts.
Authors: Bhanu Natarajan V. , Lee Y. Terry , Oneal Patricia A. , Rognerud Cheryl L. , Ou Ching-Nan , Miller Jeffery L. 
Published: April 2020

Abstract
It was recently demonstrated that erythropoietin combined with stem cell factor and transforming growth factor beta (EST; EPO+SCF+TGF-B) signals a pancellular reversal of gamma-globin gene silencing among ex vivo cultures of CD34+ cells when compared to cultures supplemented with erythropoietin (EPO) alone (Bhanu et al., Blood.2005; 105(1):387–93). This primary human erythroblast culture model is now being utilized to study the molecular basis of globin gene regulation. In this study, we sought to determine whether EST-signaled effects are restricted to the gamma-globin gene(s). For this purpose, quantitative PCR (QPCR) assays were developed for the alpha-globin (zeta, mu, alpha, and theta) and beta-globin (epsilon, gamma, delta, and beta) gene clusters. EPO versus EST matched cultures from a total of 15 donors (3 single donors and two pools, 6 donors each) were investigated using culture day 7 proerythroblasts and day 14 hemoglobinized precursors. The QPCR products were quantified by comparison with plasmid-generated standard curves (20,000,000 to 200 copies). The patterns of mu-, alpha- and theta-globin gene expression were unchanged under all culture conditions. The delta- and beta-globin transcripts showed a significant reduction in levels in response to EST. In contrast, zeta-, epsilon- and gamma-globins all demonstrated significant increases in response to EST. The increases were consistently detected in the individual and pooled samples. The most dramatic increase in the zeta-, epsilon- and gamma-globins occurred at the proerythroblast stage of differentiation. On day 7, zeta-globin levels showed 190-fold increase (EPO: 6.9E+01±5.5E+01;EST: 1.3E+04±7.7E+03; p=0.01), epsilon-globin levels, a 27-fold increase (EPO: 1.0E+03±5.8E+02; EST: 2.7E+04±1.1E+04; p=0.001), and gamma-globin levels, a 13-fold increase (EPO: 9.1E+05±4.1E+05; EST: 1.2E+07±1.8E+06; p=0.001). Consistent with the 3–4 log difference between the levels of zeta- and epsilon-, versus gamma-globin copy numbers and the low sensitivity of HPLC compared with QPCR, no embryonic proteins were detected by reverse-phase HPLC (day 14 samples studied; 9 donors). However, G-gamma and A-gamma globin peaks confirmed EST-signaled activation of both gamma-globins genes (G-gamma/A-gamma= 1.0 in EPO versus 1.9 in EST; (total gamma)/(total gamma + beta-globin) = 3.7±2.4% in EPO versus 42.4 ±5.8% in EST; p=1.6E-08). These novel data suggest that cytokines can reverse the coordinated developmental silencing of human embryonic and fetal genes in both globin loci.
Identification of zfp148 (ZBP-89) as a Novel GATA-1 Associated Transcription Factor Involved in Megakaryopoiesis and Definitive Erythropoiesis.
Authors: Woo Andrew J. , Moran Tyler B. , Choe Seong-Kyu , Schindler Yocheved L. , Sullivan Matthew R. , Fujiwara Yuko , Paw Barry H. , Cantor Alan B. 
Published: April 2020

Abstract
The zinc finger transcription factor GATA-1 plays an essential role in megakaryocytic and erythroid terminal maturation. Yet the molecular mechanisms that control GATA-1 function are incompletely understood. Many transcription factors, in addition to binding DNA, make important protein-protein interactions that modulate their activity. Here, we show that GATA-1 participates in stable multiprotein complexes ranging from ~100 kDa to greater than 600 kDa in murine L8057 megakaryoblastic cells. We generated stable L8057 cell lines expressing metabolically biotinylated and FLAG epitope tagged GATA-1, and performed tandem anti-FLAG immunoaffinity and streptavidin affinity purification of GATA-1 associated complexes. Mass spectrometry (LC/MS/MS) of co-purified proteins identified the known GATA-1 associated proteins Friend of GATA-1 (FOG-1), SCL, Ldb1, Runx-1/Cbf-β, SP1 and all components of the NuRD complex. In addition, we reproducibly co-purified zfp148 (also called ZBP-89/BERF-1/BFCOL-1, mtβ), a ubiquitously expressed Kruppel-type zinc finger transcription factor that binds GC-rich DNA elements. Zfp148 also co-purified with GATA-1 in erythroid (MEL) cells. Physical interaction between GATA-1 and zfp148 was confirmed by co-immunoprecipitation experiments using an anti-zfp148 antibody, and their interaction domains mapped to a C-terminal region of zfp148 and the zinc finger domain of GATA-1. Morpholino-mediated knock-down of zfp148 expression in zebrafish embryos ablates thrombocyte (equivalent to mammalian megakaryocyte/platelet) development, but does not significantly affect erythroid development (equivalent to mammalian primitive erythropoiesis at this stage of development). In vitro differentiation of murine ES cells containing homozygous disruption zfp148 by genetrap insertion (zfp148gt/gt) shows essentially normal primitive erythropoiesis, but markedly impaired megakaryocytic and definitive erythropoiesis. Preliminary chimeric studies in adult mice demonstrate a failure of zfp148gt/gt ES cells to contribute to mature erythrocytes. These findings suggest that zfp148 cooperates with GATA-1 to control differentiation of erythroid and megakaryocytic lineages. The differential requirement of zfp148 for definitive, but not primitive, erythropoiesis raises the possibility of a role in developmental hemoglobin switching.