bluuebunny/crossref_metadata_2025_split huggingface dataset:
Addition of Rituximab to Mobilization and Conditioning Overcomes the Predictive Value of Follicular Lymphoma International Prognostic Index (FLIPI) Score in Patients with Relapsed FL Undergoing Autologous Stem Cell Transplantation (AUTO).
Authors: Khouri Issa F , Bassett Roland , Samuels Barry , Maadani Farzaneh , Okoroji Grace-Julia , Harrell Robyn , Korbling Martin , de Padua Silva Leandro , Alousi Amin , Hosing Chitra , Giralt Sergio , de Lima Marcos , Anderlini Paolo , Popat Uday , Valverde Rosamar , Hsu Yvonne , Hagemeister Fredrick , McLaughlin Peter , Medeiros L. Jeffrey 
Published: April 2020

Abstract
FLIPI is emerging as an important prognostic factor in patients (pts) with FL. In order to determine its significance in FL pts undergoing AUTO, we examined the outcome of 75 consecutive pts transplanted at the MD Anderson Cancer Center between 02/94 and 04/08. Pts were eligible if they had relapsed chemosensitive disease, and had no HLAidentical sibling donor. Twenty-nine pts were transplanted without rituximab (AUTO-R), and 46 pts received high-dose rituximab (AUTO+R) during stem cell mobilization and on days +1 and + 8 after transplantation as previously described (Khouri, JCO, 2005). Median age (range) at AUTO was 54 (33–76) and 49 (35–63) for the AUTO+R and AUTO-R groups respectively (P =0.002). FLIPI was determined at the time of transplantation; more patients had intermediate-high risk in AUTO+R than in AUTO-R (58% vs 27.5%, respectively, P = 0.011). Other patients characteristics were balanced for gender, time from diagnosis, histology subtypes (grades 1,2, 3a, and 3b), disease stage, LDH, bulk, B-symptoms, B-2microglobulin, bone marrow involvement, number of prior chemotherapy regimens received, remission status (CR vs PR), functional imaging, and co-morbidity score. Median follow-up (range) in months was 20 (1–88) for AUTO+R and 70 (4–167) for AUTO-R. Progression-free survival (PFS) was significantly different between AUTO+R and AUTO-R (P = 0.004), with estimated three-year PFS of 48% for AUTO-R and 79% for AUTO+R. Using Cox proportional hazards regression models, the # of prior chemotherapy regimens received (&lt;3 vs &gt;/=3) (P = 0.015) was the only factor associated with PFS in the AUTO+R group, whereas both age (P=0.010), and risk based on FLIPI (P=0.019) were independently associated with PFS in the AUTO-R group. Pts with low-risk vs. intermediate/high-risk had three-year PFS of 62% and 13%, respectively, in the AUTO-R group, whereas in the AUTO+R group, three-year PFS was 90% and 76% in the low-risk and intermediate/high-risk pts, respectively (Figure).
Conclusions: These results suggest that the addition of R to the mobilization and conditioning improves the outcome in pts with relapsed chemosensitive FL treated by AUTO. The number of prior chemotherapy regimens received rather than FLIPI score is the most important determinant of outcome in this setting.
Figure Figure
Immunogenicity of the Tetravalent Protein-Conjugated Meningococcal Vaccine in Recipients of Related and Unrelated Allogeneic Hematopoietic Cell Transplants (HCT)
Authors: Mahler Michelle , Kernan Nancy A , Boulad Farid , Prockop Susan , Scaradavou Andromachi , Papadopoulos Esperanza B , Abendroth Heidi , Casson Anne , Copeland Catherine , Murphy Maura , Torok-Castanza Joanne , O’Reilly Richard J. , Small Trudy N. 
Published: April 2020

Abstract
Following the successful introduction of the highly immunogenic protein-conjugated Haemophilus influenza and pneumococcal vaccines, Neisseria meningitidis has become the most common cause of bacterial meningitis in the US. Each year, invasive disease (meningitis, sepsis, pneumonia) due to this organism occurs in approximately 500, 000 persons world-wide, including 1400–2800 in the US. Despite rapid institution of appropriate antibiotics, 10%–14% of affected patients die and significant morbidity occurs in up to 20% of survivors. In 2005, the quadrivalent (A, C, Y, W-135) protein conjugated polysaccharide vaccine (MCV4) was approved in the US and recommended for children 11–12 years of age, previously unimmunized adolescents entering college, military recruits, patients with acquired or functional asplenia, and all travelers to hyperendemic or epidemic areas such as sub-Sahara Africa. Improved disease-free survival following HCT has resulted in an increasing number of survivors entering college and traveling abroad. Due to the lack of information on the immunogenicity of this vaccine in transplant survivors, we assessed the responses of 41 patients immunized with MCV4 following an HLA matched related (n=16), mis-matched related (n=2) or unrelated (n=23) HCT. The median age at HCT and at vaccination was 14 years and 18 years, respectively. Patients were transplanted for acute or chronic leukemia (n=28), immunodeficiency disease (n=4), hemoglobinopathy (n=4), HLH (n=1), NHL (n=1), MDS or aplastic anemia (n=3). Fifty percent of patients received an unmodified HCT and four patients were splenectomized prior to vaccination. MCV4 was administered at a median (range) of 3.2 (0.7–12.5) years following transplant. Ninety percent of patients had undetectable titers to all 4 serotypes prior to immunization. Antibody responses were measured by ELISA. Positive response was defined as &gt; 4 ug/ml (serotype A), &gt;5 ug/ml (serotype C), &gt;4 ug/ml (serotype Y), and &gt;3 ug/ml for serotype W-135. Sixty-one percent of patients developed an antibody response to 31 vaccine serotypes, although only 13 developed positive titers to all 4 serotypes. Response to serotypes A, C, Y, and W-135 was observed in 20, 13, 18, and 13 patients, respectively. Responses were significantly poorer in recipients of an unrelated HCT. Of the 7 non-responders who received a second MCV4, 3 of 4 evaluated patients developed titers to all 4 serotypes. This data suggests that although HCT recipients respond to MCV4, the response is sub-optimal, that pre and post vaccine titers should be assessed to ensure adequate protection, and that a booster immunization should be explored in this patient population.
Iron Chelation by Deferoxamine Induces Autophagy
Authors: De Domenico Ivana , Ward Diane McVey , Kushner James P. , Kaplan Jerry 
Published: April 2020

Abstract
Deferoxamine (DFO) is a high affinity Fe (III) chelator produced by Streptomyces pilosus that is used clinically to remove systemic iron in secondary iron overload disorders. DFO cannot be absorbed through the intestine and must be injected. As shown previously, De Domenico et al. EMBO J (2006), expression of Ferroportin (Fpn), the only mammalian iron exporter, can deplete cells of ferritin by lowering cytosolic iron and by exporting iron from cells. Fpn-mediated iron loss induces ferritin degradation by the proteosome. In this study we show that permeable iron chelators, desferirax or deferriprone also induce the proteosomal degradation of ferritin. In contrast, DFO-mediated iron chelation at clinically useful concentrations, leads to ferritin degradation in lysosomes. Immunochemical analysis revealed that DFO-treated cells show increased levels of LC3B, a protein required for autophagy, suggesting that DFO induces autophagy. Treatment of cells with desferasirox or deferriprone did not lead to accumulation of LC3B. Studies using high molecular weight conjugates of DFO or inhibitors of endocytosis showed that the presence of DFO in lysosomes was responsible for the induction of autophagy. Incubation of DFO-treated cells with 3-methyladenine, an autophagy inhibitor, does not, however, prevent ferritin loss suggesting there may be an alternate route for ferritin degradation. This hypothesis was confirmed by examining the effect of the proteosome inhibitor, MG132, on DFOinduced autophagy in cells treated with DFO and 3-methyladenine. Addition of MG132 to 3-methyladenine treated cells prevents ferritin degradation. These results indicate that ferritin degradation occurs by two routes: a DFO-induced entry of ferritin into lysosomes and a cytosolic route in which iron is extracted from ferritin prior to degradation by the proteosome.
Long-Term T Cell Immune Reconstitution in Patients Surviving 10 or More Years after Allogeneic Stem Cell Transplantation for Hematologic Malignancies
Authors: Le Quan , Melenhorst J. Joseph , Savani Bipin N. , Hill Brenna , Memon Sarfraz , Shenoy Aarthi , Hensel Nancy F. , Koklanaris Elefteria K , Keyvanfar Keyvan , Hakim Fran , Douek Daniel , Barrett A. John 
Published: April 2020

Abstract
After allogeneic stem cell transplantation (SCT), there is a prolonged immune deficiency and delayed T cell reconstitutions results in significant morbidity and mortality. However limited data are available on immune reconstitution in patients surviving beyond a decade following SCT. Four hundred sixty two patients with hematological malignancies received SCT from an HLA identical sibling in our institute between 1993–2004. Of these, 110 patients 3 or more years post-transplantation, prospectively enrolled in a long-term evaluation protocol. Twenty one of these survived more than 10 years post SCT (median follow-up 11.8 y range 10–14.75y). Diagnoses included chronic myelogenous leukemia (17), acute myelogenous leukemia and myelodysplastic syndrome (3), and multiple myeloma (1). We studied T cell reconstitution in these patients and compared it to samples from their stem cell donors cryopreserved at time of transplant. There was no difference of age at SCT in patients (median age 35.5, range 13–56y) and in the donors (median age 34, range 14–58y). All patients received cyclophosphamide and 13.6 Gy total body irradiation. Patients received T cell depleted bone marrow (n=15) or peripheral blood SCT (n=6) with cyclosporine GVHD prophylaxis and delayed add-back of donor lymphocytes 30–90 days post transplant. Six (29%) developed acute GVHD (grade II–IV) and 18 (86%) chronic GVHD (13 limited, 5 extensive). Six (29%) patients received immunosuppressive therapy (IST) for cGVHD beyond 3 years from SCT but all were off immunosuppressive treatment at the time of study. In the 21 patients there were no significant difference in the absolute lymphocyte, neutrophil or monocyte count, compared with the donor pre-transplant absolute counts of circulating NK and T cell subsets, and B cells were measured using multicolor flow cytometric analysis in 9 patient-donor pairs. Patients had fewer naïve CD4 (p = 0.049) and naïve CD8 (p = 0.004) T cells, fewer CD4 central memory T cells (p = 0.03), fewer CD56 [int] CD16-NKG2A+2D+ NK cells (p = 0.02); and more effector CD8+ T cells (p = 0.04) in patients compared to their donors. ALC and FoxP3+ regulatory T cells were not significantly different between the patients and their donors. The T cell receptor excision circles (TRECs) and T cell receptor repertoire analyses to evaluate thymic function and T cell regeneration is ongoing. In conclusion, patients surviving 10 or more years after allogeneic SCT still show a deficit in the naïve and central memory post-thymic compartment. However these abnormalities appear to be compatible with good health.
Figure Figure
Structural Aspects of Hepcidin-Ferroportin Binding
Authors: Preza Gloria , Fernandes Augustine , Clark Richard J. , Craik David J. , Ganz Tomas , Nemeth Elizabeta 
Published: April 2020

Abstract
Hepcidin, a 25-amino acid peptide hormone, is the principal regulator of plasma iron concentrations in a wide range of organisms, from humans to fish. The hepcidin receptor is the iron channel ferroportin (Fpn), which exports iron from duodenal enterocytes, macrophages and hepatocytes into plasma. Hepcidin binding to Fpn results in internalization and degradation of the ligand-receptor complex and reduced iron efflux from cells into plasma. Abnormal production of hepcidin or abnormal interaction with Fpn causes a spectrum of iron disorders. We analyzed the nature of the interaction and critical structural features of hepcidin and Fpn. The binding of hepcidin to Fpn showed an unusual temperature dependence, with loss of binding/internalization at temperatures lower that 15C. To establish whether initiation of internalization stabilized binding, we used Fpn mutated at Tyr302 and Tyr303, which does not internalize and showed that the mutant was still able to bind 125I-hepcidin, with a similar EC50 and temperature dependence as wt Fpn. We next addressed Fpn structural features required for interaction with hepcidin. Several Fpn mutations in humans cause a phenotype consistent with resistance to hepcidin. We thus generated Fpn plasmids carrying the specific human mutations, transiently transfected cells with the mutants, and measured 125I-hepcidin binding to cells. The results showed that thiol form of Cys326 is essential for hepcidin binding since substitution of this Cys with Ser or Thr preserved the iron exporting function of Fpn but resulted in a complete loss of hepcidin binding, as did the treatment of cells with non-permeable sulfhydryl alkylating agents. The essential role of the C326 residue in hepcidin binding accounts for the early and severe iron overload in patients with C326S or Y substitution. We also showed that the N-terminus of hepcidin is essential for its binding to Fpn. The sequential truncation of five N-terminal residues resulted in a gradual reduction in activity. Ala scanning of the N-terminus showed that Phe4 and Ile6 substitutions resulted in &gt;80% and 50% decrease in binding respectively. To understand the requirements for biological activity at position 4, we tested a series of Phe4 analogues. Substitution with a similar hydrophobic residue, cyclohexylalanine, had no effect on activity; substitution with polar Tyr caused a 50% reduction in activity; substitution with charged residues Lys or Asp resulted in a complete loss of activity, as did substitution with D-Phe. The results indicated that position 4 requires a bulky hydrophobic residue and that the interaction with Fpn is stereospecific. Similarly, substitution of Ile at position 6 with charged residues caused a complete loss of activity. Understanding the molecular framework responsible for hepcidin-Fpn interaction will facilitate the development of drug leads for a range of iron disorders.
Gene Expression Profiling Differentiates Childhood Acute Lymphoblastic Leukemia in Down Syndrome Versus Non-Down Syndrome Patients.
Authors: Rabin Karen R. , Wang Jinhua , Tsimelzon Anna , Morrison Debra , Gaikwad Amos S. , Hogan Laura , Rye Cassia L. , Hilsenbeck Susan G. , Devidas Meenakshi , Heerema Nyla A. , Carroll Andrew J. , Basso Giuseppe , Carroll William L. , Pession Andrea , Bhojwani Deepa 
Published: April 2020

Abstract
Children with Down syndrome (DS) and acute lymphoblastic leukemia (ALL) form a unique biological subset. These patients have generally inferior outcomes in many studies, and an increased incidence of treatment-related toxicities. Cases of DS ALL have a much lower frequency of recurrent prognostically significant chromosomal abnormalities than cases of ALL in the general pediatric population. Global gene expression profiling provides an opportunity to gain insights into pathogenesis and potential therapeutic targets in DS ALL. We performed microarray analysis of RNA from bone marrow samples obtained at diagnosis in 30 DS ALL and 24 non-DS ALL cases using the Affymetrix Human Genome U133 Plus 2.0 array. Unsupervised hierarchical clustering separated cases into two main groups, one of which included 21 of 30 DS samples (Fisher’s exact test, p = 0.013), suggesting inherent biologic similarities. Non-DS samples clustered according to known cytogenetic features. Consistent with recently published data, a subset (13%) of our DS ALL cases were found to have JAK2 mutations. Cases of DS ALL bearing JAK2 mutations did not form a distinct subcluster, suggesting that the JAK2 pathway may be dysregulated via other events in cases of DS ALL with wild-type JAK2. Two-sample comparison of DS versus non-DS ALL cases demonstrated differential expression of 513 genes with p values &lt;0.001 (Figure 1). Oxidative phosphorylation pathway genes were most over-represented among differentially expressed genes, with 35 of 115 genes in this pathway demonstrating down-regulation in DS compared to non-DS ALL (Bonferroni corrected p value &lt; 1 ×10−9), including several cytochrome c oxidase and ubiquinone subunits. Our data indicate that DS ALL blasts may utilize oxidative phosphorylation to a lesser extent than non-DS ALL, a feature which could be exploited therapeutically.
The top 513 genes differentially expressed in DS versus non-DS ALL (Benjamini-Hochberg corrected p values &lt; 0.001) are displayed in a heatmap where genes relatively overexpressed in DS ALL are depicted in yellow, and relatively underexpressed in DS ALL in red. DS ALL cases are indicated by red circles and non-DS ALL cases by white circles. Four DS ALL cases bearing a JAK2 mutation at arginine 683 are indicated by black stars.
Figure 1. Gene expression signature of top differentially expressed genes in Down syndrome (DS) versus non-Down syndrome acute lymphoblastic leukemia (ALL). Figure 1. Gene expression signature of top differentially expressed genes in Down syndrome (DS) versus non-Down syndrome acute lymphoblastic leukemia (ALL).
PIN1 Blocks Granulocytic Differentiation Via C-Jun in Acute Myeloid Leukemia with CEBPA Mutations.
Authors: Pulikkan John Anto , Dengler Viola , Peerzada Abdul , Bohlander Stefan , Tenen Daniel G. , Behre Gerhard 
Published: April 2020

Abstract
Transcription factor CCAAT enhancer binding protein α (C/EBPα) is the master regulator of myeloid differentiation programme. Tumor suppressor function of C/EBPα is shown by the deregulation of C/EBPα in AML by various mechanisms. Mutations in the CEBPA gene are reported in around 9% of patients with acute myeloid leukemia (AML). The CEBPA mutations reported are frame shift mutation at N-terminal domain, which results in C/EBPα-p30 and point mutations at the basic region Leucine zipper. The mutant form of C/EBPα (C/EBPα-p30) displays dominant negative function over the wild type protein and induces AML in mouse model. The mechanism for the dominant negative action of C/EBPα-p30 in AML is poorly understood. Peptidyl-prolyl cis/trans isomerase, PIN1 binds to and isomerizes specific pSer/Thr-Pro motifs. Recent studies show that PIN1 is overexpressed in many types of cancers and it acts as a crucial catalyst for oncogenesis. Here we investigated the role of PIN1 in AML with CEBPA mutations. We report C/EBPα-p30 could induce PIN1 mRNA and protein levels as revealed by quantitative Real-Time RT-PCR analysis and western blot analysis, respectively. Affymetrix mRNA expression analysis shows that PIN1 mRNA is upregulated in patients with AML. Interestingly, the wild type C/EBPα down regulates PIN1 mRNA and protein levels. Chromatin immunoprecipitation assays demonstrate that induction of C/EBPα-p30 results in recruitment of E2F1 in the PIN1 promoter. Silencing PIN1 with inhibitor against PIN1 (PiB) in AML blast cells with CEBPA mutation and in Kasumi-6 cells leads to myeloid differentiation as assessed by myeloid markers by FACS analysis and quantitative Real-Time RT-PCR analysis. Furthermore, PIN1 inhibition by PiB leads to upregulation of wild type C/EBPα protein level. Next, we investigated the mechanism through which the C/EBPα-p30 blocks the wild type protein. c-Jun expression has been shown to be high in AML patients with CEBPA mutation and c-Jun blocks C/EBPα function by proteinprotein interaction. In vivo ubiquitination assay demonstrates that PIN1 increases the stability of the c-Jun protein by inhibiting c-Jun ubiquitination. We also show that c-Jun blocks granulocytic differentiation mediated by C/EBPα as assessed by myeloid specific markers. In summary, C/EBPα-p30 induces PIN1 expression and increases the stability of c-Jun and c-Jun blocks the wild type C/EBPα. Our data suggest the inhibition of PIN1 could be a potential strategy in the treatment of AML patients with CEBPA mutation.
AV513 Promotes Tissue Factor-Mediated Coagulation in Fresh Human Whole Blood from Severe and Moderate Hemophilia a Subjects.
Authors: Powell Jerry Sherman , Knappe Sabine , Harrison Janet A , Patarroyo-White Susannah , Johnson Kirk , Prasad Srinivasa 
Published: April 2020

Abstract
The sulfated polysaccharide extract AV513 accelerates effective clotting of plasma from severe hemophilia A and B subjects, primarily through the extrinsic pathway by inhibiting TFPI activity. AV513 is efficacious in normalizing bleeding times in hemophilia A dogs when administered orally or subcutaneously, either alone or in the presence of very low levels of factor VIII. In this report, we have examined the effects on hemostasis of different concentrations of AV513 (0.25 to 5 ug/mL) added to fresh whole blood from eight severe (FVIII &lt;1 %) and four moderate (FVIII 3–5 %) hemophilia A subjects. Blood was drawn on two separate occasions, 30 days apart, from each subject after receiving no FVIII infusion for 5 days and analyzed using tissue factor-triggered whole blood thromboelastography (TEG) and plasma based thrombin generation assay. In the tissue factor-induced TEG assay, AV513 reduced the whole blood R time (time to initial clot formation) of severe and moderate human hemophilia A blood in a dose dependent manner. The R time values were corrected to the normal range (≤ 27 min) at AV513 concentrations of 0.25 to 1 ug/mL in blood from both severe and moderate hemophilia A subjects. The TEG EC50 (AV513 concentration that reduces R time by 50% from baseline) values were approximately 0.7 ug/mL in both cohorts. Based on two TEG determinations for each subject, the intra-subject baseline variability of whole blood R time had a range of 3–19 % (mean: 10 %) for severe and 2–16 % (mean: 8 %) for moderate subjects. The intersubject baseline R time value varied from 29 to 91 min in the severe group and from 30 to 43 min in the moderate hemophilia A group. Further, an AV513 dose dependent increase in thrombin generation was observed in hemophilia A plasma with maximal thrombin peaks of 52 to 216 nM (mean: 110 nM). For all subjects, we observed a 2–4 fold maximum increase in thrombin peak and a 2–3 fold reduction of both the lag phase time and time to peak thrombin generation.. The EC50 values for peak thrombin generation were 0.2 ± 0.15 ug/mL and 0.7 ± 0.3 ug/mL of AV513 in severe and moderate hemophilia A plasma, respectively. These results demonstrate that AV513 in whole blood from severe and moderate hemophilia A subjects effectively shortened R time in the TEG assay to within the normal range, and that AV513 markedly enhanced thrombin generation in plasma from these subjects. These studies suggest that AV513 may prove useful to promote clotting and prevent spontaneous bleeding in clinical trials for patients with hemophilia A.