bluuebunny/crossref_metadata_2025_split huggingface dataset:
In-Vivo Immune Modulating Effects of the Human Chorionic Gonadotropine Hormone.
Authors: Elmaagacli Ahmet H. , Koldehoff Michael , Beelen Dietrich 
Published: October 2019

Abstract
Human chorionic gonadotropine (hCG) is a naturally occurring immune modulating agent, which is highly expressed during pregnancy. It is often observed that during pregnancy some autoimmune diseases such as multiple sclerosis and Crohn’s disease improves in women. Here we hypothesized that the improvement might be associated with HCG expression during pregnancy and evaluated its possible immunemodulating effects. Blood samples obtained from 34 women (median age 37, range 18–47) who underwent in-vitro fertilization (IVF) and received therefore HCG subcutaneously at three different time points (10.000 IE first, after 24 hours 5000IE, after 48 hours 5000IE) were examined prior and after HCG application. Thereafter skin transplantation was performed with HCG and without in mice. We noticed a significant increase of the number of Tr cells (CD4+CD25+) to up to 40% (p<0.04) after the first and second hCG application in the blood samples of women. A twofold increased of CTLA-4 expression after the first hCG application (p<0.049) was observed, whereas at the same time FoxP3 expression fell rapidly (p<0.006). Our analysis of Th1 (CD3+CD4+IFNγ) and Th2 (CD3+CD4+IL4+) type T cells revealed a slight shift after hCG application: the number of Th1 cells did not alter significantly, whereas the number of Th2 cells increased significantly (p<0.048). Further analyses showed that other subpopulations including B cells (CD19+), NK cells (CD16+CD56+), T helper cells (CD3+CD4+; CD3+CD4+CD45RA; CD3+CD4+CD45RO+), cytotoxic T cells (CD3+CD4+CD8+), TCRab and TCRgd positive T cells were not influenced by hCG. Also, we analyzed cytokine serum levels in women before and after each hCG application by ELISA. Hereby we found that two applications of hCG increased serum levels of both IL-8 and IL-10 significantly (p<0.013 and p<0.03, respectively) measured by ELISA assays (p<0.013), whereas the serum levels for IL-2, IL-4, TNF-α, IFN-γ, TGF- β and IL-1β (data not shown) were not significantly altered by hCG. HCG application increased the expression of anti-inflammatory interleukin-27 (IL-27) and reduced that of the inflammatory IL-17. In addition, we found increased IL-10 serum levels and increased numbers of regulatory T cells CD4+CD in peripheral blood of women after hCG application. Rejection of BALB/c skin grafts transplanted in B6 mice was significantly delayed when mice received hCG after transplantion. We conclude that hCG may be useful for the induction of immune tolerance in allogeneic transplantation.
Identification of Two Novel Homozygous HAX1 Mutations in an Autosomal Recessive Jewish and Two Unrelated Sporadic British Families with Severe Congenital Neutropenia.
Authors: Smith Bradley N. , Ancliff Phil J. , Linch David C. , Gale Rosemary E. 
Published: October 2019

Abstract
Severe chronic neutropenia (SCN) is a rare disorder characterized by profound neutropenia, recurrent bacterial infections and bone marrow arrest at the promyelocyte/myelocyte stage. Initially described as an autosomal recessive (AR) disease (Kostmann disease), autosomal dominant (AD), sporadic and X-linked forms have been reported. Pathogenic mutations in the neutrophil elastase ELA2 gene have been documented in both SCN and the related disorder cyclic neutropenia in a significant proportion of AD and sporadic but not AR patients, and mutations in the Wiskott-Aldrich syndrome (WAS) gene have been reported in X-linked SCN families. More recently, homozygous mutations resulting in AR disease were identified through linkage to chromosome 1p21 in Kurdish and the original Kostmann families, revealing mutations in the HAX1 gene that result in complete loss of this mitochondrial anti-apoptotic protein. In order to determine the frequency of these different mutations in SCN, we used denaturing HPLC WAVE analysis to investigate a cohort of 105 SCN kindreds seen in our institute or referred with a diagnosis of SCN of which 11 were presumed/known AD, 17 AR, 73 sporadic and 4 had X-linked disease. Overall, 25 different ELA2 mutations were detected in 31 kindreds (6 AD and 25 sporadic, 30% of the cohort). Mutations were distributed throughout the gene and were most frequent in exon 4 (42% of mutations), least frequent in exon 3 (10%). Two kindreds (2%) had WAS mutations as previously published, no new cases were identified. The remaining 72 cases were screened for all 7 HAX1 exons using mixtures of patient and control PCR products to detect homozygous substitutions. Four homozygous mutant kindreds were identified. One AR kindred of Kurdish descent had the previously reported p.Trp44X mutation. Two sisters of Jewish origin had a homozygous insertion of an extra G in a run of 5 Gs (nucleotides 121–125) in exon 2 resulting in a frameshift (p.Ser43LeufsX11); both parents were shown to be heterozygous for the mutation. Two unrelated sporadic SCN patients of Caucasian (British) origin had deletion of nucleotide G91 in exon 2 resulting in a frameshift (p.Glu31LysfsX54); to date, parents of one case have been confirmed as heterozygotes. Both frameshift mutations are predicted to result in a non-functional protein. The 4 HAX1-mutant kindreds have variable clinical severity (ranging from mild to severe) and G-CSF requirement (none to regular administration). All heterozygous parents are phenotypically normal. Our results indicate that HAX1 mutations are relatively uncommon (4% of our cohort) but not limited to patients with specific ethnic origin or apparent AR inheritance.
Cost-Effectiveness of Posaconazole vs Fluconazole in the Prevention of Invasive Fungal Infections among Patients with Graft-Versus-Host Disease (GVHD) in the US.
Authors: O’Sullivan Amy K. , Weinstein Milton C. , Pandya Ankur , Thompson David , Langston Amelia , Perfect John , Papadopoulos George 
Published: October 2019

Abstract
Trial data suggest that posaconazole is similar to fluconazole in preventing invasive fungal infections (IFIs) among allogeneic progenitor cell transplant recipients with graft-versus-host disease (GVHD). We estimated the cost-effectiveness of posaconazole versus fluconazole in this population in the US. A decision-analytic model was developed to estimate the average per patient treatment costs, IFIs avoided, life-years gained, and incremental cost per life-year gained of prophylaxis (2006 US$). The model extrapolates the trial results to a lifetime horizon to include long-term mortality due to GVHD. In the model, patients are assumed to receive posaconazole or fluconazole; efficacy data were obtained from the clinical trial. Long-term mortality and prophylaxis drug and IFI treatment costs were estimated from secondary sources. One-way and probabilistic sensitivity analyses were conducted. Posaconazole is associated with fewer IFIs (0.05 vs. 0.09), increased life years (7.87 vs. 7.66), and higher IFI-related costs (prophylaxis and IFI treatment) ($8,750 vs. $5,530) per patient relative to fluconazole. Costs for treatment of IFIs comprised 95% of the total cost for fluconazole and 35% for posaconazole. The incremental cost-effectiveness of posaconazole versus fluconazole is estimated to be $15,700 per life-year saved. Results are most sensitive to changes in the cost of treating an IFI and the efficacy of prophylaxis. Results from the probabilistic analysis indicate that there is an 88% probability that posaconazole is cost-effective at a $50,000 per life year saved threshold. We conclude that posaconazole is a cost-effective strategy for the prevention of IFIs in patients with GVHD.
Survivin Inhibition of p34Cdc2 Via Protection of Wee1 Correlates with Survival.
Authors: Guzman Javier Rivera , Fukuda Seiji , Pelus Louis 
Published: October 2019

Abstract
The inhibitor of apoptosis protein Survivin and p34Cdc2 (the cyclin-dependent kinase, Cdk1) are involved in cell cycle progression and apoptosis. Cdc2 and Survivin are tightly regulated in normal cells but deregulated in cancer. We have previously shown that Survivin regulates entry of hematopoietic stem cells into cell cycle. It has been established that Cdc2 phosphorylates Survivin at threonine 34 (T34), which is believed to be a stabilizing event necessary for normal Survivin function and anti-apoptotic activity. Activation of Cdc2 is required for its apoptotic activity and inhibition of the proapoptotic activity of Cdc2 can be achieved by phosphorylation at tyrosine 15 (Tyr15). Stable overexpression of a wild-type (wt) mouse Survivin-IRES-GFP construct in IL-3-dependent mouse BaF3 cells resulted in increased Tyr15 phosphorylation of Cdc2 and enhanced cell proliferation, while cells transduced with a threonine 34 to alanine (T34A) dominant negative (DN) Survivin construct showed reduced Cdc2 Tyr15 phosphorylation and accelerated apoptosis. Furthermore, when apoptosis was induced in stably transduced BaF3 cells by IL-3 withdrawal, Survivin expression and phospho-Tyr15 levels correlated with enhanced survival and decreased survival and low phospho-Tyr15 levels correlated with Survivin disruption by T34A-DN-Survivin. Since Survivin does not contain intrinsic kinase activity we sought to determine what kinase(s) could be involved in stabilization or increase in phosphoTyr-15-Cdc2 by Survivin. Since Survivin inhibits caspase 3 activity and the Cdc2-targeting kinase Wee1 is a degradation target of active caspase 3, we performed immunoblotting assays on Survivin wt and T34A-transduced BaF3 cells and showed that cells over-expressing wt Survivin contain 2-fold higher levels of Wee1 protein as compared to those expressing vector or DN-Survivin. In addition, cells overexpressing wt Survivin contain >2-fold higher intact PARP protein levels which is another target of active caspase 3, as compared to cells transduced with MIEG vector. In order to test whether mimicking wt Survivin inhibition of caspase 3 could lead to increased Cdc2-Tyr15 phosphorylation, we evaluated the specific caspase 3 inhibitor Ac-DEVD-CHO. Inhibition of caspase 3 in BaF3 cells produced an increase in Cdc2Tyr15 phosphorylation in a dose-dependent manner, with 25 mM giving >4-fold higher intact PARP and >6-fold higher phospho-Tyr15 protein levels. Taken together, these results suggest that the antiapoptotic effect of Survivin is mediated through inactivation of Cdc2 by phosphorylation on Tyr-15 as a consequence of protection of the Wee1 kinase from degradation by caspase 3.
Hoxa9+Meis1a Efficiently Transform Hematopoietic Stem Cells but Not Committed Progenitors.
Authors: Wang Yingzi , Krivtsov Andrei , Losyev Grigoriy , Armstrong Scott A. 
Published: October 2019

Abstract
The homeobox transcription factors Hoxa9 and Meis1a induce the expansion of hematopoietic stem cells (HSC) and cooperate to induce acute myeloid leukemia (AML). We have recently shown that Hoxa9 and Meis1a are part of a self-renewal program found in leukemia stem cells (LSC) isolated from murine leukemias initiated by expression of MLL-AF9 in committed granulocyte macrophage progenitors (GMP). However, it remains unclear whether the Hoxa9-Meis1a complex is sufficient to mimic the leukemogenic effects of MLL-AF9. Therefore we assessed the clonogenic and leukemogenic activity of HSC and GMP transduced with Hoxa9-Meis1a and compared this to MLL-AF9 transduced HSC and GMP. We expressed either Hoxa9-Meis1a or MLL-AF9 in HSC or GMP and sorted single cells into 96 well plates. The data demonstrate that the clonogenic potential of single HSC or GMP expressing Hoxa9-Meis1a or MLL-AF9 are similar and both produce cells that can be replated in vitro for greater than 6 weeks. Remarkably, Hoxa9-Meis1a induces leukemia with high efficiency when expressed in HSC but not committed GMP, while MLL-AF9 can fully transform both HSC and GMP. Next, we identified a population of cells from Hoxa9-Meis1a leukemias that were enriched for LSC. Even though the leukemias were initiated from HSC, the LSC population possessed an immunophenotype and global gene expression program more consistent with differentiated myeloid cells. Further characterization of gene expression in the Hoxa9-Meis1a LSC found that only a subset of the MLL-AF9 self-renewal signature is activated by Hoxa9-Meis1a. These findings show that Hoxa9-Meis1a can efficiently induce LSC from HSC but not GMP. This suggests Hoxa9 and Meis1a induced leukemogenesis is dependent upon cellular context and require programs/pathways active in HSC in order to initiate leukemia. Thus MLL-AF9 must activate pathways critical for LSC development in addition to Hoxa9-Meis1a in order to fully transform committed progenitor cells. Identification of these cooperating pathways should provide insight into MLL-rearranged and other AML.
Epigenetic Regulation of CD20 Protein Expression in B-Cell Lymphoma Cells after Rituximab-Containing Chemotherapy.
Authors: Tomita Akihiro , Hiraga Junji , Kiyoi Hitoshi , Kinoshita Tomohiro , Naoe Tomoki 
Published: October 2019

Abstract
For the past 10 years, rituximab has been used with some forms of conventional chemotherapy to treat CD20(+) B-cell malignancies as a new molecular targeting drug. Although significant improvements in disease-free survival and cure rate have been obtained, resistance to rituximab has been recognized as a considerable problem. Here we report that CD20(−) tumor transformation is one important mechanism of resistance to rituximab. We also demonstrate a possibility that CD20 protein expression is downregulated by some epigenetic mechanisms, and interestingly, the protein expression can be restored by treatment with certain epigenetic drugs. During the 5 years beginning in 2001, 124 patients with B-cell malignancies were treated with rituximab-containing induction, consolidation, or salvage chemotherapies in our hospital. Relapse or recurrence of disease were confirmed in 36 patients (29.0%), and re-biopsy of tumor tissues was performed in 19 patients. Five cases (DLBCL, 3 cases, and DLBCL transformed from FL, 2 cases) of those 19 patients (26.3%) indicated CD20 protein-negative transformation in flow cytometry (FCM) and/or immunohistochemistry (IH) analyses. We established a CD20(−) lymphoma cell line RRBL1 from a DLBCL patient with CD20(−) transformation from CD20(+) FL after repeated treatment with rituximab, and analyzed molecular mechanisms of the CD20 protein-negative phenotype. CD20 was not expressed by IH, FCM, and immunoblotting analyses, and resistance to rituximab was observed after cell culture with rituximab treatment. Expression of wild-type CD20 mRNA was confirmed by RT-PCR, and no genetic mutation in coding sequence or promoter region was observed. Quantitative RT-PCR showed that the CD20 mRNA expression level was almost 100 times lower than that of CD20(+) B-cell lymphoma cells typically obtained from DLBCL patients. These data suggest that aberrant down regulation of CD20 mRNA may be closely related to the negative CD20 surface antigen expression. Interestingly, CD20 protein re-expression was confirmed by enhancing CD20 mRNA expression using specific epigenetic drugs including histone deacetylase inhibitor Trichostatin A (TSA). In addition, after TSA treatment, sensitivity for rituximab was significantly restored. Chromatin immunoprecipitation assay suggested that recruitment of histone deacetylase complexes to CD20 promoter may be related to the down regulation of CD20 expression. Our data may provide the basis for a new therapeutic strategy, epigenetic therapy combined with molecular targeting therapy using rituximab, for rituximab-resistant CD20(−) transformed B-cell malignancies.
Directed De Novo DNA Methylation of a Genomic Locus Leads to Heritable Transcriptional Repression.
Authors: Ford Kevin G. , Hurd Paul J. , Bannister Andrew J. , Kouzarides Tony , Smith Alexander E. 
Published: October 2019

Abstract
The ability to impose exogenous targeted epigenetic changes in the genome represents an attractive goal in gene therapy for the heritable repression of target genes, while potentially enabling the generation and subsequent study of the downstream effects of de novo epigenetic events, which are known to occur in disease. Here we demonstrate the ability of zinc-finger peptides to deliver DNA cytosine methylation in vivo to a genomic target promoter, when expressed as fusions with a mutant prokaryotic DNA cytosine methyltransferase enzyme, thus mimicking cellular de novo methylation events. We show for the first time targeted gene silencing in response to directed DNA cytosine methylation via initiation of a repressive chromatin signature at a targeted genomic locus, characterised by elevation of histone H3K9Me2 and reduction of H3K4Me3 levels at that region. This transcriptional repression is maintained in the absence of sustained targeted methyltransferase action, confirming epigenetic maintenance by the cells own machinery. The inherited DNA methylation pattern is restricted to specific target sites, suggesting that the establishment of repressive chromatin structure does not drive further de novo DNA methylation in this system. Therefore, we demonstrate for the first time, targeted DNA methyltransferases as potential tools for the exogenous and heritable control of gene expression at the chromosomal level, while providing the clearest and most direct confirmation to date of the functional and mechanistic consequences of de novo DNA methylation in the cell. This work represents an important step towards the longer term goal of controlling gene expression through the inheritance of a repressive DNA state, as well as providing a valuable tool for studying spatial and temporal issues associated with ‘genuine’ de novo methylation, on transcription and chromatin structure.
High-Dose Methotrexate, Ifosfamide, Etoposide and Dexamethasone (MIED) Is an Active Salvage Regimen for Children with Recurrent or Refractory Malignant Lymphoma.
Authors: Sandlund John T. , Pui Ching-Hon , Zhou Yinmei , Lowe Eric J. , Kaste Sue C. , Kun Larry E. , Krasin Matthew J. , Onciu Mihaela , Ribeiro Raul C. , Howard Scott C. , Metzger Monika L. , Relling Mary V. , Hale Gregory A. , Rencher Renee , Darnell Kim , Hudson Melissa M. 
Published: October 2019

Abstract
Significant advances have been made in the treatment of malignant lymphomas in children; however, approximately 20–30% will have refractory or recurrent disease. These patients are felt to have a relatively poor prognosis primarily because of the comprehensive and intensive nature of their frontline therapies; therefore, they are generally considered for a novel or more aggressive salvage regimen. The purpose of this study is to determine the activity and toxicity profile of the MIED regimen (high-dose methotrexate, ifosfamide, etoposide and dexamethasone) in children with refractory or recurrent non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL). From 1991 to 2006, 62 children with refractory/recurrent NHL (n=24) and HL (n=38) were treated with 1 to 6 sequential cycles of MIED (methotrexate, 8 grams/m2 on day 1; ifosfamide, 2 grams/m2 on days 2–4; etoposide, 200 mg/m2 on days 2–4; and dexamethasone, 40 mg/m2 on days 1–4). Children with NHL also received intrathecal MHA (methotrexate, hydrocortisone, and cytarabine at age adjusted dosages) on day 1. Response evaluation was performed after 1 – 2 cycles of MIED. Children with either a PR or CR were considered for an intensification phase with hematopoietic stem cell transplantation (HSCT); patients with HL also received involved-field irradiation. Forty-six (75%) of the 61 evaluable children with refractory or recurrent lymphoma responded to MIED (CR, 23; PR, 23). Among the 24 children with NHL (large cell, 18 [anaplastic large cell, 8; diffuse large B-cell, 3; T-cell large cell, 2; large cell not otherwise specified, 5]; Burkitt, 3; lymphoblastic, 2; other, 1), responses included: CR (n=10), and PR (n=5) for a combined CR+PR rate of 63%. Among the 37 children with HL (nodular sclerosis, n = 29; mixed cellularity, n =4; lymphocyte predominant, n =1; and HL not otherwise specified, n=3) responses included: CR (n=13), and PR (n=18) for a combined CR+PR rate of 84% among 37 evaluable patients. MIED was generally well tolerated (associated with grade IV hematologic toxicity in most cases and frequently associated with mucositis and/or fever with neutropenia). Nineteen of 24 children with NHL and 31 of 37 children with HL received an intensification phase with HSCT support (autologous, 46; allogeneic, 4) at some point following MIED therapy. Nine of 24 children (38%) with NHL are alive and disease-free. Twenty-eight of 37 children (76%) with HL are currently alive (24 disease-free post HSCT). MIED is an active and generally well tolerated regimen for children with refractory or recurrent malignant lymphoma.
Diffuse Large B-Cell Lymphoma (DLBCL) with Central Nervous System (CNS) Relapse: Prognosis and Risk Factors by Retrospective Analysis from Single Center Experience.
Authors: Shimazu Yutaka , Maeda Takeshi , Notohara Kenji , Ito Takeshi , Morita Satoko , Fujiwara Yayoi , Uchiyama Tatsuki , Sato Aki , Sato Takayuki , Onishi Tatsuhito , Chisato Mizutani , Matsutama Fumio , Tsukayama Choutatsu , Ueda Yasunori 
Published: October 2019

Abstract
Background: The introduction of rituximab into the therapy of DLBCL has improved the prognosis dramatically. However, relapse in CNS is still the issue. We studied the prognosis and risk factors of CNS recurrence in DLBCL.
Method: Between Jan. 1996 and Apr. 2007, 441 patients were diagnosed to have DLBCL in our institute, of whom 31 patients were excluded due to CNS involvement at the time of initial diagnosis. We have analyzed 410 cases, in which 37 cases had relapsed in CNS. Before Sep. 2003, 168 patients were treated with the regimen based on CHOP, and after Sep. 2003, 242 patients were treated with the regimen based on CHOP plus rituximab. Once relapsing in CNS, the patients were treated with systemic chemotherapy plus high-dose methotrexate or radiation with intrathecal methotrexate. The risk category by the international prognostic index of these 411 cases was assessed as low: 36%, low-intermediate: 15%, high-intermediate: 23%, and high: 26%.
Results: The median age was 71 years old (range: 17–92). Median follow-up period was 507 days, and the median period free from relapsing in CNS was 331 days. The mean survival period of the cases with CNS relapse, of the cases relapsed outside the CNS, and of the non-relapsed cases was 1328 days, 2290 days, and 2817days, respectively. The overall survival rate of cases with CNS relapse was significantly lower than that of the cases relapsed outside the CNS, or than that of the non-relapsed cases (p=0.0233, p=0.0003, respectively). Multivariate Cox regression analysis identified the increased lactate dehydrogenase (p=0.014), the involvement of more than one extranodal site (p=0.006), and not using rituximab before CNS relapse (p=0.040) as an independent predictor of CNS recurrence.
Conclusion: CNS relapse has extremely poor prognosis than relapse outside the CNS in DLBCL. Rituximab may be effective in preventing CNS relapse. Since rituximab poorly penetrates into CNS, this may partly due to the reduction of all recurrence by rituximab. According to the risk assessment in CNS relapse, an effective CNS prophylaxis strategy should be determined.