bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic Rearrangements of FOXP1 Are Restricted to a Subset of Agressive B Cell Lymphoma with Extranodal Presentation.
Authors: Haralambieva Eugenia , Adam Patrick , Eichelbroenner Irina , Kalla Joerg , Rosenwald Andreas , Katzenberger Tiemo , Hoeller Sylvia , Banham Alison H. , Mueller-Hermelink Hans Konrad , Ott German 
Published: October 2019

Abstract
In most mature B-cell non-Hodgkin lymphoma (NHL) chromosomal translocations result in the transcriptional deregulation of an oncogene by juxtaposing it to regulatory sequences of genes that are constitutively expressed in mature B cells, most often the Ig genes. Recently, a novel recurrent translocation t(3;14)(p13;q32) that results in deregulation of the FOXP1 forkhead transcription factor has been reported in a variety of B cell lymphoma.
Here we present the analysis of 275 B-cell NHL: 102 diffuse large B cell lymphoma (DLBCL) (49 nodal and 53 extranodal cases) 122 marginal zone lymphoma (MZL) from different localization (cutenous n= 9, salivary gland n= 13, pulmonary n=50, ocular adnexae n=36, thyroid n=8, gastric n=6), 30 follicular lymphoma (FL) and 21 mantle cell lymphoma (MCL). The presence of genetic aberrations involving the FOXP1 gene was studied by interphase fluorescence in situ hybridization (FISH) and FOXP1 protein expression - by immunohistochemistry using the JC12 monoclonal antibody.
In total, 5 of 275(2%) lymphoma were found to carry a chromosomal breakpoint within the FOXP1 gene. Further FISH studies indicated the presence of a FOXP1/IgH translocation in only 2 of these samples, suggesting the likely involvement of other translocation partner. All samples that harbored a FOXP1 breakpoint represented aggressive B cell lymphoma with proliferation fraction of 70–90% defined by the Ki 67% labeling pattern. Cytogenetic analysis and/or FISH suggested a presence of the complex chromosomal rearrangements. Four of 5 tumors presented at extranodal sites: gastro-intestinal tract (N=3); thyroid gland (N=1). All samples expressed B-cell markers and lacked CD5 and CD10 - a phenotype consistent with a marginal zone derivation. Interestingly, we failed to identify a FOXP1 breakpoint in any of the “true” low grade MZL in our series.
A gain of genomic material was found in 80 (29%) of these samples, indicated by detection of more than two FISH signals in a variable number of cells and/or cytogenetic data. In the vast majority of these cases trisomy 3 was further identified. All 5 samples that harbor FOXP1 chromosomal breakpoint showed strong nuclear labeling pattern when stained with JC12 monoclonal antibody. FOXP1 nuclear expression, in a variable number of the cells was detected in 95% of the cases with genomic gain/trisomy 3, however also in 40 % of the samples without evidence of any genetic aberrations in this locus, suggesting a range of mechanisms, regulating the FOXP1 expression.
Neutrophil Elastase Modulates Granulopoiesis through the Interaction of G-CSF and G-CSF Receptor.
Authors: Sato Takashi , Habara Masakazu , Kihara Hiroki , Kawaguchi Hiroshi , Nakamura Kazuhiro , Okada Satoshi , Ishikawa Nobutsune , Ohno Norioki , Kobayashi Masao 
Published: October 2019

Abstract
Primary granule proteases provide negative feedback on granulopoiesis. Recent study showed that neutrophil elastase potentially inhibits granulopoiesis by enzymatic digestion of G-CSF. We studied the effects of neutrophil elastase on granulopoiesis in the interaction of G-CSF and G-CSF receptor (G-CSFR). Primitive myeloid cells of the bone marrow in normal subjects were purified based on the expression of CD34 and G-CSFR by FACS Vantage. The cells were incubated with or without human neutrophil elastase for 2 hours in serum-deprived media. Cells were washed once and then cultured in various serum-deprived conditions. The proliferation and colony formation of CD34+/G-CSFR+ cells in the presence of G-CSF were significantly reduced by the pretreatment of elastase. Furthermore, those of CD34+/G-CSFR+ cells in response to hematopoietic factors without G-CSF were similarly inhibited by elastase. On the other hand, the responses of CD34+/G-CSFR− cells were not affected by the treatment of elastase in the stimulation of any hematopoietic factors. When CD34+ cells were incubated with or without elastase, further G-CSFR expression was analysed by flow cytometry. The treatment of elastase did not affect the expression of surface expression of G-CSFR on CD34+ cells. Next, the binding of G-CSF to G-CSFR was examined by flow cytometry using antibody to G-CSF. The mean channel of fluorescence of G-CSF binding to G-CSFR-positive cells was reduced by the treatment of elastase, suggesting the loss of the binding of G-CSF to G-CSFR. When CD34+/G-CSFR+ cells were treated with elastase, the observation by confocal immunofluorescence microscopy revealed neither accumulation of elastase on the surface of cell membrane nor in intracellular compartment. No evidences that cells treated with elastase directly cleave the G-CSF leading to inactivation of G-CSF. Collectively, these results suggest that G-CSFR-positive cells are selectively affected by neutrophil elastase, and that neutrophil elastase as negative regulator may play a role in modulating granulopoiesis through G-CSF-G-CSFR interaction.
Reversive Loss of Pulmonary Function Induced by Acute Chest Syndrome: A Report from the National Acute Chest Syndrome Study Group (NACSG).
Authors: Neumayr Lynne , Morris C. , Wen A. , Earles A. , Robertson S. , Abboud M. , Ballas S. , Browning I. , Bellevue R. , Daeschner C. , Groncy P. , Hume H.A. , Iyer R. , McMahon L. , Moncino M. , Orringer E. , Swerdlow P. , Waldron15 P. , Ware R. , Vichinsky E. ,   National Acute Chest Study Group (NACSG)
Published: October 2019

Abstract
Acute Chest Syndrome (ACS) remains the leading cause of death and hospitalization in patients (pts) with sickle cell disease (SCD). There is limited data on the effects of ACS on lung function. From 1993 to 1997, 30 centers participated in the NACSG and prospectively analyzed 671 episodes of ACS in 538 pts. Pulmonary function tests (PFTs) included forced expiratory volume in 1 sec (FEV1), forced vital capacity (FVC), forced expiratory flow during 25% to 75% of FVC (FEF 25–75), peak expiratory flow rate (PEF) and the ratio of FEV1/FVC. Data is reported as percent-predicted of normal values based on age and height. 128 pts (mean 16yrs, 4 to 52 yr range) had PFTs during an ACS episode (within a mean of 2.5 days of diagnosis) and then 12 weeks later. 94% of pts had abnormal lung volumes, defined as either FEV1 or FVC < 80%. Mean lung volumes during ACS and at follow-up are shown below.
Table 1: Decreased Lung Volumes During ACS PFT During ACS Follow-up p-value FEV1 52% 79% <.0001 FVC 55% 83% <.0001 FEF 25–75 50% 69% <.0001 PEF 61% 83% <.0001
Pts with abnormal lung volumes (FEV1 or FVC < 80%) and considered to have an obstructive pattern if the FEV1/FVC ratio was < to 85. Obstructive patterns in pts with abnormal lung volumes and the percent of pts who responded to bronchodilators (15% improvement in either FEV1 or FVC) are shown below.
Table 2: Patterns of Abnormal Lung Volumes in SCD SCD Patients During ACS Follow-up Abnormal PFTs 94% 45% Obstructive Pattern 48% 46% Respond to bronchodilators 25% 8%
In summary, ACS resulted in decreased pulmonary function in 94% of pts. It is striking that 49% pts had their PFTs reduced by half (FEV1 52% and FVC 55%). In pts with abnormal PFTs, 48% had evidence of obstruction and 25% of all pts tested improved with a bronchodilator. This is the first description of reversible abnormalities of pulmonary function occurring during ACS compared to baseline. An obstructive pattern is identified in a higher percentage of pts with SCD than in the local Oakland African American population (asthma prevalance 16%). While some pts PFTs improved with time, 45% remained abnormal at 12-week follow-up. ACS results in acute and chronic worsening of lung function. Future studies of ACS may reveal common pathogenic mechanisms with asthma, and lead to improved therapeutic interventions.
Posttranslational Control of Beta-Catenin Signaling Regulates Peripheral Blood Lymphocyte Activation.
Authors: Chung Eun Joo , Lee Min Jung , Lee Sunmin , Oh Ho Jung , Hwang Sang-Gu , Rubin Jeffrey S. , Trepel Jane B. 
Published: October 2019

Abstract
Lymphocyte proliferation is a critical step in the immune response to antigen. Previously we demonstrated that β-catenin is constitutively expressed in hematologic malignancies and that β-catenin regulates leukemia cell proliferation. Here we report that β-catenin is highly regulated in peripheral blood lymphocytes via posttranslational mechanisms, and that β-catenin signaling promotes lymphocyte proliferation. β-catenin protein was undetectable by western blot in resting PBL and readily detectable within 30 min after activation by TCR ligation, mitogen or PMA/ionomycin. Proteasome inhibitor alone induced β-catenin accumulation in resting PBL. Transfection of β-TrCP1, an adaptor protein that recruits serine-phosphorylated β-catenin to the Skp1-Cullin-F box ubiquitin ligase complex down-regulated β-catenin in activated cells and conversely, dominant-negative β-TrCP1 upregulated β-catenin in resting cells. β-catenin was serine/threonine phosphorylated in resting PBL and rapidly dephosphorylated after activation, consistent with regulation by an activation-induced phosphatase. In resting PBL, elevation of intracellular Ca2+ stabilized β-catenin protein. In activated PBL, β-catenin stabilization was inhibited either by blocking Ca2+ flux with EGTA and BAPTA/AM, or by incubation with cyclosporine A, an inhibitor of the calcium-activated phosphatase calcineurin. In activated PBL inhibition of β-catenin nuclear signaling with dominant-negative β-catenin, dominant-negative TCF or β-catenin antisense inhibited IL-2 expression and proliferation. Conversely, wild-type β-catenin increased IL-2 expression and stimulated proliferation. We conclude that
β-catenin protein is continuously synthesized and efficiently degraded in resting lymphocytes, β-catenin is rapidly stabilized in response to activation-induced Ca2+ flux, β-catenin nuclear signaling plays a critical role in peripheral blood lymphocyte activation.
Activity of the Histone Deacetylase (HDAC) Inhibitor PXD101 in Preclinical Studies and in a Phase I Study in Patients with Advanced Haematological Tumors.
Authors: Gimsing Peter , Wu Frank , Qian Xiaozhong , Jeffers Michael , Knudsen Lene , Sehested Maxwell , Lichenstein Henri S. 
Published: October 2019

Abstract
Previous investigations have shown that the novel hydroxamate PXD101 potently inhibits the enzymatic activity of histone deacetylase (HDAC) at nanomolar concentration, and the growth of cancer cell lines derived from solid malignancies at low micromolar potency. We have now examined and present results showing the activity of PXD101 on > 20 cell lines corresponding to a variety of haematological cancer types including acute T-cell leukaemia, cutaneous T-cell lymphoma, anaplastic large T-cell lymphoma, mantle cell lymphoma, Burkitt’s lymphoma, diffuse large-cell lymphoma, plasma cell leukaemia and multiple myeloma (MM). Our data show that PXD101 strongly inhibits the growth of these cancer types at submicromolar potency. In addition, we will present in vitro data demonstrating that PXD101 efficiently inhibits the growth of doxorubicin-resistant leukemic cells, thereby supporting the possibility that this compound may be effective on drug-resistant haematological cancers. Finally, we will present results demonstrating that PXD101 used in combination with Velcade mediates greater growth-inhibition than does either drug used as monotherapy on a multiple myeloma cell line. These promising preclinical findings, taken together with previous results demonstrating the activity of PXD101 in a murine leukaemia animal model, support the evaluation of PXD101 for the treatment of haematological malignancies in a clinical setting. To this end, a Phase I trial using PXD101 in patients with advanced hematological tumors refractory to standard therapy was initiated. PXD101 is administered as a 30 minute i.v. infusion on days 1 to 5 of a 21 day cycle. Dose levels 600 mg/m2/d and 900 mg/m2/d have been examined (3 patients each) and recruitment to the dose level 1000 mg/m2/d is ongoing (5 patients to date). Patient characteristics are 8 males and 3 females with median age of 67 (range 58 – 73). Median number of prior therapies is 5 (range 4 – 7). Of the 11 patients enrolled to date, diagnoses were: MM (2), Non-Hodgkin’s lymphoma (5), CLL (4). Eleven patients have been treated with 1–8 cycles of therapy. Adverse events related to PXD101 treatment have mainly been grade 1–2. The most frequent adverse events were nausea (12/23 cycles), fatigue (9/23 treatment cycles), vomiting (8/23 cycles) and diarrhoea (7/23 cycles). Potential antineoplastic activity has been observed. One patient with MM had a possible tumor lysis syndrome with decrease in M-component, increasing urate and serum creatinine requiring dialysis. In addition, one patient with Richter transformation of CLL refractory to other treatments has now been in stable disease for > 6 months. We continue to accrue patients in this study, and updated data will be presented.
Genome-Wide Analysis of Copy Number Analysis of Myelodysplastic Syndromes Using High-Density SNP-Genotyping Microarrays.
Authors: Sanada Masashi , Nannya Yasuhito , Nakazaki Kumi , Yamamoto Go , Wang Lili , Hosoya Noriko , Hangaishi Akira , Kurokawa Mineo , Chiba Shigeru , Ogawa Seishi 
Published: October 2019

Abstract
Myelodysplastic syndromes (MDS) are clonal disorders of hematopoietic progenitors characterized by impaired blood cell production due to ineffective hematopoiesis and high propensity to acute myeloid leukemias. One of the prominent features of MDS is the high frequency of unbalanced chromosomal abnormalities that result in genetic imbalances and copy number alterations. Although the chromosomal segments involved in these abnormalities are thought to contain relevant genes to the pathogenesis of MDS, conventional analyses including FISH have failed to identify critical regions small enough to pinpoint their target genes.
Affymetrix® GeneChip® 100K/500K mapping arrays were originally developed for large-scale genotyping of more than 100,000/500,000 SNPs in two separate arrays, but the quantitative nature of the preparative whole-genome amplification and array hybridization thereafter also allows for accurate copy number estimate of the genome using these platforms at the resolutions of 21.3 kb and 5.4 kb with 116,204 and 520,000 oligonucleotide probes, respectively. Here we developed robust algorithms (CNAG) for copy number detection using 100K and/or 500K arrays and analyzed 88 MDS samples on these platforms in order to identify relevant genes for development of MDS.
With these huge numbers of uniformly distributed SNP probes, numerous copy number alterations were sensitively detected in cases with MDS with more numbers of abnormalities found in advanced diseases (RAEB and RAEB-t). In addition to large-scale alterations of various chromosomal segments previously reported in these syndromes, a number of small cryptic chromosomal abnormalities were identified that would escape conventional cytogenetic analysis or array CGH analysis. Minimum overlapping deletions in 5q, 7q, 12p, 13q, and 20q were precisely defined, although no pinpoint homozygous deletions were detected within these regions. A common 20q deletion spans a 400 kb segment harboring five transcriptomes and the common 12p deletion defines a 1.3 Mb region that contains the ETV6 gene. Other common overlapping abnormalities include deletions in 21q22, 17q13, and gains of 11q25. Genome-wide analysis of copy number changes using high-density oligonucleotide arrays provides valuable information about genetic abnormalities in MDS.
Antagonist Anti-CD40 Antibody, CHIR-12.12, Induces ADCC, Inhibits Tumor Growth, and Prolongs Survival in a Human Multiple Myeloma Xenograft Model.
Authors: Long Li , Tong Xia , Patawaran Montesa , Aukerman Sharon L. , Jallal Bahija , Luqman Mohammad 
Published: October 2019

Abstract
CD40 is expressed on all B-cell malignancies, including multiple myeloma, and represents an attractive target for antibody therapy. CHIR-12.12 is a fully human, highly potent, IgG1 antagonistic anti-CD40 monoclonal antibody generated using XenoMouse® mice (Abgenix, Inc). CHIR-12.12 can mediate antitumor activity by at least two mechanisms: blocking CD40-ligand-mediated survival signals and killing tumor cells by antibody-dependent cellular cytotoxicity (ADCC). We have previously reported that CHIR-12.12 mediates stronger in vitro killing of CD40+- and CD20+-expressing human non-Hodgkin’s lymphoma and lymphoblastoid B cells by ADCC than rituximab and significantly inhibits the growth of rituximab-responsive (Daudi) and rituximab-resistant (Namalwa) human lymphoma and lymphoblastoid B-cell (IM-9) xenografts in vivo. In this study, we examined the in vitro and in vivo efficacy of CHIR-12.12 against the human multiple myeloma cell line KMS-12-BM. CHIR-12.12 induced lysis of KMS-12-BM cells by ADCC in a dose-dependent manner, reaching maximum cell lysis at 0.1μg/ml with an EC50 of 17.5 pM. CHIR-12.12 efficacy in vivo was evaluated in orthotopic and subcutaneous KMS-12-BM xenograft models. In the staged orthotopic model, tumor cells were delivered intravenously and treatment was initiated 7 days post cell implantation. CHIR-12.12 significantly prolonged the median survival of tumor-bearing mice in a dose-dependent manner, with a median survival of 78 and 98 days in the groups treated with 1 mg/kg and 10 mg/kg CHIR-12.12 weekly, respectively, compared to a median survival time of 68 days in the control IgG1 group (P<0.0001). Bortezomib administered i.v. twice weekly at 0.5 or 1 mg/kg showed no survival benefit. In the staged subcutaneous model, CHIR-12.12 was administered weekly at 1 and 10 mg/kg after the mean tumor volume reached 100mm3. CHIR-12.12 significantly inhibited tumor growth, with a tumor volume reduction of 42% (P<0.05) and 63% (P<0.01), respectively. Bortezomib and melphalan/prednisone did not inhibit KMS-12-BM tumor growth at the doses and schedules reported for other human multiple myeloma xenograft models. Western blot analysis and immunohistochemical staining showed significantly increased levels of cleaved PARP in KMS-12-BM s.c. tumors 7 days after the initiation of CHIR-12.12 treatment, suggesting the induction of cell death by CHIR-12.12. Taken together, these data demonstrate that the anti-CD40 mAb CHIR-12.12 has potent activity against human multiple myeloma cells in vitro and in xenograft models in vivo. Currently CHIR-12.12 is in Phase I clinical trials for the treatment of B-cell malignancies.
The N-Terminus of Hepcidin Is Essential for Its Interaction with Ferroportin: Structure-Function Study.
Authors: Nemeth Elizabeta , Preza Gloria C. , Waring Alan J. , Ganz Tomas 
Published: October 2019

Abstract
Hepcidin, a small peptide produced by the liver, is the principal iron-regulatory hormone. It acts by binding to the iron exporter ferroportin, inducing its internalization and degradation, thereby blocking cellular iron efflux. The bioactive 25 amino acid peptide has a hairpin structure stabilized by 4 disulfide bonds. We synthesized a series of hepcidin derivatives and determined their bioactivity in a cell line expressing ferroportin-GFP fusion protein, by measuring the degradation of ferroportin-GFP and the accumulation of ferritin after peptide treatment. Bioactivity was also assayed in vivo, by measuring hypoferremia in mice injected with hepcidin derivatives.
Serial deletion of N-terminal amino acids caused progressive decrease in activity which was completely lost when five N-terminal aa were deleted. Synthetic 3-aa and 6-aa N-terminal peptides alone, however, did not internalize ferroportin, and did not interfere with ferroportin internalization by native hepcidin. Deletion of two C-terminal amino acids did not affect peptide activity. Removal of individual disulfide bonds by pairwise substitution of cysteines with alanines also did not impact peptide activity in vitro. However, these peptides were significantly less active in vivo, likely due to their decreased stability in circulation. Peptides with a substitution G71D or K83R, previously described in human subjects, were fully active in vitro and in vivo. Zebrafish hepcidin, which is only 60% similar to human hepcidin, but with conservative substitutions at the N-terminus, was as active as its human counterpart.
Apart from the essential nature of the N-terminus, hepcidin structure appears permissive for mutations. Further studies of hepcidin structure in relation to its function are essential for the design of hepcidin antagonists and agonists which could be used for treatment of iron disorders.
Discordant Serum Folate Result Unique to the Beckman Access Assay.
Authors: Wakeman Lisa , Munro Roger , Lewis John , Beddall Andrew , Al-Ismail Saad 
Published: October 2019

Abstract
Most current commercial assays for serum folate use folate-binding protein with chemiluminescence detection. Historically serum folate methods have been calibrated using pteroylglutamic acid (PGA) as this is more stable than 5Methyltetrahydrofolate (5MTHF) which is the form present in patients not receiving supplementation. Poor specificity of these binding assays together with different detection technologies and different method designs have highlighted the need for greater standardisation to calibration regimes so that individual folate species can be better identified. We describe here discrepant serum folate results in a patient which appear to be unrelated to the issues described above.
Consequent to a procurement evaluation of multiple analytical systems, serum ferritin, vitamin B12 and folate assays were performed on the Beckman Access, Abbott Architect 12000SR, Bayer Centaur and Roche E170 analysers according to manufacturer’s instructions. Method comparison studies using serum samples from 500 individuals showed good agreement between all analytical systems for all three parameters. However, one serum sample from a 44 year old Caucasian male who had presented with weight loss, diarrhoea and a microcytic, hypochromic anaemia (Hb 10.7 g/L) gave discrepant serum folate results and was further investigated. He had no evidence of renal impairment. His only medication was a multivitamin tablet supplement which he had been taking for several weeks. IgA anti-TTG antibodies were 33 U/mL (NR 0 – 10) and IgA endomysial antibodies were weakly positive. There was a polyclonal increase in serum IgA = 4.62 g/L (NR 0.8 – 2.8). Otherwise routine chemistry, thyroid profile and a paraprotein screen were unremarkable. Parietal cell and intrinsic factor antibodies were negative. Serum ferritin = 16 ng/mL (NR 20 – 215); Vitamin B12 = 164 pg/mL (NR 150–600). The patient’s sample showed no discrepant inter-system results for ferritin or Vitamin B12. Serum folate assays (NR 3.0 – 15.0 ng/mL) were as follows:
Technique Serum Folate Calibration method Beckman Access >20.0 PGA Roche E170 2.2 Quantaphase II Abbott Architect 1.9 Quantaphase II Bayer Centaur 1.5 5MTHF
This pattern of results was confirmed on a second sample a month later. No discrepancies were found in twenty other patients with positive TTG and endomysial antibodies.
Current methods for folate assays give different results and cannot measure the various forms of folate due to lack of calibrant standardisation with different types of automated analysers. In this patient, it may be that the folate species in the Vitamin supplement are measurable by the Beckman Access but are undermeasured with the other assay techniques. This data suggests the need for a reference method capable of identifying individual folate species in all patients.
Technique Serum Folate Calibration method Beckman Access >20.0 PGA Roche E170 2.2 Quantaphase II Abbott Architect 1.9 Quantaphase II Bayer Centaur 1.5 5MTHF