bluuebunny/crossref_metadata_2025_split huggingface dataset:
FOXP1, a Highly Expressed Gene in a Subset of DLBCL, Is Targeted by a Recurrent t(3;14)(p13;q32).
Authors: Wlodarska Iwona , Vandenberghe Peter , Nooien Peet , Hagemeijer Anne , Marynen Peter , De Wolf-Peeters Chris 
Published: April 2020

Abstract
Chromosomal translocations involving the immunoglobulin heavy chain genes cluster (IGH) at 14q32 have been found in up to 70% of B-non Hodgkin’s lymphoma. These aberrations lead to deregulation of putative oncogenes by their juxtaposition with IGH enhancer elements. So far, more than 20 genes affected by t(14q32) have been identified in B-cell malignancies. The most frequently rearranged genes include BCL1/11q13, BCL2/18q21, BCL6/3q27 and CMYC/8q24.
We report here a novel t(3;14)(p13;q32) involving IGH, as shown by FISH, in three lymphoma cases. One of these cases was diagnosed as gastric MALT-type lymphoma, the remaining two cases as diffuse large B-cell lymphoma with a focal nodular growth pattern reminiscent of follicular lymphoma.
In order to identify the gene targeted by the t(3;14)(p13;q32) we performed FISH analysis of the first case and narrowed down the breakpoint to RP11-154H23 at 3p13 that showed a split signal on both derivative chromosomes. This BAC clone covers the FOXP1 gene. Using a pair of probes selected for the 5′ and 3′ ends of FOXP1, we demonstrated rearrangement of the gene by dual color FISH in the remaining two cases. An analysis of FOXP1 expression in present cases is being performed. FOXP1 (Forkhead box-P1) is a winged-helix transcription factor that acts as a transcriptional repressor. It is expressed in a wide variety of normal and neoplastic tissues, including lymphomas. FOXP1 has been shown to be expressed in normal activated B-cells using genomic-scale expression profiling, and in B-cells within and outside the germinal center by immunohistochemistry. Its physiological role in lymphocytes, however, is unclear. Recent studies showed that FOXP1 is strongly expressed in a subset of DLBCL. Interestingly, high expression of FOXP1 carries an independent prognostic significance, what suggests a possible role of the gene in the biology of this group of lymphoma. Although genomic rearrangements of FOXP1 have not been demonstrated so far in cancer, rearrangements of other members of FOX gene family in various pathological conditions have been reported. The involvement of FOXP1 in t(3;14)(p13;q32) found in two DLBCL cases indicates that this translocation may underlie a strong expression of FOXP1 in at least part of these lymphomas. Its rearrangement in a case of gastric lymphoma is intriguing, but additional investigations are required to find out whether t(3;14)(p13;q32) is a recurrent aberration in MALT lymphoma. Further molecular, immunophenotypic and clinical studies of the three cases with t(3;14)(p13;q32) are under progress.
Chromosomal Rearrangements Affecting ABL1 in T-Cell Acute Lymphoblastic Leukemia.
Authors: Cools Jan , Graux Carlos , Boogaerts Marc , Vandenberghe Peter , Wlodarska Iwona , Marynen Peter , Hagemeijer Anne 
Published: April 2020

Abstract
T-cell Acute Lymphoblastic Leukemia (T-ALL) is a heterogeneous entity with several biologically distinct subtypes that differ in clinical outcome. Cytogenetics in T-ALL shows recurrent involvement of TCR a/d (14q11) and TCR b (7q34) rearrangements. The Philadelphia translocation, encoding the BCR-ABL1 (BCR-ABL) fusion gene, is typically found in chronic myeloid leukemia (CML) and precursor B-cell acute lymphoblastic leukemia (B-ALL), but is exceptionally rare in T-ALL. To study the potential involvement of ABL1 gene rearrangements in T-cell malignancies, we screened 90 T-ALL cases by fluorescence in situ hybridization (FISH), using BCR and ABL1 probes. No BCR-ABL1 rearrangements were detected, but 5 patients showed amplification of ABL1 and are described in a separate abstract and 2 patients showed a chromosomal rearrangement affecting ABL1. The first patient (male, age 16, 455x109 WBC/L, 99% blasts, cortical T immunophenotype) showed a cryptic t(9;14)(q34;q32). This was demonstrated in 7/12 metaphases and 60% of nuclei using FISH with the 5′/3′-ABL1 probes RACE-PCR detected a fusion between EML1 at 14q32 and ABL1 at 9q34. The fusion transcript joins exon 1–18 of EML1 to exon 2 of ABL1 and generates an ORF of 4926 nt. The functional characterization of the fusion protein is ongoing. The second patient (male, age 16, 25x109 WBC/L, 35% blasts, mature T-cell immunophenotype) showed a 47, XY, +10[5], idem, inv(9)(p21q34)[2}]/46, XY[9] karyotype. One third of the metaphases are tetraploid with the same distribution of abnormalities. The split signals obtained with the 5′-/3′ABL1 probes in the inv(9) subclone point to an ABL1 rearrangement that is being characterized at the present. These result suggest that ABL1 rearrangements are a rare but recurrent event in T-cell malignancies and support a role of ABL1 in T-cell biology. The therapeutic potential of ABL1 inhibitors for treating this group of T-ALL needs to be explored.
AML1-FOG2 Fusion Protein in Myelodysplasia.
Authors: Chan Edward , Comer Elisha , Brown Frank , Richkind Kathleen , Holmes Melissa , Chong Beng , Shiffman Roger , Zhang Dong-Er , Li Yanjun , Chan Rebecca , Heiber Devan , Vance Gail , Ramsey Heather , Hromas Robert 
Published: April 2020

Abstract
Core binding factor (CBF) participates in specification of the hematopoietic stem cell and functions as a critical regulator of hematopoiesis. Translocation or point mutation of AML1, which encodes the DNA-binding subunit of CBF, plays a central role in the pathogenesis of acute myeloid leukemia and myelodysplasia. We characterized the translocation t(X;21)(p22.3;q22.1) in a patient with myelodysplasia that fuses AML1 to the novel partner gene Friend of GATA-2 (FOG2). The reciprocal gene fusions AML1-FOG2 and FOG2-AML1 are both expressed. AML1-FOG2, which fuses the DNA-binding domain of AML1 to most of FOG2, represses transcription from the promoter of a hematopoietic target of AML1. AML1-FOG2 retains a motif that recruits the corepressor C-terminal binding protein (CtBP) and both proteins associate in a protein complex. These results suggest a role for CtBP in AML1-FOG2 transcriptional repression and implicate coordinated disruption of the AML1 and GATA developmental programs in the pathogenesis of myelodysplasia.
Single-Dose Pegfilgrastim after Chemotherapy Is Highly Effective in Enhancing the Mobilization of Autologous CD34+ Peripheral Blood Stem Cells in Patients with Lymphoid Malignancies and Solid Tumors.
Authors: Kroschinsky Frank , Hoelig Kristina , Platzbecker Uwe , Schleyer Eberhard , Ordemann Rainer , Haack Astrid , Schaich Markus , Bornhaeuser Martin , Ehninger Gerhard 
Published: April 2020

Abstract
The administration of myelosuppressive chemotherapy followed by daily injections of granulocyte-colony stimulating factor (G-CSF) is the common procedure to mobilize autologous CD34+ peripheral blood stem cells (PBPC). Pegfilgrastim (NeulastaTM, Amgen Inc., Thousand Oaks, USA) is a covalent conjugate of filgrastim and polyethylene glycol with an increased elimination half-life due to decreased serum clearance. Whereas a single injection of pegfilgrastim (PEGFIL) has been shown to be equivalent to daily filgrastim in enhancing neutrophil recovery after chemotherapy, the experiences with PEGFIL in mobilization of PBPC are limited.
We report 40 pts (22 male, 18 female, median age 53 years) who had a PBPC mobilization treatment for Hodgkin′s lymphoma (n=3), non-Hodgkin′s lymphoma (n=13), multiple myeloma (n=16), acute lymphoblastic leukaemia (n=3) or solid tumors (n=5). The mobilization regimen consisted of disease specific chemotherapy and a single subcutaneous injection of 6 mg PEGFIL administered 48 hours after the end of cytotoxic treatment (day 0). CD34+ cells in the peripheral blood (PB-CD34) were measured if white blood cells (WBC) exceeded 1.0 Gpt/L after nadir. PBPC collections started at a PB-CD34 cell count &gt;10/μl and were performed as large-volume apheresis (4x blood volume) using a Cobe Spectra (Gambro BCT Inc.). Additional conventional filgrastim (FIL) was given at a dose of 2x5μg/kg if PB-CD34 count was found to be &lt;10/μl. Blood samples for pharmacokinetics were taken in 9 pts.
The median start of aphereses was on day +9 after the administration of PEGFIL and on day +15 after start of chemotherapy regimen, respectively. Median PB-CD34 peak was 74/μl (range 9–565/μl). The median PBPC yield was 7.6 x 10^6 CD34+ cells/kg (range 1.5–88.1). The target cell dose to be collected (≥ 2.5 x 10^6 CD34+ cells/kg) was achieved in 36 (90 %) pts, in 29 pts (72.5 %) ≥ 4.0 x 10^6 CD34+ cells/kg could be obtained with a single collection. Additional FIL administrations were necessary in 7 patients (17.5 %) for 2 to 6 days. All of them were heavily pretreated including a previous autologous transplant in two of these patients. PEGFIL was well tolerated except for moderate bone pain which occurred in all patients.
The mean values (± SD) for peak plasma concentration of PEGFIL (cmax), time to reach the maximum plasma level (tmax) and elimination half-life (t1/2) were 154 (± 83) ng/ml, 56 (±21) hours and 23 (± 9) hours, respectively.
We conclude that a single dose of 6 mg PEGFIL after chemotherapy is safe and highly effective in enhancing the mobilization of CD34+ PBPC for stem cell collection. Further investigations are warranted, including comparison with non-pegylated G-CSFs and in combination with antiadhesive agents.
G-CSF as a Potent Mitogen Augments the Elimination of CML Stem Cells by Imatinib Mesylate In Vitro.
Authors: Jorgensen Heather G. , Copland Mhairi , Allan Elaine K. , Eaves Allen C. , Eaves Connie J. , Jiang Xiaoyan , Holyoake Tessa L. 
Published: April 2020

Abstract
Imatinib mesylate (IM; Glivec®, Novartis) induces an impressive frequency of complete cytogenetic remission in patients with Chronic Myeloid Leukemia (CML) but molecular disease persists in most cases. We have previously demonstrated survival and accumulation of quiescent Ph+ CD34+ cells in the presence of IM in vitro. Using Q-RT-PCR analysis of FACS-purified subsets, we have since found that granulocyte-colony stimulating factor receptor (G-CSFR) transcript levels are significantly elevated in these primitive quiescent CML cells relative to their normal counterparts. Indeed CD34+ CML cells proliferated in response to exogenous G-CSF (20 – 200 ng/mL). Both total and quiescent CD34+ cell numbers were measured to test the effects of G-CSF with IM. Primary CFSE-labelled, CD34-enriched CML cells were cultured in serum-free medium for 3 cycles of treatment, 96 hours each (12 days in total). Nine treatment conditions were compared: (1) incubation alone (no G-CSF or IM), (2) continuous G-CSF alone, (3) continuous IM alone, (4) pulsed IM (final 72 hr of each 96 hr cycle), (5) continuous G-CSF with pulsed IM, (6) pulsed G-CSF (for first 24 hr) then washed out before pulsed IM, (7) pulsed G-CSF alone, (8) pulsed G-CSF with continuous IM, and (9) continuous G-CSF and IM. Pulsed G-CSF with continuous or pulsed IM, and continuous or pulsed IM alone, reduced total viable cell numbers more than continuous G-CSF with or without IM. Notably, at the end of 3 treatment cycles, pulsed G-CSF before pulsed or continuous IM reduced the number of persisting quiescent CD34+ CML cells 5-fold more than continuous IM alone (p&lt;0.03, n = 6). Thus, use of a pulsed G-CSF and IM regimen in vivo may offer a novel therapeutic strategy for the improved elimination of primitive quiescent CML cells that are relatively IM-insensitive. A clinical protocol incorporating this strategy has been given ethical approval, and is being tested in a pilot study in the UK.
Evaluation of Physiologic and Pathologic Alterations of Coagulation and Fibrinolysis Using a New Global Assay.
Authors: Goldenberg Neil A. , Hathaway William E. , Jacobson Linda , Manco-Johnson Marilyn J. 
Published: April 2020

Abstract
BACKGROUND: The Clot Formation and Lysis (CloFAL) assay, modified from prior global assay methods by He et al., 1999, and Smith et al., 2003, involves activation of coagulation and fibrinolysis in platelet-poor plasma via addition of a physiologic reactant solution in a multi-well microassay plate. Continuous spectropohotometric data analysis allows measurement of kinetic absorbance changes of the plasma sample over three hours, which yields a unique clot formation and lysis curve. Using parameters of the curve, coagulation and fibrinolytic indices (CI and FI) are calculated relative to a simultaneously run pooled normal plasma standard.
METHODS: Platelet-poor plasma obtained from pregnant women at term (n=24), neonatal cord blood (n=29), and healthy children (n=22) were analyzed using the CloFAL assay. Healthy adult (n=22) plasma samples, as well as those of individuals with factor deficiencies, were obtained commercially. Fibrinolytic alterations in vitro were also investigated. Intra-assay coefficients of variation (CVs) for normal controls ranged from 3–12% for all assay parameters, with inter-assay CVs of 5–15%.
RESULTS: Representative CloFAL curves for healthy adults and children, pregnant women, and newborn infants are shown in Figure 1. Coagulation potential (measured by median CI) was significantly increased, while fibrinolytic capacity (measured by median FI) was markedly decreased, in pregnant women as compared to healthy adults (CI: 239% vs. 115%, FI: 59% vs. 95%; P&lt;0.001 for each). By contrast, CI was decreased, and FI notably increased, in neonatal cords versus children, although the former comparison did not achieve statistical significance (CI: 58% vs. 69%, P=0.09; FI: 210% vs. 142%, P&lt;0.001). The influence of deficiencies of coagulation factors and fibrinolytic regulators upon CloFAL parameters was also investigated. The greatest impact upon CI occurred with severe deficiency of fibrinogen or factors II, V, VII, VIII, IX, or X. Furthermore, CI was sensitive to deficiencies of factor VIII and fibrinogen in a concentration-dependent manner. In addition, FI was increased by PAI-1 deficiency and by inhibition of thrombin-activatable fibrinolysis inhibitor (TAFI) activation, and was zero in the setting of aminocaproic acid treatment. Further studies revealed that the influence of heparin concentrations of up to 2 U/mL in plasma was completely reversible by heparinase treatment of samples prior to assay.
CONCLUSION: These results indicate that the CLoFAL assay is reproducible and analytically sensitive to known physiologic and pathologic alterations in coagulation and fibrinolysis. The application of this global assay to patients with a variety of disorders of thrombosis and hemostasis is currently ongoing.
Figure Figure
Pediatric Reference Intervals for Ten Coagulation Assays.
Authors: Flanders Michele M. , Crist Ronda A. , Roberts William M. , Rodgers George M. 
Published: April 2020

Abstract
There is a lack of reliable pediatric reference intervals for many clinical laboratory tests. In 2002, the Children’s Health Improvement through Laboratory Diagnostics (CHILDx) organization initiated a project to collect blood and urine samples from healthy children 7 – 17 years of age with the goal of establishing reference intervals for many laboratory tests. The purpose of the present study was to determine pediatric reference intervals for ten coagulation proteins associated with common bleeding and thrombotic disorders. All assays were functional except for vonWillebrand factor antigen. All were measured according to manufacturer specifications and standard methods using the STA-R coagulation analyzer (Diagnostica Stago), with the exception of the ristocetin cofactor assay, which was performed on the BCS (Dade Behring). Samples used to establish adult reference intervals were purchased from George King Bio-Medical, Precision Biologic, and also drawn in-house. At each age of life, 62 individuals (31 girls/31 boys) were drawn for a minimum of 124 individuals for each age group. Reference intervals were established based on a nonparametric method (NCCLS C28-A).
RESULTS: 1. Although pediatric PTT values do not differ from adult values, the mean pediatric PT values are about 1 sec longer, 2. Pediatric FIX levels trend upward until ages 16-17 when adult levels are reached, 3. FVIII, FXI, RCF and vWFAg demonstrate higher reference values in younger ages, 4. The lower limit of pediatric AT levels is significantly higher than adults, 5. The lower limit of pediatric protein C levels is significantly lower than adults, however, this difference is not seen for protein S levels. In conclusion, a number of significant differences between pediatric and adult reference intervals have been found supporting the use of these newer reference intervals.
Age N PT PTT F VIII F IX F XI 7–9 186 13.1–15.4* 27–38 78–199* 71–138* 70–138 10–11 124 12.9–15.5* 27–38 83–226* 72–159* 63–137 12–13 124 13.1–15.2* 27–38 74–205* 73–152* 65–130* 14–15 124 12.9–15.4* 26–35 69–241* 80–162 57–125* 16–17 121 12.6–15.9* 26–35 63–225* 85–175 64–160 Adult 125 12.3–14.4 26–38 56–190 78–184 56–153 Age AT RCF VWF Ag PC PS-Male PS-Female * The t-test of the means, F-test of the SD, or both is statistically different (p&lt; 0.05) from adult reference values. 7–9 96–135* 51–172* 62–176 71–143* 64–141 58–154 10–11 92–134* 61–195* 61–201* 76–146* 68–150 68–140* 12–13 92–128* 47–183* 61–186* 68–162* 65–143 60–150 14–15 95–135* 50–215* 57–204* 69–170* 66–149 53–147* 16–17 94–131* 47–206* 51–211 70–170* 75–157* 51–150* Adult 76–128 44–195 51–185 83–168 66–143 57–131
BEX1, a Marker for Acute Myeloid Leukemia Cell Lines with MLL Rearrangements.
Authors: Quentmeier Hilmar , Dirks Wilhelm G. , Geffers Robert , Uphoff Cord C. , Drexler Hans G. 
Published: April 2020

Abstract
Patients with acute leukemias carrying MLL rearrangements have a poor prognosis. The tumor cells show characteristic gene expression profiles with increased levels of selected HOX genes (1). We have shown that acute lymphoblastic leukemia (ALL) cell lines with and without MLL rearrangements could likewise be recognized by analysis of HOX gene expression (2). In contrast, MLL wild-type (MLLwt) and mutant (MLLmu) acute myeloid leukemia (AML) cell lines could not be distinguished by analysis of HOX genes, because even wild-type cell lines had a high expression background (2). It was our aim to find out whether MLLwt and MLLmu AML cell lines could be discriminated on the basis of gene expression - other than HOX genes. We performed gene expression analysis with pooled RNAs of MLLmu (n=8) and MLLwt (n=8) cell lines applying high density oligonucleotide Genechips from Affymetrix (HG-U133A). Defensin alpha4 (83x), defensin beta1 (32x), cathepsinG (9x) and FLT3 (7x) genes were overexpressed in MLLmu cell lines, stabilin1 (82x) and galectin10 (55x) in MLLwt cell lines. PCR analysis with individual (non-pooled) cDNAs of the 16 cell lines showed that none of the above genes was exclusively expressed by MLLmu or MLLwt cells. Thus, pooling RNAs has a major disadvantage: many PCRs have to be performed to establish faithful expression profiles for individual samples. BEX1 finally proved to be a gene that was exclusively overexpressed in one group of cell lines. It had been an interesting candidate already after oligonucleotide chip analysis, being both overexpressed (18x) in MLLmu cell lines, and - in contrast to the genes listed above - not a marker of myeloid differentiation. BEX1 is reportedly expressed in brain, testis and ovary, but not in peripheral blood leukocytes, lymph node and bone marrow (3). By RT-PCR analysis we showed that 7/8 MLLmu and 0/8 MLLwt cell lines expressed BEX1. Screening a panel of 54 hematopoetic cell lines gave the same result: BEX1 expression was restricted to MLLmu AML cell lines: 8/11 (73%) MLLmu AML cell lines expressed BEX1, but 43 other hematopoetic cell lines (including Hodgkin′s disease, anaplastic large cell lymphoma, ALL and MLLwt AML cell lines) tested negative. BEX1 expression may depend on the type of MLL rearrangement or the histological background of the cells, as MLLmu ALL cell lines (0/5) also tested negative. It has been shown in the mouse system, that BEX family members may be involved in cell signalling processes. Thus it will be interesting to elucidate whether BEX1 also participates in proliferative/antiapoptotic signalling processes in MLLmu AML cell lines.
Seasonal Variation in New Adult Acute Myeloid Leukemia.
Authors: Campbell Lynda J. , Farish Stephen J. , White Joanne S. 
Published: April 2020

Abstract
Investigations into seasonal trends for the onset of leukemia have produced conflicting results. The majority of studies demonstrating seasonal variation have done so for childhood ALL and have suggested a role for an infectious agent. Few investigations have studied adult AML and none have looked at the potential differences between various AML subtypes. An infectious etiology for adult AML will more likely be reflected by cases that are truly de novo and that have not arisen by transformation from a pre-leukemic phase or from prior exposure to a carcinogenic agent. The Victorian Cancer Cytogenetics Service is the central reference laboratory for cytogenetic analysis of all new adult leukemias in the state of Victoria. We have investigated seasonal trends in the diagnosis of 635 cases of new adult AML (≥15 yrs) received for cytogenetic analysis during a five-year period, March 1999 – Feb 2004. Cases of new AML that were secondary in nature were excluded. Cases were subdivided into three recognised prognostic risk groups (favourable, intermediate and adverse) based on cytogenetic findings according to the published criteria of the UK Medical Research Council. The favourable risk group (FR) consisted of t(15;17), inv(16)/t(16;16) and t(8;21) (n = 95). The adverse risk group (AR) included complex karyotypes, abnormalities of 3q, monosomy 7 and loss of chromosome 5 or part of 5q (n = 118). The intermediate risk group (IR) consisted of all other cytogenetic findings including normal results (n = 422). The cytogenetic abnormalities comprising the FR group are rarely associated with secondary AML whereas the converse is true of the AR group. Initial descriptive statistics demonstrated that the greatest trend towards seasonal variation was in the FR group with a peak occurrence in Spring. Spectral analysis was subsequently performed on the data in order to detect if any underlying pattern was genuinely present for the three prognostic groups. The outcome of this analysis supported the possibility of an approximately 12 month cycle for the FR group with the potential peak around the month of October, the middle month of a southern hemisphere Spring. The relatively short time frame of only 5 years limited the interpretation of the analysis. However, these results suggest a possible seasonal trend in the incidence of new adult AML presenting with cytogenetic abnormalities associated with a favourable prognosis. Analysis of data covering a greater time period is proposed to further investigate these preliminary findings.