bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genome-Wide Array-Based CGH for Mantle Cell Lymphoma: Precise Mapping of Genomic Aberrations and Identification of Novel Candidate Genes.
Authors: Tagawa Hiroyuki , Karnan Siversundram , Suzuki Ritsuro , Ota Akinobu , Tsuzuki Shinobu , Morishima Yasuo , Nakamura Shigeo , Seto Masao 
Published: April 2020

Abstract
Mantle cell lymphoma (MCL) is characterized by 11q13 chromosomal translocation and CCND1 overexpression, but the additional genomic changes are also important for lymphomagenesis. To identify the genomic aberrations of MCL in higher resolution, we analyzed 29 patient samples and seven cell lines (SP-53, Z-138C, Granta 519, REC-1, NCEB-1, Jeko-1 and JVM2) using array-based comparative genomic hybridization (array CGH) that consisted of 2,304 BAC/PAC artificial chromosome clones, covering the whole genome at a 1.3 mega base resolution. Tumor specimens obtained from 29 MCL patients, comprising 16 males and 13 females all from the Aichi Cancer Center, were included in the study. The median age of the patient was 67 years (49–92 years old). 67% of cases were leukemic, 93% were in an advanced stage III-IV, 30% had elevated LDH, 18% had a poor performance status and 78% had more than one extranodal site of involvement. Genomic profiles of MCL were significantly different from those of other B-cell lymphomas such as diffuse large B-cell lymphoma (n=66) (Cancer Res 2004: 64, in press) and follicular cell lymphoma (n=13). Frequent imbalances detected by array CGH in patients were gains of chromosomes 3q26, 7p21, 6p21, 8q13-8q24, 10p12 and 17q23 (frequencies: 21%–48%), and losses of chromosomes 1p36, 1p21–p32, 1q42, 2p11, 2q13, 5q21, 6q16–q24, 8p12–p23, 9p21–p24, 10p14, 9q22, 11q22, 13q21, 13q34, 17p11.2–p13, 19p13 and 22q12 (frequencies: 17%–83%). Among these gains and losses, patents with a gain of 8q13-q24, and losses of 1p22–p32, 6q16–q24, 8p12–p23 and 17p11.2–p13 showed prognostically inferior survival rate to those without such a gain or losses (P&lt;0.001). The incidence of genomic aberrations identified by array CGH was generally higher than that of chromosomal CGH studies. For example, our data show more frequent losses of 1p21–p22 (52%) and 9p21 (41%, INK4/ARF locus) as well as of 11q22 (55%, ATM locus), than the corresponding losses detected by chromosomal CGH (e.g., loss of 1p21–p22: 24%; 9p21: 28%; 11q22: 24%). We found recurrent regions of high-level genomic gains (amplifications) at 10p12 (BMI-1 locus), 13q31–q32 and 18q21 (BCL2 locus), and homozygous losses (deletions) such as 2p11 (Igk locus), 2q13 and 9p21.3–p24.1 (INK4a/ARF locus) in either patient or cell line. Furthermore, we investigated genomic gain of 13q31–q32 and homozygous loss of 2q13 and identified the C13orf25 as a candidate gene at 13q31 gain (Cancer Res 2004: 64, p3087) and the BIM gene at 2q13 loss. Precise mapping of genomic aberrations by array CGH allowed identification of novel candidate genes that might be associated with the lymphomagenesis of MCL.
Balanced Rearrangements of Chromosome 6 in Acute Leukaemia: Clustered Breakpoints in 6q22-q23 and Possible Involvement of c-MYB/AHI1 in a New Recurrent Translocation, t(6;7)(q23;q31).
Authors: Sinclair Paul B. , Harrison Christine J. , Jarosova Marie , Foroni Letizia 
Published: April 2020

Abstract
While deletions of the long arm of chromosome 6 (6q) are common in patients with ALL, translocations are rare, most are considered sporadic and none have been cloned. Among myeloid malignancies, the recurrent translocations: t(6;11)(q27;q23), t(6;11)(q21;q23) and t(6;8)(q27;p11) give rise to known fusion oncogenes. Other uncharacterised balanced or unbalanced 6q abnormalities have occasionally been reported. Using fluorescence in-situ hybridisation (FISH) with HGMP mapped PAC and BAC clones, we investigated chromosomal rearrangements of 6q in acute leukemia. Previously we reported 24 cases with deletions of 6q (Sinclair et al 2004, Can Res 64; 4089), here we describe the analysis of 11 patients with novel balanced rearrangements.
Six of seven breakpoints in ALL and two in a single case of AML were localised to a 10.5 Mb ‘hotspot’ within 6q22–q23. Of these, five were analysed down to the level of a single clone. In two cases of childhood T ALL, both carrying a t(6;7)(q23;q31~36), split FISH signals were produced by adjacent PACs, RP1–32B1 and RP3–388E23, mapping the breakpoints to within a ~150Kb region. A search of published karyotypes identified five similar rearrangements, four also in pediatric T ALL, all present as a sole abnormality or represented in the major clone. Of genes in the region, two (c-MYB and AHI1) are tightly regulated during normal hemopoietic development and over-expression of both has been reported to occur in hemopoietic malignancies. Moreover, clusters of retroviral insertion sites occur within both genes and immediately proximal to c-MYB in murine and feline leukemias and lymphomas. Thus we have defined a new primary recurrent translocation in T ALL that is likely to target either c-MYB and/or AHI1.Three other non recurrent rearrangements of 6q22–q23, mapped in detail, interrupted regions without known genes.. Therefore, these abnormalities were unlikely to have promoted leukemia through classical oncogene activation, but may have influenced expression of one or more common target genes through a long-range position effect. Alternatively these clustered rearrangements may mark the position of a new fragile site on 6q. Additional 6q breakpoints in three cases of AML and one of ALL mapped to 6q15, 6q21, 6q25 and 6q26–q27, and were coincident with the positions of a known oncogene partner AF6q21, the haemopoietic transcription factor BACH2 and two cloned fragile sites FRA6E and FRA6F. Putative partner genes of four translocations were investigated by FISH and the involvement of MLL was demonstrated in one case with t(6;11)(q15;q23).
Acute Myeloid Leukemia with Deletion 9q Is Associated with CEBPA Loss-of-Function Mutations.
Authors: Frohling Stefan , Schlenk Richard F. , Krauter Jurgen , Ganser Arnold , Thiede Christian , Ehninger Gerhard , Haase Detlef , Harder Lana , Scholl Claudia , Caligiuri Michael A. , Bloomfield Clara D. , Dohner Hartmut , Dohner Konstanze 
Published: April 2020

Abstract
The transcription factor CCAAT/enhancer binding protein alpha (C/EBPalpha) plays an important role in the development of mature neutrophils. Two common types of mutations in the CEBPA gene encoding C/EBPalpha have been identified in approximately 10% of adults with acute myeloid leukemia (AML): N-terminal, dominant-negative frameshift mutations that result in loss of C/EBPalpha function and C-terminal in-frame mutations that result in C/EBPalpha proteins with decreased DNA-binding potential. Previous studies concluded that mutant CEBPA predicts favorable outcome in younger AML patients with intermediate-risk karyotypes or normal cytogenetics. To assess the prevalence of CEBPA mutations in specific cytogenetic subgroups, mutational analysis of the CEBPA gene was performed in 125 AML patients. No CEBPA mutations were detected in 77 patients with t(8;21), inv(16)/t(16;16), t(15;17), or balanced translocations with breakpoints in band 11q23. In 58 patients with various non-complex karyotypic abnormalities, CEBPA mutations were present in 8 (14%). Surprisingly, 5 of the 8 patients with del(9q) as the sole aberration or in combination with a single additional abnormality other than t(8;21) had CEBPA mutations associated with loss of C/EBPalpha function. Consequently, 41 additional del(9q) cases were analyzed; 9 had CEBPA loss-of-function mutations. The overall prevalence of CEBPA loss-of-function mutations in cases with del(9q) within a non-complex karyotype was 41% (14 of 34 patients), whereas none of the patients who had a del(9q) within a complex karyotype (n = 7), in combination with a t(8;21) (n = 10), or together with a t(15;17) (n = 1) demonstrated mutant CEBPA. Analysis of associated mutations indicated that alterations of the FLT3, MLL, and NRAS genes are not common cooperating events in the pathogenesis of del(9q) AML with inactivating CEBPA mutations. This is the first study to show that AML with del(9q) is strongly associated with CEBPA loss-of-function mutations. The coincidence of del(9q) with inactivating CEBPA mutations and the fact that del(9q) is a common secondary cytogenetic abnormality in t(8;21)-positive AML, that is characterized by specific down-regulation of CEBPA, raise the possibility that loss of a critical segment of 9q, most likely in 9q22, and disruption of C/EBPalpha function cooperate in the pathogenesis of these leukemias. Further refinement of the commonly deleted segment of 9q using high-resolution techniques is underway to identify the critical gene(s) involved and their role in normal hematopoiesis and leukemogenesis. A collaborative intergroup study has been initiated to define whether the relatively good prognosis associated with del(9q) is related to the presence of a CEBPA mutation.
Expansion of Bone Marrow (BM) Progenitors and Mobilization of Multilineage Progenitor Cells Associated with Once Per Cycle Administration of Long-Acting Growth Factors Neulasta and Aranesp with Chemotherapy (CT): Biology and Nature of Response.
Authors: Vadhan-Raj Saroj , Bueso-Ramos Carlos E. , Hangoc G. , Christopherson K. , Collard M. , Broxmeyer H.E. 
Published: April 2020

Abstract
Hematopoietic growth factors (HGF) G-CSF and GM-CSF have been utilized widely to facilitate mobilization of progenitor cells that can be used to support high dose CT. Recently long-acting HGF neulasta (pegfilgrastim) and aranesp (darbepoetin alfa) were developed to reduce the frequency of administration. While these agents are effective in reducing CT-induced neutropenia and anemia similar to their parent compounds, very little is known about their efficiency in mobilizing progenitor cells. The purpose of this study was to evaluate biologic effects of these agents, used in combination with CT, on progenitor cells. Chemo-naïve sarcoma patients receiving adriamycin and ifosfamide (AI) were treated once per cycle with aranesp (500 mcg) SC prior to initiating CT (day 0) and neulasta (6 mg) SC after completion of CT (day 4). BM and peripheral blood (PB) samples were studied at the baseline and around day 14 (at the time of WBC recovery) for progenitors and mediators of response. The treatment was associated with a significant increase in PB CD 34 + cells (median increase 36-fold, p=0.005) and marked mobilization (p=0.003) of CFU-GM (24-fold), BFU-E (22-fold), and CFU-GEMM (62-fold) (n=14). To better understand the biology and nature of response, we examined BM before and at the time of mobilization (n=12). There was an expansion of multi-lineage BM progenitors (p=0.06) and CD 34+ cells (P=0.001). BM exam at the time of recovery showed increased cellularity (2-fold) with increased granulopoietic elements. An increased expression of MMP-9 but unchanged expression of TIMP-1 was observed by Immunohistochemistry (IHC). c-kit ligand level by Elisa was decreased in the BM supernatant. In addition, phospho c-kit (phospho site 568) was increased in the myeloid and erythroid precursors by IHC but phospho site 823 was unaltered, indicating the specificity of activation of the downstream pathway in response to c-kit ligand-receptor activation, possibly leading to expansion of progenitor cells. Interestingly, expression of CXCR4 at the protein level (flow cytometry and western blot) and RNA level (RT-PCR) was decreased (p&lt;0.05) in the BM at the time of mobilization (day 14) as compared to the baseline. These findings indicate that long-acting HGFs, administered once per cycle of CT, are a potent stimulus for mobilization of myeloid, erythroid, and multipotential progenitors. Our findings also suggest that increased myelopiesis in the regenerating BM may be associated with increased protease activity such as MMP-9 that may result in the cleavage of c-kit leading to activation of c-kit receptors and expansion of progenitors, and the cleavage of CXCR-4 leading to release of progenitors from the BM anchorage and mobilization into PB.
The Novel Role of the Third Complement Component (C3) in Megakaryopoiesis: Implications for Pathogenesis of Reactive Thrombocytosis.
Authors: Wysoczynski Marcin , Reca Ryan , Kucia Magda , Ratajczak Janina , Ratajczak Mariusz Z. 
Published: April 2020

Abstract
An elevated platelet count is frequently observed in several clinical conditions (e.g., chronic inflammation, acute hemorrhage) that may lead to reactive thrombocytosis (RT). Recently we found that i) complement is activated/cleaved in the bone marrow with release of C3a and des-Arg C3a fragments that sensitize responses of hematopoietic cells to SDF-1 (Blood2003;101:3784), an alpha-chemokine that plays an important role in Meg maturation/proplatelet formation, and ii) C3 deficient mice display delayed recovery of platelet counts after sublethal irradiation (Leukemia 2004, in press). Thus, since levels of C3 cleavage products (C3a and des-Arg C3a) and SDF-1 are elevated in bone marrow during inflammation and acute hemorrhage, we hypothesized that they may play a role in the pathogenesis of RT by enhancing Meg maturation/platelet production. In support of this notion we found that i) the receptor for C3a (C3aR) is highly expressed and functional on CFU-Meg progenitors and maturating Megs, ii) C3a induces a calcium flux and actin polymerization in Megs and enhances chemotactic response of human CFU-Meg and maturing Megs to an SDF-1 gradient, and iii) in the presence of C3a + SDF-1, Megs secrete more VEGF and MMP-9, which play a role in proplatelet formation. These effects were not inhibited by the small molecular antagonist of C3aR, SB290157, suggesting the involvement of the C3a derivative, des-Arg-C3a, that binds another C3a receptor called C5L2. At the molecular level we observed that C3a and des-ArgC3 promote the incorporation of CXCR4 into membrane lipid rafts in hematopoietic cells, allowing for its better interaction with small GTP-ases (Rac/Rho). We conclude that C3a and des-Arg C3a modulate the responsiveness of Megs to SDF-1 and postulate that the novel crosstalk between C3aR, C5L2 and CXCR4-G-protein coupled receptors we identified here plays an important and previously unrecognized role in the final maturation of Megs and pro-platelet formation during stress. Thus our results shed more light on the pathogenesis of RT and suggest that inhibitors of both CXCR4 and C3 could find a potential novel clinical application as drugs controlling elevated platelet counts.
Randomized, Double-Blind, Placebo-Controlled Trial of Epoetin Alfa (Procrit) in Patients with Rectal and Gastric Cancer Undergoing Chemo-Radiotherapy (CT/RT) Followed by Surgery: Early Termination of the Trial Due to Increased Incidence of Thrombo-Embolic Events (TEE).
Authors: Vadhan-Raj Saroj , Skibber John M. , Crane Christopher , Bueso-Ramos Carlos E. , Rodriguez-Bigas Miguel A. , Feig Barry W. , Lin Edward H. , Ajani Jaffer A. , Collard Mindy , Johnson Marcella M. , Hamilton Stanley R. , JanJan Nora 
Published: April 2020

Abstract
Patients with resectable gastric and rectal cancer undergoing CT/RT followed by surgery are at increased risk for anemia, fatigue, and need for red cell transfusions. Anemia and tumor hypoxia may contribute to adverse treatment outcome. A multi-center, placebo-controlled trial of 184 patients was designed to determine if Procrit treatment can maintain Hb (≥13 gm/dL), reduce the need for PRBC Tx and improve treatment outcome. Procrit was administered weekly (40,000 units starting dose) for 16 wks during CT/RT (5 FU or Xeloda + 45 Gy over 5 weeks) followed by surgery. After 60 pts were randomized, the trial was terminated due to increased incidence of TEE. 59 of these pts (53 rectal and 6 gastric) received at least one dose of treatment; 31 in the placebo and 28 in the Procrit group. Baseline median Hb for the study group was 13 gm/dL. Seven (11.9%) pts experienced venous TEE; 1/31 (3.2%) pts treated with placebo compared with 6/28 (21.4%) pts treated with Procrit (p= 0.045). In exploratory analyses including the multivariate modeling, it was observed that the Procrit treatment was a predictor of TEE (p = 0.060), however this was not observed for Hb (p = 0.998). Using a mixed-effects model, Hb was significantly higher in pts treated with Procrit than pts treated with placebo (p = 0.0004) during CT/RT. In addition, Hb was significantly different across weeks (p &lt; 0.0001). During the study period, there was also a significant treatment by time interaction (p = 0.0061) with Hb maintained/increased in Procrit pts while it steadily decreased in the placebo pts. Four (14.3%) pts treated with Procrit compared with 10 (32.3%) pts treated with placebo required red cell transfusions (p = 0.133). Platelets (PLTs) decreased significantly from baseline during CT/RT (at weeks 4) for the placebo pts and for the pts treated with Procrit who did not experience TEE (p &lt; 0.0001), but there was a trend for an increase in PLT in pts who experienced TEE. The tumor response for rectal ca at MDACC site was similar between both treatment groups with 14/22 (63.6%) in each treatment group (p = 0.777). These findings indicate that treatment with Procrit may prevent anemia during CT/RT/surgery, however there is increased risk for TEE in this setting for prevention of anemia. Correlative analysis is ongoing on biomarkers and molecular markers on biopsy specimens to examine the markers predictive of pathological complete response, TEE, and the treatment outcome.
An Oral, Non-Petide, Small Molecule Thrombopoietin Receptor Agonist Increases Platelet Counts in Healthy Subjects.
Authors: Jenkins Julian , Nicholl Richard , Williams Daphne , Baidoo Charlotte , Phillips Jennifer , Deng Yanli , Kitchen Valerie , Erickson-Miller Connie 
Published: April 2020

Abstract
SB497115, is an orally bioavailable, small molecule thrombopoietin receptor agonist that induces differentiation and proliferation of megakaryocytes. In a randomized, single blind, placebo-controlled, parallel group, phase I study conducted in the UK in 72 healthy male subjects, SB497115 was administered as oral capsules once daily for 1 day and, after a 1 week washout, for 10 days at doses of 5 to 75 mg. Subjects were randomized into six groups of 12 subjects to receive either active or placebo medication in a ratio of 9:3. The study was conducted according to Good Clinical Practice and all subjects gave their written informed consent to participate in the study.
SB497115 was well tolerated in the study, there were no serious adverse events, no significant changes in laboratory or cardiovascular safety parameters and there was no observed relationship between the incidence or severity of adverse events and dose. Most adverse events were mild in intensity and self-limiting. SB497115 was shown to be orally bioavailable in humans with a linear pharmacokinetic profile suitable for a once daily oral medication. When administered at oral doses of 30mg and above for 10 days a dose dependent increase in the platelet count was observed, maximum platelet count was observed on days 14 to 16 following initiation of dosing. The dose dependent increase in platelet count is shown in the table below. On the basis of these safety, pharmacokinetic and pharmacodynamic data the oral thrombopoietin receptor agonist, SB497115, will be studied in phase II trials involving thrombocytopenic patients.
Preliminary Data: Mean Platelet Count (platelets/uL)
Oral Dose Baseline (Day 1) Maximum (Day 14 or 16) Change from Baseline Placebo 234000 255000 21000 5 mg 217000 249000 32000 10 mg 251000 291000 40000 20 mg 236000 279000 43000 30 mg 249000 323000 74000 50 mg 254000 356000 102000 75 mg 239000 357000 118000
Induction of Polyploidization in Leukemic Cell Lines and Primary Bone Marrow by Src Kinase Inhibitor SU6656.
Authors: Lannutti Brian J. , Minear Jennifer N. , Blake Noel , Drachman Jonathan G. 
Published: April 2020

Abstract
Megakaryocytes (MKs) undergo successive rounds of endomitosis during differentiation, resulting in polyploidy (typically, 16-64N). Previous studies have demonstrated that this occurs through an interruption of normal cell cycle progression during anaphase. However, the molecular mechanism(s) controlling this unique process is undefined. Our studies of Src family kinases demonstrate that Lyn and Fyn kinases are activated by thrombopoietin (TPO) and have an inhibitory effect on cellular proliferation. In fact, adding PP1 to murine bone marrow cells in culture resulted in a higher percentage of polyploid cells. In the present report, we examined the effect of SU6656 on TPO-induced growth and differentiation. SU6656 is reported to be more specific than previous inhibitors for the Src family of tyrosine kinases. Remarkably, when SU6656 (2.5 mM) was added to a megakaryocytic cell line, UT-7/TPO, the cells underwent dramatic increase in cell size and polyploidization. By 24 h, 8N cells were present. After 48 h a 16N population was identified by FACS, and continued growth in SU6656 resulted in higher ploidy states (32N and 64N). This was accompanied by cessation of cellular proliferation (i.e. cell number remained constant), increase in CD41 and CD61 expression, and was notable for the absence of apoptosis. Similarly, polyploidization was observed when SU6656 was added to expanded human bone marrow progenitors with partial MK differentiation. The ability to induce differentiation was also seen using bone marrow from two patients with myelodysplastic syndrome and thrombocytopenia, suggesting that SU6656 might be useful as a differentiation-inducing agent for MKs. Although SU6656 is clearly a potent inhibitor of the Src family kinases, we have undertaken studies to determine if an additional target can be identified. We found no affect on Jak2, STAT3, and STAT5 tyrosine phosphorylation. However, the activity of Aurora kinase B was inhibited in vitro by as little as 50 nM SU6656. We propose that SU6656 may be an important tool for understanding the molecular basis of MK endomitosis and may also have therapeutic potential for individuals with MDS, thrombocytopenia, or other disorders resulting from incomplete megakaryocyte maturation.