bluuebunny/crossref_metadata_2025_split huggingface dataset:
Stem Cell Numbers and Quality in a Group of Patients Undergoing Hip Replacement Surgery: Increasing Marrow Fat and Plasma IL-6 Concentrations with Aging.
Authors: McGuire Timothy R. , Brusnahan Susan K. , Jackson John , Berger Ann M. , Garvin Kevin L. , Lane Judy , Murphy Barbara J. , Kessinger Anne , Sharp John Graham 
Published: April 2020

Abstract
Diseases such as anemia which increase with age may be indicative of a decline in stem cell numbers and quality. Anemia in many elderly patients is thought to be mediated by inflammatory cytokines. Interleukin-6 (IL-6) has been reported to increase with age and to have negative effects on myelopoiesis. Another change which may correlate with age and a related decline in stem cell quality is an increase in marrow fat content. The present investigation was designed to evaluate stem cell numbers and quality in a group of patients undergoing hip replacement surgery and correlate stem cell characteristics with the percentage of fat in the marrow and plasma IL-6 concentrations. Marrow stem cells were obtained from the femoral head and trochanter at surgery. Quality was assessed by measuring the proportion of cells in the lower tip of the marrow side population compared to the upper side population by flow cytometry. Fat content in the marrow was measured as a percentage of total volume after sedimentation. A sandwiched-type ELISA was used to measure plasma IL-6 concentrations (R and D Systems). A total of 30 patients were analyzed (36–87 years of age). The number of side-population cells (stem cell numbers) declined with increasing fat content of the marrow. No difference was seen in the ratio between lower and upper side populations (stem cell quality) with age or fat content. Plasma IL-6 concentrations significantly increased with age confirming prior reports (r=0.37; p=0.03). IL-6 concentrations did not correlate with fat content of the marrow. This data suggests that marrow conversion from red (low fat) to yellow (high fat) increases with age along with plasma IL-6 concentrations but these are independent processes. Other inflammatory cytokines are currently under evaluation as potential mediators of the decline in the stem cell compartment with age with particular emphasis on various adipokines since the decline appears to correlate with increased marrow fat content.
A Phase II Study (Biov-121) of Clofarabine Monotherapy First Line in Patients Aged 65 Years or Older with Acute Myeloid Leukemia for Whom Standard Intensive Chemotherapy Is Not Considered Suitable.
Authors: Burnett Alan K. , Baccarani M. , Johnson Peter , Yin John , Saunders Andrew , Russell Nigel , Hills Robert K. 
Published: April 2020

Abstract
Background: The treatment of older patients with AML is unsatisfactory and not improving. A substantial proportion of patients are not offered a standard intensive (“3+7”) chemotherapy approach because they are not considered medically fit (Juliusson et al, Leukemia, 2006 (20):42-7). Such patients are usually treated with best supportive care or low-dose Ara-C with a median survival of approximately 3 months. BIOV-121 is an open-label non-randomised multicentre international study of clofarabine, a next generation purine nucleoside analogue, in elderly patients (≥ 65 yrs) with previously untreated acute myeloid leukaemia (AML) who are unsuitable for standard (“3+7”) treatment.
Methods: 66 patients aged ≥ 65 with untreated AML (WHO classification) were enrolled in study BIOV-121. Clofarabine was administered at a dose of 30mg/m2 for 5 days repeated every 28–42 days (1 course) for a maximum of 3 courses. All patients were considered unsuitable for standard intensive treatment based primarily on age, comorbidity and/or performance status. The primary endpoint of the study was overall response rate defined as the number of patients achieving a CR, CRi or PR according to the international working group guidelines.
Results: 66 patients were recruited with a median age of 71 (range 64–81). 48 patients had de novo and 16 had secondary AML. 72% had an ECOG performance sore of &lt;2; 74% had one or more comorbidities. 31% had an adverse cytogenetic profile; 69% had intermediate cytogenetics (Grimwade D et al Blood 1998). The principal reasons patients were considered unsuitable for standard intensive chemotherapy were age and comorbidity. Nineteen patients achieved a CR; 10 CRi and 3 PR, giving an overall response rate of 48%. 14 patients died (any cause) within 30 days of study start date. The CR/CRi rate in patients over 70 years (49%) was similar to that observed for younger patients (36%). 42% (8/19) of patients with adverse cytogenetics and 31% (5/16) of patients with secondary AML achieved a CR/CRi. The median times to recovery of neutrophils to 1.0 x 109/L and platelets to 100 x 109/L following course 1 were 18 and 27 days respectively. 26% of patients developed neutropenic sepsis. Liver and renal adverse events (NCI CTC grade 3+) were both observed in 23% of patients. The median duration of remission is 6 months; 12 patients have relapsed to date. The median overall survival for all patients is 5 months with a 1 year survival of 26%.
Conclusion: A complete response rate of 44% achieved with clofarabine in older AML patients unsuitable for standard intensive treatment is encouraging and potentially superior to the current standard of care, low dose Ara-C. Of note a good proportion of patients with an adverse cytogenetic profile and/or secondary disease achieved a CR/CRi when treated with clofarabine.
Low Levels of Circulating EPCs Following Bone Marrow Carcinogenic Stimulus Predict the Onset of Hematological Tumors.
Authors: Fragoso Rita , Igreja Catia , Ferreira Manuela , Dias Sergio 
Published: April 2020

Abstract
Endothelial progenitor cells (EPCs) originate in the bone marrow (BM), proliferate, migrate and differentiate into endothelial cells, contributing to the formation of new blood vessels in normalcy and in malignant tumor growth. EPCs have been detected at increased frequency in the circulation of cancer patients and lymphoma-bearing mice, and tumor VEGF production correlates with EPCs mobilization. In order to clarify the contribution and importance of endothelial progenitor cells during tumor development, we established a murine carcinogenesis model that produces hematological neoplasias, namely thymomas and acute leukemia. This model consisted of administering 3 cycles of irradiation (sub-lethally), within one month of interval between them. Every month after the last irradiation, the levels of circulating endothelial progenitor cells (Flk-1+ and Sca+ cells) and hematopoietic progenitor cells (FLT-1+ and Sca+ cells) in peripheral blood were quantified (by flow cytometry). A first assay was done using 30 mice (FVB/N strain), divided into 2 groups: the control group (not irradiated) with 10 mice and the irradiated group with 20 mice. At the end of the assay (~11 months after last irradiation) the incidence of tumors was approximately 63% in the irradiated group (of these, there was an equal incidence of thymomas and acute leukemia). About 37% of the irradiated mice presented signs of disease 2,5 moths after the last irradiation ( called early disease group) while the other 26% presented signs of disease 7,2 months after the last irradiation ( called late disease group). Surprisingly, when comparing the EPC levels between the two groups that developed tumors and the remaining irradiated mice that did not (called no disease group), the two groups of mice that developed tumors had a decreased number of circulating EPC. This decreased was more evident in the early disease group (p&lt;0.01). An inverse relation was observed for VEGF levels in circulation, since the mice with no disease presented lower VEGF levels (5pg/ml) comparied with the two groups that developed tumors (&gt;10pg/ml). At this point, we hypothesized the BM derived EPC levels somehow modulated the onset of hematological disease in irradiated mice. To modulate EPC levels, we transplanted EPCs into irradiated mice with low levels of circulating EPCs. In a preliminary experiment, mice (n=2) that received exogenous EPCs survived, while the mice that did not succumbed to hematological diseases. Taken together, the data obtained suggest a role for EPCs in modulating the BM microenvironment, thus regulating the onset of hematological malignancies. Ongoing studies are addressing possibility. Finally, these results suggest that detection of reduced circulating BM EPCs levels following cyclic whole body irradiation may predict a worse disease outcome.
Cytokines and Chemokines Involved in the Inflammatory Process Have Potent Chemoattractive Properties on MSC.
Authors: Tondreau Tatiana , Meuleman Nathalie , Dejeneffe Marielle , Massy Martine , Delforge Alain , Bron Dominique , Lagneaux Laurence 
Published: April 2020

Abstract
Background : Recent studies have demonstrated the transmigration capacity of mesenchymal stem cells (MSC) over the endothelial cell barrier into various tissues including brain, bone marrow and many others. Nevertheless, little is know about the agents that promote and control their migration.
Methods : The MSC (5.105 cells) migration potential was evaluated using matrigel invasion chamber assay in the presence/absence of SDF-1 (100ng/mL), PDGFbb (100ng/mL), IGF (500ng/mL), IL-6 (100ng/mL) and 10% of conditioned medium in the bottom chamber. The chemotactic properties of these cytokines/chemokines were compared to the spontaneous migration of MSC in DMEM medium without FCS. After 24 hours, cells that migrated through the membrane were counted. The presence of specific receptors was analysed using Raybio Assay, Western Blot and semi-quantitative RT-PCR.
Results : We observed that PDGFbb has the highest chemoattractive property on the MSC and correlates with the strongest expression of PDGF-bb receptor. We also noted that the migratory response to IL-6, IGF and SDF-1 is correlated with the expression of their respective receptors. However, a weak migration was observed in response to SDF-1 due to the low extracellular expression of CXCR4. Nevertheless, a high intracellular expression of CXCR4 was demonstrated with western blots and FACS analysis. In addition, using Raybio assay, we demonstrated the expression of various receptors and metalloproteinases involved in the migration of MSC including ALCAM, L-selectin, ICAM-1, MMP2 and MMP9.
Conclusions : Our observations suggest that chemokines or cytokines involved in the regulation of immunity or the inflammatory process promotes the migration of MSC into bone marrow or damaged tissues.
Homing, Proliferating and Surviving Sites of Human Leukemia Cells In Vivo in Immunodeficient Mice.
Authors: Naoe Tomoki , Ninomiya Manabu , Abe Akihiro , Katsumi Akira , Xu Jinglan , Kiyoi Hitoshi , Kinoshita Tomohiro 
Published: April 2020

Abstract
The cellular components of the hematopoietic stem cell (HSC) niche have been gradually identified. However, the niche for malignant hematopoiesis remains to be elucidated. Here, using human leukemia cells which could be transplanted to immunodeficient mice, we studied the in vivo homing, proliferating and surviving sites by immunohistopathology, compared with the corresponding sites for cord blood CD34+ (CBCD34+) cells. The human leukemia cells initially localized on the surface of osteoblasts in the epiphysial region, and expanded to the inner vascular and diaphysial regions within 4 weeks. The percentage of CD34+ leukemia cells in the BM was transiently increased up to 50% and associated with the entry to S phase of the cell-cycle. In vivo BrdU-labeling showed that the epiphysis was the most active site for leukemia cell proliferation. CBCD34+ cells show the similar pattern of homing and proliferation to leukemia samples. After high-dose administration of Ara-C, residual leukemia cells were localized in the perivascular endothelium as well as in contact with the trabecular endosteum. These findings suggest that xenotransplantation into immunodeficient mice provides a useful model to study the leukemia niche, and that disruption of this niche can potentially facilitate the anti-leukemia effects of various therapies.
Human Myeloid Leukemia Xenotransplant Model Demonstrates Leukemia Blood Vessels from Both Human and Mouse Origin.
Authors: Fu DongTao , Jorgensen Marda L. , Scott Edward W. , Cogle Christopher R. 
Published: April 2020

Abstract
Leukemia stem cell activity has been extensively studied and has been approached mainly in terms of self-renewal within the hematopoietic compartment. However, given the recent findings that the adult hematopoietic stem cell can provide hemangioblast activity - giving rise to both blood and blood vessels - we questioned whether leukemia also exhibits hemangioblast activity. To test this hypothesis we established a xenotransplant model whereby K562 human myeloid leukemia cells suspended in Matrigel are injected into sublethally irradiated NOD/scid mice. Leukemia loaded Matrigel plugs reliably grew in size in all (n=6) immunocompromised animals. After four weeks of leukemia growth the Matrigel plugs were excised and blood vessels evaluated. Out of six animals, two animals demonstrated human endothelial cells within the Matrigel plug, confirmed by LAMP-1 staining. Interestingly, six out of six animals demonstrated mouse endothelial cells within the Matrigel. This in vivo model demonstrates that human myeloid leukemia can provide hemangioblast activity. Moreover, it appears that within this Matrigel xenotransplant model, host blood vessels are also recruited. The significance of these results highlights the importance in recognizing the hemangioblast potential of leukemia stem cells. Ultimately, complete eradication of leukemia may depend on targeting leukemia-derived blood vessels in addition to cytotoxic therapy directed at the hematopoietic compartment.
The Ubiquitin Specific Peptidase 42 Gene (USP42) Is Recurrently Involved as a Fusion Gene with RUNX1 in Acute Myeloid Leukemia with the t(7;21)(p22;q22) Cryptic Translocation.
Authors: Giguere Amelie , Hazourli Sawcene , Meftah Douja , Fetni Raouf , Chagnon Pierre , Hebert Josee 
Published: April 2020

Abstract
The RUNX1 gene encodes the DNA-binding subunit of the heterodimeric transcription factor core binding factor (CBF) and is involved in the regulation of several genes important for hematopoiesis. RUNX1 is frequently rearranged by chromosomal translocations in a spectrum of hematologic malignancies, generating a RUNX1 fusion gene. Some of these RUNX1 fusion genes have been shown to be important in leukemogenesis, such as the ETV6/RUNX1 fusion in B-lineage acute lymphoblastic leukemia and the RUNX1/RUNX1T1 fusion in M2 acute myeloid leukemia (AML). We here describe the first case of adult AML with the t(7;21)(p22;q22) cryptic translocation. Morphologic analysis showed an AML without maturation (AML M1). The karyotype was 46, XY, del(5)(q22q33),?del(21)(q22) in twenty metaphases and analysis by spectral karyotyping (SKY) revealed a t(7;21). The translocation breakpoints at bands 21q22 and 7p22 were studied using bacterial artificial chromosomes (BACs) and showed RUNX1 and USP42 rearrangements. An in-frame fusion between RUNX1 exon 7 and USP42 exon 3 was confirmed by RT-PCR and sequencing. The RUNX1/USP42 fusion includes both the DNA binding RUNT domain of RUNX1 and the catalytic region of USP42. The RUNX1/USP42 fusion gene has recently been reported in one case of pediatric AML-M0 with normal karyotype at diagnosis (Paulsson et al., Leukemia2006;20:224). A complex karyotype including a deletion of the long arm of chromosome 5 was found at relapse in this case. Interestingly, blast cells in our t(7;21) positive leukemia share similar features with the previously published case. By flow cytometry, leukemic cells were positive for HLA-DR, CD34, CD33, CD13 markers and aberrantly expressed CD7 and CD56 without B-lineage markers. We next analyzed samples of CD7 and CD56 positive AMLs with different karyotypes (normal and complex) by FISH using probes to detect the RUNX1/USP42 fusion gene. The USP42 gene encodes a cysteine protease involved in the ubiquitin pathway as a deubiquitinating enzyme. Ubiquitin-specific proteases (USPs) are a large group of enzymes with highly conserved amino acid sequences that form the catalytic region. Some USPs have been shown to be involved in the stabilization of proteins, such as p53, and in the regulation of gene silencing. USP42 is part of a novel class of genes involved in the pathogenesis of leukemia and its role in hematologic cancers remains to be studied. To elucidate the possible implication of USP42 in hematologic malignancies, the expression of USP42 was also investigated by real-time PCR in our case with t(7;21) and in a series of acute leukemias.
Near-Tetraploidy Can Mask the Presence of Chromosome 13q Deletions in Plasma Cells of Patients with Multiple Myeloma.
Authors: Koren-Michowitz Maya , Hardan Izhar , Berghoff Janina , Yshoev Galina , Amariglio Ninette , Rechavi Gideon , Nagler Arnon , Trakhtenbrot Luba 
Published: April 2020

Abstract
Ploidy status and chromosomal aberrations are important prognostic features in multiple myeloma (MM). In particular, non-hyperdiploidy i.e. hypodiploid, pseudodiploid and near-tetraploid (NT), and chromosome 13q aberrations are associated with a worse outcome. We have used combined I-FISH and cell morphology analysis with the Duet™ system for the diagnosis of del 13q and IgH aberrations in bone marrow (BM) samples from MM patients (pts). Using this method we suspected that del 13q can be masked in plasma cell populations due to NT chromosome number.
We studied 125 consecutive BM samples from MM pts for the presence of NT. Mean pts’ age was 56±11 years, sixty percent were men, sixty-seven percent had stage III disease and forty-eight percent had IgG myeloma.
Two commercial probes were used in all FISH experiments: LSI 13 (RB1) and LSI IGH dual-color, break-apart rearrangement probe. For further clarification other probes of Vysis were used.
The measurement of plasma cells DNA content (DI) was done by determining the DAPI intensity using the Volocity Grid Confocal system controlled by the Volocity Acquisition software. To examine the accuracy of measurements DI of 2 MM cell lines: U266 and NCI-H929 were determined. DI in the two cell lines deviated only by 3.2% and 3.6%, respectively, therefore supporting accuracy of ploidy measurements. The criteria for the diagnosis of NT included:
Duplication of hybridization patterns in both 13q and IgH Normal hybridization pattern in 13q and duplication of hybridization patterns in IgH and another probe Normal hybridization pattern in IgH and duplication of hybridization patterns in 13q and another probe If normal hybridization signals were seen in both 13q and IgH probes but plasma cells had large nuclei, at least two other probes with duplication of hybridization patterns were required for NT determination.
NT was diagnosed in 45/125 BM samples (36%), median plasma cells with NT 12.5%, range 2–100% of the plasma cells population.
DI was determined in 10 BM samples suspected for NT. All the samples studied were verified as NT with a mean DI of 1.7 ± 0.14 (range 1.58–1.90).
Chromosome 13q status was normal in only 8 NT samples (18%), i.e. four hybridization signals were detected. In 32/45 (71%) NT samples there were two hybridization signals in a portion of plasma cells population, representing a duplication of del 13q in the presence of NT. Importantly, in 5 samples (11%) all plasma cells had two hybridization signals for del 13q. These cases could actually be overlooked unless NT was specifically searched for and ruled out, therefore potentially loosing important prognostic information.
In conclusion, we found a high prevalence of NT in MM pts using a sensitive novel assay. The determination of NT is important as del 13q can be masked in BM samples harboring NT DNA content.
Non-Coding RNA without ORF Is Overexpressed in Diffuse Large B-Cell Lymphoma with t(1;14)(p33;q32) Translocation.
Authors: Suzuki Ritsuro , Nakamura Shigeo , Seto Masao 
Published: April 2020

Abstract
Background: Several oncogenes, such as cyclin D1, BCL2, BCL6, and c-Myc have been identified to be translocated with immunoglobulin gene In B-cell lymphomas. These genes are overexpressed by the promoter/enhancer activity of immunoglobulin genes, and play important roles in lymphomagenesis. We investigated a translocation partner of immunoglobulin heavy chain gene in a case of diffuse large B-cell lymphoma (DLBCL) with t(1;14)(p33;q32) translocation.
Materials and methods: The patient is a 58-year-old female with stage 3AE gastric DLBCL with t(1;14)(p33;q32) translocation. High molecular weight DNA was extracted from resected specimens. Long distance inversed PCR was performed to identify the breakpoint of translocation partner. Cloned fragments were sequenced and the sequence was searched in the database. RT-PCR and 5′- and 3′-RACE (rapid amplification of cDNA end), and were performed to identify the full length of cDNA which is overexpressed as a result of translocation.
Results: The breakpoint was located in the 1p34 region. An EST located 20kb downstream from the breakpoint was overexpressed. This EST was not expressed in normal lymphocyte and most of the lymphoma samples and cell lines without t(1;14)(p33;q32). No other known genes including ESTs and hypothetical genes within 1Mb from the breakpoint was overexpressed. Therefore, we concluded that a gene including this EST is the target of t(1;14)(p33;q32) translocation. 5′- and 3′-RACE and RT-PCR revealed that a non-coding RNA without open reading frame of 20kb length was overexpressed. Several palindrome-like sequences existed in the non-coding RNA, but the expression of short length (17–25mer) RNA sequence was not detected.
Conclusion: We identified a previously unrecognized type of translocation partner activated by immunoglobulin heavy chain gene in t(1;14)(p33;q32) translocation. Although the intimate mechanism is not clarified, the cloned novel non-coding RNA plays a role in lymphomagenesis.