bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lymphoma and Whole Body CT Scan Mortality Risk
Authors: Shenoy Pareen J. , Gude Tulasi , Sinha Rajni , Flowers Christopher R. 
Published: April 2020

Abstract
Background: Recent concerns regarding the risks of cancer and cancer-related death due to radiation from computed tomography (CT) scans (Brenner, NEJM 2007) and the lack of data demonstrating a survival advantage for surveillance CT scans following lymphoma therapy have raised questions regarding their benefit. We compared the radiation-related lifetime cancer incidence (LCI) and mortality risks (LCMR) associated with CT scans for staging and surveillance of non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL) with the cumulative probability of lymphoma death (CPLD) during monitoring.
Methods: Using 2008 NCCN Guidelines for HL and NHL, we estimated that the average number of scans a patient would need during 5 years of treatment and follow-up would be 10. We utilized published estimates of the cumulative organ-specific radiation doses from full-body CT scans (Brenner, Radiology 2004) and calculated the LCI and LCMR using sex-, age-, and organ-dependent cancer risks per 0.1Gy provided by the Biological Effects of Ionizing Radiations VII report. Site-specific cancer risks were summed to yield the overall LCI and LCMR as described by Brenner (Med Phys 2001). Surveillance, Epidemiology, and End Results (SEER) data were used to identify cases between 2000 and 2005 from 17 SEER Registries and calculate CPLD for specified cohorts.
Results: LCI and LCMR were lower for males and were markedly less than the CPLD at 5 years for most patients, but relevant for younger women with HL given their low risk of HL death (Table 1). The relationship between LCMR and the number of CT scans is shown in Figure 1. Additional implications of surveillance strategies on specific cancer risks will be presented.
Conclusion: While the LCMR from CT scans is small compared to lymphoma-related deaths for most subgroups, these data should be discussed with patients in formulating plans for surveillance following lymphoma therapy.
Table 1 LCI and LCMR due to CT scans compared with CPLD for lymphoma subtypes by age at diagnosis and gender
Lymphoma Subtype (Age at Diagnosis) LCI from CT* LCMR from CT* 5-year Cumulative Probability of Lymphoma Death** Males Females Males Females Males Females * per person exposed to the cumulative radiation dose associated with 10 full-body CT scans during 5 years from diagnosis ** Age group studied were HL (20–29 & 80–84), DLBCL (60–79), FL (60–79), NHL (60–79) NHL (70 yrs) 0.0044 0.0057 0.0032 0.0044 0.31 0.28 FL (70 yrs) 0.22 0.18 DLBCL (70 yrs) 0.39 0.37 HL (20 yrs) 0.0133 0.0242 0.0070 0.0108 0.07 0.07 HL (80 yrs) 0.0022 0.0030 0.0019 0.0026 0.47 0.55
Figure 1 LCMR due to CT scans by age at diagnosis of lymphoma and gender Figure 1. LCMR due to CT scans by age at diagnosis of lymphoma and gender
Survivin Is Required for Proliferation, but Not Polyploidization of Megakaryocytes.
Authors: Wen Jeremy Q , Leung Cindy , Huang Zan , Small Sara , Crispino John 
Published: April 2020

Abstract
Survivin is a member of chromosome passenger complex, which plays an important role in chromosome alignment, separation and cytokinesis. We recently reported that survivin is necessary for the proliferation and survival of hematopoietic stem and progenitor cells. Furthermore, we previously showed that reduced levels of survivin expression facilitates megakaryocyte development, whereas elevated levels of survivin inhibit their maturation and polyploidization. However, the extent to which survivin is necessary for polyploidization and terminal differentiation of committed megakaryocytes remains unclear. To determine whether survivin is required for megakaryocyte and platelet biogenesis, we mated mice with floxed alleles of survivin (sur fl/fl) to mice that express Cre recombinase under the control of the PF4 promoter. Compound mutant animals appeared grossly normal and harbored normal platelet counts. Furthermore, survivin deleted and control littermates displayed similar expression of CD41 and CD42, as well as similar DNA content within the CD41+ population. The only significant difference detected was an increase in annexin V staining of CD41+ cells within the bone marrow of the mice with survivin deletion. Analysis of DNA extracted from these bone marrows showed no evidence of the survivin deletion, indicating that the surviving cells all escaped excision. These in vivo findings are consistent with a requirement for survivin in the survival or proliferation of megakaryocyte progenitors. Next, to induce megakaryocyte development ex vivo, we cultured bone marrow from surv fl/fl mice in vitro in the presence of TPO. Using this approach, we were able to induce survivin deletion in 75% of the cells as evidenced by PCR. Despite the deletion of survivin, polyploidization of the ex vivo generated megakaryocytes was unaffected. Finally, we induced deletion of survivin by retroviral infection of surv fl/fl progenitors with MSCV-Cre and found that megakaryocyte polyploidization was actually increased in the excised population. Taken together, our results suggest that survivin is not required for polyploidization, but is necessary for proliferation of megakaryocyte progenitors.
Role of Lipocalin 24p3 in Apoptosis and Leukemia.
Authors: Devireddy L.R. 
Published: April 2020

Abstract
Programmed cell death or Apoptosis, is a critical aspect of normal physiology as well as the genesis and treatment of cancer. Certain apoptotic pathways are transcriptionally regulated; in these cases, apoptosis is induced by the transcriptional activation of genes encoding proapoptotic proteins. We originally identified lipocalin 24p3 as the gene undergoing maximum transcriptional stimulation following induction of apoptosis by cytokine-deprivation of interleukin 3 (IL-3) dependent cells. 24p3 is a member of the lipocalin family of carrier proteins – a group of small-secreted molecules that bind and transport low-molecular weight ligands. By delivering this cargo via cell-surface receptors they are known to influence many responses. 24p3 is a secreted lipocalin, which we have found induces apoptosis when added to a variety of lymphoid cells. These and other results revealed a model in which IL-3 deprivation activates 24p3 transcription, leading to synthesis and secretion of 24p3, which induces apoptosis through an autocrine/paracrine pathway. We have isolated the 24p3 cell surface receptor (24p3R) and found that 24p3 induces apoptosis through a novel pathway culminating in a decrease in intracellular iron levels (a biological iron chelator). Interestingly, iron chelators inhibit cellular proliferation and induce apoptosis, and are under active investigation as chemotherapeutic agents. The basis by which decreased intracellular iron induces apoptosis is not well understood. We performed expression-profiling experiments to identify differentially regulated genes in 24p3 and as a control in Deferoxamine (DFO), a synthetic iron chelator, treated cells. Our preliminary results suggest that 24p3 activates the expression of a novel gene, ING-2 (inhibitor of growth-2). ING-2 prevents cell growth by inducing cell cycle arrest at the G2/M phase. In contrast, the synthetic iron chelator, DFO activates the expression of NDRG1 (n-Myc downstream-regulated gene 1), which induces cell cycle arrest at G0/G1 phase. These results suggest that 24p3 induces cell death by activating regulators of the cell cycle. Finally, we have also found that the oncogene BCR-ABL counteracts the 24p3 proapoptotic pathway by misregulating expression of 24p3 and 24p3R. To study the contribution of 24p3 apoptotic pathway in the progression of CML, we have performed CML modeling experiments in mice. BCR-ABL transformed 24p3 deficient bone marrow cells failed to induce myeloproliferative disease in recipients upon transplantation. However, wild-type bone marrow cells when transduced with BCR-ABL oncogene readily induced CML-like disease in transplanted mice. Therefore, the secretion of 24p3 by BCR-ABL transformed cells facilitates the progression of CML. We have also demonstrated that 24p3 plays an important role in Gleevec-induced cell death in BCR-ABL transformed cells. These studies have therapeutic implications for Gleevec resistant CML.
Acidic Leucine-Rich Nuclear Phosphoprotein 32 Family Member B (ANP32B), a Novel Caspase-3 Substrate, Exerts Anti-Apoptotic Effects on Acute Myeloid Leukemic Cells.
Authors: Yu Yun , Shen Shao-Ming , Wang Li-Shun , Zhao Qian , Chen Guo-Qiang 
Published: April 2020

Abstract
The acidic leucine-rich nuclear phosphoprotein 32B (ANP32B, also called APRIL) is a member of a conserved superfamily of nuclear proteins that includes ANP32A/pp32, a factor that binds histones and inhibits their acetylation and regulates cell growth and differentiation in a tissue-specific manner. Recently, ANP32B was identified as a novel histone chaperone, and it can interact with the transcription factor KLF5, leading to transcriptional repression of a KLF5-downstream gene through stimulation of promoter region-specific histone incorporation and inhibition of histone acetylation. Additionally, ANP32B and/or ANP32A also serve as adaptor molecules linking the HuR nucleocytoplasmic shuttle protein and the nuclear export receptor CRM1 to regulate the cytoplasmic accumulation of some transcripts such as c-fos and CD83. However, its biological activity is still poorly understood. By the two-dimensional electrophoresis plus MALDI-TOF/TOF tandem mass spectrometry-based analysis of subcellular protein expression profiles, we identified ANP32B protein to become a small fragment in the cytosols of apoptotic leukemic cell line induced by NSC606985, a camptothecin analog. The ongoing immunoblot analyses confirmed that ANP32B protein was cleaved during cellular context-independent and caspase-3 activation-dependent apoptosis induced by etoposide, doxorubin and arsenic trioxide besides NSC606985. Further in vitro proteolytic experiments supported that ANP32B is a direct substrate of caspase-3, and the site-directed mutagenesis analysis identified the unclassical aspartate (AEVD163) of ANP32B sequence to be the caspase-3 targeted sites. Thus, we investigated the potential role of ANP32B in apoptosis induction. Our results showed that the suppression of ANP32B expression by siRNA in acute myeloid leukemic cell line U937 cells strongly enhances NSC606985 and etoposide-induced apoptosis. Based on these findings, this work also analyzed molecular mechanism of anti-apoptotic effect of ANP32B, and some interesting findings were confirmed.
In Childhood ALL, Both Blasts with a CD20−/Low and a CD20High Immunophenotype Have the Ability to Transfer the Leukemia Onto Immune-Deficient NOD/Scid Y−/− Mice.
Authors: Wilson Kerrie , Rehe Klaus , Bomken Simon , Case Marian , Shultz Leonard , Irving Julie , Vormoor Josef 
Published: April 2020

Abstract
There is an ongoing controversy as to whether cancer is always maintained by a rare population of highly specialized cancer stem cells or whether cancer-propagating cells may be more abundant in some cancer types. We have previously shown that in a heterogeneous group of childhood ALL different blast populations, regardless of their expression of the progenitor/stem cell marker CD34 or the lymphoid differentiation antigen CD19, contain leukemia-initiating activity (Cancer Cell 2008, 14(1), 47–58). By profiling B cell transcription factor expression, these different populations appeared to mirror stages of normal B cell development. Here we extend our experiments to another lymphoid differentiation marker, CD20, to provide further evidence that ALL blasts at different stages of maturation possess the ability to re-initiate the leukemia.
Patient Transplant Mice Population Cell dose Engrafted L736 Secondary 9 CD20High 10.000–100.000 6 11 CD20−/Low 10 Tertiary 4 CD20High 10.000 4 4 CD20−/Low 1 L754 Primary 4 CD20High 100.000 2 4 CD20−/Low 3 Secondary 11 CD20High 5.000-100.000 9 11 CD20−/Low 7 A67 Secondary 6 CD20High 9.000-20.000 6 6 CD20−/Low 6
Unsorted bone marrow cells from 3 different ALL patients (L736, L754 and A67) were transplanted into 12 primary mice. Bone marrow was harvested from leukemic mice and flow sorted candidate populations (CD19+CD20−/Low and CD19+CD20High) were re-transplanted into 52 secondary and 8 tertiary mice. As expected from our previous experiments both CD19+CD20−/Low and CD19+CD20High cells were able to re-establish the disease in unconditioned NOD/scid y−/− mice (see table). Leukemic engraftment ranged from 0.5 to 73% as determined by flow cytometry on bone marrow aspirates. Both populations re-established the complete phenotype of the original leukemia including CD20−/Low and CD20High blasts. These results were confirmed by directly sorting primary ALL blasts from L754 without prior passage in the mice. Cell purity after flow sorting was high (81–99%) and low numbers of cells engrafted (5000 for both CD19+CD20−/Low and CD19+CD20High). The three patients reflected different ALL subtypes (L736 intermediate risk ALL: high WBC/MRD low risk, L754:high hyperdiploid/MRD high risk; and A67: high risk ALL/t(9;22)).
In conclusion, these results confirm our previous observation that ALL blasts irrespective of the expression of lymphoid differentiation markers are able to engraft immune-deficient mice. Therefore, leukemia-propagating cells in childhood ALL may be more abundant than previously thought.
A Cell-Autonomous Defect of Bone Marrow Hematopoietic Stem/Progenitor Cells and Impaired Stromal Function in FA-a Patients
Authors: Zhang Xiaoling , Shang Xun , Guo Fukun , Murphy Kim , Kirby Michelle , Kelly Patrick , Reeves Lilith , Smith Franklin O , Williams David A. , Zheng Yi , Pang Qishen 
Published: April 2020

Abstract
Fanconi anemia (FA) is a devastating blood disease associated with bone marrow (BM) failure. Currently the effective treatment for FA is BM transplantation. We and others showed that FA murine hematopoietic stem and progenitor cells (HSC/Ps) have defective hematopoietic reconstitution after BM transplantation. In addition, several clinical gene therapy trials in FA patients have failed to show sustained engraftment of FA HSC/Ps complemented with a functional FA gene. The mechanism underlying this engraftment defect remains unknown. To determine whether the poor engraftment of FA HSC/Ps observed in mouse knockout models and clinical gene therapy trials in FA patients results from an intrinsic defect of the FA HSC/Ps or an impaired microenvironment in the FA bone marrow, we have assessed the self-renewal ability of HSC/Ps and hematopoietic supportive capacity of BM stromal cells from FA-A patients. First, we performed quantitative cobblestone area-forming cell (CAFC) assays using MS-5 stromal layer. CAFCs were enumerated at 2 and 5 weeks of cocultures between BM mononuclear cells from a normal donor and three FA-A patients. Early-appearing CAFCs (week 2) represent transient repopulating cells equivalent to progenitor colony-forming units (CFUs), whereas late-appearing CAFCs (week 5) are representative of long-term repopulating stem cells. The frequency of FA-A CAFCs was 15–20 folds decreased compared with that of the normal donor at both week 2 and week 5. Second, we carried out long-term culture-initiating cell (LTC-IC) assays using BM mononuclear cells and BM-derived stromals from normal donors or FA-A patients. Compared to coculture with normal stromal cells, the recovery of colony forming cells (CFCs) that grew on FA-A stromal layer after 5–6 weeks incubation was significantly decreased for either normal or FA-A HSC/Ps (41.4% ± 3.1 CFC in normal HSC/Ps - normal stroma compared to 14.3% ± 1.6 CFC in normal HSC/Ps – FA-A stroma and 2.4 ± 0.6 CFC in FA-A HSC/Ps- FA-A stroma). Finally, we conducted CFC and cell-cell adhesion assays using BM-derived stromal cells from normal donors and FA-A patients. We observed that FA-A BM stroma failed to support HSC/P cells from either normal donors or FA-A patients. Specifically, severe adhesion defect was found in adhesion of normal and FA-A HSC/Ps with FA-A stromal layer (5.5% ± 0.6 CFC adhesion in normal HSC/Ps - normal stroma compared to 2.4% ± 0.5 CFC adhesion in normal HSC/Ps – FA-A stroma and 1.0 ± 0.7 CFC adhesion in FA-A HSC/Ps- FA-A stroma). These results suggest that both a cell-autonomous defect of FA HSC/Ps and an impaired FA BM microenvironment may contribute to the abnormal hematopoiesis in FA.
Phosphorylation of Runx1 by Cyclin-Dependent Kinases Regulates Its Interaction with HDAC1 and HDAC3.
Authors: Guo Hong , Friedman Alan D. 
Published: April 2020

Abstract
Runx1/AML1 is a key regulator of hematopoiesis and leukemic transformation, as RUNX1(−/−) mice do not develop definitive hematopoietic stem cells, and sever alleukemic oncogenes, e.g. AML1-ETO, CBFβ-SMMHC, or TEL-AML1, inhibit Runx1activities. We have investigated regulation of cell cycle progression by Runx1. Runx1stimulates G1 to S cell cycle progression in hematopoietic cell lines and in transduced myeloid progenitors, and inhibition of Runx1 by CBFβ-SMMHC or AML1-ETO slows G1 progression. Runx1 induces cdk4 and cyclin D3 transcription, and exogenous cdk4, cyclin D2, or c-Myc overcomes inhibition of G1 progression by CBF oncoproteins. In addition to regulating cell cycle progression, Runx1 protein levels are themselves increased as hematopoietic cells progress from G1 to S to G2/M, though mRNA levels remain constant. Runx1 contains three consensus cdk sites, (S/T)PX(R/K), S48, S303, and S424, and using phospho-specific antisera we find that each of these is modified in hematopoietic cells. Mutation of these serines to aspartic acid, mimicking phosphorylation, increases trans-activation of a reporter containing four CBF sites or the TCRβ promoter, whereas mutation to alanine reduces trans-activation. p300 interacts similarly with Runx1(tripleA) and Runx1(tripleD). We have now evaluated interaction of HDACs1–8 with these variants and Runx1 and find that both HDAC1 and HDAC3 have reduced affinity for RUNX1(tripleD), as assessed by co-immunoprecipitation from transiently transfected 293T cells. Evaluation of single serine residue mutants (S48D, S303D, and S424D) demonstrates reduced affinity of HDAC1 or HDAC3 specifically for the Runx1(S424D) mutant, consistent with previous mapping of the Runx1:HDAC1 and Runx1:HDAC3 interactions to this region of Runx1. Thus, cdk phosphorylation of Runx1 S424 reduces affinity for HDAC1 and HDAC3, increasing Runx1 trans-activation potency. Regulation of Runx1 activity by cdks may control key developmental processes, including expansion of definitive HSC during development and regulation of the balance between adult HSC quiescence and proliferation.
Cannabinoid Receptors CB1 and CB2 Regulate Mobilization of Hematopoietic Stem and Progenitor Cells.
Authors: Avraham Hava , Zagozdzon Radoslaw , Fu Yigong , Groopman Jerome E. , Jiang Shuxian 
Published: April 2020

Abstract
Endocannabinoids are lipid mediators that modulate central and peripheral neural functions as well as immune responses and bind to specific G-protein-coupled receptors:CB1 and CB2. Here, we investigated the role of CB1/CB2 and cognate cannabinoid ligands in hematopoietic stem and progenitor cell (HSPC) mobilization. CB1 and CB2receptor expression was observed in human and murine HSPCs. Cannabinoid ligands induced the chemotaxis of the human CD34+ cells and caused mobilization of murine HSPC in vivo. Inhibition of degradation of the endocannabinoid anandamide by URB597induced mobilization of HSPC and significantly augmented mobilization of these cells when URB597 was administered with G-CSF-, AMD3100- and with the combination of G-CSF+AMD3100. Moreover, the cannabinoid- or G-CSF-induced mobilization of HSPC was significantly impaired by cannabinoid receptor inhibitors and in CB1- andCB2-knockout mice. Administration of exogenous cannabinoid agonists in mice induced mobilization of progenitors as well as stem cells in vivo with long-term repopulating ability. These results demonstrate a novel pathway by which the cannabinoid system regulates HSPC cell trafficking, and may be therapeutically applied in clinical conditions, such as bone marrow transplantation.
Deletion of Fak in Hematopoietic Stem Cells Leads to Enhanced Engraftment.
Authors: Lu Jiayun , Nombela-Arrieta Cesar , Park Shin-Young , Le Yi , Chai Li , Silberstein Leslie E. 
Published: April 2020

Abstract
Hematopoietic stem and progenitor cells (HSPC) can be induced to leave the bone marrow (BM) and such mobilized hematopoietic stem cell (HSC) enriched cell populations when infused intravenously rapidly home back to the marrow and transmigrate into the extravascular compartment where they lodge in specialized niches. Niche induced signals coupled to intrinsic factors, promote HSC maintenance and regulate HSC localization, migration and/or differentiation. A better understanding of molecular pathways governing these HSC fate decisions could identify new targets for ex vivo HSC expansion and improvement of transplantation. Focal adhesion kinase (Fak) is a non-receptor protein tyrosine kinase, whose function has been well studied in fibroblasts, where it plays an important role in cell adhesion, survival and motility. Fak is also differentially expressed in HSPC, with highest expression in long-term HSCs (LT-HSCs, Lin-Sca-1+c-Kit +CD34-). Its functional role in hematopoiesis has not been well studied due to early embryonic lethality (E.8) of Fak−/− mice. We have generated conditional Fak deleted mice (Fakfl/flMx1-Cre+) to define how Fak signaling contributes to different components of HSC transplantation. We observed that the total cellularity in BM was comparable between Fak knockout (Fak−/−Mx1-Cre+) and control (Fakfl/fl) mice. The frequencies of both Lin-Sca-1+c-Kit + cells (LSKs) and short-term HSCs (ST-HSCs, Lin-Sca-1+c-Kit +CD34+) increased 2-fold in BM of Fak knockout mice compared to WT controls (n=5; p&lt;0.05), while LT-HSCs appeared unaffected. Moreover, the number of LSKs in the spleens of Fak knockout mice increased by 3-fold relative to controls (n≥7, P&lt;0.01). In vitro colony-forming assay also showed that the functionally defined progenitor cell numbers significantly increased in Fak knockout mice spleen. However, Fak deletion did not affect HPC populations including common myeloid progenitors (CMP), granulocyte macrophage progenitors (GMP), megakaryocyte erythrocyte progenitors (MEP) and common lymphoid progenitors (CLP). Importantly, in the competitive repopulation assay Fak−/− HSCs exhibited 2-fold enhanced engraftment for 20 weeks post-transplant, while lineage reconstitution in peripheral blood (PB) was similar between wild-type and knockout donor-derived cells suggesting Fak deletion did not affect PB mature B, T and myeloid cell survival under non-stress conditions. These findings indicate that FAK may play an important role in HSC homeostasis and that targeting the FAK pathway ex vivo may lead to innovative approaches in human HSPC transplantation.