bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role of the Urokinase Receptor (uPAR) in the Cross-Talk of Hematopoietic Stem Cells with the Bone Marrow Microenvironment
Authors: Montuori Nunzia , Ricci Patrizia , Serio Bianca , Visconte Valeria , La Penna Claudio , Pesapane Ada , Risitano Antonio M. , Rotoli Bruno , Rossi Guido , Ragno Pia , Selleri Carmine 
Published: April 2020

Abstract
The urokinase-type plasminogen activator receptor (uPAR) is a cell-surface receptor involved in cell adhesion and migration. uPAR binds urokinase (uPA) and vitronectin (VN) and interacts with integrins and chemotaxis receptors. Soluble forms of uPAR (suPAR) have been detected in human plasma and urine. A cleaved form of suPAR (c-suPAR), lacking the N-terminal domain and exposing the sequence SRSRY (aa 88–92), stimulates cell migration by activating fMLP receptors. We recently demonstrated uPAR involvement in G-CSF-induced CD34+ hematopoietic stem cell (HSC) mobilization. We also demonstrated that c-suPAR could induce mobilization of hematopoietic stem/progenitor cells in mice. Since HSC mobilization and homing to bone marrow (BM) are mirror image processes which utilize the same mediators and similar signaling pathways, we investigated whether uPAR and its ligands could play a role in regulating CD34+ HSC interactions with the BM stroma, thus also contributing to HSC homing and engraftment to the BM. We found expression of uPA and VN in cultures of human BM stroma cells. Interestingly, stroma cells also produced suPAR and high amounts of c-suPAR, exposing the chemotactic SRSRY sequence. The role of the different soluble forms of uPAR produced by stroma cells in regulating HSC interactions with the BM microenvironment was analyzed by long term cultures (LTC) of BM and G-CSF mobilized CD34+ HSCs, in the presence of suPAR or the uPAR-derived uPAR84–95 peptide, corresponding to the active site of c-suPAR. Both suPAR and the uPAR84–95 peptide increased the number of adherent and released clonogenic progenitors from LTC of BM and G-CSF mobilized HSCs. To elucidate the mechanism of suPAR and c-suPAR effects on CD34+ HSC interactions with the stromal microenvironment, in vitro adhesion and proliferation assays were performed on CD34+ KG1 cells. suPAR treatment determined a significant increase in CD34+ KG1 cell adhesion whereas c-suPAR increased cell proliferation. Taken together, our results indicate that BM stroma produces soluble forms of uPAR that regulate CD34+ HSC interactions with BM microenvironment, their local proliferation and trafficking from and to BM.
Monitoring of Donor Chimerism in CD34+ Peripheral Blood Progenitors Allows to Detect Minimal Residual Disease after Allogeneic Stem Cell Transplantation -Results of a Randomized Trial
Authors: Bornhaeuser Martin , Oelschlaegel Uta , Bug Gesine , Platzbecker Uwe , Lutterbeck Karin , Kiehl Michael G , Schetelig Johannes , Kiani Alexander , Illmer Thomas , Schaich Markus , Theuser Catrin , Mohr Brigitte , Brendel Cornelia , Fauser Axel A , Klein Stefan , Martin Hans , Ehninger Gerhard , Thiede Christian 
Published: April 2020

Abstract
Relapse of hematological malignancy remains a major complication after allogeneic stem cell transplantation. This is especially true for patients receiving minimal or reduced-intensity conditioning therapy. Analysis of donor chimerism (DC) is an important diagnostic tool to assess the risk of relapse after allogeneic stem cell transplantation, especially in patients lacking a specific marker suitable for monitoring of minimal residual disease. The sensitivity of a standard PCR assay amplifying short-tandem-repeat sequences can be improved significantly by investigating sorted CD34+ peripheral blood cells. We prospectively compared the serial analysis of DC in selected CD34+ cells and unmanipulated whole blood (WB) within a randomised study in 131 patients with CD34+ hematological malignancies (AML, ALL and MDS) surviving more than 100 days after transplantation. The primary end-point was the association between decreasing CD34+ DC and haematological relapse. Whenever a decreasing CD34+ or WB DC was confirmed and no signs of active GvHD were present, a rapid taper of CsA or tracolimus (50% every 5–7 days) was suggested. If no GvHD occurred within 14 days after the stop of CsA or tacolimus, patients were scheduled to receive donor lymphocyte infusions (DLI) in incremental doses. The cumulative incidence of relapse was significantly increased in patients with decreasing or incomplete CD34+ DC (62% vs. 38%, p=0.01). This was associated with a lower probability of overall survival (20% vs. 39%, p=0.03). The interval between the decrease in CD34+ DC and hematological relapse was 35 days (range 0–567) in the study group compared to only 8 days (range 0–63) in the control group monitored by WB DC analysis (p=0.05). The median time between a decrease in CD34+ DC and WB DC was 14 days (range, 0 to 445). Patients receiving preemptive therapy triggered by decreasing CD34+ DC had a significantly higher probability of disease-free survival compared to cases monitored and treated according to WB DC (19% vs. 0%, p=0.009). Multivariate analysis revealed age, disease-risk and decreasing CD34+ DC as independent risk-factors for overall survival in the study group. In summary, we could demonstrate that the quantification of DC in CD34+ selected cells is a sensitive method to predict relapse and survival after allogeneic SCT. Although this technology opens a window for preemptive therapy, new treatment approaches have to be employed to improve the overall outcome of patients with recurrence of residual disease after allogeneic stem cell transplantation.
Similar Outcomes Using Myeloablative Versus Reduced Intensity and Non-Myeloablative Allogeneic Transplant Preparative Regimens for AML or MDS: From the Center for International Blood and Marrow Transplant Research
Authors: Luger Selina , Ringden Olle , Peréz Waleska S. , Zhang Mei-Jie , DiPersio John F. , Sierra Jorge , Tallman Martin , Weisdorf Daniel J. , Pulsipher Michael 
Published: April 2020

Abstract
Use of reduced intensity conditioning (RIC) and nonmyeloablative (NMA) regimens in allogeneic transplantation (allo HCT) for AML and MDS has rapidly increased over the past decade. Efficacy of these approaches compared to myeloablative (MA) conditioning has not been clearly established. We compared disease status, donor, graft and recipient characteristics and outcomes of 3731 MA HCT with 1500 RIC/NMA procedures performed at 217 centers between 1997 and 2004 (median f/u 58 vs. 40m, MA vs. RIC/NMA). Patients in the MA group were younger (median age 42 (18–68) vs. 55 (18–69) years), more frequently in CR1, and more often were transplanted from matched sibling grafts, compared to recipients of RIC/NMA. NMA recipients were less often transplanted with &gt;10% blasts and had a lower performance scores. RIC recipients received fully matched unrelated donor (URD) grafts and PBSC as hematopoietic source more often than MApatients. Proportion with adverse cytogenetics, IPSS categories for MDS patients, median time to first relapse in AML CR2 patients, and marrow blasts at HCT were similar in the conditioning groups. 5-years univariate probabilities and multivariate relative risk (RR) outcomes of relapse, transplant-related mortality (TRM), leukemia-free (LFS) and overall survival (OS) are shown below:
Outcome: MA RIC PBSC RIC BM NMA * overall p&lt;0.001 Univariate: Relapse, % 32 (31–34) 39 (35–43) 42 (36–48) 43 (38–48) TRM,% 34 (32–36) 34 (30–38) 37 (31–43) 36 (31–41) Adjusted LFS, % 33 (31–34) 30 (26–35) 28 (23–34) 24 (20–29) Adjusted OS, % 34 (33–36) 33 (29–37) 32 (27–38) 26 (21–30) Multivariate: Relapse* 1.00 1.05 (0.92–1.21) 1.51 (1.23–1.85) 1.64 (1.38–1.94) TRM* 1.00 1.26 (1.03–1.54) 1.36 (1.01–1.83) 1.55 (1.20–1.99) Treatment 1.00 1.03 (0.90–1.17) 1.17 (1.01–1.36) 1.28 (1.12–1.45) failure* Mortality* 1.00 1.03 (0.91–1.16) 1.12 (0.96–1.30) 1.20 (1.05–1.36)
MA regimens were associated with significantly less relapse (RR with RIC/NST 1.32 (0.19–1.46), p &lt;0.001). While early TRM was substantially less with RIC/NMA approaches, 5 year TRM is equivalent (p=0.48). This leads to marginally better 5 year LFS (RR 1.08, p=0.05) but similar OS (RR 1.05, p=0.25) with MA vs. RIC/NST. These data indicate that late TRM negates any early advantage offered by RIC and NMA regimens, resulting in similar but slightly better 5 year LFS in recipients of MA conditioning. Similar outcomes with these RIC/NMA vs. MA regimens suggest the need for prospective trials comparing these transplant intensities in patients eligible for either approach.
Agricultural Pesticide Use Ã‚Â and the T(14;18) Connection to Lymphomagenesis
Authors: Roulland Sandrine , Agopian Julie , Lecluse Yannick , Navarro Jean-Marc , Gac Anne-claire , Briand Mélanie , Grenot Pierre , Gauduchon Pascal , Ruminy Philippe , Lebailly Pierre , Nadel Bertrand 
Published: April 2020

Abstract
Agricultural pesticide use has been repeatedly, but not consistently, associated with risk of non-Hodgkin lymphoma (NHL). Over the past years, it has become clear that NHL heterogeneity is setting many hurdles to this connection and that pertinent bio-markers must be identified according to malignant subtypes. Among those, t(14;18) translocation constitutes the early and promoting event of a cascade of causative effects leading to Follicular Lymphoma (FL): ectopic BCL2 expression leads to the rescue, accumulation, and developmental block of germinal center (GC) B-cells; there, protracted AID activity would favor the occurrence of complementary oncogenic hits and malignant progression, which arise from mistakes during somatic hypermutation (SHM) and class-switch recombination (CSR) processes. Although the significance of t(14;18) in blood from healthy individuals is yet unclear, evidence for a higher prevalence has been reported among farmers occupationally exposed to pesticides. Furthermore, recent findings have established that pesticide exposure is significantly associated with risk of t(14;18)+ NHL but not with t(14;18)-negative cases, suggesting that pesticides may act through a t(14;18)-dependant pathway. To get molecular insights into this connection, we followed and compared the status and clonal evolution of t(14;18)+ cells over a median of 9 years in blood samples issued from a cohort of farmers exposed to pesticides (n=112) with those of non-farmer controls (n=25). We report here that exposed individuals exhibit a much higher increase of t(14;18) frequency in blood, and that this increase result far less from a genotoxic effect of pesticides than from an immunogenic effect leading to an extensive clonal expansion of activated t(14;18)+ B cells. Strikingly, we demonstrate that such clones recapitulate the hallmark features of developmentally blocked FL cells as they 1) express high levels of BCL2/JH fusion transcripts; 2) retain the CD10 surface expression normally lost upon GC exit; and 3) sustain constitutive AID activity with the most advanced ones bearing, unexpectedly, early stigmata of AID-mediated genomic instability. Altogether these results show that expanded t(14;18)+ clones in farmers exposed to pesticides constitute bona fide FL precursors standing at various stages of tumor progression and support the notion of a direct connection between t(14;18) frequency in blood and malignant progression that could be could helpful in the identification of individuals at “high” risk for transformation to overt FL.
Signaling Diversity in Human Lymphoma B Cells and in Tumor Infiltrating T Cells Correlates with Follicular Lymphoma Patient Clinical Outcomes
Authors: Irish Jonathan M. , Houot Roch , Myklebust June H. , Czerwinski Debra K. , Nolan Garry P. , Levy Ronald 
Published: April 2020

Abstract
Introduction: Flow cytometry analysis of live cells from cryopreserved tumor samples provides the opportunity to study simultaneously the biology of both cancer cells and the patient’s immune system cells. Furthermore, single cell based approaches can identify and quantify subsets within mixed populations, such as heterogeneous primary tumors, without the need to physically separate cells. We have previously used flow cytometry to identify differences in signaling mechanism between healthy human B cells from two differentiation stages and to compare signaling kinetics of tumor and non-malignant B cells within primary human lymphoma specimens1.
Methods: Here we used barcoded phospho-specific flow cytometry to measure signaling events in live lymphoma B cells and tumor-infiltrating T cells from follicular lymphoma (FL) tumor samples obtained before patients received therapy. Patients were then stratified according to signaling and clinical outcome was examined within the resulting groups. We examined response to initial chemotherapy, which was a combination of cyclophosphamide, vincristine, and prednisone (cvp), and overall survival, measured as the time from diagnosis to last follow up or mortality.
Results: Differences in B cell receptor (BCR) signaling strength and kinetics characterized previously unappreciated diversity within the lymphoma B cell population. In some cases, BCR crosslinking triggered robust phosphorylation of AKT and ERK in one subset of lymphoma cells, while in another lymphoma subset within the same tumor sample, BCR crosslinking did not lead to phosphorylation of either protein. In these cases, both lymphoma B cell subsets expressed BCL2 and surface immunoglobulin heavy and light chain restricted to the tumor isotype. Patients whose lymphoma tumor contained a BCR insensitive cell subset (Group 2) had significantly worse responses to cvp therapy (p = 0.001) and lower overall survival (p = 0.003) than patients whose lymphoma cells displayed more homogeneous BCR signaling (Group 1). We next examined tumor infiltrating T cell signaling in the FL cases from Group 1, where no significant BCR insensitive subset was observed. Within Group 1, differences in the magnitude of IL-2, IL-7, and IL-15 mediated STAT5 phosphorylation in tumor infiltrating T cells further distinguished a set of patients with significantly higher overall survival (p = 0.04).
Conclusions: These results identify BCR signaling in lymphoma B cells and cytokine signaling in tumor infiltrating T cells as clinically relevant biomarkers for tracking and isolating lymphoma cell subsets and for monitoring immune system activity during therapy. By following patients over time, we can now determine whether cell intrinsic signaling diversity enables the emergence of therapy insensitive cancer cell subsets.
17-DMAG Targets the NF-κB Family of Proteins to Induce Apoptosis in CLL: Clinical Implications of Hsp90 Inhibition
Authors: Wagner Amy J , Hertlein Erin K , Raymond Chelsey A , West Derek A , Flynn Joseph M , Lin Thomas , Johnson Amy J , Byrd John C 
Published: April 2020

Abstract
Chronic lymphocytic leukemia (CLL) is a disease of accumulating B-cell lymphocytes for which there is currently no curative therapy. One attractive therapeutic target currently being explored in CLL is Hsp90, a chaperone which stabilizes various client proteins (Akt, Raf, ZAP-70) which are important for survival of CLL cells. Interfering with Hsp90 protein binding to these chaperone proteins leads to their rapid degradation. Our group and others have demonstrated that 17-allylamino-17-demethoxy-geldanamycin (17-AAG) depletes only select chaperone proteins and promotes only modest cytotoxicity in CLL. 17-dimethylaminoethylamino-17-demethoxy-geldanamycin (17-DMAG) is a novel Hsp90 inhibitor with improved solubility, bioavailability and cytotoxicity in other cancer cell lines as compared to 17-AAG. We demonstrate that 17-DMAG more potently induces caspase dependent apoptosis of primary CLL cells, as compared to 17-AAG, but does not mediate apoptosis of normal T-cells and NK-cells. In primary CLL cells, 17-DMAG treatment leads to cellular depletion of a broader range of Hsp90 client proteins (Akt, Cdk9, ZAP-70 and IKK). IKK is the activating kinase of the NF-kB family of transcription factors. To validate the down-stream significance of this we used EMSA to confirm that NF-kB is constitutively active in CLL as compared to normal B-cells. We demonstrate that 17-DMAG effectively reduces NF-kB DNA binding and thereby decreases subsequent transcription of known NF-kB target genes (Mcl-1 and XIAP). In addition to the direct role of NF-kB on target genes, NF-kB inhibition indirectly increases Bim transcription through regulation of the FoxO3a transcription factor. Furthermore, the reciprocal regulation transcription of Bcl-2 family members Mcl-1 and Bim are early events that initiate membrane depolarization and activation of the caspase cascade, leading to 17-DMAG induced cytotoxicity. siRNA experiments to elucidate the direct importance of Bim to 17-DMAG treatment are ongoing at this time. In conclusion, our data demonstrate that the Hsp90 inhibitor 17-DMAG represents a novel multi-targeted inhibitor of several critical kinases, transcription factors and anti-apoptosis genes relevant to CLL survival. Given its oral formulation, which allows administration of 17-DMAG by continuous dosing and uninterrupted inhibition of Hsp90, initiation of phase II clinical trials in CLL that include detailed pharmacodynamic studies monitoring NF-kB target genes are indicated.
This work is supported by the Leukemia and Lymphoma Society of America and the D. Warren Brown Foundation.
Epithelial Cells of Donor Origin after Allogeneic HCT: Result of Cell Fusion, Transdifferentiation (plasticity) or Transfer of Epithelial Cell Precursors with the Graft?
Authors: Khan Faisal , Sy Sarah , Louie Polly , Smith Megan , Chernos Judy , Lee Robyn , Berka Noureddine , Sinclair Gary D. , Leigh Richard , Proud David , Russell James A. , Storek Jan 
Published: April 2020

Abstract
Hematopoietic stem cells (HSC) appear to carry a degree of developmental plasticity that allows them to differentiate across boundaries of lineage, tissue, and germ layer, as evidenced by findings of donor-type epithelial cells in recipients of hematopoietic cell transplantation (HCT). However, these claims are often subject to criticism due to either the artifacts associated with determining the recipient versus donor origin of cells using XY-FISH or cross-lineage cell fusion. Alternatively, donor-type epithelial cells post-transplant could originate from epithelial cells or their precursors transferred with the graft. Here we wished to determine whether donor nasal epithelial cells can be detected in post-transplant patients, and if so, then the underlying mechanism. We collected nasal scrapings and whole blood from 23 allo-HCT survivors, either early (2–3 months, n=5) or late (4–22 years, n=18) post-transplant. To avoid the limitations of XY-FISH, chimerism of the epithelial cells was determined as follows: Nasal cells were stained with cytokeratin (CK) and CD45 antibodies. True epithelial cells (CK+CD45−) were laser captured. DNA extracted from the captured epithelial cells and blood leukocytes was PCR amplified for a panel of 15 autosomal short tandem repeat (STR) markers and an XY-differentiating locus (ABI-Identifiler™). In addition, a combination of immunofluorescence microscopy for CK and FISH for two autosomes was used in 8 patients to assess cross-lineage cell fusion. Magnetic separation using CD36 microbeads and staining with CK was utilized to identify epithelial cell precursors in 3 additional peripheral blood stem cell graft specimens. In all 23 HCT survivors, epithelial cells of donor origin were identified accounting for 2.4% to 12.3% of the nasal epithelial cells. The percentage of donor origin nasal epithelial cells was significantly higher (p=0.004) in late (mean=7.45%) compared to early (mean = 3.88%) post-transplant. None of the nasal epithelial cells in 8 HCT survivors exhibited the presence of cell fusion, but CD36+CK+ epithelial cells were identified in all of the three graft specimens. In conclusion, even with a method obviating the artifacts of XY-FISH; donor origin epithelial cells were identified. This appears to be due to trans-differentiation of HSC into epithelial cells or the transfer of epithelial cells (or their precursors) with the graft, but not due to cell fusion.
Incidence and Risk Factors for Hypertension during Induction Chemotherapy for Pediatric Acute Lymphoblastic Leukemia
Authors: Freiberg Andrew S. , Kees-Folts Deborah , Dyer Anne-Marie , Taylor Megan 
Published: April 2020

Abstract
Background: The most common form of cancer in children is acute leukemia, with acute lymphoblastic leukemia (ALL) comprising approximately seventy-five percent of these. The initial month of therapy (induction) for all children with ALL includes high dose steroids. One of the side effects of these steroids is hypertension.
Objective: To determine the incidence and risk factors of hypertension during induction chemotherapy for acute lymphoblastic leukemia in children.
Methods: Retrospective analysis was performed of data collected from all children diagnosed with acute lymphoblastic leukemia (ALL) at Hershey Medical Center (HMC) in 2004 and 2005 (n = 37). Each blood pressure from presentation through the four weeks of induction was recorded. To minimize the effect of a single high blood pressure measurement, median systolic and diastolic pressures were determined for each of the four weeks of induction therapy. These pressures were compared to published age matched norms. For each patient and each week of therapy, the percentile (&lt;50, 50–90, 90–95, &gt;99) was determined.
Results: Thirty-seven children (21 male, 16 female) met study criteria, with a median age of five. Thirteen of these patients received prednisone and twenty-four received dexamethasone. Overall, 95% of children had mean systolic or diastolic pressures &gt;90th percentile, 81 had pressures &gt;95th percentile, and 51% were above the 99th percentile for at least one week of induction. By contrast, only 32%, 19%, and 11% had pressures at these levels at initial presentation. The incidence of significant hypertension increased significantly during the four weeks of induction. Only three children (10%) with pressures above the 95th percentile were clearly noted in the medical record to be hypertensive, and only two children (6.7%) with pressures this high were treated.
Conclusions: Hypertension is common and underrecognized during induction chemotherapy for childhood ALL. The incidence of hypertension increases weekly during induction chemotherapy.