bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hyaluronic Acid Enhances To Differentiate into Myelo-Megakaryocytic Lineages during Ex-Vivo Expansion of Human Cord Blood(HCB) Using TPO, SCF and FL.
Authors: Mun Yeung-Chul , Ahn Jee-Young , Lee Kyung-Eun , Yoo Eun-Sun , Lee Sang min , Bae Yun-Kyung , Lee Seung-Eun , Kim Min Kyoung , Hyun Myung Soo , Seong Chu-Myong 
Published: April 2020

Abstract
Hyaluronic acid(HA) is the major glycosaminoglycan component of extracellular matrices. CD44 is a ligand for HA and expresses on a wide variety of cell types. CD44 has been implicated in many cell-cell and cell-matrix interactions. In the present study, we studied the effects of HA on proliferation, differentiation and apoptosis of CD34+ cells during HCB ex vivo expansion using TPO, SCF and FL. CD34+ cells from cord blood MNC were cultured for 4 weeks in the combination of TPO, SCF and FL on HA-coated well and CD34+cells were cultured in identical conditions except HA-coated well. At day 4, 7, 14, 21, 18, we counted the number of expanded cells and analyzed the cell surface markers (CD3, CD14, CD19, CD34, CD44, CD61, CD66b) and apoptosis using 7-AAD staining. To analyze the effects of HA on CD34+ cell differentiation, anti-CD44 antibodies (clone A3D8 and 515) were used. The morphology on the expanded cells was examined using wright’s staining. In results, cell counts were increased in HA-coated well compared with the control group until D7, but proliferation rate was decreased after D7. Apoptosis portion of CD34+ using 7-AAD staining was increased in HA-coated well and % of CD34+ cells was decreased in HA-coated wells compared with that of the control groups. The expanded cells in HA-coated well were negative for CD3 (pan T cell), CD19 (B cell) but CD14 (monocyte), CD61 (megakaryocyte) and CD66b (neutrophil) were highly expressed than those of control groups. Apoptotic portion was also increased in the HA-coated group. CD66b (neutrophil) expression in HA-coated well was significantly higher than those of control groups at D14 and above findings were confirmed by wright’s stain. CD66 expression was reduced by the anti-CD44 antibody clone, A3D8 and however CD66 expression was increased by the clone, 515. Therefore, it might be possible that A3D8 and clone 515 recognize each different epitopes of CD44. In conclusion, CD34+ cell differentiation from HCB into CD66, CD14 and CD61 positive cells was enhanced by the contact of HA during ex vivo expansion using TPO, SCF and FL. This result suggests that the expanded human cord blood graft with HA might be useful as the “post-progenitor” to shorten the severe cytopenia period after myeloablative conditioning for HCB transplantation.
Platelet Count Is a Sensitive Predictor of Bone Marrow Reserve and Autologous Peripheral Blood Progenitor Cell Mobilization.
Authors: Zubair Abba , Grant Rhonda , Tun Han , Rivera Candido , Moreno-aspitia Alvaro , Roy Vivek , Colon-Otero Gerry , Solberg Lawrence 
Published: April 2020

Abstract
Background: Previous studies have proposed combination of various factors that predict poor mobilization after GCSF stimulation. However, there is no single clinical or laboratory test that reliably correlates with bone marrow reserve and PBPC mobilization. Peripheral blood CD34+ cell count (pCD34) reliably correlates with PBPC mobilization and yield but only after GCSF administration.
Methods: We have prospectively followed 36 autologous PBPC transplant candidates, from the time of initial evaluation to transplant, to evaluate factors the correlate with bone marrow reserve and autologous PBPC mobilization.
Results: The patients median age was 63 (range 26 – 76). 21 of the 36 patients were diagnosed with dysproteinemia, primarily multiple myeloma, 10 patients had non-Hodgkin’s lymphoma while the remaining 5 had other form of hematological malignancies. Our evaluation shows baseline platelet count prior to growth factor administration significantly correlate with total CD34+ cell yield (spearman: r = 0.64, p &lt;0.001, Figure 1). In addition, daily platelet count during PBPC harvest correlate with CD34+ cell yield for the day (spearman: r = 0.6, p &lt;0.001). Using multiple linear regression model (F = 19.1, p &lt;0.001, R2 = 0.64), we have determined patients’ age (p = 0.03) and type of disease (p &lt;0.001), in addition to platelet count (p&lt;0.001), significantly correlate with total CD34+ cell yield. Further analysis showed low baseline platelet count predicts poor PBPC mobilization. Using Receiver Operating Curve (ROC), we have determined that platelet count of 174,000/ul was the best cut-off for collecting at least 2 million/Kg CD34+ cells with sensitivity of 81% and specificity of 78% and estimated correct classification of 81%. Even though pCD34 counts were slightly more sensitive and were better at identifying poor mobilizers in our cohort (best cut-off 10/ul, sensitivity 96%, specificity 67%, correct classification 89%), their clinical utility were diminished since the values were only known after GCSF administration.
Conclusion: Baseline platelet count is a sensitive predictor of bone marrow reserve and can be used prior to growth factor administration to predict poor mobilization.
Figure 1: Correlation of baseline platelet count and total CD34+ cell yield Figure 1:. Correlation of baseline platelet count and total CD34+ cell yield
Multivariate Analysis of Risk Factors for Clinically Overt Hemorrhagic Cystitis after Allogeneic Hematopoietic Stem Cell Transplantation.
Authors: Zhu Kanger , Ma Chunhui , Zhang Tao , Zhong Juan 
Published: April 2020

Abstract
Objective: To analyze the risk factors of clinically overt hemorrhagic cystitis (HC) (grade ≥II) in 114 patients undergoing allo-HSCT to predict the occurrence of HC.
Methods: We retrospectively analyzed 29 cases of clinically overt HC from a series of 114 patients given allo-HSCT from April 1997 to December 2004. The time of follow-up began from the day of initiating conditioning to day 180 post-transplant. The 11 clinical parameters were selected for univariate analysis using a Cox regression: age, sex, underlying disease, conditioning regimen, disease status at transplant, aGVHD, donor type, use of ATG, GVHD prophylaxis, platelet and neutrophil engraftment. Factors that were significant at the 0.1 level on univariate analysis were evaluated by multivariate analysis using a Cox regression. The cumulative incidence of grade ≥ II HC within the day 180 after transplantation was calculated by the method of Kaplan and Meier.
Results: 29 out of 114 patients (26%) developed HC with grade II in 12/29 cases (41.4%), grade III in 11/29 cases (37.9%) and grade IV in 6/29 cases (20.7%). The following factors were associated with an increased risk of HC by univariate analysis: male gender (RR=2.885, P=0.021),younger than 26 years (RR=3.265, P=0.007),grade III~IV aGVHD (RR=4.039, P=0.002),unrelated doner (RR=4.347, P=0),intense GVHD prophylaxis (RR=2.218, P=0.045),advanced disease (RR=2.668, P=0.009). These risk factors were entered into a multivariate model. Only male gender (RR=2.993, 95% CI 1.218–7.358; P=0.017) and unrelated donor (RR=4.478, 95% CI 2.049–9.786; P=0.000) were identified as being significantly associated with the occurrence of hemorrhagic cystitis.
Conclusion: We found that in multivariate analysis, patients were at increased risk of HC if they were male or had received graft from unrelated donors.
Acute Renal Failure Following Myeloablative Autologous and Allogeneic Haematopoietic Cell Transplantation.
Authors: Lopes José A. , de Almeida Edgar , Silva Sónia , Jorge Sofia , Abreu Fernando , Lourenço Fernanda , Martins Carlos , Lacerda João Forjaz , Carmo José Alves do , Lacerda João Manuel Forjaz , Prata Mateus Martins 
Published: April 2020

Abstract
Acute Renal Failure (ARF) is a common complication in the early period of myeloablative autologous and allogeneic haematopoietic cell transplantation (HCT). Reported incidence varies from 30% to 80%. This study evaluates retrospectively the incidence of ARF, defined as the doubling of serum creatinine within the first 100 days after HCT, associated risk factors, the need of dialytic therapy as well as mortality of HCT patients who received a myeloablative autologous or allogeneic HCT in our Hospital between January 2003 and December 2004. One-hundred and forty patients (86 men, mean age: 32,9±14,69 years) were studied: 90 patients (53 men, mean age: 33,6±13,73 years) had an allogeneic HCT and 50 (33 men, mean-age: 31,71±16,25 years) an autologous HCT; 82 patients (51 men, mean age: 33,17±14,1 years) received a peripheral blood stem cell (PBSC) transplantation and 58 (35 men, mean age: 32,51±15,61 years) a bone marrow (BM) graft. The incidence of ARF was 21,5% (30/140) (16 men, mean age: 31,53±13,21 years) but did not reach a statistically significant difference between patients who received an allogeneic or autologous HCT (27% vs 12%, p=0.07) or were transplanted with BM graft or PBSC (10% vs 17%, p=ns). Nephrotoxicity (n=20), septic shock (n=16), graft vs host disease (n=6) and veno-occlusive disease (n=3) were the most common etiologies associated with ARF. The incidence of dialysis-dependent ARF was 30% (9/30) and was higher in patients with a BM graft (50% vs 7%, p&lt;0.03) but did not differ in patients who received an allogeneic or autologous HCT (33% vs 16%, p=0.08); 4 patients were treated with intermittent hemodialysis and 5 with continuous dialytic therapy (continuous veno-venous hemodiafiltration). Among patients who received only medical therapy (n=21), 11 had complete renal function recovery (RFR) and 2 had partial RFR. Overall mortality rate was 16,4% (23/140) and was higher in patients with ARF (57% vs 6%, p=0.0001), particularly if there was a need of dialysis therapy (100% vs 38%, p=0.006).
This study shows that ARF is prevalent during the early period of HCT and increases mortality, particularly if it is dialysis-dependent. However, in our cohort of patients the incidence of ARF was lower than the previously described in other studies. Low occurrence of veno-occlusive disease could explain this phenomenon, which may be related to adequate prophylactic measures.
Peripheral Blood Stem Cell Transplantation in Fanconi Aplastic Anemia: Report of Ten Cases.
Authors: Kupesiz O. Alphan , Tezcan Gulsun , Hazar Volkan , Yesilipek M.Akif 
Published: April 2020

Abstract
Allogeneic hematopoietic stem cell transplantation (SCT) from healthy donors is the only treatment modality for the correction of hematological abnormalities in Fanconi aplastic anemia (FAA) patients. We have performed SCT by using two different non total body irradiation conditioning regimens. While anti-thymocyte globulin (ATG, 10–30mg/kg/day, 3 days), cyclophosphamide (5mg/kg/day, 4 days) and thoraco-abdominal radiation (total 5Gy) were used for six patients (regimen A), fludarabine (120–150mg/m2 totally), cyclophosphamide (10mg/kg/day, 4 days), ATG (30mg/kg/day, 3 days) were given to four patients (regimen B). Six of the patients received regimen A and 4 regimen B. Donors were HLA-matched sibling in 5, HLA-matched parent in 2, partly HLA-matched parent in 2 and HLA-matched unrelated donor in one. All patients and donors were screened by diepoxybutane (DEB) test. Seven of the patients were DEB positive. All donors were DEB negative. Median age of the patients was 10 years. All patients received antimicrobial, antifungal prophylaxis and intravenous immunoglobulin (IVIG, 500 mg/kg weekly) from day −7 to day +180. Cyclosporin A (CsA) was used for graft-versus-host disease (GVHD) prophylaxis in eight patients and CsA plus mycophenolate mofetil in one matched unrelated patient. Neutrophil and platelet engraftment occurred in all patients on day 10 (median) and day 21 (median), respectively. Grade II-IV acute GVHD occurred in two patients who received regimen A. Conditioning-related toxicity was milder in regimen B than that in regimen A. Three patients succumbed from complications of grade IV acute GVHD, post-transplant acute myeloid leukemia and fungal pulmonary infection in regimen A group. All of the regimen B group were alive with normal hematological parameters. Totally, seven patients are alive with sustained engraftment and transfusion independent with median follow-up 19 months (range 2–50). We conclude that fludarabine based conditioning regimen is well tolerated and ideally suited to reduce regimen-related toxicities while achieving sustained engraftment in FAA patients SCT using sibling, related and unrelated donor.
The Impact of Methylenetetrahydrofolate Reductase C677T Gene Polymorphism on Engraftment after Allogeneic Hematopoetic Cell Transplantation.
Authors: Soydan Ender A. , Topcuoglu Pervin , Ozcan Muhit , Arslan Onder , Gurman Gunhan , Beksac Meral , Arat Mutlu , Ilhan Osman 
Published: April 2020

Abstract
Methotrexate (MTX) is an antifolate agent used to prevent graft versus host disease (GVHD) in allogeneic hemapoietic cell transplantation (AHCT). The effectiveness of MTX is largely attributable to its role of MTHR and its gene polymorphism is a common (10–12% homozygote and 40% heterozygote) variation in the population. It was shown by Ulrich et al that C677T polymorphism leads to variations in toxicities. Depending on to this finding, we investigated whether methylenetetrahyrofolate reductase (MTHFR) C677T gene polymorphism has any affect on engraftment kinetics of patients undergoing AHCT. We retrospectively analyzed our cohort of 82 allogeneic stem cell recipients whose MTHFR gene polymorphism of C677T region was analyzed by RQ-PCR for the pretransplant evaluation of hereditary thrombophilia. The patient’s median age was 31 (range, 14–50) years, with a M/F: 50/32 and diagnosis; 35 AML, 26 CML, 12 ALL and 9 other. Nearly all the patients received ablative conditioning regimen (BU-CY) or CY-TBI. All the patients received CSA and short term MTX for GVHD prophylaxis. Stem cell source was bone marrow (BM) in 23 and peripheral blood (PB) in 59. MTHFR gene polymorphism was detected in 32 (39%) of all patients, whose 90% were heterozygote (MTHFR HeZ). When we compared the engraftment kinetics, granulocyte engraftment was found to be late in MTHFR HeZ group (neutrophil 1000 median 19 vs 17 d; p=0.01) but no difference in platelet engraftment. In order to eliminate the effect of stem cell source on engraftment kinetics we have done the same analysis for BM and PB group separately. We have observed that MTHFR gene polymorphism had a prominent effect on BM recipients, as both neutrophil 500 and 1000 and also platelet engraftments were affected (granulocyte 500 median 21 vs 15 p=0.005; granulocyte 1000 median 22.5 vs 17 p=0.0001 and plt 20 median 27 vs 21 p=0.03) significantly. On the contrary, there was no difference in the PB group. There was no difference in acute GVHD incidence. Our knowledge on epigenetic data will help us on tailoring the chemotherapy regimen for conditioning and GvHD prophylaxis in transplant recipients. Our data on a limited patient size suggests that the presence of MTHFR HeZ may have an impact on allo HCT recipients’ engraftment kinetics while using MTX for GVHD prophylaxis and BM as stem cell source.
Beta 3 Integrin Phosphorylation and VEGF Signaling.
Authors: Mahabaleshwar Ganapati H. , Philips David R. , Byzova Tatiana V. 
Published: April 2020

Abstract
The process of angiogenesis is critical for tumor survival as well as for ischemic remodeling of vasculature after thrombotic occlusion. This process is a result of finely tuned co-operation between angiogenic growth factors, primarily from the VEGF family, and their receptors and cell receptors for extracellular matrix, the integrins. The role of alpha v beta 3 integrin in neovasculature development appears to be controversial asthe blockade of this receptor with antibodies inhibited angiogenesis while the genetic ablation of the beta3 subunit resulted in increased angiogenesis due to the over-expression of VEGFR2 on endothelial cells (EC). In order to understand the role of beta 3 integrin in VEGF-induced responses, we utilized knock-in mice with a mutation within the beta 3 subunit (Y747/759 to F, DiYF) that results in beta 3 that is unable to undergo tyrosine phosphorylation, an event critical for integrin outside-in signaling. Using EC isolated from WT and DiYF mice, we have found that defective tyrosine phosphorylation resulted in impaired EC adhesion and spreading on vitronectin but not on fibronectin, laminin and collagen. Migration in response to VEGF was reduced in DIYF EC by 3 fold compared to WT when vitronectin and fibrinogen but not fibronectin and collagen were used as substrates. In a wound healing assay on vitronectin, DiYF but not WT EC failed to close the wound. Video microscopy of migrating EC revealed that WT EC form forward protrusions and then retract the back of the cell, which results in successful directed migration. DiYF EC also formed protrusions, but could not form stable adhesion and retract the tail of the cell. As a result, DiYF EC were moving forward and then back again, failing to migrate in the direction of the wound. Importantly, DiYF but not WT EC were not able to form complete capillaries on Matrigel in response to VEGF and the average length of EC tubes was 3.5 fold lower compared to WT. Interestingly, the DiYF mutation resulted in impaired integrin activation (inside-out signaling) in response to VEGF as well as PMA based on soluble fibrinogen and WOW-1 binding. We have found that VEGF treatment of WT EC resulted in beta 3 integrin phosphorylation, which occurred 5 minutes after stimulation and reached the maximum at 30 min. In DiYF EC, this response was absent. Most importantly, immediately after VEGF stimulation, VEGFR2 formed a complex with beta 3 integrin. This complex was not observed in DiYF EC. Moreover, phosphorylation of VEGFR2 (but not the total protein level) was significantly reduced in DiYF EC compared to WT. As a result, major intracellular signaling events triggered by VEGF stimulation, such as phoshorylation of Akt, ERK1/2 and p38 MAPK, were severely impaired in DiYF EC. The finding that beta 3 phosphorylation regulates an activation of VEGFR2 and subsequent signaling events in EC provides novel insights on EC biology and mechanisms of VEGF-induced angiogenesis.
Duration to Engraftment Requires Significantly Much More Time in Myelodysplastic Syndrome (MDS) Patients as Compared to Acute Myeloid Leukemia (AML) Patients Following Allogeneic Stem Cell Transplantation.
Authors: Bitan Menachem , Shapira Michael Y. , Resnick Igor B. , Gesundheit Benjamin , Zilberman Irena , Ackerstein Aliza , Samuel Simcha , Elad Sharon , Slavin Shimon , Or Reuven 
Published: April 2020

Abstract
Normal hematopoiesis is characterized by the balanced interplay between hematopoietic stem cells and the cells and molecules that forms part of the microenvironment in which blood cell production takes place. Myelodysplastic syndrome (MDS) marrow stroma cells are known to fail in supporting the growing of normal stem cells. We therefore retrospectively analyzed the duration to engraftment of absolute neutrophil count (ANC) ≥0.5 x 109/L and ≥1.0 x 109/L and the time interval to platelet recovery of ≥20 and ≥50 x 109/L in 42 MDS patients as compared to 42 patients suffering from primary acute myeloid leukemia (AML), following allogeneic stem cell transplantation (SCT). Significant shorter time to engraftment was documented in AML as compared to MDS patients in all 4 parameters. These results hold true even if we sub-grouped the patients according to gender, age, with the age of 50 years old being the cutoff between young and elderly patients, or when the donor was related to the patient. Moreover, sub-grouping the patients from each diagnosis according to the conditioning regimens that were given prior to transplantation revealed the same significant better results for the AML patients when received a non-myeloablative regimen. To the best of our knowledge, this is the first time that such a comparison is being made. We suggest that duration to engraftment in MDS patients takes significantly longer time and this may influence and worsen their course of transplantation in terms of morbidity as well as mortality.
Donor/Recipient Matching for the -174G/C SNP Polymorphism in the IL-6 Gene Promoter Influences the Outcome of Stem Cell Transplantation.
Authors: Manzano Cintia , Balsalobre Pascual , Serrano David , Carrion Rafael , Gomez-Pineda Alfonso , Diez-Martín Jose Luis , Buño Ismael 
Published: April 2020

Abstract
Background: Polymorphisms in regulatory sequences of cytokine genes are known to influence their expression and, therefore, the intensity of the immune response. Some of such polymorphisms have been associated with the outcome of stem cell transplantation (SCT), which supports the hypothesis of a genetic predisposition towards certain complications post-transplants.
Objective: To evaluate the association between donor (D) and recipient (R) genotype in the IL-6 gene -174G/C SNP polymorphism with the development of complete or mixed chimerism (MC) and, consequently, with complications such as graft rejection, graft versus host disease (GVHD) and survival after SCT.
Patients and methods: The study included 16 SCT (9 ablative, 3 T cell depleted, 4 reduced intensity conditioning). The IL-6 -174G/C SNP genotypes were determined by PCR on genomic DNA from Rs and Ds, using allele-specific oligonucleotides (ASO-PCR) as primers (forward: 5′-ccctagttgtgtcttgcc-3′ or 5-′ccctagttgtgtcttgcg-3′; reverse: 5′-gagcttctctttcgttcc-3′). Logistic regression was applied to identify associations between the polymorphism, the development of MC and of the mentioned complications. The reduced number of SCT analyzed, precluded the use of Pearson’s and/or Fisher’s p values or further statistics.
Results: The frequency of the different genotypes was 44.4% CC, 33.3% GC and 22.2% GG for Rs, and 33.3% CC, 44.4% GC and 22.2% GG for Ds. 88.9% D/R pairs were matched for the polymorphism and 11,1% mismatched. None of the patients transplanted from matched donors showed MC at any time post-SCT while all mismatched patients developed MC (Table 1). MC in the D/R mismatched group was associated with a greater rate of graft rejection and with a reduced incidence of acute GVHD (aGVHD) when compared with the D/R matched group (Table 1). No association was observed in this sample between the polymorphism analyzed and the development of chronic GVHD (cGVHD). Although graft rejection was early diagnosed and successfully treated with immunosuppression withdrawal and donor leukocyte infusion, the D/R matched group showed higher mortality rate that the mismatched group (Table 1).
Conclusions: The present study suggests an association between D/R matching for the IL-6 gene -174G/C SNP polymorphism and the development of MC and, consequently, of different complications after SCT. The analysis of a larger number of patients will eventually allow to confirm these observations as well as to establish this type of studies as a means for an improved management of transplanted patients.
Table 1 IL6 -174G/C MC rejection aGVHD cGVHD Exitus D/R matched 0% 0% 75% 87.5% 50% D/R mismatched 100% 100% 0% 100% 100%