bluuebunny/crossref_metadata_2025_split huggingface dataset:
Treosulfan-Based Reduced Toxicity Regimen Prior to Allogeneic Hematopoietic Cell Transplantation in Non-Malignant Disorders.
Authors: Wojnar Jerzy , Giebel Sebastian , Markiewicz Miroslaw , Krawczyk-Kulis Malgorzata , Wylezol Iwona , Stella-Holowiecka Beata , Kruzel Tomasz , Holowiecki Jerzy 
Published: October 2019

Abstract
Graft rejection is a major cause of failure after alloHCT in non-malignant hematopoietic disorders including severe aplastic anemia (SAA) and paroxysmal nocturnal hemaoglobinuria (PNH). For patients with high risk of this complication we introduced a novel conditioning regimens, based on treosulfan - an alkylating agent possesing both immuno- and myeloablative properties. Between 2003–2006, eleven patients (age: 23(14–35) years) with SAA (n=6) or PNH (n=5) were treated in a single institution with alloHSCT from either HLA-identical sibling (n=3) or an unrelated volunteer (n=8). For patients with SAA conditioning regimen consisted of treosulfan 10 g/m2/d on days -7, -6, cyclophosphamide 40 mg/kg/d on d. -5, -4, -3, -2, and anti-thymocyte globulin (ATG) 2 mg/kg/d on d. -3, -2, -1. PNH patients received treosulfan 14 g/m2/d on days -6, -5, -4, fludarabine 30 g/m2 on d. -6, -5, -4, -3, -2, and (ATG) 2 mg/kg/d on d. -3, -2, -1. Bone marrow was used as a source of stem cells in 5 patients and peripheral blood - in 6 cases. Graft-vs.-host disease (GVHD) prophylaxis consisted of Cyclosporin A and short-course Methotrexate.
All patients engrafted with the median time to neutrophil >0.5×10e9/L and platelet >50×10e9/L recovery of 16 (14–22) days and 21.5 (12–29) days, respectively. Complete donor chimerism was achieved on day +30 in all cases. None of the patients developed grade III-IV acute GVHD, two patients experienced grade II acute GVHD. At one year the cumulative incidence of extensive chronic GVHD equaled 22%. No severe organ toxicity was observed. With the median follow-up of 19 months, the disease-free survival at 2.5 years was 91%. A single PNH patient died of haemorrhagic cystitis.
We conclude that treosulfan-based preparative regimens are well-tolerated and allow stable engraftment in SAA and PNH patients. The use of treosulfan allows intensification of the conditioning without providing an additional non-hematological toxicity.
Selective Targeting of the p53-hDM2 Interaction Using Hydrocarbon-Stapled p53 Peptides.
Authors: Bernal Federico , Walensky Loren D. , Tyler Andrew F. , Korsmeyer Stanley J. , Verdine Gregory L. 
Published: October 2019

Abstract
p53 is a transcription factor that induces cell cycle arrest and apoptosis in response to DNA damage and cellular stress, and thereby plays a critical role in protecting cells from malignant transformation. The E3 ubiquitin ligase hDM2 controls p53 levels through a direct binding interaction that neutralizes p53 transactivation activity, exports nuclear p53, and targets it for degradation via the ubiquitination-proteasomal pathway. Loss of p53 activity, either by deletion, mutation, or hDM2 overexpression, is the most common defect in human cancer. Tumors with preserved expression of wild type p53 are rendered vulnerable to pharmacologic approaches that stabilize and upregulate p53. In this context, hDM2 inhibition has emerged as a validated approach to restore p53 activity and resensitize cancer cells to apoptosis in vitro and in vivo. The inhibition of the p53-hDM2 interaction has been studied intensively with the goal of developing novel therapeutics for cancer. Here we describe the synthesis and evaluation of hydrocarbon-stapled α-helical peptides based on the transactivation domain of the p53 tumor suppressor protein. Select p53 stapled peptides exhibit subnanomolar binding to hDM2, displaying the highest affinity hDM2 binders reported to date. We find that these structurally-stabilized peptides are resistant to proteolysis and exhibit cell permeability as documented by flow cytometry and confocal microscopy analyses. In vivo binding of p53 stapled peptides to nuclear hDM2 is highly specific as demonstrated by co-immunoprecipitation experiments. In response to stapled peptide treatment, we observe upregulation of p53 and its transcriptional targets, including p21 and Bax. As a consequence, the peptides are capable of activating apoptosis in hDM2-overexpressing tumor cells through the p53 tumor suppressor signaling pathway. Thus, we find that hydrocarbon-stapled p53 peptides can trigger apoptosis in cancer cells by effectively modulating the p53-hDM2 protein interaction.
Routine Surveillance for Bloodstream Infections in a Pediatric Hematopoietic Stem Cell Transplant (HSCT) Cohort: Do Patients Benefit?.
Authors: Fernandez Conrad , Rigby Heather , Langley Joanne , Mailman Timothy , Crooks Bruce , Higgins Ann 
Published: October 2019

Abstract
Background: HSCT recipients are at high risk of late bloodstream infection (BSI). Controversy exists regarding the benefit of surveillance blood cultures in this immunosuppressed population. Despite the common use of this practice, its practical value is not well established in non-neutropenic children following HSCT.
Methods: At the IWK Health Centre, a tertiary health care center serving 2.5 million in the three Maritime provinces of Canada, weekly surveillance blood cultures from central venous access lines (CVLs) are drawn from children following HSCT until CVL removal. We reviewed data from a prospectively collected CVL database in association with a health record review to determine the utility and cost of this practice. Eligible participants were non-neutropenic pediatric HSCT recipients with CVLs followed at the IWK between 1999 and 2005. Patients routinely received PCP and penicillin prophylaxis. Cultures were considered to be for surveillance if the child was afebrile without focus of infection. The cost of laboratory investigations, nursing time, hospital stay, and interventions for positive surveillance cultures was calculated.
Results: 43 HSCTs were performed in 41 patients of whom 21 were male (49%). The median age was 7 years (range 1–18). Donors were related in 15 cases (35%), unrelated in 18 (42%) and autologous in 10 cases (23%). The most common underlying illness leading to HSCT was leukemia (19/41; 46%) followed by solid tumour (7; 17%), inborn errors of metabolism and Fanconi Anemia (4 each; 10%) and other (4;10%). The median length of study eligibility, defined as the point at which the patient returned to the IWK from the transplant centre until the time of central line removal, was 70 days (range 7–176). There were 316 patient contacts for surveillance cultures (mean 7 per transplant) and 577 central line lumens sampled. Three patients had potentially clinically significant surveillance blood cultures that were positive (3/43; 7%). The bacteria isolated were Klebsiella pneumoniae (n=2) and Corynebacterium jeikium (n=1). Repeat cultures were done prior to initiation of antimicrobial therapy and all were sterile. Patients were admitted for antimicrobial therapy if they were not already hospitalized for HSCT care. Median hospitalization for treatment of the positive culture was 5 days. All three patients had an uncomplicated course. The estimated total cost of BSI surveillance and treatment of asymptomatic infection over 6 years was $27,989.
Conclusion: This study suggests that BSI surveillance in children post engraftment has a very low yield and significant cost. It is unclear that it contributes to improved patient outcomes.
Monitoring JAK3 mRNA Levels in Patients with GVHD after Allogeneic Hematopoietic Stem Cell Transplantation by Real-Time Quantitative PCR.
Authors: Li Qihui , Du Xin , Geng Suxia , Weng Jianyu , Guo Rong , Lu Zesheng , Xing Haizhou 
Published: October 2019

Abstract
Background: Graft-versus-host disease (GVHD) represents a major hurdle impeding the efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT). JAK3 plays pivotal roles in the initiation of cytokine-triggered signaling transduction. Recent studies about the murine GVHD model show that targeting JAK3 in donor lymphocytes with a chemical inhibitor such as WHI-P131 may be useful in the prevention of severe GVHD. However, the level of JAK3 expression in patients with GVHD has not been reported. The current study is to develop a reliable and rapid real-time quantitative PCR (Q-PCR) method using Taqman Probe for detecting JAK3 in allo-HSCT recipients.
Methods: 20 patients who received myeloablative-conditioning regimen for hematological malignancies and cyclosporine for GVHD prophylaxis have been investigated in this still ongoing study clinically. One of these patients developed acute GVHD (aGVHD), 9 patients developed chronic GVHD (cGVHD), and 10 patients showed no evidence of GVHD during the first 365 days post-transplant. RNA was extracted from white blood cells and cDNA templates were synthesized using 1μg RNA. The standard curve method was used for relative quantitation of JAK3.
Results: There is a clear trend for a increasing expression of JAK3 in 9 patients with GVHD. Interestingly, a significant decrease of JAK3 gene expression when the severity of GVHD was remission (P=0.04). One of the patient with cGVHD, the level of JAK3 gene expression has no changed before and after treatment. However, these patients post HSCT without GVHD have a comparable level of JAK3 expression before myeloablative conditioning regimen(P>0.05).
Conclusion: Based on our preliminary results, JAK3 mRNA level was obviously correlated with the development of GVHD. Analysis JAK3 mRNA expression may be useful in evaluating GVHD patients with allogeneic stem cell transplantation.
Double Syngeneic Transplantation in Plasma Cell Leukaemia.
Authors: Barrenetxea Cristina , Callis Manuel , Bueno Javier , Julia Antonio , Diaz Jose L. 
Published: October 2019

Abstract
INTRODUCTION Plasma cell leukemia (PCL) is a rare disorder, characterized by circulating clonal plasma cell.
It accounts for less than 1% of all plasma cell dyscrasias and has a fatal prognosis.
It can be primary or secondary, when there was a previously diagnosed plasma cell dyscrasia.
The median survival is 7–12 moths in the first case and 2 moths in the second.
CASE We present a 54 years old man, diagnosed in November 2003, with multiple myeloma IgA kappa, Bence Jones +, that presented weight loss, retinal hemorrhages, respiratory distress, hepatomegaly, splenomegaly, osteolytic lesions, the cariotype showed hyperploid, chromosome 13 monosomy, translocations t (1,12) and t (4,14).
He was treated upfront with tree cycles of a drug’s combination with melphalan, carmustine, vincristine and dexametasone with no response, therefore, was changed to cyclophosphamide, adriamycin, vincristine, methotrexate and citarabine.
After two cycles, the patient got complete remission.
The patient had a twin brother, and we decided, to do a double transplantation to consolidate the response. The first transplantation was condicionated with carmustine, etoposide, citarabine and melphalan (BEAM), and the second with cyclophosphamide and total body irradiation; the patient remained in complete remission.
Eight months after second transplant was admitted to the hospital with disorientation, bradypsiquia, headache, and sensoriomotor loss of lower extremity.
Laboratory examination showed differential count of leukocytes, haemoglobin and platelets were normal, LDH increase, absence of monoclonal gammophaty in blood and urine by immunofixation, and the brain’s computerized tomography showed multiple intraparenchymatous lesions, with peripheral edema, in both cerebral hemispheres, confirmed by magnetic nuclear resonance, all of that suggested a neoplastic disease.
These lesions were biopsied with the result of multiple myeloma lambda.
The patient died one day after biopsy because intracranial hypertension.
CONCLUSION Plasma cell disease has poor prognosis, and transplantation could be a good option for some patients, but in our case we only achieve to extend life a few months.
Regulation of Alpha Hemoglobin Stabilizing Protein (AHSP) mRNA Stability by a 3′ UTR Iron Response Element.
Authors: dos Santos Camila O. , Dore Louis C. , Ollala Sara T. , Costa Fernando F. , Weiss Mitchell J. 
Published: October 2019

Abstract
AHSP is an erythroid protein that binds the alpha globin subunit of hemoglobin (Hb) to maintain its structure and limit its oxidative activity. Biochemical and genetic studies demonstrate that AHSP is essential for normal Hb homeostasis and may act via at least two mechanisms: First, as a molecular chaperone to promote the folding and stability of alpha globin prior to its incorporation into HbA (alpha2beta2). Second, to bind and detoxify excess alpha globin that accumulates in normal erythroid precursors, and to a larger extent, in beta thalassemic ones. The existence of a potential iron responsive element (IRE) in the 3′-UTR of the AHSP mRNA raises the interesting possibility that iron homeostasis impacts on alpha globin stability via AHSP. IREs form stem-loop structures that bind cytosolic iron-sensing proteins (IRPs). Typically, IRP binding to the 3′ UTR stabilizes mRNA. Association with iron releases the IRP, enhancing mRNA degradation. Computational algorithms identified IRE-like stem-loop structures in AHSP mRNA of multiple species, yet the primary sequences deviate significantly from canonical IRE consensus sequences determined by studies of classical IREs, such as Transferrin receptor and Ferritin. Several lines of evidence now show that the AHSP IRE binds IRPs to regulate mRNA stability in an iron-dependent fashion:
1) in vitro gelshift competition assays demonstrate that human and mouse AHSP IREs bind tightly to IRPs. 2) AHSP mRNA co-immunoprecipitates with IRPs in erythroid cells in a fashion that depends on an intact IRE. 3) AHSP mRNA is destabilized by iron in both erythroid and heterologous cells; disruption of the IRE renders the mRNA constitutively unstable.
To study how iron regulates AHSP expression in vivo, we treated mice with iron dextran for 10 days and then examined AHSP mRNA in Ter119+ erythroid progenitors by RT-PCR. We found that short-term iron overload reduced AHSP mRNA levels by about 50% (p > 0.05). Our findings indicate that AHSP mRNA stability is regulated by iron via an atypical 3′-UTR IRE. These findings extend the potential repertoire for functional IREs that do not conform to previously defined canonical consensus sequences. In addition, they provide a potential mechanism by which erythroid cells can regulate globin stability according to iron status. For example, induction of AHSP during iron deficiency might stabilize apo- alpha globin that could accumulate from lack of heme. Conversely, iron overload could destabilize alpha globin by reducing AHSP levels. As such, iron overload, which occurs in patients with beta thalassemia, might aggravate the disease by further elevating the levels of toxic free alpha globin.
Unrelated Donor Hematopoietic Stem Cell Transplantation for High-Risk Leukemia.
Authors: Wu De Pei , Tang Xiaowen , Sun Aining , Fu Zheng-zheng , Qiu Huiying 
Published: October 2019

Abstract
objective: To investigate the efficacy of unrelated donor hematopoietic stem cell transplantation(URD-HSCT) for high-risk leukemia.
Methods: From 2001 to March, 2006, 24 patients of high-risk leukemia underwent HSCT with unrelated donor. Patients between 6 and 49 years of age(median age 21.5 years) There were 16 unrelated donor’s grafts came from Buddhist Tzu Chi Stem Cells center in Taiwan, and 8 unrelated grafts came from Red Cross Society of China Hematopoietic Stem Cell Marrow Donor Program Administration Center. Fifteen patients received bone marrow transplantation and another 9 patients received peripheral blood stem cell transplantation. Eighteen patients were fully matched with their donors for HLA loci A and B as well as for HLA-DRB1. Four of 24 patients had 1 molecular loci mismatch and 2 of 24 patients had 2 molecular locus mismatch. The conditioning regimen consisted of modified BU/CY or modified total body irradiation(TBI) plus CY. Eleven patients received cyclosporine (CSA), short-term methotrexate(MTX) and mycophenolate mofetil (MMF) as the regimen of prophylaxis of GVHD. Ten patients received CSA, MTX and MMF plus ATG/ALG for GVHD prophylaxis. The combination of CSA, MTX, MMF,ATG/ALG and CD25 monoclonal antibody for preventing GVHD in 3 patients.
Results: The incidence and severity of regimen-related toxicity were mild. The median number of MNC and CD34 positive cell was 4.18×108/kg and 7.75×106/kg respectively. The median time of the engraftment of neutrophil and platelet was 13 days and 19 days posttransplant respectively. The incidence of infection posttransplant was 70%(17/24). The complicated pneumonitis occurred frequently (13/17, 76%), The incidence of grade I-II and grade III-IV acute GVHD was 33% and 41% respectively. Limited chronic GVHD occurred in 25% patients and extensive cGVHD presented in 31% patients. Median follow up was 16 (range 1~57) months after transplantation. 75% patients achieved full donor chimerism(FDC) detected by STR-PCR and FISH. While 25% patients presented mixed chimerism(MC) and 2 of them converted to unstable MC. Decreasing values of donor chimerism were detected prior to the relapse of disease. Furthermore the treatment related mortality(TRM) was 33%(8/24), The incidence of relapse was 8%. Until now 14 patients are still alive. The median overall survival time were 26 months and 5-years expected survival was 47.7%.
Conclusion: URD-HSCT can be an effective and curable approach for leukemia with higher incidence of GVHD and infection. The treatment for the severe and deadly GVHD and pulmonary infection are still major problems need to be resolved in the future.
Mobilization of Peripheral Blood Stem Cells with Rituximab Plus ESHAP Combination Regimen in B-Cell NHL - Preliminary Results.
Authors: Kim Min Kyoung , Kim Shin , Lee Seong Sook , Sym Sun Jin , Lee Dae Ho , Kim Sang We , Jang Seongsoo , Park Chan Jeong , Chi Hyun Sook , Huh Joo Ryung , Suh Cheolwon 
Published: October 2019

Abstract
Objectives: The mobilization chemotherapy should be directed toward the dual objectives of good antilymphoma activity and adequate PBSC mobilization. Previously, we reported the ESHAP plus G-CSF is an effective mobilization regimen in patients with relapsed and high risk NHL. The purpose of this study is to assess the efficacy and feasibility of autologous stem cell collection after mobilization with Rituximab plus ESHAP (etoposide, methylprednisolone, high-dose cytarabine, and cisplatin) combination therapy in B-cell Non-Hodgkin’s lymphoma.
Patients and Methods: CD20 + B-cell NHL patients with either high risk, relapsed or refractory patients were eligible for the study. The regimen consisted of: Rituximab 375mg/m2 given on day 1, standard ESHAP therapy (etoposide 40mg/m2 IV/2hr day 2–5, methylprednisolone 500mg/m2 days 2–6, cytarabine 2g/m2 IV/3hr on day 5 and cisplatin 25mg/m2 CIV days 2–5).
In all patients, the collection of PBSC was performed during recovery after giving G-CSF (10μ/kg/day) started on day 7. The first harvest was started only if the peripheral blood hematopoietic progenitor cell (HPC) count exceeded 5/μl.
Results: Fifty-five mobilization procedures performed on 20 patients with a median of three apheresis (range 2–5) per patient. Median age was 37 years (range 15–65). At the time of PBSC mobilization, Seventeen patients were considered to be responsive (CR, PR and sensitive relapse). Aphereses were started on day 16 (range 13–18). The number of total MNCs (×106/kg) collected was 5.4 (range, 1.4–14.5) and the number of CD34+cells (× 106/kg) was 10.6 (range, 4.9–52.6). The median days of G-CSF usage was 11(range 9–15). Most non-hematologic adverse events were mild and reversible. Nineteen patients (95%) were achieved optimal response, which was defined as ≥ 5 × 106 CD34 cells/kg. In all, sixteen of the patients underwent high-dose chemotherapy. The median time to ANC ≥ 0.5 × 109/L was 10 days (range, 8–17). The median days to platelets ≥ 20 × 109/L was 12 (range, 7–27).
Conclusion: Addition of Rituximab to ESHAP chemotherpy does not show any adverse effect in autologous stem cell mobilization and collection. R-ESHAP regimen is effective as a combined mobilization and second-line regimen for patients with pretreated B-cell lymphoma.
Figure 1. Days to achieve optimal response Figure 1. Days to achieve optimal response
Reduced Rate of Infectious Complications Following Bloodless Autologous Peripheral Blood Stem Cell Transplants (APBSCT).
Authors: Ford Patricia A. , Matthews Barbara A. , Brown Nicole M. 
Published: October 2019

Abstract
While blood transfusions can be life saving, the associated risk of transfusing allogeneic blood is significant. The most common patient fears are transfusion-transmitted diseases such as HIV, Hepatitis B and C and West Nile Virus; however, the known risk of transmitting these diseases is quite small. More common complications are due to immunosuppression which can cause an increased risk of cancer recurrence in the oncologic patient and a significantly increased risk of infection. In trauma patients, it has been shown that the risk of infection increases with each additional unit of blood transfused. Currently, about 2.2 units of platelets and 3.3 units of red blood cells are administered following high-dose chemotherapy and an APBSCT. At the Center for Bloodless Medicine and Surgery at Pennsylvania Hospital, many procedures are now being completed without the use of blood products. We have previously reported the ability to perform bloodless APBSCT (Ballen, et al. J Clin Oncol2004;22:4087-4094). Knowing that blood transfusions can increase the risk of infection, we wanted to evaluate this transfusion-free population to determine if there was a correlation between infection rates and blood transfusions in the high risk transplant population. We performed a retrospective chart review of 46 patients with multiple myeloma (22), lymphoma (22) and breast cancer (2) who underwent a bloodless APBSCT in our center. Prior to transplantation, all patients recieved standard transplant doses of cyclophosphamide, carmustine and etoposide (BCV) or Melphalan. A PubMed search was performed and the closest data set in terms of patient demographics was a study by Pereira, et al. who report the rate of infectious complications in 75 patients with myeloma (30), lymphoma (30) and breast cancer (15) who were transfused liberally following high-dose chemotherapy and APBSCT (Pereira, et al. Eur J Haematol2006;76:102-108). In our bloodless patients, 37% of the patients had at least one infection, compared to Pereira and colleagues’ rate of 68% (see table). Our results are also reported in the average number of infections per patient. This comparison demonstrates a substantial reduction in the rate of infection in the bloodless population. While immunosuppression and the resulting increased infection rates have been correlated to blood transfusions in other patients populations, to the best of our knowledge this is the first report that suggests decreased infection rates in transfusion-free transplant patients. This data provides further evidence to support the practice of blood management strategies in order to reduce or eliminate blood transfusions.
Patients with at least one infection All infections per person Bacterial per person Viral per person Fungal per person Unknown per person Autologous Transplants (Pereira, et al.) 68% .64 .53 .01 .07 .03 Bloodless Autologous Transplants 37% .41 .39 0 0 .02