bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of NK Cell on Gvhd in H-2 Haploidentical Bone Marrow Transplantation in Mice
Authors: Zhang Mei , Wu Di , He Pengcheng , Li Jing , Xi Jieying , Xu Hui , Cai Ruibo , Liu Yalin 
Published: April 2020

Abstract
Allogeneic haemopoietic stem-cell transplantation (HSCT) is a definitive cure for many malignant blood diseases. Ideal donors for transplantation are those with completely matched human leukocyte antigen (HLA), kin-relative or no-kin-relative. However only about 25% to 30% people could find HLA matched related-donor and there is only 1/100,000 opportunity to find a matched HLA in unrelated group. Recent years HLA haploidentical transplantation play more and more important role in across the histocompatibility barrier and make about 90% patients possible to get transplantation. However GVHD is still main problem during the transplantation. Recent studies show that natural killer (NK) cells could specially attack recipient antigen-presenting cells (APCs), shown to be responsible for decreasing and improving GVHD. To explore the effect of NK cell on GVHD after H-2 haploidentical bone marrow transplantation(BMT) in mice, we purified NK cells by positive selection with CD49b (DX5) MicroBeads (Miltenyi Biotec product) from donor mice as ingredient in the conditioning regimens, and observed the influence of donor NK cells on GVHD and evaluated the potential role of donor NK cells in protecting against GVHD. Murine model of H-2 haploidentical BMT was established by using Balb/c(H-2d) mouse as recipient, and Balb/c (H-2d)×C57BL/6 (H-2b)(H-2d/b) mouse as donor. Lethally irradiated Balb/c(H-2d) mice were transplanted with Balb/c(H-2d)×C57BL/6(H-2b)(H-2d/b) bone marrow containing donor peripheral T cells and/or NK cells. GVHD and survival rate were studied by observing clinical manifestations and pathological changes. In the group with bone marrow plus T cells, GVHD was induced in 90% mice; but in the group plus with low concentration of NK cells, GVHD was induced in 20% mice; and in the group transplanted with high concentration of NK cells, GVHD was induced only in 10% mice. Compared with the group transplanted only with T cells, the incidences of GVHD in the latter two groups decreased obviously (P&lt;0.01) and the survival rate at 15, 30, 45 and 60 days increased obviously (P&lt;0.01). In mouse H-2 haploidentical BMT, alloreactive NK cells can reduce the incidence of GVHD and increase the survival rate after transplantation in mice.
Ex-Vivo UVA Treated Donor T-Cells for the Induction of Graft Versus Leukemia Effect in Murine Model and Clinical Application
Authors: Samuel Si mcha , Weiss Lola , Hazan Osnat , Resnick Igor B , Shapira Michael Y. , Gesundheit Benjamin , Dray Lilane , Or Reuven 
Published: April 2020

Abstract
Donor lymphocyte infusion (DLI) is a powerful immune-manipulation for the induction of Graft-vs-Leukemia (GVL) effect, but it is associated with high incidence of Graft-vs-host disease (GVHD). Furthermore, the use of DLI across MHC mismatched transplantation is almost infeasible. Extra corporal photochemotherapy for the treatment of GVHD involves extra corporal exposure of peripheral blood mononuclear cells to photoactivated 8-methoxypsorelen (8-MOP) followed by re-infusion of the treated cells. Based on the immunomodulatory effects of 8-MOP and UVA irradiation we investigated ex-vivo similar treatment of donor cells prior to cell therapy in post-transplant murine model. F1 leukemic (BCL1) recipients exposed to total body irradiation followed by bone marrow transplantation (BMT) (C57BL/6→F1). Donor splenocytes incubated with 8-MOP and 10 minuets exposure to UVA irradiation were administrated twice a week for the first 21 days post-BMT. Irradiated hosts inoculated with BCL1 and C57BL/6 cells were examined for the presence of donor cells using fluorescence-activated cell sorting analysis. At 4–6 weeks after BMT chimerism analysis revealed a ratio of 84–91% donor cells. Murine blood cells were tested for Minimal residual disease (MRD) by BCL1- specific PCR for detection of dormant BCL1 at 2 months after BMT. In comparison with the control group, DLI with ex vivo 8-MOP UVA treated splenocytes reduced GVHD and retained GVL effect. In vitro secretion of interferon gamma by treated cells was reduced only by 50%.
Clinical application of this method was performed in 4 high-risk patients after stem cell transplantation from haploidentical related donors:
GVHD T-Cell Dose Day post HSCT Disease UPN - 105/kg +175 Refractory HD+CMV disease #1935 - 104/kg 105/kg +70 +90 Metastatic testicular Ca. #2255 - 5×105/kg 106/kg +84 +127 Refractory neuroblastoma #2316 - 105/kg +130 Relapsed ALL #2323
The potential of Ex-Vivo 8-MOP UVA DLI treated cells should further be investigated for induction of GVL w/o GVHD, to improve chimerism and for anti viral therapy (CMV, EBV and PTLD - Post Transplant Lymphoproliferative Disorders)
Impact of Chemoselective Pressure on Integration Site Patterns of Lentivirally Transduced Human Hematopoietic Stem Cells
Authors: Grund Nadja , Maier Patrick , Appelt Uwe , Allgayer Heike , Wenz Frederik , Zeller W. Jens , Fruehauf Stefan , Laufs Stefanie 
Published: April 2020

Abstract
Hematologic side effects of cancer chemotherapy like myelosuppression are frequently dose-limiting. Lentiviral gene therapy with cytostatic drug resistance gene transfer to human hematopoietic stem cells (CD34+) is a promising approach to overcome this problem. In this context it is of interest if chemotherapy mediated selection has an impact on lentiviral integration site patterns of transduced hematopoietic stem cells (CD34+). Concerning this issue, human CD34+ cells transduced with a lentiviral self-inactivating (SIN) vector encoding MGMTP140K (the O6-BG resistant mutant of O6-methylguanine- DNA methyltransferase) were in vitro treated with the alkylating agent BCNU. For integration site analysis LM-PCR was performed and integration patterns of the treated and untreated CD34+ cells were analyzed and compared with an in silico set of 106 random integrations. We found different integration preferences of the lentiviral vector between either the treated (82 integrations) or the untreated (30 integrations) CD34+ cells and the in silico set: both groups showed
chromosomal preferences, a significant bias for integrations in genes (74,4% in the treated, respectively 70% in the untreated to 40% in the in silico group), especially by favouring introns, a random integration distribution regarding transcription start sites (TSS), and most importantly no significant differences concerning the number of integrations in or near cancer genes.
Concerning all integration characteristics we could not find significant differences when comparing the untreated with the treated group. In conclusion, the general distribution of lentiviral integrations in either untreated or treated human CD34+ cells showed no distinct differences between both groups but significant differences compared to the in silico integration set. These results suggest that chemoselection of cells lentivirally overexpressing a specific chemoresistence gene might not influence the integration pattern. Therefore chemotherapy pressure seems not to hamper the safety of lentiviral vectors in gene transfer studies.
RFUSIN2 - a Clinical Grade Lentiviral Vector Co-Expressing CD80/IL-2 Manufactured Under GMP for a Phase I Clinical Trial Study of Immune Gene Therapy for Poor Prognosis Acute Myeloid Leukaemia
Authors: Chan Lucas , Ingram Wendy , Hardwick Nicola , Darling David , Bhalla Joti , Kizilors Aytug , Kordasti Shahram Y , Mufti Ghulam J , Farzaneh Farzin 
Published: April 2020

Abstract
Patient derived primary AML blasts cells can be efficiently modified (40–100%) to coexpress CD80 and IL-2 following a single round of transduction using a self-inactivating lentiviral vector. This modification produces significant immune stimulation as measured by proliferation, cytokine release and NK and T-cell cytolytic activity against AML in both autologous and allogeneic settings in vitro. In mouse models of leukaemia, CD80/IL-2 modified leukaemic cells result in rejection of previously established leukaemia and the longer survival of the vaccinated animals. Following regulatory approval in the UK, we have initiated a Phase I clinical study using Lentivirus Transduced AML cells expressing CD80 and IL-2 for the potential enhancement of Graft versus Leukaemia effect in poor prognosis AML. The UK regulatory approved vector, RFUSIN2, is a self-inactivating lentivirus vector, which becomes immobile following vector integration. RFUSIN2 encodes CD80 and IL-2 as a fusion protein, which is endogenously cleaved to generate biologically active CD80 that is membrane anchored and IL-2 which is secreted. Here we describe our in-house manufacturing of RFUSIN2 under EU compliant GMP conditions, which resulted in the production of &gt;3x1010 concentrated infectious particles. Extensive safety characterisation of this vector has been carried out. The vector supernatant batch is free of viral contaminants including: Porcine and bovine viruses, other retroviruses, HepA/B/C, HIV-I/II, EBV, and CMV; it is also free of other contaminants including mycoplasma, yeast, fungus and bacteria. RFUSIN2 supernatant is absent of any replication competent lentivirus (RCL) or partial recombinants and is unable to mobilise or to achieve secondary transfer.We present a summary of the protocol for the generation of the autologous AML cell vaccine. The clinical protocol, encompassing the treatment schedule, cohorts, study end points and analytical assays are described.
Correlation Between Glucosylceramide Synthase Gene Polymorphism and Severity Score Index in Type 1 Gaucher Disease
Authors: Alfonso Pilar , Navarro Silvia , Medina Pilar , Irun Pilar , Giraldo Pilar , España Francisco , Pocovi Miguel 
Published: April 2020

Abstract
Background: Gaucher disease (GD), caused by a deficiency of the glucocerebrosidase (GC) enzyme, is characterized by the accumulation of glucosylceramide (GlcCer) within lysosomes, resulting in cellular dysfunction and damage. GlcCer is catalyzed by the glucosylceramide synthase (GCS), also known as UDP-glucose ceramide glucosyltransferase, (UGCG), EC 2.4.1.80, first enzyme in glycosphingolipids biosynthesis. Mutations in the glucocerebrosidase (GBA) gene are required to cause GD, but other factors play an important role.
Aims: GCS gene is a logical candidate to hypothesize that its variability could be involved in clinical severity.
Patients and methods: We have analyzed GCS variants (g.(−295)C&gt;T, g.(−222)ins10, g.148A&gt;G, g.166A&gt;T, g.25510C&gt;G, g.29312A&gt;G and g.34991A&gt;G) in a group of 80 [N370S]+[L444P] heterozygous and 23 N370S homozygous patients.
Results: were related with severity score index (SSI). g.(−295)C&gt;T and g.166A&gt;T SNPs were in complete linkage disequilibrium. In the N370S homozygous, carriers of g.(−222)ins10 have higher SSI than non carriers (6.6 vs 2.4, p&lt;0.004). Patient carriers of the A-allele for SNP g.148A&gt;G had higher SSI than the G-allele carriers (6.7 vs 1.5, p&lt;0.001, for [N370S]+[L444P] heterozygous and 4.3 vs 1.7, p&lt;0.001, for [N370S] homozygous). “In silico” studies and electrophoretic mobility shift assay (EMSA) indicate that 10bp insertion at the promoter region generates a new ETF binding site and the g.148a&gt;g variant at intron 1 changes the affinity for the transcription factor AP-2. GlcCer were elevated in patient carriers of one mutated allele of these two variants.
Conclusion: our results suggest that the genetic GCS variants could influence in the development and progression of GD severity.
Changes in the Atherogenic Profile in Type 1 Gaucher Disease Patients after Substrate Reduction Therapy
Authors: Giraldo Pilar , Puzo Jose , Alfonso Pilar , Irun Pilar , Pocovi Miguel 
Published: April 2020

Abstract
Gaucher disease (GD) is caused by a deficiency of the lysosomal enzyme acid β-glucosidase (GC) leading to accumulation of glucosylceramide within the macrophages of the reticuloendothelial systems. Plasma of GD patients contains low levels of total cholesterol, LDL-cholesterol and HDL-cholesterol. Enzyme replacement therapy (ERT) with imiglucerase and Substrate Reduction Therapy (SRT) with miglustat restores the haemoglobin levels, platelet counts and organomegalies. Previously we have demonstrated that ERT had significant effects on the concentration and metabolism of plasma lipoproteins. However, the effects of SRT on plasma lipid and other atherogenic profiles of GD patients have not been explored. We report the results of long term (36 months) SRT on plasma lipoprotein concentrations in 26 (11 men and 15 women) GD patients. Mean age of patients was 51 (SD ±20.7; range 22–74) years. Ten patients were therapy-naïve to SRT and 16 switched from previous enzyme replacement therapy (ERT). All patients received 100 mg of Miglustat t.i.d with recommendations of a low hydrocarbonate diet in the first weeks. Total cholesterol (TC), triglycerides (TG), low density lipoprotein cholesterol (LDL-c), high density lipoprotein cholesterol (HDL-C), Apolipoproteins (Apo AI, ApoB and Lp(a)), CRP, MPI1b, CCL18 concentrations and chitotriosidase activity were measured before (baseline) and after 12, 24 and 36 months of follow-up. Treatment resulted in a significant increases in HDL-c concentration in naïve patients during the first 24 months (p&lt;0.02) on therapy and it is maintain till 36 months. The same trend was observed in HDL-cholesterol in switch patient but with a less increase that in naïve patients. TC increase slightly in switch (p&lt;0.05) and naïve (p&lt;0.04) patients after 24 and 36 months of treatment respectively. No significant changes in LDL-c during treatment were observed in both switch and naïve patient. In naïve patients, TG, Lp(a) and CRP concentrations, as well as the atherogenic index TC/HDL-c decreased significantly in patients after 24 months therapy and no changes were observed in switch patients. Our results indicate that miglustat treatment have an apparent beneficial effects on plasma lipid, lipoprotein and CRP concentrations resulting in an apparently less atherogenic lipid profile in GD patients. However further studies will be required to determine the impact of miglustat treatment on the risk of coronary heart disease.
Langerhans Cell Histiocytosis Responding to 2-Cda and Imatinib Mesylate (IM)
Authors: Sanchez-Guerrero Sergio , Agreda Gladys , Oviedo Edgar , Lome Carmen 
Published: April 2020

Abstract
BACKGROUND: Langerhans cell histiocytosis (LCH) is a rare condition in which granulomas form in tissues through the accumulation of abnormal histiocytes (Langerhans cells), granulocytes and lymphocytes. Prognosis in patients with disseminated disease has been associated with a chronic course, and a high morbidity and mortality rate. In terms of treatment, etoposide and vinblastine are considered to be the most effective agents in monochemotherapy. Here we report the case of an adult patient with LCH who has improved considerably after treatment with 2-CDA followed by IM.
CLINICAL CASE: 37 year-old Hispanic female with history of burning epigastric pain, nausea and vomiting starting in 1998. In 1999 diarrhea and steatorrhea appeared. Whipple disease was diagnosed in another hospital but treatment was unsuccessful. She came to our hospital in 2003, complaining of the aforementioned symptoms plus severe malnutrition. Upper GI endoscopy and colonoscopy were performed and the biopsies showed infiltration with LCH. Bone marrow (BM) biopsy showed LCH infiltration too. CD117 (KIT) expression was investigated both in gastric and BM biopsies, turning out to be highly positive. Therapies and outcomes are shown in table 1.
DATE DRUGS TREATMENT DURATION WEIGHT (Kg) ALBUMIN (g/dL) GI ENDOSCOPY BIOPSY Dec/03 VBL/VP-16/PDN 5 cycles 33.5 0.99 Polyps and pseudopolyps Infiltrated by LCH. Sep/05 MTX/PDN 18 mos. 39.5 3.18 Polyps and pseudopolyps Infiltrated. Jul/07 2-CDA 9 cycles 55.3 4.0 Polyps Infiltrated. May/08 IM 6 mos. 57 4.0 Nodular pattern. No polyps Decreased infiltration by LCH
CONCLUSIONS: This case illustrates that multisystemic LCH can be successfully treated with, at least two more drug choices: 2-CDA and, in those patients with expression of KIT and/or PDGF, IM.
Risk Index Score for Bacteremia in Febrile Neutropenic Episodes in Children with Malignancies
Authors: Spasova Maria I , Grudeva Janet G. , Kostyanev Stefan S. , Genev Evgeni D. , Stoyanova Angelina A. , Kirina Veselina I. , Moumdjiev Ivan N. 
Published: April 2020

Abstract
BACKGROUND: Nowadays febrile neutropenia is regarded as heterogeneous syndrome and adequate risk stratification of patients as a basis for tailoring empiric antibiotic therapy is attempted. We conducted this prospective study to determine risk factors for bacteremia in febrile neutropenic children that could be assessed in the first days from the onset of fever and based on logistic regression analysis to construct a risk index score for prediction of bacteremia.
MATERIAL AND METHODS: We studied prospectively 199 consecutive episodes of febrile neutropenia for a 4-years period (2000 – 2004), occurring in 80 children with malignancies, treated by conventional chemotherapy. A standardized computer database with a set of variables for each febrile neutropenic episode was used. C-reactive protein was measured at the first fever and depending on its duration - on the 3-rd and 5-th day from the beginning of antibiotic therapy by immunoturbidimetric method. At the onset of fever and before initiation of antibiotic therapy blood cultures were drawn and injected directly into a culture bottle BACTEC Peds plus.
RESULTS: By multivariate logistic regression analysis we determined 5 variables as independent risk factors for bacteremia: the underlying malignant disease (leukemia, NHL-gr.IV), chills, perianal cellulitis, presence of central venous catheter and degree of CRP rise ≥34.5 mg/L between the onset of fever and the 3rd day of empiric antibiotic therapy. This logistic regression model has sensitivity of 93%, specificity of 25%, negative predictive value of 89% and positive predictive value of 36% for the presence of bacteremia (Chi-square: 44, −2 log likelihood:200, Cox & Snell R square: 0.2).
CONCLUSIONS: The present prospective study is characterized by prevalence of hematologic malignancies and relatively high frequency of bacteremia. We identified a low-risk group of 19.1%, comparable to the reported by other groups. Based on the statistical significance of serial measurement of C-reactive protein, which allows definite risk stratification of febrile neutropenic episodes on the 3rd day from the onset of fever, we would recommend sequential empiric antibiotic approach with switch to oral or even outpatient treatment in the low-risk group on the 3rd day.
Study on the Ratio and Function of Macrophages in the Patients with BMMNCCoombs Test(+) Hematocytopenia
Authors: Fu Rong , Wang Yi hao , Shao Zonghong , Chen Jin , Li Lijuan , Liu Hui , Wang Huaquan , Xing Limin , Liu Hong 
Published: April 2020

Abstract
Objective To explore the quantity and function of macrophages in the patients with BMMNC-Coombs Test(+)hematocytopenia.
Methods Sixty-one patients with BMMNCcoombs test IgG(+)hemocytopenia were enrolled in this study. The ratio of macrophages (CD68+/BMMNC), the activation status(CD68+CD69+/CD68+) were detected with Facs. The phagocytic index of macrophage was detected too.
Results There was significant difference of the macrophage ratio and phagocytic index between the patients with BMMNC-IgG(+) and those without BMMNC-IgG(P&lt;0.05);The ratio of macrophage, percentage of activated macrophages and function of macrophages in BM were in kinds of IgG dependent manner. The median value of RBC, Hb and WBC in the patients with CD34 IgG(+) were lower than those in the patients with CD34 IgG(−),but no statistical difference between them was found(P&gt;0.05).The level of WBC in the patients with CD15IgG(+) was significant lower than that of patients with CD15IgG(−)(P&lt;0.05).The levels of RBC, Hb and Reticulocyte of patients with GlycoAIgG(+) was significantly lower than those of the patients with GlycoAIgG(−)(P&lt;0.05).There were significant differences of the levels of RBC, Hb and reticulocyte between the patients with BMMNC-IgG and those without BMMNC-IgG(P&lt;0.05).There were also significant differences of the ratio of macrophage, the percentage of activated macrophages and the function of macrophages between the patients with IgG(+)and those without IgG(P&lt;0.05).
Conclusion The ratio of macrophage, percentage of activated macrophages and function of macrophages were higher in the patients with BMMNC-Coombs test-IgG(+) hematocytopenia. The pathogenic mechanism of this kind of disease might be associated with the activated macrophages phagocyting and destroying BM hematopoietic cells coated with autologous IgG.
Economic Burden of High Risk Acute Lymphoblastic Leukemia (ALL) in Adults and Children
Authors: Newton Nick , McCann Jennifer , Welner Sharon A , Ougari Khalid El 
Published: April 2020

Abstract
Background: Acute lymphoblastic leukemia is a hematological malignancy, characterized by overproduction of immature white blood cells in the bone marrow. Highrisk forms of ALL are typically characterized by poor treatment response, short remission duration, poor survival with conventional chemotherapy and incur high disease-related costs. The most common form of high-risk acute lymphoblastic leukemia in adults is Philadelphia chromosome positive (Ph+) ALL.
Objectives: This study investigated the treatment costs of high-risk ALL from a Canadian perspective.
Methods: Costs for the induction phase of ALL treatment (inpatient costs and length of stay in hospital) were obtained from the Ontario Case Costing Initiative (OCCI) acute inpatient databases. Drug costs for outpatient treatment were obtained from the Ontario Drug Benefit Program and the medical literature. Since no published Canadian guidelines were available treatment pathways and costs for consolidation and maintenance phases of chemotherapy, broken down by age and risk level of disease, were based on the medical literature and expert opinion.
Results: The average total cost of inpatient ALL treatement (induction phase) was $31,694 for both adults and children. The cost for consolidation therapy was $29,244 and $12,753 in adults and children, respectively. The maintenance therapy cost was $7,288 and $3,452 in adults and children, respectively. The high-risk therapy following relapse was $17,100 and $12,000 in adults and children, respectively. The total treatment cost for ALL is estimated at $85,326 in adults and $59,899 in children.
Conclusions: In canada, high-risk ALL exacts a substantial economic burden as a result of rapid disease progression and decreased survival duration. Imatinib (Gleevec®) in Ph+ALL has produced superior results in terms of clinical response, disease-free survival, and overall survival with a good safety and tolerability profile. More comprehensive research is recommended to investigate the economic and humanistic benefits of imatinib as compared to the current therapies in the treatment of Ph+ ALL.