bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase II Study of CC-5013 (Revlimid) and Rituximab in Waldenström’s Macroglobulinemia: Preliminary Safety and Efficacy Results.
Authors: Treon Steven P. , Patterson Christopher J. , Hunter Zachary R. , Branagan Andrew R. 
Published: October 2019

Abstract
INTRODUCTION: In previous studies, we observed that CC-5013 enhanced rituximab mediated ADCC killing of lymphoplasmacytic cells (BJH2005; 128:192). As such, we conducted a phase II study of CC-5013 with rituximab in WM patients naïve to either agent. Intended therapy was as follows: Weeks 1-48 CC-5013 (25 mg po qD for 3 weeks, then 1 week off); Weeks 2–5, 13–16 Rituximab (375 mg/m2/week).
METHODS: Twelve patients were enrolled, 10 of whom were previously untreated with a median age of 65 (range 53–76 yrs), along with baseline BM involvement of 50 (range 5–90%), serum IgM of 4175 (range 1180–7130 mg/dL), hematocrit of 31.9% (range 24–36.6%), and B2M of 3.5 (range 1.8–6.0 mg/L).
RESULTS: Four patients were taken off study due to intolerance to therapy (3 to CC-5013, 1 to CC-5013 and Rituximab) and were non-evaluable. Unexpected acute decreases in hematocrit occurred in 10/12 (85%) patients within the first 2 weeks of therapy, resulting in hospitalization for 4 patients. The median decrease in hematocrit, which coincided with CC-5013 administration was 4.2% (range 1.7-7.5%), and was not associated with blood loss, hemolysis, or generalized myelosuppression. Other grade 3/4 toxicities attributed to CC-5013 therapy were expected and included neutropenia (n=4); tinnitus (n=2); thrombocytopenia (1); myositis (n=1); and rash (n=1). Five patients had a spike in serum IgM levels following rituximab, accompanied with epistaxis (n=1), headaches and blurry vision (n=2) requiring plasmapheresis. Toxicities led to the discontinuation and dose reduction of CC-5013 for 8 and 4 patients, respectively, and discontinuation of rituximab in 1 patient due to recurring allergic reactions. Discontinuation of CC-5013 within the first 28 days of therapy occurred in 6 out of 8 patients. Responses among the 8 evaluable patients: PR (n=3); MR (n=4); SD (n=1); ORR 88% among evaluable patients. In two patients with bulky adenopathy and splenomegaly, a significant reduction in the node/spleen size was noted by week 12. Both of these pts have subsequently achieved a PR. With a median follow-up of 7+ months, no patient who received at least 2 months of CC-5013 have progressed.
CONCLUSION: The response data achieved with CC-5013 and rituximab in this study is encouraging, though the dose and schedule of CC-5013 administration, and mechanism for the unexpected acute drops in hematocrit observed in WM patients warrants further investigation. Such studies are in progress in our laboratory.
IL-7 Effects on Thymocyte Progenitors.
Authors: Kassar Nahed El , Choudhury Baishakhi , Flomerfelt Francis , Lucas Philip J. , Kapoor Veena , Telford William , Bare Catherine V. , Mahmud Semhar , Bhandoola Avinash , Gress Ronald E. 
Published: October 2019

Abstract
IL-7 is a non-redundant cytokine in T cell development. We studied the role of IL-7 in early T-cell development using a model of transgenic (Tg) mice with the murine IL-7 gene under control of the lck proximal promoter. At high IL-7 over-expression (x39 fold increase at day 1 in total thymic tissue), we observed a disruption of TCRαβ development along with increased B cell development in the thymus (7- to 13-fold increase) (El Kassar, Blood, 2004). In order to further explore abnormal T and B cell thymic development in these mice, we first confirmed that they both arise in parallel and were non-cell autonomous, by in vivo injection of neutralizing anti-IL-7 MAb and mixed bone marrow chimera experiments. Using a six color flow cytometry analysis, we found a dramatic decrease of the early thymocyte progenitors (ETPs, lin−CD44+CD25−c-kithiIL-7R−/lo) in the adult Tg mice (x4.7 fold decrease). Lin−CD44+CD25−c-kit+ thymocytes were sorted and cultured on OP9 and OP9 delta-like1 (OP9-DL1) stromal cells (kindly provided by Pr Zuniga Pflucker). At day 14, we observed an important decrease of T cell development (54% vs. 1% of DP cells) and an increase of NK cells (x5 fold increase) in the Tg-derived DN1 cell culture. DN2 (Lin−CD44+CD25−c-kit+) Tg thymocytes showed the same, but less dramatic abnormalities. While DN1 progenitors developed effectively into B220+CD19+ cells on OP9 stromal cells, no B cell development was observed on OP-DL stromal cells from DN1-Tg derived progenitors or by addition of increasingly high doses of IL-7 (x10, x40, x160) to normal B6-derived DN1 progenitors. Instead, a block of T-cell development was observed with increased IL-7. We hypothesized a down regulation of Notch signaling by IL-7 over-expression and analyzed by FACS Notch expression in the DN thymocytes. By staining the intra-cellular part of Notch cleaved after Notch 1/Notch ligand activation, Tg-derived DN2 cells showed decreased Notch signaling. More importantly, HES expression was decreased in the DN2, DN3 and DN4 fractions by semi-quantitative PCR. Sorted Pro/Pre B cells from Tg thymi showed TCR Dβ1-Jβ1 rearrangement indicating their T specific origin, in opposition to Pro/Pre B cells sorted from the bone marrow of the same mice. We suggest that more than one immature progenitor seeds the thymus from the bone marrow. While ETPs had T and NK proliferative capacity, another thymic progenitor with B potential may be responsible for thymic B cell development in normal and IL-7 Tg mice. Finally, IL-7 over-expression may induce a decreased Notch signaling in thymic progenitors, inducing a switch of T vs. B lineage development.
Phase I/II, Nine Month Study Results of Enzyme Replacement Therapy with Gene Activated Human Glucocerebrosidase (GA-GCB) in Patients with Type I Gaucher Disease.
Authors: Zimran Ari , Fratazzi Candida , Mensah Robert , Elstein Deborah 
Published: October 2019

Abstract
AIMS: Evaluation of safety and clinical activity of Gene-Activated ® human glucocerebrosidase (GA-GCB) as a new intravenous enzyme replacement therapy (ERT) for patients with type I Gaucher disease participating in a 9 month, open-label Phase I/II clinical study.
BACKGROUND: GA-GCB is human glucocerebrosidase (GCB) produced in a well-characterized, continuous human cell line using proprietary gene activation technology. GA-GCB has an identical amino acid sequence to the naturally occurring human enzyme and contains terminal mannose residues that target the enzyme to macrophages, the primary target cells in Gaucher disease. Nine month study results of GA-GCB treatment will be presented.
METHODS: Twelve adult patients (7 females /5 males) with type I Gaucher disease with clinically significant anemia, thrombocytopenia, hepatomegaly and/or splenomegaly, were enrolled in a 9 month Phase I/II clinical trial. Patients received GA-GCB every other week for a total of 40 weeks (20 infusions). A staggered dose escalation of GA-GCB was performed in the first 3 patients: these patients received 15 U/kg at the first infusion, 30 U/kg at the second infusion, and then 60 U/kg IV every other week for a total of 20 IV infusions. The remaining 9 patients received 60 U/kg beginning with their first dose. Anti-GA-GCB antibodies were tested in all patients during the 9 months of treatment. All patients were routinely evaluated for hemoglobin, platelets, liver and spleen volumes, infusion reactions and adverse events. In addition, serum samples were analyzed for disease biomarkers: chitotriosidase and CCL18.
RESULTS: Eleven of the 12 patients who were enrolled in the trial have been treated for nine months. One patient withdrew consent after three injections for reasons not related to treatment. Dose escalation from 15 U/kg to 60 U/kg was well tolerated in the first three patients. The remaining patients received 60 U/kg every other week throughout the course of the study. Anti-GA-GCB antibody test results were negative for all patients. Mean hemoglobin and platelet values, below the normal range at baseline, improved after 9 months of GA-GCB treatment to levels consistent with the therapeutic goals for ERT in Gaucher disease (Seminars in Hematology 2004). Analysis of the liver and spleen volumes decreased following 9 months of treatment. In addition, serum chitotriosidase and CCL18 levels decreased over the 9 months of GA-GCB treatment.
CONCLUSION: ERT with GA-GCB was well tolerated and demonstrated clinical activity in well-established clinical markers in patients with type 1 Gaucher disease when administered IV every other week at 60 U/kg over 9 months.
Results suggest that GA-GCB holds promise as a new therapeutic option for ERT in Gaucher disease.
Helicobater Pylori Infection and Clinical Response to Eradication Therapy in Patients with Immune Thrombocytopenic Purpura (ITP).
Authors: Fabris Fabrizio , Allemand Emanuele , Scandellari Raffaella , Vettore Silvia , Randi Maria Luigia , Luzzatto Guido 
Published: October 2019

Abstract
We performed a prospective study in order to investigate the controversial association between HP infection and immune thrombocytopenic purpura (ITP). We studied the prevalence of HP infection and the efficacy of its eradication in 57 consecutive adult patients admitted to our ward for ITP. Thirty-three patients were females and 24 were males (median age 58 years; mean platelet count 68±42 x109/L). HP infection was demonstrated by the stool antigen test in 28 patients (49.1%). Such prevalence increased with the age. No statistical difference by gender, platelet count, disease duration, presence of specific platelet autoantibodies (MACE) and therapy regimens was observed between HP-positive and negative patients. On the other HP positive patients were significantly older than HP negative ones (62 versus 54 years, p<0,03) and presented more gastroenteric symptoms (32% versus 7%, p<0,05). Thirteen patients with chronic ITP were given HP eradication since their platelet count was above 20x109/L and they do not need for starting or modifying therapy of ITP for at least 6 months. HP eradication was performed by standard triple therapy based on omeprazole plus clarithromycin and amoxicillin for 1 week. The bacteria was eradicated in all cases. Twelve HP negative ITP patients were followed as controls. The mean platelet count was significantly increased in ITP patients after 3 and 6 months from HP eradication. However, considering as end-point, a platelet count increase of more than 50% over the basal value, the platelet response to the HP eradication appears to be better in eradicated patients only after 3 months of follow-up (83% of positive response versus 57%). We also studied in HP-positive patients the presence of antibodies against CagA citotoxic protein by ELISA method. Seventeen of the patients have anti-CagA antibodies (56%) but the positivity did not correlate with platelet response to the eradication. In conclusion the prevalence of HP infection in our patients with ITP was comparable to that observed in the adult population from the same geographic area. Infection is not associated with clinical or laboratory distinctive features with the exception of tan older age and gastroenteric symptoms. The eradication of the HP infection seems to improve mean platelet count in ITP patients but larger prospective studies are required to validate this approach.
Platelet response to the HP eradication in HP positive ITP patients and in HP negative controls Platelets (x 109/L, mean ± SD) basal time 1 month 3 months 6 months 12 months * p<0.05 vs basal platelet count ITP Patients 13 HP+ eradicated 74±43 141±142 129±73* 104±54* 160±117 12 HP- controls (not eradicated) 62±35 76±33 73±40 78±51 76±48
FcRγ-Dependent Facilitating Cells Are Direct Inducers of Regulatory T Cells.
Authors: Taylor Kendra N. , Patil Vivek R. Shinde , Chittenden Meredith , Colson Yolonda L. 
Published: October 2019

Abstract
Facilitating cells (FC) are CD8+/αβγδTCR− bone marrow-derived cells that promote allogeneic stem cell (SC) engraftment without graft vs. host disease (GVHD) and induce donor-specific transplantation tolerance. However, the mechanism of FC-mediated allogeneic SC engraftment is not known. We have previously demonstrated that allogeneic SC engraftment promoted by FC result in no clinical evidence of GVHD and is associated with increased number of CD4+25+ regulatory T cells post transplant compared to recipients of bone marrow T cells that develop severe GVHD. This is consistent with the hypothesis that FC facilitate allogeneic SC engraftment and induce tolerance through the induction of a regulatory T cell network. Here we report that CpG activation of toll-like receptor 9 (TLR9) on FC induce CD4+25− naïve T cell differentiation into CD4+25+ regulatory T cells. CpG stimulated and unstimulated CD8+αβγδTCR− FC isolated from bone marrow of C57/BL6 mice by flow cytometric cell sorting FC were co-cultured with splenic CD4+25− T cells for 5 days. CpG stimulated FC co-culture gave rise to CD4+25+ T cells as determined by mRNA expression of the CD4+25+ regulatory T cell marker, FoxP3. In contrast, unstimulated FC in co-culture did not induce regulatory T cells. Because FcRγ is the dominant ITAM receptor (immunoreceptor tyrosine-based activating motif), on FC and given that in vivo studies have demonstrated a requirement for FcRγ expression on FC, we hypothesized that FcRγ gene expression is increased within activated FC. FcRγ gene expression in CpG stimulated and unstimulated FC were compared by real-time PCR analysis. CpG-mediated TLR signaling within FC result in increased gene expression of FcRγ. Taken together, these studies demonstrate that CpG stimulated FC induce the generation of CD4+25+ regulatory T cells in vitro and CpG activation results in increased gene expression of FcRγ, suggesting a requirement for FcRγ signaling in FC-mediated induction of regulatory T cells. These findings provide the first mechanistic evidence that FC are direct inducers of regulatory T cells. Further characterization of cooperative TLR and FcRγ signaling pathways in FC will be critical to defining the mechanism of FC-mediated SC engraftment and the identification of potential therapeutic targets for the clinical induction of tolerance in the future.
Establishment and Characterization of a Human Acute Myelocytic Leukemic Cell Line, SH-2, Carrying t(16;17)(q24;q12).
Authors: Qiu Hui Y. , Xue Yong Q. , Pan Jin L. , Wu Ya F. , Zhang Jun , Wang Yong , Shen Juan , Dai Ai P. 
Published: October 2019

Abstract
We present a novel human myeloid leukemic cell line, designated as SH-2 which was established from the bone marrow of a patient with acute myelocytic leukemia (AML-M2a) carrying t(16;17)(q24;q12) translocation. The cell line has proliferated continuously in vitro for more than 12 months. Its morphology showed typical features of acute myelocytic leukemia (AML). The cell line’s immunoprofile was accordant with AML (positivity for CD13, CD33, CD38, CD117, CD16, CD56 and MPO). Karyotypic analysis revealed the translocation t(16;17)(q24;q12), monosomy 17 and trisomy 19. The apoptosis related genes such as bcl-2, Fas and GST-πtranscription were detected by RT-PCR. Meanwhile, MDR1, MRP and LRP transcription were not detected by RT-PCR. The deletion of p53 gene and the translocation between chromosomes 16 and 17 were confirmed by FISH method. The SH-2 cells grew colonies in in vitro methylcellulose cultures. Tumor masses were found in 1/2 mice injected by the tail vein with the SH-2 cell line after two months. Infection of the EBV and the mycoplasma were also excluded. Cell line authentication by STR showed that the primary leukemia cell of the patient and the SH-2 cell line originated from same individual. SH-2 cells were proliferated by the addition of cytokines such as IL-3, GM-CSF and SCF. two point mutations in exon 5 of the p53 gene were detected in the SH-2 cells by PCR analysis and direct sequencing showing the conversion of T to G in both codon 349 and 417. The establishment of an myelocytic leukemia cell line with t(16;17)(q24;q12) could be valuable for the study of leukemogenesis and for the research of cloning the new gene involved in the t(16;17)(q24;q12) translocation.
Relative Effectiveness of Phenylhydrazine Treatment and Hemorrhage in the Production of an Erythropoietic Factor
Authors: JACOBSEN ELLY M. , DAVIS A. K. , ALPEN EDWARD L. 
Published: October 2019

Abstract
Active plasma extract has been prepared from rabbits made anemic by phenylhydrazine treatment, but in every case where rabbits were made equally anemic by bleeding the only peripheral evidence of erythropoietic activity found after injection of plasma filtrate was the inducement of a moderate reticulocytosis in a heterologous recipient.
In rabbits bled on successive days until their hematocrits were equal to paired animals made anemic by phenylhydrazine injection, there is, nevertheless, a lower oxygen carrying capacity in the phenylhydrazine injected animals. The latter have methemoglobin concenstrations amounting to approximately 24 per cent of the total blood pigment while in the bled rabbits the methemoglobin level is practically zero.
Plasma extracts from phenylhydrazine treated rabbits with apparently normal or very slightly damaged livers produce factor comparable in potency to that obtained from bled animals.
The most highly active preparations are obtained in phenylhydrazine treated rabbits which have severely damaged livers.
The proposed hypothesis is that the factor is produced in quantity only when the effective hematocrit is below 12 to 15 per cent and when the liver is not capable of rapid active destruction of the factor or is not producing an otherwise normally occurring inhibitor.
The factor obtained from phenylhydrazine treated rabbits with liver damage is markedly active as shown by significant increase in blood volume and red cell mass, an elevated red blood cell count and hematocrit, and an intense reticulocytosis.
Anti-A Agglutinins in Pooled Plasma as a Cause of Hemolytic Anemia
Authors: RUTZKY JULIUS , COHEN FLOSSIE , ZUELZER WOLF W. 
Published: October 2019

Abstract
Five sets of observations are presented showing the development of hemolytic anemia in group A patients as the result of prolonged administration of relatively large amounts of pooled plasma. During the hemolytic episodes, spherocytosis, increase in osmotic fragility, rising bilirubin levels and sometimes clinical jaundice and splenomegaly were observed. Antibody attached to the recipients’ erythrocytes was demonstrated by means of the direct Coombs test, and in several instances free antibody of anti-A specificity was found in the recipient’s plasma during the hemolytic episode.
Random testing of commercial pooled plasma revealed a number of instances of astonishingly high anti-A titers, indicating that neither dilution in the pool nor neutralization by natural A substance in the component A plasmas can be relied upon.
The pools implicated in the production of hemolytic reactions had anti-A1 titers of 1:64 in saline or higher, and with the usual technics showed no clear-cut "immune" characteristics except in one instance. The administration of substantial amounts of plasma pools of low titer (1:16) was not followed by adverse reactions in several instances. On the other hand, the administration of originally high titered plasmas, neutralized in vitro to a saline titer of 1:16 resulted in blood destruction, indicating that under conditions of prolonged massive administration, specific soluble substance, though effective in vitro, is inadequate in vivo. Whether the adverse effects of the moderately high and high titered plasma pools were the result of purely quantitative factors connected with the introduction of large amounts of natural anti-A agglutinins or whether special immune isoantibodies not detected by the methods used were responsible could not be determined by the data at hand.
Prolonged administration of untitered pooled plasma to recipients of blood groups A and probably B is potentially dangerous.
Studies on the Specificity of Autoantibodies in Acquired Hemolytic Anemia
Authors: CROWLEY LEONARD V. , BOURONCLE BERTHA A. 
Published: October 2019

Abstract
A significant proportion of patients with autoimmune hemolytic anemia form autoantibodies of blood group specificity, rather than nonspecific autoantibodies.
Ashby survival studies suggest that in such cases properly selected blood, lacking the antigens against which autoantibody has been formed, can be transfused successfully.
These concepts are important not only for a better understanding of the nature of autoantibodies, but also can be applied to the practical management of patients with autoimmune hemolytic anemia.
Dose Attenuation of R-CHOP for the Treatment of Elderly Patients with Diffuse Large B Cell Lymphoma.
Authors: Choi Young Jin , Lee Kyung Woo , Shin Ho-Jin , Chung Jooseop , Cho Goon-Jae 
Published: October 2019

Abstract
Backgrounds: More than half of the patients with newly diagnosed aggressive lymphomas are older than 60 years. The addition of rituximab to the conventional CHOP regimen, administered every 21 days, has conclusively demonstrated to lead to a significant improvement of the outcome in elderly patients with DLBCL and surivival benefit. The aim of this study was to evaluate the efficacy and toxicity of dose attenuated CHOP with rituximab 3 weekly in untreated elderly DLBCL.
Methods: CHOP regimen consisted of cyclophosphamide(600mg/m2), doxorubicin(30mg/m2), vincristine (1mg/m2) on day 1, and prednisolone (20mg bid) given on day 1 to 5 every 3 weeks. Rituximab (375mg/m2) was administered the same day as CHOP.
Results: This study included 37 patients with DLBCL with a median age of 70 years (range:64–81). Seventy six percent had an international prognostic index score>1, 35% had stage IV disease. Toxicity was calculated over 192 cycles administered. Grade 4 neutropenia developed in 2.6% of cycles and no grade 4 non-hematologic toxicity didn’t developed except asthenia (1 person). The overall response rate was 83.3% (complete response rate: 72.2%). 2 year overall and event free survival rates were 79.8% and 67%, respectively.
Conclusions: Dose attenuated R-CHOP is effective and tolerable for elderly patients with DLBCL.
No Significant Expression of Wt1 Gene in Multiple Myeloma Patients at Diagnosis: Is Wt1 Gene Expression Useful Marker for Minimal Residual Disease in Multiple Myeloma?.
Authors: Ozkul Yusuf , Caglayan Ahmet O. , Kocyigit Ismail , Saatci Cetin , Akalin Hilal , Demir Muzaffer , Altuntas Fevzi , Cetin Mustafa , Eser Bulent , Kaynar Leylagul 
Published: October 2019

Abstract
Monitoring of multiple myeloma patients during and after treatment for the presence of remaining myeloma cells (minimal residual disease, MRD) has been shown to give major insight into the effectiveness of treatment. However, so far applicabile genetic markers amenable to sensitive detection by PCR for MRD in myeloma patients. Previouse studies showed that Wilms tumor gene (WT1) expression level, measured by quantitative reverse transcriptase polymerase chain reaction (RT-PCR), was useful as an indicator of minimal residual disease in leukemia and myelodysplastic syndrome. In this study was to measure, by real-time polymerase chain reaction, levels of WT1 expression, in order to find a possible association between this gene and the minimall residual disease. We investigated peripheral blood WT1 expression level in 41 newly diagnosed multiple myeloma cases using quantitative reverse transcriptase polymerase chain reaction. All patients carried normal WT1-mRNA levels. WT1 expression analyse may be not useful genetic marker for monitoring MRD in routine clinical use of multiple myeloma patients.