bluuebunny/crossref_metadata_2025_split huggingface dataset:
DNA Immunization Against Melanoma Antigens Enhances Tumor Immunity in Mouse Models of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT).
Authors: Diab Adi , Perales Miguel-Angel , Cohen Adam , Hubbard Vanessa M. , Eng Jeff , Huggins Deonka , Engelhorn Manuel , Guevarra Jose A. , Alpdogan Onder , Wolchok Jedd D. , Kochman Adam , Houghton Alan N. , van den Brink Marcel 
Published: April 2020

Abstract
Allogeneic HSCT is an important therapy with curative potential for a variety of malignant diseases, including leukemias, lymphomas and some solid tumors. Despite significant progress in reducing treatment-related mortality, malignant relapse remains a major problem. We are developing DNA vaccines that encode gene products closely related to self-antigens, including xenogeneic DNA and mutated DNA, and have initiated clinical trials of DNA vaccines in patients with advanced melanoma or prostate cancer. Using the B16 mouse melanoma model, we have shown that immunization with human TRP-2 DNA (xenogeneic melanoma differentiation antigen - MDA) or Opt-Tyrp1 DNA (a mutated MDA related to TRP-2, which we have optimized for CD8 epitopes), can induce tumor protection, including against established tumors. We hypothesized that immunization of allogeneic HSCT recipients (or their donors) against specific tumor antigens could decrease the risk of relapse without enhancing graft-versus-host disease (GVHD). In an MHC-matched minor antigen-mismatched mouse HSCT model (LP into B6), we found that: (1) by day 28 after transplant, recipients of an allogeneic T-cell depleted (TCD)-HSCT have considerable numbers of splenic T cells, including de novo generated donor T cells, which suggests that vaccination aimed at T cells might be feasible; (2) post-HSCT DNA immunization against a single tumor antigen can provide protection from a tumor challenge that is comparable to that observed with a whole cell vaccine (B16-GM-CSF) and significantly greater than HSCT alone; (3) DNA immunization post-HSCT can induce tumor-specific CD8+ T cells of donor origin (detected by ELISPOT or intracellular cytokine flow cytometry assay); (4) the combination of donor leukocyte infusion (DLI) and post-HSCT DNA immunization further enhances tumor-free survival (Figure); (5) there is no evidence of GVHD in multiple experiments using a clinical GVHD score to monitor recipients; and (6) the effects of post-HSCT DNA immunization on both tumor-free survival and CD8+ T cell responses have been validated for two different DNA vaccine strategies (hTRP-2 + GM-CSF DNA, or Opt-Tyrp1 DNA). These results demonstrate that DNA immunization after allogeneic TCD-HSCT can induce potent anti-tumor effects without the induction of GVHD. This and similar investigations provide a strong rationale for the development of novel therapeutic strategies that combine allogeneic HSCT, post-transplant tumor vaccination and adoptive cell therapy in human clinical trials.
Figure Figure
DNA Immunization Against Melanoma Antigens Enhances Tumor Immunity in Mice Following Sub-Lethal Irradiation and Immune Reconstitution.
Authors: Diab Adi , Hubbard Vanessa M. , Cohen Adam , Huggins Deonka , Kochman Adam , Guevarra Jose A. , Engelhorn Manuel , Wolchok Jedd D. , van den Brink Marcel , Houghton Alan N. , Perales Miguel-Angel 
Published: April 2020

Abstract
The development of successful cancer vaccines is contingent on the ability to induce effective anti-tumor immunity against self-antigens that do not typically elicit immunity. We are working on strategies to overcome immunologic tolerance/ignorance to cancer through the use of gene products closely related to self-antigens, including xenogeneic DNA and mutated DNA, and have initiated clinical trials of DNA vaccines in patients with advanced melanoma or prostate cancer. Recent studies have demonstrated that homeostasis-driven T-cell proliferation in the reconstituted lymphodepleted host could enhance the efficacy of whole-cell tumor vaccines. We hypothesized that immunization of sub-lethally irradiated and immune reconstituted mice against specific tumor antigens could increase anti-tumor immunity. B6 mice were irradiated with 600 cGy and immediately reconstituted with 30 x 106 syngeneic splenocytes. Weekly DNA immunization using either human tyrosinase-related protein (TRP)-2 DNA (xenogeneic melanoma differentiation antigen (MDA) or Opt-Tyrp1 DNA (a mutated MDA, which has been optimized for CD8 epitopes), was begun on day 1. We have found that: (1) by day 14 after irradiation and reconstitution, recipients have considerable numbers of splenic T cells, including de novo generated donor T cells, which suggests that vaccination aimed at T cells might be feasible; (2) DNA immunization against a single tumor antigen can provide protection from a tumor challenge that is significantly greater than that observed in immunized non-irradiated hosts (Figure); (3) DNA immunization induces higher levels of tumor-specific CD8+ T cells in the irradiated and reconstituted recipients (detected by intracellular cytokine flow cytometry assay); and (4) the effects of DNA immunization after lymphodepletion with immune reconstitution on both tumor-free survival and CD8+ T cell responses have been validated for two different DNA vaccine strategies (TRP-2 DNA and Opt-Tyrp1 DNA). These results demonstrate that DNA immunization following sub-lethal irradiation and immune reconstitution can induce potent anti-tumor effects. Furthermore, they provide a strong rationale for the development of novel therapeutic strategies that combine lymphodepletion with immune reconstitution and DNA immunization in human clinical trials.
The Variable Success of Managing Bleeding Disorder Related Menorrhagia: A Multicenter Study within the Hemophilia Treatment Center Network.
Authors: Kouides Peter A. , Cohen Alice J. , DiMichele Donna , Petruzzi Mary Jane , Saidi Parvin 
Published: April 2020

Abstract
The growing awareness to screen women with menorrhagia for an underlying bleeding disorder has led to an increase in enrollment of identified cases in Hemophilia Treatment Centers (HTCs). However, the outcome of menorrhagia management in these women has not been well-described.
Objective : To determine the efficacy/outcome of the management of bleeding disorder-related menorrhagia in patients enrolled within the HTC network.
Patients and Methods : Registry study of initial data collection of retrospective obstetrical and gynecological events with prospective yearly follow-up for 5 years for new obstetrical and gynecological events.
Results : 99 women from five HTCs in New York-New Jersey Region II have been registered to date, mean age 38±16.3, median age 40. Diagnoses are: von Willebrand disease (VWD) in 71%; thrombocytopathy in 6%; factor deficiency in 23%. Menstrual status and outcomes presently:
⇒32/99 (32%) are not menstruating due to hysterectomy or post/peri-menopausal status; 13/99 have undergone a hysterectomy (n=10) or endometrial ablation (n=3) for menorrhagia control; in 7/10 of the women undergoing a hysterectomy for menorrhagia control, the diagnosis of VWD was previously established; 6/7of these women attempted medical treatment prior to hysterectomy
⇒68/99 (68%) are presently menstruating. Of those menstruating, menstrual status is as follows:
Normal menses: 23.5% (16/68) Menorrhagia under control: 23.5% (16/68); of these patients; 11/16 have achieved control with oral contraceptive(OC), the remaining 5 patients have achieved control with intranasal DDAVP or Amicar Menorrhagia presently: 53% (36/68); 22/36 (61%) have undergone a course of ineffective menorrhagia treatment including intranasal DDAVP in 17/22
Conclusions : The majority of women with menorrhagia enrolled in HTCs have persistent menorrhagia despite evaluation and management within the HTC network. Only a small proportion have menorrhagia control due to intranasal DDAVP use and a proportion still necessitate hysterectomy for menorrhagia control. The value in United States HTCs of hemostatic measures alone such as intranasal DDAVP in the management of bleeding disorder related menorrhagia is uncertain at this time. Further study of combined therapy (intranasal DDAVP and Amicar ± OC) and novel approaches (levonorgestrel-intrauterine device) is warranted as are efforts to procure tranexamic acid for use in the U.S.
Variability in Bleeding Pattern of Severe Hemophilia.
Authors: van Dijk Karin , Fischer Kathelijn , van der Bom Johanna G. , Mauser-Bunschoten Eveline P. , Roosendaal Goris , van den Berg H. Marijke 
Published: April 2020

Abstract
Introduction
The aim of this study was to describe variability in bleeding pattern in a single center cohort of severe hemophilia patients treated with prophylaxis.
Methods
At the Van Creveldkliniek, all patients with severe hemophilia born between 1944 and 2002 were followed from 1972 onwards. Data on bleeding characteristics and treatment were collected yearly and Pettersson scores were performed with five-year intervals. Prophylactic dose was adjusted always according to bleeding pattern. Since the number of accepted bleeds has decreased over the years, each treatment dependent indicator was described stratified for age. Age specific quartiles for the different indicators were used as arbitrary cut-off values.
Results
Data on prophylaxis were available for 247 patients, and a total of 2760 follow up years on prophylaxis were collected. Variability in treatment characteristics is shown in Table 1.
Treatment characteristics and clinical manifestations per age group
Year of birth 1985–2002 1968–1985 1944–1968 Values are means (interquartile range) n 66 87 94 Follow-up per patient (yr) 6.6 18.0 22.6 Age at first joint bleed (yr) 1.8 (0.7–3.7) - Annual clotting factor use (IU/kg/yr) 2790 (2282–3321) 1989 (1654–2350) 1458 (1119–1790) Joint bleeds per year 2.6 (1.0–3.7) 2.9 (1.3–5.1) 4.5 (2.2–9.9) Pettersson score (max 78 points) 0.0 (0.0–2.5) 15.1 (6.0–22.0) 44.8 (35.5–56.2)
The variation in annual clotting factor use was used as a marker of bleeding pattern. Age at first joint bleed was inversely related to annual clotting factor use in the youngest age group. Using cut off levels of the 25th and 75th percentiles (P25 and P75) of age at first joint bleed and annual clotting factor use, 10% of patients were identified as patients with a milder bleeding pattern (i.e. age at first joint bleed above P75 and annual clotting factor use below P25) and 9.3% as patients with a more severe bleeding pattern. Using annual clotting factor use and joint bleed frequency in the middle group, 8.0% of patients were identified as patients with a milder phenotype and 10.3% as patients with a more severe bleeding pattern. In the oldest group, Pettersson scores were positively associated with annual clotting factor use. Using these parameters, 14% of the patients were identified as patients with a milder bleeding pattern. Due to the ceiling effect of the Pettersson score, these parameters could not be used to identify patients with a more severe bleeding pattern.
Conclusion
There is considerable variation in bleeding pattern of patients with severe hemophilia. Combinations of bleeding and treatment characteristics could be used as indicators of phenotype identifying 8 to 14% patients with a milder bleeding pattern and 9 to 10% of patients with a more severe bleeding pattern.
The Impact of Latent Epstein-Barr Virus Infection on Outcome in Children and Adolescents with Hodgkin’s Lymphoma.
Authors: Claviez Alexander , Tiemann Markus , Lueders Heike , Parwaresch Reza , Schellong Guenther , Doerffel Wolfgang 
Published: April 2020

Abstract
The prognostic significance of latent Epstein-Barr virus (EBV) infection in Hodgkin’s lymphoma (HL) is debated controversially. Especially in the pediatric age group, no conclusive data are available due to small series.
842 children and adolescents (55% male) with a median age of 13.7 years (range, 2–20) from consecutive pediatric DAL/GPOH multicenter treatment studies HD-90 and HD-95 were studied for the presence of latent EBV infection in Hodgkin and Reed-Sternberg cells by immunostaining against latent membrane protein 1 (LMP-1). Histology subtypes were as follows: nodular sclerosis (NSHL) 549, mixed cellularity (MCHL) 190, lymphocyte predominance (NLPHL) 90, lymphocyte depletion (LDHL) 6, lymphocyte-rich classical HL (LRCHL) 5, not specified 2. 88 patients had stage I, 470 had stage II, 172 had stage III and 112 had stage IV. B symptoms were present in 274 patients (33%). LMP status was compared with clinical parameters and established risk factors.
A total of 263 patients (32%) were LMP positive. EBV infection correlated with gender (male 39% vs. female 23%; p&lt;.001), histological subtype (MCHL 69% vs. NSHL 22% vs. NLPHL 6%; p&lt;.001) and age (&lt;10 years 67% vs ≥10 years 28%, p&lt;.001. With a median follow-up of 4.9 years (0.3–12) 820 patients (97%) are alive. Probability of overall survival at 10 years (±SD) for EBV negative and positive patients was 98±1% and 95±1%, respectively (p=.017 by log-rank test). Probability of failure-free survival (FFS) in LMP positive and negative patients was 89±2% and 84±4%, respectively (p=.86). With respect to LMP status, a negative effect of latent EBV infection on overall survival became evident only for patients treated for advanced stages (p=.003), those with nodular sclerosis subtype Bennett II (p=.02) and B symptoms (p=.05). In a multivariate regression analysis, allocation to treatment group (RR=3.7) and LMP positivity (RR=3.01) were independent factors for overall survival and presence of B symptoms (RR=2.4) for FFS.
Under current highly effective polychemotherapy with or without involved field radiotherapy in pediatric HL, latent EBV infection has no influence on FFS in univariate and multivariate analysis. LMP positivity, however, seems to be associated with an inferior overall survival in some subgroups.
Effects of Biochemically-Confirmed Smoking Cessation on Periperhal Leukocyte Count.
Authors: Abel Gregory A. , Hays J. Taylor , Decker Paul , Croghan Gary , Kuter David J. , Rigotti Nancy A. 
Published: April 2020

Abstract
BACKGROUND: Previous work has demonstrated that smokers have higher white blood cell counts than nonsmokers, but the effect of biochemically-confirmed smoking cessation on peripheral leukocyte counts has not been demonstrated in a large prospective study.
METHODS: Subjects were healthy smokers enrolled in a trial of sustained-release bupropion for relapse prevention after smoking cessation. White blood cell (WBC) counts and absolute neutrophil counts (ANC) were measured at baseline, week 7 and week 52. Smoking status was assessed at weeks 7 and 52 by self-report and biochemically confirmed with expired air carbon monoxide levels. Multivariate analyses compared changes in WBC count and ANC between smokers who did and did not stop smoking, adjusting for treatment group, age, sex, and body mass index.
RESULTS: Of 784 smokers enrolled, 461 had biochemically-confirmed tobacco abstinence after 7 weeks of bupropion; 429 were randomly assigned to receive continued bupropion or placebo until week 52. At baseline, the mean WBC count was 8.4 x 109/L (SD ±2.3) and the mean ANC was 5.3 x 109/L (SD ±1.9). The baseline WBC count and ANC were higher in smokers with greater tobacco exposure, measured by daily cigarette consumption and serum cotinine level. Between baseline and week 7, there was a significantly larger decrease in WBC count in continuously abstinent subjects compared with continuing smokers (adjusted p =.031). At 52 weeks, biochemically-confirmed continuously abstinent subjects, as compared with continuing smokers, had a greater decline from baseline in WBC count (1.2 x 109/L versus 0.1 x 109/L, p&lt;0.001) and ANC (0.1 x 109/L versus 0.2 x 109/L, p&lt;0.001).
CONCLUSION: The WBC count and ANC of healthy smokers increase with increasing tobacco exposure. Biochemically-confirmed tobacco abstinence leads to a rapid and sustained decrease in WBC count and ANC, possibly reflecting a decrease in an underlying state of tobacco-induced inflammation.
A Novel Non-Cleavable Cell Surface Mutant of CD40-Ligand Induces Anti-Leukemic Immune Response and Prevent Systemic Inflammatory Reaction.
Authors: Kato Kazunori , Masuta Yukari , Tomihara Kei , Sasaki Katsunori , Hamada Hirofumi 
Published: April 2020

Abstract
CD40-ligand (CD40L), a member of the TNF family, is expressed transiently on activated CD4-positive T cells and mediates cognate interaction between T cell and antigen-presenting cell (APC) such as dendritic cells. We and other investigators have reported previously that transduction of human leukemia cells with adenovirus encoding full-length CD40-ligand resulted in upregulation of immune costimulatory molecules, enhance APC activity and generation of CTL to leukemia B cells. However, CD40L is cleaved to a soluble form (sCD40L) by metalloproteases and high levels of sCD40L may contribute to the systemic inflammatory diseases including systemic lupus erythematosus and rheumatoid arthritis, suggesting a potentially deleterious side effect of CD40L gene therapy. In this study we generated a non-cleavable mutant of CD40L to develop a potentially less toxic molecule for CD40L gene therapy. Four mutants of human CD40L (termed CD40Lm1, m2, m3 and m4) with point mutation of amino acids from E112 to P120 (suggested cleavage site) were created by RT-PCR and cloned into retrovirus and adenovirus vectors. These four mutants of CD40L were transduced into tumor cells and assessed sCD40L production by ELISA, demonstrating that all four mutants resulted in a fully non-cleavable mutant of CD40L. We also confirmed that CD40L mutants could stimulate CD40-positive B and dendritic cells and induce phenotypic alterations and IL-12 production. In order to examine systemic side effect of CD40L, we transplanted tumor cells expressing wild-type (CD40Lwt) or non-cleavable mutant of CD40L (CD40Lm3) in nude mice and have observed for one month period. Two weeks after transplantation, mice with tumors expressing CD40Lwt exhibited arthritis, systemic edema and slight diarrhea, but CD40Lm3 did not induce any systemic inflammatory effect. We also found increased plasma levels of sCD40L (&gt;800 pg/ml) in mice transplanted with CD40Lwt transfectant but not in CD40Lm3 transplanted mice. Additionally, mice with CD40Lwt resulted in increased number of infiltrating mononuclear cells in the liver and kidney, whereas no inflammatory cells were observed in the liver of mice with CD40Lm3. Overall, non-cleavable mutant of CD40L is fully capable of inducing immune response with less toxic molecule and useful tool for CD40L gene therapy of leukemia and lymphoma.
A Novel p53-PP2A Signaling Pathway Is Responsible for Regulation of Hematopoiesis Induced by TGFß.
Authors: Takimoto Rishu , Kato Junji , Takada Koichi , Takahari Daisuke , Niitsu Yoshiro 
Published: April 2020

Abstract
TGFβ has been reported to play an important role in regulating the proliferation of hematopoietic cells. Dysfunction of signal transduction pathway of TGFβ may result in leukemogenesis. It has been generally accepted that Smads mediate the TGFβ signaling to inhibit cell proliferation, while several Smad4-defective cell lines have been shown to retain certain levels of responsiveness to TGFβ, suggesting an additional TGFβ signaling pathway for cell cycle arrest. We previously demonstrated the evidence for a novel signal pathway for G1 arrest linking TGFβ and p53/Protein phosphatase 2A (PP2A) in CD4+ T lymphocyte and megakaryocytes (ASH, San Diego, 2003). We also showed that, upon TGFβ stimulation, PP2A was transiently recruited by heteromeric complex of TGFβ receptors (TβRs), released into cytosol, and activated. Subsequently, PP2A dephosphorylated p53 to import it into nucleus by interacting with importin-α/β, followed by p21Waf1 induction. In this study, we extended our observation to explore TGFβ-induced growth suppression is required for increment of PP2A activity by using SiRNA against PP2A. When PP2A of CD4+ lymphocytes was knocked-down by specific SiRNA for PP2A, the recruitment of PP2A by TβRs and TGFβ-induced growth suppression as well as nuclear import of p53 were inhibited. As a result, TGFβ stimulation induces PP2A activation and subsequently dephosphorylated-p53 was translocated into nucleus. Thus these results further define a novel pathway of TGFβ-induced growth suppression linking p53-PP2A, and suggest that dysfunction of p53 may result in the escape from growth inhibitory signal of TGFβ in hematological malignancies.
Comparison of Two Regimens for the Treatment of Elderly Patients with Acute Lymphoblastic Leukaemia (ALL).
Authors: Offidani Massimo , Corvatta Laura , Malerba Lara , Marconi Monica , Catarini Massimo , Centurioni Riccardo , Leoni Franco , Scortechini Anna Rita , Masia Maria Cristiana , Leoni Pietro 
Published: April 2020

Abstract
Acute lymphoblastic leukemia (ALL) represents a rare malignancy in the elderly and few authors have specifically focused on the treatment of ALL in this setting. We recently published the results of a prospective phase II study comprising an induction therapy with vincristine, Daunoxome, cyclophosphamide and prednisone (VDXD) given to 15 patients aged ≥ 60 years. Here, we updated the results after enrolling 17 patients treated from 1999 to 2002 (median age 69 years, range 61–79) and we compared these with the results obtained in 17 elderly patients treated according to the GIMEMA ALL 0288 protocol from 1994 to 1998 (median age 70, range 61–76). Most of patients in both groups had B-lineage ALL and an initial WBC count less than 30 x 109/L. The most frequent karyotypic abnormality resulted the Ph which was detected in 4 (23%) and in 3 patients (17%) treated with 0288 and VDXD, respectively. BCR-ABL translocation was present in 45 % of patients treated with VDXD. Comorbidities were documented in 11 (65 %) patients treated with VDXD compared with 9 (58%) receiving 0288 regimen.
With VDXD combination elderly ALL had a higher CR rate than with 0288 protocol (76.5% vs 41%; p=0.037) likely due to both lower induction mortality (17.5% vs 35%; p=0.028) and less resistant disease (6% vs 24%; p=0.025). Infectious complications rate was similar (64% vs 53%) but they were the primary cause of death in 2 and 5 patients receiving VDXD and 0288, respectively. Non-hematological side effects were comparable. Median DFS was similar and resulted 18 months and 20 months with 0288 and VDXD treatment, respectively. Median EFS was 3.9 and 12.8 months, respectively (p = 0.0486). Particularly, 1-year EFS resulted 35% in patients receiving 0288 treatment compared with 53% in those given VDXD. Median OS was 4.5 an 21 months in the first and in the latter group of patients (p = 0.0239) with a two-year OS of 29% in 0288 and 38% in VDXD group.
Our results are encouraging and show that the administration of high-dose daunorubicin as liposomal compound in elderly ALL patients is not only feasible but also able to improve CR rate, EFS and OS without increase in toxicity.