bluuebunny/crossref_metadata_2025_split huggingface dataset:
Augmentation of Post-Transplant Immunity: Antigen Encounter at Time of Hematopoietic Stem Cell Transplantation Enhances Antigen-Specific Donor T Cell Responses in the Post-Transplant Repertoire.
Authors: Mullen Craig A. , Kocak Ulker , Shaw Joanne L. , Mori Shahram 
Published: October 2019

Abstract
After transplant the immune system is reconstituted by cells derived from both hematopoietic stem cells and peripheral expansion of differentiated donor T cells. Immune function is poor despite transplantation of mature lymphocytes from immune competent donors. We tested the hypothesis that early antigen encounter at the time of cell transplant would enhance desired donor T cell responses in the post-transplant repertoire. 2 independent models of peptide-specific T cell responses were studied.
Model 1 : The model for CD4 cells employed T cells from transgenic DO11.11 mice that constitutively express the T cell receptor for the class II restricted ovalbumin (OVA) peptide 323–339. Fig 1: Early exposure to OVA antigen enhances clonal expansion of OVA specific transgenic T-cells following syngeneic BMT. Lethally irradiated BALB/c mice were injected with 300 μg of OVA peptide in CFA or CFA alone subcutaneously one day before transplantation (D-1). The transplanted mice received 2x106 transgenic OVA specific T-cells and 6x106 non-transgenic naive BALB/c bone marrow cells. At 2 days (A) and 7weeks (B) following BMT, draining lymph nodes were isolated and examined for the presence of OVA-specific T-cells using FITC-labeled KJ-126 antibody and PE-labeled anti mouse CD4 antibody. Naïve BALB/c animals were used as negative controls (C). The absolute number of antigen-specific T-cells was determined by multiplying the total cells recovered with the percentage of OVA-specific CD4+ T-cells identified by flow.
Figure Figure
Model 2: The model for CD8 cells employed nontransgenic H2-Db-restricted T cell responses to the influenza nucleoprotein peptide 366–374. Fig 2: Antigen specific CD8+ cells in antigen-exposed animals are functionally active. Donor SW mice were immunized three times by ip injection of virus-infected spleen cells. Recipient C57BL/6 animals underwent BMT using influenza-immune donors spleen cells and bone marrow (10x106 and 4x106 respectively). Some transplant recipients were exposed to influenza virus on D-1. Ten days following BMT, the animals were sacrificed and spleens were isolated and stimulated in vitro with 2 μg of NP peptide. After two rounds of stimulation, the splenocytes were assayed by intracellular cytokine assay for the secretion of IFNg by staining with PE-anti IFNγ and FITC-anti-CD8 antibodies. The results are representative of three experiments (total number n=4/experimental group).
Figure Figure
Encounter with specific antigen at the time of T cell transplantation led to clonal expansion of donor T cells and preservation of donor T cell function in the post-transplant immune environment. Antigen-specific donor T cell function was poor if antigen encounter was delayed or omitted. Severe parent>F1 graft versus host reactions blocked the effect of early antigen exposure.
Selected IL-21R Expression and Apoptosis Induction by IL-21 in Follicular Lymphoma.
Authors: Akamatsu Norihiko , Hasegawa Hiroo , Yamada Yasuaki , Makabe Koki , Asano Ryutaro , Kumagai Izumi , Murata Ken , Tsukasaki Kunihiro , Tomonaga Masao , Tsuruda Kazuto , Sugahara Kazuyuki , Kamihira Shimeru 
Published: October 2019

Abstract
IL-21 receptor (IL-21R), a member of the common gamma receptor family, is expressed on many kind cells including T-cells, B-cells, and NK cells. IL-21 promotes the proliferation and maturation of NK cells and shows anti-tumor activities in animal systems. Although these results suggest its clinical use in the treatment of malignancies, it has also been shown that IL-21 may conversely accelerate the proliferation of IL-21R-expressing tumor cells. Considering the potential for therapeutic application of recombinant IL-21, we examined IL-21R expression and response to IL-21 in hematological malignancies. Using flow cytometry, we examined IL-21R expression in primary samples from AML, ALL, B-CLL, B-NHL and adult T-cell leukemia/lymphoma (ATLL) caused by a retrovirus, HTLV-1. Among 35 primary samples, only 5 samples from 16 patients with B-NHL and one sample from 8 patients with ATL were IL-21R positive. Of note, all the IL-21R positive NHL also expressed CD10, one of the marker molecules of follicular center cells. Indeed, two of the five patients were diagnosed follicular lymphoma with t(14;18)(q32;q21). Corresponding to these results, the follicular lymphoma cell line SUDHL-4 and most ATLL and HTLV-1-infected cell lines were IL-21R positive. Interestingly, IL21 showed dual effects on these cell lines; IL-21 stimulated the proliferation of ATLL cell lines but suppressed the proliferation of SUDHL-4. Annexin V and propidium iodide staining for detection of early and late apoptosis and mitochondrial membrane potential analysis indicated that the suppression was the result of apoptosis. Exposure of SUDHL-4 to IL-21 resulted in significant time-dependent induction of caspase-8 and caspase-3 activation. More importantly, IL-21 decreased Bcl-2 expression but drastically increased Bax expression. Thus, selected expression of IL-21R in follicular lymphoma cells and induction of apoptosis by IL-21 provide a strong background for IL-21 as an anti-neoplastic agent at least in a subset of follicular lymphoma.
Cell Cycle Dysregulation Represents an Early Effect of the Proteasome Inhibitor Bortezomib in Mantle Cell Lymphoma.
Authors: Hutter Grit , Zimmermann Yvonne , Rieken Malte , Weinkauf Marc , Weigert Oliver , Hiddemann Wolfgang , Dreyling Martin H. 
Published: October 2019

Abstract
Mantle cell lymphoma (MCL) is a distinct subtype of malignant lymphoma with an especially poor clinical outcome, a median survival time of 3 years and virtually no long-term survivors. On the molecular level, MCL is characterized by the chromosomal translocation t(11;14)(q13;q32) resulting in the constitutive overexpression of cyclin D1. However, additional genetic alterations of cell cycle regulators, e.g. deletions of the INK4A gene cluster, are detectable in the majority of cases. In various phase II studies the proteasome inhibitor bortezomib (Velcade) has demonstrated a high clinical efficacy with up to 60% remission rates in relapsed MCL. Additionally, in a previous in vitro study, the inhibitor induced a downregulation of cyclin D1 expression and a concomitant G(1) cell cycle arrest. However, little is known which molecules represent the critical targets of proteosome inhibition and how different regulators of cell cycle and apoptosis (inhibitors of CDK/INK4: p15INK4A, p16INK4B -and p14ARF and other kinase inhibitor proteins/KIP: 21CIP1, p27KIP1 and p57KIP2) are affected.
4 MCL cell lines (HBL2, GRANTA 519, Jeko-1, NCEB-1) and 2 hematological control cell lines (Jurkat, Karpas 422) were exposed to bortezomib at the minimal cytotoxic concentration (25 nmol) which corresponds to clinically achieved drug levels and results in a significant cytolysis after 48 – 72 hours. Real-time RT-PCR and protein expression levels of various CDK inhibitors (INK4s, KIPs) and cyclin D1 were determined a 0, 4, 8 and 12 hours after treatment with bortezomib. In addition, RNA- and protein expression data were compared to functional cell cycle phase (FACS) and cell apoptosis. Prelimenary data indicate that downregulation of cyclin D1 RNA expression after 12 and 24h of treatment represents a rather late event whereas alterations of other cell cycle regulators (like p21CIP1) were detected siginificantly earlier in all four MCL cell lines. Thus, expression of cell cycle regulators may indicate early events of proteasome inhibition. A comparative analysis of the cell cycle regulation network is currently being performed and will be presented at the conference.
B-Lymphocyte Stimulator (BLyS) Is Highly Expressed in Waldenstrom’s Macroglobulinemia.
Authors: Ansell Stephen M. , Grote Deanna M. , Ziesmer Steven C. , Witzig Thomas E. , Kyle Robert A. , Novak Anne J. 
Published: October 2019

Abstract
Waldenstrom’s macroglobulinemia is a serious and frequently fatal illness, however many of the mechanisms leading to this disease are not yet known. It is clear, however, that there is dysregulation of the balance between cell proliferation and programmed cell death. BLyS (B-lymphocyte stimulator) is a newly identified TNF family member expressed by monocytes, macrophages, and dendritic cells. BLyS has been shown to be critical for maintenance of normal B cell development and homeostasis, and has been found to stimulate lymphocyte growth. BLyS is overexpressed in a variety of B-cell malignancies and has been shown to inhibit apoptosis in malignant B-cells. Studies of the effects of BLyS on B cell physiology have shown that it also regulates immunoglobulin secretion.
To determine the relevance of the BLyS receptor-ligand system in Waldenstrom’s macroglobulinemia, we examined malignant B cells from 5 patients with Waldenstrom’s macroglobulinemia for their ability to bind soluble BLyS and for the expression of the known BLyS receptors, TACI, BAFF-R, or BCMA. The malignant B cells were found to bind BLyS and express BAFF-R and TACI. BCMA expression was undetectable. We then determined the expression of BLyS in bone marrow specimens from 5 patients with Waldenstrom’s macroglobulinemia by immunohistochemistry and compared it to the expression in 5 normal bone marrow specimens. The lymphoplasmacytic cell infiltrate in the bone marrow of patients with Waldenstrom’s macroglobulinemia showed significantly increased BLyS expression. We further determined the serum BLyS levels by ELISA in stored serum specimens from patients with Waldenstrom’s macroglobulinemia (n=20), and compared them to serum BLyS levels in other patients with lymphoplasmacytic lymphoma without elevated immunoglobulin levels (n=10) and to serum levels in normal controls (n=50). Serum BLyS levels in Waldenstrom’s patients (mean: 49.6ng/ml) as well as those in patients with lymphoplasmacytic lymphoma (mean; 46.7ng/ml) were significantly higher than normal controls (mean 12.6ng/ml).
In conclusion, we have demonstrated that malignant B cells from patients with Waldenstrom’s macroglobulinemia express the receptors for BLyS and can bind soluble BLyS. Furthermore, we have found that serum BLyS levels are significantly elevated in patients with Waldenstrom’s macroglobulinemia when compared to controls. Strategies to inhibit BLyS may potentially have significant therapeutic efficacy in Waldenstrom’s macroglobulinemia.
Postremission Treatment with Chemotherapy or Allogeneic Stem Cell Transplantation (Allo-SCT) in Adults with Acute Myeloid Leukemia (AML) -JALSG AML-97 Trial-.
Authors: Sakamaki Hisashi , Miyawaki Shuichi , Ohtake Shigeki , Yagasaki Fumiharu , Mitani Kinuko , Matsuda Shin , Kishimoto Yuji , Miyazaki Yasushi , Asou Norio , Ogawa Yoshiaki , Honda Sumihisa , Ohno Ryuzo 
Published: October 2019

Abstract
The aim of this study was to investigate the efficacy of allo-SCT as a postremission treatment in patients (pts) with intermediate/poor risk AML in first CR. Previously untreated pts aged15–64 years were eligible. Pts received standard induction therapy consisting of cytarabine (100 mg/m2 d1–7) and idarubicin (12 mg/m2 d1- 3). If the pts did not achieve remission after the first induction therapy, the same induction therapy was given once more. The pts who achieved CR were randomized into an intensified short-course postremission regimen group (arm A) and conventional JALSG postremission regimen group (arm B). Pts were also categorized into good, intermediate or poor risk groups by risk factors based on previous JALSG AML trials using univariate and multivariate analyses. The intermediate or poor risk pts <=50 years old with an HLA-matched sibling were assigned to the allo-SCT group. The overall survival rate (OS) and the disease-free survival rate (DFS) of the pts of this group were compared with those of intermediate or poor risk pts <=50 years old without an HLA-matched donor (non-transplant group), to adhere to the intention-to-treat principle.
Result: 809 pts were registered between December 1997 and July 2001. 789 pts were evaluable (median age: 45 years). 621 pts achieved CR (78.7%) after one or two courses of induction therapy. Os of 789 evaluable pts at five years and DFS of CR pts at five years were 40.8% and 35.5%, respectively. Of the 75 pts who were assigned to the allo-SCT group, 56 pts underwent allo-SCT (38 during CR1 and 18 after relapse). For the allo-SCT group, OS and DFS at 5 years were 51.8% and 43.1%, respectively. For the non-transplant group (n=95), OS and DSF at 5 years were 32.2% and 18.3%, respectively. DFS was significantly better in the allo-SCT group compared to the non-transplant group (p=0.005). OS was marginally better in the allo-SCT group (p=0.06).
In conclusion, our study showed that allo-SCT for pts with intermediate or poor risk is effective as a postremission treatment in adult AML.
Molecular Analysis of the VH Gene Usage in a Familial Case of Waldenstrom’s Macroglobulinemia.
Authors: Siakantaris Marina P. , Kyrtsonis Marie-Christine , Lilakos Konstantinos , Angelopoulou Maria K. , Vavourakis S. , Kontopidou Flora N. , Vassilakopoulos Theodoros P. , Kalpadakis Christina , Kokoris Styliani I. , Dimitriadou Evangelia M. , Kilindireas Constantin , Pangalis Gerassimos A. 
Published: October 2019

Abstract
Waldenstrom’s Macroglobulinemia (WM) is a rare lymphoproliferative disorder characterized by lymphoplasmacytic infiltration of the bone marrow and/or other tissues and the presence of a serum monoclonal IgM. The etiology of the disease is still unknown but the identification of family clusters may contribute to the understanding of its pathogenesis. In this study we present a family with 4 members affected by WM consisting of three generations; 2 sisters of the first generation were both suffering from WM. One of them presented to our section with mild anemia, a monoclonal serum IgM compound, 80% infiltration by lymphoplasmacytes in the bone marrow and the diagnosis of WM was made. Her sister was also suffering from WM but followed in another Centre. Our patient had two sons that at the age of 52 and 46 years presented a serum monoclonal IgM. At presentation, the first one had a monoclonal IgM value of 1680 mg/dl and a 40% BM lymphoplasmacytic infiltration with no other findings, signs or symptoms; he is regularly followed in our section for 30 months and his disease is stable. The second son, presented with a serum monoclonal IgM value of 886 mg/dl and a 10% BM infiltration by monoclonal lymphoplasmacytes and plasmacytes and was initially characterized as having an IgM-MGUS; while under follow-up examination only, he developed peripheral neuropathy with positive anti-Mag antibodies and improved with rituximab administration. Nor the mother or the sons had HCV antibodies. The first son has 3 children and the second two. Buccal and blood DNA was analysed for the IgH rearrangement by PCR. The PCR products after ligation and cloning were sequenced in an automated sequencer. Sequences obtained from each sample were aligned with germline sequences in the BLAST directory. No Ig rearrangements were detected in buccal DNA. Monoclonality was demonstrated in all affected members and in 2 healthy individuals of the third generation by PCR while immunophenotyping did not show evidence of disease in those two members. VH3 family was expressed at the highest frequency (80%). Different gene segments were recognized for the analysed sequences. D segments were attributed in all sequences. All affected and 1 healthy member had mutated VH genes. This is the first study of a family with WM consisting of three generations and reporting blood monoclonality of healthy individuals by molecular methods. The biologic value of the finding remains to be seen. Further study and a long follow-up is needed to clarify this issue.
Proteomics of Acute Myeloid Leukemia: Cytogenetic Risk Groups Differ Specifically in Their Proteome, Interactome and Posttranslational Protein Modifications.
Authors: Balkhi Mumtaz Y. , Geletu Mulu , Christopeit Maximilian , Behre Hermann M. , Behre Gerhard 
Published: October 2019

Abstract
Acute Myeloid Leukemia (AML) is characterized by specific cytogenetic aberrations which are strong determinants of prognostic outcome and therapeutic response. Because the clinical outcome in AML cytogenetic groups differs considerably, we hypothesized that cytogenetic risk groups of AML might differ specifically in their proteome, protein interaction pathways and posttranslational modifications (PTMs). Thus, we determined the proteome of 30 AML patients belonging to various cytogenetic groups based on two-dimensional gel electrophoresis and Nano LC coupled MALDI-TOF-TOF tandem mass spectrometry. We could identify substantial differences in the proteome, protein expression and peak pattern between cytogenetic risk groups of AML. The interactome analysis based on computational bioinformatics using Ingenuity analysis revealed major regulating networks: MAPK8 and MYC for complex aberrant karyotype AML, TP53 for t(8;21)-AML, TP53- MYC- PRKAC for 11q23-AML, JUN and MYC for inv(16)-AML. Most interestingly, peak explorer analysis revealed a modification of O-linked acetyl glucosamine of hnRNPH1 in AML patients with a 11q23 translocation, an acetylation of calreticulin in t(8;21) translocation AML, an increased intensity of dimethylated peptide of hnRNPA2/B1 in AML patients with translocations of t(8;21) and inv(16) in comparison to healthy bone marrow. We show for the first time that cytogenetic risk groups of AML differ specifically both in their proteome, interactome and PTMs. These findings lead to a new thinking about the pathogenesis of AML and has major therapeutic implications because PTMs are the primary drug targets.
A Phase II Study of Temozolomide Therapy for Poor Risk Patients Age ≥ 60 Years with Acute Myeloid Leukemia (AML) - Low Levels of MGMT May Predict for Response.
Authors: Brandwein Joseph M. , Schimmer Aaron D. , Schuh Andre C. , Gupta Vikas , Wells Richard A. , Yang Lin , Minden Mark D. 
Published: October 2019

Abstract
A previous Phase I study (Seiter K et al, 2002) had shown antileukemic activity of temozolomide (TMZ) in acute myeloid leukemia (AML). We conducted a Phase II study of TMZ in poor risk patients aged 60 years and over with AML. Patients were eligible if they had received no prior inductions and had one of the following: poor risk cytogenetics (complex abnormalities, deletions of chromsome 7 or 5, 11q23 abnormalities, inv[3]) or secondary leukemia (prior hematologic disorder or therapy-related leukemia). Patients who had not achieved remission or had relapsed after one prior induction course, regardless of other risk factors, were also eligible. Of 43 evaluable patients, 17 had received one prior induction and 26 had received no prior therapy - of the latter group, 12 had secondary leukemia and the remaining 14 had poor risk cytogenetics. The dose of TMZ was 200 mg/m2 orally daily for 7 days. Patients achieving partial response (PR) were eligible to receive a second identical course. Patients achieving complete response (CR or CRp) were eligible to receive TMZ 200 mg/m2 orally daily for 5/28 days for up to 6 postremission cycles. The treatment was well-tolerated, with mild to moderate myelosuppression and minimal nausea. Most patients received therapy on an outpatient basis. Four patients achieved complete response (3 CR and 1 CRp), 2 achieved PR and 2 had marrow aplasia at Day 30–35; the remaining 35 patients did not respond. Of the 4 patients achieving CR, one relapsed after 3 months, while the remaining patients remain in CR after 7, 12 and 29 months respectively. The 2 PR patients did not respond further to a second induction course. Because sensitivity to TMZ has been previously linked to expression of the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT), we assessed baseline levels of MGMT in leukemia blasts pre-treatment by Western blot. Of 24 evaluable samples, 10 had no detectable MGMT; this group included all 4 CR patients, one PR and one aplasia. Of the 14 with detectable MGMT there were no antileukemic responses. The remaining samples were either not available or not evaluable for MGMT. In conclusion, TMZ therapy was well tolerated and had antileukemic activity with approximately a 10% CR rate in older poor risk AML patients. MGMT appears to be predictive of response - all of the responders had undetectable MGMT activity, while no antileukemic activity was seen in MGMT positive cases. This assay may therefore be useful in selecting potential candidates for this treatment. Confirmation of this finding in a larger series is warranted. Furthermore, pharmacologic reduction in MGMT levels could potentially increase response rates to TMZ and warrants study.
Venous Thromboembolism Prophylaxis Practices in Acutely Ill Medical Patients with Heart Failure (NYHA Class III or IV): Findings from IMPROVE.
Authors: Pavanello Ricardo , Froehlich James B. , Tapson Victor , Bergmann Jean-Francois , Nakamura Mashio , Merli Geno , Pini Mario , Piovella Franco , Spencer Frederick A. , FitzGerald Gordon , Anderson Frederick A. ,   For the IMPROVE Investigators11
Published: October 2019

Abstract
Background Acutely ill medical patients with heart failure have an increased risk for venous thromboembolism (VTE) and expert consensus guidelines recommend that they should receive VTE prophylaxis. However, little data is available on physician’s practices for providing prophylaxis to these patients. Our aim was to characterize VTE prophylaxis practices in acutely ill hospitalized medical patients with heart failure (NYHA class III or IV) enrolled in the International Medical Prevention Registry on Venous Thromboembolism (IMPROVE).
Methods Patient recruitment began in July 2002. Patients aged ≥ 18 years and hospitalized for ≥ 3 days with an acute medical illness are enrolled consecutively. Exclusion criteria are: therapeutic antithrombotic agents or thrombolytics at admission, major surgery or trauma during 3 months prior to admission, and VTE treatment within 24 hours of admission.
Results Of 6946 patients enrolled up to 31 March 2005 in 49 hospitals in 12 countries, 784 (11%) were heart failure patients. Compared with patients without heart failure, patients with heart failure were more likely to be in an ICU/CCU (13% vs 8%), immobile ≥ 4days (50% vs 30%), over 60 years old (85% vs 61%), perceived to be obese (20% vs 13%), or have respiratory failure (27% vs 17%; p<0.0001 for all). In total, only 51% of heart failure patients received pharmacologic prophylaxis and 61% received any type of prophylaxis. Pharmacologic prophylaxis type varied by region with low-molecular-weight heparin (LMWH) used less often, and unfractionated heparin (UFH) used more often in the USA compared with other participating countries (see Table). Aspirin and warfarin were used as VTE prophylaxis in 6% and 3% of heart failure patients, respectively. Intermittent pneumatic compression (IPC) was used more often in the USA than in other countries (24% vs 0.2%).
Conclusions Although acutely ill medical patients with heart failure are at risk of VTE and should receive prophylaxis, only 61% of these patients in IMPROVE actually received any type of prophylaxis. This reflects poor physician-awareness of the benefits of prophylaxis in this patient group and suggests that significant opportunity exists to improve physician practices.
Table. VTE prophylaxis in acutely ill medical patients with heart failure VTE prophylaxis (% patients) USA Other participating countries LMWH 15 46 UFH 27 13 Aspirin 8 4 Warfarin 5 1 Any pharmacologic prophylaxis 43 56 IPC 24 0.2 Elastic stockings 6 7