bluuebunny/crossref_metadata_2025_split huggingface dataset:
A New Vaccine Paradigm To Break Tolerance with Potential Applications for the Immunotherapy of B Cell Lymphoma.
Authors: Taylor Ronald P. , Whipple Emily C. , Lindorfer Margaret A. , Ditto Andrew H. , Shanahan Ryan S. 
Published: October 2019

Abstract
Complement (C) plays a critical role in the immune response by opsonizing immune complexes (IC) and thymus-independent type 2 antigens with C3 breakdown product C3dg. We investigated the in vivo fate and handling in mice of anti-CR1/CR2 mAb 7G6. We used this rat IgG mAb as a surrogate for C3dg-opsonized IC; mAb 7G6 binds to CR1/CR2 with high affinity, blocks C3dg binding and saturates mouse B cell CR2 at inputs of only 2 ug. RIA, flow cytometry, and fluorescence immunohistochemistry were used to examine the disposition of 0.5–2 ug quantities of mAb 7G6 infused i.v. in mice. The mAb binds to circulating B cells and in the spleen binds preferentially to marginal zone (MZ) B cells. However, within 24 h MZ B cells relocate and transfer the mAb to regions rich in follicular dendritic cells (FDC). Localization of intact antigen to FDC should induce a substantial immune response, and therefore we immunized mice and monkeys i.v. with low doses (1–20 ug/kg) of prototype antigens constructed with anti-CR1/2 mAb 7G6 or anti-CR2 mAb HB135, respectively. We observed a strong immune response characterized by early development of IgG antibodies and long-lasting immunity extending out to at least one year. We applied our immunization paradigm to mouse IgG idiotypes, based on i.v. infusion of mouse IgG2a mAbs which were cross-linked with mAb 7G6. The purpose of these experiments was to determine if tolerance can be broken in order to develop a more powerful vaccine strategy to induce a cytotoxic humoral immune response to malignant B cells based on targeting the idiotype of immunoglobulin molecules expressed on their surfaces. I.V. immunization with the constructs indeed generated a mouse IgG1 immune response to two different mouse IgG2a mAbs, as demonstrated by ELISA. The immune response was idiotype specific, but some anti-isotype antibodies were also detected. Moreover, sera from immunized mice immunoprecipitated the specific radiolabeled mouse mAbs in the presence of 7.5% polyethylene glycol. This humoral immune response was also demonstrable in flow cytometry assays in which IgG1 in sera of immunized mice bound to erythrocytes opsonized with bispecific mAb constructs consisting of the IgG2a mAb crosslinked with an anti-CR1 mAb. The present approach, based on coupling the targeted immunoglobulin to an anti-CR2 mAb for delivery to FDC, may lead to a more effective immunotherapeutic vaccine compared to methods currently in clinical trials which require use of glutaraldehyde to effect crosslinking of the targeted immunoglobulin to KLH.
Clinical and Quality of Life Outcomes in Patients with Multiple Sclerosis (MS) after High Dose Chemotherapy(HDCT)+Autologous Stem Cell Transplantation (ASCT).
Authors: Shevchenko Yury L. , Novik Andri A. , Afanasiev Boris V. , Lisukov Igor A. , Fedotov Yury N. , Ionova Tatiana I. , Kulagin Alexandr D. , Malysheva Olga A. , Bisaga Gennadi N. , Melnichenko Vladimir Y. , Chelombit Lubov V. , Voloshin Sergei V. , Fedorenko Denis A. , Vereschagina Inna V. , Kishtovich Anton V. 
Published: October 2019

Abstract
Objectives: HDCT+ASCT is a new and promising therapy for MS patients. Among a number of questions are the terms of conducting HDCT+ASCT. According to our concept there are 3 strategies of HDCT+ASCT depending on terms of disease stage: early, conventional and salvage. The aim of the research was to study clinical and quality of life (QoL) outcomes in MS patients with different terms of HDCT +ASCT.
Methods: Twelve patients with MS were included in the study. All the patients previously underwent conventional treatment. Clinical and QoL evaluation was provided at baseline, at discharge, at 3, 6, 9, 12 months and later every half a year after HDCT+ ASCT. MRI was conducted at baseline, in 6, 12 months and at the end of follow-up. QoL was assessed by FACT-BMT and FAMS. Integral QoL index was assessed by the method of integral profiles. Median EDSS at base-line was 6.0 (range 2 –7.5). The median follow-up duration was 18 months (range 3–60 months).
Results: Clinical examination and MRI revealed disease stabilization (DS) in ten patients and progression (DP) in two patients. EDSS decreased in seven patients; increased from 6.5 to 7.0 and from 6.0 to 6.5 in patients with DP and remained the same in three patients. Distinct QoL improvement was observed in all the patients with DS at the end of follow-up.
Three case reports with different terms of ASCT were analyzed. Patient K. underwent early ASCT (male, 21 years old; secondary progredient type; base-line EDSS - 2.0; follow-up 18 months); patient F.- conventional ASCT (female, 35 years old; secondary progredient type; base-line -EDSS 5.0; follow-up 60 months); patient P.- salvage ASCT (female, 49 years old; secondary progredient type; base-line EDSS 7.5; follow-up 48 months). Clinical examination and MRI revealed DS. EDSS decreased from 2.0 to 1.5 in patient K.; from 5.0 to 4.5 in patient F. and from 7.5 to 6.0 in patient P. at the end of follow-up. Integral QoL index increased dramatically as compared to base-line: in patient K. - from 0.6 to 0.7; in patient F. - from 0.2 to 0.7; in patient P. - 0.4 to 0.6.
Conclusion: HDCT+ASCT in MS patients resulted in DS in ten out of twelve patients under observation. Along with clinical stabilization dramatic improvement of QoL took place. Analysis of three case reports demonstrated feasibility of early, conventional and salvage ASCT in MS patients.
Dose Adjusted IV Busulfan/Cyclophosphamide (BU/CY) and Autologous (AU) Stem Cell Transplantation (SCT) for Recurrent Lymphoma.
Authors: Spitzer Thomas R. , Cox Benjamin , Sepe Paul , McAfee Steven L. , Dey Bimalangshu R. , Ballan Karen , Scadden David 
Published: October 2019

Abstract
The optimal preparative therapy for AuSCT for lymphoma is unknown. High dose Bu/CY is a generally well tolerated, and an effective regimen for allogeneic SCT for hematologic malignancy (HM), and autologous SCT for myeloid malignancies. It has, however, been less well studied for lymphoid malignancies. IV busulfan has largely replaced oral busulfan because of more predictable pharmacokinetics, and ease of administration. We have treated 46 patients (pts) with recurrent, chemosensitive lymphoma or lymphoma in which an initial complete remission was not achieved with the Bu/CY regimen and AuSCT from 2001 – 2004. 4 pts had AIDS related NHL (ARL). Patients had received a median of two chemoradiotherapeutic regimens prior to SCT. Diagnoses were indolent NHL (n = 12), aggressive NHL (n = 28) and Hodgkin’s disease (n = 6). IV busulfan was given at a dose of 0.8 mg/kg (based on actual or ideal body weight (IBW) whichever was less) every six hours for 16 doses (for patients < 50 years of age), or 14 doses (for patients = 50 years of age) on days -7 through -4. IV cyclophosphamide 60 mg/kg (based on a wt half way between actual and IBW for patients > 20% IBW) was given on days −3 and −2. AuSCT was performed on day 0. Additional autologous bone marrow was infused in pts who had less than 2 x 106/ kg CD 34+ progenitor cells (n = 2). Median (range) patient age was 56 (24–78) years. Four pts were = 70 years old at the time of transplant. Median (range) times to ANC = 0.5 and platelets = 20k were 10 (8–12) and 12 (8–64) days, respectively. Regimen related toxicities (according to the Bearman toxicity scale) included grade II-III mucosal toxicity (n = 7), hepatic VOD (n = 1), and grade II GI toxicity (n = 7). Documented infection occurred in 16 (35%) pts. Two pts (4.4%) died before day 100 from non-relapse causes (progressive pulmonary toxicity (n = 1), recurrence of melanoma (n = 1). Late (= day 100) non-relapse mortality (NRM) occurred in two pts (respiratory failure, (n = 1); hepatic VOD (n = 1). Overall NRM was 8.7% (4/46 patients). No NRM occurred in pts with ARL or pts > 70 yrs. Fourteen of 40 pts with NHL have had relapse/progression. Three of six pts with HD have had relapse/progression. Actuarial progression free survival (PFS) and overall survival (OS) probabilities are 67% and 100% at 32 mos for pts with indolent NHL and 44% and 79% at 25 mos for pts with aggressive NHL, respectively. High dose IV Bu/CY as preparation for AuSCT, with dose reduction of IV busulfan to 14 mg/kg for patients = 50 years is well tolerated and is associated with favorable PFS and OS probabilities. The regimen has also been well tolerated in pts over the age of 70 with no life threatening or fatal toxicities in this subgroup.
Differential Gene Expression in Leukemic Cells from Bone Marrow (BM) and Peripheral Blood (PB) of Pediatric Patients with Acute Lymphoblastic Leukemia (ALL).
Authors: Rhein Peter , Scheid Stefanie , Hagemeier Christian , Seeger Karl , Kirschner Renate , Schrappe Martin , Spang Rainer , Ludwig Wolf-Dieter , Karawajew Leonid 
Published: October 2019

Abstract
Although the genetic mechanisms underlying the induction of ALL are similar, the molecular events leading to diverse clinical presentation and course are not well characterized. High PB white blood cell (WBC) counts reflect tumor burden in PB and have been used in the past as a clinical risk factor in ALL. We hypothesized that, given differential microenvironment signaling provided by BM and PB, ALLs with high or low WBC counts (WBChigh and WBClow) might differ with regard to their dependence on the microenvironment. To approach this issue, we investigated gene expression changes in PB blasts as compared to their BM counterparts in patients with precursor B-cell ALL (n=15). Blasts were isolated from BM and PB samples by flow sorting and investigated for mRNA levels using Affymetrix HG U133A microarrays. Gene expression data, normalized by variance stabilization on probe level, were analysed in matched PB-BM pairs using a SAM-like analysis of log ratios in a balanced permutation test. By these procedures, a limited number of 38 genes consistently changed in PB vs BM blasts was identified (false discovery rate < 0.01). Leukemic PB cells were characterized by upregulation of genes encoding for cell adhesion- and trafficking-related proteins (CD11b, CD73, S100A4, EMP3). Furthermore, downregulation of the cell cycle- and proliferation-associated genes (thymidylate synthetase TYMS, kinesin KIF11, topoisomerase TOP2A, ribonucleotide reductase RRM2, kinetochore protein ZWINT) indicated decreased proliferative activity of leukemic cells in PB microenvironment. Finally, the gene encoding for Bcl-2 protein, known to be a powerful downstream mediator of survival signaling from microenvironment in various experimental settings, was consistently downregulated in PB as compared to BM blasts. Within the group of WBClow patients (n=8, mean WBC=17x103/μl), most of these genes retained their statistical significance. By contrast, no consistent expression changes in PB vs BM blasts were found in WBChigh patients (n=7, mean WBC=201x103/μl). In summary, investigation of differential gene expression in leukemic cells from PB and BM indicated decreased levels of proliferative and survival signaling in the PB microenvironment and a higher dependence on this signaling of leukemic cells from WBClow as compared to WBChigh patients.
Fatal Human Metapneumovirus Infection in Stem Cell Transplant Recipients.
Authors: Englund Janet A. , Nichols W. G. , Kuypers Jane , Hackman Robert C. , Morrow Rhoda , Fredricks David N. , Corey Lawrence , Boeckh Michael J. 
Published: October 2019

Abstract
The importance of human metapneumovirus (hMPV), a recently discovered human respiratory virus, in hematopoietic cell transplant (HCT) recipients is not known. We retrospectively surveyed 211 bronchoalveolar lavage samples (BAL) from symptomatic adults with new or changing pulmonary infiltrates after HCT during five-year period using a quantitative real time RT-PCR assay. Medical records, radiographic studies, biopsy specimens, and autopsy material were reviewed. hMPV was detected in 8/211 (3.8%) BAL specimens from 5/162 (3%) patients. The median titer of hMPV was 9.0 x 106 copies/ml of BAL fluid (range 5.5 x 104 to 3.5 x 108). Persistent hMPV infection was noted in all 3 patients who had multiple samples tested. hMPV was also detected in lung tissue in 1 of 2 samples tested. Infected patients were between the ages of 24–54 years, and became symptomatic within the first 40 days post transplant. Initial symptoms included fever, cough, nasal congestion, and sore throat. Clinical findings near the time of diagnosis included respiratory failure, pulmonary hemorrhage, and culture-negative septic shock. Four patients died as a result of acute respiratory distress and pulmonary disease with clinical and autopsy diagnoses of “idiopathic pneumonia.” We conclude that hMPV infection is associated with respiratory failure in immunocompromised adults and may result in fulminant respiratory decompensation in the post transplant period. Prospective studies of the role of this virus in idiopathic pneumonia syndromes of immunocompromised patients are warranted.
In Vitro Growth Regulation and the Identification of Potential Signaling Pathways in T (4; 11), Pediatric Pre-B Acute Lymphoblastic Leukemia (ALL).
Authors: Narendran Aru , Tijan Bijan , Coppes Lucas , Rhemtulah Farrah , Anderson Ron 
Published: October 2019

Abstract
Among the various chromosomal translocations found in pediatric pre-B cell acute leukemias, the t (4; 11) group contains patients of all ages as well as a clustering of children at birth or in the first year of life. As with all 11q23 abnormalities, t (4; 11) fusion confers an extremely poor prognosis. Using cell lines, many recent studies have described important molecular and cellular growth properties of these cells. We have investigated in vitro growth regulation of freshly isolated infant pre-B ALL cells with t (4; 11).
Leukemic blasts were affinity purified with anti CD19 antibodies and cultured in the presence of various cytokines including IL-3, IL-1, FLT-3 ligand (FL), SCF, IL-6, IL-7, GM-CSF, PDGF, SDF-1, VEGF, EPO and GCSF. Cell proliferation after four days in culture was quantified by Alamar blue assay. At pg/ ml concentrations, significant growth stimulation was seen in the presence of FL and IL-7. The FLT-3 effect was much less prominent against leukemic cells without t (4; 11). Then we aimed to identify the possible signaling pathways utilized by the FLT-3 mediated stimulation of these cells. Purified blasts were cultured in serum free medium for 24 hours and stimulated for 0, 5 and 10 minutes with 10 pg/ml of FL. These cells were subsequently lysed and total cellular extracts were analyzed by an antibody array technique. The arrays used consisted of antibodies against a selection of fifty proteins involved in all known signaling pathways. Changes in the amount of phosphorylated proteins following FL treatment were identified by enzyme conjugated anti phospho specific antibodies. A number of reproducible FL specific changes were observed. These include increased Ets-1/2, JNK1, 2,3, p38MAPK and Src. We describe the detail analysis of the signaling pathways potentially utilized by these cells and illustrate the use of this experimental approach to identify possible targeted therapeutic agents against this particular form of leukemia.
ZAP-70 Tyrosine Kinase Is Constituvely Expressed and Phosphorylated in B-Lineage Acute Lymphoblastic Leukemia Cells.
Authors: Guillaume Nicolas , Alleaume Celine , Capiod Jean-Claude , Pautard Brigitte , Desablens Bernard , Claisse Jean-François , Lefrere Jean-Jacques , Gouilleux Fabrice , Lassoued Kaiss , Gouilleux-Gruart Valerie 
Published: October 2019

Abstract
Zeta-associated protein 70 (ZAP-70), a member of the Syk family of protein tyrosine kinases is normally expressed in T and NK cells. ZAP-70 plays a key role in the signaling pathway of the TCR. It has been recently shown that this protein is also expressed in mouse B lineage cells. While little is known about ZAP-70 expression in normal human B cells, it has been reported that ZAP-70 is expressed in a subset of chronic lymphocytic leukemia (CLL), with a poor prognosis, that have nonmutated immunoglobulin variable region genes.
In this study, we examined the expression and phosphorylation status of ZAP-70 and Syk in B-lineage acute lymphoblastic leukemia (B-ALL) cells. ZAP-70 and Syk were constitutively expressed and phosphorylated (tyr319 for ZAP and tyr352 for Syk) in human precursor B-ALL cell lines as well as in B leukemic cells from all examined B-ALL patients (n=18). The expression of ZAP-70 was specific to these B-ALL cells as it was not detected in the K562 cell line or malignant myeloid cells. This expression was independant of maturation state of leukemic cells (pro-B or pre-B) and caryotypic status.
The expression and phosphorylation of the T-cell “specific” ZAP-70 kinase in all B-ALL cells raises important questions concerning the contribution of this protein to the leukemogenesis process resulting in B-ALL.
Possible Autocrine Mechanism of Placenta Growth Factor / Vascular Endothelial Growth Factor Receptor Type 1 in Acute Lymphoblastic Leukemia with Philadelphia Chromosome.
Authors: Ikai Toshiko , Miwa Hiroshi , Shikami Masato , Hiramatsu Akihito , Imai Noriaki , Satoh Atsushi , Itoh Masato , Miura Kazuhisa , Imamura Akira , Mihara Hidetsugu , Nishii Kazuhiro , Nitta Masakazu 
Published: October 2019

Abstract
The growth and/or survival of leukemia cells are affected by endothelial cell associated factors such as vascular endothelial growth factor (VEGF). Here, we studied the mRNA expression of VEGF and placenta growth factor (PLGF), a VEGF-related molecule, of acute lymphoblastic leukemia (ALL) cells (10 Philadelphia chromosome (Ph1) positive cases and 10 Ph1 negative cases) by real-time PCR. The expression of PLGF mRNA was significantly higher in Ph1 positive cases than Ph1 negative cases (p<0.05). The expression of VEGF mRNA was not different between Ph1 positive and negative cases. Then, recombinant PLGF was added to the culture of ALL cell lines: the growth of CRL1929 (Ph1 positive) was augmented by PLGF in a dose-dependent manner, while the growth of Nalm6 (Ph1 negative) was not affected by the addition of PLGF. Here, the growth enhancement effect of PLGF on CRL1929 was cancelled by the simultaneous addition of VEGF receptor type 1-Fc (VEGFR1-Fc), which binds to PLGF and abrogates the function. The growth enhancement effect was not cancelled by the simultaneous addition of VEGFR2-Fc, which binds to VEGF, but not to PLGF. Recombinant VEGF did not affect the growth of either cell line. Our data demonstrated that PLGF has a growth promoting effect on Ph1 positive ALL cells, and autocrine mechanism of PLGF-VEGFR1 might work in Ph1 positive ALL.
CXCL-12 Induces Prolonged Erk-Phosphorylation in Zap-70 Positive B-CLL.
Authors: Lust Sofie , Boelens Jerina , Janssens Ann , Philippé Jan , Bracke Marc , Offner Fritz 
Published: October 2019

Abstract
Introduction
Zap70 is superior to mutation status as a prognostic indicator in B-CLL, but whether it is causally implicated or just associated with progressive disease is unclear. Zap-70 transduces the TCR signal through the CD3 zeta-unit in T cells, but although it is important in preB development, it has no known function in mature B-cells. Zap-70 positive B-CLL show enhanced B cell receptor mediated Syk-phosphorylation upon surface IgM (sIgM) crosslinking, simulating antigen driven B cell proliferation. This may increase the proliferative drive in Zap-70+ B-CLL compared to Zap-70- leading to a higher risk of secondary chromosomal damage. Zap-70 was recently implied in Erk activation via CXCL-12/CXCR4 in T-cells and this is enhanced by cell adhesion through beta-1 integrins that may influence P-Erk phosphatases. Since both CXCL12/CXCR-4 and integrins influence B-CLL survival in vitro, we investigated the duration of downstream Erk activation in Zap-70 + versus Zap-70 B-CLL after CXCL-12 stimulation in the presence and absence of integrin binding by fibronectin.
Materials/methods
Peripheral blood mononuclear cells from B-CLL patients were isolated by Ficoll-gradient. Zap-70 was measured by flow cytometry (Upstate Ab), and PCR.
B-CLL cells from 6 patients were stimulated with 100 ng/ml CXCL-12 after preincubation in serum free RPMI for 2 hrs at 37°in fibronectin or BSA coated plates and in suspension culture. After CXCL-12 addition supernatant and adherent cells were separately lysed at 0, 2 and 10 minutes and studied by Western blot for total Erk, Akt, P-Erk and P-Akt. Parallel cultures were extended for 24 hours and apoptosis of supernatant versus adherent cells was performed by AnnexinV-PI staining and flow cytometry.
Results
Erk-phosphorylation was markedly stimulated by CXCL-12 after 2 minutes, both in supernatant and adherent fractions of fibronectin and BSA coated plates compared to suspension cultures. This stimulation decreased in Zap-70- B-CLL after 10 minutes but remained high in Zap-70+ B-CLL particularly in the fibronectin adherent fraction. These cells were also protected from spontaneous apoptosis at 24 hours when compared to supernatant Zap70+ and Zap-70- cells.
Conclusion
CXCL-12/CXCR4 ligation leads to prolonged Erk-phosphorylation in Zap-70+ but not in Zap70- B-CLL cells. Prolonged Erk-activation is required for nuclear translocation and effective signal transduction along this way. This effect is enhanced by concomitant fibronectin engagement of integrins, which may give Zap-70+ B-CLL cells a proliferative advantage upon homing in lymphoid tissues.