bluuebunny/crossref_metadata_2025_split huggingface dataset:
Subclinical EBV and CMV Reactivations Commonly Occur Following Antibody-Based Immunosuppressive Regimens for Patients with Severe Aplastic Anemia.
Authors: Scheinberg Phillip , Fischer Stephen H. , Li Li , Nunez Olga , Wu Colin O. , Young Neal S. , Barrett A. John 
Published: April 2020

Abstract
Although reactivation of Cytomegalovirus (CMV) and Epstein-Barr virus (EBV) during periods of immune suppression following solid organ and allogeneic hematopoietic stem cell transplantation (HSCT) can cause fatal complications, the natural history of viral reactivation and the potential for serious complications following antibody-based immunosuppressive (I/S) treatments for bone marrow failure syndromes is not defined. We monitored blood for EBV and CMV reactivation by polymerase chain reaction (PCR) weekly in 39 consecutive patients (total of 44 I/S courses) with aplastic anemia (AA). During the observation period of 3–6 months per patient, none developed clinical features of EBV or CMV reactivation, nor received antiviral therapy. Four regimens were studied: (1) HC: horse ATG + cyclosporine (CsA) (18 pts); (2) HCS: horse ATG + CsA + sirolimus (15 pts); (3) RC: rabbit ATG (Thymoglobulin®) + CsA (5 pts); and (4) CP: alemtuzumab (Campath®) (6 pts). Overall EBV reactivation occurred in 32/39 (82%) seropositive patients at a median of 14 days in the HC arm, 11 days in the HCS arm, 15 days in the RC arm and 6 days in the CP arm from starting I/S. The median peak EBV copies for HC recipients was 4,340 (0–54,250) copies/106 mononuclear cells (MNCs); for HCS 1,420 (0–466,000) copies/106 MNCs; for RC 370,000 (97,000–1,025,000) copies/106 MNCs, and for CP 965 copies/106 MNCs (0–655,000) (P= 0.026). The median duration of PCR positivity for EBV was higher in the RC group (18 weeks) compared to HC (6 weeks), HCS (4 weeks) and CP (1 week) (P=0.002). Higher peak values were associated with a longer duration of viremia following initial I/S (P&lt;0.001)(Figure). CMV reactivation occurred only in 12/29 (41%) seropositive patients, 10 CMV seronegative patients showed no reactivation by PCR. The EBV reactivations in the alemtuzumab arm were less frequent and short lived, presumably because the antibody eliminates the B cell population which is the source for reactivating virus. A more prolonged lymphocyte depletion was seen with RC and CP treated patients when compared to HC and HCS. Our results indicate that subclinical reactivation of both EBV and CMV is common in patients with AA receiving I/S and that different regimens are associated with different intensity of I/S as measured by viral load and lymphocyte count. Our data suggests that higher and longer EBV reactivations are seen following rabbit ATG compared to horse ATG or alemtuzumab, and for the whole cohort, the duration of positivity for EBV PCR correlated to the initial degree of EBV reactivation. While all reactivations were subclinical, our findings suggest that viral reactivation should be monitored when developing new and more potent I/S regimens for treatment of hematologic and non-hematologic disorders as the threshold to the development of CMV or EBV disease is not well understood.
Figure Figure
Mesenchymal Stem Cells for Treatment of Severe Acute and Extensive Chronic Graft-Versus-Host Disease.
Authors: Le Blanc Katarina , Frassoni Francesco , Ball Lynne , Uzunel Mehmet , Lanini Edoardo , Sundberg Berit , Lonnies Helena , Dini Giorgio , Bacigalupo Andrea , Locatelli Franco , Fibbe Willem E. , Ringden Olle T.H. 
Published: April 2020

Abstract
Mesenchymal stem cells (MSC) from adult bone marrow have the capacity to differentiate to several mesenchymal tissues and inhibit T-cell alloreactivity in vitro. We have used MSC to treat grades III-IV acute graft-versus-host disease (GVHD) in 14 patients and extensive chronic GVHD in two patients. The MSC dose was median 1.0 (range 0.4–9) x 10E6 cells/kg body weight of the recipient. No side-effects were seen after MSC infusions. Nine patients received one dose, six patients received two doses and one patient received three doses. MSC donors were in two cases HLA-identical sibling donors, twelve haploidentical donors and ten third-party HLA-mismatched donors. Among the 14 patients treated for severe acute GVHD, six had complete responses, four showed improvement and one had stable disease. Three were not evaluable: two due to early death and one due to short follow-up. MSC donor DNA was detected in lymph node and colon in one of the patients who died. Among the 14 patients treated for severe acute GVHD, nine are alive between two months up to three years after transplantation. Four of these patients have extensive chronic GVHD. One patient transplanted for AML in relapse has recurrent leukaemia. The two patients treated for extensive chronic GVHD had transient responses. One of them died of Epstein-Barr virus lymphoma. We conclude that MSC have immune-modulatory and tissue repairing effects and therefore may be used for treatment of severe GVHD.
HIV-Related Burkitt’s NHL (BL) vs. Diffuse Large-Cell NHL (DLCL) in the Pre- and HAART Eras: Significant Differences in Survival with Standard Chemotherapy.
Authors: Spina Michele , Simonelli Cecilia , Talamini Renato , Vaccher Emanuela , Tirelli Umberto 
Published: April 2020

Abstract
Background: The survival of patients with HIV-related NHL has significantly improved by the widespread use of HAART. However, the survival of patients with HIV-BL treated with standard chemotherapy regimens remains poor.
Methods: In order to evaluate the outcome of patients with HIV-BL in comparison to that of patients with HIV-DLCL, we reviewed our series of 253 HIV-NHL diagnosed and treated at the National Cancer Institute of Aviano, Italy from 1984 to 2003, including 125 cases in the pre-HAART era (77 HIV-DLCL and 48 HIV-BL) and in the HAART era (93 HIV-DLCL and 35 HIV-BL).
Results: All patients both with HIV-DLCL and HIV-BL were treated with the same doxorubicin containing chemotherapy regimens. The median OS of all patients was significant longer in the HAART era in comparison to that of the pre-HAART era (15 vs 8 months, p ≤ 0.0001). In addition, in the pre-HAART era, the median OS was similar in patients with HIV-BL vs patients with HIV-DLCL (7 vs 10 months, p = 0.11) whereas in the HAART era the median OS of patients with HIV-BL was significantly shorter than that of patients with HIV-DLCL (8 vs 22 months).
Conclusions: Our data confirm that the significant improvement of the outcome of patients with HIV-NHL is related to the positive impact of HAART on the survival of patients with HIV-DLCL whereas the prognosis of HIV-BL remains poor despite the use of HAART. Taking into consideration that in the HAART era patients with HIV infection are likely to tolerate intensive chemotherapy regimens, a more intensive approach similar to that employed in the general population should be employed also in patients with HIV-BL.
Activating NOTCH1 Mutations Are Associated with Good Treatment Response in Childhood T-Cell Acute Lymphoblastic Leukemia.
Authors: Breit Stephen , Stanulla Martin , Flohr Thomas , Schrappe Martin , Ludwig Wolf-Dieter , Tolle Gabriele , Happich Margit , Muckenthaler Martina M. , Kulozik Andreas E. 
Published: April 2020

Abstract
T-cell acute lymphoblastic leukemia (T-ALL) accounts for 10–15 % of pediatric ALL. Very rare cases of T-ALL (&lt; 1 %) harbor the chromosomal translocation t(7;9) that involves NOTCH1, a gene encoding a single-pass, heterodimeric transmembrane receptor. NOTCH1 has an essential function in early intrathymic T-cell development. Recently, it has been demonstrated that more than 50 % of childhood T-ALLs carry activating mutations within the NOTCH1 gene (Weng et al., Science 2004). In the present study, we systematically analyzed the impact of activating NOTCH1 mutations on treatment response in 108 pediatric T-ALLs, registered in the ongoing ALL-BFM 2000 trial. In 56 cases (51.8%) activating NOTCH1 mutations were identified, located either in the heterodimerization (38/56 mutations; 65.5%), in the PEST (10/56; 17.9%) or in both domains (8/56; 14.3%). The presence of activating NOTCH1 mutations was significantly correlated with good prednisolone (p = 0.001, c2 or Fisher’s exact test) and MRD response (p = 0.002). T-ALLs with NOTCH1 mutations were 3.7 times more likely to show a good prednisolone response (95% confidence interval = 1.64–8.33; p = 0.002) and 4.8 times more likely to show a favorable MRD response (95% confidence interval = 2.04–11.11; p = 0.0003) when compared to patients with wild type NOTCH1. Patients with mutated NOTCH1 were thus underrepresented in the high risk group of the ALL-BFM 2000 protocol. This influence of NOTCH1 mutational status on risk stratification was independent from other commonly used criteria, like age and initial white blood cell count (WBC) at the time of diagnosis. Considering the impact of NOTCH1 mutations on long term prognosis, we analyzed those 49 patients of this cohort with a median follow-up of &gt; 4 years. Eight patients relapsed within this follow-up period, 2 patients with mutated and 6 with wild type NOTCH1. With this small number of relapses, this trend towards a favorable influence of activating NOTCH1 mutations on EFS did not reach statistical significance. In conclusion, T-ALLs with NOTCH1 mutations are demonstrated to be more sensitive than those without to the ALL-BFM 2000 treatment strategy and may show a lower rate of relapse.
Searching Polymorphic Markers Associated with the Genetic Predisposition To Develop Therapy-Related Myelodysplastic Syndromes and Acute Myelogenous Leukemia T-(MDS/AML) after Myeloablative Chemotherapy.
Authors: Tormo Mar M. , Guillem Vicent V. , Mata Manuel M. , Gonzalez Marcos M. , Nomdedeu Josep J. , Esteve Jordi J. , Calasanz Maria Jose M.J. , Terol Maria Jose M.J. , Marugan Isabel I. , Solano Carlos C. 
Published: April 2020

Abstract
INTRODUCTION: Therapy-related MDS/AML constitutes the most frequent secondary neoplasia and his incidence is increasing in the last years. This incidence is especially high when myeloablative chemotherapy is used before autologous stem cell transplantation (ASCT). Since for similar treatments only a percentage of the patients ends up by developing a secondary leukemia, it has been proposed the existence of some type of genetic predisposition associated to this syndrome.
OBJETIVE: To search single nucleotide polymorphisms (SNPs) associated with the genetic predisposition to develop a t-MDS/AML by means of SNP genome screening using high density microarrays.
MATERIAL AND METHODS: Two groups of individuals were genotyped: Group A, composed by 16 patients with t-MDS/AML post-ASCT (10 NHL, 4 HD, 2 multiple myeloma) and Group B (control), formed by 16 patients submitted to ASCT and that after a period of more than 10 years have not developed t-MDS/AML(14 NHL, 2 HD). For each individual more than 10.000 SNPs were genotyped by means of the use of microarrays of high density (Mapping 10K, Affymetrix®). Those SNPs are distributed along the whole genome and have a high average heterocigosity (0,37). The alele frequencies for each SNP between two groups were compared.
RESULTS: We found a group of 4 SNPs located in the q23.3 band of the chromosome 5 in which the differences of alele frequency between the groups A and B were superior to 50 %. These SNPs are located in a region that comprises the only gene, CSS3 (chondroitin sulphate synthetase 3), being the difference of alele frequency of 57 % in the intronic SNP of this gene.
CONCLUSIONS: The results suggest that the CSS3 gene is a candidate for being studied by its possible relation with the genetic predisposition to develop LMAt/SMDt, although its putative functional implication with the disease must still be elucidated. There is known that a counterpart of CSS3, CSS1, plays a key role in the proliferation and apoptosis of myeloma cells. Thus, it is possible that CSS3 could be somehow related with the hematopoyesis pathways and implied in the development of t-MDS/AML. Financed by FIS G03/008.
CD24High / FLJ/P1Low Expression Correlates with Bad Prognosis and Shorter Survival in Adult ALL.
Authors: Coignet Lionel J. , Johnson Thimothy , Nganga Alain , Zhang Qing , Meyer Corinna , Drexler Hans G. , Ghosh Debashis , Singh Keshav , Baer Maria R. 
Published: April 2020

Abstract
Leukemia is a neoplastic proliferation of cells of hematopoietic origin that arises following somatic mutation in a single hematopoietic stem cell, the progeny of which forms a clone of leukemia cells. Genetic alterations leading to leukemia transformation of a cell are often associated with major alterations of chromosomes that can be detected by studying cells of the leukemic clone in mitosis. One of these alterations is a chromosomal translocation that is often used to identify genes potentially involved in other type of rearrangements such as deletions. Abnormalities of chromosome band 13q14 occur in hematologic malignancies of all lineages and at all stages of differentiation. Unlike other chromosomal translocations, which are usually specific for a given lineage, the chromosomal translocation t(12;13)(p12;q14) has been observed in both B-cell and T-cell precursor acute lymphoblastic leukemia (ALL), in differentiated and undifferentiated acute myeloid leukemia (AML) and in chronic myeloid leukemia at progression to blast crisis (CML-BC). Recently, we have shown the presence of a myeloid- and lymphoid-specific breakpoint cluster regions within chromosome band 13q14 in acute leukemia (Genes Chromosome Cancer 25:222–229,1999). In addition, a new cell line has been established from one of the lymphoid cases, MUTZ5, that carries a single t(12;13) translocation (Leukemia 15:1471–1474, 2001). The molecular characterization of this translocation led to the identification of a new gene, FLJ13639, that is disrupted and lost in the MUTZ5 cell line. This gene shares homologies with the large family of short-chain dehydrogenase reductase (SDR). Furthermore, three transcripts and proteins were found to be differentially expressed for this gene, where P1 is potentially the active form of dehydrogenase, while P2 and P3 are lacking the co-activator site. We report here that one of the consequences of the loss of FLJ13639 is the over-expression of CD24 that appears to provide leukemia cells with a proliferation and invasiveness advantage, as well as a certain degree of chemoresistance. FLJ13639 is a new mitochondrial protein that seems to be important for the respiration and apoptosis processes. In addition, semi-quantitative RT-PCR for CD24 and FLJ13639/P1 was performed in a series of cell lines as well as 29 adult ALL samples at diagnosis. Fifty percent of the samples showed a CD24High / FLJ/P1Low profile whereas the remaining samples showed either a balanced expression or a CD24Low / FLJ/P1High profile. These preliminary data on patient samples indicated a correlation between survival and CD24High / FLJ/P1Low expression profile (p=0.04). The current median time survival for the CD24High / FLJ/P1Low group is 9 months whereas the CD24Low / FLJ/P1High group is 28 months. Therefore, this appears to be a new potential prognostic marker for adult ALL.
Figure Figure
In Vitro Synergistic Anti-Tumor Activity by Targeting TRAIL-R1 and CD20 Antigen by Combining HGS-ETR1 (Agonistic Human Monoclonal Antibody to TRAIL Receptor 1) and Rituximab Monoclonal Antibody Against Non-Hodgkin’s Lymphoma Cells (NHL).
Authors: Czuczman Myron S. , Maddipatla Sreeram , Knight Joy , Hernandez-Ilizaliturri Francisco J. 
Published: April 2020

Abstract
Tumor necrosis factor-related apoptosis ligand (TRAIL) or agonist antibodies targeting specific TRAIL-receptors possess significant in vitro and in vivo anti-tumor activity. HGS-ETR1 (mapatumumab) and HGS-ETR2 are two fully human recombinant, high affinity IgG1λ mAbs targeting TRAIL-R1 (Death-receptor 4, DR-4) and TRAIL-R2 (Death-receptor 5, DR-5), respectively. TRAIL-receptor agonist mAbs trigger the extrinsic (mitochondria-independent) apoptotic pathway and enhance the anti-tumor effects of chemotherapy drugs against NHL. Combining TRAIL-receptor agonist mAbs with biological agents (e.g. rituximab) capable of activating the intrinsic (mitochondria-dependent) apoptotic pathway may result in synergistic effects against NHL.
Objective: To study the biological effects of rituximab when combined with either HGS-ETR1 or HGS-ETR2.
Materials and methods: A panel of NHL cell lines [Raji, SUDHL-4, SU-DHL-10, Ramos, and two rituximab resistant cell lines (RRCL), 2R and 4RH] were utilized. Expression of CD20, TRAIL-R1 and TRAIL-R2 in the NHL cells used were evaluated by flow cytometry. NHL cells were exposed to HGS-ETR1 or HGS-ETR2 followed by either rituximab, istoype control antibody or media alone. DNA synthesis and cell growth arrest were quantified by [H3] Thymidine incorporation assays at 24 and 48 hrs. Induction of apoptosis was detected by multiparameter flow cytometric analysis. For antibody-dependent cellular cytotoxicity (ADCC)/Complement mediated cytotoxicity (CMC) studies, 51Cr-labeled NHL cells were exposed to HGS-ETR1 or HGS-ETR2 (5μg/ml) +/− rituximab or isotype control antibody (10μg/ml) and peripheral blood mononuclear cells (Effector: Target ratio 40:1) or human serum, respectively. 51Cr-release was measured and the percentage of lysis was calculated. Statistical analysis of results was performed using the Chi-square test. Results: In sensitive cells in vitro exposure to HGS-ETR1 resulted in significant apoptosis (30–50%) and decrease in DNA synthesis. The combination of HGS-ETR1 and rituximab resulted in significant inhibition of cell proliferation (90% reduction) when compared to either HGS-ETR1 (60% reduction) or rituximab (5% reduction) alone at 24 and 48 hrs. In sensitive cells HGS-ETR1 induced CMC and ADCC as a single agent. No significant anti-tumor activity was observed with HGS-ETR2. The biological activity of anti-TRAIL receptors mAbs did not correlate to TRAIL-R1 or TRAIL-R2 cell surface antigen expression. Conclusions: Targeting TRAIL-R1 with HGS-ETR1 induces apoptosis, cell growth arrest and in some cell lines ADCC/CMC. The combination of HGS-ETR1 with rituximab results in significant synergistic activity (i.e. anti-proliferation) and warrants further pre-clinical and clinical evaluation in B-cell lymphomas.
Antitumor Activity and Mechanism of Action of a Novel Stat3 Inhibitor, WP1066, Against Human B-Cell Non-Hodgkin’s Lymphoma and Multiple Myeloma.
Authors: Kong Ling-Yuan , Kapuria Vaibhav , Bartholomeusz Geoffrey , Talpaz Moshe , Priebe Waldemar , Donato Nicholas J. 
Published: April 2020

Abstract
B-cell non-Hodgkin’s lymphomas (B-NHL) have the highest incidence rates among all lymphomas, comprising more than 85% of malignant lymphomas worldwide. Multiple myeloma (MM) is a plasma cell malignancy that affects 14,000 patients per year. Although new therapies have recently been introduced to treat these malignancies, patient survival has not significantly improved, illustrating the need for additional agents that target and suppress this disease. B-cell malignancies over-express c-myc and frequently retain a constitutively activated Stat3, resulting in increased survival gene expression and apoptotic protection. Targeting these transcription factors may reduce apoptotic thresholds and suppress the growth and survival of these malignancies. In this study, we refined and tested the anti-tumor activity of a novel small MW compound discovered by screening a synthetic library for agents that bock Stat3 activation. WP1066, blocked IL-6 mediated Stat3 activation in numerous human B-NHL and MM tumor cells including the Mino, LP, MM-1 and OCI-My5 at low micromolar concentrations. This compound blocks Jak2-depedent cytokine signaling (IL-3, GM-CSF, IL-6) through the rapid (15 min) down-regulation of the upstream tyrosine kinase, Jak2. WP1066 also causes rapid reduction in c-myc in B-cell malignancies but other transcription factors and signaling kinases are not affected by WP1066. The apoptotic effects of WP1066 on B-NHL and MM cells parallel its Stat inhibitory, Jak2 down-regulatory activity. Jak2 down-regulation is not dependent on proteosomal processing but requires activation of a tyrosine phosphatase, suggesting a unique mechanism of WP1066 action. Based on activities described in vitro, we further examined the antitumor activity of WP1066 in a B-NHL xenograft tumor model. Mice were inoculated (i.p.) with 25 × 106 Mino cells (CB17 SCID mice, 4–5 weeks of age) and 13 days later were treated with 10, 20, or 40 mg/kg of WP1066 (i.p.) qd x 5/week for 2 weeks. WP1066 significantly decreased tumor burden and increased the survival of Mino tumor bearing mice treated with 20 or 40 mg/kg of WP1066. These results suggest that WP1066 reduces Stat activation through a unique mechanism and may have therapeutic potential for the treatment of human B-cell non-Hodgkin’s lymphomas and multiple myeloma.
Development of Small Molecule Inhibitor of the AML1-ETO Oncoprotein.
Authors: Grembecka Jolanta , Graf Kristin , Newman Miki , Zhou Yunpeng , Cheney Mathew , Speck Nancy A. , Brown Milton L. , Bushweller John H. 
Published: April 2020

Abstract
Core binding factor (CBF) is a heterodimeric transcription factor composed of RUNX1 (CBFa) and CBFb subunits which are essential for normal blood cell development. RUNX1 binds DNA and the affinity of this interaction is regulated by the binding of CBFb to the RUNX1 subunit. The RUNX1(AML1) gene is disrupted by a variety of chromosomal translocations, including t(8;21)(q22;q22), which produces the chimeric protein AML1-ETO associated with AML (M2 subtype). The AML1-ETO fusion protein is a dominant inhibitor of wildtype RUNX1-CBFb activity in vivo and functions as a transcriptional repressor of RUNX1-CBFb target genes, causing a blockage in normal hematopoietic development and predisposing for the development of leukemia. We have validated the importance of the RUNX1 Runt domain - CBFb interface as a potential therapeutic target by assessing the effect of mutations introduced into the Runt domain of AML1-ETO on AML1-ETO activity. Therefore, treatments targeting the AML1-ETO protein and blocking its interactions with CBFb are likely to be therapeutically beneficial. We initiated efforts to develop small molecule inhibitors of the RUNX1-CBFb interaction as possible therapeutics for the treatment of the associated leukemia. Based on the X-ray structures of the RUNX1 Runt domain in complex with CBFb and on mutagenesis data, the interaction areas for the virtual screening searches were defined. The computer program LUDI was utilized for virtual screening using CAP (Chemicals Available for Purchase) database of 70,000 commercially available compounds with drug-like properties. The resultant hits were subjected to further scoring and visual inspection of the potential interactions with the RUNX1 Runt domain to select compounds for experimental testing by FRET (Fluorescence Resonance Energy Transfer). Experimental screening resulted in identification of six initial lead compounds that inhibit the interaction of RUNX1 with CBFb. These compounds were further optimized using standard medicinal chemistry approaches to increase their affinity and determine the structure-activity relationship (SAR). This resulted in a number of compounds with low micromolar affinity which effectively block the heterodimerization of CBF. These compounds represent the first small molecule inhibitors targeting RUNX1 and inhibiting its interaction with CBFb. They represent a good starting point for the development of a therapeutically useful inhibitor. Several approaches are being explored to modify these compounds to achieve selectivity towards AML1-ETO versus wild type RUNX1.