bluuebunny/crossref_metadata_2025_split huggingface dataset:
Relapse of Acute Promyelocytic Leukemia (APL) Is Associated with Increased Methylation of the Retinoic Acid Receptor-Beta2 (RARβ2) Gene Promoter.
Authors: Zhou Da-Cheng , Kim Haesook , Tallman4 Martin S. , Gallagher Robert E. 
Published: October 2019

Abstract
Increased methylation of the tumor suppressor and all-trans retinoic acid (ATRA) target gene RARβ2 has been reported in a variety of neoplasias. In APL, this has been related to the recruitment of DNA methyltransferases (DNmts) by PML-RARα to the RA response element-containing RARβ2 gene promoter (Di Croce, et al, Science295, 1079, 2002). In this study, we applied a highly quantitative method, pyrosequencing of bisulfite-converted DNA, to precisely measure the level of methylation (% of total dinucleotides;dnts) at each of 14 CpG dnts in the RARβ2 promoter from APL cases with de novo vs 1st relapse vs ≥2nd relapse disease. Additionally, we assessed whether patients with PML-RARα mutations at relapse, which increase binding to the co-repressor complex and might secondarily increase DNmt recruitment to this complex, are associated with increased methylation of this ATRA target gene. Non-parametric 2-sided Wilcoxon tests were utilized to evaluate potential differences in median values. Surprisingly, the methylation value for de novo APL cells (N = 10) was only slightly greater than that for normal peripheral blood mononuclear cells (N=4) (medians of sums of all 14 dnts were 95.9 and 68.9, respectively; p = 0.14). However, in a matched set of pretreatment and 1st relapse samples from 7 patients treated on intergroup protocol INT0129/E2491, the methylation level was significantly higher in the relapse samples at 6/14 dnts (p <0.05 each) and in the sums of all dnts (p = 0.03). Compared to these 7 1st relapse cases, the median values for each of the 14 dnts and the sums of all dnts were higher for 6 cases with ≥2 relapses (median of sums 149.8 vs 385.6, respectively) but this difference was not significant (p = 0.22), primarily related to 1 double-relapse case with exceptionally low values (excluding this case, p = 0.05). Similarly, compared to 8 relapse cases without PML-RARα mutations, 5 relapse cases with mutations had higher median values of 13/14 dnts and of the sums of all dnts (160.5 vs 402.0) but this was not statistically significant (p = 0.27). These results indicate that higher levels of RARβ2 promoter methylation are present in relapse compared to de novo APL cells and suggest that increasing methylation is frequently associated with disease progression and with mutations in PML-RARα.
18F-Fluorodeoxyglucose (FDG) Positron Emission Tomography (PET): An Important Tool in the Management of Infection in Patients with Hematological Cancer.
Authors: Anaissie Elias J. , Miceli Marisa H. , Strout Steve D. , Jones-Jackson Laurie , Walker Ronald C. , Purnell Gary , Diaz Jose A. , Saghafifar Fariba , Hollmig Klaus A. , Fassas Anasthasios , Tricot Guido , Barlogie Bart 
Published: October 2019

Abstract
Background: FDG-PET is useful for detecting cancer (ca) sites and preliminary data suggest a role in bone and joint infection, mostly in non-immunosuppressed hosts.
Purpose: To determine the role of FDG-PET in the management of infection in patients (pts) with hematological ca.
Patients and Methods: Between 10/01/2001 and 5/31/2004, FDG-PET scans performed for ca staging and /or for the diagnosis of suspected infection that were reported as showing increased radiotracer uptake at extramedullary sites were reviewed. Results of FDG-PET were correlated with clinical and laboratory findings to identify episodes of infection.
Results: 184 infections were documented by FDG-PET in 164 pts (90% multiple myeloma). Median age was 58 years (range 25–79) and 108 pts were males. 59 pts were neutropenic (<1000 neutrophils/ml) and 32 had severe immunosuppression (neutrophils, lymphocytes and / or CD4 counts <100 cells/ml).FDG-PET identified respiratory tract infections (118; including pneumonia/empyema, 112 and sinusitis, 6), vascular infections (27; septic thrombophlebitis (STP), 16 and infection of implantable catheter, 11), discitis / osteomyelitis (19), gastrointestinal tract infections (10; colitis, 5; diverticulitis and abdominal abscess (2 each) and esophagitis, 1), periodontal abscesses (10), cellulitis (2) and mastoiditis (1). 59 infections were microbiologically documented including bacterial (42), fungal (13), viral and mycobacterial (2 each). FDG-PET detected infectious foci despite severe immunosuppression (32 episodes). FDG-PET contributed to pt management including identification of the presence and site of infection (77), determination of its extent (81), modification of the diagnostic work-up and /or therapy (71) and evaluation of response (79). 58 clinically silent infections were detected among pts undergoing FDG-PET for ca staging.
Conclusion: In pts with hematological ca, FDG-PET is a useful tool for establishing the presence, site (s), and extent of infection with various pathogens and in various organs, even in the setting of severe immunosuppression. FDG-PET can identify clinically silent infections and infections not detectable by other methods (such as STP) and can result in significant changes in pt management.
Expression Profiling of ABC-Transporters in Childhood AML Reveals ABCA3 as a Potential Cause of Drug Resistance.
Authors: Steinbach Daniel , Gillet Jean-Pierre , Sauerbrey Axel , Gruhn Bernd , Dawczynski Kristin , de Longueville Francoise , Bertholet Vincent , Zintl Felix , Remacle Jose , Efferth Thomas 
Published: October 2019

Abstract
A major issue in the treatment of acute myeloid leukemia (AML) is the development of resistance to chemotherapeutic drugs. While more than 80% of children with AML may initially achieve complete remission with current therapeutic regimens, a large number of these patients relapse with resistant disease; even with aggressive therapy, the event free survival rate is only about 50%.
Several mechanisms of drug resistance have been identified. One of these is the overexpression of ATP-binding-cassette (ABC)-transporters that function as drug efflux pumps.
The best characterized member of this family is the P-glycoprotein (P-gp or MDR1 or ABCB1), which is an important cause of drug resistance in adult AML but not in children with AML. We could recently show that the multidrug resistance-associated protein 3 (MRP3 or ABCC3) and the breast cancer resistance protein (BCRP or ABCG2) are associated with a poor response to therapy in childhood AML.
The aim of the present study was to identify other members of this family of proteins which are involved in drug resistance. We were particularly interested in ABC-transporters which were overexpressed in AML samples compared to healthy bone marrow because this might be an important prerequisite for using such proteins as therapeutic targets.
A new microarray (DualChip human ABC) was developed for the simultaneous detection and quantification of 38 ABC transporter genes. Samples from 30 children with AML were analyzed with this microarray and the results were compared with normal bone marrow.
The expression of five genes (ABCA2, ABCA3, ABCB2, ABCC1, and ABCC10) which were overexpressed in most patient samples was then analyzed by real time PCR in 40 selected samples from children with previously untreated AML. Half of the patients had achieved complete remission after the first course of chemotherapy. The other 20 patients had also undergone the full induction therapy but had failed to achieve remission at this stage.
Only the expression of ABCA3 was significantly higher (p=0.015) in patients with a poor response to therapy. There was a 4-fold difference between the median expressions in both groups. The expression of ABCA3 was not significantly associated with the expression of P-gp, MRP3 or BCRP.
Our results show that ABCA3 is overexpressed in childhood AML compared to healthy bone marrow and that the expression of ABCA3 is associated with a poor response to therapy. Interestingly, there are two ways in which ABCA3 might influence the prognosis of AML. Like other ABC-transporters, it could be involved in drug efflux. On the other hand, it was recently shown that ABCA3 plays a role in apoptosis and that many cancer cell lines show amplifications of the ABCA3 gene.
Further studies are warranted to analyze the clinical and biological relevance of ABCA3 in leukemia.
Modulation of Immune Cell Responses by Human Mesenchymal Stem Cells.
Authors: Aggarwal Sudeepta , Pittenger Mark F. 
Published: October 2019

Abstract
Mesenchymal stem cells (hMSCs) are multipotent stem cells that have the capacity to differentiate into various lineages. These cells provide stromal support and can be utilized as a feeder layer for expansion of hematopoitic stem cells and embryonic stem cells. Furthermore, allo-transplanted MSCs are not rejected and have been shown to mediate immuno-modulatory functions in vitro. Also, MSCs have been found at the wound site at extended times. The mechanisms underlying MSC migration and immuno-modulation are still under investigation.
Aim: To understand the factors involved in human MSC (hMSC) migration and their interaction with various immune cell types.
Methods: Human MSCs were examined for the presence of cell surface receptors that may play a role in migration using quantitative RT-PCR. Next, hMSCs were co-cultured with purified immune cell types including dendritic cells (DCs), naïve T cells and NK cells. Following the co-culture, changes in the phenotype of the immune cells under activating conditions were analyzed using ELISA and functional assays.
Results: Human MSCs express Toll receptors, especially TLR4, on their cell surface. The TLR4 on hMSCs is functional as seen by a several-fold increase in IL-6 and chemokine IL-8 upon incubation with TLR4 exogenous ligand lipopolysaccharide (LPS) and the endogenous ligand, soluble hyaluronic acid (sHA). When hMSCs were incubated with activated dendritic cells, there was a >50% decrease in TNF-α secretion and a >50% increase in IL-10 secretion. When hMSCs were incubated with naïve T cells, hMSCs decreased IFN-γ secretion and increased IL-4 secretion. Decreased IFN-γ was also seen when MSCs were incubated with NK cells.
Conclusion: These results suggest that (i) hMSCs may respond to the signals generated by breakdown products of extracellular matrix (e.g. sHA) via TLR4 and assist in wound healing (ii) hMSCs immuno-modulatory effects are mediated by interacting with various immune cell types and altering their phenotypic response to a more tolerant and anti-inflammatory response.
Involvement of the Integrin Alpha 6 Receptor in the Homing and Engraftment of Hematopoietic Stem and Progenitor Cells to Bone Marrow.
Authors: Qian Hong , Jacobsen Sten Eirik W. , Ekblom Marja 
Published: October 2019

Abstract
Within the bone marrow environment, adhesive interactions between stromal cells and extracellular matrix molecules are required for stem and progenitor cell survival, proliferation and differentiation as well as their transmigration between bone marrow (BM) and the circulation. This regulation is mediated by cell surface adhesion receptors. In experimental mouse stem cell transplantation models, several classes of cell adhesion receptors have been shown to be involved in the homing and engraftment of stem and progenitor cells in BM. We have previously found that integrin a6 mediates human hematopoietic stem and progenitor cell adhesion to and migration on its specific ligands, laminin-8 and laminin-10/11 in vitro (Gu et al, Blood, 2003; 101:877). Using FACS analysis, the integrin a6 chain was now found to be ubiquitously (>95%) expressed in mouse hematopoietic stem and progenitor cells (lin−Sca-1+c-Kit+, lin−Sca-1+c-Kit+CD34+) both in adult bone marrow and in fetal liver. In vitro, about 70% of mouse BM lin−Sca-1+c-Kit+ cells adhered to laminin-10/11 and 40% adhered to laminin-8. This adhesion was mediated by integrin a6b1 receptor, as shown by functional blocking monoclonal antibodies. We also used a functional blocking monoclonal antibody (GoH3) against integrin a6 to analyse the role of the integrin a6 receptor for the in vivo homing of hematopoietic stem and progenitor cells. We found that the integrin a6 antibody inhibited the homing of bone marrow progenitors (CFU-C) into BM of lethally irradiated recipients. The number of homed CFU-C was reduced by about 40% as compared to cells incubated with an isotype matched control antibody. To study homing of long-term repopulating stem cells (LTR), antibody treated bone marrow cells were first injected intravenously into lethally irradiated primary recipients. After three hours, bone marrow cells of the primary recipients were analysed by competitive repopulation assay in secondary recipients. Blood analysis 16 weeks after transplantation revealed an 80% reduction of stem cell activity of integrin a6 antibody treated cells as compared to cells treated with control antibody. These results suggest that integrin a6 plays an important role for hematopoietic stem and progenitor cell homing in vivo.
Mitoxantrone, Vinblastine, and Lomustine (MVC): Long-Term Follow-Up of Patients Treated for Hodgkin’s Disease (HD).
Authors: Alexandrescu Doru T. , Karri Sirisha , Dutcher Janice P. , Wiernik Peter H. 
Published: October 2019

Abstract
Advanced-stage or relapsed/refractory HD has a poor prognosis despite aggressive chemotherapy regimens and the use of high dose therapy with autologous support. Sixty seven patients with HD(23 newly diagnosed and 45 with relapsed/refractory disease, one patient treated twice) were treated with the MVC regimen (mitoxantrone 8mg/m2/day IV days 1–3, vinblastine 8m/m2/day days 1 and 22, and CCNU 100 mg/m2 on day 1, repeated at 6 to 8 wks) in a single-arm Phase II study. This regimen combines the most effective chemotherapeutic agents of previous regimens for poor prognosis HD, and eliminates marginally active agents with unnecessary toxicities. Median age at treatment was 35 years (16–71), with 42 males and 25 females. 23 patients had previously untreated (PU) disease, staged as II (7), III (7), IV (9), and subtypes consisted of nodular sclerosis (21), mixed cellularity (1), and lymphocyte depletion (1). 45 patients were previously treated (1st relapse-20, 2nd relapse-13, 3rd relapse-12) and had relapsed after chemotherapy alone (17), radiotherapy alone (4), or combined modality treatment (24). 39 patients were relapsed and 6 refractory to treatment. This refractory/relapsed (R/R) group at diagnosis was staged II (11), III (10), IV (22), unknown (2), with 34 nodular sclerosis, 3 mixed cellularity, 1 anaplastic large cell, 1 lymphocyte predominant, 2 lymphocyte depleted, 4 unknown. All patients responded to treatment in the newly diagnosed group (OR 100%). The median response duration was 57.2 mos, and the median survival 108.1 mos. 11 complete responses are ongoing at 39+ to 189+ mos. In the prior treated patients, 41 responded to MVC (OR 91%). The median response duration for this group was 11 mos, and the median survival was 82.1 mos. Grade 3 and 4 treatment-related toxicities included neutropenia (89%), thrombocytopenia (73%), infection (40%), bleeding (20%), and two (2.9%) deaths (related to granulocytopenia and infection). Three secondary myeloid leukemias occurred, two in the de-novo, and one in the relapsed/refractory group, at a median follow-up of 16 years. In conclusion, MVC regimen for HD is very active, for both de novo and relapsed/refractory disease, with high response rates and survival that compare favorably with the results obtained by high-dose therapy with stem-cell transplantation. Although significant, the toxicities associated with this regimen were manageable.
Group OR CR PR Overall median response Overall survival CR median response CR median survival NR* = not reached, range 8.2-189+ mos PU 100% 83% 17% 57.2 mos 108 mos NR* 186 mos R/R 91% 44% 47% 11 mos 82 mos 15 mos 168 mos
TNF-α-238GA, IL-1α-889CC and IL-10–819CC Polymorphisms Confere an Increased Risk to Develop Multisystem Langerhans Cell Histiocytosis.
Authors: De Filippi Paola , Danesino Cesare , Ferrarese Diego , De Silvestri Annalisa , Badulli Carla , Trizzino Antonino , Fidani Paola , Garaventa Alberto , Lombardi Alessandra , Cuccia Mariaclara , Martinetti Miryam , Aricò Maurizio 
Published: October 2019

Abstract
Langerhans cell Histiocytosis (LCH) (OMIM 604856) is a rare disorder affecting any age, with a highly variable clinical course, usually related to the number and type of organs affected at the time of presentation. The symptoms range from a solitary bone lesion that does not require treatment to a disseminated disease with multiple-organ involvement and a high mortality rate, despite aggressive treatment.
The pathogenesis of LCH remains unclear, although deregulated growth, activity and trafficking of Langerhans cells (LC) are implicated. The ability of LC to migrate from the epidermis to regional lymph nodes is of pivotal importance for the induction of immune response and there is increasing evidence that both cytokines and chemokines are implicated in this function. We report the analysis of polymorphisms in genes coding for different cytokines in a population of patients with LCH in comparison to an Italian control population (n=140).
We studied 40 patients, with a mean age at the disease of onset of 6.1 (±5.0) years; the 15 with single-system (SS) disease had a mean age of 7.1 (±3.9) years, while the 25 with multi-system (MS) disease had a mean age of 5.3 (±5.3) years. The Cytokine Genotyping Tray (Pel-Freez, Milwaukee, USA) was used for the detection of the following polymorphisms: Il-1α-889 C/T, Il-1β (−511 C/T; +3962 T/C), IL-1R pst1 1970 C/T, IL-RA mspa1 11100 T/C, IL-4Rα +1902 G/A, IL-12 -1188 C/A, γ IFN UTR 5644 A/T, TNF α (−308 G/A; −238 G/A), IL-2 (−330 T/G; +160 G/T), IL-4 (−1098T/G; −590 T/C; −33 T/C), IL-6 (−174 G/C; nt565 G/A), IL-10 (−1082 G/A; −819 C/T; −592 C/A).
The following polymorphisms showed a different distribution in patients versus controls: IL-4–33 (p=0.048); IL-4–590 (p=0.005); IL-1α-889 (p=0.009). The correspondence analysis of these variables showed that genotypes IL-4 -33TT, IL-4 -590 TC and-1β+3962TT confer an increased risk of developing SS disease, while genotypes TNF-α-238GA, IL-1α-889CC and IL-10–819CC give an increased risk of developing MS disease. The present study supports the concept that constitutional variants affecting the cytokine network may induce susceptibility to develop LCH and also affect its manifestations.
Figure Figure
Improving the Efficacy of Rituxan by Rational Protein Engineering.
Authors: Lazar Greg , Dang Wei , Vafa Omid , Karki Sher , Vielmetter Jost , Doberstein Stephen , Carmichael David , Hayes Robert 
Published: October 2019

Abstract
Antibody-dependent cell-mediated cytotoxicity (ADCC) is a key effector function for the clinical efficacy of monoclonal antibodies (Cartron et al., 2002; Weng and Levy, 2003), and is mediated primarily through a set of closely related Fc receptors (FcRs) with both activating and inhibitory activities. Using computational design algorithms and high-throughput screening, we have engineered a series of IgG1 Fc variants with optimized FcR affinity and specificity. These variant Fc domains are readily combined with the variable domains of any antibody and consist of from 1–5 changes in the amino acid sequence. With rituximab as a model system, we have generated variants with greater affinity for the activating receptor FcgammaRIIIa and weaker affinity for the inhibitory receptor FcgammaRIIb. These variants show a marked increase (over 2 logs) in ADCC using purified natural killer cells or PMBCs from healthy human donors against WIL2-S cells, a CD20-bearing tumor cell line. Moreover, PBMC genotyping indicates that this effect occurs irrespective of whether the donor is a high responder (FcgammaRIIIa dimorphism 158V homozygous) or low responder (FcgammaRIIIa dimorphism 158F homozygous or heterozygous) to rituximab therapy. In vivo studies show that our variants deplete circulating B-cells more effectively than rituximab in cynomolgus monkeys with an improvement in half-maximal potency of over 10-fold as measured by flow cytometry. The macaques showed no unusual clinical signs or depletion of other cells types. These agents hold promise as more potent and more efficacious treatments for NHL. Because these Fc mutations display a comparable effector function enhancement in other antibodies such as anti-CD52, anti-EGFR1 and anti-Her2, our technology provides a broadly applicable means for improving the efficacy of the next generation of therapeutic antibodies.
The Canonical Wnt/β-Catenin Pathway Is Active in Pre-B Acute Lymphoblastic Leukemia (ALL) Cells and Augments Their Growyh and Survival.
Authors: Khan Navid , Bradstock Ken , Bendall Linda 
Published: October 2019

Abstract
Wnt signalling is known to play an important regulatory role in hematopoietic progenitors/stem cells during both fetal and adult development. Recently this pathway has been implicated in several hematological malignancies, however, its precise role in pathogenesis of pre-B ALL remains unknown. In this study we examined the expression of genes required for Wnt signalling in 12 ALL cases, normal bone marrow mononuclear cells, bone marrow stroma and the effect of Wnt-3a stimulation on leukemic cell growth and survival. RT-PCR analysis revealed expression of Wnt family members 2b, 5a, 10b and 16b in most ALL cases. Primary BM stroma expressed Wnt-5a alone while BM mononuclear cells expressed Wnts 3a, 5a, 10b and 16b. Wnt receptors Fz-7 and 8 were widely expressed on ALL cases while Fz-3 and 4 showed restricted expression. Together this suggests that Wnt signalling pathway may be active in pre-B ALL cells. To characterise functional consequences of Wnt pathway activation we investigated the effects of Wnt-3a on proliferation, survival and cell cycle status of blasts from three pre-B ALL cell lines, one newly derived stromal dependent cell line (STYG) and one primary patient sample under 3-day serum-free culture conditions. Exposure to Wnt-3a resulted in a mean 5.3-, 5.2-, 1.7-, 2.7- and 5.1- fold stimulation of 3H-thymidine incorporation in NALM6, Reh, LK63, STYG and primary ALL cells, respectively. Cell cycle analysis based on propidium iodide staining confirmed an increased proportion of cells progressing from G0/1 through to S/G2/M phases. Wnt3a augmented survival in all leukemic cells by 18.6% (range 11.7% – 24.6%, p<0.001) in comparison to untreated cells under serum-free conditions as measured by Annexin V/PI staining. Immunofluorescence microscopy revealed elevated nuclear b-catenin levels in Wnt-3a stimulated cells, confirming activation through the canonical pathway. Our results suggest that Wnt proteins may exert a proliferative/survival effect on leukemic cells through an autocrine/paracrine regulatory loop.