bluuebunny/crossref_metadata_2025_split huggingface dataset:
Promoter Hypermethylation of Tetraspanin Members Contributes to Their Silencing in Myeloma Cell Lines.
Authors: Drucker Liat , Tohami Tali , Tartakover-Matalon Shelly , Zismanov Victoria , Shapiro Hava , Radnay Judith , Lishner Michael 
Published: April 2020

Abstract
Multiple myeloma (MM) cell interactions with their microenvironment modulate acquired drug resistance and disease progression. Indeed, reported aberrant gene methylation underscores the possible role of epigenetic events in MM’s molecular profile. Membranal tetraspanins are often inversely correlated with cancer prognosis and metastasis, however mutations were unidentified hitherto. Their promoter characteristics and frequent down-regulation conform to transcriptional silencing by chromatin remodeling. We delineated the baseline expression of select tetraspanins in MM cell lines (RPMI 8226, U266, ARP1, ARK, CAG, and EBV transformed ARH77) and fresh bone marrow samples (n=9) for the first time and determined reduced expression of CD9, CD81, and absence of CD82. Thus, we aimed to assess their promoter methylation status. Indeed, we established CD9, CD81, and CD82 promoter methylation in MM cell lines employing: Methyl-specific-PCR of bisulfite modified G-DNA; PCR of G-DNA digested with methylation sensitive restriction enzyme (Hin6I). Re-transcription of assayed genes in the cell lines following demethylation (5-aza-dC) confirmed the mechanistic significance of methylation to their regulation. Combined de-methylation and de-acetylation (TsA) induced synergistic elevation of CD82 mRNA. We conclude that chromatin remodeling contributes to tetraspanin silencing in MM.
FDG-PET Predicts Response to Fractionated Radioimmunotherapy with 90Y-Epratuzumab Anti-CD22 MAB in Patients with NHL.
Authors: Bodet-Milin Caroline , Rousseau Caroline , Campion Loic , Ansquer Catherine , Dupas Benoit , Milpied Noel , Mahe Beatrice , Chatal Jean-Francois , Wegener William A. , Goldenberg David M. , Kraeber-Bodere Francois 
Published: April 2020

Abstract
Objective: To evaluate FDG-PET imaging for early prediction of response in patients with NHL treated with fractionated radioimmunotherapy (RIT).
Methods: Ten patients from a larger ongoing, multicenter, Phase I/II trial of fractionated RIT (2–3 injections 1-week apart of humanized anti-CD22 antibody, epratuzumab, labeled with 90Y) underwent FDG-PET imaging together with CT scans of the chest, abdomen and pelvis at baseline and 6 weeks post-RIT, and then every 3 months until progression. Tumor responses evaluated from CT images were classified using Cheson lymphoma criteria as complete response (CR), unconfirmed CR (CRu), partial response (PR), stable disease (SD) or progression of disease (PD). PET images were evaluated for abnormal focal uptake visually, using standard uptake value (SUV) quantitation, and were classified as CR when all tumor foci disappeared, incomplete response (IR) when FDG uptake decreased with persistent foci, or PD when FDG uptake increased or new foci developed.
Results: A total of 36 paired imaging studies were obtained post RIT (including 3 patients after retreatment) and evaluated as CR (n=7), CRu (n=14), SD (n=5) or PD (n=10) by CT and CR (n= 13), IR (n= 8) or PD (n=15) by PET. Of the 14 studies evaluated as CRu by CT, 7 were definitively evaluated by PET as CR, 3 as IR, and 4 as PD. Of 22 studies not evaluated as CRu by CT, PET identified PD in one case evaluated as CR by CT and was otherwise concordant with CT (10 PD/PD, 6 CR/CR, 5 SD/IR). Among PET images acquired at 6 weeks post-RIT, the mean time-to-progression (TTP) was 9.6 months for negative PET images (CR) compared to 4.1 months for positive PET findings (IR, PD) (P=0.16).
Conclusion: In our study, FDG-PET appeared superior to conventional CT in evaluating response to fractionated RIT. For CT scans frequently evaluated as CRu, PET resolved uncertainty regarding residual disease, and PET images acquired 6 weeks after RIT predicted later relapse.
Adoptive Immunotherapy with Donor Allodepleted T Cells.
Authors: Dal Cortivo L. , Mahlaoui N. , Picard C. , Neven B. , Andre-Schmutz I. , Luby J.M. , Martinache C. , Paquet T. , Ledeist F. , Fischer A. , Cavazzana-Calvo M. 
Published: April 2020

Abstract
Allogeneic hematopoietic stem cell transplantation (HSCT) is the treatment of choice for many hematological malignancies or inherited disorders. In the partially incompatible HLA setting, ex vivo T-cell depletion of the graft and post-transplantation immunosuppression effectively prevent development of graft-versus-host-disease (GVHD), but lead, in turn, to a delay in immune reconstitution and a concordant increase in the rate of incidence of opportunistic infections and disease relapse. In order to selectively deplete T cells responsible for GVHD, we have designed an ex vivo procedure to eliminate CD25 expressing alloactivated donor T cells. In a first phase I/II study based on the use of an anti-CD25 immunotoxin (IT) 15 pediatric patients with acquired or congenital hematopoietic disorders who had received HSCT were infused with 1 to 8x105 allodepleted T cells/kg. No cases of severe acute (&gt;grade II) GVHD occurred. aGVHD of grade I or II, which developed in four patients, correlated with anti-host residual proliferation above 1% in a mixed lymphocyte reaction. Evidence for early T cell expansion was shown in 3 patients with ongoing viral infections. In an attempt to improve allo-depletion and infuse larger numbers of cells, we have developed a new method based on immuno-magnetical depletion of CD25 expressing cells. In pre-clinical tests, this method lead to a more specific and efficient allo-depletion than that obtained with IT. This new procedure is currently used in a phase I/II clinical trial that will include 25 pediatric patients with inherited disorders of the immune system. 3x105 to 5x106 allo-depleted donor T cells/kg will be infused, with three to five patients per dose. Allodepleted donor T cells are cryopreserved until the obtention of quality control results Inclusion, i.e. infusion of allodepleted T cells is performed only if:1) engraftment is proven, 2) absence of GVHD 3)residual antithymoglobulin &lt;0.2microg/ml,4) allodepletion inhibition more than 99% of residual proliferation against host cells in a mixed lymphocyte reaction. Included patients will be stratified in two groups depending on the presence or absence of a viral infection with clinical symptoms. Toxicity is evaluated by occurrence of aGVHD above grade II. Efficacy is measured by CD4+CD3+ T cell counts in the blood two months post HSCT. A real time bayesian statistical approach will allow to test both criteria as primary objectives and to increase or decrease the dose according to the results obtained. Two patients have been so far included in the “infected” group and infused with 3x105 allodepleted T cells/kg. One patient developed grade II cutaneus GVHD. For both, efficacy was reached, since they presented more than 200 CD4+CD3+ T cells /mm3 as early as 60 days post HSCT. These preliminary results are encouraging but need to be further confirmed.
Clinical Outcomes in Adult T Leukemia/Lymphoma: Report of 55 Cases from Peru.
Authors: Beltrán-Gárate Brady E. , Carrasco-Yalan Antonio A. , Lopéz-Odría Olga M. , Riva-Gonzales Luis , Ríos Hugo , Chumpitáz-Anchiraico Gloria , Falcón-Lisarazo Silvia , Navarro-M Juan , de Mendoza Fernando Hurtado , Castillo-Aguirre Jorge 
Published: April 2020

Abstract
Adult T -cell leukaemia/lymphoma (ATL) is an aggressive disease associated with human T-cell lymphotropic virus type-I (HTLV-I) with heterogeneous clinical presentation and outcomes, described in Southern Japan, Europe, Caribbean and previously on Pacific coast of South America including Peru (EHA 2001, abst. 304). Shimoyama’s ATL classification (BHJ1991:79) includes four types: acute, lymphomatous, chronic and smoldering; recently a new clinical type cutaneous had been described (BJD2005:152). Herein we show our experience in ATL in our institution between October 1997 and May 2005 All our 55 cases shown positivity to HTLV-I Western Blot test; immune-histopathology, blood smears and flow cytometry showed mature T-cell lymphocyte. Median age at diagnosis 61 years old (range 23–84), female/male ratio: 1.2. Thirty-one (56%) patients had ECOG status performance at diagnosis ≥ 2. Clinical types: acute (n=26), lymphomatous (n=22), smouldering (n=2), cutaneous (n=5) with no chronic type observed. Median haemoglobin diagnosis was 12.1 g/dl (range 6.9–17), median albumin was 3.2 g/dl (range 1.8 – 4.9), median beta-2 microglobulin was 4.6 g/dl (range 1.5 – 16.9), median globulin was 2.7 g/dl (range 1.5 – 8.2) and DHL was 796 UI/ml (range 331 – 13000). Twenty-five per cent (9/36) debuted with hypercalemia (acute type=7, lymphomatous=2). Acute ATL showed median leukocytes of 48,900 cell/mm3 (range 6830–259,000). IPI risk score was: low (n=6), low intermediate (n=7), high intermediate (n=16) and high (n=27).
Treatment for acute ATL was based on acute leukaemia and lymphoma regimens without any response but one, interestingly this patient was treated with Fludarabine 25 mg/mt2 day 1–5 each 28 day for 6 cycles and got complete remission. Twenty-one over 24 lymphomatous ATL type were evaluable for treatment response: overall response 38% (9/24) with 26% complete response. Smouldering and cutaneous ATL types received mainly topic treatments. Stratify analysis for IPI, DHL, beta-2 microglobulin, globulin and albumin for acute and non-acute ATL did not show any statistic difference. Median overall survival was: acute type (2.0 months DE 0.2), lymphomatous type (10.2 months DE 3.6), smouldering type (17.2 months) and cutaneous type (36.2 months DE 19.5) (Log Rank 30,76 p=0.0)
ATL persist is a poor prognostic peripheral T-lymphocytic malignancy with bad clinical and therapeutically outcomes mainly in the acute type. Cutaneous type seems to be less aggressive.
Figure Figure
Anti-CD20 Monoclonal Antibody (Rituximab) for Therapy of T-Cell/Histiocyte-Rich Large B-Cell Non-Hodgkin Lymphoma.
Authors: Park EunSil , Lim Jae Joung , Kang Hyoung Jin , Shin Hee Young , Ahn Hyo Seop 
Published: April 2020

Abstract
T-cell/histiocyte-rich large B cell lymphoma (THR-BCL) is morphologic variants and subtypes of diffuse large B cell lymphoma (DLBCL). Four immunomorphologic criteria were applied to distinguish THR-BCL from DLBCL.
a diffuse or vaguely nodular pattern of neoplastic infiltrate, the presence of scattered large atypical lymphoid cells that are of B-cell phenotype, predominance of a reactive background infiltrate, composed of both T-cell and non-epithelioid histiocytes, minimal presence of small B-cells in neoplastic areas.
Bcl-6 protein expression, which was generally accepted markers of germinal center differentiation, was noted more than half of the THR-BCL cases. THR-BCL predominantly affected middle-aged men who present with advanced disease and an unusually high percentage of bone marrow (BM) involvement. Here we report a pediatric case of THR-BCL. 14-year-old boy was presented with both cervical mass which was observed 1 month ago. He complained generalized weakness and chest discomfort had fever. Cervical lymph node and BM biopsy were taken. Laboratory finding was as follows; Hemoglobin 10.4 mg/dL, hematocrit 31 %, leukocyte 6,730/μL, platelet 219,000/μL. Na 128 mmol/L, K 4.6 mmol/L, Cl 95.4 mmol/L, BUN 10 mg/dL, Cr 1.2 mg/dL, LDH 2,108 U/L. Lymph node specimen showed diffuse large B cell lymphoma and numerous histiocytes. Immnuohistochemical staining; CD 20(+), CD 10(−), CD 3(+), CD 68(+). Ann Arbor stage is IVB, international prognostic index is high-intermediate risk. He received induction chemotherapy with prednisolone, vincristine, cyclophosphamide, doxorubicin, rituximab and achieved remission and now he have continued chemotherapy for 7 months in state of complete remission. THR-BCL is a distinct clinicopathologic entity within DLBCL that is characterized by an aggressive behavior and high risk of treatment of failure. That is the reason why delineate this subgroup. Experimental therapeutic strategy was indicated in patients who relapsed after having obtained a complete remission or had partial response after initial chemotherapy.
Histone Deacetylase Inhibitors Induce Growth Inhibition, Cell Cycle Arrest and Apoptosis in Mantle Cell Lymphoma and Reduce VEGF Production.
Authors: Heider Ulrike , Kaiser Martin , Zavrski Ivana , Sterz Jan , Jakob Christian , Fleissner Claudia , Possinger Kurt , Sezer Orhan 
Published: April 2020

Abstract
Mantle cell lymphoma (MCL) is a B cell lymphoma characterized by the translocation t(11;14)(q13;q32) and an overexpression of cyclin D1. Since current therapy regimens are not effective enough, novel treatment strategies are urgently needed. Histone deacetylase (HDAC) inhibitors have emerged as a new group of agents effective in several human malignancies. This study evaluated the effects of HDAC inhibitors on mantle cell lymphoma.
Three human mantle cell lymphoma cell lines (JeKo-1, Hbl-2 and Granta-519) were exposed to different concentrations of the HDAC inhibitors sodium butyrate and SAHA. MTT assays showed a reduced survival of cells after exposure to these agents. After 48 hours of incubation, IC50 of viability was noted at 1.0μM in JeKo-1, at 3.9μM in Hbl-2 and at 4.3μM in Granta-519. For sodium butyrate, IC50 was observed approximately at 1.5mM in JeKo-1, 1.9mM in Hbl-2 and 11.2mM in Granta-519 after 48 hours. Annexin-V staining showed that all of the SAHA and sodium butyrate-treated cell lines underwent specific apoptosis in a time and dose dependent manner. Cell cycle analysis revealed a decreased proportion of cells in S phase and increased proportion of cells in the G0/G1 and/or G2/M phases after treatment with HDAC inhibitors. To evaluate the effects of HDAC inhibitors on cell cycle regulators, the protein levels of p21, p27, and cyclin D1 were analyzed. SAHA increased p21 in all three cell lines. Expression of p27 was enhanced in JeKo-1 and Granta-519, while it remained constant in Hbl-2. Treatment with sodium butyrate increased the expression of p21 in JeKo-1 and Hbl-2, while in Granta-519 no effect was noted. The expression of p27 remained constant in all cell lines after exposure to sodium butyrate. Incubation of cells with both HDAC inhibitors lead to a downregulation of cyclin D1. In addition, we examined the influence of SAHA on the production of the angiogenic cytokine VEGF. Interestingly, treatment with SAHA led to a decrease of VEGF secretion in comparison to untreated cells. Based on these findings, we provide evidence that HDAC inhibitors have antiproliferative effects in mantle cell lymphoma and may represent a future therapeutic option for this disease.
Lack of Lipid Raft Domain Reorganization Following Ligation of CD20 Is Associated with Resistance to Rituximab-Induced Complement-Dependent Cytotoxicity.
Authors: Olejniczak Scott H. , Hernandez-Ilizaliturri Francisco J. , Clements James L. , Czuczman Myron S. 
Published: April 2020

Abstract
The chimeric monoclonal antibody (mAb) rituximab has previously been shown to induce cell death upon binding surface CD20 of normal and malignant B-cells by three distinct and complementary mechanisms:
complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), and direct apoptosis.
The contribution of each of these mechanisms to the clinical efficacy of rituximab observed in lymphoma patients has yet to be fully elucidated. While laboratory and clinical data supports a role for CDC, ADCC, and/or direct signaling in rituximab activity, a better understanding of individual mechanisms and their interaction is necessary to develop strategies to improve rituximab’s biological activity or overcome resistance. Several previous studies have demonstrated that rituximab has the ability to induce lipid raft domain (LRD) polarization and stabilization of CD20 in LRDs. The contribution of LRD re-organization to complement activation following rituximab binding to surface CD20 was studied in rituximab-resistant B-cell NHL cells and MOLT-4 T-cell lymphoma cells transfected with wild-type and truncated forms of CD20. Rituximab-resistant cell lines (RRCL) were generated from well characterized B-cell lymphoma cell lines (Raji, RL, SU-DHL-4) by exposing them to increasing concentrations of rituximab or rituximab plus human serum as a source of complement. Individual clones were then isolated by limiting dilution from RRCL and the parental cell lines from which they were derived. Standard 51Cr-release assays were used to measure CDC-associated cell lysis following exposure of cells to rituximab in the presence of human serum. Following repeated exposure to increasing concentrations of rituximab (alone or in the presence of human serum) most clones were found to be significantly more resistant to rituximab-induced CDC than parental cells from which they were derived. Rituximab-sensitive cells were found to rapidly polarize CD20-containing lipid raft domains following rituximab binding whereas resistant cells demonstrated significant impairment of this process. Upon chemical disruption of lipid rafts in sensitive cells, the ability of rituximab to induce CDC was significantly reduced. Additionally, MOLT-4 T-cells transfected with truncated forms of CD20 were shown to have a reduced ability to polarize into lipid rafts following anti-CD20 binding and to have a significant loss of rituximab-induced CDC. Taken together these data suggest that lipid raft polarization following rituximab binding to wild-type CD20 is a required event in the induction of CDC and that impairment of lipid raft polarization is a potential mechanism contributing to rituximab resistance.
Molecular Characterization of a Novel Subtype of Pediatric Acute Lymphoblastic Leukemia.
Authors: Mullighan Charles G. , Ross Mary E. , Zhou Xiaodong , Dalton James , Behm Fred G. , Shurtleff Sheila A. , Downing James R. 
Published: April 2020

Abstract
Gene expression profiling is a powerful tool to classify and predict subtypes of pediatric acute lymphoblastic leukemia (ALL). In addition to accurately classifying known subtypes of ALL, microarray analysis of 327 cases of ALL at our institution using Affymetrix U95 arrays identified a previously uncharacterized novel subgroup of 14 cases of B-ALL with a gene expression signature distinct from other leukemias, suggesting a unique pathogenesis. These cases lacked a recurring cytogenetic anomaly, showed a high frequency of aberrant expression of CD2, lacked molecular markers of other subtypes of ALL, and had a favorable prognosis. We have used several complementary candidate and genome-wide approaches to identify the molecular basis of this novel subtype. Gene expression profiling using Affymetrix U133A and B arrays was used to refine the signature, and when applied to an additional 36 cases of cytogenetically normal B-ALL, 5 cases were identified that share the novel gene expression profile. Intriguingly, the tyrosine kinase PDGFRA was overexpressed in the majority of the novel cases, with 6 novel cases showing exceedingly high levels of PDGFRA expression, which was confirmed by western blotting and flow cytometry. Unexpectedly, 3 of these cases harbored the FIP1L1-PDGFRA fusion characteristic of idiopathic hypereosinophilic syndrome. However, FISH examination demonstrated that this fusion was present in a minor subclone only. RT-PCR and FISH approaches failed to identify alternative PDGFRA fusions, and PDGFRA sequencing failed to identify evidence of activating mutations. Furthermore, in unstimulated cultures or following PDGF-AA stimulation, PDGFRA-overexpressing ALL blasts were not sensitive to imatinib (Gleevec). Other genes in the gene expression profile with potential roles in leukemogenesis, include include the B-cell receptor signaling mediator BRDG1 and the tyrosine phosphatase PTPRM. Using FISH and genomic sequencing of multiple candidates, no potentially leukemogenic abnormality has been identified. To determine if gene amplification, deletion, or copy-neutral loss of heterozygosity is characteristic of this subtype of ALL, genome-wide array-based comparative genomic hybridization and Affymetrix 100K single nucleotide polymorphism arrays were performed on all cases. Deletion of the CDKN2A/2B locus, and deletion of a region at 8p22–23.1 flanking the SPAG11 locus were each found in multiple cases, however no single unifying abnormality was identified. In summary, we have identified and characterized a novel subtype of B-ALL with unique gene expression signature, high incidence of CD2 and PDGFRA overexpression, and favorable outcome. Although no uniform causal molecular lesion has been identified, FIP1L1-PDGFRA fusion may represent one mechanism of PDGFRA overexpression. Further studies and analysis of additional cases may prove informative.
Histamine Monitoring in Patients with CML during Treatment with Imatinib: Comparison to Monitoring by Cytogenetics and BCR/ABL.
Authors: Agis Hermine , Herndlhofer Susanne , Semper Hans , Pirc-Donoewenater Hendrati , Haas Oskar , Mannhalter Christine , Esterbauer Harald , Sperr Wolfgang R. , Geissler Klaus , Valent Peter 
Published: April 2020

Abstract
The tyrosine kinase inhibitor STI571=imatinib is highly effective in the treatment of chronic myeloid leukemia (CML). Although most patients (pts) show a complete cytogentic response (CCR) to this tyrosine kinase inhibitor, drug resistance may occur. Therefore, monitoring of minimal residual disease (MRD) during imatinib-therapy is of clinical importance. However, most MRD-parameters require special technology and equipment and are expensive. We found that histamine levels are highly upregulated at diagnosis in pts with CML (controls, n=39: median, 55.2 ng/ml, range, 19.1–108 ng/ml vs CML, n=44: median, 5,684.5 ng/ml, range, 181–47,816 ng/ml; p&lt;0.0005) and correlate with the presence of basophils (R=0.87). To define the value of whole blood histamine as a marker of MRD in CML, histamine levels were determined serially by RIA before and during treatment with imatinib in 80 pts with CML (chronic phase, CP, n=70; accelerated phase, AP, n=10). Of the pts with CML-CP, 29 were previously untreated, whereas 41 pts had received interferon-alpha or a bone marrow transplant prior to imatinib. From the 10 pts with CML-AP, 3 had received previous interferon-alpha. Imatinib was given at a dose of 400 mg/day (CML-CP) or 600 mg/day (CML-AP and CP pts who did not respond adequately to 400 mg/day) orally. The rate of complete cytogenetic response (CCR) amounted to 77.6%, the rate of major cytogenetic response was 80%. Blood histamine levels decreased significantly in CML pts during treatment with imatinib, and returned to normal levels in all pts with CCR. In most pts, loss of CCR was accompanied or was preceded by a recurrent increase in histamine as well as an increase in BCR/ABL determined by light cycler-based real time PCR. The pts who did not enter CCR exhibited higher histamine levels and higher levels of BCR/ABL compared to those with continuous CCR (p&lt;0.05). Unexpectedly, whereas the numbers of basophils were found to correlate well with histamine levels during therapy with imatinib (R=0.96), no correlation was found between histamine and Ph+ metaphases (R=0.34) or histamine and percentage of BCR/ABL (R=0.14), suggesting that basophil-histamine is an independent variable. Basophil-histamine should thus be considered as a simple and reliable additional marker to monitor MRD in pts with CML.