bluuebunny/crossref_metadata_2025_split huggingface dataset:
Individuals Expressing FcγRIIIA-158 V/V and V/F Show Increased NK Cell Surface Expression of FcgRIIIA (CD16), Rituximab Binding, and Demonstrate Higher Levels of ADCC Activity in Response to Rituximab.
Authors: Hatjiharissi Evdoxia , Santos Daniel Ditzel , Xu Lian , Verselis Sigitas , Modica Michael , Leleu Xavier , Hunter Zachary , Ho Allen W. , Manning Robert , Patterson Christopher , Anderson Kenneth C. , Fox Edward , Treon Steven P. 
Published: April 2020

Abstract
The homozygous expression of phenylalanine (F/F) at codon 158 of FcγRIIIa (CD16) is associated with inferior clinical responses to the anti-CD20 monoclonal antibody rituximab in patients with indolent non-Hodgkin’s lymphoma, in contrast to higher response rates observed for Waldenstrom’s macroglobulinemia patients expressing at least one valine (V/F, V/V) and follicular NHL patients who are homozygous for valine (V/V). We attempted elucidate the potential basic mechanism(s) behind these clinical observations by analyzing all the potential implications of this polymorphism among the 3 polymorphic subgroups at FcγRIIIA-158 (F/F, V/F, and V/V). We therefore used peripheral blood isolated natural killer (NK) cells from a pool of 52 unrelated healthy donors who were genotyped for FcγRIIIA-158. We evaluated allele-specific differences for FcγRIIIa gene expression by quantitative RT-PCR and demonstrated higher transcript levels among V/V (23.2 ng/mL) versus V/F (6.7 ng/mL) and F/F (6.2 ng/mL) (p&lt;0.0001). We then determined protein levels for CD16 in the same subgroup of donors using quantitative flow cytometry. The number of CD16 receptors per NK cell was 105,947, 94,863, and 69,130 for the V/V, V/F and F/F donors, respectively and was significantly higher among donors who expressed at least one valine (V/V and V/F) versus F/F (p=0.033). We next determined rituximab binding affinity to NK cells from V/V, V/F and F/F donors following incubation at concentrations of 10–200 ug/ml, and use of an indirect competitive assay with the anti-CD16 monoclonal antibody 3G8 (Cancer Research 64:4664). Rituximab binding to NK cells was higher among donors expressing at least one valine at all concentrations evaluated, with mean rituximab binding (defined as % of inhibition of mean fluorescence intensity for 3G8) as follow: V/V (72%); V/F (53%); and FF (37%); (p=0.017). Lastly, we assessed rituximab dependent NK cell mediated cytotoxicity (ADCC) using CD20 expressing ARH-77 B-cells and observed higher levels of ADCC killing among V/V (82%) and V/F (80%) versus F/F (23%) donors at an effector: target cell ratio of 20:1. Taken together, these studies suggest that individuals who express at least one valine at FcγRIIIA-158 might have better clinical outcomes to rituximab therapy on the basis of increased FcγRIIIA-158 receptor expression, rituximab binding and ADCC mediated killing of tumor cells.
Bortezomib Therapy Alone and in Combination with Dexamethasone for Patients with Previously Untreated Multiple Myeloma.
Authors: Jagannath Sundar , Durie B. , Wolf J. , Camacho E. , Irwin D. , Lutzky J. , McKinley M. , Gabayan E. , Mazumder A. , Crowley J. , Vescio R. , Schenkein D. 
Published: April 2020

Abstract
Introduction: Bortezomib ± dexamethasone (dex) has demonstrated impressive activity in the treatment of relapsed and refractory myeloma. Bortezomib is currently approved in the U.S. for multiple myeloma patients who have received at least 1 prior therapy. We are conducting a phase 2 trial evaluating bortezomib alone or in combination with dex as first-line therapy in patients with myeloma.
Methods: Eligible patients had measurable disease and a Karnofsky performance score (KPS) ≥ 50%. Bortezomib 1.3 mg/m2 was administered by IV bolus on days 1, 4, 8, and 11 of a 3-week cycle for a maximum of 6 cycles. Oral dex 40 mg was given to patients who achieved &lt; partial response (PR) after 2 cycles or &lt; complete response (CR) after 4 cycles. European Group for Blood and Marrow Transplantation criteria were used to assess response, with the addition of a near CR (nCR) category, defined as nondetectable M-protein by electrophoresis but positive immunofixation and normal bone marrow.
Results: Fifty patients have been accrued to the study, and 40 are evaluable for response. Median age was 58 years, and 52% were men. The major myeloma subtypes were IgG (64%) and IgA (19%). The majority of patients were Durie-Salmon stage II (29%) or IIIA (43%). The major response rate (CR + nCR + PR) was 85%. The best response was observed after cycle 2 in 41%, after cycle 4 in 75%, and after cycle 6 in 85% of patients. Dex was added for 28 patients (70%): 17 patients at cycle 3, 10 patients at cycle 5, and 1 at cycle 6. An improved response after combination therapy was observed in 18 patients: 11 improved from MR to PR, 5 improved from stable disease (SD) to PR, 1 improved from SD to CR, and 1 improved from SD to minor response (MR). Twelve patients underwent stem cell transplantation, and all had complete hematologic recovery. Thirteen patients discontinued from the study: 9 due to adverse events, 2 due to progressive disease, and 2 withdrew. The most common adverse events (grade ≥ 2) were neuropathy (26%), fatigue (22%), constipation (17%), and neutropenia (14%). Two patients developed grade 4 events, 1 with neutropenia and 1 with thrombocytopenia.
Conclusion: Bortezomib alone or in combination with dex was highly active in the first-line treatment of patients with myeloma. The combination of bortezomib + dex demonstrated additional benefit. Toxicities were manageable and reversible. Although experience has been limited to date, stem cell transplantation was successful in all attempts, indicating that bortezomib-based therapy should be further explored as an induction regimen before transplantation.
Treatment Outcome of Children over 10 Years and Young Adults with ALL in Sweden: A Comparison between Paediatric- and Adult Protocols.
Authors: Heyman Mats , Gustafsson Goran , Smedmyr Bengt , Soderhall Stefan , Hallbook Helene 
Published: April 2020

Abstract
On behalf of the Swedish Adult ALL Group and the Swedish Childhood Leukemia Group. Several recent studies have shown superior outcome for older teenagers and young adults with acute lymphoblastic leukemia (ALL) treated in pediatric oncology departments compared with adult hematology departments. However, some of these comparisons have been hampered by either biased risk-group stratification (adult protocols considering young adults as lower risk and pediatric protocols considering the same age-group as high-risk), or a markedly higher treatment-related mortality for the adult treatment. During the 1990s in Sweden, adolescents with ALL were treated in a pediatric oncology unit or in an adult haematological unit, depending on the initial referral. For both groups there were well established national (and for children Nordic) treatment protocols designed by the Swedish Adult ALL Group and the Nordic Society of Pediatric Haematology and Oncology (NOPHO), but with different treatment strategies. In the NOPHO protocol, the teenagers were excluded from the lowest risk-group, but were only treated as high-risk if additional risk-factors were present, whereas age was not a risk-factor in the adult protocol.
The clinical characteristics, treatment and outcome for patients with ALL aged 10–40 years treated either according to the NOPHO protocol NOPHO ALL-92 (1992–2000), or the Swedish Adult ALL Group protocol 1994–2000, were reviewed. The impact of these treatment protocols on remission rate and survival was analysed. In total, 243 patients with B-precursor and T-cell ALL were treated according to the protocols. There was a significant difference in remission rate between the pediatric protocol (99%, n=144) and the adult protocol (90%, n=99) (p&lt;0,01). Furthermore, the event-free survival (EFS) was superior for patients treated according the pediatric protocol compared to patients treated according to the adult protocol (p&lt;0.01). Both protocols included response to induction treatment in the treatment stratification, but the difference in outcome was significant also when only pre-treatment risk-criteria, not including initial treatment response, were considered. Patients aged 15–25 had a superior outcome compared to patients aged 26–40 within the adult protocol group (p=0.01). Both protocols had treatment related mortality rates well below 5%. Treatment protocol was identified as an independent risk-factor in multiple regression analyses and was the only independent predictor of outcome in the 15–20 year age group. The results indicate that adolescents may benefit from treatment according to the pediatric protocol. Future trials are called for to determine whether young adults could benefit from similar treatment.
Adoptive Transfer of Adenovirus Specific T-Cells in Children with Systemic Adenovirus Infection after Allogeneic Stem Cell Transplantation.
Authors: Feuchtinger Tobias F. , Matthes-Martin Susanne , Richard Celine , Lion Thomas , Hamprecht Klaus , Peters Christina , Schumm Michael , Beck Robert , Niethammer Dietrich , Handgretinger Rupert , Lang Peter 
Published: April 2020

Abstract
Allogeneic stem cell transplantation (SCT) has become an increasing treatment option for a variety of malignant and non-malignant disease. During immune reconstitution the host is at significant risk for viral infections. Human adenovirus (HAdV) infection is especially in children an important and serious complication. Virus-specific T-cells are essential for the clearance of HAdV, since antiviral chemotherapy has been insufficient to date. We present a new treatment option using virus-specific donor T-cells for adoptive transfer of immunity to patients with systemic HAdV-infection. We isolated in 6 patients with systemic HAdV-infection after SCT virus-specific T-cells of the donor, according to INF-γ secretion after short in vitro stimulation with viral antigen, resulting in a combination of CD4+ and CD8+ T-cells. Between 5-50x103/kg T-cells were infused for adoptive transfer. For follow-up, the infection and the in-vivo expansion of infused T-cells were evaluated. Isolated cells showed high specificity and markedly reduced but residual alloreactivity in-vitro. In three of four evaluable patients the infused T-cells underwent an in-vivo expansion and in these three patients the viral load decreased in peripheral blood after adoptive T-cell transfer. In-vivo expansion of specific T-cells was dose-independent. T-cell infusion was well tolerated. One patient experienced GvHD°II of the skin after T-cell transfer. In conclusion specific T-cell immunotherapy as a new treatment approach for children was performed in 6 cases of systemic HAdV-infection after allogeneic SCT. Induction of a specific T-cell response through adoptive transfer has been shown feasible and effective to protect from HAdV-related complications.
Simultaneous Loss of Mouse Dematin and beta-Adducin Results in Severe Erythrocyte Fragility and Hemolytic Anemia.
Authors: Khan Anwar A. , Chen Huiqing , Gilligan Diana M. , Peters Luanne L. , Messick Joanne , Haschek-Hock Wanda M. , Liu Fei , Ostafin Agnes E. , Chishti Athar H. 
Published: April 2020

Abstract
The mechanical strength and stability of the erythrocyte membrane are regulated by a network of proteins that participate in both horizontal and vertical interactions. The actin-containing junctional complexes, located at the tail ends of spectrin molecules, serve as the critical regulatory nodes for the maintenance of membrane stability. Dematin and beta-adducin, two actin-binding proteins of the junctional complex, are known to play essential roles in the regulation of erythrocyte shape and membrane stability, as revealed recently by the development of mouse knockout models. Here, we show that simultaneous loss of functional dematin (headpiece domain deletion) and beta-adducin results in severe fragility and abnormal shape of erythrocytes, despite the presence of major skeletal proteins. Adducin/Dematin Double Knockout (ADKO) mice are viable and can be distinguished at birth by their pallor with pronounced spleomegaly and regenerative hematopoiesis. Hematological evaluations show a reduction of erythrocytes, reduced hematocrit and hemoglobin, and a ~52% increase in the number of reticulocytes. The presence of a variety of misshapen and fragmented erythrocytes in the ADKO mice correlates with increased osmotic fragility and reduced erythrocyte life span in vivo. Despite an apparently normal composition of ghosts and skeletal proteins, the retention of spectrin in the ADKO erythrocyte plasma membrane is significantly compromised. Atomic force microscopy (AFM) revealed similar volume parameters in the four genotypes examined, but an increased grain size, and a decreased filament number in the ADKO erythrocyte membrane. In addition, highly aggregated, disassembled, and irregular features were visualized by AFM in the ADKO erythrocyte membrane. Staining of filamentous actin provided further evidence for the existence of large protein aggregates in the ADKO erythrocyte membrane. Together, these results demonstrate a crucial function of dematin and beta-adducin in the maintenance of erythrocyte shape and membrane stability, and more importantly, suggest the existence of an alternate mechanism for the linkage of junctional complexes to the plasma membrane.
Comparison of Three Radiation Dose Levels after EBVP Regimen in Favorable Supradiaphragmatic Clinical Stages (CS) I-II Hodgkin’s Lymphoma (HL): Preliminary Results of the EORTC-GELA H9-F Trial.
Authors: Eghbali Houchingue , Brice Pauline , Creemers Geert-Yan , van Marwijk Kooij Marinus , Carde Patrice , Van’t Veer Mars B. , Lugtenburg Elli , Sonet Anne , Sebban Catherine , Blanc Michel , Raemaekers John M. , Voillat Laurent , Rieux Chantal , Noordijk Ed M. , Henry-Amar Michel 
Published: April 2020

Abstract
Preventing late toxicity has become the cornerstone in the management of HL as global results greatly improved regarding event-free (EFS) and overall survival (OS) rates. With this aim, the EORTC and GELA groups conducted a trial (H9-F) comparing three radiation doses in patients in complete remission (CR/CRu) after chemotherapy. Adult patients with supradiaphragmatic CS I-II HL and favorable features (age &lt; 50, and CS I-II2–3, and A + ESR &lt; 50 or B + ESR &lt; 30, and MT ratio &lt; 0.35) were eligible. After 6 cycles of EBVP (epirubicin, bleomycin, vinblastine, prednisone), CR/CRu patients were randomized between 36 Gy involved-field radiotherapy (IF-RT), 20 Gy IF-RT and no RT. From September 1998 to May 2004, 783 patients were enrolled in 111 institutions from 10 European countries. Inclusion of patients in the no-RT arm was stopped in May 2002 because stopping rules were met (i.e. &gt; 20% of events). After 6 EBVP response rates were 50% CR, 26% CRu, 18% PR, 3% no change or progression, and 3% unspecified. Of the 591 CR/CRu patients, 13 (2%) were not randomized (6 refusals, 3 protocol violations, 4 causes unspecified). After a median follow-up of 51 months (range 14–81), 130 events (36 progressions, 91 relapses, 1 toxic death, 2 deaths of second cancer) were observed. At July 2005, the 4-year EFS and OS rates are as follows:
Treatment No. Pts. Prog. /Rel. /Death 4-yr EFS 4-yr OS 6 EBVP + IF-RT 36 Gy 239 2 /18 /0 88% 98% 6 EBVP + IF-RT 20 Gy 209 5 /16 /0 85% 100% 6 EBVP + no RT 130 1 /35 /1 69% 98% P value &lt; 0.001 0.241 6 EBVP, no random. 205 28 /22 /2 68% 93%
Non-randomized patients experienced a significantly worse OS than did complete responders (P=0.0012). Relapses in nodal sites were more frequent in the no RT arm (35 in unirradiated sites) than in RT arms (6 + 10 in irradiated sites). 15 patients have died, 10 of progressive disease, 2 of treatment-related complication, 1 of intercurrent disease and 2 of second cancer (1 AML, 1 NHL). In favorable early stage HL patients who achieve CR(u) after 6 cycles of EBVP, omission of IF-RT leads to an unacceptable failure rate; In contrast, with the current follow-up, IF-RT 20 Gy provides results equivalent to those of IF-RT 36 Gy.
Risk Adapted BEACOPP Regimen Based on Early Scintigraphy Can Reduce the Cumulative Dose of Chemotherapy for Standard and High Risk Hodgkin Lymphoma (HD) with No Impairment of Outcome.
Authors: Dann Eldad J. , Shalom Rachel Bar , Haim Nissim , Tamir Ada , Ben Shachar Menachem , Avivi Irit , Zuckerman Tsila , Kirschbaum Mark , Goor Odelia , Libster Diana , Rowe Jacob M. , Apelbaum Ron 
Published: April 2020

Abstract
A prospective study evaluating the outcome of HD pts whose chemotherapy was tailored based on results of scans performed after 1or 2 cycles of chemotherapy reducing the cumulative chemotherapy for early responders and maximizing the dose for late responders. Study was initiated in 1999 for patients with classical HD age 18–65y. Eligibility criteria were either stage I, II with unfavorable features (see table) or any stage III or IV HD. Those with I-II B or bulky or any Stage III-IV were defined according to IPS. Patients with standard risk were treated with 2 cycles of standard BEACOPP (SB). Those with high risk were treated with 2 cycles of escalated BEACOPP (EB). GA67 or FDG PET scan was performed at diagnosis and after the 1st or 2nd cycle for 57 and 55 pts respectively. If the early scan remained positive then additional 4 cycles of EB were administered, otherwise, SB was given. 108 pts 44 F64 M age 18–63y (median 33) who had at least 1 year of follow up are reported. The CR rate was 97%. The 4-yr disease free (DFS) and overall survival (OS) is 84% and 90% respectively at a median follow up of 35-month (5-70). The 4-yr DFS and OS are similar for standard and high risk patients. The disease progressed in 3/10 pts with an interim positive PET versus 1/40 negative scans (p&lt;0.03) and in 1/13 (8%) interim positive Ga67scan versus 7/44 (16%) negative scan (NS). Negative predictive value of early normal PET and GA67 scans are 98% and 84% respectively. Only one patient developed secondary leukemia following salvage therapy and high dose chemotherapy. One patient died during therapy from unrelated cause.
Conclusion: PET is a useful tool for early interim decision regarding dose of chemotherapy. Early PET allowed for chemotherapy reduction in 80% of high-risk pts. Only 14% of standard risk patients required dose intensification. Similar DFS and OS can be obtained regardless of IPS. 6 cycles of risk adapted BEACOPP are effective.
Standard Risk High Risk Standard BEACOPP Escalated BEACOPP Stage I, II ≥ Age 50yrs; ≥ 4 sites; “B” symptoms or Bulky, stage III,IV IPS 0-2 IPS 3-7
Mechanisms of γ-Globin Gene Promoter Activation by HBF-Inducing Short Chain Fatty Acid Derivatives.
Authors: Mankidy Rishikesh , Faller Douglas V. , Boosalis Michael S. , Bohacek Regine , Perrine Susan P. 
Published: April 2020

Abstract
High-level γ-globin gene expression for definitive therapy of beta globin disorders likely requires γ-globin gene promoter activation, dissociation of repressor complexes, and/or local chromatin modification. To define the molecular mechanisms employed by high-potency γ-globin inducers, the effects of butyrate on transcriptional co-regulatory protein recruitment to the human γ- and β-globin gene promoters were defined and compared to those of novel SCFAD γ-globin inducers recently identified through computational modeling. One particularly potent SCFAD inducer, RB7, which has no inhibitory effect on class I HDAC enzymes (HDAC1, HDAC2, and HDAC3), demonstrated 5-fold induction, (2.5 to 3-fold greater γ-globin gene-inducing activity than butyrate), in a transcriptional reporter assay which detects only strong γ-globin gene inducers. Chromatin immunoprecipitation (ChIP) assays performed on the integrated human gamma and beta globin gene promoters demonstrated that RB7, butyrate, and other transcriptionally-active SCFADs, induced dissociation of HDAC-3, and its adaptor protein NCoR, from the γ-globin gene promoter, with no such effect on the β-globin promoter, coincident with recruitment of RNA Polymerase II to the γ-globin promoter and initiation of γ-globin transcription. In a reciprocal fashion, as HDAC-3 dissociated, the chromatin-modifying ATPases Brg-1 and Brm were recruited specifically to the γ-globin gene promoter in response to the active SCFADs. The ability of the novel SCFADs to induce dissociation of HDAC-3 (but not HDAC-1 or -2) from the γ-globin promoter was proportional to the degree of γ-globin promoter induction by these agents. Knockdown of HDAC-3 by siRNA induced transcription of γ-globin specifically, demonstrating the functional importance of the activity of SCFADS in dissociating HDAC-3 from the γ-globin gene promoter. These studies demonstrate new dynamic alterations in transcriptional regulatory complexes specifically-associated with high-level activation of γ-globin and also identify essential molecular targets for future therapeutic interventions.
MicroRNAs 221 and 222 Inhibit Normal Erythropoiesis and Erythroleukemic Cell Growth Via Kit Receptor Downmodulation.
Authors: Felli Nadia , Fontana Laura , Pelosi Elvira , Botta Rosanna , Bonci Desirée , Facchiano Francesco , Liuzzi Francesca , Lulli Valentina , Morsilli Ornella , Santoro Simona , Valtieri Mauro , Liu Chang-Gong , Sorrentino Antonio , Croce Carlo M. , Peschle Cesare 
Published: April 2020

Abstract
MicroRNAs (miRs) are small non-coding RNAs that regulate gene expression primarily through translational repression. In unilineage erythropoietic (E) culture of cord blood (CB) CD34+ progenitor cells, the level of miR 221 and 222 is gradually and sharply downmodulated. Hypothetically, this decline could promote erythropoiesis by unblocking expression of key functional proteins. Our studies indicate that miR 221 and 222 target the Kit receptor: specifically, (a) the luciferase targeting assay showed that miR 221 and 222 directly interact with the 3′UTR of Kit mRNA; (b) in E culture the miR 221 and 222 level is inversely related to Kit protein expression, whereas the abundance of Kit mRNA is relatively stable. Functional studies show that treatment of CD34+ cells with miR 221 and 222, via oligonucleotide transfection or lentiviral vector infection, causes impaired proliferation and accelerated differentiation of E cells, coupled with downmodulation of Kit protein: this phenomenon, observed in E culture releasing endogenous Kit ligand (KL), is magnified in E culture supplemented with KL. Furthermore, transplantation experiments into NOD-SCID mice reveal that miR 221 or 222 treatment of CD34+ cells impairs their engraftment capacity and stem cell activity. Finally, miR 221 and 222 gene transfer impairs proliferation of the TF1 erythroleukemic cell line, expressing the Kit receptor. Altogether, our studies indicate that in human erythropoiesis the decline of miR 221 and 222 unblocks Kit protein production at translational level, thus leading to expansion of early E cells. Furthermore, overexpression of miR 221 and 222 inhibits proliferation of Kit+ erythroleukemic cells, suggesting a potential role of these microRNAs in cancer therapy.