bluuebunny/crossref_metadata_2025_split huggingface dataset:
Polymorphisms in FcγRIIIA Are Genetically Linked to FcγRIIA and May Account for the Primary Predictive Role Ascribed to Polymorphisms in FcγRIIIA-158 in Determining Rituximab Responses.
Authors: Hatjiharissi Evdoxia , Hansen Mark , Verselis Sigitas , Santos Daniel Ditzel , Xu Lian , Manning Robert , Hunter Zachary , Leleu Xavier , Ho Allen W. , Patterson Christopher J. , Fox Edward , Treon Steven P. 
Published: April 2020

Abstract
γWe and others have previously described polymorphisms in codon 158 and 48 for FcγRIIIα as predictors of clinical responses to the anti-CD20 monoclonal antibody rituximab in patients with low-grade non-Hodgkin’s lymphoma, including Waldenström’s Macroglobulinemia. The expression of at least one valine (V) at FcγRIIIα-158 and Leucine/Histidine (L/H) at FcγRIIIα-48 is associated with higher response rates to rituximab, though primacy for FcγRIIIα-158 over 48 polymorphisms for determining rituximab response is attributed to genetic linkage. As part of these studies, we sought to determine if polymorphisms in FCγRIIA were linked to FCγRIIIA since higher response rates have been observed in patients who express Histidine/Histidine (H/H) in FcγRIIA-131. We therefore performed sequence analysis of the whole FcγRIIa gene and exons 3 and 4 of the FcγRIIIa gene in 52 healthy donors. The genetic association between polymorphisms was calculated using the statistical program GOLD and expressed as linkage disequilibrium (D’). Single nucleotide polymorphisms were commonly found in FcγRIIIa at codons 158, 48 and in FcγRIIa at codons 131, 27. The genotype frequencies for polymorphisms are as follows: FcγRIIIa-158: 25% F/F; 63% F/V; 12% V/V; FcγRIIIa-48: 67% L/L; 10% L/R; 17% L/H; FcγRIIa-131: 29% H/H; 46% H/R; 25% R/R; FcγRIIa-27: 71% Q/Q; 27% Q/W; 2% W/W. Strong linkage was found between the FcγRIIIa-158 and −48 (D’=1, p=0.001), as well as between FcγRIIa-131 and -27 (D’=1, p=0.00082). Specifically, the expression of F at FcγRIIIa-158 was found to be associated with expression of L at FcγRIIIa-48, whereas the expression of H at FcγRIIa-131 was associated with the expression of Q at FcγRIIa-27. Importantly, we observed links among polymorphisms at FcγRIIa and FcγRIIIa. Specifically, FcγRIIIa-48 was linked to FcγRIIa-27 (D’=0.765, p&lt;0.00001) and FcγRIIa-131 (D’=1, p=0.0049), since all donors who were FcγRIIIa-48 L/L donors were also FcγRIIa-27Q/Q and -131R/R, respectively. Lastly, we also observed linkage between FcγRIIIa-158 and FcγRIIa-27 (D’=1, p=0.0008). Our results demonstrate significant genetic association between polymorphisms in FcγRIIa and FcγRIIIa genes, and may account for the primary predictive role ascribed to polymorphisms in FcγRIIIa-158 in determining rituximab responses.
Rituximab Maintenenance Therapy in CD20+ B-Cell Non-Hodgkin-Lymphoma - First Interim Results of a Prospective Randomised Phase II Study.
Authors: Witzens-Harig Mathias , Hensel Manfred , Neben Kai , Benner Axel , Schmier Johann W. , Dreger Peter , Kraemer Alwin , Ho Anthony D. 
Published: April 2020

Abstract
Clinical and pharmacokinetic data suggest that the effect of rituximab could be improved by prolonged exposure to the drug. To test for this hypothesis we performed a prospective randomized trial of rituximab maintenance therapy in patients with CD20+ B-cell Non-Hodgkins-Lymphoma. After completion of standard treatment patients were randomized to either observation or maintenance therapy with rituximab (375 mg/m2) every 3 months for 2 years. Patients with aggressive lymphoma were enrolled if they had achieved a complete response (CR) after initial treatment. Patients with aggressive lymphoma with residual tumor mass were examined with positrone emission tomography (PET) and qualified for randomization if PET showed no signs of tumor activity. Patients with indolent lymphoma qualified for the study if at least a partial response (PR) was achieved. So far 87 patients (pts) with CD20+ B-cell Non-Hodgkins-Lymphoma were enrolled in this trial. Histological subtypes included diffuse large cell lymphoma (38 pts), follicular lymphoma (17 pts), mantle cell lymphoma (16 pts), primary mediastinal lymphoma (11 pts), marginal zone lymphoma (1 pt), Burkitt’s lymphoma (2 pt), primary intestinal lymphoma (1pt) and unclassified B-cell lymphoma (1 pt). No severe adverse events were observed during rituximab maintenance therapy. We conclude that rituximab maintenance therapy is feasable, safe and well tolerated in patients with CD20+ B-cell Non-Hodgkins-Lymphoma. First results from an interim analysis including event free survival and overall survival for the observation group and for the maintenance therapy group will be presented.
Rituximab Retreatment in B-Cell Non-Hodgkins Lymphoma Patients.
Authors: Bairey Osnat , Dann Eldad J. , Herishanu Yair , Ruchlemer4 Rosa , Tadmor5 Tamar , Gavish6 Israel , Volchek7 Yulia , Yuklea8 Mona , Bulvik9 Shlomo , Ben-Shahar10 Menachem , Levy11 Itai , Rosenbaum Hanna , Quitt12 Miriam , Solomon13 Liora , Shpilberg Ofer ,   Israel Rituximab Retreatment Study Group
Published: April 2020

Abstract
Rituximab has revolutionized the treatment outcome of non-Hodgkins lymphoma (NHL) patients but its role in retreatment in all NHL patients is not yet established. Therefore, the Israel Rituximab Retreatment Study Group was organized in order to summarize retrospectively the treatment results of B-cell NHL patients who received ≥ 2 rituximab treatments. Eighty-eight NHL patients from 13 medical centers were enrolled, 39 males, 49 females with a mean age of 57.3 years (range 26–88). Sixty-four patients (73%) had indolent lymphoma (21- follicular grade I, 17 follicular grade II, 10-follicular grade III, 9-small lymphocytic, 6- MALT, 2- marginal zone, 1-lymphoplasmacytic). Eighteen patients (20%) had aggressive lymphoma [diffuse large B-cell lymphoma (DLBCL)] and 6 patients had mantle cell lymphoma. Fifty-nine patients received one regimen of chemotherapy and 23 patients received 2 chemotherapy regimens before the first treatment with rituximab. There was no significant difference in the median time to progression (TTP) after the first rituximab treatment whether the patient received no previous chemotherapy or 1 or 2 previous chemotherapy regimens (12 vs 12 vs 14 months, respectively). All patients received 2 courses of rituximab, 33 patients-3 courses, 6 patients -4 courses and 2 patients-5 courses, with a mean of 4.4 doses in each course (range 1–8). Only 45 patients received any treatment after the second course of rituximab. The first course of rituximab was administered alone in 46 patients and with chemotherapy in 42 (24 CHOP, 6 COP, 6 FC, 2 chlorambucil, 1 LMP, 1 DVIP, 1 ESHAP, 1 MACOP-B). There was no difference in the median time to next treatment (TTNT) whether the rituximab was given alone or with chemotherapy (16 and 14 months, respectively). The second course of rituximab was administered alone in 46 patients and with chemotherapy in 42 patients (13 CHOP, 11 FC, 6 COP, 5 ICE, 3 ESHAP, 2 HyperCVAD, 1 CNOP 1 VEEP). The addition of chemotherapy did not change the overall response (CR and PR) to the second rituximab treatment (72% in rituximab alone vs. 69% in rituximab with chemotherapy, in indolent lymphoma patients 76% vs. 72%, in aggressive lymphoma patients 70% vs. 62.5%, respectively). TTP after the second rituximab treatment was similar or possibly longer than after the first treatment (median 14 and 12 months, mean 23.4 and 16.2 months respectively).
Conclusions: The response to a second rituximab treatment is the same whether the rituximab is given alone or combined with chemotherapy. TTP after retreatment with rituximab is as good as after the first treatment. Prospective studies should examine the treatment benefit of adding chemotherapy to a second treatment with rituximab.
Re-Treatment with Rituximab Plus Chemotherapy in Patients with Diffuse Large-B Cell Lymphoma (DLBCL): A Spanish Multicenter Study.
Authors: Canales Miguel A. , Palacios A. , Martinez-Chamorro C. , Cruz M. A. , Moraleda J. M. , Terol M. J. , Almagro M. , Garcia-Vela J. A. , Aguiar D. , Caballero D. , Sancho J. M. , Ferrer S. , Rueda A. , Calvo J. M. , Fernandez J. A. , Diaz-Mediavilla J. , Gonzalez J. , Mayans J. , Montesinos C. , Rios E. , Ruedas A. , Sabin P. , Fernandez-Jurado A. 
Published: April 2020

Abstract
Rituximab in combination with CHOP-like chemotherapy has demonstrated to improve the results in young and elderly patients with DLBCL compared to chemotherapy alone. Re-treatment with rituximab is feasible in patients with indolent lymphoma, but there is few data on the effect of rituximab in combination with chemotherapy in the re-treatment of relapsed patients with DLBCL who have respond previously to rituximab + chemotherapy. In order to investigate the effect of rituximab in this setting, we have performed a multicenter retrospective study in 50 patients with DLBCL re-treated with rituximab in combination with chemotherapy. We have included in this study 46 patients (31 males, 15 females), median age 60 (range, 20 to 81 years), who achieved CR with the previous rituximab-containing regimen. At initial diagnosis, 32 patients had Ann-Arbor stage III or IV and 20 patients had IPI 3 or 4. The median interval between courses was 14.7 months. The most frequent regimens administered as up-front therapy in combination with rituximab were CHOP-like regimens (30 patients) and the commonest chemotherapy regimens used as salvage therapy were R-ESHAP (20 patients), R-ICE (7 patients), rituximab in combination with gemcitabine-based regimens (4 patients) and TTR (3 patients). The overall response rate in the assessable population was 81% (46% CR, 35% PR). In 25 assessable patients who have received rituximab in combination with chemotherapy as second-line therapy, the overall response rate was 92% (56% CR, 36% PR). The overall response rate was slightly lower in those patients re-treated with rituximab as third-line therapy (78% with 33% CR and 45% PR). The follow-up is too shorter (median 6 months) to assess the impact of re-treatment on duration of remission. The adverse events were not different to those usually observed with these regimens. In conclusion, the re-treatment with rituximab in relapsed patients with DLBCL who had respond previously to rituximab in combination with chemotherapy seems not to compromise the results in terms of response. Logically, larger prospective studies are necessary to confirm these encouraging results.
CDDO Increases Translation of CCAAT Enhancer Binding Protein alpha To Induce Granulocytic Differentiation.
Authors: Koschmieder Steffen , D′Alo′ Francesco , Radomska Hanna , Kobayashi Susumu , Levantini Elena , Suh Nanjoo , Sporn Michael B. , Di Ruscio Annalisa , Voso Maria Teresa , Berdel Wolfgang E. , Müller-Tidow Carsten , Serve Hubert , Tenen Daniel G. 
Published: April 2020

Abstract
The triterpenoid 2-Cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) is a novel antineoplastic drug which induces apoptosis of a wide variety of tumor cells in vitro and in vivo and leads to granulocytic differentiation of hematopoietic progenitor cells. We studied the effect of CDDO on CCAAT enhancer binding protein alpha (CEBPA), a transcription factor which is critical for granulocytic differentiation. In HL60 myeloblastic cells, CDDO (0.01 to 2 uM) dose-dependently decreased the number of cells in culture and increased the fraction of apoptotic cells. However, at doses which did not induce apoptosis, CDDO increased the number of granulocytic cells, as assessed by morphology, NBT assay, and FACS, and Northern blotting showed an increase of GCSFR and a decrease of c-myc mRNA. Phagocytosis of FITC-labeled E. coli bacteria by these cells was enhanced by CDDO. While CEBPA mRNA was decreased, CEBPA protein was significantly increased within 24 hours of treatment, and this was not abrogated by preincubation with the caspase inhibitor Z-DEVD-fmk, again suggesting that these effects were independent of apoptosis. CDDO increased the ratio of the transcriptionally active isoform p42 and the inactive p30 isoform 3-fold, and gel shift assays showed enhanced DNA binding to a GCSFR promoter probe. Since eukaryotic translation initiation factors (eIF) have been described to alter the CEBPA protein isoform ratio, we studied the effects of CDDO on eiF2 alpha and eiF4E activity. CDDO increased the phosphorylation of eIF4E and decreased the phosphorylation of eIF2 alpha within 5 hours of treatment, and this was associated with an increase of the p42/p30 CEBPA ratio. In the presence of the translation inhibitor cycloheximide, CEBPA protein levels decreased after 2 hours, suggesting that CDDO did not stabilize CEBPA and that de novo protein synthesis was required for the observed effects. The effect of CDDO on the p42/p30 ratio was mimicked by 2-AP, which inhibits eIF2 alpha phosphorylation, but was independent of PPARgamma and TGFß pathways, as demonstrated by preincubation with GW9662, or TGFß1, respectively. In primary blasts from patients with acute myeloid leukemia (AML), the p42/p30 ratio of CEBPA was enhanced by CDDO treatment. In conclusion, CDDO leads to granulocytic differentiation and translational induction of CEBPA protein. Since CEBPA function is impaired in many patients with AML, CDDO may provide a novel treatment approach for these patients.
Stroma-Activated Integrin-Linked Kinase (ILK) Supports Survival of Leukemic Cells Via Stimulation of Notch-Hes Signaling: New Therapeutic Opportunities.
Authors: Tabe Yoko , Jin Linhua , Tanaka Nobuko , Andreeff Michael , Konopleva Marina 
Published: April 2020

Abstract
We have previously demonstrated that the BM microenvironment plays a crucial role in the pathogenesis of AML by influencing tumor growth, survival, and drug resistance. Integrin-linked kinase (ILK) has been shown to directly interact with β integrins and phosphorylate AKT in a PI3-kinase (PI3K)-dependent manner to promote cell survival and proliferation. HES-1 encodes a basic helix-loop-helix transcription factor downstream of the Notch receptor, and functions as a positive regulator of hematopoietic and neuronal stem cell self-renewal. Direct co-culture of human mesenchymal stem cell (MSC) and leukemic NB4 cells results in activation of PI3K/ILK/AKT signaling (elevated phospho(p)-Akt, p-GSK3β and nuclear-localized β-catenin), increased expression of Notch1 and Hes1 proteins and upregulation of p-STAT3 detected by Western blot and confocal microscopic analyses. Both, PI3K inhibitor LY294002 (20 μM) and ILK inhibitor QLT0254 (10 μM) specifically inhibited stroma-induced activation of AKT and Stat-3 signaling, suppressed GSK phosphorylation and decreased Notch 1 and HES1 expression. This resulted in massive induction of apoptosis which was not abrogated by stromal co-culture (AnnexinV positivity %, MSC(-) vs MSC(+); control 33.8±2.5 vs 27.3±1.9 p=0.02, QLT 51.4±2.5 vs 55.8±3.5 p=0.26, LY 47.0±8.1 vs 47.9±6.1 p=0.85, 48hrs). In contrast, GSK3b inhibitor BIO (0.1 μM) prevented the serum-withdrawal-induced apoptosis of NB4 cells (AnnexinV positivity %, control 38.1±4.0 vs BIO 25.9±3.4 p=0.003, 48hrs) with marked increase in Notch1 and Hes1 expression detected by confocal microscopy. These observations indicate that Notch signaling is involved in leukemic cell survival stimulated by BM stromal interactions via activation of the ILK-AKT-GSK3β pathway. We have next investigated the effects of leukemic cells on stroma cells. Coculture with NB4 cells caused significant increase in Hes1 and Bcl2 proteins in MSC along with phosphorylation of STAT3 and Akt, which were all abrogated by the treatment with QLT0254 or LY294002. In summary, these results demonstrate that interactions of leukemic and bone marrow stromal cells result in activation of PI3K/ILK/AKT and Notch-Hes signaling in both, leukemic and stromal cells. Disruption of these interactions by specific ILK inhibitors represents a novel therapeutic approach to eradicate leukemia in the bone marrow microenvironment via direct effects on leukemic cells and by targeting activated bone marrow stromal cells.
Prostate-Apoptosis-Response-Gene-4 Increases Sensitivity to TRAIL-Induced Apoptosis.
Authors: Boehrer Simone , Nowak Daniel , Puccetti Elena , Ruthardt Martin , Sattler Nicole , Trepohl Bettina , Schneider Bernd , Hoelzer Dieter , Mitrou Paris S. , Chow Kai Uwe 
Published: April 2020

Abstract
The capacity of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) to preferentially induce apoptosis in malignant cells while sparing normal tissues renders it an attractive therapeutic agent. Nevertheless, the molecular determinants governing sensitivity towards TRAIL remain to be defined. Acknowledging the previously demonstrated deregulation of prostate-apoptosis-response-gene-4 (par-4) in ex vivo cells of patients suffering from acute and chronic lymphatic leukemia, we here tested the hypothesis that expression of par-4 influences sensitivity to TRAIL. We here show, that expression of par-4 in T-lymphoblastic Jurkat cells i) considerably increases TRAIL-induced apoptosis; ii) enforces cleavage of c-FlipL and the subsequent activation of the initiator caspases-8 and -10; iii) does not alter expression of the Bcl-2 family members Bax and Bak; iv) does not enhance the disruption of mitochondrial membrane potential; v) promotes down-regulation the inhibitor-of-apoptosis proteins cIAP-1, cIAP-2, XIAP and survivin; vi) concomitantly augments activation of the executioner caspases-6 and -7. Moreover we prove the crucial role of caspase-8 in par-4-promoted apoptosis by demonstrating that inhibition of caspase-8 considerably reduces TRAIL-induced apoptosis in mock- as well as par-4-transfected Jurkat clones and reverses the described molecular changes. In conclusion, we here provide first evidence that expression of par-4 determines sensitivity to TRAIL-induced lymphocytic cell death and outline the responsible molecular determinants.
Surface Chemistry Proteomics and Biomarker Discovery in Multiple Myeloma.
Authors: Chen Bangzheng J. , Hong Huixiao , Ge Weigong , Tong Weida , Walker Ronald , Alpe Terri L. , Barlogie Bart , Epstein Joshua 
Published: April 2020

Abstract
Introduction:
To further evaluate the utility of surface-enhanced laser desorption and ionization-time of flight mass spectroscopy (SELDI-TOF MS) proteomics in the diagnosis, prognosis, monitoring response to therapy, and follow up of patient with myeloma, we examined the ability of protein chips with 4 different surface chemistries to detect biomarkers of lytic bone disease.
Method:
Sera from 47 untreated myeloma patients were collected and stored at −80°C for future analysis. 22 serum samples were from patients with 1–26 lytic bone lesions as identified on X-ray skeletal surveys and 25 serum samples were from patients without lytic lesions. The sera were analyzed by SELDI-TOF MS using Ciphergen’s ProteinChip Biology System II (PBS II), to identify protein patterns associated with lytic bone disease. Each sample was applied in 2 replicates to randomly assigned spots on protein chips with different surface chemistries: immobilized metal affinity capture (IMAC30) activated with Cu++, weak cathion exchange (CM10), reverse phase (H50), and strong anaion exchange (Q10), all under conditions of low stringency, using a Biomek2000 robot. The mass spectra of proteins, generated using an average of 66 laser shots, were calibrated using peptide standards and normalized to total ion current using CiphergenExpress 3.0 software. We randomly selected 80% of patients for developing classification models that separate patients with lytic bone lesions from those without lesions, using a stepwise logistic regression method; 76 calibrated and normalized spectra from randomly selected patients, 18 with lytic bone lesions and 20 without lytic lesions were used for model development. The other 18 spectra from 4 patients with lytic lesions and 5 without lesions were used as a test dataset. The same datasets were used for all 4 chip types. Protein peaks that were significantly different between the two groups were used for modeling.
Results:
All 4 chip types yielded models with fit accuracies of 71%–92%. The spectra produced by each chip were different, reflecting the differences in surface chemistries, and each model used different protein peaks from each of the chip types; the IMAC30-based model used 11 protein peaks ranging in size from 2903 to 8226 kilodaltons (KDa); H50 model used 7 peaks, 2802–18837 KDa in size; CM10 model used 5 peaks, 2805–23307 KDa; and Q10 used 3 peaks, 6975–37210 KDa. Prediction accuracy was 89% for CM10, 78% for IMAC30, 76% for Q10 and only 33% for H50. CM10 and IMAC30 based models correctly assigned all patients with no lytic bone lesions. Wrongly assigned patients were different for the two chip types.
Conclusions:
Since each model wrongly assigned different patients and used different protein peaks, it is likely that a model that combines information from several surface types (consensus approach) will prove to provide the most accurate predictions, as needed for making clinical decision.
Galectin-1 Can Support the Survival of Human Myeloma Cells in In Vitro Culture.
Authors: Abroun Saeid , Li Fu-Jun , Tsuyama Naohiro , Shamsasenjan Karim , Asaoku Hideki , Gondo Toshikazu , Kawano Michio M. 
Published: April 2020

Abstract
Myeloma cells as well as other hematopoietic cells exist in the bone marrow (BM), where adhesion molecules, cytokines and chemokines may play very important roles in regulating the survival, proliferation and lodgment of myeloma cells.
Galectin-1(Gal-1) is a 14 KDa protein with the binding affinity to the molecules which carry β galactosides in their structure such as CD3, CD4, CD7, CD43, CD45 and integrins. Although Gal-1 is considered to be ubiquitously present in the BM, it remains to be clarified what is the effect of Gal-1 on the survival of myeloma cells. First, we confirmed that Gal-1 as well as SDF-1 was ubiquitously present in the extracellular space of BM samples from MM patients by the immunohistochemical staining.
Furthermore, the expression of Gal-1 gene was found in a BM stromal cell line, KM-102, and also in primary myeloma cells as well as myeloma cell lines, while the expression of SDF-1 gene was detected in KM-102 cells but not in myeloma cells. In the serum-free culture in vitro, Gal-1 could support the survival of primary myeloma cells in the combination with IL-6 and SDF-1 at least for 2 weeks. In order to clarify the mechanism of the effect of Gal-1, we examined the effect of Gal-1 on the survival of myeloma cell lines and B cell l,ines; Ga-1 could support the survival of CD45- U266 and KMS-5 cells, but not support and suppress the survival of B cell lines (Raji and KUS cells) which express CD45, CD45RA and CD45RB but not CD45RO. By using the transfectants of CD45RA, CD45RB or CD45RO in U266 cells, we confirmed that Gal-1 could suppress the survival of CD45RA+ U266 cells as well as B cell lines but not of CD45RB or CD45RO transfectants of U266 cells. These data confirmed that Gal-1 could bind to the CD45RA molecule more effectively than CD45RB or CD45RO. We also revealed that Gal-1 stimulation inhibited the phosphorylation of ERK1/2 in CD45RA+ U266 cells as well as B cell lines, while in CD45- myeloma cells as well as CD45RO+ myeloma cells Gal-1 induced the activation of Akt. Therefore, these data suggest that Gal-1 plays an important role in the supporting the survival of myeloma cells but not B cells in the BM microenvironment.