bluuebunny/crossref_metadata_2025_split huggingface dataset:
Outcome of Patients with Primary Mediastinal Large B-Cell Non-Hodgkin’s Lymphomas: A Single Institution Analysis from 1996-2004.
Authors: Hegenbart Ute , Rieger Michael , Witzens Matthias , Hensel Manfred , Ho Anthony D. 
Published: October 2019

Abstract
Primary mediastinal large B-cell lymphoma represents a distinct subset of large B cell lymphoma, and it has been shown to occur preferentially in young females with a bulky mediastinal mass. Between 1996 and 2004, a total of 43 patients (pts) with primary mediastinal lymphoma were diagnosed and treated at our institution, 34 of them are evaluable for response and long-term follow-up. Twenty females and 14 males have been treated, the median age at diagnosis was 33 years (range: 18–56), 10 pts had stage I, 19 pts stage II and 5 pts stage III disease, respectively. Fifteen pts presented with B symptoms, LDH was increased in 68% of pts. First-line chemotherapy included CHOP (2 pts), R-CHOP (3 pts), CHOEP (8 pts), R-CHOEP (13 pts) or Mega-CHOEP (8 pts). 16 pts received Rituximab in combination with chemotherapy as front-line therapy. Complete response after first-line therapy has been observed in 71% and PR in 21% of pts. Later on, two pts in CR and 1 pt with PR relapsed after conventional chemotherapy. Radiotherapy was administered in 22 pts (65%) presenting with initial bulky disease. 19 pts have been autografted, 15 of them as part of up-front therapy. Indications for up-front autologous HCT were treatment within the Mega-CHOEP protocol (n=8), PR after first-line chemotherapy (n=3), IPI Score of 2 (n=2) and individual decision in 2 pts. Allogeneic HCT was performed as relapse therapy in 4 patients. Of the 15 pts who had up-front autologous HCT, 13 remained in CR. Overall, thirty pts were alive at the date of last contact with a median follow-up since diagnosis of 25 months (range 3–99). Three of 4 pts who had undergone allogeneic HCT in a advanced phase of disease died of transplant-related complications. In conclusion, in this patient group addition of Rituximab and/or dose-intensified first-line chemotherapy lead to a high rate of complete remissions as compared to historic controls. Whether up-front high-dose chemotherapy with autologous HCT or the administration of radiotherapy to the initial bulk improve PFS and OS remains an open question for this special lymphoma entity. The achievement of complete remission with primary treatment strategies seems to be essential to achieve long-term cure for this disease.
Human Leukocyte Antigen (HLA) DR15 Is Associated with Reduced Incidence of Acute GvHD in HLA-Matched Allogeneic HSCT but Does Not Impact Survival.
Authors: Battiwalla Minoo , Hahn Theresa , Roy Hilary N. , Wahab Afrin , Duman Eileen A. , Becker Joanne , McCarthy Philip L. 
Published: October 2019

Abstract
HLA DR 15 is found more frequently in patients with bone marrow failure syndromes and is associated with response to immunosuppression. This suggests that HLA DR15 may preferentially present immunodominant myeloid antigens or that HLA DR15 positive cells may be more sensitive to immunosuppression. We investigated the role of HLA DR15 on graft-versus-leukemia effect and graft-versus-host disease (GVHD) in HLA-matched HSCTs performed for myeloid malignancies. We performed a retrospective review of 109 consecutive related and 42 consecutive unrelated allogeneic HSCT patients treated between 1991 and 2003 at Roswell Park Cancer Institute to investigate the influence of HLA DR15 on overall survival (OS), progression-free survival (PFS) and the incidence of grade 2–4 acute GVHD. HLA DR15 was determined by either molecular (n=92) or serologic (n=59) methods. The proportion of patients with one or two HLA DR15 alleles was 21% (32/151) which is similar to the general Caucasian population. Patient characteristics included: AML (n=74), CML (n=59), and MDS (n=18); median age 42 years (range 11–62); Males (n=93), Females (n=58); Caucasian (>95%); TBI-containing conditioning regimens (n=130); Busulfan + Cyclophosphamide (n=19), Busulfan + TBI (n=27), Cyclophosphamide + TBI (n=11), Etoposide + Cyclophosphamide + TBI (n=84), or other combinations (n=10). There was no difference in OS between the HLA DR15 positive versus negative groups in any disease or donor relation subgroups. There was no significant difference in PFS between the HLA DR15 positive and negative groups, however a trend toward late relapses after three years was observed in the HLA DR15 positive group. The HLA DR15 positive group experienced a significantly lower incidence of acute GVHD grade 2–4: 22% versus 41%, p=0.045. There was no difference between the HLA DR15 positive versus negative groups with respect to conditioning regimen, use of TBI or GVHD prophylaxis regimen. We are currently expanding this study to include a larger cohort from other centers. These results suggest that HLA DR15 may function as a surrogate for an altered response to the immunosuppression induced by GvHD prophylaxis. If these results are confirmed, this would be the first association between a specific HLA antigen and GvHD development, thus suggesting the need for studying GvHD prophylaxis modification based on specific HLA antigens.
A Pilot Study Evaluating the Safety and Efficacy of AMD3100 for the Mobilization and Transplantation of HLA-Matched Sibling Donor Hematopoietic Stem Cells in Patients with Advanced Hematological Malignancies.
Authors: Devine Steven M. , Bonde Jesper , Hess David A. , Edwards Terri M. , Link Daniel C. , Sempek Diane , Calandra Gary , Badel Karin , Nolta Jan A. , DiPersio John F. 
Published: October 2019

Abstract
Cytokine mobilized peripheral blood (MPB) has become the preferred allograft source for patients with advanced hematological malignancies. Procurement of MPB currently requires from 5 to 6 days of granulocyte colony stimulating factor (G-CSF) administration and is associated with some donor morbidity and high cost. Recent studies suggest G-CSF induces mobilization by indirectly targeting the interaction between the chemokine stromal derived factor 1 (SDF-1) and its receptor CXCR-4. Here we report preliminary results using a direct antagonist of the SDF-1/CXCR-4 interaction, AMD3100, as a single agent to procure MPB from allogeneic donors. Two HLA-identical siblings, both males aged 55 and 58, received one or two doses of AMD3100 at 240mcg/kg followed 4 hours later by leukapheresis (LP). After successful collection and a one week washout period, the same donors were re-mobilized using G-CSF at 10mcg/kg/day followed by LP commencing day 5. The target CD34+ cell dose following each agent was >2.0x10e6/kg recipient weight. The results of the mobilizations and allograft composition are presented in the table.
Results of Mobilization
Agent AMD3100 G-CSF Donor 1 Donor 2 Donor 1 Donor 2 Days of Drug administration 2 2 6 5 # LP Procedures 2 1 2 1 Peak fold ↑ CD34 count in PB 7 6 17 25 CD34 dose (x10e6/kg) 2.6 2.1 2.9 5.7 CD3 dose (x10e8/kg) 4.9 1.5 1.3 1.3 CD4 dose (x10e8/kg) 3.1 1.0 0.9 0.9 CD8 dose (x10e8/kg) 1.7 0.4 1.0 0.4 CD56 dose (x10e7/kg) 3.4 2.1 2.2 1.8
Following AMD3100, donor 1 did not experience any drug related toxicity and donor 2 developed only grade 1 abdominal bloating. Both donors experienced grade 2 bone pain during G-CSF mobilization. The AMD3100 mobilized cells from donor 1 were transplanted into a 51 year old woman with AML following conditioning with cyclophosphamide (120mg/kg) and total body irradiation (single dose at 550cGy). Single agent cyclosporine was used for GVHD prophylaxis. She engrafted neutrophils >500/ul promptly on day +11 and platelets > 20,000/ul on day +14. A bone marrow biopsy performed on day +30 revealed an overall cellularity of 50% with normal trilineage hematopoiesis and full donor chimerism. By day 30, the peripheral blood CD3 count had reached 531/ul, CD4 count 305/ul, and CD8 count 211/ul. The CD4/8 ratio was 1.4. She is currently being followed as an outpatient and by day +39 is without evidence of GVHD. The allograft from the second donor was not given as the recipient’s disease progressed.
This is the first demonstration that a chemokine antagonist can induce the rapid mobilization of a functionally competent hematopoietic allograft without causing significant toxicity. Accrual is ongoing and additional donor/recipient pairs will be presented.
8-Amino-Adenosine Induces Loss of Phosphorylation of ERK1/2, p38 MAPK, and Akt Kinase: Role in Induction of Apoptosis in Multiple Myeloma.
Authors: Ghias Kulsoom , Ma Chunguang , Gandhi Varsha , Krett Nancy , Rosen Steven T. 
Published: October 2019

Abstract
Multiple Myeloma (MM) is a malignancy of monoclonal plasma cell proliferation in the bone marrow, which accounts for 10% of all hematologic cancers. This slow proliferating B-cell malignancy accumulates apoptosis-resistant and replication-quiescent cell populations, posing a challenge for current chemotherapeutics, which target rapidly replicating cells. MM remains an incurable disease in need of new therapeutic approaches. We have previously shown that the nucleoside analog, 8-chloro-adenosine (8-Cl-Ado), has significant activity for MM and that its sister compound, 8-amino-adenosine (8-NH2-Ado), appears to be even more potent, exhibiting greater activity in pre-clinical studies. 8-NH2-Ado is cytotoxic to MM cell lines both sensitive and resistant to conventional chemotherapies. This cytotoxic effect requires phosphorylation of 8-NH2-Ado to its tri-phosphate form, 8-NH2-ATP, and accumulation of 8-NH2-ATP results in a concomitant loss of endogenous ATP levels. 8-NH2-Ado induces apoptosis in MM cells as measured by an increase in Annexin V binding, a decrease in mitochondrial membrane potential, an increase in caspase activity, cleavage of caspase substrates, and an increase in cells with a subG1 DNA content. Here we demonstrate the novel effect of 8-NH2-Ado on the phosphorylation status of key cellular signaling molecules. MM cells treated with 8-NH2-Ado exhibit a dramatic loss of phosphorylation of several important signaling proteins, including ERK1/2, p38 MAPK and Akt kinase, within 30–120 minutes. Cells depleted of ATP by antimycin A or 2-deoxyglucose treatments to mimic 8-NH2-Ado-induced ATP depletion do not exhibit the same decrease in phosphorylation of vital cellular proteins. Therefore, the significant shifts in endogenous ATP pools caused by 8-NH2-Ado treatment cannot account for the changes in phosphorylation levels. Instead, 8-NH2-Ado may be affecting the activity of protein phosphatases involved in the negative regulation of these signaling molecules. Based on studies using the phosphatase inhibitor okadaic acid, it appears that PP2A may play a role in the 8-NH2-Ado-induced decrease in phosphorylation of p38. The distinctive effect of 8-NH2-Ado on the phosphorylation status of cellular proteins is a novel phenomenon for a nucleoside analog drug and appears to be unique to 8-NH2-Ado among this class of drugs. The kinetics of 8-NH2-Ado-mediated changes in phosphorylation levels of critical pro-survival and apoptosis-regulating proteins suggest that the modulation of these proteins by de-phosphorylation at early time-points may be an important mechanistic step in 8-NH2-Ado-induced programmed cell death.
Sensitization of Leukemic Cells for Glucocorticoids by Inhibition of NFκB Activity.
Authors: Cloos Jacqueline , Vink Josefien , van Miltenburg Marjolein , Oerlemans Ruud , van der Heijden Joost , Dijkmans Ben A.C. , Jansen Gerrit , Kaspers Gertjan J.L. 
Published: October 2019

Abstract
Based on their immunosuppressive and cytotoxic effects, glucocorticoids (GCs) find widespread use as immune-modulatory agents and in (childhood) leukemia, lymphomas and myelomas. Unfortunately, resistance to GCs is a major adverse prognostic factor and occurs in about 20% in newly diagnosed childhood acute lymphoblastic leukemia (ALL) and in more than 50% in relapsed ALL, while acute myeloid leukemia (AML) is largely unresponsive to GCs. In addition, adult AML is more often GC resistant compared to childhood AML. Recently, we observed (van der Heijden et al, Ann Rheum Dis 63: 131-137,2004) that prolonged exposure of human CEM-C7 T cell leukemia cells to the anti-rheumatic drug sulfasalazine (SSZ) sensitized these primary sensitive cells even further for GCs. SSZ is an inhibitor of activation of NFκB that is often therapeutically used in combination with methotrexate and prednisone. Following these observations, two human myeloid leukemia cell lines (THP-1 and U937) with inherent resistance to GCs (IC50 for prednisolone > 250 μM, IC50 dexamethasone > 25 μM) were exposed to SSZ to establish whether this would provoke GC sensitization. Indeed, prolonged SSZ exposure sensitized both myeloid leukemia cells for prednisolone (IC50 < 1 μM) and dexamethasone (IC50 < 0.05 μM). In order to elicit the mechanistic basis for the GC sensitizing effect of SSZ expression levels of Glucocorticoid Receptor α (GRα), NFκB p65 and Inhibitor of NFκB (IκBα) were analyzed. In contrast to GC-sensitive CEM-C7 cells, parental THP-1 and U937 cells had no detectable and constitutive expression of GRα and NFκB p65 protein, even though mRNA levels for both parameters were readily detectable. In SSZ-exposed THP-1 and U937 cells protein expression of NFκB p65 was markedly increased although it does not represent the active form of NFκB since protein expression of IκB increased concomitantly. Consistent with the sensitization for GCs in SSZ-exposed THP-1 and U937 cells was a marked increase in GRα protein expression, suggesting that GRα is post-transcriptionally prevented from degradation. In line with this concept is that co-incubation with a 26S proteasome inhibitor Bortezomib further enhanced (5-fold) GC sensitivity in SSZ-exposed THP-1 and U937 cells. Collectively, this study reveals that SSZ-exposure impairs activation of NFκB and facilitates stabilization of GRα protein, conditions which confer GC-sensitization in leukemic cells with primary resistance to GCs. In conclusion, modulation of GC resistance in acute leukemias by NFκB inhibitors is a novel, clinically attractive approach that warrants further preclinical and subsequent clinical investigations.
Rituximab-Mediated Molecular Cell Signaling Via CD20 in B-NHL Cell Lines: Autonomy from Cross-Linking with Tumor FcRs.
Authors: Vega Mario I. , Huerta-Yepez Sara , Chinn Paul , Hariharan Hari , Hanna Nabil , Bonavida Benjamin 
Published: October 2019

Abstract
Rituximab (chimeric anti-CD20 mAb) is currently being used in the therapy of Non-Hodgkin’s B-cell Lymphoma (NHL). It has also been reported that the combination of rituximab and chemotherapy is effective in patients with NHL. Several proposed mechanisms have been suggested for rituximab-mediated effects in vivo and include ADCC, CDC and apoptosis. In addition, we have reported that rituximab can trigger the tumor cells and modifies several intracellular survival signaling pathways resulting in the sensitization of tumor cells to various chemotherapeutic drugs (Alas et al., Clin. Cancer Res.8:836, 2001; Jazirehi et al., Mol. Cancer Therapy2:1183, 2003; Vega et al., Oncogene23:3530, 2004). Rituximab-mediated signaling might have resulted from directly triggering CD20 alone or in conjunction with triggering FcRs on the tumor cells via the Fc fragment of rituximab. This study was designed to distinguish between these two possibilities. Since the CH2 domain in Fc is responsible for its interaction with the Fc receptor, we have genetically engineered a rituximab mAb in which the CH2 domain was deleted. The CHO cells secreted one monomeric form with properly formed disulfides rituximab (CH2−) and a dimeric form rituximab (CH2−) Dimer. The functions of the two CH2-deleted domain antibodies were examined in several systems and compared with those of the native rituximab. We used Ramos and 2F7 B-NHL cell lines as model systems. As expected, we demonstrate that the CH2-deleted antibodies are defective in their ability to mediate ADCC and CDC. However, their biological functions and their ability to signal the cells were not altered and were similar to those observed with rituximab. Hence, the CH2-deleted antibodies inhibited cell proliferation, induced cell aggregation in culture, and induced apoptosis when cross-linked with a secondary anti-human IgG. In addition, the CH2-deleted antibodies triggered the cells similar to rituximab and inhibited the Src kinase pLyn, the downstream p38 MAP kinase, the transcription factors NF-κB, YY1, SP1, and STAT3, and Bcl-2/Bcl-xL expression. These modifications resulted in the sensitization of B-NHL cell lines to both chemotherapeutic drugs and Fas-induced apoptosis. Altogether, these findings demonstrate that rituximab-mediated signaling and modification of intracellular signaling pathways can take place in the absence of any contribution of the Fc fragment cross-linked to the cell Fc receptors. These studies suggest that chemo and immuno-sensitization by rituximab can take place in vivo in the absence of Fc-FcR contributions and thus are of potential clinical relevance.
Cellular and Molecular Characterization of Rituximab-Resistant CD20+ NHL Ramos (Ramos RR1) and Daudi (Daudi RR1) Clones: Development of Cross-Resistance to Cytotoxic Stimuli.
Authors: Jazirehi Ali R. , Bonavida Benjamin 
Published: October 2019

Abstract
Numerous studies have documented the efficacy of rituximab (either alone and/or in combination with drugs) in eradicating tumor cells in vitro and in vivo. However, a subset of patients does not respond or relapse after initial rituximab treatment. In an attempt to recapitulate the non-responders and/or relapsed situations, rituximab-refractory B-NHL Ramos and Daudi clones were generated by growing the cells in the presence of step-wise increasing concentrations of rituximab followed by multiple rounds of limiting dilution assay. Single cells were then propagated as clones and assayed for cellular and molecular alterations when compared to the parental cell lines. This study investigates two rituximab-resistant clones, namely, Ramos RR1 and Daudi RR1. A partial decrease in surface CD20 expression, namely, decreased MFI compared to parental cells was observed in the clones. Both clones exhibited resistance to complement-dependent cytotoxicity (CDC). Rituximab was incapable of either inhibiting cellular growth or inducing apoptosis (both in monomeric and cross-linked forms). The clones developed significant cross-resistance to chemotherapeutic drugs and importantly, rituximab had lost its chemo-sensitizing effect on these clones. Detailed analysis revealed a hyper-activated status of the ERK1/2 and NF-κB signaling pathways and rituximab was inefficient in inhibiting these pathways in the clones. Strikingly, selective over-expression of Bcl-xL and the exhibition of higher resistance to a wide array of anti-neoplastic agents were observed in the clones concordant with the protective role of Bcl-xL. However, pharmacological inhibition of the NF-κB and the ERK 1/2 pathways as well as the proteasome inhibitor bortezomib (Velcade) efficiently sensitized the clones to structurally and functionally distinct drugs including topoisomerase II inhibitor, DNA damaging agents, and microtubule poisons, albeit to varying degrees. The above inhibitors also reduced Bcl-xL levels further confirming the pivotal role played by Bcl-xL is clone resistance. The generation of rituximab-resistant clones provides novel means to further investigate the underlying mechanisms that may govern rituximab resistance in patients. Further, these results provide a rational molecular basis for the utilization of pharmacological inhibitors of constitutive signaling pathways in combination with cytotoxic stimuli in the treatment of rituximab-refractory NHL cells.
A Monoclonal Antibody to High Molecular Weight Kininogen Reduces Inflammation in the HLA-B27 Transgenic Rat Model of Inflammatory Bowel Disease and Arthritis.
Authors: Pixley Robin A. , Sainz Irma M. , Keith James C. , Isordia-Salas Irma , Leatherby Yelena , Albert Leo M. , Colman Robert W. 
Published: October 2019

Abstract
The HLA-B27 rat is a well-characterized model of human bowel disease, rheumatoid arthritis and psoriasis. Previous studies of chronic inflammation in other rat models of inflammatory disease have demonstrated activation of the kallilrein-kinin system (KKS) as well as modulation by a kallikrein inhibitor and HK deficiency. The effects of C11C1, a monoclonal antibody acting to inhibit cellular binding of high molecular weight kininogen (HK), were studied in the HLA-B27 transgenic rat. Thrice weekly intraperitoneal injections of C11C1 (1.9 mg/kg) or IgG1 (6mg/kg) were given to male HLA-B27 transgenic rats for 3 weeks, beginning when the rats were 23 weeks old. Stool character was scored daily as a measure of intestinal inflammation, and the rear limbs were scored daily for clinical signs of arthritis, tarsal joint swelling and erythema. At the end of the experiment the animals were euthanized, and the colon and tarsal joint histologic lesions were examined. The histology sections were assigned a numerical score for colonic inflammation, synovitis, and cartilage damage. Activation of KKS was assessed by assays of plasma prekallikrein, HK, factor XI, and factor XII. Administration of the monoclonal antibody directed against HK rapidly decreased the clinical scores of inflammatory bowel disease from 3.0 ± 0 to 1.2 ± 0.2 (p<0.005) and arthritis from 12.0 ± 0 to 0.8 ± 0.8 (p<0.001). Histologic analyses confirmed significant reductions in colonic lesions from 7.7 ± 0.8 to 2.8 ± 0.9 (p=0.004) and synovitis from 9.5 ± 0.8 to 5.0 ± 1.0 (p=0.009). Decreased prekallikrein and HK levels were reversed by monoclonal antibody C11C1, providing evidence of KKS activation. A monoclonal antibody to kininogen appears to have therapeutic potential in human inflammatory bowel disease and arthropathies.