bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adipocyte Differentiation of SOD2−/− Mouse Bone Marrow Stromal Cells Is Associated with Decreased Antioxidant Reserves and Is Reversed by the Antioxidant WR2721 (Amifostine).
Authors: Epperly Michael W. , Lechpammer Stanislav , Nie Suhua , Glowacki Julie , Greenberger Joel S. 
Published: October 2019

Abstract
Cell lines from homozygous deletion recombinant negative manganese superoxide dismutase (SOD2 −/−) mice have intrinsic ionizing radiation sensitivity that is reversed by expression of the transgene for human SOD2 (Radiation Research154:365, 2000). This study tests whether redox status influences adipocyte differentiation potential of bone marrow stromal cells by comparing the differentiation potential of SOD2−/− and SOD2 +/+ bone marrow stromal cell lines. Cells were cultured in basal medium (Dulbecco’s Modified Eagle’s Medium, 1% fetal bovine serum (FBS), 100 U/ml penicillin and 100 μg/mL streptomycin +/− adipocytogenic supplements (10 μg/ml insulin, 1 μM dexamethasone, 100 mM indomethacin)). Adipocytogenesis was assessed by spectrophotometric content of oil red-O dye and by RT-PCR for peroxisome proliferator-activated receptor-gamma (PPARγ) and lipoprotein lipase (LPL). Glutathione peroxidase (GPX) activity or glutathione (GSH) levels were measured by a Glutathione Peroxidase, Cellular Assay Kit or Glutathione Assay Kit, respectively, by Calbiochem, Inc. SOD2+/+ cells developed adipocytes only when treated with adipocytogenic supplements and expressed PPARγ and LPL at day 5. SOD2−/− cells cultured in basal conditions demonstrated constitutive adipocytogenesis. The level of GPX activity in SOD2−/− cells (43.2 ± 3.5 mU/ml) was 52.7% (p<0.001) of that in SOD2+/+ cells (82.0 ± 2.3). The level of GSH in SOD2−/− cells (173 ± 2 μM) was 78.6% (p=0.0089) of that in SOD2+/+ cells (220 ± 4 μM). Three day treatment of SOD2−/−with 4 mM WR2721 resulted in 22% reduction in oil red-O content. In addition, in SOD2−/− cells cultured in adipocytogenic medium, 3-day treatment in 4 mM WR2721 resulted in 46% reduction in oil red-O content and undetectable expression of PPARγ and LPL. In conclusion, WR2721 limits constitutive adipocytogenesis and inhibits induced adipocytogenesis in SOD2−/− cells. These data provide evidence for the involvement of the cellular redox pathway in adipocyte differentiation of bone marrow stromal cells.
Targeting IKK Inhibits Multiple Myeloma (MM) Cell Growth in the Bone Marrow Microenvironment.
Authors: Hideshima Teru , Tassone Pierfrancesco , Chauhan Dharminder , Ishitsuka Kenji , Mitsiades Constantine , Raje Noopur , Kumar Shaji , Hamasaki Makoto , Hideshima Hiromasa , Munshi Nikhil C. , Richardson Paul G. , Schenkein David , Anderson Kenneth C. 
Published: October 2019

Abstract
NF-κB is a transcriptional factor promoting tumor cell growth and inhibition of apoptosis via regulating expression of proteins modulating cell cycle and anti-apoptosis. NF-κB is constitutively associated with an inhibitor (IκB), which is phosphorylated by IκB kinase (IKK) upon cell stimulation (ie, TNFα) and subsequently degraded by ubiquitin-proteasome pathway, thereby allowing NF-κB to translocate to nucleus. We have previously shown that an IKK inhibitor PS-1145 partially (20–50%) inhibits MM cell proliferation; however, it inhibits both IL-6 secretion from BMSCs triggered by MM cell adhesion and proliferation of MM cells adherent to BMSCs. Targeting IKKβ is therefore a possible therapeutic option for inhibition of MM cell growth in the bone marrow microenvironment by downregulating NF-κB activity.
In this study, we further delineated the biologic significance of IKK inhibition in MM cells using IKKβ specific inhibitor MLN120B (Millennium Pharmaceuticals, Cambridge, MA). MLN120B induced 60–90% growth inhibition in cells from the MM cell lines RPMI8226, RPMI/Dox40, RPMI/LR5, U266, and INA-6; on the other hand, it induced only 25–30% inhibition in MM.1S and MM.1R cells, assessed by 72 h tritiated-thymidine uptake. Importantly, neither IL-6 nor IGF-1 overcomes the growth inhibitory effect of MLN120B in both MM.1S and U266 cells. Interestingly, MLN120B significantly augmented TNFα-induced cytotoxicity in MM.1S cells. We next examined whether MLN120B could enhance the cytotoxicity of other agents. MLN120B augmented growth inhibition triggered by doxorubicin and melphalan in RPMI8226 and IL-6 dependent INA-6 cell line. We therefore studied growth inhibitory effect of MLN120B in the presence of bone marrow stromal cells (BMSCs). MLN120B inhibited 70–80% of constitutive IL-6 secretion from BMSCs, without toxicity. Importantly, MLN120B almost completely blocked stimulation of MM.1S, U266 and INA-4 cell growth and IL-6 secretion from BMSCs induced by binding of tumor cells to BMSCs. Finally, MLN120B overcame the protective effect of BMSCs, cell adhesion mediated drug resistance, against dexamethasone in MM.1S cells. Taken together, our data demonstrate that an IKKβ inhibitor induces cytotoxicity in MM cells in the BM milieu, providing the framework for clinical trials of these novel agents to improve patient outcome in MM.
Multiple B Cell Clones Producing Antibodies Directed to the Spacer and Disintegrin/TSR1 Domains of ADAMTS13 in a Patient with Acquired TTP.
Authors: Luken Brenda M. , Kaijen Paul H.P. , Turenhout Ellen A.M. , Fijnheer Rob , Voorberg Jan 
Published: October 2019

Abstract
Thrombotic thrombocytopenic purpura (TTP) is associated with a severe deficiency of the von Willebrand factor-cleaving protease ADAMTS13. In plasma of the majority of patients with acquired TTP, antibodies that inhibit ADAMTS13 activity have been detected. In this study we have used phage display to isolate anti-ADAMTS13 antibodies from the total immunoglobulin repertoire of a patient with acquired TTP. The immunoglobulin G variable heavy chain (VH) gene repertoire was amplified from CD19 positive B cells and combined with a variable light chain (VL) gene repertoire. The resulting library consisted of 3.4 x 108 individual clones. Combined VH and VL segments, expressed as single-chain Fv fragments (scFv) on the surface of filamentous phage, were selected for binding to an ADAMTS13 fragment consisting of the disintegrin/ first thrombospondin type 1 repeat (TSR1)/ cysteine-rich/ spacer domains. After three rounds of selection, six different scFv antibody clones were identified that were assigned to four groups based on the use of VH germline gene segments. ScFv 9, 10, and 27, all use the VH1–69 germline gene segments, possess the same CDR3, and show a similar pattern of somatic hypermutation. These results suggest that scFv 9, 10 and 27 are derived from a common B cell precursor. ScFv 26 also belongs to the VH1 family, but uses germline gene segment VH1–02 instead. Clones 16 and 41 are both part of the VH3 family and are derived from germline gene segments VH3–07 and VH3–09 respectively. The affinity of the scFv for the ADAMTS13 disintegrin/ TSR1/ cysteine-rich/ spacer fragment was determined by surface plasmon resonance analysis. Purified disintegrin/ TSR1/ cysteine-rich/ spacer fragment was immobilized on an activated CM5-sensor chip and subsequently different concentrations of purified scFv were added. Binding and dissociation of scFv was followed for 2 minutes and the affinity of the different scFv for the immobilized ADAMTS13 fragment was calculated from the obtained binding curves. ScFv 9 binds with high affinity to the disintegrin/ TSR1/ cysteine-rich/ spacer fragment (Kd 3.6 ± 0.8 nM); whereas scFv 10, 16, 26, 27 and 41 displayed a somewhat lower affinity (Kd ranging from 20–200 nM). Epitope mapping using several smaller ADAMTS13 fragments in the disintegrin/ TSR1/ cysteine-rich/ spacer region revealed that scFv 9, 10, and 41, bind specifically to the ADAMTS13 spacer domain. The epitope of scFv 16 however, resides in the disintegrin/ TSR1 domains. Our results indicate that multiple B cell clones that produce antibodies recognizing epitopes in the spacer and disintegrin/ TSR1 domains of ADAMTS13 are present in the immunoglobulin repertoire of a patient with acquired TTP.
Safety and Efficacy of Bortezomib (Velcade) for the Treatment of Relapsed Classical Hodgkin’s Disease.
Authors: Younes Anas , Pro Barbara , Romaguera Jorge , Dang Nam 
Published: October 2019

Abstract
The proteasome inhibitor bortezomib has demonstrated clinical activity in patients with multiple myeloma and different types of non-Hodgkin’s lymphoma. Its activity in patients with Hodgkin’s disease (HD) is unknown. We have recently reported that bortezomib had a significant activity against HD-derived cell lines in vitro (Zheng et al, Clin Cancer Res 2004), In four HD-derived cell lines, bortezomib induced cell cycle arrest and apoptosis in a dose and time dependent manner, irrespective of IkB gene mutations. Furthermore, bortezomib enhanced the activity of chemotherapy and TRAIL in these cell lines. Based on these encouraging preclinical results, we initiated a pilot study of single agent bortezomib in patients with relapsed classical HD. Eligibility: (1) relapsed classical HD with a measurable disease (2) At least 2 prior treatment regimens; (3) Patients with prior autologous stem cell transplant (ASCT) are eligible (4) platelet counts > 50,000/uL and ANC counts of > 1,500/uL (5) no HIV infection, or CNS involvement with HD, (6) bilirubin < 2mg/dL and creatinine < 2.5 mg/dL. Patients were treated with 1.3 mg/m2 bortezomib intravenously on days 1, 4, 8, 11 of 21-day cycles in an outpatient setting. Treatment was delayed if the Platelet counts on the day of therapy was < 30,000/mm3. After 3 cycles of bortezomib therapy patients were evaluated for treatment response. If there was no evidence of disease progression after 3 cycles of therapy, patients were allowed to receive a maximum of 6 cycles. To date, 11 patients are enrolled (6 men and 5 women), with a median age of 28 years (range: 21 to 68 years). All patients were heavily pretreated, with a median number of 5 prior treatment regimens (range 2 to 7 regimens), and all patients have previously failed ASCT. The median pretreatment platelet count was 126, 000/uL (range 66,000 – 339,000/uL). All patients received at least one dose of bortezomib and are evaluable for treatment toxicity. Treatment was reasonably well tolerated with the majority of toxic effects were of grade 1 and 2. Two patients had grade 3 dyspnea and one patient had grade 3 neutropenic fever. Progressive thrombocytopenia was the most common hematologic toxicity, which frequently caused delays in therapy. Nadir platelet count below 30,000/uL was observed in 3/11 patients during the first cycle, in 4/10 during the second cycle, and in 4/6 during the third cycle. Nadir ANC below 1000/uL was observed in 1/11 pts during cycle 1, in 2/10 during cycle 2, and in 1/6 during cycle 3. Eight patients completed the planned 3 cycles and are evaluable for treatment response. One patient achieved a partial remission and one had a minimal response. Our preliminary data demonstrate encouraging clinical activity of bortezomib in this heavily pretreated patients with classical HD, and warrants studying bortezomib in less heavily pretreated patients either as a single agent or in combination with chemotherapy.
Liposomal Cytarabine (DepoCyte™Injection) Is Cost-Effective Compared with Standard Cytarabine for the Intrathecal Treatment of Patients with Lymphomatous Meningitis.
Authors: Moeremans Karen , Annemans Lieven , Morris James 
Published: October 2019

Abstract
Background and Objective : The clinical benefit of liposomal cytarabine (DepoCyteTM injection) for the intrathecal treatment of lymphomatous meningitis has been demonstrated in a randomised controlled trial (Glantz M. et al. J Clin Oncol 1999;3110-3116 ). Liposomal cytarabine has recently become available in the UK at a cost considerably above that of standard cytarabine (1,250GBP per dose compared to 4GBP). A cost-utility analysis (CUA) comparing liposomal cytarabine versus standard cytarabine was conducted from the perspective of the UK National Health Service to determine whether or not liposomal cytarabine is a cost-effective treatment option for patients with lymphomatous meningitis.
Methods: Using data from the clinical trial, each patient’s survival time was partitioned according to the presence of progressive neurological disease. Utility estimates for two health states, progression and non-progression, were derived from clinical experts using a time-tradeoff exercise and assigned to each patient according to the period of time they remained in each health state. Observed response rates from the clinical trial were used to model expected quality adjusted life year (QALY) estimates for each treatment arm. Health care costs were estimated using resource data from the clinical trial and unit costs from the literature. Probabilistic analyses were used to estimate the expected cost per QALY gained with liposomal cytarabine, taking into account the uncertainty surrounding model input parameters.
Results: From a total of 33 randomised patients, response status was available for 29. 13 of 16 patients treated with liposomal cytarabine responded to treatment compared to 3 of 13 patients treated with standard cytarabine (81 vs. 23%; p=0.003). The mean total expected healthcare cost per patient was estimated to be 8,275GBP (+/−796) for patients treated with liposomal cytarabine and 3,238GBP (+/−494) for those treated with standard cytarabine. Patients treated with liposomal cytarabine accrued on average 0.27 (+/−0.027) QALYs compared to 0.15 (+/−0.025) QALYs in the standard cytarabine arm. The mean expected incremental cost per QALY gained with liposomal cytarabine was 47,764GBP (95%CI = 22,921–95,676). This estimate of cost-effectiveness was particularly sensitive to the health state utilities for progression and non-progression.
Conclusion : The results of this analysis suggest that liposomal cytarabine is a cost-effective treatment option for patients with lymphomatous meningitis. Although the incremental cost-effectiveness ratio (ICER) is close to the probable willingness-to-pay threshold, the results of this analysis should be evaluated in the context of a severe disease with few effective treatment options. Further research into patient preferences for the health states modelled here would be valuable given the sensitivity of QALY estimates to this variable.
Imatinib Interim Therapy Has Favorable Impact on the Outcome of Patients with Ph+ ALL Treated with Allogeneic SCT.
Authors: Seok Lee , Kim Yoo-Jin , Min Chang-Ki , Kim Hee-Je , Eom Ki-Sung , Kim Dong-Wook , Lee Jong-Wook , Min Woo-Sung , Kim Chun-Choo 
Published: October 2019

Abstract
Recently, we demonstrated the feasibility of first-line imatinib interim therapy (400~600 mg/day for 4 weeks) prior to allogeneic stem cell transplantation (SCT) in newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) (Blood, 2003;102:3068). Here, we report on the updated results of this strategy in 29 adult patients who completed induction chemotherapy and intended to undergo allogeneic SCT. In addition, we compared these results with those in 31 historic patients who proceeded to allogeneic SCT without imatinib therapy. There were no significant differences between the two groups with respect to presenting clinical and biologic characteristics. At the time of enrollment, 23 of the 29 patients (79.3%) had achieved a complete remission (CR) in the imatinib group, and the CR rate was not significantly different from the historic rate (26/31, 81.8%). In contrast, the relapse rate was significantly lower in the imatinib group during the post-remission treatment phase prior to SCT (3.5% vs 42.3%, p=0.002). Furthermore, 3 of the 6 refractory patients achieved a CR after the imatinib interim therapy. This study also found that the kinetics of the BCR-ABL transcript correlated well with the patients’ clinical course. Overall, the BCR-ABL/ABL ratios were decreased in 25 (86.2%) and increased in 4 (13.8%) patients after the imatinib interim therapy. A total of 57 patients (28 imatinib group, 29 historic group) underwent allogeneic SCT, and among them, 25 and 16 patients had sustained CR at the time of transplantation, respectively. The remaining 3 patients (1 imatinib group, 2 historic group) died of their disease progression before SCT. This has translated into lower relapse (4.8±4.7% vs 45.3±10.7%, p=0.004) and superior disease-free survival (75.8±12.9% vs 37.9±9.0%, p=0.001) for the imatinib group. Acute transplant-related toxicity and mortality were not different in the two groups. Considering the high frequency of relapse or refractoriness to chemotherapy-alone prior to SCT, imatinib interim therapy might provide a higher curative possibility for Ph+ ALL patients.
Durable Remission after Prophylactic Donor Lymphocyte Transfusion Following Allogeneic Stem Cell Transplantation with Reduced Conditioning for High-Risk AML and MDS.
Authors: Schleuning Michael , Schmid Christoph , Ledderose Georg , Tischer Johanna , Humann Meike , Ullmann Johanna , Schwerdtfeger Rainer , Kolb Hans-Jochem 
Published: October 2019

Abstract
Prophylactic transfusion of donor lymphocytes (pDLT) is an attractive form of maintenance therapy after allogeneic stem cell transplantation in patients with high risk of relapse. However, clinical experience is limited, and disease response is often achieved at the expense of severe graft-versus-host disease (GvHD). We here report our data on pDLT in high-risk AML and MDS. Cells were given within a prospective protocol that contained a sequence of chemotherapy, reduced intensity conditioning for allogeneic transplantation, and pDLT (FLAMSA-regimen). For pDLT, patients had to be in CR at least 120 days from transplantation, off immunosuppression for 30 days, and free of GvHD. 22/86 patients alive at day +120 fulfilled the criteria for pDLT. They had been transplanted for refractory or relapsed leukemia (n=9 each) or in CR1 because of unfavorable cytogenetics (n=4). 14 patients had an unfavorable karyotype, 8 with complex aberrations. Reasons for withholding pDLT in 64 patients included cGvHD or prolonged immunosuppression (n=38), refractory or relapsed leukemia (n=15), refusal of patient or donor (n=4 each), a history of grade IV acute GvHD (n=2), and chronic infections (n=3). The median time from transplant to first pDLT was 167 days (range 120–297). Median follow up of transfused patients is 696 days (range 209–1341). Ten patients received 1, 6 patients received 2, and 6 patients received 3 transfusions in escalating doses, containing a median of 1x106, 5x106 and 1x107 CD3+ cells/kg at pDLT 1, 2 and 3, respectively. Reasons for giving less than 3 transfusions were GvHD, relapse or refusal of the patient. Induction of GvHD was the main complication; grade III acute GvHD developed in 1, and chronic GvHD in 7 patients. So far, 5 patients have relapsed despite pDLT. One died of refractory leukemia, whereas 2 achieved secondary CR following adoptive immunotherapy. Two patients are currently under treatment. At present, 18/22 patients are alive and in CR at a median of 423 days post DLT. The current leukemia free survival at two years from first pDLT is 79%. Nineteen patients were complete chimeras at time of pDLT. pDLT converted mixed into complete bone marrow chimerism in 1, but failed in 2 cases. In our experience, pDLT is safe after allogeneic transplantation for high risk AML, when given at low doses and to a selected group of patients. Results are encouraging, and long term survival can be achieved. However, further studies need to define more precisely the contribution of pDLT to the therapeutic effect of the entire procedure.
The Use of TCR Vβ Spectratype Analysis in Allogeneic Blood and Marrow Transplantation.
Authors: Friedman Thea M. , Hopely Deborah D. , Stern Joshua L. , Filicko Joanne , Mookerjee Bijoyesh , Grosso Delores , Flomenberg Neal , Korngold Robert 
Published: October 2019

Abstract
The major complications of allogeneic blood and marrow transplantation (BMT) include graft failure, opportunistic infections, leukemic relapse and graft-versus-host disease (GVHD). The incidence of the first three complications is diminished by the presence of mature donor T cells in the transplant inoculum. Unfortunately, the transplantation of mature alloreactive donor T cells also directly induces the latter complication of acute GVHD, which can be directed against either HLA or minor histocompatibilty antigen (miHA) disparities. Efforts to deplete donor marrow inoculum of T cells have been successful in minimizing the development of disease but have been associated with increased leukemic relapse. Thus, one approach to solve this problem would be to identify and then selectively deplete alloreactive donorT cells while allowing the residual T cells to provide protection against infection and to mediate a leukemia-specific GVL response. In this regard, TCR Vβ repertoire analysis by CDR3-size spectratyping can be a powerful tool to characterize the alloreactive T cell response. As an initial test of this capability, we studied lethal GVHD in the B6->CXB-2 MHC-matched murine model, expressing multiple miHA differences. Herein, we determined the correlation between the in vitro alloreactive-specific CD8+ T cell response and their actual involvement in the development of GVHD. The results indicated a high correlation in the Vβ CDR3-size skewing patterns between the in vitro and in vivo spectratype histograms, and laid the foundation for the potential clinical application of this approach. We proceeded to test the predictive value of the in vitro spectratyping assays of donor anti-host mixed lymphocyte reactions with GVHD outcome in the clinical BMT setting. The results again indicated a high association of overlapping CDR3-size skewing. Thus, in vitro spectratyping analysis may be useful in guiding the manipulation of the donor T cell inoculum in order to provide improved BMT outcomes.
Immune Tolerance Induction (ITI) in Hemophilia A and Inhibitors using VWF Containing Factor VIII Concentrates.
Authors: Kreuz Wolfhart , Ettingshausen Carmen Escuriola , Auerswald Guenter K.H. , Brackmann Hans Herrmann , Klingebiel Thomas 
Published: October 2019

Abstract
Immune tolerance induction using the Bonn protocol (ITI) is the most successful approach to eliminate inhibitors in hemophilia A patients. The influence of the type of concentrate, particularly the content of von-Willebrand-Factor (VWF) used for ITI is under discussion and has never been investigated comparatively.
A longitudinal study at the Frankfurt center on the influence of VWF on ITI using the Bonn protocol (low responder: 50–100 IU FVIII/kg bw daily or every other day; high responder: 100–150 IU FVIII/kg bw every 12 hours; according to the bleeding tendency concomitant treatment with FEIBA®/Baxter) showed a significantly decreased success rate since the introduction of high purity plasma derived (pd) and recombinant (rec) F VIII products (success rate with pd VWF-F VIII 91% vs ultrapure F VIII 29%). Similar observations have been reported by the Bonn and Bremen centers (success rate with pd VWF-F VIII 87% vs ultrapure F VIII 54%). A meta-analysis of different ITI studies revealed a higher success rate with the use of VWF-FVIII concentrates (88% using VWF-FVIII and 63% using rec and pd/monoclonal purified F VIII).
The change to VWF-FVIII concentrates during ITI in inhibitor patients who showed an unsatisfactory treatment course with ultrapure F VIII concentrates (n=12 high responders) led to success in 10 out of 12 patients after a median treatment period of 17 months (5–36 months). Successful IT after changing to VWF-F VIII concentrates was evaluated by a questionnaire in another 10 high responders who had unsatisfactory treatment courses with ultrapure F VIII concentrates.
These observations indicate that VWF has a major impact on the success of ITI.