bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Potentials of Constitutive NF-κB Activation in U266 Cell Lines.
Authors: Amin Jakia , Otsuyama Ken-ichiro , Uchida Emi , Abroun Saeid , Shamsasenjan Karim , Islam Khademul , Kawano Michio M. 
Published: October 2019

Abstract
NF-κB has been described as a family of ubiquitously expressed transcription factors, composed of a dimer of distinct members of the Rel protein family (RelA/p65, cRel, RelB, p50, p52), and after stimulation, NF-κB dimer translocate into the nucleus to activate the transcription of various target genes. In the present study, we aimed to elucidate the mechanism of constitutive activation of NF-κB in human myeloma cells. For this purpose here, we used a human myeloma cell line, U266 cells, and performed gel shift assay and also examined the expression of different target genes of NF-κB by RT-PCR and determined the up-regulation of some of the anti-apoptopic genes (IAP-1, IAP-2, Survivin, Bcl-2, Bfl-1) and cell cycle regulators (Cox-2, Cyclin-D1, Cyclin-D2). This NF-κB-mediated gene expression provided an approach for investigating the protein expression of NF-κB family in U266. Our data revealed that the expression of p65, p50, RelB and cRel was strongly detected in the whole lysate of U266, while weak expression of p52 was found in U266. Furthermore, in the nuclear fractions of U266 cells, we strongly detected the expression of p65, RelB and p50, but not the cRel, for cRel was present in the cytoplasm. It has been recognized that dimerization is essential for NF-κB activity. Then, we performed immunoprecipitation-immunoblot analysis to demonstrate the dimer that might present in the U266, and we detected the possible dimerization such as p65-RelB in the nucleus. Therefore, these results suggest that U266 shows high constitutive activation of NF-kB, and possible hetero- and homodimer of NF-kB except for p52 may be responsible for the constitutive activation of NF-kB in U266 cells.
Combination Chemotherapy Including Velcade in Patients with Refractory or Relapsed Multiple Myeloma.
Authors: Zhou YuHong , Yu QingHong , Hu ZhiPing , Ye BaoDong , Shen YiPing , Shen JianPing , Yu LongXi 
Published: October 2019

Abstract
PURPOSE: Velcade, a proteasome inhibitor, is a remarkably active agent in patients with advanced relapsed or refractory multiple myeloma (MM). We report velcade combination chemotherapy in MM patients at our center.
METHODS: The trial opened in March 2006, and 9 patients who were refratory or relapsed MM have enrolled before August. The median age of the patients was 60 years (range 44 to 75). The median bone marrow plasma cell percentage was 20% (range 10.5% to 66%). The median serum ß2- microglobulin level was 3.8mg/l (range 1.2 to 8.6mg/l).5 patients committed renal disfunction. The regimens were as follows: The V-MPT regimen(4 patients) included oral melphalan (5 mg/m2 on days 1-5), prednisone (50 mg/m2 on days 1–5), thalidomide (100~200 mg continuously), velcade (1.3 mg/m2 on days 1, 4, 15, 22). 5 patients who were renal disfunction accepted the V-VADT regimens consist of velcade (1.0mg/m2 on days 1, 4, 8, 11), vincristine (0.4mg on days 1–4), pharmorubicin (10mg on days 1–4), dexamethasone (20mg/m2 on days 1–4,9–12,17–20), thalidomide (200 mg continuously). The V-MPT was repeated every 5 weeks and the V-VADT every 4 weeks for a total of 6 cycles. All cycles were delivered in day hospital.
RESULTS: A median 2 cycles (range 1 to 4) were administered to the all patients. Response was defined as EBMT criteria.9 patients are presently evaluable for response after therapy.8 patients responsed to treatment: 2 complete responses (CR), 1 near CR, 3 partial responses and 2 minor responses. And one patient experienced progressive disease. Interestingly, creatinine turned to normal in 5 renal disfunction patients after 1–2 cycles therapy. Most common side-effects were nausea, vomiting, fatigue and peripheral neuropathy. Grade 3 hematological toxicities included thrombocytopenia (1 patient) and neutropenia (2 patents).
CONCLUSION: The combination therapy with velcade is safe and effective in the treatment of relapsed or refractory multiple myeloma, and well tolerated, even in renal disfunction patients.
Osteonecrosis of the Jaw or Maxilla after Intravenous Bisphosphonates for Multiple Myeloma and Breast Cancer: Long-Term Follow-Up Shows a Slow Rate of Healing.
Authors: Hu Mimi I. , Hoff Ana O. , Toth Bela , Altundag K. , Johnson Marcella , Warneke Carla , Nooka Ajay , Sayegh Gilbert , Guarneri Valentina , Desrouleaux Kimberly , Jeffrey Cui , Hortobagyi Gabriel N. , Gagel Robert F. 
Published: October 2019

Abstract
Osteonecrosis of the jaw or maxilla (ONJM) is a rare but clinically significant disorder recently reviewed in a large retrospective study by our group (Hoff et al, 27th ASBMR Meeting 2005, Presentation #1218). A subset of the ONJM patients with breast cancer or myeloma was followed at the University of Texas M.D. Anderson Cancer Center (UTMDACC) dental clinic. This analysis describes the natural history of ONJM in this subset. Thirteen of 29 ONJM patients treated with intravenous bisphosphonates (IVBP) at UTMDACC and 1 ONJM patient treated elsewhere were evaluated in the dental clinic for more than 6 months (myeloma, n=7; breast cancer, n=7). Measurement of the maximum length of exposed bone was documented at each visit. Each patient received a standard regimen of conservative dental care with debridement only when indicated. All patients received zoledronic acid (mean cumulative dose 80mg; range 24–152mg) and 10 patients also received pamidronate (mean cumulative dose 1665mg; range 90–2700mg). This subset was followed for a median duration of 18.2 months (range: 7.1–67.3 months). The mean length of exposed bone at initial evaluation was 11 mm (range: 2–29 mm). The lesion from baseline to the most recent clinic visit progressed in 7 patients (50%), remained stable in 2 (14%), regressed in 2 (14%), and resolved in 3 (21%). Persistent ONJ was seen if IVBP was stopped (n=8), decreased in frequency (n=1), or continued at the same dose/frequency (n=2) (Graphs 1, 2). Complete resolution occurred in 3 multiple myeloma patients; IVBP was decreased in one and discontinued in 2 of the resolved cases (heavy lines on Graph 1). Our experience shows that ONJM is a disorder with slow resolution in most patients, lasting as long as 5 years. In the oncologic setting where there is clear benefit of bisphosphonate therapy, studies to optimize the dosing regimen may be needed.
Graph 1. Myeloma (n=7) Graph 1. Myeloma (n=7) Graph 2. Breast Cancer (n=7) Graph 2. Breast Cancer (n=7)
Biological and Clinical Responses after Intradermal and Intravenous Administrations of Mature Dendritic Cells Loaded with Tumor Lysate in Follicular Lymphoma Patients.
Authors: Baudard Marion , Conge Anne Marie , Veyrune Jean-Luc , Condomines Maud , Klein Bernard , Rossi Jean-Francois 
Published: October 2019

Abstract
New therapeutic approaches have been developed to treat follicular lymphoma (FL), the most common type of indolent non-Hodgkin’s lymphoma which should still be regarded as an incurable malignancy with a relentless relapsing course, except in the subset of patients with localized disease. For vaccination purposes, dendritic cells (DC) generated and loaded with tumor antigens ex vivo are focus of attention for already 10 years. In 07/04 we started a phase II study to evaluate a vaccination strategy based on multiple injections of autologous DC loaded with tumor lysate (DC-lysate) in FL patients. We reported here the results we observed for the first 7 enrolled patients (3F/4M, age: 44–61; 1 to 8 previous lines of treatment, including autologous PBSC transplant in 2 pts) who completed their treatment consisting in 5 to 7 DC-lysate vaccinations. At time of inclusion an excisional biopsy of a peripheral lymph node was performed in all patients; tumoral B cells were isolated by negative T cell depletion (using immunomagnetic beads and anti-CD3 antibodies) and then lysed by 5 freezing/thawing cycles to produce tumor lysate. Immature DC were obtained from mononuclear cells collected after Cyclophosphamide (2g/m2) and G-CSF (10μg/kg) administration, cultured for 5 days with GM-CSF and IL-4, pulsed with lysate, and then induced to mature with TNFa and PGE2 for 24h. All DC preparation fitted the quality criteria of viability ≥60%, ≤20% CD14+ cells, ≥60% CD83+ cells. For each vaccine 107 DC-lysate were administered, both intravenously [IV] (5×106 cells) and intradermally [ID] (5×106 cells). Vaccinations were safe and well tolerated. All patients developed significant delayed-type hypersensitivity responses to DC-lysate after several vaccines administration, testifying of the induction of a response. Among the 4 patients vaccinated with measurable disease, 2 who presented with low tumor burden (1 stage I, 1 stage II) achieved CR (with normal CT and absolutely no more FDG uptake on PET), so far persistent 3 and 6 months after the last vaccine, while disease progressed in the 2 remaining patients who presented respectively a stage IV and stage II disease at time of vaccination. The 3 patients vaccinated while in CR showed no disease progression at last tumor evaluation (9 to 12 months post last vaccination). This study demonstrated that DC-lysate vaccines might be efficient in FL patients with low tumor burden disease. Because the cause of disease recurrence is the presence of minimal residual disease after conventional treatments, the adjuvant setting might be the most appropriate therapeutic strategy for active specific immunotherapy, when the immunosuppressive effects of bulky disease are virtually absent and when the effector-target ratio is favorable.
Use and Efficacy of Stem Cells Cryopreserved for More Than One Year.
Authors: Pawson Rachel , Smythe Jon , Mcdonald Dorothy , Guttridge Martin , Lubenko Anatole , Wiggins Claire , Pamphilon Derwood , Watt Suzanne M. 
Published: October 2019

Abstract
Adequate viability after cryostorage is essential to allow engraftment of autologous haematopoietic progenitor cells (HPC). Information on the effect of prolonged cryopreservation on HPC viability in humans is limited although donations are routinely stored for over a year. Long-term storage is expensive and demonstration of clinical efficacy of HPC after long-term cryopreservation is important in order to justify the use of resources. Available reports describe only isolated cases in which old cells have been infused. We have conducted a retrospective survey of transplants using HPC stored >1 year within the National Blood Service in England. In total 75 patients received HPC that had been frozen for >1yr in NBS Laboratories. Patients had AML (21), NHL (21), myeloma (18), CML (5), Hodgkins disease (6) and other diseases (4). Fifty seven patients received PBSCs cryopreserved for >1 yr with median time in storage of 23 (12.1–65) months and median infused CD34 dose of 4.6 (1.2–85) ×106/kg. Neutrophil recovery to >0.5 × 109/l was 12 (4–49) days and platelets to > 20 × 109/l was 13 (3–43) days. Thirteen patients received bone marrow that had been cryopreserved for >1 year (median 32 (13–67) months) with infused TNC dose of 1.7 (0.91 – 3.64) × 108/kg. Time to neutrophils >0.5 × 109/l was 17 (12–95) days and platelets > 20 × 109/l 16 (12–66) days. A further 5 patients received a mixture of PBSCs and BM products all of which had been stored for > 1 year. Delayed neutrophil engraftment (neutrophils <0.5 × 109/l at 21 days) occurred in 2/55 PBSC transplants and 2/8 BM transplants. Delayed platelet engraftment (platelets <20 × 109/l at 28 days) occurred in 4/48 PBSC transplants and 4/8 BM transplants. In this survey, although the use of HPC cryopreserved for more than one year was infrequent, satisfactory engraftment was achieved in most patients. The rate of delayed engraftment was higher in BM as compared to PBSC transplants but numbers are too small for statistical analysis. In vitro viability assays were not available in this study but may help inform decisions on the use of cells stored for long periods.
Treosulfan - Fludarabine as Ablative Conditioning Regimen for Patients with High Risk Hematologic Malignancies.
Authors: Baronciani Donatella , Rambaldi Alessandro , Pilo Federica , Mico Caterina , Deplano Simona , Depau Cristina , Dessalvi Paolo , Angelucci Emanuele 
Published: October 2019

Abstract
Allogeneic stem cell transplant (allo HSCT) is a potentially curative approach for patients with hematologic malignancies but it is associated with high treatment related morbidity and mortality. Because transplant related mortality increases with age, advanced disease, and unrelated donors, patients older than 50–55 years may be excluded from this procedure. Reduced intensity conditioning regimens showed a low success rate in long-term follow-up, so new ablative reduced toxicity regimens are of striking interest. The aim of this study was to evaluate toxicity and efficacy of the combination consisting of Treosulfan (Busulphan derivative water soluble alkylating agent) and Fludarabine as a preparative regimen for patients receiving HSCs from matched siblings or unrelated donors for advanced heavily pretreated hematologic malignancies.
From July 2005 to June 2006, 21 consecutive patients (10 males, 11 females) were enrolled.
Mean age was 45 years (range 17–65). Underlying diseases were: acute leukemia (6 ALL, 5 AML), 1 CML, 3 MM, 5 MDS, 1 hystiocytic sarcoma). All patients were heavily pretreated; only 8 of them were in CR at transplant.
Conditioning consisted of Treosulfan (12–14 gr/m2 for 3 days) in combination with Fludarabine (30 mg/m2 for 5 days).
Cyclosporine plus short MTX and anti-thymocyte globulin (Thymoglobulin) were used as GVHD prophylaxis. Eleven (11) patients received HSCs from an HLA identical sibling and 10 from a matched unrelated donor. Source of stem cells was bone marrow in 4 patients, and peripheral blood in 17.
Twenty (20) patients engrafted; mean time to neutrophil recovery >500 × 109/L was 14 (range 10–24) days, to platelets >20,000 × 109/L was 14 (range 10–21) days. One patient receiving bone marrow did not engraft and died with active disease. Two (2) patients experienced GI toxicity (grade 2), 5 patients had grade 1 liver toxicity and 1 patient grade 1 renal toxicity. Four (4) pts presented acute GVHD (2 grade I, 2 grade II).
Eleven (11) patients (52%) are alive in complete remission with a follow-up ranging from 30 to 270 days; 4 died for recurrent disease; 5 patients are alive with active disease. This preliminary report shows that Treosulfan-Fludarabine-ATG conditioning regimen is well tolerated and characterized by reduced toxicity in a cohort of high risk patients with advanced age, who should otherwise be excluded from any other conventional transplant procedure.
Transplantation from Related and Unrelated Donors in Elderly Patients - Equal Toxicity and Survival.
Authors: Shapira Michael Y. , Tsirigotis Panagiotis D. , Or Reuven , Resnick Igor B. , Bitan Menachem , Gesundheit Benjamin , Slavin Shimon 
Published: October 2019

Abstract
Most of the hematological malignancies where allogeneic stem cell transplantation (SCT) is a therapeutic option occur in elderly patients. Additionally, in this age group, the probability of finding a matched sibling donor decreases due to mortality and co-morbidities of patient’s siblings which may exclude them from donation. In such case, SCT from an unrelated donor (UD) can offer a therapeutic solution for elderly patients in need although such a procedure is considered more hazardous than SCT from a matched sibling (mostly due to procedure and GVHD related morbidity and mortality). We present our data on transplantation, in 68 elderly (age>/= 55 years) patients that underwent SCT from a matched sibling (n=51) or UD (n=17) mostly using fludarabine-based regimen (table 1).
Median recipient age was 58.3y in the sibling group and 60.8y in the UD group (NS) (range 55–69.5y and 55–75y, respectively). With a median follow-up of 40 months of the survivors after sibling SCT, the 1-year OS was 32%. Similarly, in the UD group the 1-year OS was 35% (survivors’ median follow-up 48.5m) (NS). Transplant related mortality occurred in 22/49 (45%) and 9/17 (53%) of the patients transplanted from sibling or UD respectively (NS). Occurrence of acute GVHD was noted in 26/43 and 7/11 (figure 1) evaluable patients transplanted from matched sibling or UD respectively (NS). Diagnosis of chronic GVHD was made in 50% (14/28) and 63% (5/8) of the patients in the sibling and UD group correspondingly. GVHD related mortality occurred in 11 and 2 patients, respectively.
We conclude that using fludarabine based regimen, allogeneic SCT from an UD is equally effective as in patients undergoing SCT from matched family member. Age per-se should not be currently used as an exclusion criterion for either initiation of donor search or SCT from UD.
Table 1- Patients’ characteristics Figure Figure
Synergistic Growth-Inhibitory Effects of Two Tyrosine Kinase Inhibitors, Dasatinib and PKC412, on Neoplastic Mast Cells Expressing the D816V-Mutated Oncogenic Variant of KIT.
Authors: Gleixner Karoline V. , Mayerhofer Matthias , Sonneck Karoline , Gruze Alexander , Samorapoompichit Puchit , Aichberger Karl J. , Lee Francis Y. , Manley Paul W. , Fabbro Doriano , Pickl Winfried F. , Sillaber Christian , Valent Peter 
Published: October 2019

Abstract
In a majority of all patients with systemic mastocytosis (SM) including aggressive SM and mast cell leukemia (MCL), neoplastic cells display the D816V-mutated variant of KIT. The respective oncoprotein, KIT-D816V, exhibits constitutive tyrosine kinase (TK) activity and has been implicated in malignant cell growth. Therefore, several attempts have been made to identify KIT-D816V-targeting drugs. We found that the TK-inhibitor dasatinib (BMS-354825) inhibits TK activity of wild type (wt) KIT and KIT-D816V in Ba/F3 cells with doxycycline-inducible KIT-expression. In addition, dasatinib was found to inhibit KIT D816V-induced cluster formation and viability in Ba/F3 cells as well as growth of HMC-1.1 cells (KIT-D816V-negative) and HMC-1.2 cells (KIT-D816V-positive). The effects of dasatinib on growth of HMC-1 cells were dose-dependent, with 100–1,000-fold higher IC50-values in cells harbouring KIT-D816V compared to cells lacking KIT-D816V. Furthermore, dasatinib was found to inhibit the growth of primary neoplastic mast cells in SM in all patients examined. The inhibitory effects of dasatinib in HMC-1 cells were found to be associated with apoptosis and a decrease in expression of CD2 and CD63 as determined by flow cytometry. In addition, dasatinib was found to cooperate with the tyrosine kinase inhibitors PKC412 (midostaurin), AMN107 (nilotinib), and STI571 (imatinib), as well as with 2CdA (cladribine) in producing growth-inhibition in neoplastic mast cells. In HMC-1.1 cells, all drug-interactions applied were found to be synergistic. By contrast, in HMC-1.2 cells, only the combinations “dasatinib+PKC412” and “dasatinib+2CdA” were found to produce synergistic effects. These drug-combinations may thus represent an interesting pharmacologic approach for the treatment of patients with aggressive systemic mastocytosis or mast cell leukemia.
Valganciclovir Is Safe and Effective as Pre-Emptive Treatment for CMV Infection in Allogeneic Hematopoietic Stem Cell Transplantation.
Authors: Pastano Rocco , Gigli Federica , Andreola Giovanna , Calabrese Liliana , Peccatori Fedro , Martinelli Giovanni 
Published: October 2019

Abstract
RATIONALE OF STUDY: Despite significant advances in prevention and therapy, cytomegalovirus (CMV) infection still represents an important cause of morbidity and mortality in patients undergoing allogeneic haematopoietic stem cell transplant (HSCT). The standard pre-emptive treatment is based on intravenous administration of Ganciclovir (GCV). Valganciclovir (VGC), the pro-drug formulation of GCV is characterised by an excellent bio availability, making this drug suitable for oral administration.
PATIENTS: Since March 2003 all patients treated with reduced (27 patients) or fully ablative (3 patients) conditioning regimens followed by sibling HSCT, were monitored with bi-weekly CMV/PCR and pp65/assays. Overall 15 episodes of CMV positivity were detected in seven patients. Patients resulted positive (3 cells pp65+ or 1000/100000 PCR +) started oral treatment with VGC 900 mg bid, for the first fourteen days, followed by 900 mg q.d. up to at least seven days after assays normalization. The median duration of therapy was 21 days (range 10–21 days). No significant toxicity was observed. All patients had a normalization of CMV/PCR and pp65/assays within fourteen days, with a response rate (RR) of 100%. In two patients the oral VGC therapy was changed to the intravenous administration of Foscavir, because of concomitant neutropenia and acute GvHD.
CONCLUSION: Pre-emptive treatment of CMV infection with VGC is safe, feasible and effective. Furthermore, the oral administration of this drug in an outpatient setting, reduces significantly the costs compared with a therapy that needs hospitalization as intravenous Ganciclovir.
Monitoring Immune Function by the Cylex Immuknow Assay in Pediatric HSCT Patients.
Authors: Yu Lolie C. , Britz Judy , Martin Martha , Kowalski Richard 
Published: October 2019

Abstract
A observational analysis of immune function in six pediatric HSCT patients (3 allogeneic/3 autologous) ranging in age from 3 to 16 years (median = 8.6) was conducted at Children’s Hospital; Louisiana State University Health Sciences Center using ImmuKnow®, an FDA cleared assay for assessing T cell activation. This whole blood assay measures the immune function of CD4+ T-helper cells by stimulating cells with phytohemagglutinin (PHA), selecting CD4+ cells with antibody coated magnetic particles and detecting ATP by bioluminescence, an indicator of activation. The immunknow assay was obtained weekly post-HSCT. On average, the ImmuKnow value for the allogeneic patients was 109 ng/mL ATP with a median value of 63 ng/mL ATP. In two of the three allopatients, a rapid and significant rise in immuknow levels correlated with clinical complications. One ALL patient, given an allogeneic PBSCT from a HLA-ID sibling, developed Veno-occlusive disease (VOD) of the liver, 18 days post BMT with a corresponding spike in the ImmuKnow level to 500 ng/mL ATP. Following treatment with defibrotide, the VOD resolved and ImmuKnow ATP levels decreased, stabilizing between 100–150 ng/mL ATP. A second allopatient showed dramatic rise in immuknow level at day 18 post transplant to 480ng/mL ATP that corresponded with gross hematuria secondary to urethritis. In autologous BMT patients, the average ImmuKnow value was 133 ng/mL ATP with a median value of 70 ng/mL ATP. Clinical correlations were less clear in this small sample of patients with fewer test values. ImmuKnow has previously been demonstrated to have clinical utility for managing immunosuppressive therapies in solid-organ transplantation (SOT)1 The range of immune function values in pediatric patients has previously been shown to be significantly lower than adult ranges.2 Our data suggest that this assay may also be useful as a marker for the development of complications post-HSCT. Additional studies are in progress to confirm these early findings that suggest that routine immune function monitoring is of clinical value in the allogeneic HSCT recipients.