bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tumor Necrosis Factor-α Enhances DMSO-Induced Differentiation of HL-60 Cells through Activation of ERK/MAPK Pathway.
Authors: Park Jinny , Lee Young-Rae , Noh Eun-Mi , Han Myung-Kwan , Ahn Jung Ryul , Kim Young Sang , Park Se Hoon , Cho En Kyung , Shin Dong Bok , Lee Jae Hoon , Kim Jong-Suk 
Published: October 2019

Abstract
The differentiation of leukemic cells into mature cells is a major strategy for treatment of leukemia. Many trials for more efficient differentiation of leukemic cells have been performed using single uses of differentiation inducers including interferon-α (IFN-α), interleukin-4 (IL-4), tumor necrosis factor-α (TNF-α), and dimethyl sulfoxide (DMSO) or their combinations. Here we show that combination of TNF-α with DMSO enhances HL-60 cell differentiation. TNF-α enhanced DMSO-induced expression of CD11b and increase of G1 phase in the cell cycle, which are hallmarks for HL60 cell differentiation. Inhibition of ERK pathway, but not NF-κB pathway, abolished the enhancement of DMSO-induced HL-60 differentiation by TNF-α. These results suggest that TNF-α enhances HL-60 cells towards induction of differentiation by DMSO through activation of ERK/MAPK signaling pathway.
High Dose Simvastatin Has No Beneficial Effect on Markers of Bone Turn-Over in Multiple Myeloma.
Authors: Sondergaard Teis E. , Pedersen Per T. , Andersen Thomas L. , Lund Thomas , Garnero Patrick , Delaisse Jean-Marie , Plesner Torben 
Published: October 2019

Abstract
Background: Bone degradation in multiple myeloma (MM) is a result of increased bone degradation by osteoclasts that is not compensated for by bone forming osteoblasts. Ideally new drugs used for treatment of MM should target not only the myeloma cells but also the imbalance between bone resorption and bone formation. Statins have been shown to inhibit myeloma cell proliferation and induce apoptosis in vitro. Furthermore statins have been shown to stimulate osteoblasts and inhibit osteoclasts both in vitro and in animal models. Statins are normally used at doses around 20–80 mg/day, but in order to reach serum concentrations that can match the in vitro experiments MM patients were treated with 15 mg/kg/day of Simvastatin (HD-Sim) divided in two daily doses in this study. This high dose has previously been found to be safe for MM patients (Haematologica 2006, 91,542–545)
Patients and methods: Six patients with advanced MM have been included in this pilot study, 4 males and 2 females with an average age of 68 years and an average duration of disease of 43 months. The patients were treated with 2 cycles of HD-Sim for seven days followed by a break of 21 days in a 4-weeks cycle. Two of the patients were treated with bisphosphonates during the study, and 4 had previously been treated with bisphosphonates. Endpoints are change in concentrations of markers of osteoclast activity (TRAP) or bone resorption (CTX, NTX, ICTP) or markers of bone formation (Osteocalcin and PINP). Cholesterol, OPG and DDK-1 were also measured.
Results: Two patients completed the protocol with two cycles of HD-Sim at full dose, 2 patients were reduced to 7.5 mg/kg/day simvastatin in cycle 2 due to nausea and diarrhea and 2 patients left the protocol after 3 weeks (deaths not related to high dose simvastatin). All patients experienced gastrointestinal toxicity grade 1–2. Myalgia and other muscular symptoms grade 1–2 were reported by 5 patients but were not associated with an increase in creatin kinase. TRAP and NTX activity in serum increased for all 6 patients during the seven days of treatment with HD-Sim indicating that bone resorption may have been stimulated rather than inhibited. The other markers of bone resorption and the bone formation markers showed no change. All patients responded with a significantly reduced level of cholesterol in serum. None of the patients showed any reduction in free monoclonal light chains or monoclonal proteins in serum during treatment with HD-Sim and 2 of the 4 patients completing the protocol showed progression of diseases.
Conclusion: This pilot study of HD-Sim in advanced MM has been terminated due to lack of response and evidence from two markers of osteoclast activity (TRAP) and bone resorption (NTX) that HD-Sim may be harmful rather than beneficial in MM.
Bortezomib in Combination with Dexamethasone and Subsequent Thalidomide for Newly-Diagnosed Multiple Myeloma in Chinese Patients.
Authors: Cai Zhen , Zheng Weiyan , Wei Guoqing , Ye Xiujin , He Jingsong , Li Li , Wu Wenjun , Lin Maofang 
Published: October 2019

Abstract
Background: Bortezomib-dexamethasone-thalidomide has been reported to be effective in newly-diagnosed multiple myeloma (MM) with an overall response rate of 92% and a CR rate of 18% (Alexanian et al, Hematology12(3):235–239, 2007), but this regimen has not been reported in Chinese patients. We now report our experience with this combination.
Objectives: To investigate the efficacy and safety of bortezomib in combination of dexamethasone plus subsequent thalidomide as primary treatment for MM.
Patients and Method: Between June 2006 and August 2007, 11 consecutive newly-diagnosed patients with symptomatic MM were treated with bortezomib at 1.3 mg/m2 IV on days 1, 4, 8 and 11, dexamethasone at 20 mg/m2 IV daily on the day of bortezomib and the day after. All patients received daily oral thalidomide that was escalated from 100 mg to 200 mg. Seven of 11 patients were male and 4 were female. Median age was 57 years (range 47–86). Seven of 11 patients were stage 2 according to the International Staging System, 4 out of 11 patients were stage 3. Eleven patients received a median of 2 cycles of therapy (range 1–6). The Blade criteria were used for response evaluation. Toxicities were evaluated according to the NCI Common Toxicity Criteria version 3.
Results: Nine out of 11 patients (82%) achieved PR and 2 (18%) achieved CR; therefore the overall response rate was 100%. With a median follow-up duration of 5 months (1– 14 months), no patients died. Grade 3–4 toxicities included fatigue (3/11), thrombocytopenia (3/11), diarrhea (3/11) and orthostatic hypotension (2/11). Grade 2 neuropathy occurred in 3 out of 11 patients, herpes zoster occurred in 3 out of 11 patients. Routine anticoagulation or anti-thrombosis was not used. There was no DVT/PE in 11 patients.
Conclusion: Our preliminary experience indicated that bortezomib-dexamethasone-thalidomide is highly effective in newly-diagnosed MM. Grade 3 and 4 toxicities were rare after median 2 cycles of therapy. The relative lower rates of neuropathy and DVT/PE in this report with Chinese MM patients are being cautiously observed.
Hepatitis - Associated Aplastic Anaemia: Epidemiology and Treatment Results Obtained in Europe. A Report of the EBMT Aplastic Anemia Working Party.
Authors: Locasciulli Anna , Bacigalupo Andrea , Oneto Rosa , Bruno Barbara , Marsh Judith , Tichelli Andre’ , Socie’ Gerard , Passweg Jakob 
Published: October 2019

Abstract
Background. Most cases of acquired severe aplastic anaemia (SAA) are not associated with any other disease and are therefore classified as idiopathic. Hepatitis-associated aplastic anaemia (HAA) has been well described as a separate entity amongst the acquired aplastic anaemias. Aim of this study was to describe the epidemiology of HAA and to analyze treatment results obtained in Europe in the last 15 years.
Patients and methods. We evaluated 198 HAA out of 3684 AA patients reported to the SAAWP Registry between 1990 and 2005. Median age at diagnosis was 15 years (range 1–87) .132 were male and 66 female. Year, month and season of diagnosis were analyzed, as well as all variable related to the type and outcome of first line therapy.
Results.Prevalence of HAA amongst all acquired AA registered in Europe from 1990 to 2005 was 5.4% (198/3684).The majority of patients were male (66%), and median age was 15 years. The virus causing the hepatitis was unknown in most cases (94.5%) while only 11 / 198 (5.5%) were related to Hepatitis B or A virus infection. No significant differences were found in the prevalence according to the year, month or season of diagnosis. No geographic clusters could be identified. Seventy three HAA patients were treated with immunosuppression (IS) and 125 underwent Stem cell Transplantation (SCT): these were compared with 1539 and 2045 non-HAA patients given IS or SCT. The median age was significantly younger in the HAA as compared to the non-HAA patients (15 versus 20, p<0.0001). The median interval between diagnosis and treatment in IS and SCT was 8 and 67 days respectively. Median follow-up for surviving or deceased patients was 1356 and 155 days respectively. The actuarial survival at 10 years after IS was 66% for HAA and 52% for non-HAA (p=0.4). HLA identical sibling SCT produced survival of 83% in HAA and 74% in non-HAA patients (p=0.1); when the donor was unrelated, survival was respectively 63% and 52% (p=0.5). After stratification for stem cell source, actuarial survival was 83% vs 72% (p=0.06) for bone marrow, and 68% vs 57% (p=0.5) for peripheral blood.
Conclusions. The incidence of HAA in Europe is currently 5.4%, comparable with published data, and seems to be distributed homogeneously over the years, months and geographic areas. Results after IS or SCT in HAA patients are comparable to those obtained in idiopatic acquired non-HAA, treated in the same period in Europe. Therefore, HAA should be managed according to current guidelines for idiopathic aplastic anemia.
Response to Bortezomib Therapy for Multiple Myeloma (MM) in Actual Clinical Practice: Preliminary Effectiveness Findings of an International Observational Study.
Authors: Delforge Michel , Katodritou Eirini , Zervas Konstantinos , Sargin Deniz , Hulin Cyrille , Linderholm Mats , Verrou Evgenia , Poon Vicki , Dhawan Ravinder 
Published: October 2019

Abstract
Background: Bortezomib (VELCADE®) is indicated for the treatment of MM in patients (pts) who have received at least 1 prior therapy. The electronic VELCADE Observational Study (eVOBS) is designed to evaluate the clinical and outcomes benefits of bortezomib in actual clinical practice. The study is open for enrollment between October 2006 and December 2008 in Belgium, France, Greece, Russia, Spain, Sweden, and Turkey with 3-year follow up. This report includes preliminary outcomes in pts with at least 4 months of data as of July 2007.
Methods: Adults were eligible for study if they were scheduled to initiate bortezomib within the approved indication. All bortezomib dosages and concomitant treatments were permitted, except investigational therapies. Data on concomitant therapies, treatment response, and safety were collected prospectively during bortezomib therapy. Due to the non-interventional nature of the study, no predefined response criteria were mandated; response criteria could include M-protein, EBMT, SWOG, or others as defined by the investigator.
Results: A total of 86 pts with at least 4 months of data were included in this analysis. Median age was 61 yrs, and 50 (58%) pts were male. Median interval since diagnosis was 3 yrs. The number of previous therapies for MM was 1, 2–3, and ≥4 for 38%, 44%, and 11% of pts, respectively. Demographic and clinical characteristics of the initial participants were similar to those of the participants in the prospective controlled phase 3 APEX trial (Richardson, N Engl J Med, 2005:352; 2487–98). Most pts (61%) received bortezomib with dexamethasone. Adverse events (AEs) were reported in 61 (71%) pts, including Grade ≥3 AEs in 38% and Grade ≥4 AEs in 9%. AEs were treatment-related in 45% of patients and treatment-limiting in 9%. Presently, 72 of 86 pts have been evaluated for response, of whom 54 completed 4 or more cycles. Response rates are shown in the table. Updated data will be presented at the meeting.
Best Response(n = 72) Complete response (CR) 5 (7) Near complete response (nCR) 9 (13) Partial response (PR) 30 (42) Minimal response (MR) 9 (13) Stable disease (SD) 6 (8) Progressive disease (PD) 13 (18) Overall response (≥PR) 44 (61) Overall response (≥MR) 53 (74)
Conclusions: In this preliminary analysis of data from a prospective, observational study of actual clinical practice, most pts received bortezomib in combination with 1 or more other therapies for MM. Overall response in actual clinical practice was at least as common as previously reported with bortezomib monotherapy. Response rates and safety data from actual clinical practice demonstrate that bortezomib-containing regimens are effective and well-tolerated in the treatment of MM.
Simultaneous Haploidentically Mismatched Stem Cell Transplantation from Multi-Donors (MDT) in Humans Offers Better Engraftment as Compared to Single Haploidentical Donor.
Authors: Shapira Michael Y. , Resnick Igor B. , Gesundeheidt Benjamin , Samuel Simcha , Drey Liliane , Verkholevsky Yuri , Slavin Shimon , Or Reuven 
Published: October 2019

Abstract
Introduction: stem-cell-transplantation (SCT) aims to combine tumor cytoreduction and host replacement with donor cells. For patients with no matched sibling available for allogeneic SCT (approximately 70% of patients) an alternative option is SCT from a relative carrying only one identical HLA haplotype (haplo-SCT), which may provide a donor for almost every patient at optimal timing. In the small number of multi-cord blood transplants reported, it was found that usually only one unit engrafted faster, while the others were rejected. We hypothesized that multi-donors may improve the engraftment following haplo-SCT. Patients and methods: Fifteen ultra high-risk patients (median age 20y, 9–52, mostly after 1–2 previous SCTs and 13 of them with refractory disease) were included. Conditioning regimen was fludarabine based. All grafts were T cell depleted.
Results: All 14 evaluable patients engrafted but one of them later rejected the graft. The time for neutrophil engraftment (0.5 & 1.0x109/L) was fast, 11d (9–24) and 12d (10–28) respectively. Platelets engrafted even earlier (20 & 100x109/L), 10d (8–45) and 14d (12–32) respectively. Three patients demonstrate continuous bi-donor hematopoiesis (follow up 72, 128 and 168d) while 11 patients converted to single donor hematopoiesis within a median of 21d (14–39). Comparison of MDT patients to an earlier patient group receiving a similar protocol with a single donor (SDT) showed better granulocyte and platelet engraftment (p<0.001 for both, figures 1 and 2). Additionally, no primary graft failure occurred in patients undergoing MDT, while in SDT it occurred in 9/38 patients (p<0.001). One patient in-which leukemia persisted throughout the conditioning, leukemic cells disappeared upon the conversion to single donor chimerism. Despite major blood type differences, no hemolysis related side-effects were noted. Eight patients developed GVHD (mostly grade 1/2).
Conclusion: MDT is safe and induces fast and durable engraftment of both myeloid and thrombocyte lineages in patients undergoing haplo-SCT. Further studies should follow this report.
Figure Figure Figure Figure
Endothelial Dysfunction in Autologous Hematopoietic Stem Cell Transplantation.
Authors: Diaz-Ricart Maribel , Carbo Carla , Palomo Marta , Fernandez-Aviles Francesc , Rovira Montse , Escolar Gines , Carreras Enric 
Published: October 2019

Abstract
Introduction: Intensive conditioning regimen and allo-reactivity seem to be the main causes of the endothelial dysfunction observed after allogeneic HSCT. This dysfunction may be the origin of some early complications after HSCT. To evaluate if a less intensive conditioning without allo-reactivity phenomena produces endothelial dysfunction we analyzed a group of patients receiving autologous HSCT.
Methods: Blood samples were collected from patients (n=10) before receiving BEAM treatment (pre), and at days 0, 7, 14 and 21 after the HSCT. Soluble markers of endothelial damage (von Willebrand Factor [VWF], sE-selectin, sVCAM1, sICAM1, TNFalphaRI and II, MMP9) were measured in plasma samples by ELISA. Expression of the adhesion receptors E-selectin, VCAM1 and ICAM1, on endothelial cells (EC) cultured in the presence of a pool of sera, obtained at the different time points during the BEAM treatment, was analyzed by immunocytochemistry. Changes in the expression of VWF in the extracellular matrix generated by these EC were evaluated by using the same technique. Leukocyte adhesion on EC monolayers under flow conditions was also studied. The effect on cell cycle and apoptosis was also explored.
Results: Plasma levels of VWF and sICAM1 increased progressively after the HSCT, peaking on day 14 (84% and 118%, respectively, vs pre; p<0.01), although no increments were detected for sVCAM1 and sE-selectin. TNFalphaRI and RII increased from 0 (pre value) to 5, 12, respectively, and MMP9 from 0 (value at day 7) to 300ng/ml. Exposure of cultured EC to patients sera caused an increased expression of all adhesion receptors studied on the EC surface and of VWF on their extracellular matrix, more notable at day 14 and specially for VCAM1. Leukocyte adhesion on EC cultured with sera from day 14 showed a 6-fold rise compared to controls. Although no signs of apoptosis were detected, cell growth was accelerated at day 14.
Conclusions: The increases in the markers of endothelial inflammation detected both in the ex vivo and in the in vitro approaches suggest that there is endothelial damage associated with autologous HSCT. This damage seems to be more important at day 14 after HSCT. A better understanding of the mechanisms involved deserves further investigation.
Phase 1 Human Trial of Autologous Mesenchymal Stem Cell Transplantation for the Treatment of Decompensated Cirrhosis.
Authors: Alimoghaddam Kamran , Mohamadnejad Mehdi , Bagheri Mohahamd , Bashtar Maryam , Ghannati Hossein , Bonab Mandana Mohyeddin , Ghavamzadeh Ardeshir , Malekzadeh Reza 
Published: October 2019

Abstract
INTRODUCTION: Liver transplantation is the standard treatment in decompensated cirrhosis; however, it has several limitations including high cost, and several complications. Recent animal works have shown that mesenchymal stem cell (MSC) infusion through the rat tail vein can lead to regression of liver fibrosis. But there has been no human trial of autologous MSC transplantation (Tx) in cirrhosis. The aim of this study was to evaluate safety and feasibility of MSC transplantation in decompensated cirrhosis. In a recent study, infusion of CD 34+ (e.g. hematopoietic stem cells) through the hepatic artery was used to treat cirrhosis. However, we infused MSCs (e.g. non-hematopoietic stem cells) through a peripheral vein.
AIMS & METHODS: After protocol approval by the ethic committee, four patients with decompensated cirrhosis were included. 100 ml of their bone marrow was aspirated and MSCs were cultured. After two months culture, 10 to 70 million MSCs obtained which 95% of the cells were viable (as assessed by trypan blue method) and 95% of the cells were morphologically and immunophenotypically MSCs. The MSCs were infused through a peripheral vein. Outcomes were changes in liver function tests, MELD score, and liver volume (as measured by CT volumetry) 5 months after Tx. During follow up, patients’ medications (e.g duretics, or propranolol) remained the same as before MSCs Tx.
RESULTS: Four patients (1 male, 3 female) aged 30 to 56 were included. The etiology of cirrhosis was autoimmune hepatitis or cryptogenic. The follow up for the first patient has been completed, and other 3 patients have 2.5 to 4 months of follow up. In first patient, PT (18.5 to 13 seconds), and albumin (2.9 to 3.8 g/dL) normalized, and MELD score was decreased from 16 to 11. Her liver volume increased from 495 to 815 ml. In patient 2, PT decreased from 20.1 to 17.5. In patient 3, PT decreased from 19.1 to 15.7 seconds, and MELD score decreased from 17 to 14. Patient 4 has not yet been shown any significant improvement in liver function tests. The procedure was safe, and there was no any adverse effect.
CONCLUSION: MSCs Tx is a novel approach to treat cirrhosis. For the first time, we showed that this procedure is safe and feasible, and signs of improvement found in some of our patients are promising.
NK-Cell Reconstitution after HLA-Identical Blood and Marrow Transplantations for CML: The Recovery of NKG2D Is Inversely Correlated with NKG2A and It Promotes the GVL Effect.
Authors: Tong Juan , Liu Huilan , Geng Liangquan , Sun Zimin , Tang Baolin , Wu Zhentian , Qiao Chunlan , Chen Xin , Qian Bing , Song Kaidi 
Published: October 2019

Abstract
Natural killer (NK) cell alloreactivity is reported to mediate strong graft versus leukemia (GVL) effect in patients after allogeneic stem-cell transplantation. NKG2D receptors recognize human MHC class Ichain related A and B (MICA/B) and UL16-binding protein 1∼4(ULBP 1∼4) on target cells, thereby regulating NK cell activity. To examine the recovery of NKG2D, NKG2A and other receptors expression by NK cells, we used flow cytometry to evaluate samples from 11 chronic myeloid leukemia patients and their donors in the year following unmanipulated HLA completely matched peripheral blood stem cells plus bone marrow transplantation. Peripheral blood mononuclear cells from patients and their donors were tested in standard 51Cr release assays against cultured K562 targets to determine the cytotoxicity of the NK cells in the same intervals. There is no mismatched immunoglobulin-like receptor (KIR) ligand in both GVH and HVG direction. The reconstitution of KIR2DL1 (CD158a) after this transplantation protocol was very slow and these receptors didn’t reach normal value in the year and KIR2DL2 (CD158b) was much better. The NKG2D increased and the NKG2A decreased quickly at the same time after engraftment, and used linear regression analysis we demonstrated that NKG2A recovery was inversely correlated with NKG2D recovery in the year following transplantation. The ratio of NKG2D/NKG2A was directly associated with the capacity of NK-cell cytotoxicity. Thus, the reconstitution of NKG2D makes contribution to the recovery of the NK cytotoxicity. These results reveals that the NK cells generated after HLA matched blood plus bone morrow transplantation of CML patients are promoted at an immature state characterized by specific phenotypic features and enhanced functioning, having potential impact for immune responsiveness and transplantation outcome.