bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bortezomib Targets Multiple Myeloma Endothelial Cells.
Authors: Roccaro Aldo M. , Hideshima Teru , Raje Noopur , Kumar Shaji , Ishitsuka Kenji , Yasui Hiroshi , Shiraishi Norihiko , Hamasaki Makoto , Richardson Paul G. , Anderson Kenneth C. 
Published: April 2020

Abstract
Introduction: Bone marrow (BM) angiogenesis is an important hallmark of multiple myeloma (MM) which correlates with progression. Although MM remains incurable despite conventional and high-dose chemotherapy, the proteasome inhibitor Bortezomib (Velcade, formerly PS-341), can overcome conventional drug resistance in vitro and in vivo and it has recently been FDA approved for treatment of relapsed and refractory multiple myeloma. Here we evaluated whether anti-angiogenesis may contribute to the anti-MM activity of PS-341. We examined the effect of PS-341 on the angiogenic phenotype of endothelial cells (ECs) isolated from BM of patients with MM.
Methods: MMECs were extracted from BM of patients with active MM using a lectin-based method. The MMEC population contained &gt;95% factor VIII-related antigen (FVIII-RA)+ and CD31+ cells, as assessed by fluorescence activated cell sorting (FACS). Contamination by macrophages and plasma cells was &lt;5%, evaluated by FACS for CD14 and CD38 positivity, respectively, as well as by RT-PCR and Western blot for CD38. Viability, assessed by trypan blue was &gt;90%. MTT assay and [3H] thymidine uptake were used to evaluate the effects of PS-341 on survival and proliferation, respectively, of MMECs. Proliferation of MM.1S cells cocoltured with MMECs was measured by [3H] thymidine uptake. Cytokine (IL-6, VEGF) levels were quantitated by ELISA. Other in vitro angiogenesis functions examined included chemotaxis, spreading on fibronectin (FN), and morphogenesis on Matrigel. Ongoing work is looking at the effect of PS-341 on angiogenesis in vivo by using a chick embryo chorioallantoic membrane (CAM) model.
Results: PS-341, at concentrations achievable in the plasma of patients, inhibited in vitro MMEC and HUVEC functions related to angiogenesis, including proliferation, chemotaxis, spreading on FN, and capillary formation on Matrigel. All these functions were affected in a dose-dependent fashion. A significant concentration-dependent reduction of VEGF and IL-6 production was observed in the presence of PS-341, as demonstrated by ELISA. Importantly, binding of MM.1S cells to MMECs triggers tumor cell proliferation, and PS-341 inhibits proliferation of adherent MM.1S cells in a dose-dependent fashion. Similar data were demonstrated in HUVECs.
Conclusions: These data therefore demonstrate that PS-341 acts both directly and indirectly against MMECs, another mechanism which may contribute to the anti-MM activity of PS-341.
Aldehyde Dehydrogenase Activity - the Better Marker for the Quality of Hematopoietic Stem Cell Transplants?!.
Authors: Lioznov Michael V. , Freiberger Petra , Zander Axel R. , Fehse Boris 
Published: April 2020

Abstract
The use of functional rather than cell surface markers to identify and isolate stem cells has several advantages. Recently, aldehyde dehydrogenase (ALDH) enzyme activity has been shown to be a metabolic marker for primitive hematopoietic progenitor cells. We compared 7-day-expression kinetics of ALDH vs. the standard marker in human hematopoietic stem cell transplantation, CD34, and related these data to the colony-forming ability of bone marrow and leukapheresis samples. Cell probes directly taken from whole transplants were first analyzed on the day of harvest (day 0) using flow cytometry (CD34, ALDEFLUOR®) and methyl cellulose (MC) assays. To resemble usual conditions during transport of clinical transplants, cell samples were then stored without additional modification at either +4°C or room temperature (RT). Relative CD34+, ALDH+ and CFU numbers were determined at various time points (days 1, 2, 3 and 7). During this time course we found that progenitor (CFU-GM) cell activity correlated very well with ALDH enzyme function but not with CD34 expression, the commonly used parameter to evaluate the quality of hematopoietic stem cell transplants. This indicates that ALDH expression may be a more reliable marker for quality control of HSC transplants. Based on our assay systems we also could show that PBSC transplants lose most of their CFU-activity (&gt;80%) within just 48 hours if stored at room temperature, but are stable at +4°C. Thus, transport of PBSC transplants at RT should be strongly avoided. In conclusion, our data may have important implications for both quality control and transport organization of HSC transplants, especially given the permanent increase in numbers of PBSCT from matched unrelated donors.
Infections after CD34-Selected or Unmanipulated Autologous Hematopoietic Stem Cell Transplantation.
Authors: Frère Pascale , Pereira Maguy , Fillet Georges , Beguin Yves 
Published: April 2020

Abstract
Relapse remains the major cause of failure after high-dose chemotherapy and autologous peripheral blood stem cell transplantation (PBSCT). As tumor contamination of the graft may contribute to this, CD34 selection has been used as an attempt to decrease the relapse rate. However, immune reconstitution may be delayed with CD34 selection due to the removal of T cells, natural killer (NK) cells and monocytes. The result could be an increased incidence of infectious complications. Some small series of patients have reported a higher incidence of infections, and in particular of viral infections, but others have not. Therefore, we compared the incidence of infection in 25 recipients of CD34-selected PBSC (CD34 group) and 75 case-matched recipients of unmanipulated PBSC (PBSC group) transplants. There were 52 males and 48 females with an average age of 52±11 yrs. They included 32 patients with non-Hodgkin’s lymphoma, 8 with Hodgkin’s disease, 40 with multiple myeloma and 20 with breast cancer, with 42 in first-line therapy and 58 in relapse, receiving their 1st (N=63) or 2nd (N=37) transplant. The number of CD34 cells infused as well as speed of engraftment were comparable in the two groups. There were no significant increase in the CD34 compared to the PBSC group for: actuarial incidence of infection (56 vs 49% at day 30, 70 vs 64% at 1 yr); proportion of patients with at least 1 (68 vs 68%), 2 (24 vs 17%) or 3 (0 vs 3%) infections; number of infectious events per patient before (1.32 vs 1.04) or after (0.59 vs 0.71) disease progression, before day 30 (0.84 vs 0.64), within days 31–100 (0.00 vs 0.09, p&lt;0.01) or after day 100 (0.48 vs 0.31); risk of VZV (27 vs 30% at 5 yr) or CMV infection (8 vs 6%) or disease (0 vs 3%); use of antibiotics (8 vs 5 days) or antifungal therapy (0 vs 0%) or days with fever (1 vs 1 day) in the initial hospitalisation. However, bacteremias tended to be more frequent in the CD34 group (0.44 vs 0.20 episode/patient). Bacteria accounted for the majority of infections in both groups (64 vs 72%). Infection was the main or a contributing cause of death in 0% and 20% of patients in the CD34 group compared to 1% and 10% in the PBSC group (NS). In conclusion, our results indicate only a trend towards an increased risk of infection after CD34-selected autologous PBSCT. The role of extended infection prophylaxis should be evaluated.
Clostridium Difficile-Associated Disease in Allogeneic Transplant Patients.
Authors: Sadhu Justin S. , Dubberke Erik R. , Gatti Robert , Devine Steven M. , Fraser Victoria J. 
Published: April 2020

Abstract
Allogeneic transplant (allo) patients (pts) are at high risk for Clostridium difficile-associated disease (CDAD), yet there are few studies evaluating CDAD in allo pts. We carried out a retrospective chart review of all allo pts who had CDAD on a transplant (tx) unit between 8/01 and 7/03. 37 pts were identified who had CDAD during tx hospitalization (hosp) or after tx during the study period. 17 (46%) were admitted for initial tx, 13 (35%) for infection, and 7 (19%) for other reasons. 15 (40%) had acute leukemia, 6 (16%) lymphoma, 4 (11%) myelodisplastic syndrome, and 12 (32%) other underlying diseases. On admission, 17 (46%) pts were in complete remission, 4 (11%) in partial remission, 7 (19%) in relapse, and 9 (24%) presented with refractory disease. 5 pts (14%) had CDAD before day 0 (median d-2, range d-9 to d-1) and 32 pts (86%) had CDAD after tx (median d+49, d0 to d+3185). In the 60 days prior to CDAD, pts had median 1 (0–4) prior hosp and 15 days (1–50) hospitalized; 36 pts (97%) received antibiotics, 35 (95%) immunosuppressants, 33 (89%) antimotility/narcotic agents, 31 (84%) gastric acid suppression, 23 (62%) chemo, and 14 (38%) TBI. Within 48 hours of CDAD, 31 (86%) pts had diarrhea, 12 (33%) fever, 10 (28%) abdominal tenderness, 7 (19%) abdominal distention, and 7 (19%) hypothermia. 22 pts (59%) had either moderate or severe CDAD. 25 (68%) pts were treated for their primary episode of CDAD with metronizadole (met), 2 (5%) with vancomycin (vanc), 8 (22%) with met and vanc, and 2 (5%) were not treated for CDAD. 32 (86%) pts responded to therapy (median 2 days, range 0–25 days). Of the 32 pts who had CDAD post allo, 3 (9%) had gut graft-versus-host disease (GVHD) before CDAD and 8/29 (28%) developed gut GVHD after CDAD. Those 8 pts developed CDAD median d+114 (range +1 to +278) and gut GVHD d+131 (+1 to +454), with gut GVHD coming median 11 days (0 to 176) after CDAD. 7 pts (19%) died before discharge. The median survival time for all pts was 79 days after CDAD and 205 days after tx. Of the 30 (81%) pts discharged alive, 10 (33%) had recurrent CDAD episodes (median 1, range 1–3). When compared to mild CDAD, patients with severe CDAD had an increased risk of death at one year after CDAD (OR 3.3; CI 1.4–7.6). CDAD in allo pts may be associated with an increased risk of gut GVHD, death, and other adverse outcomes.
Extracorporeal Photopheresis (ECP) for Acute and Chronic GVHD, a Report of 56 Patients Treated in a Single Institution.
Authors: Dann Eldad J. , Badian Alla , Stravets Tselestina , Kertsman Elena , Avivi Irit , Elhasid Ronit , Haddad Nuhad , Fineman Riva , Zuckerman Tsila , Oliven Ana , Bonstein Lilah , Rowe Jacob M. 
Published: April 2020

Abstract
Acute and chronic GvHD remain the leading cause of morbidity and mortality of allogenic stem cells transplantation. Immunosuppressive therapy is the mainstay of prophylaxis and therapy for GvHD; however, it heavily impacts on post transplant morbidity and mortality and new modalities are continually needed. Reported here is the five-year experience in a single institution of ECP for acute and chronic GvHD patients. Mononuclear cells were collected using Cobe -Spectra version 7 manual operation for adults and version 6 for pediatric patients. 1.5–2.0 blood volumes were circulated through the cell separator with a product of approximately 5X109 mononuclear cells. When product hematocrit was less then 3%, volume was added to 300ml. With plasmacyte electrolyte solution and when the hematocrit was more then 3%, volume was added to 500 ml. 8 methoxy psoralen (8MOP) was added to a final concentration of 0.2ug/ml. Cells were then transferred to irradiation bag, exposed to 2 Joule /cm2 of UVA (365nM) (Biogenetic Vilber Lourmat) and re-transfused. The treatment protocol consisted of 2 consecutive ECP performed at bi-weekly intervals until clinical improvement. Fifty-six patients, 34 males and 22 females, age 1 to 64y (median 31 years), were treated. Patients underwent allogeneic bone marrow transplantation for the following indications. AML -21, ALL- 19, CML-8, Thalassemia 4, MDS-2, MM-1 NHL-1. Sixteen were treated for acute GvHD and 40 for chronic GvHD. Diffuse GvHD of skin was diagnosed in 43, gastro-intestinal tract 10; joint involvement 12, and liver involvement 35 patients. Patients had from 4 to 66 ECP (median 21). Results: 15 pts succumbed,10 with acute GvHD and 5 with chronic GvHD. Disease relapse was the cause of death in two patients with acute GvHD. Overall response rate was 46/56 (82%). Response rate for chronic GvHD was 37/40 (92%) and for acute GvHD was 9/16 (56%). Complete resolution of GvHD, partial response and no response were seen respectively in 33%, 60%, 7% for patients with chronic GvHD and 0%, 56% and 44% for patients with acute GvHD. Conclusions: ECP is a useful therapeutic modality for GvHD and is most effective in patients with chronic GvHD. It is most effective for both liver and skin involvement and less effective for patients with scleroderma. It is suggested that this modality should be used in early management of these patients concomitantly with immune suppressive therapy in the order to improve quality of life and reduce long-term side effects.
No. of Patients Median ECP/pt No. of CR No. of PR No response Acute GvHD 16 8 (4–41) 0 9 (56%) 5 (44%) Chronic GvHD 40 26 (4–66) 13 (33%) 24 (60%) 3 (7%)
Reconstitution of NK Cell Receptor Repertoire after Pediatric Stem Cell Transplantation.
Authors: Kobayashi Michihiro , Hiramatsu Hidefumi , Adachi So-ichi , Nakahata Tatsutoshi 
Published: April 2020

Abstract
Interaction between killer immunoglobulin-like receptors (KIRs) and HLA class I ligands influence development of natural killer cell repertoire and response to allogeneic tissue. Recently several reports suggests donor/recipient KIR-ligand imcompatibility have great influence for outcome of allogeneic Hematopoietic Stem Cell transplantation (SCT). We examined recovery of the NK cell receptor after pediatric SCT to elucidate emergence of NKR repertoire and frequency after SCT is depend on whether donor or recipient type and effect of HLA disparity. [Patients and method] Nine patients receiving allogeneic SCT were examined. Expressions and frequency of KIR on NK cells were determined by flowcytometry using anti CD158a/h, 158b/j, 158e, 158i, 159a, 94, 56,and 3 antibodies. Donor and recipient KIR repertoire frequency prior to SCT were also examined. In cord blood transplantation, donor KIR repertoire was checked using residual thawed and infused cord blood. [Result] Among 9 patients, PBSCT were performed in 3 patients, CBT in 3, unrelated BMT in 3. HLA matched SCT was all 3 cases of unrelated BMT. KIR expression frequency was various in each patient. But in early phase, relatively both high percentage and absolute number of each KIR positive repertoire were observed, and then gradually decreased toward to 1 year after SCT. NK cell receptor repertoire reconstitution was generally well and rapid except for one patient who was treated with steroid pulse therapy for severe GVHD. KIR repertoire expression pattern at 1 year after SCT was similar to donor type compare to that of pre-SCT recipient. Donor/recipient HLA mismatch did not have obvious effect for NKR repertoire reconstitution. [Conclusion] NKR repertoire reconstitution after pediatric SCT depends on donor cell type.
Harvest of Autologous Peripheral Blood Stem Cells Using Ifosfamide/Etoposide Regimen Combined with Granulocyte Colony-Stimulating Factor.
Authors: Noguchi Mitsuho , Tashiro Haruko , Goto Moritaka , Kawasugi Kazuo , Shirafuji Naoki 
Published: April 2020

Abstract
Aim: To make clear the feasibility of Ifosfamide/Etoposide (IE) regimen combined with granulocyte colony-stimulating factor (G-CSF) for the collection of autologous peripheral blood stem cells (APBSC), we evaluated the number of the collected CD34 positive cells, and the regimen-related toxicities.
Patients’ characteristics and Methods: 19 Patients (male 12, female 7) were received APBSC harvest in our hospitals during Aug. 2000 to Dec. 2003 with age of 54.3 years on average (30–66). Diagnoses were included HD (n=2), NHL (n=13), MM (n=3), and malignant synovioma (n=1). IE regimen was included with Ifomide 2000 mg/m2 (day 1), and Etoposide 200 mg/m2 (day 1–3) (4cases) or 500 mg/m2 (day 1,2) (15 cases). For the prevention of hemorrhagic cystitis patients were administered with Mesna, and NaHCO3 during and after 1 day of the administration of Ifosfamide. G-CSF was administered at the dose of 10 ug/kg (lenograstim) or 300 ug/m2 (filgrastim) when blood absolute neutrophil count came down to 1000/mm3. When the suppression of bone marrow was recovered and blood WBC count came up to 5000/m3, CD34-positive cells were counted in blood, and APBSC was harvested when blood CD34-positive cells were determined above 0.1 %. APBSC was harvested with CS-3000 plus (Fenwall).
Result: The median duration from the start of the administration of G-CSF to the finish of APBSC harvest was 6.5 days (4–11). The median number of CD34-positive cells of the harvested was 4.32 x 106/kg (1.10–13.50). All cases were harvested. The toxicities during from the conditioning to the harvest were included with grade 1 headache (2 cases), grade 2 nausea (6 cases), grade 1 bleeding (1 case), grade 1 constipation (1 case), grade 1 fever (1 case), and grade 1 thrombocytopenia (1 case).
Conclusion: IE regimen combined with G-CSF was feasible to harvest APBSC on the yield of the collection of the transplantable stem cells, and on the regimen-related toxicities.
Total Therapy 3 (TT 3) for Newly Diagnosed Myeloma, Incorporating Velcade into Remission Induction with DT PACE: Early Results Regarding Efficacy, PBSC Mobilization and Toxicities.
Authors: Barlogie Bart , Hollmig Klaus , Zangari Maurizio , Stover Julie , Jackson Lisa , Milner Teresa , Fassas Athanasios , Tricot Guido 
Published: April 2020

Abstract
TT 3 represents a further development of the Total Therapy concept after completion of accrual to TT 2 with 668 patients. Based on the high salvage potential of the Velcade + Thal + Dex (VTD) regimen for endstage MM, VTD had been added to PACE (4 day continuous infusions of cisplatin 10 mg/m2, adriamycin 10 mg/m2, cyclophosphamide 400 mg/m2 and etoposide 40 mg/m2) x 2 cycles for induction with PBSC collection with first or second cycle; followed by MEL 200 mg/m2-based autotransplant 2–3 months apart and subsequent consolidation therapy with further VTD PACE and VTD maintenance. As of July 1, 2004, allowing for a 1-month time to evaluate initial response and toxicity, 57 patients have been accrued to TT 3. M protein responses by level demonstrated ≥ near-CR in 16% prior to cycle 2; 26% after cycle 2 prior to first transplant and nearly 40% after first transplant (patients not yet evaluable for response for a particular step were considered non-responders; intent-to-treat analysis). The PBSC collection target of 20 million CD 34 cells/kg was accomplished within 2 days of collection in all 10 patients mobilized on the first cycle; among 29 patients collected on the second cycle, 17 collected at least 20 million CD 34 cells/kg during 2–3 days, especially when only 2 or 3 doses of Vel 1.0 mg/m2 were applied, whereas in case of 4 doses (day −2, +1, +5, +8) 5 of 23 patients failed to collect on this cycle and 13 reached ≥ 20 x 106/kg procurement goal. There was only 1 treatment-related death in a setting of renal failure at diagnosis. Other toxicities were mainly myelosuppression whereas non-hematologic toxicities appeared to be similar to those seen with DT PACE previously. Laboratory correlates such as gene expression profiling, after a test dose of Velcade and after VTD PACE along with early suppression of FDG uptake on PET will also be presented. These preliminary data indicate remarkable activity and safety of a regimen that incorporates all available drugs with single agent activity in a multi-combination strategy, aimed at maximizing and accelerating tumor mass reduction in an effort to overcome the negative consequences especially of metaphase cytogenetic abnormalities.
Junb Regulates Hematopoietic Stem Cell Numbers in Normal and Leukemic Mice.
Authors: Passegue Emmanuelle , Wagner Erwin F. , Weissman Irving L. 
Published: April 2020

Abstract
JunB is expressed in hematopoietic stem cells (HSC) as a partner for Fos in the composition of the AP-1 transcription factor. Previously, we have shown that junB inactivation in postnatal mice results in the development of a myeloproliferative disorder (MPD) resembling early human chronic myelogenous leukemia (CML) (Passegue et al., 2001, Cell, 104, 21-32). Here, we demonstrate that JunB is a critical transcriptional regulator of HSC numbers both in normal and leukemic mice. Overexpression of junB in long-term HSC (LT-HSC) dramatically decreases the frequency of LT-HSC, while inactivation of junB specifically expands the numbers of LT-HSC, and of granulocyte/macrophage progenitors (GMP), resulting in the development of a chronic MPD with many features of human CML, including progression to blast crisis, and death. JunB effects are mediated, at least in part, via the regulation of effectors genes such as the cell cycle inhibitor p16/INK4a, which is a direct junB-target gene and a key regulator of stem cell proliferation/senescence, as well as the anti-apoptotic proteins bcl2 and bcl-xl, two critical regulators of stem cell death. Using several models of conditional deletion of junB in hematopoietic cells, we demonstrate that junB inactivation must take place in LT-HSC, and not at later stages of myelopoiesis, to induce MPD. Most importantly, we show that only junB-deficient LT-HSC, and no other myeloid progenitor populations, are capable of transplanting the MPD to recipient mice. These results indicate a stem cell-specific role for JunB in normal and leukemic hematopoiesis, and provide an experimental demonstration that leukemia stem cells (LSC) can reside at the LT-HSC stage of development in a mouse model of chronic MPD.