bluuebunny/crossref_metadata_2025_split huggingface dataset:
Preliminary Report of Risk-Based Approach in Korean Patients with Newly Diagnosed Multiple Myeloma.
Authors: Bang Soo-Mee , Lee Jae Hoon , Yoon Sung-Soo , Park Seonyang , Lee Je-Jung , Kim Hyeoung Joon , Jo Doeg Yeon , Park Yeon Hee , Yoon Hwi-Joong , Yuh Young-Jin , Ahn Myung-Ju , Im Seock Ah , Lee Moon Hee , Lee Dong Soon 
Published: April 2020

Abstract
Purpose: The purpose of this study was to examine the impact of different approaches stratified on risk based on chromosome 13 deletion and serum beta-2 microglobulin (MG) level would lead to survival benefit in patients with newly-diagnosed multiple myeloma.
Patients and Methods: At diagnosis, fresh marrow samples for FISH and serum for beta-2 MG were sent to central laboratory and reviewed. Patients who had chromosome 13 deletion and high beta-2 MG (&gt;2.5 mg/L) were considered to have high-risk disease. Patients without chromosome 13 deletion and low beta-2 MG were classified as low-risk group. Intermediate-risk group had to have either one of these two risk factors. After VAD induction chemotherapy, autologous stem cell transplantation conditioned with MEL200 was performed in patients at high- and intermediate-risk. DECP consolidation chemotherapy was added for high-risk patients. Patients who achieved CR after VAD in low-risk did not receive any further treatment.
Results: As of Jun 2004, 50 patients were registered from 10 centers. Median age was 58 (range, 39–68) years old. Chromosome 13 deletion was detected in 18 patients (36%) and beta-2 MG was elevated in 39 patients (78%). Thirteen patients were classified as high-risk, 31 patients as intermediate-risk and 6 patients as low-risk. After median follow-up of 9 months, progression-free and overall survival at 1-year were 56% and 76%, respectively. To date, no statistically significant differences in survival were observed between risk groups (figure 1).
Conclusion: In this study, risk-based approach in patients with multiple myeloma appeared to be feasible. Study accrual is ongoing and updated results will be presented.
Figure Figure
Protective Effect of VELCADE® on Thalidomide-Associated Deep Vein Thrombosis (DVT).
Authors: Zangari Maurizio , Barlogie Bart , Lee Choon-Kee , Tricot Annick E. , Fassas Athanasios , Anaissie Elias , Hollmig Klaus , Thertulien Raymond , Talamo Giampaolo , van Rhee Frits , Stover Julie M. , Fink Louis , Tricot Guido J. 
Published: April 2020

Abstract
Cardiovascular complications during the treatment of patients with multiple myeloma (MM) are not uncommon (10%) and the frequency clearly increases with the use of regimens containing thalidomide (T) in combination with glucocorticosteroids or chemotherapy especially adriamycin. Even with prophylactic anticoagulation, DVT still occurs in 10% of such patients. The use of full anticoagulation treatment raises considerable concern of bleeding, especially during the post chemotherapy thrombocytopenic period. We now report the incidence of DVT in MM patients treated with T containing regimens where VELCADE has been added to dexamethasone (D) and adriamycin. Results are shown in table1.
The incidence of DVT was also analyzed in 24 patients enrolled on protocol UARK 2001–37, where VELCADE was administered in combination with thalidomide and dexamethasone (VTD) for a total of 98 cycles without anticoagulation. Review of the literature regarding the incidence of DVT in patients receiving DT reveals reports of 16% (Cavo, et al. Haematologica. 2004 89:826) and 12 % (Rajkumar, et al. JClinOncol. 2002 1;20: 4319). In contrast no thrombotic episodes were documented with any of these cycles. This is the first report of protective antithrombotic effect of VELCADE in a malignancy associated with a hyper-coaguable state. Further studies to elucidate the mechanism of VELCADE anticoagulant activity are currently in progress.
Table 1. DVT Rates: DTPACE vs. VDTPACE
Protocol Treatment N Pts reporting DVT (%) P=0.0006 UARK 2001–12 (DTPACE) Dexamethasone Thalidomide Cisplatin Adriamycin® Cyclophosphamide Etoposide Lovenox® (40mg sc qd) 98 10 UARK 2003–33 (VDTPACE) Velcade® (1mg/m2) Dexamethasone Thalidomide Cisplatin Adriamycin® Cyclophosphamide Etoposide Lovenox® (40mg sc qd) 69 0
Expression of Heat Shock Protein 90 and the Effects of HSP90 Inhibitor (17-AAG) in Multiple Myeloma.
Authors: Alkan Serhan , Duus Jan , Bahar Ismail H. , Izban Keith F. , Al-Masri Hytham , Maududi Tazeen , Toor Amir 
Published: April 2020

Abstract
Heat Shock Protein 90 (HSP90) is required for structural folding and maintenance of conformational integrity of various proteins, including several associated with cellular signaling. Recent studies utilizing 17-allylamino-17-demethoxygeldanamycin (17-AAG), an inhibitor of HSP90, demonstrated antitumor effect in solid tumors. In order to test whether HSP90 could be targeted in multiple myeloma (MM) patients, we first investigated expression of HSP90 by immunofluorescence and flow cytometric analysis in a myeloma cell line (U266) and primary myeloma cells. Following demonstration of HSP90 expression in myeloma cells, archival samples of 32 MM patients were analyzed by immunoperoxidase staining. Myeloma cells in all patients showed strong cytoplasmic expression of HSP90 in all samples and 55 % also demonstrated concurrent nuclear immunopositivity. Treatment of U266 and primary MM cells with 17AAG resulted in significantly increased apoptosis compared to untreated control cells. Analysis of anti-apoptotic BCL2 family proteins in MM cells incubated with 17-AAG revealed down-regulation of BCL-2, BCL-XL and MCL-1. Furthermore, while low concentration of bortezomib had no cell death, combination of 17AAG and bortezomib treatment revealed a synergistic apoptotic effect on the U266 cell line. These data suggest that targeted inhibition of HSP90 may prove to be a valid and innovative strategy for the development of future therapeutic options for MM patients.
Anti-Tumor Activity of IPI-504, a Novel Hsp90 Inhibitor in Multiple Myeloma.
Authors: Palombella Vito J. , Normant Emmanuel , Ali Janid , Barrett John , Foley Michael , Gao Yun , Ge Jennie , Georges Asimina T. , Grayzel David , Grenier Louis , Hudak Jebecka , Pak Roger , Patterson Jon , Pien Christine , Pink Melissa , Porter James , Sang Junbiao , Spear Kerry , Sydor Jens , Wright Jim , Mitsiades Constantine S. , Anderson Kenneth C. , Adams Julian , Tong Jeffrey 
Published: April 2020

Abstract
IPI-504 is a novel inhibitor of Hsp90 based on the geldanamycin pharmacophore. When placed in rat, monkey, and human blood, IPI-504 rapidly converts to the known and well-studied compound 17-allylamino-17-demethoxy-geldanamycin (17-AAG). 17-AAG is the subject of multiple clinical trials for the treatment of hematologic and solid tumors. However, 17-AAG suffers from poor aqueous solubility necessitating the use of sub-optimal formulations to deliver this agent to patients. IPI-504 is over 1000-fold more soluble than 17-AAG in aqueous solution. In vitro, both 17-AAG and IPI-504 bind tightly to, and selectively inhibit Hsp90 derived from cancer cells. The cytotoxic effect of IPI-504, as well as its ability to stimulate the degradation of Hsp90 client proteins and increase the intracellular levels Hsp70, were monitored in two human multiple myeloma cells lines (RPMI-8226 and MM1.S). The effects of IPI-504 were compared to 17-AAG. We demonstrate that the actions of IPI-504 are bioequivalent to 17-AAG and that both compounds induce apoptosis in these cells and stimulate the degradation of HER2 and c-Raf. In addition, both agents stimulate Hsp70 protein levels. In all cases the EC50s are virtually the same for both molecules (~200–400 nM). Furthermore, IPI-504 inhibits the secretion of immunoglobulin light chain from the RPMI-8226 multiple myeloma cells (EC50 ~300 nM). Importantly, IPI-504 is active in tumor xenograft models of multiple myeloma. The data indicate that active metabolites of IPI-504 accumulate in these xenografts long after these metabolites are cleared from the plasma compartment, suggesting that they preferentially accumulate in tumor cells based on their increased affinity to Hsp90 derived from tumor cells. In conclusion, we have developed IPI-504 as a novel, potent inhibitor of Hsp90 with greatly increased solubility over 17-AAG, and that IPI-504 is an active anti-tumor agent in vitro and in vivo.
CHOP Plus Rituximab (CHOP-R) in Waldenström’s Macroglobulinemia (WM).
Authors: Hunter Zachary , Branagan Andrew , Treon Steven 
Published: April 2020

Abstract
Recently, a consensus panel of experts recommended alkylator therapy, nucleoside analogues and rituximab as appropriate first line therapies for WM (Semin Oncol2003; 30:121). It was also recommended that candidates for future autologous transplantation should have limited alkylator or nucleoside analogue exposure due to potential stem cell harm. CHOP-R (cyclophosphamide, adriamycin, vincristine, prednisone, rituximab) is a highly active, stem cell sparing regimen that has been extensively evaluated in other low-grade Non-Hodgkin’s lymphoma patients. No published experience in WM exists. As such, we analyzed the outcome of 13 patients with WM who received CHOP-R at our Institution. Patients had a median age of 54 (range 44–72) yrs, and a median of 1 (range 0–5) prior therapies. 8 of 13 (62%) patients had relapsed (n=2) or were refractory (n=6) to fludarabine. Five patients had received rituximab previously. Patients received a median of 6 cycles (range 2–6) of standard dose CHOP, and 6 infusions (range 2–6) of Rituximab (375 mg/m2). Three patients received additional rituximab (4 weekly infusions every 6 months) as maintenance therapy. Median IgM for all patients declined from 4,975 (range 1,960–12,400) to 1,575 (range 62–8,230) mg/dL (p=7 x 10−5); median S.V. 2.8 (range 1.5–12) declined to 1.6 (range 1.3–4.8) CP (p=0.04). Importantly, the median hematocrit rose from 30.7 (range 21.9–35.6) to 39 (range 24.3–43.2) p=0.005. Clinical responses were as follows: 3 CR/CRu; 7 PR; 2 MR. One patient is in stable disease after 3 cycles of CHOP-R. With a median follow-up of 8 (range 3–28) months, no patient has progressed. Therapy was well tolerated for most patients. Two patients had febrile neutropenia with documented bacteremia and recovered without any complication. Circulating effector cell levels pre- and post-CHOP-R were also evaluated in 6 patients since rituximab activity is mediated in part by ADCC activity. No significant change in CD3+, CD4+, CD8+, and CD16+/CD56+ effector cell levels occurred following CHOP-R as assessed by multicolor flow cytometry.
Metaphase Cytogenetic Abnormalities (M-CA) and Interphase FISH for Deletion 13 (FISH 13) in Total Therapy 2 (TT 2): Follow up Observation among? 380 Patients with Newly Diagnosed Multiple Myeloma (MM).
Authors: Shaughnessy John , Zhan Frank , Barlogie Bart , Rasmussen Erik , Milner Teresa , Jackson Lisa , Fassas Athanasios , Zangari Maurizio , Lee Choon-Kee , Talamo Giampaolo , Thertulien Raymond , Crowley John , Tricot Guido 
Published: April 2020

Abstract
We have previously reported on the adverse prognostic implications m-CA, present in ~ 33% of newly diagnosed patients especially when involving del 13 (~ 20%). To overcome the proliferation dependency of m-CA, FISH has been applied detecting abnormalities in virtually all patients with MM; FISH 13, detected in ~ 50% has been associated with poor outcome with both standard and high dose therapies. Of a total of 668 patients accrued to Total Therapy 2, 380 had baseline evaluations for m-CA and FISH 13. We examined 2 different cut-points of FISH 13 deletion, the traditional ≥ 20% (FISH 13–20) and an 80% cut-off (FISH 13–80). In case of FISH 13–20, major differences in both EFS and OS were noted among those exhibiting CA, with an adverse effect of FISH 13–20, whereas there was no difference among the majority of patients exhibiting no CA (Figure 1). However, using FISH 13–80, adverse effects of FISH 13 were observed for both no CA and CA subgroups (FISH 2). Indeed, 4-yr estimates of EFS/OS were highest at 73%/85% among 204 patients in the no CA/FISH 13–80-negative group compared to 54%/69% among the 42 with no CA and FISH 13–80-positive group. Similarly, among 134 patients with CA, those with FISH 13–80-positive disease had 4-yr EFS/OS of only 23%/22% compared 44%/58% among the 103 without FISH 13–80. Our data confirm the overriding importance of m-CA for prognosis and, in addition, reveal the importance of the proportion of plasma cells revealing del 13 as an additional key parameter in both no CA and CA subgroups. Biologically, these data would suggest a marked clinically relevant heterogeneity of FISH 13 that deserves further evaluation.
Plasmacytoid Precursor Dendritic Cells Contribute to the Ability of CD8+TCR− Facilitating Cells Population of Enhance Hematopoetic Stem Cell Engraftment and HSC Clonogenicity.
Authors: Fugier Isabelle J. , Rezzoug Francine , Huang Yiming , Schanie Carrie L. , Ildstad Suzanne T. 
Published: April 2020

Abstract
The discovery of cells with facilitative property offers great therapeutic potential in hematopoietic stem cell (HSC) transplantation. CD8+/TCR− facilitating cells (FC) enhance engraftment of HSC in allogeneic recipients without causing GVHD and also significantly enhance the engraftment of limiting numbers of HSC in syngeneic recipients. We recently identified that plasmacytoid precursor dendritic cells (p-preDC), the main component of the heterogeneous FC population, contribute to facilitation, but with less efficiency than the total FC population. In the present study we determined the role p-preDC play in the ability of FC to 1) enhance syngeneic suboptimal HSC engraftment and 2) maintain HSC clonogenicity in vitro. 500 syngeneic HSC +/− 30,000 FC, or p-preDC from the FC (DC-FC) were transplanted into ablated (950 cGy) B6 mice. As expected, FC significantly increased HSC engraftment, with 87.5 % of recipients (n=19) surviving at 250 days after transplantation, while recipients of HSC alone exhibited significantly impaired survival (37.5%, P=0.0026, n=16) (Figure 1). However, DC-FC, which allowed a slight improvement of HSC engraftment (52.6% recipient survival, n=16, P=0.15), were significantly (P=0.034) less effective than total FC. These data show that DC-FC are less effective than FC total. We then evaluated the influence of p-preDC and DC-FC on HSC in vitro using the colony forming cell (CFC) assay that enumerates progenitors in the HSC population. HSC were cultured in the presence or absence of FC, p-preDC or DC-FC (at 1:3 ratio) in methylcellulose containing growth factors for 14 days. The number of CFC was significantly increased when HSC were cultured in the presence of FC (P&lt;0.01) compared to HSC alone (Figure 2). In contrast, the DC-FC slightly increased clonogenicity, as did p-pre-DC, but did not replace FC total. Moreover, when we preincubated HSC with FC, DC-FC or p-pre-DC for 18 hour and assessed in the CFC assay, FC significantly increased the number of CFC although no significant effect was observed with DC-FC or p-pre-DC (Figure 2). These data suggest that the effect of FC on HSC clonogenicity and HSC engraftment is only partially due to the contribution of the DC subpopulation, and that this effect on HSC requires synergistic interactions between the cells within the FC population. Moreover these data also suggest that FC facilitation on HSC involves a combination of different mechanisms: one on host alloreactivity due likely to DC-FC and one on direct interaction with HSC due to combined effects of cells in the FC.
Figure Figure Figure Figure
NF-κB Inhibitor Pyrrolidinedithiocarbamate Can Increase the Infection and Activation of Cytomegalovirus in Mesenchymal Stem Cells.
Authors: Wei Guoqing , Lin Maofang , Huang He , Cai Zhen 
Published: April 2020

Abstract
Objective Because of the central role of the transcription factor nuclear factor-κB (NF-κB) in cell survival and proliferation in many kinds of cancer cells, NF-κB inhibitor may have a potential role in the therapy of cancer. Human cytomegalovirus (CMV) infection is one of the most common complications following stem cells transplantation. Some data report that CMV infection has a very close relation with NF-κB activation. But it is unknown what effect of NF-κB inhibitor pyrrolidinedithiocarbamate (PTDC) on the infection and activation of cytomegalovirus in mesenchymal stem cells(MSCs).
Methods MSCs were infected by 1 TCID50 of CMV combined with/without 1μmol/L of PTDC. After 48h of culture with DMEM supplemented with 10% (v/v) fetal calf serum, MSCs shapes were observed. RT-PCR assay was used to detect the mRNA expression of CMV immediate early (IE) gene and GAPDH gene. Flow Cytometry was used to detect the CMV PP65 antigen positive cells.
Results Shape of some MSCs changed after the infection of 1 TCID50 of CMV. But in MSCs infected by 1 TCID50 of CMV combined with 1μmol/L of PTDC, Cell shape changed more dominantly, almost all cells changed from thin shuttle shape to round and thick ball shape. While in the cells treated only with PDTC, shape of the cells did not changed. RT-PCR assay showed that there was a very bright band of CMV IE mRNA in MSCs infected by 1 TCID50 of CMV combined with 1μmol/L of PTDC compared with the cells infected only with 1 TCID50 of CMV. More CMV pp65 antigen positive cells were found in MSCs infected by 1 TCID50 of CMV combined with 1μmol/L of PTDC with Flow Cytometry.
Conclusion NF-κB activation may affect CMV infection of cells. NF-κB inhibitor PTDC can increase the infection and activation of CMV in MSCs and we should pay more attention to CMV infection when we use NF-κB inhibitor in clinical work..
Co-Transplantation of Hematopoietic Stem Cells and GM-CSF/G-CSF/CSF-Transfected Mesenchymal Stem Cells in SCID Mice.
Authors: Han Jin-Yeong , Koh Rhee-Young , Seo Su-Yeong , Park Joo-In , Kwon Hyuk-Chan , Kim Jae-Seok , Lee Young-Ho , Kim Hyo-Jin 
Published: April 2020

Abstract
Mesenchymal stem cells (MSC) are multipotent and believed to facilitate the engraftment of hematopoietic stem cells (HSC) when transplanted simultaneously in animal studies and recently even in human trials. In this study, we transfected culture-expanded MSC with GM-CSF, G-CSF, and CSF cytokine genes and then co-transplanted with HSC to further promote HSC engraftment. Mononuclear cells were harvested from the various sources and seeded in long-term culture for ex vivo MSC expansion. The phenotype and purity of MSC were assessed by flow cytometry. We transferred the above three cytokine genes into ex vivo expanded MSC, confirmed transfection by fluorescent microscope of GFP, and thereafter did co-transplantation with HSC. A total of 1x107 HSC plus MSC/uL were introduced to tail vein of SCID mice. After 3–7 weeks later, with venous blood from the eyeballs, homing and engraftment of human cells were determined by flow cytometry and fluorescence in situ hybridization (FISH) studies. The total nucleated cell count and the engraftment of CD45+/CD34+ cells and XX/XY-positive human cells significantly increased in co-transplanted mice and even higher with the cytokine gene-transfected MSC in the order of GM-CSF, SCF, and G-CSF transfections (P&lt;0.05). These results suggest that MSC transfected with hematopoietic growth factor genes are capable of enhancing the hematopoietic engraftment. Now we are planning to deliver genes involved in homing and cell adhesions, e.g., CXCR4, VLA, or TPO into ex vivo expanded MSC and do co-transplantation with HSC to further increase the efficiency of stem cell transplantation.
An Exaggerated B Cell CpG Response in Human Chronic Graft-versus-Host Disease: A Potential Mechanism and Biomarker for Diagnosis of Chronic GVHD.
Authors: She Kevin , Gilman Andrew L. , Schultz Kirk R. 
Published: April 2020

Abstract
Chronic Graft-versus-Host Disease (GVHD) is a major limitation to successful allogeneic bone marrow transplantation (BMT). Lipopolysaccharide (LPS), a cell-wall component of gram negative bacteria that signals through Toll-like receptor 4 (TLR4), is an established contributor to acute GVHD. Our lab has previously shown that splenocytes from mice with acute GVHD were hyper-responsive to CpG, unmethylated DNA with C-G repeats from bacteria and viruses, which induce rapid responses by dendritic cells, B cells, and monocytes through TLR9. As part of Children’s Oncology Group phase III randomized trial ASCT0031 evaluating the efficacy of hydroxychloroquine in the treatment of newly diagnosed chronic GVHD, peripheral blood was drawn for immune phenotype and functional studies in patients and control (no GVHD, 80–120 days post allogeneic transplant). The non-BMT group were healthy adult volunteers. After Ficoll isolation, lymphocytes were cultured with or without synthetic human immunostimulatory CpG 2006 (6μg/mL) or LPS (1μg/mL) for 48 hours and analyzed by flow cytometry. Cell surface marker expression was evaluated as fold difference between stimulated and unstimulated cells. In some samples, B cells were purified by negative selection to determine proliferative response and/or for the quantitation of TLR9 mRNA. Chronic GVHD samples had a 3.7 +/− 1.2 fold (n=11) increase in B cell CD40 mean channel fluorescence after CpG stimulation which was significantly greater than in the control group at 1.0 +/− 0.6 fold (n=3, Mann-Whitney U test p=0.02) and the non-BMT group at 1.5 +/− 0.9 fold (n=3, p=0.01). Similarly, chronic GVHD samples had a 9.1 +/− 5.7 fold (n=10) increase in the percentage of B cells expressing CD86 after CpG stimulation which was significantly greater than the control group at 2.1 +/− 2.1 fold (n=4, p=0.008) and the non-BMT group at 2.7 +/− 0.9 fold (n=5, p=0.008). Responses to LPS stimulation or culture without stimulation were not significantly different between the three groups. Purified B cells from GVHD samples (n=3) had enhanced mitogenic response to CpG compared to the control group (n=1), non-BMT group (n=2), and to non-stimulated cells. CpG response appears to be closely correlated with TLR9 mRNA expression (R2=0.82). These findings suggest that CpG responsiveness or TLR9 mRNA expression may potentially be useful as a biomarker for diagnosis or staging of chronic GVHD. Further evaluation on larger numbers of samples is required to confirm these observations.