bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I Study of AVE1642 Anti IGF-1R Monoclonal Antibody in Patients with Advanced Multiple Myeloma.
Authors: Moreau Philippe , Hulin Cyrille , Facon Thierry , Boccadoro Mario , Mery-Mignard Dominique , Deslandes Antoine , Harousseau Jean-Luc 
Published: October 2019

Abstract
Rationale: CD221 (IGF-1R) is aberrantly expressed in multiple myeloma (MM) and is associated with disease severity (Bataille et al, Haematologica2005;90:706). IGF-1R is thus an attractive therapeutic target in patients with advanced disease.
Patients and methods: We have conducted an open-label dose escalation phase I study of AVE1642, anti IGF-1R monoclonal antibody, in patients with advanced MM. The primary objective was to determine the selected dose of AVE1642 administered every 3 weeks (q3w) based on pharmacokinetic (PK), pharmacodynamic (PD) parameters and dose limiting toxicities. The secondary objectives were to assess the safety profile, the biological activity (saturation of receptors) on peripheral granulocytes, the potential immunogenicity and preliminary clinical activity of AVE1642.
Results: 14 patients have been treated with AVE1642 as IV infusion administered q3w (day 1 = day 22) at 3 different dose levels: 3 (n = 4), 6 (n = 6) and 12 mg/kg (n = 4). A median number of 2 infusions (1–8) were administered. AVE1642 was well tolerated, except reversible grade 3 hyperglycemia observed in 2 diabetic patients. No hypersensitivity during infusion was reported. No human antibody anti AVE1642 was detected. One patient with Bence-Jones MM experienced a decrease in proteinuria and relief of bone pain. Based on PK/PD results, the dose of 12 mg/kg of AVE1642 has been selected for further clinical evaluation in MM patients. Based on the in vitro synergistic activity of AVE1642 + bortezomib (Descamps et al, ASH2006, 845a), we have started a combination trial of AVE1642, 12 mg/kg q3w + bortezomib (1.3 mg/m2 at d1, d4, d8 and d11 q3w) in patients with advanced MM.
Curcumin Downregulates NF-kB and Related Genes in Patients with Multiple Myeloma: Results of a Phase I/II Study.
Authors: Vadhan-Raj Saroj , Weber Donna M. , Wang Michael , Giralt Sergio A. , Thomas Sheeba K. , Alexanian Raymond , Zhou Xiao , Patel Priya , Bueso-Ramos Carlos E. , Newman Robert A. , Aggarwal Bharat B. 
Published: October 2019

Abstract
Although the role of NF-kB and STAT3 pathways in proliferation/metastasis of various tumor cells is well established, no agent has been described which could downregulate the activation of these transcription factors in cancer patients (pts). Curcumin has been shown to potently suppress the activation of these transcription factors in cultured cells. Based on these observations, we initiated a clinical trial of curcumin alone (administered orally at 2, 4, 6, 8, or 12 grams/day in 2 divided doses) or in combination with Bioperine (10 mg in 2 divided doses) for 12 weeks in multiple myeloma (MM) pts. The objectives of this study were to evaluate the clinical safety and biologic effects in MM pts who had asymptomatic, relapsed/refractory, or plateau phase disease. Blood was collected for PK/PD and PBMCs were examined (baseline and during treatment) for evaluating the effect of treatment on expression of NF-kB (p65), COX-2 and phospho-STAT3 as surrogate biomarkers. NF-kB activation status was also measured by electrophoretic mobility shift assay. At least 6 pts are enrolled at each dose level; 3 on the curcumin arm and 3 on the curcumin + bioperine arm. Pts with at least stable disease were allowed to continue treatment up to one year. Treatment with curcumin and bioperine has been well tolerated, with no significant adverse events. At the 12 grams dose level, 2 of the 5 pts had difficulty swallowing the large number of capsules. Of the 29 evaluable pts treated so far, no objective responses have been seen. Twelve pts continued treatment for more than 12 weeks and 5 (1 patient at 4 grams, 2 pts at 6 grams, and 2 pts at 8 grams dose levels) completed one year of treatment with stable disease. With few exceptions, little if any free drug was found in the plasma. Total curcumin levels (mostly conjugated drug) were dependent on both dose and the duration of administration. PBMCs from 28 MM pts examined showed constitutively active NF-kB (mean ± STD, 74.2% ± 14.0 positive cells), COX2 (66% ± 15.4), and STAT3 (52.8% ± 19.2). Oral administration of curcumin significantly downregulated the constitutive activation of NF-kB (at 3 months a median reduction of 77%, p<0.0001) and STAT3 (69%, p<0.001), and suppressed COX2 (66%, p<0.0001) expression in most of the pts at each of the monthly time points.
Conclusions: This is the first report to indicate that curcumin, a highly safe agent, is bioavailable and can downregulate NF-kB, STAT3 and COX2 in MM pts. These findings suggest a potential therapeutic role for curcumin that can be further investigated either alone or as a modulator of chemo-resistance in combination with other active agents.
Fucosylation of Cord Blood CD34+ Cells Improves the Rate of Engraftment without Compromising Long-Term Engraftment.
Authors: Robinson Simon N. , Yang Hong , Decker William K. , Xing Dongxia , Steiner David , Ng Jingjing , Thomas Michael W. , Champlin Richard E. , Simmons Paul J. , Brouard Nathalie , Kidd Shannon , Cooper Laurence , Shpall Elizabeth J. , Zweidler-McKay Patrick A. 
Published: October 2019

Abstract
INTRODUCTION: Delayed engraftment following cord blood (CB) transplantation remains a major challenge. While cell dose is clearly limiting, CB-derived hematopoietic stem cells (HSC) also appear to have a deficit in homing and engraftment. CB HSC have low levels of surface fucosylation. Increasing the level of surface fucosylation might improve interactions with selectins expressed by the microvasculature of the hematopoietic microenvironment, potentially improving homing and engraftment.
METHODS: Human CB CD34+ were fucosylated using a recombinant fucosyltransferase (FTVI, Engraftin™, America Stem Cell, Inc., Carlsbad, CA) prior to injection into sublethally-irradiated NOD-SCID IL-2Rγnull mice. Levels of fucosylation were determined by flow cytometry using an anti-sialyl Lewis X antibody (a fucosylated selectin ligand). Each mouse received ∼4.5x104 CD34+ cells. The rate of engraftment was measured by the appearance of human CD45+ cells in the peripheral blood (PB). Following engraftment, multi-lineage reconstitution was measured (lymphoid, myeloid, platelet and erythroid). At termination (11 weeks post-transplant), levels of multi-lineage human engraftment were measured in PB, bone marrow (BM) and spleen.
RESULTS: 1% of CD34+ cells in non-fucosylated samples were heavily fucosylated as compared to >90% in the FTVI-treated sample, confirming that significant de novo fucosylation of CD34+ cells had occurred.(Fig 1) Human engraftment was detected in mice receiving CD34+ cells treated with FTVI ∼2 weeks after transplant, and by ∼3 weeks had reached >1%. In mice receiving non-FTVI-treated CD34+ cells, 1% human engraftment was only realized >4 weeks after transplant. By this time human engraftment in the mice receiving FTVI-treated cells was 5-fold higher.(Fig 2) At 11 weeks post transplant, human engraftment was present in both groups in PB (10±1% vs. 4±1%), BM (33±1% vs. 43±1%) and spleen (42±1% vs. 31±2%). Further, in both groups, evidence of a similar pattern of multi-lineage engraftment was observed in PB, BM and spleen.
CONCLUSION: These data suggest that increasing the levels of fucosylation of CB CD34+ cells using FTVI, dramatically improved the rate of engraftment, provided multi-lineage reconstitution and did not adversely effect long-term engraftment. This study supports further clinical development of fucosylation as a method of improving CB transplantation.
Figure 1 Figure 1. Figure 2 Figure 2.
A Small Animal In Vivo Imaging Model of Expanded vs. Unexpanded UCB Stem Cells Reveals Differential Patterns of Engraftment.
Authors: Steiner David , Robinson Simon N. , Decker William K. , Marini Frank C. , Shpall Elizabeth J. , Bollard Catherine M. , Champlin Richard E. , Xing Dongxia , Yang Hong , Cooper Laurence J.N. , Gelovani Juri G. , Najjar Amer M. , Di Stasi Antonio , Quintarelli Concetta , Zweidler-McKay Patrick A. , Dotti Gianpietro 
Published: October 2019

Abstract
INTRODUCTION: Use of HLA-mismatched umbilical cord blood (UCB) allows transplant of patients who lack related HLA identical or matched unrelated donors. A major disadvantage of UCB is the limited number of stem cells available within the graft, a contributor to delayed engraftment, especially in adults. Two strategies have been adopted clinically in an attempt to overcome this barrier. 1. ex vivo expansion of some or all of critical graft subfractions; 2. transplantation of two different UCB grafts. These two strategies are not mutually exclusive and are also sometimes used in combination. Little is known about the basic biology that underlies the differential migration and homing of the graft components. To study the biology of complex UCB transplants, we have developed a small animal in vivo imaging model.
METHODS: CD34-selected UCB cells were transduced overnight with a lentiviral construct consisting of GFP or a firefly luciferase/GFP fusion. After 24 hours, SCF, FLT3, G-CSF, and thrombopoietin were added and the cells were cultured for 3 to 8 days. All cultured cells were then injected into non-lethally irradiated, immunocompetent mice (NOD/SCID/IL-2Rγ − /−). Transduced cells were tracked weekly by bioluminescent imaging.
RESULTS: On culture day 3, >99% of cells remained CD34+ and no expansion was observed. After expansion in culture between days 3 and 8, 19% +/− 18.5% of transduced cells were GFP+CD45+ (n= 8). Cells cultured for three days (non-expanded) (3-11x105 CD34+ cells/3-8.6x104 GFP+) were able to create a detectable engraftment signal by post-transplant day 8. The engraftment signal was delayed until day 10 when an 8-fold excess of the expanded cultured cells (4.2x106 total consisting of 1.21x106 CD34+ cells/2.3x105 GFP+ and 6.51x105 CD34-GFP+ cells) were injected. Long term engraftment (>30 days) was unaffected by expansion in culture. However, expanded UCB exhibited a differential pattern of homing and engraftment in comparison to unexpanded UCB. Mice receiving unexpanded UCB exhibited a strong engraftment signal from the area of the calvarium in addition to signals from other marrow spaces. The calvarium signal was only weakly and intermittently observed among mice who received the expanded UCB graft. Pathologic evaluation of these areas is in progress.
CONCLUSIONS: 1. Expanded cells were capable of supporting engraftment, though at a slower rate than their unexpanded counterparts. This delay might ultimately be addressed through the optimization of the expansion technique. 2. The physiologic significance of the differential engraftment pattern(s) is unclear and will require further study.
Figure Figure
Inhibition of Multiple Myeloma Tumor Growth and FGFR3 by the Aurora-Angiogenesis Inhibitor ENMD-981693.
Authors: Hembrough Todd A. , Chen Xiaoru , Burke Patricia A. , Swartz Glenn M. , Bengali Kathleen , Brokx Richard , LaVallee Theresa M. , Bray Mark R. 
Published: October 2019

Abstract
ENMD-981693 is a novel, orally-active antimitotic and antiangiogenic molecule that was discovered through a screening effort directed towards Aurora kinases. In addition to activity against Aurora A (AurA), ENMD-981693 is a potent inhibitor of several tyrosine kinases which drive the neo-vascularization of growing tumors, namely JAK2, VEGFR2 (KDR), PDGFRα and the FGF receptor family members FGFR1, R2, and R3. Multiple myeloma (MM) is a disease in which AurA and angiogenesis have been shown to play a role in disease progression. In addition, up to 15% of MM patients have a t(4;14) translocation, which leads to ectopic overexpression of the FGFR3, and is associated with a poor clinical outcome. In preclinical models, inhibitors of FGFR3 have exhibited antitumor activity towards t(4;14) bearing MM tumors. In in vitro proliferation assays, ENMD-981693 demonstrated an IC50 of ∼2 μM towards several MM cell lines, including H929, U266 and RPMI-8226. In immunoprecipitation studies, ENMD-981693 inhibits the kinase activity of both FGFR3 (IC50 ∼0.8 μM) and JAK2 (IC50 ∼0.5 μM) in the MM cell lines U266 and H929. These activities are in accord with the inhibitory activity of ENMD-981693 on the purified kinase domains of FGFR3 (IC50=0.5 μM) and JAK2 (IC50=0.12 μM). ENMD-981693 also inhibits activation of JAK2 activity in the HEL cell line which expresses the polycythemia vera mutated form of JAK2 (V617F). Mice implanted with H929 tumor xenografts were treated for 4 days with 75 – 225 mg/kg/d of the tartrate salt of ENMD-981693 (ENMD-2076). The amount of phosphorylated (and thus activated) FGFR3 immunoprecipitated from lysates of H929 tumors showed a significant decrease following drug treatment with no change in total FGFR3. In complementary immunoprecipitation studies, a similar decrease in JAK2 activity was seen in these H929 tumors treated with ENMD-981693 tartrate. Daily, oral treatment of RPMI-8226 xenografts with ENMD-981693 tartrate (225 mg/kg) resulted in a significant (67%) reduction in tumor burden. Follow up studies will assess the activity of ENMD-981693 tartrate on MM tumor xenografts which harbor the t(4;14) translocation, and whose growth is largely driven by FGFR3. Taken together, ENMD-981693 has been identified as a single agent that targets multiple critical mediators of MM growth, and angiogenesis. This suggests that ENMD-981693 has the potential for clinical activity in MM, particularly in patients with the t(4;14) translocation and in polycythemia vera patients with mutated JAK2. An IND filing is planned for ENMD-981693 in 2007.
A Phase II Trial of the Oral mTOR Inhibitor Everolimus (RAD001) in Relapsed Aggressive Non-Hodgkin Lymphoma (NHL).
Authors: Reeder Craig B. , Gornet Michel K. , Habermann Thomas M. , Ansell Stephen M. , Micallef Ivana N. , Porrata Luis F. , Johnston Patrick B. , Maurer Matthew J. , LaPlant Betsy , Kabat Brian , Inwards David J. , Colgan Joseph P. , Call Timothy , Markovic Svetomir , Zent Clive S. , Zeldenrust Steven R. , Tun Han W. , Witzig Thomas E. 
Published: October 2019

Abstract
Background: The phosphatidylinositol 3-kinase/mammalian target of rapamycin (mTOR) signal transduction pathway integrates signals from multiple receptor tyrosine kinases to control cell proliferation and survival. Everolimus (RAD001, Novartis Pharmaceuticals) is an oral investigational antineoplastic agent that targets mTOR.
Objectives: To learn the anti-tumor activity and toxicity of single-agent RAD001 in pts with relapsed/refractory aggressive NHL.
Patients and Methods: Patients were eligible if they had measurable disease, a platelet count >75,000, an absolute neutrophil count >1,000, and a creatinine and bilirubin <2x laboratory upper limit of normal. Patients received RAD001 10 mg PO daily and were evaluated monthly. Dose reductions to 5 mg daily and 5 mg every other day were allowed. Response was assessed after 2 cycles and periodically thereafter. Patients could remain on drug until progression or toxicity.
Results: Thirty-seven pts were treated - 20 (54%) with relapsed diffuse large cell (DLC), 14 (38%) with relapsed mantle cell (MCL), 2 high grade, and 1 follicular grade III. The median age was 72 years (range, 45–92). Patients had received a median of 4 prior therapies (range, 1–15). The overall response rate was 32% (12/37; 95% CI:20–49%) with 1 complete response and 11 partial responses. The ORR was 35% (7/20) in the DLC group and 29% (4/14) in the MCL patients. Patients have received a median of 2 cycles (range, 1–16+) of therapy. The median time to progression for all 37 patients is 3.1 months (95%CI; 2.0 – 4.7). The median duration of response for the 12 responders is 5.5 months (95% CI; 2.3 – 9.2) and 5 pts remained progression free at 6 months. Three patients are currently maintaining a response with a median time of 10.5 months (range, 2.9–15.6+months). RAD001 was well tolerated. The incidence of grade 3 anemia, neutropenia, and thrombocytopenia in this heavily pretreated pt population was 11%, 16%, and 30%. Two pts developed grade 4 neutropenia. Grade 2 hypercholesterolemia occurred in 11%; grade 2 hyperglycemia in 16%; grade 3 hyperglycemia in 11% and 1 pt had grade 4 hypertriglyceridemia.
Summary: RAD001 has single-agent activity in relapsed aggressive NHL and provides proof-of-concept that targeting the mTOR pathway in NHL is clinically relevant.
Retinoblastoma Protein and the Leukemia-Associated PLZF Transcription Factor Interact To Repress Target Gene Promoters.
Authors: Petrie Kevin R. , Guidez Fabien , Zhu Jun , Owen Gareth , Chew Yat Peng , Waxman Samuel , Licht Jonathan D. , Mittnacht Sibylle , Arthur Zelent 
Published: October 2019

Abstract
Translocations of the retinoic acid receptor alpha (RARA) locus with the PLZF or PML genes lead to expression of oncogenic PLZF-RARα or PML-RARα fusion proteins, respectively. These fusion oncoproteins constitutively repress RARα target genes, in large part through aberrant recruitment of multiprotein co-repressor complexes. PML and PML-RARα have previously been shown to associate with the retinoblastoma (Rb) tumour suppressor protein in its hypophosphorylated state. Here we demonstrate that PLZF also interacts with Rb in vitro and in vivo. The interaction between PLZF and Rb is mediated through the Rb pocket and the region of PLZF that lies between its transcriptional repression (POZ) and DNA binding (zinc-finger) domains. Additionally, Rb can simultaneously interact with PLZF and the E2F1 S phase-inducing transcription factor, suggesting that these proteins can exist in the same multiprotein complex. In contrast to the interaction between PML or E2F1 with Rb, the PLZF-Rb interaction is not dependent on hypophosphorylation of Rb. The interaction between PLZF and Rb is further underlined by chromatin immunoprecipitation analysis of PLZF binding to genomic DNA, which shows that PLZF associates with genes controlling cell proliferation known to be regulated by Rb and E2F (for example cdc6). Co-expression of PLZF and Rb results in enhancement of transcriptional repression of PLZF and E2F target genes, indicating functional co-operation between the two proteins. Both PLZF and Rb have been shown to have roles in stem cell biology and, taken together, these data provide a plausible scenario in which interactions between PLZF and Rb function in stem cell commitment or maintenance and self-renewal. The oncogenic PLZF-RARα fusion also interacts with Rb, suggesting that deregulation of Rb function may be a factor in the molecular pathogenesis of PLZF-RARα associated acute promyelocytic leukemia.
The Human Severe Congenital Neutropenia-Associated Gfi1N382S Mutant Critically Requires Deregulated Expression of CSF1 To Block Granulopoiesis.
Authors: Velu Chinavenmeni S. , Baktula Avinash M. , Bourdeau Tristan , Horman Shane R. , Grimes H. Leighton 
Published: October 2019

Abstract
Severe Congenital Neutropenia (SCN) is characterized as a deficiency of mature neutrophils, which leads to recurrent bacterial and fungal infections. Mutations in the Ela2 gene predominate in SCN, but Ela2 mutation in mice does not recapitulate SCN. The Growth factor independent-1 (Gfi1) transcriptional repressor regulates Ela2. The N382S mutation in Gfi1 is associated with human SCN. Unlike Ela2, genetic deletion of Gfi1 results in murine neutropenia. Here we show that the human-SCN-associated Gfi1N382S mutant blocks murine granulopoiesis in a Csf1 dependent manner. Gfi1 functions as a rate-limiting granulopoietic molecular switch, and the DNA-binding-defective Gfi1N382S mutant acts as a dominant negative to block granulopoiesis by selectively derepressing a subset of Gfi1 target genes. One gene repressed by Gfi1 and derepressed by Gfi1N382S is the macrophage colony stimulating factor (Csf1). Chromatin immunoprecipitation and electrophoretic mobility shift analyses demonstrate direct binding of Gfi1 to the Csf1 promoter. Importantly, both antibody absorption of Csf1 and genetic deletion of Csf1 prevent the Gfi1N382S-mediated block to granulopoiesis. These data represent the first identified Gfi1 target gene to be critically required for SCN-like phenotypes engendered by Gfi1N382S, and suggest new potential treatment avenues for Gfi1-mutant SCN patients.
Menin Regulates the Function of Lymphoid Progenitors and Hematopoietic Stem Cells.
Authors: Maillard Ivan , Chen Ya-Xiong , Tubbs Anthony T. , Shestova Olga , Pear Warren S. , Hua Xianxin 
Published: October 2019

Abstract
Menin is the product of the Men1 gene, a tumor suppressor gene that is mutated in patients with multiple endocrine neoplasia type I (MEN1). In addition to its effects in endocrine tissues, Menin interacts with the Mixed Lineage Leukemia (Mll) gene product as part of a multiprotein complex with H3K4 methyltransferase activity. Menin is required to mediate malignant transformation induced by Mll gene rearrangements, an activity associated with transcriptional activation of Homeobox (Hox) gene expression, presumably through epigenetic regulation. To explore the normal function of Menin in hematopoiesis, we studied bone marrow (BM) progenitors after inactivation of the Men1 gene in adult mice. Loss of Menin led to a modest reduction in peripheral blood neutrophil, lymphocyte and platelet counts. In the absence of hematopoietic stress, numbers of multilineage and myeloerythroid BM progenitors were preserved, but pro-B cells and downstream B lineage progenitor subsets were significantly decreased. Competitive BM transplantation assays revealed a marked defect in the function of Menin-deficient hematopoietic stem cells (HSCs), including long-term HSCs. Furthermore, Menin-deficient mice had impaired hematopoietic recovery after chemoablation with 5-fluorouracil. However, expression of Hox genes in BM HSCs was not impaired in the absence of Menin. These observations reveal an essential role of Menin in the homeostasis of hematopoietic stem and progenitor cells. Furthermore, they suggest that Menin may regulate normal hematopoiesis through mechanisms that are distinct from its role in Hox gene-dependent malignant transformation.