bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Novel Aurora Kinase Inhibitor ENMD-2076 Has Potent Single Agent Activity against Multiple Myeloma (MM) in Vitro and in Vivo, and Shows Synergistic Activity in Combination with Lenalidomide
Authors: Wang Xiaojing , Sinn Anthony L. , Suvannasankha Attaya , Crean Colin D. , Chen Li , Zhang Shuhong , Liang Jing , Zhang Genglin , Pollok Karen E. , Abonour Rafat , Sidor Carolyn , Bray Mark R. , Farag Sherif S. 
Published: October 2019

Abstract
ENMD-2076 is a novel, orally-active molecule that has been shown to have significant activity against Aurora A kinase as well as multiple receptor tyrosine kinases (RTK). We investigated the single agent activity of ENMD-2076 against MM cells in vitro and in vivo, and in combination with lenalidomide. ENMD-2076 free base showed significant cytotoxicity against MM cells with a mean LC50 of 3.84±0.86 μM at 48 hours in vitro. Cytotoxicity was associated with cleavage of caspase 3, 8, 9 and PARP, and loss of mitochondrial membrane potential as early as 6 hours. ENMD-2076 free base inhibited c-kit, FGFR-1, 3 and VEGFR1 and subsequently inhibition of downstream targets phosphorylated (p)-BAD, p-Foxo1a and p-GSK-3β was observed at 6 hours. NOD/SCID mice implanted with H929 human plasmacytoma xenografts and treated for 30 days with 50, 100, 200mg/kg/d ENMD-2076 showed a dose-dependent inhibition of tumor growth (Figure 1), with minimal toxicity as assessed by the stable weight of treated animals. Immunohistochemical staining of tumors from sacrificed animals showed significant reduction in Ki67 at all dose levels of treatment compared to control tumors. An increase in cleaved caspase-3 was observed on Western blot from the lysates of H929 tumors obtained from treated animals. ENMD-2076 free base also showed synergistic cytotoxic activity when combined with lenalidomide against H929, MM1.R and MM1.S cells as assessed by MTT assay and Annexin-V/PI staining. Using the Chou-Talalay method, the combination indices (CI) were < 1 for all three cell lines across a range of concentrations of ENMD-2076 free base (0.25–1.0 μM) plus lenalidomide (2.5–10 μM) indicating synergistic activity (CI=0.362 H929; CI=0.315 MM1.R; CI=0.415 MM1.S). Our results provide rationale for the investigation of ENMD-2076 alone and in combination with lenalidomide in patients with multiple myeloma.
Figure Figure
Results of a Phase I Study of GRN163L, a Direct Inhibitor of Telomerase, in Patients with Relapsed and Refractory Multiple Myeloma (MM)
Authors: Chanan-Khan Asher Alban , Munshi Nikhil C. , Hussein Mohamad A. , Elias Laurence , Benedetti Fabio , Smith Jennifer , Khor Soo-Peang , Huff Carol A. 
Published: October 2019

Abstract
Telomerase over-expression is the predominant mechanism by which cancer cells maintain adequate telomere length to achieve immortalization. Telomere length is often decreased and telomerase activity is often increased in MM. GRN163L is a 13-mer oligonucleotide that directly inhibits telomerase activity and has demonstrated anticancer effects in various preclinical models. We are conducting a phase I dose escalation study to define the maximum tolerated dose (MTD), safety, tolerability, efficacy as well as pharmacokinetics of GRN163L in patients with relapsed or refractory MM. Each treatment cycle consisted of 3 weekly 2 hr i.v. infusions of GRN163L. Dose escalation followed standard “3+3” dose finding rules.
To date, 12 patients, median age 61 years, have been treated in 3 dose cohorts (3.2, 4.8 and 7.2 mg/kg). Patients had received a median of 4.0 prior treatment regimens. All patients had normal baseline neutrophil and 10 had normal baseline platelet counts. Patients completed a median of 2 cycles of GRN163L treatment, with one receiving 4 and another 6 cycles. GRN163L has been generally well-tolerated to date. One patient had Gr 3 anorexia however all other related or possibly related non-hematologic AEs to date were Gr 1 or 2. Treatment related events included thrombocytopenia, neutropenia, aPTT prolongation, anemia, fatigue, nausea, anorexia, and dizziness. No dose limiting toxicity (DLT) occurred among patients in the first 2 cohorts. All patients exhibited transient dose-related aPTT prolongations, which resolved in parallel with decreasing GRN163L plasma levels. There were no bleeding episodes or clinical signs of complement activation. Two of the 5 patients in the 7.2 mg/kg cohort had transient prolongation of aPTT to > 3 fold of the upper limit of normal. One patient in the highest dose group had Gr 4 thrombocytopenia in Cycle 1, which constituted a DLT. Delayed (cycle 2 or later) Gr 3 or 4 neutropenia or thrombocytopenia was noted in 5 additional patients with no episodes of febrile neutropenia. Maximal post-infusion plasma concentrations (Cmax) of GRN163L have been linear with respect to dose. Mean (± SD) plasma concentration of GRN163L declined by 41.1 ±17.6 %, N=9, over the 2 hours following the first infusion, consistent with other previously reported studies. DLTs observed in this study were thrombocytopenia and aPTT prolongation.
The MTD for continuous weekly dosing of GRN163L in this heavily pretreated, relapsed and refractory MM population appears to be ≥ 4.8 and < 7.2 mg/kg. The most marked hematologic toxicity was observed in two patients with prior autologous stem cell transplantation. Exploration of intermediate dose levels in this range is continuing. Additional studies exploring alternative dosing schedules will be initiated.
Phase I Study of IMGN901 in Patients with Relapsed and Relapsed/Refractory CD56-Positive Multiple Myeloma
Authors: Chanan-Khan Asher Alban , Gharibo Mecide , Jagannath Sundar , Munshi Nikhil C. , Anderson Kenneth C , DePaolo Dawn , Lee Kelvin P. , Miller Kena , Guild Robin , Zildjian Sybil , Qin Albert 
Published: October 2019

Abstract
Background: IMGN901 (huN901-DM1) is a novel conjugate of the cytotoxic maytansinoid, DM1, with the humanized CD56-binding monoclonal antibody, N901. Once bound to CD56 on a cancer cell, the conjugate is internalized and releases DM1. About 70% of multiple myeloma (MM) cases have surface expression of CD56. Preclinical investigations demonstrated significant in vitro and in vivo anti-myeloma activity of IMGN901.
Objectives: To determine the maximum tolerated dose (MTD), the dose-limiting toxicities (DLTs), and pharmacokinetics (PK) of increasing doses of IMGN901 given for MM on a weekly schedule.
Methods: Patients with relapsed or relapsed/refractory MM who have failed at least one prior therapy and have CD56-expressing MM received a single IV infusion of IMGN901 on 2 consecutive weeks every 3 weeks. Patients are enrolled in cohorts of 3 at each dose level, with DLT triggering cohort expansion.
Results: Eighteen patients have received IMGN901 to date in this study - 3 patients each at 40, 60, 75, 90, 112, and 140 mg/m2/week. One patient experienced a DLT (grade 3 fatigue) on 140 mg/m2/week, and this cohort is being expanded to enroll up to 6 patients. No patients have experienced serious hypersensitivity reactions or evidence of presence of humoral responses against the huN901 antibody component (HAHA) or against the DM1 component (HADA). Preliminary PK results indicate an approximately linear relationship between dosing and observed maximal serum concentration. A confirmed minor response (MR) was documented in 3 heavily pretreated patients (1 patient each at 60, 90, and 112 mg/m2/week) using the European Bone Marrow Transplant criteria. Durable stable disease was reported at doses of 60, 90, 112, and 140 mg/m2/week. Of the 18 patients treated in the study, eight patients remained on treatment with IMGN901 for at least 15 weeks, five of these 8 patients remained on treatment for at least 24 weeks, and two of these 5 patients remained on treatment for at least 42 weeks. This phase I study provides preliminary evidence of safety as well as clinical activity of IMGN901 in patients with CD56-positive MM who have failed established MM treatments. Updated results of this ongoing study will be presented.
EXEL-8232, a Small Molecule JAK2 Inhibitor, Effectively Treats Thrombocytosis and Extramedullary Hematopoiesis in a Murine Model of Myeloproliferative Disease Induced by MPLW515L
Authors: Wernig Gerlinde , Kharas Michael G. , Leeman Dena S. , Okabe Rachel , Gozo Maricel , Paktinat Mahnaz , Haydu Erika , Ball Brian , Khandan Tulasi , Clary Douglas O. , Gilliland D Gary 
Published: October 2019

Abstract
Approximately 50% of patients with essential thrombocythemia (ET) or myelofibrosis (MF) lack activating mutations in JAK2. Among these patients, ~10% harbor an activating mutation in the thrombopoietin receptor, MPLW515L. We have reported that expression of MPLW515L in a murine bone marrow transplant model recapitulates many features of ET and MF, including severe fibrosis and thrombocytosis, that are not observed in the JAK2V617F model. These observations provide an opportunity to assess the efficacy of small molecule JAK2 inhibitors on a myeloproliferative disease (MPD) induced by MPLW515L in vivo, and to determine whether such inhibitors attenuate thrombocytosis. We have tested EXEL-8232 for efficacy in suppression of thrombocytosis in vivo, and for its ability to attenuate JAK2V617F-negative MPD mediated by MPLW515L. EXEL-8232 is a potent small molecule inhibitor of JAK2 and is structurally similar to XL019, a compound currently in clinical trials for MF and polycythemia vera. EXEL-8232 is selective for JAK2 with a biochemical IC50 of 2 nM, and abolished constitutive phosphorylation of JAK2 and STAT5, as well as cytokine-independent growth, of Ba/F3 cells in vitro. After disease was established 12 days post-bone marrow transplantation, EXEL-8232 was administered for 28 days q12h by oral gavage at doses of 30mg/kg or 100mg/kg respectively. Animals treated with 100mg/kg normalized high platelet counts in excess of2 million/ml and normalized leukocytosis from a median of 134,000/ml in vehicle treated controls. Furthermore, drug treatment eliminated extramedullary hematopoiesis in the spleen, as well as bone marrow fibrosis. Of note, EXEL-8232 had no impact on erythrocytosis in diseased animals or in wild type controls, and wild type animals treated with either dosage of 30mg/kg or 100mg/kg did not develop thrombocytopenia. Consistent with these clinical responses, the surrogate endpoints for response to treatment included a reduction of genomic disease burden in the 100mg/kg treated arm (p<0.05) as assessed by quantitative PCR, a reduction of endogenous colony growth, as well as a inhibition of activation of P-STAT5, P-STAT3 and P-S6K1 kinase as assessed by flow cytometry in immature erythroid and myeloid primary cells both in vitro and upon treatment in vivo. We conclude that EXEL-8232 has efficacy in treatment of thrombocytosis in vivo in a murine model of ET and MF, and may be of therapeutic benefit for patients with JAK2V617F-negative MPD.
NT-ProBNP Is the Strongest Prognostic Factor for Survival in Lymphoma Patients Following Treatment with Curative Intent
Authors: Salar Antonio , Sanchez-Gonzalez Blanca , Alvarez-Larrán Alberto , Comin Josep , Pedro Carmen , Gimeno Eva , Gómez Miquel , Abella Eugenia , Molina Lluis , Garcia Franscesc , Bruguera Jordi , Besses Carlos 
Published: October 2019

Abstract
Introduction: High blood levels of N-terminal pro-brain natriuretic peptide (NT-proBNP), a sensitive indicator of cardiac abnormalities, have been associated with poor outcome in patients with amyloidosis. However, its clinical value in lymphoma is unknown.
Aim: To assess the value of NT-proBNP as a prognostic variable for survival in patients with lymphoma treated with chemotherapy with curative intent.
Patients and methods: Clinical heart examination, evaluation of cardiovascular risk factors, determination of NT-proBNP (ECLIA; Roche) blood levels and high resolution ultrasound echocardiography were done at diagnosis. Clinical variables related with patient characteristics, lymphoma risk and cardiovascular risk were analyzed.
Results: 117 consecutive pts have been analyzed: median age: 63 years (range: 18–88); male: 56%; NHL: 80%; HL: 20%; ECOG/PS ≥2: 29%; III–IV: 56%; B-symptoms: 16%; LDH >1 nv: 34%; b2-microglobulin >1 nv: 57%; albumin <35 g/L: 32%; haemoglobin <105 g/L: 25%; extranodal ≥2: 20%; number of comorbidities ≥2: 51%; previous cardiac disease: 10%; median NT-proBNP: 107 pg/mL (4–9102); median left ventricular ejection fraction (LVEF): 66% (41–83). High blood levels of NT-proBNP were associated with previous cardiologic history but not with LVEF. With a median follow-up of 15.8 moths (0.2–48.9), 16 patients died. Overall survival (OS) at 24 months was 84% (95% CI: 77– 91%). In the univariate analysis, factors associated with worse OS were: NT-proBNP >900, ECOG/PS ≥2, LDH >1 nv, b2-microglobulin >1 nv, albumin < 35 g/L, haemoglobin <105 g/L, comorbidities ≥2, previous cardiologic history, extranodal sites ≥2, age >60. In multivariate analysis, factors predicting for survival were NT-proBNP >900 (HR 15, 95%CI: 3.9–57.8) (p<0.0001) and ECOG/PS ≥2.(HR 4.1, 95%CI: 1.1–16.3) (p=0.04).
Conclusions:
NT-proBNP >900 pg/mL is the strongest prognostic factor for survival in patients with lymphoma following treatment with curative intent. NT-proBNP is an easy, fast, widely available and well-standardized parameter that could be useful in addition to other well-established prognostic indexes.
Use of MicroRNA Expression Profiling to Identify Prognostic Subclasses in Mantle Cell Lymphoma: Mir-29 Family as New Prognostic Markers
Authors: Lin Jianhong , Zhao Jianjun , Lwin Tint , Dessureault Sophie , Moscinski Lynn C. , Dalton William S. , Sotomayor Eduardo , Cheng Jin , Tao Jianguo 
Published: October 2019

Abstract
Patients with mantle cell lymphoma (MCL) are typically older adults with a male predominance and usually present with stage IV disease. Response to chemotherapy usually results in a tumor response but remissions are short. It carries the poorest prognosis among non-Hodgkin’s lymphoma subtypes and the median survival is 3 to 4 years. However, recent clinical observations have identified variable clinical courses of MCL patients: some patients succumb rapidly to the disease, while others have a more chronic course and may not require treatment for prolonged periods of time. Given this clinical heterogeneity, we performed microRNA expression profiling on 34 mantle cell lymphoma (MCL) biopsy specimens to elucidate its pathogenesis and develop prognostic markers for survival of MCL patients. We identified downregulation of 18 miRNAs and upregulation of 22 miRNAs in MCL when compared with normal peripheral blood B lymphocytes, which is closely associated with molecular abnormalities. Furthermore, we found that expression levels of miR-29 family (miR-29a, miR-29b and miR-29c) were inversely correlated with MCL patient survival. A strong correlation between miR-29a, miR-29b and miR-29c values and newly described prognostic index for MCL patients, MIPI is identified. This first microRNA profling in MCL demonstrated that the miR-29a-c could be useful biomarkers for MCL prognosis and aberrant miRNA expression could contribute molecular MCL oncogenesis.
The Stage-Specific Effect of Interleukin-1 Beta (IL-1β) during Human Natural Killer Cell Development
Authors: Hughes Tiffany L , Becknell Michael Brian , Freud Aharon , Schmidt Susan E , Yu Jianhua , Mao Charlene , Gavrilin Mikhail , Wewers Mark , Caligiuri Michael A. 
Published: October 2019

Abstract
Developmental intermediates of human natural killer (NK) cells are found within secondary lymphoid tissue (SLT), and five distinct stages of these intermediates have been identified. While it is well documented that developing NK cells are reliant on interleukin (IL)-15 as a survival factor, it is likely that additional cytokines and growth factors are required for complete NK cell differentiation. Microarray transcriptional profiling of purified stage 1–4 cells from human tonsil and stage 4 and 5 cells from peripheral blood (PB) identified a developmental window of interleukin-1 receptor 1 (IL-1R1) messenger RNA (mRNA) expression restricted to stages 2 and 3. We confirmed this finding by quantitative RT-PCR, and analysis of IL-1R1 surface protein expression revealed that, on average, 81% of stage 3 immature NK cells are IL-1R1(+), whereas the majority of cells from stages 1, 2, and 4 are IL-1R1(−). When cultured in vitro with IL-1β, a physiologic ligand for IL-1R1, cells from all four stages died within 48 hours, consistent with an absolute requirement for IL-15 as a survival factor. However, the combination of IL-1β and IL-15 led to a significant and reproducible 4.64±−0.68–fold increase in stage 3 cell number over that seen with IL-15 alone (p < 0.0005). This phenomenon was completely restricted to stage 3 immature NK cells, and is attributed to increased proliferation. The effects of IL-1β were abrogated by a molar excess of IL-1 receptor antagonist (IL-1RA), a physiologic competitor for IL-1R1 binding. Collectively, our data indicate that IL-1R1 expression fluctuates dramatically during NK cell development, and that unique responses of IL-1R1(+) stage 3 cells to IL-1β and IL-15 govern the expansion of these immature NK cells. Our findings support a model in which IL-1β promotes stage 3 proliferation and survival in vivo, driving stage 3 cells to be the most prevalent NK cell intermediates within SLT.
Two Point Mutations in the MDS-Associated Protein EVI1 Abrogate the Onset of MDS in the Mouse
Authors: Laricchia-Robbio Leopoldo , Fazzina Raffaella , Dickstein Jerome , Nucifora Giuseppina 
Published: October 2019

Abstract
By forcibly expressing EVI1 in murine bone marrow (BM) we previously generated a model for myelodysplastic syndrome (MDS) characterized by megakaryocytic hyperplasia, dysplastic erythropoiesis and fatal anemia. These defects, typical of MDS patients, confirmed the association between EVI1 and MDS in the mouse thus validating our mouse model. We later ascribed the erythroid defects induced by EVI1 to its interaction with GATA1, as shown by the double point mutant EVI1(1+6Mut), unable to bind GATA1, allowing a normal erythroid differentiation of BM progenitors in vitro. We report here that in vivo expression of the mutant EVI1(1+6Mut) abrogates the onset of MDS. We show that whereas EVI1-positive mice invariably die of severe anemia and pancytopenia 11–14 months after BM reconstitution, EVI1(1+6Mut)-positive mice maintained relatively normal erythropoiesis and blood counts until the study was terminated 20 months after BM transplantation. Furthermore, unlike the EVI1-positive mice two GATA1-regulated genes, EpoR and c-Mpl, are not repressed in the BM of the EVI1(1+6Mut)-mice. The normal expression of EpoR restores the response to Epo, in vitro, of the BM cells isolated from the EVI1(1+6Mut)-mice. We thus suggest that the development of drugs interfacing with the first and sixth zinc-finger motifs could be invaluable in the treatment of EVI1-positive MDS patients.
Immunoassay for Human Hepcidin in Blood
Authors: Olbina Gordana , Pastorino Ximena , Girelli Domenico , O’Brien Kimberly O. , Nemeth Elizabeta , Ganz Tomas , Westerman Mark 
Published: October 2019

Abstract
We developed and validated the first ELISA for hepcidin, the principal iron-regulatory hormone that has been very difficult to measure. The competitive ELISA uses a biotin-tagged hepcidin as a tracer to quantify hepcidin in serum, plasma or urine. In healthy volunteers, the 5–95% range of serum hepcidin concentrations was 29–254 ng/ml in men (n=65) and 17–286 ng/ml in women (n=49), with median concentrations 112 vs. 65, p<0.001. The lower limit of detection was 5 ng/ml. Serum, EDTA plasma and heparin plasma hepcidin measurements were in agreement (r> 0.98). Serum and urinary hepcidin concentrations in 24 healthy subjects correlated well (r=0.82). Serum hepcidin appropriately correlated with serum ferritin (r=0.63) reflecting the regulation of both proteins by iron stores. Healthy volunteers showed a diurnal increase of serum hepcidin at noon and 8pm compared to 8am, and a transient rise of serum hepcidin in response to iron ingestion. In 18 young healthy women, serum hepcidin correlated well (p<0.05) with intestinal iron absorption both from a food (r=0.49) and supplemental iron source (r=0.51), as determined by a stable iron isotope technique. In a variety of clinical conditions associated with iron disturbances we observed the appropriate changes in hepcidin concentrations: undetectable or low in patients with iron deficiency anemia (ferritin<10 ng/ml), treated HFE hemochromatosis, and juvenile hemochromatosis, and abnormally high in patients with inflammation (CRP>10 mg/dl), multiple myeloma, or chronic kidney disease. The new blood hepcidin ELISA yields accurate and reproducible measurements that appropriately reflect physiologic, pathologic and genetic influences, and is informative about the etiology of iron disorders.
Hepcidin-Independent Regulation of Dietary Iron Absorption
Authors: Ajioka Richard S. , De Domenico Ivana , Kushner James P. 
Published: October 2019

Abstract
Iron homeostasis in mammals is maintained at the level of iron absorption by the gut. Hepcidin plays a central role in homeostasis by binding to ferroportin and regulating cellular iron export. We found that mice weaned onto diets ranging from 35–350 mg Fe/kg for a period of 4 wk did not change body iron levels as measured by organ iron content and hematological parameters. Direct measure of absorption of 59Fe administered by gavage revealed an inverse correlation between dietary iron content and absorption. Gavage experiments were done following a 4h fast when the stomach and proximal small bowel were free of dietary content. Although iron absorption changed, liver expression of hepcidin mRNA did not. We measured the absorptive response in mice weaned onto diets containing 35 mg Fe/kg for 4 wk and abruptly changed to 350 mg Fe/kg. There was no change in iron absorption at day 1 but by day 3 absorption was reduced nearly 3-fold compared to controls and remained at this level for at least 7d. During this time neither liver nor spleen iron content changed but transferrin saturation increased approximately 1.5-fold. Most importantly, serum hepcidin levels, measured by a competitive binding assay (De Domenico et al. Cell Metab.2008, 8:146–156), were unchanged. Mice were then changed from diets containing 350 mg Fe/kg to diets containing 35 mg Fe/kg. Within 24h mice increased absorption of 59Fe 3-fold. Elevated absorption continued for at least 3d, declined by 7d and at 14d was at a level found in mice maintained on a diet containing 35 mg Fe/kg. During this period there was no change in organ iron content or in transferrin saturation. Serum hepcidin did not change on day 1, but was reduced by approximately 40% on days 3 through 7. Increased iron absorption could be attributed in part to increased expression of Dmt1 but no change in ferroportin message was detected. Enterocyte ferritin levels doubled on day 1 but returned to control levels on days 3 through 7. Finally, mice with a targeted disruption of the hepcidin gene were challenged with an abrupt reduction in dietary iron content and absorption increased approximately 3-fold. These data suggest that iron absorption can respond to changes in dietary iron content independent of hepcidin and that response to changes in luminal iron content are at the level of uptake and storage in a manner intrinsic to the enterocyte.