bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hepcidin Inhibition by Modified Heparins without Anticoagulant Activity
Authors: Poli Maura , Girelli Domenico , Naggi Annamaria , Campostrini Natascia , Finazzi Dario , Maccarinelli Federica , Castagna Annalisa , Arosio Paolo 
Published: October 2019

Abstract
Abstract 483

Background.
There is an increasing interest in the development of pharmacological agents able to modulate hepcidin, the peptide hormone that critically regulates iron metabolism. In particular, hepcidin antagonist may have a therapeutic role in the anemia of chronic diseases, where hepcidin levels are often increased by pro-inflammatory cytokines. We previously demonstrated that heparin is a potent inhibitor of hepcidin expression in hepatic cell lines, probably by interfering with BMP/HJV/SMAD signalling, and that it was also effective in reducing hepcidin expression in mice (Poli M, Blood 2011; 117:997–1004). Since the therapeutic use of heparin for hepcidin modulation is hampered by its strong anticoagulant activity, we were interested in evaluating modified heparins without such activity.

Methods.
Heparins modified to inactivate the antithrombin binding site, with different molecular weight and degree of sulfation, were supplied to hepatic cell lines and mice to evaluate their potential modulation of hepcidin expression. We analysed their interference with the BMP/SMAD signalling, as well as serum hepcidin levels in mice by mass spectrometry.

Results.
Over 20 modified heparins were initially screened by evaluating their dose-dependent suppression of hepcidin expression before and after BMP induction. All of them showed a certain degree of anti-hepcidin activity, with two glycol-split molecules being as potent as classical unfractionated heparin. These two molecules suppressed BMP/SMAD signalling in HepG2 cells at pharmacological concentrations with maximum inhibition after 6 hours. In mice, treatments with 20 or 60 mg/Kg did not affect coagulation but strongly reduced liver pSMAD, hepcidin mRNA and serum hepcidin. Again, the maximum effect on liver hepcidin expression was observed 6 hours after the injection. This effect was observed also in conditions of high hepcidin caused by experimental inflammation or iron overload.

Conclusions.
Some non-anticoagulant heparins have strong anti-hepcidin activity both in vitro and in vivo, and may represent promising hepcidin antagonist with potential therapeutic applications.

Disclosures:
No relevant conflicts of interest to declare.
Advanced Non Small Cell Lung Cancer Patients with Fewer Numbers of Blood Myeloid Dendritic Cells and CD4 Cells Prior to Treatment Have Inferior Progression-Free Survival: Implications for Cancer Immunotherapy
Authors: DeJoubner Nutan J. , Li Qunna , Harris Wayne A.C. , Wang Zhibo , Liu Yuan , Waller Edmund K. 
Published: October 2019

Abstract
Abstract 4837

Background:
The tumor microenvironment includes tumor cells, and host-derived endothelial cells, fibroblasts, innate and adaptive immune cells. Tumors may induce neo-vascularization that supports local tumor growth or immune suppression and tolerance that facilitates tumor metastasis. We hypothesized that the patients with higher numbers of circulating CD34+ endothelial progenitor cells (CD34+/CD146+/CD45-, CEC), a cellular bio-marker for vasculogenesis, would have worse post-treatment outcomes and patients with more hematopoietic progenitor cells (CD34+/CD45+/CD45dim/CD133+, HPC) and Immune cells including T-cells would have better outcomes.

Methods:
We analyzed blood samples from sixty-two patients with advanced NSCLC at 3 time points: before chemotherapy, after cycle one, and at completion of treatment or progression of disease, in an IRB-approved protocol. CEC, HPC, and immune subsets were measured by high throughput multi-parameter flow cytometry, 2.5,000,000 events were acquired using a lyse, no-wash method optimized for rare event detection. Primary outcomes were progression free survival(PFS) and Overall Survival(OS) from the time of study entry. The patient population was stratified into groups based on optimum cut-off point for each cell subset of interest. Statistical analysis was done with log-rank test and Cox regression.

Results:
Mean age at diagnosis was 64 (37–87 years), 30 events (death) occurred with median follow-up of 9.3 months. Forty-six patients (74%) had disease progression with a median follow-up of 4.7 months. At baseline lower numbers of WBC, Neutrophil lymphocyte ratio(NLR), CEC, HPC were associated with better PFS, while only WBC and Neutrophil lymphocyte ratio (NLR) were associated with a favorable OS. While lower numbers of Immune cells were associated with worse PFS and OS (increased HR death or relapse) in univariate analysis as noted in the Table. Only covariates that were significant and non collinear were entered in the Multivariable model adjusted for age, gender, smoking, race, TNM stage, pathology, and performance status at diagnosis. This showed that baseline numbers of CD4+ T-cell (HR 0.46; 95% CI 0.33–0.98; p= 0.045), Myeloid DC (HR 0.38; 95% CI 0.39–0.81; p=0.012), HPC (continuous variable) (HR 0.78; 95% CI 0.64–0.93; p= 0.008) were significant for disease progression, while NLR was significant for death after study entry (Figure; HR 3; 95% CI 1.45–6.25; p=0 0.003).

Conclusions:
In patients with advanced NSCLC, lower numbers of HPC and NLR were associated with improved PFS and OS respectively. Lower numbers of immune subsets at diagnosis were associated with inferior outcomes to treatment, supporting the role for immune-mediated disease control.

Disclosures:
No relevant conflicts of interest to declare.
Overcoming CD28-Mediated Multi-Drug Resistance With a Novel PIM2 Inhibitor
Authors: Baldino Carmen M. , Nair Jayakumar R. , Caserta Justin , Murray Megan , Dumas Stephane , Flanders Yvonne , Lee Kelvin P. 
Published: October 2019

Abstract
Drug resistance in multiple myeloma (MM) is the major cause of treatment failure and is significantly mediated by pro-survival interactions with bone marrow microenvironment. A key myeloma receptor involved in this interaction is CD28, which has been largely characterized as the prototypic T cell costimulatory receptor. However, CD28 expression on myeloma cells is significantly correlated with disease progression, worse prognosis, and is significantly higher in the poor prognosis t(14;16) MAF subgroup. We now report that CD28 signaling mediates significant drug resistance and protects MM against death from multiple chemotherapeutics with different mechanisms of action – including dexamethasone, arsenic trioxide, melphalan or bortezomib. Inhibition of specific signaling (PI3K or Akt) or targets (Foxo3A or Bim) downstream of CD28 activation abrogates this protection. Unexpectedly, we found evidence that the PIM2 kinase (which is largely uncharacterized in MM but is also significantly overexpressed in the MAF subgroup) may be a previously unreported component of the CD28 pro-MM survival pathway. The novel small molecule PIM2 inhibitor JP_11646 (IC50 0.5 nM) abrogates CD28-mediated protection against apoptosis in MM cell lines in vitro, which we have not previously seen for any chemotherapeutic tested. In addition, blockade of CD28 activation sensitized MM cells significantly to JP_11646-induced death. Altogether, these data suggested that PIM2 inhibitors can overcome a major mechanism of multi drug resistance in MM.
Jasco’s novel and selective pan-PIM inhibitor (JP_11646) has demonstrated biochemical IC50s of 24, 0.5 and 1 nM for PIM1, PIM2 and PIM3 respectively. The PIM mechanism of action has been confirmed through cell based transphosphorylation assays, where JP_11646 decreased PIM dependent phoshphorylation of the proapoptotic protein BAD at nM levels. JP_11646 increases apoptosis and decreases cell viability in multiple myeloma cell lines with the MAF translocations (<100 nM). JP_11646 is orally bioavailable and has demonstrated in vivo efficacy, inhibiting tumor growth by >80% in a MM1.S tumor xenograft study. These data provide solid rationale for further development of JP_11646 as a targeted therapy in MM, and specifically for patients exhibiting the MAF translocation.

Disclosures:
Baldino: Jasco pharmaceuticals: Employment, Equity Ownership, Founder and President Other, Membership on an entity’s Board of Directors or advisory committees. Caserta:Jasco Pharmaceuticals: Co-Founder Other, Employment, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees. Dumas:Jasco Pharmaceuticals: Employment. Flanders:Jasco Pharmaceuticals: Employment. Lee:Jasco Pharmaceuticals: Research Funding.
Carfilzomib PLUS Melphalan and Prednisone (CMP) Is A Promising Combination Therapy For The Treatment Of Elderly Patients With NEWLY Diagnosed Multiple Myeloma: Results Of A PHASE I/II Trial In 68 CASES
Authors: Moreau Philippe , Kolb Brigitte , Hulin Cyrille , Caillot Denis , Benboubker Lotfi , Tiab Mourad , Touzeau Cyrille , Leleu Xavier , Roussel Murielle , Chaleteix Carine , Attal Michel , Facon Thierry 
Published: October 2019

Abstract
Melphalan-Prednisone + bortezomib (MPV) is one of the standard of care for the frontline treatment of patients with symptomatic multiple myeloma non eligible for high-dose therapy. In the pivotal VISTA trial for approval of MPV, the main toxicity was grade 3-4 peripheral neuropathy (PN) described in 14% of the cases. Carfilzomib (CFZ), the second-in-class proteasome inhibitor has shown promising activity and a favorable toxicity profile with low PN rates. Therefore, the option of combining CFZ with MP (CMP) is an attractive one. Therefore we designed a phase I/II study to determine the maximum tolerated dose (MTD) of CMP and to assess safety and efficacy. In the phase I portion of the trial, CFZ was started at 20mg/m2, then escalated to 27, 36, and 45mg/m2, administered IV over 30 minutes in 42-day cycles on D1/2/8/9/22/23/29/30 for 9 cycles. Melphalan 9mg/m2 and prednisone 60mg/m2 were given PO D1–4 of every 42-day cycle. MTD was based on dose-limiting toxicity (DLT) in cycle 1 defined as any grade 4 (G4) hematologic adverse event (AE), any hematologic AE preventing aministration of ≥ 2 CFZ doses except G4 thrombocytopenia without bleeding or G4 neutropenia ≤ 7days, ≥ G3 febrile neutropenia, or any ≥G3 nonhematologic AE.
As of July 6, 2013, 24 pts have been enrolled in phase I: 6 for each dose level. There were 2 DLTs at 45mg/m2 (fever plus hypotension) resulting in a MTD of 36mg/m2. In Phase II, 44 additional patients received CMP at 36mg/m2 CFZ for N=68 total PhI/II patients (50 patients overall treated at the dose pf 36mg/m2). The median age of the series was 72 years, with 36% of the patients presenting with ISS3. Overall response rate was 89.5% including 56% ≥ very good partial response. With a median follow-up of 12 months, the projected 2y OS was 87%, and the median event-free survival was 22 months. CMP was well tolerated and only 1 patient developed grade 3 PN. These promising results compare favorably to those of MPV, MP+Thalidomide, MP+lenalidomide (R), and R+dex in similar pts. CFZ 36mg/m2 + MP is tolerable and effective in elderly patients with symptomatic newly diagnosed MM. Treatment is ongoing, 20% of the patients are receiving their last cycles of CMP. Final safety and efficacy data will be presented during the meeting.

Disclosures:
Moreau: CELGENE: Honoraria, Speakers Bureau; JANSSEN: Honoraria, Speakers Bureau. Off Label Use: FRONTLINE TREATMENT WITH CARFIZOMIB. Hulin:CELGENE: Honoraria; JANSSEN: Honoraria. Leleu:CELGENE: Honoraria; JANSSEN: Honoraria. Roussel:CELGENE: Honoraria; JANSSEN: Honoraria. Attal:CELGENE: Honoraria, Speakers Bureau; JANSSEN: Honoraria, Speakers Bureau. Facon:CELGENE: Honoraria, Speakers Bureau; JANSSEN: Honoraria, Speakers Bureau.
Effect Of Immediate Prior-Line Lenalidomide Or Thalidomide Therapy On Response To Pomalidomide In Multiple Myeloma
Authors: Hwa Yi Lisa , Laumann Kristina M , LaPlant Betsy R , Buadi Francis , Dingli David , Dispenzieri Angela , Gertz Morie A , Go Ronald S. , Hayman Suzanne R , Kapoor Prashant , Kumar Shaji K , Leung Nelson , Lin Yi , Lust John A , McCurdy Arleigh , Mikhael Joseph , Roy Vivek , Russell Stephen , Zeldenrust Steven R , Rajkumar S. Vincent , Lacy Martha Q 
Published: October 2019

Abstract

Background
Pomalidomide (POM) is the newest Immunomodulatory agent (IMiDs) that has shown clinical efficacy in relapsed multiple myeloma (MM) refractory to lenalidomide (LEN) and thalidomide (THAL). Studies of MM cell microenvironment suggest that tumor subclones compete for dominance during changes in drug therapy. It was previously observed that a minor clonal population increased in prominence of MM cells after 1 year of treatment with LEN. We examined whether the patients having THAL or LEN as the most recent prior-line therapy affects response to POM.

Methods
We studied 208 patients enrolled in a phase II trial of POM / dexamethasone between November 2007 and March 2012 at Mayo Clinic, Rochester. We reviewed the immediate prior-line therapy before enrollment in our trial. Comparison of treatment duration of POM and response rates were conducted between patients who had either THAL or LEN as latest prior-line therapy, and patients who were treated with non-IMiDs immediate before enrollment in POM trial. Treatment duration of POM was estimated using Kaplan Meier method and the survival curves were compared using log-rank test. We used univariate Cox proportional hazard models to estimate the prognostic impact of different variables.

Results
The median age of patients was 63 (range from 32 to 88). 68 % were males. 80 patients (38.5%) had THAL or LEN immediate prior to POM. Median prior-line therapies were 3. Patients who received THAL or LEN immediately prior to POM had a lower response rate than those who had non-IMiDs as latest therapy (29% vs 44%, p 0.04) and shorter median duration of POM treatment (5.7 months vs 7.3 months, p 0.02). In 190 (91%) patients who were previously treated with LEN and THAL at any time, median time between the end of LEN or THAL treatment and the initiation of POM was higher for POM responders than non-responders (10 months vs 3 months, p 0.0008). Patients responded to POM had a shorter duration of prior LEN or THAL treatment compared to non-responders (9 months vs 15 months, p 0.001).

Conclusion
THAL or LEN as an immediate prior-line therapy to POM is associated with a lower response rate and shorter effective treatment duration. Longer interval between prior immunomodulatory compounds and POM, and shorter exposure to previous immunomodulatory compounds are associated with better POM treatment response.

Disclosures:
Gertz: Celgene: Honoraria. Kumar:Merck: Consultancy, Honoraria; Celgene: Consultancy, Research Funding; Millennium: The Takeda Oncology Company: Research Funding; Novartis: Research Funding; Genzyme: Research Funding. Lacy:Celgene Corporation: Research Funding.
Increased Frequencies Of Myeloid-Derived Suppressor Cells and Regulatory T-Cells Decrease Response To Donor Lymphocyte Infusions, Independent Of Graft Versus Host Disease In Multiple Myeloma
Authors: Franssen Laurens E. , Emmelot Maarten E. , van de Donk Niels W.C.J. , Lokhorst Henk , Mutis Tuna 
Published: October 2019

Abstract

Background
Allogeneic stem cell transplantation (allo-SCT) followed by donor lymphocyte infusions (DLI) can induce durable responses in multiple myeloma (MM) by virtue of the graft versus myeloma (GvM) effect. However, this is only true for a minority of patients and relapse rates after reaching an initial remission remain high. Also, transplant-related mortality and Graft-versus-Host-Disease (GvHD) are still major complications. Towards improving cellular immunotherapy we set out to identify the immune cell subsets that are involved in the GvM effect and GvHD.
Myeloid-Derived Suppressor Cells (MDSCs) are a heterogeneous population of bone marrow-derived myeloid cells, with strong immunosuppressive capacity. In general, they are divided into monocyte-like M-MDSCs en granulocyte-like G-MDSCs. In myeloma, they have been shown to be present in increased frequencies, inhibit T-cell proliferation and promote multiple myeloma cell growth in vitro. Furthermore, regulatory T-cells (T-regs) seem to suppress cellular anti-tumor responses in MM.

Methods
To determine whether MDSCs and T-regs hamper immunotherapy, we investigated MDSCs and T-regs in peripheral blood (PB) (n=43) from post-allo SCT MM patients, prior to their first DLI, and from healthy donors (n=13). All patients had persistent or progressive disease after allo-SCT. DLI dose was 107 T-cells/kg for sibling donors (n=20) and 106 T-cells/kg for matched unrelated donors (n=23).

Results
We observed a significantly higher frequency of M-MDSCs (CD14+ HLA-DR-/low) (mean 5.7 vs. 0.7%, P<0.001) and T-regs (CD4+ CD25+ CD127-/low) (11.4 vs. 5.5%, P<0.01), but not of G-MDSCs (CD11b+ HLA-DR-/low CD14-CD33+) in PB of MM patients versus healthy donors. Interestingly, patients responding to DLI had significantly lower amounts of immunosuppressive G-MDSCs (mean 0.6 vs. 1.2%, P=0.04) and T-regs (7.9 vs. 13.9%, P=0.02) in their PB prior to DLI. There was no difference in M-MDSCs between responding and non-responding patients. This effect on GvM was independent of GvHD, as levels of G-MDSCs, M-MDSCs and T-regs did not differ between GvHD+ and GvHD-groups.

Conclusion
We show that increased frequencies of G-MDSCs and T-regs are associated with resistance to DLI, independent of the occurrence of GvHD. Our data suggest that targeting G-MDSCs as well as T-regs may improve cellular immunotherapy in multiple myeloma.

Disclosures:
van de Donk: Celgene: Research Funding. Lokhorst:Genmab A/S: Consultancy, Research Funding; Celgene: Honoraria; Johnson-Cilag: Honoraria; Mudipharma: Honoraria.
Stem Cell Transplant Versus Chemotherapy in Older Adults with Acute Myelogenous Leukemia In First Remission
Authors: Berman Ellin , Maloy Molly , Devlin Sean M. , Papadopoulos Esperanza B , Jakubowski Ann A. 
Published: October 2019

Abstract

Introduction
Optimal therapy for older adults with acute myelogenous leukemia (AML) who achieve remission following induction chemotherapy has not been determined. Options include consolidation chemotherapy (CC) or stem cell transplant (SCT) if an appropriate donor is identified. In order to determine whether SCT improved overall survival (OS) or whether associated toxicity was increased, we performed a retrospective study comparing SCT with CC in this older age group.

Methods
All adult patients ages 60 to 75 years with AML in 1st remission (CR1) who underwent a SCT at MSKCC between 2001 and 2013 were reviewed and compared to age-matched patients with AML who achieved CR1 and received CC. A landmark analysis at 3 months following CR1 was used to compare OS for the 2 patient groups. Only SCT patients transplanted by landmark time were included in the analysis. Overall survival was compared using Kaplan-Meier methodology.

Results
Sixty-eight patients were identified for the SCT group. Thirty-two patients were identified for the CC group (Table). Stem cell sources included: peripheral blood (n=63), cord blood (n=4) and bone marrow (n=1). Fifty-six patients received a T cell depleted transplant (32 with ClinMACsTM and 24 with IsolexTM ) and 12 received an unmodified product. Conditioning regimens were busulfan/melphalan/ fludarabine (n=54), melphalan/fludarabine (n=4), cyclophosphamide/fludarabine/thiotepa/ TBI (n=4), fludarabine/busulfan (n=3), busulfan/melphalan (n=2) and thiotepa/fludarabine/TBI (n=1). Donors included matched unrelated (n=28), matched related (n=25), mismatched unrelated (n=11) and mismatched cord blood (n=4). For patients in the CC group, induction chemotherapy included cytarabine in combination with either idarubicin (n=21), daunorubicin (n=10), or mitoxantrone plus etoposide (n=1). Forty-four patients received their transplant by the 3 month landmark and 30 patients in the CC group were alive at the landmark and were included in the OS analysis.
Deaths in the SCT group included 4 patients from infection, 1 from treatment-related toxicity, and 1 from relapsed disease. The estimated OS at 2 years in the landmark groups were 64% in the SCT group and 42% in the CC group (p=0.04).

Conclusions
Recognizing the inherent bias when retrospective studies compare SCT and CC, these data support the use of SCT for older patients with AML in CR1 who have an appropriate donor. Despite the older age, there was a statistically significant better OS with low 100 day mortality for those patients who underwent SCT.

Disclosures:
No relevant conflicts of interest to declare.
TRIM28 Is Essential For Erythroblast Differentiation In The Mouse
Authors: Tomonori Hosoya , Clifford Mary , Engel James 
Published: October 2019

Abstract
We previously identified TRIM28 (TIF1β, KAP-1) as a component of the mammalian DRED complex that prior studies had implicated as an embryonic/fetal β-type globin gene repressor. TRIM28 has been previously characterized as a transcriptional co-repressor thst interacts with heterochromatin protein 1 (HP1) and histone H3K9 methyltransferase SETDB1. We tested the contribution of TRIM28 to globin gene regulation and erythropoiesis by employing a mutant mouse that could be inducibly ablated for the Trim28 gene during the adult stage. The Mx1Cre transgene was activated by injecting poly(I:C) 5 times into these compound mutant mice every 48 hours. We hypothesized that TRIM28 might normally contribute to silencing of the embryonic and/or fetal globin genes and therefore that one might anticipate that the mouse εY- and/or βH1-globin genes (the structural homologues of human embryonic ε− and fetal γ-globin genes, respectively) would be de-repressed in the absence of TRIM28. To our surprise, the expression of εY- and βH1-globin mRNAs was not altered after induced genetic loss of Trim28. However, we discovered that its loss results in defective immature erythropoiesis in bone marrow and consequently to normocytic anemia. To address possible mechanisms that might be responsible for this observed defect in erythropoiesis, we analyzed staged, immature erythroid cells isolated from the Trim28 mutant mice by RNA-Seq and qRT-PCR. We observed diminished expression of multiple erythroid transcription factors and heme biosynthetic enzymes in the mutant. We also discovered increased expression of multiple apoptosis-related genes, and experimentally confirmed an increase in early apoptotic cells (Annexin V+ DAPI-) in the Trim28 mutant erythroblasts. We conclude that TRIM28 is vital for immature erythropoiesis in the adult bone marrow.

Disclosures:
No relevant conflicts of interest to declare.